JPH03271273A - Production of 2-chloro-5-(aminomethyl)pyridine - Google Patents

Abstract

PURPOSE:To obtain a compound useful as an intermediate of drug or agricultural chemical at a low cost and in high yield by hydrolyzing 2-chloro-5- pyridylmethyl hexamethylenetetraammonium chloride with an aqueous solution of mineral acid in the presence of a lower alcohol. CONSTITUTION:A new compound expressed by formula I is hydrolyzed with mineral acid (e.g. hydrochloric acid) in a water solvent in the presence of methanol, etc., at room temperature under reflux to afford the aimed compound expressed by formula II. The compound expressed by formula I is obtained by reaction of 2-chloro-5-(chloromethyl)pyridine and hexamethylenetetramine in a solvent such as chlorobenzene. The aimed substance is obtainable under a modest condition at a low cost and after-treatment of the reaction is extremely ready and further treatment of by-product is readily performed by burnout or using activated sludge.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a novel method for producing 2-chloro-5-(aminomethyl)pyridine.
-(Aminomethyl)pyridine is a compound useful as an intermediate for pharmaceuticals and agricultural chemicals.

[Prior Art] As a method for producing 2-chloro-5-(agotsumethyl)pyridine, 2-chloro-5-(chloromethyl)pyridine is reacted with potassium phthalimide in a dimethylformamide solvent, and the resulting N- A method of reacting (2-chloro-5-pyridylmethyl)phthalimide with hydrazine is known and is described in German Published Patent Application No. 3727126.

However, these conventional methods require relatively expensive potash phthalimide as a raw material, and it is costly to recover relatively expensive anhydrous dimethylformamide, so it cannot be said to be an economically preferable method. Furthermore, post-treatment operations during hydrazine decomposition are complicated, and disposal of a large amount of hydrazide produced as a by-product also poses a major industrial problem.

[Means to solve the problem]

The inventors of the present invention have made intensive studies to find a production method that does not have these drawbacks, and as a result, the chloro substituent of the pyridine ring was prepared using inexpensive hexamethylenetetrayone as a starting material in an inexpensive organic solvent. Compound (1) can be easily and almost quantitatively produced without being subjected to nucleophilic substitution by hexamine, and furthermore, by hydrolyzing compound (1) with an aqueous mineral acid solution in the presence of an inexpensive lower alcohol, it can be easily and almost quantitatively produced. The present invention was completed by discovering that compound (It) can be produced in a good yield.

The reaction formula of the present invention is as follows.

(I) (II) (Dialkoxymethane) (In the formula, R represents a lower alkyl group.) Compound (1) obtained in step (a) is a new compound, and the slurry solution after the reaction is ii! Easy to meet! I
However, if a poorly water-soluble or organic solvent is used as the reaction solvent, it is also possible to add water or a dilute mineral acid aqueous solution to the slurry solution after the reaction for extraction, and the resulting compound (r ) can be acid-hydrolyzed in the presence of a lower alcohol to obtain compound (U) in the same yield as when compound (1) is isolated.

In step (a), compound (IV) is converted into compound (III)
Sufficiently good results can be obtained by using 0.1 to 1.2 equivalents per equivalent of ). As the organic solvent used in the reaction, protic organic solvents such as alcohol can also be used, but aprotic organic solvents are superior in terms of yield. Examples of aprotic organic solvents include chlorine-based solvents such as chlorobenzene and chloroform, aromatic hydrocarbon-based solvents such as toluene and xylene, ketone-based organic solvents such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, or nitrile-based organic solvents such as acetonitrile. Among them, chlorobenzene and methyl isobutyl ketone are particularly excellent industrially because they have a fast reaction rate, are inexpensive, and can be easily post-treated.

The reaction temperature varies depending on the solvent used, but when chlorobenzene or methyl isobutyl ketone is used, it is preferably 70°C or higher, and the reaction is usually carried out at 100°C or higher under reflux, and the lower the reaction temperature, the slower the reaction rate. Become.

The amount of reaction solvent is 1.0 per equivalent of compound (II[)
~2.01 is used, and if the amount of solvent is less than this, the slurry degree of precipitated compound (1) will be high and stirring will be difficult. After the reaction is completed, the reaction solution is cooled and subjected to usual treatments such as filtration and washing with chloroform to obtain compound N).
can be obtained.

In the acid hydrolysis in step (b), the mineral acid used may be hydrochloric acid or sulfuric acid, and may be used in an amount of 3.0 to 4.0 equivalents per equivalent of compound (I). In addition, examples of the lower alcohol used in the reaction include methanol, ethanol, propatool, isopropatool, etc., but industrially, inexpensive methanol is preferable, and 12.0 to 36 methanol is used per equivalent of compound (1). .0 equivalent may be used. The reaction is carried out at room temperature to reflux, and after the reaction is complete, the dialkoxymethane produced by formaldehyde, a by-product of hydrolysis of compound (1), and the lower alcohol added to the reaction system is distilled out of the reaction system. By doing so, formaldehyde produced as a by-product during hydrolysis can be easily removed. Compound (It) in the presence of formaldehyde
), a reaction occurs between compound (1) and formaldehyde, resulting in a significant decrease in both the purity and yield of compound (II).

After distilling off the dialkoxymethane, the obtained aqueous solution containing the mineral acid salt of compound (II) is made alkaline with caustic alkali, extracted with a poorly water-soluble solvent such as chloroform, and concentrated, etc., using normal treatments. By doing this, the compound (
n) can be obtained.

By-products in the method for producing compound ([) according to the present invention are dialkoxymethane and aqueous ammonia, which can be easily treated industrially by incineration or activated sludge, respectively.

(Examples) The examples shown below illustrate the present invention, and include:
It is not limited to this in any way.

Example 1 3.36 g (24rm
tno I! ) was added to 20d of chloroform, then 3.24 d of 2-chloro-5=(chloromethyl)pyridine
g (20 mmol 1 ) was added thereto and the mixture was refluxed for 8 hours while stirring. After the reaction, it is cooled to room temperature, the released crystals are filtered, washed well with chloroform, and dried to give a melting point of 19.
4.94 g of white crystals at 8-200°C (decomposition) were obtained. Yield 81.7% NMR spectrum (D, O) δP
PM: 4.27 (2H, S).

4.54-4.78 (6H, m), 5.19 (68,
S) 7.69-8.53 (3H, m) Example 2 Compound (I) Hexamethylenetetramine 3.56 g (22 mmo
41! ) was added to 40al of toluene, and then 2-
3.24 g of chloro-5-(chloromethyl)pyridine
(20 mmol) was added thereto, and the mixture was refluxed for 8 hours while stirring. After the reaction, it is cooled to room temperature, the precipitated crystals are filtered, washed well with chloroborm, and dried to give a melting point of 198~
5.73 g of white crystals of 200"C (decomposition) were obtained. Yield 94.8% Example 3 Compound (I) Hexamethylenetetramine 3.40 g (21 mmo
1. ) in methyl isobutyl ketone 4oIIl, then 2chloro-5-(chloromethyl)pyridine 3
．． 24g (2On+n+o 41!) was added and reacted at 100°C for 4 hours with stirring.

After the reaction, it is cooled to room temperature, the precipitated crystals are filtered, thoroughly washed with chloroform, and dried to give a solution with a melting point of 198-200.
5.85 g of white crystals were obtained at °C (decomposition).

Yield 96.8% Example 4 Compound (1) Hexamethylenetetramine 7.36 g (52.5 m
mo 1 ) and acetone trile 75d, then 8.10 g of 2-chloro-5(chloromethyl)pyridine
(50 mmol) was added and refluxed for 8 minutes while stirring. After the reaction, it is cooled to room temperature, the precipitated crystals are filtered, thoroughly washed with chloroform, and dried to give a melting point of 198.
14.87 g of white crystals of ˜200″C (decomposition) were obtained.

Yield 95.4% Example 5 Compound (N hexamethylenetetraton 73.6g (0,525m
Molsu chlorobenzene 750 #l! In addition to 2-chloro-5-(suolomethyl)hi! Add 81.0g (0.5mmoA) of J Syn
The reaction was carried out at 20"C for 5 hours.

At this time, the reaction situation was analyzed by high performance liquid chromatography, and it was found that 98.2% of 2-chloro-5-(chloromethyl)pyridine had reacted.

After the reaction, it is cooled to room temperature, the precipitated crystals are filtered, thoroughly washed with chloroform, and dried to obtain a crystal with a melting point of 198-200.
146.5 g of white crystals at ℃ (decomposition) were obtained.

Yield 97.0% Example 6 cpψC8! NH2 compound (II) Compound (1) obtained in Example 5 30.22 g (0.1 m
30-mol of water and 36.5 g of 35% hydrochloric acid (
0.35 nuwof) was added, then methanol 76
．． 8 g (2.4 mmo 41!) was added and refluxed for 1.5 hours while stirring. The reaction temperature at the beginning of the reaction was 63°C.
However, after 1 hour of reflux, the temperature decreased to 50.5°C.
After that it stopped changing.

After the reaction was completed, dimethoxymethane by-produced in the reaction and excess methanol were distilled off until the internal temperature reached 100°C. It was then cooled to 50"C, 50d of chloroform was added, further cooled to room temperature, and 72% of a 25% caustic soda aqueous solution was added with stirring.
．． After making the mixture alkaline by adding 0 g (0.45 m+*ol), the mixture was separated. Add 50% chloroform to the aqueous layer again.
d, combined with the previous chloroform layer, dried over magnesium sulfate, and concentrated to yield 13.64 g of slightly yellow oil.
(Solidified upon cooling) was obtained.

The obtained crude oil was subjected to vacuum distillation to give a concentration of 1 ++ uaHg.
12.96 g of a 92.5-94.5°C fraction (solidified on cooling, 125-26°C) was obtained. Yield: 90.
9% NMR spectrum (CDCl3) δppm: 1.4
9(2H,S broad), 3.90(2H,S broad)
).

7.29-8.34 (3H, +*) Example 7 CbeBC82NH2 compound (If) Compound (1) obtained in Example 5 30.22g (0,1
mn+offi) to 30 rall of water and 35% hydrochloric acid
6.5 g (0.35 mmo j2 ) was added, followed by 57.6 g (1.8 mmo+) of methanol, and the mixture was refluxed for 1.5 hours with stirring. After completion of the reaction, dimethoxymethane produced as a by-product in the reaction and excess methanol were distilled off through a rectification column (glass Raschig ring packed column: height 20 ai) until the internal temperature reached 100°C.

Then, it was cooled to room temperature, and 72.0 g of caustic soda (0,4
5a+mo 1. ) was added to make the mixture alkaline, and the mixture was extracted with chloroform.

The obtained chloroform solution was dried with magnesium sulfate and concentrated, and the objective #! 13.93 g of yjoi+ (solidified upon cooling) was obtained. Yield 97.7% Example 8 cgψGHzNFlz Compound (II
) Hexamethylenetetramine 44.2 g (0,31
5 mmol) was added to 450 mmol of chlorobenzene, and then 48.6 mmol of 2-chloro5-(chloromethyl)pyridine was added to 450 mmol of chlorobenzene.
g (0.3 mmol) and 12
The reaction was carried out at 0'C for 6 hours.

After the reaction, cool to room temperature, add 90d of water and 109d of 35% hydrochloric acid.
．． Add 5g (1,05mmol) of compound (1
) was extracted and separated.

230% methanol was added to the aqueous layer containing the obtained compound (I).
4 g (7,2n+mof) was added, and the mixture was refluxed for 1.5 hours while stirring.

After completion of the reaction, dimethoxymethane and excess methanol produced by the reaction were distilled off until the internal temperature reached 100°C, then cooled to 50°C, added 100d of chloroform, further cooled to room temperature, and cooled. While stirring, 216.0 g (1.35 mn+ol) of 25% caustic soda was added to make the mixture alkaline, and then the mixture was separated. The aqueous layer was extracted again with 100 idt of chloroform, combined with the chloroform layer obtained earlier, dried over magnesium sulfate, and concentrated, yielding 41.22 g.
The target oil was obtained. (It solidified when cooled.) Yield: 96.4% [Effects of the Invention] The method for producing compound (II) according to the present invention achieves the desired product at a low cost and in a good yield under mild conditions compared to conventional methods. In addition, post-treatment of the reaction is very easy, and by-products (
It is an advantageous industrial manufacturing method, as waste materials can also be easily treated by incineration or activated sludge.

Furthermore, as is clear from the reference examples, without isolating the compound (1) produced by the production method of the present invention, it can be hydrolyzed in the next step by an easy operation such as extraction, and the compound (
n) can also be easily produced.

Claims (6)

[Claims] (1) 2-chloro-5-pyridylmethylhexamethylenetetraammonium chloride, represented by the formula ▲Mathematical formulas, chemical formulas, tables, etc.▼(I), is hydrolyzed with mineral acid in an aqueous solvent in the presence of a lower alcohol. The method is characterized in that formaldehyde, which is produced as a by-product in the reaction, is removed by distillation out of the reaction system as dialkoxymethane with a lower alcohol. A method for producing 2-chloro-5-(aminomethyl)pyridine represented by the formula ▲Mathematical formulas, chemical formulas, tables, etc.▼(II). (2) The manufacturing method according to claim 1, wherein the lower alcohol is methanol and the mineral acid is hydrochloric acid. (3) 2-chloro-5-pyridylmethylhexamethylenetetraammonium chloride represented by the formula ▲Mathematical formulas, chemical formulas, tables, etc.▼(I). (4) 2-chloro-5-(chloromethyl)pyridine represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) and mexamethylenetetramine represented by the formula (CH_2)_6N_4 (IV) A method for producing 2-chloro-5-pyridylmethylhexamethylenetetraammonium chloride represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I), which is characterized by reacting in an organic solvent. (5) The manufacturing method according to claim 4, wherein the organic solvent is an aprotic organic solvent. (6) The manufacturing method according to claim 4, wherein the organic solvent is chlorobenzene or methyl isobutyl ketone.