Pyrimidine,2,4-diamino-5- synthesis

Pyrimido[5,4-d]pyrimidine, 6,8-diamino-4-hydroxy-2-phenyl-synthesis, 3, 364... 

For the preparation of triazolopyrimidines three main types of synthesis are in use. The first of these proceeds from a pyrimidine derivative (especially the 4,5-diamino derivatives) and closes the triazole ring. The second method proceeds, on the contrary, from derivatives of u-triazole to close the pyrimidine ring. The third method finally is one which yields the derivatives through substitution or replacement of substituents in compounds prepared by one of the first-named procedures. 

Balzarini J, Schols D, Van Laethem K, De Clercq E, Hockovd D, Masojidkova M, Holy A (2007) Pronounced in vitro and in vivo antiretroviral activity of 5-substituted 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidines, J Antimicrob Chemother 59 80-86 Beadle JR, Wan WB, Ciesla SL, Keith KA, Hartline C, Kern ER, Hostetler KY (2006) Synthesis and antiviral evaluation of alkoxyalkyl derivatives of 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)adenine against cytomegalovirus and orthopoxviruses, J Med Chem 49 2010-2015... 

Poullain and co-workers ° synthesized Af-substituted-3,5-diamino-4-nitropyrazoles by treating substituted pyrimidines with Af-alkylhydrazines. 3,5-Diamino-4-nitropyrazole (14) has been synthesized by treating the pyrimidine (13) with hydrazine hydrate. This methodology is limited in scope but the products are useful intermediates for the synthesis of insensitive high explosives. 

Pyrazine and pyrimidine heterocycles, like pyridine, are electron deficient and need the presence of an activating/electron-releasing group to allow efficient electrophilic nitration to occur. An example of this strategy is seen during the synthesis of 2,6-diamino-3,5-dinitropyrazine (ANPz) (183) where one of the chloro groups of 2,6-dichloropyrazine (180) is substituted for a... 

Millar and co-workers reported the synthesis of a number of energetic pyrimidines, pyrazines and their bicyclic analogues, including 2,5-diamino-3,6-dinitropyrazine (185) and the quina-zoline (186)." ... 

Aldehydo nitriles are readily available and can be used to prepare 4-amino-6-unsubstituted pyrimidines carrying one or more substituents in any of the other positions. Equivalents of the formyl group are also often used, for example, a 3-ethoxy-, 3-amino-, or 3-haloacrylonitrile. Most syntheses with /3-keto nitriles are carried out with equivalents thereof Such equivalents are /3-substituted /3-alkoxy-, /3-amino-, or /3-haloacrylonitriles. /3 -Ester nitrile reactions are also well established. Malononitriles and substituted malononitriles react readily with thiourea and N-substituted thioureas in refluxing ethanolic sodium ethoxide to form pyrimidine-4,6-diamines. An example is the reaction of N2-malononitrile 680 with N2-thiourea 681 to give N4- 4,6-diamino-2-(l//)-pyrimidinethione 682 which was then used in the synthesis of Ns-labeled adenine derivatives <2001JOC5463>. 

Gangjee, A. Guo, X. Queener, S. F. Cody, V. Galitsky, N. Luft, J. R. Pangborn, W. Selective pneumocystis carinii dihydrofolate reductase inhibitors design, synthesis, and biological evaluation of new 2,4-diamino-5-substituted-furo[2,3-d]pyrimidines./. Med. Chem. 1998, 42, 1263-1271. 

The same type of synthesis affords pyrazino[2,3-e]-1,2,4-triazines (329) and (330) from the diamino precursor (328), by reaction of the latter with glyoxal or phenylglyoxal, respectively. Product (329) is a dihydrate. The fully aromatic intermediate could not be isolated. Formation of (330) involves not only covalent solvation, but also an unusual TV-methylation of the presumed first-formed intermediate, and the suggested mechanism is outlined in Scheme 24 <86JHC33,93H(36)2577>. Reversing the order of polarities of the components allows [4 + 2] cyclization of pyrimidine (331) with orr/io-phenylenediamine (332), giving the benzo fused pyrazino[2,3-c][l,2,6]thiadiazine (333) (a [l,2,6]thiadiazino[3,4-6]quinoxaline]) (Equation (52)) <72ZN(B)1471>. 

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