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

Abstract

The method for preparing L-valine and D-valine by chemical resolution is a preparation technology of chiral organic compounds. The method uses racemic valine (DL-Val) as a raw material and an inorganic acid as a solvent. Use D-dibenzoyl tartaric acid (D-DBTA) and L-dibenzoyl tartaric acid (L-DBTA) as the resolving agent, and the ratio of racemic-valine to resolving agent is 1:0.5-1.2 Dissolve in dilute inorganic acid solution, stir at 60-100°C for 0.5-2.0 hours, then gradually cool to room temperature, filter out the crystalline salt, and neutralize the crystalline salt and mother liquor with alkali in water, alcohol and other solvents, namely To obtain left-handed valine (D-Val) and right-handed valine (L-Val) respectively, the process route is: see the right formula.

Description

Method for preparing L-valine and D-valine by chemical resolution

1. 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.

2. Background technology

D-valine (L-Val) is an essential amino acid for nutrition, widely used as a food and feed additive, and also used in clinical amino acid infusion. L-Valine (D-Val) is an important chiral intermediate widely used in the synthesis of medicine and pesticide. For example, it can be used to synthesize antitumor drugs diaryl boron amino acid anhydride and diaryl boron aminoethyl ester compounds; it can also be used to synthesize new high-efficiency pesticides pyrethroids and halvalerate; its diiodophthaloyl derivatives The substance has antibacterial activity; the penicillamine derivatives of D-valine have the effect of enhancing immunity against AIDS and other diseases; its α-acyl cell wall dipeptide derivatives have the effect of enhancing the organism's resistance to pathogens without itself toxicity.

Regarding the preparation of D-Val, the methods reported in the literature mainly include induced crystallization, microbial asymmetric conversion and chemical resolution.

In 1965, Susenm Tatsumi et al. reported that adding seed crystals to saturated or supersaturated racemic valine (DL-Val) hydrochloride solution could preferentially crystallize D-valine hydrochloride and neutralize D-Val. D-valine is obtained after valine hydrochloride, the optical purity is 93%, and the yield is less than 10%. In 1988, Nohira Hiroyuki et al. induced crystallization in the presence of DL-methionine hydrochloride, DL-alanine hydrochloride and sulfonic acid, allowing D-valine hydrochloride to preferentially precipitate from the solution; he is still working on Induced crystallization was carried out in the presence of xylenesulfonic acid to obtain D-valine with an optical purity of 89.8%. The production of D-valine by induced crystallization has a long period, low yield and low optical purity, and is not suitable for industrial production.

There are a large number of reports on microbial asymmetric conversion methods, representative of which are Italian scientists M.Battilotti and U.Barberini using enzymes produced by Agrobacterium radiata to catalyze the hydrolysis of DL-5-isopropylhydantoin. This bacteria is rich in hydantoin Under the catalysis of hydrolase and carbamoyl hydrolase, D-valine can be directly separated from the reaction liquid, and the yield is 60%. The disadvantage of this method is that the precursor of the reaction, DL-5-isopropylhydantoin, must be prepared with highly toxic hydrocyanic acid, and the yield is not too high, and there is still a certain distance from industrial production.

Chemical resolution is an old and young method. There are only a few reports abroad on the separation and preparation of D-valine by chemical resolution methods. In 1934, D.F.Holmes used the chiral reagent L-mentholoxyacetyl chloride synthesized by menthol and DL-valine to generate diastereomeric amides, which were separated by fractional crystallization, and the amides reacted with HBr in aqueous ethanol to obtain optical Active D-Valine. The synthesis of the chiral resolving agent used needs to be completed in four steps, the whole resolution process is more loaded down with trivial details, and the optical purity and yield of the product are not reported. In 1984, Tadashi Shiraiwa used HCl to adjust the pH value to 5.5 in an alkaline solution containing L-phenylalanine and DL-valine, and precipitated L-phenylalanine and D-valine adducts. After the compound is dissolved in water, L-phenylalanine is removed by active carbon adsorption to obtain D-valine, and its productive rate is 49-63%, and the optical purity is 84-100%, and the yield and optical purity of the product are not high enough .

3. Contents of the invention

1. Technical issues

The purpose of the present invention is to provide a new chemical resolution method for preparing D-valine and L-valine, and the product obtained by using the method to resolve DL-valine has high yield and high optical purity.

2. Technical solution

The chemical resolution method of the present invention prepares the method for L-valine and D-valine, uses racemic valine (DL-Val) as raw material, takes mineral acid as solvent, and uses D-dibenzoyl tartaric acid (DL-Val) as a raw material. D-DBTA) and L-dibenzoyl tartaric acid (L-DBTA) are the resolving agent, and the racemic-valine and the resolving agent are dissolved in dilute dilute solution in the ratio of 1:0.5-1.2 In the inorganic acid solution, stir at 60-100°C for 0.5-2.0 hours, then gradually cool to room temperature, filter out the crystalline salt, and neutralize the crystalline salt and the mother liquor with alkali in water and alcohol solvent respectively to obtain L-valamine acid (D-Val) and D-valine (L-Val), the process route is:

Wherein H ⁺ is a hydrogen ion.

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

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

The solvents used for ammoniation neutralization are water, methanol, ethanol, propanol, isopropanol, n-butanol and other lower aliphatic alcohols and acetone.

Since valine is a neutral amino acid containing only aliphatic side chains, tartaric acid was used as a raw material to synthesize stronger acidic resolving agents D-DBTA and L-DBTA with certain rigidity, which formed diastereomers with DL-Val respectively. Diastereomeric salts, because diastereomeric salts have a large difference in solubility in acidic aqueous solution, so DL-Val can be successfully split into D-Val and L-Val.

When D-DBTA is used as a resolving agent, the salt D-Val·D-DBTA has a small solubility in the solution, and after cooling, it precipitates out of the solution, and its diastereomeric salt remains in the solution. The filtered D-Val·D-DBTA can be neutralized with alkali to obtain D-Val. After splitting and concentrating the mother liquor, adjust the pH value to 5.5 with alkali to obtain L-Val. The yields of both D-Val and L-Val are above 70%, and the optical purity is greater than 98%.

A similar situation occurs when L-DBTA is used as a resolving agent. The difference is that the salt formed by L-Val and L-DBTA precipitates out of the solution during resolution, and the salt of D-Val remains in the mother liquor. The target product can also be obtained by treating the corresponding salt with alkali, with a yield of more than 70% and an optical purity of more than 98%.

Racemic valine reacts with chiral organic acids to form diastereomeric salts. Diastereomeric salts have different solubility in solution, and they can be separated by virtue of the difference in solubility. In the present invention, after adding D-DBTA in the DL-Val solution, the salt generated by D-Val and D-DBTA has less solubility in dilute acid and will be separated out from the solution, and the salt generated by L-Val has lower solubility. Larger ones remain in solution. After equilibrating for a period of time, they can be separated by filtration. Similarly, when L-DBTA is added to the DL-Val solution, the salt generated by L-Val and L-DBTA has a lower solubility in dilute acid and precipitates out of the solution, while the salt generated by D-Val has a higher solubility. stay in solution.

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

In the present invention, stronger base ammonia or triethylammonia reacts with stronger acid D-Val·D-DBTA to generate weaker acid ammonium tartrate and weaker base D-Val.

3. Beneficial effects

The synthetic raw material of the resolving agent used in the present invention is easy to get, and the synthesis process is simple; The resolving agent can be recycled and reused after the resolving;

The ammonium salt can be used in agricultural production; the use of inorganic acid is the characteristic that this invention is different from the traditional resolution process. The inorganic acid is not only beneficial to the dissolution of DL-Val, but also reduces the amount of resolution agent. Under optimal conditions, the resolution yield of D-Val (L-valine) reaches 80%, and the optical purity reaches 100%.

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

4. Specific implementation

1. Using DL-Val (racemic-valine) as raw material, using dilute hydrochloric acid or dilute sulfuric acid as solvent, prepare D-Val (L-Valine) and L-Val (D-Val) by chemical resolution -valine),

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 most suitable amount is 8-16 times of valine. The acid concentration is 0.1-1.0mol/L, and the optimum concentration is 0.2-0.8mol/L.

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

5. The solvents used for diastereomeric salt washing are ether, acetone, ethanol, water, etc.

6. The alkali required for ammoniation neutralization is ammonia gas, ammonia water, triethylamine, ammonium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, etc.

7. The solvents used for ammoniation neutralization are water, methanol, ethanol, propanol, isopropanol, n-butanol and other lower aliphatic alcohols and acetone.

Routing:

Example 1:

Dissolve 2.34g of DL-Val in 20ml of dilute hydrochloric acid, heat to 80-100°C under stirring, add 3.58g of L-DBTA, react at this temperature for half an hour, then keep at 60°C for 1 hour, gradually a precipitate forms, and then Cool to about 15°C, filter with suction, dissolve the filter cake in 30ml of ethanol and 2 times the amount of triethylamine, stir for 1 hour, filter with suction, wash with ethanol, dry to obtain 0.94g of L-Val, and the resolution yield is 80.3% , [α]D ²² =+27.5°. After splitting and concentrating the mother liquor, adjust the pH value to 5.5 with alkali, stir, a white solid precipitates out, filter with suction, wash with ethanol, and dry to obtain 0.84 g of D-Val with a yield of 71.8%, [α]D ²² =-27.5°.

Example 2:

Dissolve 2.34g of DL-Val in 20ml of dilute hydrochloric acid, stir, heat to 90-100°C, add 3.76g of D-DBTA, react at this temperature for 50 minutes, then keep at 60°C for 1 hour, gradually a precipitate forms, and then cool to At about 15°C, filter with suction and wash with water, dissolve the filter cake in 30ml of ethanol and 2 times the amount of triethylamine, stir for 1 hour, filter with suction, wash with ethanol, dry to obtain 0.94g of D-Val, and the resolution yield is 80.3 %, [α]D ²² = -30°. After splitting and concentrating the mother liquor, adjust the pH value to 5.5 with alkali, stir, a white solid precipitates out, filter with suction, wash with ethanol, and dry to obtain 0.83g of L-Val, yield 70.9%, [α]D ²² =+27.5°.

Claims (3)

1. A method for preparing L-valine and D-valine by a chemical resolution method, characterized in that racemic valine is used as a raw material, and an inorganic acid is used as a solvent, and D-dibenzoyl tartaric acid and L-valine are used as raw materials. Dibenzoyl tartaric acid is used as a resolving agent, and the racemic-valine and resolving agent are dissolved in a dilute inorganic acid solution at a ratio of 1:0.5-1.2 according to the ratio of the amount of substances, at 60-100°C Stir for 0.5-2.0 hours, then gradually cool to room temperature, filter out the crystalline salt, and neutralize the crystalline salt and the mother liquor with alkali in water and alcohol solvent respectively to obtain L-valine and D-valine respectively. The process route is :

Wherein H ⁺ is a hydrogen ion. 2. The method for preparing L-valine and D-valine by chemical resolution according to claim 1, characterized in that the inorganic acid solvent is dilute hydrochloric acid or dilute sulfuric acid aqueous solution, and the quality of the solvent is 5 to 20 times that of Valine, acid concentration is 0.1-1.0mol/L. 3. The method for preparing L-valine and D-valine by chemical resolution according to claim 1, wherein the alkali required for ammoniation neutralization is ammonia gas, ammonia water, triethylamine, ammonium carbonate , Sodium Carbonate, Potassium Carbonate, Sodium Hydroxide.