Axitinib (AG013736; trade name Inlyta) is a small molecule tyrosine kinase inhibitor developed by Pfizer. It has been shown to significantly inhibit growth of breast cancer in animal (xenograft) models^[2] and has shown partial responses in clinical trials with renal cell carcinoma (RCC)^[3] and several other tumour types.^[4] It was approved by the U.S. Food and Drug Administration after showing a modest increase in progression-free survival,^[5] though there have been reports of fatal adverse effects.^[6]

Axitinib, a small-molecule indazole derivative chemically known as (E)-N-methyl-2-(3-(2-(pyridin-2-yl)-vinyl)-1H-indazol-6-ylthio)benzamide developed by Pfizer, was approved in January 2012 by the U.S. FDA with the trade name Inlyta. It selectively inhibits vascular endothelial growth factor receptors for the treatment of renal cell carcinoma

On January 27, 2012, axitinib was approved with the trade name INLYTA for treatment of patients in the United States with advanced renal cell carcinoma after failure of one prior systemic therapy.

It has received FDA (27 January 2012), EMA (13 September 2012), MHRA (3 September 2012) and TGA (26 July 2012) approval for use as a treatment for renal cell carcinoma.^{[11][12][13][14]}

A study published in 2015^[15] showed that axitinib effectively inhibits a mutated gene (BCR-ABL1[T315I]) that is common in chronic myeloid leukemias and adult acute lymphoblastic leukemias which have become resistant to other tyrosine kinase inhibitors likeimatinib. This is one of the first examples of a new indication for an existing drug being discovered by screening known drugs using a patient’s own cells.

The discovery and development of an efficient synthesis route to axinitib is reported. The first-generation route researched by Pfizer implemented two Pd-catalyzed coupling reactions as key steps. In this work, the development of Heck-type and C–S coupling reactions catalyzed by CuI is briefly described, using an economial and practical protocol. Aspects of this route, such as selecting optimal ligands, solvent, and other conditions, are discussed in detail. The scale-up experiment was carried out to provide more than 300 g of active pharmaceutical ingredients of axitinib in Form XLI with 99.9% purity in 39% yield. In short, we provide a new choice of synthesis route to axitinib, through two copper-catalyzed coupling reactions with good yield.

(E)-N-Methyl-2-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-ylthiol)benzamide (Axitinib) Form XLI (326.4 g in 96% yield with purity 99.91%). Residual Cu content was determined to be 2.2 ppm by atomic absorption spectroscopy: mp 227.7 °C; 

1H NMR (300 MHz, DMSO-d6) δ 13.27 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.29 (d, J = 5.4 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 16.4 Hz, 1H), 7.81 (t, J = 7.5 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.63–7.44 (m, 3H), 7.29 (p, J = 7.4, 6.6 Hz, 3H), 7.19 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 7.4 Hz, 1H), 2.78 (d, J = 4.6 Hz, 3H); 

13C NMR (75 MHz, DMSO-d6) δ 167.89, 154.86, 149.54, 142.01, 141.86, 136.92, 136.88, 135.67, 132.52, 130.32, 129.99, 129.25, 127.80, 126.15, 125.59, 123.66, 122.68, 122.50, 121.79, 120.29, 114.76, 26.13.

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Axitinib (Axitinib, AG-013736, CAS: 319460-85-0) is a Pfizer research and development by the United States of new, mainly targeting VEGFR kinase GABA, inhibiting angiogenesis anticancer small molecule drug, trade name Inlyta, for other systems therapy for advanced renal cell carcinoma (Renal Cell Carcinoma, RCC), 2008 has been approved in the domestic clinical, and Pfizer’s cancer drug Sutent another similar imatinib (Sunitinib) , Axitinib also potent and selective multi-targeted tyrosine kinase inhibitor, can inhibit the vascular endothelial growth factor receptor (Vascular EndothelialGrowth Factor Rec India tor, VEGFR), including VEGFl receptor, VECF2 receptors and VECF3 receptor, can inhibit platelet-derived growth factor receptor (Platelet-derived growth factor receptor, PDGFR) and c_KIT. Axitinib is called sunitinib second generation, better than sunitinib adverse reactions.

Axitinib (II) chemical name 6- [2_ (methylcarbamoyl) phenylsulfanyl] -3-E- [2_ (Batch-2-yl) ethenyl] indazole structural formula as follows:

Axitinib (II)

Assi synthesis method for Nepal mainly in the following three ways:

(I) Patent US20060094881 (Agouron Pharmaceuticals), EP2163544 (Pfizer) reported the first synthesis method Axitinib to 3,6-diiodo-indazole as a starting material, first-iodo-6-position is substituted mercapto group, protection of the NH group, then the Heck reaction occurs (pyridine-2-yl) vinyl 3-position, after deprotection Axitinib whole synthesis route is as follows:

Axitinib Scheme I

This method although the synthesis route is shorter, but the catalyst and reagents used relatively expensive and require purified through the column, the total yield is low, is not conducive to industrial production.

[0004] (2) The second method of synthesis Axitinib e.g. W00102369 (Agouron Pharmaceuticals), US6531491 (Agouron Pharmaceuticals) reported in 6-nitro-indazole as a starting material, the 3-position first iodo, followed by the protecting group NH, Suzuki coupling reaction with boronic acid to give 3- styryl styryl-position, a nitro group reduced to an amino group, an amino diazotization reaction was iodo, the 3-position of the styrene-based ozone of the obtained aldehyde, followed by Wittig reaction to give the 3-position (pyridin-2-yl) ethenyl, 6-position is substituted mercapto iodine, alkaline hydrolysis then amidated, and finally deprotection Axitinib, the entire reaction formula as follows:

Axitinib Scheme 2

The method of synthesis route is long, harsh reaction conditions, complex process, the total yield is low, does not apply to industrial production.

[0005] (3) The third method is W02006048745 (Pfizer) discloses to 6-nitro-indazole as a starting material, the 3-position iodo first, followed by the protecting group NH, 3- bits Heck coupling reaction, a nitro group reduced to an amino group, an amino diazotization reaction was iodo, iodo-6-position is substituted mercapto group, and finally deprotected to give Axitinib, the entire reaction is as follows:

This method has an advantage over the first two methods, it is possible to enlarge the production, but the reaction was not complete in the reaction step, will generate new impurities through the column needs to be purified.

SYNTHESIS

aReagents and conditions: (a) I2, K2CO3, DMF; (b) CH2Cl2, CH3SO3H, dihydrofuran; (c) compound B, i-Pr2EtN, Pd(OAc)2, (o-Tol)3P, DMF; (d) iron, EtOH, NH4Cl; (e) AcOH, NaNO2, CH2Cl2, I2/KI; (f) compound C, Pd(dppf)Cl2, Cs2CO3, DMF; (h) 1, p-TsOH, MeOH; 2, NaHCO3; (i) AcOH, MeOH, Pd removal, recrystallization.

 http://www.google.com/patents/WO2006048745A1?cl=en

Example 15: Final deprotectioπ step to produce 6-r2-(methylcarbamoyl)phenylsulfanyll-3-E-f2- (pyridine-2-yl)ethenyllindazole

N-1 THP 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridine-2-yl)ethenyl]indazole (355 g) was suspended in 2,485 ml_ of methanol, after which p-toluenesulfonic acid monohydrate (718 g) was added. The mixture was then heated to 65 ⁰C (hard reflux) for 4 hours under argon while the reaction was monitored by HPLC (gluco method). Heating continued until less than 1% of the N-1 THP protected starting material persisted. The heating was then removed and the reaction was cooled to room temperature. The solid was filtered and the wet cake was washed with methanol (2 volumes, 710 mL) then the solids were rinsed with ethyl acetate (2 volumes, 710 mL). The wet cake was transferred to a reactor containing sodium bicarbonate (126.84 g), deionized water (1800 mL), and ethyl acetate (975 mL), which was then stirred for 2 hours at 2O⁰C. The solids were filtered and washed with 5 volumes of deionized water (1800 mL), then with 2 volumes of ethyl acetate (760 mL), and then dried in a vacuum oven at 40⁰C for 16 hours. The isolated yield for the reaction was 92.5% (274 g). The isolated material was identified as crystalline Form III free base (0.5 ethyl acetate solvate). ¹H NMR, 300 MHz, (DMSO-D6), ppm; 13.35 (1 H, s), 8.60 (1 H, d, J=3.8 Hz), 8.39 (1 H, m), 8.23 (1 H, d, J=8.5 Hz), 7.95 (1 H, d, J=16.4 Hz), 7.82 (1 H, ddd, J=7.7, 7.6, 1.8 Hz), 7.67 (1 H, d, J=7.8 Hz), 7.60 (a H, s), 7.57 (1 H, d, J=16.4 Hz), 7.49 (1 H, dd, J=7.1 , 1.6 Hz), 7.35-7.26 (3 H, m), 7.19 (1 H, d, J=8.4 Hz), 7.04 (1 H, d, J=7.8 Hz), 2.77 (3 H, d, J=4.6 Hz). ¹³C NMR, 75 MHz, (DMSO-D6) ppm: 168.23, 155.18, 149.81 , 142.35, 142.22, 137.31 , 136.00, 132.89, 130.64, 130.36, 129.51 , 128.14, 126.50, 125.93, 124.08, 123.01 , 122.85, 122.12, 120.642, 115.08, 26.45.

Example 21 : Preparation of 6-F2-(methylcarbamovDphenylsulfanyll-3-Z-r2-(pyridine-2- vDethenyllindazole

To a 100 ml_ 3-neck flask containing a solution of 0.95 g of 6-[2- (methylcarbamoyl)phenylsulfanyl]-3-[2-(pyridine-2-yl)ethynyl]indazole was added 2.5 g of phenyliodide diacetate followed by 1.0 mL of H₂NNH₂ H₂O. After the bubbling had settled, more phenyliodide diacetate and H₂NNH₂ H₂O were added in small portions, until LC/MS indicated the disappearance of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-[2-(pyridine-2-yl)ethynyl]indazole and the formation of 6-[2-(methylcarbamoyl)phenylsuIfanyl]-3-Z-[2-(pyridine-2-yl)ethenyl]indazole. Example 22: Palladium removal and polymorph control of 6-[2-(methylcarbamoyl)phenylsulfanvn- 3-E-r2-(pyridine-2-vDethenyllindazole

4) MeOH, reflux

Polymorph Form IV

5) HOAc/Xylenes

To a 12 L 3-neck flask, equipped with a mechanical stirrer, was added 160.20 g of 6-[2- (methylc’arbamoyl)phenylsulfanyl]-3-E-[2-(pyridine-2-yl)ethenyl]indazole and 1.6 L of DMA and 1.6 L of THF. After stirring for 20 minutes, the mixture became homogeneous. To the clear solution was added 800.99 g of 10% cysteine-silica and the resulting mixture was allowed to stir at room temperature overnight.

The mixture was filtered through a medium sintered glass fritted funnel, and the cake was washed with a solution of 500 mL of DMA and 500 mL of THF. The cake was further washed with 2.0 L of THF and the filtrate was collected into a separate flask. The volatile parts in the latter filtrate were removed in vacuo and the residue was combined with the main filtrate. The combined filtrate was recharged back into the 12 L flask, followed by 800 g of 10% cysteine-silica. The flask was equipped with a mechanical stirrer and stirred over the weekend at room temperature. The mixture was then filtered through a medium sintered glass fritted funnel and the silica was washed with a mixture of solvents of 500 ml. of DMA and 500 ml_ of THF, followed by 3.0 L of THF. The volatile parts in the filtrate were removed in vacuo and the remaining solution was transferred to a 22 L 3-neck flask and treated with 12 L of water (added over a 20 minute period of time), a thick precipitate formed at this stage. After stirring overnight, the mixture was filtered and the cake was washed with 2.0 L of water and sucked dry.

The cake was charged to a 5 L 3-neck flask, followed by 1.6 L of THF and 160 mL of DMF. The flask was equipped with a mechanical stirrer, a reflux condenser and the mixture was heated at reflux for 8 hours. After cooling overnight, the mixture was filtered through sharkskin filter paper and sucked dry. The cake was charged to a 5 L 3-neck flask and 1.6 L of MeOH was added. The flask was equipped with a mechanical stirrer, a water condenser and the contents were heated at reflux for 6 hours. After cooling overnight, the mixture was filtered through sharkskin filter paper and sucked dry.

The cake was dissolved into 1.6 L of HOAc with the assistance of gentle heating in the water bath of a rotary evaporator. The solution was filtered through #3 filter paper and the total volume of the filtrate was reduced to ~500 mL in volume on the rotary evaporator at 60 °C/60 mmHg. At this stage, the bulk of the mixture remained a yellow solution and a small amount of precipitate formed. To the flask was charged 500 mL of xylenes (precipitate formed) and the total volume was reduced to -500 mL in volume on the rotary evaporator at 60°C/60 mmHg. The process was repeated two more times. After cooling, the mixture was filtered, the cake was washed with 500 mL of xylenes and sucked dry. The cake was transferred to a glass dish and further dried at 80°C/27 inch vacuum overnight.

The cake was off-white in color and weighed 108.38g. X-ray powder diffraction analysis indicated that a crystalline form was present, which was characterized as Form IV by a powder X- ray diffraction pattern comprising peaks at the following approximate diffraction angles (20): 8.9, 12.0, 14.6, 15.2, 15.7, 17.8, 19.2, 20.5, 21.6, 23.2, 24.2, 24.8, 26.2, and 27.5.

While the invention has been illustrated by reference to specific and preferred embodiments, those skilled in the art will recognize that variations and modifications may be made through routine experimentation and practice of the invention. Thus, the invention is intended not to be limited by the foregoing description, but to be defined by the appended claims and their equivalents.

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Chekal, B. P.; Guinness, S. M.; Lillie, B. M.; McLaughlin, R. W.; Palmer, C. W.; Post, R. J.; Sieser, J. E.; Singer, R. A.; Sluggett, G. W.; Vaidyanathan, R.; Withbroe, G. Org. Process Res. Dev. 2014, 18, 266 http://pubs.acs.org/doi/abs/10.1021/op400088k

The manufacturing process of axitinib (1) involves two Pd-catalyzed coupling reactions, a Migita coupling and a Heck reaction. Optimization of both of these pivotal bond-formation steps is discussed as well as the approach to control impurities in axitinib. Essential to the control strategy was the optimization of the Heck reaction to minimize formation of impurities, in addition to the development of an efficient isolation of crude axitinib to purge impurities.

Babu, S.; Dagnino, R., Jr.; Ouellette, M. A.; Shi, B.; Tian, Q.; Zook, S. E. PCT Int. Appl. WO/2006/048745, 2006.

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 http://www.google.com/patents/CN103570696A?cl=en

formula:

A Axitinib intermediate (1) production method, based on 6-nitro-indazole as a starting material, in the first catalyst is reacted with 3,4-dihydro -2H- pyran, bits of NH the protecting group tetrahydro -2H- pyran-2-yl, then the three iodide, to give the key intermediate in high yield 3-iodo-6-nitro-1- (tetrahydro -2H- pyrazol pyran-2-yl) -1H- indazole (I), comprising the following synthetic steps:

(1) 6-nitro-indazole dissolved in an aprotic solvent, and 3,4-dihydro -2H- pyran catalyst, 6-nitro-indazole in the catalyst and the 3,4-dihydro -2H – pyran reaction, the protecting group NH-position, was prepared to give 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, the reaction equation is:

Wherein the 3,4-dihydro -2H- pyran an amount of 3 equivalents wide;

Aprotic solvent is acetonitrile, ethyl acetate, toluene or xylene;

The catalyst is 2,3-dichloro-5,6-dicyano-p-benzoquinone, p-toluenesulfonic acid or methanesulfonic acid;

The reaction temperature is 7 (T90 ° C, the reaction time is 1 to 4 hours;

(2) 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole dissolved in a polar aprotic solvent, iodine was added and the acid-binding agent, an inorganic base, to afford 3- iodo-6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (I), the reaction equation is:

Wherein the polar aprotic solvent is N, N- dimethylformamide (DMF), N, N- dimethylacetamide, N, N- diethylformamide, N, N- diethyl-acetamide ;

Inorganic base acid binding agent is potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium bicarbonate, sodium bicarbonate, cesium carbonate, lithium hydroxide;

The reaction temperature is 2 (T40 ° C, the reaction time is 8 to 20 hours.

[0009] A Axitinib intermediate (1) in preparation for the Nepalese Asif application, based on intermediate (1) and 2-vinyl pyridine Heck coupling reaction, followed sequentially nitro reduction and the diazotization reaction of iodine, and finally with a 2-mercapto–N- methylbenzamide was prepared by deprotection docking axitinib, including the following synthetic steps:

(I) Intermediate (1) and be given 2_ vinylpyridine Jie Heck coupling reaction to give (E) _6_ nitro _3- [2_ (P than-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, the reaction equation is:

(2) (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- nitro indazole group reduction reaction, to give (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, The reaction equation is:

(3) (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole diazo of the iodide to give (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole The reaction equation is:

(4) (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole with 2- mercapto-methylbenzamide reaction -N-, to give (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) -1- (tetrahydro -2H- pyrazol pyran-2-yl) -1H- indazol-6-yl] thio} benzamide, the reaction equation is:

(5) (E) -N- methyl-2- {[3- (2- (pyridin-2-yl) ethenyl) -1- (tetrahydro -2H- pyran-2-yl) -1H- indazol-6-yl] thio} benzamide deprotected Axitinib (II), the reaction equation is:

Example 1

A Assi intermediates for preparing Nigeria, comprising the steps of:

Synthesis of (I) 6- nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole

A 5L reaction flask was added acetonitrile (2L), followed by addition of 6-nitro-indazole (163.1g, 1.0mol), 3, 4- dihydro -2H- pyran (168.2g, 2.0mol), 2,3- dichloro-5,6-dicyano-p-benzoquinone (22.7g, 0.1mol), was heated to 820C under reflux for 2 hours to complete the reaction, cooled to room temperature, rotary evaporated to dryness, added water and dichloromethane 2L 2L, stirring I hour, delamination, the organic phase washed with brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness, and then dissolved in acetonitrile and 2L, stirring ice-salt bath chilled to _5 ° C for 2 hours, suction filtered, the filter cake washed with a small amount of cold acetonitrile, recrystallized from ethanol, 60 ° C and dried in vacuo 12 hours to give an off-white solid, 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, 236.3 g, yield 95.6%, m.p. 110 ~ 120 ° C, 1Η NMR (CDCl3): δ 1.30-1.83 (m, 6Η, Η3, _Η5,), 3.82-3.93 (m, 2Η, Η6 ‘), 5.86 (m , 1Η, Η2 ‘), 8.10-8.12 (m, 2Η, Η3, Η5), 8.31 (m, 1Η; Η4), 8.55 (s, 1Η, Η7);

The reaction equation is as follows:

(2) 3-iodo-6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (I),

5L reaction flask in DMF 700mL, followed by addition of 6-nitro-_1_ (tetrahydro -2H- pyran-2-yl) -1H- indazole (225.0g, 0.91mol, l.0eq) and potassium carbonate ( 251.6g, 1.82mol, 2.0eq), ice-cooled (10 ° C or less), followed by stirring, iodine (415.8g, 1.64mol, 1.8eq) was dissolved in DMF 300mL, was added dropwise to the reaction system, addition time 2 hours , the reaction system was stirred at 25 ° C for 16 hours to complete the reaction, sodium thiosulfate was added (223.0g, 1.41mol, 1.55eq) and 1.50g of potassium carbonate aqueous solution (1.5L), while maintaining the internal temperature 30 ° C Hereinafter, stirred for 30 minutes at room temperature, water was added with stirring 2L, solid precipitated, stirred for 30 minutes at room temperature, suction filtered, the filter cake was washed with water, 60 ° C and dried in vacuo 12 hours to give a pale yellow solid (Ι), 326.5g, yield 96.2%, m.p. 135 ~ 137 ° C / H NMR (DMS0_d6): δ 1.60-1.61 (m, 2H, H4,, H5 ‘), 1.73-1.76 (m, 1H, H5′), 2.01-2.04 (m, 2H, H3 ‘, H4′), 2.35-2.38 (m, 1H, H3 ‘), 3.81-3.87 (m, 2H, H6′), 6.11-6.14 (dd, 1H, H2 ‘), 7.70-7.72 (d , 1H, H4),

8.05-8.07 (dd, 1H, H5), 8.79 (s, 1H, H7).

The reaction equation is as follows:

A Axitinib intermediate (1) in the preparation for the Nepalese Asif applications, including the following synthetic steps:

Synthesis of (I) (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole

A 5L reaction flask was added DMF (2L), followed by addition of the intermediate (1) (312.0g, 0.84mol), 2- vinylpyridine (127.5g, 1.21mol), N, N- diisopropylethylamine ( 205.3g, 1.59mol), tri-o-tolylphosphine (22.3g, 0.073mol) and palladium chloride (4.9g, 0.028mol), nitrogen, and heated to 100 ° C for 12 hours to complete the reaction, cooled to 45 ° C, isopropanol was added 1L, stirring at 45 ° C for 30 minutes, diluted with water and 5L, stirring at room temperature for I h, suction filtered, washed with water, isopropanol was added to the filter cake 1.2L, stirred at 55 ° C for 30 minutes, then stirred at room temperature for 30 minutes, suction filtered, the filter cake washed with cold isopropanol, 50 ° C and dried under vacuum for 12 hours to give (E) -6- nitro-3- [2- (pyridin-2 – yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, 275.3g, 94.0% yield, m.p. 175 ~ 176 ^, ¾ NMR (DMSO-Cl6): δ 1.63-1.64 (m, 2H, H4 ‘, H5′), 1.79-1.81 (m, 1H, H5 ‘), 2.05-2.07 (m, 2H, H3′, H4 ‘), 2.44-2.50 (m, 1H , H3 ‘), 3.86-3.90 (m, 2H, H6′), 6.15-6.18 (dd, 1H, H2 ‘), 7.30-7.33 (dd, 1H, pyridine H5), 7.65-7.69 (d, 1H, J = 16Hz, vinyl H2), 7.72-7.74 (d, 1H, pyridine H4), 7.82-7.86 (m, 1H, pyridine H3), 7.96-8.00 (d, 1H, J = 16Hz, vinyl HI), 8.07 -8.10 (dd, 1H, H4), 8.44-8.46 (d, 1H, H5), 8.63-8.64 (d, 1H, pyridine H6), 8.77-8.78 (d, 1H, H7);

The reaction equation is as follows:

Synthesis of (2) (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2Η-) -1H- indazole

5L reaction flask in ethanol HOOmLdjC 1000mL and ammonium chloride (300.0g, 5.61mol), was dissolved with stirring, followed by addition of (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (255.0g, 0.73mol), was added iron powder (162.6g, 2.91mol), heated to 50 ° C the reaction was stirred for 2 hours to completion of the reaction, was cooled to 22 ° C, tetrahydrofuran 2L, stirred for I hour at room temperature, filtered through Celite, the filter cake washed with tetrahydrofuran and the filtrate was rotary evaporated to dryness, cooled to room temperature, water was added 2L, stirred for I hour at room temperature, pumping filtered, the filter cake washed with petroleum ether, 50 ° C and dried under vacuum for 12 hours to give a pale yellow solid 206.5g, (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole, yield 88.6%, m.p. 162 ~ 164 ° C / H NMR (CDCl3): δ 1.63-1.77 (m, 2H, H4 ‘, H5 ‘), 2.02-2.06 (m, 1H, H5′), 2.17-2.18 (m, 1H, H4 ‘), 2.55-2.60 (m, 1H, H3′) 3.70-3.72 (m, 2H, H3 ‘, H6 ‘), 3.91 (s, 2H, NH2), 4.04-4.07 (m, 1H, H6′), 5.57-5.60 (dd, 1H, H2 ‘), 6.64-6.66 (dd, 1H, H5), 6.74-6.75 (d, 1H, H7), 7.13-7.16 (dd, 1H, pyridine H5), 7.48-7.50 (d, 1H, pyridine H4), 7.49-7.53 (d, 1H, J = 16Hz, vinyl H2), 7.64 -7.68 (m, 1H, pyridine H3), 7.78-7.82 (d, 1H, J = 16Hz, vinyl Hl), 7.82-7.83 (d, 1H, H4), 8.60-8.61 (d, 1H, pyridine H6) ;

The reaction equation is as follows:

Synthesis of (3) (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole

A 5L reaction flask was added 600mL of water and sodium nitrite (70.2g, 1.02mol), stirred and dissolved, and cooled to (TC, (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl ] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (200.0g, 0.62mol) was dissolved in glacial acetic acid 1.3L, dropwise added to the system dropwise over I h, a solution process maintain an internal temperature of 0 ° C, the same temperature for I hour, dropping HCl solution (concentrated hydrochloric acid 112mL, water 200mL) at O ​​° C, the dropping time of 10 minutes, with the temperature for I h, TLC plate tracking point diazonium salt formation reaction (PE: EA = 1: 1). dropwise 800mL dichloromethane between 0 ° C, the dropping time of 5 minutes, potassium iodide (207.3g, l.25mol) and iodine (79.2g, 0.31mol) was dissolved water 600mL, in (TC dropwise added to the system at the same temperature for 2 hours to complete the reaction. The reaction mixture was poured into the system to 20% sodium thiosulfate solution (2L) and dichloromethane SOOmL and stirred, layered , the aqueous phase was extracted with dichloromethane frozen (2x800mL), dichloromethane phases were combined burning, 3M sodium hydroxide solution was added dropwise 3.5L, adjust the aqueous phase pH = 9 ~ 12, and water was added ammonia 200mL 400mL, stirred for 30 minutes , separated and the aqueous phase was extracted with dichloromethane (2×1.2L), the organic phases were combined, rotary evaporated to dryness, and purified through silica gel to give (E) -6- iodo-3- [2- (pyridin-2-yl ) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, 176.0g, 65.4% yield, m.p. 142 ~ 143 ° C, 1H NMR (DMS0_d6): δ 1.58- 1.61 (m, 2H, H4 ‘, H5,) 1.72-1.78 (m, 1H, H5,), 1.97-2.04 (m, 2H, H3,, H4,), 2.38-2.44 (m, 1H, H3,) , 3.79-3.81 (m, 1H, H6,), 3.88-3.90 (m, 1H, H6,), 5.91-5.94 (dd, 1H, H2,), 7.29-7.31 (m, 1H, pyridine H5), 7.56 -7.60 (d, 1H ,, J = 16Hz, vinyl H2), 7.57-7.59 (m, 1H, pyridine H4), 7.69-7.71 (d, 1H, pyridine H3), 7.80-7.84 (m, 1H, H4 ), 7.89-7.93 (d, 1H, J = 16Hz, vinyl HI), 8.01-8.03 (d, 1H, H5), 8.25 (s, 1H, H7), 8.61-8.62 (d, 1H, pyridine H6) ;

The reaction equation is as follows:

(4) (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H- indazole 6-ylthio} benzamide]

A 5L reaction flask was added DMF (1750mL) and (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1H- indazole (175.0g, 0.41mol), nitrogen, was added [1, I, – bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (14.9g, 0.018mmol ), cesium carbonate (198.3g, 0.61mol) and dichloromethane 20mL, was added 2-mercapto -N- methylbenzamide (84.9g, 0.5Imol), heated to 80 ° C for 16 hours to complete the reaction, spin distilled was removed DMF, cooled to room temperature, ethyl acetate was added 3L, water 4L, stirred for 40 minutes, the organic phase was separated, washed with brine, layered, dried over sodium sulfate, filtered, and rotary evaporated to dryness, to give (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) -1- (tetrahydro -2H- pyran-2-yl) -1H- indazol-6-yl] thio } benzamide, 165.6g, a yield of 86.7%, the melting point of 142 ~ 143 ° C;

The reaction equation is as follows:

(5) Synthesis of axitinib

In a 2L reaction flask was added (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H – indazol-6-yl] thio} benzamide (150.0g, 0.32mol), p-toluenesulfonic acid monohydrate (303.2g, 1.59mol), methanol (800mL) and water (150mL), nitrogen, heated to 65 ° C for 4 hours, spin evaporated to dryness and ethanol (800mL), 65 ° C was stirred for I hour, the ethanol was removed by rotary evaporation, then repeated three times, TLC spot plate tracking reaction (petroleum ether: ethyl acetate = 1: 1). Completion of the reaction, cooled to room temperature, rotary evaporated to dryness, water was added 500mL, stirred for I h, filtered, and the filter cake was washed with methanol and ice, and then added to the reaction vessel, ethyl acetate was added 450mL, stirred at 65 ° C 30 minutes. cooled to room temperature, suction filtered, the filter cake washed with ethyl acetate and freeze paint, water paint, 50 ° C and dried under vacuum for 12 hours to give a white solid 117.5g, Axitinib (II), yield 95.4%, HPLC purity 98.8 % / H NMR (DMS0_d6): δ 2.78 (d, 3H, CH3), 7.05 (dd, 1H), 7.19 (dd, 1H), 7.36-7.23 (m, 3H), 7.50 (dd, 1H), 7.58 ( d, 1H), 7.61 (s, 1H), 7.66 (d, 1H), 7.85-7.76 (m, 1H), 7.96 (d, 1H, J = 16Hz), 8.21 (d, 1H), 8.39 (q, 1H), 8.61 (d, 1H), 13.35 (s, 1H).

The reaction equation is as follows:

Example 2

A Assi intermediates for preparing Nigeria, comprising the steps of:

Synthesis of (1) 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole

A 5L reaction flask was added ethyl acetate (2L), followed by addition of 6-nitro-indazole (163.14g, 1.0mol), 3, 4- dihydro -2H- pyran (210.3g, 2.5mol), toluene acid (20.7g, 0.12mol), heated to 78 ° C under reflux for 3 hours to complete the reaction, cooled to room temperature, rotary evaporated to dryness, added water and dichloromethane 2L 2L, stirred for I hour, stratification, the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness, and then dissolved in acetonitrile and 2L, stirring ice-salt bath chilled to _5 ° C for 2 hours, suction filtered, the filter cake washed with a small amount of cold acetonitrile, recrystallized from ethanol , 60 ° C and dried in vacuo 12 hours to give an off-white solid 223.3g, 6- nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, yield 90.3%, m.p. 110 ^ 11 TC;

The reaction equation is as follows:

(2) 3-iodo-6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (I),

5L reaction flask in DMF 700mL, followed by addition of 6-nitro-_1_ (tetrahydro -2H- pyran-2-yl) -1H- indazole (200.0g, 0.81mol, l.0eq) and sodium hydroxide (64.7g, 1.62mol, 2.0eq), ice-cooled (10 ° C or less), followed by stirring, iodine (369.6g, 1.46mol, 1.8eq) was dissolved in DMF 300mL, was added dropwise to the reaction system, addition time 2 hours, the reaction system was stirred at 25 ° C for 12 hours to complete the reaction, sodium thiosulfate was added (198.2g, 1.25mol, 1.55eq) and 1.50g of potassium carbonate aqueous solution (1.5L), while maintaining the temperature of 30 ° C or less, and stirred for 30 minutes at room temperature, water was added with stirring 2L, solid precipitated, stirred for 30 minutes at room temperature, suction filtered, the filter cake was washed with water, 60 ° C and dried in vacuo 12 hours to give a pale yellow solid

(1), 294.3g, 97.5% yield, m.p. 136 ~ 137. . .

[0014] The reaction equation is as follows:

A Axitinib intermediate (1) in the preparation for the Nepalese Asif applications, including the following synthetic steps:

Synthesis (1) (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2Η-) -1H- indazole

A 5L reaction flask was added DMF (2L), followed by addition of the intermediate (1) (312.0g, 0.84mol), 2- vinylpyridine (127.5g, 1.21mol), N, N- diisopropylethylamine ( 205.3g, 1.59mol), tri-o-tolylphosphine (22.3g, 0.073mol) and palladium chloride (4.9g, 0.028mol), nitrogen, and heated to 100 ° C for 12 hours to complete the reaction, cooled to 45 ° C, isopropanol was added 1L, stirring at 45 ° C for 30 minutes, diluted with water and 5L, stirring at room temperature for I h, suction filtered, washed with water, isopropanol was added to the filter cake 1.2L, stirred at 55 ° C for 30 minutes, then stirred at room temperature for 30 minutes, suction filtered, the filter cake washed with cold isopropanol, 50 ° C and dried under vacuum for 12 hours to give (E) -6- nitro-3- [2- (pyridin _2 _-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, 275.3g, 94.0% yield, m.p. 175 ~ 176 ^, ¾ NMR (DMSO-Cl6): δ 1.63-1.64 (m, 2H, H4 ‘, H5′), 1.79-1.81 (m, 1H, H5 ‘), 2.05-2.07 (m, 2H, H3′, H4 ‘), 2.44-2.50 (m, 1H , H3 ‘), 3.86-3.90 (m, 2H, H6′), 6.15-6.18 (dd, 1H, H2 ‘), 7.30-7.33 (dd, 1H, pyridine H5), 7.65-7.69 (d, 1H, J = 16Hz, vinyl H2), 7.72-7.74 (d, 1H, pyridine H4), 7.82-7.86 (m, 1H, pyridine H3), 7.96-8.00 (d, 1H, J = 16Hz, vinyl HI), 8.07 -8.10 (dd, 1H, H4), 8.44-8.46 (d, 1H, H5), 8.63-8.64 (d, 1H, pyridine H6), 8.77-8.78 (d, 1H, H7);

The reaction equation is as follows:

Synthesis of (2) (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole

5L reaction flask in ethanol HOOmLdjC 1000mL and ammonium chloride (300.0g, 5.61mol), was dissolved with stirring, followed by addition of (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (255.0g, 0.73mol), was added iron powder (162.6g, 2.91mol), heated to 50 ° C the reaction was stirred for 2 hours to completion of the reaction, was cooled to 22 ° C, tetrahydrofuran 2L, stirred for I hour at room temperature, filtered through Celite, the filter cake washed with tetrahydrofuran and the filtrate was rotary evaporated to dryness, cooled to room temperature, water was added 2L, stirred for I hour at room temperature, pumping filtered, the filter cake washed with petroleum ether, 50 ° C and dried under vacuum for 12 hours to give a pale yellow solid 206.5g, (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole, yield 88.6%, m.p. 162 ~ 164 ° C / H NMR (CDCl3): δ 1.63-1.77 (m, 2H, H4 ‘, H5 ‘), 2.02-2.06 (m, 1H, H5′), 2.17-2.18 (m, 1H, H4 ‘), 2.55-2.60 (m, 1H, H3′) 3.70-3.72 (m, 2H, H3 ‘, H6 ‘), 3.91 (s, 2H, NH2), 4.04-4.07 (m, 1H, H6′), 5.57-5.60 (dd, 1H, H2 ‘), 6.64-6.66 (dd, 1H, H5), 6.74-6.75 (d, 1H, H7), 7.13-7.16 (dd, 1H, pyridine H5), 7.48-7.50 (d, 1H, pyridine H4), 7.49-7.53 (d, 1H, J = 16Hz, vinyl H2), 7.64 -7.68 (m, 1H, pyridine H3), 7.78-7.82 (d, 1H, J = 16Hz, vinyl Hl), 7.82-7.83 (d, 1H, H4), 8.60-8.61 (d, 1H, pyridine H6) ;

The reaction equation is as follows:

Synthesis of (3) (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole

A 5L reaction flask was added 600mL of water and sodium nitrite (70.2g, 1.02mol), stirred and dissolved, and cooled to (TC, (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl ] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (200.0g, 0.62mol) was dissolved in glacial acetic acid 1.3L, dropwise added to the system dropwise over I h, a solution process maintain an internal temperature of 0 ° C, the same temperature for I hour, dropping HCl solution (concentrated hydrochloric acid 112mL, water 200mL) at O ​​° C, the dropping time of 10 minutes, with the temperature for I h, TLC plate tracking point diazonium salt formation reaction (PE: EA = 1: 1). dropwise 800mL dichloromethane between 0 ° C, the dropping time of 5 minutes, potassium iodide (207.3g, l.25mol) and iodine (79.2g, 0.31mol) was dissolved water 600mL, in (TC dropwise added to the system at the same temperature for 2 hours to complete the reaction. The reaction mixture was poured into the system to 20% sodium thiosulfate solution (2L) and dichloromethane SOOmL and stirred, layered , the aqueous phase was extracted with dichloromethane frozen (2x800mL), dichloromethane phases were combined burning, 3M sodium hydroxide solution was added dropwise 3.5L, adjust the aqueous phase pH = 9 ~ 12, and water was added ammonia 200mL 400mL, stirred for 30 minutes , separated and the aqueous phase was extracted with dichloromethane (2×1.2L), the organic phases were combined, rotary evaporated to dryness, and purified through silica gel to give (E) -6- iodo-3- [2- (pyridin-2-yl ) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, 176.0g, 65.4% yield, m.p. 142 ~ 143 ° C, 1H NMR (DMS0_d6): δ 1.58- 1.61 (m, 2H, H4 ‘, H5,) 1.72-1.78 (m, 1H, H5,), 1.97-2.04 (m, 2H, H3,, H4,), 2.38-2.44 (m, 1H, H3,) , 3.79-3.81 (m, 1H, H6,), 3.88-3.90 (m, 1H, H6,), 5.91-5.94 (dd, 1H, H2,), 7.29-7.31 (m, 1H, pyridine H5), 7.56 -7.60 (d, 1H ,, J = 16Hz, vinyl H2), 7.57-7.59 (m, 1H, pyridine H4), 7.69-7.71 (d, 1H, pyridine H3), 7.80-7.84 (m, 1H, H4 ), 7.89-7.93 (d, 1H, J = 16Hz, vinyl HI), 8.01-8.03 (d, 1H, H5), 8.25 (s, 1H, H7), 8.61-8.62 (d, 1H, pyridine H6) ;

The reaction equation is as follows:

(4) (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H- indazole 6-ylthio} benzamide]

A 5L reaction flask was added DMF (1750mL) and (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1H- indazole (175.0g, 0.41mol), nitrogen, was added [1, I, – bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (14.9g, 0.018mmol ), cesium carbonate (198.3g, 0.61mol) and dichloromethane 20mL, was added 2-mercapto -N- methylbenzamide (84.9g, 0.5Imol), heated to 80 ° C for 16 hours to complete the reaction, spin distilled was removed DMF, cooled to room temperature, ethyl acetate was added 3L, water 4L, stirred for 40 minutes, the organic phase was separated, washed with brine, layered, dried over sodium sulfate, filtered, and rotary evaporated to dryness, to give (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) -1- (tetrahydro -2H- pyran-2-yl) -1H- indazol-6-yl] thio } benzamide, 165.6g, a yield of 86.7%, the melting point of 142 ~ 143 ° C;

The reaction equation is as follows:

(5) Synthesis of axitinib

In a 2L reaction flask was added (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H – indazol-6-yl] thio} benzamide (150.0g, 0.32mol), p-toluenesulfonic acid monohydrate (303.2g, 1.59mol), methanol (800mL) and water (150mL), nitrogen, heated to 65 ° C for 4 hours, spin evaporated to dryness and ethanol (800mL), 65 ° C was stirred for I hour, the ethanol was removed by rotary evaporation, then repeated three times, TLC spot plate tracking reaction (petroleum ether: ethyl acetate = 1: 1). Completion of the reaction, cooled to room temperature, rotary evaporated to dryness, water was added 500mL, stirred for I h, filtered, and the filter cake was washed with methanol and ice, and then added to the reaction vessel, ethyl acetate was added 450mL, stirred at 65 ° C 30 minutes. cooled to room temperature, suction filtered, the filter cake washed with ethyl acetate and freeze paint, water paint, 50 ° C and dried under vacuum for 12 hours to give a white solid 117.5g, Axitinib (II), yield 95.4%, HPLC purity 98.8 % / H NMR (DMS0_d6): δ 2.78 (d, 3H, CH3), 7.05 (dd, 1H), 7.19 (dd, 1H), 7.36-7.23 (m, 3H), 7.50 (dd, 1H), 7.58 ( d, 1H), 7.61 (s, 1H), 7.66 (d, 1H), 7.85-7.76 (m, 1H), 7.96 (d, 1H, J = 16Hz), 8.21 (d, 1H), 8.39 (q, 1H), 8.61 (d, 1H), 13.35 (s, 1H).

The reaction equation is as follows:

Example 3

A Assi intermediates for preparing Nigeria, comprising the steps of:

Synthesis of (1) 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole

5L reaction flask in toluene (2L), followed by addition of 6-nitro-indazole (163.lg, 1.0mol), 3,4- dihydro -2H- pyran (193.5g, 2.3mol), methanesulfonic acid (14.4g, 0.15mol), heated to 85 ° C under reflux for 3.5 hours, to complete the reaction, cooled to room temperature, rotary evaporated to dryness, added water and dichloromethane 2L 2L, stirred for I hour, stratification, the organic phase was washed with brine wash, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness, and then dissolved in acetonitrile and 2L, stirring ice-salt bath chilled to _5 ° C for 2 hours, suction filtered, the filter cake washed with a small amount of cold acetonitrile and paint, and recrystallized from ethanol , 60 ° C and dried in vacuo 12 hours to give an off-white solid, 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, 234.4g, 94.8% yield, m.p. 111 ~ 112.. ;

The reaction equation is as follows:

(2) 3-iodo-6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (I),

5L reaction flask in DMF 700mL, followed by addition of 6-nitro-_1_ (tetrahydro -2H- pyran-2-yl) -1H- indazole (225.0g, 0.91mol, 1.0eq) and potassium hydroxide ( 102.lg, 1.82mol, 2.0eq), ice-cooled below 10 ° C, with stirring, iodine (415.8g, 1.64mol, 1.8eq) was dissolved in DMF 300mL, was added dropwise to the reaction system dropwise over 2 hours, The reaction system was stirred at 30 ° C for 10 hours to complete the reaction, sodium thiosulfate was added (223.0g, 1.41mol, 1.55eq) and 1.50g of potassium carbonate aqueous solution (1.5L), while maintaining the internal temperature below 30 ° C , stirred for 45 minutes at room temperature, water was added with stirring 2L, solid precipitated, stirred for 45 minutes at room temperature, suction filtered, the filter cake was washed with water, 60 ° C and dried in vacuo 12 hours to give a pale yellow solid

(1), 317.2g, 93.4% yield, m.p. 135 ~ 136 ° C.

The reaction equation is as follows:

A Axitinib intermediate (1) in the preparation for the Nepalese Asif applications, including the following synthetic steps:

Synthesis (1) (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole

A 5L reaction flask was added DMF (2L), followed by addition of the intermediate (1) (312.0g, 0.84mol), 2- vinylpyridine (127.5g, 1.21mol), N, N- diisopropylethylamine ( 205.3g, 1.59mol), tri-o-tolylphosphine (22.3g, 0.073mol) and palladium chloride (4.9g, 0.028mol), nitrogen, and heated to 100 ° C for 12 hours to complete the reaction, cooled to 45 ° C, isopropanol was added 1L, stirring at 45 ° C for 30 minutes, diluted with water and 5L, stirring at room temperature for I h, suction filtered, washed with water, isopropanol was added to the filter cake 1.2L, stirred at 55 ° C for 30 minutes, then stirred at room temperature for 30 minutes, suction filtered, the filter cake washed with cold isopropanol, 50 ° C and dried under vacuum for 12 hours to give (E) -6- nitro-3- [2- (pyridin _2 _-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, 275.3g, 94.0% yield, m.p. 175 ~ 176 ^, ¾ NMR (DMSO-Cl6): δ 1.63-1.64 (m, 2H, H4 ‘, H5′), 1.79-1.81 (m, 1H, H5 ‘), 2.05-2.07 (m, 2H, H3′, H4 ‘), 2.44-2.50 (m, 1H , H3 ‘), 3.86-3.90 (m, 2H, H6′), 6.15-6.18 (dd, 1H, H2 ‘), 7.30-7.33 (dd, 1H, pyridine H5), 7.65-7.69 (d, 1H, J = 16Hz, vinyl H2), 7.72-7.74 (d, 1H, pyridine H4), 7.82-7.86 (m, 1H, pyridine H3), 7.96-8.00 (d, 1H, J = 16Hz, vinyl HI), 8.07 -8.10 (dd, 1H, H4), 8.44-8.46 (d, 1H, H5), 8.63-8.64 (d, 1H, pyridine H6), 8.77-8.78 (d, 1H, H7);

The reaction equation is as follows:

Synthesis of (2) (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole

5L reaction flask in ethanol HOOmLdjC 1000mL and ammonium chloride (300.0g, 5.61mol), was dissolved with stirring, followed by addition of (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (255.0g, 0.73mol), was added iron powder (162.6g, 2.91mol), heated to 50 ° C the reaction was stirred for 2 hours to completion of the reaction, was cooled to 22 ° C, tetrahydrofuran 2L, stirred for I hour at room temperature, filtered through Celite, the filter cake washed with tetrahydrofuran and the filtrate was rotary evaporated to dryness, cooled to room temperature, water was added 2L, stirred for I hour at room temperature, pumping filtered, the filter cake washed with petroleum ether, 50 ° C and dried under vacuum for 12 hours to give a pale yellow solid 206.5g, (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole, yield 88.6%, m.p. 162 ~ 164 ° C / H NMR (CDCl3): δ 1.63-1.77 (m, 2H, H4 ‘, H5 ‘), 2.02-2.06 (m, 1H, H5′), 2.17-2.18 (m, 1H, H4 ‘), 2.55-2.60 (m, 1H, H3′) 3.70-3.72 (m, 2H, H3 ‘, H6 ‘), 3.91 (s, 2H, NH2), 4.04-4.07 (m, 1H, H6′), 5.57-5.60 (dd, 1H, H2 ‘), 6.64-6.66 (dd, 1H, H5), 6.74-6.75 (d, 1H, H7), 7.13-7.16 (dd, 1H, pyridine H5), 7.48-7.50 (d, 1H, pyridine H4), 7.49-7.53 (d, 1H, J = 16Hz, vinyl H2), 7.64 -7.68 (m, 1H, pyridine H3), 7.78-7.82 (d, 1H, J = 16Hz, vinyl Hl), 7.82-7.83 (d, 1H, H4), 8.60-8.61 (d, 1H, pyridine H6) ;

The reaction equation is as follows:

Synthesis of (3) (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole

A 5L reaction flask was added 600mL of water and sodium nitrite (70.2g, 1.02mol), stirred and dissolved, and cooled to (TC, (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl ] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (200.0g,

0.62mol) was dissolved in glacial acetic acid 1.3L, dropwise added to the system dropwise over I hour, added dropwise to maintain the internal temperature process 0 ° C, the same temperature for I h, HCl solution was added dropwise at O ​​° C (112mL of concentrated hydrochloric acid , water 200mL), was added dropwise for 10 minutes, with the temperature for I h, TLC plate tracking point diazonium salt formation reaction (PE: EA = 1: 1). Solution of methylene chloride at 0 ° C and 800mL, dropping time of 5 minutes, potassium iodide (207.3g, l.25mol) and iodine (79.2g, 0.31mol) dissolved in water 600mL, at (TC dropwise added to the system, same temperature for 2 hours to complete the reaction. The reaction system was poured into a mixture of 20% sodium thiosulfate solution (2L) and dichloromethane SOOmL and stirred, layers were separated, the aqueous phase was extracted with dichloromethane frozen (2x800mL ), methylene chloride phases were combined burning, 3M sodium hydroxide solution was added dropwise 3.5L, adjust the aqueous phase pH = 9 ~ 12, and water was added ammonia 200mL 400mL, stirred for 30 minutes, separated and the aqueous phase extracted with dichloromethane ( 2×1.2L), the organic phases were combined, rotary evaporated to dryness, and purified through silica gel to give (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H – pyran-2-yl) -1H- indazole, 176.0g, 65.4% yield, m.p. 142 ~ 143 ° C, 1H NMR (DMS0_d6): δ 1.58-1.61 (m, 2H, H4 ‘, H5,) 1.72-1.78 (m, 1H, H5,), 1.97-2.04 (m, 2H, H3,, H4,), 2.38-2.44 (m, 1H, H3,), 3.79-3.81 (m, 1H, H6,) , 3.88-3.90 (m, 1H, H6,), 5.91-5.94 (dd, 1H, H2,),

7.29-7.31 (m, 1H, pyridine H5), 7.56-7.60 (d, 1H ,, J = 16Hz, vinyl H2), 7.57-7.59 (m, 1H, pyridine H4), 7.69-7.71 (d, 1H, pyridine H3), 7.80-7.84 (m, 1H, H4), 7.89-7.93 (d, 1H, J = 16Hz, vinyl HI), 8.01-8.03 (d, 1H, H5), 8.25 (s, 1H, H7 ), 8.61-8.62 (d, 1H, pyridine H6); reaction equation is as follows:

(4) (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H- indazole 6-ylthio} benzamide]

A 5L reaction flask was added DMF (1750mL) and (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1H- indazole (175.0g, 0.41mol), nitrogen, was added [1, I, – bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (14.9g, 0.018mmol ), cesium carbonate (198.3g, 0.61mol) and dichloromethane 20mL, was added 2-mercapto -N- methylbenzamide (84.9g, 0.5Imol), heated to 80 ° C for 16 hours to complete the reaction, spin distilled was removed DMF, cooled to room temperature, ethyl acetate was added 3L, water 4L, stirred for 40 minutes, the organic phase was separated, washed with brine, layered, dried over sodium sulfate, filtered, and rotary evaporated to dryness, to give (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) -1- (tetrahydro -2H- pyran-2-yl) -1H- indazol-6-yl] thio } benzamide, 165.6g, a yield of 86.7%, the melting point of 142 ~ 143 ° C;

The reaction equation is as follows:

(5) Synthesis of axitinib

In a 2L reaction flask was added (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H – indazol-6-yl] thio} benzamide (150.0g, 0.32mol), p-toluenesulfonic acid monohydrate (303.2g, 1.59mol), methanol (800mL) and water (150mL), nitrogen, heated to 65 ° C for 4 hours, spin evaporated to dryness and ethanol (800mL), 65 ° C was stirred for I hour, the ethanol was removed by rotary evaporation, then repeated three times, TLC spot plate tracking reaction (petroleum ether: ethyl acetate = 1: 1). Completion of the reaction, cooled to room temperature, rotary evaporated to dryness, water was added 500mL, stirred for I h, filtered, and the filter cake was washed with methanol and ice, and then added to the reaction vessel, ethyl acetate was added 450mL, stirred at 65 ° C 30 minutes. cooled to room temperature, suction filtered, the filter cake washed with ethyl acetate and freeze paint, water paint, 50 ° C and dried under vacuum for 12 hours to give a white solid 117.5g, Axitinib (II),

yield 95.4%, HPLC purity 98.8 % / H NMR (DMS0_d6): δ 2.78 (d, 3H, CH3), 7.05 (dd, 1H), 7.19 (dd, 1H), 7.36-7.23 (m, 3H), 7.50 (dd, 1H), 7.58 ( d, 1H), 7.61 (s, 1H), 7.66 (d, 1H), 7.85-7.76 (m, 1H), 7.96 (d, 1H, J = 16Hz), 8.21 (d, 1H), 8.39 (q, 1H), 8.61 (d, 1H), 13.35 (s, 1H).

The reaction equation is as follows:

SEE NMR……….

http://orgspectroscopyint.blogspot.in/2015/07/axitinib.html

………..

http://dmd.aspetjournals.org/content/suppl/2014/03/07/dmd.113.056531.DC1/Supplemental__Data_Figures_56531.pdf

MASS

References

Processes for the preparation of lorcaserin

Zydus Cadila Healthcare Ltd

WO 2015102017, 09 July2015 

On 10 May 2012, after a new round of studies submitted by Arena, an FDA panel voted to recommend lorcaserin with certain restrictions and patient monitoring. The restrictions include patients with a BMI of over 30, or with a BMI over 27 and a comorbidity such as high blood pressure or type 2 diabetes.

On 27 June 2012, the FDA officially approved lorcaserin for use in the treatment of obesity for adults with a BMI equal to or greater than 30 or adults with a BMI of 27 or greater who “have at least one weight-related health condition, such as high blood pressure, type 2 diabetes, or high cholesterol

Useful for treating obesity.

The present invention relates to stable crystalline Form I of Iorcaserin hydrochloride of Formula (IA) and processes for its preparation. The invention also relates to processes for the preparation of lorcaserin and pharmaceutically acceptable salts, solvates and hydrates thereof.

Stable crystalline form I of lorcaserin hydrochloride and its process of preparation are claimed.  Represents the first patenting from Cadila on lorcaserin, which was developed and launched by Arena Pharma and Eisai.

In July 2015, Newport Premium™ reported that Cadila is potentially interested in lorcaserin.

Lorcaserin hydrochloride is an agonist of the 5-HT_2c receptor and shows effectiveness at reducing obesity in animal models and humans developed by Arena Pharmaceuticals. It is chemically represented as (R)-8-chloro-l -methyl -2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride having Formula (I) as depicted herein below.

(IA)

U.S. Patent No. 6,953,787 B2 discloses compound of Formula (I) and pharmaceutically acceptable salt, solvates or hydrates thereof and process for preparation thereof.

U.S. Patent No. 8,168,624 B2 discloses (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride hemihydrate and process for its preparation. The patent also discloses crystalline Form I, Form II and Form III of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride. The crystalline Form

I and Form II are reported as anhydrous, non-solvated crystal forms. The crystalline Form III displays a dehydration feature calculated as a 3.7% weight loss which is consistent with the theoretical weight loss of 3.7% for a hemihydrate.

The patent discloses that anhydrous Form I and Form II readily converts to a hemihydrate, upon exposure to moisture. The dynamic vapor sorption (DVS) data for each of the three crystal forms reveals the hygroscopic nature of both Forms I and II, which readily adsorb moisture at relative humidity (RH) greater than about 40-60%. In addition, both Forms I and II were calculated to adsorb about 3.8% moisture between about 40 and about 80% RH which is consistent with conversion to the hemihydrate (Form III). X-ray powder diffraction (XRPD) carried out on both Forms I and II after the DVS cycle confirmed this conversion. In contrast, the DVS data in connection with Form III shows that it is substantially non-hygroscopic, adsorbing less than 0.5% water at 90% RH and the XRPD pattern showed no change in crystalline form after the DVS cycle.

International (PCT) Publication Nos. WO 2003/086306 Al, WO 2005/019179 Al, WO 2006/069363 Al, WO 2007/120517 Al, WO 2008/07011 1 Al and WO 2009/1 1 1004 Al disclose various synthetic approaches for the preparation of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine, its related salts, enantiomers, crystalline forms and intermediates.

International (PCT) Publication No. WO 2006/071740 Al discloses combination of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine with other agents. International (PCT) Publication No. WO 2012/030938 Al discloses various salts of lorcaserin with optically active acids.

U.S. PG-Pub No. US 2014/0187538 Al discloses amorphous lorcaserin hydrochloride and amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers and processes for their preparation.

International (PCT) Publication No. WO 2014/135545 Al discloses solid dispersion comprising amorphous lorcaserin hydrochloride and one or more pharmaceutically acceptable water soluble polymers.

see…..https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015102017&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Example-7: Preparation of crystalline Form I of lorcaserin hydrochloride. In a round bottom flask, 560g of methyl ethyl ketone and 40 ml water were taken and 100 g of 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine was added and stirred for 10 minutes. The reaction mass heated to 55 to 60°C and 19.3 g of. L-(+)-tartaric acid was added slowly and stirred for one to two hours. The reaction mass was further stirred at 10-15°C for an hour and the product was filtered and washed with a mixture of methyl ethyl ketone and water. The wet cake and 150 ml methyl ethyl ketone were taken in another flask and heated to 75-80°C. 20-25 ml water was, added and stirred for an hour. Further, the reaction mass was stirred for an hour at 0-5°C. The product was filtered and washed with methyl ethyl ketone.

100 g tartrate salt of 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine and 300 mL water were taken in another round bottom flask. 200 mL methylene dichloride was added and the reaction mass was cooled to 10-20°C. 17.2 g sodium hydroxide dissolved in 89 ml water was added into the reaction mass at 10-20°C. The reaction mass was stirred for an hour at 25-30°C and the layers were separated. The solvent was removed from the organic layer under vacuum and then 100 mL ethyl acetate was added into that and distilled out. Further, 100 mL ethyl acetate was added and stirred for 15 minutes. The reaction mass was filtered through a hyflow bed and the filtrate was treated with dry HC1 gas till a pH of 1.5 to 2.5 was obtained at 0-10°C and it was stirred for about 30 minutes to an hour. The product was then filtered and washed with ethyl acetate and then dried in a vacuum oven at 50°C to 55°C for 2 hours. The product was further dried at 90°C to 110°C for 20 hours to obtain crystalline Form I of lorcaserin hydrochloride. Yield: 87.5-98.6 %.

Example-8: Preparation of crystalline Form I of lorcaserin hydrochloride

In a round bottom flask, 2.20 g lorcaserin, 30 mL methylene chloride, 17.4 mL of 1M HCI in ether were added and the mixture was stirred for 5-15 minutes at room temperature. The solvent was removed under reduced pressure to give a white solid. This solid was again dissolved in 30 ml methylene chloride, 17.4 mL of 1M HCI solution and stirred for 5-15 minutes at room temperature. The solvent was removed under reduced pressure to give lorcaserin hydrochloride. The product was dried in a vacuum oven at 50°C to 55°C for 2 hours. The product was further dried at 90°C to 110°C for 20 hours to obtain crystalline Form I of lorcaserin hydrochloride.

Example-9: Preparation of crystalline Form I lorcaserin hydrochloride

50 g of lorcaserin hydrochloride hemihydrate and 50 g of hydroxypropylmethyl cellulose (HPMC) 3CPC were mixed in a blender at 25°C to 35°C. The mixture was mixed for 30 minutes and unloaded. The solid thus obtained was dried in a vacuum oven at 50°C to 55°C for 2 hours. The product was further dried at 90°C to 110°C for 20 hours to obtain crystalline Form I of lorcaserin hydrochloride.

Pankaj R. Patel (right), Chairman and Managing Director,

/////////

Fispemifene, HM 101

Fispemifene; UNII-3VZ2833V08;

cas 341524-89-8

2-[2-[4-[(Z)-4-chloro-1,2-diphenylbut-1-enyl]phenoxy]ethoxy]ethanol

Treatment of Hypogonadism

Androgen Decline in the Aging Male (Andropause) in phase 2

Fispemifene is the Z-isomer of the compound of formula (I)

WO 01/36360 describes a group of SERMs, which are tissue-specific estrogens and which can be used in women in the treatment of climacteric symptoms, osteoporosis, Alzheimer’s disease and/or cardiovascular diseases without the carcinogenic risk. Certain compounds can be given to men to protect them against osteoporosis, cardiovascular diseases and Alzheimer’s disease without estrogenic adverse events (gynecomastia, decreased libido etc.). Of the compounds described in said patent publication, the compound (Z)-2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}ethanol (also known under the generic name fispemifene) has shown a very interesting hormonal profile suggesting that it will be especially valuable for treating disorders in men. WO 2004/108645 and WO 2006/024689 suggest the use of fispemifene for treatment or prevention of age-related symptoms in men, such as lower urinary tract symptoms and diseases or disorders related to androgen deficiency in men.

Quatrx had been conducting phase II clinical development for the treatment of androgen decline in the aging male. Unlike testosterone replacement therapies that are typically topical or injection therapies, fispemifene is an oral treatment and is not a formulation of testosterone. Fispemifene utilizes the body’s normal feedback mechanism to increase testosterone levels. Originally developed at Hormos, QuatRx gained rights to the drug candidate following a merger of the companies pursuant to which Hormos became a wholly-owned subsidiary of QuatRx.

Known methods for the syntheses of compounds like ospemifene and fispemifene include rather many steps. WO 02/090305 describes a method for the preparation of fispemifene, where, in a first step, a triphenylbutane compound with a dihydroxysubstituted butane chain is obtained. This compound is in a second step converted to a triphenylbutene where the chain is 4-chlorosubstituted. Then the desired Z-isomer is crystallized. Finally, the protecting group is removed to release the ethanol-ethoxy chain of the molecule.

Fispemifene is a selective estrogen receptor modulator (SERM) studied in phase II clinical trials at Forendo Pharma for the treatment low testosterone in men. The compound is also in phase II clinical studies at Apricus for the treatment of men with secondary hypogonadism.

In 2013, Forendo Pharma acquired the drug from Hormos Medical for the treatment of male low testosterone.

In 2014, Apricus Biosciences acquired U.S. rights for development and commercialization

PATENT

https://www.google.com/patents/US7504530

EXAMPLE 2 2-{2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethoxy}-ethanol (Compound I)

{2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethoxy}-acetic acid ethyl ester was dissolved in tetrahydrofuran at room temperature under nitrogen atmosphere. Lithium aluminium hydride was added to the solution in small portions until the reduction reaction was complete. The reaction was quenched with saturated aqueous ammonium chloride solution. The product was extracted into toluene, which was dried and evaporated in vacuo. The residue was purified with flash chromatography with toluene/triethyl amine (9.5:0.5) as eluent. Yield 68%.

¹H NMR (200 MHz, CDCl₃):

2.92 (t, 2H, ═CH ₂CH₂Cl),

3.42 (t, 2H, ═CH₂ CH₂ Cl),

3.59-3.64 (m, 2H, OCH₂CH₂O CH₂CH ₂OH),

3.69-3.80 (m, 4H, OCH₂ CH ₂OCH ₂ CH₂OH),

3.97-4.02 (m, 2H, OCH₂CH₂OCH₂CH₂OH),

6.57 (d, 2H, aromatic proton ortho to oxygen),

6.78 (d, 2H, aromatic proton meta to oxygen),

7.1-7.43 (m, 10H, aromatic protons).

………….

PATENT

WO 2001036360

https://www.google.com/patents/WO2001036360A1?cl=en

……………

PATENT

WO 2002090305

 http://www.google.co.in/patents/WO2002090305A1?cl=en

EXAMPLE

a) [2-(2-chloroethoxy)ethoxymethyl]benzene

is prepared from benzyl bromide and 2-(2-chloroethoxy)ethanol by the method described in literature (Bessodes, 1996).

b) {4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl}phenylmethanone

The mixture of 4-hydroxybenzophenone (16.7 g, 84.7 mmol) and 48 % aqueous sodium hydroxide solution (170 ml) is heated to 80 °C. Tetrabutylammonium bromide (TBABr) (1.6 g, 5.1 mmol) is added and the mixture is heated to 90 °C. [2-(2-Chloroethoxy)ethoxymethyl]benzene (18. g, 84.7 mmol) is added to the mixture during 15 min and the stirring is continued for additional 3.5 h at 115-120 °C. Then the mixture is cooled to 70 °C and 170 ml of water and 170 ml of toluene are added to the reaction mixture and stirring is continued for 5 min. The layers are separated and the aqueous phase is extracted twice with 50 ml of toluene. The organic phases are combined and washed with water, dried with sodium sulphate and evaporated to dryness. Yield 31.2 g.

Another method to prepare {4-[2-(2-benzyloxyethoxy)ethoxy]phenyl}phenyl- methanone is the reaction of 2-(2-benzyloxyethoxy)ethyl mesylate with 4- hydroxybenzophenone in PTC-conditions.

Η NMR (CDCI3): 3.64-3.69 (m, 2H), 3.74-3.79 (m, 2H), 3.90 (dist.t, 2H), 4.22 (dist.t, 2H), 4.58 (s, 2H), 6.98 (d, 2H), 7.28-7.62 (m, 8H), 7.75 (td, 2H), 7.81 (d, 2H).

c) 1- {4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl} – 1 ,2-diphenyl -butane- 1 ,4-diol

R = BENZYL

Lithium aluminum hydride (1.08 g, 28.6 mmol) is added into dry tetrahydrofuran (60 ml) under nitrogen atmosphere. Cinnamaldehyde (6.65 g, 50 mmol) in dry tetrahydrofuran (16 ml) is added at 24-28 °C. The reaction mixture is stirred at ambient temperature for 1 h. {4-[2-(2- Benzyloxyethoxy)ethoxy]phenyl}-phenyl-methanone (14.0 g, 37 mmol) in dry tetrahydrofuran (16 ml) is added at 50-55 °C. The reaction mixture is stirred at 60 °C for 3 h. Most of tetrahydrofuran is evaporated. Toluene (70 ml) and 2 M aqueous hydrogen chloride (50 ml) are added. The mixture is stirred for 5 min and the aqueous layer is separated and extracted with toluene (30 ml). The toluene layers are combined and washed with 2M HC1 and water, dried and evaporated. The product is crystallized from isopropanol as a mixture of stereoisomers (8.8 g, 50 %).

Η NMR (CDCI3 ): 1.75-2.10 (m, 2H), 3.20-4.16 (m, 1 OH), 4.52 and 4.55 (2s, together 2H), 6.61 and 6.88 (2d, together 2H), 6.95-7.39 (m, 15H), 7.49 and 7.57 (2d, together 2H).

d) Z- 1 – {4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl} -4-chloro- 1 ,2-diphenyl-but- 1-ene

R = BENZYL

1 – {4- [2-(2-Benzyloxy-ethoxy)ethoxy]phenyl} – 1 ,2-diphenyl -butane- 1 ,4-diol (10.0 g, 19.5 mmol) is dissolved in toluene (50 ml). Triethylamine (2.17 g, 21.4 mmol) is added to the solution and the mixture is cooled to -10 °C. Thionyl chloride (6.9 g, 58.5 mmol) is added to the mixture at -10 – ±0 °C. The mixture is stirred for 1 hour at 0-5 °C, warmed up to 70 °C and stirred at this temperature for 4 hours. Solvent is evaporated, the residue is dissolved to toluene, washed three times with 1M HC1 solution and twice with water. The Z-isomer of the product is crystallized from isopropanol-ethyl acetate. Yield 3.0 g. The filtrate is purified by flash chromatography to give E-isomer.

Z-isomer: Η NMR (CDCI3): 2.91 (t, 2H), 3.41 (t, 2H), 3.55-3.85 (m, 6H), 3.99 (dist.t, 2H), 4.54 (s, 2H), 6.40 (s, 1H), 6.56 (d, 2H), 6.77 (d, 2H), 7.10- 7.50 (m, 15H)

E-isomer: 1H NMR (CDCI3): 2.97 (t, 2H), 3.43 (t, 2H), 3.65-3.82 (m, 4H), 3.88 (dist.t, 2H), 4.15 (dist.t, 2H), 4.58 (s, 2H), 6.86 -7.45 (m, 19H)

FINAL STEP

e) 2- {2-[4-(4-Chloro- 1 ,2-diphenyl-but- 1 -enyl)phenoxy]ethoxy } ethanol:

Z- 1 – {4-[2-(2-Benzyloxy-ethoxy)ethoxy]phenyl} -4-chloro- 1 ,2-diphenyl -but- 1-ene (3.8 g, 7.4 mmol) is dissolved in ethyl acetate under nitrogen atmosphere , Zn powder (0.12 g, 1.85 mmol) and acetyl chloride (1.27 g, 16.3 mmol) are added and the mixture is stirred at 50 °C for 3 h (Bhar, 1995). The reaction mixture is cooled to room temperature, water (10 ml) is added and stirring is continued for additional 10 min. The aqueous layer is separated and the organic phase is washed with 1 M aqueous hydrogen chloride solution and with water. Ethyl acetate is evaporated and the residue is dissolved in methanol (16 ml) and water (4 ml). The acetate ester of the product is hydrolysed by making the mixture alkaline with sodium hydroxide (1 g) and stirring the mixture at room temperature for 1 h. Methanol is evaporated, water is added and the residue is extracted in ethyl acetate and washed with 1 M hydrogen chloride solution and with water. Ethyl acetate is evaporated and the residue is dissolved in toluene (25 ml), silica gel (0.25 g) is added and mixture is stirred for 15 min. Toluene is filtered and evaporated to dryness. The residue is crystallised from heptane-ethyl acetate (2:1). The yield is 71 %.

Z-isomer: 1H NMR (CDCI3): 2.92 (t, 2H), 3.41 (t, 2H), 3.58-3.63 (m, 2H), 3.69-3.80 (m, 4H), 3.96-4.01 (m, 2H), 6.56 (d, 2H), 6.78 (d, 2H), 7.10-7.40 (m, 10H).

Z ISOMER IE FISPEMIFENE

E-2- {2- [4-(4-Chloro- 1 ,2-diphenyl-but- 1 -enyl)phenoxy]ethoxy} ethanol is prepared analogously starting from E-l-{4-[2-(2-benzyloxy- ethoxy)ethoxy]phenyl} -4-chloro- 1,2-diphenyl-but-l-ene. The product is purified by flash chromatography with toluene-methanol (10:0.5) as eluent.

E-isomer: 1H NMR (CDCI3): 2.97 (t, 2H), 3.43 (t, 2H), 3.65-3.79 (m, 4H), 3.85-3.90 (m, 2H), 4.13-4.17 (m, 2H), 6.85-7.25 (m, 2H).

Debenzylation of 1 – {4-[2-(2-benzyloxy-ethoxy)ethoxy]phenyl} -4-chloro- 1 ,2- diphenyl-but- 1-ene is also carried out by hydrogenation with Pd on carbon as a catalyst in ethyl acetate-ethanol solution at room temperature.

………….

PATENT

http://www.google.com/patents/US5491173

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

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///////

A new “flozin” seems to me appearing on the horizon in form of SBM-TFC-039 an SGLT Inhibitor from Sirona Biochem, picked up a list from WO 2012160218,  from TFChem…….see link , Sirona Biochem Announces SGLT2 Inhibitor and Skin Lightening Patent Granted, 29 Jun 2015, Patent entitled “Family of aryl, heteroaryl, o-aryl and o-heteroaryl carbasugars”

This led me to search, “Family of aryl, heteroaryl, o-aryl and o-heteroaryl carbasugars” 
WO 2012160218 A1, IN 2013-DN10635, CN 103649033Tf化学公司

List above as in http://www.google.com/patents/WO2012160218A1?cl=en

FROM THE ABOVE LIST, SBM-TFC-039 MAY BE PREDICTED/OR AS SHOWN BELOW

COMPD 16 as in/WO2012160218

COMPD 16, PREDICTED/LIKELY SBM-TFC-039 has CAS 1413373-30-4, name D-​myo-​Inositol, 1-​[4-​chloro-​3-​[(4-​ethoxyphenyl)​methyl]​phenyl]​-​1,​2,​3-​trideoxy-​2,​2-​difluoro-​3-​(hydroxymethyl)​-

Just scrolling through the patent gave me more insight

MORE EVIDENCE….http://www.google.com/patents/WO2012160218A1?cl=en, this patent descibes compd 16 as follows

Compound 16 according to the invention has been compared to Dapaglifozin to underline the improvement of the duration of action, i.e. the longer duration of glucosuria, of the compound when the intracyclic oxygen atom of the glucose moiety is replaced by a CF₂ moiety.

This assay has been carried out at a dose of 3 mg/ kg.

The results obtained are presented on Figure 5. It appears thus that 16 (3 mg/kg) triggered glucosuria that lasted beyond 24 hours compared to Dapagliflozin.

• Compound 16 according to the invention has been compared to the compound 9 of WO 2009/1076550 to underline the improvement of the duration of action of the compound when a mimic of glucose bearing a CH-OH moiety instead of the intracyclic oxygen atom is replaced by a mimic of glucose bearing a CF₂ in place of the CH-OH moiet .

SBM-TFC-039

PATENT

WO 2012160218

http://www.google.com/patents/WO2012160218A1?cl=en

Examples within this first subclass include but are not limited to:

Synthesis of compound 8

C35H34O5 M = 534.64 g.mol^“

Mass: (ESI ): 535.00 (M + H); 552.00 (M + H₂0); 785.87; 1086.67 (2M + H₂0)

A.

 

Procedure A:

To a solution of 4 (10.5g, 15.89mmol, leq) in toluene (400mL) were added 18-crown-6 (168mg, 0.64mmol, 0.04eq) and potassium carbonate (6.69g, 48.5mmol, 3.05eq.). The mixture was stirred overnight at room temperature, and then the remising insoluble material was filtered off and washed with toluene. The filtrate and the washings were combined, washed with 2N hydrochloric acid aqueous solution followed by saturated sodium hydrogencarbonate aqueous solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified on silica gel chromatography (cyclohexane/ethyl acetate 98:2 to 80:20) to afford cyclohexenone 8 (4.07g; 48% yield) as yellowish oil.

Procedure B:

A solution of 7 (3.27g, 5.92mmol, leq) in pyridine (14mL) was cooled to 0°C before POCl₃ (2.75mL, 29.6mmol, 5eq) was added dropwise. The mixture was stirred at this temperature for 10 min before the cooling bath was removed. The reaction mixture was stirred overnight at room temperature before being re-cooled to 0°C. POCI3 (2.75mL, 29.6mmol, 5eq) was added once again trying to complete the reaction. The mixture was stirred for an additional 20h at room temperature before being diluted with Et₂0 (20mL) and poured onto crushed ice. 1M HC1 aqueous solution (lOOmL) was added, and the mixture was extracted with Et₂0 (200mL & l OOmL). The combined organic extracts were washed with brine (lOOmL), dried over sodium sulphate, filtered and concentrated before being purified on silica gel chromatography (cyclohexane / ethyl acetate 98:2 to 80:20) to afford compound 8 (1.46g, 46% yield) as an orange oil. Synthesis of compound 9

C₁₅H₁₂BrC10₂ M = 339.61 g.moF¹

Mass: (GC-MS): 338-340

 

The synthesis of this product is described in J. Med. Chem. 2008, 51, 1 145—1149.Synthesis of compound 10

C15H14B1CIO M = 325.63 g.mof¹

 

10 The synthesis of this product is described in J. Med. Chem. 2008, 51, 1145-1 149.

Synthesis of compound 11

C50H49CIO6 M = 781.37 g.moF¹

Mass: ESI⁺): 798.20 (M + H₂0)

 

Under inert atmosphere, Mg powder (265mg, 10.9mmol, 2.4eq) was charged into a three necked flask, followed by addition of a portion of 1/3 of a solution of the 4- bromo-l-chloro-2-(4-ethylbenzyl)benzene (2.95g, 9.1mmol; 2eq) in dry THF (25mL) and 1 ,2-dibromoethane (10 mol % of Mg; 85mg; 0.45mmol). The mixture was heated to reflux. After the reaction was initiated (exothermic and consuming of Mg), the remaining solution of 2-(4-ethylbenzyl)-4-bromo-l-chlorobenzene in dry TFIF was added dropwise. The mixture was then allowed to react for another one hour under gentle reflux until most of the Mg was consumed.

The above Grignard reagent was added dropwise into the solution of cyclohexenone 8 (2.42g, 4.53mmol, leq) in dry THF (25mL) under inert atmosphere at room temperature (about 25°C), then allowed to react for 3h. A saturated aqueous solution of ammonium chloride was added into the mixture to quench the reaction. The mixture was extracted with Et₂0, washed with brine, dried over sodium sulphate, filtered and concentrated. The residue was purified on silica gel chromatography (cyclohexane/ethyl acetate 100:0 to 80:20) to afford the target compound 11 as a yellow oil (3.01g, 86%).

Synthesis of compound 12

C₅oH49C10₅ M = 765.37 g.mol^“1

+): 782.13 (M + H₂0)

 

Triethylsilane (0.210mL, 1.30mmol, 3eq) and boron-trifluoride etherate (48% BF₃, O. l lOmL, 0.866mmol, 2eq) were successively added into a solution of alcohol 1 1 (338mg, 0.433mmol, leq) in dichloromethane (5mL) under inert atmosphere at -20°C. After stirring for 2.5h, a saturated aqueous solution of sodium chloride was added to quench the reaction. The mixture was extracted with CH₂C1₂ (10mLx3) and the organic layer was washed with brine, dried over Na₂S0₄, filtrated and concentrated. The residue was purified on silica gel chromatography (cyclohexane/ethyl acetate 9.8:0.2 to 8:2) to afford the target compound 12 as a white powder (278 mg, 0.363mmol, 84%).

Synthesis of compound 13

C₅oH_5tC10₆ M = 783.39g.moF¹

Mass: (ESI⁺): 800 (M + H₂0); 1581 (2M + H₂0)

Under inert atmosphere, borane-dimethyl sulfide complex (2M in THF, 16.7mL, 33mmol, 10.5eq) was added to a solution of 12 (2.41g; 3.15mmol, leq) in dry THF (lOOmL) cooled to 0°C. The reaction mixture was then refluxed for lh,cooled to 0°C and treated carefully with sodium hydroxide (3M in H₂0, 10.5mL, 31.5mmol, lOeq), followed by hydrogen peroxide (30% in H₂0, 3.2mL, 31.5mmol, l Oeq) at room temperature (above 30°C). The mixture was allowed to react overnight at room temperature (~25°C) before a saturated aqueous solution of ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over Na₂S0₄, filtered, and concentrated. The residue was purified by silica gel chromatography (cyclohexane/ethyl acetate 97:3 to 73:27) to afford the desired compound 13 (1.05g; 43%) as a yellowish oil.

Synthesis of compound 14

C50H49CIO6 M = 781.37g.mol^“1

Mass: (ESI⁺): 798 (M + H₂0); 1471; 1579 (2M + H₂0)

 

13 14

Dess-Martin periodinane (81mg; 1.91mmol; 1.5eq) was added portion wise to a solution of alcohol 13 (l .Og; 1.28mmol, leq) in anhydrous dichloromethane (20mL) at 0°C. The reaction was then stirred overnight at room temperature before being quenched with IN aqueous solution of sodium hydroxide. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and concentrated. The residue was purified on silica gel chromatography (cyclohexane / ethyl acetate 98:2 to 82: 18), to afford the target ketone 14 (783mg, 79% yield) as a colorless oil. Synthesis of compound 15

C₅oH49ClF₂0₆ M = 803.37g.moF¹

¹⁹ F NMR (CDCU, 282.5MHz): -100.3 (d, J=254Hz, IF, CFF); -1 13.3 (td, Jl=254Hz, J2=29Hz, IF, CFF).

Mass: (ESI⁺): 820.00 (M+H₂0)

 

14 15

A solution of ketone 14 (421mg, 0.539mmol, leq) in DAST (2mL, 16.3mmol, 30eq.) was stirred under inert atmosphere at 70°C for 12h. The mixture was then cooled to room temperature and dichloromethane was added. The solution was poured on a mixture of water, ice and solid NaHC0₃. Agitation was maintained for 30min while reaching room temperature. The aqueous layer was extracted with dichloromethane and the organic phase was dried over Na₂S0₄, filtered and concentrated. The crude product was purified on silica gel chromatography (cyclohexane/ethyl acetate 98:2 to 80:20) to afford the desired compound 15 as a yellowish oil ( 182mg, 42% yield).

Synthesis of compound 16

C22H25CIF2O5 M = 442.88g.mor¹

¹⁹ F NMR (MeOD, 282.5MHz): -96.7 (d, J=254Hz, IF, CFF); 12.2 (td,

Jl=254Hz, J2=28Hz, IF, CFF).

Mass: (ESI⁺): 465.3 (M+Na)

 

o-Dichlorobenzene (0.320mL, 2.82mol, lOeq) followed by Pd/C 10% (0.342g, 0.32mol, l .leq) were added to a solution of 15 (228mg, 0.28mmol, leq) in a mixture of THF and MeOH (2: 1, v/v, 160mL). The reaction was placed under hydrogen atmosphere and stirred at room temperature for 2h. The reaction mixture was filtered and concentrated before being purified on silica gel chromatography (dichloromethane/methanol 100: 1 to 90: 10) to afford compound 16 (105mg, 83% yield).

Sirona Biochem’s SGLT Inhibitor Performs Better Than Johnson and Johnson’s SGLT Inhibitor, According to Study

……………………………………………………………………………….

Shanghai Fosun Pharmaceutical Group Co. Ltd.

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Toremifene

2-[4-[(Z)-4-chloro-1,2-diphenylbut-1-enyl]phenoxy]-N,N-dimethylethanamine

Toremifene; Acapodene; Farestone; Z-Toremifene; Toremifeno; Toremifenum

cas 89778-26-7

Launched – 1988.Orion (FI), greast cancer

1. Citrate, Toremifene, GTx-006
   NK-622
   • 89778-27-8
2. Fareston
3. FC 1157a
4. FC-1157a
5. FC1157a
6. Toremifene
7. Toremifene Citrate
8. Toremifene Citrate (1:1)
9. Toremifene, (E)-Isomer
10. • C₂₆H₂₈ClNO · C₆H₈O₇
    • Molecular Weight 598.08Toremifene Citrate

Toremifene is a first generation selective estrogen receptor modulator (SERM). Like TAMOXIFEN, it is an estrogen agonist for bone tissue and cholesterol metabolism but is antagonistic on mammary and uterine tissue.

The company GTx is conducting phase III clinical trials for the prevention of prostate cancer in men who have been diagnosed with high grade prostatic intraepithelial neoplasia (PIN).

Toremifene citrate is an oral selective estrogen receptor modulator (SERM) which helps oppose the actions of estrogen in the body. Licensed in the United States under the brand name Fareston, toremifene citrate is FDA-approved for use in advanced (metastatic)breast cancer. It is also being evaluated for prevention of prostate cancer under the brand name Acapodene.^[1]

In 2007 the pharmaceutical company GTx, Inc was conducting two different phase 3 clinical trials; First, a pivotal Phase clinical trial for the treatment of serious side effects of androgen deprivation therapy (ADT) (especially vertebral/spine fractures and hot flashes, lipid profile, and gynecomastia) for advanced prostate cancer, and second, a pivotal Phase III clinical trial for the prevention of prostate cancer in high risk men with high grade prostatic intraepithelial neoplasia, or PIN. Results of these trials are expected by first quarter of 2008^[2]

An NDA for the first application (relief of prostate cancer ADT side effects) was submitted in Feb 2009,^[3] and in Oct 2009 the FDA said they would need more clinical data, e.g. another phase III trial.^[4]

Originally developed at Orion, toremifene was subsequently licensed to Nippon Kayaku in Japan and to Asta Medica (now, part of Meda) in Germany.

Synthesis

 ……….

PATENT

http://www.google.com/patents/CN104230723A?cl=en

Toremifene (Toremifene), chemical name (Z) -4- chloro-1,2-diphenyl–1- [4- (2- (N, N- dimethylamino) ethoxy yl) phenyl] -1-butene, having the structure I.Toremifene to tamoxifen (Tamoxifen) analogues with anti-estrogenic activity, can be used in the treatment of hormone-dependent breast cancer, and its E-isomer has the presence of estrogenic activity, E isomers toremifene may counteract anti-estrogenic activity, and therefore isomeric purity is essential toremifene.Toremifene was developed in 1983 by the Finnish Famos company, listed in 1996 by the Orion company in the EU, the trade name Fareston, 2002 to enter the country, the trade name of toremifene.

RJ Toivola et al., European Patent EP95875, disclosed in U.S. Patent US4696949A synthetic route toremifene, that following a synthetic route, the synthetic route to phenol as a raw material, by acylation, rearrangement, alkyl group and an addition reaction to give 1,2-diphenyl -1- [4- [2- (N, N- dimethylamino) ethoxyphenyl]] – 1,4-diol (Compound 5) as the key intermediate, further HCl in ethanol or hydrochloric acid elimination reaction occurs, then get toremifene thionyl chloride reaction. The main problem with this approach is that the elimination reaction of the compound 5 in ethanol occurs when hydrochloric acid or concentrated hydrochloric acid, the resulting triaryl alcohol butyrate (Compound 6) having a Z / E configuration, both the ratio of 1: 2 ~ 2: 1, stereo selectivity is not high, and there are 5% of the cyclization by-product; on the Z / E configuration Miyoshi butyric fractional crystallization of alcohol, you can get pure Z-type Miyoshi butyric alcohol , but the yield is only 41%; then, Z-type Miyoshi butyric alcohol chlorination reaction occurs in the action of thionyl chloride, the purified product toremifene.

 U.S. Patent US5491173A also reported another synthetic route toremifene namely the following two synthetic routes. The route to the aryl ketone (Compound 7) with a phenyl Grignard reagent addition reaction of ketone carbonyl groups to give triaryl-butanediol (compound 5), which is the elimination of toremifene and chlorinated reaction products happen again.

 Chinese Patent Publication No. CN1125716A application reported an efficient synthesis of Z-type Miyoshi butyric alcohol (compound 6) method, US4696949A compared with the US patent, the method mild conditions, reduce the acid concentration and reaction temperature, reaction time, triarylphosphine butanediol (Compound 5) in concentrated hydrochloric acid or concentrated hydrochloric isopropanol or ethanol effect of concentrated hydrochloric acid, can be 60-78% selectivity and 95% yield of type 2 Miyoshi butyric alcohol But after Publication No. 0 02,126,969 attached eight patent applications after the inventor repeated experiments show that the technique disclosed in the patent application programs can not achieve their claimed technical effect.

 Publication No. CN102126969A of Chinese patent applications through the intermediate Miyoshi butyric alcohol occurs at a catalytic converter configuration of concentrated hydrochloric acid, while taking advantage of differences in solubility, so E- type Miyoshi butyric alcohol continuously into Z-type Miyoshi butyric alcohol (compound 6) precipitates, thereby undermining the balance, so that one of the E-type Miyoshi butyric alcohol continuously into Z-type Miyoshi butyric alcohol (compound 6) to give the Z-Miyoshi butyric alcohol ( Compound 6) and then get toremifene thionyl chloride after chlorination. Although to some extent, improve the yield, but increased operating procedure, is not conducive to industrial production.

Currently, the key intermediate is patent protected, and z-type Miyoshi butyric alcohol (compound 6) stereoselective low yield and isolated intermediates, to solve this problem, to overcome technical barriers to foreign pharmaceutical companies, urgent need to find a simple process, low cost, easy to separate and viable for large-scale production of synthetic routes.

To achieve the above object, according to one aspect of the present invention, there is provided a method of synthesizing toremifene, synthetic method comprising: a step S1, so that a compound having the structural formula II with a compound B having the structural formula III C occurs Mike Murray to give compound D having the structural formula IV; step S2, the Compound D and Compound E or Compound E of the hydrochloride salt of the formula V having a phenolic hydroxyl group on the occurrence of a selective alkylation reaction, to give a compound having the structural formula VI F; step S3, the compound F is reacted with thionyl chloride to give toremifene, wherein,

 Formula II is:

Structural formula III as follows:

Formula IV is

Of formula V is C1CH2CH2N (CH 3) 2; formula VI is

FIG. 1 illustrates the present invention obtained in Example 1 H NMR spectrum of compound D of implementation;

FIG. 2 shows the 1 H NMR spectrum of the present invention, the compound obtained in Example F;

FIG. 3 shows the present invention is a proton nuclear magnetic resonance spectrum of toremifene obtained in Example.

Figure 1, which shows a spectrum of results for Che bandit? (400 cm take, 01 ^ 0) 3 = 9.20 (! 8,1 1), 7.37 (^ = 7.4 to take, 2 1!), 7.30- 7. 23 (m, 3H), 1.22- 7. 15 (m, 2H), 7. 15 – 7. 06 ( m, 3H), 6. 61 (dd, J = 9. 0, 2. 2Hz, 2H), 6. 49 -. 6. 32 (m, 2H), 4 48 (s, 1H), 3 30 (. m, 2H), 2 55 (t, J = 7. 5Hz, 2H);. F proton nuclear magnetic resonance spectrum of the compound attached to the

Figure 2, showing spectrum results Che NMR (400MHz, DMSO) δ = 7. 36 (d, J = 7. 3Hz, 2H), 7. 31 – 7. 25 (m, 3H), 7. 21 – 7. 10 (m, 5H), 6. 75 – 6. 69 (m , 2H), 6. 59 (d, J = 8. 8Hz, 2H), 4. 49 (s, 1H), 3. 88 (t, J = 5. 8Hz, 2H), 3. 31 (d, J = 4. 3Hz, 2H), 2. 57 (t, J = 7.5Hz, 2H), 2.52 (t, J = 4.6Hz, 2H), 2 15 (s, 6H);.

Tommy remifentanil NMR hydrogen spectrum in Figure 3 attached, showing spectrum results Che NMR (400MHz, CDC13) δ = 7. 41 -. 7. 33 (m, 2H), 7 29 (dt, J = 7. 1, 2. 9Hz, 3H), 7. 20 (dd, J = 10. 0, 4. 3Hz, 2H), 7. 13 (dd, J = 7. 1, 4. 3Hz, 3H), 6.87- 6. 72 (m, 2H), 6. 57 (dd, J = 6. 8, 4. 8Hz, 2H), 3. 92 (t, J = 5. 8Hz, 2H), 3. 41 (t, J = 7. 5Hz, 2H), 2. 92 (t, J = 7. 5Hz, 2H), 2. 63 (t, J = 5. 8Hz, 2H), 2. 28 (s, 6H).

The synthetic routes above synthetic method are as follows:

Synthesis of toremifene:

To a 2L reaction flask 1. 1L of toluene, 110g (0. 28mol) obtained in the above step Z configuration compound F, mixed to obtain a sixth system, the cooling system to the sixth mixed 0~5 ° C , was slowly added dropwise 99. 93g (0. 84mol) thionyl chloride addition was complete the formation of the seventh mixed system, the mixed system was slowly warmed to a seventh ll〇 ° C, for 1 hour to obtain a third product system, stop The third product heating and cooling system to 15~25 ° C, the third product system slowly poured into 1L of water, adding NaOH solution to a pH 9~10 and get the second system, the second in and a system for liquid separation, and the resulting aqueous phase to obtain a second solution was extracted with 1L toluene extraction, the organic phase of the second extraction solution and liquid separation were combined and concentrated to give crude toremifene, the crude product was mass ratio of 1 : mixed solvent of ethyl acetate and acetone 1 crystals to give 103. 7g toremifene products.

Synthesis of toremifene:

[0062] To a 5L reaction flask 3. 3L of toluene, 110g (0. 28mol) obtained in the above step Z configuration compound F, mixed to obtain a sixth system, the cooling system to the sixth mixed 0~5 ° C , was slowly added dropwise 33. 31g (0. 28mol) thionyl chloride addition was complete the formation of the seventh mixed system, the mixed system was slowly warmed to a seventh ll〇 ° C, after the reaction for 6 hours to obtain a third product system, stop The third product heating and cooling system to 15~25 ° C, the third product system slowly poured into 1L of water, potassium carbonate solution to a pH 9~10 and get the second system, the second and system for liquid separation, and the resulting aqueous phase to obtain a second solution was extracted with 1L ethyl acetate, the organic phase after the second extraction solution and liquid separation were combined and concentrated to give crude toremifene, the crude product was quality ratio was crystallized from acetone to give 92. 2g toremifene products.

Purity of toremifene following method:

[0107] to take the product, add the mobile phase dissolved and diluted into 1ml of 1. Omg solution containing, according to HPLC octadecylsilane bonded silica as a filler to square 1% trifluoroacetic acetic acid aqueous solution (A) and acetonitrile (B) as the mobile phase gradient elution (T = Omin 10% B; T = lOmin 95% B; T = 12min 100% B; T = 15min 10% B), detection wavelength 210nm; area normalization method to calculate the Z configuration purity compound F, where F Z configuration compound retention time of 6. 76min. The purity of the above calculation or Z configuration detection obtained compound D, compound D Z configuration and E configuration of the weight ratio, toremifene yield and purity are reported in Table 1 below.

……………..

PATENT

http://www.google.com/patents/US5491173

c) 4-chloro-1,2-diphenyl-1-[4-[2-(N ,N-dimethylamino)ethoxy]phenyl]-1-butene (Z and E)

(Z)-isomer: The reaction is performed under dry conditions. 42.4 g of (Z)-1,2-diphenyl-1-[4-[2-(N,N-dimethylamino )ethoxy]phenyl]-1-buten-4-ol are dissolved in 250 ml of chloroform. Then 23.8 g of thionyl chloride areadded dropwise. The mixture is refluxed 3 h. The solvent is evaporated, after which the product is recrystallized from ethyl acetate. The yield ofthe hydrochloride salt is 36.7 g (83%), m.p. 194°-6° C. The base can be liberated from the Salt with 1M sodium carbonate solution, after which the base is extracted in toluene. The toluene solution is dried and the solvent is evaporated. The free base has m.p. 108°-10° C. (from acetone).

¹ H-NMR-spectrum (CDCl₃): δ 2.27 (6H, s), 2.63 (2H, t), 2.91 (2H, t), 3.41 (2H, t), 3.92 (2H, t), 6.54 (2H, d), 6.79 (2H. d), 7.15(5H, s), 7.31 (5H, s). MS: m/z 405/407 (M⁺, 7/3), 72 (20), 58 (100).

The citric acid salt can be prepared as follows: 40.6 g of the (Z)-isomer as a free base are dissolved in 175 ml of warm acetone and 24.3 g of citric acid are dissolved in 100 ml of warm acetone. The solutions are combined and the mixture is allowed to cool. The citrate, m.p. 160°-162° C., is collected by filtration.

(E)-isomer: The compound is prepared from (E)-1,2-diphenyl-1-[4-[2-(N ,N-dimethylamino)ethoxy]phenyl]-1-buten-4-ol in the same manner as the corresponding (Z)-isomer. The hydrochloride salt is crystallized from toluene. The yield is 35.8 g (81%) of a product having m.p. 183°-5° C. The base can be liberated from the salt in the same manner as the corresponding (Z)-isomer. It has m.p. 69°-71° C. (from hexane).

¹ H-NMR-spectrum (CDCl₃): b 2.34 (6H, s), 2.74 (2H, t), 2.97 (2H,t), 3.43 (2H, t), 4.08 (2H, t), 6.80-7.30 (14H, m).

MS: m/z 405/407 (M⁺, 7/3) 72 (19) 58 (100)

EXAMPLE 4

4-chloro-1,2-diphenyl-1-[4-[2-(N ,N-diethylamino)ethoxy]phenyl ]-1-butene (Z and E)

43.3 g of 1,2-diphenyl-1-[4-[2-(N,N-diethylamino)ethoxy]phenyl]butane-1,4-diol (pureenantiomer pairs or their mixture: m.p. of (RR,SS)-pair is 107°-9° C.)is suspended in 250 ml of toluene, after which 25ml toluene is distilled off to dry the solution. The mixture is cooled to 0° C. with stirring. While stirring and keeping the temperature at 0° C. or a little below, 47.6 g of thionyl chloride of good qualityare added. The mixture is stirred for 1 h at 0° C. and the temperature is then allowed to rise to 22° C. The mixture is stirred at 80° C. until the reaction is completed (about 3 h). After that, water is added to decompose the excess of thionyl chloride followed by 20% sodium hydroxide solution to liberate the product from itshydrochloride salt. The aqueous layer is discarded and the toluene layer iswashed with water. Then the solvent is evaporated to leave a mixture of (Z)- and (E)isomers (Z:E 7:3) as an oil in quantitative yield.

(Z)-isomer: The (Z)-isomer is isolated from the isomer mixture above as thehydrochloride salt because of the low melting point of the free base. The m.p. of the hydrochloride salt is 178°-80° C. The (Z)-isomermay be freed from its salt by any normal method.

¹ H-NMR-spectrum (CDCl₃): δ 1.01 (6H, t), 2.57 (4H, q), 2.77 (2H, t), 2.91 t), 3.41 (2H, t), 3.90 t), 6.53 (2H, d), 6.78 (2H, d), 7.15 (5H, s), 7.31 (5H, s). (E)-isomer:

¹ H-NMR-spectrum (CDCl₃): δ 1.07 (6H, t), 2.66 (4H, q), 2.89 (2H, t), 2.97 (2H, t), 3.42 (2H, t), 4.07 (2H, t), 6.90-7.20 (10H, m).

……………….

SEE

http://www.google.co.ug/patents/EP0095875B1?cl=en

………….

http://www.intechopen.com/books/topics-on-drug-metabolism/electrochemical-methods-for-the-in-vitro-assessment-of-drug-metabolism

References

1.  Price N, Sartor O, Hutson T, Mariani S. Role of 5a-reductase inhibitors and selective estrogen receptor modulators as potential chemopreventive agents for prostate cancer. Clin Prostate Cancer 2005;3:211-4. PMID 15882476
2.  “GTx’s Phase III Clinical Development of ACAPODENE on Course Following Planned Safety Review” (Press release). GTx Inc. 2007-07-12. Retrieved 2006-07-14.
3.  “GTx Announces Toremifene 80 mg NDA Accepted for Review by FDA” (Press release).
4.  “GTx and Ipsen End Prostate Cancer Collaboration due to Costs of FDA-Requested Phase III Study”. 2 Mar 2011

Toremifene

Systematic (IUPAC) name
2-{4-[(1Z)-4-chloro-1,2-diphenyl-but-1-en-1-yl]phenoxy}-N,N-dimethylethanamine
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a608003
Pharmacokinetic data
Protein binding	more than 99.5%
Biological half-life	5 days
Identifiers
CAS Registry Number	89778-26-7
ATC code	L02BA02
PubChem	CID: 3005573
IUPHAR/BPS	4325
DrugBank	DB00539
ChemSpider	2275722
UNII	7NFE54O27T
KEGG	D08620
ChEBI	CHEBI:9635
ChEMBL	CHEMBL1655
Chemical data
Formula	C26H28ClNO
Molecular mass	405.959 g/mol

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Verubecestat (MK-8931)

Merck Alzheimer’s drugs Verubecestat (MK-8931) is an oral β- amyloid precursor protein cleaving enzyme (BACE1 or β-secretase enzyme) inhibitor, is currently in Phase III clinical trials

Verubecestat
MK 8931, MK-8931, SCH 900931
2-Pyridinecarboxamide, N- (3 – ((5R) -3-amino-5,6-dihydro-2,5-dimethyl-1 , 1-dioxido-2H-1,2,4-thiadiazin-5-yl) -4-fluorophenyl) -5-fluoro-

N-[3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-6H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide

CAS : 1286770-55-5

C₁₇ H₁₇ F₂ N₅ O₃ S, 409.41
Mechanism: Oral β- amyloid precursor protein cleavage enzyme (BACE) inhibitors
Indications: Alzheimer’s disease
Development progress: phase III clinical
Companies: Merck

Verubecestat (MK-8931) is a small-molecule inhibitor of beta-secretase cleaving enzyme (BACE) 1 and BACE2 in development by Merck for the treatment of Alzheimer’s Disease.

MK-8931 is a beta-secretase 1 (BACE1) inhibitor in phase III development for the treatment of amnestic mild cognitive impairment (aMCI) due to Alzheimer’s disease at Merck & Co. The company is also conducting phase II/III trials for the treatment of Alzheimer’s type dementia.

Smiles: C [C @] 1 (CS (= O) (= O) N (C (= N1) N) C) c2cc (ccc2F) NC (= O) c3ccc (cn3) F

COSY PREDICT

PATENT

https://www.google.co.in/patents/CN102639135A?cl=en

Scheme 3a:

https://www.google.co.in/patents/CN102639135A?cl=en

Scheme 3b:

The amine A (Scheme 3a, step 4) (13.7 g) in n-butanol (150 mL) was added a slurry solution of cyanogen bromide (5M, in MeCN). The resulting mixture was heated to reflux for 4 hours. The mixture was concentrated to 1/3 of original volume. To this mixture was added Et20 (200 mL). The resulting solid was removed by filtration, and the solid was washed with Et20 (2x). The solid was partitioned between EtOAc and saturated Na2CO3 (aq). The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 10.6 g

Scheme 10:

The nitro compound (Scheme 3b) (2. 50 g, 6. 0 mmol) of Et0H (150 mL) was degassed (To this solution was bubbled with nitrogen time 3 min). To this solution was added Pd / C (10% w / w, 50% water, 698 mg). The mixture was placed in a nitrogen atmosphere. Exhaust, and backfilled with H2 (3x). The obtained mixture at room temperature, followed by stirring under H2 balloon for 2 hours. Bubbling nitrogen gas, and the mixture was purged, filtered through Celite, and concentrated.Small plug filtered through a silica gel column, eluting with EtOAc, and the product was purified to give the aniline (2. 2g, 97%).

SEE

PATENT

http://www.google.co.in/patents/WO2011044181A1?cl=en

SNAPSHOT

SYNTHESIS CONSTUCTION

AND

ON RXN WITH WITH BuLi GIVES

THIS GIVES

THIS ON TREATMENT WITH BrCN

ON BOC2O TREATMENT GIVES

GIVES ON HYDGN

REACTION WITH

GIVES

FINAL COMPD Verubecestat

1H NMR PREDICT

13C NMR PREDICT

Updated…….WATCH OUT FOR MORE

https://www.google.co.in/patents/US8729071?cl=en

Steps 1-4:

These steps were performed using similar procedures to those described in steps 1-4 of Scheme 1a.

Step 5:

To a solution of the amine from step 4 (10.5 g, 36 mmol) in CH₂Cl₂ (200 mL) was added benzoylisothiocyanate (4.3 mL, 1.1 eq.). The resulting solution was stirred at RT for 2.5 days. Additional benzoylisothiocyanate (0.86 mL, 0.2 eq.) was added and the solution was stirred at RT for an additional 2 hours. The solution was then concentrated in vacuo.

A portion of this material (6.5 g, ˜14 mmol) was dissolved in MeOH (200 mL). To this solution was added Na₂CO_{3 (s)} (1.52 g, 14 mmol). The resultant mixture was stirred at RT for 45 min. After that time, a slight excess of HOAc was added to the solution. The mixture was then concentrated. The residue was partitioned between CH₂Cl₂ and ½ sat. NaHCO_{3 (aq.)}. The aqueous layer was extracted with CH₂Cl₂ (3×). The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The thiourea (˜4.9 g) was carried onto the next reaction without further purification.

Step 6:

Example 15 was prepared using a method similar to that described in Scheme 1a step 6.

To a shiny of amine A (Scheme 3a step 4) (13.7 grams) in n-butanol (150 mL) was added a solution of cyanogen bromide (5M in MeCN). The resultant mixture was heated to reflux for 4 hours. The mixture was concentrated to ⅓ of the original volume. To the mixture was added Et₂O (200 mL). The resultant solid was removed via filtration and the solid was washed with Et₂O (2×). The solid was partitioned between EtOAc and sat. Na₂CO₃ (aq.). The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated to afford 10.6 grams of Ex. 15. This material was converted to the t-butyl carbamate using a procedure similar to that described in Scheme 3.

Step 7:

A mixture of the bromide (3.00 g, 6.92 mmol), benzophenone imine (1.39 mL, 8.30 mmol), Pd₂(dba)₃ (0.634 g, 0.692 mmol), John-Phos (0.413 g, 1.38 mmol), sodium tert-butoxide (2.13 g, 22.1 mmol), and toluene (51 mL) was degassed (vacuum/N₂). The mixture was then stirred at 65° C. under nitrogen for 3 h. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of Celite and rinsed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure. The residue was then dissolved in methanol (76 mL) and the resulting solution was charged with hydroxyl amine hydrochloride (2.16 g, 31.1 mmol) and sodium acetate (2.55 g, 31.1 mmol). The reaction mixture was stirred at room temperature for 40 min. After this time, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (100 mL), water (100 mL), and brine (100 mL). The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0-100% ethyl acetate/heptane) to afford the amino pyridine (0.880 g, 34%).

To a flame-dried flask was added a pyridyl bromide (Table IIb, Entry 15, 1.5 g, 3.3 mmol), Pd₂(dba)₃ (305 mg, 0.3 mmol), (2-biphenyl)di-tert-butylphosphine (200 mg, 0.7 mmol), sodium tert-butoxide (1.02 g, 0.011 mmol), benzophenone imine (670 ul, 4 mmol), and toluene (21 mL). The mixture was evacuated under vacuum and back-filled with N₂ (3×). The mixture was stirred at 60° C. for 1 h. After filtration through celite, the filtrate was concentrated. The crude residue was dissolved in 36 mL of methanol, and hydroxyl amine hydrochloride (458 mg, 6.6 mmol) and sodium acetate (541 mg, 6.6 mmol) were added. The reaction was stirred for 35 min and then quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, and the combined organic portions were dried over magnesium sulfate and concentrated. The crude residue was purified by a flash silica column (50% ethyl acetate/hexane) to get an aminopyridine product (730 mg, 68%).

A solution of the nitro compound (Scheme 3b) (2.50 g, 6.0 mmol) in EtOH (150 mL) was degassed by bubbling N₂ through the solution for 3 min. To this solution was added Pd/C (10% w/w, 50% H₂O, 698 mg.). The mixture was placed under an atmosphere of N₂. The atmosphere was evacuated and back-filled with H₂ (3×). The resulting mixture was stirred at RT under a H₂ balloon for 2 h. The mixture was purged by bubbling N₂ through it, filtered through Celite and concentrated. The product was purified by filtering through a small plug of silica gel column eluting with EtOAc to afford the aniline (2.2 g, 97%).

ENTRY 25

MH+: 410.0, HPLC1.79 min, LCMSMETHOD D

Method D:

• Column: Agilent Zorbax SB-C18 (3.0×50 mm) 1.8 uM

Mobile phase: A: 0.05% Trifluoroacetic acid in water

• • B: 0.05% Trifluoroacetic acid in acetonitrile

Gradient: 90:10 (A:B) for 0.3 min, 90:10 to 5:95 (A:B) over 1.2 min, 5:95 (A:B) for 1.2 min.

Flow rate: 1.0 mL/min

UV detection: 254 and 220 nm

Mass spectrometer: Agilent 6140 quadrupole

///////

ACH-3102 , Odalasvir

Odalasvir
ACH-0143102; ACH-3102
CAS : 1415119-52-6
Dimethyl N, N ‘- (tricyclo [8.2.2.24,7] hexadeca-1 (12), 4,6, 10,13,15-hexaene-5,11-diylbis {1H-benzimidazole-5,2-diyl [(2S, 3aS, 7aS) -octahydro-1H-indole-2,1-diyl] [(1S) -1 – (1-methylethyl) -2-oxoethylene]}) biscarbamate

Carbamic acid, N,N’-(tricyclo(8.2.2.24,7)hexadeca-4,6,10,12,13,15-hexaene-5,11-diylbis(1H-benzimidazole-6,2-diyl((2S,3aS,7aS)-octahydro-1H-indole-2,1-diyl)((1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl)))bis-, C,C’-dimethyl ester

Odalasvir^[1] is an investigational new drug in development for the treatment hepatitis C.

Achillion Pharmaceuticals Inc’s Odalasvir (ACH-3102) is an investigational new drug in development for the treatment hepatitis C. Achillion’s ongoing study tests its NS5A inhibitor, ACH-3102, with Sovaldi in previously untreated genotype 1 hepatitis C patients over six and eight weeks of therapy. The main goal is to achieve a cure, or sustained virological response, 12 weeks after the completion of therapy.

Odalasvir is a hepatitis C virus (HCV NS5A) inhibitor in phase II clinical studies at Achillion for the treatment of hepatitis C.

In 2012, fast track designation was assigned to the compound in the U.S. for the treatment of chronic hepatitis C.

WILL BE UPDATED………….

WO 2012166716

http://www.google.com/patents/US20120302538

General Considerations

All nonaqueous reactions were performed under an atmosphere of dry argon gas using oven-dried glassware and anhydrous solvents. The progress of reactions and the purity of target compounds were determined using one of the following two HPLC methods: (1) Waters AQUITY HPLC BEH C18 1.7 μm 2.1×50 mm column with an isocratic elution of 0.24 min at 90:10 water:acetonitrile containing 0.05% formic acid followed by a 4.26-min linear gradient elution from 90:10 to 10:90 at a flow rate of 1.0 mL/min with UV (PDA), ELS, and MS (SQ in APCI mode) detection (method 1); and (2) Waters AQUITY HPLC BEH C18 1.7 μm 2.1×50 mm column with an isocratic elution of 0.31 min at 95:5 water:acetonitrile containing 0.05% formic acid followed by a 17.47-min linear gradient elution from 95:5 to 5:95 at a flow rate of 0.4 mL/min with UV (PDA), ELS, and MS (SQ in APCI mode) detection (method 2).

Target compounds were purified via preparative reverse-phase HPLC using a YMC Pack Pro C18 5 μm 150×20 mm column with an isocratic elution of 0.35 min at 95:5 water:acetonitrile containing 0.1% trifluoroacetic acid followed by a 23.3-min linear gradient elution from 95:5 to 5:95 at a flow rate of 18.9 mL/min with UV and mass-based fraction collection.

SEE ALSO

US 2012302538

http://www.google.com/patents/US20120302538

……………

see

US 20150023913

http://www.google.com/patents/US20150023913

…………..

see

WO 2015005901

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=7B94F69052D90AA41E2DAED2AE82A5C0.wapp1nA?docId=WO2015005901&recNum=76&maxRec=2577841&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Odalasvir

Systematic (IUPAC) name
Dimethyl N,N′-(1,4(1,4)-Dibenzenacyclohexaphane-12,42-diylbis(1hbenzimidazole-5,2-diyl((2S,3aS,7aS)-octahydro-1H-indole-2,1-diyl)((2S)-3-methyl-1-oxobutan-1,2-diyl)))biscarbamate
Clinical data
Legal status	Investigational
Identifiers
CAS Registry Number	1415119-52-6
ATC code	None
Chemical data
Formula	C60H72N8O6
Molecular mass	1001.28 g/mol

//////////

Safe, small scale access to supercritical fluids

The ability to safely access high temperatures and pressures in flow reactors has implications not only on the rate of chemical reactions, but also on the types of solvents one can use. Many greensolvents such as methanol and acetone have boiling points too low for certain batch applications, whereas performing reactions at high pressure in a flow reactor may allow for their safe use at elevated temperatures.

Supercritical fluids are particularly interesting, since these solvents are entirely inaccessible without high pressure conditions. The use of supercritical fluids in a flow system offers numerous advantages over batch reactors.

Reactions may be performed on a small scale, improving safety and reducing the amount of material required. Depending on the type of reactor, it may be possible to visualize the reaction to evaluate the phase behaviour. Moreover, the reaction can be analyzed and the temperature and pressure subsequently changed without stopping the reaction and cleaning the vessel, as is necessary in a simple autoclave.

Continuous methods for utilizing supercritical fluids for extraction,¹ chromatography,² and as a reaction medium³ have all been commercialized, particularly for supercritical carbon dioxide (scCO₂).⁴ Academic examples using scMeOH, scH₂O, and scCO₂ for continuous reactions such as hydrogenations, esterifications, oxidations, and Friedel–Crafts reactions have been reported.⁵

A recent example that illustrates many of the green advantages of performing supercritical fluid chemistry in flow is in the ring opening of phthalic anhydride with methanol by Verboom and co-workers (Scheme 1).⁶ They designed a microreactor with a volume of just 0.32 μL that can withstand very high pressures.

The exceptionally small channel causes a large build-up of pressure, and supercritical conditions with pressures of up to 110 bar and temperatures up to 100 °C can occur inside the reactor, giving an ‘on-chip’ phase transition. The channel size increases near the outlet, allowing the fluid to expand to atmospheric conditions.

Thus, the total volume of scCO₂ under high pressure is exceptionally small, alleviating the major hazards of operating under supercritical conditions. The reaction was thoroughly studied on this small scale, allowing the authors to determine rate constants at several different temperatures and pressures.

	Scheme 1 Small scale continuous use of supercritical fluids.

Near- and supercritical water (scH₂O) can be an interesting green solvent only obtainable at very high temperature (T_c = 374 °C) and pressure (P_c = 221 bar). It is commonly used for completeoxidation of organic waste materials to CO₂; however, it has also been shown to be an effective solvent for selective oxidations.⁷ Given the harshness of the reaction conditions, it is not surprising that side product formation is common and highly dependent on the reaction time. For fast reactions in a batch reactor, precise control of reaction time is challenging, as the vessel takes time to heat and cool. In contrast, rapid heating, cooling, and quenching can be accomplished in a continuous process, allowing for well defined reaction times.

Fine tuning of the temperature, pressure, and time is also easier in a continuous process, as these variables can be changed without stopping and starting the reaction between samples. Thus, more data points can be obtained with less material and fewer heating and cooling cycles.

The Poliakoff group used these advantageous to perform a detailed study on the oxidation of p-xylene to terephthalic acid in scH₂O, a reaction carried out on industrial scale in acetic acid (Scheme 2).⁸ By using a flow reactor, reaction times as low as 9 seconds could be used. The equivalents of oxygen could also be finely varied on a small scale through the controlled thermal decomposition of H₂O₂.

Studying this aerobic oxidation with such precision in a batch process would prove highly challenging. Under optimal conditions, excellent selectivity for the desired product could be obtained. Further research by the same group identified improved conditions for this transformation.⁹

	Scheme 2 Selective oxidation in supercritical water.

 

Schematic Diagram of sample Supercritical CO2 system

Table 1. Critical properties of various solvents (Reid et al., 1987)

Solvent	Molecular weight	Critical temperature	Critical pressure	Critical density
	g/mol	K	MPa (atm)	g/cm3
Carbon dioxide (CO2)	44.01	304.1	7.38 (72.8)	0.469
Water (H2O) (acc. IAPWS)	18.015	647.096	22.064 (217.755)	0.322
Methane (CH4)	16.04	190.4	4.60 (45.4)	0.162
Ethane (C2H6)	30.07	305.3	4.87 (48.1)	0.203
Propane (C3H8)	44.09	369.8	4.25 (41.9)	0.217
Ethylene (C2H4)	28.05	282.4	5.04 (49.7)	0.215
Propylene (C3H6)	42.08	364.9	4.60 (45.4)	0.232
Methanol (CH3OH)	32.04	512.6	8.09 (79.8)	0.272
Ethanol (C2H5OH)	46.07	513.9	6.14 (60.6)	0.276
Acetone (C3H6O)	58.08	508.1	4.70 (46.4)	0.278
Nitrous oxide (N2O)	44.013	306.57	7.35 (72.5)	0.452

Table 2 shows density, diffusivity and viscosity for typical liquids, gases and supercritical fluids.

Comparison of Gases, Supercritical Fluids and Liquids

	Density (kg/m3)	Viscosity (µPa∙s)	Diffusivity (mm²/s)
Gases	1	10	1–10
Supercritical Fluids	100–1000	50–100	0.01–0.1
Liquids	1000	500–1000	0.001

1. F. Sahena, I. S. M. Zaidul, S. Jinap, A. A. Karim, K. A. Abbas, N. A. N. Norulaini and A. K. M. Omar, J. Food Eng., 2009, 95, 240–253
2. D. J. Dixon and K. P. Jhonston, in Encyclopedia of Separation Technology, ed. D. M. Ruthven, John Wiley, 1997, 1544–1569
3. P. Licence, J. Ke, M. Sokolova, S. K. Ross and M. Poliakoff, Green Chem., 2003, 5, 99–104
4. X. Han and M. Poliakoff, Chem. Soc. Rev., 2012, 41, 1428–1436
5. S. Marre, Y. Roig and C. Aymonier, J. Supercrit. Fluids, 2012, 66, 251–264
6. F. Benito-Lopez, R. M. Tiggelaar, K. Salbut, J. Huskens, R. J. M. Egberink, D. N. Reinhoudt, H. J. G. E. Gardeniers and W. Verboom, Lab Chip, 2007, 7, 1345–1351
7. R. Holliday, B. Y. M. Jong and J. W. Kolis, J. Supercrit. Fluids, 1998, 12, 255–260
8. P. A. Hamley, T. Ilkenhans, J. M. Webster, E. García-Verdugo, E. Vernardou, M. J. Clarke, R. Auerbach, W. B. Thomas, K. Whiston and M. Poliakoff, Green Chem., 2002, 4, 235–238
9. E. Pérez, J. Fraga-Dubreuil, E. García-Verdugo, P. A. Hamley, M. L. Thomas, C. Yan, W. B. Thomas, D. Housley, W. Partenheimer and M. Poliakoff, Green Chem., 2011, 13, 2397–2407

Google+

ANTHONY MELVIN CRASTO

Originator: Pfizer

Tofacitinib (trade names Xeljanz and Jakvinus, formerly tasocitinib,^[1] CP-690550^[2]) is a drug of the janus kinase (JAK) inhibitor class, discovered and developed by Pfizer. It is currently approved for the treatment of rheumatoid arthritis (RA) in the United States,Russia, Japan and many other countries, is being studied for treatment of psoriasis, inflammatory bowel disease, and other immunological diseases, as well as for the prevention of organ transplant rejection.

An Improved and Efficient Process for the Preparation of Tofacitinib Citrate

Yogesh S. Patil, Nilesh L. Bonde, Ankush S. Kekan, Dhananjay G. Sathe*1, and Arijit Das

 

1H NMR (CDCl3) δ 8.34 (s, 1H), δ 7.38 (d, 1H, J = 2.4 Hz), δ 6.93 (d, 1H, J = 2.4 Hz), δ 4.97 (m, 1H), δ 3.93–4.03 (m, 4H), δ 3.66 (m, 1H), δ 3.50 (m, 4H), δ 2.91 (d, 2H, J = 15.6 Hz), δ 2.80 (t, 2H, J = 12.8 Hz), δ 2.55 (m, 1H), δ 1.99 (m, 1H), δ 1.77 (m, 1H), δ 1.13–1.18 (m, 3H).

Tofacitinib, chemically known as (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3- d]pyrimidin-4-ylamino)-B-oxo-l -piperidinepi panenitrile, is represented Formula I. Tofacitinib citrate, a janus kinase inhibitor, is approved as XELJANZ® tablets for treatment .of rheumatoid arthritis.

Various intermediates and processes for preparation of tofacitinib are disclosed in patents like US7301 023 and US8232394.

Formula I or isomers or a mixture of isomers thereof by following any method provided in the prior art, for example, by following Example 14 of U.S. Patent No. RE41,783 or by following Example 6 of U.S. Patent No. 7,301,023. Tofacitinib of Formula I or isomers of tofacitinib or a mixture of isomers thereof may be converted into a salt by following any method provided in the prior art, for example, by following Example 1 of U.S. Patent No. 6,965,027 or by following Example 1 or Example 8 of PCT Publication No. WO 2012/135338. The potential significance of JAK3 inhibition was first discovered in the laboratory of John O’Shea, an immunologist at the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH).^[5] In 1994, Pfizer was approached by the NIH to form a public-private partnership in order to evaluate and bring to market experimental compounds based on this research.^[5] Pfizer initially declined the partnership but agreed in 1996, after the elimination of an NIH policy dictating that the market price of a product resulting from such a partnership would need to be commensurate with the investment of public taxpayer revenue and the “health and safety needs of the public.”^[5] The drug discovery, preclinical development, and clinical development of tofacitinib took place exclusively at Pfizer.^[6] In November 2012, the U.S. Food and Drug Administration (FDA) approved tofacitinib for treatment of rheumatoid arthritis. Once on the market, rheumatologists complained that the $2,055 a month wholesale price was too expensive, though the price is 7% less than related treatments.^[6] A 2014 study showed that tofacitinib treatment was able to convert white fat tissues into more metabolically active brown fat, suggesting it may have potential applications in the treatment of obesity.^[7] It is an inhibitor of the enzyme janus kinase 1 (JAK1) and janus kinase 3 (JAK 3) , which means that it interferes with the JAK-STAT signaling pathway, which transmits extracellular information into the cell nucleus, influencing DNA transcription.^[3] Recently it has been shown in a murine model of established arthritis that tofacitinib rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. This efficacy in this disease model correlated with the inhibition of both JAK1 and 3 signaling pathways, suggesting that tofacitinib may exert therapeutic benefit via pathways that are not exclusive to inhibition of JAK3.^[4]

Preparation of 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile citrate salt (Tofacitinib citrate, Xeljanz, CP-690550-10)

To a round-bottomed flask fitted with a temperature probe, condenser, nitrogen source, and heating mantle, methyl-[(3R,4R)-4-methyl-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (5.0 g, 20.4 mmol) was added followed by 1-butanol (15 mL), ethyl cyanoacetate (4.6 g, 40.8 mmol), and DBU (1.6 g, 10.2 mmol). The resulting amber solution was stirred at 40 °C for 20 h. Upon reaction completion, citric acid monohydrate (8.57 g, 40.8 mmol) was added followed by water (7.5 mL) and 1-butanol (39.5 mL). The mixture was heated to 81 °C and held at that temperature for 30 min. The mixture was then cooled slowly to 22 ºC and stirred for 2 h. The slurry was filtered and washed with 1-butanol (20 mL). The filter cake was dried in a vacuum oven at 80 °C to afford 9.6 g (93%) of tofacitinib citrate as an off-white solid.

1H NMR (500 MHz, d6-DMSO): δ 8.14 (s, 1H), 7.11 (d, J=3.6 Hz, 1H), 6.57 (d, J=3.6 Hz, 1H), 4.96 (q, J=6.0 Hz, 1H), 4.00-3.90 (m, 2H), 3.80 (m, 2H), 3.51 (m, 1H), 3.32 (s, 3H), 2.80 (Abq, J=15.6 Hz, 2H), 2.71 (Abq, J=15.6 Hz, 2H), 2.52-2.50 (m, 1H), 2.45-2.41 (m, 1H), 1.81 (m, 1H), 1.69-1.65 (m, 1H), 1.04 (d, J=6.9 Hz, 3H).

References:

Weiling Cai, James L. Colony,Heather Frost, James P. Hudspeth, Peter M. Kendall, Ashwin M. Krishnan,Teresa Makowski, Duane J. Mazur, James Phillips, David H. Brown Ripin, Sally Gut Ruggeri, Jay F. Stearns, and Timothy D. White; Investigation of Practical Routes for the Kilogram-Scale Production of cis-3-Methylamino-4-methylpiperidines; Organic Process Research & Development 2005, 9, 51−56

Ripin, D. H.B.; 3-amino-piperidine derivatives and methods of manufacture, US patent application publication, US 2004/0102627 A1

Ruggeri, Sally, Gut;Hawkins, Joel, Michael; Makowski, Teresa, Margaret; Rutherford, Jennifer, Lea; Urban,Frank,John;Pyrrolo[2,3-d]pyrimidine derivatives: their intermediates and synthesis, PCT pub. No. WO 2007/012953 A 2, US20120259115 A1, United States Patent US8232393. Patent Issue Date: July 31, 2012

Kristin E. Price, Claude Larrive´e-Aboussafy, Brett M. Lillie, Robert W. McLaughlin, Jason Mustakis, Kevin W. Hettenbach, Joel M. Hawkins, and Rajappa Vaidyanathan; Mild and Efficient DBU-Catalyzed Amidation of Cyanoacetates, Organic Letters, 2009, vol.11, No.9, 2003-2006

13C NMR PREDICT 

SEE…….http://newdrugapprovals.org/2015/07/24/tofacitinib-%E7%9A%84%E5%90%88%E6%88%90-spectral-visit/

COSY PREDICT सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

SEE………http://orgspectroscopyint.blogspot.in/2014/12/tofacitinib-citrate.html

……………..

PAPER

Tetrahedron Letters

Volume 54, Issue 37, 11 September 2013, Pages 5096–5098

http://dx.doi.org/10.1016/j.tetlet.2013.07.042

…………………. Tofacitinib synthesis: US2001053782A1

Synthesis of Tofacitinib Citrate

Author(s): ZHAO Fanglu, ,CHEN Guohua, ,YAO Shilun, ,ZHANG Zhenxia Journal: Chinese Journal of Pharmaceuticals, Year 2014 , Issue 3 , Page 201-204,253 Keyword:  tofacitinib citrate%; anti-rheumatoid arthritis drug%; synthesis%;

http://caod.oriprobe.com/articles/41372497/Synthesis_of_Tofacitinib_Citrate.htm

…………………. PATENT https://www.google.co.in/patents/WO2003048162A1?cl=en The crystalline form of the compound of this invention 3-{4-methyl-3-[methyl- (7H-pyrrolot2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile mono citrate salt is prepared as described below. Scheme 1

Scheme 2

Example 1 3-{(3R,4R)-4-methyl-3-rmethyl-(7H-pyrrolor2,3-dlpyrimidin-4-yl)-amino1- piperidin-1-yl}-3-oxo-propionitrile mono citrate salt Ethanol (13 liters), (3R, 4R)-methyl-(4-methyl-piperidin-3-yl)-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-amine (1.3 kg), cyano-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester (1.5 kg), and triethylamine (1.5 liters) were combined and stirred at ambient temperature. Upon reaction completion (determined by High Pressure Liquid Chromotography (HPLC) analysis, approximately 30 minutes), the solution was filtered, concentrated and azeotroped with 15 liters of methylene chloride. The reaction mixture was washed sequentially with 12 liters of 0.5 N sodium hydroxide solution, 12 liters of brine and 12 liters of water. The organic layer was concentrated and azeotroped with 3 liters of acetone (final pot temperature was 42°C). The resulting solution was cooled to 20°C to 25°C followed by addition of 10 liters of acetone. This solution was filtered and then aqueous citric acid (0.8 kg in 4 liters of water) added via in-line filter. The reaction mixture was allowed to granulate. The slurry was cooled before collecting the solids by filtration. The solids were dried to yield 1.9 kg (71 %) (3R, 4R)- 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo- propionitrile mono citrate. This material was then combined with 15 liters of a 1:1 ratio of ethanol/water and the slurry was agitated overnight. The solids were filtered and dried to afford 1.7 kg (63% from (3R, 4R)-methyl-(4-methyl-piperidin-3-yl)-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-amine) of the title compound as a white crystalline solid. ¹H NMR (400 MH2)(D₂0) δ HOD: 0.92 (2H, d, J = 7.2 Hz), 0.96 (1H, d, J = 7.6 Hz), 1.66 (1H, m), 1.80 (1H, m), 2.37 (1H, m), 2.58 (2H, ¹/₂ ABq, J = 15.4 Hz), 2.70 (2H, 3 ABq, J = 154 Hz), 3.23 (2H, s), 3.25 (1H, s), 3.33 (1H, m), 3.46 (1H, m), 3.81 (4H, m), 4.55 (1 H, m), 6.65 (1 H, d, J = 3.2 Hz), 7.20 (1 H, t, J = 3.2 Hz), 8.09 (1 H, m).

…………….

http://www.google.co.in/patents/EP1913000A2?cl=en Example 10 Preparation of methyl-[(3R, 4R)-4-methyl-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine:

KEY INTERMEDIATE

To a clean, dry, nitrogen-purged 2 L hydrogenation reactor were charged 20 wt% Pd(OH)₂/C (24.0 g, 50% water wet), water (160 ml), isopropanol (640 ml), (1-benzyl-4-methyl-piperidin-3-yI)-methyi- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (160.0 g, 0.48 mol), and acetic acid (28.65 g, 0.48 mol). The reactor was purged with three times at 50 psi with nitrogen and three times at 50 psi with hydrogen. Once purging was complete, the reactor was heated to 45-55°C and pressurized to 50 psi with hydrogen through a continuous feed. The hydrogen uptake was monitored until no hydrogen was consumed for 1 hour. The reactor was cooled to 20-30⁰C and purged three times at 50 psi with nitrogen. The reaction mixture was filtered through wet Celite and the filtrate was sent to a clean, dry, nitrogen-purged vessel. A solution of sodium hydroxide (39.33 g) in water (290 ml) was charged and the mixture was stirred for a minimum of 1 hour then heated to 75-90⁰C. The isopropanol was removed by distillation. The reaction mixture was cooled to 20-30°C and 2-methyltetrahydrofuran (1.6 L) was added. The aqueous layer was drained off and the 2-methyltetrahydrofuran was displaced with toluene (1.6 L). The distillation was continued until the final volume was 800 ml. The slurry was cooled to 20-30°C and held for a minimum of 7 hours. The resulting solids were isolated by filtration and washed with toluene (480 ml). After drying under vacuum between 40-50^DC for a minimum of 24 hours with a slight nitrogen bleed 102.3 g (87.3%) of the title compound were isolated. Mp 158.6-159.8°C. ¹H NMR (400 MHz, CDCI₃): δ 11.38 (bs, 1H), 8.30 (s, 1H), 7.05 (d, J=3.5 Hz, 1H), 6.54 (d, J=3.5 Hz, 1H), 4.89-4.87 (m, 1H), 3.39 (s, 3H), 3.27 (dd, J=12.0, 9.3 Hz, 1 H), 3.04 (dd, J=12.0, 3.9 Hz, 1H), 2.94 (td, J=12.6, 3.1 Hz, 1H0, 2.84 (dt, J=12.6, 4.3 Hz, 1H), 2.51-2.48 (m, 1H), 2.12 (bs, 2H), 1.89 (ddt, J=13.7, 10.6, 4 Hz, 1 H), 1.62 (dq, J=13.7, 4Hz, 1 H), 1.07 (d, J=7.3 Hz, 3H). ¹³C NMR (400 MHz, CDCI₃): δ 157.9, 152.0, 151.0, 120.0, 103.0, 102.5, 56.3, 46.2, 42.4, 34.7, 33.4, 32.4, 14.3. KEY INT

Example 11 Preparation of 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3- oxo-propionitrile….TOFACITINIB BASE

To a clean, dry, nitrogen-purged 1.0 L reactor were charged methyl-(4-methyl-piperidin-3-yI)-(7H- pyrroIo[2,3-d]pyrimidin-4-yl)-amine (32.0 g, 0.130 mol), toluene (160 ml), ethyl cyanoacetate (88.53 g, 0.783 mol) and triethyl amine (26.4 g, 0.261 mol). The reaction was heated to 100⁰C and held for 24 hours. The reaction was washed with water (160 ml). The organic layer concentrated to a volume of 10 ml and water (20 ml) was added. The residual toluene was removed by distillation and the mixture was cooled to room temperature. Acetone (224 ml) was added followed by citric acid (27.57 g, 0.144 mol) in water (76 ml). The resulting slurry was stirred for 7 hours. The solids were isolate by filtration, washed with acetone (96 ml), and dried under vacuum to afford 42.85 g (65.3%) of the title compound. Example 13 Preparation of 3-{(3R, 4R)~4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo- propionitrile citrate salt:…………..TOFACITINIB CITRATE To a clean, dry, nitrogen-purged 500 ml reactor were charged methyl-(4-methyl-piperidin-3-yl)-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-amine (25.0 g, 0.102 mol) and methylene chloride (250 ml). The mixture was stirred at room temperature for a minimum of 2.5 hours. To a clean, dry, nitrogen-purged 1 L reactor were charged cyanoacetic acid (18.2 g, 0.214 mol), methylene chloride (375 ml), and triethyl amine (30.1 ml, 0.214 mol). The mixture was cooled to -15.0— 5.0⁰C over one hour and trimethylacetyl chloride (25.6 ml, 0.204 mol) was added at a rate to maintain the temperature below O⁰C. The reaction was held for a minimum of 2.5 hours, then the solution of the amine was added at a rate that maintained the temperature below O⁰C. After stirring for 1 hour, the mixture was warmed to room temperature and 1 M sodium hydroxide (125 ml) was added. The organic layer was washed with water (125 ml) The methylene chloride solution.was displaced with acetone until a volume of 500 ml and a temperature of 55-65⁰C had been achieved. Water (75 ml) was charged to the mixture while maintaining the temperature at 55-65°C. A solution of citric acid (20.76 g, 0.107 mol) in water (25.0) was charged and the mixture was cooled to room temperature. The reactor was stirred for a minimum of 5 hours and then the resulting solids were isolated by filtration and washed with acetone (2×75 ml), which was sent to the filter. The salt was charged into a clean, dry, nitrogen-purged 1L reactor with 2B ethanol (190 ml) and water (190 ml). The slurry was heated to 75-85⁰C for a minimum of 4 hours. The mixture was cooled to 20-30⁰C and stirred for an additional 4 hours. The solids were isolated by filtration and washed with 2B ethanol (190 ml). After drying in a vacuum oven at 50⁰C with a slight nitrogen bleed, 34.6 g (67.3%) of the title compound were isolated. ¹H NMR (500 MHz, CZ₆-DMSO): δ 8.14 (s, 1 H), 7.11 (d, J=3.6 Hz, 1 H), 6.57 (d, J=3.6 Hz, 1 H), 4.96 (q, J=6.0 Hz, 1 H), 4.00-3.90 (m, 2H), 3.80 (m, 2H), 3.51 (m, 1 H), 3.32 (s, 3H), 2.80 (Ab_q, J=15.6 Hz, 2H), 2.71 (Ab_q, J=15.6 Hz, 2H), 2.52-2.50 (m, 1 H), 2.45-2.41 (m, 1 H), 1.81 (m, 1 H), 1.69-1.65 (m, 1 H), 1.04 (d, J=6.9 Hz, 3H)

………………

PAPER

http://pubs.acs.org/doi/full/10.1021/ol900435t

………………..

http://www.omicsonline.org/open-access/advances-in-the-inhibitors-of-janus-kinase-2161-0444.1000540.php?aid=29799   …………….. सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

Clinical trials

Rheumatoid arthritis

Phase II clinical trials tested the drug in rheumatoid arthritis patients that had not responded to DMARD therapy. In a tofacitinib monotherapy study, the ACR score improved by at least 20% (ACR-20) in 67% of patients versus 25% who received placebo; and a study that combined the drug with methotrexate achieved ACR-20 in 59% of patients versus 35% who received methotrexate alone. In a psoriasis study, the PASI score improved by at least 75% in between 25 and 67% of patients, depending on the dose, versus 2% in the placebo group.^[8] The most important side effects in Phase II studies were increased blood cholesterol levels (12 to 25 mg/dl LDL and 8 to 10 mg/dl HDL at medium dosage levels) andneutropenia.^[8] Phase III trials testing the drug in rheumatoid arthritis started in 2007 and are scheduled to run until January 2015.^[9] In April 2011, four patients died after beginning clinical trials with tofacitinib. According to Pfizer, only one of the four deaths was related to tofacitinib.^[10] By April 2011, three phase III trials for RA had reported positive results.^[11] In November 2012, the U.S. FDA approved tofacitinib “to treat adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to, or who are intolerant of, methotrexate.”^[12]

Psoriasis

As of April 2011 a phase III trial for psoriasis is under way.^[11]

Alopecia

In June 2014, scientists at Yale successfully treated a male patient afflicted with alopecia universalis. The patient was able to grow a full head of hair, eyebrows, eyelashes, facial, armpit, genitalia and other hair. No side effects were reported in the study.^[13]

Ulcerative colitis

The OCTAVE study of Tofacitinib in Ulcerative Colitis started in 2012. It is currently enrolling patients, though the NIH trials page states that they expect the trial to close in June 2015.^[14]

Vitiligo

In a June 2015 study, a 53-year-old woman with vitiligo showed noticeable improvement after taking tofacitinib for five months.^[15]

1. Herper, Matthew (2 March 2011). “Why Pfizer’s Biggest Experimental Drug Got A Name Change”. Forbes. Retrieved 3 March 2011.
2.  Kremer, J. M.; Bloom, B. J.; Breedveld, F. C.; Coombs, J. H.; Fletcher, M. P.; Gruben, D.; Krishnaswami, S.; Burgos-Vargas, R. N.; Wilkinson, B.; Zerbini, C. A. F.; Zwillich, S. H. (2009). “The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo”. Arthritis & Rheumatism 60 (7): 1895–1905. doi:10.1002/art.24567. PMID 19565475. edit
3.  “Tasocitinib”. Drugs in R&D 10 (4): 271–284. 2010. doi:10.2165/11588080-000000000-00000. PMC 3585773. PMID 21171673. edit
4.  Ghoreschi, K.; Jesson, M. I.; Li, X.; Lee, J. L.; Ghosh, S.; Alsup, J. W.; Warner, J. D.; Tanaka, M.; Steward-Tharp, S. M.; Gadina, M.; Thomas, C. J.; Minnerly, J. C.; Storer, C. E.; Labranche, T. P.; Radi, Z. A.; Dowty, M. E.; Head, R. D.; Meyer, D. M.; Kishore, N.; O’Shea, J. J. (2011). “Modulation of Innate and Adaptive Immune Responses by Tofacitinib (CP-690,550)”. J Immunol. 186 (7): 4234–4243. doi:10.4049/jimmunol.1003668. PMC 3108067. PMID 21383241. edit
5. ^ Jump up to:^{a b c} “Seeking Profit for Taxpayers in Potential of New Drug”, Jonathan Weisman, New York Times, March 18, 2013
6. Ken Garber (9 January 2013). “Pfizer’s first-in-class JAK inhibitor pricey for rheumatoid arthritis market”. Nature Biotechnology 31 (1): 3–4. doi:10.1038/nbt0113-3. PMID 23302910.
7. Jump up^ Moisan A, et al. White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nature Cell Biology, 8 December 2014. DOI 10.1038/ncb3075
8.  “EULAR: JAK Inhibitor Effective in RA But Safety Worries Remain”. MedPage Today. June 2009. Retrieved 9 February 2011.
9.  Clinical trial number NCT00413699 for “Long-Term Effectiveness And Safety Of CP-690,550 For The Treatment Of Rheumatoid Arthritis” at ClinicalTrials.gov
10.  Matthew Herper. “Pfizer’s Key Drug Walks A Tightrope”. Forbes.
11.  “Two Phase III Studies Confirm Benefits of Pfizer’s Tofacitinib Against Active RA”. 28 Apr 2011.
12.  “FDA approves Xeljanz for rheumatoid arthritis”. 6 Nov 2012.
13.  “Hairless man grows full head of hair in yale arthritis drug trial”. 19 Jun 2014.
14.  https://clinicaltrials.gov/ct2/show/NCT01465763?term=A3921094&rank=1
15. “This Drug Brought Pigment Back for Woman with Vitiligo”. TIME. June 27, 2015. Retrieved June 29, 2015.
16. Nordqvist, Christian (27 April 2013). “Pfizer’s Arthritis Drug Xeljanz (tofacitinib) Receives A Negative Opinion In Europe”. Medical News Today. Retrieved 2 August 2013.
17. “”XALEJANZ PRESCRIBING INFORMATION @ Labeling.Pfizer.com””.

SEE………http://orgspectroscopyint.blogspot.in/2014/12/tofacitinib-citrate.html

Tofacitinib

Systematic (IUPAC) name
3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile
Clinical data
Trade names	Xeljanz, Jakvinus
AHFS/Drugs.com	entry
Licence data	US FDA:link
Pregnancy category	US: C (Risk not ruled out)
Legal status	US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	74%
Protein binding	40%
Metabolism	Hepatic (via CYP3A4 andCYP2C19)
Biological half-life	3 hours
Excretion	Urine
Identifiers
CAS Registry Number	477600-75-2
ATC code	L04AA29
PubChem	CID: 9926791
IUPHAR/BPS	5677
DrugBank	DB08183
ChemSpider	8102425
UNII	87LA6FU830
ChEBI	CHEBI:71200
ChEMBL	CHEMBL221959
Synonyms	CP-690550
Chemical data
Formula	C16H20N6O
Molecular mass	312.369 g/mol

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

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//////

……

Posaconazole  泊沙康唑 ,  بوساكونازول , Позаконазол
Sch–56592
4-[4-[4-[4-[[(5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one

1. Noxafil
2. SCH 56592

U.S. Patents 5,661,151; 5,703,079; and 6,958,337.

Therap-Cat: Antifungal.

CAS 171228-49-2

Molecular Formula: C37H42F2N8O4

Molecular Weight: 700.78

CAS Name: 2,5-Anhydro-1,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4-[[4-[4-[4-[1-[(1S,2S)-1-ethyl-2-hydroxypropyl]-1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl]phenyl]-1-piperazinyl]phenoxy]methyl]-1-(1H-1,2,4-triazol-1-yl)-D-threo-pentitol

Additional Names: (3R–cis)-4-[4-[4-[4-[5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-ylmethoxy]phenyl]piperazin-1-yl]phenyl]-2-[1(S)-ethyl-2(S)-hydroxypropyl]-3,4-dihydro-2H-1,2,4-triazol-3-one

Syn……….Dominic De Souza, “PREPARATION OF POSACONAZOLE INTERMEDIATES.” U.S. Patent US20130203994, issued August 08, 2013.

Percent Composition: C 63.41%, H 6.04%, F 5.42%, N 15.99%, O 9.13%

1. Melting Point

1H NMR PREDICT

13C NMR PREDICT

COSY PREDICT

/////
सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

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RIVAROXABAN

5-Chloro-N-{[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinophenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide

5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide

Molecular formula: C₁₉H₁₈ClN₃O₅S, MW435.9

CAS 366789-02-8

BAY 59-7939, XARELTO

Patent Expiration Date:

Feb 8, 2021(US7157456),

Dec 11, 2020(US7585860 and US7592339)
Originator and Manufacturer:Bayer
Marketer in the US: Johnson & Johnson
Sales: $1.3 billion  (2013)

 

 

PAPER CONTAING SPECTRAL DATA

STRUCTURE

SIMILARITY

Chemical structures of linezolid (top) and rivaroxaban (bottom). The shared structure is shown in blue.

Rivaroxaban bears a striking structural similarity to the antibiotic linezolid: both drugs share the same oxazolidinone-derived core structure. Accordingly, rivaroxaban was studied for any possible antimicrobial effects and for the possibility of mitochondrial toxicity, which is a known complication of long-term linezolid use. Studies found that neither rivaroxaban nor its metabolites have any antibiotic effect against Gram-positive bacteria. As for mitochondrial toxicity, in vitro studies found the risk to be low

IH NMR PREDICT

 

13 C NMR PREDICT

New patent WO-2015104605

Process for preparing rivaroxaban – comprising the reaction of a thioester compound and its salts with 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one.

Wockhardt Ltd

The synthesis of (II) via intermediate (I) is described (example 7, page 15)

4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one (formula III) is (I) and rivaroxaban is (II) (claim 1, page 16).

The present invention relates to a process for the preparation of Rivaroxaban and its novel intermediates, or pharmaceutically acceptable salts thereof. The present invention provides novel intermediates, which may be useful for the preparation of Rivaroxaban or its pharmaceutically acceptable salts thereof. The process of preparation by using novel intermediate is very simple cost effective and may be employed at commercial scale. The product obtained by using novel intermediate yield the Rivaroxaban of purity 99% or more, when measured by HPLC. The present invention especially relates to a process for the preparation of Rivaroxaban from thioester of formula II, or a pharmaceutically acceptable salt thereof, wherein R is leaving group.

process includes the step of , reacting thioester of formula IIA or pharmaceutically acceptable salt thereof

Formula IIA

with 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholine-3-one of formula III,

Formula III

Formula I

EXAMPLE 7: One pot process for Rivaroxaban

The triphenylphosphine (11.5g) and mercaptobenzothiazole disulphide (15.31g) were taken in methylene chloride and reaction mixture was stirred at 28°C -30°C for 1 hr. The 5-chlorothiophene-2-carboxylic acid (7.2g) and triethylamine (3.8 g) were added to the above reaction mixture. The reaction mixture is stirred at 0°C -25 °C for 1 hr. after 1 hr 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholine-3-one (lOg) and triethylamine (3.8g) were added. The resulting reaction mixture further stirred for 2 hrs. After completion of the reaction, water was added and stirred for 10 min. aqueous layer was separated and washed with methylene chloride. The organic layer was acidified to pH 6-7 with 2N hydrochloric acid and finally the organic layer was concentrated to get desired product. The product was purified and dried to yield Rivaroxaban.

Yield: 10.0 gm

Purity: 99.3 %

EXAMPLE 8: One pot process for Rivaroxaban

Exemplified procedure in example 7 with the replacement of solvent ethyl acetate and base potassium hydroxide were used to get the rivaroxaban.

EXAMPLE 9: One pot process for Rivaroxaban

Exemplified procedure in example 7 with the replacement of solvent acetonitile and base potassium carbonate were used, methylene chloride was added in the reaction mixture to extract the Rivaroxaban.

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015104605&recNum=7&maxRec=57790&office=&prevFilter=%26fq%3DOF%3AWO%26fq%3DICF_M%3A%22C07D%22&sortOption=Pub+Date+Desc&queryString=&tab=PCTDescription

…………..

WO 01/47919 discloses ー species from 4_ (4_ aminophenyl) -3_ morpholinone (I) Preparation of rivaroxaban approach:

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US 07/149522 discloses ー kind to 5_ chlorothiophenes _2_ carbonyl chloride (IV) is a method for preparing raw rivaroxaban in:

………….

http://www.google.com/patents/CN102786516A?cl=en

Preparation 6 rivaroxaban implementation

The 12.5 g (76.9 mmol) 5- chloro-thiophene-2-carboxylic acid was suspended in 35 g of toluene was heated to 80 で, at this temperature, a solution of 11.0 g (92.5 mmol) of thionyl chloride, reaction was continued for 30 min; then warmed to the boiling point of toluene was 120 ° C, and stirring was continued under reflux until cessation of gas; cooled to room temperature, the reaction mixture was concentrated under reduced pressure to remove excess thionyl chloride and toluene to give 5-chloro-thiophene-2-carbonyl chloride;

The 11.6 g (37.0 mmol) 4- {4 – [(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl} morpholin-3 -one hydrochloride was added 40ml of water, was added 4. 64 g (43 8 mmol.) Na2CO3 stirred and dissolved; then added 50 ml of toluene, was added dropwise at 10 ° C under the mixture, the mixture is 8. 0 g ( 44. 4 mmol) 5- chloro-thiophene-2-carbonyl chloride was dissolved in 15 ml of toluene, 20 min the addition was complete, then stirring was continued at room temperature, TLC monitoring progress of the reaction, 2 h after completion of the reaction; and the filter cake washed with water and washed with acetone to give a pale yellow solid 19. 6 g, used directly ko acid recrystallization, as a white solid 15. 2 g,

mp 227. 2 – 228. 1 ° C, [a] D21 = -38 2 ° (. c = 0. 30, DMS0), rivaroxaban yield of 94%, the total yield of 87.5% 0

 1H-NMR (DMSO) 8: 3. 61 (. 2 H, t, / = 5 4 Hz), 3. 71 (2 H, t, / = 5 4 Hz.), 3.85 (IH, m ), 3.97 (2 H, t, J = 4. 5 Hz), 4. 19 (3 ​​H, t, / = 7. 5 Hz), 4.84 (IH, m), 7. 19 (IH, d, / = 4. 2Hz), 7.40 (2 H, d, /=9.0 Hz), 7. 57 (2 H, t, /=9.0 Hz), 7. 69 (IH, d, J = 4. 19 Hz), 8. 96 (IH, t, / = 5. 7 Hz).

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WO2013120465 

EXAMPLE 28 (preparation of rivaroxaban)

10 g of the salt prepared according to Example 18 were suspended in 75 ml of N- methylpyrolidone, the suspension was heated at 50°C, then 14 ml of triethylamine was added and the mixture was heated at 60°C. This was followed by addition of 15.7 ml of a solution of 5-chlorothiophene-2-carboxylic acid chloride in toluene (2.46 M) and the reaction mixture was stirred and heated at 55°C for 15 minutes, then slowly cooled below 30°C, 75 ml were added and the turbid solution was filtered. The clear filtrate was stirred at 50°C, which was followed by addition of 15 ml of water and 75 ml of ethanol and stirring for 1 hour under slow cooling. The separated product was filtered off, washed with water (15 ml, 60°C), ethanol (2 x 25 ml) and dried in vacuo. 9.1 g (yield 81%) of rivaroxaban in the form of an off-white powder with the melt, point of 229.5-231°C was obtained, HPLC 99.95%, content of the ( )-isomer below 0.03%.

1H NMR (250 MHz, DMSO-D₆), δ (ppm): 3.61 (t, 2H, CH₂); 3.71 (m, 2H, CH₂); 3.85 and 4.19 (m, 2×1 H, CH₂); 3.97 (m, 2H, CH₂); 4.19 (s, 2H, CH₂); 4.84 (pent, 1H, CH); 7.18 (d, 1H); 7.40 (m, 2H); 7.56 (m, 2H); 7.68 (d, 1H); 8.95 (bt, 1H, NH).

¹³C NMR (250 MHz, DMSO-D₆), δ (ppm): 42.2; 47.4; 49.0; 63.4; 67.7; 71.3; 1 18.3; 125.9; 128.1 ; 128.4; 133.2; 136.4; 137.0; 138.4; 154.0; 160.8; 165.9.

MS (m/z): 436.0729 (M+H)⁺. ation)

The optical isomer of rivaroxaban with the (R)- configuration was obtained by a process analogous to Example 28 starting from the salt prepared according to Example 19. The yield was 76%, HPLC 99.90%, content of the (5)-isomer below 0.03%. The NMR and MS spectra were in accordance with Example 28.

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……………………

5- chloro-thiophene-2-chloride by condensation, bromide, with 4- (4-amino-phenyl) -3-morpholinone cyclization reaction rivaroxaban, the following reaction scheme :( References : W02005068456, US20070149522, DE10300111)

5- chloro-thiophene-2-chloride by condensation, oxidation, and 4- (4-amino-phenyl) -3-morpholinone cyclization reaction racemic rivaroxaban, since the epoxidation step is not give any stereoselectivity, the final chiral separation need to get rivaroxaban, the reaction scheme is as follows :( References: W0-0147919)

 

…………

4- (4- amino-phenyl) -3-morpholinone by condensation, cyclization, and potassium phthalimide after reaction with methyl chloroformate to give (S) -2 – hydroxy -3- (I, 3- dioxo – isoindoline-2-yl) propyl-4- (3-oxo –morpholino) phenyl carbamate, by condensation, methylamine and Ethanol action under profit rivaroxaban, the following reaction scheme (Ref: US20110034465):

……….

4- (4- amino-phenyl) -3-morpholinone (R) and – epichlorohydrin, in the DMF solvent phthalimide potassium salt was reacted with ammonia solution and then prepared to succeed amino compound, and 5-chloro-thiophene-2-chloride in pyridine catalyzed system benefit rivaroxaban, the following reaction scheme (Ref: W02009023233):

………….

4- (4- amino-phenyl) -3-morpholinone after condensation with (R) – epichlorohydrin, then the 5-chloro-thiophene-2-amide lithium chloride and tert-butyl the reaction of an alcohol potassium enrichment rivaroxaban, the following reaction scheme (Ref: US7816355):

……………….

3-chloro-1,2-propanediol by cyclization, the reaction with phthalimide, then with 4- (4-aminophenyl) -3-morpholinone reaction, CDI and hydrazine to give 4- {4- [(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl} morpholin-3-one under the influence, in pyridine and under the action of tetrahydrofuran and 5-chloro-thiophene-2-chloride benefit rivaroxaban, the following reaction scheme (Reference: Gutcait, A. et al Tetrahedron:.. Asymmetry 1996, 7 (6), 1641-1648 Roehrig, .. S. et al J. Med Chem 2005,48 (19), 5900-5908)..:

…………..

http://www.google.com/patents/CN102702186A?cl=zh

Compound rivaroxaban Synthesis Example 7 formula (X), [0071] Example

[0072] Method One:

[0074] The compound of formula (VIII) of (180mg, 0. 618mmol), Ni chloride (5mL) and tris ko amine (187mg,

I. 85mmol) added to the reaction flask, stirred at room temperature for 10 minutes, cooled to 0 ° C, a solution of 5-chloro-2-thiophene chloride (224mg, 1.24mm0l), stirred at room temperature overnight; after the completion of the reaction, spin dry, rinse with anhydrous alcohol ko, filtered, washed ko anhydrous alcohol three times to obtain a white solid product rivaroxaban (215mg, embodiments of the total yield of 7,8 80%).

[0075] 1H-Mffi (DMSC) JOOMHz, δ d m):…. 3 61 (t, 2H, J = 5 6Hz), 3. 71 (t, 2H, J = 5 2Hz), 3 89 ( m, 1H), 3. 97 (t, 2H, J = 4. 4Hz), 4. 20 (m, 3H), 4. 85 (m, 1H), 7. 18 (d, 1H, J = 4. 0Hz), 7. 40 (d, 2H, J = 8. 8Hz), 7. 56 (d, 2H, J = 8. 8Hz), 7. 73 (d, 1H, J = 4. 0Hz).

The method of writing is:

[0078] The compound 5_ gas – oh -I- thiophene carboxylic acid (500mg, 3. 08mmol), MsCl (702mg, 6. 1 Bmmol) and sodium bicarbonate (. 517mg, 6 16mmol) was suspended in THF (20ml) in , heated to 60 ° C with stirring 45min, a large white suspension washed out; the reaction mixture was cooled to room temperature, the compound of formula VIII was added portionwise (800mg, 2 75mmol.), stirred for 5 hours, after completion of the reaction distilled THF, was added after the residue was cooled to room temperature, water (IOOml), at room temperature embrace Cheung 30min, filtered, and the filter cake washed with cold water, dried and added to a ko-ol (5ml) was heated at reflux for I hour. After cooling, stirred for 5 hours at room temperature After filtration to give the product of formula (X) of the compound rivaroxaban (719mg, 60%)

References

 

Rivaroxaban

Systematic (IUPAC) name
(S)-5-chloro-N-{[2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide
Clinical data
Trade names	Xarelto
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Licence data	EMA:Link, US FDA:link
Pregnancy category	AU:C US:C (Risk not ruled out)
Legal status	AU:Prescription Only (S4) CA: ℞-only UK:Prescription-only (POM) US:℞-only
Routes of administration	oral
Pharmacokinetic data
Bioavailability	80% to 100%; Cmax = 2 – 4 hours (10 mg oral)[1]
Metabolism	CYP3A4 , CYP2J2 and CYP-independent mechanisms[1]
Biological half-life	5 – 9 hours in healthy subjects aged 20 to 45[1][2]
Excretion	2/3 metabolized in liver and 1/3 eliminated unchanged[1]
Identifiers
CAS Registry Number	366789-02-8
ATC code	B01AX06
PubChem	CID: 6433119
IUPHAR/BPS	6388
DrugBank	DB06228
ChemSpider	8051086
UNII	9NDF7JZ4M3
ChEMBL	CHEMBL198362
Synonyms	Xarelto, BAY 59-7939
Chemical data
Formula	C19H18ClN3O5S
Molecular mass	435.882 g/mol

Rivaroxaban, a FXa inhibitor, is the active ingredient in XARELTO Tablets with the chemical name 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5­yl}methyl)-2-thiophenecarboxamide. The molecular formula of rivaroxaban is C₁₉H₁₈ClN₃O₅S and the molecular weight is 435.89. The structural formula is:

Rivaroxaban is a pure (S)-enantiomer. It is an odorless, non-hygroscopic, white to yellowish powder. Rivaroxaban is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and is practically insoluble in water and aqueous media.

Each XARELTO tablet contains 10 mg, 15 mg, or 20 mg of rivaroxaban. The inactive ingredients of XARELTO are: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. Additionally, the proprietary film coating mixture used for XARELTO 10 mg tablets is Opadry® Pink and for XARELTO 15 mg tablets is Opadry® Red, both containing ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide, and for XARELTO 20 mg tablets is Opadry® II Dark Red, containing ferric oxide red, polyethylene glycol 3350, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide.

 

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cas 1306760-87-1

Ozanimod, RPC1063

Receptos, Inc.  INNOVATOR

IUPAC/Chemical name: (S)-5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile

Benzonitrile, 5-(3-((1S)-2,3-dihydro-1-((2-hydroxyethyl)amino)-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-(1-methylethoxy)-

SMILES: N#CC1=CC(C2=NC(C3=CC=CC4=C3CC[C@@H]4NCCO)=NO2)=CC=C1OC(C)C

C23H24N4O3
Molecular Weight: 404.46
Elemental Analysis: C, 68.30; H, 5.98; N, 13.85; O, 11.87

Ozanimod is a selective sphingosine 1 phosphate receptor modulators and methods which may be useful in the treatment of S1P1-​associated diseases. ozanimod, a sphingosine-1-phosphate receptor 1 (S1P1) agonist in Phase III studies as a treatment for ulcerative colitis and multiple sclerosis (MS). Although Novartis’s S1P1 modulator Gilenya has been available to treat MS since 2010,

Relapsing multiple sclerosis (RMS) is a chronic autoimmune disorder of the central nervous system (CNS), characterized by recurrent acute exacerbations (relapses) of neurological dysfunction followed by variable degrees of recovery with clinical stability between relapses (remission). The CNS destruction caused by autoreactive lymphocytes can lead to the clinical symptoms, such as numbness, difficulty walking, visual loss, lack of coordination and muscle weakness, experienced by patients. The disease invariably results in progressive and permanent accumulation of disability and impairment, affecting adults during their most productive years. RMS disproportionately affects women, with its peak onset around age 30. In the past, the treatments for RMS were generally injectable agents with significant side effects. There is a substantial market opportunity for effective oral RMS therapies with improved safety and tolerability profiles.

RPC1063 is a novel, orally administered, once daily, specific and potent modulator of the sphingosine 1-phosphate 1 receptor (S1P1R) pathway. The S1P1R is expressed on white blood cells (lymphocytes), including those responsible for the development of disease. S1P1R modulation causes selective and reversible retention, or sequestration, of circulating lymphocytes in peripheral lymphoid tissue. This sequestration is achieved by modulating cell migration patterns (known as “lymphocyte trafficking”), specifically preventing migration of autoreactive lymphocytes to areas of disease inflammation, which is a major contributor to autoimmune disease. S1P1R modulation may also involve the reduction of lymphocyte migration into the central nervous system (CNS), where certain disease processes take place. This therapeutic approach diminishes the activity of autoreactive lymphocytes that are the underlying cause of many types of autoimmune disease.

WO 2015066515

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015066515&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Scheme 3:

Reagents: (i) (a) MsCl, pyridine; (b) TsCl, pyridine; (c) NsCl, pyridine; (d) SOCl₂, DCM; (e) SOCl₂, pyridine, DCM; (f) NaN₃, PPh₃, CBr₄; (ii) (a) DIEA, DMA, HNR’R”; (b) DIEA, NaBr or Nal, DMA, HNR’R”.

Enantiomerically enriched material can be prepared in the same manner outlined in Scheme 3 using the (R)- or (5)-indanols.

Scheme 4:

Reagents: (i) Zn(CN)₂, Pd(PPh₃)₄, NMP; (ii) (i?)-2-methylpropane-2-sulfmamide, Ti(OEt)₄, toluene; (iii) NaBH₄, THF; (iv) 4M HCl in dioxane, MeOH; (v) Boc₂0, TEA, DCM; (vi) NH₂OH HCl, TEA, EtOH; (vii) HOBt, EDC, substituted benzoic acid, DMF (viii) 4M HCl in dioxane; (ix) (a) R’-LG or R”-LG, where LG represents a leaving group, K₂C0₃, CH₃CN; (b) R -C0₂H or R²-C0₂H, HOBt, EDC, DMF or R -COCl or R²-COCl, TEA, DCM; (c) R -S0₂C1 or R³-S0₂C1, TEA, DCM (d) R²-CHO, HO Ac, NaBH₄ or NaCNBH₃ or Na(OAc)₃BH, MeOH; (e) R -OCOCl or R²-OCOCl, DIEA, DMF; (f) HN(R⁵R⁵), CDI, TEA, DCM; (g) H₂NS0₂NH₂, Δ, dioxane; (h)

(R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-cyano-2 ,3-dihydro- lH-inden- 1-yl)carbamate INT-16)

Prepared using General Procedure 9. To a flame-dried flask under N₂ was added {R)-tert- vXy\ 4-cyano-2,3-dihydro-iH-inden-l-ylcarbamate INT-8 (8.3 g, 32.1 mmol) in anhydrous DMF (240 mL). The reaction mixture was cooled to 0°C and sodium hydride (3.8 g, 60% in oil, 160.6 mmol) was added portionwise. After stirring at 0°C for 2.75 h, (2-bromoethoxy)(tert-butyl)dimethylsilane (16.9 mL, 70.7 mmol) was added. The ice bath was removed after 5 mins and the reaction mixture was allowed to warm to room temperature. After 1.5 h, the reaction mixture was quenched by the slow addition of sat. NaHC0₃ at 0°C. Once gas evolution was complete the reaction was extracted with EA. The organic layers were washed with water and brine, dried over MgS0₄ and concentrated. The product was purified by chromatography (EA / hexanes) to provide 10.76 g (80%) of {R)-tert-bvXy\ 2-(tert-butyldimethylsilyloxy)ethyl(4-cyano-2,3-dihydro-iH-inden-l-yl)carbamate INT-16 as a colorless oil. LCMS-ESI (m/z) calculated for C₂₃H₃₆N₂0₃Si: 416.6; found 317.2 [M-Boc]⁺ and 439.0 [M+Na]⁺, t_R = 4.04 min (Method 1). 1H NMR (400 MHz, CDC1₃) δ 7.46 (d, J = 7.6, 1H), 7.38- 7.32 (m, 1H), 7.33 – 7.18 (m, 1H), 5.69 (s, 0.5 H), 5.19 (s, 0.5 H), 3.70 (ddd, J = 48.8, 26.6, 22.9, 1.5 H), 3.50 – 3.37 (m, 1H), 3.17 (ddd, J = 16.7, 9.4, 2.2, 2H), 2.93 (m, 1.5 H), 2.45 (s, 1H), 2.21 (dd, J = 24.5, 14.5, 1H), 1.56 – 1.37 (bs, 4.5H), 1.22 (bs, 4.5H), 0.87 – 0.74 (m, 9H), -0.04 (dd, J = 26.6, 8.2, 6H). ¹³C NMR (101 MHz, CDC1₃) δ 155.03, 146.55, 145.54, 131.16, 130.76, [128.11, 127.03], 117.58, 109.20, 79.88, [63.93, 61.88], [61.44, 60.34], [49.73, 46.76], 30.30, 29.70, 28.44, 28.12, [25.87, 25.62], -5.43. (5)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-cyano-2,3-dihydro- 1 H-inden- 1 -yl)carbamate INT- 17 is prepared in an analogous fashion using INT-9.

(R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl (4-(N-hydroxycarbamimidoyl)-2,3-dihydro-lH-inden-l-yl)carbamate (INT-18)

Prepared using General Procedure 3. To a solution of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-cyano-2,3-dihydro-iH-inden-l-yl)carbamate INT-16 (12.0 g, 28.9 mmol) in EtOH (120 mL), under an atmosphere of N₂ was added hydroxylamine-HCl (6.0 g, 86.5 mmol) and triethylamine (13.4 mL, 9.7 g, 86.5 mmol). The reaction mixture was refluxed at 80°C for 4 h. The reaction mixture was cooled to room temperature and concentrated to dryness and then diluted with DCM (500 mL). The organic layer was washed with NaHC0₃, water, and brine. The combined organic layers were dried over MgSC^ and concentrated to produce 11.8 g of {R)-tert- vXy\ 2-(tert-butyldimethylsilyloxy) ethyl (4-(N-hydroxycarbamimidoyl)-2,3-dihydro-iH-inden-l-yl)carbamate INT-18 as a white foamy solid, which was used without purification in the next experiment. LCMS-ESI (m/z) calculated for C₂₃H₃9N₃0₄Si: 449.7; found 350.2 [M-Boc]⁺ and 472.2 [M+Na]⁺, t_R = 1.79 min (Method 1). 1H NMR (400 MHz, CDC13) δ 7.32 (t, J= 7.3 Hz, 1H), 7.21 – 7.07 (m, 2H), 5.69 (s, 0.5 H), 5.19 (s, 0.5 H), 4.89 (s, 2H), 3.85 – 3.50 (m, 2H), 3.31 (ddd, J = 12.2, 9.2, 2.5 Hz, 2H), 3.28 – 3.03 (m, 2H), 3.03 – 2.70 (m, 1H), 2.29 (t, J= 23.6 Hz, 1H), 1.43 (bs, 4.5H), 1.28 (bs, 4.5H), 1.16 – 1.04 (m, 1H), 0.90 – 0.71 (m, 9H), 0.08 – -0.14 (m, 6H). ¹³C NMR (101 MHz, CDC1₃) δ 170.99, [156.20, 155.62], 152.38, [144.53, 143.57], [141.82, 141.21], 129.61, 126.78, [126.59, 126.25], [125.02, 124.77], [79.91, 79.68], 64.04, 61.88, [61.57, 61.23], [46.03, 45.76], 30.76, 30.21, [28.53, 28.28], 25.95, [25.66, 25.29], 25.13, [18.28, 17.94], 3.72, -5.34. (S)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl (4-(N-hydroxycarbamimidoyl)-2,3-dihydro-lH-inden-l-yl)carbamate INT-19 is prepared in an analogous fashion using INT- 17.

(R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-lH-inden-l-yl)carbamate and (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-lH-inden-l-yl) (2-hydroxethyl) carbamate

Prepared using General Procedure 4. To a solution of 3-cyano-4-isopropoxybenzoic acid (4.5 g, 21.9 mmol) in anhydrous DMF (100 mL) was added HOBt (5.4 g, 40.0 mmol) and EDC (5.6 g, 29.6 mmol). After 1 h, (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl (4-(N-hydroxycarbamimidoyl)-2,3-dihydro-iH-inden-l-yl)carbamate INT- 18 (11.8 g, 26.3 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. LCMS analysis showed complete conversion to the intermediate, (R)-tert-butyl 2-(tert-butyldimethylsilyloxy) ethyl (4-(N-(3-cyano-4-isopropoxybenzoyloxy) carbamimidoyl)-2,3-dihydro-7H-inden-l-yl)carbamate INT-20. The reaction mixture was then heated to 80°C for 12 h. The reaction mixture was cooled to room temperature and diluted with EA (250 mL). NaHC0₃ (250 mL) and water (350 mL) were added until all the solids dissolved. The mixture was extracted with EA and the organic layers washed successively with water and brine. The organic layers were dried over MgS0₄ and concentrated to produce 15.3 g of a mixture of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5 -(3 -cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)- 2,3-dihydro-iH-inden-l-yl) carbamate INT-21, and the corresponding material without the TBS protecting group, {R)-tert-bvXy\ 4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-iH-inden-l-yl) (2-hydroxy ethyl) carbamate INT-22. The mixture was a brown oil, which could used directly without further purification or purified by chromatography (EA/hexane). INT-21: LCMS-ESI (m/z) calculated for C₃₄H₄₆N₄0₅Si: 618.8; found 519.2 [M-Boc]⁺ and 641.3 [M+Na]⁺, t_R = 7.30 min (Method 1). 1H NMR (400 MHz, CDC1₃) δ 8.43 (d, J =

2.1, 1H), 8.34 (dd, J = 8.9, 2.2, 1H), 8.07 (d, J= 8.1, 1H), 7.46 – 7.26 (m, 2H), 7.12 (d, J = 9.0, 1H), 5.85 (s, 0.5H), 5.37 (s, 0.5H), 4.80 (dt, J = 12.2, 6.1, 1H), 3.92 – 3.32 (m, 3.5 H), 3.17 (s, 2H), 2.95 (s, 0.5 H), 2.62 – 2.39 (m, 1H), 2.38 – 2.05 (m, 1H), 1.53 (s, 4.5H), 1.48 (d, J = 6.1, 6H), 1.33 – 1.27 (m, 4.5H), 0.94 – 0.77 (m, 9H), 0.01 (d, J = 20.9, 6H). ¹³C NMR (101 MHz, DMSO) δ 173.02, 169.00, 162.75, [156.22, 155.52], [145.18, 144.12], [143.39, 142.76], 134.16, 133.89, 128.20, [128.01, 127.85], [127.04, 126.90], 126.43, 123.31, 116.93, 115.30, 113.55, 103.96, [79.95, 79.68], 72.73, 67.61, 63.42, [61.91, 61.77], 60.99, 46.11, 31.78, [30.47, 29.87], [28.55, 28.26], 25.93, 21.75, 18.30, 0.00, -5.37. INT-22: LCMS-ESI calculated for C₂8H32N₄0₅: 504.6; found 527.2 [M+Na]⁺, t_R = 2.65 min (Method 1). 1H NMR (400 MHz, CDC1₃) δ 8.36 (d, J = 2.1, 1H), 8.27 (dd, J = 8.9, 2.2, 1H), 8.03 (d, J = 7.2, 1H), 7.35 – 7.26 (m, 2H), 7.06 (d, J = 9.0, 1H), 5.44 (s, 1H), 4.73 (dt, J= 12.2, 6.1, 1H), 3.64 (s, 2H), 3.44 (ddd, J= 17.5, 9.5,

3.2, 2H), 3.11 (dt, J = 17.4, 8.6, 3H), 2.54 – 2.38 (m, 1H), 2.04 (td, J = 17.6, 8.8, 1H), 1.50 – 1.24 (m, 15H).

(S)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-iH-inden-l-yl)carbamate INT-23 and {S)-tert- vXy\ 4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-iH-inden-l-yl) (2-hydroxyethyl) carbamate INT-24 were made in an analogous fashion.

 (S) IS DESIRED CONFIGURATION

……………………………………

(S)-tert-Butanesulfinamide

CAS 343338-28-3

3-CYANO-4-ISOPROPOXYBENZOIC ACID;3-cyano-4-(propan-2-yloxy)benzoic acid;5-(1-hydroxyvinyl)-2-isopropoxybenzonitrile

cas 258273-31-3

(S)-1-Amino-2,3-dihydro-1H-indene-4-carbonitrile hydrochloride

cas 1306763-57-4 HCl, 1213099-69-4 FREE BASE

4-bromo-2,3-dihydro-1H-inden-1-one

cas 15115-60-3

S CONFIGURATION

Carbamic acid, N-​[(1S)​-​4-​cyano-​2,​3-​dihydro-​1H-​inden-​1-​yl]​-​, 1,​1-​dimethylethyl ester, cas 1306763-31-4

(S) IS DESIRED CONFIGURATION

……………….

CAS 1306763-70-1, Carbamic acid, N-​[(1S)​-​2,​3-​dihydro-​4-​[(hydroxyamino)​iminomethyl]​-​1H-​inden-​1-​yl]​-​, 1,​1-​dimethylethyl ester

…………………

CAS 1306763-71-2, Carbamic acid, N-​[(1S)​-​4-​[5-​[3-​cyano-​4-​(1-​methylethoxy)​phenyl]​-​1,​2,​4-​oxadiazol-​3-​yl]​-​2,​3-​dihydro-​1H-​inden-​1-​yl]​-​, 1,​1-​dimethylethyl ester

1306760-73-5, Benzonitrile, 5-​[3-​[(1S)​-​1-​amino-​2,​3-​dihydro-​1H-​inden-​4-​yl]​-​1,​2,​4-​oxadiazol-​5-​yl]​-​2-​(1-​methylethoxy)​-

………………………..

1306763-63-2,

………………….

86864-60-0, (2-Bromoethoxy)dimethyl-tert-butylsilane

Synthesis

……………………………………

WO 2011060392

http://www.google.com/patents/WO2011060392A1?cl=en

(R)-N-(4-cyano-2,3-dihydro-lH-indene-l-ylidene)-2-methylpropane-^

(INT-4

[0304] To l-oxo-2,3-dihydro-/H-indene-4-carbonitrile INT-1 (42.5 g, 0.27 mol) and (R)-2- methylpropane-2-sulfmamide (36.0 g, 0.30 mol) in toluene (530 mL) was added titanium tetraethoxide (84.1 mL, 92.5 g, 0.40 mol) and the reaction mixture was heated at 60°C for 12 h under N₂. The crude (R)-N-(4-cyano-2,3-dihydro-lH-indene-l-ylidene)-2-methylpropane- 2-sulfinamide INT-4 was used directly in the next experiment. LCMS-ESI (m/z) calculated for C₁₄Hi₆N₂OS: 260.3; found 261.1 [M+H]⁺, t_R= 3.19 min.

[0305] (R)-N'((R)-4-cyano-2,3-dihydro-lH nden-l-yl)-2-n thylprop ne-2-sulfirmmide

(INT-5)

[0306] To a flask containing the crude suspension of (R)-N-(4-cyano-2,3-dihydro-iH-indene- l-ylidene)-2-methylpropane-2-sulfrnaniide INT -4 under N₂ was added THF (1.0 L) and the reaction mixture cooled to -78°C. Sodium borohydride (40.9 g, 1.08 mol) was added portion- wise over 30 mins. (The internal temperature did not rise during the addition). The reaction mixture was stirred at -78°C for 30 mins, half out of the bath for 30 mins, then warmed to 0°C over 1 h. The 0°C reaction mixture was placed in an ice bath and quenched with brine (100 mL) followed by saturated sodium potassium tartrate (420 mL) and the Ti salts precipitated. The reaction mixture was diluted with EA (1.5 L) and stirred at room temperature overnight. The organic layers were decanted and washed successively with saturated NH4CI, water, and brine. The organic layers were dried over MgS0₄ and filtered through a pad of MgS0₄. The filtrate was concentrated to produce 52.9 g of crude (R)-N-((/?)-4-cyano-2,3-dihydro-lH- inden-l-yl)-2-methylpropane-2-sulfmamide INT-5 as a brown oil, which was used directly in the next step. LCMS-ESI (m/z) calculated for C14H18 2OS: 262.3; found 263.1 [M+H]⁺, t_R = 2.99 min. 1H NMR (400 MHz, CDC1₃) δ 7.89 (d, J = 7.7, 1H), 7.56 (t, J = 6.8, 1H), 7.36 (t, J = 7.7, 1H), 4.97 (q, J = 7.5, 1H), 3.50 (d, J = 7.6, 1H), 3.22 (ddd, J = 16.9, 8.8, 3.9, 1H), 3.01 (dt, J = 22.4, 6.9, 1H), 2.70 – 2.53 (m, 1H), 2.15 – 1.95 (m, 1H), 1.33 – 1.20 (m, 9H).

[0307] (R)-l-amino-2,3-dihydro-lH-indene-l-yl)-4-carbonitrile (T^T-6)

[0308] To crude (R)-N-((R)-4-cyano-2,3-dihydro-iH-inden-l-yl)-2-methylpropane-2- sulfinamide INT-5 (52.9 g, 0.20 mol) in MeOH (200 mL) was added 4N HC1 in dioxane (152.0 mL, 0.60 mol) and the resulting yellow suspension was stirred at room temperature for 1.5 h. The crude reaction mixture was diluted with MeOH (500 mL) and filtered to remove some Ti by-products. The filtrate was concentrated and the resulting solid refluxed in acetonitrile (500 mL). The resulting white solid was collected to produce 13.0 g (31% over 3 steps) of the HC1 salt of (R)-l-amino-2,3-dihydro-7H-indene-l-yl)-4-carbonitrile INT-6. LCMS-ESI (m/z) calculated for Ci₀H₁₀N₂: 158.2; found 142.0 [M-NH₂]⁺, f_R = 0.84 min. Ή NMR (400 MHz, DMSO) δ 8.61 (s, 3H), 7.96 (d, J = 7.7, 1H), 7.83 (d, J = 7.5, 1H), 7.52 (t, J = 7.7, 1H), 4.80 (s, 1H), 3.23 (ddd, J = 16.6, 8.7, 5.2, 1H), 3.05 (ddd, J = 16.6, 8.6, 6.3, 1H), 2.62 – 2.51 (m, 1H), 2.15 – 2.01 (m, 1H). ¹³C NMR (101 MHz, DMSO) δ 148.09, 141.15, 132.48, 130.32, 127.89, 117.27, 108.05, 54.36, 39.08, 29.64. The free base can be prepared by extraction with IN NaHC0₃and DCM. LCMS-ESI (m/z) calculated for Ci₀H₁₀N₂: 158.2; found 142.0 [M-NH₂]⁺, t_R = 0.83 min. 1H NMR (400 MHz, CDC1₃) δ 7.52 – 7.38 (m, 2H), 7.23 (dd, 7 = 17.4, 9.8, 1H), 4.35 (t, J = 7.6, 1H), 3.11 (ddd, 7 = 16.8, 8.7, 3.2, 1H), 2.89 (dt, J = 16.9, 8.5, 1H), 2.53 (dddd, J = 12.8, 8.1, 7.3, 3.2, 1H), 1.70 (dtd, J = 12.8, 8.8, 8.0, 1H). ¹³C NMR (101 MHz, DMSO) δ 150.16, 146.67, 130.19, 128.74, 127.38, 117.77, 107.42, 56.86, 38.86, 29.14. Chiral HPLC: (R)-l-amino-2,3-dihydro-7H-indene-l-yl)-4-carbonitrile was eluted using 5% EtOH in hexanes, plus 0.05% TEA: 95% ee, ¾ = 23.02 min. The (S)- enantiomer INT-7 was prepared in an analogous fashion using (5)-2-methylpropane-2- sulfinamide. tR for (S)-enantiomer = 20.17 min.

[0309] (R)-tert-butyl 4-cyano-2,3-dihydro-lH-inden-l-ylcarbamate (INT-8)

[0310] To ( ?)-l-amino-2,3-dihydro-/H-indene-l-yl)-4-carbonitrile HC1 INT-6 (11.6 g, 59.6 mmol) in DCM (100 mL) at 0°C was added TEA (12.0 mL, 131.0 mmol). To the resulting solution was added a solution of Boc anhydride (14.3 g, 65.6 mmol) in DCM (30 mL) and the reaction mixture stirred at room temperature for 1.5 h. The reaction mixture was washed with brine, and the organic layers were dried over MgS0₄ and filtered. Additional DCM was added to a total volume of 250 mL and Norit (4.5 g) was added. The product was refluxed for 15 mins and the hot mixture filtered through a pad of celite / silica. The filtrate was concentrated and recrystallized from EA (50 mL) and hexane (150 mL) to produce 12.93 g (84%) of (/?)-tert-butyl 4-cyano-2,3-dihydro-iH-inden-l-ylcarbamate INT-8 as an off-white solid. LCMS-ESI (m/z) calculated for C₁₅H₁₈N₂0₂: 258.3; found 281.1 [M+Na]⁺, t_R = 3.45 min. Elemental Analysis determined for C^H^^O^ C calculated = 69.74%; found = 69.98%. H calculated = 7.02%; found = 7.14%. N calculated = 10.84%; found = 10.89%. 1H NMR (400 MHz, CDC1₃) δ 7.64 – 7.49 (m, 2H), 7.34 (dt, / = 7.7, 3.8, 1H), 5.36 – 5.20 (m, 1H), 4.78 (d, J = 6.8, 1H), 3.20 (ddd, J = 16.9, 8.9, 3.3, 1H), 3.02 (dt, J = 25.4, 8.4, 1H), 2.82 – 2.53 (m, 1H), 1.88 (dq, J = 13.2, 8.6, 1H), 1.55 – 1.44 (m, 9H). ¹³C NMR (101 MHz, DMSO) δ 155.52, 146.68, 146.32, 130.89, 128.70, 127.63, 117.51, 107.76, 77.98, 55.09, 31.88, 29.11, 28.19. Chiral HPLC: (R)-tert-butyl 4-cyano-2,3-dihydro-lH-inden-l- ylcarbamate was eluted using 2.5% EtOH in hexanes: >99.9% ee, tR = 19.36 min. The (5)- enantiomer INT-9 was prepared in an analogous fashion using (S)-l-amino-2,3-dihydro-7H- indene-l-yl)-4-carbonitrile HC1. tR for (5)-enantiomer = 28.98 min.

General Procedure 3. Preparation oflndane Amide Oximes

[0311] To (R)- or (5)-tert-butyl 4-cyano-2,3-dihydro-7H-inden-l-ylcarbamate (1 eq) in EtOH

(0.56 M) was added hydroxylamine hydrochloride (3 eq) and TEA (3 eq) and the reaction mixture heated at 85°C for 1-2 h. The organic soluble amide oximes were isolated by removal of the solvent and partitioning between water and DCM. The water soluble amide oximes were chromatographed or used directly in the cyclization. Pure amide oximes can be obtained by recrystallization from alcoholic solvents.

[0312] (R)-tert-butyl 4-(N -hydroxy carbamimidoyl )-2, 3-dihydro-lH-inden-l -ylcarbamate

(INT-10)

[0313] Prepared using General Procedure 3. To (R)-tert-butyl 4-cyano-2,3-dihydro-iH- inden-1 -ylcarbamate INT-8 (15.0 g, 58.2 mmol) in EtOH (100 niL) was added hydroxylamine hydrochloride (12.1 g, 174.2 mmol) and TEA (17.6 mL, 174.2 mmol) and the reaction mixture heated at 85°C for 2 h. The solvents were removed and the resulting white solid was partitioned between water and DCM. The organic layers were dried over Na₂S0_4, concentrated, and recrystallized from isopropanol (50 mL) to afford 14.4 g (85%) of (R)-tert- butyl 4-(N-hydroxycarbaniimidoyl)-2,3-dihydro-iH-inden-l-ylcarbamate INT-10 as white crystalline solid. LCMS-ESI (m/z) calculated for C₁₅H₂₁N₃0₃: 291.4; found 292.1 [M+H]⁺, ¾ = 2.04 min. 1H NMR (400 MHz, DMSO) δ 9.53 (s, 1H), 7.38 – 7.32 (m, 1H), 7.32 – 7.12 (m, 3H), 5.68 (s, 2H), 4.97 (q, J = 8.5, 1H), 3.07 (ddd, J = 16.6, 8.7, 2.6, 1H), 2.86 (dt, J = 16.8, 8.4, 1H), 2.30 (ddd, J = 12.6, 7.6, 3.6, 1H), 1.75 (dq, J = 12.3, 9.0, 1H), 1.44 (s, 9H). General Procedure 4. Cyclization to Indane Oxadiazole Amines

[0314] A solution of the appropriate acid (1 eq), HOBt (1.3 eq), and EDC (1.3 eq) in DMF

(0.08 M in acid) was stirred at room temperature under an atmosphere of N₂. After the complete formation of the HOBt- acid complex (1-3 h), the (R)- or (5)-amide oxime (1.1 eq) was added to the mixture. After complete formation of the coupled intermediate (ca. 0.5- 2 h), the mixture was heated to 75-95°C until the cyclization was complete (8-12 h). The reaction mixture was diluted with saturated NaHC0₃ and extracted with EA. The combined organic extracts were dried, concentrated, and either purified by chromatography (EA/hexanes) or taken on directly. The oxadiazole was treated with HC1 (5N in dioxane, 5 eq) at 50-60°C for 0.5-6 h. The reaction mixture could be extracted (DCM /NaHC0₃), or the resulting HC1 salt concentrated, suspended in Et₂0, and collected. Pure indane amines can be obtained by recrystallization from alcoholic solvents or by chromatography.

( R)-tert-butyl 4-(5-( 3-cyano-4-isopropoxyphenyl)-l,2, 4-oxadiazol-3-yl )-2,3-dihydro-lH- inden-l-ylcarbamate (INT- 12)

[0315] Prepared using General Procedure 4. To a solution of 3-cyano-4-isopropoxybenzoic acid (7.74 g, 37.7 mmol) in DMF (50 mL) was added HOBt (6.02 g, 44.6 mmol) and EDC (8.53 g, 44.6 mmol) at room temperature. The reaction was stirred for 2 h until complete formation of the HOBt-acid complex. (R)-tert-butyl 4-(N-hydroxycarbamimidoyl)-2,3- dihydro-iH-inden-l-ylcarbamate INT-10 (10.0 g, 34.3 mmol) was added and the reaction mixture stirred at room temperature for 2 h until the formation of INT-11, (R)-tert-butyl 4- (N-(3-cyano-4-isopropoxybenzolyloxy) carbamimidoyl)-2,3-dihydro-iH-inden-l- ylcarbamate. The mixture was partitioned between EA and NaHC0₃ and the organic layer was collected and dried over MgS0₄. INT-11 (16.3 g, 34.0 mmol) was re-dissolved in DMF (50 mL) and the mixture was heated to 95°C for 12 hrs. The reaction was diluted with NaHC0₃ (200 mL) and extracted with EA (3 X 50 mL). The organic layer was dried over Na₂S0₄and concentrated under reduced pressure to produce 12.8 g (81%) of (R)-tert-butyl 4- (5-(3-cyano-4-isopropoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)-2,3-dihydro-iH-inden- 1-ylcarbamate INT-12 as a light brown solid and used without further purification in the next step. LCMS- ESI (m/z) calculated for C₂₆H₂₈N₄0₄: 460.5; found 483.2 [M+Na]⁺, t_R = 4.25 min. Ή NMR (400 MHz, CDCI3) δ 8.43 (d, J = 2.1, 1H), 8.34 (dd, J = 8.9, 2.2, 1H), 8.09 (d, J = 7.6, 1H), 7.51 (d, / = 7.5, 1H), 7.39 (t, J = 7.6, 1H), 7.12 (d, J = 9.0, 1H), 5.28 (d, J = 8.2, 1H), 4.80 (hept, J = 6.0, 1H), 3.47 (ddd, J = 17.4, 8.9, 3.5, 1H), 3.27 – 3.03 (m, 1H), 2.68 (d, J = 8.7, 1H), 1.87 (td, J = 16.7, 8.5, 1H), 1.53 – 1.43 (m, 15H). ¹³C NMR (101 MHz, CDC13) δ 173.00, 168.82, 162.70, 155.68, 145.31, 142.96, 134.05, 133.83, 128.25, 127.21, 126.79, 123.09, 116.78, 115.24, 113.52, 103.87, 79.52, 72.70, 55.72, 33.86, 31.47, 28.39, 21.70. Chiral HPLC: (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3- dihydro-lH-inden-l-ylcarbamate was eluted using 20% /-PrOH in hexanes: >99.9% ee, ?R = 13.33 min. The (5)-enantiomer INT-13 was prepared in an analogous fashion using (S)-tert- butyl 4-cyano-2,3-dihydro-iH-inden-l-ylcarbamate using General Procedures 3 and 4 (tR for (Syenantiomer = 16.31 min).

( R )-5-( 3-(l -amino-2,3-dihydro-lH-inden-4-yl)-l,2, 4-oxadiazol-5-yl)-2-isopropoxy- benzonitrile h drochloride (Compound 49)

[0317] To (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3- dihydro-iH-inden-l-ylcarbamate(12.8 g, 27.8 mmol) in dioxane (200 mL) was added 4N HCl in dioxane (69 mL). The solution was heated to 55°C for 1 h, and product precipitated. Dioxane was removed and the resulting solid suspended in ether and collected. The material was recrystallized from MeOH (200 mL) to produce 8.11 g (81%) of (R)-5-(3-(l-amino-2,3- dihydro-iH-inden-4-yl)-l,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 as the HCl salt. LCMS-ESI (m/z): calcd for: C₂₁H₂₀N₄O₂: 360.4; found 383.2 [M+Na]⁺, t_R = 2.49 min. Elemental Analysis and NMR spectra determined for C₂₁H₂₁N₄0₂C1 * 0.5 H₂0; C calculated = 62.14%; found = 62.25%. H calculated = 5.46%; found = 5.30%. N calculated = 13.80%; found = 13.84%. CI calculated = 8.73%; found = 8.34%. 1H NMR (400 MHz, DMSO) δ 8.71 (s, 3H), 8.49 (d, J = 2.3, 1H), 8.39 (dd, J = 9.0, 2.3, 1H), 8.11 (d, J = 7.6, 1H), 7.91 (d, J = 7.6, 1H), 7.55 (t, J = 8.5, 2H), 4.97 (hept, J = 6.1, 1H), 4.80 (s, 1H), 3.47 (ddd, J = 17.4, 8.7, 5.3, 1H), 3.23 (ddd, 7 = 17.4, 8.6, 6.4, 1H), 2.55 (ddd, 7 = 13.7, 8.3, 3.2, 1H), 2.22 – 1.97 (m, 1H), 1.38 (d, J = 6.0, 6H). ¹³C NMR (101 MHz, CDC1₃) δ 173.28, 167.98, 162.53, 143.69, 141.29, 134.59, 133.80, 128.93, 128.11, 127.55, 122.72, 115.87, 115.24, 114.91, 102.46, 72.54, 54.38, 31.51, 29.91, 21.47. Chiral HPLC of the free base: (R)-5-(3-(l-amino-2,3- dihydro-lH-inden-4-yl)-l,2,4-oxadiazol-5-yl)-2-isopropoxy benzonitrile was eluted using 15% i^‘-PrOH in hexanes plus 0.3% DEA: > 99.9% ee, t_R = 30.80 min.

(S)- 5-(3-(l-amino-2,3- dihydro-lH-inden-4-yl)-l,2,4-oxadiazol-5-yl)-2-isopropoxy-benzonitrile 50 was prepared in an analogous fashion from (S)-tert-b tyl 4-cyano-2,3-dihydro-lH-inden-l-ylcarbamate: >99.9% ee, t_R for (5)-enantiomer = 28.58 min.

(R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-cyano-2,3-dihydro-lH-inden-l- yl)carbamate ( -16)

[0366] Prepared using General Procedure 9. To a flame-dried flask under N₂ was added (R)- tert-butyl 4-cyano-2,3-dihydro-iH-inden-l-ylcarbamate INT-8 (8.3 g, 32.1 mmol) in anhydrous DMF (240 mL). The reaction mixture was cooled to 0°C and sodium hydride (3.8 g, 60% in oil, 160.6 mmol) was added portionwise. After stirring at 0°C for 2.75 h, (2- bromoethoxy)(½rt-butyl)dimethylsilane (16.9 mL, 70.7 mmol) was added. The ice bath was removed after 5 mins and the reaction mixture was allowed to warm to room temperature. After 1.5 h, the reaction mixture was quenched by the slow addition of sat. NaHC0₃at 0°C. Once gas evolution was complete the reaction was extracted with EA. The organic layers were washed with water and brine, dried over MgS0₄ and concentrated. The product was purified by chromatography (EA / hexanes) to provide 10.76 g (80%) of (R)-teri-butyl 2-(tert- butyldimemylsilyloxy)emyl(4-cyano-2,3-dihydro-iH-inden-l-yl)carbamate INT-16 as a colorless oil. LCMS-ESI (m/z) calculated for C₂₃H₃₆N₂0₃Si: 416.6; found 317.2 [M-Boc]⁺ and 439.0 [M+Na]⁺, t_R = 4.04 min (Method 1). 1H NMR (400 MHz, CDC1₃) δ 7.46 (d, J = 7.6, 1H), 7.38- 7.32 (m, 1H), 7.33 – 7.18 (m, 1H), 5.69 (s, 0.5 H), 5.19 (s, 0.5 H), 3.70 (ddd, J = 48.8, 26.6, 22.9, 1.5 H), 3.50 – 3.37 (m, 1H), 3.17 (ddd, J = 16.7, 9.4, 2.2, 2H), 2.93 (m, 1.5 H), 2.45 (s, 1H), 2.21 (dd, J = 24.5, 14.5, 1H), 1.56 – 1.37 (bs, 4.5H), 1.22 (bs, 4.5H), 0.87 – 0.74 (m, 9H), -0.04 (dd, J = 26.6, 8.2, 6H).¹³C NMR (101 MHz, CDC1₃) δ 155.03, 146.55, 145.54, 131.16, 130.76, [128.11, 127.03], 117.58, 109.20, 79.88, [63.93, 61.88], [61.44, 60.34], [49.73, 46.76], 30.30, 29.70, 28.44, 28.12, [25.87, 25.62], -5.43. (5)-tert-butyl 2-(tert- butyldimemylsilyloxy)emyl(4-cyano-2,3-dihydro-lH-inden-l-yl)carbamate INT-17 is prepared in an analogous fashion using INT -9. [0367] (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl (4-(N-hydroxycarbamimidoyl)-2,3- dihydro-1 H-inden-1 -yl)carbamate (INT-18)

[0368] Prepared using General Procedure 3. To a solution of (R)-iert-butyl 2-(tert- butyldimemylsilyloxy)ethyl(4-cyano-2,3-dmydro-/H-inden-l-yl)carbamate INT-16 (12.0 g, 28.9 mmol) in EtOH (120 mL), under an atmosphere of N₂ was added hydroxylamine-HCl (6.0 g, 86.5 mmol) and triemylamine (13.4 mL, 9.7 g, 86.5 mmol). The reaction mixture was refluxed at 80°C for 4 h. The reaction mixture was cooled to room temperature and concentrated to dryness and then diluted with DCM (500 mL). The organic layer was washed with NaHC0₃, water, and brine. The combined organic layers were dried over MgS0₄ and concentrated to produce 11.8 g of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy) ethyl (4-(N- hydroxycarbamimidoyl)-2,3-dihydro-iH-inden-l-yl)carbamate INT-18 as a white foamy solid, which was used without purification in the next experiment. LCMS-ESI (m/z) calculated for C₂₃H₃₉N₃0₄Si: 449.7; found 350.2 [M-Boc]⁺ and 472.2 [M+Na]⁺, ¾ = 1.79 min (Method 1). 1H NMR (400 MHz, CDC13) δ 7.32 (t, / = 7.3 Hz, 1H), 7.21 – 7.07 (m, 2H), 5.69 (s, 0.5 H), 5.19 (s, 0.5 H), 4.89 (s, 2H), 3.85 – 3.50 (m, 2H), 3.31 (ddd, / = 12.2, 9.2, 2.5 Hz, 2H), 3.28 – 3.03 (m, 2H), 3.03 – 2.70 (m, 1H), 2.29 (t, J = 23.6 Hz, 1H), 1.43 (bs, 4.5H), 1.28 (bs, 4.5H), 1.16 – 1.04 (m, 1H), 0.90 – 0.71 (m, 9H), 0.08 – -0.14 (m, 6H). ¹³C NMR (101 MHz, CDC1₃) 6 170.99, [156.20, 155.62], 152.38, [144.53, 143.57], [141.82, 141.21], 129.61, 126.78, [126.59, 126.25], [125.02, 124.77], [79.91, 79.68], 64.04, 61.88, [61.57, 61.23], [46.03, 45.76], 30.76, 30.21, [28.53, 28.28], 25.95, [25.66, 25.29], 25.13, [18.28, 17.94], 3.72, -5.34. ^-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl (4-(N- hydroxycarbamimidoyl)-2,3-dihydro-lH-inden-l-yl)carbamate INT-19 is prepared in an analogous fashion using INT-17. [0369] (R)-tert-butyl 2-( tert-butyldimethylsilyloxy)ethyl( 4-( 5-( 3-cyano-4-isopropoxyphenyl)- l,2,4-oxadiazol-3-yl)-2,3-dihydro-lH-inden-l-yl)carbamate and (R)-tert-butyl 4-(5-(3-cyano- 4-isopropoxyphenyl )-l,2, 4-oxadiazol-3-yl)-2,3-dihydro-lH-inden-l-yl) (2-hydroxethyl) carbamate

[0370] Prepared using General Procedure 4. To a solution of 3-cyano-4-isopropoxybenzoic acid (4.5 g, 21.9 mmol) in anhydrous DMF (100 mL) was added HOBt (5.4 g, 40.0 mmol) and EDC (5.6 g, 29.6 mmol). After 1 h, {R)-tert-buiy\ 2-(tert-butyldimethylsilyloxy)ethyl (4- (N-hydroxycarbamimidoyl)-2,3-dihydro-iH-inden-l-yl)carbamate INT-18 (11.8 g, 26.3 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. LCMS analysis showed complete conversion to the intermediate, (R)-tert-b\xty\ 2-(tert- butyldimethylsilyloxy) ethyl (4-(N-(3-cyano-4-isopropoxybenzoyloxy) carbamimidoyl)-2,3- dihydro-7H-inden-l-yl)carbamate INT-20. The reaction mixture was then heated to 80°C for 12 h. The reaction mixture was cooled to room temperature and diluted with EA (250 mL). NaHC0₃ (250 mL) and water (350 mL) were added until all the solids dissolved. The mixture was extracted with EA and the organic layers washed successively with water and brine. The organic layers were dried over MgS0₄ and concentrated to produce 15.3 g of a mixture of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(3-cyano-4-isopropoxyphenyl)- 1 ,2,4- oxadiazol-3-yl)- 2,3-dihydro-iH-inden-l-yl) carbamate INT-21, and the corresponding material without the TBS protecting group, (R)-tert-butyl 4-(5-(3-cyano-4- isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-iH-inden-l-yl) (2-hydroxyethyl) carbamate INT -22. The mixture was a brown oil, which could used directly without further purification or purified by chromatography (EA hexane). INT-21: LCMS-ESI (m/z) calculated for C34H46N4O5S1: 618.8; found 519.2 [M-Boc]⁺ and 641.3 [M+Na]⁺, t_R = 7.30 min (Method 1). Ή NMR (400 MHz, CDC1₃) δ 8.43 (d, J = 2.1, 1H), 8.34 (dd, J = 8.9, 2.2, 1H), 8.07 (d, J = 8.1, 1H), 7.46 – 7.26 (m, 2H), 7.12 (d, / = 9.0, 1H), 5.85 (s, 0.5H), 5.37 (s, 0.5H), 4.80 (dt, J = 12.2, 6.1, 1H), 3.92 – 3.32 (m, 3.5 H), 3.17 (s, 2H), 2.95 (s, 0.5 H), 2.62 – 2.39 (m, 1H), 2.38 – 2.05 (m, 1H), 1.53 (s, 4.5H), 1.48 (d, J = 6.1, 6H), 1.33 – 1.27 (m, 4.5H), 0.94 – 0.77 (m, 9H), 0.01 (d, J = 20.9, 6H). ¹C NMR (101 MHz, DMSO) δ 173.02, 169.00, 162.75, [156.22, 155.52], [145.18, 144.12], [143.39, 142.76], 134.16, 133.89, 128.20, [128.01, 127.85], [127.04, 126.90], 126.43, 123.31, 116.93, 115.30, 113.55, 103.96, [79.95, 79.68], 72.73, 67.61, 63.42, [61.91, 61.77], 60.99, 46.11, 31.78, [30.47, 29.87], [28.55, 28.26], 25.93, 21.75, 18.30, 0.00, -5.37. INT-22: LCMS-ESI calculated for C₂₈H₃₂N₄O_s: 504.6; found 527.2 [M+Na]⁺, t_R = 2.65 min (Method 1). Ή NMR (400 MHz, CDC1₃) δ 8.36 (d, J = 2.1, 1H), 8.27 (dd, / = 8.9, 2.2, 1H), 8.03 (d, / = 7.2, 1H), 7.35 – 7.26 (m, 2H), 7.06 (d, / = 9.0, 1H), 5.44 (s, 1H), 4.73 (dt, J = 12.2, 6.1, 1H), 3.64 (s, 2H), 3.44 (ddd, / = 17.5, 9.5, 3.2, 2H), 3.11 (dt, J = 17.4, 8.6, 3H), 2.54 – 2.38 (m, 1H), 2.04 (td, J = 17.6, 8.8, 1H), 1.50 – 1.24 (m, 15H). (5 -teri-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(3-cyano-4- isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-iH-inden-l-yl)carbamate INT-23 and (S)-terf-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-iH- inden-l-yl) (2-hydroxyethyl) carbamate INT -24 were made in an analogous fashion.

[0371] (R)-5-(3-(l-(2-hydroxyethylamino)-2,3-dihydro-lH-inden-4-yl)-l,2,4-oxadi zol-^ 2-isopropoxybenzonitrile (Compound 85)

[0372] To a solution of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(3-cyano-4- isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-7H-inden-l-yl)carbamate INT-21 and (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)-2,3-dihydro-iH- inden-l-yl) (2-hydroxethyl) carbamate INT-22 (13.9 g, 27.5 mmol) in dioxane (70 mL) at 0°C was added 4N HCl in dioxane (68.8 g, 275.4 mmol). The reaction mixture was warmed to room temperature and then heated to 50°C for 1 h. The resulting suspension was cooled to room temperature and Et₂0 (75 mL) was added. The precipitate was collected by filtration, washed with Et₂0 and dried to produce 10.5 g of an off-white solid. The HCl salt was recrystallized from MeOH (165 mL) to produce 5.98 g (56% overall yield from (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-cyano-2,3-dihydro-iH-inden-l-yl) carbamate) of (R)-5- (3-(l-(2-hydroxyethylamino)-2,3-dihydro-iH-inden-4-yl)-l,2,4-oxadiazol-5-yl)-2- isopropoxybenzonitrile 85 as a white solid. LCMS-ESI (m/z) calculated for C₂₃H₂₄N₄0₃: 404.5; found 405.4 [M+H]⁺, t_R = 2.44 min. Ή NMR (400 MHz, DMSO) 5 9.25 (s, 2H), 8.53 (d, J = 2.3, 1H), 8.42 (dd, J = 9.0, 2.3, 1H), 8.17 (d, J = 7.7, 1H), 7.97 (d, J = 7.6, 1H), 7.63 – 7.50 (m, 2H), 5.28 (t, J = 5.0, 1H), 4.99 (hept, J = 6.1, 1H), 4.92 (s, 1H), 3.72 (q, J = 5.2, 2H), 3.57 – 3.43 (m, 1H), 3.27 (ddd, J = 17.6, 9.1, 5.0, 1H), 3.15-2.85 (m, J = 24.2, 2H), 2.53 (dtd, J = 9.0, 5.5, 5.3, 3.6, 1H), 2.30 (ddd, J = 13.4, 8.9, 4.6, 1H), 1.39 (d, J = 6.0, 6H). ¹³C NMR (101 MHz, DMSO) 6 173.25, 167.86, 162.47, 144.56, 139.13, 134.53, 133.77, 129.30, 128.93, 127.45, 122.83, 115.79, 115.15, 114.84, 102.40, 72.46, 61.04, 56.51, 46.38, 31.53, 27.74, 21.37. Elemental analysis for C₂₃H₂₅N₄0₃C1: C calc. = 62.65%; found = 62.73%; H calc. = 5.71%; found = 5.60%; N calc. = 12.71%; found = 12.64%; CI calc. = 8.04%; found = 8.16%. Chiral HRLC of the free base: (R)-5-(3-(l-(2-hydroxyemylamino)-2,3-dihydro-iH- inden-4-yl)-l,2,4-oxadiazol-5-yl)-2-isopropoxy – benzo-nitrile was eluted using 10% i^‘-PrOH in hexanes plus 0.3% DEA: >99.9% ee, t_R = 37.72 min.

(S)-5-(3-(l-(2-hydroxyethylamino)- 2,3-dihydro-iH-inden-4-yl)-l,2,4-oxadiazol-5-yl) -2-isopropoxy benzonitrile 86 was obtained in analogous fashion from (S)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(3- cyano-4-isopropoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)-2, 3-dihydro-iH-inden- 1 -yl)carbamate INT-23 and (S)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3- dihydro-iH-inden-l-yl) (2-hydroxyethyl) carbamate INT-24: >99.9% ee, t_R for (5)- enantiomer = 35.86 min.

(S) IS DESIRED CONFIGURATION

THE SYNTHESIS IS SUMMARISED BELOW

COSY PREDICT

1H NMR PREDICT

13C NMR PREDICT

note——-(CH3 )2CH-O-AR appears at 72 ppm

////////

Daclatasvir

THERAPEUTIC CLAIM Treatment of hepatitis C

 

CHEMICAL NAMES

1. Carbamic acid, N,N’-[[1,1′-biphenyl]-4,4′-diylbis[1H-imidazole-5,2-diyl-(2S)-2,1-

 pyrrolidinediyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl]]]bis-, C,C’-dimethyl ester

2. dimethyl N,N’-(biphenyl-4,4′-diylbis{1H-imidazole-5,2-diyl-[(2S)-pyrrolidine-2,1-

 diyl][(1S)-1-(1-methylethyl)-2-oxoethane-2,1-diyl]})dicarbamate

MF C40H50N8O6

MW 738.9

SPONSOR Bristol-Myers Squibb

CODE  BMS-790052

CAS  1009119-64-5

 

 

 

Hepatitis C virus (HCV) is a major global health problem, with an estimated 150-200 million people infected worldwide, including at least 5 million in Europe (Pawlotsky, Trends Microbiol, 2004, 12: 96-102). According to the World Health Organization, 3 to 4 million new infections occur each year. The infection is often asymptomatic; however, the majority of HCV-infected individuals develop chronic infection (Hoof agle, Hepatology, 2002, 36: S21-S29; Lauer et al, N. Engl. J. Med., 2001, 345: 41-52; Seeff, Semin. Gastrointest., 1995, 6: 20-27). Chronic infection frequently results in serious liver disease, including fibrosis and steatosis (Chisari, Nature, 2005, 435: 930-932).

About 20% of patients with chronic HCV infection develop liver cirrhosis, which progresses to hepatocellular carcinoma in 5% of the cases (Hoofnagle, Hepatology, 2002, 36: S21-S29; Blonski et al, Clin. Liver Dis., 2008, 12: 661-674; Jacobson et al, Clin. Gastroenterol. Hepatol, 2010, 8: 924-933; Castello et al., Clin. Immunol, 2010, 134: 237-250; McGivern et al., Oncogene, 2011, 30: 1969-1983).

Chronic HCV infection is the leading indication for liver transplantations (Seeff et al., Hepatology, 2002, 36: 1-2). Unfortunately, liver transplantation is not a cure for hepatitis C; viral recurrence being an invariable problem and the leading cause of graft loss (Brown, Nature, 2005, 436: 973-978; Watt et al, Am. J. Transplant, 2009, 9: 1707-1713). No vaccine protecting against HCV is yet available. Current therapies include administration of ribavirin and/or interferon-alpha (IFN-Cc), two non-specific anti-viral agents.

Using a combination treatment of pegylated IFN-CC and ribavirin, persistent clearance is achieved in about 50% of patients with genotype 1 chronic hepatitis C. However, a large number of patients have contraindications to one of the components of the combination; cannot tolerate the treatment; do not respond to interferon therapy at all; or experience a relapse when administration is stopped. In addition to limited efficacy and substantial side effects such as neutropenia, haemo lytic anemia and severe depression, current antiviral therapies are also characterized by high cost.

To improve efficacy of standard of care (SOC), a large number of direct acting antivirals (DAAs) targeting viral polyprotein processing and replication have been developed (Hofmann et al, Nat. Rev; Gastroenterol. Hepatol., 2011, 8: 257-264). These include small molecule compounds targeting HCV nonstructural proteins including the HCV protease, polymerase and NS5A protein.

Although a marked improvement of antiviral response was observed when protease inhibitors were combined with SOC (Hofmann et al, Nat. Rev; Gastroenterol. Hepatol, 2011, 8: 257-264; Bacon et al, New Engl. J. Med., 2011, 364: 1207-1217; McHutchison et al, New Engl. J. Med., 2010, 362: 1292-1303; Poordad et al, New Engl. J. Med., 201 1, 364: 1195-1206; Hezode et al, New Engl. J. Med., 2009, 360: 1839-1850; Kwo et al, Lancet, 2010, 376: 705-716), toxicity of the individual compounds and rapid development of viral resistance in a substantial fraction of patients remain major challenges (Pawlotsky, Hepatology, 2011, 53: 1742-1751; Pereira et al, Nat. Rev. Gastroenterol. Hepatol., 2009, 6: 403-411; Sarrazin et al, Gastroenterol., 2010, 138: 447-462).

New therapeutic approaches against HCV are therefore still needed. HCV entry into target cells is a promising target for antiviral preventive and therapeutic strategies since it is essential for initiation, spread, and maintenance of infection (Timpe et al, Gut, 2008, 57: 1728-1737; Zeisel et al, Hepatology, 2008, 48: 299-307). Indeed, HCV initiates infection by attaching to molecules or receptors on the surface of hepatocytes.

Current evidence suggests that HCV entry is a multistep process involving several host factors including heparan sulfate (Barth et al, J. Biol. Chem., 2003, 278: 41003-41012), the tetraspanin CD81 (Pileri et al, Science, 1998, 282: 938-941), the scavenger receptor class B type I (SR-BI) (Zeisel et al, Hepatology, 2007, 46: 1722-1731; Bartosch et al, J. Exp. Med., 2003, 197: 633-642; Grove et al, J. Virol, 2007, 81 : 3162-3169; Kapadia et al, J. Virol, 2007, 81 : 374- 383; Scarselli et al, EMBO J., 2002, 21 : 5017-5025), Occludin (Ploss et al, Nature, 2009, 457: 882-886) and Claudin-1 (CLDN1), an integral membrane protein and a component of tight-junction strands (Evans et al, Nature, 2007, 446: 801-805).

Furthermore, Niemann-Pick CI -like cholesterol absorption receptor has been identified as a new hepatitis C virus entry factor (Sainz et al, Nature Medicine, 2012, 18: 281-285).

Daclatasvir (BMS-790052; EBP 883) is a first-in-class, highly-selective oral HCV NS5A inhibitor. NS5A is an essential component for hepatitis C virus (HCV) replication complex.Daclatasvir (BMS-790052; EBP 883)has broad genotype coverage and exhibits picomolar in vitro potency against genotypes 1a (EC50 50pm) and 1b (EC50 9pm).Daclatasvir (BMS-790052; EBP 883) produces a robust decline in HCV RNA (-3.6 logs after 48 hours from a single 100 mg) dosefollowing a single dose in patients chronically infected with HCV genotype 1.

It may be many years before the symptoms of hepatitis C infection appear. However, once they do, the consequences are significant: patients may have developed fibrosis, cirrhosis or even liver cancer, with the end result being liver failure. Even if diagnosed early, there’s no guarantee of a cure.

Only around half of patients respond to the standard therapy of an interferon plus the antiviral drug ribavirin, and while two add-on antiviral therapies were approved in 2011, the treatment period is long with no guarantee of a cure, and for non-responders treatment options remain limited.

A new drug with a different mechanism is being developed by Bristol-Myers Squibb, in conjunction with Pharmasset. Daclatasvir targets non-structural protein 5A, which is an important component of the viral replication process, although its precise role in this remains unclear. The drug is active in single oral doses, and may have potential as part of a treatment regimen that avoids the use of interferon, and in patients who do not respond to standard therapy.

In an open label Phase IIa study, 10 patients with chronic hepatitis C genotype 1b infection who did not respond to standard therapy were given daclatasvir in once daily 60mg doses, plus another experimental drug, BMS-790052, which is an NSP 3 protease inhibitor, in initial twice-daily 600mg doses, later reduced to 200mg twice a day.2 Nine patients completed 24 weeks of treatment, with the 10th discontinuing after 10 weeks. In those who completed the course, HCV RNA was undetectable at week 8, and remained so until the end of the trial, with all achieving a sustained virologic response. It was also undetectable post-treatment in the patient who discontinued.

Daclatasvir has also been investigated as monotherapy in a double blind, placebo-controlled, sequential panel, multiple ascending dose study.3 Thirty patients with chronic geno-type 1 hepatitis C infection were randomised to receive a 14 day course of the drug, in once daily doses of 1, 10, 30, 60 or 100mg, 30mg twice a day, or placebo. There was no evidence of antiviral activity in the placebo group, but the mean maximum decline of 2.8 to 4.1 log IU/ml. Most experienced viral rebound on or before day 7 of treatment, which was associated with viral variants that had previously been implicated in resistance development. It was well tolerated in all dose groups.

 M. Gao et al. Nature 2010, 465, 96

22/11/2013

EUROPEAN MEDICINES AGENCY ADVISES ON COMPASSIONATE USE OF DACLATASVIR

Opinion concerns use in combination with sofosbuvir in patients with chronic hepatitis C in urgent need of therapy to prevent progression of liver disease

The European Medicines Agency’s Committee for Medicinal Products for Human Use(CHMP) has given an opinion on the use of daclatasvir in combination with sofosbuvir in the treatment of chronic (long-term) hepatitis C virus (HCV) infection, in a compassionate-use programme.

Compassionate-use programmes are set up at the level of individual Member States. They are intended to give patients with a life-threatening, long-lasting or seriously disabling disease with no available treatment options access to treatments that are still under development and that have not yet received amarketing authorisation. In this specific case, Sweden has requested an opinion from the CHMP on the conditions under which early access through compassionate use could be given to daclatasvir, for the use in combination with sofosbuvir, with or without ribavirin, for a specific patient population.

The recommended compassionate use is intended for adult patients at a high risk of their liver being no longer able to function normally (decompensation) or death within 12 months if left untreated, and who have a genotype 1 infection. Further, it is recognised that the potential benefit of such combination therapy may extend to patients infected with other HCV genotypes.

Daclatasvir and sofosbuvir are both first-in-class anti-viral medicines against HCV. These medicines have been studied in combination, with or without ribavirin, in aclinical trial which included treatment-naive (previously untreated) HCV genotype-1, -2 and -3 infected patients, as well as patients with genotype 1 infection who have previously failed telaprevir or boceprevir treatment. Results from the trial indicate high efficacy, also in those who have failed treatment with these protease inhibitors. Many such patients have very advanced liver disease and are in urgent need of effective therapy in order to cease the progression of liver injury.

This is the second opinion provided by the CHMP on compassionate use of medicines in development for the treatment of hepatitis C. Overall, it isthe fourth time compassionate use has been assessed by the CHMP.

The aim of the CHMP assessment and opinion on a compassionate-use programme for new medicinal products is to ensure a common approach, whenever possible, regarding the criteria and conditions of use under Member States’ legislation. The opinion provides recommendations to the EU Member States that are considering setting up such a programme, and its implementation is not mandatory. In addition to describing which patients may benefit from the medicine, it explains how to use it and gives information on safety.

The assessment report and conditions of use of daclatasvir in combination with sofosbuvir with or without ribavirin in this setting will be published shortly on the Agency’s website.

Notes

• The first compassionate-use opinion for a hepatitis C treatment was adopted by the CHMP in October 2013.
• Sofosbuvir, which is part of this compassionate-use opinion, received a positive opinion from the CHMP recommending granting of a marketing authorisation at its November 2013 meeting.
• Daclatasvir is developed by Bristol-Myers Squibb and sofosbuvir is developed by Gilead.

US2012004196	1-6-2012	Anti-Viral Compounds
US2009041716	2-13-2009	CRYSTALLINE FORM OF METHYL ((1S)-1-(((2S) -2-(5-(4′-(2-((2S)-1((2S)-2-((METHOXYCARBONYL)AMINO)-3-METHYLBUTANOYL)-2-PYRROLIDINYL) -1H-IMIDAZOL-5-YL)-4-BIPHENYLYL)-1H-IMIDAZOL-2-YL)-1-PYRROLIDINYL)CARBONYL) -2-METHYLPROPYL)CARBAMATE DIHYDROCHLORIDE SALT

Synthesis

US20090041716

https://www.google.co.in/patents/US20090041716?pg=PA1&dq=us+2009041716&hl=en&sa=X&ei=3ki4Uo-jEsTirAfzwoHQBQ&ved=0CD4Q6AEwAQ

EXAMPLES

A 1 L, 3-neck round bottom flask, fitted with a nitrogen line, overhead stirrer and thermocouple, was charged with 20 g (83.9 mmol, 1 equiv) 1,1′-(biphenyl-4,4′-diyl)diethanone, 200 mL CH₂Cl₂ and 8.7 mL (27.1 g, 169.3 mmol, 2.02 quiv) bromine. The mixture was allowed to stir under nitrogen for about 20 hours under ambient conditions. The resulting slurry was charged with 200 mL CH₂Cl₂ and concentrated down to about 150 mL via vacuum distillation. The slurry was then solvent exchanged into THF to a target volume of 200 mL via vacuum distillation. The slurry was cooled to 20-25° C. over 1 hour and allowed to stir at 20-25° C. for an additional hour. The off-white crystalline solids were filtered and washed with 150 mL CH₂Cl₂. The product was dried under vacuum at 60° C. to yield 27.4 g (69.2 mmol, 82%) of the desired product  : ¹H NMR (400 MHz, CDCl₃) δ 7.95-7.85 (m, 4H), 7.60-7.50 (m, 4H), 4.26 (s, 4H); ¹³C NMR (100 MHz, CDCl₃) 6 191.0, 145.1, 133.8, 129.9, 127.9, 30.8; IR (KBr, cm−1) 3007, 2950, 1691, 1599, 1199; Anal calcd for C₁₆H₁₂Br₂O₂: C, 48.52; H, 3.05; Br, 40.34. Found: C, 48.53; H, 3.03; Br, 40.53 HRMS calcd for C₁₆H₁₃Br₂O₂ (M+H; DCI⁺): 394.9282. Found: 394.9292. mp 224-226° C.

 

A 500 mL jacketed flask, fitted with a nitrogen line, thermocouple and overhead stirrer, was charged with 20 g (50.5 mmol, 1 equiv) of Compound 2, 22.8 g (105.9 moles, 2.10 equiv) 1-(tert-butoxycarbonyl)-L-proline and 200 mL acetonitrile. The slurry was cooled to 20° C. followed by the addition of 18.2 mL (13.5 g, 104.4 mmol, 2.07 equiv) DIPEA. The slurry was warmed to 25° C. and allowed to stir for 3 hours. The resulting clear, organic solution was washed with 3×100 mL 13 wt % aqueous NaCl. The rich acetonitrile solution was solvent exchanged into toluene (target volume=215 mL) by vacuum distillation until there was less than 0.5 vol % acetonitrile.

 

The toluene solution of Compound 3 was charged with 78 g (1.011 moles, 20 equiv) ammonium acetate and heated to 95-100° C. The mixture was allowed to stir at 95-100° C. for 15 hours. After reaction completion, the mixture was cooled to 70-80° C. and charged with 7 mL acetic acid, 40 mL n-butanol, and 80 mL of 5 vol % aqueous acetic acid. The resulting biphasic solution was split while maintaining a temperature >50° C. The rich organic phase was charged with 80 mL of 5 vol % aqueous acetic acid, 30 mL acetic acid and 20 mL n-butanol while maintaining a temperature >50° C. The resulting biphasic solution was split while maintaining a temperature >50° C. and the rich organic phase was washed with an additional 80 mL of 5 vol % aqueous acetic acid. The rich organic phase was then solvent exchanged into toluene to a target volume of 215 mL by vacuum distillation. While maintaining a temperature >60° C., 64 mL methanol was charged. The resulting slurry was heated to 70-75° C. and aged for 1 hour. The slurry was cooled to 20-25° C. over 1 hour and aged at that temperature for an additional hour. The slurry was filtered and the cake was washed with 200 mL 10:3 toluene:methanol. The product was dried under vacuum at 70° C., resulting in 19.8 g (31.7 mmol, 63%) of the desired product: ¹H NMR (400 MHz, DMSO-d₆) δ 13.00-11.00 (s, 2H), 7.90-7.75 (m, 4H), 7.75-7.60 (m, 4H), 7.60-7.30 (s, 2H), 4.92-4.72 (m, 2H), 3.65-3.49 (m, 2H), 3.49-3.28 (m, 2H), 2.39-2.1 (m, 2H), 2.10-1.87 (m, 6H), 1.60-1.33 (s, 8H), 1.33-1.07 (s, 10H); ¹³C NMR (100 MHz, DMSO-d₆) δ 154.1, 153.8, 137.5, 126.6, 125.0, 78.9, 78.5, 55.6, 55.0, 47.0, 46.7, 33.7, 32.2, 28.5, 28.2, 24.2, 23.5; IR (KBr, cm−1) 2975, 2876, 1663, 1407, 1156, 1125; HRMS calcd for C₃₆H₄₅N₆O₄ (M+H; ESI⁺): 625.3502. Found: 625.3502. mp 190-195° C. (decomposed).

 

To a 250 mL reactor equipped with a nitrogen line and overhead stirrer, 25.0 g of Compound 4 (40.01 mmol, 1 equiv) was charged followed by 250 mL methanol and 32.85 mL (400.1 mmol, 10 equiv) 6M aqueous HCl. The temperature was increased to 50° C. and agitated at 50° C. for 5 hours. The resulting slurry was cooled to 20-25° C. and held with agitation for about 18 hours. Filtration of the slurry afforded a solid which was washed successively with 100 mL 90% methanol/water (V/V) and 2×100 mL of methanol. The wet cake was dried in a vacuum oven at 50° C. overnight to give 18.12 g (31.8 mmol, 79.4%) of the desired product.

Recrystallization of Compound 5

To a 250 mL reactor equipped with a nitrogen line and an overhead stirrer, 17.8 g of Compound 5 from above was charged followed by 72 mL methanol. The resulting slurry was agitated at 50° C. for 4 hours, cooled to 20-25° C. and held with agitation at 20-25° C. for 1 hour. Filtration of the slurry afforded a crystalline solid which was washed with 60 mL methanol. The resulting wet cake was dried in a vacuum oven at 50° C. for 4 days to yield 14.7 g (25.7 mmol, 82.6%) of the purified product: ¹H NMR (400 MHz, DMSO-d₆) δ 10.5-10.25 (br, 2H), 10.1-9.75 (br, 2H), 8.19 (s, 2H), 7.05 (d, J=8.4, 4H), 7.92 (d, J=8.5, 4H), 5.06 (m, 2H), 3.5-3.35 (m, 4H), 2.6-2.3 (m, 4H), 2.25-2.15 (m, 2H), 2.18-1.96 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 156.6, 142.5, 139.3, 128.1, 127.5, 126.1, 116.9, 53.2, 45.8, 29.8, 24.3; IR (KBr, cm⁻¹) 3429, 2627, 1636, 1567, 1493, 1428, 1028. Anal calcd for C₂₆H₃₂N₆Cl₄: C, 54.75; H, 5.65; Cl, 24.86; Adjusted for 1.9% water: C, 53.71; H, 5.76; N, 14.46; Cl, 24.39. Found: C, 53.74; H, 5.72; N, 14.50; Cl, 24.49; KF=1.9. mp 240° C. (decomposed).

 

 

A 1 L jacketed flask equipped with a nitrogen line and an overhead stirrer was sequentially charged with 100 mL acetonitrile, 13.69 g (89.4 mmol, 2.5 equiv) hydroxybenzotriazole hydrate, 15.07 g (86 mmol, 2.4 equiv) N-(methoxycarbonyl)-L-valine, 16.46 g (85.9 mmol, 2.4 equiv) 1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride and an additional 100 mL acetonitrile. The resulting solution was agitated at 20° C. for 1 hour and charged with 20.4 g (35.8 mmol, 1 equiv) of purified Compound 5. The slurry was cooled to about 0° C. and 18.47 g (142.9 mmol, 4 equiv) diisopropylethylamine was added over 30 minutes while maintaining a temperature below 10° C. The solution was slowly heated to 15° C. over 3 hours and held at 15° C. for 12 hours. The resulting solution was charged with 120 mL 13 wt % aqueous NaCl and heated to 50° C. for 1 hour. After cooling to 20° C., 100 mL of isopropyl acetate was added. The biphasic solution was filtered through a 0.45 μm filter and the mixture split. The rich organic phase was washed with 2×240 mL of a 0.5 N NaOH solution containing 13 wt % NaCl followed by 120 mL 13 wt % aqueous NaCl. The mixture was then solvent exchanged into isopropyl acetate by vacuum distillation with a target volume of 400 mL. The resulting hazy solution was cooled to 20° C. and filtered through a 0.45 μm filter. The clear solution was then solvent exchanged into ethanol by vacuum distillation with a target volume of 140 mL. While maintaining a temperature of 50° C., 66.4 mL (82.3 mmol, 2.3 equiv) of 1.24M HCl in ethanol was added. The mixture was then charged with 33 mg (0.04 mmol, 0.001 equiv) of seed crystals of Compound (I) (see preparation below) and the resulting slurry was stirred at 50° C. for 3 hours. The mixture was cooled to 20° C. over 1 hour and aged at that temperature for an additional 22 hours. The slurry was filtered and the wet cake was washed with 100 mL of 2:1 acetone:ethanol. The solids were dried in a vacuum oven at 70° C. to give 22.15 g (27.3 mmol, 76.3%) of the desired product.

 

A solution of Compound (I) was prepared by dissolving 3.17 g of Compound (I) from above in 22 mL methanol. The solution was passed through a 47 mm Cuno Zeta Carbon® 53SP filter at ˜5 psig at a flow rate of ˜58 mL/min. The carbon filter was rinsed with 32 mL of methanol. The solution was concentrated down to 16 mL by vacuum distillation. While maintaining a temperature of 40-50° C., 15.9 mL acetone and 5 mg of seed crystals of Compound (I) (see procedure below) were added. The resulting slurry was then charged with 32 mL acetone over 30 minutes. The slurry was held at 50° C. for 2 hours, cooled to 20° C. over about 1 hour and held at 20° C. for about 20 hours. The solids were filtered, washed with 16 mL 2:1 acetone:methanol and dried in a vacuum oven at 60° C. to give 2.14 g (67.5%) of purified Compound (I):

¹H NMR (400 MHz, DMSO-d₆, 80° C.): 8.02 (d, J=8.34 Hz, 4 H), 7.97 (s, 2 H), 7.86 (d, J=8.34 Hz, 4 H), 6.75 (s, 2 H), 5.27 (t, J=6.44 Hz, 2 H), 4.17 (t, J=6.95 Hz, 2 H), 3.97-4.11 (m, 2 H), 3.74-3.90 (m, 2 H), 3.57 (s, 6 H), 2.32-2.46 (m, 2 H), 2.09-2.31 (m, 6 H), 1.91-2.07 (m, 2 H), 0.88 (d, J=6.57 Hz, 6 H), 0.79 (d, J=6.32 Hz, 6 H);

¹³C NMR (75 MHz, DMSO-d₆): δ 170.9, 156.9, 149.3, 139.1, 131.7, 127.1, 126.5, 125.9, 115.0, 57.9, 52.8, 51.5, 47.2, 31.1, 28.9, 24.9, 19.6, 17.7;

IR (neat, cm⁻¹): 3385, 2971, 2873, 2669, 1731, 1650.

Anal. Calcd for C₄₀H₅₂N₈O₆Cl₂: C, 59.18; H, 6.45; N, 13.80; Cl, 8.73. Found C, 59.98; H, 6.80; N, 13.68; Cl, 8.77. mp 267° C. (decomposed).

Preparation of Seed Crystals of Compound (I)

A 250 mL round-bottom flask was charged with 6.0 g (10.5 mmol, 1 equiv) Compound 5, 3.87 g (22.1 mmol, 2.1 equiv) N-(methoxycarbonyl)-L-valine, 4.45 g (23.2 mmol, 2.2 equiv) 1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.289 g (2.14 mmol, 0.2 equiv) 1-hydroxybenzotriazole, and 30 mL acetonitrile. The resulting slurry was then charged with 7.33 mL (42.03 mmol, 4 equiv) diisopropylethylamine and allowed to stir at 24-30° C. for about 18 hours. The mixture was charged with 6 mL of water and heated to 50° C. for about 5 hours. The mixture was cooled and charged with 32 mL ethyl acetate and 30 mL water. The layers were separated and the rich organic layer was washed with 30 mL of 10 wt % aqueous NaHCO₃, 30 mL water, and 20 mL of 10 wt % aqueous NaCl. The rich organic layer was then dried over MgSO₄, filtered, and concentrated down to a residue. The crude material was then purified via flash chromatography (silica gel, 0-10% methanol in dichloromethane) to provide the free base of Compound (I).

The free-base of Compound (I) (0.03 g) was dissolved in 1 mL isopropanol at 20° C. Anhydrous HCl (70 μL, dissolved in ethanol, approximately 1.25M concentration) was added and the reaction mixture was stirred. To the solution was added methyl tert-butyl ether (1 mL) and the resulting slurry was stirred vigorously at 40° C. to 50° C. for 12 hours. The crystal slurry was cooled to 20° C. and filtered. The wet cake was air-dried at 20° C. A white crystalline solid (Form N-2 of Compound (I)) was obtained.

 

…………………
Daclatasvir synthesis: WO2009020828A1

Procedure:

Step a: A 1 L, 3 -neck round bottom flask, fitted with a nitrogen line, overhead stirrer and thermocouple, was charged with 20 g (83.9 mmol, 1 equiv) 1,1′-(biphenyl-4,4′-diyl)diethanone, 200 mL Dichloromethane and 8.7 mL (27.1g, 169.3 mmol, 2.02 equiv) bromine. The mixture was allowed to stir under nitrogen for about 20 hours under ambient conditions. The resulting slurry was charged with 200 mL Dichloromethane and concentrated down to about 150 mL via vacuum distillation. The slurry was then solvent exchanged into THF to a target volume of 200 mL via vacuum distillation. The slurry was cooled to 20-25 ⁰C over 1 hour and allowed to stir at 20-25 ⁰C for an additional hour. The off-white crystalline solids were filtered and washed with 150 mL Dichloromethane. The product was dried under vacuum at 60 0C to yield 27.4 g (69.2 mmol, 82%) of the desired product: 1H NMR (400 MHz, CDCl3) d 7.95-7.85 (m, 4H), 7.60-7.50 (m, 4H), 4.26 (s, 4H); 13C NMR 100 MHz, CDCl3) d 191.0, 145.1, 133.8, 129.9, 127.9, 30.8; IR (KBr, cm-1) 3007, 2950, 1691, 1599, 1199; Anal calcd for C16H12Br2O2: C, 48.52; H, 3.05; Br, 40.34. Found: C, 48.53; H, 3.03; Br, 40.53. HRMS calcd for C16H12Br2O2 (M + H; DCI+): 394.9282. Found: 394.9292. mp 224-226 0C.

Step b: A 500 mL jacketed flask, fitted with a nitrogen line, thermocouple and overhead stirrer, was charged with 20 g (50.5 mmol, 1 equiv) of Compound 2, 22.8 g (105.9 moles, 2.10 equiv) 1-(tert-butoxycarbonyl)-L-proline and 200 mL acetonitrile. The slurry was cooled to 20 ⁰C followed by the addition of 18.2 mL (13.5 g, 104.4 mmol, 2.07 equiv) DIPEA. The slurry was warmed to 25 ⁰C and allowed to stir for 3 hours. The resulting clear, organic solution was washed with 3 x 100 mL 13 wt% aqueous NaCl. The rich acetonitrile solution was solvent exchanged into toluene (target volume = 215 mL) by vacuum distillation until there was less than 0.5 vol% acetonitrile.

Step c: The toluene solution of Compound 3 was charged with 78 g (1.011 moles, 20 equiv) ammonium acetate and heated to 95-100 ⁰C. The mixture was allowed to stir at 95-100 ⁰C for 15 hours. After reaction completion, the mixture was cooled to 70- 80 ⁰C and charged with 7 mL acetic acid, 40 mL n-butanol, and 80 mL of 5 vol% aqueous acetic acid. The resulting biphasic solution was split while maintaining a temperature > 50 ⁰C. The rich organic phase was charged with 80 mL of 5 vol% aqueous acetic acid, 30 mL acetic acid and 20 mL n-butanol while maintaining a temperature > 50 ⁰C. The resulting biphasic solution was split while maintaining a temperature > 50 ⁰C and the rich organic phase was washed with an additional 80 mL of 5 vol% aqueous acetic acid. The rich organic phase was then solvent exchanged into toluene to a target volume of 215 mL by vacuum distillation. While maintaining a temperature > 60 ⁰C, 64 mL methanol was charged. The resulting slurry was heated to 70-75 0C and aged for 1 hour. The slurry was cooled to 20-25 ⁰C over 1 hour and aged at that temperature for an additional hour. The slurry was filtered and the cake was washed with 200 mL 10:3 toluene:methanol. The product was dried under vacuum at 70 ⁰C, resulting in 19.8 g (31.7 mmol, 63%) of the desired product: 1H NMR (400 MHz, DMSO-^) d 13.00-11.00 (s, 2H), 7.90-7.75 (m, 4H), 7.75-7.60 (m, 4H), 7.60-7.30 (s, 2H), 4.92-4.72 (m, 2H), 3.65-3.49 (m, 2H), 3.49-3.28 (m, 2H), 2.39-2.1 (m, 2H), 2.10-1.87 (m, 6H), 1.60-1.33 (s, 8H), 1.33-1.07 (s, 10H); 13C NMR (100 MHz, DMSO-?fe) d 154.1, 153.8, 137.5, 126.6, 125.0, 78.9, 78.5, 55.6, 55.0, 47.0, 46.7, 33.7, 32.2, 28.5, 28.2, 24.2, 23.5; IR (KBr, cm-1) 2975, 2876, 1663, 1407, 1156, 1125; HRMS calcd for C36H45N6O4 (M + H; ESI+): 625.3502. Found: 625.3502. mp 190-195 0C (decomposed).

Step d: To a 250 mL reactor equipped with a nitrogen line and overhead stirrer, 25.0 g of Compound 4 (40.01 mmol, 1 equiv) was charged followed by 250 mL methanol and 32.85 mL (400.1 mmol, 10 equiv) 6M aqueous HCl. The temperature was increased to 50 ⁰C and agitated at 50 ⁰C for 5 hours. The resulting slurry was cooled to 20-25 ⁰C and held with agitation for about 18 hours. Filtration of the slurry afforded a solid which was washed successively with 100 mL 90% methanoI/water (WV) and 2 x 100 mL of methanol. The wet cake was dried in a vacuum oven at 50 ⁰C overnight to give 18.12 g (31.8 mmol, 79.4%) of the desired product.

CUT PASTE…….WO2009020825

Preparation of Compound (I)

A 1 L jacketed flask equipped with a nitrogen line and an overhead stirrer was sequentially charged with 100 mL acetonitrile, 13.69 g (89.4 mmol, 2.5 equiv) hydroxybenzotriazole hydrate, 15.07 g (86 mmol, 2.4 equiv) N-(methoxycarbonyl)- L-valine, 16.46 g (85.9 mmol, 2.4 equiv) l-(3-dimethyaminopropyl)-3- ethylcarbodiimide hydrochloride and an additional 100 mL acetonitrile. The resulting solution was agitated at 20 ⁰C for 1 hour and charged with 20.4 g (35.8 mmol, 1 equiv) of purified Compound 7. The slurry was cooled to about 0 ⁰C and 18.47 g (142.9 mmol, 4 equiv) diisopropylethylamine was added over 30 minutes while maintaining a temperature below 10 ⁰C. The solution was slowly heated to 15 ⁰C over 3 hours and held at 15 ⁰C for 12 hours. The resulting solution was charged with 120 mL 13 wt% aqueous NaCl and heated to 50 ⁰C for 1 hour. After cooling to 20 ⁰C, 100 mL of isopropyl acetate was added. The biphasic solution was filtered through a 0.45 μm filter and the mixture split. The rich organic phase was washed with 2 x 240 mL of a 0.5 Ν NaOH solution containing 13 wt% NaCl followed by 120 mL 13 wt% aqueous NaCl. The mixture was then solvent exchanged into isopropyl acetate by vacuum distillation with a target volume of 400 mL. The resulting hazy solution was cooled to 20 ⁰C and filtered through a 0.45 μm filter. The clear solution was then solvent exchanged into ethanol by vacuum distillation with a target volume of 140 mL. While maintaining a temperature of 50 ⁰C, 66.4 mL (82.3 mmol, 2.3 equiv) of 1.24M HCl in ethanol was added. The mixture was then charged with 33 mg (0.04 mmol, 0.001 equiv) of seed crystals of Compound (I) (see preparation below) and the resulting slurry was stirred at 50 ⁰C for 3 hours. The mixture was cooled to 20 ⁰C over 1 hour and aged at that temperature for an additional 22 hours. The slurry was filtered and the wet cake was washed with 100 mL of 2: 1 acetone:ethanol. The solids were dried in a vacuum oven at 70 ⁰C to give 22.15 g (27.3 mmol, 76.3%) of the desired product.

Alternative Preparation of Compound (I)

A jacketed reactor equipped with a mechanical agitator, a thermocouple and a nitrogen inlet was sequentially charged with 10 L acetonitrile, 0.671 kg (4.38 moles, 2.50 equiv) 1-hydroxybenzotriazole, 0.737 kg (4.21 moles, 2.40 equiv) N- (methoxycarbonyl)-L-valine and 0.790 kg (4.12 moles, 2.35 equiv) l-(3- dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was agitated at 20⁰C for 1 hour, cooled to 5 ⁰C and charged with 1 kg (1.75 moles, 1.00 equiv) Compound 7. While maintaining a temperature < 10 ⁰C, 0.906 kg (7.01 moles, 4 equiv) diisopropylethylamine was added. The mixture was heated to 15-20 ⁰C over 2 hours and agitated for an additional 15 hours. After the reaction was complete, the mixture was washed once with 6.0 L 13 wt% aqueous NaCl, twice with 6.1 L (6.12 moles, 3.5 equiv) 1.0 M aqueous NaOH containing 13 wt% NaCl and once with 6.0 L 13 wt% aqueous NaCl. Water was then removed from the rich organic solution via azeotropic distillation. The mixture was cooled to 20 ⁰C, agitated for 1 hour and filtered. The rich organic solution was then solvent exchanged into EtOH via vacuum distillation to a target volume of 5 L. While maintaining a temperature of 50 ⁰C, 3.2 L (4.0 moles, 2.3 equiv) 1.25M HCl in EtOH was charged. The mixture was seeded with 1.6 g Compound (I) (see preparation below) and agitated at 50 ⁰C for 3 hours. The resulting slurry was cooled to 20 ⁰C and agitated for at least 3 hours. The product was collected by filtration and washed with 5 L 2: 1 acetone:

EtOH to give 1.29 kg (ca. 90 wt% product) of wet crude product. A reactor equipped with an overhead agitator, nitrogen inlet and thermocouple was charged with 1.11 kg of the above crude product and 7 L methanol. The resulting solution was treated with Cuno Zeta Carbon (TM) 55SP. The carbon was washed with 15 L MeOH and the combined filtrate and wash was concentrated down to 4 L via vacuum distillation. The concentrated solution was charged with 5 L acetone and seeded with 1.6 g Compound (I) (see preparation below) while maintaining a temperature of 50 ⁰C. An additional 10 L acetone was charged and the resulting slurry was stirred at 50 ⁰C for 3 hours. The slurry was cooled to 20 ⁰C and allowed to agitate at 20⁰C for 3 hours. The product was collected by filtration, washed with 5 L 2: 1 acetone: EtOH and dried under vacuum at 50-60 ⁰C to give 0.900 kg (1.11 moles, 74% adjusted) of Compound (I)-

Carbon Treatment and Recrystallization of Compound (I) A solution of Compound (I) was prepared by dissolving 3.17 g of Compound (I) from above in 22 mL methanol. The solution was passed through a 47mm Cuno Zeta Carbon 53SP filter at ~5 psig at a flow rate of~58mL/min. The carbon filter was rinsed with 32 mL of methanol. The solution was concentrated down to 16 mL by vacuum distillation. While maintaining a temperature of 40-50 ⁰C, 15.9 mL acetone and 5 mg of seed crystals of Compound (I) (see procedure below) were added. The resulting slurry was then charged with 32 mL acetone over 30 minutes. The slurry was held at 50 ⁰C for 2 hours, cooled to 20 ⁰C over about 1 hour and held at 20 ⁰C for about 20 hours. The solids were filtered, washed with 16 mL 2: 1 acetone:methanol and dried in a vacuum oven at 60 ⁰C to give 2.14 g (67.5%) of purified Compound (I):

¹H NMR (400 MHz, DMSO-έfc, 80 ⁰C): 8.02 (d, J=8.34 Hz, 4 H), 7.97 (s, 2 H), 7.86 (d, J=8.34 Hz, 4 H), 6.75 (s, 2 H), 5.27 (t, J=6.44 Hz, 2 H), 4.17 (t, J=6.95 Hz, 2 H), 3.97 – 4.11 (m, 2 H), 3.74 – 3.90 (m, 2 H), 3.57 (s, 6 H), 2.32 – 2.46 (m, 2 H), 2.09 – 2.31 (m, 6 H), 1.91 – 2.07 (m, 2 H), 0.88 (d, J=6.57 Hz, 6 H), 0.79 (d, J=6.32 Hz, 6 H);

¹³C NMR (75 MHz, DMSO-έfc): δ 170.9, 156.9, 149.3, 139.1, 131.7, 127.1, 126.5, 125.9, 115.0, 57.9, 52.8, 51.5, 47.2, 31.1, 28.9, 24.9, 19.6, 17.7;

IR (neat, cm^“1): 3385, 2971, 2873, 2669, 1731, 1650.

Anal. Calcd for C₄₀H₅₂N₈O₆Cl₂: C, 59.18; H, 6.45; N, 13.80; Cl, 8.73. Found C, 59.98; H, 6.80; N, 13.68; Cl, 8.77. mp 267 ⁰C (decomposed).

Characteristic diffraction peak positions (degrees 2Θ + 0.1) @ RT, based on a high quality pattern collected with a diffractometer (CuKa) with a spinning capillary with 2Θ calibrated with a NIST other suitable standard are as follows: 10.3, 12.4, 12.8, 13.3, 13.6, 15.5, 20.3, 21.2, 22.4, 22.7, 23.7

Daclatasvir faces problems in USA

The US-FDA in 2014 issued a complete response letter for NS5A inhibitor daclatasvir saying it was unable to approve the drug because the marketing application was for its use in tandem with asunaprevir, an NS3/NS4A protease inhibitor discontinued in the US by BMS for commercial reasons. Daclatasvir is already on the market in Europe-where it is sold as Daklinza-and also in Japan where it was approved alongside asunaprevir in July as the country’s first all-oral HCV therapy. However, a delay in the large US market is clearly a major setback for BMS’ ambitions in hepatitis therapy.

To make the matter worse, US FDA has rescinded breakthrough therapy designation status from Bristol-Myers Squibb for Daclatasvir for the treatment of hepatitis C virus infection in Feb 2015.

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PAPER

Makonen, B.; et. al. Hepatitis C Virus NS5A Replication Complex Inhibitors: The Discovery of Daclatasvir. J Med Chem 2014, 57(5), 2013–2032.

http://pubs.acs.org/doi/abs/10.1021/jm401836p

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PATENT

http://www.google.com/patents/WO2008021927A2?cl=en

Example 24-23

methyl ((lS)-l-(((2S)-2-(5-(4′-(2-((2S)-l-((2S)-2-((methoxycarbonyl)amino)-3- methylbutanoyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)-

1 -pyrrolidinyl) carbonyl) -2-methylpropyl) carbamate

A 50 mL flask equipped with a stir bar was sequentially charged with 2.5 mL acetonitrile, 0.344 g (2.25 mmol, 2.5 equiv) hydroxy benzotriazole hydrate, 0.374 g (2.13 mmol, 2.4 equiv) N-(methoxycarbonyl)-L-valine, 0.400 g (2.09 mmol, 2.4 equiv) 1 -(3 -dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride and an additional 2.5 mL acetonitrile. The resulting solution was agitated at 20 ⁰C for 1 hour and charged with 0.501 g (0.88 mmol, 1 equiv) Example A-le-4. The slurry was cooled to about 0 ⁰C and 0.45 g (3.48 mmol, 4 equiv) diisopropylethylamine was added over 30 minutes while maintaining a temperature below 10 ⁰C. The solution was slowly heated to 15 ⁰C over 3 hours and held at 15 ⁰C for 16 hours. The temperature was increased to 20 ⁰C and stirred for 3.25 hours. The resulting solution was charged with 3.3 g of 13 wt% aqueous NaCl and heated to 50 ⁰C for 1 hour. After cooling to 20 ⁰C, 2.5 mL of isopropyl acetate was added. The rich organic phase was washed with 2 x 6.9 g of a 0.5 N NaOH solution containing 13 wt% NaCl followed by 3.3 g of 13 wt% aqueous NaCl. The mixture was then solvent exchanged into isopropyl acetate by vacuum distillation to a target volume of 10 mL. The resulting hazy solution was cooled to 20 ⁰C and filtered through a 0.45 μm filter. The clear solution was then solvent exchanged into ethanol by vacuum distillation with a target volume of 3 mL. 1.67 mL (2.02 mmol, 2.3 equiv) of 1.21 M HCl in ethanol was added. The mixture was then stirred at 25 ⁰C for 15 hours. The resulting slurry was filtered and the wet cake was washed with 2.5 mL of 2: 1 acetone:ethanol. The solids were dried in a vacuum oven at 50 ⁰C to give 0.550 g (0.68 mmol, 77 %) of the desired product.

RecrystalHzation of Example 24-23

A solution of Example 24-23 prepared above was prepared by dissolving 0.520 g of the above product in 3.65 mL methanol. The solution was then charged with 0.078 g of type 3 Cuno Zeta loose carbon and allowed to stir for 0.25 hours. The mixture was then filtered and washed with 6 ml of methanol. The product rich solution was concentrated down to 2.6 mL by vacuum distillation. 7.8 mL acetone was added and allowed to stir at 25 ⁰C for 15 h. The solids were filtered, washed with 2.5 mL 2: 1 acetone:ethanol and dried in a vacuum oven at 70 ⁰C to give 0.406 g (57.0%) of the desired product as white crystals: ¹H NMR (400 MHz, OMSO-d_6, 80 ⁰C): 8.02 (d, J=8.34 Hz, 4 H), 7.97 (s, 2 H), 7.86 (d, J=8.34 Hz, 4 H), 6.75 (s, 2 H), 5.27 (t, J=6.44 Hz, 2 H), 4.17 (t, J=6.95 Hz, 2 H), 3.97 – 4.11 (m, 2 H), 3.74 – 3.90 (m, 2 H), 3.57 (s, 6 H), 2.32 – 2.46 (m, 2 H), 2.09 – 2.31 (m, 6 H), 1.91 – 2.07 (m, 2 H), 0.88 (d, J=6.57 Hz, 6 H), 0.79 (d, J=6.32 Hz, 6 H); ¹³C NMR (75 MHz, DMSO- d₆): δ 170.9, 156.9, 149.3, 139.1, 131.7, 127.1, 126.5, 125.9, 115.0, 57.9, 52.8, 51.5, 47.2, 31.1, 28.9, 24.9, 19.6, 17.7; IR (neat, cm^“1): 3385, 2971, 2873, 2669, 1731, 1650. Anal. Calcd for C₄₀H₅₂N₈O₆Cl₂: C, 59.18; H, 6.45; N, 13.80; Cl, 8.73. Found C, 59.98; H, 6.80; N, 13.68; Cl, 8.77. mp 267 ⁰C (decomposed). Characteristic diffraction peak positions (degrees 2Θ ± 0.1) @ RT, based on a high quality pattern collected with a diffractometer (CuKa) with a spinning capillary with 2Θ calibrated with a NIST other suitable standard are as follows: 10.3, 12.4, 12.8, 13.3, 13.6, 15.5, 20.3, 21.2, 22.4, 22.7, 23.7

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Bioorganic & Medicinal Chemistry Letters (2015), 25(16), 3147-3150

http://www.sciencedirect.com/science/article/pii/S0960894X15005995

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1H NMR PREDICT

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13C NMR PREDICT

COSY PREDICT

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Daclatasvir

Names
IUPAC name Methyl [(2S)-1-{(2S)-2-[4-(4’-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-pyrrolidinyl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}-3-methyl-1-oxo-2-butanyl]carbamate
Other names BMS-790052
Identifiers
CAS Registry Number	1009119-64-5
ATC code	J05AX14
ChEBI	CHEBI:82977
ChEMBL	ChEMBL2023898 ChEMBL2303621
ChemSpider	24609522
InChI[show]
Jmol-3D images	Image
SMILES[show]
Properties
Chemical formula	C40H50N8O6
Molar mass	738.89 g·mol−1

 

References

 

• 1   Statement on a Nonproprietary Name Adopted by the USAN Council
• 2  Gao, Min; Nettles, Richard E.; Belema, Makonen; Snyder, Lawrence B.; Nguyen, Van N.; Fridell, Robert A.; Serrano-Wu, Michael H.; Langley, David R.; Sun, Jin-Hua; O’Boyle, Donald R., II; Lemm, Julie A.; Wang, Chunfu; Knipe, Jay O.; Chien, Caly; Colonno, Richard J.; Grasela, Dennis M.; Meanwell, Nicholas A.; Hamann, Lawrence G. (2010). “Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect”. Nature 465 (7294): 96–100. doi:10.1038/nature08960. PMID 20410884.
• 3  Bell, Thomas W. (2010). “Drugs for hepatitis C: unlocking a new mechanism of action”. ChemMedChem 5 (10): 1663–1665. doi:10.1002/cmdc.201000334. PMID 20821796.
• 4  Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life. Guedj, J et al. Proceedings of the National Academy of Sciences. February 19, 2013.
• 5  AASLD: Daclatasvir with Pegylated Interferon/Ribavirin Produces High Rates of HCV Suppression. Highleyman, L. HIVandHepatitis.com. 6 December 2011.
• 6Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1. Lok, A et al. New England Journal of Medicine. 366(3):216-224. January 19, 2012.
• 7“Bristol-Myers’ Daclatasvir, Asunaprevir Cured 77%: Study”. Bloomberg. Apr 19, 2012.
• 8AASLD: Daclatasvir plus Asunaprevir Rapidly Suppresses HCV in Prior Null Responders. Highleyman, L. HIVandHepatitis.com. 8 November 2011.
• 9High rate of response to BMS HCV drugs in harder-to-treat patients – but interferon-free prospects differ by sub-genotype. Alcorn, K. Aidsmap.com. 12 November 2012.
• 10AASLD 2012: Sofosbuvir + Daclatasvir Dual Regimen Cures Most Patients with HCV Genotypes 1, 2, or 3. Highleyman, L. HIVandHepatitis.com. 15 November 2012.
• 11Mark Sulkowski et al. (January 16, 2014). “Daclatasvir plus Sofosbuvir for Previously Treated or Untreated Chronic HCV Infection”. New England Journal of Medicine. doi:10.1056/NEJMoa1306218.
• 12“www.who.int” (PDF).

WO2004005264A2 *	7 Jul 2003	15 Jan 2004	Axxima Pharmaceuticals Ag	Imidazole compounds for the treatment of hepatitis c virus infections
WO2008021927A2 *	9 Aug 2007	21 Feb 2008	Squibb Bristol Myers Co	Hepatitis c virus inhibitors
WO2008021928A2 *	9 Aug 2007	21 Feb 2008	Squibb Bristol Myers Co	Hepatitis c virus inhibitors
WO2008021936A2 *	9 Aug 2007	21 Feb 2008	Squibb Bristol Myers Co	Hepatitis c virus inhibitors

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