JPH05125065A - Production of thiazolecarboxylic acid chlorides - Google Patents

Abstract

PURPOSE:To suppress formation of by-products and readily obtain the subject compounds useful as a raw material for medicines, agricultural chemicals, etc., in high purity and yield within a short time by reacting thiazolecarboxylic acids with triphosgene. CONSTITUTION:A compound expressed by formula I (R1 is 1-6C alkyl, etc.; R2 is H, 1-6C alkyl, etc.) is reacted with triphosgene in the presence or absence of a catalyst (e.g. N,N-dimethylformamide), preferably in a solvent (e.g. toluene) at a temperature from ambient temperature to the boiling point temperature of the solvent to afford the objective compounds expressed by formula II. The reaction is carried out by using 0.35-5.0mol triphosgene, 0.8-4 l solvent and 0.1-5wt.% catalyst based on 1mol compound expressed by formula I. 2- Methylthiazole-5-carboxylic acid is exemplified as the compound expressed by formula I.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing thiazolecarboxylic acid chlorides useful as a raw material for medicines, agricultural chemicals and the like.

[0002]

2. Description of the Related Art Conventionally, as a method for producing thiazolecarboxylic acid chlorides, a method using thionyl chloride (J. Chem. Soc., P. 601 (1945) and J. Heterocyc.
lic Chem., 22 , p. 1621 (1985)) and a method using oxalyl chloride (J. Chem. Soc., Perkin I, p. 159 (198).
2)) is known.

[0003]

By the way, in the above-mentioned method using thionyl chloride, a 2-alkylthiazolecarboxylic acid and thionyl chloride are reacted with each other, and a polymer or an oxide is added while the reaction solution is post-treated under heating. By-products such as Further, the reaction between the 2-alkylthiazolecarboxylic acids and thionyl chloride is accompanied by intense heat generation, and it is difficult to control the reaction. In order to avoid these obstacles, it is necessary to keep the reaction temperature at about -5 to 0 ° C and the post-treatment temperature at 45 ° C or lower, but the suitable solvent is limited, and the yield of the desired product is extremely high. Low. Furthermore, in this method, since sulfurous acid gas that is stoichiometrically corrosive is generated, an industrial apparatus and complicated labor are required for industrial treatment.

On the other hand, the method using oxalyl chloride is industrially disadvantageous because the main raw material, oxalyl chloride, is expensive. Therefore, an object of the present invention is to obtain the desired thiazolecarboxylic acid chlorides in a high purity and a high yield, because the reaction can be easily controlled and a by-product is not generated.

[0005]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventors have selected triphosgene in place of thionyl chloride or oxalyl chloride, which is one of the conventional raw materials, and The fact that it is effective to react thiazolecarboxylic acids with
The present invention has been completed.

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

[0007]

[Chemical 3] (In the formula, R ₁ is an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 1 to 3 carbon atoms substituted with a halogen atom or an alkoxy group having 1 to 3 carbon atoms, and R ₂ is hydrogen or carbon. Alkyl group having 1 to 6 carbon atoms, or 1 to 6 carbon atoms substituted with a halogen atom or an alkoxy group having 1 to 3 carbon atoms
Represents an alkyl group of. ) A thiazolecarboxylic acid represented by (hereinafter, referred to as thiazolecarboxylic acid)
General formula (2) (Chemical Formula 4) characterized by reacting with triphosgene in the presence or absence of a catalyst

[0008]

[Chemical 4] (In the formula, R ₁ and R ₂ are the same as those in the general formula (1).) The thiazolecarboxylic acid chlorides represented by
(Hereinafter, referred to as thiazolecarboxylic acid chlorides.)
Is a manufacturing method.

The present invention will be described in detail below. Examples of the thiazolecarboxylic acids used in the present invention include 2-methylthiazole-5-carboxylic acid and 2-ethylthiazole-5-
Carboxylic acid, 2-iso-propylthiazole-5-carboxylic acid, 2-n-propylthiazole-5-carboxylic acid, 2-n-butylthiazole-5-carboxylic acid, 2-iso-butylthiazole-5-carboxylic acid , 2-sec-butylthiazole-5-carboxylic acid, 2-tert-butylthiazole-5-carboxylic acid, 2-n-pentylthiazole-5-carboxylic acid, 2-n-hexylthiazole-5-carboxylic acid, 2 -Chloromethylthiazole-5-carboxylic acid, 2-trichloromethylthiazole-5-carboxylic acid, 2-fluoromethylthiazole-5-carboxylic acid, 2-trifluoromethylthiazole-5-carboxylic acid, 2-bromomethylthiazole- 5-carboxylic acid, 2-iodomethylthiazole-5-carboxylic acid, 2-methoxymethylthiazole-5-
Carboxylic acid, 2-ethoxymethylthiazole-5-carboxylic acid, 2,4-dimethylthiazole-5-carboxylic acid, 2,4-diethylthiazole-5-carboxylic acid, 2,4-di- (n-propyl)
Thiazole-5-carboxylic acid, 2,4-di- (iso-propyl) thiazole-5-carboxylic acid, 2,4-di- (n-butyl) thiazole-
5-carboxylic acid, 2,4-di- (iso-butyl) thiazole-5-carboxylic acid, 2,4-di- (sec-butyl) thiazole-5-carboxylic acid, 2,4-di- (tert- Butyl) thiazole-5-carboxylic acid,
2,4-di- (n-pentyl) thiazole-5-carboxylic acid, 2,4-
Di- (n-hexyl) thiazole-5-carboxylic acid, 2,4-di-
(Chloromethyl) thiazole-5-carboxylic acid, 2,4-di- (fluoromethyl) thiazole-5-carboxylic acid, 2,4-di- (trifluoromethyl) thiazole-5-carboxylic acid, 2,4- Di- (trichloromethyl) thiazole-5-carboxylic acid, 2,4-di- (bromomethyl) thiazole-5-carboxylic acid, 2,4-di- (iodomethyl) thiazole-5-carboxylic acid, 2,4-di -(Methoxymethyl) thiazole-5-carboxylic acid, 2,4-di- (ethoxymethyl) thiazole-5-carboxylic acid, 2-methyl-4-ethylthiazole-5-carboxylic acid, 2-methyl-4-iso -Propylthiazole-5-carboxylic acid, 2-methyl-4-n-propylthiazole-5-carboxylic acid, 2-methyl-4-n-butylthiazole-5-
Carboxylic acid, 2-methyl-4-iso-butylthiazole-5-carboxylic acid, 2-methyl-4-sec-butylthiazole-5-carboxylic acid, 2-methyl-4-tert-butylthiazole-5-carboxylic acid , 2-methyl-4-n-pentylthiazole-5-carboxylic acid, 2-methyl-4-n-hexylthiazole-5-carboxylic acid, 2-methyl-4-chloromethylthiazole-5-carboxylic acid, 2- Methyl-4-fluoromethylthiazole-5-carboxylic acid, 2-methyl-4-trifluoromethylthiazole-5-carboxylic acid, 2-methyl-4-trichloromethylthiazole-5-carboxylic acid, 2-methyl-4- Bromomethylthiazole-5-carboxylic acid, 2-methyl-4-iodomethylthiazole-5-carboxylic acid, 2-methyl-4- (β, β, β-trifluoroethyl) thiazole-5-carboxylic acid, 2- Methyl-4-methoxymethylthiazole-5-carboxylic acid, 2-methyl-4-ethoxymethylthiazole-5-carboxylic acid, 2- Chill-4-methylthiazole -5
-Carboxylic acid, 2-ethyl-4-n-propylthiazole-5-carboxylic acid, 2-ethyl-4-iso-propylthiazole-5-carboxylic acid, 2-ethyl-4-n-butylthiazole-5-carboxylic acid Acid, 2-ethyl-4-fluoromethylthiazole-5-carboxylic acid, 2-ethyl-4-trifluoromethylthiazole-5-carboxylic acid, 2-ethyl-4-chloromethylthiazole-5-carboxylic acid, 2- Ethyl-4-methoxymethylthiazole-5-carboxylic acid, 2-iso-propyl-4-methylthiazole-5-carboxylic acid, 2-iso-propyl-4-ethylthiazole-5-carboxylic acid, 2-iso-propyl -4-n-propylthiazole-5-carboxylic acid, 2-iso-propyl-4-n-butylthiazole-5-carboxylic acid, 2-iso-propyl-4-fluoromethylthiazole-5-carboxylic acid, 2- iso-propyl-4-trifluoromethylthiazole-5-carboxylic acid, 2-iso-propyl-4-chloromethylthiazole-5-ca Bon acid, 2-an iso-propyl-4-methoxymethyl-5-carboxylic acid, 2-n-propyl
-4-methylthiazole-5-carboxylic acid, 2-n-propyl-4-
Ethylthiazole-5-carboxylic acid, 2-n-propyl-4-iso
-Propylthiazole-5-carboxylic acid, 2-n-propyl-4-
n-Butylthiazole-5-carboxylic acid, 2-n-propyl-4-
Fluoromethylthiazole-5-carboxylic acid, 2-n-propyl-4-trifluoromethylthiazole-5-carboxylic acid, 2-
n-Propyl-4-methoxymethylthiazole-5-carboxylic acid, 2-tert-butyl-4-methylthiazole-5-carboxylic acid, 2-tert-butyl-4-ethylthiazole-5-carboxylic acid, 2-tert -Butyl-4-n-propylthiazole-5-carboxylic acid, 2-tert-butyl-4-trifluoromethylthiazole
-5-carboxylic acid, 2-tert-butyl-4-methoxymethylthiazole-5-carboxylic acid, 2-chloromethyl-4-methylthiazole-5-carboxylic acid, 2-chloromethyl-4-ethylthiazole-5- Carboxylic acid, 2-chloromethyl-4-ethylthiazole
-5-carboxylic acid, 2-chloromethyl-4-n-butylthiazole-5-carboxylic acid, 2-chloromethyl-4-chloromethylthiazole-5-carboxylic acid, 2-chloromethyl-4-trichloromethylthiazole- 5-carboxylic acid, 2-chloromethyl-4- (β,
β, β-trifluoromethyl) thiazole-5-carboxylic acid,
2-methoxymethyl-4-methylthiazole-5-carboxylic acid,
2-methoxymethyl-4-ethylthiazole-5-carboxylic acid,
2-Methoxymethyl-4-iso-propylthiazole-5-carboxylic acid, 2-methoxymethyl-4-tert-butylthiazole-5-
Carboxylic acid, 2-methoxymethyl-4-trifluoromethylthiazole-5-carboxylic acid, 2-methoxymethyl-4-methoxymethylthiazole-5-carboxylic acid and the like,
It is not necessarily limited to these.

Since the reaction in the present invention is carried out in a solution or suspension state, it is preferable to use a solvent. The solvent used in the present invention may be any solvent inert to the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and dioxane; esters such as ethyl acetate, butyl acetate and ethyl propionate; halogens such as tetrachloroethylene and chlorobenzene. Included are, but not limited to, modified hydrocarbons. It is also possible to mix and use one or more of these solvents.

In the reaction of the present invention, it is possible to accelerate the reaction rate by using a catalyst. Examples of the catalyst used in the present invention include N, N-dimethylformamide, N-
Methylformanilide, N-formylpiperidine, N-formylmorpholine, N, N-dibenzylformamide, N
-Methyl-N-ethylformamide, N-propyl-N-n-
Butylformamide, N, N-di-o-toluylformamide, N, N-di-p-toluylformamide, N, N-dipentylformamide, N-formylpiperazine, N-formylpyrrolidine, N-formylimidazolidine and other formamides Kinds; N, N-dimethylacetamide, N, N-di-n-
Amides such as propylacetamide, N, N-di-iso-propylacetamide, N, N-diethylpropionamide, N, N-dimethylbutyramide, N-methylacetanilide; pyridine, picoline, N, N-dimethylaniline,
Examples thereof include organic bases such as N, N-diethylaniline, triethylenediamine and triethylamine; and phosphoramides such as hexamethylphosphoramide, but not limited thereto.

The amount of triphosgene used in the present invention is usually 0.33 to 10.0 mol, preferably 0.35 to 5.0 mol, based on 1 mol of thiazolecarboxylic acid. Also,
The amount of the solvent is usually 1 mol of thiazolecarboxylic acid
It is efficient to use 0.5 to 10 lit, preferably 0.8 to 4 lit. Further, when a catalyst is used, the amount used is usually 0.05 to 10% by weight, preferably 0.1 to 5% by weight, based on the thiazolecarboxylic acid. This amount is 0.0
If it is less than 5% by weight, the effect of the addition of the catalyst is not exerted and the reaction progresses slowly. If it exceeds 10% by weight, the purity of the thiazolecarboxylic acid chlorides formed is lowered.
The reaction temperature in the present invention is between room temperature and the boiling point of each solution, and the reaction time is usually 1 to 20 hours, and it can be shortened to 1 to 8 hours by adding a catalyst.

After the completion of the reaction of the present invention, the reaction solution is filtered, and the filtrate is distilled to easily obtain thiazolecarboxylic acid chlorides. Alternatively, the reaction solution may be washed with water to decompose excess triphosgene, and the filtrate may be concentrated and directly used in the reaction of the next step, or may be purified by distillation. In some cases, the reaction solution may be concentrated and directly used for the reaction in the next step. When unreacted thiazolecarboxylic acids remain, they can be separated by filtration, recovered, and used. The thiazolecarboxylic acid chlorides thus obtained can be used as a raw material for medicines, agricultural chemicals and the like.

[0014]

The present invention will be described in detail below with reference to examples. In the following, "%" is based on weight, unless otherwise specified. The purity of thiazolecarboxylic acid chlorides is analyzed by gas chromatography.

Example 1 In a three-necked flask (capacity: 300 ml), 15.7 g (0.10 mol) of 2,4-dimethylthiazole-5-carboxylic acid was added to 10 parts of toluene.
The suspension was suspended in 0 ml, triphosgene 10.1 g (0.034 mol) was added, and the mixture was reacted under heating under reflux for 15 hours. After completion of the reaction, the reaction solution was filtered and the filtrate was concentrated to obtain 16.2 g of 2,4-dimethylthiazole-5-carboxylic acid chloride. The purity of the obtained product was 95.5%, and the yield thereof was 88.1 mol%.

Example 2 In a three-necked flask (capacity: 300 ml), 15.7 g (0.10 mol) of 2,4-dimethylthiazole-5-carboxylic acid was added to 10 parts of toluene.
Suspend in 0 ml, 0.1 g of N, N-dimethylformamide
And 10.1 g (0.034 mol) of triphosgene were added, and the mixture was reacted under heating under reflux for 5 hours. After the reaction is completed, the reaction solution is filtered,
The filtrate was concentrated to obtain 17.0 g of 2,4-dimethylthiazole-5-carboxylic acid chloride. The purity of the obtained product is 96.7.
%, And its yield was 93.4 mol%.

Example 3 In a three-necked flask (capacity: 300 ml), 10.0 g (0.07 mol) of 2-methylthiazole-5-carboxylic acid was added to 100 ml of xylene.
And 0.2 g of N, N-dimethylacetamide and 7.5 g (0.025 mol) of triphosgene were added and the mixture was heated under reflux.
Stir for hours. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated, and 10.6 g of 2-methylthiazole-5-carboxylic acid chloride was obtained by distillation. The purity of the obtained product is 98.0%,
And the yield was 91.8 mol%.

Example 4 In a three-necked flask (capacity: 300 ml), 18.8 g (0.11 mol) of 2-methyl-4-ethylthiazole-5-carboxylic acid was suspended in 150 ml of toluene, and N, N-dimethylformamide was suspended.
0.1 g and triphosgene 12.5 g (0.042 mol) were added, and the mixture was stirred with heating under reflux for 4 hours. After completion of the reaction, the reaction solution was cooled to room temperature and washed with water, and then the organic layer was concentrated to obtain 19.6 g of 2-methyl-4-ethylthiazole-5-carboxylic acid chloride.
The purity of the obtained product is 94.6%, and the yield is 88.9.
It was mol%.

Comparative Example 1 In a three-necked flask (capacity: 500 ml), 15.7 g (0.10 mol) of 2,4-dimethylthiazole-5-carboxylic acid was suspended in 300 ml of ethyl ether and 8 g (0.1 mol) of pyridine, and -3
12 g (0.10 mol) of thionyl chloride was added dropwise at 45 ° C over 45 minutes. After completion of the reaction, the reaction solution is filtered and the filtrate is concentrated 2.
7.2 g of 4-dimethylthiazole-5-carboxylic acid chloride was obtained. The purity of the obtained product is 85%, and its yield is
It was 35 mol%.

[0020]

According to the present invention, the reaction can be easily controlled, by-products are not generated, and the target thiazolecarboxylic acid chlorides can be obtained in high purity and high yield. Further, in the present invention, if a catalyst is used, the reaction time can be shortened significantly. Furthermore, the obtained high-purity thiazolecarboxylic acid chlorides can be used in the next step as a raw material for medicines, agricultural chemicals, etc., and the present invention is an industrially useful method.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yoshinori Tanaka 1900, Togo, Mobara-shi, Chiba Mitsui Toatsu Chemical Co., Ltd.

Claims (1)

[Claims] 1. The general formula (1) (chemical formula 1) (In the formula, R ₁ is an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 1 to 3 carbon atoms substituted with a halogen atom or an alkoxy group having 1 to 3 carbon atoms, and R ₂ is hydrogen or carbon. A C1 to C6 alkyl group, or a C1 to C3 alkyl group substituted with a halogen atom or a C1 to C3 alkoxy group) in the presence of a catalyst. Alternatively, the compound is reacted with triphosgene in the absence of the general formula (2) (Chemical Formula 2). (In the formula, R ₁ and R ₂ are the same as those in the general formula (1).) A method for producing a thiazolecarboxylic acid chloride represented by the formula: