Furazano[3,4-d]pyrimidines and phosphazene pteridines as new tools in organic chemistry

Abstract

This thesis explores the use of 5,7-diaminofurazano[3,4-d]pyrimidine (64) (R = NH2) for the design of a pro-drug system which is stable in media of pH less than 5 but releases the active drug at pH values greater than 5. In the course of this work, definitive methods were developed for the synthesis of 4-guanidino-3-furazancarboxylic acid in the form of its zwitterion (68), hydrochloride salt (70), monosodium salt (69), and disodium salt (71). Efforts to isolate the metronidazole ester (59) of 4-guanidino-3-furazancarboxylic acid, as a potential pro-drug, were however unsuccessful. In attempts to increase the solubility of this furazancarboxylic acid, the novel 5-N-((a,a-dimethylethoxy)carbonyl)-7(6H)-furazano[3,4-d]pyrimidinone (86) was isolated. 5-Amino-7-methylthiofurazano[3,4-d]pyrimidine (64) (R = SMe) proved to be a highly versatile tool in the synthesis of 2-amino-3-(3-hydroxypropyl)-6,7-diphenyl-4(3H)-pteridinone (113), which was successfully converted to (3-(2-N(N-dimethylaminomethyleneamino-3,4-dihydro-4-oxo-6,7-diphenyl-3-pteridinyl)-propoxy)(2-cyanoethoxy)(N,N diisopropylamino)phosphine (135). This pteridine phosphoramidite (135) was designed to be incorporated into DNA probes for use as a photosensitiser in the laser-activated site-specific cleavage of deoxyoligonucleotides. A series of novel phosphazene pteridines were successfully isolated. Phosphazene pteridines have not appeared previously in the literature. Efforts to convert some of these new phosphazenes to the corresponding nitropteridines by ozonolysis were unsuccessful. However, a new method was developed for the selective monomethylation of the 2-amino function of 3-methylpterin compounds. It involved the addition of methyl iodide to the 2 phosphazinopteridine (223) with subsequent hydrolysis ofthe phosphonium iodide salt (235).