JPH045018B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing aminoalkylsulfonic acids at low cost and in high yield. Aminoalkylsulfonic acids are compounds useful as intermediate raw materials for pharmaceuticals, surfactants, PH buffering agents, etc. Among them, 2-aminoethylsulfonic acid itself has pharmacological effects such as detoxification, fatigue recovery, and nourishment. It is an extremely useful compound with The following methods are conventionally known as methods for producing aminoalkylsulfonic acids. That is, a method of reacting ethyleneimine with sulfur dioxide gas and water (Japanese Patent Publication No. 40-23007, Special Publication No. 47-2003)
16807), ethylene chloride and sodium sulfite are reacted to produce sodium 2-chloroethylsulfonate, which is then treated with anhydrous ammonia or anhydrous under pressure.
A method of heating and reacting with a mixture of 27% ammonia water and ammonium carbonate or alkyl amines (Ind.Eng.Chem., 39 906
(1947)), a method for reacting hydroxyalkylsulfonic acid with ammonia or an alkylamine under pressure (USP1932907; USP1999614), a method for oxidizing 2,2-disubstituted thiazolidine with hydrogen peroxide (JP-A-57-26654) , Method of reacting 2-aminoethanol sulfate and sodium sulfite (J.Chem.Soc.,
1943, 4), A method for reacting a hydrogen halide of 2-halogenoethylamine with a sulfite (Ind.Eng.
Chnm., 39 906 (1947); J.Am.Chem.soc., 58
191 (1936)). However, all of these conventional methods had the following serious drawbacks. That is, the method uses ethyleneimine, which is extremely toxic, carcinogenic, and expensive, as raw materials, and sulfur dioxide gas, which causes chest pain, coughing, and difficulty in breathing when inhaled, which poses safety problems. Of these, this reaction is extremely exothermic and poses a major problem in reaction control in industrial production. In the method, ammonia or an alkylamine is added under pressure.
It is necessary to heat the reaction, and for industrial production there is a drawback that the equipment is extremely expensive. This method requires the use of hydrogen peroxide, which is highly dangerous to handle, and poses a safety problem. Furthermore, it is necessary to collect and recycle by-product ketones, which makes the operation complicated. Although the method and method have the advantage that all the compounds used as raw materials are safe compounds and are easy to handle, the following problems still remain. In other words, in this method, the reaction between sulfuric ester and sodium sulfite is extremely slow and requires long heating, but since sulfuric ester itself is a compound that easily undergoes hydrolysis, it is difficult to react with sodium sulfite by hydrolysis. The by-product of monoethanolamine cannot be avoided, resulting in an extremely low yield and various problems such as separation and recovery of the by-product monoethanolamine. Although the method provides a relatively high yield of 80% for 2-bromoethylamine, it is still insufficient for industrialization, and to further increase the yield, a large excess of sulfite is required, and its separation is difficult. , recovery was a problem. In addition, in the case of 2-chloroethylamine, the yield was even lower than in the case of the method, and the method could not be called an industrial production method as it was. As mentioned above, in conventional methods, either the raw materials used themselves have serious drawbacks, or although the raw materials are safe, the yield is low or there are many problems in post-processing, and in either case, the method is not satisfactory. I can not say. The present inventors conducted a detailed study on a method in which the raw materials are extremely safe and easy to handle, with the aim of making it an industrially practicable method. As a result, it was found that in the reaction system between sulfite and halogenated alkyl amines, three types of reactions shown by the following reaction formula occur. In the conventional method described above in which a sulfite and a halogenated alkylamine are reacted under reflux, in addition to the main reaction of reaction formula (1), the hydrolysis reaction of reaction formula (2) occurs simultaneously. There was a significant decrease in the yield of the target compound, and a previously unknown reaction formula was used.
Regarding the reaction (3), since the reaction is extremely likely to occur in the presence of a large excess of halogenated alkylamine at high temperature with respect to the aminoalkylsulfonic acid produced in reaction formula (1), it is difficult to obtain even more yield. It was confirmed that this was the cause of the decrease in the rate. The present inventors have conducted extensive studies on a method for suppressing the side reactions represented by reaction formulas (2) and (3), and have determined that the method is to add a halogenated alkylamine in portions to a heated aqueous solution of sulfite. We discovered that side reactions could be suppressed by applying this technology and filed a patent application (patent application).
57−155284). Furthermore, it has already been found that excellent effects can also be obtained by a method in which a mixed aqueous solution of a sulfite and a halogenated alkylamine is heated at regular intervals and reacted. Both of these two methods
Although this is an excellent method capable of producing aminoalkylsulfonic acid with a yield of 90% or more, it is still not a satisfactory method. That is, in the former method, side reactions at the initial stage of the reaction can be suppressed, but since the reaction is carried out by keeping the temperature approximately constant after the addition of the halogenated alkylamine, the three reactions shown in the above reaction formula occur simultaneously in the latter half of the reaction. It happens. Therefore, in order to obtain aminoalkylsulfonic acid in high yield, it was necessary to increase the amount of sulfite used. Furthermore, in the latter method, lowering the temperature at the initial stage of the reaction prolongs the reaction time, while increasing the temperature in a short period of time tends to cause side reactions, particularly the side reaction of reaction formula (2). Therefore, in order to obtain aminoalkylsulfonic acid in high yield, it was necessary to use a large amount of sulfite. For these reasons, these methods still have room for improvement in the recovery of excess sulfite. The present inventors conducted intensive studies to improve this point, and found that the halogenated alkylamine was added in portions to a heated aqueous solution of sulfite, and then the reaction temperature was raised stepwise to cause the reaction. As a result, the present inventors have discovered that highly purified aminoalkylsulfonic acids can be produced in high yield and at low cost from approximately reaction equivalents of sulfite and halogenated alkyl amines, and have completed the present invention. That is, the present invention provides 50% of sulfite represented by the general formula () M ₂ SO ₃ () (in the formula, M represents an alkali metal ion or an ammonium ion).
General formula () in an aqueous solution heated to ~60℃ (In the formula, R ₁ , R ₂ , and R ₃ represent a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an alkyl group having 1 to 3 carbon atoms having a hydroxyl group, and may be the same or different from each other. (representing chlorine, bromine, or iodine, and n is an integer of 2 or 3), the average amount of halogenated alkylamines is 0.1 to 1 mole of sulfite.
General formula () characterized by adding in portions at a rate of 1.0 mol/hr, and then dividing the reaction into at least two times within the range up to the boiling point, and raising the temperature stepwise to react. (In the formula, R ₁ , R ₂ , R ₃ and n are general formulas ()
The present invention relates to a method for producing aminoalkylsulfonic acids represented by (having the same meaning as in the case of). The sulfite used in the method of the invention is sodium sulfite, potassium sulfite, or ammonium sulfite. In addition, as the halogenated alkylamine, 2-halogenoethylamine, N-
Methyl-2-halogenoethylamine, N-ethyl-2-halogenoethylamine, N-(2-hydroxyethyl)-2-halogenoethylamine, N-
Propyl-2-halogenoethylamine, 3-halogenopropylamine, N-methyl-3-halogenopropylamine, 2-halogenopropylamine,
N-(2-hydroxypropyl)-2-halogenopropylamine, 1-methyl-2-halogenoethylamine, 2-halogenobutylamine, and the like. In these compounds, the halogen may be chlorine, bromine or iodine. These compounds can be prepared by a known method, that is, by reacting alkanolamine with thionyl chloride (ger.
Offen, 2701215 (1978)), it can be easily produced by a method of reacting alkanolamine with hydrohalic acid, etc. The method of the present invention involves heating an aqueous solution of sulfite at 50-60°C.
At this temperature, a hydrogen halide salt of a halogenated alkylamine is added as it is or as an aqueous solution at a predetermined average rate, either continuously or intermittently in portions, and then the reaction begins. The reaction is completed by raising the temperature stepwise in a predetermined manner. Hydrogen halide salts of halogenated alkylamines are often hygroscopic, so it is easier to add them in the form of an aqueous solution. The concentration of the sulfite aqueous solution is preferably from 10% to saturation. Although the reaction proceeds satisfactorily even at a concentration of 10% or less, the reaction equipment would be large and uneconomical for industrial use. Although it is possible to use the sulfite in a slurry state at a concentration higher than saturation, a sufficient effect can be obtained at a concentration lower than saturation. Further, the concentration of the aqueous solution of the hydrogen halide salt of the halogenated alkylamine is preferably from 10% to saturation. Although it may be less than 10%, it is not economical in industrial terms because the equipment becomes larger. The sulfite is used in an amount of 1.0 to 1.5 times, preferably 1.05 to 1.25 times the amount of the hydrogen halide salt of the halogenated alkylamine. If the amount is less than 1 equivalent, the yield decreases, probably because the excess halogenated alkylamine causes undesirable side reactions. Also
Even if more than 1.5 times the equivalent is used, sufficient results will be obtained within the above range, and no effect beyond this range will be obtained. On the contrary, recovery and disposal of excess sulfite become a problem, which is not preferable. The addition rate of the halogenated alkylamine is 0.1 to 1 mol/hr per mol of sulfite, and the addition time varies depending on the addition temperature and reaction molar ratio, but is usually preferably 1 hour to 10 hours. Although an addition rate of 0.1 mol/hr or less and an addition time of 10 hours or more are acceptable, sufficient effects can usually be obtained with the above-mentioned addition rate and addition time. If the addition rate is 1 mol/hr or more and the addition time is 1 hour or less, the effect of divided addition is not sufficient. The temperature when adding halogenated alkylamine is 50~
60°C is preferred. Although the reaction proceeds below 50°C, the reaction time becomes longer, which is not preferable. A temperature of 60° C. or higher is not preferable because the effect of suppressing side reactions is small. In the method of the present invention, the stepwise raising of the reaction temperature after addition of a halogenated alkylamine is a method of intermittently repeating an operation in which the temperature is raised by a predetermined temperature range at fixed time intervals and the temperature is maintained for a fixed time. More specifically, the temperature is divided into two or more times within the temperature range from the addition temperature of the halogenated alkylamine to the boiling point, and the temperature is raised within a temperature range of 5°C or more each time, and the temperature is increased by 0.5°C to the same temperature.
It is carried out by a method of keeping it for more than 2 hours, especially preferably 2 to 2 hours.
The temperature is increased by 10 to 30°C every 0.5 to 6 hours in five steps. Even if the temperature is changed within 0.5 hours, the effect of suppressing side reactions is small, which is not preferable. Even if the temperature is kept at the same temperature for 6 hours or more, the improvement in the effect is small even though the reaction time is longer, which is not preferable. The heating time after addition of the halogenated alkylamine varies depending on the temperature, but is preferably from 1 hour to 10 hours. If the reaction time is less than 1 hour, the reaction will not be completed and the yield will be low, and if it is more than 10 hours, the reaction time will be undesirably long. Methods for isolating aminoalkylsulfonic acids from the reaction solution after the reaction are known. That is, water is removed by distillation, then hydrochloric acid is added to dissolve only the aminoalkylsulfonic acid, and the inorganic salt is separated.
By concentrating this hydrochloric acid solution containing aminoalkylsulfonic acid and adding ethanol to it, the target product can be precipitated, and can be extracted by filtration. In this way, by the production method of the present invention, aminoalkylsulfonic acids can be produced in high yield and purity using extremely safe and easy-to-handle raw materials and inexpensive raw materials. Hereinafter, the present invention will be explained in more detail with reference to Examples. Example 1 In a 500 ml five-necked flask equipped with a stirrer, thermometer, addition funnel, reflux condenser and _N2 inlet, 50.4 g (0.4 mol) of anhydrous sodium sulfite and 178 g of water were added.
g and stirred under a N ₂ stream to dissolve. 55.1 g (0.38 mol) of an 80% aqueous solution of the hydrogen chloride salt of 2-chloroethylamine was placed in the dropping funnel. The sodium sulfite solution in the flask was heated to 55°C, and at this temperature, an aqueous solution of 2-chloroethylamine hydrogen chloride was added dropwise from the dropping funnel over 4 hours. On average, the dropping rate is 1
The amount of hydrogen chloride salt of 2-chloroethylamine was 0.24 mol/hr based on the mole. After the dropwise addition, stirring was continued at 55°C for 1 hour, and then heating was increased to carry out reactions at 65°C for 2 hours, at 80°C for 2 hours, at 90°C for 2 hours, and at the boiling point (105°C) for 1 hour. All of the above reactions were conducted under a N ₂ stream. After the reaction was completed, the reaction mixture was removed under reduced pressure, and 150 ml of concentrated salt was added to dissolve the produced taurine. Insoluble inorganic salts were separated, and the inorganic salts were washed five times with concentrated hydrochloric acid (the amount of hydrochloric acid was 20 to 25 ml each time).
Combine the liquid and washing liquid and concentrate under reduced pressure to approximately 100ml.
Taurine was precipitated by adding 100 ml of ethanol.
Taurine was isolated by filtration and dried under reduced pressure. Yield: 46.6 g, yield 98.1%, IR and NMR were consistent with the standard product. The results of elemental analysis of this product were as follows. Elemental analysis C ₂ H ₇ NO ₃ S as C H N S Theoretical value (%) 19.19 5.64 11.19 25.62 Analytical value (%) 19.28 5.81 11.06 25.41 Example 2 Stirrer, thermometer, dropping funnel, reflux condenser and N ₂ 34.8 g (0.22 mol) of anhydrous potassium sulfite and 35 g of water in a 300 ml five-necked flask equipped with a blowing spout.
was added and stirred under a N ₂ stream to dissolve. Furthermore, 82 g (0.2 mol) of a 50% aqueous solution of the hydrobromide salt of 2-bromoethylamine was placed in the dropping funnel. The potassium sulfite aqueous solution was heated to 55°C, and at this temperature, the 2-bromoethylamine aqueous solution was added dropwise from the dropping funnel over 5 hours. The dropping rate was on average 0.18 mol/hr per 1 mol of potassium sulfite. After dropping, increase the heating to 65℃ for 2 hours, then 80℃
The reaction was carried out for 2 hours at 90°C and for 1 hour at 90°C. All of the above reactions were conducted in a _N2 stream. After the reaction was completed, the same post-treatment as in Example 1 was carried out,
I got taurine. Yield 24.6g, yield 98.2%, IR of this,
NMR was consistent with the standard taurine, and the elemental analysis results were as follows. Elemental analysis C ₂ H ₇ NO ₃ S as C H N S Theoretical value (%) 19.19 5.64 11.19 25.62 Analytical value (%) 19.23 5.74 11.15 25.38 Example 3 Stirrer, thermometer, reflux condenser, powder inlet and In a 300 ml five-necked flask with _N2 inlet
20% sodium sulfite aqueous solution 132.3g (0.21mol)
and heated to 55°C under a stream of _N2 . Add 23.2g (0.2g) of 2-chloroethylamine hydrogen chloride to this solution.
mol) was added in portions over 2 hours. The addition rate averaged 0.48 moles/hr per mole of sodium sulfite. After addition, at 70℃ for 2 hours, at 85℃ for 2 hours,
The reaction was carried out at 100°C for 1 hour. After reaction, Example 1
The same post-treatment as above was performed to obtain taurine. The IR.NMR of this product matched that of the standard product. Yield 24.4g, yield 97.6% Elemental analysis As C ₂ H ₇ NO ₃ S C H N S Theoretical value (%) 19.19 5.64 11.19 25.62 Analytical value (%) 19.28 5.78 11.24 25.51 Examples 4 to 9 Same as Example 1 The reaction was carried out using the apparatus shown in Table 1, using the raw materials shown in Table 1, and under the conditions shown in Table 1. After the reaction, the same post-treatment as in Example 1 was carried out and the results were shown in Table 1.
The results were obtained. The obtained product was identified by IR and NMR.

[Table] Comparative Example 50.4 g (0.4 mol) of anhydrous sodium sulfite and 178 g of water were placed in a 500 ml four-necked flask equipped with a stirrer, thermometer, reflux condenser, and N ₂ inlet, and stirred under a N ₂ stream. and dissolved. 2 in this solution
-50% aqueous solution of hydrochloride salt of chloroethylamine
46.4 g (0.2 mol) was added. The mixture was heated in an oil bath and the reaction was carried out under reflux for 8 hours. After the reaction was completed, post-treatment was performed in the same manner as in Example 1 to obtain taurine. The yield was 18.4g, the yield was 73.6%, and the
IR and NMR were consistent with the standard product. Moreover, the elemental analysis values of this product were as follows. Elemental analysis As C ₂ H ₇ NO ₃ S C H N S Theoretical value (%) 19.19 5.64 11.19 25.62 Analytical value (%) 19.28 5.76 11.05 25.37

Claims (1)

[Claims] 1. 50% of sulfite represented by the general formula () M ₂ SO ₃ () (in the formula, M represents an alkali metal ion or an ammonium ion)
In an aqueous solution heated to ~60℃, the general formula () (In the formula, R ₁ , R ₂ and R ₃ represent a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an alkyl group having 1 to 3 carbon atoms having a hydroxyl group, and may be the same or different from each other. , indicates bromine or iodine,
n is an integer of 2 or 3), the average amount of halogenated alkylamines is 0.1 to 1 mole of sulfite.
General formula () characterized in that the reaction is carried out by adding in portions at a rate of 1.0 mol/hr and then raising the temperature stepwise at least twice within the range up to the boiling point. (In the formula, R ₁ , R ₂ , R ₃ and n are general formulas ()
A method for producing aminoalkylsulfonic acids represented by