Synthesis of 3‐alkylcarbonyloxymethyl derivatives of 5‐fluorouracil

Abstract

3-Alkylcarbonyloxymethyl derivatives of 5-fluorouracil have been synthesized starting with 1-ethyloxycarbonyl-5-fluorouracil. Alkylation of the starting material with alkylcarbonyloxymethyl iodides, generated from the corresponding chlorides by the Finkelstein reaction, in the presence of 1,8-bis(dimethylamino)naphthalene followed by deprotection with 1,1-dimethylethylamine gave good yields (50-60%) of the t a rget derivatives after column chromatography. A 90% yield of 3-acetyloxymethyl-5-fluorouracil was obtained when the corresponding commercially available bromide was used, instead of the in situ generated iodide, and the product could be isolated from the crude reaction by crystallization. An alternate path of sequential alkylation of 5-fluorouracil with alkylcarbonyloxymethyl chlorides in the presence of tertiary amines, exhibiting different reactivities towards the chlorides, gave an excellent yield of 1-acetyloxymethyl-3-propionyloxymethyl-5-fluorouracil in the one instance it was attempted, but subsequent deprotection of the 1-position with methylamine gave only a 24% yield of 3-propionyloxymethyl-5-fluorouracil.

Reaction of α-(n-Alkylcarbonyloxy)alkyl (ACOA) Halides with 4-Hydroxy­acetanilide and 2,2,5,7,8-Pentamethyl-6-chromanol: The Effect of Steric Hindrance­ on Reaction Path

“…[21][22][23][24][25] Unfortunately, a large portion of 3 was destroyed along with 4 when these techniques were applied to mixtures of 3 and 4. Aminolysis with hydrazine 26 and tert-butylamine 27 proved ineffective as well. Failure of these procedures in the present case is probably due to the small differences in pKa between the hydrolysis products of 4a-c (phenol 2a, pKa 9.55) 28 and 3a-c [aryl hemiacetal 8 (Figure 3) approximate pKa 11].…”