The most significant improvement was achieved in the final step: the amide formation step. Initial conditions provided the desired amide via acid chloride formation and the consequent coupling with an amine in the presence of Triethyl amine. The reaction worked well, but (despite considerable experimentation) it never provided crude material with purity above 90%. In order to achieve the required purity of 98% one had to run it through a large silica gel column followed by several recrystallizations which resulted in big product losses. Clearly, the process required some process development before scale-up could be attempted. Brief, but focused investigation of alternative reaction conditions revealed that T3P (propane phosphonic acid anhydride) is the coupling reagent of choice for this transformation. Experimental design also included such features as using DMF as a solvent followed by water to quench. Simple product filtration and a single recrystallization furnished the desired compound in a higher overall yield with a crude purity of over 97%!
In brief, Seqens chemists were able to:
- Replace hazardous Thionyl Chloride with the non-hazardous T3P reagent
- Remove completely the Dichloromethane solvent from the process
- Simplify the reaction and the work-up conditions (run in DMF, pour in water and filter the desired crude product) which led to significant time saved during this step
- Replace the Silica gel column with a recrystallization step thus shortening the process time and eliminating a burdensome operation at larger scale
- Develop a process that was amenable for scale-up!