Pyrazole acidity

In addition, the conversion of a compound collection of drug-like heterocycles as might be used in a medicinal chemistry program was investigated. An equimolar mixture of 20 pyrazole acids, synthesized by a split-and-mix approach, was treated with methyl resin 10 (Ri = CH3, 5 equiv.) for 6 h to yield the respective pyrazole esters. All 20 pyrazole acids in the starting reaction mixture and all their corresponding 20 pyrazole methyl esters in the product mixture could be identified by FT-ICR MS coupled to micro-HPLC with a relative mass error <2.2 ppm. 

Rosenmund reduction of pyrazole acid chlorides to aldehydes never causes reduction of the ring.834,635,744,745 Attempts to prepare the aldehydes by the sodium amalgam reduction of the anilides, however, gave only traces of the required products,635 but the fate of the pyrazole ring is not recorded. It is the authors experience that pyrazoles unsubstituted on nitrogen are usually unaffected by sodium and alcohol, although the reduction to pyrazoline by sodium and alcohol at 130° and 20 atmospheres pressure has been patented.746 Reduction of Ar-phonyIpyrazoles is somewhat easier sodium and alcohol reduce them to A-phenylpyrazolines,77,78, 207,235, 447,567,... 

Quinolyl)pyrazoIo[3,4-i7]pyridazincs were prepared by cyclocondensation reactions of an anilino-pyrazole acid with acetaldehyde <02JHC869>. Cyclopentadienyl-derived y-diketones and arylhydrazines condensed to 4-(l,4-diaryl-2//-cyclopent[d]pyridazin-2-yl)-benzenesulfonamides <02H(57)2383>. Sulfonated polyfphthalazinone ether sulfone)s 37 were prepared by polycondensation of 4-(4-hydroxyphenyl)phthalazinone 36 with various ratios of disodium 5,5 -sulfonylbis(2-fluorobenzenesulfonate) and bis(4-fluorophenyl)sulfone <02P5335>. 

The stable pyrazole acid from the hydrolysis of this ester is a key intermediate in Viagra production. Nitration can occur only at the one remaining free position and then amide formation and reduction complete the synthesis of the amino pyrazole amide ready for assembly into Viagra. 

An important application of thermodynamic control occurs in the manufacture of Viagra 12, Pfizer s treatment for impotence.3 The NE corner of the molecule comes from the pyrazole acid 13 removal of the hydrazine portion reveals the one piece of continuous carbon skeleton 14. 1,3-Dicarbonyl disconnection gives an unenolisable diester (an oxalate) and an unsym-metrical ketone, pentan-2-one 15. 

B.p. about 0°. Very poisonous. Powerful methylating agent. HCl — >- CHgCl. I —> CHgIg. HCN —> acetonitrile. Acetylene—pyrazole. Acids —> methyl esters. Phenols —> methyl ethers. 

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