JPS63425B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing chloroalkylamine hydrochlorides. Chloroalkylamine hydrochlorides are extremely useful substances as aminoalkylating agents, intermediates for agricultural and pharmaceutical products, dyes and pigments, and various other industrial chemicals, and raw materials for polymeric compounds. Known methods for producing this chloroalkylamine hydrochloride include the following methods. (a) A method in which hydrogen chloride gas is directly blown into alkanolamine in the presence of a solvent such as chloroform to form the alkanolamine hydrochloride, and then thionyl chloride is added to carry out the chlorination reaction (Journal of American Chemical Society (J.
Am.Chem.Soc.) 63 , 3124-6 (1941)). (b) A method in which hydrogen chloride gas is directly blown into alkanolamine to carry out a chlorination reaction in one step at a high temperature of 160°C (Chemical Abstract (Chem.
Abst.) 52 , 10867 ⁿ (1958)). (c) A method in which a 40 to 80% by weight aqueous solution of an alkanolamine is reacted with enough hydrogen chloride and a small amount of sulfuric acid to have a concentration of 40 to 70% by weight as hydrochloric acid at 150 to 180°C under a pressure of 40 atmospheres ( Ger.1,
110, 167). However, among these methods, method (a) requires the use of thionyl chloride, which is expensive and difficult to handle, as a chlorinating agent;
It also has many disadvantages, such as the generation of harmful sulfur dioxide gas as a by-product, which requires treatment. In addition, in the case of methods (b) and (c) that do not use thionyl chloride, the chlorination reaction must be carried out at high temperature and pressure, and there are problems with the equipment material for industrial implementation. However, it had the disadvantage of causing thermal decomposition of raw materials and target materials. The present inventors conducted extensive research on a method for producing chloroalkylamine hydrochlorides that does not use thionyl chloride and does not require high temperature and high pressure conditions. The chlorination reaction can proceed to a considerable extent even under relatively mild conditions, and if the chlorination reaction is allowed to proceed at a certain rate or more, the resulting crude chloroalkylamine hydrochloride can be recycled using an organic solvent. The present invention was completed by discovering that a highly pure product (purity of 98% by weight or more) can be easily obtained by crystallization. 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, n means an integer of 2 to 4. In this case, each carbon R ³ and R ⁴ attached to atoms may be the same or different) are chlorinated to form the general formula () (In the formula, R ¹ , R ² , R ³ , R ⁴ and n are general formulas ()
In the method for producing chloroalkylamine hydrochlorides ^represented by Performing the chlorination reaction at a reaction temperature of 100 to 140°C until the conversion rate to the above chloroalkylamine hydrochloride reaches at least 75%, and recrystallizing the obtained crude chloroalkylamine hydrochloride with an organic solvent. The present invention provides a method for producing high-purity chloroalkylamine hydrochlorides characterized by the following. Hereinafter, the constituent elements of the present invention will be divided and explained in detail. It is believed that the chlorination reaction of alkanolamines with hydrogen chloride in the present invention is carried out sequentially according to the following formula. In other words, overall, (In the above formulas (), ()′, (), 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. Moreover, n means an integer of 2 to 4. (At this time, R ³ and R ⁴ attached to each carbon atom may be the same or different.) The first reaction (1) in which alkanolamines () produce their hydrochloride ()' is a neutralization reaction. However, the subsequent reaction (2) in which further chlorinated chloroalkylamine hydrochlorides (2) are produced is slow and rate-limiting. The alkanolamines used as reaction raw materials in the present invention are compounds represented by the general formula () in the above formula (3), such as 2-aminoethanol, 2-dimethylaminoethanol, 2-ethylamino-propanol, 1
-Methyl-2-aminoethanol, 1-ethyl-
2-methyl-2-aminoethanol, 1,1-dimethyl-2-methyl-2-aminoethanol,
1,1,2,2-tetramethyl-2-dimethylaminoethanol, 3-amino-1-propanol, 3-dimethylaminopropanol, 2-amino-1-methyl-1-propanol, 1-amino-2-propanol , 3-dimethylamino-1.
1,2,2-tetramethyl-1-propanol,
Examples include 4-amino-1-butanol and 3-dimethylamino-1-methyl-1-butanol. In addition, the chloroalkylamine hydrochlorides obtained by the present invention are compounds represented by the general formula () in the above formula (3), such as 2-chloroethylamine hydrochloride, 2-dimethylaminoethyl chloride hydrochloride, 2-ethylamino -1-propyl chloride hydrochloride, 1-methyl-2-aminoethyl chloride hydrochloride, 1-ethyl-2-methyl-2-aminoethyl chloride hydrochloride, 1,1-dimethyl-
2-Methyl-2-aminoethyl chloride hydrochloride, 1,1,2,2-tetramethyl-2-dimethylaminoethyl chloride hydrochloride, 3-amino-
1-Propyl chloride hydrochloride, 3-dimethylamino-1-propyl chloride hydrochloride, 2-amino-1-methyl-1-propyl chloride hydrochloride, 1-amino-2-propyl chloride hydrochloride, 3-dimethylamino- 1,1,2,2-tetramethyl-1-propyl chloride hydrochloride, 4-
Examples include amino-1-butyl chloride hydrochloride and 3-dimethylamino-1-methyl-1-butyl chloride hydrochloride. The aqueous hydrochloric acid solution used as a chlorinating agent in the present invention may be produced by any method such as a synthetic method, a by-product hydrochloric acid method, or a salt decomposition method, and commercially available concentrated hydrochloric acid or industrial concentrated hydrochloric acid is sufficient. Alternatively, hydrogen chloride gas may be blown into a solution of the above alkanolamines in water or dilute hydrochloric acid to adjust the concentration to a predetermined concentration. In the present invention, the above-mentioned aqueous hydrochloric acid solution as a chlorinating agent is used at a concentration of 30 to 70% by weight, and 20Kg/cm ²
The chlorination reaction is carried out at a reaction temperature of 100 to 140° C. under pressure of G or less. If the concentration of this aqueous hydrochloric acid solution is less than 30% by weight, the reaction rate will be slow and the chlorination reaction will not only take a very long time, but also the rate at which the reaction will reach equilibrium will be low, making it impossible to carry out the desired recrystallization operation. Since the conversion rate of 75% required to obtain certain crude chloroalkylamine hydrochlorides is not substantially reached, separation and purification of the target product becomes difficult. In other words, according to the inventors' studies, when recrystallizing crude chloroalkylamine hydrochlorides in an organic solvent to produce a product with a purity of 98% or higher, which is necessary as an intermediate for various industrial chemicals such as pharmaceuticals, recrystallization is necessary. Unless the purity of the crude chloroalkylamine hydrochloride itself before crystallization is already above a certain value, surprisingly, the purity hardly improves no matter how many times the recrystallization operation is performed. Although the exact reason for this is unknown, a mixture mainly consisting of unreacted alkanolamine hydrochloride as an impurity component and chloroalkylamine hydrochloride have similar structural formulas and are resistant to recrystallization solvents. It is thought that this behavior is exhibited because the selectivities are very similar. Therefore, the present inventors found that the critical purity that allows recrystallization is
As a result of extensive research, we found that this value corresponds to a conversion rate of 75%, and completed the present invention. on the other hand,
If the concentration of the hydrochloric acid aqueous solution exceeds 37% by weight, not only will it be necessary to use a large amount of hydrogen chloride gas, but also the concentration of 37% by weight will not only be required when taking out the target product after the reaction.
The above amount of hydrogen chloride must be discharged and recovered as dilute hydrochloric acid, which is industrially disadvantageous in terms of equipment and hydrochloric acid balance. Therefore, in the reaction of the present invention, as shown in formula (3), 1 mole of chloroalkylamine hydrochloride is produced, 1 mole of water is also produced, and 2 moles of hydrogen chloride are consumed, so the reaction system The concentration of hydrochloric acid in the reactor gradually decreases as the reaction progresses. Therefore, at least in the latter half of the chlorination reaction, hydrogen chloride gas is introduced into the reaction system and absorbed,
In a preferred embodiment, the concentration of hydrochloric acid in the system is maintained at 30% by weight or more. In addition, since concentrated hydrochloric acid is used as the chlorinating agent in the present invention, glass-lined reactors are commonly used as the reactor material, so the pressure is 20 Kg/cm ²
It is desirable to apply pressure of G or less. If this value is exceeded, it will be difficult to ensure the airtightness of the reactor, which will impede long-term operation. The reaction temperature in the present invention is 100 to 140°C.
At temperatures below 100°C, the reaction rate is very slow and it takes a long time to complete the reaction, making it impractical. Furthermore, when the reaction temperature exceeds 140°C, the reaction rate increases and the reaction time is shortened, which is advantageous.
This is not preferable because the coloring of the system becomes extremely large and thermal decomposition causes a decrease in the yield and purity of the target product. The amount of the hydrochloric acid aqueous solution used in the method of the present invention is such that the equilibrium attainment rate is adjusted to the conversion rate of 75 as described above.
% or more, alkanolamines 1
At least 3 moles of hydrochloric acid are required per mole. The reaction operation is carried out as follows. First, a neutralization reaction is carried out according to equation (1), but the procedure differs slightly depending on the method of contacting the alkanolamines with concentrated hydrochloric acid. In other words, when 1 mole of alkanolamines is added to 3 times the mole of concentrated hydrochloric acid (36wt%), a rapid temperature rise occurs due to the neutralization reaction (heat generation), so the addition rate is adjusted to prevent this. While doing so, gradually raise the temperature. On the other hand, when concentrated hydrochloric acid is added to alkanolamines, it is carried out while cooling and suppressing temperature rise until the neutralization reaction is completed and no heat is generated. After the neutralization reaction is completed in this way, the temperature is raised to any temperature between 100 and 140℃,
Carry out the chlorination reaction for 10-60 hours. The reaction time is automatically determined by the reaction temperature employed. As the reaction progresses, the concentration of hydrochloric acid in the system gradually decreases, so when the pressure drops to 2 Kg/cm ² G, hydrogen chloride gas is introduced and absorbed to return the pressure to the initial level, allowing the remaining reaction to proceed. The reaction may be carried out batchwise or continuously. In the case of a batch method, the time required to introduce hydrogen chloride gas will vary depending on the temperature used, but if hydrogen chloride gas is introduced continuously from the beginning to maintain a constant pressure during the reaction, the chlorination reaction will proceed. It will be even more advantageous. In the present invention, the conversion rate (%) is defined as follows based on formula (3). Conversion rate = Number of moles of chloroalkylamine hydrochloride produced/Number of moles of charged alkanolamine x 100 When the conversion rate reaches at least 75%, preferably 85%, the chlorination reaction is terminated, and the thus obtained water and hydrogen chloride from the reaction mixture at 100 mmHg.
By distilling off almost the entire amount at 100℃ or less under the following reduced pressure and concentrating to dryness, crude chloroalkylamine hydrochloride containing unreacted alkanolamine hydrochloride and by-products (its purity is determined by the conversion rate shown above)
(almost 80% or more) compared to 75% or more. Note that if water and hydrogen chloride remain in the crude chloroalkylamine hydrochloride that has been concentrated to dryness, they will be mixed into the recrystallization solvent and accumulate, so purification will be required when the solvent is reused. During solidification, it is desirable that substantially no water or hydrogen chloride remain. In order to convert the crude chloroalkylamine hydrochloride obtained as described above into purified chloroalkylamine hydrochloride having a purity of 98% or more, the following recrystallization operation is performed. Solvents used in the recrystallization operation include polar solvents such as inorganic ones such as water, alcohols such as methanol and ethanol, esters such as ethyl acetate and isobutyl acetate, formamide, and N/N.
- Acid amides such as dimethyl formamide and acetamide, and organic solvents such as dimethyl sulfoxide can be used, but organic solvents are more preferable, and alcohols are particularly preferable because of their high solubility. Most preferred are methanol, ethanol and 2-propanol. First, an appropriate amount of the above-mentioned solvent is added to the above-mentioned crude aminochloroalkylamine hydrochloride to be treated, and then heated and heated to dissolve while stirring sufficiently to form a uniform solution. The amount of solvent to be added can be selected by considering the solubility of the solvent used, but usually it is added to 100 parts by weight of crude chloroalkylamine hydrochloride.
It ranges from 10 to 200 parts by weight. For example, in the case of methanol, add 20 to 60 parts by weight. The heating temperature at this time may be any temperature, but since solubility increases with temperature, it is desirable to increase the dissolution temperature by reducing the amount of solvent added in order to perform crystallization in a good yield. Therefore, for example, in the case of methanol, it is preferable to raise the temperature to its boiling point and dissolve it. Then, chloroalkylamine hydrochlorides are crystallized from the homogeneous solution. Any conventional method such as a solvent removal method or a cooling method may be used for this crystallization method, but cooling crystallization is preferable from the solubility curve of chloroalkylamine hydrochlorides. Although the cooling temperature is not particularly limited, it is preferably cooled to 20°C or lower, more preferably 10°C or lower for crystallization. The crystallized purified chloroalkylamine hydrochloride 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-mentioned chloroalkylamine hydrochlorides contains a considerable amount of crude chloroalkylamine hydrochlorides and some unreacted alkanolamine hydrochlorides. Although the product is dissolved, the crude product is recovered from the mother liquor and recycled to the chlorination step to recover the chloroalkylamine hydrochloride, or the unreacted amine hydrochloride can be repeatedly reacted. Finally, in effect,
The target product, purified chloroalkylamine hydrochloride, can be obtained almost quantitatively. Note that when circulating this crude product to the chlorination process, if the recrystallization solvent is entrained, impurities may form and accumulate, so the solvent should be removed by means such as vacuum drying before the circulation operation. It is preferable to do so. Hereinafter, embodiments of the present invention will be specifically illustrated and explained using Examples, but these Examples are merely illustrative and do not exceed the technical scope of the present invention (Article 70 of the Patent Law).
is not limited to these in any way. Example 1 Equipped with a stirrer, temperature control means, and pressure control means
36.7% by weight in a 500c.c. glass autoclave
of concentrated hydrochloric acid (2.37 moles as hydrogen chloride) and 2
- 30.5 g (0.5 mol) of aminoethanol was charged and the temperature was gradually raised to continue the reaction at 120°C for 24 hours. During this time, the pressure increased from 6.0Kg/cm ² G to 3Kg/cm ² G.
(Hydrochloric acid concentration 23.6% by weight). After the reaction was completed, the contents were cooled, taken out, and heated to 80°C under a reduced pressure of 30mmHg.
Concentrate to dryness at °C for 2 hours to obtain 56.0 g of crude product (purity 81.0% by weight as 2-chloroethylamine hydrochloride).
(i.e., conversion rate of 78.2%). Methanol was added at a ratio of 40 parts by weight to 100 parts by weight of this crude product, heated to the boiling point of methanol while stirring to completely dissolve it, and then cooled to 5°C to precipitate crystals. Suction the precipitated crystals,
It was dried at 60° C. for 2 hours under a reduced pressure of 30 mmHg to obtain 40 parts by weight of pure white crystals (purity 98.2%). Example 2 In the same manner as in Example 1, 36.7% by weight concentrated hydrochloric acid
2-aminoethanol in advance to 200 c.c. (2.37 mol)
A cooled mixture of 30.5 g (0.5 mol) was charged into a similar reactor, and the temperature was gradually raised to continue the reaction at 130°C. The initial pressure was 7 kg/cm ² G, but after 5 hours it had dropped to 4 kg/cm ² G, so hydrogen chloride gas was introduced and the reaction was continued for another 10 hours while maintaining the internal pressure at 7 kg/cm ² G. I went. After the reaction is complete, cool it down, take out the contents, concentrate to dryness under reduced pressure, and obtain the crude product.
57.6g was obtained. The purity of this product was measured and was 95.3% by weight as 2-chloroethylamine hydrochloride.
(i.e. conversion rate 94.5%). Ethanol was added at a ratio of 60 parts by weight to 100 parts by weight of this crude product, heated to 78°C with thorough stirring to safely dissolve it, and then cooled to 5°C to precipitate crystals. The precipitated crystals were filtered under suction, and the obtained crystals were dried under reduced pressure at 60° C. for 2 hours to obtain 62 parts by weight of pure white crystals (purity 99.4%). Example 3 Table 1 shows the results of chlorination reactions of various alkanolamines carried out in the same manner as in Example 1.

【table】

[Table] Examples 4 to 10 The recrystallized liquid separated in Example 1 was concentrated to dryness. 13.6 g of the obtained crude product was charged into the same reactor together with 30.5 g (0.5 mol) of fresh 2-aminoethanol, and the synthesis and recrystallization of 2-chloroethylamine hydrochloride were carried out in the same manner as in Example 1. The same method was repeated eight times, and the results are shown in Table 2.

[Table] Crude crystal weight comparison examples 1 to 2 In the same manner as in Example 1, 36.0% concentrated hydrochloric acid 200
cc (2.37 mol) in advance with 2-aminoethanol 30.5
g (0.5 mol) was cooled and mixed and charged into a similar reactor, and the temperature was gradually raised to continue the reaction at 120°C. Table 3 shows the purity and conversion rate of the crude product obtained with various reaction times and the purity and yield of the crystal obtained by recrystallizing the crude product with methanol.

[Table] Recrystallization weight * Yield =

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, n means an integer of 2 to 4. In this case, each R ³ and R ⁴ attached to the carbon atom may be the same or different) are chlorinated to form the general formula () (In the formula, R ¹ , R ² , R ³ , R ⁴ and n are general formulas ()
In the method for producing chloroalkylamine hydrochlorides ^represented by (having the same meaning as in the case of Performing the chlorination reaction at a reaction temperature of 100 to 140°C until the conversion rate to the above chloroalkylamine hydrochloride reaches at least 75%, and recrystallizing the obtained crude chloroalkylamine hydrochloride in an organic solvent. A method for producing high-purity chloroalkylamine hydrochlorides, characterized by: 2. In the method described in claim 1,
High purity, characterized in that in the latter half of the chlorination reaction, hydrogen chloride gas is introduced and absorbed into the reaction system to maintain the concentration of the hydrochloric acid aqueous solution in the reaction system at a concentration of at least 30% by weight or more. A method for producing chloroalkylamine hydrochlorides. 3. In the method according to claim 1 or 2, a reaction mixture having a conversion rate of 75 mol % or more to chloroalkylamine hydrochloride is obtained, and after removing hydrogen chloride and water from the mixture, A method for producing high-purity chloroalkylamine hydrochlorides, which comprises recrystallizing the obtained crude chloroalkylamine hydrochlorides in an organic solvent. 4. In the method according to any one of claims 1, 2, or 3, the crude product dissolved in the recrystallization mother liquor after crystallizing and separating the chloroalkylamine hydrochloride is A method for producing high-purity chloroalkylamine hydrochlorides, which comprises recovering and recycling the crude product to the chlorination step.