7-Amino-3 pyrazolo

Fluoroadenine, 2-chloroadenine, 2-aminoadenine, 2- and 8-aza-adenines, 4-aminopyra7.olo[3, 4-d] pyrimidine and 6-methylpurine are converted to their ribonucleosidesby adenosine phosphoribosyltransferase,and their ribonucleosides are converted to the ribonucleotides by adenosine kinase most of the ribonucleotides are then converted to the di- and triphosphates. A -Aminoadenine, A -hydroxyadenine, A -methyladenine, purine, 7-deaza-adenine, and 7-amino-pyrazolo[4, 3-d] pyrimidine are either not substrates or are very poor substrates for the phosphoribosyltransferase, but their ribonucleosides are excellent substrates for the kinase. The ribonucleotides of purine, 7-deaza-adenine and... 

Azoloazines having NH functions are weakly acidic and are also basic. TV-Alkylated derivatives act only as bases. Carbon-13 NMR studies on l-isopropyl-4-amino-pyrazolo[3,4-r/]pyrimidine and isomeric 2-isopropyl derivative indicate that N-5 and N-7 are the respective protonation sites <77JA7257>. Allopurinol as well as its derivatives have been shown by UV and NMR to form mono-and diprotonated species in sulfuric acid solutions <75KGS838>. 

The use of high pressure is also essential for preparing racemic and enantiomerically pure C4 amino pyrazolo[3,4-fi(]pyrimidines 143 in satisfactory yield by, S Ar reaction of 4-amino-6-chloro-l-phenylpyrazolo[3,4-d]pyrimidine (141) with the appropriate 2-aminopropan-amides 142 in racemic or enantiomerically pure form. At 1.5 GPa pressure the (5)-enantiomer 143 has been prepared in good yield and shows a high affinity and selectivity for the adenosine Al receptor. The same reactions at atmospheric pressure have been unsuccessful (Scheme 7.35). 

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). 

Formycins pyrimidine antibiotics (see Nucleoside antibiotics) synthesized by Nocardia interforma. For-mycin itself is 3-P-D-ribofuranosyl-7-amino-pyrazolo-(4,3-d) pyrimidine. The biogenetic precursor is adenosine. F. is converted to formycin 5 -triphosphate, which acts as an ATP analog. Mycobacterium and Xantho-monas oryzae are particularly sensitive to formycin. 

A cascade reaction involving 1,3-dipolar cycloaddition of ketenimine was reported by Li et al. [69], The transformation combines a CuAAC reaction, a Lewis add-catalyzed 6-endo cyclization of Af -(2-alkynylbenzylidene)hydrazide, a [2+3] cycloaddition, and an aromatization in a single step to afford 2-amino-//-pyrazolo[5,l-a] isoquinolines 102 in good to excellent yields (Schane 5.66). The copper-catalyzed three-component reaction of sulfonyl azides, alkynes, and nitrones also involves 1,3-dipolar cycloaddition between ketenimine and nitrone (Scheme 5.67) [70]. The nitrone substrates in this transformation could be generated in situ from benzalde-hydes and hydroxylamines. 

Not only benzylazides but also heteroaromatic azides can lead to interesting triazoles. For instance, Dimitrieva et al. reported the preparation of 5-amino-(pyrazolo[3,4-b]pyridm-3-yl)-l,2,3-triazole -carbonitrile 24 by condensation of an heterocyclic azide 22 with 23 (Scheme 7) [36]. 

The 3- or 5-aminopyrazoles are the synthons used most frequently. The second heterocyclic ring is created between the amino group and the 1-position (if unsubstituted) or between the amino group and the 4-position. Thus 3-substituted 5-aminopyrazoles react with 1,3-difunctional compounds to afford pyrazolo[l,5-a]pyrimidine derivatives (538) (Table 34). Aminopyrazolinones (R = OH) can be used instead of aminopyrazoles. Similarly 3-aminoin-dazole yields pyrimido[l,2-h]indazoles (539). 

When the 1-position is substituted, 3- and 5-aminopyrazoles react at the C-4 carbon atom, the reactivity of which is enhanced by the amino group. Thus pyrazolo[3,4-Z ]pyridines (545) are obtained either by the Skraup synthesis or from 1,3-diifunctional compounds. Here also aminopyrazolinones have been used instead of aminopyrazoles to prepare (545 R = OH). If 1,4-ketoesters (succinic acid derivatives) are used instead of /3-ketoesters, pyrazolo[3,4-Z ]azepinones (546) are obtained. 

The pyrazole analogues of anthranilic acids or anthranilonitriles are a convenient source of [5.6] fused systems (for a general review see (80T2359)). Thus 5-amino-4-cyanopyrazoles (in some examples an ester or a hydrazido group replaced the cyano group) have been transformed into pyrazolo[3,4-d]pyrimidines (552) and into pyrazolo[2,3-e]diazepinones (553), and 4-amino-5-methoxycarbonylpyrazoles have been converted into pyrazolo[4,3-d]pyrimidines (554). 

Finally, some results obtained from indazoles substituted in the carbocycle are of interest, even though in these cases the reaction does not involve the heterocyclic moiety (Section 4.04.2.3.2(ii)). For example, pyrazolo[3,4-/]- (566) and pyrazolo[4,3-/]-quinolines (567) have been obtained from aminoindazoles by the Skraup synthesis (76JHC899). Diethylethoxy-methylenemalonate can also be used to give (566 R = C02Et, R = OH) (77JHC1175). Pyrazolo-[4,3-/]- and -[4,3-g]-quinazolones (568) and (569) have been obtained from the reaction of formamide with 5-amino-4-methoxycarbonyl- and 6-amino-5-carboxyindazole, respectively (81CB1624). 

Pyrazolo[3,4-b]pyridin-4-one, 1,3,6-trimetbyl- C NMR, 5, 332 <75JHC517) Pyrazolo[3,4-b]pyridin-6-one, 1,3,4-trimetbyl- C NMR, 5, 332 <75JHC517) Pyrazolo[l,5-a]pyrimidine electron density, 5, 306 <75CJC119) Pyrazolo[3,4-d]pyrimidine electron density, 5, 306 <58JCS2973, 69CJC1129) Pyrazolo[3,4-d]pyrimidine, 4-amino- C NMR, 5, 310 <58JCS2973) Pyrazolo[4,3- /]pyrimidine electron density, 5, 306 <58JCS2973)... 

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... 

Reactions of 3-hydrazino-l,2,4-triazine 1-oxide 31 or 3-hydrazinopyrido [2,3-c]-l,2,4-triazine 1-oxide 32 with diethoxymethyl acetate or triethyl orthoformate proceed as cyclization reactions at the N(4) atom and the amino group to form the corresponding pyrazolo[3,4-c]-l,2,4-triazine 6-oxides 33 and 34 (74MI, 80JOC5421, 80MI). 

Diazotization of 4,5-diphenyl-3-amino-l//-pyrazolo[4,3-c]pyridazine gave diazonium salt 290, whose condensation with 2-naphthol gave 291, which cyclized to 292 (91H901) (Scheme 62). 

Amino-4-arylazopyrazole 338 reacted with benzoyl isothiocyanate to give the expected pyrazol-5-ylthioureas 339, which on heating with acetic acid-hydrochloric acid afforded (76JOC3781) pyrazolo[3,4-e][l,2,41-... 

A development of the reaction described above for the synthesis of pyrrolo[2,l- [l,2,4]triazines using l-aminopyrrole-2-carbonitrile and N,N-dimethyldichloromethyl-iminium chloride utilising ethyl 4-amino-3-cyanopyrazolo[5,1 -c] [ 1,2,4]triazine-8-caiboxylate 60 yields pyrazolo[5,l-c]pyrinudo[4,5-e][l,2,4]triazines 61 <96T3037>. 

Cyano-4-hydroxypyridazino[l,6- ]quinolinium betaine 67 could be isolated from the reaction mixture of 1-amino-2-ethoxycarbonylquinolinium mesitylensulfonate and acrylonitrile in a few percent. Reaction of the 2-amino-1-ethoxycarbonylisoquinolinium salt with acrylonitrile afforded only a pyrazolo[5,l- ]isoquinoline derivative. 

Further activities in research into 6-amino-7-oxotetrahydro-177,577-pyrazolo[l,2- ]pyrazole-l-carboxylic acid derivatives 677 exhibiting inhibition of penicillin-binding protein have been reported <1997JHC1323>. 

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

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