Preparation method of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine

A technology of benzonitride and oxo, which is applied in the direction of organic chemistry, etc., can solve the problems of cumbersome experimental operation, unsatisfactory yield, and increased reaction steps.

Inactive Publication Date: 2013-04-03
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In the first step of this method, p-toluenesulfonyl chloride is used to protect the primary amine, and after a series of reactions, PPA is used as a catalyst to remove the protective group. This method not only increases the reaction steps, but also makes the experimental operation cumbersome and economical unsatisfactory rate
The PPA used in the final removal of the protective group has high viscosity, is easy to absorb moisture, has high cost, and has obvious defects

Method used

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  • Preparation method of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine

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Experimental program
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Effect test

Embodiment 1

[0016]

[0017] Add compound II (10g, 53.9mmol) and potassium carbonate (14.9g, 107.8mmol) into a 250ml reaction flask, add 100ml of DMF and stir to dissolve. At -5°C, ethyl 4-bromobutyrate (10.5g, 53.9 mmol) in DMF (50ml) was slowly added dropwise to the reaction solution. After the dropwise addition, react at -5°C for 1 h, then raise the temperature to 60°C for 1 h. TLC [developing solvent: ethyl acetate-petroleum ether (1:5), the same below] After the detection reaction is complete, the reaction solution is poured into ice water, a yellow solid is precipitated, and the solid is filtered out. The obtained yellow solid was dissolved in dichloromethane, washed with saturated brine (15ml×3), the organic layers were combined, dried over anhydrous sodium sulfate, and left overnight. After filtration, the solvent was evaporated under reduced pressure to obtain a pale yellow solid (13.8 g, 85.2%) with a purity of 93.0% (HPLC normalization method).

Embodiment 2

[0019]

[0020] Compound II (10g, 53.9mmol) and triethylamine (10.9g, 107.8mmol) were added to a 250ml reaction flask, 100ml of dichloromethane was added and stirred to dissolve, at -10°C, ethyl 4-bromobutyrate ( 10.5g, 53.9mmol) of dichloromethane solution (50ml) was slowly added dropwise to the reaction solution. After the dropwise addition, react at -10°C for 1 h, then raise the temperature to reflux for 3 h. After the reaction was complete as detected by TLC, the reaction solution was poured into 100 ml of ice water, shaken to separate layers, and several layers were separated, and washed with water three times in a row. The organic layer was dried over anhydrous sodium sulfate and left overnight. It was filtered and evaporated to dryness under reduced pressure to obtain a light yellow solid (13.4 g, 83.0%) with a purity of 92.4% (HPLC normalization method).

Embodiment 3

[0022]

[0023] Add compound II (10g, 53.9mmol) and sodium hydroxide (3.2g, 80.8mmol) to a 250ml reaction flask, add 100ml tetrahydrofuran and stir to dissolve, and at -15°C, ethyl 4-bromobutyrate (10.5g , 53.9 mmol) in tetrahydrofuran (50 ml) was slowly added dropwise to the reaction solution. After the dropwise addition, react at -15°C for 1 h, then raise the temperature to 30°C for 2 h. After the completion of the reaction as detected by TLC, the reaction solution was poured into ice water, a yellow solid was precipitated, and the solid was filtered out. The obtained yellow solid was dissolved in dichloromethane, washed with saturated brine (15ml×3), the organic layers were combined, dried over anhydrous sodium sulfate, and left overnight. After filtration, the solvent was evaporated under reduced pressure to obtain a light yellow solid (14.4 g, 89.1%) with a purity of 95.1% (HPLC normalization method).

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Abstract

The invention relates to a method for preparing 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine, which is an important intermediate for preparing arginine vasopressin V2 receptor antagonist Tolvaptan. The preparation method comprises the following steps: with methyl 2-amido-5-chlorobenzoate and ethyl 4-bromobutyrate as starting raw materials, reacting under the effect of an acid binding agent to generate secondary amine, and then carrying out Dieckman condensation and hydrolysis reaction to obtain the target compound 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. Compared with the existing method, the method provided by the invention has the advantages that the reaction steps are reduced, the operation is easy and simple, the product purity is high, and the yield is also greatly improved, thus the production cost can be reduced and the benefits are increased.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, in particular to an intermediate 7-chloro-5-oxo-2,3,4,5-tetrahydro- The preparation method of 1H-1-benzazepine. Background technique [0002] 7-Chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine is an important intermediate in the synthesis of tolvaptan. Tolvaptan is a non-peptide selective V 2 Receptor antagonists, capable of reducing fluid load without affecting electrolyte balance and renal function, are effective diuretics and are suitable for the treatment of diseases such as hyponatremia. [0003] The preparation of this product has been reported in the literature at home and abroad, such as the literature Chinese Journal of Pharmaceutical Industry. 2009,40 (9): 648-650 provides the following synthetic method: [0004] [0005] In the first step of this method, p-toluenesulfonyl chloride is used to protect the primary amine, and after a series of reactions, PPA is used as a ca...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16
Inventor 刘登科牛端刘颖穆帅解晓帅张大帅王平保
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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