Improved synthesis of 6-aryl-4-amino picolinates

Abstract

The present disclosure relates to improved methods of synthesizing 6-aryl-4-amino picolinates, such as 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid aralkyl esters and 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid alkyl esters.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application Serial No. 62 / 991,284, filed March 18, 2020, the entire disclosure of which is hereby expressly incorporated by reference. Technical Field

[0003] This disclosure relates to an improved method for preparing 6-aryl-4-aminopyridine carboxylate. More specifically, this disclosure relates to an improved method for preparing 6-aryl-4-aminopyridine carboxylate from 6-bromo-4-aminopyridine carboxylate. Background Technology

[0004] 6-Aryl-4-aminopyridine carboxylates, such as 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridinecarboxylic acid alkyl ester and 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridinecarboxylic acid alkyl ester, are high-value herbicides recently developed and marketed by Dow AgroSciences LLC. U.S. Patent Application Publication 20120190857 A1 and U.S. Patents 7,314,849 B2, 8,609,853 B2, 8,609,855 B2, 8,754,231 B2, 8,836,688 B2, 10,087,164 B2, 10,544,121 B2, and 10,570,114 B2 (the disclosures of each application are expressly incorporated herein by reference) particularly describe certain 6-aryl-4-aminopyridinecarboxylate esters and their synthesis. The synthesis of these 6-aryl-4-aminopyridinecarboxylate esters involves reacting a 6-chloropyridinecarboxylic acid or 6-chloropyridinecarboxylate head with an arylboronic acid or arylboronic ester tail. The reaction scheme for 6-aryl-4-aminopyridinecarboxylate esters is shown in Scheme 1.

[0005] Option 1

[0006]

[0007] For these 6-aryl-4-aminopyridine carboxylate compounds, a high-yield process route would be useful. Summary of the Invention

[0008] This disclosure relates to an improved method for preparing 6-aryl-4-aminopyridine carboxylate having formula I.

[0009] In some embodiments, this disclosure relates to a method for preparing 6-aryl-4-aminopyridine carboxylate having formula I.

[0010]

[0011] in

[0012] R represents H, Cl-C 12 Alkyl, C3-C 12 Alkyne group, C1-C3 alkyl group substituted with CN, or C6-C 12 Aryl alkyl groups;

[0013] W represents H, halogen, C1-C4 alkyl, or C1-C3 alkoxy;

[0014] Y represents halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -CN, or -NO2; and

[0015] Z represents H, F, Cl, C1-C4 alkyl, C1-C3 alkoxy, C1-C4 haloalkyl, C1-C3 haloalkoxy, C1-C4 alkoxy-substituted C1-C4 alkyl, or -NR. 2 R 3 , where R 2 and R 3 It is independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl;

[0016] The method includes the following steps:

[0017] a) A first mixture is generated, the first mixture containing: a compound having formula A,

[0018]

[0019] in

[0020] R represents H, Cl-C 12 Alkyl, C3-C 12 Alkyne group, C1-C3 alkyl group substituted with CN, or C6-C 12 Aryl alkyl groups;

[0021] Compounds having formula B,

[0022]

[0023] in

[0024] R 1 H represents a C1-C6 alkyl group, or alternatively, two Rs. 1 It can form C2-C6 alkyl bonds, which together with B and two O atoms form a cyclic structure of 5 to 9 atoms;

[0025] W represents H, halogen, C1-C4 alkyl, or C1-C3 alkoxy;

[0026] Y represents halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -CN, or -NO2; and

[0027] Z represents H, F, Cl, C1-C4 alkyl, C1-C3 alkoxy, C1-C4 haloalkyl, C1-C3 haloalkoxy, C1-C4 alkoxy-substituted C1-C4 alkyl, or -NR. 2 R 3 , where R 2 and R 3 It is independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl;

[0028] One or more bases; and one or more solvents;

[0029] b) Add a palladium catalyst and optionally a ligand to the first mixture to form a second mixture; and

[0030] c) Heat the second mixture to a temperature between about 25°C and about 100°C.

[0031] The components of each mixture listed in the above steps, such as Formula A, Formula B, one or more bases, and one or more solvents used to form the first mixture, may be combined in a different order than specified. In this disclosure, the order in which the components are added to form the mixture is not limited to the order stated herein. Detailed Implementation

[0032] As used herein, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon moiety. Unless otherwise specified, it means C1-C2. 20 (For example, C1-C) 12 C1-C 10Alkyl groups (C1-C8, C1-C6, C1-C4). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, pentyl, and hexyl. As used herein, the term "cycloalkyl" refers to a cyclic saturated hydrocarbon moiety. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Alkyl and cycloalkyl substituents may be unsubstituted or substituted by one or more chemical moieties. Examples of suitable substituents include, for example, hydroxyl, nitro, cyano, formyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 acyl, C1-C6 alkylthio, C1-C6 haloalkoxythio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkoxycarbonyl, C1-C6 haloalkoxycarbonyl, C1-C6 carbamoyl, C1-C6 halocarbamoyl, hydroxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkylcarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, haloalkylaminocarbonyl, C1-C6 dialkylaminocarbonyl, and C1-C6 dihaloalkylaminocarbonyl, provided that the substituents are sterically compatible and satisfy the rules of chemical bonding and strain energy. Preferred substituents include cyano and C1-C6 alkoxy groups.

[0033] As used herein, the terms "haloalkyl" and "halocycloalkyl" refer to alkyl and cycloalkyl groups as defined above, respectively, wherein the hydrogen atoms of these groups may be partially or completely replaced by halogen atoms. Unless otherwise specified, they refer to C1-C 20 (For example, C1-C) 12 C1-C 10Alkyl groups (C1-C8, C1-C6, C1-C4). Examples include, but are not limited to, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, and 1,1,1-trifluoropropyl-2-yl. The haloalkyl substituents may be unsubstituted or substituted by one or more chemical moieties. Examples of suitable substituents include, for example, hydroxyl, nitro, cyano, formyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 acyl, C1-C6 alkylthio, C1-C6 haloalkoxythio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkoxycarbonyl, C1-C6 haloalkoxycarbonyl, C1-C6 carbamoyl, C1-C6 halocarbamoyl, hydroxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkylcarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, haloalkylaminocarbonyl, C1-C6 dialkylaminocarbonyl, and C1-C6 dihaloalkylaminocarbonyl, provided that the substituents are sterically compatible and satisfy the rules of chemical bonding and strain energy. Preferred substituents include cyano and C1-C6 alkoxy groups.

[0034] As used herein, the term "alkynyl" refers to a straight-chain or branched hydrocarbon moiety containing a triple bond. Unless otherwise specified, it means C2-C. 20 (For example, C2-C) 12 C2-C 10(C2-C8, C2-C6, C2-C4) ynyl groups. An ynyl group may contain more than one unsaturated bond. Examples include, but are not limited to, C2-C6-ynyl groups, such as ethynyl, 1-propynyl, 2-propynyl (or propynyl), 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-1-butynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 3-methyl-1-pentynyl, 4- The following are listed: methyl-1-pentynyl, 1-methyl-2-pentynyl, 4-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, and 1-ethyl-1-methyl-2-propynyl. The ynyl substituent may be unsubstituted or substituted by one or more chemical moieties. Examples of suitable substituents include, for example, hydroxyl, nitro, cyano, formyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 acyl, C1-C6 alkylthio, C1-C6 haloalkoxythio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkoxycarbonyl, C1-C6 haloalkoxycarbonyl, C1-C6 carbamoyl, C1-C6 halocarbamoyl, hydroxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkylcarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, haloalkylaminocarbonyl, C1-C6 dialkylaminocarbonyl, and C1-C6 dihaloalkylaminocarbonyl, provided that the substituents are sterically compatible and satisfy the rules of chemical bonding and strain energy. Preferred substituents include cyano and C1-C6 alkoxy groups.

[0035] As used herein, the term "aryl" and its derivatives, such as aryloxy, refer to a group comprising a monovalent aromatic carbocyclic group containing 6 to 14 carbon atoms. An aryl group may comprise a single ring or multiple fused rings. In some embodiments, an aryl group comprises C6-C... 10Aryl. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl, and indanyl. In some embodiments, the aryl group may be phenyl, indanyl, or naphthyl. The term "heteroaryl" and derived terms such as "heteroaryloxy" refer to a 5- or 6-membered aromatic ring containing one or more heteroatoms (i.e., N, O, or S); these heteroaromatic rings may be fused with other aromatic systems. Aryl or heteroaryl substituents may be unsubstituted or substituted by one or more chemical moieties. Examples of suitable substituents include, for example, hydroxyl, nitro, cyano, formyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 acyl, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkoxycarbonyl, C1-C6 carbamoyl, hydroxycarbonyl, C1-C6 alkylcarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, and C1-C6 dialkylaminocarbonyl, provided that the substituents are sterically compatible and satisfy the rules of chemical bonding and strain energy. Preferred substituents include halogens, C1-C2 alkyl, and C1-C2 haloalkyl.

[0036] As used herein, the term "aralkyl" refers to an alkyl group substituted with an unsubstituted or substituted aryl group. C7-C 10 Aryl groups are groups in which the total number of carbon atoms is 7 to 10, excluding the carbon atoms present in any substituents of the aryl group.

[0037] As used herein, an alkoxy group refers to a group having the formula RO-, where R is an alkyl group as defined above. Unless otherwise specified, it means an alkoxy group in which R is a C1-C8 alkyl group. Examples include methoxy, ethoxy, propoxy, 1-methyl-ethoxy, butoxy, 1-methyl-propoxy, 2-methyl-propoxy, 1,1-dimethyl-ethoxy, pentooxy, 1-methyl-butoxy, 2-methyl-butoxy, 3-methyl-butoxy, 2,2-dimethyl-propoxy, 1-ethyl-propoxy, hexoxy, 1,1-dimethyl-propoxy, 1,2-dimethyl-propoxy, 1-methyl-pentoxy, 2-methyl-pentoxy, 3-methyl-propoxy, 2-methyl-propoxy, 3-methyl-propoxy 4-methyl-pentoxy, 1,1-dimethyl-butoxy, 1,2-dimethyl-butoxy, 1,3-dimethyl-butoxy, 2,2-dimethyl-butoxy, 2,3-dimethyl-butoxy, 3,3-dimethyl-butoxy, 1-ethyl-butoxy, 2-ethyl-butoxy, 1,1,2-trimethyl-propoxy, 1,2,2-trimethyl-propoxy, 1-ethyl-1-methyl-propoxy, and 1-ethyl-2-methyl-propoxy.

[0038] As used herein, a haloalkoxy group refers to a group having the formula RO-, where R is a haloalkyl group as defined above. Unless otherwise specified, it means a haloalkoxy group in which R is a C1-C8 alkyl group. Examples include chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro,2-difluoroethoxy, 2,2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, and 1,1,1-trifluoroprop-2-oxy.

[0039] As used herein, the terms “isolate,” “isolating,” or “isolation” mean the partial or complete removal or separation of a desired product from other components of the final chemical process mixture using standard methods, such as, but not limited to, filtration, extraction, distillation, crystallization, centrifugation, grinding, liquid-liquid phase separation, or other methods known to those skilled in the art. The isolated product may have a purity ranging from <50% to >50% and can be purified to higher purity levels using standard purification methods. The isolated product may also be used in subsequent process steps, with or without purification.

[0040] As used herein, the term "palladium catalyst" refers to a molecule or compound formed from a palladium compound and a ligand, or a preformed compound containing palladium and a ligand. Examples of palladium compounds include, but are not limited to, palladium(II) acetate (Pd(OAc)2) and palladium(II) chloride (PdCl2). Examples of ligands include, but are not limited to, tri-tert-butylphosphine, tricyclohexylphosphine, di-tert-butylphenylphosphine, dicyclohexylphenylphosphine, triphenylphosphine, tris(o-tolyl)phosphine, 1,2-bis(diphenylphosphine)ethane, 1,3-bis(diphenylphosphine)propane, 1,4-bis(diphenylphosphine)butane, and 1,1′-ferrocenediyl-bis(diphenylphosphine) (dppf). Examples of preformed compounds containing palladium and a ligand include, but are not limited to, bis(triphenylphosphine)dichloride (II), bis(acetic acid)bis(triphenylphosphine)palladium (II), tetra(triphenylphosphine)palladium (O), and tris(diphenylmethyleneacetone)dipalladium (O).

[0041] As used herein, fluorinated compounds or fluorinated mixtures of compounds refer to compounds capable of inserting fluorine atoms into a compound. Examples of fluorinated compounds or fluorinated mixtures of compounds include, but are not limited to, potassium fluoride, cesium fluoride, tetramethylammonium fluoride, potassium fluoride / tetramethylammonium chloride, cesium fluoride / tetramethylammonium chloride, tetramethylammonium fluoride / tetramethylammonium chloride, or mixtures thereof.

[0042] As used herein, “acylation catalyst” refers to a compound that accelerates the addition of an acyl group (i.e., a -C(O)- group) to another compound. Examples of acylation catalysts include, but are not limited to, 4-(dimethylamino)pyridine (DMAP) and N-methylimidazole.

[0043] As used herein, “continuous flow,” “flow,” “continuous formation,” “continuous process,” or other derived terms mean a method that produces a minimum amount of reactive intermediate at any given time and provides reduced cycle time compared to conventional methods. U.S. Patent 9,145,428B2 (the disclosure of which is expressly incorporated herein by reference) describes methods and systems using continuous flow.

[0044] In the methods described herein, a 6-aryl-4-aminopyridine carboxylate having formula I (wherein R, W, Y, and Z are as previously defined) can be prepared by reacting a compound having formula A (wherein R is as previously defined) with a compound having formula B (wherein R... 1 Compounds of formula B are prepared by reaction of (W, Y, and Z as previously defined). U.S. Patents 7,314,849B2 and 7,611,647B2 (the disclosure of each application is expressly incorporated herein by reference) particularly describe the synthesis of compounds having formula B. Compounds having formula A can be prepared from 4-amino-3,5,6-trichloropyridinecarboxylic acid (toxaphene) or its esters or derivatives.

[0045]

[0046] A method for preparing a compound having formula A is described in Scheme 2. In one embodiment, 3,5,6-trichloropyridinecarboxylic acid (toxaphene, C2) can be converted into the corresponding ester D2 (where Z...) by a method... 1 These methods include, but are not limited to: using any amount of suitable activator to react an acid C2 with an alcohol ROH (where R is C1-C). 12 Alkyl, C3-C 12 Alkyne group, C1-C3 alkyl group substituted with CN, or C6-C 12Aryl alkyl groups are coupled with activators such as those used for peptide coupling, including dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI), or carbonyl diimidazole (CDI); acyl chlorides forming C2 by reacting with thionyl chloride or oxalyl chloride in the presence of an alcohol ROH (wherein R is as previously defined); contacting the acid C2 with an alcohol ROH (wherein R is as previously defined) in the presence of an acid; and in the presence of one or more bases (such as triethylamine). The compound having formula C2 is reacted with an alkylating agent (such as a substituted or unsubstituted alkyl halide, a substituted or unsubstituted aralkyl halide, or a substituted or unsubstituted alkyl sulfonate) in the presence of N,N-diisopropylethylamine, 3,5-dimethylpyridine, 2,6-dimethylpyridine, 3-methylpyridine, or lithium carbonate or potassium carbonate) in a solvent (such as tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, or 1,2-dichloroethane), as in step a of scheme 2.

[0047] Ester D2(Z) 1 It is COOR, R is not H) or nitrile C1(Z) 1 (CN) can be converted into the corresponding phthalimides E1 and E2 by reacting with phthaloyl halides (such as phthaloyl chloride) or phthalic anhydride, optionally a base, optionally an acylation catalyst, solvent or solvent mixture at temperatures ranging from ambient temperature to about 100°C. (where A represents the substitution on the phthalimide and is independently selected from H, F, Cl, Br, I, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and nitro, where n is 1, 2, 3, or 4; and Z...) 1As previously defined, such as in step b of Scheme 2. Suitable optional bases include, but are not limited to, trimethylamine, triethylamine, tripropylamine, pyridine, 2-methylpyridine, and 3-methylpyridine. Suitable optional acylation catalysts include, but are not limited to, 4-(dimethylamino)pyridine (DMAP) and N-methylimidazole. Suitable solvents include, but are not limited to, acetonitrile, toluene, N,N-dimethylformamide (DMF), propionitrile, benzyl nitrile, tetrahydrofuran (THF), 2-methyl-THF, dioxane, cyclopentylmethyl ether (CPME), monoethylene glycol ether, diethylene glycol ether, monopropylene glycol ether or dipropylene glycol ether, and methyl isobutyl ketone (MIBK), and mixtures thereof. The temperature range for performing this step can be from about 25°C to about 100°C, from about 25°C to about 90°C, from about 25°C to about 80°C, from about 25°C to about 70°C, from about 25°C to about 60°C, or from about 25°C to about 55°C, and the reaction can be carried out within a time period ranging from about 1 hour to about 72 hours, from about 1 hour to about 48 hours, from about 1 hour to about 24 hours, from about 1 hour to about 12 hours, from about 1 hour to about 6 hours, from about 2 hours to about 24 hours, from about 4 hours to about 24 hours, from about 2 hours to about 12 hours, or from about 4 hours to about 12 hours.

[0048] Phthalimide E1 and E2 (where A, n and Z) 1As previously defined, compounds F1 and F2 can be converted to difluorides by treatment with a fluorinated compound or a fluorinated mixture of compounds in the presence of a solvent, as shown in step c of Scheme 2. Suitable fluorinated compounds or fluorinated mixtures of compounds include, but are not limited to, potassium fluoride (KF), cesium fluoride (CsF), and tetramethylammonium fluoride (TMAF), mixtures thereof, or mixtures of tetramethylammonium chloride (TMAC) with KF or CsF. Suitable solvents include, but are not limited to, polar aprotic solvents such as acetonitrile, propionitrile, benzyl nitrile, dimethyl sulfoxide (DMSO), N,N′-dimethylformamide (DMF), sulfolane, N,N-dimethylacetamide (DMA), 1,1-dimethyl-2-imidazolinone (DMI), N,N′-dimethylacrylurea (DMPU), N-methylpyrrolidone (NMP), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methyl-THF), dioxane, monoethylene glycol ether, diethylene glycol ether, monopropylene glycol ether, or dipropylene glycol ether, or mixtures thereof. This reaction is generally preferably carried out under anhydrous or near-anhydrous conditions. These anhydrous or near-anhydrous conditions can be obtained by pre-drying the reactants and solvent. One way to dry the reactants and / or solvent is to remove a portion of the solvent by distillation before carrying out the reaction. Suitable reaction temperatures may be the following: at least about 0°C, at least about 10°C, at least about 20°C, at least about 25°C, at least about 30°C, at least about 40°C, at least about 50°C, at least about 60°C, at least about 70°C, at least about 80°C, at least about 90°C, or at least about 100°C. The reaction can be carried out at the following temperatures: about 0°C to about 50°C, from about 10°C to about 50°C, from about 25°C to about 50°C, from about 15°C to about 150°C, from about 25°C to about 150°C, from about 35°C to about 125°C, from about 45°C to about 115°C, from about 55°C to about 110°C, from about 65°C to about 110°C, from about 75°C to about 110°C, from about 85°C to about 110°C, from about 90°C to about 110°C, from about 50°C to about 100°C, from about 60°C to about 100°C, from about 70°C to about 100°C, from about 25°C to about 90°C, from about 25°C to about 80°C, from about 25°C to about 110°C, from about 25°C to about 70°C, or from about 25°C to about 60°C. Difluoride compounds F1 and F2 can be separated using standard separation and purification techniques.

[0049] Compounds F1 and F2 (where A, n and Z) 1 (As previously defined) can be converted to 4-amino-6-bromopyridinecarboxylic acid having formula A1 by treatment with hydrogen bromide or hydrobromic acid (HBr) and water, as in step d of scheme 2. This conversion involves halogen exchange of a 6-fluoro substituent via hydrobromic acid to provide a 6-bromo substituent, Z 1The substituent is hydrolyzed to formic acid, and the cyclic imide group is removed by hydrolysis to regenerate the 4-amino substituent. A co-solvent of acetic acid (HOAc) is useful in facilitating this conversion. The HBr salt of formula A1 can also be formed in this reaction. This step can be carried out in two stages, with the first stage conducted at a lower temperature and / or in the absence of or with a limited amount of water to achieve halogen exchange of the 6-fluoro substituent, and the second stage conducted at a higher temperature and / or in the presence of more water to achieve hydrolysis of the cyclic imide group and the ester (or cyano substituent). Suitable amounts of water, relative to compounds F1 and F2, can range from about 1 to about 30, from about 1 to about 20, from about 1 to about 10, from about 1 to about 8, from about 1 to about 6, from about 1 to about 4, from about 2 to about 5, from about 2 to about 4, or from about 3 to about 4 molar equivalents of water per mole of compounds having formulas F1 and F2. In this step, the appropriate amount of hydrobromic acid (HBr) relative to the compounds having formulas F1 and F2, in molar quantities, can be from about 50 to about 1, from about 40 to about 1, from about 30 to about 1, from about 20 to about 1, from about 10 to about 1, from about 8 to about 1, from about 6 to about 1, from about 3 to about 1, from about 2 to about 1, or from about 3 to about 2 molar equivalents of HBr. The reaction can be carried out at temperatures from about 50°C to about 150°C, from about 60°C to about 140°C, from about 70°C to about 130°C, from about 80°C to about 120°C, from about 90°C to about 120°C, or from about 100°C to about 120°C. Formula A1 can be separated by employing standard separation and purification techniques, which may include, but are not limited to, solvent extraction with organic solvents, aqueous solvents, or organic-aqueous solvents, or separation of possible byproducts by different water solubility at certain pH levels or ranges. The HBr salt of formula A1 can form in small amounts and is present in the isolated product of formula A1. This salt can be reduced or removed from formula A1 by solvent extraction with water or an alcohol-water mixture (such as methanol-water). Compounds having formula A1 can be converted into esters having formula A (where R is C1-C1) by the following methods. 12 Alkyl, C6-C 12 Aryl alkyl, C3-C 12Alkyne or C1-C3 alkyl groups substituted with CN), these methods include, but are not limited to: coupling a compound having formula A1 with an alcohol ROH (wherein R is as previously defined) using any number of suitable activators, such as those used for peptide coupling, including dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI), or carbonyl diimidazole (CDI); contacting a compound having formula A1 with an alcohol ROH (wherein R is as previously defined) in the presence of an acid; and in one or more... The compound having formula A1 is reacted with an alkylating agent (such as a substituted or unsubstituted alkyl halide, a substituted or unsubstituted alkynyl halide, a substituted or unsubstituted aralkyl halide, or a substituted or unsubstituted alkyl sulfonate) in the presence of various bases (such as triethylamine, N,N-diisopropylethylamine, 3,5-dimethylpyridine, 2,6-dimethylpyridine, 3-methylpyridine, or lithium carbonate or potassium carbonate) in a solvent (such as tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, or 1,2-dichloroethane), as in step e of scheme 2.

[0050] In one embodiment, the compound having formula A can be isolated using standard separation and purification techniques. For example, the reaction mixture product can be separated using standard methods known in the art and described herein, and purified by crystallization or recrystallization using a single solvent or a mixture of two or more solvents. The reaction mixture product can be purified by washing it with a mixture of one, two, or three components of solvent or by stirring it in a mixture of one, two, or three components of solvent. In one embodiment, the reaction mixture product can be purified by stirring it in a mixture of aqueous alcohol solvents, which can also be described as an aqueous alcohol slurry treatment. The reaction mixture product having formula A can also be purified by dissolving it in a solvent to form a solution, and then adding a second solvent to the solution to crystallize the compound having formula A from the mixture of two solvents.

[0051] In one embodiment, the compound having formula A can be further treated with another solvent and base without separation.

[0052] Option 2

[0053]

[0054] In one embodiment, a compound having Formula I can be prepared by reacting a compound having Formula A with a compound having Formula B together with one or more bases, one or more solvents, a palladium catalyst, and optionally a ligand. The reaction may be deoxygenated before the addition of the palladium catalyst and optionally the ligand. The reaction may be carried out at a temperature from about 25°C to about 100°C. Suitable bases for this reaction include, but are not limited to, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, potassium acetate, sodium acetate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium tetraborate, potassium hydroxide, sodium hydroxide, cesium fluoride, potassium fluoride, triethylamine, triisopropylamine, diisopropylamine, diethylamine, and diisopropylethylamine. Preferred bases include potassium carbonate and potassium bicarbonate. Suitable solvents include, but are not limited to, methyl isobutyl ketone (MIBK), dimethoxyethane (DME), acetonitrile (MeCN), tetrahydrofuran (THF), methanol (MeOH), benzyl alcohol, toluene, water, and mixtures thereof. Suitable ligands for palladium catalysts include, but are not limited to, bis(phosphine) ligands, trialkylphosphines, and triarylphosphines. These include, but are not limited to, tri-tert-butylphosphine, tricyclohexylphosphine, di-tert-butylphenylphosphine, dicyclohexylphenylphosphine, triphenylphosphine, tri(o-tolyl)phosphine, 1,2-bis(diphenylphosphine)ethane, 1,3-bis(diphenylphosphine)propane, 1,4-bis(diphenylphosphine)butane, 1,1′-ferrocenediyl-bis(diphenylphosphine) (dppf), crosslinked 4-diphenylphosphine-methyl polystyrene resin, sodium diphenylphosphine-3-sulfonate with 2% DVB, tri(p-tolyl)phosphine, and (±)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl. The concentration of the ligands can be varied. In some embodiments, the concentration of the ligand relative to the limiting reagent is from about 0.4% to about 8.0%, preferably 0.5% to about 6.0%, preferably 0.5% to about 4.0%, preferably 0.5% to about 2%, more preferably about 1.0%. In some embodiments, the ligand is triphenylphosphine (PPh3). Suitable palladium compounds include, but are limited to, palladium(II) acetate (Pd(OAc)2) and palladium(II) chloride (PdCl2). Suitable palladium catalysts include, but are not limited to, bis(triphenylphosphine)palladium(II) chloride (PdCl2(Ph3P)2), bis(acetic acid)bis(triphenylphosphine)palladium(II) (Pd(OAc)2(Ph3P)2), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (PdCl2(dppf)2), tetra(triphenylphosphine palladium(O) (Pd(PPh3)4), and tri(diphenylmethyleneacetone)palladium(O) (Pd2(dba)3). The concentration of the catalyst can vary. In some embodiments, the concentration is less than 4%, preferably less than 3%, and more preferably less than 1%. In some embodiments, the concentration of the catalyst relative to the limiting reagent is from about 0.1% to about 2.0%, preferably 0.2% to about 1.0%, and more preferably about 0.3%. In some embodiments, the palladium catalyst is palladium(II) acetate and a ligand.

[0055] Option 3

[0056]

[0057] The following examples illustrate this disclosure.

[0058] Example

[0059] Example 1: Preparation of methyl 4-amino-3,5,6-trichloropyridinecarboxylate (1)

[0060]

[0061] 4-Amino-3,5,6-trichloropyridinecarboxylic acid (toluidine, C2; 100 g, 414 mmol)) was suspended in methanol (800 mL). Concentrated sulfuric acid (26 mL, 487 mmol) was slowly added at room temperature. The reaction mixture was stirred at 75 °C (oil bath with condenser) for 2 days. The mixture was cooled to room temperature. Water (200 mL) was added. The light brown solution was concentrated to remove the solvent. The resulting residue was dissolved in water (200 mL) and ethyl acetate (EtOAc; 600 mL). The solution was cooled in an ice bath and neutralized to pH 8 with 4 equivalents (N) sodium hydroxide (NaOH) and saturated sodium bicarbonate (NaHCO3) solution. The organic layer was separated, and the aqueous layer was washed with EtOAc. The combined organic extracts were dried and concentrated to produce the title compound (71 g, 67%, HPLC purity 99.9%) as a pale yellow solid with a melting point of 125.8 °C–126.1 °C. 1 H NMR (400MHz, CDCl3) δ5.38 (brs, 2H), 3.97 (s, 3H).

[0062] Example 2: Preparation of isopropyl 4-amino-3,5,6-trichloropyridinecarboxylate (2)

[0063]

[0064] Toxoplasmide (C2; 4.66 g, 18.3 mmol) was suspended in isopropanol (30 mL). Concentrated sulfuric acid (0.6 g, 6.1 mmol) was added at room temperature. The reaction mixture was heated under reflux for 18 hours. The reaction mixture was cooled to room temperature. An aqueous solution of potassium carbonate (K2CO3, 23%; 10 mL) was slowly added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was extracted with EtOAc (20 mL), and the organic phase was washed with saturated brine (20 mL). The organic phase was dried, and the solvent was evaporated. The residual solid was dried in a vacuum oven to give the title compound (4.9 g, 94%, HPLC purity 96%) as a grayish-white solid with a melting point of 128.5 °C–131.0 °C. 1 ¹H NMR (400MHz, CDCl₃) δ 5.35 (br s, 2H), 5.29 (septet, J = 6.4Hz, 1H), 1.39 (d, J = 6.4Hz, 6H) ppm.

[0065] Example 3: Preparation of methyl 3,5,6-trichloro-4-(1,3-dioxoisoindolin-2-yl)pyridinecarboxylate (3)

[0066]

[0067] Methyl 4-amino-3,5,6-trichloropyridinecarboxylate (1.86 g, 337 mmol) was dissolved in acetonitrile (600 mL). Triethylamine (94 mL, 673 mmol) was added at room temperature. Phthaloyl chloride (65 mL, 404 mmol) was added dropwise. The reaction mixture was stirred overnight at 50 °C. Water (100 mL) was added to the mixture. The suspension was stirred for 1 hour and filtered through filter paper. The solid was washed with water, then with hexane, and dried. The dried solid was suspended in toluene (200 mL) and the resulting mixture was concentrated to provide the title compound (85.1 g, 66%, HPLC purity 97.7%) as a pale yellow solid with a melting point of 185.3 °C–185.9 °C. 1 H NMR (400MHz, CDCl3) δ8.02(m,2H),7.88(m,2H),4.02(s,3H).

[0068] Example 4: Preparation of 3,5,6-trichloro-4-(1,3-dioxoisoindolin-2-yl)pyridine-2-carboxynitrile (4)

[0069]

[0070] 4-Amino-3,5,6-trichloropyridine-2-carboxynitrile (C1; 64.1 g, 288 mmol) was suspended in acetonitrile (960 mL). Triethylamine (90 mL, 640 mmol) and 4-(dimethylamino)pyridine (DMAP; 3.52 g, 28.8 mmol) were added at room temperature. Phthaloyl chloride (51.2 mL, 320 mmol) was added slowly, carefully maintaining the internal reaction temperature below 50 °C during the addition. The reaction mixture was stirred at room temperature for 4 hours. Water (130 mL) was added to the reaction mixture, and the suspension was stirred for 30 minutes. The solids were collected by filtration and washed with water (4 × 150 mL) and hexane (2 × 100 mL). The solid was dried to produce the title compound (97.0 g, 96%) as a light purple solid, dissolved in dichloromethane and passed through a silica gel pad to give a grayish-white solid with an HPLC purity of 99.6% and a melting point of 233.7 °C–234.8 °C. 1 HNMR(400MHz,DMSO-d6)δ8.14(m,2H),8.04(m,2H).

[0071] Example 5: Preparation of methyl 3,5,6-trichloro-4-(1,3-dioxoisoindolin-2-yl)pyridinecarboxylate (3)

[0072]

[0073] Toluene (C2; 105.3 g, 415 mmol) was suspended in 650 mL of MeOH in a 3 L three-necked flask equipped with a mechanical stirrer and condenser. The mixture was stirred vigorously at room temperature. Thionyl chloride (0.90 mL, 12 mmol) was added dropwise. The reaction mixture was stirred at 75 °C (external temperature) for 18 hours. Methanol was concentrated (approximately 150 mL remaining). Toluene (500 mL) was added and co-evaporated to dryness under vacuum at 40 °C–55 °C. Acetonitrile (690 mL), triethylamine (134 mL, 959 mmol), and DMAP (5.33 g, 43.6 mmol) were added dropwise. Phthaloyl chloride (77 mL, 480 mmol) was added dropwise, carefully maintaining the internal reaction temperature below 55 °C during the addition. After the addition was complete, the reaction mixture was stirred for another 2 hours. Water (200 mL) was added to the mixture. The resulting suspension was stirred for 30 minutes and filtered. The wet filter cake collected on the funnel was washed with water (2 × 200 mL) and hexane (200 mL) and dried under vacuum. The title compound (154.4 g, 96% purity after two steps, HPLC purity 98%) was separated as a beige solid.

[0074] The following compounds were prepared in a manner similar to that outlined in Example 5:

[0075] Ethyl 3,5,6-trichloro-4-(1,3-dioxoisoindoline-2-yl)pyridinecarboxylate (8)

[0076]

[0077] To a 500 mL round-bottom flask, add picaridin (C2; 30 g, 122 mmol) and EtOH (200 mL). Add thionyl chloride (0.43 mL, 6.1 mmol) dropwise. Stir the white slurry at 75 °C for 6 hours. Add additional thionyl chloride (0.43 mL, 6.1 mmol). Stir the reaction mixture at 75 °C for 16 hours. Concentrate the reaction mixture to produce a yellow oil, which is then co-evaporated with acetonitrile (2 × 200 mL) to dryness to give a white solid. Dissolve the white solid in acetonitrile (200 mL). Add triethylamine (37.4 mL, 268 mmol), DMAP (1.47 g, 12.2 mmol), and phthaloyl chloride (19.3 mL, 134 mmol) sequentially. Keep the temperature below 58 °C during the additions. Stir the reaction mixture at room temperature for 2 hours, quench with water (60 mL), and filter. The filtrate was washed with water and hexane and dried to provide the title compound (43.3 g, 89%, HPLC purity 99.4%): 1 H NMR (400MHz, CDCl3) 8.10 (m, 2H), 7.87 (m, 2H), 4.47 (q, J = 7.2Hz, 2H), 1.43 (t, J = 7.2Hz, 3H).

[0078] Example 6: Preparation of isopropyl 3,5,6-trichloro-4-(1,3-dioxoisoindolin-2-yl)pyridinecarboxylate (5)

[0079]

[0080] Step 1: Toluidine (C2; 100 g, 414 mmol) and isopropanol (950 mL) were charged into a 3-L three-necked flask equipped with a mechanical stirrer, condenser, and feeding funnel. Thionyl chloride (15.1 mL, 207 mmol) was added dropwise to the slurry via the feeding funnel at room temperature, and the reaction mixture was heated under reflux for 24 h. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was co-evaporated with acetonitrile (2 × 100 mL) to produce a white solid (117.5 g) of a mixture of C2 (93.6%) and toluidine (2.84%) (by HPLC).

[0081] Step 2: In a 3-L three-necked flask equipped with a mechanical stirrer, thermometer, and feeding funnel, add the above-separated white solid, acetonitrile (700 mL), triethylamine (150 mL, 1.077 mol), and DMAP (5.05 g, 41.4 mmol). Phthaloyl chloride (90%; 73 mL, 456 mmol) is added dropwise through the feeding funnel to maintain the temperature below 55°C. The reaction mixture is stirred at room temperature for 3 hours. Water (250 mL) is added to the mixture. The resulting suspension is stirred for 30 minutes and filtered through filter paper. The solid is washed with water (3 × 100 mL) and hexane (2 × 100 mL) and dried. The solid is co-evaporated with toluene (2 × 250 mL), dried, washed with hexane (2 × 200 mL), and dried again. The title compound (151.5 g, 88%, HPLC purity 98.8%), a pale yellow solid, was isolated with a melting point of 157.0℃-157.9℃. 1 ¹H NMR (400MHz, CDCl₃) δ 8.04–8.00 (m, 2H), 7.90–7.86 (m, 2H), 5.33 (septet, J = 6.4 Hz, 1H), 1.42 (d, J = 6.4 Hz, 6H).

[0082] Example 7: Preparation of isopropyl 3,5,6-trichloro-4-(1,3-dioxoisoindolin-2-yl)pyridinecarboxylate (5)

[0083]

[0084] Compound 2 (8.1 g, 27.6 mmol) was suspended in acetonitrile (33 mL) in a 100 mL round-bottom flask equipped with a mechanical stirrer and condenser. Triethylamine (9.6 mL, 69.0 mmol) and phthalic anhydride (4.9 g, 33.1 mmol) were added at room temperature. Then DMAP (0.34 g, 2.76 mmol) was added. The yellow suspension was stirred at 80 °C (oil bath temperature) for 2 h. Additional phthalic anhydride (4.0 g, 27.0 mmol) was added to the reaction mixture at 80 °C. The reaction mixture was stirred at 80 °C for another 4.5 h. (Total reaction time: 6.5 h.) The reaction mixture was cooled to room temperature, and water (33 mL) was added to the mixture. The suspension was stirred for 30 min and filtered through filter paper. The wet solid was washed with water and hexane and dried in a vacuum oven at 55 °C. The title compound (9.8 g, 86%, HPLC purity 99.2%) was isolated as a yellow solid.

[0085] Example 8: Preparation of isopropyl 3,5,6-trichloro-4-(1,3-dioxoisoindolin-2-yl)pyridinecarboxylate (5)

[0086]

[0087] Triethylamine (2.96 mL, 21.2 mmol) and phthalic anhydride (3.26 g, 22.0 mmol) were added to a suspension of compound 2 (2.5 g, 8.82 mmol) in toluene (11 mL). The resulting suspension was stirred in an oil bath at 90 °C for 18 hours. The clear yellow solution was gradually cooled to room temperature to provide a thick beige slurry. A saturated sodium bicarbonate solution (5 mL) was slowly added at room temperature, and the resulting slurry was stirred in an ice-water bath for 1 hour. The solid was collected by vacuum filtration and washed with water (2 × 5 mL). The wet solid was dried in a vacuum oven at 55 °C for 5 hours. The title compound (3.1 g, 86%, HPLC purity 99.5%) was isolated as a grayish-white powder.

[0088] Example 9: Preparation of isopropyl 3,5,6-trichloro-4-(1,3-dioxoisoindolin-2-yl)pyridinecarboxylate (5)

[0089]

[0090] To a 2-L flask, add picaridin (C2; 101.8 g, 98.2% purity, 0.414 mol) and isopropanol (918.3 mL). Add thionyl chloride (15.6 mL, 97% purity, 0.21 mol) and heat the reaction mixture under reflux for 17 hours. Distill off the isopropanol (750 mL) at atmospheric pressure. Add toluene (600 mL) to the resulting solution. Continue distillation, and after another 2 hours, distill off the isopropanol / toluene mixture (600 mL) at 81-110 °C. Add triethylamine (144.3 mL, 1.04 mol) and phthalic anhydride (153.3 g, 1.04 mol) sequentially to the stirred suspension. Heat the reaction mixture at 88-93 °C for 17 hours and cool to room temperature. While cooling to maintain a temperature below 20°C, a saturated sodium bicarbonate aqueous solution (400 mL) was slowly added over 0.5 hours. The resulting slurry was stirred at room temperature for 2 hours and then filtered. The solid was washed with water (3 × 100 mL) and dried at 60°C for 24 hours to give the title compound (144 g, 84%, HPLC purity 99%).

[0091] Example 10: Preparation of cyclohexyl 3,5,6-trichloro-4-(1,3-dioxoisoindololin-2-yl)pyridinecarboxylate (10)

[0092]

[0093] Step 1: N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI; 17.5 g, 91.1 mmol) was added in four portions to a mixture of toxicazine (C2; 20 g, 82.8 mmol), DMAP (5.06 g, 41.4 mmol), and hexanol (7.88 g, 78.7 mmol) in dichloromethane (200 mL). The white slurry was stirred at room temperature for 16 hours, filtered directly through a silica pad, and washed with dichloromethane (3 L). The product fractions were combined to produce the ester (16.2 g, 60%).

[0094] Step 2: Phthaloyl chloride (7.9 mL, 55.1 mmol) was slowly added to a mixture of the ester (16.2 g, 50.1 mmol), DMAP (0.61 g, 5.01 mmol), and triethylamine (15.4 mL, 110 mmol) from Step 1 in acetonitrile (100 mL). The yellow suspension was stirred vigorously for 2 hours, quenched with water (100 mL), filtered, and washed with methanol. The solid was co-evaporated with toluene, filtered, and washed with hexane to give the title compound (19 g, 84%) with some toluene. The solid was further purified by silica gel column chromatography (12.9 g, 57%, HPLC purity 99.1%). 1 H NMR (400MHz, CDCl3)8.01(m,2H),7.88(m,2H),5.11(m,1H),2.02(m,2H),1.79(m,2H),1.64(m,3H),1.40(m,2H),1.33(m,1H).

[0095] Example 11: Preparation of benzyl 3,5,6-trichloro-4-(1,3-dioxoisoindolin-2-yl)pyridinecarboxylate (12)

[0096]

[0097] Step 1: Add benzyl bromide (BnBr; 2.81 mL, 23.7 mmol) to a mixture of toxicazine (C2; 5.0 g, 19.7 mmol) and potassium carbonate (3.27 g, 23.7 mmol) in DMSO (5 mL). Stir the reaction mixture at room temperature for 4 hours, quench with water, filter to provide a solid, dissolve it in EtOAc (50 mL), and precipitate it by adding hexane (50 mL). Use the solid in the next step without further processing.

[0098] Step 2: Triethylamine (6.0 mL, 43.1 mmol), DMAP (0.24 g, 1.98 mmol), and phthaloyl chloride (3.47 mL, 21.7 mmol) were added sequentially to a suspension of the solid from Step 1 in acetonitrile (35 mL). The reaction mixture was stirred at room temperature for 3 hours, quenched with water, filtered, washed with water and hexane, and dried to provide the title compound (7.41 g, 81%, HPLC purity 97.1%). 1 H NMR (400MHz, CDCl3)8.01(m,2H),7.88(m,2H),7.46(m,2H),7.36(m,3H),5.45(s,2H).

[0099] Example 12: Preparation of methyl 3-chloro-4-(1,3-dioxoisoindolin-2-yl)-5,6-difluoropyridinecarboxylate (6)

[0100]

[0101] Anhydrous tetrahydrofuran (THF; 100 mL) and tetramethylammonium fluoride (TMAF, Aldrich; 4.83 g, 51.87 mmol) were added in a single batch to compound 3 (5.00 g, 13.0 mmol) in a 250 mL round-bottom flask under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 5 h, cooled to 0 °C, quenched with water (400 mL), and stirred at 0 °C for 1 h. The solid was collected by filtration, washed with water (2 × 100 mL) and hexane (3 × 100 mL), and dried. The title compound (4.0 g, 87%, HPLC purity 92.3%) was isolated as a pale yellow solid with melting points of 180.2 °C–182.6 °C. 1 H NMR(DMSO-d6)δ8.12(d,2H),8.02(d,2H),3.94(s,3H); 19 F NMR δ -83.30, -133.05. Also contains 6.6% 3,5,6-trifluorinated byproducts.

[0102] Example 13: Preparation of methyl 3-chloro-4-(1,3-dioxoisoindoline-2-yl)-5,6-difluoropyridinecarboxylate (6)

[0103]

[0104] A mixture of cesium fluoride (CsF; 82.7 g, 545 mmol) in dimethyl sulfoxide (DMSO; 1.2 L) was distilled under vacuum at 90 °C in a laboratory to remove DMSO (250 mL). After cooling to room temperature under nitrogen (N2), compound 3 (60.0 g, 156 mmol) was added in three batches. The mixture was stirred vigorously at 25 °C under N2 for 27 h, poured into ice water (3.6 L), stirred for 1 h, and filtered. The filtered solid was washed with water (600 mL) and hexane (300 mL) and dried to provide the title compound as an off-white solid (55 g, 100% (unpurified), HPLC purity 93.6% (also containing 1.3% monofluorinated byproduct and 2.3% trifluorinated byproduct)). The off-white solid was stirred in methanol (150 mL) under reflux for 30 minutes and filtered to give the title compound as a pale beige solid (51.1 g, 92.7% yield, HPLC purity 95.7% (also containing 1.3% 6-monofluoro byproduct and 1.7% 3,5,6-trifluoro byproduct)).

[0105] The sample (1.0 g) of the pale beige solid was dissolved in a minimal amount of hot ethyl acetate (12.5 mL), and the resulting solution was diluted with methanol (25 mL). The resulting solution was gradually cooled to room temperature with stirring and then cooled in an ice-water bath. The resulting mixture was filtered, and the filtered solid was washed twice with methanol (5 mL) and dried. The title compound (0.81 g, 81% recovery, HPLC purity 98.1%, also containing 0.8% 6-monofluoro byproduct and 0.9% 3,5,6-trifluoro byproduct) was isolated as fine grayish-white crystals.

[0106] Example 14: Preparation of isopropyl 3-chloro-4-(1,3-dioxoisoindoline-2-yl)-5,6-difluoropyridinecarboxylate (7)

[0107]

[0108] Solid potassium fluoride (KF, Sigma Aldrich; 12.7 g, 219 mmol) was added to a 1-L jacketed glass reactor that had been purged with nitrogen and maintained under a nitrogen atmosphere. The reactor was fitted with a 1-inch diameter tray distillation column. DMSO (Fisher Scientific; 353.0 g) was added to the reactor. The mixture was stirred at 350 rpm. A vacuum of approximately 40 mmHg was applied, and the temperature of the reactor contents was increased to approximately 108 °C. Approximately 100 mL of the substance was distilled off the reactor using the distillation column. The temperature of the reactor contents was lowered to 75 °C, and the water content was determined to be 51 parts per million (ppm) by Karl Fischer analysis. Compound 5 (24.9 g, 60.2 mmol) was added to the reactor, and the temperature was increased to 100 °C. The reaction was maintained at 100 °C for approximately 7.5 hours. The reactor was cooled to 75°C and the reaction mixture was passed through a sintered filter to remove solids. The filtered salt was washed with DMSO (44 g), and the filtrate and washings were added to a second vessel for crystallization. The second vessel was cooled to 12°C, the contents were stirred at 250 RPM, and water (363 g) was continuously added to the second vessel over approximately 2 hours. A mixture was formed and stirred again at 12°C for one hour. The solids were collected by filtration, washed with water (approximately 68 g), and dried overnight in a vacuum oven at 60°C (25 Torr). The resulting dried solids (21.5 g, 94%) provided 93.7% of the title compound, 2.6% of the 3,5,6-trifluoro byproduct, and 2.0% of the 6-monofluoro byproduct: melting point 115.8°C–117.1°C; 1 ¹H NMR (400MHz, CDCl₃) δ 8.00–8.06 (m, 2H), 7.91–7.86 (m, 2H), 5.32 (septet, J = 6.0 Hz, 1H), 1.42 (d, J = 6.0 Hz, 6H); 19 F NMR (376MHz, CDCl3) δ-134.21(d),-82.76(d).

[0109] Example 15: Preparation of isopropyl 3-chloro-4-(1,3-dioxoisoindololin-2-yl)-5,6-difluoropyridinecarboxylate (7)

[0110]

[0111] Solid potassium fluoride (Sigma-Aldrich; 7.68 g, 132 mmol) was added to a 1-L jacketed glass reactor that had been purged with nitrogen and maintained under a nitrogen atmosphere. The reactor was fitted with a 1-inch diameter, 7-plate distillation column. DMF (Feisel Technologies, 211.7 g) and toluene (Feisel Technologies, 41.6 g) were added sequentially to the reactor. The solution was stirred at 275 RPM. A vacuum of approximately 350 mmHg was applied, and the temperature of the reactor contents was increased to approximately 110 °C. Approximately 75 mL of the substance was distilled off using the column, and removed from the reactor by reducing the pressure as the substance was distilled off. The temperature of the reactor contents was reduced to 45 °C, and the water content was determined to be 101 ppm by Karl Fischer analysis. Compound 5 (15.2 g, 36.7 mmol) was added to the reactor, and the temperature was increased to 100 °C. The reaction was maintained at 100 °C for approximately 33 hours. The reactor was cooled to 40°C and the reaction mixture was passed through a sintered filter to remove solid salt. The filtered salt was washed with DMF (36.1 g), and the filtrate and washings were added to a second vessel for crystallization. The second vessel was cooled to 10°C, the contents were stirred at 250 RPM, and water (170 g) was added continuously over approximately 2 hours. A mixture was formed and stirred again at 10°C for 4 hours. The solid was collected by filtration, washed with water (approximately 44 g), and dried overnight in a vacuum oven at 60°C (25 Torr). The resulting dried solid (12.0 g, 80%) provided 82.6% of the title compound, 1.1% of the 3,5,6-trifluoro byproduct, and 16.6% of the 6-monofluoro byproduct.

[0112] Example 16: Preparation of isopropyl 3-chloro-4-(1,3-dioxoisoindololin-2-yl)-5,6-difluoropyridinecarboxylate (7)

[0113]

[0114] Solid potassium fluoride (Sigma-Aldrich; 11.2 g, 192 mmol) was added to a 1-L jacketed glass reactor that had been purged with nitrogen and maintained under a nitrogen atmosphere. The reactor was fitted with a 1-inch diameter, 7-plate distillation column. DMSO (Feisel Technologies; 207.2 g) and solid tetramethylammonium chloride (TMAC, Sigma-Aldrich; 5.29 g, 48.3 mmol) were added sequentially to the reactor. The mixture was stirred at 350 RPM. A vacuum of approximately 100 mmHg was applied, and the temperature of the reactor contents was increased to approximately 100 °C. Approximately 35 mL of the substance was distilled off the reactor using the distillation column. The temperature of the reactor contents was decreased to 45 °C, and the water content was determined to be 102 ppm by Karl Fischer analysis. Compound 5 (19.8 g, 47.9 mmol) was added to the reactor, and the temperature of the reaction mixture was increased to 60 °C. The reaction was maintained at 60°C for approximately 3.5 hours and then increased to 70°C. The temperature was maintained at 70°C for approximately 8.5 hours and then increased and maintained at 80°C for one hour. The reactor was cooled to 75°C and the reaction mixture was passed through a sintered filter to remove the solid salt. The filtered salt was washed with DMSO (50 g) and the filtrate and washings were added to a second vessel for crystallization. The second vessel was cooled to 21°C, the contents were stirred at 250 RPM, and water (267 g) was added continuously over approximately 2 hours. The mixture was formed and stirred again at 21°C for one hour, and the solids present were collected by filtration, washed with water (approximately 66 g), and dried overnight in a vacuum oven at 60°C (25 Torr). The resulting dried solid (15.5 g, 85% yield) provided 97.5% of the title compound, and the dried solid also contained 1.7% of 3,5,6-trifluoro byproducts and 1.9% of 6-monofluoro byproducts.

[0115] Example 17: Preparation of isopropyl 3-chloro-4-(1,3-dioxoisoindololin-2-yl)-5,6-difluoropyridinecarboxylate (7)

[0116]

[0117] Solid potassium fluoride (Sigma-Aldrich; 12.7 g, 219 mmol) was added to a 1-L jacketed glass reactor that had been purged with nitrogen and maintained under a nitrogen atmosphere. The reactor was fitted with a 1-inch diameter, 7-plate distillation column. DMSO (Feisel Technologies; 408.9 g) and a solution of 35% tetramethylammonium chloride (TMAC) in methanol (SAChem; 34.6 g, 110 mmol) were added sequentially to the reactor. The mixture was stirred at 350 RPM. A vacuum of approximately 60 mmHg was applied, and the temperature of the reactor contents was increased to approximately 100 °C. Approximately 115 mL of the substance was distilled off the reactor using the column. The temperature of the reactor contents was reduced to 70 °C, and more DMSO (54 g) was added to the reactor mixture before restarting distillation and collecting approximately 35 mL of additional distillate. The temperature of the reactor contents was lowered to 75°C, and the water content was determined to be 179 ppm by Karl Fischer analysis. Compound 5 (24.9 g, 60.2 mmol) was added to the reactor, and the temperature was increased to 100°C. The reaction was maintained at 100°C for approximately 2.25 hours. The reactor was cooled to 75°C, and the reaction mixture was passed through a sintered filter to remove solid salts. The filtered salts were washed with DMSO (116 g), and the filtrate and washings were added to a second vessel for crystallization. The second vessel was cooled to 14°C, the contents were stirred at 250 RPM, and water (283 g) was added continuously over approximately 2 hours. A mixture was formed and stirred again at 14°C for one hour. The solids were collected by filtration, washed with water (approximately 64 g), and dried overnight in a vacuum oven at 60°C (25 Torr). The resulting dry solid (22.5 g, 98%) provided 98.3% of the title compound, 3.8% of the 3,5,6-trifluoro byproduct and 0.5% of the 6-monofluoro byproduct.

[0118] Example 18: Preparation of ethyl 3-chloro-4-(1,3-dioxoisoindololin-2-yl)-5,6-difluoropyridinecarboxylate (9)

[0119]

[0120] Solid potassium fluoride (Sigma-Aldrich; 5.9 g, 102 mmol) was added to a 1-L jacketed glass reactor that had been purged with nitrogen and maintained under a nitrogen atmosphere. The reactor was fitted with a 1-inch diameter, 7-plate distillation column. A solution of DMF (Feisel Technologies; 139.5 g) and 35% tetramethylammonium chloride (TMAC) in methanol (Sankai Chemicals; 15.8 g, 50.4 mmol) was added sequentially to the reactor. The solution was stirred at 350 RPM. A vacuum of approximately 90 mmHg was applied, and the temperature of the reactor contents was increased to approximately 90 °C. Approximately 75 mL of the substance was distilled off the reactor using the column. The temperature of the reactor contents was lowered to 45 °C, and the water content was determined to be 105 ppm by Karl Fischer analysis. Compound 8 (10.1 g, 25.1 mmol) was added to the reactor, and the temperature was increased to 100 °C. The reaction was maintained at 100°C for approximately 4 hours. The reactor was cooled to 50°C and the reaction mixture was passed through a sintered filter to remove the solid salt. The filtered salt was washed with DMF (73 g) and the filtrate and washings were added to a second vessel for crystallization. The second vessel was cooled to 2°C, the contents were stirred at 250 RPM, and water (172.3 g) was continuously added to the reaction mixture over approximately 2 hours to keep the temperature of the mixture below 10°C. The mixture was formed and stirred again at approximately 10°C for one hour. The solid was collected by filtration, washed with water (approximately 35 g), and dried overnight in a vacuum oven at 60°C (25 Torr). The resulting dried solid (6.44 g, 70%) provided 97.3% of the title compound, 2.4% of the 3,5,6-trifluoro byproduct, and 3.8% of the 6-monofluoro byproduct: melting point 111.2°C–116.7°C; 1 H NMR (400MHz, CDCl3) δ8.04-8.00(m,2H),7.90-7.88(m,2H),4.47(q,J=6.8Hz,2H),1.43(d,J=6.8Hz,3H); 19 F NMR (376MHz, CDCl3)-133.57(d),-82.54(d).

[0121] Example 19: Preparation of cyclohexyl 3-chloro-4-(1,3-dioxoisoindololin-2-yl)-5,6-difluoropyridinecarboxylate (11)

[0122]

[0123] Cesium fluoride (1.17 g, 7.70 mmol) was added to a 50-mL round-bottom flask equipped with a stir bar and a distillation apparatus. DMSO (25 mL) was added. The flask was placed in an oil bath, and a vacuum (approximately 1 mmHg) was applied to the system. DMSO (approximately 10 mL) was distilled off. The distillation apparatus was removed, and the system was cooled under a nitrogen balloon. When the oil bath reached 25°C, compound 10 (1.0 g, 2.17 mmol) was added in one go. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 24 hours, poured into 50 mL of ice-water, and stirred for 30 minutes. The product was collected, and the wet filter cake was washed with water (2 × 10 mL) and hexane (10 mL) and dried in a vacuum oven at 55°C. The title compound (0.89 g, 95%, HPLC purity 92.9%) was isolated as a yellow solid. 19 F NMR (376MHz, DMSO-d6) δ -83.3 (d, J = 26.7Hz), -133.7 (d, J = 26.7Hz). It also contains 2.1% 3,5,6-trifluoro byproducts.

[0124] Example 20: Preparation of benzyl 3-chloro-4-(1,3-dioxoisoindolin-2-yl)-5,6-difluoropyridinecarboxylate (13)

[0125]

[0126] Cesium fluoride (1.15 g, 7.58 mmol) was added to a 50-mL round-bottom flask equipped with a stir bar and a distillation apparatus. DMSO (25 mL) was added. The flask was placed in an oil bath, and a vacuum (approximately 1 mmHg) was applied to the system. DMSO (approximately 10 mL) was distilled off. The distillation apparatus was removed, and the system was cooled under a nitrogen balloon. Compound 12 (1.0 g, 2.17 mmol) was added in a single addition. The reaction mixture was stirred at room temperature for 24 hours, poured into 50 mL of ice-water, and stirred for 30 minutes. The product was collected, and the wet filter cake was washed with water (2 × 10 mL) and hexane (10 mL) and dried in a vacuum oven at 55 °C. The title compound (0.86 g, 93%, HPLC purity 88.4%) was isolated as a beige solid. 1 H NMR (400MHz, DMSO-d6) δ8.18-8.10(m,2H),8.06-8.00(m,2H),7.45(m,2H),7.42-7.30(m,3H),5.42(s,2H); 19 F NMR (376MHz, DMSO-d6) δ -83.2 (d, J = 26.7Hz), -133.0 (d, J = 26.7Hz). It also contains 0.7% 6-monofluoro byproducts and 7.6% 3,5,6-trifluoro byproducts.

[0127] Example 21: Preparation of 4-amino-3,6-dichloro-5-fluoropyridinecarboxylic acid (14)

[0128]

[0129] Compound 6 (5.0 g, 14.2 mmol) was suspended in a 450 mL sealed flask in a solution of hydrogen chloride (HCl) in acetic acid (HOAc, 2 M; 35.5 mL, 71 mmol). The mixture was stirred overnight at 110 °C (oil bath) and cooled to 5 °C. An aqueous HCl solution (12 N, 10 mL) was slowly added to the flask; the flask was resealed and placed in an oil bath at 110 °C overnight. The resulting mixture was cooled to 5 °C and filtered. The collected solid was suspended in a 2 N HCl aqueous solution (100 mL), stirred at 110 °C for 60 min, and filtered. The filtered solid was washed with hexane and dried. The title compound (1.88 g, 51%, HPLC purity 97.1%) was isolated as a grayish-white solid with a melting point of 211.0 °C–212.7 °C. 1 H NMR(DMSO-d6)δ13.81(br s,1H),7.21(br s,2H); 19 F NMR (DMSO-d6) δ -137.05.

[0130] Example 22: Preparation of 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylic acid (Formula A1)

[0131]

[0132] A mixture of compound 6 (3.92 g, 11.1 mmol), water (2 mL, 111 mmol), and anhydrous hydrogen bromide (HBr) in HOAc (5.7 M, 78 mL, 445 mmol) was heated at 110 °C for 18 hours in a 500 mL sealed flask. The reaction mixture was cooled to 0 °C and quenched with water (400 mL). The resulting suspension was stirred at 0 °C for 30 minutes and filtered, and the collected solid was washed with water (2 × 100 mL) and hexane (3 × 100 mL). The title compound (2.08 g, 54%, HPLC purity 96.5%) was isolated as a beige solid with a melting point of 211.3 °C–212.5 °C. 1 H NMR(DMSO-d6)δ13.72(br s,1H),7.16(br s,2H); 19 F NMR (DMSO-d6) δ -130.28.

[0133] Example 23: Preparation of 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylic acid (Formula A1)

[0134]

[0135] In a 1-L Hastelloy C276 reactor, compound 6 (50 g, 0.142 mol) was suspended in water (8.93 g, 0.496 mol), and HBr (57.5 g, 0.71 mol) in acetic acid (117 g) was added. The reactor was heated to 110 °C with stirring and maintained at 110 °C for 8 hours. The reactor was cooled to 60 °C and filtered. The wet filter cake was washed with water (2 × 150 mL) and dried. The title compound (42.6 g, 90%, 90% purity) was separated as a grayish-white solid.

[0136] Example 24: Preparation of 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylic acid (Formula A1)

[0137]

[0138] In a 1-L Hastelloy C276 reactor, compound 7 (50 g, 0.13 mol) was suspended in water (8.25 g, 0.46 mol), and HBr (53.0 g, 0.65 mol) in acetic acid (108 g) was added. The reactor was heated to 110 °C with stirring and maintained at 110 °C for 8 hours. The reactor was cooled to 60 °C and filtered. The wet filter cake was washed with water (2 × 150 mL) and dried. The title compound (39.3 g, 90%, HPLC purity 90%) was separated as a grayish-white solid.

[0139] Example 25: Preparation of 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylic acid (Formula A1)

[0140]

[0141] In a 1-L Hastelloy C276 reactor, compound 6 (50 g, 0.142 mol) was suspended in a mixture of water (8.93 g, 0.496 mol) and HBr (57.5 g, 0.71 mol) in acetic acid (117 g). The reactor was heated to 110 °C with stirring and maintained at that temperature for 8 hours, then cooled to 60 °C and filtered. The filtered wet filter cake was re-slurryed in 50 wt% aqueous methanol (150 g) at 60 °C for 1 hour and filtered. The wet filter cake was dried to provide the title compound (33.7 g, 88%, HPLC purity 99.1%) as a grayish-white solid.

[0142] Example 26: Preparation of 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylic acid (Formula A1)

[0143]

[0144] In a 1-L Hastelloy C276 reactor, compound 7 (50 g, 0.13 mol) was suspended in a mixture of water (8.25 g, 0.46 mol) and HBr (53.0 g, 0.65 mol) in acetic acid (108 g). The reactor was heated to 110 °C with stirring and maintained at that temperature for 8 hours, then cooled to 60 °C and filtered. The filtered wet filter cake was then slurried in 50 wt% aqueous methanol (150 g) at 60 °C for 1 hour and filtered again. The wet filter cake was dried to provide the title compound (31.4 g, 88%, HPLC purity 99.0%) as a grayish-white solid.

[0145] Example 27: Preparation of 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylic acid (Formula A1)

[0146]

[0147] Step 1: Compound 6 (5.0 g, 14.2 mmol) and HBr in HOAc (5.7 M, 25 mL, 142 mmol) were charged into a Chemglass autoclave (75 mL) equipped with a magnetic stirrer. The flask was sealed with a PTFE cap and heated at 50 °C for 24 hours. The reaction mixture was cooled to 0 °C and quenched with water (50 mL). The suspension was stirred at room temperature for 30 minutes and filtered. The solids were washed with water (2 × 30 mL) and dried.

[0148] Step 2: Add a mixture of sulfuric acid and water (H₂SO₄ / H₂O, 2:1 (v / v); 40 mL) to the mixture obtained from Step 1. Stir the mixture at 110 °C for 24 hours, cool to 0 °C, and quench with water (200 mL). Stir the suspension at room temperature for 30 minutes and filter. Resuspend the solid in water (200 mL) and heat the mixture at 110 °C for 1 hour. Filter the hot suspension and dry to obtain the title compound (2.67 g, 70% by two steps, HPLC purity 90.3%).

[0149] Example 28: Preparation of 4-amino-3,6-dichloro-5-fluoropyridinecarboxylic acid (14)

[0150]

[0151] Step 1: In a 75 mL sealed glass flask, compound 6 (2.5 g, 7.1 mmol) was suspended in HCl (2 M; 17.5 mL, 35 mmol) in HOAc. The mixture was stirred at 80 °C (oil bath) for 19 hours. The reaction mixture was cooled to 5 °C and poured into ice-water (60 mL). The mixture was stirred for 30 minutes and filtered. The white solid (4.5 g, wet) was used in the next reaction without further purification.

[0152] Step 2: Add a mixture of H₂SO₄ / H₂O (2:1 v / v; 20 mL) to the mixture from Step 1. Stir the mixture at 110 °C for 24 hours, cool to 0 °C, and quench with water (100 mL). Stir the suspension at room temperature for 30 minutes and filter. Suspend the solid in 100 mL of water and heat the mixture at 110 °C for 1 hour. Filter the hot suspension and dry to obtain the title compound (1.10 g, 60% from two steps, HPLC purity 91.4%).

[0153] Example 29: Preparation of benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate (Formula A2)

[0154]

[0155] 4-Amino-6-bromo-3-chloro-5-fluoropyridinecarboxylic acid (formula A1; 5.0 g, 18.6 mmol) and DMSO (20 mL) were added to a 125 mL three-necked flask equipped with a magnetic stirrer, a cold water condenser, a thermocouple, and a nitrogen pad. The mixture was stirred, and powdered K₂CO₃ (2.82 g, 20.4 mmol) was added in portions over 10 minutes. A slight exothermic reaction was observed, with the temperature rising from 20 °C to 22.5 °C. The mixture was stirred at ambient temperature for 30 minutes, and benzyl chloride (2.59 g, 20.4 mmol) was added in a single batch. The resulting mixture was stirred at ambient temperature for 15 minutes, at 40 °C for 5 hours, and at 50 °C for 2 hours. The reaction mixture was cooled to ambient temperature, water (75 mL) was added, and the resulting mixture was stirred for 30 minutes. The solid was filtered, washed with water (20 mL), dried by suction drying, and dried overnight in a vacuum oven at 50 °C. The title compound (6.5 g, 97%) was isolated: 1 H NMR(500HMz,CDCl3)δ7.44(m,2H),7.35(m,3H),5.40(s,2H),4.98(br s,2H); 19 F NMRδ-129.16.

[0156] Example 30: Preparation of benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate (Formula A2)

[0157]

[0158] In a 250 mL three-necked flask equipped with a magnetic stirrer, a cold water condenser, a thermocouple, and a nitrogen gas pad, 12.9 g of a sample of 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylic acid (formula A1; if...) was added... 1 The compound, estimated by ¹H NMR to be 82 wt% purity (39.17 mmol, containing 18 wt% (13.94 mmol) phthalic acid), was dissolved in DMSO (100 mL). The addition of powdered K₂CO₃ (9.95 g, 72 mmol) in portions over 10 minutes induced a slightly exothermic reaction, with the temperature rising from 20 °C to 25 °C. The mixture was stirred at ambient temperature for 30 minutes, and benzyl bromide (8.00 g, 46.8 mmol) was slowly added over 10 minutes while maintaining the temperature below 25 °C in a cold water bath. The resulting mixture was stirred at ambient temperature for 4 hours and poured into cold water (300 mL). The resulting slurry was stirred for 15 minutes and filtered. The solid was washed with water (100 mL), dried by suction, and washed with hexane (100 mL). Further drying was performed overnight in a vacuum oven at 45 °C to provide the title compound (13.4 g, 95%).

[0159] Example 31: Preparation of benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate (Formula A2)

[0160]

[0161] A sample of 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylic acid (Formula A1; 13.5 g, 47.6 mmol) was added to a 250 mL jacketed reactor equipped with an overhead stirrer, a cold water condenser, a thermocouple, and a nitrogen pad. THF (50 mL) was added to give a thin slurry. Triethylamine (7.1 g, 70.1 mmol) was added slowly. Benzyl chloride (8.9 g, 70.1 mmol) was added to the reaction mixture in one step. The resulting mixture was heated to 65 °C and stirred for 18 hours. Liquid chromatography analysis showed a conversion of >99%. Additional triethylamine (0.3 equivalents) was added. The reaction mixture was cooled to room temperature after 16 hours. Brine (15 wt%, 20 g) was added to the mixture. The aqueous phase was discarded.

[0162] Example 32: Preparation of benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate (Formula A2)

[0163]

[0164] Add 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylic acid (formula A1; 3.00 g, 11.1 mmol), benzyl alcohol (11.5 g), toluene, and p-toluenesulfonic acid monohydrate (p-TSA, 212 mg) to a three-necked flask equipped with a stir bar, heating mantle, and condenser. Heat the mixture at 80 °C and slowly place it under a vacuum of 30 mmHg to remove water generated in situ. After heating at 80 °C for 10 hours, cool the reaction mixture to ambient temperature. Add cyclohexane (50 mL) dropwise, and stir the resulting slurry for 2 hours, cool to 10 °C, and filter. Wash the wet filter cake with cyclohexane (10 mL) and water (20 mL), dry by suction, wash with cyclohexane (5 mL), and dry under reduced pressure in a vacuum oven at 45 °C to provide the title compound (3.29 g, 82.3%).

[0165] Example 33: The following comparative preparation:

[0166] A. Preparation of benzyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropyridinecarboxylate (Formula IA) from formula A2 (6-bromopyridine compound).

[0167]

[0168] To a 50-mL three-necked flask equipped with a stir bar, condenser, thermocouple, and nitrogen gas pad, benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate (formula A2; 1.80 g, 5.0 mmol), (4-chloro-2-fluoro-3-methoxyphenyl)boronic acid (B1; 1.12 g, 5.5 mmol), solid potassium bicarbonate (KHCO3; 1.00 g, 10 mmol), THF (15 mL), and water (5 mL) were added. The mixture was stirred and bubbled under nitrogen for 30 minutes. Triphenylphosphine (Ph3P; 26.2 mg, 0.1 mmol) and palladium acetate (Pd(OAc)2; 11.2 mg, 0.050 mmol) were added under nitrogen. The mixture was heated and stirred at 60 °C for 16 hours. HPLC analysis of the reaction mixture showed that the reaction yielded 95.6 area % of the title compound and only 3.0 area % of unreacted C2, with no boric acid present.

[0169] B. Preparation of benzyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropyridinecarboxylate (Formula IA) from 14 (6-chloropyridine compounds).

[0170]

[0171] To a 50-mL three-necked flask equipped with a stir bar, condenser, thermocouple, and nitrogen gas pad, benzyl 4-amino-3,6-dichloro-5-fluoropyridinecarboxylate (Formula A1; 1.56 g, 5.0 mmol), (4-chloro-2-fluoro-3-methoxyphenyl)boronic acid (Formula B1; 1.12 g, 5.5 mmol), solid KHCO3 (1.00 g, 10 mmol), THF (15 mL), and water (5 mL) were added. The mixture was stirred and bubbled under nitrogen for 30 minutes. Triphenylphosphine (Ph3P; 26.2 mg, 0.1 mmol) and palladium acetate (Pd(OAc)2; 11.2 mg, 0.050 mmol) were added under nitrogen. The mixture was heated and stirred at 60 °C for 16 hours. HPLC analysis of the reaction mixture showed that the reaction yielded 73.0 area % of the title compound and only 22.9 area % of unreacted Formula A1, and no boric acid was present (meaning the reaction had stopped).

[0172] Example 34: Preparation of benzyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropyridinecarboxylate (Formula IA)

[0173]

[0174] A 1-L four-necked jacketed reactor equipped with a top-mounted stirrer, distillation apparatus, thermocouple, and nitrogen pad was charged with benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate (Formula A2; 30.0 g, 83.0 mmol), (4-chloro-2-fluoro-3-methoxyphenyl)boronic acid (Formula B1; 18.8 g, 92 mmol), potassium bicarbonate (18.7 g, 187 mmol), THF (250 mL), and water (83 mL). The mixture was stirred at 400 RPM and bubbled under nitrogen for 30 min. Triphenylphosphine (438 mg, 1.67 mmol) and palladium acetate (186 mg, 0.83 mmol) were added. The mixture was heated to 60 °C for 5 h. HPLC analysis of the sample showed 91 area % of the title compound and 7.4 area % of unreacted Formula A2. Add additional (4-chloro-2-fluoro-3-methoxyphenyl)boronic acid (1.90 g, about 0.10 equivalents) and stir the reaction mixture until formula A2 is consumed. Cool the reaction mixture to ambient temperature. Separate the two phases. Extract the aqueous phase with THF (50 mL). Combine the organic phases. After removing residual palladium compounds from the combined organic phases, concentrate the organic phase to about 100 mL. Add water (300 mL) with stirring to form a suspension. Filter the suspension. Wash the wet filter cake with water (100 mL) and dry to give the title compound (36.0 g; 89%).

[0175] The compositions and methods of the claims are not limited to the specific compositions and methods described herein (which are intended to illustrate several aspects of the claims), and any functionally equivalent compositions and methods are intended to fall within the scope of these claims. Various modifications to these compositions and methods, in addition to those shown and described herein, are also intended to fall within the scope of the appended claims. Furthermore, although only certain representative compositional materials and method steps disclosed herein are specifically described, other combinations of these compositional materials and method steps are intended to fall within the scope of the appended claims, even if not specifically stated. Therefore, combinations of steps, elements, components, or elements may be expressly referred to herein; however, other combinations of steps, elements, components, and elements are included even if not expressly stated. The term “comprising” and its variations, as used herein, are used synonymously with the term “including” and its variations and are open-ended and non-limiting terms. Although the terms “comprising” and “including” have been used herein to describe various embodiments, the terms “consistently made of” and “comprises” may also be used in place of “comprising” and “including” to provide more specific embodiments of the invention and are also disclosed.

Claims

1. A method for preparing 6-aryl-4-aminopyridinecarboxylic acid or 6-aryl-4-aminopyridinecarboxylic ester having Formula I: Equation I, in R represents H, Cl-C 12 Alkyl, C3-C 12 Alkyne group, C1-C3 alkyl group substituted with CN, or C6-C 12 Aryl alkyl groups; W represents H, halogen, C1-C4 alkyl, or C1-C3 alkoxy; Y represents H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -CN, or -NO2; and Z represents H, F, Cl, C1-C4 alkyl, C1-C3 alkoxy, C1-C4 haloalkyl, C1-C3 haloalkoxy, C1-C4 alkoxy-substituted C1-C4 alkyl, or -NR. 2 R 3 , where R 2 and R 3 It is independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; The method includes the following steps: a. To generate a first mixture, the first mixture comprising: Compounds having formula C2 Formula C2; An acid or a compound that forms an acyl chloride, wherein the compound forming the acyl chloride is selected from thionyl chloride and oxalyl chloride; and Alcohol R'OH, where R' represents C1-C 12 Alkyl, C3-C 12 Alkyne group, C1-C3 alkyl group substituted with CN, or C6-C 12 Aryl alkyl groups; b. Heat the first mixture at a temperature ranging from 70°C to 90°C; c. Separating compounds having formula D2 from the first mixture. Equation D2, in R' represents C1-C 12 Alkyl, C3-C 12 Alkyne group, C1-C3 alkyl group substituted with CN, or C6-C 12 Aryl alkyl groups; d. To generate a second mixture, the second mixture comprising: the compound having formula D2; Phthaloyl halides or phthalic anhydrides ， in A is independently selected from H, F, Cl, Br, I, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and nitro; n is 1, 2, 3, or 4; and X 2 It is Cl or Br; Base; solvent or solvent mixture; and optionally acylation catalyst; e. Heating the second mixture at a temperature ranging from 25°C to 100°C; f. Separating compounds having formula E2 from the second mixture. E2, in R' represents C1-C 12 Alkyl, C3-C 12 Alkyne group, C1-C3 alkyl group substituted with CN, or C6-C 12 Aryl alkyl groups; A is independently selected from H, F, Cl, Br, I, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and nitro; and n is 1, 2, 3, or 4; g. To generate a third mixture comprising: the compound having the formula E2; a fluorinated compound or a fluorinated mixture of compounds; and a solvent; h. Heating the third mixture at a temperature ranging from 25°C to 110°C; i. Separating compounds having formula F2 from the third mixture. Formula F2, in R' represents C1-C 12 Alkyl, C3-C 12 Alkyne group, C1-C3 alkyl group substituted with CN, or C6-C 12 Aryl alkyl groups; A is independently selected from H, F, Cl, Br, I, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and nitro; and n is 1, 2, 3, or 4; j. To generate a fourth mixture, the fourth mixture comprising: the compound having the formula F2; Hydrobromic acid (HBr); acetic acid; and water; k. Heating the fourth mixture at a temperature ranging from 50°C to 110°C; l. Separate the compound having formula A or its hydrobromic acid (HBr) salt from the fourth mixture. Formula A, in R'' represents H; m. Optionally, a fifth mixture is generated, the fifth mixture comprising: the compound having formula A, wherein R'' represents H; and one of the following: i. acids, alcohols (R'OH), and optionally solvents; or ii.R'X 1 , base, and solvent in R' represents C1-C 12 Alkyl, C3-C 12 Alkyne group, C1-C3 alkyl group substituted with CN, or C6-C 12 Aryl alkyl groups; and X 1 Indicates Cl, Br, or I; and n. Heating the fifth mixture at a temperature ranging from 25°C to 80°C; o. Optionally, isolate the compound having formula A'. Formula A' Where R' represents C1-C 12 Alkyl, C1-C3 alkyl substituted with CN, C3-C 12 alkynyl group, or C6-C 12 Aryl alkyl groups; p. to generate a sixth mixture, the sixth mixture containing: a compound having formula A or formula A'; Compounds having formula B, Formula B, in R 1 H represents a C1-C6 alkyl group, or alternatively, two Rs. 1 It can form C2-C6 alkyl bonds, which together with B and two O atoms form a cyclic structure of 5 to 9 atoms; W represents H, halogen, C1-C4 alkyl, or C1-C3 alkoxy; Y represents H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -CN, or -NO2; and Z represents H, F, Cl, C1-C4 alkyl, C1-C3 alkoxy, C1-C4 haloalkyl, C1-C3 haloalkoxy, C1-C4 alkoxy-substituted C1-C4 alkyl, or -NR. 2 R 3 , where R 2 and R 3 It is independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; One or more bases; and one or more solvents; q. Add a palladium catalyst and optionally a ligand to the sixth mixture to form a seventh mixture; and r. Heating the seventh mixture to a temperature between 25°C and 100°C produces 6-aryl-4-aminopyridinecarboxylic acid or 6-aryl-4-aminopyridinecarboxylate having Formula I.

2. The method as described in claim 1, wherein, The 6-aryl-4-aminopyridinecarboxylic acid or 6-aryl-4-aminopyridinecarboxylic ester having Formula I is separated from the seventh mixture.

3. The method of claim 2, further comprising the following steps: a. To generate a mixture containing 6-aryl-4-aminopyridinecarboxylic acid or 6-aryl-4-aminopyridinecarboxylic ester having Formula I, where R in Formula I represents H, and one of the following: i. acids, alcohols R'OH, and optionally solvents; and ii.R'X 1 , base, and solvent in R' represents C1-C 12 Alkyl, C3-C 12 Alkyne group, C1-C3 alkyl group substituted with CN, or C6-C 12 Aryl alkyl groups; and X 1 Indicates Cl, Br, or I; and b. Heat the mixture at a temperature ranging from 25°C to 80°C.

4. The method of claim 3, wherein, The 6-aryl-4-aminopyridine carboxylate having formula I was isolated, wherein R represents C1-C 12 Alkyl, C3-C 12 Alkyne group, C1-C3 alkyl group substituted with CN, or C6-C 12 Aryl group.

5. The method of claim 1, wherein, The compound having formula A' is benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate.

6. The method of claim 1, wherein, The compound having formula B is (4-chloro-2-fluoro-3-methoxyphenyl)boronic acid.

7. The method of claim 1, wherein, The one or more solvents are selected from the group consisting of: methyl isobutyl ketone (MIBK), 1,2-dimethoxyethane (DME), acetonitrile (MeCN), tetrahydrofuran (THF), methanol (MeOH), benzyl alcohol, toluene, water, and mixtures thereof.

8. The method of claim 1, wherein, The one or more solvents are selected from the group consisting of acetonitrile (MeCN) and water.

9. The method of claim 1, wherein, The one or more solvents are selected from the group consisting of tetrahydrofuran (THF) and water.

10. The method of claim 1, wherein, The sixth mixture is deoxygenated before the addition of the palladium catalyst and optional ligand.

11. The method of claim 1, wherein, The ligand is selected from the group consisting of: tri-tert-butylphosphine, tricyclohexylphosphine, di-tert-butylphenylphosphine, dicyclohexylphenylphosphine, triphenylphosphine, cross-linked 4-diphenylphosphine-methyl polystyrene resin, tri(p-tolyl)phosphine, and (±)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl.

12. The method of claim 1, wherein, The ligand is triphenylphosphine.

13. The method of claim 1, wherein, The palladium catalyst is palladium acetate, i.e., Pd(OAc)2.

14. The method of claim 1, wherein, The base in step p is selected from the group consisting of: potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, potassium acetate, sodium acetate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium tetraborate, potassium hydroxide, sodium hydroxide, cesium fluoride, potassium fluoride, triethylamine, triisopropylamine, diisopropylamine, diethylamine, and diisopropylethylamine.

15. The method of claim 1, wherein, The base mentioned in step p is potassium bicarbonate.

16. A method for preparing 6-aryl-4-aminopyridine carboxylate having formula IA: Formula IA, The method includes the following steps: a. To generate a first mixture, the first mixture comprising: Compounds having formula C2 Formula C2; An acid or a compound that forms an acyl chloride, wherein the compound forming the acyl chloride is selected from thionyl chloride and oxalyl chloride; and ROH, where R represents C1-C 12 alkyl; b. Heat the first mixture at a temperature ranging from 70°C to 90°C; c. Separating compounds having formula D2 from the first mixture. Equation D2, in R represents C1-C 12 alkyl; d. To generate a second mixture, the second mixture comprising: the compound having formula D2; Phthalic anhydride ； Alkali; And solvents; e. Heating the second mixture at a temperature ranging from 25°C to 100°C; f. Separating compounds having formula E2 from the second mixture. E2, in R represents C1-C 12 alkyl; g. To generate a third mixture comprising: the compound having the formula E2; a fluorinated compound; and a solvent; h. Heating the third mixture at a temperature ranging from 25°C to 110°C; i. Separating compounds having formula F2 from the third mixture. Formula F2, in R represents C1-C 12 alkyl; j. To generate a fourth mixture, the fourth mixture comprising: the compound having the formula F2; Hydrobromic acid (HBr); acetic acid; and water; k. Heating the fourth mixture at a temperature ranging from 50°C to 110°C; l. Separate a compound having formula A1 or its hydrobromic acid (HBr) salt from the fourth mixture. Formula A1; m. to generate a fifth mixture, the fifth mixture comprising: the compound having formula A1; and R'X 1 , alkali, and solvent in R' represents benzyl; and X 1 Indicates Cl or Br; n. Heating the fifth mixture at a temperature ranging from 25°C to 80°C to form the sixth mixture; o. Add a compound having formula B1 to the sixth mixture. Formula B1; One or more bases; one or more solvents; a palladium catalyst; and optionally a ligand. To form the seventh mixture; p. Heat the seventh mixture to a temperature between 25°C and 100°C; as well as q. Separate the 6-aryl-4-aminopyridine carboxylate having formula IA from the seventh mixture.

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