JPS6313434B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing 2-mercapto-2-thiazolines in high yield and purity using halogenated alkylamines as starting materials. 2-Mercapto-2-thiazolines are useful as intermediate raw materials for pharmaceuticals. The most common method for synthesizing 2-mercapto-2-thiazolines is to add halogenated alkylamines, carbon disulfide, and alkali hydroxide all at once and react them. However, since this reaction is a rapid exothermic reaction, the temperature inside the reactor rises, which not only increases the danger when carried out in large quantities or industrially, but also promotes side reactions, resulting in a significant decrease in yield. It had the disadvantage of causing Therefore, a method is proposed in which alkali hydroxide is slowly added to a mixture of halogenated alkylamines and carbon disulfide in the presence of a very small amount of water, and the reaction is carried out under the reflux of carbon disulfide due to an exothermic reaction. proposed (U.S. Patent No.
No. 2251459) Although the yield has improved considerably, it is still not satisfactory. The inventors of the present invention have conducted various studies to overcome these drawbacks of the conventional method. As a result, a consumption reaction of alkali hydroxide and carbon disulfide occurs as a side reaction. It is sparingly soluble in alkaline aqueous solutions, and the reaction between carbon disulfide and halogenated alkylamines is a heterophasic reaction, so the conversion rate to 2-mercapto-2-thiazolines is slow, and the rate of conversion to 2-mercapto-2-thiazolines is proportional to that of carbon disulfide. As the contact time with alkali hydroxide increases, especially at high temperatures, the two react to form alkali thiocarbonate and alkali carbonate, and the amount involved in the production of 2-mercapto-2-thiazolines decreases. Put it away. In addition, as a side reaction, hydrolysis of the raw material halogenated alkylamine occurs, but since this is a heterophasic reaction, the contact time between the halogenated alkylamine and the alkali hydroxide increases, and the halogenated alkylamine is hydrolyzed to form aminoalkyl alcohols, and this reaction becomes more pronounced especially under high temperature conditions. Similarly to halogenated alkylamines, the produced aminoalkyl alcohols react with carbon disulfide and alkali hydroxide to produce the desired 2-mercapto-2-thiazolines, but when carbon disulfide is Since twice as many moles as in the case of alkylamines are required, a decrease in yield is unavoidable. Furthermore, decomposition of 2-mercapto-2-thiazolines generated as a side reaction occurs;
Since the production of mercapto-2-thiazolines is extremely rapid, even locally, if alkali hydroxide and the produced 2-mercapto-2-thiazolines coexist, especially under high temperature conditions, the alkali hydroxide will cause 2- Mercapto-2-thiazolines are decomposed. I got this knowledge. Based on these findings, the present inventors overcome the drawbacks of the conventional methods and produce 2-mercapto-2-thiazolines from halogenated alkylamines.
As a result of further intensive research to develop a method for obtaining higher purity and higher yields, we found that when adding alkali hydroxide to a mixture of halogenated alkylamines and carbon disulfide to cause a reaction, alkali hydroxide It has been discovered that the objective can be achieved by maintaining the reaction solution under a constant low temperature condition during the dropwise addition, and after the completion of the dropwise addition, by heating the reaction solution to a predetermined temperature to carry out the post-reaction. I arrived at the eggplant. That is, the present invention is based on the general formula (In the formula, R ₁ , R ₂ , R ₃ and R ₄ represent a hydrogen atom or a lower alkyl group, and may be the same or different from each other. Also, X and Y represent a halogen atom.) By reacting hydrohalides of alkylamines with carbon disulfide and alkali hydroxide, the general formula (In the formula, R ₁ , R ₂ , R ₃ and R ₄ have the same meanings as above.) In producing 2-mercapto-2-thiazolines represented by the formula, halogenated alkylamines and carbon disulfide are used. While dropping alkali hydroxide into the mixture, react at about 20℃ or less, and after the dropwise addition
The present invention provides a method for producing 2-mercapto-2-thiazolines, which is characterized by carrying out a post-reaction at 80°C. The reaction in the method of the present invention is shown by the following formula using sodium hydroxide as an example of alkali hydroxide. (In the formula, R ₁ , R ₂ , R ₃ and R ₄ and X and Y have the same meanings as above) Examples of halogenated alkylamines represented by the general formula () used in the method of the present invention is 2-halogenoethylamine, 2-ethyl-
2-halogenoethylamine, 1,2-dimethyl-
2-halogenoethylamine, 1,1,2-trimethyl-2-halogenoethylamine, 1,1,2,
2-tetramethyl-2-halogenoethylamine,
Examples include hydrohalides such as chlorine, bromine, iodine or fluorine such as 2-propyl-2-halogenoethylamine. In addition, as alkali hydroxides, Li, Na, K
Alkali metal hydroxides or alkaline earth metal hydroxides such as hydroxides of alkaline earth metals are used, but these may also be prepared from the corresponding oxides. The method of the present invention is carried out under low-temperature conditions by adding an aqueous alkali hydroxide solution with twice the molar amount of the aqueous halogenated alkylamine solution to a mixed solution of the aqueous halogenated alkylamine solution and carbon disulfide in an equal molar amount or a slightly excess amount. The addition is carried out dropwise at a temperature usually below about 20°C, preferably below about 10°C. At this time, if the reaction solution temperature exceeds about 20°C, various side reactions will be promoted as described above, resulting in a decrease in yield and making it impossible to achieve the objective. The dropwise addition of the aqueous alkali hydroxide solution needs to be carried out at a rate that allows the above-mentioned low-temperature conditions to be maintained, and is usually preferably in the range of 30 minutes to 3 hours. If it is less than 30 minutes, the production of 2-mercapto-2-thiazolines will be insufficient, and if it exceeds 3 hours, the halogenated alkylamines and the produced 2-mercapto-2-
This is undesirable because a significant decomposition reaction of thiazolines occurs. In the method of the present invention, it is preferred that a water-soluble surfactant be present in the reaction solution when adding this alkali hydroxide. By doing this,
The contact efficiency is increased by improving the dispersibility (emulsification) of carbon disulfide, and the yield is improved. Moreover, since it is a water-soluble surfactant, the generated 2-mercapto-
Contamination with 2-thiazolines can be prevented. Water-soluble surfactants used in the method of the present invention include ionic and nonionic surfactants. For example, anionic surfactants include alkyl carboxylic acids (RCH ₂ COONa) and alkyl sulfonates (RCH 2 COONa). RSO ₃ Na), alkyl sulfate ester salt (ROSO ₃ Na) (in the above, R has 11 carbon atoms)
~18 alkyl groups), and cationic ones include amino acid type (≡N・HA,
HA: acid), quaternary ammonium salt type (〓NZ),
Pyridinium salt type

[Formula] Njiru halide type

[Formula] (in the above, Z represents a halogen atom), and amphoteric ones include polyamine, sodium monochloroacetate, carboxylic acid type made from acrylic acid, etc., sodium chloroalkylsulfonate,
There is a sulfonic acid type based on sodium aminosulfonate, and a sulfuric acid type using ethylene oxide, aminoethylethanolamine, etc. as starting materials. Other nonionic types include polyethylene glycol type and polyhydric alcohol fatty acid ester type. The water-soluble surfactant is 100 to 10,000 ppm, preferably 200 to 10,000 ppm based on the total weight of the contents in the reaction system.
Used in the range of 400ppm. This amount added
If it is less than 100 ppm, the emulsification of carbon disulfide will be insufficient, while if it exceeds 10,000 ppm, not only will the effect not be improved, but foaming will be severe and inappropriate. In the method of the present invention, after the dropwise addition of the aqueous alkali hydroxide solution is completed, the reaction solution is heated to carry out a post-reaction.
The reaction temperature is usually in the range from 80°C or lower to 40°C, with 40 to 60°C being particularly preferred. If the temperature is too high, the generated 2-mercapto-2-thiazolines tend to be hydrolyzed, which is not appropriate.
Furthermore, if the temperature is lower than 40°C, the reaction will not proceed completely and the desired yield will not be achieved. In addition, the time for this post-reaction is sufficient for the unreacted carbon disulfide to be completely consumed, and is usually 15 to 15 minutes.
A range of 60 minutes is used, but even if the post-reaction is carried out for more than 60 minutes, no significant effect can be expected, and depending on the conditions, it may have the opposite effect. In this way, the method of the present invention can convert halogenated alkylamines, carbon disulfide, and alkali hydroxide into 2-mercapto-2-thiazolines with high yield and high purity while preventing rapid heat generation and suppressing side reactions. It has the excellent effect of being able to produce. Therefore, the method of the present invention is particularly suitable for industrial implementation. Next, the method of the present invention will be explained in more detail based on examples. Note that the yields in the following examples were calculated using the following formula. Yield = Number of moles of 2-mercapto-2-thiazolines obtained/Number of moles of -2-chloroethylamine charged x 100 Example 1 300 ml equipped with a stirrer, temperature control means, reflux condenser and dropping funnel. 0.1 mole of 2-chloroethylamine hydrochloride dissolved in 12.5 g of water, 0.11 mole of carbon disulfide, and Newcol 261 (trade name, manufactured by Nippon Nyukazai Co., Ltd.; dodecyl diphenol ether disulfone) as a surfactant were placed in a 12.5 g reactor. sodium acid) approx.
Add 0.1 ml (corresponding to about 1.2% by weight based on chloroethylamine hydrochloride). The temperature of the mixture was cooled to about 3 to 5° C. while stirring. Next, add 0.2 mol of sodium hydroxide to this concentration.
Add slowly via addition funnel as a 48% by weight aqueous solution. The dropwise addition time was 120 minutes, and the reaction temperature during the dropwise addition was maintained at 5°C or lower. After dropping the aqueous sodium hydroxide solution, raise the reaction temperature to 50°C and heat for 15 minutes.
Thereafter, the reaction solution is cooled to 3 to 5°C, and the crude crystals are filtered off, washed with water, and dried under reduced pressure at 80°C for 2 hours. When this purified crystal was analyzed by iodometry to quantify the -SH group, 2-mercapto-2
- It was found that thiazoline was obtained with a yield of 99.2%. The purity was 99.5%. Example 2 Using a similar reactor equipped with the same equipment as in Example 1, 0.1 mole of 2-chloroethylamine hydrochloride dissolved in 12.5 g of water and 0.11 mole of carbon disulfide were charged, and the liquid temperature was lowered while stirring. Cool to 3-5°C. Next, add 0.2 mol of sodium hydroxide to this at a concentration of 48
Add gradually via addition funnel as a wt% aqueous solution. The dropwise addition time was 120 minutes, and the reaction temperature was maintained below 5°C. After dropping the sodium hydroxide aqueous solution, raise the temperature of the solution to 50°C and heat for 15 minutes. Thereafter, purified crystals were obtained by treatment in the same manner as in Example 1, which were analyzed in the same manner as in Example 1, and it was found that 2-mercapto-2-thiazoline was obtained in a yield of 97.01%. The purity was 99.1%. Example 3 A similar reactor with the same equipment as in Example 1 was used, containing 0.1 mol of 2-bromoethylamine hydrobromide dissolved in 12.5 g of water, 0.11 mol of carbon disulfide and Newcor as surfactant. 261 to about 0.1
ml and cool the liquid temperature to 3-5℃ while stirring. Next, add 0.2 mol of sodium hydroxide to this concentration.
Add slowly via addition funnel as a 48% by weight aqueous solution. The dropping time was 120 minutes, and the reaction solution temperature was maintained at 5°C or less. After dropping the sodium hydroxide aqueous solution with a concentration of 48% by weight, the temperature of the reaction solution is raised to 50°C or higher and heated for 15 minutes. Thereafter, purified crystals were obtained by treatment in the same manner as in Example 1, and when analyzed in the same manner as in Example 1, it was found that 2-mercapto-2-thiazoline was obtained in a yield of 98.9%. The purity was 99.3%. Example 4 The reaction was carried out in the same manner as in Example 1 using the same reaction apparatus as in Example 1, except that the dropping temperature and dropping time of the sodium hydroxide aqueous solution were varied.
-Mercapto-2-thiazoline was obtained. The reaction conditions and results are shown in Table 1.

【table】

[Table] Example 5 The reaction was carried out in the same manner as in Example 1 using the same reaction apparatus as in Example 1, except that the temperature and time of the post-reaction after the completion of the dropwise addition of the aqueous sodium hydroxide solution were varied. 2-Mercapto-2-thiazoline was obtained. The reaction conditions and results are shown in Table 2.

【table】

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ , R ₂ , R ₃ and R ₄ represent a hydrogen atom or a lower alkyl group, and may be the same or different from each other. Also, X and Y represent a halogen atom.) By reacting hydrohalides of alkylamines with carbon disulfide and alkali hydroxide, the general formula (In the formula, R ₁ , R ₂ , R ₃ and R ₄ have the same meanings as above.) In producing 2-mercapto-2-thiazolines represented by the formula, halogenated alkylamines and carbon disulfide are used. While dropping alkali hydroxide into the mixture, react at about 20℃ or less, and after the dropwise addition
A method for producing 2-mercapto-2-thiazolines, which comprises performing a post-reaction at 80°C.