Purine 2,6-diamino-8- -, ring

A 2- or 6-hydroxy-substituted purine can be prepared from the corresponding 4,5-diamino-pyrimidinol by cyclization with an acid, ester, ortho ester, or amide. If the ring closure is performed with reagents such as urea, alkyl chloroformates, urethanes, phosgene, and alkyl isocyanates, the 8-hydroxypurines are formed. Various xanthine and uric acid derivatives have been prepared by the condensation of 5,6-diaminopyrimidine-2,4-diols with formic acid. Purin-2-ol (1) was prepared by this route from 4,5-diaminopyrimidin-2-ol and ethyl orthoformate. ... 

The reduction of l,7,9-trimethyl-2,8-diaminopurinium diiodide (416, R = H) gave only one product with NBH, the 2,8-diamino-4,5,6,9-tetrahy-dro-1,7,9-trimethyl-1//-purine cation (417, R = H). The 1,6,7,9-tetra-methylpurine 416 (R = Me) similarly gave the tetrahydro product 417 (R = Me). Both of these products were isolated as the dihydrochlorides in high yield and contained a cis-ring junction. ... 

The ring closure of 4,5-diamino-6-methylpyrimidin-2-one with sodium nitrite in cold, dilute acetic acid was slow enough (2 days) for nitrous acid to react with the 6-methyl-8-azapurin-2-one to give 6-hydroximino-8-aza-purin-2-one. Replacement of acetic by hydrochloric acid accelerated the cyclization, and 6-methyl-8-azapurin-2-one was produced in 75% yield. ... 

In an interesting comparative study, a number of derivatives of cAMP in which diamino-alkane chains are attached to C-2, C-6, and C-8 of the purine ring have been studied for their ability to stimulate cAMP-dependent protein kinase before and after immobilization on CNBr-Sepharose. For the soluble derivatives, the iV -substituted cAMP species were as effective as cAMP itself, and more effective than the 8- and 2-substituted derivatives. The effectiveness of the immobilized A -substituted compounds in retaining protein kinase was little affected by the length of the spacer arm, or the coupling density. 8-(2-Aminoethyl)aminoadenosine 3, 5 -monophosphate, attached to Sepharose, has been used to purify cGMP-dependent protein kinase. ... 

The preparation of 9-niethyl and 9-butyl-2-hydroxy-8,9-dihydro-7H-purine-8-thione (XXVa Table 7) is somewhat unusual. Brown [45) has obtained these compounds from carbon disulfide and respectively f-methyl and 1 -butyl-5,6-diamino-1,2-dihydropyrimidin-2-one (XXIVa.). Evidently a shift of the alkyl group from the 3-N to the 9 N atom must occur during the ring closure. The structure of these two purines has been confirmed by their independent synthesis from 4-methylamino and 4-butylamino-5-amino-2-hydroxy pyrimidine. 

A halogen atom in ortho-position to the amino group in a heterocyclic ring is also very reactive so much so in fact, that 4-chloro-5,6-diamino pyrimidines (CXX) react with carbon disulfide to give 7-amino-t,2-dihydrothiazolo[5,4-d]pyrimidine-2-thiones (XXVIa) (21) rather than 6-chloro-8,9-dihydro-7H-purine-8-thiones (XXV, Rg—Cl) (compare I.3.b). These products are listed in Table 17. 

Three methods were reported to obtain the title compounds. The first was based on a reaction sequence starting from 5,6-diamino-4-thiouracil-sodium salt, alkylation with 1,2-dibromoethane to 7,8-diamino-2,3-dihydro-5//-thiazolo-[3,2-c]pyrimidine (135) and fusion with urea or thiourea under formation of a third ring to the respective 7,8-dihydrothiazolo[2,3-/]purine-2,5(l//,3//)-dione (136) and 2,3,7,8-tetrahydro-2-thioxothiazolo[2,3- ]purin-5(l//)-one (137) (92FES1315) (Scheme 37). 

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). 

In their efforts to prepare purine ring analogs for biological studies, Temple and co-workers reported on the 85% conversion of diamino-1//-l,2,3-triazolo[4,5-c]pyridine 57 under basic condition to give the fused triazole diamino-3//-l,2,3-triazolo[4,5-6]pyridine 58. This reaction was shown to proceed through a diazo intermediate. 

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