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Method for preparing terazosin hydrochloride of optical activity

A terazosin hydrochloride, optically active technology, applied in the field of organic synthesis, can solve the problems of low reaction selectivity, high toxicity of intermediates, difficult to obtain raw materials, etc., and achieves simple process conditions, good selectivity and easy synthesis reaction. The effect of industrial production

Inactive Publication Date: 2005-01-12
DAOXIN MEDICINES INST HAINANDAO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] There are obvious deficiencies in this method: (1), the raw materials used are not easy to obtain, and the intermediates produced are highly toxic
(2), 4-amino-6,7-dimethoxy-2-piperazinyl-4-quinazoline and optically active tetrahydrofuran-2-formic acid in dicyclohexylcarboimide (DCC) and N The acylation reaction in the presence of -hydroxysuccinimide is a reversible ester acylation reaction, because in the molecular structure of 4-amino-6,7-dimethoxy-2-piperazinyl-4-quinazoline There are two nitrogen atoms that can be acylated, so the reaction selectivity is not high, which makes the product not only have many impurities, difficult to separate and purify, but also low yield and difficult to control the quality

Method used

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  • Method for preparing terazosin hydrochloride of optical activity
  • Method for preparing terazosin hydrochloride of optical activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] Preparation of R-(+)-N-(tetrahydro-2-furoyl)piperazine

[0015] R-(+)-tetrahydro-2-furoic acid 50ml ([α] 29℃ =+33.0°, C=1, CHCl 3 ) was added to a 2L three-necked flask, and SOCL was added dropwise at room temperature 2 60ml, the dropwise addition was completed, continued to stir for 4 hours, raised the temperature and refluxed for 1 hour, and distilled under reduced pressure to obtain 57.5g of R-(+)-tetrahydro-2-furoyl chloride.

[0016] Add 91.3g1 of piperazine hexahydrate to a 2L three-necked flask, adjust the pH value to 3.6 with about 85ml of concentrated hydrochloric acid, add 10ml of chloroform and stir the mixture to lower the temperature below 10°C, and add the obtained R- (+)-Tetrahydro-2-furoyl chloride, add anhydrous sodium acetate to adjust the pH of the reactant between 3.5 and 4.0 during the dropwise addition, after the dropwise addition is completed (3~3.5 hours), keep warm at 10~15°C React for 3 hours, adjust the pH of the reaction solution to 2.5 w...

Embodiment 2

[0018] Preparation of R-(+)-terazosin hydrochloride

[0019] 65.8g of 4-amino-2-chloro-6,7-dimethoxyquinazoline, R-(+)-N-(tetrahydro-2-furoyl)piperazine 60g and ethylene glycol monomethyl Add 200ml of ether into a 500ml three-necked flask in turn, pass N2↑ protection, control the temperature at 120-123°C, react for 2 hours, add 150ml of isopropanol and keep it at 65°C, stir and react for 1 hour, cool down, and adjust the pH to 2.5 with concentrated hydrochloric acid After stirring for 10 minutes, filter with suction, wash the filter cake twice with isopropanol, take out the filter cake, add 250ml of 95% ethanol, stir well, adjust the pH value to 8.5 with ammonia water, stir for 40 minutes, filter with suction, filter the cake, Distilled water 500ml, add concentrated hydrochloric acid at 10°C to adjust the pH value to 2.5, stir for 30 minutes, filter, adjust the pH value of the filtrate to 8.5 with ammonia water, keep warm at 40-45°C and stir for 30 minutes, cool to 10-15°C, su...

Embodiment 3

[0022] Preparation of S-(-)-N-(tetrahydro-2-furoyl)piperazine

[0023] The method for preparing R-(+)-N-(tetrahydro-2-furoyl)piperazine in Example 1 was used to prepare S-(-)-N-(tetrahydro-2-furoyl)piperazine. b.p.110-116℃ / 1.8Pa, n D 25.5℃ = 1.5188, [a] D 25.5℃ =-25.0° (C=1, H 2 O).

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Abstract

This invention relates to optically active terazosin hydrochloride i.e. R-(+)-1-(4-amino-6,7-dimethoxy- 2-quinazolyl)-4-[(tetrahydrofuran) carbonyl] piperazine hydrochloride dihydrate; or S-(-)-1-(4-amino-6,7-dimethoxy-2- quinazolyl)-4-[(tetrahydrofuran) carbonyl] piperazine hydrochloride dihydrate. In the prodn. of said product, optically active tetrahydrofuran-2-formic acid and piperazine are used as raw materials to produce optically active N-(tetrahydro-2-(furanformyl) piperazine, then reacting with 2-chloro-4-amino-6,7-dimethoxy quinazole to obtain final product, with high purity, and commercialization prodn.

Description

technical field [0001] The invention belongs to the field of organic synthesis. technical background [0002] Terazosin hydrochloride is selective alpha 1 Beta blockers are widely used in the treatment of urinary obstruction symptoms caused by high blood pressure and benign prostatic hyperplasia. Terazosin has a chiral center and can exist as two optical stereoisomers. Since the structures of receptors and enzymes that interact with drugs in the human body are also three-dimensional, different stereoisomers will have different affinities with receptors and enzymes in different arrangements in the air, resulting in different Therapeutic activity and toxicological properties. U.S. Patent: US5212176 reports that two completely resolved optical isomers of terazosin hydrochloride racemic compound pair α 1 - The affinity for the receptor is comparable, while for α 2 - The affinity of the receptor is 8 times that of the left-handed body is that of the right-handed body. There...

Claims

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Application Information

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IPC IPC(8): C07D405/12
Inventor 万保坤
Owner DAOXIN MEDICINES INST HAINANDAO
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