Study On Synthesis Of Nitrogenous Polyheterocyclic Compounds And Its Intermediates

Carbostyril and their derivatives are widely applied as drugs. Carteolol and its key intermediate 5-hydroxy-3, 4-dihydrocarbostyril , loratadine and its intermediate 8-chloro-5,6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b] pyridine- 11-one are two typical examples.Based on the analysis and evaluation of bibliographer, the applications of carbostyril in cardiovascular drugs , its intermediates and loratadine and its intermediate were reviewed. The processes for synthesis of them were summarized. The synthesis of Carteolol(l-3) and its intermediate 5-hydroxy-3,4- dihydrocarbostyril (3-1) were studied in the dissertation; The study on synthesis of loratadine and its intermediate 8-chloro-5,6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b] pyridine -11-one was also disclosed in the dissertation.Starting from 1,3-cyclohexanedione, 5-hydroxy-3,4-dihydro -carbostyril (3-1) was prepared in three steps with the yield of 73.1%. In the process the novel agent of ammonolysis reaction was evaluated and the solvent of dehydrogenation reaction was replaced by 1,2-dichloroethane.The yield of the dehydrogenation reaction was improved from 68% to 84%.Starting from 5-hydroxy-3,4-dihydro-carbostyril (3-1), Carteolol(l-3) was synthesized. The reaction of 5-hydroxy-3,4-dihydro -carbostyril (3-1) and epichlorothydrine was studied and the optimized process parameters were evaluated by expememtals.8-Chloro-5,6-dihydro-l IH-benzo [5,6] cyclohepta [1,2-b] pyridine-11-one was synthesized from 3-[2-(3-chlorophenyl)ethyl]-N -(1,1-dime-thylethyl)- 2-pyridine carboxamide via cyanidation, hydrolysis and cycl-ization under mild condition. The total yield attained was 32.8%.Loratadine was synthesized from 8-chloro-5,6-dihydro-llH-benzo [5,6] cyclohepta [1,2-b] pyridine-11-one as the starting material and ethyl 4-oxopiperidine-l-carboxylate, the conversion of the starting compounds took place in the presence of low valent titanium and the organic solvent THF, the yield attained was 39.2%. This novel process avoided the use of corrosive reagent superacids.The chemical structures of the product and intermediates were identified and confirmed by IR, NMR, MS. Furthermore the methods of analysis for the products and intermediates were studied.