CRIXIVAN® (Indinavir Sulfate), a critical HIV protease inhibitor developed at Merck, played a vital role in the global fight against HIV/AIDS. Due to the virus’s ability to cross the blood-brain barrier, maintaining effective drug levels throughout the body was a significant challenge. As a result, CRIXIVAN had to be administered in large daily doses—up to 3 grams per person—to ensure adequate therapeutic coverage, including the central nervous system.

Given the high daily dosage and the need to produce CRIXIVAN on a multi-ton scale, the synthesis had to be exceptionally efficient. This requirement led to the implementation of a convergent synthetic strategy, which minimized reaction steps and maximized yield, making large-scale production more feasible. Additionally, cost-effectiveness was a crucial factor, as the drug needed to be affordable for distribution in poorer, resource-limited countries where the HIV/AIDS epidemic was most severe. The synthesis was designed not only to be highly efficient but also economical, ensuring global accessibility and affordability.

The retrosynthesis of Crixivan centers around two enantiopure building blocks, an epoxide fragment and an (-)-cis-aminoindanol.