WO2021260617A1 - Procédé amélioré de préparation de monohydrate de dapagliflozine-propanediol - Google Patents

Procédé amélioré de préparation de monohydrate de dapagliflozine-propanediol Download PDF

Info

Publication number
WO2021260617A1
WO2021260617A1 PCT/IB2021/055609 IB2021055609W WO2021260617A1 WO 2021260617 A1 WO2021260617 A1 WO 2021260617A1 IB 2021055609 W IB2021055609 W IB 2021055609W WO 2021260617 A1 WO2021260617 A1 WO 2021260617A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
acid
solvent
reaction mixture
Prior art date
Application number
PCT/IB2021/055609
Other languages
English (en)
Inventor
Sudhir Nambiar
Goverdhan Gilla
Rahul Bhalerao
Hemant PIMPARKAR
Mahesh DEVGIRKAR
Anil Pawar
Original Assignee
Hikal Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hikal Limited filed Critical Hikal Limited
Publication of WO2021260617A1 publication Critical patent/WO2021260617A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
    • C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
    • C07C29/78—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment by condensation or crystallisation
    • 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

Definitions

  • the present invention relates to an improved process for the preparation of Dapagliflozin propanediol monohydrate of formula (I).
  • the invention further relates to an improved process for the preparation of substantially pure intermediate of formula (VI) having des-bromo impurity of formula (VIII) less than 0.15%.
  • Dapagliflozin (S)-propylene glycol (propanediol) monohydrate is chemically known as (lS)-l,5-anhydro-l-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol compounded with (2S)-1, 2 -propanediol, hydrate (1:1:1). It is a sodium-glucose cotransporter 2 (SGLT2) inhibitor and indicated for the treatment of type -2 diabetes. It is marketed under the brand name FARXIGA ® .
  • the U.S. Patent no. 6,515,117B2 discloses Dapagliflozin, or a pharmaceutically acceptable salt, a stereoisomer thereof, or a prodrug ester thereof. It also disclosed the preparation of Dapagliflozin by preparing unprotected O-methyl compound, removing methyl group using triethyl silane, boron trifluoride etherate (BF3.Et20), workup using ethyl acetate and water, followed by preparing tetra acetylated Dapagliflozin using acetic anhydride in presence of pyridine and dimethyl aminopyridine (DMAP) and finally deprotecting tetra acetylated dapagliflozin using lithium hydroxide monohydrate to provide dapagliflozin as an off-white solid with purity 94%.
  • DMAP dimethyl aminopyridine
  • the U.S. Patent no. 7,919,598B2 discloses the crystalline form (form SC-3) of Dapagliflozin (S) -propylene glycol ((S)-PG) monohydrate and its preparation by treating acetyl substituted dapagliflozin in an organic solvent such as methyl t-butyl ether, an alkyl acetate such as ethyl acetate, methyl acetate, isopropyl acetate, or butyl acetate with base and (S)-propylene glycol, optionally adding seeds of crystalline Dapagliflozin (S)-PG monohydrate.
  • an organic solvent such as methyl t-butyl ether
  • an alkyl acetate such as ethyl acetate, methyl acetate, isopropyl acetate, or butyl acetate with base
  • (S)-propylene glycol optionally adding seeds of crystalline Dapagliflozin (S)
  • the U.S. Patent no. 7,375,213B2 discloses preparation of Dapagliflozin by isolating unprotected O -methyl compound, acylation of hydroxy groups of O -methyl compound using acetic anhydride in presence of N,N'-diisopropylethylamine and DMAP to get tetra acetylated O-methyl Dapagliflozin, followed by reducing tetra acetylated O-methyl dapagliflozin using triethyl silane, boron trifluoride etherateand finally deprotecting using lithium hydroxide monohydrate to provide Dapagliflozin.
  • the U.S. Patent publication no. 2016/0237054A1 discloses preparation and purification of Dapagliflozin by acetylating dapagliflozin in the absence of pyridine to obtain tetra acetylated dapagliflozin (HPLC purity 95 to 98%), then deacetylating using base such as sodium hydroxide and lithium hydroxide to obtain Dapagliflozin.
  • base such as sodium hydroxide and lithium hydroxide
  • the known processes have one or more disadvantages, for example, those as mentioned as follows: (i) the intermediate for manufacturing Dapagliflozin is either having higher impurities or involve further purification (ii) more number of reaction steps (iii)more unit operations, long cycle time (iv)involve harmful reaction/reagents for instance use of pyridine.
  • the intermediate for manufacturing Dapagliflozin is either having higher impurities or involve further purification
  • more number of reaction steps iii)more unit operations, long cycle time
  • iv involve harmful reaction/reagents for instance use of pyridine.
  • the inventors of the present invention have developed a process for preparing Dapagliflozin propanediol monohydrate having minimum number of solid isolations, controlling the impurity formation during the reaction transformations thereby the desired product is obtained with high yield and purity.
  • One aspect of the present invention is to provide an improved process for the preparation of Dapagliflozin propanediol monohydrate of formula (I).
  • the present invention relates to an improved process for the preparation of Dapagliflozin propanediol monohydrate of formula (I) using suitable catalyst and Lewis acid.
  • the present invention relates to an improved process for the preparation of substantially pure compound of formula (VI) having des-bromo impurity less than 0.15%.
  • the present invention relates to an improved process for the preparation of Dapagliflozin propanediol monohydrate of formula (I) comprising steps: a) coupling compound of formula (II) with glycoside compound of formula (III) where TMS is trimethyl silyl, in presence of organolithium compound in solvent, followed by methylation using methanol in presence of acid in solvent to obtain compound of formula (IV), b) demethoxylating of the compound of formula (IV) using a reducing agent in presence of Lewis acid in solvent to obtain compound of formula (V); c) reacting compound of formula (V) with acylating agent in presence of base and catalyst in solvent, followed by treating with cyclohexane and methanol to obtain substantially pure compound of formula (VI) where Ac is acetyl group; wherein compound of formula (VI) having des-bromo impurity of formula (VIII) less than 0.15%; d) hydrolysing compound of formula (VI) in presence of base in solvent to obtain compound
  • the present invention relates to an improved process for the preparation of substantially pure compound of formula (VI) having des-bromo impurity of formula (VIII) less than 0.15%, by treating compound of formula (VI) with cyclohexane and methanol.
  • des-bromo impurity of formula (VIII) used herein refers to l-chloro-2- [(4- ethoxy phenyl) methyl] -benzene as shown below.
  • substantially pure used herein refers to the purity of compound greater than 98%, preferably greater than 99%.
  • solvent used herein refers to single solvent or mixture of solvents.
  • the instant invention is an improved process for the preparation of Dapagliflozin propanediol monohydrate of formula (I), illustrated in the following synthetic scheme:
  • the instant invention provides the preparation of Dapagliflozin propanediol monohydrate of formula (I), wherein the compounds of formula (IV), (V), (VII) are not isolated, which makes present process economic.
  • the organolithium compound is selected from the group consisting of n-, sec- or ieri-butyllithium (BuLi), n- hexyllithium and the like.
  • solvent used for coupling reaction is selected from the group consisting of tetrahydrofuran (THF), hexane, heptane, dioxane, dimethyl sulfoxide (DMSO), toluene, diethyl ether, chlorinated solvents such as dichloromethane (DCM), and the like.
  • THF tetrahydrofuran
  • DMSO dimethyl sulfoxide
  • DCM dichloromethane
  • coupling reaction is carried at temperature -90°C to -70°C, as this reaction temperature plays critical role, which gives better reaction profile in terms of significantly reduced impurities thus to provide good yield and purity.
  • step (a) wherein the acid used in step (a) is selected from methanesulfonic acid, toluene sulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, or hydrochloric acid.
  • the solvent used in methylation reaction is selected from the group consisting of chlorinated solvents such as dichloromethane (DCM), tetrahydrofuran (THF), hexane, heptane, toluene, diethyl ether, and the like.
  • DCM dichloromethane
  • THF tetrahydrofuran
  • hexane hexane
  • heptane hexane
  • toluene diethyl ether
  • the reducing agents used in step (b) is selected from triethyl silane, trimethyl silyl hydride, tripropyl silane, triisopropylsilane, diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, diisobutylaluminum hydride and the like.
  • the Lewis acidused in step (b) is selected from aluminium chloride, boron trifluoride etherate, boron trifluoride acetic acid complex (BF 3 .2CH 3 COOH), trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, copper(II) triflate, zinc iodide, hydrochloric acid, toluene sulfonic acid, trifluoroacetic acid, or acetic acid and the like.
  • the Lewis acidused in step (b) is selected from aluminium chloride, boron trifluoride etherate, boron trifluoride acetic acid complex (BF 3 .2CH 3 COOH), trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, copper(II) triflate, zinc iodide, hydrochloric acid, toluene s
  • step (b) wherein the solvent used in step (b) is selected from acetonitrile, dichloromethane, chloroform, toluene, hexane, diethyl ether, tetrahydrofuran, dioxane, ethanol, water and the like.
  • the demethoxylation reaction is performed at temperature belowl5°C.
  • acylating agent used in step (c) is selected from the group consisting of acetic anhydride or acetyl chloride.
  • step (c) wherein the base used in step (c) is selected from group consisting of triethylamine (TEA), diisopropylethylamine, dibutyl amine, tributyl amine, diisopropyl amine, N-methylmorpholine and the like.
  • TAA triethylamine
  • diisopropylethylamine dibutyl amine
  • tributyl amine diisopropyl amine
  • N-methylmorpholine N-methylmorpholine
  • step (c) wherein the catalyst used in step (c) is selected from the group consisting of dimethylaminopyridine (DMAP), boron trifluoride etherate, trimethyl silyl chloride or triflate and the like.
  • DMAP dimethylaminopyridine
  • boron trifluoride etherate trimethyl silyl chloride or triflate and the like.
  • step (c) wherein the solvent used in step (c) is selected from dichloromethane, toluene, acetonitrile, chloroform, toluene, hexane, diethylether, tetrahydrofuran, and the like.
  • the base used in step (d) is selected from the group consisting of alkali metal hydroxide such as lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH) and the like.
  • alkali metal hydroxide such as lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH) and the like.
  • step (d) wherein the solvent used in step (d) is selected from the group consisting of water, tetrahydrofuran, methanol, ethanol, isopropyl alcohol (IPA), isopropyl acetate and the like.
  • the solvent used in step (d) is selected from the group consisting of water, tetrahydrofuran, methanol, ethanol, isopropyl alcohol (IPA), isopropyl acetate and the like.
  • step (e) wherein the solvent used in step (e) is selected from group consisting of water, cyclohexane, and isopropyl acetate.
  • the preparation of the starting materials and reagents used in the present invention are well known in prior art.
  • the reaction mixture was cooled to 0°C to 15°C, the pH was adjusted between pH 6.0 to 7.5 using 5% aq. sodium bicarbonate (NaHCCF) solution.
  • the reaction mixture was concentrated till to arrive a minimum volume and allowed it to 20°C to 40°C.
  • 500 ml (5V) of dichloromethane (DCM) was charged in reaction mixture at room temperature and stirred for 20 to 30 min.
  • the aqueous and organic layers were separated.
  • the aqueous layer was extracted with DCM and layers were separated.
  • the combined organic layer was washed with brine and organic layer was separated and concentrated till to a minimum volume and cooled to room temperature.
  • 500 ml DCM (5.0 V) was charged to the reaction mixture and stirred to get clear solution.
  • the reaction mixture was concentrated till to a minimum volume and cooled to room temperature.
  • reaction mixture in second RBF, the reaction mixture from first RBF was added at temperature below 15°C and maintained at 15°C to 25°C for 3 to 5 hrs.
  • the reaction mixture was cooled to 10°C to 15°C and 500 ml (5V) of water was added to the reaction mixture.
  • the reaction mixture was warmed to20°C to 35°C and stirred for 20 to 30min.
  • the aqueous and organic layer were separated.
  • the aqueous layer was extracted with 200 ml (2 V) of DCM.
  • the lower organic layer was separated.
  • the organic layers were combined and further washed with 2.0 % NaHCOs solution and 10 % brine solution.
  • the DCM was distilled out till minimum volume of reaction mixture remained.
  • 500 ml DCM (5.0 V) was charged to the reaction mixture and stirred to get clear solution.
  • the reaction mixture was concentrated till to
  • the solid was filtered and washed with 200 ml cyclohexane (2.0V) and suck dried.
  • the content of des-bromo impurity was checked by HPLC and it was not more than 0.5%. (If content of des bromo impurity is more than 0.5%, then the wet solid was washed with cyclohexane and suck dried).
  • the wet solid and 800 ml (8.0 V) methanol was charged into flask and further 200 ml methanol (2.0 V) was added and stirred at 55°C to 65°C for 30 to 40 min. The reaction mixture was cooled to 20°C to 30°C and stirred for 1 to 2 hrs.
  • the organic solvents were distilled under reduced pressure, till minimum volume of reaction mixture remained.
  • the reaction mixture was cooled to 20 °C to 35°C.150 ml (3.0 V) purified water and 200 ml (4.0 V) isopropyl acetate were charged to the reaction mixture and stirred for 20 to 30 min at same temperature.
  • the aqueous and organic layer were separated.
  • the aqueous layer was extracted with 100 ml (1 V) of isopropyl acetate.
  • the organic layer was separated.
  • the organic layers were combined and further washed with water.
  • To the organic layer 2.5 g Norite charcoal (5.0 % w/w) was added at 20°C to 35°C and reaction mixture was heated to 50°C to 55°C and stirred for 30 to 40 min.
  • the hot reaction mixture was filtered and washed with hot isopropyl acetate.
  • the solvent was distilled out till minimum volume of reaction mixture remained in the flask.
  • the reaction mixture was

Abstract

La présente invention concerne un procédé amélioré de préparation du monohydrate de dapagliflozine propanediol de formule (I). L'invention concerne en outre un procédé amélioré pour la préparation d'un intermédiaire sensiblement pur de formule (VI) ayant un taux d'impuretés des-bromo de formule (VIII) inférieur à 0,15 %.
PCT/IB2021/055609 2020-06-25 2021-06-24 Procédé amélioré de préparation de monohydrate de dapagliflozine-propanediol WO2021260617A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202021027042 2020-06-25
IN202021027042 2020-06-25

Publications (1)

Publication Number Publication Date
WO2021260617A1 true WO2021260617A1 (fr) 2021-12-30

Family

ID=79282650

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2021/055609 WO2021260617A1 (fr) 2020-06-25 2021-06-24 Procédé amélioré de préparation de monohydrate de dapagliflozine-propanediol

Country Status (1)

Country Link
WO (1) WO2021260617A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020137903A1 (en) * 1999-10-12 2002-09-26 Bruce Ellsworth C-aryl glucoside SGLT2 inhibitors and method
US20040138439A1 (en) * 2003-01-03 2004-07-15 Deshpande Prashant P. Methods of producing C-aryl glucoside SGLT2 inhibitors
WO2015040571A1 (fr) * 2013-09-23 2015-03-26 Ranbaxy Laboratories Limited Méthode de préparation de dapagliflozine
US20160237054A1 (en) * 2013-09-27 2016-08-18 Sun Pharmaceutical Industries Limited Process for the purification of dapagliflozin

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020137903A1 (en) * 1999-10-12 2002-09-26 Bruce Ellsworth C-aryl glucoside SGLT2 inhibitors and method
US20040138439A1 (en) * 2003-01-03 2004-07-15 Deshpande Prashant P. Methods of producing C-aryl glucoside SGLT2 inhibitors
WO2015040571A1 (fr) * 2013-09-23 2015-03-26 Ranbaxy Laboratories Limited Méthode de préparation de dapagliflozine
US20160237054A1 (en) * 2013-09-27 2016-08-18 Sun Pharmaceutical Industries Limited Process for the purification of dapagliflozin

Similar Documents

Publication Publication Date Title
TWI465458B (zh) 製備經葡萄哌喃糖基取代之苯甲基苯衍生物之方法
JPWO2006006496A1 (ja) アズレン誘導体の製造方法及びその合成中間体
CA2512389A1 (fr) Procedes de production d'inhibiteurs de c-aryle glucoside sglt2
WO2016041508A1 (fr) Procédé de préparation d'un composé oxazolidinone et de son intermédiaire
WO2018142422A1 (fr) Procédé de préparation de dapagliflozine
JP2021193102A (ja) １−シアノ−２−（４−シクロプロピル−ベンジル）−４−（β−Ｄ−グルコピラノス−１−イル）−ベンゼン、Ｌ−プロリンおよび水からなる１：１：１共結晶の合成
WO2016147197A1 (fr) Nouveau procédé de préparation de (2s,3r,4r,5s,6r)-2-[4-chloro-3-(4-éthoxybenzyl)phényl]-6-(hydroxyméthyl)tétrahydro-2h-pyran-3,4,5-triol et sa forme amorphe
WO2007049295A2 (fr) Procede en recipient unique ameliore pour generer un produit intermediaire cle de gemcitabine hcl
CN113874359A (zh) 用于制备1-脱氧-1-甲基氨基-d-葡萄糖醇2-(3,5-二氯苯基)-6-苯并噁唑羧酸盐的方法
CN112771035A (zh) 用于制备甘露糖衍生物的方法
WO2008009970A2 (fr) Procédé
WO2021260617A1 (fr) Procédé amélioré de préparation de monohydrate de dapagliflozine-propanediol
US11661406B2 (en) Method for producing intermediate useful for synthesis of SGLT inhibitor
WO2017071813A1 (fr) Procédé de préparation d'un agent pharmaceutique
US10703772B2 (en) Processes for the preparation of SGLT-2 inhibitors, intermediates thereof
WO2016142950A1 (fr) Nouveau procédé de préparation de (2s,3r,4r,5s,6r)-2-{3-[5-[4-fluoro-phényl)-thiophén-2-ylméthyl]-4-méthyl-phényl}-6-hydroxyméthyl-tétrahydro-pyran-3,4,5-triol et de sa forme semi-hydratée amorphe stable
RU2394835C2 (ru) Способ получения тиофенгликозидных производных
EP4320137A1 (fr) Procédé de synthèse de chlorure de nicotinamide riboside (nrcl)
JP3138834B2 (ja) フコピラノース類縁体の製造方法およびその合成中間化合物
US11548906B2 (en) Processes for the preparation of SGLT-2 inhibitors, intermediates thereof
CN114456217A (zh) 一种烯糖化合物的合成方法
WO2017060925A1 (fr) Nouveau co-cristaux d'acide pipécolique de dapagliflozine et leur procédé de préparation
WO2018220513A1 (fr) Procédé amélioré de préparation d'acide obéticholique
EP3521293B1 (fr) Procédé de préparation d'un inhibiteur de la phosphodiestérase 4
US20180319833A1 (en) Method of preparation of 6-azido-2,4-diacetamido-2,4,6-trideoxy-D-mannose

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21828552

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21828552

Country of ref document: EP

Kind code of ref document: A1