The Development of Scalable and Efficient Methods for the Preparation of Dicyclopropylamine HCl Salt

The unique chemical properties of dicyclopropylamine (DCPA) 1 render its synthesis a challenge for process chemists despite its structural simplicity. Chemical instability and high aqueous solubility further complicate the process for DCPA's preparation, isolation, and purification. In this note we describe the development of three strategies for the synthesis of DCPA 1, all of which provide material with excellent purity profiles (>99 GC area %). Our final route provides significant improvements in terms of cost-efficiency, safety, scalability, and impurity content. Highlights of this strategy include two chemo-selective, Pd-catalyzed, deallylation reactions and an efficient reductive amination protocol. To circumvent the chemical instability of DCPA 1, an innovative isolation procedure was developed which reliably reduced the amount of Pd residue to less than 20 ppm. Following this protocol, impurities such as N-propylcyclopropyl-, mono-cyclopropyl-, and N-ethyl-cyclopropylamines (3, 4, and 17) were minimized to 0.06, not detectable, and 0.02%, respectively.