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

A technology of benzonitride and oxo, applied in the direction of organic chemistry, etc., can solve the problems of unsatisfactory yield, high viscosity of PPA, and cumbersome experimental operation.

Active Publication Date: 2013-04-03
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • 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 has long reaction steps, cumbersome experimental operations, and high yield not as expected
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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014]

[0015] Add compound II (10g, 53.9mmol) and sodium methoxide (5.8g, 107.8mmol) into a 250ml reaction flask, add 100ml of DMF and stir to dissolve. mmol) in DMF (50ml) was slowly added dropwise to the reaction solution. After the dropwise addition, react at -20°C for 3h, then raise the temperature to 150°C for 1h. 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 white solid is precipitated, and the solid is filtered out. The obtained white solid was dissolved in dichloromethane, washed with saturated brine (30ml×3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain white solid III.

[0016] Put the obtained white solid III in a 250ml reaction bottle, add 100ml of 25% dilute sulfuric acid, react at 60°C for 2h, after TLC detection shows that the reaction ...

Embodiment 2

[0018]

[0019] Add compound II (10g, 53.9mmol) and sodium ethoxide (5.5g, 80.8mmol) into a 250ml reaction flask, add 100ml of acetonitrile and stir to dissolve, at -10°C, add 4-bromobutyric acid ethyl ester (10.5g, 53.9 mmol) of acetonitrile solution (50 ml) was slowly added dropwise to the reaction solution. After the dropwise addition, react at 20°C for 0.5h, then raise the temperature to 80°C for 6h. After the completion of the reaction as detected by TLC, the reaction solution was poured into ice water, a white solid was precipitated, and the solid was filtered out. The obtained white solid was dissolved in dichloromethane, washed with saturated brine (30ml×3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain white solid III.

[0020] Put the obtained white solid III in a 250ml reaction bottle, add 100ml of 15% dilute sulfuric acid, and react at 80°C for 3h. 2 CO 3 soluti...

Embodiment 3

[0022]

[0023] Add compound II (10g, 53.9mmol) and potassium tert-butoxide (6.1g, 53.9mmol) into a 250ml reaction flask, add 100ml of toluene and stir to dissolve. At 0°C, ethyl 4-bromobutyrate (10.5g , 53.9 mmol) in toluene (50 ml) was slowly added dropwise to the reaction solution. After the dropwise addition, react at 0° C. for 6 h, then raise the temperature to reflux for 2 h. After the completion of the reaction as detected by TLC, the reaction solution was poured into ice water, extracted with dichloromethane (20ml×3), and the solvent was evaporated under reduced pressure to obtain white solid III.

[0024] Put the obtained white solid III in a 250ml reaction bottle, add 100ml of 20% dilute sulfuric acid, and react at 50°C for 2.5h. After the TLC test shows that the reaction is complete, cool to room temperature and adjust with KOH solution (1mol / L) in an ice bath. The pH of the reaction system was 7~8, and vacuum filtration gave the target product 7-chloro-5-oxo-2,...

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Abstract

The invention relates to a preparation method of 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 at a low temperature under the effect of an acid binding agent to generate secondary amine first, then carrying out Dieckman condensation reaction at a raised temperature to generate an intermediate mixture III, and finally carrying out hydrolysis 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 two-step reaction is simplified to one-step reaction through temperature control, so the operation is simple, the processing is convenient, 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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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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