Diversity-orientated synthesis of 3,5-bis(arylamino)pyrazoles

Tetrahedron Letters

Volumn 52, Issue 50, 2011, Pages 6719-6722

  Degorce, Sébastien ^a   Jung, Frédéric H ^a   Harris, Craig S ^a   Koza, Patrice ^a   Lecoq, Jonathan ^a   Stevenin, Arnaud ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

3,5 BIS(ARYLAMINO)PYRAZOLE; PYRAZOLE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; BIODIVERSITY; COMBINATORIAL CHEMISTRY; SYNTHESIS;

EID: 80755140573     PISSN: 00404039     EISSN: 18733581     Source Type: Journal    
DOI: 10.1016/j.tetlet.2011.09.150     Document Type: Article

References (19)

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17. 3CN; flow rate, 2.5 mL/min; run time, 4.5 min; gradient, from 0 to 100% solvent B; mass detector, micro mass ZMD; (b) Preparative LCMS was carried out using Waters 600 Pumps linked to a Waters 2700 Sample Manager and a Waters micromass ZMD mass detector. Column C18 Waters X-Bridge 30 × 150 mm, 5 μ. Eluant: 40 mL/mn 10 to 100% Acetonitrile-Buffer Ammonium Carbonate 2 g/L over 14 mn.
18. General process: To a stirred suspension/solution of aryl isothiocyanate 1 (0.5 equiv) and aryl isothiocyanate 2 (0.5 equiv) in 2-methoxyethanol (1.5 mL/1 mmol) pre-saturated with argon, was added sodium acetylacetonate hydrate (1.0 equiv) in one portion and the resulting solution/suspension was stirred for 48 h at room temperature giving a clear solution. Hydrazine hydrate (1.1 equiv) was added in one portion and the resulting solution was stirred at 85 °C for 2 h. The reaction mixture was purified by mass-triggered preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/min) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compounds were evaporated to dryness to afford separately the most hydrophilic BAPyr A (5-15%), the desired BAPyr B (22-61%) and the least hydrophilic BAPyr C (4-15%) in that order, usually as solids.
19. During our investigations, mono-acetyl impurities arising through retro-Claisen of 21 before addition of the second isothiocyanate (particularly present when EtOH was used as the solvent) did not react further during the reaction before adding hydrazine which led to contamination of the final desired 3,5-bis(arylamino)pyrazole libraries with close-running 3-arylamino-5- methylpyrazole impurities.