Library production

These conceptual goals are attained by several combinatorial methods and tools. Characteristic for combinatorial chemistry is the synthesis on solid support or by polymer-supported synthesis, allowing for much higher efficiency in library production. Synthesis can be conducted either in automated parallel synthesis or by split-and-recombine synthesis. Centerpieces of combinatorial methods further include specific analytical methods for combinatorial... 

Solid-supported technologies are already well established methods in medicinal chemistry and automated synthesis. Over the last couple of years new trends have evolved in this field which are of utmost importance as they have the potential to revolutionize the way chemical synthesis especially for library production is performed. Microchip-based synthesis technologies and multistep sequences with solid-supported catalysts or reagents in flow-through systems are only two spectacular examples. A new approach is the use of solid-supported systems for the scale-up of chemical reactions thereby enabling the rapid and smooth transition from discovery to development units. 

In both the second and third approaches, the use of activity scores based on the positions in chemistry space of the virtual library products relative to the positions of known ligands of each individual target incorporates all of the information about known ligands, rather than just the common pharmacophoric features. The structural elements that convey specificity are not excluded in the design, as they may be in the first approach. 

The analogous reaction with 1,2-diaminobenzene 201 was reported by Komberg and coworkers in another quinoxaline library production <99JHC1271>. Quinoxaline 202 was a key intermediate in this methodology. 

Reagents with multiple reactive chemical groups should be avoided in library enumeration because their presence most likely requires specific protections of certain functional groups which complicates chemical reactions and makes library production unpractical. 

Make decision directly on individual product which yields a cherry-picking library (best product property profile but lower library production efficiency) ... 

Make decision on monomers based on property profile of their corresponding products (Combinatorial-shaping). This leads to a fully combinatorial library design to retain efficiency in library production ... 

We would like to express our gratitude toward other members of the Chkl project team for their design input and their efforts in library production (Haresh Vazir and Dr. Ming Teng), bio-assays... 

Attachment of library substrates to the support and final release of library products introduce two additional steps in a synthesis. 

Anionic resin capture of solution-phase library products has also been reported. The anion exchange resin A-26 hydroxide 6 was used in a dual capacity to mediate Dieckmann condensations of solution-phase library intermediates and also to affect resin capture of the formed tetramic acids as polymer-bound intermediates (Scheme 7).79 Rinsing, followed by tri-... 

For the development of new reaction sequences for solid-phase synthesis, the optimum conditions for each step must be identified. This includes determination of the minimum reaction time and temperature, and the minimum amounts of reagents required to obtain sufficiently pure products with a representative selection of different reagents. If reaction times or amounts of reagents are excessive, library production will be costly and inefficient. 

---