Method for continuously synthesizing methyl 3-aminocrotonate

Abstract

The invention relates to a method for continuously preparing methyl 3-aminocrotonate, and belongs to the technical field of chemical preparation. The method comprises the following steps: respectively pumping methyl acetoacetate and ammonia water into a tubular reactor through a metering pump; methyl acetoacetate and ammonia water are subjected to a reaction in a tubular reactor; and after the reaction in the tubular reactor is finished, cooling and crystallizing to obtain the methyl 3-aminocrotonate. According to the method, the conversion rate of the raw material methyl acetoacetate reaches 100%, the reaction time is greatly shortened to be within 10-30 seconds from 2-3 hours, no solvent is needed, the reaction conversion rate is high, no by-product is generated, the yield reaches 95-96%, the gas phase purity reaches 99.5% or above, and the method is suitable for industrial continuous production and has good application prospects.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical preparation and relates to a method for continuously synthesizing 3-aminocrotonic acid methyl ester. Background Art

[0002] 3-aminocrotonic acid methyl ester is an intermediate for the synthesis of dihydrochloric acid drugs and one of the important raw materials for drug synthesis. The current synthesis method is as follows: using methanol as solvent, NH3, NH3·H2O or NH4HCO3 as ammonia sources, NH3 is introduced into methyl acetoacetate for amination reaction to synthesize 3-aminocrotonic acid methyl ester ("Synthesis of 3-aminocrotonic acid methyl ester, an intermediate of dihydrochloric acid drugs" by Han Pengzhao, Xie Zhiyu, Xi Junjie, etc., "Chemical Engineer" CSTPCD 2018 Issue 3). Because this process usually passes ammonia into a methanol solution under low temperature conditions, it is easy to escape and difficult to control, and ammonia is listed in the "List of Hazardous Chemicals", which has potential safety risks during transportation and storage.

[0003] CN202011507772.6 also reported "a method for preparing 3-aminocrotonic acid methyl ester", which uses methanol as solvent, ammonia and methyl acetoacetate for amination reaction to synthesize 3-aminocrotonic acid methyl ester. This process easily produces methanol waste liquid and has a long reaction time, and cannot achieve continuous production.

[0004] The preparation method of 3-aminocrotonic acid methyl ester reported in the literature has a yield of about 75-85%, and the reaction time is generally 2-3 hours. Studies have shown that as the reaction time is prolonged, the proportion of by-products increases, resulting in a decrease in product purity.

[0005]

[0006] It can be seen that the current preparation method of 3-aminocrotonic acid methyl ester has potential safety hazards in industrial applications and is prone to environmental pollution. In addition, the purity and yield of the product need to be improved, and process improvement is urgently needed. Summary of the invention

[0007] In view of the shortcomings of the prior art, the object of the present invention is to provide a method for preparing 3-aminocrotonic acid methyl ester in a continuous manner without solvent and with high reaction conversion rate, so as to meet the needs of industrial production.

[0008] To achieve the purpose of the present invention, the synthetic route is as follows:

[0009]

[0010] The steps include:

[0011] Methyl acetoacetate and aqueous ammonia are respectively pumped into a tubular reactor through metering pumps; methyl acetoacetate and aqueous ammonia react in the tubular reactor; after the reaction inside the tubular reactor is completed, cooling and crystallization are performed to obtain methyl 3-aminocrotonate.

[0012] Furthermore, the tubular reactor is a horizontal dynamic tubular reactor equipped with a high and low temperature integrated machine, and the metering pump is a stainless steel horizontal flow pump with flow control. Preferably, the liquid holding capacity of the tubular reactor is 50 mL.

[0013] Furthermore, the flow rate of ethyl acetoacetate is 20-100 mL / min, the flow rate of aqueous ammonia is 20-200 mL / min, and the flow rate ratio of the two is 1:(1.2-2.0).

[0014] Furthermore, the molar ratio of methyl acetoacetate to aqueous ammonia is 1:1.10-1.20.

[0015] Furthermore, the temperature in the tubular reactor is set to 15-25° C., and the reaction time is 10-25 seconds.

[0016] As a preferred technical solution, the molar ratio of methyl acetoacetate to ammonia water is 1:1.10, the temperature in the tubular reactor is set to 15°C, the reaction time is set to 27 seconds, the conversion rate of methyl acetoacetate is 100%, the product content in the reaction solution is 99.70%, and 3-aminocrotonic acid methyl ester is obtained by cooling and crystallization, with a yield of 95.77% and a gas phase purity of 99.89%.

[0017] As a preferred technical solution, the molar ratio of methyl acetoacetate to ammonia water is 1:1.15, the temperature in the tubular reactor is set to 20°C, the reaction time is set to 15 seconds, the conversion rate of methyl acetoacetate is 100%, the product content in the reaction solution is 99.72%, and 3-aminocrotonic acid methyl ester is obtained by cooling and crystallization, with a yield of 95.59% and a gas phase purity of 99.84%.

[0018] As a preferred technical solution, the molar ratio of methyl acetoacetate to ammonia water is 1:1.2.0, the temperature in the tubular reactor is set to 25°C, the reaction time is set to 10 seconds, the conversion rate of methyl acetoacetate is 100%, the product content in the reaction solution is 99.69%, and 3-aminocrotonic acid methyl ester is obtained by cooling and crystallization, with a yield of 95.63% and a gas phase purity of 99.85%.

[0019] The ammonia water used in the present invention preferably has a mass percentage of 25-28%, and the methyl acetoacetate preferably has a mass percentage of more than 98%.

[0020] The present invention controls the flow rate and amount of the raw material by a metering pump, which is connected to a tubular reactor to achieve continuous preparation of 3-aminocrotonic acid methyl ester, and has the following beneficial effects:

[0021] Compared with patent CN202011507772.6 and the literature "Synthesis of 3-aminocrotonic acid methyl ester, an intermediate of dihydrochloric acid drugs" (Chemical Engineer, 2018 (3): 5-7.), this process realizes a solvent-free reaction, uses a dynamic tubular reactor, accurately controls the material ratio, and shortens the reaction time from 2 to 3 hours to 10 to 30 seconds. There is no side reaction, the raw material conversion rate reaches 100%, the yield reaches 95 to 96%, and the yield is increased by 12 to 22%. The gas phase purity is as high as 99.50% or more, and no methanol waste liquid is generated, realizing green continuous industrial production. Compared with traditional intermittent reactions, dynamic tubular reactors have the following advantages:

[0022] 1. High efficiency: Tubular reactors have the characteristics of small volume, large specific surface, and large heat transfer area per unit volume, and are particularly suitable for reactions with large thermal effects. Since the reactants react quickly and flow fast in tubular reactors, their production capacity is high.

[0023] 2. Continuous production: Tubular reactors are suitable for large-scale and continuous chemical production. They can realize continuous addition of raw materials and continuous discharge of reaction products, improve production efficiency and product quality stability.

[0024] 3. Reaction conditions are easy to control: In a tubular reactor, the molecular residence time of the reactants is equal, and the reactant concentration and chemical reaction rate at any point in the reactor do not change with time, but only with the length of the tube, which helps to accurately control the reaction conditions.

[0025] 4. Low back-mixing degree: Compared with the kettle reactor, the back-mixing degree of the tubular reactor is relatively small. Under low flow conditions, the flow pattern in the tube is close to the ideal fluid flow pattern, which helps to improve the selectivity and yield of the reaction.

[0026] 5. Strong adaptability: Tubular reactors are suitable for both liquid phase reactions and gas phase reactions, especially for pressure reactions. In addition, tubular reactors can also achieve segmented temperature control to meet the needs of different reaction processes. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0028] Figure 1 The schematic diagram of the process for continuously preparing 3-aminocrotonic acid methyl ester of the present invention;

[0029] Figure 2 This is a GC test result diagram of the 3-aminocrotonic acid methyl ester product prepared in Example 1;

[0030] Figure 3 The 3-amino methyl crotonate product prepared in Example 1 1 H NMR spectra. DETAILED DESCRIPTION

[0031] The following detailed descriptions are all illustrative and are intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used in the present application have the same meanings as those commonly understood by those skilled in the art to which the present application belongs.

[0032] Embodiment 1:

[0033] A horizontal tubular reactor suitable for this experiment was selected, equipped with a high and low temperature integrated machine, and the liquid holding capacity of the reactor was 50 mL.

[0034] Methyl acetoacetate was pumped into the tubular reactor via a metering pump, and the flow rate of methyl acetoacetate was 50 mL / min;

[0035] Ammonia water with a mass percentage of 25-28% is introduced into the tubular reactor through a metering pump, and the flow rate of the ammonia water is 60 mL / min; the flow rate ratio of the two is 1:1.2.

[0036] In the above two steps, methyl acetoacetate and aqueous ammonia react simultaneously through a tubular reactor, the temperature in the tubular reactor is set to 15° C., and the reaction time is 27 seconds;

[0037] The molar ratio of methyl acetoacetate to aqueous ammonia is 1:1.10. After the reaction inside the tubular reactor is completed, high-purity 3-aminocrotonic acid methyl ester is obtained by cooling and crystallization at 5-10°C. The yield is 95.77% and the gas phase purity is 99.89%. The conversion rate of methyl acetoacetate is 100%.

[0038] Embodiment 2:

[0039] A horizontal tubular reactor suitable for this experiment was selected, equipped with a high and low temperature integrated machine, and the liquid holding capacity of the reactor was 50 mL.

[0040] Methyl acetoacetate was pumped into the tubular reactor via a metering pump, and the flow rate of methyl acetoacetate was 70 mL / min;

[0041] Ammonia water with a mass percentage of 25-28% is introduced into the tubular reactor through a metering pump, and the flow rate of the ammonia water is 129 mL / min; the flow rate ratio of the two is 1:1.8.

[0042] In the above two steps, methyl acetoacetate and aqueous ammonia react simultaneously through a tubular reactor, the temperature in the tubular reactor is set to 20° C., and the reaction time is 15 seconds.

[0043] The molar ratio of methyl acetoacetate to aqueous ammonia is 1:1.15. After the reaction inside the tubular reactor is completed, high-purity 3-aminocrotonic acid methyl ester is obtained by cooling and crystallization at 5-10°C. The yield is 95.59%, the gas phase purity is 99.84%, and the conversion rate of methyl acetoacetate is 100%.

[0044] Embodiment 3:

[0045] A horizontal tubular reactor suitable for this experiment was selected, equipped with a high and low temperature integrated machine, and the liquid holding capacity of the reactor was 50 mL.

[0046] Methyl acetoacetate was pumped into the tubular reactor via a metering pump, and the flow rate of methyl acetoacetate was 98 mL / min;

[0047] Ammonia water with a mass percentage of 25-28% is introduced into the tubular reactor through a metering pump, and the flow rate of the ammonia water is 196 mL / min; the flow rate ratio of the two is 1:2.0.

[0048] In the above two steps, methyl acetoacetate and aqueous ammonia react simultaneously through a tubular reactor, the temperature in the tubular reactor is set to 25° C., and the reaction time is 10 seconds.

[0049] The molar ratio of methyl acetoacetate to aqueous ammonia is 1:1.20. After the reaction inside the tubular reactor is completed, high-purity 3-aminocrotonic acid methyl ester is obtained by cooling and crystallization at 5-10°C. The yield is 95.63%, the gas phase purity is 99.85%, and the conversion rate of methyl acetoacetate is 100%.

[0050] The invention adopts closed automatic operation to avoid the volatilization of ammonia water, realizes continuous automatic control production, the raw material conversion rate reaches 100%, and the reaction time is greatly shortened from 2 to 3 hours to 10 to 30 seconds.

[0051] The above description is only a preferred embodiment of the present application, and does not impose any form of limitation on the present invention, and is not used to limit the present application. For those skilled in the art, several improvements and modifications may be made without departing from the principles of the present invention, and these improvements and modifications should also be deemed to be included in the scope of protection of the present application.

Claims

1. A method for continuously preparing 3-aminocrotonic acid methyl ester, characterized in that: The method comprises the following steps: injecting methyl acetoacetate and ammonia water into a tubular reactor through metering pumps respectively; reacting methyl acetoacetate and ammonia water in the tubular reactor; cooling and crystallizing to obtain 3-aminocrotonic acid methyl ester after the reaction inside the tubular reactor is completed; The molar ratio of methyl acetoacetate to aqueous ammonia is 1:1.10-1.20; the flow rate of methyl acetoacetate is 20-100 mL / min, the flow rate of aqueous ammonia is 20-200 mL / min, and the flow rate ratio of the two is 1:(1.2-2.0).

2. The method for continuously preparing 3-aminocrotonic acid methyl ester according to claim 1, characterized in that, The tubular reactor used is equipped with a high and low temperature circulation integrated machine.

3. The method for continuously preparing 3-aminocrotonic acid methyl ester according to claim 1 or 2, characterized in that, The molar ratio of methyl acetoacetate to aqueous ammonia is 1:1.10, the temperature in the tubular reactor is set to 15° C., and the reaction time is set to 27 seconds.

4. The method for continuously preparing 3-aminocrotonic acid methyl ester according to claim 1 or 2, characterized in that, The molar ratio of ethyl acetoacetate to aqueous ammonia is 1:1.15, the temperature in the tubular reactor is set to 20° C., and the reaction time is set to 15 seconds.

5. The method for continuously preparing 3-aminocrotonic acid methyl ester according to claim 1 or 2, characterized in that, The molar ratio of methyl acetoacetate to aqueous ammonia is 1:1.20, the temperature in the tubular reactor is set to 25° C., and the reaction time is set to 10 seconds.

Images