The Synthesis Research Of Antiepileptic Drug Brivaracetam

Brivaracetam(BRV,1),as the third generation antiepileptic drug developed by Belgium UCB Pharmaceuticals,can excert its antiepileptic effect by affecting synaptic function through selective reversible binding to central synaptic vesicle protein 2A(SV2A).It has been approved in Europe and the USA on Jan 1,2016 and Feb 18,2016,respectively,for the adjunctive treatment of focal-onset seizures with or without secondary generalization in patients aged 16 years or older.It obtained FDA Supplemental New Drug Application Approval on Sep 15,2017,which can be used as a monotherapy for focal seizures in patients with epilepsy over 16 years or older.And it has been applied for import registration in China on March 6,2017 by UCB,with no domestic manufacturers reported.In this dissertation,we studied the synthesis methods of BRV,and an asymmetric synthesis route was determined as the final one.We have optimized the synthesis process,completed scale-up experiments,synthesized related impurities and established a quality standards,which laid a solid foundation for CFDA registeration and industrialized production.The specific research content and results are as follows:Study on chemical resolution synthesis of BRV:A preliminary synthetic study was conducted on the BRV racemate(7).Using valeraldehyde(2)and glyoxylic acid hydrate(3)as raw materials,the racemate 7 was obtained through condensation,ionization,aminolysis and hydrogenation in four steps,yield 44.8%,with a chemical purity of 100%.Based on the synthesis route of the racemate,a chemical resolution route was designed.Starting from 5-hydroxy-4-propylfuran-2-one(4),chemical precursor 16 was obtained with a yield of 21.6% and the required configuration 72.21% through condensation,hydrogenation and hydrolysis in three steps.However,an attempt to revolve 16 through chiral amines did not succeed.Study on asymmetric synthesis of BRV:Based on previous investigations,an asymmetric synthesis route was designed to obtain BRV using chiral auxiliaries: valeric acid(57)and chiral auxiliary(S)-4-benzyl-2-oxazolidone(58)as the raw material,the final product 1 was obtained through amidation,? substitution,hydrolysis,ring formation,ring opening,esterification,and condensation in 7 steps,and the yield was 20.51%,with a chemicalpurity of 99.86%,e.e.value 100% and d.e.value 100%,better than literature reported(e.e.value 97.1%).The main achievements and innovations of this route are illustrated as follows:1)An asymmetric synthesis route with mild conditions,simplized synthesis and high overall yield was designed and developed to prepare high-purity BRV;2)Obtained qualified final chrial product,with structural confirmation,chemical and optical purity higher than literature reported;3)Optimized reaction conditions and workup process,completed 100-gram scale preparation.The unit operations are simple and the raw materials are cheap and easy to obtain,the yield of four steps were higher than literature reported,all provide a practical synthesis suitable for industrial scale-up;4)Synthesized 9 synthetic process impurities and 5 related substances of BRV,established quality control method of final product and key intermediate.In summary,the synthesis of BRV was studied in this dissertation,and an asymmetric synthesis route was determined as the final route.We optimized the process,synthesized related impurities,established an analysis method and completed100-gram scale amplification experiment,which laid a solid foundation for CFDA registeration and industrialized production.