JPH10310562A - Production of benzylamine salts - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound large in the diameters of its crystals and useful as an intermediate for synthesizing dyestuffs, agrochemicals, medicines, etc., in a high yield and in a high purity by reacting a benzyl bromide with hexamethylenetetramine and subsequently hydrolyzing the obtained ammonium salt in the presence of an acid in an alcohol-water mixture solvent. SOLUTION: This method for producing a benzylamine salt of formula II (M is a counter ion of n-valent benylammonium ion) comprises thermally reacting a benzyl bromide of formula I (R is H, a halogen, trifluoromethyl, etc.) such as benzyl bromide or 2-bromobenyzl bromide with the equivalent amount of hexamethylenetetramine, hydrolyzing the obtained quaternary ammonium salt in the presence of an acid, e.g. an inorganic acid such as hydrochloric acid, nitric acid or sulfuric acid in the water mixture solvent with a low boiling point alcohol such as methanol, ethanol or propanol preferably at 15-50 deg.C, filtering off the generated crystals and subsequently washing the obtained crystals with water or a diluted acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing benzylamine salts. Benzylamine salts are extremely useful substances as synthetic intermediates for dyes, agricultural chemicals, medicines and the like, and as other various industrial chemicals.

[0002]

2. Description of the Related Art Conventional methods for producing benzylamines include, for example, a method of directly aminating a benzyl halide with ammonia (Am. Chem. J., 3 , 24).
6-252 (1881/82)), a method by reduction of benzonitrile (JP-A-7-138209), and a method by reductive amination of benzaldehydes (J. Amer. Chem. Soc., 61 , 3566).
６７3567 (1939)) and a quaternary ammonium salt obtained by reacting benzyl iodide with hexamethylenetetramine in an alcohol with an acid gas, neutralizing with an alkali, and selecting benzylamines by distillation. (J. Amer. Chem. Soc., 6
1 , 3585-3586 (1939)) and the like.

Further, in order to obtain a desired benzylamine salt, it is necessary to neutralize the benzylamine obtained by the above method with a suitable acid.

[0004]

In these methods, for example, in the above method, a large amount of dibenzylamine is produced as a by-product, and the selectivity to benzylamine is low.
Poor yield. In each of the methods (1) and (2), the starting materials are relatively expensive, and since hydrogen is used in the reaction, a special reactor is required, or there is a risk of explosion. In the method of (1), when a starting material is benzyl halide other than expensive benzyl iodide, for example, benzyl chloride or benzyl bromide, the reactivity is poor. The reaction is carried out after conversion to benzyl iodide, which is problematic from an economical point of view as an industrial production method.

In order to obtain a desired benzylamine salt, it is necessary to neutralize the benzylamine obtained by the above-mentioned method with at least equimolar acid in a suitable solvent. The benzylamine salts formed by neutralization with an acid have a problem that the crystal diameter is very small and the burden of the separation and recovery step such as filtration is large.

The present inventors have also proposed that a quaternary ammonium salt obtained from inexpensive nuclear-substituted or unsubstituted benzyl bromide and hexamethylenetetramine is acid-hydrolyzed in an aqueous solvent to obtain a high-purity quaternary ammonium salt. It has been found that benzylamine salts can be produced. However, the benzylamine salts formed at this time become very fine crystals, and these fine crystals are very difficult to perform a normal filtration and separation operation. Since the moisture content of the wet crystal obtained later is high, the drying step requires a long time, and the load on the separation and recovery step is large. In addition, there is a problem that the yield is reduced due to the passage of the target fine crystals into the filtrate. In order to perform efficient filtration and separation of the target substance, aging is further performed for several tens of hours to several days after the reaction,
It is necessary to increase the crystal grain size.

In the production of benzylamine salts by the acid hydrolysis reaction of the quaternary ammonium salt, an excellent production method capable of efficiently obtaining a target substance having a large crystal diameter and good filtration separation efficiency in a short time. Development is desired.

[0008]

SUMMARY OF THE INVENTION In view of the above situation,
The present inventors have conducted intensive studies on a method for producing high-purity benzylamine salts efficiently and with good operability and high yield using inexpensive raw materials. The quaternary ammonium salt obtained from methylenetetramine is subjected to acid hydrolysis in a mixed solvent of alcohol and water, whereby the number of steps in the process is simplified without using any special apparatus, and a high yield is obtained. The inventors have found that high-purity benzylamine salts can be produced with good operability, and that the generated benzylamine salts can be obtained as large particles, which can reduce the burden of the separation and recovery step, and have completed the present invention. .

That is, the present invention provides the following general formula (1)

[0010]

Embedded image Wherein R represents hydrogen, a halogen atom, a trifluoromethyl group or a lower alkyl group. A quaternary ammonium salt obtained by reacting benzyl bromide with hexamethylenetetramine is mixed with an alcohol-water mixed solvent. General formula (2), characterized in that it undergoes acid hydrolysis in

[0011]

Embedded image (Wherein, R represents a hydrogen atom, a halogen atom, a trifluoromethyl group or a lower alkyl group, and M represents a counter ion of a benzylammonium ion having a valence of -n). Is the way.

Hereinafter, the present invention will be described in more detail.

The benzyl bromide used in the method of the present invention is a compound represented by the above general formula (1), and is not particularly limited. For example, benzyl bromide,
2-bromobenzyl bromide, 3-bromobenzyl bromide, 4-bromobenzyl bromide, 2-chlorobenzyl bromide, 3-chlorobenzyl bromide,
4-chlorobenzyl bromide, 2-fluorobenzyl bromide, 3-fluorobenzyl bromide, 4-fluorobenzyl bromide, 4-methylbenzyl bromide, 4-ethylbenzyl bromide, 4-trifluoromethylbenzyl bromide, etc. . In addition, as a lower alkyl group used as R in the said General formula (1), a C1-C4 alkyl group is illustrated as a suitable thing.

The quaternary ammonium salt obtained by reacting benzyl bromide of the general formula (1) with hexamethylenetetramine can be obtained by a general known method. For example, in a solvent generally used as a reaction solvent or in a mixed solvent thereof, benzyl bromide of the general formula (1) and hexamethylenetetramine are mixed in equal amounts and heated to obtain a high yield. it can.

The acid used for the acid hydrolysis reaction of the quaternary ammonium salt may be any of inorganic acids and organic acids, and may be any of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid and hydroiodic acid. Acids are preferred, and acids corresponding to the desired benzylamine salts are preferred because the reaction can be completed in one step. The amount of the acid used is usually required to be equal to or more than 1 atom of nitrogen in the quaternary ammonium salt, but is preferably equivalent to 1.5 times equivalent in consideration of economy.

The alcohol used in the method of the present invention is
Saturated aliphatic alcohols or saturated alicyclic alcohols may be used. For example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, cyclopropanemethanol, cyclobutanol, Examples thereof include cyclopentanol and cyclohexanol. Among these, methanol, ethanol, propanol and the like, which are inexpensive and have a low boiling point, are particularly preferred.

The proportion of water mixed in the alcohol is usually selected from 5 to 90% by weight based on the total amount of the solvent. If the amount is less than 5% by weight, the amount of the target compound dissolved in the solvent is increased, so that the yield is reduced or the rate of the hydrolysis reaction is sometimes reduced, so that it is not practical. If it exceeds 90% by weight, as in the case where only water is used as the reaction solvent, the precipitated benzylamine salts may become very fine crystals, which may make the filtration and separation operation difficult. For example, when concentrated hydrochloric acid is used for acid hydrolysis, water contained in concentrated hydrochloric acid can be used as it is without adding water again.

The most appropriate amount of the alcohol-water mixed solvent used in the present invention is used depending on the solubility of the target compound and the by-produced ammonium salt in the alcohol.
For example, when a methanol-water mixed solvent is used as the solvent, the amount of the solvent is 1 to 1 with respect to the quaternary ammonium salt.
A 10-fold weight is chosen. If the weight is less than 1 weight, the operability is poor because the slurry concentration is high. If the weight exceeds 10 weight, the amount of the target compound dissolved in the solvent increases, and the yield may decrease. In order to further improve operability and yield,
Triple weight is more preferred.

In addition, when an organic solvent other than alcohol is used, the reaction often becomes a complete two-phase system, and the reaction rate is low.

In the acid hydrolysis reaction, the reaction temperature is usually selected from 0 to 80 ° C. Below 0 ° C, the reaction rate is slow,
If the temperature exceeds 80 ° C., side reactions increase and the selectivity decreases.
In order to further improve the reaction rate and selectivity, 15 to
50 ° C. is particularly preferred.

Since the reaction time depends on individual reaction conditions, it is preferable to select a reaction time that meets those conditions.

After completion of the acid hydrolysis reaction, the precipitated crystals are filtered and washed with water or a dilute acid two to three times to obtain
By-product ammonium salts are removed, and high-purity benzylamine salts corresponding to the acid used for hydrolysis are obtained. The characteristics of the benzylamine salts obtained by the method of the present invention are exemplified by the above-mentioned general formula (2), and the crystal shape has a short axis diameter of about 10 to 30 μm and a long axis diameter of about 20 to 150 μm.
m columnar crystal and the purity is 99% or more.

The benzylamine salts obtained by the above method have sufficiently high purity as they are, and can be used as a product without performing any special purification method.
If necessary, purification such as recrystallization may be further performed. If it is necessary to perform acid exchange, further neutralize with alkali,
The formation of the appropriate acid and salt can also provide the desired benzylamine salts.

[0024]

As described above, according to the method of the present invention, benzylamine salts can be obtained in high yield and high purity by using inexpensive benzyl bromide as a raw material among benzyl halides, and the number of operation steps can be reduced. Since the benzylamine salts can be produced and the benzylamine salts are obtained as large solid particles, the burden of the separation and recovery step can be reduced, and the industrial utility value is great.

From the above facts, the method of the present invention is extremely useful for industrially producing benzylamine salts.

[0026]

EXAMPLES The present invention will be described below in detail with reference to examples, but the present invention is not limited to these examples.

Reference Example 1 Production of a quaternary ammonium salt of p-bromobenzyl bromide and hexamethylenetetramine Hexamethylenetetramine was placed in a 1-liter reactor equipped with a stirrer, thermometer, reflux condenser and dropping funnel.
4 g (0.671 mol) of monochlorobenzene containing alcohol is charged, and p-
158 g of bromobenzyl bromide (0.632 mol
l) and a mixed solution of monochlorobenzene with an internal temperature of 60 ° C
For 2 hours, and the reaction was performed for 4 hours.

After the completion of the reaction, the reaction mixture was cooled to room temperature, and the precipitated crystals were filtered, washed with methanol and dried, and 240 g of white crystals of the quaternary ammonium salt (97.3% yield based on p-bromobenzyl bromide). I got

Example 1 Preparation of p-bromobenzylamine hydrochloride 240 g of the quaternary ammonium salt obtained in Reference Example in a 1-liter reactor equipped with a stirrer, thermometer, reflux condenser and dropping funnel ( 0.615 mol) and 356 g (450 ml) of methanol were charged, and 362 g (3.574 mol) of 36% hydrochloric acid was added dropwise from a dropping funnel at room temperature over 30 minutes in a nitrogen stream, and the reaction was carried out at an internal temperature of 40 ° C. for 6 hours. .

After the completion of the reaction, the mixture was cooled to an internal temperature of 5 ° C., and the precipitated crystals were filtered. The wet crystals were returned to the reactor, 346 g of water was added, and the mixture was stirred at an internal temperature of 40 ° C. for 2 hours, cooled to an internal temperature of 10 ° C., and filtered. Further, the same operation was carried out with 4% hydrochloric acid 3 instead of water.
This was carried out using 46 g, and after filtration, washed with 104 ml of acetone. After drying, 104 g (yield 75.9%, purity 99.6%) of white crystals of p-bromobenzylamine hydrochloride were obtained. According to the micrograph (× 400), this crystal was a large columnar crystal having a short axis diameter of about 10 to 30 μm and a long axis diameter of about 20 to 150 μm.

Example 2 The reaction and post-treatment were carried out in the same manner as in Example 1 except that the reaction was carried out at an internal temperature of 40 ° C. for 17.5 hours.
108 g of white crystals of bromobenzylamine hydrochloride (yield 78.9%, purity 99.8%) were obtained. Micrograph (4
According to (00 ×), the crystal had the same size and shape as in Example 1.

Example 3 The reaction solvent was changed to methanol, and 353 g of ethanol (4
The reaction and post-treatment were carried out in the same manner as in Example 2 except for using 50 ml), whereby 71 g of white crystals of p-bromobenzylamine hydrochloride (yield 51.9%, purity 9) were obtained.
9.6%). According to the micrograph (400 times),
The crystal had the same size and shape as in Example 1.

Example 4 Isopropanol 353 was used instead of methanol as the reaction solvent.
The reaction and post-treatment were carried out in the same manner as in Example 2 except that g (450 ml) was used. As a result, 62 g of white crystals of p-bromobenzylamine hydrochloride (yield 45.3%, purity 99.3) were obtained. %). According to the micrograph (× 400), the crystal had the same size and shape as in Example 1.

Example 5 The reaction and post-treatment were carried out in the same manner as in Example 2, except that the reaction solvent was changed to methanol and a mixed solvent of 222 g of water and 180 g of methanol (450 ml of water-methanol) was used. 102 g (yield 74.3%, purity 99.5%) of white crystals of p-bromobenzylamine hydrochloride were obtained. According to the micrograph (× 400), the crystal had the same size and shape as in Example 1.

Example 6 In a 1-liter reactor equipped with a stirrer, thermometer, reflux condenser and dropping funnel, 24 g (0.062 mol) of the quaternary ammonium salt obtained in the same manner as in Reference Example 1,
418 g (529 ml) of methanol was charged, and 36 g of 36% hydrochloric acid (0.357 mol) was added from a dropping funnel in a nitrogen stream.
1) was added dropwise at room temperature over 30 minutes, and the reaction was carried out at an internal temperature of 40 ° C. for 16 hours. The solution after the reaction was concentrated under reduced pressure at 40 ° C. and cooled to −10 ° C., and p-bromobenzylamine having the same size and shape as p-bromobenzylamine hydrochloride obtained in Example 1 was obtained. 8 g of white crystals of hydrochloride
(Yield: 71.0%, purity: 99.5%).

Comparative Example 1 A reaction and a post-treatment were carried out in the same manner as in Example 1 except that 450 g of water was used instead of methanol as a reaction solvent, and white crystals of p-bromobenzylamine hydrochloride were obtained.
g (68.0% yield, 99.8% purity). However, the filtration operation was very difficult because the generated crystals were very small, and it took a long time. Micrograph (400x)
According to this, it was a fine crystal having a particle size of about 1 to 5 μm.

Comparative Example 2 The reaction and post-treatment were carried out in the same manner as in Comparative Example 1 except that the reaction was carried out at an internal temperature of 40 ° C. for 144 hours (6 days), and a white color of p-bromobenzylamine hydrochloride was obtained. 94g crystal
(68.7% yield, 99.5% purity). According to the micrograph (× 400), it was a crystal having a particle size of about 5 to 30 μm.

Reference Example 2 Production of quaternary ammonium salt of benzylpromide and hexamethylenetetramine 16 g of hexamethylenetetramine (0.1 g) was placed in a reactor having a 100 ml internal volume equipped with a stirrer, thermometer, reflux condenser and dropping funnel. 114 mol) and dichloromethane and 17 g of benzyl bromide from a dropping funnel.
(0.1 mol) and a mixed solution of dichloromethane were added dropwise at an internal temperature of 40 ° C. over 2 hours, and the reaction was carried out for 4 hours.

After completion of the reaction, the precipitated crystals were filtered, washed with dichloromethane, and dried to obtain 30 g of the quaternary ammonium salt as white crystals (yield based on benzyl bromide: 97.70 g).
2%).

Reference Example 3 Production of a quaternary ammonium salt of p-chlorobenzyl bromide and hexamethylenetetramine 16 g of hexamethylenetetramine was placed in a reactor having an inner volume of 100 ml equipped with a stirrer, thermometer, reflux condenser and dropping funnel. (0.114 mol) and dichloromethane, and a mixed solution of 21 g (0.1 mol) of p-chlorobenzyl bromide and dichloromethane was dropped from a dropping funnel, and the reaction and post-treatment were performed in the same manner as in Reference Example 2. 34 g of white crystals of a quaternary ammonium salt (97.0% yield based on p-chlorobenzyl bromide) was obtained.

Example 7 Production of benzylamine hydrochloride 30 g (0.4 g) of the quaternary ammonium salt obtained in Reference Example 2 was placed in a 300-ml reactor equipped with a stirrer, thermometer, reflux condenser and dropping funnel. 097 mol) and 45 g (57 ml) of methanol were charged, and 56 g (0.564 mol) of 36% hydrochloric acid was added dropwise from a dropping funnel in a nitrogen stream, and the reaction and post-treatment were carried out in the same manner as in Example 1. 10 g of salt (68.5% yield,
Purity 99.0%). These crystals have the same size as p-bromobenzylamine hydrochloride obtained in Example 1,
It was of a shape.

Example 8 Preparation of p-chlorobenzylamine hydrochloride 34 g of the quaternary ammonium salt obtained in Reference Example 3 was placed in a reactor having an internal volume of 300 ml equipped with a stirrer, thermometer, reflux condenser and dropping funnel. (0.097 mol) and 50 g (63 ml) of methanol were charged, and 56 g (0.564 mol) of 36% hydrochloric acid was added dropwise from a dropping funnel in a nitrogen stream, and the reaction and post-treatment were performed in the same manner as in Example 1. 12 g of p-chlorobenzylamine hydrochloride (yield 7
0.5%, purity 99.3%). The crystals had the same size and shape as the p-bromobenzylamine hydrochloride obtained in Example 1.

Comparative Example 3 In a 1-liter reactor equipped with a stirrer, thermometer, reflux condenser and dropping funnel, 24 g (0.062 mol) of the quaternary ammonium salt obtained in the same manner as in Reference Example 1,
562 g (584 ml) of methanol was charged, and 36 g of 36% hydrochloric acid was added dropwise from a dropping funnel. After reaction and post-treatment as in Example 6, the solution was cooled to -10 ° C, but no crystals were precipitated. Was. The analysis of the reaction mixture revealed that the amount of the contained p-bromobenzylamine hydrochloride was 7.6 g (reaction yield: 66.0%), and isolation and purification of the compound were difficult.

COMPARATIVE EXAMPLE 4 342 g (0.877 mol) of a quaternary ammonium salt obtained in the same manner as in Reference Example 1 in a 1-liter reactor equipped with a stirrer, thermometer, reflux condenser and blowing tube
Together with 343 g (434 ml) of methanol,
When hydrochloric acid gas was blown in from the blowing pipe at an internal temperature of 40 ° C., a white precipitate supposed to be p-bromobenzylamine hydrochloride was remarkably adhered to the vicinity of the blowing pipe and clogged with the progress of the reaction. It was difficult to continue the reaction.

[Brief description of the drawings]

FIG. 1 is a micrograph (× 400) showing a particle structure of a crystal obtained in Example 1.

FIG. 2 is a micrograph (× 400) showing a particle structure of a crystal obtained in Example 3.

FIG. 3 is a micrograph (× 400) showing a particle structure of a crystal obtained in Comparative Example 1.

FIG. 4 is a micrograph (× 400) showing a particle structure of a crystal obtained in Comparative Example 2.

Claims (5)

[Claims] [Claim 1] The following general formula (1) Wherein R represents hydrogen, a halogen atom, a trifluoromethyl group or a lower alkyl group. A quaternary ammonium salt obtained by reacting benzyl bromide with hexamethylenetetramine is mixed with an alcohol-water mixed solvent. Wherein the compound is subjected to acid hydrolysis in the following general formula (2): (Wherein, R represents a hydrogen atom, a halogen atom, a trifluoromethyl group or a lower alkyl group, and M represents a counter ion of a benzylammonium ion having a valence of -n). Method. 2. The method for producing benzylamine salts according to claim 1, wherein the alcohol is at least one selected from the group consisting of a saturated aliphatic alcohol and a saturated alicyclic alcohol. 3. The method for producing a benzylamine salt according to claim 1, wherein the acid is an inorganic acid. 4. The process for producing benzylamine salts according to claim 1, wherein the acid hydrolysis is carried out at a reaction temperature of 0 to 80 ° C. 5. The following general formula (2): Wherein R represents hydrogen, a halogen atom, a trifluoromethyl group or a lower alkyl group, and M represents a counter ion of a benzylammonium ion having a valence of -n. Shaft diameter about 10-30 μm, long shaft diameter about 2
Benzylamine salts, which are columnar crystals of 0 to 150 μm and have a purity of 99% or more.