The present invention concerns the method for producing 5-fluorouracil. In accordance with the said method uracil is brought to interact with fluorine in diluent medium which partly or completely dissolves uracil without interacting with fluorine, in an atmosphere of inert gas with subsequent separation of the formed end product. It is preferable to employ acetic acid as diluent, and nitrogen as the inert gas. The end product 5-fluorouracil finds wide application in cancer therapy of the mammary gland and gastrointestinal tract. It is also the initial product for the synthesis of 5-fluor-2'-desoxyuridine and N-2'-tetrahydrofuryl-5-fluorouracil which are also employed in medicine as antitumor agents. Besides the above, 5-fluorouracil finds application for biochemical investigations.
A facile process for the production of Ftorafur [1-(tetrahydro-2-furanyl)-5-fluorouracil] which comprises reacting 2,4-bis-trimethylsilyl uracil with 2-chlorotetrahydrofuran to produce 1-tetrahydro-2-furanyluracil at low temperatures in a dry non-aqueous solvent, e.g. a halogenated hydrocarbon solvent such as methylene chloride. Subsequently the desired final product is produced by direct fluorination of the uracil ring as the last step utilizing a fluorinating agent such as trifluoromethylhypofluorite. This step is conducted in the cold and again in the presence of a halogenated hydrocarbon solvent such as chloroform. Ftorafur has been utilized as a pyrimidine analog for the management of carcinoma in the breast and large intestine and with less side effects than 5-fluorouracil (5-FU).
A method of producing 5-fluorouracil which includes the fluorination of uracil with elementary fluorine diluted with an inert gas in a glacial acetic acid medium under hydrodynamic conditions of Re=35,000-45,000 at a temperature of from 15.degree. to 35.degree. until the uracil disappears from the reaction mixture, whereafter said mixture is heated at a temperature of from 90.degree. to 95.degree.C until 5-fluoro-6-acetoxy-dihydrouracil formed during the fluorination disappears therefrom, followed by isolation of the desired product. The 5-fluorouracil compound is useful as a chemotherapeutical remedy for treating cancer of the alimentary tract and also as a starting material for synthesizing other antitumoric substances.
Direct fluorination of uracil, cytosine and their derivatives, in the presence of a non-aqueous solvent, by fluorine gas to produce 5-fluorouracil, 5-fluorocytosine, 5-fluorouracil derivatives and 5-fluorocytosine derivatives is disclosed. The non-aqueous solvent is an acid or alcohol, which can be partly or fully fluorinated or chlorinated, of up to 8 carbon atoms, such as trifluoroacetic acid. Novel compounds produced by the reaction, such as 5,5-difluoro-5,6-dihydro-6-(2,2,2-trifluoroethoxy) uracil are also disclosed. The derivatives and 5-fluorocytosine are useful as germicidal and antineoplastic agents while 5-fluorouracil itself is a known cancer chemotherapy agent.
An improved process for fluorination of uracil, which comprises treating uracil with fluorine which is optionally diluted with an inert gas (e.g. nitrogen gas) at a temperature of -10.degree. to 15.degree. C in a 50 to 85% by weight aqueous solution of hydrofluoric acid as the reaction medium to form 5-fluorouracil, and optionally subjecting the reaction mixture to a heat treatment at a temperature higher than the reaction temperature, to give 5-fluorouracil in a high yield.
Direct fluorination of uracil and its derivatives, in the presence of an aqueous solvent, by fluorine gas to produce 5-fluorouracil and 5-fluorouracil derivatives is disclosed. Novel compounds produced by the reaction, such as 5,5-difluoro-6-hydroxy-5,6-dihydrouracil are also disclosed. The derivatives of 5-fluorouracil are useful as germicidal agents while 5-fluorouracil itself is a known cancer chemotherapy agent.
