TW201817716A - Synthesis of 6-aryl-4-aminopicolinates and 2-aryl-6-aminopyrimidine-4-carboxylates by direct suzuki coupling - Google Patents

Abstract

Improved methods of synthesizing 6-aryl-4-aminopicolinates, such as arylalky and alkyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylates and arylalkyl and alkyl 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylates, are described herein. The improved methods include a direct Suzuki coupling step, which eliminates the protection/de-protection steps in the current chemical process, and therefore eliminates or reduces various raw materials, equipment and cycle time as well as modification of other process conditions including use of crude AP, use of ABA-diMe, and varying pH, catalyst concentration, solvent composition, and/or workup procedures. This invention was expanded to include synthesis of 2-aryl-6-aminopyrimidine-4-carboxylates.

Description

 Synthesis of 6-aryl-4-aminopyridinecarboxylate and 2-aryl-6-aminopyrimidine-4-carboxylate by direct Suzuki coupling reaction  

This application claims priority from Provisional Application Nos. 62/338,562 and 62/416,811, filed on May 19, 2016, and on November 3, 2016, in the U.S. Patent. The complete disclosure is by reference and in this specification.

This specification describes an improved synthesis of 6-aryl-4-aminopyridinecarboxylates and 2-aryl-4-aminopyrimidine-4-carboxylates, wherein the number of reaction steps is reduced from current literature methods and Various reaction conditions were modified.

6-aryl-4-aminopicolinate such as methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridinecarboxylate, and 6 -Aryl-4-amino-5-fluoropicolinate, such as 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl) Benzyl picoformate is a high value herbicide recently developed and marketed by Dow AgroSciences LLC. The current synthesis of 6-aryl-4-aminopyridinecarboxylates and 6-aryl-4-amino-5-fluoropicolinates involves a multi-step process for coupling the head to tail of the molecule via a Suzuki coupling reaction. . For the synthesis of 6-aryl-4-aminopicolinate, the process typically involves the protection of 4-amino-2-chloropyridinecarboxylate, for example 4-amino-2-chloropyridine The acid ester is acetylated to cause a high yield of Suzuki coupling reaction with the aryl boronic acid. The deprotection reaction is followed by deacetylation to produce the final desired product. This method is represented by the current reaction scheme for methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate. The section is shown in Flowchart 1:

In addition, procedures not involving the protection of amine groups have been used in the Suzuki coupling reaction shown in Scheme 2 from 4-amino-6-chloropicolinate and 6-amino-2-chloropyrimidine-4 - Carboxylesters 6-Aryl-4-aminopyridinecarboxylates and 2-aryl-6-aminopyrimidine-4-carboxylates were prepared separately.

Scheme 2: Synthesis of 6-aryl-4-aminopyridinecarboxylate and 2-aryl-6-aminopyrimidine-4-carboxylate

For a series of reactions shown in Scheme 1, reducing the number of reaction steps reduces the cost of the synthetic compound by reducing or reducing feedstock, unit operations, equipment, and cycles. For the reactions shown in Scheme 2, reducing the amount of palladium catalyst required for the Suzuki coupling reaction step also reduces the cost of synthesizing the compound. For example, currently used to produce 6-aryl-4-amino picolinate from 4-amino-6-chloropicolinate and 6-amino-2-chloropyrimidine-4-carboxylate The use of 2-aryl-6-aminopyrimidine-4-carboxylate for the production of Suzuki coupling reaction conditions requires 4% or more of the palladium catalyst loading to produce a desired greater than 60% coupling product. Considering the high palladium cost and the inevitable loss of certain palladium catalysts in the Suzuki coupling reaction process and the catalyst recovery step, reducing the required palladium catalyst loading to produce 6-aryl-4-aminopyridine carboxate, 6 The reaction conditions of the improved Suzuki coupling reaction of -aryl-4-amino-5-fluoropyridinecarboxylate and 2-aryl-6-aminopyrimidine-4-carboxylate can significantly reduce the production cost of these molecular classes .

This specification describes 6-aryl-4-aminopyridinecarboxylates, such as methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridinecarboxylate And an improved synthesis of 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate benzyl ester. In particular, the reaction conditions are approved to permit unprotected 4-amino-6-chloropicolinate such as methyl 4-amino-3,6-dichloropicolinate and 4-amino-3 Benzyl 6-dichloro-5-fluoropicolinate using less than 4% palladium catalyst, for example from about 0.25% to about 3%, from about 0.25% to about 2.5%, from about 0.25% to about 2.0% Direct Suzuki coupling reaction from about 0.25% to about 1.5%, from about 0.25% to about 1.0%, or from about 0.25% to about 0.5% to produce high yields (eg, greater than 60%, 65%, 70%) , 75%, 80% or 85%) of 6-aryl-4-aminopicolinate, such as 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxy Methyl phenyl)pyridine-2-carboxylate and 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate Benzyl acrylate. In certain embodiments, the concentration of the palladium catalyst is about 0.5%. In certain embodiments, the concentration of the palladium catalyst is about 0.5%.

Other improvements in the production of 6-aryl-4-aminopicolinate include: (1) the use of crude 4-amino-2-chloropicolinate which is not purified and/or isolated; (2) use ( Dimethyl 4-chloro-2-fluoro-3-methoxyphenyl)borate in place of (4-chloro-2-fluoro-3-methoxyphenyl)boronic acid; and (3) pH, catalyst concentration, Procedure for solvent composition and/or product separation.

Finally, the reaction conditions are approved for use of less than 4% or less, such as less than about 3.5%, such as less than about 3%, less than about 2.5%, less than about 2%, less than about 1.5%, less Direct Suzuki coupling reaction of unprotected 6-amino-2-chloropyrimidine-4-carboxylate to yield high yields (eg, greater than 60%, 65%) at about 1%, or about 0.5% palladium catalyst loading , 70%, 75%, 80%, or 85%) 2-aryl-6-aminopyrimidine-4-carboxylate, such as 6-amino-5-chloro-2-(4-chloro-2 Methyl-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylate and 6-amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-methoxy Methyl pyrimidine-4-carboxylate.

In certain embodiments, the 6-aryl-4-aminopicolinate is one or more compounds of Formula I:

Wherein Q represents H, halo (eg F or Cl), C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkoxy, C ₂ -C ₄ alkenyl, or C ₂ -C ₄ alkene R represents H, alkyl (for example C _1-6 alkyl), aryl, or aralkyl (eg benzyl); X represents H; and aryl represents a substituted or unsubstituted aryl Or heteroaryl.

In certain embodiments, the 6-aryl-4-aminopicolinate is one or more compounds of Formula II: Wherein Q represents H, halo (eg F or Cl), C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkoxy, C ₂ -C ₄ alkenyl, or C ₂ -C ₄ alkene R represents H, alkyl (for example C _1-6 alkyl), or aralkyl (for example benzyl); X represents halo (for example F or Cl), C _1-3 alkyl, C _1-3 Alkoxy, or -NO ₂ ; and aryl represents a substituted or unsubstituted aryl or heteroaryl.

In certain embodiments, the aryl groups of Formulas I and II are

Wherein W represents H, F, Cl, C _1-3 alkyl, or C _1-3 alkoxy; Y represents halo, C _1-4 alkyl, C _1-4 haloalkyl, C _1-3 Alkoxy, C _1-3 haloalkoxy, -CN, or -NO ₂ ; and Z represents H, F, Cl, C _1-4 alkyl, C _1-3 alkoxy, C ₁ -C ₄ Haloalkyl, C _1-3 haloalkoxy, C ₁ -C ₃ alkoxy substituted C ₁ -C ₃ alkyl, or -NR ₁ R ₂ wherein R ₁ and R _{2 are} independently hydrogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl.

In certain embodiments, the aryl groups of Formulas I and II are

Wherein W ₁ represents H or F; W ₂ represents H, F, Cl, C _1-3 alkyl, or C _1-3 alkoxy; Y represents halo, C _1-4 alkyl, C _1-4 Haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, -CN, or -NO ₂ ; Z represents H, F, Cl, C _1-4 alkyl, C _1-3 alkoxy a C ₁ -C ₄ haloalkyl group, a C _1-3 haloalkoxy group, a C ₁ -C ₃ alkoxy substituted C ₁ -C ₃ alkyl group, or -NR ₁ R ₂ , wherein R ₁ and R ₂ independently hydrogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl; or Y and Z or Z and W ₂ together are a five or six member aromatic or non-aromatic, carbocyclic Or a heterocyclic ring. Specific examples of such aryl groups can be found in the international patent applications WO/2014/151005 and WO/2014/151009, which are incorporated by reference herein in the present specification and including but not limited to the following Examples A1-A36:

R ⁵ , if applied to the A group, is hydrogen, halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, cyclopropyl, halocyclopropyl, C ₂ -C ₄ alkenyl , C ₂ -C ₄ haloalkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkoxy, C ₁ -C ₃ sulfanyl, C ₁ -C ₃ -halosulfanyl, amino, C ₁ -C ₄ alkylamino, C ₂ -C ₄ haloalkylamino, OH, or CN; R ⁶ , R ^6' and R ^6" , if applicable to A group a group independently of hydrogen, halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, cyclopropyl, halocyclopropyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ halo Alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkoxy, C ₁ -C ₃ sulfanyl, C ₁ -C ₃ halosulfanyl, Amino, C ₁ -C ₄ alkylamino or C ₂ -C ₄ haloalkylamino, OH, CN, or NO ₂ ; R ⁷ and R ^{7' are} independently hydrogen, halo, C ₁ -C ₄ alkyl , C ₁ -C ₄ haloalkyl, cyclopropyl, halocyclopropyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ haloalkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₃ alkane Oxy, C ₁ -C ₃ haloalkoxy, C1-C ₃ sulfanyl, C ₁ -C ₃ halosulfanyl, amine, C ₁ -C ₄ alkylamino, C ₁ -C ₄ halo an alkoxy group, or a phenyl group; R ⁸ is hydrogen, Ci-C ₆ alkyl Ci-C ₆ haloalkyl, C ₃ -C ₆ alkenyl, C _{3 3-C 6} haloalkenyl, C ₃ -C ₆ alkynyl group, methyl acyl, C ₁ -C ₃ alkylcarbonyl, C ₁ - C ₃ C1-C3 haloalkylcarbonyl, C1-C ₆ alkoxycarbonyl, C1-C ₆ alkylaminecarbamyl, C1-C ₆ alkylsulfonyl, C1-C ₆ trialkyldecyl, Or phenyl.

In other embodiments, the aryl group is as defined above, wherein Y and Z or Z and W ₂ are taken together to form a five member non-aromatic heterocyclic ring. Specific examples of such aryl groups can be found in International Patent Application No. WO/2014/151008, which is incorporated herein by reference.

In certain embodiments, the compound is a compound of formula I, wherein the aryl group is 4-chloro-2-fluoro-3-methoxyphenyl, or an ester thereof, such as a methyl ester. In other embodiments, the compound is of the formula II wherein X is fluoro and the aryl is 4-chloro-2-fluoro-3methoxyphenyl, or an ester thereof, such as benzyl ester. In other embodiments, the compound is a compound of formula II wherein X is fluoro and the aryl is 7-fluoroindole or an ester thereof, such as a methyl ester.

In certain embodiments, the 2-aryl-4-aminopyrimidine is one or more compounds of formula III:

Wherein Q represents H, halo (eg F or Cl), C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkoxy, C ₂ -C ₄ alkenyl, or C ₂ -C ₄ alkene And R represents an H, an alkyl group (for example, a C _1-6 alkyl group), or an aralkyl group (for example, a benzyl group); and an aryl group represents a substituted or unsubstituted aryl or heteroaryl group.

In certain embodiments, the aryl group of formula III is

Wherein W represents H, F, Cl, C _1-3 alkyl, or C _1-3 alkoxy; Y represents halo, C _1-4 alkyl, C _1-4 haloalkyl, C _1-3 Alkoxy, C _1-3 haloalkoxy, -CN, or -NO ₂ ; and Z represents H, F, Cl, C _1-4 alkyl, C _1-3 alkoxy, C ₁ -C ₄ Haloalkyl, C _1-3 haloalkoxy, C _{1 1} -C ₃ alkoxy substituted C ₁ -C ₃ alkyl, or -NR ₁ R ₂ wherein R ₁ and R _{2 are} independently hydrogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl.

In certain embodiments, the aryl group of formula III is

Wherein W ₁ represents H or F; W ₂ represents H, F, Cl, C _1-3 alkyl, or C _1-3 alkoxy; Y represents halo, C _1-4 alkyl, C _1-4 Haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, -CN, or -NO ₂ ; Z represents H, F, Cl, C _1-4 alkyl, C _1-3 alkoxy a C ₁ -C ₄ haloalkyl group, a C _1-3 haloalkoxy group, a C ₁ -C ₃ alkoxy substituted C ₁ -C ₃ alkyl group, or -NR ₁ R ₂ , wherein R ₁ and R ₂ independently hydrogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl; or Y and Z or Z and W ₂ together are a five or six member aromatic or non-aromatic, carbocyclic Or a heterocyclic ring.

In other embodiments, the aryl group is as defined above, wherein Y and Z or Z and W ₂ are taken together to form a five or six member aromatic or non-aromatic, carbocyclic or heterocyclic ring. Specific examples of such aryl groups can be found in International Patent Application No. WO/2014/151005 and WO/2014/151009, which are incorporated herein by reference in its entirety by reference in its entirety in the the the the the the the the the

In other embodiments, the aryl group is as defined above, wherein Y and Z or Z and W ₂ are taken together to form a five member non-aromatic heterocyclic ring. Specific examples of such aryl groups can be found in International Patent Application No. WO/2014/151008, which is incorporated herein by reference.

The reaction conditions are considered to permit unprotected 4-amino-6-chloropicolinate, such as methyl 4-amino-3,6-dichloropicolinate and 4-amino-3,6-di Benzyl-5-fluoropicolinate is subjected to a direct Suzuki coupling reaction to produce a high yield (eg, greater than 60%, 70%, 80%, or 90%) of 6-aryl-4-aminopicolinate, Such as methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate and 4-amino-3-chloro-5-fluoro Benzyl 6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate. Other modifications to 6-aryl-4-aminopyridinecarboxylates include the use of crude 4-amino-2-chloropyridinecarboxylate without purification, using (4-chloro-2-fluoro-3-methyl) The oxyphenyl) dimethyl borate is used without (4-chloro-2-fluoro-3-methoxyphenyl)boronic acid, and the procedure for changing the pH, catalyst concentration, solvent composition, and/or product separation. Finally, the reaction conditions are believed to permit unprotected 6-amino-2-chloropyrimidine-4-carboxylates to undergo direct Suzuki coupling reactions to yield high yields (eg, greater than 60%, 65%, 70%, 75). %, 80%, 85% or 90%) 2-aryl-6-aminopyrimidine-4-carboxylate, such as 6-amino-5-chloro-2-(4-chloro-2-fluoro- Methyl 3-methoxyphenyl)pyrimidine-4-carboxylate and 6-amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-methoxypyrimidine-4 - Methyl carboxylate.

I. Definition

"Aminopyridine" or "aminopyrimidine" or "AP" as used in this specification means substituted or unsubstituted 4-amino-6-chloropicolinate (or ester thereof) or 6-amine. Pyrimidine-4-carboxylic acid (or its ester). "Substituted" as used in this specification with respect to pyridine or pyrimidine refers to one or more substituents on the pyridine or pyrimidine ring. Examples of suitable substituents include, but are not limited to, for example, hydroxy, nitro, cyano, decyl, halo (e.g., Cl, Br, I, and F), C ₁ -C ₆ alkoxy, C ₁ -C ₆ Haloalkoxy, C ₁ -C ₆ fluorenyl, C ₁ -C ₆ sulfanyl C ₁ -C ₆ halosulfanyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ halo Alkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ haloalkylsulfonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkoxycarbonyl , C ₁ -C ₆ -aminomethylindenyl, C ₁ -C ₆ halocarbamyl, hydroxycarbonyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl, aminocarbonyl, C ₁ a -C ₆ alkylaminocarbonyl group, a haloalkylaminocarbonyl group, a C ₁ -C ₆ dialkylaminocarbonyl group, and a C ₁ -C ₆ dihaloalkylaminocarbonyl group. In certain embodiments, 4-aminopyridine-2-carboxylic acid or an ester thereof is substituted with fluorine at the 5-position.

"Ester" as used in this specification refers to a -(C=O)OR group wherein R is alkyl, haloalkyl, alkenyl, alkynyl, or aralkyl. In certain embodiments, AP is used as the ester, such as a methyl or benzyl ester.

"Arylboronic acid" or "ABA" as used in this specification refers to a substituted or unsubstituted aromatic carbocyclic group such as phenylboronic acid ("PBA") or heteroarylboronic acid ("HBA"). "Substituted" as used in this specification refers to one or more substituents on a phenyl or heteroaryl (eg, 7-fluorofluorene) ring. Examples of suitable substituents include, but are not limited to: hydroxyl, nitro, cyano, methyl acyl, halo (e.g. Cl, Br, I and F), C ₁ -C ₆ alkoxy, C ₁ -C ₆ halo Alkoxy, C ₁ -C ₆ fluorenyl, C ₁ -C ₆ thioalkyl, C ₁ -C ₆ halosulfanyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ halo Alkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ haloalkylsulfonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkoxycarbonyl , C ₁ -C ₆ -aminocarboxamidine, C ₁ -C ₆ haloamine, mercaptocarbonyl, hydroxycarbonyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl, aminocarbonyl, C ₁ a -C ₆ alkylaminocarbonyl group, a haloalkylaminocarbonyl group, a C ₁ -C ₆ dialkylaminocarbonyl group, and a C ₁ -C ₆ dihaloalkylaminocarbonyl group. In certain embodiments, the ABA is 4-chloro-2-fluoro-3-methoxy-phenylboronic acid or (7-fluoro-1H-indol-6-yl)boronic acid.

"Dialkyl aryl borate" or "ABA-diMe" as used in this specification means a substituted or unsubstituted aromatic carbocyclic group such as phenyl boronate ("PBA-diMe") or heteroaryl. Boronate ("HBA-diMe"). "Substituted" as used in this specification refers to one or more substituents on the phenyl ring. Examples of suitable substituents include, but are not limited to: hydroxyl, nitro, cyano, methyl acyl, halo (e.g. Cl, Br, I and F), C ₁ -C ₆ alkoxy, C ₁ -C ₆ halo Alkoxy, C ₁ -C ₆ fluorenyl, C ₁ -C ₆ thioalkyl, C ₁ -C ₆ halosulfanyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ halo Alkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ haloalkylsulfonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkoxycarbonyl , C ₁ -C ₆ -aminomethylindenyl, C ₁ -C ₆ halocarbamyl, hydroxycarbonyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl, aminocarbonyl, C ₁ a -C ₆ alkylaminocarbonyl group, a haloalkylaminocarbonyl group, a C ₁ -C ₆ dialkylaminocarbonyl group, and a C ₁ -C ₆ dihaloalkylaminocarbonyl group. In certain embodiments, ABA-diMe is dimethyl (4-chloro-2-fluoro-3-methoxyphenyl)borate or 7-fluoro-6-(4,4,5,5-tetramethyl Base-1,3,2-dioxaborolan-2-yl)-1-(triisopropyldecyl)-1H-indole.

The term "alkyl" as used in this specification refers to a saturated, straight or branched saturated hydrocarbon moiety. Unless otherwise indicated, we mean a radical of C ₁ -C ₂₀ (eg C ₁ -C ₁₂ , C ₁ -C ₁₀ , C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ )alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethyl Ethyl ethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1 - dimethyl-propyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1- Dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3- Dimethyl-butyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl- 1-methylpropyl, and 1-ethyl-2-methyl-propyl. . The alkyl substituent may be unsubstituted or partially substituted with one or more chemical molecules. Examples of suitable substituents include, but are not limited to, hydroxy, nitro, cyano, decyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ fluorenyl, C _1- C ₆ sulfanyl, C ₁ -C ₆ halosulfanyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ haloalkylsulfinyl, C ₁ -C ₆ alkane Sulfosyl group, C ₁ -C ₆ haloalkylsulfonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ haloalkoxycarbonyl group, C ₁ -C ₆ amine carbenyl group, C ₁ -C ₆ haloaminecarbamyl, hydroxycarbonyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl, aminocarbonyl, C ₁ -C ₆ alkylaminocarbonyl, haloalkylaminocarbonyl C ₁ -C ₆ dialkylaminocarbonyl and C ₁ -C ₆ dihaloalkylaminocarbonyl, provided that the substituent is stereocompatible and meets the rules for chemical bonding and strain energy. In certain embodiments, the substituent includes a cyano group and a C ₁ -C ₆ alkoxy group.

As used herein, the term "haloalkyl" refers to a straight or branched alkyl group in which a hydrogen atom may be partially or completely substituted with a halogen atom. Unless otherwise indicated, we mean C ₁ -C ₂₀ (eg C ₁ -C ₁₂ , C ₁ -C ₁₀ , C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ )alkyl groups . Examples include, but are not limited to, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chloro Difluoromethyl, 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-trifluoropropan-2-yl. The haloalkyl substituent can be unsubstituted or partially substituted with one or more chemical molecules. Examples of suitable substituents include, for example, hydroxy, nitro, cyano, decyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ fluorenyl, C ₁ -C ₆ sulfanyl, C ₁ -C ₆ halosulfanyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ haloalkylsulfinyl, C ₁ -C ₆ alkyl Sulfonyl, C ₁ -C ₆ haloalkylsulfonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkoxycarbonyl, C ₁ -C ₆ aminecarbamyl, C ₁ - C ₆ haloamine, mercaptocarbonyl, hydroxycarbonyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl, aminocarbonyl, C ₁ -C ₆ alkylaminocarbonyl, haloalkylaminocarbonyl, C ₁ -C ₆ dialkylaminocarbonyl and C ₁ -C ₆ dihaloalkylaminocarbonyl, provided that the substituent is stereocompatible and meets the rules for chemical bonding and strain energy. In certain embodiments, the substituent includes a cyano group and a C ₁ -C ₆ alkoxy group.

As used herein, the term "alkenyl" refers to an unsaturated, straight-chain, or branched hydrocarbon moiety comprising a double bond. Unless otherwise indicated, we mean C ₂ -C ₂₀ (eg C ₂ -C ₁₂ , C ₂ -C ₁₀ , C ₂ -C ₈ , C ₂ -C ₆ , C ₂ -C ₄ )alkenyl. An alkenyl group can contain more than one unsaturated bond. Examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1 -propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentene Base, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butene Base, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl 3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl 1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl 1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl , 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl- 3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentene , 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl 1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2 ,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1 -butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butene Base, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-Ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl. The term "vinyl" refers to a group having the structure -CH=CH ₂ ; the 1-propenyl group refers to a group having the structure -CH=CH-CH ₃ ; and the 2-propenyl group refers to having the structure -CH ₂ -CH=CH ₂ group. The alkenyl substituent may be unsubstituted or partially substituted with one or more chemical molecules. Examples of suitable substituents include, but are not limited to, hydroxyl, nitro, cyano, decyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ fluorenyl, C ₁ -C ₆ sulfanyl, C ₁ -C ₆ halosulfanyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ haloalkylsulfinyl, C ₁ -C ₆ Alkylsulfonyl, C ₁ -C ₆ haloalkylsulfonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkoxycarbonyl, C ₁ -C ₆ aminecarbamyl, C _1- C ₆ haloamine, hydroxycarbonyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl, aminocarbonyl, C ₁ -C ₆ alkylaminocarbonyl, haloalkylamino Carbonyl, C ₁ -C ₆ dialkylaminocarbonyl and C ₁ -C ₆ dihaloalkylaminocarbonyl, if the substituent is stereocompatible and meets the rules for chemical bonding and strain energy. In certain embodiments, the substituent includes a cyano group and a C ₁ -C ₆ alkoxy group.

The term "haloalkenyl" as used in this specification refers to an alkenyl group as defined above substituted by one or more halogen atoms.

The term "alkynyl" as used herein refers to a portion of a hydrocarbon molecule comprising a straight or branched triple bond. Unless otherwise indicated, it is meant C ₂ -C ₂₀ (eg, C ₂ -C ₁₂ , C ₂ -C ₁₀ , C ₂ -C ₈ , C ₂ -C ₆ , C ₂ -C ₄ ) alkynyl. An alkynyl group can contain more than one unsaturated bond. Examples include, but are not limited to, C ₂ -C ₆ -alkynyl, such as ethynyl, 1-propynyl, 2-propynyl (or propargyl), 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-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-butyne 1,1,1-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. An alkynyl substituent can be unsubstituted or partially substituted with one or more chemical molecules. Examples of suitable substituents include, but are not limited to, hydroxyl, nitro, cyano, decyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ fluorenyl, C _1- C ₆ sulfanyl, C ₁ -C ₆ halosulfanyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ haloalkylsulfinyl, C ₁ -C ₆ alkane Sulfosyl group, C ₁ -C ₆ haloalkylsulfonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ haloalkoxycarbonyl group, C ₁ -C ₆ amine carbenyl group, C ₁ -C ₆ haloamine, hydroxycarbonyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl, aminocarbonyl, C ₁ -C ₆ alkylaminocarbonyl, haloalkylaminocarbonyl C ₁ -C ₆ dialkylaminocarbonyl and C ₁ -C ₆ dihaloalkylaminocarbonyl, provided that the substituent is stereocompatible and meets the rules for chemical bonding and strain energy. In certain embodiments, the substituent includes a cyano group and a C ₁ -C ₆ alkoxy group.

As used herein, the term "aryl" and derivatives, such as aryloxy, refer to a radical containing a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms. The aryl group may include a single ring or multiple condensed rings. In certain embodiments, an aryl group includes a C ₆ -C ₁₀ aryl group. Examples of aryl groups include, but are not limited to, phenyl, diphenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl, and fluorenyl. In certain embodiments, the aryl group can be phenyl, indenyl or naphthyl. The term "heteroaryl" and the term "heteroaryloxy" as used herein mean a five or six membered aromatic ring containing one or more heteroatoms (ie, N, O or S); Fusion to other aromatic systems. The aryl or heteroaryl substituent may be unsubstituted or partially substituted with one or more than one chemical molecule. Examples of suitable substituents include, but are not limited to, hydroxy, nitro, cyano, decyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ fluorenyl, C ₁ -C ₆ thioalkyl, C ₁ -C ₆ alkyl sulfin Mercapto, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ -aminomethylcarbonyl, hydroxycarbonyl, C ₁ -C ₆ alkylcarbonylaminocarbonyl, C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₆ dialkylaminocarbonyl, provided that the substituent is stereocompatible and meets the rules for chemical bonding and strain energy. In certain embodiments, the substituent includes a halo group, a C ₁ -C ₂ alkyl group, and a C ₁ -C ₂ haloalkyl group. In certain embodiments, the substituent includes a halo group, a C ₁ -C ₂ alkyl group, and a C ₁ -C ₂ haloalkyl group.

As used herein, the term "aralkyl" refers to an alkyl group substituted with an unsubstituted or substituted aryl group. The C ₇ -C ₁₀ aralkyl group means a group having a total of 7 to 10 carbon atoms in the group, but does not include a carbon atom existing in any substituent of the aryl group.

Alkoxy as used herein refers to a radical of the formula RO- wherein R is alkyl as defined above. Unless otherwise specified, R in the alkoxy group means C ₁ -C ₈ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkyl, or C ₁ -C ₃ group. Examples include, but are not limited to, methoxy, ethoxy, propoxy, 1-methyl-ethoxy, butoxy, 1-methyl-propoxy, 2-methyl-propoxy, 1 ,1-dimethyl-ethoxy, pentyloxy, 1-methyl-butoxy, 2-methyl-butoxy, 3-methyl-butoxy, 2,2-dimethyl- Propyloxy, 1-ethyl-propoxy, hexyloxy, 1,1-dimethyl-propoxy, 1,2-dimethyl-propoxy, 1-methyl-pentyloxy, 2-methyl-pentyloxy, 3-methyl-pentyloxy, 4-methylpentyloxy, 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-ethylbutoxy, 1,1,2-trimethyl-propoxy, 1,2,2-trimethyl-propoxy, 1-ethyl-1- Methyl-propoxy, and 1-ethyl-2-methyl-propoxy.

As used herein, haloalkoxy refers to a radical of the formula RO- wherein R is haloalkyl as defined above. Unless otherwise indicated, we mean a haloalkoxy group wherein R is C ₁ -C ₈ alkyl. Examples include, but are not limited to, chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy , dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoro Oxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro, 2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy Base, 2,2,2-trichloroethoxy, pentafluoroethoxy and 1,1,1-trifluoroprop-2-yloxy.

As used herein, a sulfanyl group refers to a radical of the formula RS- wherein R is an alkyl group as defined above. Unless otherwise indicated, we mean a sulfanyl group wherein R is C ₁ -C ₈ alkyl. Examples include, but are not limited to, methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methyl-propylthio, 2-methylpropylthio, 1,1 - dimethylethylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio, 2,2-di-methylpropylthio, 1- Ethylpropylthio, hexylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 1-methylpentylthio, 2-methylpentylthio, 3- Methyl-pentylthio, 4-methyl-pentylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2 , 2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethylbutylthio, 2-ethylbutylthio, 1, 1,2-trimethylpropylthio, 1,2,2-trimethylpropylthio, 1-ethyl-1-methylpropylthio and 1-ethyl-2-methylpropylthio.

The halosulfinyl group as used herein refers to a sulfanyl group as defined above wherein the carbon atom is partially or completely substituted with a halogen atom. Unless otherwise indicated, means wherein R is C ₁ -C ₈ alkyl halide ylsulfanyl. Examples include, but are not limited to, chloromethylthio, bromomethylthio, dichloromethylthio, trichloromethylthio, fluoromethylthio, difluoromethylthio, trifluoromethylthio, chlorofluoromethylthio , dichlorofluoro-methylthio, chlorodifluoromethylthio, 1-chloroethylthio, 1-bromoethylthio, 1-fluoroethylthio, 2-fluoroethylthio, 2,2-difluoro Ethylthio, 2,2,2-trifluoroethylthio, 2-chloro-2-fluoroethylthio, 2-chloro-2-difluoroethylthio, 2,2-dichloro-2-fluoro Sulfuryl, 2,2,2-trichloroethylthio, pentafluoroethylthio and 1,1,1-trifluoroprop-2-thio. As used herein, "direct Suzuki coupling reaction" or "direct coupling" means that the aminopyridine or aminopyrimidine (AP) and the aryl boronic acid (ABA) or the aryl boronic acid dialkyl ester (ABA-diMe) are not used. The amine group is protected and the reaction of the protective (e.g., acetylation and deacetylation) steps is removed.

II. Direct Suzuki coupling

Currently used in the literature to prepare 6-aryl-4-aminopyridinecarboxylates and 2-aryl-6-aminopyrimidine-4-carboxylates, such as 4-amino-3-chloro-6- ( Aralkyl and alkyl esters of 4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid, and 4-amino-3-chloro-5-fluoro-6-(4-chloro The method of arylalkyl esters and alkyl esters of 2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid is a multi-step process and includes the steps of protecting and removing the protection. This method is shown in Flowchart 1 above. The improved method described in this specification reduces the steps of protection and removal of protection, thus reducing or reducing various materials, equipment and cycles. Other improvements to the production of 6-aryl-4-aminopicolinate include: (1) the use of crude unpurified and/or isolated AP; (2) the use of ABA-diMe in place of ABA; and (3) Procedures for changing pH, catalyst concentration, solvent composition, and/or product separation. An example of an improved reaction flow diagram is shown in Flowchart 3 below: Scheme 3: Improved method for the synthesis of 6-aryl-4-aminopyridinecarboxylates

A. Direct coupling using crude AP and / or ABA-diMe

Currently producing 6-aryl-4-aminopyridinecarboxylates such as 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate The method of methyl ester involves a palladium catalyzed Suzuki coupling reaction between the isolated, protected AP and ABA, followed by removal of the coupling product. During the process of producing ABA, ABA-diMe as an intermediate product and LiOMe as a by-product are produced, which are first neutralized before being charged into the subsequent coupling reaction. Since the esterification of AP is catalyzed by sulfuric acid, sulfuric acid can be used as an acid for neutralizing LiOMe. Therefore, it has been found that crude AP and crude ABA-diM can be used directly in the direct coupling reaction to give good yields under optimized conditions. The yield is typically greater than 50%, preferably greater than 55%, such as about 60% or greater, 65% or greater, 70% or greater, 75% or greater, 80% or greater, or 85%. Or bigger.

B. pH of direct coupling reaction

The pH of the Suzuki coupling reaction affects the reaction yield. Adjusting the pH of the given AP can significantly improve the reaction yield. In certain embodiments, the pH is from about 7 to about 12, preferably from about 7 to about 10, more preferably from about 8 to about 10. In certain embodiments, the pH is from about 7 to about 8, from about 8 to about 9, or from about 9 to about 10. Adjusting the pH of the reaction mixture improves the arylalkyl and alkyl esters of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate and 4- Total aryl aryl-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate and alkyl ester in direct Suzuki coupling reaction Yield, but does not significantly affect the extent of the reaction. The pH can be adjusted with one or more bases. In certain embodiments, the pH is adjusted with a mixture of potassium carbonate and potassium bicarbonate. In other embodiments, the pH is adjusted only with potassium carbonate or with only potassium bicarbonate. The pH can also be adjusted with one or more bases in combination with carbon dioxide and water. Other inorganic bases such as sodium carbonate (including hydrogencarbonate), potassium acetate, sodium acetate, basic potassium phosphate (mono, di and tribasic salts), sodium tetraborate, potassium hydroxide, sodium hydroxide, fluorine may also be used. Antimony and potassium fluoride and organic bases such as tetraethylamine, triisopropylamine, diisopropylamine, diethylamine and diisopropylethylamine. In another embodiment, the reaction mixture can be pretreated with carbon dioxide to adjust the pH prior to the Suzuki coupling reaction. Alternatively, the Suzuki coupling reaction can be carried out in the presence of CO _2, CO _{2 is} for example filled bubbles into the reaction mixture.

C. Catalyst selection and concentration

The Suzuki coupling reaction involves the use of a catalyst, including a ligand. Suitable catalysts include palladium (II) catalysts (eg, palladium(II) acetate Pd(OAc) ₂ , palladium (II) chloride (PdCl ₂ )) and Pd(PPh ₃ ) ₄ ; nickel catalysts such as NiCl ₂ (dppf) And G ₃ DenP-Ni; an iron catalyst; a copper catalyst; and a rhodium catalyst. The concentration of the catalyst can vary. In certain embodiments, the concentration is less than 4%, preferably less than 3%, preferably about 2%. In certain embodiments, the concentration of the catalyst is from about 0.2% to about 2.0%, preferably from 0.4% to about 1.0%, more preferably about 0.5%, relative to the limiting reagent system. In certain embodiments, the palladium catalyst is palladium (II) acetate. Suitable ligands for the catalyst system include, but are not limited to, trialkylphosphines and triarylphosphines. These include, but are not limited to, gin-tertiary butylphosphine, tricyclohexylphosphine, bis-tertiary butylphenylphosphine, dicyclohexylphenylphosphine, triphenylphosphine, 4-diphenylphosphinomethyl cross-linked polyphenylene Vinyl resin, sodium diphenylphosphinobenzene-3-sulfonate with 2% DVB, cis (p-tolyl) phosphine, (±)-2,2'-bis(diphenylphosphino)-1,1'- Di-naphthyl. The concentration of the ligand can vary. In certain embodiments, the concentration of the ligand is from about 0.4% to about 8.0%, preferably from 0.5% to about 6.0%, preferably from 0.5% to about 4.0%, preferably from 0.5% to about 2%, relative to the limiting reagent system. It is better to be about 1.0%. In certain embodiments, the ligand is triphenylphosphine (PPh ₃ ).

D. Effect of solvent on direct coupling

As discussed above, the Suzuki coupling reaction can be carried out on a crude AP without protection and removal of the protection step. However, the reaction rate may be slow, and even at optimized pH, the reaction time is still long. The direct coupling route of the AP is carried out in an organic solvent mixture comprising methyl isobutyl ketone (MIBK), dimethoxyethane (DME), acetonitrile (MeCN) and methanol (MeOH). Improved direct coupling conditions were found to exist in systems including solvent mixtures such as MIBK, MeCN, MeOH, and water. Other solvent systems that can be effective in direct coupling reactions using AP include, for example, MIBK ketones and/or alcohols such as benzyl alcohol and/or aromatic solvents such as toluene.

Another improvement to the solvent system is the reduction of water from the reaction mixture. The improved synthetic route involves the Suzuki coupling reaction between crude AP and ABA or crude ABA-diME under non-aqueous conditions. By "non-aqueous" used in the context of the present specification is meant that the base is added in a solid rather than aqueous solution and no water is added to the reaction mixture to adjust the concentration. Although the reaction solvent and/or reagent (for example, crude AP-Me) is dried before use, water may remain. This residual water can be present in the "non-aqueous" system. An exemplary non-aqueous solution system is shown in Example 5.

Instance

Example 1: Direct Suzuki Coupling

Methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate

4-Amino-3,6-dichloropyridine-2-carboxylic acid methyl ester (AP-Me) (8.00 g, 36.19 mmol), 25.55 wt% 4-chloro-2-fluoro-3-methoxy A solution of phenylboronic acid (ABA) (33.30 g, 41.60 mmol), acetonitrile (23.9 mL) and water (28.0 mL) were added to a round bottom flask. The contents of the flask were degassed by nitrogen for 30 minutes, and a 47 wt% aqueous solution of K ₂ CO ₃ (26.6 g, 90.50 mmol) was also separately degassed by nitrogen. After loading the K ₂ CO ₃ solution, triphenylphosphine (0.190 g, 0.724 mmol) and palladium acetate (0.081 g, 0.362 mmol) were added to the flask. The reaction was heated at 50 ° C for 22 hours. After 22 hours, the reaction was heated to 65 ° C and the phases were separated. Analysis of the organic phase gave methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate in a yield of 81.4%.

Methyl 4-amino-3-chloro-5-fluoro-6-(7-fluoro-1-(triisopropyldecyl)-1H-indol-6-yl)pyridinecarboxylate

In a round bottom flask, methyl 4-amino-3,6-dichloro-5-fluoropicolinate (AP) (0.5 g, 2.17 mmol), 7-fluoro-6-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(triisopropyldecyl)-1H-indole (ABA-diMe) (1.1 g, 2.61 mmol) Methanol (1.0 g, 31.0 mmol), 4-methyl-2-pentanone (1.2 g, 11.6 mmol), acetonitrile (1.3 g, 30.7 mmol) and water (1.9 g, 104.5 mmol) were combined. After the mixture was degassed by nitrogen for 30 minutes, triphenylphosphine (0.02 g, 0.09 mmol) and palladium acetate (0.01 g, 0.04 mmol) were added in one portion. The reaction was heated to 50 ° C and stirred for 1 hour at which time a 47 wt% K ₂ CO ₃ solution (0.13 g, 0.44 mmol) was then. The reaction was stirred for an additional 2 hours, additional 47wt% K ₂ CO ₃ solution (0.15g, 0.51mmol) at this time. The reaction was stirred for an additional 2 hours, additional 47wt% K ₂ CO ₃ solution (0.29g, 0.99mmol) at this time. After 22 hours, the reaction was heated to 65 ° C and then phase separated. The organic phase was analyzed to give a yield of 72.1% of 4-amino-3-chloro-5-fluoro-6-(7-fluoro-1-(triisopropyldecyl)-1H-indol-6-yl). Methyl picolinate.

Methyl 6-amino-5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylate

In a round bottom flask, methyl 6-amino-2,5-dichloropyrimidine-4-carboxylate (AP) (3.0 g, 13.5 mmol), (4-chloro-2-fluoro-3-methyl) Oxyphenyl)boronic acid (ABA) (3.4 g, 16.2 mmol), methanol (3.0 g, 94.3 mmol), 4-methyl-2-pentanone (3.5 g, 35.2 mmol) and acetonitrile (7.8 g, 191.0 mmol) )mixing. Water (29.0 g) and potassium bicarbonate (3.4 g, 34.0 mmol) were combined in a separate vial to give a 10.5 wt% alkaline solution. Both the reaction mixture and the alkali solution were degassed with nitrogen for 30 minutes. An alkali solution (13.8 g, 14.5 mmol), triphenylphosphine (0.14 g, 0.54 mmol) and palladium acetate (0.06 g, 0.27 mmol) were added to the reaction mixture. The reaction was heated to 50 °C. After 22 hours, the reaction was heated to 65 ° C and then phase separated. Analysis of the organic phase gave 68.1% yield of 6-amino-5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylic acid methyl ester.

Methyl 6-amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-methoxypyrimidine-4-carboxylate

In a round bottom flask, methyl 6-amino-2-chloro-5-methoxypyrimidine-4-carboxylate (AP) (0.98 g, 4.7 mmol), (4-chloro-2-fluoro- 3-methoxyphenyl)boronic acid (ABA) (1.0 g, 4.8 mmol), methanol (1.3 g, 40.6 mmol), 4-methyl-2-pentanone (1.1 g, 11.0 mmol) and acetonitrile (2.6 g) , 63.3 mmol) mixed. Water (9.7 g) and potassium bicarbonate (1.1 g, 11.0 mmol) were combined in a separate vial to give a 10.2 wt% alkaline solution. Both the reaction mixture and the alkali solution were degassed with nitrogen for 30 minutes. An alkali solution (5.2 g, 5.3 mmol), triphenylphosphine (0.05 g, 0.19 mmol) and palladium acetate (0.02 g, 0.09 mmol) were added to the reaction mixture. The reaction was heated to 50 °C. After 22 hours, the reaction was heated to 65 ° C and then phase separated. Analysis of the organic phase gave a yield of 75.6% of methyl 6-amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-methoxypyrimidine-4-carboxylate.

4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate benzyl ester

4-Amino-3,6-dichloro-5-fluoropicolinate benzyl (AP) (1.5 g, 4.8 mmol), (4-chloro-2-fluoro-3-methoxy) in a round bottom flask Phenyl) boric acid (ABA) (1.1 g, 5.3 mmol), methanol (1.0 g, 31.0 mmol), 4-methyl-2-pentanone (1.2 g, 11.6 mmol), acetonitrile (2.8 g, 68.2 mmol) Mix with water (4.2g). The mixture was degassed by nitrogen for 30 minutes, then 47 wt% potassium carbonate (0.45 g, 1.5 mmol), triphenylphosphine (0.05 g, 0.19 mmol) and palladium acetate (0.02 g, 0.10 mmol) were added. The reaction was heated to 60 ° C and stirred for 30 minutes at which time a 47 wt% K ₂ CO ₃ solution (0.47 g, 1.6 mmol) was then. The reaction was stirred for an additional 30 minutes, additional 47wt% K ₂ CO ₃ solution (0.10g, 0.3mmol) at this time. The reaction was stirred for an additional 30 minutes, additional 47wt% K ₂ CO ₃ solution (0.10g, 0.3mmol) at this time. After 2.5 hours, the reaction was heated to 65 ° C and then phase separated. Analysis of the organic phase gave 67.9% yield of benzyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate.

Methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate

4-Amino-3,6-dichloro-5-fluoropicolinic acid methyl ester (AP) (3.1 g, 13.0 mmol), (4-chloro-2-fluoro-3-methoxy) in a round bottom flask Phenyl) boric acid (ABA) (3.0 g, 14.5 mmol), methanol (2.7 g, 84.3 mmol), 4-methyl-2-pentanone (3.1 g, 31.0 mmol), acetonitrile (7.6 g, 185.1 mmol) Mix with water (11.3g). The mixture was degassed by nitrogen for 30 minutes, and then 47 wt% potassium carbonate (1.2 g, 4.1 mmol), triphenylphosphine (0.07 g, 0.27 mmol) and palladium acetate (0.03 g, 0.13 mmol) were added in one portion. The reaction was heated to 60 ° C and stirred for 30 minutes at which time a 47 wt% K ₂ CO ₃ solution (1.2 g, 4.1 mmol) was added. The reaction was stirred for an additional 30 minutes, additional 47wt% K ₂ CO ₃ solution (0.8g, 2.7mmol) at this time. The reaction was stirred for an additional 30 minutes, additional 47wt% K ₂ CO ₃ solution (0.6g, 2.0mmol) at this time. After 5.5 hours, the reaction was heated to 65 ° C and then phase separated. Analysis of the organic phase gave a yield of 88.1% of methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate.

Example 2 Direct coupling with crude AP and/or ABA-diMe

In a round bottom flask, 174.0 g of a crude 4-amino-3,6-dichloropyridine-2-carboxylic acid methyl ester (AP Me) solution (corresponding to 38.5 g, 174 mmol of AP-Me) was decompressed. Distilled into a paste. The paste was poured into a 1 liter reactor with a heat-insulated jacket and rinsed with acetonitrile (112.0 g, 2728 mmol). ^{The 1} H NMR analysis mixture indicated that there were 574.2 of the expected 1037 mmol of methanol. Methanol (15.1 g, 471.3 mmol), water (189.0 g) and K ₂ CO ₃ solution (47 wt%, 11.6 g, 39.4 mmol) were added to reach neutral pH, then 4-chloro-2-fluoro-3-methyl was added Oxy-phenylboronic acid (ABA) (36.9 g, 178.4 mmol) (1.01 molar equivalent of ABA confirmed by HPLC) and 4-methyl-2-pentanone (38.7 g, 386.4 mmol). The mixture was degassed by nitrogen sparge for 45 minutes then add additional 47wt% K ₂ CO ₃ solution (16.0g, 54.4mmol), triphenylphosphine (0.46g, 1.8mmol) and palladium acetate (0.20g, 0.9mmol). The reaction was heated to 60 °C. After reaching 60 ° C, an additional 47 wt% K ₂ CO ₃ solution was added over 30 minutes (16.0 g, 54.4 mmol), 60 minutes (12.2 g, 41.5 mmol) and 90 minutes (9.0 g, 30.6 mmol). After 19 hours, the reaction was heated to 65 ° C and then phase separated. Analysis of the organic phase gave methyl ester of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate in a yield of 80.3%.

In a reactor with a heat-insulating jacket, 179.8 g of a crude 4-amino-3,6-dichloropyridine-2-carboxylic acid methyl ester (AP-Me) solution (corresponding to 40.5 g, 183.2 mmol of AP) was added. -Me), followed by addition of 4-methyl-2-pentanone (225 g, 2250 mmol) and 12 wt% potassium hydrogencarbonate (54.6 g, 65.4 mmol) to a neutral pH. A salt solution is added to the neutralized solution and then phase separated. The organic phase was distilled under reduced pressure to 30.6 wt% of AP-Me. Add acetonitrile (118.3 g, 2882 mmol), methanol (18.5 g, 577 mmol) and 4-chloro-2-fluoro-3-methoxy-phenylboronic acid (ABA) (41.1 g, 201.1 mmol) and remove the mixture by nitrogen Gas for 45 minutes. A degassed solution of 23 wt% potassium hydrogencarbonate (45.1 g, 540 mmol), triphenylphosphine (0.47 g, 1.8 mmol) and palladium acetate (0.20 g, 0.9 mmol) was added to the reactor. The reaction was heated to 50 °C. After 21 hours, the reaction was heated to 65 ° C and then phase separated. Analysis of the organic phase gave a yield of 94.6% of methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.

A crude AP-Me solution (41.4 g, which corresponds to 8.8 g, 40 mmol of AP-Me) was charged with 1.7 g of sulfuric acid (98%). The mixture was fed, and 73.4 g of an ABA-diMe solution (tested to be 13.4 wt% ABA) was slowly added. The solvent was removed with a rotary evaporator until the residue was approximately 55 g. To the oily mixture was added 26.2 g of MeCN, 10 g of MIBK and 44 g of water. To the mixture was added 15.8 g of 47 wt% potassium carbonate. The paste was degassed by nitrogen for 20 minutes, followed by the addition of 3.6 g of 47 wt% potassium carbonate, palladium acetate (45 mg) and triphenylphosphine (105 mg). The reaction mixture will be allowed to warm to 55 °C. Two additional 3.6 g of a 47 wt% potassium carbonate solution were added one hour and two hours after the mixture reached 55 °C. The mixture was subjected to an additional 12 hours of reaction at 55 ° C and then filtered to remove solids.

The in-process yield of methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate is 60%

Example 3 is a direct coupling of the pH function

4-Amino-3,6-dichloropyridine-2-carboxylic acid methyl ester (AP-Me) (8.00 g, 36.19 mmol), 25.55 wt% 4-chloro-2-fluoro-3-methoxy A solution of phenylboronic acid (ABA) (33.30 g, 41.60 mmol), acetonitrile (23.9 mL) and water (28.0 mL) were added to a round bottom flask. The contents of the flask were degassed by nitrogen for 30 minutes, and a 47 wt% aqueous solution of K ₂ CO ₃ (26.6 g, 90.50 mmol) was also separately degassed by nitrogen. After charging the K ₂ CO ₃ solution (pH of the mixture ~11.5), triphenylphosphine (0.190 g, 0.724 mmol) and palladium acetate (0.081 g, 0.362 mmol) were added to the flask. The reaction was heated at 50 °C for 22 hours. After 22 hours, the reaction was heated to 65 ° C and phase separation was carried out. Analysis of the organic phase gave a yield of 81.4% of methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.

4-Chloro-2-fluoro-3-methoxy-phenylboronic acid (ABA) solution (32.0 g), 4-amino-3,6-dichloropyridine-2-carboxylic acid methyl ester (AP-Me (7.50 g, purity 95.99%, 33.9 mmol) and acetonitrile (29.3 mL, 23.0 g) were added to a round bottom flask. The resulting solution was orange-red. A solution of K ₂ CO ₃ (3.91 g) and KHCO ₃ (5.66 g) dissolved in water (40.1 mL) was prepared in a 100 mL bottle. The reactor and the aqueous solution of the aqueous solution were degassed by nitrogen for 30 minutes. The K ₂ CO ₃ -KHCO ₃ solution was then added to the reactor with a syringe (mixture pH~9), followed by the addition of triphenylphosphine (0.178 g, 0.02 eq.) and palladium acetate (0.076 g, 0.01 eq) in one pass. .). The mixture was stirred at 50 ° C overnight and monitored by GC and LC. The reaction was terminated after 18 hours. After the hot solution was phase separated, the organic phase was analyzed to obtain 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl) with a yield of 90.8%. Methyl pyridine-2-carboxylate.

The crude 4-amino-3,6-dichloropyridine-2-carboxylic acid methyl ester (AP-Me) solution (348.0 g, which corresponds to 75.9 g, 343.3 mmol of AP-Me) was distilled under reduced pressure into a paste. Shape. Add acetonitrile (225.5 g, 5493 mmol), water (347.4 g) and K ₂ CO ₃ solution (47 wt%, 21.9 g, 74.5 mmol) to reach a neutral pH, then add 4-chloro-2-fluoro-3-methyl Oxy-phenylboronic acid (ABA) (79.4 g, 383.8 mmol) and MIBK (83.4 g). The mixture was degassed by nitrogen for 45 minutes, then an additional 47 wt% K ₂ CO ₃ solution (30.5 g, 103.7 mmol), triphenylphosphine (1.35 g, 5.1 mmol) and palladium acetate (0.58 g, 2.6 mmol) were added. The reaction was heated to 55 °C. An additional 47 wt% K ₂ CO ₃ solution (30.5 g, 103.7 mmol) (pH ~ 7-8 of the mixture) was added after reaching one hour at 55 ° C, then added again after reaching two hours at 55 ° C (30.5 g, 103.7 mmol) ). After 21 hours, the reaction was heated to 65 ° C and then phase separated. Analysis of the organic phase gave a yield of 74.9% of methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.

The crude AP-Me feed (which contained 8.8 g, 40 mmol of AP-Me) was neutralized and extracted with methyl isobutyl ketone (MIBK). The solvent was partially removed with a rotary evaporator and the residue was redissolved with acetonitrile (26.2 g, 16 eq.) and MIBK (9.9 g, 2.46 eq.). ABA (9.4 g, 1.15 eq.), methanol (4.2 g, 3.3 eq.) and water (19.5 g, diluted KF to 23 wt%) were added to the reaction flask. The mixture was degassed by nitrogen for 30 minutes, followed by KF (5.8 g, 2.5 eq.), palladium acetate (45 mg) and triphenylphosphine (105 mg). The reaction mixture was then heated to 50 °C and monitored using LC. The reaction was terminated after 24 hours, yielding a yield of 69.8% of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid. ester.

The crude AP-Me feed (which contained 2.2 g, 10 mmol of AP-Me) was neutralized and extracted with MIBK. The solvent was partially removed with a rotary evaporator and the residue was redissolved with MeCN (6.6 g, 16 eq.) and MIBK (5.9 g, 2.46 eq). ABA (2.35 g, 1.15 eq.), MeOH (1 g, 3.3 eq.) and water (7.8 g, diluted 47 wt% K ₂ CO ₃ to 12 wt%) were added to the reaction flask. The mixture was degassed by nitrogen for 30 minutes, followed by the addition of 47% K ₂ CO ₃ (0.88 g, 0.302 eq.), palladium acetate (11 mg) and triphenylphosphine (26 mg). The reaction mixture was then heated to 50 ° C and maintained at this temperature. After the reaction temperature reached 50 ° C, a second and a third portion of 47% K ₂ CO ₃ (0.88 g) were added with a syringe after one hour and two hours. After 9 hours, the reaction was terminated to give a yield of 88.3% of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid. ester.

The crude AP-Me feed (which contained 2.2 g, 10 mmol of AP-Me) was neutralized and extracted with MIBK. The solvent was partially removed with a rotary evaporator and the residue was redissolved with MeCN (6.6 g, 16 eq.) and MIBK (5.9 g, 2.46 eq.). The ABA (2.35g, 1.15eq.), MeOH (1g, 3.3eq.) And water (7.8g, diluted 47wt% K ₂ CO ₃ to 12wt%) was added to the reaction flask. The mixture was degassed by nitrogen for 30 minutes, followed by the addition of 47% K ₂ CO ₃ (0.88 g, 0.302 eq.), palladium acetate (11 mg) and triphenylphosphine (26 mg). The reaction mixture was then heated to 50 ° C and maintained at this temperature. After the reaction temperature reached 50 ° C, a second and a third portion of 47% K ₂ CO ₃ (0.88 g) were separately added with a syringe after one hour and two hours. 0.2 g of 47% K ₂ CO _{3 was} added 4 hours after reaching 50 °C. The reaction was monitored by LC. The reaction was terminated after 8.5 hours, yielding a yield of 89.7% of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid. ester.

Methyl 4-amino-3,6-dichloropyridine-2-carboxylate (AP-Me) (8.00 g, 36.2 mmol), 4-chloro-2-fluoro-3-methoxy-phenylboronic acid (ABA) (8.6 g, 41.6 mmol), acetonitrile (23.8 g), MIBK (8.6 g), methanol (3.7 g), aqueous K ₂ CO ₃ (47 wt%, 11.2 g, 38.1 mmol) and water (11.5 g) Add to a round bottom flask. The pH of the mixture was ~10.5. The contents of the flask were degassed with carbon dioxide (CO ₂ ) until the solution reached a steady state of pH 8.6. Triphenylphosphine (0.1 g, 0.36 mmol) and palladium acetate (0.04 g, 0.18 mmol) were then added to the flask. The reaction was heated at 55 ° C for 24 hours. After 24 hours, the reaction was heated to 65 ° C and phase separation was carried out. Analysis of the organic phase gave a yield of 86.4% of methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.

Example 4 Direct Coupling Catalyst

4-Chloro-2-fluoro-3-methoxy-phenylboronic acid (ABA) solution (32.0 g), 4-amino-3,6-dichloropyridine-2-carboxylic acid methyl ester (AP-Me (7.50 g, purity 95.99%, 33.9 mmol) and acetonitrile (29.3 mL, 23.0 g) were added to a round bottom flask. A solution of K ₂ CO ₃ (3.91 g) and KHCO ₃ (5.66 g) dissolved in water (40.1 mL) was prepared in a 100 mL flask. Both the reactor and the aqueous solution of the aqueous solution were degassed by nitrogen for 30 minutes. The K ₂ CO ₃ -KHCO ₃ solution was then added to the reactor with a syringe, followed by the addition of triphenylphosphine (0.178 g, 0.02 eq.) and palladium acetate (0.076 g, 0.01 eq.) in one portion. The mixture was stirred at 50 ° C until overnight. The reaction was terminated after 18 hours. After separating the hot solution phase, the organic phase was analyzed to obtain 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine with a yield of 90.8%. Methyl 2-carboxylate.

The crude 4-amino-3,6-dichloropyridine-2-carboxylic acid methyl ester (AP-Me) solution (348.0 g, which corresponds to 75.9 g, 343.3 mmol of AP-Me) was distilled under reduced pressure into a paste. Shape. Acetonitrile (225.5 g, 5493 mmol), water (347.4 g) and ₂ CO ₃ aqueous solution (47 wt%, 21.9 g, 74.5 mmol) were added to reach a neutral pH, then 4-chloro-2-fluoro-3-methoxy Base-phenylboronic acid (ABA) (79.4 g, 383.8 mmol) and MIBK (83.4 g). The mixture was sparged with nitrogen was degassed over 45 minutes then add additional 47wt% K ₂ CO ₃ solution (30.5g, 103.7mmol), triphenylphosphine (1.35g, 5.1mmol) and palladium acetate (0.58g, 2.6mmol). The reaction was heated to 55 °C. Adding additional 47wt% K ₂ CO ₃ solution (30.5g, 103.7mmol) reaches 55 ℃ after one hour and then at 55. After two hours, it was added again (30.5 g, 103.7 mmol). After 21 hours, the reaction was heated to 65 ° C and then phase separated. Analysis of the organic phase gave a yield of 74.9% of methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.

The crude AP-Me feed (41.4 g, corresponding to 8.8 g, 40.0 mmol of AP-Me) was distilled under reduced pressure to remove ~2/3 of methanol until the weight of the residue reached 20.5 g. The thick paste was retained and redissolved with 26.2 g of acetonitrile. ABA (9.4 g, 1.15 eq.), MIBK (9.8 g), and water (40.4 g) were added to the AP-Me solution. 3.37 g of a 47 wt% K ₂ CO ₃ solution was added and the resulting mixture was degassed by nitrogen for 30 minutes. After nitrogen venting, 3.56 g of 47% K ₂ CO _{3 was} added to the mixture, followed by addition of palladium acetate (47 mg) and triphenylphosphine (105 mg) in one portion. The reaction mixture was then heated to 55 ° C and maintained at this temperature. After the reaction temperature reached 55 ° C, two additional portions of 47% K ₂ CO ₃ (3.56 g) were added via syringes after one hour and two hours. Four hours after the reaction temperature reached 55 ° C, another portion of 47% K ₂ CO ₃ (3.56 g) was added by syringe. After 9 hours, the reaction was terminated to give a methyl ester of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate with a yield of 90.4%. .

A solution of the crude 4-amino-3,6-dichloropyridine-2-carboxylate (AP Me) in a round bottom flask (348.0 g, which corresponds to 77.2 g, 349.0 mmol of AP-Me) Distilled under reduced pressure into a paste. The paste was poured into a 1 liter reactor with a heat-insulated jacket and rinsed with acetonitrile (224.0 g, 5456 mmol). ^{The 1} H NMR analysis mixture indicated 1117 mmol of methanol expected at 1047. Methanol (2.2 g, 68.7 mmol), water (378.0 g) and K ₂ CO ₃ solution (47 wt%, 23.5 g, 79.9 mmol) were added to reach neutral pH, then 4-chloro-2-fluoro-3-methyl was added Oxy-phenylboronic acid (ABA) (78.7 g, 380.4 mmol) and 4-methyl-2-pentanone (82.7 g, 825.7 mmol). The mixture was degassed by nitrogen for 45 minutes, then an additional 47 wt% K ₂ CO ₃ solution (31.9 g, 108.5 mmol), triphenylphosphine (0.46 g, 1.8 mmol) and palladium acetate (0.20 g, 0.9 mmol). The reaction was heated to 60 °C. Additional 47wt% K ₂ CO ₃ solution for 60 minutes (31.9g, 108.5mmol), 120 minutes (24.5g, 83.3mmol) and 240 minutes (18.1g, 61.6mmol) added after reaching 60 ℃. After 20 hours, the reaction was heated to 65 ° C and then phase separated. Analysis of the organic phase gave a yield of 79.4% of methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.

Example 5 Effect of Solvent on Direct Coupling

The crude AP-Me feed (41.4 g, corresponding to 8.8 g, 40.0 mmol of AP-Me) was distilled to remove ~2/3 methanol until the residue weighed 20.5 g. The thick paste was retained and redissolved with 26.2 g of MeCN (16 eq.). ABA (9.4 g, 1.15 eq.), MIBK (9.8 g), MeOH (4.3 g), and water (40.4 g) were added to the AP-Me solution. 3.2 g of a 47 wt% K ₂ CO ₃ solution was added, and the resulting mixture was degassed by nitrogen for 30 minutes. After degassing, 3.56 g of 47% K ₂ CO _{3 was} added to the mixture, followed by addition of palladium acetate (47 mg) and triphenylphosphine (105 mg) in one portion. The reaction mixture was then heated to 55 ° C and maintained at this temperature. After the reaction temperature reached 55 ° C, a second and a third portion of 47% K ₂ CO ₃ (3.56 g) were added with a syringe after one hour and two hours. After 9 hours, the reaction was terminated to give a methyl ester of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate with a yield of 91.8%. .

The crude AP-Me feed (41.4 g, corresponding to 8.8 g, 40.0 mmol of AP-Me) was distilled to remove ~2/3 methanol until the residue weighed 21.2 g. A thick paste was retained and redissolved with 13.1 g of MeCN (8 eq.) and 23.1 g of MIBK. ABA (9.4 g, 1.15 eq) and water (40.4 g) were added to the AP-Me solution. 3.2 g of a 47 wt% K ₂ CO ₃ solution was added and the resulting mixture was degassed by nitrogen for 30 minutes. After degassing, 3.56 g of 47% K ₂ CO _{3 was} added to the mixture, followed by addition of palladium acetate (47 mg) and triphenylphosphine (105 mg) in one portion. The reaction mixture was then heated to 55 ° C and maintained at this temperature. After the reaction temperature reached 55 ° C, a second and a third portion of 47% K ₂ CO ₃ (3.56 g) were separately added with a syringe after one hour and two hours. After the reaction reached 55 ° C, the reaction was monitored by LC. After 24 hours, the reaction was terminated to give a yield of 70.4% of methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate. .

The crude AP-Me feed (41.4 g, corresponding to 8.8 g, 40.0 mmol of AP-Me) was distilled to remove ~2/3 methanol until the residue weighed 20 g. The thick paste was retained and redissolved with 26.2 g of MeCN (16 eq.). ABA (9.4 g, 1.15 eq) and water (40.4 g) were added to the AP-Me solution. 3.2 g of a 47 wt% K ₂ CO ₃ solution was added and the resulting mixture was degassed by nitrogen for 30 minutes. After degassing, 3.56 g of 47% K ₂ CO _{3 was} added to the mixture, followed by addition of palladium acetate (47 mg) and triphenylphosphine (105 mg) in one portion. The reaction mixture was then heated to 55 ° C and maintained at this temperature. After the reaction temperature reached 55 ° C, a second and a third portion of 47% K ₂ CO ₃ (3.56 g) were separately added with a syringe after one hour and two hours. The reaction was monitored by LC. After 24 hours, the reaction was terminated to give a yield of 77.2% of methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate. .

The crude AP-Me feed (41.4 g, corresponding to 8.8 g, 40.0 mmol of AP-Me) was distilled to remove ~2/3 methanol until the residue weighed 21.5 g. The thick paste was retained and redissolved with 36.2 g MIBK, ABA (9.4 g, 1.15 eq) and water (40.4 g). 3.2 g of a 47 wt% K ₂ CO ₃ solution was added and the resulting mixture was degassed by nitrogen for 30 minutes. After degassing, 3.56 g of 47% K ₂ CO _{3 was} added to the mixture, followed by addition of palladium acetate (47 mg) and triphenylphosphine (105 mg) in one portion. The reaction mixture was then heated to 55 ° C and maintained at this temperature. After the reaction temperature reached 55 ° C, a second and a third portion of 47% K ₂ CO ₃ (3.56 g) were separately added with a syringe after one hour and two hours. After the reaction reached 55 ° C, the reaction was monitored by LC. After 24 hours, the reaction was terminated to give a yield of 78.1% of methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate. .

In a round bottom flask, 174.0 g of a crude 4-amino-3,6-dichloropyridine-2-carboxylic acid methyl ester (AP Me) solution (which corresponds to 38.5 g, 174.0 mmol of AP-Me) was reduced. Press to distill into a paste. 4-Methyl-2-pentanone (MIBK) (~120 g) was added and the solution was again distilled under reduced pressure to a paste. Additional MIBK (~120 g) was added and the solution was distilled under reduced pressure for the last time into a paste. Acetonitrile (112.0 g, 2728 mmol) was added and the mixture was analyzed by ¹ H NMR to indicate that it was free of methanol. The mixture was poured into a 1 liter reactor with a heat-insulated jacket and rinsed with additional acetonitrile (35.1 g, 855 mmol). Water (189 g) and K ₂ CO ₃ solution (47 wt%, 11.9 g, 40.5 mmol) were added to reach a neutral pH, followed by the addition of 4-chloro-2-fluoro-3-methoxy-phenylboronic acid (ABA) ( 39.6 g, 91.4 mmol). The mixture was degassed by nitrogen sparge for 45 minutes then add additional 47wt% K ₂ CO ₃ solution (16.0g, 54.4mmol), triphenylphosphine (0.46g, 1.8mmol) and palladium acetate (0.20g, 0.9mmol). The reaction was heated to 60 °C. After reaching 60 ° C, an additional 47 wt% K ₂ CO ₃ solution was added over 30 minutes (16.0 g, 54.4 mmol), 60 minutes (12.2 g, 41.5 mmol) and 90 minutes (9.0 g, 30.6 mmol). After 19 hours, the reaction was heated to 65 ° C and then phase separated. Analysis of the organic phase gave methylamine 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate in a yield of 85.0%.

A crude AP-Me solution (22.5 wt%, 28 g, corresponding to 6.3 g, 28.5 mmol of AP-Me) was added to a round bottom flask. ABA (6.7 g), methanol (10 g) and triethylamine (11.5 g) were added. The mixture was degassed by nitrogen for 25 minutes, then palladium acetate (64 mg) and triphenylphosphine (150 mg) were added. The mixture was heated to 50 ° C and sampled by GC after 18 hours to give a conversion of 81%. The mixture was further heated to 65 ° C and the conversion was 85% after 6 hours at 65 °C.

A crude AP-Me solution (22.5 wt%, 20 g, containing 4.5 g, 20.4 mmol of AP-Me) was added to a round bottom flask. ABA (4.8 g), methanol (10 g) and diisopropylamine (8.94 g) were added. The mixture was degassed by nitrogen for 15 minutes, then palladium acetate (46 mg) and triphenylphosphine (107 mg) were added. The mixture was heated to 50 °C. The reaction conversion rate after 22 hours was 84%.

Example 6 product separation before direct coupling

4-Amino-3,6-dichloropyridine-2-carboxylic acid (AP) (40.0 g, 193.2 mmol) was added to a reactor with a heat-resistant jacket, followed by methanol (129.3 g, 4035 mmol). Concentrated sulfuric acid (7.1 g, 72.1 mmol) was added dropwise with another funnel. The resulting paste was heated to reflux (~65 ° C) and allowed to react for 16 hours at which time the resulting clear solution was allowed to cool to room temperature. 4-Methyl-2-pentanone (MIBK) (206.6 g, 2063 mmol) was added to the crude reaction mixture, followed by a 12 wt% solution of potassium bicarbonate (79.6 g, 95.4 mmol) to afford pH 8.0. After stirring for 15 minutes, saturated aqueous sodium chloride (59.4 g) was added and stirred for 15 min. An organic solution containing methyl 4-amino-3,6-dichloropyridine-2-carboxylate (AP-Me) was added back to the reactor with a heat-insulated jacket and distilled under reduced pressure to a concentration of 35.5 wt% AP-Me. . The obtained paste was cooled to room temperature, and at this time, 4-chloro-2-fluoro-3-methoxy-phenylboronic acid (ABA) (38.42 g, 188.5 mmol), methanol (17.3 g, 539.6 mmol) was added. And acetonitrile (110.5 g, 2693 mmol). Water (168.5 g) and potassium hydrogencarbonate (42.1 g, 420.7 mmol) were added to a flask. The contents of the reactor and the aqueous solution of the aqueous solution were both degassed by nitrogen for 45 minutes, at which time an aqueous alkaline solution was added to the reactor. Triphenylphosphine (0.441 g, 1.683 mmol) and palladium acetate (0.189 g, 0.841 mmol) were added in one portion and the reactor contents were heated at 50 °C for 23 hours. The reactor temperature was increased to 65 ° C, then the contents were poured into a hot separation funnel and phase separated to give a yield of 84.2% 4-amino-3-chloro-6-(4-chloro- Methyl 2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.

The crude AP-Me feed (which contained 8.8 g, 40 mmol of AP-Me) was diluted with 41.4 g of MIBK. The MeOH, water and MIBK were removed with a rotary evaporator until the residue weight reached 21.5 g. An oily mixture was left in the flask containing approximately 10 g of MIBK. MeCN (26.2 g, 16 eq.) was added followed by ABA solid (9.4 g, 1.15 eq.), MeOH (4.3 g) and water (41.6 g). 3.37 g of a 47 wt% K ₂ CO ₃ solution was added, and the resulting mixture was degassed by nitrogen for 30 minutes. After degassing, 3.56 g of 47% K ₂ CO _{3 was} added to the mixture, followed by the addition of palladium acetate (47 mg) and triphenylphosphine (105 mg). The reaction mixture was then heated to 55 ° C and maintained at this temperature. After the reaction temperature reached 55 ° C, a second and a third portion of 47% K ₂ CO ₃ (3.56 g) were separately added with a syringe after one hour and two hours. After 16 hours, the reaction was terminated to give a yield of 92.6% of methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate. .

The crude AP-Me feed (which contained 8.8 g, 40.0 mmol of AP-Me) was charged to a rotary evaporator to remove ~2/3 methanol until the residue weighed 20.5 g. The viscous paste was retained and redissolved in 26.2 g of MeCN (16 eq.). ABA (9.4 g, 1.15 eq.), MIBK (9.8 g), MeOH (4.3 g), and water (40.4 g) were added to the AP-Me solution. 3.37 g of a 47 wt% K2CO3 solution was added and the resulting mixture was degassed by nitrogen for 30 minutes. After degassing, 3.56 g of 47% K ₂ CO _{3 was} added to the mixture, followed by the addition of palladium acetate (47 mg) and triphenylphosphine (105 mg). The reaction mixture was then heated to 55 ° C and maintained at this temperature. After the reaction temperature reached 55 ° C, a second and a third portion of 47% K ₂ CO ₃ (3.56 g) were separately added with a syringe after one hour and two hours. After 9 hours, the reaction was terminated to give a methyl ester of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate with a yield of 91.8%. .

The crude AP-Me feed (189.2 g, which contained 40.0 g, 181.0 mmol of AP-Me) was distilled on a rotary evaporator to remove ~2/3 methanol until the residue weight reached 86.8 g. The viscous paste was retained and 11.3 g of MeOH was charged to achieve the desired MeOH concentration. MeCN (118.7 g, 16 eq.), ABA solid (42.5 g, 1.15 eq.), MeOH (19.1 g), MIBK (44.7 g) and water (182.9 g) were added to the mixture. 14.5 g of a 47 wt% K ₂ CO ₃ solution was added and the resulting mixture was degassed by nitrogen for 45 minutes. After degassing, 16.1 g of 47% K ₂ CO _{3 was} added to the mixture, followed by addition of palladium acetate (203 mg) and triphenylphosphine (474 mg) in one portion. The reaction mixture was then heated to 55 ° C and maintained at this temperature. After the reaction temperature reached 55 ° C, a second and a third portion of 47% K ₂ CO ₃ (16.1 g) were separately added with a syringe after one hour and two hours. The reaction was terminated after 10 hours, yielding a process yield of 89.1%.

Claims (72)

A method for preparing 6-aryl-4-aminopicolinate of the formula: Wherein Q represents hydrogen or a halogen group; R represents hydrogen, alkyl, aryl or aralkyl; W represents H, halo, C _1-4 alkyl or C _1-3 alkoxy; X represents H; Y represents a halogen group, a C _1-4 alkyl group, or a C _1-3 alkoxy group; and Z represents H, a halogen group, a C _1-4 alkyl group, or a C _1-3 alkoxy group; the method includes The Suzuki coupling reaction couples an aminopyridine (AP) and a phenylboronic acid (PBA) in the presence of a catalyst, wherein the catalyst concentration is less than or equal to about 3% relative to the limiting reagent system, and the 6-aryl-4-aminopyridine The yield of formate is at least about 60%. A method for preparing 6-aryl-4-aminopicolinate of the formula: Wherein Q represents hydrogen or a halogen group; R represents hydrogen, an alkyl group, an aryl group, or an aralkyl group; W represents H, a halogen group, a C _1-4 alkyl group, or a C _1-3 alkoxy group; and X represents F. , Cl, C _1-4 alkyl, C _1-3 alkoxy, or -NO ₂ ; Y represents a halogen group, a C _1-4 alkyl group, or a C _1-3 alkoxy group; and Z represents H, a halogen a group, a C _1-4 alkyl group, or a C _1-3 alkoxy group; the method comprising coupling an aminopyridine (AP) and a phenylboronic acid (PBA) in the presence of a catalyst by direct Suzuki coupling reaction, wherein the catalyst concentration The yield is less than or equal to about 3% relative to the limiting reagent and the yield of 6-aryl-4-aminopicolinate is at least about 60%.  The method of claim 1, wherein the AP is methyl 4-amino-3,6-dichloropyridine-2-carboxylate (AP-Me).    The method of claim 2, wherein the AP is 4-amino-3,6-dichloropyridine-5-fluoro-2-carboxylic acid benzyl ester (AP-Bz).    The method of any of claims 1-4, wherein the AP is crude.    The method of any one of claims 1 to 5, wherein the PBA is 4-chloro-2-fluoro-3-methoxy-phenylboronic acid.    The method of any one of claims 1 to 5, wherein the PBA is dimethyl (4-chloro-2-fluoro-3-methoxyphenyl)borate.    The method of any of claims 1-7, wherein the catalyst is a palladium catalyst.    The method of claim 8 wherein the palladium catalyst is a palladium (II) catalyst.   The method of claim 9, wherein the palladium (II) catalyst is palladium acetate, Pd(OAc) ₂ .  The method of any one of claims 1 to 10, wherein the concentration of the catalyst is from about 0.2% to about 2.0% relative to the limiting reagent system.    The method of claim 11, wherein the concentration of the catalyst is from about 0.4% to about 1.0%.    The method of claim 11, wherein the concentration of the catalyst is about 0.5%.    The method of any of claims 1-13, wherein the pH of the Suzuki coupling reaction is from about 7 to about 12.    The method of claim 14, wherein the pH of the Suzuki coupling reaction is from about 7 to about 10.    The method of claim 14, wherein the pH of the Suzuki coupling reaction is from about 8 to about 10.   The method of any of claims 1 to 16, wherein the pH is adjusted by the addition of a base and/or CO ₂ . The method of claim 17, wherein the base comprises K ₂ CO ₃ .  The method of claim 17 or 18, wherein the base is added in more than one portion during the direct Suzuki coupling reaction.    The method of claim 19, wherein the plurality of portions are added over a period of at least two hours.    The method of any one of claims 1 to 20, wherein the direct Suzuki coupling reaction is carried out in a solvent system comprising a mixture of methyl isobutyl ketone, acetonitrile and methanol.    The method of any of claims 1-17 and 21, wherein the direct Suzuki coupling reaction is carried out in a non-aqueous system.    A 6-aryl-4-aminopicolinate produced by the method of any one of claims 1-22.    The 6-aryl-4-aminopicolinate as claimed in claim 23, wherein the yield is greater than about 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84% , 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95%.   A method for preparing 6-aryl-4-aminopicolinate of the formula: Wherein Q represents H, Cl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkoxy, C ₂ -C ₄ alkenyl, or C ₂ -C ₄ haloalkenyl; R represents H, alkane a group, or an aralkyl group; X represents H, F, Cl, _1-4 alkyl, C _1-3 alkoxy, or -NO ₂ ; Ar represents a substituted or unsubstituted aryl or heteroaryl The method comprises coupling an aminopyridine (AP) and an aryl boronic acid (ABA) in the presence of a catalyst by a direct Suzuki coupling reaction.  The method of claim 25, wherein X is F or Cl.    The method of claim 26, wherein X is F.   The method of any of claims 25-27, wherein Ar is: Wherein W ₁ represents H or F; W ₂ represents H, F, Cl, C _1-4 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, or C _1-3 haloalkoxy Y represents a halogen group, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-3 alkoxy group, a C _1-3 haloalkoxy group, -CN, or -NO ₂ ; and Z represents H , F, Cl, C _1-4 alkyl, C _1-3 alkoxy, C ₁ -C ₄ haloalkyl, C _1-3 haloalkoxy, C ₁ -C ₃ alkoxy substituted C ₁ -C ₃ alkyl, or -NR ₁ R ₂ , wherein R ₁ and R _{2 are} independently hydrogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl; or Y and Z or Z and W ₂ Together they are a five-membered aromatic or non-aromatic, carbocyclic or heterocyclic ring.  The method of any one of claims 25-28, wherein the AP is 4-amino-3,6-dichloropyridine-5-fluoro-2-carboxylic acid benzyl ester (AP-Bz).    The method of any one of claims 25-28, wherein the AP is methyl 4-amino-3,6-dichloropyridine-5-fluoro-2-carboxylate.    The method of any of claims 25-30, wherein the AP is crude.    The method of any one of claims 25-31, wherein the ABA is 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- 2-yl)-1-(triisopropyldecyl)-1H-indole.    The method of any of claims 25-32, wherein the catalyst is a palladium catalyst.    The method of claim 33, wherein the palladium catalyst is a palladium (II) catalyst.   The method of claim 34, wherein the palladium (II) catalyst is palladium acetate, Pd(OAc) ₂ .  The method of any one of claims 25-35, wherein the concentration of the catalyst is from about 0.2% to about 2.0% relative to the limiting reagent system.    The method of claim 36, wherein the concentration of the catalyst is from about 0.4% to about 1.0%.    The method of claim 36, wherein the concentration of the catalyst is about 0.5%.    The method of any one of claims 25-38, wherein the pH of the Suzuki coupling reaction is from about 7 to about 12.    The method of claim 39, wherein the pH of the Suzuki coupling reaction is from about 7 to about 10.    The method of claim 39, wherein the pH of the Suzuki coupling reaction is from about 8 to about 10.   The method of any one of claims 25-41, wherein the pH is adjusted by the addition of a base and/or CO ₂ . The method of claim 42, wherein the base comprises K ₂ CO ₃ .  The method of claim 42 or 43, wherein the base is added in more than one portion during the direct Suzuki coupling reaction.    The method of claim 44, wherein the plurality of portions are added over a period of at least two hours.    The method of any one of claims 25-45, wherein the direct Suzuki coupling reaction is carried out in a solvent system consisting of a mixture of methyl isobutyl ketone, acetonitrile and methanol.    The method of any of claims 25-45, wherein the direct Suzuki coupling reaction is carried out in a non-aqueous system.    A 6-aryl-4-aminopicolinate produced by the method of any one of claims 25-47.    The 6-aryl-4-aminopyridine carboxylic acid of claim 48, wherein the yield is greater than about 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84% , 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95%.   A method for preparing a 2-aryl-6-aminopyrimidinecarboxylate of the formula: Wherein Q represents H, Cl, C _1-3 alkoxy, C _1-3 haloalkoxy, C _2-4 alkenyl, or _2-4 haloalkenyl; R represents H, alkyl, or aralkyl Ar represents a substituted or unsubstituted aryl or heteroaryl; the process involves coupling an aminopyridine (AP) and an aryl boronic acid (ABA) in the presence of a catalyst by direct Suzuki coupling. The method of claim 50, wherein Ar is: Wherein W ₁ represents H or F; W ₂ represents H, F, Cl, C _1-4 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, or _1-3 haloalkoxy; Y represents a halogen group, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a C _1-3 alkoxy group, a C _1-3 haloalkoxy group, -CN, or -NO ₂ ; and Z represents H, F, Cl, C _1-4 alkyl, C _1-3 alkoxy, C ₁ -C ₄ haloalkyl, C _1-3 haloalkoxy, C ₁ -C ₃ alkoxy-substituted C ₁ -C ₃ alkyl, or -NR ₁ R ₂ , wherein R ₁ and R ₂ are independently hydrogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl; or Y and Z or Z and W ₂ Together they are a five-membered aromatic or non-aromatic, carbocyclic or heterocyclic ring.  The method of any one of claims 50 or 51, wherein the AP is 6-amino-2,5-dichloropyrimidine-4-carboxylic acid methyl ester or 6-amino-2-chloro-5-methoxy Methyl pyrimidine-4-carboxylate.    The method of any of claims 50-52, wherein the AP is crude.    The method of any one of claims 50-53, wherein the ABA is 4-chloro-2-fluoro-3-methoxy-phenylboronic acid.    The method of any one of claims 50-53, wherein the ABA is dimethyl (4-chloro-2-fluoro-3-methoxyphenyl)borate.    The method of any one of claims 50-55, wherein the catalyst is a palladium catalyst.    The method of claim 56, wherein the palladium catalyst is a palladium (II) catalyst.   The method of claim 57, wherein the palladium (II) catalyst is palladium acetate, Pd(OAc) ₂ .  The method of any one of claims 50-58, wherein the concentration of the catalyst is from about 0.2% to about 2.0% relative to the limiting reagent system.    The method of claim 59, wherein the concentration of the catalyst is from about 0.4% to about 1.0%.    The method of claim 59, wherein the concentration of the catalyst is about 0.5%.    The method of any one of claims 50-61, wherein the pH of the Suzuki coupling reaction is from about 7-12.    The method of claim 62, wherein the pH of the Suzuki coupling reaction is from about 7 to about 10.    The method of claim 62, wherein the pH of the Suzuki coupling reaction is from about 8 to about 10.   The method of any of claims 50-64, wherein the pH is adjusted by the addition of a base and/or CO ₂ . The method of claim 65, wherein the base comprises K ₂ CO ₃ .  The method of claim 65 or 66, wherein the base is added in more than one portion during the direct Suzuki coupling reaction.    The method of claim 67, wherein the plurality of portions are added over a period of at least two hours.    The method of any one of claims 50-68, wherein the direct Suzuki coupling reaction is carried out in a mixture of methyl isobutyl ketone, acetonitrile, and methanol.    The method of any one of claims 50-68, wherein the direct Suzuki coupling reaction is carried out in a non-aqueous system.    A 2-aryl-6-aminopyrimidinecarboxylate produced by the method of any one of claims 50-70.    The 2-aryl-6-aminopyrimidinecarboxylate of claim 71, wherein the yield is greater than about 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84 %, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95%.