Reaction of 4,6-dimethylpyridin-2-amine (I) with isoamyl nitrite and HCl gives 2-chloro-4,6-dimethylpyridine (II), which is treated with hydrazine in diethylene glycol at 140 C yielding 2-hydrazino-4,6-dimethylpyridine (III). Cyclization of (III) with cyclohexanone (IV) in refluxing diethylene glycol affords the tetrahydro-alpha-carboline (V), which is dehydrogenated with Pd in refluxing diethylene glycol, giving the alpha-carboline (VI). The alkylation of (VI) with the benzyl bromide (VII) by means of potassium tert-butoxide in DMF yields the adduct (VIII), which is hydrolyzed with concentrated H2SO4 to provide the carboxylic acid (IX). Finally, this acid is condensed with (R)-2-hydroxy-1-phenylethylamine (X) by means of HOBT and EDC in CH2Cl2, giving a diastereomeric mixture of the corresponding amides that is resolved by column chromatography. The benzyl bromide intermediate (VII) has been obtained as follows: Esterification of 2-(4-methylphenyl)acetic acid (XI) with tert-butanol and DCC and DMAP in CH2Cl2 gives the corresponding tert-butyl ester (XII), which is condensed with cyclopentyl bromide (XIII) by means of t-BuOK in DMF to yield racemic 2-cyclopentyl-2-(4-methylphenyl)acetic acid tert-butyl ester (XIV). Finally, this compound is brominated with NBS and AIBN in refluxing CCl4.

Esterification of 2-(4-methylphenyl)acetic acid (XI) with L-menthol (XV) by means of MsOH in refluxing toluene gives the ester (XVI), which is diastereoselectively condensed with cyclopentyl bromide (XIII) by means of t-BuOK in DMF, affording 2(S)-cyclopentyl-2-(4-methylphenyl)acetic acid L-menthyl ester (XVII). Bromination of (XVII) with 1,3-dibromo-5,5-dimethylhydantoin (DBMH) in hot chlorobenzene gives the chiral benzyl bromide (XVIII), which is condensed with the already described alpha-carboline (VI) by means of t-BuOK in DMF to yield the adduct (XIX). Hydrolysis of (XIX) with HBr in formic acid affords the chiral cyclopentylacetic acid (XX), which is treated with SOCl2 in refluxing CH2Cl2 to provide the corresponding acyl chloride (XXI). Finally, this compound is condensed with (R)-2-hydroxy-1-phenylethylamine (X) by means of TEA in hot toluene.

Reaction of 4,6-dimethylpyridin-2-amine (I) with isoamyl nitrite and HCl gives 2-chloro-4,6-dimethylpyridine (II), which is treated with hydrazine in diethylene glycol at 140 C yielding 2-hydrazino-4,6-dimethylpyridine (III). Cyclization of (III) with cyclohexanone (IV) in refluxing diethylene glycol affords the tetrahydro-alpha-carboline (V), which is dehydrogenated with Pd in refluxing diethylene glycol, giving the alpha-carboline (VI). The alkylation of (VI) with the benzyl bromide (VII) by means of potassium tert-butoxide in DMF yields the adduct (VIII), which is hydrolyzed with concentrated H2SO4 to provide the carboxylic acid (IX). Finally, this acid is condensed with (R)-2-hydroxy-1-phenylethylamine (X) by means of HOBT and EDC in CH2Cl2, giving a diastereomeric mixture of the corresponding amides that is resolved by column chromatography. The benzyl bromide intermediate (VII) has been obtained as follows: Esterification of 2-(4-methylphenyl)acetic acid (XI) with tert-butanol and DCC and DMAP in CH2Cl2 gives the corresponding tert-butyl ester (XII), which is condensed with cyclopentyl bromide (XIII) by means of t-BuOK in DMF to yield racemic 2-cyclopentyl-2-(4-methylphenyl)acetic acid tert-butyl ester (XIV). Finally, this compound is brominated with NBS and AIBN in refluxing CCl4.

Esterification of 2-(4-methylphenyl)acetic acid (XI) with L-menthol (XV) by means of MsOH in refluxing toluene gives the ester (XVI), which is diastereoselectively condensed with cyclopentyl bromide (XIII) by means of t-BuOK in DMF, affording 2(S)-cyclopentyl-2-(4-methylphenyl)acetic acid L-menthyl ester (XVII). Bromination of (XVII) with 1,3-dibromo-5,5-dimethylhydantoin (DBMH) in hot chlorobenzene gives the chiral benzyl bromide (XVIII), which is condensed with the already described alpha-carboline (VI) by means of t-BuOK in DMF to yield the adduct (XIX). Hydrolysis of (XIX) with HBr in formic acid affords the chiral cyclopentylacetic acid (XX), which is treated with SOCl2 in refluxing CH2Cl2 to provide the corresponding acyl chloride (XXI). Finally, this compound is condensed with (R)-2-hydroxy-1-phenylethylamine (X) by means of TEA in hot toluene.