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Method for preparing (S)-carvedilol

A technology of reaction and water agent, applied in the field of using 4-hydroxycarbazole to produce-carvedilol and preparing-carvedilol, can solve the problems of reducing the yield of compound 12, etc., and achieves low price, convenient regeneration, and improved The effect of product yield

Active Publication Date: 2013-06-19
SHANDONG CHUANGXIN PHARMA RES & DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in this process, the first step of the reaction will be accompanied by a large amount of water, and then under the catalysis of the base, the epoxy bond in the product compound 12 molecule is prone to ring-opening hydrolysis reaction, which finally reduces the yield of compound 12.

Method used

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  • Method for preparing (S)-carvedilol
  • Method for preparing (S)-carvedilol
  • Method for preparing (S)-carvedilol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] The external circulation water removal system in this embodiment is a single water removal column filled with water removal agent, the size of the water removal column is 1 m×0.12 m inner diameter, and the filling rate of water removal agent is 80%.

[0050] The qualitative and quantitative detection method of reaction substrate and product HPLC is: Alltech Prevail C 18 (250 mm×0.46 mm×5 μm) chromatographic column; mobile phase: methanol:water=75:25; column temperature: 30 ℃; flow rate: 1 mL / min; injection volume: 20 μL; UV detection wavelength: 243 nm .

[0051] 4-Hydroxycarbazole and ( R )-epichlorohydrin with a molar ratio of 1:1, 4-hydroxycarbazole and catalyst sodium hydroxide are mixed with a molar ratio of 1:1.5 to prepare a reaction substrate for subsequent use. Pump 2.45 kg of the mixed reaction substrate into a 3 L reactor, heat to 90 °C and vigorously stir the reaction. During the reaction, the reaction feed liquid is passed into the external circulation fi...

Embodiment 2

[0053] The external circulation water removal system in this embodiment is a parallel combination of two water removal columns filled with water removal agents. The size of the water removal columns is 1 m×0.12 m in inner diameter, and the filling rate of water removal agents is 80%.

[0054] Reaction substrate and product HPLC qualitative and quantitative detection method and operation are all the same as in Example 1, and the implementation steps of changing catalyst dewatering agent and each operating parameter are as follows:

[0055] 4-Hydroxycarbazole and ( R )-epichlorohydrin in a molar ratio of 1:2, 4-hydroxycarbazole and catalyst potassium hydroxide are mixed in a molar ratio of 1:2 to prepare a reaction substrate for subsequent use. Pump 2.45 kg of the mixed reaction substrate into a 3 L reactor, heat to 60 °C and vigorously stir the reaction. The water system is returned to the reactor, and the reaction is stopped after 1 h, and the discharge valve at the bottom of...

Embodiment 3

[0057] The external circulation water removal system in this embodiment is a series combination of three water removal columns filled with water removal agents. The size of the water removal columns is 1 m×0.12 m in inner diameter, and the filling rate of water removal agents is 80%.

[0058] Reaction substrate and product HPLC qualitative and quantitative detection method and operation are all the same as in Example 1, and the implementation steps of changing catalyst dewatering agent and each operating parameter are as follows:

[0059] 4-Hydroxycarbazole and ( R )-epichlorohydrin with a molar ratio of 1:4.5, 4-hydroxycarbazole and catalyst potassium carbonate are mixed with a molar ratio of 1:1 to prepare a reaction substrate for subsequent use. Pump 2.45 kg of the mixed reaction substrate into a 3 L reactor, heat to 45 °C and vigorously stir for reaction. Return to the reaction kettle, stop after reacting for 8 h, open the discharge valve at the bottom of the kettle to di...

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Abstract

The invention belongs to the technical field of medicinal chemistry and particularly relates to a method for preparing (S)-carvedilol. The method comprises: pumping 4-hydroxy carbazole and (R)-epoxy chloropropane into a reaction kettle, wherein in a reaction process, reaction feed liquid is pumped into an external circulation water removing system filled with a water remover; and reacting prepared (S)-4-(2,3-epoxyropoxy)-9H-carbazole with N-benzyl-2-(2-methoxy phenoxy)ethyl amine to obtain (S)-carvedilol. In the reaction process of the first step, water generated in the reaction process is effectively removed by an external circulation water removing device, so that the loss of (S)-4-(2,3-epoxyropoxy)-9H-carbazole is reduced; low-energy-consumption simple and quick production is realized;the conversion rate of the product of the first step, namely (S)-4-(2,3-epoxyropoxy)-9H-carbazole, is over 90 percent; the final (S)-carvedilol yield is over 85 percent; and the utilization rate of the reaction substrate is improved obviously.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical engineering, in particular to a method for preparing (S)-carvedilol, in particular to a method for producing (S)-carvedilol by utilizing 4-hydroxycarbazole ( S )-carvedilol method. Background technique [0002] The chemical name of Carvedilol is 1-(9 H -carbazole-4-oxy)-3-[2-(2-methoxyphenoxy)ethylamino]-2-propanol. Its chemical structural formula is as follows: [0003] [0004] Carvedilol has a strong β-receptor blocking effect, and at the same time blocks α 1 - The pharmacological mechanism of receptors and vasodilation. It has calcium antagonism at high concentrations and can block the renin-angiotensin-aldosterone system. It is mainly used for the treatment of essential hypertension and angina pectoris. Clinical studies have also found that the drug has multiple effects of neurohormone antagonism, can strongly protect vascular endothelial cells, inhibit the migration and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/88
Inventor 卢定强王翠凌岫泉陈佳欧阳平凯江鸿
Owner SHANDONG CHUANGXIN PHARMA RES & DEV