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).
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.
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.
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.
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 methanoland 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 withtoluene. 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 gN-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 withmethanol. The filtrate was distilled under vacuum to remove methanol completely, 350 mLmethylene 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 dichlorideand the combined organic layers were washed with 20% sodium dihydrogen phosphate dihydrate solution, water and brine. The separated organic layer was dried over sodium sulfateand 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 withmethylene 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 etheratewas 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 inethyl 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 mLtoluene 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 inisopropyl 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 acetateand 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 methanolwere 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 acetonewas 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
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
