A Semi-Continuous Flow Platform for the Direct Preparation of Novel Cyclic Phosphate Monomers from Bulk Chemicals and Their Further Polymerization Toward Functional Polyphosphoesters
03 мая 2021 года
12:58
A Semi-Continuous Flow Platform for the Direct Preparation of Novel Cyclic Phosphate Monomers from Bulk Chemicals and Their Further Polymerization Toward Functional Polyphosphoesters
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Title: A Semi-Continuous Flow Platform for the Direct Preparation of Novel Cyclic Phosphate Monomers from Bulk Chemicals and Their Further Polymerization Toward Functional Polyphosphoesters
Author, co-author: Morodo Martinez, Romain; Riva, Raphaël; Jérôme, Christine; Monbaliu, Jean-Christophe
Abstract: 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.

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A Semi-Continuous Flow Platform for the Direct Preparation of Novel Cyclic Phosphate Monomers from Bulk Chemicals and Their Further Polymerization Toward Functional Polyphosphoesters
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[en] 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.
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Автоматическая система мониторинга и отбора информации
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