Routes to Essential Medicines. Peter J. Harrington

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       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).

      Extended Discussion

      List the amine protecting groups that have been used in alternative syntheses of amlodipine. List the conditions used and amlodipine yields obtained in deprotection of each group in the final step. Why is the phthalimide group preferred?

Amodiaquine

      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).

      Extended Discussion

      Draw the structures of the retrosynthetic analysis of an alternative route from 3‐chloroaniline to 7‐chloro‐4‐hydroxyquinoline utilizing a Conrad–Limpach Reaction. Include the structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical or biochemical raw materials. List pros and cons for the two routes and select one route as the preferred route.

Amoxicillin

      Anti‐Infective Medicines/Antibacterials/Beta‐Lactam Medicines

       Penicillins are produced by fermentation or are semisynthetic. A semisynthetic penicillin is often formed by acylation of the amine of 6‐aminopenicillanic acid (6‐APA). 6‐APA is produced from penicillin G (benzylpenicillin) by enzyme‐mediated hydrolysis of the side‐chain amide.

      Discussion. Amoxicillin is a semisynthetic penicillin. The final step is СКАЧАТЬ