The Synthesis And Process Optimization Of A New Route Of Buvasitan

Buvacetam is the third generation of antiepileptic drugs developed by Youshibi Pharmaceutical Co.,Ltd.It is used to treat partial seizures of epilepsy patients aged over 16 years and adults,and adjuvant therapy is accompanied or not accompanied by secondary generalized seizures.Bovacetam was approved by the European Medical Administration on January 14,2016 and by the Food and Drug Administration on February 18,2016.The main topic of this project includes,1.Two new synthetic routes of Bovacetam were designed and completed.In the first route,butyraldehyde was used as the starting material,and racemic 3-(2-amino-2-oxoethyl)-hexanoic acid was obtained by Knoevenagel condensation reaction,Micheal addition reaction and anhydride method,then R-3-aminomethyl-hexanoic acid was obtained by resolution and Holfman degradation reaction,and then Buvacetam was synthesized by docking with R-2-bromobutyramide and binding ring.Pentene-3-alcohol was used as starting material to obtain brominated products of non-enantiomers through rearrangement reaction and free radical reaction.The non-enantiomers were separated by column chromatography to obtain R-brominated products.The products were obtained by Ueno-Stork reaction,hydrolysis and oxidation to obtain R-4-propyl-dihydrofuran-2-one.After iodization reaction,substitution with S-2-aminobutyric amide and cyclization,the final product of Buvacetam was obtained.2.In the first route,butyraldehyde was used as starting material to obtain 3-propylglutaric acid by Knoevenagel condensation reaction and Micheal addition reaction with ethyl cyanoacetate and diethyl malonate.During the experiment,we selected a series of suitable conditions such as alkali,solvent and temperature to reduce the amount of solvent used in extraction,and the yield was about 80%.The structure of monosubstituted amides was obtained and the product could be precipitated directly by using ethyl acetate in the process of experimental exploration.In Holfman degradation reaction,the experimental conditions were optimized,the target product was obtained and the post-treatment method was improved to greatly increase the yield.In the synthesis of the target product,it was found that when isopropyl acetate was chosen as solvent,the reaction could proceed smoothly and the product could be produced.Direct precipitation simplifies the steps of post-treatment and purification.The whole purification method is simple,the reaction conditions are mild and the yield is high.3.In the second route,chiral additives were screened,and it was found that[(1S,2R)-2-phenyl-1-cyclohexanol]benzene was synthesized in high yield under the catalysis of palladium acetate with(1S,2R)-2-(vinyloxy)cyclohexyl]benzene as chiral additives.The compound reacted freely with 2-pentene-1-alcohol in solvent-free condition and[(1S,2R)-2-bromo-1-(2-pentene-l-oxy)ethoxy]benzene was obtained within 1 h.Chiral acetal centers were obtained from[(1S,2R)-2-(1R)-2-bromo-1-(2-pentene-1-oxo)ethoxy]cyclohexyl]benzene by column purification,de>99%.In Ueno-stork reaction,the reaction could take place rapidly when the reaction temperature was elevated to 111 0C.In subsequent oxidation reaction,R-4-propyl-dihydrofuran-2-one could be obtained in 3 hours with Jones reagent at-5?.The reaction time of the whole route is short,the chiral additives can be recovered,and the optical purity of the products is high.