Improved Synthesis Of New Drug TW9186

TW9186 was the first launched poly(ADP-ribose)polymerase inhibitor developed by AstraZeneca for the treatment of BRCA mutation-associated ovarian cancer.It has received EMA and FDA approval in December 2014.This drug has not been launched in China and the cost is expensive.The preparation process study of TW9186 has great practical value.This paper consists three parts:Part One: Selected a better synthetic method through comparing the TW9186 synthetic methods reported in literatures: TW9186 was synthesized including 2-carboxybenzaldehyde reacting with dimethyl phosphonate to get phosphorus ylide,Wittig-Horner reaction,hydrolyzation,cyclization to get the key intermediate 2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid,chloroformylation and reaction with 4-cyclopropyl carbonyl piperazine.The process were improved including the preparation of phosphorus ylide,Wittig-Horner reaction and acylation.The overall yield was 38.9%(starting from 2-carboxybenzaldehyde)which was 7% higher than the yield reported in literature.The improved process has lowered the cost,shortened the reaction time and simplified the operation which may be more suitable for industrial production.Part Two: A new synthetic route to 2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid has been designed: It was synthesized from 2-carboxybenzaldehyde via reacting with dimethyl phosphonate,Wittig-Horner reaction and cyclization.Reaction conditions for all steps were optimized.The overall yield was 70.9%(starting from 2-carboxybenzaldehyde)which was 5% higher than the yield reported in literature.The advantages of this route included high yield,mild reaction condition,easy to control,simple post-processing and suitable for industrial production.Part Three: A new synthetic route to TW9186 has been designed: TW9186 was synthesized including 2-fluoro-5-formylbenzonitrile's hydrolyzation,chloroformylation,reacting with 4-cyclopropyl carbonyl piperazine to get the key intermediate 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)-4-fluorobenzaldehyde,WittigHorner reaction and cyclization.The overall yield was 36.7%(starting from 2-fluoro-5-formylbenzonitrile)which was higher than the yield reported in literature.The structures of intermediate and TW9186 were confirmed by HRMS,IR and 1H NMR.The advantages of this route included high yield,low cost,short reaction time and simple operation.