80360-09-4Relevant articles and documents
Synthesis and Biological Activities of 5-Deaza Analogues of Aminopterin and Folic Acid
Su, Tsann-Long,Huang, Jai-Tung,Burchenal, Joseph H.,Watanabe, Kyoichi A.,Fox, Jack J.
, p. 709 - 715 (2007/10/02)
N-pyrimidin-6-yl)methyl>amino>benzoyl>-L-glutamic acid (1a, 5-deazaaminopterin) and the 5-methyl analogue (1b) were synthesized in 14 steps from 5-cyanouracil (4a) and 5-cyano-6-methyluracil (4b), respectively, by exploitation of the novel pyrimidine to pyridopyrimidine ring transformation reaction.The 5-cyanouracils 4 were treated with chloromethyl methyl ether to the 1,3-bis(methoxymethyl)uracils (5, which were treated with malononitrile in NaOEt/EtOH to give the pyridopyrimidines 6.Diazotization of 6 in concentrated HCl afforded the 7-chloro derivatives 8 in high yield.After reduction of 8, the 7-unsubstituted products 9 were reduced in the presence of Ac2O and the products, 6-(acetamidomethyl)pyridopyrimidines 10, were converted into the 6-acetoxymethyl derivatives 12 via nitrosation.After removal of the N-methoxymethyl groups from 12, the 6-(acetoxymethyl)pyridopyrimidine 2,4(1H,3H)-diones 14 were converted into 2,4-diamino-6-(hydroxymethyl)pyridopyrimidine (15a) and its 5-methyl analogue 15b by the silylation-amination procedure.Compounds 15 were brominated to the 6-bromomethyl derivatives 16, which were treated with diethyl (p-aminobenzoyl)-L-glutamate, and the products 17 were saponified to afford 5-deazaaminopterin (1a) and its 5-methyl analogue 1b.Compopund 1b was also prepared by an alternative procedure in 10 steps from cyanothioacetamide and ethyl β-(ethoxymethylene)acetoacetate via 2,4-diamino-6-(hydroxymethyl)-5-methylpyridopyrimidine (15b). 5-Deaza-5-methylfolic acid (2) was also prepared in four steps from 15b.The aminopterine analogues 1 showed significant anticancer activity in vitro and in vivo, whereas thefolic acid analogue 2 did not exhibit any significant toxicity.
Syntheses and Antifolate Activity of 5-Methyl-5-deaza Analogues of Aminopterin, Methotrexate, Folic Acid, and N10-Methylfolic Acid
Piper, J. R.,McCaleb, G. S.,Montgomery, J. A.,Kisliuk, R. L.,Gaumont, Y.,Sirotnak, F. M.
, p. 1080 - 1087 (2007/10/02)
Evidence indicating that modifications at the 5- and 10-positions of classical folic acid antimetabolites lead to compounds with favorable differential membrane transport in tumor vs. normal proliferative tissue prompted an investigation of 5-alkyl-5-deaz
2,4-Diamino-6-(hydroxymethyl)pyrido[2,3-d]pyrimidine
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, (2008/06/13)
There is disclosed a novel intermediate useful in the preparation of pyrido [2,3-d] pyrimidines, which includes N-[4-[(2-amino-4(3H)-oxopyrido[2,3-d]pyrimidin-6-yl)methylamino]benzoyl]-L-glutamic acid (5-deazafolic acid), N-[4-[[2-amino-4(3H)-oxopyrido[2,3-d]-pyrimidin-6-yl)methyl]methylamino]benzoyl]-L-glutamic acid (5-deaza-N10 -methylfolic acid), N-(4-[(2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)methylamino]benzoyl]-L-glutamic acid (5-deazaaminopterin), and N-[4-[[2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)methyl]methylamino]benzoyl]-L-glutamic acid (5-deazamethotrexate). This intermediate is the compound 2,4-diamino-6-(hydroxymethyl)pyrido-[2,3-d]pyrimidine.
Pyrido[2,3-d]-pyrimidines
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, (2008/06/13)
There is disclosed a novel intermediate useful in the preparation of pyrido[2,3-d]pyrimidines, which includes N-[4- [(2-amino-4(3H)-oxopyrido[2,3-d]pyrimidin-6-yl)methylamino]benzoyl]-L-glutamic acid (5-deazafolic acid), N-[4-[[(2-amino-4(3H)-oxopyrido[2,3-d]-pyrimidin-6-yl)methyl]methylamino]benzoyl]-L-glutamic acid (5-deaza-N10 -methylfolic acid), N-[4-[(2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)methylamino]benzoyl]-L-glutamic acid (5-deazaaminopterin), and N-[4-[[(2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)methyl]methylamino]benzoyl]-L-glutamic acid (5-deazamethotrexate). This intermediate is the compound 2,4-diaminopyrido[2,3-d]pyrimidine-6-carboxaldehyde.
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.
