The present invention reports novel processes for the preparation of crystalline Empagliflozin.
BACKGROUND OF THE 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 structure:

There are various patents of Empagliflozin reported in literature e.g., US patent number 7,579,449 which discloses Empagliflozin, stereoisomers of Empagliflozin, mixtures and salts thereof, and a pharmaceutical composition containing Empagliflozin.
US patent number 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 Form 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.
The 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)).
US patent number 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 affected 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.
US patent application 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: US patent number 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: US patent number 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. US patent application 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 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 were 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 were 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 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. 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.

Morepen’s own previous patent applications IN201711011423 and IN201911008294 also provide novel processes for the preparation of Empagliflozin Form I. The existing patent is an extension of these inventions to provide novel processes for the preparation of crystalline Empagliflozin Form I which are easy to handle at commercial scale.
SUMMARY OF THE 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 any crystalline form 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 or Empagliflozin as starting raw materials for the preparation of crystalline Empagliflozin Form I.
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 is disclosed which comprises (Example 1):
i. Heating any polymorphic form of Empagliflozin in an aliphatic amide selected from N,N-dimethyl formamide (DMF), N-butylformamide, N,N-dimethylmethanamide, N,N-dimethy ethanamide, dimethylsulphoxide or a mixture thereof and water at 30-40°C to obtain a clear solution.
ii. Stirring the reaction mass followed by cooling to 0-10°C.
iii. Stirring of reaction mass at 0-10°C for 1-2 hours to ensure proper crystallization.
iv. Filtering the product as wet cake by routine filtration and running washing with water.
v. Isolating the product crystalline Empagliflozin Form I by drying of solid mass at 50-60°C for 8-12 hours.
According to the second embodiment of the present invention, a novel process for the preparation of crystalline form I of Empagliflozin is disclosed which comprises (Example 2):
i. Dissolving any polymorphic form of Empagliflozin in cyclic or acyclic ethers selected from tetrahydrofuran, dioxane, diisopropyl ether(IPE), tert-butylmethyl ether (MTBE), 2-Methyl Tetrahydrofuran, cyclopentyl methyl ether (CPME) or a mixture thereof at 60-70°C.
ii. Stirring for 10-15 minutes.
iii. Removing about 10-40% of solvent from reaction mass under vacuum at elevated temperature followed by cooling of reaction mass to 0-10°C.
iv. Stirring of reaction mass at 0-10°C for 3-4 hours to ensure proper crystallization.
v. Filtering the product as wet cake by routine filtration and running washing with water.
vi. Isolating the product crystalline Empagliflozin Form I by drying of solid mass at 50-60°C for 8-12 hours.
According to the third embodiment of the present invention, a novel process for the preparation of crystalline form I of Empagliflozin is disclosed which comprises (Example 3):
i. Dissolving any polymorphic form of Empagliflozin in an aliphatic ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone, methylisobutyl ketone, diisobutylketone and water, in any ratio, by heating the reaction mass at 50-60°C to obtain a clear solution.
ii. Fine filtering the hot reaction mass.
iii. Removing 30-70% of solvent from reaction mass under vacuum and allowing the reaction mass to attain ambient temperature.
iv. Cooling the reaction mass to 0-10°C.
v. Stirring of reaction mass at 0-10°C for 1-2 hours to ensure proper crystallization.
vi. Filtering the product as wet cake by routine filtration and running washing with water.
vii. Isolating the product crystalline Empagliflozin Form I by drying of solid mass at 50-60°C for 8-12 hours.
According to the fourth embodiment of the present invention, a novel process for the preparation of crystalline Form I of Empagliflozin is disclosed which comprises (Example 4):
i. Dissolving any polymorphic form of Empagliflozin in an aliphatic ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone, methylisobutyl ketone, diisobutylketone and water, in any ratio, by heating the reaction mass at 40-45°C to obtain a clear solution.
ii. Fine filtering the hot reaction mass.
iii. Adding water to the reaction mass at 40-45°C and allowing the reaction mass to attain ambient temperature.
iv. Cooling the reaction mass to 0-10°C.
v. Stirring of reaction mass at 0-10°C for 1-2 hours to ensure proper crystallization.
vi. Filtering the product as wet cake by routine filtration and running washing with water.
vii. Isolating the product crystalline Empagliflozin Form I by drying of solid mass at 50-60°C for 8-12 hours.
According to the fifth embodiment of the present invention, a novel process for the preparation of crystalline Form I of Empagliflozin is disclosed which comprises (Example 5):
i. Dissolving any polymorphic form of Empagliflozin in cyclic or acyclic ethers selected from tetrahydrofuran, dioxane, diisopropyl ether (IPE), tert-butylmethyl ether (MTBE), 2-Methyl Tetrahydrofuran, cyclopentyl methyl ether (CPME) or a mixture thereof at 60-70°C.
ii. Stirring for 10-15 minutes.
iii. Adding water to the reaction mass at 40-45°C and allowing the reaction mass to attain ambient temperature.
iv. Cooling the reaction mass to 10-20°C.
v. Stirring of reaction mass at 10-20°C for 4-6 hours to ensure proper crystallization.
vi. Filtering the product as wet cake by routine filtration and running washing with water.
vii. Isolating the product crystalline Empagliflozin Form I by drying of solid mass at 50-60°C for 8-12 hours.
Brief Description of figures:
1) Figure 1 – Crystalline Empagliflozin Form I obtained as per Example 1
2) Figure 2 – Crystalline Empagliflozin Form I obtained as per Example 2
3) Figure 3 – Crystalline Empagliflozin Form I obtained as per Example 3
4) Figure 4 – Crystalline Empagliflozin Form I obtained as per Example 4
5) Figure 5 – Crystalline Empagliflozin Form I obtained as per Example 5
The above-mentioned invention is supported by the following non limiting examples.
EXAMPLES:
Example 1
Empagliflozin (10 g) is dissolved in N,N-Dimethylformamide (30 ml) and water (30 ml) in a round bottom flask with stirring at 30-40°C. The resulting solution is further stirred at 0-10°C for 1-2 hours to ensure proper crystallization. The crystallized material is filtered as wet cake by routine filtration and dried at 50-60°C for 8-12 hours to get 7.6 g of crystalline Empagliflozin Form I as confirmed from its XRD pattern (Figure 1).
Example 2
Empagliflozin (10 g) is dissolved in Tetrahydrofuran (40 ml) in a round bottom flask with stirring at 60-70°C. After stirring for 10-15 minutes, about 10 ml of Tetrahydrofuran is recovered under vacuum followed by the cooling of reaction mass to 0-10°C. The resulting solution is further stirred at 0-10°C for 3-4 hours to ensure proper crystallization. The crystallized material is filtered as wet cake by routine filtration and dried at 50-60°C for 8-12 hours to get 8.0 g of crystalline Empagliflozin Form I as confirmed from its XRD pattern (Figure 2).
Example 3
Empagliflozin (10 g) is dissolved in Acetone (100 ml) and Water (5 ml) in a round bottom flask with stirring at 50-60°C. The hot solution is finely filtered and almost 50 ml reaction mass is recovered under vacuum followed by the cooling of reaction mass to 0-10°C. The resulting solution is further stirred at 0-10°C for 1-2 hours to ensure proper crystallization. The crystallized material is filtered as wet cake by routine filtration and dried at 50-60°C for 8-12 hours to get 8.4 g of crystalline Empagliflozin Form I as confirmed from its XRD pattern (Figure 3).
Example 4
Empagliflozin (10 g) is dissolved in Acetone (50 ml) and Water (5 ml) in a round bottom flask with stirring at 50-60°C. Fine The hot solution is finely filtered and then Water (30 ml) is added at 40-45°C. The reaction mass is cooled to 0-10°C. The resulting solution is further stirred at 0-10°C for 1-2 hours to ensure proper crystallization. The crystallized material is filtered as wet cake by routine filtration and dried at 50-60°C for 8-12 hours to get 8.1 g of crystalline Empagliflozin Form I as confirmed from its XRD pattern (Figure 4).
Example 5
Empagliflozin (10 g) is dissolved in Tetrahydrofuran (40 ml) in a round bottom flask with stirring at 60-70°C. The hot solution is finely filtered and then Water (30 ml) is added at 40-45°C. The reaction mass is cooled to 10-20°C. The resulting solution is further stirred at 10-20°C for 4-6 hours to ensure proper crystallization. The crystallized material is filtered as wet cake by routine filtration and dried at 50-60°C for 8-12 hours to get 8.0 g of crystalline Empagliflozin Form I as confirmed from its XRD pattern (Figure 5). ,

WE CLAIM

A novel process for the preparation of crystalline Form I of Empagliflozin which comprises:
I. dissolving any polymorphic form of Empagliflozin in an aliphatic amide selected from N,N-dimethyl formamide (DMF), N-butylformamide, N,N-dimethylmethanamide, N,N-dimethy ethanamide, dimethylsulphoxide or a mixture thereof and water at 30-40°C to obtain a clear solution;
II. stirring and cooling the reaction mass to 0-10°C;
III. stirring the reaction mass at 0-10°C for 1-2 hours;
IV. isolating Empagliflozin as wet cake by routine filtration; and
V. drying of the wet cake at 50-60°C for 8-12 hours to get crystalline Empagliflozin Form I.

2. A novel process for the preparation of crystalline Form I of Empagliflozin which comprises:
I. dissolving any polymorphic form of Empagliflozin in cyclic or acyclic ethers selected from tetrahydrofuran, dioxane, diisopropyl ether(IPE), tert-butylmethyl ether (MTBE), 2-Methyl Tetrahydrofuran, cyclopentyl methyl ether (CPME) or a mixture thereof at 60-70°C;
II. stirring for some time;
III. preferably removing 10-40% of solvent, more preferably removing 20-30% or most preferably removing 25% from reaction mass under vacuum at elevated temperature;
IV. cooling of reaction mass to 0-10°C;
V. stirring for 3-4 hours at 0-10°C;
VI. isolating Empagliflozin as wet cake by routine filtration; and
VII. drying of the wet cake at 50-60°C for 8-12 hours to get crystalline Empagliflozin Form I.

3. A novel process for the preparation of crystalline Form I of Empagliflozin which comprises:
I. dissolving any polymorphic form of Empagliflozin in an aliphatic ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone, Methylisobutyl ketone and water, in any ratio, by heating the reaction mass at 50-60°C to obtain a clear solution;
II. finely filtering the hot reaction mass to remove undissolved material.;
III. preferably removing 30-70% of solvent, more preferably removing 40-60% or most preferably removing 50% from reaction mass under vacuum at elevated temperature;
IV. cooling of reaction mass to 0-10°C;
V. stirring for 1-2 hours at 0-10°C;
VI. isolating Empagliflozin as wet cake by routine filtration; and
VII. drying of the wet cake at 50-60°C for 8-12 hours to get crystalline Empagliflozin Form I.

4. A novel process for the preparation of crystalline Form I of Empagliflozin which comprises:
I. dissolving any polymorphic form of Empagliflozin in an aliphatic ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone, methylisobutyl ketone, diisobutylketone and water, in any ratio, by heating the reaction mass at 40-45°C to obtain a clear solution;
II. finely filtering the hot reaction mass to remove undissolved material;
III. adding water at 40-45°C and cooling reaction mass to room temperature;
IV. cooling of reaction mass to 0-10°C;
V. stirring for 1-2 hours at 0-10°C;
VI. isolating Empagliflozin as wet cake by routine filtration; and
VII. drying of the wet cake at 50-60°C for 8-12 hours to get crystalline Empagliflozin Form I.

5. A novel process for the preparation of crystalline Form I of Empagliflozin which comprises:
I. dissolving any polymorphic form of Empagliflozin in cyclic or acyclic ethers selected from tetrahydrofuran, dioxane, diisopropyl ether (IPE), tert-butylmethyl ether (MTBE), 2-Methyl Tetrahydrofuran, cyclopentyl methyl ether (CPME) or a mixture thereof at 60-70°C;
II. stirring for 10-15 minutes;
III. adding water at 40-45°C and cooling reaction mass to room temperature;
IV. cooling of reaction mass to 10-20°C;
V. stirring for 4-6 hours at 10-20°C;
VI. isolating Empagliflozin as wet cake by routine filtration; and
VII. drying of the wet cake at 50-60°C for 8-12 hours to get crystalline Empagliflozin Form I.