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A kind of preparation method of quetiapine hemifumarate

A technology of quetiapine fumarate and preparation process, applied in the field of medicine, can solve the problems of low purity of final product, difficult synthesis of intermediates, unstable properties, etc., and achieves simple and easy operation of reaction route, few side reactions, and reduced The effect of separation loss

Inactive Publication Date: 2016-06-29
渭南畅通药化科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The purpose of the present invention is to overcome the shortcomings of the above-mentioned prior art, solve the technical problems that the synthesis of important intermediates in the existing synthesis process is difficult, and the properties are unstable, the total yield is low, and the purity of the final product is not high, and a Can obtain the synthetic method of quetiapine hemifumarate with high purity and high yield

Method used

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  • A kind of preparation method of quetiapine hemifumarate
  • A kind of preparation method of quetiapine hemifumarate
  • A kind of preparation method of quetiapine hemifumarate

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Embodiment 1

[0019] Embodiment 1: Synthesis of quetiapine hemifumarate through the following steps,

[0020] (1) take o-nitrochlorobenzene and thiophenol as raw materials, carry out etherification reaction in a toluene solvent, and dry to obtain 2-nitrodiphenyl sulfide;

[0021] (2) Ethanol is pumped into the reaction tank, put into 2-nitrodiphenyl sulfide and disposable reduced iron powder for hydrogenation reaction, filter, adjust the pH value of the filtrate with hydrochloric acid, and dry to obtain 2-aminodiphenyl sulfide salt salt;

[0022] (3) Pump chloroform into the reaction tank, add triphosgene, stir, then add 2-aminodiphenyl sulfide hydrochloride, reflux, recover chloroform, without separation and purification, add polyphosphoric acid and p-toluenesulfonic acid, heat , put into purified water, precipitate crystals, and dry to obtain 10-H-dibenzo[b,f][1,4]thiazepin-11-one;

[0023] (4) Chlorinating 10-H-dibenzo[b, f][1,4]thiazepine-11-one and phosphorus oxychloride to obtain 11...

Embodiment 2

[0024] Embodiment 2: Synthesis of quetiapine hemifumarate through the following steps,

[0025] (1) 180kg toluene, 40kg thiophenol, and 100kg concentration of 50% sodium carbonate solution are sucked into the 500L reaction tank successively, then drop into 50kg o-nitrochlorobenzene, cover the feeding port, reflux reaction at 80°C for 1 hour, and cool to Stand at 40°C for stratification, wash the organic layer twice with water, concentrate under reduced pressure, crystallize, centrifuge, and dry to obtain 79kg of 2-nitrodiphenyl sulfide (yield: 87.4%, HPLC content: 98.5%, melting point: 79-80°C);

[0026] (2) 180kg of ethanol is pumped into the reaction tank, while stirring, drop into 75kg2-nitrodiphenyl sulfide and 20kg disposable reduced iron powder successively, cover the feeding port, open the steam valve, and reflux reaction for 1.5 hours, down to 15°C, filter, adjust the pH value of the filtrate to 1 with hydrochloric acid, precipitate crystals, centrifuge and dry to obt...

Embodiment 3

[0029] Embodiment 3: Synthesis of quetiapine hemifumarate through the following steps,

[0030] (1) 220kg toluene, 50kg thiophenol, and 140kg concentration of 50% sodium carbonate solution are sucked into the 500L reaction tank successively, then drop into 80kg o-nitrochlorobenzene, cover the feeding port, reflux reaction at 90°C for 1.5 hours, and cool to 35°C, let stand to separate layers, wash the organic layer twice with water, concentrate under reduced pressure, crystallize, centrifuge, and dry to obtain 86kg of 2-nitrodiphenyl sulfide (yield: 88.9%, HPLC content: 98.1%, melting point: 80-81°C);

[0031](2) 220kg of ethanol is pumped into the reaction tank, while stirring, drop into 90kg2-nitrodiphenyl sulfide and 40kg disposable reduced iron powder successively, cover the feeding port, open the steam valve, reflux reaction for 2 hours, and drop to 20°C, filter, adjust the pH value of the filtrate to 2 with hydrochloric acid, precipitate crystals, centrifuge and dry to o...

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Abstract

The invention discloses a preparation method of quetiapine hemifumarate. The preparation method of quetiapine hemifumarate comprises the following steps: etherifying, hydrogenating, condensing and carrying out chlorination by taking o-chloronitrobenzene and thiophenol as raw materials, and finally salifying with fumaric acid, thereby obtaining quetiapine hemifumarate. The production technology is simple to operate and convenient for large-scale production, the cost is saved and the high-purity high-yield quetiapine hemifumarate can be obtained.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a preparation method of an antipsychotic drug, in particular to a new method for synthesizing quetiapine hemifumarate. Background technique [0002] Quetiapine hemifumarate (chemical name: 11-[4-[2-(2-hydroxyethoxy)ethyl]-1 piperazinyl]dibenzo[b,f][1,4]sulfur Azapine hemifumarate) is a kind of atypical antipsychotic drug developed by the British Zeneca company, which achieves the effect of treating schizophrenia (positive, negative) by blocking receptors in the brain such as dopamine and serotonin. It is suitable for the treatment of most schizophrenia; at the same time, it can also improve the cognitive ability of patients. Therefore, the market demand for quetiapine hemifumarate is large, and the clinical application prospect is very broad. [0003] In 1987, Warawa et al. [EP: 240228] first reported the synthetic route of quetiapine hemifumarate. In the report, 2-aminodipheny...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D281/16C07D295/088
CPCC07D281/16C07D295/088
Inventor 畅水平
Owner 渭南畅通药化科技有限公司
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