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Preparation method for 7-chlorine-5-oxo-2,3,4,5-tetrahydro-1H-1-benzoazepine

A technology of benzonitrogen and oxo substitution, applied in the direction of organic chemistry, can solve the problems of long reaction route, easy moisture absorption cost, many impurities, etc., and achieve the effect of simplifying the post-processing method, shortening the reaction time and simplifying the reaction route

Active Publication Date: 2012-01-25
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Abstract
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Problems solved by technology

[0005] There are obvious defects in this method. In the synthesis of 7-chloro-5-oxo-4-alkoxycarbonyl-1-p-toluenesulfonyl-2,3,4,5-tetrahydro-1-benzazepine In the process of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine, the reaction is carried out in two steps, and the reaction speed with hydrochloric acid is slow, the yield is low and the impurity Many, the PPA used in the last step has high viscosity, easy to absorb moisture and high cost
In addition, in Chinese patent CN101273017A, PPA was changed to concentrated sulfuric acid during the last step of synthesizing 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine, but after Two-step reaction, long reaction route, low yield, high cost, not suitable for industrial production

Method used

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  • Preparation method for 7-chlorine-5-oxo-2,3,4,5-tetrahydro-1H-1-benzoazepine

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Experimental program
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Effect test

Embodiment 1

[0017] Take 98% concentrated sulfuric acid (14.15ml) and dilute it to 85%, add it into a three-necked flask, stir for 10min under ice bath, get 7-chloro-5-oxo-4-alkoxycarbonyl-1-p-toluenesulfonyl- 2,3,4,5-Tetrahydro-1-benzazepine (2.87g, 0.0065mol) was added to the reaction flask, and after stirring for 15 minutes, the reaction system was removed from the ice bath and heated for reaction. The temperature of the reaction system was controlled at 90 ℃, after 1 hour of reaction, TLC detects that the reaction is over, stop the reaction, cool to room temperature, adjust the pH of the reaction system to 7-8 with NaOH solution (1mol / L) in an ice bath, and vacuum filter to obtain the dark yellow solid target product 7-chloro -5-Oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (1.47 g, 99%), purity 99% (HPLC, normalization method).

Embodiment 2

[0019] Take 98% concentrated sulfuric acid (14.15ml), add it to a three-necked flask, stir for 10min under ice bath, get 7-chloro-5-oxo-4-alkoxycarbonyl-1-p-toluenesulfonyl-2,3, 4,5-tetrahydro-1-benzazepine (2.30g, 0.0052mol) was added to the reaction flask, and after stirring for 15 minutes, the reaction system was removed from the ice bath, 30ml of distilled water was added to dilute concentrated sulfuric acid, and the reaction was carried out at room temperature. After 0.5h, TLC detects that the reaction is over, stop the reaction, cool to room temperature, adjust the pH of the reaction system to 9-10 with KOH solution (1mol / L) in an ice bath, and vacuum filter to obtain the dark yellow solid target product 7-chloro-5 -Oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (1.16 g, 97%), purity 98.5% (HPLC, normalization method).

Embodiment 3

[0021] Take 98% concentrated sulfuric acid (14.15ml) and dilute it to 50%, add it into a three-necked flask, stir for 10min under ice bath, get 7-chloro-5-oxo-4-alkoxycarbonyl-1-p-toluenesulfonyl- 2,3,4,5-Tetrahydro-1-benzazepine (3.28g, 0.0074mol) was added to the reaction flask, and after stirring for 15 minutes, the reaction system was removed from the ice bath and heated for reaction. The temperature of the reaction system was controlled at 100 ℃, after 5 hours of reaction, TLC detects that the reaction is over, stop the reaction, cool to room temperature, and use Na 2 CO 3 solution (10mol / L) to adjust the pH of the reaction system to 7-8, vacuum filtration to obtain the dark yellow solid target product 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzo Azepine (1.66 g, 98%), purity 98% (HPLC, normalization method).

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Abstract

The invention relates to a preparation method for 7-chlorine-5-oxo-2,3,4,5-tetrahydro-1H-1-benzoazepine. The 7-chlorine-5-oxo-2,3,4,5-tetrahydro-1H-1-benzoazepine is an important intermediate for preparing arginine pitressin V2 receptor antagonist Tolvaptan. In the preparation method, the target product 7-chlorine-5-oxo-2,3,4,5-tetrahydro-1H-1-benzoazepine is prepared by removing tosyl and carbalkoxy from 7-chlorine-5-oxo-4-carbalkoxy-1-tosyl-2,3,4,5-tetrahydro-1-benzoazepine serving as a raw material under the action of sulfuric acid and by a 'one-pot method'. The sulfuric acid is used for performing 'one-pot method' reaction, so reaction steps are reduced and reaction time is greatly shortened. The preparation method has the advantages of simpleness and convenience for operation, equipment and cost saving, simpleness and practicability in separation and purification, short reaction time, high yield and high product purity and is applicable to industrialized production.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, in particular to a novel arginine vasopressin V 2 The preparation method of receptor antagonist tolvaptan intermediate 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. Background technique [0002] 7-Chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine is an important intermediate for 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 literature at home and abroad, such as the literature China Pharmaceutical Industry Journal. 2009, 40 (9): 648-650 provides the following synthetic method: [0004] [0005] There are obvious defects in this method. In the synthesis of 7-chloro-5-oxo-4-alkoxycarbonyl-1-p-t...

Claims

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Application Information

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IPC IPC(8): C07D223/16
Inventor 刘登科穆帅刘冰妮陈旭刘颖张晓凯牛端王景阳
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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