FIELD OF THE INVENTION:
The present invention primarily discloses Novel Processes for the preparation of Amorphous Empagliflozin in a mixture of solvents using spray drying technique.
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 7,579,449 which discloses Empagliflozin, stereoisomers of Empagliflozin, mixtures and salts thereof, and a pharmaceutical composition containing Empagliflozin.

US patent 7,713,938 discloses the crystalline form of l-chloro-4-(P-D-glucopyranos-l-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 29±0.05 degrees 29. 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 P-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 P-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 P-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 US Patent 7,375,213).
US patent 7,847,074 discloses the metalated glucal method, preparation of SGLT2 inhibitors that involves coupling of a hydroxy-protected glucal that is metalated at CI 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 CI and C2 carbon atoms.
US patent application 2005/0233988 discloses utilization of a Suzuki reaction between a Cl-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, comprises 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 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 P-C-arylglucoside or the P-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 P-C-arylglucoside, magnesium ions provide the a- and P-C-arylglucosides, and aluminum (i.e., organoaluminum reagents) ions provide the a-C-arylglucoside.
The glycosyl leaving group substitution method: US 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. 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 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 P-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 P-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 1-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 P-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-methoxy phenyl-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 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 preparation of Empagliflozin are also disclosed, wherein Rl and R2 are independently hydrogen or hydroxyl protecting groups.

Mylan's patent application 4964/CHE/2014 provides a procedure to prepare amorphous Empagliflozin using a pharmaceutically acceptable carrier such a/ p7y-cyclodextrin or Plasdone S-630 besides the routine spray/freeze drying techniques. Somewhat similar method is also disclosed in 1985-MUM-2013, US 2013/0245267 and WO 2014/056434.
Cadila's patent application 1985/MUM/2013 also provides a method of preparation of amorphous Empagliflozin using spray drying techniques. It makes use of various

solvent systems such as Acetone, Methanol-MTBE, Methanol-Water. It also makes use of various pharmaceutical^ acceptable carriers such as PVP K-30 & HPMC-AS. It also lays special emphasis on particle size of amorphous material.
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 primarily describes a novel process for preparation of amorphous Empagliflozin using spray drying technique in various solvent mixture. To start with feed stock solution of Empagliflozin is conveniently prepared by dissolving solvents that may include but are not limited to a mixture of one or more of alcohols such as methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol and the like chlorinated aliphatic hydrocarbons such as methylene dichloride, chloroform, carbon tetrachloride, ethylene dichloride. The second step involves isolation of an amorphous form of Empagliflozin from the fine filtered feed solution. The isolation may be affected by removing the solvent. Suitable techniques which may be used for the removal of solvent include using a rotational distillation device such as a Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), and the like or any other suitable technique.
In current invention, there is provided spray drying a solution of Empagliflozin that involves the spray drying of feed stock wherein any crystalline form of

Empagliflozin may be used. The feedstock is dozed into the spray-drying instrument JISL Mini Spray-drier LSD-48 and spray drying is carried out under the specific parameters which elaborated in further part of the current invention.
In another preferred feature, the spray drying of Empagliflozin may be performed on JISL Mini Spray-drier LSD-48 by maintaining following parameter a) maintaining the feed rate of the feed stock preferably 20-25 ml/hour; b) maintaining the inlet temperature 70°C-85°C; c) maintaining the aspirator rate between 50-80 rpm; d) maintaining the outlet temperature in the range of 26°C to 35° C; e) maintaining air flow at 2-4 Kg/cm, preferably 2 Kg/cm; f) maintaining the vacuum at 60-80 mm of Hg.
In the present invention, feedstock of Empagliflozin in solvent system is spray-dried. Thus obtained spray-dried compound is in amorphous form, this fact is again confirmed by the X-ray powder diffractogram of spray-dried Empagliflozin. The parameters of obtaining the XRD diffractogram are mentioned below:
a) Scan Axis - Gonio
b) Start Position [°20] - 4.00
c) End Position [°20] -50.00
d) Step Size [°20] - 0.0170
e) Scan Step Time [s] -40.0050
f) Scan Type - Continuous
g) PSD Mode - Scanning
h) PSD Length [°20] -2.12
i) Offset [°20] -0.0000
j) Divergence Slit Type - Fixed

k) Divergence Slit Size [°] - 0.4354
1) Specimen Length [mm] - 10.00
m) Measurement Temperature [°C] - 25.00
n) Anode Material - Cu
o) K-Alphal [A] - 1.54060
p) K-Alpha2[A] - 1.54443
q) K-Beta[A] - 1.39225
r) K-A2 / K-Al Ratio - 0.50000
s) Generator Settings- 40 mA, 45 kV
t) Diffractometer Type - 0000000011023505
u) Diffractometer Number - 0
v) Goniometer Radius [mm] - 240.00
w) Dist. Focus-Diverg. Slit [mm] - 100.00
x) Incident Beam Monochromator - No
y) Spinning- Yes
The complete process details are disclosed in the next section.
DETAILED DESCRIPTION OF THE INVENTION:
According to the current embodiment of the present invention, a novel process for preparation of amorphous (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 amorphous Empagliflozin is disclosed which comprises:
i. dissolving crystalline form of l(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 in suitable solvent mixture of two or more solvents in a

specific ratio, first of which may be selected from aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol and second solvent is selected from a halogenated aliphatic hydrocarbon such as methylene dichloride, chloroform, carbon tetrachloride or mixture thereof;
ii. stirring the reaction mass to 25-35°C for 30 minutes to ensure complete dissolution followed by fine filtration and using it as feed stock/solution in spray dryer;
iii. the spray drying of Empaglifiozin is to be performed on JISL Mini Spray-drier LSD-48 by a) maintaining the feed rate of the feed stock preferably 20-25 ml/hour; b) maintaining the inlet temperature 70°C-85°C; c) maintaining the aspirator rate between 50-80 rpm; d) maintaining the outlet temperature in the range of 26°C to 35° C; e) maintaining air flow at 2-4 kg/cm, preferably 2 kg/cm; f) maintaining the vacuum at 60-80 mm of Hg; and
iv. isolating the pure amorphous Empaglifiozin from cyclone flask in almost powdered form which is further dried at 50-60°C for 8-12 hours.
The current invention is supported by following non limited examples.
Example 1:
25g of Empaglifiozin was added in a mixture of methanol-methylene chloride (6:5). The reaction mass was stirred for 30 minutes at 25 to 35°C to get a clear solution. After fine filtration, the solution was followed by spray drying under below conditions.

S.No. Parameter Conditions
a) Feed Pump Rate 22rpm
b) Inlet Temperature 80°C
c) Outlet Temperature 28.5-30°C
d) Aspiration Rate 50 to 80 rpm
e) Vacuum 60-80 mm of Hg
f) Hot Air Supply 2 Kg/cm2
After completion of feeding, the product was collected from the cyclone and dried for 8-12 hours at 50-60°C. The obtained solid (10.Og) was amorphous Empaglifiozin as shown by X-Ray Diffraction pattern, Fig 1.
Example 2:
25g of Empaglifiozin was added in a mixture of methanol-methylene chloride (7:5). The reaction mass was stirred for 30 minutes at 25 to 35°C to get a clear solution. After fine filtration, the solution was followed by spray drying under below conditions.

S.No. Parameter Conditions
g) Feed Pump Rate 24 rpm
h) Inlet Temperature 77°C
i) Outlet Temperature 30-32°C
J) Aspiration Rate 60 to 70 rpm
k) Vacuum 60-80 mm of Hg
1) Hot Air Supply 2 kg/cm2

After completion of feeding, the product was collected from the cyclone and dried for 8-12 hours at 50-60°C. The obtained solid (13.5g) was amorphous Empaglifiozin as shown by X-Ray Diffraction pattern, Fig. 2.
Example 3:
25g of Empaglifiozin was added in a mixture of methanol-methylene chloride (9:5). The reaction mass was stirred for 30 minutes at 25 to 35°C to get a clear solution. After fine filtration, the solution was followed by spray drying under below conditions.

S.No. Parameter Conditions
a) Feed Pump Rate 23 rpm
b) Inlet Temperature 82°C
c) Outlet Temperature 32-35°C
d) Aspiration Rate 75 to 80 rpm
e) Vacuum 60-80 mm of Hg
f) Hot Air Supply 2 kg/cm2
After completion of feeding, the product was collected from the cyclone and dried for 8-12 hours at 50-60°C. The obtained solid (13.5g) was amorphous Empaglifiozin as shown by X-Ray Diffraction pattern, Fig. 3.
Example 4:
25g of Empaglifiozin was added in a mixture of methanol-methylene chloride (4:5). The reaction mass was stirred for 30 minutes at 25 to 35°C to get a clear solution. After fine filtration, solution was followed by Spray drying under below conditions.

S.No. Parameter Conditions
a) Feed Pump Rate 20rpm
b) Inlet Temperature 85°C
c) Outlet Temperature 26-28°C
d) Aspiration Rate 60 to 70 rpm
e) Vacuum 60-80 mm of Hg
f) Hot Air Supply 2 Kg/cm2
After completion of feeding, the product was collected from the cyclone and dried for 8-12 hours at 50-60°C. The obtained solid (13.5g) was amorphous Empagliflozin as shown by X-Ray Diffraction pattern, Fig. 4.

WE CLAIM:

An improved process for the preparation of amorphous (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 amorphous Empagliflozin which comprises:
i. dissolving crystalline form of l(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 in a solvent mixture of two or more solvents in a specific ratio;
ii. stirring the reaction mass at 25-35°C for 30 minutes and using it as feed stock/solution in JISL Mini Spray-drier LSD-48;
iii. maintaining the feed rate of the feed stock preferably 20-25 ml/hour;
iv. maintaining the inlet temperature in the range of 70°C-85°C;
v. maintaining the aspirator rate between 50-80 rpm;
vi. maintaining the outlet temperature in the range of 26°C to 35°C;
vii. maintaining air flow at 2-4 Kg/cm, preferably 2 Kg/cm;
viii. maintaining the vacuum at 60-80 mm of Hg;
ix. isolating the pure amorphous Empagliflozin from cyclone flask in powdered form; and
x. further drying the powder at 50-60°C for 8-12 hours to get final amorphous Empagliflozin.

The process as claimed in claim l(i), wherein the solvent mixture consists of two solvents, first of which is an aliphatic alcohol selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol & second solvent is a halogenated aliphatic hydrocarbon selected from methylene dichloride, chloroform, carbon tetrachloride in ratio varying from 0.8:1 to 1.8:1.