4-[4-[2-(difluoromethyl)benzimidazol-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl]morpholine

ZSTK474; 475110-96-4; 4,4′-(6-(2-(Difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)dimorpholine; ZSTK-474; ZSTK 474; TCMDC-137004;

2-(2-Difluoromethylbenzimidazol-1-yl)-4,6-bis(morpholino)-1,3,5-triazine

2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine

Zenyaku Kogyo (Innovator)

phase2………Treatment of Solid Tumors Therapy

ZSTK474 is a cell permeable and reversible P13K inhibitor with an IC₅₀ at 6nm. It was identified as part of a screening library, selected for its ability to block tumor cell growth. ZSTK474 has shown strong antitumor activities against human cancer xenographs when administered orally to mice without a significant toxic effect.

Phosphatidylinositol 3-kinase (PI3K) has been implicated in a variety of diseases including cancer. A number of PI3K inhibitors have recently been developed for use in cancer therapy. ZSTK474 is a highly promising antitumor agent targeting PI3K. We previously reported that ZSTK474 showed potent inhibition against four class I PI3K isoforms but not against 140 protein kinases.

However, whether ZSTK474 inhibits DNA-dependent protein kinase (DNA-PK), which is structurally similar to PI3K, remains unknown. To investigate the inhibition of DNA-PK, we developed a new DNA-PK assay method using Kinase-Glo. The inhibition activity of ZSTK474 against DNA-PK was determined, and shown to be far weaker compared with that observed against PI3K. The inhibition selectivity of ZSTK474 for PI3K over DNA-PK was significantly higher than other PI3K inhibitors, namely NVP-BEZ235, PI-103 and LY294002.

Other Names: ZSTK-474

Chemical Formula:  C₁₉H₂₁F₂N₇O₂

CAS Number: 475110-96-4

Molecular Weight: 417.41

WO 2002088112

http://www.google.co.in/patents/EP1389617A1?cl=en

The condensation of 2,4-dichloro-6-(4-morpholinyl)-1,3,5-triazine

with 2-(difluoromethyl)-1H-benzimidazole  by means of K2CO3 in DMF gives

2-chloro-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazine ,

which is then condensed with morpholine by means of K2CO3 in DMF to afford the target trisubstituted triazine.

^aReagents and conditions: (i) K₂CO₃, DMF, room temp; (ii) morpholine, DMF or THF, room temp; (iii) NaH or K₂CO₃, DMF or DMSO, 120 °C.

• 2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine(compound 19)
  Melting point: 211-214°C
  NMR(CDCl₃) δ : 3.79(8H, t, J=4Hz), 3.88(8H, t, J=4Hz), 7.3-7.4(2H, m), 7.56(1H, t, J=53Hz), 7.88(1H, d, J=7Hz), 8.32(1H, d, J=7Hz)
  MS m/z: 417(M⁺

……………………

TRIAZINE, PYRIMIDINE AND PYRIDINE ANALOGS AND THEIR USE AS THERAPEUTIC AGENTS AND DIAGNOSTIC PROBES [US2011275762]2011-11-10

…………..

Zenyaku Kogyo

Otsuka

Bunkyo

β-Sitosterol

http://www.herbdb.co.kr/herb/dbsearch3/separation_view.asp?key=302

β-Sitosterol (β-谷甾醇); CAS: 83-46-5

(300 MHz, CDCl3) δ: 5.36 (1H, d, J = 5.2 Hz, H-6), 3.53 (1H, m, H-3),1.01 (3H, s, CH3-19), 0.94 (3H, d, J = 6.5 Hz, CH3-21), 0.92 (3H, d, J = 6.5 Hz,CH3-26), 0.83 (3H, t, J = 6.6 Hz, CH3-29), 0.69 (3H, s, CH3-18)

13c nmr

(75 MHz, CDCl3) δ: 37.2 (C-1), 32.1 (C-2), 72.0 (C-3), 42.5 (C-4), 141.0 (C-5), 121.9 (C-6), 32.1 (C-7), 31.9 (C-8), 50.4 (C-9), 36.7 (C-10), 21.3 (C-11), 40.0 (C-12), 42.5 (C-13), 57.0 (C-14), 24.5 (C-15), 28.4 (C-16), 56.3 (C-17), 12.2 (C-18), 19.2 (C-19), 36.3 (C-20), 19.0 (C-21), 34.2 (C-22), 26.4 (C-23),46.1 (C-24), 29.4 (C-25), 19.6 (C-26), 20.0 (C-27), 23.3 (C-28),12.0 (C-29)

Regulatory and Commercial Status

STATUS FOR MS:Phase III

HIGHEST STATUS ACHIEVED (FOR ANY CONDITION):

Marketing Authorization Application for the treatment of pancreatic cancer has been filed with the European Medicines Agency (16 October 2012)

Marketing Authorization Application for the conditional approval in the treatment of pancreatic cancer has been accepted by the European Medicines Agency (30 October 2012)

Masitinib is a tyrosine-kinase inhibitor used in the treatment of mast cell tumors in animals, specifically dogs.^[1][2] Since its introduction in November 2008 it has been distributed under the commercial name Masivet. It has been available in Europe since the second part of 2009. In the USA it is distributed under the name Kinavet and has been available for veterinaries since 2011.

Masitinib is being studied for several human conditions including cancers. It is used in Europe to fight orphan diseases.^[3]

Mechanism of action

Masitinib inhibits the receptor tyrosine kinase c-Kit which is displayed by various types of tumour.^[2] It also inhibits the platelet derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR).

……………………..

http://www.google.com/patents/US7423055

Compound Synthesis

General: All chemicals used were commercial reagent grade products. Dimethylformamide (DMF), methanol (MeOH) were of anhydrous commercial grade and were used without further purification. Dichloromethane and tetrahydrofuran (THF) were freshly distilled under a stream of argon before use. The progress of the reactions was monitored by thin layer chromatography using precoated silica gel 60F 254, Fluka TLC plates, which were visualized under UV light. Multiplicities in ¹H NMR spectra are indicated as singlet (s), broad singlet (br s), doublet (d), triplet (t), quadruplet (q), and multiplet (m) and the NMR spectrum were realized on a 300 MHz Bruker spectrometer.

3-Bromoacetyl-pyridine, HBr Salt

Dibromine (17.2 g, 108 mmol) was added dropwise to a cold (0° C.) solution of 3-acetyl-pyridine (12 g, 99 mmol) in acetic acid containing 33% of HBr (165 mL) under vigourous stirring. The vigorously stirred mixture was warmed to 40° C. for 2 h and then to 75° C. After 2 h at 75° C., the mixture was cooled and diluted with ether (400 mL) to precipitate the product, which was recovered by filtration and washed with ether and acetone to give white crystals (100%). This material may be recrystallised from methanol and ether.

IR (neat): 3108, 2047, 2982, 2559, 1709, 1603, 1221, 1035, 798 cm⁻¹—⁻¹H NMR (DMSO-d⁶) δ=5.09 (s, 2H, CH₂Br); 7.88 (m, 1H, pyridyl-H); 8.63 (m, 1H, pyridyl-H); 8.96 (m, 1H, pyridyl-H); 9.29 (m, 1H, pyridyl-H).

Methyl-[4-(1-N-methyl-piperazino)-methyl]-benzoate

To methyl-4-formyl benzoate (4.92 g, 30 mmol) and N-methyl-piperazine (3.6 mL, 32 mmol) in acetonitrile (100 mL) was added dropwise 2.5 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 1 h. After slow addition of sodium cyanoborohydride (2 g, 32 mmol), the solution was left stirring overnight at room temperature. Water (10 mL) was then added to the mixture, which was further acidified with 1N HCl to pH=6-7. The acetonitrile was removed under reduced pressure and the residual aqueous solution was extracted with diethyl ether (4×30 mL). These extracts were discarded. The aqueous phase was then basified (pH>12) by addition of 2.5N aqueous sodium hydroxyde solution. The crude product was extracted with ethyl acetate (4×30 mL). The combined organic layers were dried over MgSO₄ and concentrated under reduced pressure to afford a slightly yellow oil which became colorless after purification by Kugelrohr distillation (190° C.) in 68% yield.

IR(neat): 3322, 2944, 2802, 1721, 1612, 1457, 1281, 1122, 1012—¹H NMR(CDCl₃) δ=2.27 (s, 3H, NCH₃); 2.44 (m, 8H, 2×NCH₂CH₂N); 3.53 (s, 2H, ArCH₂N); 3.88 (s, 3H, OCH₃); 7.40 (d, 2H, J=8.3 Hz, 2×ArH); 7.91 (d, 2H, J=8.3 Hz, 2×ArH)—³C NMR (CDCl₃) δ=45.8 (NCH₃); 51.8 (OCH₃); 52.9 (2×CH₂N); 54.9 (2×CH₂N); 62.4 (ArCH₂N); 128.7 (2×ArC); 129.3 (2×ArC); 143.7 (ArC); 166.7 (ArCO₂CH₃)-MS CI (m/z) (%) 249 (M+1, 100%).

2-Methyl-5-tert-butoxycarbonylamino-aniline

A solution of di-tert-butyldicarbonate (70 g, 320 mmol) in methanol (200 mL) was added over 2 h to a cold (−10° C.) solution of 2,4-diaminotoluene (30 g, 245 mmol) and triethylamine (30 mL) in methanol (15 mL). The reaction was followed by thin layer chromatography (hexane/ethyl acetate, 3:1) and stopped after 4 h by adding 50 mL of water. The mixture was concentrated in vacuo and the residue was dissolved in 500 mL of ethyl acetate. This organic phase was washed with water (1×150 mL) and brine (2×150 mL), dried over MgSO₄, and concentrated under reduced pressure. The resulting light brown solid was washed with small amounts of diethyl ether to give off-white crystals of 2-methyl-5-tert-butoxycarbonylamino-aniline in 67% yield.

IR (neat): 3359; 3246; 2970; 1719; 1609; 1557; 1173; 1050 cm⁻¹—¹H NMR (CDCl₃): δ=1.50 (s, 9H, tBu); 2.10 (s, 3H, ArCH₃); 3.61 (br s, 2H, NH₂); 6.36 (br s, 1H, NH); 6.51 (dd, 1H, J=7.9 Hz, 2.3 Hz, ArH); 6.92 (d, 1H, J=7.9 Hz, ArH); 6.95 (s, 1H, ArH)—¹³C NMR (CDCl₃) δ=16.6 (ArCH₃); 28.3 (C(CH₃)₃); 80.0 (C(CH₃)₃); 105.2 (ArC); 108.6 (ArC); 116.9 (ArC); 130.4 (ArC—CH₃); 137.2 (ArC—NH); 145.0 (ArC—NH₂); 152.8 (COOtBu) MS ESI (m/z) (%): 223 (M+1), 167 (55, 100%).

N-(2-methyl-5-tert-butoxycarbonylamino)phenyl-thiourea

Benzoyl chloride (5.64 g, 80 mmol) was added dropwise to a well-stirred solution of ammonium thiocyanate (3.54 g, 88 mmol) in acetone (50 mL). The mixture was refluxed for 15 min, then, the hydrobromide salt of 2-methyl-5-tert-butoxycarbonylamino-aniline (8.4 g, 80 mmol) was added slowly portionswise. After 1 h, the reaction mixture was poured into ice-water (350 mL) and the bright yellow precipitate was isolated by filtration. This crude solid was then refluxed for 45 min in 70 mL of 2.5 N sodium hydroxide solution. The mixture was cooled down and basified with ammonium hydroxide. The precipitate of crude thiourea was recovered by filtration and dissolved in 150 mL of ethyl acetate. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane/ethyl acetate, 1:1) to afford 63% of N-(2-methyl-5-tert-butoxycarbonylamino)phenyl-thiourea as a white solid.

IR (neat): 3437, 3292, 3175, 2983, 1724, 1616, 1522, 1161, 1053 cm^{−1— 1}H NMR (DMSO-d₆) δ=1.46 (s, 9H, tBu); 2.10 (s, 3H, ArCH₃); 3.60 (br s, 2H, NH₂); 7.10 (d, 1H, J=8.29 Hz, ArH); 7.25 (d, 1H, J=2.23 Hz, ArH); 7.28 (d, 1H, J=2.63 Hz, ArH); 9.20 (s, 1H, ArNH); 9.31 (s, 1H, ArNH)—¹³C NMR (DMSO-d⁶) δ=25.1 (ArCH₃); 28.1 (C(CH₃)₃); 78.9 (C(CH₃)₃); 16.6 (ArC); 117.5 (ArC); 128.0 (ArC); 130.4 (ArC—CH₃); 136.5 (ArC—NH); 137.9 (ArC—NH); 152.7 (COOtBu); 181.4 (C═S)—MS CI(m/z): 282 (M+1, 100%); 248 (33); 226 (55); 182 (99); 148 (133); 93 (188).

2-(2-methyl-5-tert-butoxycarbonylamino)phenyl-4-(3-pyridyl)-thiazole

A mixture of 3-bromoacetyl-pyridine, HBr salt (0.81 g, 2.85 mmol), N-(2-methyl-5-tert-butoxycarbonylamino)phenyl-thiourea (0.8 g, 2.85 mmol) and KHCO₃ (˜0.4 g) in ethanol (40 mL) was heated at 75° C. for 20 h. The mixture was cooled, filtered (removal of KHCO₃) and evaporated under reduced pressure. The residue was dissolved in CHCl₃ (40 mL) and washed with saturated aqueous sodium hydrogen carbonate solution and with water. The organic layer was dried over Na₂SO₄ and concentrated. Colum chromatographic purification of the residue (hexane/ethyl acetate, 1:1) gave the desired thiazole in 70% yield as an orange solid

IR(neat): 3380, 2985, 2942, 1748, 1447, 1374, 1239, 1047, 938—¹H NMR (CDCl₃) δ=1.53 (s, 9H, tBu); 2.28 (s, 3H, ArCH₃); 6.65 (s, 1H, thiazole-H); 6.89 (s, 1H); 6.99 (dd, 1H, J=8.3 Hz, 2.3 Hz); 7.12 (d, 2H, J=8.3 Hz); 7.35 (dd, 1H, J=2.6 Hz, 4.9 Hz); 8.03 (s, 1H); 8.19 (dt, 1H, J=1.9 Hz, 7.9 Hz); 8.54 (br s, 1H, NH); 9.09 (s, 1H, NH)—¹³C NMR (CDCl₃) δ=18.02 (ArCH₃); 29.2 (C(CH₃)₃); 81.3 (C(CH₃)₃); 104.2 (thiazole-C); 111.6; 115.2; 123.9; 124.3; 131.4; 132.1; 134.4; 139.5; 148.2; 149.1; 149.3; 153.6; 167.3 (C═O)—MS Cl (m/z) (%): 383 (M+1, 100%); 339 (43); 327 (55); 309 (73); 283 (99); 71 (311).

2-(2-methyl-5-amino)phenyl-4-(3-pyridyl)-thiazole

2-(2-methyl-5-tert-butoxycarbonylamino)phenyl-4-(3-pyridyl)-thiazole (0.40 g, 1.2 mmol) was dissolved in 10 mL of 20% TFA/CH₂Cl₂. The solution was stirred at rool temperature for 2 h, then it was evaporated under reduced pressure. The residue was dissolved in ethyl acetate. The organic layer was washed with aqueous 1N sodium hydroxide solution, dried over MgSO₄, and concentrated to afford 2-(2-methyl-5-amino)phenyl-4-(3-pyridyl)-thiazole as a yellow-orange solid in 95% yield. This crude product was used directly in the next step.

A 2M solution of trimethyl aluminium in toluene (2.75 mL) was added dropwise to a cold (0° C.) solution of 2-(2-methyl-5-amino)phenyl-4-(3-pyridyl)-thiazole (0.42 g, 1.5 mmol) in anhydrous dichloromethane (10 mL) under argon atmosphere. The mixture was warmed to room temperature and stirred at room temperature for 30 min. A solution of methyl-4-(1-N-methyl-piperazino)-methyl benzoate (0.45 g, 1.8 mmol) in anhydrous dichloromethane (1 mL) and added slowly, and the resulting mixture was heated at reflux for 5 h. The mixture was cooled to 0° C. and quenched by dropwise addition of a 4N aqueous sodium hydroxide solution (3 mL). The mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×20 mL) and dried over anhydrous MgSO₄. (2-(2-methyl-5-amino)phenyl-4-(3-pyridyl)-thiazole) is obtained in 72% after purification by column chromatography (dichloromethane/methanol, 3:1)

IR (neat): 3318, 2926, 1647, 1610, 1535, 1492, 1282, 1207, 1160, 1011, 843—

¹H NMR (CDCl₃) δ=2.31 (br s, 6H, ArCH₃+NCH₃); 2.50 (br s, 8H, 2×NCH₂CH₂N); 3.56 (s, 2H, ArCH₂N); 6.89 (s, 1H, thiazoleH); 7.21-7.38 (m, 4H); 7.45 (m, 2H); 7.85 (d, 2H, J=8.3 Hz); 8.03 (s, 1H); 8.13 (s, 1H); 8.27 (s, 1H); 8.52 (br s, 1H); 9.09 (s, 1H, NH)—

¹³C NMR (CDCl₃) δ 17.8 (ArCH₃); 46.2 (NCH₃); 53.3 (NCH₂); 55.3 (NCH₂); 62.8 (ArCH₂N); 99.9 (thiazole-C); 112.5; 123.9; 125.2; 127.5; 129.6; 131.6; 133.7; 134.0; 137.6; 139.3; 142.9; 148.8; 149.1; 166.2 (C═O); 166.7 (thiazoleC-NH)—

MS CI (m/z) (%): 499 (M+H, 100%); 455 (43); 430 (68); 401 (97); 374 (124); 309 (189); 283 (215); 235 (263); 121 (377); 99 (399).

………………………

http://www.google.com/patents/WO2012136732A1?cl=en

In a preferred embodiment of the above-depicted treatment, the active ingredient masitinib is administered in the form of masitinib mesilate; which is the orally bioavailable mesylate salt of masitinib – CAS 1048007-93-7 (MsOH); C28H30N6OS.CH3SO3H; MW 594.76:

http://www.google.com/patents/WO2004014903A1?cl=en

003 : 4-(4-Methyl-piperazin-l-ylmethyl)-N-[3-(4-pyridin-3-yl-thiazol-2-ylamino)- phenyl] -benzamide

4-(4-Methyl-piperazin-l-yl)-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylmethyl)- phenyl] -benzamide

beige brown powder mp : 128-130°C

1H RMN (DMSO-d⁶) δ = 2.15 (s, 3H) ; 2.18 (s, 3H) ; 2.35-2.41 (m, 4H) ; 3.18-3.3.24 (m, 4H) ; 6.94 (d, J = 8.9 Hz, 2H) ; 7.09 (d, J = 8.4 Hz, IH) ; 7.28-7.38 (m, 3H) ; 7.81 (d, J = 8.9 Hz, 2H) ; 8.20-8.25 (m, IH) ; 8.40 (dd, J = 1.6 Hz, J = 4.7 , IH) ; 8.48 (d, J = 1.9 Hz, IH) ; 9.07 (d, J = 1.5 Hz, IH) ; 9.35 (s, IH) ; 9.84 (s, IH)

……………

http://www.google.com/patents/WO2008098949A2?cl=en

EXAMPLE 4 N- [4-Methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino)-phenyl] -benzamide derivatives

Method A In a reactor and under low nitrogen pressure, add 4-Methyl-N3-(4-pyridin-3-yl-thiazol- 2-yl)-benzene-l,3-diamine (95 g, 336.45 mmol), dichloromethane (2 L). To this suspension cooled to temperature of 5°C was added dropwise 2M/n-hexane solution of trimethylaluminium (588 mL). The reaction mixture was brought progressively to 15°C, and maintained for 2 h under stirring. 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid methyl ester (100 g, 402.71 mmol) in dichloromethane (200 mL) was added for 10 minutes. After 1 h stirring at room temperature, the reaction mixture was heated to reflux for 20 h and cooled to room temperature. This solution was transferred dropwise via a cannula to a reactor containing 2N NaOH (2.1 L) cooled to 5°C. After stirring for 3 h at room temperature, the precipitate was filtered through Celite. The solution was extracted with dichloromethane and the organic layer was washed with water and saturated sodium chloride solution, dried over MgSO₄ and concentrated under vacuum. The brown solid obtained was recrystallized from /-Pr₂O to give 130.7 g (78%) of a beige powder.

Method B Preparation of the acid chloride

To a mixture of 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid dihydrochloride (1.0 eq), dichloromethane (7 vol) and triethylamine (2.15 eq), thionyl chloride (1.2 eq) was added at 18-28°C . The reaction mixture was stirred at 28-32°C for 1 hour. Coupling of acid chloride with amino thiazole To a chilled (0-5⁰C) suspension of 4-Methyl-N3-(4-pyridin-3-yl-thiazol-2-yl)-benzene- 1,3-diamine (0.8 eq) and thiethylamine (2.2 eq) in dichloromethane (3 vol), the acid chloride solution (prepared above) was maintaining the temperature below 5°C. The reaction mixture was warmed to 25-30⁰C and stirred at the same temperature for 1O h. Methanol (2 vol) and water (5 vol) were added to the reaction mixture and stirred. After separating the layers, methanol (2 vol), dihloromethane (5 vol) and sodium hydroxide solution (aqueous, 10%, till pH was 9.5-10.0) were added to the aqueous layer and stirred for 10 minutes. The layers were separated. The organic layer was a washed with water and saturated sodium chloride solution. The organic layer was concentrated and ethanol (2 vol) was added and stirred. The mixture was concentrated. Ethanol was added to the residue and stirred. The product was filtered and dried at 50-55⁰C in a vaccum tray drier. Yield = 65-75%.

Method C

To a solution of 4-methyl-N3-(4-pyridin-3-yl-thiazol-2-yl)-benzene-l,3-diamine (1.0 eq) in DMF (20 vol) were added successively triethylamine (5 eq), 2-chloro-l- methylpyridinium iodide (2 eq) and 4-(4-methyl-piperazin-l-ylmethyl)-benzoic acid (2 eq). The reaction mixture was stirred for 7 h at room temperature. Then, the mixture was diluted in diethyl ether and washed with water and saturated aqueous NaHCO3, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using an elution of 100% EtOAc to give a yellow solid.

Yield = 51%.

¹H NMR (CDCl₃) : δ = 9.09 (IH, s, NH); 8.52 (IH, br s); 8.27 (IH, s); 8.13 (IH, s);

8.03 (IH, s); 7.85 (2H, d, J= 8.3Hz); 7.45 (2H, m); 7.21-7.38 (4H, m); 6.89 (IH, s);

3.56 (2H, s); 2.50 (8H, br s); 2.31 (6H, br s).

MS (CI) m/z = 499 (M+H)⁺.

An additional aspect of the present invention relates to a particular polymorph of the methanesulfonic acid salt of N-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]- benzamide of formula (IX).

(VI)

Hereinafter is described the polymorph form of (IX) which has the most advantageous properties concerning processability, storage and formulation. For example, this form remains, dry at 80% relative humidity and thermodynamically stable at temperatures below 200⁰C.

The polymorph of this form is characterized by an X-ray diffraction pattern illustrated in FIG.I, comprising characteristic peaks approximately 7.269, 9.120, 11.038, 13.704, 14.481, 15.483, 15.870, 16.718, 17.087, 17.473, 18.224, 19.248, 19.441, 19.940, 20.441, 21.469, 21.750, 22.111, 23.319, 23.763, 24.120, 24.681, 25.754, 26.777, 28.975, 29.609, 30.073 degrees θ, and is also characterized by differential scanning calorimetry (DSC) illustrated in FIG.II, which exhibit a single maximum value at approximately 237.49 ± 0.3 ⁰C. X-ray diffraction pattern is measured using a Bruker AXS (D8 advance). Differential scanning calorimetry (DSC) is measured using a Perking Elmer Precisely (Diamond DSC).

This polymorph form can be obtained by treatement of 4-(4-Methyl-piperazin-l- ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide with 1.0 to 1.2 equivalent of methanesulfonic acid, at a suitable temperature, preferably between 20-80⁰C.

The reaction is performed in a suitable solvent especially polar solvent such as methanol or ethanol, or ketone such as acetone, or ether such as diethylether or dioxane, or a mixture therof. This invention is explained in example given below which is provided by way of illustration only and therefore should not be construed to limit the scope of the invention. Preparation of the above-mentioned polymorph form of 4-(4-Methyl-piperazin-l- ylmethyl)-N- [4-methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino)-phenyl] -benzamide methanesulfonate .

4-(4-Methyl-piperazin- 1 -ylmethyl)-N- [4-methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino) phenyl] -benzamide (1.0 eq) was dissolved in ethanol (4.5 vol) at 65-70⁰C. Methanesulfonic acid (1.0 eq) was added slowly at the same temperature. The mixture was cooled to 25-30⁰C and maintained for 6 h. The product was filtered and dried in a vacuum tray drier at 55-60⁰C. Yield = 85-90%. Starting melting point Smp = 236°C.

NMR PREDICT

CAS NO. 1048007-93-7, methanesulfonic acid,4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-yl-1,3-thiazol-2-yl)amino]phenyl]benzamide H-NMR spectral analysis

CAS NO. 1048007-93-7, methanesulfonic acid,

4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-yl-1,3-thiazol-2-yl)amino]phenyl]benzamide C-NMR spectral analysisPREDICT

References

1. Hahn, K.A.; Oglivie, G.; Rusk, T.; Devauchelle, P.; Leblanc, A.; Legendre, A.; Powers, B.; Leventhal, P.S.; Kinet, J.-P.; Palmerini, F.; Dubreuil, P.; Moussy, A.; Hermine, O. (2008). “Masitinib is Safe and Effective for the Treatment of Canine Mast Cell Tumors”. Journal of Veterinary Internal Medicine 22 (6): 1301–1309. doi:10.1111/j.1939-1676.2008.0190.x. ISSN 0891-6640.
2. Information about Masivet at the European pharmacy agency website
3. Orphan designation for Masitinib at the European pharmacy agency website

WO2004014903A1	Jul 31, 2003	Feb 19, 2004	Ab Science	2-(3-aminoaryl)amino-4-aryl-thiazoles and their use as c-kit inhibitors
WO2008098949A2	Feb 13, 2008	Aug 21, 2008	Ab Science	Process for the synthesis of 2-aminothiazole compounds as kinase inhibitors
EP1525200B1	Jul 31, 2003	Oct 10, 2007	AB Science	2-(3-aminoaryl)amino-4-aryl-thiazoles and their use as c-kit inhibitors
US7423055	Aug 1, 2003	Sep 9, 2008	Ab Science	2-(3-Aminoaryl)amino-4-aryl-thiazoles for the treatment of diseases
US20080207572 *	Jul 13, 2006	Aug 28, 2008	Ab Science	Use of Dual C-Kit/Fgfr3 Inhibitors for Treating Multiple Myeloma

Systematic (IUPAC) name
4-[(4-Methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)-1,3-thiazol-2-yl]amino}phenyl)benzamide
Clinical data
Trade names	Masivet, Kinavet
AHFS/Drugs.com	International Drug Names
Identifiers
CAS Registry Number	790299-79-5
ATC code	L01XE22
PubChem	CID 10074640
ChemSpider	8250179
ChEMBL	CHEMBL1908391
Chemical data
Formula	C28H30N6OS
Molecular mass	498.64 g/mol

Patent	Submitted	Granted
2-(3-Aminoaryl)amino-4-aryl-thiazoles for the treatment of diseases [US7423055]	2004-06-10	2008-09-09
2-(3-aminoaryl)amino-4-aryl-thiazoles and their use as c-kit inhibitors [US2005239852]	2005-10-27
Use of C-Kit Inhibitors for Treating Fibrosis [US2007225293]	2007-09-27
Use of Mast Cells Inhibitors for Treating Patients Exposed to Chemical or Biological Weapons [US2007249628]	2007-10-25
Use of c-kit inhibitors for treating type II diabetes [US2007032521]	2007-02-08
Use of tyrosine kinase inhibitors for treating cerebral ischemia [US2007191267]	2007-08-16
Use of C-Kit Inhibitors for Treating Plasmodium Related Diseases [US2008004279]	2008-01-03
Tailored Treatment Suitable for Different Forms of Mastocytosis [US2008025916]	2008-01-31
2-(3-AMINOARYL) AMINO-4-ARYL-THIAZOLES AND THEIR USE AS C-KIT INHIBITORS [US2008255141]	2008-10-16
Use Of C-Kit Inhibitors For Treating Inflammatory Muscle Disorders Including Myositis And Muscular Dystrophy [US2008146585]	2008-06-19

Patent	Submitted	Granted
Aminothiazole compounds as kinase inhibitors and methods of using the same [US8940894]	2013-05-10	2015-01-27
Aminothiazole compounds as kinase inhibitors and methods of using the same [US8492545]	2012-03-08	2013-07-23

Patent	Submitted	Granted
Use of Dual C-Kit/Fgfr3 Inhibitors for Treating Multiple Myeloma [US2008207572]	2008-08-28
PROCESS FOR THE SYNTHESIS OF 2-AMINOTHIAZOLE COMPOUNDS AS KINASE INHIBITORS [US8153792]	2010-05-13	2012-04-10
COMBINATION TREATMENT OF SOLID CANCERS WITH ANTIMETABOLITES AND TYROSINE KINASE INHIBITORS [US8227470]	2010-04-15	2012-07-24
Anti-IGF antibodies [US8580254]	2008-06-19	2013-11-12
COMBINATIONS FOR THE TREATMENT OF B-CELL PROLIFERATIVE DISORDERS [US2009047243]	2008-07-17	2009-02-19
TREATMENTS OF B-CELL PROLIFERATIVE DISORDERS [US2009053168]	2008-07-17	2009-02-26
Anti-IGF antibodies [US8318159]	2009-12-11	2012-11-27
SURFACE TOPOGRAPHIES FOR NON-TOXIC BIOADHESION CONTROL [US2010226943]	2009-08-31	2010-09-09
EGFR/NEDD9/TGF-BETA INTERACTOME AND METHODS OF USE THEREOF FOR THE IDENTIFICATION OF AGENTS HAVING EFFICACY IN THE TREATMENT OF HYPERPROLIFERATIVE DISORDERS [US2010239656]	2010-05-10	2010-09-23
ANTI CD37 ANTIBODIES [US2010189722]	2008-08-08	2010-07-29

1. ChemIDplus Advanced

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

Note: Compound name must be entered under “Substance Identification” and then “Names and Synonyms” selected to view synonyms.

2. “Human Medicines” page

AB Science website

Accessed on 22 Feb 2012 from http://www.ab-science.com/.

3. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT.

Dubreuil P, Letard S, Ciufolini M, Gros L, Humbert M, Castéran N, Borge L, Hajem B, Lermet A, Sippl W, et al.

PLoS One. 2009; 4(9):e7258. Epub 2009 Sep 30. PMID: 19789626. Abstract

4. Masitinib mesylate application for conditional approval

Food and Drug Administration, 15 Dec 2010

Accessed on 22 Feb 2012 from http://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/UCM245243.pdf.

5. Scientific discussion for the approval of Masivet

European Medicines Agency, Nov 2008

Accessed on 22 Feb 2012 from http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/veterinary/000128/WC500064714.pdf.

6. Masitinib as an adjunct therapy for mild-to-moderate Alzheimer’s disease: a randomised, placebo-controlled phase 2 trial.

Piette F, Belmin J, Vincent H, Schmidt N, Pariel S, Verny M, Marquis C, Mely J, Hugonot-Diener L, Kinet J-P, et al.

Alzheimers Res Ther. 2011; 3(2):16. Epub 2011 Apr 19. PMID: 21504563. Abstract

7. Masitinib in the treatment of active rheumatoid arthritis: results of a multicentre, open-label, dose-ranging, phase 2a study.

Tebib J, Mariette X, Bourgeois P, Flipo R-M, Gaudin P, Le Loët X, Gineste P, Guy L, Mansfield CD, Moussy A, et al.

Arthritis Res Ther. 2009; 11(3):R95. Epub 2009 Jun 23. PMID: 19549290. Abstract

8. AB Science announces recruitment of first patient in phase 3 study of masitinib in progressive multiple sclerosis

Businesswire.com, 6 Sep 2011

Accessed on 22 Feb 2012 from http://www.businesswire.com/news/home/20110906006398/en/AB-Science-announces-recruitment-patient-phase-3.

9. Masitinib in Patients with Progressive or Relapse-Free Secondary Multiple Sclerosis

ClinicalTrials.gov, 13 Sep 2011

Accessed on 22 Feb 2012 from http://clinicaltrials.gov/ct2/show/study/NCT01433497.

10. Masitinib in Patients with Primary Progressive Multiple Sclerosis (PPMS) or Relapse-Free Secondary Multiple Sclerosis (SPMS)

ClinicalTrials.gov, 10 Oct 2011

Accessed on 22 Feb 2012 from http://clinicaltrials.gov/ct2/show/NCT01450488.

11. Phase II study of oral masitinib mesilate in imatinib-naïve patients with locally advanced or metastatic gastro-intestinal stromal tumour (GIST).

Le Cesne A, Blay J-Y, Bui B N, Bouché O, Adenis A, Domont J, Cioffi A, Ray-Coquard I, Lassau N, Bonvalot S, et al.

Eur J Cancer. 2010 May; 46(8):1344-51. Epub 2010 Mar 06. PMID: 20211560. Abstract

12. “Veterinary Medicines” page

AB Science website

Accessed on 22 Feb 2012 from http://www.ab-science.com/.

Editors’ Pick

13. Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study.

Vermersch P, Benrabah R, Schmidt N, Zéphir H, Clavelou P, Vongsouthi C, Dubreuil P, Moussy A, Hermine O

BMC Neurol. 2012 Jun 12; 12(1):36. PMID: 22691628. Abstract

14. AB Science confirms the filing for the Marketing Authorization Application to the European Medicines Agency of masitinib in the treatment of pancreatic cancer

AB Science, 16 Oct 2012

Accessed on 1 Nov 2012 from http://www.ab-science.com/file_bdd/1350403049_absciencepancreasemafilingvdefven.pdf.

15. European Medicines Agency accepts Marketing Authorization Application for conditional approval of masitinib in the treatment of pancreatic cancer

AB Science, 30 Oct 2012

Accessed on 1 Nov 2012 from http://www.ab-science.com/file_bdd/1351622639_abscienceresultph3pancreasvdefuk.pdf.

16. Launch of a phase 3 clinical trial in the treatment of Alzheimer’s disease with masitinib

AB Science, 20 May 2013

Accessed on 21 May 2013 from http://www.ab-science.com/file_bdd/1369064860_absciencepressreleasephase3alzenfinal.pdf.

17. Masitinib is being investigated in the treatment of amyotrophic lateral sclerosis (ALS)

The Wall Street Journal, 4 Nov 2013

Accessed on 6 Nov 2013 from http://online.wsj.com/article/PR-CO-20131104-908831.html?dsk=y.

18. BRIEF-AB Science says DSMB recommends continuation of phase 3 masitinib study

Reuters, 6 Oct 2014

Accessed on 14 Oct 2014 from http://www.reuters.com/article/2014/10/06/absciencesa-brief-idUSFWN0S100120141006.

19. Neuroprotective effect of masitinib in rats with postischemic stroke.

Kocic I, Kowianski P, Rusiecka I, Lietzau G, Mansfield C, Moussy A, Hermine O, Dubreuil P

Naunyn Schmiedebergs Arch Pharmacol. 2014 Oct 26. Epub 2014 Oct 26. PMID: 25344204.Abstract

AB SCIENCE HEADQUARTER
3, Avenue George V
75008 PARIS – FRANCE
Tel. : +33 (0)1 47 20 00 14
Fax. : +33 (0)1 47 20 24 11

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.

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.

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.

TAJIKISTAN

Tajikistan – Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Tajikistan

The territory that now constitutes Tajikistan was previously home to several ancient cultures, including the city of Sarazm of the Neolithic and the Bronze Age, …

‎Dushanbe – ‎Tajik language – ‎Emomali Rahmon – ‎Civil war in Tajikistan

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vx 787

Janssen Pharmaceuticals, under license from Vertex Pharmaceuticals, is developing VX-787 and its back-up compound VX-353, an influenza A viral replication inhibitor, for treating influenza A virus infection, including pandemic and avian influenza strains. In May 2015, VX-787 was in phase II clinical trial.

Useful for treating influenza virus infection. For concurrent filing see WO2015073476 (claiming the polymorphic forms of VX-787) and WO2015073491 (claiming the composition comprising the hydrochloride salt of VX-787).

Polymorphic forms of hydrochloride (A,F and D) and tosylate salts (form A) of VX-787 are claimed. , useful for treating influenza virus infection. For concurrent filing see WO2015073481 (claiming the processes for the synthesis of VX-787 ) and WO2015073491 (claiming the composition comprising the hydrochloride salt of VX-787).

WO2010148197

http://www.google.com/patents/WO2010148197A1?cl=en

(1070) (2S,3S)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridm-3-yl)-5- fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

(1070) (2S,3S)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridm-3-yl)-5- fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Compound 1070 was made in a similar fashion as described above for compounds 946 and 947.

………………….

WO 2013019828

http://www.google.com/patents/WO2013019828A1?cl=en

WO 2012083122

http://www.google.co.in/patents/WO2012083122A1?cl=en

Synthetic Scheme 1

(a) CHC1₃; (b) NaOMe, MeOH; (c) DPPA, Et₃N, BnOH; (d) H₂, Pd/C;

Synthetic Scheme 2

(a) Et₃N, CH₃CN; (b) cone. H₂S0₄; (c) 9M H₂S0₄; (d) Ag₂C0₃, HOAc, DMSO, 100 °C; (e) X- phos, Pd₂(dba)₃, K3PO4, 2-methyl THF, H₂0, 120 °C (f) LiOH, THF, MeOH, 70 °C

Synthetic Scheme 3

(a) Et₃N, THF; (b) chiral SFC separation; (c) 5-fluoro- l -(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-

………………………

See new patents

WO-2015073481

WO-2015073476

WO2015073491

……………………………..

Discovery of a Novel, First-in-Class, Orally Bioavailable Azaindole Inhibitor (VX-787) of Influenza PB2

J. Med. Chem., 2014, 57 (15), pp 6668–6678

DOI: 10.1021/jm5007275

http://pubs.acs.org/doi/abs/10.1021/jm5007275

Vertex Pharmaceuticals Inc

Vertex Licenses VX-787 to Janssen Pharmaceuticals for the Treatment of Influenza

Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced that it has entered into a licensing agreement with Janssen Pharmaceuticals, Inc. for the worldwide development and commercialization of VX-787, a novel medicine discovered by Vertex for the treatment of influenza. As part of the agreement, Vertex will receive an up-front payment of $30 million from Janssen and has the potential to receive additional development and commercial milestone payments as well as royalties on future product sales. Vertex completed a Phase 2a study of VX-787 in 2013 that showed statistically significant improvements in viral and clinical measurements of influenza infection. VX-787 is designed to directly inhibit replication of the influenza virus.

“With a deep history in developing new medicines for viral infections and diseases, Janssen is well-positioned to advance the global development of VX-787 for the treatment of influenza,” said Jeffrey Leiden, M.D., Ph.D., Chairman, President and Chief Executive Officer of Vertex. “This collaboration provides important support for the continued development of VX-787 in influenza and contributes to our financial strength to enable continued investment in our key development programs for cystic fibrosis and in research aimed at discovering new medicines.”

About the Collaboration

Under the terms of the collaboration, Janssen will have full global development and commercialization rights to VX-787. Vertex will receive a $30 million up-front payment from Janssen and could receive additional development and commercial milestone payments as well as royalties on future product sales. The collaboration, and the related $30 million up-front payment, is subject to the expiration of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act.

About VX-787

VX-787 is an investigational medicine that is designed to directly inhibit replication of influenza A, including recent H1 (pandemic) and H5 (avian) influenza strains, based on in-vitro data. VX-787’s mechanism represents a new class of potential medicines for the treatment of influenza, distinct from neuraminidase inhibitors, the current standard of care for the treatment of influenza. VX-787 is intended to provide a rapid onset of action and an expanded treatment window.

In a Phase 2a influenza challenge study, statistically significant improvements in viral and clinical measurements of influenza infection were observed after treatment with VX-787. The study met its primary endpoint and showed a statistically significant decrease in the amount of virus in nasal secretions (viral shedding) over the seven-day study period. In addition, at the highest dosing regimen evaluated in the study, there was a statistically significant reduction in the severity and duration of influenza-like symptoms. In this study, VX-787 was generally well-tolerated, with no adverse events leading to discontinuation. Those who took part in the study volunteered to be experimentally exposed to an attenuated form of live H3N2 influenza A virus. H3N2 is a common type of influenza virus and was the most common type observed in the 2012/2013 influenza season in the United States.

VX-787 was discovered by Vertex scientists.

About Influenza

Often called “the flu,” seasonal influenza is caused by influenza viruses, which infect the respiratory tract.¹ The flu can result in seasonal epidemics² and can produce severe disease and high mortality in certain populations, such as the elderly.³ Each year, on average 5 to 20 percent of the U.S. population gets the flu⁴ resulting in more than 200,000 flu-related hospitalizations and 36,000 deaths.⁵ The overall national economic burden of influenza-attributable illness for adults is $83.3 billion.⁵ Direct medical costs for influenza in adults totaled $8.7 billion including $4.5 billion for adult hospitalizations resulting from influenza-attributable illness.⁵ The treatment of the flu consists of antiviral medications that have been shown in clinical studies to shorten the disease and reduce the severity of symptoms if taken within two days of infection.⁶ There is a significant need for new medicines targeting flu that provide a wider treatment window, greater efficacy and faster onset of action.

About Vertex

Vertex is a global biotechnology company that aims to discover, develop and commercialize innovative medicines so people with serious diseases can lead better lives. In addition to our clinical development programs focused on cystic fibrosis, Vertex has more than a dozen ongoing research programs aimed at other serious and life-threatening diseases.

Founded in 1989 in Cambridge, Mass., Vertex today has research and development sites and commercial offices in the United States, Europe, Canada and Australia. For four years in a row, Science magazine has named Vertex one of its Top Employers in the life sciences. For additional information and the latest updates from the company, please visit www.vrtx.com.

Vertex’s press releases are available at www.vrtx.com.

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Vertex Pharmaceuticals’ Boston Campus, United States of America

Lynette Hopkinson VP Commercial Regulatory Affairs, Global Regulatory Affairs Vertex Pharmaceuticals Incorporated, United States

swati Patel, a lead analyst, shared a toast with Mir Hussain, a systems engineer, at Vertex Pharmaceuticals during the Friday beer hour, which features beer and chips for employees.

On Fridays around 5 o’clock, after a hard week of work, Frank Holland likes to unwind with a beer. And he doesn’t have to leave work to get one.

Holland is a research scientist at Vertex Pharmaceuticals, which every Friday rings in “beer hour,” offering free adult beverages and munchies to its 1,300 Boston employees.

For Holland, the weekly ritual is a chance to escape the bubble of his chemistry lab and bump into colleagues from other departments — as well as Vertex’s top executives, who regularly attend. For those who prefer grapes to hops, there is also wine.

“Some of the other companies I worked at, you really had to go out of your way to meet people,” said Holland, 32. “At Vertex all you have to do is show up in the cafeteria on a Friday afternoon.”

Sure, free beer is common at hip tech offices; some even have their own bars. But Vertex, best known for its treatment for cystic fibrosis, was doing this way before it was cool. The beer-hour tradition goes back to the company’s founding days, in 1989. Back then, it was just two dozen people in a small office in Cambridge. Someone went to a corner store, bought a case of beer and some chips, and beer hour was born.

Virginia Carden Carnahan
Vice President, New Product Planning and Strategy, Vertex Pharmaceuticals

A scientist works in the lab at Boston-based Vertex Pharmaceuticals.

Vertex Pharmaceuticals Headquarters Lobby

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India’s Strides to buy Aspen’s Australian generic pharmaceutical business
India-based Strides Arcolab has signed an agreement with subsidiaries of South African drugmaker Aspen Pharmacare Holdings to acquire its generic pharmaceutical business in Australia and certain branded pharmaceutical assets for around A$380m ($300m).

see

http://www.pharmaceutical-technology.com/news/newsindias-strides-buy-aspens-australian-generic-pharmaceutical-business-4583399?WT.mc_id=DN_News

  About Strides

Chandos Street, St Leonards

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Pirarubicin Hydrochloride  

(7S,9S)-7-((2R,4S,5S,6S)-4-amino-6-methyl-5-((R)-tetrahydro-2H-pyran-2-yloxy)-tetrahydro-2H-pyran-2-yloxy)-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione HCl

(CAS 95343-20-7)

THP Hydrochloride

(7S,9S)-7-((2R,4S,5S,6S)-4-amino-6-methyl-5-((R)-tetrahydro-2H-pyran-2-yloxy)-tetrahydro-2H-pyran-2-yloxy)-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione HCl

_{MF C32}H₃₈ClNO₁₂

MW 664.1

BASE 72496-41-4

Pirarubicin
or Pinorubicin
or Therarubicin
or (8S,10S)-10-(((2R,4S,5S,6S)-4-Amino-6-methyl-5-(((R)-tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione
or Pirarubicin

Pirarubicin Hcl is an analogue of the anthracycline anti-neoplastic doxorubicin, which is an inhibitor of Topo II.
Target: Topoisomerase
Pirarubicin is an anthracycline drug. An analogue of the anthracycline antineoplastic antibiotic doxorubicin. Pirarubicin intercalates into DNA and interacts with topoisomerase II, thereby inhibiting DNA replication and repair and RNA and protein synthesis. This agent is less cardiotoxic than doxorubicin and exhibits activity against some doxorubicin-resistant cell lines.

Pirarubicin (THP-adriamycin or THP-doxorubicin) was found during a search of new anthracycline antibiotics among 4′-O-substituted compounds having less toxicities than other anthracycline anticancer drugs in 1979 by Umezawa et al. In its preclinical studies, this compound possessed almost similar antitumor efficacies to doxorubicin, but was effective against doxorubicin-resistant P388 and other murine tumor cell lines. This compound was rapidly incorporated into tumor cells, inhibiting DNA polymerase alpha and subsequently DNA synthesis.

Inhibition of RNA synthesis was also noted. In the clinical studies, clinical responses were established against head and neck cancer, breast cancer, urogenital cancers, ovarian cancer, uterine cancer, acute leukemia, and malignant lymphoma, showing a wide antitumor spectrum clinically. Among the side effects, cardiac toxicity, alopecia and disturbance of the digestive organs were mild. From these results, THP-adriamycin seems to be a useful clinical drug for human solid tumors.

Pirarubicin (INN) is an anthracycline drug. An analogue of the anthracycline antineoplastic antibiotic doxorubicin. Pirarubicin intercalates into DNA and interacts with topoisomerase II, thereby inhibiting DNA replication and repair and RNA and protein synthesis. This agent is less cardiotoxic than doxorubicin and exhibits activity against some doxorubicin-resistant cell lines

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EP 0014853

https://www.google.com/patents/EP0014853B1?cl=en

Pirarubicin

Systematic (IUPAC) name
(3S)-3-glycoloyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxy-4-O-[(2R)-tetrahydro-2H-pyran-2-yl]-α-L–lyxo-hexopyranoside
Clinical data
AHFS/Drugs.com	International Drug Names
Legal status	℞ (Prescription only)
Identifiers
CAS Registry Number	72496-41-4
ATC code	L01DB08
PubChem	CID 3033521
ChemSpider	2298189
UNII	D58G680W0G
KEGG	D01885
ChEMBL	CHEMBL1398373
Synonyms	(9S)-7-[(2R,4S,5S,6S)-4-amino-6-methyl-5-[(2R)-oxan-2-yl]oxyoxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione
Chemical data
Formula	C32H37NO12
Molecular mass	627.63 g/mol

TAKE A TOUR

Bijapur, Karnataka, INDIA

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GOLCONDA

Badami Cave Temple, near Bijapur

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(1S)-(1)-beta-Pinene, (1S)-(-)-beta-Pinene

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13C NMR

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APT

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DEPT

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COSY

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HETCOR

IR

MASS

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RAMAN

(1S)-(1)-beta-Pinene CAS No. 18172-67-3 Chemical Name: (1S)-(1)-beta-Pinene Synonyms: β-Pinen;FEMA 2903;PINENE BETA;(1S)-(-)-B-PINENE;LAEVO-BETA-PINENE;(1s)-(-)-á-pinene;ALPHA,BETA-PINENE;(1S)-(-)-SS-PINENE;PINENE, (1S)-(-)-B-;(1s)-(1)-beta-pinene CBNumber: CB8270232 Molecular Formula: C10H16 Formula Weight: 136.23 MOL File: 18172-67-3.mol (1S)-(1)-beta-Pinene Property mp : −61 °C(lit.) bp : 165-167 °C(lit.) alpha : -18.5 º (c=neat 25 ºC) density : 0.866 g/mL at 25 °C vapor density : 4.7 (vs air) vapor pressure : ~2 mm Hg ( 20 °C) FEMA : 2903 refractive index : n20/D 1.478 Fp : 91 °F storage temp. : 2-8°C Water Solubility : insoluble Merck : 14,7446 BRN : 2038282 CAS DataBase Reference: 18172-67-3(CAS DataBase Reference) NIST Chemistry Reference: Bicyclo[3.1.1]heptane, 6,6-dimethyl-2-methylene-, (1S)-(18172-67-3) EPA Substance Registry System: Bicyclo[3.1.1]heptane, 6,6-dimethyl-2-methylene-, (1S,5S)-(18172-67-3) Safety Hazard Codes : Xn,N,Xi Risk Statements : 10-20/21/22-36/37/38-43-51-65-51/53 Safety Statements : 16-26-36/37-46-61-62 RIDADR : UN 2319 3/PG 3 WGK Germany : 3 RTECS : DT5077000 HazardClass : 3 PackingGroup : III HS Code : 29021910

take a tour

Amalner,  Jalgaon, Maharashtra, India

Amalner – Wikipedia, the free encyclopedia

Amalner, India is a city and a municipal council in Jalgaon district in the state of Maharashtra, India, situated on the bank of the Bori River. Amalner is the …

10000 devout Hindus were present for the Hindu Dharmajagruti Sabha at Amalner, Maharashtra

end of amalner…………

Daulatabad Fort Market

Daulatabad, Maharashtra – Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Daulatabad,_Maharashtra

Daulatabad also known as Devagiri is a town which includes the Devagiri-Daulatabad fort It carries the distinction of remaining undefeated in battle.

‎Fort of Daulatabad – ‎The City – ‎Monuments – ‎Transport

 

 

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BMS-564929; BMS564929; 627530-84-1; 2-Chloro-4-[(7r,7as)-7-Hydroxy-1,3-Dioxotetrahydro-1h-Pyrrolo[1,2-C]imidazol-2(3h)-Yl]-3-Methylbenzonitrile; hydantoin,

CAS 627530-84-1, Squibb Bristol Myers Co

4-[(7R,7aS)-7-Hydroxy-1,3-dioxoperhydropyrrolo[1,2-c]imidazol-2-yl]-2-chloro-3-methylbenzonitrile

7-K,7aS)-2-Chloro-4-(7-hydroxy-l,3-dioxotetrahydropyrrolo[l,2- c]imidazol-2-yl)-3-methylbenzonitrile

4-[(7R,7aS)-7-hydroxy-1,3-dioxo-5,6,7,7a-tetrahydropyrrolo[1,2-c]imidazol-2-yl]-2-chloro-3-methylbenzonitrile

BMS-564929 is a highly potent, orally active and nonsteroidal tissue selective modulator of androgen receptor (AR) with Ki value of 2.11 nM.

BMS-564929 is a selective androgen receptor (AR) modulator with Ki value of 2.11 ± 0.16 nM [1].
The AR is a type of nuclear receptor that is activated by the androgenic hormones, testosterone, or dihydrotestosterone. The important function is regulating gene expression.
BMS-564929 is a muscle-tissue specific agonist for AR with a bicyclic hydantoin structure [2]. BMS-564929 is about 400-fold selective for AR vs. PR and more than 1000-fold selective for AR vs. GR, MR and ERα and β. In the C2C12 myoblast cell line, BMS-564929 shows a potency of 0.44 ± 0.03 nM compared with 2.81 ± 0.48 nM measured for testosterone
In castrated male rats, BMS-564929 is substantially more potent than testosterone (T) in promoting the growth of the levator ani muscle, and is highly selective for muscle vs. Prostate. Because of its potent oral activity and tissue selectivity, BMS-564929 is expected to yield beneficial clinical effects in muscle and other tissues with a more favorable safety way

BMS-564,929 is an investigational selective androgen receptor modulator, which is being developed by Bristol-Myers Squibb for treatment of the symptoms of age-related decline in androgen levels in men (“andropause“). These symptoms may includedepression, loss of muscle mass and strength, reduction in libido and osteoporosis. Treatment with exogenous testosterone is effective in counteracting these symptoms but is associated with a range of side effects, the most serious of which is enlargement of the prostate gland, which can lead to benign prostatic hypertrophy and even prostate cancer. This means there is a clinical need for selective androgen receptor modulators, which produce anabolic effects in some tissues such as muscle and bone, but without stimulating androgen receptors in the prostate.^[1]

BMS-564,929 is one such compound currently in early human clinical trials, which is an orally active, potent and selective agonist for androgen receptors (Ki 2.1nM, 20x functional selectivity for muscle tissue over prostate) and in studies on castrated rats it was shown to counteract decrease in muscle mass over time, and at higher doses even increased muscle mass, without significantly affecting prostate tissue.^[2] It does however vastly reduce luteinizing hormone levels, it being an astonishing 33x more suppressive compound than testosterone,^[3] which may be a problem in human clinical use.^[4]

Selective androgen receptor modulators may also be used by athletes to assist in training and increase physical stamina and fitness, potentially producing effects similar to anabolic steroids but with significantly fewer side effects. For this reason, SARMs have already been banned by the World Anti-Doping Agency since January 2008 despite no drugs from this class yet being in clinical use, and blood tests for all known SARMs are currently being developed.^[5][6]

WO 2003096980

http://www.google.com/patents/WO2003096980A2?cl=en

Example 23

(7-K,7aS)-2-Chloro-4-(7-hydroxy-l,3-dioxotetrahydropyrrolo[l,2- c]imidazol-2-yl)-3-methylbenzonitrile

23 A. 3-Chloro-2-methylphenyIacetamide

To a solution of 3-chloro-2-methylaniline (3.00 g, 21.2 mmol) in 25 mL of EtOH at rt was added acetic anhydride (2.40 mL, 25.4 mmol), and the solution was stirred at rt for 2 h. The mixture was concentrated under reduced pressure to give 3.89 g (100%) of the desired acetamide. 1H NMR (DMSO- ) δ 2.05 (s, 3H), 2.20 (s, 3H), 7.16 (t, J = 1.1, 8.3, 1H), 7.25 (d, J = 8.3, 1H), 7.31 (d, J = 8.3, 1H), 9.55 (s, 1H); ¹³C NMR (DMSO- ) δ 15.1, 23.1, 124.4, 125.8, 126.7, 130.3, 133.7, 138.0, 168.3; HPLC a) column: Phenominex ODS C18 4.6 x 50 mm, 4 min gradient, 10% MeOH/90% H₂O/0.1% TFA to 90% MeOH/10% H₂O/0.1% TFA; 1 min hold, 4 mL/min UV detection at 220 nm, 2.32 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS CI 8 4.6 x 50 mm, 4 min gradient, 10% MeOH/90% H₂O/0.1% TFA to 90% MeOH/10% H₂O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 2.20 min retention time (99%); MS (ES) m/z 184 [M+H]⁺.

no 23B. 4-Bromo-3-chloro-2-methylphenylacetamide

To a suspension of acetamide 23A (2.00 g, 10.9 mmol) in 15 mL of glacial AcOH cooled to approximately 15 °C was added bromine (1.67 mL, 32.7 mmol) over 20 min. The ice bath was removed and the solution was stirred for

2 h, poured into ice water with stirring, and the solid was then filtered and dried to give 2.75 g (96%) of the desired bromide. 1H NMR (DMSO-_i₆) δ 2.05 (s,

3H), 2.28 (s, 3H), 7.29 (d, J = 8.3, 1H), 7.56 (d, J = 8.8, 1H), 9.60 (s, 1H); ¹³C NMR (DMSO–i₆) δ 16.7, 23.1, 118.1, 125.5, 130.4, 132.7, 133.4, 137.1, 168.4;

HPLC a) column: Phenominex ODS C18 4.6 x 50 mm, 4 min gradient, 10%

MeOH/90% H₂O/0.1% TFA to 90% MeOH/10% H₂O/0.1 % TFA, 1 min hold,

4 mL/min, UV detection at 220 nm, 2.95 min retention time; HPLC b) column:

Shimadzu Shim-Pack VP-ODS C18 4.6 x 50 mm, 4 min gradient, 10% MeOH/90% H₂O/0.1% TFA to 90% MeOH/10% H₂O/0.1% TFA, 1 min hold,

4 mL/min, UV detection at 220 nm, 2.87 min retention time (98%); MS (ES) m/z 263 [M+H]⁺.

23C. 3-Chloro-4-cyano-2-methylphenylacetamide

A suspension of bromide 23B (2.70 g, 10.3 mmol) and copper cyanide (0.92 g,

10.3 mmol) in DMF (30 mL) was heated to 150 °C for 4 h. The suspension was cooled, poured into water with stirring, and the solid was filtered and dried to give 1.44 g (67%) of the desired nitrile. 1H NMR (DMSO-d₆) δ 2.12 (s, 3H),

i n 2.29 (s, 3H), 7.72 (d, J = 8.8, 1H), 7.75 (d, J = 8.2, 1H), 9.73 (s, 1H); ¹³C NMR (DMSO- ) δ 15.3, 23.5, 107.7, 116.5, 123.0, 130.1, 131.5, 135.7, 142.3, 168.8; HPLC a) column: Phenominex ODS C18 4.6 x 50 mm, 4 min gradient, 10% MeOH/90% H₂O/0.1% TFA to 90% MeOH/10% H₂O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.23 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6 x 50 mm, 4 min gradient, 10% MeOH/90% H₂O/0.1% TFA to 90% MeOH/10% H₂O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.13 min retention time (95%); MS (ES) m/z 209 [M+H]⁺.

23D. 3-Chloro-4-cyano-2-methylphenylaniline

A solution of cyanoacetamide 23C (9.90 g, 47.4 mmol) in 100 mL of concentrated HCl EtOH (1 :1) was refluxed 30 min. The solution was then concentrated and dried under reduced pressure to give 9.41 g (98%) of the desired aniline as the hydrochloride salt. The free base of the aniline was obtained by suspending the salt in EtOAc and washing with saturated aqueous NaHC0₃ solution. The organic layer was then dried (MgS0₄), filtered and concentrated under reduced pressure. Η NMR (OMSO-d_β) δ 2.12 (s, 3H), 6.30 (s, 2H), 6.61 (d, J = 8.23, 1H), 7.36 (d, J = 8.23, 1H); ¹³C NMR DMSO-d₆) δ 13.8, 96.9, 112.1, 118.3, 118.85, 132.2, 135.6, 152.5; HPLC a) column: Phenominex ODS C18 4.6 x 50 mm, 4 min gradient, 10% MeOH/90% H₂O/0.1% TFA to 90% MeOH/10% H₂O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.43 min retention time; HPLC b):column: Shimadzu Shim-Pack VP-ODS C18 4.6 x 50 mm, 4 min gradient, 10% MeOH/90% H₂O/0.1% TFA to 90% MeOH/10% H₂O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.31 min retention time (99%); MS (ES) m/z 167 [M+H]⁺.

23E. 2-Chloro-4-isocyanato-3-methylbenzonitriIe

5

The title compound was prepared from compound 23D in a manner similar to that described in Experiments 2D to 2E.

l o 23F. (2S,3-R)-l-(3-Chloro-4-cyano-2-methylphenylcarbamoyl)-3-hydroxy- pyrrolidine-2-carboxylic acid methyl ester

To a solution of hydroxyproline compound IF (493 mg, 3.40 mmol) in CH₂C1₂

15 (15 mL) was added 4 A molecular sieves (~ 3.0 g), followed by isocyanate 23E (725 mg, 3.22 mmol), and the resulting mixture was stirred at rt overnight, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0.5% MeOH in EtOAc/hexane, 1: 1) to afford the title compound (736 mg) as an off-white solid. HPLC column: YMC S-5 0 C18 (4.6 x 50 mm), 0% to 100% B, 4 min gradient, 1 min hold (A = 90% H₂0 – 10% CH₃CN – 0.1% TFA and B = 10% H₂0 – 90% CH₃CN – 0.1% TFA), flow rate at 4 mL/min, UV detection at 220 nm, 1.57 min retention time (100%); MS (ES) m/z 338 [M+H]⁺. 23G. (7-R,7a5)-2-Chloro-4-(7-hydroxy-l,3-dioxotetrahydropyrroIo[l,2- c]imidazoI-2-yl)-3-methyIbenzonitrile.

To a suspension of cz^‘s-3-hydroxyproline methyl ester, HCl salt (4.91 g, 27 mmol) in CH₂C1₂ (100 mL) cooled to 0 °C was added -Pr₂NEt (4.79 mL, 27.5 mmol). After stirring at rt for 15 min, isocyanate 23E was added as a solid in one portion through a powder addition funnel, rinsing with 50 mL CH₂C1₂. The resulting light brown solution was stirred at rt until urea formation was complete (~ 2 h). To the mixture was then added DBU (4.6 mL, 30 mmol), and the resulting brown colored solution was stirred at rt until hydantoin formation was complete (~ 15 h). The product (4.72 g, 62%) was collected by filtration and washing with CH₂C1₂ (2x). The mother liquor was then diluted with CH₂C1₂ and washed with H₂0 (2x), 1 N HCl (2x) and brine. After removal of most of the solvent under reduced pressure, further product (1.2 g, 16%) was collected by filtration and washing with CH₂C1₂ (2x). Recrystallization of the 4.72 g of crude product from hot THF and hexane gave 4.5 g of analytically pure product.

1H NMR (DMSO- ) δ 2.05-2.11 (m, 1H), 2.15-2.22 (m, 1H), 2.20, 2.24 (s, 3H), 3.29-3.33 (m, 1H), 3.59-3.68 (m, 1H), 4.42-4.50 (m, 2H), 5.64, 5.72 (d, J = 3.9, 3.3, 1H), 7.22, 7.51 (d, J = 8.3, 1H), 7.96 (d, I = 8.2,1H);

¹³C NMR (OMSO-d₆) δ 15.4, 15.6, 35.5, 35.6, 43.3, 43.4, 68.8, 69.3, 69.8, 112.9, 113.1, 115.8, 128.1, 128.7, 132.1, 136.3, 136.4, 136.9, 137.1, 158.6, 169.1, 169.6;

HPLC a) column: Phenominex ODS C18 4.6 x 50 mm, 4 min gradient, 10% MeOH/90% H₂O/0.1% TFA to 90% MeOH 10% H₂O/0.1% TFA; 1 min hold; 4 mL/min, UV detection at 254 nm, 2.07 and 2.32 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 (4.6 x 50 mm), 4 min gradient, 10% MeOH/90% H₂O/0.1% TFA to 90% MeOH/10% H₂O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 254 nm, 1.93 and 2.23 min retention time; Chiral HPLC column: Daicel Chiralcel OD 4.6 x 250 mm, isocratic, 30 min, 25% isopropanol/hexanes, 1 mL/min, UV detection at 254 nm; Shimadzu HPLC: 17.99 min retention time (>99%): Column: Hypercarb 5μ, 4.6 x 100 mm, 25 °C, isocratic, 30 min ACN/Η₂0 (35:65); 1 mL/min,

10.99 min retention time; MS (ES) m/z 306 [M+H]⁺. Alternatively, compound 23G can also be prepared by the following procedure: A solution of 22C (0.10 g, 0.28 mmol) and copper cyanide (0.03 g, 0.34 mmol) in DMF (1 mL) was refluxed for 3 h, cooled to rt, and diluted with water. The resulting solid was filtered, washed with water, dried and purified using preparative HPLC to afford the title compound (27 mg).

Alternatively, compound 23G can also be prepared by the following procedures: A solution of 22C (0.10 g, 0.278 mmol) and copper cyanide (0.03g, 0.334 mmol) in DMF (1 mL) was refluxed for 3 h, cooled to rt and diluted with water. The resulting solid was filtered, washed with water, dried and purified using preparative HPLC to afford the title compound (27 mg). HPLC: 99% at 2.06, 2.34 min (retention time) (Conditions: Phenom. Lura C18 (4.6 x 50 mm); Eluted with 0% to 100% B, 4 min gradient (A = 90% H₂0 – 10% MeOH – 0.1% TFA and B = 10% H₂0 – 90% MeOH – 0.1% TFA); Flow rate at 4.0 mL/min. UV detection at 220 nm). Chiral HPLC: retention time = 11.04 min (99%); Conditions: OD (4.6 x 250 mm); Eluted with 25% isopropanol in hexane for 30 min at 1 mL/min. MS (ES) m/z 306 [M+l]⁺.

References

External links

• Crystal Structure Of The Rat Androgen Receptor Ligand Binding Domain Complex With Bms-564929 at Protein Data Bank

BMS-564,929

Systematic (IUPAC) name
(7R,7aS)-2-Chloro-4-(7-hydroxy-1,3-dioxotetrahydropyrrolo[1,2-c]imidazol-2-yl)-3-methylbenzonitrile
Clinical data
Legal status	Investigational new drug
Identifiers
PubChem	CID 9882972
DrugBank	DB07286
ChemSpider	8058647
Chemical data
Formula	C14H12ClN3O3
Molecular mass	305.716 g/mol

//////////

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Jejuri,  Pune district, Maharashtra, INDIA

1. Jejuri – Wikipedia, the free encyclopedia

   en.wikipedia.org/wiki/Jejuri

   Jejuri is a city and a municipal council in Pune district in the Western Indian state of Maharashtra. It is famous for the main temple of Lord Khandoba.

   ‎Geography – ‎How to reach – ‎Demographics – ‎Temple

Jejuri is situated 48 km from Pune in Maharashtra State. Jejuri can be reached is by Road or Rail from Pune. Number of State Transport buses ply from Pune. It can be reached by Express trains from Pune Railway Station. GKP LTT Express Train no.15018 departure 0450 hrs from Pune PN arrival Jejuri JJR 0548 hrs, Maharshtra Express Train no.11040 departure 0450 hrs from Pune PN arrival Jejuri JJR 0549 hrs Koyana Express Train no.11029 departure 0045 hrs from Pune PN arrival Jejuri JJR 0148 hrs Sahyadri Express Train no.11023 departure 2205 hrs from Pune PN arrival Jejuri JJR 2308 hrs.These trains runs all days.

Jejuri is one of the most famous religious places in Maharashtra. The Village Jejuri is popularly known as Khanderayachi Jejuri.

Jejuri’s Khandoba Temple is built on a hill, which is approximately 51 kilometers away from Pune Railway Station. As the Temple is on the hill, one has to ascend more than 200 steps. But the ascending is not so tough and the wonderful view of Jejuri village is superb. If weather permits, One can easily see the spectacular view of Dive and Saswad Ghat. One can enjoy number of `Deep Mala’ (lamp post) while climbing the hill. Jejuri is really popular for its old Deep Malas.

The Jejuri temple was constructed in 1608. The Sabhamandap (Audience Hall) and other parts of the structure were completed subsequently. In 1742, Holkars constructed pillars and completed battlements and tank. The devotees added gateways, stairways, lamp pillars, cloisters etc.

The Idol of Lord khandoba in the Temple is beautiful.

The shepherd community considers Khandoba as their family deity.

One must visit Jejuri to look the Crystal Stands. Jejuri is one of the important temples in Maharashtra with historical significance.

Khandobacha Yelkot, Yelkot Yelkot Jay Malhar, Sadanandacha Yelkot, Kadepathar Maharaj Ki Jay are some of the popular terms here.

One can find many idols in and nearby the Jejuri Temple.

Chaitra Pournima, Dussehra, Champa Shashthi, Paush Pournima, Magh Pournima, Mahashivratri, Somvati Amavasya, Guru Pournima

Upadhye Guruji-9850150797, 02115-253152

Shree Siddhi Lodge and Hotel # 02115-253090

Throughout the year

Jejuri Railway Station

Mumbai – Jejuri – 206 Kilometers (By Road) Via Mumbai Pune Express Way

Shree Mayureshwar Temple, Morgaon (Ashta Vinayak)
Pandeshwar
Bhuleshwar
Saswad
Kanifnath Temple
Balaji Temple

 

A painting depicts Khandoba riding a white horse with Mhalsa, accompanied with a dog and attendants including a Waghya dancing before him.

Khandoba and Mhalsa killing demons Mani-Malla — a popularoleograph, c.1880.

Khandoba
Khandoba (center) in his four armed form, the two metal images depict him with his wives. The sanctum of the newer Jejuri temple.

17-Hydroxyprogesterone caproate

630-56-8

[(8R,9S,10R,13S,14S,17R)-17-Acetyl-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-17-yl] hexanoate
Molecular Weight: 428.6041 g/mol
Molecular Formula: C₂₇H₄₀O₄

Pregn-4-ene-3,20-dione,17-hydroxy-, hexanoate (7CI,8CI);Progesterone, 17-hydroxy-, hexanoate (6CI);Hexanoic acid, ester with 17-hydroxypregn-4-ene-3,20-dione (8CI);17a-Caproyloxypregn-4-ene-3,20-dione;17a-Hydroxypregn-4-ene-3,20-dionecaproate;17a-Hydroxypregn-4-ene-3,20-dionehexanoate;17a-Hydroxyprogesteronecaproate;17a-Hydroxyprogesteronen-caproate;Delalutin;Depo-proluton;Hormofort;Pregn-4-ene-3,20-dione,17-[(1-oxohexyl)oxy]-;NSC 17592;Neolutin;Primolut Depot;Procyte Depo;Proge;Syngynon;Teralutil;

FDA grants orphan drug status for Lipocine’s LPCN 1107 to prevent preterm birth
Specialty pharmaceutical firm Lipocine has received orphan drug designation from the US Food and Drug Administration (FDA) for its LPCN 1107 to prevent preterm birth (PTB).

http://www.pharmaceutical-technology.com/news/newsfda-grants-orphan-drug-status-lipocines-lpcn-1107-prevent-preterm-birth-4592067?WT.mc_id=DN_News

LPCN 1107 is an oral product candidate of 17-alpha hydroxyprogesterone caproate under development for the indication of prevention of recurrent preterm birth. LPCN 1107 has the potential to become the first oral HPC product for the prevention of preterm birth in women with a prior history of at least one preterm birth. Potential benefits of our oral product candidate relative to current injectable products include the elimination of pain and site reactions associated with weekly injections, elimination of weekly doctor visits or visits from the nurse, and elimination of interference/disruption of personal, family or professional activities associated with weekly visits.

 

LPCN 1107: A Novel Oral Alternative

LPCN 1107 Product Attributes:

• Designed for oral administration twice daily of hydroxyprogesterone caproate (same active as in the only FDA approvd injectable product for the prevention of recurrent PTB).
• Eliminates site reaction and pain at the site of injection
• Eliminates regular doctor office visits or visits from the nurse (weekly visits for 16 – 20 weeks)
• Significant absorption upon oral dosing of LPCN 1107 in healthy non-pregnant women
• Good dose response demonstrated in healthy non-pregnant women
• LPCN 1107 was well tolerated in single dose study
• LPCN 1107 may be eligible for orphan drug designation

LPCN 1107, Lipocine’s oral hydroxyprogesterone caproate (HPC) product candidate has the potential to become the first oral HPC product for the prevention of preterm birth in women with a prior history of at least one preterm birth. Potential benefits of our oral product candidate relative to current once-a-week intramuscular (IM) injectable product include the elimination of pain and site reactions associated with weekly injections, elimination of weekly doctor visits or visits from the nurse, and elimination of interference/disruption of personal, family or professional activities associated with weekly visits. Lipocine has successfully completed a Phase 1 study under a US IND designed to determine the pharmacokinetics and bioavailability of LPCN 1107 relative to an IM HPC, as well as safety and tolerability, in healthy non-pregnant female volunteers.

17α-Hydroxyprogesterone caproate is a synthetic, steroidalprogestin that is similar to medroxyprogesterone acetate andmegestrol acetate. It is an ester derivative of 17α-hydroxyprogesterone formed from caproic acid (hexanoic acid).

17α-Hydroxyprogesterone caproate was previously marketed under the trade name Delalutin by Squibb, which was approved by the U.S. Food and Drug Administration (FDA) in 1956 and withdrawn from marketing in 1999.

The US FDA approved Makena from KV Pharmaceutical (previously named as Gestiva) on February 4, 2011 for prevention ofpreterm delivery in women with a history of preterm delivery, sparking a pricing controversy.

Synthesis

Hydroxyprogesterone caproate can be prepared by the following sequence:^[13]

It is made from 16-dehydropregnenolone acetate (16-DPA),^[14] product of the Marker degradation.

Ringold, H. J.; Loken, B.; Rosenkraz, G.; Sondheimer, F.; J. Amer. Chem. Soc. 1956, 78, 816.

……………………………….

PATENT

http://www.google.com/patents/CN104017041A?cl=en

method of synthesizing progesterone caproate, comprising the steps of:

[0006] Step one to 17 α- hydroxy progesterone as a raw material, and n-hexyl acid in pyridine and p-toluene sulfonic acid catalysis by esterification reaction mixture esterified, the reaction is as follows

 Step two, to the mixture of step one described esterified in an alcohol solution of acid catalysis to give progesterone caproate

Ketone crude reaction is as follows:

 Step one to obtain a mixture containing progesterone caproate ester compound of step two the mixture is esterified in an alcohol solution of acid catalysis to give progesterone caproate crude. The reaction process of the present invention avoids the costly esterification agent n-hexyl anhydride used materials costs and recovery costs are significantly reduced.

Example 1

17 a – hydroxy progesterone 20g, n-caproic acid 40ml, topiramate 唳 16ml, p-toluenesulfonic acid 1.6g, toluene 300ml, 500ml three-necked flask were put, the reaction temperature was raised to between 110 ~ 120 ° C 3 hours TLC sampling The reaction was monitored. The reaction is as follows:

[0016] 17 a – hydroxy progesterone concentration treatment made after completion of the reaction, as a method for the enrichment process concentrated under reduced pressure and toluene, pyridine, and the unfinished batch reaction of n-hexanoic acid.

After the end of the [0017] concentrated in the three-necked flask was added 100mL ethanol, 3ml of concentrated hydrochloric acid was heated to reflux alcohol solution 2 hours, the reaction was monitored sampling TLC, complete hydrolysis of the diester into progesterone caproate stop the reaction. The reaction is as follows:

 cooled to below 5 ° C, filtered and dried to obtain crude progesterone caproate 24g, crude yield of 120%.Progesterone caproate crude was purified with ethanol to give progesterone caproate boutique 19.Sg, progesterone caproate Collectibles yield based on the crude progesterone caproate 82.5% of the total yield of 99.0% o

 Example 2

17 α – hydroxy progesterone 20g, n-caproic acid 50ml, topiramate 唳 30ml, p-toluenesulfonic acid 3g, toluene 300ml, 500ml three-necked flask were put, the reaction temperature was raised to between 110 ~ 120 ° C 3 hours TLC monitoring sampling reaction. 17 α – hydroxy progesterone concentration treatment made after completion of the reaction, as the concentration treatment method evaporated toluene, pyridine and n-hexyl Unreacted acid.

After the end of the [0022] concentrated in the three-necked flask was added 100mL ethanol, 5ml of concentrated hydrochloric acid was heated to reflux alcohol solution I hour, the reaction was monitored sampling TLC, complete hydrolysis of the diester into progesterone caproate stop the reaction. Cooled to below 5 ° C, filtered and dried to obtain crude progesterone caproate 23.5g, crude yield of 117.5%. Progesterone caproate crude was purified with ethanol to give progesterone caproate boutique 19.2g, progesterone caproate Collectibles yield based on the crude progesterone caproate 81.7%, the total yield was 96.0%.

Example 3

 17 α – hydroxy progesterone 20g, n-caproic acid 60ml, topiramate 唳 40ml, p-toluenesulfonic acid 4g, toluene 300ml, 500ml three-necked flask were put, the reaction temperature was raised to between 110 ~ 120 ° C 2.5 hours TLC monitoring sampling reaction. 17 α – hydroxy progesterone concentration treatment made after completion of the reaction, as the concentration treatment method evaporated toluene, pyridine and n-hexyl Unreacted acid.

After the end of the [0025] concentrated in the three-necked flask was added 100mL ethanol, 8ml of concentrated hydrochloric acid was heated to reflux alcohol solution 40 minutes, the reaction was monitored sampling TLC, complete hydrolysis of the diester into progesterone caproate stop the reaction. Cooled to below 5 ° C, filtered and dried to obtain crude progesterone caproate 23g, crude yield of 115%. Progesterone caproate crude was purified with ethanol to give progesterone caproate fine 19g, progesterone caproate Collectibles yield based on the crude progesterone caproate 82.6% of the total yield of 95.0%.

 Example 4

 17 α – hydroxy progesterone 20g, n-caproic acid 60ml, topiramate 唳 40ml, p-toluenesulfonic acid 4g, benzene, 300ml, 500ml three-necked flask were put, the reaction temperature was raised to between 110 ~ 120 ° C 2.5 hours TLC monitoring sampling reaction. 17 α- hydroxy progesterone concentration treatment made after completion of the reaction, as a method for the enrichment process concentrated under reduced pressure benzene, pyridine and non-completion of the reaction of n-hexanoic acid.

After the end of the [0028] concentrated in the three-necked flask was added 100mL of methanol, 8ml of concentrated sulfuric acid was heated to reflux alcohol solution 40 minutes, the reaction was monitored sampling TLC, complete hydrolysis of the diester into progesterone caproate stop the reaction. Cooled to below 5 ° C, filtered and dried to obtain crude progesterone caproate 23g, crude yield of 115%. Progesterone caproate crude was purified with ethanol to give progesterone caproate fine 19g, progesterone caproate Collectibles yield based on the crude progesterone caproate 82.6% of the total yield of 95.0%.

Notes

1. SMFM Clinical Guideline: Progesterone and preterm birth prevention: translating clinical trials data into clinical practice, AJOG May 2012
2. Meirs et al. NEJM 2003
3. Dodd JM, Flenady V, Cincotta R, Crowther CA; The Cochrane Database of Systematic Reviews 2006 Issue 1
4. Keirse, MJNC; Progesterone (2004). “déjà vu” or “still to be seen”?.”. Birth 31: 3.
5. Johnson, JWC; Austin, KL; Jones, GS; Davis, GH; King, TM (1975). “Efficacy of 17 alpha-hydroxyprogesterone caproate in the prevention of premature labor”. NEJM 293 (14): 675.doi:10.1056/nejm197510022931401.
6. Yemini, M; Borenstein, R; Dreazen et al. (1985). “Prevention of premature labor by 17 alpha-hydroxyprogesterone caproate”. Am J Obstet Gynecol 151 (5): 574–7. doi:10.1016/0002-9378(85)90141-3.
7. Meis PJ et al. Prevention of Recurrent Preterm Delivery by 17 Alpha-hydroxyprogesterone Caproate. NEJM, 2003: vol 348, no 24, pg 2379-2385.
8. Keirse MJNC, Progestogen administration in pregnancy may prevent preterm delivery. Br J Obstet Gynecol 1990 February; 97:149.
9. Advisory Committees: CDER 2006 Meeting Documents
10. Hendrix AG, et al. Embriotoxicity of sex steroidal hormones in nonhuman primates: II. Hydroxyprogesterone caproate, estradiol valerate. Teratology 1987 February. 35 (1): 129.
11. Duke University Medical Center, New England Journal of Medicine, correspondence, vol 349.
12. Hauth, JC; Gilstrap, LC; Brekken, AL; Hauth, JM (1983). “The effect of 17 alpha-hydroxyprogesterone caproate on pregnancy outcome in an active-duty military population”. Am J Obstet Gynecol 146 (2): 187.
13. Ringold, H. J.; Loken, B.; Rosenkraz, G.; Sondheimer, F. (1956). “Steroids. LXXIII. The Direct Oppenauer Oxidation of Steroidal Formate Esters. A New Synthesis of 17α-Hydroxyprogesterone”. J. Amer. Chem. Soc. 78 (4): 816. doi:10.1021/ja01585a030.
14. Goswami, A.; Kotoky, R.; Rastogi, R. C.; Ghosh, A. C. (2003). “A One-Pot Efficient Process for 16-Dehydropregnenolone Acetate”. Organic Process Research & Development 7 (3): 306.doi:10.1021/op0200625. 
15. Armstrong J (May 2011). “Unintended consequences — the cost of preventing preterm births after FDA approval of a branded version of 17OHP”. N. Engl. J. Med. 364 (18): 1689–91.doi:10.1056/NEJMp1102796. PMID 21410391.

Sources

• FDA Reproductive Health Drugs Advisory Committee. August 29, 2006 Meeting to discuss NDA 21-945 Gestiva (Adeza Biomedical)
  17α-hydroxyprogesterone caproate injection, 250 mg/mL, for the proposed indication: prevention of preterm delivery in women with a history of a prior preterm delivery.
• Adeza Biomedical (October 23, 2006) Receives FDA Approvable Letter For Gestiva
• Adeza gets orphan drug designation for Gestiva (January 31, 2007)
• Cytyc Acquires Adeza Biomedical Corporation (April 3, 2007)
  Adeza’s name changed to Cytyc Prenatal Products Corp.

TAKE A TOUR

KODAIKANAL, TAMILNADU, INDIA

1. Kodaikanal – Wikipedia, the free encyclopedia

   en.wikipedia.org/wiki/Kodaikanal

   Kodaikanal is a city in the hills of the Dindigul district in the state of Tamil Nadu, India. Its name in the Tamil language means “The Gift of the Forest”. Kodaikanal …

   ‎History of Kodaikanal – ‎Kodaikanal taluk – ‎Kodaikanal block – ‎Category:Kodaikanal

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CUISINE OF TAMILNADU

Like all other South Indian states, Tamil Nadu is also known for a wide variety of delicious food both for the vegetarians as well as the non-vegetarians. Grains, lentils, rice and vegetables are the main ingredients of the traditional foods of Tamil Nadu. Spices add flavor and give a distinctive taste to the Tamil cuisines. Some of the most common and popular dishes of the region are idly, dosai, vada, pongal and Uppuma. Coconut chutney and sambhar invariably form a part of most of the Tamil dishes.

The typical Tamil breakfast includes dosai, which is a pancake made from a batter of rice, idly (steamed rice cakes) and lentils (crisp fried on a pan), vada (deep fried doughnuts prepared from a batter of lentils), pongal (a mash of rice and lentils boiled together and seasoned with cashew nuts, ghee, pepper and cummin seed), uppuma (cooked semolina seasoned in oil with mustard, pepper, cummin seed and dry lentils). These are the main local dishes but there are several variations that are eaten with coconut chutney and mulaga podi.For lunch and the main course, the food consists of boiled rice, which is served with an assortment of vegetable dishes, sambar, chutneys, rasam (a hot broth prepared from tamarind juice and pepper) and curd. On the other hand, the non-vegetarian lunch and dinner include curries and dishes cooked with chicken, mutton or fish. Crispy Papad/Papar and appalam form an important part of a typical Tamil meal.Filter coffee is a famous and popular beverage of the people of Tamil Nadu in general and Chennai in particular. It is interesting to note that making of filter coffee is like a ritual as the coffee beans are first roasted and then powdered. After the grinding work is over, the powder is put into a filter set and then boiling water is added to prepare the decoction, which is allowed to set for about 15-18 minutes. The decoction is ready and can be added to milk with sugar according to taste. The coffee is poured from one container to another in quick succession so that the ideal frothy cup of filter coffee is ready.

Chettinad Cuisine

Chettinad cuisine is one of the spiciest and most aromatic in India. The name Chettinad cuisine comes from the place of its origin, Chettinad. Chettinad cuisine and delicacy is a specialty of Tamil Nadu and is a delight for non-vegetarian food lovers. The Chettinad cuisine consists of several variations of mutton, fish, and chicken items. The Chettinad Pepper Chicken is a specialty of all the non-vegetarian dishes. Dishes like biryani and paya are popular Tamil style of Mughali food. Paya is a type of spiced trotters broth and is usually eaten with either parathas or appam.

Tapioca Masala

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AG014699, 

AG014699, the phosphate salt of AG14447, which has improved aqueous solubility, has been selected for clinical trial.AG014699 is a tricyclic indole poly(ADP-Ribose) polymerase (PARP) inhibitor with potential antineoplastic activity.

M.Wt: 421.3593
Formula: C19H21FN3O5P
CAS No: 459868-92-9

Rucaparib, PF-01367338283173-50-2  cas 6H-​Pyrrolo[4,​3,​2-​ef]​[2]​benzazepin-​6-​one, 8-​fluoro-​1,​3,​4,​5-​tetrahydro-​2-​[4-​[(methylamino)​methyl]​phenyl]​-6H- ​Azepino[5,​4,​3-​cd]​indol-​6-​one, 8-​fluoro-​1,​3,​4,​5-​tetrahydro-​2-​[4-​[(methylamino)​methyl]​phenyl] ​-8-​Fluoro-​2-​[4-​[(methylamino)​methyl]​phenyl]​-​1,​3,​4,​5-​ tetrahydro-​6H-​azepino[5,​4,​3-​cd]​indol-​6-​one;8-Fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one8-Fluoro-2-(4-methylaminomethyl-phenyI)-l,3,4,5-tetrahydro-azepino[5,4,3- cd]indol-6-one

MW..C₁₉ H₁₈ F N₃ O

cas of csa salt—–1327258-57-0

773059-19-1 (hydrochloride)
773059-22-6 (L-tartrate)
773059-23-7 (acetate)

459868-92-9  PHOSPHATE

AG-014699
AG-14699
CO-338
PF-01367338
AG-014447 (free base)
AG-14447 (free base) 

Agouron (Originator)
Pfizer (Originator)

Clovis Oncology

WO 2014052550, WO 2014037313, WO 2000042040WO 2004087713WO 2005012305

Rucaparib (AG 014699) is a PARP inhibitor being investigated as a potential anti-cancer agent.

Rucaparib inhibits “the contraction of isolated vascular smooth muscle, including that from the tumours of cancer patients. It also reduces the migration of some cancer and normal cells in culture.”^[1]

It can be taken orally in tablet form.^[2]

It has undergone phase I clinical trials for patients with advanced solid tumours.^[3] It is in phase II clinical trials for metastatic breastand ovarian cancer with known BRCA1 or BRCA2 mutation.^[4][2]

It is thought that 20% of women with ovarian cancer who are not BRCA positive might also benefit from PARP inhibitors. Clinical trials are beginning (as of April, 2014)

As of November 2012 four clinical trials of rucaparib were recruiting patients.^[5]
Inhibition of poly(ADP ribose) polymerase, or PARP, is an exciting new mechanism for the treatment of cancer.(1) The PARP enzyme is responsible for repair of damaged DNA in both normal and tumor cells, and inhibition of this repair mechanism is expected to make the cell more likely to undergo apoptosis. Preclinical work has shown that PARP inhibitors coadministered with a standard chemotherapuetic agent are more effective than the standard treatment aloneRucaparib is a NAD+ ADP-ribosyltransferase inhibitor in phase II clinical development at Cancer Research UK for the treatment of patients with advanced ovarian cancer and in patients with locally advanced or metastatic breast cancer. Clovis Oncology is conducting early clinical evaluation of rucaparib for the treatment of triple negative breast cancer or ER/PR +, HER2 negative with known BRCA1/2 mutations p2 and for the treatment of gBRCA mutation breast cancer.. Pfizer discontinued development of rucaparibin 2011.In 2011, the compound was licensed to Clovis Oncology by Pfizer for the treatment of cancer. In 2012, orphan drug designation was assigned in the U.S. and the E.U. for the treatment of ovarian cancer.

The compound 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H-azepino[5,4,3- cd]indol-6-one represented by formula

is a small molecule inhibitor of poly(ADP-ribose) polymerase (PARP). 8-Fluoro-2-{4- [(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one and salts thereof, is disclosed in U.S. Patent No. 6,495,541 and PCT Application No. PCT/IB2004/000915, International Publication No. WO 2004/087713, the disclosures of which are incorporated herein by reference in their entireties. U.S. Provisional Patent Applications No. 60/612,459 and 60/679,296, entitled “Polymorphic Forms of the Phosphate Salt of 8-Fluoro-2-{4-[(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H- azepino[5,4,3-cd]indol-6-one,” the disclosures of which are incorporated herein by reference in their entireties, describe novel polymorphic forms of the phosphate salt of 8-fluoro-2-{4- [(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one, and methods for their preparation. U.S. Provisional Patent Applications No. 60/612,458; and 60/683,006, entitled “Therapeutic Combinations Comprising Poly(ADP-Ribose) Polymerases Inhibitor,” the disclosures of which are incorporated herein by reference in its entirety, describe pharmaceutical combinations of 8-fluoro-2-{4- [(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one.

………………………………………

PATENT

http://www.google.com/patents/WO2000042040A1?cl=enExample IIII:8-Fluoro-2-(4-methylaminomethyl-phenyI)-l,3,4,5-tetrahydro-azepino[5,4,3- cd]indol-6-one

4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-lH-azepino[5,4,3-cd]indol-2-yl)- benzaldehyde (100 mg, 0.32 mmol; prepared in a manner similar to that described for compound 12 for 2-bromo-8-fluoro-l,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one and 4-formylphenylboronic acid) was reacted with methylamine (1.62 mmol) as described for Compound PPP to yield 8-fluoro-2-(4-methylaminomethyl-phenyl)- l,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 32 mg (31%) as a yellow solid: m.p. 1543-155 °C; Η NMR (300 MHz, d₆-DMSO) 2.28 (s, 3H), 3.04 (m, 2H), 3.40 (m, 2H), 3.69 (s, 2H), 7.32 (dd, 7= 9.0, 2.4 Hz, IH), 7.44 (m, 3H), 7.57 (d, 7= 8.1 Hz, 2H), 8.25 (br t, IH), 11.67 (br s, IH). HRMS (MALDI MH+) Calcd for C₁₉H₁₈N₃OF: 324,1512. Found: 325.1524. Anal. (C₁₉H₁₈N₃OF03 H₂O) C, H, N.

……………………………..

PAPER

http://pubs.acs.org/doi/full/10.1021/op200238pNovel PARP inhibitor 1 is a promising new candidate for treatment of breast and ovarian cancer. A modified synthetic route to 1 has been developed and demonstrated on 7 kg scale. In order to scale up the synthesis to multikilogram scale, several synthetic challenges needed to be overcome. The key issues included significant thermal hazards present in a Leimgruber–Batcho indole synthesis, a low-yielding side-chain installation, a nonrobust Suzuki coupling and hydrogen cyanide generation during a reductive amination. In addition to these issues, changing from intravenous to oral delivery required a new salt form and therefore a new crystallization procedure. This contribution describes development work to solve these issues and scaling up of the new process in the pilot plant.

8-Fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (1)

To a solution of aqueous sodium hydroxide (40% w/w, 3.6 kg, 2.0 equiv) in water (88 L, 14 L/kg) and methanol (35 L, 5.5 L/kg) was added 12 ……………………………………………………deleted……………………..and dried at 45 °C under vacuum to give 1 as a 1:1 THF solvate (5.57 kg, 14.08 mol, 84% yield);

mp (THF) dec at 220 °C;

δ_H: (400 MHz, DMSO-d₆) 2.25 (s, 3H), 2.99–3.01 (m 2H), 3.65 (s, 2H), 7.27 (dd, 1H, J = 2.4, 9.3 Hz), 7.39 (dd, 1H, J = 2.4, 9.3 Hz), 7.42 (d, 2H, J = 8.5 Hz), 7.53 (d, 2H, J = 8.3 Hz), 8.18 (t, br, 1H, J = 5.7 Hz), 11.60 (s, 1H);

δ_C: (100 MHz, DMSO-d₆) 28.74, 35.58, 41.84, 54.74, 100.47 (d, J = 25.8 Hz), 109.44 (d, J = 25.8 Hz), 111.47, 123.19, 125.72 (d, J = 8.8 Hz), 127.55, 128.20, 129.86, 135.38 (d, J = 3.7 Hz), 136.67 (d, J = 12.4 Hz), 140.52, 158.31 (d, J = 233), 168.39.

8-Fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (S)-camphorsulfonate Salt (21)

To a slurry of 1 (5.32 kg, 13.48 mol) in isopropanol (30 L, 5.5 L/kg) and water (39 L, 7.3 L/kg) was added a solution of (S)-camphorsulfonic acid (3.75 kg, 16.18 mol, 1.2 equiv) in water (10.6 L, 2 L/kg). The resultant slurry was then heated to 70 °C and held for 1 h to ensure dissolution. …………………………..deleted…………………..C to give 21 as a white crystalline solid (7.09 kg, 12.76 mol, 95% yield); mp (IPA/water) 303 °C;

δ_H: (400 MHz, DMSO-d₆) 0.74 (s, 3H), 1.05 (s, 3H), 1.28 (m, 1H), 1.80 (d, 1H, J = 18.0 Hz), 1.81–1.88 (m, 1H), 1.93 (app t, 1H, J = 4.5 Hz), 2.24 (m, 1H), 2.41 (d, 1H, J = 14.6 Hz), 2.62 (s, 3H), 2.66–2.72 (m, 1H), 2.91 (d, 1H, J = 14.7 Hz), 3.04–3.07 (m, br, 2H), 3.36–3.45 (m, br, 2H), 4.20 (s, 2H), 7.37 (dd, 1H, J = 2.4, 9.3 Hz), 7.44 (dd, 1H, J = 2.4, 11.0 Hz), 7.63 (d, 2H, J = 8.3 Hz), 7.71 (d, 2H, J = 8.3 Hz), 8.26 (t, br, 1H, J = 5.5 Hz), 11.76 (s, 1H);

δ_C: (100 MHz, DMSO-d₆) 19.51, 20.02, 24.14, 26.37, 28.74, 32.28, 41.77, 42.13, 42.22, 46.71, 47.00, 51.06, 58.21, 100.65 (d, J = 25.8 Hz), 109.72 (d, J = 25.8 Hz), 112.41, 123.03, 126.04 (d, J = 8.7 Hz), 127.98, 130.19, 131.22, 132.22, 134.50, 136.83 (d, J = 12.0 Hz), 158.52 (d, J = 235 Hz), 168.27, 216.24.

………………….

PATENT

WO 2006033003

http://www.google.com/patents/WO2006033003A1?cl=en

The compound 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H-azepino[5,4,3- cd]indol-6-one represented by formula

 

is a small molecule inhibitor of poly(ADP-ribose) polymerase (PARP). 8-Fluoro-2-{4- [(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one and salts thereof, is disclosed in U.S. Patent No. 6,495,541 and PCT Application No. PCT/IB2004/000915, International Publication No. WO 2004/087713, the disclosures of which are incorporated herein by reference in their entireties.

 

U.S. Provisional Patent Applications No. 60/612,459 and 60/679,296, entitled “Polymorphic Forms of the Phosphate Salt of 8-Fluoro-2-{4-[(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H- azepino[5,4,3-cd]indol-6-one,” the disclosures of which are incorporated herein by reference in their entireties, describe novel polymorphic forms of the phosphate salt of 8-fluoro-2-{4- [(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one, and methods for their preparation. U.S. Provisional Patent Applications No. 60/612,458; and 60/683,006, entitled “Therapeutic Combinations Comprising Poly(ADP-Ribose) Polymerases Inhibitor,” the disclosures of which are incorporated herein by reference in its entirety, describe pharmaceutical combinations of 8-fluoro-2-{4- [(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one.

 

Example 13. Synthesis of 8-Fluoro-2-(4-methylaminomethyl-phenyl)-1,3.4.5-tetrahvdro-azepinor5.4.3- ccflindol-6-one (15) i

 

Lactam 14 (14.42 g, 0.038 mol) was dissolved in hydrobromic acid in acetic acid (30%-32%, 140 ml). The reaction solution was stirred for 46 hours at room temperature in a 500ml flask that was connected to an ethanolamine scrubber system. HPLC analysis indicated the completion of the reaction. Ice (30 g) was added to the reaction solution followed by addition of aqueous NaOH (327 ml, 10 M, 3.27 mol) while the temperature was maintained between 25 ⁰C and 35 ⁰C. When addition of NaOH was complete, the pH was 10. The resulting solid was collected by filtration, washed with water (2 x 50 ml). The filter cake was then suspended in water (125 ml) and stirred for 2 hours. The solid was collected by filtration, washed with water (2 x 25 ml) and dried to afford 10.76 g of product (88% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 2.577(s, 3H), 3.053(m, 2H), 3.406(m, 2H), 4.159(s, 2H), 7.36(dd, 1 H, J= 2.4 Hz and J= 9.3 Hz), 7.44(dd, 1 H, J= 2.4 Hz and J= 11.1 Hz), 7.63(d, 2H, J=8.1 Hz), 7.70(d, 2H, J= 8.1 Hz), 8.265(t, 1H, J= 5.7 Hz), 11.77(s, 1 H). Exact mass calculated for C₁₉H₁₉FN₃O: 324.1512. Found: 324.1497.

Rucaparib

Names
IUPAC name 8-Fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one
Other names AG014699
Identifiers
CAS Registry Number	283173-50-2
ChemSpider	8107584
InChI[show]
Jmol-3D images	Image
KEGG	D10079
PubChem	9931954
SMILES[show]
Properties
Chemical formula	C19H18FN3O
Molar mass	323.37 g·mol−1

References

1. http://www.qub.ac.uk/schools/SchoolofPharmacy/Filestore/Filetoupload,121186,en.pdf
2. “Cancer Research launches new drug trial”. 11 Jan 2011.
3. “First in human phase I trial of the PARP inhibitor AG-014699 with temozolomide (TMZ) in patients (pts) with advanced solid tumors”.
4. http://science.cancerresearchuk.org/research/loc/newcastle/newcastle_univ/plummerr/plummerrfr/plummerrfrp2/?version=1 URL no longer relevant
5. Rucaparib trials

Clovis Oncology receives Breakthrough Therapy designation for rucaparib for treatment of advanced ovarian cancer in patients with BRCA-mutated tumours

7 April 2015  •  Author: Victoria White

2525 28th Street
Suite 100
Boulder, CO 80301
Tel: 303.625.5000
Fax: 303.245.0360

are a biopharmaceutical company focused on acquiring, developing and commercializing cancer treatments in the United States, Europe and other international markets. Our development programs are targeted at specific subsets of cancer, combining personalized medicine with companion diagnostics to direct therapeutics to those patients most likely to benefit from them.

We have three product candidates in clinical development: rociletinib (CO-1686), which is in Phase II development for the treatment of non-small cell lung cancer; rucaparib, which is in Phase II and Phase III clinical trials for the treatment of ovarian cancer; and lucitanib, which is in Phase II clinical trials for the treatment of breast and lung cancers. We have received Breakthrough Therapy designation from the FDA for rociletinib and rucaparib. We maintain global rights for rociletinib and rucaparib, and U.S. and Japanese rights to lucitanib.

Boulder, Colorado

1. Boulder, Colorado – Wikipedia, the free encyclopedia

   en.wikipedia.org/wiki/Boulder,_Colorado

   Location in Boulder County and the State of Colorado. Coordinates: … ZIP codes,80301-80310, 80314, 80321-80323, 80328, 80329. Area code(s), Both 303  …

   ‎Boulder County – ‎Naropa University – ‎Flatirons – ‎Category:Boulder, Colorado
    

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AN 3485

AN3485,

6-(4-(aminomethyl)-2-chlorophenoxyl)benzo[c][1,2]oxaborol-1(3H)-ol,
was synthesized at Anacor Pharmaceuticals as described in patent application WO 2010028005
A1

6-[4-(Aminomethyl)-2-chlorophenoxy]-2,1-benzoxaborol-1(3H)-ol hydrochloride

Anacor Pharmaceuticals, Inc.

http://jpet.aspetjournals.org/content/early/2012/11/28/jpet.112.200030.full.pdf

Pro-inflammatory cytokines play a critical role in the development of autoimmune and
inflammatory diseases. Targeting the cytokine environment has proven efficient for averting
inflammation. In this study, we reported that 6-(4-(aminomethyl)-2-
chlorophenoxyl)benzo[c][1,2]oxaborol-1(3H)-ol (AN3485), a benzoxaborole analog, inhibited
TLR2-, TLR3-, TLR4- and TLR5-mediated TNF-α, IL-1β and IL-6 release from human PBMCs
and isolated monocytes with IC50s ranging from 18 to 580 nM, and the inhibition was mediated
at the transcriptional level. Topical administration of AN3485 significantly reduced PMAinduced contact dermatitis and oxazolone-induced delayed-type hypersensitivity in mice,
indicating its capability of penetrating skin and potential topical application in skin
inflammation. Oral administration of AN3485 showed dose-dependent suppression of LPSinduced TNF-α and IL-6 production in mice with an ED90 of 30 mg/kg. Oral AN3485, 35
mg/kg, twice a day, suppressed collagen-induced arthritis in mice over a 20-day period. The
potent anti-inflammatory activity in in vitro and in vivo disease models makes AN3485 an
attractive therapeutic lead for a variety of cutaneous and systemic inflammatory diseases

A new class of boron-containing small molecules has been developed over the past several
years as potential drugs. Different from carbon, boron contains an electrophilic empty p-orbital
which can form transient bonds with nucleophiles in an enzyme active site, which mimics a
tetrahedral transition state of peptide bond cleavage in an enzymatic reaction (Baker et al., 2011).
The benzoxaboroles, in which the boron atom is incorporated into a heteroaromatic ring system,
are able to inhibit a number of important enzymes, including bacterial and fungi Leucyl-tRNA
synthetase (Rock et al., 2007), human phosphodiesterase-4 (PDE4) (Akama et al., 2009) and
HCV NS3/4A protease (Li et al., 2010). Three benzoxaboroles, AN2690 (Tavaborole), AN2728
and AN3365 (GSK’052) are in clinical trials for treatment of onychomycosis, psoriasis/atopic dermatitis and Gram-negative bacterial infection, and have been proven safe in human when
applied topically or systemically

……………………………………………………….

Structure-activity relationships of 6-(aminomethylphenoxy)-benzoxaborole derivatives as anti-inflammatory agent
Bioorg Med Chem Lett 2013, 23(6): 1680

http://www.sciencedirect.com/science/article/pii/S0960894X13001054

• Synthesis of 6-(4-(aminomethyl)-2-chlorophenoxy)benzo[c][1,2]oxaborol-1(3H)-ol (9e): To a solution of 3H-benzo[c][1,2]oxaborole-1,6-diol (8) (300 mg, 2.00 mmol) in DMSO (30 mL) were added K₂CO₃(828 mg, 6.00 mmol) and 3-chloro-4-fluoro-benzonitrile (7b) (933 mg, 6.00 mmol). The reaction was heated at 90 °C for 7 h. After cooling the reaction mixture to room temperature, EtOAc (50 mL) was added. The organic layer was washed with water (5 × 50 mL). The organic layer was evaporated under vacuum. The residue was purified by reverse phase chromatography to afford 3-chloro-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yloxy)-benzonitrile (9b) (190 mg, 33%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.24 (s, 1H), 8.22 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.34 (s, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 4.99 (s, 2H); ESIMS (m/z): 284 (M−H)⁻; HPLC: 96.4% (220 nm), 96.0% (maxplot).

• To a solution of compound 9b (136 mg, 0.480 mmol) in anhydrous THF (60 mL) was added lithium aluminum hydride (1 M/ether, 1.19 mL, 1.19 mmol) at 0 °C. The reaction was stirred for 2 h. Then the reaction was quenched with 1 M HCl (30 mL). MeOH (50 mL) was added and the solution was filtered. The filtrate was evaporated under vacuum. The residue was purified by reverse phase chromatography (biotage, gradient MeOH/H₂O from 10% to 100%). To a suspension of 9e free base in MeOH (5 mL) was added 4 M HCl in 1,4-dioxane (0.2 mL). The mixture became a clear solution then precipitates formed, which were collected by filtration to afford 9e (106 mg, 68%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.19 (s, 1H), 8.18 (br s, 3H), 7.75 (s, 1H), 7.44–7.39 (m, 2H), 7.19–7.10 (m, 3H), 4.98 (s, 2H), 4.03 (q, J = 5.5 Hz, 2H); ESIMS (m/z): 290 (M+H)⁺; HPLC: 95.9% (220 nm), 96.9% (maxplot).

…………………………………………………………

Patent

https://www.google.com/patents/WO2010028005A1?cl=en

(X) IS AN 3485

Compound 2:

To a solution of 2-hydroxy-4-methoxy-benzaldehyde (30 g, 197 mmol) in DCM (anhydrous, 120 rnL) was added pyridine (79 mL, 986 mmol) at room temperature. After the mixture was cooled to -10 ⁰C, the Tf₂O (50 mL, 296 mmol) was slowly added to the reaction between -10 ⁰C to 0 ⁰C. The addition took about 2.5 hours. After the addition, the stirring was kept for 30 minutes. The EtOAc (200 mL) was added. The organic layer was washed with 1 M HCl (3 X 80 mL), dried over MgSO₄, filtered, and evaporated under vacuum. The residue was purified over silica gel, eluting with 5% EtOAc / hexanes to give trifluoro-methanesulfonic acid 2- formyl-5-methoxy-phenyl ester (2) 46 g in 82% yield. ¹H NMR (400 MHz,

CHLOROFORM-^) δ ppm 10.13 (s, 1 H), 7.95 (d, J=8.99 Hz, 1 H), 7.03 (dd, J=8.60, 2.34 Hz, 1 H), 6.88 (d, J=2.34 Hz, 1 H), 3.93 (s, 3 H)

Compound 3:

To a solution of trifluoro-methanesulfonic acid 2-formyl-5-methoxy-phenyl ester (2) (46 g, 160 mmol) in 1,4-dioxane (anhydrous, 360 rnL) were added bis(pinacolato)diboron (82.3 g, 320 mmol), [l,l ‘-bis(diphenylphosphino)ferrocene] palladium(II)chloride (23.7 g, 32 mmol) and KOAc (47.6 g, 480 mmol). The mixture was stirred at room temperature with N₂bubbling for 30 minutes. Then the reaction was heated at 100 ⁰C for 3 hours. The solution was filtered, evaporated under vacuum. The residue was purified over silica gel, eluting with 20% EtOAc / hexanes to afford 4-methoxy-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzaldehyde (3) 37.8 g in 90% yield. ¹H NMR (400 MHz, CHLOROFORM- d) δ ppm 10.34 (s, 1 H), 7.90 (d, J=8.60 Hz, 1 H), 7.26 (s, 1 H), 6.99 (d, J=8.60 Hz, 1 H), 3.86 (s, 3 H), 1.36 (s, 12 H)

Compound 4:

To a clear solution of 4-methoxy-2-(4,4,5,5-tetramethyl-

[l,3,2]dioxaborolan-2-yl)-benzaldehyde (3) (48 g, 180 mmol) in MeOH (anhydrous, 300 mL) was slowly added NaBH₄ (6.96 g, 180 mmol). The reaction was stirred at room temperature for 2 hours. Then IM HCl (100 mL) was slowly added. After stirring for overnight, the MeOH was evaporated under vacuum. The solid was filtered, washed with water and air-dried to afford 6-methoxy-3H- benzo[c][l,2]oxaborol-l-ol (4) 23 g in 77% yield. ¹H NMR (400 MHz, DMSO-J₆) δ ppm 9.11 (s, 1 H), 7.29 (d, J=8.21 Hz, 1 H), 7.23 (d, J=2.34 Hz, 1 H), 7.03 (dd, J=8.40, 2.54 Hz, 1 H), 4.90 (s, 2 H), 3.75 (s, 3 H).

Compound 5:

To a clear solution of 6-methoxy-3H-benzo[c][l,2]oxaborol-l-ol (4) (600 mg, 3.66 mmol) in DCM (anhydrous, 60 mL) was slowly added BBr₃ (1M/DCM, 8.05 mL, 8.05 mmol) at -10 ⁰C. The reaction was stirred for 3 hours, with monitoring by NMR. After all 4 had gone, 30 mL of cold water was added. Then 50 mL of EtOAc was added to extract all organic compounds. The organic layer was washed with cold brine, until the pH of aqueous layer changed to pH 7. The organic layer was dried over Na₂SO₄, filtered, evaporated under vacuum. The residue (-85% HPLC purity) was used directly for the next step reaction without further purification. ¹H NMR (400 MHz, DMSO-J₆) δ ppm 9.29 (s, 1 H), 9.04 (s, 1 H), 7.17 (d, J=8.21 Hz, 1 H), 7.07 (d, J=2.34 Hz, 1 H), 6.85 (dd, J=8.21, 2.34 Hz, 1 H), 4.85 (s, 2 H). ESMS (m/z): 149 (M- H)^“. HPLC: 88.31% (220 nm), 85.02% (maxplot).

Compound 6:

To a solution of 3H-benzo[c][l,2]oxaborole-l,6-diol (5) (300 mg, 2 mmol) in DMSO (30 mL) were added K₂CO₃ (828 mg, 6 mmol) and 3-chloro-4-fiuoro- benzonitrile (933 mg, 6 mmol). The reaction was heated at 90 ⁰C for 7 hours. After the cooling of reaction solution, EtOAc (50 mL) was added. The organic layer was washed with water (5 X 50 mL). The organic layer was evaporated under vacuum. The residue was purified by reverse phase chromatography to afford 3-chloro-4-(l- hydroxy-l,3-dihydro-benzo[c][l,2]oxaborol-6-yloxy)-benzonitrile (6) 190 mg in 33.3% yield. ¹H NMR (400 MHz, DMSO-J₆) δ ppm 9.24 (s, 1 H), 8.22 (s, 1 H), 7.77 (d, J=7.81 Hz, 1 H), 7.50 (d, J=8.20 Hz, 1 H), 7.34 (s, 1 H), 7.28 (d, J=8.20 Hz, 1 H), 7.01 (d, J=8.59 Hz, 1 H), 4.99 (s, 2 H). ESMS (m/z): 284 (M-H)^“. HPLC: 96.41% (220 nm), 96.0% (maxplot).

(X): IS AN 3485

To a clear solution of 3-chloro-4-(l-hydroxy-l,3-dihydro- benzo[c][l,2]oxaborol-6-yloxy)-benzonitrile (6) (136 mg, 0.48 mmol) in THF

(anhydrous, 60 mL) was added lithium aluminum hydride (lM/ether, 1.19 mL, 1.19 mmol) at 0 ⁰C. The reaction was stirred for 2 hours. Then the reaction was quenched with IM HCl (30 mL). MeOH (50 mL) was added and the solution was filtered. The filtrate was evaporated under vacuum. The residue was purified by reverse phase chromatography (biotage, gradient MeOH / H₂O from 10% to 100%) to afford (X) 106 mg (white solid) in 68% yield. ¹H NMR (400 MHz, DMSO-J₆) δ ppm 9.19 (s, 1 H), 8.18 (br, s, 3 H), 7.75 (s, IH), 7.44-7.39 (m, 2 H), 7.19-7.10 (m, 3 H), 4.98 (s, 2 H), 4.03 (q, J=5.50 Hz, 2 H).

ESMS (m/z): 290 (M+H)⁺.

HPLC: 95.9% (220 nm), 96.85% (maxplot).

.

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BEZ235 (NVP-BEZ235)Dactolisib

4-​[2,​3-​dihydro-​3-​methyl-​2-​oxo-​8-​(3-​quinolinyl)-​1H-​imidazo[4, ​5-​c]quinolin-​1-​yl]-​α,​α-​dimethyl-​benzeneacetonitrile

2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-1H,2H,3H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile

2-Methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)- phenyl]-propionitrile

Chemical Formula:  C₃₀H₂₃N₅O

CAS Number: 915019-65-7

Molecular Weight: 469.54

PHASE 2, NOVARTIS

CANCER, BLADDER

NVP-BEZ235 is a dual inhibitor of phosphatidylinositol 3-kinase (P13K)and the downstream mammalian target of rapamycin (mTOR) by binding to the ATP-binding cleft of these enzymes. It specifically blocks the dysfunctional activation of the P13K pathway and induce G(1) arrest. NPV-BEZ235 has been shown to inhibit VEGF induced cell proliferation and survival in vitro and VEGF induced angiogenesis in vivo. It has also been shown to inhibit the growth of human cancer in animal models.

BEZ-235 is an orally active phosphatidylinositol 3-kinase (PI3K) inhibitor in early clinical trials at Novartis for the treatment of advanced breast cancer, renal cell carcinoma, solid tumors and castration-resistant prostate cancer. Phase I clinical trials were also under way at the company for the treatment of glioma, however, no developments in this indication has been reported. Phase II clinical trials are ongoing at Johann Wolfgang Goethe Universität for the treatment of relapsed or refractory acute leukemia.
PI3Ks perform various functions, promoting cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. Mutations leading to increased activity of PI3Ks, including faulty production or action of PI3K antagonists, have been found in many cancers.

……………………………..

WO 2006122806

http://www.google.com/patents/WO2006122806A2?cl=en

…………………………..

WO 2008064093

2-methyl-2-[4-(3-methyl- 2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile of formula I (compound I),

Example 1

2-Methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)- phenyl]-propionitrile

In a suitable lab glass reactor are placed 45.0 g of starting 2[4-(8-bromo-3-methyl-2-oxo-2,3- dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]2-methyl-propionitrile together with 2.25 g of bistriphenylphosphine’palladium dichloride in 445 ml N,N-dimethylformamide. This mixture is heated to 95 ⁰C and then a solution of 22.2 g of 3-quinoline boronic acid in a mixture of 225 ml DMF, 300 ml H₂O and 60 g of KHCO₃ is added. This mixture is heated for 2 h at 95 ⁰C. Then 1080 ml H₂O are added. The product 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl- 2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]propionitrile precipitates. The mixture is cooled within 1.5 h to 0 – 5 °C. After stirring at that temperature for 2 h the crude product is filtered and washed with 300 ml H₂O. This product is dried in vacuo at 60 ⁰C for 18 h, to yield crude product.

40 g of this crude product is dissolved in 200 ml formic acid at 60 ⁰C. 8 g of active charcoal and Smopex 234 are added. The mixture is stirred at 60 ⁰C for 1 h, the charcoal is filtered, the residue washed with 80 ml formic acid and then 175 ml formic acid are distilled off in vacuo. Then 320 ml methanol are added and the mixture is heated at reflux for 3 h. The purified product precipitates from the reaction mixture. The mixture is cooled to 0 – 5 ⁰C within 1 h, then stirred 2 h at that temperature is finally filtered and washed with 80 ml cold methanol. This recrystallisation procedure is repeated again. Finally the twice recrystallised material is dried in vacuo at 60 ⁰C to yield purified 2-Methyl-2-[4-(3-methyl-2-oxo-8-quinolin- 3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]propionitrile.

Example 1a 5-Bromo-2-(2-nitro-vinylamino)-benzoic acid

A suspension of 25 g (16 mmol) of 2-amino-5-bromo-benzoic acid (Fluka, Buchs, Switzerland) in H₂O-HCI (37%) (10:1) is stirred for 8 h and then filtered (solution A). 8.17 g (255 mmol) of nitromethane (Fluka, Buchs, Switzerland) are added over 10 min to an ice- bath cooled mixture of 35 g of ice and 15.3 g (382 mmol) of NaOH. After stirring for 1 h at 0 ⁰C and 1 h at rt, the solution is added at 0 ⁰C to 28 g of ice and 42 ml of HCI (37%) (solution B). Solutions A and B are combined and the reaction mixture is stirred for 18 h at rt. The yellow precipitate is filtered off, washed with H₂O and dried in vacuo at 40⁰C to give the title compound. ES-MS: 287, 289 (M + H)⁺, Br pattern; ¹H NMR (DMSO-d₆): δ 13.7-14.6/br s (1 H), 12.94/d (1 H), 8.07/d (1 H), 8.03/dd (1 H), 7.83/dd (1 H), 7.71/d (1 H), 6.76/d (1 H).

Example 1b 6-Bromo-3-nitro-quinolin-4-ol

29 g (101 mmol) of 5-bromo-2-(2-nitro-vinylamino)-benzoic acid (Example 1a) and 11.9 g (121 mmol) of potassium acetate in 129 ml (152 mmol) of acetic anhydride are stirred for 1.5 h at 120 ⁰C. The precipitate is filtered off and washed with acetic acid until the filtrate is colorless, then is washed with H₂O and dried in vacuo to give the title compound. ES-MS: 269, 271 (M + H)⁺, Br pattern; analytical HPLC: W= 2.70 min (Grad 1).

Example 1c 6-Bromo-4-chloro-3-nitro-quinoline

20 g (74.3 mmol) of 6-bromo-3-nitro-quinolin-4-ol (Example 1b) in 150 ml (1.63 mol) of POCI₃ are stirred for 45 min at 120 °C. The mixture is cooled to rt and poured slowly into ice- water. The precipitate is filtered off, washed with ice-cold water, and dissolved in CH₂CI₂. The organic phase is washed with cold brine, and the aqueous phase is discarded. After drying over MgSO₄, the organic solvent is evaporated to dryness to provide the title compound. ¹H NMR (CDCI₃): J9.20/S (1H), 8.54/d (1H), 8.04/d (1H), 7.96/dd (1H); analytical HPLC: W= 4.32 min (Grad 1).

Example 1d 2-Methyl-2-(4-nitro-phenyl)-propionitrile

O .

To 15 g (92.5 mmol) of (4-nitro-phenyl)-acetonitrile (Fluka, Buchs, Switzerland), 1.64 mg (5.09 mmol) of tetrabutylammonium bromide (Fluka, Buchs, Switzerland) and 43.3 g (305 mmol) of iodomethane in 125 mL of CH₂CI₂ are added 1O g (250 mmol) of NaOH in 125 ml of water. The reaction mixture is stirred for 20 h at RT. After this time, the organic layer is separated, dried over MgSO₄, and evaporated to dryness. The residue is dissolved in diethylether and treated with black charcoal for 30 min, filtered over Celite and evaporated in vacuo to give the title compound as a pale yellow solid. Analytical HPLC: t_ret= 3.60 minutes (Grad 1).Example 1e (2-(4-Amino-phenyl)-2-methyl-propionitrile

16 g (84.1 mmol) of 2-methyl-2-(4-nitro-phenyl)-propionitrile (Example 1d) and 4.16 g of Raney-Ni are shacked in 160 ml of THF-MeOH (1:1) under 1.1 bar of H₂ for 12 h at rt. After completion of the reaction, the catalyst is filtered-off and the filtrate is evaporated to dryness. The residue is purified by flash chromatography on silica gel (hexane-EtOAc 3:1 to 1:2) to provide the title compound as an oil. ES-MS: 161 (M + H)⁺; analytical HPLC: t_ret= 2.13 minutes (Grad 1).

Example 1f 2-[4-(6-Bromo-3-nitro-quinolin-4-ylamino)-phenyl]-2-methyl-propionitrile

18 g (62.6 mmol) of 6-bromo-4-chloro-3-nitro-quinoline (Example 1c) and 11 g (68.9 mmol) of (2-(4-amino-phenyl)-2-methyl-propionitrile (Example 1e) are dissolved in 350 ml of acetic acid and stirred for 2 h. After this time, water is added and the yellow precipitate is filtered off and washed with H₂O. The solid is dissolved in EtOAc-THF (1 :1), washed with sat. aqueous NaHCO₃ and dried over MgSO₄. The organic phase is evaporated to dryness to give the title compound as a yellow solid. ES-MS: 411 , 413 (M + H)⁺, Br pattern; analytical HPLC: t_ret= 3.69 min (Grad 1).

Example 1q 2-[4-(3-Amino-6-bromo-quinolin-4-ylamino)-phenyl]-2-methyl-propionitrile

24 g (58.4 mmol) of 2-[4-(6-bromo-3-nitro-quinolin-4-ylamino)-phenyl]-2-methyl-propionitrile (Example 1e) is shacked in 300 ml of MeOH-THF (1:1) under 1.1 bar of H₂ in the presence of 8.35 g of Raney-Ni for 1 h. After completion of the reaction, the catalyst is filtered off and the filtrate is evaporated to dryness to give the title compound as a yellow foam. ES-MS: 381 , 383 (M + H)⁺, Br pattern; analytical HPLC: W= 3.21 min (Grad 1).

Example 1h

2-[4-(8-Bromo-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-2-methyl- propionitrile

A solution of 5 g (13.1 mmol) of 2-[4-(3-amino-6-bromo-quinolin-4-ylamino)-phenyl]-2- methyl-propionitrile (Example 1g) and 1.59 g (15.7 mmol) of triethylamine in 120 ml CH₂CI₂ is added over 40 min to a solution of 2.85 g (14.4 mmol) of trichloromethyl chloroformate (Fluka, Buchs, Switzerland) in 80 ml of CH₂CI₂ at 0⁰C with an ice-bath. The reaction mixture is stirred for 20 min at this temperature then is quenched with sat. aqueous NaHCO₃, stirred for 5 min and extracted with CH₂CI₂. The organic layer is dried over Na₂SO₄, filtered and evaporated in vacuo to give crude title compound as a brownish solid. ES-MS: 407, 409 (M + H)⁺, Br pattern; analytical HPLC: t_ret= 3.05 min (Grad 1). Example 1i

2-[4-(8-Bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-2- methyl-propionitrile

To a solution of 3.45 g (8.47 mmol) of 2-[4-(8-bromo-2-oxo-2,3-dihydro-imidazo[4,5- c]quinolin-1-yl)-phenyl]-2-methyl-propionitrile (Example 1h), 1.8 g (12.7 mmol) of iodomethane (Fluka, Buchs, Switzerland) and 273 mg (0.847 mmol) of tetrabutylammonium bromide (Fluka, Buchs, Switzerland) in 170 ml of CH₂CI₂ is added a solution of 508 mg (12.7 mmol) of NaOH (Fluka, Buchs, Switzerland) in 85 ml of H₂O. The reaction mixture is stirred for 2 days and 900 mg (6.35 mmol) of iodomethane and 254 mg (6.35 mmol) of NaOH in 5 ml of H₂O are added. The reaction mixture is stirred for 1 day at rt . After this time, the reaction is quenched with H₂O and extracted with CH₂CI₂ (2*). The organic layer is washed with brine, dried over Na₂SO₄, filtered and evaporated in vacuo to give the title compound as a beige solid. ES-MS: 421 , 423 (M + H)⁺, Br pattern; analytical HPLC: t_ret= 3.15 min (Grad 1).

Example 2

2-Methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)- phenyl]propionitrile p-toluenesulfonate salt

26.5 g of 2-Methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1- yl)-phenyl]propionitrile are placed together with 55 ml formic acid into a glass reactor. This mixture is heated to 60 ⁰C to get a clear solution. This solution is clearfiltered and washed with 36 ml formic acid. Then formic acid is distilled off until the volume of the residual solution is 55 ml. Then a solution of 11.3 g of p-toluenesulfonic acid in 228 ml acetone is added at 50 ⁰C, followed by further addition of 822 ml acetone within 30 minutes. The salt precipitates from the reaction mixture. The mixture is cooled to 0 ⁰C within 2 h, stirred at that temperature for 3 h, is then filtered and washed with 84 ml acetone. The product^‘ is dried at 60 ⁰C in vacuo for 18 h to yield 29.8 g (82.4 %) of the 2-Methyl-2-[4-(3-methyl-2-oxo-8- quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]propionitrile p-toluenesulfonate salt (crystalline form A). The crystalline forms of the present invention are synthesized in accordance with the following examples which are illustrative without limiting the scope of the present invention.

Example 3:

Preparation of form A of 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro- imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile

Form A of compound I can be manufactured in the following way: 241 g of free base are dissolved 2.4 I acetic acid at 50 ⁰C. The solution is clearfiltered, washed with 250 ml acetic acid and then at 50 ⁰C 7.2 I of water are added. The free base starts precipitating. The mixture is cooled within 1 h to 25 ⁰C, is then filtered and washed with 10 I H₂O. The free base is then dried in vacuo at 50 ⁰C over night to yield 204 g of free base.

References

Gefitinib

N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine

Gefitinib (INN, /ɡɛˈfɪtɨnɪb/, trade name Iressa, marketed by AstraZeneca and Teva), is a drug used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor(EGFR) in target cells. Therefore, it is only effective in cancers with mutated and overactive EGFR.

Mechanism of action

Gefitinib is the first selective inhibitor of epidermal growth factor receptor‘s (EGFR) tyrosine kinase domain. Thus gefitinib is an EGFR inhibitor. The target protein (EGFR) is a family of receptors which includes Her1(erb-B1), Her2(erb-B2), and Her 3(erb-B3). EGFR is overexpressed in the cells of certain types of human carcinomas – for example in lung and breast cancers. This leads to inappropriate activation of the anti-apoptotic Ras signalling cascade, eventually leading to uncontrolled cell proliferation. Research on gefitinib-sensitive non-small cell lung cancers has shown that a mutation in the EGFR tyrosine kinase domain is responsible for activating anti-apoptotic pathways.^[1][2] These mutations tend to confer increased sensitivity to tyrosine kinase inhibitors such as gefitinib and erlotinib. Of the types of non-small cell lung cancer histologies, adenocarcinoma is the type that most often harbors these mutations. These mutations are more commonly seen in Asians, women, and non-smokers (who also tend to more often have adenocarcinoma).

Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme.^[3] Thus the function of the EGFR tyrosine kinase in activating the anti-apoptotic Ras signal transduction cascade is inhibited, and malignant cells are inhibited.^[4]

Clinical uses

The FDA approved Gefitinib in May 2003 for NSCLC a type of lung cancer,^[5] Gefitinib is currently marketed in over 64 countries.

In June 2005 the FDA withdrew approval for use in new patients due to lack of evidence that it extended life.^[6]

In Europe gefitinib is indicated since 2009 in advanced NSCLC in all lines of treatment for patients harbouring EGFR mutations. This label was granted after gefitinib demonstrated as a first line treatment to significantly improve progression-free survival vs. a platinum doublet regime in patients harbouring such mutations. IPASS has been the first of four phase III trials to have confirmed gefitinib superiority in this patient population.^[7] In most of the other countries where gefitinib is currently marketed it is approved for patients with advanced NSCLC who had received at least one previous chemotherapy regime. However, applications to expand its label as a first line treatment in patients harbouring EGFR mutations is currently in process based on the latest scientific evidence.As at August 2012 New Zealand has approved gefitinib as first line treatment for patients with EGFR mutation for naive locally advanced or metastatic, unresectable NSCLC. This publicly funded for an initial 4 month term and renewal if no progression. ^[8]

In 2014 in the TRANSCOG study Petty et al., demonstarted gefitinib was effective in esophageal cancer patients whose tumours harboured additional copies of the EGFR gene.^[9] While gefitinib has yet to be proven to be effective in other cancers, there is potential for its use in the treatment of other cancers where EGFR overexpression is involved.

Erlotinib is another EGFR tyrosine kinase inhibitor that has a similar mechanism of action to gefitinib.

Experimental Uses

In August 2013, the BBC reported that researchers in Edinburgh and Melbourne found, in a small-scale trial of 12 patients, that the effectiveness of Methotrexate for treating ectopic pregnancy was improved when Gefitinib was also administered.^[10]

Studies

IPASS (IRESSA Pan-Asia Study) was a randomized, large-scale, double-blinded study which compared Gefitinib vs. carboplatin/ paclitaxel as a first line treatment in advanced NSCLC.^[11] IPASS studied 1,217 patients with confirmed adenocarcinoma histology who were former or never smokers. A pre-planned sub-group analyses showed that progression-free survival (PFS) was significantly longer for Gefitinib than chemotherapy in patients with EGFR mutation positive tumours (HR 0.48, 95 per cent CI 0.36 to 0.64, p less than 0.0001), and significantly longer for chemotherapy than Gefitinib in patients with EGFR mutation negative tumours (HR 2.85, 95 per cent CI 2.05 to 3.98, p less than 0.0001). This, in 2009, was the first time a targeted monotherapy has demonstrated significantly longer PFS than doublet chemotherapy.

EGFR Diagnostic tests

Genzyme, QIAGEN, Argenomics S.A. & other companies make tests to detect EGFR mutations, designed to help predict which lung cancer patients may respond best to some therapies, including Gefitinib and Erlotinib.

The tests examine the genetics of tumors removed for biopsy for mutations that make them susceptible to treatment.

The EGFR mutation test may also help AstraZeneca win regulatory approval for use of their drugs as initial therapies. Currently the TK inhibitors are approved for use only after other drugs fail. In the case of gefitinib, the drug works only in about 10% of patients with advanced non-small cell lung cancer, the most common type of lung cancer.

Adverse effects

As gefitinib is a selective chemotherapeutic agent, its tolerability profile is better than previous cytotoxic agents. Adverse drug reactions (ADRs) are acceptable for a potentially fatal disease.

Acne-like rash is reported very commonly. Other common adverse effects (≥1% of patients) include: diarrhoea, nausea, vomiting, anorexia, stomatitis, dehydration, skin reactions, paronychia, asymptomatic elevations of liver enzymes, asthenia, conjunctivitis, blepharitis.^[12]

Infrequent adverse effects (0.1–1% of patients) include: interstitial lung disease, corneal erosion, aberrant eyelash and hair growth.^[12]

Iressa was approved and marketed from July 2002 in Japan, making it the first country to import the drug.

Gefitinib is an anilinoquinazoline which is useful in the treatment of a certain type of lung cancer (non-small cell lung cancer or NSCLC) that has not responded to chemotherapy. The chemical name for gefitinib is 4-(3′-chloro-4′-fluoroanilino)-7- methoxy-6-(3-morpholinopropoxy) quinazoline. Its structural formula is :

Gefitinib

The earliest known synthesis of gefitinib was first disclosed in the patent application WO 96/33980. The synthetic method employed is depicted in the following reaction scheme 1.

The process involves selective demethylation of 6,7-dimethoxy quinazoline-4-one using methanesulfonic acid and L-methionine to get its 6-hydroxyl derivative, which is protected by acetylation. The acetoxy compound is chlorinated and condensed with chloro-fluoroaniline. Hydrolysis of the acetoxy compound followed by etherification with 3-morpholinopropyl chloride gives crude gefitinib which is purified by column chromatography. The process suffers from many disadvantages as it involves several protection and deprotection steps. The selective demethylation using methionine results in isomeric impurities and has to be purified or else the impurity carries over to subsequent steps in the preparation of gefitinib making it more difficult to isolate a pure product. The process also leads to formation of an N-alkylated impurity at the final stage which must be separated by column chromatography to obtain gefitinib.

Several other approaches are also described in the literature to make gefitinib.

WO 2004/024703 discloses a process for the preparation of gefitinib starting from 3- hydroxy-4-methoxy benzonitrile which involves condensation of 3-hydroxy-4-methoxy benzonitrile with morpholino propyl chloride, nitration, reduction with sodium dithionite to amino compound, hydrolysis of nitrile to amide, cyclisation in the presence of formamide to obtain quinazoline, chlorination with phosphorous oxychloride and finally condensation with chloro-fluoro aniline to obtain gefitinib. The process involves multiple steps and hence is time consuming.

WO 2005/023783 discloses a process for the manufacture of gefitinib starting from 2- amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile. The process involves a rearrangement reaction of 3-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)3,4-dihydroqunazoline-4-imine. The process is not feasible industrially, as the basic raw material is not readily available on a commercial scale and involves the use of excess 3-chloro-4-fluoroaniline which is expensive. A further draw back of the process is in the isomerization of the 4-imine compound which requires anhydrous conditions at high temperature for a longer duration of 96 hours. All the problems associated with this prior art process are overcome by the novel process of the present invention.

WO2005/070909 discloses a process for the preparation of gefitinib starting from isovanillin as depicted in scheme 2

The WO’ 909 process has disadvantages as it forms cis-trans geometrical isomers of the oxime, which have different reactivities. Furthermore, the process uses a large excess of acetic anhydride to convert the oxime to the nitrile at higher temperature.

The patent applications 901 /CHE/2006 and 903/CHE/2006 disclose another route for preparing gefitinib starting from isovanillin. The process involves formation of a formamido compound [N’-[2-cyano-4-{3-(4-morpholinyl)propoxy}phenyl]-N,N-dimethyl formamide], which is unstable and may result in undesired impurities in the final condensation with 3-chloro-4-fluoro aniline, thereby making the process less feasible on an industrial scale. The processes disclosed in the prior art are cumbersome. Therefore, there exists a need for a more economical and efficient method of making gefitinib which is suitable for industrial scale-up.

The process of the present invention avoids use of reagents such as sodium dithionite, acetic anhydride and allows substantial reduction in the number of problems associated with these reagents.

…………………

CLIP

Gefitinib A mixture of compound 1 starting acid 1 is heated in a closed loop to obtain ammonium 2 in 2 classic resonant3 , the 7 – Bit methoxy given electron, so to 6 – position methoxy-electron density is low, so that the acidic conditions demethylase (with methionine and methanesulfonic acid) may optionally occur in the 6 – position, to give compound 4 , 4 of the phenolic hydroxyl group with an acetyl group after protection thionyl chloride to get five , five and six occurred SNAr reaction 7 , 7deacetylated with ammonia and chloride 8 reaction gefitinib.

……………..

CLIP

……………….

\PATENT

http://www.google.com/patents/EP2155656A2?cl=en

Detailed Description of the Invention In an embodiment of the present invention, there is provided an improved synthesis of gefitinib from isovanillin , as depicted below in reaction scheme 3.

isovanillin Formula II Formula in

Formula V Formula IV

W

Gefitinib Formula I

An alternate route for the synthesis of gefitinib from isovanillin according to the present invention is depicted below in reaction scheme 4.

Nitration

Step a Step b

Isovanillin Formula VIII Formula IX

Formula XII Formula XI Formula X

Formula XIII Formula XIV

…………

http://www.allindianpatents.com/patents/236843

The process of preperation of 4-(3-chloro-4-flurophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-quinazoline is substantially as herein described with reference to the foregoing example.
a) 4-methoxy-3-[3-(4-morpholinyl)-propoxy] benzaldehyde:
A mixture of 3-hydroxy -4- methoxy benzaldehyde (20g), 3-
morpholinopropyl chloride (28g), potassium carbonate (50g) and DMF
(140ml) was stirred and heated to 100°C for 3 hours. The reaction mixture
was cooled and filtered. The filtrate was evaporated and the residue
obtained was dissolved in ethyl acetate (200ml). The ethyl acetate layer was
washed with water, dried over anhydrous sodium sulphate. Evaporation of
ethyl acetate yielded 4-methoxy-3-[3-(4-morpholinyl)-propoxy]
benzaldehyde (34.8 gms,95%) of the formula II.
b) 4-methoxy -3[3-(4-morpholinyl)-propoxy] benzonitrile:
The above 34.8 gms of compound was dissolved in 200 ml methanol, and to this added 34.8 g of hydroxylamine hydrochloride and 35 ml of pyridine. The reaction mixture was heated to reflux for 3 hours and then cooled to 10 °C. The material precipitated mass was filtered and the solid mass obtained was washed with chilled methanol (50ml) and dried at room temperature. To this dried material was added 2 volumes of acetic anhydride and heated to 110°C for 4 hours. Then quenched the reaction mass in water and adjusted the pH to 8.0 with sodium bicarbonate and extracted with methylene dichloride. Washed the methylene dichloride layer with water and dried over calcium chloride. On evaporation of the solvent 4-methoxy -3[3-(4-morphoinyl)-propoxy] benzonitrile (31 gms, 90%) of the formula III.
NMR spectrum (CDCI3): 5 2.05 (m, 2H), 2.53 (m, 6H), 3.72 (m, 4H), 3.91 (s, 3H). 4.10(mf 2H), 6.89 (d, 1H), 7.25 (d, 1H), 7.28 (dd, 1H).
c) 4-Methoxy-5-[3-(4-morpholinyl)-propoxy]- 2-nitro benzonitrile: The above compound (31 gms) of the formula III was dissolved in 30 ml of 70% nitric acid and this was added to 55°C preheated 30 ml of 70% nitric acid slowly over a period of 2 hours under stirring. After completion of the addition, continued stirring at the same temperature for further an hour. Cooled the reaction mixture and quenched in cool water and

adjusted the pH to 8.0. The precipitate obtained was filtered and washed with ice cold water and dried the material at 50°C to get 27 gms yellow solid 4-Methoxy-5-[3-(4-morphoiinyl)-propoxy]- 2-nitro benzonitrile (75%) of the formula IV.
NMR spectrum (DMSO-d6): 5 2.18 (m, 2H), 3.26 (m, 4H), 3.53 (m, 4H), 3.99 (s, 3H), 4.04 (m, 2H), 4.29 (m, 2H), 7.73 (s, 1H), 7.91 (s, 1H). d) Synthesis of 2-amino-4-methoxy-5-(3-morpholinopropoxy) benzonitrile: To 4-methoxy-5-[3-(4-morpholinyl) propoxy]-2-nitro benzonitrile (10 g) was added acetic acid (75ml) and water(75ml), stirred the reaction mass for about 10 min, added Iron powder (7g) in portions over a period of 2hrs, Stirred the reaction mixture for about Vi hr at room temperature adjusted PH of the reaction mass to 8 using ammonia solution, extracted the material into ethylacetate, the organic layer was dried over sodium sulfate and concentrated to get product(6g)
1HNMR (CDCI3): 5 2.01 (m, 2H), 2.51 (m. 6H), 3.72 (t, 4H), 3.84 (s, 3H), 3.97 (t, 2H), 4.14 (brs, 2H), 6.23 (s, 1H), 6.85 (s, 1H).
(e) Synthesis of N’-(3-chloro-4-fluorophenyl) N,N-dimethyl formamidine.
To 3-chloro-4-flouro aniline (10g, 0.0687moles) was added Toluene (40ml), N,N-dimethylformamide dimethyl acetal (18.3ml, 0.1374moles) and acetic acid (0.5ml), heated the reaction mixture to 110°C and stirred for about 2hrs, distilled off toluene to yield dark brown liquid (11g)
1HNMR (CDCI3): 5 3.0 (s, 6H), 6.75 (m, 1H) 6.94 (m, 1H), 6.98 (m, 1H), 7.45 (s, 1H).
(f) Synthesis of Gefitinib:
To 2-amino-4-methoxy-5-(3-morpholinopropoxy) benzonitrile (5g, 0.0172moles) was added toluene (30ml), N’-(3-chloro-4-fluorophenyl) N, N-dimethyl formamidine (3.44g, 0.0172moles) and acetic acid (0.5ml) refluxed the reaction mixture for about 4hrs cooled the reaction mass to room temperature, toluene layer was separated washed with water and chilled toluene layer to yield crude gefitinib and which was further recrystallized from
methano! to get pure off-white crystalline compound(3g) having the mp
194-198°C
UV, IR, NMR spectral data together with elemental analysis is in complete
agreement with those of standard substance of Gefitinib

………………

NMR

http://nopr.niscair.res.in/bitstream/123456789/29472/1/IJCB%2053B(10)%201269-1274.pdf

MP 193-95

……………….

PAPER

An efficient, economical and large-scale convergent synthesis of epidermal growth factor receptor- tyrosine kinase inhibitors gefitinib (1, Iressa) and erlotinib (2, Tarceva) approved by U.S. FDA for the treatment of non-small-cell lung cancer is described. The formation of 4-anilinoquinazolines are achieved in a simple one-pot reaction of suitable formamidine intermediates and substituted anilines involving Dimroth rearrangement, thereby avoiding the need to make quinazolin-4(3H)-one intermediates, which require a large experimental inputs. Using this process, we have produced drug candidates 1 with overall yield of 66% from 4-methoxy-5-[3-(4-morpholinyl) propoxy]-2-nitrobenzonitrile (3) and 2 with 63% from 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile (6) on a multigram scale.

1as off-white solid (304 g, 70% yield). Mp 193–195 °C. HPLC purity >99%.

¹H NMR (CDCl_3, 200 MHz): δ 2.11 (m, 2H), 2.46–2.59 (m, 6H), 3.74 (dd, J = 4.5 and 4.4Hz, 4H), 3.98 (s, 3H), 4.17 (t,J = 6.5Hz, 2H), 7.09 (s, 1H), 7.16 (t, J = 8.8Hz, 1H), 7.26 (s, 1H), 7.34 (brs, 1H, exchangeable with D₂O), 7.50–7.58 (m, 1H), 7.84–7.88 (m, 1H), 8.66 (s, 1H). MS (m/z): 446(M⁺),128, 100.

Elemental Anal. Calcd for C₂₂H₂₄ClFN₄O₃: C, 59.19; H, 5.38; N, 12.55. Found: C, 59.17; H, 5.21; N, 12.33.

NMR

MASS

………

SEE

http://aerodrive.ccchwc.edu.hk/~lck/1011_7s/10117sgp05ppt.pdf

http://shodhganga.inflibnet.ac.in:8080/jspui/bitstream/10603/18581/4/04_list%20of%20figures.pdf.pdf

http://industrialgreenchem.com/pdf-docs/presentations/igcw%202013/pharma/Dr.%20Manjunatha.pdf

…………..

Synthesis of Gefitinib[J]. CJPH, 2013, 44(11): 1081-1083..

http://www.cjph.com.cn/EN/abstract/abstract583.shtml

Gefitinib was synthesized from 3-hydroxy-4-methoxybenzaldehyde via conversion of aldehyde to nitrile, condensation with N-(3-chloropropy1)morpholine, nitration and reduction to give 2-amino-4-methoxy-5-(3-morpholin-4-ylpropoxy)benzonitrile, which was subjected to amidination with 3-chloro-4-fluoroaniline and cyclization in the presence of formic acid with an overall yield of about 44％.

…………..

References

Updates

CAS NO. 184475-35-2, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine H-NMR spectral analysis

CAS NO. 184475-35-2, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine C-NMR spectral analysis

SYNTHESIS

Marzaro, Giovanni; Guiotto, Adriano; Pastorini, Giovanni; Chilin, Adriana Tetrahedron, 2010 , vol. 66,  4 pg. 962 – 968

Chandregowda, Venkateshappa; Venkateswara Rao, Gudapati; Chandrasekara Reddy, Goukanapalli Heterocycles, 2007 , vol. 71,  1 p. 39 – 48

Chandregowda, Venkateshappa; Rao, Gudapati Venkateswara; Reddy, Goukanapalli Chandrasekara Synthetic Communications, 2007 , vol. 37,  19 pg. 3409 – 3415

Ming, Dong Li; You, Guang Zheng; Ji, Min Molecules, 2007 , vol. 12,  3 pg. 673 – 678

Knesl, Petr; Roeseling, Dirk; Jordis, Ulrich Molecules, 2006 , vol. 11, 4 pg. 286 – 297

Heterocycles, , vol. 71,  1 p. 39 – 48

Journal of Labelled Compounds and Radiopharmaceuticals, , vol. 48,  11 pg. 829 – 843

Synthetic Communications, , vol. 37,  19 pg. 3409 – 3415

WO2013/180403 A1, ;

…………………..

http://www.google.com/patents/WO2013180403A1?cl=en

N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib) represented by Chemical Formula 1 below is a quinazoline derivative useful in treatment of non-small cell lung cancer. The structure of gefitinib is shown in the following Chemical Formula 1.

[Chemical Formula 1]

WO 96/33980 discloses the gefitinib synthesis method as represented in Scheme 1 below.

[Scheme 1]

According to the synthesis method of Scheme 1, 6,7-dimethoxy quinazolin-4-one as a starting material is subjected to selective demethylation, condensation with chlorofluoroaniline and then etherification with 4-(3-morpholinopropyl)chloride, thereby synthesizing gefitinib. Because gefitinib thus synthesized contains an excess of an N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine in the final step, the impurity should be separated via column chromatography, undesirably lowering the yield and making it difficult to achieve commercial production.

To solve such problems, WO 2004/024703 discloses a method of synthesizing gefitinib from a start material of 3-hydroxy-4-methoxy benzonitrile as shown in Scheme 2 below.

[Scheme 2]

In the synthesis method of Scheme 2, a morpholinopropyl group is introduced before forming a quinazoline ring, thus suppressing the production of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine which is the N-alkylated impurity. However, reduction of a nitro compound, formation of a quinazoline ring, and chlorination of the quinazoline ring in the final step to carry out condensation with chlorofluoroaniline are performed in the presence of the morpholinopropyl group, undesirably complicating the reaction process and lengthening the reaction time.

WO 2008/125867 discloses a method of synthesizing gefitinib from a start material of isovanilin as shown in Scheme 3 below.

[Scheme 3]

In the synthesis method of Scheme 3, propoxychloride is introduced before forming the quinazoline ring, thus suppressing the production of the N-alkylated impurity. After a quinazoline ring is formed and a morpholine group is introduced, chlorofluoroaniline is introduced, thus synthesizing gefitinib. However, a chloropropyl group and a morpholine group are separately introduced, instead of the morpholinopropyl group, thus increasing the number of synthesis steps, and also, the nitro reduction and the quinazoline ring reaction are performed in the presence of the chloropropyl group, undesirably causing the production of an impurity.

Additionally, WO 2005/023783 discloses a method of synthesizing gefitinib from imine via a rearrangement reaction, and WO 2005/070909 discloses a method of synthesizing gefitinib by performing nitrilization of oxime and then forming a quinazoline ring.

However, the preparation methods mentioned in the prior techniques produce an excess of impurity or include other routes to suppress the formation of the impurity, undesirably increasing the number of preparation steps and thus resulting in complicated processes and a long synthesis time, and thereby these methods are unsuitable for commercial production.

Therefore, there is required a method of efficiently and simply preparing gefitinib, which may minimize the production of an impurity and be suitable for use in industrial production.

[Citation List]

[Patent Literature]

(Patent Document 1) WO 96/33980

(Patent Document 2) WO 2004/024703

(Patent Document 3) WO 2008/125867

(Patent Document 4) WO 2005/070909

<Example 3-1> Preparation of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib)

About 123.0 g of 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol and about 1100.0 mL of N,N-dimethylformamide were placed in a flask. The resulting mixture was suspended with stirring while about 186.0 g of potassium carbonate and about 4.7 g of N,N-dimethylaminopyridine were added. The reaction mixture was cooled to about -10℃, slowly added with about 77.0 g of iodotrimethylsilane while paying attention to heat generation, and stirred at about 15℃ for about 1 hr. Then about 75.5 g of 4-(3-chloropropyl)morpholine was diluted with about 130.0 mL of N,N-dimethylformamide and then slowly added. The reaction mixture was heated to about 80℃ and stirred for about 2 hr. The termination of the reaction was confirmed using HPLC and TLC. The reaction product was cooled to about 20℃, slowly added with 2460.0 mL of purified water, and stirred for 30 min, and the produced solid was filtered. The obtained solid was washed with about 490.0 mL of purified water and then dried in a vacuum at about 50℃ for about 3 hr, yielding about 154.7 g of the title compound N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib) as pale yellow powder.

HPLC purity: 99.21% (N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine: 0.3%)

¹H-NMR (400MHz, DMSO-d₆): 2.0 (m,2H), 2.4 (m,6H), 3.7 (m,4H), 3.9 (s,3H), 4.2 (t,2H), 7.2 (s,1H), 7.4 (t,1H), 7.8 (m,2H), 8.2 (m,1H), 8.5 (s,1H), 9.6 (s,1H)

<Example 3-3> Preparation of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib)

About 8.3 g of the title compound N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib) as pale yellow powder was obtained in the same manner as in Example 3-2, with the exception that dimethylsulfoxide (DMSO) was used as the solvent, instead of N,N-dimethylacetamide (DMAC).

HPLC purity: 98.89% (N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine: 0.7%)

<Example 4-2> Purification of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib)

About 8.6 g of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine obtained in Example 3-2 was suspended with stirring in about 129.0 mL of toluene and about 65.0 mL of anhydrous ethanol, and heated to about 40℃ so as to be thoroughly dissolved. About 1.9 g of neutral activated carbon was added into the resulting solution, stirred for about 1 hr, and filtered to thus remove the activated carbon. The filtrate was concentrated to about 90 mL, and stirred for about 30 min, and the produced solid was filtered. The obtained solid was washed with about 20.0 mL of toluene, and dried at about 40℃ for about 3 hr, thus obtaining about 7.3 g of white gefitinib.

The purified gefitinib was added to about 125.0 mL of anhydrous ethanol to prepare a suspension, which was then refluxed with stirring at about 75℃ so that gefitinib was thoroughly dissolved, and then further stirred for about 1 hr. The solution was gradually cooled to about 20℃ and the produced solid was stirred for about 30 min and then further stirred at about 5℃ for about 1 hr. The obtained solid was filtered, washed with about 7.0 mL of anhydrous ethanol, and dried in a vacuum at about 45℃ for about 5 hr, yielding about 6.5 g of purified white N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib).

HPLC purity: 99.89% (without N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine)

<Example 4-3> Purification of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib)

About 6.2 g of purified white N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib) was obtained in the same manner as in Example 4-1, with the exception that the gefitinib prepared in Example 3-3 was used.

HPLC purity: 99.87% (N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine: 0.03%)

Erlotinib

N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)
quinazolin-4-amine

Erlotinib hydrochloride (trade name Tarceva) is a drug used to treat non-small celllung cancer, pancreatic cancer and several other types of cancer. It is a reversibletyrosine kinase inhibitor, which acts on the epidermal growth factor receptor (EGFR). It is marketed in the United States by Genentech and OSI Pharmaceuticals and elsewhere by Roche

Erlotinib is an EGFR inhibitor. The drug follows Iressa (gefitinib), which was the first drug of this type. Erlotinib specifically targets the epidermal growth factor receptor (EGFR)tyrosine kinase, which is highly expressed and occasionally mutated in various forms of cancer. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor.^[1] For the signal to be transmitted, two EGFR molecules need to come together to form a homodimer. These then use the molecule of ATP to trans-phosphorylate each other on tyrosine residues, which generates phosphotyrosine residues, recruiting the phosphotyrosine-binding proteins to EGFR to assemble protein complexes that transduce signal cascades to the nucleus or activate other cellular biochemical processes. By inhibiting the ATP, formation of phosphotyrosine residues in EGFR is not possible and the signal cascades are not initiated.

• Official Tarceva website
• Tarceva Discussion Group for Cancer Patients

Erlotinib hydrochloride (1), chemically named as N-(3-ethynylphenyl)-6,7-bis-(2-meth- oxyethoxy)-4-qumazolimmine monohydro chloride, is an inhibitor of oncogenic and proto- oncogenic protein tyrosine kinases, e.g. epidermal growth factor receptor (EGFR). Erlotinib is therefore useful in the treatment of proliferative disorders and is currently marketed for the treatment of lung cancer and pancreatic cancer.

(Erlotinib Hydrochloride)

(1)

It has been reported that erlotinib hydrochloride can exist in different polymorphic forms. The manufacturing process for many pharmaceuticals is hindered by the fact that the organic compound which is the active ingredient can exist in more than one polymorphic form. It is essential in pharmaceutical development to ensure that the manufacturing process for the preparation of the active ingredient affords a single polymorph with a consistent level of polymorphic purity. If the manufacturing process produces a product with varying degrees of polymorphic purity and/ or or where the process does not control polymorphic inter-conversion, it could lead to serious problems in dissolution and/ or bioavailability in the finished pharmaceutical composition comprising the active ingredient, Erlotinibhydrochloride is disclosed in patent US 5,747,498 and details of the disclosed method for the preparation of erlotinib hydrochloride are described in Scheme 1.

Scheme 1

4-Chloro-6,7-bis-(2-methoxyed oxy)qiunazoline (2) was reacted with 3-emynylaniline (3) or its hydrochloride salt using various solvents and pyridine as a base to yield erlotinib hydrochloride (1) which was treated widi a biphasic mixture consisting of saturated aqueous NaHC0₃, chloroform and methanol, to formerlotinib base (4). The base (4) obtained in the organic phase was purified by flash chromatography to afford purified erlotinib base. The purified base was further treated with hydrochloric acid in the presence of diethyl ether and chloroform to yield erlotinib hydrochloride.

This isolation of purified erlotinib base required the use of a lengthy workup process including column chromatography and required the chlorinated solvent, chloroform, which is not particularly suitable £01 commercial production of pharmaceuticals. Furthermore, the p irification by column chromatography is neither economical nor feasible at industrial scale. In addition, substantially pure erlotinib could not be obtained.

Two crystalline forms of erlotinib hydrochloride (polymorph A and polymorph B), were characterized by XRPD in patent application, WO 01/34574. Erlotinib hydrochloride can be obtained in form A or in a mixture of polymorph A and B, by refluxing 3-ethynylaniline and 4-chloro-6,7-bis-(2-methoxyemoxy)-qitiiiazoline in a mixture of toluene and acetonitrile. This afforded polymorph A or a mixture of polymorph A and B. It was also disclosed that the formation of polymorph A was favoixred by reducing the amounts of acetonitrile with respect to toluene.

Furthermore, erlotinibhydrochloride polymorph A can be converted into polymorph B by refluxing the polymorph A with alcohol/water. Consequently, in the disclosed methods, there was always contamination of form A with form B and vice-versa. In addition, the products of the reaction are not chemically pure and difficult to purify thereafter. Consequently, these methods are not suitable for preparation of commercial quantities of pure polymorph A.

A process for the preparation of erlotinib hydrochloride, polymorph E by condensation reaction of 3-emynylaiiiline and 4-chloro-6,7-bis-(2-memoxyethoxy)quii azoline in ( , , )- trifiuorotoluene and HC1 was disclosed in U.S. Patent application 2004/0162300. Polymorph E was characterized by XRPD, IR and melting point. However, (α,α,α)- trifluorotoluene is a highly flammable and dangerous solvent for the environment and is not suitable for commercial production. A process for the preparation of erlotinib hydrochloride, polymorph A by reaction of erlotinib base widi aqueous or gaseous HC1 was disclosed in US 2009/0131665. In this method, toluene, a mixture of toluene and methanol, TBME, ethyl acetate, 1-butanol or MIBK were used as a solvent.

However, when DCM, diethyl ether, isopropyl acetate, was used as a solvent, polymorph B was formed. In practice, it has been found that the disclosed methods are inconsistent and afford polymorphic mixtures. In particular, example 1 of US 2009/131665 was repeated and erlotinib hydrochloride was obtained with only 97% purity. In addition, XRPD analysis showed d at the example afforded form B or mixtures of forms A and B. Furthermore, several crystallizations of erlotinib hydrochloride, obtained from repetition of the example, using various solvents and their combinations would not yield a product pure enough to comply with ICH guidelines.

A process for the preparation of a hydrate of erlotinib hydrochloride comprising crystallization of erlotinib hydrochloride using water as solvent, preferably in the absence of organic solvent was disclosed in US 20080167327. This patent also disclosed the process to prepare hemihydrate polymorph form I as well as form II.

A process for the preparation of erlotinib hydrochloride, polymorph M, N and P by reaction of erlotinib base and aqueous or gaseous HC1 dissolved in organic solvents was disclosed in WO 2008/102369.

A process for the preparation of erlotinib hydrochloride by condensation reaction of 4- chloro~6,7-bis-(2-me oxyemoxy)-quinazoline and 3-ethynylaniline in isopropyl alcohol as a solvent and pyridine as a base was disclosed in Molecules Journal (Vol, 11, 286, 2006) but no details on the polymorph were disclosed.

A method for the preparation of erlotinib hydrochloride polymorph A comprising passing hydrochloride gas onto solid erlotinib base containing residual amounts of isopropanol was disclosed in WO 2010/040212. However, in practice it was found that the process did not afford chemically or polymorphically pure product. Repetition of example 1 (page 8) of WO 2010/040212 to prepare erlotinibhydrochloride, by reaction of erlotinib base and gaseous HQ in IPA as a solvent, afforded a mixture of polymorph A and polymorph B (as checked by XRPD).

A process for the preparation of acid salts of erlotinib by reaction of 4-chloro-6,7-bis-(2- memoxyemoxy)-quinazoline and 3-emynykniline or an acid salt of 3-emynylaniline under acidic conditions to form the corresponding erlotinib salt was disclosed in US 2010/0094004.

In order to complete the reaction, several hours (6 hours) of reflux was required and hence it is not a cost effective process. In addition, in practice it was found that the process did not afford chemically or polymorplxLcally pure product. A process £oi the preparation of erlotinib base, polymorph Gl, G2 and G3 was disclosed in WO 2009/002538 and WO 2010/05924.

Scheme 2

A method for the preparation of eiiotinib hydrochloride was disclosed in US 2009/0306377. The method, illustrated in Scheme 2, involves treating 6,7-dimethoxy- 4(3H)-quinazolone (5) with hydrobiOmic acid or pyridine-hydrochloric acid to afford 6,7- dihydroxy-4(3H)-quinazolone (6), which was diacetylated with acetic anhydride to afford diester (7), which was treated with oxalyl chloride/DMF to afford 4-chloro-6,7- ctiacetoxyquinazoline (8). Compound (8) was condensed with 3-e ynylaniline to afford JV- (3-ethynylphenyl)-6,7-dihydfoxy-4-quinazolinamine hydrochloride (9), which was converted into the diol N-(3-emynylphenyl)-6,7-dmyckOxy-4-quinazolinamine (10) by treatment with aqueous ammonia/methanol.

The diol (10) was treated with 2-iodo-ethylmethyl ether to yield compound (4) which on treatment with HC1 afforded erlotinib hydrochloride (1). However, this preparation of erlotinib hydrochloride is a long synthetic route and gives low yields and requires very toxic reagents like pyridine, HBi and controlled reagents like acetic anhydride. Hence, it is not suitable for large scale production. Object of the invention

The priot art processes described above for the preparation of erlotinib and its salts have major disadvantages with respect to the formation and removal of process related chemical and polymorphic impurities; poor commercial viability due to die use of hazardous reactants; expensive, time consuming separation methods such as column chromatography and/ or low yields and purity of final and intermediate products.

As the commercial production of erlotinib hydrochloride is of great importance, for the treatment of cancer, and in view of the above disadvantages associated with the prior art there is a real need for alternative and improved processes for the preparation of erlotinib hydrochloride which do not involve multiple steps and further eliminates the need for cumbersome purification techniques, particularly for the removal of the chemical and polymorphic impurities. The alternative processes must be economical and high yielding and provide erlotinib and its salts with a high degree of chemical and polymorphic purity.

U.S. Patent No. 5,747,498 disclosed 4-(substituted phenylamino) quinazoline derivatives, processes for their preparation, pharmaceutical compositions in which they are present and method of use thereof. These compounds are Tyrosine Kinase Inhibitors and are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. Among them, erlotinib hydrochloride, chemically N-(3-ethynylphenyl)-6,7-bis(2-methoxy ethoxy)-4-quinazolinamine hydrochloride is a selective inhibitor of the erbB family of oncogenic and protooncogenic protein tyrosine kinases, such as epidermal growth factor receptor (EGFR), and is useful for the treatment of proliferative disorders, such as cancers, particularly non small cell lung cancer, pancreatic cancer, ovarian cancer, breast cancer, glioma, head cancer or neck cancer.

Polymorphism is defined as “the ability of a substance to exist as two or more crystalline phases that have different arrangement and /or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and / or different configurations of the molecules”. Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).

Solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other.

Erlotinib hydrochloride can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.

The U.S. Patent No. 5,747,498 (herein after referred to as the ‘498 patent) makes no reference to the existence of specific polymorphic forms of erlotinibhydrochloride. In this patent, it is disclosed that the compound is isolated according to conventional techniques; more precisely, according to the embodiments exemplified, crude erlotinib hydrochloride residue (obtained by reaction of 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline with 3-ethynylaniline or its hydrochloride salt in a solvent such as a d-Cβ-alcohol, dimethylformamide, N-methylpyrrolidin-2-one, chloroform, acetonitrile, tetrahydrofuran, 1,4-dioxane, pyridine or other aprotic solvents, preferably isopropanol) is basified with saturated aqueous NaHCO₃ in the presence of methanol and chloroform followed by flash chromatography on silica using 30% acetone in hexane to afford erlotinib free base, which is further treated with hydrochloric acid in the presence of diethyl ether and chloroform to give erlotinib hydrochloride (melting point: 228° – 230⁰C).

PCT Patent Publication No. WO 99/55683 disclosed erlotinib mesylate anhydrate and hydrate polymorphic forms, their method of preparation and pharmaceutical compositions containing thereof.

PCT Patent Publication No. WO 01/34574 A1 (herein after referred to as the ‘574 patent publication) described two crystalline forms of erlotinib hydrochloride (polymorph A and polymorph B), characterized by powder X-ray diffraction (p-XRD) pattern. The publication further taught that the synthetic procedure described and exemplified in the ‘498 patent produces the erlotinib hydrochloride as a mixture of the polymorphs A and B.

TARCEVA (erlotinib), a kinase inhibitor, is a quinazolinamine with the chemical name N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. TARCEVA contains erlotinib as the hydrochloride salt that has the following structural formula:

Erlotinib hydrochloride has the molecular formula C₂₂H₂₃N₃O₄•HCl and a molecular weight of 429.90. The molecule has a pKa of 5.42 at 25oC. Erlotinib hydrochloride is very slightly soluble in water, slightly soluble in methanol and practically insoluble in acetonitrile, acetone, ethyl acetate and hexane.

Aqueous solubility of erlotinib hydrochloride is dependent on pH with increased solubility at a pH of less than 5 due to protonation of the secondary amine. Over the pH range of 1.4 to 9.6, maximal solubility of approximately 0.4 mg/mL occurs at a pH of approximately 2.

WO2012028861

wo2007060691

………………….

PATENT

http://www.google.com/patents/WO2008122776A2?cl=en

Erlotinib is a Human Epidermal Growth Factor Receptor Type 1 /Epidermal Growth Factor Receptor (HER1/EGFR) tyrosine kinase inhibitor.

Erlotinib is described chemically as N-(3-ethynylpheny!)-6,7-bis(2- methoxyethoxy)quinazolin-4-amine, and its hydrochloride salt is represented by the compound of Formula I.

Erlotinib is disclosed in EP0817775 which also a discloses process for its preparation, which involves adding 3-ethynylaniline and 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline in isopropanol containing pyridine and then refluxing the mixture for 4 hours under the atmosphere of dry nitrogen. The solvent is removed and residue is extracted in 10% methanol in CHCI₃ and saturated aqueous NaHCO₃. N-(3-ethynylphenyl)-6,7-bis(2- methoxyethoxy)quinazolin-4-amine base is separated chromatographically and converted to the hydrochloride salt in a solvent such as CHCI₃ using hydrochloric acid.

EP1044969 claims a method for preparing intermediates and compounds covering erlotinib. This patent discloses a process for preparing N-(3-ethynylphenyl)-6,7-bis(2- methoxyethoxy)quinazolin-4-amine which involves stirring 4-[3-[[6,7-bis(2-methoxyethoxy)- 4-quinazolinyl]amino]phenyl]-2-methyl-3-butyn-2-ol with anhydrous sodium hydroxide and 2-methoxyethanol and heating at reflux for 47 hours. The reaction mixture is cooled to 20- 25°C and concentrated HCI is added to it. The resulting mixture is granulated at 20-25°C to crystallize the product.

Indian patent application 902/CHE/2006 discloses a process for preparation of N-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine hydrochloride. The process involves reacting 3,4-dihydroxy benzaldehyde with substituted ethylmethyl ether in the presence of an inert solvent and base to obtain 3,4-bis(2-methoxyethoxy) benzaldehyde. This 3,4-bis(2-methoxyethoxy) benzaldehyde is converted to 3,4-bis(2-methoxyethoxy) benzaldoxime in the presence of a base and organic solvent and is further dehydrated to 3,4-bis(2-methoxyethoxy) benzonitrile. The benzonitrile so obtained is nitrated to obtain 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile which is further reduced to obtain 2-amino- 4,5-bis(2-methoxyethoxy) benzonitrile. N’-(3-ethynylphenyl)-N,N-dimethyl formamidine obtained on formylation of 3-ethynylaniline with N,N-dimethyl formamidine is coupled with 2-amino-4,5-bis(2-methoxyethoxy) benzonitrile to obtain erlotinib free base which on treatment with a polar solvent containing hydrochloric acid gives erlotinib hydrochloride.

Indian patent application 904/CHE/2006 also discloses a process for preparation of N-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine hydrochloride. The process involves reacting 3,4-dihydroxy benzaldehyde with substituted ethylmethyl ether in the presence of an inert solvent and base to obtain 3,4-bis(2-methoxyethoxy) benzaldehyde. This 3,4-bis(2-methoxyethoxy) benzaldehyde is converted to 3,4-bis(2-methoxyethoxy) benzaldoxime in the presence of a base and organic solvent and is further dehydrated to 3,4-bis(2-methoxyethoxy) benzonitrile. The benzonitrile so obtained is nitrated to obtain 4,5-bis(2-methoxyethoxy)-2~nitrobenzonitrile which is further reduced to get 2-amino-4,5- bis(2-methoxyethoxy) benzonitrile. 2-amino-4,5-bis(2-methoxyethoxy) benzonitrile is formylated with a formylating agent in the presence of formic acid derivative to obtain N’- [2-cyano-4,5-bis(2-methoxyethoxy)phenyl]-N,N-dimethylformamidine which is coupled with an aniline derivative to obtain erlotinib free base which on treatment with a polar solvent containing hydrochloric acid gives erlotinib hydrochloride.

EXAMPLES:

Example – 1a:

Preparation of Erlotinib Hydrochloride : 5.O g of 4-chloro-6,7-bis (2-methoxyethoxy) quinazoline was suspended in 75 ml water and 2.55 g of 3-aminophenyl acetylene was charged at 25 – 30⁰C. Further 1.0 ml 50 % hydrochloric acid was added. The reaction mass was stirred at 25 – 30⁰C for 2 hours. The solid obtained was filtered and washed with water. The product was dried at 40 – 45°C to obtain 6.1 g of erlotinib hydrochloride. In a similar manner, different solvents were used for preparing erlotinib hydrochloride under acidic conditions as given in table 1 below :

Table 1

Example – 2a:

Preparation of Erlotinib Hydrochloride :

5.0 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 75 ml of water and 2.55 g of 3-aminophenyl acetylene was added at 25 – 30⁰C followed by 1.0 ml of 50 % hydrochloric acid. The reaction mass was heated at 35 – 40⁰C for 1 hour. The solid obtained was filtered and washed with water. The product was dried at 40 – 45°C to obtain 5.8 g of erlotinib hydrochloride.

In a similar manner, different solvents were used for preparing erlotinib hydrochloride under acidic conditions as given in table 2 below :

Table 2

Example – 3:

Preparation of Erlotinib Hydrochloride :

5 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 150 ml denatured spirit (SPDS) and 4.6 g of 3-aminophenyl acetylene was charged at 25 – 30⁰C. Further 1.0 ml of methane sulphonic acid was added. The reaction mass was stirred at 25 – 30⁰C for 3 hours. Solid obtained was filtered, washed with SPDS and dried under vacuum. This solid was suspended in water, basified with ammonia and stirred for 10 minutes. The resulting erlotinib base was isolated, washed with water and dried under vacuum. The base was suspended in water and acidified to pH 1.0 – 2.0 using hydrochloric acid. The reaction mixture was stirred for 2 hours, filtered, washed with water and dried at 40 – 45⁰C to obtain 5.8 g of erlotinib hydrochloride.

Example – 4: Preparation of Erlotinib Hydrochloride :

10.0 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 300 ml methanol and 9.2 g of 3-aminophenyl acetylene was charged at 25 – 30⁰C. Further 2.0 ml of benzoic acid was added. The reaction mass was stirred at 25 – 30⁰C for 4 hours. Solid obtained was filtered, washed with methanol and dried under vacuum. This solid was suspended in water and then basified with sodium hydroxide and stirred for 10 minutes. The resulting erlotinib base was isolated, washed with water and dried under vacuum. The base was suspended in water and acidified to pH 1.0 – 2.0 using hydrochloric acid. The reaction mixture was stirred for 2 hours, filtered, washed with water and dried to obtain 11.2 g of erlotinib hydrochloride. Example – 5:

Preparation of Erlotinib Hydrochloride :

15.0 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 450 ml ethanol and 13.8 g of 3-aminophenyl acetylene was added at 25 – 30°C. Further 3.0 g tartaric acid was added. The reaction mass was stirred at 25 – 30⁰C for 6 hours. Solid obtained was filtered, washed with water and dried under vacuum. This solid was suspended in water, basified with potassium hydroxide and stirred for 10 minutes. The resulting erlotinib base was isolated by filtration, washed with ethanol and dried under vacuum. The solid obtained was then suspended in water and acidified to pH 1.0 – 2.0 using hydrochloric acid. The reaction mixture was stirred for 2 hours, filtered, washed with water and dried at 40 – 45°C to obtain 18.3 g of erlotinib hydrochloride.

Example – 6: Preparation of Erlotinib Hydrochloride :

50 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 1500 ml acetonitrile and 46 g of 3-aminophenyl acetylene was added at 25 – 30⁰C, followed by 10 ml acetic acid. The reaction mass was stirred at 25 – 30°C for 30 minutes. Solid obtained was filtered, washed with water and dried under vacuum. This solid was suspended in water, basified with potassium hydroxide and stirred for 10 minutes. The resulting erlotinib base was isolated, washed with acetonitrile and dried under vacuum. The solid obtained was then suspended in water and acidified to pH 1.0 – 2.0 using hydrochloric acid. The reaction mixture was stirred for 2 hours, filtered, washed with water and dried at 40 – 45°C to obtain 63 g of erlotinib hydrochloride.

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An efficient, economical and large-scale convergent synthesis of epidermal growth factor receptor- tyrosine kinase inhibitors gefitinib (1, Iressa) and erlotinib (2, Tarceva) approved by U.S. FDA for the treatment of non-small-cell lung cancer is described. The formation of 4-anilinoquinazolines are achieved in a simple one-pot reaction of suitable formamidine intermediates and substituted anilines involving Dimroth rearrangement, thereby avoiding the need to make quinazolin-4(3H)-one intermediates, which require a large experimental inputs. Using this process, we have produced drug candidates 1 with overall yield of 66% from 4-methoxy-5-[3-(4-morpholinyl) propoxy]-2-nitrobenzonitrile (3) and 2 with 63% from 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile (6) on a multigram scale.

2 as crude material, which was further recrystallized from ethyl acetate (1 L) and then with methanol (500 mL) to give off-white crystalline compound 2 (350 g, 66% yield). FREE BASE ERLOTINIB

HPLC >99%.

Mp 149–153 °C.

¹H NMR (CDCl₃): δ 3.08 (s, 1H), 3.43 (s, 6H), 3.80 (m, 4H), 4.22 (m, 4H), 7.17 (s, 1H), 7.24–7.37 (m, 3H), 7.61 (brs, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.85 (s, 1H), 8.63 (s, 1H).

MS (m/z): 393 (M⁺), 334, 276, 230, 59.

[6,7-Bis(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)Amine Hydrochloride (Erlotinib Hydrochloride, 9)

SYNTHESIS

APOTEX PHARMACHEM INC.; KOTHAKONDA, Kiran Kumar; REY, Allan W.; GUNTOORI, Bhaskar Redd Patent: WO2010/40212 A1, 2010 ; Location in patent: Page/Page column 8 ;

Esteve Química, S.A. Patent: EP2348020 A1, 2011 ; Location in patent: Page/Page column 9 ;

Ube Industries, Ltd. Patent: EP1481971 A1, 2004 ; Location in patent: Page 9 ;

F.I.S. Fabbrica Italiana Sintetici S.p.A. Patent: EP2433931 A1, 2012 ; Location in patent: Page/Page column 12 ;

Norris, Timothy; Santafianos, Dinos Journal of the Chemical Society. Perkin Transactions 2, 2000 , # 12 p. 2498 – 2502

Bulletin of the Korean Chemical Society, , vol. 32, # 3 p. 909 – 914

Synthetic Communications, , vol. 37, # 19 p. 3409 – 3415

Heterocycles, , vol. 71, # 1 p. 39 – 48

Molecules, , vol. 11, # 4 p. 286 – 297

WO2011/76813 A1, ;

EP2433931 A1, ;

Journal of the Chemical Society. Perkin Transactions 2, , # 12 p. 2498 – 2502

NMR

MASS

GATIFLOXACIN

BMS-206584, CG-5501, AM-1155, Zymar, Bonoq, Gatiflo, AM-1155

(±)-1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

Gatifloxacin sold under the brand names Gatiflo, Tequin and Zymar, is an antibiotic of the fourth-generation fluoroquinolonefamily,^[1] that like other members of that family, inhibits the bacterial enzymes DNA gyrase and topoisomerase IV. Bristol-Myers Squibb introduced Gatifloxacin in 1999 under the proprietary name Tequin for the treatment of respiratory tract infections, having licensed the medication from Kyorin Pharmaceutical Company of Japan. Allergan produces it in eye-drop formulation under the names Zymar and Zymaxid. In many countries, gatifloxacin is also available as tablets and in various aqueous solutions forintravenous therapy.

Originally developed at Kyorin, gatifloxacin was first licensed to Gruenenthal in Europe, and that company still maintains rights to the oral and injectable formulations of the product. In October 1996, Kyorin licensed gatifloxacin to BMS, granting the company development and marketing rights in the U.S., Canada, Australia, Mexico, Brazil and certain other markets. In 2006, rights to the compound were returned by BMS. Subsequently, Senju and Kyorin signed a licensing agreement regarding the development of ethical eye drops containing the fluoroquinolone. In April 2000, Sumitomo Dainippon Pharma agreed to comarket the oral formulation in Japan. In August of that year, Allergan in-licensed gatifloxacin from Kyorin, gaining development and commercialization rights to the drug in all territories except Japan, Korea, China and Taiwan. The India-based Lupin Pharmaceuticals signed an agreement in June 2004 with Allergan to promote the ophthalmic solution of gatifloxacin in the pediatric specialty area in the U.S. PediaMed Pharmaceuticals also holds rights to the drug. In 2009, Kyorin licensed the drug candidate to Senju in China.

Gatifloxacin is the common name for (±)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (1), one of the most important broad-spectrum antibacterial agents and a member of the fourth-generation fluoroquinolone family.(1)Fluoroquinolones inhibit the enzyme DNA gyrase (topoisomerase II), which is responsible for the supercoiling of the DNA double helix, preventing the replication and repair of bacterial DNA and RNA.(2) Gatifloxacin (1) reached the market in 1999 under the brand name Tequin for the treatment of respiratory tract infections. The drug is available as tablets and aqueous solutions for intravenous therapy as well as eye drop formulation (Zymar).

To date, there are several processes described for the preparation of gatifloxacin, which can be grouped into two main categories: direct substitution of the 7-position fluorine atom of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (2) by 2-methylpiperazine (Scheme 1),(3-5) and through boron chelate-type intermediates to overcome the diminished reactivity induced by the 8-methoxy group, which uses as starting material the ethyl ester derivative 3 (Scheme 2).(6-9)

SCHEME1

1. 1.
   Mather, R.; Karenchak, L. M.; Romanowski, E. G.; Kowalski, R. P. Am. J. Ophthalmol.2002, 133 ( 4) 463
2. 2.
   Corey, E. J.; Czakó, B.; Kürti, L. Molecules and Medicine; Wiley: NJ, 2007; p 135.
3. 3.
   Masuzawa, K.; Suzue, S.; Hirai, K.; Ishizaki, T. 8-Alkoxyquinolonecarboxylic acid and salts thereof excellent in the selective toxicity and process of preparing the same EP 0 230 295 A3, 1987.
4. 4.
   Niddam-Hildesheim, V.; Dolitzky, B.-Z.; Pilarsky, G.; Steribaum, G. Synthesis of Gatifloxacin WO 2004/069825 A1, 2004.
5. 5.
   Ruzic, M; Relic, M; Tomsic, Z; Mirtek, M. Process for the preparation of Gatifloxacin and regeneration of degradation products WO 2006/004561 A1, 2006.
6. 6.
   Iwata, M.; Kimura, T.; Fujiwara, Y.; Katsube, T. Quinoline-3-carboxylic acid derivatives, their preparation and use EP 0 241 206 A2, 1987.
7. 7.
   Sanchez, J. P.; Gogliotti, R. D.; Domagala, J. M.; Garcheck, S. J.; Huband, M. D.; Sesnie,J. A.; Cohen, M. A.; Shapiro, M. A. J. Med. Chem. 1995, 38, 4478
8. 8.
   Satyanarayana, C.; Ramanjaneyulu, G. S.; Kumar, I. V. S. Novel crystalline forms of Gatifloxacin WO 2005/009970 A1 2005.
9. 9.
   Takagi, N.; Fubasami, H.; Matsukobo, H.; (6,7-Substituted-8-alkoxy-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid-O3,O4)bis(acyloxy-O)borates and the salts thereof, and methods for their manufacture EP 0 464 823 A1, 1991.

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WO 2005009970

http://www.google.com/patents/WO2005009970A1?cl=en

preparation of Gatifloxacin hemihydrate from Ethyl-1- Cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-l, 4-dihydro-3-quinoline carboxylate through boron difluoride chelate. Ethyl-1-cyclopropyl- 6, 7-difluoro-8-methoxy-4-oxo-l, 4-dihydro-3-quinoline carboxylate is reacted with aqueous hydrofluoroboric acid followed by condensation with 2-methyl piperazine in polar organic solvent resulting in an intermediate l-Cyclopropyl-7- (3-methyl piperazin-1- yl). -6-fluoro-8-methoxy-4-oxo-l, 4-dihydro-3-quinoline carboxylic acid boron difluoride chelate. This intermediate may be further hydrolyzed to yield Gatifloxacin. Gatifloxacin so obtained may needs purification to yield high purity product. However to obtain directly high purity Gatifloxacin it is desirable to isolate the intermediate by cooling to low temperatures . Treating with an alcohol or mixture of alcohols purifies this intermediate. The purified condensed chelate in aqueous ethanol on hydrolysis with triethylamine followed by crystallization in ethanol gives Gatifloxacin hemihydrate with high purity.

STAGE – I:

 

Ethyl l-cyclopropyl-6,7-difluoro-8-met oxy l-Cycloproρyl-6, 7-difluoro-8-methoxy -4-oxo-l, -dihydro-3-quinoline -4-oxo-l, 4-dihydro-3-quinoline carboxylate carboxylic acid boron difluoride chelate

STAGE – II :

 

l-Cycloprop l-7- ( 3-methylpiperazin-l-yl.

6-fluoro~8-methoxy-4-oxo-l , 4-dihydro-3- carboxylicacid borondifluoride chelate quinoline carboxylicacid borondifluoride chelate

STAGE -III :

 

l-Cyclopropyl-7- (3- ethylpiperaz.in-l-yl . GATIFLOXACIN

-6-fluoro-8-methoxy-4-oxo-l , 4-dihydro-3- quinoline carboxylicacid borondifluoride chelate

Example-I: Preparation of Gatifloxacin • with isolation of intermediate (boron difluoride chelate derivative)

Stage-1: Preparation of l-cyclopropyl-6, 7-di luoro-8-methoxy-4-oxo- 1, 4-dihydro-3-quinoline carboxylic acid boron difluoride chelate. Ethyl-l-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-l, -dihydro-3- quinόline carboxylate (100g)is suspended in ,40%aq..hydrofluoroboric acid -(1000 ml). Temperature of • the reaction mass is raised and maintained at 95°C to 100°C for 5hrs followed by cooling to 30°C – 35°C. Water (400 ml) is added and maintained at 25°C – 30°C for 2hrs . Product is filtered, washed with water (500 ml) and dried at 40°C – 45°C to constant weight. Dry weight of the product: 101.6 g (Yield: 95.8 %)

Stage-2: Preparation of 1- Cyclopropyl-7- (3-methylpiperazin-l-yl) – 6-fluoro-8-methoxy-4-oxo-l, -dihydro-3-quinoline carboxylic acid boron difluoride chelate

100 g of Boron difluoride chelate derivative prepared as above in stage-1 is suspended in acetonitrile (800 ml) , to that 2-methyl piperazine (44.0 g, 1.5 mole equiv.) is added and mixed for 15 min to obtain a clear solution. The reaction mass is maintained at 30°C – 35°C for 12 hrs followed by cooling to -10°C to -5°C. The reaction mass is maintained at -10°C to -5°C for 1 hr. The product is filtered and dried at 45°C – 50°C to constant weight. Dry weight of the product: 116.0 g (Yield: 93.9 %) .

The condensed chelate (100 g) prepared as above is suspended in methanol (1500 ml), maintained at 40°C – 45°C for 30 min. The reaction mass is gradually cooled, maintained for 1 hr at -5°C to 0°C. The product is filtered, washed with methanol (50 ml) and dried at 45°C – 50°C to constant weight. Dry weight of the product: 80.0 g (Yield: 80.0 %)

Stage -3: Preparation of Gatifloxacin (Crude)

The pure condensed chelate (100.0 g) prepared as above in stage-2 is suspended in 20% aq. ethanol (1000 ml) , the temperature is raised and maintained at 75°C to 80°C for 2 hrs. The reaction mass is cooled, filtered to remove insolubles, distilled under vacuum to remove solvent. Fresh ethanol (200 ml) is added and solvent is removed under vacuum at temperature below 50°C. Ethanol (200 ml) is added to the residue and gradually cooled to -10°C to -5°C. The reaction mass is mixed at -10°C to -5°C for 1 hr and then filtered. The wet cake is washed with ethanol (25 ml) and dried at 45°C – 50°C to constant weight.

The dry weight of the Gatifloxacin is 83.3 g (Yield: 91.7 %)

Stage- 4: Purification of crude Gatifloxacin

Crude Gatifloxacin (100.0 g) prepared as above in stage-3 is suspended in methanol (4000 ml), the temperature is raised and maintained at 60°C to 65°C for 20 min. to get a clear solution. Activated carbon (5 g) is added, maintained for 30 min and the solution is filtered. The filtrate is concentrated to one third of its original volume under vacuum at temperature below 40°C. The reaction mass is gradually cooled and maintained at -10°C to -5°C for 2 hrs. The product is filtered, washed with methanol (50 ml) and dried at 45°C – 50°C to constant weight. The dry weight of the pure Gatifloxacin is 76.0 g (Yield: 76.0 %)

Example-II: Preparation of Gatifloxacin without isolation of intermediate (boron difluoride chelate derivative)

Stage-1: Preparation of l-cyclopropyl-6, 7-difluoro-8-methoxy-4- oxo-1, 4-dihydro-3-quinoline carboxylic acid boron difluoride chelate.

Ethyll-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-l, 4-dihydro-3- quinoline carboxylate (lOOg) is suspended in 40% aq. hydrofluoroboric acid (1000 ml) . Temperature of the reaction mass is raised and maintained at 95°C to 100°C for 5 hrs followed by cooling to 30°C – 35°C. 400 ml DM water is added, maintained at 25°C – 30°C for 2hrs . The product is filtered, washed with DM water (500 ml) and dried at 40°C – 45°C to constant weight. The dry wt is 102.5 g (Yield: 96.6 %)

Stage – 2: Preparation of Gatifloxacin (Crude)

The boron difluoride chelate derivative (100 g) prepared as above in stage-1 is suspended in acetonitrile (800 ml) , 2-methyl piperazine (44 g, 1.5 mole equiv.) is added and mixed for 15 min to obtain a clear solution. The reaction mass is maintained at 30°C – 35°C for 12 hrs. Removed the solvent by vacuum distillation. 20% Aq. ethanol (1000 ml) is added, raised the temperature and maintained at 75°C to 80°C for 2 hrs. The reaction mass is cooled, filtered to remove insolubles. The filtrate is distilled under vacuum to remove solvent completely. Fresh ethanol (250 ml) is added and distilled under vacuum at temperature below 50°C. Fresh Ethanol (250 ml) is added to the residue and gradually cooled to -10°C to -5°C. The reaction mass is maintained at -10°C to -5°C for 1 hr and filtered. The wet cake is washed with ethanol (30 ml) and dried at 45°C – 50°C to constant weight.

The dry weight of the Gatifloxacin is 73.5 g (Yield: 65.4 %)

Stage -3: Purification of crude Gatifloxacin

Crude Gatifloxacin (80.0 g) prepared as above in stage-2 is suspended in methanol (2000 ml) , the temperature is raised and maintained at 60°C to 65°C for 20 min. to get a clear solution. The reaction mixture is filtered. The filtrate is gradually cooled and maintained at -10°C to -5°C for 2 hrs. The product is filtered, washed with methanol (50 ml) and dried at 45°C – 50°C to constant weight.

The dry weight of the pure Gatifloxacin is 56.0 g (Yield: 70.0 %)

……………………….

WO 2005047260

http://www.google.co.in/patents/WO2005047260A1?cl=en

Gatifloxacin is the international common name of l-cyclopropyl-6-fluoro-l, 4-dihydro-8-methoxy- 1- (3-methyl-l-piperazinyl) -4-oxo-3-guinolin-carboxylic acid of formula (I) , with application in medicine and known for its antibiotic activity:

 

European patent application EP-A-230295 discloses a process for obtaining gatifloxacin that consists on the reaction of compound (II) with 2-

 

In this process the gatifloxacin is isolated in the form of a hemihydrate after a laborious process of column chromatography and recrystallisation in methanol, which contributes towards making the final yield lower than 20% by weight. Moreover, in said process an undesired by-product is formed, resulting from demethylation at position 8 of the ring. European patent application EP-A-241206 discloses a process for preparing gatifloxacin, whose final steps are as follows:

 

(III) H ft N Me H DMSO

Gatifloxacin (I)

(IV) This process uses the intermediate compound (III) , which has been prepared and isolated in a separate operation, while the intermediate compound (IV) is also isolated before proceeding to its conversion into gatifloxacin by treatment with ethanol in the presence of triethylamine. The overall yield from these three steps is lower than 40%. These disadvantages — a synthesis involving several steps, low yields, and the need to isolate the intermediate products — hinder the production of gatifloxacin on an industrial scale. There is therefore a need to provide a process for preparing gatifloxacin with a good chemical yield, without the need to isolate the intermediate compounds and that substantially avoids demethylation in position 8 of the ring. The processes termed in English “one pot” are characterised in that the synthesis is carried out in the same reaction vessel, without isolating the intermediate compounds, and by means of successive addition of the reacting compounds. The authors of the present invention have discovered a simplified process for preparing gatifloxacin which does not require isolation of the intermediate compounds .

 

Example 1: Preparing gatifloxacin from compound (II) 10 g (0.0339 moles, 1 equivalent) of compound

(II) is placed in a flask, 30 ml of acetonitryl (3 volumes) is added and this is heated to a temperature of 76-80° C.

Once reflux has been attained, and being the temperature maintained, 3.28 g (0.0203 moles, 0.6 equivalents) of hexamethyldisilazane (HMDS) is added with a compensated adding funnel. Once addition is completed, the reaction is maintained with stirring for 1 hour at a temperature of 76-80° C. Once this period has elapsed, the reaction mixture is cooled to a temperature ranging between 0 and 15° C, and 5.78 g (0.0407 moles, 1.2 equivalents) of boron trifluoride ethyletherate is added while keeping the temperature below 15° C. Once addition is completed, the temperature is allowed to rise to 15- 25° C and it is kept under these conditions for approximately 2 hours. The pH of the mixture is then adjusted to an approximate value of 9 with triethylamine (approximately 2 ml) . To the resulting suspension is added a solution of 10.19 g (0.1017 moles, 3 equivalents) of 2-methylpiperazine in 28 ml of acetonitryl, while maintaining the temperature between 15 and 25° C. The resulting amber solution is kept with stirring under these conditions for approximately 3 hours . Once the reaction has been completed, the solution is distilled at low pressure until a stirrable paste is obtained. At this point 50 ml of methanol is added, the resulting suspension is raised to a temperature of 63-67° C and is kept under these conditions for approximately 5 hours . Once the reaction has been completed, the mixture is cooled to a temperature of 25-35° C in a water bath, and then at a temperature of 0-5° C in a water/ice bath for a further 1 hour. The resulting precipitate is filtered, washed with cold methanol (2 x 10 ml) and dried at 40° C in a vacuum oven to constant weight. 10.70 g of crude gatifloxacin is obtained, having a water content of 2.95% by weight. The yield of the process is 81.8%.

The crude product is crystallised in methanol by dissolving 20 g of crude gatifloxacin in 1 1 of methanol (50 volumes) at a temperature of 63-67° C. Once all the product has been dissolved, the solution is left to cool to a temperature of 30-40° C, and then to a temperature of 0-5° C in a water/ice bath, maintaining it under these conditions for 1 hour. The resulting suspension is filtered and the solid retained is washed with 20 ml (1 volume) of cold methanol. The solid obtained is dried at 40° C in a vacuum oven to provide 18.65 g of gatifloxacin with a water content of 2.36% by weight.

The overall yield from the compound (II) is 77.7%, with a purity exceeding 99.8% as determined by HPLC chromatography. The content of by-product resulting from demethylation in position 8 of the ring is lower than 0.1% as determined by HPLC chromatography.

Systematic (IUPAC) name
1-cyclopropyl-6-fluoro- 8-methoxy-7-(3-methylpiperazin-1-yl)- 4-oxo-quinoline-3-carboxylic acid
Clinical data
Trade names	Zymar
AHFS/Drugs.com	monograph
MedlinePlus	a605012
Legal status	℞ (Prescription only)
Routes of administration	Oral (discontinued), Intravenous(discontinued) ophthalmic
Pharmacokinetic data
Protein binding	20%
Half-life	7 to 14 hours
Identifiers
CAS Registry Number	112811-59-3
ATC code	J01MA16 S01AE06
PubChem	CID: 5379
DrugBank	DB01044
ChemSpider	5186
UNII	81485Y3A9A
KEGG	D08011
ChEBI	CHEBI:5280
ChEMBL	CHEMBL31
NIAID ChemDB	044913
Chemical data
Formula	C19H22FN3O4
Molecular mass	375.394 g/mol

PAPER

An improved process to obtain gatifloxacin (1) through use of boron chelate intermediates has been developed. The methodology involves an initial activation step which accelerates the formation of the first chelate under low-temperature conditions and prevents demethylation of the starting material. To increase the overall yield and to avoid the isolation and manipulation of the resulting intermediates, the process has been designed to be carried out in one pot. As a result, we present here an easy, scaleable and substantially impurity-free process to obtain gatifloxacin (1) in high yield.

A High-Throughput Impurity-Free Process for Gatifloxacin

F. Javier Villasante *, Lourdes Gude , Sara P. Fernández , Olga Alonso , Elena García and Antonio Cosme

Department of Research & Development, Química Sintética S.A., c/ Dulcinea s/n, 28805 Alcalá de Henares, and Department of Organic Chemistry, University of Alcalá, 28871 Madrid, Alcalá de Henares, Spain

Org. Process Res. Dev., 2008, 12 (5), pp 900–903

DOI: 10.1021/op800042a

http://pubs.acs.org/doi/full/10.1021/op800042a

gatifloxacin (1) as white crystals. Yield 32.3 kg, (93%); purity by HPLC 99.87%; Assay by HPLC 100.8%; mp 167−168 °C(18) (Lit. (J. Med. Chem. 1995, 38, 4478)159−162 °C).

18

DSC analysis showed two endothermic peaks at 166.2 °C (T onset = 164.3 °C) and 190.0 °C (T onset = 188.2 °C) and an exothermic one at 168.1 °C. The shape of this DSC curve is characteristic of a monotropic transition between crystalline forms

Water content by Karl Fischer 3.0%(19) MS m/z 376 (M+ + H);

19

Although there are several hydrates described for gatifloxacin such as, among others, the hemimydrate, sesquihydrate, and pentahydrate(Raghavan, K. S.; Ranadive, S. A.;Gougoutas, J. Z.; Dimarco, J. D.; Parker, W. L.; Dovich, M.; Neuman, A.Gatifloxacin pentahydrate. WO 2002/22126 A1, 2002) , the Gatifloxacin obtained by the present procedure does not seem to form a stoichometric hydrate, but instead it retains moisture.

Thus, the product is usually obtained with a Karl-Fischer value below 1% after drying, but it can absorb moisture until a final content of about 3%. This water content can vary between 2.0% and 3.5%, depending on the relative humidity of the environment. DSC analysis revealed a broad endothermic signal with minimum at 76 °C, while TGA analysis showed that the product loses all the water below 80 °C.

No loss of weight is registered when the product melts, and the weight is constant until the decomposition of the material at about 200 °C. On the basis of these results, it can be said that the water content of the gatifloxacin obtained by the present process is retained moisture instead of water belonging to the lattice. The shape of the derivative of the weight curve at the beginning of the analysis shows that the sample has already lost part of the moisture when the register starts. This is probably due to the sample starting to lose weight when makes contact with the dry atmosphere of the TGA oven that could explain the different values obtained for water content of the analyzed sample by TGA (1.90%) and Karl-Fischer (2.64%) methods.

 1H NMR (DMSO-d6) δ 0.97 (d, J = 6.1 Hz, 3H), 1.04 (m, 2H), 1.15 (m, 2H), 2.75−2.94 (m, 4H) 3.14 (m, 1H), 3.30 (m, 2H), 3.74 (s, 3H), 4.15 (m, 1H), 7.70 (d, JH−F = 12.2 Hz, 1H), 8.67 (s, 1H). 

13C NMR (DMSO-d6) δ 8.40, 8.42, 18.66, 40.28, 45.46, 50.17, 50.29 (d, JC−F = 3.44 Hz), 57.36 (d, JC−F = 3.74 Hz), 62.15, 106.0 (d, JC−F = 22.7 Hz), 106.04, 120.05 (d, JC−F = 8.6 Hz), 133.6 (d, JC−F = 1.1 Hz), 138.9 (d, JC−F = 11.9 Hz), 145.2 (d, JC−F = 5.87 Hz), 149.88, 155.06 (d, JC−F = 249.2 Hz), 165.56, 175.56 (d, JC−F = 3.3 Hz).

 19F NMR (DMSO-d6) δ −120.4 (d, J = 12.2 Hz).

Anal. Calcd for C19H22N3O4F + 3.0% H2O; C, 58.95; H, 6.07; N, 10.85. Found: C, 58.90; H, 5.82; N, 10.90.

Boron content 170 ppm.(The respective boron contents found for batches 2 and 3 were 160 and 300 ppm)

Side-effects and removal from the market

A Canadian study published in the New England Journal of Medicine in March 2006 claims Tequin can have significant side effectsincluding dysglycemia.^[2] An editorial by Dr. Jerry Gurwitz in the same issue called for the Food and Drug Administration (FDA) to consider giving Tequin a black box warning.^[3] This editorial followed distribution of a letter dated February 15 by Bristol-Myers Squibb to health care providers indicating action taken with the FDA to strengthen warnings for the medication.^[4] Subsequently it was reported on May 1, 2006 that Bristol-Myers Squibb would stop manufacture of Tequin, end sales of the drug after existing stockpiles were exhausted, and return all rights to Kyorin.^[5]

Union Health and Family Welfare Ministry of India on 18 March 2011 banned the manufacture, sale and distribution of Gatifloxacin as it caused certain adverse side effects^[6]

Contraindications

Diabetes^[7]

Availability

Gatifloxacin is currently available only in the US and Canada as an ophthalmic solution.

In China it is sold in tablet as well as in eye drop formulations.

Ophthalmic anti-infectives are generally well tolerated. The concentration of the drug observed following oral administration of 400 mg gatifloxacin systemically is approximately 800 times higher than that of the 0.5% Gatifloxacin eye drop. Given as an eye drop, Gatifloxacin Ophthalmic Solution 0.3% & 0.5% cause very low systemic exposures. Therefore, the systemic exposures resulting from the gatifloxacin ophthalmic solution are not likely to pose any risk for systemic toxicities.

• The reaction of 1-bromo-2,4,5-trifluoro-3-methoxybenzene (I) with CuCN and N-methyl-2-pyrrolidone at 150 C gives 2,4,5-trifluoro-3-methoxybenzonitrile (II), which by treatment with concentrated H2SO4 yields the benzamide (III) The hydrolysis of (III) with H2SO4 -. water at 110 C affords 2,4,5-trifluoro-2-methoxybenzoic acid (IV), which by reaction with SOCl2 is converted into the acyl chloride (V). The condensation of (V) with diethyl malonate by means of magnesium ethoxide in toluene affords diethyl 2- (2,4,5-trifluoro-3-methoxybenzoyl) malonate (VI), which by treatment with p-toluenesulfonic acid in refluxing water gives ethyl 2- (2,4,5-trifluoro-3-methoxybenzoyl) acetate (VII). The condensation of (VII) with triethyl orthoformate in refluxing acetic anhydride yields 3-ethoxy -2- (2,4,5-trifluoro-3-methoxybenzoyl) acrylic acid ethyl ester (VIII), which is treated with cyclopropylamine (IX) to afford the corresponding cyclopropylamino derivative (X). The cyclization of (X) by means of NaF in refluxing DMF gives 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (XI), which is hydrolyzed with H2SO4 in acetic acid to yield the corresponding free acid (XII). Finally, this compound is condensed with 2-methylpiperazine (XIII) in hot DMSO.

 

Title: Gatifloxacin CAS Registry Number: 112811-59-3 CAS Name: 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid Trademarks: Tequin (BMS); Zymar (Allergan) Molecular Formula: C19H22FN3O4 Molecular Weight: 375.39 Percent Composition: C 60.79%, H 5.91%, F 5.06%, N 11.19%, O 17.05% Literature References: Fluorinated quinolone antibacterial. Prepn: K. Masuzawa et al., EP 230295; eidem, US 4980470 (1987, 1990 both to Kyorin); J. P. Sanchez et al., J. Med. Chem. 38, 4478 (1995); of the sesquihydrate: T. Matsumoto et al., US5880283 (1999 to Kyorin). In vitro antibacterial activity: A. Bauernfeind, J. Antimicrob. Chemother. 40, 639 (1997); H. Fukuda et al., Antimicrob. Agents Chemother. 42, 1917 (1998). Clinical pharmacokinetics: M. Nakashima et al., ibid. 39, 2635 (1995). Clinical study in urinary tract infection: H. Nito, 10th Mediterranean Congr. Chemother. 1996, 327; in respiratory tract infection: S. Sethi, Expert Opin. Pharmacother. 4, 1847 (2003). Properties: Pale yellow prisms from methanol as hemihydrate, mp 162°. Melting point: mp 162°   Derivative Type: Sesquihydrate CAS Registry Number: 180200-66-2 Manufacturers’ Codes: AM-1155 Molecular Formula: C19H22FN3O4.1½H2O Molecular Weight: 384.40 Percent Composition: C 59.37%, H 6.03%, F 4.94%, N 10.93%, O 18.73% Therap-Cat: Antibacterial. Keywords: Antibacterial (Synthetic); Quinolones and Analogs

References

1.  Burka JM, Bower KS, Vanroekel RC, Stutzman RD, Kuzmowych CP, Howard RS (July 2005). “The effect of fourth-generation fluoroquinolones gatifloxacin and moxifloxacin on epithelial healing following photorefractive keratectomy”. Am. J. Ophthalmol. 140 (1): 83–7. doi:10.1016/j.ajo.2005.02.037.PMID 15953577.
2.  Park-Wyllie, Laura Y.; David N. Juurlink; Alexander Kopp; Baiju R. Shah; Therese A. Stukel; Carmine Stumpo; Linda Dresser; Donald E. Low; Muhammad M. Mamdani (March 2006).“Outpatient Gatifloxacin Therapy and Dysglycemia in Older Adults”. The New England Journal of Medicine 354 (13): 1352–1361. doi:10.1056/NEJMoa055191. PMID 16510739. Retrieved 2006-05-01. Note: publication date 30 March; available on-line 1 March
3.  Gurwitz, Jerry H. (March 2006). “Serious Adverse Drug Effects — Seeing the Trees through the Forest”. The New England Journal of Medicine 354 (13): 1413–1415.doi:10.1056/NEJMe068051. PMID 16510740. Retrieved2006-05-01.
4.  Lewis-Hall, Freda (February 15, 2006). “Dear Healthcare Provider:” (PDF). Bristol-Myers Squibb. Retrieved May 1, 2006.
5.  Schmid, Randolph E. (May 1, 2006). “Drug Company Taking Tequin Off Market”. Associated Press. Archived from the original on November 25, 2007. Retrieved 2006-05-01.^{[dead link]}
6.  “Two drugs banned”. The Hindu (Chennai, India). 19 March 2011.
7.  Peggy Peck (2 May 2006). “Bristol-Myers Squibb Hangs No Sale Sign on Tequin”. Med Page Today. Retrieved 24 February2009.

 

EP0610958A2 *	20 Jul 1989	17 Aug 1994	Ube Industries, Ltd.	Intermediates in the preparation of 4-oxoquinoline-3-carboxylic acid derivatives
ES2077490A1 *				Title not available

Citing Patent	Filing date	Publication date	Applicant	Title
WO2008126384A1	31 Mar 2008	23 Oct 2008	Daiichi Sankyo Co Ltd	Method for producing quinolone carboxylic acid derivative
CN101659654B	28 Aug 2008	6 Nov 2013	四川科伦药物研究有限公司	2-Methylpiperazine fluoroquinolone compound and preparation method and application thereof
CN102351843A *	18 Aug 2011	15 Feb 2012	张家口市格瑞高新技术有限公司	Synthesis method of 2-methyl piperazine lomefloxacin
EP1832587A1 *	2 Mar 2007	12 Sep 2007	Quimica Sintetica, S.A.	Method for preparing moxifloxacin and moxifloxacin hydrochloride
US7365201	2 Mar 2006	29 Apr 2008	Apotex Pharmachem Inc.	Process for the preparation of the boron difluoride chelate of quinolone-3-carboxylic acid
US7875722	30 Sep 2009	25 Jan 2011	Daiichi Sankyo Company, Limited	Method for producing quinolone carboxylic acid derivative

EP0464823A1 *	Jul 4, 1991	Jan 8, 1992	Kyorin Pharmaceutical Co., Ltd.	(6,7-Substituted-8-alkoxy-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid-O3,O4)bis(acyloxy-O)borates and the salts thereof, and methods for their manufacture
US4997943 *	Mar 31, 1987	Mar 5, 1991	Sankyo Company Limited	Quinoline-3-carboxylic acid derivatives

Citing Patent	Filing date	Publication date	Applicant	Title
CN101659654B	Aug 28, 2008	Nov 6, 2013	四川科伦药物研究有限公司	2-Methylpiperazine fluoroquinolone compound and preparation method and application thereof
CN102351843A *	Aug 18, 2011	Feb 15, 2012	张家口市格瑞高新技术有限公司	Synthesis method of 2-methyl piperazine lomefloxacin

* Cited by examiner

TAKE A TOUR

 

 

TAKE A TOUR

 

Amritsar, punjab, India

1. Amritsar – Wikipedia, the free encyclopedia

   https://en.wikipedia.org/?title=Amritsar

   Amritsar is one of the largest cities of the Punjab state in India. The city origin lies in the village of Tung, and was named after the lake founded by the fourth Sikh  …

   ‎Sri Guru Ram Dass Jee – ‎Amritsar district – ‎Amritsar Cantonment – ‎Category:Amritsar

   GOLDEN TEMPLE
   

   .

   Tandoori chicken at Surjit Food Plaza. amritsar

   Bullet marks on the walls of the park premises

   The Jallianwalla Bagh in 1919, months after the massacre

   Mealtime at the Golden Temple Amritsar

    

   Golden Temple – Harmandir Sahib: Free food for everyone

   Sri Guru Ram Dass Jee International Airport in Amritsar

   Amritsar – Wagah Border – Street food stall | Explore bernic… |

   Charles W. Bartlett, Amritsar (The Lake by the Golden Temple) 1920

   tandoori chicken

   Khalsa College

   • Golden Temple

   • Maharaja Ranjit Singh’s Ram Bagh Gardens

   • Golden Temple

   • Durgiana Temple

   • The holy water

   • Jallianwala Bagh

   • Jallianwala Bagh

   • The holy water

   • Golden Temple

   • Golden Temple

   • Sikh Gurdwara

   • The holy water

   Night view of the Harmandir Sahib

   ///////////

…………………………..

BIOCON LIMITED Patent: WO2005/19155 A1, 2005 ; Location in patent: Page/Page column 8 ;http://google.com/patents/WO2005019155A1?cl=en

The present invention relates to a novel process for the preparation of substantially pure l^^^^^δa-hexahydro-beta,delta_/6-trihydroxy-2-methyl-8-[(2S)-2-methyl-l-oxobutoxy]-_/ (beta R, delta R, lS,2S,6S,8S,8aR)- 1-Naphthaleneheptanoic acid, sodium salt.
BACKGROUND OF THE INVENTION