5- Fluorouracil preparation

Fluorinated Heterocyclic Compounds. HeterocycHc compounds containing the CF group are prepared by methods similar to those used in the fluorination of aHphatic compounds. The direct action of fluorine on uracil yields the cancer chemotherapy agent, 5-fluorouracil [51-21-8] as one special example of a selective fluorination on a commercial scale (25). 

Selective fluonnation in polar solvents has proved commercially successful in the synthesis of 5 fluorouracil and its pyrimidine relatives, an extensive subject that will be discussed in another section Selective fluonnation of enolates [47], enols [48], and silyl enol ethers [49] resulted in preparation of a/phn-fluoro ketones, fieto-diketones, heta-ketoesters, and aldehydes The reactions of fluorine with these functionalities is most probably an addition to the ene followed by elimination of fluonde ion or hydrogen fluoride rather than a simple substitution In a similar vein, selective fluonnation of pyridmes to give 2-fluoropyridines was shown to proceed through pyridine difluondes [50]... 

An amount of enzyme preparation equivalent to 900 mg of wet cells was made up to 25 ml with the above potassium phosphate buffer solution. 150 mg (1.15 mmol) of 5-fluorouracil and 1.0 gram of thymidine (4.12 mmol) were dissolved in 15 ml of the above potassium phosphate buffer solution. The mixture was incubated at 37°C for 18 hours. After this time, enzyme action was stopped by the addition of four volumes of acetone and one volume of peroxide-free diethyl ether. The precipitated solids were removed by filtration, and the filtrate was evaporated under nitrogen at reduced pressure until substantially all volatile organic solvent had been removed. About 20 ml of aqueous solution, essentially free of organic solvent, remained. This solution was diluted to 100 ml with distilled water. 

The preparation of 5-fluorouracil is given under "Fluorouracil." As described in U.S. Patent 3,040,026, 5-fluorouracil is then subjected to the following steps to give flucytosine. 

Chlorotrifluoroethylene was converted in one step using nBuLi to dieth-ylfluoromalonate, which was a useful precursor for 5-fluorouracil (84CL1573). Fluorinated pyrimidinones can also be obtained from a,fi-unsaturated carboxylic acid derivatives prepared from 1-phosphonyloxy-perfluoroalkyl-l-alkenephosphonates (86TL2879). 

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

The 5-fluorouracil (5-FU) and NONOate conjugates (Fig. 1.7) were prepared and their cytotoxicity was tested [90]. The median effect doses of the conjugates for DU145 and HeLa cancer cell lines were 2-4-fold lower than that of 5-FU. In another study by Wink et al, the cytotoxicity of cisplatin was enhanced about 60-fold after NONOate pretreatment for 30 min [91]. The enhancement of cytotoxicity of 5-FU/NONOate conjugates and cisplatin-NONOate combination has shown that there is a synergistic effect between anticancer drugs and NO. Another study by Jia et al. demonstrated that the cytotoxicity of Taxol was enhanced by S-nitrosocaptopril (Fig. 1.7) [92]. This effect is primarily mediated via the increased influx of Taxol by NO into intracellular compartments, while NO-induced cytotoxicity cannot be excluded. 

M. Boisdron-Celle, J. M. Ruiz, and J. P. Benoit, Preparation and characterisation of 5-fluorouracil-loaded microspheres as biodegradable anti-cancer drug carriers, in 1992 6th International Conference on Pharmaceutical Technology, pp. 52-61. 

Sugibayashi K, Morimoto Y, Nadai T, Kato Y, Hasegawa A, Arita T (1979b) Drug-carrier property of albumin microspheres in chemotherapy. II. Preparation and tissue distribution in mice of microsphere-entrapped 5-fluorouracil. Chem Pharm Bull 27 204-209. 

Turning our attention first to alkyl carbamates of cyclic amides, we find interesting attempts to improve the pharmaceutical and pharmacokinetic properties of 5-fluorouracil (8.152, R = H) [194-196], This antitumor agent, while clinically useful, suffers from poor water solubility, unsatisfactory delivery properties and low tissue selectivity. A variety of prodrug candidates were prepared, in particular the alkyl and aryl carbamates presented in Table 8.12. With the exception of the more-lipophilic derivatives, these compounds exhibited somewhat improved water solubility. More importantly, both rectal and oral bioavailability were markedly improved. The activation... 

Addition of P F]F2 (or CH3C02f F]F) at the double bond of substituted 2,4-dioxypyrimidines (Scheme 16) allows the preparation of the fluorine-18-labelled nucleic acid base 5-[ F]fluorouracil [91-94] and the nucleoside 2 -deoxy-5-[ F]fluorouridine [95-97]. The reaction, usually carried out in acetic acid, demonstrates an excellent regioselectivity, with only the 5-[ F]fluoro derivatives obtained because the C-5 position is the unique activated position for reaction with an electrophile in these systems. The mechanism of this reaction has been studied and the intermediate 5,6-fluoro-acetoxy adduct (or the 5,6-fluoro-hydroxy adduct if the solvent is water) has been isolated and characterised [92]. 

Consistent radiochemical yields of 20-30% were obtained for the preparation of 5-[ F]fluorouracil with either reagent and in a variety of solvents (tiifluoroacetic acid, acetic acid, water). Similar fluorine-18-labelled products like 5 -deoxy-5-[ F]fluorouridine [95,98], 5-[ F]fluorouiidine [95,99] and others [99] have been obtained in the same way. 

The exceptional case where no activating group is required is the use of diaryliodonium salts as precursors for labelling, permitting the fluorine-18-labelling of relatively electron-rich structures [192-194], A recent example of successful application is the preparation of 5-[ F]fluorouracil in 40% radiochemical yield (Scheme 44) [202], However, this methodology appears to be relatively difficult to use with complex structures [203-205],... 

M. Diksic, S. Farrokhzard, Y.L. Yamamoto, W.A. Ferridel, A simple synthesis of F-labelled 5-fluorouracil using acetylhypofluorite, Nucl. Med. Biol. 11 (1984) 141-142. F. Oberdorfer, E. Hofmann, W. Maier-Borst, Preparation of F-labelled 5-fluorouracil of very high purity, J. Label. Compds Radiopharm. 27 (1989) 137-145. 

Fluorouracil and its derivatives are still important dmgs in the chemotherapy of numerous cancers (doxifluridine, tegafur, carmofur) (cf. Chapter 8). Studies on the mechanism of action of 5-FU had great influence on the development of other antitumor drugs that are derived from pyrimidine and purine. 5-FU is industrially prepared by fluorination of uracil with elemental fluorine (cf. Figure 2.6, Chapter 2). 

Fluorouracil has been used for some time for cancer treatment. Its preparation using fluorine is operated commercially (RC.R. Inc) and has been the focus of numerous studies [12, 150] in the past. In a more recent study, the products obtained upon fluorination of uracil, usually carried out in acetic acid solvent, indicate that the reactions proceed via an addition-elimination process involving radical cation intermediates (Fig. 63) [156]. 

Antipyrine (10) is converted into the 3- and 4-fluoro-substituted products, while the 18F-labeled products of antipyrine and 5-(18F)fluorouracil (11) are prepared by in situ generation of hypofluorous acid starting from l8F2.14 Bcnzothiophene is readily converted into the 1,1-dioxide 12 in 74% yield.9... 

Solutions. Wear goggles and protective gloves and clothing. Cover spill with a 1 1 1 mixture by weight of soda ash, clay cat litter (bentonite), and sand. Scoop the mixture into a container and transport to the fume hood. Estimate the weight of fluorouracil in the spilled liquid and add 10% calcium hypochlorite solution (see waste disposal for preparation), allowing 100 mL for each 500 mg of fluorouracil. Allow to stand overnight,... 

Wear goggles and protective gloves and clothing. To each 10 mL of solution containing 500 mg of fluorouracil, add 40 mL of an aqueous solution of calcium hypochlorite (prepared by stirring 10 g of calcium hypochlorite in 100 mL of water for 2 hours, and then removing the undissolved material by filtration). Stir the solution at room temperature for 5 hours, remove the precipitated calcium fluoride by filtration, and discard as normal refuse. Wash the filtrate into the drain with water.3... 

An amount of enzyme preparation equivalent to 900 mg of wet cells was made up to 25 ml with the above potassium phosphate buffer solution. 150 mg (1.15 mmol) of 5-fluorouracil and 1.0 gram of thymidine (4.12 mmol) were dissolved in 15 ml of the above potassium phosphate buffer solution. 

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