Library pyrimidines

Scheme 7.108 Generation of a pyrimidine library through a capture and release strategy.

Finally, some miscellaneous fused systems containing thiophene rings have attracted some interest. The electrophilic chemistry of several thia-PHAs has been investigated, among others benzo[Z>]naphtho[2,l-c/]thiophene , whereas an approach to related partially saturated systems from tetrahydrothiophene-3-one has been published <07TL4715>. It should also be mentioned that a 4-armno-7-ar ithieno 3,2-<7 pyrimidine library has been prepared <07JCC431>. 

Bagley MC, Hughes DD, Lubinu MC, Merritt EA, Taylor PH, Tomkinson NCO (2004) Microwave-assisted synthesis of pyrimidine libraries. QSAR Comb Sci 23 859-867... 

Discovery and Development The core structure of pluripotin was identified from screening of the compound controlling the self-renewal of ES cells, which was derived from heterozygous Oct4 (marker protein of undifferentiated ES cells)-GFP transgenic OG2 mice. From a library of 50,000 discrete heterocycles, a class of 3,4-dihydropyrimido[4,5-dose-dependent manner. After analyses of structure-activity relationships of a second-generation focused 3,4-dihydropyrimido[4,5-[Pg.265]

Scheme 8.2 Utilization of PS-isocyanate for amine scavenging in Triazolo pyrimidine library synthesis.

Another example of the capture and release strategy, use of polystyrene-bound piperazine for generation of a pyrimidine library, was recently reported [121]. In a... 

Reddy and collaborators reported a new one-pot, three-component procedure toward the synthesis of novel 4-phenyl-2-[3-(alkynyl/alkenyl/aryl) phenyl] pyrimidine libraries starting with the Michael addition of enaminone 64 with 3-bromobenzimidamide hydrochloride (65) (Scheme 28) (13S75). This was followed by a cyclization, an isomerization, a dehydration, and a subsequent Sonogashira reaction with terminal alkynes or a Suzuki reaction with arylboronic acids or a Heck coupling reaction with alkenes. 

The structures of six standards (and QC compounds) of a 1,2,5-trisubstituted benzimidazole library and a 4,5,6-trisubstituted pyrimidine library are shown in Figs. 1 and 2. 

Determine the quantitative purity (see Note 2) from the ratio of determined quantity to the total sample weight. A flow chart describing this analysis process is shown in Fig. 4. The quantitative purity data for QC compounds in the 1,2,5-trisubstituted benzimidazole and 4,5,6-trisubstituted pyrimidine libraries are listed in Tables 1 and 2. The quantity and quantitative purity of these QC compounds were also determined by qNMR. 

Quantitative Analyses of QC Compounds in 4,5,6-Trisubstituted Pyrimidines Library... 

A library of l,3,7-substituted-perhydropyrazino[l,2-f]pyrimidine-2,6,8-triones was built by preparation of functionalized ketopiperazines on the solid phase, followed by N-acylation with 2-bromoacetic acid, reaction with isocyanate and with concomitant cyclization using trifluoroacetic acid (TFA) <2003W02003/013740>. 

Libraries of 3,4-dihydropyrimido[l,2- ]pyrimidines were formed by reacting 2-aminopyrimidines with an aldehyde and an olefin in a one-pot reaction in the presence of acid, for example, TFA <2002W0030934>. 

All three systems are amenable to sequential substitutions, giving opportunities for use as scaffolds and also, particularly for pyrimidines, rapid muticomponent, often one pot , ring constructions are possible. Both these features give great potential for combinatorial chemistry and library construction. 

A regiospecific strategy to A-7-substituted purines 65 and its application to a library of 2,6,8-trisubstituted purines has been reported. The three-step synthetic strategy involves cyclization reactions of suitably substituted pyrimidines 63 with either a carboxylic acid or an aldehyde <06JC0410>. 

A test library with three novel p38a inhibitory activity has been prepared, among them pyrazolo[3,4-c/]pyrimidine and pyrazolo[3,4-h]pyrazine with potent in vivo activity <06BMCL262>. A convenient route for the synthesis of pyrazolo[3,4-<7]pyrimidine involving Friedlander condensation of 5-aminopyrazole-4-carbaldehyde with formamide or benzamide has been reported <06JHC1169>. A facile synthesis of pyrazolo[3,4-<7]pyrimidines and pyrimido[4,5-<7]pyrimidin-4-one derivatives has been published <06SC2963>. 

Aldehydes and the corresponding 2-aminopyridine, pyrazine, or pyrimidine are admixed in presence of a catalytic amount of clay (50 mg) to generate iminium intermediate. Isocyanides are subsequently added to the same container and the reactants are further exposed to MW to afford the corresponding imidazo[l,2-a]pyridines, imi-dazo[l,2-a]pyrazines and imidazo[l,2-a]pyrimidines (Scheme 6.48). The process is general for all the three components, e. g. aldehydes (aliphatic, aromatic and vinylic), isocyanides (aliphatic, aromatic and cyclic) and amines (2-aminopyridine, 2-amino-pyrazine and 2-aminopyrimidine). A library of imidazo[l,2-a]pyridines, imidazo[l,2-ajpyrazines and imidazo[l,2-a]pyrimidines can be readily obtained by varying the three components [151]. 

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>. 

The first example describes the synthesis of a pyrimidine derivative. Starting from a, 3-unsaturated ketones (see Schemes 1, 8), a library of different heterocycles was prepared in research (Felder and Marzinzik 1998). In preparation for any large-scale synthesis, the availability of starting materials is always considered (Lee and Robinson 1995). For this work, we had to replace Rink amide resin B (Rink 1987), which was used by our colleagues in research for the synthesis of pyrimidine 1 due to its unavailability in large quantities (see Fig. 1). It was replaced with the Rink amide acetamido resin 4, which is well established in peptide amide synthesis (Bernatowicz et al. 1989) and easily accessible. 

The authors also applied this procedure to a 90-member combinatorial library of 5,7-disubstituted-2-aryl-pyrimidotriazines 159 using the same set of l-cyano-3-(pyrimidin-4-ylamino)-2-methylisothiourea intermediates 158 (see Table 10/Scheme 27) with aryldiazonium salts derived from the range of arylamines A-O that is shown in Scheme 27. Isolated yields are shown in Table 10 for indicative amines A-E, and yield ranges are indicated in Scheme 27 for amines F-O <2004TL9319>. 

---