WO2021250565A1 - Procédé amélioré de préparation d'empagliflozine et de son polymorphe cristallin - Google Patents

Procédé amélioré de préparation d'empagliflozine et de son polymorphe cristallin Download PDF

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Publication number
WO2021250565A1
WO2021250565A1 PCT/IB2021/055030 IB2021055030W WO2021250565A1 WO 2021250565 A1 WO2021250565 A1 WO 2021250565A1 IB 2021055030 W IB2021055030 W IB 2021055030W WO 2021250565 A1 WO2021250565 A1 WO 2021250565A1
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WIPO (PCT)
Prior art keywords
empagliflozin
formula
acid
preparation
solid
Prior art date
Application number
PCT/IB2021/055030
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English (en)
Inventor
Sudhir Nambiar
Goverdhan Gilla
Suresh DOKE
Ramshanker SINGH
Ramesh Mokal
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Hikal Limited
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Publication date
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Publication of WO2021250565A1 publication Critical patent/WO2021250565A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to an improved process for preparation of Empagliflozin of formula (I).
  • the invention further relates to preparation of crystalline form of Empagliflozin and its particle size having coarser particle or Dsoequal or greater than 60 pm and D ⁇ equal or greater than 180 pm.
  • Empagliflozin is chemically known as l-chloro-4-(p-D-glucopyranos-l-yl)-2-[4-((S)- tetrahydrofuran-3-yloxy)-benzyl]-benzene. It is indicated for the treatment of type-2 diabetes. It is marketed under the brand name JARDIANCE ® .
  • the U.S. Patent no. 7,579,449B2 discloses Empagliflozin, stereoisomers, mixtures and salts thereof, and a pharmaceutical composition containing Empagliflozin. It also disclosed the preparation of Empagliflozin using tetrahydrofuran-3-yl(R)-toluene-4- sulphonate. The document does not disclose the preparation and process for isolation of its crystalline form.
  • the U.S. Patent no. 7,772,191B2 discloses the preparation of Empagliflozin by coupling of 2,3,4,6-tetrakis-0-(trimethylsilyl)-D-glucopyranone (TMS-gluconolactone) with (S)-3-[4-(5-bromo-2-chloro-benzyl)-phenoxy]-tetrahydrofuran (Bromo intermediate) using butyllithium (BuLi) in presence of C3-C4-alkylmagnesium chloride or bromide such as isopropylmagnesium chloride (i-PrMgCl) or butylmagnesium chloride (BuMgCl) and with or without lithium chloride (LiCl), followed by methylation, reduction using triethylsilane, boron trifluoride etherate and finally Empagliflozin isolated in isopropyl acetate and water.
  • TMS-gluconolactone 2,3,
  • the U.S. Patent no. 7,713,938B2 discloses the crystalline form of Empagliflozin which is isolated inmethanol, ethanol, isopropanol, ethyl acetate, diethylether, acetone, water and mixture.
  • the patent application no. IN201621015480 discloses the preparation of pure stable crystalline Empagliflozin by coupling of TMS-glucono lactone and Bromo intermediate using n-BuLi, methylation using methanesulphonic acid, methanol, followed by reduction using triethyl silane, boron trifluoride etherate and crystallization of Empagliflozin using methanol, ethanol, isopropanol or n-propanol.
  • the patent application no. IN201711011423 discloses the preparation of Empagliflozin by coupling TMS-gluconolactone and (3S)-3-[4-[(2-Chloro-5- iodophenyl)methyl]phenoxy]-tetrahydrofuran (Iodo compound), methylation, reduction, acetylation to formtetraacetyl Empagliflozin & further deacetylation to obtain Empagliflozin.
  • solvents methanol, ethanol, isopropanol, n-propanol or mixture thereof or using ethyl acetate, propyl acetate, butyl acetate or mixture thereof with anti solvents such as cyclopentane, cyclohexane, cycloheptane, cycloctane, n-pentane, n- hexane
  • the patent pubhcation W02010092126A1 discloses composition of Empagliflozin wherein particle size distribution Dyolcss than 200 pm provides good dissolution profile, good bioavailability and allows high content uniformity.
  • Another patent publication W02020058095A1 discloses a composition of Empagliflozin where Empagliflozin particle size distribution D90 in arrange between 25 pm up to 500 pm to exhibit good dissolution profile and high bioavailability.
  • the supply and maintenance of inventory of various particle size as per demand of formulators is practically difficult.
  • One aspect of the present invention is to provide an improved process for the preparation of Empagliflozin of formula (I).
  • the present invention relates to an improved process for the preparation of Empagliflozin of formula (I) using organolithium reagent, Lewis acid and catalyst.
  • the present invention relates to an improved process for the preparation of Empagliflozin of formula (I) which involve single step for solid isolation, where the process comprising of sequential reaction steps: a) coupling a glycoside of formula (II) where TMS is trimethylsilyl, with compound of formula (III) using organolithium reagent in presence of a catalyst in a solvent to obtain compound of formula (IV); b) methylating the hydroxy group using methanol in presence of acid to obtain compound of formula (V), and; c) demethoxylation using a reducing agent in presence of Lewis acid in a solvent to obtain Empagliflozin of formula (I).
  • the present invention where Empagliflozin is further isolated in ethanol and o-xylene to obtain crystalline form of Empagliflozin.
  • the present invention relates to an improved process for the preparation of crystalline form of Empagliflozin of formula (I) which comprising the steps of: a) dissolving Empagliflozin of formula (I) in a mixture of ethanol and o-xylene; b) cooling the reaction mixture to precipitate the solid; c) isolating the obtained solid; d) drying the solid.
  • the present invention where Empagliflozin is further isolated in water to obtain a coarser particle size D50 equal or greater than 450 pm and D90 equal or greater than 900 pm.
  • the present invention relates to a process to obtain coarser particle size of Empagliflozin of formula (I) having particle size D50 equal or greater than 450 pm and D90 equal or greater than 900 pm which comprising the steps of: a) heating Empagliflozin of formula (I) in water; b) cooling the reaction mixture to precipitate the solid; c) isolating the obtained solid; d) drying the solid.
  • the present invention relates to a process to obtain Empagliflozin of formula (I) having particle size Dsoequal or greater than 60 pm and D ⁇ equal or greater than 180 pm which comprising the steps: a) dissolving Empagliflozin of formula (I) in a mixture of ethanol and o-xylene; b) cooling the reaction mixture to precipitate the solid; c) isolating the obtained solid; d) drying the solid.
  • FIG. 1 shows an X-ray powder diffractogram of the crystalline form of Empagliflozin of formula (I) prepared as per example 2.
  • FIG. 2 shows the DSC thermogram of the crystalline form Empagliflozin of formula (I) prepared as per example 2.
  • FIG. 3 shows the specimen of particle size distribution data of Empagliflozin of formula (I) prepared as per example 2.
  • FIG. 4 shows the specimen of particle size distribution data of Empagliflozin of formula (I) prepared as per example 3.
  • Dsoequal or greater than 60pm refers to 50% of the volume of particles of Empagliflozin of formula (I) have a diameter equal or greater than 60 pm.
  • Dsoequal or greater than 450pm refers to 50% of the volume of particles of Empagliflozin of formula (I) have a diameter equal or greater than 450 pm.
  • Dyoequal or greater than 180pm refers to 90% of the volume of particles of Empagliflozin of formula (I) have a diameter equal or greater than 180 pm.
  • Dyoequal or greater than 900 pm refers to 90% of the volume of particles of Empagliflozin of formula (I) have a diameter equal or greater than 900 pm.
  • the instant invention provides the preparation of Empagliflozin, wherein the compounds of formula (IV), (V) were not isolated, thus the process is economic.
  • the present invention relates to an improved process for the preparation of Empagliflozin of formula (I) without using alkyl magnesium halide or lithium halide in coupling reaction.
  • the organohthium reagent is selected from the group consisting of n-, sec- or tert-butyllithium (BuLi), n-hexyllithium and the like.
  • the catalyst is selected from the group consisting of boron trifluoride etherate, trimethylsilyl chloride or triflate and the like.
  • the solvent used in coupling reaction is selected from the group consisting of toluene, diethylether, tetrahydrofuran (THF), hexane, heptane, dioxane, dimethyl sulfoxide (DMSO), chlorinated solvents such as dichloro methane (DCM), and the like or mixture of solvents thereof.
  • the acid used in methylation step is selected from methane sulfonic acid, toluene sulfonic acid, sulfuric acid, acetic acid, trifluoro acetic acid, and hydrochloric acid.
  • the methylation reaction is carried at temperature -80°C to 40°C.
  • the reducing agents used is selected from triethyl silane, tripropylsilane, triisopropylsilane, diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, and diisobutylaluminum hydride.
  • the Lewis acid used is selected from aluminium chloride, boron trifluoride etherate, trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, copper(II) triflate, zinc iodide, hydrochloric acid, toluene sulfonic acid, trifluoroacetic acid, and acetic acid.
  • the solvent used in step of demethoxylation is selected from acetonitrile, dichloro methane, chloroform, toluene, hexane, diethylether, tetrahydrofuran, dioxane, ethanol, water, or mixtures thereof.
  • the solvent used for preparing crystalline form of Empagliflozin of formula (I) is mixture of ethanol and oxylene.
  • the present invention relates to an improved process for the preparation of crystalline form of Empagliflozin of formula (I) or an improved process for the preparation of Empagliflozin of formula (I) with particle size Dsoequal or greater than 60 pm and D 9 oequal or greater than 180 pm wherein the solution of Empagliflozin of formula (I) is cooled to 20°C to 30°C for 4 to 12 hours (hr).
  • drying of the solid in is carried at 25°C to 30°C for 2 to 3 hours and/or further dried at 70°C to 80°C for 8 to 12hours.
  • the Empagliflozin having coarser particles or particle size Dsoequal or greater than 60 pm and Dwequal or greater than 180 pm can further micronized or milled by the conventional methods like jet milling, cad milling or multi milling to get smaller particle size required to meet the need of formulator.
  • the Empagliflozin particle size may differ based on type of reactor and speed of the agitator, which should not be construed to limit the scope of the invention in anyway.
  • the crystalline Empagliflozin of formula (I) is having an X-ray diffraction pattern that comprises peaks at 14.69, 18.84, 19.16, 19.50, 20.36 and 25.21 degrees 2Q ⁇ 0.05 degrees 2Q.
  • the X-ray diffraction pattern is shown in FIG. 1.
  • crystalline Empagliflozin of formula (I) is further characterized using Differential Scanning Calorimetry (DSC 3+), measured using a Differential Scanning calorimeter from Mettler Toledo.
  • particle size is measured by using Malvern particle size analyzer MS 3000.
  • Example 3 Preparation of Empagliflozin of formula (I)particle size D50 equal or greater than 450 pm and D90 equal or greater than 900 pm

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé amélioré pour l'élaboration d'Empagliflozine de formule (I). L'invention concerne en outre la préparation d'une forme cristalline d'Empagliflozine et sa grosseur de particule présentant une particule plus grossière ou un D50 égal ou supérieur à 60 µm et un D90 égal ou supérieur à 180 µm. (I)
PCT/IB2021/055030 2020-06-10 2021-06-08 Procédé amélioré de préparation d'empagliflozine et de son polymorphe cristallin WO2021250565A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202021024385 2020-06-10
IN202021024385 2020-06-10

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WO2021250565A1 true WO2021250565A1 (fr) 2021-12-16

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4378455A1 (fr) 2022-11-29 2024-06-05 Sanovel Ilac Sanayi Ve Ticaret A.S. Formulation pharmaceutique comprenant de l'empagliflozine

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006117359A1 (fr) * 2005-05-03 2006-11-09 Boehringer Ingelheim International Gmbh FORME CRISTALLINE DE 1-CHLORO-4-(ß-D-GLUCOPYRANOS-1-YL)-2-[4-((S)-TETRAHYDROFURAN-3-YLOXY)-BENZYL]-BENZENE, SON PROCEDE DE PREPARATION ET SON UTILISATION DANS LA PREPARATION DE MEDICAMENTS
WO2006120208A1 (fr) * 2005-05-10 2006-11-16 Boehringer Ingelheim International Gmbh Procedes de preparation de derives de benzylbenzene a substitution glucopyranosyl et intermediaires obtenus selon ces procedes
US7579449B2 (en) * 2004-03-16 2009-08-25 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
WO2011039107A1 (fr) * 2009-09-30 2011-04-07 Boehringer Ingelheim International Gmbh Procédé de préparation d'une forme cristalline de 1-chloro-4-(β-d-glucopyranos-1-yl)-2-[4-((s)-tétrahydrofuran-3-yloxy)-benzyl]-benzène
WO2018011721A1 (fr) * 2016-07-15 2018-01-18 Granules India Limited Nouvelles formes polymorphes de ((1s,2s,3s,4r,5s))-2,3,4-(tris-benzyloxy)-5-(4-chloro-3-(4-éthoxy-benzyl)phényl)-6,8-dioxa-bicyclo[3.2.1]oct-1-yl-méthanol
US20200331946A1 (en) * 2017-05-30 2020-10-22 Emmennar Pharma Private Limited Processes for the preparation of sglt-2 inhibitors, intermediates thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7579449B2 (en) * 2004-03-16 2009-08-25 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
WO2006117359A1 (fr) * 2005-05-03 2006-11-09 Boehringer Ingelheim International Gmbh FORME CRISTALLINE DE 1-CHLORO-4-(ß-D-GLUCOPYRANOS-1-YL)-2-[4-((S)-TETRAHYDROFURAN-3-YLOXY)-BENZYL]-BENZENE, SON PROCEDE DE PREPARATION ET SON UTILISATION DANS LA PREPARATION DE MEDICAMENTS
WO2006120208A1 (fr) * 2005-05-10 2006-11-16 Boehringer Ingelheim International Gmbh Procedes de preparation de derives de benzylbenzene a substitution glucopyranosyl et intermediaires obtenus selon ces procedes
WO2011039107A1 (fr) * 2009-09-30 2011-04-07 Boehringer Ingelheim International Gmbh Procédé de préparation d'une forme cristalline de 1-chloro-4-(β-d-glucopyranos-1-yl)-2-[4-((s)-tétrahydrofuran-3-yloxy)-benzyl]-benzène
WO2018011721A1 (fr) * 2016-07-15 2018-01-18 Granules India Limited Nouvelles formes polymorphes de ((1s,2s,3s,4r,5s))-2,3,4-(tris-benzyloxy)-5-(4-chloro-3-(4-éthoxy-benzyl)phényl)-6,8-dioxa-bicyclo[3.2.1]oct-1-yl-méthanol
US20200331946A1 (en) * 2017-05-30 2020-10-22 Emmennar Pharma Private Limited Processes for the preparation of sglt-2 inhibitors, intermediates thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4378455A1 (fr) 2022-11-29 2024-06-05 Sanovel Ilac Sanayi Ve Ticaret A.S. Formulation pharmaceutique comprenant de l'empagliflozine

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