Field of the Invention:
The present invention relates to an improved process for the preparation of (1S)-1,5-
anhydro-l-[3-[[5-(4-fluorophenyl)-24hien^ compound
of formula-1, represented by the following structural formula.

Background of the Invention:
Inhibitors of sodium glucose co-transporter 2 (SGLT2) have recently been developed as a novel potential therapeutic option for the treatment of type 2 diabetes. SGLT2 inhibitors (gliflozins) lower the plasma glucose concentration by inhibition of glucose re-uptake in the kidney? without weight gain. As the mechanism of action of SGLT2 inhibitors is in dependent of insulin secretion and insulin action, they lower the plasma glucose concentration with lower risk of hypoglycemia.
(15)-l35-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.

Brief description of the Invention:

The first aspect of the present invention is to provide an improved process for the preparation of (15)"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 a process for the preparation of (2S,3R,4S,5S,6R)-2-(3-((5<4-fluoropte (hydroxylmethyl) tetrahydro-2H-pyran-2,3,4,5-tetraol compound of formula-8.

The third aspect of the present invention is to provide novel (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-8.

The fourth aspect of the present invention is to provide a process for the preparation of (15)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)«2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1.

The fifth aspect of the present invention is to provide novel (2R,3R,4S,5R,6R)-6-(acetoxymethyl)-2-(3-((5«(4-fluorophenyl)thiophen-2«yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-2,3,4,5-tetrayltetraacetate compound of formula-lQ.

The sixth aspect of the present invention is to provide a process for the preparation of (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1, comprising reducing (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-8 with a suitable reducing agent in a suitable solvent to provide compound of formula-1.

The seventh aspect of the present invention is to provide a crystalline form of (2S53RJ4S95S36R)-2K3<(5K4-fluorophenyl)thiophen-2.yl)me%l)-4-methylphenyl)-6-(hydroxylmethyl)tetrahydro>2H-pyran-233,435-tetraol compound of formula-8.

The eight aspect of the present invention is to provide a process for the preparation of amorphous (15)4,5-anhydro4434[5-(4-fluorophenyl)-24hienyl]methyl]«4-methylphenyl]-D-glucitol compound of formula-1.

Brief description of Drawings:
Figure 1: Illustrates the PXRD pattern of amorphous form of (15}-l55-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 an improved process for the preparation of (15)-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-heptane, cyclohexane, pet ether, benzene, toluene, pentane, cycloheptane, methylcyclohexane, ethylbenzene, m-, o-, or p-xylene, octane and the like; "ether solvents" such as dimethoxymethane, tetrahydroflxran, 1,3-dioxane, 1,4-dioxane, fizran, 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), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, 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 ethoxide, potassium tert-butoxide and the like; ammonia, methanolic ammonia; and organic bases such as triethyl amine, methyl amine, ethyl amine, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo (4.3.0)non-5-ene (DBN), lithium dioisoporpylamide (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethyl aminopyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methyl imidazole, 1,2,4-triazole, l,4-diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.

As used herein the term suitable "chlorinating agent" include but are not limited to chlorine, oxalyl chloride, sulfuryl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, pivaloyl chloride, antimony pentachloride, iodine trichloride, sulfur dichloride, manganese tetra chloride and the like.

As used herein the term suitable "Lewifs acid" is selected from aluminium chloride, boran trichloride, ferric chloride, tin tetrachloride, stibium penta chloride and TiCU. .

The first aspect of the present invention provides an improved process for the preparation of (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl phenyl]-D-glucitol compound of formula-13 comprising of the following steps:

a) Reacting 5-iodo-2-methylbenzoic acid compound of formula-2 with a suitable chlorinating agent in a suitable solvent to provide 5-iodo-2-methylbenzoyl chloride, which further reacts with 2-(4-fluorophenyl)thiophene compound of formula-3 in presence of Lewi's acid to provide (5-(4-fluorophenyl)thiophen-2-yl)(5-iodo-2-methylphenyl)methanone compound of formula-4,

b) reducing the compound of formula-4 with a suitable reducing agent in a suitable solvent to provide 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene compound of formula-5,

c) reacting the compound of formula-5 with (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy) -6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one compound of formula-6 in presence of methyl lithium in a suitable solvent to provide (2S,3R54S,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-3,4,5-tris(trimethylsilyl oxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-ol compound of formula-7,

d) treating the compound of formula-7 in-situ with methane sulfonic acid in a suitable solvent to provide (2S93R,4S35S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro«2H-pyran-253,4,5-tetraol compound of formula-8,

e) reducing the compound of formula-8 in-situ with a suitable reducing agent in a suitable solvent to provide (lS)-l35-anhydro-l-[3-[[5-(4-fluorophenyl)-2«thienyl] methyl]-4-methylphenyl]-D-glucitol compound of formula-1,

f) 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-93

g) optionally, purifying the compound of formula-9 using a suitable solvent,

h) reacting the compound of formula-9 with a suitable base 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.
Wherein,
in step-a) the suitable chlorinating agent is selected from chlorine, oxalyl chloride, sulfuryl
chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, pivaloyl chloride; the suitable lewi's acid is selected from aluminium chloride, boran trichloride, ferric chloride, tin tetrachloride;
in step-b) & e) 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, sodiumcyano borohydride, lithium borohydride, lithium aluminium hydride, diisobutyl aluminium hydride (DIBAL-H), lithium triethylborohydride (LiEtaBH), L-selectride, sodium bis(2-methoxyethoxy)aluminium hydride (vitride), sodium borohydride/BF3-etherate, sodium boro hydride/aluminium chloride, borane/aluminium chloride, sodiumboro hydride/iodine, Trifluoroacetic acid/sodium borohydride, Zn-Hg, sodiumboro hydride/tosylhydrazone, 9-BBN and the like;
in step-f) & h) the suitable base is selected from organic (or) inorganic base;
in step-f) the suitable acetylating agent is selected from acetic anhydride or acetyl chloride;
in step-a) to step-h) the suitable solvent is selected from alcohol solvents, ether solvents,
chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, polar aprotic
solvents, polar solvents like water or mixtures thereof.

The preferred embodiment of the present invention provides an improved process for the preparation 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) Reacting 5-iodo-2-methylbenzoic acid compound of formula-2 with thionyl chloride in a mixture of dimethyl formamide and dichloromethane to provide 5-iodo-2-

methylbenzoyl chloride, which further reacts with 2-(4-fluorophenyl)thiophene compound of formula-3 in presence of aluminium chloride provides (5-(4-fluoro phenyl)thiophen-2-yl)(5-iodo-2-methylphenyl)methanone compound of formula-4,
b) reducing the compound of formula-4 with triethylsilane/BF3-etherate in acetonitrile to provide 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene compound of formula-5,
c) reacting the compound of formula-5 with (3R54S,5R36R)-3,4,5-tris(trimethylsilyl oxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one compound of formula-6 in presence of methyl lithium in tetrahydrofuran to provide (2S,3RJ4SJ5R?6R)-2-(3-((5-(4-fluorophenyl)thiophen«2-yl)methyl)-4-methylphenyl)-33455-tris(trimethylsilyl oxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-ol compound of formula-7,
d) treating the compound of formula-7 in-situ with methane sulfonic acid in methanol to provide (2S?3R54S35S36R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methyl phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-253,4,5-tetraol compound of formula-8,
e) reducing the compound of formula-8 iri-situ 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,
f) acetylating the compound of formula-1 with acetic anhydride in presence of dimethyl aminopyridine in dichloromethane to provide (2R,3R,4R35S?6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-354,5-triyltriacetate compound of formula-9,
g) purifying the compound of formula-9 using a mixture of ethyl acetate and methanol,
h) reacting the compound of formula-9 with sodium carbonate in aqueous methanol to
provide (1 S)-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 provides a process for the 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 compound of formula-8, comprising of
the following steps:
8

a) Reacting 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene compound of formula-5 with (3R54S55R56R)-35455-tris(trimethylsilyloxy)-6-((trimethylsilyloxy) methyl)tetrahydro-2H-pyran-2-one compound of formula-6 in presence of methyl lithium in a suitable solvent to provide (2S,3R,4S,5R,6R)-2-(3-((5-(4-fluoro phenyl)thiophen-2-yl)methyl)-4-methylphenyl)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-ol compound of formula-7,
b) treating the compound of formula-7 in-situ with methane sulfonic acid in a suitable solvent to provide (2S33R54S55S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-253,4,5-tetraol compound of formula-8.
Wherein,
in step-a) & b) the suitable solvent is selected from alcohol solvents, ether solvents, chloro
solvents, ketone solvents, ester solvents, hydrocarbon solvents, polar aprotic solvents,
polar solvents like water or mixtures thereof.
The preferred embodiment of the present invention provides a process for the preparation of (2S,3R,4S,5S,6R)-2-(3-((5<4-fluorophenyl)thiophen-2-yl)methyl)-4"methyl phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-2,3,4,5-tetraol compound of formula-8, comprising of the following steps:
a) Reacting 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene compound of formula-5 with (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy) methyl)tetrahydro-2H-pyran-2-one compound of formula-6 in presence of methyl lithium in tetrahydrofuran to provide (2S,3R,4S,5R,6R)-2-(3-((5-(4-fluorophenyl) thiophen-2-yl)methyl)-4-methylphenyl)-3,4,5-tris(trimethylsilyloxy)-6-((trimethyl silyloxy)methyl)tetrahydro-2H-pyran-2-ol compound of formula-7,
b) treating the compound of formula-7 in-situ with methane sulfonic acid in methanol to provide (2S,3R,4S,5S,6R)-2-(3-((5"(4-fluorophenyl)thiophen-2-yl)methyl)-4-methyl phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol compound of formula-8.

The third aspect of the present invention provides novel (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-pyran-2,3,4,5-tetraol compound of formula-8.
CH3 r^rF
JLOH
^^ Y^OH OH
Formula-8 The compound of formula-8 is useful in the preparation of pure (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glueitol compound of formula-
1.
The fourth aspect of the present invention provides a process for the preparation of (lS)-l,5-anhydro-l-[3-[[5-(4-fluoroph compound of formula-1, comprising of the following steps:
a) Acetylating(2S53R,4S?5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)"6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,455-tetraol compound of formula-8 with a suitable acetylating agent in presence of a suitable base in a suitable solvent to provide (2R,3R54S55R56R)-6-(acetoxymethyl)-2-(3-((5-(4-fluorophenyl) thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-2,354,5-tetrayl tetraacetate compound of formula-10,
b) reacting the compound of formula-10 with a suitable base in a suitable solvent to provide (2SJ3R54S>5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methyl phenyl)-6*(hydroxymethyl)tetrahydro-2H-pyran-2,35455-tetraol compound of formula-8,
c) reducing the compound of formula-8 with a suitable reducing agent in a suitable solvent to provide pure (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 acetylating agent is same as defined in step-f) of the first aspect of the
present invention; in step-a) & b) the suitable base is selected from organic or inorganic base; in steprc) the suitable reducing agent is same as defined in step-e) of the first aspect of the
present invention; in step-a), b) & c) the suitable solvent is selected from alcohol solvents, ether solvents, chloro
solvents, ketone solvents, ester solvents, hydrocarbon solvents, polar aprotic solvents,
polar solvents like water or mixture thereof.
The fifth aspect of the present invention provides novel (2R,3R,4S,5R,6R)-6-(acetoxy methyl)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-2,3,4,5-tetrayltetraacetate compound of formula-10.

The compound of formula-10 is useful in the preparation of pure (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1.
The sixth aspect of the present invention provides a process for the preparation of (lS>l,5-anhydro-l-[3-[[5-(4-fluoropheny
compound of formula-1, comprising reducing (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-8 with a suitable reducing agent in a suitable solvent to provide compound of formula-1.

The seventh aspect of the present invention provides a crystalline form of (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)to^^^ (hydroxylmethyl)tetrahydro-2H-pyran-25354,5-tetraol compound of formula-8.
The eighth aspect of the present invention provides a 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) Adding (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl phenyl]-D-glucitol compound of formula-1 to a suitable solvent,
b) heating the reaction mixture,
c) stirring the reaction mixture,
d) cooling the reaction mixture,
e) adding a suitable anti-solvent to the reaction mixture,
f) filtering the precipitated solid to get 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 solvent is selected from alcohol solvents, ketone solvents, ester solvents, chloro solvents, polar aprotic solvents, ether solvents and polar solvents like water or mixture thereof; in step-b) the suitable temperature is ranging from 0°C to the reflux temperature of solvent
used in the reaction; in step-d) the suitable temperature is ranging from -70°C to 30°C; In step-e) the suitable anti-solvent is hydrocarbon solvent such as toluene, hexane,
cyclohexane, heptane, cycloheptane, o-xylene, m-xylene, or p-xylene, pet ether,
pentane, methylcyclohexane or mixture thereof.
The preferred embodiment of the present invention provides a 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) Adding (lS)-l55-anhydro-143-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl phenyl]-D-glucitol compound of formula-1 to dichloromethane,
b) heating the reaction mixture to 40-45°C,
c) stirring the reaction mixture,
d) cooling the reaction mixture to -25 to -30°C,
e) adding n-heptane to the reaction mixture,
f) filtering the precipitated solid to get amorphous (lS)-l,57anhydro-l-[3-[[5-(4-fluoro phenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1.
The amorphous compound of formula-1 can be prepared by using the compound of formula-1 which is obtained from the process described in the present invention or from the process known in the art.
The invention also encompasses pharmaceutical compositions comprising (15)-1,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol 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.
(15)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1 produced by the present invention can be further micronized or milled by the 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.
P-XRD Method of Analysis:

PXRD analysis of compounds produced by the present invention were carried out using BRUKER D8 ADVANCE/AXS X-Ray diffractometer. using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
The process of the present invention can be represented schematically as follows:

Scheme-I:



The following impurities are formed during the preparation of compound of formula-1, which are controlled well within the ICH limits:

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:

Preparation of (5-(4-fluorophenyl)thiophen-2-yl)(5-iodo-2methyl)phenyl)methanone (Formula-4)
A mixture of dichloromethane (250 ml), dimethyl formamide (0.5 ml) and 5-iodo-2-methylbenzoic acid (50 gms) compound of formula-2 were cooled to 15-20°C. Thionyl chloride (3118 gms) was slowly added to the reaction mixture at 15-20°C and stirred for 6 hours at the same temperature. Distilled off the solvent completely under reduced pressure. Dichloromethane (110 ml) was added to the obtained compound under nitrogen atmosphere. Cooled the reaction mixture to 0-5°C. Aluminium chloride (21.61 gms) was added to the reaction mixture at 0-5°C and stirred for 20 minutes at the same temperature. 2-(4-fluorophenyl)thiophene solution (34.0 gms) in dichloromethane (55 ml)} was added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 4 hours at the same temperature. The reaction mixture was slowly added to a pre-cooled aqueous hydrochloric acid solution (50 ml HC1 in 25 ml of water) at 0-5°C and stirred for 15 minutes at the same temperature. Raised the temperature of the reaction mixture to 25-30°C. Both the organic and aqueous layers were separated and aqueous layer was extracted with dichloromethane. Combined both the organic layers and washed with aqueous sodium bicarbonate solution and dried over sodium sulfate. Distilled off the solvent completely under reduced pressure. Methanol (150 ml) was added to the obtained compound at 25-30°C and stirred for 45 minutes at the same temperature. Filtered the solid, washed with methanol and dried to get the title compound. Yield: 60 gms; Melting point: 135.1-137.2°C.

Example-2: Preparation of 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene (Formula-5)
Triethyl silane (164 gms) was added to a mixture of (5-(4-fluorophenyl)thiophen-2-yl)(5-iodo-2-methylphenyl)methanone (200 gms) and acetonitrile (500 ml) at 25-30°C. Cooled the reaction mixture to 0-5°C. BF3-etherate (160 gms) was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 4 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Filtered the compound and washed with acetonitrile. Water (600 ml) was added to the obtained wet compound at 25-30°C. Neutralizing the pH of the reaction mixture to 6-8 using aqueous sodium bicarbonate solution at 25-30°C and stirred

for 1 hour at the same temperature. Filtered the compound, washed with water and dried to
get the title compound. Yield: 172 gms; Melting point: 110-115°C.

Example-3:
Preparation of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)
methyl)tetra hydro-2H-pyran-2-one (Formula-6)
A mixture of tetrahydrofuran (400 ml), (3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxyl methyl)tetrahydro-2H-pyran-2-one (50 gms) and N-methyl morpholine (205.92 gms) was cooled to 0-5°C and stirred for 20 minutes at the same temperature. Trimethyl silyl chloride (182.4 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 arid stirred for 12 hours at the same temperature. Cooled the reaction mixture to 0-5°C. n-heptane (200 ml) followed by water (200 ml) was 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. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Example-4:
Preparation of (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methyIphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol (Formula-8)
2-(4-Fluorophenyl)-5-(5-iodo-2-methylben2yl)thiophene (50 gms) compound of formula-5 and tetrahydrofuran (350 ml) were added to the compound obtained in example-3 at 25-30°C under nitrogen atmosphere. Cooled the reaction mixture to -75 to -70°C. Methyl lithium (116 ml) was added to the reaction mixture at -75 to -70°C and stirred for 1 hour at the same temperature under nitrogen atmosphere. Methane sulfonic acid solution (11.8 gms) in (250 ml) of methanol was slowly added to the reaction mixture at -75 to -70°C. Water (50 ml) was added to the reaction mixture at -75°C under nitrogen atmosphere. Sodium bicarbonate solution [(20) gms of sodium bicarbonate in (100 ml) of water] was slowly added to the reaction mixture at -75°C. Raised the temperature of the reaction mixture to 25-30°C. 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. Distilled off the solvent completely under reduced pressure to get the title
compound.

Example-5:
Preparation of (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl
phenyl]-D-glucitol (Formula-1)
Dichloromethane (350 ml) was added to the compound obtained in example-4 at 25-30°C. Cooled the reaction mixture to - 25°C to - 20°C. Triethyl silane (48.04 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 (55.2 gms) was slowly added to the above reaction mixture at - 25°C to - 20°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 4 hours at the same temperature. Ethyl acetate and followed by water was added to the reaction mixture 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. Combined the organic layers and washed with aqueous sodium bicarbonate solution and followed by aqueous sodium chloride solution. Distilled off the organic layer completely under reduced pressure to get the title compound. Example-6:
Preparation of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluoro phenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Formula-9)
Dichloromethane (350 ml) and dimethyl aminopyridine (3.46 gms) was added to the compound obtained in example-5 at 25-30°C. Acetic anhydride (72.5 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 and co-distilled with methanol. To the obtained compound, methanol (200 ml) was added to the reaction mixture and stirred for 2 hours at 25-30°C. Filtered the precipitated solid, washed with methanol and dried to get the title compound. Yield: 21 gms.

Example-7:
Purification of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluoro phenyl)thiophen-
2-yl)methyl)-4-methyIphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Formula-9)
Ethyl acetate (375 ml) was added to (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)ttaophen-2-yl)methyl)-4-m
triacetate (50 gms) at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 15 minutes at the same temperature. Carbon (5 gms) was added to the reaction mixture at 55-60°C and stirred for 15 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. Distilled off the solvent completely from the filtrate under reduced pressure. Ethyl acetate (25 ml) and methanol (250 ml) were added to the obtained compound at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 45 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and further cooled to 15-20°C and stirred for 1 hour at the same temperature. Filtered the compound and washed with methanol. To the obtained wet compound, ethyl acetate (250 ml) was added at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 15 minutes at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Ethyl acetate (25 ml) and methanol (250 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 45 minutes at the same temperature. Cooled the reaction mixture to 25-30°C. Further cooled the reaction mixture to 15-20°C and stirred for 1 hour at the same temperature. Filtered the solid, washed with methanol and dried to get the title compound. Yield: 35.5 gms. ExampIe-8:
Preparation of (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl phenyl]-D-gluci to 1 (Formula-1)
Methanol (225 ml) was added to (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (25 gms) compound of formula-9 at 25-30°C. Sodium carbonate (75 gms) and followed by water (25 ml) was added to the reaction mixture at 25-30°C. Heated the reaction mixture 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 from the filtrate under reduced pressure. Cooled the reaction mixture to 25-30°C. Activated carbon (2.5 gms) was added to the reaction mixture and stirred for 30 minutes at 25-30°C. Filtered the reaction mixture and washed with methanol. The reaction mixture was slowly added to water (250 ml) at 25-30°C and stirred for 45 minutes at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 17 gms; Melting point: 100-110°C; Purity by HPLC: 99.85%,
The P-XRD pattern of the obtained compound of formula-1 is matching with the P-XRD pattern of canagliflozin hemihydrate disclosed in US 7,943,582 B2.

Example-9:
Purification 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-triyI triacetate (Formula-9)
Acetonitrile (250 ml) was added to (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6»(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5»triyl triacetate (50 gms) at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 20 minutes at the same temperature. Cooled the reaction mixture to 10-15°C and stirred for 1 lA hour at the same temperature. Filtered the precipitated solid, washed with acetonitrile and dried to get the title compound.
Yield: 32 gms; Melting point: 156-160°C; Purity by HPLC: 99.59%.

Example-10:
Preparation of Amorphous (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-methylphenyl]-D-glucitol (Formula-1)
Dichloromethane (70 ml) was added to (lS)-l,5-anhydro-l-[3»[[5-(4-fluorophenyl)-2« thienyl]methyl]-4-methylphenyl]-D-glucitol (10 gms) at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 45 minutes at the same temperature. Slowly cooled the reaction mixture to -30 to -25 °C and stirred for 10 minutes at the same temperature, n-heptane (400 ml) was added to the reaction mixture at -30 to -25°C and stirred for 30 minutes at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 9.0 gms. The P-XRD pattern of the obtained compound was depicted in figure-1.