阅读说明：本技术 一种连续生产o-叔丁基-l-苏氨酸叔丁酯的方法 (Method for continuously producing O-tert-butyl-L-threonine tert-butyl ester ) 是由 熊飞龙 于 2019-10-23 设计创作，主要内容包括：本发明涉及一种连续生产O-叔丁基-L-苏氨酸叔丁酯的方法,经过选用ZSM-5担载硅钨酸作为催化剂,采用两个管式反应串联的方式,提供了一种适应于工业化生产的连续生产O-叔丁基-L-苏氨酸叔丁酯的方法,该制备方法收率大于80％,纯度大于99％,且工艺简单、适合工业化生产的要求。(The invention relates to a method for continuously producing O-tert-butyl-L-threonine tert-butyl ester, which is suitable for industrial production by selecting ZSM-5 supported silicotungstic acid as a catalyst and adopting a mode of connecting two tubular reactions in series, wherein the yield of the preparation method is more than 80 percent, the purity of the preparation method is more than 99 percent, and the preparation method is simple and is suitable for the requirements of industrial production.)

1. A method for continuously producing O-tert-butyl-L-threonine tert-butyl ester is characterized in that the preparation method of the O-tert-butyl-L-threonine tert-butyl ester is carried out according to the following processes:

1) introducing L-threonine and tert-butyl methyl ether into a static mixer according to a certain proportion, fully mixing, and then feeding into a first tubular reactor, wherein a solid acid catalyst is loaded in advance in the first tubular reaction, and under the action of the catalyst, the hydroxyl at the 3-position of L-threonine and tert-butyl methyl ether are subjected to tert-butylation reaction to obtain a reaction mixture containing O-tert-butyl-L threonine;

2) and introducing the reaction mixture containing O-tert-butyl-L threonine obtained in the first tubular reactor and tert-butyl methyl ether into a second tubular reactor simultaneously, wherein the second tubular reactor is loaded with a solid acid catalyst in advance, the reaction mixture containing O-tert-butyl-L threonine and tert-butyl methyl ether continue to react under the action of the catalyst to obtain a product mixture containing O-tert-butyl-L-threonine tert-butyl ester, and the product mixture is subjected to reduced pressure distillation to collect a fraction of 70 ℃/0.05mmHg to obtain the O-tert-butyl-L-threonine tert-butyl ester.

2. The process for the continuous production of tert-butyl O-tert-butyl-L-threonine as claimed in claim 1, characterized in that: the reaction temperature of the first tubular reactor is 30-50 ℃, the agent-oil ratio is 1:10-20, and the liquid hourly space velocity of the raw materials is 1-7h^-1。

3. The process for the continuous production of tert-butyl O-tert-butyl-L-threonine as claimed in claim 1, characterized in that: the reaction temperature of the second tubular reactor is 70-90 ℃, the agent-oil ratio is 1:2-8, and the liquid space-time velocity of the raw material is 0.1-0.5h^-1。

4. The process for the continuous production of tert-butyl O-tert-butyl-L-threonine as claimed in claim 1, characterized in that: the second tubular reaction is provided with a baffle for increasing turbulent mass transfer of material flow, so that the product flow of the first tubular reaction is mixed with tert-butyl methyl ether more uniformly, and the conversion per pass is improved.

5. The process for the continuous production of tert-butyl O-tert-butyl-L-threonine as claimed in claim 1, characterized in that: the molar ratio of L-threonine to tert-butyl methyl ether in the feed of the first tubular reactor is 1.8-3.2 times; in the feed stream of the second tubular reaction, tert-butyl methyl ether is added in an amount of 1.5 to 3 times the molar amount of the L-threonine feed to the first tubular reactor.

6. The process for the continuous production of tert-butyl O-tert-butyl-L-threonine as claimed in claim 1, characterized in that: the solid acid catalyst is ZSM-5 supported silicotungstic acid, and the dosage of the solid acid catalyst is 0.5-2% of the mass of L-threonine.

7. The method for continuously producing O-tert-butyl-L-threonine tert-butyl ester according to claim 6, characterized in that the ZSM-5 supported silicotungsten catalyst is prepared by the following method:

1) dissolving silicate and tungstate with a molar ratio of 1:0.5-5 in distilled water, uniformly mixing, adding a ZSM-5 molecular sieve, performing ultrasonic dispersion for 3-10 minutes, stirring for reaction for 1-3 hours, adding liquid acid to enable the pH value of reaction liquid to be 1-3, heating to 50-60 ℃, continuing to react for 3-5 hours, fully loading silicate ions and tungstate ions on the ZSM-5 molecular sieve, and filtering to obtain a catalyst precursor;

2) washing the catalyst precursor obtained in the step 1) with 0.1mol/L diluted hydrochloric acid, then washing with deionized water, then carrying out vacuum drying at 80-100 ℃, and roasting at 400-500 ℃ for 3-5 hours to obtain the ZSM-5 supported silicotungstic acid catalyst.

8. The process for the continuous production of tert-butyl O-tert-butyl-L-threonine according to any of claims 1 to 6, characterized in that preferably at least 50% of the L-threonine is converted into O-tert-butyl-L-threonine in the first tubular reaction.

Technical Field

The invention belongs to the field of polypeptide and protein synthesis, and particularly relates to a method for continuously producing O-tert-butyl-L-threonine tert-butyl ester.

Background

O-tert-butyl-L-threonine tert-butyl ester is an important raw material for synthesizing polypeptides and proteins, and in the polypeptide synthesis, since amino acid tert-butyl ester is easily decomposed by acid, it is often used as a carboxyl protecting group to participate in the reaction. The tert-butyl amino acid can be prepared by reacting amino acid with tert-butyl acetate and perchloric acid, or by reacting amino acid with isobutene in a mixed solution of dioxane and concentrated sulfuric acid, and the latter reaction is simple and easy to operate.

U.S. Pat. No. 5,430,1852 discloses the use of O-tert-butyl-L-threonine tert-butyl ester in the artificial synthesis of human insulin, and there are only two methods reported at home and abroad for the continuous production of O-tert-butyl-L-threonine tert-butyl ester, the first method is to use L-threonine and isobutene as raw materials to produce the target compound under the catalysis of concentrated sulfuric acid. This method is divided into a one-step method and a three-step method depending on whether L-threonine is protected or not.

Journarof American chemical society85,201-207(1963) described a three-step process in which the amino group in L-threonine was protected with benzyloxycarbonyl, then reacted with isobutylene and concentrated sulfuric acid, and finally the protective group benzyloxycarbonyl was removed with 10% palladium on charcoal to give the final product in a total yield of 30%. WO2005023756 reports a method for continuously producing O-tert-butyl-L-threonine tert-butyl ester by carrying out one-step reaction on L-threonine and isobutene under the catalysis of concentrated sulfuric acid to generate a target product, but the yield is only 43.22%. The second method is the method introduced in tetrahedron letters53(2012)641 and 645, i.e. L-threonine and methyl tert-butyl ether are used as raw materials and react at room temperature in the presence of concentrated sulfuric acid and a molecular sieve to obtain the target product, and the yield is only 35%.

Chinese patent CN106478439A discloses adding L-threonine and organic solvent into a reaction kettle, and dripping organic acid catalyst at-20 ℃; the organic solvent is C3-C8 ether solvent; after the reaction is finished, adding isobutene at the temperature of between 50 ℃ below zero and 0 ℃, and then continuing the reaction for 12 to 144 hours at the temperature to finish the reaction; adding water and ammonia water at-5 ℃ until the pH value is 7.5-8.0, separating out an organic phase, adding ethyl acetate into a water phase for extraction, combining the organic phases, washing the organic phase with water, drying and concentrating the organic phase under reduced pressure to obtain a crude product of O-tert-butyl-L-threonine tert-butyl ester, and salifying the crude product with acetic acid to purify the crude product. But the boiling point of the isobutene is-6.9 ℃, in order to keep homogeneous reaction, the isobutene needs to be added at the low temperature of-50 ℃, the equipment requirement is high, the energy consumption is high, the industrial production is not facilitated, the isobutene is flammable and explosive gas, the transportation and the storage are not facilitated, the great potential safety hazard is brought to the production, and the cost reduction and the environmental protection requirement of the industrial production are not benefited.

Therefore, a method which is beneficial to industrial life and production, high in raw material conversion rate and high in product selectivity needs to be found out urgently.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a method for continuously producing O-tert-butyl-L-threonine tert-butyl ester, which is carried out according to the following process:

1) introducing L-threonine and tert-butyl methyl ether into a static mixer according to a certain proportion, fully mixing, and then feeding into a first tubular reactor, wherein a solid acid catalyst is loaded in advance in the first tubular reaction, and under the action of the catalyst, the hydroxyl at the 3-position of L-threonine and tert-butyl methyl ether are subjected to tert-butylation reaction to obtain a reaction mixture containing O-tert-butyl-L threonine;

2) and introducing the reaction mixture containing O-tert-butyl-L threonine obtained in the first tubular reactor and tert-butyl methyl ether into a second tubular reactor simultaneously, wherein the second tubular reactor is loaded with a solid acid catalyst in advance, the reaction mixture containing O-tert-butyl-L threonine and tert-butyl methyl ether continue to react under the action of the catalyst to obtain a product mixture containing O-tert-butyl-L-threonine tert-butyl ester, and the product mixture is subjected to reduced pressure distillation to collect a fraction of 70 ℃/0.05mmHg to obtain the O-tert-butyl-L-threonine tert-butyl ester.

The reaction temperature of the first tubular reactor is 30-50 ℃, the agent-oil ratio is 1:10-20, and the liquid hourly space velocity of the raw materials is 1-7h^-1。

The reaction temperature of the second tubular reactor is 70-90 ℃, the agent-oil ratio is 1:2-8, and the liquid space-time velocity of the raw material is 0.1-0.5h^-1。

Preferably, a baffle plate for increasing turbulent mass transfer of the material flow is arranged in the second tubular reaction, so that the product flow of the first tubular reaction is mixed with the tert-butyl methyl ether more uniformly, and the conversion per pass is improved.

The molar ratio of L-threonine to tert-butyl methyl ether in the feed of the first tubular reactor is 1.8-3.2 times; in the feed stream of the second tubular reaction, tert-butyl methyl ether is added in an amount of 1.5 to 3 times the molar amount of the L-threonine feed to the first tubular reactor.

The present invention preferably converts at least 50% of the L-threonine to O-tert-butyl-L-threonine in the first tubular reaction.

The reaction of L-threonine and a butylated reagent is carried out by firstly substituting hydroxyphenyl tert-butyl on carbon at 3-position to generate O-tert-butyl-L-threonine, then continuously reacting to generate O-tert-butyl-L-threonine tert-butyl ester, wherein the activities of two steps of reactions are obviously different, the reactivity of carboxyl in an amino acid structure is obviously lower than that of hydroxyl at 3-position, the reaction conditions required by the two steps of reactions are obviously different, particularly, the activity of tert-butyl alcohol or tert-butyl methyl ether is lower than that of isobutene when the tert-butyl alcohol or tert-butyl methyl ether is used as the butylated reagent, and if the activity of the catalyst is not enough, the reaction conditions of the second step are too harsh, and the defects of low repeatability and the like.

According to different activities of two-step reactions, a ZSM-5 supported silicotungstic acid catalyst with catalytic activity far higher than that of sulfuric acid is adopted, at least 50% of L threonine is converted into O-tert-butyl-L-threonine under the reaction condition of a first tubular reaction in a mode of connecting two tubular reactions in series, then the O-tert-butyl-L-threonine is further butylated in a second reactor to obtain O-tert-butyl-L-threonine tert-butyl ester, the conversion per pass can reach more than 50%, and the selectivity of the O-tert-butyl-L-threonine reaches more than 88%.

The solid acid catalyst is ZSM-5 supported silicotungstic acid, and the dosage of the solid acid catalyst is 0.5-2% of the mass of L-threonine.

The preparation method of the ZSM-5 supported silicotungstic solid acid catalyst comprises the following steps:

1) dissolving silicate and tungstate with a molar ratio of 1:0.5-5 in distilled water, uniformly mixing, adding a ZSM-5 molecular sieve, performing ultrasonic dispersion for 3-10 minutes, stirring for reaction for 1-3 hours, adding liquid acid to enable the pH value of reaction liquid to be 1-3, heating to 50-60 ℃, continuing to react for 3-5 hours, fully loading silicate ions and tungstate ions on the ZSM-5 molecular sieve, and filtering to obtain a catalyst precursor;

2) washing the catalyst precursor obtained in the step 1) with 0.1mol/L diluted hydrochloric acid, then washing with deionized water, then carrying out vacuum drying at 80-100 ℃, and roasting at 400-500 ℃ for 3-5 hours to obtain the ZSM-5 supported silicotungstic acid catalyst.

The invention has the advantages and effects that:

the invention provides a method for continuously producing O-tert-butyl-L-threonine tert-butyl ester, which is suitable for industrial production, by selecting ZSM-5 supported silicotungstic acid as a catalyst and adopting a mode of connecting two tubular reactions in series, wherein the yield of the preparation method is more than 80%, the purity of the preparation method is more than 99%, and the preparation method is simple in process and suitable for the requirements of industrial production.

Detailed Description

The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.

[ example 1 ]

The preparation method of the ZSM-5 supported silicotungstic solid acid catalyst comprises the following steps:

1) dissolving 0.1mol of silicate and 0.1mol of tungstate in 2L of distilled water, uniformly mixing, adding 300g of ZSM-5 molecular sieve, carrying out ultrasonic dispersion for 10 minutes, stirring for reaction for 3 hours, adding liquid acid to enable the pH value of reaction liquid to be 1, heating to 60 ℃, continuing to react for 3 hours, fully loading silicate ions and tungstate ions on the ZSM-5 molecular sieve, and filtering to obtain a catalyst precursor;

2) washing the catalyst precursor obtained in the step 1) with 0.1mol/L diluted hydrochloric acid, washing with deionized water, then carrying out vacuum drying at 100 ℃, and roasting at 500 ℃ for 5 hours to obtain the ZSM-5 supported silicotungstic acid catalyst.

[ example 2 ]

1) Introducing L-threonine and tert-butyl methyl ether in a molar ratio of 1:1.8 into a static mixer for fully mixing, and then feeding the mixture into a first tubular reactor, wherein the first tubular reactor is loaded with a ZSM-5 supported silicotungstic acid catalyst prepared in example 1 in advance, and under the action of the catalyst, the 3-hydroxyl of L-threonine and tert-butyl methyl ether are subjected to tert-butylation reaction to obtain a reaction mixture containing O-tert-butyl-L threonine; the reaction temperature of the first tubular reactor is 50 ℃, the agent-oil ratio is 1:15, and the liquid hourly space velocity of the raw materials is 5h^-1；

2) The reaction mixture containing O-tert-butyl-L threonine obtained in the first tubular reactor was introduced simultaneously with tert-butyl methyl ether into a second tubular reactor, which had been previously loaded with the ZSM-5 supported silicotungstic acid catalyst prepared in example 1 and acted as a catalystThen, the reaction mixture containing O-tert-butyl-L-threonine and tert-butyl methyl ether are continuously reacted to obtain a product mixture containing O-tert-butyl-L-threonine tert-butyl ester, a baffle plate for increasing turbulent mass transfer of material flow is arranged in the second tubular reaction, the reaction temperature of the second tubular reactor is 70 ℃, the agent-oil ratio is 1:2, and the liquid space-time velocity of the raw material is 0.1h^-1. In the feed stream to the second tubular reaction, t-butyl methyl ether was added in an amount of 1.5 times the molar amount of the L-threonine feed to the first tubular reactor.

3) The product mixture was distilled under reduced pressure to recover the unreacted starting materials, and the O-tert-butyl-L-threonine tert-butyl ester was obtained by collecting a fraction of 70 ℃ C./0.05 mmHg, and the results of gas chromatography analysis before distillation of the product mixture were as shown in Table 1.

[ example 3 ]

1) Introducing L-threonine and tert-butyl methyl ether in a molar ratio of 1:2 into a static mixer for fully mixing, and then feeding the mixture into a first tubular reactor, wherein the first tubular reactor is loaded with a ZSM-5 supported silicotungstic acid catalyst prepared in example 1 in advance, and under the action of the catalyst, the hydroxyl at the 3-position of L-threonine and tert-butyl methyl ether are subjected to tert-butylation reaction to obtain a reaction mixture containing O-tert-butyl-L threonine; the reaction temperature of the first tubular reactor is 30 ℃, the agent-oil ratio is 1:10, and the liquid hourly space velocity of the raw materials is 1h^-1；

2) Introducing a reaction mixture containing O-tert-butyl-L threonine obtained in the first tubular reactor and tert-butyl methyl ether into a second tubular reactor at the same time, wherein the second tubular reactor is loaded with a ZSM-5 supported silicotungstic acid catalyst prepared in example 1 in advance, the reaction mixture containing O-tert-butyl-L threonine and tert-butyl methyl ether continue to react under the action of the catalyst to obtain a product mixture containing O-tert-butyl-L-threonine tert-butyl ester, a baffle plate for increasing turbulent mass transfer of material flow is arranged in the second tubular reactor, the reaction temperature of the second tubular reactor is 80 ℃, the ratio of solvent to oil is 1:3, and the liquid hourly space velocity of the raw material is 0.2h^-1. In the feed stream to the second tubular reaction, t-butyl methyl ether was added in an amount of 2 times the molar amount of the L-threonine feed to the first tubular reactor.

3) The product mixture was distilled under reduced pressure to recover the unreacted starting materials, and the O-tert-butyl-L-threonine tert-butyl ester was obtained by collecting a fraction of 70 ℃ C./0.05 mmHg, and the results of gas chromatography analysis before distillation of the product mixture were as shown in Table 1.

[ example 4 ]

1) Introducing L-threonine and tert-butyl methyl ether in a molar ratio of 1:1.8-3.2 into a static mixer for fully mixing, and then feeding the mixture into a first tubular reactor, wherein the first tubular reactor is loaded with a ZSM-5 supported silicotungstic acid catalyst prepared in example 1 in advance, and under the action of the catalyst, the hydroxyl at the 3-position of L-threonine and tert-butyl methyl ether are subjected to tert-butylation reaction to obtain a reaction mixture containing O-tert-butyl-L threonine; the reaction temperature of the first tubular reactor is 30 ℃, the agent-oil ratio is 1:10, and the liquid hourly space velocity of the raw materials is 7h^-1；

2) Introducing a reaction mixture containing O-tert-butyl-L threonine obtained in the first tubular reactor and tert-butyl methyl ether into a second tubular reactor at the same time, wherein the second tubular reactor is loaded with a ZSM-5 supported silicotungstic acid catalyst prepared in example 1 in advance, the reaction mixture containing O-tert-butyl-L threonine and tert-butyl methyl ether continue to react under the action of the catalyst to obtain a product mixture containing O-tert-butyl-L-threonine tert-butyl ester, a baffle plate for increasing turbulent mass transfer of material flow is arranged in the second tubular reactor, the reaction temperature of the second tubular reactor is 90 ℃, the ratio of solvent to oil is 1:2, and the liquid hourly space velocity of the raw material is 0.1h^-1. In the feed stream to the second tubular reaction, t-butyl methyl ether was added in an amount of 1.5 times the molar amount of the L-threonine feed to the first tubular reactor.

3) The product mixture was distilled under reduced pressure to recover the unreacted starting materials, and the O-tert-butyl-L-threonine tert-butyl ester was obtained by collecting a fraction of 70 ℃ C./0.05 mmHg, and the results of gas chromatography analysis before distillation of the product mixture were as shown in Table 1.

Comparative example 1

1) Introducing L-threonine and tert-butyl methyl ether with the molar ratio of 1:3.3 into a static mixer for fully mixing, and then feeding into a tubular reactor, wherein the first tubular reactor is loaded with a ZSM-5 supported silicotungstic acid catalyst prepared in example 1 in advance, and L-threonine 3 is carried out under the action of the catalystCarrying out tert-butylation reaction on the-hydroxyl and tert-butyl methyl ether to obtain a reaction mixture containing O-tert-butyl-L threonine tert-butyl ester; the reaction temperature of the tubular reactor is 70 ℃, the agent-oil ratio is 1:2, and the liquid hourly space velocity of the raw materials is 0.1h^-1。

2) The product mixture was distilled under reduced pressure to recover the unreacted starting materials, and the O-tert-butyl-L-threonine tert-butyl ester was obtained by collecting a fraction of 70 ℃ C./0.05 mmHg, and the results of gas chromatography analysis before distillation of the product mixture were as shown in Table 1.

TABLE 1

The foregoing description has disclosed fully preferred embodiments of the present invention. It should be noted that those skilled in the art can make modifications to the embodiments of the present invention without departing from the scope of the appended claims. Accordingly, the scope of the appended claims is not to be limited to the specific embodiments described above.