Further Development of a Robust Workup Process for Solution-Phase High-Throughput Library Synthesis To Address Environmental and Sample Tracking Issues

Abstract

During further improvement of a high-throughput, solution-phase synthesis system, new workup tools and apparatus for parallel liquid-liquid extraction and evaporation have been developed. A combination of in-house design and collaboration with external manufacturers has been used to address (1) environmental issues concerning solvent emissions and (2) sample tracking errors arising from manual intervention. A parallel liquid-liquid extraction unit, containing miniature high-speed magnetic stirrers for efficient mixing of organic and aqueous phases, has been developed for use on a multichannel liquid handler. Separation of the phases is achieved by dispensing them into a newly patented filter tube containing a vertical hydrophobic porous membrane, which allows only the organic phase to pass into collection vials positioned below. The vertical positioning of the membrane overcomes the hitherto dependence on the use of heavier-than-water, bottom-phase, organic solvents such as dichloromethane, which are restricted due to environmental concerns. Both small (6-mL) and large (60-mL) filter tubes were developed for parallel phase separation in library and template synthesis, respectively. In addition, an apparatus for parallel solvent evaporation was developed to (1) remove solvent from the above samples with highly efficient recovery and (2) avoid the movement of individual samples between their collection on a liquid handler and registration to prevent sample identification errors. The apparatus uses a diaphragm pump to achieve a dynamic circulating closed system with a heating block for the rack of 96 sample vials and an efficient condenser to trap the solvents. Solvent recovery is typically >98%, and convenient operation and monitoring has made the apparatus the first choice for removal of volatile solvents.

Solution-Phase Parallel Synthesis of Novel Spirooxazolinoisoxazolines

“…It was recognized that optimization of the liquid−liquid extraction processes was crucial to the formation of high-purity products without the need for tedious chromatography because addition of appropriate organic extraction solvents and aqueous washing solutions could remove impurities or water soluble reagents and therefore improve product purities. Modern automated liquid handlers , are able to detect the phase boundary of solutions by virtue of their different electric conductivities, and therefore, selective transfer or aspiration of most an organic or aqueous phase is straightforward.…”

N-(4-Chlorophenyl)-4-methoxybenzamide

“…For the biological activity of amides, see: Chen et al (2011); El Rayes et al (2008); Regiec et al (2006); Kuroda et al (2006). For related structures, see: Gowda et al (2008); Saeed et al (2008).…”

“…Data collection: CrysAlis PRO (Oxford Diffraction, 2010); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 (Farrugia, 1997); software used to prepare material for publication: PLATON (Spek, 2009 Globally, multidrug-resistant bacteria are a major health problem leading to severe consequences; anilides have shown antimycobacterial activity against classical mycobacterium tuberculosis (El Rayes et al, 2008), thiobenzanilides also belong to a group of biologically active compounds possessing antimicobacterial activities. In addition, N-substituted carboxamide isothiazoles (Regiec et al, 2006) produced a remarkable immunotropic, antiviral and anti-inflammatory activities, N-acylamino benzamides (Kuroda et al, 2006), constitute an important class of potent insecticides.…”

High Throughput Chemistry in Drug Discovery

“…109 Of much greater impact and lasting effect was the development of simpler parallel reaction equipment, many examples of which were developed in pharmaceutical laboratories and subsequently commercialised through equipment manufacturer partnerships. 103 Many examples are available and in use today, but examples include parallel tube based reaction blocks introduced by companies such as STEM, 110 allowing controlled stirring and heating of arrays of solution-based reactions at significant scale, whilst Radleys introduced equipment based on commercialising the common practices of having several reactions on a single stirrer hotplate.…”