DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“AN IMPROVED PROCESS FOR THE PREPARATION OF EMPAGLIFLOZIN, FREE OF ACID AND FURANOSE IMPURITIES”

GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd Block, Madhapur, Hyderabad,
Telangana, INDIA -500 081

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

AN IMPROVED PROCESS FOR THE PREPARATION OF EMPAGLIFLOZIN, FREE OF ACID AND FURANOSE IMPURITIES

FIELD OF INVENTION:
The present invention directs to an improved process for the preparation of Empagliflozin with higher purity.

BACKGROUND OF THE INVENTION:
Empagliflozin is chemically known as 1-chloro-4-(ß-D-glucopyranos-1-yl)-2-[4-((S)- tetrahydrofuran-3-yloxy)-benzyl]-benzene. It is indicated for the treatment of type-2 diabetes. It is marketed under the brand name Jardiance®, having structural formula as represented by Formula I:

Formula I

U.S. Patent No. 7,579,449 disclosed a process for the preparation of empagliflozin, which comprises protection of 4-(5-bromo-2-chlorobenzyl) phenol with tert-butyldimethylsilylchloride and triethylamine followed by reaction of [4-(5-bromo-2-chlorobenzyl) phenoxy]-tert-butyl dimethylsilane with 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in the presence of tert-butyllithium and then reaction with methanesulfonic acid in methanol. The obtained product is then reduced with triethyl silane and boron trifluoride etherate to obtain 1-chloro-4-(ß-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl) benzene which is further reacted with (R)-3-(4- methylphenylsulfonyloxy) tetrahydrofuran to obtain empagliflozin. The above reduction step involves a tedious work-up like multiple extractions with ethyl acetate and chromatographic purification, which is not desirable for commercial scale production.

U.S. Patent No. 7,772,191 discloses other alternative process wherein the compound of 1-Chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzyl)-benzene is reduced with triethylsilane and boron trifluoride etherate, followed by protection with acetic anhydride and deprotection with aqueous potassium hydroxide to obtain empagliflozin.

U.S. Patent No. 9,024,010 discloses another process for the preparation of Empagliflozin, comprises reaction of 1-Chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzyl)-benzene with triethylsilane, aluminum chloride in presence of acetonitrile and dichloromethane.

U.S. Patent No. 9,834,533 discloses another process for the preparation of Empagliflozin, comprises reduction of [2-chloro-5-[(3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-2-yl] phenyl]-[4-[(3S)-tetrahydrofuran-3-yl] oxyphenyl] methanone in presence of Et3SiH, BF3Et2O by using mixture of solvents acetonitrile/ dichloromethane and further processing to get empagliflozin.

PCT Publication No. No. 2021250565A1 discloses another process for the preparation of Empagliflozin, comprises reaction of (3S)-3-[4-[(2-Chloro-5-iodophenyl)methyl]phenoxy]-tetrahydrofuran with 2,3,4,6-tetrakis-O-trimethylsilyl-D-glucono-1,5-lactone in the presence of borontrifluoride diethyl etherate to give a-D-Glucopyranose, 1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-2,3,4,6-tetrakis-O-(trimethylsilyl) in-situ followed by O-methylation to give a-D-Glucopyranoside, methyl 1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl] in-situ and then reduction in the presence of aluminum chloride, triethyl silane and acetonitrile- dichloromethane solvent mixture to give empagliflozin.

The above prior-art methods involve reduction of O-methylated empagliflozin in presence of mixture of solvents i.e. acetonitrile and dichloromethane. The present inventors surprisingly found that reduction of O-methylated empagliflozin in the presence of single solvent system i.e. preferably in the presence of dichloromethane solvent to give highly pure Empagliflozin with substantially free of furanose impurities and this reduction step plays an important role in the preparation of pure empagliflozin.

Further the present invention avoids multiple isolation steps at intermediate stages and involves single isolation step to get empagliflozin. Therefore, the present invented process is suitable for large scale operations and thereby commercially viable.

OBJECTIVES OF THE INVENTION:
In one aspect of the present invention provides an improved process for the preparation of Empagliflozin of formula (I), which is substantially free of the furanose impurities.

In another aspect of the present invention provides an improved process for the preparation of O-methylated Empagliflozin of formula VI or Empagliflozin of formula (I), which is completely free of the acid impurity.

In another aspect of the present invention relates to an improved process for the preparation of Empagliflozin of formula (I), which involves the single isolation step.

SUMMARY OF THE INVENTION:
The main aspect of the present invention provides an improved process for the preparation of Empagliflozin of formula (I), which is substantially free of the following furanose impurities:

Furanose Impurity 1

Furanose Impurity 2

In another aspect of the present invention provides an improved process for the preparation of Empagliflozin of formula (I), which involves the single isolation step, wherein the process comprising following reaction steps:
a) reacting D-Gluconolactone compound of formula II with Hexamethyldisilazane or trimethylsilane in a suitable solvent to provide a compound of formula III (in-situ);

b) condensing the compound of formula III (in-situ) with a compound of formula IV in presence of coupling agent in a suitable solvent to provide a compound of formula V (in-situ);

c) reacting the compound of formula V (in-situ) with methanol in presence of acid to provide a compound of formula VI (in-situ), and

d) reducing the compound of formula VI (in-situ) with a suitable reducing agent in presence of Lewis acid in a suitable solvent to provide Empagliflozin (I).

In another aspect of the present invention provides an improved process for the preparation of O-methylated Empagliflozin of formula VI or Empagliflozin of formula (I), which is completely free of the following acid impurity:

Acid Impurity

DETAILED DESCRIPTION:
The main embodiment of the present invention provides an improved process for the preparation of Empagliflozin free of acid and furanose impurities.

In an embodiment, the “suitable solvent” used in the present invention is selected from the group comprising of water, alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons and halogenated hydrocarbons; wherein alcohol is selected from the group consisting of methanol (MeOH), ethanol, iso-propanol, n-butanol, iso-butanol and the like; ester is selected from the group consisting of ethyl acetate, isopropyl acetate; ketone is selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone; ether is selected from the group consisting of methyl tert-butyl ether, diisopropyl ether, diethyl ether, tetrahydrofuran (THF), 2-methyl tetrahydrofuran, cyclopentyl methyl ether, dioxane and the like; halogenated solvent is selected from the group consisting of dichloromethane (DCM), chloroform, chlorobenzene, bromobenzene and the like; hydrocarbons is selected from the group consisting of toluene, xylene, cyclohexane and the like; nitrile is selected from the group consisting of acetonitrile (ACN), propionitrile and the like; amide is selected from the group consisting of N,N-dimethylformamide, N,N-dimethyl acetamide and the like; sulfoxide such as dimethyl sulfoxide; sulfone; or mixtures thereof.

The term “substantially free of” used in the present invention is means that less than about 0.3 area-% as measured by HPLC.

In one embodiment, the present invention relates to an improved process for the preparation of Empagliflozin of formula (I) which involves single isolation step, wherein the process comprising following reaction steps:
a) reacting D-Gluconolactone compound of formula II with Hexamethyldisilazane (HMDS) or trimethylsilane in a suitable solvent to provide a compound of formula III (in-situ);

b) condensing the compound of formula III (in-situ) with a compound of formula IV in presence of coupling agent in a suitable solvent to provide a compound of formula V (in-situ);

c) reacting the compound of formula V (in-situ) with methanol in presence of acid to provide a compound of formula VI (in-situ), and

d) reducing the compound of formula VI (in-situ) with a suitable reducing agent in a suitable solvent to provide Empagliflozin (I).


In an embodiment, in step b) process the Grignard or Lithium reagent of benzylbenzene (IV) may be prepared from the benzylbenzene IV either via a so-called halogen-metal exchange reaction or by inserting the metal into the carbon-halogen bond. The halogen-metal exchange to synthesize the corresponding lithium compound IV may be carried out for example with an organolithium compound such as e.g. n-butyllithium (n-BuLi), sec-butyllithium or tert-butyllithium; preferably n-butyllithium.

The analogous magnesium compound may also be generated by a halogen-metal exchange with a suitable Grignard reagent such as C3-4-alkylmagnesium chloride or bromide, for example isopropyl- or sec-butylmagnesium bromide or chloride or diisopropyl- or di-sec-butylmagnesium without or in the presence of an additional salt such as e.g. lithium chloride that may accelerate the metalation process.

In an embodiment, in step b) the desilylation process can be carried out in the presence of “acid” selected from but not limited to methane sulfonic acid (MsOH), toluene sulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, and hydrochloric acid; preferably methane sulfonic acid.

In an embodiment, in step c) the methylation process can be carried out in the presence of “acid” selected from but not limited to methane sulfonic acid (MsOH), toluene sulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, and hydrochloric acid; preferably methane sulfonic acid.

In an embodiment, in step c) the reaction of a compound of formula V with methanol in presence of acid is carried out by the addition of a mixture of an acid and methanol in single lot to provide a compound of formula VI.

In an embodiment, in step d) the reduction may be conducted with one or more ‘reducing agents” in the presence of one or more Lewis acids or without a Lewis acid. Suitable reducing agents include for example silanes (such as e.g. triethylsilane (Et3SiH), 1,1,3,3-tetramethyldisiloxane (TMDS), tripropylsilane, triisopropylsilane (TIPS), diphenylsilane), borane complexes (such as e.g. sodium cyanoborohydride (NaCNBH3), zinc borohydride) or aluminium hydrides (such as e.g. lithium aluminium hydride (LiAlH4), diisobutylaluminum hydride or lithium triisopropyl-aluminum hydride (Li(iPr)3AlH)); preferably triethylsilane. Suitable Lewis acids are for example aluminium chloride, boron trifluoride etherate (BF3.Et2O), trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, zinc iodide, or copper (II) triflate; preferably boron trifluoride etherate.

In another embodiment the present invention relates to an improved process for the preparation of Empagliflozin of formula (I) which involves single isolation step, wherein the process comprising following reaction steps:
a) reacting D-Gluconolactone of compound of formula II with Hexamethyldisilazane in dichloromethane to provide a compound of formula III (in-situ);

b) condensing the compound of formula III (in-situ) with a compound of formula IV in presence of n-BuLi in THF and toluene and followed by methanesulphonic acid to provide a compound of formula V (in-situ);

c) reacting the compound of formula V (in-situ) with methanol in presence of methanesulfonic acid to provide a compound of formula VI (in-situ), and

d) reducing the compound of formula VI (in-situ) with triethylsilane and boron trifluoride etherate in presence of DCM to provide Empagliflozin (I).

In another embodiment, the instant invention provides the preparation of Empagliflozin, wherein the compounds of formula (III), (V) and (VI) were not isolated, thus the process is economic.

In another embodiment, the present invention relates to an improved process for the preparation of O-methylated Empagliflozin of formula VI or Empagliflozin of formula (I), comprising reacting compound of formula V with a mixture of methanesulphonic acid and methanol in single lot to obtain a compound of formula VI.

In another embodiment, use of a single lot addition of a mixture of methanesulphonic acid and methanol in methylation of compound of formula V facilitate to completely free of following acid impurity:

Acid Impurity

In another embodiment, the present invention relates to an improved process for the preparation of Empagliflozin of formula (I), comprising reducing compound of formula VI to empagliflozin in presence of single solvent system using dichloromethane.

In an embodiment, reduction step may be conducted with one or more ‘reducing agents” in the presence of one or more Lewis acids or without a Lewis acid. Suitable reducing agents include for example silanes (such as e.g. triethylsilane, 1,1,3,3-tetramethyldisiloxane (TMDS), tripropylsilane, triisopropylsilane (TIPS), diphenylsilane), borane complexes (such as e.g. sodium cyanoborohydride (NaCNBH3), zinc borohydride) or aluminium hydrides (such as e.g. lithium aluminium hydride (LiAlH4), diisobutylaluminum hydride or lithium triisopropyl-aluminum hydride (Li(iPr)3AlH)). Suitable Lewis acids are for example aluminium chloride, boron trifluoride etherate, trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, zinc iodide, or copper (II) triflate.

In an embodiment, compound of formula VI can be obtained according to the methods described above. Further, the compound of formula VI can be isolated form or without isolation as directly obtained in reaction mass from previous reaction step.

In another embodiment, use of a single solvent such as dichloromethane in reduction process of O-methylated empagliflozin of formula VI facilitate to substantially free of following furanose impurities:

Furanose Impurity 1

Furanose Impurity 2

The starting materials used in the present invention is known in the art and the same can be prepared by the methods known in the art.

Analysis of acid and furanose impurity levels:
To summarize, we have used HPLC as an analytical method for validating and estimating acid and furanose impurities content in empagliflozin.

Table 1: Describes the batch analysis results for reduction step i.e. o-methyl empagliflozin to empagliflozin in process using different solvent system dichloromethane (DCM), acetonitrile (CH3CN), and mixture of dichloromethane & acetonitrile.

Table 1:
Batch Solvent Purity by HPLC (% area)

EMP/C057/1B/23 EMP 1B Alpha isomer Methoxy int. Fura
nose-1 Fura
nose-2 Des Bromo SM UI Total imp
DCM (In process) 85.95 0.13 ND 1.04 2.77 ND 3.0 14.05
EMP/C049/1B/38 CH3CN
(In process) 65.88 0.30 ND 10.85 14.15 ND 1.36 34.12
EMP/C057/1B/24 DCM / CH3CN
(In process) 84.44 0.20 0.25 3.17 6.79 ND 0.50 15.56

Table 2: Describes the batch analysis results for methylation step i.e. methylation of compound of formula V to O-methylated Empagliflozin of formula VI in process using different mode of addition of a mixture of methanesulphonic acid and methanol.

Table 2:
Batch Mode of addition Purity by HPLC (% area)

EMP/C114/1(iii)B/04-P2 Acid impurity Remarks
Slow addition / Lot wise addition
(In process) 4-6% Gummy residue of EMP-1B
EMP-C114-1B-09 Single lot addition
(In process) ND Solid

The following examples are provided as further detailed non-limiting illustrations of the technical solutions of the present application. They should not be construed as limiting the scope of the present application, but as merely illustrations and typical representatives of the present application.

EXAMPLES:
Example-1: Preparation of a compound of formula III:
To a stirred solution of 100 g of D-Gluconolactone in 600 mL of Dichloromethane were added 271.8 g (3.0 eq.) of Hexamethyldisilazane and 0.6 g of Iodine at 25-35oC under Nitrogen atmosphere as a single lot. Then warmed the reaction mass to 35-40oC and stirred the reaction mass for 6-8 h at 35-40oC under Nitrogen atmosphere. After completion of reaction distilled the dichloromethane at below 45oC and co-Distilled with 2 x 100 mL of Toluene at below 45oC under vacuum. 262.1 g of Stage-1A with quantitative yield and having ~90% purity.

Example-2: Preparation of a compound of formula III:
To a stirred solution of 100 g of D-Gluconolactone in 800 mL of Toluene was added the 0.2 eq. of DMAP at RT under nitrogen atmosphere. Then cooled the reaction mass to 0 to 5oC and added the 7.0 eq. of Triethyl amine followed by drop wise addition of 6 eq. of Trimethyl silyl chloride at 0 to 5oC. Then slowly warmed to RT and stirred at RT for 12 h. After completion of reaction, cooled to 0 to 5oC and quenched with 400 mL of water at below 10oC. Then stirred for 10 min and separated the Toluene layer and washed with 4 V of water and 2 V of 10 % Sodium chloride solution. Then distilled the organic layer and co-Distilled with 2 x 100 mL of Toluene at below 45oC under vacuum. 262.1 g of in situ formula III with quantitative yield and having ~90% purity.

Example-3: Preparation of Empagliflozin (compound I):
To a stirred solution of 100 g of a compound of formula IV in 2.5 V of THF and 5.0 V of Toluene solution was added 130.6 mL of 2.5 M of n-BuLi in n-hexane solution (1.2 eq.) dropwise over a period of 1-2 h at -70 to -85oC under Nitrogen atmosphere and stirred for 1 h at -70 to -85oC. Then added the 165.1 g (1.3 eq.) of in situ formula III in 200 mL of toluene via dropwise within 1-2 h at -70 to -85oC and stirred the reaction mass for 2 h at -70 to -85oC. After 2 h, 26.15 g of Methane sulfonic acid (1.0 eq.) in 300 Methanol solution added to reaction mass over a period of 1-2 h at below -50oC. Then slowly warmed the reaction mass to 25-30oC and 26.15 g of Methane sulfonic acid (1.0 eq.) in 300 Methanol solution added to reaction mass over a period of 1-2 h at 25-30oC. Then stirred the reaction mass for 20-24 h at 25-35oC. After 24 h (completion of reaction), cooled the reaction mass to 0-10oC and added the 500 mL of 3 % aq. Sodium hydroxide solution. Then warmed to RT and stirred at RT for 10 min and separated the Aq. Layer. The compound was extracted into 3 x 2 V of Aqueous Methanol (Methanol: Water: 8:1) from organic layer. Then distilled the solvents from combined aq. Layer and compound was extracted from 3 x 3 V of Dichloromethane. The combined DCM layer was washed with 3 V of 10 % Aq. Sodium chloride solution. Then water was removed through azeotropic distillation at reflux temperature, then cooled the reaction mass to -15 to -5oC then added the 1.53 eq. of Triethylsilane followed by 1.53 eq. of Boron trifluoride etherate at -15 to -5oC under nitrogen atmosphere. Then stirred the reaction mass at -15 to -5oC for 2 h followed by stirred for 4 h 0-5oC. After completion of reaction, quenched with 10 V of 8% aqueous sodium bicarbonate solution. Then slowly warmed to RT and stirred at RT for 3-4 h. Then filtered the solid, washed with 1V of DCM and 1V of water followed by 5V of water slurry wash to the wet solid. The wet solid was dissolved into 5 V of Ethyl acetate and 3 V of water at 60-80oC within 1-2 h time, then separated the organic layer at 60-80oC and cooled the organic layer to 0-5oC and stirred at 0-5oC for 2-3 h. Then filtered the solid and wash with 1 V of chilled Ethyl acetate. Then dried the solid under vacuum oven at below 60oC to get constant weight and obtained the 61.3 g of pure ICH quality of Empagliflozin with 50.0 % overall yield.

Example-4: Preparation of Empagliflozin (compound I):
To a stirred solution of 100 g of compound of formula IV in 2.5 V of THF and 5.0 V of toluene solution was added 130.6 mL of 2.5 M of n-BuLi in n-hexane solution (1.2 eq.) dropwise over a period of 1-2 h at -70 to -95oC under nitrogen atmosphere. Then added the 165.1 g (1.3 eq.) of in situ formula III in 200 mL of toluene solution via dropwise within not less than 30 minutes at -70 to -95oC and stirred the reaction mass for 2-3 h at -70 to -95oC. After completion of reaction, 52.3 g of methane sulfonic acid (2.0 eq.) in 600 methanol solution slowly added to reaction mass at below -20 to 0°C. Then warmed the reaction mass to 25-35oC and stirred the reaction mass for 22-26 h at 25-35oC. After completion of reaction, cooled the reaction mass to 0-10oC and slowly added the 500 mL of 3 % aq. sodium hydroxide solution. Then warmed to RT and stirred at RT for 10 min and separated the aqueous layer. The compound was extracted into 2 V of aqueous methanol (methanol: water: 1.6 V: 0.4 V) from organic layer and extracted into 2 x 2 V of aqueous methanol (methanol: water: 1.4 V: 0.6 V). Then distilled the solvents from combined aqueous layer and compound was extracted from 5 V of dichloromethane followed by 2 x 3 V of dichloromethane. The combined DCM layer was washed with 3 V of 10 % aqueous sodium chloride solution. Then water was removed through azeotropic distillation at reflux temperature, then cooled the reaction mass to -15 to -5oC then added the 1.53 eq. of triethylsilane as a single lot followed by drop wise addition of 1.53 eq. of boron trifluoride etherate at -15 to -5oC under nitrogen atmosphere and stirred the reaction mass for 2-3 h at -15 to -5oC. After completion of reaction, warmed the reaction mass to 0-5oC and stirred for 2-3 h at 0-5oC. Then quenched the reaction mass with 10 V of 8% aqueous sodium bicarbonate solution at below 30oC. Then slowly warmed to 20-30oC and stirred at 20-30oC for 3-4 h. Then filtered the solid, washed with 1V of water and 1V of DCM. Then slurry wash of wet solid with 5V of water at 25-35oC for 1-2 h followed by filter the solid and washed with 1 V of water. The wet solid was dissolved into 5 V of ethyl acetate and 3 V of water at 60-80oC within 1-2 h time, then cool the reaction mass to 50-70oC and separated the organic layer at 50-70oC. Then gradually cooled the organic layer to 0-5oC and stirred at 0-5oC for 3-4 h. Then filtered the solid and washed with 1 V of pre cooled ethyl acetate. The wet solid was dissolved into 3 V of Ethyl acetate and 1 V of water at 60-80oC within 1-2 h time, then gradually cooled the organic layer to 0-5oC and stirred at 0-5oC for 3-4 h. Then filtered the solid and washed with 0.5 V of pre cooled ethyl acetate. Then dried the solid under vacuum oven at 50-60oC to get constant weight and obtained the 61.3 g of pure ICH quality of Empagliflozin with 50.0 % yield.

Dated this: 29th day of December, 2023.
Signature:
Name: Mr. Rama Rao Javvaji
Patent Agent Reg. No.: IN/PA-1669
GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd Block,
Madhapur, Hyderabad, Telangana, INDIA-500 081
,CLAIMS:We claim:
1. An improved process for the preparation of Empagliflozin of formula (I), in a single isolation step, which comprises:
a) reacting D-Gluconolactone of compound of formula II with Hexamethyldisilazane or trimethylsilane in a suitable solvent to provide a compound of formula III (in-situ);

b) condensing the compound of formula III (in-situ) with a compound of formula IV in presence of coupling agent in a suitable solvent to provide a compound of formula V (in-situ);

c) reacting the compound of formula V (in-situ) with methanol in presence of acid to provide a compound of formula VI (in-situ), and

d) reducing the compound of formula VI (in-situ) with a suitable reducing agent in presence of Lewis acid in a suitable solvent to provide Empagliflozin (I).

2. The process as claimed in claim 1, wherein in step b) the coupling agent is selected from Grignard reagent such as n-butyllithium, sec- butyllithium or tert-butyllithium or Lithium reagent such as C3-4-alkylmagnesium chloride or bromide.

3. The process as claimed in claim 1, wherein in step c) the acid is selected from methane sulfonic acid, toluene sulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid or hydrochloric acid.

4. The process as claimed in claim 1, wherein in step d) the suitable reducing agent is selected from silanes, borane complexes or aluminium hydrides; and the Lewis acid is selected from aluminium chloride, boron trifluoride etherate, trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, zinc iodide or copper (II) triflate.

5. The process as claimed in claim 1, wherein in step a) & b) the suitable solvent is selected from alcohols, ethers, amides, esters, nitriles sulfoxides, ketones, hydrocarbons, halogenated hydrocarbons, water or mixture thereof.

6. The process as claimed in claim 1, wherein in step d) the suitable solvent is dichloromethane.

7. An improved process for the preparation of O-methylated Empagliflozin of formula VI or Empagliflozin of formula (I), which is completely free of acid impurity:

Acid Impurity
comprising reacting compound of formula V with a mixture of methanesulphonic acid and methanol in single lot to provide a compound of formula VI.

8. An improved process for the preparation of Empagliflozin of formula (I), which is substantially free of furanose impurity 1 & 2:

Furanose Impurity 1

Furanose Impurity 2
comprising reducing O-methylated Empagliflozin of formula VI in presence of dichloromethane as a single reaction solvent to provide Empagliflozin (I).

9. The process as claimed in claim 8, wherein the reduction is carried out in presence of reducing agent and Lewis acid.

10. An improved process for the preparation of Empagliflozin of formula (I), in a single isolation step, which comprises:
a) reacting D-Gluconolactone of compound of formula II with Hexamethyldisilazane in dichloromethane to provide a compound of formula III (in-situ);

b) condensing the compound of formula III (in-situ) with a compound of formula IV in presence of n-BuLi in THF and toluene and followed by methanesulphonic acid to provide a compound of formula V (in-situ);

c) reacting the compound of formula V (in-situ) with methanol in presence of methanesulfonic acid to provide a compound of formula VI (in-situ), and

d) reducing the compound of formula VI (in-situ) with triethylsilane and boron trifluoride etherate in presence of dichloromethane to provide Empagliflozin of formula (I).

Dated this: 29th day of December, 2023.
Signature:
Name: Mr. Rama Rao Javvaji
Patent Agent Reg. No.: IN/PA-1669
GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd Block,
Madhapur, Hyderabad, Telangana, INDIA-500 081