Synthesis Process Optimization Of RDEA3170 And Synthesis Of Talazoparib Derivatives

RDEA3170 is a new generation drug which can promote uric acid excretion for the treatment of hyperuricemia.The PARP inhibitor Talazoparib is a targeted anticancer drug that can be used in combination to kill cancer cells,or it can be used alone to kill cancer cells with BRCA deficiency.The research content consists of two parts:?1?Synthetic Process Optimization of RDEA3170:a synthesis method of4-bromo-1-naphthonitrile?4?from 1,4-dibromonaphthalene was optimized by bromo-magnesium exchange reaction,carboxylation,amidation and dehydration.In the presence of catalyst Pd?PPh₃?₂Cl₂,the Miyaura borylation of 4-bromo-1-naphthonitrile to form 4-?4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl?-1-naphthonitrile?5?and the Suzuki coupling 5with ethyl 2-?3-bromopyridin-2-ylthio?-2-methylpropanoate?1?to generate ethyl2-?3-?4-cyanonaphthalen-1-yl?pyridin-2-ylthio?-2-methylpropanoate?6?were realized by a continuous reaction procedure.The optimum conditions were as follows:n[?BPIN?₂]:n?4?:n?1?:n[Pd?PPh₃?₂Cl₂]:n?KOAc?:n?K₂CO₃?=1.1:1:1:0.06:3:3.KOAc and K₂CO₃used as bases respectively for the Miyaura borylation and Suzuki coupling were added in turn,and the corresponding reaction temperature and time were 80?for 2 h and 110?for 12 h.RDEA3170 was obtained by hydrolysis of compound 6 and was characterized by¹HNMR.The overall yield of RDEA3170 is up to 42%and this optimized synthetic process is suitable for industrial production.?2?Synthesis of Talazoparib derivatives:three keto-ester compounds were firstly prepared by nucleophilic addition and lactone ring-opening of6-fluoro-4-nitro-3H-isobenzofuran-1-one with benzaldehyde,4-fluorobenzaldehyde and4-?4-?cyclopropanecarbonyl?piperazine-1-carbonyl?benzaldehyde respectively.And then five novel Talazoparib derivatives were produced by aldol condensation and cyclization of the keto-ester compounds with benzo[d][1,3]dioxole-5-carbaldehyde and benzofuran-5-carbaldehyde.The overall yield is up to 32.9-42.6%.Their bioactivity test is ongoing.