Intermediate compounds for the preparation of fungicides

Abstract: Compounds of the formulae: in which A, R¹, R² and R⁵ have various specified values, are useful intermediates for the preparation of the agricultural chemicals described in EP-A-370629.

Description: This invention relates to certain chemical intermediates useful for preparing fungicidal, insecticidal and miticidal derivatives of propenoic acid. European patent No. 0370629, of which the present application is a divisional, claims in respect of the Contracting State GR a compound having the formula (I): and stereoisomers thereof, wherein A is hydrogen, halo, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, phenoxy, nitro or cyano; R 1 and R 2 , which may be the same or different, are hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted cycloalkylalkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted heteroaryloxy, nitro, halo, cyano, -NR 3 R 4 , -CO 2 R 3 , -CONR 3 R 4 , -COR 3 , -S(O) n R 3 wherein n is 0, 1 or 2, (CH 2 ) m PO(OR 3 ) 2 wherein m is 0 or 1, or R 1 and R 2 join to form a carbocyclic or heterocyclic ring system; and R 3 and R 4 , which may be the same or different are hydrogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl or optionally substituted heteroaryl. In respect of the Contracting States AT, BE, CH, DE, FR, GB, IT, LI, LU, NL and SE the same compounds are claimed with the proviso that when A is hydrogen, neither R 1 nor R 2 is optionally substituted heteroarylalkyl or R 1 and R 2 do not join to form a heterocyclic ring system. This proviso takes account of compounds disclosed in EP-A-0403618. The compounds contain at least one carbon-nitrogen double bond and at least one carbon-carbon double bond, and are sometimes obtained in the form of mixtures of geometric isomers which can be separated into individual isomers. The individual isomers which result from the unsymmetrically substituted double bond of the propenoate group and the oxime are identified by the commonly used terms " E " and " Z ". These terms are defined according to the Cahn-Ingold-Prelog system which is fully described in the literature (see, for example, J March, "Advanced Organic Chemistry", 3rd edition, Wiley-Interscience, page 109 et seq ). For the carbon-carbon double bond of the propenoate groups, usually one isomer is more active fungicidally than the other, the more active isomer usually being the one wherein the group -CO 2 CH 3 and -OCH 3 are on opposite sides of the olefinic bond of the propenoate group (the ( E )-isomer). These ( E )-isomers form a preferred embodiment. The present invention relates to certain intermediates which can be used to prepare the compounds of EP 370629. Thus, according to this invention there is provided a compound of the formula (VI), (IX) or (XI): or a stereoisomer thereof, wherein R 1 , R 2 and A have the meanings given above with the same proviso in respect of the Contracting States AT, BE, CH, DE, FR, GB, IT, LI, LU, NL and SE, and R 5 is hydrogen or a metal atom. Halo includes fluoro, chloro, bromo and iodo. Alkyl and the alkyl moieties of alkoxy, aralkyl and aryloxyalkyl can be in the form of straight or branched chains and, unless otherwise stated, suitably contain from 1 to 6 carbon atoms. Examples are methyl, ethyl, iso -propyl and tert -butyl. Optional substituents include halo (especially chloro and fluoro), hydroxy and C 1-4 alkoxy. Examples of substituted alkyl and substituted alkoxy are trifluoromethyl and trifluoromethoxy. Cycloalkyl is suitably C 3-6 cycloalkyl, for example cyclopropyl and cyclohexyl, and cycloalkylalkyl is suitably C 3-6 cycloalkyl(C 1-4 )alkyl, for example cyclopropylethyl. Alkenyl and alkynyl suitably contain from 2 to 6 carbon atoms, typically 2 to 4 carbon atoms, in the form of straight or branched chains. Examples are ethenyl, allyl and propargyl. Substituted alkenyl and alkynyl groups include optionally substituted arylalkenyl (especially optionally substituted phenylethenyl) and arylalkynyl. Aryl and the aryl moieties of aralkyl, arylalkenyl, arylalkynyl, aryloxy and aryloxyalkyl include phenyl and naphthyl. The carbocyclic or heterocyclic ring system which R 1 and R 2 may form together is suitably a C 5-10 aliphatic, aromatic or mixed aliphatic/aromatic carbocyclic ring system, for example cyclopentyl, cyclohexyl, cyclohexadienonyl and such groups carrying a fused benzene ring and/or substituents such as methyl; or it may be a 5- to 10-membered heterocyclic ring system, for example tetrahydropyranyl. The term heteroaryl is used to described aromatic heterocyclic groups. Heteroaryl and heterocyclyl and the heteroaryl and heterocyclyl moieties of other groups, such as heteroaryloxyalkyl and heterocyclylalkyl, are typically 5- or 6-membered rings containing one or more O, N or S heteroatoms which may be fused to one or more other aromatic, heteroaromatic or heterocyclic rings such as a benzene ring. Examples are thienyl, furyl, pyrrolyl, triazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl and quinoxalinyl groups and N -oxides thereof. Substitutents which may be present in optionally substituted aryl and heteroaryl moieties include one or more of the following: halo, hydroxy, mercapto, C 1-4 alkyl (especially methyl and ethyl), C 2-4 alkenyl (especially allyl), C 2-4 alkynyl (especially propargyl), C 1-4 alkoxy (especially methoxy), C 2-4 alkenyloxy (especially allyloxy), C 2-4 alkynyloxy (especially propargyloxy), halo(C 1-4 )alkyl (especially trifluoromethyl), halo(C 1-4 )alkoxy (especially trifluoromethoxy), C 1-4 alkylthio (especially methylthio), hydroxy(C 1-4 )alkyl, C 1-4 alkoxy(C 1-4 )alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl(C 1-4 )alkyl, optionally substituted aryl (especially optionally substituted phenyl), optionally substituted heteroaryl (especially optionally substituted pyridyl or pyrimidinyl), optionally substituted aryloxy (especially optionally substituted phenoxy), optionally substituted heteroaryloxy (especially optionally substituted pyridyloxy or pyrimidinyloxy), optionally substituted aryl(C 1-4 )alkyl (especially optionally substituted benzyl, optionally substituted phenethyl and optionally substituted phenyl n -propyl) in which the alkyl moiety is optionally substituted with hydroxy, optionally substituted heteroaryl(C 1-4 )alkyl (especially optionally substituted pyridyl- or pyrimidinyl(C 1-4 )alkyl), optionally substituted aryl(C 2-4 )alkenyl (especially optionally substituted phenylethenyl), optionally substituted heteroaryl(C 2-4 )alkenyl (especially optionally substituted pyridylethenyl or pyrimidinylethenyl), optionally substituted aryl(C 1-4 )alkoxy (especially optionally substituted benzyloxy), optionally substituted heteroaryl(C 1-4 )alkoxy (especially optionally substituted pyridyl-, or pyrimidinyl(C 1-4 )alkoxy), optionally substituted aryloxy(C 1-4 )alkyl (especially phenoxymethyl), optionally substituted heteroaryloxy(C 1-4 )alkyl (especially optionally substituted pyridyloxy- or pyrimidinyloxy(C 1-4 )alkyl), acyloxy, including C 1-4 alkanoyloxy (especially acetyloxy) and benzoyloxy, cyano, thiocyanato, nitro, -NR'R'', -NHCOR' , -NHCONR'R'', -CONR'R'', -COOR , -OSO 2 R', -SO 2 R', -COR', -CR'=NR'' or -N=CR'R'' in which R' and R'' are independently hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 3-6 cycloalkyl, C 3-6 cycloalkyl(C 1 - 4 )alkyl, phenyl or benzyl, the phenyl and benzyl groups being optionally substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy. Substitutents which may be present in the aryl or heteroaryl rings of any of the foregoing substituents include one or more of the following: halo, hydroxy, mercapto, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 2-4 alkenyloxy, C 2-4 alkynyloxy, halo(C 1-4 )alkyl, halo(C 1-4 )alkoxy, C 1-4 alkylthio, hydroxy(C 1-4 )alkyl, C 1-4 alkoxy(C 1-4 )alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl(C 1-4 )alkyl, alkanoyloxy, benzoyloxy, cyano, thiocyanato, nitro, -NR'R", -NHCOR', -NHCONR'R", -CONR'R", -COOR', -SO 2 R', -OSO 2 R', -COR', -CR'=NR" or -N=CR'R" in which R' and R" have the meanings given above. In one aspect the invention includes a compound of formula (VI), (IX) or (XI) wherein A is hydrogen, halo, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, C 1-2 alkylcarbonyl, C 1-2 alkoxycarbonyl, phenoxy, nitro or cyano; R 1 is C 1-4 alkyl, halo(C 1-4 )alkyl, C 1-4 alkoxy, halo(C 1 - 4 )alkoxy, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, cyano, phenyl(C 1-4 )alkyl, phenyl, a 5- or 6-membered aromatic heterocycle containing one or more O, N or S atoms and optionally fused to a benzene ring, the aromatic or heteroaromatic moieties of any of the foregoing being optionally substituted with one or more of halo, hydroxy, C 1-4 alkyl, halo(C 1-4 )alkyl, C 1-4 alkoxy, halo(C 1-4 )alkoxy, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, nitro, cyano, phenyl, phenoxy, benzyl or benzyloxy; and R 2 is hydrogen, halo, C 1-4 alkyl, halo(C 1-4 )alkoxy, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, cyano or phenyl; or R 1 and R 2 join together to form a C 5-10 carbocyclic ring system; with the proviso for the Contracting States AT, BE, CH, DE, FR, GB, IT, LI, LU, NL and SE that when A is hydrogen, R 1 is not a 5- or 6-membered heterocycle containing one or more O, N or S atoms fused to a benzene ring, and independently R 2 is not halo(C 1-4 )alkyl. In another aspect the invention includes a compound of formula (VI), (IX) or (XI) wherein A is hydrogen or halo; R 1 is C 1-4 alkyl, benzyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, cyano, phenyl, thienyl, triazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl or quinoxalinyl, the aromatic or heteroaromatic moieties of any of the foregoing being optionally substituted with one or more of halo, C 1-4 alkyl, trifluoromethyl, C 1-4 alkoxy, trifluoromethoxy, nitro, cyano, phenyl or benzyloxy; and R 2 is hydrogen, C 1-4 alkyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, cyano or phenyl; or R 1 and R 2 join together to form a cyclopentyl or cyclohexyl ring to which is optionally fused a benzene ring; with the proviso for the Contracting States AT, BE, CH, DE, FR, GB, IT, LI, LU, NL and SE that when A is hydrogen, R 1 is not triazolyl, thiazolyl or quinolinyl. The compounds listed in Table I which follows illustrate compounds described in EP 370629 which can be made using the compounds of the present invention. Throughout Table I the methyl 3-methoxypropenoate group has the ( E )-configuration. SELECTED PROTON NMR DATA Table II shows selected proton NMR data for certain compounds described in Table I. Chemical shifts are measured in ppm from tetramethylsilane, and deuterochloroform was used as solvent throughout. The column headed 'frequency' refers to the operating frequency of the NMR spectrometer. The following abbreviations are used: br = broad s = singlet d = doublet t = triplet q = quartet m = multiplet COMPOUND NO. FREQUENCY MHz 1 270 3.69(3H,s), 3.82(3H,s), 3.83(3H,s), 5.12(2H,s), 6.84-6.99(2H,m), 7.11-7.2(1H,m), 7.25-7.4(3H,m), 7.5-7.62(1H,m), 7.60(1H,s), 7.74-7.8(1H,m), 8.50(1H,s) ppm. 2 400 3.70(3H,s), 3.80(3H,s), 3.81(3H,s), 5.13(2H,s), 6.9-7.54(8H,m), 7.60(1H,s) ppm. 6 270 (major isomer) 2.36(3H,s), 3.68(3H,s), 3.80(3H,s), 5.10(2H,s), 7.1-7.5(8H,m), 7.60(1H,s), 8.07(1H,s) ppm. 11 270 3.70(3H,s), 3.81(3H,s), 5.14 (2H,s), 7.15-7.20(1H,m), 7.24-7.43(5H,m), 7.48-7.54(1H,m), 7.58-7.62(1H,m), 7.59(1H,s), 8.04(1H,s) ppm. 17 270 3.70(3H,s), 3.84(3H,s), 5.17 (2H,s), 7.16-7.22(1H,m), 7.32-7.39(2H,m), 7.49-7.58(2H,m), 7.60(1H,s), 7.88(1H,d), 8.14(1H,s), 8.17-8.23(1H,m), 8.42(1H,m) ppm. 20 270 3.70(3H,s), 3.83(3H,s), 5.16(2H,s), 7.14-7.20(1H,m), 7.31-7.38(2H,m), 7.46-7.55(2H,m), 7.55-7.64(1H,m), 7.60(1H,s), 7.7-7.77(1H,d), 7.83(1H,s), 8.12(1H,s) ppm. 23 270 2.25(3H,s), 3.69(3H,s), 3.81(3H,s), 5.16(2H,s), 7.13-7.20(1H,m), 7.3-7.4(5H,m), 7.5-7.55(1H,m), 7.59(1H,s), 7.6-7.66(2H,m) ppm. 29 270 3.68(3H,s), 3.80(3H,s), 5.08 (2H,s), 5.13(2H,s), 6.94-7.07(1H,m), 7.07-7.56(12H,m), 7.60(1H,s), 8.06(1H,s) ppm. 32 270 3.70(3H,s), 3.83(3H,s), 5.14(2H,s), 7.1-7.9(8H,m), 7.60(1H,s), 8.07(1H,s) ppm. 37 270 3.69(3H,s), 3.81(3H,s), 5.18(2H,s), 7.16-7.82(7H,m), 7.60(1H,s), 8.19(1H,s), 8.6(1H,m) ppm. 38 270 3.69(3H,s), 3.82(3H,s), 5.14(2H,s), 7.14-7.53(5H,m), 7.601H,s), 7.90-7.96(1H,m), 8.10(1H,s), 8.55-8.62(1H,m), 8.72(1H,m) ppm. 40 270 2.34(3H,s), 3.69(3H,s), 3.81(3H,s), 5.19(2H,s), 7.1-7.7(6H,m), 7.60(1H,s), 7.89(1H,d), 8.59(1H,d) ppm. 42 270 1.32-1.40(3H,t), 3.63(3H,s), 3.77(3H,s), 4.33-4.44(2H,q), 5.25(2H,s), 7.13-7.20(1H,m), 7.26-7.42(4H,m), 7.56(1H,s), 7.7-7.77(2H,m), 7.66-7.71(1H,m) ppm. 47 270 2.24(3H,s), 3.69(3H,s), 3.82(3H,s), 5.11(2H,s), 6.9-7.55(7H,m), 7.58(3H,s) ppm. 49 270 1.3(6H,q), 3.70(3H,s), 3.83(3H,s), 4.36(4H,q), 5.28(2H,s), 7.1-7.5(4H,m), 7.58(1H,s) ppm. 55 270 2.85-3.12(4H,m), 3.69(3H,s), 3.82(3H,s), 5.14(2H,s), 7.1-7.7(8H,m), 7.58(1H,s) ppm. 65 270 (major isomer) 2.24(3H,s), 3.68(3H,s), 3.81(3H,s), 5.16(2H,s), 7.1-7.5(5H,m), 7.60(1H,s), 7.9(1H,m), 8.57(1H,m), 8.83(1H,m) ppm. 66 270 1.22(6H,d), 3.57(1H,m), 3.69(3H,s), 3.82(3H,s), 5.13(2H,s), 7.1-7.5(4H,m), 7.60(1H,s), 8.81(2H,s), 9.18(1H,s) ppm. 67 270 1.14(6H,d), 2.83(1H,m), 3.66(3H,s), 3.78(3H,s), 5.00(2H,s), 7.1-7.4(4H,m), 7.53(1H,s), 8.66(2H,s), 9.17(1H,s) ppm. 92 270 2.26(3H,s), 3.68(3H,s), 3.80(3H,s), 4.00(3H,s), 5.21(3H,s), 7.1-7.6(4H,m), 7.58(1H,s), 8.08(1H,d), 8.16(1H,d) ppm. 93 270 (major isomer) 2.30(3H,s), 3.69(3H,s), 3.83(3H,s), 4.03(3H,s), 5.24(2H,s), 7.1-7.55(4H,m), 7.60(1H,s), 9.20(1H,m), 9.23(1H,m), (minor isomer) 2.30(3H,s), 3.64(3H,s), 3.80(3H,s), 4.03(3H,s), 5.12(2H,s), 7.1-7.55(4H,m), 7.57(1H,s), 9.32(1H,m), 9.37(1H,m) ppm. 102 270 2.22(3H,s), 3.68(3H,s), 3.83(3H,s), 5.12(2H,s), 7.15-7.55(7H,m), 7.60(1H,s) ppm. 108 270 2.20(3H,s), 3.67(3H,s), 3.80(3H,s), 3.83(3H,s), 5.14(2H,s), 6.87-7.60(8H,m), 7.57(1H,s) ppm. 111 270 2.20(3H,s), 2.30(3H,s), 3.68(3H,s), 3.80(3H,s), 5.13(2H,s), 7.15-7.4(7H,m), 7.54(1H,m), 7.58(1H,s) ppm. 112 270 2.23(3H,s), 2.37(3H,s), 3.68(3H,s), 3.81(3H,s), 5.16(2H,s), 7.1-7.55(8H,m), 7.58(1H,s) ppm. 113 270 2.22(3H,s), 2.35(3H,s), 3.68(3H,s), 3.81(3H,s), 5.13(3H,s), 7.1-7.5(8H,m), 7.58(1H,s) ppm. 114 270 2.26(3H,s), 3.68(3H,s), 3.81(3H,s), 5.16(2H,s), 7.0-7.55(8H,m), 7.59(1H,s) ppm. 115 270 2.02(3H,s), 3.68(3H,s), 3.82(3H,s), 5.15(2H,s), 7.0-7.55(8H,m), 7.60(1H,s) ppm. 116 270 2.22(3H,s), 3.68(3H,s), 3.82(3H,s); 5.13(2H,s), 6.99-7.65(8H,m), 7.59(1H,s) ppm. 118 270 2.21(3H,s), 3.69(3H,s), 3.81(3H,s), 5.16(2H,s), 7.14-7.66(8H,m), 7.59(1H,s) ppm. 121 270 2.21(3H,s), 3.69(3H,s), 3.82(3H,s), 5.16(2H,s), 7.1-7.55(7H,m), 7.59(1H,s), 7.81(1H,m) ppm. 127 270 2.26(3H,s), 3.69(3H,s), 3.83(3H,s), 5.18(2H,s), 7.15-7.92(8H,m), 7.60(1H,s) ppm. 131 270 2.22(3H,s), 3.68(3H,s), 3.82(3H,s), 5.18(2H,s), 7.1-7.8(8H,m), 7.59(1H,s) ppm. 143 270 (major isomer) 2.28(3H,s), 2.53(3H,s), 3.69(3H,s), 3.83(3H,s), 5.22(2H,s), 7.1-7.5(4H,m), 7.60(1H,s), 7.72(1H,s), 9.06(1H,s) ppm. (minor isomer) 2.27(3H,s), 2.48(3H,s), 3.69(3H,s), 3.83(3H,s), 5.21(2H,s), 7.1-7.5(4H,m), 7.61(1H,s), 7.77(1H,s), 9.10(1H,s) ppm. 144 270 (major isomer) 2.22(3H,s), 2.50(3H,s), 3.67(3H,s), 3.81(3H,s), 5.14(2H,s), 7.1-7.5(4H,m), 7.58(1H,s), 8.53(1H,s), 9.02(1H,s) ppm. (minor isomer) 2.17(3H,s), 2.40(3H,s), 3.65(3H,s), 3.77(3H,s), 5.00(2H,s), 7.1-7.5(4H,m), 7.52(1H,s), 8.37(1H,s), 9.05(1H,s) ppm. 145 270 2.39(3H,s), 2.57(3H,s), 3.68(3H,s), 3.81(3H,s), 5.33(2H,s), 7.11(1H,d), 7.1-7.55(4H,m), 7.57(1H,s), 8.64(1H,d) ppm. 152 270 2.92(2H,t), 3.68(3H,s), 3.82(3H,s), 4.18(2H,t), 5.14(2H,s), 6.8-7.0(2H,m), 7.1-7.5(5H,m), 7.58(1H,s), 7.87(1H,m) ppm. 154 270 2.22(3H,s), 3.61(3H,s), 3.75(3H,s), 5.08(2H,s), 7.0-7.5(7H,m), 7.52(1H,s), 8.12(1H,m) ppm. 158 270 2.08(3H,s), 3.67(6H,s), 3.80(3H,s), 5.06(2H,s), 6.08(1H,m), 6.38(1H,m), 6.06(1H,m), 7.1-7.5(4H,m), 7.57(1H,s) ppm. 160 270 3.69(3H,s), 3.82(3H,s), 5.19(2H,s), 5.42(2H,s), 7.1-7.5(7H,m), 7.61(1H,s), 7.77(1H,s), 8.05(1H,s) ppm. 162 270 2.21(3H,s), 2.46(3H,s), 2.62(3H,s), 3.68(3H,s), 3.82(3H,s), 5.10(2H,s), 7.1-7.5(4H,m), 7.58(1H,s) ppm. 163 270 2.16(3H,s), 3.68(3H,s), 3,81(3H,s), 5.17(2H,s), 6.42(1H,m), 6.61(1H,m), 7.1-7.55(6H,m), 7.58(1H,s) ppm. 165 270 3.63(3H,s), 3.76(3H,s), 5.22(2H,s), 7.1-7.8(10H,m), 7.56(1H,s), 8.55(1H,d), 8.70(1H,d) ppm. 177 270 2.29(3H,s), 2.51(3H,s), 2.53(3H,s), 3.68(3H,s), 3.81(3H,s), 5.15(2H,s), 7.1-7.5(4H,m), 7.59(1H,s), 8.24(1H,s) ppm. 183 270 2.24(3H,s), 3.03(3H,s), 3.68(3H,s), 3.82(3H,s), 5.20(2H,s), 7.1-7.5(4H,m), 7.59(1H,s), 7.8-8.0(4H,m) ppm. 184 270 2.18(3H,s), 3.67(3H,s), 3.78(3H,s), 3.80(2H,br.s), 5.11(2H,s), 6.59(2H,d), 7.1-7.55(6H,m), 7.58(1H,s) ppm. 188 270 (major isomer) 0.65(2H,m), 0.90(2H,m), 2.32(1H,m), 3.67(3H,s), 3.80(3H,s), 5.13(2H,s), 7.1-7.6(9H,m), 7.57(1H,s) ppm. (minor isomer) 0.65(2H,m), 2.32(1H,m), 3.63(3H,s), 3.76(3H,s), 4.97(2H,s), 7.1-7.6(9H,m), 7.77(1H,s) ppm. 190 270 1.41(3H,t), 3.64(3H,s), 3.76(3H,s), 4.05(2H,q), 5.18(2H,s), 6.8-7.55(8H,m), 7.55(1H,s) ppm. 191 270 2.04(3H,s), 3.66(3H,s), 3.78(3H,s), 5.19(2H,s), 7.1-7.4(8H,m), 7.5-7.6(1H,m), 7.57(1H,s) ppm. 194 270 1.10(9H,s), 1.81(3H,s), 3.68(3H,s), 3.81(3H,s), 4.99(2H,s), 7.1-7.5(4H,m), 7.57(1H,s) ppm. 196 270 1.76(3H,s), 3.46(2H,s), 3.67(3H,s), 3.80(3H,s), 5.06(2H,s), 7.1-7.5(9H,m), 7.57(1H,s) ppm. 198 270 2.10(3H,s), 3.69(3H,s), 3.82(3H,s), 5.11(2H,s), 6.85(2H,s), 7.1-7.5(9H,m), 7.58(1H,s) ppm. 225 270 3.60(3H,s), 3.70(3H,s), 3.78(3H,s), 4.94(2H,s), 7.1-7.5(7H,m), 7.53(1H,s), 7.77-7.81(2H,m) ppm. 226 270 3.66(3H,s), 3.77(3H,s), 3.98(3H,s), 5.04(2H,s), 7.10-7.58(7H,m), 7.58(1H,s), 7.60-7.70(2H,m) ppm. 227 270 2.88(3H,s), 3.67(3H,s), 3.79(3H,s), 5.18(2H,dd), 7.1-7.5(7H,m), 7.60(1H,s), 7.6-7.7(2H,m) ppm. 228 270 3.20(3H,s), 3.67(3H,s), 3.80(3H,s), 5.30(2H,s), 7.1-7.6(9H,m), 7.60(1H,s) ppm. The compounds of formula (I) described in EP-A-370629 may be prepared by the step shown in Scheme 1. The terms A, R 1 and R 2 are as defined above and X is a leaving group such as halogen (chlorine, bromine or iodine). The compounds of formula (I) may be prepared by treating oximes of general formula (III) with a suitable base (such as sodium hydride or sodium methoxide), in a suitable solvent (such as N , N -dimethylformamide or tetrahydrofuran), to form the anion and then adding a compound of formula (II). Oximes of the general formula (III) are well known in the chemical literature. The compound of general formula (II) where X is bromine and the propenoate group has the ( E )-configuration is described in EP-A-0203606. Alternatively compounds of formula (I) may be prepared by the steps shown in Scheme 2. The terms A, R 1 , R 2 and X are as defined above, R 5 is hydrogen or a metal (such as sodium or potassium), L is a leaving group such as a halide (chloride, bromide or iodide), a CH 3 SO 4 anion, or a sulphonyl anion. Each transformation is performed at a suitable temperature and usually, though not always, in a suitable solvent. The compounds of formula (I) can be prepared from phenylacetates of formula (VI) or the ketoesters of formula (X) by the steps shown in Scheme 2. Thus compounds of formula (I) can be prepared by treatment of phenylacetates of formula (VI) with a base (such as sodium hydride or sodium methoxide) and methyl formate. If a species of formula CH 3 L, wherein L is as defined above, is then added to the reaction mixture, compounds of formula (I) may be obtained. If a protic acid is added to the reaction mixture, compounds of formula (IX), wherein R 5 is hydrogen, are obtained. Alternatively the species of formula (IX), wherein R 5 is a metal (such as sodium), may themselves be isolated from the reaction mixture. Compounds of formula (IX), wherein R 5 is a metal, can be converted into compounds of formula (I) by treatment with a species CH 3 L, wherein L is as defined above. Compounds of formula (IX), wherein R 5 is hydrogen, can be converted into compounds of formula (I) by successive treatment with a base (such as potassium carbonate) and a species of general formula CH 3 L. Alternatively, compounds of formula (I) can be prepared from acetals of formula (IV) by elimination of methanol under either acidic or basic conditions. Examples of reagents or reagent mixtures which can be used for this transformation are lithium di-isopropylamide; potassium hydrogen sulphate (see, for example, T Yamada, H Hagiwara and H Uda, J. Chem. Soc. Chemical Communications, 1980, 838, and references therein); and triethylamine often in the presence of a Lewis acid such as titanium tetrachloride (see, for example, K Nsunda and L Heresi, J. Chem. Soc. Chemical Communications , 1985, 1000). Acetals of formula (IV) can be prepared by treatment of methyl silyl ketene acetals of formula (V), wherein R is an alkyl group, with trimethyl orthoformate in the presence of a Lewis acid such as titanium tetrachloride (see, for example, K Saigo, M Osaki and T Mukaiyama, Chemistry Letters , 1976, 769). Methyl silyl ketene acetals of formula (V) can be prepared from phenylacetates of formula (VI) by treatment with a base and trialkylsilyl halide of formula R 3 SiCl or R 3 SiBr, such as trimethylsilyl chloride, or a base (such as triethylamine) and a trialkylsilyl triflate of formula R 3 Si-OSO 2 CF 3 (see, for example, C Ainsworth, F Chen and Y Kuo, J. Organometallic Chemistry , 1972, 46, 59). It is not always necessary to isolate the intermediates (IV) and (V); under appropriate conditions compounds of formula (I) may be prepared from phenylacetates of formula (VI) in "one pot" by the successive addition of suitable reagents listed above. Phenylacetates of formula (VI) may be prepared from phenylacetates of formula (VII). Thus, if an oxime of general formula (III) is treated with a suitable base (such as sodium hydride or sodium methoxide) and the phenyl acetates of formula (VII) are added, phenylacetates of formula (VI) are obtained. Phenylacetates of formula (VII) are obtained from isochromanones of formula (VIII) by treatment with HX, wherein X is a halogen (such as bromine), in methanol. This transformation may also be accomplished in 2 steps if the isochromanone (VIII) is treated with HX in a non-alcoholic solvent, and the resulting phenylacetic acid is then esterified using standard procedures (see, for example, I Matsumoto and J Yoshizawa, Jpn. Kokai (Tokkyo Koho) 79 138 536, 27.10.1979, Chem. Abs., 1980, 92 , 180829h; and G M F Lim, Y G Perron and R D Droghini, Res. Discl., 1979, 188, 672, Chem. Abs., 1980, 92 , 128526t). Isochromanones of formula (VIII) are well known in the chemical literature. Alternatively, compounds of formula (I) can be prepared by treatment of ketoesters of formula (XI) with methoxymethylenation reagents such as methoxymethylenetriphenylphosphorane (see, for example, W Steglich, G Schramm, T Anke and F Oberwinkler, EP 0044 448, 4.7.1980). Ketoesters of formula (XI) may be prepared from ketoesters of formula (X), by treatment with the anion of oximes of general formula (III) as described above. Ketoesters of formula (X) are described in EP 0331 061.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A compound of the formula (VI), (IX) or (XI) : or a stereoisomer thereof, wherein A is hydrogen, halo, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, phenoxy, nitro or cyano; R 1 and R 2 , which may be the same or different, are hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted cycloalkylalkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted heteroaryloxy, nitro, halo, cyano, -NR 3 R 4 , -CO 2 R 3 , -CONR 3 R 4 , -COR 3 , -S(O) n R 3 wherein n is 0, 1 or 2, (CH 2 ) m PO(OR 3 ) 2 wherein m is 0 or 1, or R 1 and R 2 join to form a carbocyclic or heterocyclic ring system; R 3 and R 4 , which may be the same or different are hydrogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl or optionally substituted heteroaryl; and R 5 is hydrogen or a metal atom; provided that when A is hydrogen, neither R 1 nor R 2 is optionally substituted heteroarylalkyl or R 1 and R 2 do not join to form a heterocyclic ring system. A compound according to claim 1 wherein A is hydrogen, halo, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, C 1-2 alkylcarbonyl, C 1-2 alkoxycarbonyl, phenoxy, nitro or cyano; R 1 is C 1-4 alkyl, halo(C 1-4 )alkyl, C 1-4 alkoxy, halo(C 1-4 )alkoxy, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, cyano, phenyl(C 1-4 )alkyl, phenyl, a 5- or 6-membered aromatic heterocycle containing one or more O, N or S atoms and optionally fused to a benzene ring, the aromatic or heteroaromatic moieties of any of the foregoing being optionally substituted with one or more of halo, hydroxy, C 1-4 alkyl, halo(C 1-4 )alkyl, C 1-4 alkoxy, halo(C 1-4 )alkoxy, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, nitro, cyano, phenyl, phenoxy, benzyl or benzyloxy; and R 2 is hydrogen, halo, C 1-4 alkyl, halo(C 1-4 )alkyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, cyano or phenyl; or R 1 and R 2 join together to form a C 5-10 carbocyclic ring system; provided that when A is hydrogen, R 1 is not a 5-or 6-membered heterocycle containing one or more O, N or S atoms fused to a benzene ring, and independently R 2 is not halo(C 1-4 )alkyl, A compound according to claim 1 wherein A is hydrogen or halo; R 1 is C 1-4 alkyl, benzyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, cyano, phenyl, thienyl, triazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl or quinoxalinyl, the aromatic or heteroaromatic moieties of any of the foregoing being optional substituted with one or more of halo, C 1-4 alkyl, trifluoromethyl, C 1-4 alkoxy, trifluoromethoxy, nitro, cyano, phenyl or benzyloxy; and R 2 is hydrogen, C 1-4 , alkyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, cyano or phenyl; or R 1 and R 2 join together to form a cyclopentyl or cyclohexyl ring to which is optionally fused a benzene ring; provided that when A is hydrogen, R 1 is not triazolyl, thiazolyl or quinolinyl. A compound according to any one of the preceding claims wherein R 5 is a hydrogen, sodium or potassium atom. A process for preparing a compound of the formula (VI) according to claim 1 which comprises treating an oxime of general formula (III): wherein R 1 and R 2 have the meanings given in claim 1, with a base and adding a phenyl acetate of formula (VII): wherein A has the meaning given in claim 1 and X is a leaving group. A process for preparing a compound of the formula (IX) according to claim 1 wherein R 5 is a metal atom, which comprises treating a phenylacetate of formula (VI) as defined in claim 1 with a base and methyl formate. A process for preparing a compound of the formula (IX) according to claim 1 wherein R 5 is hydrogen, which comprises treating a phenylacetate of formula (VI) as defined in claim 1 with a base and methyl formate and adding a protic acid. A process for preparing a compound of the formula (XI) according to claim 1 which comprises treating a ketoester of formula (X): wherein A has the meaning given in claim 1 and X is a leaving group, with an anion of an oxime of general formula (III): wherein R 1 and R 2 have the meanings given in claim 1. Claims for the following Contracting State : GR A compound of the formula (VI), (IX) or (XI) : or a stereoisomer thereof, wherein A is hydrogen, halo, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, phenoxy, nitro or cyano; R 1 and R 2 , which may be the same or different, are hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted cycloalkylalkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted heteroaryloxy, nitro, halo, cyano, -NR 3 R 4 , -CO 2 R 3 , -CONR 3 R 4 , -COR 3 , -S(O) n R 3 wherein n is 0, 1 or 2, (CH 2 ) m PO(OR 3 ) 2 wherein m is 0 or 1, or R 1 and R 2 join to form a carbocyclic or heterocyclic ring system; R 3 and R 4 , which may be the same or different are hydrogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl or optionally substituted heteroaryl; and R 5 is hydrogen or a metal atom. A compound according to claim 1 wherein A is hydrogen, halo, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, C 1-2 alkylcarbonyl, C 1-2 alkoxycarbonyl, phenoxy, nitro or cyano; R 1 is C 1-4 alkyl, halo(C 1-4 )alkyl, C 1-4 alkoxy, halo(C 1-4 )alkoxy, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, cyano, phenyl(C 1-4 )alkyl, phenyl, a 5- or 6-membered aromatic heterocycle containing one or more O, N or S atoms and optionally fused to a benzene ring, the aromatic or heteroaromatic moieties of any of the foregoing being optionally substituted with one or more of halo, hydroxy, C 1-4 alkyl, halo(C 1-4 )alkyl, C 1-4 alkoxy, halo(C 1-4 )alkoxy, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, nitro, cyano, phenyl, phenoxy, benzyl or benzyloxy; and R 2 is hydrogen, halo, C 1-4 alkyl, halo(C 1-4 )alkyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, cyano or phenyl; or R 1 and R 2 join together to form a C 5-10 carbocyclic ring system. A compound according to claim 1 wherein A is hydrogen or halo; R 1 is C 1-4 alkyl, benzyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, cyano, phenyl, thienyl, triazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl or quinoxalinyl, the aromatic or heteroaromatic moieties of any of the foregoing being optional substituted with one or more of halo, C 1-4 alkyl, trifluoromethyl, C 1-4 alkoxy, trifluoromethoxy, nitro, cyano, phenyl or benzyloxy; and R 2 is hydrogen, C 1-4 alkyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, cyano or phenyl; or R 1 and R 2 join together to form a cyclopentyl or cyclohexyl ring to which is optionally fused a benzene ring. A compound according to any one of the preceding claims wherein R 5 is a hydrogen, sodium or potassium atom. A process for preparing a compound of the formula (VI) according to claim 1 which comprises treating an oxime of general formula (III): wherein R 1 and R 2 have the meanings given in claim 1, with a base and adding a phenyl acetate of formula (VII): wherein A has the meaning given in claim 1 and X is a leaving group. A process for preparing a compound of the formula (IX) according to claim 1 wherein R 5 is a metal atom, which comprises treating a phenylacetate of formula (VI) as defined in claim 1 with a base and methyl formate. A process for preparing a compound of the formula (IX) according to claim 1 wherein R 5 is hydrogen, which comprises treating a phenylacetate of formula (VI) as defined in claim 1 with a base and methyl formate and adding a protic acid. A process for preparing a compound of the formula (XI) according to claim 1 which comprises treating a ketoester of formula (X): wherein A has the meaning given in claim 1 and X is a leaving group, with an anion of an oxime of general formula (III): wherein R 1 and R 2 have the meanings given in claim 1. Claims for the following Contracting State : ES A process for preparing a compound of the formula (VI), (IX) or (XI) : or a stereoisomer thereof, wherein A is hydrogen, halo, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, phenoxy, nitro or cyano; R 1 and R 2 , which may be the same or different, are hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted cycloalkylalkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted heteroaryloxy, nitro, halo, cyano, -NR 3 R 4 , -CO 2 R 3 , -CONR 3 R 4 , -COR 3 , -S(O) n R 3 wherein n is 0, 1 or 2, (CH 2 ) m PO(OR 3 ) 2 wherein m is 0 or 1, or R 1 and R 2 join to form a carbocyclic or heterocyclic ring system; R 3 and R 4 , which may be the same or different are hydrogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl or optionally substituted heteroaryl; and R 5 is hydrogen or a metal atom; provided that when A is hydrogen, neither R 1 nor R 2 is optionally substituted heteroarylalkyl or R 1 and R 2 do not join to form a heterocyclic ring system; which (a) in respect of the compound of formula (VI), comprises treating an oxime of general formula (III): wherein R 1 and R 2 have the meanings given above, with a base and adding a phenyl acetate of formula (VII): wherein A has the meaning given above and X is a leaving group; or (b) in respect of the compound of formula (IX) wherein R 5 is a metal atom; comprises treating a phenylacetate of formula (VI) as defined above with a base and methylformate; or (c) in respect of the compound of formula (IX) wherein R 5 is hydrogen, comprises treating a phenylacetate of formula (VI) as defined above with a base and methylformate and adding a protic acid; or (d) in respect of the compound of formula (XI), comprises treating a ketoester of formula (X): wherein A has the meaning given above and X is a leaving group, with an anion of an oxime of general formula (III): wherein R 1 and R 2 have the meanings given above. A process according to claim 1 wherein in the compounds of formulae (VI), (IX) and (XI) A is hydrogen, halo, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, C 1-2 alkylcarbonyl, C 1-2 alkoxycarbonyl, phenoxy, nitro or cyano; R 1 is C 1-4 alkyl, halo(C 1-4 )alkyl, C 1-4 alkoxy, halo(C 1-4 )alkoxy, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, cyano, phenyl(C 1-4 )alkyl, phenyl, a 5- or 6-membered aromatic heterocycle containing one or more O, N or S atoms and optionally fused to a benzene ring, the aromatic or heteroaromatic moieties of any of the foregoing being optionally substituted with one or more of halo, hydroxy, C 1-4 alkyl, halo(C 1-4 )alkyl, C 1-4 alkoxy, halo(C 1-4 )alkoxy, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, nitro, cyano, phenyl, phenoxy, benzyl or benzyloxy; and R 2 is hydrogen, halo, C 1-4 alkyl, halo(C 1-4 )alkyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, cyano or phenyl; or R 1 and R 2 join together to form a C 5-10 carbocyclic ring system; provided that when A is hydrogen, R 1 is not a 5-or 6-membered heterocycle containing one or more O, N or S atoms fused to a benzene ring, and independently R 2 is not halo(C 1-4 )alkyl. A process according to claim 1 wherein in the compounds of formulae (VI), (IX) and (XI) A is hydrogen or halo; R 1 is C 1-4 alkyl, benzyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, cyano, phenyl, thienyl, triazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl or quinoxalinyl, the aromatic or heteroaromatic moieties of any of the foregoing being optional substituted with one or more of halo, C 1-4 alkyl, trifluoromethyl, C 1-4 alkoxy, trifluoromethoxy, nitro, cyano, phenyl or benzyloxy; and R 2 is hydrogen, C 1-4 alkyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, cyano or phenyl; or R 1 and R 2 join together to form a cyclopentyl or cyclohexyl ring to which is optionally fused a benzene ring; provided that when A is hydrogen, R 1 is not triazolyl, thiazolyl or quinolinyl. A process according to any one of the preceding claims wherein in the compound of formula (IX) R 5 is a hydrogen, sodium or potassium atom.

Inventors: DE FRAINE PAUL JOHN, MARTIN ANN, DE FRAINE, PAUL JOHN, MARTIN, ANN
Applicants: ZENECA LTD, ZENECA LIMITED
Application year: 1989
Main classification: C07C251
IPC codes: C07D307, A01N43, C07D333, C07C251, C07D277, C07D239, C07C255, A01N37, C07D213, A01N47, C07D241, C07D215, C07D207, A01N41