Research on the Synthesis of Levetiracetam
|Keywords||Levetiracetam monoalkylation dialkylation (S)-2-Aminobutana mide hydrochloride 4-Chlorobutyryl chloride Methyl 4-chlorobutyrate|
Levetiracetam is a new antiepileptic drug, which has a unique antiepileptic mechanism. It has a high therapeutic index. The pharmacokinetic profile of le vetiracetam closely approximates the ideal characteristics expected of an antiepil eptic drug. With broad market prospects, research on its synthesis has great po tentials both on social and economic benefits.Researches mainly focus on the two synthesis routes using (S)-2-Aminobut anamide hydrochloride as the started material. First, we discuss the method usi ng 4-Chlorobutyryl chloride as raw material, confirming the existent problems a re:(1) Due to the application of strong alkali we can’t avoid the occurrence o f racemization and strong alkali systems can also cause difficulties in filtration; (2) Raw material 4-Chlorobutyryl chloride is not stable thus lead to unwanted reaction such as hydrolysis; (3) The added sodium sulfate decreases the rate o f hydrolysis but brings new difficulties in mixing.Based on the analysis of various literatures, here we discuss a new synthe tic route:adopting Methyl 4-chlorobutyrate as a new initial raw material. First, let it react with (S)-2-Aminobutanamide hydrochloride catalyzing by the sodiu m iodide, obtained the monoalkylation intermediates. Then through amidation g et the cyclizated final product levetiracetam, with a yield ratio of 65%. This p aper discusses the affect of solvent, temperature and ratios between raw materi als to the reaction.Our research successfully isolated two new materials:the intermediate and the by-product hydrochloride of the reaction occurred between 4-Chlorobutyryl chloride and (S)-2-Aminobutanamide hydrochloride. We determine the physical property of the intermediate is white solid powder, whose melting point is 60-62℃; by NMR and MS we confirm the chemical structure of the intermediate is a monoalkylation compound and the by-product is a dialkylation compound. There is no reported presence of the two substances.We ingeniously find out that with no catalyst the reaction of amide into rings can also be carried out; then we did further study about their varied synthesis conditions.This paper has discussed a new synthetic route of manufacturing levetirace tarn. Comparing with former synthetic methods, this route possesses wide sourc e of raw materials with chemical stability, which is easy for transportation and storage. With low-cost of raw materials and technological process, our way is more suitable for industrial production.