JPS60258158A - Preparation of cysteine derivative - Google Patents

Abstract

PURPOSE:To obtain easily the titled compound expected to be useful as an intermediate for medicines and agricultural chemicals, by reacting specific thiols with beta-chloroalanine in an aqueous solution of specific pH. CONSTITUTION:A thiol expressed by the formula R-SH (R represents lower alkyl) and beta-chloroalanine are reacted in an aqueous solution of 10-13pH, preferably 11-12pH to obtain a cysteine derivative expressed by the formula. beta- chloroalanine used in the process can be easily prepared by hydrolyzing alpha-amino- beta-chloropropionitrile with an acid. An alkali to be present in the reaction is NH3, NaOH, etc., for example. As for the thiol, methyl mercaptan, ethyl mercaptan, etc. are mentioned.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing cysteine derivatives represented by the formula R-SH (where R is a lower alkyl group), which is expected to have a promising future.

Cysteine is one of the merging amino acids and has S in its molecule, so it is useful as a raw material for medicines, agricultural chemicals, etc. S-substituted cysteine derivatives have conventionally been synthesized by reacting cysteine with alkyl chloride. Cystine, which is a raw material in this method, is generally obtained by electrolytically reducing cystine obtained by hydrolyzing a natural substance containing keratin, such as hair, with an acid. However, there are few suitable natural substances that can be used in this method;
There is a limit to the amount of cysteine that can be produced. In addition, various methods for obtaining cysteine by chemical synthesis have been attempted, but
It is hard to say that either of them are cheap. In addition to these raw material circumstances, some cysteine derivatives according to the present invention:
There is a fundamental problem in that the reactivity of the other raw material in the reaction, the chlorine compound, is low. For that purpose, S-
In order to obtain phenyl-substituted cysteine derivatives, a method using a dehydroalanine type intermediate has been used, but the steps required to obtain these raw materials are complicated, and it cannot be said that this is an industrially advantageous production method.

The present inventors have conducted intensive research on the above-mentioned cysteine derivatives, and have determined that a thiol represented by the formula R-SH (where R is as defined above) and β-chloroaraene are reacted in an aqueous solution with a pH of 10 to 13. The inventors have now discovered that the desired product can be easily obtained by producing S-substituted cysteine, and have completed the present invention.

β-chloroalanine, the raw material used in the method of the present invention, can be easily produced by hydrolyzing α-amino-β-chloropropionitrile with an acid. (Japanese Patent Publication No. 57-57466) Furthermore, the alkali to be present when reacting β-chloroalanine and thiol in the method of the present invention is not particularly limited, and for example, ammonia or an alkali such as sodium hydroxide or potassium hydroxide. Metal hydroxides or alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide can be used.

The other raw material, thiol, is represented by the general formula R-8H, and more specific examples include methyl mercaptan,
Ethyl mercaptan, n-propyl mercaptan, 1s
o-propyl mercaptan, 1so-butyl mercaptan, 5eC-butyl mercaptan, and the like.

The reaction is usually carried out in an aqueous solution, but methanol.

Organic solvents compatible with water such as ethanol may also be used.

The order of mixing the reaction raw materials is to add β-chloroalanine to the mixture of thiol and alkali, or
Add an alkali to the mixture of thiol and β-chloroalanine. Mixing chloroalanine and an alkali in the absence of thiol is not preferable because it causes decomposition of β-chloroalanine.

It is sufficient that the amount of alkali present in the reaction system is 2 to 20 times the amount of β-chloroalanine, and the pH of the reaction solution is 10 to 13, more preferably 11 to 12. Even if it is alkaline, if the pH is as low as 10 or less, a sufficient reaction rate cannot be obtained.

In addition, if the pH is higher than 13, there is sufficient reaction.
.

This method is preferable because it increases the speed, but the yield of the target product decreases. When a strong alkali such as sodium hydroxide is used as the alkali, care must be taken because if the molar ratio to β-chloroalanine is increased, the yield will decrease as described above unless the PI] is 13 or more. When ammonia is used as the alkali, the PI] will not exceed 13, so there is no limit to the amount used.

The reaction temperature and time are 10-50°C for 2-50 hours, preferably 15-25°C for 20-40 hours.

Although it is possible to shorten the reaction time by raising the reaction temperature, this is not preferable because it causes decomposition of the raw material chloroalanine.

To recover the desired cysteine derivative from the reaction-completed solution, adjust the pH of the reaction solution to 4 to 6 with an appropriate acid such as hydrochloric acid or sulfuric acid.The cysteine derivative will precipitate, so centrifugation is necessary. It can be easily separated and recovered by conventional means such as

Hereinafter, the present invention will be explained in more detail along with representative synthesis examples.

Example-1 10% β-chloroalanine in 100ml water. Of, and methyl mercaptan standard hydrate 619- were added, and then an aqueous solution of caustic soda and water were added to adjust the pH to 12.
5 to a total volume of 200 ml. 20% of the above reaction solution
The reaction was maintained at ℃ for 3 Q hr. pH 4 after reaction
The mixture was neutralized with concentrated hydrochloric acid and the precipitated crystals were separated. White crystals 331 of S-methylcysteine were obtained. Yield 60% based on methyl mercaptan.

Example-2 To 100 ml of water, add 10.07 ml of β-chloroalanine and 2.59 ml of ethyl mercaptan, and further add caustic potash aqueous solution and water to adjust the pH to 12.5 and total amount to 200 ml.
The volume was adjusted to ml. The reaction solution was kept at 30°C for 20 hours to react. After the reaction was completed, it was neutralized to pH 4 with concentrated sulfuric acid to obtain 4.4P of white crystals of S-ethylcysteine. Yield 72% based on ethyl mercaptan. .

Example-3 β-chloroalanine i in 100 ml of 30% ethanol
After adding 3.11 o, oFI and n-propyl mercaptan, and adjusting the pH to 12.0 and total liquid volume 2001117 by adding caustic potash aqueous solution and 30% ethanol,
The reaction mixture was maintained at 0°C for 2Q hr. After the reaction was completed, the reaction solution was analyzed by liquid chromatography.
Propylcystine 4.17 was produced. n-
The yield was 63 cm based on propyl mercaptan.

Examples 4 and 5 In the same manner as in Example 1, various thiols were reacted with β-chloroalanine. The reaction conditions and the yield obtained are
Shown in the table.

Claims (1)

[Claims] A thiol represented by the formula R-8H (wherein R represents a lower alkyl group) and β-chloroalanine are combined in a range of -10 to 1
A method for producing a cysteine derivative represented by the formula % (2 (where R is the same as above), characterized by carrying out the reaction in an aqueous solution of 3.