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Synthetic method of thiazepine compound

A condensation and salt-forming technology, which is applied in the field of preparation of atypical antipsychotics, can solve problems such as severe operating conditions, unstable intermediates, and many impurities in the product, and achieve simple and safe operation, eliminate troublesome handling, and reduce the amount of three wastes Effect

Inactive Publication Date: 2014-05-07
CHENGDU YILUKANG MEDICAL TECH & SERVICE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This type of method has high reagent toxicity, severe operating conditions, and unstable intermediates, which may easily cause problems such as many impurities in the product and low yield.

Method used

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  • Synthetic method of thiazepine compound
  • Synthetic method of thiazepine compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Example 1: Preparation of intermediate Z1 (2-nitro-2'-carboxydiphenylsulfide):

[0019] Add 300ml of absolute ethanol to the reaction flask, add o-bromonitrobenzene (20g, 0.1mol) and thiosalicylic acid (15.4g, 0.1mol) while stirring, add sodium hydroxide (12g, 0.3mol) while stirring , slowly heated to reflux, reacted for 5 hours, cooled to room temperature, stirred for 2 hours, and filtered to obtain yellow solid intermediate Z1 (25.6g, yield 93.0%, mp164~165°C).

Embodiment 2

[0020] Embodiment 2: Preparation of intermediate Z2 (2-amino-2'-carboxydiphenylsulfide):

[0021] Add 200ml of purified water into the reaction flask, add intermediate Z1 (10g, 0.03mol) under stirring, add 150ml of ammonia water dropwise, stir for 15-20 minutes, add ferrous sulfate (15g, 0.1mol), stir and heat to reflux, and react After 6 hours, cool the reaction solution to 40-42°C, add 60ml of methanol, keep stirring for 20 minutes, continue to cool to 10-15 degrees, stir and crystallize for 6 hours, filter, wash the filter cake with a large amount of water, and dry to obtain an off-white solid Intermediate Z2 (6.5g, yield 88%, mp157-158°C).

Embodiment 3

[0022] Example 3: Preparation of intermediate Z3 (10H-dibenzo[b,f][1,4]thiazepin-11-one):

[0023] Add the mixed solvent of toluene / water (90ml / 10ml) into the reaction flask, add the intermediate Z2 (10g, 0.04mol) under stirring and slowly raise the temperature to 90-100 degrees, add concentrated sulfuric acid dropwise, after the addition is complete, raise the temperature to reflux, React for 4 to 5 hours until the Z2 content is less than 1%, slowly cool to room temperature, filter, soak the filter cake with a small amount of methanol, drain it, and dry it to obtain an off-white solid intermediate Z3 (8.5g, yield 92%, mp259~260℃).

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PUM

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Abstract

The invention discloses a synthetic method of a thiazepine compound, in particular to a production process of quetiapine hemifumarate. O-bromonitrobenzene and thiosalicylic acid are used as starting materials and are subjected to displacement, reduction, condensation, halogenation and re-condensation, and then salt formation is performed with fumaric acid to obtain quetiapine hemifumarate. The production process has simple reaction operation and mild conditions and is easy for industrialized production.

Description

technical field [0001] The invention relates to a preparation method of an atypical antipsychotic drug, which belongs to the technical field of medicine, in particular to a production process of quetiapine hemifumarate. Background technique [0002] The chemical names of quetiapine hemifumarate are: [0003] 11-[4-[2-(2-Hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepine hemifumarate, its structure as follows: [0004] [0005] It is an atypical antipsychotic drug first launched in the UK in November 1997 by the British company Zeneca, and it is clinically used as a first-line treatment for schizophrenia. [0006] Most of the synthetic methods reported in the literature use 2-aminodiphenyl sulfide as the starting material, and the amino group is esterified with toxic reagents such as phenyl chloroformate / triphosgene, and then cyclized, substituted, condensed and salt-formed. Method to prepare quetiapine hemifumarate. This type of method has high reagent tox...

Claims

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Application Information

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IPC IPC(8): C07D281/16
CPCC07D281/16
Inventor 李文军陶长戈彭超骆均勇向玲
Owner CHENGDU YILUKANG MEDICAL TECH & SERVICE
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