Deazapteridines and Deazapurines, Inhibitory Analogues of Folic Acid and Guanine

Ethambutol. Synthesis of an unsaturated analog

“…Anal. (CsoH^NsOs) C, , N. Ethyl 3-[(p-Methoxycarbonyl-lV-methylanilino)methyl]-5(6H)-oxopyrido [3,4-fe]pyrazine-7-carbamate (5). A stirred suspension of finely powdered 4 (100 mg, 0.242 mmol) in H20 (10 ml), EtOH (1 ml), and 1 N NaOH (0.32 ml, 0.32 mmol) was treated dropwise with a 0.27% solution of KMn04 (9.44 ml, 0.161 mmol) in H20.…”

“…p-[[(7-Amino-5(6JY)-oxopyrido [3,[4][5][6]pyrazin-3-yl)methyl]methylaminojbenzoic Acid (6). A stirred solution of 5 (2.23 g, 5.43 mmol) and KOH (11.2 g) in EtOH (200 ml) was refluxed under N2 for 16 hr and evaporated to dryness in vacuo.…”

“…Anal. (CiSHi7N5O4.0.5HC1) C, , N. Diethyl lV-[p-[[(7-Acetamido-5(6H)-oxopyrido [3,[4][5][6]pyrazin-3-yl)methyl]methylamino]benzoyl]-L-glutamate Hydrate (5:4) (8). A suspension of 7 (1.01 g, 2.62 mmol) and N,N'-dicyclohexylcarbodiimide (540 mg, 2.62 mmol) in anhydrous pyridine (50 ml) was treated with diethyl-l -glutamiate hydrochloride (628 mg, 2.62 mmol), stirred at 25°for 44 hr, filtered to remove N,N'dicyclohexylurea, and evaporated to dryness in vacuo.…”

“…N-[p-[ [(7-Amino-1,2,5,6-tetrahydro-5-oxopyrido [3,[4][5][6]pyrazin-3-yl)methyl]methylamino]benzoyl]-L-glutamic Acid (10). A solution of 9 (24 mg, 0.06 mmol) in 1 N NaOH (8 ml) was hydrogenated for 80 min at 25°in the presence of 5% palladium on charcoal (25 mg) to absorb 1.2 ml (0.05 mmol) of hydrogen.…”

“…The same intermediate has now been employed for the synthesis of (+)-2,2'-(ethylenediimino)di-3-buten-l-ol (4b), an unsaturated analog of ethambutol. Although the biological activity of this compound has been found inferior to that of the parent compound, its potential use in the preparation of tritium-labeled ethambutol warrants in our opinion the report of the details of its synthesis.t 2-Chloro-3-buten-l-yl chloroformate (1) was condensed in chloroform solution with ethylenediamine to give the symmetric bisurethane 2 that, by treatment with KOH, yielded a 50:50 mixture of meso and dl forms of 3,3'-ethylene-di(4-vinyl-2-oxazolidone) (3). Separation of the two forms was achieved by fractional crystallization from cyclohexylamine, in which the meso form is less soluble, and from pyridine, in which on the contrary the dl form is less soluble.…”