Manufacturing Process
The racemic 2-azabicyclo[2.2.1]heptane-3-carboxylic acid was obtained by
alkaline hydrolysis (24 h reflux in 4 N NaOH/MeOH 3/1; yield 78%) of the 4-
phenyl-2,4-diazatricyclo[5.2.1.0 2,6 ]decane-3,5-dione-(1)- hydantoin obtained according to Ben Ishai. Starting from 2-azabicyclo[2.2.1]heptane-3-carboxylic
acid, the (-)-tartaric acid salt of it crystallized from EtOH (yield 87 %) was
obtained from this salt by ion-exchange on Dowex 50 WX 8 (H+ form) and
elution with 0.3 N NaOH. (yield 98 %) (GLC after esterification with CH 2 N 2
and amidation with (-)-camphanyl chloride). 2-Azabicyclo[2.2.1]heptane-3-
carboxylic acid was esterified to benzyl ester with benzyl alcohol in toluene
using p-toluenesulfonic acid as catalyst. The second chiral intermediate - 4-
phenylbutyric acid ethyl ester; compound with 2-amino-propionic acid
(alanine) was prepared according to Kaltenbronn S. It was coupled with the
above prepared benzyl ester using dicyclohexylcarbodiimideoxybenztriasole
(DCC-HOBT)-Et 3 N in DMF, thus producing the benxyl ester 2-[2-(1-
ethoxycarbonyl-3-phenylpropylamino)propionyl]-2-azabicyclo[2.2.1]heptane-
3-carboxylic acid benzyl ester (yield 97 %). The high yield of this coupling is
probably due to the high reactivity of the rigid bulky nucleophile 2-[2-(1-
ethoxycarbonyl-3-phenylpropylamino)propionyl]-2-azabicyclo[2.2.1]heptane-
3-carboxylic acid benzyl ester and to the low reactivity of the sterically
hindered secondary amine intermediate - 4-phenylbutyric acid ethyl ester;
compound with 2-amino-propionic acid, so that the formation of by-products
(racemates, diketopiperazine from two acylurea by addition of acid on DCC)
was not observed (TLC). Benzyl ester was submitted to hydrogenolysis on
palladium charcoal in EtOH at room temperature (yield 98%). It crystallized
as its t-butylamine salt from ether and finally transformed to more stable
hydrochloride - zabicipril (yield 95 %). Careful saponification of t-butylamine
salt with 1 N NaOH at room temperature gave crude zabiciprilate, which was
purified by ion-exchange on Dowex 50 WX 8 (H + form) and elution with
water/pyridine 9:1, then crystallization from 2-propanol (yield 80%).
Structure of all described compounds is confirmed with NMR spectrum and X-
Ray crystal structure analysis.
