JPS5952234B2 - Method for producing mercaptopropionylglycine and its derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing α- or β-mercaptopropionylglycine or its derivatives.

More specifically, α,β′- or α,β′-dithiobispropionylglycine or a derivative thereof.

The present invention relates to a method for industrially and inexpensively producing α- or β-monoylglycine or its derivatives by using as a raw material and subjecting it to electrolytic reduction. α- or β-mercaptopropionylglycine and its derivatives are useful substances known for the treatment and prevention of toxic diseases caused by heavy metals or the earliest symptoms caused by anticancer drugs or radiation, and as an antidote for poisonous snakes. It is.

Conventionally, mercaptopropionylglycine (hereinafter referred to as MPG)
or its derivatives, the mercapto group of α- or β-mercaptopropionic acid is protected with a group that is easily eliminated later (e.g., benzyl group, benzoyl group), and then reacted with glycine. , and then remove the protecting group to obtain α- or β-MPG (hereinafter referred to as method A) (Japanese Patent Publication No. 39-5464). A method of reacting with benzoic acid, alkali xanthate, etc., and hydrolyzing this as a propionylglycine derivative having an α- or β-sulfur-containing substituent to obtain the desired product (hereinafter referred to as method B) (Japanese Patent Publication No. 39-1
1616), dithiobispropionylglycine [hereinafter referred to as
(abbreviated as MPG)] or its derivatives with aluminum amalgam or zinc and acetic acid (hereinafter referred to as method C) (Japanese Patent Publication No. 39-11616
)It has been known.

However, these production methods require complicated reaction operations;
Moreover, it is difficult to say that it is an industrially advantageous method because the raw materials are expensive and the reaction yield is low. Namely, among these methods, method A is a production method that is more industrially practicable than methods B and C, but after protecting the mercapto group, it is reacted with glycine as an acid halide, and then the protecting group is removed. There are problems in terms of complicated steps such as separation, expensive raw materials, and reaction yield. In Method B, when producing propionylglycine derivatives having α- or β-mono-sulfur-containing substituents, it is necessary to use expensive thioacetic acid or thiobenzoic acid to produce a compound that will become a mercapto group in the subsequent hydrolysis reaction. Furthermore, it has the disadvantage that reagents that are difficult to handle must be used, and furthermore, the purification operation is complicated.

Furthermore, in the method C of chemically reducing a propionylglycine derivative having a sulfur-containing substituent to MPG or a derivative thereof, liquid ammonia, sodium amalgam, or a metal such as zinc must be used.
Therefore, when using liquid ammonium, a low temperature of about -50°C is required, which is difficult to handle industrially, and chemical reduction with metals requires the use of foul-smelling gases such as hydrogen sulfide gas to remove metals. In addition to the need to use metals and the problem of disposal of metals after use, the purification process is complicated to avoid contamination of trace metals into products, making it difficult to implement industrially. . The present inventors conducted various studies with the aim of industrially producing MPG at low cost.

As a result, α,β″- or α,β″-bis(MPG)
or derivatives thereof (e.g. salts such as ammonium salts, organic amine salts, derivatives such as amides or esters)
High purity MPG is produced by electrochemically reducing
The present invention was completed based on the discovery that the product can be produced extremely easily with good yield and at low cost. To explain the present invention in more detail, the reaction of the present invention may include α, β″- or α, β″
- electrolytic reduction in the form of salts such as bis(MPG) or its ammonium salts, organic amine salts such as triethylamine and diethylamine, anolekali metal salts such as sodium and potassium salts, or alkaline earth metal salts such as canolecium, or α, β″- or α, β″-bis (
MPG) in the form of amides (including substituted amides of alkyls such as methyl and ethyl) or esters thereof (including lower alkyls such as methyl and ethyl).

This reaction can be carried out using a conventional electrolytic reduction tank. For example, an electrolytic cell equipped with an anode and a cathode may or may not have a diaphragm, but it is preferable to have a diaphragm such as an ion exchange membrane. Although commonly used electrodes can be used, the material of the electrodes must be selected depending on the liquid properties of the electrolyte. Generally, platinum, silver,
Mercury, lead, peroxide salt, carbon, zinc, nickel, copper, titanium, palladium, etc. can be used. It is preferable that the electrolytic cell be configured so that the reaction solution can be circulated by mechanical stirring or by a pump or the like. There are no particular restrictions on the voltage, current density, or temperature in electrolytic reduction, but the electrolytic voltage is 0.5 to 50 V, preferably 1 to 50 V.
At 10V, the current density is 50A/Dm2 or less, 0.01
A small amount of A/Dm2 may be sufficient. Generally 0.02~25A
Preferably, a current density of /Dm. is used. The electrolytic reduction can be carried out at a temperature of 80°C or lower, but may be -10°C. A suitable temperature is 0 to 55°C. As the solvent for the reductant, any solvent containing a normal electrolyte may be used.

Is it best to use water? Other organic solvents can also be added in order to increase the solubility of the reductant, although this is preferable for economical reasons. For example, methanol, ethanol, dioxane, tetrahydrofuran, N. N-dimethylformamide, sulfolane, etc. can be used. As for the concentration of the reductant, it is more economical to have a high concentration within the range allowed by the solubility, and a concentration as low as 1% by weight may be used, although a concentration of 60% by weight (based on the solvent) can be used.

Generally, 10 to 40% by weight is preferred. When adding an organic solvent to increase the solubility of the reductant, the solubility of the reductant and the reduced product in water is high.
It is sufficient that the amount of the organic solvent added is 60% by weight or less based on the water solvent. Common electrolytes used in the electrolytic reaction include sodium hydroxide, sodium acetate, sodium phosphate, potassium carbonate, ammonium hydroxide, hydrochloric acid, sodium sulfate, and the like.

Generally, it is used in an amount of 0.1 to 15% by weight as an electrolyte per electrolyte solution. The electrolytic reaction can be carried out for at least 0.5 hours or more, but is generally preferably carried out for 1 to 15 hours. MP produced according to the present invention
The desired product can be easily obtained from a reaction solution containing G and its derivatives by a conventional method.

For example, by simply adding a mineral acid, or by removing the electrolyte in the reaction solution using electrodialysis or an ion exchange resin, the solution is concentrated to dryness and then reconstituted from an organic solvent such as ethanol to ethyl acetate. You can get what you want. α, β″- or α, β″-bis (MPG) and its derivatives used in this reaction are known substances, and can be easily produced industrially, for example, by the method shown below.

That is, for example, bis(α-
or β-mercaptopropionic acid) is converted into an acid halide with a halogenating reagent such as thionyl chloride, glycine or an ester of glycine is added thereto while maintaining the medium- or weakly basicity. or β-MPG) or its ester. This product can be subjected to an electrolytic reduction reaction without being purified. For purification, bis(MP) is acidified with hydrochloric acid and separated.
G) and its derivatives can be easily purified by recrystallization with water or a suitable organic solvent (eg, ethyl acetate). Moreover, when obtaining an amide derivative, the ester of bis(MPG) may be treated with ammonia by a conventional method.

The present invention will be explained in more detail with reference to Examples below.

Example-1 α, β″-dithiobispropionylglycine [α, β″
-Bis(MPG)] (Mpl 98°C) 50g was dissolved in 50ml of concentrated ammonia water, the volume was made up to 250ml with water, and this was used as a catholyte.

On the other hand, 10% sulfuric acid is used as the anolyte. The electrolytic cell has a silver plate (1/2 dm2) on the cathode and a carbon plate (1/2 dm) on the anode.
A cation exchange membrane is used as the diaphragm, and the catholyte and anolyte are each circulated through each electrode cell at a rate of 1.41/Hr using a pump. Electrolytic reduction is carried out at 20 to 25° C. with a DC voltage of 3.5 V to 4.2 V and a current density of 6 to 7 A/Dm2. α, β″-bis (MPG) is reduced with a current efficiency of about 70% and a reduction time of 6.5 hr. After the electrolysis is completed, the catholyte is taken out and concentrated to 150 ml under reduced pressure.
220ml of strongly acidic cation exchange resin (H type)
The mixture was passed through a column, extruded with 300 ml of water, and the eluate was concentrated to dryness to obtain 48.5 g of white powdery β-MPG (yield 97%).

If this product is reconstituted from isopropyl alcohol and petroleum ether, MplOl. Obtain purified β-MPG at 5°C.
Example-2 50g of α,β″-dithiobispropionylglycine ethyl ester [α,β″bis(MPG)]
Suspend in 200ml of N-hydrochloric acid and hydrolyze at 90°C for 3 hours.

Reduction was carried out in the same manner as in Example 11, except that the obtained homogeneous solution was used as the catholyte. Take out the electrolytically reduced solution and add 250ml of weakly basic anion exchange resin (0H type) to this solution.
and extrude with 300ml of water.

When the concentrated solution is concentrated to dryness, α-MPG4 is obtained as white crystals.
l. Obtain 5g. (Yield 97.4%). If this product is recrystallized from ethyl acetate, purified α-MPG with an Mp of 96.5°C is obtained. Example-3 In the method of Example-1, α
, β″-bis(MPG) was replaced with α,β″-dithiobispropionylglycinamide (50 g) under the same conditions, and the electrolyzed solution was concentrated to dryness to obtain crude α-menole as a white powder. Obtain 49 g of captopropioninoleglycinamide (yield 98%).

Claims (1)

[Claims] 1. A method for producing α- or β-mercaptopropionylglycine or a derivative thereof, which comprises electrolytically cyclizing α: β′- or β,β′-dithiobispropionylglycine or a derivative thereof.