Pyrazolo pyridine from pyrazoles

New pyrazolo[l,5-a]pyrimidine derivatives have been synthesized. These compounds are potent angiotensin-ll receptor antagonists <99CPB928>. Pyrazolot3,4-ri]dihydropyridazinone derivatives have been obtained by the reaction of 5-methyl-4-methoxycarbonyl-3-acetyl-1-phenylpyrazole with different hydrazines <99TL3891>. A direct synthesis of pyrazolo [3,4-b]pyridines 69 from pyrazole 67 and benzothiazole 68, through a Friendlander condensation, has been described <99SC655>. 

A range of trifluoromethyl-containing pyrazolo[3,4- ]pyridines have been prepared, in good yield, from the reaction of 4,4,4-trifluoro-3-oxobutanoates with electron-rich amino pyrazoles (Equation 53 Table 29) <2003S1531>. 

A series of pyrazolo[3,4-, pyridazinones 430 and analogues, potentially useful as peripheral vasodilators, were synthesized and evaluated as inhibitors of PDE5 extracted from human platelets. Several of them showed ICso values in the range 0.14-1.4 pM. A good activity and selectivity profile versus PDE6 was found for compound 430 (6-benzyl-3-methyl-l-isopropyl-4-phenylpyrazolo[3,4-r/]pyridazin-7(6/7)-one). Structure-activity relationship studies demonstrated the essential role played by the benzyl group at position 6 of the pyrazolopyridazine system. Other types of pyridazinones fused with five- and six-membered heterocycles (pyrrole, isoxazole, pyridine, and dihydropyridine), as well as some open-chain models were prepared and evaluated. Besides the pyrazole, the best of the fused systems proved to be isoxazole and pyridine <2002MI227>. 

Molecular ions (generally, base peaks in this series of compounds) are often the only peaks reported. The mass spectra of a number of pyrazolo-[l,5-a]pyridines have, however, been analyzed more fully,260-262 with loss of HCN or RCN from the pyrazole ring being the principal fragmentation for each molecular ion. 

When 14 was heated in ethanol under reflux with hydrochloric acid, (Z)-[4-(5-hydroxy-3-methyl-l-phenyl-lH-pyrazol-4-ylmethyhdene)-5-oxo-l-phenyl-4,5-dihydro-lH-pyrazol-3-yl] acetate (17) was obtained in 75% yield, identical with the compound prepared from 14 and 12 in 90% yield. Apparently, partial hydrolysis of enamine 14 took place to furnish in situ pyrazole 12, which reacted as the C-nucleophile with the non-hydrolysed enaminone 14 to afford 17. Compounds 15 were heated with 2 equivalents of DMFDMA in DMF under reflux to give pyrazolo[4,3-c] pyridines 18 in moderate yields. Cyclization proceeds by incorporation of DMFDMA as a Ci synthon between the nucleophilic NH and CH2 groups. In the reaction of 15 (R =4-hydroxyphenyl) with DMFDMA, methylation of the phenolic hydroxy group also took place to give the 5-(4-methoxyphenyl)pyrazolo[4,3-c]pyridine (18 R=4-methoxyphenyl) (Scheme 7). 

Pyrazole and fused heterocychc systems such as dipyrazolo[3,4-l> 3 4 -material chemistry. Sackus, Holzer, and coworkers have developed a new copper-free tandem cycHzation for the synthesis of pyrazolo[4, 3h3,4]pyr-ido[l,2-ii]perimidine 71 from 5-alkynylpyrazole-4-carbaldehydes 69 and 8-naphthalenediamine 70 (2015T(71)3385). They have found that conventional heating of the 5-aIkynylpyrazole-4-carbaldehydes 69 with... 

The reaction of isatin, 3-methyl-l-phenyl-5-aminopyrazole 111, and diketones 112 afforded the spiro-pyrazolo[3,4-b]pyridine-oxindoles 113 (Scheme 37). There could be two possible products 115 and 116 from the latter two N-rmsubstituted pyrazoles 114 due to the presence of an additional nitrogen nucleophilic center but the reaction was completely regioselective and afforded only product 115 (Scheme 38). This outcome of the reaction was explained by high nucleophilicity of the C-4 in comparison to N-1 in 3-phenyl- and 3-methyl-5-aminopyrazoles. 

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