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Preparation method for quetiapine intermediate

An intermediate, quetiapine technology, applied in the field of synthesis of chemical drug intermediates, can solve the problems of limiting industrial development prospects, environmental pollution, long production cycle, etc., to improve the reduction reaction yield, shorten the reaction time, and improve the reaction yield. rate effect

Active Publication Date: 2014-12-03
XUCHANG HENGSHENG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the use of column chromatography for purification, the production cost is high and the production cycle is long, which is not conducive to mass production, thus limiting its industrial development prospects
[0006] The preparation methods disclosed in patents WO2004047722A2, US5607929, CN101891707A and CN101925587A are easy to cause environmental pollution in actual production, and the production cost is high, the production cycle is long, and it is not conducive to energy saving and emission reduction, thus limiting its large-scale production

Method used

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  • Preparation method for quetiapine intermediate
  • Preparation method for quetiapine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Add thiosalicylic acid (30.8 g, 0.2 mol) and 200 mL (2.5 mol / L) of aqueous sodium hydroxide solution into a 500 mL three-necked reaction flask, and stir. The temperature was raised to 40° C., o-bromonitrobenzene (44.4 g, 0.22 mol) was added, the temperature was raised to 100° C. and kept for 3 hours until the reaction was complete. The reaction solution was extracted with ethyl acetate to remove impurities, and the aqueous layer was acidified with hydrochloric acid until the pH was 1-2, and a large amount of yellow solid was precipitated to obtain 2-nitro-2'-carboxydiphenylsulfide (52.8 g, Yield 95.9%).

[0020] Put the prepared 2-nitro-2'-carboxydiphenylsulfide (52.8g, 0.19mol) into a 1000mL three-necked reaction flask, add 400mL of anhydrous methanol and stir to dissolve, add 5mL of concentrated sulfuric acid (98%) dropwise, drop After the addition was complete, the reaction was carried out at 60° C. for 8 hours to obtain the reaction liquid of (iii).

[0021] Add 2...

Embodiment 2

[0024] Add thiosalicylic acid (30.8 g, 0.2 mol) and 200 mL (2.5 mol / L) of potassium hydroxide aqueous solution into a 500 mL three-necked reaction flask, and stir. The temperature was raised to 40°C, o-fluoronitrobenzene (34.7 g, 0.22 mol) was added, the temperature was raised to 100°C and kept for 4 hours until the reaction was complete. The reaction solution was extracted with ethyl acetate to remove impurities, and the aqueous layer was acidified with hydrochloric acid until the pH was 2-3, and a large amount of yellow solid was precipitated to obtain 2-nitro-2'-carboxydiphenylsulfide (48.2 g, Yield 87.5%).

[0025] Put the prepared 2-nitro-2'-carboxydiphenylsulfide (48.2g, 0.17mol) into a 1000mL three-necked reaction flask, add 400mL of absolute ethanol and stir to dissolve, add 5mL of concentrated sulfuric acid (98%) dropwise, drop After the addition was complete, the reaction was carried out at 80° C. for 8 hours to obtain the reaction liquid of (iii).

[0026] Add 2.0...

Embodiment 3

[0029] Add thiosalicylic acid (30.8 g, 0.2 mol) and 200 mL (2.5 mol / L) of potassium hydroxide aqueous solution into a 500 mL three-necked reaction flask, and stir. The temperature was raised to 40°C, o-chloronitrobenzene (34.7 g, 0.22 mol) was added, the temperature was raised to 80°C and kept for 8 hours until the reaction was complete. The reaction solution was extracted with ethyl acetate to remove impurities, and the aqueous layer was acidified with hydrochloric acid until the pH was 1-2, and a large amount of yellow solid was precipitated to obtain 2-nitro-2'-carboxydiphenylsulfide (51.5 g, Yield 93.5%).

[0030] Put the prepared 2-nitro-2'-carboxydiphenylsulfide (51.5g, 0.19mol) into a 1000mL three-necked reaction flask, add 400mL of anhydrous methanol and stir to dissolve, add 5mL of concentrated sulfuric acid (98%) dropwise, drop After the addition was complete, the reaction was carried out at 65° C. for 8 hours to obtain the reaction liquid of (iii).

[0031] Add 2.0 ...

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Abstract

The invention discloses a preparation method for a quetiapine intermediate. The preparation method comprises: taking thiosalicylic acid as an initial raw material to prepare 2-nitro-2'-carboxyldiphenyl sulfide, esterifying and reducing, and then performing intramolecular amino-ester exchange reaction for cyclization, so as to obtain the quetiapine intermediate 10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepine. The preparation method is simple, the target product is high in purity, the reaction yield is relatively high, the production cost is effectively reduced, and industrialized production of the high-purity quetiapine intermediate is facilitated to be realized.

Description

technical field [0001] The invention belongs to the field of synthesis of chemical drug intermediates, in particular to a preparation method of quetiapine intermediates. Background technique [0002] Quetiapine, namely 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepine, its The structure is as follows [0003] [0004] Quetiapine is a new type of atypical antipsychotic drug, which can block multiple neurotransmitter receptors such as dopamine (DA) and 5-hydroxytryptamine (5-HT) in the brain. The fourth non-classical antipsychotic drug after azapine, it has good curative effect on schizophrenia, mood disorder and senile mental disorder, and has small side effects and good tolerance. It is clinically used as the first-line treatment of schizophrenia drug use. The currently clinically used quetiapine drug is its fumarate, ie quetiapine hemifumarate. Quetiapine is very effective in the treatment of acute schizophrenia, and it also has a good effect...

Claims

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Application Information

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IPC IPC(8): C07D281/16
CPCC07D281/16
Inventor 吕亚军郭培蚩晓娜谷志勇徐安娜杨豪杰
Owner XUCHANG HENGSHENG PHARMA
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