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

作者：Ripin David H Brown^*; Teager David S; Fortunak Joseph; Basha Sheik Mahaboob; Bivins Nylea; Boddy Christopher N; Byrn Stephen; Catlin Kelly K; Houghton Stephen R; Jagadeesh S Tirumala; Kumar K Anesh; Melton Jack; Muneer Shaik; Rao L Nagaprasada; Rao R Venkateswara; Ray Puma Chandra; Reddy Nadia Gopal; Reddy Ravi Mallikarjuna; Shekar K Chandra; Silverton Tricia; Smith Daniel T; Stringham Rodger W; Subbaraju Gottumukkala V; Talley Frajovon; Williams Adrian

来源：Organic Process Research & Development, 2010, 14(5): 1194-1201.

DOI：10.1021/op1001337

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.

• 出版日期2010-10