Study On Synthesis Of Pregabalin

(S)-3-aminomethyl-5-methylhexanoic acid,named pregabalin,is a new type of receptor antagonist.Pregabalin is mainly used for the treatment of peripheral neuralgia and the auxiliary treatment of localized partial epileptic.The drug has fewer side effects,less use times and good analgesic effec.It is believed that the drug has broad market perspective.There are many methods for the synthesis of pregabalin.In the work,chiral(R)-(-)-3-(carbamyl methyl)-5-methyl hexanoic acid was as raw material,and crude pregabalin was directly obtained by Hoffman rearrangement reaction.Then,the crude products were refined to obtain higher purity products.In this paper,synthesis stage and refined process were optimized and a relevant pilot design was performed on the basis of the bench scale results.The main contents are as follows:1.Pregabalin was obtained by hoffman rearrangement reaction in the laboratory scale.In the process of reaction,the influences of factors such as the additive amount of raw materials and heat preservation time on the yield were investigated.Then the optimal conditions were obtained.The ratio of isopropanol in aqueous solution and the amount of mixed solution in the refining process was analyzed to optimize refining process.It is concluded that for every 58.3 g raw material the additive amount was 50g water,135g 30%liquid alkali and 199.5g 11.1%sodium hypochlorite.Then system temperature was kept between 5? and 0? for 1 h after adding sodium hypochlorite.Finally,the heat preservation time for heating up to 30? and 45? was kept within 1.5 h.For the refined process,optimum condition was 12 equivalent of 60%isopropanol.The yield of pregabalin can reach up to 83%and purity is 99%.2.The 45 tons pregabalin pilot production process which includes syhthesis of crude product,refined of pregabalin,and recycle of isopropanol was designed according to the results of the small trial.The process flow chart is drawn for each section,and the simple equipment design is carried out.And key equipments in the process,such as main reactor and distillation column were focused on design and optimization.3.The pilot test is implemented.The operation process is designed in details.The purity of pregabalin was 99.4%and the yield was up to 83%.4.Based on economic feasibility analysis,annual profit is estimated about 23000 thousand yuan.