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Chemical and Biochemical Engineering Quarterly, Vol. 32 No. 2, 2018.

Original scientific paper

https://doi.org/10.15255/CABEQ.2017.1200

Process Optimization and DOE Application in the Synthesis of Rociletinib Intermediate

S. Kapić ; Pliva Croatia LTD, TAPI Croatia, TAPI R&D, Prilaz baruna Filipovića 25, 10000 Zagreb, Croatia
I. Nekola ; Pliva Croatia LTD, TAPI Croatia, TAPI R&D, Prilaz baruna Filipovića 25, 10000 Zagreb, Croatia
F. Jović orcid id orcid.org/0000-0001-7666-5680 ; Pliva Croatia LTD, TAPI Croatia, TAPI R&D, Prilaz baruna Filipovića 25, 10000 Zagreb, Croatia
M. Mihovilović ; Pliva Croatia LTD, TAPI Croatia, TAPI R&D, Prilaz baruna Filipovića 25, 10000 Zagreb, Croatia

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Abstract

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).







This work is licensed under a Creative Commons Attribution 4.0 International License.

Keywords

organic synthesis; Quality by Design (QbD); statistical DoE

Hrčak ID:

203167

URI

https://hrcak.srce.hr/203167

Publication date:

5.7.2018.

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