CombiCHEM system

CombiCHEM System (Fig. 3.9) For small-scale combinatorial chemistry applications, this barrel-type rotor is available. It can hold two 24- to 96-well microtiter plates utilizing glass vials (0.5-4 mL) at up to 4 bar at 150 °C. The plates are made of Weflon (graphite-doped Teflon) to ensure uniform heating and are sealed by an inert membrane sheet. Axial rotation of the rotor tumbles the microwell plates to admix the individual samples. Temperature measurement is achieved by means of a fiber-optic probe immersed in the center of the rotor. 

The group of Grieco has presented a method for efficiently performing macrocy-clizations on a solid phase (Scheme 7.31) [48]. The preparation of the macrocyclic peptides required several standard transformations, which are not described in detail herein. The final intramolecular nucleophilic aromatic substitution step was carried out under microwave irradiation at 50 °C in a dedicated CombiCHEM system (see Fig. 3.9) utilizing microtiter plates in a multimode batch reactor. The cycli-zation product was obtained in good yield after a reaction time of 10 min and sub-... 

A recent study concerned the microwave-assisted parallel synthesis of di- and tri-substituted ureas utilizing dedicated 96-well plates in the CombiCHEM system [60], In a typical procedure, modification of the Marshall resin utilized was achieved by treatment with p-nitrophenyl chloroformate and N-methylmorpholine (NMM) in dichloromethane at low temperatures. The resulting resin was further modified by attaching various amines to obtain a set of polymer-bound carbamates (Scheme 7.48). 

The development of the first HPLC system with MW-triggered fraction collection was described by Zeng et al. [50] at CombiChem. This system was a dual analytical-preparative instrument with parallel-column format, termed parallel Analyl/PrepLCMS." developed by the modification of commercially available instrumentation. This system had software-controlled valves that applied sample to each path from a single autosampler and had the capacity to purify and analyze more than 100 samples per day. Initial analytical LC-MS data acquired by the system allowed the identification of samples that require... 

The systems reported above all rely on detection by ultraviolet absorbance, and require some separate means of identifying the desired product among the various components (and thus collected fractions) of the reaction mixture. Efficiency and throughput can be considerably enhanced by real-time detection and identification of products. Two groups have now reported preparative HPLC systems where fractionation decisions are based upon output from a mass spectrometer detector. The first preliminary report of such a system came from a collaboration between CombiChem and Sciex [21]. This system bases fractionation decisions on the output of a single ion mass chromatogram for the predicted molecular ion of the desired product. Reverse phase preparative HPLC is used in conjunction with electrospray ionization mass detection. A full report of this work has appeared in early 1998 [22]. The second report of such a system came from a collaboration between Pfizer and Micromass [23]. This system uses a flexible combination of UV and/or ion chromatograms to control fractionation. Unlike other systems, fractionation parameters are set by the mass spectrometer control software. Variants of both of the above systems will probably become commercially available in late 1997 [24]. 

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