Process for synthesis of methoxy-substituted benzaldehyde compounds

Abstract

The invention provides, inter alia, a process for the preparation of compounds of formula (I) wherein the substituents are as defined in claim 1. # imgabs0 #

Description

[0001] The present invention relates to a novel process for the synthesis of certain methoxy-substituted benzaldehyde compounds and 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 the preparation of such compounds or intermediates thereof are also known.

[0002] The copper-catalyzed 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, No. 43, pp. 3525-3550; DE 2721643A1 (LUDWIG HEUMANN AND CO) 23.11.1978; and EP 0520815 A2 (NIPPON CHEM.IND.CO.LTD.) 30.12.1992. The copper-catalyzed coupling of cyclohexylimine-substituted aryl iodides with methoxides is disclosed in ADESOMOJU A. et al., Total synthesis of leucoxylonine, The Journal of Organic Chemistry, 1984, Vol. 49, No. 17, pp. 3220-3222.

[0003] The copper-catalyzed Ullmann coupling reaction can be carried out in the presence of a ligand, see, for example, ZHANG et al., CuI / DMPAO Catalyzed N-Arylation of Acyclic Secondary Amines, Org. Lett., 2012, Vol. 14(12), pp. 3056-3059 or EP3326715A1 (SHANGHAI INSTITUTE OF ORGANIC CHEMISTRY) 30.05.2018. Furthermore, it is known to use directing groups 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, pp. 3421-3422; KALININ et al. The Directed Ortho Metalation-Ullmann Connection, J. Org. Chem. 1999, vol. 64, pp. 2986-2987; or XU et al. Org. Lett. 2014, vol. 16, pp. 3942-3945. Ligand-free and copper-free methods for the O-arylation of benzaldehyde derivatives have 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-catalystand ligand, Tetrahedron Letters, 2015, Vol. 56, pp. 2340-2344. However, these are not suitable for large-scale production and / or have high yield losses and require additional purification of the product. Therefore, a new and more efficient synthesis method that utilizes more favorable reaction conditions and avoids the production of undesirable by-products is needed.

[0004] The present invention provides a process for the O-arylation of benzaldehyde derivatives which provides (i) high levels of regioselectivity and (ii) good levels of conversion to the desired product. Surprisingly, we have now found that selective O-arylation can be achieved in the process of the present invention to provide the desired monomethoxylated product, i.e. a compound of formula (I), which in turn can be converted to the desired propynyl-phenyl herbicidal compound.

[0005] Thus, according to the present invention, there is provided a process for preparing a compound having formula (I),

[0006]

[0007] in,

[0008] X is a halogen;

[0009] The method comprises the following steps:

[0010] (i) making a compound having formula (II)

[0011]

[0012] wherein Y is selected from the group consisting of bromine, chlorine, iodine, CF3SO3-, CH3C6H4SO3- and CH3SO3-, R 1 is C1-C6 alkyl and X is as defined above for compounds of formula (I);

[0013] reacting with methanol in the presence of a copper source to obtain a compound having formula (III);

[0014]

[0015] wherein X is as defined above for compounds of formula (I) and R 1 is as defined above for the compound of formula (II);

[0016] as well as

[0017] (ii) hydrolyzed to a compound of formula (I).

[0018] According to a second aspect of the present invention, there is provided an intermediate compound having the formula (III),

[0019]

[0020] Where X and R 1is as defined herein, with the proviso 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-tert-butyl-1-(5-chloro-2-methoxy-phenyl)methanimine and N-tert-butyl-1-(5-bromo-2-methoxy-phenyl)methanimine.

[0021] As used herein, the term "halogen" refers to fluorine (fluorine / fluoro), chlorine (chlorine / chloro), bromine (bromine / bromo), or iodine (iodine / iodo).

[0022] As used herein, the term "hydroxyl" or "hydroxy" refers to an -OH group.

[0023] As used herein, cyano refers to a -CN group.

[0024] As used herein, nitro refers to a -NO2 group.

[0025] As used herein, oxo refers to a =0 group (eg, as in a carbonyl (C=0) group).

[0026] As used herein, the term "C1-C6 alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon atoms and hydrogen atoms, containing no unsaturation, having one to six carbon atoms, and attached to the remainder of the molecule by a single bond. C1-C4 alkyl and C1-C2 alkyl should be interpreted accordingly. Examples of C1-C6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, and 1-dimethylethyl (tert-butyl).

[0027] “C 1- The "C2 alkylene" group refers to a C 1- The corresponding definition for C2 alkyl, except that this group is attached to the rest of the molecule via two single bonds. 1- Examples of C2 alkylene are -CH2- and -CH2CH2-.

[0028] As used herein, the term "C1-C6 alkoxy" refers to a group having the formula -OR a A group in which R a is C as defined above 1- C6 alkyl group. C1-C4 alkoxy should be interpreted accordingly. 1-4Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and tert-butoxy.

[0029] As used herein, the term "C1-C6 haloalkyl" refers to a C1-C6 alkyl group as generally defined above that is substituted with one or more identical or different halogen atoms. C1-C4 haloalkyl should be interpreted accordingly. Examples of C1-C6 haloalkyl include, but are not limited to, chloromethyl, fluoromethyl, fluoroethyl, difluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl.

[0030] As used herein, the term "C1-C6 haloalkoxy" refers to a C1-C6 alkoxy group as defined above that is substituted with one or more identical or different halogen atoms. C1-C4 haloalkoxy should be interpreted accordingly. Examples of C1-C6 haloalkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, fluoroethoxy, trifluoromethoxy, and trifluoroethoxy.

[0031] As used herein, the term "C2-C6 alkenyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond which may have an (E)- or (Z)-configuration, having two to six carbon atoms, attached to the remainder of the molecule by a single bond. C2-C4 alkenyl should be interpreted accordingly. 2- Examples of C6 alkenyl groups include, but are not limited to, prop-1-enyl, allyl (prop-2-enyl), and but-1-enyl.

[0032] As used herein, the term "C2-C6 alkynyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having two to six carbon atoms, and attached to the remainder of the molecule by a single bond. Examples of C3-C6 alkynyl groups include, but are not limited to, prop-1-ynyl and propargyl (prop-2-ynyl).

[0033] As used herein, the term "C1-C3 alkoxy C1-C3 alkyl-" refers to a b -OR a - a group, wherein R b is a C1-C3 alkyl group as generally defined above, and R a is a C1-C3 alkylene group as generally defined above.

[0034] As used herein, the term "C1-C6 alkylcarbonyl" refers to a a C(O)-, where R a is a C1-C6 alkyl group as generally defined above.

[0035] As used herein, the term "C1-C6 alkoxycarbonyl" refers to aa OC(O)-, where R a is a C1-C6 alkyl group as generally defined above.

[0036] As used herein, the term "C3-C6 cycloalkyl" refers to a stable monocyclic group that is saturated and contains 3 to 6 carbon atoms. C3-C4 cycloalkyl should be interpreted accordingly. Examples of C3-C6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0037] As used herein, the term "C3-C6 cycloalkylC1-C3 alkyl-" refers to a C1-C3 alkylene group as defined above attached to the remainder of the molecule via a C1-C3 alkylene group as defined above. 3- C6 cycloalkyl ring. The term "C3-C4 cycloalkyl C1-C2 alkyl-" should be interpreted accordingly. Examples of C3-C6 cycloalkyl C1-C3 alkyl- include, but are not limited to, cyclopropylmethyl- and cyclobutylethyl-.

[0038] As used herein, the term "C3-C6 cycloalkenyl" refers to a stable monocyclic group that is partially unsaturated and contains 3 to 6 carbon atoms. C3-C4 cycloalkenyl should be interpreted accordingly. Examples of C3-C6 cycloalkenyl include, but are not limited to, cyclopentene-1-yl and cyclohexene-1-yl.

[0039] As used herein, the term "C3-C6 cycloalkenyl C1-C3 alkyl-" refers to a C1-C3 alkylene group as defined above attached to the remainder of the molecule via a C1-C3 alkylene group as defined above. 3- C6 cycloalkenyl ring. The term "C3-C4 cycloalkyl C1-C2 alkyl-" should be interpreted accordingly.

[0040] As used herein, the term "N-C1-C4 alkylamino" refers to a a NH-group, where R a is a C1-C4 alkyl group as generally defined above.

[0041] As used herein, the term "N,N-diC1-C4 alkylamino" refers to a a (R b )N-, wherein R a and R b are the same or different C1-C4 alkyl groups as generally defined above.

[0042] As used herein, the term "N-C1-C4 alkylaminocarbonyl" refers to a a NHC(O)-, where R a is a C1-C4 alkyl group as generally defined above.

[0043] As used herein, the term "N,N-diC1-C4 alkylaminocarbonyl" refers to a a (R b )NC(O)-, wherein R a and R b are the same or different C1-C4 alkyl groups as generally defined above.

[0044] As used herein, the term "phenyl C1-C3 alkyl-" refers to a benzene ring attached to the remainder of the molecule via a C1-C3 alkylene group as generally defined above.

[0045] As used herein, unless otherwise expressly stated, the term "heteroaryl" refers to a 5- or 6-membered monocyclic aromatic ring containing 1, 2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur. The heteroaryl group can be attached to the remainder of the molecule via a carbon atom or a heteroatom. Examples of heteroaryl include furanyl, pyrrolyl, imidazolyl, thienyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyridyl.

[0046] As used herein, the term "heteroaryl C1-C3 alkyl-" refers to a C 1- The C3 alkylene group is attached to a heteroaryl ring as defined above of the rest of the molecule.

[0047] As used herein, unless otherwise expressly stated, the term "heterocyclyl" or "heterocyclic" refers to a stable 3- to 6-membered non-aromatic monocyclic group containing 1, 2 or 3 heteroatoms individually selected from nitrogen, oxygen and sulfur. The heterocyclyl group can be bonded to the remainder of the molecule via a carbon atom or a heteroatom. Examples of heterocyclyl groups include, but are not limited to, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydroisoxazolyl, dioxolanyl, morpholinyl or δ-lactamyl.

[0048] As used herein, the term "heterocyclyl C1-C3 alkyl-" refers to a heterocyclyl ring as defined above attached to the remainder of the molecule via a C1-C3 alkylene group as generally defined above.

[0049] As used herein, the term "heterobiaryl" refers to a 9- or 10-membered aromatic fused bicyclic radical containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The heteroaryl group can be bonded to the remainder of the molecule via a carbon atom or a heteroatom. Examples of heterobiaryl groups include indolyl, indazolyl, benzimidazolyl, pyrrolopyridinyl or triazolopyridinyl.

[0050] As used herein, the term "heterodiaryl C1-C3 alkyl-" refers to a C 1- The C3 alkylene group is attached to a heterobiaryl ring as defined above of the rest of the molecule.

[0051] The skilled person will appreciate that compounds of formula (II) and compounds of formula (III) may exist as E and / or Z isomers. The present invention encompasses methods and compounds including all such isomers and mixtures thereof in all ratios.

[0052] For example, a compound having formula (II) can be drawn as a compound having formula (II-I) or (II-II) shown below

[0053]

[0054] Likewise, the compound having formula (III) can be drawn as a compound having formula (III-I) or (III-II) shown below

[0055]

[0056] Likewise, a compound having formula (IIa-I) can be drawn as a compound having formula (IIa-Ia) or (IIa-Ib)

[0057]

[0058] Likewise, a compound having formula (IIIa-I) can be drawn as a compound having formula (IIIa-Ia) or (IIIa-Ib)

[0059]

[0060] The method of the present invention can be carried out in a separate method step, wherein the intermediate compound can be separated at each stage. Alternatively, the method can be carried out in a one-step procedure, wherein the intermediate compound produced is not separated. Therefore, the method of the present invention can be carried out in batches or in a continuous manner.

[0061] The following list provides information about the substituents X, Y, Z, G, X a , R 1 , R 2 , R 3 , R 4 and R 5 definitions, including preferred definitions.

[0062] X is a halogen. Preferably, X is chlorine, bromine or iodine. More preferably, X is chlorine or bromine. Even more preferably, X is chlorine. Most preferably, X is 4-chlorine.

[0063] Y is selected from the group consisting of bromine, chlorine, iodine, CF3SO3-, CH3C6H4SO3- and CH3SO3-. Preferably, Y is selected from the group consisting of bromine, chlorine and iodine. More preferably, Y is bromine or chlorine. Even more preferably, Y is chlorine.

[0064] Z is NH or O. In one embodiment, Z is NH. In another embodiment, Z is O.

[0065] R 1 is a C1-C6 alkyl group. Preferably, R 1 is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl and tert-butyl. More preferably, R 1 is selected from the group consisting of methyl, ethyl, and tert-butyl. Even more preferably, R 1 is methyl or tert-butyl. Most preferably, R 1 It's methyl.

[0066] R 2 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C3 alkyl-, C3-C6 cycloalkenyl, C3-C6 cycloalkenylC1-C3 alkyl-, phenyl, naphthyl, heterocyclyl, heteroaryl, heterodiaryl, phenylC1-C3 alkyl-, heterocyclylC1-C3 alkyl-, heteroarylC1-C3 alkyl- and heterodiarylC1-C3 C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C3 alkyl-, C3-C6 cycloalkenyl, C3-C6 cycloalkenylC1-C3 alkyl-, phenyl, naphthyl, heterocyclyl, heteroaryl, heterodiaryl, phenylC1-C3 alkyl-, heterocyclylC1-C3 alkyl-, heteroarylC1-C3 alkyl- or heterodiarylC1-C3 alkyl-, where applicable, may be optionally replaced by 1, 2 or 3 R which may be the same or different 4 Substituents are substituted, and wherein the heterocyclyl is a 3- to 6-membered non-aromatic ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the heteroaryl is a 5- or 6-membered monocyclic aromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the heterodiaryl is a 9- or 10-membered aromatic fused bicyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Preferably, R 2is selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl, naphthyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolyl, benzyl, phenethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl and quinolylmethyl, wherein the phenyl, naphthyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolyl, benzyl, phenethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl or quinolylmethyl is optionally replaced by 1, 2 or 3 R which may be the same or different if feasible. 4 More preferably, R 2 is selected from the group consisting of hydrogen, phenyl, pyrrolyl, benzyl and phenethyl, wherein the phenyl, pyrrolyl, benzyl or phenethyl is optionally substituted, where feasible, by 1, 2 or 3 R which may be the same or different 4 Substituent substitution.

[0067] R 3 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C3 alkyl-, C3-C6 cycloalkenyl, C3-C6 cycloalkenylC1-C3 alkyl-, phenyl, naphthyl, heterocyclyl, heteroaryl, heterodiaryl, phenylC1-C3 alkyl-, heterocyclylC1-C3 alkyl-, heteroarylC1-C3 alkyl- and heterodiarylC1-C3 C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C3 alkyl-, C3-C6 cycloalkenyl, C3-C6 cycloalkenylC1-C3 alkyl-, phenyl, naphthyl, heterocyclyl, heteroaryl, heterodiaryl, phenylC1-C3 alkyl-, heterocyclylC1-C3 alkyl-, heteroarylC1-C3 alkyl- or heterodiarylC1-C3 alkyl-, where applicable, may be optionally replaced by 1, 2 or 3 R which may be the same or different 4 Substituents are substituted, and wherein the heterocyclyl is a 3- to 6-membered non-aromatic ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the heteroaryl is a 5- or 6-membered monocyclic aromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the heterodiaryl is a 9- or 10-membered aromatic fused bicyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Preferably, R 3is selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl, naphthyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolyl, benzyl, phenethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl and quinolylmethyl, wherein the phenyl, naphthyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolyl, benzyl, phenethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl or quinolylmethyl is optionally replaced by 1, 2 or 3 R which may be the same or different if feasible. 4 More preferably, R 3 is selected from the group consisting of phenyl, pyrrolyl, benzyl and phenethyl, wherein the phenyl, pyrrolyl, benzyl or phenethyl is optionally substituted, where feasible, by 1, 2 or 3 R which may be the same or different 4 Substituent substitution.

[0068] Each R 4 R is independently selected from the group consisting of halogen, nitro, cyano, -OH, -C(O)OH, N-C1-C4 alkylamino, N,N-diC1-C4 alkylamino, C1-C4 alkylcarbonyl, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, N-C1-C4 alkylaminocarbonyl, N,N-diC1-C4 alkylaminocarbonyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, phenyl and phenoxy. Preferably, each R 4 is independently selected from the group consisting of bromine, chlorine, fluorine, nitro, -OH, -C(O)OH, dimethylamino, diethylamino, methoxycarbonyl, methyl, ethyl, isopropyl, tert-butyl, methoxy, isopropoxy, trifluoromethyl, phenyl and phenoxy. More preferably, each R 4 Independently selected from the group consisting of chloro, methyl, ethyl, isopropyl, tert-butyl and methoxy.

[0069] G is selected from the group consisting of: hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 alkoxy, C1-C3 alkyl-, -C(O)-R 5 、-C(O)-X a -R 5 and -S(O)2-R 5 Preferably, G is selected from the group consisting of hydrogen, -C(O)-R 5 、-C(O)-X a -R 5 and -S(O)2-R 5 More preferably, G is selected from the group consisting of hydrogen, -C(O)-R 5 and -C(O)-Xa -R 5 Even more preferably, G is hydrogen or -C(O)-R 5 Most preferably, G is -C(O)-R 5 .

[0070] X a Preferably, X a It's oxygen.

[0071] R 5 is selected from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, phenyl and 4-fluorophenyl. 5 is selected from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl and phenyl. More preferably, R 5 is selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl. Even more preferably, R 5 It is a C1-C6 alkyl group.

[0072] The reactions of the invention are described in more detail in Scheme 1 below. Substituent definitions are as defined herein.

[0073] Scenario 1:

[0074]

[0075] Step (a) Imine formation:

[0076] A compound having formula (II),

[0077]

[0078] Where X, Y and R 1 is as defined herein,

[0079] The compound of formula (IV) can be

[0080]

[0081] wherein X and Y are as defined herein,

[0082] reacting with a compound having formula (V),

[0083]

[0084] Where R 1 is as defined herein.

[0085] Typically, the process described in step (a) can be carried out as a pure reaction mixture, however, it can also be carried out in a solvent or solvent mixture, the solvent being, but not limited to, methanol, ethanol, propanol, isopropanol, tert-butyl alcohol, butanol, 3-methyl-1-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, tert-amyl methyl ether, cyclopentyl methyl ether, dimethoxymethane, diethoxymethane, dipropoxymethane, 1,3-dioxolane, dimethyl carbonate, dichloromethane, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone (NMP), acetonitrile, propionitrile, butyronitrile, benzonitrile (or its derivatives, such as 1,4-dicyanobenzene), toluene, a mixture of xylene isomers, 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.

[0086] The skilled person will appreciate that in process step (a) various methods known to shift the reaction equilibrium toward the desired product may be used including but not limited to azeotropic removal of produced water or increasing the number of equivalents of the compound of formula (V).

[0087] Typically, the process described in step (a) may be carried out at a temperature of 0°C to 120°C, preferably 20°C to 85°C, more preferably 20°C to 70°C.

[0088] Scenario 2:

[0089]

[0090] Step (b) Ullmann type coupling:

[0091] Compounds having formula (III)

[0092]

[0093] Where X and R 1 is as defined herein,

[0094] By making a compound having formula (II)

[0095]

[0096] Where Y and R 1 is as defined herein,

[0097] React with methanol in the presence of a copper source.

[0098] Typically, the process described in step (b) can be carried out as a pure reaction mixture, however, it can also be carried out in a solvent or solvent mixture, the solvent such as but not limited to methanol, ethanol, propanol, isopropanol, tert-butyl alcohol, butanol, 3-methyl-1-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, tert-amyl methyl ether, cyclopentyl methyl ether, dimethoxymethane, diethoxymethane, dipropoxymethane, 1,3-dioxolane, dimethyl carbonate, dichloromethane, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone (NMP), acetonitrile, propionitrile, butyronitrile, benzonitrile (or its derivatives, such as 1,4-dicyanobenzene), toluene, xylene isomer mixtures, cumene, isopropylbenzene, p-xylene, mesitylene, 1,4-dioxane or sulfolane. Preferably, process step (b) is carried out in methanol, acetonitrile or toluene or a mixture thereof. More preferably, process step (b) is carried out in methanol.

[0099] The method 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 (I) salts and copper (II) salts. More preferably, the copper source is a copper (I) salt. Even more preferably, the copper source is copper (I) chloride.

[0100] Typically, the copper source is present in an amount of 0.01 mol% to 40 mol% based on the compound of formula (II). Preferably, the copper source is present in an amount of 0.01 mol% to 20 mol% based on the compound of formula (II). More preferably, the copper source is present in an amount of 0.01 mol% to 5 mol% based on the compound of formula (II). Even more preferably, the copper source is present in an amount of 0.01 mol% to 1 mol% based on the compound of formula (II).

[0101] Preferably, the method 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, oxalamides, hydroxyquinolines, carboxylic acids, oximes and amino sugars.

[0102] In a preferred case, the method described in step (b) can also be carried out in the presence of a polymerization inhibitor to prevent unwanted polymerization of the ligand. Such polymerization inhibitors include but are not limited to boric acid.

[0103] In one embodiment of the present invention, the ligand is an oxalamide compound having formula (VI),

[0104]

[0105] in,

[0106] Z is NH or O;

[0107] R 2is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C3 alkyl-, C3-C6 cycloalkenyl, C3-C6 cycloalkenylC1-C3 alkyl-, phenyl, naphthyl, heterocyclyl, heteroaryl, heterodiaryl, phenylC1-C3 alkyl-, heterocyclylC1-C3 alkyl-, heteroarylC1-C3 alkyl- and heterodiarylC1-C3 C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C3 alkyl-, C3-C6 cycloalkenyl, C3-C6 cycloalkenylC1-C3 alkyl-, phenyl, naphthyl, heterocyclyl, heteroaryl, heterodiaryl, phenylC1-C3 alkyl-, heterocyclylC1-C3 alkyl-, heteroarylC1-C3 alkyl- or heterodiarylC1-C3 alkyl-, where applicable, may be optionally replaced by 1, 2 or 3 R which may be the same or different 4 Substituents are substituted, and wherein the heterocyclyl is a 3- to 6-membered non-aromatic ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the heteroaryl is a 5- or 6-membered monocyclic aromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the heterobiaryl is a 9- or 10-membered aromatic fused bicyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0108] R 3 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C3 alkyl-, C3-C6 cycloalkenyl, C3-C6 cycloalkenylC1-C3 alkyl-, phenyl, naphthyl, heterocyclyl, heteroaryl, heterodiaryl, phenylC1-C3 alkyl-, heterocyclylC1-C3 alkyl-, heteroarylC1-C3 alkyl- and heterodiarylC1-C3 C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C3 alkyl-, C3-C6 cycloalkenyl, C3-C6 cycloalkenylC1-C3 alkyl-, phenyl, naphthyl, heterocyclyl, heteroaryl, heterodiaryl, phenylC1-C3 alkyl-, heterocyclylC1-C3 alkyl-, heteroarylC1-C3 alkyl- or heterodiarylC1-C3 alkyl-, where applicable, may be optionally replaced by 1, 2 or 3 R which may be the same or different 4 Substituents are substituted, and wherein the heterocyclyl is a 3- to 6-membered non-aromatic ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the heteroaryl is a 5- or 6-membered monocyclic aromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the heterodiaryl is a 9- or 10-membered aromatic fused bicyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and

[0109] Each R 4Independently selected from the group consisting of halogen, nitro, cyano, -OH, -C(O)OH, N-C1-C4 alkylamino, N,N-diC1-C4 alkylamino, C1-C4 alkylcarbonyl, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, N-C1-C4 alkylaminocarbonyl, N,N-diC1-C4 alkylaminocarbonyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, phenyl and phenoxy.

[0110] Preferably, in the compound having formula (VI),

[0111] Z is NH or O; R 2 is selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl, naphthyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolyl, benzyl, phenethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl and quinolylmethyl, wherein the phenyl, naphthyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolyl, benzyl, phenethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl or quinolylmethyl is optionally replaced by 1, 2 or 3 R which may be the same or different if feasible. 4 Substituent substitution; R 3 is selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl, naphthyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolyl, benzyl, phenethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl and quinolylmethyl, wherein the phenyl, naphthyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolyl, benzyl, phenethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl or quinolylmethyl is optionally replaced by 1, 2 or 3 R which may be the same or different if feasible. 4 Substituents; and each R 4 Independently selected from the group consisting of bromine, chlorine, fluorine, nitro, -OH, -C(O)OH, dimethylamino, diethylamino, methoxycarbonyl, methyl, ethyl, isopropyl, tert-butyl, methoxy, isopropoxy, trifluoromethyl, phenyl and phenoxy.

[0112] More preferably, in the compound having formula (VI), Z is NH or O; R 2 is selected from the group consisting of hydrogen, phenyl, pyrrolyl, benzyl and phenethyl, wherein the phenyl, pyrrolyl, benzyl or phenethyl is optionally substituted, where feasible, by 1, 2 or 3 R which may be the same or different 4 Substituent substitution;

[0113] R 3 is selected from the group consisting of phenyl, pyrrolyl, benzyl and phenethyl, wherein the phenyl, pyrrolyl, benzyl or phenethyl is optionally substituted, where feasible, by 1, 2 or 3 R which may be the same or different 4 Substituents; and each R 4 Independently selected from the group consisting of chloro, methyl, ethyl, isopropyl, tert-butyl and methoxy.

[0114] 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)- oxamide, N,N'-bis(2,6-dimethylphenyl)oxamide, N,N'-bis(2,4,6-trimethoxyphenyl)oxamide, N,N'-bis(2,5-dimethylpyrrol-1-yl)oxamide, N,N'-dibenzyloxamide, N,N'-bis(2-phenylethyl)oxamide and N,N'-bis(2-pyridylmethyl)oxamide.

[0115] 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, )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.

[0116] Yet 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 and 2-(2-tert-butylanilino)-2-oxo-acetic acid.

[0117] In another preferred embodiment of the present invention, the ligand is selected from the group consisting of trans-N,N'-dimethylcyclohexane-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, 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)oxamide, 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'-dimethylcyclohexane-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.

[0118] Typically, the ligand is present in an amount of 0.01mol% to 40mol% based on the compound of formula (II). Preferably, the ligand is present in an amount of 0.01mol% to 20mol% based on the compound of formula (II). More preferably, the ligand is present in an amount of 0.01mol% to 5mol% based on the compound of formula (II). Even more preferably, the ligand is present in an amount of 0.01mol% to 1mol% based on the compound of formula (II).

[0119] Typically, the method 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 cesium carbonate, potassium carbonate, tripotassium phosphate, sodium hydroxide and sodium methoxide. Even more preferably, the base is potassium carbonate, tripotassium phosphate or sodium methoxide.

[0120] The skilled person will 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 continuous charges over a period of time. Preferably, the base is added continuously over a period of time.

[0121] In one embodiment, method step (b) is carried out in the presence of a base, wherein the base is sodium methoxide. Preferably, methoxide is added continuously over a period of time with multiple loadings and / or over a period of time. More preferably, methoxide is added continuously over a period of time. Even more preferably, methoxide is added continuously over a period of time of 1 to 3h (technicians will appreciate that the time period for adding methoxide will depend on many different factors, such as reaction scale, wt% concentration of methoxide and / or wt% concentration of starting reagent).

[0122] Typically, this step may be carried out at a temperature of 50 to 120°C, preferably 60 to 120°C, more preferably 60 to 90°C, even more preferably 75 to 90°C.

[0123] Scenario 3:

[0124]

[0125] Step (c) hydrolysis:

[0126] A compound having formula (I),

[0127]

[0128] wherein X is as defined herein,

[0129] Prepared by hydrolysis of a compound having formula (III),

[0130]

[0131] Where X and R 1 is as defined herein.

[0132] The hydrolysis can be carried out using methods known to those skilled in the art. The hydrolysis is typically carried out using suitable conditions, including but not limited to alkaline 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 carried out under acidic conditions. More preferably, the hydrolysis is carried out with hydrochloric acid.

[0133] Typically, the process described in step (c) is carried out in the absence of an additional solvent or in the presence of a solvent or solvent mixture such as, but not limited to, water, acetic acid, propionic acid, diethyl ether, tert-butyl methyl ether, tert-amyl methyl ether, cyclopentyl methyl ether, dimethoxymethane, diethoxymethane, dipropoxymethane, dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, butylene carbonate, diphenyl carbonate, glycerol carbonate, dichloromethane, dichloroethane, cyclohexane, n-hexane, methylcyclohexane, heptane, chlorobenzene, 1,2-dichlorobenzene, methyl acetate, ethyl acetate, isopropyl acetate, propyl acetate, tert-butyl acetate, butyl acetate, toluene, a xylene isomer mixture, 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 a solvent mixture selected from the group consisting of water, cyclohexane, n-hexane, methylcyclohexane 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 a solvent mixture selected from water and / or methylcyclohexane.

[0134] The skilled person will appreciate that the choice of solvent for use in the process described in step (c) will depend on whether basic or acidic conditions are used.

[0135] Typically, this step may be carried out at a temperature of -20°C to 120°C, preferably -10°C to 80°C, more preferably 0°C to 50°C, even more preferably 10°C to 30°C.

[0136] The skilled person will appreciate that the temperature of the process according to the invention may vary in each of steps (a), (b) and (c). In addition, this variability in temperature may also reflect the choice of solvent or diluent, for example based on its boiling point and / or its effectiveness in promoting the desired reaction, and based on the rate at which the reaction proceeds.

[0137] The process of the present invention can be carried out at any reasonable pressure, depending on the choice of solvent and reaction temperature. Preferably, the reaction can be carried out at a pressure of 0.01 to 10 bar, more preferably 0.5 to 5 bar, even more preferably 0.8 to 2 bar (e.g., at ambient pressure).

[0138] Preferably, the process of the present invention is carried out under an inert atmosphere such as nitrogen or argon.

[0139] The skilled person will 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, process steps (a), (b) and (c) can be carried out in a streamlined procedure, wherein the intermediate compounds produced are not isolated. Thus, the process of the invention can be carried out in a batch, semi-batch or continuous manner.

[0140] The skilled person will appreciate that steps (a), (b) and (c) may be equivalently represented in a single scheme, see Scheme 4 below.

[0141] Solution 4:

[0142]

[0143] In a preferred embodiment of the present invention, there is provided a process for preparing a compound having formula (Ia),

[0144]

[0145] in,

[0146] X is halogen (preferably, X is chlorine, bromine or iodine, more preferably, X is chlorine or bromine, even more preferably, X is chlorine);

[0147] The method comprises the following steps:

[0148] (i) making a compound having formula (IIa)

[0149]

[0150] wherein Y is selected from the group consisting of bromine, chlorine, iodine, CF3SO3-, CH3C6H4SO3- and CH3SO3- (preferably, Y is selected from the group consisting of bromine, chlorine and iodine, more preferably, Y is bromine or chlorine, even more preferably, Y is chlorine), R 1 is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl and tert-butyl (preferably, R 1 is selected from the group consisting of: methyl, ethyl, and tert-butyl, more preferably, R 1 is methyl or tert-butyl, most preferably, R 1is methyl) and X is as defined above for compounds of formula (Ia);

[0151] reacting with methanol in the presence of a copper source and a ligand to obtain a compound having formula (IIIa);

[0152]

[0153] wherein X is as defined above for compounds of formula (Ia) and R 1 is as defined above for the compound of formula (IIa);

[0154] and wherein the ligand is an oxalamide compound having formula (VI),

[0155]

[0156] in,

[0157] Z is NH or O;

[0158] R 2 is selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl, naphthyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolyl, benzyl, phenethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl and quinolylmethyl, wherein the phenyl, naphthyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolyl, benzyl, phenethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl or quinolylmethyl is optionally replaced by 1, 2 or 3 R which may be the same or different if feasible. 4 Substituent substitution;

[0159] R 3 is selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl, naphthyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolyl, benzyl, phenethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl and quinolylmethyl, wherein the phenyl, naphthyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolyl, benzyl, phenethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl or quinolylmethyl is optionally replaced by 1, 2 or 3 R which may be the same or different if feasible. 4 Substituents are substituted; and

[0160] Each R 4independently selected from the group consisting of bromine, chlorine, fluorine, nitro, -OH, -C(O)OH, dimethylamino, diethylamino, methoxycarbonyl, methyl, ethyl, isopropyl, tert-butyl, methoxy, isopropoxy, trifluoromethyl, phenyl, and phenoxy;

[0161] or the ligand is selected from the group consisting of trans-N,N'-dimethylcyclohexane-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;

[0162] as well as

[0163] (ii) hydrolysis to a compound of formula (Ia).

[0164] In a more preferred embodiment of the present invention, there is provided a method for preparing a compound having formula (Ia-I),

[0165]

[0166] The method comprises the following steps:

[0167] (i) making a compound having the formula (IIa-I)

[0168]

[0169] reacting with methanol in the presence of a copper (I) salt (preferably copper (I) chloride) and a ligand to obtain a compound having formula (IIIa-I);

[0170]

[0171] in,

[0172] 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 )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)oxalamide, N,N'-bis(2,4,6-trimethoxyphenyl)oxalamide, N,N'-bis(2,5-dimethylpyrrol-1-yl)oxalamide, N,N'-dibenzyloxalamide, N,N'-bis(2-phenylethyl)oxalamide and N,N'-bis(2-pyridylmethyl)oxalamide (preferably 2-(2-methylphenyl)oxalamide). acetic acid, 2-(2,6-trimethylanilino)-2-oxo-acetic acid, 2-(2,6-triisopropylanilino)-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);

[0173] or the ligand is trans -N,N'-dimethylcyclohexane-1,2-diamine;

[0174] as well as

[0175] (ii) hydrolysis to a compound of formula (Ia-I).

[0176] In another preferred embodiment of the present invention, there is provided a method for preparing a compound having formula (Ia),

[0177]

[0178] in,

[0179] X is halogen (preferably, X is chlorine, bromine or iodine, more preferably, X is chlorine or bromine, even more preferably, X is chlorine);

[0180] The method comprises the following steps:

[0181] (a) making a compound having the formula (IVa),

[0182]

[0183] wherein Y is selected from the group consisting of bromine, chlorine, iodine, CF3SO3-, CH3C6H4SO3- and CH3SO3- (preferably, Y is selected from the group consisting of bromine, chlorine and iodine, more preferably, Y is bromine or chlorine, even more preferably, Y is chlorine), and X is as defined above for compounds having formula (Ia),

[0184] reacting with a compound having formula (V),

[0185]

[0186] Where R 1 is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl and tert-butyl (preferably, R 1 is selected from the group consisting of: methyl, ethyl, and tert-butyl, more preferably, R 1 is methyl or tert-butyl, most preferably, R 1 is methyl),

[0187] To obtain a compound having formula (IIa),

[0188]

[0189] as well as

[0190] (b) making a compound having formula (IIa)

[0191] wherein Y is as defined above for compounds of formula (IVa), R 1 is as defined above for compounds of formula (V) and X is as defined above for compounds of formula (Ia);

[0192] reacting with methanol in the presence of a copper source and a ligand to obtain a compound having formula (IIIa);

[0193]

[0194] wherein X is as defined above for compounds of formula (Ia) and R 1 is as defined above for the compound of formula (IIa);

[0195] and wherein the ligand is an oxalamide compound having formula (VI),

[0196]

[0197] in,

[0198] Z is NH or O;

[0199] R2 is selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl, naphthyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolyl, benzyl, phenethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl and quinolylmethyl, wherein the phenyl, naphthyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolyl, benzyl, phenethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl or quinolylmethyl is optionally replaced by 1, 2 or 3 R which may be the same or different if feasible. 4 Substituent substitution;

[0200] R 3 is selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl, naphthyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolyl, benzyl, phenethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl and quinolylmethyl, wherein the phenyl, naphthyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolyl, benzyl, phenethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl or quinolylmethyl is optionally replaced by 1, 2 or 3 R which may be the same or different if feasible. 4 Substituents are substituted; and

[0201] Each R 4 independently selected from the group consisting of bromine, chlorine, fluorine, nitro, -OH, -C(O)OH, dimethylamino, diethylamino, methoxycarbonyl, methyl, ethyl, isopropyl, tert-butyl, methoxy, isopropoxy, trifluoromethyl, phenyl, and phenoxy;

[0202] or the ligand is selected from the group consisting of trans-N,N'-dimethylcyclohexane-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;

[0203] as well as

[0204] (c) hydrolysis to a compound of formula (Ia).

[0205] In another more preferred embodiment of the present invention, there is provided a method for preparing a compound having formula (Ia-I),

[0206]

[0207] The method comprises the following steps:

[0208] (a) making a compound having the formula (IVa-I),

[0209]

[0210] reacting with a compound having formula (VI),

[0211] CH3-NH2

[0212] (VI)

[0213] To obtain a compound having formula (IIa),

[0214]

[0215] as well as

[0216] (b) making a compound having formula (IIa-I)

[0217]

[0218] reacting with methanol in the presence of a copper (I) salt (preferably copper (I) chloride) and a ligand to obtain a compound having formula (IIIa-I);

[0219]

[0220] in,

[0221] 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 )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)oxalamide, N,N'-bis(2,4,6-trimethoxyphenyl)oxalamide, N,N'-bis(2,5-dimethylpyrrol-1-yl)oxalamide, N,N'-dibenzyloxalamide, N,N'-bis(2-phenylethyl)oxalamide and N,N'-bis(2-pyridylmethyl)oxalamide (preferably 2-(2-methylphenyl)oxalamide). acetic acid, 2-(2,6-trimethylanilino)-2-oxo-acetic acid, 2-(2,6-triisopropylanilino)-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);

[0222] or the ligand is trans -N,N'-dimethylcyclohexane-1,2-diamine;

[0223] as well as

[0224] (c) hydrolysis to a compound of formula (Ia-I).

[0225] In an embodiment of the present invention, there is provided a compound having the formula (III),

[0226]

[0227] in,

[0228] X is halogen (preferably, X is chlorine, bromine or iodine, more preferably, X is chlorine or bromine, even more preferably, X is chlorine, most preferably, X is 4-chlorine),

[0229] And R 1 is a C1-C6 alkyl group (preferably, R 1 is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl and tert-butyl, more preferably, R 1is selected from the group consisting of methyl, ethyl, and tert-butyl, and even more preferably, R 1 is methyl or tert-butyl, most preferably, R 1 is methyl);

[0230] 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-tert-butyl-1-(5-chloro-2-methoxy-phenyl)methanimine and N-tert-butyl-1-(5-bromo-2-methoxy-phenyl)methanimine.

[0231] In a preferred embodiment, a compound having the formula (IIIa-I) (1-(4-chloro-2-methoxy-phenyl)-N-methyl-formanimine) is provided,

[0232]

[0233] In another embodiment of the present invention, the method further comprises converting the compound having formula (I) into a compound having formula (VII),

[0234]

[0235] Wherein G is selected from the group consisting of hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 alkoxy, C1-C3 alkyl-, -C(O)-R 5 、-C(O)-X a -R 5 and -S(O)2-R 5 ;

[0236] X a is oxygen or sulfur; and

[0237] R 5 Selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, phenyl and 4-fluorophenyl.

[0238] In a preferred embodiment of the present invention, the method further comprises converting the compound having formula (I) into a compound having formula (VII),

[0239]

[0240] Wherein G is selected from the group consisting of hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 alkoxy, C1-C3 alkyl-, -C(O)-R 5、-C(O)-X a -R 5 and -S(O)2-R 5 ;

[0241] X a is oxygen or sulfur; and

[0242] R 5 Selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, phenyl and 4-fluorophenyl;

[0243] The method further comprises the steps as described on page 54 of WO 2015 / 197468.

[0244] Examples:

[0245] The following examples further illustrate (but do not limit) the present invention. One skilled in the art will quickly recognize appropriate variations from these procedures regarding reactants as well as regarding reaction conditions and techniques.

[0246] The following abbreviations are used: s = singlet; br s = broad singlet; d = doublet; dd = double of doublets; dt = double of triplets; t = triplet, tt = triplet of triplets, q = quartet, quin = quintet, sept = septet; m = multiplet; GC = gas chromatography, RT = retention time, T i =Internal temperature, MH + = molecular weight of the molecular cation, M = mole, Q 1 HNMR = quantitative 1 HNMR, RT = room temperature, UFLC = ultra fast liquid chromatography.

[0247] Unless otherwise stated, 1 H NMR spectra were recorded at 400 MHz and chemical shifts are reported in ppm.

[0248] Some chemical yields have been accurately calculated using quantitative 1H NMR and 1,3,5-trimethoxybenzene as an internal standard. When chemical yields are based on quantitative 1H NMR, the nature of any relevant counterions is assumed based on the reaction conditions used, however, the skilled artisan will appreciate that the crude reaction mixture may also include (but is not limited to) other counterions such as chloride, bromide, iodide, fluoride, bisulfate, methanesulfonate, oxalate, tartrate, and trifluoroacetate.

[0249] Example 1: Ligand Screening Procedure

[0250]

[0251] program:

[0252] The ligand (0.10 mmol, 0.20 eq) was weighed into a 4 ml Supelco vial under air. Copper (I) chloride (9.9 mg, 0.10 mmol, 0.20 eq) and potassium carbonate (76.8 mg, 0.55 mmol, 1.1 eq) were weighed into a second 4 ml vial under argon and a stirrer was added. A stock solution of 1-(2,4-dichlorophenyl)-N-methyl-formimine (about 12.5 mmol) in dry, degassed methanol (25 ml) was prepared under argon and 1 ml (about 0.5 mmol) was transferred to each of the 24 vials containing the ligand. The ligand and 1-(2,4-dichlorophenyl)-N-methyl-formimine solution were transferred to the vial containing CuCl and potassium carbonate. The reaction block was sealed and transferred to a heater / drum stirrer. The block was heated to 75 °C for 4 hours. 1 ml of standard stock solution (about 0.5 g of tetramethylbenzene in 50 ml of DCM) was added to each reaction vessel. 200 μL was aliquoted from each reaction and placed in 1300 μL of DCM and then filtered using a CHROMAFIL 45 μm syringe filter. The samples were run on a GCMS (chemical ionization, 70°C-320°C, at 40°C / min, column: Phenomenex ZB-5ms, 15m, diameter 0.25mm, 0.25 μm). Tetramethylbenzene was used as an internal standard to calculate yield and selectivity. The conversion of the starting material and the selectivity of the desired product were calculated from the GC results. The results are shown in Table 1 below.

[0253] Table 1. Results of ligand screening.

[0254]

[0255]

[0256] Table A. Ligand structures.

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267] Example 2: Amine Screening Procedure

[0268]

[0269] program:

[0270] Amine (6.28mmol, 1.1 equivalent) was added to a solution of 2,4-dichlorobenzaldehyde (1g, 5.71mmol, 1.00 equivalent) in methanol (6.3ml) in a screening vial. The reaction mixture was heated to 40°C and stirred at 40°C for 60min. Potassium phosphate (1.33g, 6.28mmol, 1.10 equivalent), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.166g, 1.14mmol, 0.20 equivalent) and copper (I) chloride (0.112g, 1.14mmol, 0.20 equivalent) were added to the obtained solution in sequence. The vial was closed and the reaction mixture was heated to 65°C for 16h. Then, the pH was adjusted to 3 with 2N HCl, and the reaction mixture was stirred for an additional 60min at 65°C, and then analyzed by GC. The conversion of the starting material and the selectivity of the desired product were calculated from the GC results. The results are shown in Table 2 below.

[0271] Table 2: Amine Screening

[0272] serial number amine Conversion rate [%] Selectivity [%] 1 (Comparative Example) none 62 21 2 <![CDATA[Me-NH2]]> 99 76 3 <![CDATA[Et-NH2]]> 100 45 4 <![CDATA[iPr-NH2]]> 100 38 5 <![CDATA[iBu-NH2]]> 100 22 6 <![CDATA[tBu-NH2]]> 92 70

[0273] Example 3: Preparation of 2-methoxy-4-chlorobenzaldehyde from 2,4-dichlorobenzaldehyde

[0274]

[0275] program:

[0276] To 2,4-dichlorobenzaldehyde (20g, 114mmol, 1.00 equivalent) in methanol (95ml) solution, methylamine solution in methanol (40w-%, 9.32g, 120mmol, 1.05 equivalent) was added at one time. The reaction mixture was heated to 40 ° C and stirred at 40 ° C for 30min. The colorless solution obtained was cooled to room temperature and transferred to a pressure autoclave. Then, potassium phosphate (26.7g, 126mmol, 1.11 equivalents), [(2,6-dimethylphenyl) amino] (oxo) acetic acid (1.09g, 5.64mmol, 0.05 equivalent), boric acid (0.353g, 5.71mmol, 0.05 equivalent) and copper (I) chloride (0.560g, 5.65mmol, 0.05 equivalent) were added to the solution in sequence. The pressure autoclave was closed, and the reaction mixture was heated to 80 ° C for 16h. The maximum pressure of about 2 bar was observed. After cooling to room temperature and releasing the remaining pressure, the pressure autoclave was opened and the reaction mixture was transferred to a 500ml double-jacketed reactor. Water (70ml) was added to the reaction mixture and the mixture was stirred at room temperature for 10min. Methanol was distilled off and methylcyclohexane (115ml) was added to the obtained suspension. The mixture was heated to 55°C and each phase was separated. 2M hydrochloric acid (48g, 99.9mmol, 0.88 equivalent) was added to the organic phase and the mixture was stirred at 55°C for 1h. After phase separation, the product was crystallized by cooling the organic phase to 0°C for 4h. The suspension was stirred for an additional 30min at 0°C and the mixture was then filtered. The crude product obtained was washed with cold (0°C-5°C) methylcyclohexane (2×50ml) and dried at 50°C for 14h to obtain the title compound (14.9g, 93% purity, as determined by quantitative NMR, 71% yield)

[0277] 1 H NMR (400MHz, CDCl3) δppm: 10.40 (s, 1H), 7.80 (d, 1H, J = 8.0), 6.88-7.16 (m, 2H), 3.98 (s, 3H)

[0278] Example 4: Preparation of 2-methoxy-4-bromobenzaldehyde from 2,4-dibromobenzaldehyde

[0279]

[0280] program:

[0281] To 2,4-dichlorobenzaldehyde (5.0g, 18.9mmol, 1.00 equivalent) in methanol (150ml) solution, methylamine solution in methanol (40w-%, 1.57g, 20.2mmol, 1.07 equivalent) was added at one time. The reaction mixture was heated to 40 ° C and stirred at 40 ° C for 30min. The colorless solution obtained was cooled to room temperature and transferred to a pressure autoclave. Then, potassium phosphate (4.42g, 20.8mmol, 1.10 equivalents), [(2,6-dimethylphenyl) amino] (oxo) acetic acid (0.181g, 0.94mmol, 0.05 equivalents), boric acid (0.059g, 0.95mmol, 0.05 equivalents) and copper (I) chloride (0.093g, 0.94mmol, 0.05 equivalents) were added to the solution in sequence. The pressure autoclave was closed, and the reaction mixture was heated to 80 ° C for 16h. Observe the maximum pressure of about 2 bar.After cooling to room temperature and releasing the remaining pressure, open the pressure autoclave and transfer the reaction mixture to a 500ml double-jacketed reactor.Water (30ml) is added to the reaction mixture and the mixture is stirred at room temperature for 10min. Methanol is distilled off and methylcyclohexane (30ml) is added to the obtained suspension. The mixture is heated to 55°C and each phase is separated. Water (65ml) and 2M hydrochloric acid (8.8g, 17.6mmol, 0.93 equivalent) are added to the organic phase and the mixture is stirred for 1h at 55°C. After phase separation, the product is crystallized by cooling the organic phase to 0°C through 4h. The suspension is stirred for an additional 20min at 0°C and then the mixture is filtered. The crude product obtained is washed with cold (0°C-5°C) methylcyclohexane (1×10ml) and dried at 50°C for 18h to obtain the title compound (2.5g, 96% purity, as determined by quantitative NMR, 59% yield)

[0282] 1 H NMR (400MHz, CDCl3) δppm: 10.41 (s, 1H), 7.69 (d, 1H, J = 4.8), 7.10-7.25 (m, 2H), 3.95 (s, 3H)

[0283] Example 5: Comparative Example

[0284] It is found that the prior art examples (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) disclosed

[0285] Item 1) of Table 5 is not reproducible, as detailed below:

[0286]

[0287] Four 20 mL glass vials were each charged with 2,4-dichlorobenzaldehyde (99%, 5.7 mmol, 1 g), 10 mL of methanol was added and stirred at room temperature to produce a clear yellowish solution. 0.02 equivalents of Na2CO3, K2CO3, Cs2CO3 or Li2CO3 were added to each vial at once. The values ​​can be seen in the following material table 3. The reaction mixture was then heated to 65°C for a total of 22 hours (clear solution, except for the Li2CO3 experiment = suspension).

[0288] Multiple in-process controls via GC showed that the conversion of the starting material to the desired compound (4-chloro-2-methoxybenzaldehyde) was absent or insignificant (<1%).

[0289] Table 3: Materials table for comparative experiments

[0290]

[0291] Thus, based on the above results, the skilled person will appreciate that the process for preparing 4-chloro-2-methoxybenzaldehyde disclosed in KUMAR and NEGI is not achievable and therefore will not follow the teachings of this reference with any reasonable expectation of success when faced with the technical problem of developing a new process.

Claims

1. A method for preparing a compound of formula (I), in, X is a halogen; The method comprises the following steps: (i) making a compound having formula (II) wherein Y is selected from the group consisting of bromine, chlorine, iodine, CF3SO3-, CH3C6H4SO3- and CH3SO3-, R 1 is C1-C6 alkyl and X is as defined above for compounds of formula (I); reacting with methanol in the presence of a copper source to obtain a compound having formula (III); wherein X is as defined above for compounds of formula (I) and R 1 is as defined above for the compound of formula (II); as well as (ii) hydrolyzed to a compound of formula (I).

2. The method according to claim 1, wherein: The compound having formula (II) is formed by: making a compound having formula (IV), wherein Y and X are as defined in claim 1, reacting with a compound having formula (V), R 1 -NH2 (V) Where R 1 is as defined in claim 1, To obtain a compound having formula (II).

3. The method according to claim 2, wherein: The intermediate compounds of formula (II) and formula (III) were not isolated.

4. The method according to any one of claims 1 to 3, wherein: X and Y are independently chlorine or bromine.

5. The method according to any one of claims 1 to 4, wherein: Y is chloro and X is 4-chloro.

6. The method according to any one of claims 1 to 5, wherein: R 1 It's methyl.

7. The method according to any one of claims 1 to 6, wherein: The copper source is a copper (I) salt.

8. The method according to any one of claims 1 to 7, wherein: The copper source is copper (I) chloride.

9. The method according to any one of claims 1 to 8, wherein: Step (i) is carried out in the presence of a ligand.

10. The method according to claim 9, wherein: The ligand is selected from the group consisting of diamines, oxalamides, hydroxyquinolines, carboxylic acids, oximes and amino sugars.

11. The method according to claim 9 or 10, wherein: The ligand is an oxalamide compound having formula (VI), in, Z is NH or O; R 2 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C3 alkyl-, C3-C6 cycloalkenyl, C3-C6 cycloalkenylC1-C3 alkyl-, phenyl, naphthyl, heterocyclyl, heteroaryl, heterodiaryl, phenylC1-C3 alkyl-, heterocyclylC1-C3 alkyl-, heteroarylC1-C3 alkyl- and heterodiarylC1-C3 C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C3 alkyl-, C3-C6 cycloalkenyl, C3-C6 cycloalkenylC1-C3 alkyl-, phenyl, naphthyl, heterocyclyl, heteroaryl, heterodiaryl, phenylC1-C3 alkyl-, heterocyclylC1-C3 alkyl-, heteroarylC1-C3 alkyl- or heterodiarylC1-C3 alkyl-, where applicable, may be optionally replaced by 1, 2 or 3 R which may be the same or different 4 Substituents are substituted, and wherein the heterocyclyl is a 3- to 6-membered non-aromatic ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the heteroaryl is a 5- or 6-membered monocyclic aromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the heterobiaryl is a 9- or 10-membered aromatic fused bicyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 3 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C3 alkyl-, C3-C6 cycloalkenyl, C3-C6 cycloalkenylC1-C3 alkyl-, phenyl, naphthyl, heterocyclyl, heteroaryl, heterodiaryl, phenylC1-C3 alkyl-, heterocyclylC1-C3 alkyl-, heteroarylC1-C3 alkyl- and heterodiarylC1-C3 C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C3 alkyl-, C3-C6 cycloalkenyl, C3-C6 cycloalkenylC1-C3 alkyl-, phenyl, naphthyl, heterocyclyl, heteroaryl, heterodiaryl, phenylC1-C3 alkyl-, heterocyclylC1-C3 alkyl-, heteroarylC1-C3 alkyl- or heterodiarylC1-C3 alkyl-, where applicable, may be optionally replaced by 1, 2 or 3 R which may be the same or different 4 Substituents are substituted, and wherein the heterocyclyl is a 3- to 6-membered non-aromatic ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the heteroaryl is a 5- or 6-membered monocyclic aromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the heterodiaryl is a 9- or 10-membered aromatic fused bicyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and Each R 4 Independently selected from the group consisting of halogen, nitro, cyano, -OH, -C(O)OH, N-C1-C4 alkylamino, N,N-diC1-C4 alkylamino, C1-C4 alkylcarbonyl, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, N-C1-C4 alkylaminocarbonyl, N,N-diC1-C4 alkylaminocarbonyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, phenyl and phenoxy.

12. The method according to claim 11, wherein: In the compound having formula (VI), Z is NH or O; R 2 is selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl, naphthyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolyl, benzyl, phenethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl and quinolylmethyl, wherein the phenyl, naphthyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolyl, benzyl, phenethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl or quinolylmethyl is optionally replaced by 1, 2 or 3 R which may be the same or different if feasible. 4 Substituent substitution; R 3 is selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl, naphthyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolyl, benzyl, phenethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl and quinolylmethyl, wherein the phenyl, naphthyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolyl, benzyl, phenethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl or quinolylmethyl is optionally replaced by 1, 2 or 3 R which may be the same or different if feasible. 4 Substituents are substituted; and Each R 4 Independently selected from the group consisting of bromine, chlorine, fluorine, nitro, -OH, -C(O)OH, dimethylamino, diethylamino, methoxycarbonyl, methyl, ethyl, isopropyl, tert-butyl, methoxy, isopropoxy, trifluoromethyl, phenyl and phenoxy.

13. The method according to claim 11 or claim 12, wherein: In the compound having formula (VI), Z is NH or O; R 2 is selected from the group consisting of hydrogen, phenyl, pyrrolyl, benzyl and phenethyl, wherein the phenyl, pyrrolyl, benzyl or phenethyl is optionally substituted, where feasible, by 1, 2 or 3 R which may be the same or different 4 Substituent substitution; R 3 is selected from the group consisting of phenyl, pyrrolyl, benzyl and phenethyl, wherein the phenyl, pyrrolyl, benzyl or phenethyl is optionally substituted, where feasible, by 1, 2 or 3 R which may be the same or different 4 Substituents are substituted; and Each R 4 Independently selected from the group consisting of chloro, methyl, ethyl, isopropyl, tert-butyl and methoxy.

14. The method 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-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)oxalamide, N,N'-bis(2,4,6-trimethoxyphenyl)oxalamide, N,N'-bis(2,5-dimethylpyrrol-1-yl)oxalamide, N,N'-dibenzyloxalamide, N,N'-bis(2-phenylethyl)oxalamide and N,N'-bis(2-pyridylmethyl)oxalamide.

15. The method according to claim 9 or 10, wherein: The ligand is selected from the group consisting of: trans-N,N'-dimethylcyclohexane-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. The method according to any one of claims 1 to 15, wherein: The method further comprises converting the compound having formula (I) into a compound having formula (VII), Wherein G is selected from the group consisting of hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 alkoxy, C1-C3 alkyl-, -C(O)-R 5 、-C(O)-X a -R 5 and -S(O)2-R 5 ; X a is oxygen or sulfur; and R 5 Selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, phenyl and 4-fluorophenyl.

17. A compound having formula (III), Where X and R 1 is as defined in any one of claims 1 to 6, with the proviso 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-tert-butyl-1-(5-chloro-2-methoxy-phenyl)methanimine and N-tert-butyl-1-(5-bromo-2-methoxy-phenyl)methanimine.

18. The compound according to claim 17, wherein the compound of formula (III) is a compound of formula (IIIa-I),

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