Improved synthesis of mozavaptan

Mozavaptan(1),a new type of vasopressin V2 receptor antagonist,has been used for the treatment of hyponatremia caused by heart failure with good efficiency and reliability.A confluent synthetic route was designed and used to prepare the target compound in this paper.The key intermediate 8,5-N,N-dimethylamino-2,3,4,5-tetrahydro-1H-benzazepine,was synthesized via N-sulfonic acylation,alkylation,cyclization,decarboxylation,N-methylation and reduction amination starting from methyl anthranilate.Another key intermediate 11,4-(2-methylbenzoylamino) benzoyl chloride,was synthesized from methyl p-aminobenzoate via N-acylation,ester hydrolysis and chlorination.Then 8 was reacted with 11 in acetone to give target compound and the overall yield was 14.2%(based on methyl anthranilate).The structure of the target compound was identified by 1H-NMR and MS.In this improved procedure,the yield of intermediate 3,γ-N-(2-methoxycarbonylphenyl)-N-(4-methylbenzenesulfonylamino) buterate,was increased by 16%,intermediate 6,5-N-methylamino-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrohydro-1H-benzazepine,was synthesized in a shortened reaction time by adding a catalytic amount of toluenesulfonic acid and intermediate 7,5-N,N-dimethylamino-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine,was obtained at a lower reaction temperature without any by-product almost.This improved synthetic process has the advantages of mild reaction conditions,relatively convenient operation procedures and being suitable for industrial application.