Synthetic method of 7-chloro-1,2,3,4-tetrahydrobenzo[b]azepine-5-one

A synthesis method and technology of tetrahydrobenzene are applied in the field of synthesis of 7-chloro-1,2,3,4-tetrahydrobenzo[b]azepine-5-one, which can solve the difficulties of post-treatment purification, High cost, low yield and other problems, to achieve the effect of short steps, high total yield and environmental friendliness

Active Publication Date: 2015-02-11
ASTATECH CHENGDU BIOPHARM CORP
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0007] The technical problem to be solved in the present invention is that the existing method for synthesizing 7-chloro-1,2,3,4-tetrahydrobenzo[b]azepine-5-one has low yield, high cost and difficulty in post-treatment purification

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  • Synthetic method of 7-chloro-1,2,3,4-tetrahydrobenzo[b]azepine-5-one

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preparation example Construction

[0024] The specific operation steps of the synthetic method of 7-chloro-1,2,3,4-tetrahydrobenzo[b]azepine-5-one include:

[0025] A. Synthesis of 4-(4-chloroanilino)-4-oxobutanoic acid: dissolve 4-chloroaniline and succinic anhydride in an organic solvent, then heat and reflux for 4 to 8 hours, and remove the organic compound after the reaction. Solvent, add cold 1N hydrochloric acid to the residue, stir for 10-15 minutes; filter out the solid to obtain 4-(4-chloroanilino)-4-oxobutanoic acid;

[0026] Synthesis of B, 7-chloro-3,4-tetrahydrobenzo[b]azepine-2,5-dione: the above-mentioned 4-(4-chloroanilino)-4-oxobutanoic acid was dissolved in In dichloroethane, add anhydrous AlCl3, and then react at 55-70 degrees for 4-6 hours; then cool the above reaction solution to room temperature, control the temperature not to exceed 35 degrees, add 3N-6N hydrochloric acid; then separate and reserve The organic phase, then the aqueous phase is extracted with dichloroethane, the organic ph...

Embodiment 1

[0040] A. Synthesis of 4-(4-chloroanilino)-4-oxobutanoic acid: 127g of 4-chloroaniline and 100g of succinic anhydride were dissolved in 600mL of dichloroethane, and then heated under reflux for 6 hours. After the reaction was completed, dichloroethane was distilled off under pressure. Add 300 mL of cold 1N hydrochloric acid to the residue, and stir for 10 minutes; 212 g of 4-(4-chloroanilino)-4-oxobutyric acid are filtered as a white solid. The yield is 93.4%.

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Abstract

The invention belongs to the organic synthesis field, and specifically relates to a synthetic method of 7-chloro-1,2,3,4-tetrahydrobenzo[b]azepine-5-one. According to the invention, the technical problems to be solved are low yield, high cost and difficult after-treatment purification of the existing synthetic method; a technical scheme for solving the technical problems is to provide a synthetic method of 7-chloro-1,2,3,4-tetrahydrobenzo[b]azepine-5-one; the synthetic method comprises the following steps of: carrying out an acylation reaction between 4-chloroaniline and succinic anhydride to obtain 4-(4-chloroaniline)-4-oxobutyric acid; carrying out an intramolecular Friedel-Craft reaction on 4-(4-chloroaniline)-4-oxobutyric acid to obtain 7-chloro-3,4-tetrahydrobenzo[b]azepine-2,5-one; reacting 7-chloro-3,4-tetrahydrobenzo[b]azepine-2,5-one with ethylene glycol to obtain 7-chloro-3,4-tetrahydrobenzo[b]azepine-2-one-5-glycol ketal; reducing 7-chloro-3,4-tetrahydrobenzo[b]azepine-2-one-5-glycol ketal, and carrying out de-ketalation under an acidic condition to obtain 7-chloro-1,2,3,4-tetrahydrobenzo[b]azepine-5-one. The invention provides a new method which is short in steps and high in total yield.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and specifically relates to a synthesis method of 7-chloro-1,2,3,4-tetrahydrobenzo[b]azepin-5-one. Background technique [0002] 7-Chlorobenzoheptanone is the core intermediate for the preparation of tolvaptan. Tolvaptan is a non-peptide selective antidiuretic hormone V2 receptor antagonist developed by Otsuka (Otsuka, Japan). In May 2009, the FDA approved tolvaptan tablets (tolvaptan, Samsca) for the treatment of hyponatremia , is the only oral selective vasopressin antagonist approved for the treatment of this disorder. It is mainly used to treat hyponatremia caused by congestive heart failure, liver cirrhosis, and antidiuretic hormone deficiency syndrome. Tolvaptan can significantly reduce the patient's body weight and edema without disrupting the blood electrolyte balance. Tolvaptan was well tolerated, and water intake did not need to be restricted during treatment. The market prospect is...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D223/16
CPCC07D223/16
Inventor 魏庚辉黄湘川郭鹏
Owner ASTATECH CHENGDU BIOPHARM CORP
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