Discovery of tricyclic dipyrrolopyridine derivatives as novel JAK inhibitors

A Practical and Scalable Method for Manufacturing JAK Inhibitor ASP3627

“…Synthesis of ASP3627 via the discovery route is shown in Scheme . Protection of 4-chloro-1 H -pyrrolo­[2,3- b ]­pyridine-5-carbonitrile ( 2 ) with SEMCl gave 3 .…”

“… a Except for the solvent peak. b Discovery conditions (ref ): rac - 4 (1.1 equiv), DIPEA (3.0 equiv), NMP, 180 °C, 2 h, column chromatography. c (3 R ,4 R )- 4 (1.2 equiv), base (3.0 equiv), 130 °C, overnight. d (3 R ,4 R )- 4 (1.2 equiv), base (1.2 equiv), 120 °C, 7–20 h. e Crystallization with EtOH/H 2 O (7/3). DBU = 1,8-diazabicyclo[5.4.0]­undec-7-ene; NMM = 4-methylmorpholine; DMSO = dimethyl sulfoxide; DMAc = N , N -dimethylacetamide. …”

“… b Discovery conditions (ref ): rac - 4 (1.1 equiv), DIPEA (3.0 equiv), NMP, 180 °C, 2 h, column chromatography. …”

“… a Discovery conditions (ref ). b HPLC A%. DME = 1,2-dimethoxyethane; IPA = 2-propanol; IPE = diisopropyl ether. …”

“…Several JAK inhibitors (e.g., tofacitinib and ruxolitinib) have been approved by the U.S. Food and Drug Administration (FDA) and a number of others are under development. ASP3627 ( 1 ) (Figure ), a tricyclic dipyrrolopyridine derivative, was discovered by Astellas Pharma Inc. as a highly potent JAK inhibitor with good oral bioavailability, and is a promising candidate for the treatment of acute and chronic rejection in cardiac transplantation . While a discovery synthetic approach appears to be suitable for large-scale synthesis of ASP3627, there are a number of problems associated with manufacturing 30 kg of an active pharmaceutical ingredient (API).…”