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Preparation method of quetiapine fumarate intermediate

A technology of quetiapine fumarate and an intermediate, applied in the field of medicine, can solve the problems of high production cost, unfavorable environmental protection, high risk, etc., and achieve the effects of improving yield and quality, reducing the generation of waste water, and speeding up the reaction speed.

Active Publication Date: 2019-04-02
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method all has the following disadvantages: (1) a large amount of phosphorus oxychloride is used, the risk is relatively large, and it is not suitable for industrial production; (2) N, N-dimethylaniline is used as a genotoxic impurity, according to ICH regulations, N, N -Dimethylaniline residue in quetiapine finished product will be less than 0.002%, in order to meet the requirements, need to wash with a large amount of water, so just produce a large amount of waste water, be unfavorable for environmental protection; (3) owing to use phosphorus oxychloride, in In the process of washing with water, the water will contain a large amount of phosphorus, which will have an adverse impact on the ecological environment
The shortcoming of this method is mainly that the yield is low, only 66.0%, and the production cost is on the high side

Method used

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  • Preparation method of quetiapine fumarate intermediate
  • Preparation method of quetiapine fumarate intermediate
  • Preparation method of quetiapine fumarate intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Add 135ml of toluene, 15.0g of dibenzo[b,f][1,4]thiazepine-11-[10H]ketone, 8.8g of oxalyl chloride, 4.96g of pyridine and 0.81g of 4- Dimethylaminopyridine, stirred. The temperature was raised to reflux, and the reaction was carried out for 5.0 hours. After the reaction was completed, the temperature dropped below 20°C, 80ml of water was added, stirred for 20-30 minutes, and the layers were separated after standing for 15-20 minutes, and the water layer was discarded. The toluene phase was distilled under reduced pressure to obtain 14.9 g of 11-chloro-dibenzo[b,f][1,4]sulfur nitrogen oil, yield: 91.9%, HPLC: 97.32%.

Embodiment 2

[0034] Add 150ml of toluene, 15.0g of dibenzo[b,f][1,4]thiazepine-11-[10H]ketone, 10.47g of oxalyl chloride, 6.26g of pyridine and 0.81g of 4- Dimethylaminopyridine, stirred. The temperature was raised to reflux, and the reaction was carried out for 4.0 hours. After the reaction was completed, the temperature dropped below 20°C, 80ml of water was added, stirred for 20-30 minutes, and the layers were separated after standing for 15-20 minutes, and the water layer was discarded. The toluene phase was distilled under reduced pressure to obtain 14.7 g of 11-chloro-dibenzo[b,f][1,4]sulfur nitrogen oil, yield: 90.7%, HPLC: 97.41%.

Embodiment 3

[0036] Add 140ml of toluene, 15.0g of dibenzo[b,f][1,4]thiazepine-11-[10H]ketone, 9.5g of oxalyl chloride, 4.96g of pyridine and 0.98g of 4- Pyrrolidinylpyridine, stirred. The temperature was raised to reflux, and the reaction was carried out for 4.5 hours. After the reaction was completed, the temperature dropped below 20°C, and 80ml of water was added, stirred for 20-30 minutes, allowed to stand for 15-20 minutes, and the layers were separated, and the water layer was discarded. The toluene phase was distilled under reduced pressure to obtain 14.8 g of 11-chloro-dibenzo[b,f][1,4]sulfur nitrogen oil, yield: 91.4%, HPLC: 97.38%.

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Abstract

The invention discloses a preparation method of a quetiapine fumarate intermediate. The method comprises the following steps: taking 10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepine and oxalyl chlorideas raw materials to prepare 11-chloro-dibenzo[b,f][1,4]thiazepine in an anhydrous organic solvent under the combined action of 4-substituted pyridine and pyridine, wherein the purity of the product is larger than or equal to 97.0%, and the yield is larger than or equal to 90%. The method has mild reaction conditions, good environmental protection performance and a high product yield, and is easyfor industrial production.

Description

technical field [0001] The invention relates to a preparation method of an antipsychotic drug quetiapine fumarate intermediate, belonging to the technical field of medicine. Background technique [0002] Quetiapine fumarate, chemical name: 11-{4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl}dibenzo[b,f][1,4]sulfur Azapine fumarate. Quetiapine Fumarate (Quetiapine Fumarate) is an antipsychotic drug developed by AstraZeneca, which was first launched in the UK in July 1997. On September 26, 1997, the FDA approved quetiapine to be launched in the United States under the trade name of Seroquel. Quetiapine interacts with a variety of neurotransmitter receptors and is mainly used to treat schizophrenia. It can also reduce the emotional symptoms associated with schizophrenia, such as depression, anxiety and cognitive deficit symptoms. [0003] Quetiapine fumarate structural formula: [0004] [0005] 11-Chloro-dibenzo[b,f][1,4]thiazepine (compound 2) is an intermediate in the synt...

Claims

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Application Information

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IPC IPC(8): C07D281/16
CPCC07D281/16
Inventor 陈中南杨庆坤李洪云刘瑜郑长胜李卓华周显峰
Owner 山东安信制药有限公司
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