Process for the synthesis of methoxy substituted benzaldehyde compounds

Abstract

The present invention provides, inter alia, a process for preparing a compound of formula (I) wherein the substituents are as defined in claim 1.

Description

The present invention relates to a novel process for the synthesis of certain methoxy substituted benzaldehyde compounds as well as novel intermediates used in the process. Such compounds are useful intermediates in the synthesis of herbicidal propynyl-phenyl compounds, which are known, for example from WO 2015 / 197468 and processes for making such compounds or intermediates thereof are also known. The copper catalysed synthesis of alkyl aryl ethers is known, see for example SAMBIAGO et al., Copper catalysed Ullmann type chemistry: from mechanistic aspects to modern development, Chem. Soc. Rev 2014, Vol. 43, p. 3525-3550, DE2721643 A1 (LUDWIG HEUMANN AND CO) 23.11.1978 and EP0520815 A2 (NIPPON CHEM. IND. CO. LTD.) 30.12.1992. The copper catalysed coupling of a cyclohexylimine substituted aryl iodide with methoxide is disclosed in ADESOMOJU A. et al., Total synthesis of leucoxylonine, The Journal of Organic Chemistry, 1984, Vol. 49, no.17, p. 3220-3222. Copper catalysed Ullmann coupling reactions may be carried out in the presence of a ligand, see for example ZHANG et al. Cul / DMPAO Catalyzed N-Arylation of Acyclic Secondary Amines, Org. Lett., 2012, Vol. 14(12), p. 3056-3059 or EP3326715 A1 (SHANGHAI INSTITUTE OF ORGANIC CHEMISTRY) 30.05.2018. Furthermore, the use of a directing group is known to improve regioselectivity, see for example NICOLAOU et al. New Synthetic Technology for the Synthesis of Aryl Ethers, J. Am. Chem. Soc. 1997, Vol. 119, p. 3421-3422, KALININ et al. The Directed Ortho Metalation-Ullmann Connection, J. Org. Chem. 1999, Vol. 64, p. 2986-2987 or XU et al. Org. Lett. 2014, Vol. 16, p. 3942-3945. A ligand free, copper free process for the O-arylation of benzaldehyde derivatives has also been reported, see for example, KUMAR and NEGI, A frank synthesis of alkyl—aryl ethers from 2-halobenzaldehydes and aromatic olefins without transition metal co-catalyst and ligand, Tetrahedron Letters, 2015, Vol. 56, p.2340-2344. However, these are either unsuitable for large scale production and / or have high yield losses and the need for additional purification of the product. Thus, there is the need for a new, more efficient synthesis method utilising more favourable reaction conditions and avoiding the generation of undesirable by-products. The present invention provides a process for the O-arylation of a benzaldehyde derivative which (i) provides a high level of regioselectivity and (ii) a good level of conversion to the desired product. Surprisingly, we have now found that a selective O-arylation to deliver the desired mono methoxylated product, a compound of formula (I), can be achieved in the process of the present invention which in turn can be converted to the desired propynyl-phenyl herbicidal compounds. Thus, according to the present invention there is provided a process for the preparation of a compound of formula (I), (I) wherein, X is halogen; comprising the steps of; (i) reacting a compound of formula (II); (II) wherein Y is selected from the group consisting of bromo, chloro, iodo, CF3SO3-, CH3C6H4SO3- and CH3SO3-, R1 is Ci-Cealkyl and X is as defined above for a compound of formula (I); with methanol in the presence of a copper source to give a compound of formula (III); (HI) wherein X is as defined above for a compound of formula (I) and R1 is as defined above for a compound of formula (II); and, (ii) hydrolysis to a compound of formula (I). According to a second aspect of the invention, there is provided an intermediate compound of formula (HI), WO 2024 / 089225                                                 PCT / EP2023 / 080025 3 (HI) wherein X and R1 are as defined herein, provided that the compound of formula (III) is not a compound selected from the group consisting of N-butyl-1-(4-chloro-2-methoxy-phenyl)methanimine, N-tert-butyl-1-(4-fluoro-2-methoxy-phenyl)methanimine, 1-(5-bromo-2-methoxy-phenyl)-N-methyl-methanimine, N-tert-butyl-1 -(5-fluoro-2-methoxy-phenyl)methanimine,               N-te rt- butyl-1 -(5-chloro-2-methoxy- phenyl)methanimine and N-tert-butyl-1 -(5-bromo-2-methoxy-phenyl)methanimine. As used herein, the term "halogen" refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo). As used herein, the term “hydroxyl” or “hydroxy” means an -OH group. As used herein, cyano means a -CN group. As used herein, nitro means an -NO2 group. As used herein, oxo means an =O group (eg, as in a carbonyl (C=O) group). As used herein, the term "Ci-Cealkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond. Ci-C4alkyl and C1-C2alkyl are to be construed accordingly. Examples of Ci-Cealkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, and 1-dimethylethyl (f-butyl). A “Ci-C2alkylene” group refers to the corresponding definition of Ci-C2alkyl, except that such radical is attached to the rest of the molecule by two single bonds. Examples of Ci-C2alkylene, are -CH2- and -CH2CH2-. As used herein, the term "Ci-Cealkoxy" refers to a radical of the formula -ORa where Ra is a Ci-Cealkyl radical as generally defined above. Ci-C4alkoxy is to be construed accordingly. Examples of Ci-4alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy and f-butoxy. As used herein, the term "Ci-Cehaloalkyl" refers to a Ci-Cealkyl radical as generally defined above substituted by one or more of the same or different halogen atoms. Ci-C4haloalkyl is to be construed accordingly. Examples of Ci-Cehaloalkyl include, but are not limited to chloromethyl, fluoromethyl, fluoroethyl, difluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl. As used herein, the term "Ci-Cehaloalkoxy" refers to a Ci-Cealkoxy group as defined above substituted by one or more of the same or different halogen atoms. Ci-C4haloalkoxy is to be construed accordingly. Examples of Ci-Cehaloalkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, fluoroethoxy, trifluoromethoxy and trifluoroethoxy. As used herein, the term "C2-C6alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond that can be of either the (E)- or (Z)-configuration, having from two to six carbon atoms, which is attached to the rest of the molecule by a single bond. C2-C4alkenyl is to be construed accordingly. Examples of C2-Cealkenyl include, but are not limited to, prop-1-enyl, allyl (prop-2-enyl) and but-1-enyl. As used herein, the term "C2-C6alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to six carbon atoms, and which is attached to the rest of the molecule by a single bond. Examples of C3-Cealkynyl include, but are not limited to, prop-1-ynyl and propargyl (prop-2-ynyl). As used herein, the term "Ci-CsalkoxyCi-Csalkyl-" refers to a radical of the formula Rb-O-Ra- where Rb is a Ci-Csalkyl radical as generally defined above, and Ra is a Ci-Csalkylene radical as generally defined above. As used herein, the term "Ci-Cealkylcarbonyl" refers to a radical of the formula RaC(O)-, wherein Ra is a Ci-Cealkyl radical as generally defined above. As used herein, the term "Ci-Cealkoxycarbonyl" refers to a radical of the formula RaOC(O)- where Ra is a Ci-Cealkyl radical as generally defined above. As used herein, the term "Cs-Cecycloalkyl" refers to a stable, monocyclic ring radical which is saturated and contains 3 to 6 carbon atoms. C3-C4cycloalkyl is to be construed accordingly. Examples of C3-Cecycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. As used herein, the term "Cs-CecycloalkylCi-Csalkyl-" refers to a Cs-Cecycloalkyl ring as defined above attached to the rest of the molecule by a Ci-Csalkylene radical as defined above. The term "C3-C4cycloalkylCi-C2alkyl-" is to be construed accordingly. Examples of Cs-CecycloalkylCi-Csalkyl- include, but are not limited to cyclopropylmethyl- and cyclobutylethyl-. As used herein, the term "Cs-Cecycloalkenyl" refers to a stable, monocyclic ring radical which is partially unsaturated and contains 3 to 6 carbon atoms. C3-C4cycloalkenyl is to be construed accordingly. Examples of Cs-Cecycloalkenyl include, but are not limited to, cyclopenten-1-yl and cyclohexen-1-yl. As used herein, the term "Cs-CecycloalkenylCi-Csalkyl-" refers to a Cs-Cecycloalkenyl ring as defined above attached to the rest of the molecule by a O-Csalkylene radical as defined above. The term "C3-C4cycloalkylCi-C2alkyl-" is to be construed accordingly. As used herein, the term “N-Ci-C4alkylamino” refers to a radical of the formula RaNH- wherein Ra is a Ci-C4alkyl radical as generally defined above. As used herein, the term “N,N-diCi-C4alkylamino” refers to a radical of the formula Ra(Rb)N- wherein Ra and Rb are the same or different Ci-C4alkyl radicals as generally defined above. As used herein, the term “N-Ci-C4alkylaminocarbonyl” refers to a radical of the formula RaNHC(O)-wherein Ra is a Ci-C4alkyl radical as generally defined above. As used herein, the term “N,N-diCi-C4alkylaminocarbonyl” refers to a radical of the formula Ra(Rb)NC(O)- wherein Ra and Rb are the same or different Ci-C4alkyl radicals as generally defined above. As used herein, the term “phenylCi-Csalkyl-” refers to a phenyl ring attached to the rest of the molecule by a Ci-Csalkylene radical as generally defined above. As used herein, except where explicitly stated otherwise, the term "heteroaryl" refers to a 5- or 6membered monocyclic aromatic ring which comprises 1,2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur. The heteroaryl radical may be attached to the rest of the molecule via a carbon atom or a heteroatom. Examples of heteroaryl include, furyl, pyrrolyl, imidazolyl, thienyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl or pyridyl. As used herein, the term "heteroarylCi-Csalkyl-" refers to a heteroaryl ring as defined above attached to the rest of the molecule by a O-Csalkylene radical as generally defined above. As used herein, except where explicitly stated otherwise, the term "heterocyclyl" or "heterocyclic" refers to a stable 3- to 6-membered non-aromatic monocyclic ring radical which comprises 1, 2, or 3 heteroatoms individually selected from nitrogen, oxygen and sulfur. The heterocyclyl radical may be bonded to the rest of the molecule via a carbon atom or heteroatom. Examples of heterocyclyl include, but are not limited to, pyrrolinyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidyl, piperazinyl, tetrahydropyranyl, dihydroisoxazolyl, dioxolanyl, morpholinyl or 6-lactamyl. As used herein, the term "heterocyclylCi-Csalkyl-" refers to a heterocyclyl ring as defined above attached to the rest of the molecule by a O-Csalkylene radical as generally defined above. As used herein, the term “heterodiaryl” refers to a 9 or 10-membered aromatic fused bicyclic ring radical which comprises 1, 2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur. The heteroaryl radical may be bonded to the rest of the molecule via a carbon atom or heteroatom. Examples of heterodiaryl include, indolyl, indazolyl, benzimidazolyl, pyrrolopyridinyl or triazolopyridinyl. As used herein, the term "heterodiarylCi-Csalkyl-" refers to a heterodiaryl ring as defined above attached to the rest of the molecule by a O-Csalkylene radical as generally defined above. The skilled person would appreciate that compounds of formula (II) and compounds of formula (III) may exist as E and / or Z isomers. This invention covers processes and compounds including all such isomers and mixtures thereof in all proportions. For example, a compound of formula (II) may be drawn as a compound of formula (ll-l) or (ll-ll) shown below Likewise, a compound of formula (III) may be drawn as a compound of formula (lll-l) or (lll-ll) shown below Likewise, a compound of formula (lla-l) may be drawn as a compound of formula (Ila-la) or (lla-lb) Cl                          Cl (lla-la)                          (lla-lb). Likewise, a compound of formula (llla-l) may be drawn as a compound of formula (llla-la) or (llla-lb) Cl                             Cl (llla-la)                          (llla-lb). The process of the present invention can be carried out in separate process steps, wherein the intermediate compounds can be isolated at each stage. Alternatively, the process can be carried out in a one-step procedure wherein the intermediate compounds produced are not isolated. Thus, it is possible for the process of the present invention to be conducted in a batch wise or continuous fashion. The following list provides definitions, including preferred definitions, for substituents X, Y, Z, G, Xa, R1, R2, R3, R4 and R5 with reference to the process according to the invention. X is halogen. Preferably, X is chloro, bromo or iodo. More preferably, X is chloro or bromo. Even more preferably, X is chloro. Most preferably, X is 4-chloro. Y is selected from the group consisting of bromo, chloro, iodo, CF3SO3-, CH3C6H4SO3- and CH3SO3-. Preferably, Y is selected from the group consisting of bromo, chloro and iodo. More preferably, Y is bromo or chloro. Even more preferably, Y is chloro. Z is NH or O. In one embodiment Z is NH. In another embodiment Z is O. R1 is Ci-Cealkyl. Preferably, R1 is selected from the group consisting of methyl, ethyl, / so-propyl, isobutyl and f-butyl. More preferably, R1 is selected from the group consisting of methyl, ethyl, and f-butyl. Even more preferably, R1 is methyl orf-butyl. Most preferably, R1 is methyl. R2 is selected from the group consisting of hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, C3-Cecycloalkyl, Cs-CecycloalkylCi-Csalkyl-, Cs-Cecycloalkenyl, Cs-CecycloalkenylCi-Csalkyl-, phenyl, naphthalenyl, heterocyclyl, heteroaryl, heterodiaryl, phenylCi-Csalkyl-, heterocyclylCi-Csalkyl-, heteroarylCi-Csalkyl- and heterodiarylCi-Csalkyl- wherein said Cs-Cecycloalkyl, Cs-CecycloalkylCi-Csalkyl-, Cs-Cecycloalkenyl, Cs-CecycloalkenylCi-Csalkyl-, phenyl, naphthalenyl, heterocyclyl, heteroaryl, heterodiaryl, phenylCi-Csalkyl-, heterocyclylCi-Csalkyl-, heteroarylCi-Csalkyl- or heterodiarylCi-Csalkyl- are optionally substituted where feasible by 1,2 or 3 R4 substituents, which may be the same or different, and wherein said heterocyclyl is a 3- to 6- membered non-aromatic ring which comprises 1 or 2 heteroatoms individually selected from nitrogen, oxygen and sulfur, and said heteroaryl is a 5-or 6-membered monocyclic aromatic ring which comprises 1, 2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur, and said heterodiaryl is a 9 or 10-membered aromatic fused bicyclic ring radical which comprises 1,2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur. Preferably, R2 is selected from the group consisting of hydrogen, Ci-Cealkyl, phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl and quinolinylmethyl wherein said phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl or quinolinylmethyl are optionally substituted where feasible by 1,2 or 3 R4 substituents, which may be the same or different. More preferably, R2 is selected from the group consisting of hydrogen, phenyl, pyrrolyl, benzyl and phenylethyl, wherein said phenyl, pyrrolyl, benzyl or phenylethyl are optionally substituted where feasible by 1,2 or 3 R4 substituents, which may be the same or different. R3 is selected from the group consisting of hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, C3-Cecycloalkyl, Cs-CecycloalkylCi-Csalkyl-, Cs-Cecycloalkenyl, Cs-CecycloalkenylCi-Csalkyl-, phenyl, naphthalenyl, heterocyclyl, heteroaryl, heterodiaryl, phenylCi-Csalkyl-, heterocyclylCi-Csalkyl-, heteroarylCi-Csalkyl- and heterodiarylCi-Csalkyl- wherein said Cs-Cecycloalkyl, Cs-CecycloalkylCi-Csalkyl-, Cs-Cecycloalkenyl, Cs-CecycloalkenylCi-Csalkyl-, phenyl, naphthalenyl, heterocyclyl, heteroaryl, heterodiaryl, phenylCi-Csalkyl-, heterocyclylCi-Csalkyl-, heteroarylCi-Csalkyl- or heterodiarylCi-Csalkyl- are optionally substituted where feasible by 1,2 or 3 R4 substituents, which may be the same or different, and wherein said heterocyclyl is a 3- to 6- membered non-aromatic ring which comprises 1 or 2 heteroatoms individually selected from nitrogen, oxygen and sulfur, and said heteroaryl is a 5-or 6-membered monocyclic aromatic ring which comprises 1, 2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur, and said heterodiaryl is a 9 or 10-membered aromatic fused bicyclic ring radical which comprises 1,2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur. Preferably, R3 is selected from the group consisting of hydrogen, Ci-Cealkyl, phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl and quinolinylmethyl 9 wherein said phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl or quinolinylmethyl are optionally substituted where feasible by 1,2 or 3 R4 substituents, which may be the same or different. More preferably, R3 is selected from the group consisting of phenyl, pyrrolyl, benzyl and phenylethyl, wherein said phenyl, pyrrolyl, benzyl or phenylethyl are optionally substituted where feasible by 1,2 or 3 R4 substituents, which may be the same or different. each R4 is independently selected from the group consisting of halogen, nitro, cyano, -OH, -C(O)OH, N-Ci-C4alkylamino, N,N-diCi-C4alkylamino, Ci-C4alkylcarbonyl, Ci-C4alkoxycarbonyl, Ci-C4alkylcarbonyloxy, N-Ci-C4alkylaminocarbonyl, N,N-diCi-C4alkylaminocarbonyl, Ci-C4alkyl, Ci-C4alkoxy, Ci-C4haloalkyl, Ci-C4haloalkoxy, phenyl and phenoxy. Preferably, each R4 is independently selected from the group consisting of bromo, chloro, fluoro, nitro, -OH, -C(O)OH, dimethylamino, diethylamino, methoxycarbonyl, methyl, ethyl, / so-propyl, te / Y-butyl, methoxy, / so-propyloxy, trifluoromethyl, phenyl and phenoxy. More preferably, each R4 is independently selected from the group consisting of chloro, methyl, ethyl, / so-propyl, te / Y-butyl and methoxy. G is selected from the group consisting of hydrogen, C2-C6alkenyl, C2-C6alkynyl, Ci-CealkoxyCi-Cealkyl-, -C(O)-R5, -C(O)-Xa-R5 and -S(O)2-R5. Preferably, G is selected from the group consisting of hydrogen, -C(O)-R5, -C(O)-Xa-R5 and -S(O)2-R5. More preferably, G is selected from the group consisting of hydrogen, -C(O)-R5 and -C(O)-Xa-R5. Even more preferably, G is hydrogen or -C(O)-R5. Most preferably, G is -C(O)-R5. Xa is oxygen or sulfur. Preferably, Xa is oxygen. R5 is selected from the group consisting of Ci-Cealkyl, C2-Cealkenyl, phenyl and 4-fluorophenyl. Preferably, R5 is selected from the group consisting of Ci-Cealkyl, C2-Cealkenyl and phenyl. More preferably, R5 is selected from the group consisting of Ci-Cealkyl and C2-Cealkenyl. Even more preferably, R5 is Ci-Cealkyl. Scheme 1 below describes the reactions of the invention in more detail. The substituent definitions are as defined herein. Scheme 1: (IV) (II) Step (a) Imine formation: Compounds of formula (II), (II) wherein X, Y and R1 are as defined herein, can be prepared by reaction of a compound of formula (IV) (IV) wherein X and Y are as defined herein, with a compound of formula (V), R1—NH2 (V) wherein R1 is as defined herein. Typically the process described in step (a) can be carried out as a neat reaction mixture, however it may also be carried out in a solvent, or mixture of solvents, such as but not limited to, methanol, ethanol, propanol, isopropanol, tert-butanol, butanol, 3-methyl-1 -butanol, tetrahydrofuran, 2-methyltetrahydrofuran, te / Y-butylmethylether, tert-amyl methyl ether, cyclopentyl methyl ether, dimethoxymethane, diethoxymethane, dipropoxy methane, 1,3-dioxolane, dimethyl carbonate, dichloromethane, dichloroethane, / V, / V-dimethylformamide, / V, / V-dimethylacetamide, N-methyl pyrrolidone (NMP), acetonitrile, propionitrile, butyronitrile, benzonitrile (or derivative thereof e.g 1,4-dicyanobenzene), toluene, xylene iso-mix, cumene, isopropylbenzene, p-xylene, mesitylene, 1,4-dioxane or sulfolane. Preferably process step (a) is carried out in methanol and / or toluene. Even more preferably, process step (a) is carried out in toluene. The skilled person would appreciate that in process step (a), various methods know to shift the reaction equilibria towards the desired product may be used, including, but not limited to azeotropic removal of the water generated or increasing the number of equivalents of a compound of formula (V). Typically the process described in step (a) can be carried out at a temperature of from 0 °C to 120 °C, preferably, from 20 °C to 85 °C. More preferably, from 20 °C to 70 °C. Scheme 2: Step (b) Ullmann-type Coupling: Compounds of formula (III) (HI) wherein X and R1 are as defined herein, are prepared by reaction a compound of formula (II) (II) wherein Y and R1 are as defined herein, with methanol in the presence of a copper source. Typically the process described in step (b) can be carried out as a neat reaction mixture, however it may also be carried out in a solvent, or mixture of solvents, such as but not limited to, methanol, ethanol, propanol, isopropanol, tert-butanol, butanol, 3-methyl-1 -butanol, tetrahydrofuran, 2-methyltetrahydrofuran, te / Y-butylmethylether, tert-amyl methyl ether, cyclopentyl methyl ether, dimethoxymethane, diethoxymethane, dipropoxy methane, 1,3-dioxolane, dimethyl carbonate, dichloromethane, dichloroethane, / V, / V-dimethylformamide, / V, / V-dimethylacetamide, N-methyl pyrrolidone (NMP), acetonitrile, propionitrile, butyronitrile, benzonitrile (or derivative thereof e.g 1,4-dicyanobenzene), toluene, xylene iso-mix, cumene, isopropylbenzene, p-xylene, mesitylene, 1,4- dioxane or sulfolane. Preferably process step (b) is carried out in methanol, acetonitrile or toluene or mixtures thereof. More preferably, process step (b) is carried out in methanol. The process described in step (b) is carried out in the presence of a copper source. Preferably, the copper source is selected from the group consisting of metallic copper, copper(l) salts and copper(ll) salts. More preferably, the copper source is a copper(l) salt. Even more preferably, the copper source is copper(l) chloride. Typically, the copper source is present in an amount of from 0.01 mol% to 40 mol% based on a compound of formula (II). Preferably, the copper source is present in an amount of from 0.01 mol% to 20 mol% based on a compound of formula (II). More preferably, the copper source is present in an amount of from 0.01 mol% to 5 mol% based on a compound of formula (II). Even more preferably, the copper source is present in an amount of from 0.01 mol% to 1 mol% based on a compound of formula (II). Preferably the process described in step (b) is carried out in the presence of a ligand. More preferably, the ligand is selected from the group consisting of diamines, oxalic acid amides, oxyquinolines, carboxylic acids, oximes and amino sugars. The process described in step (b) may also be carried out in the presence of a polymerisation inhibitior where preferable to prevent undesired polymerisation of the ligand. Such polymerisation inhibitors include, but are not limited to boric acid. In one embodiment of the invention, the ligand is an oxalic acid amide compound of formula (VI), O ’■'W' 0 (VI) wherein, Z is NH or O; R2 is selected from the group consisting of hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, C3-Cecycloalkyl, Cs-CecycloalkylCi-Csalkyl-, Cs-Cecycloalkenyl, Cs-CecycloalkenylCi-Csalkyl-, phenyl, naphthalenyl, heterocyclyl, heteroaryl, heterodiaryl, phenylCi-Csalkyl-, heterocyclylCi-Csalkyl-, heteroarylCi-Csalkyl- and heterodiarylCi-Csalkyl- wherein said Cs-Cecycloalkyl, Cs-CecycloalkylCi-Csalkyl-, Cs-Cecycloalkenyl, Cs-CecycloalkenylCi-Csalkyl-, phenyl, naphthalenyl, heterocyclyl, heteroaryl, heterodiaryl, phenylCi-Csalkyl-, heterocyclylCi-Csalkyl-, heteroarylCi-Csalkyl- or heterodiarylCi-Csalkyl- are optionally substituted where feasible by 1,2 or 3 R4 substituents, which may be the same or different, and wherein said heterocyclyl is a 3- to 6- membered non-aromatic ring which comprises 1 or 2 heteroatoms individually selected from nitrogen, oxygen and sulfur, and said heteroaryl is a 5-or 6-membered monocyclic aromatic ring which comprises 1, 2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur, and said heterodiaryl is a 9 or 10-membered aromatic fused bicyclic ring radical which comprises 1,2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur; R3 is selected from the group consisting of hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, C3-Cecycloalkyl, Cs-CecycloalkylCi-Csalkyl-, Cs-Cecycloalkenyl, Cs-CecycloalkenylCi-Csalkyl-, phenyl, naphthalenyl, heterocyclyl, heteroaryl, heterodiaryl, phenylCi-Csalkyl-, heterocyclylCi-Csalkyl-, heteroarylCi-Csalkyl- and heterodiarylCi-Csalkyl- wherein said Cs-Cecycloalkyl, Cs-CecycloalkylCi-Csalkyl-, Cs-Cecycloalkenyl, Cs-CecycloalkenylCi-Csalkyl-, phenyl, naphthalenyl, heterocyclyl, heteroaryl, heterodiaryl, phenylCi-Csalkyl-, heterocyclylCi-Csalkyl-, heteroarylCi-Csalkyl- or heterodiarylCi-Csalkyl- are optionally substituted where feasible by 1,2 or 3 R4 substituents, which may be the same or different, and wherein said heterocyclyl is a 3- to 6- membered non-aromatic ring which comprises 1 or 2 heteroatoms individually selected from nitrogen, oxygen and sulfur, and said heteroaryl is a 5-or 6-membered monocyclic aromatic ring which comprises 1, 2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur, and said heterodiaryl is a 9 or 10-membered aromatic fused bicyclic ring radical which comprises 1,2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur; and each R4 is independently selected from the group consisting of halogen, nitro, cyano, -OH, -C(O)OH, N-Ci-C4alkylamino, N,N-diCi-C4alkylamino, Ci-C4alkylcarbonyl, Ci-C4alkoxycarbonyl, C1-C4alkylcarbonyloxy, N-Ci-C4alkylaminocarbonyl, N,N-diCi-C4alkylaminocarbonyl, Ci-C4alkyl, C1-C4alkoxy, Ci-C4haloalkyl, Ci-C4haloalkoxy, phenyl and phenoxy. Preferably, in the compound of formula (VI), Z is NH or O; R2 is selected from the group consisting of hydrogen, Ci-Cealkyl, phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl and quinolinylmethyl wherein said phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl or quinolinylmethyl are optionally substituted where feasible by 1,2 or 3 R4 substituents, which may be the same or different; R3 is selected from the group consisting of hydrogen, Ci-Cealkyl, phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl and quinolinylmethyl wherein said phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl or quinolinylmethyl are optionally substituted where feasible by 1,2 or 3 R4 substituents, which may be the same or different; and each R4 is independently selected from the group consisting of bromo, chloro, fluoro, nitro, -OH, -C(O)OH, dimethylamino, diethylamino, methoxycarbonyl, methyl, ethyl, / so-propyl, te / Y-butyl, methoxy, / so-propyloxy, trifluoromethyl, phenyl and phenoxy. More preferably, in the compound of formula (VI), Z is NH or O; R2 is selected from the group consisting of hydrogen, phenyl, pyrrolyl, benzyl and phenylethyl, wherein said phenyl, pyrrolyl, benzyl or phenylethyl are optionally substituted where feasible by 1, 2 or 3 R4 substituents, which may be the same or different; R3 is selected from the group consisting of phenyl, pyrrolyl, benzyl and phenylethyl, wherein said phenyl, pyrrolyl, benzyl or phenylethyl are optionally substituted where feasible by 1, 2 or 3 R4 substituents, which may be the same or different; and each R4 is independently selected from the group consisting of chloro, methyl, ethyl, / so-propyl, te / Y-butyl and methoxy. Even more preferably, the compound of formula (VI) is selected from the group consisting of 2-(2-methylanilino)-2-oxo-acetic acid, 2-(2,6-diisopropylanilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethoxyanilino)acetic acid, 2-(2-ethyl-6-methyl-anilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethylanilino)acetic acid, 2-(2,6-dimethylanilino)-2-oxo-acetic acid, 2-(3,5-dimethylanilino)-2-oxo-acetic acid, 2-(2-tert-butylanilino)-2-oxo-acetic acid, 2-anilino-2-oxo-acetic acid, 2-(4-chloroanilino)-2-oxo-acetic acid, 2-(4-methoxyanilino)-2-oxo-acetic acid, 2-(4-methylanilino)-2-oxo-acetic acid, N,N'-bis(2,6-dimethylphenyl)oxamide, N,N'-bis(2,4,6-trimethoxyphenyl)oxamide, N,N'-bis(2,5-dimethylpyrrol-1-yl)oxalamide, N,N'-dibenzyloxamide, N,N'-bis(2-phenylethyl)oxamide and N,N'-bis(2-pyridylmethyl)oxamide. Even more preferably still, the compound of formula (VI) is selected from the group consisting of 2-(2-methylanilino)-2-oxo-acetic acid, 2-(2,6-diisopropylanilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethoxyanilino)acetic acid, 2-(2-ethyl-6-methyl-anilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethylanilino)acetic acid, 2-(2,6-dimethylanilino)-2-oxo-acetic acid, 2-(3,5-dimethylanilino)-2-oxo-acetic acid, 2-(2-tert-butylanilino)-2-oxo-acetic acid, 2-anilino-2-oxo-acetic acid, 2-(4-chloroanilino)-2-oxo-acetic acid, 2-(4-methoxyanilino)-2-oxo-acetic acid and 2-(4-methylanilino)-2-oxo-acetic acid. Yet even more preferably still, the compound of formula (VI) is selected from the group consisting of 2-(2-methylanilino)-2-oxo-acetic acid, 2-(2,6-diisopropylanilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethoxyanilino)acetic acid, 2-(2-ethyl-6-methyl-anilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethylanilino)acetic acid, 2-(2,6-dimethylanilino)-2-oxo-acetic acid, 2-(3,5-dimethylanilino)-2-oxo-acetic acid and 2-(2-tert-butylanilino)-2-oxo-acetic acid. In another preferred embodiment of the invention the ligand is selected from the group consisting of trans-N,N'-dimethylcyclohexan-1,2-diamine, tetramethylethylenediamine, 2-(2-methylanilino)-2-oxo-acetic acid, 2-(2,6-diisopropylanilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethoxyanilino)acetic acid, 2-(2-ethyl-6-methyl-anilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethylanilino)acetic acid, 2-(2,6-dimethylanilino)-2-oxo-acetic acid, 2-(3,5-dimethylanilino)-2-oxo-acetic acid, 2-(2-tert-butylanilino)-2-oxo-acetic acid, 2-anilino-2-oxo-acetic acid, 2-(4-chloroanilino)-2-oxo-acetic acid, 2-(4-methoxyanilino)-2-oxo-acetic acid, 2-(4-methylanilino)-2-oxo-acetic acid, N,N'-bis(2,6-dimethylphenyl)oxamide, N,N'-bis(2,4,6-trimethoxyphenyl)oxamide, N,N'-bis(2,5-dimethylpyrrol-1-yl)oxalamide, N,N'-dibenzyloxamide, N,N'-bis(2-phenylethyl)oxamide, N,N'-bis(2-pyridylmethyl)oxamide, 8- hydroxyquinoline, 6-methylquinolin-8-ol, 5-chloro-8-hydroxyquinoline, pyrrole 2-carboxylic acid, trans-4-hydroxy-L-proline, proline, dimethylglyoxime and D-glucosamine. Preferably, the ligand is selected from the group consisting of trans-N,N'-dimethylcyclohexan-1,2-diamine, 2-(2-methylanilino)-2-oxo-acetic acid, 2-(2,6-diisopropylanilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethoxyanilino)acetic acid, 2-(2-ethyl-6-methyl-anilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethylanilino)acetic acid and 2-(2,6-dimethylanilino)-2-oxo-acetic acid. Typically, the ligand is present in an amount of from 0.01 mol% to 40 mol% based on a compound of formula (II). Preferably, the ligand is present in an amount of from 0.01 mol% to 20 mol% based on a compound of formula (II). More preferably, the ligand is present in an amount of from 0.01 mol% to 5 mol% based on a compound of formula (II). Even more preferably, the ligand is present in an amount of from 0.01 mol% to 1 mol% based on a compound of formula (II). Typically, the process described in step (b) is carried out in the presence of a base. Preferably, the base is selected from the group consisting of alkali metal carbonates, alkali metal phosphates, alkali metal hydroxides and alkali metal alkoxides. More preferably, the base is selected from the group consisting of caesium carbonate, potassium carbonate, tripotassium phosphate, sodium hydroxide and sodium methoxide. Even more preferably, the base is potassium carbonate, tripotassium phosphate or sodium methoxide. The skilled person would appreciate that the base used in step (b) may be added in any number of alternative ways, such as, but not limited to, a single charge, multiple charges over a period of time and / or continuously over a period of time. Preferably, the base is added continuously over a period of time. In one embodiment process step (b) is carried out in the presence of a base, wherein the base is sodium methoxide. Preferably, the methoxide is added in multiple charges over a period of time and / or continuously over a period of time. More preferably, the methoxide is added continuously over a period of time. Even more preferably, the methoxide is added continuously over a period of from 1 to 3 h (The skilled person will appreciate that the period of time over which the methoxide is added will be dependent upon a number of different factors, such as, the scale of the reaction, the wt% concentration of methoxide and / or the wt% concetration of the starting reagents). Typically, this step can be carried out at a temperature of from 50 °C to 120 °C, preferably, from 60 °C to 120 °C, more preferably from 60 °C to 90 °C, even more preferably from 75 °C to 90 °C. Scheme 3: Compounds of formula (I), (I) wherein X is as defined herein, are prepared by hydrolysis of a compound of formula (III), (HI) wherein X and R1 are as defined herein. The hydrolysis can be performed using methods known to a person skilled in the art. The hydrolysis is typically performed using suitable conditions, including, but not limited to basic conditions (such as aqueous sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate), or acidic conditions (such as aqueous sulfuric acid or hydrochloric acid). Preferably, the hydrolysis is performed under acidic conditions. More preferably, the hydrolysis is performed with hydrochloric acid. Typically the process described in step (c) is carried out in the absence of additional solvent, or in the presence of a solvent, or mixture of solvents, such as but not limited to, water, acetic acid, propionic acid, diethylether, te / Y-butylmethylether, tert-amyl methyl ether, cyclopentyl methyl ether, dimethoxymethane, diethoxymethane, dipropoxy methane, dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, butylene carbonate, diphenyl carbonate, glycerol carbonate, dichloromethane, dichloroethane, cyclohexane, n-hexane, methyl cyclohexane, heptane, chlorobenzene, 1,2-dichlorobenzene, methyl acetate, ethyl acetate, isopropyl acetate, propyl acetate, t-butyl acetate, butyl acetate, toluene, xylene iso-mix, cumene, isopropylbenzene, p-xylene, mesitylene, nitrobenzene, o-xylene, m-xylene or ethylbenzene,. Preferably the process described in step (c) is carried out in the absence of additional solvent, or in the presence of a solvent, or mixture of solvents, selected from the group consisting of water, cyclohexane, n-hexane, methyl cyclohexane and heptane. Preferably the process described in step (c) is carried out in the absence of additional solvent, or in the presence of a solvent, or mixture of solvents, selected from water and / or methyl cyclohexane. The skilled person would appreciate that the choice of solvent for the process described in step (c) will depend upon whether basic or acidic coniditons are used. Typically this step can be carried out at a temperature of from -20 °C to 120 °C, preferably, from -10 °C to 80 °C, more preferably from 0 °C to 50 °C, even more preferably from 10 °C to 30 °C. The skilled person would appreciate that the temperature of the process according to the invention can vary in each of steps (a), (b) and (c). Furthermore, this variability in temperature may also reflect the choice of solvent or diluent, for example on its boiling point and / or its effectiveness for promoting the desired reaction, and on the rate at which the reaction is to be carried out. The process of the invention can be carried out at any reasonable pressure depending on the choice of solvent and reaction temperature. Preferably, the reaction may be carried out at a pressure of from 0.01 to 10 Bar, more preferably from 0.5 to 5 Bar, even more preferably from 0.8 to 2 Bar (for example at ambient pressure). Preferably, the process of the present invention is carried out under an inert atmosphere, such as nitrogen or argon. The skilled person would appreciate that process steps (a), (b) and (c) can be carried out in separate process steps, wherein the intermediate compounds can be isolated at each stage. Alternatively, the process steps (a), (b) and (c) can be carried out in a telescoped procedure wherein the intermediate compounds produced are not isolated. Thus, it is possible for the process of the present invention to be conducted in a batch wise, semi-batch wise or continuous fashion. The skilled person would appreciate that steps (a), (b) and (c) could equally be represented in a single scheme, see scheme 4 below. Scheme 4: In a preferred embodiment of the invention there is provided a process forthe preparation of a compound of formula (la), X (la) wherein, X is halogen (preferably, X is chloro, bromo or iodo, more preferably, X is chloro or bromo, even more preferably, X is chloro); 10 comprising the steps of; (i) reacting a compound of formula (Ila); X (Ha) wherein Y is selected from the group consisting of bromo, chloro, iodo, CF3SO3-, CH3C6H4SO3- and 15 CH3SO3- (preferably, Y is selected from the group consisting of bromo, chloro and iodo, more preferably, Y is bromo or chloro, even more preferably, Y is chloro), R1 is selected from the group consisting of methyl, ethyl, / so-propyl, / so-butyl and / -butyl (preferably, R1 is selected from the group consisting of methyl, ethyl, and f-butyl, more preferably, R1 is methyl or f-butyl, most preferably, R1 is methyl) and X is as defined above for a compound of formula (la); with methanol in the presence of a copper source and a ligand to give a compound of formula (Illa); (IHa) wherein X is as defined above for a compound of formula (la) and R1 is as defined above for a compound of formula (Ila); and wherein the ligand is an oxalic acid amide compound of formula (VI), O 0 (VI) wherein, Z is NH or O; R2 is selected from the group consisting of hydrogen, Ci-Cealkyl, phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl and quinolinylmethyl wherein said phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl or quinolinylmethyl are optionally substituted where feasible by 1,2 or 3 R4 substituents, which may be the same or different; R3 is selected from the group consisting of hydrogen, Ci-Cealkyl, phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl and quinolinylmethyl wherein said phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl or quinolinylmethyl are optionally substituted where feasible by 1,2 or 3 R4 substituents, which may be the same or different; and each R4 is independently selected from the group consisting of bromo, chloro, fluoro, nitro, -OH, -C(O)OH, dimethylamino, diethylamino, methoxycarbonyl, methyl, ethyl, / so-propyl, te / Y-butyl, methoxy, / so-propyloxy, trifluoromethyl, phenyl and phenoxy; or the ligand is selected from the group consisting of trans-N,N'-dimethylcyclohexan-1,2-diamine, tetramethylethylenediamine, 8-hydroxyquinoline, 6-methylquinolin-8-ol, 5-chloro-8-hydroxyquinoline, pyrrole 2-carboxylic acid, trans-4-hydroxy-L-proline, proline, dimethylglyoxime and D-glucosamine; and, (ii) hydrolysis to a compound of formula (la). In a more preferred embodiment of the invention there is provided a process for the preparation of a compound of formula (la-l), Cl (la-l) comprising the steps of; (i) reacting a compound of formula (I la-l); with methanol in the presence of a copper(l) salt (preferably, copper(l) chloride) and a ligand to give a compound of formula (llla-l); wherein, the ligand is an oxalic acid amide compound selected from the group consisting of 2-(2-methylanilino)-2-oxo-acetic acid, 2-(2,6-diisopropylanilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethoxyanilino)acetic acid, 2-(2-ethyl-6-methyl-anilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethylanilino)acetic acid, 2-(2,6-dimethylanilino)-2-oxo-acetic acid, 2-(3,5-dimethylanilino)-2-oxo-acetic acid, 2-(2-tert-butylanilino)-2- WO 2024 / 089225                                                 PCT / EP2023 / 080025 21 oxo-acetic acid, 2-anilino-2-oxo-acetic acid, 2-(4-chloroanilino)-2-oxo-acetic acid, 2-(4-methoxyanilino)-2-oxo-acetic acid, 2-(4-methylanilino)-2-oxo-acetic acid, N,N'-bis(2,6-dimethylphenyl)oxamide, N,N'-bis(2,4,6-trimethoxyphenyl)oxamide, N,N'-bis(2,5-dimethylpyrrol-1-yl)oxalamide, N,N'-dibenzyloxamide, N,N'-bis(2-phenylethyl)oxamide and N,N'-bis(2-pyridylmethyl)oxamide (preferably, 2-(2-methylanilino)-2-oxo-acetic acid, 2-(2,6-diisopropylanilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethoxyanilino)acetic acid, 2-(2-ethyl-6-methyl-anilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethylanilino)acetic acid and 2-(2,6-dimethylanilino)-2-oxo-acetic acid); or the ligand is trans-N,N'-dimethylcyclohexan-1,2-diamine; and, (ii) hydrolysis to a compound of formula (la-l). In another preferred embodiment of the invention there is provided a process for the preparation of a compound of formula (la), O. X (la) wherein, X is halogen (preferably, X is chloro, bromo or iodo, more preferably, X is chloro or bromo, even more preferably, X is chloro); comprising the steps of; (a) reacting a compound of formula (IVa), X (IVa) wherein Y is selected from the group consisting of bromo, chloro, iodo, CF3SO3-, CH3C6H4SO3- and CH3SO3- (preferably, Y is selected from the group consisting of bromo, chloro and iodo, more preferably, Y is bromo or chloro, even more preferably, Y is chloro), and X is as defined above, for a compound of formula (la), with a compound of formula (V), R1—NH2 (V) wherein R1 is is selected from the group consisting of methyl, ethyl, / so-propyl, / so-butyl and / -butyl (preferably, R1 is selected from the group consisting of methyl, ethyl, and f-butyl, more preferably, R1 is methyl orf-butyl, most preferably, R1 is methyl), to give a compound of formula (Ila), r1 / NS X (Ila); and (b) reacting a compound of formula (Ila); wherein Y is as defined above for a compound of formula (IVa), R1 is as defined above for a compound of formula (V) and X is as defined above fora compound of formula (la); with methanol in the presence of a copper source and a ligand to give a compound of formula (Illa); r1 / N^ X (IHa) wherein X is as defined above for a compound of formula (la) and R1 is as defined above for a compound of formula (Ila); and wherein the ligand is an oxalic acid amide compound of formula (VI), O wherein, Z is NH or O; R2 is selected from the group consisting of hydrogen, Ci-Cealkyl, phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl and quinolinylmethyl wherein said phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl or quinolinylmethyl are optionally substituted where feasible by 1,2 or 3 R4 substituents, which may be the same or different; R3 is selected from the group consisting of hydrogen, Ci-Cealkyl, phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl and quinolinylmethyl wherein said phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl or quinolinylmethyl are optionally substituted where feasible by 1,2 or 3 R4 substituents, which may be the same or different; and each R4 is independently selected from the group consisting of bromo, chloro, fluoro, nitro, -OH, -C(O)OH, dimethylamino, diethylamino, methoxycarbonyl, methyl, ethyl, / so-propyl, te / Y-butyl, methoxy, / so-propyloxy, trifluoromethyl, phenyl and phenoxy; or the ligand is selected from the group consisting of trans-N,N'-dimethylcyclohexan-1,2-diamine, tetramethylethylenediamine, 8-hydroxyquinoline, 6-methylquinolin-8-ol, 5-chloro-8-hydroxyquinoline, pyrrole 2-carboxylic acid, trans-4-hydroxy-L-proline, proline, dimethylglyoxime and D-glucosamine; and, (c) hydrolysis to a compound of formula (la). In another more preferred embodiment of the invention there is provided a process for the preparation of a compound of formula (la-l), (la-l) comprising the steps of; (a) reacting a compound of formula (IVa-l), Cl (IVa-l) with a compound of formula (V-l), CH3—nh2 (V-l) to give a compound of formula (Ila), Cl (Ha-I); and (b) reacting a compound of formula (lla-l); Cl (lla-l) with methanol in the presence of a copper(l) salt (preferably, copper(l) chloride) and a ligand to give a compound of formula (llla-l); Cl (llla-l) wherein, the ligand is an oxalic acid amide compound selected from the group consisting of 2-(2-methylanilino)-2-oxo-acetic acid, 2-(2,6-diisopropylanilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethoxyanilino)acetic acid, 2-(2-ethyl-6-methyl-anilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethylanilino)acetic acid, 2-(2,6-dimethylanilino)-2-oxo-acetic acid, 2-(3,5-dimethylanilino)-2-oxo-acetic acid, 2-(2-tert-butylanilino)-2-oxo-acetic acid, 2-anilino-2-oxo-acetic acid, 2-(4-chloroanilino)-2-oxo-acetic acid, 2-(4-methoxyanilino)-2-oxo-acetic acid, 2-(4-methylanilino)-2-oxo-acetic acid, N,N'-bis(2,6-dimethylphenyl)oxamide, N,N'-bis(2,4,6-trimethoxyphenyl)oxamide, N,N'-bis(2,5-dimethylpyrrol-1-yl)oxalamide, N,N'-dibenzyloxamide, N,N'-bis(2-phenylethyl)oxamide and N,N'-bis(2-pyridylmethyl)oxamide (preferably, 2-(2-methylanilino)-2-oxo-acetic acid, 2-(2,6-diisopropylanilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethoxyanilino)acetic acid, 2-(2-ethyl-6-methyl-anilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethylanilino)acetic acid and 2-(2,6-dimethylanilino)-2-oxo-acetic acid); or the ligand is trans-N,N'-dimethylcyclohexan-1,2-diamine; and, (c) hydrolysis to a compound of formula (la-l). In an embodiment of the invention there is provided a compound of formula (III), (HI) wherein, X is halogen (preferably, X is chloro, bromo or iodo, more preferably, X is chloro or bromo, even more preferably, X is chloro, most preferably, X is 4-chloro), and R1 is O-Cealkyl (preferably, R1 is selected from the group consisting of methyl, ethyl, / so-propyl, / so-butyl and / -butyl, more preferably, R1 is selected from the group consisting of methyl, ethyl, and t-butyl, even more preferably, R1 is methyl orf-butyl, most preferably, R1 is methyl); provided that the compound of formula (III) is not a compound selected from the group consisting of N-butyl-1 -(4-chloro-2-methoxy-phenyl)methanimine,                   N-te rt- butyl-1 -(4-fluoro-2-methoxy- phenyl)methanimine, 1-(5-bromo-2-methoxy-phenyl)-N-methyl-methanimine, N-tert-butyl-1-(5-fluoro-2- methoxy-phenyl)methanimine, N-tert-butyl-1-(5-chloro-2-methoxy-phenyl)methanimine and N-tert-butyl-1-(5-bromo-2-methoxy-phenyl)methanimine. In a preferred embodiment there is provided a compound of formula (llla-l) (1-(4-chloro-2-methoxy-phenyl)-N-methyl-methanimine), Cl (llla-l). In a further embodiment of the invention the process further comprises converting a compound of formula (I) to a compound of formula (VII), (VII) wherein G is selected from the group consisting of hydrogen, C2-Cealkenyl, C2-Cealkynyl, Ci-C3alkoxyCi-C3alkyl-, -C(O)-R5, -C(O)-Xa-R5 and -S(O)2-R5; Xa is oxygen or sulfur; and R5 is selected from the group consisting of Ci-Cealkyl, C2-Cealkenyl, phenyl and 4-fluorophenyl. In a preferred embodiment of the invention, the process further comprises converting a compound of formula (I) to a compound of formula (VII), wherein G is selected from the group consisting of hydrogen, C2-C6alkenyl, C2-C6alkynyl, Ci-C3alkoxyCi-C3alkyl-, -C(O)-R5, -C(O)-Xa-R5 and -S(O)2-R5; Xa is oxygen or sulfur; and R5 is selected from the group consisting of Ci-Cealkyl, C2-Cealkenyl, phenyl and 4-fluorophenyl; wherein the process further comprises the steps as described on page 54 of WO 2015 / 197468. Examples: The following examples further illustrate, but do not limit the invention. Those skilled in the art will promptly recognise appropriate variations from the procedures both as to the reactants and as to the reaction conditions and techniques. The following abbreviations are used: s = singlet; brs = broad singlet; d = doublet; dd = double doublet; dt = double triplet; t = triplet, tt = triple triplet, q = quartet, quin = quintuplet, sept = septet; m = multiplet; GC = gas chromatography, RT = retention time, Ti = internal temperature, MH+ = molecular mass of the molecular cation, M = molar, Q1HNMR = quantitative 1HNMR, RT = room temperature, UFLC = Ultrafast liquid chromatography. 1H NMR spectra are recorded at 400 MHz unless indicated otherwise and chemical shifts are recorded in ppm. Some chemical yields have been calculated precisely using quantitative 1H NMR and 1,3,5-trimethoxybenzene as an internal standard. Where the chemical yield is based on quantative 1H NMR the nature of any relevant counterion is assumed based on the reaction conditions used, however, the skilled person would appreciate that the crude reaction mixture may also include (but are not limited to) other counter ions such as chloride, bromide, iodide, fluoride, hydrogen sulfate, mesylate, oxalate, tartrate and trifluoroacetate. Example 1: Ligand screening procedure Cl Cl Procedure: Ligands (0.10 mmol, 0.20 eq.) were weighed into 4 ml Supelco vials under air. Copper(l) chloride (9.9 mg, 0.10 mmol, 0.20 eq.) and potassium carbonate (76.8 mg, 0.55 mmol, 1.1 eq.) weighed into second 4 ml vial under Argon, stirrers added. A stock solution of 1-(2,4-dichlorophenyl)-N-methyl-methanimine (ca. 12.5 mmol) in dried, degassed methanol (25 ml) was prepared under Argon and 1 ml (ca 0.5 mmol) 5 transferred to each of the 24 vials containing ligand. Ligand and 1-(2,4-dichlorophenyl)-N-methyl-methanimine solutions were transferred to vials containing CuCI and potassium carbonate. The reaction block was sealed and transferred to heater / tumble stirrer. Block was heated to 75 °C for 4 hours. 1 ml of standard stock solution (ca 0.5 g of tetramethylbenzene in 50 ml of DCM) was added to each of the reaction vessels. 200 pL was aliquoted from each reaction into 1300 pL DCM and then filtered using a 10 CHROMAFIL 45 pm syringe filter. The samples were run on GCMS (Chemical Ionisation, 70-320 °C at 40 °C / min, column; Phenomenex ZB-5ms, 15 m, diam 0.25 mm, 0.25 pm). Tetramethylbenzene was used as internal standard to calculate yield and selectivity. Conversion of starting material and selectivity for the desired product were calculated from the GC results. The results are shown below in Table 1. 15 Table 1. Results of ligand screening. No. Ligand Conversion [%] Selectivity [%] 1 2-(2,4,6-trimethoxyanilino)-2-oxo-acetic acid 97% 96% 2 2-((2,6-dimethylphenyl)amino)-2-oxo-acetic acid 96% 81% 3 f / 'ans-N.N'-dimethylcyclohexan-l ,2-diamine 95% 77% 4 2-(2,4,6-trimethylanilino)2-oxoacetic acid 94% 94% 5 2-(2-ethyl-6-methyl-anilino)-2-oxo-acetic acid 93% 95% 6 2-(2-methylanilino)-2-oxo-acetic acid 89% 93% 7 2-(2,6-diisopropylanilino)-2-oxo-acetic acid 87% 97% 8 / V, / V'-bis(2-pyridylmethyl)oxamide 86% 32% 9 / V, / V'-bis(2,6-dimethylphenyl)oxamide 85% 78% 10 2-(3,5-dimethylanilino)-2-oxo-acetic acid 82% 100% 11 / V, / V'-bis(2,4,6-trimethoxyphenyl)oxamide 81% 78% 12 / V, / V'-bis(2,5-dimethylpyrrol-1-yl)oxamide 80% 76% 13 D-glucosamine 74% 25% 14 2-(2-tert-butylanilino)-2-oxo-acetic acid 74% 100% 15 dimethylglyoxime 71% 49% 16 2-anilino-2-oxo-acetic acid 59% 100% 17 8-hydroxyquinoline 55% 78% 18 N, N -dibenzyloxamide 53% 87% 19 2-(4-chloroanilino)-2-oxo-acetic acid 53% 100% 20 pyrrole 2-carboxylic acid 48% 88% 21 2-(4-methoxyanilino)-2-oxo-acetic acid 42% 100% 22 6-methylquinolin-8-ol 42% 92% 23 / V, / V'-bis(2-phenylethyl)oxamide 38% 94% 24 2-(4-methylanilino)-2-oxo-acetic acid 35% 100% 25 / V, / V'-Dimethylethane-1,2-diamine 31% 37% 26 L-ascorbic acid 28% 25% 27 5-chloro-8-hydroxyquinoline 27% 54% 28 pentane-2,4-dione 25% 3% 29 2-acetyl-cyclohexanone 23% 6% 30 trans-4-hydroxy-L-proline 22% 56% 31 2-isobutyrylhexanone 20% 23% 32 2-ethoxycarbonyl-cyclohexanone 20% 9% 33 2-[(methylamino)methyl]pyridine 20% 42% 34 8-Quinolinol N-oxide 18% 39% 35 DL-proline 18% 45% 36 8-methoxyquinoline 15% 26% 37 / V, / V'-dimethyl-1,2-phenylenediamine 15% 28% 38 / V-methylg lycine 13% 9% 39 4,7-dimethoxy-1,10-phenanthroline 13% 35% 40 no ligand 12% 6% 41 2-(2-naphthylamino)-2-oxo-acetic acid 12% 86% 42 2-(cyclopropylamino)-2-oxo-acetic acid 11% 86% 43 2-picolinic acid 10% 6% 44 dimethylglycine 9% 7% 45 oxamic acid 8% 66% 46 furoic acid 8% 0% 47 2-thiophenecarboxylic acid 7% 0% 48 2-(methylamino)-2-oxo-acetic acid 5% 43% 49 4-imidazole carboxylic acid 4% 45% 50 6-oxo-1 H-pyridine-2-carboxylic acid 2% 40% 51 2,9-dimethyl-1,10-phenanthroline 2% 41% 52 1,4-dihydroquinoxaline-2,3-dione 2% 50% 53 / V, / V, A / ', / V-tetramethylethane-1,2-diamine 1% 78% Table A. Ligand Structures. Ligand IUPAC Name Ligand Structure 2-(2,4,6-trimethoxyanilino)-2-oxo-acetic acid 0 / ° 2-((2,6-dimethylphenyl)amino)-2-oxo-acetic acid HO^.0 O^^NH / / 'ans-N,N'-dimethylcyclohexan-1,2-diamine H H 2-(2,4,6-trimethylanilino)2-oxoacetic acid OH I 2-(2-ethyl-6-methyl-anilino)-2-oxo-acetic acid °%^0H Ligand IUPAC Name Ligand Structure 2-(2-methylanilino)-2-oxo-acetic acid OH ° NH 2-(2,6-diisopropylanilino)-2-oxo-acetic acid HC C 3 JH 1 / V, / V'-bis(2-pyridylmethyl)oxamide N HN^ .NH W,W'-bis(2,6- dimethylphenyl)oxamide HN ^NH Ligand IUPAC Name Ligand Structure 2-(3,5-dimetiiylanilino)-2-oxo-acetic acid / V, / V'-bis(2,4,6- trimethoxyphenyl)oxamide a c  —* / —\  ° —O   z—x I \ I fl—Z    ° o' / =\ O-- o / V, / V'-bis(2,5-dimethylpyrrol-1-yl)oxamide N HN^.0 O^^NH N D-glucosamine OH OH O HO JI        JL OH NH2 2-(2-tert-butylanilino)-2-oxo-acetic acid OH O. ^0 NH Ligand IUPAC Name Ligand Structure dimethylglyoxime __ N—OH HO—N 2-anilino-2-oxo-acetic acid OH O. Js. ^O NH 8-hydroxyquinoline OH / V, / V'-dibenzyloxamide °\ HN^ NH ^O 2-(4-chloroanilino)-2-oxo-acetic acid 01^ ( OH ^o NH pyrrole 2-carboxylic acid H     0 Ligand IUPAC Name Ligand Structure 2-(4-methoxyanilino)-2-oxo-acetic acid OH O. NH 6-methylquinolin-8-ol OH / V, / V'-bis(2-phenylethyl)oxamide 0 2-(4-methylanilino)-2-oxo-acetic acid OH O. / V, / V'-Dimethylethane-1,2-diamine H N-- --N H L-ascorbic acid HO    OH HO 5-chloro-8-hydroxyquinoline OH Cl Ligand IUPAC Name Ligand Structure pentane-2,4-dione o 2-acetyl-cyclohexanone / 0 trans-4-hydroxy-L-proline HO /  \    OH H     O 2-isobutyrylhexanone \-O 2=° 2-ethoxycarbonyl-cyclohexanone 0 0 ) 2-[(methylamino)methyl]pyridine 1 HN^ 8-Quinolinol N-oxide o OH f JI OQ Ligand IUPAC Name Ligand Structure DL-proline H    ?H N       / 8-methoxyquinoline o^ N / V, / V'-dimethyl-1,2-phenylenediamine NH H / V-methylg lycine H -\ OH 4,7-dimethoxy-1,10-phenanthroline O Z=\   O- N   N= / 2-(2-naphthylamino)-2-oxo-acetic acid OH 0. Js. ^0 / NH 2-(cyclopropylamino)-2-oxo-acetic acid L— o Ligand IUPAC Name Ligand Structure 2-picolinic acid OH N. Jx. Qj° dimethylglycine OH --N oxamic acid O \—OH h2n— / o furoic acid OH O      / 2-thiophenecarboxylic acid o s 2-(methylamino)-2-oxo-acetic acid 0^ OH --N     0 H 4-imidazole carboxylic acid HO H 6-oxo-1 H-pyridine-2-carboxylic acid OH I        H U.    N. .O Ligand IUPAC Name Ligand Structure 2,9-dimethyl-1,10-phenanthroline 1,4-dihydroquinoxaline-2,3-dione H CXI H / V, / V, / V', / V'-tetramethylethane-1,2-diamine \- -\ Example 2: Amine Screening Procedure Cl                       Cl                          Cl                       Cl 5 Procedure: To a solution of 2,4-dichlorobenzaldehyde (1 g, 5.71 mmol, 1.00 eq.) in methanol (6.3 ml) in a screening vial the amine (6.28 mmol, 1.1 eq.) was added. The reaction mixture was heated to 40 °C and stirred for 60 min at 40 °C. To the obtained solution tripotassium phosphate (1.33 g, 6.28 mmol, 1.10 eq.), 10 frans- / V, / V'-dimethylcyclohexan-1,2-diamine (0.166 g, 1.14 mmol, 0.20 eq.) and copper(l)chloride (0.112 g, 1.14 mmol, 0.20 eq.) were added successively to the solution, vials were closed and the reaction mixtures heated to 65 °C for 16 h. Afterwards, the pH was adjusted to 3 with 2 N HCI and the reaction mixture stirred for an additional 60 min at 65 °C and then analyzed by GC. Conversion of starting material and selectivity for the desired product were calculated from the GC results. The results are shown below 15 in Table 2. Table 2: Amine Screening WO 2024 / 089225                                                 PCT / EP2023 / 080025 39 No. Amine Conversion [%] Selectivity [%] 1 (Comparative Example) None 62 21 2 Me-NH2 99 76 3 Et- NH2 100 45 4 iPr- NH2 100 38 5 iBu- NH2 100 22 6 tBu- NH2 92 70 Example 3: Preparation of 2-methoxv-4-chlorobenzaldehyde from 2,4-dichlorobenzaldehyde Procedure: To a solution of 2,4-dichlorobenzaldehyde (20 g, 114 mmol, 1.00 eq.) in methanol (95 ml) a solution of methylamine in methanol (40 w-%, 9.32 g, 120 mmol, 1.05 eq.) was added in one portion. The reaction mixture was heated to 40 °C and stirred for 30 min at 40 °C. The obtained colorless solution was cooled to room temperature and transferred to a pressure autoclave. Then tripotassium phosphate (26.7 g, 126 mmol, 1.11 eq.), [(2,6-dimethylphenyl)amino](oxo)acetic acid (1.09 g, 5.64 mmol, 0.05 eq.), boric acid (0.353 g, 5.71 mmol, 0.05 eq.) and copper(l)chloride (0.560 g, 5.65 mmol, 0.05 eq.) were added successively to the solution. The pressure autoclave was closed and the reaction mixture heated to 80 °C for 16 h. A maximum pressure of approx. 2 bar was observed. After cooling to room temperature and release of remaining pressure, the pressure autoclave was opened and the reaction mixture transferred to a 500 ml double jacketed reactor. Water (70 ml) was added to the reaction mixture and and the mixture was stirred for 10 min at room temperature. Methanol was distilled off and methylcyclohexane (115 ml) was added to the obtained suspension. The mixture was heated to 55 °C and phases were separated. To the organic phase 2 M hydrochloric acid (48 g, 99.9 mmol, 0.88 eq.) was added and the mixture stirred at 55 °C for 1 h. After phase separation the product was crystallized by cooling the organic phase over 4 h to 0 °C. The suspension was stirred at 0 °C for additional 30 min and afterwards the mixture was filtered. The obtained crude product washed with cold (0-5 °C) methylcyclohexane (2 x 50 ml) and dried at 50 °C for 14 h to give the title compound (14.9 g, 93% purity as determined by quant. NMR, 71% yield) 1H NMR (400 MHz.CDCh) 6 ppm: 10.40 (s, 1H), 7.80 (d, 1H, J=8.0), 6.88-7.16 (m, 2H), 3.98 (s, 3H) Example 4: Preparation of 2-methoxv-4-bromobenzaldehyde from 2,4-dibromobenzaldehyde Br                    Br                       Br                    Br Procedure: To a solution of 2,4-dichlorobenzaldehyde (5.0 g, 18.9 mmol, 1.00 eq.) in methanol (150 ml) a solution of methylamine in methanol (40 w-%, 1.57 g, 20.2 mmol, 1.07 eq.) was added in one portion. The reaction mixture was heated to 40 °C and stirred for 30 min at 40 °C. The obtained colorless solution was cooled to room temperature and transferred to a pressure autoclave. Then tripotassium phosphate (4.42 g, 20.8 mmol, 1.10 eq.), [(2,6-dimethylphenyl)amino](oxo)acetic acid (0.181 g, 0.94 mmol, 0.05 eq.), boric acid (0.059 g, 0.95 mmol, 0.05 eq.) and copper(l)chloride (0.093 g, 0.94 mmol, 0.05 eq.) were added successively to the solution. The pressure autoclave was closed and the reaction mixture heated to 80 °C for 16 h. A maximum pressure of approx. 2 bar was observed. Aftercooling to room temperature and release of remaining pressure, the pressure autoclave was opened and the reaction mixture transferred to a 500 ml double jacketed reactor. Water (30 ml) was added to the reaction mixture and and the mixture was stirred for 10 min at room temperature. Methanol was distilled off and methylcyclohexane (30 ml) was added to the obtained suspension. The mixture was heated to 55 °C and phases were separated. To the organic phase water (65 ml) and 2 M hydrochloric acid (8.8 g, 17.6 mmol, 0.93 eq.) were added and the mixture stirred at 55 °C for 1 h. After phase separation the product was crystallized by cooling the organic phase over 4 h to 0 °C. The suspension was stirred at 0 °C for additional 20 min and afterwards the mixture was filtered. The obtained crude product washed with cold (0-5 °C) methylcyclohexane (1x10 ml) and dried at 50 °C for 18 h to give the title compound (2.5 g, 96% purity as determined by quant. NMR, 59% yield) 1H NMR (400 MHz.CDCb) 6 ppm: 10.41 (s, 1H), 7.69 (d, 1H, J= 4.8), 7.10-7.25 (m, 2H), 3.95 (s, 3H) Example 5: Comparative Example The prior art example, entry 1 of table 5 disclosed in KUMAR and NEGI, A frank synthesis of alkyl—aryl ethers from 2-halobenzaldehydes and aromatic olefins without transition metal co-catalyst and ligand, Tetrahedron Letters, 2015, Vol. 56, p.2342 was found to be unreproducible as detailed below: M is Na, K, Cs or Li           Cl Four 20 mL glass-vials were charged with 2,4-dichlorobenzaldehyde (99%, 5,7mmol, 1g) each, 10mL of methanol was added and stirred at room temperature resulting in clear slightly yellow solutions. To each vial 0.02eq of either Na2CO3, K2CO3, CS2CO3 or Li2COs was added in one portion. Values can be found in the material table 3 below. The reaction mixtures were then heated to 65°C for a total of 22 hours (clear solutions except Li2COs experiment = suspension). Multiple in process controls via GC showed no or insignificant (<1%) conversion from the starting material to the desired compound (4-chloro-2-methoxybenzaldehyde). Table 3: Material Table for Comparative Experiments Name Purity [%] M [g / mol] n [mol] eq Mass [g] 2.4- Dichlorobenzaldehyde 99.0 175.01 0.0057 1.00 1.0 Li2COs 99 73.89 0.0001 0.02 0.0084 K2CO3 99 138.20 0.0001 0.02 0.016 CS2CO3 99 325.82 0.0001 0.02 0.037 Na2COs 99.5 105.99 0.0001 0.02 0.012 Methanol 100.0 32.04 0.2489 44.00 8.0 Theoretical value for desired product 4-chloro-2-methoxybenzaldehyde 100 219.32 0.0057 1.00 1.24 Therefore, based on the above results the skilled person would appreciate that the process disclosed in KUMAR and NEGI to make 4-chloro-2-methoxybenzaldehyde is not enabled and thus when faced with the technical problem of developing a new process would not have followed the teaching of this reference with any reasonable expectation of success. 2023366305   30 Sep 2026 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. 5 The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. 10

Claims

1. A process for the preparation of a compound of formula (I),(I)wherein,X is halogen;comprising the steps of;(i) reacting a compound of formula (II);(II)wherein Y is selected from the group consisting of bromo, chloro, iodo, CF3SO3-, CH3C6H4SO3-and CH3SO3-, R1 is Ci-Cealkyl and X is as defined above for a compound of formula (I);with methanol in the presence of a copper source to give a compound of formula (III);(HI)wherein X is as defined above for a compound of formula (I) and R1 is as defined above for a compound of formula (II);and,(ii) hydrolysis to a compound of formula (I).

2. A process according to claim 1, wherein the compound of formula (II) is formed by reacting a compound of formula (IV),(IV)wherein Y and X are as defined in claim 1, with a compound of formula (V),R1—NH2(V)wherein R1 is as defined in claim 1, to give a compound of formula (II).

3. A process according to claim 2, wherein the intermediate compounds of formula (II) and formula (III) are not isolated.

4. A process according to any one of claims 1 to 3, wherein X and Y are independently chloro or bromo.

5. A process according to any one of claims 1 to 4, wherein Y is chloro and X is 4-chloro.

6. A process according to any one of claims 1 to 5, wherein R1 is methyl.

7. A process according to any one of claims 1 to 6, wherein the copper source is a copper(l) salt.

8. A process any one of claims 1 to 7, wherein the copper source is copper(l) chloride.

9. A process according to any one of claims 1 to 8, wherein step (i) is carried out in the presence of a ligand.

10. A process according to claim 9, wherein the ligand is selected from the group consisting of diamines, oxalic acid amides, oxyquinolines, carboxylic acids, oximes and amino sugars.

11. A process according to claim 9 or 10, wherein the ligand is an oxalic acid amide compound of formula (VI),O0(VI)wherein,Z is NH or O;R2 is selected from the group consisting of hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Cs-Cecycloalkyl, Cs-CecycloalkylCi-Csalkyl-, Cs-Cecycloalkenyl, Cs-CecycloalkenylCi-Csalkyl-, phenyl, naphthalenyl, heterocyclyl, heteroaryl, heterodiaryl, phenylCi-Csalkyl-, heterocyclylCi-Csalkyl-, heteroarylCi-Csalkyl- and heterodiarylCi-Csalkyl- wherein said Cs-Cecycloalkyl, C3-CecycloalkylCi-Csalkyl-, Cs-Cecycloalkenyl, Cs-CecycloalkenylCi-Csalkyl-, phenyl, naphthalenyl, heterocyclyl, heteroaryl, heterodiaryl, phenylCi-Csalkyl-, heterocyclylCi-Csalkyl-, heteroarylCi-Csalkyl- or heterodiarylCi-Csalkyl- are optionally substituted where feasible by 1, 2 or 3 R4 substituents, which may be the same or different, and wherein said heterocyclyl is a 3- to 6membered non-aromatic ring which comprises 1 or 2 heteroatoms individually selected from nitrogen, oxygen and sulfur, and said heteroaryl is a 5-or 6-membered monocyclic aromatic ring which comprises 1,2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur, and said heterodiaryl is a 9 or 10-membered aromatic fused bicyclic ring radical which comprises 1,2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur;R3 is selected from the group consisting of hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Cs-Cecycloalkyl, Cs-CecycloalkylCi-Csalkyl-, Cs-Cecycloalkenyl, Cs-CecycloalkenylCi-Csalkyl-, phenyl, naphthalenyl, heterocyclyl, heteroaryl, heterodiaryl, phenylCi-Csalkyl-, heterocyclylCi-Csalkyl-, heteroarylCi-Csalkyl- and heterodiarylCi-Csalkyl- wherein said Cs-Cecycloalkyl, C3-CecycloalkylCi-Csalkyl-, Cs-Cecycloalkenyl, Cs-CecycloalkenylCi-Csalkyl-, phenyl, naphthalenyl, heterocyclyl, heteroaryl, heterodiaryl, phenylCi-Csalkyl-, heterocyclylCi-Csalkyl-, heteroarylCi-Csalkyl- or heterodiarylCi-Csalkyl- are optionally substituted where feasible by 1, 2 or 3 R4 substituents, which may be the same or different, and wherein said heterocyclyl is a 3- to 6membered non-aromatic ring which comprises 1 or 2 heteroatoms individually selected from nitrogen, oxygen and sulfur, and said heteroaryl is a 5-or 6-membered monocyclic aromatic ring which comprises 1,2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur, and said heterodiaryl is a 9 or 10-membered aromatic fused bicyclic ring radical which comprises 1,2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur; and each R4 is independently selected from the group consisting of halogen, nitro, cyano, -OH, -C(O)OH, N-Ci-C4alkylamino, N,N-diCi-C4alkylamino, Ci-C4alkylcarbonyl, Ci-C4alkoxycarbonyl, Ci-C4alkylcarbonyloxy, N-Ci-C4alkylaminocarbonyl, N,N-diCi-C4alkylaminocarbonyl, C1-C4alkyl, Ci-C4alkoxy, Ci-C4haloalkyl, Ci-C4haloalkoxy, phenyl and phenoxy.Z is NH or O;R2 is selected from the group consisting of hydrogen, Ci-Cealkyl, phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl and quinolinylmethyl wherein said phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl or quinolinylmethyl are optionally substituted where feasible by 1, 2 or 3 R4 substituents, which may be the same or different;R3 is selected from the group consisting of hydrogen, Ci-Cealkyl, phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl and quinolinylmethyl wherein said phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl or quinolinylmethyl are optionally substituted where feasible by 1, 2 or 3 R4 substituents, which may be the same or different; andeach R4 is independently selected from the group consisting of bromo, chloro, fluoro, nitro, -OH, -C(O)OH, dimethylamino, diethylamino, methoxycarbonyl, methyl, ethyl, / so-propyl, te / Y-butyl, methoxy, / so-propyloxy, trifluoromethyl, phenyl and phenoxy.

13. A process according to claim 11 or claim 12, wherein in the compound of formula (VI), Z is NH or O;R2 is selected from the group consisting of hydrogen, phenyl, pyrrolyl, benzyl and phenylethyl, wherein said phenyl, pyrrolyl, benzyl or phenylethyl are optionally substituted where feasible by 1,2 or 3 R4 substituents, which may be the same or different;R3 is selected from the group consisting of phenyl, pyrrolyl, benzyl and phenylethyl, wherein said phenyl, pyrrolyl, benzyl or phenylethyl are optionally substituted where feasible by 1,2 or 3 R4 substituents, which may be the same or different; andeach R4 is independently selected from the group consisting of chloro, methyl, ethyl, / so-propyl, te / Y-butyl and methoxy.

14. A process according to claim 11, 12 or 13, wherein the compound of formula (VI) is selected from the group consisting of 2-(2-methylanilino)-2-oxo-acetic acid, 2-(2,6-diisopropylanilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethoxyanilino)acetic acid, 2-(2-ethyl-6-methyl-anilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethylanilino)acetic acid, 2-(2,6-dimethylanilino)-2-oxo-acetic acid, 2-(3,5-dimethylanilino)-2-oxo-acetic acid, 2-(2-tert-butylanilino)-2-oxo-acetic acid, 2-anilino-2-oxo-acetic acid, 2-(4-chloroanilino)-2-oxo-acetic acid, 2-(4-methoxyanilino)-2-oxo-acetic acid, 2-(4-methylanilino)-2-oxo-acetic acid, N,N'-bis(2,6-dimethylphenyl)oxamide, N,N'-bis(2,4,6-trimethoxyphenyl)oxamide, N,N'-bis(2,5-dimethylpyrrol-1-yl)oxalamide, N,N'-dibenzyloxamide, N,N'-bis(2-phenylethyl)oxamide and N,N'-bis(2-pyridylmethyl)oxamide.

15. A process according to claim 9 or 10, wherein the ligand is selected from the group consisting of trans-N,N'-dimethylcyclohexan-1,2-diamine, 2-(2-methylanilino)-2-oxo-acetic acid, 2-(2,6-diisopropylanilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethoxyanilino)acetic acid, 2-(2-ethyl-6-methyl-anilino)-2-oxo-acetic acid, 2-oxo-2-(2,4,6-trimethylanilino)acetic acid and 2-(2,6-dimethylanilino)-2-oxo-acetic acid.

16. A process according to any one of claims 1 to 15, wherein the process further comprises converting a compound of formula (I) to a compound of formula (VII),(VII)Wherein G is selected from the group consisting of hydrogen, C2-Cealkenyl, C2-Cealkynyl, Ci-C3alkoxyCi-C3alkyl-, -C(O)-R5, -C(O)-Xa-R5 and -S(O)2-R5;Xa is oxygen or sulfur; andR5 is selected from the group consisting of Ci-Cealkyl, C2-Cealkenyl, phenyl and 4-fluorophenyl.

17. A compound of formula (III),r1 / NS^^X(III)wherein X and R1 are as defined in any one of claims 1 to 6, provided that the compound of formula (III) is not a compound selected from the group consisting of N-butyl-1-(4-chloro-2-methoxy-phenyl)methanimine, N-tert-butyI-1 -(4-fluoro-2-methoxy-phenyl)methanimine, 1 -(5-bromo-2-methoxy-phenyl)-N-methyl-methanimine,         N-tert-butyl-1-(5-fluoro-2-methoxy-phenyl)methanimine, N-tert-butyl-1-(5-chloro-2-methoxy-phenyl)methanimine and N-tert-butyl-1-(5-bromo-2-methoxy-phenyl)methanimine.

18. A compound according to claim 17 wheren the compound of formula (III) is a compound of formula (llla-l),Cl(llla-l).