Rapid On-Demand Synthesis of Lomustine under Continuous Flow Conditions

Lomustine, an important agent for treatment of brain tumors and Hodgkin's lymphoma, has been synthesized using continuous flow methodology. Desorption electrospray ionization mass spectrometry (DESI-MS) was used to quickly explore a large number of reaction conditions for one of the reaction steps and guide the efficient translation of optimized conditions to continuous lomustine production. Using only four inexpensive commercially available starting materials and a total residence time of 9 min, lomustine was prepared via a linear sequence of two chemical reactions performed separately in two telescoped flow reactors. Sequential offline extraction and filtration resulted in a 63% overall yield of pure lomustine at a production rate of 110 mg/h. The primary advantages of this approach are the rapid manufacture of lomustine with two telescoped steps to avoid isolation and purification of a labile intermediate and the mild conditions used in the nitrosylation step, thereby significantly increasing the purity and yield of this active pharmaceutical ingredient.