A process for the preparation of N-ethoxyoxalyl alaninate

Abstract

The application discloses a method for preparing N-ethoxyl oxalyl alanine ester by using a dynamic tubular reactor, which 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 solution; (3) reacting the reaction solution after removing the light components and ethanol in the dynamic tubular reactor; and (4) obtaining N-ethoxyl oxalyl alanine ester after removing the light components. Compared with traditional kettle reactors and tubular reactors, the method adopts the dynamic tubular reactor to prepare N-ethoxyl oxalyl alanine ester, and through the regulation of reaction parameters, the selectivity of key by-products N-oxamide and double N-oxamide can be effectively controlled below 2%. The process has the advantages of high reaction yield, high degree of continuous operation, significantly shortened reaction time and no use of high-toxicity materials such as benzene.

Description

Technical Field

[0001] This invention relates to a method for preparing N-ethoxyoxaloylalanine ester, belonging to the field of organic chemical synthesis. Background Technology

[0002] Vitamin B6 is an important water-soluble vitamin that plays a vital role in regulating human physiological functions and promoting growth and development. N-ethoxyoxalool alanine ester is an important intermediate in the synthesis of vitamin B6. Its synthesis methods all use L-alanine as a starting material and proceed through different processes to obtain the final N-ethoxyoxalool alanine ester.

[0003] US3646061 describes a method involving the reaction of alanine, oxalic acid, and ethanol. Unreacted ethanol and water are then distilled off, followed by the addition of more ethanol. This process is repeated until N-ethoxyoxaloyl alanine ester is obtained. While this method does not use a highly toxic dehydrating agent, the steps are cumbersome and the reaction time is long, making it unsuitable for industrial production.

[0004] CN86101512A involves a reflux reaction of alanine, oxalic acid, ethanol, hydrochloric acid, and benzene with added water. While this improves the reaction efficiency, the reaction time remains very long. The use of large amounts of hydrochloric acid is highly corrosive to equipment. Furthermore, the use of benzene in the water-removed operation poses a significant risk of human toxicity, thus limiting its industrialization potential.

[0005] CN104725262 proposes a method for the continuous preparation of N-ethoxyoxaloyl alanine ester. Although this method achieves the continuous production of N-ethoxyoxaloyl alanine ester, it still fails to solve the problem of low production efficiency. Summary of the Invention

[0006] To address the above problems, this invention develops a method for preparing N-ethoxyoxaloyl alanine ester, which can effectively solve the problems of low yield, low continuity, long reaction time, and the use of highly toxic materials such as benzene.

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

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

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

[0010] (2) The reaction solution removes light components;

[0011] (3) The reaction solution after light removal and ethanol react in a two-stage dynamic tubular reactor;

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

[0013] The reaction equation of the reaction is as follows:

[0014]

[0015] Key by-products:

[0016]

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

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

[0019] Preferably, in step (2), the temperature of the reaction liquid in the light component removal tower kettle is 120-150℃, and the light component 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.

[0021] Preferably, step (3) is carried out in two-stage dynamic tubular reactors, first in III-stage dynamic tubular reactor, the reaction temperature is 50-80℃, the pressure is 0.1MPa-1.0MPa, the residence time is 0.2-0.8h, and the rotation speed is 200-500rpm, then into IV-stage dynamic tubular reactor, the reaction temperature is 100-150℃, 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 in the light component removal tower kettle is 120-150℃, and the light component removal pressure is 0.01MPaA-0.03MPaA.

[0023] The process first uses a dynamic tubular reactor to realize the acylation reaction of L-alanine ester to generate N-ethoxyl oxalyl alanine ester, and through catalyst 4-dimethylaminopyridine dosage regulation and two-stage gradient temperature regulation, the selectivity of key by-products N-oxamide and double N-oxamide is effectively controlled, and the yield of main product N-ethoxyl oxalyl alanine ester is effectively improved.

[0024] The technical scheme of the present application has the following positive effects:

[0025] (1) The dynamic tubular reactor can effectively enhance the mass transfer and heat transfer effect, realize continuous production, and greatly shorten the reaction time;

[0026] (2) No high-toxic material such as benzene is used as a water-carrying agent, and no corrosive material such as hydrochloric acid is used, so the industrialization prospect is broad;

[0027] (3) Through catalyst 4-dimethylaminopyridine dosage regulation and two-stage gradient temperature regulation, the selectivity of key by-products N-oxamide and double N-oxamide is effectively controlled. The process for preparing N-ethoxyl oxalyl alanine ester can control the total reaction selectivity of key by-products N-oxamide and double N-oxamide to be less than 2%, and the selectivity of main product N-ethoxyl oxalyl alanine ester is greater than 97%. DETAILED DESCRIPTION

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

[0029] The preparation method of the present application will be described in more detail by more specific examples, but the present application is not limited to the following examples.

[0030] The main raw material information used in the following examples and comparative examples is as follows:

[0031] L-alanine, oxalic acid diethyl ester, 4-dimethylaminopyridine, ethanol, analytical pure, Aldrich;

[0032] Dynamic tubular reactor, manufacturer: Shandong Weiwei Chemical Technology Co., Ltd.

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

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

[0035] (2) Injection port temperature: 40℃;

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

[0037] (4) Temperature program: 40 °C for 0.5 min, then 10 °C / min to 200 °C for 2 min, then 8 °C / min to 280 °C for 2 min;

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

[0039] Example 1

[0040] L-alanine, diethyl oxalate and 4-dimethylaminopyridine were fed into two-stage dynamic tubular reactors according to a molar ratio of 1:1:0.01, wherein the reaction temperature of the first-stage dynamic tubular reactor was 100 °C, the reaction pressure was 1.0 MPa, the residence time was 0.4 h, and the rotation speed was 200 rpm; the reaction temperature of the second-stage dynamic tubular reactor was 150 °C, the reaction pressure was 0.1 MPa, the residence time was 0.3 h, and the rotation speed was 200 rpm. Then the obtained reaction liquid was subjected to light-removing treatment, the light-removing column temperature was 150 °C, and the light-removing pressure was 0.1 MPaA. Then the light-removing reaction liquid was mixed with ethanol (the molar amount of ethanol was 6 times that of L-alanine) and fed into a dynamic tubular reactor, wherein the reaction temperature of the third-stage dynamic tubular reactor was 60 °C, the reaction pressure was 0.5 MPa, the residence time was 0.6 h, and the rotation speed was 300 rpm; the reaction temperature of the fourth-stage dynamic tubular reactor was 100 °C, the reaction pressure was 0.5 MPa, the residence time was 0.4 h, and the rotation speed was 300 rpm. Then the reaction liquid was subjected to light-removing treatment, the light-removing column temperature was 140 °C, and the light-removing pressure was 0.03 MPaA, thereby obtaining N-ethoxyl oxalyl alaninate product. The conversion rate of L-alanine was 99.5%, the selectivity of the main product N-ethoxyl oxalyl alaninate was 97.8%, and the total selectivity of the key by-products N-oxamide and bis-N-oxamide was 1.8%.

[0041] Example 2

[0042] L-alanine, diethyl oxalate, 4-dimethylaminopyridine were fed into two-stage dynamic tubular reactors according to the molar ratio of 1:5:0.04, wherein the reaction temperature of the first-stage dynamic tubular reactor was 50℃, the reaction pressure was 0.1 MPa, the residence time was 0.6 h, and the rotation speed was 400 rpm; the reaction temperature of the second-stage dynamic tubular reactor was 200℃, the reaction pressure was 0.1 MPa, the residence time was 0.2 h, and the rotation speed was 400 rpm; then the obtained reaction liquid was subjected to light-removing treatment, the light-removing column temperature was 130℃, and the light-removing pressure was 0.06 MPaA; then the light-removing reaction liquid was mixed with ethanol (the molar amount of ethanol was 4 times of L-alanine) and fed into a dynamic tubular reactor, wherein the reaction temperature of the third-stage dynamic tubular reactor was 70℃, the reaction pressure was 0.4 MPa, the residence time was 0.4 h, and the rotation speed was 400 rpm; the reaction temperature of the fourth-stage dynamic tubular reactor was 120℃, the reaction pressure was 0.4 MPa, the residence time was 0.6 h, and the rotation speed was 400 rpm; then the reaction liquid was subjected to light-removing treatment, the light-removing column temperature was 150℃, and the light-removing pressure was 0.03 MPaA, thereby obtaining N-ethyloxalylalanine ester product, the conversion rate of L-alanine was 99.7%, the selectivity of main product N-ethyloxalylalanine ester was 97.9%, and the total selectivity of key by-products N-oxamide and bis-N-oxamide was 1.6%.

[0043] Example 3

[0044] L-alanine, diethyl oxalate, 4-dimethylaminopyridine were fed into two-stage dynamic tubular reactors according to the molar ratio of 1:3:0.05, wherein the reaction temperature of I-stage dynamic tubular reactor was 60℃, the reaction pressure was 0.5 MPa, the residence time was 0.8 h, and the rotation speed was 300 rpm; the reaction temperature of II-stage dynamic tubular reactor was 180℃, the reaction pressure was 0.5 MPa, the residence time was 0.6 h, and the rotation speed was 300 rpm; then the obtained reaction liquid was subjected to light-removing treatment, the light-removing column temperature was 120℃, and the light-removing pressure was 0.01 MPaA; then the light-removing reaction liquid was mixed with ethanol (the molar amount of ethanol was 2 times of L-alanine) and fed into dynamic tubular reactors, wherein the reaction temperature of III-stage dynamic tubular reactor was 80℃, the reaction pressure was 0.1 MPa, the residence time was 0.2 h, and the rotation speed was 500 rpm; the reaction temperature of IV-stage dynamic tubular reactor was 150℃, the reaction pressure was 0.1 MPa, the residence time was 0.3 h, and the rotation speed was 500 rpm; then the reaction liquid was subjected to light-removing treatment, the light-removing column temperature was 120℃, and the light-removing pressure was 0.01 MPaA, thereby obtaining N-ethoxyl oxalyl alanine ester product, the conversion rate of L-alanine was 99.6%, the selectivity of main product N-ethoxyl oxalyl alanine ester was 98.2%, and the total selectivity of key by-products N-oxamide and bis-N-oxamide was 1.4%.

[0045] Example 4

[0046] L-alanine, diethyl oxalate, 4-dimethylaminopyridine were fed into two-stage dynamic tubular reactors according to the molar ratio of 1:2:0.03, wherein the reaction temperature of I-stage dynamic tubular reactor was 90°C, the reaction pressure was 0.7 MPa, the residence time was 0.2 h, and the rotation speed was 500 rpm; the reaction temperature of II-stage dynamic tubular reactor was 120°C, the reaction pressure was 0.7 MPa, the residence time was 0.8 h, and the rotation speed was 500 rpm; then the obtained reaction liquid was subjected to light-removing treatment, the light-removing column temperature was 140°C, and the light-removing pressure was 0.04 MPaA; then the light-removing reaction liquid was mixed with ethanol (the molar amount of ethanol was 10 times of L-alanine), and was fed into dynamic tubular reactors, wherein the reaction temperature of III-stage dynamic tubular reactor was 50°C, the reaction pressure was 0.8 MPa, the residence time was 0.8 h, and the rotation speed was 200 rpm; the reaction temperature of IV-stage dynamic tubular reactor was 130°C, the reaction pressure was 0.8 MPa, the residence time was 0.2 h, and the rotation speed was 200 rpm; then the reaction liquid was subjected to light-removing treatment, the light-removing column temperature was 130°C, and the light-removing pressure was 0.02 MPaA, thereby obtaining N-ethoxyl oxalyl alanine ester product, the conversion rate of L-alanine was 99.4%, the selectivity of main product N-ethoxyl oxalyl alanine ester was 97.4%, and the total selectivity of key by-products N-oxamide and bis-N-oxamide was 1.9%.

[0047] Example 5

[0048] L-alanine, diethyl oxalate and 4-dimethylaminopyridine were fed into two-stage dynamic tubular reactors according to a molar ratio of 1:4:0.02, wherein the reaction temperature of the first-stage dynamic tubular reactor was 70°C, the reaction pressure was 0.6 MPa, the residence time was 0.5 h, and the rotation speed was 400 rpm; the reaction temperature of the second-stage dynamic tubular reactor was 160°C, the reaction pressure was 0.6 MPa, the residence time was 0.5 h, and the rotation speed was 400 rpm; then the obtained reaction liquid was subjected to light-removing treatment, the light-removing column temperature was 120°C, and the light-removing pressure was 0.01 MPaA; then the light-removing reaction liquid was mixed with ethanol (the molar amount of ethanol was 8 times that of L-alanine) and fed into a dynamic tubular reactor, wherein the reaction temperature of the third-stage dynamic tubular reactor was 60°C, the reaction pressure was 1.0 MPa, the residence time was 0.5 h, and the rotation speed was 400 rpm; the reaction temperature of the fourth-stage dynamic tubular reactor was 140°C, the reaction pressure was 1.0 MPa, the residence time was 0.8 h, and the rotation speed was 400 rpm; then the reaction liquid was subjected to light-removing treatment, the light-removing column temperature was 130°C, and the light-removing pressure was 0.02 MPaA, thereby obtaining N-ethoxyl oxalyl alaninate product, the conversion rate of L-alanine was 99.8%, the selectivity of the main product N-ethoxyl oxalyl alaninate was 98.1%, and the total selectivity of the key by-products N-oxamide and bis-N-oxamide was 1.5%.

[0049] Comparative Example 1

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

[0051] Although the content of the present application has been described in detail through the above preferred examples, it should be recognized that the above description should not be considered as a limitation of the present application. Those skilled in the art can understand that some modifications or adjustments can be made to the present application under the teaching of the present specification. These modifications or adjustments should also be within the scope defined by the claims of the present application.

Claims

1. A method for preparing N-ethoxyoxalyl amino acid ester using a dynamic tubular reactor, characterized by, The method comprises the following steps: (A) reacting L-alanine, diethyl oxalate and 4-dimethylaminopyridine in two-stage dynamic tubular reactors; wherein, the reaction is first carried out in the I-stage dynamic tubular reactor, the reaction temperature of the I-stage dynamic tubular reactor is 50-100℃, and the reaction temperature of the II-stage dynamic tubular reactor is 120-200℃; (B) removing light components from the reaction solution; (C) reacting the reaction solution after removing light components and ethanol in two-stage dynamic tubular reactors; wherein, the reaction is first carried out in the III-stage dynamic tubular reactor, the reaction temperature of the III-stage dynamic tubular reactor is 50-80℃, and the reaction temperature of the IV-stage dynamic tubular reactor is 100-150℃; (D) removing light components to obtain N-ethoxyl oxalyl alanine ester.

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

05.

3. The method of claim 1, wherein, In step (A), the reaction temperature of the I-stage dynamic tubular reactor is 50-100℃, the pressure is 0.1MPa-1.0MPa, the residence time is 0.2-0.8h, and the rotation speed is 200-500rpm.

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

5. The method of claim 1, wherein, In step (B), the temperature of the column bottom of the reaction solution is 120-150℃, and the pressure is 0.01MPaA-0.1MPaA.

6. The method of claim 1, wherein, In step (C), the molar amount of ethanol is 2-10 times of that of L-alanine.

7. The method of claim 1, wherein, In step (C), the reaction temperature of the III-stage dynamic tubular reactor is 50-80℃, the pressure is 0.1MPa-1.0MPa, the residence time is 0.2-0.8h, and the rotation speed is 200-500rpm.

8. The method of any one of claims 1, 6-7, wherein, In step (C), the reaction temperature of the IV-stage dynamic tubular reactor is 100-150℃, the pressure is 0.1MPa-1.0MPa, the residence time is 0.2-0.8h, and the rotation speed is 200-500rpm.

9. The method of claim 1, wherein, In step (D), the temperature of the column bottom of the reaction solution is 120-150℃, and the pressure is 0.01MPaA-0.03MPaA.

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