JPH0421674A - Production of 2-chloro-5-(aminomethyl)thiazole - Google Patents

Abstract

PURPOSE:To obtain a compound useful as an intermediate for medicines and agricultural chemicals in high yield at a low cost by hydrolyzing a 2-chloro-5- thiazolylmethylhexamethylenetetraammonium chloride with an aqueous solution of a mineral acid in the presence of a lower alcohol. CONSTITUTION:A new compound expressed by formula I is hydrolyzed in the presence of a lower alcohol (e.g. methanol) using an aqueous solution of a mineral acid (e.g. hydrochloric acid) at ambient temperature or under refluxing conditions to afford the objective compound expressed by formula II. Formaldehyde formed as a by-product in hydrolysis is converted into a dialkoxymethane with the lower alcohol, and the resultant dialkoxymethane is distilled away and removed to the outside of the reaction system. The compound expressed by formula I is obtained by reacting a 2-chloro-5-(chloromethyl)thiazole expressed by formula III with hexamethylenetetramine in a solvent such as chloroform.

Description

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

[Conventional technology]

As a method for producing 2-chloro-5-(aminomethyl)thiazole, 2-chloro-5-(chloromethyl)thiazole is reacted with potassium phthalimide in a dimethylformamide solvent, and the resulting N-(2-chloro-5 A method of reacting -thiazolylmethyl)phthalimide with hydrazine is known and is described in European Patent Publication No. 302,389.

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 conducted intensive studies to find a production method that does not have these drawbacks, and as a result, the chloro substituent of the thiazole ring was prepared using inexpensive hexamethylenetetramine as a starting material in an inexpensive organic solvent. Compound (I) can be easily and almost quantitatively produced without undergoing nucleophilic substitution by It was discovered that compound (II) could be produced in high yield, and the present invention was completed.

The reaction formula of the present invention is as follows.

(I[) (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 passed through. If a poorly water-soluble organic solvent is used as the reaction solvent, it can be extracted by adding water or a dilute mineral acid aqueous solution to the slurry solution after the reaction. Compound(
By subjecting the extract containing I) to acid hydrolysis in the presence of a lower alcohol, compound (II) can be obtained in a yield equivalent to that obtained when compound (I) is isolated.

In step (a), sufficiently good results can be obtained by using 1.0 to 1.2 equivalents of compound (IV) per equivalent of compound (■). Can protic organic solvents such as alcohol be used as the organic solvent for the reaction?
Aprotic organic solvents are superior in terms of yield. As aprotic organic solvents, chlorine solvents such as chlorohensen and chloroform, aromatic hydrocarbon solvents such as toluene and xylene, nitrile solvents such as acetonitrile,
Examples include ketone solvents such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, and acetonitrile is preferred in terms of yield.

The reaction temperature varies depending on the solvent used, and the reaction can be carried out from 70°C to reflux. Low-boiling solvents, such as acetone or chloroform, slow the reaction rate. The amount of reaction solvent is 1.0 to 2 per equivalent of compound (III).
．． If the amount of solvent is less than this, the degree of slurry of the precipitated compound (I) will be high and stirring will be difficult. After the reaction is completed, compound (I) can be obtained by cooling the reaction solution and subjecting it to conventional treatments such as washing with a filtrate.

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 (■). or,
Examples of the lower alcohol used in the reaction include methanol, ethanol, propatool, and impropatol. From an industrial perspective, methanol is preferred because it is inexpensive. , 0 equivalents 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 (I), 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. When compound (II) is taken out in the presence of formaldehyde, a reaction occurs between compound (I) and formaldehyde, resulting in a significant decrease in both the purity and yield of compound (II).

After distilling off the dialkoxymethane, the resulting 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 subjected to usual treatments such as concentration. By doing this, the compound (
II) can be obtained.

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

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

Example 1 Compound (I) Hexamethylenetetramine 71.7g (0.51mol
) was added to 700 ml of acetonitrile, and then 78.1 g of 2-chloro-5(chloromethyl)thiazole (0,
465 mol) was added thereto, and the mixture was reacted at 75 to 78° C. for 5 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 melting point of 199-205.
143.1 g of white crystals were obtained at °C (decomposition).

(Yield 99.9%) NMR spectrum (D20) δPPM: 4.55
(2H, S).

4.62-4.84 (6H, m), 5.28 (6H,
s), 7.94 (IH, s) Example 2 Compound (I) Hexamethylenetetramine 4.63 g (33, Ommo
I) was added to 45 ml of chloroform, and then 2-
Chloro-5(riDDmethyl)thiazole 5.29g (3
0,0 mmol) was added thereto, and the mixture was refluxed for 7 hours while stirring. After the reaction, it is cooled to 5°C, the precipitated crystals are filtered, thoroughly washed with chloroform, and dried until the melting point is 1.
7.88 g of pale yellow crystals at 99-205°C (decomposition) were obtained. (Yield 85.3%) Example 3 Compound (1) Hexamethylenetetramine 4.63g (33, Ommo
l) in 45 ml of methyl isobutyl ketone,
2chloro-5-(chloromethyl)thiazole5.
Add 29g (30.0mmol) and stir at 80°.
The reaction was carried out for C4 hours.

After the reaction, the mixture was cooled to 58C, and the precipitated crystals were filtered, thoroughly washed with chloroform, and dried to obtain 7.95 g of cream-colored crystals. (Yield 8G, 0%) Example 4 Compound (I) Hexamethylenetetramine 4.63g (33.0mmol
1) was added to 51 ml of chlorobenzene, followed by 5.29 g of 2-chloro-5(chloromethyl)thiazole (30
, Ommol) was added thereto, and the mixture was reacted at 120°C for 4 hours with stirring. After the reaction, the mixture was cooled to room temperature, and the precipitated crystals were filtered, thoroughly washed with chloroform, and dried to obtain 9.32 g of yellow crystals. (Yield] 00%) Example 6 Compound (I) Hexamethylenetetramine 4.63 g (33,0 mmo
l) into 55 ml of toluene, and then 2-chloro-
5-(chloromethyl)thiazole 5.29g (30,
0 mmol) was added thereto, and the mixture was reacted for 908C hours with stirring. After the reaction, the mixture was cooled to room temperature, and the precipitated crystals were filtered, thoroughly washed with chloroform, and dried to obtain 9.15 g of yellow crystals. (Yield 99.0%) Example 5 Compound (I) obtained in Example 1 143.1 g (0.4
65 mol), 140 ml of water and 169.8 ml of 35% hydrochloric acid
g (1,63 mol) and then methanol 470
ml was added and the mixture was refluxed for 1.5 hours while stirring. The reflux temperature at the beginning of the reaction was 62°C, but after refluxing for 1 hour, it decreased to 50°C, and did not change thereafter.

After the reaction was completed, dimethoxymethane produced as a by-product in the reaction and excess methanol were distilled off until the internal temperature reached 100°C. After cooling to room temperature, 450ml of chloroform was added, and while stirring, 334.8g (2,10ml) of 25% aqueous sodium hydroxide solution was added.
After making the mixture alkaline by adding ol), the mixture was separated. The aqueous layer was extracted again with 450 ml of chloroform, combined with the previous chloroform layer, dried over magnesium sulfate, and concentrated.
．． 5 g of pale yellow liquid was obtained.

Crude yield: 90.5% The obtained pale yellow liquid was subjected to vacuum distillation to 1.5 mmHg.
A fraction of 80.0-80.8°C was obtained.

NMR spectrum (CDCl2) δppm2.18 (
2H,S broad), 4.03(2H,s),
7.36(IH,s)Hexamethylenetetramine13.
3 g (100 mmol I) was added to 170 ml of toluene, then 16.1 g (86.6 mmol) of 2-chloro-5-direct chloromethyl)thiazole was added, and the mixture was dissolved under stirring for 9 hours.
The reaction was carried out at 0°C for 8 hours. After the reaction, it was cooled to room temperature, and 35 ml of water and 35 g of 35% hydrochloric acid (0,335 mol
1) was added to extract compound (I) and the liquid was separated.

77 g of methanol was added to the obtained aqueous layer containing compound (I), and the mixture was refluxed for 1.5 hours while stirring.

After the reaction was completed, dimethoxymethane and excess methanol produced by the reaction were distilled off until the internal temperature reached 100°C.

Then, the mixture was cooled to 50° C., 45 ml of chloroform was added thereto, further cooled to room temperature, and while cooling, 67.5 g (0,422 mol) of 25% caustic soda was added to make it alkaline, followed by liquid separation. Remove the aqueous layer with chloroform again.
It was extracted with 5 ml of water, dried with magnesium sulfate, and concentrated with the chloroform layer obtained earlier to obtain 11.7 g of the target product.
I got l.

〔Effect of the invention〕

Compared to conventional methods, the method for producing compound (I[) according to the present invention allows the desired product to be obtained at low cost and in a good yield under mild conditions, and post-reaction post-treatment is also very easy. Furthermore, it is an advantageous industrial production method because by-products (waste) can be easily treated by incineration or activated sludge treatment.

Furthermore, as is clear from Example 7, without isolating the compound (I) 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 (II) ) can also be easily produced.

Claims (6)

[Claims] 2-chloro-5-thiazolylmethylhexamethylenetetraammonium chloride represented by the formula (1) ▲ includes mathematical formulas, chemical formulas, tables, etc. There are formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (II) that are characterized by hydrolyzing and removing formaldehyde, which is a by-product of the reaction, by distilling it out of the reaction system as dialkoxymethane using a lower alcohol. A method for producing 2-chloro-5-(aminomethyl)thiazole. (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-thiazolylmethylhexamethylenetetraammonium chloride represented by the formula ▲Mathematical formulas, chemical formulas, tables, etc.▼(I). (4) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) 2-chloro-5-(chloromethyl)thiazole and hexamethylenetetramine represented by the formula (CH_2)_6N_4 (IV) A method for producing 2-chloro-5-thiazolylmethylhexamethylenetetraammonium 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 acetonitrile, chlorobenzene, methyl isobutyl ketone, or chloroform.