Method for preparing N-ethyoxyl oxalyl alanine ester

Abstract

The invention discloses a method for preparing N-ethyoxyl oxalyl alanine ester by utilizing a dynamic tubular reactor. The method comprises the following steps: (1) reacting L-alanine, diethyl oxalate and 4-dimethylaminopyridine in the dynamic tubular reactor; (2) removing light components from the reaction liquid; (3) reacting the reaction liquid subjected to light component removal with ethanol in a dynamic tubular reactor; and (4) removing light components to obtain the N-ethyoxyl oxalyl alanine ester. Compared with a traditional tank reactor and a tubular reactor, the method has the advantages that the N-ethoxy oxalyl alanine ester is prepared by adopting the dynamic tubular reactor, and the selectivity of key byproducts, namely N-oxamide and bis-N-oxalyl, can be effectively controlled to be 2% or below through regulation and control of reaction parameters. The process has the advantages that the reaction yield is high, the continuous degree is high, the reaction time is remarkably shortened, and high-toxicity materials such as benzene are not used.

Description

Technical Field

[0001] The invention relates to a preparation method of N-ethoxy oxalyl alanine ester, and belongs to the field of organic chemical synthesis. Background Art

[0002] Vitamin B6 is an important water-soluble vitamin that plays a very important role in regulating human physiological functions and growth and development. N-ethoxy oxalyl alanine ester is an important intermediate for the synthesis of vitamin B6. Its synthesis method uses L-alanine as the starting material and obtains the final N-ethoxy oxalyl alanine ester through different process operations.

[0003] US3646061 mixed alanine, oxalic acid and ethanol for reaction, then distilled off the unreacted ethanol and water, then added ethanol, reacted for a certain period of time, then distilled off the unreacted ethanol and water, and repeated this process to finally obtain N-ethoxy oxalyl alanine ester. Although this method does not use highly toxic water-carrying agents, it has complicated steps and a long reaction time, and is not suitable for industrial production.

[0004] CN86101512A uses alanine, oxalic acid, ethanol, hydrochloric acid and benzene to react with water in a reflux process. Although the reaction efficiency is improved, the reaction time is still very long. A large amount of hydrochloric acid is used, which is highly corrosive to equipment. Benzene is used for water-containing operations, which is highly toxic to the human body. Therefore, the prospect of industrialization is still weak.

[0005] CN104725262 proposes a method for continuously preparing N-ethoxy oxalyl alanine ester. Although the method realizes the continuous production of N-ethoxy oxalyl alanine ester, the problem of low production efficiency is still not solved. Summary of the invention

[0006] In order to solve the above problems, the present invention develops a preparation method for N-ethoxy oxalyl alanine ester, which can effectively solve the problems of low yield, low degree of continuity, long reaction time, and use of highly toxic materials such as benzene.

[0007] To achieve the above invention object, the technical solution of the present invention is as follows:

[0008] A method for preparing N-ethoxy oxalyl alanine ester using a dynamic tubular reactor comprises the following steps:

[0009] (1) reacting L-alanine, diethyl oxalate and 4-dimethylaminopyridine in a two-stage dynamic tubular reactor;

[0010] (2) removing light components from the reaction solution;

[0011] (3) the reaction liquid after light removal and ethanol are reacted in a two-stage dynamic tubular reactor;

[0012] (4) After removing the light components, N-ethoxy oxalyl alanine ester is obtained.

[0013] The reaction equation for this reaction is as follows:

[0014]

[0015] Key by-products:

[0016]

[0017] Preferably, in step (1), the molar feed ratio of L-alanine, diethyl oxalate and 4-dimethylaminopyridine is 1:1-5:0.01-0.05.

[0018] Preferably, step (1) is carried out in a two-stage dynamic tubular reactor, first reacting in stage I, where the reaction temperature of the stage I dynamic tubular reactor is 50-100°C, the pressure is 0.1MPa-1.0MPa, the residence time is 0.2-0.8h, and the rotation speed is 200-500rpm, and then entering the stage II dynamic tubular reactor, the reaction temperature is 120-200°C, the pressure is 0.1MPa-1.0MPa, the residence time is 0.2-0.8h, and the rotation speed of the dynamic tubular reactor is 200-500rpm.

[0019] Preferably, in step (2), the temperature of the reaction liquid light removal tower is 120-150°C, and the light removal pressure is 0.01MPaA-0.1MPaA.

[0020] Preferably, in step (3), the molar amount of ethanol is 2-10 times the amount of L-alanine fed.

[0021] Preferably, step (3) is carried out in a two-stage dynamic tubular reactor, first reacting in the stage III dynamic tubular reactor, the reaction temperature is 50-80°C, the pressure is 0.1MPa-1.0MPa, the residence time is 0.2-0.8h, and the rotation speed is 200-500rpm, and then entering the stage IV dynamic tubular reactor, the reaction temperature is 100-150°C, the pressure is 0.1MPa-1.0MPa, the residence time is 0.2-0.8h, and the rotation speed is 200-500rpm.

[0022] Preferably, in step (4), the temperature of the reaction liquid light removal tower is 120-150°C, and the light removal pressure is 0.01MPaA-0.03MPaA.

[0023] This process uses a dynamic tubular reactor for the first time to realize the acylation reaction of L-alanine ester to produce N-ethoxyoxalylalanine ester. By controlling the dosage of the catalyst 4-dimethylaminopyridine and the two-stage gradient temperature increase, the selectivity of the key by-products N-oxamide and bis-N-oxalyl compounds is effectively controlled, thereby effectively improving the yield of the main product N-ethoxyoxalylalanine ester.

[0024] The present invention adopts the above technical solution and has the following positive effects:

[0025] (1) Dynamic tubular reactors can effectively enhance mass transfer and heat transfer, achieve continuous production, and significantly shorten reaction time;

[0026] (2) No highly toxic materials such as benzene are used as water-carrying agents, and no corrosive materials such as hydrochloric acid are used, so the industrialization prospects are broad;

[0027] (3) By regulating the amount of catalyst 4-dimethylaminopyridine and two-stage gradient temperature control, the selectivity of key by-products N-oxamide and bis-N-oxalyl can be effectively controlled. This process for preparing N-ethoxy oxalyl alanine ester can control the overall reaction selectivity of key by-products N-oxamide and bis-N-oxalyl to be less than 2%, and the selectivity of the main product N-ethoxy oxalyl alanine ester to be greater than 97%. DETAILED DESCRIPTION

[0028] In order to better understand the technical solution of the present invention, the following examples will further illustrate the method provided by the present invention, but the present invention is not limited to the listed examples, and should also include any other known changes within the scope of the claims of the present invention.

[0029] The preparation method of the present invention is described in detail below through more specific examples, but the present invention is not limited to the following examples.

[0030] The main raw materials used in the following examples and comparative examples are as follows:

[0031] L-alanine, diethyl oxalate, 4-dimethylaminopyridine, ethanol, analytical grade, Aladdin;

[0032] Dynamic tubular reactor, the manufacturer is Shandong Weijing Chemical Technology Co., Ltd.

[0033] The gas chromatography reaction test conditions of the present invention are as follows:

[0034] (1) Chromatographic column: non-polar column, DB-5;

[0035] (2) Inlet temperature: 40°C;

[0036] (3) Split ratio: 1:10;

[0037] (4) Heating program: hold at 40 °C for 0.5 min, then increase the temperature to 200 °C at a heating rate of 10 °C / min and hold for 2 min; then increase the temperature to 280 °C at a heating rate of 8 °C / min and hold for 2 min;

[0038] (5) Gas phase detector temperature: 240°C.

[0039] Example 1

[0040] L-alanine, diethyl oxalate and 4-dimethylaminopyridine are introduced into a two-stage dynamic tubular reactor in a molar ratio of 1:1:0.01 for reaction, wherein the reaction temperature of the I-stage dynamic tubular reactor is 100°C, the reaction pressure is 1.0MPa, the residence time is 0.4h, and the rotation speed is 200rpm, and the reaction temperature of the II-stage dynamic tubular reactor is 150°C, the reaction pressure is 0.1MPa, the residence time is 0.3h, and the rotation speed is 200rpm; then the obtained reaction solution is subjected to light removal treatment, the temperature of the light removal tower kettle is 150°C, and the light removal pressure is 0.1MPaA; then the light removal reaction solution is mixed with ethanol (the molar amount of ethanol feed is 6 times that of L-alanine) and introduced into the dynamic tubular reactor for reaction The reaction temperature of the dynamic tubular reactor in stage III is 60° C., the reaction pressure is 0.5 MPa, the residence time is 0.6 h, and the rotation speed is 300 rpm. The reaction temperature of the dynamic tubular reactor in stage IV is 100° C., the reaction pressure is 0.5 MPa, the residence time is 0.4 h, and the rotation speed is 300 rpm. Then, the reaction liquid is subjected to light removal treatment, the temperature of the light removal tower bottom is 140° C., and the light removal pressure is 0.03 MPaA, so as to obtain N-ethoxy oxalyl alanine ester product. The L-alanine conversion rate of the reaction is 99.5%, the selectivity of the main product N-ethoxy oxalyl alanine ester is 97.8%, and the total selectivity of the key by-products N-oxamide and bis-N-oxalyl is 1.8%.

[0041] Example 2

[0042] L-alanine, diethyl oxalate and 4-dimethylaminopyridine are introduced into a two-stage dynamic tubular reactor in a molar ratio of 1:5:0.04 for reaction, wherein the reaction temperature of the I-stage dynamic tubular reactor is 50°C, the reaction pressure is 0.1MPa, the residence time is 0.6h, and the rotation speed is 400rpm, and the reaction temperature of the II-stage dynamic tubular reactor is 200°C, the reaction pressure is 0.1MPa, the residence time is 0.2h, and the rotation speed is 400rpm; then the obtained reaction solution is subjected to light removal treatment, the temperature of the light removal tower kettle is 130°C, and the light removal pressure is 0.06MPaA; then the light removal reaction solution is mixed with ethanol (the molar amount of ethanol feed is 4 times that of L-alanine) and introduced into the dynamic tubular reactor for reaction The reaction temperature of the dynamic tubular reactor in stage III is 70° C., the reaction pressure is 0.4 MPa, the residence time is 0.4 h, and the rotation speed is 400 rpm. The reaction temperature of the dynamic tubular reactor in stage IV is 120° C., the reaction pressure is 0.4 MPa, the residence time is 0.6 h, and the rotation speed is 400 rpm. Then, the reaction liquid is subjected to light removal treatment, the temperature of the light removal tower bottom is 150° C., and the light removal pressure is 0.03 MPaA, so as to obtain N-ethoxy oxalyl alanine ester product. The L-alanine conversion rate of the reaction is 99.7%, the selectivity of the main product N-ethoxy oxalyl alanine ester is 97.9%, and the total selectivity of the key by-products N-oxamide and bis-N-oxalyl is 1.6%.

[0043] Example 3

[0044] L-alanine, diethyl oxalate and 4-dimethylaminopyridine are introduced into a two-stage dynamic tubular reactor in a molar ratio of 1:3:0.05 for reaction, wherein the reaction temperature of the I-stage dynamic tubular reactor is 60°C, the reaction pressure is 0.5MPa, the residence time is 0.8h, and the rotation speed is 300rpm, and the reaction temperature of the II-stage dynamic tubular reactor is 180°C, the reaction pressure is 0.5MPa, the residence time is 0.6h, and the rotation speed is 300rpm; then the obtained reaction solution is subjected to light removal treatment, the temperature of the light removal tower kettle is 120°C, and the light removal pressure is 0.01MPaA; then the light removal reaction solution is mixed with ethanol (the molar amount of ethanol feed is twice that of L-alanine) and introduced into the dynamic tubular reactor for reaction The reaction temperature of the dynamic tubular reactor in stage III is 80° C., the reaction pressure is 0.1 MPa, the residence time is 0.2 h, and the rotation speed is 500 rpm. The reaction temperature of the dynamic tubular reactor in stage IV is 150° C., the reaction pressure is 0.1 MPa, the residence time is 0.3 h, and the rotation speed is 500 rpm. Then, the reaction liquid is subjected to light removal treatment, the temperature of the light removal tower bottom is 120° C., and the light removal pressure is 0.01 MPaA, so as to obtain N-ethoxy oxalyl alanine ester product. The L-alanine conversion rate of the reaction is 99.6%, the selectivity of the main product N-ethoxy oxalyl alanine ester is 98.2%, and the total selectivity of the key by-products N-oxamide and bis-N-oxalyl is 1.4%.

[0045] Example 4

[0046] L-alanine, diethyl oxalate and 4-dimethylaminopyridine are introduced into a two-stage dynamic tubular reactor in a molar ratio of 1:2:0.03 for reaction, wherein the reaction temperature of the I-stage dynamic tubular reactor is 90°C, the reaction pressure is 0.7MPa, the residence time is 0.2h, and the rotation speed is 500rpm, and the reaction temperature of the II-stage dynamic tubular reactor is 120°C, the reaction pressure is 0.7MPa, the residence time is 0.8h, and the rotation speed is 500rpm; then the obtained reaction solution is subjected to light removal treatment, the temperature of the light removal tower kettle is 140°C, and the light removal pressure is 0.04MPaA; then the light removal reaction solution is mixed with ethanol (the molar amount of ethanol feed is 10 times that of L-alanine) and introduced into the dynamic tubular reactor The method comprises the following steps: the first step is to carry out a reaction in which the reaction temperature of the dynamic tubular reactor of stage III is 50° C., the reaction pressure is 0.8 MPa, the residence time is 0.8 h, and the rotation speed is 200 rpm; the reaction temperature of the dynamic tubular reactor of stage IV is 130° C., the reaction pressure is 0.8 MPa, the residence time is 0.2 h, and the rotation speed is 200 rpm; and then the reaction liquid is subjected to light removal treatment, the temperature of the light removal tower bottom is 130° C., and the light removal pressure is 0.02 MPaA, so as to obtain the N-ethoxy oxalyl alanine ester product, the L-alanine conversion rate of the reaction is 99.4%, the selectivity of the main product N-ethoxy oxalyl alanine ester is 97.4%, and the total selectivity of the key by-products N-oxamide and bis-N-oxalyl is 1.9%.

[0047] Example 5

[0048] L-alanine, diethyl oxalate and 4-dimethylaminopyridine are introduced into a two-stage dynamic tubular reactor in a molar ratio of 1:4:0.02 for reaction, wherein the reaction temperature of the I-stage dynamic tubular reactor is 70°C, the reaction pressure is 0.6MPa, the residence time is 0.5h, and the rotation speed is 400rpm, and the reaction temperature of the II-stage dynamic tubular reactor is 160°C, the reaction pressure is 0.6MPa, the residence time is 0.5h, and the rotation speed is 400rpm; then the obtained reaction solution is subjected to light removal treatment, the temperature of the light removal tower kettle is 120°C, and the light removal pressure is 0.01MPaA; then the light removal reaction solution is mixed with ethanol (the molar amount of ethanol feed is 8 times that of L-alanine) and introduced into the dynamic tubular reactor for reaction The reaction temperature of the dynamic tubular reactor in stage III is 60° C., the reaction pressure is 1.0 MPa, the residence time is 0.5 h, and the rotation speed is 400 rpm. The reaction temperature of the dynamic tubular reactor in stage IV is 140° C., the reaction pressure is 1.0 MPa, the residence time is 0.8 h, and the rotation speed is 400 rpm. Then, the reaction liquid is subjected to light removal treatment, the temperature of the light removal tower bottom is 130° C., and the light removal pressure is 0.02 MPaA, so as to obtain N-ethoxy oxalyl alanine ester product. The L-alanine conversion rate of the reaction is 99.8%, the selectivity of the main product N-ethoxy oxalyl alanine ester is 98.1%, and the total selectivity of the key by-products N-oxamide and bis-N-oxalyl is 1.5%.

[0049] Comparative Example 1

[0050] Compared with Example 1, 4-dimethylaminopyridine was not added, and other conditions were consistent with Example 1. The reaction conversion rate was 25.8%, the selectivity of the main product N-ethoxyoxalylalanine ester was 90.4%, and the total selectivity of the key by-products N-oxalamide and bis-N-oxalyl was 8.2%.

[0051] Although the content of the present invention has been described in detail through the above preferred embodiments, it should be appreciated that the above description should not be considered as limiting the present invention. Those skilled in the art will appreciate that, under the guidance of this specification, some modifications or adjustments may be made to the present invention. These modifications or adjustments should also be within the scope defined by the claims of the present invention.

Claims

1. A method for preparing N-ethoxy oxalyl alanine ester using a dynamic tubular reactor, characterized in that: The following steps are involved: (1) reacting L-alanine, diethyl oxalate and 4-dimethylaminopyridine in a two-stage dynamic tubular reactor; (2) removing light components from the reaction solution; (3) the reaction liquid after light removal and ethanol are reacted in a two-stage dynamic tubular reactor; (4) After removing the light components, N-ethoxy oxalyl alanine ester is obtained.

2. The method according to claim 1, characterized in that In step (1), the molar ratio of L-alanine, diethyl oxalate and 4-dimethylaminopyridine is 1:1-5:0.01-0.

05.

3. The method according to any one of claims 1 to 2, characterized in that: In step (1), the reaction temperature of the dynamic tubular reactor in stage I is 50-100° C., the pressure is 0.1 MPa-1.0 MPa, the residence time is 0.2-0.8 h, and the rotation speed is 200-500 rpm.

4. The method according to any one of claims 1 to 3, characterized in that: In step (1), the reaction temperature of the II stage dynamic tubular reactor is 120-200° C., the pressure is 0.1 MPa-1.0 MPa, the residence time is 0.2-0.8 h, and the rotation speed is 200-500 rpm.

5. The method according to any one of claims 1 to 4, characterized in that: In step (2), the temperature of the reactor of the reaction liquid light removal tower is 120-150°C, and the light removal pressure is 0.01MPaA-0.1MPaA.

6. The method according to any one of claims 1 to 5, characterized in that: In step (3), the molar amount of ethanol is 2-10 times that of L-alanine.

7. The method according to any one of claims 1 to 6, characterized in that: In step (3), the reaction temperature of the dynamic tubular reactor in section III is 50-80° C., the pressure is 0.1 MPa-1.0 MPa, the residence time is 0.2-0.8 h, and the rotation speed is 200-500 rpm.

8. The method according to any one of claims 1 to 7, characterized in that: Step (3) IV stage dynamic tubular reactor reaction temperature is 100-150°C, pressure is 0.1MPa-1.0MPa, residence time is 0.2-0.8h, rotation speed is 200-500rpm.

9. The method according to any one of claims 1 to 8, characterized in that: In step (4), the temperature of the reaction liquid light removal tower kettle is 120-150°C, and the light removal pressure is 0.01MPaA-0.03MPaA.

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