JPS5813563A - Purification and separation of 2-aminoethanethiol hydrohalides - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a raw material for drugs, etc. in easily separating way in high yield without using the recrystallization operation of complicated process, by adding a specific aliphatic alcohol to a 2-aminoethanethiol hydrohalide containing by-products. CONSTITUTION:A <=4C monohydric aliphatic alcohol (e.g., methanol, ethanol, n-propanol, etc.) shown by the formula III (n is 1,2,3, or 4) or a mixed solvent of the aliphatic alcohol and water is added to a mixture of a 2-aminoethanethiol hydrohalide shown by the formulaI(R1-R4 are H or lower alkyl; X is halogen) and a (2-aminoethyl)disulfide hydrohalide shown by the formula II, and the compound (e.g., 2-aminoethanethiol, etc.) shown by the formulaIis selectively dissolved in the solvent and separated. Since the difference of the solubility in the aliphatic alcohol is used, the cooling operation is made unnecessary in the recrystallization operation, and the reaction is carried out simply in a short time.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for separating a mixture of 2-aminoethanethiol water halide hydrohalide steel and bis(2-aminoethyl,)disulfide hydrohalides.

2-aminoethanethiol hydrohalide salts are li
The synthesis of 02-aminoethanethiol halogenated water fluoride steel, which is a useful compound widely used as a pharmaceutical layer raw material and cosmetic raw material, is generally carried out by the following method: ■ Hydrolyzing thiazolines with hydrohalic acid ■ A method of reacting alkylene ζ ions with hydrogen sulfide and treating them with hydrohalic acid■
Methods such as reacting 2-halogenoethylamine^p hydrogenates with hydrogen sulfide in the presence of an alkali and then treating with hydrohalic acid have been carried out.

1 However, the 2-aminoethanethiol halogenated water fluoride steel synthesized by these methods usually contains the by-product bis(2
-aminoethyl) disulfide hydrohalide salts as the main impurities. In addition, 2-aminoethanethiol/10 hydrogenates are easily oxidized to bis(2-aminoethyl) disulfide hydrohalides, so 2-aminoethanethiol/10
Hydrogenide salts form bis(2-aminoethyl) during storage.
There are some compounds that form a mixture with disulfide hydrohalide salts.

For various purposes such as rounding, pharmaceutical raw materials, cosmetic raw materials, etc.
For IIK, the impurity bis(2-aminoethyl) is added to the 2-aminoethanethiol halide water fluoride steel.
It is necessary to separate and purify it from the disulfide hydrohalide salts.Especially when this is used as an intermediate raw material for pharmaceutical synthesis, it is necessary to purify it to a high degree of purity. On the other hand, bis(2-aminoethyl) disulfide decahydrogenide can also be used as a pharmaceutical raw material, so
It would also be desirable if this could be separated and purified and used effectively as a by-product, rather than simply as an impurity.

In general, k to purify crystals containing impurities is conventional.

A recrystallization operation is used in which the crystals are first heated and dissolved in a solvent, then cooled and crystallized to separate the crystals. However, this method has drawbacks such as: (1) the active ingredient remains in the mother liquor together with impurities, and its recovery requires additional time and expense; (2) it requires a cooling operation, which complicates the process and takes time; The present inventors used the method described above to separate 2-aminoethanethiol hydrohalides and bis(2-aminoethyl) disulfide hydrohalides. As a result of intensive research on separation methods to overcome the shortcomings of recrystallization operations, we found that there is a significant difference in the solubility of the two in certain aliphatic alcohols, and that the aliphatic alcohol or aliphatic alcohol and water It was discovered that by carrying out the specified washing using a mixed solvent of It is.

2- represented by: Aminoethanethiol halogenated water fluoride steel and bis(2 - (a) When separating disulfide hydrohalides (noethyl), a monohydric aliphatic alcohol having 4 or less carbon atoms or a mixed solvent of this aliphatic alcohol and water is added to the mixture. , characterized in that 2-aminoethanethiol hydrohalides represented by the general formula (1) are selectively dissolved and separated from 2-aminoethanethiol hydrohalides and bis(2-aminoethanethiol). 2-aminoethanethiol hydrohalide represented by the general formula (1) applied to the method of the present invention and the 2-aminoethanethiol hydrohalide salt represented by the general formula (1) applied to the method of the present invention and the general formula ( bis(2-aminoethyl) represented by II)
As a mixture of disulfide hydrohalides,
For example, when the 2-aminoethanethiol hydrohalides are partially oxidized, 2-aminoethanethiol hydrohalides and bis(2-aminoethyl)
There are nine mixtures of disulfide hydrohalide salts.

In the method of the present invention, 2-7 minoethanethiol hydrohalides mean those based on the ethanethiol structure having an amino group at the 2-position, as represented by the general formula As a specific example, for example 2-
7 Minoethanethiol 2-72 Nopropanethiol, 2
-amino-2-methylpropanthiol, 2-aminobutanethiol, 2-amino-2-ethylbutanethiol, 2-amino-1-methylethanethiol, 2-amino-1-ethylethanethiol, 2-anno-1 .1-diethyl ethanethiol, 2-annor-1-methylpropanethiol, 2-amino-1゜1-dimethylpropanethiol, 2-amino-1-ethylpropanthiol, 2
Examples include hydrohalides of chlorine, bromine, iodine, or fluorine, such as -az)-1-ethyl-1-methyl human antithiol residue.

t+, bis(2-aminoethyl) disulfide acid...Genization--i refers to a disulfide represented by the above general formula (II), which is based on an ethylene structure and has an amino group at the 2-position. Specific examples include bis(2-aminoethyl) disulfide, bis(2-7 minoflovir) disulfide, bis(2-amino-2-methyl-n-propyl) disulfide, bis(2-amino- n-butyl) disulfide, bis(2-
yi Mino-ethyl-n-butyl) disulfide, bis(2-amino-1-methylethyl) disulfide, bis(2-amino-1-ethylethyl) disulfide, bis(2-amino-1,1-dimethylethyl) Disulfide, bis(2-amino-1-methyl-n-propyl)disulfide, bis(2-a(/-1-ethyl-n-propyl)disulfide, bis(2-amino-l-ethyl-1)
Examples include hydrogen halides and acid salts such as chlorine, bromine, iodine, and fluorine, such as -methyl-n-propyl) disulfide.

The monohydric aliphatic alcohol having 4 or less carbon atoms to be used in the method of the present invention may be used regardless of whether the aliphatic chain is saturated or unsaturated. .2.3 or 4) methanol,
Ethanol, n-propertool, 2-propertool, n
-butanol is mentioned as a preferred example. When the aliphatic alcohol has 5 or more carbon atoms, the 2-aminoethanethiol hydrohalide salt hardly dissolves or does not dissolve at all. Therefore, if an attempt was made to dissolve it, the amount of aliphatic alcohol used as a solvent would be extremely large, making it unsuitable for industrial implementation. Furthermore, in the case of polyhydric alcohols, the amount of rounding solvent that has low solubility is used, and since the boiling point of the solvent is high, the cost of recovering the solvent becomes large, and therefore, k is not suitable for industrial use. Other aliphatic hydrocarbons, aromatic hydrocarbons, hydrogenated hydrocarbons,
Esters, ethers, ketones, etc. cannot be used because the solubility of 2-aminoethanethiol hydrohalides is low or they do not dissolve. In the method of the present invention, the above aliphatic alcohol contains a small amount of water. May be used. The content of water allowed for neutralizing the aliphatic alcohol is preferably 5% by weight or less in the case of methanol or ethanol, and 15% by weight or less in the case of propatool or butanol. When the amount of water exceeds this range, the difference in solubility between 2-aminoethanethiol hydrohalides and bis(2-aminoethyl) disulfide hydrohalides becomes small, resulting in poor separation effect. Moreover, water alone cannot be used for papermaking in which this solubility difference is even smaller.

In the method of the present invention, the temperature of the dissolution treatment with aliphatic alcohol or a mixed solvent of aliphatic alcohol and water is I
! There is no limit to #, but it is usually selected appropriately within the range of 20° C. to the boiling point of the solvent. Of course, the temperature may be lower than 20°C, but this is not very advantageous because the lower the temperature, the more the amount of solvent used.

Next, in the method of the present invention, the amount of aliphatic alcohol or a mixed solvent of aliphatic alcohol and water used as a solvent is appropriately determined depending on the type of solvent, the dissolution treatment temperature, etc. For example, if the treatment temperature is 20°C, 30 to 70 parts by weight for methanol and 250 to 5 parts by weight for ethanol to 100 parts by weight of 2-aminoethanethiol hydrohalide in the mixture.
00 parts by weight, 4,500 to 8,000 parts by weight for propatool, and 25,000 to 50,000 parts by weight for butanol. Also, if the processing temperature is set to 60℃,
3 to 6 parts by weight for methanol, 10 parts by weight for ethanol
A suitable range is 20 parts by weight, 800 to 1500 parts by weight for propatool, and 3000 to 7000 parts by weight for butanol. If the amount of solvent used is less than the above range, the purity of the bis(2-aminoethyl) disulfide hydrohalide salts after separation will be low. The purity of the 2-aminoethanethiol hydrohalide salt category tends to be low, and the separation effect is poor.

The solvent used in the method of the present invention is determined depending on the #I scale treatment temperature, the amount of solvent, the content ratio of 2-aminoethanethiol hydrohalides and bis(2-aminoethyl) disulfide hydrohalides, etc. Therefore, it can be selected as appropriate. Furthermore, the amount of solvent used increases as the number of carbon atoms in the aliphatic alcohol increases, since the solubility of the 2-aminoethanethiol hydrohalide salts decreases.

When the treatment temperature is lowered, b % 2-7' the content ratio of the minoethanethiol hydrohalide salts increases, the amount of solvent used increases. Moreover, if the solvent contains water, the amount of solvent used will be reduced. Optimal operating conditions and solvents can be selected with these points in mind.

Specific example of separating and purifying a mixture of 2-aminoethanethiol hydrohalides and bis(2-aminoethyl) disulfide hydrohalides using the above aliphatic alcohol or a mixed solvent of aliphatic alcohol and water. Specifically, after heating and stirring at 20°C or the boiling point of the solvent,
Filter off undissolved crystals. Then, by drying the crystals, more than 5 llulass of bis(2-aminoethyl) disulfide hydrohalides can be isolated from K. On the other hand, by heating the mother liquor under reduced pressure and distilling off the solvent, 2-aminoethanethiol hydrohalides having a purity of 98 or higher can be isolated.

In the conventional recrystallization operation in which the entire amount of crystals is dissolved by heating, cooled and crystallized, and then the crystals are separated, it is inevitable that the active ingredients remain in the mother liquor together with impurities, so the recovery rate of the active ingredients is low. In order to improve this, K requires more money and time.

Additionally, the solvent was recovered from the mother liquor and reused.

However, in the present invention, after selectively dissolving 2-aminoethanethiol hydrohalide salts by utilizing the difference in solubility in aliphatic alcohol, undissolved bis(
Since the 2-aminoethyl disulfide hydrohalide salts are filtered out, this method has the excellent advantage that, compared to recrystallization, there is no cooling operation, the process is simple, and it can be carried out in a short time.

9. From the mother liquor, the solvent is recovered and highly purified 2-
An excellent effect is achieved in that annoethanethiol hydrohalide salts can be almost completely recovered in a single line.

As described above, according to the method of the present invention, 2-7minoethanethiol hydrogenates and bis(2-aminoethyl ) By washing the mixture containing disulfide hydrohalide salts, both can be separated very efficiently with high purity, which is extremely advantageous as an industrially implemented method. Further details will be explained based on examples.

Example 1 12.5 g of crystals containing 80 weight of 2-aminoethanethiol hydrochloride and more than 20 weight of bis(2-aminoethyl) di-delta phide dihydrochloride were added, and 6 g of methanol was added, and the mixture was heated at 25°C.
It was stirred with After filtering off undissolved crystals, dry under reduced pressure,
Obtain 2.25 g of white crystals.

This crystal was analyzed by 'H-NMR and the purity was found to be 99.
41 g of bis(2-aminoethyl)disulfide dihydrochloride. On the other hand, from the mother liquor, the solvent was distilled off by heating under reduced pressure to obtain 9.9 g of white crystals.90 This crystal was 2-aminoethanethiol hydrochloride, and it was determined that the 10R group was determined by iodometric titration. The purity was 98.511G.

Example 2 2-amino-2-methylpropanethyl hydrochloride 60 wt., bis(2-amino-2-methyl-n-propyl)
4 g of methanol containing 3 weight of water was added to 15 g of crystals having a composition of 40 weight of disulfide dihydrochloride, and the mixture was stirred at 20°C. The undissolved crystals were filtered off and then dried under reduced pressure to obtain 8 g of white crystals. This was analyzed in the same manner as in Example 1 and found to be 99.1- of bis(2-7<no-2-butyl-n-propyl)disulfide dihydrochloride. Example 3 2-Aminoethanethiol hydrobromide 90% by weight 8.7 g of white crystals of 2-amino-2-methylpropanethiol hydrochloride with a purity of 98.7 was obtained by the same treatment as in 1. , bis(2-aminoethyl) disulfide dihydrobromide 1
20 g of crystals having a composition of 0% by weight and 20 g of ethanol were added, heated to 40° C., and stirred. The undissolved crystals were treated in the same manner as in Example 1 to obtain N1199.51 bis(2
1.8 g of white crystals of 2-aminoethyl) disulfide dihydrobromide were obtained. On the other hand, 17.6 g of white crystals of 2-aminoethanethiol hydrobromide were obtained from the mother liquor in the same manner as in Example 1. was obtained with a purity of 99.1 hours.

Example 4 50% by weight of 2-aminoethanethiol hydrochloride, bis(2
10 g of ethanol was added to 20 g of crystals having a composition of -aminoethyl)disulfide dihydrochloride 50 weight, and the mixture was heated for 40 CK and stirred. The undissolved crystals were treated in the same manner as in Example 1 to obtain bis(2-aminoethyl) with a purity of 99.011G.
9.8 g of white crystals of disulfide dihydrochloride were obtained. On the other hand, 9.7 g of white crystals of 2-aminoethanethiol hydrochloride were obtained from the mother liquor in the same manner as in Example 1 with a purity of 98.9.

Example 5 2-aminoethanethiol hydrobromide 90 wt., bis(2-aminoethyl)disulfide dihydrobromide 5
20 g of crystals with a composition of 0 weight - K2-glopanol 100
g was added, heated to 60'cK and stirred, and the undissolved crystals were treated in the same manner as in Example 1 to obtain □bis(2-aminoethyl).
9.7 g of white crystals of disulfide dihydrobromide were obtained with a purity of 99.311G. On the other hand, from the mother liquor, 9.7 g of white crystals of 2-aminoethanethiol hydrobromide were obtained with a purity of 98.811 in the same manner as in Example 1.

Example 6 2-aminoethanethiol hydrochloride 30% by weight, bis(2
-Aminoethyl)disulfide dihydrochloride 70wt - 30g of crystals with a composition of 150g of K2-glopanol were added,
After heating and stirring to 0°C and filtering off undissolved crystals, the same procedure as in Example 1 was carried out to obtain bis(2
-7minoethyl) disulfide dihydrochloride white crystals 20
．． 7g was obtained from the mother liquor of ◇-2 in the same manner as in Example 1.
-White crystals of Annoeta/thiol hydrochloride 8.9gt#
Obtained at 11 degrees 99.1-.

Example 7 2-propanol containing 20 g K of crystals with the composition of 2-anno-1-methylethanethiol hydrochloride 40 wt., bis(2-amino-1-methylethyl) disulfide dihydrochloride 60 wt., and water 10 wt. 70g was added, heated to 60°C and stirred. Undissolved crystals were filtered out and treated in the same manner as in Example 1 to obtain bis(2-amino-1-
White crystals of methylethyl) disulfide dihydrochloride 11.
8g was obtained. On the other hand, from the mother liquor, 2-
White crystals of amino-1-methylethanethiol hydrochloride 7
．． Obtain 8 g with a purity of 99.2-.

Example 8 2-Annoethanethio monohydrochloride 10% by weight, bis(2
- 20 g of crystals with the composition of -Annoethyl) disulfide dihydrochloride 90 weight - Add 60 g of Kn-butanol, and add 60 g of Kn-butanol.
K and stirred. Undissolved crystals were filtered off and treated in the same manner as in Example 1 to obtain 17.9 g of white crystals of bis(2-aminoethyl) disulfide disulfide with a purity of 99.41 g. 1.85 g of white crystals of 2-aminoethanethiol hydrochloride was obtained with a purity of 98.
．． Obtained at 8-.

Example 9 20 g of crystals having a composition of 70% by weight of 2-akino-1-methylethanethiol hydrochloride and 30% by weight of bis(2-amino-1-methylethyl)disulfide dihydrochloride were added with 8.5 g of methanol, The undissolved crystals were stirred at 90 °C and treated in the same manner as in Example 1 to obtain 9 g of white crystals of bis(2-anno-l-methylethyl) disulfide dihydrochloride with a purity of 99.51. On the other hand, mother liquor was treated in the same manner as in Example 1 to obtain 13.8 g of white crystals of 2-annor-1-methylethanethiol salt in pure and modified 99.3-g.

Comparative Example 2 - Aminoethanethiol hydrochloride 15 weight -, bis(2
20 g of crystals of -annoethyl) disulfide dihydrochloride (85 weight) - 100 g of K ethylene glycol were added, and the mixture was heated to 60°C and stirred. The undissolved crystals were filtered and treated in the same manner as in Example 1. The resulting crystals weighed 19 g, #1, which was hardly dissolved and could not be purified and separated.

Claims (1)

[Claims] General formula % Formula % (In the formula, Ro, R, , R, and R4 represent a hydrogen atom or a lower alkyl group, and may be the same or different from each other. Also, X represents a halogen atom. 2-aminoethanethiol norogen RI represented by
R1 l゛I S-? -υNH2・HX R, R4 (In the formula, R11R, IR, R4 and By adding a monohydric aliphatic alcohol having 4 or less carbon atoms or a mixed solvent of this aliphatic alcohol and water to KfiD and a mixture thereof, 2, 2, represented by the general formula (I), A method for purifying and separating 2-aminoethanethiol hydrohalides and bis(2-aminoethyl) disulfide hydrohalides, which comprises selectively dissolving and separating ethanethiol and hydrohalides.