JPS62297481A - Production of n-(2-mercaptoisobutyryl)cysteine - Google Patents

Abstract

PURPOSE:To produce N-(2-mercaptoisobutyryl)cysteine at a low cost in a high yield by reacting N,N'-bis(2-halogenoisobutyryl)cystine with a polysulfide in an aqueous solvent and carrying out electrolytic reduction. CONSTITUTION:Cystine is reacted with alpha-halogenoisobutyryl halogenide in an aqueous solvent to obtain N,N'-bis(2-halogenoisobutyryl)cystine. This cystine is reacted with >=about 2 times as much alkali metal or ammonium polysulfide as the cystine by mol in an aqueous solvent at about 5-80 deg.C. The preferred number of S atoms in the polysulfide is 2-4. The resulting liq. reaction product is neutralized and the unreacted S and H2S are removed to prepare an electrolytic soln. About 0.1-20wt% electrolyte such as NaOH is added to the electrolytic soln., a Pb cathode and a Pt anode are placed and electrolytic reduction is carried out preferably at about 5-60 deg.C and about 0.1-50A/dm<2> current density to obtain N-(2-mercaptoisobutyryl)cysteine.

Description

Detailed Description of the Invention 3. Detailed Description of the Invention A. Field of Industrial Application The present invention relates to a novel method for producing N-(2-mercaptoisobutyryl) cysteine.

N-(2-mercaptoisobutyryl)cysteine of the present invention is useful as a rheumatism treatment drug and a lysing agent.
It is a pharmaceutically important substance.

Conventional techniques and problems Conventional techniques for producing N-(2-mercaptoisobutyryl)cysteine include: (1) 2-pendylmercaptoisobutyryl halide and S-benzylcysteine are combined into N-(2-benzylmercaptoisobutyryl)-8-benzylcysteine, which is obtained by reacting with the Uman method etc., is debenzylated with a reducing agent to produce N-(2-mercaptoisobutyryl).
Method for obtaining cysteine (Japanese Patent Publication No. 56-5388).

(2) Method of reacting cysteine with polythioester of 2-mercaptoisobutyric acid (Japanese Patent Publication No. 12119/1989)
.

However, (1) the raw materials 2-pendylmercabutisobutyryl halide and S-benzylcysteine are expensive, and the reduction requires liquid ammonia-metallic sodium, so there are safety and operational issues. I have a sexual problem. (2) The raw material 2-mercaptoisobutyric acid is expensive, unstable, and complicated to handle, which has industrial disadvantages.

Means for Solving Problems The present inventors have conducted extensive research with the aim of producing N-(2-mercaptoisobutyryl)cysteine at a low cost, and have found that it can be produced easily and at a low cost. N, N'-bis(
By reacting 2-halogenoisobutyryl)cystine with an alkali metal or ammonium polysulfide in an aqueous solvent and then electrolytically reducing it, N-(2-mercaptoisobutyryl)cystine can be produced in high yield and at low cost. The present inventors have discovered that this can be obtained, and have completed the present invention.

The raw material N,N'-bis(2-halogenoisobutyryl)cystine is represented by the following general formula (1), (wherein X represents a chlorine, bromine, or iodine atom). , is represented by the following general formula (2).

CH3 CH3-C-C0Y (2)
(In the formula, X and Y are the same or different, chlorine, bromine,
Alternatively, α-octahegenoisobutyryl halide (representing an iodine atom) was dissolved in an aqueous solvent at 5-40°C, pH 8-1.
In the present invention, N,N'-bis(2
-halogenoisobutyryl)cystine can be used, but the above reaction solution can also be used only by adjusting the pH.

In the present invention, the reaction between N,N'-bis(2-halogenoisobutyryl)cystine and an alkali metal or ammonium polysulfide uses approximately twice the molar amount of the latter relative to the former in an aqueous solvent. However, the latter may be used in excess. Usually the molar ratio is 1:2.
A value of about 0-6.0 is used. Using more than that
This is not preferable because it is uneconomical and the separation operation of unreacted raw materials becomes complicated.

The solvent used is usually water, but solvents that are miscible with water, such as methanol, ethanol, dioxane, and THF-a7ton, can also be used alone or in combination.

The polysulfide to be subjected to the reaction is expressed as M2Sn, and M is an alkali metal such as lithium, sodium, or potassium, or ammonium.

Further, n represents the number of sulfur atoms, and 1-5 is appropriate, and 2-4 is preferably used.

This polysulfide can be easily produced from sulfide and sulfur, but there is no need to use any particular method for producing it.

The reaction temperature is 5-80°C, preferably 10-50°C.
It is ℃.

The reaction pressure is usually normal pressure, but if necessary, the reaction may be carried out under increased pressure.

A reaction time of about 20 minutes to 4 hours is sufficient.

Further, there is no limit to the concentration of N,N'-bis(2-halogenoisobutyryl)cystine, but it is usually 5-5-30%.

As the electrolytic solution, a solution obtained by neutralizing the above reaction solution and removing unreacted sulfur and hydrogen sulfide can be provided as a catholyte.

For neutralization, inorganic acids such as hydrochloric acid and sulfuric acid are used, but organic acids such as formic acid and acetic acid may also be used.

As electrolytes, sodium hydroxide, potassium hydroxide,
Sodium acetate, potassium carbonate, sulfuric acid, hydrochloric acid, sodium sulfate, etc. are used. The electrolyte concentration in the electrolyte is 0.1
A range of -20% by weight is used.

It is preferable that the electrolytic solution be stirred mechanically or circulated and stirred using a pump or the like.

For the electrode, lead, lead alloy, mercury, mercury amalgam alloy, silver, carbon, etc. are used as a cathode. For the anode, platinum
White metals such as rhodium, ruthenium, and iridium are used alone or in alloys, and their usage forms include:
Usually used as plating. As the plating base material, titanium-exposed tantalum or the like is used. Furthermore, it is also possible to use lead, lead alloy-carbon, etc.

The diaphragm is not necessary, but it is preferable to have a diaphragm.
As the diaphragm material, an unglazed magnetic diaphragm, an asbestos fiber diaphragm, a porous plastic diaphragm, an ion exchange diaphragm, etc. are used.

The current density in electrolytic reduction is 0.1-50A/drrf
but preferably 2-30A
/dm'. The liquid temperature can be lower than 80℃, but
Preferably it is 5-60°C.

2. Examples Hereinafter, the present invention will be explained in more detail with reference to Examples, but these are merely illustrative and the present invention is not limited by these in any way.

Example l Sodium sulfide nonahydrate 107.7g (0,446mol
) was heated and melted at 80°C, and 28.5 g of sulfur (0.89
2 mol) and reacted for 30 minutes with stirring.
The reaction was then cooled to 10°C and added with N,N
'-bis(2-bromoisobutyryl)cystine 59.
350 g of a pH 6 solution containing 8 g (0,111 mol)
is added over 30 minutes at 10-20°C. After the addition is complete, the reaction is further carried out at 10-20°C for 1 hour.

Next, hydrochloric acid was added to this reaction solution to adjust the pH to 7.

Add 1.0 g of activated carbon and stir at 50°C for 30 minutes. Activated carbon and unreacted sulfur are filtered off, and the filtrate is used as a catholyte.

As the anolyte, a 1N sulfur tuna aqueous solution is used. As the diaphragm, a cation exchange membrane Selemion CMV (manufactured by Asahi Glass) was used. The anode uses a platinum-coated titanium plate measuring 10 cm x 10 cm, and the cathode uses a 10 cm x 10 cm platinum-coated titanium plate.
A silver plate of cm was used.

1 at an electrolytic current of 7 A while mechanically stirring the catholyte.
Electrolysis was conducted for 8.5 hours. Electrolysis voltage is 6.5-8
．． The test was carried out at a voltage of 5V and a liquid temperature of 25-35°C.

After the electrolysis, the catholyte was analyzed by liquid chromatography, and the results showed that N-(2-mercaptoisobutyryl)
It was confirmed that 37.3 g (0,167 mol) of cysteine was produced. The yield was 75.3% based on N,N'-bis(2-bromoisobutyryl)cystine.

Example 2 Sodium sulfide nonahydrate 161.3g (0,672mol
) was heated and melted at 80°C, and 43.0 g of sulfur (1,34
4 mol) and allowed to react under stirring for 30 min. Next, the reaction was cooled to 10°C and added with N
, N'-bis(2-chloroisobutyryl)cystine 5
Solution 3 at pH 6 containing 0.2 g (0,112 mol)
83 g are added over 30 minutes at 10-20°C.

After the addition is complete, the reaction is further carried out at 10-20°C for 1 hour.

Next, hydrochloric acid was added to this reaction solution to adjust the pH to 7, 1.0 g of activated carbon was added, and the mixture was stirred at 50°C for 30 minutes. The filtrate is used as the catholyte.

A 1N sulfur aqueous solution is used as the anolyte. As the diaphragm, a cation exchange membrane Selemion CMV (manufactured by Asahi Glass) was used. A 10 cm x 10 cm platinum-coated titanium plate was used as the anode, and a 10 cm x 10 cm platinum coated titanium plate was used as the cathode.
A silver plate of cm was used.

1 at an electrolytic current of 7 A while mechanically stirring the catholyte.
The electrolytic amount was measured for 9.5 hours. Electrolysis voltage is 6.5-8
．． 5V and the liquid temperature was 25-35℃. After the electrolysis, the catholyte was analyzed by liquid chromatography and it was found that N-(2-mercaptoisobutyryl)
It was confirmed that 40.3 g (0,181 mol) of cysteine was produced. The yield was 80.8% based on N,N'-bis(2-chloroisobutyryl)cystine.

Claims (1)

[Claims] N-(2-mercapto), which is characterized by reacting N,N'-bis(2-halogenoisobutyryl)cystine with an alkali metal or ammonium polysulfide in an aqueous solvent, and then electrolytically reducing it. Method for producing (isobutyryl) cysteine.