Translating solid state organic synthesis from a mixer mill to a continuous twin screw extruder

Cao, Qun; Howard, Joseph L.; Crawford, Deborah E.; James, Stuart L.; Browne, Duncan L.

doi:10.1039/c8gc02036a

Cited by 67 publications

(38 citation statements)

References 43 publications

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“…10,11 Furthermore, we see no reason why the herein presented reaction sequences should not be compatible with industrial-scale roller mills and/or continuous mechanochemical manufacture via twin screw extrusion, 56 as has recently been done in the context of small organic molecule targets and metal-organic frameworks. 57,58 Finally, we note that the ability to obtain functional oligonucleotide structures without a bulk solvent might suggest the potential role of solid-state transformations in the early stages of chemical evolution, as recently highlighted by Trapp and co-workers 59 , and Hernández and co-workers 60 .…”

Section: Scheme 5 Synthesis Phosphorothioate Dimers Via Phosphoramidsupporting

confidence: 52%

Mechanochemical Synthesis of Short DNA Fragments

Thorpe

O'Reilly

Friščić

et al. 2020

Chemistry A European J

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We report the general and rapid synthesis of short DNA fragments of controllable sequence and length using multi-step, one-pot mechanochemical reactions, without bulk solvent or the need to isolate intermediates. We demonstrate, for the first time, the multi-step ball milling synthesis of DNA dimers and trimers via phosphoramidite and H-phosphonate chemistries. The use of mechanochemistry allowed for coupling of phosphoramidite monomers to the 5'-hydroxyl group of nucleosides, iodine/water oxidation of the resulting phosphite triester linkage, and removal of the 5'-dimethoxy (DMTr) protecting group in situ and in good yields (up to 60% over three steps) to produce DNA dimers in one-pot manner. Sulphurization of phosphite triester linkages was possible using elemental sulfur yielding the corresponding phosphorothioate DNA dimers in good yield (up to 80% over two steps). By using H-phosphonate chemistry under milling conditions, it was possible to couple, protect the H-phosphonate linkage, and remove the 5'-DMTr protecting group in situ, enabling an one-pot process with good yields comparable to existing solvent-based procedures (up to 65% over three steps, or ca. 87% per step). This work opens the door to creation of solvent-free methodologies for the assembly of complex DNA and RNA therapeutics. File list (2) download file view on ChemRxiv ChemRxiv_manuscript.pdf (537.19 KiB) download file view on ChemRxiv SI_ChemRxiv.pdf (1.50 MiB)

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Section: Scheme 5 Synthesis Phosphorothioate Dimers Via Phosphoramidsupporting

confidence: 52%

Mechanochemical Synthesis of Short DNA Fragments

Thorpe

O'Reilly

Friščić

et al. 2020

Chemistry A European J

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“…This synthetic route relies on the generation of reactive sites in polymer chains and chemical reaction that is induced by the direct absorption of mechanical energy . In contrast to batch process using ball milling, the solid‐state co‐extrusion provides fine temperature control and facilitates the scale‐up for industrial purposes . Two sets of copolymers were prepared according to the composition given in Table 1 .…”

Section: Methodsmentioning

confidence: 99%

Chitosan‐g‐Polyester Microspheres: Effect of Length and Composition of Grafted Chains

Демина

Sevrin

Kapchiekue

et al. 2019

Macro Materials & Eng

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Hydrophobic segments made of oligo(l,l‐ or d,l‐lactides) or poly(l,l‐lactide) are grafted onto chitosan backbone in order to use their amphiphilic behavior to prepare degradable microcarriers intended to be used for tissue engineering. Hydrophilic–lipophilic balance of these copolymers is adjusted playing on the respective length of their hydrophilic and hydrophobic moieties. Thanks to their self‐emulsifying properties, these graft copolymers are processed into microspheres in the absence of hydrophilic emulsifier commonly added in the aqueous phase of the oil/water emulsion. The copolymers containing amorphous oligolactide segments of medium length are demonstrated to be the most effective ones for microparticle fabrication. The microparticles are characterized using SEM, EDX, and FTIR. The reactivity of amine group is demonstrated using fluorescein isothiocyanate staining. The resulting microspheres disclose a porous core and a shell enriched by the hydrophilic polysaccharide moieties. Stabilization of the oil/water interface during the microsphere fabrication, total yield, size distribution, and microparticle surface morphology are mainly affected by the macromolecular features of the copolymers.

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“…Relatively low reaction temperatures (150 °C or 180 °C) had to be used to prevent the evaporation of starting materials (aniline and 3-ethyl aniline), which might have led to the poor yields of 18 (23%) and 19 (33%). For aniline reactants bearing various ring substituents such as -OMe, -OEt, -NO2, -Br, and phenyldiazenyl, fair to very good yields of PDIs (20)(21)(22)(24)(25)(26)(27) could be obtained. These products include three commercial pigments known as "Pigment Red 123, 178 and 190".…”

Section: Communicationmentioning

confidence: 99%

“…[13] Twin screw extrusion (TSE), widely used for blending and processing in the pharmaceutical, [14] polymer, [15] and food industries, [16] is now being explored for scalable, continuous mechanochemical synthesis. Example products demonstrated include metal organic frameworks (MOFs), [17] deep eutectic solvents (DESs), [18] metal complexes, [19] condensation products, [20] as well as chemoenzymatic oligomerisation, [21] fluorination reactions [22] and multi-component reactions (MCR). [23] Although the broad application of reactive extrusion to the diverse types of chemical synthesis is still in its infancy, it was selected in 2019 by IUPAC as one of the ten chemical innovations that will change the world.…”

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confidence: 99%

Greener Dye Synthesis: Continuous, Solvent‐Free Synthesis of Commodity Perylene Diimides by Twin‐Screw Extrusion

et al. 2020

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A continuous, scalable, and solvent‐free method for the synthesis of various naphthalic imides and perylene diimides (PDIs) using twin‐screw extrusion (TSE) is reported. Using TSE, naphthalic imides were obtained quantitatively without the need for excess amine reactant or product purification. With good functional‐group tolerance, alkyl and benzyl amine derived PDIs (incl. commercial dyes) were obtained in 50–99 % yield. Use of K2CO3, enabled synthesis of more difficult aniline‐derived PDIs. Furthermore, an automated continuous TSE process for Pigments Black 31 and 32 is demonstrated, with a throughput rate of about 1500 g day−1, corresponding to a space time yield of about 30×103 kg m−3 day−1, which is 1–2 orders of magnitude greater than for solvent‐based batch methods. These methods provide substantial waste reductions and improved efficiency compared to conventional solvent‐based methods.

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Translating solid state organic synthesis from a mixer mill to a continuous twin screw extruder

Abstract: A study on the translation of a solid-state fluorination reaction from a mechanochemical mixer-mill to a continuous twin-screw extruder is discussed herein.

Cited by 67 publications

References 43 publications

Mechanochemical Synthesis of Short DNA Fragments

Mechanochemical Synthesis of Short DNA Fragments

Chitosan‐g‐Polyester Microspheres: Effect of Length and Composition of Grafted Chains

Greener Dye Synthesis: Continuous, Solvent‐Free Synthesis of Commodity Perylene Diimides by Twin‐Screw Extrusion

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