85597-17-7Relevant articles and documents
Synthesis and Biological Activity of L-5-Deazafolic Acid and L-5-Deazaaminopterin: Synthetic Strategies to 5-Deazapteridines
Taylor, Edward C.,Palmer, David C.,George, Thomas J.,Fletcher, Stephen R.,Tseng, Chi Ping,et al.
, p. 4852 - 4860 (2007/10/02)
Condensation of 2,4-diamino-6(1H)-pyrimidinone with triformylmethane gives 6-formyl-5-deazapterin (13).Acetylation to 14, followed by reductive amination with dimethyl p-aminobenzoyl-L-glutamate and saponification of the resulting acetylated dimethyl ester 16 then gives L-5-deazafolic acid (12).Condensation of α-cyanothioacetamide with 2-methyl-3-ethoxyacrolein gives 3-cyano-5-methyl-2(1H)-pyridinethione (17), which is converted to 2--3-cyano-5-methylpyridine (18) by arylation with p-nitrofluorobenzene.Free-radical bromination of 18 to the 5-bromomethyl derivate, conversion to the corresponding aldehyde 21 by the Kroehnke procedure, formation of the acetal 22, and amination then gives 2-amino-3-cyano-5-(dimethoxymethyl)pyridine (23).This is condensed with guanidine and the product hydrolyzed selectively with formic acid to give 2,4-diamino-6-formyl-5-deazapteridine (26).Reductive amination of 26 with dimethyl p-aminobenzoyl-L-glutamate followed by saponification then gives L-5-deazaaminopterin (6).An alternative synthesis of 13 results from alkaline hydrolysis of 24 followed by acid cleavage of the resulting acetal 25.Two syntheses of 2,4-diamino-6-methyl-5-deazapteridine (32) are described; functionalization of the C-6 methyl group, however, was not possible.Syntheses of 3-formylthietane (45) and its dimethyl and ethylene acetals (44 and 46, respectively) are described, and their utilization as synthons for the pyridine ring in the 5-deazapteridines 51 and 52 is explored.Difficulties militating against this alternate strategy for the preparation of 26 are dicussed.L-5-Deazaaminopterin (6) is equipotent with methotrexate both as an inhibitor of bovine liver dihydrofolate reductase and of L1210 murine leukemia cells.It is also equipotent with methotrexate in vivo both against L1210 and P388 leukemia in BDF1 mice.
Pyridopyrimidines. Synthesis of the 5-Deaza Analogues of Aminopterin, Methotrexate, Folic Acid, and N10-Methylfolic Acid
Temple, Carroll,Elliott, Robert D.,Montgomery, John A.
, p. 761 - 764 (2007/10/02)
Reaction of bromoacetic acid with N,N-dimethylformamide and phosphorus oxychloride gave a triformylmethane derivative, which was condensed with 2,4-diaminopyrimidin-6(1H)-one (2) in water at reflux to give 2-amino-4(3H)-oxopyridopyrimidine-6-carboxaldehyde (4).The structure of 4 was confirmed by conversion to the 2,4-dinitrophenylhydrazone and oxidation to the known 6-carboxylic acid (6).Similarly, condensation of 1 with 2,4,6-triaminopyrimidine gave 2,4-diaminopyridopyrimidine-6-carboxaldehyde (5).Reductive alkylation of diethyl (p-aminobenzoyl)-L-glutamate (9) with 5 in 70percent acetic acid over Raney nickel gave diethyl N-pyrimidin-6-yl)methyl>amino>benzoyl>-L-glutamate (10), which was saponified with base to give the corresponding glutamic acid 11 (5-deazaaminopterin).The latter was methylated with formaldehyde and sodium cyanoborohydride to give 5-deazamethotrexate (12).Reductive alkylation of 9 with 4 gave diethyl N-pyrimidin-6-yl>methyl>amino>benzoyl>-L-glutamate (13), which was converted to the corresponding glutamic acid 14 (5-deazafolic acid).The preferred route for the preparation of 14 involved the hydrolysis of 10 with base at reflux, which resulted in replacement of the 4-amino group and saponification of the ester groups.Methylation of 14 with formaldehyde and sodium cyanoborohydride gave 5-deaza-10-methylfolic acid (15), which was also prepared by alkaline hydrolysis of the 4-amino group of 12.
