The intermediate 4-(4-methoxyphenyl)-2-methylpyridine (IV) was obtained by two different procedures. Acylation of 2-picoline (I) with ethyl chloroformate, followed by addition of the Grignard reagent (II), prepared from 4-bromoanisole and magnesium, furnished the 4-aryl dihydropyridine (III). Aromatization of (III) by heating at 200 C with sulfur in decahydronaphthalene produced the phenylpyridine (IV). In an alternative method, 2-methylpyridine (I) was converted to the N-aminopyridinium salt (V) by reaction with hydroxylamine-O-sulfonic acid. This was then condensed with dehydroacetic acid (VI) under acidic conditions to produce the bipyridinium derivative (VII), which was isolated as the tetrafluoroborate salt. Alternatively, addition of 4-methoxyphenylmagnesium bromide (II) to (VII) yielded the phenyl bipyridinone (VIII), which upon elimination of the dimethylpyridone moiety in refluxing DMF generated the intermediate phenyl pyridine (IV). Methyl ether cleavage of (IV) in refluxing HBr afforded phenol (IX). This was then alkylated with 3-chloro-3-methylbutyne (X) to yield the aryl propargyl ether (XI) ,which was subjected to a Claisen rearrangement in hot ortho-dichlorobenzene to produce chromene (XII).

Electrophilic bromination of chromene (XII) with N-bromosuccinimide in moist DMSO produced the trans-bromohydrin (XIII). The racemic (XIII) was then resolved by esterification with (R)-alpha-methoxyphenylacetic acid (XIV), using DCC as the coupling reagent, and subsequent chromatographic separation of the diastereomeric mixture. Hydrolysis of the desired bromoester isomer (XV) under basic conditions gave rise to the chiral cis-epoxide (XVI). The target amino alcohol (XVII) was then obtained by regioselective ring opening of epoxide (XVI) with ethanolic ammonia in a pressure vessel. Finally, coupling of (XVII) with nicotinoyl chloride (XVIII) furnished the title amide.

The intermediate 4-(4-methoxyphenyl)-2-methylpyridine (IV) was obtained by two different procedures. Acylation of 2-picoline (I) with ethyl chloroformate, followed by addition of the Grignard reagent (II), prepared from 4-bromoanisole and magnesium, furnished the 4-aryl dihydropyridine (III). Aromatization of (III) by heating at 200 C with sulfur in decahydronaphthalene produced the phenylpyridine (IV). In an alternative method, 2-methylpyridine (I) was converted to the N-aminopyridinium salt (V) by reaction with hydroxylamine-O-sulfonic acid. This was then condensed with dehydroacetic acid (VI) under acidic conditions to produce the bipyridinium derivative (VII), which was isolated as the tetrafluoroborate salt. Alternatively, addition of 4-methoxyphenylmagnesium bromide (II) to (VII) yielded the phenyl bipyridinone (VIII), which upon elimination of the dimethylpyridone moiety in refluxing DMF generated the intermediate phenyl pyridine (IV). Methyl ether cleavage of (IV) in refluxing HBr afforded phenol (IX). This was then alkylated with 3-chloro-3-methylbutyne (X) to yield the aryl propargyl ether (XI) ,which was subjected to a Claisen rearrangement in hot ortho-dichlorobenzene to produce chromene (XII).

Electrophilic bromination of chromene (XII) with N-bromosuccinimide in moist DMSO produced the trans-bromohydrin (XIII). The racemic (XIII) was then resolved by esterification with (R)-alpha-methoxyphenylacetic acid (XIV), using DCC as the coupling reagent, and subsequent chromatographic separation of the diastereomeric mixture. Hydrolysis of the desired bromoester isomer (XV) under basic conditions gave rise to the chiral cis-epoxide (XVI). The target amino alcohol (XVII) was then obtained by regioselective ring opening of epoxide (XVI) with ethanolic ammonia in a pressure vessel. Finally, coupling of (XVII) with nicotinoyl chloride (XVIII) furnished the title amide.