CN1186313C

CN1186313C - Methof for preparing l-valine and d-valine by using chemical resolution process

Info

Publication number: CN1186313C
Application number: CNB031321372A
Authority: CN
Inventors: 蒋立建; 徐海青; 张征林; 未本美; 邹建忠
Original assignee: Southeast University
Current assignee: Southeast University
Priority date: 2003-07-01
Filing date: 2003-07-01
Publication date: 2005-01-26
Anticipated expiration: 2023-07-01
Also published as: CN1477096A

Abstract

The present invention relates to a method for preparing L-valine and D-valine by a chemical resolution method, which is a preparation technology of a chiral organic compound. In the method, racemic valine (DL-Val) is used as raw materials; inorganic acid is used as solvent; D-dibenzoyltartaric acid (D-DBTA) and L-dibenzoyltartaric acid (L-DBTA) are used as resolution agents; the DL-Val and the resolution agents are dissolved in a diluted inorganic acid solution in the proportion of 1:0.5 to 1.2, stirred at 60 to 100 DEG C for 0.5 to 2.0 hours, and then, gradually cooled to room temperature; crystal salt is filtered out; the crystal salt and mother liquid are respectively neutralized by alkali in solvent of water, ethanol, etc.; the L-valine (L-Val) and the D-valine (D-Val) are respectively prepared. A technical route is disclosed in the specification.

Description

Method for preparing levovaline and dextrovaline by chemical resolution method

One, the technical field

The invention relates to a preparation technology of chiral organic compounds, in particular to a preparation method of L-valine and D-valine.

Second, background Art

L-valine (L-Val) is an essential nutrient amino acid and is widely used as a food and feed additive and also used for clinical amino acid transfusion, L-valine (D-Val) is an important chiral intermediate and is widely applied to the synthesis of medicines and pesticides, such as diarylboron amino acid anhydride and diarylboron amino ethyl ester compounds which can be used for synthesizing antitumor drugs, and also can be used for synthesizing novel high-efficiency pesticides pyrethroid and fluthrin, the diiodobenzene diformyl derivative of the D-Val has antibacterial activity, the penicillamine derivative of the D-Val has the function of enhancing immunity and resisting AIDS and other diseases, and the α -acyl muramyl dipeptide derivative has the function of enhancing organisms to resist pathogens without toxicity.

As for the preparation of D-Val, methods reported in the literature mainly include an induced crystallization method, a microbial asymmetric transformation methodand a chemical resolution method.

In 1965, Susenm Tatsumi et al reported that D-valine hydrochloride can be preferentially crystallized by adding seed crystals to a saturated or supersaturated racemic valine (DL-Val) hydrochloride solution, and D-valine can be obtained after neutralization of the D-valine hydrochloride, with an optical purity of 93% and a yield of less than 10%. Nohira Hiroyuki et al in 1988 preferentially precipitated D-valine hydrochloride from solution by inducing crystallization in the presence of DL-methionine hydrochloride, DL-alanine hydrochloride and sulfonic acid; he also induced crystallization in the presence of p-xylene sulfonic acid to give D-valine with an optical purity of 89.8%. The method for preparing D-valine by the induced crystallization method has the advantages of long period, low yield and low optical purity, and is not suitable for industrial production.

There are many reports of the microbial asymmetric transformation method, and representative methods are those of Italian scientists M.Battiloti and U.Barberini which hydrolyze DL-5-isopropylhydantoin by the enzyme produced by Agrobacterium radiobacter, which is rich in hydantoin hydrolase and carbamoyl hydrolase, and under the catalysis of which D-valine can be directly separated from the reaction solution with a yield of 60%. The method has the disadvantages that the precursor DL-5-isopropyl hydantoin of the reaction needs to be prepared by using virulent hydrocyanic acid, the yield is not too high, and a certain distance is left from the industrial production.

Chemical resolution is an old and young process. The resolution and preparation of D-valine by a chemical resolution method are only reported in a small amount abroad. Chiral reagents L-menthol oxyacetyl chloride synthesized in D.F. Holmes with menthol produced diastereomeric amides with DL-valine in 1934, which were separated by fractional crystallization, and the amides reacted with HBr in aqueous ethanol to give optically active D-valine. The synthesis of the chiral resolving agent needs four steps, the whole resolving process is relatively complicated, and the optical purity and yield of the product are not reported. Tadashi Shiraiwa adjusted pH to 5.5 with HCl in an alkaline solution containing L-phenylalanine and DL-valine in 1984 precipitated an adduct of L-phenylalanine and D-valine, which was dissolved in water and then removed by adsorption on activated carbon to give D-valine in 49-63% yield and 84-100% optical purity, and the product was not sufficiently high in yield and optical purity.

Third, the invention

1. Technical problem

The invention aims to provide a novel chemical resolution method for preparing D-valine and L-valine, and the method is used for resolving DL-valine to obtain a product with high yield and high optical purity.

2. Technical scheme

The invention discloses a method for preparing levo-valine and dextro-valine by a chemical resolution method, which comprises the following steps of taking racemic valine (DL-Val) as a raw material, taking inorganic acid as a solvent, taking dextro-dibenzoyl tartaric acid (D-DBTA) and levo-dibenzoyl tartaric acid (L-DBTA) as resolving agents, dissolving the racemic-valine and the resolving agents into a dilute inorganic acid solution according to the mass ratio of 1: 0.5-1.2, stirring for 0.5-2.0 hours at the temperature of 60-100 ℃, then gradually cooling to room temperature, filtering out crystalline salt, and neutralizing the crystalline salt and mother liquor with alkali in water and an alcohol solvent respectively to obtain the levo-valine (D-Val) and the dextro-valine (L-Val) respectively, wherein the process route is as follows:

wherein H⁺Is a hydrogen ion.

The inorganic acid solvent is dilute hydrochloric acid or dilute sulfuric acid water solution, the amount of the solvent is 5-20 times of that of valine, and the concentration of the acid is 0.1-1.0 mol/L.

The alkali required by ammoniation neutralization is ammonia gas, ammonia water, triethylamine, ammonium carbonate, sodium carbonate, potassium carbonate and sodium hydroxide.

The solvent used in ammoniation neutralization is water, lower aliphatic alcohol such as methanol, ethanol, propanol, isopropanol, n-butanol, etc., and acetone.

Because valine is a neutral amino acid only containing a fat side chain, tartaric acid is used as a raw material to synthesize resolving agents D-DBTA and L-DBTA which have strong acidity and certain rigidity, the resolving agents D-DBTA and L-DBTA respectively form diastereomer salts with DL-Val, and the solubility difference of the diastereomer salts in an acidic aqueous solution is large, so that the DL-Val can be successfully resolved into the D-Val and the L-Val.

When D-DBTA is used as a resolving agent, the salt D-Val.D-DBTA has low solubility in the solution, and is separated out from the solution after cooling, and the diastereomer salt is remained in the solution. The D-Val is obtained by neutralizing the filtered D-Val.D-DBTA with alkali. And (4) concentrating the split mother liquor, and adjusting the pH value to 5.5 by using alkali to obtain the L-Val. The yields of D-Val and L-Val are both above 70%, and the optical purity is higher than 98%.

The use of L-DBTA as resolving agent is similar except that the salt formed by L-Val and L-DBTA precipitates out of the solution during resolutionand the salt of D-Val remains in the mother liquor. The corresponding salt is treated by alkali, the target product can be obtained, the yield is more than 70%, and the optical purity is more than 98%.

Racemic valine reacts with chiral organic acids to give diastereomeric salts which differ in solubility in the solution and can be separated by virtue of the difference in solubility. In the invention, after D-DBTA is added into a DL-Val solution, the salt generated by the D-Val and the D-DBTA has low solubility in dilute acid and is precipitated out of the solution, and the salt generated by the L-Val has high solubility and is left in the solution. After a period of equilibration, they can be separated by filtration. Similarly, when L-DBTA is added to a DL-Val solution, the salt formed by L-Val and L-DBTA has a lower solubility in dilute acid and precipitates out of the solution, while the salt formed by D-Val has a higher solubility and remains in the solution.

The preparation of D-Val or L-Val by ammoniation of diastereomeric salts relies on a simple acid-base neutralization reaction principle.

In the present invention, stronger alkaline ammonia or triethylamine reacts with stronger acid D-Val.D-DBTA to produce weaker acid tartrate ammonium salt and weaker alkaline D-Val.

3. Advantageous effects

The resolving agent used in the invention has easily obtained synthetic raw materials and simple synthetic process; the resolving agent can be recycled after the resolution; the solvent used for the resolution is dilute acid aqueous solution, the production cost is low, the environmental pollution is little, and inorganic acid by-products are generated

The ammonium salt of (A) can be used in agricultural production; the use of the inorganic acid is different from the traditional resolution process, and the inorganic acid is beneficial to the dissolution of DL-Val and reduces the dosage of the resolving agent. Under the optimal conditions, the resolution yield of the D-Val (L-valine) reaches 80 percent, and the optical purity reaches 100 percent.

In conclusion, the invention solves the problems of low yield, high cost and the like in the process of preparing D-Val and L-Val from DL-Val. Therefore, the process for preparing D-Val and L-Val from DL-Val by using DBTA as a resolving agent can be used for industrial production.

Fourth, detailed description of the invention

1. Preparing D-Val (L-valine) and L-Val (D-valine) by using DL-Val (racemic-valine) as a raw material and dilute hydrochloric acid or dilute sulfuric acid as a solvent through a chemical resolution method,

2. the resolving agent is dibenzoyl tartaric acid D-DBTA and L-DBTA.

3. The resolution solvent is dilute hydrochloric acid, dilute sulfuric acid or other dilute inorganic strong acid aqueous solution. The amount of solvent is 5-20 times of valine, and the optimal amount is 8-16 times of valine. The concentration of the acid is 0.1-1.0mol/L, and the optimal concentration is 0.2-0.8 mol/L.

4. The temperature of the resolution reaction is 70-100 deg.C, and the optimum temperature is 75-95 deg.C.

5. The solvent used for washing the diastereoisomer salt is diethyl ether, acetone, ethanol, water and the like.

6. The alkali required by ammoniation neutralization is ammonia gas, ammonia water, triethylamine, ammonium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide and the like.

7. The solvent used in ammoniation neutralization is water, lower aliphatic alcohol such as methanol, ethanol, propanol, isopropanol, n-butanol, etc., and acetone.

The process route is as follows:

example 1:

dissolving 2.34g DL-Val in 20ml dilute hydrochloric acid, heating to 80-100 deg.C under stirring, adding 3.58g L-DBTA, reacting at the temperature for half an hour, maintaining at 60 deg.C for 1 hr to gradually generate precipitate, cooling to about 15 deg.C, suction filtering, dissolving filter cake in 30ml ethanol and 2 times of triethylamine, stirring for 1 hr, suction filtering, washing with ethanol, drying to obtain 0.94g L-Val with resolution yield of 80.3%, [ α]]D²²Concentrating the mother solution at 27.5 deg.C, adjusting pH to 5.5 with alkali, stirring, precipitating white solid, filtering, washing with ethanol, and drying to obtain 0.84g D-Val with yield of 71.8%, [ α]]D²²＝-27.5°。

Example 2:

2.34g DL-Val was dissolved in 20ml dilute hydrochloric acid, stirred, heated to 90-100 ℃ and 3.76g D-DBTA added, reacted at this temperature for 5 g0 minute, then 60 ℃ is kept for 1 hour, gradually precipitate is generated, then the temperature is cooled to about 15 ℃, the filtration and the washing are carried out, the filter cake is dissolved in 30ml of ethanol and 2 times of triethylamine, the stirring is carried out for 1 hour, the filtration and the washing are carried out by ethanol, the drying is carried out to obtain 0.94g D-Val, the resolution yield is 80.3 percent and the yield is α percent]D²²Concentrating the mother solution at-30 deg.C, adjusting pH to 5.5 with alkali, stirring, precipitating white solid, filtering, washing with ethanol, and drying to obtain 0.83g L-Val with yield of 70.9%, [ α]]D²²＝+27.5°。

Claims

1. A chemical resolution method for preparing levo-valine and dextro-valine is characterized in that racemic valine is used as a raw material, inorganic acid is used as a solvent, dextro-dibenzoyl tartaric acid and levo-dibenzoyl tartaric acid are used as resolving agents, racemic-valine and the resolving agents are dissolved in a dilute inorganic acid solution according to the mass ratio of 1: 0.5-1.2, the solution is stirred for 0.5-2.0 hours at the temperature of 60-100 ℃, then the solution is gradually cooled to the room temperature, crystal salt is filtered out, the crystal salt and mother liquor are neutralized by alkali in water and alcohol solvents respectively, and the levo-valine and the dextro-valine are obtained respectively, and the process route is as follows:

wherein H⁺Is a hydrogen ion.

2. The method for preparing L-valine and D-valine by chemical resolution according to claim 1, wherein the inorganic acid solvent is dilute hydrochloric acid or dilute sulfuric acid aqueous solution, the mass of the solvent is 5-20 times of that of valine, and the acid concentration is 0.1-1.0 mol/L.

3. The method for preparing L-valine and D-valine by chemical resolution according to claim 1, wherein the alkali required for ammoniation and neutralization is ammonia gas, ammonia water, triethylamine, ammonium carbonate, sodium carbonate, potassium carbonate or sodium hydroxide.