Preparation method for crystalline dibenzothiazepine derivative

A technology of benzothiazepine and thiazepine, which is applied in the field of chemical drug synthesis, can solve the problems of harsh production conditions, high price and high production cost, and achieve the effects of reducing pollution, reducing the generation of by-products and improving the reaction rate.

Inactive Publication Date: 2015-11-25
XUCHANG HENGSHENG PHARMA
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  • Abstract
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Problems solved by technology

[0009] The authorized Chinese patent CN10891707B discloses the alkoxy compound Ti(OR) of metal titanium 4 As a condensation agent, 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4] is prepared by intramolecular condensation reaction The method of thiazepine, the patent describes that the preferred temperature of the intramolecular condensation reaction is 150°C to 180°C, and there is palladium carbon catalytic hydrogenation reaction, industrialization requires hydrogenation autoclave, and the production conditions are relatively harsh; at the same time, metal titanium The alkoxy compounds and palladium carbon are relatively expensive, and the production cost is high

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  • Preparation method for crystalline dibenzothiazepine derivative
  • Preparation method for crystalline dibenzothiazepine derivative

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Embodiment 1

[0027]Add toluene 200g in the 500ml reaction flask, add dibenzo[b,f][1,4]thiazepin-11-[10H]ketone (50.0g, 0.22mol), triethylamine (33.4g , 0.33mol), N,N-dimethylformamide 12g and oxalyl chloride (41.9g, 0.33mol), the temperature was raised to 100-105°C, and the reaction was kept for 6 hours until the reaction was complete. After the reaction is complete, lower the temperature to 60°C, keep warm at 60-65°C and distill under reduced pressure for 1 hour, then cool the frozen brine to 0°C, add the cooled reaction solution to 330 g of ice water, separate the layers, collect the organic layer and dry it with anhydrous magnesium sulfate to obtain 250 g of 11-chloro-dibenzo[b,f][1,4]thiazepine toluene solution.

[0028] Add 250 g of the obtained 11-chloro-dibenzo[b,f][1,4]thiazepine toluene solution into a 500ml reaction flask, and add potassium carbonate (60.0g, 0.40mol), benzyltriethyl Ammonium chloride (2.3 g, 0.01 mol) was heated to 100° C., and the reaction was kept for 0.5 hour...

Embodiment 2

[0032] Add 300 g of toluene to a 500 ml reaction flask, and add dibenzo[b, f][1,4]thiazepin-11-[10H]one (50.0 g, 0.22 mol), N, N-diiso Propylethylamine (28.4g, 0.22mol), 8g of N,N-dimethylformamide and oxalyl chloride (55.8g, 0.44mol) were heated up to 100-105°C and kept for 4 hours until the reaction was complete. After the reaction is complete, lower the temperature to 60°C, keep warm at 60-65°C and distill under reduced pressure for 1 hour, then cool the frozen brine to 0°C, add the cooled reaction solution to 400g of ice water, separate the layers, collect the organic layer and dry it with anhydrous magnesium sulfate to obtain 350 g of 11-chloro-dibenzo[b,f][1,4]thiazepine toluene solution.

[0033] Add 350 g of the obtained 11-chloro-dibenzo[b,f][1,4]thiazepine toluene solution into a 100ml reaction flask, add anhydrous sodium carbonate (42.4g, 0.40mol) under stirring, tetrabutyl Ammonium bromide (6.4g, 0.02mol), the temperature was raised to 100°C, and the reaction was ...

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Abstract

The invention discloses a preparation method for a crystalline dibenzothiazepine derivative. The crystalline dibenzothiazepine derivative is synthesized through chlorination reaction, condensation reaction and salt forming reaction by taking dibenzo[b,f][1,4]thiazepine-11-[10H]one as an initial raw material. According to the preparation method, in preparation of 11-chlorine-dibenzo[b,f][1,4]thiazepine, phosphorus oxychloride which is high in toxicity and pollution is replaced by oxalyl chloride which is low in toxicity and pollution; the use of N,N-dimethyl aniline which is high in pollution is prevented, so that the pollution on the environment is greatly reduced; by virtue of salification by crystalline 11-[4-[2-(2-hydroxyl ethoxyl)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepine free alkali, acquisition of high quality fumarate is ensured, the production cost is effectively lowered, and the batch production is facilitated.

Description

technical field [0001] The invention belongs to the field of chemical drug synthesis, and in particular relates to a preparation method of crystalline dibenzothiazepine derivatives. Background technique [0002] A crystalline dibenzothiazepine derivative, namely 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][ 1,4]thiazepine, its pharmaceutically acceptable salt is 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f ][1,4]thiazepine hemifumarate, its structure is shown in (iV) below [0003] [0004] Quetiapine hemifumarate, chemical name 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4] Thiazepine hemifumarate can block multiple neurotransmitter receptors such as dopamine (DA) and 5-hydroxytryptamine (5-HT) in the brain. The fourth type of atypical antipsychotic drug has good curative effect on schizophrenia, mood disorders and senile mental disorders, and has few side effects and good tolerance. It is clinically used as a first-line ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D281/16C07C51/41C07C57/15
CPCC07D281/16C07B2200/13
Inventor 蚩晓娜谷志勇吕亚军郭培杨豪杰徐安娜
Owner XUCHANG HENGSHENG PHARMA
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