Читать книгу Routes to Essential Medicines - Peter J. Harrington - Страница 34

Cardiovascular Medicines/Antihypertensive Medicines

A dihydropyridine is often formed by Hantzsch Synthesis. The key step in the Hantzsch Synthesis is formation of a C3─C4 bond of the ring by Michael Addition of an enamine to an α,β‐unsaturated ketone or ester.

Discussion. While the (S)‐enantiomer is a thousand times more active than the (R)‐enantiomer, amlodipine is sold as the racemate. Racemic amlodipine is constructed in just four steps! The primary amine is formed using a Gabriel Synthesis. The final step is release of the primary amine from the phthalimide. The 1,4‐dihydropyridine is formed from methyl 3‐aminocrotonate and an enone by C─C bond formation (Michael Addition) followed by C─N bond formation to close the ring (Hantzsch Dihydropyridine Synthesis). The enone is formed by condensation of a β‐ketoester with 2‐chlorobenzaldehyde (Knoevenagel Condensation). The ether on C4 of the β‐ketoester is formed by chloride displacement from ethyl 4‐chloro‐3‐oxobutanoate by the alcohol of N‐(2‐hydroxyethyl)phthalimide (Williamson Ether Synthesis).