Field of Invention
The present invention relates to an improved process for preparing (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol i.e, Dapagliflozin or stereoisomers, solvates or hydrates thereof. Also, the products obtained from the present invention may be used for the preparation of medicaments for the prevention and/or treatment of diseases and conditions in which Dapagliflozin is indicated.
Background of the Invention
The present invention is directed to a process for preparing (1S)-1, 5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol, i.e. Dapagliflozin.
Dapagliflozin is an orally active sodium glucose co-transporter 2 (SGLT 2) inhibitor, approved by the FDA in January, 2014 in the form of oral tablets for human use under the proprietary name, FARXIGA®. The active ingredient of the approved product is chemically designated as (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]~D-glucitol, (2S)-propylene glycol, monohydrate and is marketed for the treatment of type 2 Diabetes mellitus. The empirical formula is C21H25CIO6.C3H8O2.H2O and the molecular weight is 502.98. The structural formula is;

U.S. Patent No. 6,515,117 discloses the compound dapagliflozin and a process for its preparation wherein the process involves preparation of halogenated benzene derivative by reaction oi 5-bromo-2-chlorobenzoyl chloride with phenetole thereby isolating S-bromo^-chloro^'-ethoxybenzophenone, which upon reduction in acetonitrile at 50°C gives 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene of Formula III, coupling of TMS protected gluconolactone of Formula IV with halogenated benzene derivative of Formula 111 in presence of n-butyl lithium followed by methane sulfonic acid solution in presence of methanol to obtain O-methyiglucoside intermediate of Formula V. By the reduction of resulting O-methylglucoside intermediate of Formula V

with triethylsilane and boron trifluoride gives crude dapagliflozin, which upon
purification by first converting it into tetra acetylated dapagliflozin of Formula VI
followed by hydrolysis with lithium hydroxide gives pure dapagliflozin as an amorphous j
glassy off-white solid with purity 94%.

U.S. Patent No. 7,375,213 discloses the similar product patent route to prepare dapagliflozin by coupling of the gluconolactone with halogenated benzene derivative to obtain hydroxyl glucoside intermediate as solid, later glycosidation of -OH group to -OMe and simultaneous removal of acid-labile groups of glucoside moiety to yield above compound of Formula V.
U.S. Patent No. 8,952,139 discloses an alternate process for preparation of dapagliflozin by coupling 1,6-anhydro-2,4-di-0-tert-butyldiphenylsilyl-p-D-glucopyranose with 4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl magnesium bromide to yield 2l4-di-0-tert-butyldiphenylsilyl-1-C-(4-chloro-3-(4-ethoxybenzyl)phenyl)-p-D-glucopyranoside followed by deprotection in the presence of tetrahydrofuran (THF), TBAF and calcium carbonate to yield dapagliflozin.

PCT Publication No. WO2010/022313 discloses a process for preparation of dapagliflozin by coupling of TMS protected gluconolactone (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)"6-((trimethylsilyloxy)methyl)-tetrahydro-2H-pyran-2-one) with halogenated benzene derivative (4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene) to obtain O-methylglucoside intermediate ((2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyOphenylJ-e^hydroxymethyO-^-methoxytetrahydro^H-pyran-S^.S-triol) followed by reduction to obtain crude dapagliflozin. The crude dapagliflozin was purified by formation of dapagliflozin bis L-proline complex and which upon treatment with EtOH/water provides pure dapagliflozin.
Chinese patent publication No. 105294624 discloses the preparation of dapagliflozin by coupling sulfonoylated glucone moiety with halogenated benzene compound in presence of Grignard reagent and Lewis acid to get tetra acetyl dapagliflozin and finally deacetylation of acetyl groups provides dapagliflozin.
PCT Publication No. WO 2015/132803, WO 2015/0040571, WO 2015/044849 disclose processes for preparation of dapagliflozin by deacetylation of tetra-acetyl dapagliflozin.
Other patent publication No(s) WO2015/063726, IN3942/CHE/2010, CN103570510A, CN104086379B and CN104478670A disclose the preparation of dapagliflozin intermediate of 4-halo-1-chloro-2-(4-ethoxybenzyl)benzene.
PCT Publication No. WO2016/147197 discloses the preparation of Dapagliflozin by coupling sulfonoylated glucone moiety with halogenated benzene compound, glycosidation of OH group of the resulting compound with alcohols such as allyl alcohol, isopropyl alcohol or propargyl alcohol resulting in allyl, isopropyl or propargyl glucoside intermediate, followed by the reduction of resulting intermediate with triethylsilane and boron trifluoride gives dapagliflozin.

PCT Publication No. WO2018/029264 discloses a process for preparing dapagliflozin comprising reacting a compound of formula VI i.e., (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl) phenyl)-6-(hydroxy-methyl) tetrahydro-2H-pyran-3,4,5-triol with suitable ethylating agent in the presence of a solvent and a base to form crude dapagliflozin, which is further protected with substituted or unsubstituted benzaldehyde acetal to provide (4aR,6S,7R,8R,8aS)-6-(4-chioro-3-(4-ethoxybenzyl) phenyl)-2-phenylhexahydropyrano[3,2-d][l,3]dioxine-7,8-diol of formula (VII!). Deprotecting the compound VIII to form pure dapagliflozin.
Though existence of various processes for the preparation of dapagliflozin and its intermediates, there remains a need for an alternative process for the preparation of dapagliflozin producing high yields and purity, which is suitable for industrial scale.
The present invention provides an industrially viable process for preparing dapagliflozin or stereoisomers, solvates or hydrates thereof which avoids multiple purification steps, particularly avoiding the formation of isomeric and other process related impurities, while providing the desired product in high yield and purity.
Object of Invention
An object of the invention is to provide an industrially viable, improved process for the preparation of (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl] phenyl]-D-glucitol, i.e. Dapagliflozin, useful as an SGLT 2 inhibitor.
Another object of the invention is to provide an economical process for preparing dapagliflozin or stereoisomers, solvates or hydrates thereof, resulting in higher yield and better optical purity.
Further an object is to use the product obtainable from the process of the present invention to prepare medicaments useful for the prevention and treatment of diseases and conditions in which dapagliflozin is indicated.
Summary of Invention
The present disclosure relates to an industrially viable, economical process for preparing dapagliflozin, also chemically known as (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxypheny!)methyl] phenyl]-D-glucitol, or stereoisomers, solvates or hydrates thereof.

In one embodiment, the present invention provides an improved process for preparing dapagliflozin, comprising reacting a compound (7) in a suitable solvent with compound (8) in the presence of a base, represented as follows:

Wherein Ri is hydrogen or a hydroxy protecting group, R2 is Ci-4alkyl group; or an aryl group optionally substituted on ortho, meta or para positions with one or more halogen; electron withdrawing groups such as -NO2, -NH3+h -CN, -CHO, -COOH; C1-4 alkyl which is further optionally substituted with one or more halogen and R3 is ethyl.
In a second embodiment, the improved process of the present invention comprises preparing a compound (7) wherein a compound (6) is subjected to O-demethylation in the presence of a suitable solvent,

Wherein PG is a hydroxy protecting group and R1 is a hydroxyl protecting group.
In a third embodiment, the present invention provides a process for preparing compound (6), wherein the process comprises the following steps: (a) Coupling compound (2) with protected gluconolactone compound (3) in the presence of an alkyl lithium and suitable solvent to obtain an adduct, which is further treated with an alcohol in the presence of an acid to form compound (4);

Wherein in compound (3), PG is a hydroxy protecting group.

(b.1) the compound obtained from step (a) is treated with a suitable reagent in the presence of a base, wherein the hydroxy! groups are protected to form compound (5),

Wherein PG denotes a hydroxyl protecting group;
(Or) (b.2) the compound obtained from step (a) is subjected to reduction to obtain compound 5a; and

(c.1) the compound obtained from step (b.1) is further reacted with a reducing agent in the presence of a Lewis acid and a suitable solvent to form compound (6);

(c.2) the compound 5a obtained from step (b.2) is reacted with a suitable reagent in the presence of a base, wherein the hydroxyl group are protected to form compound (6).


In a fourth embodiment, the present invention provides a process for preparing ■
a compound (2), comprising reducing a compound (1) in the presence of a suitable reducing agent and Lewis acid;

The compound (1) may be prepared according to synthetic procedures well known in the art.
In a fifth embodiment, the products obtained from the improved process of the present invention may be used for the preparation of medicaments useful for the prevention and/or treatment of diseases and conditions associated with the inhibition of SGLT 2.
Detailed description of the invention
The present inventors have surprisingly found an industrially viable, cost-effective process for the preparation of (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol, i.e. Dapagliflozin, useful as an SGLT 2 inhibitor.
According to the present invention, the industrially viable process provides dapagliflozin or stereoisomers, solvates or hydrates thereof in higher yields and greater HPLC purity when compared to existing synthetic methods.
Unless defined otherwise, al! technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
As used herein, the term "SGLT2" refers to sodium glucose co-transporter 2, which is a sodium-dependent glucose transport protein. SGLT2 is the primary co-

transporter involved in renal glucose reabsorption. As used herein, "SGLT2 inhibitor" refers to any molecule that can modulate SGLT 2 activity in vitro or in vivo, preferably being dapagliflozin or stereoisomers, solvates or hydrates thereof.
The term "medicament" as used herein refers to a pharmaceutical composition containing the compounds prepared by the present invention, wherein the pharmaceutical composition may be used for human or non-human therapy of various diseases or disorders in a therapeutically effective dose.
As used herein, the term "protecting group" refers to a compound that is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection" occurs after the completion of the reaction or reactions in which the functionality would interfere. Thus, when a sequence of reagents is specified, as it is in the processes of the invention, the person of ordinary skill can readily envision those groups that would be suitable as "protecting groups". Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry [See e.g. Protective Groups in Organic Synthesis by T. W. Greene and P. G. M. Wuts, 2nd Edition; John Wiley & Sons, New York (1991)].
The "solvent" as used herein, unless until specified is selected from hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, ether, benzene, toluene, pentane, cycloheptane, methylcyclohexane, ethyl benzene or m-, o-, or p-xylenes and the like; ether solvents such as 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, t-butyl methyl ether or diisopropylether and the like; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; chlorinated solvents such as dichloromethane, chloroform and the like; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile and the like; alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n~butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl

alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol or glycerol and the like; polar solvents such as water or mixtures thereof.
The "base" as used herein unless until specified is selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; ammonia; and organic bases such as triethyl amine, methyl amine, ethyl amine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithium diisopropylamide (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethylaminopyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methylimidazole, 1,2,4-triazole, 1,4-diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.
The "reducing agent" as used herein unless until specified is selected from silanes such as e.g. triethylsilane, tripropylsilane, triisopropylsilane, or diphenylsilane; borohydrides such as sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes; aluminum hydride such as lithium aluminum hydride, diisobutylaluminum hydride, vitride.
The term "pharmaceutically acceptable" as used herein means suited for normal pharmaceutical applications, i.e. giving rise to no adverse events in patients etc.
In one embodiment, the present invention provides an improved, industrially viable process for preparing dapagliflozin or stereoisomers, solvates or hydrates thereof, wherein the process comprises reacting compound (7) in a suitable solvent with compound (8) in the presence of a base to form compound (9);

Wherein Ri is hydrogen or a hydroxy protecting group (PG); R2 is C1-4 alkyl group; or an aryl group optionally substituted on ortho, meta or para positions with one or more halogen; electron withdrawing groups such as -NO2, -Nhte*, -CN, -CHO, -COOH; C1-4 alkyl which is further optionally substituted with one or more halogen,; and R3 is ethyl. In preferred embodiments, the solvent used is acetonitrile and the base is potassium carbonate.
According to the present disclosure, the hydroxy protecting group (PG) is
selected from the group consisting of acetyl (Ac), propionyl, benzyl(Bn), 2-nitrobenzyl,
4-nitrobenzyl, p-methoxybenzyi (PMB),p-methoxybenzyl carbonyl (Moz or MeOZ),
2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl,3,4-dimethoxybenzyl1 benzoyl(Bz),
benzyloxycarbonyl (Cbz), p-methoxybenzyloxycarbonyl, phenethyl, carboethoxy,
carbomethoxy, t-butoxycarbonyl (BOC), 2,2,2-trichloroethoxy carbonyl(Troc), 2-
(trimethylsilyl)ethoxycarbonyl (Teoc),2-(4-trifluoromethylphenylsulfonyl)
ethoxycarbonyl (Tsc), tri(Ci-4-alkyl)silyl, tert-butyldimethyisiiyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methoxymethyl ethers, 2-tetrahydropyranyl (THP), Ci-Ce alkylsulfonylsuch as methanesulfonyl, allylether, 9-fluorenyimethyl,9-fiuorenylmethyl oxycarbonyl (FMOC), 1-adamantyloxycarbonyl (Adoc), 2-adamantylcarbonyl(2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl (Doc), cyclohexyloxycarbonyl(Hoc)( 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl (TcBOC), vinyl, 2-chforoethyl, 2-phenyisulfonylethyl, diphenyl-4-pyridylmethyl, N'.N'-dimethylhydrazinyl, t-butoxymethyl (Bum), benzyloxy methyl (BOM), 1-(ethoxy)ethyl, triphenylmethyl, diphenylmethyi, hydroxy methyl, N-pivaloyloxymethyl (POM), 1,1-diethoxymethyl. in preferred embodiments of the invention, PG is acetyl (Ac) and R2 is an aryl group preferably phenyl.
In one embodiment, where R1 is hydrogen, compound (7) in a suitable solvent is reacted with compound (8) in the presence of a base, where R2 and R3 are defined as hereinbefore to form dapagliflozin, solvates or hydrates thereof.
In an alternative embodiment, where R1 is a hydroxy protecting group, compound (7) in a suitable solvent is reacted with compound (8) in the presence of a

base, where R2 and R3 are defined as hereinbefore to form an adduct, which is further subjected to deprotection to yield dapagliflozin, solvates or hydrates thereof.

Deprotection may be carried out in the presence of a base or an acid. Preferably the base is same as used hereinbefore. The acid may be selected from mineral and organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, acetic acid, formic acid or mixtures thereof.
The reaction of compound (7) with compound (8) may be carried out at temperature of about 75-90°C.
In another embodiment, the present invention provides an improved process for preparing compound (7), wherein the process comprises subjecting the compound (6) to O-demethylation in the presence of a suitable solvent and a reagent-pair, wherein PG and R1 are as defined hereinbefore.

In the present context, thiourea and aluminium chloride (AlCb) form together a reagent pair. In thiourea/AICh reagent pair, the sulphur atom acts as a weak nucleophile and is capable of cleaving a methyl group from a methoxy, similar to the AlCb/Triethylsilane reagent.
Demethylation step may be carried out using a suitable reagent known in the art such as hydrogen bromide, boron tribromide, thiols such as dodecanethiol, decanethiol, cyclohexane thiol, cyclopentane thiol, cyclobutane thiol, thiophenol, methanethiol, ethanethiol, 1-propanethiol, 2-propanethiol, n-butanethiol, tert-butanthiol, furan-2-ylmethanethiol, ethandithiol, 1,2-propanedithiol, 1,3-propanedithiol, 1,3-butanedithiol, 1,4-butanedithiol in the presence of a suitable

solvent to yield a compound (7). The choice of solvent depends on the type of reagent used.
Surprisingly the present inventors have found that O-demethylation using dodecanethiol and thiourea-aluminium chloride reagent pair in dichloromethane resulted in the desired compound with higher purity and better yields compared to dodecanethiol or any other thiol reagent which when used alone or hydrogen bromide, boron tribromide.
In one preferred embodiment, where PG is a hydroxy protecting group preferably acyl, compound (6) is subjected to hydrolysis to first cleave the hydroxy protecting groups, followed by cleaving the phenolic methyl ether to yield a compound (7), wherein Ri is hydrogen.
In another preferred embodiment, where PG is a hydroxy protecting group preferably acyl, compound (6) is subjected to O-demethylation using thiourea-AICb and dodecanethiol in dichloromethane to form compound (7), wherein Ri is hydroxy protecting group, preferably an acyl group.
In the present disclosure, an acyl protecting group is cleaved for example hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroaeetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide, potassium hydroxide or alkali metal carbonates such as lithium carbonate sodium carbonate, potassium carbonate, cesium carbonate or amines such as, ammonia, methylamine, dimethylamine or aprotically, e.g. in the presence of iodotrimethylsilane.
In another embodiment, present invention provides an economical, industrially viable process for preparing compound (6), wherein the process comprises following steps:
(a) Reacting a diphenylketone compound (1) with a reducing agent in the presence of
a Lewis acid and a solvent to obtain diphenylmethane compound (2);

(b) Coupling diphenylmethane compound (2) with the protected gluconolactone (3) in
the presence of an alkyl lithium and suitable solvent to obtain an adduct, which is

further treated with a solvent in the presence of an acid to obtain compound (4),
wherein in compound (3), PG is a hydroxy protecting group preferably trimethylsilyl;
pi

(c) Treating compound (4) with a suitable reagent in the presence of
dimethylaminopyridine, wherein the hydroxy groups are protected to form a compound
(5), wherein PG denotes a hydroxy protecting group;

(d) Compound (5) is further reacted with a reducing agent in the presence of a Lewis
acid and a suitable solvent to form compound (6).

Wherein in step (a) reduction may be conducted with a reducing agent in the presence of or without a Lewis acid. Suitable reducing agents include for example silanes such as triethylsilane, tripropylsilane, triisopropylsilane, or diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, lithium aluminum hydride, diisobutylaluminum hydride. Suitable Lewis acids are such as e.g. boron trifluoride etherate (BF3.Etherate), aluminum chloride, trimethylsilyl triflate, trifluoroacetic acid, titanium tetrachloride, tin tetrachloride, scandium triflate, copper(ll) triflate, zinc chloride, indium (III) chloride and the like; or suitable Bronsted acids such as e.g. hydrochloric acid, toluenesulfonic acid, trifluoroacetic acid, or acetic acid.

The reaction may be carried out in a solvent such as for example dichloromethane, chloroform, acetonitrile, diethyl ether, tetrahydrofuran, dioxane or mixtures thereof, and at temperature ranging between 60-75°C. The solvent is preferably selected in view of the reducing agent and the optional Lewis acid. In preferred embodiments, step (a) is performed using sodium borohydride in the presence of aluminum chloride and tetrahydrofuran.
In the present context, compound (1) used in step (a) may be prepared according to the methods known in the art.
In step (b), the alkyl lithium may be selected from n-, sec-, and tert-butyl lithium, preferably n-butyl lithium is used. Suitable solvents include diethyl ether, tetrahydrofuran, toluene, hexane or dichloromethane, preferably tetrahydrofuran is used. Examples for acid include without limitation, methanesulphonic acid, hydrochloric acid, sulphuric acid, acetic acid and the like. The reaction may be carried out at temperature ranging between 100-120°C.
The compound (3) may be obtained from commercially available sources or prepared according to methods known in the literature.
In step (c), reaction may be carried out in the presence of a suitable reagent for introducing the hydroxy protecting group. In preferred embodiments, compound (4) is treated with acetic anhydride in the presence of N,N-dimethylaminopyridine (DMAP) and dichloromethane. This step may be carried out a temperature of about 20-30°C.
\n step (d), the reduction may be carried out using a reducing agent mentioned as hereinbefore. In preferred embodiments, reduction is carried out using triethylsilane in the presence of boron trifluoride etherate and dichloromethane.
In one preferred embodiment, the improved process for preparing (1S)-1, 5-anhydro-1 -C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol i.e. Dapagliflozin is represented in Scheme-A.

In another preferred embodiment, the improved process for preparing (1S)-1,5-anhydro-1-C-[4~chloro~3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol i.e. dapagliflozin is represented in Scheme-B.
According to Scheme B, the compound (4) obtained after coupling diphenylmethane compound (2) with a protected gluconolactone (3) is subjected to reduction with a reducing agent in the presence of a Lewis acid and a suitable solvent to form a compound (5a). The reducing agent and lewis acid may be used from the reagents described as hereinbefore. Preferably, triethylsilane and boron trifluoride etherate are used.
Further the compound (5a) is subjected to acylation using acetic anhydride in the presence of a base such as dimethylaminopyridine and dichloromethane to form compound (6).
Compound (6) is then subjected to O-demethylation in the presence of thiourea/AICb reagent pair and dodecanethioi in the presence of dichforomethane to yield compound (7), which is further reacted with compound (8) in the presence of a base and a solvent, to yield dapagliflozin.

In an embodiment, each compound obtained in each of the above-mentioned reaction schemes may be isolated and purified from the reaction mixture by for example, cooling the reaction mixture, applying an isolation operation of filtration, concentration, extraction and the like to separate a crude reaction product, and applying a general purification operation such as column chromatography, recrystallization and the like..
In another embodiment, each compound obtained in each of the above-mentioned reaction schemes may be proceeded to further steps without isolation and with or without drying in case if the compound is isolated.
In some embodiments, dapagliflozin obtained from the processes of the present invention mentioned in reaction schemes may be obtained as hydrates or solvates.
The solvates of dapagliflozin may be prepared by: (a) preparing a solution of dapagliflozin in one or more solvents described as hereinafter, (b) addition of solvents such as methanol, ethanol, ethylene glycol, 1,2-propanediol, 1,2-butanediol, 1,2-pentanediol, 1,2-hexanediol, 1,2-heptanediol to the above solution, (c) stirring the

above reaction mixture, followed by removal of the solvent(s) to form a dapagliflozin solvate.
The starting material (dapagliflozin) used for preparing solvates may be in reaction solution, suspension, or crude form.
In some other embodiments, dapagliflozin, solvates or hydrates thereof from the processes of the present invention mentioned in reaction schemes may be obtained in crystalline or amorphous form.
In one embodiment, the crystalline compound may be obtained by dissolving dapagliflozin, solvates or hydrates thereof in one or more solvents, precipitating the crystalline compound and/or removing the solvent(s),
Precipitation may be effected by conventional means such as partial removal of solvent, lowering the temperature or by adding anti-solvent or a combination thereof.
In an embodiment, the solvents for preparing solvates, crystalline or amorphous forms of dapagliflozin may be selected from alcohols such as methanol, ethanol, isopropyl alcohol, tert- butyl alcohol or n- butyl alcohol; ketones such as acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and methyl propyl ketone; esters such as ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate and methyl formate; chlorinated solvents such as dichloromethane and chloroform; ethers such as tetrahydrofuran, methyl tert-butylether, diisopropylether; hydrocarbons such as toluene, xylene and a mixture thereof. Preferable anti-solvents are n-heptane, cyclohexane, diisopropylether, petroleum ether and n-hexane.
The solvent(s) may be removed by one or more techniques known in the art such as filtration, filtration under vacuum, centrifugation, decantation, distillation and distillation under vacuum.
For the purpose of the present invention, the dapagliflozin starting material used for crystallization may be in reaction solution, suspension, crude or in anhydrous, hydrated or solvated form.
In one preferred embodiment, present invention provides preparation of dapagliflozin 1, 2-propanedioI wherein the process comprises; (a) dissolving the crude compound or reaction mixture containing dapagliflozin obtained from the improved processes of present invention in one or more solvents mentioned as hereinbefore, (b) addition of propane-1,2-dio! to the above reaction mass, (c) stirring the reaction mixture followed by addition of one or more anti-solvents described as hereinbefore, (d) removal of solvent(s) to form dapagliflozin propane-1,2-diol.

Optionally, the propane-1, 2-diol solvate may be purified using one or more solvents selected from chlorinated solvents, ethers, followed by addition of an anti-solvent selected from n-hexane, n-heptane, and the like.
In another embodiment, the amorphous compound may be obtained by dissolving dapagliflozin, solvates or hydrates thereof in one or more solvent(s), optionally followed by addition of anti-solvent(s), and removal of the solvent. The solvent(s) may be removed by techniques known in the art such as evaporation, distillation, spray drying, filtration, lyophilization, by using an agitated thin film drier (ATFD).
In an embodiment, the processes of the present invention described in reaction schemes above, provide dapagliflozin, solvates or hydrates thereof having a purity of 99% or more by HPLC. In preferred embodiments, the novel processes of the present invention provide dapagliflozin, solvates or hydrates thereof having a purity of 99.5% or more by HPLC.
In some other embodiments, dapagliflozin, solvates or hydrates thereof obtained from the processes of the present invention may be formulated in the form of solid dispersions with pharmaceutical^ acceptable polymers, solid complexes with pharmaceutically acceptable carriers, either in crystalline or amorphous form.
In another embodiment, the process of the present invention provides amorphous solid dispersions/solutions of dapagliflozin with pharmaceutically acceptable polymers, such as water soluble and water insoluble polymers. Examples of water soluble polymers include polyvinyl pyrrolidone (povidone), copovidone, polyvinyl alcohol, hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, polyethylene glycol, polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol copolymers (Soluplus™), and the like. Examples of water insoluble polymers include methylcellulose, ethylcellulose, polymethacrylates, hypromellose phthalate, hypromellose succinate, hypromellose acetate succinate (HPMC AS), cellulose acetate phthalate, carboxymethyl ethyl cellulose, and the like.
In yet another embodiment, the dapagliflozin, solvates or hydrates thereof obtained from the processes of the present invention may be formulated in the form of solid complexes with pharmaceutically acceptab]e earners including without limitation, cyclodextrins, saccharides, oligosaccharides, polysaccharides, amino acids, fats, waxes, urea etc. Examples of cyclodextrins include without limitation a-cyclodextrin, a p-cyclodextrin, or a y-cyclodextrin.

In another embodiment, the solid dispersions, solid complexes of dapagliflozin, solvates or hydrates thereof from present invention may be formulated into pharmaceutical compositions useful for the prevention and/or treatment of diseases or conditions in which it is indicated.
Advantages of Present invention:
1. Use of anisole in the preparation of compound (1), which is further used for preparing dapagliflozin reduces purification steps, and provides better yields and purity when compared to use of phenetole as observed in the prior art.
2. Use of reducing agents in the conversion of compound (1) to compound (2) is known in the art. However, the present invention uses aluminium chloride which is better and safe reducing agent when compared to titanium tetrachloride as used in the prior art. Also, titanium tetrachloride is difficult to handle as it releases fumes.
3. O-demethylation using dodecanethiol and thiourea-aluminium chloride reagent pair provides the desired compound with higher purity and better yields compared to dodecanethiol, or any other thiol reagent when used alone, or with the use of other reagents such as boron tribromide, HBr in acetic acid.
4. Coupling of compound (7) and compound (8) gives pure dapagliflozin, without
requiring additional purification steps.
From the above advantages, the process of the present invention is cost-effective due to less purification steps, easy to handle and providing improvement over the prior art.
Further the process for preparing dapagliflozin and intermediates thereof according to the present invention are illustrated in the following examples. The following specific and non-limiting examples are to be construed as merely illustrative, and do not limit the present disclosure in any way whatsoever.
Examples
Example 1: Preparation of (5-bromo-2-chlorophenyl)(4-methoxyphenyl)
methanone (1)
A solution of 5-bromo-2-chloro benzoic acid (150.0g) in dichlorometbane (750 mL) was stirred for 15-30 minutes. Dimethylformamide (0.6mi) and thionyl chloride (138.7mL) was charged to the above reaction mass (RM), stirred for 10-15 min. The RM was heated to 40-45°C and maintained for 2 hours. After completion of reaction,

distilled the RM completely under vacuum at 45°C, Charged dichloromethane (1200mL) in to the mass, cooled to 0-5°C. Charged aluminum chloride (101.9g) into the RBF, slowly added anisole (74.2g) into the mass at same temperature. After the reaction is complete, water (750 mL) was added to the RM, and slightly warmed to 20-30DC. The organic and aqueous layers were separated, the aqueous layer was extracted with dichloromethane (2 X 750ml_). Then the organic layer was washed with 2N hydrochloric acid solution, dichloromethane (2 X 750mL), followed by washing with sodium bicarbonate (2 X 750mL). The organic layer was then washed with sodium chloride solution (750mL) and dried over sodium sulfate. Then distilled the organic layer completely under vacuum at 40°C to remove the solvent completely. The solid obtained was washed with methanol (300.0mL),cooled to 0-5°C and stirred for 60 min. Filtered the mass and the compound was washed with 100.0mL of chilled (about 10 °C) methanol. Then air dried the compound for 6hrs to obtain the title compound (168.5g, 81.24%). (Purity by HPLC: 99.22%)
Example 2: Preparation of 2-(4-methoxybenzyl)-4-bromo-1-chlorobenzene (2)
A solution of compound 1(50.0g) and tetrahydrofuran (100ml_) was stirred for 10min. Cooled the RM to 0-5°C. Aluminum chloride (42.9g) was charged to the RM at the same temperature, stirred for 30 min at 0-5°C. Sodium borohydride (18g) was added into the RM, stirred for GO min at 5-10°C. RM was heated to 65-70°C and maintained for 15 hrs. After completion of reaction, the RM was cooled to 20-30°C and then to 0-5°C. Slowly added water (500.OmL) in to the mass at 5-10°C.Charged ethyl acetate (500 mL) to the RM and stirred for 10min at 20-30°C.The aqueous and organic layers were separated, aq. layer was extracted with ethyl acetate (250.OmL). Organic layer was washed with saturated sodium bicarbonate solution (2 X 250.OmL).Combined organic layers were dried over sodium sulfate. The organic layer was distilled completely under vacuum at 40°C and residue was treated with methanol (100.OmL). Stirred and, cooled the mass to -5 to 0°C and maintained for 60 min. Filtered the mass and compound was washed with 30.OmL of chilled (about 10 °C) methanol. Then the compound was air dried for 6hrs to obtain the title compound (36.2g, 75.65%). (Purity by HPLC: 99.63%)

Example 3: Preparation of Compound (4)
A mixture of toluene (300mL) and 50g of compound (2) was heated to 110-115°C and stirred for 90min. Charged 113.0gm of protected lactone (3) (wherein PG = trimethylsilyl) and tetrahydrofuran (350.OmL) in to the RM. Cooled the mass to -70 to -75°C and slowly added n-butyl lithium (216.OmL) to the RM at same temperature. After completion of reaction, slowly added 85.5gm of methane sulfonic acid in methanol solution. Then the mass was warmed to 20-30°C and stirred for 15hrs.The pH of the mass was adjusted to 8.0 by using saturated sodium bicarbonate solution. Aqueous and organic layers were separated. The organic layer was distilled completely under vacuum at 50°C.After removal of solvent, ethyl acetate was added and stirred for 10min.Aq and organic layers were separated and combined organic layers were washed with sat. Sodium chloride solution (200 mL).Organic layer dried with sodium sulfate and distilled the organic layer under vacuum at 50°C to obtain a wet residue containing the title compound (4).
Note: Methane sulfonic acid solution was prepared by mixing 85.5gm of methane sulfonic acid in 250.0 ml of methanol.
Example 4: Preparation of Compound (5) (PG = Acetyl)
To the residue obtained from Example 3, was added dichloromethane (400.OmL), followed by addition of dimethylaminopyridine (3.5 g) and acetic anhydride (82.3 g).The RM was stirred for 12hrs at 20-30°C.After the completion of reaction, water (250.0ml) was added to the RM and stirred for 10 min. Aqueous and organic layers were separated. The aqueous layer was extracted with dichloromethane (100.OmL).Total organic layer were combined and 250.0ml of 2N hydrochloric acid solution was added. Stirred the mass for 5min.Layers were separated, followed by washing with water (250.OmL) and stirred for 10min, until the compound is no longer present. Combined organic layers were dried with 20.0gm of sodium sulfate. The organic layer was distilled completely under vacuum at 45°C. After distillation methanol (100.OmL) was charged and distilled completely under vacuum, to obtain a residue containing the compound (5).
Example 5: Preparation of compound (6)
To the residue obtained from Example-4 was added dichloromethane (250.0 ml) and acetonitrile (250.OmL) in to the RB flask. The reaction mass was cooled to -60 ± 5°C

and slowly added triethylsilane (35.5gm) at the same temperature and stirred for 5 min. Borontrifluoride etherate (52.0gm) was slowly added to the reaction mass at -60 ± 5°C. Warmed the mass to 20-30°C. After completion of reaction, charged ethyl acetate (500.OmL) in to the mass and stirred for 5min, Aqueous and organic layers were separated and extracted with ethyl acetate (500.OmL). Combined the total organic layers and dry over sodium sulfate. Distilled the organic layer completely under vacuum at 55°C followed by washing with methanol and removing the solvent to yield the compound (6) (36g). (Purity by HPLC: 99.16%)
Example 6: Preparation of compound (5a)
The compound 5a was prepared from compound 4 using the conditions and reagents as described under Example 5.
Example 7: Preparation of compound (6) from compound 5a
Compound 6 was prepared from compound 5a using the conditions and reagents described under Example 4.
Example 8: Preparation of compound (7)
To compound 6 (2.0 gm) obtained from example 5 or example 7, was added dichloromethane (15.OmL), and cooled the mass to -5 to -10°C. Slowly added 20.0 mL of dodecanethioi & thiourea-AICta to the reaction mass. After completion of reaction, water (50.OmL) and dichloromethane (20.OmL) was added at 0-5°C.Stirred and aqueous and organic layers were separated. The aqueous layer was extracted with dichloromethane. Combined organic layers were dried with sodium sulfate after washing with water. The organic layer was distilled completely under vacuum at 40°C and dried for 4hrs to yield the title compound (1.8g, 92.31 %) (Purity by HPLC: 98.65%)
Example 9: Preparation of compound (8)
To a solution of ethanol (5 g), DMAP (3.5 g) and triethylamine (22 g) in toluene (25 mL), at 0-5°C, was added benzenesulfonyl chloride (23 g) in three portions. The RM was stirred at RT for 13 h. The RM was cooled to 0-5°C, and pH was adjusted to 1-2 using 2N HCl and stirred at RT for 15 min. The aqueous and organic layers were separated and the aqueous layer was extracted with toluene (2x25 mL). The combined organic layers were washed with 10% aq. sodium bicarbonate (2x20 mL), dried over anhydrous sodium sulphate and the solvent was removed under vacuum at 40°C to

obtain compound (8) as crude which was used in the next step without further purification.
Example 10: Preparation of compound (9) or Dapagliflozin
To the compound (7) (25.0gm) obtained from example 8, Acetonitrile (250.OmL) was charged followed by addition of potassium carbonate (25.0 g). Stirred the mass for 10min at20-30°C. Charged 15gm of compound (8) (where R2 = phenyl, R3 = ethyl) to the mass, heated to 70-75°C. Stirred the mass for 15hrs at70-75°C. After completion of reaction, cooled the mass to 10-15°C. Slowly added 250.OmL of water in to the mass followed by ethyl acetate (250.OmL). Stirred the mass for 10min. Separate aqueous and organic layers. Distilled the organic layer followed by purifying the residue through column in methanol and dichloromethane solvent system to obtain title compound (15g). (Purity by HPLC: 99.72%)
Example 11: Preparation of Dapagliflozin propane-1, 2-diol
To the compound (7) (2.0 gm) obtained form Example 8, was charged acetonitrile (40.0 mL) followed by addition of potassium carbonate (1.0 gm) and 1.5 gm of compound (8) (where R2 = benzyl, R3 = ethyl). Stirred the mass for 10 min. The reaction mass was heated to 80-85°C and stirred for 15 hr. After completion of reaction, the reaction mass was filtered, followed by washing with methanol (10.0 mL). The solvent was removed by distillation under vacuum at 50°C to give a gummy solid. To the solid obtained, was charged ethyl acetate (10.0 mL), water (6.0 mL) and stirred for 15 mins. The aqueous and organic layers were separated, extracted with ethyl acetate. The combined organic layer was charged with 1, 2-propanedioi (0.15 gm) and stirred for 15 mins. The reaction mass was cooled to 0-5°C and stirred for 15 mins. Slowly n-hexane was added and the mass for stirred for 30 mins. A solid obtained was filtered, washed with chilled n-hexane and dried to yield propane-1, 2-diol solvate of dapagliflozin. (Purity by HPLC: 99.68%)
Example 12: Purification of Dapagliflozin propane-1,2-diol:
To the compound obtained from Example 11 (1.2 gm), was charged dichloromethane (4.0 mL) and stirred for 15 min. To the above mass, was charged methyl tert-butyl ether (MTBE) (4.0 mL) and n-hexane (4.0 mL), stirred for 1 hr at RT. The solid obtained was filtered, washed with MTBE and dried to yield pure dapagliflozin propane-1, 2-diol. (Purity by HPLC: 99.81%)

The above examples are merely illustrative, and do not limit the scope of the invention in anyway.
The foregoing embodiments and advantages are merely exemplary and are not to be construed as limiting the scope of the present invention. The description of the exemplary embodiments of the present invention is intended to be illustrative and not to limit the scope of the invention. Various modifications, alterations and variations, which are apparent to a person skilled in the art, are intended to fall within the scope of the invention.

We Claim,
1. A process for the preparation of Dapagliflozin, stereoisomers, solvates or hydrates |
thereof represented by compound (9) comprising, reacting compound (7) with
compound (8),

Wherein Ri is hydrogen or hydroxy protecting group, R2 is C1-4 aikyl group; or an aryl group optionally substituted on ortho, meta or para positions with one or more halogen, electron withdrawing groups such as -NO2, -NH3+, -CN, -CHO, -COOH;Ci-4 alkyl which is further optionally substituted with one or more halogen, and R3 is ethyl.
2. A process for preparing (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]
phenyl]-D-glucitol i.e., dapagliflozin (9) as claimed in claim 1, comprising reacting
compound (7) with compound (8) in presence of a base and solvent,

Wherein a base is selected from inorganic bases like alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides, organic bases or mixtures thereof, and the solvent is selected from alcohols, ketones, esters, chlorinated solvents, ethers, hydrocarbon solvents.
3. A process for preparing compound (7) comprising;
(a) reducing the compound (1) to obtain diphenylmethane compound (2);

(b) Coupling diphenylmethane compound (2) with the protected gluconolactone (3),
followed by treatment with an acid to obtain compound (4),


Wherein in compound (3), PG is a hydroxyl protecting group;
(c.1) treating compound (4) with a suitable reagent, wherein the hydroxy groups are
protected to form compound (5), wherein PG denotes a hydroxyl protecting group;

(or) (c.2) compound (4) obtained from step (b) is subjected to reduction to obtain compound 5a;

(d.1) compound (5) from step (c.1) is further reacted with a reducing agent to form compound (6);

(d.2) compound (5a) obtained from step (c.2) is reacted with suitable reagent to protect the hydroxy groups to form compound (6).


(e) Subjecting compound (6) to O-demethylation in the presence of a reagent-pair, wherein Ri is hydrogen or a hydroxyl protecting group (PG).

4. A process as claimed in claim 3, wherein reduction is carried out using silanes such as e.g. triethylsilane, tripropylsilane, triisopropylsilane, or diphenylsilane; borohydrides such as sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, lithium aluminum hydride, diisobutylaiuminum hydride, vitride and the like; Lewis acid selected from aluminum chloride, boron trifluoride etherate (BF3.Et20), copper (II) triflate, tin tetrachloride, titanium tetrachloride, trimethylsilyl triflate, scandium triflate, zinc chloride, indium (111) chloride and the like; or Bronsted acids such as hydrochloric acid, toluenesulfonic acid, trifluoroacetic acid or acetic acid;
coupling is carried out using alkyllithium selected from n-, sec-, and tert-butyl lithium; the acid is selected from methanesulfonic acid, hydrochloric acid, sulphuric acid, acetic acid, and the like;
the suitable reagent for introducing the hydroxyl protecting group is selected from acetic anhydride, acetyl chloride;
the reagent pair is thiourea/AICb reagent pair; demethylation is carried out using reagents selected from dodecanethiol, decanethiol, cyclohexane thiol, cyclopentane thiol, cyclobutane thiol, thiophenol, methanethiol, ethanethiol, 1-propanethiol, 2-propanethiol, n-butanethiol, tert-butanthiol, furan-2-yl-methanethiol, ethandithiol, 1,2-propanedithiol, 1,3-propanedithiol, 1,3-butanedithiol, 1,4-butanedithiol.

5. A process for preparing compound (7) as claimed in preceding claims, comprising:
(a) reacting compound (1) with sodium borohydride in the presence of aluminium
chloride and tetrahydrofuran to obtain diphenylmethane compound (2);

(b) coupling diphenylmethane compound (2) with the protected gluconolactone (3) in
the presence of n-butyllithium and tetrahydrofuran, followed by treatment with
methanesulfonic acid in methanol to obtain compound (4);

(c.1) treating compound (4) with acetic anhydride in the presence of N,N-dimethylaminopyridine, wherein the hydroxy groups are protected to form compound (5);

(c.2) compound (4) obtained from step (b) is subjected to reduction using triethysilane and boron trifluoride etherate to obtain compound 5a;


(d.1) compound (5) from step (c.1) is further reacted with triethylsilane in the presence of borontrifluoride etherate and dichloromethane to form compound (6);

(d.2) compound (5a) obtained from step (c.2) is reacted with acetic anhydride to protect the hydroxy groups in the presence of N,N-dimethylamtnopyridine to form compound (6);

(e) Subjecting compound (6) to O-demethylation in the presence of thiourea-AICb reagent pair and dodecanethiol to form compound (7).

6. A process for preparing propane-1, 2-diol solvate of Dapagliflozin comprising:
(a) Reducing the compound (1) to obtain diphenylmethane compound (2);

(b) Coupling diphenylmethane compound (2) with the protected gluconoiactone (3),
followed by treatment with an acid to obtain compound (4),


Wherein in compound (3), PG is a hydroxyl protecting group;
(c.1) treating compound (4) with a suitable reagent, wherein the hydroxy groups are
protected to form compound (5), wherein PG denotes a hydroxyl protecting group;

(or) (c.2) compound (4) obtained from step (b) is subjected to reduction to obtain compound 5a;

(d.1) compound (5) from step (c.1) is further reacted with a reducing agent to form compound (6);

(d.2) compound (5a) obtained from step (c.2) is reacted with suitable reagent to protect the hydroxy groups to form compound (6).


(e) Subjecting compound (6) to O-demethylation in the presence of a reagent-pair,
wherein Ri is hydrogen or a hydroxyl protecting group (PG).

(f) Reacting compound (7) with compound (8) to form a crude (1S)-1,5-anhydro-1-C-
[4-chloro-3-[(4-ethoxyphenyl)methyl] phenyl]-D-glucitol i.e., dapagliflozin (9);

(g) dissolving the crude compound from step (f) in one or more solvents,
(h) Adding propane-1,2-diol to reaction mixture from step (f),
(h) Stirring the reaction mixture followed by addition of an anti-solvent,
(i) removal of the solvent(s) to form propane-1,2-diol solvate of dapagliflozin.
7. A process as claimed in claim 6, wherein one or more solvents in step (f) are selected from alcohols such as methanol, ethanol, isopropyl alcohol, tert- butyl alcohol or n-butyl alcohol; ketones such as acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and methyl propyl ketone; esters such as ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate and methyl formate; chlorinated solvents such as dichloromethane and chloroform; ethers such as tetrahydrofuran, methyl tert-butylether, diisopropylether; hydrocarbons such as toluene, xylene and a mixture thereof;

an anti-solvent in step (h) is selected from n-heptane, cyclohexane, diisopropylether, petroleum ether, n-hexane and the like.