Combichem synthesis

Because most commercially developed “high-speed” synthesis instrumentation for combinatorial chemistry (CC) has evolved from peptide-synthesis equipment, adapting it to the needs of less-developed areas of organic synthesis can prove time-consuming and frustrating, according to Ashis K. Saha and colleagues at the Janssen Research Foundation (Spring House, PA). In their recent paper (J. Comb. Chem. 2001, 3, 181–188), Saha et al. describe an inexpensive apparatus for solid-phase chemistry and parallel synthesis that produces small libraries in multimilligram amounts without robotics.

Individual glass reaction tube capacities in their system ranged from 4 to 500 mL of operating liquid volume. The ability to access and monitor the reactions separately was an important part of the design. Insert tubes with frit ends acted as filter sticks for resin wash and for maintenance of an inert atmosphere. Agitation was provided by the electronically programmable insertion of pulses of inert gas for mixing the resin; vacuum could be used for resin wash. The system was designed to deliver 100 or more target-based, single, pure compounds per month per chemist, with a dry weight of each final compound of 7 mg or more. The final compounds had to prove >90% pure as determined by HPLC; and NMR characterization had to be easily performed on all new and representative library structures. The entire apparatus was designed to operate in a normal chemistry fume hood and could be set up (with reflux heating and cooling) for conditions ranging from –78 to 150 °C.

To prove the utility of their system, Saha and colleagues used itto synthesize several libraries based on 4-methane amine imidazoles pertinent to their medicinal chemistry lead exploration program. The system easily synthesized a 72-compound library, which met their purity and yield criteria, in 2–3 days. Designed not for massive automation but for experimental ease and flexibility, the apparatus has great potentialfor use in small research programs or laboratories and for handling the unique demands of organic chemists interested in solid-phase synthesis following an adaptable CC approach.