Pyrazole synthesis from pyrimidine with

Although only a few condensed 5 6 or 5 5 aromatic pyrazole derivatives can be isolated from biological sources, the chemistry of condensed pyrazoles has received considerable interest. Condensed pyrazoles with an indene skeleton can be considered as purine analogues and, as such, are expected to have biological activity. The discovery of the xanthene oxidase inhibitory action of pyrazolo[3,4-fiT pyrimidine and the cAMP phos-phodiasterase inhibitory action of pyrazolo[l,5-a]pyrimidines has stimulated considerable interest in the synthesis of analogues of both ring systems. 

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>. 

Cyclocondensation routes also provide access to pyrimidines. 2,3-Disubstituted pyrido[2,3-/i]-quinazolin-4(3//)-ones are obtained via cyclocondensation of 5-aminoquinoline-6-caiboxylic acid with acid chlorides <02SC235>. 5,6,8-Trialkyl-7-methoxy-2-aminoquinazolines are obtained from 1,3-dimethoxybenzenes via cyclocondensation of intermediate dihydrobenzenes with guanidine carbonate <02TL3295>. Diastereoselective intramolecular hetero Diels-Alder cyclization of a pyrazole carboxaldehyde condensed onto 1,3-dimethylbarbituric acid (101) gave polycyclic heterocycle 102 <02T531>. An efficient one-step synthesis of cyclobutene-annelated pyrimidinones 103 from methyl 2-chloro-2-cyclopropylideneacetate and amidines has been... 

A synthesis of sildenafil, which contains a bicyclic system (a l//-pyrazolo[4,3- f pyrimidine) isomeric with that of a purine, starts with a routine synthesis of a pyrazole (cf. 25.12.1.1) followed by M-methylation and ring nitration. Functional group manipulation provides a pyrazole equivalent to AICA (27.11.1.2) from which the pyrimidone ring is formed via reaction with an aromatic acid chloride. 

The synthesis of pyrazolo[5,1 -6]purin-2-ones 261 started from ethyl 7-amino-pyrazolo[l,5-a]pyrimidine-6-carboxylates 262, following hydrazinolysis and reaction with HN02 gave the corresponding azide and the modified Curtius reaction closed the third pyrazole ring of 261. The final tricyclic 261 can be hydrolyzed to 6,7-diamino-pyrazolo[l, 5-a]purines (68CPB2195) (Scheme 77). 

An extremely simple one-pot synthesis of pyrazoles, pyrimidines, and isoxazoles has been realized by reacting enamino ketones, formed in situ with the appropriate bidentate nucleophile, under the action of microwaves [38]. Another approach to pyrazole from 4-alkoxy-l,l,l-trichloro-3-alken-2-ones and hydrazines, with toluene as solvent, is also possible under microwave conditions [39]. The Ullman coupling of (S)-[l-(3-bromophenyl)ethyl]ethylamine with N-H-containing heteroarenes such as pyrazole in N-methylpyrrolidone afforded the N-arylated compounds in high yields under microwave heating conditions at 198 °C [40]. 

More recently, to find more effective methods to construct bis(heterocycle)s containing a pyrimidine ring from MBH derivatives, the solid-phase parallel synthesis of new annulated pyrimidinone derivatives was disclosed (Scheme 4.219). " The resin-bound allyl amine derivatives 742 were treated with cyanogen bromide to yield the pyrazole derivatives 743 in good yields under standard conditions. The subsequent lactonization with cleavage of the resin afforded the pyrimidinone derivative 744 in good yields in the presence of 20% triethylamine in chloroform under reflux. 

SCHEME 2.108 Synthesis of 6-thioxo-4,5,6,7-tetrahydro-4//-pyrazolo[3,4-their reactions with CS2. 

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