Claims:
1. An improved process for preparation of Empagliflozin of formula (A) and its (R)-isomer or salts thereof, comprising the step of:
a) coupling a compound of formula (I) and a compound of formula (II) in presence of a predefined base and a predefined solvent at a predefined temperature;
wherein, R3 is selected from (C1-C4) alkyl, phenyl substituted by groups selected from methyl, nitro, cyano, aldehyde, -CHO, -COOH, trifluoroalkyl, halogen.

2. The process as claimed in claim 1, wherein the base is selected from the group of alkali metal carbonate, alkali metal hydroxide, potassium phosphate, triethylamine, diisopropylethylamine, DBU or DABCO.
3. The process as claimed in claim 2, wherein the alkali metal carbonate base is selected form potassium carbonate, sodium carbonate, sodium bicarbonate or potassium bicarbonate.
4. The process as claimed in claim 2, wherein the alkali metal hydroxide base is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide.
5. The process as claimed in claim 1, wherein the solvent is selected from the group of alcohols, ethers or ketones.
6. The process as claimed in claim 5, wherein the solvent is selected from methanol, ethanol isopropanol, butanol, methanol, methyl ethyl ketone, acetone, methyl ethyl ether or cyclopentyl methyl ether.
7. The process as claimed in claim 1, wherein the coupling reaction is carried out at a temperature of 50°C to 110°C.
8. The process as claimed in claim 1, wherein the coupling reaction is carried out in presence of the alcoholic solvent at a temperature of about 60°C- 100°C.
9. The process as claimed in claim 1, wherein the coupling reaction is carried out in presence of the ketonic solvent at a temperature of about 50°C- 100°C.
10. The process as claimed in claim 1, wherein the coupling reaction is carried out in presence of the etheral solvent at a temperature of about 50°C- 100°C.
11. The process as claimed in claim 1, wherein synthesis of the compound of formula (I) comprising the steps of:
d) converting a compound of formula (IV) to an organometallic compound of formula (IVa) by halogen-metal exchange or by inserting a metal in the carbon-halogen bond of a halogen-benzylbenzene compound of formula IV,
e) adding a predefined quantity of the compound of formula (IVa) to a predefined quantity of D-gluconolactone or a derivative of formula (III) at a predefined temperature in presence of a predefined inert solvent to obtain a compound of formula (V), wherein optionally isolating the of compound of formula (V);
,
wherein R1 is selected from benzyl, acetyl, benzoyl, trimethylsilyl; X is bromo, iodo; R2 is selected from TBDMS, benzyl; and
f) reacting the compound of formula (V) with a predefined quantity of a reducing agent in presence of a Lewis or Bronsted acid, wherein a predefined protective group (s) are cleaved simultaneously or subsequently to obtain a compound of formula (I).

12. The process as claimed in claim 11, wherein the organometallic compound in stage a) is prepared by halogen-metal exchange using organolithium compound or a predefined Grignard reagent.
13. The process as claimed in claim 12, wherein the organolithium compound is selected from n-butyllithium, Sec-butyllithium or tert-butyllithium.
14. The process as claimed in claim 12, wherein Grignard reagent is selected from isopropylmagnesium bromide or diisopropyl magnesium.
15. The process as claimed in claim 11, wherein the step b) is carried out at a temperature between 0°C to -100°C.
16. The process as claimed in claim 11, wherein the inert solvent is selected from diethyl ether, tetrahydrofuran, toluene, hexane, methylene dichloride (MDC), and a mixture thereof.
17. The process as claimed in claim 11, wherein the reducing agent in step c) is selected from triethylsilane, tripropylsilane, triisopropylsilane, diphenylsilane, borohydrides such as sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, lithium aluminum hydride, diisobutylaluminum hydride.
18. The process as claimed in claim 10, wherein the Lewis acid in step c) of the reaction is selected from boron trifluoride etherate, trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, copper(II) triflate trimethyl silyl chloride and zinc iodide, preferably Boron trifluoride etherate.
19. The process as claimed in claim 10, wherein the Bronsted acid in step c) is selected from hydrochloric acid, toluenesulfonic acid, trifluoroacetic acid, or acetic acid.
20. The process as claimed in claim 10, wherein the solvent in step c) is selected from methylene chloride, chloroform, acetonitrile, toluene, hexane, diethylether, tetrahydrofuran, dioxane, ethanol, water, or mixtures thereof.
21. The process as claimed in claim 10, wherein the step c) reaction temperature is between -80° C. and 120° C.
22. The process as claimed in claim 1, wherein the compound (A) has about 94 % to 96 % HPLC purity with about 76 % to 80% yield .
, Description:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)

&

THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
[See Section 10, Rule 13]

“IMPROVED PROCESS FOR THE PREPARATION OF EMPAGLIFLOZIN”

AARTI INDUSTRIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ADDRESS, 71, UDYOG KSHETRA, 2ND FLOOR, MULUND GOREGAON LINK ROAD, MULUND (W) MUMBAI, 400080, MAHARASHTRA, INDIA

THE FOLLOWING SPECIFICATION DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

Field of the Invention
The present disclosure relates to a sodium glucose co-transporter-2 (SGLT-2) inhibitor and more particularly to an improved process for the preparation of Empagliflozin and its pharmaceutically active salts with higher yield, higher chiral and HPLC purity.

Background
Diabetes mellitus is a lifelong condition requiring continuous medical care. Type-2 diabetes mellitus (T2DM), which accounts for approximately 90% to 95% of all diagnosed diabetes, is a progressive disease resulting from an insulin secretory defect characterized by insulin resistance and some degree of insulin deficiency. Metformin is the preferred medication because it has high efficacy in reducing HbA1c levels. Agents that can be added to metformin include: sulfonylureas, thiazolidinediones, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and insulin.

Empagliflozin, chemically referred as (2S,3R,4R,5S,6R)-2-[4-Chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol is an inhibitor of sodium glucose co-transporter-2 (SGLT-2). Empagliflozin is part of the newest class of oral hypoglycemic agents, which includes canagliflozin and dapagliflozin. Empagliflozin is approved for the treatment of type 2 diabetes to lower blood glucose levels. Empagliflozin has a low side-effect profile when used in combination with other anti diabetic medications.

US7579449 describes preparation of Empagliflozin, by coupling 1-chloro-4-(ß-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene with tetrahydrofuran-3-yl (R)-toluene-4-sulphonate. The reaction proceeds in presence of Caesium carbonate in dimethyl formamide. However, the yield obtained by the process is low (about 50-60%). Although the reported yield is in the range of 50-60%, from the comparative example stated below it is clear that the actual yield is very low around 25-35%. Also, caesium carbonate is costly as compared to the bases used in the present invention. Thus, the prior art process with Caesium carbonate is not cost effective at higher scale.

Further, CN107163092A discloses coupling of 1-chloro-4-(2,3,4,6-tetra-O-acetyl-ß-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene with (3R)-tetrahydrofuran-3-yl-p-toluenesulfonate. The reaction is carried out in presence of potassium carbonate in acetonitrile. Also the disclosure states that the base used is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, pyridine, Dimethylamino pyridine, DBU and DABCO. The yield reported is 87%.

Furthermore, WO2017/130217 discloses reaction of (((2S,38,4R,5R,6R)-2-(4-chloro-3-(4 ((trimethylsilyl)oxy)benzyl)phenyl)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl)tris(oxy))tris(trimethylsilane) with (R)-Tetrahydrofuran-3-yl-4-nitrobenzene sulfonate in presence of potassium carbonate in acetonitrile. The yield obtained in the reaction is 17% molar.

There are many disclosed process patents related to the preparation of various forms of Empagliflozin. Such processes disclosed in the literature involve several chemical steps and provide the product in a very low overall yield and result into expensive processes for the preparation of the intermediate and the final Empagliflozin API. In most of the conventional processes, the reaction requires protection of 1-chloro-4-(ß-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene with acetyl or silyl before condensation. The de-protection step after condensation is needed for isolation of Empagliflozin. Also isolation of Empagliflozin requires extensive extractive work up for isolation of pure Empagliflozin, which is tedious and time consuming. Further, known processes result in impurities as well as becomes expensive because of the overall process set ups.

Thus, there is a need for an improved process for the synthesis of Empagliflozin and its (R)-isomer or salts thereof, which avoids additional protection and de-protection steps, involves easy reaction work up, thereby resulting in high purity product and which allows the low production costs and high yields.

Objects of the invention

An object of present invention is to provide a process for the preparation of Empagliflozin and its (R)-isomer or salts thereof that avoids unnecessary protection and de-protection steps and provides simple reaction work up for isolation of Empagliflozin and/or its R-isomer or its salts.

Another object of present invention is to provide a process for the preparation of Empagliflozin and its (R)-isomer or salts thereof with higher HPLC and chiral purity, and with higher yield.

Further object of present invention is to provide a process for the preparation of Empagliflozin and its (R)-isomer or salts thereof, which is industrially feasible and avoids tedious work up required for isolation of Empagliflozin.

Summary of the invention
In one aspect, described herein is an improved process for the preparation of Empagliflozin and its (R)-isomer or salts thereof. The process comprises the step of coupling a compound of formula (I) and a compound of formula (II) in presence of a predefined base and a predefined solvent at a predefined temperature; wherein, R3 is selected from (C1-C4) alkyl, phenyl substituted by groups selected from methyl, nitro, cyano, aldehyde, -CHO, -COOH, trifluoroalkyl, halogen.

The base is selected from the group of alkali metal carbonate, alkali metal hydroxide, potassium phosphate, triethylamine, diisopropylethylamine, DBU or DABCO. The alkali metal carbonate base is selected form potassium carbonate, sodium carbonate, sodium bicarbonate or potassium bicarbonate. The alkali metal hydroxide base is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide. The solvent is selected from the group of alcohols, ethers or ketones such as methanol, ethanol isopropanol, butanol, methanol, methyl ethyl ketone, acetone, methyl ethyl ether or cyclopentyl methyl ether. The coupling reaction is carried out at a temperature of 50°C to 110°C. The coupling reaction is carried out in presence of the alcoholic solvent at a temperature of about 60°C- 100°C. The coupling reaction is carried out in presence of the ketonic solvent or etheral solvent at a temperature of about 50°C- 100°C.

Further, the process of the present invention requires synthesis of the compound of formula (I) which comprises an initial step of converting a compound of formula (IV) to an organometallic compound of formula (IVa) by halogen-metal exchange or by inserting a metal in the carbon-halogen bond of a halogen-benzylbenzene compound of formula IV. The second step includes addition of a predefined quantity of the compound of formula (IVa) to a predefined quantity of D-gluconolactone or a derivative of formula (III) at a predefined temperature in presence of a predefined inert solvent to obtain a compound of formula (V), wherein optionally isolating the of compound of formula (V);
,
wherein R1 is selected from benzyl, acetyl, benzoyl, trimethylsilyl; X is bromo, iodo; R2 is selected from TBDMS, benzyl.
The final step includes reacting the compound of formula (V) with a predefined quantity of a reducing agent in presence of a Lewis or Bronsted acid, wherein a predefined protective group (s) are cleaved simultaneously or subsequently to obtain a compound of formula (I).

The organometallic compound in first step for the synthesis of compound of formula (I) is prepared by halogen-metal exchange using organolithium compound or a predefined Grignard reagent. The organolithium compound is selected from n-butyllithium, Sec-butyllithium or tert-butyllithium. The Grignard reagent is selected from isopropylmagnesium bromide or diisopropyl magnesium. The second step for the synthesis of compound of formula (I) is carried out at a temperature between 0°C to -100°C. The inert solvent is selected from diethyl ether, tetrahydrofuran, toluene, hexane, methylene dichloride (MDC), and a mixture thereof.

The reducing agent used in the final step for the synthesis of compound of formula (I) is selected from triethylsilane, tripropylsilane, triisopropylsilane, diphenylsilane, borohydrides such as sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, lithium aluminum hydride, diisobutylaluminum hydride. The Lewis acid used in the final step of the reaction is selected from boron trifluoride etherate, trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, copper(II) triflate trimethyl silyl chloride and zinc iodide, preferably Boron trifluoride etherate. The Bronsted acid used in the final step is selected from hydrochloric acid, toluenesulfonic acid, trifluoroacetic acid, or acetic acid. The solvent is selected from methylene chloride, chloroform, acetonitrile, toluene, hexane, diethylether, tetrahydrofuran, dioxane, ethanol, water, or mixtures thereof. The reaction temperature in the final step for the synthesis of compound of formula (I) is between -80° C. and 120° C. The compound (A) has about 94 % to 96 % HPLC purity with about 76 % to 80% yield.

Detailed description of the invention
The foregoing objects of the present invention are accomplished and the problems and shortcomings associated with the prior art, techniques and approaches are overcome by the present invention as described below in the preferred embodiments.

All materials used herein were commercially purchased as described herein or prepared from commercially purchased materials as described herein.

Although specific terms are used in the following description for sake of clarity, these terms are intended to refer only to particular structure of the invention selected for illustration in the drawings and are not intended to define or limit the scope of the invention.

References in the specification to “preferred embodiment” means that a particular feature, structure, characteristic, or function described in detail thereby omitting known constructions and functions for clear description of the present invention.

In general aspect, the present invention relates to a process for the preparation of Empagliflozin of formula (A) and its (R)-isomer or salts thereof.

In another aspect, the present invention relates to a process of synthesis of a compound of formula (I) to obtain Empagliflozin of formula (A).

In a preferred embodiment, an improved process for the preparation of Empagliflozin of formula (A) and its (R)-isomer or its pharmaceutically acceptable salts thereof is disclosed. The process comprises:
a) coupling a compound of formula (I) and a compound of formula (II) in presence of a predefined base and a predefined solvent at a predefined temperature;
wherein, R3 is selected from(C1-C4) alkyl, phenyl substituted by groups selected from methyl, nitro, cyano, aldehyde, -CHO, -COOH, trifluoroalkyl, halogen, provided that base is not Caesium carbonate.

In this preferred embodiment, the base is selected from the group of alkali metal carbonate, alkali metal hydroxide, potassium phosphate, triethylamine, diisopropylethylamine, DBU or DABCO. The alkali metal carbonate base is selected form potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate. The alkali metal hydroxide base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide. The base is not a caesium carbonate base.

In this preferred embodiment, the solvent is selected from alcohol, ether or ketonic solvent. The alcoholic solvent is selected from methanol, ethanol isopropanol, butanol, preferably methanol. The ketonic solvent is selected from methyl ethyl ketone and acetone. The etheral solvent is preferably selected from methyl ethyl ether and cyclopentyl methyl ether. The reaction is carried out at a temperature range of 50°C -110°C. The final product of compound (A) has about 94 % to 96 % HPLC purity with about 76 % to 80% yield.

In an embodiment, a process for the preparation of Empagliflozin of formula (A) and its (R)-isomer or its pharmaceutically acceptable salts thereof is disclosed. The process comprises coupling of a compound of formula (I) and a compound of formula (II) in presence of a predefined base and an alcoholic solvent, wherein said coupling reaction temperature maintained is 60°C -100°C.

In another embodiment, a process for the preparation of Empagliflozin of formula (A) and its (R)-isomer or its pharmaceutically acceptable salts thereof is disclosed. The process comprises coupling of a compound of formula (I) and a compound of formula (II) in presence of a predefined base and a ketonic solvent, wherein said coupling reaction temperature maintained is 50°C -100°C.

In yet another embodiment, a process for the preparation of Empagliflozin of formula (A) and its (R)-isomer or its pharmaceutically acceptable salts thereof is disclosed. The process comprises coupling of a compound of formula (I) and a compound of formula (II) in presence of a predefined base and an etheral solvent, wherein said coupling reaction temperature maintained is 50°C -100°C.
In another embodiment, a process for the preparation of a compound of formula (I) is disclosed. The process comprises the steps of:
a) converting a compound of formula (IV) to an organometallic compound of formula (IVa) by halogen-metal exchange or by inserting a metal in the carbon-halogen bond of a halogen-benzylbenzene compound of formula IV,
b) adding a predefined quantity of the compound of formula (IVa) to a predefined quantity of D-gluconolactone or a derivative of formula (III) at a predefined temperature in presence of a predefined inert solvent to obtain a compound of formula (V), wherein optionally isolating the compound of formula (V);

wherein R1 is selected from benzyl, acetyl, benzoyl, trimethylsilyl; X is bromo, iodo; R2 is selected from TBDMS, benzyl; and
c) reacting the compound of formula (V) with a predefined quantity of a reducing agent in presence of a predefined Lewis or Bronsted acid at a predefined temperature to obtain a compound of formula (I).

In this embodiment, the compound of formula (IV) is benzylbenzene. The compound of formula (IVa) is an organometallic compound. The compound of formula (III) is D-glucopyranone. The compound of formula (V) is 1-chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene. The organometallic compound of formula (IVa) is obtained by halogen-metal exchange or by Grignard reaction i.e by inserting a metal in the carbon-halogen bond of a halogen-benzylbenzene compound of formula IV. The halogen-metal exchange with halogen, preferably bromine or iodine-substituted formula (IV) is carried out with an organilithium compound selected from n-butyllithium, Sec-butyllithium or tert-butyllithium to form the organometallic compound of formula (IVa) i.e corresponding lithiated compound of formula (IVa). The Grignard reagent is selected from isopropylmagnesium bromide or diisopropyl magnesium.

The addition of organometallic compound of formula (IVa) to gluconolactone compound of formula (III) is preferably carried out at temperature between 0°C to -100°C, preferably at -30°C to -80°C in an inert solvent selected from diethyl ether, tetrahydrofuran, toluene, hexane and methylene dichloride (MDC) and mixture thereof to yield compound of formula (V). Compound of formula (V) is optionally isolated using suitable isolating techniques known in the art. Alternatively, compound of formula (V) is directly converted to the compound of formula (I) by reduction using suitable reducing agents in presence of Lewis acid or Bronsted acid.

In this embodiment, the reducing agent is selected from triethylsilane, tripropylsilane, triisopropylsilane, diphenylsilane, borohydrides such as sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, lithium aluminum hydride, diisobutylaluminum hydride. Lewis acid of step c) of the reaction is selected from boron trifluoride etherate, trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, copper(II) triflate trimethyl silyl chloride and zinc iodide, preferably Boron trifluoride etherate. The Bronsted acid of step c) is selected from hydrochloric acid, toluenesulfonic acid, trifluoroacetic acid, or acetic acid. The solvent of step c) is selected from methylene chloride, chloroform, acetonitrile, toluene, hexane, diethylether, tetrahydrofuran, dioxane, ethanol, water, or mixtures thereof. The step c) reaction temperature is between -80° C. and 120° C, more preferably between -30°C and 80° C.

In an embodiment, in the halogen exchange step, the analogous magnesium compounds may also be generated by a halogen metal exchange with suitable Grignard reagent such as isopropylmagnesium bromide or diisopropyl magnesium. The reactions are preferably carried out at lower temperature between 0 to -100°C, preferably reaction performs better at temperature -10°C to -80°C, in an inert solvent selected from diethyl ether, tetrahydrofuran, toluene, hexane, MDC and mixture thereof. The magnesium or lithium compounds obtained may optionally be transmetallised with metal salt such as cerium trichloride to form organometallic compound.

In another embodiment, the organometallic compound of formula (IVa) is prepared by inserting metal into carbon-halogen bond of the compound of formula (IV) in a Grignard’s reaction. The metals are selected from lithium or magnesium for said reaction.

In an embodiment, compound of formula (V) is optionally isolated using suitable isolating techniques known in the art.

In another embodiment, compound of formula (V) is directly converted to the compound of formula (I) by reduction using suitable reducing agents in presence of Lewis acid or Bronsted acid.

The reaction scheme of preparing the compound of formula I is represented below:

OR

EXAMPLES
Only a few examples and implementations are disclosed. Variations, modifications, and enhancements to the described examples and implementations and other implementations can be made based on what is disclosed.

Examples are set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that can be utilized in practicing the disclosure. It will be apparent, however, that the disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples, and the resulting devices various different properties and uses in accordance with the disclosure above and as pointed out hereinafter.

Comparative Example
Preparation of (2S,3R,4R,5S,6R)-2-[4-Chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl] methyl] phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol (Empagliflozin)
1-chloro-4-(ß-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene (20 g) was charged to dimethylformamide (100 ml) to get clear solution. Tetrahydrofuran-3-yl-(R)-toluene-4-sulphonate (15.3 g) was charged to the solution. The mass was heated to 50 ± 3°C and Caesium Carbonate (43 g) was added. The reaction mass was stirred for 7 hours. The mass was cooled gradually at 28 ± 3°C and water (500 ml) was added. The mass was extracted with ethyl acetate (100 ml x 4). The combined ethyl acetate was washed with 10% NaCl (100 ml). The organic layer was dried on sodium sulfate. The solvent was distilled on rotary evaporator at 55 ± 3°C to yield Empagliflozin (7 g) (29.6% yield), HPLC Purity: 94%

Example 1
Preparation of (2S,3R,4R,5S,6R)-2-[4-Chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl] methyl] phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol (Empagliflozin)
Tetrahydrofuran-3-yl-(R)-toluene-4-sulphonate (475 g) was charged to the mixture of potassium carbonate (545 g) and 1-chloro-4-(ß-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl) -benzene (100 g). Ethanol (1000 ml) was added to the reaction mixture. The reaction mixture was heated to 78-81°C for 18-21 hours. Ethanol was distilled completely and water (2500 ml) was added to the mass. The mass was heated to 50°C to get clear solution. The solution was cooled gradually to 28-31°C and stirred for 2 hours. The suspension obtained was filtered and washed with water (500 ml). The solid was dried at 60-63°C for 3 hours to yield Empagliflozin (90 g) (76% molar yield), HPLC purity: 95%

Example 2
Preparation of (2S,3R,4R,5S,6R)-2-[4-Chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl] methyl] phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol (Empagliflozin)
1-chloro-4-(ß-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene (5 g) was charged in Methyl ethyl ketone (50 ml). DBU (2 ml) was charged to the reaction mixture. Tetrahydrofuran-3-yl-(R)-toluene-4-sulphonate (4.8 g) was charged to the reaction mixture and mixture was heated to 80 ± 3°C for overnight. The mass was cooled gradually to 28 ± 3°C and the solvent was distilled at 55± 3°C. Water (100 ml) was charged to the residue and the reaction mass was extracted with ethyl acetate (100 ml x 4). The combined ethyl acetate layer was washed with 10% NaCl (100 ml). The solvent was evaporated on rotary evaporator at 55 ± 3°C to yield Empagliflozin (4.5 g, Yield 76%).

Example 3
Preparation of (2S,3R,4R,5S,6R)-2-[4-Chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl] methyl] phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol (Empagliflozin)
A solution was prepared by dissolving 1-chloro-4-(ß-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene (5 g) and potassium hydroxide (1.1 g) in 50 ml ethanol. Tetrahydrofuran-3-yl-(R)-toluene-4-sulphonate (4.75 g) was charged to the solution. The reaction mixture was heated to 78 ± 3°C for 22 hours. The solvent was distilled out on rotary evaporator at 55 ± 3°C. Water (50 ml) was charged to the residue and the reaction mass was extracted with ethyl acetate (100 ml x 4). The combined ethyl acetate layer was washed with 10% NaCl (50 ml). The solvent was evaporated on rotary evaporator at 55 ± 3°C to yield Empagliflozin (3.5 g, Yield 59%).

Example 4
Preparation of (2S,3R,4R,5S,6R)-2-[4-Chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl] methyl] phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol (Empagliflozin)
To 1-chloro-4-(ß-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene (5 g) and sodium carbonate (4.17 g) ethanol (50 ml) was charged. Tetrahydrofuran-3-yl-(R)-toluene-4-sulphonate (4.76 g) was charged to the solution. The reaction mixture was heated to 78 ± 3°C for 21 hours. The solvent was distilled out on Rota evaporator at 55 ± 3°C. Water (100 ml) was charged to the residue and the reaction mass was extracted with ethyl acetate (100 ml x 4). The combined ethyl acetate layer was washed with 10% NaCl (50 ml). The solvent was evaporated on rotary evaporator at 55 ± 3°C to yield Empagliflozin (3.4 g, Yield 57%).

Example 5
Preparation of 1-chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene
Tert-butyl-[4-[(2-chloro-5-iodo-phenyl)methyl]phenoxy]-dimethyl-silane (100 g) was charged to Tetrahydrofuran (500 ml). To the solution prepared above was added 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (152.6 g). The reaction mixture was chilled at -70± 3°C. To the chilled mass was added n-BuLi (210 ml) slowly at -70± 3°C and mass was stirred for 2 hours. A solution of methane sulphonic acid (56.50 g) in methanol (800 ml) was added gradually and reaction mixture was stirred for 20 hours at 33±3°C. After completion of the reaction, the reaction mass was extracted with toluene (500 ml x 2). Methanol and THF was distilled on rotary evaporator at 50±3°C and mass was extracted with ethyl acetate (500 ml x 3). The organic layer was washed with 10% NaCl solution (500 ml). The organic layer was dried over sodium sulfate. The solvent was distilled on rotary evaporator at 50±3°C. The compound was stripped with acetone (500 ml x 2) followed by stripping with cyclohexane (500 ml x 2) and 1-chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene (85 g ) was isolated light yellow solid. (95% Yield, 96% Purity).

Example 6
Preparation of 1-chloro-4-(ß-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene
MDC (1000 ml) was charged to the mixture of Boron trifluoride etherate (198.6 g) and Triethylsilane (101.9 g). The reaction mixture was chilled at -20±3°C. The solution of 1-chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene (100g) in acetonitrile (1000 ml) was added slowly in the above chilled reaction mixture. The reaction mass was stirred for 1 hour at -20±3°C. 25% solution sodium carbonate (800 ml) was added slowly and the mass was stirred for 30 minutes at 28±3°C. Acetonitrile and MDC were distilled at 50±3°C. Further reaction mass was stirred for 5 hours at 50±3°C. The mass was extracted with ethyl acetate (500 ml x 4). The combined ethyl acetate layer was washed with 10% NaCl solution (500 ml). The organic layer was dried on sodium sulfate. The solvent was distilled on rotary evaporator at 55±3°C and substance obtained was degassed for 1 hour at 55±3°C. The material was stripped with acetone (500 ml). Acetone (400 ml) and cyclohexane (400 ml) was charged to the residue and stirred for 17-20 hours. The solid was filtered and washed with the mixture of acetone (50 ml) and cyclohexane (50 ml). The solid isolated was dried at 55±3°C for 3 hours to obtain 1-chloro-4-(ß-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene (70 g) (76% yield), HPLC purity: 97%

In the context of the present invention, the process of the present invention is an eco-friendly and a cost effective process. The process of the present invention advantageously eliminates the steps of additional protection and de-protection. The process of the present invention results in high yield of the end product of the present invention with maximum chiral and HPLC purity.

The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.

The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.

It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the present invention.