Study On Synthesis Of Novel Nitrogenous Polyheterocyclic Compounds As Cardiovascular Drugs And Its Intermediates

Tetrazole and carbostyril and their derivatives are widely applied as cardiovascular drugs.Based on the analysis and evaluation of bibliographer, the applications of tetrazole and carbostyril in cardiovascular drugs and its intermediates were reviewed. The processes for synthesis of them were summarized. Pilozol (1-1) and its intermediates N-cyclohexyl-5-(4-chlorobutyl)-lH-tetrazole (3-1) and 6-hydroxy-3,4-dihydrocarbostyril (4-1) were synthesized in the dissertation, 7-hydroxy-3,4- dihydrocarbostyril (4-2) and 8-hydroxyl-3,4-dihydrocarbostyril (4-3) were similarly prepared by the intramolecular Friedel-Crafts reaction. 5-hydroxy -3,4-dihydrocarbostyril (5-1) was synthesized starting from 1,3-cyclohexanedione as the important intermediates of Carteollol (2-48).In chapter 3, starting from 5 -valerolactone and cyclohexylamine, N-cyclohexyl -5-hydroxyl-valeroamide (3-2) was prepared. And N-cyclohexyl-5-(4-chlorobutyl) -IH-tetrazole (3-1) was prepared by the chlorination reaction of compound (3-2) with phosphorous pentachloride and the cyclic-reaction with NaNa. The total yield of compound (3-1) was 71%. The mechanism of the reaction of preparation for tetrazole was studied and phase transfer catalyst was probed primarily. The optimal reaction conditions were evaluated.In chapter 4, 6-hydroxy-3,4-dihydrocarbostyril (4-1) was synthesized from N-(4-hydroxyphenyl)-3-chloropropionamide with the yield of 92% in the presence of Lewis acid catalyst. N-(4-hydroxyphenyl)-3-chloropropionamide was synthesized by the condensation of p-aminophenol with 3-chloropropionyl chloride. 7-hydroxy-3,4-dihydrocarbostyril (4-2) and 8-hydroxy-3,4-dihydrocarbostyril (4-3) were similarly prepared by the intramolecular Friedel-Crafts reaction.In chapter 5, starting from 1,3-cyclohexanedione, 5-hydroxy-3,4-dihydro -carbostyril (5-1) was prepared in three steps with the yield of 73.4%. In theprocess the novel agent of ammonolysis reaction was evaluated and the solvent of dehydrogenation reaction was replaced by toluene. The yield of the dehydrogenation reaction was improved from 68% to 84%.In chapter 6, Pilozol (1-1) was prepared by the dehalohydrogen reaction of 6-hydroxy-3,4-dihydrocarbostyril (4-1) with N-cyclohexyl-5-(4-chlorobutyl)-lH -tetrazole (3-1) with the yield of 87% in the presence of TEBA as the phase transfer catalyst.The chemical structures of the product and intermediates were identified and confirmed by IR, NMR, MS. Furthermore the methods of analysis were studied.It provided the theoretical basis and the feasible process parameters for the industrialization of Pilozol (1-1) and its intermediates N-cyclohexyl-5-(4-chlorobutyl) -IH-tetrazole (3-1) and 6-hydroxy-3,4-dihydrocarbostyril (4-1) in the dissertation.