PREPARATION OF PROPENOIC ACID DERIVATIVES

Abstract: Compounds of formula (I) and salts thereof, wherein m is 0 to 18, R<1> is alkyl, and R is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyl(thio)carbonyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted N-substituted iminomethylene or substituted heterocyclylidenemethyl are obtained by (A) attaching a protecting group, W, on the hydroxy group of a compound of formula (II) to give a compound of formula (III); (B) replacing a hydrogen on the methyl of the compound of formula (III) with a leaving group, Z, to give a compound of formula (IV); (C) treating the compound of formula (IV) with a compound of formula (V): R-(CH2)m-SH to give a compound of formula (VI) and (D) removing the protecting group. The compounds of formula (I) are novel and have fungicidal activity and are intermediates for the preparation of other useful fungicidal compounds. Many of the compounds of formula (VI) are also fungicidal.

Description: Title: Preparation of Propenoic Acid Derivatives Field of the invention This invention relates to a new process for the preparation of certain propenoic acid derivatives. Prior Art Alkyl 2-aryl-3-alkoxy-2-propenoate derivatives have been disclosed as having pesticidal activity. Compounds of this type are disclosed for example in EPs 178826, 203606, 203608, 206523, 229974, 226917, 242070, 242081, 243012, 243014, 251082, 256667, 260794, 260832, 267734, 270252, 273572, 274825, 278595, 291196, 299694, 307101, 307103, 310954, 312221, 312243, 329011 and 336211. Numerous processes and intermediates for their preparation have been disclosed in these and other publications. In EP 310954 for example certain 3-hydroxy intermediates are disclosed. Description of the Invention We ha *τ e now found an improved process for the manufacture of compounds which can be used as intermediates to certain of such compounds. Thus according to one aspect of the invention there is provided a process for preparing a compound of formula I or a salt thereof, wherein m is 0 to 18, R 1 is alkyl, and R is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyl(thio)carbonyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted N-substituted iminomethyl or substituted heterocyclylidenemethyl which comprises A) attaching a protecting group, W, on the hydroxy group of a compound of formula II to give a compound of formula III B) replacing a hydrogen on the methyl of the compound of formula III with a leaving group, Z, to give a compound of formula IV C) treating the compound of formula IV with a compound of formula V R-(CH 2 ) m -SH (V) to give a compound of formula VI and D) removing the protecting group. Compounds of formula I and their salts and of formula VI are novel and form part of the invention. Many of them have pesticidal, especially fungicidal, activity. The compounds of formula I obtained by the process of the invention can be alkylated to give compounds of formula VII where R 2 is alkyl. Compounds of this type are disclosed in our EP 299694. If desired the compounds of formula VII can be obtained without first isolating the compounds of formula I. In EP 299694, compounds of this type were generally obtained by the following reaction sequence. Alkylate R-(CH 2 ) m -SH R-(CH 2 ) It is usually desired that products of formula VII are obtained in the E-form. However in the reaction sequence shown above the compound of formula IX is obtained as a mixture of E and Z isomers. Z-isomer of the compound of formula IX gives the desired E-isomer of the compound of formula VII. The E-isomer was associated with large amounts of impurity and to remove the impurity it was generally necessary to discard the E-isomer leading to a loss of yield. However the process of the present invention results in essentially the desired iso er only, resulting in an improvement in yield. In reaction A) , the protecting group is preferably an acyl and especially an acetyl group. The reaction in steps B) and C) can be carried out under similar conditions to those described in our EP 299 694. Removal of the protecting group can be carried out in conventional manner, usually under basic conditions, eg in the presence of an alkali metal base, especially an alkoxide, in which case the compound of formula I is usually obtained as a salt. Alkylation of the compound of formula I can be carried out in known manner, eg using an alkyl halide or sulphate, preferably under basic conditions, eg in the presence of a metal (especially sodium) hydride. Of the groups covered by the term R: Alkyl groups are preferably of 1 to 20, eg 1 to 4, carbon atoms, especially methyl or ethyl. Alkenyl and alkynyl groups are generally of three to six carbon atoms. Substituents, when present on any alkyl, alkenyl or alkynyl group, include halogen, alkoxy (e.g. of 1 to 4 carbon atoms) , haloalkoxy (e.g. difluoromethoxy) hydroxy, alkylthio, nitro, optionally substituted amino, carboxy, alkoxycarbonyl, cyano, acyloxy and aryl. Aryl groups are usually phenyl, optionally substituted, e.g. by halogen, optionally substituted alkyl or alkoxy, aryl, aryloxy, nitro, amino, COOH, COOR 2 , CN, CONR 2 R 2 or S(0) n R 2 . The terms heteroaryl and heterocyclyl include groups such as thienyl, furyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, thiazolinyl, oxazolyl, benzimidazolyl, tetrazolyl, benzoxazolyl, thiadiazolyl, dioxolanyl, imidazopyridinyl, 1,3-benzoxazinyl, 1,3-benzothiazinyl, oxazolopyridinyl, triazolyl, triazinyl, imidazolyl, orpholino, benzofuranyl, pyrazolinyl, quinolinyl, quinazolinyl, dihydroquinazolinyl or benzothiazolyl, which themselves may be substituted, e.g. as for phenyl. The term "acyl" includes the residue of sulphonic and phosphorus containing acids as well as carboxylic acids. Acyl groups are preferably alkanoyl e.g. of 1 to 4 carbon atoms. 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. Iminomethyl groups can be substituted both on the nitrogen and carbon. Examples of substituents on the nitrogen include aryl and alkyl. Examples of substituents on the carbon include aryl, alkyl, alkylthio, alkoxy and cyano. Since it is generally desired that the product is obtained in the E-form, the product is generally heated under acidic conditions to convert any Z-isomer into E-isomer. R 1 and R 2 are both preferably methyl. 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. Example 1 A mixture of methyl 3-hydroxy-2-(o-tolyl)-2-propenoate (50 g) , acetic anhydride (500 ml) and potassium acetate (10 g) was stirred and heated under reflux for 2 hours, cooled and allowed to stand overnight. The acetic anhydride was removed by vacuum distillation. The crude product was stirred well with distilled water (500 ml) for 1 hour at 20°. The mixture was extracted with diethyl ether (2x250 ml) and the extract washed with 5% sodium bicarbonate solution (2x200 ml) , water (2x250 ml) and dried (MgS0 ) . The ether was removed by vacuum distillatio to give crude product shown by NMR, IR and mass spectroscopy to be methyl (E)-3-acetoxy-2-(o-tolyl)- 2-propenoate. This product (50 g) , carbon tetrachloride (200 ml) , N-bromosuccinimide (38 g) , and azodicarbonamide (1.0 g) were stirred and heated under reflux for 4 hours. After cooling, the reaction mixture was filtered. The filtrate was distilled under vacuum to leave a crude product which was dissolved in warm diisopropyl ether and treated twice with charcoal (2x1 g) . The charcoal was filtered off and the solvent removed by vacuum distillation. The product crystallised out at low volume. After cooling most of the supernatant was decanted and the solid filtered and washed with cold diisopropyl ether (30 ml) to leave a white solid after drying. Spectral identification proved the compound to be methyl (E)-3-acetoxy-2-(α-bromo-o-tolyl)- 2-propenoate. To sodium hydroxide (0.5 g) in water (3.0 ml), was added 4,4-dimethyl-5-methylene-2-thiazolidinethione (1.6 g) and tetrabutylammonium bromide (38 mg) . The slurry was warmed to 60°C to ensure completion of reaction and allowed to cool. To the well stirred slurry at 20° was added methyl (E)-3-acetoxy-2-(α-bromo-o-tolyl)-2-propenoate (3.1g) in carbon tetrachloride (13 ml) solution. The mixture was stirred overnight and quenched with water (12 ml) . The organic layer was separated off and the aqueous layer extracted with carbon tetrachloride (6 ml) . The combined carbon tetrachloride layers were treated at 20° with a small amount of activated charcoal (100 g) and filtered. The solvent was removed under vacuum to leave a crude oil, which was purified by column chromatography and shown to be methyl (E)-3-acetoxy-2-[α-(4,4-dimethyl-5-methylene- 2-thiazolin-2-ylthio)-o-tolyl]-2-propenoate. (compound la) This product (0.63 g) was dissolved in methanol (1 ml) and a solution of sodium methoxide (86 mg) in methanol (1 ml) was added with stirring. The mixture was stirred at 20° for 1% hours. A solution of dimethyl sulphate (242 mg) in methanol (1 ml) was added to the mixture, which now comprised crude methyl (E)-2-[α-(4,4-dimethyl-5-methylene- 2-thiazolin-2-ylthio)-o-tolyl]-3-hydroxy-2-propenoate, as the sodium salt. The mixture was stirred at 20° for 1% hours and then heated under reflux for 1 hour. Methanol was removed under vacuum. Water (5 ml) was added and the oil extracted with dichloromethane (2x3 ml) . The combined dichloromethane layers were washed with water, dried and evaporated to give a light brown oil (0.4 g) . By spectral and analytical investigation this was shown to be methyl (E)-2-[α-(4,4-dimethyl-5-methylene-2-thiazolin-2-ylthio)- o-tolyl]-3-methoxy-2-propenoate. A sample of pure methyl (E)-2-[α-(4,4-dimethyl- 5-methylene-2-thiazolin-2-ylthio)-o-tolyl]-3-hydroxy- 2-propenoate, was isolated from the crude material, as an oil (compound lb) . Example 2 In a similar manner to Example 1, there was obtained: methyl (E)-3-benzoyloxy-2-(o-tolyl)-2-propenoate, mp 86-88°, which was converted, via the α-bromo compound, to: methyl (E)-3-benzoyloxy-2-[α-(4,4-dimethyl-5-methylene- 2-thiazolin-2-ylthio)-o-tolyl]-2-propenoate, as a wax (compound 2) , which in turn was converted, via the 3-hydroxy compound, to the final compound of Example 1. Example 3 In a similar manner to Example 1, A) methyl (E)-3-acetoxy-2-(α-bromo-o-tolyl)-2- propenoate, was converted to (i) methyl (E)-3-acetoxy-2-{α-[ (methylthio)- ( henylimino)methylthio]-o-tolyl}-2-propenoate, mp 106-107.5°, (compound 3a) which in turn was converted, via the 3-hydroxy compound, to (ii) methyl (E)-3-methoxy-2-{α-[ (methylthio)- (phenylimino)methylthio]-o-tolyl}-2-propenoate, as a gum. B) methyl (E)-3-acetoxy-2-(α-bromo-o-tolyl)-2- propenoate, was converted to (i) methyl (E)-3-acetoxy-2-[α-(5,6-dimethyl- benzothiazol-2-ylthio)-o-tolyl]-2-propenoate, m.p. 133-135°, (Compound 3b) which in turn was converted, via the 3-hydroxy compound, to (ii) methyl (E)-2-[α-(5,6-dimethyl-benzothiazol- 2-y1thio)-o-toly1]-3-methoxy-2-propenoate, m.p. 112.5-115°. C) methyl (E)-3-acetόxy-2-(α-bromo-o-tolyl)-2- propenoate, was converted to (i) methyl (E)-3-acetoxy-2-[α-(4-methyl-5-phenyl- thiazol-2-in-2-ylthio)-o-tolyl]-2-propenoate, as an oil, (Compound 3c) , which in turn was converted, via the 3-hydroxy compound, to (ii) methyl (E)-2-[α-(4-methyl-5-phenylthiazolin- 2-ylthio)-o-tolyl]-3-methoxy-2-propenoate, as a gum. Test Example Compounds are assessed for activity against one or more of the following: Plasmopara viticola: vine downy mildew (PV) Pyricularia oryzae: rice blast (PO) Venturia inaequalis: apple scab (VI) Septoria nodorum: glume blotch (SN) 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 environment conditions suitable for maintaining plant growth and development of the disease. After an appropriate time, the degree of infection of the leaf surface was visually estimated. Compounds were considered active if they gave greater than 50% control of the disease at a concentration of 500 ppm (w/v) or less. Compounds la, lb, and 3b were active against PV; compounds lb and 3b were active against PO; compounds lb, 3a, 3b and 3c were active against VI and compound 2 was active against SN.

Claims: CLAIMS A process for preparing a compound of formula I or a salt thereof, wherein m is 0 to 18, R 1 is alkyl, and R is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyl(thio)carbonyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted N-substituted iminomethylene or substituted heterocycly1idenemethy1 which comprises A) attaching a protecting group, W, on the hydroxy group of a compound of formula II to give a compound of formula III B) replacing a hydrogen on the methyl of the compound of formula III with a leaving group, Z, to give a compound of formula IV C) treating the compound of formula IV with a compound of formula V R-(CH 2 ) m -SH (V) to give a compound of formula VI and D) removing the protecting group. 2. Compounds of formula I, and salts thereof, as defined in claim 1. 3. Compounds of formula VI as defined in claim 1. 4. Compounds of formula I, and salts thereof, as defined in claim 1, when obtained by a process claimed in claim 1. 5. A process for the preparation of compounds of formula VII where R 2 is alkyl, which comprises alkylating a compound claimed in claim 2 or 4. 6. A process according to claim 5, in which R 1 and R 2 are methyl.

Inventors: FOSTER RICHARD WINSTON GORDON, FOSTER, RICHARD, WINSTON, GORDON
Applicants: SCHERING AGROCHEMICALS LTD, SCHERING AGROCHEMICALS LIMITED
Application year: 1991
Main classification: C07D277
IPC codes: A01N37, A01N43, C07C323, C07D277