CLIAMS:We claim,

1. A process for preparing (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Formula-I) comprising

Formula-I
(a) Reacting 2-(5-Bromo-2-methyl-benzyl)-5-(4-fluoro-phenyl)-thiophene with 3,4,5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one in presence of mixture of polar aprotic solvent and non-polar solvent, organolithium reagent, alkyl sulfonic acid, unsaturated aliphatic alcohol;
(b) Bringing pH neutral to alkaline to isolate 2-R1-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol.
(c) Reacting 2-R1-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol with organosilane in presence of acid, mixture of non-polar solvent and polar aprotic solvent under argon atmosphere and
(d) Quenching with sat. sodium bicarbonate solution to isolate(2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.

2. The process according to claim 1, whereinthepolar aprotic solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, ethyl acetate, acetone, dimethylformamideanddimethylsulfoxide.

3. The process according to claim 1, wherein the non-polar solvent is selected from the group consisting ofDichloromethane, Toluene, Hexane, 1,4-Dioxane, Chloroform, Diethyl ether,n-Heptane.

4. The process according to claim 1, wherein R1 is allyl, prop-2ynyl,.

5. The process according to claim 1, wherein the organolithium reagent is alkyllithium reagents selected from the group consisting of n-butyl lithium, methyl lithium, t-butyl lithium.

6. The process according to claim 1, whereinthealkyl sulfonic acid is methane sulfonic acid.

7. The process according to claim 1, whereinthe unsaturated aliphatic alcohol is selected from the group consisting of allyl alcohol, propargyl alcohol.

8. The process according to claim 1, whereintheacid is borontrifloride in diethylether, trifluoroacetic acid, methanesulfonic acid.

9. The process according to claim 1, whereintheorganosilaneisalkylsilane or polyalkylsilane selected from the group consisting of trimethylsilane, triethylsilane, tetramethylsilane, dimethylsilane.

10. The process according to claim 1, wherein the reaction temperature for step (a) and (e) is -70 to -80οC and -40 to -55 οC respectively.

11. A process for preparing stable amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol comprising
(a) Stirring (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol with non-polar solvent at ambient temperature and
(b) Isolating stable amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

12. The process according to claim 11, where innon-polar solvent is n-heptane.

13. A process for preparing L-prolin complex of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol comprising
(a) Reacting (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol with L-proline in presence of polar aprotic solvent under argon atmosphere;
(b) Adding non-polar solvent and
(c) Isolating L-proline complex of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.

14. The process according to claim 13, whereinthepolar aprotic solvent is ethyl acetate or acetone and non-polar solvent is n-Heptane.

15. The process according to any of the preceding claims, wherein the purity of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol and L-proline complex of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol is 99.8% and 98-99.8% respectively.

16. The compound, 2-R1-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol of formula V.

17. The compound according to claim 17 is selected from the group consisting of
a) 2 - allyl -2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol;
b) 2- prop-2ynyl -2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol; and

18. A process for preparing des-bromo impurities (2-(4-fluoro-phenyl)-5-(2-methyl-benzyl)-thiophene) which comprises (Formula-VI);

Formula-VI
(a) Reacting 2-(5-bromo-2-methyl-benzyl)-5-(4-fluoro-phenyl)-thiophene with alkyllithium in presence of mixture of polar aprotic solvent and non-polar solvent
(b) Adding ammonium chloride solution and
(c) Isolating 2-(4-fluoro-phenyl)-5-(2-methyl-benzyl)-thiophene
19. The process according to claim 19, wherein the alkyllithium reagents selected from the group consisting of n-butyl lithium, methyl lithium, t-butyl lithium.
20. The process according to claim 19, wherein the non-polar solvent is selected from the group consisting of Dichloromethane, Toluene, Hexane, 1,4-Dioxane, Chloroform, Diethyl ether,n-Heptane.
21. The process according to claim 19, wherein the polar aprotic solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide and dimethylsulfoxide.
22. The process according to claim 19, wherein the reaction temperature is -70 to -80οC.

Dated this 11th day of March, 2015

Dr. P. Aruna Sree
(Regn.No.: IN/PA 998)
Agent for the Applicant
Gopakumar Nair Associates ,TagSPECI:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:

“A novel process for preparing (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol and its stable amorphous hemihydrate form”

2. APPLICANT:

(a) NAME: HARMAN FINOCHEM LIMITED

(b) NATIONALITY: Indian Company incorporated under the Indian
Companies Act, 1956

(c) ADDRESS: 107, Vinay Bhavya Complex, 159–A , C.S.T. Road, Kalina,
Mumbai - 400098, Maharashtra, India.

3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION:
The present invention relates to anindustrially feasible process for preparation of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.

BACKGROUND OF INVENTION:
(2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Formula-I) is having an inhibitory activity against sodium dependent glucose transporter (SGLT), the transporter is responsible for reabsorbing the majority of glucose filtered by the kidney and is marketed under the trade name “Invokana”.

(2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol is also known as (1S)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol.

Formula-I
(2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolis first disclosed in US8222219, for the treatment of diabetes and related disorders.

US 7,943,788 B2 discloses(2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol and its pharmaceutically acceptable salts and its preparation process as depicted in Scheme-I.

Scheme-1
US’788 discloses the reaction of 2-(4-fluoro phenyl)-5-(5-iodo-2-methylbenzyl)-thiophene with 2,3,4,6-tetrakis-O-trimethylsilyl-D-glucono-1,5-lactone in presence of n-butyl lithium in hexane, tetrahydrofuran, toluene to obtain lactol compound which further reacts with methane sulfonic acid in methanol to give methyl ether compound whichreacts with triisopropylsilane and boron trifluoridediethylether complex in presence of dichloromethane to get residue of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol which further purified with silica gel chromatograph to get pure (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.

WO 2009035969 A1 and WO 2010043682 A2 disclose novel process for preparing(2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.
WO’969 describes reaction of 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene with 2,3,4,6-tetra-o-trimethylsilyl-β-D-glucolacone in presence of tetrahydrofuran,(trimethylsilyl) methyllithium in hexane to get an intermediate as a thick oil which further reacts with triethylsilane, boron trifluoridediethyletherate in presence of dichloromethane to get 1-(β-D-glucopyranosyl)-4-methyl-3-(5-(4-flurophenyl)-2-thienylmethyl) benzene as a green foam which further reacts with acetic anhydride in presence of 4-methyl morpholine, DAMP and tetrahydrofuran to get acetylprotected compound which further undergoes for deprotection in presence of lithium hydroxide as a brittle foam which is further crystallized using ethyl acetate, water and n-heptane to get off white crystalline solid.

Prior artprocess (US’788) describe purification method by using silica gel columnchromatographywhich is major drawback of the said process. Final compound is purified by chloroform:methanol (19:1) which is not industrially applicable. More over column chromatography is very tedious, time consuming and industrially not viable process.When practically the said methodfollowed α-Isomerof the final product is formed in the range of 5-8% along with Des-bromo impurity formed in the range of 18- 20 %, which increases after addition of n-butyllithium and kept for overnight reaction. Moreoverlactone ring cleavage is observed in the range of 3-4% after addition ofMethanesulphonic Acid/Methanol and maintained overnight for reaction completion, the removal of which is difficult from the final product and hence results in lower yield, lower purity. Moreover, the reaction is lengthy and the separation of the final product from the reaction are also time consuming makes the process cumbersome and uneconomical. Prior art process (WO’969) results an intermediate 2-hydroxy-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triolas an oil, form which is difficult to pure and handle for next step. Moreover, WO’969 describes multiple process steps to get pure crystalline compound which makes the process lengthy, tedious and uneconomical.

US 7,943,582 B2 describesa novel crystal form of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzenehemihydrates,methods for its preparation and isolation, as well as pharmaceutical compositions.
US 8,772,512 B2 describes a crystallization procedure to obtain 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene hemihydrate crystals.

WO 2013064909 A2 provides amorphous forms and the crystalline complexes of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol which are designated as Forms CS1, CS2, CS3, CS4 and CS5.

US 20080146515 Al discloses a crystalline hemihydrate form of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolas well asa process for the preparation of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolhemihydrates.

In the light of the above drawbacks, there is a need in the art to provide robust, safe and commercially viable process for preparing (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.

Accordingly, it is an objective of the present invention to provide a commercially viable process for the preparation of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol, prepared via novel intermediates which gives higher yield and purity and facilitates easy recovery of final compound. The purification process does not involve column chromatography or any costly technique/equipment, however, carried out with solvents which is commercially feasible, that makes the present invention cost-effective over the teachings of prior art.

SUMMARY OF THE INVENTION:
The present invention provides the process for preparation of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(Formula-I)and its stable amorphous hemihydrate form.

Formula-I
In one aspect, the present invention describes the silylation process for preparing 3,4,5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one from 3,4,5-Trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-onewhich comprises;
(a) Reacting 3,4,5-Trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-one with trimethylsilyl chloride in presence of solvent and organic base at ambient temperature;
(b) Maintaining pH 7-8 by adding sat. sodium bicarbonate;
(c) Separating organic layer and distilled and
(d) Isolating 3,4,5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one.

In another aspect, the present invention discloses the process for preparing 2-R1-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol from 3,4,5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one which comprises;
(a) Reacting 2-(5-Bromo-2-methyl-benzyl)-5-(4-fluoro-phenyl)-thiophene with 3,4,5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one in presence of mixture of polar aprotic solvent and non-polar solvent, organolithium reagent, alkyl sulfonic acid, monohydric or unsaturated aliphatic alcohol;
(b) Bringing pH neutral to alkaline;
(c) Separating organic layer and
(d) Isolating 2-R1-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol.

In one another embodiment the present invention describes process for preparing (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol by reduction of 2-R1-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol which comprises;
(a) Reacting 2-R1-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol with organosilane in presence of acid, mixture of non-polar solvent and polar aprotic solvent under argon atmosphere;
(b) Quenching with sat. sodium bicarbonate solution;
(c) Separating layers; and
(d) Isolating (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.

In one another embodiment the instant invention provides process for preparing stable amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol from (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol which comprises;
(a) Stirring (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol with non-polar solvent at ambient temperature and
(b) Isolating stable amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.

In another embodiment the present invention describes the preparation of L-proline complex of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol from (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol which comprises;
(a) Reacting (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol with proline in presence of polar aprotic solvent under argon atmosphere;
(b) Adding non-polar solvent and
(c) Isolating L-proline complex of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.

In another embodiment the present invention describes the process for preparing amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol from L-proline complex of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol which comprises;
(a) Stirring (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol in presence of ethyl acetate;
(b) Adding sat. sodium bicarbonate solution;
(c) Adding n-Heptane and
(d) Isolating stable amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.

The present process gives α- Isomer in the range of 1-1.8 %., which is removed during purification; further, the Des-bromoimpuirity (2-(5-2-methyl-benzyl)-5-(4-fluoro-phenyl)-thiophene) formation is restricted to 10-13 %during purification. After adding Methanesulphonic acid/alcohol the reaction is kept only for 5 hrs. Further work up disclosed in present invention is advantageous over the teachings of prior art as the purification process does not involve column chromatography or any costly technique. The purification process simply carried out with solvents which is commercially feasible. Thus the instant invention provides time saving, cost effective and commercially viable process for preparing (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.

DETAILED DESCRIPTION OF THE INVENTION:
The instant invention provides an efficient, advantageous and economical process for preparing (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(Formula-I)and its stable amorphous hemihydrate form..

Formula-I
In one embodiment, the present invention describes the silylation process for preparing 3,4,5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one from 3,4,5-Trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-onewhich comprises;
(a) Reacting 3,4,5-Trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-one with trimethylsilyl chloride in presence of solvent and organic base at ambient temperature;
(b) Maintaining pH 7-8 by adding sat. sodium bicarbonate;
(c) Separating organic layer and distilled and
(d) Isolating 3,4,5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one.
The process for preparing 3,4,5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one depicted in the following reaction Scheme II.

Scheme-II
The term solvent refers to polar aprotic solvents selected from the group consisting of tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide. The organic base is selected from the group consisting of triethylamine, diisopropyl ethylamine, N-methyl morpholine& N-methyl pyrrolidine.

According to above process, the reaction is carried out at -5 to 0οC.

In another embodiment, the instant invention discloses aprocess for preparing 2-R1-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol from 3,4,5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one which comprises;
(a) Reacting 2-(5-Bromo-2-methyl-benzyl)-5-(4-fluoro-phenyl)-thiophene with 3,4,5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one in presence of mixture of polar aprotic solvent and non-polar solvent, organolithium reagent, alkyl sulfonic acid, unsaturated aliphatic alcohol;
(b) Bringing pH neutral to alkaline;
(c) Separating organic layer and
(d) Isolating 2-R1-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol.

The reaction scheme for preparing 2-R1-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triolis given in Scheme III.

Scheme-III
In above said process, the polar aprotic solvent is selected from the group consisting of tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide. The non-polar solvent is selected from the group consisting ofToluene, Hexane, 1,4-Dioxane, Chloroform, Diethyl ether, Dichloromethane.

According to above process the reaction temperature is -70 to -80οC.

The term organolithium reagent refers to alkyllithium reagents selected from the group consisting of n-butyl lithium, methyl lithium, t-butyl lithium. The term alkyl sulfonic acid refers to methane sulfonic acid. The unsaturated aliphatic alcohol is selected from the group consisting of allyl alcohol, propargyl alcohol, 3,7-dimethylocta-2,6-dien-1-ol.

The present process gives α- Isomer in the range of 1-1.8 %., which is removed during purification, Des-bromoimpuirity (2-(5-2-methyl-benzyl)-5-(4-fluoro-phenyl)-thiophene) formation is restricted to 10-13 %during purification.
In above process R1is allyl or prop-2ynyl.
The main advantage of above said process is that the deprotection process undergoes insitu simultaneously. Therefore additional and multiple steps/ work up can be avoided which results in economical, time saving and safe process.Accordingly, the invention encompasses the compound 2-R1-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol of formula V.

Wherein, R1is allyl, prop-2ynyl,.
Therefore, the invention encompasses the novel intermediate compounds of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol, viz.,
a) 2- allyl -2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol;
b) 2- prop-2ynyl -2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol;

The novel intermediate is having better leaving groups- allyl, propargyl as compare to hydroxyl, alkyl which increases reaction rate and gives higher yield with reducedreaction time.
In another embodiment the instant invention discloses process for preparing des-bromo (2-(4-fluoro-phenyl)-5-(2-methyl-benzyl)-thiophene) impurities which comprises;
(a) Reacting 2-(5-bromo-2-methyl-benzyl)-5-(4-fluoro-phenyl)-thiophene with alkyllithiumin presence of mixture of polar aprotic solvent and non-polar solvent;
(b) Adding ammonium chloride solution and
(c) Isolating 2-(4-fluoro-phenyl)-5-(2-methyl-benzyl)-thiophene.

The alkyllithiumis selected from the group consisting of n-butyl lithium, methyl lithium, t-butyl lithium. The polar aprotic solvent is selected from the group consisting of tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide. The non-polar solvent is selected from the group consisting ofToluene, Hexane, 1,4-Dioxane, Chloroform, Diethyl ether, Dichloromethane. According to above process the reaction temperature is -70 to -80οC.

The main object is achieved by removing the des-bromo impurity the p during purification of 2-R1-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol, without invoving any special techniques., that makes the process less cumbersome and cost-effective.

In one another embodiment the present invention describes process for preparing (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol by reduction of 2-R1-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol which comprises;
(a) Reacting 2-R1-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol with organosilane in presence of acid, mixture of non-polar solvent and polar aprotic solvent under argon atmosphere;
(b) Quenching the reaction mass with sat. sodium bicarbonate solution;
(c) Separating layers and
(d) Isolating (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.
The reaction scheme for said process is given in Scheme-IV.

Scheme-IV

According to above said process the term organosilane refers to alkylsilane or polyalkylsilanewhichis selected from the group consisting of trimethylsilane, triethylsilane, tetramethylsilane, dimethylsilane. The non-polar solvent is selected from the group consisting of Dichloromethane, Toluene, Hexane, 1,4-Dioxane, Chloroform, Diethyl ether and the polar aprotic solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, dimethyl sulfoxide. The acid for the above said process is selected from the group consisting of borontrifloride in diethylether, trifluoroacetic acid, methanesulfonic acid.
The above reaction is carried out at -40 to 55 οC.
In above process R1is allyl or prop-2ynyl.
In one another embodiment the instant invention provides process for preparing stable amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol from (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol which comprises;
(a) Stirring(2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol with non-polar solvent at ambient temperature and
(b) Isolating stable amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.

The non-polar solvent for said process is selected from the group consisting of n-Heptane, Dichloromethane, Toluene, Hexane, 1,4-Dioxane, Chloroform, Diethyl ether. The ambient temperature is 25-30οC.

In prior art WO 2014195966 A2 (herein after WO’966) preparation of amorphous form of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol by spray drying method is disclosed. In WO’966 JISL Mini spray drier LSD-48 is used to get stable amorphous form of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol which makes the process very tedious, expensive and time consuming. The main object of the present invention process is to get stable amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol without using spray drier technique which makes the process simple, cost- effective and time saving.

In another embodiment the present invention describes the preparation of L-proline complex/cocrystal of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol from (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol which comprises;
(a) Reacting (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol with L-proline in presence of polar aprotic solvent under argon atmosphere;
(b) Adding non-polar solvent and
(c) Isolating L-proline complex of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.
The reaction scheme for said process is given in Scheme-V.

Scheme-V
The polar aprotic solvent for above said process is selected from the group consisting of ethyl acetate, acetone, acetonitrile, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide and the non-polar solvent is selected from the group consisting of n-Heptane, Dichloromethane, Toluene, Hexane, 1,4-Dioxane, Chloroform, Diethyl ether. The temperature for the above said process is 60-65οC.

In another embodiment the present invention describes the process for preparing amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol from L-proline complex of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol which comprises;
(a) Stirring L-proline complex of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol in presence of ethyl acetate;
(b) Adding sat. sodium bicarbonate solution;
(c) Adding n-Heptane and
(d) Isolating stable amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples:

Example-1: Preparation of 3,4,5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one
To 750 cc of dry THF added 1.12 mole 3,4,5-Trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-one at ambient temperature and stirred for 20 min. To the reaction mass added 9.0 mole N-Methyl morpholine and stirred for another 30.0 min at ambient temperature. Reaction mass is cooled to -5 οCto 0οCand stirred for 30.0 min. Added 18.0 mole Trimethylsillyl chloride at the temperature of -5 οC to 0 οCand stirred for 30.0 min. The temperaturewasraised to 25 οC to 30 οC and maintained for 18-20hrs. After reaction complies by GC, reaction mass was cooled to -5 deg to 0 deg. Added Sat.Sodium bicarbonate solution to obtain the pH 7-8and stirred for 1 hr at 0 οC. Added 500 cc toluene and stirred for 1hr. Reaction mass was settled down for 30.0 min and layers separated. To the Aqueous layer added 250 cc of toluene and stirred for 30.0 min. Layers separated and both the organic layers were combined and back washed with sat.brine solution. Organic layer was distilled under reduced pressure at a temperature of about 40 – 48 degοCandunloaded 91 to 93% of oily mass.
HPLC purity: 92-96%

Example-2: Preparation of 2-Allyloxy-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol
To themixture of 10 ccTHF and 10 cc Toluene added 0.138 mole 2-(5-Bromo-2-methyl-benzyl)-5-(4-fluoro-phenyl)-thiopheneatambient temperature. The reaction mass was stirred for 15 min. Cooled to -70 to -80°C in dry ice /acetone bath and stirred for 15 min. Added a solution of 0.014 mole n-Butyl lithium (1.9M in hexanes) at -70 to -80°C. and stirred for 1hr. Added solution of 3, 4, 5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one in 5 cc of Toluene at -70 to -80°C and stirred for 2 to 3hrs. After the compliance of the reaction,thereaction mass was quenched with Methane sulphonic acid and Allyl alcohol mixture at -70 to -80°C.Temperature was raised to ambient temperature and stirred over night. Reaction mass was quenched with 30 cc sat.sodiumbicarbonate solution to bring the pH neutral to alkaline. Reaction mass stirred for 30.0 min. Layers separated and aqueous was extracted with 10 cc of Toluene. Organic layer was combined and washed with water 30cc and sat. brine solution 50 cc. Organic layer was distilled under reduced pressure to recover the toluene. Solid compound thus obtainedwas dissolved in 50cc of toluene and quenched in n-Hexane to obtain 75-79% the titled compound as crystalline solid.
HPLC purity:88-94 %.
IR data:Aromatic C- F stretching: 832 cm-1
Lactones C – O stretching: 1045 – 1092 cm-1
Allylic C- O stretching: 1161 cm-1
Anomeric C-O stretching: 1231 cm-1
Aromatic C=C stretching: 1510 , 1548 , 1603 , 1703 cm-1
Alkane C – H stretching: 2892 , 2950 cm-1
Allylic C- H stretching: 2990 – 3120 cm-1
Aromatic C – H stretching: 3050 - 3090 cm-1
Lactones O – H stretching: 3240 – 3380 cm-1
Dip – Mass
(M+Na) 523.28 m/z
(M+K) 539.38 m/z

Example 3: Preparation of 2- prop-2ynyl -2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol
To themixture of 10 ccTHF and 10 cc Toluene added 0.138 mole 2-(5-Bromo-2-methyl-benzyl)-5-(4-fluoro-phenyl)-thiopheneatambient temperature. The reaction mass is stirred for 15 min. Cooled to -70 to -80°C in dry ice /acetone bath and stirred for 15 min. Added a solution of 0.014 mole n-Butyl lithium (1.9M in hexanes) at -70 to -80°C. and stirred for 1hr. Added solution of 3, 4, 5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one in 5 cc of Toluene at -70 to -80°C and stirred for 2 to 3hrs. After the compliance of the reaction, reaction mass is quenched with Methane sulphonic acid and propargyl alcohol mixture at -70 to -80°C. Temperature was raised to ambient temperature and stirred over night. Reaction mass was quenched with 30 cc sat.sodiumbicarbonate solution to bring the pH neutral to alkaline. Reaction mass stirred for 30.0 min;layers separated and aqueous layer was extracted with 10 cc of Toluene. Organic layer was combined and washed with water 30cc and sat. brine solution 50 cc. Organic layer was distilled under reduced pressure to recover the toluene. Solid compound thus obtained was dissolved in 50cc of toluene and quenched in n-Hexane to obtain 75-79% of the titled compound as crystalline solid.
HPLC purity:88-94 %.
IR data:Aromatic C- F stretching: 878 cm-1
Lactones C – O stretching: 1045 – 1092 cm-1
Propargylic C- O stretching: 1161 cm-1
Anomeric C-O stretching: 1231 cm-1
Aromatic C=C stretching: 1510 , 1548 , 1603 , 1703 cm-1
Propargylic C- H stretching: 2125 cm-1
Alkane C – H stretching: 2892 , 2950 cm-1
Aromatic C – H stretching: 3050 - 3090 cm-1
Lactones O – H stretching: 3240 – 3380 cm-1
Dip-Mass ;
(M+Na) 521.31 m/z
(M+K) 537.31 m/z

Example-4: Preparation of 2-{3-[5-(4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
To themixture of 20 cc(1:1 MDC + ACN) added 0.11 mole 2-Allyloxy-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-3,4,5-tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran under argon atmosphere. Stirred the reaction mass for 30.0 min.Cooled the reaction mass to -40 to -55°C in a dry ice/acetone bath under argon atmosphere. Charged 3 mole Triethylsilane at -40 to -55°Candstirred the reaction mass for 30.0 min at -50 to -55°C. Slowly addedBorontrifloride in diethyl ether solution at -40 to -55°C and stirred the reaction mass for 2 hrs. Quenched the reaction mass with 50 cc sat. sodium bicarbonate solution at -40 to -55°C . andStirred the reaction mass for 30.0 min. Slowly raised the temperature to 25 to 30°C. Settled downthe reaction mass and separated the layers, extracted the aqueous layer with 100 cc of MDC. Combined the organic layer and washed with 500 cc water. Washed the organic layer with 500 cc of sat.Brinesolution.Distilled out the MDC under reduced pressure below 40°C.to get 85-87% titled compound as light yellow solid.
HPLC purity: 90-95%

Example5: Preparation of 2-{3-[5-(4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
To themixture of 20 cc(1:1 MDC + ACN) added 0.11 mole 2- prop-2ynyl -2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triolunder argon atmosphere. Stirred the reaction mass for 30.0 min.Cooled the reaction mass to -40 to -55°C in a dry ice/acetone bath under argon atmosphere. Charged 3 mole Triethylsilane at -40 to -55°Candstirred the reaction mass for 30.0 min at -50 to -55°C. Slowly addedBorontrifloride in diethyl ether solution at -40 to -55°C and stirred the reaction mass for 2 hrs. Quenched the reaction mass with 50 cc sat. sodium bicarbonate solution at -40 to -55°C . andstirred the reaction mass for 30.0 min. Slowly raised the temperature to 25 to 30°C. Settled downthe reaction mass and separated the layers, extracted the aqueous layer with 100 cc of MDC. Combined the organic layers and washed with 500 cc water. Washed the organic layer with 500 cc of sat.Brinesolution.Distilled out the MDC under reduced pressure below 40°C.to get85-87% titled compound aslight yellow solid.
HPLC purity: 90-95%

Example 6:
Preparation of amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
To the solid obtained from example 4 charged 500cc of n-heptane and stirred for ½hrs at ambient temperature. Heated the reaction mass to 55-60°C and stirred it for 2-3 hrs.; cooled to room temperature and maintained for 4-5 hrs. Filtered the solid and washed the cake with 100 cc n-heptane. Dried at 40-45°C to get amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.

Example 7:
Preparation of amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
To the solid obtained from example 5 charged 500cc of n-heptane and stirred for ½ hrs at ambient temperature. Heated the reaction mass to 55-60°C and stirred it for 2-3 hrs., cooled to room temperature and maintained for 4-5 hrs. Filtered the solid and washed the cake with 100 cc n-heptane. Dried at 40-45°C to get amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.

Example 8: Preparation of L-Proline – (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol co crystal
To the 10 cc of Ethyl acetate charged 1.0 mole (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolunder argon atmosphere at ambient temperature andstirred for 30.0 min to get clear solution. Slowly heated the reaction mass to 60 – 65°C andstirredfor 1 hr. Slowly addedL-proline at 60 – 65°C andmaintained for 1 hr. Slowly added 15 cc n-Heptane to the reaction mass at 60 – 65°C andstirred the mass for 2.5 hrs. Cooled the mass to ambient temperature for 3-4 hrs and maintained for 5 hrs.Filteredthe mass under argon atmosphere.Washed the cake with 10 cc n-Heptane.Dried the cake at 50-55°C under reduced pressure to get 85-93% titled compound.
HPLC purity: 98-99.8%

Example 9: Preparation of L-Proline – (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol co crystal
To the 10 cc of acetonecharged 1.0 mole (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolunder argon atmosphere at ambient temperature andstirred for 30.0 min to get clear solution. Slowly heated the reaction mass to 60 – 65°C andstirredfor 1 hr. Slowly addedL-proline at 60 – 65°C andmaintained for 1 hr. Slowly added 15 cc n-Heptane to the reaction mass at 60 – 65°C andstirred the mass for 2.5 hrs. Cooled the mass to ambient temperature for 3-4 hrs and maintained for 5 hrs.Filteredthe mass under argon atmosphere.Washed the cake with 10 cc n-Heptane.Dried the cake at 50-55°C under reduced pressureto get 85-93% titled compound.
HPLC purity:98-99.8%

Example 10: Preparation of amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
To the 15 cc ethyl acetate added(2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol at ambient temperatureandstirred for 30.0 min. Slowly added 5- 8 cc sat. sodium bicarbonate solution at ambient temperature and stirred for 1.5 hr to get the clear solution.Settleddownthe mass and separatedlayers.Extracted the aqueous layer with 25 cc ethyl acetate. Combined the organic layers and washed the ethyl acetate layer with 50 cc sat. Sodium chloride solution.Distilled out ethyl acetate under reduced pressure at 40 – 45°C to get fluffy solid. Charged50 cc n-Heptane and stirred for 5 hrs to get 60-65% the title compound as Amorphous solid.
HPLC purity:99.8 %

Example 11: Preparation of 2-(4-Fluoro-phenyl)-5-(2-methyl-benzyl)-thiophene (impurity)
To the mixture of 20 cc THF and 20 cc Toluene charged 0.25 mole 2-(5-Bromo-2-methyl-benzyl)-5-(4-fluoro-phenyl)-thiopheneand Cooled to - 78°C. Added n-Butyl lithium (1.9 M in hexane) and Stirred for 30 min at - 78°C. Slowly added 20 % Ammonium chloride solution to the reaction mass and raised the temperature from – 78°C to -50°C. slowlybrought the reaction mass to ambient temperature and stirred for 30 min. Settled and separated layers, extracted the aqueous layer with 50 cc toluene. Washed the organic layer with 500 cc brine solution. Distilled out the toluene and charged heptane and stirred for 2 to 3 hrs at ambient temperature. Filtered the product and dried at 45 – 50°C under reduced pressure to obtain 88 %titled product
Mass: (m+1) 283 m/z found 283.51
HPLC Purity : 97.5 %