ChEBI: A benzazepine that is benazeprilat in which the carboxy group of the 2-amino-4-phenylbutanoic acid moiety has been converted to the corresponding ethyl ester. It is used (generally as its hydrochloride salt) as a prodrug for the angiotensin-converting enzy
e inhibitor benazeprilat in the treatment of hypertension and heart failure.
The synthesis of benzazepril based on a benzazepinone. It started by
chlorination of lactam - 1,2,4,5-tetrahydrobenzo[b]azepin-2-one to the
dichloro derivative 3,3-dichloro-1,2,4,5-tetrahydrobenzo[b]azepin-2-one.
Catalytic reduction removed one of the gem chloro substituents to give 3-
chloro-1,2,4,5-tetrahydrobenzo[b]azepin-2-one; the halogen was then
displaced with sodium azide to give 3-azido-1,3,4,5-
tetrahydrobenzo[b]azepin-2-one. Alkylation of the amide with ethyl
bromoacetate in the presence of base yielded the ester (3-azido-2-oxo-
2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)acetic acid ethyl ester. Hydrogenation
then converted the azide to an amino group to give 3-amino-2-oxo-2,3,4,5-
tetrahydrobenzo[b]azepin-1-yl)acetic acid ethyl ester. It was then resolved by
classical salt formation and crystallization. Saponification of the S enantiomer
- S-(3-amino-2-oxo-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)acetic acid ethyl
ester with sodium hydroxide afforded (3-amino-2-oxo-2,3,4,5-
tetrahydrobenzo[b]azepin-1-yl)acetic acid. Reductive alkylation of it with 2-
oxo-4-phenylbutyric acid ethyl ester and sodium cyanoborohydride gave the
desired product as 70:30 mixture of diastereoisomers. The isolation of the
predominant isomer gave benazepril. The epimerization occurred thermally
and therefore required a sufficiently high temperature. The high temperature
condition can be achieved by either using a high boiling-point solvent such as
xylene or by heating the reaction mixture under pressure to increase its
boiling-point temperature. Good results can be achieved in both polar and
non-polar solvent systems. For example, both p-xylene and ethylene glycolwater
systems are found suitable to conduct this process. The crude product
acid 3-[(1-ethoxycarbonyl)-3-phenyl-(1S)-propylamino]-2,3,4,5-tetrahydro-2-
oxo-1H-1-benzazepine-1-acetic acid was heated to reflux temperature for 30
hours in p-xylene. The mixture was cooled down to room temperature.
Solvent removal resulted in a solid, which was then dried at reduced pressure
to give a 98:2 diasteriomeric mixture as determined by HPLC, MP: 287°-
290°C. IR and 1H-NMR spectrum analysis. was confirmed the structure of
product.
This ACE-directed pro-drug (FWfree-acid = 424.50 g/mol; CAS 86541-75-5), also known as 3-((1-(ethoxycarbonyl)-3-phenylpropyl)amino)-2,3,4,5- tetrahydro-2-oxo-(S-(R*,R*))-1H-1-benzazepine-1-acetic acid, Lotensin and CGS 14824A, is rapidly metabolized to its diacid benazeprilat (CGS 14831; FWfree-diacid = 396.44 g/mol), the latter a potent, long-acting inhibitor of peptidyl-dipeptidase A, or angiotensin I-converting enzyme, IC50 = 1.7 nM. Lotensin is used to treat hypertension, congestive heart failure, and chronic renal failure. The antihypertensive effects of benazepril begin as early as 30 min after a single dose, and those effects during consecutive dosing are also sustained for 24 h with a lesser diurnal variation in blood pressure
