GB2223490A - Preparation of benzoyl urea derivatives - Google Patents

Abstract

A process for the preparation of a 2,6-difluorobenzoyl urea of formula <IMAGE> wherein R<1> represents a hydrogen, fluorine or chlorine atom, and R<2> and R<2> independently represent fluorine and chlorine atoms, provided that when R<1> represents a fluorine atom, R<3> is also a fluorine atom, comprises oxidising a 2,6-difluorobenzoyl thiourea of formula <IMAGE> wherein R<1>, R<2> and R<3> are as defined above. The ureas of formula I are known insecticides.

Description

PROCESS FOR THE PREPARATION OF BENZOYL UREA DERIVATIVES This invention relates to the preparation of certain insecticidal benzoyl urea derivatives, more particularly of 2,6-difluorobenzoyl ureas.

US Patent No. 4,457,943 discloses, inter alia, N-(2,4-difluoro-3,5-dichlorophenyl)-N'-t2,6-difluoro- benzoyl)urea and its use as an insecticide. This compound is also known as teflubenzuron. US Patent No. 4,457,943 also indicates that N-(2,4-difluoro-3,5-dichlorophenyl)-N'-(2,6-difluorobenzoyl)thiourea is one of a group of compounds which are considered to be particularly effective.

In US Patent No. 4,457,943, teflubenzuron is prepared by reaction of 2,4-difluoro-3,5-dichloroaniline with 2,6-difluorobenzoyl isocyanate. The 2,6-difluorobenzoyl isocyanate is itself prepared by reaction of 2,6-difluorobenzamide with oxalyl chloride.

An alternative synthesis exemplified in US Patent No. 4,457,943 involves reaction of 2,4-difluoro-3,5-dichlorophenyl isocyanate with an appropriate benzamide derivative. The 2,4-difluoro-3,5-dichlorophenyl isocyanate is prepared from 2, 4-difluoro-3 , 5-dichioroaniline by reaction with phosgene.

International Patent Application PCT/EP86/00116 (publication No. WO-A-86/ & 487) discloses the preparation, inter alia, of teflubenzuron and the analogous compound N-(2,3,4-trifluoro-5-chlorophenyl) -N'-(2,6-difluorobenzoyl) urea. Teflubenzuron is prepared by reacting 2,4-difluoro-3,5-dichlorobenzoyl fluoride with sodium azide, thermally decomposing the resulting carboxylic acid azide in situ (Curtius rearrangement) to form 2,4-difluoro-3,5-dichlorophenylisocyanate, and reacting this isocyanate with 2,6-difluorobenzamide to obtain teflubenzuron.

EP-A-176 868 discloses a class of insecticidal N- (3, 5-dichloro-4-halophenyl) -N'-benzoylureas, including, inter alia, N- (3,4, 5-trichlorophenyl) -N' - 2,6-difluorobenzoyl)urea and N-(3,5-dichloro-4fluorophenyl)-N'-2,6-difluorobenzoyl urea. These compounds are prepared by methods analogous to those disclosed in US Patent No. 4,457,943 and WO-A-86/05487, discussed above in relation to teflubenzuron.

EP-A-255 678 discloses advantageous reaction conditions for the preparation of teflubenzuron and its close analogues in the reaction of the appropriate phenylisocyanate with the appropriate benzamide. The phenylisocyanate is preferably obtained as in WO-A-86/05487.

There has now been discovered a route by which teflubenzuron may be prepared without using oxalyl chloride, phosgene or sodium azide.

According to the present invention there is provided a process for the preparation of a 2,6-difluorobenzoyl urea of formula

wherein Rl represents a hydrogen, fluorine or chlorine atom and R2 and R3 independently represent fluorine or chlorine atoms, provided that when R1 represents a fluorine atom, R3 is also a fluorine atom, characterised in that the process comprises oxidising a 2,6-difluorobenzoyl thiourea of formula

wherein Rl, R2 and R3 are as defined above.

Preferably R1is a hydrogen atom and R2 and R3 are both chlorine atoms, or, more preferably, R1 and R3 are both fluorine atoms and R2 is a chlorine atom.

Oxidation of compounds of formula II to compounds of formula I may conveniently be achieved, for example, using sodium hypochlorite in alcoholic medium, e.g. tertiary butyl alcohol, conveniently at 350C to 40etc, using silver nitrate in a two-solvent system, e.g. water/ethylacetate, conveniently at ambient temperature, or preferably, using iodine and a dialkyl sulphoxide, e.g. a di(Cl 6alkyl)sulphoxide, preferably dimethyl sulphoxide, conveniently at a temperature in the range 40etc, to 100C, preferably in the range 70"C to 90'C, advantageously at about 80"C.

Advantageously in accordance with the present invention the urea of formula I is prepared in an integrated process which comprises reacting a 2,6-difluorobenzoyl halide of formula

wherein X represents a chlorine or bromine atom with an alkali metal or ammonium thiocyanate, followed by reacting the resulting 2,6-difluorobenzoyl isothiocyanate with an aniline of formula

wherein R11 R2 and R3 are as defined above to produce a thiourea of formula II and oxidising the thiourea of formula II to produce the urea of formula I.

The compounds of formula III may readily be prepared in known manner. In particular 2,6-difluorobenzoyl chloride is a known material.

Reaction of the compound of formula III with ammonium thiocyanate (ammonium rhodanide) or the alkali metal thiocyanate, e.g. potassium or sodium thiocyanate, may conveniently be effected in the presence of a ketone solvent, e.g. acetone or methylethylketone, at a temperature in the range from ambient temperature to reflux temperature, preferably at reflux temperature.

The anilines of formula IV may be prepared in known manner from the corresponding nitrobenzene, e.g. as described for the preparation of 2,4-difluoro-3,5-dichloroaniline in US Patent No.

4,457,943 or as described for the preparation of 3,4,5-trichloroaniline in EP-A-176 868.

Reaction of 2,6-difluorobenzoyl isothiocyanate with the aniline of formula IV is suitably carried out in the presence of an inert solvent. Examples of suitable solvents are aromatic solvents such as benzene, toluene, xylene, or chlorobenzene, hydrocarbons such as petroleum fractions, chlorinated hydrocarbons such as chloroform, methylene chloride or dichloroethane, ethers such as diethyl ether, dibutyl ether, or dioxan and ketones, such as acetone and methylethylketone. Mixtures of solvents are also suitable.

The reaction may conveniently be effected at temperatures in the range from O0C to the reflux temperature of the reaction mixture, e.g. ambient temperature. Preferably the molar ratio of isocyanate to amine is from 1:1 to 2:1. Preferably the reaction is carried out under anhydrous conditions.

The invention will be further understood from the following illustrative Examples, in which Example 1 relates to the preparation cf starting material, and Examples 2 and 3 relate to the processes in accordance with the invention.

Example 1 Preparation of 2,6-difluorobenzoyl chloride A mixture of 2,6-difluorobenzoic acid (21g, 0.133 mol) and thionyl chloride (60g, 0.465 mol) was slowly heated to reflux temperature, with vigorous evolution of gas (hydrogen chloride and sulphur dioxide). After 45 minutes at reflux temperature, evolution of gas ceased, and the mixture was kept at that temperature for a further hour, after which excess thionyl chloride was distilled off.

Fractional distillation gave 2,6-difluorobenzoyl chloride (80%), bp 90 C at 30 mmHg (4 x 10 3 Pa.s), 77 C at 25 mmHg (3.3 x 103 Pa.s).

Example 2 Preparation of N-(2,4-difluoro-35-dichlorophenyl)-N' - (2, 6-difluorobenzoyl)urea (a) Preparation of N-(2,4-difluoro-3,5-dichloro phenyl)-N'-(2,6-difluorobenzoyl)thiourea 2,6-Difluorobenzoyl chloride (3.6g, (97%), 0.02 mol) was added to a solution of potassium thiocyanate (2g, 0.0206 mol) in acetone (30 ml) at ambient temperature (20"C). The resulting mixture was heated at reflux temperature under stirring for 15 minutes before being cooled to ambient temperature (20"C).

To the resulting solution containing 2,6-difluorobenzoyl isothiocyanate was added 2,4-difluoro-3,5-dichloroaniline (4g, 0.02 mol), during which the temperature of the mixture rose to about 30"C. The mixture was then heated at reflux temperature for 1 hour, before being cooled to ambient temperature (20to) and filtered (to remove potassium chloride). The clear filtrate was evaporated, the residue being dissolved in ethyl acetate (40 ml), washed with water, dried (Na2SO4), filtered and evaporated.

The residue was stirred in methanol (50 ml).

Filtration gave 3.4g of a white solid. The filtrate was evaporated to give a further 0.9g of white solid. The white solid was found by high performance liquid chromatography (HPLC) to be 100% pure N-(2,4-difluoro-3,5-dichloro phenyl)-N'-(2,6-difluorobenzoyl) thiourea (43gut 72%) m.p. 152"C.

(b) Preparation of N-(2 ,4-difluoro-3 ,5-dichloro- phenyl-N'-(2,6-difluorobenzoyl)urea The product of Example 2a (2.8g, 0.007 mol) was dissolved in dimethyl sulphoxide (5 ml) and iodine (0.07 mg) was added. The mixture was then heated at 800C with stirring for 10 hours, and after filtration dimethyl sulphoxide was evaporated off. The residue was stirred in methanol (20 ml) at ambient temperature (20"C).

Filtration afforded a white solid which was found by HPLC to be pure N-(2,4-difluoro-3,5 dichloro-phenyl)-N'-(2,6-difluorobenzoyl)urea (0.4g, 14.9%) mp.22l-224C.

No attempt was made to recover additional product from the methanolic filtrate.

Example 3 Preparation of N-(2,4-difluoro-3,5-dichlorophenyl) N'-(2,6-difluorobenzoyl)urea.

The product of Example 2a (0.8g, 0.002 mol) was dissolved in ethyl acetate (10 ml), a solution of silver nitrate (0.7g) in water (2 ml) was added and the resulting mixture was stirred for 2 hours at ambient temperature (20'C). More water (8 ml) was added, the resulting mixture was filtered to remove black precipitate, the aqueous layer was separated off and the organic layer was washed with water, dried (Na2SO4), filtered and evaporated to yield a residue, which was stirred in methanol (20 ml) at ambient temperature and filtered to afford a white solid product which was found by HPLC to be pure N-(2,4-difluoro-3,5-dichlorophenyl)-N'-(2,6-difluorobenzoyl)urea (0.3g) m.p. 221-224'C.

The black precipitate was extracted with tetrahydrofuran (10ml x 3) and the extract was separated off and evaporated to afford additional white solid product, which was also found to be pure N-(2,4-difluoro-3,5-dichlorophenyl)-N'-(2,6-difluorobenzoyl)urea (0.3g) m.p. 221-224iC.

The combined product (0.6g) represents an overall yield of 78%.

Claims (9)

1. A process for the preparation of a 2,6-difluorobenzoyl urea of formula

wherein R1 represents a hydrogen, fluorine or chlorine atom and R2 and R3 independently represent fluorine and chlorine atoms, provided that when R1 represents a fluorine atom, R3 is also a fluorine atom, characterised in that the process comprises oxidising a 2,6-difluorobenzoyl thiourea of formula

wherein Rl, R2 and R3 are as defined above.

2. A process according to Claim 1 wherein Rl is a hydrogen atom and R2 and R3 are both chlorine atoms, or R1 and R3 are both fluorine atoms and R2is a chlorine atom.

3. A process according to Claim 1 or 2 wherein R1 and R3 are both fluorine atoms and R2 is a chlorine atom.

4. A process according to any one of Claims 1 to 3 which comprises oxidising the thiourea of formula II using iodine and dimethylsulphoxide.

5. A process according to Claim 4 which comprises oxidising the thiourea of formula II at a temperature in the range 40 C to 100 C.

6. A process according to any one of Claims 1 to 5 which is characterised by reacting a 2,6-difluorobenzoyl halide of formula

which X represents a chlorine or bromine atom with an alkali metal or ammonium thiocyanate, followed by reacting the resulting 2,6-difluorobenzoylisothiocyanate with an aniline of formula

wherein R1, R2 and R3 are as defined in Claim 1, 2 or 3, to produce a thiourea of formula II and oxidising the urea of formula II to produce the urea of formula I.

7. A process according to Claim 1 substantially as hereinbefore described with reference to Example 2 or 3.

8. A process according to Claim 6 substantially as hereinbefore described with reference to Example 2 or 3.

9. A 2,6-difluorobenzoyl urea of formula I whenever prepared by a process according to any one of Claims 1 to 8.