Welcome to 1号注册 為夢而年輕!

技術分類

搜索

  • MSDS:
  • (COA):
  • NMR:
  • MS:
  • IR:

多肽定制合成

瀚鴻化工擁有固相合成和液相合成多肽的核心技術,并且具有自有保護氨基酸的優勢,因此可以給客戶提供質優價廉的多肽定制合成業務,是中國主要的多肽定制合成商。

DNA,RNA定制合成

瀚鴻化工在自己生産核苷亞磷酰按單體的基礎上,結合我們的固相合成能力,可以為客戶提供不同規模的DNA,RNA定制合成業務。低價、質量和快速是我們的目标。

有機化合物定制合成

瀚鴻擁有60多位有機合成人員,有15個有機合成實驗室,有2個多功能車間,可以為國内外客戶提供從克、公斤到噸位的定制合成産品。定制合成是我們的主業方向之一。

聯系我們

021-64541543

上海瀚鴻化工科技有限公司

地址:上海市徐彙區嘉川路245号2号樓707

傳真:021-54291107

郵件:info@sina-zjg.com

網址:www.sina-zjg.com

Tolvaptan的合成

作者:N/A    | 發布時間:2015-01-12

【藥物名稱】

Tolvaptan, OPC-41061

【化學名】

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

【CAS登記号】

150683-30-0

【結構式】

【分子式】

C26-H25-Cl-N2-O3

【分子量】

448.9475

【原研廠家】

Otsuka (Originator)

【作用類别】

CARDIOVASCULAR DRUGS, Heart Failure Therapy, Vasopressin V2 Antagonists

【研發狀态】

Phase II

【合成情況】

 

〖來源〗

Bioorg Med Chem

〖合成路線〗

〖标題〗

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

〖合成方法〗

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.

〖參考〗

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?

〖出處〗

Bioorg Med Chem1999,7,(8):1743

〖備注〗

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)

〖來源〗

Drugs Fut

〖合成路線〗

〖标題〗

Tolvaptan

〖合成方法〗

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.

〖參考〗

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

〖出處〗

Drugs Fut2002,27,(4):350

〖備注〗

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.

〖來源〗

US 5985869

〖合成路線〗

〖标題〗

Benzoheterocyclic cpds

〖合成方法〗

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.)

〖參考〗

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

〖出處〗

US 5985869,,():

Sales Department :Room 707, NO.2 Building , NO.245,Jiachuan Road, Xuhui District, Shanghai, China . E-Mail:info@sina-zjg.com