A Semi-Continuous Flow Platform for the Direct Preparation of Novel Cyclic Phosphate Monomers from Bulk Chemicals and Their Further Polymerization Toward Functional Polyphosphoesters

Polyphosphoesters have recently emerged as new materials for biomedical applications thanks to their biocompatibility and biodegradability properties that can be finely tuned by varying their functional side-chains linked to a pentavalent phosphorus. The preparation of polyphosphoesters frequently relies on the ring-opening polymerization of 5-membered cyclic phosphate monomers (CPMs), which are generally synthetized through a 3-step procedure. Starting from bulk chemicals the preparation of such monomers by a batch process is time-consuming, difficult to scale-up and involves safety concerns such as the uncontrolled generation of HCl by-product and the handling of sensitive and corrosive intermediates. To this end, we developed a semi-continuous flow platform allowing the direct preparation of CPMs starting from PCl3 and a 1,2-diol derivative without isolation of the intermediates. The first step involved the preparation of cyclic chlorophosphite derivatives by reacting a neat diol with a highly concentrated organic solution of PCl3 at room temperature with an associated residence time of 1 minute in a compact coil reactor. This procedure allowed to produce a wide range of novel cyclic chlorophosphites starting from various diols in moderate to high yields and with a daily productivity of up to ~500 g. The scope was also extended to thioalcohol, dithiol, aminoalcohol and diamine derivatives and the process was eventually adapted to a base-involving procedure allowing the conversion of more demanding substrates such as highly hindered pinacol-type diols. The next oxidation step toward cyclic chlorophosphates was directly concatenated with the upstream production of chlorophosphites in a single continuous flow system. A high pressure and an improved mixing capacity allowed to perform the oxidation using 4 equivalents of molecular oxygen in only 21 seconds of residence time at 65 °C toward a quantitative conversion while batch procedures usually require tens of hours or days of reaction time. A final functionalization of chlorophosphates toward various CPMs was subsequently integrated in a semi-continuous flow platform where the effluent coming from the oxidation step is directly reacted in a batch reactor. The system allowed to produce the CPMs directly from PCl3 in an extremely shortened time by a single process without purification and isolation of the sensitive intermediates while mitigating the hazards linked the corrosive derivatives produced. Among the novel monomers prepared, a bifunctional derivative was successfully copolymerized by ring-opening polymerization allowing the introduction of a typical alkoxy pendant group linked to a pentavalent phosphorus and an additional convertible chloromethyl function directly linked to a main-chain carbon. The introduction of such functionalizations opens new opportunities for the preparation of novel materials with various properties which could be time-dependent through the quick (P-linked group) or slower (C-linked group) degradation of the polyphosphoester linkages.