Process Improvements for the Manufacture of Tenofovir Disoproxil Fumarate at Commercial Scale

Abstract

The three-step manufacturing process used in the synthesis of tenofovir disoproxil fumarate ( 1 ) was studied and optimized, leading to a more productive and robust process. The yield was improved from about 13% overall to 24%. Key process improvements identified included implementation of a telescoped process for the second stage that obviated the need for an extraction and solvent exchange, and significant optimization of the final reaction, including the beneficial effect of adding a quaternary ammonium salt to the alkylation reaction and development of a nonaqueous process for removal of NMP and triethylamine from the product mixture to decrease the level of decomposition of product during the isolation.