Tolvaptan, OPC-41061

合成路线:5-Chloro-2-nitrobenzoic acid (I) was converted into methyl ester (II) using dimethyl sulfate and K2CO3 in acetone.The nitro group of (II) was then reduced with SnCl2 to afford aniline (III),which was protected as the p-toluenesulfonamide (IV) with tosyl chloride in pyridine.Alkylation of (IV) with ethyl 4-bromobutyrate (V) yielded diester (VI).Subsequent Dieckmann cyclization of (VI) in the presence of potassium tert-butoxide provided benzazepinone (VIIa-b) as a mixture of ethyl and methyl esters,which was decarboxylated to (VIII) by heating with HCl in AcOH.Deprotection of the tosyl group of (VIII) was carried out in hot polyphosphoric acid.The resulting benzazepinone (IX) was condensed with 2-methyl-4-nitrobenzoyl chloride (X) to give amide (XI).After reduction of the nitro group of (XI) to the corresponding aniline (XII),condensation with 2-methylbenzoyl chloride (XIII) provided diamide (XIV).Finally,ketone reduction in (XIV) by means of NaBH4 led to the target compound.

参考文献标题:7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-41061): A potent,orally active nonpeptide arginine vasopressin V2 receptor antagonist
文献作者:Kondo,K.; Ogawa,H.; Yamashita,H.; Miyamoto,H.; Tanaka,M.; Nakaya,K.; Kitano,K.; Yamamura,Y.; Nakamura,S.; Onogawa,T.; Mori,T.; Tominaga,M.
参考来源:Bioorg Med Chem 1999,7(8),1743


合成路线:5-Chloro-2-nitrobenzoic acid (I) was converted into methyl ester (II) using dimethyl sulfate and K2CO3 in acetone.The nitro group of (II) was then reduced with SnCl2 to afford aniline (III),which was protected as the p-toluenesulfonamide (IV) with tosyl chloride in pyridine.Alkylation of (IV) with ethyl 4-bromobutyrate (V) yielded diester (VI).Subsequent Dieckmann cyclization of (VI) in the presence of potassium tert-butoxide provided benzazepinone (VIIa-b) as a mixture of ethyl and methyl esters,which was decarboxylated to (VIII) by heating with HCl in AcOH.Deprotection of the tosyl group of (VIII) was carried out in hot polyphosphoric acid.The resulting benzazepinone (IX) was condensed with 2-methyl-4-nitrobenzoyl chloride (X) to give amide (XI).After reduction of the nitro group of (XI) to the corresponding aniline (XII),condensation with 2-methylbenzoyl chloride (XIII) provided diamide (XIV).Finally,ketone reduction in (XIV) by means of NaBH4 led to the target compound.
参考文献标题:Tolvaptan
文献作者:Sorbera,L.A.; Silvestre,J.S.; Castar,J.; Bay閟,M.
参考来源:Drugs Fut 2002,27(4),350


产品链接: CAS No. 150683-30-0››