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Preparation method of labetalol hydrochloride

A technology of labetalol hydrochloride and molar ratio, applied in the field of medicine, can solve the problem of low atomic utilization rate

Active Publication Date: 2021-11-26
安徽美致诚药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] However, the above synthetic method uses dibenzylamine as the amino source, and the atom utilization rate of the raw material is not high.

Method used

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  • Preparation method of labetalol hydrochloride
  • Preparation method of labetalol hydrochloride
  • Preparation method of labetalol hydrochloride

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preparation example Construction

[0037] The invention provides a kind of preparation method of labetalol hydrochloride, comprising the following steps:

[0038] (1) Carrying out the first nucleophilic substitution reaction between compound II and benzylamine to obtain compound III;

[0039] (2) Carrying out the second nucleophilic substitution reaction between the compound III and the compound IV to obtain the compound V;

[0040] (3) The compound V is subjected to a catalytic hydrogenation reaction under the action of a catalyst to obtain compound VIII;

[0041] (4) The compound VIII is mixed with hydrochloric acid solution to carry out a salt-forming reaction to obtain labetalol hydrochloride having a structure shown in formula I;

[0042]

[0043] X in the compound II and compound IV is halogen.

[0044] In the present invention, unless otherwise specified, all raw material components are commercially available products well known to those skilled in the art.

[0045] In the present invention, compou...

Embodiment 1

[0069] (1) Preparation of 2-hydroxyl-5-{2-[(phenylmethyl)amino]acetyl}-benzamide (compound III)

[0070] Add 500mL of tetrahydrofuran, 42g of benzylamine and 59g of triethylamine into a four-neck flask, drop the temperature to -10°C and add 200mL of compound II (X=Br, 5-bromoacetyl salicylamide) dropwise with a concentration of 0.5g / L The tetrahydrofuran solution, control the temperature not to exceed -5 °C, keep stirring for 1 hour after the dropwise addition is completed, warm up to room temperature for the first nucleophilic reaction reaction for 2 hours, add 200mL of water to wash, and extract twice with ethyl acetate (300mL each time) , the obtained organic layer was washed once with 100mL saturated sodium bicarbonate, washed once with 100mL saturated brine, dried over anhydrous sodium sulfate, filtered, and the resulting filtrate was concentrated under reduced pressure to constant weight to obtain compound III (100.62g, yield 91.0%), which was directly used in the next r...

Embodiment 2

[0079] Other preparation conditions are the same as in Example 1, and the difference with Example 1 is only: in step (1), formula 5-bromoacetyl salicylamide is replaced by 5-chloroacetyl salicylamide (i.e. X= Cl) to obtain compound III (93.48g, yield 84.54%).

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Abstract

The invention provides a preparation method of labetalol hydrochloride, and belongs to the technical field of medicines. The invention provides a preparation method. The method comprises the following steps: carrying out nucleophilic substitution reaction on 5-halogenated acetyl salicylamide serving as an initial raw material and benzylamine, and then carrying out nucleophilic substitution reaction on the obtained product and 3-halogenated butylbenzene (or carrying out amine-ester exchange reaction on the obtained product and an esterification reaction product of 3-hydroxybutylbenzene and p-toluenesulfonyl chloride); and carrying out catalytic hydrogenation reaction and salifying to obtain the labeolol hydrochloride. According to the preparation method provided by the invention, benzylamine is adopted to replace dibenzylamine, so that the raw materials are high in atom utilization rate and environment-friendly, and atom economy of green chemistry is embodied; wherein the amine-ester exchange reaction is high in selectivity, and the obtained product is directly used for the next-step reaction. The one-step method is adopted to remove the protective agent and reduce carbonyl, so that the process route is shortened; meanwhile, the preparation method is simple and convenient to operate, high in stability and controllability, high in production cost, high in yield and suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of labetalol hydrochloride. Background technique [0002] Labetalol hydrochloride, the chemical name is 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzamide hydrochloride Salt (structural formula below), is an antihypertensive drug with non-selective β-receptor blockade and selective postsynaptic α1 blockade, can reduce peripheral vascular resistance, has membrane stabilizing effect but has no intrinsic sympathomimetic Active, can rapidly lower blood pressure, suitable for the treatment of hypertensive emergencies, such as acute aortic dissection, pheochromocytoma, pregnancy-induced hypertension syndrome. [0003] [0004] Shang Yun etc. (Shang Yun, Wang Yijun, Feng Juncai. Nanjing University Journal, 1980 (1): 61-64.) disclose a kind of synthetic method of labetalol hydrochloride, with 5-bromoacetyl salicylate methyl ester The start...

Claims

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Application Information

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IPC IPC(8): C07C237/30C07C231/12
CPCC07C231/12C07C237/30
Inventor 史卫明史惠忠
Owner 安徽美致诚药业有限公司
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