Pesticidal 4-benzoylisoxazoles, particularly 5- cyclopropylisoxazole herbicides and intermediate compounds in their synthesis, are described in the literature. for example in European Patent PublicationNos. 0418175, 0527036 0560482.0609798 and 0682659.

Various methods for preparing these compounds are known. The present invention seeks to provide an improved method for the preparation of intermediate compounds in their synthesis.

The present invention provides a process for the preparation of a compound of formula (I): wherein: R2 is C16 straight- or branched- chain alkylthio, C16 alkyl, C16 haloalkyl, CH2SRD, C16 alkoxy, C16 haloalkoxy. or halogen; or a N- linked imidazole, pyrazole, 1,2,3,4-tetrazole, 1.2.3-triazole or 1 1,2,4- 4- triazole ring which ring systems are optionally substituted by one or more groups selected from halogen C 1-6 alkyl. C 1-6 haloalkyl or C 1-6 straight- or branched- chain alkylthio; R3 is C16 straight- or branched- chain haloalkyl, C16 straight- or branched- chain alkyl. C16 alkoxy, C16 haloalkoxy, halogen, C1-6

straight- or branched- chain alkylthio or nitro ; or a N-linked imidazole, pyrazole. 1,2,3,4-tetrazole, 1.2.3-triazole or 1,2,4-triazole riny which ring systems are optionally substituted by one or more groups selected from halogen. C 1-6 alkyl. C 1-6 haloalkyl or C16 straight- or branched- chain alkyithio; R4 is hydrogen, C1 -6 straight- or branched- chain haloalkyl, C1-6 straight- or branched- chain alkyl, C1-6 alkoxy, C1-6 haloalkoxy, halogen. C16 straight- or branched- chain alkylthio; or a 5 or 6- membered heterocyclic ring (which may be unsaturated or partially saturated) containing 1 to 3 hetero atoms selected from oxygen, nitrogen and sulphur. optionally substituted by halogen, C1-6 haloalkyl, C1-6 alkyl, C1-6 haloalkoxy. C16 alkoxy. SOnR5, nitro or cyano; or R3 and R4 together with the carbon atoms to which they are attached, form a 5 to 7 membered saturated or unsaturated heterocyclic ring containing up to three ring heteroatoms selected from nitrogen, oxygen and sulfur. which ring is optionally substituted by one or more groups selected from halogen, nitro. C16 straight- or branched- chain alkylthio. C1-4 alkyl. C1-4 alkoxy. C14 haloalkyl. C14 haloalkoxy, =0 and =NO-R5; R5 represents C16 straight- or branched- chain alkyl; and n represents zero. one or two; which process comprises the reaction of a compound of formula (II):

wherein R1 is C16 straight- or branched- chain alkyl. and R2. R3 and R. are as hereinbefore defined. with a compound of formula (III): in an aprotic solvent in the presence of a base.

When R4 represents a heterocyclic ring, preferred rings include 3-isoxazolyl. 5-isoxazolyl. 2-thiazolyl. 5-oxazolyl, 2-furyl. 3-furyl, 2- thienyl and 3-thienyl.

R1 preferably represents methyl.

R2 preferably represents methylthio or methylthiomethyl.

R3 preferably represents trifluoromethyl or bromo.

R4 preferably represents hydrogen.

In an especially preferred embodiment of the invention R1 represents C 1-6 alkyl (methyl is most preferred); R2 represents methylthiomethyl: R3 represents bromo: and R4 represents hydrogen.

In a most especially preferred embodiment of the invention R1 represents C16 alkyl (methyl is most preferred); R2 represents C16 alkylthio (methylthio is most preferred); R3 represents C16 haloalkyl (trifluoromethyl is most preferred); and R4 represents hydrogen.

Using these reaction conditions it has been found that the reaction gives high yields of the desired final product.

Certain compounds of formula (I) and a number of processes for their preparation have been described in the European Patent

Applications cited above. Compounds (Il) are known or may be prepared by known methods. Compound (III) and methods for its preparation are known.

The aprotic solvents which may be used may be nonpolar or polar.

Nonpolar aprotic solvents which are suitable include aromatic or aliphatic hydrocarbons, particularly toluene and xylenes (toluene is preferred); aromatic halogenated hydrocarbons (chlorobenzene is preferred) or ethers such as tert-butyl methyl ether, dioxan or tetrahydrofuran. Examples of suitable polar aprotic solvents include dimethylsulphoxide. N-methylpyrrolidinone, N,N-dimethylformamide or N,N-dimethylacetamide (dimethylsulphoxide and N- methylpyrrolidinone are preferred). Chlorobenzene and toluene are especially preferred because of the good results obtained. and cost and suitability of such solvents for large scale preparations.

Generally the reaction temperature used in the above process is from about 0°C to the boiling point of the solvent. preferably from about O"C to about 100"C: for non-polar solvents such as toluene or chlorobenzene a temperature of from about 40°C to about 90"C is especially preferred. whilst for polar aprotic solvents such as dimethylsulphoxide and N-methylpyrrolidinone chlorobenzene a temperature of from about 20"C to about 40"C is especially preferred.

Generally the reaction takes place in the presence of a strong base which is most preferably selected from an alkoxide of an alkali or alkaline earth metal. notably sodium ethoxide sodium methoxide, sodium or potassium t-butoxide; and a metal hydride (notably sodium hydride). Sodium methoxide is an especially preferred base for reasons of effectiveness in the reaction.

According to a preferred variant of the process of the present invention the reaction is performed with continuous distillation of the alcohol R1-OH formed in the course of the reaction, at atmospheric pressure or under reduced pressure (preferably from 150 to 250 mbars).

Alternatively the alcohol R1-OH formed may be removed by the use of a suitable molecular sieve for example a 4 Angstrom molecular sieve.

Compounds of formula (II) wherein R2 represents C 1-6 alkylthio; R3 represents C1 -6 haloalkyl and R4 represents hydrogen may be prepared by the reaction of a compound of formula (IV): wherein R1 and R3 are as defined above and K6 represents a halogen atom selected from fluorine, chlorine and bromine (preferably fluorine or chlorine), with an alkylthiol (or metal salt thereof) of formula R2-X wherein R2 is as defined above (preferably methylthio) and X represents hydrogen or an alkali metal (preferably sodium, potassium or lithium).

Preferably the above reaction to prepare intermediates of formula (II) is performed under substantially anhydrous conditions using a polar aprotic solvent preferably N-methylpyrrolidinone, acetonitrile or dimethylsulphoxide, at a temperature of from about -20" to about 150"C, preferably 0° to about 50"C.

The following non-limiting examples illustrate the invention.

Example 1 Preparation of 1 -cvclonrovvl-3-(2-methvlthioA- trifluoromethvlphenvl)propane-1,3-dione (small scale).

Sodium methoxide (3.51g. 0.065M) was added to a mixture of methyl 2-methylthio-4-trifluoromethylbenzoate (12.5 g 0.050M) and cyclopropyl methyl ketone (7ml, 0.070M) in toluene. The mixture was heated at 55-570C for 1 hour. Methanol was distilled under reduced pressure. After cooling to 200C the mixture was acidified and the organic phase washed (sodium bicarbonate solution and with water) and evaporated to give 1 -cyclopropyl-3 -(2-methy lthio-4- trifluoromethylphenyl)propane- 1,3 -dione as yellow crystals (14.03 g), m.p. 64"C. A yield of 92.9% was obtained. The purity of the product was 95%.

Example 2 Preparation of 1 -cvcloropvl-3-(2-methvlthio4- trifluoromethylphenyl)propane-1,3-dione (large scale).

Sodium methoxide (64g, 1.15M) was added to a mixture of methyl 2-methylthio-4-trifluoromethylbenzoate (200g, 0.8M) in chlorobenzene (380g). The mixture was heated to 75"C and cyclopropyl methyl ketone (75g. 0.88M) added during 2 hours whilst maintaining stirring at 75 "C.

After 4 hours methanol was distilled under reduced pressure the mixture cooled to 50°C, and water followed by sulphuric acid (53g of 36N) added. The organic phase was distilled under reduced pressure to give 1 -cyclopropy 1-3 -(2-methylthio-4-tri fluoromethylphenyl)propane- 1,3-dione as yellow crystals (240g), m.p. 58-60"C. A yield of 88% was obtained. The purity of the product was 90%.

Example 3 Preparation of 1 -cvclopropvl-3-(2-methylthio-4- trifluoromethvlphenvl)propane-1.3-dione (small scale).

Sodium methoxide (0.54g. 0.01M) was added to a mixture of methyl 9-methylthio-4-tritluoromethylbenzoate (1 .25g 0.005M) and cyclopropyl methyl ketone (0.5g. 0.006M) in anhydrous N-methylpyrrolidinone and heated at 30"C for 3 hours. The cooled mixture was acidified, extracted (ether), washed (water) and evaporated to give 1 cyclopropyl3-(2-methylthio4-tnfluoromethylphenyl)propane 1,3-dione (1.43g), m.p.68°C in a yield of 94%. The purity of the product was greater than 95%.

The above experiment was repeated but replacing the N-methylpyrrolidinone by dimethylsulphoxide to give the desired product in a yield of 97%. The purity of the product was greater than 95%.

Example 4 By proceeding according to the method described in Example 1 but using sodium methoxide (1.5 equivalents) and cyclopropyl methyl ketone (1.5 equivalents) and replacing the toluene by tert-butyl methyl ether. there was obtained. after 3 hours at 55"C (with distillation of methanol). a 92% yield of 1-cyclopropyl-3-('-methvlthio- 4-trifluoromethylphenyl)propane- 1.3 -dione purity 95%).

Examnle 5 By proceeding according to the method described in Example 1 but using cyclopropyl methyl ketone (1.5 equivalents) and replacing the toluene by tetrahydrofuran. there was obtained after 5 hours at 40"C (without distillation of methanol), a 75% yield of the desired product.

Reference Example 1 Dry sodium thiomethoxide (0.385g, 0.0055M) was added to a solution of methyl 2-chloro-4-trifluoromethylbenzoate (1.19g, 0.005M) in anhydrous N-methylpyrrolidinone (10ml) at 5"C. After 3 hours the mixture was acidified, extracted (ether) washed (water) and evaporated to give methyl 2-methylthio-4-trifluoromethylbenzoate (1.1 8g, 94% yield), 'H NMR 2.44(s,3H), 3.89(s,3H), 7.33(1H), 7.41(1H), 8.02(1H).