JPH0217544B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing 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
Vol. 869, 1960). The produced aminoalkylthiols are crystallized with ethanol ether or the like after hydrogen halide and water are distilled off under reduced pressure, separated and dried under reduced pressure to obtain a product. 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-mercaptothiazolines with hydrohalic acid, alkyl thiol is converted via bis-(2-aminoalkyl)-dithiocarbonate In addition to the above sequential reaction, as shown in equation (3), (In the formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as in formulas (1) and (2).) Direct reactions to directly form aminoalkylthiol are occurring simultaneously, 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 solution, 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, 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 represented by
Hydrolyze using twice the mole or more, and stop the hydrolysis reaction when the conversion rate to the aminoalkylthiol is in the range of 80 to 95%, and recrystallize the obtained crude aminoalkylthiol with an organic solvent. A method for producing highly purified aminoalkylthiols, characterized by the following. It provides: Hereinafter, the constituent elements of the present invention will be explained separately. As the hydrohalic acid in the present invention, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, etc. can be used, and among them, hydrochloric acid and hydrobromic acid are preferable, and chlorinated acid Hydrogen acid is most preferred. One of the requirements of the present invention is to stop the hydrolysis reaction when the hydrolysis conversion rate to aminoalkylthiols is in the range of 80 to 95%, and the conditions for this hydrolysis reaction are as described above. It is desirable to adopt the following conditions that give priority to direct reaction (3). That is, first, hydrohalic acid is used in a ratio of 4 to 8 moles per mole of 2-mercaptothiazolines. By selecting such conditions, the target
It becomes possible to obtain a hydrolysis conversion rate of 80 to 95% within a temperature range of 120 to 130° C., which allows production of industrially viable equipment materials, and in a relatively short period of 10 to 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, concentrated hydrochloric acid (36
In the above-mentioned known method, in which the reaction is carried out at 115°C using 3 times the mole of 5%), as shown in Figure 1, the reaction to produce the intermediate is given priority, and a hydrolysis conversion rate of 80% is obtained. It takes an extremely long time of 230 hours to obtain a hydrolysis conversion rate of 95%, and 300 hours to obtain a hydrolysis conversion rate of 95%, which 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 Figure 2, almost no intermediate was produced and the direct reaction was not carried out. Prioritizing the reaction, it takes only 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,
This is because the vapor pressure of hydrogen chloride becomes high at the industrially acceptable maximum temperature of 130°C, which is unfavorable in terms of 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. Next, the hydrolysis reaction is stopped when the hydrolysis conversion rate to aminoalkylthiols reaches 80 to 95%, preferably 88 to 92%. To do this, the reaction system must be stopped by stopping the heating, performing a cooling operation, or, if the reaction was carried out under pressure, returning the pressure to normal pressure or reduced pressure to lower the partial pressure of the hydrogen halide. Just by making it milder, the hydrolysis reaction, which was already slowing down considerably, can be easily stopped. In order to convert the crude aminoalkylthiols obtained as described above into purified aminoalkylthiols with a purity of 98% or more, the following purification operation is 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 may cause deliquescent properties, 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, 2-
In the case of aminoethanethiol, the temperature is 70°C or higher. 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, the recrystallization mother liquor (liquid) after crystallizing and separating the above aminoalkylthiols contains a considerable amount of aminoalkylthiols, some unreacted 2-mercaptothiazolines, and intermediate dithiocarbonates. A crude product consisting of
By recycling to the hydrolysis step, aminoalkylthiols are recovered and unreacted 2-
Since mercaptothiazolines and the like can be subjected to repeated reactions, the target purified aminoalkylthiols can finally be obtained substantially and almost quantitatively. 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 or ethanol in the reaction system greatly inhibits the hydrolysis reaction, and therefore it has become clear that the presence of even a small amount of organic solvents such as methanol or ethanol in the reaction system greatly inhibits the hydrolysis reaction. It is necessary that the crude product is substantially free of recrystallization mother liquor (liquid). 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. Hereinafter, embodiments of the present invention will be specifically described with reference to Examples. Note that these Examples are merely illustrative, and the technical scope of the present invention is not limited thereto. Example 1 In the glass autoclave of 1, 119.3 g (1.0 mol) of 2-mercaptothiazoline and 21% hydrochloric acid were added.
650CC (4.23 mol) was charged, and the reaction was carried out under heating and reflux at 120° C. for 45 hours under a pressure of 2.5 Kg/cm ² G. After the reaction has stopped, the pressure is gradually returned to normal, and the reaction solution is heated to 80°C under reduced pressure for 1 hour using a rotary evaporator.
Hydrogen chloride and water were completely distilled off for 1 hour and the mixture was concentrated to dryness. Subsequently, this concentrate is used as a recrystallization solvent.
Add 60cc of methanol (purity 99.9%) and heat and stir to fully dissolve, then heat to 5℃ while stirring well.
The resulting crystals were dried under reduced pressure at 40° C. for 2 hours to obtain 56.8 g of pure white crystals. The melting point of this product was 69-70°C, and the purity as determined by the iodine method was 99.5%. On the other hand, the liquid
Concentrate to dryness under reduced pressure at 80℃ for 2 hours and use the iodine method.
When the SH group was quantified, it was 80.4%. The hydrolysis conversion rate to 2-aminoethanethiol determined from the quantitative value of the -SH group was 91.0%. Example 2 2-mercaptothiazoline 119.3g (1.0mol)
and 58.3 g of the liquid concentrate obtained in Example 1 at 21
% hydrochloric acid (4.23 mol) and heated to reflux at 120° C. under a pressure of 2.5 kg/cm ² G. After 45 hours, the reaction was stopped, and concentration was carried out while gradually returning to normal pressure. After 1 hour, the pressure was further reduced to dryness at 80° C. for 1 hour to completely distill off hydrogen chloride and water. Subsequently, 85cc of methanol was added to this concentrate as a recrystallization solvent, and the mixture was cooled to 5°C with good stirring, and the crystals that formed were filtered off by suction. The obtained crystals were dried under reduced pressure at 40°C for 2 hours to give 84.5g. Pure white crystals were obtained. The melting point of this substance is 69-70℃, and the purity by the iodine method is
It was 99.7%. The liquid was treated in the same manner as in Example 1, but the -SH group quantitative value of the liquid concentrate was 81.4.
It was %. The hydrolysis conversion rate to 2-aminoethanethiol determined from the quantitative value of the -SH group was 91.1%. Examples 3 to 10 87.2 g of the liquid concentrate obtained in Example 2 was subjected to hydrochloric acid hydrolysis along with 119.3 g of fresh 2-mercaptothiazoline in the same manner as in Example 2, and the same method was repeated 7 times. The results obtained are shown in Table 1.

【table】

[Table] Examples 11-12 and Comparative Examples 1-3 The effects of the recrystallization treatment on the product were investigated under the same conditions as in Example 1, only the reaction time was varied, and the results are shown in Table 2.

[Table] Example 13 4-Methyl-2-mercaptothiazoline 133.3
g (1.0 mol) to 20% hydrobromic acid 1400CC (4.0 mol)
The mixture was heated to reflux at 120° C. under a pressure of 2.5 kg/cm ² G. After 15 hours, the reaction was stopped, and the same treatment as in Example 1 was carried out to obtain 65.0 g of crystals. The melting point of this substance is 91-92℃, and the purity by the iodine method is 98.5%.
It was hot. As is clear from the above examples and comparative examples,
The hydrolysis conversion rate to aminoalkylthiols is
High purity aminoalkylthiols with a purity of 98% or more can be easily obtained by stopping the hydrolysis reaction in a range of 80% or more and recrystallizing the obtained crude aminoalkylthiols with an organic solvent; , by repeating the process of substantially removing the mother liquor from the crude product dissolved in the mother liquor after crystallizing and separating the aminoalkylthiols, and then circulating it to the hydrolysis step, finally approximately It can be seen that the target purified aminoalkylthiols can be quantitatively obtained, and even if the above circulation is repeated many times, there is no noticeable decrease in the purity of the obtained product. It is also clear that when the hydrolysis conversion rate is less than 80%, the recrystallization operation becomes extremely difficult. Example 14 16.3 g (0.1 mol) of 2-mercapto-4-(2-hydroxyethyl)2-thiazoline and 65 c.c. (0.42 mol) of 21% hydrochloric acid were placed in a 100-inch glass autoclave to produce 2.5 Kg/cm ² G. The procedure was as in Example 2, except that the mixture was heated and carbonized at 120° C. for 50 hours under pressure. However, the methanol for recrystallization was changed to 15 c.c. The purity was 87.7% by weight at the time of concentration after completion of the reaction, and 99.7% by weight after recrystallization and drying. The conversion rate to 2-amino-2-(2'-hydroxyethyl)ethanethiol was 90.6 mol%. Example 15 Hydrolysis and recrystallization were carried out in the same manner as in Example 14, except that 16.3 g (0.1 mol) of 4-ethyl-4-methyl-2-2-mercapto-2-thiazoline was used. At the time of concentration after completion of the reaction, the purity of the target product, 1-ethyl-1-methyl-2-aminoethaneothyl, was 83.0% by weight, and the conversion rate was 86.9% by mole. The purity of the target product after recrystallization was 99.4% by weight.

[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 is hydrolyzed with hydrohalic acid HX to obtain the general formula () (In the formula, R ¹ , R ² , R ³ and R ⁴ are general formulas ()
In producing the aminoalkyl thiols shown in A method for producing high-purity aminoalkylthiols, which comprises stopping the hydrolysis reaction at an addition rate of 80 to 95%, and recrystallizing the obtained crude aminoalkylthiols with an organic solvent. . 2. In the method described in claim 1,
Conversion rate to aminoalkylthiols is 80-95%
A reaction mixture containing aminoalkylthiols is obtained by stopping the hydrolysis reaction in a range of A method for producing highly purified aminoalkylthiols, characterized by the following. 3. In the method according to claim 1 or 2, the crude product dissolved in the recrystallization mother liquor after crystallizing and separating the aminoalkylthiols is recovered, and the crude product is recovered. A method for producing high-purity aminoalkylthiols, characterized in that the product is recycled to a hydrolysis step. 4. In the method described in claim 3,
A method for producing high-purity aminoalkylthiols, characterized in that the crude product recycled to the hydrolysis step does not substantially contain recrystallization mother liquor.