An improved synthesis of homopteroic and homofolic acids

Abstract

A more practical synthesis of homopteroic and homofolic acids involving condensation of 2,4,5‐triamino‐6(1H)pyrimidinone (3) with 1‐acetoxy‐4‐[N‐acetyl‐(p‐carbethoxyphenyl)amino]‐2‐butanone (7) is described. The biological activities of homofolic (1‐b) and homopteroic (2‐b) acids were compared and found to be identical with the activities of these products prepared by the unambiguous route.

Methotrexate analogs. 3. Synthesis and biological properties of some side-chain altered analogs

“…Chemistry. Early methods lor the synthesis of MTX and its analogs led to mixtures of compounds which were very difficult to purify.14 Improved syntheses were later developed for folic acid.15 folate analogs,16 18 and MTX analogs19-20 which involve multiple steps. In the work reported here, we chose to utilize a versatile synthetic method for the unequivocal synthesis of 6-substituted pteridines developed by Taylor and coworkers.21 •22 This method involves, in the present instance, the use of the key intermediate 2-amino-3-cyano-5-chloromethylpyrazine 1-oxide (2, Scheme I) , 22 The intermediate p-(methylamino)benzoyl derivatives 3a,c,d used in this synthesis were prepared according to the method of Santi23 by reaction of ¿Y-tosyl-p-(methylamino)benzoyl chloride with the appropriate amine to give la,c,d, followed by detosylation with HBr in glacial AcOH in the presence of phenol.…”

“…On the other hand, it may be related to the detrimental geometrical effect observed for substituents in the 7 position of pteridine antifolates. [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] Enzyme inhibition studies were performed on the same compounds with purified dihydrofolate reductase from three different sources. The results are tabulated in Table II.…”

Synthesis of 7H-pyrimido [4,5-b] [1,4] thiazines related to 7,8-dihydropteridines of biological importance

“…5-Nitro-2-furyl Phenyl Ketone O-Benzoyloxime (15). Benzoyl chloride (1.8 g, 0.013 mol) was added dropwise to a solution of 2.3 g (0.01 mol) of 10 in 15 ml of pyridine with stirring.…”

“…To a solution of 1 (2.2 g, 0.01 mol) and AcONa (4 g, 0.048 mol) in H20-EtOH (300 ml, 1:1) was added l-bromo-4-N-(p-carbethoxyphenyl)amino-2-butanone. 15 The heterogeneous mixture was stirred for 5 hr at room temperature. Tic analysis indicated that the reaction went to completion.…”

5-methyltetrahydrohomofolate

“…Homofolic acid is an analog of folic acid containing an additional methylene group between the pteridine ring and the p-aminobenzoate moiety [3]. Reduced forms of this compound have been shown to be potent inhibitors of bacterial growth [4][5][6] and to increase the mean survival time of mice inoculated with MTX-resistant L1210/FR8 leukemia cells [7].…”