WO2017072790A1 - Procédé amélioré pour la synthèse de ticagrelor - Google Patents

Procédé amélioré pour la synthèse de ticagrelor Download PDF

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Publication number
WO2017072790A1
WO2017072790A1 PCT/IN2016/050362 IN2016050362W WO2017072790A1 WO 2017072790 A1 WO2017072790 A1 WO 2017072790A1 IN 2016050362 W IN2016050362 W IN 2016050362W WO 2017072790 A1 WO2017072790 A1 WO 2017072790A1
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WIPO (PCT)
Prior art keywords
ticagrelor
amino
dioxol
oxy
improved
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PCT/IN2016/050362
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English (en)
Inventor
Ramakrishna Rao
Ramadevi Nandipati
Mukesh Padmakar SHEWALKAR
Veerabhadra Reddy BOGIREDDY
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Avra Laboratories Pvt. Ltd.
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Application filed by Avra Laboratories Pvt. Ltd. filed Critical Avra Laboratories Pvt. Ltd.
Publication of WO2017072790A1 publication Critical patent/WO2017072790A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to an improved and cost effective process for preparation of Ticagrelor in good yield and purity.
  • the invention further relates to novel Polymorphic Form of Ticagrelor and its process for preparation thereof.
  • Ticagrelor is indicated for the treatment or prevention of thrombotic actions such as stroke, acute coronary syndrome or myocardial infections, heart attack, other coronary and arterial disorders. It is marketed by Astra Zeneca under the trade name Brilinta in USA and Russia, Brilique and Possia in E urope.
  • Ticagrelor The synthetic process for Ticagrelor is reported in W 000034283 by AstraZeneca. Five to six known synthetic process variants are described in said basic patent application WO 83.
  • the improved processes for preparation of Ticagrelor are provided in WO01/92263 and WO10/ 030224 respectively derived from the origi nator A stra Z eneca.
  • Patent/Patent A pplications which describe the synthesis of Ticagrelor or its related salts, enantiomers are described in U.S. Patent Nos. 6,251,910; 6,525,060; 6,974,868; 7,067,663; and 7,250,419; U.S. Patent application Nos. 2007/0265282, 2007/0293513 and 2008/0214812; and E uropean Patent Nos. E P0996621, E P1135391, E P2570405, E P2586773 and PCT published documents viz. WO2011017108, WO2012138981 , WO2013150495 and WO2014102830.
  • a MA L C INA with isopentyl nitrite (iAmONO) produced 3aR- (3a , 4 , 6 , 6a )-6- 7-Chloro-5- (propylthio)-3H-1,2, 3-triazolo[4,5-d]pyrimidin-3-yl-tetrahydro-2,2-dimethyl4H- cyclopenta-1,3-dioxol-4-ol (C LTA M) which was treated with ammonia to form 3aR- (3a , 4 , 6 , 6a )-6- 7-Amino-5- (propylthio)-3H-1,2,3-triazolo [4,5- d] pyri mi di n-3-yl -tetrahydro-2,2-di methyl -4H -cycl openta- 1 , 3-di oxol -4-ol
  • ATA M The side chain was introduced by reacting ATA M with n-butyl lithium and methyl2-((( trifluoromethyl)sulfonyl)oxy)acetate to 3aR- (3a , 4 , 6 , 6a )]- [[6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl-tetrahydro- 2,2-dimethyl-4H-cyclo penta-1, 3-dioxol-4-ol oxy] acetic acid, methyl ester (MATA M).
  • Ticagrelor deprotection of the diol group using trifluoroacetic acid yielded Ticagrelor.
  • the process described is lengthy, uses toxic chemicals such as C H Br3, triflic anhydride and methyl 2-((( trifluoromethyl)sulfonyl)oxy)acetate.
  • a MA LA is then reacted with 4, 6-dichloro-2- (propylsulfanyl)-5-pyrimidinamine (C L INA) in presence of triethylamine to form [3aR- (3a , 4 , 6 , 6a )]-2- [ [6- [ [5-amino-6-chloro-2- ( propyl thio) -4- pyrimidinyl] amino] tetrahydro-2,2-dimethyl-3aH-cyclopenta [d] [1,3] dioxol-4yl] oxy] ethanol (A MAL CINAA).
  • the triazole ring is further introduced by reacting A MAL C INAA with NaN0 2 /AcOH to give [3aR- (3a , 4 , 6 , 6a )]-2- [ [6- [7- chloro-5- (propylthio)-3- [1, 2,3] triazolo [4,5-d] pyriinidin-3-yl] tetrahydro-2,2- dimethyl-3aHcyclopenta [d] [1, 3] dioxol-4-yl] oxy] ethanol (C LTA M).
  • the process disclosed in WO ⁇ 108 is lengthy and employs corrosive chemicals such as LiAlhU. Further, W 00192262 has reported the Polymorphic Forms I to IV of Ticagrelor.
  • the process for preparing Polymorph I comprises obtaining a few seed crystals of Polymorph I from the slow crystal growth of Polymorph I from a melt of Polymorph II, and using this to seed a reaction mixture comprising of the compound of formula (I), and a suitable mixed solvent system such as methanol /water.
  • the process for preparing Polymorph II comprises crystallisation in a suitable solvent such as ethyl acetate.
  • Preparation of Polymorph III comprises crystallisation in a suitable solvent such as an alcohol, for example ethanol or isopropyl alcohol (IPA), in particular seeding with crystals of Polymorph III or slurrying a compound of formula (I) in a suitable solvent such as IPA.
  • a suitable solvent such as an alcohol, for example ethanol or isopropyl alcohol (IPA)
  • Polymorph IV is obtained by crystallisation from a suitable solvent such as acetonitrile, in particular seeding with crystals of Polymorph IV or a period of slurrying a compound of formula (I) in a suitable solvent such as acetonitrile.
  • the present inventors therefore felt a need to provide a process which is short, industrially feasible and economically improved.
  • the present invention provides optimized reaction conditions and optimal use of reagents and avoiding hazardous chemicals.
  • the process according to the present invention increases the efficiency of the reaction and results in product with high purity and improved yield.
  • the present invention in its preferred aspect discloses an improved and cost effective process for synthesis of Ticagrelor comprising the steps of:
  • step (ii) Reacting compound of step (i) with sodium nitrite and acetic acid in DC M as solvent to obtain [3aR- (3a , 4 , 6 , 6a )]-2- [ [6- [7-chloro-5- ( propyl thio) -3- [1, 2,3] triazolo [4,5-d] pyrimidin-3-yl] tetrahydro-2,2- di methyl -3aHcyclopenta [d] [1, 3] dioxol-4-yl] oxy] ethanol and the organic layer is taken as such without isolation;
  • step (iii) Reacting organic layer of step (ii) with (1 R,2S)-2-(3,4difluorophenyl) cyclopropyl amine HCI in presence of potassium carbonate to obtain ⁇ 3aR- [3a , 4 , 6a (IR*, 2S*), 6a ] ⁇ -2- [6- ( ⁇ 7- [2- (3, 4-difluorophenyI) cyclopropyl] amino- 5- (propylthio)-3H-1, 2,3-triazolo [4,5-d] pyrimidin-3- yl ⁇ tetrahydro-2,2dimethyl-4H-cyclopenta-1, 3-dioxol-4-yl) oxy] ethanol followed by purification using non-polar solvent; and
  • step (iv) Deprotecting compound of step (iii) in methanol using sulfuric acid to obtai n crude T i cagrel or.
  • the crude Ticagrelor is further crystallized from isobutyl acetate alone or in combination with aliphatic or aromatic hydrocarbon to obtain pure crystallized Ticagrelor Polymorph Form II.
  • the present invention provides a novel polymorphic Form of Ticagrelor, which is herein after referred as Form-V, characterized by PX RD pattern as shown in Fig 1, TGA in Fig 2 and DSC as shown in Fig 3 and to the process for preparation thereof.
  • F ig 1 depict the PX RD of Ticagrelor Polymorph Form-V
  • F ig 2 depict the TGA of Ticagrelor Polymorph Form-V
  • F ig 3 depict the DSC of Ticagrelor Polymorph Form-V
  • the present invention relates to a cost effective and industrially feasible process for preparation of Ticagrelor employing optimized reagents and reaction conditions.
  • step 1 comprises condensation of 4,6- Dichloro-2-propylthio-pyrimidine-5-amine with 2- ⁇ [(3aR,4S,6R,6aS)-6-amino- 2,2-dimethyl tetrahydro-3aH-cyclopenta[d][1,3]-dioxol-4-yl]oxy ⁇ -1 -ethanol,L- tartaric acid salt.
  • the reaction can be performed in presence of inorganic base selected from alkali or alkaline earth metal carbonates; preferably the reaction is carried using cesium carbonate.
  • concentration of cesium carbonate can be varied in the range of 1 to 2 mol equivalence.
  • the temperature of the reaction is maintained in the range of 50-110eC for a period of 6 to 24 hrs.
  • the reaction mixture is filtered and the solid is washed with water.
  • the obtained solid is further stirred with about 5 to 15 volumes of non- polar solvent selected from aliphatic or aromatic hydrocarbon such as n-hexane, iso- hexane, n- heptane, i so- heptane, toluene or the like either alone or in combination to obtain a slurry.
  • the temperature is maintained at either r.t or the reaction mixture is heated to about 80-90eC.
  • Step 2 of the present process comprises adding [3aR- (3a , 4 , 6 , 6a )]-2-[6-[5- amino-6-chloro-2-(propylthio)-4- pyrimidinyl] amino] tetrahydro-2,2-dimethyl- 3aH-cyclopenta [d] [1,3] dioxol-4yl] oxy] ethanol of step 1, acetic acid and DC M to the RB flask.
  • step 3 to the organic layer of step 2 is added (1 R,2S)-2- (3,4di fluorophenyl) cyclopropyl amine. HCI and stirred for about 10-20 minutes.
  • Added inorganic base selected from alkali or alkaline earth metal carbonates; preferably potassium carbonate in the concentration ranging from 1 mol% to 3 mol% and stirring for about 4 to 5 hours to obtain the compound ⁇ 3aR- [3a , 4 , 6 (IR*, 2S*) f 6a ] ⁇ -2- [6- ( ⁇ 7- [2- (3, 4-difluorophenyI) cyclopropyl] amino- 5- (propylthio)-3H-1, 2,3-triazolo [4,5-d] pyrimidin-3-yl ⁇ tetrahydro-2, 2di methyl - 4H-cyclopenta-1, 3-dioxol-4-yl) oxy] ethanol.
  • non- polar solvent selected from aliphatic or aromatic solvent such as n-hexane, iso-hexane, n-heptane, iso- heptane, toluene or the like either alone or in combination; followed by filtration to obtain the pure product.
  • Step 4 of the process comprises adding pure ⁇ 3aR- [3a , 4 , 6 (IR* 2S*), 6a ] ⁇ - 2- [6- ( ⁇ 7- [2- (3, 4- di fluorophenyl) cyclopropyl] amino- 5- (propylthio)-3H-1, 2,3-triazolo [4,5-d] pyrimidin-3-yl ⁇ tetrahydro-2,2dimethyl-4H-cyclopenta-1, 3- dioxol-4-yl) oxy] ethanol of step 3 and methanol to the RB flask and stirring for about 10 mins. This is followed by addition of 1 to 2 volumes of sulphuric acid at a temperature ranging from OeC to r.t.
  • pH of the reaction mixture is adjusted to 7-7.5 using 5 to 40% of aqueous solution of base selected from NaOH, KOH, carbonates or bi carbonates of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or the like.
  • base selected from NaOH, KOH, carbonates or bi carbonates of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or the like.
  • the solid obtained is filtered and dried to obtain crude Ticagrel or.
  • the crude Ticagrelor is crystallized in isobutyl acetate either alone or in combination with non-polar solvents selected from aliphatic or aromatic hydrocarbons at a temperature ranging from room temperature to 80eC to yield crystalline Ticagrelor.
  • the solvent for crystallization preferably is isobutyl acetate and toluene.
  • crude Ticagrelor is heated with isobutyl acetate using 2 volumes to 6 volumes, preferably 3 volumes, to a temperature in the range of 70-80eC for about an hour.
  • the reaction mass is cooled to room temperature and filtered to obtain pure crystalline Ticagrelor Polymorph, Form-II as shown in F ig A
  • crude Ticagrelor is heated with isobutyl acetate using 2 volumes to 6 volumes, preferably 3 volumes, in combination with non-polar solvent selected from aliphatic or aromatic solvent such as n-hexane, iso-hexane, n- heptane, iso-heptane, toluene or the like; preferably toluene, using 4 volumes to 12 volumes, preferably 6 volumes, at a temperature in the range of 70-80eC for about an hour.
  • the reaction mass is cooled to room temperature and filtered to obtain pure crystal line Ticagrelor Polymorph II as shown in F ig.4
  • the present invention discloses a novel Polymorph of Ticagrelor Form V, which is characterised by X -ray powder diffraction peaks at 5.5e (e0.2e), 5.7e (e0.2e), 6.9e (e0.2e), 11.1 e (e0.2e), 12.5e (e0.2e), 13.9e (e0.2e), 17.4e (e0.2e), 18.3e (e0.2e), 18.9e (e0.2e), 21.3e (e0.2e), 22.7e (e0.2e) 2 : :as shown in Fig 1.
  • novel polymorph Form V exhibits an endotherm at 133.9eC and an exotherm at 315.6eC as shown in Fig 3; the TGA analysis indicate that Polymorph Form V loses about 99.9% volatiles at 305eC as shown in Fig 2.
  • the process for preparation of novel Polymorph Form V of Ticagrelor comprises dissolving Ticagrelor in acetone at a temperature ranging from ambient temperature to about 60eC and precipitating the product using anti- solvent such as water or lower alcohols such as methanol or ethanol either alone or mixture thereof at a temperature ranging from ambient temperature to about 80eC, preferably at ambient temperature.
  • anti-solvent is preferably water.
  • the quantity of acetone used in the process is in the range of three to ten volumes, preferably about 3 volumes.
  • the quantity of the anti-solvent is used in the range of five to twenty five vol umes, preferably about ten vol umes.
  • reaction mixture was filtered and the solid was washed with 50 mL of water.
  • the solid was further stirred with 100 mL (2 vol) of heptane, filtered and the filter cake was washed with 50 mL of heptane and dried at 25-30eC for 2hr to obtain 16.2 g of product with 92% yield and H PLC purity 99%.
  • the crude Ticagrelor (16g, 0.0306 moles) was added to Isobutyl acetate (3vol.) and heated to 70-75eC for 1 hr. The reaction mass was cooled and Toluene (6 vol.) was further added. The solid formed was filtered to obtain pure crystalline Ticagrelor with Polymorph Form-II.
  • Ticagrelor was dissolved in three volumes acetone at ambient temperature and the product was precipitated by adding 10 volumes of water and the mixture was stirred for 2hr. The precipitate was filtered and dried. The product was obtained with 90% yield. It was characterized by, PX RD and DSC which confirmed that substantially pure Polymorph Form V has been formed.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne un procédé amélioré et économique de préparation de ticagrélor avec un bon rendement et une pureté satisfaisante. L'invention concerne en outre une nouvelle forme polymorphe de ticagrélor et son procédé de préparation.
PCT/IN2016/050362 2015-10-26 2016-10-26 Procédé amélioré pour la synthèse de ticagrelor WO2017072790A1 (fr)

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IN5743CH2015 2015-10-26
IN5743/CHE/2015 2015-10-26

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112457316A (zh) * 2020-11-05 2021-03-09 南通常佑药业科技有限公司 一种应用连续流反应技术制备替卡格雷高级中间体的方法

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US20070293513A1 (en) * 2000-06-02 2007-12-20 Astrazeneca Ab Cristalline and amorphous form of a triazolo (4,5-d) pyridimine compound
US20110218330A1 (en) * 2000-06-02 2011-09-08 Astrazeneca Ab Novel triazolo pyrimidine compounds
US20120101274A1 (en) * 2008-09-09 2012-04-26 Astrazeneca Ab Process For Preparing [1S-[1-alpha, 2-alpha, 3-beta (1S*,2R*) 5-beta]]-3-[7-[2-(3,4-difluorophenyl)-cyclopropylamino]-5-(propylthio)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-1,2-diol And To Its Intermediates
WO2013150495A2 (fr) * 2012-04-05 2013-10-10 Dr. Reddy's Laboratories Limited Préparation de ticagrelor
WO2014044846A1 (fr) * 2012-09-24 2014-03-27 Evotec (Uk) Ltd. Dérivés de 3-(aryl- ou hétéroaryl-amino)-7-(3,5-diméthoxyphényl)isoquinoline comme inhibiteurs de fgfr utiles pour le traitement de troubles prolifératifs ou de la dysplasie

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070293513A1 (en) * 2000-06-02 2007-12-20 Astrazeneca Ab Cristalline and amorphous form of a triazolo (4,5-d) pyridimine compound
US20110218330A1 (en) * 2000-06-02 2011-09-08 Astrazeneca Ab Novel triazolo pyrimidine compounds
US20120101274A1 (en) * 2008-09-09 2012-04-26 Astrazeneca Ab Process For Preparing [1S-[1-alpha, 2-alpha, 3-beta (1S*,2R*) 5-beta]]-3-[7-[2-(3,4-difluorophenyl)-cyclopropylamino]-5-(propylthio)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-1,2-diol And To Its Intermediates
WO2013150495A2 (fr) * 2012-04-05 2013-10-10 Dr. Reddy's Laboratories Limited Préparation de ticagrelor
WO2014044846A1 (fr) * 2012-09-24 2014-03-27 Evotec (Uk) Ltd. Dérivés de 3-(aryl- ou hétéroaryl-amino)-7-(3,5-diméthoxyphényl)isoquinoline comme inhibiteurs de fgfr utiles pour le traitement de troubles prolifératifs ou de la dysplasie

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Title
PELLON, RF ET AL.: "Mild Method for Ullmann Reaction of 2-Chlorobenzoic Acids and Aminothiazoles or Aminobenzothiazoles under Ultrasonic Irradiation.", SYNTHETIC COMMUNICATIONS, vol. 37, 2007, pages 1853 - 1864, XP055379006 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112457316A (zh) * 2020-11-05 2021-03-09 南通常佑药业科技有限公司 一种应用连续流反应技术制备替卡格雷高级中间体的方法

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