| Conivaptan hydrochloride(N-[4-(2-methyl-4,5-dihydro-3H-imidazo[4,5-d][1]benzazepine-6-formyl)phenyl]-2-phenyl benzamide hydrochloride)is produced by Astellas Pharma,which is an arginine vasopressin Vla and V2 receptor non-peptide dualinhibitors.Conivaptan hydrochloride was agreed to enter the market by the U.S.Food and Drug Administration(FDA)on December 29,2005.The brand name of Conivaptan hydrochloride is Vaprisol.The Conivaptan hydrochloride is mainly used to naprapath for hyponatremia of the normal blood volume.In this paper,we analyzed the structure of Conivaptan hydrochloride and the existing synthetic route,a synthetic route of high yield,easy to operate and less environmental pollution was found.First,Cheaper methyl anthranilate were selected as the raw materials reacting p-toluenesulfonyl chloride to get the corresponding amide through the acylation reaction.Then Methyl 2-{(3-cyanopropyl)[(4-methylphenyl)sulfonyl]amino}benzoate was synthesized through the acylation reaction with 4-chlorobutanenitrile.And then,it worked with Potassium t-butoxide for 1-[(4-Methylphenyl)sulfonyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carbonitrile by Dieckmann condensation reaction.The compound was got by hydrolysis decarboxylation reaction in heated acidic solution.And then it was cyclized with acetamidine hydrochloride.This compound was detosylated with hot H2SO4 to provide 2-Methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine Monohydrate.Finally,Conivaptan hydrochloride was synthesized by the acylation reaction.We analyzed the synthetic route of every intermediates.The synthetic temperature,the solvent and purification methods were investigated,and the optimum reaction conditions were obtained for industrial production.We got rid of the cumbersome steps and optimized the synthetic route,the yield was improved.The structure of each intermediate was determined.In this paper,melting point was tested,and the nuclear magnetic resonance chemical analyzer was used to confirm the compound structure.And some key intermediates was confirmed by MS,so we can know the molecular weight of the intermediate.And the compound was confirmed by 1H NMR and MS. |
