DAPAGLIFLOZIN

DAPAGLIFLOZIN, BMS-512148

ダパグリフロジン;

(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol,

Cas 461432-26-8

Dapagliflozin propandiol monohydrate; 960404-48-2

Bristol-Myers Squibb (Originator)
AstraZeneca

TYPE 2 DIABETES,SGLT-2 Inhibitors

launched 2012,  as forxiga in EU, FDA 2014, JAPAN PMDA 2014

Dapagliflozin propanediol monohydrate was first approved by European Medicine Agency (EMA) on November 12, 2012, then approved by the U.S. Food and Drug Administration (FDA) on January 8, 2014, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on March 24, 2014. It was co-developed and co-marketed as Forxiga^® by Bristol-Myers Squibb and AstraZeneca in EU.

Dapagliflozin propanediol monohydrate is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Forxiga^® is available as tablet for oral use, containing 5 mg or 10 mg of free Dapagliflozin. The recommended starting dose is 5 mg once daily in the morning.

Dapagliflozin propanediol is a solvate containing 1:1:1 ratio of the dapagliflozin, (S)-(+)-1,2-propanediol, and water.

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002322/WC500136024.pdf

US——-In 2011, the product was not recommended for approval by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee. In 2011, the FDA assigned a complete response letter to the application. A new application was resubmitted in 2013 by Bristol-Myers Squibb and AstraZeneca in the U.S

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM262996.pdf

WILMINGTON, Del. & PRINCETON, N.J.--(BUSINESS WIRE)--December 12, 2013--


USFDA

Sales：$518.7 Million (Y2015); 
$235.8 Million (Y2014);
$33 Million (Y2013);ATC Code：A10BX09

Approved Countries or AreaUpdate Date：2015-07-29

• US
• EU
• JP

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MoreChemical Structure

AstraZeneca (NYSE:AZN) and Bristol-Myers Squibb Company (NYSE:BMY) today announced the U.S. Food and Drug Administration’s (FDA) Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) voted 13-1 that the benefits of dapagliflozin use outweigh identified risks and support marketing of dapagliflozin as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The Advisory Committee also voted 10-4 that the data provided sufficient evidence that dapagliflozin, relative to comparators, has an acceptable cardiovascular risk profile.

The FDA is not bound by the Advisory Committee’s recommendation but takes its advice into consideration when reviewing the application for an investigational agent. The Prescription Drug User Fee Act (PDUFA) goal date for dapagliflozin is Jan. 11, 2014.

Dapagliflozin is being reviewed by the FDA for use as monotherapy, and in combination with other antidiabetic agents, as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. It is a selective and reversible inhibitor of sodium-glucose cotransporter 2 (SGLT2) that works independently of insulin to help remove excess glucose from the body. Dapagliflozin, an investigational compound in the U.S., was the first SGLT2 inhibitor to be approved anywhere in the world. Dapagliflozin is currently approved under the trade name [Forxiga](TM) for the treatment of adults with type 2 diabetes, along with diet and exercise, in 38 countries, including the European Union and Australia.

http://online.wsj.com/article/PR-CO-20131212-910828.html?dsk=y

PATENTRoute 1

Reference：1. WO03099836A1 / US6515117B2.

2. WO2010048358.

3. J. Med. Chem. 2008, 51, 1145–1149.

4. WO2004063209A2 / US7375213B2.

5. WO2008002824A1 / US7919598B2.Route 2

Reference：1. WO2010022313 / US8283454B2.Route 3

Reference：1. WO2013068850.Route 4

Reference：1. Org. Lett. 2012, 14, 1480-1483.

PAPER

https://www.future-science.com/doi/10.4155/fmc-2020-0154

PATENT

https://patents.google.com/patent/WO2017206808A1/enDaggliflozin (English name: Dapagliflozin) is a new Sodium glucose co-transporters 2 (SGLT-2) inhibitor developed by Bristol-Myers Squibb and AstraZeneca. Approved by the European Commission on November 14, 2012, and marketed in the United States on January 8, 2014, to improve glycemic control in adult patients with type 2 diabetes by combining diet and exercise; the trade name is Farxiga, currently offering 5 mg and 10 mg tablets. At the same time, a combination of dapagliflozin and metformin hydrochloride has also been marketed.The chemical name of dapagliflozin is (2S,3R,4R,5S,6R)-2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H – pyran-3,4,5-triol, the chemical formula is C ₂₁ H ₂₅ ClO ₆ , CAS No. 461432-26-8, the structural formula is shown as 2, clinically used as a pharmaceutical for dapagliflozin (S) -1,2-propanediol monohydrate, the structural formula is as shown in 1.

The synthesis of β-type C-aryl glycosidic bonds is a key point in the synthetic route during the preparation of dapagliflozin. At present, there are four synthetic methods for the synthesis of dapagliflozin reported in the literature and patents.Route 1: The synthetic route of dapagliflozin reported in patent WO03099836A1 is as follows:

The route uses 2-chloro-5-bromobenzoic acid (12) as raw material to react with phenethyl ether to form intermediate 11 and then triethylsilane to obtain intermediate 10; intermediate 10 and n-butyl The lithium is reacted at -78 ° C, and then subjected to a nucleophilic addition reaction with the intermediate 9, and then methoxylated to obtain the intermediate 8; the intermediate 8 is subjected to acylation reduction and deprotection to obtain the intermediate 2. The disadvantage of this method is that the β-type C-aryl glycosidic bond synthesis of the compound is carried out at a low temperature of -78 ° C, which is obviously difficult to meet the needs of industrial production; and, through nucleophilic addition, methoxylation, The five-step reaction of acetylation, reduction and hydrolysis can synthesize the β-type C-aryl glycosidic bond. The procedure is relatively long, and the purity of the intermediate 2 is only 94%.Route 2: The synthetic route of dapagliflozin reported in the literature OrgLett.2012, 14, 1480 is as follows:

The intermediate 14 of the route is reacted with di-n-butyl-n-hexylmagnesium for 48 hours at 0 ° C, and then reacted with zinc bromide to prepare an organozinc reagent by Br/Mg/Zn exchange reaction, and then with intermediate 4 Intermediate 3 was prepared by nucleophilic substitution reaction; finally, intermediate 2 was obtained by deprotection with sodium methoxide. The synthesis method is relatively novel, and the synthesis step is short. However, the research experiment is conducted only as a synthesis method, and the post treatment of the intermediate 3 is performed by column chromatography. The purity of the intermediate 2 produced was not reported. Moreover, the di-n-butyl-n-hexylmagnesium reagent used in the route is not a commonly used reagent, and is not commercially available in China. It can only be prepared by reacting dibutylmagnesium with n-hexyllithium reagent before the test, and the operation is cumbersome and difficult to mass. use.Route 3: The synthetic route of dapagliflozin reported in patent WO2013068850A2 is as follows:

The route uses 1,6-anhydroglucose (20) as a raw material, protects the 2,4-hydroxyl group by tert-butyldiphenylchlorosilane, and then protects the 3-position hydroxyl group with phenylmagnesium bromide. Intermediate 18. The intermediate 14 is subjected to an Br/Mg/Al exchange reaction to prepare an organoaluminum reagent 16, which is reacted with an intermediate 18 to form an intermediate 15, and finally, deprotected to obtain an intermediate 2. The synthesis method is very novel and is also used as a synthetic methodological study. The purification of the intermediates is carried out by column chromatography. The 1,6-anhydroglucose (20) used in the route is very expensive; and the multi-step reaction in the route uses a format reagent, a preparation format reagent or an organoaluminum reagent, which is cumbersome and cumbersome to perform, and is difficult to scale synthesis. The purity of the intermediate 2 produced was not reported.Route 4: The synthetic route of dapagliflozin reported in patent WO2013152476A1 is as follows:

The route uses 2-chloro-5-iodobenzoic acid (24) as raw material to form intermediate 22 by Friedel acylation and reduction reaction, and exchange with I-Mg at -5 ° C with isopropyl magnesium chloride lithium chloride. The intermediate 8 is obtained by nucleophilic addition and methoxylation with the intermediate 9, and then the intermediate 2 is obtained by reduction with triethylsilane, and the intermediate 2 is further purified by co-crystallizing with L-valine. Finally, The pure intermediate 2 was obtained by removing L-valine. This route is a modified route of Route 1, which replaces n-butyllithium with isopropylmagnesium chloride chloride to raise the reaction temperature of the reaction from -78 °C to -5 °C. However, the problem of a long step of synthesizing a β-type C-aryl glycosidic bond still exists. The obtained intermediate 2 is not optically pure, and needs to be purified by co-crystallizing with L-valine, and the work amount of post-treatment is increased, and finally the purity of the intermediate 2 is 99.3%.Among the four synthetic routes described above for dapagliflozin, route one and route four are commonly used synthetic methods for β-type C-aryl glycosidic bonds, and the route is long, and the optical purity of the obtained product is not high, and further purification is required. Post processing is cumbersome. Moreover, the reaction required at -78 °C in Route 1 requires high equipment and high energy consumption, which undoubtedly increases the cost. Although both Route 2 and Route 3 are new methods, most of the purification of intermediates used is column chromatography. Such a process is not suitable for scale production in factories; and some of the synthetic routes are used. Reagents are not commercially available or expensive, and there is no advantage in such route costs. Therefore, there is an urgent need to find a new method for the synthesis of dapagliflozin, and to enable industrial production, and the route has a cost advantage.Repeating the procedure reported in the literature in Equation 2, the yield of Intermediate 3 was only 46%. The organic zinc reagent is prepared by Br/Mg/Zn exchange reaction, and the exchange reaction yield is 78%; and the raw material is prepared by X/Li/Zn exchange reaction to prepare an organic zinc reagent, and the exchange reaction yield is 98.5%, which is also the two Different reaction pathways lead to the essential reason for the different yields of intermediate 3. Moreover, the price of commercially available 1.0 mol/L di-n-butyl magnesium n-heptane solution 500 mL is 1380 yuan, and the price of 1.6 mol/L n-hexyl lithium n-hexane solution 500 mL is 950 yuan, and 2.5 mol/L n-butyl lithium. The price of 500 mL of n-hexane solution is only 145 yuan. Therefore, the method for preparing dapagliflozin by preparing an organozinc reagent by X/Li/Zn and then synthesizing the β-type C-aryl glycosidic bond designed by the invention has the advantages of cost, ease of operation and industrialization. Very obvious advantage.In order to solve this problem, the original compound company uses a eutectic method in the production of dapagliflozin to make dapagliflozin together with a solvent or an amino acid compound, since the compound 2 sugar ring structure contains four hydroxyl groups and is easy to absorb moisture and deteriorate. The crystal is made into a relatively stable solid, easy to store, stable and controllable in quality, and easy to prepare. Among them, the marketed dapagliflozin forms a stable eutectic with (S)-1,2-propanediol and water (1). The original crystal form patent (CN101479287B, CN103145773B) reported that all 11 crystal forms are dapagliflozin solvate or dapagliflozin. Crystal. Among them, there are two preparation methods for the da forme (S)-1,2-propanediol monohydrate (1) having a crystal structure of type Ia:Method 1: The preparation method is as follows:

Compound 7 is deprotected with sodium hydroxide to obtain compound 2, then compound 2 is extracted with isopropyl acetate, (S)-1,2-propanediol ((S)-PG) is added, and seed crystal of compound 1 is added. Then, cyclohexane was added to crystallize and separated to obtain a eutectic of the compound (1) of the type Ia.Method 2: The preparation method is as follows:

Compound 8 is subjected to reduction of methoxy group by triethylsilane and boron trifluoride diethyl ether complex, and then the reaction solution is extracted with methyl tert-butyl ether (MTBE), and (S)-1,2-propanediol ( (S)-PG), a seed crystal of the compound 1 is added, and then cyclohexane is added to crystallize, and the mixture is separated and dried to obtain a eutectic of the compound (1) of the type Ia.The above two methods for preparing the eutectic are all used in the cyclohexane solvent, which is listed in the appendix of the 2015 edition of the Pharmacopoeia (four parts) as the second type of solvent that should be restricted, with a residual limit of 0.388%. The solvent residue of the final product obtained must reach the specified limit, and the post-treatment process is complicated, time-consuming and labor-intensive, and the production cost is correspondingly increased. The invention finds a suitable solvent on the basis of the synthetic route to prepare a medicinal crystal form, and has obvious advantages in both the method and the process operation steps.The synthetic route is as follows:

Comparative Example 1, (1S)-2,3,4,6-tetra-O-pivaloyl-1,5-anhydro-1-[3-(4-ethoxyphenylmethyl)-4- Preparation of chlorophenyl]glucosamine (Compound 3)Under nitrogen protection, 1.0 mol/L di-n-butylmagnesium-n-heptane solution (16 mL) was cooled to 0 ° C, and 1.6 mol/L n-hexane lithium n-hexane solution (10 mL) was slowly added dropwise. After the addition was completed, 0 ° C After stirring for 15 h, dry n-butyl ether (2.5 mL) was added to prepare a solution of di-n-butyl-n-hexylmagnesium lithium solution, which was calibrated with iodine and stored for use.Zinc bromide (2.7 g) and lithium bromide (1.04 g) were added with n-butyl ether (20 mL), heated to 50 ° C for 4 h, and cooled for use. 4-(2-Chloro-5-bromo-benzyl) phenyl ether (6.513 g) was added with toluene (8 mL) and n-butyl ether (5 mL) under nitrogen, cooled to 0 ° C, and 0.61 mol/L was added dropwise. n-Butyl-n-hexylmagnesium lithium solution (13.1 mL), after the addition is completed, the reaction was kept at 0 ° C for 48 h, and the above-mentioned alternate zinc bromide and lithium bromide n-butyl ether solution were added, and the reaction was kept at 0 ° C for 1 h, and added 2 , 3,4,6-tetra-O-pivaloyl-α-D-bromoglucopyranose (14.49 g) in toluene (25 mL), heated to 100 ° C to stir the reaction, after TLC detection reaction, add 1 mol / L diluted hydrochloric acid (60 mL), taken after stirring extraction, the organic phase was washed with water (40 mL), then washed with saturated brine (40 mL), dried over anhydrous Na ₂ SO _4, concentrated under reduced pressure, column chromatography (petroleum ether / Ethyl acetate = 20:1) 10.38 g of Compound 3 as a pale yellow oil. Yield: 46%. Purity: 99.02%. The organozinc reagent prepared by the method has an iodine calibration yield of 78%.The calibration method of the concentration of the prepared organic zinc reagent: accurately weighed iodine (1 mmol), placed in a three-necked flask, replaced nitrogen, and added anhydrous 0.5 mol/L LiCl tetrahydrofuran solution (5 mL), stirred and dissolved, and cooled to 0 ° C. The prepared organozinc reagent was slowly added dropwise until the color of the brownish yellow solution disappeared.Example 2 (1S)-2,3,4,6-tetra-O-pivaloyl-1,5-anhydro-1-[3-(4-ethoxyphenylmethyl)-4-chloro Preparation of phenyl]glucitol (compound 3)Zinc bromide (2.25 g) and lithium bromide (0.87 g) were added with n-butyl ether (30 mL), heated to 50 ° C for 2 h, and cooled for use. 4-(2-Chloro-5-iodo-benzyl) phenyl ether (7.45 g) was added with toluene (10 mL) and n-butyl ether (10 mL) under nitrogen, cooled to -20 ° C, and slowly added dropwise 1.6 mol / L-n-hexyl lithium n-hexane solution (14mL), control the internal temperature does not exceed -10 ° C, after the completion of the addition, the temperature is incubated at -20 ° C for 0.5 h, adding the above-mentioned spare zinc bromide and lithium bromide n-butyl ether solution, The reaction was stirred at 20 ° C for 3 h. Add 2,3,4,6-tetra-O-pivaloyl-α-D-bromoglucopyranose (11.59g) toluene (50mL) solution, heat to 120 ° C and stir the reaction for 4h, after TLC detection reaction, was added 1mol / L diluted hydrochloric acid (40 mL), water (20 mL), and extracted, the organic phase was washed with water (40 mL), dried over anhydrous Na ₂ SO _4, concentrated with n-heptane (15mL) and methanol (60 mL) and recrystallized 10.8 g of Compound 3 as a white solid was obtained in a yield: 72.42%. Purity: 99.47%. Melting point: 99.5 to 101.6 °C. (The organic zinc reagent prepared by this method was iodine-calibrated in a yield of 98.5%.) ESI-MS (m/z): 767.30 [M+Na] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.33 (1H, d), 7.14-7.17 (2H, m), 7.05 (2H, d), 6.79-6.81 (2H, dd), 5.39 (1H, t ), 5.21-5.31 (2H, m), 4.33 (1H, d), 4.17-4.20 (1H, dd), 3.94-4.11 (5H, m), 3.79-3.83 (1H, m), 1.39 (3H, t ), 1.20 (9H, s), 1.16 (9H, s), 1.11 (9H, s), 0.86 (9H, s).Example 3, (1S)-2,3,4,6-tetra-O-pivaloyl-1,5-anhydro-1-[3-(4-ethoxyphenylmethyl)-4-chloro Preparation of phenyl]glucitol (compound 3) PrepareZinc bromide (3.38 g) and lithium bromide (1.3 g) were added with n-butyl ether (40 mL), heated to 50 ° C for 2 h, and cooled for use. 4-(2-Chloro-5-iodo-benzyl) phenyl ether (7.45 g) was added with toluene (20 mL) and n-butyl ether (5 mL) under nitrogen, cooled to -50 ° C, and slowly added dropwise 2.5 mol / L-butyllithium hexane solution (8mL), control the internal temperature does not exceed -30 ° C, after the addition is completed, the reaction is kept at -50 ° C for 10 h, adding the above-mentioned alternate zinc bromide and lithium bromide n-butyl ether solution, The reaction was stirred at -20 ° C for 10 h. Add 2,3,4,6-tetra-O-pivaloyl-α-D-bromoglucopyranose (34.77g) toluene (80mL) solution, heat to 100 ° C and stir the reaction for 24h, after TLC detection reaction, was added 1mol / L diluted hydrochloric acid (60 mL), water (50 mL), and extracted, the organic phase was washed with water (40 mL), dried over anhydrous Na ₂ SO _4, concentrated with n-heptane (15mL) and methanol (60 mL) and recrystallized 10.854 g of Compound 3 as a white solid. Yield: 72.81%. Purity: 99.53%.Example 4, (1S)-2,3,4,6-tetra-O-pivaloyl-1,5-anhydro-1-[3-(4-ethoxyphenylmethyl)-4-chloro Preparation of phenyl]glucitol (compound 3)N-butyl ether (50 mL) was added to zinc iodide (3.19 g) and lithium iodide (1.34 g), and the mixture was heated to 50 ° C for 1.5 h, and cooled for use. 4-(2-Chloro-5-iodo-benzyl) phenyl ether (7.45 g) was added with toluene (15 mL) and n-butyl ether (5 mL) under nitrogen, cooled to -60 ° C, and slowly added dropwise 1.6 mol / L-n-hexyl lithium n-hexane solution (13.8mL), control the internal temperature does not exceed -20 ° C, after the addition is completed, the reaction is kept at -60 ° C for 5 h, and the above-mentioned alternate zinc iodide and lithium iodide n-butyl ether solution is added. The reaction was stirred at 25 ° C for 1 h. Add 2,3,4,6-tetra-O-pivaloyl-α-D-bromoglucopyranose (23.2g) toluene (50mL) solution, heat to 140 ° C reflux reaction for 0.5h, after TLC detection reaction was added 1mol / L diluted hydrochloric acid (50 mL), water (50 mL), and extracted, the organic phase was washed with water (40 mL), dried over anhydrous SO ₄ Na _2, concentrated by weight of n-heptane (15mL) and methanol (60 mL) Crystallization gave 10.51 g of Compound 3 as a white solid, yield 70.5%. Purity: 99.41%.Example 5, (1S)-2,3,4,6-tetra-O-pivaloyl-1,5-anhydro-1-[3-(4-ethoxyphenylmethyl)-4-chloro Preparation of phenyl]glucitol (compound 3)To the zinc bromide (2.25 g) and lithium bromide (0.87 g), cyclopentyl methyl ether (30 mL) was added, and the mixture was heated to 50 ° C for 3 hours, and cooled for use. 4-(2-Chloro-5-iodo-benzyl) phenyl ether (7.45 g) was added with toluene (10 mL) and cyclopentyl methyl ether (10 mL) under nitrogen, cooled to -5 ° C, and slowly added dropwise. Mol / L n-hexyl lithium n-hexane solution (12.5mL), control the internal temperature does not exceed 0 ° C, after the addition is completed, the reaction is kept at -5 ° C for 3 h, adding the above-mentioned spare zinc bromide and lithium bromide cyclopentyl methyl ether The solution was incubated at -5 ° C for 4 h, and a solution of 2,3,4,6-tetra-O-pivaloyl-α-D-bromoglucopyranose (17.39 g) in toluene (40 mL) was added and heated to 80 ℃ reaction was stirred 6h, after completion of the reaction by TLC, was added 1mol / L diluted hydrochloric acid (50 mL), water (50 mL), and extracted, the organic phase was washed with water (40 mL), dried over anhydrous ₂ SO ₄ Na, and concentrated under reduced pressure, Recrystallization of n-heptane (15 mL) and methanol (60 mL) gave 8.15 g of Compound 3 as a white solid. Purity: 99.39%.Example 6, (1S)-2,3,4,6-tetra-O-pivaloyl-1,5-anhydro-1-[3-(4-ethoxyphenylmethyl)-4-chloro Preparation of phenyl]glucitol (compound 3)Zinc bromide (4.5 g) and lithium bromide (1.74 g) were added with n-butyl ether (60 mL), heated to 50 ° C for 3 h, and cooled for use. 4-(2-Chloro-5-bromo-benzyl) phenyl ether (6.513 g) was added with toluene (15 mL) and n-butyl ether (5 mL) under nitrogen, cooled to -30 ° C, and slowly added dropwise 2.5 mol / L-butyllithium n-hexane solution (8.4mL), control the internal temperature does not exceed -20 ° C, after the addition is completed, the reaction is kept at -30 ° C for 3 h, and the above-mentioned alternate zinc bromide and lithium bromide n-butyl ether solution is added. The reaction was incubated at -5 ° C for 4 h, and a solution of 2,3,4,6-tetra-O-pivaloyl-α-D-bromoglucopyranose (14.49 g) in toluene (50 mL) was added and heated to 120 ° C for stirring. the reaction 4h, after completion of the reaction by TLC, was added 1mol / L diluted hydrochloric acid (50 mL), water (40 mL), and extracted, the organic phase was washed with water (40 mL), dried over anhydrous Na ₂ SO _4, and concentrated under reduced pressure, n-heptyl Recrystallization of the alkane (15 mL) and methanol (60 mL) gave 10.38 g of Compound 3 as a white solid. Purity: 99.54%.Example 7, (1S)-2,3,4,6-tetra-O-pivaloyl-1,5-anhydro-1-[3-(4-ethoxyphenylmethyl)-4-chloro Preparation of phenyl]glucitol (compound 3)Methyl bromide (40 mL) was added to zinc bromide (2.25 g) and lithium bromide (0.87 g), and the mixture was heated to 50 ° C for 3 h, and cooled for use. 4-(2-Chloro-5-iodo-benzyl) phenyl ether (7.45 g) was added with toluene (15 mL), methyl tert-butyl ether (15 mL), cooled to -40 ° C, and slowly added dropwise. 1.6mol/L n-hexyl lithium n-hexane solution (13.8mL), control the internal temperature does not exceed -30 ° C, after the addition is completed, the reaction is kept at -40 ° C for 4 h, and the above-mentioned alternate zinc bromide and lithium bromide are added. The butyl ether solution was incubated at 5 ° C for 7 h, and a solution of 2,3,4,6-tetra-O-pivaloyl-α-D-bromoglucopyranose (17.39 g) in toluene (50 mL) was added and heated. to 90 deg.] C the reaction was stirred 8h, after completion of the reaction by TLC, was added 1mol / L diluted hydrochloric acid (40 mL), water (40 mL), and extracted, the organic phase was washed with water (40 mL), dried over anhydrous Na ₂ SO _4, and concentrated under reduced pressure Recrystallization from n-heptane (15 mL) and methanol (60 mL) gave 9.41 g of Compound 3 as a white solid. Purity: 99.42%. Example 8. Preparation of dapagliflozin (S)-1,2-propanediol monohydrate eutectic (Compound 1)To the compound 3 (37.27 g), methanol (190 mL) was added, and sodium methoxide (10.8 g) was added thereto, and the mixture was heated under reflux for 3 hours. After the TLC reaction was completed, methanol was concentrated, and isopropyl acetate (100 mL) was added to the residue, and water was added. (60 mL), extracted with stirring and the organic phase washed with water (50 mL). (S)-1,2-propanediol (3.8g) and water (0.9g) were added to the organic phase, stirred until it was dissolved, and n-heptane (200 mL) was added, and the mixture was stirred for 2 hours under ice-cooling, suction filtration, filter cake Washing with n-heptane and drying at 30 ° C gave 23.89 g of Compound 1 as a white solid. Yield: 95%. Purity: 99.79%. Melting point: 69.1 to 75.6 °C. The product obtained was subjected to KF = 3.74% (theoretical value: 3.58%). ESI-MS (m/z): 431.22 [M+Na] ⁺ . ¹ H-NMR (400 MHz, CD ₃ OD): δ 7.33 – 7.37 (2H, m), 7.28-7.30 (1H, dd), 7.11 (2H, d), 6.80-6.83 (2H, dd), 4.1 ( 1H, d), 3.98-4.05 (4H, m), 3.88-3.91 (1H, dd), 3.74-3.82 (1H, m), 3.68-3.73 (1H, m), 3.37-3.49 (5H, m), 3.28-3.34 (1H, m), 1.37 (1H, t), 1.15 (3H, d).The crystal form of the obtained product was subjected to thermogravimetric analysis (TGA) by a Universal V4.7A TA instrument, and the TGA curve (Fig. 1) showed a weight loss of about 18.52% from about room temperature to about 240 ° C. The original form Ia crystal form The TGA plot shows a value of 18.7%.The crystal form of the obtained product was subjected to differential scanning calorimetry (DSC) by a Universal V4.7A TA instrument, and the DSC curve (Fig. 2) showed endotherm in the range of about 60 ° C to 85 ° C. The DSC plot shows a range of approximately 50 ° C to 78 ° C.

The crystal form of the obtained product was examined by a Bruker D8advance instrument for powder X-ray diffraction (PXRD), and the 2X value of the PXRD pattern (Fig. 3) (CuKα).

There are characteristic peaks at 3.749°, 7.52°, 7.995°, 8.664°, 15.134°, 15.708°, 17.069°, 18.946°, 20.049°, which are completely consistent with the characteristic peaks of the PXRD pattern of the Ia crystal form in the original patent.In combination with the nuclear magnetic data and melting point of the prepared crystal form, the crystal form of the product (Compound 1) obtained by the present invention is consistent with the pharmaceutically acceptable crystalline form Ia reported in the original patent.

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TitleCHEN DEJIN ET AL., CHINA MASTER’S THESES FULL-TEXT DATABASE, ENGINEERING TECHNOLOGY I, vol. B016-731, no. 3, 15 March 2016 (2016-03-15) *LEMAIRE S. ET AL.: “Stereoselective C-glycosylation of furanosyl halides with arylzinc reagents”, PURE APPL. CHEM., vol. 86, no. 3, 4 March 2014 (2014-03-04), pages 329 – 333 *LEMAIRE S. ET AL.: “Stereoselective C-Glycosylation Reactions with Arylzinc Reagents”, ORGANIC LETTERS, vol. 14, no. 6, 2 March 2012 (2012-03-02), pages 1480 – 1483, XP055069093 ** Cited by examiner, † Cited by third partyCLIP

Chemical Synthesis

Dapagliflozin propanediol hydrate, an orally active sodium glucose cotransporter type 2 (SGLT-2) inhibitor, was developed by Bristol-Myers Squibb (BMS) and AstraZeneca for the once-daily treatment of type 2 diabetes. As opposed to competitor SGLT-2 inhibitors, dapagliflozin was not associated with renal toxicity or long-term deterioration of renal function in phase III clinical trials. The drug exhibits excellent SGLT2 potency with more than 1200 fold selectivity over the SGLT1 enzyme.

Dapagliflozin propanediol monohydrate

PAPER

https://link.springer.com/article/10.1007/s12039-020-1747-x

PATENTS

WO 2010138535

WO 2011060256

WO 2012041898

WO 2012163990

WO 2013068850

WO 2012163546

WO 2013068850

WO 2013079501

The IC₅₀ for SGLT2 is less than one thousandth of the IC₅₀ for SGLT1 (1.1 versus 1390 nmol/l), so that the drug does not interfere with the intestinal glucose absorption.^[7

dapagliflozin being an inhibitor of sodiumdependent glucose transporters found in the intestine and kidney (SGLT2) and to a method for treating diabetes, especially type II diabetes, as well as hyperglycemia, hyperinsulinemia, obesity, hypertriglyceridemia, Syndrome X, diabetic

complications, atherosclerosis and related diseases, employing such C-aryl glucosides alone or in combination with one, two or more other type antidiabetic agent and/or one, two or more other type therapeutic agents such as hypolipidemic agents.

Approximately 100 million people worldwide suffer from type II diabetes (NIDDM – non-insulin-dependent diabetes mellitus), which is characterized by hyperglycemia due to excessive hepatic glucose production and peripheral insulin resistance, the root causes for which are as yet unknown. Hyperglycemia is considered to be the major risk factor for the development of diabetic complications, and is likely to contribute directly to the impairment of insulin secretion seen in advanced NIDDM. Normalization of plasma glucose in NIDDM patients would be predicted to improve insulin action, and to offset the development of diabetic complications. An inhibitor of the sodium-dependent glucose transporter SGLT2 in the kidney would be expected to aid in the normalization of plasma glucose levels, and perhaps body weight, by enhancing glucose excretion.

Dapagliflozin can be prepared using similar procedures as described in U.S. Pat. No. 6,515,117 or international published applications no. WO 03/099836 and WO 2008/116179

WO 03/099836 A1 refers to dapagliflozin having the structure according to formula 1 .

formula 1

WO 03/099836 A1 discloses a route of synthesis on pages 8-10, whereby one major step is the purification of a compound of formula 2

formula 2

The compound of formula 2 provides a means of purification for providing a compound of formula 1 since it crystallizes. Subsequently the crystalline form of the compound of formula 2 can be deprotected and converted to dapagliflozin. Using this process, dapagliflozin is obtained as an amorphous glassy off-white solid containing 0.1 1 mol% of EtOAc. Crystallization of a pharmaceutical drug is usually advantageous as it provides means for purification also suitable for industrial scale preparation. However, for providing an active pharmaceutical drug a very high purity is required. In particular, organic impurities such as EtOAc either need to be avoided or further purification steps are needed to provide the drug in a

pharmaceutically acceptable form, i.e. substantially free of organic solvents. Thus, there is the need in the art to obtain pure and crystalline dapagliflozinwhich is substantially free of organic solvents.

WO 2008/002824 A1 discloses several alternative solid forms of dapagliflozin, such as e.g. solvates containing organic alcohols or co-crystals with amino acids such as proline and phenylalanine. For instance, the document discloses crystalline

dapagliflozin solvates which additionally contain water molecules (see e.g.

Examples 3-6), but is silent about solid forms of dapagliflozin which do not contain impurities such as organic alcohols. As described above, it is desirable to provide the pharmaceutical active drug in a substantially pure form, otherwise triggering further expensive and time-consuming purification steps. In contrast, the document relates to dapagliflozin solvates where an alcohol and water are both incorporated into the crystal lattice. Hence, there is the need in the art to obtain pure and crystalline dapagliflozin suitable for pharmaceutical production.

WO 2008/1 16179 A1 refers to an immediate release pharmaceutical composition comprising dapagliflozin and propylene glycol. Propylene glycol is a chiral

substance and (S)-propylene glycol used is very expensive. Consequently, also the immediate release pharmaceutical composition is more expensive.

Crystalline forms (in comparision to the amorphous form) often show desired different physical and/or biological characteristics which may assist in the manufacture or formulation of the active compound, to the purity levels and uniformity required for regulatory approval. As described above, it is desirable to provide the pharmaceutical active drug in a substantially pure form, otherwise triggering further expensive and time-consuming purification steps.

PATENT

WO 2008/ 1 16179 Al seems to disclose an immediate release formulation comprising dapagliflozin and propylene glycol hydrate. WO 2008/ 116195 A2 refers to the use of an SLGT2 inhibitor in the treatment of obesity

http://www.google.com/patents/US20120282336

http://www.tga.gov.au/pdf/auspar/auspar-dapagliflozin-propanediol-monohydrate-130114.pdf

Example 2 Dapagliflozin (S) PGS—(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (S)-propane-1,2-diol hydrate (1:1:1)

Dapagliflozin (S) propylene glycol hydrate (1:1:1) can be prepared using similar procedures as described in published applications WO 08/002824 and WO 2008/116179, the disclosures of which are herein incorporated by reference in their entirety for any purpose. SGLT2 EC₅₀=1.1 nM.

Example 3 Dapagliflozin (R) PGS—(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (R)-propane-1,2-diol hydrate (1:1:1)

Dapagliflozin (R) propylene glycol hydrate (1:1:1) can be prepared using similar procedures as described in WO 08/002824 and WO 2008/116179, the disclosures of which are herein incorporated by reference in their entirety for any purpose. SGLT2 EC₅₀=1.1 nM.

WO 2008/002824 A1 discloses several alternative solid forms of dapagliflozin, such as e.g. solvates containing organic alcohols or co-crystals with amino acids such as proline and phenylalanine. For instance, the document discloses crystalline

dapagliflozin solvates which additionally contain water molecules (see e.g.

Examples 3-6), but is silent about solid forms of dapagliflozin which do not contain impurities such as organic alcohols. As described above, it is desirable to provide the pharmaceutical active drug in a substantially pure form, otherwise triggering further expensive and time-consuming purification steps. In contrast, the document relates to dapagliflozin solvates where an alcohol and water are both incorporated into the crystal lattice. Hence, there is the need in the art to obtain pure and crystalline dapagliflozin suitable for pharmaceutical production.

WO 2008/1 16179 A1 refers to an immediate release pharmaceutical composition comprising dapagliflozin and propylene glycol. Propylene glycol is a chiral

substance and (S)-propylene glycol used is very expensive. Consequently, also the immediate release pharmaceutical composition is more expensive.

Surprisingly, amorphous dapagliflozin can be purified with the process of the present invention. For instance amorphous dapagliflozin having a purity of 99,0% can be converted to crystalline dapagliflozin hydrate having a purity of 100% (see examples of the present application). Moreover, said crystalline dapagliflozin hydrate does not contain any additional solvent which is desirable. Thus, the process of purifying dapagliflozin according to the present invention is superior compared with the process of WO 03/099836 A1 .

Additionally, the dapagliflozin hydrate obtained is crystalline which is advantageous with respect to the formulation of a pharmaceutical composition. The use of expensive diols such as (S)-propanediol for obtaining an immediate release pharmaceutical composition as disclosed in WO 2008/1 16179 A1 can be avoided

PAPER

In Vitro Characterization and Pharmacokinetics of Dapagliflozin …

dmd.aspetjournals.org/content/…/DMD29165_supplemental_data_.doc

Dapagliflozin (BMS-512148), (2S,3R,4R,5S,6R)-2-(3-(4-Ethoxybenzyl)-4-chlorophenyl)

-6-hydroxymethyl-tetrahydro-2H-pyran-3,4,5-triol. 1H NMR (500 MHz, CD3OD) δ 7.33

(d, J = 6.0, 1H), 7.31 (d, J = 2.2, 1H), 7.31 (dd, J = 2.2, 6.0, 1H), 7.07 (d, J = 8.8, 2H),

6.78 (d, J = 8.8, 2H), 4.07-3.90 (m, 7H), 3.85 (d, J = 10.6, 1H), 3.69 (dd, J = 5.3, 10.6,

1H), 3.42-3.25 (m, 4H), 1.34 (t, J = 7.0, 3H). 13C NMR (125 MHz, CD3OD) δ 158.8,

140.0, 139.9, 134.4, 132.9, 131.9, 130.8, 130.1, 128.2, 115.5, 82.9, 82.2, 79.7, 76.4, 71.9,

64.5, 63.1, 39.2, 15.2.

HRMS calculated for C21H25ClNaO6 (M+Na)+

For C21H25ClO6: C, 61.68; H, 6.16. Found: C, 61.16; H, 6.58.

: 431.1237; found 431.1234. Anal. Calcd

SECOND SETJ. Med. Chem., 2008, 51 (5), pp 1145–1149DOI: 10.1021/jm701272q

¹H NMR (500 MHz, CD₃OD) δ 7.33 (d, J = 6.0, 1H), 7.31 (d, J = 2.2, 1H), 7.31 (dd, J = 2.2, 6.0, 1H), 7.07 (d, J = 8.8, 2H), 6.78 (d, J = 8.8, 2H), 4.07–3.90 (m, 7H), 3.85 (d, J = 10.6, 1H), 3.69 (dd, J = 5.3, 10.6, 1H), 3.42–3.25 (m, 4H), 1.34 (t, J = 7.0, 3H);

¹³C NMR (125 MHz, CD₃OD) δ 158.8, 140.0, 139.9, 134.4, 132.9, 131.9, 130.8, 130.1, 128.2, 115.5, 82.9, 82.2, 79.7, 76.4, 71.9, 64.5, 63.1, 39.2, 15.2;

HRMS calcd for C₂₁H₂₅ClNaO₆ (M + Na)⁺ 431.1237, found 431.1234. Anal. Calcd for C₂₁H₂₅ClO₆: C, 61.68; H, 6.16. Found: C, 61.16; H, 6.58.

HPLC

• HPLC measurements were performed with an Agilent 1100 series instrument equipped with a UV-vis detector set to 240 nm according to the following method:
  Column: Ascentis Express RP-Amide 4.6 x 150 mm, 2.7 mm;
  Column temperature: 25 °C
  – Eluent A: 0.1 % formic acid in water
  – Eluent B: 0.1 % formic acid in acetonitrile
  – Injection volume: 3 mL
  – Flow: 0.7 mL/min
  – Gradient:Time [min][%] B0.02525.06526.07029.07029.52535.025……………………..

PATENT

http://www.google.com/patents/WO2013068850A2?cl=en

EXAMPLE 24 – Synthesis of 2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(4-chloro-3-(4- ethoxybenzyl)phenyl)- -D-glucopyranoside 2,4-di-6>-TBDPS-dapagliflozin; (IVj”))

[0229] l-(5-Bromo-2-chlorobenzyl)-4-ethoxybenzene (1.5 g, 4.6 mmol) and magnesium powder (0.54 g, 22.2 mmol) were placed in a suitable reactor, followed by THF (12 mL) and 1,2- dibromoethane (0.16 mL). The mixture was heated to reflux. After the reaction had initiated, a solution of l-(5-bromo-2-chlorobenzyl)-4-ethoxybenzene (4.5 g, 13.8 mmol) in THF (28 mL) was added dropwise. The mixture was allowed to stir for another hour under reflux, and was then cooled to ambient temperature, and then titrated to determine the concentration. The above prepared 4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl magnesium bromide (31 mL, 10 mmol, 0.32 M in THF) and A1C1₃ (0.5 M in THF, 8.0 mL, 4.0 mmol) were mixed at ambient temperature to give a black solution, which was stirred at ambient temperature for 1 hour. To a solution of

I, 6-anhydro-2,4-di-6>-ieri-butyldiphenylsilyl- -D-glucopyranose (0.64 g, 1.0 mmol) in PhOMe (3.0 mL) at ambient temperature was added phenylmagnesium bromide (0.38 mL, 1.0 mmol, 2.6 M solution in Et₂0). After stirring for about 5 min the solution was then added into the above prepared aluminum mixture via syringe, followed by additional PhOMe (1.0 mL) to rinse the flask. The mixture was concentrated under reduced pressure (50 torr) at 60 °C (external bath temperature) to remove low-boiling point ethereal solvents and then PhOMe (6mL) was added. The reaction mixture was heated at 130 °C (external bath temperature) for 8 hours at which time HPLC assay analysis indicated a 51% yield of 2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(4-chloro-3- (4-ethoxybenzyl)phenyl)- -D-glucopyranoside. After cooling to ambient temperature, the reaction was treated with 10% aqueous NaOH (1 mL), THF (10 mL) and diatomaceous earth at ambient temperature, then the mixture was filtered and the filter cake was washed with THF. The combined filtrates were concentrated and the crude product was purified by silica gel column chromatography (eluting with 1:30 EtOAc/77-heptane) affording the product 2,4-di-6>- ieri-butyldiphenylsilyl- 1 – -(4-chloro-3 -(4-ethoxybenzyl)phenyl)- β-D-glucopyranoside (0.30 g, 34%) as a white powder.

1H NMR (400 MHz, CDC1₃) δ 7.56-7.54 (m, 2H), 7.43-7.31 (m, 13H), 7.29-7.22 (m, 6H), 7.07- 7.04 (m, 2H), 7.00 (d, J= 2.0 Hz, IH), 6.87 (dd, J= 8.4, 2.0 Hz, IH), 6.83-6.81 (m, 2H), 4.18 (d, J= 9.6 Hz, IH), 4.02 (q, J= 6.9 Hz, 2H), 3.96 (d, J= 10.8 Hz, 2H), 3.86 (ddd, J= 11.3, 7.7, 1.1 Hz, IH), 3.76 (ddd, J= 8.4, 8.4, 4.8 Hz, IH), 3.56 (ddd, J= 9.0, 6.4, 2.4 Hz, IH), 3.50 (dd, J=

I I.4, 5.4 Hz, IH), 3.44 (dd, J= 9.4, 8.6 Hz, IH), 3.38 (dd, J= 8.8, 8.8 Hz, IH), 1.70 (dd, J= 7.8, 5.4 Hz, IH, OH), 1.42 (t, J= 6.8 Hz, 3H), 1.21 (d, J= 5.2 Hz, IH, OH), 1.00 (s, 9H), 0.64 (s, 9H); ¹³C NMR (100 MHz, CDC1₃) δ 157.4 (C), 138.8 (C), 137.4 (C), 136.3 (CH x2), 136.1 (CH x2), 135.2 (CH x2), 135.0 (C), 134.9 (CH x2), 134.8 (C), 134.2 (C), 132.8 (C), 132.0 (C), 131.6 (CH), 131.1 (C), 129.9 (CH x2), 129.7 (CH), 129.6 (CH), 129.5 (CH), 129.4 (CH), 129.2 (CH), 127.58 (CH x2), 127.57 (CH x2), 127.54 (CH x2), 127.31 (CH), 127.28 (CH x2), 114.4 (CH x2), 82.2 (CH), 80.5 (CH), 79.3 (CH), 76.3 (CH), 72.7 (CH), 63.4 (CH₂), 62.7 (CH₂), 38.2 (CH₂), 27.2 (CH₃ x3), 26.6 (CH₃ x3), 19.6 (C), 19.2 (C), 14.9 (CH₃). EXAMPLE 25 -Synthesis of dapagliflozin ((25,3R,4R,55,6/?)-2-[4-chloro-3-(4- ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (Ij))

IVj’ U

[0230] A solution of the 2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(4-chloro-3-(4- ethoxybenzyl)phenyl)- -D-glucopyranoside (60 mg, 0.068 mmol) in THF (3.0 mL) and TBAF (3.0 mL, 3.0 mmol, 1.0 M in THF) was stirred at ambient temperature for 15 hours. CaC0₃ (0.62 g), Dowex^{^} 50WX8-400 ion exchange resin (1.86 g) and MeOH (5mL) were added to the product mixture and the suspension was stirred at ambient temperature for 1 hour and then the mixture was filtrated through a pad of diatomaceous earth. The filter cake was rinsed with MeOH and the combined filtrates was evaporated under vacuum and the resulting residue was purified by column chromatography (eluting with 1 : 10 MeOH/DCM) affording dapagliflozin (30 mg).

1H NMR (400 MHz, CD₃OD) δ 7.37-7.34 (m, 2H), 7.29 (dd, J= 8.2, 2.2 Hz, 1H), 7.12-7.10 (m, 2H), 6.82-6.80 (m, 2H), 4.10 (d, J= 9.6 Hz, 2H), 4.04 (d, J= 9.2 Hz, 2H), 4.00 (q, J= 7.1 Hz, 2H), 3.91-3.87 (m, 1H), 3.73-3.67(m, 1H), 3.47-3.40 (m, 3H), 3.31-3.23 (m, 2H), 1.37 (t, J= 7.0 Hz, 3H);

¹³C NMR (100 MHz, CD₃OD) δ 157.4 (C), 138.6 (C), 138.5 (C), 133.1 (C), 131.5 (C), 130.5 (CH), 129.4 (CH x2), 128.7 (CH), 126.8 (CH), 114.0 (CH x2), 80.5 (CH), 80.8 (CH), 78.3 (CH), 75.0 (CH), 70.4 (CH), 63.0 (CH₂), 61.7 (CH₂), 37.8 (CH₂), 13.8 (CH₃);

LCMS (ESI) m/z 426 (100, [M+NH₄]⁺), 428 (36, [M+NH₄+2]⁺), 447 (33, [M+K]⁺).

Example 1 – Synthesis of l,6-anhydro-2,4-di-6>-ieri-butyldiphenylsilyl- -D-glucopyranose (II”)

III II”

[0206] To a suspension solution of l,6-anhydro- -D-glucopyranose (1.83 g, 11.3 mmol) and imidazole (3.07 g, 45.2 mmol) in THF (10 mL) at 0 °C was added dropwise a solution of TBDPSC1 (11.6 mL, 45.2 mmol) in THF (10 mL). After the l,6-anhydro-P-D-gJucopyranose was consumed, water (10 mL) was added and the mixture was extracted twice with EtOAc (20 mL each), washed with brine (10 mL), dried (Na₂S0₄) and concentrated. Column

chromatography (eluting with 1 :20 EtOAc/rc-heptane) afforded 2,4-di-6>-ieri-butyldiphenylsilyl- l,6-anhydro- “D-glucopyranose (5.89 g, 81%).

1H NMR (400 MHz, CDC1₃) δ 7.82-7.70 (m, 8H), 7.49-7.36 (m, 12H), 5.17 (s, IH), 4.22 (d, J= 4.8 Hz, IH), 3.88-3.85 (m, IH), 3.583-3.579 (m, IH), 3.492-3.486 (m, IH), 3.47-3.45 (m, IH), 3.30 (dd, J= 7.4, 5.4 Hz, IH), 1.71 (d, J= 6.0 Hz, IH), 1.142 (s, 9H), 1.139 (s, 9H); ¹³C NMR (100 MHz, CDCI₃) δ 135.89 (CH x2), 135.87 (CH x2), 135.85 (CH x2), 135.83 (CH x2), 133.8 (C), 133.5 (C), 133.3 (C), 133.2 (C), 129.94 (CH), 129.92 (CH), 129.90 (CH), 129.88 (CH), 127.84 (CH₂ x2), 127.82 (CH₂ x2), 127.77 (CH₂ x4), 102.4 (CH), 76.9 (CH), 75.3 (CH), 73.9 (CH), 73.5 (CH), 65.4 (CH₂), 27.0 (CH₃ x6), 19.3 (C x2).

PATENT

WO 2016147197, DAPAGLIFLOZIN, NEW PATENT, HARMAN FINOCHEM LIMITED

LINK>>> (WO2016147197) A NOVEL PROCESS FOR PREPARING (2S,3R,4R,5S,6R)-2-[4-CHLORO-3-(4-ETHOXYBENZYL)PHENY 1] -6-(HY DROXY METHYL)TETRAHYDRO-2H-PY RAN-3,4,5-TRIOL AND ITS AMORPHOUS FORM

PATENT

PATENT

WO2016018024, CRYSTALLINE COMPOSITE COMPRISING DAPAGLIFLOZIN AND METHOD FOR PREPARING SAME

HANMI FINE CHEMICAL CO., LTD. [KR/KR]; 59, Gyeongje-ro, Siheung-si, Gyeonggi-do 429-848 (KR)

Dapagliflozin, sold under the brand name Farxiga among others, is a medication used to treat type 2 diabetes and, with certain restrictions, type 1 diabetes.^[2] It is also used to treat adults with certain kinds of heart failure.^[3][4][5]

Common side effects include hypoglycaemia (low blood sugar), urinary tract infections, genital infections, and volume depletion (reduced amount of water in the body).^[6] Diabetic ketoacidosis is a common side effect in type 1 diabetic patients.^[7] Serious but rare side effects include Fournier gangrene.^[8] Dapagliflozin is a sodium-glucose co-transporter-2 (SGLT-2) inhibitor and works by removing sugar from the body with the urine.^[9]

It was developed by Bristol-Myers Squibb in partnership with AstraZeneca. In 2018, it was the 227th most commonly prescribed medication in the United States, with more than 2 million prescriptions.^[10][11]

Medical uses

Dapagliflozin is used along with diet and exercise to improve glycemic control in adults with type 2 diabetes and to reduce the risk of hospitalization for heart failure among adults with type 2 diabetes and known cardiovascular disease or other risk factors.^[12][3] It appears more useful than empagliflozin.^{[13][verification needed]}

In addition, dapagliflozin is indicated for the treatment of adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure.^[3][4][5] It is also indicated to reduce the risk of kidney function decline, kidney failure, cardiovascular death and hospitalization for heart failure in adults with chronic kidney disease who are at risk of disease progression.^[14]

In the European Union it is indicated in adults:

• for the treatment of insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise:
  • as monotherapy when metformin is considered inappropriate due to intolerance;
  • in addition to other medicinal products for the treatment of type 2 diabetes;
• for the treatment of insufficiently controlled type 1 diabetes mellitus as an adjunct to insulin in patients with BMI ≥ 27 kg/m², when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy; and
• for the treatment of heart failure with reduced ejection fraction.^[5]

Adverse effects

Since dapagliflozin leads to heavy glycosuria (sometimes up to about 70 grams per day) it can lead to rapid weight loss and tiredness. The glucose acts as an osmotic diuretic (this effect is the cause of polyuria in diabetes) which can lead to dehydration. The increased amount of glucose in the urine can also worsen the infections already associated with diabetes, particularly urinary tract infections and thrush (candidiasis). Rarely, use of an SGLT2 drug, including dapagliflozin, is associated with necrotizing fasciitis of the perineum, also called Fournier gangrene.^[15]

Dapagliflozin is also associated with hypotensive reactions. There are concerns it may increase the risk of diabetic ketoacidosis.^[16]

Dapagliflozin can cause dehydration, serious urinary tract infections and genital yeast infections.^[3] Elderly people, people with kidney problems, those with low blood pressure, and people on diuretics should be assessed for their volume status and kidney function.^[3] People with signs and symptoms of metabolic acidosis or ketoacidosis (acid buildup in the blood) should also be assessed.^[3] Dapagliflozin can cause serious cases of necrotizing fasciitis of the perineum (Fournier gangrene) in people with diabetes and low blood sugar when combined with insulin.^[3]

To lessen the risk of developing ketoacidosis (a serious condition in which the body produces high levels of blood acids called ketones) after surgery, the FDA has approved changes to the prescribing information for SGLT2 inhibitor diabetes medicines to recommend they be stopped temporarily before scheduled surgery. Canagliflozin, dapagliflozin, and empagliflozin should each be stopped at least three days before, and ertugliflozin should be stopped at least four days before scheduled surgery.^[17]

Symptoms of ketoacidosis include nausea, vomiting, abdominal pain, tiredness, and trouble breathing.^[17]

Use is not recommended in patients with eGFR < 45ml/min/1.73m², though data from 2021 shows the reduction in the kidney failure risks in people with chronic kidney disease using dapagliflozin.^[18]

Mechanism of action

Dapagliflozin inhibits subtype 2 of the sodium-glucose transport proteins (SGLT2) which are responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter mechanism causes blood glucose to be eliminated through the urine.^[19] In clinical trials, dapagliflozin lowered HbA_1c by 0.6 versus placebo percentage points when added to metformin.^[20]

Regarding its protective effects in heart failure, this is attributed primarily to haemodynamic effects, where SGLT2 inhibitors potently reduce intravascular volume through osmotic diuresis and natriuresis. This consequently may lead to a reduction in preload and afterload, thereby alleviating cardiac workload and improving left ventricular function.^[21]

Selectivity

The IC₅₀ for SGLT2 is less than one thousandth of the IC₅₀ for SGLT1 (1.1 versus 1390 nmol/L), so that the drug does not interfere with intestinal glucose absorption.^[22]

Names

Dapagliflozin is the International nonproprietary name (INN),^[23] and the United States Adopted Name (USAN).^[24]

There is a fixed-dose combination product dapagliflozin/metformin extended-release, called Xigduo XR.^[25][26][27]

In July 2016, the fixed-dose combination of saxagliptin and dapagliflozin was approved for medical use in the European Union and is sold under the brand name Qtern.^[28] The combination drug was approved for medical use in the United States in February 2017, where it is sold under the brand name Qtern.^[29][30]

In May 2019, the fixed-dose combination of dapagliflozin, saxagliptin, and metformin hydrochloride as extended-release tablets was approved in the United States to improve glycemic control in adults with type 2 diabetes when used in combination with diet and exercise. The FDA granted the approval of Qternmet XR to AstraZeneca.^[31] The combination drug was approved for use in the European Union in November 2019, and is sold under the brand name Qtrilmet.^[32]

History

In 2012, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion on the drug.^[5]

Dapagliflozin was found effective in several studies in participants with type 2 and type 1 diabetes.^[5] The main measure of effectiveness was the level of glycosylated haemoglobin (HbA1c), which gives an indication of how well blood glucose is controlled.^[5]

In two studies involving 840 participants with type 2 diabetes, dapagliflozin when used alone decreased HbA1c levels by 0.66 percentage points more than placebo (a dummy treatment) after 24 weeks.^[5] In four other studies involving 2,370 participants, adding dapagliflozin to other diabetes medicines decreased HbA1c levels by 0.54-0.68 percentage points more than adding placebo after 24 weeks.^[5]

In a study involving 814 participants with type 2 diabetes, dapagliflozin used in combination with metformin was at least as effective as a sulphonylurea (another type of diabetes medicines) used with metformin.^[5] Both combinations reduced HbA1c levels by 0.52 percentage points after 52 weeks.^[5]

A long-term study, involving over 17,000 participants with type 2 diabetes, looked at the effects of dapagliflozin on cardiovascular (heart and circulation) disease.^[5] The study indicated that dapagliflozin’s effects were in line with those of other diabetes medicines that also work by blocking SGLT2.^[5]

In two studies involving 1,648 participants with type 1 diabetes whose blood sugar was not controlled well enough on insulin alone, adding dapagliflozin 5 mg decreased HbA1c levels after 24 hours by 0.37% and by 0.42% more than adding placebo.^[5]

Dapagliflozin was approved for medical use in the European Union in November 2012.^[5] It is marketed in a number of European countries.^[33]

Dapagliflozin was approved for medical use in the United States in January 2014.^[34][14]

In 2020, the U.S. Food and Drug Administration (FDA) expanded the indications for dapagliflozin to include treatment for adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure.^[3] It is the first in this particular drug class, sodium-glucose co-transporter 2 (SGLT2) inhibitors, to be approved to treat adults with New York Heart Association’s functional class II-IV heart failure with reduced ejection fraction.^[3]

Dapagliflozin was shown in a clinical trial to improve survival and reduce the need for hospitalization in adults with heart failure with reduced ejection fraction.^[3] The safety and effectiveness of dapagliflozin were evaluated in a randomized, double-blind, placebo-controlled study of 4,744 participants.^[3] The average age of participants was 66 years and more participants were male (77%) than female.^[3] To determine the drug’s effectiveness, investigators examined the occurrence of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits.^[3] Participants were randomly assigned to receive a once-daily dose of either 10 milligrams of dapagliflozin or a placebo (inactive treatment).^[3] After about 18 months, people who received dapagliflozin had fewer cardiovascular deaths, hospitalizations for heart failure, and urgent heart failure visits than those receiving the placebo.^[3]

In July 2020, the FDA granted AstraZeneca a Fast Track Designation in the US for the development of dapagliflozin to reduce the risk of hospitalisation for heart failure or cardiovascular death in adults following a heart attack.^[35]

In August 2020, it was reported that detailed results from the Phase III DAPA-CKD trial showed that AstraZeneca’s FARXIGA® (dapagliflozin) on top of standard of care reduced the composite measure of worsening of renal function or risk of cardiovascular (CV) or renal death by 39% compared to placebo (p<0.0001) in patients with chronic kidney disease (CKD) Stages 2-4 and elevated urinary albumin excretion. The results were consistent in patients both with and without type 2 diabetes (T2D)^[36]

In April 2021, the FDA expanded the indications for dapagliflozin (Farxiga) to include reducing the risk of kidney function decline, kidney failure, cardiovascular death and hospitalization for heart failure in adults with chronic kidney disease who are at risk of disease progression.^[14] The efficacy of dapagliflozin to improve kidney outcomes and reduce cardiovascular death in people with chronic kidney disease was evaluated in a multicenter, double-blind study of 4,304 participants.^[14]

Research

One study found that it had no benefit on heart disease risk or overall risk of death in people with diabetes.^[37] Another study found that in heart failure with a reduced ejection fraction, dapagliflozin reduced the risk of worsening of heart failure or progression to death from cardiovascular causes, irrespective of diabetic status.^[38]

References

1. ^ Jump up to:^a b “Dapagliflozin (Farxiga) Use During Pregnancy”. Drugs.com. 30 August 2018. Retrieved 5 May 2020.
2. ^ Jump up to:^a b “Farxiga- dapagliflozin tablet, film coated”. DailyMed. 3 February 2020. Retrieved 5 May 2020.
3. ^ Jump up to:^{a b c d e f g h i j k l m n o} “FDA approves new treatment for a type of heart failure”. U.S. Food and Drug Administration (FDA) (Press release). 5 May 2020. Retrieved 5 May 2020.  This article incorporates text from this source, which is in the public domain.
4. ^ Jump up to:^a b National Institute for Health and Care Excellence (24 February 2021). “Dapagliflozin for treating chronic heart failure with reduced ejection fraction”. NICE Technology Appraisal Auidance [TA679]. NICE. Retrieved 9 May 2021.
5. ^ Jump up to:^{a b c d e f g h i j k l m n} “Forxiga EPAR”. European Medicines Agency (EMA). Retrieved 17 February 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
6. ^ Ptaszynska, Agata; Johnsson, Kristina M.; Parikh, Shamik J.; De Bruin, Tjerk W. A.; Apanovitch, Anne Marie; List, James F. (2014). “Safety Profile of Dapagliflozin for Type 2 Diabetes: Pooled Analysis of Clinical Studies for Overall Safety and Rare Events”. Drug Safety. 37 (10): 815–829. doi:10.1007/s40264-014-0213-4. PMID 25096959. S2CID 24064402.
7. ^ Dandona, Paresh; Mathieu, Chantal; Phillip, Moshe; Hansen, Lars; Tschöpe, Diethelm; Thorén, Fredrik; Xu, John; Langkilde, Anna Maria; DEPICT-1 Investigators (2018). “Efficacy and Safety of Dapagliflozin in Patients with Inadequately Controlled Type 1 Diabetes: The DEPICT-1 52-Week Study”. Diabetes Care. 41(12): 2552–2559. doi:10.2337/dc18-1087. PMID 30352894. S2CID 53027785.
8. ^ Hu, Yang; Bai, Ziyu; Tang, Yan; Liu, Rongji; Zhao, Bin; Gong, Jian; Mei, Dan (2020). “Fournier Gangrene Associated with Sodium-Glucose Cotransporter-2 Inhibitors: A Pharmacovigilance Study with Data from the U.S. FDA Adverse Event Reporting System”. Journal of Diabetes Research. 2020: 1–8. doi:10.1155/2020/3695101. PMC 7368210. PMID 32695827.
9. ^ FARXIGA- dapagliflozin tablet, film coated. DailyMed. Retrieved 6 May 2021.
10. ^ “The Top 300 of 2021”. ClinCalc. Retrieved 18 February 2021.
11. ^ “Dapagliflozin – Drug Usage Statistics”. ClinCalc. Retrieved 18 February 2021.
12. ^ “FDA Approves Farxiga to Treat Type 2 Diabetes” (Press release). U.S. Food and Drug Administration (FDA). 8 January 2014. Archived from the original on 9 January 2014. Retrieved 15 November 2016.  This article incorporates text from this source, which is in the public domain.
13. ^ Zelniker TA, Wiviott SD, Raz I, et al. (January 2019). “SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials”. Lancet. 393(10166): 31–9. doi:10.1016/S0140-6736(18)32590-X. PMID 30424892. S2CID 53277899. However, in patients with atherosclerotic cardiovascular disease, the effect of empagliflozin on cardiovascular death was more pro-nounced than that of canagliflozin or dapagliflozin
14. ^ Jump up to:^a b c d “FDA Approves Treatment for Chronic Kidney Disease”. U.S. Food and Drug Administration (FDA) (Press release). 30 April 2021. Retrieved 30 April 2021.  This article incorporates text from this source, which is in the public domain.
15. ^ “FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes”. U.S. Food and Drug Administration (FDA). 9 February 2019.  This article incorporates text from this source, which is in the public domain.
16. ^ “SGLT2 inhibitors: Drug Safety Communication – FDA Warns Medicines May Result in a Serious Condition of Too Much Acid in the Blood”. U.S. Food and Drug Administration (FDA). 15 May 2015. Archived from the original on 27 October 2016. Retrieved 15 November 2016.  This article incorporates text from this source, which is in the public domain.
17. ^ Jump up to:^a b “FDA revises labels of SGLT2 inhibitors for diabetes to include warning”. U.S. Food and Drug Administration. 19 March 2020. Retrieved 6 June 2020.  This article incorporates text from this source, which is in the public domain.
18. ^ McMurray, John J.V.; Wheeler, David C.; Stefánsson, Bergur V.; Jongs, Niels; Postmus, Douwe; Correa-Rotter, Ricardo; Chertow, Glenn M.; Greene, Tom; Held, Claes; Hou, Fan-Fan; Mann, Johannes F.E.; Rossing, Peter; Sjöström, C. David; Toto, Roberto D.; Langkilde, Anna Maria; Heerspink, Hiddo J.L.; DAPA-CKD Trial Committees Investigators (2021). “Effect of Dapagliflozin on Clinical Outcomes in Patients with Chronic Kidney Disease, with and Without Cardiovascular Disease” (PDF). Circulation. 143 (5): 438–448. doi:10.1161/CIRCULATIONAHA.120.051675. PMID 33186054. S2CID 226948086.
19. ^ “Life Sciences – Clarivate”. Clarivate. Archived from the original on 5 November 2007.
20. ^ “UEndocrine: Internet Endocrinology Community”. uendocrine.com. Archived from the original on 5 February 2013.
21. ^ Lan NS, Fegan PG, Yeap BB, Dwivedi G (October 2019). “The effects of sodium-glucose cotransporter 2 inhibitors on left ventricular function: current evidence and future directions”. ESC Heart Fail. 6 (5): 927–935. doi:10.1002/ehf2.12505. PMC 6816235. PMID 31400090.
22. ^ Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel 2008/2009
23. ^ “International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 59” (PDF). World Health Organization. 2008. p. 50. Retrieved 15 November 2016.
24. ^ “Statement on a Nonproprietary Name Adopted by the USAN Council” (PDF). American Medical Association. Archived from the original (PDF) on 7 February 2012. Retrieved 15 November2016.
25. ^ “US FDA Approves Once-Daily Xigduo XR Tablets for Adults with Type 2 Diabetes”. AstraZeneca. 30 October 2014.
26. ^ “Drug Approval Package: Xigduo XR (dapagliflozin and metformin HCl) Extended-Release Tablets”. U.S. Food and Drug Administration (FDA). 7 April 2015. Retrieved 5 May 2020.
27. ^ “Xigduo XR- dapagliflozin and metformin hydrochloride tablet, film coated, extended release”. DailyMed. 3 February 2020. Retrieved 5 May 2020.
28. ^ “Qtern EPAR”. European Medicines Agency (EMA). Retrieved 7 May 2020.
29. ^ “Drug Approval Package: Qtern (dapagliflozin and saxagliptin)”. U.S. Food and Drug Administration (FDA). 10 October 2018. Retrieved 8 May 2020.
30. ^ “Qtern- dapagliflozin and saxagliptin tablet, film coated”. DailyMed. 24 January 2020. Retrieved 17 February 2020.
31. ^ “Drug Approval Package: Qternmet XR”. U.S. Food and Drug Administration (FDA). 27 January 2020. Retrieved 17 February2020.
32. ^ “Qtrilmet EPAR”. European Medicines Agency (EMA). Retrieved 30 March 2020.
33. ^ “Forxiga”. Drugs.com. 4 May 2020. Retrieved 5 May 2020.
34. ^ “Drug Approval Package: Farxiga (dapagliflozin) Tablets NDA #202293”. U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 5 May 2020.
35. ^ “FARXIGA Granted Fast Track Designation in the US for Heart Failure Following Acute Myocardial Infarction Leveraging an Innovative Registry-Based Trial Design”. http://www.businesswire.com. 16 July 2020. Retrieved 20 July 2020.
36. ^https://www.businesswire.com/news/home/20200830005009/en/FARXIGA-Demonstrated-Unprecedented-Reduction-Risk-Kidney-Failure
37. ^ “Type 2 diabetes. Cardiovascular assessment of dapagliflozin: no advance”. Prescrire International. 29 (211): 23. January 2020. Retrieved 2 February 2020.
38. ^ McMurray JJ, Solomon SD, Inzucchi SE, et al. (November 2019). “Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction”. New England Journal of Medicine. 381 (21): 1995–2008. doi:10.1056/NEJMoa1911303. PMID 31535829.

External links

• “Dapagliflozin”. Drug Information Portal. U.S. National Library of Medicine.
• “Dapagliflozin mixture with metformin hydrochloride”. Drug Information Portal. U.S. National Library of Medicine.
• “Dapagliflozin mixture with saxagliptin”. Drug Information Portal. U.S. National Library of Medicine.

Clinical trials

• Clinical trial number NCT00528372 for “A Phase III Study of BMS-512148 (Dapagliflozin) in Patients With Type 2 Diabetes Who Are Not Well Controlled With Diet and Exercise” at ClinicalTrials.gov
• Clinical trial number NCT00643851 for “An Efficacy & Safety Study of BMS-512148 in Combination With Metformin Extended Release Tablets” at ClinicalTrials.gov
• Clinical trial number NCT00859898 for “Study of Dapagliflozin in Combination With Metformin XR to Initiate the Treatment of Type 2 Diabetes” at ClinicalTrials.gov
• Clinical trial number NCT00528879 for “A Phase III Study of BMS-512148 (Dapagliflozin) in Patients With Type 2 Diabetes Who Are Not Well Controlled on Metformin Alone” at ClinicalTrials.gov
• Clinical trial number NCT00660907 for “Efficacy and Safety of Dapagliflozin in Combination With Metformin in Type 2 Diabetes Patients” at ClinicalTrials.gov
• Clinical trial number NCT00680745 for “Efficacy and Safety of Dapagliflozin in Combination With Glimepiride (a Sulphonylurea) in Type 2 Diabetes Patients” at ClinicalTrials.gov
• Clinical trial number NCT01392677 for “Evaluation of Safety and Efficacy of Dapagliflozin in Subjects With Type 2 Diabetes Who Have Inadequate Glycaemic Control on Background Combination of Metformin and Sulfonylurea” at ClinicalTrials.gov
• Clinical trial number NCT00683878 for “Add-on to Thiazolidinedione (TZD) Failures” at ClinicalTrials.gov
• Clinical trial number NCT00984867 for “Dapagliflozin DPPIV Inhibitor add-on Study” at ClinicalTrials.gov
• Clinical trial number NCT00673231 for “Efficacy and Safety of Dapagliflozin, Added to Therapy of Patients With Type 2 Diabetes With Inadequate Glycemic Control on Insulin” at ClinicalTrials.gov
• Clinical trial number NCT02229396 for “Phase 3 28-Week Study With 24-Week and 52-week Extension Phases to Evaluate Efficacy and Safety of Exenatide Once Weekly and Dapagliflozin Versus Exenatide and Dapagliflozin Matching Placebo” at ClinicalTrials.gov
• Clinical trial number NCT02413398 for “A Study to Evaluate the Effect of Dapagliflozin on Blood Glucose Level and Renal Safety in Patients With Type 2 Diabetes (DERIVE)” at ClinicalTrials.gov
• Clinical trial number NCT01730534 for “Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI58)” at ClinicalTrials.gov
• Clinical trial number NCT03036124 for “Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure (DAPA-HF)” at ClinicalTrials.gov

///////////DAPAGLIFLOZIN, ダパグリフロジン, BMS 512148, TYPE 2 DIABETES, SGLT-2 Inhibitors, EU 2012,  forxiga, FDA 2014, JAPAN 2014, DIABETES

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