CN101830821B - Chemical synthesis method of N-alcoxyloxalyl alanine ester - Google Patents

Abstract

The invention relates to a chemical synthesis method of N-alcoxyloxalyl alanine ester shown as a formula (I). The method comprises the following steps of: reacting alanine shown and oxalic acid which are shown as the formula (I) in alcohol of C1-C8 for 5-150 hours at 50-150 DEG C under the catalysis of bisulfate shown as a formula (II), wherein water generated in the reaction is timely evaporatedout with a water taking agent through a rectifying column and a water knockout drum; and after the reaction ends, carrying out after-treatment on reaction liquid to obtain the N-alcoxyloxalyl alanineester, wherein the mass ratio of the alanine to the oxalic acid to the bisulfate is 1:(1-10):(0.001-1), and the bisulfate is sodium bisulfate or potassium bisulfate or a mixture of the sodium bisulfate and the potassium bisulfate in arbitrary proportion. In the invention, since the bisulfate is used as a catalyst, and the method has high esterification speed, high reaction yield, low production cost, high catalyst activity, good selectivity, basically no monoesterification by-product, high product purity, easy separation and purification, moderate reaction condition and easy industrialization.

Description

A kind of chemical synthesis method of N-alkoxy oxalyl alanine ester

(1) Technical field

The invention relates to a chemical synthesis method of N-alkoxy oxalyl alanine ester, in particular to a method for producing N-alkoxy oxalyl alanine ester with high yield.

(2) Background technology

N-Alkoxyoxalylalanine ester is widely used in medicine, pesticide and chemical industry, and has high practical value. For example, N-ethoxyoxalylalanine ethyl ester is a key intermediate of vitamin B6.

Before the present invention was made, the chemical synthesis method of prior art N-alkoxy oxalyl alanine ester was to use alanine or alanine ester as raw material, through esterification or acylation synthesis target product, such as (1) Under the catalysis of concentrated hydrochloric acid, alanine, oxalic acid, oxalic acid diester, and ethanol are dehydrated and esterified by continuous distillation under the action of water-carrying agent benzene [China Pharmaceutical Industry Journal, 1994, 25 (9), 385; China Pharmaceutical Industry Journal , 2004, 35(1), 1]. This method takes a long time to react, and uses a large amount of concentrated hydrochloric acid, and the equipment is seriously corroded, and the operation is inconvenient. (2) Alanine ethyl ester and hydrochloric acid are salified, and then under the catalysis of triethylamine, react with oxalic diester to synthesize the target compound [Bull.Chem.Soc.Jpn, 1969, 1435]. This method is relatively expensive Ethyl alanine is a raw material, and the consumption of triethylamine is large and the cost is high. (3) Under non-acidic conditions or in the presence of an organic base catalyst, alanine, oxalic acid, and oxalic diester react in an alcohol solution to prepare the target product. This method is easy to generate a by-product of alanine monoesterification, and is not easy to separate , the yield is not high [CN200480009214.X; WO2004087640]. Other synthetic methods of N-alkoxyoxalylalanine esters have more or less disadvantages such as low yield, cumbersome operation, difficult separation and purification of products, harsh reaction conditions, etc. New methods for the synthesis of alanine esters are urgently needed.

(3) Contents of the invention

The technical problem to be solved by the present invention is to provide a chemical synthesis method of N-alkoxyoxalylalanine ester with reasonable process, high reaction yield, low production cost and easy industrial production.

In order to solve the problems of the technologies described above, the present invention prepares N-alkoxy oxalyl alanine ester with alanine and oxalic acid in the presence of catalyzer, and the specific technical scheme is as follows:

A chemical synthesis method of N-alkoxy oxalylalanine ester shown in formula (I): in C1～C8 alcohol, alanine and oxalic acid shown in formula (II) are in formula (III) Under the catalysis of the shown bisulfate, react at 50°C to 150°C for 5 to 150 hours. During the reaction process, the water produced by the reaction is steamed out in time through the rectification column and the water separator through the water-carrying agent. After the reaction, the reaction liquid passes through Post-treatment to obtain the N-alkoxy oxalylalanine ester; the molar ratio of the alanine, oxalic acid and hydrogen sulfate is 1:1～10:0.001～1; the hydrogen sulfate The salt is sodium bisulfate or potassium bisulfate, or a mixture of the two in any proportion;

MHSO₄  (III)

MHSO ₄ (III)

In formula (I), R is selected from C1-C8 alkyl groups, and in formula (III), M is sodium or potassium. The mass dosage of the water-carrying agent is usually 1 to 10 times the mass of alanine.

The specific operation steps of the method of the present invention are as follows: in the reaction tank with rectification column, water separator and condensation pipe device, first heat and dissolve alanine and oxalic acid in C1-C8 alcohol, and then add catalyst bisulfate react with the water-carrying agent at 50°C-150°C for 5-150 hours, the mass dosage of the water-carrying agent is 1 to 10 times the mass of alanine, and the reaction solution is post-treated to obtain the N-alkoxazol Acyl alanine ester.

Further, the present invention recommends that the reaction temperature is 60-100° C., and the reaction time is 10-40 hours.

Still further, the preferred water-carrying agent of the present invention is one of the following or a mixture of any several in any proportion: benzene, toluene, n-hexane, cyclohexane. The alcohol described in the present invention is preferably one of the following: ethanol, n-propanol or n-butanol.

Furthermore, the preferred mass ratio of alanine, oxalic acid and bisulfate is 1:1-3:0.05-0.1; the preferred mass ratio of alcohol to alanine is 1-100:1.

The post-treatment method recommended by the present invention is: after the reaction is completed, add water to the reaction solution to wash, separate the water layer, take the organic phase and dry it with anhydrous sodium sulfate, evaporate the solvent at normal pressure until the internal temperature reaches 120°C, and recover the grass under reduced pressure. Diester, obtains described N-alkoxy oxalyl alanine ester.

Specifically, the preparation method recommended by the present invention is carried out according to the following steps: in the reaction tank with rectification column, water separator and condensation tube device, first heat alanine and oxalic acid in C1-C8 alcohol Dissolve, then add bisulfate and water-carrying agent, heat up to 60-100°C after the addition, and the reaction time is 10-40 hours: After the reaction is completed, the reaction solution is washed with water, and the water layer is separated, and the organic phase is used for dry After drying with sodium sulfate in water, distill off the solvent until the internal temperature reaches 120°C, and then recover the oxalyl diester under reduced pressure to obtain the N-alkoxyoxalylalanine ester; the amino acid, oxalic acid, hydrogen sulfate The molar ratio of the substances is 1:1～3:0.05～0.1, the mass dosage of the water-carrying agent is 1～5 times of the quality of alanine, and the molar ratio of the alcohol and alanine is 5～10:1 times, Described alcohol is ethanol, n-propanol or n-butanol. The reaction device is shown in Figure 1.

The yield of the product prepared by the synthesis method of the invention can reach more than 80%.

Compared with the prior art, the present invention has the following advantages:

1. Using bisulfate as a catalyst, the esterification speed is fast, the reaction yield is high (generally above 80%), and the production cost is low;

2. The catalyst has high activity, good selectivity, basically no mono-esterification by-products, high product purity, and easy separation and purification;

3. Add a water-carrying agent during the reaction, and take away the raw water in time during the reaction to reduce side reactions.

4. Advanced process route, mild reaction conditions and easy industrialization.

(4) Drawings of the instruction manual

Fig. 1 is a schematic diagram of the reaction device used in the embodiment of the present invention, 1 is a condenser, 2 is a water separator, 3 is a rectifying column, and 4 is a reaction bottle.

(5) Specific implementation methods

The present invention will be further described below in conjunction with specific examples, but the protection scope of the present invention is not limited thereto.

Example 1

Add 89g (1mol) of alanine, 180g (2mol) of oxalic acid, and 460g of ethanol into a 2L four-neck flask equipped with a thermometer, a rectifying column, a water separator, a reflux condenser, and mechanical stirring, heat to dissolve, and add hydrogen sulfate Sodium 6g (0.05mol), with water agent toluene 200g, heated to reflux, rectified water for 40 hours. After the reaction is complete, add 50 mL of water, separate the water layer, dry the organic phase with 50 g of anhydrous sodium sulfate, evaporate the solvent at normal pressure until the internal temperature reaches 120 ° C, and recover the oxalyl diester under reduced pressure at 2 mmHg below 120 ° C to obtain light yellow Liquid N-ethoxyoxalylalanine ethyl ester 198.7g, gas chromatography detection content 95%, yield 87%, MS (EI): 217.3.

Example 2

In a 2L four-neck flask equipped with a thermometer, rectifying column, water separator, reflux condenser and mechanical stirring, add 89g (1mol) of alanine, 180g (2mol) of oxalic acid, 600g of n-propanol, heat to dissolve, add 6 g (0.05 mol) of sodium bisulfate, 100 g of n-hexane with water agent, the temperature was raised to reflux, and the water was distilled for 40 hours. After the reaction is complete, add 50 mL of water, separate the water layer, dry the organic phase with 50 g of anhydrous sodium sulfate, evaporate the solvent at normal pressure until the internal temperature reaches 120 ° C, and recover the oxalyl diester under reduced pressure at 2 mmHg below 120 ° C to obtain light yellow Liquid n-propyl N-propoxyoxalylalanine 213.7g, content 94%, yield 82%, MS (EI): 245.2.

Example 3

In a 2L four-neck flask equipped with a thermometer, rectifying column, water separator, reflux condenser and mechanical stirring, add 89g (1mol) of alanine, 180g (2mol) of oxalic acid, 740g of n-butanol, heat to dissolve, add Sodium bisulfate 6g (0.05mol), water-carrying benzene 200g, warm up to reflux, rectify water for 40 hours. After the reaction is completed, add 50 mL of water, separate the water layer, dry 50 g of the organic phase with anhydrous sodium sulfate, evaporate the solvent at normal pressure until the internal temperature reaches 120 ° C, and recover the oxalyl diester under reduced pressure at 2 mmHg below 120 ° C to obtain light yellow Liquid n-butyl N-butoxyoxalylalanine 246.9g, content 94%, yield 85%, MS (EI): 273.3.

Example 4

The feeding amount of oxalic acid is 90g (1mol), and other operation is the same as embodiment 1, obtains pale yellow liquid N-ethoxyoxalylalanine ethyl ester 168.8g, content 90%, yield 70%.

Example 5

The feeding amount of oxalic acid is 900g (10mol), and other operation is the same as embodiment 1, obtains light yellow liquid ethyl N-ethoxyoxalylalanine 188.1g, content 90%, yield 78%.

Example 6

Catalyst sodium bisulfate consumption is 24g (0.2mol), other operation is the same as embodiment 1, obtains pale yellow liquid N-ethoxyoxalylalanine ethyl ester 188.4g, content 91%, yield 79%.

Example 7

Catalyst sodium bisulfate consumption is 120g (1mol), other operation is the same as embodiment 1, obtains pale yellow liquid N-ethoxyoxalylalanine ethyl ester 175.6g, content 89%, yield 72%.

Example 8

Catalyst is potassium bisulfate, consumption is 6.8g (0.05mol), other operation is the same as embodiment 1, obtains light yellow liquid ethyl N-ethoxyoxalylalanine 205.5g, content 94%, yield 89%.

Example 9

The reflux and water separation time was 5 hours, and the other operations were the same as in Example 1 to obtain 167.9 g of light yellow liquid N-ethoxyoxalylalanine ethyl ester with a content of 84% and a yield of 65%.

Example 10

The reflux water separation time was 150 hours, and other operations were the same as in Example 1 to obtain 187.4 g of brownish yellow liquid N-ethoxyoxalylalanine ethyl ester with a content of 88% and a yield of 76%.

Claims (9)

1. the chemical synthesis process of the N-alcoxyl oxalyl alanine ester shown in the formula (I), it is characterized in that described synthetic method is: in the alcohol of C1～C8, L-Ala shown in the formula (II) and oxalic acid reacted 5～150 hours in 50 ℃～150 ℃ under the catalysis of the hydrosulfate shown in the formula (III), in time steam the water that reaction produces by the band aqua through rectifying column and water trap in the reaction process, after reaction finished, reaction solution obtained described N-alcoxyl oxalyl alanine ester through aftertreatment; The amount of substance of described L-Ala, oxalic acid, hydrosulfate is than being 1:1～10:0.001～1; Described hydrosulfate is sodium pyrosulfate or sal enixum, or the mixing of both arbitrary proportions;

In the formula (I), R is selected from the alkyl of C1～C8, and M is sodium or potassium in the formula (III).

2. the method for claim 1, it is characterized in that described synthetic method is: in the retort that has rectifying column, water trap and prolong device, earlier with L-Ala, oxalic acid heating for dissolving in the alcohol of C1～C8, add catalyst sulfuric acid hydrogen salt and band aqua then 50 ℃～150 ℃ reactions 5～150 hours, the quality consumption of described band aqua is 1～10 times of L-Ala quality, and reaction solution obtains described N-alcoxyl oxalyl alanine ester through aftertreatment.

3. method as claimed in claim 2 is characterized in that described temperature of reaction is 60～100 ℃, and the reaction times is 10～40 hours.

4. the method for claim 1 is characterized in that described band aqua can be the mixture of one of following or any several arbitrary proportions: benzene, toluene, normal hexane, hexanaphthene.

5. the method for claim 1 is characterized in that the amount of substance of L-Ala, oxalic acid, hydrosulfate is than being 1:1～3:0.05～0.1.

6. as the described method of one of claim 1～4, it is characterized in that described alcohol and L-Ala amount of substance ratio are 1～100:1.

7. as the described method of one of claim 1～4, it is characterized in that described post-treating method is: after reaction finishes, reaction solution adds water washing, branch vibration layer, get organic phase with anhydrous sodium sulfate drying after, normal pressure boils off solvent, reaches 120 ℃ to interior temperature, reclaim under reduced pressure grass diester obtains described N-alcoxyl oxalyl alanine ester again.

8. as the described method of one of claim 1～4, it is characterized in that described alcohol is one of following: ethanol, n-propyl alcohol, propyl carbinol.

9. the method for claim 1, it is characterized in that described preparation method carries out according to following steps: having rectifying column, in the retort of water trap and prolong device, elder generation is heating for dissolving in the alcoholic solution of C1～C8 with L-Ala and oxalic acid, add hydrosulfate and band aqua then, be warmed up to 60～100 ℃ after finishing, reaction times is 10～40 hours, the water that divides the dereaction generation in the reaction process by the band aqua through rectifying column and water trap, after reaction finishes, reaction solution adds water washing, branch vibration layer, get organic phase with anhydrous sodium sulfate drying after, boil off solvent, reach 120 ℃ to interior temperature, reclaim under reduced pressure grass diester obtains described N-alcoxyl oxalyl alanine ester again; The amount of substance of described L-Ala, oxalic acid, hydrosulfate is than being 1:1～3:0.05～0.1, and band aqua quality consumption is 1～5 times of L-Ala quality, and described alcohol is 5～10:1 with L-Ala amount of substance ratio.

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