Development of a Second-Generation, Highly Efficient Manufacturing Route for the HIV Integrase Inhibitor Raltegravir Potassium

A manufacturing route for the synthesis of raltegravir potassium 1 was developed via a thermal rearrangement of amidoxime DMAD adducts 6 to construct the key, highly functionalized hydroxypyrimidinone core 7. Utilizing this route 1 was prepared in nine linear chemical steps with 22% overall yield. A second-generation synthesis was subsequently developed that solved the key chemical, productivity, and environmental impact issues of the initial synthesis. Highlights of the new synthesis include a highly selective methylation, 3−4-fold higher productivity, and a 65% reduction of combined organic and aqueous waste produced. The efficient second-generation manufacturing route provides raltegravir potassium 1 in 35% overall yield.