NZ243020A

NZ243020A - 2-[2-(substituted methyl)thiophenyl]-3-methoxypropenoic acid methyl ester

Info

Publication number: NZ243020A
Application number: NZ24302092A
Authority: NZ
Inventors: Ian Christopher Richards; Donald James Simpson; Anthony Edward Whalley
Original assignee: Schering Agrochemicals Ltd
Priority date: 1991-06-05
Filing date: 1992-06-04
Publication date: 1994-02-25

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £43020 U30SL0 NEW ZEALAND PATENTS ACT, 1953 Priority Date(s): . .Tuo. mI.... Complete Specification Filed: Class: CQ^V.ZSfiJzh,. ££>!£}+&[<?£:,. .CQZDjTfjJ.&p}. .CPz£>tt?Jt,q6It ' 2 5 FEB 1994 Publication Date: . P.O. Journal, No: ...13:7.7 I • I I D I J Ctes.Com: .^te(rt.W/ig;^D.5...... PiQi I?tor ks,ns:r&x No.: Date: COMPLETE SPECIFICATION PROPENOIC ACID DERIVATIVES /I We, SCHERING AGROCHEMICALS LIMITED, a British Company of Hauxton, Cambridge CB2 5HU, England hereby declare the invention for which if / we pray that a patent may be granted to me/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 - (followed by page la) 24 3 Case 9112038 Title: Propenoic Acid Derivatives 5 Field of the invention This invention relates to propenoic acid derivatives, having fungicidal activity. Prior Art 10 Alkyl 2-aryl-2-propenoate derivatives have been disclosed as having pesticidal activity. In our EP 2 99694, we have disclosed compounds of this type and in particular 2-pheny1-2-propenoic acid derivatives in which the phenyl group is substituted in the 2-position by substituted thio 15 groups. Analogous compounds have also been disclosed in EP 251082. Although many of these compounds have outstanding fungicidal activity, some compounds of this type appear to be unstable when exposed to light and the activity is thus not always maintained over a long period. Description of the Invention We have now found that introduction of certain substituents in the 3-position of the aryl ring results in compounds having good fungicidal activity coupled with 25 greater stability. Thus according to one aspect of the invention there is provided a compound of formula I 20 30 (I) MeO-X=C-COOMe 35 wherein X is CH or N; n is 0, 1, 2 or 3; R1 and R3, which may be the same or different, are alkyl, alkoxy or alkylthio, each of which is optionally 5 substituted, halogen, nitro, cyano, COOR4, -NR5R6, CONR5R6, COR7 or R8S(0)q; or R1 and an adjacent R3 group, or two adjacent R3 groups, together with the carbon atoms to which they are attached can form a 5 to 8 membered ring which can include 1 to 3 10 heteroatoms and may be substituted; R2 is an optionally substituted aliphatic hydrocarbon radical, which may be unsaturated, aryl or heterocyclyl; R4 is hydrogen or an ester forming group; 15 R5 and R6 are the same or different and are hydrogen, optionally substituted alkyl, acyl or aryl, or together with the nitrogen to which they are attached, form a 5 to 7 membered ring which can contain other hetero atoms; 20 R7 is hydrogen, optionally substituted alkyl or aryl; R8 is optionally substituted alkyl or aryl; and q is 1 or 2. Aliphatic hydrocarbon radicals are generally of up 10 25 carbon atoms and can be cyclic or acyclic. Alkyl groups may branched or straight chained. If R2 is alkyl it is generally of 4 to 9 carbon atoms. Substituents, when present on any aliphatic hydrocarbon radical group, include halogen, alkoxy (e.g. of 1 to 4 carbon atoms), 30 haloalkoxy (e.g. difluoromethoxy), hydroxy, alkylthio, nitro, optionally substituted amino, carboxy, alkoxycarbonyl, cyano, acyloxy and aryl. Cyclic aliphatic groups are generally of 3 to 8 carbon atoms. Aryl groups are usually phenyl, optionally substituted, e.g. by 35 halogen, optionally substituted alkyl or alkoxy, aryl, 24 3 0 2 3 aryloxy, nitro, amino, COOH, alkoxycarbonyl, CN, CONR5R6 or S(0)pR8 (p = 0, 1 or 2). In some cases two substituents, together with the phenyl to which they are attached, can form a fused ring which itself can be optionally 5 substituted as for phenyl. The terms heterocyclyl includes aromatic and non-aromatic rings which usually contain 5 to 7 ring atoms and including up to three hetero atoms usually selected from nitrogen, oxygen and sulfur. Examples of such groups include thienyl, furyl, pyridyl, 10 pyrimidinyl, pyrazolyl, thiazolyl, thiazolinyl, thiazolone, oxazolyl, benzimidazolyl, tetrazolyl, benzoxazolyl, thiadiazolyl, dioxolanyl, imidazopyridinyl, 1,3-benzoxazinyl, 1,3-benzothiazinyl, oxazolopyridinyl, triazolyl, triazinyl, imidazolyl, morpholino, 15 benzofuranyl, pyrazolinyl, quinolinyl, quinazolinyl, dihydroquinazolinyl or benzothiazolyl. The heterocyclyl group may be substituted, e.g. as described for phenyl. The term "acyl" includes the residue of sulfonic and phosphorus containing acids as well as carboxylic acids. 20 Amino groups may be substituted, e.g. by one or two alkyl groups or two substituents can form a ring, e.g. to form a morpholino or piperidino ring. In the compounds of the invention, alkyl groups, which may be branched or straight chains, are preferably of 1 to 8 carbon atoms. R1 is 25 generally of 1 to 4 carbon atoms, especially methyl or ethyl. Alkenyl and alkynyl groups are generally of three to ten carbon atoms. It is generally preferred that n is 0 or 1, especially 0. 30 R1 is preferably methyl, ethyl, methoxy, ethoxy or halogen, e.g. chlorine or bromine. It is particularly preferred that R1 is methyl, methoxy or chlorine. 35 R2 is preferably heteroaryl or phenyl, optionally 2430 2 4 substituted by one or more of the same or different halogen, alkyl, haloalkyl, Cj^-cycloalkyl, alkoxy, haloalkoxy, cyanoalkoxy, alkylthio, alkanoyl, alkoxycarbonyl, alkoxyalkoxy, optionally substituted phenyl, optionally substituted phenylalkoxy, optionally substituted phenylalkyl, optionally substituted phenoxyalkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, alkylsulfonyl, haloalkylsulfonyl, alkoxycarbonylalkyl, alkoxyiminoalkyl, cyano, nitro, dialkylaminoalkyl or heterocyclyl, in which substituents on any optionally substituted phenyl group are halogen, alkyl, haloalkyl, alkoxy, nitro or cyano, any aliphatic group is of 1 to 8 carbon atoms and any heteroaryl group comprises 5 or 6 ring atoms including up to 3 hetero atoms selected from nitrogen, sulfur and oxygen, and any heterocyclyl substituent is itself optionally substituted by alkyl, halo or optionally substituted phenyl. Compounds of the invention exist as structural isomers and the invention includes individual isomers as well as mixtures of these. Preferred compounds are those where the methoxypropenoate or (methoxyimino)acetate attached directly to the benzene ring shown in formula I is in the E-conf iguration. The compounds of formula I have pesticidal activity and especially fungicidal activity. This activity manifests itself especially against fungal diseases of plants, e.g. mildews and particularly barley powdery mildew (Ervsiphe graminis) and vine downy mildew (Plasmopara viticola), rice blast (Pvricularia orvzae), cereal eyespot (Pseudocercosporella herpotrichoides), grey mould (Botrvtis cinerea), wheat brown rust fPuccinia recondita^, late tomato or potato blight (Phvtophthora infestans), apple scab (Venturia inaequalis^, rice sheath blight 24 3 0 2 5 (Pellicularia sasakii), glume blotch (Leptosphaeria nodorum) . Other fungi against which the compounds may be active include other powdery mildews, other rusts, and general pathogens of Deuteromycete, Ascomycete, 5 Phycomycete and Basidiomycete origin. Some compounds of the invention also have insecticidal, acaricidal and nematicidal activity and are particularly useful in combating a variety of economically important 10 insects, acarids and plant nematodes, including animal ectoparasites. They may also have herbicidal activity. The invention thus also provides a method of combating pests (i.e. fungi, insects, nematodes, acarids and weeds, 15 but especially fungi) at a locus infested or liable to be infested therewith, which comprises applying to the locus a compound of formula I. The invention also provides an agricultural composition 20 comprising a compound of formula I in admixture with an agriculturally acceptable diluent or carrier. The composition of the invention may of course include more than one compound of the invention. 25 In addition the composition can comprise one or more additional active ingredients, for example compounds known to possess plant-growth regulant, herbicidal, fungicidal, insecticidal or acaricidal properties. Alternatively the 30 compounds of the invention can be used in sequence with the other active ingredient. The diluent or carrier in the composition of the invention can be a solid or a liquid optionally in association with 35 a surface-active agent, for example a dispersing agent, 24302 emulsifying agent or wetting agent. Suitable surface-active agents include anionic compounds such as a carboxylate, for example a metal carboxylate of a long chain fatty acid; an N-acylsarcosinate; mono- or di-esters 5 of phosphoric acid with fatty alcohol ethoxylates or salts of such esters; fatty alcohol sulfates such as sodium dodecyl sulfate, sodium octadecyl sulfate or sodium cetyl sulfate; ethoxylated fatty alcohol sulfates; ethoxylated alkylphenol sulfates; lignin sulfonates; petroleum 10 sulfonates; alkyl-aryl sulfonates such as alkyl-benzene sulfonates or lower alkylnaphthalene sulfonates, e.g. butyl-naphthalene sulfonate; salts of sulfonated naphthalene-formaldehyde condensates; salts of sulfonated phenol-formaldehyde condensates; or more complex 15 sulfonates such as the amide sulfonates, e.g. the sulfonated condensation product of oleic acid and N-methyl taurine or the dialkyl sulfosuccinates, e.g. the sodium sulfonate of dioctyl succinate. Nonionic agents include condensation products of fatty acid esters, fatty 20 alcohols, fatty acid amides or fatty-alkyl- or alkenyl-substituted phenols with ethylene oxide, fatty esters of polyhydric alcohol ethers, e.g. sorbitan fatty acid esters, condensation products of such esters with ethylene oxide, e.g. polyoxyethylene sorbitan fatty acid 25 esters, block copolymers of ethylene oxide and propylene oxide, acetylenic glycols such as 2,4,7, 9-tetramethyl-5-decyne-4,7-diol, or ethoxylated acetylenic glycols. Examples of a cationic surface-active agent include, for 30 instance, an aliphatic mono-, di-, or polyamine as an acetate, naphthenate or oleate; an oxygen-containing amine such as an amine oxide or polyoxyethylene alkylamine; an amide-linked amine prepared by the condensation of a carboxylic acid with a di- or polyamine; or a quaternary 35 ammonium salt. 24 3 0 7 The compositions of the invention can take any form known in the art for the formulation of agrochemicals, for example, a solution, a dispersion, an aqueous emulsion, a dusting powder, a seed dressing, a fumigant, a smoke, a 5 bait, a dispersible powder or granule, an emulsifiable concentrate or granules. Moreover it can be in a suitable form for direct application or as a concentrate or primary composition which requires dilution with a suitable quantity of water or other diluent before application. 10 An emulsifiable concentrate comprises a compound of the invention dissolved in a water-immiscible solvent which is formed into an emulsion with water in the presence of an emulsifying agent. 15 A dusting powder comprises a compound of the invention intimately mixed and ground with a solid pulverulent diluent, for example, kaolin. 20 A granular solid comprises a compound of the invention associated with similar diluents to those which may be employed in dusting powders, but the mixture is granulated by known methods. Alternatively it comprises the active ingredient absorbed or adsorbed on a pre-granular diluent, 25 for example, Fuller's earth, attapulgite or limestone grit. Wettable powders, granules or grains usually comprise the active ingredient in admixture with a suitable surfactant 30 and an inert powder diluent such as china clay. Another suitable concentrate is a flowable suspension concentrate which is formed by grinding the compound with water or other liquid, a wetting agent and a suspending 35 agent. 2430 8 The concentration of the active ingredient in the composition of the present invention, as applied to plants is preferably within the range of 0.0001 to 3.0 per cent by weight, especially 0.001 to 0.1 per cent by weight. In 5 a primary composition the amount of active ingredient can vary widely and can be, for example, from 5 to 95 per cent by weight of the composition. In the method of the invention the compound is generally 10 applied to seeds, plants or their habitat. Thus the compound can be applied directly to the soil before, at or after drilling so that the presence of active compound in the soil can control the growth of fungi which may attack seeds. When the soil is treated directly the active 15 compound can be applied in any manner which allows it to be intimately mixed with the soil such as by spraying, by broadcasting a solid form of granules, or by applying the active ingredient at the same time as drilling by inserting it in the same drill as the seeds. A suitable 20 application rate is within the range of from 0.05 to 20 kg per hectare, more preferably from 0.1 to 10 kg per hectare. Alternatively the active compound can be applied directly 25 to the plant by, for example, spraying or dusting either at the time when the fungus has begun to appear on the plant or before the appearance of fungus as a protective measure. In both such cases the preferred mode of application is by foliar spraying. It is generally 30 important to obtain good control of fungi in the early stages of plant growth as this is the time when the plant can be most severely damaged. The spray or dust can conveniently contain an insecticide if this is thought necessary. Sometimes, it is practicable to treat the 35 roots of a plant before or during planting, for example, 24 3 0 9 by dipping the roots in a suitable liquid or solid composition. When the active compound is applied directly to the plant a suitable rate of application is from 0.001 to 5 kg per hectare, preferably from 0.01 to 5 0.5 kg per hectare. The compounds of the invention may be obtained by various methods. For example when X is CH, a compound of formula II 10 where R9 is methyl, can be reacted with a phosphorus ylide derived from a phosphonium salt of formula Ph3P+CH2OMe Hal" under basic conditions. 20 When X is N, the compound of formula II can be reacted with methoxyamine hydrochloride. Alternatively when X is CH, a compound of formula III 25 (III) basic conditions, can be reacted with methyl formate under followed by methylation of the resulting hydroxypropenoate. 2 4 3 10 15 20 The compounds of formula II, where R9 is hydrogen, can be obtained by reacting a benzo[b]thiophene-2,3-dione of formula IV 0 (R3)n (IV) with a compound of formula V R2-CH2-Z (V) 10 where Z is a leaving group, e.g. halogen, generally under basic conditions. This can then be esterified to a compound of formula II, where R9 is methyl, e.g. by reacting with methyl chloroformate in the presence of a tertiary amine. The compounds of formula III can be obtained by reacting a benzo[b]thiophen-2(3H)-one of formula VI (VI) with a compound of formula V R2-CH2-Z (V) where Z is a leaving group, eg halogen, generally under 25 basic conditions, followed by esterification in conventional manner. The compounds of formula III can also be obtained by reducing the compounds of formula II, preferably where 3 0 where R9 is hydrogen, in a Wolff-Kischner reduction, e.g. by using hydrazine in the presence of a base e.g. an alkali metal alkoxide. When R9 is hydrogen, the Wolff-Kischner reduction is followed by esterification to the methyl ester. 35 24 n The compounds of formulae IV, V and VI are known or can be obtained in known manner. The compounds of formula II and III are novel and the 5 invention also includes these compounds of this type. Many of these compounds also have pesticidal activity. The compounds of the invention may also be obtained by the method described in our PCT application WO 91/07385. 10 The invention is illustrated in the following Examples. Structures of isolated novel compounds were confirmed by elemental and/or other appropriate analyses. Temperatures are in °C. 15 Example 1 A mixture of 7-methylbenzo[b]thiophene-2,3-dione (4.1 g) and aqueous sodium hydroxide (1.84 g in 80 ml water) was heated under reflux for one hour. To the resulting 20 solution at 50°, was added 4-chloro-3-methoxybenzyl bromide (5.42 g) and the mixture refluxed for a further 2 hours and allowed to cool. It was acidified to pH 1, extracted with ether and the extract dried and evaporated. The residue was recrystallised from diisopropyl ether to 25 give 2-[2-(4-chloro-3-methoxybenzylthio)-3-methylphenyl]-2-oxoacetic acid, m.p. 117-8°. (Intermediate A) To a solution of Intermediate A (5.8 g) in dichloromethane (100 ml) was added triethylamine (1.84 g), followed by 30 dropwise addition of methyl chloroformate (1.64 g). The mixture was heated under reflux for 0.5 hours, cooled, washed with aqueous sodium hydrogen carbonate, dried and evaporated. The residue was recrystallised from diisopropyl ether to give methyl 2-[2-(4-chloro-3-methoxy-35 benzylthio)-3-methylphenyl]-2-oxoacetate, m.p. 118-9° 24 3 0 20 12 (Intermediate B). A solution of Intermediate B (4.2 g) in ether (60 ml) was added dropwise to a mixture of potassium tert butoxide 5 (2.6 g) and a suspension of (methoxymethyl)triphenyl- phosphonium chloride (7.9 g) in ether (100 ml), which had been stirred for 45 minutes. The reaction mixture was stirred for 4 hours, washed with water, dried and evaporated. The residue was dissolved in dichloromethane, 10 filtered through silica gel and evaporated. The residue was recrystallised from diisopropyl ether to give methyl (E)-3-methoxy-2-[2-(4-chloro-3-methoxybenzylthio)-3-methylphenyl]prop-2-enoate, m.p. 100-2°. (Compound 1) 15 In a similar manner the following compounds of formula I, and their type A and B intermediates were obtained. Where no parameters are given for an intermediate then it was not isolated in a pure form but used in its crude form in 20 the next reaction stage. Generally the compounds are obtained as E-isomers; compounds obtained as Z-isomers are indicated by an asterisk (*), and are obtained from the reaction mixture by chromatography on silica gel using ethyl acetate/petoleum ether as eluent. m.p.(°) or physical state Cpd. R1 R2 (R3)n Compound of Intermediates No. formula I A B 30 2 Me 3-Me-Ph - 141-3 131-3 oil 3 Me 4-CF3-Ph - 103-5 105-7 70-2 4 Me 3-MeO-Ph - 89-90 73-5 55-7 5 Me 3-F-Ph - 110-2 122-4 55-7 6 Me 2-Br-Ph - 130-1 141-3 68-70 35 7 Me 2-Cl-Ph - 100-2 105-7 68-70 2 4 3 0 2 0 13 m.p.(°) or physical state Cpd. R1 R2 (R3)n Compound of Intermediates No. formula I A B 5 8 Me 4-Et-Ph — 68-70 84-5 oil 9 Me 3,5-Me2-Ph - 120-2 142-4 68-70 10 Me 2,5-Me2-Ph - 132-3 110-2 82-3 11 Me Ph - 120-2 103-5 44-5 12 Me 2-(PhCH2CH2) -Ph - 75-7 107-9 oil 10 13 Me 2,5-(CF3)2-Ph - oil* 75-6 80-1 14 Me 3,5-Cl2-Ph - 130-1 131-3 101-3 15 Me 3-(4-Cl-Ph)-1,2,4-triazol-l -yi — 107-9 197-9 95-6 16 Et 4-Me-Ph - 92-3 79-80 oil 15 17 Me 4-F-3-Me-Ph - 142-3 112-4 73-4 18 Me 3-MeO-Ph - 83-5* 73-5 55-7 19 Me Ph - 103-5* 103-5 44-5 20 Me 3-(PhCH20) -Ph - 102-4 98-100 88-90 21 Me 3-EtO-Ph - 80-1 110-2 oil 20 22 Me 3-(C5HnO)-Ph - 78-80 oil 23 Me 3-(C6H13OCO) -Ph - oil* oil 24 Me 3~(C6H13OC°)"Ph - 74-6 oil 25 Me 2 , 5- (CF3) 2~Ph - 77-8 75-6 80-1 26 CI 3-Me-Ph - 101-2 133-4 80-1 25 27 Me 4-(CF30) -Ph - 79-80 116-7 oil 28 Me 4-(CF30) -Ph - 87-8* 116-7 oil 29 Me 4-Cl-Ph - 95-7* 135-7 68-70 30 Me 3-(3-Me-Ph)-1,2 triazol-l-yl ,4- — gum oil 30 31 Me 4-MeCONH-Ph - 70-2 130-2 32 Et 3-F-Ph - 96-8 97-9 73-5 33 Me 4-Cl-Ph - 115-7 135-7 68-70 34 Et 3-MeO-Ph - oil 74-4.5 51.5-2 35 Et 3-F-Ph — oil* 73-75 2430 20 14 m.p.(°) or physical state Cpd. R1 R2 (R3)n Compound of Intermediates No. formula I A B 5 36 Me 3-Bu-Ph - oil* oil 37 Et 4-Cl-Ph - 86-7 89.5-90. 5 gum 38 Me 2-CF3-Ph - 84-6 123-4 73-4 39 Me 3-Bu-Ph - oil oil 40 Me 2-CF3-Ph - 76-7* 123-4 73-4 10 41 Et 3,5-Me2-Ph - 116.5-8 .5 80-1 52-3.5 42 Me 3,5-(MeO)2-Ph - 115-6 156-8 80-1 43 Me 3/5-(MeO)2-Ph - oil* 156-8 80-1 44 Me 3-CF3-Ph - oil* 45 Et 3-(C5HnOCO) -Ph - oil oil oil 15 46 Et 3-(C5HnOCO) -Ph - oil* oil oil 47 Me 2-Me-Ph - 105-6 123-4 45-6 48 Me 2-Me-Ph - 99-100* 123-4 45-6 49 Me 2,5-Cl2-Ph - 111-2 148-9 110-1 50 Me 2,5-Cl2—Ph - 105-6* 148-9 110-1 20 51 Me 3-CF30-Ph - 52.5-4 100.5- ■2 oil 52 Me 3,5-F2-Ph - 86-7* 117-8 63-4 53 Me 3-CF30-Ph - gum* 100.5- 2 oil 54 Me 2-CF30-Ph - 72.5-3. 5 124-5 61.5-3 55 Me 3-CF3-Ph - 90-1 103-4 72-3 25 56 Me 3-CHF20—5-Me-Ph - gum 127-8. 5 oil 57 Me 3-CHF20—5-Me-Ph - 93-4* 127-8. 5 oil 58 Me 3-Cl-5-Me-Ph - 132-3.5 150-1 98-9.5 59 Me 3-MeO-5-Me-Ph - 88-9 112-3 50-1.5 60 Me 3,5-F2-Ph - 118-9 117-8 63-4 30 61 Et 3,5-Cl2-Ph - 126-7 100-1 55-7 62 Me 3-MeOCO-Ph - oil 115-6 63 Me 3-Cl-Ph - 126-7 127-9 99-100.5 64 Me 3-MeO-5—Me-Ph - 74-5.5* 112-3 50-1.5 65 Et 3 ,5-Cl2-Ph - 118-9* 100-1 56-7 24 3 0 2^ 15 m.p. (°) or physical state Cpd. R1 R2 (R3)n Compound of Intermediates No. formula I A B 5 66 Et Ph 61—2* 108-10 43-4 67 Me 2-MeO-Ph 108-9 121-2 83-4 68 Me 2-MeO-Ph 112-3* 121-2 83-4 69 Et Ph 86-7 108-10 43-4 70 Et 4-Et-Ph 60* oil 52-4 10 71 Me 3-(C5HnOCO)-5-Me-Ph - oil oil oil 72 Me 4-(4, 6-Me2-pyrimidin-2-yl)-Ph 158-8.5 182.5-3. 5 103.5-6 73 Me 3-(4,6-Me2- 128- 209.5- 109- pyrimidin-2-yl)-Ph 129 .5 212.5 111.5 15 74 Me 3-(4,6-Me2-pyr- - 110.5- 209.5- 109.5- imidin-2-yl)-Ph 112.5* 212.5 111.5 75 Et 4-Et-Ph 87-9 oil 52-4 76 Me 4-MeO-Ph 76-7 100-0.5 oil 77 Me 4-MeO-Ph 108.5-9. 5* 100-0. 5 oil 20 78 Me 2-Et-Ph 98-9 105-6 54-5 79 Me 2-Et-Ph 58-60* 105-6 54-5 80 Me 2,5-F2-Ph 123-4* 92-5 67-8 81 Me 3,4-Me2-Ph 129-31 118-20 55-6 82 Me 3-Et-Ph 103-5 oil 25 83 Me 3-(CH2=CH-)-Ph 104-7 211 oil 84 Me 3 - ( CH2=CH-) -Ph gum* 211 oil 85 Et 3-(C5HnOCO)-5-Me-Ph - oil* oil oil 86 Me 3- (CHF20) -Ph 111-2* 200(dec) oil 87 Me 3-(pyrimidin-2-yl)-Ph - 115-6* 135-7 88-9 30 88 Me 3-(CHF20)-Ph gum 200(dec) oil 89 Me 3-(pyrimidin-2-yl)-Ph - 110-2 135-7 88-9 90 Me 2,5-F2-Ph 104-6 92-5 67-8 91 Me 3-Et-Ph 69.5-71* oil 92 Me 2,4, 5-Me3-Ph 169-70 148-9.5 66.5—66.8 24 3 0 2 16 m.p.(°) or physical state Cpd. R1 R2 (R3)a Compound of Intermediates No. formula I A B 5 93 Me 2-F-5-CF3-Ph - 94 Me 2-F-5-CF3-Ph - 95 Me 2-F-6—CF3-Ph - 96 Me 2-F-6-CF3-Ph - 97 Me 4-F-3-CF3-Ph - 10 98 Me 4-F-3—CF3-Ph - 99 Me 3-F-5-CF3-Ph - 100 Me 3- (1-Me-penty1 -OCO) -Ph 101 Me 4-(MeOCO)-Ph - 102 Me 4-(MeOCO)-Ph - 15 103 Et 4-(MeOCO)-Ph - 104 Me 4-(pyrimidin-2 -yl)- ■Ph ■ 105 Me 4-(pyrimidin-2 -yi)- ■Ph • 106 Et 3-cyano-Ph - 107 Me 3-Pr'O-Ph - 20 108 Me 3-F-Ph - 109 Et 4-(MeOCO)-Ph - 110 Et 3-MeO-Ph - 111 Me 2,4-Me2-Ph - 112 Me 3-F-5-Me-Ph - 25 113 Me 3-F-5—Me-Ph - 114 Me 4-(CHF20) -Ph - 115 Me 4-(CHF20)-Ph - 116 Me 3-I-Ph - 117 Me 3-I-Ph - 30 118 Me 3-Br-5-Me-Ph - 119 Me 3-Br-5-Me-Ph - 120 Me 3-Pr'o-Ph - 121 Me 2-Cl-5-MeS-Ph - 122 Me 2-Cl-5-MeS-Ph — 78-80 96-8* 80-2 98-100* 82.5-4 88-9* 93-5 93-5 125-6 125-6 140-1.5 100-2 100-2 73-5 73-5 82.5-3.5 140-1.5 82.5-3.5 87.5-8.5* 97.5-8.5 50-0.5 oil oil 92-2.5 110.5-11 80-1 80-82.5* 110.5-11 80-1 k * 81.5-2 . * 89.5-90.5 54-5.50 131-3' 141-3 133-4 103-5 141-3 133-4 98.5-9.5 137.5-8.5 82.5-3.5 65-6 87-88 oil 98-100* 122-4 55-7 80-1 89.5-90.5 54-5.5 100.5-1.5* 74-4.5 51.5-2.5 114-6 121-22.5 124-6 124-6 oil oil 140-3 127-8.5 109-110* 88.5-89 89-91* 88-90 108-9.5 140-3 113-5 105-7* oil* 130-1 85-6* 138-40 138-40 87-88 116-8 116-8 61.5-2 61.5-2 102-4 102-4 96-8 96-8 oil 79-80 79-80 17 m.p.(°) or physical state Cpd. R1 R2 (r3)d Compound of Intermediates No. formula I A B 5 123 Me 3-MeCOO-5-Me- •Ph — oil oil 96-8 124 Me 4- (4-N02—PhCH2Q) -Ph - 82-3.5 127-8.5 oil 125 Me 3-Me-5—EtOCO- •Ph - 89-90 103-4.5 67-8.5 126 Me 3-Me-5-EtOCO- •Ph - oil* 103-4.5 67-8.5 127 Me 3-MeS-Ph - 108-10 128-9 oil 10 128 Me 3-MeS-Ph - 65-6* 128-9 oil 129 Et 2,5-Cl2-Ph - 99-100 118-20 102-3 130 Et 2,5-Cl2-Ph - oil* 118-20 102-3 131 Me 3-F-5-CF3-Ph - 42.5-4.5 97.5-8. 5 50-50.5 132 Et 3-cyano-Ph - 98-9* 137.5-8 .5 82-3.5 15 133 Et 2,5-Me2-Ph - 69.5-70. 5* 96.5-7.5 oil 134 Et 2,5-Me2-Ph . - 130-1 96.5-7. 5 oil 135 Me 3-EtOCO—Ph - 76-8 93.5-4 48.5-50 136 Me 2-MeOCOCH2-Ph - 101-3 70-2 137 Me 4-Me-Ph 5-Me 142-3 123-4 82-3 20 138 Me 4-Me-Ph 5-Me 129-30* 123-4 82-3 139 Me 3-MeO-Ph 5-Me 140-1 108-9 oil 140 Me 3-MeO-Ph 5-Me 82-3* 108-9 oil 141 Me 2-F-Ph 5-Me 92-3 130-1 67-8 142 Me 2-F-Ph 5-Me 101-3* 130-1 67-8 25 143 Me 4-Me-Ph 6-Me oil* 99-100 79-80 144 Me 3-MeO-Ph 6-Me oil* 70-1 65-6 145 Me 4-Me-Ph 5-C1-6—Me oil* 156-7 79-80 146 Me 2-F-Ph 6-Me oil* 121-2 124-5 147 Me 3,5-Me2-Ph 5-Me 115-7 131-3 85-7 30 148 Me 3,5-Me2-Ph 6-Me oil* 125-6 112-3 149 Me 4-F-Ph 5-Me 122-3* 152-4 61-2 150 Me 3-F-Ph 5-Me 99-100 124-5 oil 151 Me 4-F-Ph 5-Me 116-8 152-4 61-2 152 Me Ph 4-Me 110-1 132-3 oil 18 m.p.(°) or physical state Cpd. R1 R2 (R3)n Compound of Intermediates No. formula I A B 5 153 Me 154 Me 155 Me 156 Me 157 Me 10 158 Me 159 Me 160 CI 161 CI 162 CI 15 163 CI 164 CI 165 CI 166 CI 167 CI 20 168 Br 169 Br 170 Br 171 Br 172 CI 25 173 CI 174 CI 175 Br 176 Br 177 Br 30 178 Br 179 CI 180 CI 181 CI 182 CI 4-Me-Ph 3,5-Me2-Ph 3,5-Me2-Ph 2-F-Ph 3-MeO-Ph 3-PhCH20-Ph 4-Me-Ph 3-MeO-Ph 4-Me-Ph 4-Me-Ph 2,5-Me2-Ph 2,5-Me2-Ph Ph Ph 2,5-(CF3)2-Ph 3-MeO-Ph 4-Me-Ph 3,5-Me2-Ph 2,5-Me2-Ph 2,5-(CF3)2-Ph 3-(nC6H13OCO)-Ph 3-(nC6H13OCO) -Ph 3-Cl-Ph 3-F-Ph 3-F-Ph 3-Cl-5-Me-Ph 4-Et-Ph 4-Et-Ph 3-MeOCO-Ph 3-MeOCO-Ph 4-Me 99-100* 4-Me 94-5 4-Me 82-3* 6-Me 113-4+ 4-Me oil 4-Me oil 5-F 124-5* 82-3 86-7 122-3* 120-2 108-9* 100-1 127-8* 109-10* 75-6 96-7 119-20 136-7 84-5 52-4 oil* 121-2 106-8 114-6* 132-3* - gum 84-6* oil* oil 128-30 92-3 150-1 83-4 150-1 83-4 121-2 124-5 95-7 101-2 104-5 94-5 148-9 78-9 89-92 58-60 122-3 75-6 122-3 75-6 117-8 83-4 117-8 83-4 266—82 58-60 266—82 58-60 105-7 70-2 112-4 52-3 141-3 64-5 132-3 82-3 109-10 84-5 105-7 70-2 oil oil oil oil 135-6 123-4 131-3 75-6 131-5 75-6 88-9 oil oil 86-8 86-8 24 3 0 2 19 m.p.(°) or physical state Cpd. R1 R2 (R3)n Compound of Intermediates No. formula I A B 5 183 Br 3-Cl-5-Me-Ph — 110-2 88-9 184 CI 3-F-5-Me-Ph - 92-5 129-31 74-5 185 CI 3-F-5-Me-Ph - 107-8* 129-31 74-5 186 Br 4-Et-Ph - gum 187 Br 4-Et-Ph - gum* 10 188 Br 3-MeO-5-Me-Ph - 95-7* 63-5 189 CI 3-Cl-5-Me-Ph - 95-7 94-5 190 CI 3-Cl-5-Me-Ph - 120-1* 94-5 191 Br 3-MeO-5-Me-Ph - 62-3 63-5 192 CI 3-F-Ph - 110-2 72-3 15 193 CI 3-F-Ph - 115-6* 72-3 194 CI 4-Cl-Ph - gum 83-4.5 195 CI 3,5-Me2-Ph - 121-2.5* 140-1 85.5-6.5 196 CI 3,5-Me2-Ph - 100-2 140-1 85.5-6.5 197 CI 3-DC5HnO-Ph - 57-9 oil 20 198 MeO 4-Me-Ph - 112-3 115-6 82-3 199 MeO 3-MeO-Ph - 88-9 124-6 77-8 200 MeO 3-MeO-Ph - 73-4* 124-6 77-8 201 MeO 3-Cl-Ph - 81-2 153-4 72-3 202 MeO 3-Cl-Ph - 84-5* 153-4 72-3 25 203 MeO 3,5-Me2-Ph - 127-8 140-1 79-80 204 MeO 3,5-Me2-Ph - 83-4* 140-1 79-80 205 EtO Ph - 101-2 76-78 206 MeO 3-F-Ph - 87-8 135-6 69-70 207 MeO 3-F-5-Me-Ph - 100-1 135-6 82-3 30 208 MeO 4-Et-Ph - 76-7 34-5 209 MeO 4-Et-Ph - 60-1* 34-5 210 MeO 3-MeOCO-Ph - 80-1 95-6 211 MeO 3-Cl-5-Me-Ph - 108-9 149-51 99-101 212 MeO 2,5-Me2-Ph - 98-9 142-4 68-70 35 213 MeO 2,5-Me2-Ph - 120-2* 142-4 68-70 24 3 0 20 20 m.p.(°) or physical state Cpd. R1 R2 (R3)n Compound of Intermediates No. formula I A B 5 214 EtO 4-Me-Ph - 110-1 91-2 215 EtO 4-Me-Ph - 114—5* 91-2 216 MeO 3-Me-Ph - 81-2 130-31 65-6 217 MeO 3-Me-Ph - 82-3* 130-1 65-6 218 MeO 4-F-Ph - 113-4.5 113.5-15 97-100 10 219 MeO 3-PhCH20-Ph - gum 90-91 63-4 220 MeO 4-F-Ph - 105-7* 113.5-1E i 97-100 221 MeO 4-CF30-Ph - 68-70 118-19.5 67-9 222 MeO 4-CF30-Ph - 79-81* 118-19.5 67-9 223 MeO Ph - 108-9 132-4 81.5-3 15 224 MeO Ph - 137-8.5* 132-4 81.5-3 225 MeO 3-CF3-Ph - gum 125-7 81-3 226 MeO 3-CF3-Ph - 103-4.5* 125-7 81-3 227 MeO 2-CF3-Ph - 85-7 146-7 96-7 228 MeO 2-CF3-Ph - 93-5.5* 146-7 96-7 20 229 Me 4-Me-Ph 4- -Me 123-4 128-30 92-3 230 MeO 3-Me0-5-Me-Ph - 130-1 85-6 231 Me 3-PhCH20-Ph 4- -Me . 99-100* 104-5 94-5 232 Me 5-Cl-2-F-Ph - 85-7 117-20 78-80 233 Me 5-Cl-2-F-Ph - 85-7* 117-20 78-80 25 234 Me 3-Br-Ph - 97-8* 136-7 104-5 235 Me 2-F-3-CF3-Ph - 50-2 111-2 93-4 236 Me 2-F-3-CF3—Ph - 81-2* 111-2 93-4 237 Me 4-MeO-3-Me-Ph - 72-4* 238 Me 3-Br-Ph - 115-7 136-7 104-5 30 239 Me 3-[3-(4-Cl-Ph)-1,2, oxadiazol-5-yl]-Ph 4- 166-8* 157-9 110-20 240 BuSCH2 3-MeO-Ph - oil oil 241 Me 2-Br-5-F-Ph - 96-7* 242 Me 2-Br-5-F-Ph — 97-8 2 4 3 0 2 21 m.p.(°) or physical state Compound of Interme No. formula I A B Cpd. R1 R2 (r3)d Compound of Intermediates 5 243 Me 2-F-4-CF3-Ph — 93-4 109-11 64-5 244 Me 2-F-4-CF3-Ph - 84—5* 109-11 64-5 245 Me 2-F-3-Me-Ph - 98-101 70-2 246 Me 2-F-3-Me-Ph - 72-5* 70-2 247 Me 3-[3-(4-Cl-Ph)-1 ,2,4 - 123-4 157-9 110-20 10 oxadiazol-5-yl]- Ph 248 MeSCH2 2,5-Me2-Ph - oil oil 249 MeSCH2 2,5-Me2-Ph - oil* oil 250 Me 4-Ph-Ph - 87-8.5 137-8 95-6.5 251 Me 4-Ph-Ph - * in • CO CO 137-8 95-6.5 15 252 Et 4—Cl-3—MeO-Ph - 108.5-9 .5 129-30 101-2.! 253 Me 4-F-2-CF3-Ph - 74-5.5 145-7 108-9 254 Me 4-F-2-CF3-Ph - 70-2* 145-7 108-9 255 Me 2-F-5-MeO-Ph - 86-7* 256 Me 4-Me-Ph 5-F 124-5* 148-9 78-9 20 257 Me 3-(thiazol-2-yl) -Ph - gum* 171-3 65-6 258 CI 2-Me-Ph - 121-3 120-2 73-5 259 CI 2-Me-Ph - 116-7* 120-2 73-5 260 Me 2-(4-Cl-Ph) thiazol-4-yl — 85-7 175-7 73-5 25 261 CI 3—Pr'O-Ph - oil* 98-100 67-8 262 CI 5-Cl-2-Me-Ph - 112-3* 142-4 120-1 263 Me 2-F-5-MeO-Ph - 77-8 264 Cl 2-F-5-MeO-Ph - 58-9* 122-3 71-3 265 Cl 4-F-Ph - 93-4 151-2 100-1 30 266 Cl 3-CF3-Ph - 58-60 118-9 81-2 267 Me 4-Me-Ph 5-F 102-3 148-9 78-9 268 Me 4-Me-Ph 4-F 115-6 134-5 oil 269 Me 4-Me-Ph 4-F 97-8* 134-5 oil 270 Me 3-(thiazol—2—yl) -Ph - gum 171-3 65-6 35 271 MeO 4-Cl-3-MeO-Ph - 88-90* 135-7 109-11 2 4 3 0 2 0 22 Cpd. No. R1 R2 (R')„ m.p.(°) or physical state Compound of Intermediates formula I A B 5 272 Cl 3,5-Cl2-Ph - 89-90 111-3 273 Cl 3,5-Cl2-Ph - 127-8* 111-3 274 Cl 5-Cl-2-Me-Ph - 144-6 142-4 120-1 275 MeO 4-MeO-3-Me-Ph - 84-6 276 Me 4-Cl-3-CF3-Ph - 107.5-9 135-6 55-6 10 277 Me 4-Cl-3-CF3-Ph - 77-8* 135-6 55-6 278 MeO 3/5-Cl2-Ph - 116-8 153-4.5 120-121.1 279 MeO 3,5-Cl2-Ph - 109.5-11* 153-4.5 120-1.5 280 MeO 4-CF3-Ph - 83.5-4.5 114-5.5 85-6 281 MeO 4-CF3-Ph - 106.5-8* 114-5.5 85-6 15 282 Me 3-Ph-Ph - 124-6 89-91 82-3.5 283 Me 3-(Me-C=C—)-Ph - 71.5-85 166-8 71-83.5 284 Me 4-Cl-3-CHF20-Ph - Oil 114.5-6 65.5-6.5 285 Me 5-C1-2-Me-Ph - 137-8 116-7 90-1 286 Me 5-Cl-2-Me-Ph - 121-2* 116-7 90-1 20 287 Me 2-Cl-5-MeO-Ph - 91-2 141-2 83-4 288 Cl 2-F-5-MeO-Ph - oil 122-3 71-3 289 Cl 2-Cl-5-MeO-Ph - 97-8 143-5 78-91 290 Cl 2-Cl-5-MeO-Ph - 80-1* 143-5 79-81 291 MeO 4-Cl-3-MeO-Ph - 116-8 135-7 109-11 25 292 Me 3 -Bul-5 -Me-Ph . - oil oil oil 293 Me 3-6^-5-Me-Ph - oil* oil oil 294 Me 3-(Me-C=C)-Ph - 120.5-4* 166-8 71-83.5 295 Me 3-cyclopropy1-Ph - gum 115.5-8 oil 296 Me 5-Cl-2-MeO-Ph - 100-1 129-30 99-100 30 297 Me 5-C1-2-MeO-Ph - 92-3* 129-30 99-100 298 Me 2-Br-5-Me-Ph - 137-8 121-2 63-4 299 Me 2-Br-5-Me-Ph - 124-5* 121-2 63-4 300 Me 3-(2-thiazolin-2—yl) -Ph - 110-1 72-4 301 Cl 2,5-Cl2-Ph - 142-3 115-20 112-4 35 302 Cl 2,5-Cl2-Ph - 103-4* 115-20 112-4 2430 2 23 m.p.(°) or physical state Cpd. R1 R2 (R3)n Compound of Intermediates No. formula I A B 5 303 Et 4-Cl-3-MeO-Ph - gum 129-30 101-2 304 Me 3-Ph-Ph - oil* 89-91 82-3. 305 MeO 2,5-Cl2-Ph - 119-20* 159-60 104-5 306 MeO 2,5-Cl2-Ph - 94-5.5 159-60 104-5 3 07 Me 3-cyclopropy1-Ph - • CO m • VO in 5* 115.5- ■8 oil 10 308 Cl 3-Me-Ph - * 0 CTi 1 00 CO 133-4 80-1 309 Cl 4-CF3-Ph - 85-6 135-7 62-3 310 Cl 4-CF3-Ph - oil* 135-7 62-3 311 Me 2,5-Br2-Ph - 124-5 90-5 107-9 312 Me 2,5-Br2-Ph - 87-8* 90-5 107-9 15 313 Me 3- [PhO- (CH2) 2-0] -Ph - 95-7 314 Cl 4-Me-Ph 5-Me 128-9 85-6 315 Me 4 - [MeO- (CH2) 2-0 ] -Ph - 96-7 oil 316 Me 3-(CH=C-CH2) -Ph - 83-5 317 Me 2-MeS-5-Cl-Ph - 92-4 143-5 89-90 20 318 Me 2-MeS-5-Cl-Ph - 93.5-4. 5* 143-5 89-90 319 Me 4-MeS-Ph - 93-4 128-30 81-3 320 Me 4-MeS-Ph - 104-6* 128-30 81-3 321 Me 4-F-Ph - 124-5 117-9 78-80 322 Me 4-F-Ph — 118-20* 117-9 78-80 25 2 = Na salt + = contains 14% Z-isomer 30 24 3 0 20 24 Example 2 A mixture of 7-methylbenzo[b]thiophen-2(3H)-one (5.0 g) , sodium hydroxide (2.44 g) and water (50 ml) was heated under reflux for one hour. 4-Methylbenzyl chloride 5 (4.49 g) was added and the^mixture refluxed for a further 1% hours. It was then cooled, acidified with hydrochloric acid and the solid precipitate filtered off, washed with water and dried to give [2-(4-methylbenzylthio)-3-methylphenyl] acetic acid, m.p. 110-2°. 10 To a solution of this compound (7.1 g) in dichloromethane (50 ml) was added triethylamine (2.62 g), followed by methyl chloroformate (2.43 g) . The mixture was heated under reflux for 0.5 hours, cooled, washed with water and 15 aqueous sodium hydrogen carbonate, dried and evaporated to give methyl [2-(4-methylbenzylthio)-3-methylphenyl]-acetate, as an oil. This compound (5.5 g) was added to a stirred suspension of 20 sodium hydride (0.58 g, 80% dispersion in mineral oil) in dimethylformamide (75 ml). After a further 1 hour methyl formate (5.5 g) was added dropwise. The mixture was stirred overnight at room temperature to give methyl [(E)-3-hydroxy-2-[2-(4-methylbenzylthio)-25 3-methylphenyl]prop-2-enoate, which was not isolated. Methyl iodide (2.73 g) was added, the reaction mixture stirred for 3 hours and evaporated. Diethyl ether and water were added, the organic phase separated and washed with water, dried and evaporated to give methyl 30 [(E)-3-methoxy-2-[2-(4-methylbenzylthio)-3-methylphenyl ]prop-2-enoate, m.p. 109-11°, (compound 2a). 2 4 3 0 2 25 Example 3 In a similar manner to Example 1, there was obtained 2-[2-(4-methylbenzylthio)-3-methylphenyl]-2-oxoacetic acid, m.p. 128-9°, which was converted to the methyl 5 ester, m.p. 42-3°. Methoxyamine hydrochloride (1.67 g) was added to a solution of this (6 g) in methanol (100 ml) and the mixture heated under reflux, with stirring, for 24 hours. The mixture was poured into water and extracted with ether. The extract was dried and evaporated and the 10 residue recrystallised from diisopropyl ether up to give methyl 2-methoxyimino-2-[2-(4-methylbenzylthio)-3-methylphenyl] acetate, m.p. 93-5°. (Compound 400) In a similar manner there was obtained: 15 (i) methyl 2-[3-chloro-2-(4-methylbenzyl-thio)phenyl]-2-(methoxyimino)acetate, m.p. 86-7°. (Compound 401) and (ii) methyl 2-[3-bromo-2-(4-methylbenzylthio)phenyl]- 2-(methoxyimino)-acetate, m.p. 97-8°. (Compound 402) 20 Example 4 In a similar manner to Example 1, 7-methylbenzo[b]-thiophene-2,3-dione was reacted with l-bromo-6,6-dimethyl-hept-2-en-4-yne to give 2-[2-(6,6-dimethylhept-2-en-25 4-ynylthio)-3-methylphenyl]-2-oxoacetic acid, as an oil. This was obtained as a 2:1 mixture of the E:Z isomers. This was then methylated to give the methyl ester, as an oil, in a 2:1 mixture of the E:Z isomers. This in turn was converted to methyl 2-[2-(6,6-dimethylhept-2-en-4-ynyl-30 thio)-3-methylphenyl]-3-methoxyprop-2-enoate, as an oil. The oil was subjected to chromatographic separation and the following isomers were obtained: i) E-propenoate-E/Z-enyne (compound 451a) ii) Z-propenoate-E-enyne, (compound 451b) and 35 iii) Z-propenoate-Z-enyne (compound 451c). 24 3 0 2 26 In a similar manner to Example l, 7-chlorobenzo[b]-thiophene-2,3-dione was reacted with l-bromo-6,6-dimethyl-hept-2-en-4-yne to give 2-[3-chloro-2-(6,6-dimethylhept-2-en-4-ynylthio)phenyl]-2-oxoacetic acid, as an oil. This 5 was obtained as a 2:1 mixture of the E:Z isomers. This was then methylated to give the methyl ester, as an oil, in a 2:1 mixture of the E:Z isomers. This in turn was converted to methyl 2-[3-chloro-2-(6,6-dimethyl-hept-2-en-4-ynyl-thio)phenyl]-3-methoxyprop-2-enoate, as an oil. The oil 10 was subjected to chromatographic separation and the following isomers were obtained: i) E-propenoate-E-enyne (compound 452a) ii) E-propenoate-Z-enyne, (compound 452b) and iii) a 2:1 mixture of Z-propenoate-E-enyne and 15 Z-propenoate-Z-enyne (compound 453c). In a similar manner, there was obtained: 2-[3-bromo-2-(6, 6-dimethylhept-2-en-4-ynylthio)phenyl]-2-oxoacetic acid, as an oil, obtained as a 2:1 mixture of 20 the E:Z isomers, which was then methylated to give the methyl ester, as an oil, in a 2:1 mixture of the E:Z isomers. This in turn was converted to methyl 2-[3-bromo-2-(6,6-dimethyl-hept-2-en-4-ynylthio)phenyl]-3-methoxy-prop-2-enoate, as an oil. The oil was subjected to 25 chromatographic separation and the following isomers were obtained, as oils: i) E-propenoate-E/Z-enyne (compound 453a), ii) E-propenoate-Z-enyne, (compound 453b), and ii) E-propenoate-Z-enyne, (compound 4 53c). 30 Example 5 In a similar manner to that described in Example 1, 7-methylbenzo[b]thiophen-2(3H)-one was reacted with 2-bromomethyl-5-phenylpyrimidine to give crude 35 [2-(5—phenylpyrimidin-2-ylmethylthio)-3-methyl- 243 0 2 27 phenyl]acetic acid, which was esterified to give the caLer. a mixture of this product (5 g) , dimethylformamide dimethylacetal (2.5 ml) and pyridinium tosylate (0.4 g) in toluene (100 ml) was heated at 105° for 2\ hours. The mixture was distilled to remove methanol, toluene and then the excess dimethylformamide dimethylacetal was evaporated in vacuo. Further dimethylformamide dimethylacetal (1.8 ml) was added and the mixture heated at 10 5° for a further 2 hours. The mixture was again distilled and the cycle repeated three times. The mixture was evaporated and the residue worked up to give methyl 3-dimethylamino-2-[2-(5-phenylpyrimidin-2-ylmethylthio)-3-methylphenyl]prop-2-enoate. A mixture of this crude product (1 g), dissolved in acetone (100 ml) and Amberlyst 15 (an acidic ion-exchange resin; 5 g) and water (0.5 ml) was stirred at room temperature for 1 hour. The mixture was filtered and the filtrate evaporated to give crude methyl 3-hydroxy-2-[2-(5-phenylpyrimidin-2-ylmethyl-thio)-3-methylphenyl]prop-2-enoate. This (0.4 g) was dissolved in dimethylformamide (20 ml) and sodium hydride (0.44 g of 60% dispersion in oil) was added and the mixture stirred for 1 hour at room temperature. A solution of methyl iodide (1 ml) in dimethylformamide (19 ml) was added and the mixture stirred at room temperature overnight. Solvent was evaporated and the resulting oil was partitioned between ether and water and the organic phase washed with water, dried and evaporated. The residue was purified by silica gel chromatography to give methyl 3-methoxy-2-[2-(5-phenylpyrimidin-2-ylmethylthio)-3-methylphenyl]prop-2-enoate, m.p. 124-7°. (compound 5a) 24302 28 In a similar manner there was obtained: a) methyl 3-methoxy-2-{2-[5-(4-chlorophenyl)pyrimidin- 2-ylmethylthio]-3-methylphenyl}prop-2-enoate, m.p. 123-5°. (compound 5b), and 5 b) methyl 3-methoxy-2-[2-(3-methyl-5-nitrobenzylthio)- 3-methylphenyl]prop-2-enoate, m.p. 135-6°. (compound 5c) Example 6 This example illustrates an alternative method of 10 preparing compound 163. A solution of sodium methoxide (lO.l.g) in ethanol (300 ml) was added to a mixture of intermediate A to compound 163 (6.2.g) and hydrazine hydrate (4.65 g) with 15 stirring. The mixture was heated, ethanol and excess hydrazine hydrate distilled off and the residue maintained at 185° for 15 minutes. Excess 5% hydrochloric acid was added to the cooled residue, followed by diethyl ether. The organic phase was separated, washed with water, dried 20 over magnesium sulfate, evaporated and the residue recrystallised from diisopropyl ether to give [3-chloro-2-(2,5-dimethylbenzylthio)phenyl]acetic acid, m.p. 132-3°. Then, following the method described in Example 2, this 25 was converted to the methyl ester, m.p. 79-80°, which in turn was converted to methyl [(E)-3-hydroxy-2-[3-chloro-2-(2,5-dimethylbenzylthio)phenyl]prop-2-enoate, m.p. 76-8°, which then was methylated to give compound 163. 30 Example 7 Meta-chloroperbenzoic acid (0.128 g, 60%) in dichloromethane (5 ml) was added dropwise to a stirred 35 solution of compound 248 (0.18 g) in dichloromethane 2 k 3 0 2 29 (10 ml). The resultant solution was then stirred for 30 minutes at room temperature. The reaction mixture was washed with 10% aqueous sodium bicarbonate, the organic layer dried over magnesium sulfate and the solvent removed 5 in vacuo to give a yellow oil. The product was purified by silica gel flash chromatography with ethyl acetate as the eluent to give methyl 2-[2-(2,5-dimethylbenzylthio)-3-(methylsulfinylmethyl)phenyl]-3-methoxyprop-2-enoate, as a yellow oil. (compound 7a) 0 In a similar manner, there was obtained from compound 2 40, methyl 2-[3-(butylsulfinylmethyl)-2-[(3-methoxybenzyl)-thio]phenyl]-3-methoxyprop-2-enoate, m.p. 94-7°. (compound 7b) 24 3 0 2 30 Preparation of starting materials 7-Methvlbenzorblthiophen-2(3H)-one 7-Methylbenzo[b]thiophene (18.95 g) was dissolved in ether 5 under nitrogen and the solution cooled to 0°. Butyl lithium (51.1 ml of 2.5M in hexane) was added whilst maintaining the temperature at 0-5°. The mixture was stirred at 0° for 10 minutes, then for 45 minutes at room temperature. It was cooled to 0° and tributyl borate (34.3 10 ml) added dropwise. After stirring for 1 hour at 0°, the mixture was warmed to room temperature and allowed to stand overnight. It was cooled and 2M hydrochloric acid (225 ml) added. The aqueous phase was extracted with ether and the extract extracted with aqueous sodium hydroxide 15 (2M). The basic extract was acidified with concentrated hydrochloric acid to pH 2. The precipitate was filtered and washed with water to give tris-(7-methylbenzo[b]-thiophen-2-yl)cyclotriboroxane. This product (21.4 g) was suspended in water, the mixture heated to 50° and hydrogen 20 peroxide (19.7 ml) added dropwise whilst maintaining the temperature between 55° and 60°. The temperature was kept at 60-68° after the addition. After 1 hour, the mixture was allowed to cool down to room temperature, then extracted with ethyl acetate. The extract was washed with 25 aqueous sodium sulfite (10%) , dried and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane 1:2), followed by recrystallisation from hexane to give 7-methylbenzo[b]thiophen-2(3H)-one. 30 7-Ethylbenzorblthiophene-2,3-dione 2-Ethylbenzenethiol (9.10 g) was added dropwise with stirring and cooling to a solution of oxalyl chloride (12.56 g) in diethyl ether (100 ml). The mixture was 35 stirred at room temperature for 1 hour then evaporated. 31 The residual oil was dissolved in carbon disulfide (100 ml) and cooled to 5°C. Aluminium chloride (13.2 g) was added portionwise over 10 minutes with stirring. The mixture was allowed to warm to room temperature. A black 5 tar was deposited and the stirring became difficult. The mixture was warmed on a warm water bath for 20 minutes, cooled and the carbon disulfide decanted off. Hydrochloric acid (1M) was added and the black tar decomposed to give a sticky red solid. This was extracted with ethyl acetate 10 and the extract washed with water, dried and evaporated to give 7-ethylbenzo[b]thiophene-2,3-dione, m.p. 57-58°. In a similar manner, there was obtained: 5,7-dimethylbenzo[b]thiophene-2,3-dione, m.p. 148-50°. 15 and 4,7-dimethylbenzo[b]thiophene-2,3-dione. m.p. 123-4°. 5-Chloro-4.7-dimethvlbenzo fblthiophene-2.3-dione 4-Chloro-2,5-dimethylbenzenethiol (40.9 g) was added to 20 30% sodium hydroxide solution (200 ml). The mixture was stirred vigorously and chloroacetic acid (45.3 g) was added portionwise. The mixture was stirred at 90° for 2 hours, cooled and poured onto ice (750 g). Concentrated hydrochloric acid (60 ml) was added with brisk stirring. 25 The white solid was filtered, washed well with water and dried in vacuo to give (4-chloro-2,5-dimethylphenyl-thio)acetic acid. This was suspended in chlorobenzene (3 00 ml) and phosphorus trichloride (41.2 g) was added dropwise with stirring. The mixture was heated on a steam 30 bath for 40 minutes and the supernatant liquid decanted from a sticky yellow oil. The supernatant was cooled to room temperature and aluminium trichloride (33.8 g) was added portionwise. The mixture was stirred and heated on a steam bath for 30 minutes to give a deep red solution, 35 poured onto ice (1000 g) and filtered. The solid was 24302 32 washed with water to give 5-chloro-4,7-dimethylbenzo[b]-thiophen-3(2H)-one. This was suspended in 10% sodium hydroxide solution (400 ml) and warmed to 60°. A suspension of N,N-dimethy1-4-nitrosoaniline (34.3 g) in 5% 5 hydrochloric acid (2 00 ml) was added with vigorous stirring. The mixture was stirred for 3 0 minutes and filtered. The purple solid was washed with water, treated with 15% hydrochloric acid (700 ml) and the mixture heated under reflux with stirring for 45 minutes, cooled, 10 filtered and the solid washed with water. It was then treated with 20% aqueous sodium carbonate (700 ml) and the mixture heated under reflux with stirring for 40 minutes. It was filtered hot to remove purple solid by-product. The cooled filtrate was acidified to give an orange solid 15 which was filtered and washed well with water and dried in vacuo to give the title product, m.p. 144-5°. 7-methoxvbenzo fblthiophene-2.3-dione 20 A solution of 2-methoxybenzenethiol (21 g) in ether (100 ml) was added dropwise to a mixture of N,N,N/, N'-tetramethylethylenediamine (34.9 g) and butyl lithium (2.5 M in hexane) (120 ml) in ether (500 ml) at 0° under nitrogen. The mixture was stirred at room 25 temperature for 18 hours and then cooled to -40°. A solution of dimethyl oxalate (17.7 g) in ether (200 ml) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour, poured onto crushed ice and stirred vigorously. The aqueous layer was acidified to pH 30 1, extracted with dichloromethane and the extract dried and evaporated. The residue was purified silica gel column chromatography to give the title compound, m.p. 156-157°. In a similar manner there was obtained 7-ethoxy-35 benzo[b]thiophene-2,3-dione, m.p. 116-8°. 24 3 0 33 7-chlorobenzorblthiophene-2.3-dione Sodium nitrite (203 g) was added portionwise with stirring at room temperature over 2 hours to a solution of 5 7-chlorobenzo[b]thiophen-3(2H)-one (113g) in acetic acid (1200 ml). The mixture was stirred for 2 hours, poured into ice/water (2000 ml), the solid filtered off, washed well with water and filtered dry to give 7-chlorobenzo[b]thiophene-2,3-dione 2-oxime, m.p. 205-10°. 10 This was then treated with 50% sulfuric acid at reflux, with stirring for 2 hours. The mixture was cooled and poured into ice/water (2500 ml), filtered and washed well with water and recrystallised from ethanol to give the title product. 15 In a similar manner there was obtained: a) 5-fluoro-7-methylbenzo[b]thiophene-2,3-dione 2-oxime, m.p. 22 0° (dec), which was converted to the dione, m.p. 105-6°, 20 b) 6-fluoro-7-methylbenzo[b]thiophene-2,3-dione 2-oxime, m.p. 218-20° (dec), which was converted to the dione, m.p. 101-2°, and c) 7-chloro-5-methylbenzo[b]thiophene-2,3-dione 2-oxime, m.p. 23 0° (dec), which was converted to the dione, 25 m.p. 152-3°, Example 8 Tests were carried out to determine the photostability of a number of compounds of the inventions. Acetone solutions 30 of the compounds were applied to pre-coated silica-gel tic plates at a rate of 10 jug/cm"2. After the solvent had evaporated the plates were exposed for one hour in a Sol 2 sunlight simulator (manufactured by Dr K Honle GmbH, Germany). The plates were then developed in 35 dichloromethane/ethyl acetate (95:5). For the purpose of 34 comparison, certain analogues were similarly treated in which R1 is hydrogen and in some cases the phenyl is substituted by methyl at the 4 position. 5 Examination of the plates of the comparison compounds indicated formation of significant amounts of sulfoxide, whereas in the case of the compounds of the invention, little or no sulfoxide was obtained. 10 The compounds tested were as follows: a) R2 = Ph Compound No R1 (R3) n 11 Me 19 Me - 15 69 Et 152 Me 4-Me 205 EtO 20 Comparison H ■n b) R2 = 3-MeO-Ph Compound No R1 fR3) 4 Me 34 Et 25 139 Me 5-Me 144 Me 6-Me 157 Me 4-Me 160 Cl 168 Br 30 199 MeO Comparison H H 4-Me 35 35 20 c) R2 = 4-Me-Ph Compound No R1 fR3)n 2 Me 16 Et 5 138 Me 5-Me 161 Cl 169 Br 198 MeO 214 EtO 10 229 Me 4-Me Comparison H H 4-Me 15 d) R2 = 3-CF3-Ph 3- Compound No R1 CR3^n 55 Me 225 MeO 226 MeO Comparison H e) R2 = 3-F-Ph Compound No R1 (R3^ n 25 5 Me 32 Et 108 Me 150 Me 5-Me 176 Br - 30 192 Cl 206 MeO Comparison H - 35 36 Test Example A Compounds are assessed for activity against one or more of the following: 5 Phvtophthora infestans: late tomato blight (PI) Plasmopara viticola: vine downy mildew (PV) Ervsiphe graminis: barley powdery mildew (EG) Pvricularia orvzae: rice blast (PO) Pellicularia sasakii: rice sheath blight (PS) 10 Botrvtis cinerea: grey mould of tomato (BC) Venturia inaeoualis: apple scab (VI) Leptosphaeria nodorum: glume blotch (LN) Pseudocercosporella herpotrochoides; eyespot (PH) 15 Aqueous solutions or dispersions of the compounds at the desired concentration, including a wetting agent, were applied by spray or by drenching the stem base of the test plants. These plants were then inoculated with appropriate test pathogens and kept under controlled 20 environment conditions suitable for maintaining plant growth and development of the disease. After an appropriate time, the degree of infection of the leaf surface or stem base, as appropriate, was visually estimated. Compounds were considered active if they gave 25 greater than 50% control of the disease at a concentration of 500 ppm (w/v) or less. 24 3 0 37 Activities were demonstrated as follows (+ = active). Compound PI PV EG PO PS BC VI LN PH 5 1 + + + + + + + + 2 + + 3 + + + + 4 + + + + + 5 + + + + + + 10 6 + + + 7 + + + + 8 + + + 9 + + + + + + 10 + + + + + + 15 11 + + + + + 12 + 14 + + + + + 15 + + 16 + + + + + 20 17 + + + + + 18 + + 19 + + + 20 + + + + 21 + + + + 25 22 + + 24 + + 25 + + + + + 27 + + + + + 28 + + 30 30 + + + + 32 + + + + 33 + + + 34 + 35 + 35 37 + + m 2 4 3 38 Compound PI PV EG PO PS BC VI LN PH 38 + + + 5 39 + + + 41 + + + 42 + 43 + 45 + + + 10 47 + + + + + 49 + + + + + + 51 + + + 53 + 54 + + + + + 15 55 + + + 56 + + + + 57 + + 58 + + + 59 + + + + 20 60 + + + + + 61 + + 62 + + 63 + + + 64 + + + 25 65 + + 66 + + + + 67 + + + + 69 + + + 70 + 30 71 + + + 72 + + + + 73 + + 74 + + 75 + + 35 76 + + + + + 243 39 Compound PI PV EG PO PS BC VI LN PH 77 + 5 78 + + + + 79 + + 80 + 81 + + + + + 82 + + 10 83 + + + + + 84 + + 85 + + 86 + + + 87 + 15 88 + + + + 89 + + + + + 90 + + + + + + 91 + + + 92 + + + 20 93 + + + + + + 94 + 95 + + + + + + 97 + + + 100 + + + 25 101 + + + 102 + + 103 + + 104 + + + + 105 + + + + + 30 136 + 137 + + + + 138 + + 139 + + + 140 + + + 35 141 + + + 40 Compound PI PV EG PO PS BC VI LN PH 142 + + 5 143 + + + 145 + + 146 + + + 147 + + + + 148 + 10 149 + 150 + + + 151 + + 152 + + 154 + + + 15 155 + 156 + + 160 + + + 161 + + + + + + + 163 + + + 20 165 + + + + + 167 + + + 168 + + + + + 169 + + + + + 170 + + + + 25 171 + + + + 172 + + + 173 + + 174 + + 175 + + + 30 176 + + + + 177 + + 178 + 179 + + + 180 + + 35 181 + + 24 3 41 Compound PI PV EG PO PS BC VI LN PH 182 + 5 183 + + 184 + + + 185 + 186 + + + 187 + + + 10 188 + 189 + + + + 190 + 191 + + 192 + + 15 193 + 195 + + 197 + + 198 + + + + 199 + + + 20 200 + + + 201 + + + 202 + + + + 203 + + 204 + + + 25 205 + + 206 + + 207 + + + + 208 + + 210 + + + + 30 211 + + + + 212 + + + + 213 + 214 + 216 + + 35 217 + + + + + + 24 42 Compound PI PV EG PO PS BC VI LN PH 10 15 20 25 30 35 218 + + + + + 219 + + 220 + + + 221 + + 222 + 223 + + + + 225 + + + + 226 + + 227 + + + + + 228 + + + 229 + + + + 230 + + + + 231 + + 232 + + + + + + 233 + + + 234 + + 235 + + + + 236 + 237 + + 238 + + + 239 + 240 + + + 241 + + 242 + + + 243 + + + + 244 + 245 + + 247 + + 248 + 250 + + ■ + + 251 + + 252 + + + + 24 3 0 2 43 Compound PI PV EG PO PS BC VI LN PH 253 + + + + 5 254 + + + + 255 + 257 + 258 + + ■+■ 259 + 10 260 + 263 + + + + 264 + 265 + + 2 66 + + 15 267 + 268 + + 270 + 271 + + 272 + + 20 274 + + 275 . + + + + 276 + 277 + 278 + + 25 279 + + 280 + + 281 + + 282 + + 313 + + 30 314 + 400 + + + + 401 + + + + + 402 + + + + + 451a + 35 451c + 24 3 0 20 44 Compound PI PV EG PO PS BC VI LN PH 452a. + + 5 452b + 452c + 453a + + 2a + + + + + 5a + + + + 10 5b + + + + + + 5c + + 15 24 3 0 2 45 The following intermediates demonstrated activity as follows: Intermediate 5 to Compound PI PV EG PO PS BC VI LN PH No (A or B type) IB + 2A + + + 10 3B + + + + 4B + + 5A + 5B + + + + 6A + + 15 6B + + 8B + 9A + 10B + 14A + 20 14B + 17A + 2 OA + 2 OB + + 22B + 25 24B + 29B + + 32A + + 32B + 38A + 30 38B + + 42A + + + 42B + + + + 45A + + 45B + 35 49B + 2430 20 46 Intermediate to Compound PI PV EG PO PS BC VI LN PH No (A or B type) 47A + 51B + + 52A + + 52B + 10 53A + + + 54A + + . 55A + + 55B + + 56A + 15 56B + 58A ' + 58B + 66A + + 66B + 20 67A + + + + 67B + 7 OA + + 7 OB 4- 7 IB + 25 72A + 72B + 73A + 74B + + 76A + + 30 78A + 79B + + 81A + 83B + 84A + 35 85A + 2430 2 47 Intermediate to Compound PI PV EG PO PS BC VI LN PH No (A or B type) 5 86A + 86B + 94B + + + 96B + + + 10 98B + + + 99A + + + 106A + + 107A + + 107B + + + 15 109A + 118A + 118B + + 122A + 122B + 20 123B + + 124A + + 12 7A + 127B + + 13 OA + + 25 130B + + 133B + 135A + + 136B + + + 13 7A + + 30 138B + + 139A + + + 14 OB + + 141A + + + 141B + + 35 143A 4- + + 48 Intermediate to Compound PI PV EG PO PS BC VI LN PH No (A or B type) 5 143B + 144A ' + 145A 145B 10 14 6A 146B 147A 147B 149A 15 150A 150B + 152A + 152B 153A 20 153B 154A + 154B + 157A + 157B + 25 158A + 160B 161B 168A + 168B + 30 169A + 169B + 17 OB + 171A + 17 IB + 35 175A + + + + + + + + + + + + + + + + + + + + </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 10 15 20 25 30 24 3 0 20 49 Intermediate to Compound PI PV EG PO PS BC VI LN PH No (A or B type) 35 181B + 184B + 188B + 189B + 192B + 194A + + 195B + + + 198A + 199A + 199B + 2 01A + 2 01B + + 207A + 211B + + 212A + 212B + 216A + + 219A + 219B + + 2 21A + 223A 223B + 227A + 227B 23 OB + 234A + 238B + 2 65A + + 266A + 266B + + + + 24 3 0 20 WHAT tfWE CLAIM IS: 50 CLAIMC-

1. A compound of formula I (r3)u - S-CH2-R2 (I) MeO-X=C-COOMe wherein 10 X is CH or N; n is 0, 1, 2 or 3; R1 and R3, which may be the same or different, are alkyl, alkoxy or alkylthio, each of which is optionally substituted, halogen, nitro, cyano, COOR4, -NR5R6, 15 CONR5R6, COR7 or R8S(0)q; or R1 and an adjacent R3 group, or two adjacent R3 groups, together with the carbon atoms to which they are attached can form a 5 to 8 membered ring which can include 1 to 3 heteroatoms and may be substituted; 20 R2 is an optionally substituted aliphatic hydrocarbon radical, which may be unsaturated, aryl or heterocyclyl; R4 is hydrogen or an ester forming group; R5 and R6 are the same or different and are hydrogen, 25 optionally substituted alkyl, acyl or aryl, or together with the nitrogen to which they are attached, form a 5 to 7 membered ring which can contain other hetero atoms; R7 is hydrogen, optionally substituted alkyl or aryl; -30 R8 is optionally substituted alkyl or aryl; and q is 1 or 2. 94 3 0 20 51

2. A compound of formula II <r3)„ s-ch2-r (ii) 0=C-C00R9 wherein R1, R2, R3 and n have the meanings given in claim 1 and R9 is hydrogen or methyl. 10

3. A compound of formula III <r3>„ 15 — s-ch2-r (III) CH2-COOMe wherein R1, R2, R3 and n have the meanings given in claim 1.

4) A fungicidal composition comprising a compound as claimed claim 1, in admixture with an agriculturally acceptable diluent or carrier. 20 25

5) A method of combating phytopathogenic fungi which comprises applying to the fungus or its locus a compound claimed in claims 1.

6. A compound of formula I as defined in claim 1 substantially as herein described with reference to any example thereof.

7. A compound of formula II as defined in claim 2 substantially as herein described with reference to any example thereof. * 52 243020

8. A compound of formula III as defined in claim 3 substantially as herein described with reference to any example thereof.

9. A fungicidal composition as defined in claim 4 substantially as herein described with reference to any example thereof.

10. A method as defined in claim 5 of combating phytopathogenic fungi substantially as herein described with reference to any example thereof. <&MeCLitCCx /~t rv By the authorised agents A J PARK & SON </div>