Routes to Essential Medicines. Peter J. Harrington

      Extended Discussion

      Draw the structures of the retrosynthetic analysis of one alternative route to 3‐aminopyrazine‐2‐carboxylic acid. Include the structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical or biochemical raw materials. List the pros and cons for both routes and select one route as the preferred route.

4‐Aminosalicylic Acid

      Anti‐Infective Medicines/Antibacterials/Antituberculosis Medicines

       A 2‐hydroxybenzoic acid is often formed by carboxylation of the phenol (Kolbe–Schmitt Reaction).

Discussion. 4‐Aminosalicylic acid is formed from 3‐aminophenol and carbon dioxide (Kolbe–Schmitt Reaction) (Draw the structure of one side product formed in this reaction. How is pure 4‐aminosalicylic acid isolated from the product mixture?).

      Extended Discussion

      A preferred route to 3‐aminophenol is from benzene via resorcinol. Draw the structures of a retrosynthetic analysis of one alternative route to 3‐aminophenol. 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.

Amiodarone

      Cardiovascular Medicines/Antihypertensive Medicines

       An aromatic ketone is often formed by Friedel–Crafts Acylation.

      Discussion. The ether is formed in the final step by displacement of the chloride of 2‐chloro‐N,N‐diethylethanamine by the phenol (Williamson Ether Synthesis).

The phenol is iodinated in both ortho positions. The phenol is formed by demethylation of the ether. The ketone is formed by acylation of 2‐butyl‐2,3‐benzofuran with 4‐methoxybenzoyl chloride (Friedel–Crafts Acylation). 4‐Methoxybenzoyl chloride is formed from para‐anisic acid.

      2‐Butylbenzofuran is formed by rearrangement of the chlorohydrin. The tertiary alcohol of the chlorohydrin is formed by addition of butylmagnesium chloride to the ketone (Grignard Reaction). Butylmagnesium chloride is formed from 1‐chlorobutane. 2‐Chloro‐2′‐hydroxyacetophenone is formed from phenol and chloroacetonitrile (Sugasawa Reaction).

      Extended Discussion

      Draw the structures of the retrosynthetic analysis of one alternative route to 2‐butylbenzofuran. Include the structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical or biochemical raw materials. List the pros and cons for both routes and select one route as the preferred route.

Amitriptyline

      Medicines for Pain and Palliative Care/Medicines for Other Common Symptoms in Palliative Care

      Medicines for Mental and Behavioral Disorders/Medicines Used in Mood Disorders/Medicines Used in Depressive Disorders

       An alkene conjugated to two aromatic rings is often formed by dehydration of an alcohol.

      Discussion. The alkene is formed in the final step by dehydration of the tertiary alcohol. The tertiary alcohol is formed by addition of the alkylmagnesium chloride to dibenzosuberone (Grignard Reaction). The alkylmagnesium chloride is formed from 3‐chloro‐N,N‐dimethylpropan‐1‐amine. Dibenzosuberone is formed by cyclization of 2‐phenethylbenzoic acid (Friedel–Crafts Acylation). 2‐Phenethylbenzoic acid is formed by reduction of benzalphthalide. Benzalphthalide is formed from phthalic anhydride and phenylacetic acid.

      Extended Discussion

      Dibenzosuberone is also formed from 2‐bromobenzyl bromide and carbon dioxide (Parham Cyclization). List the pros and cons for the two dibenzosuberone routes and select one route as the preferred route.

Amlodipine

      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).

      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