JPS637539B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an efficient method for producing aminoalkylthiols.

Aminoalkylthiols are extremely useful substances as raw materials for various pharmaceuticals, intermediate raw materials for hair care cosmetics, etc., and substances that have a protective effect against radiation damage. The following methods are known as methods for producing these aminoalkylthiols.

(a) A method in which alkylene imine is applied to a large excess of hydrogen sulfide in an alcoholic solution (Ann, 566,
210 (1950); J.Chem.Soc., 1944, 5).

(b) A method in which alkylene imine and dialkyl ketone are reacted and then treated with hydrogen sulfide and then with hydrohalic acid (Bull.soc.chim.Fr.1964,
2493; Ann.566, 210 (1950); Special Publication Showa 50-29444
No.: Special Publication No. 54-41569).

(c) A method in which oxazoline is treated with hydrogen sulfide and then hydrolyzed in an aqueous hydrochloric acid solution (Unexamined Japanese Patent Publication No. 1983-
No. 128509).

(d) A method in which an aminoalkyl sulfate is reacted with ammonium hydrosulfide or an alkali hydrosulfide, and then treated with hydrochloric acid (Japanese Patent Publication No. 53-3365).

(e) Method of hydrolyzing 2-mercaptothiazoline with hydrochloric acid or hydrobromic acid (J.Org.Chem.,
25, 869 (1960); Ber., 31, 2832 (1898)).

However, among these methods, (a) to (c)
Method (2) has the disadvantage of using carcinogenic alkylene imine or toxic hydrogen sulfide, and method (2) requires alkaline reaction conditions, so it cannot be used in addition to the target substance 2-aminoethanethiol. The by-product of bis(2-aminoethyl) disulfides, which are oxidized dimers of bis(2-aminoethyl) sulfides and 2-aminoethanethiols, which are difficult to separate, is unavoidable.
Therefore, there is a problem that the purity and yield of 2-aminoethanethiols decrease. Furthermore, the method (e) has the disadvantage that toxic hydrogen sulfide is produced as a by-product in an equivalent amount to the product. As described above, each of the known manufacturing methods has problems from an industrial perspective.

The present inventors have conducted various studies to develop a method for producing aminoalkylthiols that does not use toxic alkylene imines and do not produce hydrogen sulfide as a by-product.
It has been discovered that the desired aminoalkylthiols can be obtained relatively easily and in high yields by hydrolyzing -2-thiazoline hydrohalide derivatives with hydrohalic acid, and based on this knowledge, the present invention has been made. I've reached it.

That is, the present invention is based on the general formula _{2- (} 2' _{- mercaptoethylamino} )
- General formula characterized by hydrolyzing a 2-thiazoline hydrohalide derivative with hydrohalic acid (wherein R ₁ , R ₂ , R ₃ , R ₄ and X have the same meanings as above)

2-(2'-mercaptoethylamino)- represented by the general formula () used in the present invention
Examples of 2-thiazoline hydrohalide derivatives include 2-(2'-mercaptoethylamino)-2-
Thiazoline hydrobromide, 2-(2'-mercaptoethylamino)-2-thiazoline hydrochloride, 2-(2'-mercapto-1'-methylethylamino)-4-methyl-2-thiazoline hydrochloride, 2-( 2′-Mercapto-2′-
methylethylamino)-5-methyl-2-thiazoline hydrochloride, 2-(2'-mercapto-2'-hydroxymethylethylamino)-5-hydroxymethyl-2-thiazoline hydrochloride, 2-(2'-mercapto −1′-dimethyl-2′−
dimethylethylamino)-4-dimethyl-5-dimethyl-2-thiazoline hydrochloride, 2
-(2'-mercapto-2'-n-butylethylamino)-5-n-butyl-2-thiazoline hydrochloride, 2-(2'-mercapto-1'-n-butylethylamino)-4-n -butyl-2-thiazoline hydroiodide and the like. The 2-(2′-mercaptoethylamino)-2-thiazoline hydrohalide derivative of this general formula () is
According to the inventors' study, the general formula (wherein R ₁ , R ₂ , R ₃ and R ₄ have the same meanings as above) and a 2-mercaptothiazoline derivative represented by the general formula (In the formula, R ₁ , R ₂ , R ₃ and R ₄ and X have the same meanings as above.) A 2-halogenoethylamine hydrohalide derivative represented by , can be easily obtained in high yield by reacting in a polar solvent such as dimethyl sulfoxide. The reaction temperature at this time is usually 50 to 150 degrees Celsius.The reaction time varies depending on the type of reactants, but is usually 1 to 20 hours.
It is carried out in an equimolar to excess amount relative to the compound.

Examples of the 2-mercaptothiazoline derivatives represented by the general formula () include 2-mercaptothiazoline, 4-methyl-2-mercaptothiazoline, 4,4-dimethyl-2-mercaptothiazoline, 5,5-dimethyl-2 -Mercaptothiazoline, 5-ethyl-2-mercaptothiazoline,
4,5-dimethyl-2-mercaptothiazoline,
4,4,5-trimethyl-2-mercaptothiazoline, 4,4,5,5-tetramethyl-2-mercaptothiazoline, 4-propyl-2-mercaptothiazoline, 4-ethyl-2-mercaptothiazoline, 5-propyl -2-mercaptothiazoline, 5-methyl-2-mercaptothiazoline, etc. Examples of the 2-halogenoethylamine hydrohalide derivatives represented by the above general formula () include 2-chloroethylamine, 1-methyl-
2-aminoethyl chloride, 1-ethyl-2-
Aminoethyl chloride, 1-methyl-2-ethyl-2-aminoethyl chloride, 1,1-dimethyl-2-methyl-2-aminoethyl chloride, 1,1,2,2-tetramethyl-2-aminoethyl chloride There are hydrohalides such as chlorine, bromine, iodine or fluorine.

Next, as the hydrohalic acid used in the hydrolysis, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, etc. can be used, and among them, hydrochloric acid and hydrobromic acid are preferable, and Hydrochloric acid is most preferred. Furthermore, it is preferable to use the same hydrohalic acid as the halogen atom of the compound of general formula (). If different hydrohalic acids are used, the aminoalkylthiol produced will be a mixture of salts of different hydrohalic acids, making separation complicated.

Hydrolysis of the compound of general formula () with hydrohalic acid produces the object of the present invention,
Aminoalkylthiols represented by the above general formula () are produced. Examples of the aminoalkylthiols include 2-aminoethanethiol,
2-aminopropanethol, 2-amino-2-
Methylpropanethiol, 2-aminobutanethiol, 2-amino-2-ethylbutanethiol,
2-amino-1-methylethanethiol, 2-amino-1,1-diethylethanethiol, 2-amino-1-methylpropanethiol, 2-amino-1,1-dimethylpropanethiol, 2-amino-1- ethyl-1-methylpropanethyl,
Halogens such as chlorine, bromine, iodine or fluorine such as 3-amino-3-methyl-2-methyl-2-butanethiol, 1-amino-2-hexanethiol, 2-amino-1-hydroxymethyl-ethanethiol, etc. Examples include hydrochloride.

The amount of hydrohalic acid used for hydrolysis in the present invention is such that the amount of hydrogen halide contained is 2 to 20% of the compound of general formula () to be hydrolyzed.
It may be used in molar equivalents. If the amount is less than this, the hydrolysis will be extremely slow and it is not practical, and if the amount is more than 20 molar equivalents, the decomposition rate will not be increased.

The concentration of the hydrohalic acid used for hydrolysis is, for example, 15% (by weight) or more in the case of hydrochloric acid,
In the case of hydroiodic acid, it is preferably 10% (by weight) or more. At concentrations lower than this, the decomposition rate is slow and impractical.

The reaction temperature for this hydrolysis is the reflux temperature (100~
Although it is sufficient to carry out the reaction at a temperature of 127°C, decomposition can be further accelerated by increasing the reaction temperature by applying pressure. The reaction time varies depending on the reaction temperature, acid concentration, type of acid, etc., but is usually in the range of 10 to 90 hours.

After the reaction is completed, the mixture is concentrated to dryness to obtain a hydrohalide salt of aminoalkylthiols represented by the general formula () as highly pure crystals in a high yield.

As described above, the present invention hydrolyzes the compound of the general formula () without producing toxic hydrogen sulfide as a by-product, and also produces bis(2-aminoethyl) sulfide which is difficult to separate from the target substance. And it is possible to easily produce aminoalkylthiols of the general formula () in high yield and purity without producing bis(2-aminoethyl) disulfides, which are oxidized dimers of the target substance. It has an excellent effect on the appearance.

Next, the present invention will be explained in more detail based on examples.

Example 1 24.3 g (0.1 mol) of 2-(2'-mercaptoethylamino)-2-thiazoline hydrobromide was placed in a reactor equipped with a stirrer, temperature control means, and reflux device.
was dissolved in 100 ml (0.2 mol) of 15% hydrobromic acid and heated under reflux for 30 hours. Then, it was concentrated to dryness under reduced pressure to obtain 30.7 g of white crystals of 2-aminoethanethiol hydrobromide (melting point 159-160°C).
I got it. Yield 97%. Purity by iodine was 98.5%.

Example 2 A reactor similar to Example 1 was used, and 2-
(2'-Mercaptoethylamino)-2-thiazoline hydrochloride 19.9 (0.1 mol) in 36% hydrochloric acid
A solution of 100 ml (1.2 mol) was added and heated under reflux for 60 hours. Then, it was concentrated to dryness under reduced pressure.
White crystals of 2-aminoethanethiol hydrochloride 22.3
g (melting point 71-72°C) was obtained. Yield 98%. Purity by iodine method was 99.0%.

Example 3 Using the same reactor as in Example 1, 2-
(2'-mercapto-1'-methylethylamino-4
-Methyl-2-thiazoline hydrochloride
A solution of 22.7 g (0.1 mol) dissolved in 100 ml of 36% hydrochloric acid was charged and heated under reflux for 16 hours under a pressure of 3 to 4 kg/cm ² . Then, it was concentrated to dryness at normal pressure to obtain 24.8 g of white crystals of 2-amino-1-propanethyl hydrochloride.
(melting point 90-91°C) was obtained. Yield 97%. The purity determined by the iodine method was 98.0%.

Example 4 Using the same reactor as in Example 1, 2-
(2'-mercapto-2'-methylethylamino)-5
-Methyl-2-thiazoline hydrochloride
22.7 g (0.1 mol) was dissolved in 100 ml (0.6 mol) of 20% hydrochloric acid and heated under reflux for 80 hours. Then, the concentration was dried under reduced pressure to give 1-amino-2-propanethiol (2
25.0 g of white crystals (melting point: 91-92°C) of (amino-1-methylethanethiol) hydrochloride were obtained. Yield 98
%. The purity determined by the iodine method was 98.3%.

Example 5 Using the same reactor as in Example 1, 2-
(2'-mercapto-2'-dimethyl-1'-dimethylethylamino)-4-dimethyl-5-dimethyl-2
- A solution of 31.1 g (0.1 mol) of thiazoline hydrochloride dissolved in 120 ml (0.74 mol) of 20% hydrochloric acid was charged and heated under reflux for 80 hours. Then, it was concentrated to dryness under reduced pressure to obtain white crystals of 3-amino-3-methyl-2-methyl-2-butanethiol hydrochloride (32.9 g).
I got g. Yield 97%. Purity by iodine method is 98.7
It was %.

Example 6 Using the same reactor as in Example 1, 2-
(2'-mercapto-2'-n-butylethylamino)
A solution of 31.1 g (0.1 mol) of -5-n-butyl-2-thiazoline hydrochloride dissolved in 100 ml of 36% hydrochloric acid was charged and heated under reflux for 60 hours. The mixture was then concentrated to dryness under reduced pressure to obtain 32.9 g of white crystals of 1-amino-2-hexanethiol hydrochloride. Yield 97
%. The purity determined by the iodine method was 98.4%.

Example 7 Using the same reactor as in Example 1, 2-
(2'-mercapto-2'-hydroxymethylethylamino)-5-hydroxymethyl-2-thiazoline hydrochloride 26.1 g (0.1 mol) at 36%
Dissolved in 100ml of hydrochloric acid and prepare 3~4kg/
The mixture was heated under reflux for 20 hours under a pressure of cm ² . The mixture was then concentrated to dryness under normal pressure to obtain 25.4 g of white crystals of 2-amino-1-hydroxymethyl-ethanethiol (3-amino-2-mercapto-1-propanol) hydrochloride. Yield 97%. The purity determined by the iodine method was 98.0%.

Claims (1)

[Claims] 1. General formula _{2- (} 2' _{- mercaptoethylamino} )
- General formula characterized by hydrolyzing a 2-thiazoline hydrohalide derivative with hydrohalic acid (In the formula, R ₁ , R ₂ , R ₃ , R ₄ and X have the same meanings as above.) A method for producing aminoalkylthiols represented by the following.