阅读说明：本技术 L-正缬氨酸的制备方法 (Process for producing L-norvaline ) 是由 施晓旦 金霞朝 于 2021-09-03 设计创作，主要内容包括：本发明公开了一种L-正缬氨酸的制备方法。该L-正缬氨酸的制备方法包括如下步骤：在第一溶剂和碱性催化剂存在条件下,正丁醛和氰基化试剂在第一微通道反应器中进行氰基化反应,得物料A；物料A去除碱性催化剂和第一溶剂后得物料B,物料B在第二溶剂存在下与液氨在第二微通道反应器中进行氨化反应,得物料C；物料C脱氨后得物料D,在第三溶剂存在下,物料D与碱溶液进行水解反应,得物料E；物料E去除未反应的碱和第三溶剂后得物料F,在第四溶剂存在下物料F和手性拆分试剂进行手性共晶,得到物料G；物料G经水解后得L-正缬氨酸。本发明能够有效缩短生产时间、提高生产效率、降低能耗、减少副反应、提高产品收率、提高生产安全性。(The invention discloses a preparation method of L-norvaline. The preparation method of the L-norvaline comprises the following steps: carrying out cyanation reaction on n-butyl aldehyde and a cyanation reagent in a first microchannel reactor in the presence of a first solvent and an alkaline catalyst to obtain a material A; removing the alkaline catalyst and the first solvent from the material A to obtain a material B, and carrying out an ammoniation reaction on the material B and liquid ammonia in a second microchannel reactor in the presence of a second solvent to obtain a material C; deaminating the material C to obtain a material D, and carrying out hydrolysis reaction on the material D and an alkali solution in the presence of a third solvent to obtain a material E; removing unreacted alkali and a third solvent from the material E to obtain a material F, and carrying out chiral eutectic on the material F and a chiral resolution reagent in the presence of a fourth solvent to obtain a material G; hydrolyzing the material G to obtain the L-norvaline. The invention can effectively shorten the production time, improve the production efficiency, reduce the energy consumption, reduce the side reaction, improve the product yield and improve the production safety.)

1. A preparation method of L-norvaline comprises the following steps:

s1: carrying out cyanation reaction on n-butyl aldehyde and a cyanation reagent in a first microchannel reactor in the presence of a first solvent and an alkaline catalyst to obtain a material A containing 2-hydroxypentanenitrile, wherein the reaction temperature is 5-25 ℃, the retention time is 3-10 min, and the material flow rate in the first microchannel reactor is not lower than 0.1 m/s;

s2: removing the alkaline catalyst and the first solvent from the material A to obtain a material B, carrying out an ammoniation reaction on the material B and liquid ammonia in a second microchannel reactor in the presence of a second solvent to obtain a material C containing aminopentanenitrile, wherein the reaction temperature is 5-30 ℃, the retention time is 5-20 min, and the material flow rate in the second microchannel reactor is not lower than 0.1 m/s;

s3: deaminating the material C to obtain a material D, and carrying out hydrolysis reaction on the material D and an alkali solution in the presence of a third solvent to obtain a material E;

s4: removing unreacted alkali and the third solvent from the material E to obtain a material F, and performing chiral eutectic reaction on the material F and a chiral resolution reagent in the presence of a fourth solvent to obtain a material G containing L-2-aminobutanamide;

s5: and hydrolyzing the material G after ion exchange to obtain the L-norvaline.

2. The process according to claim 1, wherein the first solvent in S1 is one or more selected from the group consisting of water, methanol, ethanol, acetone, dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, acetonitrile and 1, 4-dioxane, preferably ethanol or methanol;

and/or, in S1, the basic catalyst is one or more of potassium hydroxide, sodium hydroxide, calcium hydroxide, potassium carbonate and sodium carbonate;

and/or in S1, the molar ratio of the n-butyraldehyde to the cyanation reagent is 1 (0.8-1.5), preferably 1 (1-1.2), for example 1: 1.1;

and/or in S1, the mass ratio of the basic catalyst to the n-butyraldehyde is 1 (20-100), and preferably 1: (30-80), e.g., 1: 48;

and/or in S1, the mass ratio of the first solvent to the basic catalyst is (2-8): 1, and preferably (3-5): 1;

and/or in S1, the reaction temperature is 10-15 ℃;

and/or, in S1, the retention time is 4-8 min, such as 5min, 6min or 7 min;

and/or, in S1, the material flow rate in the first microchannel reactor is 0.1-1 m/S, preferably 0.2-0.5 m/S, such as 0.3 m/S.

3. The process according to claim 1, wherein in S1, the reaction temperature is 10 ℃, the residence time is 5min, and the mass flow rate in the first microchannel reactor is 0.3 m/S;

or in S1, the reaction temperature is 15 ℃, the residence time is 5min, and the material flow rate in the first microchannel reactor is 0.2 m/S.

4. The process for producing L-norvaline according to claim 1, wherein in S2, the basic catalyst is removed by mixing the material A with an acid and then subjecting the mixture to solid-liquid separation; wherein the pH value of the mixture of the material A and the acid is preferably 1-4, more preferably 2-3; the equipment for mixing the material A and the acid is preferably a dynamic tubular reactor;

and/or, in S2, the method for removing the first solvent is evaporation; wherein the evaporation device is preferably a thin film evaporator; the vacuum degree of the evaporation is preferably 0.06MPa to 0.1 MPa; the temperature of the evaporation is preferably 20 to 80 ℃.

5. The process for producing L-norvaline according to claim 1, wherein the second solvent is water in S2;

and/or in S2, the mass ratio of the material B, the liquid ammonia and the second solvent is 1 (0.2-0.6): 0.1-0.5, preferably 1 (0.3-0.5): 0.1-0.3), for example 1:0.4: 0.2;

and/or, in S2, the reaction temperature is 15-25 ℃, such as 20 ℃;

and/or, in S2, the retention time is 8-15 min, such as 10min or 12 min;

and/or, in S2, the flow rate of the material in the second microchannel reactor is 0.1-1 m/S, preferably 0.3-0.8 m/S, such as 0.5 m/S.

6. The process according to claim 1, wherein in S2, the reaction temperature is 20 ℃, the residence time is 10min, and the mass flow rate in the second microchannel reactor is 0.5 m/S;

or in S2, the reaction temperature is 20 ℃, the residence time is 12min, and the material flow rate in the second microchannel reactor is 0.5 m/S.

7. The process according to claim 1, wherein in S3, the third solvent is one or more selected from the group consisting of methanol, ethanol, acetone, dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, acetonitrile and 1, 4-dioxane, preferably acetone;

and/or, in S3, the alkali solution is a potassium hydroxide solution and/or a sodium hydroxide solution;

and/or in S3, the mass concentration of the alkali solution is 20-40%, such as 30% or 32%;

and/or in S3, the mass ratio of the alkali solution to the material D is (5-20): 100, preferably (10-20): 100;

and/or, in S3, the reactor for the hydrolysis reaction is a dynamic tubular reactor;

and/or in S3, the temperature of the hydrolysis reaction is 15-40 ℃, preferably 15-30 ℃, for example 20 ℃;

and/or in S3, the time of the hydrolysis reaction is 8-15 min, such as 10 min.

8. The process according to claim 1, wherein in S4, the fourth solvent is one or more selected from the group consisting of methanol, ethanol, acetone, dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, acetonitrile and 1, 4-dioxane, preferably methanol;

and/or, in S4, the chiral resolving agent is one or more of L-tartaric acid, malic acid, camphoric acid, camphorsulfonic acid, diacetone-L-gulonic acid, mandelic acid, phenoxypropionic acid and hydratropic acid, preferably L-tartaric acid;

and/or, in S4, the chiral resolution reagent and the fourth solvent are mixed to form a chiral resolution reagent solution, and then the chiral resolution reagent solution reacts with the material F; the mass ratio of the material F to the chiral resolution reagent solution is preferably (1), (3-6), more preferably (1), (4-5), for example 1: 4.5;

and/or, in S4, the mass ratio of the chiral resolution reagent to the fourth solvent is 1: (1-4), preferably 1: 2.

9. The process for producing L-norvaline according to claim 1, wherein in S5, the ion exchange method comprises mixing the material G with a cation exchange resin to remove the chiral resolving agent;

and/or, in S5, the method for hydrolyzing is to hydrolyze the amide by heating;

and/or, in S5, after the ion exchange operation and before the hydrolysis operation, washing the column filled with the cation exchange resin to neutrality by using water, recovering washing liquid, and recovering L-tartaric acid by concentrating;

and/or, in S5, the step of ion exchange is preceded by a step of recrystallization.

10. The process for producing L-norvaline according to claim 9, wherein the cationic resin is an acidic cationic resin;

and/or the heating temperature is 80-180 ℃, preferably 100-150 ℃, for example 120 ℃;

and/or the heating time is 0.8-3 h, preferably 2 h.

Technical Field

The invention particularly relates to a preparation method of L-norvaline.

Background

L-norvaline, a non-natural straight-chain amino acid, is an important raw material and an intermediate of some chiral medicines, in particular to a key intermediate of perindopril which is a medicine for treating hypertension and congestive heart failure. In addition, the L-norvaline can also be used for synthesizing other medical intermediates and other chemical products. The market demand of L-norvaline is extremely vigorous at present, and the demand amount is greatly increased every year.

L-norvaline is mainly prepared by two methods, namely biosynthesis and chemical synthesis. The chemical synthesis method generally uses n-butyraldehyde as a starting material to perform an addition reaction by using a cyanation reagent, as disclosed in chinese patent documents CN1651400A and CN101007772A, and then obtains a final L-norvaline product through the steps of ammoniation, hydrolysis, resolution, recrystallization, column chromatography, hydrolysis, purification, drying and the like. The prior chemical synthesis method for producing the L-norvaline adopts batch kettle type reaction. The batch kettle type reaction has the defects of large occupied area, poor mass and heat transfer effects of the reaction, long reaction time (the total reaction and treatment time exceeds 3 days), more side reactions, low product yield, high energy consumption, poor safety and the like, and the large-scale production of the L-norvaline is limited to a great extent. Therefore, the development of a method which can effectively shorten the production time of L-norvaline, improve the production efficiency, reduce side reactions and improve the production safety and environmental protection is of great significance.

Disclosure of Invention

The invention solves the technical problem of overcoming the defects of large occupied area, poor reaction mass and heat transfer effect, long reaction time, more side reactions, low product yield, high energy consumption, poor safety and the like of the conventional batch kettle type reaction synthesis of L-norvaline and provides a preparation method of L-norvaline. The preparation method of the L-norvaline can effectively shorten the production time of the L-norvaline, improve the production efficiency, reduce the energy consumption, reduce the side reaction, improve the product yield and improve the production safety.

The invention adopts the following technical scheme to solve the technical problems:

the invention provides a preparation method of L-norvaline, which comprises the following steps:

s1: carrying out cyanation reaction on n-butyl aldehyde and a cyanation reagent in a first microchannel reactor in the presence of a first solvent and an alkaline catalyst to obtain a material A containing 2-hydroxypentanenitrile, wherein the reaction temperature is 5-25 ℃, the retention time is 3-10 min, and the material flow rate in the first microchannel reactor is not lower than 0.1 m/s;

s2: removing the alkaline catalyst and the first solvent from the material A to obtain a material B, carrying out an ammoniation reaction on the material B and liquid ammonia in a second microchannel reactor in the presence of a second solvent to obtain a material C containing aminopentanenitrile, wherein the reaction temperature is 5-30 ℃, the retention time is 5-20 min, and the material flow rate in the second microchannel reactor is not lower than 0.1 m/s;

s3: deaminating the material C to obtain a material D, and carrying out hydrolysis reaction on the material D and an alkali solution in the presence of a third solvent to obtain a material E;

s4: removing unreacted alkali and the third solvent from the material E to obtain a material F, and carrying out chiral eutectic reaction on the material F and a chiral resolution reagent in the presence of a fourth solvent to obtain a material G;

s5: and hydrolyzing the material G after ion exchange to obtain the L-norvaline.

When the cyanating agent in S1 is acetone cyanohydrin, the process for producing L-norvaline of the present invention may comprise the following reaction:

in S1, the first solvent may be a solvent which is conventional in the art and can dissolve the n-butyraldehyde, the cyanation agent and the basic catalyst, and is preferably one or more of water, methanol, ethanol, acetone, dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, acetonitrile and 1, 4-dioxane, more preferably ethanol or methanol.

In S1, the basic catalyst may be a base conventional in the art, preferably one or more of potassium hydroxide, sodium hydroxide, calcium hydroxide, potassium carbonate and sodium carbonate.

In S1, the cyanating reagent may be conventional in the art, and is preferably one or more of sodium cyanide, potassium cyanide, hydrogen cyanide and acetone cyanohydrin.

In S1, the molar ratio of the n-butyraldehyde to the cyanation reagent is conventional in the art, and is preferably 1 (0.8-1.5), more preferably 1 (1-1.2), for example 1: 1.1.

In S1, the amount of the basic catalyst may be conventional in the art, and preferably, the mass ratio of the basic catalyst to the n-butyraldehyde is 1 (20-100), more preferably 1: (30-80), for example 1: 48.

In S1, the amount of the first solvent may be conventional in the art, and preferably, the mass ratio of the first solvent to the basic catalyst is (2-8): 1, more preferably (3-5): 1.

In S1, preferably, the basic catalyst is dissolved in the first solvent and then added to the first microchannel reactor.

In S1, the reaction temperature is preferably 10-15 ℃.

In S1, the residence time is preferably 4-8 min, such as 5min, 6min or 7 min.

In S1, the flow rate of the material in the first microchannel reactor is preferably 0.1-1 m/S, more preferably 0.2-0.5 m/S, such as 0.3 m/S.

In a preferred embodiment of the present invention, in S1, the reaction temperature is 10 ℃, the residence time is 5min, and the material flow rate in the first microchannel reactor is 0.3 m/S.

In a preferred embodiment of the present invention, in S1, the reaction temperature is 15 ℃, the residence time is 5min, and the material flow rate in the first microchannel reactor is 0.2 m/S.

In S2, the method for removing the basic catalyst may be conventional in the art, and preferably the material a is mixed with an acid and then subjected to solid-liquid separation.

Wherein the acid may be conventional in the art, preferably sulfuric acid.

The addition amount of the acid can be conventional in the art, and preferably, the pH of the mixture of the acid and the material a is 1 to 4, more preferably 2 to 3, for example 2.2.

The equipment for mixing the material a with the acid may be conventional in the art, and is preferably a dynamic tubular reactor.

The temperature of the dynamic tube reactor may be conventional in the art, preferably 8 to 20 ℃, e.g. 10 ℃.

The residence time in the dynamic tube reactor may be conventional in the art, preferably 0.5 to 2 min.

The solid-liquid separation method may be conventional in the art, and may be filtration in general.

The filtration apparatus may be conventional in the art, and is preferably a microfiltration filter.

In S2, the method for removing the first solvent may be conventional in the art, and is preferably evaporation. Wherein the evaporation device is preferably a thin film evaporator.

Wherein, the vacuum degree of the evaporation can be conventional in the field, and is preferably 0.06 MPa-0.1 MPa.

Wherein, the temperature of the evaporation can be conventional in the field, and is preferably 20-80 ℃.

In S2, the second solvent may be a solvent that is conventional in the art and dissolves the liquid ammonia and the 2-hydroxypentanenitrile, and is preferably water.

In S2, the mass ratio of the material B, the liquid ammonia and the second solvent is conventional in the art, and is preferably 1 (0.2-0.6): 0.1-0.5), more preferably 1 (0.3-0.5): 0.1-0.3), such as 1:0.4: 0.2.

In S2, the reaction temperature is preferably 15 to 25 ℃, for example, 20 ℃.

In S2, the residence time is preferably 8-15 min, such as 10min or 12 min.

In S2, the flow rate of the material in the second microchannel reactor is preferably 0.1-1 m/S, more preferably 0.3-0.8 m/S, such as 0.5 m/S.

In a preferred embodiment of the present invention, in S2, the reaction temperature is 20 ℃, the residence time is 10min, and the material flow rate in the second microchannel reactor is 0.5 m/S.

In a preferred embodiment of the present invention, in S2, the reaction temperature is 20 ℃, the residence time is 12min, and the material flow rate in the second microchannel reactor is 0.5 m/S.

In S3, the deamination method may be conventional in the art, preferably evaporation, more preferably evaporation in a thin film evaporator.

Wherein the vacuum degree of the thin film evaporator can be conventional in the field, and is preferably 0.06MPa to 0.1MPa, such as 0.09 MPa.

Wherein the temperature in the thin film evaporator can be conventional in the art, preferably 20-50 ℃, for example 30 ℃.

In S3, the third solvent may be a solvent which is conventional in the art and can dissolve the aminopentanenitrile and the alkali solution, preferably one or more of methanol, ethanol, acetone, dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, acetonitrile and 1, 4-dioxane, more preferably acetone.

In S3, the alkali solution may be an aqueous solution of an alkali conventional in the art, preferably a potassium hydroxide solution and/or a sodium hydroxide solution.

The mass concentration of the alkali solution may be conventional in the art, and is preferably 20 to 40%, for example 30% or 32%.

In S3, the amount of the alkali solution may be conventional in the art, and preferably, the mass ratio of the alkali solution to the material D is (5-20): 100, more preferably (10-20): 100.

In S3, the reactor for the hydrolysis reaction may be conventional in the art, and is preferably a dynamic tubular reactor.

In S3, the hydrolysis reaction temperature may be conventional in the art, preferably 15 to 40 ℃, more preferably 15 to 30 ℃, for example 20 ℃.

In S3, the time of the hydrolysis reaction is preferably 8 to 15min, for example, 10 min.

In S4, the method for removing the unreacted base may be a method conventionally used in the art, and preferably includes neutralizing with an acid, crystallizing, and performing solid-liquid separation. Wherein the acid may be conventional in the art, preferably sulfuric acid. The pH value after neutralization is preferably 6-8. The solid-liquid separation method is preferably filtration, more preferably microfiltration.

In S4, the method for removing the third solvent may be conventional in the art, and is preferably evaporation. Wherein the evaporation equipment may be conventional in the art, preferably a thin film evaporator.

In S4, the fourth solvent may be a solvent which is conventional in the art and can dissolve the material F and the chiral resolving agent, and is preferably one or more of methanol, ethanol, acetone, dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, acetonitrile and 1, 4-dioxane, and is more preferably methanol.

In S4, the chiral resolving agent may be conventional in the art, and is preferably one or more of L-tartaric acid, malic acid, camphoric acid, camphorsulfonic acid, diacetone-L-gulonic acid, mandelic acid, phenoxypropionic acid, and hydroatropic acid, and more preferably L-tartaric acid.

In S4, preferably, the chiral resolving agent and the fourth solvent are mixed to form a chiral resolving agent solution, and then the chiral resolving agent solution is reacted with the material F.

In S4, the mass ratio of the chiral resolving agent to the fourth solvent may be conventional in the art, and is preferably 1: (1-4), preferably 1: 2.

The mass ratio of the material F to the chiral resolution reagent solution can be conventional in the art, and is preferably 1 (3-6), more preferably 1 (4-5), for example 1: 4.5.

In S5, the method of ion exchange may be conventional in the art, and generally, the material G and the cation exchange resin are removed from the chiral resolving agent. Among them, the cation exchange resin is preferably an acidic cation resin.

In S5, the amide may be hydrolyzed by a method conventional in the art, generally by heating.

The heating temperature may be conventional in the art, preferably 80-180 ℃, more preferably 100-150 ℃, for example 120 ℃.

The heating time can be conventional in the art, and is preferably 0.8 to 3 hours, and more preferably 2 hours.

Wherein, preferably, after the ion exchange operation and before the hydrolysis operation, the column filled with the cation exchange resin is washed to neutrality with water, and the washing liquid is recovered and concentrated to recover L-tartaric acid.

In S5, preferably, after the hydrolysis, the column packed with the cation exchange resin is washed with ammonia water, and the precipitated liquid is collected and subjected to a post-treatment to obtain L-norvaline.

The concentration of the ammonia water can be conventional in the art, preferably 3-10%, more preferably 5%.

The post-treatment may employ purification methods conventional in the art, preferably including decolorization, dehydration, washing, and drying.

The decolorization is preferably performed using activated carbon.

The dehydration may be concentrated by heating as is conventional in the art.

The washing is preferably rinsed with methanol.

In S5, the ion exchange step is preferably preceded by a recrystallization step.

The recrystallization can be carried out by adopting a conventional method in the field, preferably, the material G is mixed with water and activated carbon and then subjected to solid-liquid separation, the obtained filtrate is mixed with methanol, and the mixture is concentrated and cooled to separate out solid, so that the recrystallized L-amino valeryl amide tartrate is obtained.

On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows:

(1) the production time of the L-norvaline can be shortened to dozens of minutes from dozens of hours, the production efficiency is greatly improved, and the energy consumption is greatly reduced;

(2) the occurrence of side reaction is inhibited, and the product yield is greatly improved; the product yield can be increased to more than 32 percent from 25 percent of the batch kettle type reaction;

(3) the batch reaction is changed into continuous production, so that the safety and the operation convenience of the production process are greatly improved.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

Example 1

S1: cyanation reaction

Respectively and continuously pumping ethanol solutions of n-butyl aldehyde, hydrogen cyanide and potassium hydroxide (1 part of potassium hydroxide is dissolved in 3 parts of ethanol) into a first microchannel reactor from three feed inlets for cyanation reaction to obtain a material A containing 2-hydroxypentanenitrile, wherein the mass flow ratio of the three liquids is 16:6:1, the reaction temperature is 10 ℃, the retention time is 5 minutes, and the material flow rate in the first microchannel reactor is 0.3 m/s.

S2: dealkalization and solvent

And respectively feeding the material A and the sulfuric acid obtained in the step S1 into a dynamic tubular reactor 1 for neutralization, wherein the weight flow ratio of the two materials is adjusted on the basis that the pH value of the mixture reaches 2.2, and the temperature of the dynamic tubular reactor is controlled at 10 ℃. And (3) removing precipitated crystals from the neutralized product by a microfiltration filter with a back flushing function (which can be automatically cleaned subsequently), pumping the filtrate into a film evaporator for reduced pressure distillation at the distillation temperature of 50 ℃ and the vacuum degree of 0.09MPa, and removing the solvent ethanol to obtain a material B.

S3: ammoniation reaction

And respectively feeding the material B obtained in the step S2, liquid ammonia and water into a second microchannel reactor for ammoniation reaction to obtain a material C containing the aminopentanenitrile, wherein the mass flow ratio of the material B, the liquid ammonia and the water is 5:2:1, the retention time of the reaction liquid in the microchannel reactor is 10 minutes, the reaction temperature is controlled at 20 ℃, and the material flow rate in the second microchannel reactor is 0.5 m/S.

S4: deaminizing and hydrolyzing reaction

Deaminating the material C by a film evaporator at the temperature of 30 ℃ and the vacuum degree of 0.09MPa to obtain a material D. And (3) feeding the material D, a potassium hydroxide solution with the mass concentration of 30% and acetone into a dynamic tubular reactor at the mass flow ratio of 10:1:2 for hydrolysis reaction to obtain a material E, wherein the reaction temperature is 20 ℃, and the retention time is 10 minutes.

S5: dealkalization and solvent, chiral cocrystal

And adding sulfuric acid into the material E to neutralize the material E until the pH value is 6-8, removing precipitated crystals through a microfiltration filter, evaporating a solvent from a filtrate through a film evaporator to obtain a material F, and allowing the material F and a methanol solution of L-tartaric acid (the mass ratio of L-tartaric acid to methanol is 1:2) to enter a dynamic tubular reactor together for chiral eutectic to obtain a material G. The mass flow ratio of the material F to the methanol solution of the L-tartaric acid was 1: 5.

S6: purification, hydrolysis and work-up

And centrifuging the material G in a centrifuge, and carrying out post-treatment steps such as recrystallization, hydrolysis, decoloration, concentration, drying and the like on the obtained solid to obtain the high-purity L-norvaline.

A recrystallization step: mixing the solid obtained by centrifugation with water and activated carbon, filtering, mixing the obtained filtrate with methanol, concentrating, cooling to separate out solid, and filtering.

A hydrolysis step: dissolving the solid obtained by recrystallization in 15 times of water, allowing the solution to flow through a column filled with a cationic resin, washing the column to neutrality with water after the solution is finished, recovering the washing liquid, and concentrating to recover L-tartaric acid. Then heating the column to 120 ℃ and preserving the temperature for 2 hours to hydrolyze the amide; then, the column was washed with 10% aqueous ammonia, and the eluate was collected and collected until the optical rotation became 0.

Decoloring, concentrating and drying: decolorizing the eluate with active carbon, concentrating, dehydrating, eluting with methanol, and drying to obtain L-norvaline.

Example 2

S1: cyanation reaction

Respectively and continuously pumping methanol solutions of n-butyl aldehyde, hydrogen cyanide and sodium hydroxide (1 part of sodium hydroxide is dissolved in 5 parts of methanol) into a first microchannel reactor from three feed inlets for cyanation reaction to obtain a material A containing 2-hydroxyvaleronitrile, wherein the mass flow ratio of the three liquids is 16:6:2, the reaction temperature is 10 ℃, the retention time is 5 minutes, and the material flow rate in the first microchannel reactor is 0.3 m/s.

S2: dealkalization and solvent

The dealkalization procedure was the same as in example 1. And pumping the dealkalized filtrate into a film evaporator for reduced pressure distillation at the distillation temperature of 40 ℃ and the vacuum degree of 0.09MPa, and removing the solvent ethanol to obtain a material B.

S3: ammoniation reaction

The residence time of the reaction liquid for the amination in the microchannel reactor was 12 minutes, and the rest was the same as in S3 of example 1.

S4: deaminizing and hydrolyzing reaction

The deamination step was the same as S4 of example 1 to give feed D. And (3) feeding the material D, a sodium hydroxide solution with the mass concentration of 32% and acetone into a dynamic tubular reactor at the mass flow ratio of 10:1:2 for hydrolysis reaction to obtain a material E, wherein the reaction temperature is 20 ℃, and the retention time is 10 minutes.

S5: dealkalization and solvent, chiral cocrystal

The procedure for dealkalization and solvent was the same as S5 of example 1 to obtain feed F. And (3) feeding the material F and a methanol solution of L-tartaric acid (the mass ratio of L-tartaric acid to methanol is 1:2) into a dynamic tubular reactor together for chiral eutectic to obtain a material G. The mass flow ratio of the material F to the methanol solution of the L-tartaric acid was 2: 9.

Purification, hydrolysis and work-up of S6

S6L-norvaline was obtained in the same manner as in S6 of example 1.

Example 3

S1: cyanation reaction

Respectively and continuously pumping ethanol solutions of n-butyl aldehyde, acetone cyanohydrin and potassium hydroxide (1 part of potassium hydroxide is dissolved in 3 parts of ethanol) into a first microchannel reactor from three feed inlets for cyanation reaction to obtain a material A containing 2-hydroxypentanenitrile, wherein the mass flow ratio of the three liquids is 14:18:2, the reaction temperature is 15 ℃, the retention time is 5 minutes, and the material flow rate in the first microchannel reactor is 0.2 m/s.

S2: dealkalization and solvent

S2 was the same as S2 of example 1 to obtain B.

S3: ammoniation reaction

And respectively feeding the material B obtained in the step S2, liquid ammonia and water into a second microchannel reactor for ammoniation reaction to obtain a material C containing the aminopentanenitrile, wherein the mass flow ratio of the material B, the liquid ammonia and the water is 5:3:1, the retention time of the reaction liquid in the microchannel reactor is 10 minutes, the reaction temperature is controlled at 20 ℃, and the material flow rate in the second microchannel reactor is 0.5 m/S.

S4: deaminizing and hydrolyzing reaction

S4 was the same as S4 of example 1 to obtain feed E.

S5: dealkalization and solvent, chiral cocrystal

The dealkalization and solvent procedure of S5 was the same as S5 of example 1 to give feed F. And (3) feeding the material F and a methanol solution of L-tartaric acid (the mass ratio of L-tartaric acid to methanol is 1:2) into a dynamic tubular reactor together for chiral eutectic to obtain a material G. The mass flow ratio of the material F to the methanol solution of the L-tartaric acid was 2: 9.

S6: purification, hydrolysis and work-up

S6L-norvaline was obtained in the same manner as in S6 of example 1.

Comparative example 1

S1: cyanation reaction

Adding 28 parts of n-butyl aldehyde and 36 parts of acetone cyanohydrin into the bottom of a reaction kettle, uniformly stirring, controlling the temperature of the reaction kettle to be 10 ℃, dropwise adding 4 parts of potassium hydroxide ethanol solution (1 part of potassium hydroxide is dissolved in 3 parts of ethanol) within 3 hours, controlling the temperature of the whole process to be within 20 ℃, and continuously preserving heat for 5 hours after dropwise adding is finished to obtain a material A.

S2: dealkalization and solvent

The material A and the sulfuric acid respectively enter a dynamic tubular reactor for neutralization, and the pH value is adjusted to 2.2. And filtering the neutralization product to remove precipitated crystals, then carrying out reduced pressure distillation to remove the solvent ethanol, and distilling at the distillation temperature of 80 ℃ for about 8 hours to obtain a material B.

S3: ammoniation reaction

Adding the material B and water into an ammoniation kettle, stirring uniformly, introducing liquid ammonia inwards for ammoniation reaction to obtain a material C, controlling the reaction temperature at 10 ℃, controlling the total introduction amount of the liquid ammonia to be 60% of the weight of the material B, introducing the liquid ammonia and reacting for 12 hours.

S4: deaminizing and hydrolyzing reaction

And distilling the material C under reduced pressure to remove ammonia for 8 hours to obtain a material D. And adding the material D, 30% potassium hydroxide solution and acetone into a hydrolysis kettle together, wherein the weight ratio of the three materials is 10:1:2, the reaction temperature is 20 ℃, and the reaction time is 8 hours, so as to obtain a material E.

S5: dealkalization and solvent, chiral cocrystal

And adding sulfuric acid into the material E to neutralize until the pH value is 6-8, filtering to remove precipitated crystals, and then carrying out reduced pressure distillation to recover acetone to obtain a distilled material F. And adding the material F, methanol and L-tartaric acid into a resolution kettle for chiral eutectic, wherein the mass ratio of the material F to the methanol to the L-tartaric acid is 2:3:6, and thus obtaining a material G.

S6: purification, hydrolysis and work-up

S6L-norvaline was obtained in the same manner as in S6 of example 1.

Comparative example 2

S1: cyanation reaction

Respectively and continuously pumping ethanol solutions of n-butyl aldehyde, acetone cyanohydrin and potassium hydroxide (1 part of potassium hydroxide is dissolved in 3 parts of ethanol) into a first microchannel reactor from three feed inlets for cyanation reaction to obtain a material A containing 2-hydroxypentanenitrile, wherein the mass flow ratio of the three liquids is 14:18:2, the reaction temperature is 15 ℃, the retention time is 1 minute, and the material flow rate in the first microchannel reactor is 0.3 m/s.

S2: dealkalization and solvent

S2 was the same as S2 of example 1 to obtain B.

S3: ammoniation reaction

And respectively feeding the material B obtained in the step S2, liquid ammonia and water into a second microchannel reactor for ammoniation reaction to obtain a material C containing the aminopentanenitrile, wherein the mass flow ratio of the material B, the liquid ammonia and the water is 5:3:1, the retention time of a reaction liquid in the microchannel reactor is 1 minute, the reaction temperature is controlled at 20 ℃, and the material flow velocity in the second microchannel reactor is 0.5 m/S.

S4: deaminizing and hydrolyzing reaction

The deamination step was the same as S4 of example 1 to give feed D. And (3) feeding the material D, a potassium hydroxide solution with the mass concentration of 30% and acetone into a dynamic tubular reactor at the mass flow ratio of 10:1:2 for hydrolysis reaction to obtain a material E, wherein the reaction temperature is 20 ℃, and the retention time is 1 minute.

S5: dealkalization and solvent, chiral cocrystal

The dealkalization and solvent procedure was the same as S5 of example 1 to give feed F. And (3) feeding the material F and a methanol solution of L-tartaric acid (the mass ratio of L-tartaric acid to methanol is 1:2) into a dynamic tubular reactor together for chiral eutectic to obtain a material G. The mass flow ratio of the material F to the methanol solution of the L-tartaric acid was 1: 5.

S6: purification, hydrolysis and work-up

S6L-norvaline was obtained in the same manner as in S6 of example 1.

Effects of the embodiment

The results of measuring the product purity of L-norvaline obtained in examples 1 to 3 and comparative examples 1 to 2 by high performance liquid chromatography using pure L-norvaline as a standard substance and calculating the product yield of L-norvaline based on the amount of n-butyraldehyde used are shown in Table 2:

specific conditions for HPLC determination of product purity are set up as shown in table 1.

TABLE 1 set of conditions for HPLC determination of L-norvaline product purity

HPLC Instrument model	Agilent 1220
		Detector	VWDDetector
Chromatographic column	CROWNPAK CR (+) column
		Column temperature	20℃
Mobile phase	Perchloric acid aqueous solution
		Flow rate of flow	0.8ml/min

TABLE 2 purity and yield results for the products obtained in the examples and comparative examples

The results of Table 2 show that the purity and yield of the products obtained in examples 1-3 are respectively above 99.5% and 30%, and the batch-type reaction of the proportion 1 is obviously higher, which indicates that the preparation method of L-norvaline effectively inhibits side reactions and improves the yield of the products. Meanwhile, the product purity and yield of the invention are obviously higher than those of the comparative example 2, which shows that the effect of the invention can be achieved by not simply transferring the preparation method of L-norvaline in the prior art to a microchannel reactor, and the invention can achieve the effects of high product purity and high yield just by matching the optimized reaction conditions. Compared with the comparative example 1, the production time of the L-norvaline in the embodiments 1 to 3 of the invention is greatly shortened, and is shortened from dozens of hours to dozens of minutes of the batch kettle type reaction, so that the production efficiency is greatly improved, the production process is safer, and the operation is simpler.