An Improved and Enantioselective Preparation of the Telaprevir Bicyclic [3.3.0] Proline Intermediate and Reuse of Unwanted Enantiomer

An improved, concise, and efficient preparation of the telaprevir bicyclic [3.3.0] proline intermediate is presented. The key steps, control points, and the whole process are optimized. The synthesis of racemic intermediate was accomplished in five steps in above 56% overall yield up to 100 g scale with only some simple separations and treatments in the whole process. The new and crucial chiral resolution of the proline intermediate was systematically studied, and the target chiral intermediate was obtained in acceptable yield (30%) and excellent ee value (>99% ee) by a simple washing. The cost of the target chiral intermediate and wastes of the whole process were at least doubly reduced after the effective reuse of the unwanted chiral amino acid by successful decarboxylation.