阅读说明：本技术 一种连续合成甲乙胺的微通道反应工艺 (Microchannel reaction process for continuously synthesizing methyl ethylamine ) 是由 毛苏雅 徐铮 王辉 杨扬 于 2020-04-27 设计创作，主要内容包括：本发明公开了一种连续合成甲乙胺的微通道反应工艺。甲乙胺是合成卡巴拉汀的关键原料之一,卡巴拉汀可用于治疗中度阿尔茨海默症。合成中,N-苯亚甲基甲胺和硫酸二乙酯反应或N-苯亚甲基乙胺和硫酸二甲酯反应均为强放热反应,会导致控温困难,很难进行放大生产；造成副反应增多,导致纯化困难。为解决这一工程问题,本发明提出了一种基于微通道反应器合成甲乙胺的新工艺。具体操作步骤为：将N-苯亚甲基甲胺和硫酸二乙酯、或者N-苯亚甲基乙胺和硫酸二甲酯分别用进料泵注入微混合器,控制反应参数,反应液在碱性条件下分解,即制得甲乙胺。本发明工艺,具有操作简便、反应温和可控和连续生产的优点,显著提高了操作的安全性,极大的降低了操作成本。(The invention discloses a microchannel reaction process for continuously synthesizing methylethylamine. The methyl ethylamine is one of key raw materials for synthesizing the rivastigmine, and the rivastigmine can be used for treating moderate Alzheimer disease. In the synthesis, the reaction of N-benzylidene methylamine and diethyl sulfate or the reaction of N-benzylidene ethylamine and dimethyl sulfate are strong exothermic reactions, which causes difficult temperature control and difficult amplification production; resulting in increased side reactions and difficulty in purification. In order to solve the engineering problem, the invention provides a novel process for synthesizing the methylethylamine based on a microchannel reactor. The specific operation steps are as follows: respectively injecting N-benzylidene methylamine and diethyl sulfate or N-benzylidene ethylamine and dimethyl sulfate into a micro mixer by using a feed pump, controlling reaction parameters, and decomposing a reaction solution under an alkaline condition to obtain the methyl ethylamine. The process has the advantages of simple operation, mild and controllable reaction and continuous production, obviously improves the operation safety and greatly reduces the operation cost.)

1. A microchannel reaction process for continuously synthesizing methylethylamine comprises the following steps: respectively injecting Schiff base N-benzylidene methylamine and diethyl sulfate into a feed inlet of a micro mixer by adopting a plunger pump, adjusting the pressure of a back pressure valve, and controlling the reaction temperature and the flow rate, wherein when a mixture flows from an inlet of the micro mixer to an outlet of the micro mixer, the reaction temperature of at least one reaction module is required to be maintained at 80-180 ℃, and at least one reaction module is required to pass through, and the generated reaction liquid is collected and then further decomposed and then treated to prepare the methyl ethylamine.

2. A microchannel reaction process for continuously synthesizing methylethylamine comprises the following steps: and respectively injecting Schiff base N-benzylidene ethylamine and dimethyl sulfate into a feed inlet of a micro mixer by adopting a plunger pump, adjusting the pressure of a back pressure valve, and controlling the reaction temperature and the flow rate, wherein when the mixture flows from an inlet of the micro mixer to an outlet of the micro mixer, the reaction temperature of at least one reaction module is required to be maintained at 80-180 ℃, and at least one reaction module is required to pass through, and the generated reaction liquid is collected and then further decomposed for post-treatment to prepare the methyl ethylamine.

3. The reaction process of claim 1 and claim 2, wherein: the micro mixer comprises a membrane dispersion micro mixer, a micro sieve pore dispersion mixer, a micro channel mixer and a micro packed bed mixer, and the optimal micro mixer is preferably a micro channel reactor.

4. The reaction process of claim 1 and claim 2, wherein: the reaction temperature is 80-180 ℃, the preferred reaction temperature is 130-180 ℃, and the most preferred reaction temperature is 170 ℃.

5. The reaction process of claim 1 and claim 2, wherein: the material flow rate is 10-200 mL/min, the preferable material flow rate is 30-100 mL/min, and the optimal material flow rate is 60 mL/min.

6. The reaction process of claim 1 and claim 2, wherein: the back pressure valve pressure is 0-8 bar, the preferable back pressure valve pressure is 1-6 bar, and the optimal back pressure valve pressure is 3 bar.

7. The reaction process of claim 1 and claim 2, wherein: the number of the reaction modules is 1-10, the preferable number of the reaction modules is 1-8, and the optimal number of the reaction modules is 5.

8. The reaction process of claim 1, wherein: the molar ratio of the diethyl sulfate to the Schiff base N-benzylidene methylamine is 1:1-2.5:1, the preferable molar ratio is 1:1-1.5:1, and the optimal molar ratio is 1.1: 1.

9. The reaction process of claim 2, wherein: the molar ratio of the dimethyl sulfate to the Schiff base N-benzylidene ethylamine is 1:1-2.5:1, the preferable molar ratio is 1:1-1.5:1, and the optimal molar ratio is 1.1: 1.

Technical Field

The invention belongs to the field of synthesis of raw material medicines for treating Alzheimer's disease, and particularly relates to a microchannel reaction process for continuously synthesizing methylethylamine.

Background

The methyl ethylamine is a key intermediate for synthesizing the rivastigmine, and the rivastigmine is a carbamate acetylcholinesterase inhibitor and can be used for treating moderate Alzheimer's Disease (AD). Research in literature shows that the synthesis of methylethylamine is more, and the preparation process of methylethylamine mainly comprises the following three processes.

The Hainan Shengke life science research institute, kang-Yan-Long (CN101062901A), uses ethylamine and formic ether as initial raw materials, and they firstly undergo the condensation reaction to produce formylethylamine, and the formylethylamine can be further reduced to obtain methyl ethylamine. The process for preparing the methylethylamine has short route and higher yield, but the risk of reduction operation is very high because the metal reducing agents such as lithium aluminum hydride, red aluminum and the like are sensitive to water and can be combusted when meeting water, and in addition, the two reducing agents have higher cost and objectively limit the industrial application of the process. On the basis of the above, researchers (chemical reagent, vol. 32, 6, page 575 & 576) such as Shenyang pharmaceutical university propose an improvement scheme, that is, phosphorus oxychloride/sodium borohydride is used instead of lithium aluminum hydride and sodium borohydride. The production cost is reduced and the operation risk is reduced by adopting the process to synthesize the methylethylamine, but the phosphorus oxychloride is a high-toxicity substance, and in addition, the process can generate a large amount of phosphorus-containing wastewater during the post-treatment, so that the process is difficult to be practically applied under the increasingly severe environmental protection requirements.

Christophe Ruppin et al (US 2011/0166387A 1) adopt acetaldehyde and methylamine as starting materials, raney nickel as a catalyst, and the materials are subjected to hydrogenation reduction in a high-pressure reaction kettle to synthesize the methylethylamine. The synthesis of the methylethylamine by adopting the process has high reaction selectivity, small content of the byproduct N, N-dimethylethylamine and easy separation and purification of the product. However, the process needs to be operated at high temperature and high pressure, so that the requirement on operators is high, and the synthesis risk is high.

A classical Synthesis process of methylethylamine is reported by Organic Synthesis (Vol 5: 758), and a specific Synthesis process route is shown in FIG. 1. Benzaldehyde and methylamine are firstly condensed to generate Schiff base, the Schiff base reacts with methyl iodide to generate quaternary ammonium salt, and the generated quaternary ammonium salt is further decomposed under the alkaline condition to prepare the methyl ethylamine. In the synthesis process, the methylating agent is highly toxic iodomethane, so that the use risk is high; furthermore, methyl iodide has a low boiling point of only 41-43 ℃, and the reaction is required to be carried out at 100 ℃ or higher, so that the reaction vessel needs to be sealed at high pressure, which limits the industrial application of the process.

On the basis of the process, EISAI Chemicals and ANAN Corporation (EP0714885A2) propose that methyl ethylamine can be efficiently synthesized by adopting dimethyl sulfate instead of methyl iodide, and a specific synthetic process route is shown in FIG. 2. Unfortunately, the reaction between schiff base and dimethyl sulfate is a strong exothermic reaction, which causes difficulty in controlling temperature during operation, and if the temperature is too high, side reactions are increased, so it is important to accurately control the reaction temperature.

Compared with the conventional reactor, the microchannel reactor has the characteristics of large specific surface area, small volume, continuous process, easy amplification, good rapid mixing effect, good heat transfer effect and the like. The excellent mass transfer and heat transfer performance is just needed for synthesizing the methylethylamine. So far, no report of process research or equipment technology for continuously synthesizing the methylethylamine based on a microchannel reactor is found.

Disclosure of Invention

The invention aims to provide an improved technology of a preparation process of methylethylamine, and particularly, the invention realizes effective control of the reaction temperature of Schiff base and diethyl sulfate or dimethyl sulfate by innovating a reactor, inhibits side reaction to the maximum extent, improves the conversion rate of raw materials and the safety of operation, simplifies post-treatment operation and reduces the production cost.

The technical scheme of the invention is as follows:

a micro-channel reaction process for continuously synthesizing methylethylamine comprises the following steps: respectively injecting Schiff base N-benzylidene methylamine and diethyl sulfate into a feed inlet of a micro mixer by adopting a plunger pump, adjusting the pressure of a back pressure valve, and controlling the reaction temperature and the flow rate, wherein when a mixture flows from an inlet of the micro mixer to an outlet of the micro mixer, the reaction temperature of at least one reaction module is required to be maintained at 80-180 ℃, and at least one reaction module is required to pass through, and the generated reaction liquid is collected and then further decomposed and then treated to prepare the methyl ethylamine.

A micro-channel reaction process for continuously synthesizing methylethylamine comprises the following steps: and respectively injecting Schiff base N-benzylidene ethylamine and dimethyl sulfate into a feed inlet of a micro mixer by adopting a plunger pump, adjusting the pressure of a back pressure valve, and controlling the reaction temperature and the flow rate, wherein when the mixture flows from an inlet of the micro mixer to an outlet of the micro mixer, the reaction temperature of at least one reaction module is required to be maintained at 80-180 ℃, and at least one reaction module is required to pass through, and the generated reaction liquid is collected and then further decomposed for post-treatment to prepare the methyl ethylamine.

In the two reaction processes, the micro mixer comprises a membrane dispersion micro mixer, a micro sieve pore dispersion mixer, a micro channel mixer and a micro packed bed mixer, and the optimal micro mixer is preferably the micro channel mixer.

In the two reaction processes, the reaction temperature is 80-180 ℃, the preferred reaction temperature is 130-180 ℃, and the most preferred reaction temperature is 170 ℃.

In the two reaction processes, the reaction flow rate is 10-200 mL/min, the preferable reaction flow rate is 30-100 mL/min, and the optimal reaction flow rate is 60 mL/min.

In the two reaction processes, the pressure of the backpressure valve is controlled to be 0-8 bar, the preferable backpressure valve pressure is 1-6 bar, and the optimal backpressure valve pressure is 3 bar.

In the two reaction processes, the number of the reaction modules is 1-10, the preferable number of the reaction modules is 1-8, and the optimal number of the reaction modules is 5.

In the two reaction processes, the molar ratio of diethyl sulfate to Schiff base N-benzylidene methylamine or the molar ratio of dimethyl sulfate to Schiff base N-benzylidene ethylamine is 1:1-2.5:1, the preferred molar ratio is 1:1-1.5:1, and the optimal molar ratio is as follows: 1.1:1.

The invention has the advantages that:

1. the micro-channel reactor is adopted to synthesize the methyl ethyl amine, and the diethyl sulfate or the dimethyl sulfate and the Schiff base can be pumped into the micro-mixing reactor by adopting a plunger pump respectively, so that the instantaneous reaction materials are less, the reaction heat release is small, and the methyl ethyl amine can be quickly synthesized by being assisted with proper temperature reduction. Compared with the traditional synthesis mode, the method has the advantages that the micro mixer is adopted to synthesize the methylethylamine, so that the safety of production operation is greatly improved;

2. the microchannel reactor has excellent heat transfer and mass transfer performance, shortens the operation time, simultaneously realizes accurate control on the temperature, inhibits the occurrence of side reaction to the maximum extent, and improves the conversion rate and the selectivity of raw materials;

3. compared with a kettle type reactor, the microchannel reactor can be operated continuously, the production efficiency is higher, and the operation cost is lower.

Drawings

FIG. 1: a classical synthesis process route of methylethylamine;

FIG. 2: an improved synthesis process route of the methylethylamine;

FIG. 3: representative methylethylamines¹H NMR spectrum.

Detailed Description

The above-described scheme is further illustrated below with reference to specific examples. It should be noted that these examples are for illustrating the present invention and are not intended to limit the scope of the present invention.

Example 1:

in the embodiment, diethyl sulfate and N-benzylidene methylamine (the molar ratio is 1:1) are respectively injected into a microchannel reactor by a plunger metering pump, the temperature is controlled at 80 ℃, the material flow rate is 10 mL/min, a back pressure valve is adjusted to be 0 bar, the materials are received at an outlet after passing through 10 reaction modules, the collected materials are further subjected to post-treatment, and the methylethylamine can be prepared, wherein the product purity is more than 99area%, and the reaction yield is 95%.

Example 2:

in the embodiment, diethyl sulfate and N-benzylidene methylamine (the molar ratio is 2.5:1) are respectively injected into a microchannel reactor by a plunger metering pump, the temperature is controlled at 180 ℃, the material flow rate is 200 mL/min, a back pressure valve is adjusted to be 8 bar, the materials are received at an outlet after passing through 1 reaction module, the collected materials are further subjected to post-treatment, and the methylethylamine can be prepared, wherein the product purity is more than 99area%, and the reaction yield is 96%.

Example 3:

in the embodiment, dimethyl sulfate and N-benzylidene ethylamine (the molar ratio is 1:1) are respectively injected into a microchannel reactor by a plunger metering pump, the temperature is controlled at 80 ℃, the material flow rate is 10 mL/min, a back pressure valve is adjusted to be 0 bar, the materials are received at an outlet after passing through 10 reaction modules, the collected materials are further subjected to post-treatment, and the methyl ethylamine can be prepared, wherein the product purity is more than 99area%, and the reaction yield is 97%.

Example 4:

in the embodiment, dimethyl sulfate and N-benzylidene ethylamine (the molar ratio is 2.5:1) are respectively injected into a microchannel reactor by a plunger metering pump, the temperature is controlled at 180 ℃, the material flow rate is 200 mL/min, a back pressure valve is adjusted to be 8 bar, the materials are received at an outlet after passing through 1 reaction module, the collected materials are further subjected to post-treatment, and the methyl ethylamine can be prepared, wherein the product purity is more than 99area%, and the reaction yield is 94%.

The structure of methylethylamine was confirmed by nuclear magnetic detection, and the nuclear magnetic spectrum of representative methylethylamine is shown in fig. 3.

It should be emphasized that the above-described embodiments are merely illustrative of the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the contents of the present invention and implement the invention, and the protection scope of the present invention is not limited thereby. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.