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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Canagliflozin , New patent, WO 2016016774, SUN PHARMACEUTICAL INDUSTRIES LIMITED


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WO2016016774, CRYSTALLINE FORMS OF CANAGLIFLOZIN

SUN PHARMACEUTICAL INDUSTRIES LIMITED [IN/IN]; Sun House, Plot No. 201 B/1 Western Express Highway Goregaon (E) Mumbai, Maharashtra 400 063 (IN)

SANTRA, Ramkinkar; (IN).
NAGDA, Devendra, Prakash; (IN).
THAIMATTAM, Ram; (IN).
ARYAN, Satish, Kumar; (IN).
SINGH, Tarun, Kumar; (IN).
PRASAD, Mohan; (IN).
GANGULY, Somenath; (IN).
WADHWA, Deepika; (IN)

The present invention relates to crystalline forms of canagliflozin, processes for their preparation, and their use for the treatment of type 2 diabetes mellitus. A crystalline Form R1of canagliflozin emihydrate. The crystalline Form R1 of canagliflozin hemihydrate of claim 1, characterized by an X-ray powder diffraction peaks having d-spacing values at about 3.1, 3.7, 4.6, and 8.9 A

The present invention relates to crystalline forms of canagliflozin, processes for their preparation, and their use for the treatment of type 2 diabetes mellitus.

Canagliflozin hemihydrate, chemically designated as (l<S)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate, is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Its chemical structure is represented by Formula I.

Formula I

U.S. Patent Nos. 7,943,582 and 8,513,202 disclose crystalline forms of canagliflozin hemihydrate.

PCT Publication No. WO 2009/035969 discloses a crystalline form of

canagliflozin, designated as I-S.

PCT Publication No. WO 2013/064909 discloses crystalline complexes of canagliflozin with L-proline, D-proline, and L-phenylalanine, and the processes for their preparation.

PCT Publication No. WO 2014/180872 discloses crystalline non-stoichiometric hydrates of canagliflozin (HxA and HxB), and the process for their preparation.

PCT Publication No. WO 2015/071761 discloses crystalline Forms B, C, and D of canagliflozin.

Chinese Publication Nos. CN 103980262, CN 103936726, CN 103936725, CN 103980261, CN 103641822, CN 104230907, CN 104447722, CN 104447721, and CN 104130246 disclose different crystalline polymorphs of canagliflozin.

In the pharmaceutical industry, there is a constant need to identify critical physicochemical parameters of a drug substance such as novel salts, polymorphic forms, and co-crystals, that affect the drug’s performance, solubility, and stability, and which may play a key role in determining the drug’s market acceptance and success.

The discovery of new forms of a drug substance may improve desirable processing properties of the drug, such as ease of handling, storage stability, and ease of purification. Accordingly, the present invention provides novel crystalline forms of canagliflozin having enhanced stability over known crystalline forms of canagliflozin.

 

EXAMPLES

Example 1 : Preparation of a crystalline Form Rl of canagliflozin hemihydrate

Amorphous canagliflozin (5 g) was suspended in an aqueous solution of sodium formate (80 mL of a solution prepared by dissolving 137.7 g of sodium formate in 180 mL of de-ionized water). The suspension was stirred at room temperature for 20 hours to obtain a reaction mixture. De-ionized water (100 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 1.5 hours. De-ionized water (50 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 30 minutes. The reaction mixture was filtered, then washed with de-ionized water (300 mL), and then dried under vacuum for 12 hours to obtain a solid. The solid was further dried under vacuum at 60°C for 6 hours.

Yield: 4.71 g

Example 2: Preparation of a crystalline Form R2 of canagliflozin monohydrate

Amorphous canagliflozin (5 g) was suspended in an aqueous solution of sodium formate (80 mL of a solution prepared by dissolving 137.7 g of sodium formate in 180 mL of de-ionized water). The suspension was stirred at room temperature for 20 hours to obtain a reaction mixture. De-ionized water (100 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 1.5 hours. De-ionized water (50 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 30 minutes. The reaction mixture was filtered, then washed with de-ionized water (300 mL), and then dried under vacuum for 12 hours at room temperature.

Yield: 4.71 g

Example 3 : Preparation of a crystalline Form R2 of canagliflozin monohydrate

Canagliflozin hemihydrate (0.15 g; Form Rl obtained as per Example 1) was suspended in de-ionized water (3 mL). The suspension was stirred at room temperature for 24 hours. The reaction mixture was filtered, then dried at room temperature under vacuum for 5 hours.

Yield: 0.143 g

Example 4: Preparation of a crystalline Form R3 of canagliflozin hydrate

Amorphous canagliflozin (100 g) was suspended in an aqueous solution of sodium formate (1224 g of sodium formate in 1600 mL of de-ionized water). The suspension was stirred at room temperature for 20 hours to obtain a reaction mixture. De-ionized water

(2000 mL) was added to the reaction mixture, and then the reaction mixture was stirred for one hour. De-ionized water (1000 mL) was added to the reaction mixture, and then the reaction mixture was stirred for another one hour. The reaction mixture was filtered, then washed with de-ionized water (6000 mL), and then dried under vacuum for 30 minutes to obtain a solid. The solid was then dried under vacuum at 30°C to 35°C until a water content of 8% to 16% was attained.

Yield: 100 g

Sun Pharma's Dilip Shanghvi has become the stuff of legends

From top left: Abhay Gandhi (CEO-India Business-Sun Pharma), Kal Sundaram (CEO-TARO). Middle row (L-R): Israel Makov (chairman, Sun Pharma), Dilip Shanghvi (Founder and MD, Sun Pharma) Uday Baldota (CFO, Sun Pharma). Bottom: Kirti Ganorkar (Senior VP, Business development, Sun Pharma)

 

./////////////Canagliflozin , New patent, WO 2016016774, SUN PHARMACEUTICAL INDUSTRIES LIMITED

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New Patent from Zydus Cadila, Canagliflozin, US 20160002275


US-20160002275

CADILA HEALTHCARE LIMITED [IN]

DESAI, Sanjay Jagdish [IN]
PARIHAR, Jayprakash Ajitsingh [IN]
PATEL, Jagdish Maganlal [IN]
SURYAWANSHI, Uday Suresh [IN]
BHALALA, Jaisukh Bhupatbhai [IN]

(2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is also known as Canagliflozin, is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2) which is chemically represented as compound of Formula (I).

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U.S. Pat. No. 7,943,788 B2 discloses canagliflozin and a process for its preparation.

U.S. Pat. No. 7,943,582 B2 (the ‘582 patent) discloses crystalline form of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate and process for preparation thereof.

U.S. PG-Pub. No. 2011/0212905 discloses crystalline form of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate and process for preparation thereof.

U.S. PG-Pub. Nos. 2009/0233874, 2010/099883 and 2008/0146515 discloses similar process for the preparation of canagliflozin substantially as same as shown in scheme-1 below.

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International (PCT) Publication No. WO 2011/079772 discloses a process for the preparation of canagliflozin by reduction of keto group of acetyl protected compound followed by hydrolysis.

U.S. PG-Publication No. 2014/0128595 discloses a process for the preparation of canagliflozin from anhydroglucopyranose derivative substantially as same as shown in scheme-2 below.

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The prior-art processes requires sequence of protection/deprotection of canagliflozin obtained in the course of the reactions and further purification or crystallization to obtain canagliflozin in reasonably pure form. This sequences of processes results in high amount of yield loss.

In view of the above prior art, there is provided a novel, efficient and convenient process for preparation of canagliflozin which is at least a useful alternative to the prior art as well as an efficient and convenient method for purification of canagliflozin without sequence of protection and deprotection.

Scheme-3.

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Ahmedabad-based pharma giant Cadila Healthcare’s chairman and managing director, Pankaj Patel,

 

 

EXAMPLES

Example-1Preparation of (3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (III)

In 500 mL three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel were added 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (Va) (5 g) and 150 mL toluene at 25° C. 1.5 mL (1.6M) n-butyl lithium in hexane was added dropwise at room temperature and the solution was stirred for 30 minutes. This solution was cooled to −78° C. and added dropwise to a solution of 3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (IV) (6.4 g) in 100 mL toluene and the mixture was stirred for 3 hours. The reaction mixture was treated with 2.5 g methanesulfonic acid in 100 mL methanol and stirred for 1 hour. The reaction mass was warmed to 25° C. and then added to pre-cool saturated sodium bicarbonate solution and resulting mass was extracted with ethyl acetate. The extract was washed with brine, dried over Na2SO4 and evaporated under reduced pressure to obtain compound of Formula (III).

Example-1APreparation of (3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (III)

In 500 mL three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel were added 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (Va) (5 g) and 150 mL toluene at 25° C. 1.5 mL (1.6M) n-butyl lithium in hexane was added dropwise at room temperature and the solution was stirred for 30 minutes. This solution was cooled to −78° C. and added dropwise to a solution of 3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (IV) (6.4 g) in 100 mL toluene and the mixture was stirred for 3 hours. The reaction mixture was treated with 2.5 g methanesulfonic acid in 100 mL methanol and stirred for 1 hour. The reaction mixture warmed to room temperature and stirred for 8 hours. Saturated sodium bicarbonate solution was added to the reaction mixture and the separated aqueous layer was extracted with toluene. The organic layer was distilled to remove toluene and the residue was dissolved in 50 mL methylene dichloride, washed with brine, dried over Na2SO4 and evaporated under reduced pressure to obtain residue. The residue was treated with 150 mL diisopropyl ether and stirred at 55° C. for 30 min, cooled, filtered and washed withdiisopropyl ether to obtain compound of Formula (III).

Example-1BPreparation of (3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (III)

In 5 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel were added 100 g 2-(5-iodo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (Vb), 114.35 g 3,4,5-tris((trimethylsilyl)oxy)-6-(((tri-methylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (IV), 2 L toluene and 1 Ltetrahydrofuran at 30° C. The reaction mixture was cooled to −78° C. and 171.45 mL n-butyl lithium in hexane (1.6M) was added and the solution was stirred for 3 hours. The reaction mixture was treated with 94.16 g methanesulfonic acid in 1500 mL methanol and stirred for 1 hour. The reaction mixture warmed to 25° C. and stirred for 8 hours. The reaction mixture was cooled to 5° C. and saturated sodium bicarbonate solution was added to the reaction mixture and stirred for 30 min. The separated aqueous layer was extracted with toluene. The organic layer was distilled to remove toluene and the residue was dissolved in 300 mL methylene dichloride and 200 g silica gel of 60-120 mesh was added. The reaction mixture was stirred for 30 min at 30° C., washed with brine, dried over Na2SO4 and evaporated under reduced pressure to obtain residue. The residue was treated with 1 L diisopropyl ether and stirred at 55° C. for 30 min, cooled, filtered and washed with diisopropyl ether to obtain compound of Formula (III).

Example-2APreparation of (3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2-methoxy-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol (IIa1)

In 500 mL three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel were added 10 g compound of Formula (III), 80 mL methylene dichloride and 4.3 g N-methylmorpholine at −5 to 5° C. 2.7 g trimethylsilyl chloride was added slowly and stirred for 1 hour. After confirming the reaction completion TLC, 30 mL pre-cool water was slowly added, stirred and layers were separated. The separated aqueous layer was extracted with methylene dichloride and the combined organic layers were washed with 20% sodium dihydrogen phosphate dihydrate solution, water and brine. The organic layer was evaporated under reduced pressure to obtain compound of Formula (IIa).

Example-2BPreparation of (3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2-methoxy-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol (IIa1)

In 1 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel were added 100 g compound of Formula (III) and 900 mL methanol at 30° C. and stirred for 1 hour. The reaction mixture was filtered to remove silica gel and washed with methanol. The filtrate was distilled under vacuum to remove methanol completely, 350 mL methylene dichloride and 42.63 g N-methylmorpholine were added to the residue and cooled to at −5 to 5° C., 34.34 g trimethylsilyl chloride was lot-wise added and stirred for 45 min. After confirming the reaction completion TLC, 300 mL pre-cool water was slowly added, stirred and layers were separated. The separated aqueous layer was extracted with methylene dichloride and the combined organic layers were washed with 20% sodium dihydrogen phosphate dihydrate solution, water and brine. The separated organic layer was dried over sodium sulfate and filtered to obtain compound of Formula (IIa1).

Example-3APreparation of Canagliflozin of Formula (I)

In 1 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel was added solution of compound (IIa) prepared in example-2B and cooled to −70° C. 8 mL triethylsilane and 5.5 mL boron trifluoridediethyl etherate were added dropwise within 1 hour maintaining the reaction temperature between −70° C. The reaction was warmed to −30° C. and stirred for 30 min. The reaction mixture was then added to freshly preparedsodium bicarbonate solution at 5° C. and then allowed to warm to room temperature and stirred for 20 mints to adjust the pH of 7-8. The reaction mass was then slowly added to cold water. The resulting mass was extracted with ethyl acetate. The combined organic layers were washed with saturated bicarbonatesolution, dried over Na2SO4 and evaporated under reduced pressure to obtain canagliflozin having purity 86% by HPLC.

Example-3BPreparation of Canagliflozin of Formula (I)

In 2 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel was added the solution of compound (IIa) prepared in example-2B and cooled to −70° C. 67.38 g triethylsilane and 83.08 g boron trifluoridediethyl etherate were added dropwise within 1 hour maintaining the reaction temperature between −70° C. The reaction was warmed to −30° C. and stirred for 3 hours. The reaction mixture was then added to freshly prepared sodium bicarbonate solution at 5° C. and then allowed to warm to room temperature and stirred for 20 mints to adjust the pH of 7-8. The reaction mixture was then slowly added to cold water. The separated aqueous layer was extracted with 200 mL methylene dichloride. The combined organic layer was washed with 300 mL water and distilled completely to remove methylene dichloride. The resulting residue extracted with 500 mL ethyl acetate and stirred to obtain clear solution. The reaction mixture was treated with brine and saturated bicarbonate solution to separate the layers. The separated organic layer was dried over sodium sulfate, charcoalized and filtered. The filtrate is distilled to remove ethyl acetate completely under vacuum. The residue was dissolved in 300 mL methylene dichloride and 200 g silica gel of 60-120 mesh was added. The reaction mixture was stirred for 30 min at 30° C. and distilled completely under reduced pressure to obtain residue. The residue was treated with 500 L diisopropyl ether and stirred at 55° C. for 30 min, cooled, filtered and washed with diisopropyl ether to obtain canagliflozin (I) having purity 87% by HPLC.

Example-4Preparation of (3R,4S,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2-methoxy-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl)tris(oxy)tris(trimethylsilane) (IIb1)

In 500 mL three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel were added 10 g compound of Formula (III), 100 mL methylene dichloride and 15 g N-methylmorpholine at 0 to 5° C. 12.7 g trimethylsilyl chloride was added slowly and stirred for 1 hour. After confirming the reaction completion by TLC, 300 mL pre-cool water was slowly added, stirred and layers were separated. The separated aqueous layer was extracted with methylene dichloride and the combined organic layers were washed with 20% sodium dihydrogen phosphate dihydrate solution, water and brine. The organic layer was evaporated under reduced pressure to obtain compound of Formula (IIb1).

Example-5Preparation of Canagliflozin

In 500 mL three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel was added 20 g compound (IIb1) prepared in example-4 and 100 mL methylene dichloride at −25° C. to −30° C. 11 mL triethylsilane and 7.8 mL boron trifluoridediethyl etherate was added drop wise within 1-2 hours maintaining the reaction temperature between −25° C. to −30° C. The reaction was stirred for 30 min and then allowed to warn to room temperature and stirred for 1.5-2 hours. The reaction mixture was then slowly added to cold water. The reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated bicarbonate solution, dried over sodium sulfate and evaporated under reduced pressure to obtain canagliflozin having purity 86% by HPLC.

Example-6Purification of Canagliflozin

In 250 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel 10 g canagliflozin (purity 85%) and 100 mLtoluene were stirred to obtain a clear solution. 10 g Polyvinylpyrrolidone was added to the solution and stirred for 2-3 hours. The reaction mixture was filtered and washed with toluene. The solid was stirred in ethyl acetate and water mixture for 30 min. The separated ethyl acetate layer was evaporated to dryness to obtain pure canagliflozin. (7.1 g. Purity 96.55% by HPLC).

Example-7Purification of Canagliflozin

In 250 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel 10 g canagliflozin (purity 87%) and 100 mLtoluene were stirred in in a round bottom flask to obtain a clear solution. 10 g β-cyclodextrin was added to the solution and stirred for 2-3 hours. The reaction mixture was filtered and washed with toluene. The solid was stirred in ethyl acetate and water mixture for 30 min. The separated ethyl acetate layer was treated with activated carbon, filtered and evaporated to dryness to obtain pure canagliflozin. (7.9 g, Purity 98.93% by HPLC).

Example-8Purification of Canagliflozin

In 250 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel 10 g canagliflozin (purity 87%) and 0.25 g activated carbon were stirred in 100 mL toluene for 15-20 min and filtered. 10 g β-cyclodextrin was added to the filtrate and stirred for 2-3 hours. The reaction mixture was filtered and washed with toluene. The solid was stirred in isopropyl acetate and water mixture for 30 min. The separated isopropyl acetate layer was evaporated to dryness to obtain pure canagliflozin. (7.7 g, Purity 99.12% by HPLC).

Example-9Purification of Canagliflozin

In 250 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel, 10 g canagliflozin (purity 87%) and 100 mLtoluene were stirred to obtain a clear solution. 10 g hydroxy propyl methyl cellulose was added to the solution and stirred for 2-3 hour. The reaction mixture was filtered, washed with toluene. The solid was stirred in isopropyl acetate and water mixture for 30 min and dried to obtain pure canagliflozin. (Purity 97-98% by HPLC).

Example-10Purification of Canagliflozin

In 2 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel, 100 g canagliflozin (purity 87%) obtained in example-3B and 900 mL methanol were stirred for 45 min at 30° C. The reaction mixture was filtered to remove silica gel. The filtrate was distilled under vacuum completely below 45° C. 400 mL toluene was added and heated to 55° C. to obtain a clear solution. The reaction mixture was filtered and the filtrate was added 100 g β-cyclodextrine. The reaction mixture was heated at 75° C. for 30 min and cooled to 30° C. and further stirred for 30 min. 5 g canagliflozin β-cyclodextrin complex was added to the solution and further cooled to 5° C. The reaction mixture was stirred for 3 hours and filtered. The wet-cake was treated with 300 mL isopropyl acetate and heated at 75° C. for 30 min. The reaction mixture was cooled to 30° C. and stirred for 6 hours and further cooled to 5° C. and stirred for 3 hours. The reaction mixture was filtered and washed with isopropyl acetate and dried at 30° C. to obtain crystalline canagliflozin β-cyclodextrine complex having 40 g pure canagliflozin with 99% purity by HPLC.

Example-11Preparation of Amorphous Canagliflozin

In 1 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel, 100 g canagliflozin β-cyclodextrine (purity 98%) obtained in example-10 and 400 mL acetone were stirred for 30 min at 30° C. The reaction mixture was filtered to remove β-cyclodextrine. The filtrate was distilled under vacuum completely below 45° C. 400 mL acetone was added to the residue to get clear solution at 30° C. 5 g activated charcoal was added and stirred for 20 min. The reaction mixture was filtered and the filtrate was spray dried using JISL Mini spray drier LSD-48 keeping feed pump at 30 rpm, inlet temperature at 60° C., outlet temperature at 40° C. and 2 Kg/cm2 hot air supply. The product was collected from cyclone and is further dried at 40° C.±5° C. under vacuum for 12 hours to get 80 g of amorphous canagliflozin having 99.6% purity by HPLC.

 

WO2014195966

https://www.google.co.in/patents/WO2014195966A2?cl=un

Canagliflozin is inhibitor of sodium dependent glucose transporter inhibitor (SGLT) which is chemically represented as (25′,3i?,4/?,55,,6 ?)-2-{3-[5-[4-Fluoro-phenyl]-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol having (I).

Formula (I)

U.S. Patent No, 7,943,788 B2 (the ‘788 patent) discloses canagliflozin or salts thereof and the process for its preparation.

U.S. Patent Nos. 7,943,582 B2 and 8,513,202 B2 discloses crystalline form of 1 -(P-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene hemihydrate and process for preparation thereof. The US ‘582 B2 and US ‘202 B2 further discloses that preparation of the crystalline form of hemi-hydrate canagliflozin typically involves dissolving in a good solvent (e.g. ketones or esters) crude or amorphous compound prepared in accordance with the procedures described in WO 2005/012326 pamphlet, and adding water and a poor solvent (e.g. alkanes or ethers) to the resulting solution, followed by filtration.

U.S. PG-Pub. No. 2013/0237487 Al (the US ‘487 Al) discloses amorphous dapagliflozin and amorphous canagliflozin. The US ‘487 Al also discloses 1:1 crystalline complex of canagliflozin with L-proline (Form CS1), ethanol solvate of a 1: 1 crystalline complex of canagliflozin with D-proline (Form CS2), 1 :1 crystalline complex of canagliflozin with L-phenylalanine (Form CS3), 1:1 crystalline complex of canagliflozin with D-proline (Form CS4).

The US ‘487 Al discloses preparation of amorphous canagliflozin by adding its heated toluene solution into n-heptane. After drying in vacuo the product was obtained as a white solid of with melting point of 54.7°C to 72.0°C. However, upon repetition of the said experiment, the obtained amorphous canagliflozin was having higher amount of residual solvents. Therefore, the amorphous canagliflozin obtained by process as disclosed in US ‘487 Al is not suitable for pharmaceutical preparations.

The US ‘487 Al further discloses that amorphous canagliflozin obtained by the above process is hygroscopic in nature which was confirmed by Dynamic vapor sorption (DVS) analysis. Further, it was observed that the amorphous form underwent a physical change between the sorption/desorption cycle, making the sorption/desorption behavior different between the two cycles. The physical change that occurred was determined to be a conversion or partial conversion from the amorphous state to a crystalline state. This change was supported by a change in the overall appearance of the sample as the humidity increased from 70% to 90% RH.

The canagliflozin assessment report EMA/718531/2013 published by EMEA discloses that Canagliflozin hemihydrate is a white to off-white powder^ practically insoluble in water and freely soluble in ethanol and non-hygroscopic. Polymorphism has been observed for canagliflozin and the manufactured Form I is a hemihydrate, and an unstable amorphous Form II. Form I is consistently produced by the proposed commercial synthesis process.

Therefore, it is evident from the prior art that the reported amorphous form of canagliflozin is unstable and hygroscopic as well as not suitable for pharmaceutical preparations due to higher amount of residual solvents above the ICH acceptable limits.

Hence, there is a need to provide a stable amorphous form of canagliflozin which is suitable for pharmaceutical preparations.

Crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non-crystalline form. It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form (Econno T., Chem. Pharm. Bull., 1990; 38: 2003-2007). For some therapeutic indications, one bioavailability pattern may be favoured over another.

An amorphous form of some of the drugs exhibit much higher bioavailability than the crystalline forms, which leads to the selection of the amorphous form as the final drug substance for pharmaceutical dosage from development. Additionally, the aqueous solubility of crystalline form is lower than its amorphous form in some of the drugs, which may resulted in the difference in their in vivo bioavailability. Therefore, it is desirable to have amorphous forms of drugs with high purity to meet the needs of regulatory agencies and also highly reproducible processes for their preparation.

In view of the above, it is therefore, desirable to provide canagliflozin amorphous form as well as an efficient, economical and eco-friendly process for the preparation of highly pure canagliflozin amorphous form.

Example-l:

Preparation of amorphous form of Canagliflozin

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel, 25.0 g of canagliflozin was dissolved in 250.0 mL of methanol mixture at 25°C to 30°C. The content was stirred for 30 minutes at 25°C to 30°C. To this, 1.0 g charcoal was added and stirred for 30 minutes at 25°C to 30°C. The content was filtered through Hyflo-supercel, and the Hyflo-supercel pad was washed with 50.0 mL methanol. The filtrate was concentrated under vacuum below 45°C followed by spray drying in JISL Mini spray drier LSD-48 under the below conditions. The product was collected from cyclone and is further dried at 55°C±5°C under vacuum for 16 hours to get 19.0 g of amorphous canagliflozin.

The spray-dried canagliflozin is amorphous in nature. The obtained product contains residual solvent well within ICH limit.

The obtained solid was amorphous canagliflozin as is shown by the X-ray diffraction pattern shown in FIG.1.

Example-2:

Preparation of amorphous form of Canagliflozin

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel, 25.0 g of canagliflozin was dissolved in 250.0 mL of acetone mixture at 25°C to 3O°C. The content was stirred for 30 minutes at 25°C to 30°C. To this, 1.0 g charcoal was added and stirred for 30 minutes at 25°C to 30°C. The content was filtered through Hyflo-supercel, and the Hyflo-supercel pad was washed with 50.0 mL acetone. The filtrate was concentrated under vacuum below 45°C followed by spray drying in JISL Mini spray drier LSD-48 under the below conditions. The product was collected from cyclone and is further dried at 55°C±5°C under vacuum for 16 hours to get 20.0 g of amorphous canagliflozin.

The spray-dried canagliflozin is amorphous in nature. The compound is having residual acetone less than 0.5% by GC.

The obtained solid was amorphous canagliflozin as is shown by the X-ray diffraction pattern shown in FIG.2.

Example-3:

Preparation of amorphous form of canagliflozin

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel, 10 g of canagliflozin was dissolved in 125 mL methanol and heated to obtain clear solution at 65°C. The solution was distilled to remove methanol completely. The compound thus obtained was amorphous canagliflozin.

Example-4:

Preparation of amorphous form of canagiiflozin

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel, 10 g of canagiiflozin was dissolved in 125 mL acetone and heated to obtain clear solution at 65°C. The solution was distilled to remove acetone completely. The compound thus obtained was amorphous canagiiflozin. The compound is having residual acetone less than 0.5% by GC.

Example 5:

Preparation of amorphous form of canagiiflozin

In 100 ml three necked round bottom flask equipped with mechanical stirrer, thermometer and an addition funnel, canagiiflozin (0.5 gm, 1.02 mmol), PVP K-30 (4 gm, 8 times) and 88% methanol in water (12.5ml, 25V) were heated to 65-70°C to get clear solution. The reaction mixture was stirred for 1 hour, concentrated under vacuum (1.5 mbar) at 65-70°C and degassed under vacuum (1.5 mbar) for 1 hour at 70°C to obtain the title compound in amorphous form.

Example 6:

Preparation of amorphous form of canagiiflozin

In 100 ml three necked round bottom flask equipped with mechanical stirrer, thermometer and an addition funnel, canagiiflozin (0.5 gm, 1.02 mmol), HPMC-AS (1 gm, 2 times) in 88% methanol in water (12.5 ml, 25V) were heated at 65 to 70°C to get clear solution. The reaction mixture was stirred for 2 hours, concentrated under vacuum (1.5 mbar) at 70°C and degassed under vacuum (1.5 mbar) for lhr at 70°C to obtain the title compound in amorphous form.

Example-7:

Preparation of canagliflozin-L-Proline crystalline complex

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel; 25.0 g of canagiiflozin, 6.06 g L-proline and 250 mL ethanol were heated to 75-80°C, stirred for 15 min and then cooled down to 25-30°C. The mass was filtered and washed with ethanol to obtain canagliflozin-L-proline crystalline complex.

Example-8:

Preparation of amorphous canagliflozin from canagliflozin-L-proline crystaUine complex

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel 25.0 g of Canagliflozin-L-Proline Crystalline Complex and 250 mL of ethyl acetate were stirred to get a clear solution, washed with 2×150 mL of water and the organic layer was distilled. To the residue 100 mL of isopropyl acetate and 2.5 mL of water was added and heated to 75-80°C, stirred for 15 min and cooled down to 25-30°C. The mass filtered and washed with isopropyl acetate to obtain canagliflozin. The obtained canagliflozin was subjected to spray dyring under conditions of example-2 using acetone solvent to obtain amorphous canagliflozin. Purity > 99.5% by HPLC. The compound is having residual acetone less than 0.5% by GC.

The obtained solid was amorphous canagliflozin as shown by the X-ray diffraction pattern shown in FIG.2.

HPLC Purity of amorphous canagliflozin was measured by using following chromatographic conditions:

Equipment: Shimadzu LC2010C HPLC system equipped with a dual

wavelength UV-VIS detector or equivalent

Column: romasil C-8 (250mmx4.6 mm, 5 μπι) or equivalent

Flow rate: 1.5 mL/minute

Column oven temp.: 30°C

Wavelength: 210 nm

Injection Volume: 10 μΐ, .

Diluent: Mobile Phase A: Mobile Phase B (30:70)

Mobile Phase A: Buffer:Acetonitrile:Methanol (60:30: 10)

Mobile Phase B: Acetonitrile: Methanol (80:20)

Example-9:

Preparation of amorphous form of Canagliflozin as per Example-2 of US ‘487 Al In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel 25.0 g of canagliflozin and 150 mL of ethyl acetate were stirred to get clear solution. 100 mL of n-heptane was added to the solution and the reaction mixture was filtered and dried to obtain amorphous canagliflozin. The obtained amorphous canagliflozin were dried at 65°C under vacuum for 72 hours. The residual n-heptane was 44000 ppm by GC after 72 hours drying.

Example-10:

Replacing toluene with ethyl acetate in above example-9

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel 25.0 g of canagliflozin and 150 mL of ethyl acetate were stirred to obtain clear solution. 100 mL of n-heptane was added to the solution and the reaction mixture was filtered and dried to obtain amorphous canagliflozin. The obtained amorphous canagliflozin were dried at 65°C under vacuum for 72 hours. The residual n-heptane was -44000 ppm by GC after 72 hours drying.

Example-11:

Replacing n-heptane with cyclohexane in above example-9

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel 25.0 g of canagliflozin and 150 mL of ethyl acetate were stirred to obtain clear solution. 100 mL of cyclohexane was added to the solution and the reaction mixture was filtered and dried to obtain amorphous canagliflozin. The obtained amorphous canagliflozin were dried at 55°C under vacuum for 72 hours. The residual cyclohexane was >5000 ppm by GC after 72 hours drying.

Example-12:

Preparation of amorphous form of Canagliflozin

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel; 25.0 g of canagliflozin and 250 mL of ethyl acetate were stirred to get clear solution and then ethyl acetate was removed under reduced pressure to obtain 20.0 g of amorphous canagliflozin. The obtained amorphous canagliflozin were dried at 55°C under vacuum for 72 hours. The residual ethyl acetate was -8450 ppm by GC after 72 hours drying.

///////////////New Patent, Zydus Cadila, Canagliflozin, US 20160002275

Mitsubishi Tanabe seeks manufacturing, marketing approval for TA-7284, Canagliflozin in Japan


read all at

http://regulatoryaffairs.pharmaceutical-business-review.com/news/mitsubishi-tanabe-seeks-manufacturing-marketing-approval-for-ta-7284-in-japan-270513

CANAGLIFLOZIN

300px
CANAGLIFLOZIN
Canagliflozin
Canagliflozin is a highly potent and selective subtype 2 sodium-glucose transport protein (SGLT2) inhibitor to CHO- hSGLT2, CHO- rSGLT2 and CHO- mSGLT2 with IC50 of 4.4 nM, 3.7 nM and 2 nM, respectively.


M.F.C24H25FO5S
M.Wt: 444.52
CAS No: 842133-18-0
(1S)-1,5-Anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol
1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene
NMR…..http://file.selleckchem.com/downloads/nmr/S276003-Canagliflozin-HNMR-Selleck.pdf

Canagliflozin Hemihydrate
(1S)-1,5-Anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hydrate (2:1)
928672-86-0

Canagliflozin (INN, trade name Invokana) is a drug of the gliflozin class, used for the treatment of type 2 diabetes.[1][2] It was developed by Mitsubishi Tanabe Pharma and is marketed under license by Janssen, a division of Johnson & Johnson.[3]
U.S. Patent No, 7,943,788 B2 (the ‘788 patent) discloses canagliflozin or salts thereof and the process for its preparation.
U.S. Patent Nos. 7,943,582 B2 and 8,513,202 B2 discloses crystalline form of 1 -(P-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene hemihydrate and process for preparation thereof. The US ‘582 B2 and US ‘202 B2 further discloses that preparation of the crystalline form of hemi-hydrate canagliflozin typically involves dissolving in a good solvent (e.g. ketones or esters) crude or amorphous compound prepared in accordance with the procedures described in WO 2005/012326 pamphlet, and adding water and a poor solvent (e.g. alkanes or ethers) to the resulting solution, followed by filtration.
U.S. PG-Pub. No. 2013/0237487 Al (the US ‘487 Al) discloses amorphous dapagliflozin and amorphous canagliflozin. The US ‘487 Al also discloses 1:1 crystalline complex of canagliflozin with L-proline (Form CS1), ethanol solvate of a 1: 1 crystalline complex of canagliflozin with D-proline (Form CS2), 1 :1 crystalline complex of canagliflozin with L-phenylalanine (Form CS3), 1:1 crystalline complex of canagliflozin with D-proline (Form CS4).
The US ‘487 Al discloses preparation of amorphous canagliflozin by adding its heated toluene solution into n-heptane. After drying in vacuo the product was obtained as a white solid of with melting point of 54.7°C to 72.0°C. However, upon repetition of the said experiment, the obtained amorphous canagliflozin was having higher amount of residual solvents. Therefore, the amorphous canagliflozin obtained by process as disclosed in US ‘487 Al is not suitable for pharmaceutical preparations.
The US ‘487 Al further discloses that amorphous canagliflozin obtained by the above process is hygroscopic in nature which was confirmed by Dynamic vapor sorption (DVS) analysis. Further, it was observed that the amorphous form underwent a physical change between the sorption/desorption cycle, making the sorption/desorption behavior different between the two cycles. The physical change that occurred was determined to be a conversion or partial conversion from the amorphous state to a crystalline state. This change was supported by a change in the overall appearance of the sample as the humidity increased from 70% to 90% RH.
The canagliflozin assessment report EMA/718531/2013 published by EMEA discloses that Canagliflozin hemihydrate is a white to off-white powder^ practically insoluble in water and freely soluble in ethanol and non-hygroscopic. Polymorphism has been observed for canagliflozin and the manufactured Form I is a hemihydrate, and an unstable amorphous Form II. Form I is consistently produced by the proposed commercial synthesis process. Therefore, it is evident from the prior art that the reported amorphous form of canagliflozin is unstable and hygroscopic as well as not suitable for pharmaceutical preparations due to higher amount of residual solvents above the ICH acceptable limits.
Medical use

    1. Canagliflozin is an antidiabetic drug used to improve glycemic control in people with type 2 diabetes. In extensive clinical trials, canagliflozin produced a consistent dose-dependent reduction in HbA1c of 0.77% to 1.16% when administered as monotherapy, combination with metformin, combination with metformin & Sulfonyulrea, combination with metformin & pioglitazone and In combination with insulin from a baselines of 7.8% to 8.1%, in combination with metformin, or in combination with metformin and a sulfonylurea. When added to metformin Canagliflozin 100mg was shown to be non-inferior to both Sitagliptin 100mg and glimiperide in reductions on HbA1c at one year, whilst canagliflozin 300mg successfully demontrated statistical superiority over both Sitagliptin and glimiperide in HbA1c reductions. Secondary efficacy endpoint of superior body weight reduction and blood pressure reduction (versus Sitagliptin and glimiperide)) were observed as well. Canagliflozin produces beneficial effects on HDL cholesterol whilst increasing LDL cholesterol to produce no change in total cholesterol.[4][5]

      Contraindications

      Canagliflozin has proven to be clinically effective in people with moderate renal failure and treatment can be continued in patients with renal impairment.

      Adverse effects

      Canagliflozin, as is common with all sglt2 inhibitors, increased (generally mild) urinary tract infections, genital fungal infections, thirst,[6] LDL cholesterol, and was associated with increased urination and episodes of low blood pressure.
      There are concerns it may increase the risk of diabetic ketoacidosis.[7]
      Cardiovascular problems have been discussed with this class of drugs.[citation needed] The pre-specified endpoint for cardiovascular safety in the canagliflozin clinical development program was Major Cardiovascular Events Plus (MACE-Plus), defined as the occurrence of any of the following events: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or unstable angina leading to hospitalization. This endpoint occurred in more people in the placebo group (20.5%) than in the canagliflozin treated group (18.9%).
      Nonetheless, an FDA advisory committee expressed concern regarding the cardiovascular safety of canagliflozin. A greater number of cardiovascular events was observed during the first 30 days of treatment in canagliflozin treated people (0.45%) relative to placebo treated people (0.07%), suggesting an early period of enhanced cardiovascular risk. In addition, there was an increased risk of stroke in canagliflozin treated people. However none of these effects were seen as statistically significant. Additional cardiovascular safety data from the ongoing CANVAS trial is expected in 2015.[8]

      Interactions

      The drug may increase the risk of dehydration in combination with diuretic drugs.
      Because it increases renal excretion of glucose, treatment with canagliflozin prevents renal reabsorption of 1,5-anhydroglucitol, leading to artifactual decreases in serum 1,5-anhydroglucitol; it can therefore interfere with the use of serum 1,5-anhydroglucitol (assay trade name, GlycoMark) as a measure of postprandial glucose excursions.[9]

      Mechanism of action

      Canagliflozin is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2), which is responsible for at least 90% of the renal glucose reabsorption (SGLT1 being responsible for the remaining 10%). Blocking this transporter causes up to 119 grams of blood glucose per day to be eliminated through the urine,[10] corresponding to 476 kilocalories. Additional water is eliminated by osmotic diuresis, resulting in a lowering of blood pressure.
      This mechanism is associated with a low risk of hypoglycaemia (too low blood glucose) compared to other antidiabetic drugs such as sulfonylurea derivatives and insulin.[11]

      History

      On July 4, 2011, the European Medicines Agency approved a paediatric investigation plan and granted both a deferral and a waiver for canagliflozin (EMEA-001030-PIP01-10) in accordance with EC Regulation No.1901/2006 of the European Parliament and of the Council.[12]
      In March 2013, canagliflozin became the first SGLT2 inhibitor to be approved in the United States.[13]
      SYNTHESIS

…………
CANA1CANA2

………….

Canagliflozin is an API that is an inhibitor of SGLT2 and is being developed for the treatment of type 2 diabetes mellitus.[0011] The IUPAC systematic name of canagliflozin is (25,,3/?,4i?,55′,6 ?)-2-{3-[5-[4-fluoro- phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol, and is also known as (15)-l,5-anhydro-l-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4- methylphenyl]-D-glucitol and l-( -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2- thienylmethyl]benzene. Canagliflozin is a white to off-white powder with a molecular formula of C24H25F05S and a molecular weight of 444.52. The structure of canagliflozin is shown as compound B.

Compound B – Canagliflozin
[0012] In US 2008/0146515 Al, a crystalline hemihydrate form of canagliflozin (shown as Compound C) is disclosed, having the powder X-ray diffraction (XRPD) pattern comprising the following 2Θ values measured using CuKa radiation: 4.36±0.2, 13.54±0.2, 16.00±0.2, 19.32±0.2, and 20.80±0.2. The XRPD pattern is shown in Figure 24. A process for the preparation of canagliflozin hemihydrate is also disclosed in US 2008/0146515 Al.

Compound C – hemihydrate form of canagliflozin
[0013] In US 2009/0233874 Al, a crystalline form of canagliflozin is disclosed.

……..

WO 2005/012326 pamphlet discloses a class of compounds that are inhibitors of sodium-dependent glucose transporter (SGLT) and thus of therapeutic use for treatment of diabetes, obesity, diabetic complications, and the like. There is described in WO 2005/012326 pamphlet 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene of formula (I):

Example 1 Crystalline 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene was prepared in a similar manner as described in WO 2005/012326.

(1) To a solution of 5-bromo-1-[5-(4-fluorophenyl)-2-thienylmethyl]-2-methylbenzene (1, 28.9 g) in tetrahydrofuran (480 ml) and toluene (480 ml) was added n-butyllithium (1.6M hexane solution, 50.0 ml) dropwise at −67 to −70° C. under argon atmosphere, and the mixture was stirred for 20 minutes at the same temperature. Thereto was added a solution of 2 (34.0 g) in toluene (240 ml) dropwise at the same temperature, and the mixture was further stirred for 1 hour at the same temperature. Subsequently, thereto was added a solution of methanesulfonic acid (21.0 g) in methanol (480 ml) dropwise, and the resulting mixture was allowed to warm to room temperature and stirred for 17 hours. The mixture was cooled under ice—water cooling, and thereto was added a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the combined organic layer was washed with brine and dried over magnesium sulfate. The insoluble was filtered off and the solvent was evaporated under reduced pressure. The residue was triturated with toluene (100 ml)—hexane (400 ml) to give 1-(1-methoxyglucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]-benzene (3) (31.6 g). APCI-Mass m/Z 492 (M+NH4).
(2) A solution of 3 (63.1 g) and triethylsilane (46.4 g) in dichloromethane (660 ml) was cooled by dry ice-acetone bath under argon atmosphere, and thereto was added dropwise boron trifluoride•ethyl ether complex (50.0 ml), and the mixture was stirred at the same temperature. The mixture was allowed to warm to 0° C. and stirred for 2 hours. At the same temperature, a saturated aqueous sodium hydrogen carbonate solution (800 ml) was added, and the mixture was stirred for 30 minutes. The organic solvent was evaporated under reduced pressure, and the residue was poured into water and extracted with ethyl acetate twice. The organic layer was washed with water twice, dried over magnesium sulfate and treated with activated carbon. The insoluble was filtered off and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (300 ml), and thereto were added diethyl ether (600 ml) and H2O (6 ml). The mixture was stirred at room temperature overnight, and the precipitate was collected, washed with ethyl acetate-diethyl ether (1:4) and dried under reduced pressure at room temperature to give 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate (33.5 g) as colorless crystals.
mp 98-100° C. APCI-Mass m/Z 462 (M+NH4). 1H-NMR (DMSO-d6) δ 2.26 (3H, s), 3.13-3.28 (4H, m), 3.44 (1H, m), 3.69 (1H, m), 3.96 (1H, d, J=9.3 Hz), 4.10, 4.15 (each 1H, d, J=16.0 Hz), 4.43 (1H, t, J=5.8 Hz), 4.72 (1H, d, J=5.6 Hz), 4.92 (2H, d, J=4.8 Hz), 6.80 (1H, d, J=3.5 Hz), 7.11-7.15 (2H, m), 7.18-7.25 (3H, m), 7.28 (1H, d, J=3.5 Hz), 7.59 (2H, dd, J=8.8, 5.4 Hz).
Anal. Calcd. for C24H25FO5S.0.5H2O: C, 63.56; H, 5.78; F, 4.19; S, 7.07. Found: C, 63.52; H, 5.72; F, 4.08; S, 7.00.
1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene
Figure US07943582-20110517-C00001

Example 2An amorphous powder of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene (1.62 g) was dissolved in acetone (15 ml), and thereto were added H2O (30 ml) and a crystalline seed. The mixture was stirred at room temperature for 18 hours, and the precipitate was collected, washed with acetone—H2O (1:4, 30 ml) and dried under reduced pressure at room temperature to give 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate (1.52 g) as colorless crystals. mp 97-100° C.

……..

there are a significant number of other β-C-arylglucoside derived drug candidates, most of which differ only in the aglycone moiety (i.e., these compounds comprise a central 1-deoxy-glucose ring moiety that is arylated at CI). It is this fact that makes them attractive targets for a novel synthetic platform technology, since a single methodology should be able to furnish a plurality of products. Among β-C-arylglucosides that possess known SGLT2 inhibition also currently in clinical development are canagliflozin, empagliflozin, and ipragliflozin.

Dapagliflozin                             Canagliflozin

Ipragliflozin …………………Empagliflozin
[0007] A series of synthetic methods have been reported in the peer-reviewed and patent literature that can be used for the preparation of β-C-arylglucosides. These methods are described below and are referred herein as the gluconolactone method, the metalated glucal method, the glucal epoxide method and the glycosyl leaving group substitution method.
[0008] The gluconolactone method: In 1988 and 1989 a general method was reported to prepare C-arylglucosides from tetra-6>-benzyl protected gluconolactone, which is an oxidized derivative of glucose (see J. Org. Chem. 1988, 53, 752-753 and J. Org. Chem. 1989, 54, 610- 612). The method comprises: 1) addition of an aryllithium derivative to the hydroxy-protected gluconolactone to form a hemiketal (a.k.ci., a lactol), and 2) reduction of the resultant hemiketal with triethylsilane in the presence of boron trifluoride etherate. Disadvantages of this classical, but very commonly applied method for β-C-arylglucoside synthesis include:
1) poor “redox economy” (see J. Am. Chem. Soc. 2008, 130, 17938-17954 and Anderson, N. G. Practical Process Research & Development, 1st Ed.; Academic Press, 2000 (ISBN- 10: 0120594757); pg 38)— that is, the oxidation state of the carbon atom at CI, with respect to glucose, is oxidized in the gluconolactone and then following the arylation step is reduced to provide the requisite oxidation state of the final product. 2) due to a lack of stereospecificity, the desired β-C-arylglucoside is formed along with the undesired a-C-arylglucoside stereoisomer (this has been partially addressed by the use of hindered trialkylsilane reducing agents (see Tetrahedron: Asymmetry 2003, 14, 3243-3247) or by conversion of the hemiketal to a methyl ketal prior to reduction (see J. Org. Chem. 2007, 72, 9746-9749 and U.S. Patent 7,375,213)).
Oxidation Reduction

Glucose Gluconoloctone Hemiketal a-anomer β-anomer
R = protecting group
[0009] The metalated glucal method: U.S. Patent 7,847,074 discloses preparation of SGLT2 inhibitors that involves the coupling of a hydroxy-protected glucal that is metalated at CI with an aryl halide in the presence of a transition metal catalyst. Following the coupling step, the requisite formal addition of water to the C-arylglucal double bond to provide the desired C-aryl glucoside is effected using i) hydroboration and oxidation, or ii) epoxidation and reduction, or iii) dihydroxylation and reduction. In each case, the metalated glucal method represents poor redox economy because oxidation and reduction reactions must be conducted to establish the requisite oxidation states of the individual CI and C2 carbon atoms.
[0010] U.S. Pat. Appl. 2005/0233988 discloses the utilization of a Suzuki reaction between a CI -boronic acid or boronic ester substituted hydroxy-protected glucal and an aryl halide in the presence of a palladium catalyst. The resulting 1- C-arylglucal is then formally hydrated to provide the desired 1- C-aryl glucoside skeleton by use of a reduction step followed by an oxidation step. The synthesis of the boronic acid and its subsequent Suzuki reaction, reduction and oxidation, together, comprise a relatively long synthetic approach to C-arylglucosides and exhibits poor redox economy. Moreover, the coupling catalyst comprises palladium which is toxic and therefore should be controlled to very low levels in the drug substance.

R = protecting group; R’ = H or alkyl
[0011] The glucal epoxide method: U.S. Patent 7,847,074 discloses a method that utilizes an organometallic (derived from the requisite aglycone moiety) addition to an electrophilic epoxide located at C1-C2 of a hydroxy-protected glucose ring to furnish intermediates useful for SGLT2 inhibitor synthesis. The epoxide intermediate is prepared by the oxidation of a hydroxy- protected glucal and is not particularly stable. In Tetrahedron 2002, 58, 1997-2009 it was taught that organometallic additions to a tri-6>-benzyl protected glucal-derived epoxide can provide either the a-C-arylglucoside, mixtures of the a- and β-C-arylglucoside or the β-C-arylglucoside by selection of the appropriate counterion of the carbanionic aryl nucleophile (i.e., the
organometallic reagent). For example, carbanionic aryl groups countered with copper (i.e., cuprate reagents) or zinc (i.e., organozinc reagents) ions provide the β-C-arylglucoside, magnesium ions provide the a- and β-C-arylglucosides, and aluminum (i.e., organoaluminum reagents) ions provide the a-C-arylglucoside.

or Zn[0012] The glycosyl leaving group substitution method: U.S. Patent 7,847,074, also disclosed a method comprising the substitution of a leaving group located at CI of a hydroxy-protected glucosyl species, such as a glycosyl halide, with a metalated aryl compound to prepare SGLT2 inhibitors. U.S. Pat. Appl. 2011/0087017 disclosed a similar method to prepare the SGLT2 inhibitor canagliflozin and preferably diarylzinc complexes are used as nucleophiles along with tetra- >-pivaloyl protected glucosylbromide.

Glucose Glucosyl bromide β-anomer
[0013] Methodology for alkynylation of 1,6-anhydroglycosides reported in Helv. Chim. Acta. 1995, 78, 242-264 describes the preparation of l,4-dideoxy-l,4-diethynyl^-D-glucopyranoses (a. La., glucopyranosyl acetylenes), that are useful for preparing but-l,3-diyne-l,4-diyl linked polysaccharides, by the ethynylating opening (alkynylation) of partially protected 4-deoxy-4-C- ethynyl-l,6-anhydroglucopyranoses. The synthesis of β-C-arylglucosides, such as could be useful as precursors for SLGT2 inhibitors, was not disclosed. The ethynylation reaction was reported to proceed with retention of configuration at the anomeric center and was rationalized (see Helv. Chim. Acta 2002, 85, 2235-2257) by the C3-hydroxyl of the 1,6- anhydroglucopyranose being deprotonated to form a C3-0-aluminium species, that coordinated with the C6-oxygen allowing delivery of the ethyne group to the β-face of the an oxycarbenium cation derivative of the glucopyranose. Three molar equivalents of the ethynylaluminium reagent was used per 1 molar equivalent of the 1,6-anhydroglucopyranose. The
ethynylaluminium reagent was prepared by the reaction of equimolar (i.e., 1:1) amounts of aluminum chloride and an ethynyllithium reagent that itself was formed by the reaction of an acetylene compound with butyllithium. This retentive ethynylating opening method was also applied (see Helv. Chim. Acta. 1998, 81, 2157-2189) to 2,4-di-<9-triethylsilyl- 1,6- anhydroglucopyranose to provide l-deoxy-l-C-ethynyl- -D-glucopyranose. In this example, 4 molar equivalents of the ethynylaluminium reagent was used per 1 molar equivalent of the 1,6- anhydroglucopyranose. The ethynylaluminium regent was prepared by the reaction of equimolar (i.e., 1: 1) amounts of aluminum chloride and an ethynyl lithium reagent that itself was formed by reaction of an acetylene compound with butyllithium.
[0014] It can be seen from the peer-reviewed and patent literature that the conventional methods that can be used to provide C-arylglucosides possess several disadvantages. These include (1) a lack of stereoselectivity during formation of the desired anomer of the C- arylglucoside, (2) poor redox economy due to oxidation and reduction reaction steps being required to change the oxidation state of CI or of CI and C2 of the carbohydrate moiety, (3) some relatively long synthetic routes, (4) the use of toxic metals such as palladium, and/or (5) atom uneconomic protection of four free hydroxyl groups. With regard to the issue of redox economy, superfluous oxidation and reduction reactions that are inherently required to allow introduction of the aryl group into the carbohydrate moiety of the previously mention synthetic methods and the subsequent synthetic steps to establish the required oxidation state, besides adding synthetic steps to the process, are particular undesirable for manufacturing processes because reductants can be difficult and dangerous to operate on large scales due to their flammability or ability to produce flammable hydrogen gas during the reaction or during workup, and because oxidants are often corrosive and require specialized handling operations (see Anderson, N. G. Practical Process Research & Development, 1st Ed.; Academic Press, 2000 (ISBN-10: 0120594757); pg 38 for discussions on this issue).
[0015] In view of the above, there remains a need for a shorter, more efficient and
stereoselective, redox economic process for the preparation of β-C-arylglucosides. A new process should be applicable to the industrial manufacture of SGLT2 inhibitors and their prodrugs,
EXAMPLE 22 – Synthesis of 2,4-di-0-feri-butyldiphenylsUyl-l-C-(3-((5-(4- fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)- -D-glucopyranoside (2,4-di-6>-TBDPS- canagliflozin; (IVi”))

[0227] 2-(5-Bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (1.5 g, 4.15 mmol) and magnesium powder (0.33 g, 13.7 mmol) were placed in a suitable reactor, followed by THF (9 mL) and 1,2-dibromoethane (95 μί). The mixture was heated to reflux. After the reaction was initiated, a solution of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (2.5 g, 6.92 mmol) in THF (15mL) was added dropwise. The mixture was stirred for another 2 hours under reflux, and was then cooled to ambient temperature and titrated to determine the concentration. The thus prepared 3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl magnesium bromide (0.29 M in THF, 17 mL, 5.0 mmol) and A1C13 (0.5 M in THF, 4.0 mL, 2.0 mmol) were mixed at ambient temperature to give a black solution, which was stirred at ambient temperature for 1 hour. To a solution of l ,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 rc-BuLi (0.4 mL, 1.0 mmol, 2.5 M solution in Bu20). 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 PhOMe (6 mL) was then added. The remaining mixture was heated at 150 °C (external bath temperature) for 5 hours at which time HPLC assay analysis indicated a 68% yield of 2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(3-((5- (4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)- -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 :20 MTBE/rc-heptane) to give the product 2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4- methylphenyl)- -D-glucopyranoside (0.51 g, 56%) as a white powder.
1H NMR (400 MHz, CDC13) δ 7.65 (d, J= 7.2 Hz, 2H), 7.55 (d, J= 7.2 Hz, 2H), 7.48 (dd, J= 7.6, 5.6 Hz, 2H), 7.44-7.20 (m, 16H), 7.11-6.95 (m, 6H), 6.57 (d, J= 3.2 Hz, IH), 4.25 (d, J= 9.6 Hz, IH), 4.06 (s, 2H), 3.90-3.86 (m, IH), 3.81-3.76 (m, IH), 3.61-3.57 (m, IH), 3.54-3.49 (m, 2H), 3.40 (dd, J= 8.8, 8.8 Hz, IH), 2.31 (s, 3H), 1.81 (dd, J= 6.6, 6.6 Hz, IH, OH), 1.19 (d, J= 4.4 Hz, IH, OH), 1.00 (s, 9H), 0.64 (s, 9H); 13C NMR (100 MHz, CDC13) δ 162.1 (d, J= 246 Hz, C), 143.1 (C), 141.4 (C), 137.9 (C), 136.8 (C), 136.5 (C), 136.4 (CH x2), 136.1 (CH x2), 135.25 (C), 135.20 (CH x2), 135.0 (CH x2), 134.8 (C), 132.8 (C), 132.3 (C), 130.9 (d, J= 3.5 Hz, C), 130.5 (CH), 130.0 (CH), 129.7 (CH), 129.5 (CH), 129.4 (CH), 129.2 (CH), 127.6 (CH x4), 127.5 (CH x2), 127.2 (CH x2), 127.1 (d, J= 8.2 Hz, CH x2), 127.06 (CH), 126.0 (CH), 122.7 (CH), 115.7 (d, J= 21.8 Hz, CH x2), 82.7 (CH), 80.5 (CH), 79.4 (CH), 76.3 (CH), 72.9 (CH), 62.8 (CH2), 34.1(CH2), 27.2 (CH3 x3), 26.7 (CH3 x3), 19.6, (C), 19.3 (CH3),19.2 (C); LCMS (ESI) m/z 938 (100, [M+NH4]+), 943 (10, [M+Na]+).
EXAMPLE 23 – Synthesis of canagliflozin (l-C-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)- 4-methylphenyl)- -D-glucopyranoside; (Ii))

[0228] A mixture of the 2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(3-((5-(4-fluorophenyl)thiophen- 2-yl)methyl)-4-methylphenyl)- -D-glucopyranoside (408 mg, 0.44 mmol) and TBAF (3.5 mL, 3.5 mmol, 1.0 M in THF) was stirred at ambient temperature for 4 hours. CaC03 (0.73 g), Dowex 50WX8-400 ion exchange resin (2.2 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 filtered 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 :20 MeOH/DCM) affording canagliflozin (143 mg, 73%).

1H NMR (400 MHz, DMSO-J6) δ 7.63-7.57 (m, 2H), 7.28 (d, J= 3.6 Hz, 1H), 7.23-7.18 (m, 3H), 7.17-7.12 (m, 2H), 6.80 (d, J= 3.6 Hz, 1H), 4.93 (br, 2H, OH), 4.73 (br, 1H, OH), 4.44 (br,IH, OH), 4.16 (d, J= 16 Hz, 1H), 4.10 (d, J= 16 Hz, 1H), 3.97 (d, J= 9.2 Hz, 1H), 3.71 (d, J=I I.6 Hz, 1H), 3.47-3.43 (m, 1H), 3.30-3.15 (m, 4H), 2.27 (s, 3H);

13C NMR (100 MHz, DMSO- d6) δ 161.8 (d, J= 243 Hz, C), 144.1 (C), 140.7 (C), 138.7 (C), 137.8 (C), 135.4 (C), 131.0 (d, J= 3.1 Hz, C), 130.1 (CH), 129.5 (CH), 127.4 (d, J= 8.1 Hz, CH x2), 126.8 (CH), 126.7 (CH), 123.9 (CH), 116.4 (d, J= 21.6 Hz, CH x2), 81.8 (CH), 81.7 (CH), 79.0 (CH), 75.2 (CH), 70.9 (CH), 61.9 (CH2), 33.9 (CH2), 19.3 (CH3);

LCMS (ESI) m/z 462 (100, [M+NH4]+), 467 (3, [M+Na]+).

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).

……..
FIG. 1:
X-ray powder diffraction pattern of the crystalline of hemihydrate of the compound of formula (I).
FIG. 2:
Infra-red spectrum of the crystalline of hemihydrate of the compound of formula (I).http://www.google.com/patents/US7943582
………….
FIGS. 3 and 4 provide the XRPD pattern and IR spectrum, respectively, of amorphous canagliflozin.
………………
Canagliflozin
300px
Systematic (IUPAC) name
(2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
Clinical data
Trade names Invokana
AHFS/Drugs.com entry
Pregnancy
category
  • US:C (Risk not ruled out)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 65%
Protein binding 99%
Metabolism Hepaticglucuronidation
Biological half-life 11.8 (10–13) hours
Excretion Fecal and 33% renal
Identifiers
CAS Registry Number 842133-18-0 Yes
ATC code A10BX11
PubChem CID: 24812758
IUPHAR/BPS 4582
DrugBank DB08907 Yes
ChemSpider 26333259 
UNII 6S49DGR869 
ChEBI CHEBI:73274 
ChEMBL CHEMBL2103841 
Synonyms JNJ-28431754; TA-7284; (1S)-1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol
Chemical data
Formula C24H25FO5S
Molecular mass 444.52 g/mol

References

  1. “U.S. FDA approves Johnson & Johnson diabetes drug, canagliflozin”. Reuters. Mar 29, 2013. U.S. health regulators have approved a new diabetes drug from Johnson & Johnson, making it the first in its class to be approved in the United States.
WO2005012326A1 Jul 30, 2004 Feb 10, 2005 Tanabe Seiyaku Co Novel compounds having inhibitory activity against sodium-dependant transporter
WO2013064909A2 * Oct 30, 2012 May 10, 2013 Scinopharm Taiwan, Ltd. Crystalline and non-crystalline forms of sglt2 inhibitors
CN103655539A * Dec 13, 2013 Mar 26, 2014 重庆医药工业研究院有限责任公司 Oral solid preparation of canagliflozin and preparation method thereof
US7943582 Dec 3, 2007 May 17, 2011 Mitsubishi Tanabe Pharma Corporation Crystalline form of 1-(β-D-glucopyransoyl)-4-methyl-3-[5-(4-fluorophenyl)-2- thienylmethyl]benzene hemihydrate
US7943788 Jan 31, 2005 May 17, 2011 Mitsubishi Tanabe Pharma Corporation Glucopyranoside compound
US8513202 May 9, 2011 Aug 20, 2013 Mitsubishi Tanabe Pharma Corporation Crystalline form of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate
US20130237487 Oct 30, 2012 Sep 12, 2013 Scinopharm Taiwan, Ltd. Crystalline and non-crystalline forms of sglt2 inhibitors
WO2008002824A1 * Jun 21, 2007 Jan 3, 2008 Squibb Bristol Myers Co Crystalline solvates and complexes of (is) -1, 5-anhydro-l-c- (3- ( (phenyl) methyl) phenyl) -d-glucitol derivatives with amino acids as sglt2 inhibitors for the treatment of diabetes
US6774112 * Apr 8, 2002 Aug 10, 2004 Bristol-Myers Squibb Company Amino acid complexes of C-aryl glucosides for treatment of diabetes and method
US20090143316 * Apr 4, 2007 Jun 4, 2009 Astellas Pharma Inc. Cocrystal of c-glycoside derivative and l-proline
US20110087017 * Oct 14, 2010 Apr 14, 2011 Vittorio Farina Process for the preparation of compounds useful as inhibitors of sglt2
US20110098240 * Aug 15, 2008 Apr 28, 2011 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a sglt2 inhibitor in combination with a dpp-iv inhibitor
Reference
1 * OGURA H. ET AL.: ‘5-FLUOROURACIL NUCLEOSIDES. SYNTHESIS OF A STEREO-CONTROLLED NUCLEOSIDE SYNTHESIS FROM ANHYDRO SUGARS‘ NUCLEIC ACID CHEM. vol. 4, 1991, pages 109 – 112, XP000607288
Citing Patent Filing date Publication date Applicant Title
WO2014195966A2 * May 30, 2014 Dec 11, 2014 Cadila Healthcare Limited Amorphous form of canagliflozin and process for preparing thereof
US9006188 May 23, 2014 Apr 14, 2015 Mapi Pharma Ltd. Co-crystals of dapagliflozin

///////////

1H NMR PREDICT

  13C NMR PREDICT

  COSY PREDICT

Figure

CAS 1672658-93-3
C24 H25 F O6 S, 460.52
D-Glucopyranose, 1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-
str1
str1
CAS 1809403-04-0
C24 H25 F O6 S, 460.52
D-Glucose, 1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-
WO2017/93949

Figure

(2R,3S,4R,5R)-1-(3-((5-(4-Fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2,3,4,5,6-pentahydroxyhexan-1-one    12

From the FT-IR spectra of 12 contain a signal at 1674 cm–1, this signal is strongly indicative of a carbonyl ketone being present in 12

In 13C NMR and HMBC correlations spectra, the chemical shift at 199.75 ppm was observed. Analysis of the NMR data  confirmed that the structure of 12 is a ring-opened keto form

Synthesis of (2R,3S,4R,5R)-1-(3-((5-(4-Fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2,3,4,5,6-pentahydroxyhexan-1-one 12

title compound 12 (84.23% yield) and having 99.4% purity by HPLC;
DSC: 160.84–166.44 °C;
Mass: m/z 459 (M+–H);
IR (KBr, cm–1): 3313, 2982, 1674.7, 1601, 1507.5, 1232.7;
1H NMR (600 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.80 (dd, J = 1.8 Hz, 1H), 7.61–7.58 (m, 2H), 7.33 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 3.6 Hz, 1H), 7.21–7.18 (m, 2H), 6.84 (d, J = 3.6 Hz, 1H), 5.17 (dd, J = 3.6, 3.0 Hz, 1H), 5.02 (d, J = 6.6 Hz, 1H), 4.57 (d, J = 4.8 Hz, 1H), 4.43–4.39 (m, 3H), 4.22 (s, 2H), 4.02–4.01 (m, 1H), 3.53–3.51 (m, 3H), 3.38–3.37 (m, 1H), 2.35 (s, 3H);
13C NMR (101 MHz, DMSO-d6) δ 199.7, 162.6, 160.2, 142.8, 142.1, 140.5, 138.8, 133.3, 130.5, 130.4, 130.4, 129.3, 127.2, 127.0, 127.0, 126.7, 123.5, 116.0, 115.8, 75.2, 72.3, 71.8, 71.3, 63.2, 33.2, 19.2.
HRMS (ESI): calcd m/zfor [C24H25FO6S + Na]+ = 483.1248, found m/z 483.1244.
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00281

References

  1. “U.S. FDA approves Johnson & Johnson diabetes drug, canagliflozin”. Reuters. Mar 29, 2013. U.S. health regulators have approved a new diabetes drug from Johnson & Johnson, making it the first in its class to be approved in the United States.
WO2005012326A1 Jul 30, 2004 Feb 10, 2005 Tanabe Seiyaku Co Novel compounds having inhibitory activity against sodium-dependant transporter
WO2013064909A2 * Oct 30, 2012 May 10, 2013 Scinopharm Taiwan, Ltd. Crystalline and non-crystalline forms of sglt2 inhibitors
CN103655539A * Dec 13, 2013 Mar 26, 2014 重庆医药工业研究院有限责任公司 Oral solid preparation of canagliflozin and preparation method thereof
US7943582 Dec 3, 2007 May 17, 2011 Mitsubishi Tanabe Pharma Corporation Crystalline form of 1-(β-D-glucopyransoyl)-4-methyl-3-[5-(4-fluorophenyl)-2- thienylmethyl]benzene hemihydrate
US7943788 Jan 31, 2005 May 17, 2011 Mitsubishi Tanabe Pharma Corporation Glucopyranoside compound
US8513202 May 9, 2011 Aug 20, 2013 Mitsubishi Tanabe Pharma Corporation Crystalline form of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate
US20130237487 Oct 30, 2012 Sep 12, 2013 Scinopharm Taiwan, Ltd. Crystalline and non-crystalline forms of sglt2 inhibitors
WO2008002824A1 * Jun 21, 2007 Jan 3, 2008 Squibb Bristol Myers Co Crystalline solvates and complexes of (is) -1, 5-anhydro-l-c- (3- ( (phenyl) methyl) phenyl) -d-glucitol derivatives with amino acids as sglt2 inhibitors for the treatment of diabetes
US6774112 * Apr 8, 2002 Aug 10, 2004 Bristol-Myers Squibb Company Amino acid complexes of C-aryl glucosides for treatment of diabetes and method
US20090143316 * Apr 4, 2007 Jun 4, 2009 Astellas Pharma Inc. Cocrystal of c-glycoside derivative and l-proline
US20110087017 * Oct 14, 2010 Apr 14, 2011 Vittorio Farina Process for the preparation of compounds useful as inhibitors of sglt2
US20110098240 * Aug 15, 2008 Apr 28, 2011 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a sglt2 inhibitor in combination with a dpp-iv inhibitor
Reference
1 * OGURA H. ET AL.: ‘5-FLUOROURACIL NUCLEOSIDES. SYNTHESIS OF A STEREO-CONTROLLED NUCLEOSIDE SYNTHESIS FROM ANHYDRO SUGARS‘ NUCLEIC ACID CHEM. vol. 4, 1991, pages 109 – 112, XP000607288
Citing Patent Filing date Publication date Applicant Title
WO2014195966A2 * May 30, 2014 Dec 11, 2014 Cadila Healthcare Limited Amorphous form of canagliflozin and process for preparing thereof
US9006188 May 23, 2014 Apr 14, 2015 Mapi Pharma Ltd. Co-crystals of dapagliflozin

////////////

FDA Approves Canagliflozin, Invokana – First in New Class of Type 2 Diabetes Drugs


CANAGLIFLOZIN

FRIDAY March 29, 2013

The first in a new class of type 2 diabetes drugs was approved Friday by the U.S. Food and Drug Administration.

Invokana (canagliflozin) tablets are to be taken, in tandem with a healthy diet and exercise, to improve blood sugar control in adults with type 2 diabetes.

Invokana belongs to a class of drugs called sodium-glucose co-transporter 2 (SGLT2) inhibitors. It works by blocking the reabsorption of glucose (sugar) by the kidney and increasing glucose excretions in urine, the FDA said in a news release.

Canagliflozin (Invokana) is drug for the treatment of type 2 diabetes developed by Johnson & Johnson.[1][2] In March 2013, canagliflozin became the first in a new class of drugs for diabetes treatment to be approved.[3] It is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2), which is responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter causes blood glucose to be eliminated through the urine

  1. New J&J diabetes drug effective in mid-stage study, Jun 26, 2010
  2.  Edward C. Chao (2011). “Canagliflozin”. Drugs of the Future 36 (5): 351–357. doi:10.1358/dof.2011.36.5.1590789.
  3.  “U.S. FDA approves Johnson & Johnson diabetes drug, canagliflozin”. Reuters. Mar 29, 2013. “U.S. health regulators have approved a new diabetes drug from Johnson & Johnson, making it the first in its class to be approved in the United States.”
  4. Prous Science: Molecule of the Month November 2007

The agency told drug maker Janssen Pharmaceuticals that it must conduct five post-approval studies of the drug to determine the risk of problems such as heart disease, cancer, pancreatitis, liver abnormalities and pregnancy complications.

updated

CANAGLIFLOZIN

300px
CANAGLIFLOZIN
Canagliflozin
Canagliflozin is a highly potent and selective subtype 2 sodium-glucose transport protein (SGLT2) inhibitor to CHO- hSGLT2, CHO- rSGLT2 and CHO- mSGLT2 with IC50 of 4.4 nM, 3.7 nM and 2 nM, respectively.


M.F.C24H25FO5S
M.Wt: 444.52
CAS No: 842133-18-0
(1S)-1,5-Anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol
1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene
NMR…..http://file.selleckchem.com/downloads/nmr/S276003-Canagliflozin-HNMR-Selleck.pdf

Canagliflozin Hemihydrate
(1S)-1,5-Anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hydrate (2:1)
928672-86-0

Canagliflozin (INN, trade name Invokana) is a drug of the gliflozin class, used for the treatment of type 2 diabetes.[1][2] It was developed by Mitsubishi Tanabe Pharma and is marketed under license by Janssen, a division of Johnson & Johnson.[3]
U.S. Patent No, 7,943,788 B2 (the ‘788 patent) discloses canagliflozin or salts thereof and the process for its preparation.
U.S. Patent Nos. 7,943,582 B2 and 8,513,202 B2 discloses crystalline form of 1 -(P-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene hemihydrate and process for preparation thereof. The US ‘582 B2 and US ‘202 B2 further discloses that preparation of the crystalline form of hemi-hydrate canagliflozin typically involves dissolving in a good solvent (e.g. ketones or esters) crude or amorphous compound prepared in accordance with the procedures described in WO 2005/012326 pamphlet, and adding water and a poor solvent (e.g. alkanes or ethers) to the resulting solution, followed by filtration.
U.S. PG-Pub. No. 2013/0237487 Al (the US ‘487 Al) discloses amorphous dapagliflozin and amorphous canagliflozin. The US ‘487 Al also discloses 1:1 crystalline complex of canagliflozin with L-proline (Form CS1), ethanol solvate of a 1: 1 crystalline complex of canagliflozin with D-proline (Form CS2), 1 :1 crystalline complex of canagliflozin with L-phenylalanine (Form CS3), 1:1 crystalline complex of canagliflozin with D-proline (Form CS4).
The US ‘487 Al discloses preparation of amorphous canagliflozin by adding its heated toluene solution into n-heptane. After drying in vacuo the product was obtained as a white solid of with melting point of 54.7°C to 72.0°C. However, upon repetition of the said experiment, the obtained amorphous canagliflozin was having higher amount of residual solvents. Therefore, the amorphous canagliflozin obtained by process as disclosed in US ‘487 Al is not suitable for pharmaceutical preparations.
The US ‘487 Al further discloses that amorphous canagliflozin obtained by the above process is hygroscopic in nature which was confirmed by Dynamic vapor sorption (DVS) analysis. Further, it was observed that the amorphous form underwent a physical change between the sorption/desorption cycle, making the sorption/desorption behavior different between the two cycles. The physical change that occurred was determined to be a conversion or partial conversion from the amorphous state to a crystalline state. This change was supported by a change in the overall appearance of the sample as the humidity increased from 70% to 90% RH.
The canagliflozin assessment report EMA/718531/2013 published by EMEA discloses that Canagliflozin hemihydrate is a white to off-white powder^ practically insoluble in water and freely soluble in ethanol and non-hygroscopic. Polymorphism has been observed for canagliflozin and the manufactured Form I is a hemihydrate, and an unstable amorphous Form II. Form I is consistently produced by the proposed commercial synthesis process. Therefore, it is evident from the prior art that the reported amorphous form of canagliflozin is unstable and hygroscopic as well as not suitable for pharmaceutical preparations due to higher amount of residual solvents above the ICH acceptable limits.
Medical use

    1. Canagliflozin is an antidiabetic drug used to improve glycemic control in people with type 2 diabetes. In extensive clinical trials, canagliflozin produced a consistent dose-dependent reduction in HbA1c of 0.77% to 1.16% when administered as monotherapy, combination with metformin, combination with metformin & Sulfonyulrea, combination with metformin & pioglitazone and In combination with insulin from a baselines of 7.8% to 8.1%, in combination with metformin, or in combination with metformin and a sulfonylurea. When added to metformin Canagliflozin 100mg was shown to be non-inferior to both Sitagliptin 100mg and glimiperide in reductions on HbA1c at one year, whilst canagliflozin 300mg successfully demontrated statistical superiority over both Sitagliptin and glimiperide in HbA1c reductions. Secondary efficacy endpoint of superior body weight reduction and blood pressure reduction (versus Sitagliptin and glimiperide)) were observed as well. Canagliflozin produces beneficial effects on HDL cholesterol whilst increasing LDL cholesterol to produce no change in total cholesterol.[4][5]

      Contraindications

      Canagliflozin has proven to be clinically effective in people with moderate renal failure and treatment can be continued in patients with renal impairment.

      Adverse effects

      Canagliflozin, as is common with all sglt2 inhibitors, increased (generally mild) urinary tract infections, genital fungal infections, thirst,[6] LDL cholesterol, and was associated with increased urination and episodes of low blood pressure.
      There are concerns it may increase the risk of diabetic ketoacidosis.[7]
      Cardiovascular problems have been discussed with this class of drugs.[citation needed] The pre-specified endpoint for cardiovascular safety in the canagliflozin clinical development program was Major Cardiovascular Events Plus (MACE-Plus), defined as the occurrence of any of the following events: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or unstable angina leading to hospitalization. This endpoint occurred in more people in the placebo group (20.5%) than in the canagliflozin treated group (18.9%).
      Nonetheless, an FDA advisory committee expressed concern regarding the cardiovascular safety of canagliflozin. A greater number of cardiovascular events was observed during the first 30 days of treatment in canagliflozin treated people (0.45%) relative to placebo treated people (0.07%), suggesting an early period of enhanced cardiovascular risk. In addition, there was an increased risk of stroke in canagliflozin treated people. However none of these effects were seen as statistically significant. Additional cardiovascular safety data from the ongoing CANVAS trial is expected in 2015.[8]

      Interactions

      The drug may increase the risk of dehydration in combination with diuretic drugs.
      Because it increases renal excretion of glucose, treatment with canagliflozin prevents renal reabsorption of 1,5-anhydroglucitol, leading to artifactual decreases in serum 1,5-anhydroglucitol; it can therefore interfere with the use of serum 1,5-anhydroglucitol (assay trade name, GlycoMark) as a measure of postprandial glucose excursions.[9]

      Mechanism of action

      Canagliflozin is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2), which is responsible for at least 90% of the renal glucose reabsorption (SGLT1 being responsible for the remaining 10%). Blocking this transporter causes up to 119 grams of blood glucose per day to be eliminated through the urine,[10] corresponding to 476 kilocalories. Additional water is eliminated by osmotic diuresis, resulting in a lowering of blood pressure.
      This mechanism is associated with a low risk of hypoglycaemia (too low blood glucose) compared to other antidiabetic drugs such as sulfonylurea derivatives and insulin.[11]

      History

      On July 4, 2011, the European Medicines Agency approved a paediatric investigation plan and granted both a deferral and a waiver for canagliflozin (EMEA-001030-PIP01-10) in accordance with EC Regulation No.1901/2006 of the European Parliament and of the Council.[12]
      In March 2013, canagliflozin became the first SGLT2 inhibitor to be approved in the United States.[13]
      SYNTHESIS

…………
CANA1CANA2

………….

Canagliflozin is an API that is an inhibitor of SGLT2 and is being developed for the treatment of type 2 diabetes mellitus.[0011] The IUPAC systematic name of canagliflozin is (25,,3/?,4i?,55′,6 ?)-2-{3-[5-[4-fluoro- phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol, and is also known as (15)-l,5-anhydro-l-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4- methylphenyl]-D-glucitol and l-( -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2- thienylmethyl]benzene. Canagliflozin is a white to off-white powder with a molecular formula of C24H25F05S and a molecular weight of 444.52. The structure of canagliflozin is shown as compound B.

Compound B – Canagliflozin
[0012] In US 2008/0146515 Al, a crystalline hemihydrate form of canagliflozin (shown as Compound C) is disclosed, having the powder X-ray diffraction (XRPD) pattern comprising the following 2Θ values measured using CuKa radiation: 4.36±0.2, 13.54±0.2, 16.00±0.2, 19.32±0.2, and 20.80±0.2. The XRPD pattern is shown in Figure 24. A process for the preparation of canagliflozin hemihydrate is also disclosed in US 2008/0146515 Al.

Compound C – hemihydrate form of canagliflozin
[0013] In US 2009/0233874 Al, a crystalline form of canagliflozin is disclosed.

……..

WO 2005/012326 pamphlet discloses a class of compounds that are inhibitors of sodium-dependent glucose transporter (SGLT) and thus of therapeutic use for treatment of diabetes, obesity, diabetic complications, and the like. There is described in WO 2005/012326 pamphlet 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene of formula (I):

Example 1 Crystalline 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene was prepared in a similar manner as described in WO 2005/012326.

(1) To a solution of 5-bromo-1-[5-(4-fluorophenyl)-2-thienylmethyl]-2-methylbenzene (1, 28.9 g) in tetrahydrofuran (480 ml) and toluene (480 ml) was added n-butyllithium (1.6M hexane solution, 50.0 ml) dropwise at −67 to −70° C. under argon atmosphere, and the mixture was stirred for 20 minutes at the same temperature. Thereto was added a solution of 2 (34.0 g) in toluene (240 ml) dropwise at the same temperature, and the mixture was further stirred for 1 hour at the same temperature. Subsequently, thereto was added a solution of methanesulfonic acid (21.0 g) in methanol (480 ml) dropwise, and the resulting mixture was allowed to warm to room temperature and stirred for 17 hours. The mixture was cooled under ice—water cooling, and thereto was added a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the combined organic layer was washed with brine and dried over magnesium sulfate. The insoluble was filtered off and the solvent was evaporated under reduced pressure. The residue was triturated with toluene (100 ml)—hexane (400 ml) to give 1-(1-methoxyglucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]-benzene (3) (31.6 g). APCI-Mass m/Z 492 (M+NH4).
(2) A solution of 3 (63.1 g) and triethylsilane (46.4 g) in dichloromethane (660 ml) was cooled by dry ice-acetone bath under argon atmosphere, and thereto was added dropwise boron trifluoride•ethyl ether complex (50.0 ml), and the mixture was stirred at the same temperature. The mixture was allowed to warm to 0° C. and stirred for 2 hours. At the same temperature, a saturated aqueous sodium hydrogen carbonate solution (800 ml) was added, and the mixture was stirred for 30 minutes. The organic solvent was evaporated under reduced pressure, and the residue was poured into water and extracted with ethyl acetate twice. The organic layer was washed with water twice, dried over magnesium sulfate and treated with activated carbon. The insoluble was filtered off and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (300 ml), and thereto were added diethyl ether (600 ml) and H2O (6 ml). The mixture was stirred at room temperature overnight, and the precipitate was collected, washed with ethyl acetate-diethyl ether (1:4) and dried under reduced pressure at room temperature to give 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate (33.5 g) as colorless crystals.
mp 98-100° C. APCI-Mass m/Z 462 (M+NH4). 1H-NMR (DMSO-d6) δ 2.26 (3H, s), 3.13-3.28 (4H, m), 3.44 (1H, m), 3.69 (1H, m), 3.96 (1H, d, J=9.3 Hz), 4.10, 4.15 (each 1H, d, J=16.0 Hz), 4.43 (1H, t, J=5.8 Hz), 4.72 (1H, d, J=5.6 Hz), 4.92 (2H, d, J=4.8 Hz), 6.80 (1H, d, J=3.5 Hz), 7.11-7.15 (2H, m), 7.18-7.25 (3H, m), 7.28 (1H, d, J=3.5 Hz), 7.59 (2H, dd, J=8.8, 5.4 Hz).
Anal. Calcd. for C24H25FO5S.0.5H2O: C, 63.56; H, 5.78; F, 4.19; S, 7.07. Found: C, 63.52; H, 5.72; F, 4.08; S, 7.00.
1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene
Figure US07943582-20110517-C00001

Example 2An amorphous powder of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene (1.62 g) was dissolved in acetone (15 ml), and thereto were added H2O (30 ml) and a crystalline seed. The mixture was stirred at room temperature for 18 hours, and the precipitate was collected, washed with acetone—H2O (1:4, 30 ml) and dried under reduced pressure at room temperature to give 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate (1.52 g) as colorless crystals. mp 97-100° C.

……..

there are a significant number of other β-C-arylglucoside derived drug candidates, most of which differ only in the aglycone moiety (i.e., these compounds comprise a central 1-deoxy-glucose ring moiety that is arylated at CI). It is this fact that makes them attractive targets for a novel synthetic platform technology, since a single methodology should be able to furnish a plurality of products. Among β-C-arylglucosides that possess known SGLT2 inhibition also currently in clinical development are canagliflozin, empagliflozin, and ipragliflozin.

Dapagliflozin                             Canagliflozin

Ipragliflozin …………………Empagliflozin
[0007] A series of synthetic methods have been reported in the peer-reviewed and patent literature that can be used for the preparation of β-C-arylglucosides. These methods are described below and are referred herein as the gluconolactone method, the metalated glucal method, the glucal epoxide method and the glycosyl leaving group substitution method.
[0008] The gluconolactone method: In 1988 and 1989 a general method was reported to prepare C-arylglucosides from tetra-6>-benzyl protected gluconolactone, which is an oxidized derivative of glucose (see J. Org. Chem. 1988, 53, 752-753 and J. Org. Chem. 1989, 54, 610- 612). The method comprises: 1) addition of an aryllithium derivative to the hydroxy-protected gluconolactone to form a hemiketal (a.k.ci., a lactol), and 2) reduction of the resultant hemiketal with triethylsilane in the presence of boron trifluoride etherate. Disadvantages of this classical, but very commonly applied method for β-C-arylglucoside synthesis include:
1) poor “redox economy” (see J. Am. Chem. Soc. 2008, 130, 17938-17954 and Anderson, N. G. Practical Process Research & Development, 1st Ed.; Academic Press, 2000 (ISBN- 10: 0120594757); pg 38)— that is, the oxidation state of the carbon atom at CI, with respect to glucose, is oxidized in the gluconolactone and then following the arylation step is reduced to provide the requisite oxidation state of the final product. 2) due to a lack of stereospecificity, the desired β-C-arylglucoside is formed along with the undesired a-C-arylglucoside stereoisomer (this has been partially addressed by the use of hindered trialkylsilane reducing agents (see Tetrahedron: Asymmetry 2003, 14, 3243-3247) or by conversion of the hemiketal to a methyl ketal prior to reduction (see J. Org. Chem. 2007, 72, 9746-9749 and U.S. Patent 7,375,213)).
Oxidation Reduction

Glucose Gluconoloctone Hemiketal a-anomer β-anomer
R = protecting group
[0009] The metalated glucal method: U.S. Patent 7,847,074 discloses preparation of SGLT2 inhibitors that involves the coupling of a hydroxy-protected glucal that is metalated at CI with an aryl halide in the presence of a transition metal catalyst. Following the coupling step, the requisite formal addition of water to the C-arylglucal double bond to provide the desired C-aryl glucoside is effected using i) hydroboration and oxidation, or ii) epoxidation and reduction, or iii) dihydroxylation and reduction. In each case, the metalated glucal method represents poor redox economy because oxidation and reduction reactions must be conducted to establish the requisite oxidation states of the individual CI and C2 carbon atoms.
[0010] U.S. Pat. Appl. 2005/0233988 discloses the utilization of a Suzuki reaction between a CI -boronic acid or boronic ester substituted hydroxy-protected glucal and an aryl halide in the presence of a palladium catalyst. The resulting 1- C-arylglucal is then formally hydrated to provide the desired 1- C-aryl glucoside skeleton by use of a reduction step followed by an oxidation step. The synthesis of the boronic acid and its subsequent Suzuki reaction, reduction and oxidation, together, comprise a relatively long synthetic approach to C-arylglucosides and exhibits poor redox economy. Moreover, the coupling catalyst comprises palladium which is toxic and therefore should be controlled to very low levels in the drug substance.

R = protecting group; R’ = H or alkyl
[0011] The glucal epoxide method: U.S. Patent 7,847,074 discloses a method that utilizes an organometallic (derived from the requisite aglycone moiety) addition to an electrophilic epoxide located at C1-C2 of a hydroxy-protected glucose ring to furnish intermediates useful for SGLT2 inhibitor synthesis. The epoxide intermediate is prepared by the oxidation of a hydroxy- protected glucal and is not particularly stable. In Tetrahedron 2002, 58, 1997-2009 it was taught that organometallic additions to a tri-6>-benzyl protected glucal-derived epoxide can provide either the a-C-arylglucoside, mixtures of the a- and β-C-arylglucoside or the β-C-arylglucoside by selection of the appropriate counterion of the carbanionic aryl nucleophile (i.e., the
organometallic reagent). For example, carbanionic aryl groups countered with copper (i.e., cuprate reagents) or zinc (i.e., organozinc reagents) ions provide the β-C-arylglucoside, magnesium ions provide the a- and β-C-arylglucosides, and aluminum (i.e., organoaluminum reagents) ions provide the a-C-arylglucoside.

or Zn[0012] The glycosyl leaving group substitution method: U.S. Patent 7,847,074, also disclosed a method comprising the substitution of a leaving group located at CI of a hydroxy-protected glucosyl species, such as a glycosyl halide, with a metalated aryl compound to prepare SGLT2 inhibitors. U.S. Pat. Appl. 2011/0087017 disclosed a similar method to prepare the SGLT2 inhibitor canagliflozin and preferably diarylzinc complexes are used as nucleophiles along with tetra- >-pivaloyl protected glucosylbromide.

Glucose Glucosyl bromide β-anomer
[0013] Methodology for alkynylation of 1,6-anhydroglycosides reported in Helv. Chim. Acta. 1995, 78, 242-264 describes the preparation of l,4-dideoxy-l,4-diethynyl^-D-glucopyranoses (a. La., glucopyranosyl acetylenes), that are useful for preparing but-l,3-diyne-l,4-diyl linked polysaccharides, by the ethynylating opening (alkynylation) of partially protected 4-deoxy-4-C- ethynyl-l,6-anhydroglucopyranoses. The synthesis of β-C-arylglucosides, such as could be useful as precursors for SLGT2 inhibitors, was not disclosed. The ethynylation reaction was reported to proceed with retention of configuration at the anomeric center and was rationalized (see Helv. Chim. Acta 2002, 85, 2235-2257) by the C3-hydroxyl of the 1,6- anhydroglucopyranose being deprotonated to form a C3-0-aluminium species, that coordinated with the C6-oxygen allowing delivery of the ethyne group to the β-face of the an oxycarbenium cation derivative of the glucopyranose. Three molar equivalents of the ethynylaluminium reagent was used per 1 molar equivalent of the 1,6-anhydroglucopyranose. The
ethynylaluminium reagent was prepared by the reaction of equimolar (i.e., 1:1) amounts of aluminum chloride and an ethynyllithium reagent that itself was formed by the reaction of an acetylene compound with butyllithium. This retentive ethynylating opening method was also applied (see Helv. Chim. Acta. 1998, 81, 2157-2189) to 2,4-di-<9-triethylsilyl- 1,6- anhydroglucopyranose to provide l-deoxy-l-C-ethynyl- -D-glucopyranose. In this example, 4 molar equivalents of the ethynylaluminium reagent was used per 1 molar equivalent of the 1,6- anhydroglucopyranose. The ethynylaluminium regent was prepared by the reaction of equimolar (i.e., 1: 1) amounts of aluminum chloride and an ethynyl lithium reagent that itself was formed by reaction of an acetylene compound with butyllithium.
[0014] It can be seen from the peer-reviewed and patent literature that the conventional methods that can be used to provide C-arylglucosides possess several disadvantages. These include (1) a lack of stereoselectivity during formation of the desired anomer of the C- arylglucoside, (2) poor redox economy due to oxidation and reduction reaction steps being required to change the oxidation state of CI or of CI and C2 of the carbohydrate moiety, (3) some relatively long synthetic routes, (4) the use of toxic metals such as palladium, and/or (5) atom uneconomic protection of four free hydroxyl groups. With regard to the issue of redox economy, superfluous oxidation and reduction reactions that are inherently required to allow introduction of the aryl group into the carbohydrate moiety of the previously mention synthetic methods and the subsequent synthetic steps to establish the required oxidation state, besides adding synthetic steps to the process, are particular undesirable for manufacturing processes because reductants can be difficult and dangerous to operate on large scales due to their flammability or ability to produce flammable hydrogen gas during the reaction or during workup, and because oxidants are often corrosive and require specialized handling operations (see Anderson, N. G. Practical Process Research & Development, 1st Ed.; Academic Press, 2000 (ISBN-10: 0120594757); pg 38 for discussions on this issue).
[0015] In view of the above, there remains a need for a shorter, more efficient and
stereoselective, redox economic process for the preparation of β-C-arylglucosides. A new process should be applicable to the industrial manufacture of SGLT2 inhibitors and their prodrugs,
EXAMPLE 22 – Synthesis of 2,4-di-0-feri-butyldiphenylsUyl-l-C-(3-((5-(4- fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)- -D-glucopyranoside (2,4-di-6>-TBDPS- canagliflozin; (IVi”))

[0227] 2-(5-Bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (1.5 g, 4.15 mmol) and magnesium powder (0.33 g, 13.7 mmol) were placed in a suitable reactor, followed by THF (9 mL) and 1,2-dibromoethane (95 μί). The mixture was heated to reflux. After the reaction was initiated, a solution of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (2.5 g, 6.92 mmol) in THF (15mL) was added dropwise. The mixture was stirred for another 2 hours under reflux, and was then cooled to ambient temperature and titrated to determine the concentration. The thus prepared 3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl magnesium bromide (0.29 M in THF, 17 mL, 5.0 mmol) and A1C13 (0.5 M in THF, 4.0 mL, 2.0 mmol) were mixed at ambient temperature to give a black solution, which was stirred at ambient temperature for 1 hour. To a solution of l ,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 rc-BuLi (0.4 mL, 1.0 mmol, 2.5 M solution in Bu20). 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 PhOMe (6 mL) was then added. The remaining mixture was heated at 150 °C (external bath temperature) for 5 hours at which time HPLC assay analysis indicated a 68% yield of 2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(3-((5- (4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)- -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 :20 MTBE/rc-heptane) to give the product 2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4- methylphenyl)- -D-glucopyranoside (0.51 g, 56%) as a white powder.
1H NMR (400 MHz, CDC13) δ 7.65 (d, J= 7.2 Hz, 2H), 7.55 (d, J= 7.2 Hz, 2H), 7.48 (dd, J= 7.6, 5.6 Hz, 2H), 7.44-7.20 (m, 16H), 7.11-6.95 (m, 6H), 6.57 (d, J= 3.2 Hz, IH), 4.25 (d, J= 9.6 Hz, IH), 4.06 (s, 2H), 3.90-3.86 (m, IH), 3.81-3.76 (m, IH), 3.61-3.57 (m, IH), 3.54-3.49 (m, 2H), 3.40 (dd, J= 8.8, 8.8 Hz, IH), 2.31 (s, 3H), 1.81 (dd, J= 6.6, 6.6 Hz, IH, OH), 1.19 (d, J= 4.4 Hz, IH, OH), 1.00 (s, 9H), 0.64 (s, 9H); 13C NMR (100 MHz, CDC13) δ 162.1 (d, J= 246 Hz, C), 143.1 (C), 141.4 (C), 137.9 (C), 136.8 (C), 136.5 (C), 136.4 (CH x2), 136.1 (CH x2), 135.25 (C), 135.20 (CH x2), 135.0 (CH x2), 134.8 (C), 132.8 (C), 132.3 (C), 130.9 (d, J= 3.5 Hz, C), 130.5 (CH), 130.0 (CH), 129.7 (CH), 129.5 (CH), 129.4 (CH), 129.2 (CH), 127.6 (CH x4), 127.5 (CH x2), 127.2 (CH x2), 127.1 (d, J= 8.2 Hz, CH x2), 127.06 (CH), 126.0 (CH), 122.7 (CH), 115.7 (d, J= 21.8 Hz, CH x2), 82.7 (CH), 80.5 (CH), 79.4 (CH), 76.3 (CH), 72.9 (CH), 62.8 (CH2), 34.1(CH2), 27.2 (CH3 x3), 26.7 (CH3 x3), 19.6, (C), 19.3 (CH3),19.2 (C); LCMS (ESI) m/z 938 (100, [M+NH4]+), 943 (10, [M+Na]+).
EXAMPLE 23 – Synthesis of canagliflozin (l-C-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)- 4-methylphenyl)- -D-glucopyranoside; (Ii))

[0228] A mixture of the 2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(3-((5-(4-fluorophenyl)thiophen- 2-yl)methyl)-4-methylphenyl)- -D-glucopyranoside (408 mg, 0.44 mmol) and TBAF (3.5 mL, 3.5 mmol, 1.0 M in THF) was stirred at ambient temperature for 4 hours. CaC03 (0.73 g), Dowex 50WX8-400 ion exchange resin (2.2 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 filtered 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 :20 MeOH/DCM) affording canagliflozin (143 mg, 73%).

1H NMR (400 MHz, DMSO-J6) δ 7.63-7.57 (m, 2H), 7.28 (d, J= 3.6 Hz, 1H), 7.23-7.18 (m, 3H), 7.17-7.12 (m, 2H), 6.80 (d, J= 3.6 Hz, 1H), 4.93 (br, 2H, OH), 4.73 (br, 1H, OH), 4.44 (br,IH, OH), 4.16 (d, J= 16 Hz, 1H), 4.10 (d, J= 16 Hz, 1H), 3.97 (d, J= 9.2 Hz, 1H), 3.71 (d, J=I I.6 Hz, 1H), 3.47-3.43 (m, 1H), 3.30-3.15 (m, 4H), 2.27 (s, 3H);

13C NMR (100 MHz, DMSO- d6) δ 161.8 (d, J= 243 Hz, C), 144.1 (C), 140.7 (C), 138.7 (C), 137.8 (C), 135.4 (C), 131.0 (d, J= 3.1 Hz, C), 130.1 (CH), 129.5 (CH), 127.4 (d, J= 8.1 Hz, CH x2), 126.8 (CH), 126.7 (CH), 123.9 (CH), 116.4 (d, J= 21.6 Hz, CH x2), 81.8 (CH), 81.7 (CH), 79.0 (CH), 75.2 (CH), 70.9 (CH), 61.9 (CH2), 33.9 (CH2), 19.3 (CH3);

LCMS (ESI) m/z 462 (100, [M+NH4]+), 467 (3, [M+Na]+).

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).

……..
FIG. 1:
X-ray powder diffraction pattern of the crystalline of hemihydrate of the compound of formula (I).
FIG. 2:
Infra-red spectrum of the crystalline of hemihydrate of the compound of formula (I).http://www.google.com/patents/US7943582
………….
FIGS. 3 and 4 provide the XRPD pattern and IR spectrum, respectively, of amorphous canagliflozin.
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Canagliflozin
300px
Systematic (IUPAC) name
(2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
Clinical data
Trade names Invokana
AHFS/Drugs.com entry
Pregnancy
category
  • US:C (Risk not ruled out)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 65%
Protein binding 99%
Metabolism Hepaticglucuronidation
Biological half-life 11.8 (10–13) hours
Excretion Fecal and 33% renal
Identifiers
CAS Registry Number 842133-18-0 Yes
ATC code A10BX11
PubChem CID: 24812758
IUPHAR/BPS 4582
DrugBank DB08907 Yes
ChemSpider 26333259 
UNII 6S49DGR869 
ChEBI CHEBI:73274 
ChEMBL CHEMBL2103841 
Synonyms JNJ-28431754; TA-7284; (1S)-1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol
Chemical data
Formula C24H25FO5S
Molecular mass 444.52 g/mol

References

  1. “U.S. FDA approves Johnson & Johnson diabetes drug, canagliflozin”. Reuters. Mar 29, 2013. U.S. health regulators have approved a new diabetes drug from Johnson & Johnson, making it the first in its class to be approved in the United States.
WO2005012326A1 Jul 30, 2004 Feb 10, 2005 Tanabe Seiyaku Co Novel compounds having inhibitory activity against sodium-dependant transporter
WO2013064909A2 * Oct 30, 2012 May 10, 2013 Scinopharm Taiwan, Ltd. Crystalline and non-crystalline forms of sglt2 inhibitors
CN103655539A * Dec 13, 2013 Mar 26, 2014 重庆医药工业研究院有限责任公司 Oral solid preparation of canagliflozin and preparation method thereof
US7943582 Dec 3, 2007 May 17, 2011 Mitsubishi Tanabe Pharma Corporation Crystalline form of 1-(β-D-glucopyransoyl)-4-methyl-3-[5-(4-fluorophenyl)-2- thienylmethyl]benzene hemihydrate
US7943788 Jan 31, 2005 May 17, 2011 Mitsubishi Tanabe Pharma Corporation Glucopyranoside compound
US8513202 May 9, 2011 Aug 20, 2013 Mitsubishi Tanabe Pharma Corporation Crystalline form of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate
US20130237487 Oct 30, 2012 Sep 12, 2013 Scinopharm Taiwan, Ltd. Crystalline and non-crystalline forms of sglt2 inhibitors
WO2008002824A1 * Jun 21, 2007 Jan 3, 2008 Squibb Bristol Myers Co Crystalline solvates and complexes of (is) -1, 5-anhydro-l-c- (3- ( (phenyl) methyl) phenyl) -d-glucitol derivatives with amino acids as sglt2 inhibitors for the treatment of diabetes
US6774112 * Apr 8, 2002 Aug 10, 2004 Bristol-Myers Squibb Company Amino acid complexes of C-aryl glucosides for treatment of diabetes and method
US20090143316 * Apr 4, 2007 Jun 4, 2009 Astellas Pharma Inc. Cocrystal of c-glycoside derivative and l-proline
US20110087017 * Oct 14, 2010 Apr 14, 2011 Vittorio Farina Process for the preparation of compounds useful as inhibitors of sglt2
US20110098240 * Aug 15, 2008 Apr 28, 2011 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a sglt2 inhibitor in combination with a dpp-iv inhibitor
Reference
1 * OGURA H. ET AL.: ‘5-FLUOROURACIL NUCLEOSIDES. SYNTHESIS OF A STEREO-CONTROLLED NUCLEOSIDE SYNTHESIS FROM ANHYDRO SUGARS‘ NUCLEIC ACID CHEM. vol. 4, 1991, pages 109 – 112, XP000607288
Citing Patent Filing date Publication date Applicant Title
WO2014195966A2 * May 30, 2014 Dec 11, 2014 Cadila Healthcare Limited Amorphous form of canagliflozin and process for preparing thereof
US9006188 May 23, 2014 Apr 14, 2015 Mapi Pharma Ltd. Co-crystals of dapagliflozin

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1H NMR PREDICT

  13C NMR PREDICT

  COSY PREDICT

update……..

Figure

CAS 1672658-93-3
C24 H25 F O6 S, 460.52
D-Glucopyranose, 1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-
str1
str1
CAS 1809403-04-0
C24 H25 F O6 S, 460.52
D-Glucose, 1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-
WO2017/93949

Figure

(2R,3S,4R,5R)-1-(3-((5-(4-Fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2,3,4,5,6-pentahydroxyhexan-1-one    12

From the FT-IR spectra of 12 contain a signal at 1674 cm–1, this signal is strongly indicative of a carbonyl ketone being present in 12

In 13C NMR and HMBC correlations spectra, the chemical shift at 199.75 ppm was observed. Analysis of the NMR data  confirmed that the structure of 12 is a ring-opened keto form

Synthesis of (2R,3S,4R,5R)-1-(3-((5-(4-Fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2,3,4,5,6-pentahydroxyhexan-1-one 12

title compound 12 (84.23% yield) and having 99.4% purity by HPLC;
DSC: 160.84–166.44 °C;
Mass: m/z 459 (M+–H);
IR (KBr, cm–1): 3313, 2982, 1674.7, 1601, 1507.5, 1232.7;
1H NMR (600 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.80 (dd, J = 1.8 Hz, 1H), 7.61–7.58 (m, 2H), 7.33 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 3.6 Hz, 1H), 7.21–7.18 (m, 2H), 6.84 (d, J = 3.6 Hz, 1H), 5.17 (dd, J = 3.6, 3.0 Hz, 1H), 5.02 (d, J = 6.6 Hz, 1H), 4.57 (d, J = 4.8 Hz, 1H), 4.43–4.39 (m, 3H), 4.22 (s, 2H), 4.02–4.01 (m, 1H), 3.53–3.51 (m, 3H), 3.38–3.37 (m, 1H), 2.35 (s, 3H);
13C NMR (101 MHz, DMSO-d6) δ 199.7, 162.6, 160.2, 142.8, 142.1, 140.5, 138.8, 133.3, 130.5, 130.4, 130.4, 129.3, 127.2, 127.0, 127.0, 126.7, 123.5, 116.0, 115.8, 75.2, 72.3, 71.8, 71.3, 63.2, 33.2, 19.2.
HRMS (ESI): calcd m/zfor [C24H25FO6S + Na]+ = 483.1248, found m/z 483.1244.
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00281

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