(1r, 2s) - (-) - Ephedrine Synthesis Process Research

(1R,2S)-(-)-Ephedrine is a widely used drug , and also a starting material for pseudoephedrine. To prevent the serious desertication in the west of China and meet the market demand, the industrial manufacture of ephedrine was investigated.Here in, ephedrine had been synthesized by two methods.Method 1 (Asymmetric Transformation , Route7.2)Method 2 (Asymmetric Induction , Route 8 )Method 2 is a novel route designed to synthesize (lR,2S)-(-)-ephedrine. A pair of diastereoisomers: (S,S)-55HCl and (R,S)-55HCl were obtained by introducing (S)-phenylethanamine into compound 53. The key technics were the separation of (.S,S)-55HCl from (R,S)-55'HCl by the solubility difference , and the transformation of the latter to the former. Due to the inductive effect of the asymmetric a-C of thecarbonyl group, almost all of the reduced product was (R,S,S)-56 HC1 which via Leuckart reaction and debenzylation, (R,2S)- (-)-ephedrine was obtained.Method 2 is not suitable to industrialization because of the cost of (S)-phenylethanamine and Pd/C, more attention was paid to method 1.Started from propanoic acid, ( )-2-methylamino-l-phenyl-l-propanoneHCl [( )-54 HC1] was synthesized in "one pot"; some unreported phenomena of methylamination were observed by separating the by-products and the mechanisms were explained to optimize reaction conditions, and the yield of ( )-54HCl was improved; a new way was adopted to achieve the asymmetric resolution of ()-54. After the factors affecting the process were studied, [(S)-(-)-54]2 (-)-DBTA was obtained in 156% optical yield, with d.e. of 97.3%; [(5)-(-)-54]2 (-)-DBTA was reduced by KBH4 in CH3OH or H2O, most of the product was ephedrine(erythro), and product of more than 99.5% purity was obtained by recrystallization for once .It was explained that the intramolecular hydrogen bonding might be found to be responsible for the specific reaction, the reduction method was unprecedentedly reported.Method I has been scaled up in industry in overall yield 41%, the optical purity of the product was 99.4%.The new approaches of resolution and reduction were filed in Chinese patents-application No. 200410024865. 8 and 200110024953.8 .respectively.