An alternative method differs from the first only in that a previously protected ieri-butyl ester of L-proline (22.7.6) undergoes acylation using 3-acetylthio-2-methylpropionic acid chloride (22.7.2). This is synthesized by the following scheme. L-proline is acylated by phenylacetyl chloride, giving N-benzyloxycarbonyl L-proline (22.7.7), which is reacted with isobutylene in order to obtain ieri-butyl ester of N-benzyloxycarbonyl—L-proline (22.7.8). This is reduced using hydrogen and a palladium-on-carbon catalyst, which gives the L-proline ieri-butyl ester 22.7.9. After acylation of the resulting 22.7.9 with the acid chloride 22.7.2, ieri-butyl ester of 1-(3-actylthio-2-methylpropanoyl)-L-proline (22.7.10)

is synthesized, from which the protecting groups are subsequently removed. The ester part of the molecule is hydrolyzed using trifluoroacetic acid, giving 1-(3-acetylthio-2-methyl-propanoyl)-L-proline (22.7.3), after separation of diastereomers of which, 1-(3-acetylthio-2-D-methylpropanoyl)-L-proline is isolated, which undergoes ammonolysis analogous to that mentioned earlier, forming captopril (22.7.4) [17-23].

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Captopril is the most studied of the angiotensin-converting enzyme inhibitors proposed as an antihypertensive drug. It blocks angiotensin-converting enzyme, which suppresses formation of angiotensin II and relieves its vasoconstricting effect on arterial and venous vessels. Overall vascular peripheral tension is reduced, which results in the lowering of arterial pressure.

It is used for hypertension and chronic cardiac insufficiency. Synonyms of this drug are capoten, capril, and others.

Enalapril: Enalapril, (S)-1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline (22.7.12), is synthesized by reacting the benzyl ester of L-alanyl-L-proline with the ethyl ester of 3-benzoylacrylic acid, which forms the product 22.7.11, the reduction of which with hydrogen using a Raney nickel catalyst removes the protective benzyl group, giving the desired enalapril (22.7.12) [24]. Alternative methods of syntheses have also been proposed [25-29].

22.7.11 22.7.12

Like captopril, enalapril selectively suppresses the rennin-angiotensin-aldosterone system, inhibits angiotensin-converting enzyme, and prevents conversion of angiotensin I into angiotensin II.

It is used for hypertension and chronic cardiac insufficiency. Synonyms of this drug are vasotec, tenitec, naprilene, and others.

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