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Method for preparing 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepino-5-ketone

A technology for benzoazepines and zebralines is applied in the field of preparation of benzoazepines, can solve the problems of high cost, low yield, and cannot be well applied to industrialized production, and achieves the effect of reducing industrial costs

Active Publication Date: 2011-06-15
宁波人健药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] This route is to construct an azepine ring through Beckmann rearrangement, which is very innovative, but the method shown above cannot be well applied to industrial production due to the limitation of low yield and high cost

Method used

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  • Method for preparing 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepino-5-ketone
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  • Method for preparing 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepino-5-ketone

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Experimental program
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Effect test

Embodiment 1

[0037] p-Chloroaniline (89.3g, 0.70mol) and dichloromethane (250mL) were placed in a 2L reaction flask, and pyridine (60.9g, 62.3mL, 0.77mol) was added. The reaction solution was cooled to 0-5°C in an ice-water bath, and a solution of p-toluenesulfonyl chloride (139.2 g, 0.73 mol) and dichloromethane (250 mL) was added dropwise with stirring, and the drop was completed within 1 h. After dropping, the reaction was stirred at room temperature for 10 h. Water (500 mL) was added to the reaction solution, stirred for 10 min, and the layers were separated. The aqueous layer was extracted once with dichloromethane (100 mL). The organic layers were combined, washed with saturated brine (400 mL), and dried over anhydrous sodium sulfate. Dichloromethane was evaporated to dryness under reduced pressure, the resulting solid was added to methanol (400mL) and heated to dissolve, cooled to 0-5°C, slowly added water (400mL), kept stirring at 0-5°C for 30min, filtered, and cooled a little to...

Embodiment 2

[0039] p-Chloroaniline (89.3g, 0.70mol) and dichloromethane (250mL) were placed in a 2L reaction flask, and pyridine (55.4g, 56.6mL, 0.70mol) was added. The reaction solution was cooled to 0-5°C in an ice-water bath, and a solution of p-toluenesulfonyl chloride (160.2 g, 0.84 mol) and dichloromethane (250 mL) was added dropwise with stirring, and the drop was completed within 1 h. After dropping, the temperature was raised to dichloromethane reflux, and the reaction was stirred for 7h. Water (500 mL) was added to the reaction solution, stirred for 10 min, and the layers were separated. The aqueous layer was extracted once with dichloromethane (100 mL). The organic layers were combined, washed with saturated brine (400 mL), and dried over anhydrous sodium sulfate. Dichloromethane was evaporated to dryness under reduced pressure, the resulting solid was added to methanol (400mL) and heated to dissolve, cooled to 0-5°C, slowly added water (400mL), kept stirring at 0-5°C for 30m...

Embodiment 3

[0041] p-Chloroaniline (89.3g, 0.70mol) and dichloromethane (250mL) were placed in a 2L reaction flask, and pyridine (83.0g, 85.0mL, 1.05mol) was added. The reaction solution was cooled to 0-5°C in an ice-water bath, and a solution of p-toluenesulfonyl chloride (152.5 g, 0.80 mol) and dichloromethane (250 mL) was added dropwise with stirring, and the drop was completed within 1 h. After dropping, the temperature was raised to dichloromethane reflux, and the reaction was stirred for 5h. Water (500 mL) was added to the reaction solution, stirred for 10 min, and the layers were separated. The aqueous layer was extracted once with dichloromethane (100 mL). The organic layers were combined, washed with saturated brine (400 mL), and dried over anhydrous sodium sulfate. Dichloromethane was evaporated to dryness under reduced pressure, the resulting solid was added to methanol (400mL) and heated to dissolve, cooled to 0-5°C, slowly added water (400mL), kept stirring at 0-5°C for 30m...

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Abstract

The invention relates to a preparation method of benzazepine compounds, particularly a preparation method of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepino-5-ketone. The 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepino-5-ketone can be used as an intermediate for preparing a pitressin antagonist medicament Tolvaptan. The method comprises the following steps: by using parachloroaniline as a raw material, reacting with paratoluensulfonyl chloride in a condensation mode under the alkaline condition to firstly protect amino groups; under the alkaline condition, coupling with ethyl 4-bromobutyrate to obtain a compound; in the presence of alkali, hydrolyzing the obtained compound, and acidifying; in dichloromethane, preparing acyl chloride from the acidified compound under the action of thionyl chloride; under the action of Lewis acid, carrying out Friedel-Crafts acylation reaction to perform intramolecular cyclization; and finally, removing tosyl groups to obtain the target product. The invention has the advantages of simple technique and low cost, and is convenient for industrial large-scale production.

Description

technical field [0001] The present invention relates to the preparation method of benzazepine compound, specifically a kind of preparation 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepine-5-one A new method; the compound is an important intermediate for preparing the vasopressin antagonist drug Tolvaptan. Background technique [0002] Tolvaptan is a high-efficiency and low-toxicity arginine vasopressin (AVP) antagonist, successfully developed by Otsuka Pharmaceutical Company and launched in 2009. Its English trade name is Samsca (Tolvap tan), and its chemical name is N-[4-[(5R)-7-chloro-5-hydroxyl-2,3,4,5-tetrahydro-1-benzazepine Zhuo-1-formyl]-3-methylphenyl]-2-methylbenzamide, the English chemical name is N-[4-[(5R)-7-Chloro-5-hydroxy-2,3, 4,5-tetra hydro-1-benzazepine-1-carbonyl]-3-methylphenyl]-2-methylbenz amide. The molecular structural formula is as follows: [0003] Compound 3 [0004] Tolvaptan can effectively antagonize arginine vasopressin (AVP). Systemic vaso...

Claims

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Application Information

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IPC IPC(8): C07D223/16
Inventor 顾华平丁同健鲍继胜
Owner 宁波人健药业集团股份有限公司
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