DESC:FIELD OF THE INVENTION
The invention is directed to a process for the preparation of canagliflozin. The invention further comprises novel intermediate compounds and method of preparing the same, which are useful in the preparation of canagliflozin. The invention is further directed to a process for the preparation of amorphous form 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 transporter which is chemically represented as (1S)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate having structural formula

US patent No. 7,943,788 (B2) discloses canagliflozin or a pharmaceutically acceptable salt, or a stereoisomer thereof or a prodrug thereof.

A variety of processes for the preparation of canagliflozin have been disclosed in the prior art. US patent No. 7,943,788 (B2) describes the process for the synthesis of canagliflozin which is schematically mentioned below:

The process for the preparation of canagliflozin is disclosed in US 9,024,009 represented by scheme below:

US 2013/0237487 (A1) discloses a process for preparation of amorphous canagliflozin by adding heated solution of canagliflozin in toluene into n-heptane. WO 2014/195966 (A2) discloses stable amorphous form of canagliflozin and its process.

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 environmentally friendly crystallization process for the preparation of amorphous canagliflozin and consequently a product obtained from this process lacking residual solvents is highly desirable.

In view of the problem in commercialization of process, there is a need for simple, cost effective, commercially feasible, industrially scalable and environmentally friendly process for the preparation of canagliflozin, its intermediates and the amorphous form of canagliflozin.

SUMMARY OF THE INVENTION
The invention is directed to a process for the preparation of canagliflozin.

The invention further comprises novel intermediate compounds and method of preparing the same, which are useful in the preparation of canagliflozin.

The invention is further directed to a process for the preparation of amorphous form of canagliflozin.

In one aspect of the present invention, there is provided a process for the preparation of canagliflozin of formula (I)

or a pharmaceutically acceptable salt, or a prodrug thereof;
comprising the steps of:
(a) reacting a compound of formula (II), wherein R1 is bromo or iodo; with a compound of formula (III) in the presence of alkyl lithium followed by treatment with an alcohol of formula (IV), wherein R2 is lower alkyl; in the presence of an acid to yield the corresponding compound of formula (V);

(b) reacting the compound of formula (V) with silane reagent in the presence of acid to yield the corresponding compound of formula (VI);

(c) protecting the hydroxyl group on the compound of formula (VI) to yield the corresponding compound of formula (VII), wherein P is oxygen protecting group;

(d) removing the protecting group from the compound of formula (VII) to yield the compound of formula (I);

In another aspect of the present invention, there are provided novel intermediate compounds of formula (VII)

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;
wherein,
P is oxygen protecting group selected from the group consisting of propanoyl, isopropanoyl, butanoyl, isobutanoyl, isovaleryl and valeryl;

Yet another aspect of the invention relates to the use of compound of formula (VII), or any salt thereof as an adduct or intermediates in a method of producing the compound of formula (I).

In yet another aspect of the present invention, there is provided a process for the preparation of amorphous form of canagliflozin comprising the steps of
(i) providing solution of canagliflozin;
(ii) treating the solution of step (i) with an antisolvent; and
(iii) isolating amorphous form of canagliflozin.

In an embodiment, the present invention is directed to a process for the preparation of canagliflozin of formula (I)

or a pharmaceutically acceptable salt, or a prodrug thereof;
comprising the steps of:
(a) reacting a compound of formula (IIa) with a compound of formula (III) in the presence of alkyl lithium such as n-butyl lithium, tert-butyl lithium or hexyl lithium followed by treatment with methanol; in the presence of acid to yield the corresponding compound of formula (Va);

(b) reacting the compound of formula (Va) with trialkylsilane in the presence of Lewis acid to yield the corresponding compound of formula (VI);

(c) protecting the hydroxyl group on the compound of formula (VI) to yield the corresponding compound of formula (VII), wherein P is oxygen protecting group selected from the group consisting of propanoyl, isopropanoyl, butanoyl, isobutanoyl, isovaleryl and valeryl;

(d) removing the protecting group from the compound of formula (VII) to yield the compound of formula (I);

In another embodiment, the present invention is directed to a process for the preparation of amorphous form of canagliflozin comprising the steps of:
(i) providing solution of canagliflozin in the mixture of ethyl acetate and methyl tert-butyl ether (MTBE);
(ii) adding solution of step (i) into n-heptane;
(iii) isolating amorphous form of canagliflozin.

In yet another embodiment, the present invention is directed to a process for the preparation of amorphous form of canagliflozin comprising the steps of
(a) reacting a compound of formula (IIa) with a compound of formula (III) in the presence of alkyl lithium such as n-butyl lithium, tert-butyl lithium or hexyl lithium followed by treatment with methanol; in the presence of methane sulfonic acid to yield the corresponding compound of formula (Va);

(b) reacting the compound of formula (Va) with trialkylsilane in the presence of Lewis acid to yield the corresponding compound of formula (VI);

(c) protecting the hydroxyl group on the compound of formula (VI) to yield the corresponding compound of formula (VII), wherein P is oxygen protecting group selected from the group consisting of propanoyl, isopropanoyl, butanoyl, isobutanoyl, isovaleryl and valeryl.

(d) removing the protecting group from the compound of formula (VII) to yield the compound of formula (I);

(e) providing solution of canagliflozin of formula (I) in the mixture of ethyl acetate and methyl tert-butyl ether (MTBE);
(f) adding solution of step (e) into n-heptane;
(g) isolating amorphous form of canagliflozin.

BRIEF DESCRIPTION OF THE FIGURE
FIG. 1: depicts the X-ray powder diffraction pattern of the amorphous form of canagliflozin

DETAILED DESCRIPTION OF THE INVENTION
The invention is directed to a process for the preparation of canagliflozin of formula (I)

or a pharmaceutically acceptable salt, or a prodrug thereof;

The invention further comprises novel intermediate compounds and method of preparing the same, which are useful in the preparation of canagliflozin.

The invention is further directed to a process for the preparation of amorphous form of 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.

As used herein, unless otherwise noted, the term "oxygen protecting group" shall mean a group which may be attached to a oxygen atom to protect said oxygen atom from participating in a reaction and which may be readily removed following the reaction. Suitable examples of the oxygen protecting groups include alkanoyl {for e.g., propanoyl, isopropanoyl, butanoyl, isobutanoyl, isovaleryl and valeryl and the like}, arylalkyl (such as benzyl, tolyl, anisyl, and the like), alkylsilyl (such as trimethylsilyl, t-butyldimethylsilyl, triethylsilyl, and the like). Further, the oxygen protecting group may form acetal or silylacetal together with adjacent hydroxyl group(s). Examples of such protecting groups include alkylidene such as isopropylidene, s-butylidene, benzylidene, or dialkylsilylene such as di-tert-butylsilylene. Other suitable oxygen protecting groups may be found in texts such as T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

Powder X-ray diffraction of amorphous canagliflozin can be obtained under following conditions:
XRPD pattern is made using Cu K-a1 radiation at a voltage 40 mA & 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.

The invention is directed to a process for the preparation of compounds of formula (I) as outlined in scheme 1 given below.

Scheme 1
Compound of formula (V) can be prepared by reacting a compound of formula (II), wherein R1 is bromo or iodo; with a compound of formula (III) in the presence of alkyl lithium (for e.g., n-butyl lithium, tert-butyl lithium or hexyl lithium) in an organic solvent at a temperature in the range of from 0°C to -120°C; followed by treatment with a suitably substituted alcohol of formula (IV), wherein R2 is lower alkyl, preferably with methanol, ethanol, n-propanol, i-propanol, n-butanol, and the like; in the presence of a suitably selected acid such as an inorganic acid (for e.g., hydrochloric acid, nitric acid, sulfuric acid, and the like), or an organic acid (for e.g., p-toluenesulfonic acid, methanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, and the like); at lower, ambient, or elevated temperature. Organic solvent is selected from tetrahydrofuran (THF), 2-methyl THF, heptane, hexane, pentane, methyl tert-butyl ether (MTBE), dioxane, toluene and the like or a mixture of these solvents.

The corresponding compound of formula (VI) can be prepared by reacting the compound of formula (V) with a suitably selected silane reagent such as a trialkylsilanes (for e.g., triethylsilane, triisopropylsilane, and the like) or a polyalkyl silanes (for e.g., poly(methylhydrosiloxane), and the like); in the presence of a suitably selected acid, such as Lewis acid (for e.g., boron trifluoride diethyl ether complex, aluminum chloride, titanium tetrachloride, and the like), or organic acids (for e.g., trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, and the like); in a suitably selected solvent such as acetonitrile, toluene, dichloroethane, dichloromethane, and the like or a mixture of these solvents.

The compound of formula (VI) is protected according to known methods, to yield the corresponding compound of formula (VII), wherein each P is a suitably selected oxygen protecting group. The protection may be carried out with conventional methods well known to those skilled in the art. The protection reaction may be carried out at lower, ambient, or elevated temperature. Preferably, the reaction is carried out at a temperature in the range of from about -10°C to about 100°C. Protecting group is selected from those conventionally used as oxygen protecting groups. The protection is carried out in the presence of an organic base such as N-methylmorpholine (NMM), N,N diisopropylethyl amine, triethyl amine, pyridine, and the like; optionally in the presence of a catalyst such as 4-dimethylaminopyridine (DMAP), and the like; neat or in an organic solvent such as dichloromethane (DCM), methanol, tetrahydrofuran (THF), acetonitrile, and the like or a mixture of these solvents.

The compound of formula (VII) is de-protected according to known methods such as reduction, hydrolysis, acid treatment, or fluoride treatment, preferably by hydrolysis to yield the corresponding compound of formula (I). More particularly, the compound of formula (VII) is de-protected by treating with a suitably selected base; such as an alkali metal hydroxides (for e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, NaOCH3 and the like), or an alkali metal alkoxide (for e.g., sodium methoxide, sodium ethoxide, and the like); in a suitably selected solvent such as an ether (for e.g., tetrahydrofuran, dioxane, and the like), alcohol (for e.g., methanol, ethanol, and the like), water, or a mixture of these solvents. Deprotection reaction can be carried out at lower, ambient, or elevated temperature.

In an embodiment, the invention is directed to a process for the preparation of canagliflozin of formula (I), as outlined in scheme 2 given below.

Scheme 2

Compound of formula (Va) can be prepared by reacting a compound of formula (IIa) with a compound of formula (III) in the presence of alkyl lithium in an organic solvent at a temperature in the range of from 0°C to -120°C; followed by treatment with methanol; in the presence of a suitably selected acid such as an inorganic acid (for e.g., hydrochloric acid, nitric acid, sulfuric acid, and the like), or an organic acid such as, p-toluenesulfonic acid, methanesulfonic acid, formic acid, acetic acid and trifluoroacetic acid, and the like; at lower, ambient, or elevated temperature.

Compound of formula (IIa) 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). Alkyl lithium may be selected from n-butyl lithium, n-hexyl lithium, tert-butyl lithium and the like. Organic solvent may be selected from THF, 2-methyl THF, heptane, hexane, pentane, MTBE, dioxane, toluene and the like or a mixture of these solvents.

The corresponding compound of formula (VI) can be prepared by reacting the compound of formula (Va) with a suitably selected trialkylsilanes such as triethylsilane, triisopropylsilane, and the like; in the presence of a suitably selected Lewis acid such as 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.

The compound of formula (VI) is protected according to known methods, to yield the corresponding compound of formula (VII), wherein each P is oxygen protecting group such as of propanoyl, isopropanoyl, butanoyl, isobutanoyl, isovaleryl, valeryl and the like. The protection may be carried out with conventional methods well known to those skilled in the art. The protection reaction may be carried out at lower, ambient, or elevated temperature. Preferably, the reaction is carried out at a temperature in the range of from about -10°C to about 100°C. The protection is carried out in the presence of an organic base such as N-methylmorpholine, N,N diisopropylethyl amine, triethyl amine, pyridine, and the like; optionally in the presence of a catalyst such as 4-dimethylaminopyridine, and the like; neat or in an organic solvent such as DCM, methanol, THF, acetonitrile, and the like or a mixture of these solvents.

The compound of formula (VII) is de-protected according to known methods such as reduction, hydrolysis, acid treatment, or fluoride treatment preferably by hydrolysis to yield the corresponding compound of formula (I). More particularly, the compound of formula (VII) is de-protected by treating with a suitably selected base; such as an alkali metal hydroxides (for e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, NaOCH3 and the like), or an alkali metal alkoxide (for e.g., sodium methoxide, sodium ethoxide, and the like); in a suitably selected solvent such as an ether (for e.g., tetrahydrofuran, dioxane, and the like), alcohol (for e.g., methanol, ethanol, and the like), water, DCM, or a mixture of these solvents. Deprotection reaction can be carried out at lower, ambient, or elevated temperature.

In yet another aspect of the present invention, there is provided a process for the preparation of amorphous form of canagliflozin comprising the steps of
(i) providing solution of canagliflozin;
(ii) treating the solution of step (i) with an antisolvent; and
(iii) isolating amorphous form of canagliflozin.
Providing solution of canagliflozin in step (i) can be obtained by:
• direct use of reaction mixture containing canagliflozin that is obtained during its synthesis; or
• dissolving canagliflozin in suitable solvent.

Suitable solvents that may be used in step (d) include but are not limited to alcohol, ketone, ester, ether, hydrocarbon, acetonitrile, 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, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, acetonitrile, tetrahydrofuran, methyltert-butyl ether, ethyl tert-butyl ether, 1,2-dimethoxy ethane and the like or mixture thereof in any suitable proportion. More preferably ethyl acetate, methyl tert-butyl ether or mixture thereof may be used.

Optionally, the solution obtained above 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 (ii) 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.

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 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 -10°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 85°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 preferred embodiment, the present invention is directed to a process for the preparation of amorphous form of canagliflozin comprising the steps of:
(i) providing solution of canagliflozin in the mixture of ethyl acetate and methyl tert-butyl ether (MTBE);
(ii) adding the solution of step (i) into the n-heptane;
(iii) isolating amorphous form of canagliflozin.

The treatment with the n-heptane may be carried out, for example, by adding the solution of canagliflozin into the n-heptane at temperature about -30°C to 50°C, preferably at -10°C to 5°C. The treatment with n-heptane may be followed by stirring the mixture for about 10 minutes to 20 hours, preferably about 30 minutes to 2 hour. The stirring may be carried out at about -30°C to 50°C, preferably at -10°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 85°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 form of 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 embodiment, the present invention is directed to a process for the preparation of amorphous form of canagliflozin comprising the steps of
(a) reacting a compound of formula (IIa) with a compound of formula (III) in the presence of alkyl lithium such as n-butyl lithium, tert-butyl lithium or hexyl lithium followed by treatment with methanol; in the presence of methane sulfonic acid to yield the corresponding compound of formula (Va);

(b) reacting the compound of formula (Va) with trialkylsilane in the presence of Lewis acid to yield the corresponding compound of formula (VI);

(c) protecting the hydroxyl group on the compound of formula (VI) to yield the corresponding compound of formula (VII), wherein P is oxygen protecting group selected from the group consisting of propanoyl, isopropanoyl, butanoyl, isobutanoyl, isovaleryl and valeryl.

(d) removing the protecting group from the compound of formula (VII) to yield the compound of formula (I);

(e) providing solution of canagliflozin of formula (I) in the mixture of ethyl acetate and methyl tert-butyl ether (MTBE);
(f) adding solution of step (e) into n-heptane;
(g) isolating amorphous form of canagliflozin.

Compound of formula (Va) can be prepared by reacting a compound of formula (IIa) with a compound of formula (III) in the presence of alkyl lithium in an organic solvent at a temperature in the range of from 0°C to -120°C; followed by treatment with methanol; in the presence of methanesulfonic acid; at lower, ambient, or elevated temperature.

Compound of formula (IIa) 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). Alkyl lithium may be selected from n-butyl lithium, n-hexyl lithium, tert-butyl lithium and the like. Organic solvent may be selected from THF, 2-methyl THF, heptane, hexane, pentane, MTBE, dioxane, toluene and the like or a mixture of these solvents.

The corresponding compound of formula (VI) can be prepared by reacting the compound of formula (Va) with a suitably selected trialkylsilanes such as triethylsilane, triisopropylsilane, and the like; in the presence of a suitably selected Lewis acid such as 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.

The compound of formula (VI) is protected according to known methods, to yield the corresponding compound of formula (VII), wherein each P is oxygen protecting group such as of propanoyl, isopropanoyl, butanoyl, isobutanoyl, isovaleryl, valeryl and the like. The protection may be carried out with conventional methods well known to those skilled in the art. The protection reaction may be carried out at lower, ambient, or elevated temperature. Preferably, the reaction is carried out at a temperature in the range of from about -10°C to about 100°C. The protection is carried out in the presence of an organic base such as N-methylmorpholine, N,N diisopropylethyl amine, triethyl amine, pyridine, and the like; optionally in the presence of a catalyst such as 4-dimethylaminopyridine, and the like; neat or in an organic solvent such as DCM, methanol, THF, acetonitrile, and the like or a mixture of these solvents.

The compound of formula (VII) is de-protected according to known methods such as reduction, hydrolysis, acid treatment, or fluoride treatment preferably by hydrolysis to yield the corresponding compound of formula (I). More particularly, the compound of formula (VII) is de-protected by treating with a suitably selected base; such as an alkali metal hydroxides (for e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, NaOCH3 and the like), or an alkali metal alkoxide (for e.g., sodium methoxide, sodium ethoxide, and the like); in a suitably selected solvent such as an ether (for e.g., tetrahydrofuran, dioxane, and the like), alcohol (for e.g., methanol, ethanol, and the like), water, DCM, or a mixture of these solvents. Deprotection reaction can be carried out at lower, ambient, or elevated temperature.

The treatment with the anti-solvent may be carried out, for example, by adding the solution of canagliflozin into the n-heptane at temperature about -30°C to 50°C, preferably at -10°C to 5°C. The treatment with n-heptane may be followed by stirring the mixture for about 10 minutes to 20 hours, preferably about 30 minutes to 2 hour. The stirring may be carried out at about -30°C to 50°C, preferably at -10°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 85°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 form of 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.

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-O-trimethylsilyl-ß-D-glucolactone
Solution of D-gluconolactone (1 kg, 0.0056 mol) and N-methylmorpholine (4.21 kg, 0.0416 mol) in THF (10 L) was stirred at -10 to -5°C. Trimethylsilyl chloride (3.16 kg, 0.0290 mol) was added to the reaction mixture. After 1 hour, the reaction was heated to 40-45°C for 5-6 hours whereupon it was allowed to cool to 0-10°C. After dilution with toluene, water was slowly added. The layers were separated and the organic phases washed with 5% potassium dihydrogen phosphate solution and water. The organic layer was dried over sodium sulphate and after concentration to yield tilted oily residue.

Example 2
(3R,4S,5S,6R)-2-(3-((5-(4-Fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol

Hexyl lithium (0.37 kg, 0.004 mol) was slowly added to a stirred suspension of 2-(5-bromo-2-methyl-benzyl)-5-(4-fluorophenyl)-thiophene (1 kg, 0.0027 mol) in THF (4 L) and toluene (4 L) at -75°C to -65°C. After stirring for 10-15 minutes, solution of 2,3,4,6-tetra-O-trimethylsilyl-ß-D-glucolactone (1.89 kg, 0.004 mol) in toluene (1 L) was slowly added by maintaining the reaction at -65 to -75°C and mixture was stirred for 1 to 1.5 hours at same temperature. The reaction mixture was quenched by solution of methane sulfonic acid (0.78 kg, 0.0081 mol) in methanol (6 L) at -65 to -75°C and stirred for 30-45 minutes. The reaction mixture was further stirred for 2 hours at room temperature. The resultant mixture was quenched by 8% NaHCO3. After phase separation, the organic layer was washed with brine, dried over sodium sulphate and after concentration to yield oily residue. The oily residue was dissolved in toluene. The resulting solution was poured into n-heptane. The obtained precipitate was collected by filtration; washed with n-heptane and then dried to yield the titled compound.

Example 3
(2S,3S,4R,5R,6R)-2-(3-((5-(4-Fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-((propionyloxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl tripropionate

To a stirred solution of (3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1 kg, 0.0021 mol) in DCM (5 L) was added triethylsilane (0.735 kg, 0.0063 mol) followed by addition of BF3Et2O (1.121 kg, 0.0078 mol) at a temperature -35 to -25°C. The reaction mixture was further stirred for 2 hours at room temperature. The resultant mixture was quenched by 8% NaHCO3. After phase separation, the organic layer was washed with brine, dried over sodium sulphate and concentrated to obtain residue. After dissolution of this residue in DCM (4 L), diisopropylethylamine (1.65 kg, 0.0127 mol) and DMAP (0.007 kg, 0.0127 mol) were added. The reaction mixture was cooled at 0-10°C with stirring, then propionic anhydride (1.6 kg, 0.0122 mol) was added dropwisely. The reaction mixture was further stirred for 30-60 minutes at room temperature. The resultant mixture was diluted with 10% phosphoric acid (5 L). After phase separation, the organic layer was washed with 8% NaHCO3 solution, water, dried over sodium sulphate and after concentration to yield residue. Ethanol was added to the residue and mixture was stirred for 5-6 hours. The resultant precipitate was filtered, further washed with ethanol and dried to yield titled compound. 1HNMR (CDCl3) (ppm) 7.54-7.57 (dd, 2H), 7.06-7.23 (dd, 6H), 6.69 (d, 1H), 5.09-5.42 (dd, 3H), 4.19-4.90 (dd, 6H), 2.18-2.34 (t, 11H), 2.00-2.39 (q, 8H), 0.85-1.16 (t, 12H); Mass (m/z): 686.35 (M+18).

Example 4
Preparation of canagliflozin
To a stirred solution of (2S,3S,4R,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-((propionyloxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl tripropionate (1 kg) in THF/MeOH (5 L) was added LiOH.H2O (0.256 kg in 2 L, 0.0061 mol) and mixture was strieed for 30-60 minutes. After completion of reaction, DCM and water were added to the mixture. The pH (6.5-7.00) of mixture was adjusted using Dil. HCl; after phase separation, the organic layer was washed with water and after concentration to yield titled compound.

Example 5
(2R,3R,4R,5S,6R)-2-((Butyryloxy)methyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl tributyrate

To a stirred solution of (2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (25 gm, 0.0562 mol) in DCM (125 ml); NMM (23 gm, 0.2272 mol) and DMAP (0.25 gm, 0.002 mol) were added. To this mixture butyric anhydride (35.5 gm, 0.224 mol) was added dropwisely. The reaction mixture was stirred for 60-90 minutes at room temperature. The resultant mixture was diluted with DCM & water. After phase separation, the organic layer was washed with water, dried over sodium sulphate and after concentration to yield residue. Ethanol was added to the residue and mixture was stirred. After cooling the mixture precipitation occurs, which was filtered, further washed with IPA. The resultant compound was charged with IPA and mixture was heated and further cooled. The resultant precipitate was filtered, dried to yield titled compound. 1HNMR (CDCl3) (ppm) 7.021-7.511(dd, 8H), 6.625-6.63 (s, 1H), 5.17-5.365 (dd, 3H), 3.84-4.41 (d, 6H), 1.28-1.65 (m, 8H), 0.60-0.96 (t, 12H); Mass (m/z): 742.55 (M+18).

Example 6
Preparation of canagliflozin
To a stirred solution of (2R,3R,4R,5S,6R)-2-((butyryloxy)methyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl tributyrate (10 gm, 0.0138 mol) in THF/MeOH (60 ml) was added LiOH.H2O (2.6 gm in 30 ml water, 0.0621 mol). After stirring for 30-60 minutes, DCM and water were added to the mixture. The pH (6.5-7.0) was adjusted using Dil. HCl; after phase separation, the organic layer was washed with water and after concentration to yield titled compound.

Example 7
(2R,3R,4R,5S,6R)-2-((Butyryloxy)methyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl) methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl tributyrate

To a stirred solution of (2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (5 gm, 0.0112 mol) in THF (25 ml); DIPEA (10.42 gm, 0.0806 mol) and DMAP (0.027 gm, 0.0002 mol) were added. The reaction mixture was cooled at 0-10°C with stirring, then butyric anhydride (12.1 gm, 0.0765 mol) was added dropwisely. The reaction mixture was further stirred for 60-90 minutes at room temperature. The resultant mixture was diluted with DCM & Water. After phase separation, organic layer was washed with 10% phosphoric acid (5 L), 8% NaHCO3 solution, water, dried over sodium sulphate and after concentration to yield titled compound. 1HNMR (CDCl3) (ppm) 7.021-7.511(dd, 8H), 6.625-6.63 (s, 1H), 5.17-5.365 (dd, 3H), 3.84-4.41 (d, 6H), 1.28-1.65 (m, 8H), 0.60-0.96 (t, 12H); Mass (m/z): 742.55 (M+18).

Example 8
Preparation of amorphous form of canagliflozin
Canagliflozin (5 gm) was dissolved in the mixture of ethyl acetate (2.5 ml) and methyl tert-butyl ether (15 ml). The resultant solution was added slowly to the chilled solution of n-heptane (75 ml) and stirring was continued at same temperature. The solid precipitated was filtered and dried at 75°C to obtain amorphous canagliflozin.

Example 9
Preparation of amorphous form of canagliflozin
Mixture of canagliflozin (20 gm) and ethyl acetate (140 ml) was heated to get clear solution. The ethyl acetate was removed under reduced pressure (in such way that 0.5 times ethyl acetate was kept) to get flazy/oily residue. This residue was dissolved in MTBE (60 ml) and further stirred to obtain clear solution. The resultant solution was added slowly to the chilled solution of n-heptane (75 ml) and stirring was continued at same temperature. The solid precipitated was filtered, washed with n-heptane and dried at 75°C to obtain amorphous canagliflozin.

Example 10
Preparation of amorphous form of canagliflozin
Mixture of canagliflozin (25 gm) and ethyl acetate (250 ml) was heated to get clear solution. The ethyl acetate was removed under reduced pressure (in such way that 1 test tube ethyl acetate was kept) to get oily residue which was dissolved in MTBE (75 ml) and further stirred to obtain clear solution. The resultant solution was added slowly to the chilled solution of n-heptane (375 ml) and stirring was continued at same temperature. The solid precipitated was filtered, washed with n-heptane and dried at 75°C to obtain amorphous canagliflozin.
,CLAIMS:1. A process for the preparation of canagliflozin of formula (I)

or a pharmaceutically acceptable salt, or a prodrug thereof;
comprising the steps of:
(a) reacting a compound of formula (II), wherein R1 is bromo or iodo; with a compound of formula (III) in the presence of alkyl lithium followed by treatment with an alcohol of formula (IV), wherein R2 is lower alkyl; in the presence of an acid to yield the corresponding compound of formula (V);

(b) reacting the compound of formula (V) with silane reagent in the presence of Lewis acid to yield the corresponding compound of formula (VI);

(c) protecting the hydroxyl group on the compound of formula (VI) to yield the corresponding compound of formula (VII), wherein P is oxygen protecting group selected from the group consisting of propanoyl, isopropanoyl, butanoyl, isobutanoyl, isovaleryl and valeryl.

(d) removing the protecting group from the compound of formula (VII) to yield the compound of formula (I);

2. The process according to claim 1, wherein the alkyl lithium reagent is n-butyl lithium, tert-butyl lithium or hexyl lithium.

3. The process according to claim 1, wherein acid is organic or inorganic selected from hydrochloric acid, nitric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, formic acid, acetic acid and trifluoroacetic acid.

4. The process according to claim 1, wherein the silane reagent is trialkylsilane or polyalkyl silanes selected from triethylsilane, triisopropylsilane and poly(methylhydrosiloxane); and wherein the Lewis acid is boron trifluoride diethyl ether complex, aluminum chloride, or titanium tetrachloride.

5. The process according to claim 1, wherein step (c) is carried out in the presence of an organic base selected from N-methylmorpholine, N,N diisopropylethyl amine, triethyl amine and pyridine.

6. The process according to claim 1, wherein step (d) is carried out by treating compound of formula (VII) with base.

7. A compound of formula (VII)

or a pharmaceutically acceptable salt, or a prodrug thereof;
wherein, P is oxygen protecting group selected from the group consisting of propanoyl, isopropanoyl, butanoyl, isobutanoyl, isovaleryl and valeryl.

8. Use of compound of formula (VII) in a method of producing canagliflozin.

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;
wherein,
P is oxygen protecting group selected from the group consisting of propanoyl, isopropanoyl, butanoyl, isobutanoyl, isovaleryl and valeryl.

9. A process for the preparation of amorphous form of canagliflozin comprising the steps of:
(i) providing solution of canagliflozin;
(ii) treating the solution of step (i) with an antisolvent; and
(iii) isolating amorphous form of canagliflozin.

10. The process according to claim 9, wherein solution in step (i) is obtained by dissolving canagliflozin in suitable solvent selected from alcohol, ketone, ester, ether, hydrocarbon, and acetonitrile, or mixtures thereof.

11. The process according to claim 9, wherein anti-solvent for step (ii) comprises n-hexane, n-heptane, n-pentane, cyclohexane, methylcyclohexane; diethyl ether, diisopropyl ether, dibutyl ether or mixtures thereof.

12. A process for the preparation of amorphous form of canagliflozin
comprising the steps of:
(a) reacting a compound of formula (IIa) with a compound of formula (III) in the presence of alkyl lithium such as n-butyl lithium, tert-butyl lithium or hexyl lithium followed by treatment with methanol; in the presence of methane sulphonic acid to yield the corresponding compound of formula (Va);

(b) reacting the compound of formula (Va) with trialkylsilane in the presence of Lewis acid to yield the corresponding compound of formula (VI);

(c) protecting the hydroxyl group on the compound of formula (VI) to yield the corresponding compound of formula (VII), wherein P is oxygen protecting group selected from the group consisting of propanoyl, isopropanoyl, butanoyl, isobutanoyl, isovaleryl and valeryl.

(d) removing the protecting group from the compound of formula (VII) to yield the compound of formula (I);

(e) providing solution of canagliflozin of formula (I) in the mixture of ethyl acetate and methyl tert-butyl ether (MTBE);
(f) adding solution of step (e) into n-heptane;
(g) isolating amorphous form of canagliflozin.