La. Sorbera et al., Implitapide. Hypolipidemic, Treatment of atherosclerosis, MTP inhibitor, ApoB secretion inhibitor., DRUG FUTURE, 25(11), 2000, pp. 1138-1144
Implitapide has been obtained by two related ways:
1) 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 degreesC yielding 2-hydrazino-4,6-dimethylpyrid
ine (III). Cyclization of (III) with cyclohexanone (IV) in refluxing diethy
lene glycol affords the tetrahydro-alpha -carboline (V), which is dehydroge
nated with Pd in refluxing diethylene glycol, giving the alpha -carboline (
VI). The alkylation of (VI) with the benzyl bromide (VII) by means of potas
sium tert-butoxide in DMF yields the adduct (VIII), which is hydrolyzed wit
h concentrated H2SO4 to provide the carboxylic acid (IX). Finally, this aci
d is condensed with (R)-2-hydroxy-1-phenylethylamine (X) by means of HOBT a
nd EDC in dichloromethane, giving a diastereomeric mixture of the correspon
ding amides that is resolved by column chromatography (1). Scheme 1.
The benzyl bromide intermediate (VII) has been obtained as follows: Esterif
ication of 2-(4-methylphenyl)acetic acid (XI) with tert-butanol and DCC and
DMAP in dichloromethane gives the corresponding tertbutyl ester (XII), whi
ch is condensed with cyclopentyl bromide (XIII) by means of potassium tert-
butoxide in DMF to yield racemic 2-cyclopentyl-2-(4-methylphenyl)acetic aci
d tert-butyl ester (XIV). Finally, this compound is brominated with NBS and
AIBN in refluxing CCl4 (1). Scheme 1.
2) Esterification of 2-(4-methylphenyl)acetic acid (XI) with L-menthol (XV)
by means of MeSO3H in refluxing toluene gives the ester (XVI), which is di
astereoselectively condensed with cyclopentyl bromide (XIII) by means of t-
BuOK in DMF, affording 2(S)-cyclopentyl-2-(4-methylphenyl)acetic acid L-men
thyl ester (XVII). Bromination of (XVII) with 1,3-dibromo-5,5-dimethylhydan
toin (DBMH) in hot chlorobenzene gives the chiral benzyl bromide (XVIII), w
hich 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 i
n formic acid affords the chiral cyclopentylacetic acid (XX), which is trea
ted with SOCl2 in refluxing dichloromethane to provide the corresponding ac
yl chloride (XXI). Finally, this compound is condensed with (R)-2-hydroxy-1
-phenylethylamine (X) by means of TEA in hot toluene (2). Scheme 2.