Study On The Synthesis Of Pharmaceutical Intermediate (S)-3-Benzoyl Sulfydryl-2-methyl Propionate

Pharmaceutical intermediate (S)-3-benzoyl sulfydryl-2-methyl propionate is an importantpharmaceutical raw material, it’s used for synthesizing Angiotensin-converting enzymeinhibitor Zofenopril calcium, which has a good effect on hypertension and heart failure. Themethods of synthetic (S)-3-benzoyl sulfydryl-2-methyl propionate reported recently have highcost of raw material and poor-security, in order to solve these problem, a new synthetic routewas designed in this paper. As the main raw materials, thioacetic acid and methyl acrylate areall cheap and easy to get, after their addition reaction and sodium hydroxide’s hydrolyzingand benzoyl chloride’s esterification, chiral3-benzoyl-sulfydryl-2-methyl propionate wasprepared. Then these products are split with resolution agent and generate (S)-3-benzoylsulfydryl-2-methyl propionate.3-benzoylthio-2-methylpropionic acid racemate was synthesized by condensation andhydrolysis-esterification reaction of thioacetic acid with methacrylic acid, then(S)-3-benzoylthio-2-methylpropionic acid was obtained by chemical resolution. Theinfluencing factors in each step were taken into account. The results showed that3-acetyl-mercapto-2-methyl-propionic acid was obtained with the yield of96.0%when themolar ratio of thioacetic acid to methacrylic acid was1.4:1, reaction time was2h and reactiontemperature was93℃.3-acetyl-mercapto-2-methyl-propionic acid was hydrolyzed in11.8%sodium hydroxide aqueous solution with kettle temperature below20℃, then the hydrolysisproduct3-mercaptoisobutyric acid reacted with benzoyl chloride with the same moles byesterification for2h. Later, the product was obtained by acidifying the reaction mixture withhydrochloric acid, the yield of product in hydrolysis-esterification reaction was96.7%.D-(+)-N-benzyl-α-phenylethylamine was used as the resolving agent to split the product, theyield in this step was38.0%. Taking all the procedures above into consideration, the yield offinal product was35.2%. The product was characterized with MS,1HNMR and FT-IRanalysis, and proved to be with high crystallinity by X ray diffraction.