Several
variations to the synthesis of aprepitant (II) have been
published by the Merck group. The latest optimized
synthesis utilizing a novel crystallization-induced
diastereoselective synthesis of aprepitant is highlighted in the
Scheme. The synthetic approach entailed (1) the
synthesis and coupling of the key pieces, N-benzyl lactam
lactol 13 and sec-phenethyl alcohol 7, to provide lactam
acetal 14, (2) stereoselective elaboration to the key
intermediate 14, and (3) conversion to the final compound
via either intramolecular cyclization or intermolecular
coupling with triazolinone chloride 24. The intermediate secphenethyl
alcohol 7 was synthesized in 97% yield and 95%
e.e. (improved to 99% e.e. after recrystallization) via the
enantioselective borane reduction of ketone 6 in the presence
of 2 mol % of (S)-oxazaborolidine catalyst 8. The optimized
conditions involved the slow addition of ketone 6 to a solution containing catalyst 8 and BH3?¤PhNEt2 complex in
MTBE at ¨C10 to 0??C. The synthesis of lactam 12 was done
by reacting N-benzylethanolamine (9) with slight excess of
aqueous glyoxylic acid (10, 2.3 equivalent of 50% aqueous
solution) in refluxing THF. Adjustment of the solvent
composition from predominantly THF to predominantly
water resulted in the crystallization of lactam 12 directly
from 11 in the reaction mixture in 76% yield. Lactam 12
was treated with trifluoroacetic anhydride (1 equiv) to give
trifluoroacetate 13, which was reacted in situ with chiral
alcohol 7 in the presence of BF3?¤OEt2 to give, after workup,
a 55:45 mixture of the acetals 14 and 15 in 95-98% overall
yield. To obtain the desired diastereomer from the 55:45
mixture of 14 and 15, an optimized crystallization sequence
was developed. To a solution of the crude mixture in
heptane, 3,7-dimethyl-3-octanol (17) (0.9 equiv) was added,
cooled to ¨C10 to ¨C5??C and, after seeding the mixture with
pure 14, potassium salt of 3,7-dimethyl-3-octanol (16) (0.3
equiv) was added to initiate the crystallization-induced
epimerization of 15 to 14. After 5 hr, the mixture was
transformed into a 96:4 mixture from which 14 was isolated
in 83-85% yield and ￡?99% e.e. Under an optimized
condition, the lactam 1 4 was reacted with 4-
fluorophenylmagnesium bromide (18) (1.3 equiv) in THF at
ambient temperature followed by methanol quench and
addition of p-toluenesulfonic acid (1.8-2.2 equiv).
Immediate hydrogenation of this mixture in the presence of
5% Pd/C gave the addition product 19, which was isolated
as hydrochloride salt in 91% yield. Under these conditions,
no cleavage of the benzylic ether group was seen, even after
extended hydrogenation periods. Elaboration to aprepitant
(II) was done by the initial alkylation of 19 in the presence
of a base with amidrazone chloride 20, which was prepared
from chloroacetonitrile, to give the intermediate 21.
Thermolysis of 21 in toluene provided aprepitant (II) in
85% overall yield. Alternatively, the hydrochloride salt 19
has also been alkylated directly with the triazolinone
chloride 24 to give aprepitant (II).
