Internediate for preparing quetiapin and preparation method of the intermediate

A derivative, piperazine technology, applied in the field of new intermediates, can solve problems such as uneconomical, reduced yield, and polluted final products

Inactive Publication Date: 2004-10-20
EGIS GYOGYSZERGYAR NYILVANOSAN MUKODO RESZVENY TARSASAG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The production of this known process on an industrial scale is considered difficult and very uneconomical, for the reasons respectively: crystalline products of acceptable purity can only be obtained after purification by column chromatography; and the gem-haloimides of formula XI are less Stable, easily hydrolyzed in moist air
This side reaction reduces yield when processed in large quantities, and hydrolysis products contaminate the final product
Another disadvantage is that the preparation of 1-(2-hydroxyethoxy)ethylpiperazine requires several reaction steps, making the known process even more uneconomical

Method used

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  • Internediate for preparing quetiapin and preparation method of the intermediate
  • Internediate for preparing quetiapin and preparation method of the intermediate
  • Internediate for preparing quetiapin and preparation method of the intermediate

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0065] Preparation of formula IV starting compound

[0066] Phenyl 2-phenylthiophenylcarbamate

[0067] 20.13 g (0.1 mole) of 2-aminodiphenyl sulfide was dissolved in 250 ml of dichloromethane, and the resulting solution was cooled to 5°C. Half of the solution in which 18.79 g (15.1 ml, 0.12 moles) of phenyl chloroformate was dissolved in 26 ml of dichloromethane was slowly added to the above stirred 2-aminodiphenyl sulfide solution, and then, the chloroformic acid The other half of the phenyl ester solution was added simultaneously with a solution of 3.0 g (0.075 mol) sodium hydroxide and 9.2 g (0.0875 mol) sodium carbonate in 50 ml of water, taking care that the internal temperature did not exceed 10°C. After addition of the above solution, the reaction mixture was stirred at room temperature for 3 hours, the organic phase was separated, washed 3 times with a total of 250 ml of dilute hydrochloric acid, dried over anhydrous magnesium sulfate and evaporated. The residue was...

Embodiment 1

[0074] N-[4-(2-hydroxyethyl)piperazine-1-carbonyl]-2-aminodiphenylsulfide-compound of formula VI

[0075] 32.1g (0.1 moles) of phenyl 2-phenylthiophenylcarbamate were dissolved in 600ml of toluene, and then 13.0g (0.1 moles) of 1-(2-hydroxyethyl)piperene was added to the solution under stirring Zinc. The reaction mixture was allowed to stir at boiling temperature for 2 hours, then cooled to room temperature, washed with 600 ml of 1N sodium hydroxide solution and then twice with 200 ml of water each time. The organic phase was dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from a 10:1 mixture of n-hexane-ethyl acetate, filtered, washed with n-hexane and dried.

[0076] This gave 33.9 g (94.8%) of the title compound in the form of white crystals. Melting point: 96-98°C.

[0077] Analysis: C 19 h 23 N 3 o 2 S(357.478)

[0078] Calculated: C 63.84%, H 6.49%, N 11.75%, S 8.97%;

[0079] Found values: C 63.57%, H 6.52%, N 11.71%, S 9....

Embodiment 2

[0081] N-[4-(2-chloroethyl)piperazine-1-carbonyl]-2-aminodiphenyl sulfide-formula VII title compound

[0082] 18.8g (0.05mol) N-[4-(2-hydroxyethyl)piperazine-1-carbonyl]-2-aminodiphenylsulfide was heated under reflux in 65ml of thionyl chloride for 15 minutes, then evaporated, leaving The compound was crystallized from n-hexane. 18.5 g (89.7%) of product were obtained as the hydrochloride salt of the title compound.

[0083] Melting point: 180-183°C.

[0084] Base formation:

[0085] 2.78g (0.0275 moles) of triethylamine were added to 10.31g (0.025 moles) of the above-mentioned hydrochloride in 250ml of isopropanol solution, the reaction mixture was stirred at room temperature for 1 hour, poured into water, and washed with dichloromethane Extracted, dried over anhydrous magnesium sulfate and evaporated. This gave 8.0 g (85.1%) of the title compound.

[0086] Salts with benzenesulfonic acid

[0087] A solution of 3.48 g (0.022 mol) of benzenesulfonic acid in 10 ml of etha...

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Abstract

The invention refers to a novel process for the preparation of 11-[4-/2-(2-hydroxyethoxy)ethyl/-1-piperazinyl]dibenzo[b,f]-1,4-thiazepine of the formula (I) known as quetiapine. According to the invention, a haloethylpiperazinylthiazepine derivative of the formula (VIII), wherein Hal stands for a halo atom, is reacted with ethylene glycol.

Description

[0001] The present invention is a divisional application of the Chinese patent application with the application number 018040993 and the title of the invention "Preparation method of quetiapine and its intermediate". technical field [0002] The present invention relates to the preparation of 11-[1-[4- / 2-(2-hydroxyethoxy) ethyl / -1-piperazinyl]dibenzo[b,f]-1,4 represented by the following formula - A new approach to thiazepines: [0003] [0004] Its international nonproprietary name is quetiapine. The compound has anti-dopamine and / or serotonin receptor antagonist activity, and is clinically used as an antipsychotic or a neuroleptic. [0005] In addition, the present invention also relates to novel intermediates used in the novel process of the present invention. Background technique [0006] It is known that according to the method described in EP240228, the compound of formula I passes through the geminal imine halide of the following formula [0007] [0008] And...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D281/16C07D295/10C07D295/215
CPCC07D281/16C07D295/215
Inventor D·博茨辛格G·科万因拉克斯G·斯米格G·拉科茨P·托普G·克拉茨奈G·维尔克基尼多纳斯K·纳吉
Owner EGIS GYOGYSZERGYAR NYILVANOSAN MUKODO RESZVENY TARSASAG
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