Pyrazolo pyrimidine, synthesis

In a recent report, Gregg and coworkers outline the use of conventional resin-bound isocyanates in scavenging amines for the synthesis of a large library of aryl pyrazolo-pyrimidine carboxamides (Scheme 8.4). Various primary as well as secondary amines were utilized in the amidation of activated nitro phenyl ester. Subsequent scavenging of amines with polystyrene isocyanate afforded the target... 

Scheme 8.4 Utilization of PS-isocyanate for amine scavenging in pyrazolo pyrimidine library synthesis.

Cyclopent-2-en-l-one, 2-hydroxy-3-methyl-synthesis, 3, 693 Cyclopentenone, 4-methoxy-formation, 1, 423 Cyclopenthiazide as diuretic, 1, 174 Cyclopent[2,3-d]isoxazol-4-one structure, 6, 975 Cyclophane conformation, 2, 115 photoelectron spectroscopy, 2, 140 [2,2]Cyclophane conformation, 2, 115 Cyclophanes nomenclature, 1, 27 Cyclophosphamide as pharmaceutical, 1, 157 reviews, 1, 496 Cyclopiloselloidin synthesis, 3, 743 Cyclopolymerization heterocycle-forming, 1, 292-293 6H-Cyclopropa[5a,6a]pyrazolo[l,5-a]pyrimidine pyrazoles from, 5, 285 Cydopropabenzopyran synthesis, 3, 700 Cyclopropachromenes synthesis, 3, 671 Cyclopropa[c]dnnolines synthesis, 7, 597 Cyclopropanation by carbenes... 

Pyrazolo[3,4-d]pyrimidine, 4-amino-tautomerism, 5, 310 Pyrazolopyrimidinediones synthesis, 5, 324 Pyrazolopyrimidines acidity, 5, 309 anions... 

Pyrazolopyrimidines, amino-acidity, 5, 309 alkylation, 5, 310 N-oxide synthesis, 5, 324 synthesis, 4, 525 5, 328 Pyrazolopyrimidines, dimethyl-synthesis, 5, 316 Pyrazolo[ 1,5-a]pyrimidines electrophilic attack, 5,311 synthesis, 5, 271, 320, 331 Pyrazolo[ 1,5-c]pyrimidines electrophilic attack, 5, 312 Pyrazolo[3,4- d]pyrimidines nucleophilic attack, 5, 313 synthesis, 5, 161, 272, 323, 334 tautomerism, 5, 309 Pyrazolo[4,3-d]pyrimidines alkylation, 5, 310 synthesis, 5, 272... 

The inverse electron demand reactions of 2,4,6-tris(ethoxycarbonyl)-1,3,5-triazine and 5-aminopyrazoles to provide a one-step synthesis of pyrazolo[3,4-. 

Microwave-assisted regiospecific shyntesis of 2-trifluoromethyl-7-trihalomethylated pyrazolo[l,5-a]pyrimidines has been reported <06MI358>. A one-step synthesis of pyrazolo[ 1,5-a]pyrimidine via an intermolecular aza-Witting reaction has been achieved <06JHC523>. 

A test library with three novel p38a inhibitory activity has been prepared, among them pyrazolo[3,4-c/]pyrimidine and pyrazolo[3,4-h]pyrazine with potent in vivo activity <06BMCL262>. A convenient route for the synthesis of pyrazolo[3,4-<7]pyrimidine involving Friedlander condensation of 5-aminopyrazole-4-carbaldehyde with formamide or benzamide has been reported <06JHC1169>. A facile synthesis of pyrazolo[3,4-<7]pyrimidines and pyrimido[4,5-<7]pyrimidin-4-one derivatives has been published <06SC2963>. 

An efficient one-pot synthesis of some novel azolo[l,5-a]pyrimidines, via enaminonitriles, has been described <00SC1985>. The utility of 3-aminocinnamonitrile in the synthesis of new pyrazolo[l,5-a]pyrimidines has been reported <00ZN(B)321>. The synthesis of novel arylaminopyrazolo[3,4-d]pyrimidin-4-ones has been described <99IJC(B)1075>. The synthesis and properties of a-Thiagra, a substituted 5-(2-thienyl)pyrazolo[4,3-d]pyrimidin-7-one bioisostere of Viagra, have been described <00H(53)2643>. Imidazo[4,5-b]pyrazines are obtained by the reaction of 4-amino- 5-imino-imidazole derivatives with acetophenone dimethylacetal . 

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. 

Move 3] This work surveys complementary routes for the synthesis of pyrazolo[f,5-a] pyrimidine-7-ones 1 and pyrazolo[l,5-a]pyrimidin-5-ones 2. The use of 1,3-dimeth-yluracil 3 as an electrophile for pyrimidine ring construction affords pyrazolo[f,5-a] pyrimidin-5-ones 2, contrary to literature reports. Novel use of trans-3-ethoxyacrylate 4 as an electrophile also afforded 2, and the isolated intermediates from this reaction support our proposed mechanism. (55 words)... 

While the alkynyl ketone route occurs under mild conditions, and can provide 4-substituted pyrimidines both substituted and unsubstituted at the 6-position, it cannot provide products substituted at the 5-position. However, this can be achieved by use of an oxidative enone cyclization, as demonstrated by the synthesis of the 3-(5-methylpyrimidinyl)pyrazolo[l,5- ]pyridine 1006 from 1002, where air oxidation of the initial adduct was catalyzed by the addition of palladium on carbon <2003T9001>. 

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>. 

Plenty of such routes devoted to the synthesis of pyrazolo[3,4- / pyrimidines, pyrazolo[4,3-tf pyrimidines, as well as pyrazolopyridazines are described in CHEC-II <1996CHEC-II(7)431>. This route is still extensively utilized. Thus, reacting 253 with the amidine acetate 254 in refluxing ethanol yielded 255 (Equation 29) <2006BML731> yields of individual derivatives were not given. 

Ethyl 5-aminopyrazole -carboxylates are converted into pyrazolo[3,4- / pyrimidines via condensation with Ph3P/Bt2 subsequent reaction with an arylazocyanate and further reacting two carbodiimide with amines. Yields ranged from 13 to 65% dependant on the substituent <2006MI1584, 2007BMCL2203>. A similar approach was used for synthesis of triazolo[4,5- / pyrimidine-7(6)ones from ethyl 4-aminothiazolo-5-carboxylates <2007MIxx>. 

When the synthesis of a heterocyclic system containing a diazole fused onto l,2,3-triazin-4-one (e.g., imidazo[4,5-i [l,2,3]tnazin-4-one (Section 10.13.9.1.l(i)) and pyrazolo[3,4-rf [l,2,3]triazin-4-one (Section 10.13.9.1.1(ii))) or 1,2,3-triazole fused onto pyrimidin-4(7)-(di)one (e.g., [l,2,3]triazolo[4,5-rf pyrimidin-4(7)-(di)one (Section 10.13.9.1.l(iv))) is required, the synthesis of the six-membered ring is the most reliable method. There are several recent accounts of six-membered annulations onto 1,2,3-triazoles to give [l,2,3]triazolo[4,5-r/ pyrimidines (Section 10.13.9.1.l(iv)), which are valuable alternatives to 1,2,3-triazole annulation using nitrosation techniques <1996CHEC-II(7)489>. 

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