WO2018020506A1 - Processus pour la préparation des formes amorphes de canagliflozine - Google Patents

Processus pour la préparation des formes amorphes de canagliflozine Download PDF

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Publication number
WO2018020506A1
WO2018020506A1 PCT/IN2016/050322 IN2016050322W WO2018020506A1 WO 2018020506 A1 WO2018020506 A1 WO 2018020506A1 IN 2016050322 W IN2016050322 W IN 2016050322W WO 2018020506 A1 WO2018020506 A1 WO 2018020506A1
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WO
WIPO (PCT)
Prior art keywords
canagliflozin
formula
carboxylic acid
methyl
piperidine
Prior art date
Application number
PCT/IN2016/050322
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English (en)
Inventor
Shankarreddy BUDDETI
Shyam Sunder Reddy TALASANI
Srinivasa Krishna Murthy Konduri
Venkateswarlu BANDLA
Santosh Kumar KOKKU
Pulla Reddy Muddasani
Venkaiah Chowdary Nannapaneni
Original Assignee
Natco Pharma Ltd
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Publication date
Application filed by Natco Pharma Ltd filed Critical Natco Pharma Ltd
Publication of WO2018020506A1 publication Critical patent/WO2018020506A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention is related to an improved process for the preparation of amorphous form of Canagliflozin with high purity and high yield.
  • Canagliflozin is sodium glucose co transporter! (SGLT) inhibitor, chemically known as (2S, 3R, 4R, 5S, 6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl] -4-methyl-phenyl] -6- (hydroxymethyl) tetrahydropyran-3, 4, 5-triol and structurally represented as below
  • Canagliflozin is first disclosed in US 7943788 and marketed as canagliflozin hemi hydrate under the brand name INVOKANA ® .
  • U.S. Patent No. 7,943,582 discloses crystalline hemihydrate form of canangliflozin and its preparation, wherein dissolving canagliflozin in a polar solvent (e.g. ketones or esters) crude or amorphous compound prepared in accordance with the procedures described in WO 2005/012326, and adding water and non-polar solvent (e.g. alkanes or ethers) to the resulting solution, followed by filtration.
  • a polar solvent e.g. ketones or esters
  • water and non-polar solvent e.g. alkanes or ethers
  • U.S. Patent No. 8,999,941 discloses amorphous dapagliflozin and amorphous canagliflozin and also discloses 1: 1 crystalline complex of canagliflozin with L-proline (Form CS 1), 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). It also discloses preparation of amorphous canagliflozin by adding its heated toluene solution into n-heptane.
  • the inventors of the present of invention have developed an alternate improved process for the preparation of amorphous form of canagliflozin with high yield and purity.
  • the present process is cost effective and feasible in large scale production also.
  • One aspect of the present invention is to provide an improved process for the preparation of amorphous form of Canagliflozin of formula (1)
  • Another aspect of the present invention is related to the preparation of amorphous form of canagliflozin, comprising the steps of:
  • Yet another aspect of the present invention is related to purification of amorphous form canagliflozin, comprising the steps of:
  • step b) adding piperidine-4-carboxylic acid to step a) mixture to get piperidine-4-carboxylic acid complex of canagliflozin, and
  • Yet another aspect of the present invention is to provide a crystalline piperidine-4-carboxylic acid complex of canagliflozin (CPl) having the XRPD pattern as 3.48, 10.38, 11.36, 11.96, 13.86, 16.27, 16.61, 17.24, 17.60, 18.00, 19.01, 19.93, 20.47, 21.05, 21.77, 21.99, 22.25, 22.8, 23.4, 24.05, 24.61, 24.86, 25.58, 26.02, 26.23,26.71, 28.34, 29.10, 31.33, 32.21, 33.61( ⁇ 0.2° ⁇ ).
  • CPl canagliflozin
  • Yet another aspect of the present invention to provide a crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP2) having the XRPD pattern as 10.35, 12.72, 12.99, 14.15, 15.70, 17.29, 17.66, 18.46, 18.81, 19.34, 20.80, 21.23, 22.63, 22.99, 23.63, 24.31, 26.03, 26.51 , 28.31( ⁇ 0.2° ⁇ ).
  • Yet another aspect of the present invention is to provide a process for the preparation of crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP1) comprising reacting canagliflozin of formula (1) with piperidine-4-carboxylic acid in ketone-water solvent mixture and isolating the crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP1).
  • Yet another aspect of the present invention is to provide a process for the preparation of crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP2) comprising reacting canagliflozin of formula (1) with piperidine-4-carboxylic acid in alcohol- water solvent mixture and isolating the crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP2).
  • CP2 canagliflozin
  • the present invention relates to an improved process for the preparation of amorphous form of canagliflozin, wherein one step is related to the direct isolation of amorphous form of canagliflozin from reaction mixture and other step is related to purification of amorphous form of canagliflozin through piperidine-4-carboxylic acid complex of canagliflozin.
  • One embodiment of the present invention is to provide an improved process for the preparation of amorphous form of Canagliflozin of formula (1)
  • step (i) of the present invention Gluconolactone of formula (2) is reacted with trimethyl silyl chloride in presence of N-methylmorpholine in tetrahydrofuran at about 40° C for 5-6h. After completion of reaction, the reaction mixture is cooled to ambient temperature and stirred for overnight. Later the reaction mixture is quenched in to chilled water and the product can be extracted with organic solvent. The organic solvent may be hexane or cyclohexane. Concentration under reduced pressure afforded quantitative yield of 2,3,4,6-tetra-o-Trimethylsilyl-P-D-Gluconolactone of formula (3) as yellow oil.
  • step (ii) of the present invention compound of 2-[(5-bromo-2-methyl-phenyl) methyl] -5-(4-fluorophenyl) thiophene of formula (4) is reacted with 2,3,4,6-tetra-O Trimethylsilyl-P-D-Gluconolactone of formula (3) in THF-toluene mixture at -90 to -100°C in the presence of n-BuLi under inert atmosphere for lh followed by quenching the reaction mixture by adding methane sulfonic acid-methanol mixture in to the reaction mass. After quenching, the mixture is stirred for overnight and neutralized with saturated sodium bicarbonate solution.
  • the organic layer is separated, washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate.
  • the organic layer is filtered and distilled out solvent completely under reduced pressure to afford thick oily syrup which is triturated using organic solvent mixture to afford 77% yield of (3R,4S,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2- thienyl]methyl]-4-methyl-phenyl]-6-(hydroxymethyl)-2-methyl-tetrahydropyran-3,4,5-triol of formula (5) as off-white solid.
  • the organic solvent can be toluene-heptane, toluene- cyclohexane mixture.
  • step (iii) of the present invention compound of (3R,4S,5S,6R)-2-[3-[[5-(4- fluorophenyl)-2-thienyl] methyl] -4-methyl -phenyl] -6-(hydroxymethyl)-2-methyl-tetrahydro pyran-3,4,5-triol of formula (5) is reduced using triethylsilane in the presence of boron trifluoride-dietherate in dichloromethane at 0-5° C for about 3h. After completion of reaction, the reaction mixture is quenched with saturated sodium bicarbonate solution and the layers are separated. The organic layer is washed with water followed by saturated sodium chloride solution. The excess solvent is distilled off completely under reduced pressure to yield >90% of crude Canagliflozin of formula (1) as foamy solid having purity > 90% by HPLC.
  • step (iv) of the present invention compound of (2S,3R,4R,5S,6R)-2-[3-[[5-(4- fluorophenyl)-2-thienyl] methyl] -4-methyl-phenyl]-6-(hydroxymethyl) tetrahydropyran-3,4,5- triol of formula (1) is complexed with acid reagent in an organic solvent-water mixture at about 40° C for 6h.
  • the organic solvent can be acetone, isopropyl alcohol or methanol.
  • the acid reagent can be piperidine-4-carboxylic acid, piperidine-3-carboxylic acid, piperidine-2- carboxylic acid, nicotinic acid or isonicotinic acid preferably piperidine-4-carboxylic acid.
  • the resulting precipitated complex is cooled to 0-5° C and stirred for about lh and filtered.
  • the wet product is dried under reduced pressure to afford crystalline Canagliflozin complex of formula (6) as off-white solid with about 80% yield.
  • the purity of crystalline Canagliflozin complex is >99.5% by HPLC.
  • step (v) of the present invention crystalline Canagliflozin complex of formula (6) is stirred in water-organic solvent mixture for about lh and resulting organic layer is separated.
  • the organic solvent can be methyl tertiary butyl ether, diisopropyl ether preferably methyl tertiary butyl ether.
  • the organic layer is clarified with activated charcoal and filtered. The excess solvent is distilled out partially under atmospheric pressure.
  • the concentrated reaction mass is added into co-solvent and the product is filtered and dried under vacuum to afford about 80% yield of off-white to white amorphous Canagliflozin.
  • the co-solvent can be cyclohexane, hexane or heptane. The purity of the product is >99.8% by HPLC.
  • One embodiment of the present invention is related to preparation of amorphous form of canagliflozin, comprising the steps of:
  • RB flask is charged (3R, 4S, 5S, 6R)-2-[3-[[5-(4- fluorophenyl)-2-thienyl] methyl] -4-methyl -phenyl] -6-(hydroxymethyl)-2-methyl- tetrahydropyran-3,4,5triol, of formula (5) is reacted with triethyl silane in the presence of BF3.
  • 0(Et)2 in dichloromethane at -40° C to -30° C followed by quenching the reaction mixture with base at -5° to 0° C, extraction and distillation of methylene chloride to get amorphous form of Canagliflozin of formula (1) as foamy solid.
  • base is selected form sodium bicarbonate and potassium bicarbonate preferably sodium bicarbonate.
  • Another embodiment of the present invention is related to purification of amorphous form canagliflozin, comprising the steps of:
  • step b) adding piperidine-4-carboxylic acid to step a) mixture to get piperidine-4- carboxylic acid complex of canagliflozin, and
  • organic solvent is selected from ketone /alcohol solvents.
  • ketone solvent is selected from acetone, butanone, cyclopentanone, 2-pentanone, methyl ethyl ketone, methylisobutyl ketone and methylisopropyl ketone preferably acetone.
  • alcohol solvent is selected from methanol, ethanol, propanol, isopropanol and butanol preferably isopropanol.
  • Pure amorphous form of Canagliflozin of formula (1) is regenerated from (2S,3R,4R,5S,6R)- 2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-(hydroxy methyl) tetrahydro pyran-3,4,5-triol complex of formula (6) in DM Water-ether solvent medium at RT and the resulting Canagliflozin of formula (1) is separated, followed by distillation and isolation from ether- alkane solvent mixture to get pure amorphous form of Canagliflozin of formula (1) as white solid.
  • ether solvent is selected from diethyl ether, diisopropyl ether, and methyl tert-butyl ether preferably methyl tert-butyl ether.
  • alkane solvent is selected from pentane, hexane, heptane, cyclohexane preferably cyclohexane.
  • Yet another embodiment of the present invention is to provide a crystalline piperidine-4- carboxylic acid complex of canagliflozin (CP1) having the XRPD pattern as 3.48, 10.38, 11.36, 11.96, 13.86, 16.27, 16.61, 17.24, 17.60, 18.00, 19.01, 19.93, 20.47, 21.05, 21.77, 21.99, 22.25, 22.8, 23.4, 24.05, 24.61, 24.86, 25.58, 26.02, 26.23,26.71, 28.34, 29.10, 31.33, 32.21, 33.61( ⁇ 0.2° ⁇ ).
  • Yet another embodiment of the present invention is to provide a crystalline piperidine-4- carboxylic acid complex of canagliflozin (CP2) having the XRPD pattern as 10.35, 12.72, 12.99, 14.15, 15.70, 17.29, 17.66, 18.46, 18.81, 19.34, 20.80, 21.23, 22.63, 22.99, 23.63, 24.31, 26.03, 26.51 , 28.31( ⁇ 0.2° ⁇ ).
  • CP2 canagliflozin
  • Yet another embodiment of the present invention is to provide a process for the preparation of crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP1) comprising reacting canagliflozin of formula (1) with piperidine-4-carboxylic acid in ketone- water solvent mixture and isolating the crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP1).
  • ketone solvent is selected from acetone, butanone, cyclopentanone, 2-pentanone, methylisobutyl ketone and methylisopropyl ketone preferably acetone.
  • Yet another embodiment of the present invention is to provide a process for the preparation of crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP2) comprising reacting canagliflozin of formula (1) with piperidine-4-carboxylic acid in alcohol- water solvent mixture and isolating the crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP2).
  • CP2 canagliflozin
  • alcohol solvent is selected from methanol, ethanol, propanol, isopropanol and butanol preferably isopropanol.
  • Fig-1 XRPD pattern of amorphous form of canagliflozin.
  • Fig-2 XRPD pattern of crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP1).
  • Fig-3 IR spectrum of crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP1).
  • Fig-4 XRPD pattern of crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP2).
  • Fig-5 IR spectrum of crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP2).
  • Fig-6 XRPD pattern of amorphous form of canagliflozin prepared from crystalline piperidine- 4-carboxylic acid complex of canagliflozin.
  • Example-I Process for preparation of amorphous form of Canagliflozin from novel crystalline complex
  • reaction mixture was warmed to 0°C and stirred for 3 hrs.
  • the reaction mixture was then quenched with satd.NaHC0 3 solution (1.5 L) at 0°C and the layers were separated.
  • the organic layer was washed with DM water (650 ml) and aq. saturated sodium chloride solution (650 ml).
  • the solvent distilled off completely under reduced pressure to yield (97. lg, > 90%) titled compound of formula (1) as a foamy solid.
  • IR (cm-1) KBr 3477, 3355, 2970, 2915, 2524, 2489, 1699, 1644, 1576, 1509, 1369, 1225, 1045, 1013.
  • PXRD (°2 ⁇ ( ⁇ 0.2°): 3.48, 10.38, 11.36, 11.96, 13.86, 16.27, 16.61, 17.24, 17.60, 18.00,19.01,19.93, 20.47, 21.05, 21.77, 21.99, 22.25, 22.8, 23.4, 24.05, 24.61, 24.86, 25.58, 26.02, 26.23,26.71,28.34, 29.10, 31.33, 32.21, 33.61.
  • IR (cm-1) KBr 3406, 3076, 3007, 2928, 2853, 1641, 1571, 1505, 1367, 1228, 1096, 1126, 1041.
  • IR (cm "1 ) KBr 3404, 3072, 2918, 1509, 1231, 1048, 1159.

Abstract

La présente invention concerne un procédé amélioré de préparation de formes amorphes de Canagliflozine de pureté élevée avec un rendement élevé. En particulier, la présente invention concerne l'isolation directe des formes amorphes de Canagliflozine à partir d'un mélange de réaction et concerne aussi la purification de la forme amorphe de Canagliflozine par un complexe d'acide pipéridine-4-carboxylique de Canagliflozine.
PCT/IN2016/050322 2016-07-25 2016-09-24 Processus pour la préparation des formes amorphes de canagliflozine WO2018020506A1 (fr)

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IN201641025330 2016-07-25

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005012326A1 (fr) 2003-08-01 2005-02-10 Tanabe Seiyaku Co., Ltd. Nouveaux composes possedant une activite inhibitrice dirigee contre le transporteur dependant du sodium
US7943582B2 (en) 2006-12-04 2011-05-17 Mitsubishi Tanabe Pharma Corporation Crystalline form of 1-(β-D-glucopyransoyl)-4-methyl-3-[5-(4-fluorophenyl)-2- thienylmethyl]benzene hemihydrate
WO2013064909A2 (fr) * 2011-10-31 2013-05-10 Scinopharm Taiwan, Ltd. Formes cristallines et non cristallines d'inhibiteurs de sglt2
WO2014195966A2 (fr) 2013-05-30 2014-12-11 Cadila Healthcare Limited Forme amorphe de canagliflozine et son procédé de préparation
CN104402946A (zh) * 2014-11-17 2015-03-11 连云港恒运医药科技有限公司 卡格列净中间体及其无定形的制备方法
WO2016098016A1 (fr) * 2014-12-17 2016-06-23 Dr. Reddy’S Laboratories Limited Procédé de préparation d'inhibiteurs de sglt2

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005012326A1 (fr) 2003-08-01 2005-02-10 Tanabe Seiyaku Co., Ltd. Nouveaux composes possedant une activite inhibitrice dirigee contre le transporteur dependant du sodium
US7943788B2 (en) 2003-08-01 2011-05-17 Mitsubishi Tanabe Pharma Corporation Glucopyranoside compound
US7943582B2 (en) 2006-12-04 2011-05-17 Mitsubishi Tanabe Pharma Corporation Crystalline form of 1-(β-D-glucopyransoyl)-4-methyl-3-[5-(4-fluorophenyl)-2- thienylmethyl]benzene hemihydrate
WO2013064909A2 (fr) * 2011-10-31 2013-05-10 Scinopharm Taiwan, Ltd. Formes cristallines et non cristallines d'inhibiteurs de sglt2
US8999941B2 (en) 2011-10-31 2015-04-07 Scinopharm Taiwan, Ltd. Crystalline and non-crystalline forms of SGLT2 inhibitors
WO2014195966A2 (fr) 2013-05-30 2014-12-11 Cadila Healthcare Limited Forme amorphe de canagliflozine et son procédé de préparation
CN104402946A (zh) * 2014-11-17 2015-03-11 连云港恒运医药科技有限公司 卡格列净中间体及其无定形的制备方法
WO2016098016A1 (fr) * 2014-12-17 2016-06-23 Dr. Reddy’S Laboratories Limited Procédé de préparation d'inhibiteurs de sglt2

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