JP3173210B2 - Method for producing 2-aminothiazole derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a 2-aminothiazole derivative.

[0002]

2. Description of the Related Art
As a method for producing -aminothiazoles, for example, a method is known in which a mixture of thiourea and propionaldehyde is reacted with sulfuryl chloride to obtain 2-aminothiazole (Japanese Patent Application No. 56-87586). ). However, when 2-amino-5-methylthiazole is produced by this method, the yield is as low as 24%, which cannot be said to be an industrially satisfactory production method.

[0003]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies on a method for producing a 2-aminothiazole derivative. As a result, the acid is allowed to act on the thiourea derivative to obtain a 2-aminothiazole derivative with good yield and easily. And found that the present invention was completed.

That is, the present invention relates to a thiourea derivative represented by the general formula [I] (formula 3).

Embedded image (Wherein, R ¹ represents a hydrogen atom, an alkyl group, it may be multiply substituted ant - group, may be multiply substituted ants - represents ylcarbonyl group, an alkylcarbonyl group, R ²
Represents a hydrogen atom or an alkyl group, and R ³ , R ⁴ and R ⁵
Are the same or different and represent a hydrogen atom, an alkyl group or an aryl group, and X represents a halogen atom. ) A compound of the general formula [II] characterized by the action of an acid

Embedded image (Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent the same groups as in the above-mentioned general formula [I]).

Hereinafter, the present invention will be described. In the present invention, the substituent in the thiourea derivative represented by the general formula [I] and the 2-aminothiazole derivative represented by the general formula [II], R ¹ is a hydrogen atom, an alkyl group, and a plurality of optionally substituted ants. -Represents an aryl group, an optionally substituted arylcarbonyl group or an alkylcarbonyl group. Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s
Examples thereof include those having 1 to 8 carbon atoms such as ec-butyl, tert-butyl, hexyl, and octyl groups. Ants
The phenyl group includes, for example, phenyl, α-naphthyl, β-naphthyl and the like. Examples of the arylcarbonyl group include benzoyl, α-naphthoyl, β-naphthoyl and the like. Examples of the alkylcarbonyl group include an acetyl, propionyl, butyryl, isobutyryl, pivaloyl group and the like.

A plurality of aryl groups and arylcarbonyl groups may be substituted. Examples of such substituents include halogen atoms such as chloro, bromo, iodo and fluoro, methyl, ethyl, propyl and isopropyl. Butyl, sec-butyl, tert-butyl, hexyl, octyl and other alkyl groups having 1 to 8 carbon atoms, trifluoromethyl, alkyl groups substituted with a plurality of halogens such as 2,2,2-trifluoroethyl, Methoxy, ethoxy, propyloxy, isopropyloxy, butoxy,
Examples thereof include alkoxy groups having 1 to 8 carbon atoms such as sec-butoxy, tert-butoxy, hexyloxy and octyloxy, aryl groups such as phenyl, α-naphthyl and β-naphthyl, and nitro groups. It is not limited to a substituent.

R ² represents a hydrogen atom or an alkyl group, and examples of the alkyl group include the same as those described above for R ¹ . R ³ , R ⁴ and R ⁵ may be the same or different and represent a hydrogen atom, an alkyl group, or an aryl group.
Same as ¹ . X includes a halogen atom such as a chlorine atom, a bromine atom, an iodine atom and a fluorine atom, and usually a chlorine atom or a bromine atom is used.

Typical examples of the compound represented by the general formula [I] include N- (2-chloro-2-propenyl) thiourea, N- (2-chloro-1-methyl-2-propenyl) thiourea, N- (2-bromo-2-propenyl) thiourea, N- (2-chloro-2-butenyl) thiourea, N- (2-chloro-2-propenyl) -N '
-Phenylthiourea, N- (2-chloro-2-propenyl) -N'-butylthiourea, N- (2-chloro-
2-propenyl) -N ′, N′-dimethylthiourea;
N- (2-chloro-2-propenyl) -N '-(3,5
-Dichlorophenyl) thiourea, N- (2-chloro-
2-propenyl) -N '-(3,5-dichlorobenzoyl) thiourea, N- (2-chloro-2-propenyl)
-N'-benzoylthiourea, N- (2-chloro-2
-Propenyl) -N'-acetylthiourea and the like.

In the present invention, the acid used for converting the thiourea derivative [I] to the 2-aminothiazole derivative [II] includes a strongly acidic protic acid or a combination of a Lewis acid and a protic acid. Can be As a strongly acidic protonic acid, its concentration is 40 to 98%,
Preferably, 70 to 90% of sulfuric acid, a strongly acidic inorganic acid or a strongly acidic organic acid having an acid strength equal to or higher than that of sulfuric acid are used. Strongly acidic inorganic acids include, for example, fluorosulfonic acid, and strongly acidic organic acids include, for example, trifluoromethanesulfonic acid, methanesulfonic acid, trifluoroacetic acid, and the like. The amount of the strongly acidic protonic acid used is usually 1 to 1000 moles per 1 mole of the thiourea derivative.

When a strongly acidic protonic acid is used, the reaction is usually carried out without a solvent, but a solvent inert to the acid may be used together. Such solvents include, for example, heptane, aliphatic hydrocarbon solvents such as hexane, benzene, toluene, aromatic hydrocarbon solvents such as xylene, monochlorobenzene, halogenated hydrocarbon solvents such as 1,2-dichloroethane, formic acid, Organic acid-based solvents such as acetic acid, or a mixture of these solvents. The used amount is usually 1 to 100 times by weight based on the thiourea derivative [I]. The reaction temperature is usually 0 to 150 ° C, preferably 20 to 120 ° C.
The reaction time is usually 0.2 to 24 hours.

After completion of the reaction, for example, water is added to the reaction solution, neutralized by adding an alkaline solution such as sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, etc., and if necessary, ethyl acetate, chloroform, methyl isobutyl ketone, etc. After extraction with an organic solvent, the extract is concentrated to obtain 2
-Aminothiazole derivative [II] can be obtained.
Further, if necessary, it can be purified by ordinary purification operations such as recrystallization and column chromatography.

Next, when the Lewis acid and the protic acid are used in combination, examples of the Lewis acid include tin halides such as stannic chloride and stannic bromide, zinc chloride, and the like.
Examples thereof include zinc halides such as zinc bromide and zinc iodide, copper halides such as cupric chloride, and aluminum halides such as aluminum chloride. These may be anhydrous or contain water of crystallization. Examples of the protonic acid include hydrochloric acid, sulfuric acid, phosphoric acid, and the like. When the Lewis acid is solvolyzed in the reaction solution to generate a protonic acid, it is not always necessary to add the protonic acid. The amount ratio of the raw materials used is usually 0.1 mol of Lewis acid to 1 mol of the thiourea derivative represented by the general formula [I].
The amount is from 01 to 20 mol, preferably from 0.2 to 2 mol, and the amount of the protonic acid used together with the Lewis acid is usually from 1 to 100 mol.

When a Lewis acid and a protic acid are used in combination, the reaction is usually carried out in a solvent such as an aliphatic hydrocarbon solvent such as heptane or hexane, or an aromatic solvent such as benzene, toluene or xylene. Hydrocarbon solvents, monochlorobenzene, halogenated hydrocarbon solvents such as 1,2-dichloroethane, dimethoxyethane, tetrahydrofuran, ether solvents such as dioxane, acetone, carbonyl solvents such as methyl isobutyl ketone,
Alcohol solvents such as methanol and ethanol, 1,3
Solvents such as -dimethyl-2-imidazolidone, N, N-dimethylformamide, dimethylsulfoxide, water, or a mixture of these solvents. The used amount is usually 1 to 100 times by weight based on the thiourea derivative [I].

The reaction temperature is usually 0 to 150 ° C., preferably 20 to 120 ° C., and the reaction time is usually 0.2 to 24 hours. After completion of the reaction, the same treatment as in the case of using the strongly acidic protonic acid described above can be performed to obtain the desired 2-aminothiazole derivative [II].

The thiourea derivative represented by the general formula [I] as a starting material in the present invention is, for example,

Embedded image It can be manufactured by a route as shown by:

First, the route 1 will be described. General formula [III] (Chemical formula 6)

A thiocyanate compound represented by M-SCN [III] (M represents a potassium atom, a sodium atom or an ammonium group) and a general formula [IV]

Embedded image (Wherein R ³ and R ⁴ represent a hydrogen atom, an alkyl group, or an aryl group. X represents a halogen atom;
Represents a leaving group. By reacting with an alkenyl halide derivative represented by

Formula [V] (Formula 8)

Embedded image (Wherein R ³ , R ⁴ and X have the same meanings as in the above-mentioned general formula [IV]), which is further rearranged to obtain a thiocyanate derivative of the general formula [VI] )

Embedded image (Wherein R ³ , R ⁴ and X have the same meaning as in the above formula [IV]).

Here, in the formula, R ³ and R ⁴ are a hydrogen atom, and the same alkyl group and aryl group as R ³ and R ⁴ in the general formula [I] can be mentioned. X also represents a halogen atom such as, for example, a chlorine atom, a bromine atom, an iodine atom and a fluorine atom, as in the general formula [I]. Examples of Y include a leaving group such as a chlorine atom, a bromine atom, a mesyloxy group, and a tosyloxy group. Examples of the thiocyanate compound represented by the general formula [III] include potassium thiocyanate, sodium thiocyanate, and ammonium thiocyanate. Examples of the alkenyl halide represented by the general formula [IV] include 3,4- Dichloro-2
-Pentene, 2,3-dibromo-1-propene, 2,3
-Dichloro-1-propene and the like.

In reacting the thiocyanate compound [III] with the alkenyl halide derivative [IV], an organic solvent such as methanol or ethanol is usually used. The amount used is 1 to 100 times by weight based on the alkenyl halide derivative [IV]. The molar ratio of the thiocyanate compound [III] to the alkenyl halide derivative [IV] is 0.2 to 5 times mol. Reaction temperature is 30-80 ° C
And the reaction time is 0.5 to 20 hours. The generated thiocyanate derivative [V] may be taken out or may be used as it is in the next reaction without being taken out. The rearrangement reaction is
The reaction is performed without solvent or in the presence of a solvent. As the solvent, an organic solvent such as toluene, xylene, chlorobenzene, cyclobenzene, octane and decane is usually used. The amount used is usually based on the thiocyanate derivative [V].
It is 1 to 20 times by weight. The reaction temperature is 80-200 ° C,
The reaction time is 0.5 to 10 hours.

The isothiocyanate derivative [VI] obtained as described above has the general formula [VII]

Embedded image (Wherein R ¹ and R ² have the same meanings as in the above formula [I]) by reacting with an ammonia derivative represented by the above formula [I].

Embedded image (Wherein, R ¹ represents a hydrogen atom, an alkyl group, it may be multiply substituted ant - group, may be multiply substituted ants - represents ylcarbonyl group, an alkylcarbonyl group, R ²
Represents a hydrogen atom or an alkyl group; R ³ and R ^{4 are the} same or different and represent a hydrogen atom, an alkyl group or an aryl group; and R ⁵ represents a hydrogen atom. X represents a halogen atom. ) Can be obtained.

In the general formula [VII], R ¹ and R ² have the same meanings as in the above-mentioned general formula [I].
], For example, ammonia, methylamine, dimethylamine, butylamine, aniline, 3,5-dichloroaniline, benzamide, 3,5-dichlorobenzamide, acetamide and the like.

In reacting the isothiocyanate derivative [VI] with the ammonia derivative [VII], usually,
Water or an organic solvent such as methanol or ethanol is used. The used amount is 1 to 100 times by weight based on the thiocyanate compound [III]. The molar ratio of the isothiocyanate derivative [VI] to the ammonia derivative [VII] is 0.5 to 5. The reaction temperature is 30-100 ° C, and the reaction time is 0.5-10 hours.

Next, the route 2 will be described. General formula [VIII] (Chemical formula 12)

Embedded image (Wherein, R ¹ and R ² have the same meanings as in the above-mentioned general formula [I]) and a thiourea compound represented by the general formula [IX]

Embedded image (Wherein R ³ , R ⁴ and R ⁵ are the same or different,
X represents a halogen atom, Y represents a leaving group, or a hydrogen atom, an alkyl group or an aryl group. By reacting with an alkenyl halide derivative represented by

Formula [I] (Formula 14)

Embedded image (Wherein, R ¹ represents a hydrogen atom, an alkyl group, it may be multiply substituted ant - group, may be multiply substituted ants - represents ylcarbonyl group, an alkylcarbonyl group, R ²
Represents a hydrogen atom or an alkyl group, and R ³ , R ⁴ and R ⁵
Are the same or different and represent a hydrogen atom, an alkyl group or an aryl group, and X represents a halogen atom. )) Can be obtained.

In Route 2, in the formula of the general formula [VIII], R ¹ and R ² have the same meaning as in the above-mentioned general formula [I]. R ³ , R ⁴ and R ⁵ of the alkenyl halide derivative represented by the general formula [IX] are a hydrogen atom, an alkyl group similar to R ³ , R ⁴ and R ⁵ in the general formula [I], -Represents a phenyl group. X represents a halogen atom such as a chlorine atom, a bromine atom, an iodine atom and a fluorine atom as in the general formula [I], and Y represents a chlorine atom, a bromine atom, a mesyloxy group,
Represents a leaving group such as a tosyloxy group.

Examples of the thiourea compound represented by the general formula [VIII] include thiourea, N-methylthiourea, N, N-dimethylthiourea, N-butylthiourea, N-phenylthiourea, and N- (3,5-dichlorophenyl) Thiourea, N-benzoylthiourea, N
-(3,5-dichlorobenzoyl) thiourea, N-acetylthiourea and the like. The general formula (I
X) as the alkenyl halide represented by, for example,
3,4-dichloro-2-pentene, 2,3-dibromo-
Examples thereof include 1-propene and 2,3-dichloro-1-propene.

In the reaction between the thiourea compound [VIII] and the alkenyl halide derivative [IX], an organic solvent such as methanol, ethanol, toluene, or xylene is usually used.
1] to 1 to 100 times by weight. The molar ratio of the thiourea compound [VIII] to the alkenyl halide derivative [IX] is 0.2 to 5. A base may be present in the reaction system, and examples of the base used include sodium hydroxide, potassium carbonate, and sodium carbonate. The amount of the base to be used is generally 0.5 to 5 moles per 1 mole of the thiourea compound [VIII]. The reaction can be promoted by adding a phase transfer catalyst. Examples of the phase transfer catalyst include tetra-n-butylammonium bromide,
Tetra-n-butylphosphonium bromide, benzyltriethylammonium chloride and the like. The amount of the phase transfer catalyst to be added is usually 0.001 to 0.2 times mol per 1 mol of the thiourea compound [VIII]. Reaction temperature is 30
At １００100 ° C., the reaction time is from 1 to 20 hours.

[0028]

According to the present invention, a 2-aminothiazole derivative can be easily produced at a high yield.

[0029]

The present invention will be described in more detail with reference to the following examples. It goes without saying that the present invention is not limited to the embodiments. In the examples, the yield and purity were determined using high performance liquid chromatography. The analysis conditions are as shown below. Column: Sumipax ODS A-212 (manufactured by Sumika Chemical Analysis Service, Ltd.) Mobile phase: Phosphate standard buffer aqueous solution (pH 6.86): water: methanol = 1: 20: 2 Mobile phase flow rate: 1 ml / min. Column temperature; 35 ° C

Example 1 N- (2-chloro-2-propenyl) thiourea 30
1.3 mg of 80% which was previously cooled on ice and thoroughly stirred
The mixture was added to 2.46 g of sulfuric acid, and then heated to 90 ° C., and reacted by stirring at the same temperature for 1.5 hours. After cooling, the reaction solution was added with ice water and neutralized with sodium hydrogen carbonate. Ethyl acetate was added thereto to extract the product into an organic layer, and the extracted organic layer was washed with water. The solvent was distilled off under reduced pressure to give a yellow-brown white solid 5-methyl-2-aminothiazo-
184.7 mg were obtained. Purity 95.5%, yield 7
7%. _{^{1 H-NMR (CDCl 3,}} 270MH Z) δ (pp
m) 6.7 (1H, q), 4.9 (2H, br), 2.3
(3H, d) mass (EI): m / e = 114 (parent peak) Melting point: 92-95 ° C

Example 2 N- (2-chloro-2-propenyl) thiourea, 1
To a mixture of 6.1 mg and toluene, 0.6 ml, 25 μl of stannic chloride (SnCl ₄ ) was added, and then 90 ° C.
To 35% after stirring for 1 hour at the same temperature.
Hydrochloric acid (0.5 ml) was added, and the mixture was stirred at the same temperature for 1 hour to react. After cooling, ice water was added to the reaction solution, neutralized with sodium bicarbonate, diluted to a predetermined amount with acetonitrile, and the yield was determined by high performance liquid chromatography. The yield of 5-methyl-2-aminothiazole is 95%.
Met.

Reference Example 1 Potassium thiocyanate (48.6 g) was added to 300 ml of ethanol at room temperature with stirring, and the temperature was raised to 50 ° C. While stirring at 50 ° C., 55.5 g of 2,3-dichloro-1-propene was added over 1.75 hours, and the mixture was reacted at the same temperature with stirring for 9.5 hours. The precipitated inorganic salt was filtered, the filtrate was concentrated under reduced pressure, and the residue was distilled to obtain a distillate having a boiling point of 77-78 ° C./11 mgHg 44.3.
g was obtained. According to the result of ¹ H-NMR analysis of the distillate, the purity of 2-chloro-2-propenyl isothiocyanate was 51.
% And the balance was 2-chloro-2-propenyl thiocyanate. The distillate was heated in a 120 ° C. oil bath for 4 hours to obtain 42.7 g of 2-chloro-2-propenyl isothiocyanate (yield: 64%). ¹ H-N
Purity was 94% by MR analysis. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm):
5.6 (1H, m), 5.5 (1H, m), 4.3 (2
H, t) mass (EI): m / e (parent peak) = 133

42.6 g of the thus obtained 2-chloro-2-propenyl isothiocyanate was added dropwise to a 25% aqueous ammonia solution at room temperature with stirring over 0.5 hours, and the temperature was raised to 80 ° C. The mixture was stirred at the same temperature for 1.0 hour. After cooling to about 10 ° C., 25 ml of cold water was added for dilution, and the precipitated crystals were filtered. The crystals are washed with cold water and dried under vacuum to give N- (2-chloro-2-propenyl) thiourea,
37.2 g were obtained (77% yield). Purity was higher than 99% by high performance liquid chromatography analysis. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm):
6.4 (1H, br), 5.8 (2H, br), 5.4
(1H, s), 5.3 (1H, s), 4.1 (2H, b)
r) mass (EI): m / e (parent peak) = 150

Claims (3)

(57) [Claims] 1. A compound of the general formula [I] (Wherein, R ¹ represents a hydrogen atom, an alkyl group, it may be multiply substituted ant - group, may be multiply substituted ants - represents ylcarbonyl group, an alkylcarbonyl group, R ²
Represents a hydrogen atom or an alkyl group, and R ³ , R ⁴ and R ⁵
Are the same or different and represent a hydrogen atom, an alkyl group or an aryl group, and X represents a halogen atom. (2) wherein an acid acts on the thiourea derivative represented by the formula (II). (Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above). 2. The method for producing a 2-aminothiazole derivative according to claim 1, wherein the acid is a strongly acidic protonic acid. 3. The process according to claim 1, wherein the acid is a mixture of a Lewis acid and a protonic acid.