4-Aminobenzonitrile → 4-[(5-Bromo-4,6-dichloropyrimidin-2-yl)amino]benzonitrile

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Drugs of the Future 2005, 30(5): 462-468 discloses that 4-guanidinobenzonitrile is cyclized with diethylmalonate by means of sodium ethoxide to give 4-(4,6-dihydroxypyrimidine-2-yl-amino)-benzonitrile, which upon treatment with POCl3 yields the corresponding dichloro derivative. Further bromination with bromine and sodium bicarbonate in aqueous methanol affords 4-(5-bromo-4,6-dichloropyrimidin-2-ylamine)-benzonitrile, which on condensation with the sodium salt of cyano-2,6-dimethylphenolate in presence of N-methylpyrrolidone and dioxane gives 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]benzonitrile, followed by the aminolysis of the same intermediate yields Etravirine. It also discloses another process in which 5-bromo-2,4,6-trichloropyrimidine is reacted with 4-aminobenzonitrile in presence of diisopropylethylamine to give 4-(5-Bromo-4,6-dichloro-pyrimidin-2-ylamino)-benzonitrile, which is then reacted with 4-hydroxy-3,5-dimethylbenzonitrile to give 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]benzonitrile. The aminolysis of the same intermediate yields Etravirine.

Provenance & Evidence