WO2017060924A1 - A novel pipecolic acid co-crystal of canagliflozin and process for the preparation thereof - Google Patents

A novel pipecolic acid co-crystal of canagliflozin and process for the preparation thereof Download PDF

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WO2017060924A1
WO2017060924A1 PCT/IN2016/050344 IN2016050344W WO2017060924A1 WO 2017060924 A1 WO2017060924 A1 WO 2017060924A1 IN 2016050344 W IN2016050344 W IN 2016050344W WO 2017060924 A1 WO2017060924 A1 WO 2017060924A1
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methyl
phenyl
tetrahydro
pyran
fluoro
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PCT/IN2016/050344
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French (fr)
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Vijay Trimbak KADAM
Saikrishna
Shrikrushna Ramrao BHOSLE
Harpreet Singh Minhas
Gurpreet Singh Minhas
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Harman Finochem Limited
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Abstract

The present invention discloses 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 and its pipecolic acid co-crystal. The invention also discloses novel intermediate, acetic acid 4, 5-diacetoxy-6- acetoxymethyl-2-R1-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl- phenyl}-tetrahydro-pyran-3-yl ester, wherein, R1 is allyl or prop-2-ynyl, as an intermediate for the preparation of 4, 5-diacetoxy-6-acetoxymethyl-2-R1-2-{3-[5- (4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-tetrahydro-pyran-3-yl ester, wherein, R1 is allyl or prop-2-ynyl.

Description

A NOVEL PIPECOLIC ACID CO-CRYSTAL OF CANAGLIFLOZIN AND PROCESS FOR THE PRE PARATION T H E RE OF

FIELD OF INVENTION:

The present invention relates to an industrially feasible process for the preparation of (2S, 3R, 4R, 5S, 6R)-2-{3-[5-[^FIuoro-phenyl)-thiophen-2-ylmethyl]-^ methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3, 4, 5-triol (Canagliflozin) and its stable amorphous hemi hydrate form. The invention further relates to novel intermediates of Canagliflozin and cocrystal forms.

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-fluoro henyl)-2-thienyl]methyl]-4- methyl phenyl] - D-gl ucitol .

Figure imgf000002_0001

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-triol is first disclosed in US 8222219, 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)- thi ophen-2-y I methyl] -4- methyl - phenyl } - 6- hydroxy methyl -tetrahydro- py ran- 3,4, 5- triol and its pharmaceutically acceptable salts and its preparation process as depicted in Scheme-I.

Figure imgf000003_0001

Scheme-1

US 788 discloses the reaction of 2-(4-fluoro phenyl)-5-(5-iodo-2-methylbenzyl)- thiophene with 2,3,4,6-tetrakis-0-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 which reacts with tri isopropylsilane and boron tri fluoride diethyl ether 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- pheny I ) -thi ophen-2-y I methyl ] -4- methyl - phenyl }- 6- hydroxy methyl -tetrahydro- pyran-3,4,5-triol.

WO 2009035969 A 1 and WO 2010043682 A 2 disclose novel process for preparing(2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4- methy I - phenyl } -6- hydroxy methyl -tetrahydro- py ran- 3,4, 5- tri ol .

WO "969 describes reaction of 2-(4-fluorophenyl)-5-(5-iodo-2- methyl benzyl )thiophene with 2,3,4,6-tetra-o-trimethylsilyl- -D-glucolactone in presence of tetrahydrofuran,(trimethylsilyl) methyllithium in hexane to get an intermediate as a thick oil which further reacts with tri ethyl si lane, boron tri fluoridedi ethyl etherate in presence of dichloromethane to get 1-(<f-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, DA MP and tetrahydrofuran to get acetyl protected 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 crystal I i ne sol i d.

Prior art process (US 788) describes purification method by using silica gel column chromatography which is major drawback of the said process. Final compound is purified by chloroform: methanol (19:1) which is not industrially applicable. Moreover column chromatography is very tedious, time consuming and industrially not viable process. When practically the said method is followed -Isomer of 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-butyl lithium and kept for overnight reaction. Moreover lactone ring cleavage is observed in the range of 3-4% after addition of Methane sul phonic 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 and makes the process cumbersome and uneconomical. Prior art process (WO "969) results in an intermediate, 2- hydroxy-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol as an oil form which is difficult to purify 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 describes a novel crystal form of 1-(<f-D-glucopyranosyl)-4- methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemi hydrates, methods for its preparation and isolation, as well as pharmaceutical compositions.

US 8,772,512 B2 describes a crystallization procedure to obtain 1-(<f-D- glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene hemi hydrate crystals.

WO 2013064909 A 2 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 A I discloses a crystalline hemi hydrate 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 as well as a process for the preparation of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2- y I methyl ] -4- methyl - phenyl }- 6- hydroxy methyl -tetrahydro- py ran- 3,4, 5- tri ol hemi hydrates.

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- F I uoro- phenyl )-thi ophen-2-yl methyl] -4- methyl - phenyl} -6- hydroxy methyl - tetrahydro- pyran-3,4, 5- tri ol .

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- pheny I ) -thi ophen-2-y I methyl ] -4- methyl - phenyl }- 6- hydroxy methyl -tetrahydro- pyran-3,4,5-triol, prepared via novel intermediates and co-crystal forms which gives higher yield and purity and facilitates easy recovery of the 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.

SU M MA RY OF T H E INV E NTION:

The present invention provides the process for preparation of (2S,3R,4R,5S,6R)- Z-iB-CS-C^FIuoro-phenyO-thiophen-Z-ylmethyn-^methyl-pheny^ -e- hydroxymethyl-tetrahydro-pyran-3,4,5-triol(Formula-I) and its stable amorphous hemi hydrate form. The invention further relates to novel intermediates of Canagliflozin; its cocrystal forms and process for preparation thereof.

Figure imgf000006_0001

Formula-I

In one aspect, the present invention describes the silylation process for preparing 3,4,5-Tris-tri methylsi lanyloxy-6-tri methylsi lanyl oxymethyl-tetrahydro-pyran-2- one from 3,4,5-Trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-one which comprises;

(a) Reacting 3,4,5-Trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-one with tri methylsi lyl chloride in presence of solvent and organic base at ambient temperature;

( b) M ai ntai ni ng pH 7- 8 by addi ng sat. sodi um bi carbonate;

( c) S eparati ng organi c I ayer f ol I owed by di sti 11 ati on and

(d) Isolating 3, 4, 5-T ris- tri methyl si lanyl oxy- 6- tri methyl si I any I oxy methyl - 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- tri methyl si I any I oxy- 6-tri methyl si I any I oxy methyl -tetrahydro- py ran-2-one whi c h comprises;

( a) R eacti ng 2-( 5- B romo-2- methyl - benzyl ) - 5-(4-f I uoro- phenyl ) -thi ophene with 3,4,5-T ri s-tri methyl si I anyl oxy-6-tri methyl si I anyl oxymethyl- 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) B ri ngi ng pH neutral to al kal i ne;

( c) S eparati ng organi c I ayer 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 another preferred aspect the present invention discloses a novel intermediate, acetic acid 4, 5-diacetoxy-6-acetoxymethyl-2-allyloxy-2-{3-[5-(4-fluoro-phenyl)- thi ophen-2-yl methyl] -4- methyl - phenyl} -tetrahydro- pyran-3-yl ester and preparation thereof.

Accordingly, the invention provides process for preparation of acetic acid 4, 5- diacetoxy-6-acetoxymethyl-2-allyloxy-2-{3-[5-(4-fluoro-phenyl)-thiophen-2- ylmethyl]-4-methyl-phenyl}-tetrahydro-pyran-3-yl ester, which comprises;

a) Reacting 2-allyloxy-2-{3-[5-(4-fluoro-phenyl)-thiophen-2- yl methyl] -4- methyl -phenyl} -6- hydroxy methyl -tetrahydro- pyran- 3,4,5-triol with acetic anhydride in presence of base in an organic solvent

b) S eparati ng organi c I ayer and

c) Isolating acetic acid 4, 5-diacetoxy-6-acetoxymethyl-2-allyloxy-2- { 3- [ 5-(4-f I uoro- phenyl )-thi ophen-2-y I methyl ] -4- methyl - phenyl } - tetrahydro- pyran-3-yl ester.

In one another embodiment the present invention discloses process for the preparation of 2-Allyloxy-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4- methyl-phenyl} -6-hydroxymethyl-tetrahydro-pyran-3, 4, 5-triol, which process comprises;

a) reacting acetic acid 4, 5-diacetoxy-6-acetoxymethyl-2-allyloxy-2-{3-[5- (4-f I uoro- phenyl ) -thi ophen-2-y I methyl ] -4- methyl - phenyl } -tetrahydro- pyran-3-yl ester with sodium methoxide in presence of an organic solvent; b) S eparati ng organi c I ayer and

c) Isolati ng 2-A I lyl oxy-2-{ 3- [5-(4-f I uoro-phenyl )-thi ophen-2-yl methyl] -4- methy I - phenyl } -6- hydroxy methyl -tetrahydro- py ran- 3,4, 5- tri ol .

In one another embodiment the present invention describes process for preparation of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2- yl methyl] -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) R eacti ng 2- R 1 -2-{ 3- [ 5-(4-f I uoro- phenyl )-thi ophen-2-y I methyl ] -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- yl methyl] -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)- thi ophen-2-y I methyl] -4- methyl - phenyl } - 6- hydroxy methyl -tetrahydro- py ran- 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- tri ol which comprises;

(a) Stirring (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2- y I methyl] -4- methyl - phenyl } - 6- hydroxy methyl -tetrahydro- py ran-3,4, 5- tri ol with non- polar solvent at ambient temperature and (b) Isolating stable amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5- [4- F I uoro- phenyl ) -thi ophen-2-y I methyl ] -4- methyl - phenyl } - 6- hydroxymethyl -tetrahydro- pyran-3,4,5-tri ol .

In another embodiment the present invention describes pipecolic acid 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 and the preparation thereof 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- y I methyl] -4- methyl - phenyl } - 6- hydroxy methyl -tetrahydro- py ran-3,4, 5-tri ol with pipecolic acid in presence of polar aprotic solvent under nitrogen atmosphere;

(b) Adding non- polar solvent and

(c) Isolating pipecolic acid complex of (2S,3R,4R,5S,6R)-2-{3-[5-[4- F I uoro- phenyl ) -thi ophen-2-y I methyl ] -4- methyl - phenyl } -6- hydroxy methyl - tetrahydro- pyran-3,4, 5-tri ol .

In a further embodiment, the pipecolic acid complex of (2S,3R,4R,5S,6R)-2-{3- [ 5- [4- F I uoro- phenyl )-thi ophen-2-y I methyl ] -4- methyl - phenyl } -6- hydroxy methyl - tetrahydro- pyran-3,4, 5-tri ol is characterized by X RD as shown in figure I.

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)- thi ophen-2-y I methyl] -4- methyl - phenyl } - 6- hydroxy methyl -tetrahydro- pyran-3,4, 5- triol from pipecolic acid complex of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro- pheny I ) -thi ophen-2-y I methyl ] -4- methyl - phenyl }- 6- hydroxy methyl -tetrahydro- pyran- 3,4, 5-tri ol which comprises;

(a) Stirring pipecolic acid complex of (2S,3R,4R,5S,6R)-2-{3-[5-[4- F I uoro- phenyl )-thi ophen-2-y I methyl ] -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-tri ol .

The present process yields - 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 Methane sulphonic 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.

DE SC RIPTION OF DRAWING :

Figure I depicts X -ray powder diffraction pattern of pipecolic acid co-crystal of Canagliflozin according to the present invention.

DE TAIL E D DE SC RIPT ION OF T H E INV E NTION:

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-tri ol ( F or mu I a-I) and its stable amorphous hemihydrate form. The invention further relates to novel intermediates of Canagliflozin; its cocrystal forms and process for preparation thereof.

Figure imgf000010_0001
Formula-I

In one embodiment, the present invention describes the silylation process for prepari ng 3,4, 5-T ri s-tri methyl si I anyl oxy- 6-tri methyl si I any I oxy methyl -tetrahydro- pyran-2-one from 3,4,5-Tri hydroxy-6-hydroxymethyl-tetrahydro-pyran-2-one which 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) M ai ntai ni ng pH 7- 8 by addi ng sat. sodi um bi carbonate;

( c) S eparati ng organi c I ayer f ol I owed by di sti 11 ati on and

( d) Isol ati ng 3,4, 5-T ri s-tri methyl si I anyl oxy- 6-tri methyl si I anyl oxy methyl - tetrahydro-pyran-2-one.

The process for preparing 3,4, 5-T ri s-tri methyl si I anyl oxy-6- trimethylsilanyloxymethyl-tetrahydro-pyran-2-one depicted in the following reaction Scheme II.

MS

Figure imgf000011_0001

Formula-II Formula-m Scheme-II

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

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

In another embodiment, the instant invention discloses a process for preparing 2-

R 1 -2-{ 3- [ 5-(4-f I uoro- phenyl ) -thi ophen-2-y I methyl ] -4- methyl - phenyl } - 6- hydroxy methyl -tetrahydro- py ran- 3,4, 5-tri ol from 3,4, 5-T ri s-tri methyl si I any I oxy- 6-tri methyl si I anyl oxymethyl -tetrahydro- pyran-2-one whi ch compri ses;

( a) R eacti ng 2-( 5- B romo-2- methyl - benzyl ) - 5-(4-f I uoro- phenyl ) -thi ophene with 3,4,5-T ri s-tri methyl si I anyl oxy-6-tri methyl si I anyl oxymethyl- 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) B ri ngi ng pH neutral to al kal i ne;

( c) S eparati ng organi c I ayer 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- yl methyl] -4- methyl -phenyl} -6- hydroxymethyl -tetrahydro- pyran- 3,4, 5-tri ol is given i

Figure imgf000012_0001

Scheme-Ill

In above said process, the polar aprotic solvent is selected from the group consisting of tetrahydrofuran, ethyl acetate, acetone, di methyl formamide, 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 -80C.

The term organolithium reagent refers to alkyl lithium 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- di methyl octa- 2, 6- di en- 1 - ol .

The present process gives - Isomer in the range of 1-1.8 %, which is removed during purification. Further, 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- hydroxy methy I -tetrahydro- pyran-3,4,5-triol of formula V.

Figure imgf000013_0001

Wherein, R1 is 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 reduced reaction 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) A ddi ng ammoni um chl ori de sol uti on and

(c) Isolating 2-(4-fluoro-phenyl)-5-(2-methyl-benzyl)-thiophene.

The alky I lithium is 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, di methyl formamide, acetonitrile, dimethyl sulfoxide. The non-polar solvent is selected from the group consisting ofToluene, Hexane, 1,4-Dioxane, Chloroform, Diethyl ether, D i chl oromethane. According to above process the reaction temperature is -70 to - 80C.

The main object is achieved by removing the des-bromo impurity during purif i cati on of 2- R 1 -2-{ 3- [5-(4-f I uoro- phenyl )-thi ophen-2-yl methyl] -4- methyl - phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol, without involving any special techniques., that makes the process less cumbersome and cost-effective. In another embodiment the present invention discloses a novel intermediate acetic acid 4, 5-diacetoxy-6-acetoxymethyl-2-R1-2-{3-[5-(4-fluoro-phenyl)-thiophen-2- ylmethyl]-4-methyl-phenyl}-tetrahydro-pyran-3-yl ester, wherein, R1 is allyl or prop-2-ynyl and process for preparation thereof as given in scheme- IV. Accordingly, the invention provides process for preparation of acetic acid 4, 5- diacetoxy-6-acetoxymethyl-2-R1-2-{3-[5-(4-fluoro-phenyl)-thiophen-2- yl methyl] -4- methyl -phenyl} -tetrahydro-pyran-3-yl ester 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 acetic anhydride (wherein, R1is allyl, prop-2ynyl), in presence of base and an organic solvent;

b) S eparati ng organi c I ayer and c) Isolating acetic acid 4, 5-diacetoxy-6-acetoxymethyl-2-R1-2-{3-[5-(4- fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-tetrahydro-pyran- -yl ester, wherein, R1 is allyl or prop-2-ynyl.

Figure imgf000015_0001

Scheme-IV

In one another embodiment the present invention discloses process for the preparation of 2-Allyloxy-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4- methyl-phenyl} -6-hydroxymethyl-tetrahydro-pyran-3, 4, 5-triol as described in Scheme-V, which comprises;

a) reacting acetic acid 4, 5-diacetoxy-6-acetoxymethyl-2-allyloxy-2-{3- [5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}- tetrahydro-pyran-3-yl ester with sodium methoxide in presence of an organic solvent;

b) S eparati ng organi c I ayer and

c) Isolati ng 2-A I lyl oxy-2-{ 3- [5-(4-f I uoro-phenyl )-thi ophen-2-yl methyl] -4- methy I - phenyl } -6- hydroxy methyl -tetrahydro- py ran- 3,4, 5- tri ol .

Figure imgf000015_0002

Scheme-V In one another embodiment the present invention describes process for preparing (2S,3 ,4 ,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- hydroxy methy I - tetrahydro-pyran-3,4,5-triol which comprises;

( a) R eacti ng 2- R 1 -2-{ 3- [ 5-(4-f I uoro- phenyl )-thi ophen-2-y I methyl ] -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- yl methyl] -4- methyl -phenyl} -6-hydroxymethyl-tetrahydro-pyran-3,4,5- triol.

The reaction scheme for said process is given in Scheme-V I.

Figure imgf000016_0001

Formula-V

Formula-I where R-| = allyl, prop-2-ynyl

Scheme-VI

According to above said process the term organosilane refers to alkylsilane or polyal kylsilane which is selected from the group consisting of tri methyl si lane, tri ethyl si I ane, tetramethylsilane, dimethyl si I ane. 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 diethyl ether, trifluoroacetic acid, methanesulfonic acid.

The above reaction is carried out at -40 to 55C.

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)- thi ophen-2-y I methyl] -4- methyl - phenyl } - 6- hydroxy methyl -tetrahydro- py ran- 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- y I methyl] -4- methyl - phenyl } - 6- hydroxy methyl -tetrahydro- py ran-3,4, 5-tri ol with non- polar solvent at ambient temperature and

(b) Isolating stable amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5- [4- F I uoro- phenyl ) -thi ophen-2-y I methyl ] -4- methyl - phenyl } - 6- hydroxymethyl -tetrahydro- pyran-3,4,5-tri ol .

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 25-30C.

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 J IS L 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-y I methyl ] -4- methyl - phenyl } -6- hydroxy methyl -tetrahydro- py ran-3,4, 5-tri ol 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 pipecolic acid complex/co-crystal of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2- yl methyl] -4- methyl -phenyl} -6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol and the process for preparation thereof. Accordingly, pipecolic acid complex/co- crystal of (ZS^R^R^S^RJ-Z-iB-CS-C^FIuoro-phenyO-thiophen-Z-ylmethyl]-^ methyl-phenyl} -6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol is prepared 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 by a process which comprises;

(a) Reacting (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2- y I methyl] -4- methyl - phenyl } - 6- hydroxy methyl -tetrahydro- py ran-3,4, 5-tri ol with pipecolic acid in presence of ethanol under nitrogen atmosphere;

(b) Adding non- polar solvent and

(c) Isolating pipecolic acid complex of (2S,3R,4R,5S,6R)-2-{3-[5-[4- F I uoro- phenyl ) -thi ophen-2-y I methyl ] -4- methyl - phenyl } -6- hydroxy methyl - tetrahydro- pyran-3,4, 5-tri ol .

The reaction scheme for said process is given in Scheme-V II.

Figure imgf000018_0001

Formula-I(a)

Scheme-VII

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 60-65C.

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)- thi ophen-2-y I methyl] -4- methyl - phenyl } - 6- hydroxy methyl -tetrahydro- pyran-3,4, 5- triol from pipecolic acid complex of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro- phenyl)-thiophen-2-ylmethyl]-^methyl-phenyl}-6-hydroxymethyl-tetrahy pyran-3,4,5-triol which comprises;

(a) Stirring pipecolic acid complex of (2S,3R,4R,5S,6R)-2-{3-[5-[4- F I uoro- phenyl )-thi ophen-2-y I methyl ] -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-tri ol .

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.

E xamples:

E xample-1 : Preparation of 3,4,5-Tris-trimethylsilanyloxy-6- trimethylsilanyloxymethyl-tetrahydro-pyran-2-one

To 750 cc of dry TH F 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 -5Cto 0Cand stirred for 30.0 min. Added 18.0 mole Tri methyl silyl chloride at the temperature of -5C to 0C and stirred for 30.0 min. The temperature was raised to 25C to 30C 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 C. Added 500 cc toluene and stirred for 1 hr. 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 sa brine solution. Organic layer was distilled under reduced pressure at a temperature of about 40 " 48C and unloaded 91 to 93% of oily mass.

H PL C purity: 92-96%

E xample-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 the mixture of 10 cc TH F 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 -80eC 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 -80eC. and stirred for 1 hr. Added solution of 3, 4, 5-Tris- trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one in 5 cc of Toluene at -70 to -80eC and stirred for 2 to 3hrs. After the compliance of the reaction, the reaction mass was quenched with Methane sulphonic acid and Allyl alcohol mixture at -70 to -80eC .Temperature was raised to ambient temperature and stirred over night. Reaction mass was quenched with 30 cc sa sodiumbi carbonate 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 obtained was dissolved in 50cc of toluene and quenched in n-Hexane to obtain 75-79% the titled compound as crystalline solid. H PL C purity: 88-94 %.

IR data: Aromatic C- F stretching: 832 cm1

Lactones C " O stretching: 1045 " 1092 cm1

Allylic C- O stretching: 1161 cm1

Anomeric C-0 stretching: 1231 cm1

Aromatic C=C stretching: 1510 , 1548 , 1603 , 1703 cm1

Alkane C " H stretching: 2892 , 2950 cm1 A Hylic C- H stretching: 2990 " 3120 cm1

Aromatic C " H stretching: 3050 - 3090 cm1

Lactones 0 " H stretching: 3240 " 3380 cm1

Dip " Mass

(M+Na) 523.28 m z

(M+K) 539.38 m/z

E xample 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 the mixture of 10 cc TH F and 10 cc Toluene added 0.138 mole 2-(5-Bromo-2- methyl-benzyl)-5-(4-fluoro-phenyl)-thiophene at ambient temperature. The reaction mass is stirred for 15 min. Cooled to -70 to -80eC 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 -80eC. and stirred for 1 hr. Added solution of 3, 4, 5-Tris- trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one in 5 cc of Toluene at -70 to -80eC and stirred for 2 to 3hrs. After the completion of the reaction, reaction mass was quenched with Methane sul phonic acid and propargyl alcohol mixture at -70 to -80eC. Temperature was raised to ambient temperature and stirred over night. Reaction mass was quenched with 30 cc sa sodiumbi carbonate 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.

H PL C purity: 88- 94 %.

IR data: Aromatic C- F stretching: 878 cm1

Lactones C " O stretching: 1045 " 1092 cm1

Propargyl ic C- O stretching: 1161 cm1 Anomeric C-0 stretching: 1231 cm 1

Aromatic C=C stretching: 1510 , 1548 , 1603 , 1703 cm1

Propargylic C- H stretching: 2125 cm1

Alkane C " H stretching: 2892 , 2950 cm1

Aromatic C " H stretching: 3050 - 3090 cm1

Lactones O " H stretching: 3240 " 3380 cm1

Dip-Mass ;

(M+Na) 521.31 m z

(M+K) 537.31 m/z

E xample-4: Preparation of Acetic acid 4, 5-diacetoxy-6-acetoxymethyl-2- allyloxy-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}- tetrahydro-pyran-3-yl ester:

Charged 100 gms of 2-Allyloxy-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]- 4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol in clean dry Round bottom flask, fitted with reflux condenser, in an water bath. Charged MDC, 800 ml, stirred to dissolve the contents. Added Diisopropyl ethyl amine to the reaction mass at room temperature and stirred for 10 mins at RT. Slowly added Acetic Anhydride, 23.85 mmole, at room temperature. Stirrred for 10 mins and added DMA P 0.8 mmole at once to the reaction mass, slight exotherm was observed. Stirrred the reaction mass for 6-8 hrs at RT. Monitor the reaction by T LC. Distilled out MDC solvent under vacuum below 40° C. To the obtained crude added water and ethyl acetate, 2 vol, stirrred the reaction mass., separated the layers, extracted the aqueous layer 3 times with ethyl acetate. Combined the ethyl acetate layers and washed with 4 vol brine solution. Distilled out the ethylacetate to obtain the crude. Recrystallized the crude material using Cyclohexane to obtain the title product. E xample-5: Preparation of 2-Allyloxy-2-{3-[5-(4-fluoro-phenyl)-thiophen-2- ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol Charged 100 gms Acetic acid 4,5-diacetoxy-6-acetoxymethyl-2-allyloxy-2-{3-[5- (4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl} -tetrahydro-pyran-3-yl ester, in clean dry round bottom flask under N2 atmosphere. Charged Methanol, 5 vol, and stirrred for 10 mins. Slowly added Sodium Methoxide controlling exothermicity. Stirred for 15 " 20 mins at RT. Slowly raised the temperature to 60 " 65°C. Maintained the reflux for 5- 6 hrs, monitored the reaction by T LC. Cooled the reaction mass to RT. Distilled out the solvent under vacuum below 45°C. Added water and ethyl acetate. Adjusted the pH of the reaction mass to neutral using Conc.HCI. Stirred the reaction mass for 20 mins and separated the layers. Extracted the aqueous layer with 3 times ethyl acetate, distilled out the solvent under vacuum below 45°C. Crystallized the compound using the mixture of Toluene and heptanes.

E xample-6: Preparation of 2-prop-2-ynyl-2-{3-[5-(4-fluoro-phenyl)-thiophen- 2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol Charged 100 gms Acetic acid 4,5-diacetoxy-6-acetoxymethyl-2- prop-2-ynyl -2- {3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl} -tetrahydro- pyran-3-yl ester, in clean dry round bottom flask under N2 atmosphere. Charged Methanol, 5 vol, and stirrred for 10 mins. Slowly added Sodium Methoxide controlling exothermicity. Stirred for 15 " 20 mins at RT. Slowly raised the temperature to 60 " 65°C. Maintained the reflux for 5- 6 hrs, monitored the reaction by T LC. Cooled the reaction mass to RT. Distilled out the solvent under vacuum below 45°C. Added water and ethyl acetate. Adjusted the pH of the reaction mass to neutral using Conc.HCI. Stirred the reaction mass for 20 mins and separated the layers. Extracted the aqueous layer with 3 times ethyl acetate, distilled out the solvent under vacuum below 45°C. Crystallized the compound using the mixture of Toluene and heptanes. E xample-7: Preparation of 2-{3-[5-(4-F luoro-phenyl)-thiophen-2-ylmethyl]-4- methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3, 4, 5-triol

To the mixture of 20 cc(1 :1 M DC + ACN) added 0.11 mole 2-Allyloxy-2-{3-[5- (4-f I uoro- phenyl )-thi ophen-2-yl methyl] -4- methyl - phenyl} -6- hydroxymethyl - tetrahydro-pyran- 3,4, 5-triol under nitrogen atmosphere. Stirred the reaction mass for 30.0 min. Cooled the reaction mass to -40 to -55eC in a dry ice/acetone bath under argon atmosphere. Charged 3 mole Tri ethyl si lane at -40 to -55eC and stirred the reaction mass for 30.0 min at -50 to -55eC. Slowly added Boron trifloride in diethyl ether solution at -40 to -55eC and stirred the reaction mass for 2 hrs. Quenched the reaction mass with 50 cc sat. sodium bicarbonate solution at -40 to - 55eC . and Stirred the reaction mass for 30.0 min. Slowly raised the temperature to 25 to 30eC. 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. Brine solution. Distilled out the MDC under reduced pressure below 40eC.to get 85-87% titled compound as I i ght yel I ow sol i d.

H PL C purity: 90-95%

E xample-8: Preparation of 2-{3-[5-(4-F luoro-phenyl)-thiophen-2-ylmethyl]-4- methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

To the mixture 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-triol under nitrogen atmosphere. Stirred the reaction mass for 30.0 min. Cooled the reaction mass to -40 to -55eC in a dry ice/acetone bath under argon atmosphere. Charged 3 mole Tri ethyl si lane at -40 to -55eCandstirred the reaction mass for 30.0 min at -50 to -55eC. Slowly added Borontri fluoride in diethyl ether solution at -40 to -55eC and stirred the reaction mass for 2 hrs. Quenched the reaction mass with 50 cc sat. sodium bicarbonate solution at -40 to - 55eC . andstirred the reaction mass for 30.0 min. Slowly raised the temperature to 25 to 30eC. Settled downthe reaction mass and separated the layers, extracted the aqueous layer with 100 cc of M DC. Combined the organic layers and washed with 500 cc water. Washed the organic layer with 500 cc of sa Brinesolution. Distilled out the M DC under reduced pressure below 40eC.to get85-87% titled compound as light yellow solid.

H PL C purity: 90-95%

E xample 9:

Preparation of amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro- pheny I ) -thi ophen-2-y I methyl ] -4- methyl - phenyl }- 6- hydroxy methyl -tetrahydro- pyran-3,4,5-triol

To the solid obtained from example 6 charged 500cc of n-heptane and stirred for hrs at ambient temperature. Heated the reaction mass to 55-60eC 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 40-45eC to get amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)- thi ophen-2-y I methyl] -4- methyl - phenyl } - 6- hydroxy methyl -tetrahydro- py ran- 3,4, 5- triol.

E xample 10:

Preparation of amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro- pheny I ) -thi ophen-2-y I methyl ] -4- methyl - phenyl }- 6- hydroxy methyl -tetrahydro- pyran-3,4,5-triol

To the solid obtained from example 7 charged 500cc of n-heptane and stirred for hrs at ambient temperature. Heated the reaction mass to 55-60eC 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 40-45eC to get amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)- thi ophen-2-y I methyl] -4- methyl - phenyl } - 6- hydroxy methyl -tetrahydro- py ran- 3,4, 5- triol.

E xample 11 : Preparation of pipecolic acid " (2S,3R,4R,5S,6R)-2-{3-[5-[4- F luoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl- tetrahydro-pyran-3,4,5-triol co crystal

Charged 100gms canagliflozin crude to a clean, dry round bottom flask fitted with reflux condenser in a water bath. Charged ethanol 7.5 vol. stirred to get clear solution. Slowly heated the reaction mass to reflux and maintained the reflux for 30 mins. Added pipecolic acid 15 mmolein a single lot. Stirred for 1 hr at reflux, material slowly precipitates stirred for another 1 hr at reflux. Slowly added heptanes 7.5 vol. maintained for another 1 hr at reflux. Slowly cooled the reaction mass to room temperature and stirred for 5- 6 hrs at room temperature. Filtered the mass and washed the cake with heptanes 2 vol. suck dried the cake and dried the wet cake i n ai r dri er f or 8 " 10 hrs.

E xample 12: Preparation of amorphous hemihydrate of (2S,3R,4R,5S,6R)-2-

{3-[5-[4-F luoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Charged 100 gms Canagliflozin " pipecolic acid co-crystal in a clean dry round bottom flask. Charged 5 vol ethyl acetate and water 5vol. Stirred to get clear solution. Extracted the aqueous layer 3 times with ethyl acetate. Washed the ethyl acetate layer with water 5 vol. Distilled out ethyl acetate and degassed it for 30 mins till white foamy material is obtained. Charged heptanes and stirred for 2 hrs. Filtered the compound and washed the cake with heptanes. Dried the compound under vacuum at 45- 50°C .

E xample 13: Preparation of 2-(4-F luoro-phenyl)-5-(2-methyl-benzyl)- thiophene (impurity)

To the mixture of 20 cc TH F and 20 cc Toluene charged 0.25 mole 2-(5-Bromo-2- methyl-benzyl)-5-(4-fluoro-phenyl)-thiophene and Cooled to - 78eC. Added n- Butyl lithium (1.9 M in hexane) and Stirred for 30 min at - 78eC. Slowly added 20 % Ammonium chloride solution to the reaction mass and raised the temperature from " 78eC to -50eC. Slowly brought 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 " 50eC under reduced pressure to obtain 88 % titled product

Mass: (m+1) 283 m/z found 283.51

H PLC Purity : 97.5 %

Claims

We C laim,
1. A novel pipecolic acid co-crystal of Canagliflozin.
2. The pipecolic acid co-crystal of Canagliflozin according to claim 1 characterized by X -ray powder diffraction pattern as shown in Fig-1.
3. The process for the preparation of pipecolic acid co-crystal of Canagliflozin comprises:
(a) reacting (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2- y I methyl] -4- methyl - phenyl } - 6- hydroxy methyl -tetrahydro- py ran-3,4, 5-tri ol with pipecolic acid in presence of polar aprotic solvent under nitrogen atmosphere;
(b) adding non-polar solvent and
(c) isolating pipecolic acid complex of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro- pheny I ) -thi ophen-2-y I methyl ] -4- methyl - phenyl } - 6- hydroxymethyl - tetrahydro- py ran-3,4, 5-tri ol ( C anagl i f I oz i n) .
4. The process according to claim 3 wherein the polar aprotic solvents used in step (a) and step (c) is selected from the solvents such as chlorinated hydrocarbons, alcohols, ethers, cyclic ethers, esters, nitriles, dimethyl formamide, dimethyl sulfoxide or mixtures thereof.
5. A process for preparation of stable amorphous Canagliflozin comprises;
(a) stirring Canagliflozin pipecolic acid complex in an ester solvent;
(b) adding sat. sodium bicarbonate solution;
(c) adding a non-polar solvent and
(d) isolating stable amorphous of (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro- pheny I ) -thi ophen-2-y I methyl ] -4- methyl - phenyl } - 6- hydroxymethyl - tetrahydro- py ran-3,4, 5-tri ol ( C anagl i f I oz i n) .
6. T he process accordi ng to clai m 5, wherei n the ester solvent used i n step (a) is selected from ethyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate and mixtures thereof.
7. T he process accordi ng to clai m 5, wherei n the non-polar solvent used i n step (c) is selected from n-hexane, n- heptane and mixture thereof.
8. Acetic acid 4, 5-diacetoxy-6-acetoxymethyl-2-R1-2-{3-[5-(4-fluoro- phenyl)-thiophen-2-ylmethyl]-^methyl-phenyl}-tetrahydro-pyran-3-yl ester, wherein, R1 is allyl or prop-2-ynyl.
9. A process for preparation of acetic acid 4, 5-diacetoxy-6- acetoxymethyl -2- R 1 -2-{ 3- [5-(4-f I uoro- phenyl )-thi ophen-2-yl methyl] -4- methyl-phenyl} -tetrahydro-pyran-3-yl ester, according to claim 8 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 acetic anhydride (wherein, R1 is allyl or prop-2-ynyl) in presence of Diisopropyl ethyl amine in methylene di chloride;
b) S eparati ng organi c I ayer and
c) Isolating acetic acid 4, 5-diacetoxy-6-acetoxymethyl-2-R1-2-{3-[5- (4-f I uoro- phenyl ) -thi ophen-2-y I methyl ] -4- methyl - phenyl } - tetrahydro-pyran-3-yl ester( wherein, R1 is allyl or prop-2-ynyl).
PCT/IN2016/050344 2015-10-09 2016-10-08 A novel pipecolic acid co-crystal of canagliflozin and process for the preparation thereof WO2017060924A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040138439A1 (en) * 2003-01-03 2004-07-15 Deshpande Prashant P. Methods of producing C-aryl glucoside SGLT2 inhibitors
WO2012154812A1 (en) * 2011-05-09 2012-11-15 Janssen Pharmaceutica Nv L-proline and citric acid co-crystals of (2s, 3r, 4r, 5s, 6r )- 2- (3- ((5- (4-fluorophenyl)thiophen-2-yl) methyl) -4-methylphenyl)-6- (hydroxymethyl)tetrahydro-2h-pyran-3,4,5-triol
WO2014195966A2 (en) * 2013-05-30 2014-12-11 Cadila Healthcare Limited Amorphous form of canagliflozin and process for preparing thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040138439A1 (en) * 2003-01-03 2004-07-15 Deshpande Prashant P. Methods of producing C-aryl glucoside SGLT2 inhibitors
WO2012154812A1 (en) * 2011-05-09 2012-11-15 Janssen Pharmaceutica Nv L-proline and citric acid co-crystals of (2s, 3r, 4r, 5s, 6r )- 2- (3- ((5- (4-fluorophenyl)thiophen-2-yl) methyl) -4-methylphenyl)-6- (hydroxymethyl)tetrahydro-2h-pyran-3,4,5-triol
WO2014195966A2 (en) * 2013-05-30 2014-12-11 Cadila Healthcare Limited Amorphous form of canagliflozin and process for preparing thereof

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Title
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