Synthesis of 4-(piperidyl)(2-pyridyl)methanone-(E)-O-methyloxime and salts

A process for preparing a compound of the Formula:

• where R1 and R4 are defined below, m is 1 or 2, and n is a number from 1 to 4, and wherein said compound is in its E-isomer form in at least about 90% stereochemical purity, from a compound of Formula III:
• and from a compound of Formula IV:
• where R2 is defined below and X is a halogen, said process comprising:
• (a) converting the compound of Formula IV, where R2 is defined below and X is a halogen, into its Grignard form of Formula IVA:
• by reacting said compound of Formula IV with magnesium in a solvent selected from the group consisting of toluene, xylene, 1,2-dimethoxyethane, 1,2-diethoxyethane, diglyme, 1,4-dioxane, tetrahydrofuran, methyl tetrahydrofuran and mixtures thereof, at about −10° C. to reflux of said solvent;
• (b) reacting the compound of Formula III with the compound of Formula IVA in the presence of an initiator at about −10 to 10° C. to obtain a compound of Formula V:
• (c) reacting the compound of Formula V with an alkyl chloroformate of Formula VI:
• R3—OCOCl VI
• where R3 is defined below, in a solvent selected from the group consisting of toluene, xylene, chlorobenzene, methylene chloride, ethylene chloride, ethyl acetate, isobutyl acetate, n-butyl acetate, 1,2-dimethoxyethane, 1,2-diethoxyethane, diglyme, 1,4-dioxane, tetrahydrofuran, methyl tetrahydrofuran and mixtures thereof, at about 25-100° C., for about 1-5 hours, to yield a compound of Formula VII:
• (d) hydrolyzing the compound of Formula VII into its free base of Formula VIIA, by acid hydrolysis or base hydrolysis:
• (e) Forming the acid salt (Formula VIII) from the compound of Formula VIIA by reacting with aqueous sulfuric acid, hydrochloric acid, or trifluoroacetic acid:
• wherein said acid salt refers to sulfate, hydrochloride or trifluoroacetate;
• (f) reacting the acid salt of Formula VIII with an alkoxyamine (NH2OR4) or its hydrochloride in a protic solvent in the presence of a weak acid to form an oxime of Formula IX:
• where R4 is defined below, and
• (g) isomerizing the compound of Formula IX by treatment with a strong acid and simultaneously converting to the desired acid salt of Formula IX with an enriched E isomer, wherein the E isomer predominates over the Z-isomer by at least a 90:10 ratio,
• wherein R1, R2, R3 and R4 may be the same or different and are independently selected from the group consisting of H, halogen, alkyl, aryl, alkoxy, aryloxy, arylalkyl (with the alkyl being the linker), alkylaryl (with the aryl being the linker), heteroalkyl, heteroaryl, alkyl-heteroaryl, heteroaralkyl, cycloalkyl and cycloalkylalkyl, and wherein said alkyl, aryl, alkoxy, aryloxy, arylalkyl, alkylaryl, heteroalkyl, heteroaryl, alkyl-heteroaryl, heteroaralkyl, cycloalkyl and cycloalkylalkyl may optionally be substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic and halogen.