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Critical step of Rociletinib synthesis, regioselective nucleophilic aromatic substitution of C-2 chlorine at pyrimidine molecule 3 with amine 2, was optimised by implementation of pre-DoE screening and DoE-based algorithms. The synthesis reaction was developed and optimised by following a quality by design (QbD) approach, whereby a control strategy was developed for enhanced level of quality assurance. Optimisation of three main parameters (volume of solvent mixture, solvent ratio, and NaOAc quantity) resulted with good isomer ratio of over 8:1 with respect to desired C-2 isomer 4 with minimum of di-substituted impurity 6. The crude product was, however, contaminated with Zn-based inorganics and had to be recrystallized to achieve acceptable purity and assay. Interaction of process variables and their corresponding effects on the percent conversion of maleic acid were discussed. Consistency of statistical model was verified by analysis of variance (ANOVA). API quality specifications (purity, impurity levels) are described across the modelling of process space, which was defined through quality target specifications (conversion NLT 70 %; Product Compound 4 NLT 50 %, Impurity 5 NMT 20 %, and Impurity 6 NMT 0.5).

Process Optimization and DOE Application in the Synthesis of Rociletinib Intermediate