JPS5826865A - Purification of 2-aminoethanethiol hydrohalide - Google Patents

Abstract

PURPOSE:A crude product of 2-aminoethanethiol hydrohalide containing sulfide and impurities is subjected to crystallization under specific cooling conditions to produce the titled compound used as a starting material for medicines in high purity and high yield. CONSTITUTION:A crude product containing 80-97% 2-aminoethanethiol hydrohalide of the formula (R1, R2, R3, R4 are H, lower alkyl; X is halogen) and impurities of sulfide, dithiocarbonate and other compounds is dissolved in 25- 65pts.wt per 100pts. of the crude product, of methanol, then cooled under stirring so that the whole volume may not solidify into a lump to effect crystallization, thus giving a slurry of crystals of 2-aminoethanethiol hydrohalide. Then, the mother liquor is removed from the crystals to give the objective substance. EFFECT:The volume of methanol as a solvent is reduced greatly and it is advantageous from view points of energy saving and miniaturization of facilities.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for purifying 2-aminoethanethiol hydrohalide salts.

2-aminoethanethiol hydrologenic acid salts are useful compounds that are widely used as pharmaceutical raw materials, cosmetic raw materials, and the like. The synthesis of 2-aminoethanethiolno-hydrologenated salts is generally carried out by: ■ A method in which thiazolines are hydrolyzed with hydrohalic acid. ■ A method in which alkylene imines are reacted with hydrogen sulfide and treated with hydrohalic acid. ■ 2- This is carried out by a method such as □-, in which a halogenoethylamine hydrologenic acid salt is reacted with hydrogen sulfide in the presence of an alkali, and then treated with 10-hydrogenic acid.

However, the 2-aminoethanethiol hydrohalide salts synthesized by these methods contain impurities such as bis(2-aminoethyl)dithiocarbonate hydrohalide and bis(2-aminoethyl). ) Sulfide hydrohalide, bis(2-aminoethyl) disulfide hydrohalide, etc. are included to some extent.

Therefore, when using 2-aminoethanethiolno-hydrogenated salts as the above-mentioned pharmaceutical intermediate raw materials or cosmetic raw materials, it is necessary to remove these impurities and refine them to high purity.

As the purification method, since 2-aminoethanethiol hydrohalide salts are crystals, the most suitable method is recrystallization.

In general, the methods of recrystallization include: - Cooling a saturated solution to supersaturation and precipitating crystals - Appropriately concentrating the solution to supersaturation and precipitating crystals - Mixing other liquids with the solution to dissolve solutes There are methods to precipitate crystals by reducing the solubility of , but among these methods, the cooling crystallization method (2) is the most suitable for obtaining high-purity crystals. Furthermore, in this case, the smaller the amount of solvent, the more advantageous it is from an industrial perspective, as long as the purity increases to a desired degree and the slurry concentration after crystallization does not become too high, making handling difficult. This is because in order to first create a saturated solution, crystals are dissolved in a solvent under heating, but the thermal energy used at this time is removed by cooling water or a refrigerant during cooling crystallization, resulting in an energy loss. It is. That is, if the amount of solvent is large, the amount of heat required during melting will be large, that is, the energy loss will be large. Furthermore, if the amount of solvent is small, equipment such as a dissolution tank and a crystallization tank can be small, which is advantageous for industrial implementation.

Therefore, in the purification of 2-aminoethanethiol hydrohalides as well, in order to obtain highly pure products, it is most preferable to carry out the cooling crystallization described in (1) above using a small amount of solvent.

In this case, the recrystallization solvent for the 2-aminoethanethiolno-hydrogenide salts includes ethanol other than methanol, 2-propanol, ethanol and ether,
Ethanol and ethyl acetate are known. However, these solvents are still not fully satisfactory in terms of the above-mentioned amount of solvent and thermal energy. Furthermore, in order to use these solvents, it is necessary to use an anhydrous solution containing as little water as possible, since 2-aminoethanethiol/hydrologenate salts are highly hygroscopic (deliquescent) substances. There is a restriction that it must be
Therefore, in order to reuse the solvent, dehydration and purification were necessary.

On the other hand, as mentioned above, methanol has not been used at all as a recrystallization solvent for 2-aminoethanethiol hydrohalides. The reason why methanol is not used is that, for example, the solubility of 2-aminoethanethiol hydrochloride in methanol is lower than that of ethanol or 2-aminoethanethiol hydrochloride.
- Compared to property tools, it is much more expensive as shown in the table below. Since the amount of solvent for dissolving the crystals is very small, recrystallization of 2-amineethanethiolno-10hydrogenide from such a small amount of methanol was thought to be difficult in practice. - Solubility temperature of aminoethanethiol hydrochloride Methanol Ethanol 2-Propatool 20℃ 184
．． 2 22.3 1.550℃ 1286
．． 8 309.5 5.9 units; 2-aminoethanethiol hydrochloride g/100g of solvent In fact, 2-aminoethanethiol hydrochloride is produced using ethanol or 2-propanol in a crystallization tank generally used in industry. When crystallization is carried out by cooling, the mother liquor and crystals are mixed into a slurry state, which can be easily processed in subsequent operations without any problems. However, when similar cooling crystallization is performed using methanol as the solvent, solidification begins from the cooling surface, and eventually the entire solution solidifies, with the solvent being contained in the crystals. , it becomes extremely difficult to remove the crystals for the next crystal separation operation.

However, the present inventors focused on the fact that when methanol is used as a solvent, the amount of solvent can be significantly reduced and energy loss can be reduced. As a result of extensive research in order to overcome the disadvantage of solidification, we have found that solid mixers such as conical screw mixers, double-shaft paddles, etc. are used for cooling crystallization of 2-aminoethanethiol hydrohalides dissolved in methanol. By using a mold mixer, it is possible to prevent the entire solution from caking and form the crystals into sherbet-like or soft-cream-like forms that are easy to separate from solid to liquid, and it is possible to obtain highly pure target compounds. I found it. The present invention has been completed based on this knowledge.

That is, the present invention uses dithiocarbonate as an impurity,
General formula % formula % containing one or more of sulfide and disulfide (In the formula, R1R2R3 and R4U represent hydrogen atoms or lower alkyl groups, which may be the same or different from each other. Also, X represents a halogen atom.) Purity of 2-aminoethanethiol hydrohalide salts represented by 80-97
In purifying the crude product of H by cooling crystallization, 100 parts by weight of the above crude product is dissolved by adding 25 to 60 parts by weight of methanol, and the solution system is stirred and cooled while preventing the entire solidification. 2-aminoethanethiol halogen, which is characterized by crystallizing to produce crystals of 2-aminoethanethiol hydrohalide salts in the form of sherbet-like or soft cream, and then separating the mother liquor from the crystallized particles. A method for purifying hydrochloric acid salts is provided.

The crude product of 2-aminoethanethiol hydrohalide used in the method of the present invention can be obtained by the various conventional synthesis methods described above.

In the method of the present invention, 2-aminoethanethiol hydrohalides refer to those based on the ethanethiol structure having an amine group at the 2-position as represented by the above general formula (I); Specific examples include 2-aminoethanethiol, 2-aminopropanethiol, 2-amino-2-methylpropanethiol, 2-aminobutanethiol, 2-amino-2-ethylbutanethiol, 2-amino-1- Methylethanethiol, 2-
Amino-1-ethylethanethiol, 2-amino-1,
1-diethyl ethanethiol, 2-amino-1-methylpropanethiol, 2-amino-1,1=dimethylpropanethiol, 2-amino-1-ethylpropanethiol, 2-amino-1-ethyl-1-methylpropane Examples include hydrohalides such as chlorine, bromine, iodine, or fluorine such as thiol.

In the process of the present invention, the purity of the crude 2-aminoethanethiol hydrohalide salts ranges from 80 to 97% by weight. When the purity is lower than 80% by weight, it becomes difficult to obtain a highly pure target product in good yield.

On the other hand, the amount of methanol used as a solvent is suitably in the range of 25 to 60 parts by weight based on 100 parts by weight of the crude product. If the amount of solvent used is less than the above range, the intended effect of improving purity may not be achieved sufficiently, and if it is used in large quantities exceeding the upper limit of the above range, the purpose of improving purity may not be achieved. , the yield is reduced and it is not economical.

The methanol used in the method of the present invention may contain water in an amount of 10% by weight or less. If the water content exceeds this range, the solubility of the target product increases, the crystal yield decreases, and it is not economical.

In the method of the present invention, recrystallization is possible not only with anhydrous methanol but also with methanol containing water. This is completely unexpected since known solvents such as ethanol need to be in an anhydrous state in order to avoid this problem.

In the present invention, cooling crystallization is carried out while stirring the entire material gently to prevent solidification of the entire material. As the mixer used for cooling crystallization, a so-called solid mixer is used, but particularly preferred examples are ribbon type, slurry type, etc., which have a cooling jacket attached to the outside to prevent crystals from sticking to the machine wall. There are solid mixers with internal stirring blades, such as conical scree mixers (Nauta mixer double-shaft paddle mixers). It is also possible to use a kneader having a kneader.

As a specific method of the present invention, a predetermined amount of methanol is added to a crude product of 2-aminoethanethiol hydrohalide salts, and after dissolving by heating at 40 to 70°C, the mixture is mixed in a solid mixer. While io-.

Cool to ℃ to precipitate crystals. Next, the crystals are sent to a crystal separation process using a screw or paddle of a solid mixer, separated, and then dried.
-Aminoethanethiol hydrohalide salts can be obtained. In order to further increase the purity, it is preferable to wash the filtered crystals with methanol, methanol-water or ethanol to replace the mother liquor adhering to the crystals.

In this case, the amount of solvent used for washing is 20 to 20 parts by weight of methanol or methanol-water per 100 parts by weight of the crude product.
Appropriate amounts are 40 parts by weight, and 100 to 200 parts by weight for ethanol. However, industrially, two types of solvents are used;
Since it is not economical, it is usually desirable to perform the cleaning with methanol only. Through such recrystallization treatment, purity of 99
2-aminoethanethiol hydrohalide salts purified to a higher than 10% can be obtained in a yield of 40 to 70% by weight.

According to the method of the present invention, crystals of extremely high purity can be obtained in good yield, and the amount of methanol used as a solvent is extremely small compared to other solvents, resulting in improvements in energy efficiency and miniaturization of equipment. This method is very advantageous in terms of aspects and is suitable for industrial implementation. Furthermore, when reusing the recrystallization solvent, it is possible to recycle it without requiring any special purification treatment for the dehydration tank until the permissible content of water to methanol (10% by weight) is reached. It has excellent effects. Moreover, as a solvent, methanol is cheaper than ethanol or 2-gropanol, and in this respect, the method of the present invention is extremely advantageous over conventional methods.

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

Example 1゜Crystals of 2-aminoethanethiol hydrochloride with a purity of 90% (
Add 3.2 g of methanol to 10 g of s, s'-bis(2-aminoethyl)dithiocarbonate dihydrochloride (contains s, s'-bis(2-aminoethyl) dithiocarbonate dihydrochloride as an impurity), heat vigorously at 50°C to dissolve the crystals, and then cone-shape 7. - Cooled to 5° C. with a mixer (Nauta mixer) and crystallized. The precipitated sherbet-like crystals were filtered, washed with 2.4 g of methanol, and dried under reduced pressure.
6.3 g of crystals were obtained. (Yield 70%) As a result of quantitative determination of SH groups by iodometric titration, it was found that this crystal had a purity of 99.9% as 2-aminoethanethiol hydrochloride.

Example 2 Crystals of 2-amino-2-methylpropanethiol hydrochloride with a degree of M of 85% (containing s,s'-bis(2-amino-2-methylglobyl)dithiocarbonate dihydrochloride and bis(2-methylglobin) as impurities) To 10 g of amino-2-methylpropylene (containing disulfide dihydrochloride), 3.5 g of methanol
g was added and heated to 50°C to dissolve the crystals, and then cooled to 5°C in a solid mixer to crystallize in the same manner as in Example 1. The precipitated sherbet-like crystals were filtered, washed with 2.5 g of methanol, and dried under reduced pressure to obtain 5.4 g of crystals. (Yield: 63.5%) As a result of quantification of SH groups by iodometric titration, it was found that this crystal had a purity of 99.7% as 2-amino-2-methylpropanethiol hydrochloride.

Example 3 10 g of crystals of 2-aminoethanethiol hydrobromide (contains bis(2-aminoethyl) sulfide dihydrobromide as an impurity) with an Mi of 92% are mixed with methanol containing 3% by weight of water. After adding 2.8 g and heating to 60° C. to dissolve the crystals, the mixture was cooled to 5° C. in a solid mixer in the same manner as in Example 1 to cause crystallization.

The precipitated sherbet-like crystals were filtered, washed with 2.6 g of methanol containing 3% by weight of water, and dried under reduced pressure 1.
4.4 g of crystals were obtained. (Yield 47.8%) As a result of quantification of SH groups by iodometric titration, this crystal had an N degree of 99.6%.
was found to be 2-aminoethanethiol hydrobromide.

Example 4 10 g of crystals of 2-amino-1-methylethanethiol hydrochloride with a purity of 87% (contains s, s'-bis(2-amino-1-methylethane 4-+V) disulfide dihydrochloride as an impurity) 3.2 g of methanol containing 3% water by weight
was added and heated to 50°C to dissolve the crystals, and then cooled to 5°C in the same manner as in Example 1 in a solid mixer to cause crystallization.

The precipitated soft cream-like crystals were filtered, washed with 2.4 g of methanol containing 3% by weight of water, and dried under reduced pressure.
4.3 g of crystals were obtained. (Yield: 49.4%) As a result of quantitative determination of SH groups by iodometric titration, the purity of this crystal was 99.5%.
was found to be 2-amino-1-methylethanethiol hydrochloride.

Comparative Example 1 Crystals of 2-aminoethanethiol hydrochloride with a purity of 90% (
25 g of ethanol containing 3% by weight of water was added to 10 g of bis-(2-aminoethyl)melfidonihydrochloride as an impurity, heated to 50°C to dissolve the crystals, and then cooled to 5°C to crystallize. . The precipitated crystals were filtered, washed with 18 g of ethanol containing 3% by weight of water, and dried under reduced pressure.
．． 8 g of crystals were obtained. (Yield: 53.31 As a result of quantification of SH groups by iodometric titration, it was found that this crystal had a purity of 95.3% as 2-aminoethanethiol hydrochloride.

Comparative Example 2 Crystals of 2-aminoethanethiol hydrochloride with a purity of 90% (
Add 400 g of 2-propatol containing 5% by weight of water to 10 g of s,s'-bis(2-aminoethyl)dithiocarbonate dihydrochloride as an impurity, and heat to 70°C to dissolve the crystals. It was cooled to ℃ and allowed to crystallize. The precipitated crystals were filtered, washed with 50 g of 2-propanol containing 5 weight of water, and dried under reduced pressure to obtain 5.2 g of crystals. (Yield: 57.8 L) As a result of quantitative determination of the SR group by iodometric titration, it was found that this crystal had a purity of 94.6% as 2-aminoethanethiol hydrochloride.

Comparative Example 3 Crystals of 2-aminoethanethiol hydrochloride with a purity of 70% (
(contains s,s'-bis(2-aminoethyl)dithiocarbonate dihydrochloride and bis(2-aminoethyl)disulfide dihydrochloride as impurities) and 3 methanol.
．． 5 g was added, heated to 50°C to dissolve, and then cooled to 5°C in a solid mixer in the same manner as in Example 1 to cause crystallization. The precipitated crystals were filtered, washed with 2.5 g of methanol, and then dried under reduced pressure to obtain 2.8 g of crystals. (Yield 28 cm)
As a result of quantification of SH groups by iodometric titration, this crystal is 2-
The purity of aminoethanethiol hydrochloride was 53.6%. The filtrate and washing solution were combined and concentrated under reduced pressure to obtain 6.9 g of crystals. As a result of determination of SH group by iodometric titration, this crystal was found to be 2-aminoethanethiol hydrochloride with a purity of 76.
．． It was 8%.

Claims (2)

[Claims] (1) Contains one or more of dithiocarbonate, sulfide, and disulfide as impurities, and has the general formula (wherein R1, R2, R3, and R4 represent a hydrogen atom or a lower alkyl group, and may be the same or different from each other. The purity of the 2-aminoethanethiol hydrohalide salts represented by (X represents a halogen atom) is 80-9
When purifying a 7% crude product by cooling crystallization, 25 to 6 parts by weight of methanol was added and dissolved in 100 parts by weight of the above crude product, and the solution system was stirred to prevent the entire solidification. 2-aminoethane, which is characterized in that it is cooled and crystallized to produce sherbet-like or soft cream-like crystals of 2-aminoethanethiolno-hydrogenide salts, and then the mother liquor is separated from the crystallized particles. Method for purifying thiol hydrohalides. (2) A method for purifying 2-aminoethanethiol hydrohalides according to claim 1, wherein cooling crystallization is carried out in a solid mixer.