Process for synthesizing methoxy-substituted benzaldehyde compounds

Abstract

The present invention, in particular, is based on formula (I) [Formula 1] JPEG2026512768000067.jpg31160 (wherein the formula, the substituents are as defined in claim 1) This provides a process for preparing the compound.

Description

[Technical Field]

[0001] The present invention relates to a novel process for synthesizing specific methoxy-substituted benzaldehyde compounds and novel intermediates used in the process. Such compounds are useful intermediates in the synthesis of the herbicide propynylphenyl compounds, for example, known from International Publication No. 2015 / 197468, and processes for producing such compounds or their intermediates are also known. [Background technology]

[0002] Copper-catalyzed synthesis of alkylaryl ethers is known; see, for example, SAMBIAGO et al., Copper Catalyzed Ullmann type chemistry: from mechanistic aspects to modern development, Chem. Soc. Rev 2014, Vol. 43, pp. 3525-3550, German Patent Application Publication No. 2721643 (LUDWIG HEUMANN AND CO), November 23, 1978, and European Patent Application Publication No. 0520815 (Nippon Chemical Industry Co., Ltd.), December 30, 1992. Copper-catalyzed coupling of cyclohexyl hymine-substituted aryl iodides and 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. [Overview of the Initiative] [Problems that the invention aims to solve]

[0003] Copper-catalyzed Ullmann coupling reactions can be carried out in the presence of ligands; 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 European Patent Application Publication No. 3326715 (SHANGHAI INSTITUTE OF ORGANIC CHEMISTRY), May 30, 2018. Furthermore, the use of directing groups 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, 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, copper-free processes 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-catalyst and ligand, Tetrahedron Letters, 2015, Vol. 56, pp. 2340-2344. However, these are either unsuitable for large-scale production or / or involve high yield losses and the need for additional product purification. Therefore, there is a need for new, more efficient synthetic methods that utilize more favorable reaction conditions and avoid the formation of undesirable by-products. [Means for solving the problem]

[0004] The present invention provides an O-arylation process for benzaldehyde derivatives that offers (i) a high level of regioselectivity and (ii) a good level of conversion to a desired product. Surprisingly, the inventors have found that selective O-arylation to yield a desired monomethoxylated product, a compound of formula (I), which can be converted in turn to a desired propynylphenyl herbicide compound, can be achieved in the process of the present invention.

[0005] Therefore, according to the present invention, formula (I) [ka] (In the formula, X is a halogen. A process for preparing the compound, (i) Equation (II) [ka] (In the formula, Y is selected from the group consisting of bromo, chloro, iodine, CF3SO3-, CH3C6H4SO3- and CH3SO3-, R 1 (where is a C1-C6 alkyl group, and X is as defined above for the compound of formula (I)) The compound was reacted with methanol in the presence of a copper source to obtain formula (III). [ka] (wherein X is as defined above for the compound of formula (I), and R 1 (This is as defined above for compounds of formula (II).) The step of obtaining the compound, (ii) Steps of hydrolysis of the compound of formula (I) and A process including this is provided.

[0006] According to a second aspect of the present invention, formula (III) [ka] (wherein X and R in the formula) 1 (as defined herein) An intermediate compound is provided, provided that it is not a compound selected from the group consisting of N-butyl-1-(4-chloro-2-methoxyphenyl)methanymine, N-tert-butyl-1-(4-fluoro-2-methoxyphenyl)methanymine, 1-(5-bromo-2-methoxyphenyl)-N-methylmethanymine, N-tert-butyl-1-(5-fluoro-2-methoxyphenyl)methanymine, N-tert-butyl-1-(5-chloro-2-methoxyphenyl)methanymine, and N-tert-butyl-1-(5-bromo-2-methoxyphenyl)methanymine. [Modes for carrying out the invention]

[0007] As used herein, the term "halogen" refers to fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iod).

[0008] As used herein, the terms "hydroxyl" or "hydroxy" mean the -OH group.

[0009] As used herein, cyano refers to the -CN group.

[0010] As used herein, nitro means the -NO2 group.

[0011] As used herein, oxo means an =O group (for example, as in a carbonyl (C=O) group).

[0012] As used herein, the term "C1-C6 alkyl" refers to a linear or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing no unsaturation, having 1 to 6 carbon atoms, and bonded to the remainder of the molecule by single bonds. 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 (t-butyl).

[0013] The term "C1-C2 alkylene" refers to the corresponding definition of C1-C2 alkyl, except that such a group is attached to the rest of the molecule by two single bonds. Examples of C1-C2 alkylenes are -CH2- and -CH2CH2-.

[0014] As used herein, the term "C1-C6 alkoxy" refers to the formula -OR a (In the formula, R a C refers to a group of C1-C6 alkyl groups as generally defined above. C1-C4 alkoxys should be interpreted accordingly. 1-4 Examples of alkoxys include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and t-butoxy.

[0015] As used herein, the term "C1-C6 haloalkyl" refers to a C1-C6 alkyl group as generally defined above, which is substituted by one or more of the same or different halogen atoms. C1-C4 haloalkyls should be interpreted accordingly. Examples of C1-C6 haloalkyls include, but are not limited to, chloromethyl, fluoromethyl, fluoroethyl, difluoromethyl, trifluoromethyl, and 2,2,2-trifluoroethyl.

[0016] As used herein, the term "C1-C6 haloalkoxy" refers to a C1-C6 alkoxy group as defined above, substituted by one or more of the same or different halogen atoms. C1-C4 haloalkoxy should be construed accordingly. Examples of C1-C6 haloalkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, fluoroethoxy, trifluoromethoxy and trifluoroethoxy.

[0017] As used herein, the term "C2-C6 alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one double bond which may be in either the (E) or (Z) configuration, having 2 to 6 carbon atoms and attached to the remainder of the molecule by a single bond. C2-C4 alkenyl should be construed accordingly. Examples of C2-C6 alkenyl include, but are not limited to, prop-1-enyl, allyl (prop-2-enyl) and but-1-enyl.

[0018] As used herein, the term "C2-C6 alkynyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one triple bond, having 2 to 6 carbon atoms and attached to the remainder of the molecule by a single bond. Examples of C3-C6 alkynyl include, but are not limited to, prop-1-ynyl and propargyl (prop-2-ynyl).

[0019] As used herein, the term "C1-C3 alkoxy C1-C3 alkyl-" refers to a group of the formula R b -O-R a -(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).

[0020] As used herein, the term "C1-C6 alkylcarbonyl" refers to a group of the formula R aC(O)-(wherein, R a This refers to a group of C1-C6 alkyl groups as generally defined above.

[0021] As used herein, the term "C1-C6 alkoxycarbonyl" refers to the formula R a OC(O)-(wherein, R a This refers to the group of a C1-C6 alkyl group as generally defined above.

[0022] As used herein, the term "C3-C6 cycloalkyl" refers to a saturated and stable monocyclic ring group containing 3 to 6 carbon atoms. C3-C4 cycloalkyl should be interpreted accordingly. Examples of C3-C6 cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0023] As used herein, the term "C3-C6 cycloalkyl C1-C3 alkyl-" refers to a C3-C6 cycloalkyl ring, as defined above, bonded to the remainder of the molecule by a C1-C3 alkylene group, as defined above. 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.

[0024] As used herein, the term "C3-C6 cycloalkenyl" refers to a partially unsaturated and stable monocyclic ring group containing 3 to 6 carbon atoms. C3-C4 cycloalkenyls should be interpreted accordingly. Examples of C3-C6 cycloalkenyls include, but are not limited to, cyclopenten-1-yl and cyclohexen-1-yl.

[0025] As used herein, the term "C3C6 cycloalkenyl C1-C3 alkyl-" refers to a C3-C6 cycloalkenyl ring, as defined above, bonded to the remainder of the molecule by a C1-C3 alkylene group, as defined above. The term "C3-C4 cycloalkyl C1-C2 alkyl" should be interpreted accordingly.

[0026] As used herein, the term "N-C1~C4 alkylamino" refers to formula R a NH-(wherein, R a This refers to a group of C1-C4 alkyl groups as generally defined above.

[0027] As used herein, the term "N,N-diC1~C4 alkylamino" refers to the formula R a (R b )(wherein, R a and R b This refers to a group of the same or different C1-C4 alkyl groups as generally defined above.

[0028] As used herein, the term "N-C1~C4 alkylaminocarbonyl" refers to the formula R a NHC(O)-(wherein, R a This refers to a group of C1-C4 alkyl groups as generally defined above.

[0029] As used herein, the term "N,N-di(C1-C4 alkylaminocarbonyl)" refers to the formula R a (R b )NC(O)-(wherein, R a and R b This refers to a group of the same or different C1-C4 alkyl groups as generally defined above.

[0030] As used herein, the term "phenyl C1-C3 alkyl" refers to a phenyl ring attached to the remainder of a molecule by a C1-C3 alkylene group as generally defined above.

[0031] As used herein, unless otherwise specifically stated, the term “heteroaryl” refers to a five- or six-membered monocyclic aromatic ring containing one, two, three, or four heteroatoms individually selected from nitrogen, oxygen, and sulfur. The heteroaryl group may be bonded to the remainder of the molecule via carbon atoms or heteroatoms. Examples of heteroaryls include furyl, pyrrolyl, imidazolyl, thienyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridadinyl, pyrimidyl, or pyridyl.

[0032] As used herein, the term "heteroaryl C1-C3 alkyl-" refers to a heteroaryl ring as defined above, which is bonded to the remainder of the molecule by a C1-C3 alkylene group as generally defined above.

[0033] As used herein, unless otherwise specifically stated, the terms “heterocyclyl” or “heterocyclic” refer to a stable 3- to 6-membered non-aromatic monocyclic ring group containing one, two, or three heteroatoms individually selected from nitrogen, oxygen, and sulfur. The heterocyclyl group may be bonded to the remainder of the molecule via carbon atoms or heteroatoms. Examples of heterocyclyls include, but are not limited to, pyrrolinyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydrothiopyranil, piperidyl, piperazinyl, tetrahydropyranil, dihydroisoxazolyl, dioxolanil, morpholinyl, or δ-lactamyl.

[0034] As used herein, the term "heterocyclyl C1-C3 alkyl" refers to a heterocyclyl ring as defined above, which is bonded to the remainder of the molecule by a C1-C3 alkylene group as generally defined above.

[0035] As used herein, the term "heterodiaryl" refers to a nine- or ten-membered aromatic condensed bicyclic ring group containing one, two, three, or four heteroatoms individually selected from nitrogen, oxygen, and sulfur. The heteroaryl group may be bonded to the remainder of the molecule via carbon atoms or heteroatoms. Examples of heterodiaryls include indolyl, indazolyl, benzimidazolyl, pyrrolopyridinyl, or triazolopyridinyl.

[0036] As used herein, the term "heterodiaryl C1-C3 alkyl" refers to a heteroaryl ring as generally defined above, which is bonded to the remainder of the molecule by a C1-C3 alkylene group as generally defined above.

[0037] Those skilled in the art will understand that the compounds of formula (II) and (III) may exist as E and / or Z isomers. The present invention encompasses processes and compounds containing all such isomers and mixtures thereof in all proportions.

[0038] For example, the compound of formula (II) is the compound of formula (II-I) or (II-II) shown below. [ka] It can be depicted as a compound of [the compound].

[0039] Similarly, compounds of formula (III) are those of formula (III-I) or (III-II) shown below. [ka] It can be depicted as a compound of [the compound].

[0040] Similarly, compounds of formula (IIa-I) are (IIa-Ia) or (IIa-Ib) [ka] It can be depicted as a compound of [the compound].

[0041] Similarly, compounds of formula (IIIa-I) are (IIIa-Ia) or (IIIa-Ib) [ka] It can be depicted as a compound of [the compound].

[0042] The process of the present invention may be carried out in separate process steps in which intermediate compounds can be isolated at each stage. Alternatively, the process may be carried out in a one-step procedure in which the resulting intermediate compounds are not isolated. Thus, the process of the present invention can be carried out in batch or continuous form.

[0043] The following list is related to the process according to the present invention, with substituents X, Y, Z, G, X a , R 1 , R 2 , R 3 , R 4 and R 5 Provides a definition (including preferred definitions) for [the term].

[0044] X is a halogen. Preferably, X is chloro, bromo, or iodine. More preferably, X is chloro or bromo. Even more preferably, X is chloro. Most preferably, X is 4-chloro.

[0045] Y is selected from the group consisting of bromo, chloro, iodine, CF3SO3-, CH3C6H4SO3-, and CH3SO3-. Preferably, Y is selected from the group consisting of bromo, chloro, and iodine. More preferably, Y is bromo or chloro. Even more preferably, Y is chloro.

[0046] Z is either NH or O. In one embodiment, Z is NH. In another embodiment, Z is O.

[0047] R 1 is a C1-C6 alkyl group. Preferably, R 1is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl and t-butyl. More preferably, R 1 is selected from the group consisting of methyl, ethyl, and t-butyl. More preferably, R 1 is methyl or t-butyl. Most preferably, R 1 It is methyl.

[0048] R 2 It consists 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, naphthalenyl, heterocyclyl, heteroaryl, heterodiaryl, phenyl C1-C3 alkyl-, heterocyclyl C1-C3 alkyl-, heteroaryl C1-C3 alkyl-, and heterodiaryl C1-C3 alkyl-. Selected from the group, the C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C3 alkyl-, C3-C6 cycloalkenyl, C3-C6 cycloalkenylC1-C3 alkyl-, phenyl, naphthalenyl, heterocyclyl, heteroaryl, heterodiaryl, phenyl C1-C3 alkyl-, heterocyclyl C1-C3 alkyl-, heteroaryl C1-C3 alkyl-, or heterodiaryl C1-C3 alkyl may, where feasible, be the same or different of 1, 2, or 3 R 4 The heterocyclyl may be optionally substituted with substituents, and the heterocyclyl is a 3-6 membered non-aromatic ring containing one or two heteroatoms individually selected from nitrogen, oxygen, and sulfur, the heteroaryl is a 5 or 6 membered monocyclic aromatic ring containing one, two, three, or four heteroatoms individually selected from nitrogen, oxygen, and sulfur, and the heterodiaryl is a 9 or 10 membered aromatic condensed bicyclic ring group containing one, two, three, or four heteroatoms individually selected from nitrogen, oxygen, and sulfur. Preferably, R 2The R is selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl, and quinolinylmethyl, wherein the phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl, or quinolinylmethyl may be the same or different 1, 2, or 3 R's where feasible. 4 It may be optionally substituted with substituents. More preferably, R 2 R is selected from the group consisting of hydrogen, phenyl, pyrrolyl, benzyl, and phenylethyl, and the phenyl, pyrrolyl, benzyl, or phenylethyl may, where feasible, be the same or different of 1, 2, or 3 R 4 It may be optionally substituted with substituents.

[0049] R 3 It consists 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, naphthalenyl, heterocyclyl, heteroaryl, heterodiaryl, phenyl C1-C3 alkyl-, heterocyclyl C1-C3 alkyl-, heteroaryl C1-C3 alkyl-, and heterodiaryl C1-C3 alkyl-. Selected from the group, the C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C3 alkyl-, C3-C6 cycloalkenyl, C3-C6 cycloalkenyl C1-C3 alkyl-, phenyl, naphthalenyl, heterocyclyl, heteroaryl, heterodiaryl, phenyl C1-C3 alkyl-, heterocyclyl C1-C3 alkyl-, heteroaryl C1-C3 alkyl or heterodiaryl C1-C3 alkyl- may be the same or different if feasible, one, two or three R 4The heterocyclyl may be optionally substituted with substituents, and the heterocyclyl is a 3-6 membered non-aromatic ring containing one or two heteroatoms individually selected from nitrogen, oxygen, and sulfur, the heteroaryl is a 5 or 6 membered monocyclic aromatic ring containing one, two, three, or four heteroatoms individually selected from nitrogen, oxygen, and sulfur, and the heterodiaryl is a 9 or 10 membered aromatic condensed bicyclic ring group containing one, two, three, or four heteroatoms individually selected from nitrogen, oxygen, and sulfur. Preferably, R 3 The R is selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl, and quinolinylmethyl, wherein the phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl, or quinolinylmethyl may be the same or different 1, 2, or 3 R's where feasible. 4 It may be optionally substituted with substituents. More preferably, R 3 The R is selected from the group consisting of phenyl, pyrrolyl, benzyl, and phenylethyl, and the phenyl, pyrrolyl, benzyl, or phenylethyl may, where feasible, be the same or different of 1, 2, or 3 R 4 It may be optionally substituted with substituents.

[0050] Each R 4 The following are 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 R4 R is independently selected from the group consisting of bromo, chloro, fluoro, nitro, -OH, -C(O)OH, dimethylamino, diethylamino, methoxycarbonyl, methyl, ethyl, isopropyl, tert-butyl, methoxy, isopropyloxy, trifluoromethyl, phenyl, and phenoxy. More preferably, each R 4 The compound is independently selected from the group consisting of chloro, methyl, ethyl, isopropyl, tert-butyl, and methoxy.

[0051] G represents hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 alkoxy, C1-C3 alkyl-, and -C(O)-R. 5 -C(O)-X a -R 5 and -S(O)2-R 5 Selected from the group consisting of the following. Preferably, G is hydrogen, -C(O)-R 5 -C(O)-X a -R 5 and -S(O)2-R 5 Selected from the group consisting of the following. More preferably, G is hydrogen, -C(O)-R 5 and -C(O)-X a -R 5 Selected from the group consisting of the following. More preferably, G is hydrogen or -C(O)-R 5 Therefore, most preferably, G is -C(O)-R 5 That is the case.

[0052] X a is oxygen or sulfur. Preferably, X a It is oxygen.

[0053] R 5 The is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, phenyl, and 4-fluorophenyl. Preferably, R 5 R is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, and phenyl. More preferably, 5 is selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl. More preferably, R5 These are C1-C6 alkyl groups.

[0054] The following Scheme 1 illustrates the reaction of the present invention in more detail. The definitions of substituents are as defined herein. Scheme 1: [ka]

[0055] Step (a) Imine formation: Formula (II) [ka] (In the formula, X, Y and R 1 (as defined herein) The compound is given by formula (IV) [ka] (wherein X and Y are as defined herein) Compound and formula (V) R 1 -NH2(V) (In the formula, R 1 (as defined herein) It can be prepared by reaction with a compound.

[0056] Typically, the process described in step (a) may be carried out as a neat reaction mixture, but it may also be carried out in solvents or mixtures of solvents such as, but are not limited to, methanol, ethanol, propanol, isopropanol, tert-butanol, butanol, 3-methyl-1-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether, tert-amylmethyl 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, e.g., 1,4-dicyanobenzene), toluene, xylene isomer mixtures, cumene, isopropylbenzene, p-xylene, mesitylene, 1,4-dioxane, or sulfolane. Preferably, process step (a) is carried out in methanol and / or toluene. More preferably, process step (a) is carried out in toluene.

[0057] Those skilled in the art will understand 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 the generated water or increasing the equivalent number of the compound of formula (V).

[0058] 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, and more preferably 20°C to 70°C.

[0059] Scheme 2: [ka] Step (b) Ullmann type coupling: Formula (III) [ka] (wherein X and R in the formula) 1 (as defined herein) The compound is, in the presence of a copper source, formula (II) [ka] (In the formula, Y and R 1 (as defined herein) It is prepared by the reaction of the compound with methanol.

[0060] Typically, the process described in step (b) may be carried out as a neat reaction mixture, but it may also be carried out in solvents or mixtures of solvents such as, but are not limited to, methanol, ethanol, propanol, isopropanol, tert-butanol, butanol, 3-methyl-1-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether, tert-amylmethyl 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, e.g., 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.

[0061] 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(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.

[0062] 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 to 1 mol% based on the compound of formula (II).

[0063] 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, oxalamides, oxyquinolines, carboxylic acids, oximes, and amino sugars.

[0064] The process described in step (b) may also be carried out in the presence of a polymerization inhibitor, if preferred to prevent undesirable polymerization of the ligand. Examples of such polymerization inhibitors include, but are not limited to, boric acid.

[0065] In one embodiment of the present invention, the ligand is given by formula (VI) [ka] (In the formula, Z is either NH or O. R 2It consists 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, naphthalenyl, heterocyclyl, heteroaryl, heterodiaryl, phenyl C1-C3 alkyl-, heterocyclyl C1-C3 alkyl-, heteroaryl C1-C3 alkyl-, and heterodiaryl C1-C3 alkyl-. Selected from the group, the C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C3 alkyl-, C3-C6 cycloalkenyl, C3-C6 cycloalkenylC1-C3 alkyl-, phenyl, naphthalenyl, heterocyclyl, heteroaryl, heterodiaryl, phenyl C1-C3 alkyl-, heterocyclyl C1-C3 alkyl-, heteroaryl C1-C3 alkyl-, or heterodiaryl C1-C3 alkyl- may be the same or different if feasible, one, two or three R 4 The heterocyclyl may be optionally substituted with substituents, and the heterocyclyl is a 3-6 member non-aromatic ring containing one or two heteroatoms individually selected from nitrogen, oxygen, and sulfur; the heteroaryl is a 5 or 6 member monocyclic aromatic ring containing one, two, three, or four heteroatoms individually selected from nitrogen, oxygen, and sulfur; and the heterodiaryl is a 9 or 10 member aromatic condensed bicyclic ring group containing one, two, three, or four heteroatoms individually selected from nitrogen, oxygen, and sulfur. R 3It consists 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, naphthalenyl, heterocyclyl, heteroaryl, heterodiaryl, phenyl C1-C3 alkyl-, heterocyclyl C1-C3 alkyl-, heteroaryl C1-C3 alkyl-, and heterodiaryl C1-C3 alkyl-. Selected from the group, the C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C3 alkyl-, C3-C6 cycloalkenyl, C3-C6 cycloalkenylC1-C3 alkyl-, phenyl, naphthalenyl, heterocyclyl, heteroaryl, heterodiaryl, phenyl C1-C3 alkyl-, heterocyclyl C1-C3 alkyl-, heteroaryl C1-C3 alkyl-, or heterodiaryl C1-C3 alkyl- may be the same or different if feasible, one, two or three R 4 The heterocyclyl may be optionally substituted by substituents, and the heterocyclyl is a 3-6 member non-aromatic ring containing one or two heteroatoms individually selected from nitrogen, oxygen, and sulfur; the heteroaryl is a 5 or 6 member monocyclic aromatic ring containing one, two, three, or four heteroatoms individually selected from nitrogen, oxygen, and sulfur; and the heterodiaryl is a 9 or 10 member aromatic condensed bicyclic ring group containing one, two, three, or four heteroatoms individually selected from nitrogen, oxygen, and sulfur; and Each R 4 (This is independently selected from the group consisting of halogens, 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.) It is an oxalamide compound.

[0066] Preferably, in the compound of formula (VI), Z is either NH or O, and R 2 The R is selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl, and quinolinylmethyl, wherein the phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl, or quinolinylmethyl may be the same or different 1, 2, or 3 R's where feasible. 4 They may be optionally substituted by substituents, R 3 The R is selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl, and quinolinylmethyl, wherein the phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl, or quinolinylmethyl may be the same or different 1, 2, or 3 R's where feasible. 4 They may be optionally substituted with substituents, and each R 4 The following are independently selected from the group consisting of bromo, chloro, fluoro, nitro, -OH, -C(O)OH, dimethylamino, diethylamino, methoxycarbonyl, methyl, ethyl, isopropyl, tert-butyl, methoxy, isopropyloxy, trifluoromethyl, phenyl, and phenoxy.

[0067] More preferably, in the compound of formula (VI), Z is NH or O, and R 2is selected from the group consisting of hydrogen, phenyl, pyrrolyl, benzyl and phenylethyl, and said phenyl, pyrrolyl, benzyl or phenylethyl may be the same or different and may be optionally substituted by 1, 2 or 3 R 4 substituents, R 3 is selected from the group consisting of phenyl, pyrrolyl, benzyl and phenylethyl, and said phenyl, pyrrolyl, benzyl or phenylethyl may be the same or different and may be optionally substituted by 1, 2 or 3 R 4 substituents, and each R 4 is independently selected from the group consisting of chloro, methyl, ethyl, isopropyl, tert-butyl and methoxy.

[0068] Even more preferably, the compound of formula (VI) is 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)oxal amide, N,N'-dibenzyloxamide, N,N'-bis(2-phenylethyl)oxamide and N,N'-bis(2-pyridylmethyl)oxamide.

[0069] More preferably, the compound of formula (VI) is 2-(2-methylanilino)-2-oxoacetic acid, 2-(2,6-diisopropylanilino)-2-oxoacetic acid, 2-oxo-2-(2,4,6-trimethoxyanilino)acetic acid, 2-(2-ethyl-6-methylanilino)-2-oxoacetic acid, 2-oxo-2-(2,4,6-trimethylanilino)acetic acid, 2-(2,6-di Selected from the group consisting of methylanilino)-2-oxoacetic acid, 2-(3,5-dimethylanilino)-2-oxoacetic acid, 2-(2-tert-butylanilino)-2-oxoacetic acid, 2-anilino-2-oxoacetic acid, 2-(4-chloroanilino)-2-oxoacetic acid, 2-(4-methoxyanilino)-2-oxoacetic acid, and 2-(4-methylanilino)-2-oxoacetic acid.

[0070] More preferably, the compound of formula (VI) is selected from the group consisting of 2-(2-methylanilino)-2-oxoacetic acid, 2-(2,6-diisopropylanilino)-2-oxoacetic acid, 2-oxo-2-(2,4,6-trimethoxyanilino)acetic acid, 2-(2-ethyl-6-methylanilino)-2-oxoacetic acid, 2-oxo-2-(2,4,6-trimethylanilino)acetic acid, 2-(2,6-dimethylanilino)-2-oxoacetic acid, 2-(3,5-dimethylanilino)-2-oxoacetic acid, and 2-(2-tert-butylanilino)-2-oxoacetic acid.

[0071] In another preferred embodiment of the present invention, the ligand is trans-N,N'-dimethylcyclohexane-1,2-diamine, tetramethylethylenediamine, 2-(2-methylanilino)-2-oxoacetic acid, 2-(2,6-diisopropylanilino)-2-oxoacetic acid, 2-oxo-2-(2,4,6-trimethoxyanilino)acetic acid, 2-(2-ethyl-6-methylanilino)-2-oxoacetic acid, 2-oxo-2-(2,4,6-trimethylanilino)acetic acid, 2-(2,6-dimethylanilino)-2-oxoacetic acid, 2-(3,5-dimethylanilino)-2-oxoacetic acid, 2-(2-tert-butylanilino)-2-oxoacetic acid, 2-anilino-2-oxoacetic acid, 2-(4-chloroanilino)-2-oxo -Selected from the group consisting of acetic acid, 2-(4-methoxyanilino)-2-oxoacetic acid, 2-(4-methylanilino)-2-oxoacetic acid, N,N'-bis(2,6-dimethylphenyl)oxamide, N,N'-bis(2,4,6-trimethoxyphenyl)oxamide, N,N'-bis(2,5-dimethylpyrrole-1-yl)oxalamide, N,N'-dibenzyloxamide, N,N'-bis(2-phenylethyl)oxamide, N,N'-bis(2-pyridylmethyl)oxamide, 8-hydroxyquinoline, 6-methylquinoline-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-oxoacetic acid, 2-(2,6-diisopropylanilino)-2-oxoacetic acid, 2-oxo-2-(2,4,6-trimethoxyanilino)acetic acid, 2-(2-ethyl-6-methylanilino)-2-oxoacetic acid, 2-oxo-2-(2,4,6-trimethylanilino)acetic acid, and 2-(2,6-dimethylanilino)-2-oxoacetic acid.

[0072] Typically, the ligand is present in an amount of 0.01 mol% to 40 mol% based on the compound of formula (II). Preferably, the ligand is present in an amount of 0.01 mol% to 20 mol% based on the compound of formula (II). More preferably, the ligand is present in an amount of 0.01 mol% to 5 mol% based on the compound of formula (II). Even more preferably, the ligand is present in an amount of 0.01 mol% to 1 mol% based on the compound of formula (II).

[0073] 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 cesium carbonate, potassium carbonate, tripotassium phosphate, sodium hydroxide, and sodium methoxide. Even more preferably, the base is potassium carbonate, tripotassium phosphate, or sodium methoxide.

[0074] Those skilled in the art will understand that the base used in step (b) can be added in any number of alternative ways, but are 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.

[0075] In one embodiment, process step (b) is carried out in the presence of a base, which 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 time of 1 to 3 hours (those skilled in the art will understand that the duration over which the methoxide is added depends on several different factors, such as the scale of the reaction, the weight % concentration of the methoxide and / or the weight % concentration of the starting reagents).

[0076] Typically, this step can be carried out at a temperature of 50°C to 120°C, preferably 60°C to 120°C, more preferably 60°C to 90°C, and even more preferably 75°C to 90°C.

[0077] Scheme 3: [ka] Step (c) Hydrolysis: Equation (I) [ka] (wherein X is as defined herein) The compound is given by formula (III) [ka] (wherein X and R in the formula) 1 (as defined herein) It is prepared by hydrolysis of the compound.

[0078] Hydrolysis may be carried out using methods known to those skilled in the art. Hydrolysis is typically carried out using suitable conditions, including, but not limited to, basic conditions (e.g., aqueous sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate) or acidic conditions (e.g., aqueous sulfuric acid or hydrochloric acid). Preferably, hydrolysis is carried out under acidic conditions. More preferably, hydrolysis is carried out using hydrochloric acid.

[0079] Typically, the process described in step (c) is carried out in the absence of additional solvents or in the presence of a solvent or mixture of solvents such as 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, t-butyl acetate, butyl acetate, toluene, 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 an additional solvent or in the presence of a solvent or mixture of solvents 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 an additional solvent or in the presence of a solvent or mixture of solvents selected from water and / or methylcyclohexane.

[0080] Those skilled in the art will understand that the choice of solvent for the process described in step (c) depends on whether basic or acidic conditions are used.

[0081] Typically, this step can 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, and even more preferably 10°C to 30°C.

[0082] Those skilled in the art will understand that the temperature of the process according to the present invention may vary in each of steps (a), (b), and (c). Furthermore, this variation in temperature may also reflect the choice of solvent or diluent, for example, in terms of its boiling point and / or its effectiveness in promoting the desired reaction and the rate at which the reaction is carried out.

[0083] The process of the present invention can be carried out at any reasonable pressure depending on the selection 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, and even more preferably 0.8 to 2 bar (e.g., ambient pressure).

[0084] Preferably, the process of the present invention is carried out under an inert atmosphere such as nitrogen or argon.

[0085] Those skilled in the art will understand that process steps (a), (b), and (c) may be carried out as separate process steps, and that intermediate compounds may be isolated at each stage. Alternatively, process steps (a), (b), and (c) may be carried out as a snap-fit ​​procedure in which the resulting intermediate compounds are not isolated. Thus, the process of the present invention can be carried out in batch, semi-batch, or continuous form.

[0086] Those skilled in the art will understand that steps (a), (b), and (c) can be equally represented in a single scheme. See Scheme 4 below. Scheme 4: [ka]

[0087] In a preferred embodiment of the present invention, formula (Ia) [ka] (In the formula, X is a halogen (preferably X is chloro, bromo, or iodine, more preferably X is chloro or bromo, and even more preferably X is chloro)). A process for preparing the compound of (i) Formula (IIa)

Chemical formula

Chemical formula

Chemical formula

[0088] In a more preferred embodiment of the present invention, formula (Ia-I) [ka] A process for preparing the compound, (i) Equation (IIa-I) [ka] The compound is reacted with methanol in the presence of a copper(I) salt (preferably copper(I) chloride) and a ligand to obtain the compound of formula (IIIa-I). [ka] A step that yields the compound, The ligands are 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-methylanilino)-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-oxoacetic acid, 2-(2-tert-butylanilino)-2-oxoacetic acid, 2-anilino-2-oxoacetic acid, 2-(4-chloroanilino)-2-oxoacetic acid, 2-(4-methoxyanilino)-2-oxoacetic acid, 2-(4-methylanilino)-2-oxoacetic acid, N,N'-bis(2,6-dimethylphenyl)oxaacetic acid The oxalamide compound selected from the group consisting of mid, N,N'-bis(2,4,6-trimethoxyphenyl)oxamide, N,N'-bis(2,5-dimethylpyrrole-1-yl)oxalamide, N,N'-dibenzyloxamide, N,N'-bis(2-phenylethyl)oxamide and N,N'-bis(2-pyridylmethyl)oxamide (preferably 2-(2-methylanilino)-2-oxoacetic acid, 2-(2,6-diisopropylanilino)-2-oxoacetic acid, 2-oxo-2-(2,4,6-trimethoxyanilino)acetic acid, 2-(2-ethyl-6-methylanilino)-2-oxoacetic acid, 2-oxo-2-(2,4,6-trimethylanilino)acetic acid and 2-(2,6-dimethylanilino)-2-oxoacetic acid), or The ligand is trans-N,N'-dimethylcyclohexane-1,2-diamine, step, (ii) Steps of hydrolysis of the compound of formula (Ia-I) and A process including this is provided.

[0089] In another preferred embodiment of the present invention, formula (Ia) [ka] (In the formula, X is a halogen (preferably X is chloro, bromo, or iodine, more preferably X is chloro or bromo, and even more preferably X is chloro)). A process for preparing the compound, (a) Equation (IVa) [ka] (wherein Y is selected from the group consisting of bromo, chloro, iodine, CF3SO3-, CH3C6H4SO3-, and CH3SO3- (preferably Y is selected from the group consisting of bromo, chloro, and iodine, more preferably Y is bromo or chloro, and even more preferably Y is chloro), and X is as defined above for the compound of formula (Ia)) The compound of formula (V) R 1 -NH2(V) (In the formula, R 1 is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl and t-butyl (preferably R 1 is selected from the group consisting of methyl, ethyl and t-butyl, and more preferably R 1 is methyl or t-butyl, most preferably R 1 It is methyl.)) When reacted with the compound, formula (IIa) [ka] The step of obtaining the compound, (b) Formula (IIa) (In the formula, Y is as defined above for the compound of formula (IVa), and R 1 (wherein X is defined above for the compound of formula (V), and X is defined above for the compound of formula (Ia)) The compound is reacted with methanol in the presence of a copper source and a ligand to obtain formula (IIIa). [ka] (wherein X is as defined above for the compound of formula (Ia), and R 1 (This is as defined above for the compound of formula (IIa)). A step that yields the compound, The ligand is given by equation (VI) [ka] (In the formula, Z is either NH or O. R 2 The R is selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl, and quinolinylmethyl, wherein the phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl, or quinolinylmethyl may be the same or different 1, 2, or 3 R's where feasible. 4 They may be optionally substituted by substituents, R 3 The R is selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl, and quinolinylmethyl, wherein the phenyl, naphthalenyl, furanyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, quinolinyl, benzyl, phenylethyl, furanylmethyl, pyrrolylmethyl, thienylmethyl, pyridylmethyl, benzofuranylmethyl, or quinolinylmethyl may be the same or different 1, 2, or 3 R's where feasible. 4 They may be optionally substituted by substituents, and Each R 4(This is independently selected from the group consisting of bromo, chloro, fluoro, nitro, -OH, -C(O)OH, dimethylamino, diethylamino, methoxycarbonyl, methyl, ethyl, isopropyl, tert-butyl, methoxy, isopropyloxy, trifluoromethyl, phenyl, and phenoxy.) It is an oxalamide compound, or The ligand is selected from the group consisting of trans-N,N'-dimethylcyclohexane-1,2-diamine, tetramethylethylenediamine, 8-hydroxyquinoline, 6-methylquinoline-8-ol, 5-chloro-8-hydroxyquinoline, pyrrole 2-carboxylic acid, trans-4-hydroxy-L-proline, proline, dimethylglyoxime, and D-glucosamine, in the step of... (c) Steps of hydrolysis of the compound of formula (Ia) and A process including this is provided.

[0090] In another more preferred embodiment of the present invention, formula (Ia-I) [ka] A process for preparing the compound, (a) Equation (IVa-I) [ka] The compound of formula (VI) CH3-NH2(VI) When reacted with the compound, formula (IIa) [ka] The step of obtaining the compound, (b) Equation (IIa-I) [ka] The compound is reacted with methanol in the presence of a copper(I) salt (preferably copper(I) chloride) and a ligand to obtain the compound of formula (IIIa-I). [ka] A step that yields the compound, The ligands are 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-methylanilino)-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-oxoacetic acid, 2-(2-tert-butylanilino)-2-oxoacetic acid, 2-anilino-2-oxoacetic acid, 2-(4-chloroanilino)-2-oxoacetic acid, 2-(4-methoxyanilino)-2-oxoacetic acid, 2-(4-methylanilino)-2-oxoacetic acid, N,N'-bis(2,6-dimethylphenyl)oxaacetic acid The oxalamide compound selected from the group consisting of mid, N,N'-bis(2,4,6-trimethoxyphenyl)oxamide, N,N'-bis(2,5-dimethylpyrrole-1-yl)oxalamide, N,N'-dibenzyloxamide, N,N'-bis(2-phenylethyl)oxamide and N,N'-bis(2-pyridylmethyl)oxamide (preferably 2-(2-methylanilino)-2-oxoacetic acid, 2-(2,6-diisopropylanilino)-2-oxoacetic acid, 2-oxo-2-(2,4,6-trimethoxyanilino)acetic acid, 2-(2-ethyl-6-methylanilino)-2-oxoacetic acid, 2-oxo-2-(2,4,6-trimethylanilino)acetic acid and 2-(2,6-dimethylanilino)-2-oxoacetic acid), or The ligand is trans-N,N'-dimethylcyclohexane-1,2-diamine, step, (c) Steps of hydrolysis of the compound of formula (Ia-I) and A process including this is provided.

[0091] In one embodiment of the present invention, formula (III) [ka] (In the formula, X is a halogen (preferably X is chloro, bromo, or iodine, more preferably X is chloro or bromo, even more preferably X is chloro, and most preferably X is 4-chloro), R 1 is a C1-C6 alkyl group (preferably R 1 is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl and t-butyl, and more preferably R 1 is selected from the group consisting of methyl, ethyl and t-butyl, and more preferably R 1 is methyl or t-butyl, most preferably R 1 It is methyl.)) A compound is provided, provided that it is not a compound selected from the group consisting of N-butyl-1-(4-chloro-2-methoxyphenyl)methanymine, N-tert-butyl-1-(4-fluoro-2-methoxyphenyl)methanymine, 1-(5-bromo-2-methoxyphenyl)-N-methylmethanymine, N-tert-butyl-1-(5-fluoro-2-methoxyphenyl)methanymine, N-tert-butyl-1-(5-chloro-2-methoxyphenyl)methanymine, and N-tert-butyl-1-(5-bromo-2-methoxyphenyl)methanymine.

[0092] In a preferred embodiment, formula (IIIa-I) [ka] The compound (1-(4-chloro-2-methoxyphenyl)-N-methylmethanymine) is provided.

[0093] In a further embodiment of the present invention, the process involves using a compound of formula (I) of formula (VII). [ka] (In the formula, G is 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 Selected from the group consisting of, 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.) This further includes converting to a compound.

[0094] In a preferred embodiment of the present invention, the process involves using a compound of formula (I) of formula (VII). [ka] (In the formula, G is 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 Selected from the group consisting of, 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.) The process further includes converting to a compound, and further includes steps such as those described on page 54 of International Publication No. 2015 / 197468. [Examples]

[0095] The following examples further illustrate, but do not limit, the present invention. Those skilled in the art will immediately recognize appropriate variations from the procedures relating to both reactants and reaction conditions and techniques.

[0096] The following abbreviations are used: s = singlet; br s = broad singlet; d = doublet; dd = double doublet; dt = double triplet; t = triplet; tt = triple triplet; q = quadruplet; quin = quintet; sept = sextet; m = multiplet; GC = gas chromatography; RT = retention time; T i = internal temperature, MH + = Molecular weight of molecular cation, M = moles, Q 1 HNMR=quantitative 1 1H NMR, RT = room temperature, UFLC = ultrafast liquid chromatography.

[0097] Unless otherwise instructed, 1 The 1H NMR spectrum was recorded at 400 MHz, and the chemical shift was recorded in ppm.

[0098] Several chemical yields were 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 properties of any relevant counterions are estimated based on the reaction conditions used, but those skilled in the art will understand that the crude reaction mixture may also contain other counterions such as (but not limited to) chloride ions, bromide ions, iodide ions, fluoride ions, bisulfate ions, mesylate ions, oxalate ions, tartrate ions, and trifluoroacetate ions.

[0099] Example 1: Ligand Screening Procedure [ka] procedure: Ligand (0.10 mmol, 0.20 equivalents) was weighed into a 4 ml Supelco vial under air. Copper(I) chloride (9.9 mg, 0.10 mmol, 0.20 equivalents) and potassium carbonate (76.8 mg, 0.55 mmol, 1.1 equivalents) were weighed into a second 4 ml vial under argon, and a stirring bar was added. A stock solution of 1-(2,4-dichlorophenyl)-N-methylmethanymine (approximately 12.5 mmol) in dried and degassed methanol (25 ml) was prepared under argon, and 1 ml (approximately 0.5 mmol) was transferred to each of the 24 vials containing the ligand. The ligand and 1-(2,4-dichlorophenyl)-N-methylmethanymine solution were transferred to vials containing CuCl and potassium carbonate. The reaction block was sealed and transferred to a heater / tumble stirrer. The blocks were heated at 75°C for 4 hours. 1 ml of standard stock solution (approximately 0.5 g of tetramethylbenzene in 50 ml of DCM) was added to each reaction vessel. 200 μL was divided equally from each reaction into 1300 μL of DCM, and then filtered using a 45 μm syringe filter of Chromafil. The samples were run by GC-MS (Chemical Ionization, 70-320°C at 40°C / min, column: Phenomenex ZB-5 ms, 15 m, diameter 0.25 mm, 0.25 μm). Yield and selectivity were calculated using tetramethylbenzene as an internal standard. The conversion rate of the starting materials and the selectivity to the desired product were calculated from the GC results. The results are shown in Table 1 below.

[0100] [Table 1-1]

[0101] [Table 1-2]

[0102] [Table 2-1]

[0103] [Table 2-2]

[0104] [Table 2-3]

[0105] [Table 2-4]

[0106] [Table 2-5]

[0107] [Table 2-6]

[0108] [Table 2-7]

[0109] [Table 2-8]

[0110] Example 2: Amine Screening Procedure [ka] procedure: In a screening vial, a solution of 2,4-dichlorobenzaldehyde (1 g, 5.71 mmol, 1.00 equivalent) in methanol (6.3 ml) was mixed with an amine (6.28 mmol, 1.1 equivalent). The reaction mixture was heated to 40°C and stirred at 40°C for 60 minutes. To the resulting solution, tripotassium phosphate (1.33 g, 6.28 mmol, 1.10 equivalent), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.166 g, 1.14 mmol, 0.20 equivalent), and copper(I) chloride (0.112 g, 1.14 mmol, 0.20 equivalent) were subsequently added. The vial was closed, and the reaction mixture was heated at 65°C for 16 hours. The pH was then adjusted to 3 with 2N HCl, the reaction mixture was stirred at 65°C for another 60 minutes, and then analyzed by GC. The conversion rate of the starting material and the selectivity to the desired product were calculated from the GC results. The results are shown in Table 2 below.

[0111] [Table 3]

[0112] Example 3: Preparation of 2-methoxy-4-chlorobenzaldehyde from 2,4-dichlorobenzaldehyde [ka] procedure: A solution of 2,4-dichlorobenzaldehyde (20 g, 114 mmol, 1.00 equivalent) in methanol was suddenly mixed with a solution of methylamine in methanol (40% by weight, 9.32 g, 120 mmol, 1.05 equivalent). The reaction mixture was heated to 40°C and stirred at 40°C for 30 minutes. The resulting colorless solution was cooled to room temperature and transferred to a pressure autoclave. Subsequently, tripotassium phosphate (26.7 g, 126 mmol, 1.11 equivalent), [(2,6-dimethylphenyl)amino](oxo)acetic acid (1.09 g, 5.64 mmol, 0.05 equivalent), boric acid (0.353 g, 5.71 mmol, 0.05 equivalent), and copper(I) chloride (0.560 g, 5.65 mmol, 0.05 equivalent). The pressure autoclave was closed and the reaction mixture was heated at 80°C for 16 hours. A maximum pressure of approximately 2 bar was observed. After cooling to room temperature and releasing the residual pressure, the pressure autoclave was opened and the reaction mixture was transferred to a 500 ml double-jacketed reactor. Water (70 ml) was added to the reaction mixture and the mixture was stirred at room temperature for 10 minutes. Methanol was removed by distillation and methylcyclohexane (115 ml) was added to the resulting suspension. The mixture was heated to 55°C and the phases were separated. 2M hydrochloric acid (48 g, 99.9 mmol, 0.88 equivalents) was added to the organic phase and the mixture was stirred at 55°C for 1 hour. After phase separation, the product was crystallized by cooling the organic phase to 0°C over 4 hours. The suspension was stirred at 0°C for a further 30 minutes, and then the mixture was filtered. The crude product obtained was washed with cold (0-5°C) methylcyclohexane (2 × 50 ml) and dried at 50°C for 14 hours to obtain the title compound (14.9 g, 93% purity as determined by quantitative NMR, 71% yield). 1 H NMR(400MHz,CDCl3)δ ppm:10.40(s,1H),7.80(d,1H,J=8.0),6.88-7.16(m,2H),3.98(s,3H)

[0113] Example 4: Preparation of 2-methoxy-4-bromobenzaldehyde from 2,4-dibromobenzaldehyde [ka] procedure: A solution of 2,4-dichlorobenzaldehyde (5.0 g, 18.9 mmol, 1.00 equivalent) in methanol was suddenly mixed with a solution of methylamine in methanol (40% by weight, 1.57 g, 20.2 mmol, 1.07 equivalents). The reaction mixture was heated to 40°C and stirred at 40°C for 30 minutes. The resulting colorless solution was cooled to room temperature and transferred to a pressure autoclave. Subsequently, tripotassium phosphate (4.42 g, 20.8 mmol, 1.10 equivalents), [(2,6-dimethylphenyl)amino](oxo)acetic acid (0.181 g, 0.94 mmol, 0.05 equivalents), boric acid (0.059 g, 0.95 mmol, 0.05 equivalents), and copper(I) chloride (0.093 g, 0.94 mmol, 0.05 equivalents) were added to the solution. The pressure autoclave was closed and the reaction mixture was heated at 80°C for 16 hours. A maximum pressure of approximately 2 bar was observed. After cooling to room temperature and releasing the residual pressure, the pressure autoclave was opened and the reaction mixture was transferred to a 500 ml double-jacketed reactor. Water (30 ml) was added to the reaction mixture and the mixture was stirred at room temperature for 10 minutes. Methanol was removed by distillation and methylcyclohexane (30 ml) was added to the resulting suspension. The mixture was heated to 55°C and the phases were separated. Water (65 ml) and 2 M hydrochloric acid (8.8 g, 17.6 mmol, 0.93 equivalents) were added to the organic phase and the mixture was stirred at 55°C for 1 hour. After phase separation, the product was crystallized by cooling the organic phase to 0°C over 4 hours. The suspension was stirred at 0°C for a further 20 minutes, and then the mixture was filtered. The crude product obtained was washed with cold (0-5°C) methylcyclohexane (1 × 10 ml) and dried at 50°C for 18 hours to obtain the title compound (2.5 g, 96% purity, 59% yield as determined by quantitative NMR). 1 H NMR(400MHz,CDCl3)δ ppm:10.41(s,1H),7.69(d,1H,J=4.8),7.10-7.25(m,2H),3.95(s,3H)

[0114] Example 5: Comparative Example Entry 1 in Table 5, disclosed in the prior art 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. 2342, was found to be unreproducible, as detailed below. [ka]

[0115] Four 20 mL glass vials were each loaded with 2,4-dichlorobenzaldehyde (99%, 5.7 mmol, 1 g), 10 mL of methanol was added, and the mixture was stirred at room temperature to yield a clear, slightly yellowish solution. 0.02 equivalents of either Na₂CO₃, K₂CO₃, Cs₂CO₃, or Li₂CO₃ were added to each vial in a single step. The values ​​can be found in Materials Table 3 below. The reaction mixture was then heated at 65°C for a total of 22 hours (Li₂CO₃ experiment = colorless, clear solution except for the suspension). Multiple in-step controls by GC showed zero or slight (less than 1%) conversion from the starting materials to the desired compound (4-chloro-2-methoxybenzaldehyde).

[0116] [Table 4]

[0117] Therefore, based on the results above, those skilled in the art will understand that if they face a technical problem in which the process disclosed in KUMAR and NEGI for producing 4-chloro-2-methoxybenzaldehyde is not usable and thus a new process is to be developed, they would not follow the teachings of this reference with any reasonable expectation of success.

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