The Safe Use of Sodium Hydride on Scale: The Process Development of a Chloropyrimidine Displacement

Sodium hydride was found to be the best base for a displacement reaction on a chloropyrimidine. Due to the insolubility of sodium hydride in all solvents and high reactivity with atmospheric moisture, solutions dealing with the associated safety concerns on kilogram scale are described. The use of sodium hydride in premeasured dissolvable bag packaging (SecuBags), online process analytical technology (PAT) to monitor the hydrogen off-gas, and the development of analytical methods to monitor residual polymer and potential degradation products allowed for a successful scale-up and on-time delivery of a quality product.