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Quetiapine hemifumarate synthesis technology

A technology of quetiapine fumarate and synthesis process, applied in the direction of organic chemistry and the like, can solve problems such as unfavorable finished product quality control, a large amount of phosphorus-containing waste water, long production cycle, etc., and achieve easy industrial production, high yield, and product quality. excellent effect

Active Publication Date: 2016-12-21
广安凯特制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The shortcoming of this route is: in the first step reaction, use the phosphorus oxychloride of great excess (about 25 times), depressurize steaming out again after reaction finishes, cause a large amount of phosphorus-containing waste waters to be produced, bring more serious problems to environmental treatment. High pressure; in addition, the second step reaction condensation needs 30 hours, resulting in too long production cycle and low overall yield
In this route, the chlorinated product needs to be isolated in solid form, and this product is extremely unstable, which is not conducive to the quality control of the finished product

Method used

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  • Quetiapine hemifumarate synthesis technology
  • Quetiapine hemifumarate synthesis technology
  • Quetiapine hemifumarate synthesis technology

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048](1) Add 113g of isopropanol and 25ml of water into a No. 1 three-necked flask, add 50g of mercaptosalicylic acid and 51.1g of o-chloronitrobenzene under stirring, replace with nitrogen, the system is a cloudy liquid, and then add 32.43g of hydroxide Sodium and 33.1g water solution and 61g water; reflux reaction for 10-12h, TLC detection of mercaptosalicylic acid after the reaction is completed, cool down to 20-30°C, adjust pH<1 with concentrated hydrochloric acid, stir and crystallize for 1h, filter with suction, Washed twice with water and toluene respectively, and dried under reduced pressure at 55°C to obtain 80.3g of 2-(2-nitrophenylmercapto)benzoic acid (compound of formula (I)), with a molar yield of 90% and a purity of 98.5%.

[0049] (2) Add 10.0g of 2-(2-nitrophenylmercapto)benzoic acid and 80g of dichloromethane into No. 2 three-necked flask, add 8.3g of thionyl chloride dropwise, keep warm at 40°C for 4-5h, spin dry, The oil was diluted with 50g of dichloromet...

Embodiment 2

[0055] (1) Add 226g of isopropanol and 50ml of water into a 500ml No. 1 three-neck flask, add 100g of mercaptosalicylic acid and 102.2g of o-chloronitrobenzene under stirring, replace with nitrogen, the system is a turbid liquid, and then add 64.86g of The solution prepared by sodium hydroxide and 66.2g water and 122g water; reflux reaction for 10-12h, TLC detection of mercaptosalicylic acid after the reaction is completed, cool down to 20-30°C, adjust PH<1 with concentrated hydrochloric acid, stir and crystallize for 1h, pump Filter, wash with water and toluene twice respectively, and dry under reduced pressure at 55° C. to obtain 162.4 g of 2-(2-nitrophenylmercapto) benzoic acid (ie, the compound of formula (I)), with a molar yield of 91.0% and a purity of 98.8%.

[0056] (2) Add 40.0g of 2-(2-nitrophenylmercapto)benzoic acid and 320g of dichloromethane into No. 2 three-necked flask, add 33.2g of thionyl chloride dropwise, keep warm at 40°C for 4-5h, spin dry, The oil was di...

Embodiment 3

[0060] (1) Add 452g of isopropanol and 100ml of water into a 1000ml No. 1 three-neck flask, add 200g of mercaptosalicylic acid and 204.4g of o-chloronitrobenzene under stirring, replace with nitrogen, the system is a cloudy liquid, and then add 129.72g of The solution prepared by sodium hydroxide and 132.4g water and 244g water; reflux reaction for 10-12h, TLC detection of mercaptosalicylic acid after the reaction is completed, cool down to 20-30°C, adjust PH<1 with concentrated hydrochloric acid, stir and crystallize for 1h, pump Filter, wash with water and toluene twice respectively, and dry under reduced pressure at 55° C. to obtain 332.8 g of 2-(2-nitrophenylmercapto) benzoic acid (ie the compound of formula (I)), with a molar yield of 90.5% and a purity of 99.0%.

[0061] (2) Add 160.0g 2-(2-nitrophenylmercapto)benzoic acid (compound of formula (I)) and 1280g dichloromethane into No. 2 three-neck flask, add 132.8g thionyl chloride dropwise, and keep warm at 40°C React for...

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Abstract

The invention discloses a quetiapine hemifumarate synthesis technology. The technology comprises the following steps: mixing a compound of formula (II) and C1-C4 alkyl acid, heating the compound of formula (II) and the C1-C4 alkyl acid to 80-100 DEG C, adding zinc powder or iron powder, and carrying out a heat insulation reaction for 4-6 h to obtain quetiapine; and carrying out salt formation on the obtained quetiapine and fumaric acid to obtain quetiapine hemifumarate, wherein a feeding molar ratio of quetiapine to fumaric acid is 1:0.5. The technology has the advantages of simplicity in operation, high yield, high purity of the above obtained product, and easy realization of industrialization.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a synthesis process of quetiapine hemifumarate. Background technique [0002] Quetiapine hemifumarate (Quetiapine Fumarate), is a novel thienazine antipsychotic drug developed by the British Zeneca company, approved by the FDA in 1997, with the trade name Seroquel (Seroquel), mainly applicable to schizophrenia It can also be used to reduce the affective symptoms associated with schizophrenia, such as depression, anxiety and cognitive deficits. [0003] The structural formula of quetiapine hemifumarate is as follows: [0004] [0005] European patent EP282236 discloses the preparation method of hemi-quetiapine fumarate, which uses dibenzothiazepine Ketone as raw material, under the action of phosphorus oxychloride, the chlorinated product 11-chloro-dibenzo[b,f][1,4]thiazepine was obtained 11-Chloro-dibenzo[b,f][1,4]thiazepine Substitution reaction with piperazine ...

Claims

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Application Information

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IPC IPC(8): C07D281/16
CPCC07D281/16
Inventor 谭超周旭东王廷圣邹鑫张稳稳
Owner 广安凯特制药有限公司
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