JPH0243734B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing recrystallizable crude aminoalkylthiols by hydrolyzing 2-mercaptothiazolines 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. There are various methods for producing aminoalkylthiols, but the method for producing aminoalkylthiols using 2-mercaptothiazolines as a starting material is to convert 2-mercaptothiazolines into hydrochloric acid or hydrobromic acid. A method of hydrolysis with hydrohalic acid such as
Volume 25, page 869, 1960). However, the above-mentioned known method for obtaining aminoalkylthiols by hydrolyzing 2-mercaptothiazolines with hydrochloric acid or the like has the following drawbacks. That is, in this case, the reaction is mostly based on equation (1)
As shown in (2), the intermediate bis(2-aminoalkyl)-dithiocarbonate (2) is first produced, which is then hydrolyzed to form aminoalkylthiol (2) as shown in formula (2). (In the formula, R ¹ , R ² , R ³ and R ⁴ represent a hydrogen atom, a lower alkyl group, or a hydroxy-substituted lower alkyl group, and may be the same or different from each other.
HX indicates hydrogen halide such as HCl. ) However, since the above-mentioned intermediate bis(2-aminoalkyl)-dithiocarbonate () is extremely difficult to hydrolyze, this hydrolysis step becomes the rate-limiting step, and in the end, it takes about 10 minutes to complete the overall reaction. It takes a very long time, about a week. In addition, by increasing the reaction temperature under pressure, for example,
If the temperature is about 150℃, the reaction time will be considerably shortened, but
When the reaction temperature exceeds 130°C, there is no inexpensive equipment material that can withstand hydrohalic acid such as hydrochloric acid for a long period of time, making it difficult to carry out the process industrially. However, when the present inventor investigated the above reaction mechanism in detail, it was found that in the hydrolysis reaction of 2-methylcaptothiazolines with hydrohalic acid, alkyl In addition to the above sequential reaction to form thiol, in fact, as shown in formula (3), (In the formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as in formulas (1) and (2).) A direct reaction to directly form an aminoalkylthiol occurs concurrently, and chlorination By adopting reaction conditions in which a 4-fold molar excess of hydrohalic acid such as hydrogen acid is used, sequential reactions via the above intermediates can be suppressed and direct reactions can be prioritized, resulting in 80-95 % hydrolytic conversion can be obtained relatively easily. (requires time reaction). The present invention is based on the knowledge that by adopting the above reaction conditions, sequential reactions can be suppressed and direct reactions can be prioritized, and an overall hydrolysis conversion of 80 to 95% can be achieved in a relatively short period of time. This was originally done, but upon further study by the present inventors, the above-mentioned hydrolysis conversion rate was ``80% or more''.
It has become clear that the value has the following important significance. That is, as mentioned above, the aminoalkylthiols that are the object of the present invention are important substances as raw materials for pharmaceuticals, etc., and the standards for this require fairly high purity (at least 98% or more). Therefore, the crude aminoalkylthiols obtained by the above-mentioned hydrolysis cannot be used as they are for the above-mentioned purposes, and are required to include at least a step of recrystallizing with an organic solvent or the like to increase the purity. Surprisingly, however, aminoalkylthiols must have a purity higher than a certain level before recrystallization, otherwise when dissolved in an organic solvent, the entire solution will simply turn into syrup even after cooling. It is a substance that forms a unique system in which crystallization of the target purified aminoalkylthiol does not occur (that is, recrystallization is impossible), and this recrystallization is possible. It has become clear that the critical purity corresponds to the above-mentioned hydrolysis conversion rate of 80% or more. In the present invention, the hydrolysis conversion rate is defined as follows based on equation (3). Hydrolysis conversion rate (%) = Number of moles of aminoalkylthiols produced/Number of moles of 2-mercaptothiazolines used x 100 The present invention was made based on the above findings, and has the general formula () ^{2 - mercaptothiazolines} represented ^by Hydrolyzed with hydrohalic acid HX, the general formula () (In the formula, R ¹ , R ² , R ³ and R ⁴ are general formulas ()
It has the same meaning as in . ), the above-mentioned hydrohalic acid is used in a ratio of 4 to 8 mol per 1 mol of the 2-mercaptothiazoline, which can be recrystallized. A method for producing aminoalkylthiols is provided. Hereinafter, the constituent elements of the present invention will be explained separately. As the hydrohalic acid used in the present invention,
Examples include hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid. Among them, hydrochloric acid and hydrobromic acid are preferred, and hydrochloric acid is most preferred. The method of the present invention is characterized in that the above-mentioned hydrohalic acid is used in an amount of at least 4 times the mole of the 2-mercaptothiazoline. By selecting such conditions, it is possible to achieve a critical hydrolysis conversion rate of 80% or more, which allows the recrystallization operation as described above, within a temperature range of 120 to 130°C, which provides equipment material that can be carried out industrially. Ten~
This can be achieved in a relatively short time of 35 hours. If the molar ratio of the hydrohalic acid is less than 4 times the mole, the reaction for producing the intermediate dithiocarbonate described above will take priority, and the time required for the reaction will increase rapidly. For example, in the above-mentioned known method, the reaction is carried out at 115°C using 3 times the mole of concentrated hydrochloric acid (36%) as the hydrohalic acid.
As shown in Figure 1, the production reaction of the intermediate dithiocarbonate takes priority, and it takes 230 hours to obtain a hydrolysis conversion of 80%, and 300 hours to obtain a hydrolysis conversion of 95%. This takes an extremely long time and is completely impractical from an industrial perspective. On the other hand, when the reaction was carried out at 130°C using 4 times the mole of 21% hydrochloric acid as in the example of the present invention, as shown in Fig. 2, the intermediate dithiocarbonate was hardly produced and directly Reaction takes priority,
The reaction takes 15 hours to achieve a hydrolysis conversion rate of 80% and 30 hours to achieve a hydrolysis conversion rate of 95%, which is an extremely short period of time. In addition, increasing the molar ratio of hydrohalic acid will further shorten the reaction time, but if it exceeds 8 times the molar ratio, the effect of increasing the molar ratio will diminish and the reactor capacity will only needlessly increase. Therefore, it is economically meaningless. For example, when using hydrochloric acid, the concentration of the hydrohalic acid used in the present invention is preferably in the range of 18 to 25% by weight. If it is less than 18% by weight, even if the molar ratio of hydrochloric acid is 4 times or more, the reaction rate of the direct reaction itself will be extremely slow, making it impractical, and if it exceeds 25% by weight,
At an industrially acceptable maximum temperature of 130°C, the vapor pressure of hydrogen chloride becomes high, which is unfavorable for equipment maintenance. In addition, the reaction temperature for hydrolysis in the present invention is suitably 120°C or higher from the viewpoint of reaction rate.
From the viewpoint of the equipment material, 130°C is adopted as the upper limit. As described above, according to the present invention, a hydrolysis conversion rate of 80% or more, which allows recrystallization, can be obtained in a relatively short period of time. To obtain alkylthiols, the following operations are performed. First, residual hydrogen halide and water are distilled off from the reaction product under normal pressure and/or reduced 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 will cause deliquescent properties, so it is preferable to remove these as much as possible. This concentrated crude product is then recrystallized from an organic solvent. Usable organic solvents include alcohols, esters, ketones, and ethers, but alcohols such as methanol, ethanol, and 2-propanol, or ethanol-ethers are preferred. As a crystallization operation, following the distillation of hydrogen halides such as hydrogen chloride, while the concentrate is still hot and molten, for example, in the case of methanol solvent, it is added at a weight ratio of about 0.3 to 0.7 to the above crude product. However, it is preferable to thoroughly mix and dissolve, and then cool to 10°C or less to crystallize. The precipitated purified aminoalkylthiol crystals (purity of 98% or more) are separated and dried under reduced pressure to produce a product. In addition,
This recrystallization mother liquor (liquid) contains a considerable amount of aminoalkylthiols and some unreacted 2-
Mercaptothiazolines, etc. are dissolved, but this liquid is concentrated to dryness under reduced pressure and recycled to the hydrolysis step to recover aminoalkylthiols, and unreacted 2-mercaptothiazolines, etc. are repeatedly recovered. Since it can be subjected to a reaction,
The target aminoalkylthiols can be obtained substantially quantitatively. Hereinafter, embodiments of the present invention will be specifically illustrated and explained with reference to Examples. Example 1 In the glass autoclave of 1, 119.3 g (1.0 mol) of 2-mercaptothiazoline and 21% hydrochloric acid were added.
(4.56 mol) was charged, and the reaction was carried out at 125° C. for 20 hours under a pressure of 2.5 Kg/cm ² G. After the reaction was stopped, the pressure was gradually returned to normal, and the reaction solution was concentrated using a rotary evaporator at 80° C. under reduced pressure for 2 hours to completely remove hydrogen chloride and water, yielding 115.1 g of a crude product. Subsequently, this concentrate is used as a recrystallization solvent.
After adding 60 c.c. of methanol and heating and stirring to fully dissolve the mixture, it was cooled to 5°C and the crystals that had crystallized were filtered off by suction, and the obtained crystals were dried under reduced pressure at 40°C for 2 hours.
58.2 g of white crystals were obtained. The melting point of this thing is 69
The purity was 98.8% by the iodine method at ~70°C. Furthermore, the hydrolytic conversion rate to 2-aminoethanethiol was 87.4% as determined by the quantitative determination of the -SH group. Example 2 An experiment was conducted on the influence of hydrochloric acid concentration in the same manner as in Example 1, and the results shown in Table 1 were obtained.

[Table] * It became syrupy and could not be recrystallized.
Example 3 The same method as in Example 1 was carried out at 130° C. using 21% hydrochloric acid at various molar ratios, and the results are shown in Table 2.

[Table] Ivy.
Example 4 21% hydrochloric acid (molar ratio 4) in the same manner as in Example 1
The effect of reaction temperature was investigated using the following method, and the results shown in Table 3 were obtained.

[Table] Example 5 Using the same apparatus as in Example 1, 4-methyl-2
- 133.3 g (1.0 mol) of mercaptothiazoline in 20
% hydrobromic acid 1400c.c. (4.0mol) plus 2.5Kg/cm ²
The mixture was heated to reflux at 120° C. under pressure of G. After 15 hours, the reaction was stopped, and the reaction solution was concentrated to dryness under reduced pressure at 80°C for 2 hours using a rotary evaporator. Subsequently, 500 c.c. of this concentrate was added as a recrystallization solvent.
2-propanol was added and stirred with heating to fully dissolve, then cooled to 8°C, the crystallized crystals were filtered under suction, and the obtained crystals were dried under reduced pressure at 40°C for 2 hours to obtain 80.5g of white. Obtained crystals. The melting point of this product was 91-92°C, and the purity as determined by the iodine method was 98.2%. In addition, the hydrolysis conversion rate to 2-methyl-2aminotaenethiol was 91.5% by quantitative determination of the -SH group. As is clear from the examples above, if the hydrolysis conversion rate to aminoalkylthiol is less than 80%, the recrystallization operation cannot be performed at all, and if this value is 80% or more, the recrystallization operation cannot be performed. It can be seen that a product with a purity of 98% or higher can be easily obtained. Furthermore, it is understood that by employing the hydrolysis conditions of the present invention, the conversion rate that allows the above-mentioned recrystallization operation can be obtained in a relatively short time.

[Brief explanation of drawings]

FIG. 1 is a graph showing the relationship between yield and reaction time under conventionally known hydrolysis conditions, and FIG. 2 is a graph showing the relationship between yield and reaction time under the hydrolysis conditions of the present invention. In the figure, represents mercaptothiazoline,
represents the target aminoalkylthiol, and represents the intermediate bis(2-aminoalkyl)-dithiocarbonate, respectively.

Claims (1)

[Claims] 1 General formula () ^{2 - mercaptothiazolines} represented ^by Hydrolyzed with hydrohalic acid HX, the general formula () (In the formula, R ¹ , R ² , R ³ and R ⁴ are general formulas ()
It has the same meaning as in . ) In producing the aminoalkylthiols shown in 2-
A method for producing recrystallizable crude aminoalkylthiols, characterized in that the above-mentioned hydrohalic acid is used in a ratio of 4 to 8 moles per mole of mercaptothiazolines.