Quinazoline library

A one-pot preparation of pyrrolo[l,2-a]quinazoline libraries with three points of diversification by condensation of a-cyano-ketones and 2-hydrazino-benzoic acids has been developed by Hulme and coworkers (Scheme 6.252) [439]. The protocol simply involved heating a solution of equimolar amounts of the two building blocks in acetic acid at 150 °C for 5 min. In many cases, the final products precipitated directly from the reaction mixture. In such cases, simple washing with diethyl ether yielded the products in >95% purity. A 63-member library was prepared by employing seven a-cyano-ketones and nine 2-hydrazino-benzoic acids. 

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. 

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>. 

Quinazolines, the benzo derivatives of pyrimidines, were prepared in a variety of ways, from methods analogous to those for synthesizing pyrimidines to vastly different condensation schemes. In analogous fashion to many pyrimidine preparations, Yang and coworkers reported the condensation of polymer-tethered amidines 109 with cyclic anhydrides 110 to yield a library of 2-amino-4(3//)-quinazoIinones 111 after cleavage from the resin <00TL7005>. 

Polystyrene grafted SynPhase Lanterns were used by Makino et al.33 at Ajinomoto to synthesize a diverse quinazoline-2-thioxo-4-one library. Lanterns functionalized with long-chain HMP (hydroxymethylphenoxyvaleric amide) linker were coupled with nitrophenols by the action of DIC/ HOAt/DMAP to give nitrobenzenes 14 (Scheme 6). The nitro group was... 

In a different application scenario, tagged nodes can be used to define a known common anchor point in a set of molecules. A set of approximately 400 R-group instances from a combinatorial library (based around a quinazoline core) forms an example of such a set of molecules, where the functional attachment point forms the tagged Feature Tree node. A Feature Tree similarity... 

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/... 

Scheme 3.22 Fluorous synthesis of a library of substituted quinazoline-2,4-diones (46) [22]. The key to this approach is a fluorous benzyloxycarbonyl group on which the target molecules are stepwise constructed and which keeps the different synthetic intermediates bound to fluorous reversed-phase silica gel (FRPSG) during the purification cycles. The structural diversity of the target compound library (46) is introduced by the different anthranilic acid derivatives and primary amines in boxes) (TBTU = 0-(benzotriazol-1-yl)-N,/ /,N, N -tetramethyluronium tetrafluoroborate).

MW-assisted synthesis of acridine and quinazolines was performed on thin layer chromatographic plates that were readily amenable to parallel synthesis of their libraries (05JHC703). 

Changing the pATa of an acidic or basic group in a molecule so that more of the compound exists in the ionized form at physiological pH lowers logD (at about pH 7) and, in general, should improve aqueous solubility. The improvement in solubility is limited, however, if the solubility of the neutral form of the compound (the inherent solubility) is very low. The situation is worsened if the starting pATa is far from 7. We find this to be a particular problem with weak bases. Weakly basic pyridines, quinolines, quinazolines and thiazoles seem to be frequent members of combinatorial libraries. 

In combinatorial chemistry FRPSG can also be used as a solid support for organic synthesis. As a first example of this strategy, the synthesis of a library of 16 quinazoline-2,4-diones starting from perfluoro-tagged benzyl alcohol was described [74]. 

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-... 

Anthranilic acids and derivatives are often used as starting materials for the preparation of quinazolinones. For example, Drizin and co-workers applied this strategy to build a library of quinazolinones in the search for selective aiA subtype antagonists. Anlhranilate esters 65 reacted with isocyanates to generate quinazolin-2,4-diones 66 <01JMC1971>. Similarly, quinazolin-4-ones 69 were synthesized by first converting 67 to 68 followed by cyclization with an isocyanate under acidic conditions. 

Scheme 9 Benzodiazepine-quinazoline alkaloids library by polymer supported phosphine-mediated aza-Wittig reaction [170]...

Monocyclic and Bicyclic aromatic heterocycles such as imidazoles, thiazoles, thiadiazoles, oxazoles, oxadiazoles quinazolines, indoles, benzimidazoles, purines pyrido[43-d]pyri-midines, thiazolo[5,4-d]pyrimidines, thiazolo[4,5-d]pyrimidines, oxazolo[5,4-d]pyrimi-dines and thieno[2,3-d]pyrimidines are renowned pharmacophores in drug discovery. These special structures are well explained and exemplified in chemical compound libraries. In this chapter, several types of thiazole based heterocyclic scaffolds such as mono-cyclic or bicyclic systems synthesis and their biological activities studies are presented, which are not frequently present in books and reviews. We mention the first importance of synthetic route of various thiazole based compounds and their applications in medicinal chemistry in this chapter. 

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