CN100391934C - Method for preparing L-glutamic acid - Google Patents

Abstract

The present invention relates to a method for preparing L-glutamic acid, which belongs to technology for preparing chiral materials. The method comprises: L-glutamic acid firstly reacts with anhydrous ethanol under the catalysis of acid based on a known method, and L-glutaminic acid ethyl ester is obtained; the L-glutaminic acid ethyl ester is racemized under the existence of a catalyst, and DL-glutaminic acid ethyl ester is obtained; the DL-glutaminic acid ethyl ester acts with a resolution agent L-2 and 3-dibenzoyltartaric acid to form diastereomer salt; D-glutaminic acid with the optical rotation purity of more than 99% is obtained by the amination and the hydrolysis of separated D-glutaminic acid ethyl ester. The action of the DL-glutaminic acid ethyl ester and the resolution agent comprises: the DL-glutaminic acid ethyl ester and the resolution agent are dissolved in water with the purity of 0.5 to 10 times of that of the DL-glutaminic acid ester, and the proportion of the DL-glutaminic acid ester and the resolution agent is 1: 0.5 to 1.2; the DL-glutaminic acid ethyl ester and the resolution agent are stirred for 0.5 to 5.0 hours at a temperature of 60 to 100 DEG C and are cooled to a room temperature. Crystals are filtered out and are washed with water. The present invention solves the technology for preparing the D-glutaminic acid by steps of esterification, racemization, separation, hydrolysis, etc., of the L-glutamic acid.

Description

The method for preparing D-glutamicacid

Technical field

The invention belongs to the technology of preparing of chiral material, especially the preparation method of D-glutamicacid (D-L-glutamic acid).

Technical background

D-L-glutamic acid is as a kind of important chiral source material, at new drug development, organic synthesis, polypeptide synthetic with and ester derivative is synthetic etc. that vital role that the field played more and more causes people's attention.Alfonso de Dios etc. are that raw material has synthesized the 4-replacement D-glutamic acid-type with anti-microbial activity with D-L-glutamic acid, and they also are L-glutamic acid racemization inhibitor; People such as calendar year 2001 Joseph R. are that raw material has synthesized the novel cpd that a class has analgesic activity with D-L-glutamic acid; Sayah etc. are with D-L-glutamic acid and tetrahydrochysene-2, and 5-dimethoxy furans is that chiral source has been synthesized optically active compound (R)-(+)-Myrmicarin 217 first; Ksander etc. are vasotonia saccharase co-inhibitors with D-L-glutamic acid and other amino acid synthetic dipeptide compounds, and this dipeptides has remarkable effect to treatment hypertension.

Deep day by day along with the applied research of D-L-glutamic acid, also increasing to the demand of D-L-glutamic acid, press for the method for producing D-L-glutamic acid is furtherd investigate.Nineteen sixties United States Patent (USP) (L.F.Harold, Resolution of DL-Glutamic acid.UP 2,929,842; S.Ingmar, Resolution of DL-Glutamic acid.UP 2,945,879; L.Joseph, Resolution ofDL-Glutamic acid UP 2,987,543.) reported that preferential crystallization method separation DL-L-glutamic acid obtains D-L-glutamic acid, later similar approach is seen in report again successively.The preferential crystallization legal system gets that D-L-glutamic acid yield is low, and optical purity is not high, in order to make racemic mixture saturated, must adopt the intermittent type crystallization in process of production, has prolonged the cycle of producing, and has increased production cost.Japanese Patent (Soda K., Manufacture of D-amino acid from ketocarboxylic acid by enzymes.JP62205790 in 1987; Sato, H., Microbal manufacture of D-glutamic acid.JP 6402595.) reported under enzyme catalysis method by alpha-ketoacid asymmetric synthesis D-L-glutamic acid, GalkinAndrey (A.Galki et al in 1997, Conversion of α-keto acid to D-amino acids bycompling of four enzyme reactions.J.Ferment.Bioeng.1997,83 (3): 299-300.) wait the people, still because chiral source is difficult for obtaining and the reactions steps complexity makes this method not obtain practical application to also reporting by the method for alpha-ketoacid asymmetric synthesis D-L-glutamic acid.Along with the biological chemistry industrial expansion, biological method obtains people's attention and furthers investigate, and this is at a series of Japanese Patents (K.Y.Isobu, Enzymic manufacture of D-amino.JP 11103887; Manufacture of D-Glutamic acid with Lactobacillus.JP 0253494; Microbalmanufacture of D-glutamic acid JP 6402595.) in report is arranged all, the key of this method is a biological catalyst, and it can be complete microorganism cells or the enzyme that extracts from microorganism cells.The advantage of this method is that stereoselectivity is strong, reaction conditions is gentle, public hazards are few, can finishes the reaction that some chemical synthesiss are difficult to finish.Shortcoming be that bacterial screening difficulty, zymin are difficult for preservation, long reaction time, reaction substrate concentration is rare and the product postprocessing workload big etc.Chemical resolution method is to study one of method the earliest, (S.Sugasawa such as nineteen twenty-six S.Sugasawa, J.Pharm.Soc.Japan, 1926:934.) be that resolving agent splits by Pyrrolidonecarboxylic acid and obtains D-L-glutamic acid with the quinine, H.Frederick (H.Frederic et al in 1954, Resolution of Glutamic Acid with l-Hydroxy-2-aminobutane.J.Am.Chem.Soc., 1954,76 (10): 2801-2803.) wait the people to report and split DL-L-glutamic acid with 1-hydroxyl-2-butylamine, obtained optically pure D-L-glutamic acid, Francine Acher in 1994 and RobertAzerad (A.Francine, A.Robert, Resolution and Regioselective Protection ofGlutamic Acid Analogues.I-Resolution of Diastereomeric α-BoroxazolidoneDerivatives.Tetrahedron:Asymmetry 5 (4): 731-744.) the alkyl derivative separation hydrolysis by DL-L-glutamic acid has obtained D-L-glutamic acid.The yield that has in the aforementioned institute reported method is lower, and the resolution reagent costliness that has is unsuitable for suitability for industrialized production.Therefore, be necessary to study new method for splitting.

Summary of the invention

Technical problem; The objective of the invention is provides the method for preparing D-L-glutamic acid that a kind of production cost is low, environmental pollution is little, yield is higher at the existing problem of the above preparation D-L-glutamic acid.

Technical scheme: we at first make L-L-glutamic acid obtain the L-ethyl glutamate with the dehydrated alcohol reaction under acid catalysis according to currently known methods, make its racemization in the presence of catalyzer obtain the DL-ethyl glutamate.Make DL-ethyl glutamate and L-2 then, 3-dibenzoyl tartaric acid (L-DBTA) effect forms diastereoisomeric salt.D-ethyl glutamate L-DBTA salt solubility is less, and at first crystallization is separated out from system.This crystal obtains the D-L-glutamic acid of polarimetry purity more than 99% through two one-step hydrolysis after the separation.This route cost is lower, and experiment condition is easy to control, and the product purity height along with the increase of market to D-L-glutamic acid demand, will be the synthetic route of a great exploitation potential for its.As far as we know, this is to be that resolving agent prepares D-L-glutamic acid with chemical resolution method first with L-DBTA.

Operational path is:

Splitting condition is:

DL-ethyl glutamate and resolving agent effect, be that DL-ethyl glutamate and resolving agent are dissolved in 0.5～10 times in the water of DL-ethyl glutamate in 1: 0.5～1.2 ratio, stirred 0.5～5.0 hour down at 60～100 ℃, be cooled to room temperature again, leach crystallization and wash with water.Crystal salt amination in water, alcohol equal solvent promptly obtains the higher D-ethyl glutamate of optical purity.The needed alkali of amination is dimethylamine, Trimethylamine 99, diethylamine, triethylamine, thyl methyl amine, propylamine, butylamine.The used solvent of amination is water and methyl alcohol or ethanol or propyl alcohol or Virahol or propyl carbinol or acetone.

Its principle is: optically active amino acid and derivative thereof are in the presence of catalyzer, by forming the schiff bases intermediate, racemization at a certain temperature, be transformed into racemic modification, the latter and chiral organic acid effect generate diastereoisomeric salt, can they be separated by diastereoisomeric salt difference of solubleness in solution, and then the preparation optically active amino acids.Among the present invention, when add resolving agent in DL-ethyl glutamate solution after, salt solubleness in solution that D-ethyl glutamate and resolving agent are generated is less, separates out from solution, and the salt solubility that the L-ethyl glutamate is generated is more then stayed in the solution.Balance can be separated them by filtering after for some time.

Be based on the acid-base neutralisation reaction principle by diastereoisomeric salt amination system D-ethyl glutamate.In the present invention, stronger alkali triethylamine generates more weak sour tartrate ammonium salt with stronger sour D-ethyl glutamate L-DBTA effect and reaches more weak alkali D-ethyl glutamate.

D-L-glutamic acid L-DBTA+NH ₃→ D-ethyl glutamate+L-DBTA ammonium salt

The hydrolysis under acid catalysis of D-ethyl glutamate can obtain D-L-glutamic acid.

Beneficial effect: the easily synthetic and raw material of the used resolving agent of the present invention is easy to get, and splitting the back resolving agent can recycling; Technology such as esterification, hydrolysis is simple; Splitting solvent for use is water, and production cost is low, and environmental pollution is little.Under top condition, D-ethyl glutamate resolution yield reaches 76%, and D-L-glutamic acid optical purity reaches more than 99%.

In sum, the invention solves by L-L-glutamic acid and prepare D-L-glutamic acid technology by steps such as esterification, racemization, fractionation, hydrolysis.This technology can be used for industrial production.

Embodiment

Example 1:

In the 100mL there-necked flask, add 20g (0.11mol) DL-L-glutamic acid-γ-ethyl ester, 10～200mL water, slowly stir and be warming up to the solid part dissolving, add 0.055mol～0.132molDL-DBTA, continue to be warming up to solid dissolving in 80 ℃ of this moment reaction systems, stirring reaction is 1 hour under this temperature, be cooled to below 20 ℃, stirring reaction made crystallization complete in two hours, filtering separation obtains white crystal then, water washing repeatedly, dry 23.2g D-ethyl glutamate L-DBTA salt, fusing point: 158-162 ℃.Split mother liquor and can be used for reclaiming L-L-glutamic acid-γ-ethyl ester.Place the 250mL there-necked flask to add under 30～150mL ethanol and 1～3 times amount triethylamine normal temperature ammonification two hours D-ethyl glutamate L-DBTA salt, filtering-depositing obtains 7.6gD-L-glutamic acid-γ-ethyl ester, yield 76%, m.p.168-172 ℃, [α] _D ²⁷=-11.86 (C=1, H ₂O).

Example 2:

7.6g D-L-glutamic acid-γ-ethyl ester places the 100mL round-bottomed flask, add 80mL dilute hydrochloric acid, boiled 2～4 hours, and with about reaction solution evaporation concentration to 1/10, under 20 ℃, regulated the pH value to 3.3-3.5 with ammoniacal liquor, continue stirring reaction standing over night in the refrigerator after 1 hour, filter, and the water flushing, oven dry, obtain 5.6g D-L-glutamic acid, yield 87.97%.m.p.201-204℃。[α] _D ²³＝-31.02°(C＝2，5mol/L?HCl)。

Claims (3)

1. a method for preparing D-glutamicacid is characterized in that at first making L-L-glutamic acid obtain the L-ethyl glutamate with the dehydrated alcohol reaction under acid catalysis according to currently known methods, makes the racemization in the presence of catalyzer of L-ethyl glutamate obtain the DL-ethyl glutamate; Make DL-ethyl glutamate and resolving agent L-2 then, the effect of 3-dibenzoyl tartaric acid forms diastereoisomeric salt; Separating obtained D-ethyl glutamate L-DBTA salt obtains the D-L-glutamic acid of polarimetry purity more than 99% through amination, hydrolysis; DL-ethyl glutamate and resolving agent effect, be that DL-ethyl glutamate and resolving agent are dissolved in 0.5～10 times in the water of DL-ethyl glutamate in 1: 0.5～1.2 ratio, stirred 0.5～5.0 hour down at 60～100 ℃, be cooled to room temperature again, leach crystallization and wash with water.

2. the method for preparing D-glutamicacid according to claim 1 is characterized in that the needed alkali of amination is dimethylamine, Trimethylamine 99, diethylamine, triethylamine, thyl methyl amine, propylamine, butylamine.

3. the method for preparing D-glutamicacid according to claim 1 is characterized in that the used solvent of amination is water and methyl alcohol or ethanol or propyl alcohol or Virahol or propyl carbinol or acetone.