Pyrazolo pyrimidines, from

Ready formation of pyrazolo[3,4-4 pyrimidines from reaction of 5-aminopyrazole -carboxylic acid derivatives is a well-established route to derivatives of this ring system. A recent application is the conversion of 286 into 288 by reaction with formamide and NIS 287 (Equation 40) <2002BML1687>. 

Several other syntheses of differently substituted pyrazolo[3,4-r/]-pyrimidines from 5-aminopyrazoles have been reported (83CB1547 83JPR41). The most interesting are summarized in Scheme 2 (74ZOR1088 76IJC(B)688 82OPP403). 

SCHEME 2.109 Synthesis of pyrazolo[l,5-a]pyrimidines from 5-amino-3-(pyrrol-2-yl)pyr-azoles by their reaction with dicarbonyl compounds. 

Pyrazoles can be prepared by ring opening reactions of fused systems already containing the pyrazole nucleus. Thus several [5.5], [5.6] and [5.7] fused heterocycles have been opened to substituted pyrazoles, usually in basic medium. In general, the method has little preparative interest since another pyrazole derivative has usually been used to build the ring-fused system. However, due to the unexpected structures obtained, two publications are worthy of notice. 6//-Cyclopropa[5a,6a]pyrazolo[l,5-a]pyrimidine (638) was readily obtained from the corresponding pyrazolopyrimidine by the action of diazomethane at room temperature (Scheme 59) (81H(15)265). When (638) was treated with potassium hydroxide, the pyrazole (640) was formed, probably via the diazepine (639). 

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... 

A series of interesting pyrazolo[3,4-(f pyrimidine derivatives was obtained by a thermal denitrocyclization reaction of hydrazones, e.g. 164 or 166, easily formed from the corresponding aldehyde or ketone hydrazones with halo-nitrouracil derivatives, e.g. 163 (71CC1442, 72CC298). Intermediates 164 or 166 can be isolated and their cyclization in suitable solvents (methanol, DMF, DMSO) provided high yields of the products. Aldehyde hydrazones yielded the corresponding l,7-dihydropyrazolo[3,4-J]pyrimidines, e.g. 165, whereas ketone hydrazones gave l,5-dihydropyrazolo[3,4-pyrimidine derivatives, e.g. spirocyclic compound 167 (Scheme 26). 

Very recently (84) this specific binding of alloxanthine-like compounds to active xanthine oxidase has been made the basis of a method of separating the active from the inactivated enzyme, using a pyrazolo-(3,4) pyrimidine attached to agarose. 

A convenient regioselective one-pot approach to pyrazolo[l,5-o]- and imidazolo[l,2-a]pyrimidine derivatives 79 from aminoheterocycles 78 and a,(3-unsaturated imines 77,... 

A series of antimicrobial pyrazolo[3,4-<7]pyrimidines containing 8-(trifluoromethyl)quinoline have been synthesized from 5-amino-1-[8-... 

Pyrazolo[l,5-a]pyrimidine, the central scaffold in zaleplon, is present in 5, 6 and 7. Compound 5 inhibits the binding of tritiated benzodiazepine in synaptosomal fractions from rat cortex [20] and 6 and 7 inhibit the al GABAa subunit with K, — 53 nM and 17nM, respectively, and showed sedative-hypnotic action following i.p. administration to mice (<90% inhibition of motor activity)... 

The pyrazolo[3, 4-d] pyrimidines are substrates for and inhibitors of xanthine oxidase [266, 267]. 4-Hydroxypyrazolo[3,4-d] pyrimidine was first investigated for its ability to protect 6-mercaptopurine and other analogues from oxidation by xanthine oxidase [384], but it also inhibits the oxidation of the natural purines, hypoxanthine, and xanthine. Its profound effect on uric acid metabolism made it an obvious choice for the treatment of gout and its utility in the control of this disease has been demonstrated [385, 386]. 

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)... 

Pyrazolo[l,5-fc]-l,2,4-triazole 154 " and l,2,4-triazolo[l,5-a]pyridine 156 ring systems were successfully obtained from the corresponding formamidoximes or related ami-doximes 153 and 155, respectively, and acylating agent (TsCl or TFAA) (equations 67 and 68). Similarly, l,2,4-triazolo[l,5-a]pyrimidines were obtained from pyrimidine formamidoximes . 

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>. 

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>. 

The synthesis of fused 1,2,3-triazoles is nearly always achieved by treating 1,2-diamines attached to diazines with nitrous acid (e.g., [l,2,3]triazolo[4,5-f]pyridazine (Section 10.13.9.2.1(iii)) and [l,2,3]triazolo[4,5-rf pyrimidine (Section 10.13.9.2.1(iv)), <1996CHEC-II(7)489>). When a heterocyclic system containing a diazole fused onto 1,2,4-triazine is required, annulation of the five-membered heterocycle is nearly always the most facile route (e.g., imidazo[4,5-r ][l,2,4]triazine (Section 10.13.9.2.l(i)) and pyrazolo[4,3-r ][l,2,4]triazine (Section 10.13.9.2.1(ii))). In support of the latter, the synthesis of the fused six-membered ring of pyrazolo[3,4-r ][l,2,4]triazine from the pyrazo-ledione was reported as low yielding <1996CHEC-II(7)489>. 

B. Synthesis of PYRAZOLo[3,4-r/]pyrimidine 1. From Pyrazole Intermediates... 

The hydrazine 173 reacts with the ethoxymethylene derivative 46 to yield 174. The pyrazolo[3,4-d]pyrimidine 175 is formed from 174 and 165 (84MI2). 

Generally pyrazolo[4,3-d]pyrimidines are prepared from pyrazole-5-carboxylic acid derivatives 180 via nitration to yield 181, which on esterification and reduction affords 184 (72CCC2786 78M11 79BCJ208 80MI35 ... 

Similar to haloazoles and haloazines, 7-halo-substituted pyrazolo[l,5-a]-pyrimidine underwent nucleophilic substitution with a variety of nucleophilic reagents to yield substituted pyrazolo[l,5-a]pyrimidines (74GEP2343702 76JAP761789 83AP697). Thus, 7-chloropyrazolo[l,5-a]pyrimidines 228, generally prepared from the 7-oxo derivatives 227 and phosphorus oxychloride, are converted into the 7-thioxo derivative 229 by the action of thio-... 

Pyrazolo[l,5-a]pyrimidines are the usual cyclization products of N-unsubstituted 3(5)-aminopyrazoles.49 5 3 Reimlinger et al.,54 however, isolated a pyrazolo[3,4-b]pyridine in low yield from 51 and ethyl 2-ethoxyacry-... 

---