Structure-controlled automated purification of parallel synthesis products in drug discovery

Kiplinger, Jeffrey P.; Cole, Roderic O.; Robinson, Shaughnessy; Roskamp, Eric J.; Ware, R.; O’Connell, Henry J.; Brailsford, Andrew; Batt, J.

doi:10.1002/(sici)1097-0231(19980529)12:10<658::aid-rcm211>3.0.co;2-p

Cited by 33 publications

(19 citation statements)

References 13 publications

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“…Utilizing a batch‐based purification model on the Waters Prep100, focused gradients were preferred over isocratic methods as focused gradients yield sharper peaks and allow more room for error when scaling up from the 5% to 55% analytical method. Historical use of focused, shallow gradients has been highly successful for chiral HPLC, achiral HPLC, and SFC OA methods and was no different in this case. Focused gradients maximize resolution of target substrate(s) to allow for increased loading when scaling to preparative chromatography.…”

Section: Designing the Platformmentioning

confidence: 99%

“…The use of OA analytical LC‐MS to monitor synthetic chemistry reactions and purity of new products in drug discovery has been standard practice in the pharmaceutical industry . Automated and OA purification platforms have been used for many years as a quick and simple generic platform to increase medicinal chemistry productivity …”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3][4] Automated and OA purification platforms have been used for many years as a quick and simple generic platform to increase medicinal chemistry productivity. 5,6 Additionally, there is a high demand for quick and efficient chiral purifications in early drug discovery. For drug candidates containing one or more chiral centers, different epimers may have very different pharmacological activity or toxicity.…”

Section: Introductionmentioning

confidence: 99%

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Enabling chiral separations in discovery chemistry with open‐access chiral supercritical fluid chromatography

et al. 2019

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Work from this paper details a novel walk‐up open‐access (OA) approach to enable chiral analytical method development and preparative separation of enantiomers in early discovery chemistry using supercritical fluid chromatography (SFC). We have demonstrated the success of this OA approach using immobilized chiral stationary phases (CSPs). After screening a diverse set of racemic drug candidates, we have concluded that a simplified OA chiral SFC platform can successfully purify approximately 60% of the analysed racemates. This streamlined OA workflow enables medicinal chemists with limited expertise in chiral method development to successfully and rapidly purify enantiomers for their projects using Waters UPC2 and Prep100‐SFC instrumentation.

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Section: Designing the Platformmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Enabling chiral separations in discovery chemistry with open‐access chiral supercritical fluid chromatography

et al. 2019

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“…Fraction triggering on the system is controlled by the Waters FractionLynx software 15 with parameters set via the standard FractionLynx interface. Triggering options include UV at specified wavelength, MS-extracted ion chromatogram as specified mass, or Boolean logic combining both detection methods.…”

Section: Evaluation Of Fraction Triggeringmentioning

confidence: 99%

Evaluation of a New Preparative Supercritical Fluid Chromatography System for Compound Library Purification: The TharSFC SFC-MS Prep-100 System

Ebinger

Weller

Kiplinger³

et al. 2011

JALA: Journal of the Association for Laboratory Automation

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Preparative HPLC-MS is often the method of choice for purification of small amounts (<100 mg) of diverse new molecules, such as compound libraries for drug discovery. The method is robust, well proven, and widely applicable. In contrast, preparative supercritical fluid chromatography coupled with mass spectrometry (SFC-MS) has seen only slow acceptance for the same application—despite some potential scientific and economic advantages. One of the reasons for slow adoption of SFC-MS is the lack of well-proven, robust, and commercially available instrumentation. In early 2009, TharSFC (a Waters Company, Pittsburgh, PA) introduced a new fully integrated system for preparative SFC-MS: The SFC-MS Prep-100. We report herein an objective evaluation of the SFC-MS Prep-100, including tests for pump and autosampler performance, sample recovery, sample carryover, fraction triggering, detector/fraction collector synchronization, and overall robustness. Our results suggest that the SFC-MS Prep-100 represents a significant advance over previous generation instrumentation.

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“…In order to carry out the purification of compound libraries more efficiently and rapidly, the steps of HPLC purification and mass spectrometric analysis may be combined into automated mass-directed fractionation [8][9][10]. Depending on the scale required, various HPLC column sizes may be selected such as analytical, semi-preparative, or preparative separation.…”

Section: Mass Spectrometry-based Hplc Purification Of Combinatorial Lmentioning

confidence: 99%

Analysis and screening of combinatorial libraries using mass spectrometry

Shin

Breemen

2001

Biopharm & Drug Disp

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Mass spectrometry is a highly selective and high throughput analytical technique that is ideally suited for the identification and purity determination of large numbers of compounds prepared using combinatorial chemistry or for the dereplication of natural products. Compounds may be characterized based on molecular weight, elemental composition and structural features based on fragmentation patterns. When coupled to a separation technique such as highperformance liquid chromatography (HPLC) or capillary electrophoresis, mass spectrometric applications may be expanded to include analysis of complex mixtures. However, the slower speed of the separation step reduces the throughput of the analysis. This review concerns the application of mass spectrometry to the characterization of combinatorial libraries and the screening of library and natural product mixtures. Strategies to enhance the throughput of LC-MS are discussed including fast HPLC and parallel LC-MS. Also, mass spectrometry-based screening methods are described including frontal affinity chromatography-mass spectrometry, gel permeation chromatography LC-MS, direct electrospray mass spectrometry of receptor-ligand complexes, affinity chromatography-mass spectrometry, and pulsed ultrafiltration mass spectrometry.

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Structure-controlled automated purification of parallel synthesis products in drug discovery

Cited by 33 publications

References 13 publications

Enabling chiral separations in discovery chemistry with open‐access chiral supercritical fluid chromatography

Enabling chiral separations in discovery chemistry with open‐access chiral supercritical fluid chromatography

Evaluation of a New Preparative Supercritical Fluid Chromatography System for Compound Library Purification: The TharSFC SFC-MS Prep-100 System

Analysis and screening of combinatorial libraries using mass spectrometry

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