DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR PREPARATION OF DAPAGLIFLOZIN”

Glenmark Pharmaceuticals Limited;
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of amorphous dapagliflozin. The present invention relates to 2,3-butanediol solvate of dapagliflozin and process for its preparation.
BACKGROUND OF THE INVENTION
Dapagliflozin, also known as D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, (1S)-, is represented by the structure of formula I.
I
The object of the present invention is to provide a process for the preparation of amorphous dapagliflozin with high purity.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of dapagliflozin in amorphous form, the process comprising:
(a) reducing a compound of formula II to a compound of formula III in the presence of a Lewis acid;

(b) silylating a compound of formula IV with hexamethyldisilazane to form a compound of formula V;

(c) reacting the compound of formula III with the compound of formula V in the presence of a strong base followed by treatment with an acid in the presence of an alcohol to prepare a compound of formula VII, wherein R is an alkyl group selected from C1-5 alkyl;
VII
(d) converting the compound of formula VII to dapagliflozin;
(e) acetylating dapagliflozin to give D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, 2,3,4,6-tetraacetate, (1S)-, a compound of formula VIII;
VIII
(f) optionally, purifying the compound of formula VIII with a solvent selected from halogenated hydrocarbons, alcohols, ethers, or mixtures thereof;
(g) hydrolyzing the compound of formula VIII obtained in step (f) to give dapagliflozin;
(h) dissolving dapagliflozin of step (g) in a solvent selected from halogenated hydrocarbons, alcohols, hydrocarbons, or mixtures thereof to form a solution; and
(i) recovering amorphous dapagliflozin from the solution of step (h).
In another embodiment, the present invention provides a process for the preparation of dapagliflozin in amorphous form, the process comprising:
(i) dissolving dapagliflozin in isopropyl alcohol to form a solution;
(ii) optionally, completely evaporating isopropyl alcohol from the solution of step (i) to give a residue;
(iii) adding cyclohexane to the solution of step (i) or the residue of step (ii); and
(iv) isolating amorphous dapagliflozin.
In another embodiment, the present invention provides a process for the preparation of D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, 2,3,4,6-tetraacetate, (1S)-, a compound of formula VIII, in a purity of =99.6% and wherein the level of impurity G and impurity H is less than 0.15%,
G H
the process comprising:
(a) treating the compound of formula VIII with an ether solvent to form a reaction mass;
(b) heating the reaction mass of step (a);
(c) cooling the reaction mass of step (b);
(d) obtaining the compound of formula VIII from the reaction mass of step (c);
(e) optionally, crystallizing the compound of formula VIII obtained in step (d) with an alcohol solvent; and
(f) isolating the compound of formula VIII with a purity of =99.6% and wherein the level of impurity G and impurity H is less than 0.15%.
In another embodiment, the present invention provides a crystalline 2,3-butanediol solvate of dapagliflozin characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 3.7, 9.6, 14.7, 16.7 and 18.4 ±0.2 degrees 2 theta.
In another embodiment, the present invention provides a process for the preparation of crystalline 2,3-butanediol solvate of dapagliflozin, the process comprising:
(a) treating dapagliflozin with 2,3-butanediol, optionally in the presence of a solvent, to form a solution;
(b) obtaining crystalline 2,3-butanediol solvate of dapagliflozin from the solution of step (a); and
(c) isolating the crystalline 2,3-butanediol solvate of dapagliflozin.
In another embodiment, the present invention provides a process for the preparation of dapagliflozin in amorphous form, the process comprising:
(a) dissolving 2,3-butanediol solvate of dapagliflozin in a solvent to form a solution; and
(b) recovering dapagliflozin in amorphous form from the solution of step (a) by:
(i) removing the solvent from the solution obtained in step (a); or
(ii) treating the solution of step (a) with an anti-solvent.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic XRPD of amorphous dapagliflozin as obtained in example 32.
Figure 2 is a characteristic XRPD of crystalline 2,3-butanediol solvate of dapagliflozin as obtained in Example 6.
Figure 3 is a proton NMR spectrum of crystalline 2,3-butanediol solvate of dapagliflozin as obtained in Example 6.
Figure 4 is a TGA thermogram of crystalline 2,3-butanediol solvate of dapagliflozin as obtained in Example 6.
Figure 5 is an IR spectrum of crystalline 2,3-butanediol solvate of dapagliflozin as obtained in Example 6.
Figure 6 is a characteristic XRPD of dapagliflozin in amorphous form as obtained in Example 28.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of dapagliflozin in amorphous form, the process comprising:
(a) reducing a compound of formula II to a compound of formula III in the presence of a Lewis acid;
(b) silylating a compound of formula IV with hexamethyldisilazane to form a compound of formula V;
(c) reacting the compound of formula III with the compound of formula V in the presence of a strong base followed by treatment with an acid in the presence of an alcohol to prepare a compound of formula VII, wherein R is an alkyl group selected from C1-5 alkyl;
(d) converting the compound of formula VII to dapagliflozin;
(e) acetylating dapagliflozin to give D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, 2,3,4,6-tetraacetate, (1S)-, a compound of formula VIII; (f) optionally, purifying the compound of formula VIII with a solvent selected from halogenated hydrocarbons, alcohols, ethers, or mixtures thereof;
(g) hydrolyzing the compound of formula VIII obtained in step (f) to give dapagliflozin;
(h) dissolving dapagliflozin of step (g) in a solvent selected from halogenated hydrocarbons, alcohols, hydrocarbons, or mixtures thereof to form a solution; and
(i) recovering amorphous dapagliflozin from the solution of step (h).
In the present application, the term “room temperature” means a temperature of about 25°C to about 30°C.
In (a) of the process for the preparation of dapagliflozin in amorphous form, the compound of formula II is reduced to the compound of formula III in the presence of a Lewis acid.
The Lewis acid may be selected from the group consisting of aluminium chloride, boron trifluoride, titanium tetrachloride and ferric chloride.
The reduction of the compound of formula II may be performed with a reducing agent, for example triethylsilane.
In one embodiment, step (a) comprises reducing the compound of formula II with triethylsilane in presence of boron trifluoride in a mixture of methylene dichloride and acetonitrile to give the compound of formula III.
In (b) of the process for the preparation of dapagliflozin in amorphous form, the compound of formula IV is silylated with hexamethyldisilazane to form the compound of formula V.
In one embodiment, step (b) comprises silylating the compound of formula IV with hexamethyldisilazane in presence of methylene dichloride as solvent and iodine as catalyst to form the compound of formula V.
In (c) of the process for the preparation of dapagliflozin in amorphous form, the compound of formula III is reacted with the compound of formula V in the presence of a strong base.
The strong base may include an alkyl lithium such as methyl lithium, n-butyl lithium, lithium diisopropylamide and lithium bis(trimethylsilyl)amide.
In one embodiment, step (c) comprises reacting the compound of formula III with the compound of formula V in the presence of a strong base to obtain a compound of formula VI; and reacting the compound of formula VI with an acid in the presence of an alcohol to prepare the compound of formula VII wherein R is an alkyl group selected from C1-5 alkyl
VI VII.
In one embodiment, the alcohol may be a C1-5 alcohol. C1-5 alcohol, for example, may include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, n-pentyl alcohol and the like.
In one embodiment, the acid may be a sulfonic acid which may include methanesulfonic acid, benzenesulfonic acid and the like.
In one embodiment, step (c) comprises reacting the compound of formula III with the compound of formula V in presence of n-butyl lithium in tetrahydrofuran, followed by treatment with methanesulfonic acid in presence of methanol to prepare the compound of formula VII, wherein R is methyl.
In one embodiment, step (c) comprises reacting the compound of formula III with the compound of formula V in presence of n-butyl lithium in tetrahydrofuran to prepare the compound of formula VI which is further reacted with methane sulfonic acid in presence of methanol to prepare the compound of formula VII, wherein R is methyl.
In one embodiment, the compound of formula V may be isolated before further treatment. In one embodiment, the compound of formula VI may be isolated before further treatment. In one embodiment, the compound of formula VII may be isolated before further treatment. In one embodiment, the compound of formula VI may not be isolated. In one embodiment, steps (b) and (c) may be performed as one-pot process.
In (d) of the process for the preparation of dapagliflozin in amorphous form, the compound of formula VII is converted to dapagliflozin.
The reaction may be carried out in the presence of a reducing agent, for example triethylsilane. The reaction may be carried out in the presence of a Lewis acid selected from the group consisting of aluminium chloride, boron trifluoride, titanium tetrachloride and ferric chloride.
In one embodiment, step (d) comprises reducing the compound of formula VII with triethylsilane in presence of boron trifluoride in a mixture of methylene dichloride and acetonitrile to give dapagliflozin.
In (e) of the process for the preparation of dapagliflozin in amorphous form, dapagliflozin is acetylated to give D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, 2,3,4,6-tetraacetate, (1S)-, the compound of formula VIII.
The acetylating agent includes, but is not limited to acetyl chloride, acetic anhydride.
The reaction may be carried out in the presence of a suitable base, for example N,N-diisopropylethylamine, 4-dimethylaminopyridine.
In one embodiment, step (e) comprises acetylating dapagliflozin using acetic anhydride and N,N-diisopropylethylamine in presence of 4-dimethylaminopyridine in methylene dichloride.
In one embodiment, the compound of formula VIII is optionally purified with a solvent selected from halogenated hydrocarbons, alcohols, ethers, or mixtures thereof.
In (f) of the process for the preparation of dapagliflozin in amorphous form, the compound of formula VIII is purified with a solvent selected from halogenated hydrocarbons, alcohols, ethers, or mixtures thereof.
In one embodiment, halogenated hydrocarbons may include methylene dichloride, chloroform, ethylene dichloride and the like; alcohols may include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol and the like; and ethers may include dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like.
In one embodiment, the alcohol is methanol and the ether is diisopropyl ether.
In one embodiment, the present invention provides a process for the purification of the compound of formula VIII, the process comprising: (i) treating the compound of formula VIII with methanol to form a reaction mass; (ii) heating the reaction mass of step (i); (iii) cooling the reaction mass of step (ii); (iv) isolating the compound of formula VIII from the reaction mass of step (iii); (v) treating the compound of formula VIII obtained in step (iv) with diisopropyl ether to form a reaction mass; (vi) heating the reaction mass of step (v); (vii) cooling the reaction mass of step (vi); (viii) isolating the compound of formula VIII from the reaction mass of step (vii); (ix) treating the compound of formula VIII obtained in step (viii) with methanol to form a reaction mass; (x) heating the reaction mass of step (ix); (xi) cooling the reaction mass of step (x); (xii) isolating the compound of formula VIII from the reaction mass of step (xi).
The reaction mass of step (ii) may be optionally treated with charcoal and filtered.
In (g) of the process for the preparation of dapagliflozin in amorphous form, the compound of formula VIII obtained in step (f) is hydrolyzed to give dapagliflozin.
The reaction may be carried out in the presence of a suitable base. The suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate. Preferably the base selected is sodium hydroxide.
In one embodiment, step (g) comprises hydrolyzing the compound of formula VIII obtained in step (f) in presence of sodium hydroxide in tetrahydrofuran-methanol-water mixture.
In (h) of the process for the preparation of dapagliflozin in amorphous form, dapagliflozin of step (g) is dissolved in a solvent selected from halogenated hydrocarbons, alcohols, hydrocarbons, or mixtures thereof to form a solution.
In one embodiment, the halogenated hydrocarbon solvent may include methylene dichloride, chloroform, ethylene dichloride and the like; the alcohol solvent may include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol and the like; and the hydrocarbon solvent may be an aromatic or an aliphatic hydrocarbon solvent such as toluene, n-hexane, n-heptane, cyclohexane and the like.
In one embodiment, the alcohol is isopropyl alcohol and the hydrocarbon is cyclohexane.
Suitable temperature for dissolution of dapagliflozin in the solvent may range from about 25°C to about the reflux temperature of the solvent. The stirring time may range from about 30 minutes to about 1 hour, or longer. The solution may be optionally treated with charcoal and filtered to get a particle-free solution.
In (i) of the process for the preparation of dapagliflozin in amorphous form, amorphous dapagliflozin is recovered from the solution of step (h).
In one embodiment, dapagliflozin in amorphous form is recovered by removing the solvent from the solution obtained in step (h). Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg, or evaporated by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying, agitated nutsche filter dryer.
In one embodiment, dapagliflozin in amorphous form is recovered by adding an anti-solvent to the solution obtained in step (h) to form a mixture and optionally, cooling and stirring the obtained mixture. The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 30°C.
The anti-solvent is selected such that dapagliflozin in amorphous form is precipitated out from the solution.
In one embodiment, dapagliflozin is dissolved in isopropyl alcohol to form a solution. Cyclohexane was then added to the solution and the obtained mixture was stirred and filtered to give amorphous dapagliflozin.
In one embodiment, dapagliflozin is dissolved in isopropyl alcohol to form a solution. The solution was then concentrated by completely evaporating isopropyl alcohol from the solution to obtain a residue. To the residue, cyclohexane was added and the obtained mixture was stirred and filtered to give amorphous dapagliflozin.
In one embodiment, the amorphous dapagliflozin is obtained in a purity of =99.8% and wherein the level of impurity A and impurity B is less than 0.15%
A B
In one embodiment, the present invention provides a process for the preparation of dapagliflozin in amorphous form, the process comprising:
(i) dissolving dapagliflozin in isopropyl alcohol to form a solution;
(ii) optionally, completely evaporating isopropyl alcohol from the solution of step (i) to give a residue;
(iii) adding cyclohexane to the solution of step (i) or the residue of step (ii); and
(iv) isolating amorphous dapagliflozin.
In one embodiment, the present invention provides a process for the preparation of D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, 2,3,4,6-tetraacetate, (1S)-, a compound of formula VIII, in a purity of =99.6% and wherein the level of impurity G and impurity H is less than 0.15%, the process comprising:
G H
(a) treating the compound of formula VIII with an ether solvent to form a reaction mass;
(b) heating the reaction mass of step (a);
(c) cooling the reaction mass of step (b);
(d) obtaining the compound of formula VIII from the reaction mass of step (c);
(e) optionally, crystallizing the compound of formula VIII obtained in step (d) with an alcohol solvent; and
(f) isolating the compound of formula VIII with a purity of =99.6% and wherein the level of impurity G and impurity H is less than 0.15%.
In one embodiment, the ether solvent may include diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; the alcohol solvent may include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol and the like.
In one embodiment, the alcohol is methanol and the ether is diisopropyl ether.
In one embodiment, the process further comprises converting the compound of formula VIII to amorphous dapagliflozin as discussed supra.
In one embodiment, the present invention provides use of the compound of formula VIII, as obtained by above process, in the preparation of dapagliflozin.
The present invention provides the compound of formula VIII wherein the level of impurity G and impurity H is less than 0.15% w/w relative to the amount of the compound of formula VIII, obtained by above process, as analyzed by chemical purity using high performance liquid chromatography (HPLC) with the conditions described below:
Reagents and Solvents: Sodium perchlorate monohydrate (AR grade), Perchloric acid 70% (AR grade), Acetonitrile (HPLC grade), Water (Milli Q or equivalent); Chromatographic Conditions: Apparatus: A High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and integrator software; Column: Inertsil ODS 3V, 250 x 4.6mm, 5µ; Column temperature: 25°C; Sample Cooler temperature: 25°C; Mobile Phase A: Buffer; Buffer: 0.01M Sodium perchlorate monohydrate in water. Adjust pH 2.5 with diluted Perchloric acid; Mobile Phase B: Acetonitrile; Diluent: Acetonitrile: Water (1: 1, v/v); Flow Rate: 1.0 mL/min; Detection: UV 220nm; Injection Volume: 10µL
The retention time of the compound of formula VIII is about 61.0 minutes under these conditions. Relative retention time for impurity G is about 1.03 and impurity H is about 1.05 with respect to the compound of formula VIII.
In one embodiment, the present invention provides a process for the purification of dapagliflozin wherein, the process comprises purification of crude dapagliflozin from a halogenated hydrocarbon. The halogenated hydrocarbon used may include methylene dichloride, chloroform, ethylene dichloride and the like.
The present invention provides a crystalline 2,3-butanediol solvate of dapagliflozin characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 3.7, 9.6, 14.7, 16.7 and 18.4 ±0.2 degrees 2 theta.
The present invention provides a crystalline 2,3-butanediol solvate of dapagliflozin characterized by an X-ray powder diffraction (XRPD) pattern as depicted in Figure 1, a TGA thermogram as depicted in Figure 3, an IR spectrum as depicted in Figure 4.
In one embodiment, the present invention provides a crystalline 2,3-butanediol solvate of dapagliflozin characterized by TGA thermogram, showing a weight loss of about 18 weight% to 26 weight% up to 250°C determined over the temperature range of 0°C to 350°C and heating rate 10°C/min.
In one embodiment, the present invention provides a crystalline 2,3-butanediol solvate of dapagliflozin characterized by TGA thermogram, showing a weight loss of about 18 weight% to 26 weight% up to 250°C determined over the temperature range of 0°C to 350°C and heating rate 10°C/min which is in accordance with Figure 3.
In one embodiment, the present invention provides a crystalline 2,3-butanediol monohydrate of dapagliflozin characterized by TGA thermogram, showing a weight loss of about 24.3 weight% up to 250°C determined over the temperature range of 0°C to 350°C and heating rate 10°C/min which corresponds to one mole of water and one mole of butanediol per mole of structure analyzed.
In one embodiment, the crystalline 2,3-butanediol solvate of dapagliflozin is a mono-butanediol solvate of dapagliflozin (1:1 solvate).
In one embodiment, the crystalline 2,3-butanediol solvate of dapagliflozin is in the form of a hydrate / monohydrate/ dihydrate.
In one embodiment, the present invention provides a crystalline 2,3-butanediol solvate of dapagliflozin characterized by a proton NMR spectrum having peak positions at 7.40-7.25 (m,2H), 7.25-7.18 (d,1H), 7.12-7.00 (d,2H), 6.81-6.75 (d,2H), 4.97 (brs,2H), 4.84 (brs,1H), 4.46 (brs,1H), 4.32 (brs,2H), 4.10-3.90 (m,4H), 3.80-3.60 (m,1H), 3.55-3.05 (m,8H), 1.29 (t,3H), 1.05-0.85 (m,6H) ppm.
In one embodiment, the present invention provides a crystalline 2,3-butanediol solvate of dapagliflozin characterized by DSC thermogram having an endothermic peak at about 61 ±2°C.
In another embodiment, the present invention provides a process for the preparation of crystalline 2,3-butanediol solvate of dapagliflozin, the process comprising:
(a) treating dapagliflozin with 2,3-butanediol, optionally in the presence of a solvent, to form a solution;
(b) obtaining crystalline 2,3-butanediol solvate of dapagliflozin from the solution of step (a); and
(c) isolating the crystalline 2,3-butanediol solvate of dapagliflozin.
In (a) of the process for the preparation of crystalline 2,3-butanediol solvate of dapagliflozin, dapagliflozin is treated with 2,3-butanediol, optionally in the presence of a solvent, to form a solution.
The 2,3-butanediol used may be the (2R,3R)-enantiomer, or the (2S,3S)-enantiomer, or the meso compound (2R,3S) (or equivalently (2S,3R)), or the racemic compound. Preferably, racemic 2,3-butanediol is used.
The solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water; or mixtures thereof.
The reaction may be carried out at a temperature in the range from about 20°C to about 120°C. Preferably, the reaction is carried out at about 25°C to about 80°C. The stirring time may range from about 30 minutes to about 10 hours, or longer. The solution may be optionally treated with charcoal and filtered to get a particle-free solution.
In (b) of the process for the preparation of crystalline 2,3-butanediol solvate of dapagliflozin, crystalline 2,3-butanediol solvate of dapagliflozin is obtained from the solution of step (a).
In one embodiment, the step (b) of obtaining crystalline 2,3-butanediol solvate of dapagliflozin comprises:
(i) optionally cooling and stirring the solution obtained in (a); or
(ii) removing the solvent from the solution obtained in (a); or
(iii) treating the solution of step (a) with an anti-solvent to form a mixture and optionally, cooling and stirring the obtained mixture.
In (i) of the above process, crystalline 2,3-butanediol solvate of dapagliflozin is obtained by optionally cooling and stirring the solution obtained in step (a). The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 90°C.
In (ii) of the above process, crystalline 2,3-butanediol solvate of dapagliflozin is obtained by removing the solvent from the solution obtained in step (a). Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may be completely evaporated as discussed supra. The solution may also be completely evaporated as discussed supra, adding a second solvent, optionally cooling and stirring the obtained mixture and filtering the obtained solid.
In (iii) of the above process, crystalline 2,3-butanediol solvate of dapagliflozin is obtained by adding an anti-solvent to the solution obtained in step (a) to form a mixture and optionally, cooling and stirring the obtained mixture. The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 90°C. The anti-solvent is selected such that crystalline 2,3-butanediol solvate dapagliflozin is precipitated out from the solution.
The second solvent and anti-solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water; or mixtures thereof.
In (c) of the process for the preparation of crystalline 2,3-butanediol solvate of dapagliflozin, the crystalline 2,3-butanediol solvate of dapagliflozin is isolated by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.
The present invention provides a process for the preparation of dapagliflozin in amorphous form, the process comprising:
(a) dissolving 2,3-butanediol solvate of dapagliflozin in a solvent to form a solution; and
(b) recovering dapagliflozin in amorphous form from the solution of step (a).
In (a) of the process for the preparation of dapagliflozin in amorphous form, 2,3-butanediol solvate of dapagliflozin is dissolved in a solvent to form a solution.
The solvent used for dissolution of 2,3-butanediol solvate of dapagliflozin may be as discussed supra for preparation of 2,3-butanediol solvate of dapagliflozin.
Suitable temperature for dissolution of 2,3-butanediol solvate of dapagliflozin in a solvent may range from about 0°C to about the reflux temperature of the solvent. Stirring may be continued for any desired time period to achieve a complete dissolution of the compound. The stirring time may range from about 30 minutes to about 1 hour, or longer. The solution may be optionally treated with charcoal and filtered to get a particle-free solution.
In (b) of the process for the preparation of dapagliflozin in amorphous form, dapagliflozin in amorphous form is recovered from the solution of step (a).
In one embodiment, dapagliflozin in amorphous form is recovered by removing the solvent from the solution obtained in step (a). Removal of solvent may be accomplished as discussed supra.
In one embodiment, dapagliflozin in amorphous form is recovered by adding an anti-solvent to the solution obtained in step (a) to form a mixture and optionally, cooling and stirring the obtained mixture. The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 30°C.
The anti-solvent is selected such that dapagliflozin in amorphous form is precipitated out from the solution. The anti-solvent is as discussed supra.
The present invention provides use of 2,3-butanediol solvate of dapagliflozin in the preparation of amorphous dapagliflozin.
In one embodiment, the present invention provides amorphous dapagliflozin in a purity of about 99.9% w/w, as determined by HPLC.
In one preferred embodiment, the present invention provides pure amorphous dapagliflozin in stable form with a purity of about 99.9% w/w, as determined by HPLC.
In one embodiment, the present invention provides pharmaceutical composition/ formulation comprising crystalline 2,3-butanediol solvate of dapaglifozin and at least one pharmaceutically acceptable carrier. In one embodiment, the crystalline 2,3-butanediol solvate of dapagliflozin formulation is in a form selected from the group consisting of a tablet, a stock granulation, and a capsule. In one embodiment, the present invention provides a method for treating or delaying the progression or onset of Type I and Type II diabetes, impaired glucose tolerance, insulin resistance, nephropathy, retinopathy, neuropathy, cataracts, hyperglycemia, hyperinsulinemia, hypercholesterolemia, dyslipidemia, elevated blood levels of free fatty acids or glycerol, hyperlipidemia, hypertriglyceridemia, obesity, wound healing, tissue ischemia, atherosclerosis, hypertension, or Syndrome X (Metabolic Syndrome) comprising administering to a mammalian subject or patient in need of such treatment a therapeutically effective amount of an immediate release pharmaceutical formulation comprising crystalline 2,3-butanediol solvate of dapagliflozin and a pharmaceutically acceptable carrier.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES
EXAMPLE 1: Preparation of 2,3,4,6-tetra-O-(trimethylsilyl)-D-glucono-1,5-lactone
To a mixture of D-glucono-1,5-lactone (10g) and iodine (0.28g) in methylene dichloride (80mL), hexamethyldisilazane (36.1g) was added and the reaction mixture was refluxed. After completion of reaction, the reaction mixture was concentrated and degassed to give 2,3,4,6-tetra-O-(trimethylsilyl)-D-glucono-1,5-lactone as liquid (25g). HPLC purity: 95%
EXAMPLE 2: Preparation of D-glucopyranoside, methyl 1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl] (compound of Formula VII wherein R is methyl)
To a mixture of 2,3,4,6-tetra-O-(trimethylsilyl)-D-glucono-1,5-lactone (25g) and 5-bromo-2-chloro-4'-ethoxydiphenylmethane (8.7g) in tetrahydrofuran (174mL), cooled to about -75°C to about -88 °C under nitrogen atmosphere, n-butyl lithium in hexane (50mL) was slowly added. The reaction mixture was stirred at about the same temperature and then mixture of methanol and methanesulphonic acid was added to it. The reaction mixture was quenched into sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with saturated sodium chloride solution and concentrated under vacuum to obtain a residue. The residue was purified with a mixture of toluene and cyclohexane. Yield: 11g as thick mass with 80-85% HPLC purity.
EXAMPLE 3: Preparation of D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl) methyl]phenyl]: To a mixture of D-glucopyranoside, methyl 1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl] in methylene dichloride (40mL) and acetonitrile (40mL), cooled to about -40°C to about -45°C, triethylsilane (8.74g) was added followed by addition of boron trifluoride etherate (10.67g) maintaining the temperature at about -40°C to about -45°C. The reaction mixture was quenched in sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was separated, concentrated and degassed under vacuum to give title compound (11g) as thick residue with 80-85% HPLC purity.
EXAMPLE 4: Preparation of D-Glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, 2,3,4,6-tetraacetate, (1S)-
To a cooled solution of D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl) methyl]phenyl]- (11g) in methylene dichloride (55mL) at about 0°C to about 5°C, diisopropylethylamine, dimethylaminopyridine and acetic anhydride were added and the reaction mixture was stirred. After completion of reaction, the reaction mixture was quenched by adding water. The aqueous layer was separated and extracted with methylene dichloride. The organic layer was separated, washed with sodium bicarbonate solution and concentrated under vacuum to obtain residue which was stripped out with methanol. The residue was purified with methanol and charcoal, followed by diisopropyl ether and methanol crystallization. Yield: 10g; HPLC purity: 99.6%
EXAMPLE 5: Preparation of D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl] (Dapagliflozin)
To a stirred solution of D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, 2,3,4,6-tetraacetate, (1S)-, (10g) in THF:methanol:water mixture (50mL:50mL:30mL), sodium hydroxide was added and the reaction mixture was stirred. After completion of reaction, the solvents were distilled out under vacuum and the residue obtained was dissolved in methylene dichloride and washed with water and brine and dried over sodium sulfate. The reaction mixture was concentrated and degassed to give off-white to white solids of D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]- (dapagliflozin) Yield: 7g (XRD matches with amorphous form) HPLC purity: 99.8%
EXAMPLE 6: Preparation of 2,3-butanediol solvate of dapagliflozin
Dapagliflozin (2g) was dissolved in ethyl acetate (10mL) and 2,3-butanediol (0.463g) and water (0.13g) were added to it. The reaction mixture was concentrated and cyclohexane (30mL) was added to it. The reaction mixture was stirred overnight. The solid obtained was filtered and dried. Yield: 1.8g; Water content: 2.92%
1H NMR (300 MHz in DMSO-d6): d 7.40-7.25 (m,2H), 7.25-7.18 (d,1H), 7.12-7.00 (d,2H), 6.81-6.75 (d,2H), 4.97 (brs,2H), 4.84 (brs,1H), 4.46 (brs,1H), 4.32 (brs,2H), 4.10-3.90 (m,4H), 3.80-3.60 (m,1H), 3.55-3.05 (m,8H), 1.29 (t,3H), 1.05-0.85 (m,6H)
1H NMR (300 MHz in DMSO-d6+D2O): 7.40-7.25 (m,2H), 7.25-7.18 (d,1H), 7.12-7.00 (d,2H), 6.81-6.75 (d,2H), 4.10-3.90 (m,4H), 3.80-3.60 (m,1H), 3.55-3.05 (m,8H), 1.29 (t,3H), 1.05-0.85 (m,6H)
TGA analysis of 2,3-butanediol solvate of dapagliflozin: 24.3% weight loss up to 250°C corresponds to one mole of water and one mole of butanediol per mole of structure analyzed.
XRPD peaks of 2,3-butanediol solvate of dapagliflozin:
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
2.11 41.77 0.45 20.64 4.30 6.23 29.54 3.02 5.60
3.69 23.91 100.00 21.34 4.16 16.12 30.02 2.97 3.80
8.65 10.21 6.13 22.04 4.03 2.66 30.49 2.93 2.53
9.56 9.24 7.14 22.79 3.90 2.90 31.99 2.79 4.12
10.72 8.24 6.31 23.47 3.78 6.38 32.46 2.75 5.45
14.60 6.03 50.84 24.20 3.67 4.77 33.30 2.68 0.91
15.78 5.61 8.65 24.73 3.59 5.27 34.21 2.62 3.29
16.10 5.50 2.09 25.22 3.53 3.13 37.22 2.41 3.63
16.63 5.33 77.16 25.81 3.45 3.75 38.43 2.34 1.45
18.34 4.83 19.62 26.96 3.30 5.04 39.81 2.26 2.13
18.62 4.76 6.49 27.39 3.25 3.74 40.97 2.20 3.65
19.97 4.44 16.57 28.44 3.13 1.13 42.49 2.12 0.92
20.20 4.39 5.96 28.92 3.08 1.09 43.23 2.09 0.49

The following examples follow similar process as described in EXAMPLE 13 for preparation of 2,3-butanediol solvate of dapagliflozin wherein ethyl acetate (first solvent) and cyclohexane (second solvent) are replaced by below combinations.
EXAMPLE No. First Solvent Second Solvent
EXAMPLE 7 isopropyl acetate cyclohexane
EXAMPLE 8 methyl acetate cyclohexane
EXAMPLE 9 methylene chloride cyclohexane
EXAMPLE 10 ethylene dichloride cyclohexane
EXAMPLE 11 butyl acetate cyclohexane
EXAMPLE 12 isopropyl acetate hexane
EXAMPLE 13 ethyl acetate hexane
EXAMPLE 14 methyl acetate hexane
EXAMPLE 15 butyl acetate hexane

EXAMPLE 16: Preparation of 2,3-butanediol solvate of dapagliflozin
Dapagliflozin (2g) was dissolved in ethyl acetate (10mL) and 2,3-butanediol (0.463g) and water (0.13g) were added to it. The reaction mixture was stirred for about 30min. Cyclohexane was added to the reaction mixture which was stirred overnight. The solid obtained was filtered and dried.
The following examples follow similar process as described in EXAMPLE 23 for preparation of 2,3-butanediol solvate of dapagliflozin wherein ethyl acetate (first solvent) and cyclohexane (second solvent) are replaced by below combinations.
EXAMPLE No. First Solvent Second Solvent
EXAMPLE 17 methyl acetate cyclohexane
EXAMPLE 18 isopropyl acetate cyclohexane
EXAMPLE 19 butyl acetate cyclohexane
EXAMPLE 20 methylene chloride cyclohexane
EXAMPLE 21 ethylene dichloride cyclohexane
EXAMPLE 22 ethyl acetate hexane
EXAMPLE 23 methyl acetate hexane
EXAMPLE 24 isopropyl acetate hexane
EXAMPLE 25 butyl acetate hexane
EXAMPLE 26 methylene chloride hexane
EXAMPLE 27 ethylene dichloride hexane

EXAMPLE 28: Preparation of amorphous dapagliflozin
To a stirred solution of 2,3-butanediol solvate of dapagliflozin (2g) in ethyl acetate, water was added and stirred for about 30min. The two layers were separated and the organic layer was concentrated under reduced pressure. Isopropyl alcohol was added to the obtained residue and the reaction mixture was concentrated under reduced pressure and degassed for about 4h to give amorphous dapagliflozin.
EXAMPLE 29: Preparation of amorphous dapagliflozin
To a stirred solution of 2,3-butanediol solvate of dapagliflozin (2g) in methylene dichloride, water was added and the reaction mixture was stirred for about 30min. The two layers were separated and the organic layer was concentrated under reduced pressure. Isopropyl alcohol was added to the obtained residue and the reaction mixture was concentrated under reduced pressure and degassed for about 4h to give amorphous dapagliflozin.
EXAMPLE 30: Preparation of amorphous dapagliflozin
To a stirred solution of D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, 2,3,4,6-tetraacetate, (1S)-, in tetrahydrofuran: methanol: water mixture, was added sodium hydroxide and the reaction mixture was stirred for about 6h. The reaction mixture was concentrated to give a residue and ethyl acetate and water were added it. The two layers were separated and the organic layer was concentrated and degassed to give amorphous dapagliflozin.
EXAMPLE 31: Preparation of amorphous dapagliflozin
To a stirred solution of 2,3-butanediol solvate of dapagliflozin (2g) in ethyl acetate, water was added and stirred for 30min. The two layers were separated and the organic layer was concentrated under reduced pressure. Isopropyl alcohol was added to the obtained residue and the reaction mixture was concentrated under reduced pressure and degassed for 12h. Cyclohexane was added to the obtained residue and stirred. The solid obtained was filtered to give amorphous dapagliflozin.
EXAMPLE 32: Preparation of amorphous dapagliflozin
To a stirred solution of D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, 2,3,4,6-tetraacetate, (1S)-, (10g) in tetrahydrofuran: methanol: water mixture, was added sodium hydroxide and the reaction mixture was stirred. The solvents were distilled out under vacuum and the residue obtained was treated with methylene dichloride, water and neutralized by using dilute hydrochloric acid. The two layers were separated and the organic layer washed with brine solution. The organic layer was concentrated and isopropyl alcohol was added to it. The organic layer was concentrated and degassed. The solid obtained was stirred with cyclohexane, filtered and dried to give amorphous dapagliflozin (7g). HPLC purity: 99.8%
After jet-milling:
D10 D50 D90
2.608µm 15.013µm 64.645µm

EXAMPLE 33: Preparation of D-Glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, 2,3,4,6-tetraacetate, (1S)- from D-glucono-1,5-lactone
To a mixture of D-glucono-1,5-lactone (10g) in methylene dichloride (80mL), hexamethyldisilazane (36.1g) was added and the reaction mixture was refluxed. After completion of reaction, the reaction mixture was concentrated and degassed. The residue obtained was dissolved in tetrahydrofuran. 5-Bromo-2-chloro-4'-ethoxydiphenylmethane (8.7g) was added to the reaction mixture which was cooled to about -75°C to about-85°C under nitrogen atmosphere. n-Butyl lithium in hexane (50mL) was slowly added to the reaction mixture maintaining the temperature between -75°C to about -85°C. The reaction mixture was stirred at about the same temperature and then mixture of methanol and methanesulphonic acid was added to it. The reaction mixture was quenched into sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with saturated sodium chloride solution and concentrated under vacuum to obtain a residue. This residue was purified by a mixture of toluene and cyclohexane. To the product obtained, methylene dichloride and acetonitrile were added and the reaction mixture was cooled to about -20°C to about -30°C. Triethylsilane (8.74g) was added to the reaction mixture followed by addition of boron trifluoride etherate (10.67g) maintaining temperature at about -20°C to about -30°C. The reaction mixture was quenched in sodium bicarbonate solution. The aqueous layer was separated and extracted with ethyl acetate. The organic layer was separated, concentrated and degassed under vacuum. The thick residue obtained was dissolved in methylene dichloride and cooled to about 0°C to about 5°C. Diisopropylethylamine, dimethylaminopyridine and acetic anhydride were added to the reaction mixture which was stirred. After completion of reaction, the reaction mixture was quenched by adding water. The aqueous layer was separated and extracted with methylene dichloride. The organic layer was separated, washed with sodium bicarbonate solution and concentrated under vacuum to obtain residue which was stripped out with methanol. The residue obtained was recrystallized with methanol and charcoal. The residue obtained was recrystallized with diisopropyl ether and then with methanol to give title compound (10g). HPLC purity: =99.8%
Compound VIII Impurity G Impurity H
Before purification 86.97% 4.21 1.82
1st methanol purification 98.76 0.05 0.08
Diisopropyl ether purification 99.08 Not detected 0.02
2nd methanol purification 99.85 Not detected 0.01
,CLAIMS:WE CLAIM
1. A process for the preparation of dapagliflozin in amorphous form comprising:
(a) reducing a compound of formula II to a compound of formula III in the presence of a Lewis acid;

(b) silylating a compound of formula IV with hexamethyldisilazane to form a compound of formula V;

(c) reacting the compound of formula III with the compound of formula V in the presence of a strong base followed by treatment with an acid in the presence of an alcohol to prepare a compound of formula VII, wherein R is an alkyl group selected from C1-5 alkyl;
VII
(d) converting the compound of formula VII to dapagliflozin;
(e) acetylating dapagliflozin to give D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, 2,3,4,6-tetraacetate, (1S)-, a compound of formula VIII;
VIII
(f) optionally, purifying the compound of formula VIII with a solvent selected from halogenated hydrocarbons, alcohols, ethers, or mixtures thereof;
(g) hydrolyzing the compound of formula VIII obtained in step (f) to give dapagliflozin;
(h) dissolving dapagliflozin of step (g) in a solvent selected from halogenated hydrocarbons, alcohols, hydrocarbons, or mixtures thereof to form a solution; and
(i) recovering amorphous dapagliflozin from the solution of step (h).
2. The process of claim 1, wherein the amorphous dapagliflozin is obtained in a purity of =99.8% and wherein the level of impurity A and impurity B is less than 0.15%
A B.
3. The process of claim 1, wherein in step (f), the alcohol is methanol and the ether is diisopropyl ether and in step (h), the alcohol is isopropyl alcohol and the hydrocarbon is cyclohexane.
4. A process for the preparation of dapagliflozin in amorphous form comprising:
(i) dissolving dapagliflozin in isopropyl alcohol to form a solution;
(ii) optionally, completely evaporating isopropyl alcohol from the solution of step (i) to give a residue;
(iii) adding cyclohexane to the solution of step (i) or the residue of step (ii); and
(iv) isolating amorphous dapagliflozin.
5. A process for the preparation of D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, 2,3,4,6-tetraacetate, (1S)-, a compound of formula VIII, in a purity of =99.6% and wherein the level of impurity G and impurity H is less than 0.15%, the process comprising:
G H
(a) treating the compound of formula VIII with an ether solvent to form a reaction mass;
(b) heating the reaction mass of step (a);
(c) cooling the reaction mass of step (b);
(d) obtaining the compound of formula VIII from the reaction mass of step (c);
(e) optionally, crystallizing the compound of formula VIII obtained in step (d) with an alcohol solvent; and
(f) isolating the compound of formula VIII with a purity of =99.6% and wherein the level of impurity G and impurity H is less than 0.15%.
6. The process of claim 5, wherein the ether solvent is selected from the group consisting of diethyl ether, diisopropyl ether, methyl tert-butyl ether, and the alcohol solvent is selected from the group consisting of methanol, ethanol, n-propyl alcohol, isopropyl alcohol.
7. A crystalline 2,3-butanediol solvate of dapagliflozin characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 3.7, 9.6, 14.7, 16.7 and 18.4 ±0.2 degrees 2 theta.
8. The solvate of claim 7, characterized by a proton NMR spectrum having peak positions at 7.40-7.25 (m,2H), 7.25-7.18 (d,1H), 7.12-7.00 (d,2H), 6.81-6.75 (d,2H), 4.97 (brs,2H), 4.84 (brs,1H), 4.46 (brs,1H), 4.32 (brs,2H), 4.10-3.90 (m,4H), 3.80-3.60 (m,1H), 3.55-3.05 (m,8H), 1.29 (t,3H), 1.05-0.85 (m,6H) ppm.
9. A process for the preparation of crystalline 2,3-butanediol solvate of dapagliflozin, the process comprising:
(a) treating dapagliflozin with 2,3-butanediol, optionally in the presence of a solvent, to form a solution;
(b) obtaining crystalline 2,3-butanediol solvate of dapagliflozin from the solution of step (a); and
(c) isolating the crystalline 2,3-butanediol solvate of dapagliflozin.
10. A process for the preparation of dapagliflozin in amorphous form comprising:
(a) dissolving 2,3-butanediol solvate of dapagliflozin in a solvent to form a solution; and
(b) recovering dapagliflozin in amorphous form from the solution of step (a) by:
(i) removing the solvent from the solution obtained in step (a); or
(ii) treating the solution of step (a) with an anti-solvent.
Dated this 4th day of May, 2016

(Signed)____________________
DR. MADHAVI KARNIK
GENERAL MANAGER-IPM
GLENMARK PHARMACEUTICALS LIMITED