JPS6217997B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing cysteine from β-chloroalanine. Cysteine, as one of the sulfur-containing amino acids, is a substance useful as medicines, food additives, cosmetics, feeds, etc., and has conventionally been produced mainly by extraction methods from natural products such as hair. Various chemical synthesis methods have also been proposed. For example, as a method using β-chloroalanine as a raw material, which is the same as the method of the present invention, a method of reacting it with barium hydrosulfide in an alkaline aqueous solution is known. (Ber, No. 41
Volume 893). However, this method has the disadvantage that the reaction solution is quite alkaline, which causes decomposition of the raw material β-chloroalanine and the produced cysteine, making it difficult to obtain a high yield. There has also been an attempt to convert β-chloroalanine into a cysteine derivative in an organic solvent by bonding protective groups to the amino and carboxyl groups (J.Org.Chem. Vol. 15, p. 438), It has little utility value. The present inventors have conducted intensive research on a method for easily converting β-chloroalanine into cysteine, and as a result, have completed the method of the present invention. That is, the present invention involves reacting β-chloroalanine with an alkali metal or alkaline earth metal hydrosulfide or ammonium hydrosulfide in the presence of an alkali metal, alkaline earth metal, or ammonium halide in a polar aprotic solvent. It is an object of the present invention to provide a method for producing cysteine, which is characterized by: According to the method of the present invention, by reacting in a highly polar aprotic solvent, β
- Suppresses the decomposition of chloroalanine, and due to this solvent effect and the effect of promoting the substitution reaction of halides,
The reaction can be carried out at a relatively low temperature, which also exhibits the excellent advantage of suppressing the decomposition of the raw material β-chloroalanine and the produced cysteine. The highly polar aprotic solvents mentioned here have a dielectric constant (ε) of 15 or more and a dipole efficiency (μ).
2.5D or more, and means a solvent with an ET(30) value of 40 to 47, which is one of the solvent polarity parameters. Typical examples of these solvents include dimethyl sulfoxide (DMSO), dimethylformamide (DMF), diethylformamide, dimethylacetamide, diethylacetamide, propylene carbonate, ethylene carbonate, acetonitrile, sulfolane, dimethylsulfolane, Dimethylsulfolane, acetone, acetophenone, nitrobenzene, benzonitrile,
Examples include 1-methyl-2-pyrrolidinone, tetramethylurea, and the like. Although these solvents may contain a small amount of water or other organic solvents without much effect, they must be stable under the reaction conditions. In the method of the present invention, the reaction between free β-chloroalanine and hydrosulfide is carried out in a polar aprotic solvent using twice the mole of hydrosulfide, but if necessary, more than twice the mole of hydrosulfide may be used. You can also use objects. However, excessive use must be avoided since it is uneconomical and requires extra effort for separation. Usually, when using free β-chloroalanine, it is preferable to use a molar ratio of about 1:2.0 to 5.0, and a concentration in a polar aprotic solvent of about 1 to 10 wt%, respectively. There are no particular restrictions on the hydrosulfide to be subjected to the reaction.
For example, alkali metal hydrosulfides such as lithium, sodium, and potassium, alkaline earth metal hydrosulfides such as magnesium and calcium, or ammonium hydrosulfide are used as appropriate. The alkali metal, alkaline earth metal, or ammonium halide to be added is used in an amount of 0.05 to 0.20 times mole relative to β-chloroalanine. The alkali metals and alkaline earth metals include, but are not particularly limited to, lithium, sodium, potassium, rubidium, magnesium,
Calcium, strontium, barium, etc. are used. Although the halide is not particularly limited, for example, chloride, bromide, iodide, etc. are used. The reaction temperature is usually 0°C to 150°C, preferably 5°C to 30°C. Normal pressure is usually used as the reaction pressure, but pressure may be increased if necessary. A reaction time of about 5 minutes to 5 hours is sufficient. The produced cysteine is separated and precipitated as a metal salt from the polar non-phroton solvent, so it can be easily taken out from the reaction system. The separated metal salt or ammonium salt of cysteine is hydrolyzed with an acid in an aqueous solution, stabilized as a hydrochloride or sulfate, and the accompanying hydrosulfide is decomposed. Cysteine can be easily isolated from an aqueous solution containing coexisting alkali metal ions and the like produced by the decomposition of hydrosulfide, for example, by electrodialysis. Alternatively, it can be separated from the solution as a crystalline tosylate by forming a salt with para-toluenesulfonic acid;
Next, it can be appropriately isolated by a known method such as dissolving this in alcohol and neutralizing it with triethylamine or the like to precipitate cysteine crystals. Hereinafter, typical examples of the method of the present invention will be shown and explained in more detail, but these are merely illustrative examples to facilitate understanding of the present invention, and the present invention is not limited to these. Of course, it goes without saying that there are no limitations to these. Example 1 A solution of 3.2 g (40 mmol) of sodium hydrosulfide (NaSH・xH ₂ O, NaSH content 70 wt%) and 0.4 g (2 mmol) of magnesium chloride (MgCl ₂・6H ₂ O) dissolved in 50 g of dimethylformamide was 1.25 g of free β-chloroalanine under stirring while keeping at ℃
(10 mmol) of powder is slowly added. After addition
Incubate at 10°C for 1 hour. After the reaction is completed, the reaction solution is filtered to remove the precipitate, which is dissolved in water and analyzed by liquid chlorotography. β-chloroalanine reaction rate: 91.8% Cysteine yield: 85% Comparative example The reaction was carried out in the same manner as in the example except that magnesium chloride was not added, and analysis revealed that the β-chloroalanine reaction rate was 77% and the cysteine yield was 44%. It was hot. Examples 2 to 14 Various halides were added and reacted in the same manner as in Example 1. The results are shown in Table 1.

[Table] Examples 15 to 19 Reaction with β-chloroalanine was carried out in the same manner as in Example 1, except that the types of hydrosulfide, catalyst, and solvent were changed. Table 2 shows the reaction conditions and the products obtained.

【table】

Claims (1)

[Claims] 1. A method characterized by reacting β-chloroalanine with an alkali metal or alkaline earth metal hydrosulfide or ammonium hydrosulfide in the presence of an alkali metal, alkaline earth metal or ammonium halide in a polar aprotic solvent. A method for producing cysteine.