JPH0819112B2 - Hydantoin derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel hydantoin derivative. More specifically, it relates to a hydantoin derivative having an alkylidene substituent at the 5-position. The derivative is useful as a herbicide.

[Conventional technology]

It is known that among hydantoin derivatives, there are compounds showing physiological activity such as bactericidal activity such as herbicidal activity. Examples of compounds having herbicidal activity include Japanese Patent Publication No. 30-3069.
5, 51-36332, gazette, JP-A-57-58672, 57-197268, 5
Hydantoin derivatives described in 8-219167 and 61-69763 are known.

[Problems to be solved by the invention]

However, conventionally, hydantoin derivatives having herbicidal activity have been insufficient in herbicidal activity against highly damaging weeds, and new compounds capable of weeding these weeds in a low dose have been desired.

[Means for Solving Problems] As a result of studying various hydantoin derivatives, the present inventors have found that [In the formula, X and Y represent a halogen atom. R ¹ represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group or an alkynyl group, and R ² represents a hydrogen atom, an alkyl group, an alkenyl group or an alkynyl group. R ³ and R ⁴ each independently represent a hydrogen atom or a lower alkyl group. The present invention has been completed by discovering that the novel hydantoin derivative having an alkylidene group at the 5-position shown in the formula] shows a strong herbicidal activity at a low dose and can be a sufficiently practical herbicide.

The novel hydantoin derivative represented by the general formula (1), which is the active ingredient of the present invention, can be produced, for example, by the following method.

That is, the general formula (A) [in the formula, X, Y, R ³ and R ⁴
Represents the same meaning as described above. This is represented by the general formula (1)
In the compound group represented by, both R ¹ and R ² are hydrogen atoms. ] In the presence of a base, a hydantoin derivative represented by the formula [ ^1] is used for R ¹ Z or R ² Z represented by the general formulas (2) and (3) [wherein R ¹ and R ² have the same meanings as described above]. Z is a leaving group. ] Sequentially or simultaneously on the oxygen atom and the nitrogen atom to form R ¹
Group and R ² group by introducing the general formula (B),
(C) and (D) [wherein X, Y, R ¹ , R ² , R ³ and
R ⁴ has the same meaning as described above. ] The hydantoin derivative shown by these can be manufactured easily.

The reaction is preferably carried out in an organic solvent. Examples of the organic solvent include tetrahydrofuran, diethyl ether, dimethoxyethane, dimethylformamide, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, benzene, toluene and the like.

The reaction is carried out in the presence of a base, for example n-
Use butyl lithium, sec-butyl lithium, methyl lithium, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, calcium hydroxide, etc. You can

The reaction temperature varies depending on the base and solvent used,
It is selected from the range of -78 ° C to 150 ° C.

In this reaction, the product can be isolated as crystals by a usual post-treatment after the completion of the reaction, but if necessary, it is purified by silica gel column chromatography, recrystallization or the like.

Moreover, the hydantoin derivative represented by the general formula (A) can be produced by the following method.

That is, general formula (4) [wherein X, Y, R ³ and R ⁴
Represents the same meaning as described above. R ⁵ represents a lower alkyl group or an aralkyl group. The hydantoin derivative represented by the general formula (A) can be obtained by removing the carbonate group in the presence of a base.

Further, the hydantoin derivative represented by the general formula (C) can be produced by the same production method. That is, the hydantoin derivative represented by the general formula (4) is converted into the compound R ² Z represented by the general formula (3) in the presence of a base, wherein R ² and Z have the same meanings as described above. ] And a nitrogen atom is alkylated to form a hydantoin derivative (5) [wherein
X, Y, R ² , R ³ , R ⁴ , and R ⁵ have the same meanings as described above. ] Then, by treating with a base to remove the carbonate group, the hydantoin derivative represented by the general formula (C) can be produced.

Examples of the halogen atom represented by X and Y in the novel hydantoin derivative represented by the general formula (1) of the present invention which can be produced in this manner include chlorine, bromine, fluorine and iodine. . As the alkyl group represented by R ¹ , a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group,
sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, octyl group, 1-methyloctyl group ,
Examples of the cycloalkyl group such as 2-ethylhexyl group, decyl group and dodecyl group include cyclopropyl group, cyclopentyl group, cyclohexyl group and cyclododecyl group. As the alkenyl group, an allyl group, a methallyl group, a crotyl group, a 1-methylallyl group, 1,
1-dimethylallyl group, prenyl group, 3-methyl-3-
Butenyl group, 3-pentenyl group, 2-methyl-3-butenyl group, neryl group, geranyl group, 1-chloroallyl group,
Examples of the alkynyl group such as 2-chloroallyl group, 3-chloroallyl group, 3-bromoallyl group, 2-bromo-2-butenyl group are propargyl group, 1-methylpropargyl group, 1,1-dimethylpropargyl group and 1-ethyl group. Examples include propargyl group, 2-butynyl group, 1-methyl-2-butynyl group, 3-pentynyl group, 3-butynyl group and 2-pentynyl group.

Examples of the lower alkyl group represented by R ³ and R ⁴ include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and a sec-butyl group.

Table 1 shows representative ones of the novel hydantoin derivatives of the present invention.

The compounds represented by the general formulas (2) and (3), which are raw materials for producing the compound of the present invention, are easily available,
And compounds that can be easily prepared from commercially available raw materials, and examples of the compound represented by the general formula (2) include methyl bromide, methyl iodide, ethyl bromide, ethyl iodide, propyl bromide, propyl iodide, isopropyl bromide, isopropyl iodide, Butyl bromide, butyl iodide, isobutyl bromide, sec-butyl bromide, pentyl iodide, isopentyl iodide, hexyl iodide, 1-methylpentyl bromide,
Alkyl halogen compounds such as 2-methylpentyl iodide, octyl bromide, octyl iodide, dodecyl bromide, cycloalkyl bromides such as cyclopropyl bromide, cyclopentyl bromide, cyclohexyl bromide, allyl chloride, allyl bromide, methallyl chloride, methallyl Bromide, crotyl bromide, crotyl chloride, 3-bromo-1-butene, 3-
Bromo-3-methyl-1-butene, prenyl bromide,
4-bromo-2-methyl-1-butene, 1-bromo-3
-Unsaturated halogen compounds having a double bond such as pentene, geranyl bromide, 1,3-dichloropropene, 2,3-dichloropropene, 2,3-dibromo-1-butene, propargyl chloride, propargyl bromide, propargyl iodide , 1-bromo-2-butyne, 1-chloro-2
-Butyne, 3-chloro-1-butyne, 3-bromo-1-
Butyne, 3-bromo-1-pentyne, 3-bromo-3-
Methyl-1-butyne, 3-chloro-3-methyl-1-butyne, 2-bromo-2-pentyne, 6-chloro-1-hexyne, 1-bromo-3-pentyne, 4-bromo-1-
Unsaturated halogen compounds having a double bond such as butyne,
Or allyl alcohol, methallyl alcohol, 3-
Methyl-3-buten-1-ol, 2-methyl-3-buten-2-ol, prenyl alcohol, galaniol, nerol, propargyl alcohol, 1-butyl-
3-ol, 3-methyl-1-butyl-3-ol, 1
-Unsaturated alcohols such as butyn-4-ol and benzene sulfonic acid esters of normal aliphatic alcohols,
A p-toluenesulfonic acid ester, a sulfuric acid ester, or the like can be used. Examples of the compound represented by the general formula (3) include methyl bromide, methyl iodide, ethyl bromide, ethyl iodide, isopropyl bromide, isopropyl iodide, butyl bromide, butyl iodide, isobutyl bromide, sec-butyl bromide, pentyl iodide, isopentyl iodide. Alkyl halogen compounds such as de, hexyl iodide, 1-methylpentyl bromide, 2-methylpentyl iodide, octyl bromide, octyl iodide, dodecyl bromide,
Cycloalkyl halogen compounds such as cyclopropyl bromide, cyclopentyl bromide, cyclohexyl bromide, allyl chloride, allyl bromide, methallyl chloride, methallyl bromide, crotyl bromide, crotyl chloride, 3-bromo-1-butene, 3-bromo- 3-
Methyl-1-butene, prenyl bromide, 4-bromo-
2-methyl-butene, 4-bromo-3-methyl-1-butene, 1-bromo-3-pentene, geranyl bromide,
1,3-dichloropropene, 2,3-dichloropropene, 2,3
-Unsaturated halogen compounds having a double bond such as dibromo-1-butene, propargyl chloride, propargyl bromide, propargyl iodide, 1-bromo-2-butyne, 1-chloro-2-butyne, 1-chloro-2- Butyne, 3-chloro-1-butyne, 3-bromo-1-butyne, 3-bromo-1-pentyne, 3-bromo-3-methyl-1-butyne, 3-chloro-3-methyl-1-butyne, 2-bromo-3-pentyne, 1-bromo-3-pentyne, 1-bromo-2-pentyne, 6-chloro-1-hexyne, 1-bromo-3-pentyne, 4-bromo-1-
Unsaturated halogen compounds having a triple bond such as butyne,
Or allyl alcohol, methallyl alcohol, 3-
Methyl-3-buten-1-ol, 2-methyl-3-buten-2-ol, prenyl alcohol, galaniol, nerol, propargyl alcohol, 1-butyne-
3-ol, 3-methyl-1-butyn-3-ol, 1
-Unsaturated alcohols such as butyn-4-ol and benzene sulfonic acid esters of normal aliphatic alcohols,
A sulfonic acid ester such as p-toluenesulfonic acid ester, or a sulfuric acid ester can be used.

The general formula (4) which is a precursor for the synthesis of the compound of the present invention
The hydantoin derivative represented by can be produced, for example, by the method shown below.

That is, the nitrobenzene derivative (5) [wherein, X and Y have the same meanings as described above. R ⁵ is a lower alkyl group or an aralkyl group. ] In the presence of hydrogen, platinum oxide,
An aniline derivative (6) [wherein X, Y and R ⁵ have the same meanings as described above] by reduction using a catalyst of platinum-carbon or palladium-carbon. ] Then, by treating this with phosgene gas or trichloromethyl chloroformate, an isocyanate derivative (7) [in the formula,
X, Y and R ⁵ have the same meanings as described above. ] Can be converted to. Next, this isocyanate derivative (7) and α-amino-α, β-unsaturated carboxylic acid ester (8) [in the formula, R ³ and R ⁴ each independently represent a hydrogen atom or a lower alkyl group, and R ⁶ Represents a lower alkyl group. ] General formula (9) obtained by reacting with [in the formula, X, Y, Z, R < ³ >, R < ⁴ >, R < ⁵ > and R < ⁶ > represent the same meaning as the above. ] The hydantoin derivative represented by the general formula (4) can be obtained by treating the urea derivative represented by the above formula in the presence of an acid or a base. (See Reference Example below) The urea conductor represented by the general formula (9), which is a raw material for producing the hydantoin derivative represented by the general formula (4), can also be produced by the following method.

That is, the general formula (7) that can be produced from the nitrobenzene derivative (5) shown above by the above-mentioned method.
A urea derivative (10) obtained by reacting an isocyanate derivative represented by
X, Y and R ⁵ have the same meanings as described above. ], In which R ³ , R ⁴ and R ⁶ have the same meanings as described above. ] It can be converted to the urea derivative represented by the general formula (9) by reacting the α-ketocarboxylic acid ester represented by the following in the presence of an acid catalyst. Then, this compound is treated in the presence of an acid or a base in the same manner as above to obtain the hydantoin derivative represented by the general formula (4). (See Reference Example below) Next, the present invention will be described in more detail with reference to Examples. The method for producing the raw materials used for producing the compound of the present invention is also shown below as a reference example.

Example 1 Put 3- (2'-fluoro-4'-chloro-5'-hydroxyphenyl) -5-isopropylidenehydantoin (25mg, 91.7μmol) in a screw cap test tube and add N, N-dimethylformamide (3ml) to dissolve. Let Add potassium carbonate (70 mg) and methyl iodide (100 μl), and add 9 at 40 ℃.
Stir for hours. After completion of the reaction, saturated aqueous ammonium chloride solution was added and the mixture was extracted with ether (3 ml × 3 times). The ether layer was washed with water (2 ml × 3 times) and dried over anhydrous magnesium sulfate. The desiccant was removed and the white solid that precipitated by concentrating the ether solution under reduced pressure was isolated by filtration. This is 1-methyl-3- (2'-fluoro-
4'-chloro-5'-methoxyphenyl) -5-isopropylidenehydantoin, 22 mg (80% yield)
%)Met.

Example 2 Add 3- (2 ', 4'-dichloro-5'- to an eggplant-shaped flask.
Hydroxyphenyl) -5-isopropylidenehydantoin (200 mg, 0.66 mmol) was added and N, N-dimethylformamide (20 ml) was added to dissolve it, and then potassium carbonate (914 mg) and methyl iodide (4 g) were added to 40 ° C. And reacted for 9 hours. After completion of the reaction, the mixture was acidified with 1N hydrochloric acid and extracted with ether (20 ml × 3 times). The organic layer is water (10 ml x 3)
After that, it was dried with anhydrous magnesium sulfate. The drying agent was removed, and the solution was concentrated under reduced pressure to give a colorless transparent oily substance. Ethanol was added, the mixture was cooled to −78 ° C., and the precipitated white solid (amount 213 mg, yield 98%) was collected by filtration. From the spectrum this is 1-methyl-3-
(2 ', 4'-dichloro-5'-methoxyphenyl) -5
-It was confirmed to be isopropylidene hydantoin.

Example 3 1-Methyl-3- (2'-fluoro-4'-chloro-5'-hydroxyphenyl) -5-isopropylidenehydantoin (965 mg, 3.2 mmol) was placed in an eggplant-shaped flask, and N, N-dimethylformamide (25 ml) was added. ) Was added and dissolved. Then, potassium carbonate (1.0 g) and 1,3-dichloropropene (2.8 ml) were added, and the mixture was stirred at 40 ° C. for 4 hours. After completion of the reaction, acidify with 1N hydrochloric acid and ether (10 ml x 3
Times). The organic layer was washed with water (5 ml x 3 times) and then dried over anhydrous magnesium sulfate. Remove the desiccant,
The solution was concentrated under reduced pressure to give a yellow oil (1.12 g). Purified using silica gel column chromatography (benzene / ethyl acetate = 4/1), 1-methyl-3- {2 '
-Fluoro-4'-chloro-5 '-(3 "-chloro-
2 ″ -propenyl) oxyphenyl} -5-isopropylidenehydantoin yellow oil (415 mg, yield 36%)
I got This product can be isolated as a pale yellow solid by recrystallization from ethanol.

Example 4 1-Methyl-3- (2′-fluoro-4′-chloro-5′-hydroxyphenyl) -5-isopropylidenehydantoin (500 mg, 1.7 mmol) was placed in an eggplant-shaped flask, and N, N-dimethylformamide (20 ml) was added. ) Was added and dissolved. Potassium carbonate (1.14 g) and 2,3-dichloropropene (1.54 ml) were added and the mixture was stirred at 40 ° C for 5 hours. After completion of the reaction, the mixture was acidified with 1N hydrochloric acid and extracted with ether (10 ml × 3 times). The organic layer was washed with water (5 ml x 3 times) and dried over anhydrous magnesium sulfate. The desiccant was removed and the solution was concentrated under reduced pressure to give a yellow oil. Add methanol-
After cooling to 78 ° C, the precipitated solid (135 mg, yield 22%) was collected by filtration. This spectrum shows that this is 1-methyl-3-
{2 ', 4'-dichloro-5'-(2 "-chloro-2"-
It was confirmed to be propenyloxy) phenyl} -5-isopropylidenehydantoin.

Example 5 1-Methyl-3- (2'-fluoro-4'-bromo-5'-hydroxyphenyl) -5-isopropylidenehydantoin (101 mg, 0.34 mmol) was placed in an eggplant-shaped flask, and N, N-dimethylformamide (10 ml) was added. ) Was added and dissolved. Potassium carbonate (200 mg) and propargyl bromide (350 mg) were added, and the mixture was stirred at 40 ° C for 5 hours. After completion of the reaction, the mixture was acidified with 1N hydrochloric acid and extracted with ether (10 ml × 3 times). The organic layer was washed with water (2 ml x 3 times) and dried over anhydrous magnesium sulfate. The desiccant was removed and the solution was concentrated under reduced pressure to give a colorless transparent oil. Ethanol was added and the mixture was cooled to -78 ° C and precipitated as a white solid (60 mg, yield 52%).
Was collected by filtration. The spectrum shows that this is 1-methyl-
It was confirmed to be 3- (2'-fluoro-4'-bromo-5'-propargyloxyphenyl) -5-isopropylidenehydantoin.

Example 6 Put 1-methyl-3- (2'-fluoro-4'-bromo-5'-hydroxyphenyl) -5-isopropylidenehydantoin (130mg, 0.38mmol) in an eggplant-shaped flask, and add acetonitrile (15ml) to dissolve. Let Potassium carbonate (275mg) and isopropyl iodide (650mg)
Was added and the mixture was stirred at 40 ° C. for 20 hours. After completion of the reaction, the mixture was acidified with 1N hydrochloric acid and extracted with ether (10 ml × 3 times). The organic layer was washed with water (5 ml x 3 times) and dried over anhydrous magnesium sulfate. The desiccant was removed and the solution was concentrated under reduced pressure to give a brown oil. Ethanol was added, the mixture was cooled to -78 ° C, and the precipitated colorless solid (70 mg, yield 47%) was collected by filtration. From the spectrum, this shows that 1-methyl-3 (2'-fluoro-4'-bromo-5'-isopropoxyphenyl)-
It was confirmed to be 5-isopropylidenehydantoin.

Example 7 Add 3- (2 ', 4'-dichloro-5'- to an eggplant-shaped flask.
Propargyloxyphenyl) -5-isopropylidenehydantoin (150 mg, 0.44 mmol) was added, and N, N-dimethylformamide (20 ml) was added and dissolved. Put potassium carbonate (300mg) and methyl iodide (630mg) at 60 ℃
It was stirred for 14 hours. After completion of the reaction, the mixture was acidified with 1N hydrochloric acid and extracted with ether (10 ml × 3 times). The organic layer was washed with water (5 ml x 3 times) and dried over anhydrous magnesium sulfate. The desiccant was removed and the solution was concentrated under reduced pressure to give a pale yellow oil. Ethanol was added, the mixture was cooled to -78 ° C, and the white solid (124 mg, yield 80%) that precipitated was collected by filtration. The spectrum confirmed that this was 1-methyl-3- (2 ', 4'-dichloro-5'-propargyloxyphenyl) -5-isopropylidenehydantoin.

Example 8 Add 3- (2 ', 4'-dichloro-5'- to an eggplant-shaped flask.
Isopropoxyphenyl) -5-isopropylidenehydantoin (140 mg, 0.41 mmol) was added, and N, N-dimethylformamide (15 ml) was added and dissolved. Add potassium carbonate (283mg) and methyl iodide (600mg) at 50 ℃ for 1
Stir for hours. After completion of the reaction, the mixture was acidified with 1N hydrochloric acid and extracted with ether (5 ml × 3 times). The organic layer is water (3 ml x 3)
And washed with water) and dried over anhydrous magnesium sulfate. The desiccant was removed and the solution was concentrated under reduced pressure to give a colorless transparent oil (120 mg, yield 83%). From the spectrum, this was confirmed to be 1-methyl-3- (2 ', 4'-dichloro-5'-isopropoxyphenyl) -5-isopropylidenehydantoin.

Example 9 Put 1-methyl-3- (2'-fluoro-4'-chloro-5'-hydroxyphenyl) -5-isopropylidenehydantoin (900mg, 3.0mmol) in an eggplant-shaped flask and add acetonitrile (30ml) to dissolve. Let Potassium carbonate (1.02g) and propargyl bromide (2.6ml)
Was added and the mixture was stirred at 40 ° C. for 4 hours. After completion of the reaction, acidify with saturated aqueous ammonium chloride and add ether (10 ml x 3
Times). The organic layer was washed with water (5 ml x 3 times) and dried over anhydrous magnesium sulfate. The desiccant was removed, and the white solid precipitated by concentrating under reduced pressure was collected by filtration and recrystallized from ethanol to obtain a white solid (264 mg, yield 26%). This product has a spectrum of 1-methyl-3-
It was confirmed to be (2'-fluoro-4'-chloro-5'-propargyloxyphenyl) -5-isopropylidenehydantoin.

Example 10 Put 3- (2'-fluoro-4'-chloro-5'-propargyloxyphenyl) -5-isopropylidenehydantoin (113 mg, 0.35 mmol) in an eggplant-shaped flask,
N, N-dimethylformamide (15 ml) was added and dissolved. Potassium carbonate (246 mg) and ethyl iodide (550
mg) was added and the mixture was stirred at 50 ° C. for 5 hours. After completion of the reaction, 1/10 N hydrochloric acid was added to acidify the mixture, and the mixture was allowed to cool, and the colorless solid (93 mg, yield 77%) that precipitated was collected by filtration. From the spectrum, it was confirmed that this product was 1-ethyl-3- (2'-fluoro-4'-chloro-5'-propargyloxyphenyl) -5-isopropylidenehydantoin.

Example 11 Add 3- (2 ', 4'-dichloro-5'- to an eggplant-shaped flask.
Hydroxyphenyl) -5-isopropylidenehydantoin (300 mg, 1.0 mmol) was added and acetonitrile (25 ml) was added.
And dissolved. Potassium carbonate (650 mg) and isopropyl iodide (1.7 g) were added, and the mixture was stirred at 50 ° C for 2 hours. After completion of the reaction, acidify with 1N hydrochloric acid and add ether (20
(ml x 3 times). The organic layer was washed with water (10 ml × 3 times) and dried over anhydrous magnesium sulfate. The desiccant was removed, and the solution was concentrated under reduced pressure to give a colorless transparent oil (330) m.
got g. This was recrystallized from chloroform-hexane to obtain a white solid (290 mg). This product was confirmed by spectrum to be 3- (2 ', 4'-dichloro-5'-isopropoxyphenyl) -5-isopropylidenehydantoin.

Example 12 1-Methyl-3- (2'-fluoro-4'-bromo-5'-methoxycarbonyloxyphenyl) -5-isopropylidenehydantoin (1.03 g,
2.57 mmol) was added, and methanol (10 ml) was added and dissolved. Potassium carbonate (50 mg) was added thereto, and the mixture was stirred at 50 ° C for 2 hours. After completion of the reaction, the mixture was acidified with 1N hydrochloric acid and extracted with ether (40 ml × 3 times). The organic layer is water (20 ml x 3)
And washed with anhydrous magnesium sulfate. The desiccant was removed and the solution was concentrated under reduced pressure to give a yellow oil. (1.04 g) This was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain an oil (430 mg). This spectrum shows almost pure 1-methyl-3- (2'-fluoro-4 'by spectrum.
It was confirmed to be -bromo-5'-hydroxyphenyl) -5-isopropylidenehydantoin. Further purified by silica gel column chromatography (ethyl acetate / chloroform = 1/2) to give a colorless transparent oil (319 mg, yield 3
6%).

Example 13 1-Methyl-3- (2'-fluoro-4'-bromo-5'-methoxycarbonyloxyphenyl) -5-isopropylidenehydantoin (6.5 g, 1
7.6 mmol) was added, and methanol (60 ml) was added and dissolved. Potassium carbonate (2.5 g) was added and the mixture was stirred at 40 ° C for 4 hours. After completion of the reaction, saturated aqueous ammonium chloride solution was added to acidify, and the mixture was extracted with ether (30 ml × 3 times). The organic layer was washed with water (10 ml × 3 times) and then dried over anhydrous magnesium sulfate. After removing the desiccant, the solution was concentrated under reduced pressure to obtain a brown oily substance. This was separated and purified by silica gel column chromatography (ethyl acetate). From the spectrum, it was confirmed that this was 1-methyl-3- (2'-fluoro-4'-chloro-5'-hydroxyphenyl) -5-isopropylidenehydantoin.

Example 14 Add 3- (2 ', 4'-dichloro-5'- to an eggplant-shaped flask.
Methoxycarbonyloxyphenyl) -5-isopropylidenehydantoin (2.3 g, 6.4 mmol) was added and dissolved in methanol (40 ml). Add potassium carbonate (500m
g) was added and the mixture was stirred at 60 ° C. for 1 hour. After completion of the reaction, the reaction solution was acidified with 1N hydrochloric acid and extracted with ether (20 ml × 3 times). The organic layer was washed with water (10 ml × 3 times) and then dried over anhydrous magnesium sulfate. After removing the desiccant, the solution was concentrated under reduced pressure to obtain a pale yellow oil (1.93 g). Ether was added to this to precipitate 3- (2 ', 4'-dichloro-).
A white solid (1.02 g) of 5'-hydroxyphenyl) -5-isopropylidenehydantoin was collected by filtration. Further, the mother liquor was concentrated and ether was added to obtain a white solid (0.9 g).
The reaction was quantitative.

Example 15 Put 3- (2'-fluoro-4'-chloro-5'-methoxycarbonyloxyphenyl) -5-isopropylidenehydantoin (110 mg, 0.31 mmol) and potassium carbonate (54 mg) in a screw cap test tube, and add methanol (5 ml). ) Was added and dissolved. This was stirred at 40 ° C. for 3 hours. After completion of the reaction, saturated aqueous ammonium chloride solution was added to acidify and the mixture was extracted with ether (2 ml × 3 times). The organic layer was washed with water (2 ml × 3 times) and dried over anhydrous magnesium sulfate. The desiccant was removed and the ether solution was concentrated under reduced pressure to give a brown oil (67
mg, yield 77%) was obtained. From the spectrum, this one is 3
It was confirmed to be-(2'-fluoro-4'-chloro-5'-hydroxyphenyl) -5-isopropylidenehydantoin.

Example 16 A solution of 3- (2'-fluoro-4'-chloro-5'-ethoxycarbonyloxyphenyl) -5-isopropylidenehydantoin (204mg, 0.57mmol) and sodium carbonate (50mg) in methanol (20ml) at 40 ° C was added at 3 ° C. Stir for hours. After the reaction was completed, a saturated ammonium chloride aqueous solution was added,
It was extracted with ether (5 ml x 3 times). The organic layer was washed with water and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solution was concentrated under reduced pressure to give a brown oil. Ether was added to this and the precipitated white crystals (162 mg) were isolated by filtration. This product has a 3-
It was confirmed to be (2'-fluoro-4'-chloro-5'-hydroxyphenyl) -5-isopropylidenehydantoin.

Example 17 3- (2'-Fluoro-4'-chloro-5'-methoxycarbonyloxyphenyl) -5- (2 "-butylidene) hydantoin (1.02 g, 3.0 mmol) was placed in an eggplant-shaped flask, and methanol (40 ml) was added. Potassium carbonate (230 mg) was added, and the mixture was reacted at room temperature for 15 hours.After completion of the reaction, the mixture was acidified with 1N hydrochloric acid and ether (10 ml × 3).
Times). The organic layer was washed with water (5 ml x 3 times) and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to give a colorless transparent oil (895 mg). This is almost pure 3- (2'-fluoro-4'-chloro-5 '
It was confirmed from NMR spectrum and the like that it was -hydroxyphenyl) -5- (2 "-butylidene) hydantoin.

Example 18 In an eggplant-shaped flask, 1-methyl-3- (2'-fluoro-4'-chloro-5'-hydroxyphenyl) -5-
Isopropylidene hydantoin (200 mg, 0.63 mmol) was added and dissolved in N, N-dimethylformamide (20 ml). Next, potassium carbonate (45 mg) was added and the mixture was stirred at room temperature for 30 minutes. Cyclopropyl bromide (750 mg) was added and reacted at room temperature for 18 hours. After the reaction was completed, 1N hydrochloric acid was added to acidify the mixture, and the mixture was extracted with ether (5 ml × 3 times). The organic layer was washed with water and dried over anhydrous magnesium sulfate. After removing the desiccant, the solution was concentrated under reduced pressure to obtain a pale yellow oily substance.
This was purified using silica gel column chromatography. This is 1-methyl-3- (2'-fluoro-4'-chloro-5'-cyclopropyloxyphenyl) -5-isopropylidenehydantoin (110 mg, 49
%) Was confirmed by NMR spectrum and the like.

Example 19 3- (2 ', 4'-Dichloro-5'-hydroxyphenyl) -5-isopropylidenehydantoin (105 mg, 0.35 mmol) was placed in a screw cap test tube and acetonitrile (5 ml) was added and dissolved. Next, potassium carbonate (60 mg) and cyclohexyl bromide (350 mg) were added, and the mixture was reacted at 50 ° C for 24 hours. After completion of the reaction, the mixture was directly concentrated under reduced pressure to remove the solvent and excess cyclohexyl bromide. Methyl iodide (200 mg) and N, N-dimethylformamide (5 ml) as a solvent were added to the obtained mixture, and the mixture was stirred at 40 ° C for 2 hr. After completion of the reaction, add 0.1N hydrochloric acid to acidify and ether (2m
l × 3 times). The organic layer was washed with water and dried over anhydrous magnesium sulfate. After removing the desiccant, the solution was concentrated under reduced pressure to give a colorless transparent oily substance. This product was purified by silica gel column chromatography to give 1-methyl-3- (2 ', 4'-dichloro-5'-
A colorless transparent oily substance (60 mg) of cyclohexyloxyphenyl) -5-isopropylidenehydantoin was obtained. Recrystallized from ethanol to obtain the desired white solid (20 mg, yield 14
%) Was obtained.

Example 20 3- (2 ', 4'-dichloro-5'-isopropoxyphenyl) -5-isopropylidenehydantoin (152 mg,
0.446 mmol) was placed in an eggplant-shaped flask and dissolved in N, N-dimethylformamide (20 ml). Potassium carbonate (362m
g) and propargyl bromide (600 mg) were added at room temperature for 13
Stir for hours. After completion of the reaction, the mixture was acidified with 1N hydrochloric acid and extracted with ether (5 ml × 3 times). The organic layer is water (3 ml x 3)
The extract was washed with water and dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure to give a pale yellow oil (170 mg). This was confirmed to be 1-propargyl-3- (2 ', 4'-dichloro-5-isopropoxyphenyl) -5-isopropylidenehydantoin by NMR spectrum and the like. The yield was quantitative.

Example 21 3- (2 ', 4'-dichloro-5'-hydroxyphenyl) -5-isopropylidenehydantoin (970 mg, 3.22
mmol) in N, N-dimethylformamide (40 ml) solution,
Potassium carbonate (702mg) and propargyl bromide (2.9m
l) was added and the mixture was stirred at 50 ° C. for 4 hours and further at 80 ° C. for 8 hours. After completion of the reaction, add 1N hydrochloric acid to acidify and ether (20 ml
X 3 times). The organic layer was washed with water and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solution was concentrated under reduced pressure to give a pale yellow oil (1.95 g). Ether was added, the mixture was cooled, and the precipitated white solid (193 mg) was collected by filtration. From this NMR spectrum, etc., 3- (2 ', 4'- was obtained by introducing a propargyl group into the hydroxyl group at the 5-position of the phenyl ring.
Dichloro-5'-propargyloxyphenyl) -5-
It was confirmed to be isopropylidene hydantoin.
Further, the filtrate was concentrated and recrystallized from chloroform-hexane to obtain a 1-propargyl-3- (2 ', 4') in which a propargyl group was introduced on the 1-position N of the hydantoin ring.
-Dichloro-5'-propargyloxyphenyl) -5
-White crystals of isopropylidenehydantoin (694 mg, 57% yield) were obtained.

Example 22 3- (2'-Fluoro-4'-bromo-5'-hydroxyphenyl) -5-isopropylidenehydantoin (210 mg, 0.64 mmol) was placed in an eggplant-shaped flask and acetonitrile (10 ml) was added to dissolve it. To this, add potassium carbonate (470 mg) and propargyl bromide (800 mg),
The mixture was stirred at 40 ° C for 4 hours. After the reaction was completed, 1N hydrochloric acid was added to make an acidic solution and the mixture was left at room temperature. Precipitated crystals (240 mg, yield 93
%) Was isolated by filtration. This product shows 1-propargyl-3- (2'-fluoro-4 '
-Bromo-5'-propargyloxyphenyl) -5-
It was confirmed to be isopropylidene hydantoin.

Example 23 3- (2 ', 4'-dichloro-5'-hydroxyphenyl) -5-isopropylidenehydantoin (1.0 g, 3.3 mm
ol) in an eggplant-shaped flask, and acetonitrile (40 ml)
Was added and dissolved. Potassium carbonate (2.4 g) and 1,3-dichloropropene (3.7 g) were added, and the mixture was stirred at 60 ° C for 10 hours.
After completion of the reaction, the precipitated solid matter was filtered off and the filtrate was washed with water (20 ml x 3
After that, it was dried over anhydrous magnesium sulfate.
The drying agent was filtered, and the filtrate was concentrated under reduced pressure to give a yellow oily substance (1.62 g). This product was separated and purified by silica gel column chromatography to obtain the desired 1- (3 '
-Chloro-2'-propenyl) -3- {2 ", 4" -dichloro-5 "-(3-chloro-2-propenyloxy) phenyl} -5-isopropylidenehydantoin (1.41 g, 94% yield) This is a mixture of four kinds of chloropropenyl group on the nitrogen atom at the 1-position of the hydantoin ring and olefins of the chloropropenyl group on the oxygen atom at the 5-position of the phenyl ring, which are different in stereochemistry, and are in the EZ form. , Z-
For the E form and the E-E form, column chromatography. Alternatively, the crystal was separated by recrystallization and 400 MHz ¹ H-NMR spectrum was measured to confirm the structure.

Example 24 3- (2'-Fluoro-4'-bromo-5'-hydroxyphenyl) -5-isopropylidenehydantoin (210 mg, 0.64 mmol) in acetonitrile (10 ml) was added to potassium carbonate (470 mg) and 1,3-dichloropropene. (710m
g) was added and the mixture was stirred at 80 ° C for 3 hours. After completion of the reaction, 1N hydrochloric acid was added and the mixture was extracted with ether (5 ml × 3 times). Water the organic layer (3
(ml x 3 times) and then dried over anhydrous magnesium sulfate. After removing the desiccant, the solution was concentrated under reduced pressure to give a yellow oil (310 mg). This product was separated and purified by silica gel column chromatography (ethyl acetate / hexane = 1/2) to give 1- (3′-chloro-2′-propenyl) -3- {2 ″ -fluoro-4 ″ -bromo-5. ″ −
(3-chloro-2-propenyloxy) phenyl}
-5-isopropylidenehydantoin (202 mg, yield 58
%) Was obtained. This is a mixture of four isomers having different stereochemistry of the olefins of the chloropropenyl group on the nitrogen atom and oxygen atom. The EE form was separated and purified by column chromatography to obtain 400 MHz ¹ H -NMR
The structure was confirmed by the spectrum.

Example 25 3- (2'-Fluoro-4'-bromo-5'-hydroxyphenyl) -5-isopropylidenehydantoin (214 mg, 0.65 mmol) in acetonitrile solution (12 ml) potassium carbonate (450 mg) and 2,3-dichloropropene (750m
g) was added and the mixture was stirred at 50 ° C. for 5 hours. After completion of the reaction, 0.1N hydrochloric acid was added, and the mixture was extracted with ether (4 ml × 3 times). The organic layer was washed with water (2 ml × 3 times) and dried over anhydrous magnesium sulfate. The desiccant was removed and the solution was concentrated under reduced pressure to give a yellow oil. This product was separated and purified by silica gel column chromatography (ethyl acetate / hexane = 1/2) to give 1- (2'-chloro-2'-propenyl) -3.
-{2 "-Fluoro-4" -bromo-5 "-(2-chloro-2-propenyloxy) phenyl} -5-isopropylidenehydantoin pale yellow oil (230 mg, yield
74%).

Example 26 3- (2'-Fluoro-4'-chloro-5'-hydroxyphenyl) -5- (2 "-butylidene) hydantoin (170 mg, 0.57 mmol) N, N-dimethylformamide (2
Potassium carbonate (170 mg) and methyl iodide (500 μl) were added to the solution (0 ml) and the mixture was stirred at room temperature for 2 hours. 3N hydrochloric acid was added, and the mixture was extracted with ether (10 ml × 3 times). The organic layer was washed with water (5 ml × 2 times) and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting pale yellow oily substance was separated and purified by silica gel column chromatography to give 1-methyl-3- (2'-fluoro-4'-.
Chloro-5'-methoxyphenyl) -5- (2 "-butylidene) hydantoin colorless oil (180 mg, yield 97%)
I got

Reference example 1 2-Fluoro-4-chloro-5-methoxycarbonyloxynitrobenzene (52.1g, 0.24mol) in ethanol (600ml) solution was added with platinum dioxide (1.5g) until hydrogen gas absorption stopped under hydrogen atmosphere at normal pressure. The reaction was carried out at room temperature. After completion of the reaction, the catalyst was filtered off, and the solvent was distilled off from the obtained pale yellow transparent solution under reduced pressure to obtain a pale reddish brown oily substance.
From the NMR spectrum, this was confirmed to be almost pure 2-fluoro-4-chloro-5-methoxycarbonyloxyaniline. This product can be purified by silica gel column chromatography, but can be used as it is in the next reaction. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 3.86 (3H, s), 4.13 (2
H, br s), 6.48 (1H, d, J _HF = 8Hz), 6.92 (1H, d, J _HF = 10H
z). Reference example 2 Platinum dioxide (1.0 g) was added to a solution of 2-fluoro-4-bromo-5-methoxycarbonyloxynitrobenzene (30.4 g, 0.1 mol) in ethanol (300 ml), and the mixture was stirred under a hydrogen atmosphere until hydrogen absorption stopped. After the reaction,
The catalyst was filtered off, and the solvent was distilled off from the solution under reduced pressure to give 2-fluoro-4-bromo-5-methoxycarbonyloxyaniline as a brown solid (28.0 g). ¹ H-NMR (CCl ₄ , TMS, ppm): δ 3.83 (3H, s), 5.01 (2H,
br s), 6.63 (1H, d, J _HF = 7.6Hz), 7.06 (1H, d, J _HF = 9.8
Hz). Reference example 3 Trichloromethyl chloroformate (19 ml, 158 mmol) in a 500 cc three-necked flask equipped with a dropping funnel and a distillation device.
In ethyl acetate (200 ml) was added thereto, and a solution of 2-fluoro-4-chloro-5-methoxycarbonyloxyaniline (21.9 g, 100 mmol) in ethyl acetate (100 ml) was added dropwise thereto over 20 minutes. After completion of dropping, the mixture was heated to 80 ° C., and ethyl acetate was distilled off. After allowing to cool, carbon tetrachloride (150 ml) was added and the mixture was allowed to stand overnight. After the insoluble matter was filtered off, the solvent was distilled off from the filtrate under reduced pressure to give 2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl isocyanate (20.6 g, yield 84
%) As a light brown solid. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 3.88 (3H, s), 6.97 (1
H, d), 7.37 (1H, d). IR (KBr disk, cm ^-1 ): 2260,1770. Reference example 4 Trichloromethyl chloroformate (15 ml, 125 mmol) in a 500 ml three-necked flask equipped with a dropping funnel and a distillation device.
In ethyl acetate (150 ml) was added thereto, and a solution of 2-fluoro-4-bromo-5-methoxycarbonyloxyaniline (28.0 g, 113 mmol) in ethyl acetate was added dropwise over 20 minutes. After completion of dropping, the mixture was heated to 80 ° C., and ethyl acetate was distilled off.
After allowing to cool, carbon tetrachloride (150 ml) was added, the insoluble matter was filtered off,
The solvent was distilled off from the filtrate under reduced pressure to obtain a brown solid of 2-fluoro-4-bromo-5-methoxycarbonyloxyphenylisocyanate (29.1 g, yield 94%). ¹ H-NMR (CCl ₄ , TMS, ppm): δ 3.87 (3H, s), 6.89 (1H,
d, J _HF = 6.8Hz), 7.31 (1H, d, J _HF = 8.6Hz). IR (KBr disk, cm ^-1 ): 2260,1770. Reference example 5 Ammonia gas was introduced into a solution of 2-fluoro-4-chloro-5-ethoxycarbonyloxyphenylisocyanate (16.7 g, 64 mmol) in benzene (300 ml) with vigorous stirring under ice cooling. Immediately, precipitation of a white solid was observed. After 30 minutes, the precipitated solid was collected by filtration, thoroughly washed with benzene, and dried. This was the target 2-fluoro-4-chloro-5-ethoxycarbonyloxyphenylurea (14.2 g, yield 80%). ¹ H-NMR (CDCl ₃ -CD ₃ OD, TMS, ppm): δ 1.37 (3H, t, J =
7.2Hz), 4.30 (2H, q, J = 7.2Hz), 7.10 (1H, d, J _HF = 10.2
Hz), 8.07 (1H, d, J _HF = 7.2Hz). Reference example 6 Ammonia gas was introduced into a benzene (100 ml) solution of 2-fluoro-4-chloro-5-methoxycarbonyloxyphenylisocyanate (12.3 g, 50 mmol) under vigorous stirring under ice cooling. After 30 minutes, the white solid deposited was filtered, thoroughly washed with benzene, and dried. It was confirmed from the NMR spectrum and the like that this was the target 2-fluoro-4-chloro-5-methoxycarbonyloxyphenylurea (10.3 g, yield 78%). ¹ H-NMR (DMSO-d ₆ , TMS, ppm): δ 3.87 (3H, s), 5.81
(2H, br s), 7.12 (1H, d, J _HF = 10Hz), 8.28 (1H, d, J _HF
= 7.2Hz), 8.48 (1H, br s). Reference example 7 By the same operation as in Reference Example 6, 2-fluoro-4-bromo-5-methoxycarbonyloxyphenylisocyanate (47.7 g, 164 mmol) to 2-fluoro-4-bromo-5-methoxycarbonyloxyphenylurea (37.7 g,
Yield 75%). ¹ H-NMR (CDCl ₃ -CD ₃ OD, TMS, ppm): δ 3.83 (3H, s),
7.28 (1H, d, J _HF = 10Hz), 7.99 (1H, d, J _HF = 7.2Hz). Reference example 8 Benzene of 2,4-dichloro-5-methoxycarbonyloxyphenylisocyanate (5.04 g, 19.2 mmol) synthesized by the same operation as in Reference Examples 1 to 4 using 2,4-dichloro-5-methoxycarbonyloxynitrobenzene as a raw material. Ammonia gas was introduced into the (120 ml) solution with vigorous stirring under ice cooling. After 30 minutes, the precipitated white solid was filtered and thoroughly washed with benzene. It was confirmed from ¹ H-NMR that this was the desired 2,4-dichloro-5-methoxycarbonyloxyphenylurea (4.68 g, yield 88%). ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , TMS, ppm): δ 3.88 (3H,
s), 6.35 (2H, br), 7.45 (1H, s), 8.20 (1H, br), 8.32
(1H, s). Reference example 9 Add 2-fluoro-4-chloro-5-methoxycarbonyloxyphenylisocyanate (2.45
g, 10 mmol) was added and dissolved in benzene (100 ml), dehydrovaline ethyl ester (1.41 g, 10 mmol) was added, and the mixture was reacted at room temperature for 10 hours. The precipitated solid is removed,
To the solution was added saturated aqueous ammonium chloride solution (10
It was extracted with 0 ml × 3 times). The organic layer was washed with water (50 ml x 3 times) and then dried over anhydrous magnesium sulfate. The desiccant was removed and the solution was concentrated under reduced pressure. Precipitated N- (2
-Fluoro-4-chloro-5-methoxycarbonyloxyphenyl) -N '-(1'-ethoxycarbonyl-
2'-Methyl-1'-propenyl) urea white solid (3.
45 g) was collected by filtration. The yield was 92%. ¹ H-NMR (CD ₃ SOCD ₃ -CDCl ₃ , TMS, ppm): δ 1.27 (3H, t,
J = 6.9Hz), 1.87 (3H, s), 2.12 (3H, s), 3.86 (3H, s)
s), 4.20 (2H, q, J = 6.9Hz), 6.74 (1H, br s), 7.05 (1
H, d, J _HF = 9.9Hz), 7.35 (1H, br s), 8.11 (1H, d, J _HF =
7.2Hz). IR (KBr disk, cm ^-1 ): 1770,1730. Reference example 10 Add 2-fluoro-4-bromo-5-methoxycarbonyloxyphenylisocyanate (1.28
g, 4.41 mmol) was added, the solution was dissolved in benzene (100 ml), dedovaline methyl ester (630 mg, 4.88 mmol) was added, and the mixture was reacted at room temperature for 10 hours. The precipitated solid is removed,
Saturated ammonium chloride aqueous solution was added to the solution, and ether (10
It was extracted with 0 ml × 3 times). The organic layer was washed with water (50 ml x 3 times) and then dried over anhydrous magnesium sulfate. The desiccant was removed and the solution was concentrated under reduced pressure. Precipitated N- (2
-Fluoro-4-bromo-5-methoxycarbonyloxyphenyl) -N '-(1'-methoxycarbonyl-
White solid of 2'-methyl-1'-propenyl) urea (48
3 mg) was collected by filtration. By adding ether to the filtrate and cooling, a white solid (385 mg) of the target substance that was further precipitated could be obtained by filtration. The total yield was 47%. ¹ H-NMR (CD ₃ SOCD ₃ -CDCl ₃ , TMS, ppm): δ 1.83 (3H,
s), 2.03 (3H, s), 3.67 (3H, s), 3.86 (3H, s), 7.25 (1
H, d, J _HF = 10.5Hz), 7.84 (1H, br s), 8.23 (1H, d, J _HF =
6.9Hz), 8.58 (1H, br s). IR (KBr disk, cm ^-1 ): 1770,1730. Reference example 11 2,4-Dichloro-5-methoxycarbonyloxynitrobenzene was used as a starting material and 2,4-dichloro-5-methoxycarbonyloxyphenylisocyanate (1.31 g, 5 mmol) synthesized according to the method shown in Reference Examples 1 to 4 was added to an eggplant-shaped flask. Benzene (100 ml) was added, then dehydrovaline methyl ester (0.65 g, 5 mmol) was added, and the mixture was reacted at room temperature for 7 hours. A small amount of precipitated solid was removed, and the solution was washed with an aqueous solution of ammonium chloride (50 ml x 3 times) and water (50 ml x 3 times). After drying, the solvent was distilled off from the solution under reduced pressure to give a brown oil (1.35 g). A mixed solution of ethyl acetate-hexane was added to this to precipitate N- (2,4
-Dichloro-5-methoxycarbonyloxyphenyl)
-N '-(1'-methoxycarbonyl-2'-methyl-
White solid of 1'-propenyl) urea (1.31 g, yield 58%)
Was collected by filtration. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.91 (3H, s), 2.17 (3
H, s), 3.68 (3H, s), 3.88 (3H, s), 6.63 (1H, br s), 7.
31 (1H, br s), 7.35 (1H, s), 8.30 (1H, s). IR (KBr disk, cm ^-1 ): 1770,1725. Reference example 12 2-Fluoro-4-chloro-5-ethoxycarbonyloxyphenylurea (10.1 g, 36.4 mmol) was added in a small excess of 2-
Methyl oxoisovalerate (5.2g) in benzene (100ml)
The solution contained a catalytic amount of p-toluenesulfonic acid (60 mg, 0.35 mmo
l) was added and the mixture was heated under reflux for 4 hours. Allow to cool after the reaction,
The precipitated solid was filtered off. The filtrate was concentrated under reduced pressure to obtain a light brown oil. Recrystallization from ether-pentane gave a pale yellow solid (15.5 g). This one is ¹
From the 1 H-NMR spectrum, although the cyclized product 3- (2'-fluoro-4'-chloro-5'-ethoxycarbonyloxyphenyl) -5-isopropylidenehydantoin was contained in a small amount, the target N- ( 2-fluoro-4
-Chloro-5-ethoxycarbonyloxyphenyl)-
N '-(1'-ethoxycarbonyl-2'-methyl-
1'-propenyl) urea.

This mixture was used for the next reaction without separation and purification.

Reference example 13 In a 200 ml eggplant-shaped flask equipped with a Dean-Stark apparatus, 2-fluoro-4-bromo-5-methoxycarbonyloxyphenylurea (15.2 g, 50 mmol), ethyl 2-oxoisovalerate (12 ml) and toluene as a solvent ( 140ml), then sodium ethoxide (169m
g) was added and the mixture was heated under reflux for 20 hours.

After completion of the reaction, saturated ammonium chloride aqueous solution (100 ml) was added to the reaction solution to make it acidic, followed by extraction with ether (100 ml × 3 times). The organic layer was washed with water and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solution was concentrated under reduced pressure. The precipitated pale yellow solid (4.6 g) was isolated by filtration. Ether was added to the filtrate, and the precipitated pale yellow solid was filtered off. Each of these products is the desired N- (2-fluoro-4-bromo-5-methoxycarbonyloxyphenyl) -N '-(1'-ethoxycarbonyl-2'-
Methyl-1′-propenyl) urea, ¹ H-NM
Confirmed from R. The total yield was 28%. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.26 (3H, t, J = 7.2H
z), 1.83 (3H, s), 2.07 (3H, s), 3.87 (3H, s), 4.19 (2
H, q, J = 7.2Hz), 7.08 (1H, br s), 7.18 (1H d, J _HF = 10.
5Hz), 7.74 (1H br s), 8.16 (1H, d, J _HF = 7.2Hz). Reference example 14 In a 200 ml eggplant-shaped flask equipped with a Dean-Stark apparatus, 2,4-dichloro-5-methoxycarbonyloxyphenylurea (10.3 g, 37 mmol), ethyl 2-oxoisovalerate (9.0 g) and benzene (150 ml as a solvent) ) Was added, and then p-toluenesulfonic acid (644 m
g) was added and the mixture was heated under reflux for 7 hours. After completion of the reaction, the organic layer was washed with water and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solution was concentrated under reduced pressure to give a brown oil (1
7.4 g) was obtained. N- (2,4-dichloro-5-methoxycarbonyloxyphenyl) -N '-(1'-ethoxycarbonyl-2'-methyl-1'-propenyl) urea by recrystallization from ethyl acetate-hexane solvent system (7.
0 g, yield 47%) was obtained as a white powder. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.27 (3H, t, J = 7.5H
z), 1.93 (3H, s), 2.18 (3H, s), 3.88 (3H, s), 4.22 (2
H, q, J = 7.5Hz), 6.62 (1H, br s), 7.31 (1H br s), 7.3
6 (1H, s) 8.30 (1H, s). Reference example 15 N- (2-fluoro-4-chloro-
5-methoxycarbonyloxyphenyl) -N'-
(1′-Methoxycarbonyl-2′-methyl-1′-propenyl) urea (2.53 g, 6.5 mmol) and sodium acetate (140 mg) were added, toluene (80 ml) was added, and the mixture was refluxed to 7
Allowed to react for hours. After completion of the reaction, add ethyl acetate (30 m
l) was added and washed with water (20 ml × 3 times). The solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give a brown oil. 3- (2 ') precipitated by adding ether
A white solid (1.11 g) of -fluoro-4'-chloro-5'-methoxycarbonyloxyphenyl) -5-isopropylidenehydantoin was collected by filtration. The mother liquor was further concentrated, an ether-hexane mixed solvent was added, and the precipitated solid (386 mg) was collected by filtration. The total yield was 67%. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.87 (3H, s), 2.26 (3
H, s), 3.91 (3H, s), 7.26 (1H, d, J _HF = 6.9Hz), 7.31 (1
H, d, J _HF = 9.0Hz), 9.10 (1H, br s). IR (KBr disk, cm ^-1 ): 1780,1730,1680. Reference example 16 N- (2-fluoro-4-bromo-) in an eggplant-shaped flask.
5-methoxycarbonyloxyphenyl) -N'-
(1'-Methoxycarbonyl-2'-methyl-1'-propenyl) urea (5.66g, 13.5mmol) was added and toluene (90
ml) was added and dissolved. Sodium acetate (114 mg) was added and the mixture was heated under reflux for 3 hours. The reaction mixture was cooled, the precipitated solid was removed, the solution was washed with water (50 ml × 3 times), and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and ether was added to precipitate 3- (2'-fluoro-4'-bromo-5'-methoxycarbonyloxyphenyl) -5-isopropylidenehydantoin as white crystals (1.50 g). . The filtrate was concentrated and ether was added to collect a white solid (1.94 g) by filtration. The total yield was 68%. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.86 (3H, s), 2.25 (3
H, s), 3.91 (3H, s), 7.29 (1H, d, J _HF = 8.7Hz), 7.50 (1
H, d, J _HF = 9.0Hz), 9.07 (1H, br s). IR (KBr disk, cm ^-1 ): 1780,1730,1680. Reference example 17 N- (2,4-dichloro-5-methoxycarbonyloxyphenyl) -N '-(1'-methoxycarbonyl-2'-methyl-1'-propenyl) urea (6.76 g, 17.3 mmol) was placed in an eggplant-shaped flask. Add benzene (60 ml).
Then, sodium acetate (149 mg) was added and the mixture was heated under reflux for 7 hours. After completion of the reaction, the reaction solution was cooled to remove the precipitated solid. After the filtrate was washed with water (50 ml x 3 times) and dried,
The solvent was distilled off under reduced pressure to obtain a brown oily substance.
Chloroform (100 ml) was added and precipitated 3- (2 ', 4'
A white crystal (3.97 g, yield 64%) of -dichloro-5'-methoxycarbonyloxyphenyl) -5-isopropylidenehydantoin was obtained. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.89 (3H, s), 2.28 (3
H, s), 3.92 (3H, s), 7.28 (1H, s), 7.63 (1H, s), 8.96
(1H, br s). IR (KBr disk, cm ^-1 ): 1780,1720,1680. Reference example 18 N- (2-fluoro-4-chloro-5-ethoxycarbonyloxyphenyl) -N '-(1'-methoxycarbonyl-2'-methyl-1'-propenyl) urea (1.37
Sodium acetate (300 mg) was added to a benzene (20 ml) solution of g, 3.5 mmol) and the mixture was heated under reflux for 20 hours. After completion of the reaction, sodium acetate deposited was filtered off, and the filtrate was concentrated under reduced pressure. Recrystallize from ether-pentane solvent system to give 3-
A pale yellow solid of (2'-fluoro-4'-chloro-5'-ethoxycarbonyloxyphenyl) -5-ipropylidenehydantoin (1.24 g, 96% yield) was obtained. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.40 (3H, t, J = 6.8H
z), 1.94 (3H, s), 2.30 (3H, s), 4.35 (2H, q, J = 6.8H
z), 7.28 (1H, s), 7.41 (1H, d, J _HF = 2.8Hz), 8.02 (1H,
br s). Reference example 19 N- (2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl) urea (4g, 15.2mmol) and methyl 3-methyl-2-oxovalerate (3.4g, 23.6mmol) and p-toluene as a catalyst A solution of sulfonic acid (500 mg) in benzene (100 ml) was heated under reflux for 5 hours. After completion of the reaction, the precipitated solid was filtered off, the filtrate was washed with water and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off, then ether was added and the precipitated white solid was isolated by filtration. This product is N- (2-fluoro-4
-Chloro-5-methoxycarbonyloxyphenyl)-
N '-(1'-methoxycarbonyl-2'-methyl-
It was confirmed from the NMR spectrum that it was 1'-butenyl) urea. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.03and1.12 (total 3
H, each t, J ＝ 7.5Hz), 1.87and2.10 (total 3H, each
s), 2.25and2.50 (total 2H, each q, J = 7.5Hz), 3.75
(3H, s), 3.87 (3H, s), 6.48 (1H, br s), 7.08 (1H, d, J
_HF = 10.5Hz), 7.18 (1H, br s), 8.15and8.18 (total 1
H, each, d, J _HF = 8.0Hz). Then, the obtained disubstituted urea was heated to reflux for 9 hours in a solvent of toluene (100 ml) using p-toluenesulfonic acid (500 mg) as a catalyst. After completion of the reaction, the precipitated solid was filtered off and the filtrate was washed with water. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off and recrystallized from an ether-hexane solvent system to give 3- (2'-fluoro-4'-).
Chloro-5-methoxycarbonyloxyphenyl) -5
White crystals of-(2 "-butylidene) hydantoin (2.05
g, yield 38%) was obtained. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.07and1.18 (total 3
H, each t, J = 7.5Hz), 1.65and1.87 (total 3H, each
s), 2.17and2.75 (total 2H, each q, J = 7.5Hz), 3.98
(3H, s), 7.25 (1H, d, J _HF = 3Hz), 7.35 (1H, d, J _HF = 4.5
Hz), 8.78 (1H, m). Reference example 20 Add 3- (2'-fluoro-4'-chloro-5'-methoxycarbonyloxyphenyl) -5- to an eggplant-shaped flask.
Isopropylidene hydattoin (8.1 g, 22.7 mmol) was added, and N, N-dimethylformamide (200 ml) was added and dissolved. Potassium carbonate (16.9g) and methyl iodide (1
5 ml) was added and the mixture was stirred at 40 ° C. for 4 hours. After completion of the reaction, acidify with saturated aqueous ammonium chloride solution and add ether (10
It was extracted with 0 ml × 3 times). The organic layer was washed with water (50 ml x 3 times) and dried using anhydrous magnesium sulfate. The desiccant was removed and the solution was concentrated under reduced pressure to a brown oil (6.5
g, yield 78%) was obtained. This one is 1-
Methyl-3- (2'-fluoro-4'-chloro-5'-
It was confirmed to be methoxycarbonyloxyphenyl) -5-isopropylidenehydantoin. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 2.17 (3H, s), 2.34 (3
H, s), 3.42 (3H, s), 3.85 (3H, s), 7.27 (1H, d, J _HF = 2.
9Hz), 7.40 (1H, d, J _HF = 4.5Hz). Reference example 21 N-type flask was charged with 3- (2'-fluoro-4'-bromo-5-methoxycarbonyloxyphenyl) -5-isopropylidenehydantoin (1.5 g, 3.7 mmol) N,
N-dimethylformamide (70 ml) was added and dissolved.
Potassium carbonate (2.51 g) and methyl iodide (3.4 ml) were added, and the mixture was stirred at 50 ° C for 2 hours. After completion of the reaction, the mixture was acidified with 1N hydrochloric acid and extracted with ether (40 ml × 3 times). The organic layer was washed with water (20 ml x 3 times) and dried over anhydrous magnesium sulfate. The desiccant was removed and the solution was concentrated under reduced pressure to give a colorless transparent oil (1.27 g, yield 81%). It was confirmed from the spectrum that this compound was 1-methyl-3- (2'-fluoro-4'-bromo-5'-methoxycarbonyloxyphenyl) -5-isopropylidenehydantoin. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 2.17 (3H, s), 2.34 (3
H, s), 3.44 (3H, s) 3.83 (3H, s), 6.78 (1H, d, J _HF = 6H
z), 7.41 (1H, d, J _HF = 9Hz). Reference example 22 Add 3- (2 ', 4'-dichloro-5'- to an eggplant-shaped flask.
Methoxycarbonyloxyphenyl) -5-isopropylidenehydantoin (602 mg, 1.68 mmol) was added, and N, N-
Dimethylformamide (30 ml) was added and dissolved. Add potassium carbonate (1.2g) and methyl iodide (2.5g)
The mixture was stirred at 50 ° C for 2 hours. After completion of the reaction, the mixture was acidified with 1N hydrochloric acid and extracted with ether (20 ml × 3 times). The organic layer was washed with water (10 ml × 3 times) and dried using anhydrous magnesium sulfate. The desiccant was removed and the solvent was concentrated under reduced pressure to give a colorless transparent oil (570 mg, yield 91%). It was confirmed from the spectrum that this product was 1-methyl-3- (2 ', 4'-dichloro-5'-methoxycarbonyloxyphenyl) -5-isopropylidenehydantoin. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 2.16 (3H, s), 2.33 (3
H, s), 3.39 (3H, s) 3.88 (3H, s), 7.28 (1H, s), 7.60
(1H, s). The compound of the present invention thus obtained has excellent properties as a herbicide as described above.

In using the compound of the present invention as a herbicide,
Although it can be used as it is, generally, one or several kinds of auxiliary agents can be mixed and used as a herbicide.
Usually, as an auxiliary agent, various carriers, fillers, solvents, surfactants, stabilizers and the like may be blended and used by formulating them in the form of wettable powder, emulsion, powder, granules, etc. by a conventional method. preferable.

Examples of the solvent which is one of the auxiliary agents in the herbicides containing the compound of the present invention as an active ingredient include, for example, water, alcohols,
Ketones, ethers, aliphatic and aromatic hydrocarbons,
Halogenated hydrocarbons, acid amides, esters, nitriles and the like are suitable, and one kind or a mixture of two or more kinds thereof is used.

Further, as the extender, kaolin, clay such as pentonite, talc, talc such as pyrophyllite, diatomaceous earth, mineral powder such as oxides such as white carbon and soybean powder,
Vegetable powders such as CMC are preferable, and one kind or a mixture of two or more kinds thereof is used.

Further, a surfactant may be used as a spreading agent, a dispersant, an emulsifier, or a penetrant. Examples of the surfactant include nonionic surfactants, cationic surfactants, anionic surfactants and amphoteric surfactants. These surfactants are utilized as one kind or a mixture of two or more kinds depending on the application.

Preferred methods of using the herbicide containing the compound of the present invention as the active ingredient include soil treatment, water surface treatment, foliage treatment, and the like, and particularly excellent effects can be obtained by applying the weeds before germination to at the time of larvae. You can

Further, the present herbicide, other active ingredients that do not inhibit the herbicidal activity of the present active ingredient, for example, other herbicides, insecticides,
It is also possible to use a mixture of a bactericidal agent and a plant growth regulator, or to use them together.

Next, a formulation example of a herbicide containing the compound of the present invention as an active ingredient,
The present invention will be described in more detail with reference to test examples of herbicidal effect of the present herbicide. The parts are parts by weight.

Formulation Example 1 (emulsion) 20 parts of the compound of the present invention, 35 parts of xylene, cyclohexanone
Emulsion is prepared by uniformly mixing 40 parts and 5 parts of Solbol 900A (manufactured by Toho Kagaku).

Emulsion Example 2 (Wettable powder) A mixture of 50 parts of the compound of the present invention, 25 parts of diatomaceous earth, 22 parts of clay and 3 parts of Lunox R100C (manufactured by Toho Kagaku Co., Ltd.) is uniformly mixed and ground to obtain a wettable powder.

Formulation Example 3 (granules) 5 parts of the compound of the present invention, 35 parts of pentonite, 55 talc
Part and 5 parts of sodium lignin sulfonate are uniformly mixed and pulverized, water is added and kneaded, granulated by an extrusion granulator, dried and sized to obtain granules.

Test Example 1 (Effects on paddy field weeds) Paddy soil was filled in a Wagner pot of 1 / 5,000 are, and seeds of millet, konjac, scutellaria and seedlings of 3-4 leaf stage (variety: Nihonbare) were sown or It was transplanted and kept in a flooded condition. After 5 days, the active ingredient of the herbicide of the present invention as granules according to Formulation Example 3 is 20, 10, 5 g per are.
A predetermined amount of water was surface-treated so that Thirty days after the treatment with granules, the herbicidal effect on the test plants and the phytotoxicity against rice were investigated by the following criteria, and the results shown in Table 4 were obtained.

Judgment Criteria Degree of killing: Percentage of residual grass (%) 0:81 to 100 1:61 to 80 2:41 to 60 3:21 to 40 4: 6 to 20 5: 0 to 5 Chemical damage: Growth rate − : None ＋: Slight harm ＋ ： Small harm ＋＋＋ ： Intermediate harm ＋＋＋＋ ： Severe harm ×: Withered Test Example 2 (Effect of Field Soil Treatment) Field soil was filled in a Wagner pot of 1 / 5,000 are, and weeds were used as weeds, such as Japanese clover, white squirrel, and yellowtail.
Soybean seeds were sown as a crop, and 1 cm of soil was covered on it. The next day, the diluting solution of the wettable powder shown in Formulation Example 2 was uniformly sprayed onto the soil cover so that the active ingredient was 20, 10, and 5 g per are, and the herbicidal effect and phytotoxicity were observed 20 days after the treatment. Was examined in the same manner as in Test Example 1. Table 5 shows the results.

Test Example 3 (Effect of foliar treatment) Wagner pots of 1 / 5,000 are were filled with upland soil, and weeds such as corn, white azalea, Japanese soybean, and Inoubiyu were sown on the foliage of weeds grown 20 days later. Each test compound prepared in the emulsion shown in Formulation Example 1 was diluted with water, and a chemical solution having a predetermined concentration was uniformly spray-treated on the test plant at a spray water amount of 100 l / 10a. On the 20th day after the treatment, the herbicidal effect and the chemical damage were evaluated in the same manner as in Test Example 1. The results are shown in Table 6.

Claims (1)

[Claims] 1. A general formula [In the formula, X and Y represent a halogen atom. R ¹ represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group or an alkynyl group, and R ² represents a hydrogen atom, an alkyl group, an alkenyl group or an alkynyl group. R ³ and R ⁴ each independently represent a hydrogen atom or a lower alkyl group. ] The hydantoin derivative shown by these.