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Preparation method of valsartan intermediate

An intermediate, the technology of valsartan, which is applied in the field of preparation of valsartan intermediate, can solve the problems of long reaction route and low yield, and achieve the effects of short reaction time, simple post-treatment and easy operation

Pending Publication Date: 2020-07-10
河南豫辰药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Based on the above-mentioned related technical problems, the purpose of the present invention provides a kind of preparation method of valsartan intermediate, to overcome the valsartan intermediate (N-[(2'-cyano-1,1'-linked Benzene-4-base) methyl]-L-valine methyl ester hydrochloride) reaction route is long, the problem that yield is not high

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Embodiment 1

[0028] A preparation method of a valsartan intermediate (N-[(2'-cyano-1,1'-biphenyl-4-yl)methyl]-L-valine methyl ester hydrochloride), the The synthetic route of described valsartan intermediate is:

[0029]

[0030] Preparation method, concrete steps are as follows:

[0031] (1) Add 600kg of methanol to the 2000L reactor, add 200kg of L-valine under constant stirring, lower the temperature in the reactor to -5°C-0°C, slowly add 223.4kg of thionyl chloride dropwise, this process Keep the temperature in the reactor ≤ 10°C. After the dropwise addition, transfer the liquid in the reactor to a 1000L distillation still, slowly raise the temperature until it dissolves in the still, then raise the temperature to 53-55°C, reflux for 6 hours, L-valline Esterification reaction between acid and thionyl chloride to obtain a reaction solution containing L-valine methyl ester hydrochloride; raise the temperature of the reaction solution to <72°C, carry out atmospheric distillation, and ...

Embodiment 2

[0035] A preparation method of valsartan intermediate (N-[(2'-cyano-1,1'-biphenyl-4-yl)methyl]-L-valine methyl ester hydrochloride), specifically Proceed as follows:

[0036] (1) Add 600kg of methanol to the 2000L reactor, add 200kg of L-valine under constant stirring, lower the temperature in the reactor to -5°C-0°C, and slowly add 233.6kg of thionyl chloride dropwise. The temperature in the reaction kettle is ≤10°C. After the dropwise addition, transfer the liquid in the reaction kettle to a 1000L still, slowly heat up to dissolve in the still, then raise the temperature to 53-55°C, reflux for 7 hours, L-valine and Thionyl chloride undergoes an esterification reaction to obtain a reaction solution containing L-valine methyl ester hydrochloride; the temperature of the reaction solution is raised to <72°C, and atmospheric distillation is carried out until no methanol is distilled out, and the atmospheric pressure is stopped. Distillation; reduce the temperature in the still t...

Embodiment 3

[0040] A preparation method of valsartan intermediate (N-[(2'-cyano-1,1'-biphenyl-4-yl)methyl]-L-valine methyl ester hydrochloride), specifically Proceed as follows:

[0041] (1) Add 600kg of methanol to the 2000L reactor, add 200kg of L-valine under constant stirring, drop the temperature in the reactor to -5°C-0, slowly add 223.8kg of thionyl chloride dropwise, the process keeps The temperature in the reactor is less than or equal to 10°C. After the dropwise addition, transfer the liquid in the reactor to a 1000L still, slowly raise the temperature until it dissolves in the still, then raise the temperature to 53-55°C, reflux for 6 hours, L-valine and Thionyl chloride undergoes an esterification reaction to obtain a reaction solution containing L-valine methyl ester hydrochloride; the temperature of the reaction solution is raised to <72°C, and atmospheric distillation is carried out until no methanol is distilled out, and the atmospheric pressure is stopped. Distillation; ...

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Abstract

The invention belongs to the technical field of preparation of medical intermediates, and particularly relates to a preparation method of a valsartan intermediate. The method comprises the following steps: using L-valine and thionyl chloride as raw materials, in the presence of an organic solvent, carrying out esterification reaction to obtain L-valine methyl ester hydrochloride, then reacting theL-valine methyl ester hydrochloride, with 4-Bromomethyl-2-cyanobiphenyl under an alkaline condition, carrying out organic solvent extracting, crystallization, centrifugation and drying to obtain a crude product of N-[(2 '-cyano-1, 1'-biphenyl-4-yl) methyl]-L-valine methyl ester hydrochloride, and refining to obtain the product with main content of 99.5% or above and individual impurity content of0.1% or below. The method is mild in reaction condition, short in reaction time, simple and convenient to operate, simple in aftertreatment, high in yield, few in obtained product impurity, small inenvironmental pollution, low in cost and easy for industrial production.

Description

technical field [0001] The invention belongs to the technical field of preparation of pharmaceutical intermediates, and in particular relates to a preparation method of a valsartan intermediate. Background technique [0002] Hypertension is a common cardiovascular and cerebrovascular disease, and its prevalence is on the rise. According to the latest diagnostic criteria of the WTO, there are at least 100 million hypertensive patients in my country, and hypertension is closely related to the occurrence and development of atherosclerosis and left ventricular hypertrophy. According to data, for every 5-6mmHg decrease in diastolic blood pressure, the incidence of stroke and cardiac complications can be reduced by 30%, so the prevention and treatment of hypertension is of great significance. [0003] Valsartan is the first non-peptide angiotensin P receptor antagonist without an imidazole ring. It has strong antagonistic activity, long half-life, small side effects, good toleran...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C255/58C07C253/30C07C253/34
CPCC07C253/30C07C253/34C07C227/18C07B2200/07C07C255/58C07C229/08
Inventor 傅收吴银强刘培鸿马彦召刘玉层刘文俊郭有钢张增学
Owner 河南豫辰药业股份有限公司
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