JPS6023360A - Preparation of aminoalkylsulfonic acids - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a drug, etc. inexpensively in high purity in high yield with sppressing side reactions, by subjecting an aqueous solution containing both a sulfite and a halogenoethylamine to reactions with raising the reaction temperatures stepwise in a specific temperature range. CONSTITUTION:An aqueous solution containing a halogenated alkylamine shown by the formula I (R1-R3 are C, or 1-3C alkyl containing 1-3C alkyl; X is Cl, Br, etc.; n is 2 or 3) and a sulfite (e.g., sodium sulfate, etc.) is subjected to reactions in such a way that at least one or more time constant temperature reactions are carried out in a temperature range of normal temperature -65 deg.C and in a temperature range of 50 deg.C- the reflux temperature of the aqueous solution, respectively, and the temperatures are raised at least two times, to give an aminoalkylsulfonic acid shown by the formula II. The reactions suppress side reactions such as hydrolysis, etc., and result in suppression of by-products. The raw material compounds are extremely safe, easily treatable and inexpensive.

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 used in pharmaceuticals, surfactants,
It is a compound useful as an intermediate raw material for H buffering agents, etc. Among them, 2-aminoethylsulfonic acid itself is an extremely useful compound having pharmacological effects such as detoxification, fatigue recovery, and nourishment and tonicity.

Conventionally, methods for producing aminoalkylsulfonic acids include
The following methods are known.

■Method of reacting ethyleneimine with sulfur dioxide gas and water (Special Publication No. 40-23007, Special Publication No. 47-16807)
, ■React ethylene chloride and sodium sulfite to produce 2-
A method of producing sodium chloroethyl sulfonate and reacting it with anhydrous ammonia or a mixture of 27% aqueous ammonia and ammonium carbonate, or alkylamines under pressure (Ind, Eng, Chem,
, 39906 (194,7) ), ■ Method for reacting hydroxyalkylsulfonic acid with ammonia or alkylamine under pressure 1'U, S, P, 1,932,
907; U, S, P, 1,999,614. ),■
2. Method of oxidizing 2-disubstituted thiazoline with hydrogen peroxide (JP-A-57-26654), ■ Method of reacting 2-amine ethanol sulfate with sodium sulfite (J, Chem, Soc, 1)
,943.

4), ■ A method of reacting a hydrogen halide of 2-halogenoethylamine with a sulfite (Ind, Eng, Chem,
.

39906 (1947); J, A+n, Chem.
Soc, 58191 (1936)).

However, all of these conventional methods have the following serious drawbacks. That is, in method ①, as raw materials,
There are safety concerns because it uses ethyleneimine, which is extremely toxic (and carcinogenic and expensive), and sulfur dioxide gas, which causes sore throat, coughing, and difficulty breathing when inhaled. There is also a big problem in terms of anti-old control in industrial production.

Methods (1) and (2) require ammonia or alkylamine to be reacted under pressure and heat, and have the disadvantage that the equipment is extremely expensive for industrial production.

Method (2) requires the use of hydrogen peroxide, which is highly dangerous to handle, and there is a safety-F problem. Furthermore, it is necessary to collect and recycle by-product ketones, which makes the operation complicated.

Methods (1) and (2) have the advantage that the compounds used as raw materials are both safe and easy to handle; however, the following problems still remain. That is, in method (2), the reaction between the sulfuric ester and sodium sulfite is extremely slow and requires long heating, but since the sulfuric ester itself is a compound that easily undergoes hydrolysis, it does not undergo hydrolysis during the reaction with sodium sulfite. The by-product of monoethanolamine cannot be avoided, and the yield is extremely low, and there are various problems such as separation and recovery of the monoethanolamine produced as a by-product.

Although method Ⅰ gives a relatively high yield of 80% for 2-bromoethylamine, it is still insufficient for industrialization, and a large excess of sulfite is required to further increase the yield. Separation and recovery were problems.

In addition, in the case of 2-chloroethylamine, the yield was even lower than in the case of method (1), and it could not be called an industrial production method as it was.

As described above, in conventional methods, the raw materials used themselves have serious drawbacks, or if the raw materials are safe, the yield is low, or there are many problems in post-processing (both of which are not satisfactory methods). I can't say that.

The present inventors have conducted detailed studies on method (2), in which the raw materials are extremely safe and easy to handle, with the aim of making it an industrially viable method.

As a result, it has been found that in the reaction system between sulfite and rhodanated alkylamines, three types of reactions 5- shown in the following reaction formula occur.

In the conventional method of reacting the sulfite and the halogenated alkyl amine under reflux, the hydrolysis reaction of reaction formula (2) occurs simultaneously in addition to the main reaction of reaction formula (1), which makes it difficult to obtain the target compound. In addition, the previously unknown reaction of reaction formula (3) involves the reaction of a large excess of alkyl halide with respect to the aminoalkylsulfonic acid produced in reaction formula (1) at high temperatures. It was assumed that the presence of an amine, which was a condition in which the reaction was extremely likely to occur, was the cause of further lowering the yield.

The present inventors conducted conceptual studies on methods for suppressing the side reactions in reaction formulas (2) and (3), and surprisingly found that while gradually increasing the temperature of an aqueous solution containing sulfite and halogenoethylamines, It was discovered that aminoalkyl sulfonic acids can be produced with a yield of 90% or higher by the reaction, and the present invention was completed.

That is, the present invention is based on the general formula (■) (wherein R, , Rλ and 穆 are hydrogen atoms, and have 1 to 3 carbon atoms.
represents an alkyl group or an alkyl group having 1 to 3 carbon atoms and having a hydroxyl group, and may be the same or different from each other. X represents chlorine, bromine, or iodine, and n is an integer of 2 or 3) An aqueous solution containing a sulfite and a halogenated alkylamine represented by
A step of carrying out at least one constant temperature reaction in each temperature range of C to reflux temperature of the aqueous solution,
The reaction is carried out at least twice by raising the temperature stepwise.It is expressed by the general formula (TI) (wherein R1, R1, R, and n have the same meanings as in the general formula (■)). This is a method for producing aminoalkylsulfonic acids.

The halogenated alkylamines used in the method of the present invention are represented by the above general formula (I), and specifically,
2-halogenoethylamine, N-methyl-2-halogenoethylamine, N-ethyl-2-halogenoethylamine, N-(2-hydroxylethyl)-2-halogenoethylamine, N-propyl-2-halogenoethylamine, 3-halogenopropyl Amine, N-methyl-3-halogenopropylamine, 2-halogenopropylamine, N
-(2-hydroxypropyl)-2-no)lochenoflobilamine, ■-Methyl-2-halogenoethylamine, 2
- Examples include halogenbutylamine.

These compounds may be any of chlorine, bromine, and iodine.
5 (1978)) ■ It can be easily produced by a method in which alkanolamine is treated with hydrohalic acid.

The sulfite used in the method of the present invention is an alkali metal salt of sulfite, such as sodium sulfite or potassium sulfite, or ammonium sulfite.

The method for producing aminoalkylsulfonic acids of the present invention includes dissolving a sulfite and a halogenide salt of a halogenated alkylamine in water to form an aqueous solution containing both.
The temperature is increased step by step over at least two sessions.

The aqueous solution concentrations of both the sulfite and the halogenated alkylamine are preferably in the range of 10 to saturation. 10
Although the reaction proceeds satisfactorily even at a concentration of % or less, the reaction apparatus would be large and uneconomical from an industrial perspective. It is possible to add sulfite at a concentration above saturation to form a slurry, but a concentration below saturation will produce the desired effect.

The sulfite is preferably used in an equivalent amount of 1 to 3 times the amount of the hydrogen halide 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. Further, since sufficient results can be obtained within the above range, there is no need to use more than 3 equivalents, which is rather undesirable as it may cause problems such as collection and disposal of excess sulfite.

In the method of the present invention, the reaction is carried out by raising the temperature in stages in order to achieve the object of the present invention. That is, the temperature is increased stepwise at least twice within the range from room temperature to the reflux temperature of the aqueous solution.

=10- In particular, room temperature to 65°C, preferably room temperature to 60°C,
and 50°C to the reflux temperature of the aqueous solution, preferably 65°C.
℃ to the reflux temperature of the aqueous solution, and the reaction is carried out by raising the temperature stepwise in at least two or more steps. In order not to satisfy such conditions, for example, the temperature is divided into 2 to 5 times within the range of room temperature to the reflux temperature of the aqueous solution, and once every 0.5 to 4 hours.
An example is a method in which the reaction is carried out by raising the temperature in steps of 0 to 30°C. Further, the constant temperature reaction in each of the above temperature ranges is carried out at least once in the temperature range of room temperature to 60°C, preferably for 0.5 to 10 hours/at a predetermined temperature, and in the range of 50°C to the reflux temperature of the aqueous solution. , means a step of reacting at a predetermined temperature for 0.5 to 4 hours, and the reaction is carried out in a manner that includes at least two or more constant temperature reactions as described above, and the temperature is raised stepwise to complete the reaction. .

By reaction at room temperature to 60°C under the above conditions,
The reaction shown in the above reaction formula (3) can be carried out by suppressing the hydrolysis reaction shown in the above reaction formula (2), and then carrying out the reaction while raising the temperature stepwise from 50°C to reflux temperature. As a result, the production of by-products is suppressed, and the desired aminoalkylsulfonic acids can be obtained in high yield.

The heating time in the present invention is preferably 3 to 20 hours, although it varies depending on the heating rate or temperature 1. If the heating time is less than 3 hours, the reaction will not be completed, resulting in a low yield, and if it is more than 20 hours, the reaction time will be This is not desirable as it becomes long.

After the reaction is completed, the aminoalkylsulfonic acids can be isolated from the reaction solution by a known method. For example, after water is removed from the reaction solution by distillation, hydrochloric acid is added to dissolve only the aminoalkylsulfonic acids, and the inorganic salts are separated. This hydrochloric acid solution containing aminoalkylsulfonic acid is concentrated, ethanol is added thereto to precipitate the target product, and this can be extracted by filtration.

According to the method of the present invention, highly purified aminoalkylsulfonic acids can be produced in high yield using extremely safe and easy-to-handle (and inexpensive) raw materials.

Next, the method of the present invention will be explained in more detail by way of examples.

Example-1 50.4 g (0.4 mol) of anhydrous sodium sulfite and 178 q of water were added to a 500 d four-eye flask equipped with a stirrer, thermometer, reflux condenser, and N□ inlet, and the mixture was heated under a stream of N. Stir to dissolve. Add to this solution 46.49 (0,2
mol) was added. The mixture was heated to an internal temperature of 55°C in a hot water bath and stirred at this temperature for 5 hours. Increase the heating to reach an internal temperature of 65°C.
The reaction mixture was heated and stirred for 2 hours at 80°C, 2 hours at 90°C, and 1 hour at the boiling point. All of the above reactions were performed in a N gas stream.

After the reaction was completed, water was removed under reduced pressure, and 150 g of concentrated hydrochloric acid was added to dissolve the produced taurine. Separate the insoluble inorganic salts, and add concentrated hydrochloric acid to the inorganic salts five times (the amount of hydrochloric acid is 20
~25rnl) was washed. The r solution and the washing solution were combined and concentrated under reduced pressure to about 100.

13- Taurine was precipitated by adding 100 d of ethanol, isolated by filtration, and dried under reduced pressure.

Yield 23.9 g, yield 95.6 h, IR and NMR
, were consistent with the standard product. The elemental analysis values were as follows.

Elemental analysis CHN S as C2H, N03S Theoretical value C%) 19,19 5,64 11,19 2
5.62 Analysis value (%) 19,31 5,78 11.
03 25, 35 Comparative Example Example-1 (sulfite)
The same operation as in Example 1 was performed except that the mixture was mixed with an aqueous solution of hydrogen chloride salt of chloroethylamine, and then heated and reacted at an internal temperature of 100° C. for 8 hours.

Post-treatment was performed in the same manner as in Example-1 to obtain taurine.

Yield 1.8.1g, yield 72.4%, IR and NM
R was consistent with the standard product. The elemental analysis values of this product were as follows.

=14- Elemental analysis CT-I N S as H7No, S Theoretical value (explosion) 19,19 5.64 11,19 2
5.62 analysis value (Hime) 19,28 5.76 11,
05 25.37 Examples 2 to 7 Using the same apparatus as in Example 1, a reaction was carried out using the raw materials shown in Table 1 under the conditions shown in Table 1. The same post-treatment as in Example-1 was carried out to obtain the results shown in Table-1.

The obtained product was identified by IR and NMR.

15-

Claims (1)

[Scope of Claims] 1) General formula (D (wherein, R1 and R1 represent a carbon 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 are the same as each other) (X represents a chlorine atom, bromine atom, or iodine atom, and n is an integer of 2 or 3) and a sulfite are heated at room temperature to It includes a step of carrying out at least one constant-temperature reaction in each temperature range from 65°C and 50°C to the reflux temperature of the aqueous solution, and is characterized by raising the temperature and reacting in two or more steps. A method for producing aminoalkylsulfonic acids represented by the general formula (II) (wherein R1, R1, R and n have the same meanings as in the general formula (I)).