Quinazoline library solid-phase

The same approach was readily adaptable to solid-phase synthesis. A small library of unnatural derivatives of 140 was prepared with variation of the configuration and nature of R1 and R4 and with substitution on the benzene ring <2000JC0186>. Three natural alkaloids, Verrucine A, B, and Anacine, were synthesized by a similar pathway and the pyrazino[2,l- ]quinazoline as opposed to the benzodiazepine structure of Anacine was proved <2001JNP1497>. Fiscalin B and other derivatives were prepared by solid-phase synthesis using polyethylene glycol (PEG) resin <2002USP6376667>. 

As a consequence, a quest for more extensive exploitation in drug discovery by solid-phase syntheses of quinazoline libraries vs as initiated [182], In general, the quinazolinedione template is synthesized from polymer-bound anthranilic acids, as presented schematically in Scheme 31. 

A recent example of the parallel synthesis of different quinazoline-2,4-dione derivatives (46) demonstrates how to combine the advantages of fluorous synthesis with those of solid-phase chemistry without using expensive perfluorinated solvents [22] (Scheme 3.22). In the beginning, a fluorous benzyl alcohol (47) is adsorbed on fluorous reversed-phase silica gel (FRPSG). Then, in a sequence of splits and reactions, the linker group, which remains bound to the FRPSG by fluorophilic interactions, is converted into a library of differently substituted carboxamido-urethanes (48). These are cyclized and the liberated quinazoline-2,4-diones (46) are eluted from the support with the fluorophobic solvents water and CHjCN/... 

Some of the syntheses of pyrimidines and quinazolines were automated so that combinatorial libraries of compounds could be generated. For instance, 2-thioxo-4-dihydropyrimidinones were prepared in this fashion by reductive alkylation of p-amino acids with aldehydes, addition of isothiocyanates, and then cyclization <97JOC9358>. The use of highly fluorinated substrates in the Ugi and Biginelli multicomponent reactions led to a combinatorially-suitable preparation of dihydropyrimidines 15 <97JOC2917>, and efficient solid phase syntheses of chiral quinazoline-... 

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