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Novel preparation method of quetiapine

A kind of technology of quetiapine and piperazine, applied in directions such as carboxylate preparation, organic chemistry, etc., can solve the problems of time-consuming, difficult to adopt, long route and the like

Inactive Publication Date: 2014-04-16
WUXI QIANHAO BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These traditional process routes are long, time-consuming, and the total yield is low, and there are great defects in industrialized production, so it is difficult to adopt

Method used

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  • Novel preparation method of quetiapine
  • Novel preparation method of quetiapine

Examples

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Effect test

example 1

[0017] Heat 100 grams (1.2mol) of anhydrous piperazine and 240 grams (1.5mol) of piperazine dihydrochloride to 120 degrees Celsius, add dropwise 150 grams (1.2mol) of 2-(2-chloroethoxy)ethanol, add Continue heating and stirring after completion, raise the temperature to 136-140 degrees Celsius, and keep it for 1 hour, and stop heating after TLC shows that the reaction is complete. When the temperature drops to 80 degrees Celsius, add 500 milliliters of 95% ethanol, cool overnight in the refrigerator, filter and recover piperazine dihydrochloride the next day, wash the filter cake fully with a small amount of ethanol, combine the filtrates, and add 30% sodium hydroxide solution 200 grams of alkalization, filtered off insoluble inorganic salts; concentrated to remove the solvent, extracted the residue with ethyl acetate, passed through dry hydrogen chloride gas, filtered and dried to obtain a white solid 1-[2-(2-hydroxyethoxy Base) ethyl] piperazine hydrochloride; the solid cont...

example 2

[0019] Heat 100 grams (1.2mol) of anhydrous piperazine and 240 grams (1.5mol) of piperazine dihydrochloride to 120 degrees Celsius, add dropwise 150 grams (1.2mol) of 2-(2-chloroethoxy)ethanol, add Continue heating and stirring after completion, raise the temperature to 136-140 degrees Celsius, and keep it for 1 hour, and stop heating after TLC shows that the reaction is complete. When the temperature drops to 80 degrees Celsius, add 500 milliliters of 95% ethanol, cool overnight in the refrigerator, filter and recover piperazine dihydrochloride the next day, wash the filter cake fully with a small amount of ethanol, combine the filtrates, and add 30% sodium hydroxide solution 200 grams of alkalization, filter out insoluble inorganic salts; after concentrating to remove the solvent, vacuum distillation collects the fraction at 168-172 degrees Celsius / 10 mmHg to obtain 145 grams of colorless to light yellow transparent liquid 1-[2-( 2-Hydroxyethoxy)ethyl]piperazine, the yield i...

example 3

[0021] Dissolve 100 g (1.2 mol) of anhydrous piperazine in 1 L of toluene, heat to reflux, add dropwise 150 g (1.2 mol) of 2-(2-chloroethoxy)ethanol, and continue to reflux and stir for 5 hours , TLC showed that the reaction was complete and the heating was stopped. When the temperature drops to room temperature, add 200 grams of 30% sodium hydroxide solution to alkalinize, filter out insoluble inorganic salts; after concentrating to remove the solvent, extract the residue with ethyl acetate, pass through dry hydrogen chloride gas, and obtain White solid 1-[2-(2-hydroxyethoxy)ethyl]piperazine hydrochloride; after recrystallization once with 90% ethanol aqueous solution, 180 grams of white crystals can be obtained, the yield is 60%, and the content can reach 99% above;

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Abstract

The invention discloses a high-efficient and simple method used for preparing high purity 1-[2-(2-hydroxyethoxy)ethyl]piperazine hydrochloride. The preparation method is used for replacing a method used for preparing quetiapine by reacting a free alkali derivative with 11-chloro-dibenzo[b, f](1, 4)thiazepine. According to the preparation method, low-temperature recrystallization is adopted for purifying 1-[2-(2-hydroxyethoxy)ethyl]piperazine hydrochloride so as to avoid residue of unknown piperazidine impurities in high-temperature purification processes, and high purity quetiapine can be obtained in subsequent reactions.

Description

technical field [0001] The invention provides an economical and practical method for preparing quetiapine key intermediate 1-[2-(2-hydroxyethoxy)ethyl]piperazine hydrochloride and using it as a key raw material to prepare high-purity quetiapine fumarate A new approach to thiapine. Background technique [0002] Quetiapine fumarate is an atypical antipsychotic drug that can block a variety of neurotic receptors such as dopamine and serotonin in the brain. Quetiapine fumarate was first reported by the US patent US4879288 on its preparation method and antipsychotic activity, and then FDA approved quetiapine fumarate to be listed in the United States for the treatment of schizophrenia and depression; because of its obvious curative effect And the side effects are small, which has attracted the attention of many pharmaceutical companies and R&D institutions. Quetiapine has the following structure: [0003] [0004] The preparation method reported by U.S. Patent US4879288 is ...

Claims

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Application Information

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IPC IPC(8): C07D295/088C07D281/16C07C57/15C07C51/41
CPCC07D281/16C07D295/088
Inventor 彭海燕蒲小涛
Owner WUXI QIANHAO BIOPHARMA
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