FORM 2
THE PATENT ACT, 1970
(39 OF 1970)
AND
The Patents Rules, 2003
PROVISIONAL/COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
< 'PROCESS FOR THE PREPARATION OF EMPAGLIFLOZIN"
2. APPLICANT:
a. NAME: 1NDOCO REMEDIES LIMITED
b. NATIONALITY: INDIAN
c. ADDRESS: Indoco House, 166 C.S.T. Road, Santacruz East,
Mumbai - 400 098, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner
in which it is to be performed.

FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of empagliflozin.
The present invention further relates to a process for preparation of novel intermediates during the preparation of empagliflozin.
BACKGROUND OF THE INVENTION:
Empagliflozin is chemically named as (2S,3R,4R?5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, having structural formula as represented by Formula (I).

Empagliflozin marketed under the proprietary name JARDIANCE® is an inhibitor of sodium glucose co-transporter-2 (SGLT2), which is found almost exclusively in the proximal tubules of nephronic components in the kidneys. SGLT-2 accounts for about 90 percent of glucose reabsorption into the blood. Blocking SGLT-2 reduces blood glucose by blocking glucose reabsorption in the kidney and thereby excreting glucose (i.e., blood sugar) via the urine. Empagliflozin belongs to a class of pyranosyloxy-substituted benzene derivatives and has enhanced inhibitory effect on SGLT2 in vitro and in vivo, while having improved pharmacological or pharmacokinetic properties when compared with other type-2 diabetic medications.
Empagliflozin and its process for preparation are described in the patent, US 7,579,449 (US'449 Patent). The process described in US'449 patent involves reacting (4-(5-bromo-2-chlorobenzyl)phenoxy)(tert-butyl)dimethylsilane of Formula A with 2,3,4,6-tetrakis-0-(trimethylsilyl)-D-gluconolactone of Formula

B in the presence of tert-butyllithium in diethyl ether at -80°C to form lactol, which is treated with methanesulfonic acid in methanol to give (2S,3R,4S,5S,6R)-2-(3-(4-((tert-butyldimethylsilyl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyI)-2-methoxytetrahydro-2H-pyran-354,5-triol of Formula C. The compound of Formula C in dichloromethane and acetonitrile is treated with triethylsilane and Boron trifluoride diethyl etherate at -10°C to obtain crude (2S,3R,4R,5Ss6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol of Formula D as 6:1 mixture of p/a which can be converted into the pure P-anomer by total acetylation of the hydroxy groups with acetic anhydride and pyridine in dichloromethane and recrystallising the product in ethanol solution, and the product thus obtained is reacted with 4M potassium hydroxide solution in methanol to get (2S,3R;4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol of Formula D. The compound of Formula D is reacted with tetrahydrofuran-3-yl (R)-toluene-4-sulphonate in the presence of cesium carbonate in N,N-dimethylformamide, the product formed is extracted with ethyl acetate, the solvent is removed and the residue is purified using silica gel (dichloromethane/methanol 1:0->5:1) to get empagliflozin of Formula I. The reaction sequence is represented as given in Scheme I.


The drawback in the prior art includes, lack of stereo selectivity during formation of P-anomer of the C-arylglucoside, protection and deprotection increasing the number of steps and loss of final yield making the process cumbersome and uneconomical.
In view of the above, there remains a need for stereoselective, more efficient and economic process for the preparation of empagliflozin of Formula I.
Thus, it is an objective of the present invention to develop a stereoselective and cost effective economical process for the preparation of empagliflozin, the compound of Formula I.
SUMMARY OF THE INVENTION:
Accordingly, the present invention provides a process for preparing empagliflozin, the compound of Formula I using readily available, cost effective, and industrially safe starting materials and reagents.
According to primary object of the present invention, there is provided a simple, cost effective process for the preparation of empagliflozin of Formula I,

which comprises the steps of;
a. reacting the compound, 4-(2-chloro-5-iodobenzyl)phenol of Formula VIII with a compound of Formula IX in presence of a base and a catalyst to get benzylated compound of Formula II;


wherein X is chlorine, bromine or iodine; and R1 and R2 are same or independently selected from hydrogen, chlorine, methyl, methoxy and nitro;
b. the benzylated compound of Formula II is reacted with the compound (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-tetrahydro-2H-pyran-2-one of Formula III to get the compound of Formula IV;

wherein R1 & R2 are as defined above;

wherein R1 & R2 are as defined above;
c. reacting the compound of Formula IV with a reducing agent in the presence of boron trifluoride-diethyl etherate and a solvent to get the dehydroxy compound of Formula V;

d. deprotecting the compound of Formula V to obtain the compound (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol of Formula VI.

e. reacting the compound of Formula VI with compound (R)-tetrahydrofuran-3-yl methanesulfonate of Formula VII in presence of a base and solvent to isolate compound crude empagliflozin of Formula I; and

f. purifying crude empagliflozin using either single or mixture of solvent to isolate the compound pure empagliflozin of Formula 1.
In another aspect of the present invention provides a novel compound of Formula
II;

wherein X is chlorine, bromine or iodine; and R1 and R2 are same or independently selected from hydrogen, chlorine, methyl, methoxy and nitro.
In another aspect of the present invention provides a novel compound of Formula IV;


wherein X is chlorine, bromine or iodine; and R1 and R2 are same or independently selected from hydrogen, chlorine, methyl, methoxy and nitro.
In another aspect of the present invention provides a novel compound of Formula
V;

wherein X is chlorine, bromine or iodine; and R1 and R2 are same or independently selected from hydrogen, chlorine, methyl, methoxy and nitro.
Within the context of the present invention "Bn" is always "benzyl.
These and the other objects of the present invention will be apparent from the following detailed description.
DETAILED DESCRITION OF THE INVENTION:
Unless specified otherwise, all 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. To describe the invention, certain terms are defined herein specifically as follows:

In the present invention description wherever "Bn" appears, unless and until it is specified is always "benzyl".
The present invention relates to a process for preparing empagliflozin, the compound of Formula I.

Formula I
The present invention discloses novel synthetic route for the preparation of empagliflozin. Within the context of the present disclosure, novel intermediates are generated which provide an improved and efficient method for the synthesis of empagliflozin of Formula I.
In an aspect, the present invention relates to a process for the preparation of empagliflozin of Formula I, which comprises the steps of:
a. reacting the compound, 4-(2-chloro-5-iodobenzyl)phenol of Formula VIII with a compound of Formula IX in presence of a base and a catalyst to get the benzylated compound of Formula II,

wherein X is chlorine, bromine or iodine; and R1 and R2 are same or independently selected from hydrogen, chlorine, methyl, methoxy and nitro;
b. the benzylated compound of Formula II is reacted with the compound (3R54S,5R,6R)-3,4,5-trisbenzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-one of Formula III to get the compound of Formula IV;


wherein R1 & R2 are as defined above; and "Bn" is benzyl;
c. reacting the compound of Formula IV with a reducing agent in the presence of boron trifluoride-diethyl etherate and a solvent to get the dehydroxy compound of Formula V;

wherein R1 & R2 are as defined above; and "Bn" is benzyl;
d. deprotecting the compound of Formula V to obtain the compound (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol of Formula VI;

wherein R1 & R2 are as defined above; and "Bn" is benzyl;
e. reacting the compound of Formula VI with compound (R)-tetrahydrofuran-3-yl methanesulfonate of Formula VII in presence of a base and solvent to isolate compound crude empagliflozin of Formula I; and


f. purifying crude empagliflozin using either single or mixture of solvent to isolate the compound pure empagliflozin of Formula I.
In an embodiment of the present invention, the base used in step (a) of the process is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine and diisopropylethylamine.
In an embodiment of the present invention, the base used in step (a) of the process is potassium carbonate.
In an embodiment of the present invention, the reaction in step (a) is carried out in presence of solvents selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, methyl ethyl ketone, N,N-dimethylformamide, dimethylsulfoxide and N-methylpyrrolidine, wherein the preferred solvent used for the reaction is acetone.
In an embodiment of the present invention, the catalyst used for the reaction in step (a) is selected from potassium iodide and sodium iodide, wherein the preferred catalyst used is potassium iodide.
In an embodiment of the present invention, the reaction in step (a) is carried out at a temperature in the range of 60°C to 70°C till completion of the reaction. The completion of the reaction was monitored on TLC. The reaction after completion is quenched with water and worked up to isolate the benzylated compound of Formula II.
The compound 4-(2-chloro-5-iodobenzyl)phenol of Formula VIII used in the present invention in step (a) is available commercially otherwise can be prepared as per the process disclosed in the prior art.

In an embodiment of the present invention the compound of Formula II as obtained in the above step (a) is reacted with the compound (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6((benzyloxy)methyl)tetrahydro-2H-pyran-2-one of Formula III as in step (b) above in a solvent at temperature range of -80°C to -60°C in presence of abase.
In an embodiment of the present invention, the solvent used in the reaction of step (b) is selected from the group consisting of tetrahydrofuran, ether, diethyl ether, dibutyl ether, toluene, xylene; or a mixture thereof.
In an embodiment of the present invention, the base used in the reaction of step (b) is selected from the group consisting of organometallic reagents such as n-butyllithium, sec-butyllithium, or mixture of n-hexyllithium and (trimethylsilyl)methyllithium, wherein the preferred base used for the reaction is n-butyl lithium.
In an embodiment of the present invention, the reaction in step (b) after completion the reaction mass is quenched using 10% solution of sodium bi carbonate at -80°C to 75°C. The reaction mass after work up yields the hemiketal compound of Formula IV.
The compound of Formula IV optionally purified from the group of solvent selected from ethyl acetate, acetone, methanol, ethanol, isopropanol, methyl ethyl ketone, methyl isobutyl ketone and petroleum ether or combination thereof to get purified hemiketal compound of Formula IV.
In an embodiment of the present invention the hemiketal compound of Formula IV as obtained in step (b) is subjected to reduction reaction using reducing agent in the presence of boron trifluoride diethyl etherate and solvent as in step (c) to isolate the dehydroxy compound of Formula V.
In an embodiment of the present invention, the reducing agent in step (c) was
selected from the group of reagents, phenylsilane, tri-n-propylsilane,
dimethylphenylsilane, triethylsilane, tris(trimethylsilyl)silane, triisobutylsilane,
triphenylsilane, tert-butyldimethylsilane, triisopropylsilane and

diisobutylaluminium hydride. The preferred reagent for the reduction used is triethylsilane.
In an embodiment of the present invention, the solvent used in step (c) was selected from the group of solvents such as dichloromethane, dichloroethane, chloroform, toluene, xylene, tetrahydrofuran, ether, ethyl acetate and acetonitrile or combination thereof. The reduction reaction was carried out at the temperature in the range of 20°C to 35°C, wherein the preferred temperature for the reduction is 25°C to 30°C.
In an embodiment of the present invention, the reduction reaction in step (c) after completion was quenched with water and neutralized the reaction solution by using ammonia solution. The reaction solution after work up results in dehydroxy compound of Formula V.
In an embodiment of the present invention, the dehydroxy compound is optionally purified using solvent selected from the group of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide and water or in combination thereof. The preferred solvent for purification is the mixture of tetrahydrofuran and methanol.
In another embodiment of the present invention, the deprotection reaction of step (d), the compound of Formula V as obtained in step (c) above is carried out in presence of a reducing agent and solvent to get the compound (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol of Formula VI.
In an embodiment of the present invention the reducing agent used in step (d) is selected from the group of sodium iodide/boron trifluoride-diethyl etherate, Palladium/carbon, iodotrimethylsilane or mixture thereof. The preferred reducing agent used is sodium iodide/boron trifluoride-diethyl etherate.
In an embodiment of the present invention, the solvent used for deprotection reaction in step (d) is selected from the group consisting of acetonitrile, methanol, ethyl acetate, tetrahydrofuran, diethyl ether and toluene or in combinations

thereof. The temperature of the reaction is maintained in the range of 20°C to 40°C.
In an embodiment of the present invention, after completion of the deprotection reaction of step (d), the reaction mass was quenched with triethyl amine at 25°C to 30CC and stirred for few hours. The quenched reaction after work up results in the residual mass, which was treated with solvent methyl isobutyl ketone and water to get the solid mass of the deprotected compound (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol of Formula VI.
In an embodiment of the present invention, in the reaction of step (e), the
compound, (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol of Formula VI as obtained in the above step (d) is condensed with (R)-tetrahydrofuran-3-yl methanesulfonaie of Formula VII in presence of a base and solvent to obtain crude empagliflozin, the compound of Formula I.
In an embodiment of the present invention, the base used in step (e), of the process is selected from the group consisting of cesium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine and diisopropylethylamine. The preferred base used for the condensation reaction is cesium carbonate, potassium carbonate and triethylamine, wherein the most preferred base used for the reaction is cesium carbonate.
In an embodiment of the present invention, the solvent used in the condensation reaction of step (e) is an aprotic solvent selected from the group consisting of N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide and N-methylpyrrolidone or a mixture thereof. In a preferred embodiment, the solvent used for the condensation reaction is dimethyl sulfoxide and N,N-dimethylacetamide.

In an embodiment of the present invention, the reaction of step (e) is carried out at a temperature in the range of 20°C to 50°C. In a preferred embodiment, the reaction is carried out at 40°C to 45°C.
The compound (R)-tetrahydrofuran-3-yl methanesulfonate of Formula VII used in the present invention in step (e) is available commercially otherwise can be prepared as per the process disclosed in the prior art.
In an embodiment of the present invention, the crude empagliflozin as obtained in step (e) is purified, which comprises the steps of;
i. suspending crude empagliflozin in solvent;
ii. heating the reaction mass to 35°C to 40°C;
iii. cooling and stirring the slurry; and
iv. filter the solid mass to isolate the pure empagliflozin of Formula I.
In an embodiment of the present invention, the solvent in step (i) is selected from the group of ethyl acetate, isopropyl acetate, methyl ethyl ketone, acetonitrile, methanol, isopropanol and water or combination thereof.
In another embodiment, the present invention provides the benzylated compound 4-(2-chloro-5-iodobenzyl)phenol of Formula II;

wherein Ri and R2 are same or independently selected from hydrogen, chlorine, methyl, methoxy and nitro.
In yet another embodiment, the present invention provides the compound of Formula IV;


wherein R1 and R2 are same or independently selected from hydrogen, chlorine, methyl, methoxy and nitro; and "Bn" is benzyl.
In yet another embodiment, the present invention provides the compound of Formula V;

wherein R1 and R2 are same or independently selected from hydrogen, chlorine, methyl, methoxy and nitro; and "Bn" is benzyl.
The following examples, which fully illustrate the practice of the preferred embodiments of the present invention, are intended to be for illustrative purpose only, and should not be considered to be limiting to the scope of the present invention.
EXAMPLES:
Example 1: Preparation of 2-(4-(benzyIoxy)benzyl)-l-chloro-4-iodobenzene:

A four neck round bottom flask was charged with 4-(2-chloro-5-iodobenzyl)phenol (175 gm, 0.5082 mol), acetone (2625 ml), potassium carbonate (210.42 gm, 1.524 mol), potassium iodide (16.87 gm, 0.1016 mol), and benzyl chloride (96.44 gm, 0.7624 mol) at 25-30°C. Raised temperature of the reaction mass to 65-70°C and maintained for 10-12 hours. The reaction mass was quenched with purified water and the aqueous layer extracted with ethyl acetate (1800 ml). Combined the organic layer and washed with purified water, 5% sodium hydroxide solution and 5% sodium chloride solution. Then the organic layer was distilled out on rotavapour to obtain solid. The crude compound was recrystallized in methanol to obtain 2-(4-(benzyloxy)benzyl)-l-chloro-4-iodobenzene (175 gm, 79% yield).
'H-NMR (CDC13, 400 MHz): 5 7.66 (d, 1H), 7.56-7.58 (m, 1H), 7.31-7.43 (m, 5H), 7.20-7.22 (d, 1H), 7.10-7.12 (d, 2H), 6.92-6.94 (s, 2H), 3.94 (s, 2 H), MS ESI (m/z): 432.81 [M-lf; IR: 3661, 3030, 2929, 2873, 1605, 1508, 1458, 1238
(cm-1)-
Example 2: Preparation of (3R,4S,5R,6R)-3,4,5«tris(benzyloxy)-2-(3-(4-
(benzy!oxy)benzyl)-4-chlorophenyI)-6-((benzyloxy)methyl)tetrahydro-2H-
pyran-2-ol:
In a four neck round bottom flask, charged a solution of 2-(4-(benzyloxy)benzyl)-l-chloro-4-iodobenzene (174 gm, 0.400 mol), (3R,4S,5R,6R)-3,4,5-tris (benzyloxy)methyl)tetrahydro-2H-pyran-2-one (237.2 gm, 0.440 mol) in tetrahydrofuran (3232 ml) and cooled to -78°C under nitrogen atmosphere. A 1.6 M solution of n-butyllithium in hexane (33.4 gm, 0.5205 mol) was added dropwise to the reaction mass and stirred the reaction mass at -78°C for 2 hours. The reaction mass was quenched with 10% sodium bicarbonate solution at -78°C. Raised the temperature of the reaction mass to 25°C - 30°C. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic layer was washed with 5% sodium chloride solution. Then the organic layer was distilled on rotavapour to obtain the residual mass. The crude compound was recrystallized in ethyl acetate and pet ether to obtain

(3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-(3-(4-(benzyloxy)benzyl)-4-chloro-phenyl)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-ol (210 gm, 59% yield).
'H-NMR (CDCb, 400* MHz): 5 7.55 (s, 1H), 7.19-7.43 (m, 26H), 7.03-7.05 (d, 2H), 6.92-6.94 (t, 1H), 6.88 (s, 1H), 6.80-6.82 (d, 1H), 4.99 (s, 2 H), 4.75- 4.78 (m, 3H), 4.47-4.59 (m, 3H), 4.32-4.35 (d, 1H), 3.95-4.0 (m, 4H), 3.61-3.75 (m, 4H), 3.33-3.38 (d, 2H); IR: 3304, 3029, 2877, 1631, 1511, 1454, 1244, 1096 (cm"
Example 3: Preparation of (2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-2-(3-(4-
(benzyloxy)benzyI)-4-chlorophenyl)-6-((benzyloxy)methyl)tetrahydro-2H-
pyran:
In a four neck round bottom flask, boron trifluoride-diethy 1 etherate (50.2 gm, 0.3537 mol) was added dropwise into a solution of (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-(3-(4-(benzyloxy)benzyl)-4-chlorophenyl)-6-((benzyloxy)-methyl)tetrahydro-2H-pyran-2-ol (200 gm, 0.2358 mol), triethylsilane (41.12 gm, 0.3537 mol) in mixture of acetonitrile:ethyl acetate (200 ml: 1000 ml) at 20-25°C. Then reaction mixture was stirred for 2 hours at 28-30°C and quenched with water and adjusted the pH 8 to 10 with aqueous ammonia. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layer was washed with 5% sodium chloride solution. Then the organic layer was concentrated and the residual mass was leached in methanol to get crude product. The crude product was recrystallized in tetrahydrofuran:methanol to obtain (2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-2-(3-(4-(benzyloxy)benzyl)-4-chlorophenyl)-6-((benzyloxy)methyl)tetrahydro-2H-pyran (100 gm, 50% yield).
'H-NMR (CDC13, 400 MHz): 5 7.25-7.44 (m, 20H), 7.17-7.19 (m, 5H), 7.03-7.07 (d, 2H), 6.81-6.85 (t, 5H), 4.99 (s, 2H), 4.74-4.79 (t, 3H), 4.44-4.57 (m, 3H), 4.34- 4.36 (m, 1H), 4.25-4.28 (s, 1H), 3.96-3.98 (q, 2H), 3.75-3.80 (m, 2H), 3.61-3.64 (m,4H), 3.49 (m, 1H); IR: 3030, 3029, 2863, 1945, 1875, 1612, 1512, 1242, 1092 (cm-1).

Example 4: Preparation of (2S,3R,4R,5S,6R)-2-(4-chIoro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound of Formula VI):
In a four neck round bottom flask, charged (2S,3S,4R,5R,6R)-3,4?5-tris(benzyloxy)-2-(3-(4-(benzyloxy)benzyl)-4-chlorophenyl)-6-((benzyloxy)-methy!)tetrahydro-2-H-pyran (80 gm, 0.0961 mol), acetonitrile (560 ml), sodium iodide (242.5 gm, 1.6188 mol) and purified water (20 ml) at 25-30°C, followed by addition of boron trifluoride-diethyl etherate (229.3 gm, 1.6160 mol) at 25°C -30°C. Maintained the reaction mass at 33°C - 35°C till the reaction complies on TLC. The reaction mass was cooled to 25°C - 30°C and added triethylamine (200 ml) slowly into the reaction mass. Stirred the reaction mixture at room temperature for 4 hours. Charged 6% sodium hydroxide solution into the reaction mass and stirred for 30 minutes. Separated the layers and aqueous layer was washed with three times five volumes of dichloromethane. The layers were separated, and the aqueous layer was cooled at 15°C - 20°C. Adjusted the pH of the reaction mass between 1-2 using concentrated hydrochloric acid and stirred the reaction mass for 30 minutes. The aqueous layer was extracted with ethyl acetate and washed with 2% hydrochloric acid solution. Washed the ethyl acetate layer with 25% sodium thiosulphate solution. Organic layer separated and was distilled and degassed to get residual oily mass. The oily mass was dissolved in methyl isobutyl ketone and charged water to isolate (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (32.8 gm, 89.6% yield).
Example 5: Preparation of (2S,3R,4R,5S,6R)«2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yI)oxy)benzyl)phenyI)-6-(hydroxymethyI)tetrahydro-2H-pyran-3,4,5-triol (compound of Formula I; crude empagliflozin).
In a four neck round bottom flask, charged (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyi)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4?5-triol (2.5 gm, 0.0065 mol), (R)-tetrahydrofiiran-3-yl methanesulfonate (2.38 gm, 0.0149

mol), cesium carbonate (9.6 gm, 0.0299 mol) and dimethylsulfoxide (25 ml) at 25°C - 30°C. Heated the reaction mass to 40°C - 42°C and continued to stir the reaction mass till completion of the reaction. Cooled the reaction mass to 25°C -30°C. Quenched with ethyl acetate (80 ml) and water (40 ml) and maintained under stirring for 60 minutes. Separated the organic layer and the aqueous layer was re-extracted with ethyl acetate (60 ml), combined the organic layer and washed with.water. The organic layer was distilled and degassed to get the residual solid mass. Further the solid mass was dissolved in mixture of solvent dichioromethane:methanol and charcolised. Distilled the solvent under reduced pressure to obtain solid compound. The solid compound was treated with ethyl acetate to isolate crude compound (2S,3R,4R,5S56R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol of Formula I (2.0 g, 80% yield) (Crude empagliflozin).
Example 6: Purification of crude empagliflozin.
In a four neck round bottom flask, charged crude empagliflozin (2.8 gm) and ethyl acetate (15 ml) at 25°C - 30°C. The reaction mass was heated to 35°C -38°C and charged methanol (0.5 ml). Reaction mass was stirred at 35°C - 38°C for 30 minutes and cooled the reaction mass to 20°C - 25°C and continued to stir the slurry mass further for 1 hour. Filtered the product and washed with mixed solvent ethyl acetate:methanol (2 ml, 1:1) to isolate pure empagliflozin (2.0 gm, 70% yield).

We claim;
1. A process for the preparation of empagliflozin of Formula I,

which comprises the steps of;
a. reacting a compound 4-(2-chloro-5-iodobenzyl)phenol of Formula VIII with a compound of Formula IX in presence of base and catalyst to get the benzylated compound of Formula II;

wherein X is chlorine, bromine or iodine; and R1 and R2 are same or independently selected from hydrogen, chlorine, methyl, methoxy and nitro;
b. the compound of Formula II is reacted with the compound (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetra-hydro-2H-pyran-2-one of Formula III to get the compound of Formula IV;


c. reacting the compound of Formula IV with a reducing agent in the presence of boron trifluoride-diethyl etherate in presence of solvent to get the dehydroxy compound of Formula V;

wherein Rl & R2 is as defined above; and "Bn" is benzyl;
d. deprotecting the compound of Formula V to obtain the compound (2S,3R,4R,5S56R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2-H-pyran-3,4,5-triol of Formula VI.

e. reacting the compound of Formula VI with compound (R)-tetrahydrofuran-3-yl methanesulfonate of Formula VII in presence of ' a base and solvent to isolate compound crude empagliflozin of Formula I; and

f. purifying crude empagliflozin using either single or combination of solvents to isolate the compound pure empagliflozin of Formula I. 2. The process according to claim 1, wherein the base used in step a) is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine and diisopropylethylamine

The process according to claim 1, wherein the catalyst used in step a) is selected from the group consisting of sodium iodide and potassium iodide.
The process according to claim 1, wherein the reaction of step (b) is carried out in the presence of base and a solvent at a temperature range of -80°C to 30°C.
The process according to claim 4, wherein the base used in step b) is organometallic compounds selected from the group of n-butyllithium, sec-butyllithium, n-hexyllithium, (trimethylsilyl)methyllithium, and mixtures thereof.
The process according to claim 4, wherein the solvent used in step b) is selected from the group consisting of tetrahydrofuran, diethyl ether, dibutyl ether, toluene, xylene; or a mixture thereof.
The process according to claim 1, wherein the reducing agent used in step c) is selected from the group consisting of phenylsilane, tri-n-propylsilane, dimethylphenylsilane, triethylsilane, triisobutylsilane, tris(trimethylsilyl)silane, triphenylsilane, tert-butyldimethylsilane, triisopropylsilanei diisobutylaluminium hydride, and mixtures thereof.
The process according to claim 1, wherein the solvent used in step c) is selected from the group consisting of dichloromethane, dichloroethane, chloroform, toluene, xylene tetrahydrofuran, diethyl ether, ethyl acetate, acetonitrile and mixtures thereof.
The process according to claim 1, wherein the deprotection reaction of Formula V in step d) is carried out in presence of a reducing agent and a solvent at a temperature range of 20°C to 40°C.
The process according to claim 9, wherein the reducing agent used is sodium iodide/boron trifluoride-diethyl etherate, Palladium/carbon, iodotrimethylsilane reagent, or a mixture thereof.
The process according to claim 9, wherein the solvent used for deprotection reaction is selected from the group acetonitrile, methanol, ethyl acetate, tetrahydrofuran, diethyl ether and toluene or a mixture thereof.

The process according to claim 1, wherein the base used in step e) is selected from the group consisting of cesium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine and diisopropylethylamine.
The process according to claim 1, wherein the solvent used in step e) is selected from the group consisting of N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide and N-methylpyrrolidone or a mixture thereof.
The process according to claim 1, wherein the crude empagliflozin is purified from the solvent selected from the group of ethyl acetate, isopropyl acetate, methyl ethyl ketone, acetonitrilc, methanol, isopropanol and water or combination thereof.
The compounds
a. benzylated 4-(2-chloro-5-iodobenzyl)phenol of Formula II;

wherein X is chlorine, bromine or iodine; and Ri and R2 are same or independently selected from hydrogen, chlorine, methyl, methoxy and nitro;
b. a compound of Formula IV; and


wherein R1 and R2 are same or independently selected from hydrogen, chlorine, methyl, methoxy and nitro; and "Bn" is benzyl;
c. a compound of Formula V;

wherein Ri and R2 are same or independently selected from hydrogen, chlorine, methyl, methoxy and nitro; and "Bn" is benzyl.