Читать книгу Routes to Essential Medicines - Peter J. Harrington - Страница 10

Antiviral Medicines/Antiretrovirals/Nucleoside or Nucleotide Reverse Transcriptase Inhibitors

When two chiral carbons are separated by one or more atoms, disconnections often lead back to an intermediate with the two chiral carbons next to each other and formed in the same reaction.

Discussion. Cyclopropanamine is introduced by chloride displacement in the final step (the chloropurine partner is also used to make the AIDS drug carbovir.) The imidazole ring of the purine is formed from the formamide (Traube Purine Synthesis). A C─N bond is formed by displacement of chloride from the symmetrical dichloropyrimidine by the amine of (1S,4R)‐4‐amino‐2‐cyclopentene‐1‐methanol.

The 2,5‐diaminopyrimidine 5‐formamide is formed from the 2,5‐diaminopyrimidine and formic acid. 2,5‐Diamino‐4,6‐dichloropyrimidine is formed from 2,5‐diamino‐4,6‐dihydroxypyrimidine. 2,5‐Diamino‐4,6‐dihydroxypyrimidine is formed by hydrolysis of the 5‐acetamide. 5‐Acetamido‐2‐amino‐4,6‐dihydroxypyrimidine ring is formed from guanidine and diethyl acetamidomalonate (Pinner Pyrimidine Synthesis).

(1S,4R)‐4‐Amino‐2‐cyclopentene‐1‐methanol and the (1R,4S)‐enantiomer are separated by resolution. The amino alcohols are formed by reduction of the amides (Vince Lactam). The amides are formed by displacement of methanesulfinate by hydroxide.

The 2‐azabicyclo[2.2.1]hepta‐2,5‐dienes are formed by [4 + 2]‐cycloaddition of cyclopentadiene with methanesulfonyl cyanide (Diels–Alder Cycloaddition). Methanesulfonyl cyanide is formed from sodium methanesulfinate and cyanogen chloride. Sodium methanesulfinate is formed by reduction of methanesulfonyl chloride.