Читать книгу Routes to Essential Medicines - Peter J. Harrington - Страница 36

Anti‐Infective Medicines/Antiprotozoal Medicines/Antimalarial Medicines/For Curative Treatment

A nitrogen substituent at C2 or C4 on a quinoline ring is often introduced by displacement of chloride. The substitution is facilitated by the quinoline ring nitrogen and can be further facilitated by an electron‐withdrawing group (NO ₂ , SO ₂ R, COOR, CN) on C3.

Discussion. A C─N bond is formed by displacement of a chloride at the quinoline 4‐position by nitrogen of the 4‐aminophenol.

4,7‐Dichloroquinoline is formed from 7‐chloro‐ 4‐hydroxyquinoline (7‐chloroquinolin‐4‐one). 7‐Chloro‐ 4‐hydroxyquinoline is formed by thermolysis/decarboxylation of the 4‐hydroxyquinoline‐3‐carboxylic acid. The carboxylic acid is formed by ester hydrolysis. The quinoline ring is formed by an intramolecular acylation at C6 of the 3‐chloroaniline. An enamine is formed by reaction of the enol ether of ethyl ethoxymethylenemalonate with 3‐chloroaniline (The four‐step sequence from 3‐chloroaniline to 7‐chloro‐4‐hydroxyquinoline is an example of the Gould–Jacobs Reaction).

The 4‐aminophenol is formed by hydrolysis of the acetanilide. Another essential medicine, 4‐acetamidophenol (para‐acetamol or acetaminophen) is alkylated by reaction with formaldehyde and N,N‐diethylamine (Betti Reaction).