Pyrazolo-pyrimidines, 4-amino

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. 

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). 

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). 

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... 

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

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 . 

CPX, 1,3-dip ropyl-8-cyclopentylxanthine MRE3008F20,5N-(4-methoxyphenylcarbamoyl)amino-8-propyl-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[l,5-c]pyrimidine (human only) NECA, 5 -N-ethylcarboxamidoadenosine SPT,p-sulfophenyltheophylline SCH58261, 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-[4,3-8]-l,2,4-triazolo[l,5-c)pyrimidine IB-MECA N6-(2-iodo)benzyl-5 -N-methylcarboxami-dodiadenosine ZM241385,4-(2-[7-amino-2-[2-fhryl] [l,2,4]triazolo[2,3-a] [l,3,5]triazin-5-yl-amino]ethyl)phenol. 

Both amino groups of 3,5-diamino-4-phenylpyrazole reacted with EMME during 2 min. at reflux [83JCS(P1)11], The amino group at position 3 underwent a cyclocondensation reaction to form the bicyclic pyraz-olo[l,5-a]pyrimidine, while the amino group at position 5 participated in an addition reaction to give a (2,2-diethoxycarbonyl-l-ethoxyethyl)amino side-chain. Pyrazolo[l,5-a]pyridine (25) was obtained in 27% yield. 

At the same time, the cyclization of N-( 1 -substituted 3-pyrazolyl)amino-methylenemalonates (1104) by refluxing in a 1 4.4 mixture of polyphos-phoric acid and phosphoryl chloride for 30 min gave 1-substituted pyrazolo[l,5-u]pyrimidine-6-carboxylates (1105) in good yields (83GEP-3309432). 

Pyrazolo[l,5-a]pyrimidine-6-carboxylates (1402) were prepared in 70% yields in the reaction of 3-aminopyrazoles and diethyl amino(trichloro-methyl)methylenemalonate in boiling ethanol in the presence of sodium ethoxide for 6 hr (78JPR533). 

The reactivity of amino functions on diazotization and condensation with dimethylformamide dimethyl acetal has been discussed in CHEC-II <1996CHEC-II(7)431>. The diamine 220 is readily converted into a variety of tricyclic pyrazolo[3,4-r/ pyrimidines under a variety of conditions <2004T5093>. Thus with chloroacetyl chloride the chlor-oacetyl derivative 221 was formed. This could not be further cyclized into 222. Refluxing 220 with diethyl oxalate afforded 223 while 224 was formed when the reaction was conducted at 40 °C. Treatment of 224 with POCI3 afforded 223. Reacting 220 with carbon disulfide afforded 225 (Scheme 14) <2004T5093>. 

Reaction of 5-amino-l-phenyl-177-pyrazole-l-carboxamide with aromatic aldehydes in the presence of heteropolyacid Hi4[NaP5W3oMoOio] gave derivatives of 6-aryl-l-pyrazolo[3,4-t/]pyrimidin-4-[5//]ones <2006MI1>. 

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