title: An efficient and safe process for the preparation of ticagrelor, a platelet aggregation inhibitor via resin-NO2 catalyzed formation of triazole ring.
abstract: An efficient, safe and improved process for the preparation of ticagrelor 1, a platelet aggregation inhibitor is described. Synthesis comprises the condensation of pyrimidine amine derivative 14 with cyclopentyl derivative 13 in ethylene glycol followed by construction of triazole compound 16 by diazotization of the obtained intermediate 15 with a green and safer reagent "Resin-NO2" in water and acetonitrile mixture. Condensation of 16 with cyclopropylamine derivative 10 followed by deprotection of compound 12 with hydrochloric acid in dichloromethane (DCM) furnished ticagrelor 1 with an overall yield of 65 % and purity of 99.78 % by HPLC. Each reaction stage was optimized independently to establish the scalable and plant friendly process. An efficient and a safe process for key intermediate 14 which involve nitration reaction has also been developed. Safety parameters were established by understanding the thermal events of the reaction by DSC analysis.Graphical abstractSynthesis of ticagrelor via resin-NO2 catalysed formation of triazole ring.
authors.affiliation: Department of Process Research and Development, Megafine Pharma (P) Ltd., 201, Lakhmapur, Dindori, Nashik, 422 202 Maharashtra India.
authors.forename: Gorakshanath B
authors.initials: GB
authors.lastname: Shinde
authors.affiliation: Department of Process Research and Development, Megafine Pharma (P) Ltd., 201, Lakhmapur, Dindori, Nashik, 422 202 Maharashtra India.
authors.forename: Pravin K
authors.initials: PK
authors.lastname: Mahale
authors.affiliation: Department of Process Research and Development, Megafine Pharma (P) Ltd., 201, Lakhmapur, Dindori, Nashik, 422 202 Maharashtra India.
authors.forename: Santhosh A
authors.initials: SA
authors.lastname: Padaki
authors.affiliation: Department of Process Research and Development, Megafine Pharma (P) Ltd., 201, Lakhmapur, Dindori, Nashik, 422 202 Maharashtra India.
authors.forename: Navnath C
authors.initials: NC
authors.lastname: Niphade
authors.affiliation: Department of Chemistry, Organic Chemistry Research Center, KTHM College, Gangapur Road, Nashik, 422002 India.
authors.forename: Raghunath B
authors.initials: RB
authors.lastname: Toche
authors.affiliation: Department of Process Research and Development, Megafine Pharma (P) Ltd., 201, Lakhmapur, Dindori, Nashik, 422 202 Maharashtra India.
authors.forename: Vijayavitthal T
authors.initials: VT
authors.lastname: Mathad
keywords: Arterial thrombosis; Diazotization; Nitration; Resin-NO2; Ticagrelor; Triazole