Research On Synthesis Of Pregabalin

Pregabalin is the 3-isobutyl substituent of ?-aminobutyric acid agonists(GABA), which exploited by Warner-lambert Co.Ltd. It is a calcium channel modulator and therefore is useful as a therapeutic agent for the peripheral neuropathy and anticonvulsant therapy. Pregabalin first appeared on the UK market in September 2004. For its strong analgesic effect and favorable side profile, it provides an effective alternative drug to solve this medical problem and has a wide prospect of market development. The research on synthesis of pregabalin has an important academic value and application value.We research the synthetic routes and synthesis process of pregabalin. Various literatures about Pregabalin had been reported and can be divided into two types: One is asymmetric synthesis, which use chiral pool or chiral reagent to reacting to the target compounds. But those preparation methods are not easy to realize large-scale production, because the methods which use chiral pool needs multi-step and complicated process, and the other also has some shortcomings such as high costs, difficult reclaim. The other is combination of chemical synthesis and resolution of raceme, which includes enzyme resolution and chemical resolution method. The enzyme resolution method has harsh reaction conditions and poor quality of product, However a large number of literature using the method of chemical resolution which can overcome these disadvantages.We focused on the synthesis of prebagalin with the chemical resolution method. The raceme of pregabalin was obtained by five steps, then through chemical resolution method to get the prebagalin. The synthetic process of racemic is similar to the reported. But according to the chemical resolution method of the reported method, it is difficult to get qualified optical isomers with repeated experiments. So the chemical resolution method was researched particularly, and the results were got as follows:(1) The preparation of racemeUsing methyl cyanoacetate and isovaleraldehyde as material, the route to obtain the raceme mainly contains several experimental procedures in proper order as follows: Knoevenagel condensation reaction, Michael addition, Cyclization, Aminolysis, Hoffmann rearrangement. Compared with the reported literatures,there are three primary new improvements: The first, triethylamine was used as catalyst which can reduce the reaction temperature in the Michael addition reaction. The second, the yield was increased to 77 % by using petroleum ether instead of MTBE in Aminolysis reaction. The last one, yield of the raceme can be increased by 8% by optimizing the reaction temperature during the Hofmann rearrangement.(2)The chemical resolution of racemeRacemic Pregabalin was resolved to S-Pregabalin by using(S)-(+)-Mandelic acid as the resolving agent, and the content of each component in the resolution process were determined by HPLC method. Two methods were used and compared to carry out decomposition of S,S-salt in the resolution process. While the first method can get qualified product which S, S-Pregabalin mandelic acid salt was decomposes into S-Pregabalin by the solvent of THF-H2 O, it has weakness in large-scale production such as harsh reaction conditions, product of instability. The second method is more suitable for industrial production which S,S-pregabalin mandelic acid salt decomposes into S-Pregabalin by useing hydrochloric acid. It can avoid the racemization of product caused by hyperacidity and get high quality product with high yield.