WO2017064679A1 - Process for the preparation of amorphous canagliflozin - Google Patents
Process for the preparation of amorphous canagliflozin Download PDFInfo
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- WO2017064679A1 WO2017064679A1 PCT/IB2016/056192 IB2016056192W WO2017064679A1 WO 2017064679 A1 WO2017064679 A1 WO 2017064679A1 IB 2016056192 W IB2016056192 W IB 2016056192W WO 2017064679 A1 WO2017064679 A1 WO 2017064679A1
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- canagliflozin
- proline
- formula
- compound
- solvent
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- XTNGUQKDFGDXSJ-ZXGKGEBGSA-N Cc1ccc([C@@H]([C@@H]([C@H]2O)O)O[C@H](CO)[C@H]2O)cc1Cc1ccc(-c(cc2)ccc2F)[s]1 Chemical compound Cc1ccc([C@@H]([C@@H]([C@H]2O)O)O[C@H](CO)[C@H]2O)cc1Cc1ccc(-c(cc2)ccc2F)[s]1 XTNGUQKDFGDXSJ-ZXGKGEBGSA-N 0.000 description 1
Classifications
-
- 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 relates to a process for the preparation of amorphous canagliflozin.
- the present invention also relates to a process for the preparation of canagliflozin.
- SGLT 2 Sodium glucose cotransporter 2
- SGLT 2 is mainly distributed in renal proximal tubules. It was responsible for atleast 90% of the glucose reabsorption in the kidney.
- Canagliflozin hemihydrate (designated as INVOKANA ) is inhibitor of sodium dependent glucose cotransporter which is chemically represented as (15)-l,5-anhydro-l- [3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate having structural
- US patent No. 7,943,788 discloses canagliflozin or a pharmaceutically acceptable salt, or a stereoisomer thereof or a prodrug thereof.
- Various processes for the preparation of canagliflozin and its amorphous form have been known via US Patent Application Nos. 2005233988, 20120289694, 20130237487 and 2016083374.
- the amorphous canagliflozin is hygroscopic in nature and contain higher amount of residual solvents. Residual solvents are often not completely removed from API by regular manufacturing techniques. They should be decreased to a minimum amount to meet the ICH guidelines. Therefore an environmental friendly crystallization process for the preparation of amorphous canagliflozin and consequently a product obtained from this process lacking residual solvents is highly desirable.
- the present invention relates to a process for the preparation of amorphous canagliflozin.
- step (e) providing solution of the canagliflozin obtained in step (d) into the mixture of ethyl acetate and methanol;
- step (h) adding solution of step (g) into the suitable anti-solvent such as n-heptane;
- alkyl lithium is selected from the group consisting of n-butyl lithium, teri-butyl lithium and hexyl lithium; at a temperature in the range of from about -120°C to about -85°C; followed by treatment with methane sulfonic acid in
- step (d) adding solution of step (c) into the suitable anti-solvent such as n-heptane;
- Fig. 1 depicts the X-ray powder diffraction pattern of amorphous canagliflozin.
- the present invention relates to a process for the preparation of amorphous canagliflozin.
- alkyl group means a straight or branched saturated monovalent hydrocarbon chain having 1 to 12 carbon atoms.
- the straight chain or branched chain alkyl group having 1 to 6 carbon atoms is preferable, and the straight chain or branched chain alkyl group having 1 to 4 carbon atoms is more preferable.
- Examples thereof are methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, isobutyl group, pentyl group, hexyl group, isohexyl group, heptyl group, 4,4- dimethylpentyl group, octyl group, 2,2,4-trimethylpentyl group, nonyl group, decyl group, and various branched chain isomers thereof. Further, the alkyl group may optionally substituted.
- Powder X-ray diffraction of amorphous canagliflozin can be obtained under following conditions:
- XRPD pattern is made using Cu K-al radiation at a voltage 40 niA & 45 kV. XRPD pattern was observed at 25°C and scanned from 3.5 to 40 two theta values.
- reaction conditions such as reagents, catalysts, solvents and temperature given are meant to provide preferred ranges and examples for the respective transformation that can be principally applied but are not supposed to restrict them to the selection given.
- step (e) providing solution of the canagliflozin obtained in step (d) into the mixture of ethyl acetate and methanol;
- step (h) adding solution of step (g) into the suitable anti-solvent such as n-heptane;
- Compound of formula (IV) can be prepared by reacting a compound of formula (II) with a compound of formula (III), in the presence of alkyl lithium in an organic solvent; at a temperature in the range of from about -120°C to about -85°C; followed by treatment with methanesulfonic acid in methanol; at lower, ambient, or elevated temperature.
- Alkyl lithium may be selected from the group consisting of n-butyl lithium, teri-butyl lithium and hexyl lithium.
- Organic solvent may be selected from tetrahydrofuran, 2-methyl tetrahydrofuran, heptane, hexane, pentane, methyl tert-butyl ether, dioxane, toluene and the like or a mixture of these solvents.
- lithiation reaction may be carried under cryogenic condition (i.e., at a temperature about -78 °C) which provides the lower yield of product. While developing the process of making canagliflozin, the inventors come across the process for lithiation, by minimizing the temperature in the range of from -120°C to about -85°C of lithiation reaction which results higher yield of the product.
- the corresponding compound of formula (V) can be prepared by reacting the compound of formula (IV) with trialkylsilanes selected from the group consisting of triethylsilane, triisopropylsilane, poly(methylhydrosiloxane and the like; in the presence of Lewis acid selected from the group consisting of boron trifluoride diethyl ether complex, aluminium chloride, titanium tetrachloride, and the like; in a suitably selected solvent such as acetonitrile, toluene, dichloroethane, dichloromethane, and the like or a mixture of these solvents at lower, ambient, or elevated temperature.
- dichloromethane may be used as suitable solvent and reduction reaction may be carried out at temperature from about -40°C to about -20°C.
- L-proline co-crystal of canagliflozin may be obtained by adding L-proline into the solution of canagliflozin in the suitable solvents.
- suitable solvents that may be used in step (c) include but are not limited to alcohol, ketone, ester, ether, hydrocarbon, water, nitrile or mixtures thereof in any suitable proportion.
- Particularly preferred solvents include methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, 2-pentanol, amyl alcohol, acetone, butanone, 2-pentanone, 3-pentanone, methylbutyl ketone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, toluene, xylene, water, methyl tert-butyl ether, ethyl tert-butyl ether, ethyl ether, isopropyl ether or mixtures thereof in any suitable proportion. More preferably dichloromethane may be used as suitable solvent.
- the process for the preparation of L-proline co-crystal of canagliflozin is carried out at temperature of room temperature to reflux temperature for few minutes to few hours; preferably reaction mixture is heated at about 35°C to about 40°C for a period of 1-5 hours.
- the co-crystal of canagliflozin is optionally isolated from the reaction mixture by suitable techniques such as filtration, evaporation, distillation, vacuum drying, centrifugation and the like.
- the isolated co-crystal of canagliflozin is dried at temperature ranging from room temperature to 80°C, more preferably from about 45°C to about 80°C for a time preferably from 1 hour to 48 hours.
- the obtained L-proline co-crystal of canagliflozin may be converted to canagliflozin in step (d) by using conventional techniques known in the art.
- canagliflozin may be obtained by adding water into the solution of L-proline co-crystal of canagliflozin in suitable solvent or mixture thereof; at lower, ambient, or elevated temperature.
- suitable solvents that may be used include but are not limited to alcohol, ketone, ester, ether, hydrocarbon, nitrile or mixtures thereof in any suitable proportion.
- Particularly preferred solvents include methanol, ethanol, isopropanol, 2-propanol, 1- butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, acetone, butanone, 2- pentanone, 3-pentanone, methylbutyl ketone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, toluene, xylene, water, methyl tert- butyl ether, ethyl tert-butyl ether, ethyl ether, isopropyl ether or mixtures thereof in any suitable proportion.
- dichloromethane methyl teri-butyl ether or ethyl acetate may be used as suitable solvent.
- L-proline co-crystal of canagliflozin may be converted to canagliflozin by comprising the steps of :
- the canagliflozin obtained in step (d) is optionally isolated from the reaction mixture by suitable techniques known in the art such as filtration, evaporation, distillation, vacuum drying, centrifugation and the like. Canagliflozin may optionally be further dried. Drying may be suitably carried out in equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperature from about 45°C to about 85°C, optionally under reduced pressure.
- the canagliflozin obtained in step (d) may be dissolved into the mixture of ethyl acetate and methanol in any suitable proportion.
- the solution obtained in step (e) may be filtered to remove any insoluble particles.
- the solution may optionally be treated with carbon, hyflow or any other suitable material to remove colour and/or to clarify the solution.
- the reaction mixture may be distilled out till 1.0 to 4.0 volumes of solvent remains behind.
- the solution obtained after addition of methyl tert butyl ether in step (g) may be filtered to remove any insoluble particles.
- the solution may optionally be treated with carbon, hyflow or any other suitable material to remove colour and/or to clarify the solution.
- the anti-solvent for step (h) comprises n-hexane, n-heptane, n-pentane, cyclohexane, methylcyclohexane, diethyl ether, diisopropyl ether, dibutyl ether or mixtures thereof in any suitable proportion. More preferably n-heptane may be used as anti-solvent.
- the treatment with the antisolvent may be carried out, for example, by adding the solution of canagliflozin into the antisolvent or vice versa at temperature about -30°C to about 50°C, preferably at -10°C to 5°C.
- the treatment with antisolvent may be followed by stirring the mixture for about 10 minutes to 20 hours, preferably about 1 hour to 2 hours.
- the stirring may be carried out at about -30°C to about 50°C, preferably at -15°C to 5°C.
- the obtained precipitate may be isolated using conventional techniques known in the art.
- One skilled in the art may appreciate that there are many ways to separate a solid from the mixture, for example it may be separated by using any techniques such as filtration, centrifugation, decantation and the like.
- the solid may optionally be washed with a suitable solvent.
- the amorphous canagliflozin may optionally be further dried. Drying may be suitably carried out in equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperature about 45°C to about 80°C, optionally under reduced pressure.
- Amorphous canagliflozin obtained by the process of the invention characterised by an X-ray pattern.
- the powder XRD pattern of canagliflozin (Fig. 1) obtained by process of the present invention shows product to be in amorphous form.
- the obtained amorphous canagliflozin is stable during storage and drying.
- Compound of formula (IV) can be prepared by reacting a compound of formula (II) with a compound of formula (III), in the presence of alkyl lithium in an organic solvent; at a temperature in the range of from about -120°C to about -85°C; followed by treatment with methanesulfonic acid in methanol; at lower, ambient, or elevated temperature.
- Compound of formula (II) is first reacted with alkyl lithium to yield the corresponding lithiated species, followed by the reaction of the lithiated species with the compound of formula (III) to form protected form of compound.
- Alkyl lithium may be selected from the group consisting of n-butyl lithium, teri-butyl lithium and hexyl lithium.
- Organic solvent may be selected from tetrahydrofuran, 2-methyl tetrahydrofuran, heptane, hexane, pentane, methyl tert-butyl ether, dioxane, toluene and the like or a mixture of these solvents.
- the protected compound is then deprotected by reaction with methane sulfonic acid in methanol to form the compound of formula (IV).
- lithiation reaction may be carried under cryogenic condition (i.e., at a temperature about -78 °C) which provides the lower yield of product. While developing the process of making canagliflozin, the inventors come across the process for lithiation, by minimizing the temperature in the range of from -120°C to about -85°C of lithiation reaction which results higher yield of the product.
- the corresponding compound of formula (V) can be prepared by reacting the compound of formula (IV) with trialkylsilanes selected from the group consisting of triethylsilane, triisopropylsilane, poly(methylhydrosiloxane and the like; in the presence of Lewis acid selected from the group consisting of boron trifluoride diethyl ether complex, aluminium chloride, titanium tetrachloride, and the like; in a suitably selected solvent such as acetonitrile, toluene, dichloroethane, dichloromethane, and the like or a mixture of these solvents at lower, ambient, or elevated temperature.
- dichloromethane may be used as suitable solvent and reduction reaction may be carried out at about -40°C to about -20°C.
- L-proline co-crystal of canagliflozin may be obtained by adding L-proline into the solution of canagliflozin into the suitable solvents.
- suitable solvents that may be used in step (c) include but are not limited to alcohol, ketone, ester, ether, hydrocarbon, water, nitrile or mixtures thereof in any suitable proportion.
- Particularly preferred solvents include methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, 2-pentanol, amyl alcohol, acetone, butanone, 2-pentanone, 3-pentanone, methylbutyl ketone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, toluene, xylene, water, methyl tert-butyl ether, ethyl tert-butyl ether, ethyl ether, isopropyl ether or mixtures thereof in any suitable proportion. More preferably dichloromethane may be used as suitable solvent.
- the process for the preparation of L-proline co-crystal of canagliflozin is carried out at temperature of room temperature to reflux temperature for few minutes to few hours; preferably reaction mixture is heated at temperature from about 35°C to about 40°C for a period of 1 hour to 5 hours.
- the co-crystal of canagliflozin is optionally isolated from the reaction mixture by suitable techniques such as filtration, evaporation, distillation, vacuum drying, centrifugation and the like.
- the isolated co-crystal of canagliflozin is dried at temperature ranging from room temperature to about 80°C, more preferably from about 45°C to about 80°C for a time preferably from 1 hour to 48 hours.
- the obtained L-proline co-crystal of canagliflozin may be converted to canagliflozin in step (d) by using conventional techniques known in the art.
- canagliflozin may be obtained by adding water into the solution of L-proline co-crystal of canagliflozin in suitable solvent or mixture thereof; at lower, ambient, or elevated temperature.
- suitable solvents that may be used include but are not limited to alcohol, ketone, ester, ether, hydrocarbon, nitrile or mixtures thereof in any suitable proportion.
- Particularly preferred solvents include methanol, ethanol, isopropanol, 2-propanol, 1- butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, acetone, butanone, 2- pentanone, 3-pentanone, methylbutyl ketone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, toluene, xylene, water, methyl tert- butyl ether, ethyl tert-butyl ether, ethyl ether, isopropyl ether or mixtures thereof in any suitable proportion.
- dichloromethane methyl teri-butyl ether or ethyl acetate
- L-proline co-crystal of canagliflozin may be converted into canagliflozin by comprising the steps of : (i) dissolving L-proline co-crystal of canagliflozin in dichloromethane, methyl tert-butyl ether or ethyl acetate;
- the canagliflozin obtained in step (d) may be isolated using conventional techniques known in the art.
- One skilled in the art may appreciate that there are many ways to separate a solid from the mixture, for example it may be separated by using any techniques such as filtration, centrifugation, decantation and the like. After separation, the solid may optionally be washed with a suitable solvent.
- the canagliflozin may optionally be further dried. Drying may be suitably carried out in equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperature from about 45 °C to about 80 °C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a product with desired purity such as from about 1 hour to about 25 hours or longer.
- step (d) adding solution of step (c) into the suitable anti-solvent such as n-heptane;
- Canagliflozin that may be utilized for providing the solution of canagliflozin in step (a).
- Canagliflozin that may be used as the input for the process of the present invention may be obtained by any process including the process described in the art.
- the canagliflozin may be dissolved in the mixture of ethyl acetate and methanol in any suitable proportion.
- the solution obtained in step (a) may be filtered to remove any insoluble particles.
- the solution may optionally be treated with carbon, hyflow or any other suitable material to remove colour and/or to clarify the solution.
- the reaction mixture may be distilled out till 1.0 to 4.0 volumes of solvent remains behind.
- the solution obtained after addition of methyl tert butyl ether in step (c) may be filtered to remove any insoluble particles.
- the solution may optionally be treated with carbon, hyflow or any other suitable material to remove colour and/or to clarify the solution.
- the anti-solvent for step (d) comprises n-hexane, n-heptane, n-pentane, cyclohexane, methylcyclohexane, diethyl ether, diisopropyl ether, dibutyl ether or mixtures thereof in any suitable proportion. More preferably n-heptane may be used as anti-solvent.
- the treatment with the antisolvent may be carried out, for example, by adding the solution of canagliflozin into the antisolvent or vice versa at temperature about -30°C to about 50°C, preferably at -10°C to 5°C.
- the treatment with antisolvent may be followed by stirring the mixture for about 10 minutes to 20 hours, preferably about 1 hour to 2 hours.
- the stirring may be carried out at about -30°C to about 50°C, preferably at -15°C to 5°C.
- the obtained precipitate may be isolated using conventional techniques known in the art.
- One skilled in the art may appreciate that there are many ways to separate a solid from the mixture, for example it may be separated by using any techniques such as filtration, centrifugation, decantation and the like.
- the solid may optionally be washed with a suitable solvent.
- the amorphous canagliflozin may optionally be further dried. Drying may be suitably carried out in equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperature about 45°C to about 80°C, optionally under reduced pressure.
- the drying may be carried out for any time periods necessary for obtaining a product with desired purity such as from about 1 hour to about 25 hours or longer.
- the amorphous canagliflozin obtained by the process of the invention characterised by an X-ray pattern.
- the powder XRD pattern of canagliflozin (Fig. 1) obtained by process of the present invention shows product to be in amorphous form.
- the obtained amorphous canagliflozin is stable during storage and drying.
- amorphous canagliflozin obtained along with residual solvent levels within the permissible ICH limits which is suitable for pharmaceutical preparation.
- a process for the preparation of amorphous canagliflozin of formula (I) comprising the steps of:
- step (d) providing solution of the canagliflozin obtained in step (c) into the mixture of ethyl acetate and methanol;
- step (g) adding solution of step (f) into the suitable anti-solvent such as n-heptane; (h) isolating amorphous canagliflozin.
- step (e) providing solution of canagliflozin obtained in step (d) in suitable solvent or mixture thereof;
- step (f) treating the solution of step (e) with an antisolvent
- Compound of formula (IV) can be prepared by reacting a compound of formula (II) with a compound of formula (III), in the presence of alkyl lithium in an organic solvent; at a temperature in the range of from about -120°C to about -85°C; followed by treatment with methanesulfonic acid in methanol; at lower, ambient, or elevated temperature.
- Compound of formula (II) is first reacted with alkyl lithium to yield the corresponding lithiated species, followed by the reaction of the lithiated species with the compound of formula (III) to form protected form of compound.
- Alkyl lithium may be selected from the group consisting of n-butyl lithium, teri-butyl lithium and hexyl lithium.
- Organic solvent may be selected from tetrahydrofuran, 2-methyl tetrahydrofuran, heptane, hexane, pentane, Methyl tert-butyl ether, dioxane, toluene and the like or a mixture of these solvents.
- the protected compound is then deprotected by reaction with methane sulfonic acid in methanol to form the compound of formula (IV).
- lithiation reaction may be carried under cryogenic condition (i.e., at a temperature about -78 °C) which provides the lower yield of product.
- the corresponding compound of formula (V) can be prepared by reacting the compound of formula (IV) with trialkylsilanes selected from the group consisting of triethylsilane, triisopropylsilane, poly(methylhydrosiloxane and the like; in the presence of Lewis acid selected from the group consisting of boron trifluoride diethyl ether complex, aluminium chloride, titanium tetrachloride, and the like; in a suitably selected solvent such as acetonitrile, toluene, dichloroethane, dichloromethane, and the like or a mixture of these solvents at lower, ambient, or elevated temperature.
- trialkylsilanes selected from the group consisting of triethylsilane, triisopropylsilane, poly(methylhydrosiloxane and the like
- Lewis acid selected from the group consisting of boron trifluoride diethyl ether complex, aluminium chloride, titanium te
- dichloromethane may be used as suitable solvent and reduction reaction may be carried out at temperature from about -40°C to about -20°C.
- L-proline co-crystal of canagliflozin may be obtained by adding L-proline into the solution of canagliflozin in suitable solvents.
- suitable solvents that may be used in step (c) include but are not limited to alcohol, ketone, ester, ether, hydrocarbon, water, nitrile or mixtures thereof in any suitable proportion.
- Particularly preferred solvents include methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2- pentanol, amyl alcohol, acetone, butanone, 2-pentanone, 3-pentanone, methylbutyl ketone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, toluene, xylene, water, methyl tert-butyl ether, ethyl tert-butyl ether, ethyl ether, isopropyl ether or mixtures thereof in any suitable proportion.
- the process for the preparation of L-proline co-crystal of canagliflozin is carried out at temperature of room temperature to reflux temperature for few minutes to few hours; preferably reaction mixture is heated at temperature from 35°C to 40°C for a period of 1 to 5 hours.
- the co-crystal of canagliflozin is optionally isolated from the reaction mixture by suitable techniques such as filtration, evaporation, distillation, vacuum drying, centrifugation and the like.
- the isolated co-crystal of canagliflozin is dried at temperature ranging from room temperature to 80°C, more preferably at temperature from about 45°C to about 80°C for a time preferably from 1 hour to 48 hours.
- the obtained L-proline co-crystal of canagliflozin may be converted to canagliflozin in step (d) by using conventional techniques known in the art.
- canagliflozin may be obtained by adding water into the solution of L-proline co-crystal of canagliflozin in suitable solvent or mixture thereof; at lower, ambient, or elevated temperature.
- suitable solvents that may be used include but are not limited to alcohol, ketone, ester, ether, hydrocarbon, nitrile or mixtures thereof in any suitable proportion.
- Particularly preferred solvents include methanol, ethanol, isopropanol, 2-propanol, 1- butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, acetone, butanone, 2- pentanone, 3-pentanone, methylbutyl ketone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, toluene, xylene, water, methyl tert- butyl ether, ethyl tert-butyl ether, ethyl ether, isopropyl ether or mixtures thereof in any suitable proportion. More preferably dichloromethane, methyl teri-buty
- the canagliflozin obtained in step (d) is optionally isolated from the reaction mixture by suitable techniques known in the art such as filtration, evaporation, distillation, vacuum drying, centrifugation and the like. Canagliflozin may optionally be further dried. Drying may be suitably carried out in equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperature about 45 °C to about 85°C, optionally under reduced pressure.
- Providing a solution of canagliflozin in step (e) includes:
- step (i) direct use of reaction mixture containing canagliflozin that is obtained during its synthesis in step (d); or
- step (ii) dissolving canagliflozin obtained in step (d) in suitable solvent or mixtures thereof.
- Suitable solvents that may be used in step (e) include but are not limited to alcohol, hydrocarbon, ketone, ester, ether, hydrocarbon, nitrile or mixtures thereof in any suitable proportion.
- Particularly preferred solvents include methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3-pentanone, methylbutyl ketone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, toluene, xylene, dichloromethane, ethylene dichloride, chlorobenzene, acetonitrile,
- ethyl acetate, methyl teri-butyl ether (MTBE), methanol or mixtures thereof may be used in any suitable proportion.
- the solution may optionally be treated with carbon, hyflow or any other suitable material to remove colour and/or to clarify the solution.
- the anti-solvent for step (f) comprises n-hexane, n-heptane, n-pentane, cyclohexane, methylcyclohexane, diethyl ether, diisopropyl ether, dibutyl ether or mixtures thereof in any suitable proportion. More preferably n-heptane may be used as anti-solvent.
- the treatment with the antisolvent may be carried out, for example, by adding the solution of canagliflozin into the antisolvent or vice versa at temperature about -30°C to about 50°C, preferably at -10°C to 5°C.
- the treatment with antisolvent may be followed by stirring the mixture for about 10 minutes to 20 hours, preferably about 1 to 2 hours.
- the stirring may be carried out at about -30°C to 50°C, preferably at -15°C to 5°C.
- the obtained precipitate may be isolated using conventional techniques known in the art.
- One skilled in the art may appreciate that there are many ways to separate a solid from the mixture, for example it may be separated by using any techniques such as filtration, centrifugation, decantation and the like.
- the solid may optionally be washed with a suitable solvent.
- the amorphous canagliflozin may optionally be further dried. Drying may be suitably carried out in equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperature about 45°C to about 80°C, optionally under reduced pressure.
- the drying may be carried out for any time periods necessary for obtaining a product with desired purity such as from about 1 hour to about 25 hours or longer.
- Amorphous canagliflozin obtained by the process of the invention characterised by an X-ray pattern.
- the powder XRD pattern of canagliflozin (Fig. 1) obtained by process of the present invention shows product to be in amorphous form.
- the obtained amorphous canagliflozin is stable during storage and drying.
- amorphous canagliflozin prepared according to the processes of the present invention can be substantially pure having a chemical purity greater than about 99% or greater than about 99.5% by weight as determined using high performance liquid chromatography.
- canagliflozin prepared according to the processes of the present invention can be substantially pure having a chemical purity greater than about 99% or greater than about 99.5% by weight as determined using high performance liquid chromatography.
- additional starting compounds and/or reagents are commercially available or may be easily prepared according to conventional methods well known to these skilled in the art.
- reaction conditions for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention.
- Hexyl lithium (0.50 kg, 0.0054 mol) was slowly added to a stirred solution of 2- (5-bromo-2-methyl-benzyl)-5-(4-fluorophenyl)-thiophene (1 kg, 0.0027 mol) in tetrahydrofuran (12 L) and toluene (12 L) at -70°C to -65 °C.
- solution of 2,3,4,6-tetra-0-trimethylsilyl- -D-glucolactone (2 kg, 0.0042 mol) in toluene (3 L) was slowly added by maintaining the reaction at -70°C to - 65 °C and mixture was stirred for 2 hours at same temperature.
- Hexyl lithium (0.50 kg, 0.0054 mol) was slowly added to a stirred solution of 2- (5-bromo-2-methyl-benzyl)-5-(4-fluorophenyl)-thiophene (1 kg, 0.0027 mol) in tetrahydrofuran (12 L) and toluene (12 L) at -100°C to -90°C.
- solution of 2,3,4,6-tetra-0-trimethylsilyl- -D-glucolactone (2 kg, 0.0042 mol) in toluene (3 L) was slowly added by maintaining the reaction at -100 to -90°C and mixture was stirred for 2 hours at same temperature.
- Canagliflozin 700 gm was dissolved in ethyl acetate (5.6 L) and methanol (0.35 L). The resultant solution was stirred at room temperature for 1 hr. Reaction mixture was distilled out till 1.0 to 4.0 volumes of solvent remains behind. Methyl teri-butyl ether (2.8 L) was added to the above solution and resultant solution was filtered through micron filter. The resultant solution was added slowly to the pre-chilled solution of n-heptane (10.5 L) at -10°C and stirring was continued at same temperature. The solid precipitated was filtered and dried to obtain amorphous canagliflozin (yield: 88.6%).
Abstract
The present invention relates to a process for the preparation of amorphous canagliflozin. The present invention also relates to a process for the preparation of canagliflozin.
Description
PROCESS FOR THE PREPARATION OF AMORPHOUS CANAGLIFLOZIN
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of amorphous canagliflozin. The present invention also relates to a process for the preparation of canagliflozin.
BACKGROUND OF THE INVENTION
Diabetes is a global epidemic affecting more than 200 million people worldwide. The incidence of this disease is growing fast. Each year more than 4 million people die from complications of diabetes including heart diseases, strokes & kidney failure. Sodium glucose cotransporter 2 (SGLT 2) has been discovered to be a new target for treating diabetes in recent years. SGLT 2 is mainly distributed in renal proximal tubules. It was responsible for atleast 90% of the glucose reabsorption in the kidney.
Canagliflozin hemihydrate (designated as INVOKANA ) is inhibitor of sodium dependent glucose cotransporter which is chemically represented as (15)-l,5-anhydro-l- [3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate having structural
US patent No. 7,943,788 (B2) discloses canagliflozin or a pharmaceutically acceptable salt, or a stereoisomer thereof or a prodrug thereof. Various processes for the preparation of canagliflozin and its amorphous form have been known via US Patent Application Nos. 2005233988, 20120289694, 20130237487 and 2016083374.
According to the prior disclosures, the amorphous canagliflozin is hygroscopic in nature and contain higher amount of residual solvents. Residual solvents are often not completely removed from API by regular manufacturing techniques. They should be decreased to a minimum amount to meet the ICH guidelines. Therefore an environmental friendly crystallization process for the preparation of amorphous canagliflozin and consequently a product obtained from this process lacking residual solvents is highly desirable.
Though, there are processes available in the literature for the preparation of amorphous canagliflozin, still there remains a need for the environmental friendly, stable, highly pure, cost effective and industrially applicable process for the preparation of amorphous canagliflozin.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of amorphous canagliflozin.
In one aspect of the present invention, there is provided a process for the preparation of amorphous
or a pharmaceutically acceptable salt thereof;
comprising the steps of:
(a) reacting a compound of formula (II) with a compound of formula (III), in the presence of an alkyl lithium; followed by treatment with methanesulfonic acid in methanol; to yield the corresponding compound of formula (IV);
(b) reacting the compound of formula (IV) with trialkylsilane, in the presence of
(c) reacting compound of formula (V) with L-proline to yield L-proline co-crystal of canagliflozin;
(d) converting L-proline co-crystal of canagliflozin to canagliflozin;
(e) providing solution of the canagliflozin obtained in step (d) into the mixture of ethyl acetate and methanol;
(f) distilling off the solvent till 1.0 to 4.0 volumes of solvent remains behind;
(g) adding methyl tert-butyl ether into the reaction mixture;
(h) adding solution of step (g) into the suitable anti-solvent such as n-heptane;
(i) isolating amorphous canagliflozin.
In another aspect of the present invention, there is provided a process for the preparation of canagliflozin of formula (I)
or a pharmaceutically acceptable salt thereof;
comprising the steps of:
(a) reacting a compound of formula (II) with a compound of formula (III), in the presence of an alkyl lithium, wherein alkyl lithium is selected from the group consisting of n-butyl lithium, teri-butyl lithium and hexyl lithium; at a temperature in the range of from about -120°C to about -85°C; followed by treatment with methane sulfonic acid in
(c) reacting compound of formula (V) with L-proline to yield L-proline co-crystal of canagliflozin;
(d) converting L-proline co-crystal of canagliflozin to canagliflozin;
In yet another aspect of the present invention, there is provided a process for the preparation of amorphous canagliflozin of formula (I);
comprising the steps of:
(a) providing solution of the canagliflozin into the mixture of ethyl acetate and methanol;
(b) distilling off the solvent till 1.0 to 4.0 volumes of solvent remains behind;
(c) adding methyl tert-butyl ether into the reaction mixture;
(d) adding solution of step (c) into the suitable anti-solvent such as n-heptane;
(e) isolating amorphous canagliflozin.
BRIEF DESCRIPTION OF THE FIGURE
Fig. 1 : depicts the X-ray powder diffraction pattern of amorphous canagliflozin.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of amorphous canagliflozin.
The term "alkyl group" means a straight or branched saturated monovalent hydrocarbon chain having 1 to 12 carbon atoms. The straight chain or branched chain alkyl group having 1 to 6 carbon atoms is preferable, and the straight chain or branched chain alkyl group having 1 to 4 carbon atoms is more preferable. Examples thereof are methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, isobutyl group, pentyl group, hexyl group, isohexyl group, heptyl group, 4,4- dimethylpentyl group, octyl group, 2,2,4-trimethylpentyl group, nonyl group, decyl group, and various branched chain isomers thereof. Further, the alkyl group may optionally substituted.
Analytical Methods:
Powder X-ray diffraction of amorphous canagliflozin can be obtained under following conditions:
XRPD pattern is made using Cu K-al radiation at a voltage 40 niA & 45 kV. XRPD pattern was observed at 25°C and scanned from 3.5 to 40 two theta values.
In the following the process according to this invention are described in detail. The reaction conditions such as reagents, catalysts, solvents and temperature given are meant to provide preferred ranges and examples for the respective transformation that can be principally applied but are not supposed to restrict them to the selection given.
In one aspect of the present invention, there is provided a process for the preparation of amorphous canagliflozin of formula (I)
or a pharmaceutically acceptable salt thereof;
comprising the steps of:
(a) reacting a compound of formula (II) with a compound of formula (III), in the presence of an alkyl lithium; followed by treatment with methane sulfonic acid in methanol; to yield the corresp la (IV);
acid
(II) Methanol
(b) reacting the compound of formula (IV) with trialkylsilane, in the presence of Lewis acid, to yield the corresponding compound of formula (V);
(c) reacting compound of formula (V) with L-proline to yield L-proline co-crystal of canagliflozin;
(d) converting L-proline co-crystal of canagliflozin to canagliflozin;
(e) providing solution of the canagliflozin obtained in step (d) into the mixture of ethyl acetate and methanol;
(f) distilling off the solvent till 1.0 to 4.0 volumes of solvent remains behind;
(g) adding methyl tert-butyl ether into the reaction mixture;
(h) adding solution of step (g) into the suitable anti-solvent such as n-heptane;
(i) isolating amorphous canagliflozin.
Compound of formula (IV) can be prepared by reacting a compound of formula (II) with a compound of formula (III), in the presence of alkyl lithium in an organic solvent; at a temperature in the range of from about -120°C to about -85°C; followed by treatment with methanesulfonic acid in methanol; at lower, ambient, or elevated temperature.
Compound of formula (II) is first reacted with alkyl lithium to yield the corresponding lithiated species, followed by the reaction of the lithiated species with the compound of formula (III) to form protected form of compound. Alkyl lithium may be selected from the group consisting of n-butyl lithium, teri-butyl lithium and hexyl lithium. Organic solvent may be selected from tetrahydrofuran, 2-methyl tetrahydrofuran, heptane, hexane, pentane, methyl tert-butyl ether, dioxane, toluene and the like or a mixture of these solvents. The protected compound is then deprotected by reaction with methane sulfonic acid in methanol to form the compound of formula (IV). In the conventional methods, lithiation reaction may be carried under cryogenic condition (i.e., at a temperature about -78 °C) which provides the lower yield of product. While developing the process of making canagliflozin, the inventors come across the process for lithiation, by minimizing the temperature in the range of from -120°C to about -85°C of lithiation reaction which results higher yield of the product.
The corresponding compound of formula (V) can be prepared by reacting the compound of formula (IV) with trialkylsilanes selected from the group consisting of triethylsilane, triisopropylsilane, poly(methylhydrosiloxane and the like; in the presence of Lewis acid selected from the group consisting of boron trifluoride diethyl ether complex, aluminium chloride, titanium tetrachloride, and the like; in a suitably selected solvent such as acetonitrile, toluene, dichloroethane, dichloromethane, and the like or a mixture of these solvents at lower, ambient, or elevated temperature. Preferably dichloromethane may be used as suitable solvent and reduction reaction may be carried out at temperature from about -40°C to about -20°C.
L-proline co-crystal of canagliflozin may be obtained by adding L-proline into the solution of canagliflozin in the suitable solvents. Suitable solvents that may be used in
step (c) include but are not limited to alcohol, ketone, ester, ether, hydrocarbon, water, nitrile or mixtures thereof in any suitable proportion. Particularly preferred solvents include methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, 2-pentanol, amyl alcohol, acetone, butanone, 2-pentanone, 3-pentanone, methylbutyl ketone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, toluene, xylene, water, methyl tert-butyl ether, ethyl tert-butyl ether, ethyl ether, isopropyl ether or mixtures thereof in any suitable proportion. More preferably dichloromethane may be used as suitable solvent.
The process for the preparation of L-proline co-crystal of canagliflozin is carried out at temperature of room temperature to reflux temperature for few minutes to few hours; preferably reaction mixture is heated at about 35°C to about 40°C for a period of 1-5 hours. The co-crystal of canagliflozin is optionally isolated from the reaction mixture by suitable techniques such as filtration, evaporation, distillation, vacuum drying, centrifugation and the like. The isolated co-crystal of canagliflozin is dried at temperature ranging from room temperature to 80°C, more preferably from about 45°C to about 80°C for a time preferably from 1 hour to 48 hours. The obtained L-proline co-crystal of canagliflozin may be converted to canagliflozin in step (d) by using conventional techniques known in the art. Preferably, canagliflozin may be obtained by adding water into the solution of L-proline co-crystal of canagliflozin in suitable solvent or mixture thereof; at lower, ambient, or elevated temperature. Suitable solvents that may be used include but are not limited to alcohol, ketone, ester, ether, hydrocarbon, nitrile or mixtures thereof in any suitable proportion. Particularly preferred solvents include methanol, ethanol, isopropanol, 2-propanol, 1- butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, acetone, butanone, 2- pentanone, 3-pentanone, methylbutyl ketone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, toluene, xylene, water, methyl tert- butyl ether, ethyl tert-butyl ether, ethyl ether, isopropyl ether or mixtures thereof in any suitable proportion. Preferably dichloromethane, methyl teri-butyl ether or ethyl acetate
may be used as suitable solvent. More preferably L-proline co-crystal of canagliflozin may be converted to canagliflozin by comprising the steps of :
(i) dissolving L-proline co-crystal of canagliflozin in dichloromethane, methyl tert-butyl ether or ethyl acetate;
(ii) adding water into the solution of step (i);
(iii) optionally heating the reaction mixture;
(iv) separating the organic layer;
(v) optionally seeded with previously prepared material & stirring at suitable temperature;
(vi) optionally isolated the product.
The canagliflozin obtained in step (d) is optionally isolated from the reaction mixture by suitable techniques known in the art such as filtration, evaporation, distillation, vacuum drying, centrifugation and the like. Canagliflozin may optionally be further dried. Drying may be suitably carried out in equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperature from about 45°C to about 85°C, optionally under reduced pressure. The canagliflozin obtained in step (d) may be dissolved into the mixture of ethyl acetate and methanol in any suitable proportion. Optionally, the solution obtained in step (e) may be filtered to remove any insoluble particles. The solution may optionally be treated with carbon, hyflow or any other suitable material to remove colour and/or to clarify the solution.
The reaction mixture may be distilled out till 1.0 to 4.0 volumes of solvent remains behind. Optionally, the solution obtained after addition of methyl tert butyl ether in step (g) may be filtered to remove any insoluble particles. The solution may optionally be treated with carbon, hyflow or any other suitable material to remove colour and/or to clarify the solution.
The anti-solvent for step (h) comprises n-hexane, n-heptane, n-pentane, cyclohexane, methylcyclohexane, diethyl ether, diisopropyl ether, dibutyl ether or mixtures thereof in any suitable proportion. More preferably n-heptane may be used as anti-solvent.
The treatment with the antisolvent may be carried out, for example, by adding the solution of canagliflozin into the antisolvent or vice versa at temperature about -30°C to about 50°C, preferably at -10°C to 5°C. The treatment with antisolvent may be followed by stirring the mixture for about 10 minutes to 20 hours, preferably about 1 hour to 2 hours. The stirring may be carried out at about -30°C to about 50°C, preferably at -15°C to 5°C.
The obtained precipitate may be isolated using conventional techniques known in the art. One skilled in the art may appreciate that there are many ways to separate a solid from the mixture, for example it may be separated by using any techniques such as filtration, centrifugation, decantation and the like. After separation, the solid may optionally be washed with a suitable solvent. The amorphous canagliflozin may optionally be further dried. Drying may be suitably carried out in equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperature about 45°C to about 80°C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a product with desired purity such as from about 1 hour to about 25 hours or longer. Amorphous canagliflozin obtained by the process of the invention characterised by an X-ray pattern. The powder XRD pattern of canagliflozin (Fig. 1) obtained by process of the present invention shows product to be in amorphous form. The obtained amorphous canagliflozin is stable during storage and drying. By performing the crystallization process disclosed in present invention, amorphous canagliflozin obtained along with residual solvent levels within the permissible ICH limits, which is suitable for pharmaceutical preparation.
In another aspect of the present invention, there is provided a process for the preparation of canagliflozin of formula (I)
or a pharmaceutically acceptable salt thereof;
comprising the steps of:
(a) reacting a compound of formula (II) with a compound of formula (III), in the presence of an alkyl lithium, wherein alkyl lithium is selected from the group consisting of n-butyl lithium, teri-butyl lithium and hexyl lithium; at a temperature in the range of from about -120°C to about -85°C; followed by treatment with methane sulfonic acid in methanol; to yield the corresp la (IV);
acid
(II) Methanol
(b) reacting the compound of formula (IV) with trialkylsilane, in the presence of Lewis acid, to yield the corresponding compound of formula (V);
(c) reacting compound of formula (V) with L-proline to yield L-proline co-crystal of canagliflozin;
(d) converting L-proline co-crystal of canagliflozin to canagliflozin;
Compound of formula (IV) can be prepared by reacting a compound of formula (II) with a compound of formula (III), in the presence of alkyl lithium in an organic
solvent; at a temperature in the range of from about -120°C to about -85°C; followed by treatment with methanesulfonic acid in methanol; at lower, ambient, or elevated temperature. Compound of formula (II) is first reacted with alkyl lithium to yield the corresponding lithiated species, followed by the reaction of the lithiated species with the compound of formula (III) to form protected form of compound. Alkyl lithium may be selected from the group consisting of n-butyl lithium, teri-butyl lithium and hexyl lithium. Organic solvent may be selected from tetrahydrofuran, 2-methyl tetrahydrofuran, heptane, hexane, pentane, methyl tert-butyl ether, dioxane, toluene and the like or a mixture of these solvents. The protected compound is then deprotected by reaction with methane sulfonic acid in methanol to form the compound of formula (IV). In the conventional methods, lithiation reaction may be carried under cryogenic condition (i.e., at a temperature about -78 °C) which provides the lower yield of product. While developing the process of making canagliflozin, the inventors come across the process for lithiation, by minimizing the temperature in the range of from -120°C to about -85°C of lithiation reaction which results higher yield of the product.
The corresponding compound of formula (V) can be prepared by reacting the compound of formula (IV) with trialkylsilanes selected from the group consisting of triethylsilane, triisopropylsilane, poly(methylhydrosiloxane and the like; in the presence of Lewis acid selected from the group consisting of boron trifluoride diethyl ether complex, aluminium chloride, titanium tetrachloride, and the like; in a suitably selected solvent such as acetonitrile, toluene, dichloroethane, dichloromethane, and the like or a mixture of these solvents at lower, ambient, or elevated temperature. Preferably dichloromethane may be used as suitable solvent and reduction reaction may be carried out at about -40°C to about -20°C.
L-proline co-crystal of canagliflozin may be obtained by adding L-proline into the solution of canagliflozin into the suitable solvents. Suitable solvents that may be used in step (c) include but are not limited to alcohol, ketone, ester, ether, hydrocarbon, water, nitrile or mixtures thereof in any suitable proportion. Particularly preferred solvents
include methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, 2-pentanol, amyl alcohol, acetone, butanone, 2-pentanone, 3-pentanone, methylbutyl ketone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, toluene, xylene, water, methyl tert-butyl ether, ethyl tert-butyl ether, ethyl ether, isopropyl ether or mixtures thereof in any suitable proportion. More preferably dichloromethane may be used as suitable solvent.
The process for the preparation of L-proline co-crystal of canagliflozin is carried out at temperature of room temperature to reflux temperature for few minutes to few hours; preferably reaction mixture is heated at temperature from about 35°C to about 40°C for a period of 1 hour to 5 hours. The co-crystal of canagliflozin is optionally isolated from the reaction mixture by suitable techniques such as filtration, evaporation, distillation, vacuum drying, centrifugation and the like. The isolated co-crystal of canagliflozin is dried at temperature ranging from room temperature to about 80°C, more preferably from about 45°C to about 80°C for a time preferably from 1 hour to 48 hours.
The obtained L-proline co-crystal of canagliflozin may be converted to canagliflozin in step (d) by using conventional techniques known in the art. Preferably, canagliflozin may be obtained by adding water into the solution of L-proline co-crystal of canagliflozin in suitable solvent or mixture thereof; at lower, ambient, or elevated temperature. Suitable solvents that may be used include but are not limited to alcohol, ketone, ester, ether, hydrocarbon, nitrile or mixtures thereof in any suitable proportion. Particularly preferred solvents include methanol, ethanol, isopropanol, 2-propanol, 1- butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, acetone, butanone, 2- pentanone, 3-pentanone, methylbutyl ketone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, toluene, xylene, water, methyl tert- butyl ether, ethyl tert-butyl ether, ethyl ether, isopropyl ether or mixtures thereof in any suitable proportion. Preferably dichloromethane, methyl teri-butyl ether or ethyl acetate may be used as suitable solvent. More preferably L-proline co-crystal of canagliflozin may be converted into canagliflozin by comprising the steps of :
(i) dissolving L-proline co-crystal of canagliflozin in dichloromethane, methyl tert-butyl ether or ethyl acetate;
(ii) adding water into the solution of step (i);
(iii) optionally heating the reaction mixture;
(iv) separating the organic layer;
(v) optionally seeded with previously prepared material & stirring at suitable temperature;
(vi) optionally isolated the product. The canagliflozin obtained in step (d) may be isolated using conventional techniques known in the art. One skilled in the art may appreciate that there are many ways to separate a solid from the mixture, for example it may be separated by using any techniques such as filtration, centrifugation, decantation and the like. After separation, the solid may optionally be washed with a suitable solvent. The canagliflozin may optionally be further dried. Drying may be suitably carried out in equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperature from about 45 °C to about 80 °C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a product with desired purity such as from about 1 hour to about 25 hours or longer.
In yet another aspect of the present invention, there is provided a process for the preparation of amorphous canagliflozin comprising the steps of:
(a) providing solution of the canagliflozin into the mixture of ethyl acetate and methanol;
(b) distilling off the solvent till 1.0 to 4.0 volumes of solvent remains behind;
(c) adding methyl tert-butyl ether into the reaction mixture;
(d) adding solution of step (c) into the suitable anti-solvent such as n-heptane;
(e) isolating amorphous canagliflozin.
Any physical form of canagliflozin that may be utilized for providing the solution of canagliflozin in step (a). Canagliflozin that may be used as the input for the process of
the present invention may be obtained by any process including the process described in the art.
The canagliflozin may be dissolved in the mixture of ethyl acetate and methanol in any suitable proportion. Optionally, the solution obtained in step (a) may be filtered to remove any insoluble particles. The solution may optionally be treated with carbon, hyflow or any other suitable material to remove colour and/or to clarify the solution.
The reaction mixture may be distilled out till 1.0 to 4.0 volumes of solvent remains behind. Optionally, the solution obtained after addition of methyl tert butyl ether in step (c) may be filtered to remove any insoluble particles. The solution may optionally be treated with carbon, hyflow or any other suitable material to remove colour and/or to clarify the solution. The anti-solvent for step (d) comprises n-hexane, n-heptane, n-pentane, cyclohexane, methylcyclohexane, diethyl ether, diisopropyl ether, dibutyl ether or mixtures thereof in any suitable proportion. More preferably n-heptane may be used as anti-solvent. The treatment with the antisolvent may be carried out, for example, by adding the solution of canagliflozin into the antisolvent or vice versa at temperature about -30°C to about 50°C, preferably at -10°C to 5°C. The treatment with antisolvent may be followed by stirring the mixture for about 10 minutes to 20 hours, preferably about 1 hour to 2 hours. The stirring may be carried out at about -30°C to about 50°C, preferably at -15°C to 5°C.
The obtained precipitate may be isolated using conventional techniques known in the art. One skilled in the art may appreciate that there are many ways to separate a solid from the mixture, for example it may be separated by using any techniques such as filtration, centrifugation, decantation and the like. After separation, the solid may optionally be washed with a suitable solvent. The amorphous canagliflozin may optionally be further dried. Drying may be suitably carried out in equipment such as tray
dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperature about 45°C to about 80°C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a product with desired purity such as from about 1 hour to about 25 hours or longer.
The amorphous canagliflozin obtained by the process of the invention characterised by an X-ray pattern. The powder XRD pattern of canagliflozin (Fig. 1) obtained by process of the present invention shows product to be in amorphous form. The obtained amorphous canagliflozin is stable during storage and drying. By performing the crystallization process disclosed in present invention, amorphous canagliflozin obtained along with residual solvent levels within the permissible ICH limits, which is suitable for pharmaceutical preparation. In yet another aspect of the present invention, there is provided a process for the preparation of amorphous canagliflozin of formula (I) comprising the steps of:
(a) providing solution of crude canagliflozin in suitable solvent or mixture thereof;
(b) preparation of L-proline co-crystal of canagliflozin by adding L-proline;
(c) converting L-proline co-crystal of canagliflozin to canagliflozin;
(d) providing solution of the canagliflozin obtained in step (c) into the mixture of ethyl acetate and methanol;
(e) distilling off the solvent till 1.0 to 4.0 volumes of solvent remains behind;
(f) adding methyl tert-butyl ether into the reaction mixture;
(g) adding solution of step (f) into the suitable anti-solvent such as n-heptane; (h) isolating amorphous canagliflozin.
In yet another aspect of the present invention, there is provided a process for the preparation of amorphous canagliflozin of formula (I)
comprising the steps of:
(a) reacting a compound of formula (II) with a compound of formula (III), in the presence of an alkyl lithium; followed by treatment with methane sulfonic acid in
(c) reacting crude compound of formula (V) with L-proline to yield L-proline co- crystal of canagliflozin;
(d) converting L-proline co-crystal of canagliflozin to canagliflozin;
(e) providing solution of canagliflozin obtained in step (d) in suitable solvent or mixture thereof;
(f) treating the solution of step (e) with an antisolvent;
(g) isolating amorphous canagliflozin.
Compound of formula (IV) can be prepared by reacting a compound of formula (II) with a compound of formula (III), in the presence of alkyl lithium in an organic solvent; at a temperature in the range of from about -120°C to about -85°C; followed by treatment with methanesulfonic acid in methanol; at lower, ambient, or elevated temperature.
Compound of formula (II) is first reacted with alkyl lithium to yield the corresponding lithiated species, followed by the reaction of the lithiated species with the compound of formula (III) to form protected form of compound. Alkyl lithium may be selected from the group consisting of n-butyl lithium, teri-butyl lithium and hexyl lithium. Organic solvent may be selected from tetrahydrofuran, 2-methyl tetrahydrofuran, heptane, hexane, pentane, Methyl tert-butyl ether, dioxane, toluene and the like or a mixture of these solvents. The protected compound is then deprotected by reaction with methane sulfonic acid in methanol to form the compound of formula (IV). In the conventional methods, lithiation reaction may be carried under cryogenic condition (i.e., at a temperature about -78 °C) which provides the lower yield of product. While developing the process of making canagliflozin, the inventors come across the process for lithiation, by minimizing the temperature in the range of from -120°C to about -85°C of lithiation reaction which results higher yield of the product. The corresponding compound of formula (V) can be prepared by reacting the compound of formula (IV) with trialkylsilanes selected from the group consisting of triethylsilane, triisopropylsilane, poly(methylhydrosiloxane and the like; in the presence of Lewis acid selected from the group consisting of boron trifluoride diethyl ether complex, aluminium chloride, titanium tetrachloride, and the like; in a suitably selected solvent such as acetonitrile, toluene, dichloroethane, dichloromethane, and the like or a mixture of these solvents at lower, ambient, or elevated temperature. Preferably dichloromethane may be used as suitable solvent and reduction reaction may be carried out at temperature from about -40°C to about -20°C. L-proline co-crystal of canagliflozin may be obtained by adding L-proline into the solution of canagliflozin in suitable solvents. Suitable solvents that may be used in step (c) include but are not limited to alcohol, ketone, ester, ether, hydrocarbon, water, nitrile or mixtures thereof in any suitable proportion. Particularly preferred solvents include methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2- pentanol, amyl alcohol, acetone, butanone, 2-pentanone, 3-pentanone, methylbutyl ketone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride,
acetonitrile, toluene, xylene, water, methyl tert-butyl ether, ethyl tert-butyl ether, ethyl ether, isopropyl ether or mixtures thereof in any suitable proportion. More preferably dichloromethane may be used as suitable solvent. The process for the preparation of L-proline co-crystal of canagliflozin is carried out at temperature of room temperature to reflux temperature for few minutes to few hours; preferably reaction mixture is heated at temperature from 35°C to 40°C for a period of 1 to 5 hours. The co-crystal of canagliflozin is optionally isolated from the reaction mixture by suitable techniques such as filtration, evaporation, distillation, vacuum drying, centrifugation and the like. The isolated co-crystal of canagliflozin is dried at temperature ranging from room temperature to 80°C, more preferably at temperature from about 45°C to about 80°C for a time preferably from 1 hour to 48 hours.
The obtained L-proline co-crystal of canagliflozin may be converted to canagliflozin in step (d) by using conventional techniques known in the art. Preferably, canagliflozin may be obtained by adding water into the solution of L-proline co-crystal of canagliflozin in suitable solvent or mixture thereof; at lower, ambient, or elevated temperature. Suitable solvents that may be used include but are not limited to alcohol, ketone, ester, ether, hydrocarbon, nitrile or mixtures thereof in any suitable proportion. Particularly preferred solvents include methanol, ethanol, isopropanol, 2-propanol, 1- butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, acetone, butanone, 2- pentanone, 3-pentanone, methylbutyl ketone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, toluene, xylene, water, methyl tert- butyl ether, ethyl tert-butyl ether, ethyl ether, isopropyl ether or mixtures thereof in any suitable proportion. More preferably dichloromethane, methyl teri-butyl ether or ethyl acetate may be used as suitable solvent.
The canagliflozin obtained in step (d) is optionally isolated from the reaction mixture by suitable techniques known in the art such as filtration, evaporation, distillation, vacuum drying, centrifugation and the like. Canagliflozin may optionally be further dried. Drying may be suitably carried out in equipment such as tray dryer, vacuum
oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperature about 45 °C to about 85°C, optionally under reduced pressure. Providing a solution of canagliflozin in step (e) includes:
(i) direct use of reaction mixture containing canagliflozin that is obtained during its synthesis in step (d); or
(ii) dissolving canagliflozin obtained in step (d) in suitable solvent or mixtures thereof.
Suitable solvents that may be used in step (e) include but are not limited to alcohol, hydrocarbon, ketone, ester, ether, hydrocarbon, nitrile or mixtures thereof in any suitable proportion. Particularly preferred solvents include methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3-pentanone, methylbutyl ketone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, toluene, xylene, dichloromethane, ethylene dichloride, chlorobenzene, acetonitrile, tetrahydrofuran, methyl tert-butyl ether, ethyl tert-butyl ether, ethyl ether, isopropyl ether, 1 ,2-dimethoxy ethane or mixtures thereof in any suitable proportion. More preferably ethyl acetate, methyl teri-butyl ether (MTBE), methanol or mixtures thereof may be used in any suitable proportion. The solution may optionally be treated with carbon, hyflow or any other suitable material to remove colour and/or to clarify the solution. The anti-solvent for step (f) comprises n-hexane, n-heptane, n-pentane, cyclohexane, methylcyclohexane, diethyl ether, diisopropyl ether, dibutyl ether or mixtures thereof in any suitable proportion. More preferably n-heptane may be used as anti-solvent. The treatment with the antisolvent may be carried out, for example, by adding the solution of canagliflozin into the antisolvent or vice versa at temperature about -30°C to about 50°C, preferably at -10°C to 5°C. The treatment with antisolvent may be followed
by stirring the mixture for about 10 minutes to 20 hours, preferably about 1 to 2 hours. The stirring may be carried out at about -30°C to 50°C, preferably at -15°C to 5°C.
The obtained precipitate may be isolated using conventional techniques known in the art. One skilled in the art may appreciate that there are many ways to separate a solid from the mixture, for example it may be separated by using any techniques such as filtration, centrifugation, decantation and the like. After separation, the solid may optionally be washed with a suitable solvent. The amorphous canagliflozin may optionally be further dried. Drying may be suitably carried out in equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperature about 45°C to about 80°C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a product with desired purity such as from about 1 hour to about 25 hours or longer.
Amorphous canagliflozin obtained by the process of the invention characterised by an X-ray pattern. The powder XRD pattern of canagliflozin (Fig. 1) obtained by process of the present invention shows product to be in amorphous form. The obtained amorphous canagliflozin is stable during storage and drying. By performing the crystallization process disclosed in present invention, amorphous canagliflozin obtained along with residual solvent levels within the permissible ICH limits, which is suitable for pharmaceutical preparation.
In an aspect of the present invention, amorphous canagliflozin prepared according to the processes of the present invention can be substantially pure having a chemical purity greater than about 99% or greater than about 99.5% by weight as determined using high performance liquid chromatography.
In an aspect of the present invention, canagliflozin prepared according to the processes of the present invention can be substantially pure having a chemical purity greater than about 99% or greater than about 99.5% by weight as determined using high performance liquid chromatography.
One skilled in the art will recognize that additional starting compounds and/or reagents are commercially available or may be easily prepared according to conventional methods well known to these skilled in the art.
EXAMPLES
Following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be interpreted as a limitation thereon. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention.
Example 1
2,3,4,6-Tetra-0-trimethylsilyl- -D-glucolactone
Solution of D-gluconolactone (1 kg) and N-Methylmorpholine (5.50 kg) in tetrahydrofuran (10 L) was cooled to -10°C. Trimethylsilyl chloride (3.63 kg) was added to the reaction mixture. After stirring for 1 hour, the mixture was heated to 40°C-45°C for 5 hours whereupon it was allowed to cool to 0°C. After dilution with toluene, water was slowly added. The layers were separated and the organic phases washed with aqueous potassium dihydrogen phosphate solution followed by water. The organic layer was dried over sodium sulphate and after concentration to yield oily residue (Yield: 95.41%).
Example 2
Preparation of L-proline co-crystal of canagliflozin
Hexyl lithium (0.50 kg, 0.0054 mol) was slowly added to a stirred solution of 2- (5-bromo-2-methyl-benzyl)-5-(4-fluorophenyl)-thiophene (1 kg, 0.0027 mol) in tetrahydrofuran (12 L) and toluene (12 L) at -70°C to -65 °C. After stirring for 45 minutes at same temperature, solution of 2,3,4,6-tetra-0-trimethylsilyl- -D-glucolactone (2 kg, 0.0042 mol) in toluene (3 L) was slowly added by maintaining the reaction at -70°C to - 65 °C and mixture was stirred for 2 hours at same temperature. Subsequently, a solution of methane sulfonic acid (0.80 kg, 0.0083 mol) in methanol (5 L) was added to the reaction mixture at -70°C to -65 °C and stirred for 1 hour. The reaction mixture was further stirred for 2 hours at room temperature. Water was added to the resultant mixture followed by
addition of 30% aqueous Na2CC>3 solution. After phase separation, the organic layer was washed with brine solution, and after concentration to yield oily residue.
The obtained oily mass was added into dichloromethane (10 L) and resultant mass was stirred under nitrogen atmosphere at room temperature. The reaction mixture was cooled at -30°C. To this stirred solution was added triethylsilane (0.62 kg, 0.0053 mol) followed by addition of BF3Et20 (0.896 kg, 0.0063 mol). Approximately 30 minutes after addition was complete, the resulting mixture was stirred at room temperature. After completion of reaction, the mixture was cooled at 0°C and further quenched by the addition of aqueous NaHCC>3 solution. After phase separation, L-proline (0.30 kg; 0.0026 mol) was added into the organic layer containing product. The reaction mixture was heated at 40°C for 1 hour. The reaction mixture was cooled at room temperature and further stirred for 1 hour. The resultant precipitate was filtered and dried. (Yield: 38.70 %). Example 3
Preparation of L-proline co-crystal of Canagliflozin
Hexyl lithium (0.50 kg, 0.0054 mol) was slowly added to a stirred solution of 2- (5-bromo-2-methyl-benzyl)-5-(4-fluorophenyl)-thiophene (1 kg, 0.0027 mol) in tetrahydrofuran (12 L) and toluene (12 L) at -100°C to -90°C. After stirring for 45 minutes at same temperature, solution of 2,3,4,6-tetra-0-trimethylsilyl- -D-glucolactone (2 kg, 0.0042 mol) in toluene (3 L) was slowly added by maintaining the reaction at -100 to -90°C and mixture was stirred for 2 hours at same temperature. Subsequently, a solution of methane sulfonic acid (0.80 kg, 0.0083 mol) in methanol (5 L) was added to the reaction mixture at -100°C to -90°C and stirred for 1 hour. The reaction mixture was further stirred for 2 hours at room temperature. Water was added to the resultant mixture followed by addition of 30% aqueous Na2CC>3 solution. After phase separation, the organic layer was washed with brine solution, and after concentration to yield oily residue.
The obtained oily mass was added into dichloromethane (10 L) and resultant mass was stirred under nitrogen atmosphere at room temperature. The reaction mixture was cooled at -30°C. To this stirred solution was added triethylsilane (0.62 kg, 0.0053 mol) followed by addition of BF3Et20 (0.896 kg, 0.0063 mol). Approximately 30 minutes after
addition was complete, the resulting mixture was stirred at room temperature. After completion of reaction, the mixture was cooled at 0°C and further quenched by the addition of aqueous NaHCC>3 solution. After phase separation, L-proline (0.30 kg; 0.0026 mol) was added into the organic layer containing product. The reaction mixture was heated at 40°C for 1 hour. The reaction mixture was cooled at room temperature and further stirred for 1 hour. The resultant precipitate was filtered and dried. (Yield: 54.80 %).
Example 4
Preparation of canagliflozin
To a stirred solution of L-proline co-crystal of canagliflozin (1 kg; 0.00178 mol) in dichloromethane (5 L) was added water (2 L). The reaction mixture was heated at 35°C for 30 minutes. The reaction mixture was further cooled to room temperature and stirred for 30 minutes. After phase separation, the organic layer was stirred at 20°C-30°C for overnight. The resultant precipitate was filtered, and dried to yield title compound.
Example 5
Preparation of amorphous canagliflozin
Canagliflozin (700 gm) was dissolved in ethyl acetate (5.6 L) and methanol (0.35 L). The resultant solution was stirred at room temperature for 1 hr. Reaction mixture was distilled out till 1.0 to 4.0 volumes of solvent remains behind. Methyl teri-butyl ether (2.8 L) was added to the above solution and resultant solution was filtered through micron filter. The resultant solution was added slowly to the pre-chilled solution of n-heptane (10.5 L) at -10°C and stirring was continued at same temperature. The solid precipitated was filtered and dried to obtain amorphous canagliflozin (yield: 88.6%).
Example 6
Preparation of canagliflozin
To a stirred solution of L-proline co-crystal of canagliflozin (5 gm) in methyl tert- butyl ether (30 ml) was added water (15 ml). The reaction mixture was stirred at room temperature for 1 hour. After phase separation, the organic layer was further stirred at
room temperature for 2 hours. The resultant precipitate was filtered, and dried to yield title compound.
Example 7
Preparation of canagliflozin
To a stirred solution of L-proline co-crystal of canagliflozin (5 gm) in ethyl acetate (30 ml) was added water (15 ml). The reaction mixture was stirred at room temperature for 1 hr. After phase separation, the organic layer was further stirred at room temperature for 2 hr. The resultant precipitate was filtered, and dried to yield title compound.
Claims
1. A process for the prepar formula (I)
or a pharmaceutically acceptable salt thereof;
comprising the steps of:
(a) reacting a compound of formula (II) with a compound of formula (III), in the presence of an alkyl lithium; followed by treatment with methane sulfonic acid in methanol; to yield the corresponding compound of formula (IV);
(c) reacting compound of formula (V) with L-proline to yield L-proline co-crystal of canagliflozin;
(d) converting L-proline co-crystal of canagliflozin to canagliflozin;
(e) providing solution of the canagliflozin obtained in step (d) into the mixture of ethyl acetate and methanol;
(f) distilling off the solvent till 1.0 to 4.0 volumes of solvent remains behind;
(g) adding methyl teri-butyl ether into the reaction mixture;
(h) adding solution of step (g) into the suitable anti-solvent such as n-heptane;
(i) isolating amorphous canagliflozin.
2. The process according to claim 1, wherein alkyl lithium is selected from the group consisting of n-butyl lithium, teri-butyl lithium and hexyl lithium.
3. The process according to claim 1, wherein the lithiation reaction in step (a) is conducted at a temperature in the range of from about -120°C to about -85°C; in suitable solvent such as tetrahydrofuran, toluene or mixture thereof.
4. The process according to claim 1, wherein trialkylsilane is selected from the group consisting of triethylsilane, triisopropylsilane and poly(methylhydrosiloxane); and wherein the Lewis acid is selected from the group consisting of boron trifluoride diethyl ether complex, aluminium chloride, and titanium tetrachloride.
5. The process according to claim 4, wherein trialkylsilane is triethylsilane and Lewis acid is boron trifluoride diethyl ether complex.
6. The process according to claim 1, wherein reaction in step (c) is carried out in dichloromethane.
7. The process according to claim 1, wherein reaction in step (d) is carried out by adding water into the solution of L-proline co-crystal of canagliflozin in dichloromethane, methyl teri-butyl ether or ethyl acetate.
8. A process for the prepar
or a pharmaceutically acceptable salt thereof;
comprising the steps of:
(a) reacting a compound of formula (II) with a compound of formula (III), in the presence of an alkyl lithium, wherein alkyl lithium is selected from the group consisting of n-butyl lithium, teri-butyl lithium and hexyl lithium; at a temperature in the range of from about -120°C to about -85°C; followed by treatment with methane sulfonic acid in
(c) reacting compound of formula (V) with L-proline to yield L-proline co-crystal of canagliflozin;
(d) converting L-proline co-crystal of canagliflozin to canagliflozin;
9. The process according to claim 8, wherein the lithiation reaction in step (a) is conducted in suitable solvent such as tetrahydrofuran, toluene or mixture thereof.
10. The process according to claim 8 wherein trialkylsilane is selected from the group consisting of triethylsilane, triisopropylsilane and poly(methylhydrosiloxane); and wherein the Lewis acid is selected from the group consisting of boron trifluoride diethyl ether complex, aluminium chloride, and titanium tetrachloride.
11. The process according to claim 10, wherein trialkylsilane is triethylsilane and Lewis acid is boron trifluoride diethyl ether complex.
12. The process according to claim 8, wherein reaction in step (c) is carried out in dichloromethane.
13. The process according to claim 8, wherein reaction in step (d) is carried out by adding water into the solution of L-proline co-crystal of canagliflozin in dichloromethane, methyl teri-butyl ether or ethyl acetate.
14. A process for the preparation of amorphous canagliflozin
comprising the steps of:
(a) providing solution of the canagliflozin into the mixture of ethyl acetate and methanol;
(b) distilling off the solvent till 1.0 to 4.0 volumes of solvent remains behind;
(c) adding methyl teri-butyl ether into the reaction mixture;
(d) adding solution of step (c) into the suitable anti-solvent such as n-heptane;
(e) isolating amorphous canagliflozin.
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CN109336875A (en) * | 2017-08-15 | 2019-02-15 | 江苏工程职业技术学院 | A kind of synthetic method of canagliflozin |
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