Synthesis And Thiolation Of Captopril Disulfide Intermediate

Symmetrical disulfides, which are found abundantly in nature, hold wide applicationsin the biopharmaceutical, industrial and energy storage materials areas. Captopril disulfide,as an useful intermediate in the synthesis of captopril, is mainly used for preparingfinished product and scientific research. A number of methods for the preparation andthiolation of symmetrical disulfides have been reported. Previous research groups reportedthe route of using sodium thiosulfate pentahydrate and sodium sulfide nonahydrateas rawmaterials for the synthesis of captopril disulfide, which have further being deoxidated withzinc powder and sulfuric acid to give captopril. However, the reaction conditions have notbeen studied clearly. In order to cope with this problem, we further explored the routeintensively. Furthermore, we set up high performance liquid analysis method.Firstly, the preparation of1-（3-bromo-2-D-methylpropiony）-L-proline aspharmaceutical material for captopril disulfide was taken. A process of choosing2-methylpropenoic acid as starting material involved reaction sequence consisting ofaddition, chlorination, amidation, and split to yield1-（3-bromo-2-D-methylpropiony）tetrahydropyrrole-L-prolinebis（cyclohexylammonium）salt. Then it was hydrolyzed for1.5h at room temperature in potassium hydrogen sulfate solution. Purification of extraction3times with ethyl acetate, concentration and crystallization was operated sequentially togive the pharmaceutical material. The temperature of bis （cyclohexylammonium）salt beinghydrolyzed in potassium hydrogen sulfate solution was studied. It was found emulsifyingphenomenon would happen if the hydrolyzation was taken at high temperatures. So thehydrolyzation was taken at room temperaturebut and the reaction time was extended to1.5h.Secondly, the above product reacted with sodium thiosulfate pentahydrate andsodium sulfide nonahydrate. Then solidification with hydrochloric acid afforded captopril disulfide. The main factors including reflux time, concentration of sodium sulfidenonahydrate solution andcarboxylic acid/sodium sulfide nonahydrate mole ratio whichdetermined if the reaction could succeed or not were also studied. The test results revealedthat refluxing for2.5h at75℃was ideal, and the best concentration was37.3%and ratiowas1:0.62. Thus captopril disulfide was synthesized successfully. The yield was97.84%.Finally, captopril disulfide reacted with zinc and diluted sulfuric acid in theprotection of inert gas to yield captopril. This paper used orthogonal design andestablished HPLC test methods. HPLC analyses determined the best conditions:1mol/LH₂SO₄, reaction for3hours, the mole ratio of disulfide/zinc powder/sulfuric acid was1:10.5:6.5. The yield was84.74%.In summary, the two stages of captopril disulfide preparation and thiolation, as keyreactions in the synthesis of captopril, optimization of the total yield is82.91%. Thehigh-yielding and convenient procedure has important significance for the practicalapplication of bromination route to produce captopril at large scale.