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多肽定制分解

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Tolvaptan的分解

作者:N/A    | 公布工夫:2015-01-12

【药物称号】

Tolvaptan, OPC-41061

【化学名】

(?-N-[4-(7-Chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-1-ylcarbonyl)-3-methylphenyl]-2-methylbenzamide

【CAS登暗号】

150683-30-0

【结构式】

【分子式】

C26-H25-Cl-N2-O3

【分子量】

448.9475

【本研厂家】

Otsuka (Originator)

【感化种别】

CARDIOVASCULAR DRUGS, Heart Failure Therapy, Vasopressin V2 Antagonists

【研发状况】

Phase II

【分解状况】

 

〖泉源〗

Bioorg Med Chem

〖分解道路〗

〖题目〗

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

〖分解要领〗

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.

〖作者〗

Kondo, K.; Yamashita, H.; Ogawa, H.; et al.

〖参考〗

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 1dced?

〖出处〗

Bioorg Med Chem1999,7,(8):1743

〖备注〗

Synthesis of 255241: 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 HOAc. 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. (Scheme 25524101a)

〖泉源〗

Drugs Fut

〖分解道路〗

〖题目〗

Tolvaptan

〖分解要领〗

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.

〖作者〗

Sorbera, L.A.; Silvestre, J.S.; Casta馿r, J.; Bay閟, M.

〖参考〗

Sorbera, L.A.; Silvestre, J.S.; Casta馿r, J.; Bay閟, M.; Tolvaptan. Drugs Fut 2002, 27, 4, 350

〖出处〗

Drugs Fut2002,27,(4):350

〖备注〗

Synthesis of Tolvaptan (EN:255241): Treatment of 5-chloro-2-nitrobenzoic acid (I) with dimethyl sulfate and K2CO3 in acetone yields the methyl ester (II), which is reduced at the nitro group with SnCl2 in HCl/EtOH to afford aniline (III). Protection of aniline (III) with tosyl chloride in pyridine gives the p-toluenesulfonamide (IV), which is alkylated with 4-bromobutyric acid ethyl ester (V) by means of K2CO3 in DMF to afford the diester (VI). Dieckmann cyclization of (VI) with potassium tert-butoxide in refluxing toluene provides benzazepinone (VIIa-b) as a mixture of ethyl and methyl esters, which is decarboxylated to (VIII) by heating with HCl in AcOH. Deprotection of the tosyl group of (VIII) with hot polyphosphoric acid furnishes benzazepinone (IX), which is condensed with 2-methyl-4-nitrobenzoyl chloride (X) by means of Et3N in dichloromethane to give amide (XI). Reduction of the nitro group of (XI) with SnCl2 in HCl/EtOH provides the corresponding aniline (XII), which is condensed with 2-methylbenzoyl chloride (XIII) by means of Et3N in dichloromethane to provide diamide (XIV). Finally, tolvaptan is obtained by reduction of the ketone group of (XIV) by means of NaBH4 in MeOH (1, 2) (Scheme 25524101a).  Source  Otsuka Pharmaceutical Co., Ltd. (JP).  References  1. Kondo, K., Ogawa, H., Yamashita, H. et al. 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 1999, 7: 1743-54.  2. Ogawa, H., Miyamoto, H., Kondo, K., Yamashita, H., Nakaya, K., Komatsu, H., Tanaka, M., Kora, S., Tominaga, M., Yabuuchi, Y. (Otsuka Pharmaceutical Co., Ltd.). Benzoheterocyclic cpds. US 5985869.

〖泉源〗

US 5985869

〖分解道路〗

〖题目〗

Benzoheterocyclic cpds

〖分解要领〗

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.

〖作者〗

Yabuuchi, Y.; Kora, S.; Tanaka, M.; Miyamoto, H.; Komatsu, H.; Kondo, K.; Yamashita, H.; Tominaga, M.; Ogawa, H.; Nakaya, K. (Otsuka Pharmaceutical Co., Ltd.)

〖参考〗

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

〖出处〗

US 5985869,,():

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