Purines from 4,5-diaminopyrimidines

Table 7 Preparation of purines from 4,5-diaminopyrimidines and formate equivaients...

Similarly, Dang and co-workers reported the displacement of one chloride from pyrimidine 44 with various amines to give diaminopyrimidines 45 <00TL6559>. These compounds were then subjected to a FeCb-SiOz-promoted cyclocondensation with various aldehydes to produce trisubstituted purines 46 in moderate to good yields as potential adenosine regulating agents. 

The Traube purine synthesis using 5,6-diaminopyrimidines is well known (1900CB1371, 1900CB3035). According to this method, uric acids are formed from 5,6-diaminouracils and one carbon (Cl) reagents, such as... 

Almost all recorded purine syntheses from imidazoles involve the cyclization of 5(4)-aminoimidazole-4(5)-carboxylic acid derivatives especially the carboxamides, thiocar-boxamides, carboxamidines, carboxamidoximes, nitriles and esters. The intermediates used for completion of the purine ring are much the same as have been used for Traube cyclization of diaminopyrimidines (Section 4.09.7.3), especially formic and carbonic acid derivatives, and cyclization generally occurs-under much milder conditions. This feature has been of special value in the synthesis of purine nucleosides from imidazole nucleoside precursors. The resultant purine will have variable substituents at C-2 and C-6 and it is convenient to discuss and classify the various preparations largely in terms of the introduced 2-substituents. The C-6 substituents largely reflect the type of carboxylic acid moiety used and do not vary very much between amino, oxo and thioxo. 

Purine is probably best prepared by the Traube route from 4,5-diaminopyrimidine and formic acid in an atmosphere of carbon dioxide (83% yield) (54JA6073), or, better, using diethoxymethyl acetate as the cyclizing agent (82% yield) (60JOC395). 

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. ... 

Thus, the synthesis of purine may start from 4,5-diaminopyrimidine 14 to which the imidazole moiety is added, or fi om 4(5)-amino-5(4)(iminomethyl)imidazole 15 onto which the pyrimidine part is cyclized. 

To date, no methods for directly accessing 6,8-ditrifluoromethylpurines from purine starting materials exist. It is, however, possible to prepare these compounds from the corresponding 4,5-diaminopyrimidines. Subjecting either 4,5-diamino-2-chloro-6-trifluoromethylpyrimidine or 2,4,5-tiiamino-6-trifluoromethylpyrimidine to a mixture of trifluoroacetic acid and trifluoroacetic anhydride at reflux, gave the corresponding 2-substituted-6,8-ditrifluoromethylpurine in 28 % (133) and 22 % (134), respectively [60, 149] (Scheme 48). 

Outstanding among drugs which inhibit the production of DNA from several stages back in the biosynthetic pathway are the sulphonamides and the 2,4-diaminopyrimidines used so much as antibacterials and anti-malarials. All of the chemotherapeutic sulphonamides, whether simple sulphanilamide (4.5a) or its more complex heterocyclic derivatives 4.5b) including sulphadiazine, competitively inhibit the enzymes dihydrofolate synthetase which produces dihydrofolic acid 2.14) (see p. 28). The basis of this inhibition, as outlined in Section 2.1 (p. 28), is the similarity in the steric and electronic properties of p-aminobenzoic acid 2,13) (which the enzyme is ready to build into new molecules of dihydrofolic acid) and the sulphonamides (4.5) which, when taken up by the enzyme, merely block it. The basis of the selectivity of these antibacterial sulphonamides depends on two factors, which reinforce one another (i) mammals lack the enzymes necessary for the synthesis of dihydrofolic acid, and hence they tolerate these sulphonamides very well (ii) pathogenic bacteria lack the permease with the aid of which mammals absorb dihydrofolic acid from the diet. Further relevant data will be foimd in Section 9.3. Dihydrofolic acid is only two steps away from the coenzyme required for biosynthesis of thymine and all the purine bases. Deprived of the substrates, especially thymine, bacteria soon die because they can make no new DNA. 

---