Synthesis of 6-aryl-4-aminopicolinates

A process for the preparation of a 6-aryl-4-aminopicolinate of Formula I-A:

• the process comprising the following steps:
• a. creating a first mixture containing a compound of Formula C2
• an acid, wherein the acid is concentrated sulfuric acid, or an acid-chloride forming compound, wherein the acid-chloride-forming compound is selected from the group consisting of thionyl chloride and oxalyl chloride, and an alcohol ROH, wherein R represents C1-C12 alkyl;
• b. heating the first mixture at a temperature from about 70° C. to about 90° C.;
• c. isolating from the first mixture the compound of Formula D2
• wherein
• R represents C1-C12 alkyl;
• d. creating a second mixture containing the compound of Formula D2;
• phthalic anhydride
• a base selected from the group consisting of trimethylamine, triethylamine, tripropylamine, pyridine, 2-picoline, and 3-picoline;
• and
• a solvent selected from the group consisting of acetonitrile, toluene, N,N-dimethylformamide (DMF), propionitrile, benzonitrile, tetrahydrofuran (THF), 2-methyl-THF, dioxane, cyclopentyl methyl ether (CPME), monoethyleneglycol ethers, diethyleneglycol ethers, monopropyleneglycol ethers, dipropyleneglycol ethers, and methyl isobutyl ketone (MIBK), and mixtures thereof;
• e. heating the second mixture at a temperature from about 25° C. to about 100° C.;
• f. isolating from the second mixture the compound of Formula E2
• wherein
• R represents C1-C12 alkyl;
• g. creating a third mixture containing the compound of Formula E2;
• a fluorinating compound selected from the group consisting of potassium fluoride (KF), cesium fluoride (CsF), tetramethylammonium fluoride (TMAF), and mixtures thereof, or a mixture of tetramethylammonium chloride (TMAC) with KF or CsF;
• and a solvent selected from the group consisting of acetonitrile, propionitrile, benzonitrile, dimethylsulfoxide (DMSO), N,N′-dimethylformamide (DMF), sulfolane, N,N-dimethylacetamide (DMA), 1,1-dimethyl-2-imidazolidinone (DMI), N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (NMP), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methyl-THF), dioxane, monoethyleneglycol ethers, diethyleneglycol ethers, monopropyleneglycol ethers, dipropyleneglycol ethers, and mixtures thereof;
• h. heating the third mixture at a temperature from about 25° C. to about 110° C.;
• i. isolating from the third mixture a compound of Formula F2
• wherein
• R represents C1-C12 alkyl;
• j. creating a fourth mixture containing the compound of Formula F2;
• hydrobromic acid (HBr);
• acetic acid;
• and water;
• k. heating the fourth mixture at a temperature from about 50° C. to about 110° C.;
• l. isolating from the fourth mixture the compound of Formula A1 or the hydrobromide (HBr) salt thereof
• m. creating a fifth mixture containing the compound of Formula A1;
• and
• arylalkyl halide RX1, a base selected from the group consisting of triethylamine, N,N-diisopropylethylamine, 3,5-lutidine, 2,6-lutidine, 3-methylpyridine, lithium carbonate, and potassium carbonate, and a solvent selected from the group consisting of tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, and 1,2-dichloroethane
• wherein
• R represents C6-C12 arylalkyl;
• and
• X1 represents Cl or Br;
• n. heating the fifth mixture at a temperature from about 25° C. to about 80° C. to form a sixth mixture;
• o. adding to the sixth mixture a compound of Formula B1
• one or more bases selected from the group consisting of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, potassium acetate, sodium acetate, potassium phosphate monobasic, potassium phosphate dibasic, potassium phosphate tribasic, sodium tetraborate, potassium hydroxide, sodium hydroxide, triethylamine, triisopropylamine, diisopropylamine, diethylamine, and diisopropylethylamine;
• one or more solvents selected from the group consisting of methyl isobutyl ketone (MIBK), dimethoxyethane (DME), tetrahydrofuran (THF), methanol (MeOH), benzyl alcohol, toluene, water, and mixtures thereof;
• a palladium catalyst selected from the group consisting of palladium (II) acetate (Pd(OAc)2) and palladium (II) chloride (PdCl2);
• and optionally a ligand selected from the group consisting of tri-tert-butylphosphine, tricyclohexylphosphine, di-tert-butylphenylphosphine, dicyclohexylphenylphosphine, triphenylphosphine, 4-diphenylphosphinomethyl polystyrene resin crosslinked, sodium diphenylphosphinobenzene-3-sulfonate with 2% DVB, tri (p-tolyl)phosphine, and (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl;
• p. heating the sixth mixture to a temperature of between about 25° C. and about 100° C.;
• and
• q. isolating the 6-aryl-4-aminopicolinate of Formula I-A from the sixth mixture.