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【结 构 式】

【药物名称】Tolvaptan, OPC-41061

【化学名称】(±)-N-[4-(7-Chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-1-ylcarbonyl)-3-methylphenyl]-2-methylbenzamide

【CA登记号】150683-30-0

【 分 子 式 】C26H25ClN2O3

【 分 子 量 】448.95375

【开发单位】Otsuka (Originator)

【药理作用】CARDIOVASCULAR DRUGS, Heart Failure Therapy, Vasopressin V2 Antagonists

合成路线1合成路线2合成路线3合成路线4合成路线5

合成路线1

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 中间体
【1】 Sorbera, L.A.; Silvestre, J.S.; Castañer, J.; Bayes, M.; Tolvaptan. Drugs Fut 2002, 27, 4, 350.
【2】 Kondo, K.; Yamashita, H.; Ogawa, H.; et al.; 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. Bioorg Med Chem 1999, 7, 8, 1743.
【3】 Yabuuchi, Y.; Kora, S.; Tanaka, M.; Miyamoto, H.; Komatsu, H.; Kondo, K.; Yamashita, H.; Tominaga, M.; Ogawa, H.; Nakaya, K. (Otsuka Pharmaceutical Co., Ltd.); Benzoheterocyclic cpds. US 5985869 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIIa) 33001 methyl 7-chloro-1-[(4-methylphenyl)sulfonyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylate C19H18ClNO5S 详情 详情
(VIIb) 33002 ethyl 7-chloro-1-[(4-methylphenyl)sulfonyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylate C20H20ClNO5S 详情 详情
(I) 32996 5-chloro-2-nitrobenzoic acid 2516-95-2 C7H4ClNO4 详情 详情
(II) 32997 methyl 5-chloro-2-nitrobenzoate 51282-49-6 C8H6ClNO4 详情 详情
(III) 32998 methyl 2-amino-5-chlorobenzoate 5202-89-1 C8H8ClNO2 详情 详情
(IV) 32999 methyl 5-chloro-2-[[(4-methylphenyl)sulfonyl]amino]benzoate C15H14ClNO4S 详情 详情
(V) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(VI) 33000 methyl 5-chloro-2-[(4-ethoxy-4-oxobutyl)[(4-methylphenyl)sulfonyl]amino]benzoate C21H24ClNO6S 详情 详情
(VIII) 33003 7-chloro-1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one C17H16ClNO3S 详情 详情
(IX) 33004 7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one C10H10ClNO 详情 详情
(X) 33005 2-methyl-4-nitrobenzoyl chloride C8H6ClNO3 详情 详情
(XI) 33006 7-chloro-1-(2-methyl-4-nitrobenzoyl)-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one C18H15ClN2O4 详情 详情
(XII) 33007 1-(4-amino-2-methylbenzoyl)-7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one C18H17ClN2O2 详情 详情
(XIII) 14770 2-methylbenzoyl chloride; o-Toluoyl chloride 933-88-0 C8H7ClO 详情 详情
(XIV) 33008 N-[4-[(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide C26H23ClN2O3 详情 详情

合成路线2

　

参考文献 中间体
【1】 Kondo K, Ogawa H, Yamashita H, et al.1999.7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoyl-amino) benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-41061): A potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist. Bioorg Med Chem, 7: 1743～1754.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 32996 5-chloro-2-nitrobenzoic acid 2516-95-2 C7H4ClNO4 详情 详情
(II) 32999 methyl 5-chloro-2-[[(4-methylphenyl)sulfonyl]amino]benzoate C15H14ClNO4S 详情 详情
(III) 33000 methyl 5-chloro-2-[(4-ethoxy-4-oxobutyl)[(4-methylphenyl)sulfonyl]amino]benzoate C21H24ClNO6S 详情 详情
(IV) 33003 7-chloro-1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one C17H16ClNO3S 详情 详情
(V) 33004 7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one C10H10ClNO 详情 详情
(VI) 33006 7-chloro-1-(2-methyl-4-nitrobenzoyl)-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one C18H15ClN2O4 详情 详情
(VII) 33007 1-(4-amino-2-methylbenzoyl)-7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one C18H17ClN2O2 详情 详情
(VIII) 33008 N-[4-[(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide C26H23ClN2O3 详情 详情

合成路线3

　

参考文献 中间体
【1】 Cordero-Vargas A, Quiclet-Sire B, Zard SZ.2006.A flexible approach for the preparation of substituted benzazepines: Application to the synthesis of tolvaptan. Bioorg Med Chem, 14: 6165～6173.
【2】 Cordero-Vargas A, Perea-Martin I, Quiclet-Sire B, et al.2004.Synthesis of substituted naphthalenes from α-tetralones generated by a xanthate radical addition-cyclisation sequence. Org Biomol Chem, 2: 3018～3025.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 67450 S-(2-(4-chlorophenyl)-2-oxoethyl) O-ethyl carbonodithioate 　 C11H11ClO2S2 详情 详情
(II) 67451 4-(4-chlorophenyl)-1-((ethoxycarbonothioyl)thio)-4-oxobutyl pivalate 　 C18H23ClO4S2 详情 详情
(III) 67452 7-chloro-4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl pivalate 　 C15H17ClO3 详情 详情
(IV) 67453 (E)-7-chloro-4-(hydroxyimino)-1,2,3,4-tetrahydronaphthalen-1-yl pivalate 　 C15H18ClNO3 详情 详情
(V) 67454 3,3,7-trichloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl pivalate 　 C15H16Cl3NO3 详情 详情
(VI) 67455 7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl pivalate 　 C15H18ClNO3 详情 详情
(VII) 67456 7-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl pivalate 　 C15H20ClNO2 详情 详情
(VIII) 67457 7-chloro-1-(2-methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl pivalate 　 C23H25ClN2O5 详情 详情
(IX) 67458 1-(4-amino-2-methylbenzoyl)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl pivalate 　 C23H27ClN2O3 详情 详情
(X) 67459 7-chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl pivalate 　 C31H33ClN2O4 详情 详情

合成路线4

　

参考文献 中间体
【1】 Torisawa Y, Furuta T, Nishi T, et al.2007.Aminocarbonylation route to Tolvaptan. Bioorg Med Chem Lett, 17: 6455～6458.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 33004 7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one C10H10ClNO 详情 详情
(II) 67460 N-(4-bromo-3-methylphenyl)-2-methylbenzamide 　 C15H14BrNO 详情 详情
(III) 33008 N-[4-[(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide C26H23ClN2O3 详情 详情

合成路线5

　

参考文献 中间体
【1】 Yamashita H, Ohtani T, Morita S, et al.2002.Practical synthesis of both enantiomers of vasopressin V2 receptor antagonist OPC-41061 using the catalytic asymmetric hydrogenation, Heterocycles, 56: 123～128.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 33008 N-[4-[(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide C26H23ClN2O3 详情 详情
(II) 67461 (S)-N-(4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carbonyl)-3-methylphenyl)-2-methylbenzamide 　 C26H25ClN2O3 详情 详情
(III) 67462 (S)-7-chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl benzoate 　 C33H29ClN2O4 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(2)