Iterative synthesis of monodisperse PEG homostars and linear heterobifunctional PEG

Székely, György; Schaepertoens, Marc; Gaffney, Piers R. J.; Livingston, Andrew G.

doi:10.1039/c3py01367g

Cited by 40 publications

(48 citation statements)

References 12 publications

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“…Also, further improvements in yield and purity can be made by parallel tuning of the size of the soluble support and the membrane separation performance, to make the purification more efficient. Notably, monodisperse PEG homostars have been prepared up to 8,000 Da 30,41 , and the membrane separation performance can be roughly controlled using polymer fraction in the dope and the solvent to co-solvent ratio 42 . It should be noted that even though a bigger soluble support may exhibit higher rejection, it also decreases the oligo loading (mmols.g -1 of PEG support) while increasing the solution viscosity.…”

Section: Further Discussion: Advantages and Current Challengesmentioning

confidence: 99%

“…An octagol homostar (1224 Da) was chosen as the monodisperse support 30 for this work because once the second residue (cytidine in the present work) is attached, the size of the dinucleotidyl PEG homostar conjugate has already become large enough (2245 Da) to be highly rejected by the PBI 17DBX membrane (>99%). In addition, as the oligo chains grow, the rejection is expected to approach 100%.…”

Section: Justification For Using a Branched Peg Homostar Supportmentioning

confidence: 99%

“…The methods are summarized briefly below. The preparation of the monodisperse octagol homostar 1 synthesis support was adapted from the literature synthesis 30 . The term homostar used in this manuscript refers to the branched polymer support having three arms with a site on the end of each on which an oligo is grown.…”

Section: Overall Process and Oligonucleotide Synthesis Chemistrymentioning

confidence: 99%

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Organic Solvent Nanofiltration (OSN): A New Technology Platform for Liquid-Phase Oligonucleotide Synthesis (LPOS)

Kim

Gaffney

Valtcheva

et al. 2016

Org. Process Res. Dev.

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Organic Solvent Nanofiltration (OSN) technology is a membrane process for molecular separation in harsh organic media. However, despite having well-documented potential applications, development hurdles have hindered the widespread uptake of OSN technology. One of the most promising areas of application is as an iterative synthesis platform, for instance for oligonucleotides or peptides, where a thorough purification step is required after each synthesis cycle, preferably in the same working solvent. In this work, we report a process development study for liquid-phase oligonucleotide synthesis (LPOS) using OSN technology. Oligonucleotide (oligo) based drugs are being advanced as a new generation of therapeutics functioning at the protein expression level. Currently, over one hundred oligo based drugs are undergoing clinical trials, suggesting that it will soon be necessary to produce oligos at a scale of metric tons per year. However, there are as yet no synthesis platforms that can manufacture oligos at >10 kg batch-scale. With the process developed here, we have successfully carried out 8 iterative cycles of chain extension and synthesized 5-mer and 9-mer 2'-O-methyl oligoribonucleotide phosphorothioates, all in liquid phase media. This paper discusses the key challenges, both anticipated and unexpected, faced during development of this process, and suggests solutions to reduce the development period. An economic analysis has been carried out, highlighting the potential competitiveness of the LPOS-OSN process, and the necessity for a solvent recovery unit.

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Section: Further Discussion: Advantages and Current Challengesmentioning

confidence: 99%

Section: Justification For Using a Branched Peg Homostar Supportmentioning

confidence: 99%

Section: Overall Process and Oligonucleotide Synthesis Chemistrymentioning

confidence: 99%

See 1 more Smart Citation

Organic Solvent Nanofiltration (OSN): A New Technology Platform for Liquid-Phase Oligonucleotide Synthesis (LPOS)

Kim

Gaffney

Valtcheva

et al. 2016

Org. Process Res. Dev.

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“…to the procedure recently reported and similarly azeotropically dried 30. Dibutyltinoxide (DBTO, 98%, Sigma-Aldrich) was dried at 200 o C in vacuo for 30 min prior to use.…”

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confidence: 99%

Synthesis and characterization of branched fullerene-terminated poly(ethylene glycol)s

et al. 2015

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ARTICLEThis journal is Poly(ethylene glycol) [1, PEG~4(OH) 2 , M n ~ 200], glycerol ethoxylate [2, PEG~2 1 (OH) 3 , M n ~ 1000] and pentaerythritol ethoxylate [3, PEG~1 5 (OH) 4 , M n ~ 797] react directly with phenyl-C 61 -butyric acid methyl ester (PCBM), in the presence of dibutyltinoxide (DBTO) catalyst at 140 o C, to give a mixture of fullerene [C 60 ] end-capped PEGs via transesterification.Among these PEG linkers, only PEG~4(OPCB) 2 (4a) (OPCB: ester oxygen linked phenyl-C 61 -butyryl group) was successfully isolated from the crude product mixture in the fully endcapped form. Fully acylated PEG~2 1 (OPCB) 3 (5) and PEG~1 5 (OPCB) 4 (6) could not be separated chromatographically from incompletely reacted species due to the polydispersity in branch lengths. This purification challenge was overcome by using a monodisperse branched core, 1,3,5-tris(octagoloxymethyl)benzene [7, PEG 24 (OH) 3 ] to give a monodisperse trisfullerene homostar, PEG 24 (OPCB) 3 (8). The structures of the bis-and tris-fullerene products were confirmed by MALDI-TOF mass spectrometry and 1 H NMR spectroscopy with supporting FTIR and UV-vis spectroscopic analysis.

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“…12,13 The new generation of OSN membranes can withstand aggressive solvents and exhibit high flux while completely rejecting relatively small solutes such as crown ethers which are at the lower end of the nanofiltration range. [14][15][16] OSN was suggested for the separation of Williamson etherification reaction mixtures 17,18 and homogeneous catalyst recovery. 19 Schaepertoens et al recently proposed a three-stage membrane cascade for the purification of dibenzo-18-crown-6 ether and in situ solvent recycle.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and determination of pKa values of new enantiopure pyridino- and piperidino-18-crown-6 ethers

Kupai

Kisszékelyi

Rojik

et al. 2016

Arkivoc

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This paper reports the preparation of eight new enantiopure amide type crown ethers and their optically active precursors. Chiral diamines were transformed to amide type pyridino-crown ethers reacting them with pyridine dicarbonyl dichlorides by high dilution technique. Two of the new pyridino-crown ethers were reduced to their piperidino analogues. A preliminary study for the potential application of nanofiltration in the purification and recovery of crown ethers is presented. According to the pK a measurements these eight new macrocycles are potential organocatalysts (for instance in Michael addition reactions) thanks to their acidic and basic moieties and chiral skeletons, respectively.

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Iterative synthesis of monodisperse PEG homostars and linear heterobifunctional PEG

Cited by 40 publications

References 12 publications

Organic Solvent Nanofiltration (OSN): A New Technology Platform for Liquid-Phase Oligonucleotide Synthesis (LPOS)

Organic Solvent Nanofiltration (OSN): A New Technology Platform for Liquid-Phase Oligonucleotide Synthesis (LPOS)

Synthesis and characterization of branched fullerene-terminated poly(ethylene glycol)s

Synthesis and determination of pKa values of new enantiopure pyridino- and piperidino-18-crown-6 ethers

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