Accelerating the end-to-end production of cyclic phosphate monomers with modular flow chemistry

R. Morodo, R. Riva, N.M.S. van den Akker, D.G.M. Molin, C. Jerome, J.C.M. Monbaliu*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The biocompatibility, tunable degradability and broad functionalities of polyphosphoesters and their potential for biomedical applications have stimulated a renewed interest from Chemistry, Medicinal Chemistry and Polymer Sciences. Commercial applications of polyphosphoesters as biomaterials are still hampered because of the time and resource-intensive sourcing of their corresponding monomers, in addition to the corrosive and sensitive nature of their intermediates and by-products. Here, we present a groundbreaking challenge for sourcing the corresponding cyclic phosphate monomers by a different approach. This approach relies on the use of continuous flow technologies to intensify the end-to-end preparation of cyclic phosphate monomers with a semi-continuous modular flow platform. The applied flow technology mitigates both safety and instability issues related to the more classical production of cyclic phosphate monomers. The first flow module allows safe synthesis of a library of cyclic chlorophosphite building blocks and features in-line P-31 NMR real-time monitoring. After optimization on the microfluidic scale, this first module is successfully transposed toward mesofluidic scale with a daily throughput of 1.88 kg. Downstream of the first module, a second module is present, allowing the quantitative conversion of cyclic chlorophosphites with molecular oxygen toward chlorophosphate derivatives within seconds. The two modules are concatenable with a downstream semi-batch quench of intermediate chlorophosphate with alcohols, hence affording the corresponding cyclic phosphate monomers. Such a continuous flow setup provides considerable unprecedented advantages to safely and efficiently synthesize a library of versatile high value-added cyclic phosphate monomers at large scale. These freshly produced monomers can be successfully (co)polymerized, using either batch or flow protocols, into well-defined polyphosphoesters with assessed thermal properties and cytotoxicity.
Original languageEnglish
Pages (from-to)10699-10706
Number of pages9
JournalChemical Science
Volume13
Issue number36
DOIs
Publication statusPublished - 21 Sept 2022

Keywords

  • POLY(ETHYLENE GLYCOL)
  • BLOCK-COPOLYMERS
  • IN-VITRO
  • POLYPHOSPHOESTER
  • DELIVERY
  • PLATFORM
  • ACID
  • DRUG
  • FUNCTIONALIZATION
  • POLYMERIZATION

Fingerprint

Dive into the research topics of 'Accelerating the end-to-end production of cyclic phosphate monomers with modular flow chemistry'. Together they form a unique fingerprint.

Cite this