Resolution Of The Key Intermediates Of Brivaracetam

The chiral character of drugs is a key factor in drug efficacy and safety.In recent years,the effectiveness of chiral drugs against many deadly diseases is well established,and the demand for chiral drugs is increasing.More than half of the marketed drugs are chiral drugs.Therefore,chiral drugs have become a hot topic in drug research in recent years.Although the asymmetric synthesis of chiral drugs has made remarkable progress,the chiral resolution is still an ancient and important method to obtain chiral drugs.Brivaracetam is a third generation antiepileptic drug,which is a derivative of the previous generation antiepileptic drug levetiracetam.It is mainly used for the treatment of partial seizures in young people over 16 of age and adults,and for the adjuvant treatment of generalized seizures.Compared with levetiracetam,the affinity of brivaracetam is about 15-30 times,and the dosage of brivaracetam is much lower than that of levetiracetam for the same effect.The structure of brivaracetam contains two chiral carbon atoms,and these two chiral centers are a major challenge in designing cheap and readily available synthesis processes.Among them,(R)-4-propyldihydrofuran-2(3H)-one(R-PDFO)is the key intermediate in the synthesis of brivaracetam,and also the difficulty in the synthesis process of brivaracetam.Therefore,the acquisition of optically pure(R)-4-propyldihydrofuran-2(3H)-one has very important economic and social significance for the synthesis of brivaracetam.At present,asymmetric synthesis is usually used in the synthesis process,but racemes of 4-propyldihydrofuran-2(3H)-one are cheap and easy to obtain.Therefore,we adopted the method of resolution to obtain,optically pure(R)-4-propyldihydrofuran-2(3H)-one.First of all,the types of resolution agents were screened,and tartaric acid and its derivatives as well as common basic resolution agents such as(S)-phenylethylamine,functional chiral amino resolution agents were screened for their resolution effect.The functional chiral amino resolution agents were screened for better resolution effect.Secondly,the influence of solvent system and water content on the resolution effect during the separation process was studied in depth.By infrared and thermogravimetric analysis of diastereoisomer salts of two configurations,the differences between the two isomers were analyzed.It has been shown that optically pure(R)-4-propyldihydrofuran-2(3H)-one can be obtained by recrystallization with dioxane for more than three times in the solvent of 95%ethanol and ethyl acetate.