Method for preparing high-purity 7-chloro-5-phenyl-benzodiazepine-2-one

A benzodiazepine, high-purity technology, applied in the field of pharmaceutical synthesis technology, can solve the problems of inability to separate out materials, low HPLC purity of intermediates, blockage of condensers, etc., to avoid blockage of condensers, avoid material discharge difficulties, The effect of avoiding material loss

Inactive Publication Date: 2014-05-21
HUAZHONG PHARMA
View PDF2 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The HPLC purity of the intermediate prepared according to the literature process is not high, and without further refining treatment, a large amount of impurities will be brought into the subsequent process, which will eventually lead to the detection of related substances in the quality index of the finished alprazolam exceeding the limit
The main problem in the intermediate preparation process is: in the reaction process, the phenomenon that the condenser is blocked due to the sublimation of ammonium bicarbonate or ammonium carbonate often occurs, and there is a potential safety hazard; the concentration end point at the end of the reaction is not easy to control, and the solvent evaporates Too little amount directly affects the cyclization yield, and the situation that the material is colloidal a...

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Method for preparing high-purity 7-chloro-5-phenyl-benzodiazepine-2-one
  • Method for preparing high-purity 7-chloro-5-phenyl-benzodiazepine-2-one
  • Method for preparing high-purity 7-chloro-5-phenyl-benzodiazepine-2-one

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032]Put 400ml of industrial ethanol, 40g (0.130mol) of 2-chloroacetamido-5-chloro-benzophenone, and 34g of hexamethylenetetramine into the reaction bottle in turn. After stirring evenly, add dropwise at room temperature with a concentration of more than 35% by mass 15ml of refined hydrochloric acid. After the addition, the temperature was raised to reflux for 7 hours. Concentrate under reduced pressure to nearly dryness, cool down to room temperature, add 600ml of chloroform, stir to dissolve. Wash with 100ml×3 purified water, remove the water layer, and add 48ml (0.144mol) of 3mol / L dilute nitric acid dropwise to the chloroform solution under temperature control below 20°C, and gradually precipitate yellow solid particles. After the addition is complete, continue to stir and react at 20°C to 25°C for 2 hours. Filter, put the filter cake into 400ml of purified water and stir for 1 hour, cool down to below 10°C and add a saturated aqueous solution of sodium bicarbonate drop...

Embodiment 2

[0034] Put 300ml of industrial ethanol, 30g (0.097mol) of 2-chloroacetamido-5-chloro-benzophenone, and 25.5g of hexamethylenetetramine into the reaction bottle in turn. After stirring evenly, add dropwise at room temperature with a mass percentage concentration of 35% The above refined hydrochloric acid 12ml. After the addition, the temperature was raised to reflux for 7 hours. Concentrate under reduced pressure to nearly dryness, cool down to room temperature, add 600ml of chloroform, stir to dissolve. Wash with 75ml×3 purified water, remove the water layer, and then add 42ml (0.126mol) of 3mol / L dilute nitric acid dropwise to the chloroform solution under temperature control below 20°C, and gradually precipitate yellow solid particles. After the addition is complete, continue to stir and react at 20°C to 25°C for 2 hours. Filter, put the filter cake into 300ml of purified water and stir for 1 hour, cool down to below 10°C and add a saturated aqueous solution of sodium bica...

Embodiment 3

[0036] Put 500ml of industrial ethanol, 50g (0.162mol) of 2-chloroacetamido-5-chloro-benzophenone, and 42.5g of hexamethylenetetramine into the reaction bottle in turn. After stirring evenly, add dropwise at room temperature with a mass percentage concentration of 35% The above refined hydrochloric acid 19ml. After the addition, the temperature was raised to reflux for 7 hours. Concentrate under reduced pressure to nearly dryness, cool down to room temperature, add 875ml of chloroform, stir to dissolve. Wash with 125ml×3 purified water, remove the water layer, and then add 65ml (0.195mol) of 3mol / L dilute nitric acid dropwise to the chloroform solution under temperature control below 20°C, and gradually precipitate yellow solid particles. After the addition is complete, continue to stir and react at 20°C to 25°C for 2 hours. Filter, put the filter cake into 500ml of purified water and stir for 1 hour, cool down to below 10°C and add a saturated aqueous solution of sodium bic...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention relates to a method for preparing a high-purity important intermediate of alprazolam, namely 7-chloro-5-phenyl-benzodiazepine-2-one. The method comprises the following steps: after a ring-closure reaction taking 2-chloroacetylamino-5-chloro-diphenyl ketone and hexamethylenetetramine as main raw materials, performing vacuum concentration to dryness, and directly adding a refining solvent for clear dissolution; then, washing and layering, and dropwise adding dilute acid for salifying; adding alkaline water into the separated salt in purified water, and freeing to obtain 7-chloro-5-phenyl-benzodiazepine-2-one of which the HPLC (high performance liquid chromatography) purity is not lower than 99.0%. In the method, the end point of the concentration operation after complete reaction is easy to control, the HPLC purity of the product is remarkably increased, and the interference of unavoidable impurities on later preparation of alprazolam is avoided.

Description

technical field [0001] The invention relates to a method for preparing high-purity alprazolam important intermediate 7-chloro-5-phenyl-benzodiazepin-2-one, which belongs to the technical field of pharmaceutical synthesis technology. Background technique [0002] 7-Chloro-5-phenyl-benzodiazepine-2-one is a key intermediate in the synthesis of benzodiazepine sedative-hypnotics such as alprazolam and diazepam. The chemical name of alprazolam is 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-α]benzodiazepine. CNS depressants developed. Because it contains a metabolically stable triazole ring in its molecule, its physiological activity is stronger than that of general benzodiazepines, and its sedative and hypnotic effects are 25-30 times and 3.5-11.3 times that of diazepam, respectively. And it also has obvious antiepileptic and antidepressant effects. The existing alprazolam synthesis process has the phenomenon that the purity of the intermediates is not high, and the fina...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C07D243/28C07D243/26
CPCC07D243/28C07D243/26
Inventor 付林廖俊汤鑫欣薛俊李桂莲仇玲玲喻致蓉魏旭力曾建华刘小波冯旋
Owner HUAZHONG PHARMA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap