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Preparation method of tolvaptan key intermediate

A technology of tolvaptan and intermediates, applied in the field of medicinal chemistry, can solve the problems of large fluctuation of yield and strong instability, and achieve the effects of simplified operation, simple operation and high yield

Inactive Publication Date: 2015-08-12
广安凯特制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The yield of the product obtained by this method fluctuates greatly, and the instability is strong

Method used

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  • Preparation method of tolvaptan key intermediate
  • Preparation method of tolvaptan key intermediate
  • Preparation method of tolvaptan key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] (1) Mix 100g of p-aminochlorobenzene, 100g of DMF (N,N-dimethylformamide), 266.5g of potassium carbonate, add 132.7g of methyl 4-chlorobutyrate dropwise at 10-20°C, and heat up to 40 After reaction at -50°C for 4 hours, add 400g of water dropwise at 40-50°C, cool down to 10-15°C for crystallization for 2.0 hours, and filter to obtain 172.6g of methyl 4-((4-chlorophenyl)amino)butyrate , yield 96.7%.

[0037] (2) Add 161.7g of methyl 4-((4-chlorophenyl)amino)butanoate and 161.7g of water to 70.0g of 98% sulfuric acid dropwise at 10-20°C, and raise the temperature to 90-100°C for 3 hours, Then lower the temperature to 0-15°C, add 323.4g of dichloromethane, then dropwise add 30wt% sodium hydroxide solution to adjust the pH=9.0-10.0, let stand to separate the liquids, and obtain a dichloromethane layer. Evaporate to dryness under reduced pressure at Mpa to obtain 144.4 g of solid 4-((4-chlorophenyl)amino)butanoic acid, with a yield of 95.2%.

[0038](3) Add 273.0g of thion...

Embodiment 2

[0041] (1) Mix 100g p-aminochlorobenzene, 100g DMSO (dimethyl sulfoxide), 266.5g sodium carbonate, add 132.7g methyl 4-chlorobutyrate dropwise at 10-20°C, heat up to 40-50°C and keep warm After reacting for 4 hours, keep warm at 40-50°C and add 400g of water dropwise, cool down to 10-15°C for crystallization for 2.0 hours, and filter to obtain 173.3g of methyl 4-((4-chlorophenyl)amino)butyrate with a yield of 97 %.

[0042] (2) 162.0 g of methyl 4-((4-chlorophenyl)amino)butanoate and 162.0 g of water were added dropwise with 70.0 g of 98% sulfuric acid at 10-20°C, and the temperature was raised to 90-100°C for 3 hours. Then lower the temperature to 0-15°C, add 323.4g of dichloromethane, then dropwise add 30% sodium hydroxide solution to adjust the pH=9-10, let stand to separate the liquids, and obtain a dichloromethane layer, Evaporate to dryness under reduced pressure at Mpa to obtain 145.9 g of solid 4-((4-chlorophenyl)amino)butanoic acid, with a yield of 96%.

[0043] (3)...

Embodiment 3

[0045] (1) Mix 100g of p-aminochlorobenzene, 100g of DMF, and 266.5g of potassium carbonate, add 132.7g of methyl 4-chlorobutyrate dropwise at 10-20°C, raise the temperature to 40-50°C and keep it warm for 4 hours, then keep it warm for 40- 400g of water was added dropwise at 50°C, the temperature was lowered to 10-15°C for crystallization for 2.0 hours, and 174.6g of methyl 4-((4-chlorophenyl)amino)butyrate was obtained by filtration, with a yield of 97.8%.

[0046] (2) Add 161.7g of methyl 4-((4-chlorophenyl)amino)butanoate and 161.7g of water to 70.0g of 98% sulfuric acid dropwise at 10-20°C, and raise the temperature to 90-100°C for 3 hours, Then lower the temperature to 0-15°C, add 323.4g of dichloromethane, then dropwise add 30% sodium hydroxide solution to adjust the pH=9-10, let stand to separate the liquids, and obtain a dichloromethane layer, Evaporate to dryness under reduced pressure at Mpa to obtain 147.8 g of solid 4-((4-chlorophenyl)amino)butanoic acid with a yi...

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Abstract

The invention discloses a preparation method of tolvaptan key intermediate 7-chloro-5-oxo-1,2,3,4-tetrahydro-benzazepine. The preparation method comprises the steps of condensing parachloroaniline, which is taken as a starting raw material, with 4-chlorobutyric acid methyl ester, carrying out hydrolysis de-esterification and acylating chlorination, and carrying out ring closure under an acidic condition, so as to obtain a target product, wherein the total yield of the target product can reach above 80%, and the HPLC (High Performance Liquid Chromatography) purity reaches above 99.5%.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a tolvaptan key intermediate 7-chloro-5-oxo-1,2,3,4-tetrahydro-benzazepine method of preparation. Background technique [0002] Tolvaptan is an oral selective non-peptide novel arginine vasopressin V developed by Otsuka Corporation of Japan 2 Receptor antagonist, approved by FDA in 2009, its structural formula is as follows: [0003] [0004] Tolvaptan structure [0005] As a key intermediate in the preparation of tolvaptan, 7-chloro-5-oxo-1,2,3,4-tetrahydro-benzazepine There have been many reports in the literature on the synthesis of , for example, the Chinese Journal of Pharmaceutical Industry, 2009, 40 (9): 648-650 reported the following synthesis process: [0006] [0007] The disadvantage of this preparation process is that the yield is low, and PPA is used in the last step, which has high viscosity, easy moisture absorption, and high cost, so it is ...

Claims

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Application Information

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IPC IPC(8): C07D223/16
CPCC07D223/16
Inventor 王廷圣游洪全周旭东邹鑫
Owner 广安凯特制药有限公司
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