A Systematic Study towards the Synthesis, Isolation, and Recrystallization of Atovaquone, an Antimalarial Drug: A Sustainable Synthetic Pathway

In the present work, studies were conducted towards the synthesis of 2-[trans-4-(4-chlorophenyl) cyclohexyl]-3-hydroxy-1 ,4-naphthoquinone 5 with systematic reaction and recrystallization condition optimization to isolate 5 in high yield with better purity. Synthesis of 5 was done by the hydrolysis of 2-[trans-4-(4-chlorophenyl) cyclohexyl]-3-chloro-1, 4-naphthoquinone 4, which was isolated by the decarboxylative condensation of trans-4-(4-chlorophenyl) cyclohexanecarboxylic acid 3 with naphthoquinone moiety. After the hydrolysis of 4, isolation of crude 5 was done by the use of acetic acid instead of dilute hydrochloric acid, product 5 was isolated in good purity with very less polar impurities. The study extends to provide the polymorphic form I of 5 by the useof solvent combination for the recrystallization, prior artreports the use of a large volume of solvent for theisolation of polymorphic form I of 5. The use of a largevolume of solvent becomes a bottleneck for thecommercial synthesis of 5.