Study On The Synthesis Of Antifolate PT523

PT523 is a non-classical dihydrofolate reductase inhibitor under development by Hana Biosciences company for the treatment of cancer. Because PT523 is close to the patent term, and the synthetic routes of the product in the patent and literature are in low yield, expensive raw material. It is very necessary for us to bring the whole synthetic route of PT523 success and to exploit an economical and practical synthetic route of it's intermediates. This will bring us a good economical and social foreground.The thesis determined a eight-step route to synthesize PT523 by the methods of literature. Cyclization between 2,4,5,6-tetraminopyrimidine andβ-bromopyruvaldo- xime gaved 2,4-diamino-6-bromomethylpteridine(2). The key intermediate, 4-amino- 4-deoxy-N10-formyl pteroic acid(4) was obtained from 2 via condensation, acylation. Condensation between bis-(L-ornithinato)copper and N-carbethoxy phthalimide(6) followed by esterification yielded methyl Nδ-phthaloyl-L-ornithinate (8). Hydrolysis of the intermediate followed by condensation between 4 and 8 gave PT523.The improvement of the method main reflelect: cyclization between 2,4,5,6-tetra minopyrimidine andβ-bromopyruvaldoxime gaved compound 2, the yield of this method is increased by about 10% in contrast with the route that cyclization with 1,3-dihydroxyacetone; in contrast with acylation only via formic acid, the yield of compound 4 is raised by about 12% after adding high activity acylation catalyst DMAP; raising the yield of compound 7 by use sodium sulfide as deproctection agent; determine the best reaction time (30minutes) and solvent (methonal-dimethyl sulf- oxide) to improve the reaction and have a covenient post-processing, during the hydrolysis reaction of methyl Nα-(4-amino-4-deoxy-N10-formylpteroyl)-Nδ-phthaloyl- L-ornithinate(9).The overall yield of PT523 sythesized by the method is 22.78 % on the basis of dikente. The structure of PT523 was confirmed by IR, 1HNMR and ESI-MS. The result indicates that the method is simple , convenient and its yield was increased by about 7% higher than the methods reported in literature.