Alacepril is an angiotensin-converting enzyme (ACE) inhibitor useful in the treatment of
essential and renal hypertension. Compared with captopril, alacepril is a weaker ACE
inhibitor in vino, yet clinically it has a longer duration of action and appears to be more
active due to an added component of norepinephrine antagonism.
N-Methylmorpholine (1.03 g) was added to a solution of 1-(D-3-acetylthio-2-
methylpropanoyl)-L-proline (2.65 g) in dry tetrahydrofuran (50 ml). The
resulting solution was stirred and cooled at -20° to -15°C. Phenyl
chloroformate (1.61 g) was added, and after 5 min, a solution of Lphenylalanine
t-butyl ester hydrochloride (2.4 g) and N-methylmorpholine
(1.03 g) in dry tetrahydrofuran (30 ml) was added. The mixture was stirred at
-20° to -15°C for 1 h and then at room temperature overnight.
After removal of insoluble materials by filtration, the filtrate was concentrated
under reduced pressure and the residue was dissolved in chloroform.
The chloroform solution was washed successively with 1 N sodium hydroxide,
water, 10% citric acid, and water, dried and concentrated under reduced
pressure. The residue was chromatographed on silica gel with chloroformmethanol
(99:1) to give 4.2 g the 1-(D-3-acetylthio-2-methylpropanoyl)-Lprolyl-
L-phenylalanine tert-butyl ester.
1-(D-3-Acetylthio-2-methylpropanoyl)-L-prolyl-L-phenylalanine tert-butyl ester (2.5 g) was dissolved in a mixture of anisole (18 ml) and trifluoroacetic acid
(37 ml). The solution was allowed to stand at room temperature for 1 h and
then concentrated to dryness under reduced pressure. The residue was
crystallized from diethyl ether. The 1-(D-3-acetylthio-2-methylpropanoyl)-Lprolyl-
L-phenylalanine was obtained (1.8 g), melting point 155°-156°C
(recrystallization from ethanol/n-hexane).
