Studies On The Synthesis Of Pregabalin And Related Reactions

Pregablin(S-(+)-3-aminomethyl-5-methylhexanoic acid) has structural similarities compared to GABA, so it is used as an anti-convulsion drug. Compared with drugs of the same category, Pregabalin can be used with less dosage amounts when treating convulsions and with minor toxicity and prolonged healing effects. In our experiments, a new synthetic route was designed with merits of being economic, with fewer steps and almost non-contaminative. Additionally, we attempted to conduct the synthesis of the chiral phosphine ligand R,R-DuPHOS, which can be used in asymmetric hydrogenation of the precursor of Pregabalin.(2S,5S)-2,5-hexanediol, the chiral precursor of R,R-DuPHOS, was synthesized by biotransformation. Details are listed as follows.1. Pregabalin was synthesized using iso-butylaldehyde and acrylonitrile as cheap starting materials. The synthetic route includes Baylis-Hillman reaction, acetylation, carbonylation-elimination, hydrogenation and resolution. Our studies concentrated on the acceleration of Baylis-Hillman reaction and carbonylation-elimination. As to the Baylis-Hillman reaction between so-butylaldehyde and acrylonitrile, aqueous solution of Na2SO4could speed up the reaction to a good extent, that is,85%yield was obtained in24h. As to the carbonylation-elimination, Pd(OAc)2/PPh3=1:4was used to catalyze the reaction, and substrate concentration of1.32mol·L-1was favorable for the carbonylation. The hydrogenation of3-cyano-5-methyl-hex-3-enoic acid ethyl ester gave racemic Pregabalin, and (S)-pregabalin was gained via resolution with (S)-mandelic acid.2. Dried activated Bakers’Yeast manufactured in Guangdong DanBaoli Corp. was used in the biotransformation of2,5-hexanedinone. Substrate concentration, co-substrate, the amount of Bakers’Yeast, surfactants and solvents and their effects on yield and optical purity of crude products were investigated. And the results showed that the optimum conditions for the transformation are:subtrate5.7g-L-1,Tween80lg·L-1, pH7.0, Bakers’yeast100g·L-1, temperature30℃, at180rpm on a rotary shaker. It was also found that immobilized Bakers’Yeast has the potential to enantioselectively reduce2,5-hexanedinone, but the conditions of immobilization need to be studied further due to the relatively low specific rotation of the products.3.By using Saccharomyces cerevisiae LXY0692,(2S,5S)-2,5-hexanediol can be obtained with little impurities that do not interfere the access to (R,R)-DuPHOS backbone, and its cyclic sulfate to be used in the ligand synthesis shows99.2%ee, which indicates that the crude diol can be used in subsequent reactions without purification. The chosen Saccharomyces cerevisiae LXY0692is tolerant to2,5-hexanedinone with the concentration up to100mmol·L-1at pH5.0. The cyclic sulfate can be used in the synthesis of (R,R)-DuPHOS with62%yield.