DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present application relates to novel crystalline form of Empagliflozin, process for its preparation and pharmaceutical composition thereof.

BACKGROUND OF THE INVENTION
The drug compound having the adopted name Empagliflozin, has a chemical name 1-chloro-4(beta-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl)-benzene, and is represented by the structure of formula I.

Empagliflozin is a sodium-dependent glucose cotransporter 2 (SGLT 2) inhibitor and is used for the treatment of patients with type 2 diabetes mellitus.
Empagliflozin and its synthetic methods are described in US Patent No. 7,579,449 (US ‘449). Example 3 of US ‘449 describes the isolation of Empagliflozin by drying the organic phase (ethyl acetate phase) over sodium sulphate and the solvent is removed, then the residue is purified using silica gel column chromatography (dichloromethane/ methanol 1:0?5:1).
US Patent No. 7,713,938 (US ‘938) discloses a crystalline form of Empagliflozin and a pharmaceutical composition comprising the crystalline form. The US ‘938 also discloses that “the method of manufacturing Empagliflozin as described in product patent process does not yield a crystalline form”.
Indian patent application (IN1985MUM2013A), PCT applications (WO2016051368A1, WO2016131431A1, WO2016169534A1 and WO2017046730A1), and Chinese patent applications (CN104788438A, CN105384730A1, CN105481843A, CN105496966A, CN106188021A and CN106317035A) describe various solid state forms and co-crystals of empagliflozin and processes for preparation thereof.
Polymorphism, the occurrence of different crystal forms, is a phenomenon of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties. Polymorphs in general will have different melting points, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray powder diffraction (XRPD or powder XRD) pattern, infrared absorption fingerprint, and solid state nuclear magnetic resonance (NMR) spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
Discovering new polymorphic forms, hydrates and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional solid forms of Empagliflozin.

SUMMARY OF THE INVENTION
Aspects of the present application relate to a novel crystalline form of Empagliflozin, its preparative processes and pharmaceutical compositions thereof.
In an aspect, the present application provides a crystalline Form N of Empagliflozin, characterized by a PXRD pattern comprising the peaks at about 4.13, 7.79, 11.55, 16.74, 23.20 and 27.87 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form N of Empagliflozin, comprising the step of treating Empagliflozin with N-methyl pyrrolidine or a mixture thereof.
In another aspect, the present application provides a pharmaceutical composition comprising crystalline Form N of Empagliflozin and atleast one pharmaceutically acceptable carrier.
In another aspect, the present application provides a process for preparation of (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having greater than about 99.8% of chiral purity, comprising
(a) reacting (R)-tetrahydrofuran-3-ol with 4-methylbenzene-1-sulfonyl chloride in presence of pyridine

(b) slurrying the crude compound (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate with a mixture of ethylacetate and cyclohexane, and
(c) isolating the (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having chiral purity of greater than about 99.8%.
In another aspect, the present application provides a process for preparation of empagliflozin having greater than about 99.8% of chiral purity, comprising:
(a) slurrying crude (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate with a mixture of ethylacetate and cyclohexane to get (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having chiral purity of greater than about 99.8%, and
(b) reacting the (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having greater than about 99.8% of chiral purity with (1R,2R,3S,6R)-4-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)cyclohexane-1,2,3-triol in presence of a base.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline Form N of Empagliflozin prepared by the method of Example No 3.

DETAILED DESCRIPTION
Aspects of the present application relate to a novel crystalline form of Empagliflozin, its preparative processes and pharmaceutical compositions thereof. The present application also encompasses the use of novel crystalline form of Empagliflozin provided herein, for the preparation of other solid forms of Empagliflozin, for the purification of Empagliflozin and for the preparation of pharmaceutical dosage forms.
In an aspect, the present application provides a crystalline Form N of Empagliflozin, characterized by a PXRD pattern comprising the peaks at about 4.13, 7.79, 11.55, 16.74, 23.20 and 27.87 ± 0.2° 2?. In an embodiment, the present application provides a crystalline Form N of Empagliflozin, characterized by a PXRD pattern having one or more additional peaks at about 7.16, 15.51, 15.86, 16.36, 22.08, 23.65, 24.47 and 26.65 ±0.2° 2?. In an embodiment, the application provides crystalline Form N of Empagliflozin, characterized by a PXRD pattern of figure 1.
In another aspect, the present application provides a process for the preparation of crystalline Form N of Empagliflozin, comprising the step of treating Empagliflozin with N-methyl pyrrolidine or a mixture thereof.
In an embodiment, crystalline Form N of Empagliflozin may be obtained by treating Empagliflozin with N-methyl pyrrolidine.
In an embodiment, crystalline Form N of Empagliflozin may be obtained by treating Empagliflozin with a mixture of N-methyl pyrrolidine and atleast one additional solvent. In an embodiment, additional solvent may be selected from the group comprising of diethyl ether, di isopropyl ether, methyl tert. butyl ether, methanol, ethanol, 2-propanol, acetone, methyl isobutyl ketone, water or mixtures thereof.
In an embodiment, treating Empagliflozin with N-methyl pyrrolidine or a mixture thereof may be carried out by combining Empagliflozin and N-methyl pyrrolidine or a mixture thereof.
In an embodiment, the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof may form a homogeneous mixture in the form of a solution.
In an embodiment, the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof is a heterogeneous mixture in the form a suspension.
In an embodiment, combining Empagliflozin with N-methyl pyrrolidine or a mixture thereof may be carried out optionally by heating a mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof at about 0°C to reflux temperature.
In an embodiment, when the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture forms a homogenous solution, it may be filtered to make it particle free and optionally treated with decolorizing agents such as charcoal, prior to filtration.
In an embodiment, optionally seeds of crystalline Form N of Empagliflozin may be added to the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof, when the mixture forms a homogenous solution. In an embodiment, seeds may be added at a suitable temperature and sufficient quantity such that the seeds are not dissolved.
In an embodiment, optionally the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof may be contacted with an anti-solvent, when the mixture forms a homogenous solution. The anti-solvent may be a solvent in which Empagliflozin has low solubility or is insoluble. Anti-solvent may include, but not limited to water, diethyl ether, di isopropyl ether, methyl tert. butyl ether, n-propanol, 2-propanol, ethyl acetate, toluene, acetonitrile or mixtures thereof.
In an embodiment, anti-solvent may be contacted at a temperature and duration, suitable for the formation of crystalline form III of Empagliflozin. In an embodiment, anti-solvent may be contacted either by adding the anti-solvent to the mixture of Empagliflozin and N-methyl pyrrolidine or by adding the mixture to anti-solvent. In an embodiment, anti-solvent may be contacted in single lot or multiple lots.
In an embodiment, the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof may be stirred for sufficient time to complete the formation of Form N and at suitable temperature where crystalline Form N is stable and do not convert to any other form of Empagliflozin.
In an embodiment, the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof may be stirred for atleast 1 hour or more. In an embodiment, the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof may be stirred at a temperature of about 0°C to reflux temperature.
In an optional embodiment, the mixture of Empagliflozin and N-methyl pyrrolidine or a mixture thereof may be cooled to a relatively lower temperature. In an embodiment, the mixture may be cooled to a suitable temperature before or after addition of seeds and / or contacting with anti-solvent. In an embodiment, the mixture comprising Empagliflozin and N-methyl pyrrolidine or a mixture thereof may be further stirred at the same temperature for time sufficient, after cooling, to obtain crystalline Form N of Empagliflozin.
Isolation of crystalline Form N of Empagliflozin may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline Form N may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In an embodiment, the crystalline Form N of Empagliflozin may be optionally dried under suitable drying conditions, at which the Form N is stable. In an alternate embodiment, the crystalline Form N of Empagliflozin may be directly converted to any other solid form of Empagliflozin, without drying.
In another embodiment, the present application provides a pharmaceutical composition comprising the crystalline Form N of Empagliflozin and atleast pharmaceutically acceptable carrier.
In another aspect, the present application provides crystalline Form N of Empagliflozin or their pharmaceutical compositions comprising Empagliflozin having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.
In another aspect, the present application provides crystalline Form N of Empagliflozin or their pharmaceutical composition, wherein particle size (D90) of Empagliflozin may be less than 100 microns or less than 50 microns or less than 20 microns.
In another aspect, the present application provides a method of treating or preventing type 2 diabetes, comprising administering to a subject in need thereof an effective amount of crystalline Form N of Empagliflozin or a pharmaceutical composition thereof. “A therapeutically effective amount” as used herein refers to an amount of an agent which is effective, upon single or multiple dose administration to the subject in providing a therapeutic benefit to the subject. In one embodiment, the therapeutic benefit is maintaining glucose homeostasis, or regulating blood glucose levels.
In additional embodiments, the crystalline Form N of Empagliflozin is used for the preparation of a medicament for treating conditions mediated by SLGT2, preferably type 2 diabetes.
In another aspect, the present application provides a process for preparation of (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having greater than about 99.8% of chiral purity, comprising
(a) reacting (R)-tetrahydrofuran-3-ol with 4-methylbenzene-1-sulfonyl chloride in presence of pyridine

(b) slurrying the crude compound (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate with a mixture of ethylacetate and cyclohexane, and
(c) isolating the (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having chiral purity of greater than about 99.8%.
The step (a) is carried out using a suitable solvent such as dichloromethane, chlorobenzene or acetonitrile and the like. After completion of the reaction the crude product is slurried in a solvent or a mixture of solvents such as a mixture of ethylacetate and cyclohexane or a mixture of ethylacetate and n-hexane. The specific process of the reaction and purification are described in the examples section.
In another aspect, the present application provides a process for preparation of empagliflozin having greater than about 99.8% of chiral purity, comprising:
(a) slurrying the crude compound (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate with a mixture of ethylacetate and cyclohexane to get (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having chiral purity of greater than about 99.8%, and
(b) reacting the (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having greater than about 99.8% of chiral purity with (1R,2R,3S,6R)-4-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)cyclohexane-1,2,3-triol in presence of a base.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

DEFINITIONS
The following definitions are used in connection with the present invention unless the context indicates otherwise.
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
The terms “crystalline" indicates that the Empagliflozin is present in substantially crystalline Form. Substantially crystalline denotes that atleast 80 %, preferably 90 % or 95 %, more preferably all of the Empagliflozin is crystalline form. In other words, "crystalline form" of Empagliflozin denotes Empagliflozin, which does not contain substantial amounts, preferably does not contain noticeable amounts, of any other crystalline portions of Empagliflozin e.g. measurable upon X-ray powder diffraction analysis. Celite is flux-calcined diatomaceous earth. Hyflo is flux-calcined diatomaceous earth treated with sodium carbonate.
X-ray powder diffraction patterns described herein were generated using a Bruker AXS D8 Advance powder X-ray diffractometer with a copper K-alpha radiation source. Generally, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ±0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2°. Accordingly, the present invention includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.2°. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2?) ±0.2° of 6.3°" means "having a diffraction peak at a diffraction angle (2?) of 6.1° to 6.5°. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peak relationships and the peak locations are characteristic for a specific polymorphic form. The relative intensities of the PXRD peaks may vary somewhat, depending on factors such as the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrumental variation and other factors may slightly affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments may vary by plus or minus about 0.2°. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a filter is used or not).

EXAMPLES
Example 1: Preparation of crystalline Form N of Empagliflozin.
Empagliflozin (0.5 g) was dissolved in N-methyl pyrrolidine (0.5 mL) at 25°C and methyl tert. butyl ether (7.5 mL) was added slowly at the same temperature. Stirred the mixture for 15.5 hours at 25°C and the solid was filtered to obtain the title compound.
Example 2: Preparation of crystalline Form N of Empagliflozin.
Empagliflozin (0.5 g) was dissolved in N-methyl pyrrolidine (0.5 mL) at 22°C and methyl tert. butyl ether (7.5 mL) was added slowly at the same temperature. Stirred the mixture for 15 hours at 22°C and the solid was filtered to obtain the title compound.
Example 3: Preparation of crystalline Form N of Empagliflozin.
Empagliflozin (5 g) was dissolved in N-methyl pyrrolidine (5 mL) at 23°C and methyl tert. butyl ether (75 mL) was added slowly in 8 minutes at the same temperature. Stirred the mixture for 15 hours at 23°C and the solid was filtered to obtain 4.9 g of the title compound. PXRD pattern: Figure 1.

Example 4: Preparation of Empagliflozin
(a) Preparation of (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate

(R)-Hydroxy-THF (20 g), dichloromethane (300 mL) and Pyridine (71.8 g) were charged into a 1000 mL round bottom flask and the mixture was cooled to 5 °C. 4-methylbenzene-1-sulfonyl chloride (47.6 gm) was charged into the flask at 5 °C and the mixture was stirred for 10 hours at 28 °C. Water (500 mL) was charged to the flask and stirred for 15 minutes. Layers separated and the organic layer was washed with dilute hydrochloric acid (50 mL of HCl in 150 mL of water). The organic layer was washed with aqueous sodium bicarbonate solution (200 mL) and water (200 mL). The organic layer was concentrated under vacuum to yield 48 gm of (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate.
The crude compound was taken into another round bottom flask and ethylacetate (30 mL) was added and stirred for 10 minutes. The clear solution was cooled to 15 °C and 50 mg seed compound was added. Cyclohexane (300 mL) was added slowly over a period of 30 minutes at 15 °C. The obtained suspension was stirred for 1 hour at 15 °C. The precipitation was filtered and wet material was washed with chilled cyclohexane (80 mL). The wet compound was dried under vacuum for 2 hours at 30 °C to yield 42 gm of title compound. Purity by HPLC: 99.87%.
(b) Preparation of 4-(2-chloro-5-iodobenzyl)phenol

In a clean and dried round bottom flask, 2-chloro-5-iodobenzoic acid (30 g), chlorobenzene (300 mL), and catalytic amount of N,N-dimethylformamide (1.5 mL) were charged. The reaction mixture was cooled to 10 °C and oxalyl chloride (17.52 g) was added drop wise over 15 minutes. At the end of the addition, reaction mixture was warmed to 25 °C and stirred for 3 hours. The reaction mixture was concentrated under vacuum and to this crude material, 300 mL of chlorobenzene was added under nitrogen atmosphere and the mixture was cooled to 5 °C. To this, AlCl3 (15.58 g) was charged. To the reaction mixture, anisole (12.06 g) was added drop wise at 5 °C. The reaction mixture was stirred for 1.5 h at 5 °C. Fresh AlCl3 (28.3 g) was charged at 5 °C and the reaction mixture heated to 60 °C. The reaction mixture was cooled to 5 °C. At this temperature, TMDS (49.9 g) was added drop wise over a period of 0.5 h. The reaction mixture was then warmed to 25 °C and stirred for 5 hours. The reaction mixture was quenched by pouring the RM into 450 mL ice cold water. Ethyl acetate (600 mL) was added to this RM and stirred for 10 minutes at 20 °C. Layers were separated and aqueous layer extracted with ethyl acetate (90 mL). The combined organic layers were washed with 5% aqueous NaHCO3 (600 mL) and saturated brine solution (300 mL). The organic layer was concentrated under vacuum at 50 °C. n-Hexane (150 mL) was added to the crude and stirred for 1h at 60 °C. The heterogeneous mixture was cooled to 10 °C and stirred for further 1h. The solid was filtered and washed with n-Hexane (50 mL). The white solid obtained was dried under vacuum at 40 °C (White solid, 28.8 g, Yield: 78.69 %, HPLC purity 97.7 %.
(c) Preparation of tert-butyl(4-(2-chloro-5-iodobenzyl)phenoxy)dimethylsilane

4-(2-chloro-5-iodobenzyl)phenol (30 g), dichloromethane (300 mL) were charged into a 1000 mL round bottom flask and the clear solution was cooled to 5 °C. A solution of tert-butylchlorodimethylsilane (14.43 g of TBDMSCl in 150 mL of DCM) was added to the flask at 5 °C. N,N-dimethylpyridin-4-amine (1.064 g) and triethylamine (13.21 g) were added to the reaction mass at 5 °C. The reaction mass was stirred at 28 °C for 3 hours. Water (150 mL) was charged to the reaction mass and the mixture was stirred for 30 minutes. Layers separated and the organic layer was washed with 1% aqueous HCl (150 mL) and with saturated sodium bicarbonate solution (150 mL), and with water (150 mL). The organic layer was concentrated under vacuum to yield 40 g crude material. The crude material and methanol (120 mL) were charged into a round bottom flask and 0.5 g of seed material was added. The solution was cooled to 10 °C and stirred for 2 hours. The suspension was filtered and was with 20 mL of methanol and the wet cake was dried under vacuum to yield 30 g of the title compound. Purity 98% by HPLC.

(d) Preparation of Empagliflozin

Tert-butyl(4-(2-chloro-5-iodobenzyl)phenoxy)dimethylsilane (1.0 Kg), tetrahydrofuran (6.0 L) and (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy) methyl)tetrahydro-2H-pyran-2-one (1.221 Kg) were charged into a 20 L flask under Nitrogen atmosphere. Toluene (6.0 L) was charged into the flask and the resulted mixture was cooled to -80 °C. n-Butyl Lithium in hexane (1.6M, 2.8 Kg) was added slowly over a period of 3 hours at -80 °C. The reaction mixture was maintained for 1 hour at -80 °C. A solution of methanesulfonic acid (1.46 Kg of methanesulfonic acid in 9.0 L of methanol) was added to the reaction mass at -70 °C. The reaction mass was heated to -10 °C and stirred for 30 minutes and heated to 30 °C and stirred for 12 hours at 30 °C. The reaction mass was cooled to 5 °C and sodium bicarbonate solution (2.0 Kg of sodium bicarbonate in 23 L of water) was added slowly. The reaction mass was stirred for 30 minutes at 30 °C. The reaction mass was washed with Toluene (6.0 L ? 3) and the reaction mass was concentrated under vacuum until 20 volumes remains in the flask. The reaction mass was extracted with ethylacetate (10.0 L ? 5) and the ethylacetate layer was washed with water (3.0 L). The ethylacetate layer was charged into a 100 L reactor and concentrated under vacuum to 3 volumes remained in the reactor. The concentrated ethylacetate layer was stripped off with acetonitrile (3.0 L ? 3) then dichloromethane (7.0 L) and acetonitrile (1.2 L) were charged into the reactor and the reaction mass was cooled to -30 °C. Triethylsilane (0.57 Kg) and Borontrifluoride etherate solution (1.307 Kg) were charged into the reactor and the reaction mass was stirred for 3 hours at -30 °C. Temperature was raised to -5 °C and stirred for 6 hours. A solution of sodium carbonate (2.0 Kg of sodium carbonate in 20.0 L of water) was added to the reaction mass over a period of 30 minutes at 5 °C. The reaction mass was heated to 30 °C and stirred for 30 minutes. The reaction mass was concentrated under vacuum until 25 volumes remained in the reactor. The mass was washed with toluene (4.0 L) and extracted with ethylacetate (8.0 L ? 2 and 4.0 L ? 4) and the ethylacetate layer washed with water (2.0 L ? 2) The organic layer was concentrated under vacuum until 2 volumes remained in the reactor then the crude mass was stripped off with ethylacetate (3.0 L ? 2) and with DMF (1.4 L). Tosyl-THF (0.634 Kg) and DMF (0.20 L) were charged into the reactor and the resulted mass was stirred for 30 minutes at 30 °C. Cesium carbonate lot 1 (0.57 Kg) was added to the reaction mass. Reaction mass was heated to 45 °C and stirred for 2 hours at 45 °C. Cesium carbonate lot 2 (0.57 Kg) was added to the reaction mass and the reaction mass was stirred for 2 hours. Cesium carbonate lot 3 (0.57 Kg) was added to the reaction mass the reaction mass was stirred for 20 hours at 45 °C. The reaction mass was cooled to 30 °C and water (4.0 L) was added to the mass and stirred for 30 minutes. Layers were separated and the aqueous layer was washed with toluene (4.0 L). The aqueous layer was concentrated at 70 °C under vacuum until 1.0 volume remained in the reactor. The concentrated mass was cooled to 30 °C and water (10.0 L) and acetonitrile 1.0 L) were charged into the reactor at 30 °C and the resulted mixture was heated to 45 °C and the mixture was stirred for 6 hours at 45 °C. The suspension was cooled to 25 °C and stirred for 7 hours at 25 °C. The precipitation was filtered and the wet solid was washed with water (3.0L) and the solid was suck dried. The wet compound and DMF (1.0 L) were charged into another reactor and the solution was heated to 45 °C. Acetonitrile (1.0 L) charged followed by water (10.0 L) into the reactor at 45 °C and stirred for 6 hours. The suspension was cooled to 25 °C and stirred for 6 hours. The precipitation was fileted and the wet cake was washed with water. The wet material was suck dried. The wet material was dried under vacuum at 60 °C for 6 hours to yield 0.55 Kg of crystalline empagliflozin. Purity by HPLC: 99%.

Example 5: Purification of Empagliflozin

Empagliflozin (75 g), acetonitrile (1500 mL) and water (15 mL) were charged into a round bottom flask and the resulted mixture was heated to 75 °C and stirred for 30 minutes to form clear solution. L-proline lot 1 (19.2 g) was charged into the flask and stirred for 2 hours at 75 °C. L-proline lot 2 (19.2 g) was charged into the flask and stirred for 6 hours at 75 °C. Reaction mass was cooled to 25 °C and stirred for 6 hours. The precipitation was filtered and suck dried for 30 minutes. The wet solid was washed with acetonitrile (375 mL) and suck dried for 2 hours. The wet compound was dried under vacuum at 65 °C for 4 hours. The dry compound was charged into a round bottom flask and acetonitrile (337 mL) and water (225 mL) were added to the flask and stirred for 20 minutes to get clear solution. The reaction mass was heated to 45 °C and stirred for 1 hour. Water (900 mL) was charged into the flask slowly over a period of 30 minutes. The reaction mass was cooled to 25 °C and stirred for 10 hours. The precipitation was filtered and the wet material suck dried for 30 minutes. The wet material was washed with water (225 mL ? 2) and suck dried for 30 minutes. The wet material was charged into a round bottom flask. Methanol (300 ml) and water (45 mL) was added and the mass was heated to 50 °C to form clear solution. Water (1200 mL) was added to the clear solution and stirred the mass at 60 °C for 3 hours. Solid was isolated. The precipitation was cooled to 25 °C and stirred for 8 hours. The precipitation was filtered and suck dried for 30 minutes. The wet material was washed with water (225 mL) and suck dried for 30 minutes. The wet material was dried under vacuum at 65 °C for 6 hours to get 64 g of crystalline empagliflozin. Purity by HPLC: 99.8%.
Example 6: Purification of Empagliflozin

Empagliflozin (75 g), acetonitrile (1500 mL) and water (15 mL) were charged into a round bottom flask and the resulted mixture was heated to 75 °C and stirred for 30 minutes to form clear solution. L-proline lot 1 (19.2 g) was charged into the flask and stirred for 2 hours at 75 °C. L-proline lot 2 (19.2 g) was charged into the flask and stirred for 6 hours at 75 °C. Reaction mass was cooled to 25 °C and stirred for 6 hours. The precipitation was filtered and suck dried for 30 minutes. The wet solid was washed with acetonitrile (375 mL) and suck dried for 2 hours. The wet compound was dried under vacuum at 65 °C for 4 hours. The dry compound was charged into a round bottom flask and DMF (200 mL) and water (200 mL) were added to the flask and stirred for 20 minutes to get clear solution. The clear solution was filtered through a micron filter to get a particle free clear solution. The reaction mass was heated to 55 °C and stirred for 1 hour. Water (600 mL) was charged into the flask slowly over a period of 30 minutes. The reaction mass was cooled to 25 °C and stirred for 3 hours. The precipitation was filtered and the wet material suck dried for 30 minutes. The wet material was washed with water (500 mL) and suck dried for 30 minutes. The wet material was charged into a round bottom flask. Methanol (300 ml) and water (45 mL) was added and the mass was heated to 50 °C to form clear solution. Water (1200 mL) was added to the clear solution and stirred the mass at 60 °C for 3 hours. Solid was isolated. The precipitation was cooled to 25 °C and stirred for 8 hours. The precipitation was filtered and suck dried for 30 minutes. The wet material was washed with water (225 mL) and suck dried for 30 minutes. The wet material was dried under vacuum at 65 °C for 6 hours to get 65 g of crystalline empagliflozin. Purity by HPLC: 99.8%.
,CLAIMS:CLAIMS
We claim
1. A crystalline Form N of Empagliflozin, characterized by a PXRD pattern comprising the peaks at about 4.13, 7.79, 11.55, 16.74, 23.20 and 27.87 ± 0.2° 2?.
2. A process for the preparation of crystalline Form N of Empagliflozin, comprising the step of treating Empagliflozin with N-methyl pyrrolidine or a mixture thereof.
3. A pharmaceutical composition comprising crystalline Form N of Empagliflozin and at least one pharmaceutically acceptable carrier.
4. A process for preparation of (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having greater than about 99.8% of chiral purity, comprising
(a) reacting (R)-tetrahydrofuran-3-ol with 4-methylbenzene-1-sulfonyl chloride in presence of pyridine

(b) slurrying the crude compound (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate with a mixture of ethylacetate and cyclohexane, and
(c) isolating the (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having chiral purity of greater than about 99.8%.
5. A process for preparation of empagliflozin having greater than about 99.8% of chiral purity, comprising:
(a) slurrying the crude compound (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate with a mixture of ethylacetate and cyclohexane to get (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having chiral purity of greater than about 99.8%, and
(b) reacting the (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate having greater than about 99.8% of chiral purity with (1R,2R,3S,6R)-4-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)cyclohexane-1,2,3-triol in presence of a base.