JP3206157B2 - Method for producing 2-iminothiazoline derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an intermediate for pharmaceuticals and agricultural chemicals, particularly an intermediate for herbicides (EP-EP-EP).
A-446802 published specification, US patent application 7694
No. 85, European Patent Application 9211407
3.7 described in the specification of application No. 3.7, etc.).

[0002]

2. Description of the Related Art Conventionally, as a method for producing a 2-iminothiazoline derivative, for example, the following reaction formula 4 is used.

Embedded image Is described in J. Chem. Soc. Perkin Trans. I, Volume 3,
P. 639 (1987). However, this method has a problem with the regioselectivity of the reaction as described above,
The range of application was limited, and it was not always sufficient as a method for producing a 2-iminothiazoline derivative.

[0003]

Means for Solving the Problems The present inventors have conducted various studies on a method for producing a 2-iminothiazoline derivative represented by the following general formula 6, and as a result, have obtained a thiourea derivative represented by the following general formula 5. The inventors have found that a 2-iminothiazoline derivative represented by the following general formula (6) can be obtained by treating with an acid, thereby completing the present invention. That is, the present invention provides a compound represented by the general formula:

Embedded image [Wherein, R ¹ represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, and R ² represents A hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group,
An aryl group which may be substituted, an alkylcarbonyl group which may be substituted, a cycloalkylcarbonyl group which may be substituted, an arylcarbonyl group which may be substituted, an alkoxycarbonyl group which may be substituted; Represents an optionally substituted cycloalkyloxycarbonyl group or an optionally substituted aryloxycarbonyl group, wherein R ³ , R ⁴ and R ⁵ are the same or different and are a hydrogen atom, an optionally substituted alkyl A group or an aryl group which may be substituted;
Represents a halogen atom. Wherein the thiourea derivative represented by the formula is treated with an acid.

Embedded image[Wherein, R¹, R^Two, R^Three, R^FourAnd R^FiveIs the same as above
Means the same. 2-iminothiazoline derivative represented by the formula:
It provides a method for producing the body. In the present invention, R
¹Specific examples of
An alkyl group having 1 to 8 primes (as a substituent, 1 to 8 carbon atoms)
8 alkoxy groups, aryl groups, and cycloalkyl having 3 to 8 carbon atoms
Alkyl group, etc.), and may be plurally substituted
A cycloalkyl group having 3 to 8 carbon atoms (as a substituent,
C1-C8 alkyl group, C1-C8 alkoxy
Group, aryl group, etc.),
An aryl group (as a substituent, a halogen atom
An alkyl group having 1 to 8 carbon atoms which may be substituted,
1 to 8 carbon atoms which may be substituted by a plurality of
Alkoxy group, aryl group, nitro group, halogen atom, etc.
And heteroaryls optionally substituted
A group (substituted by a halogen atom
An alkyl group having 1 to 8 carbon atoms, a halogen atom
Having 1 to 8 carbon atoms which may be substituted by a plurality of
Group, aryl group, nitro group, halogen atom, etc.
). R^TwoAs a specific example of
And alkyl having 1 to 8 carbon atoms which may be substituted
Group (as a substituent, an alkoxy group having 1 to 8 carbon atoms,
Examples include a reel group and a cycloalkyl group having 3 to 8 carbon atoms.
), A cycle having 3 to 8 carbon atoms which may be substituted
Loalkyl group (as a substituent, alkyl having 1 to 8 carbon atoms)
Group, an alkoxy group having 1 to 8 carbon atoms, an aryl group and the like.
), An optionally substituted aryl group (position
As the substituent, an alkyl group having 1 to 8 carbon atoms,
8 alkoxy, aryl, nitro, halogen
And an optionally substituted alkyl
(C1-8) carbonyl group (as a substituent,
Alkoxy group having 1 to 8 primes, aryl group, 3 to 8 carbons
And the like) is substituted with a plurality of
Cycloalkyl (C3-8) carbonyl which may be present
Group (as a substituent, an alkyl group having 1 to 8 carbon atoms,
And alkoxy groups of 1 to 8 and aryl groups.
), An optionally substituted arylcarbonyl group
(As the substituent, an alkyl group having 1 to 8 carbon atoms,
1 to 8 alkoxy, aryl, nitro, halogen
And the like may be substituted.
Lucoxy (C1-8) carbonyl group (as a substituent
Is an alkoxy group having 1 to 8 carbon atoms, an aryl group,
3 to 8 cycloalkyl groups, etc.), multiple substitution
Optionally substituted cycloalkyl (C3-8) oxo
Cicarbonyl group (as a substituent, an alkyl group having 1 to 8 carbon atoms)
A kill group, an alkoxy group having 1 to 8 carbon atoms, an aryl group, or the like.
Or multi-substituted aryl
An oxycarbonyl group (as a substituent, a halogen atom
An alkyl group having 1 to 8 carbon atoms which may be substituted,
1 to 8 carbon atoms which may be substituted by a plurality of halogen atoms
Alkoxy, aryl, nitro, and halogen atoms
And the like). R ^Three, R^FourAnd R^Five
Specific examples of a hydrogen atom,
A C 1-8 alkyl group (for the substituent, carbon
Alkoxy group having 1 to 8 primes, aryl group, 3 to 8 carbons
And the like) is substituted with a plurality of
An aryl group (optionally having 1 to 8 carbon atoms as a substituent)
An alkyl group, an alkoxy group having 1 to 8 carbon atoms, aryl
Group, nitro group, halogen atom, etc.)
It is. In the above, “alkyl” refers to, for example, methyl
, Ethyl, propyl, isopropyl, butyl, isobu
Chill, sec-butyl, tert-butyl, hexyl, octyl
And "cycloalkyl" is, for example, cycloalkyl
Propyl, cyclobutyl, cyclopentyl, cyclohexyl
Represents sil, cyclooctyl, and "alkoxy"
For example, methoxy, ethoxy, propyloxy, iso
Propyloxy, butoxy, isobutyloxy, sec-
Butyloxy, tert-butyloxy, hexyloxy,
Represents octyloxy, and “aryl” is, for example,
Represents, for example, phenyl, α-naphthyl, β-naphthyl,
“Heteroaryl” includes, for example, pyridyl, pyrimidyl
Zinyl, thienyl, imidazolyl, thiazolyl, oxa
Represents zolyl, and “halogen atom” is chlorine
Atom, bromine atom, iodine atom, fluorine atom,
“A plurality may be substituted” means, for example, that a hydrogen atom is
Indicates that 1 to 3 substituents may be substituted
You. X is usually a chlorine atom or a bromine atom.
You. The raw material compound used in the present invention is represented by the general formula
For example, the following thiourea derivatives are listed.
I can do it. N- (3- (trifluoromethyl) phenyl) -N-
(2-chloro-2-propenyl) thiourea N- (3,5-dichlorophenyl) -N- (2-chloro
-2-propenyl) thiourea N- (4-methoxyphenyl) -N- (2-chloro-2
-Propenyl) thiourea N- (3-chlorophenyl) -N- (2-chloro-2-
Propenyl) thiourea N- (3- (trifluoromethoxy) phenyl) -N-
(2-chloro-2-propenyl) thiourea N- (4-fluoro-3- (trifluoromethyl) fe
Nyl) -N- (2-chloro-2-propenyl) thioure
A N-butyl-N- (2-chloro-2-propenyl)-
N'-phenylthiourea N- (3- (trifluoromethyl) phenyl) -N-
(2-chloro-1-methyl-2-propenyl) thioure
A N- (2-chlorophenyl) -N- (2-chloro-2-
Propenyl) thiourea N- (3- (trifluoromethyl) phenyl) -N-
(2-Bromo-2-propenyl) thiourea N-butyl-N- (2-chloro-2-propenyl)-
N'-butylthiourea N-butyl-N- (2-chloro-2-propenyl)-
N'-benzylthiourea N- (3- (trifluoromethyl) phenyl) -N-
(2-chloro-2-butenyl) thiourea N- (3- (trifluoromethoxy) phenyl) -N-
(2-chloro-2-butenyl) thiourea N- (4-fluoro-3- (trifluoromethoxy) phenyl
Enyl) -N- (2-chloro-2-butenyl) thiouree
(A) a 2-iminothiazoline derivative represented by the following general formula:
For example, the following may be mentioned. 2-imino-3- (3- (trifluoromethyl) phenyl
) -5-methyl-4-thiazoline 2-imino-3- (3,5-dichlorophenyl) -5
Methyl-4-thiazoline 2-imino-3- (4-methoxyphenyl) -5-methyl
Ru-4-thiazoline 2-imino-3- (3-chlorophenyl) -5-methyl
-4-thiazoline 2-imino-3- (3- (trifluoromethoxy) fe
Nil) -5-methyl-4-thiazoline 2-imino-3- (4-fluoro-3- (trifluoro
Methyl) phenyl) -5-methyl-4-thiazoline 2- (N-phenylimino) -3-butyl-5-methyl
-4-thiazoline 2-imino-3- (3- (trifluoromethyl) phenyl
) -4,5-dimethyl-4-thiazoline 2-imino-3- (2-chlorophenyl) -5-methyl
-4-thiazoline 2- (N-butylimino) -3-butyl-5-methyl-
4-thiazoline 2- (N-benzylimino) -3-butyl-5-methyl
-4-thiazoline 2-imino-3- (3- (trifluoromethyl) phenyl
) -5-ethyl-4-thiazoline 2-imino-3- (3- (trifluoromethoxy) phenyl
Nil) -5-ethyl-4-thiazoline 2-imino-3- (4-fluoro-3- (trifluoro
Methyl) phenyl) -5-ethyl-4-thiazoline The acid used in the present invention includes a protonic acid,
Metal salts having chair acidity and mixtures thereof
It is.

[0004] In one embodiment of the acid treatment of the present invention, a thiourea derivative represented by the general formula (5) is treated with a strongly acidic protonic acid, wherein the iminothiazoline derivative represented by the general formula (6) is treated. Manufacturing method.
Here, as a specific example of the strongly acidic protonic acid, sulfuric acid (concentration is usually 98 to 50%, preferably 98 to 75%
And strongly acidic organic acids such as trifluoromethanesulfonic acid, methanesulfonic acid, trifluoroacetic acid and the like, which have an acid strength equal to or higher than that of sulfuric acid.
The reaction is usually carried out without a solvent, but a solvent inert to an acid may coexist. Solvents that can be used in the reaction include
Aliphatic hydrocarbon solvents such as heptane and hexane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, halogenated hydrocarbon solvents such as monochlorobenzene, chloroform and ethylene dichloride, and carboxylic acid solvents such as formic acid and acetic acid And the like, and mixtures thereof.
The reaction is usually carried out for 0.2 to 24 hours, usually for 0 to 150 hours.
C., preferably at a temperature of 20 to 120.degree.
Performed at a temperature in the range of The amount ratio of the reagent used is such that the amount of the strongly acidic protic acid is usually 1 to 1000 mol per 1 mol of the thiourea derivative represented by the general formula (5). After completion of the reaction, the reaction solution is neutralized with an alkali by adding water, and then subjected to a normal treatment such as extraction and concentration with an organic solvent, and, if necessary, purified by an operation such as chromatography to obtain the desired solution. An iminothiazoline derivative represented by the following general formula 6 can be obtained.

[0005] Another embodiment of the acid treatment of the present invention is as follows.
The thiourea derivative represented by the general formula (5) is converted to a Lewis acid
Characterized by treatment with a metal salt having a carbon atom and a protonic acid
An iminothiazoline derivative represented by the general formula:
Body manufacturing methods. Where it has Lewis acidity
Specific examples of metal salts include stannic chloride (SnCl _Four)
 , Stannic bromide (SnBr_Four), Stannic iodide (SnI_Four)
 Tin halides such as zinc chloride (ZnCl_Two), Bromide
Zinc (ZnBr_Two), Zinc iodide (ZnI_Two) Etc. zinc halo
Genide, cupric chloride (CuCl_Two) Etc.
Material, aluminum chloride (AlCl_Three) Etc.
Logenates. These metal salts are anhydrous
It is not necessary to use crystallization water. Protic acid
Specific examples of inorganic acids such as hydrochloric acid and sulfuric acid, meta
Sulfonic acid, trifluoroacetic acid, trifluoromethane
Organic acids such as sulfonic acid may be mentioned.
Metal salt is solvolyzed in the reaction system to form a protonic acid.
If it occurs, it is not necessary to add it. The reaction proceeds
Usually, the reaction is carried out in a solvent.
Aliphatic hydrocarbon solvents such as butane and hexane,
Aromatic solvents such as toluene, xylene,
Nochlorobenzene, chloroform, ethylene dichlori
Halogenated hydrocarbon solvents such as
Ether solvents such as tetrahydrofuran and dioxane,
Carbonyl solvents such as acetone and methyl isobutyl ketone
Medium, alcoholic solvents such as methanol and ethanol,
1,3-dimethyl-2-imidazolidone, N, N-dimethyl
Such as tylformamide, dimethyl sulfoxide, etc.
Include mixtures thereof. The reaction is usually carried out at 0.2
24 hours, usually at a temperature within the range of 0 to 150 ° C
And preferably at a temperature in the range of 20 to 120 ° C.
You. The quantitative ratio of the reagent used is represented by the general formula (5).
Lewis acidity per mole of thiourea derivative
Metal salt is usually 0.01 to 20 mol, post-treatment and reaction rate
Is preferably 0.2 to 2 mol due to the effect of
Tonic acid is usually in a proportion of 1 to 100 mol. After the reaction
As a post-treatment method, water is added to the reaction solution after the reaction is completed.
Neutralized with alkali and, if necessary, filtered or otherwise treated
After that, normal processing such as extraction and concentration with an organic solvent is performed,
If necessary, purify by operations such as chromatography.
Thus, the 2-imine represented by the general formula 6 of the target product is obtained.
A nothiazoline derivative can be obtained.

As another embodiment of the acid treatment of the present invention, a thiourea derivative represented by the general formula (5) is reacted in the presence of a metal salt having Lewis acidity (hereinafter referred to as reaction a).
Let the general formula

Embedded image [Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent the same meaning as described above. A method for producing a 2-iminothiazoline derivative represented by the general formula (6), which comprises treating a 2-iminothiazolidine derivative represented by the following formula (1) with a protonic acid (hereinafter referred to as reaction b). Is mentioned. Specific examples of metal salts having Lewis acidity in the reaction a include tin halides such as stannic chloride (SnCl ₄ ), stannic bromide (SnBr ₄ ), and stannic iodide (SnI ₄ ). Chloride, zinc chloride (ZnCl ₂ ), zinc bromide (ZnBr ₂ ),
Examples include zinc halides such as zinc iodide (ZnI ₂ ), copper halides such as cupric chloride (CuCl ₂ ), and aluminum halides such as aluminum chloride (AlCl ₃ ). Further, these metal salts do not need to be anhydrous, and may include water of crystallization. The reaction is usually performed in a solvent, and as a solvent that can be used for the reaction, heptane,
Aliphatic hydrocarbon solvents such as hexane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, halogenated hydrocarbon solvents such as monochlorobenzene, chloroform and ethylene dichloride, and ether solvents such as dimethoxyethane, tetrahydrofuran and dioxane Solvent, acetone,
Examples thereof include carbonyl solvents such as methyl isobutyl ketone, alcohol solvents such as methanol and ethanol, 1,3-dimethyl-2-imidazolidone, N, N-dimethylformamide, dimethyl sulfoxide and the like, and mixtures thereof. The reaction is carried out usually at a temperature in the range of 0 to 150 ° C., preferably at a temperature in the range of 50 to 120 ° C., for 0.2 to 24 hours. The amount ratio of the reagent used is such that a metal salt having Lewis acidity is usually used per mole of the thiourea derivative represented by the general formula (5).
The ratio is preferably 0.01 to 20 mol, and more preferably 0.2 to 2 mol from the influence of the post-treatment and the reaction rate. Specific examples of the protonic acid in the reaction b include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as methanesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid. The reaction is usually performed in a solvent, and solvents that can be used in the reaction include aliphatic hydrocarbon solvents such as heptane and hexane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, monochlorobenzene, and chloroform. , Solvents such as dimethoxyethane, tetrahydrofuran and dioxane, carbonyl solvents such as acetone and methyl isobutyl ketone, alcohol solvents such as methanol and ethanol, acetic acid, trifluoroacetic acid Carboxylic acid solvents such as
Examples thereof include 1,3-dimethyl-2-imidazolidone, N, N-dimethylformamide, dimethylsulfoxide, water, and the like, and a mixture thereof. The reaction is usually performed at 0.
The reaction is usually carried out at a temperature in the range of 0 to 150 ° C., preferably at a temperature in the range of 20 to 100 ° C., for 2 to 24 hours. The amount ratio of the reagent used is such that the acid is usually 1 to 100 mol per 1 mol of the 2-iminothiazolidine derivative represented by the general formula (7). As a specific treatment method for the protonic acid, the isolated 2-iminothiazolidine derivative represented by the general formula (7) may be treated, or the thiourea derivative represented by the general formula (5) may be used. The reaction solution after completion of the reaction as a 2-iminothiazolidine derivative represented by the formula (1) may be treated in the presence of a metal salt having Lewis acidity. As a post-treatment method after the completion of the reaction of the reaction a and the reaction b, water is added to the reaction solution after the completion of the reaction, the mixture is neutralized with an alkali, and if necessary, filtered and the like, extracted with an organic solvent, The compound represented by the general formula (6) or (7) can be obtained by performing a usual treatment such as concentration and purifying by an operation such as chromatography if necessary.

The starting compound used in the present invention has the general formula
The thiourea derivative represented by the chemical formula 5 is, for example, represented by the following reaction formula
Chemical formula 8

Embedded image [Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ represent the same meaning as described above, and Y represents a leaving group (for example, chlorine atom, bromine atom, mesyloxy group, tosyloxy group). Represent. ] Can be obtained.

[0008]

EXAMPLES Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to these Examples. In addition, the purity of the obtained product was determined from the result of NMR spectrum and liquid chromatography. NM
Those in which no impurity peak was observed in the R spectrum and liquid chromatography were regarded as pure. The yield of the obtained product is determined from the weight of the isolated product, or an external standard method using liquid chromatography (LC-ES method) or an internal standard method using gas chromatography (GC -IS method). In the LC-ES method, the detection intensity of the isolated pure target substance in liquid chromatography at a constant concentration is determined, and then the reaction solution after the reaction is adjusted to a constant concentration to detect the target substance in the liquid chromatography. The yield was calculated from the intensity.
The liquid chromatography column used was a reverse phase OD
Using SA212 (manufactured by Sumika Chemical Analysis Service, Ltd.), the developing solvent is pH 7.2 phosphate buffer aqueous solution: methanol: tetrahydrofuran = 40: 55: 5. In the GC-IS method, the ratio of the detected intensity of the isolated pure target substance to the internal standard substance (biphenyl) detected by gas chromatography is determined. The substance was added, and the yield was calculated based on the detection intensity ratio of gas chromatography. The gas chromatography column used was a wide bore capillary column D
B-1 (manufactured by J & W Scientific Inc.)
Using 53mm x 30m, carrier is helium 10ml / mi
n.

Example 1 N- (3- (trifluoromethyl) phenyl) -N-
1.00 g of (2-chloro-2-propenyl) thiourea
Was added to 9.96 g of 98% sulfuric acid while stirring at room temperature.
And stirred at the same temperature for 1.0 hour. After cooling, ice water was added to the reaction solution, neutralized with sodium carbonate, extracted with ethyl acetate, and the organic layer was washed with water. The solvent was distilled off under reduced pressure to give oily 2-imino-3- (3- (trifluoromethyl) phenyl) -5-methyl-4-thiazoline.
835 g (yield 81% (corrected value based on purity described later) was obtained. The purity was 8 based on the result of liquid chromatography analysis.
5%. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 7.9 to 7.5 (4H, m), 6.3 (1
H, q), 5.3 (1H, br), 2.1 (3H, d) mass (FD): m / e parent peak 258 Example 2 N- (3- (trifluoromethyl) phenyl) -N-
29.5 mg of (2-chloro-2-propenyl) thiourea was added to 1.0 ml of 90% sulfuric acid with stirring at room temperature, the temperature was raised to 90 ° C., and the mixture was stirred at the same temperature for 1 hour. After cooling, the reaction solution was diluted to a predetermined amount with ice water and acetonitrile. According to the LC-ES method, the yield of 2-imino-3- (3- (trifluoromethyl) phenyl) -5-methyl-4-thiazoline was 60%.
Met. Example 3 N- (3- (trifluoromethyl) phenyl) -N-
29.5 mg of (2-chloro-2-propenyl) thiourea was added to 1.0 ml of trifluoromethanesulfonic acid while stirring at room temperature, and the mixture was stirred at 25 ° C for 1 hour. After cooling, the reaction solution was diluted to a predetermined amount with ice water and acetonitrile. LC-ES
According to the method, the yield of 2-imino-3- (3- (trifluoromethyl) phenyl) -5-methyl-4-thiazoline was 86%. Example 4 0.30 g of N- (3,5-dichlorophenyl) -N- (2-chloro-2-propenyl) thiourea was added to 9
The mixture was added to 3.5 g of 0% sulfuric acid, heated to 90 ° C., and stirred at the same temperature for 1 hour. After cooling, water was added to the reaction solution, neutralized with sodium hydrogen carbonate, extracted with ethyl acetate, and the organic layer was washed with water. The solvent was distilled off under reduced pressure, and the resulting oily substance was subjected to silica gel column chromatography to give 2-
0.16 g (62% yield) of imino-3- (3,5-dichlorophenyl) -5-methyl-4-thiazoline was obtained. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 7.4 (2H, d), 7.2 (1H,
t), 6.3 (1H, q), 5.3 (1H, br), 2.0 (3H, d) Example 5 N-butyl-N- (2-chloro-2-propenyl)-
0.2% of N'-phenylthiourea was stirred at room temperature for 90%.
The mixture was added to 2.5 g of sulfuric acid, heated to 50 ° C., and stirred for 1.5 hours. After cooling, water was added to the reaction solution, neutralized with sodium hydrogen carbonate, extracted with ethyl acetate, and the organic layer was washed with water. The solvent was distilled off under reduced pressure to obtain 0.09 g of oily 2- (N-phenylimino) -3-butyl-5-methyl-4-thiazoline (yield 34%). ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 7.4 to 7.2 (5H, m), 6.5 (1
H, q), 4.1 (2H, t), 2.0 (3H, d), 1.8 (2H, tt), 1.4 (2H,
tq), 1.0 (3H, t)

Example 6 N- (3- (trifluoromethyl) phenyl) -N-
2.94 g of (2-chloro-2-propenyl) thiourea and 6.08 g of zinc chloride were added to 50 ml of xylene at room temperature, and 90
C. and the mixture was stirred at the same temperature for 1.5 hours. After cooling, water was added to the reaction solution, neutralized with potassium hydrogen carbonate, extracted with ethyl acetate, and the organic layer was washed with water. The oil obtained by evaporating the solvent under reduced pressure was subjected to preparative liquid chromatography, and 2-imino-3- (3- (trifluoromethyl)
1.92 g of phenyl) -5-methylidenethiazolidine was obtained (yield 74%). From the results of liquid chromatography,
Purity was over 99%. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 7.9 to 7.3 (4H, m), 6.9 (1
H, br), 5.3 (1H, dd), 5.1 (1H, dd), 4.6 (2H, t) mass (FD): m / e parent peak 258 2-imino-3- (3 29.4 mg of-(trifluoromethyl) phenyl) -5-methylidenethiazolidine was added to 0.5 ml of 90% sulfuric acid, heated to 40 ° C and stirred at the same temperature for 1 hour. After cooling, the mixture was neutralized with sodium hydrogen carbonate, extracted with ethyl acetate, and the organic layer was washed with water. After the solvent was concentrated under reduced pressure, it was dissolved in acetonitrile together with biphenyl. According to the GC-IS method, 2-imino-3- (3- (trifluoromethyl) phenyl) -5-
The yield of methyl-4-thiazoline is 98% [2-imino-
3- (3- (trifluoromethyl) phenyl) -5-methylidenethiazolidine]. The above 2-
Imino-3- (3- (trifluoromethyl) phenyl)
59.4% of methylidenethiazolidine in 35% hydrochloric acid
The mixture was added to 0.5 ml, heated to 40 ° C., and stirred at the same temperature for 1 hour. After cooling, the mixture was neutralized with sodium hydrogen carbonate, extracted with ethyl acetate, and the organic layer was washed with water. After the solvent was concentrated under reduced pressure, it was dissolved in acetonitrile together with biphenyl.
According to the GC-IS method, the yield of 2-imino-3- (3- (trifluoromethyl) phenyl) -5-methyl-4-thiazoline was 96% [2-imino-3- (3- (trifluoromethyl) )) Phenyl) -5-methylidenethiazolidine. Example 7 N- (3- (trifluoromethyl) phenyl) -N-
29 mg of (2-chloro-2-propenyl) thiourea and 63 mg of zinc bromide were added to about 2 g of xylene at room temperature to give 90 mg.
C. and the mixture was stirred at the same temperature for 1 hour. After cooling, the mixture was diluted to a predetermined amount with water and acetonitrile. According to the LC-ES method, the yield of 2-imino-3- (3- (trifluoromethyl) phenyl) -5-methylidenethiazolidine was 85%.
Met. The thus obtained 2-imino-3- (3-
(Trifluoromethyl) phenyl) -5-methylidenethiazolidine was prepared in the same manner as described in the latter half of Example 9 by using 2-imino-3- (3- (trifluoromethyl)
Phenyl) -5-methyl-4-thiazoline. Example 8 N- (3- (trifluoromethyl) phenyl) -N-
294 mg of (2-chloro-2-propenyl) thiourea and 24 μl of stannic chloride anhydride were added to 1.0 ml of trifluoroacetic acid.
At room temperature, and the mixture was heated to 75 ° C. and stirred at the same temperature for 3 hours. After cooling, water was added and neutralized with sodium hydrogen carbonate, and then diluted to a predetermined amount with acetonitrile. LC
According to the -ES method, the yield of 2-imino-3- (3- (trifluoromethyl) phenyl) -5-methyl-4-thiazoline was 84%. Example 9 N- (3- (trifluoromethyl) phenyl) -N-
1.47 g of (2-chloro-2-propenyl) thiourea and 0.09 g of stannic chloride n-hydrate (n = 4 to 5) were added to 7.50 g of methyl isobutyl ketone at room temperature, and the temperature was raised to 90 ° C. For 7 hours. After cooling, 0.52 g of 35% hydrochloric acid
Was added with stirring, the temperature was raised to 90 ° C., and the mixture was stirred at the same temperature for 2.5 hours. After cooling, water was added, the mixture was neutralized with sodium hydrogen carbonate, extracted with methyl isobutyl ketone, and the organic layer was washed with water. The solvent was distilled off under reduced pressure to give 2-imino-3- (3
-(Trifluoromethyl) phenyl) -5-methyl-4
1.08 g of thiazoline [yield 75% (corrected from the purity described later)] was obtained. The purity was 89% based on the result of liquid chromatography. Example 10 N- (3- (trifluoromethyl) phenyl) -N-
295 mg of (2-chloro-2-propenyl) thiourea and 64 mg of zinc chloride were added to 2.50 g of methyl isobutyl ketone at room temperature, and 100 mg of 35% hydrochloric acid was further added at room temperature with stirring.
The temperature was raised to 0 ° C., and the mixture was stirred at the same temperature for 9 hours. After cooling, 137 mg of zinc chloride was added with stirring, the temperature was raised to 90 ° C., and the mixture was stirred at the same temperature for 2 hours. After cooling, the reaction solution was diluted to a predetermined amount with acetonitrile. According to the LC-ES method, 2-imino-
The yield of 3- (3- (trifluoromethyl) phenyl) -5-methyl-4-thiazoline was 65%. Example 11 N- (4-methoxyphenyl) -N- (2-chloro-2
- propenyl) the n-hydrate (n = 4 to 5) 0.14 g of stannic chloride and thiourea 0.2 1 g was added under stirring at room temperature to 1,3-dimethyl-2-imidazolidone 2.5g, to 90 ° C. The mixture was heated and stirred at the same temperature for 1 hour. Next, 0.16 g of 35% hydrochloric acid was added with stirring at 90 ° C., and the mixture was stirred at 90 ° C. for 11 hours. After cooling, water was added to the reaction solution, neutralized with sodium hydrogen carbonate, extracted with ethyl acetate, and the organic layer was washed with water. The solvent was distilled off under reduced pressure to give oily 2-imino-3- (4-methoxyphenyl) -5-methyl-4-thiazoline and 1,3
0.28 g of a mixture of -dimethyl-2-imidazolidone were obtained. ^{According to 1} H-NMR, the yield of 2-imino-3- (4-methoxyphenyl) -5-methyl-4-thiazoline was 53%.
Met.

Next, a production example of a thiourea derivative represented by the general formula (5), which is a raw material compound used in the present invention, will be described. Reference Example 1 18.6 g of N- (3- (trifluoromethyl) phenyl) cyanamide was dissolved in 93.0 g of dimethylformamide, and 20.7 g of potassium carbonate and 1.7 g of potassium iodide were added thereto with stirring at room temperature. Further, 2,3-dichloropropene was added dropwise at room temperature with stirring, then the temperature was raised to 50 ° C., and the mixture was stirred at the same temperature for 1 hour. After cooling to room temperature, water was added and extracted with ethyl acetate,
The organic layer was washed with water. The solvent was distilled off under reduced pressure, and oily N- (3- (trifluoromethyl) phenyl) -N-
25.8 g (99% yield) of (2-chloro-2-propenyl) cyanamide was obtained. According to the result of liquid chromatography, the purity was 99% or more. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 7.8 to 7.3 (4H, m), 5.6 (2
H, s), 4.4 (2H, s) mass (EI): m / e parent peak 260 N- (3- (trifluoromethyl)
23.2 g of phenyl) -N- (2-chloro-2-propenyl) cyanamide was dissolved in ethanol, and the S content was 0.6.
% Ammonium sulfide aqueous solution was added dropwise with stirring at room temperature, then the temperature was raised to 50 ° C., and the mixture was stirred at the same temperature for 8 hours. After cooling to room temperature, ethanol was distilled off under reduced pressure, followed by extraction with ethyl acetate, and the organic layer was washed with water. The solvent was distilled off under reduced pressure to obtain solid N- (3- (trifluoromethyl) phenyl) -N- (2-chloro-2-propenyl) thiourea.
25.2 g (96% yield) was obtained. According to the result of liquid chromatography, the purity was 99% or more. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 7.8 to 7.6 (4H, m), 5.9 (2
H, br), 5.4 (2H, s), 5.1 (2H, s) mass (FD): m / e parent peak 294

[0012]

According to the present invention, a 2-iminothiazoline derivative represented by the general formula 6 can be easily produced.

──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Akihiko Nakamura 2-10-1 Tsukahara, Takatsuki City, Osaka Prefecture Inside Sumitomo Chemical Co., Ltd. (56) References JP-A-53-90222 (JP, A) (58) Surveyed fields (Int. Cl. ⁷ , DB name) C07D 277/00-277/593 CA (STN) REGISTRY (STN) WPI (DIALOG)

Claims (7)

(57) [Claims] 1. A compound represented by the general formula: [Wherein, R ¹ represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, and R ² represents A hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group,
An aryl group which may be substituted, an alkylcarbonyl group which may be substituted, a cycloalkylcarbonyl group which may be substituted, an arylcarbonyl group which may be substituted, an alkoxycarbonyl group which may be substituted; Represents an optionally substituted cycloalkyloxycarbonyl group or an optionally substituted aryloxycarbonyl group, wherein R ³ , R ⁴ and R ⁵ are the same or different and are a hydrogen atom, an optionally substituted alkyl A group or an aryl group which may be substituted;
Represents a halogen atom. Wherein the thiourea derivative represented by the general formula (1) is treated with an acid. [Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent the same meaning as described above. ] The method for producing a 2-iminothiazoline derivative represented by the formula: 2. The method according to claim 1, wherein the acid is a strongly acidic protic acid. 3. The method according to claim 1, wherein the acid is a metal salt having Lewis acidity and a protic acid. 4. The thiourea derivative represented by the general formula 1 is treated with a metal salt having Lewis acidity to obtain a thiourea derivative represented by the general formula 3 [Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent the same meaning as described above. A method for producing a 2-iminothiazoline derivative represented by the above general formula 2, wherein a 2-iminothiazolidine derivative represented by the following general formula (2) is obtained and treated with a protonic acid. 5. A method for producing a 2-iminothiazolidine derivative represented by the general formula 3, wherein the thiourea derivative represented by the general formula 1 is treated with a metal salt having Lewis acidity. 6. A method for producing a 2-iminothiazoline derivative represented by the general formula 2, wherein the 2-iminothiazolidine derivative represented by the general formula 3 is treated with a protonic acid. 7. In the above-mentioned general formula 1 , R ¹ is ( C 1-8 alkoxy, phenyl, α
-A naphthyl group, a β-naphthyl group and a C3-8
A plurality of substituents selected from
An alkyl group having 1 to 8 carbon atoms which may be
To 8 alkyl groups, 1 to 8 carbon alkoxy groups,
Nyl, α-naphthyl and β-naphthyl groups)
Having 3 carbon atoms which may be substituted by a plurality of substituents
To 8 cycloalkyl groups, (multiple substituted with halogen atoms
An alkyl group having 1 to 8 carbon atoms which may be
Alkoxy having 1 to 8 carbon atoms which may be substituted by a plurality of
Si group, phenyl group, α-naphthyl group, β-naphthyl group,
Nitro group and halogen atom)
A phenyl group which may be substituted plural times;
Alkyl having 1 to 8 carbon atoms which may be substituted by a plurality of
A group having 1 or more carbon atoms which may be substituted by a plurality of halogen atoms
To 8 alkoxy groups, phenyl groups, α-naphthyl groups, β
-Naphthyl group, nitro group and halogen atom)
Α-naphthyl optionally substituted by a plurality of substituents
Group, (a carbon atom optionally substituted by multiple halogen atoms)
A plurality of alkyl groups of the formulas 1 to 8,
An alkoxy group having 1 to 8 carbon atoms, a phenyl group,
α-naphthyl group, β-naphthyl group, nitro group and halo
Multiply substituted by a substituent selected from
Β-naphthyl group, which may be substituted with multiple halogen atoms.
An alkyl group having 1 to 8 carbon atoms which may be
Alkoxy having 1 to 8 carbon atoms which may be substituted by a plurality of
Si group, phenyl group, α-naphthyl group, β-naphthyl group,
Nitro group and halogen atom)
A pyridyl group optionally substituted with a
Alkyl having 1 to 8 carbon atoms which may be substituted by a plurality of
A group having 1 or more carbon atoms which may be substituted by a plurality of halogen atoms
To 8 alkoxy groups, phenyl groups, α-naphthyl groups, β
-Naphthyl group, nitro group and halogen atom)
Pyrimidini which may be substituted by a plurality of substituents
Group, (a carbon atom optionally substituted by multiple halogen atoms)
A plurality of alkyl groups of the formulas 1 to 8,
An alkoxy group having 1 to 8 carbon atoms, a phenyl group,
α-naphthyl group, β-naphthyl group, nitro group and halo
Note that a plurality of substituted with a substituent selected from plasminogen atoms)
Thienyl group, which may be substituted with multiple halogen atoms
An alkyl group having 1 to 8 carbon atoms, a halogen atom
C1-C8 alkoxy optionally substituted
Group, phenyl group, α-naphthyl group, β-naphthyl group,
A substituent selected from toro and halogen)
A plurality of imidazolyl groups which may be substituted, (halogen
Alkyl having 1 to 8 carbon atoms which may be substituted by a plurality of atoms
The number of carbon atoms which may be plurally substituted with
1 to 8 alkoxy groups, phenyl groups, α-naphthyl groups,
β-naphthyl group, nitro group and halogen atom)
Thiazolyl which may be substituted by a plurality of substituents
Group, (a carbon atom optionally substituted by multiple halogen atoms)
A plurality of alkyl groups of the formulas 1 to 8,
An alkoxy group having 1 to 8 carbon atoms, a phenyl group,
α-naphthyl group, β-naphthyl group, nitro group and halo
Multiply substituted by a substituent selected from
An oxazolyl group which may be represented by the formula : R ² is a hydrogen atom, (an alkoxy group having 1 to 8 carbon atoms,
Nyl group, α-naphthyl group, β-naphthyl group and carbon number
3 to 8 cycloalkyl groups)
An alkyl group having 1 to 8 carbon atoms which may be substituted,
(C1-C8 alkyl group, C1-C8 alkoxide
Si, phenyl, α-naphthyl and β-naphthyl
A plurality of substituents selected from
A cycloalkyl group having 3 to 8 carbon atoms;
Alkyl group, alkoxy group having 1 to 8 carbon atoms, phenyl
Group, α-naphthyl group, β-naphthyl group, nitro group and
Halogen atom)
An optionally substituted phenyl group, (alkyl having 1 to 8 carbon atoms)
Group, an alkoxy group having 1 to 8 carbon atoms, a phenyl group, α-na
Phthyl group, β-naphthyl group, nitro group and halogen atom
A plurality of substituents selected from
Α-naphthyl group, (alkyl group having 1 to 8 carbon atoms, carbon
An alkoxy group of the formulas 1 to 8, a phenyl group, α-naphthyl
Group, β-naphthyl group, nitro group and halogen atom)
Β- which may be plurally substituted by a selected substituent
Naphthyl group, (alkoxy group having 1 to 8 carbon atoms, phenyl
Group, α-naphthyl group, β-naphthyl group and 3 to
8 cycloalkyl groups)
Optionally substituted alkyl [C1-8] carbo
Nyl group, (C1-8 alkyl group, C1-8
Alkoxy, phenyl, α- naphthyl and β-
Naphthyl group)
Cycloalkyl [3 to 8 carbon atoms] carbonyl
Group, (alkyl group having 1 to 8 carbon atoms, alkyl group having 1 to 8 carbon atoms)
Coxy group, phenyl group, α-naphthyl group, β-naphthyl
Group, nitro group and halogen atom)
Optionally substituted by phenylcarbonyl
Group, (alkyl group having 1 to 8 carbon atoms, alkyl group having 1 to 8 carbon atoms)
Coxy group, phenyl group, α-naphthyl group, β-naphthyl
Group, nitro group and halogen atom)
Α-naphthyl carbonyl which may be plurally substituted by
Group, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms.
Lucoxy group, phenyl group, α-naphthyl group, β-naphthyl
, Nitro and halogen)
Β-naphthylcarbo which may be substituted by a plurality of groups
Nyl group, (alkoxy group having 1 to 8 carbon atoms, phenyl group,
α-naphthyl group, β-naphthyl group and C 3-8
Multiple substitution with a substituent selected from cycloalkyl group)
Optionally substituted alkoxy [C1-8] carbonyl
Group, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms.
Lucoxy, phenyl, α-naphthyl and β-na
A plurality of substituents selected from
Cycloalkyl [C3-8] oxycarbo
Nil group, (the number of carbon atoms which may be
1 to 8 alkyl groups, even when plurally substituted with halogens
Good alkoxy group having 1 to 8 carbon atoms, phenyl group, α-na
Phthyl group, β-naphthyl group, nitro group and halogen atom
A plurality of substituents selected from
Phenyloxycarbonyl group, (multiple substitution with halogen
An alkyl group having 1 to 8 carbon atoms which may be
Having 1 to 8 carbon atoms which may be substituted by a plurality of
Group, phenyl group, α-naphthyl group, β-naphthyl group,
A substituent selected from toro and halogen)
Optionally substituted plural-substituted α-na
A phenyloxycarbonyl group, (multiple substituted with halogen
An alkyl group having 1 to 8 carbon atoms which may be
A C1-C8 alkoxy group which may be substituted,
Phenyl group, α-naphthyl group, β-naphthyl group, nitro
Group and a halogen atom)
Β-naphthy which may be substituted
And R ¹ and R ² are the same
Sometimes, (alkoxy group having 1 to 8 carbon atoms, phenyl group, α
-A naphthyl group, a β-naphthyl group and a C3-8
A plurality of substituents selected from
Which is not an alkyl group having 1 to 8 carbon atoms which may be substituted, R ³ , R ⁴ and R ⁵ represent a hydrogen atom,
Coxy group, phenyl group, α-naphthyl group, β-naphthyl
And cycloalkyl groups having 3 to 8 carbon atoms)
1 to 8 carbon atoms which may be substituted by a plurality of substituents
An alkyl group, (an alkoxy group having 1 to 8 carbon atoms, phenyl
Group, α-naphthyl group, β-naphthyl group, nitro group and
And halogen atoms)
An optionally substituted phenyl group which may be substituted,
(C1-C8 alkoxy, phenyl, α-naph
Tyl group, β-naphthyl group, nitro group and halogen atom
A plurality of substituents selected from
A plurality of optionally substituted α-naphthyl groups,
1 to 8 alkoxy groups, phenyl groups, α-naphthyl groups,
β-naphthyl group, nitro group and halogen atom)
Multi-substitution which may be plurally substituted by the same substituent
Β-naphthyl group optionally having 1 to 8 carbon atoms
A thiourea derivative wherein X is a halogen atom .