The synthesis of pyrido[2,3-d] pyrimidine derivatives as potential antitumor and antibacterial agents
Creators: name: Shim, Jaewon Lee
Publisher: name: University of Utah
Year: 2012
Subjects: Tumors
Experimental Studies
Pharmacology

description: The significant anti-tumor activity of 4-oxopyrido[2,3-d]-pyrimidine (1), 2,4-dioxopyrido[2,3-d]pryimidine (2) and 2-methylthio-4,5-dioxo-6carbethoxypyrido[2,3-d]pryimidine (3) prompted the development of new approaches to the synthesis of this ring system.  The reagent selected for the conversion of a series of 6-aminouracil derivatives (57) to the corresponding pyrido[2,3-d]-pyrimidines was dimethyl acetylenedicarboxylate.  The condensation was carried out in two different sets of reaction condition using aprotic media.  The two sets of reaction condition gave, in fair yield, entirely different products.  In aprotic media such as dimethyl formamide (DMF), 1, 1,2-dimethoxyethane and dioxane, the 6-aminouracil derivatives (57a-c) gave C-5 acylated compounds (58a-c) upon reaction with dimethyl acetylenedicarboxylate.  The following three compounds, 1,3-dimethyl-6-aminouracil (57a), 1-methyl-6 aminouracil (57b) and 1, 3-dibenzyl-6-aminouracil (57c) in DMF gave, in fair yield, 1,3-dimethyl-6-amino-5-(3-carbomethoxy-wpropynoyl)uracil (58a), 1-methyl-6-amino-5-(3-carbomethoxy-2-propynoyl)uracil (58b( and 1,3-dibenzyl-6-amino-5-3-carbomethoxy-2-propynoy)uracil (58c) respectively.  However, 6-aminouracil itself (57d) gave no such product.  To resolve this apparent anomaly, acetylation of 6-aminouracil derivatives was evaluated as a model system.  1,3-Dimethyl-6-amino-uracil (57a) and 1-methyl-6-aminouracil (57b), both of which have N-1 substituents, gave 5-acetyl products (60a, 60b) whereas 6-aminouracil (57d) and 3-methyl-6-aminouracil (61), which have no N-1 substituents, yield N-6-acetyl derivatives (62am 62b).  A plausible reaction mechanism for this difference in position of acylation is presented and discussed.  Catalytic hydrogenation of 1,3-dimethyl-6-amino-5-(e-carbomethoxy-2-propynoyl)uracil (58a) gave the cis olefin 65.  This olefin is very resistant to further reduction.  The trans isomer 66 was prepared by C-t acylation of 1,3-dimethyl-6-aminouracil (57a) with methyl-3-choroformyl-tans-acrylate.  The condensation of 6-aminouracil derivatives (57) with dimethyl acetylenedicarboxylate in protic media such as water and methanol produce the initially sought pyrido[2,3-d]pyrimidines.  Treatment of 1,3-dimethyl-6-aminouracil (57a), 1-methyl-6-aminouracil (57a), 1-methyl-6-aminouracil (57b), 1,3-dibenzyl-6-amiouracil (57c) and 6-aminouracil (57d) with dimethyl acetylenedicarboxylate in refluxing methanol or water gave yields of substituted 2,4,5-troxo-7-carbomethoxypryido-[2,3-d]pyrimidines (67), regardless of presence of N-1 substituents.  This was confirmed by establishing as identical the products (78) obtained by diazomethane methylation of both 1,3-dimethy1-2,4,5-trioxo-7-carbomethoxpyrido[2,3-d]pyrimidine (67a) and 2,4,5-troxo-7-carbomethoxyprido[2,3-d]pyrimidine (67d).  6-Aminouracil (57d) and 1, 3-dimethyl-6-aminouracil (57a) have also been shown to undergo the same type of condensation with diethyl ethoxymethylene-malonate to give 2,4,5,-trioxo-6-carbethoxypyrido [2,3-d]pyrimidine (71) and 1,3-dimethyl-2,4,5-trioxo-6-carbethoxyprido[2,3-d]-pyrimidine (72), respectively.  A key intermediate, diethyl-N-(2,4-dioxo-6-pyrimidinyl)aminomethylenemalonate (70), was isolated from the reaction of 6-aminouracil (56d) with diethyl ethoxymethylene-malonate and subsequently cyclized thermally to compound 71.  The structure assignment of the substituted 2,4,5-troxo-7-carbo-methoxypyrido[2, 3-d]pyrimidines (67 was established by preparing 1,3,-dimethyl-2,4,5-trioxopyrido[2,3-d]pyrimidine (80) from both of 1,3-dimethyl-2,4,5-trioxo-7-carbomethoxypyrido[2,3-d]pyrimidine (67a) and 1,3-dimethyl-2,4,5-troxo-6-carbethoxypyrido[2,3-d]-pyrimidine (72) by hydrolysis and decarboxylation.  A relationship between product ratio (C-5 acylated vs. ring cyclized compound) and the effective proton concentration of reaction of reaction media in the reaction of 6-aminouracil derivatives (57) and dimethyl acetylenedicarboxylate, mechanistic considerations for the pyrido[2,3-d]pyrimidine ring cyclization and the pmr spectra of the new compounds synthesized were discussed in detail