WO2017060925A1 - Novel pipecolic acid co-crystals of dapagliflozin and process for the preparation thereof - Google Patents

Novel pipecolic acid co-crystals of dapagliflozin and process for the preparation thereof Download PDF

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WO2017060925A1
WO2017060925A1 PCT/IN2016/050345 IN2016050345W WO2017060925A1 WO 2017060925 A1 WO2017060925 A1 WO 2017060925A1 IN 2016050345 W IN2016050345 W IN 2016050345W WO 2017060925 A1 WO2017060925 A1 WO 2017060925A1
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tetrahydro
phenyl
pyran
chloro
hydroxymethyl
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PCT/IN2016/050345
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French (fr)
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Vijay Trimbak KADAM
. Saikrishna
Ajit Balasaheb SANSARE
Harpreet Singh Minhas
Gurpreet Singh Minhas
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Harman Finochem Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical

Definitions

  • the present invention relates to an industrially feasible process for preparation of Dapagliflozin.
  • the invention further relates to novel co-crystals of dapagliflozin and its process for preparation thereof.
  • the invention further relates to novel intermediate Acetic acid 4,5-diacetoxy-6-acetoxymethyl-2-R1-2-[4-chloro-3-(4- ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-yl ester, wherein R1 isallyl or2-prop- 2ynyl useful for preparation 2-R1-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxymethyl -tetrahydro- pyran-3,4, 5-tri ol .
  • (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is sodium dependent glucose transporter (SGLT) which is currently under investigation for the treatment of type-2 diabetes.
  • (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is marketed under the tradename Farxiga or Forxiga.
  • (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is also known as D-glucitol, 1,5- anhydro- 1 -C - [4-chl oro-3- [(4ethoxyphenyl ) methyl] phenyl] -, ( 1 S) .
  • (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is a white to off-white powder with a molecular formula of C21H25CIO6 and a molecular weight of 408.87.
  • WO 2008002824 A 1 discloses crystalline forms of (2S,3R,4R,5S,6R)-2-[4- chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran- 3,4,5- triol comprising (S)-propylene glycol (PG), (R)-PG, EtOH, ethylene glycol (EG), 1 :2 L-proline, 1 : 1 L-proline, 1 : 1 L-proline hemi hydrate, 1 : 1 L- phenyl alanine and its preparation processes.
  • the present invention provides the process for preparation of (2S,3R,4R,5S,6R)- 2-[4-chl oro-3-(4-ethoxybenzyl) phenyl] -6-( hydroxymethyl)tetrahydro-2H -pyran- 3,4,5-triol(Formula-I) and its stable annorphous formJhe invention further provides novel co-crystal of dapagliflozin; and process for preparation thereof.
  • the present invention describes the silylation process for preparing 3,4,5-Tris-tri methyl si I anyl oxy- 6-tri methylsi lanyl oxymethyl -tetrahydro- py ran- 2- one from 3,4,5-Trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-one which comprises;
  • the present invention discloses the process for preparing 2-R 1 -2- [4- chl oro-3-(4- ethoxy- benzyl )- phenyl ]- 6- hydroxy methyl -tetrahydro- py ran- 3,4, 5- tri ol from 3,4, 5-T ri s-tri methyl si I anyl oxy- 6-tri methyl si I anyl oxymethyl -tetrahydro- pyran-2-one which comprises; (a) Reacting 4-(5-bromo-2-chlorobenzyl)phenyl ethyl ether with 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 in presence of mixture of polar aprotic solvent and non-polar solvent, organolithium reagent, alkyl sulfonic acid, monohydric or unsaturated aliphatic alcohol;
  • the present invention describes a novel intermediate, Acetic acid 4,5-diacetoxy-6-acetoxymethyl-2-allyloxy-2-[4-chloro-3-(4-ethoxy- benzyl)-phenyl]-tetrahydro-pyran-3-yl esterand process for the preparation thereof.
  • the present invention provide the process for preparation of 2-Allyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxymethyl -tetrahydro- pyran- 3,4, 5- triol which comprises;
  • the instant invention provides process for preparing stable amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4- ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triolfrom (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- ( hydroxymethyl )tetrahydro-2H -pyran-3,4,5-tri ol whi ch comprises;
  • the present invention describes the preparation of pipecolic acid complex of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4- ethoxybenzyl) phenyl] -6-(hydroxymethyl )tetrahydro-2H -pyran-3,4,5-triolfrom
  • the present process gives -Isomer in the range of 3-5 %., which is removed during purification; further, the Des-bromoimpuirity (2-chloro ⁇ 4 ⁇ - ethoxydi phenyl methane)formati on is restricted to 3-4 %during purification. Further work up disclosed in present invention is advantageous over the teachings of prior art as the purification process does not involve multiple step workup. The purification process is simply carried out with solvents which is commercially feasible.
  • the instant invention provides time saving, cost effective and commercially viable process for preparing (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4- ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.
  • F ig 1 depict PX RD of pipecolic acid co-crystal of Dapagliflozin
  • the instant invention provides an efficient, advantageous and economical process for preparing (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Formula-I) and its amorphous formJhe invention further provides novel intermediates of dapagliflozin; its co- crystal forms and process for preparation thereof.
  • 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;
  • 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.
  • the reaction is carried out at -5 to 0 ⁇ C.
  • the instant invention discloses the process for preparing 2- R 1 -2- [4- chl oro-3-(4- ethoxy- benzyl )- phenyl ]- 6- hydroxy methyl -tetrahydro- pyran-3,4,5-triol from 3,4,5-Tris-trimethylsilanyloxy-6- trimethylsilanyloxymethyl-tetrahydro-pyran-2-one which comprises;
  • R allyl, prop-2-ynyl,isopropyl
  • 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.
  • reaction temperature is -70 to -80 ⁇ C.
  • organolithium reagent refers to alky I lithium reagents selected from the group consisting of n-butyl lithium, methyl lithium, t-butyl lithium.
  • alkyl sulfonic acid refers to methane sulfonic acid.
  • the unsaturated aliphatic alcohol i selected from the group consisting of allyl alcohol, propargyl alcohol.
  • the present process gives - Isomer in the range of 3-4 %., which is removed during purification. Des-bromoimpuirity (2-chloro ⁇ 4 ⁇ - ethoxydi phenyl methane) formation is restricted to 3-5 % during purification.
  • R 1 is allyl, prop-2ynyl.
  • the invention encompasses the compound 2-R 1 -2-[4-chloro-3-(4- ethoxy- benzyl ) - phenyl ] - 6- hydroxy methyl -tetrahy dro- py ran- 3,4, 5-tri ol of f ormul a V.
  • R 1 is selected from allyl or prop-2ynyl.
  • the present invention describes the process for the preparation of Acetic acid 4,5-diacetoxy-6-acetoxymethyl-2-allyloxy-2-[4-chloro- 3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-yl ester which comprises;
  • R 1 Allyl or prop-2-ynyl
  • the present invention provide the process for the preparation of 2-R1 -2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl- tetrahydro-pyran-3,4,5-triol which comprises;
  • R 1 Allyl or prop-2-ynyl
  • the instant invention discloses process for preparing des- bromo (4-(5-2-chlorobenzyl) phenyl ethyl ether) impurities which comprises;
  • the alkyl lithiums 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 of Toluene, Hexane, 1,4-Dioxane, Chloroform, Diethyl ether, D i chl oromethane. According to above process the reaction temperature is -70 to - 80 ⁇ C.
  • the main object is achieved by removing the des-bromo impurity during purification of 2-R 1 -2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl- tetrahydro-pyran-3,4,5-triol, without involving any special techniques, that makes the process less cumbersome and cost-effective.
  • the present invention describes process for preparing (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triolby reduction of 2-R 1 -2-[4-chloro- 3-(4-ethoxy-benzyl )- phenyl] -6- hydroxymethyl -tetrahydro- pyran-3,4, 5-tri ol whi ch comprises; (a) Reacting 2-R 1 -2-[4-chloro-3-(4-ethoxy-benzyl)-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;
  • organosilane refers to alkylsilane or polyal kylsilane is selected from the group consisting of tri methyl si lane, tri ethyl si lane, tetramethylsilane, dimethyl si lane.
  • 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 borontri fluoride in diethyl ether, trifluoroacetic acid, methanesulfonic acid. The above reaction is carried out at -40 to 55 ⁇ C.
  • R 1 is selected from allyl, prop-2ynyl.
  • the instant invention provides process for preparing stable amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4- ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triolfrom (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- ( hydroxymethyl )tetrahydro-2H -pyran-3,4,5-tri ol whi ch comprises;
  • 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 25-30 ⁇ C.
  • the main object of the present invention process is to get stable amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- ( hydroxymethyl )tetrahydro-2H-pyran-3, 4,5- triol without using any special technique which makes the process simple, cost- effective and time saving.
  • 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 60-65 ⁇ C.
  • the present invention describes the process for preparing amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- ( hydroxymethyl )tetrahydro-2H-pyran-3, 4,5- triolfrom pipecolic acid complex of (2S,3R,4R,5S,6R)-2-[ ⁇ chloro-3-( ⁇ ethoxybenzyl)phenyl]-6- ( hydroxymethyl )tetrahydro-2H -pyran-3,4,5-tri ol whi ch comprises;
  • reaction mass is cooled to -5 ⁇ C to 0 ⁇ C and stirred for 30.0 min.
  • reaction mass is cooled to -5 ⁇ C to 0 ⁇ C and stirred for 30.0 min.
  • Added 18.0 mole Tri methyl si I lyl chloride at the temp -5 ⁇ C to 0 ⁇ C and stirred for 30.0 min.
  • Aromatic C C stretching: 1510 , 1548 , 1603 , 1703 cm 1
  • the pipecolic acid co-crystal of Dapagliflozin was characterized by X -ray powder diffraction pattern (Fig-1).
  • Aromatic C C stretching: 1510 , 1548 , 1603 , 1703 cm 1
  • E xample 14 Preparation of Acetic acid 4, 5-diacetoxy-6-acetoxymethyl-2- allyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-yl ester Charged 100 gms of 2-Allyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxy methyl-tetrahydro-pyran-3,4,5-triol in clean dry Round bottom flask, fitted with reflux condenser, in an water bath. Charged M DC, 800 ml, stirred to dissolve the contents.

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Abstract

The present invention discloses the process for preparation of (2S,3R,4R,5S,6R)- 2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran- 3,4,5-trioland its amorphous form. The invention further discloses novelco- crystals of dapagliflozin,and process for preparation thereof. The invention further discloses novel intermediateAcetic acid 4,5-diacetoxy-6-acetoxymethyl-2-R1-2- [4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-yl ester, wherein R1 is allyl or 2-prop-2ynyl useful for preparation 2-R1-2-[4-Chloro-3-(4-ethoxy- benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.

Description

^NOVEL PIPECOLIC ACID CO-CRYSTALS OF DAPAGLIFLOZIN AND PROCESS FOR THE PREPARATION THEREOF
FIELD OF INVENTION:
The present invention relates to an industrially feasible process for preparation of Dapagliflozin.. The invention further relates to novel co-crystals of dapagliflozin and its process for preparation thereof. The invention further relates to novel intermediate Acetic acid 4,5-diacetoxy-6-acetoxymethyl-2-R1-2-[4-chloro-3-(4- ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-yl ester, wherein R1 isallyl or2-prop- 2ynyl useful for preparation 2-R1-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxymethyl -tetrahydro- pyran-3,4, 5-tri ol .
BACKGROUND OF INVENTION:
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is sodium dependent glucose transporter (SGLT) which is currently under investigation for the treatment of type-2 diabetes. (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is marketed under the tradename Farxiga or Forxiga.
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is also known as D-glucitol, 1,5- anhydro- 1 -C - [4-chl oro-3- [(4ethoxyphenyl ) methyl] phenyl] -, ( 1 S) .
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, is a white to off-white powder with a molecular formula of C21H25CIO6 and a molecular weight of 408.87.
Figure imgf000003_0001
Formula-I
US 6,515,117 B2discloses (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4- ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol and its pharmaceutically acceptable salts. US 6,515,117 B1 also describes preparation process of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol which comprises reaction of 5- bromo-2-chl oro-4~-ethoxydi phenyl methane with 2,3,4,6-tetra-O-tri methyl si lyl -§- D-glucolactone in presence of TH F/Toluene, methansulfonic acid to yield o- methylglucoside product which further reacts with Et3SiH, BFsEtO in presence of MDC and acetonitrile to yield yellow solidified foam which is dissolved in M DC, pyridine and followed by acetyl ati on with acetic anhydride, D MA P to yield tetra acetylated- <f-C-glucoside as a white solid which further deprotected with L iOH H20 in presence of TH F/MeOH/H20 to get (2S,3R,4R,5S,6R)-2-[4-chloro- 3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.
The drawback of said prior art is having multiple step process which makes the process very lengthy and tedious. Moreover the process discloses use of hazardous chemicals like pyridine which is not applicable to industry.
Process for preparation of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4- ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is disclosed in US 7,375,213 B2 and J .M ed.C hem.2008,51, 1145-1149. Preparation process is depicted in Scheme-I.
Figure imgf000004_0001
Scheme-1
Prior art US 13 describes reaction of 2-chloro-5-bromo-4~-ethoxy- di phenyl methane with 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone, n-BuL i in presence of T H F and Heptane. After basifi cation with TEA oily residue of methyl - 1-C-(2-chloro-4~-ethoxy-diphenylmethan-3-yl)- -D-glucopyranose obtained which after workup obtained as solid compound which reacts with acetic anhydride in presence of T H F, DIPEA and DMA P to get oily residue of methyl- 2,3,4,6 tetra-0-acetyl-1-C-(2-chloro-4"-ethoxydiphenylmethan-3-yl)- -D- glucopyranose which further undergoes reduction reaction in presence of acetonitirle, tri ethyl si lane, boron trifluorideetherate to yield 2,3,4,6-tetra-O-acetyl- 1-C-(2-chloro-4"-ethoxydiphenylmethan-3-yl)- -D-glucopyranose which further deprotected by reacting with LiOHmonohydrate in presence of TH F/MeOH/H20 to get (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-
( hydroxymethyl )tetrahydro-2H -pyran-3,4,5-tri ol .
The said prior art describes multiple, time consuming process which describes getting oily residue which is difficult to purify and handle for further process. More over the workup involves multiple evaporation of product which may result in decomposition. Another drawback is that the process describes n-BuL i reaction with two pot reaction. It is very difficult to transfer the material from one reactor to second reactor at -78≠C at industry level with highly moisture sensitive reaction mass. This makes process uneconomical, cumbersome and commercially not viable. Further when practically the said methodfollowed -Isomerof the final product is formed in the range of 6-8% along with Des-bromo impurity formed in the range of 7-9 %, which increases after addition of n- butyl lithium and kept the mass for overnight reaction. Moreoverlactone ring cleavage is observed in the range of 3-4% after addition of Methanesul phonic Acid/Methanol and maintained overnight for reaction completion, the removal of which is difficult from the final product.
WO 2008002824 A 1 discloses crystalline forms of (2S,3R,4R,5S,6R)-2-[4- chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran- 3,4,5- triol comprising (S)-propylene glycol (PG), (R)-PG, EtOH, ethylene glycol (EG), 1 :2 L-proline, 1 : 1 L-proline, 1 : 1 L-proline hemi hydrate, 1 : 1 L- phenyl alanine and its preparation processes.
In the light of the above drawbacks, it is necessitated to provide economical, robust, safe and commercially viable process for preparing (2S,3R,4R,5S,6R)-2- [4-chloro-3-(4-ethoxybenzyl) phenyl] -6-( hydroxymethyl)tetrahydro-2H -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-[4-chloro-3-(4- ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, prepared via novel intermediates and co-crystal forms which gives higher yield and purity and facilitates easy recovery of final compound. The purification process does not involve any costly technique/equipment however, carried out with solvents which areindustrially feasible. Moreover present invention discloses the n-BuL iinsitu reaction 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)- 2-[4-chl oro-3-(4-ethoxybenzyl) phenyl] -6-( hydroxymethyl)tetrahydro-2H -pyran- 3,4,5-triol(Formula-I) and its stable annorphous formJhe invention further provides novel co-crystal of dapagliflozin; 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 methyl si I anyl oxy- 6-tri methylsi lanyl oxymethyl -tetrahydro- py ran- 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 satsodi 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 oxymethyl - tetrahydro- pyran-2-one.
In another aspect the present invention discloses the process for preparing 2-R1-2- [4- chl oro-3-(4- ethoxy- benzyl )- phenyl ]- 6- hydroxy methyl -tetrahydro- py ran- 3,4, 5- tri ol from 3,4, 5-T ri s-tri methyl si I anyl oxy- 6-tri methyl si I anyl oxymethyl -tetrahydro- pyran-2-one which comprises; (a) Reacting 4-(5-bromo-2-chlorobenzyl)phenyl ethyl ether with 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 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-chloro-4-(4-ethoxy-benzyl)-phenyl]-6- hydroxymethyl -tetrahydro- pyran-3,4,5-tri ol .
In another embodiment the present invention describesa novel intermediate, Acetic acid 4,5-diacetoxy-6-acetoxymethyl-2-allyloxy-2-[4-chloro-3-(4-ethoxy- benzyl)-phenyl]-tetrahydro-pyran-3-yl esterand process for the preparation thereof.
Accordingly, the process for preparation of Acetic acid 4,5-diacetoxy-6- acetoxymethyl-2-allyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro- pyran-3-yl ester comprises;
(a) Reacting 2-Allyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol with acetic anhydride in the presence of diisopropyl ethyl amine and methylene chloride;
( b) S eparati ng organi c I ayer; and
(c) Isolating Acetic acid 4,5-diacetoxy-6-acetoxymethyl-2-allyloxy-2-[3- chl oro-4-(4-ethoxy- benzyl )-phenyl] -tetrahydro-pyran-3-yl ester.
In yet one another embodiment the present invention provide the process for preparation of 2-Allyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxymethyl -tetrahydro- pyran- 3,4, 5- triol which comprises;
(a) Reacting Acetic acid 4,5-diacetoxy-6-acetoxymethyl-2-allyloxy-2-[4- chl oro-3-(4-ethoxy- benzyl )-phenyl] -tetrahydro-pyran-3-yl ester with sodium methoxide in presence of an organic solvent; ( b) S eparati ng the organi c I ayer; and
(c) Isolating 2-R1-2-[^chloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol (R1 is allyl or prop-2-yn-yl).
In one another embodiment the present invention describes process for preparing
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-
( hydroxymethyl )tetrahydro-2H-pyran-3,4,5-triol by reduction of 2-R1-2-[4-chloro-
3-(4-ethoxy-benzyl )- phenyl] -6- hydroxymethyl -tetrahydro- pyran-3,4, 5-tri ol whi ch comprises;
(a) Reacting 2-R1-2-[4-chloro-3-(4-ethoxy-benzyl)-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 nitrogen atmosphere (wherein (R1 is allyl or prop-2-ynyl)
(b) Quenching with saturtaed sodium bicarbonate solution;
(c) Separating the layers; and
(d) Isolating (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- ( hydroxymethyl )tetrahydro-2H -pyran-3,4,5-tri ol .
In one another embodiment the instant invention provides process for preparing stable amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4- ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triolfrom (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- ( hydroxymethyl )tetrahydro-2H -pyran-3,4,5-tri ol whi ch comprises;
(a) Stirring (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- ( hydroxymethyl )tetrahydro-2H-pyran-3, 4,5- triol with non-polar solvent at ambient temperature; and
(b) Isolating amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4- ethoxybenzyl ) phenyl] -6-( hydroxymethyl )tetrahydro-2H -pyran-3,4, 5-tri ol .
In another embodiment the present invention describes the preparation of pipecolic acid complex of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4- ethoxybenzyl) phenyl] -6-(hydroxymethyl )tetrahydro-2H -pyran-3,4,5-triolfrom
(2S,3R,4R,5S,6R)-2-[^chloro-3-(^ethoxybenzyl)phenyl]-6-
( hydroxymethyl )tetrahydro-2H -pyran-3,4,5-tri ol whi ch comprises;
(a) Reacting (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- ( hydroxymethyl )tetrahydro-2H-pyran-3, 4,5- triol 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-[4-chloro-3-(4- ethoxybenzyl ) phenyl] -6-( hydroxymethyl )tetrahydro-2H -pyran-3,4, 5-tri ol .
In another embodiment the present invention describes the process for preparing stable amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4- ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triolfrom pipecolic acid complex of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4- ethoxybenzyl) phenyl] -6-(hydroxy methyl)tetrahydro-2H -pyran- 3,4,5- tri ol whi ch comprises;
(a) Stirring pipecolic acid co-crystal of (2S,3R,4R,5S,6R)-2-[4-chloro-3- (4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran- 3,4,5-triolin presence of ethyl acetate;
(b) Adding sat. sodium bicarbonate solution;
(c) Adding n- Heptane; and
(d) Isolating stable amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3- (4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran- 3,4,5-triol.
The present process gives -Isomer in the range of 3-5 %., which is removed during purification; further, the Des-bromoimpuirity (2-chloro ~4~- ethoxydi phenyl methane)formati on is restricted to 3-4 %during purification. Further work up disclosed in present invention is advantageous over the teachings of prior art as the purification process does not involve multiple step workup. The purification process is 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-[4-chloro-3-(4- ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.
DE SC RIPTION OF DRAWING S:
F ig 1 depict PX RD of pipecolic acid co-crystal of Dapagliflozin
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-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(Formula-I) and its amorphous formJhe invention further provides novel intermediates of dapagliflozin; its co- crystal 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 caronate;
( 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 any I 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 0≠C.
In another embodiment the instant invention discloses the process for preparing 2- R 1 -2- [4- chl oro-3-(4- ethoxy- benzyl )- phenyl ]- 6- hydroxy methyl -tetrahydro- pyran-3,4,5-triol from 3,4,5-Tris-trimethylsilanyloxy-6- trimethylsilanyloxymethyl-tetrahydro-pyran-2-one which comprises;
(a) Reacting 4-(5-bromo-2-chlorobenzyl)phenyl ethyl ether with 3, 4,5-Tris- tri methyl si I anyl oxy- 6-tri methyl si I anyl oxy methyl -tetrahydro- py ran-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-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxymethyl -tetrahydro- pyran-3,4,5-tri ol .
The reaction scheme for preparing 2-R1-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]- 6- hydrox methyl -tetrahydro- pyran- 3,4, 5-triol is given in Scheme III.
Figure imgf000012_0001
1
where R = allyl, prop-2-ynyl,isopropyl
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 -80≠C.
The term organolithium reagent refers to alky I 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 i s selected from the group consisting of allyl alcohol, propargyl alcohol.
The present process gives - Isomer in the range of 3-4 %., which is removed during purification. Des-bromoimpuirity (2-chloro ~4~- ethoxydi phenyl methane) formation is restricted to 3-5 % during purification. In above process R1 is allyl, 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-[4-chloro-3-(4- ethoxy- benzyl ) - phenyl ] - 6- hydroxy methyl -tetrahy dro- py ran- 3,4, 5-tri ol of f ormul a V.
Figure imgf000013_0001
Formula-V wherein, R1 is selected from allyl or prop-2ynyl.
T heref ore, the invention encompasses the novel intermediate compounds of
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-
( hydroxymethyl )tetrahydro-2H -pyran-3,4, 5-tri ol, viz.,
(a) 2-Allyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl- tetrahydro- pyran-3,4, 5-tri ol ,
(b) 2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-2-prop-2- ynyl oxy- tetrahydro-pyran-3,4,5-tri ol .
In one another embodiment the present invention describes the process for the preparation of Acetic acid 4,5-diacetoxy-6-acetoxymethyl-2-allyloxy-2-[4-chloro- 3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-yl ester which comprises;
a) Reacting 2-R 1-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol with acetic anhydride in the presence of diisopropyl ethyl amine and methylene chloride; b) S eparati ng organi c I ayer; and
c) Isolating Acetic acid 4,5-diacetoxy-6-acetoxymethyl-2- 1 - 4-(
Figure imgf000014_0001
R 1= Allyl or prop-2-ynyl
Scheme-IV
In yet another embodiment the present invention provide the process for the preparation of 2-R1 -2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl- tetrahydro-pyran-3,4,5-triol which comprises;
a) Reacting Acetic acid 4,5-diacetoxy-6-acetoxymethyl-2-R1 -2-[4-chloro- 3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-yl ester with sodium methoxide in presence of an organic solvent;
b) S eparati ng the I ayer and
c) Isolating 2-R1-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol (R1 is allyl or prop-2-ynyl).
Figure imgf000014_0002
R1= Allyl or prop-2-ynyl
Scheme-V The novel intermediates are having better leaving groups- allyl, propargyl as compared 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 (4-(5-2-chlorobenzyl) phenyl ethyl ether) impurities which comprises;
(a) Reacting 4-(5-bromo-2-chlorobenzyl) phenyl ethyl ether with alkyllithium in 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-chloro "4"- ethoxydi phenyl methane.
The alkyl lithiums 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 of Toluene, Hexane, 1,4-Dioxane, Chloroform, Diethyl ether, D i chl oromethane. According to above process the reaction temperature is -70 to - 80≠C.
The main object is achieved by removing the des-bromo impurity during purification of 2-R1-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl- tetrahydro-pyran-3,4,5-triol, without involving 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-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triolby reduction of 2-R1-2-[4-chloro- 3-(4-ethoxy-benzyl )- phenyl] -6- hydroxymethyl -tetrahydro- pyran-3,4, 5-tri ol whi ch comprises; (a) Reacting 2-R1-2-[4-chloro-3-(4-ethoxy-benzyl)-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 the layers; and
(d) Isolating (2S,3R,4R,5S,6R)-2-[^chloro-3-(^ethoxybenzyl)phenyl]-6- ( hydroxymethyl )tetrahydro-2H -pyran-3,4,5-tri ol .
The reaction scheme for said process is given in Scheme-V I.
Figure imgf000016_0001
where R = allyl, prop-2-ynyl
Scheme-VI
According to above said process the term organosilane refers to alkylsilane or polyal kylsilane is selected from the group consisting of tri methyl si lane, tri ethyl si lane, tetramethylsilane, dimethyl si lane. 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 borontri fluoride in diethyl ether, trifluoroacetic acid, methanesulfonic acid. The above reaction is carried out at -40 to 55≠C.
In the above process R1 is selected from allyl, prop-2ynyl.
In one another embodiment the instant invention provides process for preparing stable amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4- ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triolfrom (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- ( hydroxymethyl )tetrahydro-2H -pyran-3,4,5-tri ol whi ch comprises;
(a) Stirring(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-
( hydroxymethyl )tetrahydro-2H-pyran-3, 4,5- triol with non-polar solvent at ambient temperature; and
(b) Isolating stable amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3- (4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-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 25-30≠C.
The main object of the present invention process is to get stable amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- ( hydroxymethyl )tetrahydro-2H-pyran-3, 4,5- triol without using any special technique which makes the process simple, cost- effective and time saving.
In another embodiment the present invention describes pipecolic acid complex of
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-
( hydroxymethyl )tetrahydro-2H-pyran-3, 4,5- triolfrom (2S,3R,4R,5S,6R)-2-[4- chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran- 3,4,5- trioland the process for preparation thereof. Accordingly, the process for preparation of pipecolic acid co-crystal of
(2S,3R,4R,5S,6R)-2-[^chloro-3-(^ethoxybenzyl)phenyl]-6-
( hydroxymethyl )tetrahydro-2H -pyran-3,4,5-tri ol comprises;
(a) Reacting (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- ( hydroxymethyl )tetrahydro-2H-pyran-3, 4,5- triol 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-[4-chloro-3-(4- ethoxybenzyl ) phenyl] -6-( hydroxymethyl )tetrahydro-2H -pyran-3,4, 5-tri ol .
The reaction scheme for said process is given in Scheme-V II.
Figure imgf000018_0001
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 60-65≠C.
In another embodiment, the present invention describes the process for preparing amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- ( hydroxymethyl )tetrahydro-2H-pyran-3, 4,5- triolfrom pipecolic acid complex of (2S,3R,4R,5S,6R)-2-[^chloro-3-(^ethoxybenzyl)phenyl]-6- ( hydroxymethyl )tetrahydro-2H -pyran-3,4,5-tri ol whi ch comprises;
(a) Stirringpipecolic acid complex of(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4- ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran- 3,4,5- triolin presence of ethyl acetate;
(b) Adding sat. sodium bicarbonate solution;
(c) Adding n- Heptane; and
(d) Isolating stable amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3- (4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-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.
E xamples:
E xample-1 : Preparation of 3,4,5-Tris-trimethylsilanyloxy-6- trimethylsilanyloxymethyl-tetrahydro-pyran-2-one
To 750 cc of dry T H 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 -5≠C to 0≠C and stirred for 30.0 min. Added 18.0 mole Tri methyl si I lyl chloride at the temp -5≠C to 0≠C and stirred for 30.0 min. Temperature raised to 25≠C to 30≠C and maintained for 18-20hrs. After reaction complies by GC, reaction mass is cooled to -5 deg to 0 deg. Added Sa Sodium bicarbonate solution to obtain the pH 7-8 and 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 mixed and back washed with sat. brine solution. Organic layer is distilled under reduced pressure at a temperature of about 40 " 48 deg. U nl oaded the oi ly mass, purity: 92-96 % E xample-2: Preparation of 2-A llyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)- 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 4-(5-bromo-2- chlorobenzyl) phenyl ethyl ether at ambient temperature and 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, the reaction mass is quenched with Methane sulphonic acid and Allyl alcohol mixture at -70 to -80eC. Temperature raised to ambient temperature and stirred overnight. Reaction mass quenched with 30 cc sa sodiumbi carbonate solution to bring the pH neutral to alkalineand stirred for 30.0 min. Layers separated and aqueous layer extracted with 10 cc of Toluene. Organic layer combined and washed with water 30cc and sat. brine solution 50 cc. Organic layer distilled under reduced pressure to recover toluene. Solid compound dissolved in 50cc of toluene and quenched in n-Hexane to obtain 83 % the compound as crystalline solid.
H PL C purity: 88 " 91 %
IR data:
Anomeric C-0 stretching: 1242 cm1
Allylic C- O stretching: 1177 cm1
A Hylic C- H stretching: 3010 " 3120 cm1
Aromatic C- CI stretching: 820 cm1
Lactones O " H stretching: 3240 " 3380 cm1
Lactones C " O stretching: 1045 " 1092 cm1
Aromatic C=C stretching: 1510 , 1548 , 1603 , 1703 cm1
Alkane C " H stretching: 2877,2866, 2956, 2958, 2962 cm1
Aromatic C " H stretching: 3050 - 3090 cm1
Dip-Mass
(M+Na) 487.19 m z
(M+K) 503.17 m/z E xample-3: Preparation of Dapagliflozin " pipecolic acid co-crystal.
Charged 100gms Dapagliflozin crude to a clean,dry round bottom flask fitted with reflux condenser in a water bath. Charged7.5 vol. of ethanol and stirred to get clear solution. Slowly heated the reaction mass to reflux and maintained the reflux for 30 mins. Addedpipecolic acid 18 mmole in a single lot,stirred for 1 hr at reflux, material slowly precipitates, stirred for another 1 hr at reflux. Slowly addedheptanes 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 anddried the wet cake in air drier for 8 " 10 hrs to obtain the co-crystal. 2. The pipecolic acid co-crystal of Dapagliflozin was characterized by X -ray powder diffraction pattern (Fig-1).
E xample-4: Preparation of Amorphous Dapagliflozin Pure:
Charged 100 gm Dapagliflozin " 2-pipecolic acid co-crystal in a clean dry round bottom flask. Charged 5 vol of 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 5: Preparation of 2-prop-2ynyl-2-[4-C hloro-3-(4-ethoxy-benzyl)- 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 4-(5-bromo-2- chlorobenzyl) phenyl ethyl ether at ambient temperature and 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, the reaction mass is quenched with Methane sulphonic acid and propargyl alcohol mixture at - 70 to -80eC. Temperature raised to ambient temperature and stirred overnight. Reaction mass is 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 extracted with 10 cc of Toluene. Organic layer combined and washed with 30cc water and50 cc sat. brine solution. Organic layer is distilled under reduced pressure to recover toluene. Solid compound dissolved in 50cc of toluene and quenched in n-Hexane to obtain 75 - 80 %the compound as crystalline solid. H PL C purity: 88 " 93 %
IR data:
Anomeric C-0 stretching: 1242 cm1
Propargyl ~c C H stretching: 2125 cm 1
Propargyl C- H stretching : 3010 " 3120 cm1
Aromatic C- CI stretching: 820 cm1
Lactones O " H stretching: 3240 " 3380 cm1
Lactones C " O stretching: 1045 " 1092 cm1
Aromatic C=C stretching: 1510 , 1548 , 1603 , 1703 cm1
Alkane C " H stretching: 2877, 2866,2956,2958,2962 cm1
Aromatic C " H stretching: 3050 - 3090 cm1
Dip-Mass
(M+Na) 485.25 m z
(M+K) 501.25 m/z
E xample-6: Preparation of 2-[4-C hloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol
To the mixture of 20 cc (1 :1 M DC + AC N) added 0.11 mole 2-Allyloxy-2-[4- chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol under argon atmosphere, and 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 Borontri fluoride in diethyl ether solution at -40 to -55eC and sti rred 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 down 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. Brine solution. Distilled out the M DC under reduced pressure below 40eC to get 85 %the light yellow solid.
H PL C purity: 92-95 %
E xample 7: Preparation of 2-[4-C hloro-3-(4-ethoxy-benzyl)-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-2-ynyl-2-[4- C hi oro-3-(4-ethoxy- benzyl )- phenyl] -6- hydroxymethyl -tetrahydro- pyran-3,4, 5- triol under argon 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 Borontrifloride 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 down 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. Brine solution. Distilled out the M DC under reduced pressure bel ow 40eC to get 85%the I ight yel I ow sol i d.
H PL C purity: 90%
E xample-8: Preparation of Dapagliflozin " pipecolic acid co-crystal.
Charged 100gms Dapagliflozin crude to a clean,dry round bottom flask fitted with reflux condenser in a water bath. Charged7.5 vol. of ethanol stirred to get clear solution. Slowly heated the reaction mass to reflux and maintained the reflux for 30 mins. Addedpipecolic acid 18 mmole in a single lot. Stirred for 1 hr at reflux, material slowly precipitates, stirred for another 1 hr at reflux. Slowly addedheptanes 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. D ri ed the wet cake i n ai r dri er f or 8 " 10 hrs.
E xample-9: Preparation of Amorphous Dapagliflozin pure :
Charged 100 gmsDapagliflozin " 2-pipecolic acid co-crystal in a clean dry round bottom flask. Charge 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. Chargedheptanes 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 10: Preparation of amorphous form of (2S,3R,4R,5S,6R)-2-[4- chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H -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 under vacuum to get 85% amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4- ethoxybenzyl)phenyl]-6-(hydroxyl methyl)tetrahydro-2H-pyran-3,4,5-triol.
H PL C purity: 91-93%
E xample 11 : Preparation of amorphous form of (2S,3R,4R,5S,6R)-2-[4- chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H -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 under vacuum to get 85-88% amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4- ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.
H PL C purity: 89-91 %
E xample 12: Preparation of amorphous form of (2S,3R,4R,5S,6R)-2-[4- chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H -pyran-
3,4,5-triol
To the 15 cc ethyl acetate added (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4- ethoxybenzyl) phenyl] -6-(hydroxymethyl )tetrahydro-2H -pyran- 3,4,5- triol co- crystal of example 3 at ambient temperature and stirred 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. Settled down the mass and separated layers. 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 " 45eC to get fluffy solid. Charged 50 cc n- Heptane and stirred for 5 hrs to get 70-78% the title compound as Amorphous solid.
H PL C purity: 99.8-99.95 %
E xample 13: Preparation of 2-chloro "4"- ethoxydi phenyl methane (impurity) To the 20 cc TH F and 20 cc Toluene added 0.25 mole 2-chloro- 5-bromo-4" ethoxydi phenyl methane under argon atmosphere. Cooled the reaction mass to - 78° C. Slowly added n- Butyl lithium (1.9 M in hexane) at " 78° C and stirred for 30 min. Slowly added 20 % Ammonium chloride solution to the reaction mass. Brought the reaction mass to ambient temperature and stirred for 30 min. Settled the mass 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 heptanes, stirred for 2 " 3 hrs at ambient temperature. Filtered the product and dried the product at 45 " 50°C under reduced pressure to get 93 % titled compound.
M ass: ( m+ 1 ) 247 m/z found 247.11
H PL C purity: 96.33 %.
E xample 14: Preparation of Acetic acid 4, 5-diacetoxy-6-acetoxymethyl-2- allyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-yl ester Charged 100 gms of 2-Allyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxy methyl-tetrahydro-pyran-3,4,5-triol in clean dry Round bottom flask, fitted with reflux condenser, in an water bath. Charged M DC, 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. Stirred for 10 mins and added DMA P 0.8 mmole at once to the reaction mass, slight exotherm was observed. Stirred the reaction mass for 6-8 hrs at RT. Monitored 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, stirred the reaction mass., separated the layers, extracted the aqueous layer 3 times with ethyl acetate. Combined the ethylacetate 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-15: Preparation of 2-Allyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)- phenyl]-6-hydroxy methyl-tetrahydro-pyran-3,4,5-triol
Charged 100 gms Acetic acid 4,5-diacetoxy-6-acetoxymethyl-2-allyloxy-2-[4- chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-yl ester, in clean dry round bottom flask under N2 atmosphere. Charged 5 vol of Methanol and stirred for 10 mins. Slowly added sodium methoxi decontrol ling 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 and distilled out the solvent under vacuum below 45°C. Added water and ethyl acetate and 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 16: Preparation of Acetic acid 4,5-diacetoxy-6-acetoxymethyl-2- prop-2ynyl-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-yl ester
Charged 100 gms of 2-prop-2ynyl-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxy methyl-tetrahydro-pyran-3,4,5-triol in clean dry Round bottom flask, fitted with reflux condenser, in an water bath. Charged M DC, 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. Stirred for 10 mins and added DMA P 0.8 mmole at once to the reaction mass, slight exotherm was observed. Stirred the reaction mass for 6-8 hrs at RT. Monitored the reaction by T LC. Distilled out MDC solvent under vacuum below 400 C. To the obtained crude added water and ethyl acetate, 2 vol, stirred the reaction mass., separated the layers, extracted the aqueous layer 3 times with ethyl acetate. Combined the ethylacetate 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-17: Preparation of 2- prop-2ynyl-2-[4-chloro-3-(4-ethoxy-benzyl)- phenyl]-6-hydroxy methyl-tetrahydro-pyran-3,4,5-triol
Charged 100 gmsAcetic acid 4,5-diacetoxy-6-acetoxymethyl-2-prop-2ynyl-[4- chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-yl ester, in clean dry round bottom flask under N2 atmosphere. Charged 5 vol of Methanol and stirred 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 and distilled out the solvent under vacuum below 45°C. Added water and ethyl acetate and 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.

Claims

We claim;
1. Novel pipecolic acid co-crystal of Dapagliflozin.
2. The pipecolic acid co-crystal of Dapagliflozin according to claim 1 characterized by X -ray powder diffraction pattern as shown in Fig-1.
3. A process for preparation of pipecolic acid co-crystal of Dapagliflozin comprising;
(a) Reacting (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4' ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran- 3,4,5-triol (Dapagliflozin) with pipecolic acid in the 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-[4-chloro- 3-(4-ethoxybenzyl ) phenyl] -6-( hydroxymethyl )tetrahydro-2H - py ran-3,4, 5-tri ol ( D apagl i f I oz i n) .
4. T he process accordi ng to clai m 2, wherei n the used i n step (a) and (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 hemihydrateof Dapagliflozin comprising;
(a) stirring D apagl i f I oz i n- pi pecol i c acid complex in an ester solvent;
(b) adding sat. sodium bicarbonate solution;
(c) adding non-polar solvent; and
(d) isolating stable amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro- 3-(4-ethoxybenzyl ) phenyl] -6-( hydroxymethyl )tetrahydro-2H - py ran-3,4, 5-tri ol ( D apagl if I ozi 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 or mixtures thereof.
7. The process according to claim 5, wherein thenon- polar solvent used in step (c) is selected from n-hexane, n-heptane or mixture thereof.
8. Acetic acid 4,5-diacetoxy-6-acetoxymethyl-2-R1-2-[4-chloro-3-(4- ethoxy-benzyl)- phenyl] -tetrahydro-pyran-3-yl ester, wherein R1 is allyl or 2-prop-2ynyl.
9. Theprocess for preparing Acetic acid 4,5-diacetoxy-6-acetoxymethyl-2- R1-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-yl ester, wherein R1 is allyl or 2-prop-2ynyl according to claim 8,comprising;
(a) Reacting 2-R1-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxy methyl-tetrahydro-pyran-3,4,5-triol (wherein R1 is allyl or 2- prop-2ynyl)with acetic anhydride in the presence of di isopropyl ethyl amine and methylene chloride;
(b) Separating organic layer; and
(c) Isolating Acetic acid 4,5-diacetoxy-6-acetoxymethyl-2-R1-2-[3-
-4-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-yl ester.
Figure imgf000030_0001
R1= Allyl or prop-2-ynyl
PCT/IN2016/050345 2015-10-09 2016-10-08 Novel pipecolic acid co-crystals of dapagliflozin and process for the preparation thereof WO2017060925A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020168155A1 (en) * 2019-02-15 2020-08-20 Ebers Tech Inc. L-pipecolic acid cocrystal of cannabidiol
US11427555B2 (en) * 2016-08-09 2022-08-30 Laurus Labs Limited Processes for preparation of dapagliflozin or its solvates or co-crystals thereof

Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2002083066A2 (en) * 2001-04-11 2002-10-24 Bristol-Myers Squibb Company Amino acid complexes of c-aryl glucosides for treatment of diabetes and method
WO2008002824A1 (en) * 2006-06-28 2008-01-03 Bristol-Myers Squibb Company Crystalline solvates and complexes of (is) -1, 5-anhydro-l-c- (3- ( (phenyl) methyl) phenyl) -d-glucitol derivatives with amino acids as sglt2 inhibitors for the treatment of diabetes
WO2014178040A1 (en) * 2013-04-29 2014-11-06 Mapi Pharma Ltd. Co-crystals of dapagliflozin

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002083066A2 (en) * 2001-04-11 2002-10-24 Bristol-Myers Squibb Company Amino acid complexes of c-aryl glucosides for treatment of diabetes and method
WO2008002824A1 (en) * 2006-06-28 2008-01-03 Bristol-Myers Squibb Company Crystalline solvates and complexes of (is) -1, 5-anhydro-l-c- (3- ( (phenyl) methyl) phenyl) -d-glucitol derivatives with amino acids as sglt2 inhibitors for the treatment of diabetes
WO2014178040A1 (en) * 2013-04-29 2014-11-06 Mapi Pharma Ltd. Co-crystals of dapagliflozin

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11427555B2 (en) * 2016-08-09 2022-08-30 Laurus Labs Limited Processes for preparation of dapagliflozin or its solvates or co-crystals thereof
WO2020168155A1 (en) * 2019-02-15 2020-08-20 Ebers Tech Inc. L-pipecolic acid cocrystal of cannabidiol

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