Zofenopril

Originator

Zofenopril Calcium,ZYF Pharm Chemical

The Uses of Zofenopril

Zofenopril-d5 is intended for use as an internal standard for the quantification of Zofenopril by GC- or LC-mass spectrometry.

What are the applications of Application

Zofenopril-d5 Calcium Salt is a compound that is de-esterified into the active inhibitor, Zefenoprilat

Background

Zofenopril is employed as both a cardioprotective and anti-hypertensive agent. It is an angiotensin-converting enzyme (ACE) inhibitor.

Definition

ChEBI: A proline derivative that is 4-(phenylsulfanyl)-L-proline in which the amine proton is replaced by a (2S)-3-(benzoylsulfanyl)-2-methylpropanoyl group. A prodrug for zofenoprilat.

Manufacturing Process

9.9 g (0.031 mole) of cis-4-phenylthio-L-proline is suspended in 100 ml of water (pH 5.6) and the pH is adjusted to 10.2 by the addition of about 20 ml of 10% sodium bicarbonate to provide a clear solution. The pH is then adjusted to 9.5 by the addition of about 4.5 ml of concentrated HCl. The solution is kept at 30°C while 8.1 g (0.033 mole) of (D)-3-(benzoylthio)-2- methylpropanoic acid chloride in 30 ml of toluene is added simultaneously with 100 ml of 10% sodium bicarbonate to keep the pH at 9.3. After about 1/4 of the acid chloride is added, a slimy precipitate begins to form which persists throughout the reaction. After stirring the reaction mixture at pH 9.3 for 2.5 h, it is made strongly acidic by adding 20% HCl in the presence of ethyl acetate. The aqueous layer is extracted twice with 350 ml portions of ethyl acetate and the combined organic layers are washed with 300 ml of saturated brine and dried (MgSO 4 ). The solvent is removed to yield 11.8 g of foamy solid cis-1-[D-3-(benzoylthyo)-2-methyl-1-oxopropyl]-4-(phenylthio)-L-proline hydrochloride.
To a solution of this cis-1-[D-3-(benzoylthyo)-2-methyl-1-oxopropyl]-4- (phenylthio)-L-proline hydrochloride 11.8 g (0.027 mole) in 70 ml of acetonitrile there is added about 6.0 g of dicyclohexylamine in 25 ml of ether. A white crystalline precipitate forms immediately. After standing overnight in the cold room, the solid is filtered and washed with ether to yield (cis)-1-[D- 3-(benzoylthio)-2-methyl-1-oxopropyl]-4-(phenylthio)-L-proline, dicyclohexylamine salt (1:1).
he slightly moist (cis)-1-[D-3-(benzoylthio)-2-methyl-1-oxopropyl]-4- (phenylthio)-L-proline dicyclohexylamine salt is stirred for 2.5 h in a mixture of 300 ml of ethyl acetate and 200 ml of 10% potassium bisulfate. Two clear layers form. The aqueous layer is extracted with two 200 ml portions of ethyl acetate and the combined organic layers are dried (MgSO 4 ). The solvent is removed to yield 10.1 g of foamy solid (cis)-1-[D-3-(benzoylthio)-2-methyl-1- oxopropyl]-4-(phenylthio)-L-proline; melting point 42-44°C.
In practice it is usually used as calcium salt (2:1).

brand name

Zoprace (Bristol-Myers Squibb).

Therapeutic Function

Antihypertensive

Synthesis Reference(s)

The Journal of Organic Chemistry, 33, p. 1675, 1968 DOI: 10.1021/jo01268a091

Metabolism

Not Available