Patent ID: 8053451

Claim:
A process for preparing (2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridinyl)-4-penten-2-amine or a corresponding hydroxybenzoate salt, comprising the steps of: a) performing a Heck coupling reaction between a 3-halo-5-isopropoxypyridine and a compound of the formula (S)—CH 2 ═CH—(CH 2 )—CH(CH 3 )—N(CH 3 )(pg), where pg is a protecting group for an amine, and b) deprotecting the protected amine group, or c) performing a Heck coupling reaction between a 3-halo-5-isopropoxypyridine and a compound of the formula (R)—CH 2 ═CH—(CH 2 )—CH(CH 3 )—OH and d) converting the OH group to an NHCH 3 group, to form a mixture of compounds including (2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridinyl)-4-penten-2-amine, the related Z-metanicotine compound, and other isomers, e) forming a hydroxybenzoate salt by reaction of the mixture with a hydroxybenzoic acid of the formula: where the hydroxy group can be present at a position ortho, meta or para to the carboxylic acid group, Z represents a non-hydrogen substituent selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, F, Cl, Br, I, NR′R″, CF 3 , CN, NO 2 , C 2 R′, SH, SCH 3 , N 3 , SO 2 CH 3 , OR′, (CR′R″) q , OR′, O—(CR′R″) q C 2 R′, SR′, C(═O)NR′R″, NR′C(═O)R″, C(═O)R′, C(═O)OR′, OC(═O)R′, (CR′R″) q , OCH 2 C 2 R′, (CR′R″) q C(═O)R′, (CR′R″) q C(CHCH 3 )OR′, O(CR′R″) q C(═O)OR′, (CR′R″) q , C(═O)NR′R″, (CR′R″) q , NR′R″, CH═CHR′, OC(═O)NR′R″, and NR′C(═O)OR″, where q is an integer from 1 to 6 and R′ and R″ are individually hydrogen, C 1-10 alkyl, cycloalkyl, a non-aromatic heterocyclic ring wherein the heteroatom of the heterocyclic moiety is separated from any other nitrogen, oxygen or sulfur atom by at least two carbon atoms, or an aromatic group-containing species selected from the group consisting of pyridinyl, quinolinyl, pyrimidinyl, furanyl, phenyl, and benzyl, where any of the foregoing can be suitably substituted with at least one substituent group, such as alkyl, hydroxyl, alkoxyl, halo, or amino substituents, and j is a number from zero to three, representing the number of Z substituents that can be present on the ring, wherein the molar ratio of the E-metanicotine to hydroxybenzoic acid ranges from 1:2 to 2:1, f) isolating the (2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridinyl)-4-penten-2-amine hydroxybenzoate salt, and g) optionally converting the (2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridinyl)-4-penten-2-amine hydroxybenzoate salt to (2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridinyl)-4-penten-2-amine.