Field of the Invention:
The present invention relates to process for the preparation of amorphous (1S)-1,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1, represented by the following structural formula.
Background of the Invention:
(lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol, also known as Canagliflozin, belongs to a novel therapeutic class of sodium-glucose co-transporter 2 inhibitors. US drug regulatory approval was received in march 2013 for canagliflozin (INVOKANA™) as an adjunct to diet and exercise to improve glycemic control in adults with type-2 diabetes mellitus.
US Patent No, 7,943,788 B2 first discloses canagliflozin or salts thereof and the process for its preparation.
US Patent Nos. 7,943,582 B2 (herein after referred as US'582) and 8,513,202 B2 (herein after referred as US'202) discloses crystalline form of canagliflozin hemihydrate and process for preparation thereof.
US Publication No. 2013/0237487 Al (herein after referred as US'487 Al) discloses amorphous dapagliflozin and amorphous canagliflozin. The US'487 Al also discloses 1:1 crystalline complex of canagliflozin with L-proline (Form CS1), ethanol solvate of a 1:1 crystalline complex of canagliflozin with D-proline (Form CS2), 1:1 crystalline complex of canagliflozin with L-phenylalanine (Form CS3), 1:1 crystalline complex of canagliflozin with D-proline (Form CS4).

The US'487 Al discloses preparation of amorphous canagliflozin by adding toluene solution into n-heptane. After drying in vacuo the product was obtained as a white solid of with melting point of 54.7°C to 72.0°C. However, upon repetition of the said experiment, the obtained amorphous canagliflozin was having higher amount of residual solvents. Therefore, the amorphous canagliflozin obtained by process as disclosed in US'487 Al is not suitable for pharmaceutical preparations.
The USf487 Al further discloses that amorphous canagliflozin obtained by the above process is hygroscopic in nature which was confirmed by Dynamic vapor sorption (DVS) analysis. Further, it was observed that the amorphous form underwent a physical change between the sorption/desorption cycle, making the sorption/desorption behavior different between the two cycles. The physical change that occurred was determined to be a conversion or partial conversion from the amorphous state to a crystalline state. This change was supported by a change in the overall appearance of the sample as the humidity increased from 70% to 90% RH.
The US'487 Al uses n-heptane has several disadvantages like, it hold static charge (i.e. build-up of static charge is a safety concern due to potential for fire therefore a special equipment configuration to improve grounding is needed when processing with n-heptane); processing with heptane cannot be done in glass-lined vessels because of static dissipation issues; n-heptane has an R50/53 risk phrase (indicating very toxic to aquatic organisms, and may cause long-term adverse effects in the aquatic environment).
Furthermore, WO2008/069327 Al mentions that amorphous (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol suffers from stability and handling issues such as poor filterability.
Therefore, there is art to provide an improved process for the preparation of stable amorphous form of (1S)-1,5-anhydro-1 -[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl phenyl] -D-glucitol.

Brief description of the Invention:
The first aspect of the present invention is to provide a process for the preparation of amorphous form of (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl phenyl]-D-glucitol compound of formula-1.
The second aspect of the present invention is to provide an improved process for the preparation of amorphous (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1.
Brief description of the Drawings:
Figure 1: Illustrates the PXRD pattern of amorphous form of (lS)-l,5-anhydro-l-[3-[[5-(4-
fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1.
Figure 2: Illustrates the DSC thermogram of amorphous form of (lS)-l,5-anhydro-l-[3-[[5-(4-
fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1.
Detailed description of the Invention:
The present invention provides a process for the preparation of amorphous form of (1S)-1,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1.
As used herein the term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptarie, cyclohexane, pet ether, toluene, pentane, cycloheptane, methylcyclohexane, m-, o-, or p-xylene, and the like; "ether solvents" such as dimethoxy methane, tetrahydrofurari, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl, ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloro methane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile

and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; "polar solvents" such as water or mixtures thereof.
The term "suitable base" used herein the present invention until unless specified is selected from inorganic bases like "alkali metal hydroxides" such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium epoxide, potassium tert-butoxide and the like; ammonia, methanolic ammonia; and organic i bases such as triethyl amine, methyl amine, ethyl amine, 1,8-Diazabicyclo[5.4.0]undec-?7-ene (DBU), 1,5-Diazabicyclo (4.3.0)non-5-ene (DBN), lithium
**- ■
dioisoporpylamide (LDAX n-butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethyl amino pyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methylimidazole, 1,2,4-triazole, l,4-diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.
; -v
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-' st -
The first aspect Jxif the present invention provides a process for the preparation of amorphous form of/;0S)-l,5-aiihydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl phenyl]-D-glucitol compound of formula-1, comprising of the following steps:
a) Treating (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl) methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate compound of formula-2 with a suitable base in a suitable solvent,
b) absorbing the obtained compound on silica gel or silicon dioxide or neutral alumina in a suitable solvent,
c) adding a suitable solvent or mixture of solvents to the compound obtained in step-b),
d) filtering the reaction mixture,

e) adding a suitable solvent to the compound obtained in step-d) and heating the reaction mixture,
f) stirring and filtering the reaction mixture,
g) adding a suitable solvent to the filtrate obtained in step-f),
h) optionally, treating the reaction mixture with carbon,
i) distilling off the solvent completely from the reaction mixture to provide amorphous (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1.
Wherein,
in step-a) the suitable base is selected from organic or inorganic base; preferably inorganic base;
in step^a), b), c), e) and g) the suitable solvent is selected from alcohol solvents, ether solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, polar aprotic solvents and polar solvents like water or mixture thereof
The preferred embodiment of the present invention provides a process for the preparation of amorphous form of (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl phenyl]-D-glucitol compound of formula-1, comprising of the following steps:
a) Treating (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl) methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate compound of formula-2 with sodium carbonate in methanol,
b) absorbing the obtained compound on silica gel in dichloromethane,
c) adding a mixture of methanol and water to the compound obtained in step-b),
d) filtering the reaction mixture,
e) adding dichloromethane to the compound obtained in step-d) and heating the reaction mixture,
f) stirring and filtering the reaction mixture optionally using hy-flow,
g) adding ethyl acetate to the filtrate obtained in step-f),
h) optionally, treating the reaction mixture with carbon,

i) distilling off the solvent completely from the reaction mixture to provide amorphous (lS)-lJ5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1.
In another preferred embodiment of the present invention provides a process for the preparation of amorphous form of (lS)-l55-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl phenyl]-D-glucitol compound of formula-1, comprising of the following steps:
a) Treating (2R53R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3J4,5-triyltriacetate compound of formula-2 with sodium carbonate in methanol,
b) absorbing the obtained compound on silica gel in dichloromethane,
c) adding methanol to the compound obtained in step-b),
d) stirring the reaction mixture,
e) adding water and stirring the reaction mixture,
f) filtering the reaction mixture,
g) adding dichloromethane to the compound obtained in step-f) and heating the reaction mixture,
h) stirring and filtering the reaction mixture,
i) adding ethyl acetate to the filtrate obtained in step-f),
j) optionally, treating the reaction mixture with carbon,
k) distilling off the solvent completely from the reaction mixture to provide amorphous
(lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-
glucitol compound of formula-1.
The powder X-ray diffractogram of amorphous form of (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1 obtained according to the present invention was depicted in figure-1.
Further, (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1 of the present invention is having purity greater than 99% as measured by HPLC and residual solvents less than 0.5%.

The second aspect of the present invention provides an improved process for the preparation of amorphous (1 S)-l ,5-anhydro-1 -[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1, comprising of the following steps:
a) Reacting (3R,4S,5S,6R)-35435-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-one compound of formula-2 with trimethyl silyl chloride in presence of a suitable base in a suitable solvent to provide (3R?4S35R,6R)-35435-tris(trimethylsilyloxy)-6-((trimethyl silyloxy)methyl)tetrahydro-2H-pyran-2-one compound of formula-3,
b) reacting (3R,4S>5R56R)-3,4>5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl) tetrahydro-2H-pyran-2-one compound of formula-3 with 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene compound of formula-4 in presence of n-butyl lithium w.r.to compound of formula-3 in a suitable solvent, at a temperature in the range of from about 0°C to about -78°C to provide (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl) thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2)3,4,5-tetraol compound of formula-5; and wherein the n-butyl lithium is added to a mixture of the compound of formula-3 and the compound of formula-4,
c) reducing the compound of formula-5 with a suitable reducing agent in a suitable solvent to provide (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl phenyl]-D-glucitol compound of formula-1,
d) acetylating the compound of formula-1 with a suitable acetylating agent in presence of a suitable base in a suitable solvent to provide (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-. ((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl) tetrahydro-2H-pyran-3,4,5-triyltriacetate compound of formula-6,
e) treating the compound of formula-6 with a suitable base in a suitable solvent to provide (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1.
f) absorbing the compound of formula-1 obtained compound on silica gel or silicon dioxide or neutral alumina in presence of a suitable solvent,
g) adding a suitable solvent to the compound obtained in step-f),
h) stirring the reaction mixture,
i) adding a suitable solvent and stirring the reaction mixture, j) filtering the reaction mixture,

k) adding a suitable solvent to the compound obtained in step-j) and heating the reaction
mixture, 1) stirring and filtering the reaction mixture, m) adding a suitable solvent to the filtrate obtained in step-1), n) optionally, treating the reaction mixture with carbon, o) distilling off the solvent completely from the reaction mixture to provide amorphous
(lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-
glucitol compound of formula-1.
Wherein,
in step-a), d) and e) the suitable base is selected from organic or inorganic base;
in step b) n-butyl t lithium is used at least 1.0 mole equivalents and at most 4.0 mole equivalents w.r.to compound of formula-3
in step-c) the suitable reducing agent is selected from trialkyl silanes such as trimethyl silane, triethylsilane optionally in combination with a suitable lewi's acid or trifluoroacetic acid or BF3-etherate; trichlorosilane, sodium borohydride optionally in combination with BF3-etherate, diborane, potassium borohydride, sodium 25 cyanoborohydride, lithium borohydride, lithium aluminium hydride, diisobutylaluminium hydride (DIBAL-H), lithium triethylborohydride (LiEdBH), L-selectride, sodium bis(2-methoxyethoxy)aluminium hydride (vitride), sodium borohydride/BF3-etherate, sodium boro hydride/aluminium chloride, borane/aluminium chloride, sodium borohydride/iodine, Trifluoroacetic acid/sodium 30 borohydride, Zn-Hg, sodium borohydride/tosylhydrazone, 9-BBN and the like;
in step-d) the suitable acetylating agent is selected from acetic anhydride or acetyl chloride;
in step-a), b), c), d), e), f), g), i), k) and m) the suitable solvent is selected from alcohol solvents, ether solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, polar aprotic solvents and polar solvents like water or mixture thereof.
The preferred embodiment of the present invention provides an improved process for the preparation of amorphous (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1, comprising of the following steps:

a) Reacting (3R,4S,5S56R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-one compound of formula-2 with trimethyl silyl chloride in presence of a n-methyl morpholine in tetrahydrofuran to provide (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one compound of formula-3,
b) Reacting (3R54S,5RJ6R)-354,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl) tetrahydro-2H-pyran-2-one compound of formula-3 with 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene compound of formula-4 in presence of at least 1.0 mole equivalents and at most 4.0 mole equivalents of n-butyl lithium w.r.to compound of formula-3 in tetrahydrofuran at a temperature in the range of from about 0°C to about -78°C to provide (2S53R,4S55S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-233»4,5-tetraor compound of formula-5 and wherein the n-butyl lithium is added to a mixture of the compound of formula-3 and the compound of formula-4,
c) reducing the compound of formula-5 with triethylsilane/BF3-etherate in dichloromethane to provide (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl phenyl]-D-glucitol compound of formula-1,
d) acetylating the compound of formula-1 with acetic anhydride in presence of dimethylamino pyridine in dichloromethane to provide (2R,3R,4R,5S,6S)-2-(acetoxy methyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl) tetrahydro-2H-pyran-3,4,5-triyltriacetate compound of formula-6,
e) treating the compound of formula-6 with sodium carbonate in methanol to provide (1S)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1.
f) absorbing the compound of formula-1 obtained compound on silica gel in presence of dichloromethane,
g) adding methanol to the compound obtained in step-f),
h) stirring the reaction mixture,
i) adding a water and stirring the reaction mixture, j) filtering the reaction mixture,
k) adding a dichloromethane to the compound obtained in step-j) and heating the reaction mixture,

1) stirring and filtering the reaction mixture,
m) adding ethyl acetate to the filtrate obtained in step-1),
n) optionally, treating the reaction mixture with carbon,
o) distilling off the solvent completely from the reaction mixture to provide amorphous
(lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-
glucitol compound of formula-1.
Amorphous form of canagliflozin of the present invention is substantially free from residual solvents. The term "substantially free" means residual solvents within the permissible ICH limits suitable for pharmaceutical preparations. For example but not limited to less than 0.5%, particularly less than 0.3% or more particularly less than 0.2%.
Amorphous (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl
phenyl]-D-glucitol compound of formula-1 obtained according to the present invention is free of crystalline forms.
Amorphous (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl
phenyl]-D-glucitol compound of formula-1 produced by the present invention can be further micronized or milled in a conventional techniques to get the desired.particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
Amorphous (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl
phenyl]-D-glucitol compound of formula-1 produced by the present invention containing less than about 0.1% area by HPLC of one or more of the following impurities:

The invention also encompasses pharmaceutical compositions comprising compound of formula-1 or salts thereof of the present invention. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
P-XRD Method of Analysis:
PXRD analysis of compounds produced by the present invention were carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
DSC method of Analysis:
Differential scanning calorimetric (DSC) analysis was performed with Q10 V9.6 Build 290 calorimeter. Samples of about 2 to 3 milligrams held in a closed pan were analyzed at a heating rate of 10° per minute.

HPLC Method of Analysis of Amorphous (lS)-l,5-anhydro»l-[3-[[5-(4-fluorophenyI)-2-thienyl]methyl]-4-methyl phenyl]-D-glucitol compound of formulal
Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Unison UK-C18, 150 x 4.6 mm, 3 jam (or) equivalent; Flow rate: 1.0 ml/min; Wavelength: 290 nm; Column Temperature: 35°C; Injection volume: 10 pL; Run time: 40 min; Auto sampler temperature: 5°C; Diluent: Acetonitrile : Water (90:10 v/v); Needle wash: Methanol; Elution: Gradient; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile: Water (90:10 v/v); Buffer: Transfer 1.0 ml of Orthophosphoric acid (85%) into 1000 ml of Milli-Q-water, mix well and filter this solution through 0.22pm Nylon membrane filter paper.
The process of the present invention can be represented schematically as follows:

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples: Example-1
One-pot process for the preparation of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyI)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Formula-6)
a) Preparation of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)
methyl)tetrahydro-2H-pyran-2-one (Formula-3)
A mixture of tetrahydrofuran (200 ml), (3R,4S,5S,6R)-3A5-trihydroxy-6-(hydroxyl methyl)tetrahydro-2H-pyran-2-one (20 gms) compound of formula-2 and N-methyl morpholine (102.96 gms) was cooled to 0-5°C and stirred for 20 minutes at the same temperature. Trimethyl silyl chloride (91.2 gms) was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 40-45°C and stirred for 5 hours at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 12 hours at the same temperature. Cooled the reaction mixture to 0-5°C. n-heptane (100 ml), followed by water (100 ml) was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture 25-30°C. Both the organic and aqueous layers were separated and aqueous layer was extracted with n-heptane. Combined both the organic layers and washed with disodium hydrogen phosphate solution and followed by sodium chloride solution. Dried the organic layer with sodium sulfate. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.
b) Preparation of (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-
4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol (Formiila-5)
2-(4-Fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene (25 gms) compound of formula-4 and tetrahydrofuran (175 ml) were added to the title compound of formula-3 in the above example at 25-30°C under nitrogen atmosphere. Cooled the reaction mixture to -75 to -70°C. n-butyl lithium (71 ml) was added to the reaction mixture at -75 to -70°C and stirred for 1 hour at the same temperature under nitrogen atmosphere. Methanol (10 ml) was slowly added to the reaction mixture at -75 to -70°C and stirred for 1 hour at the same temperature. Sodium bicarbonate solution (sodium carbonate 5 gms in 50 ml of water) was slowly added tQ the

reaction mixture at -75°C under nitrogen atmosphere. Raised the temperature of the reaction mixture to 25-30°C. Water (250 ml) was added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Both the organic and aqueous layers were separated and aqueous layer was extracted with ethyl acetate. Combined both the organic layers and washed with aqueous sodium chloride solution. Dried the organic layer with sodium sulfate. Distilled off the solvent completely under reduced pressure to get the title compound.
c) Preparation of (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-
methylphenyl]-D-glucitoI (Formula-1)
Dichloromethane (175 ml) was added to the title compound of formula-5 obtained in the above example at 25-30°C and stirred for 10 minutes at the same temperature. Cooled the reaction mixture to - 25°C - 20°C. Triethyl silane (24.02 gms) was slowly added to the above pre-cooled reaction mixture at - 25°C to - 20°C and stirred for 45 minutes at the same temperature. BF3-etherate (27.6 gms) was slowly added to the reaction mixture at - 25°C to -20°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Ethyl acetate and followed by water was slowly added to the reaction mixture at 25-30°C and stirred for 15 minutes at the sane temperature. Both the organic and aqueous layers were separated and aqueous layer was extracted with ethyl acetate. Aqueous sodium bicarbonate solution was added to the organic layer. Adjusted the pH of the reaction mixture to 7-8 using acetic acid. Separated the organic and aqueous layers and washed the organic layer using aqueous sodium bicarbonate solution and then followed by aqueous sodium chloride solution. Dried the organic layer using sodium sulfate. Distilled off the organic layer completely under reduced pressure to get the title compound.
d) Preparation of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)
thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate
(Formula-6)
Dichloromethane (175 ml) was added to the title compound of formula-1 in the above example at 25-30°C and stirred for 10 minutes, dimethyl aminopyridine (1.73 gms) and followed by acetic anhydride (36.14 gms) was slowly added to the reaction mixture at 25-30°C and stirred for 3 hours at the same temperature. Water was added to the reaction mixture at 25-30°C. Both the organic and aqueous layers were separated and aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with aqueous hydrochloric acid

solution. Organic layer was washed with aqueous sodium bicarbonate solution and followed by sodium chloride solution. Distilled off the solvent completely from the organic layer and then co-distilled with methanol. To the obtained compound, methanol (75 ml) was added at below 50°C. Cooled the reaction mixture to 25-3Q°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound. Yield: 19.23 gms. Example-2
Preparation of Amorphous (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol (Formula-1)
A mixture of methanol (225 ml), (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluoro
phenyl)thiophen-2-yl)methyl)-4-methylphehyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (25
gms), sodium carbonate (75 gms) and water (25 ml) was heated to 60-65 °C and stirred for 20 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered the reaction mixture and washed with methanol. Distilled off the solvent completely from the filtrate under reduced pressure. Dichloromethane (175 ml) and silica gel (50 gms) were added to the obtained compound at 25-30°C. Distilled off the solvent completely from the reaction mixture under reduced pressure. Methanol (100 ml) was added to the obtained compound at 25-30°C and stirred 15 minutes at the same temperature. Water (200 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 45 minutes at the same temperature. Filtered the reaction mixture and washed with water. To the obtained wet compound, dichloromethane (175 ml) was added at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 20 minutes at the same temperature. Filtered the reaction mixture through hy-flow bed and washed with dichloromethane. To the obtained filtrate, ethyl acetate (25 ml) and carbon (2.5 gms) were added at 25-30°C. Filtered the reaction mixture and distilled off the solvent completely under reduced pressure to get the title compound.
Yield: 12.9 gms; M.R: 60-70°C; Purity by HPLC: 99.93 %;
Alpha isomer: 0.01%; 2-methyl phenyl impurity: N/D; Acetyl impurity: N/D; Methyl impurity: N/D; Iodo impurity: N/D; HIUI: 0.06%.
Particle size distribution: D(0.9): 14.5 ^m; D(0.5): 7.69 ^m; D(0.1): 3.29 |am. The P-XRD pattern of the obtained compound was depicted in figure-1.

Example-3
Preparation of Amorphous (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-
methy!phenyl]-D-gIucitol (Formula-1)
A mixture of methanol (225 ml), (2R,3R54RJ5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluoro
phenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (25
gms), sodium carbonate (75 gms) and water (25 ml) was heated to 60-65°C and stirred for 20 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered the reaction mixture and washed with methanol. Distilled off the solvent completely from the filtrate under reduced pressure. Dichloromethane (175 ml) and silica gel (50 gms) were added to the obtained compound at 25-30°C. Distilled off the solvent completely from the reaction mixture under reduced pressure. Methanol (100 ml) and water (200 ml) was added to the obtained compound at 25-30°C and stirred 45 minutes at the same temperature. To the obtained wet compound, dichloromethane (175 ml) was added at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 20 minutes at the same temperature. Filtered the reaction mixture through hy-flow bed and washed with dichloromethane. To the obtained filtrate, ethyl acetate (25 ml) and carbon (2.5 gms) were added at 25-30°C. Filtered the reaction mixture and distilled off the solvent completely under reduced pressure to get the title compound. Yield: 12.4 gms.
The P-XRD pattern of the obtained compound was depicted in figure-1.
ExampIe-4
Preparation of Amorphous (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-
methylphenyl]-D-glucitol (Formula-1)
A mixture of dichloromethane (700 ml) and (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol (50 gms) were stirred for 30 minutes at 40-45°C. Filtered the reaction mixture and distilled off the solvent completely under reduced pressure, n-Heptane (250 ml) was added to the obtained compound and distilled off the solvent completely from the reaction mixture under reduced pressure. n-Heptane (250 ml) was added to the obtained compound at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the solid, washed with n-heptane and suck dried under vacuum. Dried the compound at 50-55°C and sieve the compound with 100 mesh to get the title compound.

Yield: 42 gms; Purity by HPLC: 99.94%;
Particle size distribution: D(0.9): 116.4 ^m; D(0.5): 61.4 ^m; D(0.1): 28.7 ^m.
ExampIe-5
Preparation of Amorphous (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-
methylphenyl]-D-glucitol (Formula-1)
A mixture of methanol (90 Its), (2R,3R34R35S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluoro
phenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (10
kgs), sodium carbonate (30 kgs) and water (10 Its) was heated to 60-65°C and stirred for 20 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered the reaction mixture and washed with methanol. Distilled off the solvent completely from the filtrate under reduced pressure. Dichloromethane (45 Its) and silica gel (40 kgs) were added to the obtained compound at 25-30°C. Distilled off the solvent completely from the reaction mixture under reduced pressure. Methanol (60 Its) was added to the obtained compound at 25-30°C and stirred 15 minutes at the same temperature. Water (120 Its) was slowly added to the reaction mixture at 25-30°C and stirred for 45 minutes at the same temperature. Filtered the reaction mixture and washed with water. To the obtained wet compound, dichloromethane (105 Its) was added at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 20 minutes at the same temperature. Filtered the reaction mixture through hy-flow bed and washed with dichloromethane. To the obtained filtrate, ethyl acetate (10 Its) and carbon (1 kg) were added at 25-30°C and stirred for 10 minutes at the same temperature. Filtered the reaction mixture and distilled off the solvent completely under reduced pressure to get the title compound. Yield: 5 kgs.
The P-XRD pattern of the obtained compound was depicted in figure-1.

We Claim:
1. A process for the preparation of amorphous form of (lS)-l,5-anhydro-l-[3-[[5-(4-
fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1,
comprising of the following steps:
>
a) Treating (2R,3R54R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-
yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-354,5-triyltriacetate compound of formula-2 with a suitable base in a suitable solvent,
b) absorbing the obtained compound on silica gel or silicon dioxide or neutral alumina in a suitable solvent,
c) adding a suitable solvent or mixture of solvents to the compound obtained in step-b),
d) filtering the reaction mixture,
e) adding a suitable solvent to the compound obtained in step-d) and heating the reaction mixture,
f) stirring and filtering the reaction mixture,
g) adding a suitable solvent to the filtrate obtained in step-f),
h) optionally, treating the reaction mixture with carbon,
i) distilling off the solvent completely from the reaction mixture to provide amorphous (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol.
2. A process according to claim-1, wherein,
in step-a) the suitable base is selected from organic or inorganic base; preferably inorganic base;
in step-a), b), c), e) and g) the suitable solvent is selected from alcohol solvents, ether solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, polar aprotic solvents and polar solvents like water or mixture thereof.
3. A process for the preparation of amorphous form of (lS)-l,5-anhydro-l-[3-[[5-(4-
fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1,
comprising of the following steps:

a) Treating (2R,3R54R55S)6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-354,5-triyltriacetate compound of formula-2 with sodium carbonate in methanol,
b) absorbing the obtained compound on silica gel in dichloromethane,
c) adding a mixture of methanol and water to the compound obtained in step-b),
d) filtering the reaction mixture,
e) adding dichloromethane to the compound obtained in step-d) and heating the reaction mixture,
f) stirring and filtering the reaction mixture,
g) adding ethyl acetate to the filtrate obtained in step-f),
h) optionally, treating the reaction mixture with carbon,
i) distilling off the solvent completely from the reaction mixture to provide amorphous (IS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1.
4. A process for the preparation of amorphous form of (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-methylphenyl]-D-glucitol compound of formula-1, comprising of the following steps:
a) Treating (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate compound of formula-2 with sodium carbonate in methanol,
b) absorbing the obtained compound on silica gel in dichloromethane,
c) adding methanol to the compound obtained in step-b),
d) stirring the reaction mixture,
e) adding water and stirring the reaction mixture,
f) filtering the reaction mixture,
g) adding dichloromethane to the compound obtained in step-d) and heating the reaction mixture,
h) stirring and filtering the reaction mixture,
i) adding ethyl acetate to the filtrate obtained in step-f),
j) optionally, treating the reaction mixture with carbon,

k) distilling off the solvent completely from the reaction mixture to provide amorphous (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1.
5. An improved process for the preparation of amorphous (lS)-l,5-anhydro-l-[3-[[5-(4-
fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1,
comprising of the following steps:
a) Reacting (3RJ4S55R56R)-3?455-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)
*
tetrahydro-2H-pyran-2-one compound of formula-3 with 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene compound of formula-4 in presence of at least 1.0 mole equivalents and at most 4.0 mole equivalents of n-butyl lithium w.r.to compound of formula-3 in a suitable solvent, at a temperature in the range of from about 0°C to about -78°C to provide (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)
thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3) 4,5-tetraol compound of formula-5; and wherein the n-butyl lithium is added to a mixture of the compound of formula-3 and the compound of formula-4,
b) reducing the compound of formula-5 with a suitable reducing agent in a suitable solvent to provide (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1,
c) acetylating the compound of formula-1 with a suitable acetylating agent in presence of a suitable base in a suitable solvent to provide (2R,3R,4R,5S,6S)-2-(acetoxy methyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl) tetrahydro-2H-pyran-3,4,5-triyltriacetate compound of formula-6,
d) treating the compound of formula-6 with a suitable base in a suitable solvent to provide amorphous (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl phenyl] -D-glucitol compound of formula-1.
6. An improved process for the preparation of amorphous (lS)-l,5-anhydro-l-[3-[[5-(4-
fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1,
comprising of the following steps:

a) Reacting (3R,4S55R56R)-3,4,5-tris(trimethylsilyloxy)-6<(trimethylsilyloxy)methyl) tetrahydro-2H-pyran-2-one compound of formula-3 with 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene compound of formula-4 in presence of at least 1.0 mole equivalents and at most 4.0 mole equivalents of n-butyl lithium w.r.to compound of formula-3 in tetrahydrofiiran at a temperature in the range of from about 0°C to about -78°C to provide (2S,3R,4S?5S56R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-233,4,5-tetraol compound of formula-5 and wherein the n-butyl lithium is added to a mixture of the compound of formula-3 and the compound of formula-4,
b) reducing the compound of formula-5 with triethylsilane/BF3-etherate in dichloromethane to provide (lS)-l?5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-methylphenyl]-D-glucitol compound of formula-1,
c) acetylating the compound of formula-1 with acetic anhydride in presence of dimethyl amino pyridine in dichloromethane provide (2R,3R,4R,5S,6S)-2-(acetoxy methyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate compound of formula-6,
d) treating the compound of formula-6 with sodium carbonate in methanol to provide amorphous (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl phenyl]-D-glucitol compound of formula-1.

7. The process according to any of the preceding claims, the (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1 is substantially free of acetyl impurity; Methyl impurity; 3-Acetyl impurity; Iodo impurity as measured by HPLC.
8. The process according to any of the preceding claims, the (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1 having Alpha isomer impurity less than 0.1 %; preferably less than 0.05 %; more preferably less than 0.02 % as measured by HPLC.

9. (lS)-l,5-anhydro-l-[3-[[5-(4-fluoropheny^
glucitol compound of formula-1 obtained according to any one of the preceding claims
having purity greater than 99.95% as measured by HPLC. s
10. A pharmaceutical composition comprising amorphous (lS)-l,5-anhydro-l-[3-[[5-(4-
fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1 and
one or more pharmaceutically acceptable carriers, excipients or diluents.