Synthesis Of Chiral Intermediates For Diltiazem

Diltiazem is one of the most potent calcium antagonists and used as a remedy for angina and hypertension. Diltiazem has two asymmetric carbons in its chemical struture, among the four possible stereoisomers, only the (2S, 3S)-isomer exhibits potent coronary vasodilating activity. Diltiazem has been developed and marketed as a single isomer. Compared to resolution methods, asymmetric synthesis with high catalytic activity and excellent enantioselectivity have been noticed in recent years. In this thesis, two different kinds of key chiral intermediates for diltiazem were obtained by asymmetric dihydroxylation and asymmetric epoxidation.The synthesis method of 1,4-bis(9-O-quininyl)- phthalazine[(QN)₂PHAL] was improved by using KOH as acid-binding agent in refluxing toluene in 81% yield. The crude product was purified by recrystallization from ethyl acetate. The reaction time and cost were reduced and the experimental operation was simplified. This method was used to synthesize other cinchona alkaloid-derived ligands and achieved desirable effects. The chiral ligand (QN)₂PHAL was applied to asymmetric dihydroxylation of ethyl trans-p-methoxycinnamate with K₃Fe(CN)₆ as co-oxidant in H2O-'BuOH system to afford chiral vicinal diol ethyl (2R,3S)-2,3-dihydroxy-3-(4-metho-xyphenyl) propionate in 87% yield and 99% ee. The chiral vicinal diol was then treated with thionyl chloride to give (4S,5R)- 4-(4-mothoxyphenyl)-5-carboxyethyl) -1,3-dioxathiolane 2-oxide, which is a key chiral intermediate for diltiazem, in 85% yield.The chiral ketone 1,2:4,5-di-O-isopropylidene-erythro-2,3-hexodiulopyranose was synthesized from fructose via condensation and oxidation. The chiral dioxiranes generated in situ from potassium peroxomonosulfate (oxone) and the chiral ketone was applied to asymmetric epoxidation of ethyl trans-p-methoxycinnamate and ethyl (2R,3S) -3-(4-methoxyphenyl)glycidate was obtained in 48% yield and 82% ee. The effects of phase transfer catalyst, pH value, reaction temperature and oxidant were examined. The chiral ketone showed to be highly enantioselective for asymmetric epoxidation with little pollution, low cost and mild reaction conditions.