Studies of antitumor-active 5-fluorouracil derivatives. I. Synthesis of N-phthalidyl 5-fluorouracil derivatives.

Kamata, Satsuo; Haga, Nobuhiro; Matsui, Toshiyasu; Nagata, Wataru

doi:10.1248/cpb.33.3160

Cited by 11 publications

(13 citation statements)

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“…Previously, Kamata et al 21 had shown that for the alkylation of 5-FU with a cyclic ACOM halide (phthalidyl halide), greater selectivity for alkylation of the 1-position could be achieved by converting the halide-leaving group to a poorer leaving group, a quaternary ammonium ion, by reacting the halide with an appropriate tertiary amine. Subsequent reaction of the quaternary salt with 5-FU required a catalytic amount of base for alkylation to take place.…”

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confidence: 99%

1-Alkylcarbonyloxymethyl Prodrugs of 5-Fluorouracil (5-FU): Synthesis, Physicochemical Properties, and Topical Delivery of 5-FU

Taylor

Sloan

1998

Journal of Pharmaceutical Sciences

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1-Alkylcarbonyloxymethyl (1-ACOM) prodrugs of 5-fluorouracil (5-FU) have been synthesized and characterized by their solubilities in isopropyl myristate (SIPM) and pH 4.0 buffer (SH2O), by their partition coefficients between isopropyl myristate (IPM) and pH 4.0 buffer (K) and by their abilities to deliver total 5-FU species into (Cs) and through (Ji) hairless mouse skin from an IPM vehicle. All of the prodrugs were much more lipophilic (SIPM) than 5-FU (> 60 times), and two members of the series (alkyl = C1 and C2, acetyl- and propionyloxymethyl) were also more soluble in water than 5-FU. The two more water-soluble members gave larger Ji values than the other members of the series, with C2 exhibiting the best biphasic solubility and the largest Ji value (16 times that of 5-FU). The ability of the 1-ACOM-5-FU prodrugs to deliver total 5-FU species into skin (Cs) was greater than the delivery of 5-FU by 5-FU, except for the last two members of series (alkyl = C7 and C9, octanoyl- and decanoyl-oxymethyl). However, the ratios of normalized Cs to Ji for the series was less than that exhibited by 5-FU, except for C7 and C9. Also, except for C9, significant amounts of intact prodrug as percentages of total 5-FU species were found in the receptor phases during the course of the diffusion cell experiments, ranging from 55% for C1 to 12% for C7.

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Section: Resultsmentioning

confidence: 99%

1-Alkylcarbonyloxymethyl Prodrugs of 5-Fluorouracil (5-FU): Synthesis, Physicochemical Properties, and Topical Delivery of 5-FU

Taylor

Sloan

1998

Journal of Pharmaceutical Sciences

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“…Somewhat higher yields (40-50%) were obtained from the aminolysis of the 1,3-bisphthalidyl-5-fluorouracil derivatives in the corresponding cyclic series [7]. The best yields in the cyclic series (50-94%) were obtained by hydrolysis of 1-acyl-3-phthalidyl-5-fluorouracil derivatives [7,8]; the yields were somewhat lower (35-72%) if based on the starting 1-acyl-5-fluorouracil. However, application of this approach of acylating the 1-position then alkylating the 3-position and hydrolyzing the 1-acyl group of 5-fluorouracil has not been reported for the syntheses of the acyclic series of 3-alkylcarbonyloxymethyl derivatives of 5-fluorouracil.…”

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confidence: 98%

“…H o w e v e r, it was not known which 1-acyl derivative ( 1-alkylcarbonyl, 1-arylcarbonyl or 1-alkyloxycarbonyl) would be sufficiently stable under the required alkylation conditions to give good yields of 1-acyl-3-alkylcarbonyloxymethyl-5-fluorouracils. Previously, the analogous cyclic compounds had been obtained by alkylation of 1-alkyloxycarbonyl-5-fluorouracil with 3-bromophthalide and triethylamine [7] or 1-acetyl-5-fluorouracil with 3-bromophthalide and sodium hydride [8]. Thus, any 1-acyl group appeared to be sufficiently stable to be an appropriate choice.…”

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confidence: 99%

“…The competing formation of the quaternary salt was apparently not significant in the reaction of 3-bromophthalide and triethylamine with 1-alkyloxycarbonyl-5-fluorouracil [7] because of the additional steric hindrance to the formation of the quaternary salts posed by the phenyl group attached to the same carbon as the bromide. The solution to the problem here was to use the non-nucleophilic, strong base -1,8-bis(dimethylamino)naphthaleneand an alkyl bromide or iodide in the alkylation of the 1-a c y l -5-fluorouracil starting material (Scheme 2).…”

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Synthesis of 3‐alkylcarbonyloxymethyl derivatives of 5‐fluorouracil

Roberts

Sloan

2002

Journal of Heterocyclic Chem

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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.

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“…In practice most reported syntheses of 3-alkylcarbonyloxymethyl type derivatives of 5-fluorouracil have involved syntheses of symmetrical 1,3-bisalkylcarbonyloxymethyl-5-fluorouracil derivatives and their hydrolyses to give 20-30% yields of the 3-mono derivative from the 1,3-bis derivative in this acyclic series [3,6]. Somewhat higher yields (40-50%) were obtained from the aminolysis of the 1,3-bisphthalidyl-5-fluorouracil derivatives in the corresponding cyclic series [7]. The best yields in the cyclic series (50-94%) were obtained by hydrolysis of 1-acyl-3-phthalidyl-5-fluorouracil derivatives [7,8]; the yields were somewhat lower (35-72%) if based on the starting 1-acyl-5-fluorouracil.…”

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confidence: 99%