FIELD OF INVENTION:
The present invention discloses two novel processes for the preparation of Crystalline Empagliflozin as disclosed in U.S. Patent 7,713,938 and hereinafter termed as Crystalline Form I.
BACKGROUD OF INVENTION:
Empagliflozin is an inhibitor of the Na+-glucose cotransporter 2 (SGLT2) and is marketed under the proprietary name JARDIANCE®. It is indicated for prevention and/or treatment of metabolic disorders, particularly type-2 diabetes. Empagliflozin belongs to a class of pyranosyl-oxy-substituted benzene derivatives and has an 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 is chemically named 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 and has the following structural
There are various patents of Empagliflozin reported in literature e.g. U.S. Patent. 7,579,449, discloses Empagliflozin, stereoisomers of Empagliflozin, mixtures and salts thereof, and a pharmaceutical composition containing Empagliflozin.
U.S. Patent 7,713,938 discloses the crystalline form of 1-chloro-4-(ß-D-glucopyranos-1-yl)-2-[4-(S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene having an X-ray diffraction pattern that comprises peaks at 18.84, 20.36 and 25.21 degrees 2?±0.05 degrees 2?. This crystalline form is hereinafter referred to as From I.
A series of synthetic methods have been reported in the peer-reviewed and patent literature that can be used for the preparation of ß-C-arylglucosides. These methods are described below and are referred herein as the gluconolactone method, the metalated glucal method, the glucal epoxide method and the glycosyl leaving group substitution method.
The gluconolactone method: In 1988 and 1989 a general method was reported to prepare C-arylglucosides from tetra-benzyl protected gluconolactone, which is an oxidized derivative of glucose (see J. Org. Chem. 1988, 53, 752-753 and J. Org. Chem. 1989, 54, 610- 612). The method comprises: 1) addition of an aryllithium derivative to the hydroxy-protected gluconolactone to form a hemiketal (a.k.ci., a lactol), and 2) reduction of the resultant hemiketal with triethylsilane in the presence of boron trifluoride etherate. Disadvantages of this classical, but very commonly applied method for ß-C-arylglucoside synthesis include:
Poor "redox economy" (see J. Am. Chem. Soc. 2008, 130, 17938-17954 and Anderson, N. G. Practical Process Research & Development, 1st Ed.; Academic Press, 2000 (ISBN- 10: 0120594757); pg 38)— that is, the oxidation state of the carbon atom at CI, with respect to glucose, is oxidized in the gluconolactone and then following the arylation step is reduced to provide the requisite oxidation state of the final product. 2) due to a lack of stereospecificity, the desired ß-C-arylglucoside is formed along with the undesired a-C-arylglucoside stereoisomer (this has been partially addressed by the use of hindered trialkylsilane reducing agents (see Tetrahedron: Asymmetry 2003, 14, 3243-3247) or by conversion of the hemiketal to a methyl ketal prior to reduction (see J. Org. Chem. 2007, 72, 9746-9749 and U.S. Patent 7,375,213))
U.S. Patent 7,847,074 discloses, the metalated glucal method, preparation of SGLT2 inhibitors that involves the coupling of a hydroxy-protected glucal that is metalated at C1 with an aryl halide in the presence of a transition metal catalyst. Following the coupling step, the requisite formal addition of water to the C-arylglucal double bond to provide the desired C-aryl glucoside is effected using i) hydroboration and oxidation, or ii) epoxidation and reduction, or iii) dihydroxylation and reduction. In each case, the metalated glucal method represents poor redox economy because oxidation and reduction reactions must be conducted to establish the requisite oxidation states of the individual C1 and C2 carbon atoms.
U.S. Pat. Appl. 2005/0233988 discloses the utilization of a Suzuki reaction between a C1 -boronic acid or boronic ester substituted hydroxy-protected glucal and an aryl halide in the presence of a palladium catalyst. The resulting 1- C-arylglucal is then formally hydrated to provide the desired 1- C-aryl glucoside skeleton by use of a reduction step followed by an oxidation step. The synthesis of the boronic acid and its subsequent Suzuki reaction, reduction and oxidation, together, comprise a relatively long synthetic approach to C-arylglucosides and exhibits poor redox economy. Moreover, the coupling catalyst comprises palladium which is toxic and therefore should be controlled to very low levels in the drug substance.
The glucal epoxide method: U.S. Patent 7,847,074 discloses a method that utilizes an organometallic (derived from the requisite aglycone moiety) addition to an electrophilic epoxide located at C1-C2 of a hydroxy-protected glucose ring to furnish intermediates useful for SGLT2 inhibitor synthesis. The epoxide intermediate is prepared by the oxidation of a hydroxy- protected glucal and is not particularly stable. In Tetrahedron 2002, 58, 1997-2009 it was taught that organometallic additions to a tri-6>-benzyl protected glucal-derived epoxide can provide either the a-C-arylglucoside, mixtures of the a- and ß-C-arylglucoside or the ß-C-arylglucoside by selection of the appropriate counterion of the carbanionic aryl nucleophile (i.e., the organometallic reagent). For example, carbanionic aryl groups countered with copper (i.e., cuprate reagents) or zinc (i.e., organozinc reagents) ions provide the ß-C-arylglucoside, magnesium ions provide the a- and ß-C-arylglucosides, and aluminum (i.e., organoaluminum reagents) ions provide the a-C-arylglucoside.
The glycosyl leaving group substitution method: U.S. Patent 7,847,074, also disclosed a method comprising the substitution of a leaving group located at CI of a hydroxy-protected glucosyl species, such as a glycosyl halide, with a metalated aryl compound to prepare SGLT2 inhibitors. U.S. Pat. Appl. 2011/0087017 disclosed a similar method to prepare the SGLT2 inhibitor canagliflozin and preferably diarylzinc complexes are used as nucleophiles along with tetra- >-pivaloyl protected glucosylbromide.
Methodology for alkynylation of 1,6-anhydroglycosides reported in Helv. Chim. Acta. 1995, 78, 242-264 describes the preparation of l,4-dideoxy-l,4-diethynyl^-D-glucopyranoses (a. La., glucopyranosyl acetylenes), that are useful for preparing but-l,3-diyne-l,4-diyl linked polysaccharides, by the ethynylating opening (alkynylation) of partially protected 4-deoxy-4-C- ethynyl-l,6-anhydroglucopyranoses. The synthesis of ß-C-arylglucosides, such as could be useful as precursors for SLGT2 inhibitors, was not disclosed. The ethynylation reaction was reported to proceed with retention of configuration at the anomeric center and was rationalized (see Helv. Chim. Acta 2002, 85, 2235-2257) by the C3-hydroxyl of the 1,6- anhydroglucopyranose being deprotonated to form a C3-0-aluminium species, that coordinated with the C6-oxygen allowing delivery of the ethyne group to the ß-face of the an oxycarbenium cation derivative of the glucopyranose. Three molar equivalents of the ethynylaluminium reagent was used per 1 molar equivalent of the 1,6-anhydroglucopyranose. The ethynylaluminium reagent was prepared by the reaction of equimolar (i.e., 1:1) amounts of aluminum chloride and an ethynyllithium reagent that itself was formed by the reaction of an acetylene compound with butyllithium. This retentive ethynylating opening method was also applied (see Helv. Chim. Acta. 1998, 81, 2157-2189) to 2,4-di-<9-triethylsilyl- 1,6- anhydroglucopyranose to provide l-deoxy-l-C-ethynyl- -D-glucopyranose. In this example, 4 molar equivalents of the ethynylaluminium reagent was used per 1 molar equivalent of the 1,6- anhydroglucopyranose. The ethynylaluminium regent was prepared by the reaction of equimolar (i.e., 1: 1) amounts of aluminum chloride and an ethynyl lithium reagent that itself was formed by reaction of an acetylene compound with butyllithium.
WO 2013068850 of Scinopharm Taiwan Limited, provides novel and redox economic processes for preparing C- arylglucosides that can be useful as drugs, including SGLT2 inhibitors, prodrugs or synthetic building blocks. The particular focus of the present processes is for, but not limited to, the manufacture of SGLT2 inhibitors. The glucoside may be in the D- or L-configuration. The present invention can also be applied to the preparation of C-arylglycosides that are derived from carbohydrates other than glucose such as mannose or galactose or that are derived from carbohydrate derivatives such as deoxycarbohydrates
WO 2013/068850 describes process of preparation ß-C-arylglycosides by coupling of 2,4- di-O-protected 1 ,6-anhydroglucopyranose or 2,3,4-tri-O-protected 1 ,6- anhydroglucopyranose derivatives with nucleophilic aryl compounds. US 2007/0073046 mentions an option of 1 -arylation of glucopyranosides via 1 ,2-epoxides, but the article does not describe any experimental results and therefore it does not show results of cis/trans selectivity. The cited reference in this publication (Tetrahedron 58, 1997-2009 (2002)) only shows unpredictability of cis/trans selectivity which depends on reagents catalyst and substituents.
CN 105153137 of Shanghai Institute of technology, discloses a preparation method of empagliflozin. The preparation method comprises the steps of firstly, reacting 5-bromo-2-chlorobenzoic acid and anisole to obtain 5-bromo-2-chlorphenyl-4-methoxyphenyl-ketone; carrying out reduction reaction on 5-bromo-2-chlorphenyl-4-methoxyphenyl-ketone to obtain 5-bromo-2-chloro-4'-methoxydiphenylmethane; carrying out coupling reaction on 5-bromo-2-chloro-4'-methoxydiphenylmethane and 2,3,4,6-O-tetrapivaloyl-a-D-bromo-glucopyranose to obtain a key intermediate; demethylating this key intermediate to obtain another key intermediate; and forming ether by using this second key intermediate and (S)-3-iodo-tetrahydrofuran under an alkaline condition, and removing pivaloyl to obtain empagliflozin. Empagliflozin is synthesized by using cheap and available 5-bromo-2-chlorobenzoic acid as a raw material, the synthesis route is simple, and the preparation method has the advantages of simplicity and convenience in operation, low cost, environment friendliness and the like.
US2016/0318965 of Mylan provides improved process for the preparation of Empagliflozin is disclosed. Novel intermediates of formulas (13) and (14) as given below, for the preparation of Empagliflozin are also disclosed, wherein R1 and R2 are independently hydrogen or hydroxyl protecting groups.
SUMMARY OF INVENTION:
The present invention cites novel processes for the preparation of crystalline Empagliflozin Form I. The polymorphic confirmation was done with the help of PXRD diffractogram of samples obtained by the examples mentioned herein. The novel processes disclosed herein uses (3S)-3-(4-(2-chloro-5-iodobenzyl) phenoxy) tetrahydrofuran & 2,3,4,6-tetra-O-trimethyl silyl-ß-D-glucolactone as starting raw materials for the preparation of Crystalline Empagliflozin.
Also disclosed is a universal method, for conversion of any polymorphic form of Empagliflozin to crystalline Empagliflozin form , with XRD pattern as given in prior art.
DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, a novel process for the preparation of Crystalline form I of Empagliflozin which comprises (Example 1):
i. A solution of (3S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy) tetrahydro furan in mixture of a cyclic or acyclic ethers like tetrahydrofuran, dioxane, diisopropyl ether, tert-butyl methyl & aromatic hydrocarbons like benzene, toluene, xylenes etc or a mixture thereof.
ii. Cooling of resulting reaction mass to -80 to -85 °C.
iii. Simultaneously addition of n-Butyl Lithium, 2,3,4,6-tetra-O-trimethyl silyl-ß-D-glucolactone in an aromatic hydrocarbon such as benzene, toluene, xylenes etc or a mixture thereof.
iv. Stirring the reaction mass at this temperature for reaction completion.
v. Further treated reaction mass with methanesulphonic acid & C1-C4 aliphatic alcohol like methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol or a mixture thereof
vi. Raising the reaction temperature to 5-15 °C.
vii. Addition of aq sodium bicarbonate to the reaction mass
viii. Extraction of product in an organic solvent followed by complete recovery under vacuum < 50 °C.
ix. Re-dissolution of resulting product of step viii in a mixture of a halogenated hydrocarbon selected from methylene chloride, chloroform or carbon tetrachloride and an aliphatic nitrile such as acetonitrile, propionitrile.
x. Cooling of reaction solution to -20 to -25 °C.
xi. addition of triethylsilane & boron trifluoride-THF solution under stirring.
xii. Raising temperature to 0-10 °C, & stirring till reaction completion.
xiii. Quenching of reaction mas using aq sodium bicarbonate solution.
xiv. Extraction of product in a halogenated hydrocarbon such as methylene dichloride, chloroform, carbon tetrachloride or mixture thereof and complete recovery of solvent under vacuum below 50 °C to give as residue. .
xv. Redissolution of the residue thus obtained in a halogenated hydrocarbon.
xvi. Cooling of reaction mass to 0-5 °C followed by addition of an organic basic such as N,N-diisopropylethylamine or triethyamine & acetic anhydride, with stirring.
xvii. Raising reaction temperature to 25-35 °C followed by addition of 4-Dimethyl aminopyridine.
xviii. Stirred of the reaction mass till reaction completion
xix. quenching of reaction mass by addition of water .
xx. Extraction of product in an organic solvent followed by complete recovery of solvent to get Tetraacetyl Empagliflozin as residue
xxi. Recrystallization of residue of step xx in a mixture of C1-C4 aliphatic alcohol and an aliphatic ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or mixture thereof
xxii. or a mixture thereof at 10-15 °C,
xxiii. Isolation of product by filtration & drying.
xxiv. Reacting Tetraacetyl Empagliflozin with caustic in in C1-C4 aliphatic alcohol at 40-50 °C till completion of reaction.
xxv. Quenched of reaction mass by addition of 1N Hydrochloric acid at ambient temperature and extraction of product using C1-C3 aliphatic ester. e.g. ethyl acetate, propyl acetate, butyl acetate or a mixture thereof.
xxvi. Charcoalization of organic layer of Step xxiv
xxvii. Partial recovery of organic solvent u/ vacuum
xxviii. crystallization of product Empagliflozin by adding anti-solvent such as cyclic or acyclic aliphatic hydrocarbon selected from cyclopentane, cyclohexane, cycloheptane, cycloctane, n-pentane, n-hexane, n-heptane, octane or a mixture thereof.
xxix. isolation of product (Crystalline Empagliflozin Form I) by filtration and drying at 50-55 °C for 8-12 hours.
According to one aspect of the current invention, the ratio between the cyclic ether & aromatic hydrocarbons is critical. If ratio of aromatic hydrocarbon used is increased then reaction is comparatively slow but impurity content is low while on the other hand if ratio of cyclic ether is increased reaction is comparatively fast but degradation product formation is there, which leads to higher content. The ideal ratio is 3:5 (3 parts of cyclic ether & 5 parts of aromatic hydrocarbon).
According to the Second embodiment of the present invention, a novel process for the preparation of crystalline Empagliflozin Form I, using any polymorphic form of Empagliflozin (This process can also be optionally used as purification process for crude Empagliflozin), is disclosed, which comprise (Example 2):
a) Dissolving any polymorphic form of Empagliflozin in a C1-C3 aliphatic ester. e.g. ethyl acetate, propyl acetate, butyl acetate or a mixture thereof at 45-50 °C.
b) Partial recovery of solvent under vacuum
c) Dropwise addition of cyclic or acyclic aliphatic hydrocarbon selected from cyclopentane, cyclohexane, cycloheptane, cycloctane, n-pentane, n-hexane, n-heptane, octane or a mixture thereof at 0-20 °C to ensure complete crystallization.
d) Isolation of product by filtration and drying of the wet cake under vacuum at 50-55 ºC for 8-12 hours to get Crystalline Empagliflozin form I.
According to the third embodiment of the present invention, a novel process for the Preparation/ Purification of Empagliflozin Crystalline form I is disclosed, which comprise (Example 3):
a) dissolving any polymorphic form of Empagliflozin in C1-C4 aliphatic alcohol such as methanol, ethanol, propanol or isopropanol or mixture thereof at 20-30 °C.
b) heating the reaction mass to 60-70 °C under stirring for 30-60 min.
c) Cooling of reaction mass to 40-50 °C, followed by addition of DI water.
d) Further stirred the reaction mass followed by its cooling to 0-10 °C.
e) Stirred the reaction mass at this temperature for 2-5 hours to ensure proper crystallization.
f) Isolation of product by filtration and provide slurry washing with water.
g) Re-filtration to get pure Empagliflozin as wet cake.
h) Drying of the wet cake under vacuum at 50-55 ºC for 8-12 hours to get Crystalline Empagliflozin form I (ICH Grade).
Brief Description of figures:
1) Figure 1 – Crystalline Empagliflozin obtained as per Example 1
2) Figure 2 – Crystalline Empagliflozin obtained as per Example 2
3) Figure 3 – Crystalline Empagliflozin obtained as per Example 3
The above mentioned invention is supported by the following non limiting examples.
EXAMPLES:
Example 1: Charging of (3S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy) tetrahydro furan (25 g) in THF (750 ml) & toluene (125 ml). Stirring to dissolve & cooled the reaction mass to -80 to -85 °C. Performed slow addition of 2.5 M n-Butyl Lithium (50 ml) & 2,3,4,6-tetra-O-trimethyl silyl-ß-D-glucolactone in Toluene. Stirred the reaction mass till reaction completion. After confirmation of reaction completion on TLC/HPLC added methanesulphonic acid (16 g) & methanol to it. Allowed the temperature to rise to 5-15 °C and stirred the reaction mass for 1-2 hours. Added sodium bicarbonate solution (150 ml) to it keeping temperature below 25 °C. Performed stirred settling & layer separation. Now organic layer containing product is recovered under vacuum keeping temperature below 50 °C, then triturated with methylene chloride to give residue.
This residue is again taken in methylene chloride (75 ml) & acetonitrile (75 ml) & stirring till dissolution. The reaction mass is then cooled to -20 to -25 °C, followed by slow addition of triethylsilane (22.5 g) & boron trifluoride in Tetrahydrofuran (17.5 g) at this temperature only. Continued stirring & allowed the temperature to rise till 0-10 °C. Stirred the reaction mass for 3-4 hours till reaction completion. After confirmation of reaction completion via HPLC/TLC, added sodium bicarbonate solution (150 ml), stirred & did layer separation. Now organic layer containing product is given brine (75 ml) washing & recovered under vacuum to give as residue.
This residue is again dissolved in methylene chloride (125 ml) under stirring. Now cooled the reaction mass to 0-5 °C & performed slow addition of N,N-diisopropylethyl amine (30 g), acetic anhydride (22.5 g). Allowed the temperature to rise to 25-35 °C & continued stirring. Added 4-Dimethyl aminopyridine (0.5 g) & further stirred reaction mass till reaction completion. Upon reaction completion, added water (125 ml) to the reaction mass. Performed layer separation & organic layer containing product was recovered under vacuum to give crude Tetraacetyl Empagliflozin as residue. This residue may be purified by its dissolution in methanol (25 ml) & acetone (25 ml) at 50-55 °C followed by recrystallization at 10-15 °C to give Tetraacetyl Empagliflozin (8.0 gm) as solid.
This Tetraacetyl Empagliflozin (8.0 g) thus obtained is taken in methanol (40 ml) followed by addition of caustic solution (24 ml). Heated the reaction mass to 40-50 °C. & stirred for 2 hours for reaction completion. After reaction completion confirmation via HPLC/TLC, cooled the reaction mass to 25-30 °C followed by addition of 1N hydrochloric acid (48 ml) so as to adjust its pH. Now extracted product in ethyl acetate (40 ml) & water (40 ml). After layer separation ethyl acetate layer containing product is charcoalized, then fine filtered from hyflow bed. Now again solvent is recovered partially under vacuum and recrystallized the product by addition of hexane / hexanes / cyclohexane (50 ml). Now cooled the reaction mass at 15-20 °C to ensure complete crystallization. Filtered the reaction mass & dried the wet cake at 50-55 °C to give final product, Crystalline Empagliflozin , which is characterized by the XRD as given in Figure 1.
Yield = 0.16
Purity by HPLC = 97.9 %
Single highest impurity = 1.3 %
Example 2:
Empagliflozin (10.0 g) was taken in a round bottom flask & ethyl acetate (50 ml) under stirring. Heated the reaction mass to 45-50 °C to ensure complete dissolution. Removed ethyl acetate from reaction mass using vacuum distillation so as to be left with only one time of initial volume. Now allowed the temperature to fall to ambient and started slow addition of cyclohexane (50 ml) drop wise. Reduced the temperature to 0-20 °C & stirred reaction mass to ensure complete crystallization. Isolated the product via filtration & dried wet cake at 50-55 °C for 8-12 hours to get final product which is Crystalline Empagliflozin & is having XRD as per figure 2.
Yield = 0.80
Purity by HPLC = 99.64%
Single highest impurity = 0.10 %
Example 3:
Empagliflozin (10.0 g) was taken in a round bottom flask & methanol (30 ml) under stirring. Heated the reaction mass to 60-70 °C to ensure complete dissolution. Now stirred the reaction mass for 30-60 minutes followed by cooling of reaction mass at 40-50° C. Then the addition of DI water (50 ml) was performed & reaction mass was first stirred at 40-50 °C for 30-60 min followed by stirring under cooling at 0-10°C for 2-5 hours. Isolated the product via filtration, slurry washed with water (20 ml) & dried wet cake at 50-60 °C for 8-12 hours to get final product which is Crystalline Empagliflozin Form I & is having XRD as per figure 3.
Yield = 0.95
Purity by HPLC = 99.94%
Single highest impurity = 0.04%
Having described the invention in detail, those skilled in the art will appreciate that, given the present disclosure, modifications may be made to the invention without departing from the spirit of the inventive concept described herein. For example, different features of the different devices described above may be omitted or combined with feature from other different. Therefore, it is not intended that the scope of the invention be limited to the specific embodiments illustrated and described.

WE CLAIM:
1. A novel process for the preparation of Crystalline form I of Empagliflozin which comprises :
i. dissolution of (3S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy) tetrahydrofuran in mixture of a cyclic or acyclic ethers which may be selected from tetrahydrofuran, dioxane, diisopropyl ether, tert-butyl methyl & aromatic hydrocarbons like benzene, toluene, xylenes etc or a mixture thereof;
ii. cooling of reaction mass to -80 To -85 °C;
iii. slow addition of n-Butyl Lithium and 2,3,4,6-tetra-O-trimethyl silyl-ß-D-glucolactone in an aromatic hydrocarbon such as benzene, toluene, xylenes etc or a mixture thereof;
iv. further stirring of reaction mass till completion of reaction at this temperature;
v. thereafter treating reaction mass with methanesulfonic acid in the presence of C1-C4 aliphatic alcohol like methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol or a mixture thereof;
vi. allowing the temperature of reaction mass to go up to 5-15 °C followed by its addition of sodium bicarbonate solution;
vii. extracting the product in a halogenated hydrocarbon such as methylene dichloride, chloroform, carbon tetrachloride or mixture thereof followed by its complete recovery under reduced pressure;
viii. re-dissolution of resulting product of step (vii) in a mixture of a halogenated hydrocarbon selected from methylene chloride, chloroform or carbon tetrachloride or mixture thereof and an aliphatic nitrile such as acetonitrile, propionitrile or mixture thereof;
ix. cooling of reaction mass to -20 to -25 °C followed by addtition of triethylsilane and boron trifluoride solution in tetrahydrofuran under stirring;
x. allowing the reaction mass to rise to 0-10 °C & stirred till reaction completion;
xi. quenching of reaction mass with aq. Sodium bicarbonate solution followed by its extraction in halogenated hydrocarbon which may be selected from methylene chloride, chloroform or carbon tetrachloride or mixture thereof;
xii. the product residue thus obtained is dissolved in halogenated hydrocarbon as used in above step;
xiii. re-cooling of this reaction mass to 0-5 °C and performed addition of an organic basic such as N,N-diisopropylethylamine or triethyamine & acetic anhydride;
xiv. raising the temperature of reaction mass to 25-35 °C followed by addition of 4-Dimethyl aminopyridine;
xv. stirring of reaction mass at this temperature till reaction completion followed by its quenching in water;
xvi. extraction of product in halogenated hydrocarbon which may be selected from methylene chloride, chloroform or carbon tetrachloride or mixture thereof followed by its complete recovery under vacuum to give Tetraacetyl Empagliflozin;
xvii. Tetraacetyl Empagliflozin may be optionally purified in C1-C4 aliphatic alcohol and an aliphatic ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone at 10-15 °C by recrystallization;

xviii. Tetraacetyl Empagliflozin is deprotected by its reaction with caustic solution in a C1-C4 aliphatic alcohol such as methanol, ethanol or isopropanol, at 40-50 °C under stirring till completion of reaction;
xix. quenching the reaction with 1N Hydrochloric acid, followed by its extraction in C1-C3 aliphatic ester, which may be selected from ethyl acetate, propyl acetate, butyl acetate or a mixture thereof;
xx. charcoaling of reaction mass followed by its fine filtration via hyflow bed;
xxi. partial recovery of reaction solvent under vacuum followed by addition of anti-solvent such as cyclic or acyclic aliphatic hydrocarbon selected from cyclopentane, cyclohexane, cycloheptane, cycloctane, n-pentane, n-hexane, n-heptane, octane or a mixture thereof;
xxii. stirring till complete crystallization; and
xxiii. isolation of product using routine filtration & drying at 50-55 °C for 8-12 hours to ive Empagliflozin Crystalline Form I.

2. The cyclic ether being used in step i) of claim 1 is ideally tetrahydrofuran & similarly aromatic hydrocarbon is toluene; the ratio of ether-hydrocarbon is very important for control on impurity formation; the ideal ratio is 3:5 (3 parts of tetrahydrofuran & 5 parts of toluene) to control impurity formation.
3. A novel process for the preparation/purification of Crystalline form I of Empagliflozin which comprises:
i. dissolving any polymorphic form Empagliflozin in a C1-C3 aliphatic ester. which may be selected from ethyl acetate, propyl acetate, butyl acetate or a mixture thereof at 45-50 °C;
ii. partial recovery of solvent under vacuum;
iii. dropwise addition of cyclic or acyclic aliphatic hydrocarbon selected from cyclopentane, cyclohexane, cycloheptane, cycloctane, n-pentane, n-hexane, n-heptane, octane or a mixture thereof, under stirring at 0-20 °C;
iv. stirring to ensure complete crystallization; and
v. isolation of product using routine filtration & drying at 50-55 °C for 8-12 hours to give Empagliflozin Crystalline Form I.
4. A novel process for the preparation/purification of Crystalline form I of Empagliflozin which comprises:
i. dissolving any polymorphic form Empagliflozin in C1-C4 aliphatic alcohol such as methanol, ethanol, propanol or isopropanol or mixture thereof at 20-30 °C;
ii. heating the reaction mass to 60-70 °C & stirred for 30-60 min;
iii. cooling the reaction mass to 40-50 °C, followed by addition of DI water;
iv. further stirred reaction mass followed by its cooling to 0-10 °C;
v. stirring the reaction mass at this temperature for 2-5 hours to ensure proper crystallization;
vi. isolating product by filtration and provide slurry washing with water;
vii. re-filtering to get pure Empagliflozin as wet cake; and
viii. drying of wet cake at 50-55 °C for 8-12 hours to give Empagliflozin Crystalline Form I.
Dated this 30th day of March 2017
NEHA CHUGH
PATENT AGENT
IN/PA-862