JPS58105959A - Preparation of aminoalkylthiols - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as a raw material of pharmaceuticals, etc., in high purity and yield, by hydrolyzing 2-(2'-mercaptoethylamino)-2-thiazoline hydrohalide derivative with hydrohalogenic acid until the conversion reaches a specific level. CONSTITUTION:The objective compound of formula II is prepared by hydrolyzing a 2-(2'-mercaptoethylamino)-2-thiazoline hydrohalide derivative of formulaI (R1- R4 are H, lower alkyl or hydroxy-substituted lower alkyl; X is halogen) with hydrohalogenic acid. The hydrolysis is stopped when the conversion to the objective compound reaches 75-79%, and the resultant crude aminoalkylthiols are recrystallized in an organic solvent. The crude product remaining in the recrystallization mother liquor after the cystallization is recovered and recycled to the hydrolysis step.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 2-(2'-mercaptoethylamino)-2
- A method for producing highly pure aminoalkylthiols by hydrolyzing a thiazoline hydrohalide derivative with hydrohalic acid.

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. Methods for producing these aminoalkylthiols include the following methods.

0) A method in which a large excess of hydrogen sulfide in an alcoholic solution is reacted with an alkylene imine when cold (Ann, 566゜210
(1950); J, Chem, 5oe-e 194
4.5).

(b) A method in which an alkylene imine and a dialkyl ketone are reacted and then treated with hydrogen sulfide and then with hydrohalic acid (Bull, Soe, Chim, Fr, 1
964°2493; Ann, 566.2□10 (19
50); Special Publication No. 50-29444; Special Publication No. 54-41
No. 569).

(c) A method in which oxazoline is treated with hydrogen sulfide and then hydrolyzed in an aqueous hydrochloric acid solution (U.S. Patent No. 4,086.2)
No. 74; JP-A-54-128509).

B) 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. 3365/1983).

(e) Method of hydrolyzing 2-mercaptothiazoline with hydrochloric acid or hydrobromic acid (J, Org-Chem,
.

25, 869 (1960); Her, 31.2
832 (1898)) However, among these methods, methods (a) to (c) have the disadvantage of using carcinogenic alkylene imine or toxic hydrogen sulfide, and method (2) does not react well. Because the conditions are alkaline, in addition to the target substance 2-aminoethanethiol, there are bis(2-aminoethyl) sulfides and oxidized dimers of 2-aminoethanethiol that are difficult to separate from this. The by-product of bis(2-aminoethyl) disulfides is unavoidable.

Therefore, there is a problem that the purity and yield of 2-aminoethanethiols decrease. Furthermore, the method described in (e) has the disadvantage that toxic hydrogen sulfide is produced as a by-product in an equivalent amount. As described above, each of the known manufacturing methods has problems from an industrial perspective.

The present inventors have conducted intensive research on a method for producing aminoalkylthiols that does not use toxic alkylene imines and do not produce hydrogen sulfide as a by-product. We have found that aminoalkylthiols can be produced relatively easily by hydrolysis with hydrohalic acid, but the crude aminoalkylthiols obtained by this hydrolysis cannot be used as is! Therefore, it has been necessary to improve the purity by recrystallizing it in at least an organic solvent or the like.

Therefore, the present inventors conducted further research on this production method, and found that when the reaction was continued further in an attempt to obtain a hydrolysis conversion rate close to IOO* in order to increase purity, the reaction rate suddenly decreased. However, surprisingly, the crude aminoalkylthiols must be purified to a certain level or dissolved in an organic solvent. In this case, even when cooled, the entire solution simply becomes syrupy, and the target purified aminoalkylthiol does not crystallize (i.e., recrystallization is impossible). Therefore, in order to enable this recrystallization, the purity of the crude aminoalkylthiol must be above a certain value, and it is necessary that the purity of the crude aminoalkylthiol exceeds a certain value at the above hydrolysis conversion rate.
The two present inventions, which have been found to correspond to the above, have been made based on these findings.

That is, the present invention provides 2-(
2'-Mercaptoethylamino)-2-thiazoline hydrohalide derivative is hydrolyzed with hydrohalic acid to give the general formulas R and R.

(In the formula, RX, R2, R3, R4 and X have the same meanings as above.) In producing the aminoalkylthiols represented by:
The present invention provides a method for producing highly purified aminoalkylthiols, which comprises stopping the above hydrolysis reaction within a range of 97% and recrystallizing the obtained crude aminoalkylthiols in an organic solvent. .

Examples of the 2-(2'-mercaptoethyl aξ))-2=thiazoline bitrobary, 1° derivative represented by the general formula (I) used in the present invention 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-thiacyly/hydrochloride, 2-(2'-
Mercapto-2'-hydroxymethylethylamino)-
5-hydroxymethyl-2-thiazoline hydrochloride, 2-(2'-mercapto-1'-dimethyl-21
-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 hydroiodite and the like. According to the studies of the present inventors, the 2-(2'-mercaptoethylamino)-2-thiazoline hydrohalide derivative of the general formula 〇) has the general formula 2-mercaptothiazoline derivatives represented by (having the same meanings as above) and 2-halogenoethylamine hydrogen halide represented by the general formula (wherein R1, R2, R3 and R4 and X have the same meanings as above) When the acid salt derivative is reacted with a polar solvent such as alcohol, acetone, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, etc., it can be easily obtained in a higher yield. The reaction temperature at this time is usually 50 to 150°C.The reaction time varies depending on the type of reactants, but is usually 1 to 25 hours. It is carried out to the extent of excess.

Examples of the 2-mercaptothiazoline derivative represented by the general formula (I[I) include 2-mercaptothiazoline, 4-methyl-2-mercaptothiazoline, 4.4-dimethyl-2-mercaptothiazoline, and 5.5-mercaptothiazoline. 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-
Examples of the 2-halogenoethylamine hydrohalide derivatives represented by the general formula (IV) include 2-chloroethylamine, 1-mercaptothiazoline, etc.
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
Examples include hydrohalides of chlorine, bromine, iodine, or fluorine, such as -tetramethyl-2-aminoethyl chloride.

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 〇). If different hydrohalic acids are used, the aminoalkylthiol produced will be a mixture of salts of different hydrohalic acids, making separation complicated.

By hydrolyzing the compound of general formula (D) with hydrohalic acid, the compound of the general formula (2), which is the object of the present invention, is obtained.
Aminoalkylthiols represented by are produced. Examples of the aminoalkylthiols include 2-aminoethanethiol, 2-aminopropanethiol, and 2-amino-21? Rufu a panthiol, 2-aminobutanethiol, 2-amino-2-ethylbutanethiol, 2-
Amino-1-methylethanethiol, 2-amino-1゜1-diethylethanethiol, 2-amino-1-methylpropanethiol, 2-amino-1,1-dimethylpropanethyl, 2-amino-1-ethyl- Examples include hydrohalides of chlorine, bromine, iodine, or fluorine such as 1-methylpropanethiol.

In the present invention, it is necessary for the above hydrolysis reaction to be expressed as a hydrolysis conversion rate defined by the following formula, and to be within the range of 75 to 97 degrees.

Hydrolysis Conversion Rate @) This hydrolysis reaction is preferably carried out under the following conditions.

That is, the amount of hydrohalic acid used is such that the amount of hydrohalic acid contained ranges from 1 molar equivalent to 9 molar equivalents of the compound of general formula (I) that is hydrolyzed. If the amount is less than this, the hydrolysis will be extremely slow, making it impractical.If the molar equivalent used is increased, the reaction time will be shortened, but if it exceeds 9 molar equivalents, the effect will be attenuated.
This is not economical as it only results in redness that unnecessarily increases the reactor capacity.

The concentration of the hydrohalic acid used in the present invention is preferably in the range of 5 to 25% by weight, for example, when hydrochloric acid is used. , when the weight is less than 5, the hydrogen chloride becomes 1
Even if it is more than the molar equivalent, the decomposition rate will be slow and it is not practical, and if it exceeds 25% by weight, the vapor pressure of hydrogen chloride will be This is because it becomes expensive, which is not desirable in terms of maintenance of the device.

Further, a reaction temperature of 50° C. or higher is sufficient for this hydrolysis, but in consideration of the decomposition rate, it is preferable to carry out the reaction under reflux. Decomposition can be further accelerated by increasing the reaction temperature by applying pressure. Further, the reaction time varies depending on the temperature, the concentration and number of equivalents of the acid, and the type of acid, but is employed for 10 to 50 hours.

Next, the hydrolysis conversion rate to aminoalkylthiols was 7.
The hydrolysis reaction is stopped when it reaches 5 to 97%, more preferably 82 to 92%. To do this, turn off the heat and
Alternatively, if the reaction was carried out under pressure, the reaction system can be brought into a milder state by cooling, or by returning the pressure to normal or reduced pressure to lower the partial pressure of hydrogen halide. The hydrolysis reaction, which had already slowed down considerably, is easily stopped.

The crude amino alkylthiols can be separated and purified from the reaction product thus obtained by the following operations.

First, residual hydrogen halide and water are distilled off from the reaction product under normal pressure and/or hydraulic pressure. If hydrogen halide is not removed sufficiently, it will be mixed into the product and the pH value will be off-spec, and residual water may cause deliquescence, complicate the process for reuse, and worsen selectivity. Therefore, it is preferable to remove these as much as possible. In reality, distillation is carried out until the crude product is concentrated to dryness, but during this time it is desirable to maintain the temperature at which the crude aminoalkylthiol remains in a molten state. This temperature is, for example, 70°C or higher in the case of 2-aminoethanethiol.

This concentrated crude product is then recrystallized from an organic solvent. Organic solvents include alcohol, ester, ketone,
Commonly used substances such as ether can be used, but alcohols such as methanol, ethanol, and 2-propanol, or ethanol-ether are preferable. In the crystallization operation, following the distillation of hydrogen chloride, etc. and hydrogen tetragenide, while the concentrate is still hot and molten, for example, in the case of methanol solvent, 0.3 to 0.0% of the crude product is added. It is preferable to add them at a weight ratio of about 7, mix and dissolve well, and then cool to 10° C. or lower to crystallize. The precipitated purified aminoalkylthiol crystals (purity 98% or higher) are filtered and dried under reduced pressure to obtain a product.

Note that the recrystallization mother liquor (filtrate) after crystallizing and separating the above aminoalkylthiols contains a considerable amount of aminoalkylthiols and unreacted 2=(2'-mercaptoethylamino)-2- A crude product consisting of a thiazoline hydrohalide derivative is dissolved, and by recovering this crude product from the mother liquor and circulating it to the hydrolysis step, the aminoalkylthiols are recovered and the unreacted 2- Since the (2'-mercaptoethylamino)-2-thiazoline hydrohalide derivative can be subjected to repeated reactions, it is possible to obtain the target purified aminoalkylthiols in a substantially quantitative manner. I can do it.

Furthermore, it has become clear from the study results of the present inventors that the presence of even a small amount of organic solvents such as methanol and ethanol in the reaction system greatly inhibits the hydrolysis reaction.
The crude product recycled to the above hydrolysis step is recrystallized mother liquor (
filtrate).

For this purpose, it is desirable to adopt an operation in which the recrystallization mother liquor is completely concentrated to dryness, preferably under reduced pressure, and the resulting crude product is recycled to the hydrolysis step.

As described above, the method of the present invention is an excellent method in that aminoalkylthiols can be efficiently produced with high purity and high yield, and these aminoalkylthiols can be used as they are as raw materials for pharmaceuticals. be effective.

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

Example 1 Reactor equipped with a stirrer, temperature control means, and reflux device [,2-
24.0 g (0.1 mol) of (2'-mercaptoethylamino)-2-thiazoline hydrobromide at 20%
A solution dissolved in 100 ml (0.3 mol) of hydrobromic acid was charged, and the mixture was heated under reflux for 10 hours.

After the reaction has stopped, the reaction solution is concentrated to dryness under reduced pressure using a rotary enoborator to completely remove hydrogen bromide and water to obtain crude crystals of 2-aminoethanethiol hydrobromide 29. 4 g of this product was obtained.The hydrolysis conversion rate of this product was determined by quantitative analysis of -8H groups and was 89.71.Subsequently, 50 mt of ethanol was added to the crude crystals as a recrystallization solvent and stirred with heating to sufficiently dissolve. , 5℃ while stirring well.
The resulting crystals were dried under reduced pressure at 40°C for 2 hours to give 14.7 g of white crystals (melting point 6).
9-70°C). The purity determined by the iodine method was 99.0 or better.

Example 2 Using the same apparatus as in Example 1, 2-(2'-mercaptoethylamino)-2-thiazoline hydrochloride 19.
6 g (0.1 mol) of 20% hydrochloric acid 130 mt (0.8
mol) and heated under reflux for 30 hours. Thereafter, the crude crystals of 2-aminoethanethiol hydrochloride 2 were concentrated to dryness under reduced pressure.
2.4g was obtained. The hydrolysis conversion rate of this product was 88.5 as determined by quantitative determination of -8H groups. Subsequently, 2 ml/1 g of crude crystals of ethanol was added as a recrystallization solvent to the crude crystals, and the mixture was thoroughly dissolved by heating and stirring.Then, the mixture was cooled to 5°C while stirring well, and the crystals that crystallized were filtered by suction. The resulting crystals were dried under reduced pressure at 40°C for 2 hours to obtain 10.4 g of white crystals (melting point 69-70°C). Purity by iodine method was 98.81.

Example 3 2-(2'-
Mercapto-2-methylethylamino)-4-methyl-
2-thiazoline hydrochloride 26.3g (0,1
mol) and 25-euhydrochloric acid 100 mA (0,8%/lz
) was charged and heated at 130°C under a pressure of 3 to 4"l/via, and the reaction was carried out for 15 hours. After the reaction was stopped, the pressure was gradually returned to normal pressure, and the reaction solution was concentrated to dryness under reduced pressure. Crude crystal 25
．． After adding 12 mt of methanol as a recrystallization solvent to 3 g (hydrolysis conversion rate 90.4%) and stirring with heating to sufficiently dissolve the mixture, cooling crystallization was performed while stirring well. The crystals were filtered and dried to obtain 14.4 g of white crystals of 1-amino-2-propanethiol hydrochloride (melting point 90-91°C). The purity determined by the iodine method was 98.3%.

Example 4 2-(2'-mercapto-1'-methylethylamino)
-5-methyl-2-thiazoline hydrochloride 26
．． 3 g (0.1 mol) in 110 mt (0.1 mol) of 15% hydrochloric acid
5 mol) K was dissolved and heated under reflux for 40 hours.

After that, it was concentrated to dryness under reduced pressure and 25.3g (hydrolysis rate 8
6,71) was obtained. This was recrystallized in the same manner as in Example 1 to obtain white crystals of 2-amino-1-propanethiol hydrochloride tz, ag (melting point 91° to 92°C). The purity determined by the iodine method was 98.4%.

Examples 5-9 2-(2′-Mercaptoethylamino)-2-thiazoline hydrochloride 23. ,．． 5 g (0.1 mol)
and concentrate 10.4 of the recrystallized filtrate obtained in Example 2.
Dissolve g in 120 mt (0.83 mol) of 25% hydrochloric acid and make 2
．． The mixture was heated to reflux at 130° C. under a pressure of 5 KvcIAc.

After 15 hours, the reaction was stopped, and the pressure was gradually returned to normal while concentrating, and the pressure was further reduced to completely distill off hydrogen chloride and water.

The hydrolysis conversion rate of the obtained crude crystals (33.4 g) was 90
．． It was 3%. The crude crystals were recrystallized in the same manner as in Example 1 to obtain 16.1 g of white crystals of 2-aminoethanethiol hydrochloride. Thereafter, the same method was repeated and the results obtained are shown in Table 1.

Examples 10 to 13 and Comparative Examples 1 to 3 A hydrolysis reaction was carried out in the same manner as in Example 2 to produce 2-aminoethanethiol sulfate, except that the reaction time was varied. Recrystallization treatment i was performed and the purity of the product was tested.

The results are shown in Table 2.

As is clear from the above Examples and Comparative Examples, the hydrolysis reaction is stopped when the hydrolysis conversion to aminoalkylthiols is 80 or more, and the obtained crude aminoalkylthiols are recrystallized with an organic solvent. Possibly purity 98
- The above-mentioned highly purified aminoalkylthiols can be easily obtained, and since the crude product dissolved in the mother liquor after crystallizing and separating the above-mentioned aminoalkylthiols, the mother liquor can be substantially By repeating the process of removing and then circulating to the hydrolysis process, it is possible to finally obtain the target purified aminoalkylthiols almost quantitatively, and even after repeating the above cycle many times, the resulting product remains unchanged. It can be seen that no decrease in purity is observed. It is also clear that when the hydrolysis conversion rate is less than 75, the recrystallization operation becomes extremely difficult.

Claims (1)

[Claims] (1) General formula (wherein RIR2R3 and R4 represent a hydrogen atom, a lower alkyl group, or a hydroxyl-substituted lower alkyl group,
2-(2'-mercaptoethylamino)-2-thiazoline hydrohalide derivative represented by (X represents a halogen atom) is hydrolyzed with hydrohalic acid to obtain the general formula % formula % (wherein R,, R2 , R, and R4 and X have the same meanings as above) In producing the aminoalkylthiols represented by
A method for producing high-purity aminoalkylthiols, which comprises stopping the hydrolysis reaction within a range of 97ts, and recrystallizing the obtained crude aminoalkylthiols in an organic solvent. (2) After stopping the hydrolysis reaction and substantially removing hydrohalic acid and water from the reaction mixture containing aminoalkylthiols, the obtained crude aminoalkylthiols are recrystallized in an organic solvent. A method for producing high purity aminoalkylthiols according to claim 1, which comprises: (8) A crude product dissolved in the recrystallization mother liquor after the aminoalkylthiols are crystallized and separated is recovered, and this crude product is recycled to the hydrolysis step, as claimed in claim 1. Or the method for producing high purity aminoalkylthiols according to item 2.