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Method for preparing D-valine by using asymmetric transformation method

A valine, asymmetric technology, applied in the field of preparation of chiral amino acid compounds, can solve the problems of long D-valine cycle, cumbersome splitting process, low concentration in the conversion process, etc., and achieves improved splitting efficiency, The operation is simple and easy to avoid the effect of entrainment and precipitation

Active Publication Date: 2014-09-10
河北凯力昂生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Induced crystallization method to prepare D-valine has a long period, low yield and low optical purity
The preparation of D-valine by chemical resolution method has also been reported at home and abroad, such as 1D.F.Holmes using the chiral reagent L-menthol oxyethylphthalein chloride synthesized by menthol to resolve racemic valine; domestic patents are also useful Dibenzoyl tartaric acid is used as a chiral reagent for chemical resolution, but the synthesis of the chiral resolution agent used needs to be completed in four steps, and the entire resolution process is cumbersome
The induced crystallization method and the chemical resolution method have the characteristics of low cost, but the optical purity of the product is low, and multiple recrystallizations are required to meet the requirements, and the single yield limit is 50%
[0004] There are a large number of reports on the microbial asymmetric conversion method. This method has the advantage of high optical purity of the product, but its disadvantage is that the precursor DL-5-isopropylhydantoin of the reaction needs to be prepared with highly toxic hydrocyanic acid, and the conversion process is The concentration is too low, causing a lot of waste of water resources

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] In 27mL acetic acid and 3mL acetonitrile solvent, add 4.68g (0.04mol) racemic valine, 7.44g (0.04mol) (+)-1-phenylethanesulfonic acid, and 0.488g (0.004mol) salicylaldehyde and After 0.8mL of acetone was heated to reflux, stirred for 5h, cooled to room temperature, and filtered to obtain a mother liquor and a filter cake, the filter cake was washed with 10mL of acetic acid and 10mL of diethyl ether successively, and dried to obtain 11.2g of a filter cake.

[0029] Dissolve the above filter cake into 10 mL of water, adjust the pH to 5.96 with NaOH, filter, wash with ethanol, and dry to obtain 4.22 g of D-valine, (C=1, 5M hydrochloric acid), D-valine was determined to be 99.7% e.e. by HPLC. The overall yield is 90.2%. The filtrate was spin-dried to obtain the sodium salt of (+)-1-phenylethanesulfonic acid, which was ion-exchanged with Amberlite IR-120 ion exchange resin to obtain (+)-1-phenylethanesulfonic acid aqueous solution, which was concentrated and dried 6.71g (...

Embodiment 2

[0037] Add 5.23g (0.044mol) racemic valine, 8.31g (0.044mol) (+)-1-phenylethanesulfonic acid, and 0.6g (0.005mol) salicylaldehyde and 5mL of 2-butanone was heated to reflux, stirred for 5h, cooled to room temperature, and filtered to obtain a mother liquor and a filter cake. The filter cake was washed with 10mL of acetic acid and 10mL of diethyl ether successively, and dried to obtain 13.2g of a filter cake. Adding racemic valine and (+)-1-phenylethanesulfonic acid to the primary mother liquor continues the next asymmetric conversion process.

[0038] Dissolve the above filter cake in 15 mL of water and ethanol, adjust the pH to 5.96 with triethylamine, filter, wash with ethanol, and dry to obtain 4.82 g of D-valine, (C=1, 5M hydrochloric acid), D-valine was determined to be 99.4% e.e. by HPLC. The overall yield is 92.2%. The filtrate was spin-dried to obtain the sodium salt of (+)-1-phenylethanesulfonic acid, which was ion-exchanged with Amberlite IR-120 ion exchange resin...

Embodiment 3

[0041] Add 6.5 g (0.055 mol) of racemic valine, 11.37 g (0.061 mol) of (+)-1-phenylethanesulfonic acid, and 1.35 g (0.011 mol) of salicylaldehyde to 40 mL of butyric acid and 3.1 mL of DMF solvent Heat reflux with 5mL 3-pentanone, stir for 5h, cool down to room temperature, filter to obtain a mother liquor and filter cake, wash the filter cake with 18mL butyric acid, filter cake with 10ml ether, and dry to obtain 16.9g of filter cake. Adding racemic valine and (+)-1-phenylethanesulfonic acid to the primary mother liquor continues the next asymmetric conversion process.

[0042] Dissolve the above filter cake in 16 mL of water, adjust the pH to 5.96 with sodium carbonate, filter, wash with ethanol, and dry to obtain 6.0 g of D-valine, (C=1, 5M hydrochloric acid), D-valine was determined to be 99.1% e.e. by HPLC. The overall yield is 92.3%. The filtrate was spin-dried to obtain the sodium salt of (+)-1-phenylethanesulfonic acid, which was ion-exchanged with Amberlite IR-120 io...

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Abstract

The invention belongs to the technical field of chiral amino-acid compound preparation, and specifically relates to a method for preparing D-valine by using an asymmetric transformation method. The method is implemented through the following steps of: carrying out asymmetric transformation on a chiral resolution reagent (+)-1-phenyl ethanesulfonic acid and a dl-valine under the catalytic action of a solvent and a catalyst so as to obtain a corresponding target double salt solution; and sequentially carrying out separation, washing and dissociation on the obtained target double salt solution so as to obtain the D-valine, wherein the total yield is more than 90%, the resolution reagent (+)-1-phenyl ethanesulfonic acid can be recycled, and a mother solution also can be reapplied to the next asymmetric transformation process. By using the method provided by the invention, a racemization step in a classical resolution method is saved, the loss of another enantiomers is avoided, the resolution efficiency is improved, the operation is simplified, and an entrained separation phenomenon caused by that the concentration of enantiomers is increased in the classical resolution method is avoided, so that the optical purity (greater than 99% ee) of the D-valine is ensured. The chiral reagent and the mother solution can be recycled, so that the production cost is greatly lowered, therefore, the method provided by the invention is suitable for industrial production processes.

Description

technical field [0001] The invention relates to a method for preparing D-valine by an asymmetric conversion method, and belongs to the technical field of preparation of chiral amino acid compounds. Background technique [0002] D-valine (D-valine, abbreviated D-Val) is an important organic chiral source, mainly used in the synthesis of chiral drugs, chiral additives, chiral auxiliary agents and other compounds, such as D-valine The insecticidal activity of permethrin is 5000 times that of L-valine permethrin. D-valine is used as a chiral source for chiral synthesis in the pharmaceutical industry, and is widely used in medical research and pharmaceutical synthesis, such as the synthesis process of vornicolane. [0003] Regarding the preparation of D-valine, the methods reported in the literature mainly include induced crystallization, chemical resolution and microbial asymmetric conversion. The preparation of D-valine by induced crystallization has a long period, low yield ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C229/08C07C227/34
CPCY02P20/582
Inventor 孙凤霞
Owner 河北凯力昂生物科技有限公司