Picolinic acid → (6-Chloropyridin-2-yl)methanol

Scheme C depicts a general method for preparing compounds of Formula 1 in which L is —CH2O—. As shown in Scheme C, a picolinic acid derivative (CO is reacted with methanol and sulfuric acid at elevated temperature (e.g., about 65° C.). The resulting methyl picolinate derivative (C2) is activated via treatment with m-chloroperoxybenzoic acid in a compatible solvent (e.g., DCM) to give and N-oxide intermediate (C3) which is subsequently reacted with phosphoryl trichloride at elevated temperature (e.g., about 100° C.). The resulting methyl 6-chloropicolinate derivative (C4) is treated with sodium borohydride and methanol to give a (6-chloropyridin-2-yl)methanol derivative (CS) which is reacted with zinc cyanide in the presence of a palladium catalyst (e.g. Pd2(dba)3), an optional ligand (e.g., XPhos) and solvent (e.g., DMF, DMA, etc.) at elevated temperature (e.g., about 150-165° C.). The resulting 6-(hydroxymethyl)picolinonitrile derivative (C6) is reacted with tribromophosphine in a compatible solvent (e.g., THF) to give a brominated intermediate (C7) which is reacted with an alcohol (A2) in the presence of a base to give a nitrile (C8) in which L2 is —CH2O—. As in Scheme A, the nitrile (C8) is combined with ethyl hydrazinecarboxylate in a compatible solvent and is heated to give a triazolone intermediate (C9). Subsequent removal of the amine protective group and reaction with an acyl chloride (A7) in the presence of a nonnucleophilic base and a compatible solvent gives the desired compound of Formula 1B.

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ORD record

ord-a57c1757949b420888a6c995f63447d8

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09402841B2