Preparation Of Optically Active Dihydropyridine Calcium Antagonists And Analogues By Resolution

Compounds ADHPA are important intermediates for preparing 1,4-dihydropyridine Ca²⁺ antagonists. Many reseach works have been done to prepare the intermediates through hydrogenolysis, acidic and basic hydrolysis. The yields were better when DHPCE with nitro group in meta or ortho position of the benzene ring were hydrolyzed in basic conditions, while the hydrogenolysis and acidic reactions gave very poor yields.CSP-HPLC( AGP) was adopted to resolve racemic ADHPA, DHP calcium antagonists and analogues. Based on lot of works, MDHPA can be easily resolved in a relatively short time (17 min, R=6.0).The synthetical resolving agents, such as optically activeα-phenylethylamine, meglumine, aminodiol, N-octly-glucamine and (S)-amlodipine (prepared by ourselves) were mainly used to resolve MDHPA. The salt of (S)-amlodipine·(R)-MDHPA preferential crystallized in ethanol when (S)-amlodipine was used as resoving agent. After workup, the salt gave high optically active (R)-MDHPA with 83% e.e.. But the crystalline was very poor and the amount of the crystalline was very small. According to the principle of three-point interaction, ultrasonic wave accelerated deconstruction of the pair of MDHPA enantiomers when N-octly-glucamine was used as resolving agent. And the e.e. value rose up to 21% from 12%. Other synthetical resolving agents have no predominantly resolving effect on resovling MDHPA.Six optically active calcium antagonists plus 21 analogues were synthesized. Among them 22 samples were determined by CSP-HPLC. There is no racemization happened during the esterification process through DCC coulpling or corresponding acid chlorides.