Title of Invention	"AN IMPROVED PROCESS FOR THE PREPARATION OF A 1-ARYL-3-CYCLOPROPYL-1,3-PROPANEDIONE OF FORMULA (I)"
Abstract	"AN IMPROVED PROCESS FOR THE PREPARATION OF A l-ARYL-3-CYCLOPROPYL-l,3-PROPANEDIONE OF FORMULA (I)" Which comprises reacting a compound of the formula: Wherein R1 is C1-6 straight -or branched-chain alkyl, with a compound of the formula: in an aprotic solvent in the presence of base.

Full Text

The present, invention relates to an improved process for the preparation of a 1 -aryl-3-cyclopropyl-l,3-propanedione of formula (I) This invention relates to a process for preparing 1,3-diketone compounds and the products obtained by this process. More particularly the invention relates to the preparation of intermediate compounds in the manufacture of pesticides. Pesticidal 4-benzoylisoxazoles, particularly 5-cyclopropylisoxazole herbicides and intermediate compounds in their synthesis, are described in the literature, for example in European Patent Publication Nos. 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. Accordingly, there is provided an improved process for the preparation of a compound of formula (I) for use as an intermediate in the manufacture of pesticides (Formula Removed) wherein R2 is Cl-6 straight- or branched- chain alkylthio, Cl-6 alkyl, Cl-6 haloalkyl, CH2SR5, C1-6 alkoxy, Cl-6 haloalkoxy, or halogen; or a N-linked imidazole, pyrazole, 1,2,3,4-tetrazole, 1,2,3-triazole or 1,2,4-triazole ring which ring systems are optionally substituted by one or more groups selected from halogen, C1-6 alkyl, C1-6 haloalkyl or C1-6 straight- or branched- chain alkylthio; R3 is Cl-6 straight- or branched- chain haloalkyl, Cl-6 straight- or branched- chain alkyl, Cl-6 alkoxy, Cl-6 haloalkoxy, halogen, Cl-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 ring which ring systems are optionally substituted by one or more groups selected from halogen, C1-6 alkyl, C1-6 haloalkyl or C1-6 straight- or branched- chain alkylthio; R4 is hydrogen,C1-6 straight- or branched- chain haloalkyl, C1-6 straight-or branched- chain alkyl, C1-6 alkoxy,C1-6 haloalkoxy, halogen,C1-6 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 haloalkyC1-6 alkyl, C1-6 haloalkoxy, C1-6 alkoxy, SOnRs, 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, C1-6 straight- or branched- chain alkylthio, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4haloalkoxy, =0 and =N0R.5; and R5 represents C1-6straight- or branched- chain alkyl; and n represents zero, one or two; which process comprises the reaction of a compound of formula (II): (Formula Removed) wherein R1 is C1-6 straight- or branched- chain alkyl, and R2, R3 and R4 are as hereinbefore defined, with a compound of formula (III): (Formula Removed) at a temperature of from 0°C to the boiling point of the solvent in an aprotic solvent in the presence of a base, and with distillation of the alcohol Ri-OH formed, or with removal of the alcohol R1-OH using a molecular sieve. The present invention provides a process for the preparation of a compound of formula (I): (Formula Removed) wherein: R2 is C1-6 straight- or branched- chain alkylthio, C1-6 alkyl,C1-6 haloalkyl, CH2SR5, C1-6 alkoxyC1-6 haloalkoxy, or halogen; or a N- Hnked imidazole, pyrazole, 1,2,3,4-tetrazole , 1,2,3-triazole or 1,2,4-triazole ring which ring systems are optionally substituted by one or more groups selected from halogen, C1-6 alkyl,C1-6 haloalkyl orC1-6 straight- or branched- chain alkylthio; R3 is C1-6 straight- or branched- chain haloalkyl,C1-6 straight- or branched- chain alkyl, C1-6 alkoxy,C1-6 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-triazoie ring which ring systems are optionally substituted by one or more groups selected from halogen, Cj.g alkyl, Cj.g haloalkyl or Cj.g straight- or branched- chain alkylthio; R4 is hydrogen, Cj.g straight- or branched- chain haloalkyl, C[_6 straight- or branched- chain alkyl, Cj.g alkoxy, Cj.6 haloalkoxy, halogen, Cj.g 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, Cj.g haloalkyl, Cj.g alkyl, C]_5 haloalkoxy, Cj.g 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. Cj.g straight- or branched- chain alkylthio, Cj_4 alkyl, Cj_4 alkoxy, Cj_4 haloalkyl, C\_4 haloalkoxy, =Oand=NO-R5; R5 represents Cj.6 straight- or branched- chain alkyl; and n represents zero, one or two; which process comprises the reaction of a compound of formula (II): (Figure Removed) in an aprotic solvent in the presence of a base. Ft is to be understood that, in this specification including the accompanying claims, alkyl groups and moieties are, unless otherwise specified, straight or branched chain. 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. R! 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 R| represents Cj.g alkyl (methyl is most preferred); R2 represents methylthiomethyl; R} represents bromo; and R4 represents hydrogen. In a most especially preferred embodiment of the invention R\ represents Cj.g alkyl (methyl is most preferred); R2 represents Cj.g alkylthio (methylthio is most preferred); R3 represents Ci_6 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 (II) 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 0°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 Rj-OH formed in the course of the reaction, at atmospheric pressure or under reduced pressure (preferably from 150 to 250 mbars). .Alternatively the alcohol Ri-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 Cj_5 alkylthio; R3 represents Cj.g haloalkyl and R4 represents hydrogen may be prepared by the reaction of a compound of formula (IV): (Figure Removed) (IV) wherein R] and R3 are as defined above and R£ 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. Compounds of formula (IV) are known in the literature or may be prepared by known methods or the adaptation of such methods. The following non-limiting examples illustrate the invention. Example 1 Preparation of l-cyclopropvl-3-(2-methylthio-4-trifluoromethylphenvl)propane-l,3-dione (small scale). Sodium methoxide (3.5 Ig, 0.065M) was added to a mixture of methyl 2-methylthio-4-trinuoromethylbenzoate (12.5g. 0.050M) and cyclopropyl methyl ketone (7ml, 0.070M) in toluene. The mixture was heated at 55-57T for 1 hour. Methanol was distilled under reduced pressure. After cooling to 20°C the mixture was acidified and the organic phase washed (sodium bicarbonate solution and with water) and evaporated to give l-cyclopropyl-3-(2-methylthio-4-trifluoromethylphenyl)propane-l,3-dione as yellow crystals (14.03g). m.p. 64°C. A yield of 92.9% was obtained. The purity of the product was 95%. Example 2 Preparation of l-cyclopropvl-3-(2-methylthio-4-trifluoromethvlphenvl)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 -cyclopropyl-3 -(2-methylthio-4-trifluoromethylphenyl)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 l-cyclopropyl-3-(2-methylthio-4-trifluoromethylphenvl)propane-1.3-dione (small scale). Sodium methoxide (0.54g. 0.01M) was added to a mixture of methyl 2-methylthio-4-trifluoromethylbenzoate (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 -cyclopropyl-3-(2-methylthio-4-trifluoromethylphenyl)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 l-cyclopropyl-3-(2-methylthio-4-trifluoromethylphenyl)propane-l,3-dione (purity 95%). Example 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 (1.18g, 94% yield), 'H NMR2.44(s,3H), 3.89(s,3H), 7.33(1H), 7.41(1H), 8.02(1H). WE CLAIM: 1. An improved process for the preparation of a l-aryl-3-cyclopropyl-l,3-propanedione of formula (I) for use as an intermediate in the manufacture of pesticides (Formula Removed) wherein R2 is C1-6 straight- or branched- chain alkylthio, C1-6 alkyl, C1-6 haloalkyl, CH2SR5, C1-6 alkoxy, C1-6 haloalkoxy, or halogen; or a N-linked imidazole, pyrazole, 1,2,3,4-tetrazole, 1,2,3-triazole or 1,2,4-triazole ring which ring systems are optionally substituted by one or more groups selected from halogen, C1-6 alkyl, C1-6 haloalkyl or C1-6 straight- or branched- chain alkylthio; R3 is C1-6 straight- or branched- chain haloalkyl, C1-6 straight- or branched- chain alkyi, C1-6 alkoxy, C1-6 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 ring which ring systems are optionally substituted by one or more groups selected from halogen, C1-6 alkyl, C1-6 haloalkyl or C1-6 straight- or branched- chain alkylthio; R4 is hydrogen, C1-6 straight- or branched- chain haloalkyl, C1-6 straight- or branched- chain alkyl, C1-6 alkoxy, C1-6 haloalkoxy, halogen, C1-6 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 base, characterized in that the process comprises distillation of the alcohol Ri-OH formed, or alcohol R1-OH is removed using a molecular sieve. 2. A process as claimed in claim 1 wherein the solvent is toluene, chlorobenzene, dimethylsulphoxide or N-methylpyrrolidinone. 3. A process as claimed in claim 1 or 2 wherein the base is selected from alkali metal and alkaline earth metal alkoxides and metal hydrides. 4. A process as claimed in any one of claims 1 to 3 which is performed with continuous distillation of the alcohol Ri-OH formed in the course of the reaction at atmospheric pressure or under reduced pressure. 5. A process as claimed in claim 4 wherein the distillation is performed under a pressure of 150 to 250 mbar. 6. A process as claimed in anyone of claims 1 to 5 wherein the aprotic solvent is toluene. 7. A process as claimed in any one of claims 1 to 5 wherein the aprotic solvent is chlorobenzene. 8. A process as claimed in any one of claims 1 to 7 wherein Ri represents Ci-6 alkyl; R2 represents C1-6 alkylthio; R3 represents C1-6 haloalkyl and R4 represents hydrogen. 9. A process as claimed in any one of claims 1 to 8 in which Ri represents methyl; R2 represents methylthio; R3 represents trifluoromethyl and R4 represents hydrogen. 10. A process as claimed in any one of claims 1 to 9 in which Ri represents C1-6 alkyl; R2 represents methylthiomethyl; R3 represents bromine and R4 represents hydrogen. 11. A process substantially as hereinbefore described with reference to the foregoing examples 1 to 5.

Documents:

1931-DEL-1998-Abstract-(02-01-2009).pdf

1931-DEL-1998-Abstract-(16-06-2008).pdf

1931-DEL-1998-Abstract-(31-12-2008).pdf

1931-del-1998-abstract.pdf

1931-DEL-1998-Claims-(16-06-2008).pdf

1931-DEL-1998-Claims-(31-12-2008).pdf

1931-del-1998-claims.pdf

1931-del-1998-complete specification (granted).pdf

1931-DEL-1998-Correspondence-Others-(16-06-2008).pdf

1931-DEL-1998-Correspondence-Others-(31-12-2008).pdf

1931-del-1998-correspondence-others.pdf

1931-DEL-1998-Description (Complete)-(02-01-2009).pdf

1931-del-1998-description (complete)-02-01-2009.pdf

1931-del-1998-description (complete)-16-06-2008.pdf

1931-del-1998-description (complete).pdf

1931-DEL-1998-Form-1-(02-01-2009).pdf

1931-DEL-1998-Form-1-(16-06-2008).pdf

1931-del-1998-form-1.pdf

1931-del-1998-form-18.pdf

1931-DEL-1998-Form-2-(02-01-2009).pdf

1931-DEL-1998-Form-2-(16-06-2008).pdf

1931-del-1998-form-2.pdf

1931-DEL-1998-Form-3-(16-06-2008).pdf

1931-del-1998-form-4.pdf

1931-del-1998-form-6.pdf

1931-del-1998-gpa.pdf

1931-DEL-1998-Petition-137-(16-06-2008).pdf

1931-DEL-1998-Petition-138-(16-06-2008).pdf

abstract.jpg