Method for preparing 7-chloro-2,3,4,5-tetrahydro-1H-1-benzoazepine-2,5-diketone

A kind of technology of benzoazepine and benzodiazepines, which is applied in the field of preparation of benzoazepine compounds, can solve the problems of unsuitable application of industrialized production, low yield, high cost, etc. Easy to obtain, simple process effect

Inactive Publication Date: 2011-09-07
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

[0024] This route is to construct an azepine ring through Beckman 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-benzoazepine-2,5-diketone
  • Method for preparing 7-chloro-2,3,4,5-tetrahydro-1H-1-benzoazepine-2,5-diketone
  • Method for preparing 7-chloro-2,3,4,5-tetrahydro-1H-1-benzoazepine-2,5-diketone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Preparation of Compound 4:

[0049] Put 4-chloroaniline (12.7g, 0.1mol) in a 250mL reaction flask, add toluene (100mL), stir to dissolve 4-chloroaniline, add succinic anhydride (10.0g, 0.1mol) at room temperature, stir for 10min, and the reaction solution Gradually was a paste. The reaction solution was heated to reflux for 1 hour. The reaction solution was allowed to cool to room temperature, filtered, and a little toluene washed the filter cake. The obtained solid was air-dried at 50° C. to obtain a white flaky solid, compound 4 (22.5 g, 0.0988 mol), with a yield of 98.8%. Melting point: 159.1-161.4°C.

Embodiment 2

[0051] Preparation of compound 4:

[0052] Put 4-chloroaniline (12.7g, 0.1mol) in a 250mL reaction flask, add dichloromethane (100mL), stir to dissolve 4-chloroaniline, add succinic anhydride (10.0g, 0.1mol) at room temperature, stir for 10min, The reaction solution gradually became a paste. The reaction solution was heated to reflux for 1.5 hours. Dichloromethane was distilled off under reduced pressure, anhydrous methanol (90 mL) was added, the temperature was raised to reflux, slowly cooled to room temperature, cooled to 0-5°C in an ice-water bath, stirred for 30 min, filtered, and a little methanol washed the filter cake. The obtained solid was air-dried at 50° C. to obtain a white flaky solid, compound 4 (21.1 g, 0.0927 mol), with a yield of 92.7%. Melting point: 159.7-161.5°C.

Embodiment 3

[0054] Preparation of Compound 4:

[0055] Put 4-chloroaniline (12.7g, 0.1mol) in a 250mL reaction flask, add dichloromethane (40mL), stir to dissolve 4-chloroaniline, add succinic anhydride (11.0g, 0.11mol) at room temperature, stir for 10min, The reaction solution gradually became a paste. The reaction was carried out at room temperature for 2 hours. Dichloromethane was distilled off under reduced pressure, anhydrous methanol (90 mL) was added, the temperature was raised to reflux, slowly cooled to room temperature, cooled to 0-5°C in an ice-water bath, stirred for 30 min, filtered, and a little methanol washed the filter cake. The obtained solid was air-dried at 50° C. to obtain a white flaky solid, compound 4 (20.8 g, 0.0915 mol), with a yield of 91.5%. Melting point: 159.0-161.5°C.

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Abstract

The invention relates to a method for preparing a benzoazepine compound, in particular to a novel method for preparing 7-chloro-2,3,4,5-tetrahydro-1H-1-benzoazepine-2,5-diketone. The compound can be used as an intermediate for preparing pitressin antagonist medicament Tolvaptan. By using 4-chloroaniline as a raw material, the method comprises the following steps of: (1) reacting 4-chloroaniline with succinic anhydride in a solvent environment to obtain 4-(4- chlorphenyl amino)-4-oxo-butyric acid; (2) protecting the amino of the compound 4-(4- chlorphenyl amino)-4-oxo-butyric acid by paratoluensulfonyl chloride under the action of alkali in the solvent environment to obtain 4-(N-(4-chlorphenyl)-4-(4-methyl benzolsulfonamido)-4-oxo-butyric acid; and (3) carrying out intramolecular cyclization on the 4-(N-(4-chlorphenyl)-4-(4-methyl benzolsulfonamido)-4-oxo-butyric acid under the action of a condensing agent and removing paratoluensulfonyl to obtain a target product. The process route disclosed by the invention has the advantages of low cost and easiness in acquisition of raw materials, few steps, simple process and convenience for obtaining the target product at high yield and high purity at an industrial production scale.

Description

technical field [0001] The present invention relates to a kind of preparation method of benzazepine compound, specifically a kind of preparation method of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepine-2, A new approach to 5-diketones; this compound can be used as an intermediate for the preparation of the vasopressin antagonist drug Tolvaptan. Background technique [0002] 7-Chloro-2,3,4,5-tetrahydro-1H-1-benzoazepine-2,5-dione (hereinafter referred to as compound 1) can obtain an important intermediate through several chemical reactions 7-chloro-5-hydroxyl-2,3,4,5-tetrahydro-1H-1-benzazepine (hereinafter referred to as compound 6), compound 6 can obtain its chiral isomer (R )-7-chloro-5-hydroxyl-2,3,4,5-tetrahydro-1H-1-benzazepine (hereinafter referred to as compound 7), compound 7 can be used as a novel vasopressin antagonist An important intermediate of the drug Tolvaptan. The structures of compounds 1, 6, and 7 are as follows: [0003] Compound 1 Compound 6 Comp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16
Inventor 顾华平邹华军鲍继胜
Owner 宁波人健药业集团股份有限公司
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