JPS62149655A - Haloacetylurea derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [A is group shown by formula II - formula IV (R<1> is H, alkyl, phenyl, etc.; R<2> is alkyl; R<3> is H, alkyl etc.; R<4> and R<5> are H or methyl; n is 0 or 1; Y<1> and Y<2> are H or alkyl); R is H, alkyl or 1-alkoxycarbonylethyl; X is halogen]. EXAMPLE:1-Chloroacetyl-3-(3-trifluoromethyl-5-isoxazolyl)urea. USE:A medical antifungal agent or an agricultural fungicide. PREPARATION:An amine shown by the formula A-NHR is reacted with chloroacetyl isocyanate shown by the formula OCN-COCH2Cl in a solvent such as benzene, etc., at 50-130 deg.C to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to haloacetylurea derivatives useful as medical antifungal agents or agricultural fungicides.

[Sub] There are many documents regarding isoxazoles having a J-order 1-chamber haloacetamide group (for example, JP-A-59-128;
326), but no haloacetylurea derivatives are known.

Disclosure of the Invention The present invention is based on the general formula R is hydrogen, alkyl, or 1-alkoxycarbonylethyl, R1 is hydrogen, alkyl, cycloalkyl, perfluoroalkyl, or phenyl, R1 is alkyl, and R3 is hydrogen, alkyl, or substituted. phenyl which may have a group; R4 and R6 each represent hydrogen or methyl; n is an integer of 0 or 1; X is halogen; Y' and Y' each represent hydrogen or alkyl. ).

To supplement the explanation of the terms that can be used in the above definition,
Examples of alkyl include 01-C6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and 1-methyl-1-enalbropyl; examples of cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cyclohebutyl, and 1-ethyl. C, -C, such as cyclohexyl and 1-adamantyl. Examples of cycloalkyl and perfluoroalkyl include trifluoromethyl, pentafluoroethyl, heptafluoropropyl, etc. PerfluoroC,-C,alkyl, and 1-alcoquinecarbonylethyl include 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, Substituents that may exist on phenyl, such as 1-butoxycarbonylethyl, include methyl,
Examples include lower alkyl such as ethyl and propyl, lower alkoxy such as methoxy, ethoxy, and propokine, and halogen such as fluorine, chlorine, bromine, and iodine.

The compound (I) of the present invention can be produced by the process according to the following reaction formula.

(In the formula, M represents an alkali metal, and A and R have the same meanings as above.) Route A Chloroacetyl isocyanate (
II[) is reacted to lead to chloroacetylurea (Ia). This reaction is carried out in a suitable solvent at a temperature of 50 to 130°C, and the solvent used may be benzene, toluene, chloroform, dioxane, diglyme, dimethylformamide, or the like. Chloroacetylisocyanate (I[[>) used as a reagent may be a commercially available product, but it may also be prepared by reacting oxalyl chloride with chloroacetic acid amide before use.

Route B Bromoacetylisocyanate (
(2) is allowed to react, leading to bromoacetylurea (1b). This reaction is carried out in a suitable solvent at a temperature of 0 to 100°C, and the solvents exemplified in Route A are used.

Bromoacetylisocyanate used as a reagent (
IV> may be prepared by reacting oxalyl chloride with bromoacetamide at the time of use.

Route C/Route D React the loloacetylurea (1a) or bromoacetylurea <Ib> obtained in the above route/route B with alkali iodide (V) to lead to the corresponding iodoacetyl probe (1c) . This reaction is carried out in an appropriate solvent with 15 to 10
The reaction can be carried out at a temperature of 0 DEG C., preferably at room temperature, and acetone, dioxane, dime-F-L sulfoxide, chloroform and benzenato are used as solvents. Examples of the alkali iodide (V) used in the iodination reaction include sodium iodide and potassium iodide.

A method for producing amines (I[) used as raw materials, such as 5-trifluoromethyl-3-aminoisoxazole, is disclosed in a patent application dated October 23, 1985. On the other hand, 5-t-butyl-3-amino-2-yne oxazoline can be obtained from chloral hydrate in five steps according to the following reaction formula.

(Left below) NH, OH-containing H2So, Cl2CCI,
CHOCH30COC) I-=i (OH-1→H30H gC12)
ida albicans, Aspergillus
fumigatus.

It is useful as a medical or veterinary antifungal agent because it exhibits sterilizing properties against bacteria such as Tricophyton astaroides.

When the compound of the present invention is used as a medicine, it is mixed appropriately with pharmaceutically acceptable carriers, excipients, disintegrants, flavoring agents, fragrances, surfactants, etc., and prepared into tablets, capsules, injections, ointments, etc.
It is formulated into a gel and administered orally or parenterally. When used as a veterinary drug, it is similarly formulated and administered according to commonly used methods.

The compound (I>) of the present invention is also useful as an agricultural fungicide.

Examples are given below to illustrate embodiments of the present invention. The meanings of the abbreviations are shown below.

Me methyl, Et ethyl, Pr propyl,
Bu Butyl Example 1 1-chloroacetyl-3-(3-trifluoromethyl-
Preparation of urea (5-inoxacylyl) To 13.09 g (0,140 mol) of chloroacetamide was added 140 g of dry benzene.
ml, 17.77 g (0,140 mol) of oxalyl chloride was added, and the mixture was heated under reflux for 1.5 hours. After cooling to room temperature, insoluble matter was filtered off to obtain a benzene solution of chloroacetyl isocyanate.

15.21 g (0,100 mol) of 3-trifluorofmethyl-5-aminoisoxazole and 200 g of dry benzene
m1 and the benzene solution of chloroacetyl isocyanate obtained above were added, heated under reflux for one hour, cooled to room temperature, and the precipitated crystals were collected by filtration and washed with benzene to give the title compound 25.513 as colorless needle-like crystals. (yield 93.9%). Melting point 159.5-160.5°C.

Elemental analysis Calculated values as C1H@N, O, CF, (%
) C, 30,96; H, 1,86: N, 15.47
;F, 20.99 ;cl, 13.05 Actual value (%
) C, 30,0LH, 2,06; N, 15.51;
F, 21.22; C1, 13, 35 Example 2-35 Example 2-35 was conducted in the same manner as Example 1. The results are shown in Tables 1 and 2.

(Left below) Example 36 1-Bromoacetyl-3-(5-trifluoromethyl-
Preparation of 610 mg (4.42 mmol) of bromoacetamide and 4.4 g of dry benzene
ml and 561 mg (4.42 mmol) of oxalyl chloride were added thereto, and the mixture was heated under reflux for one hour to obtain a benzene solution of bromoacetyl isocyanate. Add 4.4 ml of dry methylene chloride and cool to 0-5°C. While keeping at this temperature, 395.4 mg (2.60 mmol) of 5-trifluoromethyl-3-aminoisoogisazole is chlorinated. Add 7.8 ml of methylene solution dropwise over about 30 minutes, and
．． After stirring for 5 hours, the mixture was left at room temperature overnight. The reaction solution was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 822.3 mg of crystals. This was recrystallized from benzene to give 748.1 mg of the title compound as colorless needle crystals (
A yield of 91.0%) was obtained. Melting point 174-176°C.

Elemental analysis CtHaNsOsB r Calculated value as Fs (X) C, 26,60; H, 1,5! llN, 13
．． 30; Br, 25.28 Actual value (%) C, 26,
46:H, 1,82; N, 13.37; Br, 25.3
7 Example 37 1-iodoacetyl-3-g-5-trifluoromethyl-
Preparation of 4-methyl-3-ynoxasilyl) urea 1-chloroacetyl-3-(5-1-lifluoromethyl-4-methyl-3-ynoxasilyl) urea (Example 9)
485.5 mg (1.7 mmol) of the compound), 3.4 ml of acetone, 331 mg (2.2 mmol) of sodium iodide
1 mmol) was added thereto, and the mixture was stirred at room temperature for 4 hours. The reaction solution was distilled off under reduced pressure, 10 ml of water was added to the residue, extracted with methylene chloride, a small amount of aqueous sodium sulfite solution was added to the methylene chloride layer to remove free iodine, and then dried over anhydrous sodium sulfate. Distillation under reduced pressure yielded 637.2 mg of crystals. This was recrystallized from benzene-cyclohexane atlR to give 589.3 mg of the title compound as colorless needle crystals.
(yield 91.9%). Melting point 152.0-153.
5°C (decomposition).

Elemental analysis Cs Hy N s Os F s I To L, Te calculated value (X) C, 25, 48; H, 1, 8
7; N, 11.14; I, 33.66 actual value (X>
C, 25,41; H, 2,00; N, 11.66; 1.
33.69 Example 3B 1-iodoacetyl-3-(5-trifluoromethyl-
Preparation of 1-bromoacetyl-3-(5-trifluoromethyl-3-ynoxasilyl)urea (compound of Example 36) (569 mg (1.8 mmol)), 3.6 ml of acetone, Sodium iodide 0.
35 g (2.34 mmol) was added and stirred at room temperature for 4 hours. The reaction solution was distilled off under reduced pressure, 15 ml of water and a small amount of sodium sulfite aqueous solution were added to the residue, extracted using chloroform-acetic acid ethyl ester (4: 1 v/v) U solution, and dried over anhydrous sodium sulfate. Distillation under reduced pressure yielded 652 mg of colorless crystals. This was recrystallized from benzene to give 617 mg of the title compound as colorless plate crystals (yield: 9
4.3%). Melting point 183-184°C (decomposed).

Elemental analysis Calculated values as C, H, N, O, F, I (X)
C, 23, 16; H, L, 39; N, 11.57;
1.34.96 Actual value (X) C, 23, 1LH, 1
59;N, 11.63;I, 35.19 Example 39~
78 Examples 39-78 were conducted similarly to Examples 36-38. The results are shown in Tables 3 and 4.

(Left below) Example 79 Production of 1-chloroacetyl-3-(5-methyl-2-isooimazazolin-3-yl)urea 5-Methyl-3-amino-2-yne oxazoline 601 mg (6.0 mmol) 12 ml of dry benzene and 78 ml of chloroacetamide
A benzene solution of chloroacetylisocyanate synthesized from 5 mg (8.4 mmol) was mixed, stirred at room temperature for one hour, and left at room temperature overnight, and the precipitated crystals were collected by filtration.
Title compound 1, 267 g as a pale yellow powder (yield: 9
6.1%) was obtained. Melting point 157.5-160.0°C (
Disassembly).

Elemental analysis Ct H1゜N, O, CI calculated value (X
) C, 38, 28: H, 4, 59; N, 19.13
Actual value (X) C, 37, 89; H, 4, 33; N,
18.83 Example 80 Production of 1-bromoacetyl-3-(5-t-butyl-2-isoxazolin-3-yl)urea Benzene of bromoacetyl isocyanate synthesized from 468 mg (3.4 mmol) of bromoacetamide Add 4 ml of dry methylene chloride to the solution, and while keeping it at 0-5°C, 5-t-
Butyl-3-amino-2-isoxazoline 284mg
(2.0 mmol) in 6 ml of dry methylene chloride was added dropwise over about 30 minutes, and after drying at room temperature for 2.5 hours, the reaction solution was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to form colorless crystals. 572 mg was obtained.

This was mixed with n-hexane-1,2-dichloromethane (1:2
v/v) was recrystallized from the mixed solution to obtain the title compound 440a+g (yield 71.9%) as colorless needle crystals. Melting point 1
65.0-166.0°C (decomposition).

Elemental analysis C+ o H+ a N s Os B r
Calculated value as (X) C, 39, 23; H, 5, 27
;N, 13.72 actual value (%) C, 39,09;H
, 5, 10; N, 13.86 Example 81 Preparation of 1-iodoacetyl-3-(5-methyl-2-inoxazolin-3-yl)urea 1-chloroacetyl-
3-(5-methyl-2-ynoxazolin-3-yl)
439 mg (2.0 mmol) of urea (compound of Example 79), 18 ml of acetone, and 0.39 g of sodium iodide
(2.6 mmol) was added, stirred at room temperature for 4 hours, the reaction solution was distilled off under reduced pressure, 10 ml of water and a small amount of sodium bisulfite aqueous solution were added to the residue, and extracted with methylene chloride.
The methylene chloride layer was dried over anhydrous sodium sulfate and then distilled off under reduced pressure to obtain 591 mgt of pale yellow crystals. This was recrystallized from a mixture of n-hexane-ethyl acetate (2nia v/v) to give 306 mg of the title compound (
A yield of 49.2%) was obtained. Melting point 164.0-165.0
°C (decomposition).

Elemental analysis CyH+eNsOsI and 1. -7T calculated value (
%) C, 27,03; H, 3,24; N, 13.5
1 Actual measurement value (X) C, 27,04; H, 3,19:N
, 13.43 Examples 82-84 Examples 82-84 were carried out similarly to Examples 79-81. The results are shown in Table 5.

(Left below) Example 85 Production of 1-chloroacetyl-3-phenylurea 0.84 g (9.0 mmol) of aniline and 18 ml of dry benzene
A benzene solution of chloroacetyl isocyanate synthesized from 1.18 g (12.6 mmol) of chloroacetylamide and chloroacetyl isocyanate was added, stirred at room temperature for 2 hours, and left at room temperature for 3 days. 1.58 g (yield: 82.6%) of the title compound was obtained as crystals. Melting point 156
．． 0-158.0℃.

Elemental analysis Calculated value as C*HsN*O*CI (X)
C, 50,84; H, 4,27; N, 13.17; C
1, 16, 67 actual measurement value (X) C, 50, 56:H,
4,15;N,13.15;C1,16,63 Example
86 Production of 1-bromoacetyl-3-benzylurea 5.4+nl of dry methylene chloride was added to a benzene solution of bromoacetyl isocyanate synthesized from 0.75 g (5.44 mmol) of bromoacetylamide, and the mixture was heated at 0 to 5°C. A solution of 342.9 mg (3.20 mmol) of benzylamine in 9.6 ml of dry medelene chloride was added dropwise over about 30 minutes while maintaining the temperature at room temperature, and after stirring at room temperature for 1.5 hours, it was left at room temperature overnight to precipitate. The resulting crystals were collected by filtration to obtain 686.0 mg (yield 79.1%) of the title compound as colorless needle-like crystals. Melting point 173.5-175.0°C (decomposed).

Elemental analysis Calculated value as C8゜H□1N, ○, Br (X
) C, 44,30; H, 4,09; N, 10.33
;Br, 29.47 Actual value (X) C, 44,08;
H, 3,95; N, 10.28; Br, 29.62 Example 87 Production of 1-iodoacetyl-3-(1-methoxycarbonylethyl)-(2,6-dimethylaminophenyl)urea 1 -Chloroacetyl-3-(1-methoxycarbonylethyl)-(2,6-dimethylaminophenyl)urea (compound of Example 94) 522.81 ng (1,60 mmol), acetone 3.2 ml, iodide Sodium 0.31
g (20.8 mmol) was added, stirred at room temperature for 4 hours, the reaction solution was distilled off under reduced pressure, 10 ml of water and a small amount of sodium sulfite aqueous solution were added to the residue, and extracted with methylene chloride.
The methylene chloride layer was dried over anhydrous sodium sulfate and then distilled off under reduced pressure to obtain 665.2 mg of pale yellow crystals. This was dissolved in 4 ml of acetone, 50 ml of n-hexane was gradually added, and the precipitated crystals were collected by filtration to obtain 514.3 mg (yield 76.9%) of the title compound as colorless prism crystals. Melting point: 119.0-120.0°C (decomposed).

Elemental analysis Calculated value (%) as C+aHtsNtOaI
C, 43,08; H, 4,58; N, 6.70; I
, 30.34 actual value (1) C, 42,93; H, 4
, 46; N, 6.65; 1.30.30 Example 8B-
98 Examples 88-98 were conducted similarly to Examples 85-87. The results are shown in Table 6.

(Margin below) birth transfer υ迩釆 Compound (I) of the present invention exhibits excellent antifungal activity.

The results of the in vitro antifungal test of the compound (I) of the present invention were
Shown in the table. However, the compound No. in the table means the product of the corresponding Example No.

Table 7 note)

Claims (1)

[Claims] General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, A is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ Numerical formulas, chemical formulas , tables, etc.▼ R is hydrogen, alkyl, or 1-alkoxycarbonylethyl, R^1 is hydrogen, alkyl, cycloalkyl, perfluoroalkyl, or phenyl, R^2 is alkyl, R^3 is hydrogen, alkyl, or substituted phenyl which may have a group, R^4 and R^5 each represent hydrogen or methyl, n is an integer of 0 or 1, X is halogen, Y^1 and Y^2 each represent hydrogen or alkyl.) The compound shown in