Читать книгу Routes to Essential Medicines - Peter J. Harrington - Страница 64

Anti‐infective Medicines/Antibacterials/Antituberculosis Medicines

A tertiary alcohol is often formed by addition of an organometallic reagent RLi or RMX (M = Mg, Zn, X = Cl, Br, I) to a ketone.

Discussion. Bedaquiline, the (1R,2S)‐enantiomer, is separated from a 1 : 1 mixture of (1R,2S)‐ and (1S,2R)‐enantiomers by resolution in the final step. (Draw the structures of the chiral acids used for the resolution. What is the yield of bedaquiline for the two‐step resolution process associated with each chiral acid?) The addition of an alkyllithium to a ketone results in a mixture of four stereoisomers. The undesired (1S,2S)‐ and (1R,2R)‐enantiomers are separated from the mixture by crystallization. The desired (1R,2S)‐ and (1S,2R)‐enantiomers are then isolated by crystallization. (What is the highest diastereoselectivity for the addition reaction? What reagents and reaction conditions are associated with the highest diastereoselectivity?) The alkyllithium is formed from 3‐benzyl‐6‐bromo‐2‐methoxyquinoline. The β–dimethylamino ketone is formed from 1‐acetonaphthone, formaldehyde, and dimethylamine (Mannich Reaction).

The 2‐methoxyquinoline is formed from the 2‐chloroquinoline by chloride displacement. 3‐Benzyl‐6‐bromo‐2‐chloroquinoline is formed from N‐(4‐bromophenyl)‐3‐phenylpropanamide, and N,N‐dimethylformamide (Vilsmeier–Haack Reaction). N‐(4‐Bromophenyl)‐3‐phenylpropanamide is formed from 4‐bromoaniline and the acid chloride. The acid chloride is formed from 3‐phenylpropanoic acid (dihydrocinnamic acid).