Pyrazole library

The pyrazole library was created sequentially using 10 mM solutions of the 1,3-dicarbonyl compound and 0.8 M solutions of the hydrazines, each introduced as a 2.5 pi slug [20]. This requires control of feeding of both reactant solutions so that the slugs enter the chip at the same time and mix thereafter. The residence time was 210 s. Thereafter, the reaction slugs were diluted on-chip by a 1 1 methanol-water stream at 8 pi min and detected. Analysis of the nature of the products and the degree of conversion was done using standards of reactant and product materials. 

The groups of Giacomelli and Taddei have developed a rapid solution-phase protocol for the synthesis of 1,4,5-trisubstituted pyrazole libraries (Scheme 6.194) [356]. The transformations involved the cyclization of a monosubstituted hydrazine with an enamino-/8-ketoester derived from a /8-ketoester and N,N-dimethylformamide dimethyl acetal (DMFDMA). The sites for molecular diversity in this approach are the substituents on the hydrazine (R3) and on the starting j3-keto ester (R1, R2). Subjecting a solution of the /8-keto ester in DMFDMA as solvent to 5 min of microwave irradiation (domestic oven) led to full and clean conversion to the corresponding enamine. After evaporation of the excess DMFDMA, ethanol was added to the crude reaction mixture followed by 1 equivalent of the hydrazine hydrochloride and 1.5 equivalents of triethylamine base. Further microwave irradiation for 8 min provided - after purification by filtration through a short silica gel column - the desired pyrazoles in >90% purity. 

Figure 5. Construction of a pyrazole library yielding four points of diversity...

Figure 8. Plot of % compounds falling within CLogP bin size for a Pyrazole library (994 compounds) versus the SDF-derived dataset (24082 compounds)...

Synthesis of a pyrazole library using purification by solid phase extraction... 

Solid-phase scavenger methods are employed with increasing frequency as a prehminary reaction cleanup step in combinatorial chemistry, and have recently become commercially available (Argonaut, Calbiochem-Novabiochem, Varian, Alltech). lilly researchers first reported on this approach, employing sohd supported electrophiles and nucleophiles for reaction purification in acylation and alkylation reactions. Yield and purity values reported were 90-95% and 50-99%, respectively, for a library generated by reductive amination. Parke-Davis researchers achieved the removal of known reaction product impurities by the application of custom synthesized polymer supported reagents, specifically polystyrene-divinylbenzene supported derivatives of methylisocyanate and tm(2-aminomethyl)amine for cleanup of by-products resulting from urea, thiourea,sulfonamide,amide, and pyrazole libraries. 

As for the solid support, several polymer-supported amines were tested (Fig. 2). For either the pyrazole and isoxazole synthesis, the best results were given by aniline-functionalized cellulose, which has also the advantage of a relatively low cost. For the 2-aminopyrimidine library, polystyrene-based piperazine and piperidine gave products with a much higher purity compared with other secondary non-cyclic or primary amines, hi both cases, the resins could be reused for up to four times before degradation in their behavior was observed. This reusability could be further enhanced (up to 10 cycles for cellulose-based aniline) when the microwave-assisted protocols were used. 

Organ et al. from York University demonstrated that a diarylated IH-pyrazole-based library, based on the structure of the potent COX II inhibitor Celecoxib [4-(3-trifluoromethyl-5-(4-methylphenyl)-lH-pyrazol-l-yl)benzenesulfonamide], could be rapidly prepared using MAOS [59]. Microwave-accelerated Suzuki reaction on 4-(5-iodo-3-methyl-lH-pyrazol-l-yl)-benzenesulfonamide using heterogeneous Pd/C was the principal diversification step investigated (Scheme 41). The interest of the team in microwave... 

A library of fifteen 6,7,9,9a-tetrahydro-57/-pyrazolo[l,2-tf]pyrrolo[3,4-ir]pyrazole-l,3,5(2/7,3a7/)-triones 712 was prepared by combinatorial stereoselective cycloadditions of compounds 320 to A-substituted maleimides. 

In the context of the preparation of a library of pyrazole-based cyclooxygenase II (COX-II) inhibitors, the Organ group has described the microwave-assisted decarboxylation of a pyrazole carboxylic ester with 20% sulfuric acid (Scheme 6.160 a) [49]. While the conventional protocol (reflux, 100 °C) required 96 h to provide a yield of 86%, full conversion could be achieved within 5 min at 200 °C under micro-wave heating, leading to an 88% isolated product yield. 

Scheme 7.34 Generation of pyrazole and oxazole libraries on cellulose beads.

PDE4 (Table 1, entry 10) A library of about 20,000 "scaffold" compounds with molecular weights of 125-350 Da were screened in a combination of biochemical assays and crystallography studies to identify the PDE4 inhibitor pyrazole ester derivative 38 [45]. A 4000-fold increase in potency was achieved after only two rounds of chemical synthesis to give 39. 

Scheme 80. Preparation of combinatorial libraries of new pyrazole 277 and piperidine 278 derivatives [127]...

Kumaravel K, Vasuki G (2009) Four-component catalyst-free reaction in water combinatorial library synthesis of novel 2-amino-4-(5-hydroxy-3-methyl-lH-pyrazol-4-yl) H-chro-mene-3-carbonitrile derivatives. Green Chem 11 1945-1947... 

A small library of pyrazoles was synthesized in a MCR of cyclic 1,3-diketones, DMF-DMA and hydrazines [64], Although the reaction presumably proceeds via cyclodehydration of the intermediate hydrazonoketone 34, the use of wa-... 

Another example of fully automated PASP synthesis is the preparation of a 192-member 2D array of 1,5-biaryl pyrazoles. " The 1,5-biaryl pyrazole moiety is found in a number of important pharmaceuticals, such as the selective COX-2 inhibitor Celecoxib and the nonsteroidal antiinflammatory agent Tepoxaline. The synthetic route to the 1,5-biaryl pyrazoles, exemplified by the library member 42... 

Pellegrino G, Leonetti F et al (2010) Solid phase synthesis of a molecular library of pyrimidines, pyrazoles, and isoxazoles with biological potential. Tetrahedron Lett 51 1702-1705... 

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