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Method for synthesizing benserazide hydrochloride through continuous flow

A technology of benserazide hydrochloride and benzylhydrazone hydrochloride, which is applied in the fields of hydrazide preparation, hydrazone preparation, organic chemistry, etc., can solve the problems that are not conducive to improving production capacity and unavoidable excessive reaction impurities, and achieve small footprint and easy The effect of industrialized production and low operating costs

Active Publication Date: 2021-07-20
济南同路医药科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] CN103951587A / CN104788338A / US3178476A / WO2015197909A1 patents report the synthesis and preparation method of benserazide hydrochloride. The above-mentioned preparation method has the following technical defects: or the traditional batch reaction requires multi-step separation, which is not conducive to improving production capacity; or in the synthesis of intermediates Unavoidable overreaction impurity B produced during the process

Method used

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  • Method for synthesizing benserazide hydrochloride through continuous flow
  • Method for synthesizing benserazide hydrochloride through continuous flow
  • Method for synthesizing benserazide hydrochloride through continuous flow

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Effect test

Embodiment 1

[0038] refer to figure 1 Flow chart of continuous flow synthesis of benserazide hydrochloride, figure 1 Among them, A is a heat exchanger, B is a flow divider, and the intermediate can be separated by valve adjustment or directly proceed to the next step of reaction: C is a tubular reactor, including a mixer, a horizontal tubular reactor, a vertical tubular reactor, Coiled tube reactors, U-shaped tube reactors, multi-tube parallel tube reactors, etc., D is a back pressure valve, which can automatically adjust the system pressure in real time, trace the process conditions of the flow chemical process, and then achieve reproducible reactions sex.

[0039] A method for continuous flow synthesis of benserazide hydrochloride, the method comprises the following steps:

[0040] S1: Pump 2mol / L ethanol solution of hydrazide hydrochloride (starting material) into heat exchanger A with a residence time of 0.5s, and then transport it to the first tubular reactor C at a flow rate of 10m...

Embodiment 2

[0046] S1: Pump 2mol / L ethanol solution of hydrazide hydrochloride (starting material) into heat exchanger A with a residence time of 0.5s, and then flow into the first tubular reactor C at a flow rate of 12ml / min 1 , the ethanol solution of the trihydroxybenzaldehyde of 2mol / L flows into the first tubular reactor C according to the flow velocity of 12ml / min 1 , react to obtain benzsilhydrazone hydrochloride;

[0047] S2: The benzsilhydrazone hydrochloride ethanol suspension obtained in S1 flows into the second tubular reactor C filled with palladium carbon catalyst 2 , the total flow rate is 30ml / min, and the residence time of 20s is maintained, while the second tubular reactor C 2 Into the hydrogen, to ensure that the second tubular reactor C 2 The internal pressure is 0.1Mpa;

[0048] S3: After continuously collecting the reaction solution, the organic phase is concentrated under reduced pressure, and ethanol is recovered to obtain crude product benserazide hydrochloride...

Embodiment 3

[0051] S1: Pump 2mol / L ethanol solution of hydrazide hydrochloride (starting material) into heat exchanger A with a residence time of 0.5s, then flow into the first tubular reactor C at 13ml / min 1 , the ethanolic solution of trihydroxybenzaldehyde with a concentration of 2mol / L flows into the first tubular reactor C according to the flow velocity of 13ml / min 1, the reaction obtains the ethanol solution of benzylhydrazone hydrochloride;

[0052] S2: The benzsilhydrazone hydrochloride ethanol suspension obtained in S1 flows into the second tubular reactor C filled with palladium carbon catalyst 2 , with a total flow rate of 40ml / min, maintaining a residence time of 20, while feeding the second tubular reactor C 2 Into the hydrogen, to ensure that the second tubular reactor C 2 The internal pressure is about 1.0Mpa;

[0053] S3: After continuously collecting the reaction solution, the organic phase is concentrated under reduced pressure, and ethanol is recovered to obtain crud...

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Abstract

The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method for synthesizing benserazide hydrochloride through continuous flow. The method comprises the following steps: S1, conveying an ethanol solution of a starting material hydrazide hydrochloride to a heat exchanger, then feeding the ethanol solution into a reactor, conveying an ethanol solution of trihydroxy benzaldehyde to the reactor, and conducting reacting to obtain an ethanol suspension of bensezone hydrochloride; S2, feeding the ethanol suspension of the bensezone hydrochloride into another reactor, and introducing hydrogen into the reactor at the same time; and S3, continuously collecting the reaction liquid, carrying out vacuum concentration on the organic phase, recovering ethanol, and obtaining a crude product. According to the benserazide hydrochloride synthesized through the continuous flow reaction method, the highest yield can reach about 88%, the highest purity can reach about 99.7%, an impurity B generated by excessive reaction is reduced, and the content of the impurity B is only 0.23% and is far lower than 0.5% required by pharmacopoeia. In addition, the method disclosed by the invention is simple to operate, easy for industrial production, small in occupied area and low in operation cost.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a continuous flow method for synthesizing benserazide hydrochloride. Background technique [0002] Parkinson's disease is a common chronic disease of the central nervous system. The global anti-Parkinson's disease treatment market has reached a scale of 10 billion US dollars. Pramipexole and levodopa benserazide are the main varieties in clinical medicine. According to the Medical Economic News in 2016, the most commonly used levodopa drugs in clinical practice are dopaserazide and compound levodopa carbidopa. Busrazide Tablets is a compound preparation made of levodopa and benserazide at a ratio of 4:1, and it is a category B variety in the medical insurance catalogue. There are few manufacturers of benserazide hydrochloride bulk drug currently on the market, so it is urgent to develop a preparation method suitable for industrial production. [0003] A...

Claims

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Application Information

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IPC IPC(8): C07C243/34C07C241/04
CPCC07C241/04C07C249/16C07C243/34C07C251/86
Inventor 王海波陈日星刘鸽白瑞刘学森赵海峰
Owner 济南同路医药科技发展有限公司
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