A Facile Synthesis of 1-(2-Tetrahydrofuryl)-5-fluorouracil (Ftorafur)

A number of N-acyl and N-(alkoxycarbonyl)-5-fluorouracil derivatives possessing, for example, benzoyl, o-toluyl, acetyl, propionyl, heptanoyl, ethoxycarbonyl, phenoxycarbonyl, and benzyloxycarbonyl groups as N1 and/or N3 substituents were synthesized, and their antitumor activities were evaluated. The synthesis was achieved by a direct and two-step acylation of 5-fluorouracil and by selective N1-deacetylation of N1-acetyl-N3-substituted-5-fluorouracil under appropriate reaction conditions. Several N3-benzoyl- and N3-o-toluyl-5-fluorouracil derivates and showed significant activity against experimental tumor, and N1-acetyl-N3-o-toluyl-5-fluorouracil was found to be most promising among them. Further investigation revealed 12 to retain higher activity toward various tumors, with lower toxicity and good blood level, than either 1 or FT-207, even for oral administration.

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“…T/C > 130% is the criterion for activity; see Experimental Section. 6 Decrease of body weight was observed.…”

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confidence: 96%

Studies on the syntheses of heterocyclic compounds. 845. Studies on the synthesis of chemotherapeutics. 10. Synthesis and antitumor activity of N-acyl- and N-(alkoxycarbonyl)-5-fluorouracil derivatives

Kametani¹,

Kigasawa²,

Hiiragi³

et al. 1980

J. Med. Chem.

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“…The CHC13 layer was separated, and aqueous 1 N NaOH solution was added to adjust the pH to 10-12. The mixture was kept at room temperature for 2 h, maintaining the pH of the aqueous layer at [10][11][12] with vigorous stirring. The aqueous layer was then adjusted to pH 4-6 with dilute HC1 and the CHC13 layer was separated.…”

Section: Methodsmentioning

confidence: 99%

Studies on antitumor agents. 2. Syntheses and antitumor activities of 1-(tetrahydro-2-furanyl)-5-fluorouracil and 1,3-bis(tetrahydro-2-furanyl)-5-fluorouracil

Yasumoto¹,

Yamawaki²,

Marunaka³

et al. 1978

J. Med. Chem.

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Convenient and efficient methods were developed for preparing 1-(tetrahydro-2-furanyl)-5-fluorouracil (Thf-FU, 3) [trade name, Futraful (Ftorafur) or FT-207], which is used clinically as an antitumor agent, and 1,3-bis(tetrahydro-2-furanyl)-5-fluorouracil (Thf2-FU, 4). For the syntheses, 2,4-bis(trimethylsily)-5-fluorouracil (Me3Si-FU, 1) and 2-acetoxytetrahydrofuran (Thf-OAc, 2) were condensed in the presence of Friedel-Crafts catalysts, such as SnCl4 and BF3-Et2O in dichloromethane, or in the presence of NaI in acetonitrile to give Thf-Fu or Thf2-FU depending on the reaction conditions and workup procedure. A trace of 3-(tetrahydro-2-furanyl)-5-fluorouracil (3-Thf-FU, 5) was formed in these reactions. Thf2-FU was easily hydrolyzed to Thf-FU. 2-Methoxytetrahydrofuran can be used instead of Thf-OAc for preparation of Thf-FU under similar conditions. The optimal ratios of Me3Si-FU, Thf-OAc, and SnCl4 or NaI for preparation of Thf-FU and Thf2-FU were determined. In all cases, 2-2.5 equiv of Thf-OAc with respect to Me3Si-FU gave the best results. The yields of Thf-FU and more especially of Thf2-FU were greatly dependent on the relative amount of SnCl4, and 0.01-0.1 equiv of the catalyst with respect to Me3Si-FU gave the best results. Thf2-FU was found to be effective against murine solid tumors and it was less toxic than Thf-FU when given orally. The antitumor activity of 3-Thf-FU is also reported.

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“…A series of 2-alkoxyderivatives was used, the best results being achieved with the 2-tert-butoxytetrahydrofuran 69 (67% yield). 75 The small amount of disubstituted by-product 67 was quantitatively converted into tegafur by treatment with acetic acid (Scheme 37).…”

Section: Synthesis Of Antitumor Fluorinated Pyrimidine Nucleosides 21mentioning

confidence: 99%

Synthesis of Antitumor Fluorinated Pyrimidine Nucleosides

Ferraboschi

Ciceri

Grisenti

2017

Organic Preparations and Procedures International

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5-Fluorouracil35 Interest in the fluoropyrimidines stemmed from studies of the metabolism of uracil in rat hepatoma cells. The observation that these cells utilize uracil more avidly than normal rat intestinal mucosa prompted the preparation of fluorinated pyrimidines in order to improve disruption of tumor DNA biosynthesis. 3 In 1957 5-fluorouracil (5-FU) 1 was synthesized by Heidelberger et al., 4 with the aim of 40 blocking metabolism in malignant cells. The replacement of a hydrogen atom at C-5 by the fluorine atom modifies the interaction with the active sites of enzymes involved in metabolism. This antimetabolite, although toxic, is still one of the most widely used agents against solid tumors. Its action is due to two different mechanisms: 5 after penetration into the cell, 5-FU 1 is transformed into the 5-fluorouridine triphosphate that mimics UTP, is recognized by RNA 45 polymerase and consequently incorporated into RNA. The most significant action, however, is due to the 5-FU conversion into 5-fluoro-2 0 -deoxyuridine (FdUMP) 2, a known inhibitor of thymidylate synthetase (TS), a key enzyme in the DNA synthesis. 6,7 TS, in the presence of methylene tetrahydrofolate and deoxyuridine monophosphate (dUMP) 3 forms a ternary complex that catalyzes the substitution of 5-H uracil with a methyl group, affording thymine. If FdUMP 50 2 is present, the above ternary complex is not able to carry out this reaction, due to the presence of fluorine in the 5-position: the formation of TMP 4 (2 0 -deoxythymidine 5 0 -monophosphate), the only nucleotide precursor specific to DNA, is, therefore, blocked (Scheme 1), decreasing the availability of TTP (2 0 -deoxythymidine 5 0 -triphosphate) for DNA synthesis.Scheme 1 2 Ferraboschi, Ciceri, and GrisentiLater two additional mechanisms were proposed for 5-FU 1 antitumor activity: the 55 incorporation of 5-FU into DNA and the alteration of the membrane function of 5-FU 1 treated cells. Recent studies indicate that the TS-direct mechanism predominates when 1 is administered at low doses for a prolonged time, whereas the RNA-mediated process is more active following a bolus administration. 8-10 Synthesis of 5-FU 1, by construction of the pyrimidine ring, was first realized by Hei-60 delberger et al. in 1957 4,11,12 by reaction of a thiourea derivative 5 with the enolate of ethyl a-fluoro, a-formyl acetate 6 which, in turn, was obtained from methyl formate and ethyl fluoroacetate (Scheme 2). Depending on the chosen a-fluoro-b-ketoester the method is also applicable to the synthesis of other 5-fluoropyrimidines.An alternative method for the total synthesis is the direct fluorination of the pyrimi-65 dine ring of compound 7 by means of trifluoromethyl hypofluorite (CF 3 OF) 13 proposed by Robins in 1971. In the case of CF 3 OF in methanol/fluorotrichloromethane an intermediate was formed that, after treatment with triethylamine, afforded 5-FU 1 in 84% yield. 13 If the reaction was carried out with CF 3 OF in trifluoroacetic acid 1 was directly isolated in 85% yield. 14 The meth...

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A Facile Synthesis of 1-(2-Tetrahydrofuryl)-5-fluorouracil (Ftorafur)

Cited by 10 publications

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Studies on the syntheses of heterocyclic compounds. 845. Studies on the synthesis of chemotherapeutics. 10. Synthesis and antitumor activity of N-acyl- and N-(alkoxycarbonyl)-5-fluorouracil derivatives

Studies on the syntheses of heterocyclic compounds. 845. Studies on the synthesis of chemotherapeutics. 10. Synthesis and antitumor activity of N-acyl- and N-(alkoxycarbonyl)-5-fluorouracil derivatives

Studies on antitumor agents. 2. Syntheses and antitumor activities of 1-(tetrahydro-2-furanyl)-5-fluorouracil and 1,3-bis(tetrahydro-2-furanyl)-5-fluorouracil

Synthesis of Antitumor Fluorinated Pyrimidine Nucleosides

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