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    • 专利摘要:
    New derivatives of the formula: <IMAGE> (wherein X is O or NH; R1 is -OH which may optionally be etherified or esterified, etherified mercapto or -NH2 which may optionally be substituted; R2 and R3, respectively, mean H, lower alkyl or <IMAGE> and Y is an esterified or amidated carboxyl group, or CN). These derivatives are produced, by fluorination of corresponding 1,2,3,4-tetrahydro-2,4-dioxopyrimidine compounds and can be converted into 5-fluorouracil derivatives under hydrolytic conditions. The new derivatives are able to prolong the lives of animals having carcinomas or have antiviral activity.
    公开号:SU795467A3
    申请号:SU772466666
    申请日:1977-03-31
    公开日:1981-01-07
    发明作者:Миясита Осаму；Мацумура Коичи；Симадзу Хироси；Хасимото Наото
    申请人:Такеда Кемикал Индастриз Лтд(Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD FOR OBTAINING URACIL DERIVATIVES
    The invention relates to a method for producing new biologically active derivatives of uracil, which can be used in medicine. The method of obtaining derivatives of 6-o. si-5-haloduracils by halogenating the corresponding uracils in water, alcohols or aliphatic α-acids is known fl fl and C2J. The aim of the invention is the synthesis of novel uracil derivatives. This goal is achieved by the described method of obtaining uracil derivatives of the general formula (I) e, where the Y-alkoxycarbonyl group containing from 1 to 18 carbon atoms in the alkyl chain, or the -CN group, or the -CONR group Rg, where T and Rg are the same or different and means hydrogen or alkyl containing 1-4 carbon, or R) and Rg together with the nitrogen atom form a morpholino ring; R is hydroxyl, lower alkoxy or lower acyloxy; R, is hydrogen or lower alkyl. The method consists in the fact that the compound of the formula (II) N, where Y, I / I, and RJ have your indicated values, is subjected to fluoridation in the presence of water, a lower alcohol, or an aliphatic carboxylic acid. Due to the fact that the compounds described by formula (I) contain an asymmetric carbon atom in positions 5 and 6, there may be two isomers containing a hydrogen atom in the cis or trans configurations with respect to the fluorine atom in position 5, and with respect to each isome), there may be a d or t form of optical isomers. Therefore, the compounds described by formula (I) include each of the isomers and a mixture consisting of at least two kinds of isomers.
    The method is carried out as follows.
    Compounds of formula {G) are prepared by fluorinating compounds of formula (11) in the presence of water, alcohol or carboxylic acid. Examples of alcohols used in this reaction are alkanols or cycloalkanols containing from 1 to 8 carbon atoms, such as methanol, ethanol and propanol, butanol, pentanol, hexanol and octanol, as well as their isomers, cyclopynthanol, and cyclohexanol And substitute , alkaj ply, for example, three fluoroethanol, trichloroethanol, ethylene glycol, trimethylene glycol, epichlorohydrin, ethylene glycol monomethyl ether, diethylene glycol monomethyl ether, etc.
    Carboxylic acids containing up to 4 carbon atoms, for example, acetic acid, acid, propionic acid, butyric acid, isobutyric acid, cyclopropanecarboxylic acid, cyclobutanecarboxylic acid, and their the corresponding halogenated acids, for example trifluoroacetic acid, pentafluoropropionic acid.
    Water, alcohol or carboxylic acid can also behave as solvents.
    In this reaction, the residual part of the molecule, which forms when the hydrogen atom is removed from the hydroxyl group in the molecule of water, alcohol or carboxylic acid that is used in this reaction, is introduced into the compound of formula (I) as the symbol RJ.
    If the reaction is carried out in the presence of a mixture consisting of two or more components comprising water, alcohol and carboxylic acid, a mixture of compounds described by formula (I) containing various residues as RJ or one of the possible compounds described by formula (t), as the predominant product.
    This fluorination reaction can be carried out using a fluorination agent. Exposing the above are the sulfonates, such as pentafluorosulfoxyfluorone, furanosulfonylphenol, such as trifluoromethylgiphtorite, perfluoropropylfluorite as well as difluorooxy compounds such as.
    as 1,2-difluoro-oxydifluoroethane and difluoro-oxydifluoromethane. Molecular fluorine can also be used. In cases where a gaseous fluorination agent is used, such
    5 as molecular fluorine, it is recommended to be diluted with an inert solution, such as nitrogen or argon, before being introduced into the reaction system. To the number of preferred agents for fluorination
    fluorine gas and trifluoromethylhypofluorite. The fluorination agent can be used in an amount of from 1 to about 10 molar equivalents, preferably about
     from 1.2 to 2.5 molar equivalents based on the compound of formula (II).
    The reaction temperature may be between about (-) 78 and (+), preferably between about (-) 20 and
    0 (+) 30C, more preferably, in the range between about (+) 14 and (+) 30 ° C,
    The compound described by formula (I) and obtained by the method described above can be easily isolated from the reaction mixture by a conventional and known method. For example, the compound described by formula (I) may be resolved by stripping
    Q solvent under reduced pressure, as well as adding a reducing agent, for example sodium bisulfite, to the reaction mixture to remove oxidized by-products,
    , neutralizing the mixture with sodium bicarbonate, calcium carbonate or magnesium carbonate, filtering to remove insoluble substances and removing the solvent from the filtrate by distillation under reduced pressure. The product obtained in this way can be further purified by one of the usual methods, for example, by recrystallization, chromatography on silica or alumina, etc.
    The original compound described by formula (II) can be easily obtained by known methods.
    It was found that the connection
    Q described by formula (III)
    tt, .A.COOR, (inv
    d
    in which the symbol Rp is a lower alkyl group included in the starting materials used, can be obtained in very high yield using the silylation steps of the compound described by formula IV n-KV rtiikv in which the symbol Rjj has the meaning given above, with the help of an agent. silylation to obtain the bisyl compound described by the formula V 0 &amp; 1 (OL5) C COORfi (C%) C $ 10 in which the symbol Rj has the meaning given above, reacting between the compound described by formula (V) and.; - chlortetrahydrofur or with 2,3-dihydrofuran, in the presence of hydrogen chloride. A lower alkyl group, represented by the symbol K (,, may contain up to 4 carbon atoms, for example, a methyl group, an ethyl, propane, isopropyl group, as well as an essential group and its isomers. The above silylated reaction may be carried out by a conventional method. For example, a bis-silyl derivative of the compound described by formula (IV) can be obtained by conducting a reaction between compound (III) and trimethylsilyl chloride in the presence of a base, for example, triethylamine, pyridine, or with hexamethylsilylane m in the presence of a catalyst, for example, trimethylsilyl chloride or ammonium sulfate. The reaction between such a bilyl derivative and 2-chloro-tetrahydrofuran or with 2,3-dihydrofuran in the presence of hydrogen chloride can be carried out at a temperature of (-) / C to (+) 100 ° C , preferably, C. (-) 70 to (4-) 40С, preferably at a temperature from (7) 20 to (4-) ZOOc, either in the presence or in the absence of a solvent, for example in the presence of an aprotic solvent, such as 1,2-dimethoxyethane, dimethylformamide, methylene chloride or acetonitrile 1. Compound, describing Formula (III) can also be obtained by reacting between the compound described by formula (IV) and 2,3-dihydrofuran in a closed reaction vessel. If one of the starting materials, for example 2,3-dihydro-furan, is used in large excess, this reaction does not require the presence of a solvent. However, the reaction usually proceeds successfully in the presence of a solvent, in many cases when for each mole of the compound described by formula (tV) an equivalent amount or a slight molar excess of 2,3-dihydrofuran is used. The solvent is preferably a highly polar solvent, due to the solubility of the pyrimidine base. For example, such solvents are amides of acids, for example, dimethylformamide, dimethylacetamide, formamide, or hexamethylphosphoramide, complex esters, for example methyl formate, ethyl formate, and tertiary amines, for example triztilamine, pyridine, as well as suitable mixtures of these solvents. The reaction temperature is usually chosen between about 200 ° C, preferably between about 130 and, although it may be higher or lower than the specified range. Despite the fact that the duration of the reaction depends on other conditions, it usually ranges between about 2 and 24 hours. The compound described by formula (IV) can be easily obtained by the method described in the literature. The compounds described by formula (I) are valuable because they not only have potent inhibitory properties against the growth and reproduction of tumor cells, for example, HC cell groups (cultured cells derived from human carcinoma or nasopharynx), C-34 cell groups ( mouse kidney fibroblast cells) and AS cell groups (rat astrocytic cells), but also have a life-long effect on mice with P-388, X-121o leukemia). The compounds described by formula (I) inhibit the growth and reproduction of various tumor cells in mammals (such as rats, mice and humans) and also have a prolonged lifespan effect on mammals suffering from leukemia. The compounds described by formula (I) may be administered orally or non-orally, since they are or are manufactured in the form of preparations containing a pharmaceutically acceptable carrier, diluent or excipient, which are prepared by conventional methods, in the form of drugs such as tablets, powders , granules, anhydrous syrups, capsules, suppositories and injections. Depending on the type of animal, the disease and its symptoms, the individual compound, the route of administration, etc. The dosage is usually selected between about 25 and 800 mg / kg of body weight per day. Despite the fact that. the upper limit is about 400 mg / kg body weight, in many cases a dose of about 200 mg / kg body weight is more preferable and there are cases where it is desirable to use a higher or lower dose. The compounds described by formula (I) penetrate the blood in a sufficiently high concentration that is maintained for an extended period of time. Usually, from the point of view of pharmacological characteristics, including toxicity, the compounds described by formula (I) are preferred if the symbol y is an esterified carboxyl group, the symbol R represents an esterified hydroxyl group, the symbol Rj is em is hydrogen or g is a symbol RT, it represents a hydrogen atom. It is better if the symbol Y is an esterified carboxyl group containing from 2 to 9 carbon atoms, the symbol R., is an esterified hydroxyl group containing from 1 to 12 carbon
    Methyl 5-fluoro-b-methoxy-1, 2,3,4,5,6-hexahydro-2, 4-dioxypyrimidine-5-carboxylic
    acids
    B-ethoxy-5-fluoro-1, 2, 3,4,5 ethyl ester, b-hexahydro-2,4-dioxypyrimidine carboxylic acid
    Inhibitory effect on the proliferation of tumor cells.
    Test method: inhibition of the proliferation of KV cells.
    210 cells were suspended in 1 ml of Eagle's minimal essential medium (MEM) + .10% fetal calf serum (MEM ,, 10 FCS) and seeded in a 1.8 cm glass dish covered with a 1.5 cm round lid
    On the first day after seeding, three samples were taken (per group of test cells) and transferred to a 4.5 cm glass dish with 5 ml of MEM, 10 FCS and with different concentrations of the test compound. On the fourth day after sowing, determine the number
    160 143 130
    cells per cap (3 samples for each concentration level) using a counter. Coulter. The results were expressed by the concentration of the drug substance, which on the fourth day was taken as 100%.
    Inhibition of cell proliferation induction in C34 cells infected with vause.
    1 10 10 cells were suspended in 1 ml of MEM (Eagle) + 10% fetal calf serum (MEM, 10 Fes) and seeded in a glass dish with a diameter of 1.8 cm with a round lid with a diameter of 1.5 cm.
    . On the second day after seeding, infection was made (, 120 min of imitation infection or viral infection (in the case of the latter, on cellular atoms, the symbol R represents 0, O however, it is the case that the symbol X represents an oxygen atom, the symbol Y represents an esterified carboxyl group containing from 2 to 5 carbon atoms, the symbol R represents an esterified hydroxyl group containing 1 to 8 carbon atoms, and the two symbols R / j and Rj are hydrogen atoms. WDR mice weighing from 18 to 25 g. The suspension of the test compound was administered intraperitoneally, at a constant rate of 0.1 ml / 10 g body weight, a similar description of the experimental method is given in 2}. Results were recorded according to T / C calculated on the basis of the average life expectancy of the treated and control animals. The results of the experiments are given in table. 1. Table
    ku entered 100-20.0 RRU). After this operation, one test group (| 3 portions) was removed and transferred to a glass dish with a diameter. 4.5 cm with 5 ml MEM, 2 PCS. with each of the tested drug concentrations.
    On the sixth day after seeding, the number of cells per sample was counted using a Coulter counter. For each experimental group, the difference for all members between virus-infected cells (V) and those infected with a parody of the virus (M) was calculated.
    The results were expressed, as the concentration of the drug substance, the giving (Y-M) value of 50% (Efljj) relative to the control group that did not receive the drug substance, which was taken as 100%
    Example 1. In 400 ml of water, 15.04 g (80 mmol) of methyl 1,1,3,4-tetrahydro-2,4-dioxopyriG 1idin-5-carboxylate monohydrate are suspended and the suspension is intensively stirred at room temperature. Then a stream of fluorine gas, pre-diluted with nitrogen to a ratio of fluorine to nitrogen of 1: 3 by volume, is passed through the suspension at a rate of about 45 ml per 1 minute (6.6 hours), during which the reaction system is cooled with water so that the reaction temperature does not exceed 28 ° C (-pai fluorine run of 1.95 molar equivalents). Then, while cooling the reaction mixture, 15.6 g of calcium carbonate is added to neutralize hydrogen fluoride. After adding 5.2 g sodium bisulfite is filtered out insoluble in the filtrate is concentrated under reduced pressure. The residue is dried in vacuo to give 23.7 g of powder. 500 ml of acetone is added to the powder and after removing insoluble substances by filtration, the acetone is distilled off under reduced pressure.
    Inhibition of the proliferation of AS cells.
    1 "10 AS cells (2 ml of MEM Needles with 10% fetal calf serum) were sown in a Falcon cup, internal research institute diameter 3.5 cm.
    After 24 hours, the substitution was made using the above culture medium containing different concentrations of the drug substance. The number of cells was determined
    0 on the third day after the medium change. The pharmacological effect was defined as Eflgp (drug concentration, resulting in 50% of the counted cells for the drug treated group) compared with the group for which the number of cells considered to be control was taken as 100%.
    The results of the experiments are given in
    0 tab. 2,
    Table
    pressure. The residue is purified by chromatography on a column of silica gel (solvent acetone-chloroform is 1: 3 and its volume in order to obtain 13.0 g of methyl 5-FTOR-6-OXY-1, 2,3,4,5,6-hexahydro-4 α-dioxopyrimidine-5-carboxylate.
    T. pl. 171-1720С.
    Nuclear Magnetic Resonance Spectrum (DMSO-dg) cr: 3.80 (3N, s) .; 4.90 (1H, t; after adding deuterium oxide d, Jnr (31H, .- d, J 5H-j); 8.53 (IH, broad).
    Elementary analysis:
    Calculated,%: C 34.96, H 3.42, U1 13.59.
    C.R-FNnOg.
    Found,%: C 35.07, H 3.41, tt 13.58.
    Example 2. In a tubular reactor from pressure-resistant glass with a capacity of 100 ml, 510 mg (3.0 mmOl) of methyl-1,2,3,4-tetrahydro-2, 4-dioxopyrimidine-5-carboxylate are suspended in 20 ml of water and frozen in ane of dry ice and ethanol. To such a loading, 20 ml of fluorotrichloromethane is added. In the above cooling bath, trifluoromethylhypofluorite (approximately 400 mg) is dissolved there.
    After the reactor was tightly closed, the cooling bath was removed and the reactor was allowed to return to room temperature. The material reacts quickly and dissolves in water. After stirring the reaction mixture overnight, solids appear. The excess trifluoromethyl hypofluorite is removed by passing nitrogen gas and after adding anhydrous sodium acetate (400 m solution is concentrated to dryness under reduced pressure. The resulting solid is washed with acetone. The acetone solution is concentrated under reduced pressure to obtain 700 mg of methyl 5-fluoro-6-hydroxy -1,2,3,4,5-6-gexahydrb -2,4-dioxopyrimidine-t-5-carboxylate as a yellow glass of a visible solid. The identity of this compound was determined from the nuclear magnetic resonance spectrum. dinstvennoe it dry spot on silica gel thin layer plate (hlorof.orm-methanol 6: 1 by volume.
    Example Z. In a tubular reactor of 50 ml resistant glass with a capacity of 50 ml, 510 mg (3.0 mmol) of methyl 1,2,3,4-tetrahydro-2, 4-dioxopyrimidine-5-carboxylate are suspended in 20 ml of water. and the suspension is frozen in a bath of cVxoro ice and ethanol. After the addition of 20 ml of trifluoroacetic acid, approximately 290 mg of trifluoromethylhypofluorite is dissolved. After the reactor was tightly closed, the reaction mixture was allowed to spontaneously warm to room temperature. With increasing temperature, the reaction quickly proceeds to form a homogeneous solution. This reaction mixture is stirred overnight. Nitrogen gas is bubbled through the mixture to remove excess trifluoromethyl hypofluorite, after which sodium bicarbonate (540 mg) is added. The solvent is distilled off under reduced pressure, whereby a colorless syrupy product is obtained ... After adding 30 ml of acetone, insoluble materials are filtered off and the acetone solution is concentrated under reduced pressure, 1.15 g of pale yellow syrup is added. The results of thin-layer chromatography on silica gel and NMR confirm that this product. is methyl 5-fluoro-b-axi-1,2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine-5-carboxylate.
    Example 4. In a tubular reactor from pressure-resistant glass of capacity ZOO ml, 25 ml of methanol are mixed with 50 ml of fluorotrichloromethane and the mixture is sufficiently cooled in a bath of dry ice and ethanol, approximately 1.1 g of trifluoromethyl hypofluorite is dissolved in this mixture, and then suspended 1 , 36 g (8.0 mmol) of methyl-1.24, 3-tetrahydro-2,4-dioxopyrimidine-5-carboxylate, after which 80 ml of methanol, previously sufficiently cooled in a ban of dry ice and ethanol, are added. After the reactor is tightly closed, the reaction is allowed to return spontaneously to room temperature with continuous stirring. When the temperature rises, the starting material reacts quickly to form a homogeneous solution. The solution is stirred overnight, after which nitrogen gas is bubbled through the solution to remove excess trimethylene methyl hypofluorite. The solvent is then distilled off to obtain a solid at the same time, which is purified by chromatography on silica gel.
    column solvent: chloroform containing from 1 to 10% by volume of methanol) to obtain 1.52 g of methyl 5-fluoro-6-methoxy-1, 2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine -5-carboxylate, as well as 0.31 g of unreacted starting material. Recrystallization of this product from acetone and hexane gives 1.26 g of colorless flakes.
    M.p. 165-16 bOs
    NMR spectrum (DMSO-D) S;
    3.38 (ZN, S); 3.85 {3H, S
    4.77
    (IH, dxd,
    2H,
    ng
    J 5Hj; after to HF 2Hj);
    deuterium oxide d, J 8.77 (IH, broad); 10.92 (Gn, wide).
    Elementary analysis:
    H 4.12,
    From 38.19,
    Calculated: 12.76, F 8.63, N
    C7HpFN2.05,
    Found,%: C 38.49, H 4.06,
    0 N 12.06, F 7.92.
    five.  920 ml of ethyl-1,2,3,4-tetrahydro-2, 4-dioxopyrimidine-5-carboxylate are injected into 200 ml of water with sodium. A mixture of fluorine (25% by volume) is fed with vigorous stirring at room temperature. %) and nitrogen, during the reaction, the starting material is dissolved to form a homogeneous solution.  After the supply of 2.6 molar equivalents of the indicated gas mixture, the ultraviolet absorption spectrum of the reaction mixture was measured.  When the absence of unreacted starting compounds was confirmed by spectrum, the reaction was stopped.  After adding 1.10 g of calcium carbonate, the reaction mixture was stirred for some time, after which the insoluble matter was filtered.  The filtrate was concentrated to dryness under reduced pressure, whereby a white solid was obtained.  This product was suspended in 50 ml of acetone and insoluble materials were filtered off.  Acetone-soluble substances were subjected to chromatography on a silica gel column (solvent chloroform containing 1.5 vol.% % methanolJ, and then the fraction containing the desired compound was concentrated under reduced pressure to isolate a white solid.  Recrystallization from a mixture of methanol, chloroform and hexane gives 561 mg of colorless prismatic crystals of ethyl 5-fluoro-6-hydroxy-1, 2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate.  T.  square  163-165C.  NMR spectrum (DMSO-d (,) cG: 1.22 (3N, t, J 7H: j), 4.28 (2H, q, J 7H), 4.93 (1H, dxd, J, after adding oxides of dimers, d, 6.3 (1H, broad, ka), 8.48 (iH, wide, 10.80 (1H wide).  Elementary analysis: Calculated,%: C 38.19, H 4.12, 12.73.  .  Found,%: C 37.90, H 3.94, 12.87.  Example 6  1.54 g of isopropyl-1,2,3, tetrihydro-2,4-dioxopyrimidine-5-carboxylate was suspended in 200 ml of water and 3 mol-equivalents of a gaseous fluorine gas mixture (25 vol. %) and nitrogen in suspension to carry out fluoridation.  The reaction mixture was treated by the method of Example 1 and the product was purified by chromatography on a Fractional silica gel column concentrated under reduced pressure, isolating 1.44 g of a white solid.  Recrystallization from acetone and hexane gives 1.06 isopropyl-5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate as colorless needles B.  square  179-181 ° C.  Nuclear Magnetic Resonance Spectrum (DMSO-d) cr: 1.22 (6H, d, J bH-j); 4.92 (IH, m; after adding deuterium oxide, d.  nr ZN); 5.02 (1H, t); 7.07 (1H, d, J 5H); 8.52 (IH, wide), 10.83 (IH, wide).  Elementary analysis: Calculated,%: C 41.03, H 4.74, 11.96.  Cъ, ftiiO Found, I; from 41.08, H 4.52, 11.80.  7  3.18 g of p-butyl-1,2, 3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylate was suspended in 150 ml of water of Prime, and a gaseous fluorine gas mixture (25% by volume) was fed with vigorous stirring. %) and. . .  nitrogen.  During this procedure, the starting material dissolved to form a homogeneous solution.  After feeding 4 mol equivalents to the specified gas mixture, the reaction mixture was treated in the same manner as described in Example 1 to isolate a white solid.  This product was mixed with a white solid obtained by fluorinating 2.12 g of the same starting material, and then purified by chromatography on a silica gel column.  The desired fraction was concentrated under reduced pressure to isolate 4.63 g of a white solid.  Recrystallization of the solid from acetone and chloroform gives 3.08 g of n-butyl-5-fluoro-6-hydroxy-1,2,3,4, 5,6-hexahydro-24, dioxopyrimidine-5-carboxylate as colorless flakes. .  T.  square  162-163 ° C.  Nuclear Magnetic Resonance Spectrum (DMSO-d): 0.90 (MN, t); 1.1-1.9 (4H, t); 4.22 {2H, t, J 6H. ; , 90 (1H, t; after the addition of deuterium oxide d; 3N-E); 7.07 (1H, d, J 5H); 8.53 (IH, wide), 10.87 (1H, wide).  Elementary analysis; Calculated: C 43.55, H 5.28, N 11.29.  C9H, / N, 05.  Found: C, 43.26; H, 5.16; N, 11.46.  Example 8  In ZOO ml of water, 4.24 g of sec-butyl-1,2,3,4-tetrahydro-2, 4-dioxopyrimidine-5-carboxylate are suspended and with continuous vigorous stirring of the suspension, fluorine gas is fed, previously diluted with 3.3-fold volume of nitrogen, and the reaction temperature is maintained at 24-28C.  Only 1.8 mole equivalents of fluoride are calculated based on the substrate, whereby a colorless transparent solution is obtained.  After adding 2.5 g of sodium bisulfite and then 7.5 g of calcium carbonate, the reaction mixture is filtered off and the filtrate is concentrated to dryness under reduced pressure.  After adding 300 ml of acetone and mixing thoroughly, the mixture is filtered and the filtrate is concentrated to dryness under reduced pressure to obtain 4.59 g of a white powder.  1.59 g of this powder is taken and chromatographed on a silica gel column (benzene-acetone solvent 2: 1 by volume to make as a white crystalline solid, sec-butyl-5-fluoro-6-ok7 si-1,2,3 , 4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate.  T.  square  183-184 C (with decomposition).  Nuclear Magnetic Resonance Spectrum (DMSO-d) cf: 0.86 (3N, t, J 7H: j); 1.21 (-ZH, d, J 7Hj); 1.59 (2H, m, J 7Hi); 4.7-5.1 (2H, m); 7.16 (IH, wide), 8.60 (IH, wide), 10.89 (IH, iroka).  Elementary analysis.  Calculated,%: C 43.55, H 5.28, N 11.29.  .  Found: C, 43.40; H, 5.26; N, 11.19.  Example 9  1.77 g of 2-chloroethyl-1,2,3, -tetrahydro-2,4-dioxopyrimidine-5-carboxylate is hydrated in 200 ml of water and a gaseous fluorine mixture (25% by volume) is fed with vigorous stirring of the suspension. %) and nitrogen.  After a 4.2 mol eq valence of the gas mixture was supplied, the consumption of the raw material was checked by the ultraviolet absorption spectrum, and the reaction product was isolated in a manner similar to that described in Example 1.  The product is purified by chromatography on a silica gel column and then recrystallized from a mixture of acetone, chloroform and hexane to obtain 370 ml of 2-chloroethyl-5-fluoro-6-hydroxy-1, 4,5,6-hexahydro-2,4-dioxopyrimidine- 5-carboxylate as colorless prisms.  T.  square  180-182s.  NMR spectrum (OMSO-da) cP; 3.83 {2H, t); 4.52 (2H, t); 4.9 (1H, t; after adding deuterium oxide, d.  JHP ZN); 7.17 (1H, d, J 5H); 8.53 (1H, wide 10.90 (in, broad).  Elementary analysis: Calculated,%: C 33.02, H 3.17, N 11.01.  C HgClFN Os.  Found,%: C 33.44, H 3.05, N 11.11.  Example 10  BZ00 ml of water are suspended with 1.84 g of methyl 3-methyl-1, 2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylate and, with vigorous stirring, 3 mol equivalent of a gaseous fluorine mixture (25 vol. %) and nitrogen.  After this fluorination, the reaction mixture is treated in the same manner as described in Example 1, and the resulting yellow solid is purified by chromatography on a silica gel column.  The fractions obtained give 1.27 g of a white solid. of the company.  By recrystallization from a mixture of acetone, chloroform and hexane, methyl 5-fluoro-6-hydroxy-3-methyl-1,2,3,4,5-hexahydro-2,4-dioxopyrimidine-5-carboxylate is obtained in the form of colorless flakes .  t.  square  160-161C.  NMR spectrum (OMSO-dt,) C /. 3, 07 (ЗН, S); 3.80 (3N, S); 4.95 (1H, ha; after addition of oxide, dey7, 17 (1H, d, teri, d, JHP 3N J 5H; 8.85 (1H, broad).  Elementary analysis: Calculated,%: C 38.19, H 4.12, N 12.73.   Found,%: C 38.33, H 4.04, N 12.84.  Example 11 in a glass reactor by 5. 00 ml equipped with a Teflon paddle stirrer, a Teflon gas inlet, a thermometer and a gas outlet connected to the fluorine gas trap are suspended 980 mg of methyl 1- (2,4-tetrahydrofuryl) -1, 2,3,4-tetrahydro-2 , 4,3-dioxo-pyrimyrimidine-5-carboxylate in 200 ml of labor, and also serves the gas mixture of fluorine gas (25 vol. %) and nitrogen at room temperature.  During this treatment, the starting material is dissolved to form a homogeneous solution.  After 4 mol-equivalents of the gas mixture are supplied, the ultraviolet absorption spectrum is measured to confirm the absence of the starting material.  The reaction is then terminated.  2.0 g of calcium carbonate is added to the reaction mixture to neutralize hydrogen fluoride. - Then, after adding 20 ml of a 1M aqueous solution of sodium bisulfite, the resulting precipitate is filtered off and the filtrate is concentrated to dryness under reduced pressure to obtain a white solid mass.  This product is suspended in 50 ml of acetone and insoluble materials are filtered off.  The acetone-soluble substances are chromatographed on a silica gel column (solvent: chloroform, comprising 1 vol. % methanol and fractions containing the desired compound are concentrated under reduced pressure to isolate a white solid.  Recrystallization from a mixture of acetone chloroform and hexane gives 485 mg of methyl 5-fluoro-1- (2-tetrahydrofuryl) -6-hydroxy-1, 2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate in the form of colorless. flakes.  T.  square  1b5-170 ° C.  NMR spectrum (DMSO-d) cr; 1.7-2.2 (4H, t); 3.75 and 3.82 (5H); 5.0-5.2 (1H, t; after adding deuterium oxide, d, 3.5H): 5.73 lH, m) - 7.28 and 7.33 (iH, disappears when adding deuterium oxide), 11 , 08 (1H / wide).  Elementary analysis: Calculated: С 43.48, H 4.74; N 10.14.  C ,, On.  Found,%: C 43.45, H 4.65, N 10.02.  Example 12  850 mg ethyl-1,2,3,4-tetrahydro-2,4-dioxoirimidine-5-carboxylate are suspended in 200 ml of glacial acetic acid and, with vigorous stirring, a mixture of fluorine is fed (. 1 L on. %) and nitrogen, and the reaction temperature support 18,0-19,0C.  In the course of this reaction, the starting material is dissolved to form a homogeneous thief.  This reaction mixture is concentrated under reduced pressure to obtain a pale yellow glassy solid.  This product is subjected to chromatography on a silica gel column and the solvent is benzene and acetone. 4: 1 by volume} and the fractions enriched in the desired compound are concentrated under reduced pressure to obtain 1. 00g methyl-b-acetoxy-5-fluoro. -.  -1,2, 3,, 6-hexahydro-2, 4-dioxopirimidine-5-carboxylate in the form of colorless needles.  NMR spectrum (DMSO - db) orj 2.08 (3H, S); 3.83 (3N, S); 6.23 (IH, dxd,, J 6Hi; after adding deuterium oxide d, 2Nd,) 9.10 (IH, wide) ;.  one. 1.33 (IH, si-rock).  Example 13  Fluorine gas mixture (10 vol. %) and nitrogen containing 2. 1 mole equivalents of fluorine; 1.07 g of p-octyl-1,2,3,4-tetrahydro-2, 4-dioxopyrimidine-5-carboxylate in 200 ml of acetic acid is introduced into suspension in 200 ml of acetic acid, at 20-25 ° C for 4 h.  The resulting colorless transparent mixture was concentrated to dryness under reduced pressure to obtain 1.44 g of crude p-octyl-5-fluoro-b-acetoxy-1, 2,3,4,5,6-hexahydropyrimidine-5-carboxylate as a white solid. substances.  NMR spectrum (OMSO - d |,) cf,.  0.87-1.83 (15H, m); 2, -08 (3N, S); 4.28 (2H, t); 6.19 (1H, dxd, J 2H after adding deuterium oxide, d, J 2ri, j); 9.1, 11.3 (each IH, wide).  Example 14  Fluorine gas mixture (15 vol.% %) and nitrogen, containing 5 mol equivalents of fluorine, are added to suspension 2.04 g of stearyl-1, 2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylate in 200 ml of acetic acid. For 8.5 hours, insoluble substances are filtered off to isolate 89% of unreacted starting material, and the filtrate is concentrated under reduced pressure.  The residue is dissolved in 10 ml of ethanol and heated under reflux overnight.  The solvent is distilled off as well.  the residue is chromatographed on silica gel (solvent chloroform and ethyl acetate 1: 1 by volume of J, to isolate 54 mg of stearyl-5-fluoro-b-hydroxy-1, 2,3,4,5,6-hexahyd ro-2,4 - di6xopyrimidiline-5-carb. hydroxy lat.  T.  square  104-106 C (recrystallized from a mixture of chloroform and hexane. NMR spectrum (DMSO - d,) cG0, 6-1.8 (38H, t); 3.3-3.93 (2H, t); 2.93-4 , 42 (2H, t); 4.82 (lH, m; after adding deuterium oxide, d ,.  J 2H: j); 8.70, 10.83 (each IH, wide).  Elementary analysis: Calculated,%: C 62.34, H 9.62, N 5.82.  CrsH-l / NgO, c 62.52, H 9. , 45; Found, 5 N 5.85.  Example 15  B200ML of water is suspended with 1.55 g of 1,2,3,4, tetraHydro-2, 4-dioxopyrimidine-5-carb zsamide, and gaseous fluorine, pre-diluted with a 3-fold volume of nitrogen, is bubbled through the suspension.  Maintaining the temperature of re. , stocks at 23-3 ° C, added about 5 mole equivalents of fluoride per substrate (within about 4 hours and after removing unreacted starting material by filtration, 2.5 g of sodium bisulfite and 9.0 g of calcium carbonate were added.  After thorough mixing, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.  The concentrate was dissolved in 200 ml of acetone.  The solution was concentrated to dryness and the resulting solid was recrystallized from a solvent mixture of acetone and chloroform to obtain 0.74 g of 5-fluoro-6-OXI-1, 2,4,5,6-hexahydro-2,4-dioxopyrimidine-5- carboxamide as a crystalline powder.  T.  square  188-189 ° С (with decomposition).  NMR spectrum (DMSO - d) (/: 4.86 (lH, m); 6.82 (IH, d, J 5H); 7.75 (IH, wide); 7.93 (IH, wide); 8 48 (IH, wide); 10.63 (IH, wide).  Elementary analysis. C: Calculated,%: C 31.42, H 3.16, N 21.99.   C5He, FN, 0.  Found: C, 31.25; H, 3.21; N, 22.09.  Example 16  With vigorous stirring of the suspension, 1.89 g of 1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5- {I-methyl} -carboxyamide, 200 ml of water are fed with gaseous fluorine previously diluted with a 3-fold volume of nitrogen, the reaction temperature is maintained 25-27s.  When approximately 3.5 mol equivalents of fluorine are supplied, per mole of substrate (within about 3.5 hours) the reactive mixture becomes colorless and transparent.  At this time, it is neutralized with calcium carbonate (4.3 g) and filtered.  .  The filtrate is concentrated to dryness, and the concentrate is dissolved in methanol.  The solution is concentrated to dryness and chromatographed on a silica gel column (solvent: benzene and acetone 1: 1-1: 5) to obtain 0.73 g of 5-fluoro-b-oxy-1, 2.3.4 / 5, b-teksahydr-2 , 4-DIOXOPYRIMIDIN-5- (I-methyl) -carboxamide as a white powder T.  square  193-194 50 (with decomposition NMR spectrum (OMSO - b (e) s / 2.63 (3N, d, J S); 4.86 (1H, t; after adding oxide, dimer, d,. J 2H); 6.84; (1H, wide 8.40 (2H, wide) 10.61 (1H, wide).  Elementary analysis: calculated,%: C 35.13, H 3.93, N 20.48.  Sndrdm O.  Found,%: C 34.92, H 3.93, N 20.51.  Example 17  In 50 ml of water, 1.06 g of 1,2,3,4-tetrahydro-2-dioxopyrimidine-5- {N, N-diethyl) -carbonamide is dissolved in 1 ml of fluorine and diluted 3 with vigorous stirring -fold volume of nitrogen (reaction temperature 27-29c).  When 5 mol equivalents of fluorine are supplied per 1 mol of the substrate (for about 2.5 h, the reaction mixture is directly concentrated to dryness, and the concentrate is chromatographed on a silica gel column (solvent: benzene and acetone 2: 1), yielding 0.17 g 5-fluoro-6-hydroxy-1,2,3,4-hexahydro-2,4-dioxopyrimidine-5N-diethyl) -carboxamide.  NMR spectrum (DMSO - df,) o; 0.85-1.33 (6H, t); 3.05-3.70 (4 t); 4.99 (1H, wide, d, J 5H after adding deuterium oxide, 5 wide); 6.6-7.4 (1H, wide); 8.37 (1H, wide); 10.7 (1H, wide).  Example 18  Fluorine gas, previously diluted with a 3-fold volume of nitrogen, barborates T-mixture of 1.57 g of N - (1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carbonyl morpholine and 150 ml of water at constant stirring, the reaction temperature being maintained for 15-23 seconds.  When about 3 mol equivalent of fluoride per 1 mol of substrate is supplied (1, O g of sodium bisulfite and 5, O g of calcium carbonate are added over about 2.5 hours.  The mixture is filtered, and the filtrate is concentrated. The residue is dissolved in acetone and chromatographed on silica gel (solvent: benzene- and acetone 1.6) to give 0.33 g of H- (5-fluoro-6-hydroxy-1, 2.3 , 4,5,6-hexahydro-2,4-dioxo-pyrimidine-5-carbonyl) -morpholine in de white powder.  T.  square  183-184 0 (with decomposition NMR spectrum (DMSQ - d,).  3.60 (8H, S); 5.03 (1H, t, J 5 6.92 (IH, d, J - 5Ht); 8.40 (IH, w-rock); 10.77 (IH, broad).  Elementary analysis: Calculated,%: C 41.38, H 4.63, 16.09.  CgH FNjOg.  Found%: C 41.20, H 4.54, 16.23.  Example 19  1.06 F of 1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5- (M-tert-butyl) -carboxamide is dissolved in 200 ml of acetic acid and, with vigorous stirring, fluorine gas, previously diluted 9- This is a multiple of nitrogen.  When 2 moles are equivalent.  fluorine per 1 mol of the substrate (for about 2 hours), the reaction mixture is concentrated to dryness.  The residue is dissolved in a small amount of acetone, and then benzene is added.  The resulting precipitate was recovered by filtration to obtain 0.94 g of 5-fluoro-6-acetoxy-1,2,3, 4,5,6-hexahydro-2,4-dioxopyrimidine-5- (N-tert-butyl) -carboxamide in the form of a white powder.  T.  square  191-193 ° C (with decomposition).  Nuclear Magnetic Resonance Spectrum (OMSO - d6) 1.29 (9H, S); 2.10 (3H, S); 6.14 (IH, wide, d, J bH-r); 8.19 (1H, wide, -S); 9.09 (IH, wide 11.01 (IH, wide).  Elementary analysis: Calculated,%: C 45.68, H 5.58, 14.53.  q, H, FN ,, 04 Found: C 44.92, H 5.36, N14.89.  Example 20  In a tubular reactor of pressure-resistant glass, with a capacity of 100 ml, 1.10 g (8.0 mmol) of 1,2,3,4-tetrahydro-2, 4-dioxopyrimidine-5-carbonitrile are suspended in 35 ml of water and the suspension is frozen in dry ice and ethanol bath.  To this mixture is added 35 ml of fluorotrichloromethane and in the above cooling bath in a mixture of trifluoromethylhypofluorite C (about 1.2 g) is dissolved.  After the reactor was sealed, the mixture was stirred at room temperature for 40 hours, at which time the starting compound reacted and dissolved.  The excess trifluoromethyl hypofluorite is removed by passing nitrogen gas and, after adding sodium bicarbonate (690 mg), the solvent is distilled off under reduced pressure.  Through the above procedure, 1.74 g of a brownish glassy solid are obtained.  Two separate spots appear on silica gel thin layer chromatography.  By nuclear magnetic resonance, the compound is identified as a mixture (approximately 1: 1) of 5-fluoro-6-hydroxy-1, 2,3,4,5,6-hexahydro-2,4-dioxypyrimidine-5-carbonitrile and Hjp5-difluoro-b -oxy-1, 2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine-5-carbonitrile.  NMR spectrum (DMSO -.  5.33 (IH, m; after the addition of ox de duterium d,); 7.7-8.2 (IH, C broad; 9.00 (IH, broad); 10.3-11.0 (1 / 2H, broad, attributable to N 2, - H).  Example 21  B150ML of water is suspended with 2.05 g of 1,2,3,4-tetrahydro-2, 4-dioxopyrimidine-5-carbonitrile and with vigorous stirring gaseous fluorine, previously diluted with 3 times the volume of gaseous nitrogen, is added. C When approximately 4.5 mol-equivalent of fluorine is supplied (for about 5 hours, the reaction mixture is concentrated to dryness and the residue is chromatographed on a silica gel column (chloroform solvent and 13: 1 methanol) to obtain 1.86 g of 5-fluoro -b-hydroxy-1,2,3, -4,5-hexahydro-2,4-dioxopyrimidine-5-carbonitrile as a white crystal lytic powder.  T.  square  158-1600С (with decomposition) NMR spectrum (DMSO - dj,) 5; 5.35 (IH, m); 7.75 (IH, wide 9.00 (IH, wide), 11.40 (IH, wide).  Elementary analysis: Calculated,%: C 34.69, H 2.33, N 24.27.  .  Found: C, 34.39; H, 2.27; N, 24.16.  Example 22  B150 ml of acetic acid is suspended with 1.05 g of 1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5- (N, M-diethyl) -carboxamide, followed by passing fluorine gas, previously diluted with 9-fold volume asova gas at room temperature.  When 2.8 mole equivalents of fluorine were supplied per substrate (for 6.5 hours), the reaction mixture was evaporated to dryness under reduced pressure, whereby a pale yellow syrupy residue was obtained.  This residue is dissolved in 50 ml of water and the solution is stirred at room temperature for 2 hours and then concentrated to dryness under reduced pressure.  The resulting viscous product is subjected to chromatography on a silica gel column (solvent: benzene and acetone 2: 1), to give 0.3-9 g of a white powder.  The powder is recrystallized from ethyl acetate to give 0.12 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro -2,4-dioxopyrimidine-5- {M, I-diethyl} -carboxamide, as white microscopic crystals.  T.  square  190-192 hc with decomposition NMR spectrum (DMSO - dj,) cf: 0.9-1.4 (6H, ni); 3.1-3.8 (4H, m); 5.04 (IH, t, J 5H-g); 6.97 (IH, d, J 5H); 8.5 (IH, wide); fO, 76 (IH, wide).  .  Elementary analysis: Calculated,%: C 43.72; H 5.71; N 17.00,  Found: C, 43.61; H, 5.57; N, 16.98.  Example 23 (comparative).  In 750 ml of anhydrous dimethylformamide, 156 g of 1,2,3,4-tetrahydro-2, 4-dioxopyrimidine-5-carboxylic acid are suspended, and 238 g of thionyl chloride is added to this suspension with stirring at a temperature not exceeding 5 ° C for 1 h and 10 min.  Then the resulting reaction mixture is heated at 45-50 s for 1 h and at 50-60 s for another 1 h.  The mixture is then left to stand at room temperature overnight and the resulting precipitate is isolated by filtration.  It is washed with anhydrous dimethylformamide, and then with benzene, followed by drying at 80 ° C. under reduced pressure.  In this way, 210 g of 1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-K arbonyl chloride dimethylformamide of the semi-acidic complex are obtained in the form of a white powder.  T.  square  ISO-C (with decomposition).  Elementary analysis: Calculated,%: C 36.14, H 3.93, N 15.80.  CgH oCINJO. j / aHCl.  Found: C, 36.04; H, 3.73; N, 15.82.  Nuclear Magnetic Resonance Spectrum (DMSO - dj,) cr: 2.7 (3H, S); 2.87 (3H, S); 7.88 (IH, S); 8.18. (1H, wide); 11.77-12.2 (IH, wide); 13.4 (IH, wide).  Example 24 (comparative).  Synthesis of 1,2, 3,4-tetrahydro-2, 4-dioxopyrimidine-5-carboxylic acid esters.  In 50-100 ml of anhydrous toluene, 13.3 g of 1,2,3,4-tetrahydro-2, 4-dioxopyrimidine-5-carbonylchloride dimethylformamide of a semi-acidic loric complex are suspended with subsequent addition of 1.1 mol equivalents of the corresponding alcohol or phenol.  Mons are heated under reflux for 20 minutes.  After cooling, the precipitate is filtered, rummaged with a solvent, such as an oluol, acetone or ether, dried to give ester 1, 3,4-tetrahydro-2,4-dioxopyrimiin-5-carboxylic acid.  In many of the x-rays, the product thus obtained is sufficiently pure so that it could be used directly as a starting material in the subsequent procedure.
    Substances of the following general formula can be indicated as examples of new esters that can be obtained using the Bfcjme method:
    n-propyl isopropyl
    Isobutyl
    Sec-butyl
    n-amil
    n-hexyl
    n-heptyl (hemihydrate). Dioxane 210-216
    n-octyl
    n-stearyl
    2-Chloroethyl
    Example 25 (comparative). 6.0 g of 1,2,3,4 tetrahydro-2,4-dioxopyrimidine-5-carboxylic acid is suspended in 20 ml of toluene, followed by the addition of 7 ml of piperidine. With stirring and with heating, 4-ml of phosphorus oxychloride is added dropwise and the mixture is heated under reflux for 30 minutes. After cooling, the toluene is poured off and the residue is boiled with 50 ml of water. The resulting crystalline precipitate is filtered and recrystallized in 50 ml of water to give 2.3 N- (1,2,3,4-tetrahydro-2, 4-dioxopyrimidine-5-carboxyl) -piperidine, in the form of white flakes.
    Physical and chemical data bringing tab. 3
    Table 3
    -231-232
    243-244
    (with decomposition)
    253-254
    (with decomposition)
    255-226 228-229 196-199
    224-226 206-207
    245-246
    (with decomposition)
    m.p. (with decomposition). Examples 26-28 (comparative). In a manner similar to that described above, the following compounds are prepared:
    N- (1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carbonyl) -morpholine, m.p. 306-307s (with decomposition), white microscopic crystals
    1,2,3,4-tetrahydro-2,4-dioxopyrimidine-4- (M, H-diethyl) -carboxamide, m.p. 248-249s (with decomposition) pale yellow prisms,
    1,2,3,4-tvtrahydro-2.4; α-dioxopyrimidine-5- (N-phenyl) -carboxamide. m.p. 359-ZbOOc (with decomposition of j blou-yellow powder. Example 29 (comparative). A mixture of 5 g of 1,2,3,4-tetrahydro-2,4-di oxopyrimidine-5-carboxylate, 50 Ml DMF (dimethylformamide) and 20 ml of benzine amine is heated at 130 ° C for 7 hours, and then the reaction mixture is concentrated under reduced pressure. Water and a solid are added to the residue by filtration, then washed with ethanol to obtain 2.2 g of 1,2,3,4-tetrahydro -2,4-dioxopyrimidine-5- (N-benzyl) -carboxamide, in the form of white flakes, mp 321-322 ° C (with decomposition). Example 30 (comparative). In 7 g of acetic acid are suspended 1.3 g of 1,2,3,4-tetrahydro-2,4-dioxo-pyrimidine-5-carbonitrile, followed by the addition of 0.7 g of tert-butyl alcohol and 1.0 g of sulfuric acid. The mixture is stirred at room temperature in for 2 days. 20 g of ice-cold water is added to the white turbid reaction mixture and the precipitate is filtered, rinsed with water, and then dried to obtain 1.2 g of 1,2,3,4-tetrahydro-2,4-dioxopyrimidine -5- (m-tert-butyl) -carboxamide as a white powder. M.p. 310-311 ° С (with decomposition). Example 31 (comparative). A 200 ml glass reaction vessel was charged with 15.3 g of urea methyl, 30.1 g of formic ethyl ethyl oether and 27.1 g of dimethyl maloate. Heat the mixture with vigorous stirring in an oil bath at. N-methyl urea is dissolved to give a homogeneous solution. After some time, colorless flakes fall out. The resulting ethanol is distilled off for approximately 50 minutes. After cooling, the crystals are isolated by filtration, washed with ethanol and then with hexane. The NMR spectrum of this product confirms that it is N, (N-6HC-methylcarbamoyl) -formamidine. Yield 4.9 g. NMR spectrum (DMSO - d) (f; 2.67 (6H, d, J 5HJ; 7.20 (2H, broad); 8.73 (1H, S); 9.80 (1H , wide). From the mother liquor an additional portion of colorless crystals is obtained.These crystals are chromatographed on a silica gel column, 6.5 g of colorless needles of dimethyl-HM-methylcarbamoyl) -aminomethylenemalonate are separated off. NMR spectrum (OMSO - dj,) f; 2.73 (3H, d, J 4.5H :); 3.67 (3H, S); 3.72 (3H, S); 7.97 (IH, broad); 8.50 (lH, d, J 12H-); 10.37 (lH, d. J} 2H). Example 32 (comparative). 11.35 g of dimethyl-K- (m-methylcarbamoyl) aminomethylenemalonate are suspended in 120 ml of methanol, followed by the addition of 15 ml of 28% - new meta sodium methoxide tin solution. This mixture is stirred for some time at room temperature. After dissolving the starting material with the formation of a homogeneous solution, the mixture is heated under reflux for 20 minutes. As a result of heating under reflux, a precipitate forms. hydrochloric acid to acidify the mixture, and the precipitate is converted to crystals. After cooling on ice, the crystals were collected by filtration, washed with water and then with acetone and dried in air to obtain 6.59 g of methyl 3-methyl-1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylate in the form of colorless needles. Recrystallization from water gives 4.28 g of pure material in the form of colorless flakes, m.p. 262264 ° C. Example 33. B400MP acetic acid is suspended with 2.05 g of 1,2,3,4-tetrahydro-2, 4-dioxopyrimidine-5-carbonitrile and with vigorous stirring a gas mixture of fluorine and nitrogen (15:35 by volume) is supplied. When about 1.5 mole equivalents of fluoride are applied to the substrate, the reaction mixture is evaporated to dryness. Ethanol (70 mdr is added to the residue and the mixture is heated under reflux for 2 hours and then CHOfia is evaporated to dryness. The resulting syrup is subjected to chromatography on a Kagel column (solvent, benzene and acetone, 4: 1 by volume), 1, 54 g of 5-FTOR-6-ETOXI-1,2,3,4,5,: 6-hexahydro-2,4-dioxopyrimidine-5-, -carbonitrile, in the form of white crystals, mp 196-1950C. NMR spectrum (OMSO - d (,) ol 1.07 (3H, t, J 7Hg); 3.64 (2H, gxd, J 7H and J 2H: j); 5.42 (IH, dxd, J 4Hg and J 2H |, 9.38 (IH, wide); 11.59 (IH, wide). Elementary analysis: Calculated: С 41.80, H 4.01, N 20.89. C-HoFNiOj. Found,% : C 41.44, H 3.95, N 20.70 Example 34. In a 100 ml pressure-resistant tubular glass reactor with a capacity of 100 ml, methyl-1, 2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylate (510 mg, 3.0 mmol in 20 ml of water) is suspended and Freeze in a dry ice and ethanol bath. Pour 20 ml of fluorotrichloromethane into the frozen solid and dissolve trifluoromethylhypofluorite (approximately 40 mg) while cooling in the same bath. After the reactor is tightly closed, the cooled bath is removed to allow the mixture to warm to room temperature. The starting material reacts quickly and dissolves in water. The reaction mixture is stirred overnight, with no undissolved solid remaining. Excess trifluoromethylhypofluorite is removed by passing gaseous nitrogen through the solution and anhydrous sodium acetate (400 mg) is added to the solution. The solution is concentrated to dryness under reduced pressure and the residue is washed with acetone. The acetone solution is concentrated under reduced pressure to obtain 700 mg of methyl 5-fluoro-6-hydroxy-1, 2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine-5-carboxylate, in the form of a yellow vitreous solid matter. The product is identified with the desired compound according to the spectrum of nuclear magnetic resonance. His thin-layer chromatogram on silica gel (chloroform-methanol 6: 1 by volume) is only clear.
    NMR spectrum (OMSO - d) cf:
    3.80 (3N, S); 4.90 (1H, t; after adding deuterium oxide, d, JHP - "H); 7.13 (1I, d, J 5H); , 8.53 (1H, wide); 10.85. (Lil / wide).
    Example 35. Methyl-1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylate (510 mg, 3.0 mmol) in 20 ml is suspended in a glass tubular pressure resistant reactor of 50 ml capacity. water and suspension are frozen in a bath of dry ice and ethanol.
    To the frozen solid is added 20 ml of trifluoroacetic acid, followed by the dissolution of trifluoromethyl hypofluorite (approximately 2.90 mg). The reactor is tightly closed and the slurries are allowed to spontaneously warm to room temperature. With increasing temperature, the reaction proceeds, giving a homogeneous solution. This reaction mixture is stirred overnight. The excess trifluoromethyl hypofluorite is removed by passing nitrogen gas through the solution, and then after adding sodium bicarbonate (540 mg) the solvent is removed under reduced pressure, leaving a colorless syrup. 30 ml of acetone is added to this syrup and insoluble materials are filtered off. The acetone solution is concentrated under reduced pressure, and 1.15 g of a pale yellow syrup are isolated. Using thin-layer chromatography on silica gel and nuclear magnetic resonance spectrum, this product is identified with methyl 5-fluoro-b-oxy-1, 2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate.
    Example 36. In a pressure-resistant glass tubular reactor with a capacity of 100 ml, 1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carbonitrile (1.10 g of 3.0 liters in 35 ml of water and the suspension is frozen in a mixture of dry ice and ethanol. 35 ml of fluorotrichloromethane is poured on this frozen solid and trifluoromethylhypofluorite (about 1.2 g) is dissolved in it while cooling in the same cooling bath. After being tightly closed, stir the contents at room temperature within 0 hours, while not remaining undissolved source m The excess trifluoromethylhypofluorite was removed by passing nitrogen gas through a solution. After adding sodium bicarbonate (690 mg), the solvent was evaporated under reduced pressure. Acetone was added to the brownish syrup and the pepacTBOpHNbiie was filtered off. 74 g brownish glassy solid The thin-layer chromatogram of this solid on silica gel (chloroform-methanol 6: 1 by volume) shows two separate spot, and using its nuclear magnetic resonance spectrum, it was found to be approximately 1: 1 mixture of 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine -5-carbonitrile.
    NMR spectrum (OMSO - d),
    5.33 (IH, m, after adding deuterium oxide, d, 30N); 7.7-8.2 (IH, wide); 9.90. (1H, wide); 10.3-11.0 (1 / 2H, wide, attributed to N).
    Example 37. A cylindrical pyrex glass reactor with a diameter of 40 mm and a height of 300 mm, equipped with a thermometer, an inlet teflon pipe and an outlet pipe leading to a trap containing a potassium iodide solution, is charged with 3.25 g (25 mmol) methyl-1, 2,3,4-tetrahydro-2, 4-dioxopyrimidine-5-carboxylate and 250 ml of water. When cooled with cold water, the contents are magnetically stirred. The content is fed with a stream of fluorine gas, previously diluted with nitrogen to a fluorine to nitrogen ratio of 1: 9 (by volume), at a flow rate of about 100 ml / min for about 1.5 hours until the solid starting material is completely dissolved. material. Approximately 1.5 mole equivalents of fluorine gas were consumed. After supplying nitrogen gas to the reaction system for some time, the reaction mixture is concentrated under reduced pressure and then evaporated in vacuo. 4.32 g of crude methyl 5-fluoro-6-hydroxy-1, .2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine-5-carboxylate are obtained in the above method as a white vitreous substance. Example 38 In a 300 ml glass tube pressure resistant reactor, 25 ml of methanol are mixed with 50 ml of fluorotrichloromethane. The mixture is well cooled in a ba of dry ice and ethanol. In this mixture, trifluoromethylhypofluorite (approximately 1.1 g) is dissolved, and then methyl-1,2,3,4-tetrahydro-2, 4-dioxopyrimidine-5-carbox is suspended lat (1.36 g, 8.0 mmol), followed by VO added with ml of methanol, pre-cooled in a bath of dry ice and ethanol. After the reactor is tightly closed, the reaction mixture is allowed to spontaneously warm to room temperature with stirring. As the temperature rises, the starting material quickly dissolves to form a homogeneous solution. The solution is stirred overnight. Nitrogen gas is then bubbled into the solution to remove excess trifluoromethyl hypofluorite, and then the reaction mixture is evaporated under reduced pressure to obtain a white solid. This solid is chromatographed on a silica gel column (solvent: chloroform, containing 110% by volume (methanol); 1.52 g of methyl 5-fluoro-6-methoxy-1,2,3,4,5,6-hexahydro -2, 4-dioxopyrimidine-5-carboxylate and 0.31 g of unreacted starting material The desired product is recrystallized from acetone and hexane to give 1.26 g of pure compound as colorless flakes, mp 16-166 ° C. NMR spectrum (DMSO - db) (/; i, 38 (3H, S), / 3.85 / (3H, S); / t, 77 / (1H, dxd, J (p 2H, J 5 N7., After adding deuterium oxides d, 2H: j); / 8.77 / (1H, wide, / 10-, 92 / (IH, wide). Elementary analysis: Calculated,%: 38 , 19; H 4.12, N 12.7 amp; F 8.63. CyKpFN O. Found: C 38.49; H 4.08: N 12.50 / F 7.92. Example p 39 B25ml1 and hydrochloric acid are heated under reflux for 1 hour. Methyl5-FTOR-6-OXI-1, 2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine-5-carboxylate (1.20 g , 5.8 mmol.) The reaction mixture is treated with activated charcoal and evaporated under reduced pressure, in this way a brownish solid is obtained. This solid was rinsed with acetone and dried over 695 m of yellow prisms. The crystals are further purified by dissolving them in. mixtures of 50 ml of water and 1 ml of 1 and. hydrochloric acid followed by passing the solution through a column of activated carbon. The column was washed well with water, and the adsorbed organic material was eluted with 350 ml of a mixture of methanol, water and benzene 25: 6: 3. The eluate was evaporated under reduced pressure, yielding 490 g of a white powder. In thin-layer chromatography on silica gel (chloroform-methanol-6: 1, this powder is consistent with an authentic sample of 5-fluorouracil. Based on the following physical constants, this product is further identified with 5-fluorouracil. PH 7, nm. NMR spectrum (OMSO - d ( ,) cP; 7.72 (1H, dxd, J 6H: j, after adding, Deuterium oxide pressure, d,); 10.82 (1H, wide); 11.47 (1H, wide). Example 40. In a pressure-resistant glass tube reactor, 1,2,3,4-tetrahydro-2, 4-dioxopyrimidine-5-carboxy-amide (460 mg, 3 mmol) is suspended in 20 ml of water. The suspension is frozen in a bath of dry ice and ethanol followed by the addition of 20 ml of fluorotrichloromethane. When cooled in the same bath, trifluoromethylhypofluorite (approximately 990 mg) is added. After the reactor is tightly closed, the contents are stirred at room temperature for 160 hours. an addition of anhydrous sodium acetate (1.3 g), the solvent was evaporated under reduced pressure. The resulting red solid is washed with a mixture of methanol and acetone (1:10 by volume) and insoluble materials are filtered off (part of the starting material and some organic salts). The filtrate is concentrated under reduced pressure to obtain 1.55 g of a red syrup, which, according to the nuclear magnetic resonance spectrum, is 3,5-difluoro-6-hydroxy-1, 2,3,4,5,6-hexahydro-2.4 dioxopyrimidine-5-carboxamide. NMR spectrum (SMSO - 1 (,) cG: 4.93 (1H, t, after adding deuterium oxide, d, Jftf 2.5H, -CF-CH-; 8.35, (1H, broad, NH). No the peak cannot be attributed to the NJ-proton. The above red syrupy substance is heated under reflux in concentrated hydrochloric acid for 5 hours, then the pH is adjusted to 1 with the required amount of potassium carbonate. The reaction mixture is desalted, passed through a column of activated carbon. Organic material adsorbed on carbon is eluted with a mixture of solvents from 300 ml of methanol and 100 ml of benzene. and then the eluate is evaporated under reduced pressure, obtaining 230 ml of a white powder. Based on its current-layer chromatogram on silica gel and the following physical constants, this powder was identified with 5-fluorouracil. Ultraviolet spectrum: 267 nm. NMR spectrum (DMSO - db) - 7.70 (1H, dxd. J 5H, and u „p bN. 10.68 (1H, wide); 11.47 (1H, wide). T. pl. 282-283 s (colorless when recrystallized from water) Elementary analysis: Calculated,%: C 36.93, H 2.32; N 21.54; F 14.61. . Found,%: C 36.90; H 2.24; N 21.46; F 14.37. Example 41.-1.38 g of methyl 1- / 2-tetrahydrofuryl} -1,2,3,4-tetrahydro-2, 4-dioxopyrimidine-5-carboxylate is dissolved in 200 ml of glacial acetic acid and fluoridated at a temperature of 18-24 ° C, using a gas mixture of fluorine (15 vol.%) and nitrogen. When a gas mixture is supplied equivalent to 2.2 mol of fluorine, the absence of any residual starting material is confirmed by the ultraviolet absorption spectrum. The solvent is then distilled off under reduced pressure to obtain a methyl-6-acetoxy-5-fluoro-1- (2-tetrahydrofuryl) -1,2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine-5 colorless syrup -carboxylate NMR spectrum- {OM50 - d6) cf: 2.07 (4H, t); 2.17 (3H, S); 3.92 (3N, and 2H) T5.90 (1H, t); 6.67 (1H, d, 2H); 9.40 (1H, broad). The above syrup without subsequent Purification is dissolved in 200 ml of a 1N aqueous solution of sodium hydroxide and the solution is left to stand at room temperature (about 22 to 3B-C) for 1 hour. Then, with ice cooling, the mixture is neutralized with concentrated hydrochloric acid and the yield of 5-fluoro-1- (2-tetrahydrofuryl) uracil is determined spectrophotometrically, which is 62%. The solution was adjusted to pH-4 by adding hydrochloric acid and adsorbed on a column of activated carbon (20 g). After the column was washed with water (pH 6-7), the adsorbed material was eluted with 1 L of methanol. The methanol solution is concentrated under reduced pressure, and 0.74 g of a white solid is isolated. This solid is chromatographed on a silica gel column (25 g of solvent chloroform and m-tanol — 20: 1 by volume) and fractions rich in the desired compound are concentrated by iodine: low pressure, and 0.40 g of 5-fluoro-1- (2 tetrahydrofuryl) uracil, in the form of a white solid. NMR spectrum (OMSO - d); 2.04 (4H, t); 3.7-4.5 (2H, t); 5.93 (1H, t); 7.80 (lH, .d,); 11.77 (1H, wide). Example 42. The acetic acid, B150ML, is dissolved. 0.94 g of ethyl 1- (2-tetrahydrofuryl) -1,2,3,4-tetrahydro-2, 4-dioxypyrimidine-5-carboxylate. Fluorination is carried out at 18-24 ° C with a gas mixture of fluorine / (15 vol.%) And nitrogen. When 2.0 mol-equivalent of the L-mixture is supplied, the spectrum of the ultraviolet & violet absorption is measured to confirm that the reaction is complete. The solvent is evaporated under reduced pressure. The resulting colorless syrup is dissolved in 150 ml of 1N. an aqueous solution of sodium hydroxide, and the solution is left to stand at room temperature (about 22-25 ° C) for 1 hour. Then, with ice-cooling, the reaction mixture is neutralized with concentrated hydrochloric acid. By changing the ultraviolet absorption spectrum, the product is found to be a 5-fluoro-1- (2-tetrahydrofuryl) -acyl. The yield based on its molecular extinction ratio is 59%. Ultraviolet spectrum: pH 7.0 270 nm s 270 nm PRI m e r43. 2.40 g (10 mmol) of methyl 1- (2-tetrahydrofuryl -1-2,3,4-tetrahydro-2-4-dioxopyrimidine-5-carboxylate) are fluorinated with 1.7 mol-equivalents of fluorine in 200 ml of acetic acid. The solvent was distilled off under reduced pressure. 200 ml of a 1N aqueous solution of sodium hydroxide was added to the resulting colorless syrup to hydrolyze at 22–35 s for 1 hour. The reaction mixture was cooled with ice and neutralized with 7 ml of concentrated hydrochloric acid. The yield of 5-fluoro-1- (2-tetrahydrofuryl) -uracil based on the results of ultraviolet absorption is 62%. The reaction mixture is diluted to 1 l and desalted by chromatography on an activated carbon column (40 g). The elution is carried out with 3 l of methanol. The methanol is evaporated under reduced pressure, thus obtaining 1.40 g of a white solid. the product is dissolved in 250 ml of water and purified on a XAD resin column (210 m as a suspension in water}.) The by-product 5-fluorouracil leaves the column (1.2 mmol based on the UV spectrum) as an effluent. The adsorbed desired is eluted with a mixture of ethanol (17% by volume
    权利要求:
    Claims (1)
    [1]
    Formula ’of the invention A method for producing derivatives of the general. Formula (I) (P
    R t alkoxycarbonyl holding 1 to 18 carbon atoms in the alkyl chain, or —CN group or —CONR ^ Rj group where R ^ and Rg are the same or different and mean hydrogen or alkyl containing 1-4 carbon atoms, or R ^ and R g together with the nitrogen atom form a morpholine ring; hydroxyl, lower alkoxy or lower acyloxy group, R 2 group, carbon atoms of the carbon group;
    hydrogen hydrogen
    the unity of the formula (II) or lower alkyl, and with the fact that they have the above where Y, the values of / are fluorinated in the presence of water, a lower alcohol or a lower aliphatic carboxylic acid.
    Priority by signs: 03/31/76 at Y - methoxycarbonyl group, -CONH ^ ~ or -CN group, R ^ - hydroxyl or lower alkoxy group; and Rj is hydrogen.
    10.27.76 at Y - all values, R 1 - hydroxyl, or lower alkoxy or lower acyloxy group; Rjt - water or group ^ r - hydrogen lower alkyl.
    12/06/76 at Y - alkoxycarbonyl group; R <is acetyloxy group; R “2 - to groups /) R 3“ hydrogen.
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    同族专利:
    公开号 | 公开日
    DE2714392A1|1977-12-22|
    CA1081226A|1980-07-08|
    FR2346337B1|1983-05-13|
    PT66374A|1977-04-01|
    FR2346337A1|1977-10-28|
    FI770904A|1977-10-01|
    DD132790A5|1978-11-01|
    NL7703541A|1977-10-04|
    SE7703721L|1977-10-01|
    ES469098A1|1979-09-16|
    US4329460A|1982-05-11|
    CH632748A5|1982-10-29|
    PL106917B1|1980-01-31|
    PT66374B|1978-08-25|
    NO771124L|1977-10-03|
    DK142029B|1980-08-11|
    DK142029C|1981-01-05|
    GB1546346A|1979-05-23|
    DD137353A5|1979-08-29|
    GR68935B|1982-03-29|
    DK141177A|1977-10-01|
    PL197045A1|1978-02-13|
    PH14553A|1981-09-24|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    FR3455M|1963-05-02|Hoffmann La Roche|Fluoropyrimidine nucleoside-based drug.|
    FR3456M|1963-05-02|Hoffmann La Roche|Fluoropyrimidines based drug.|
    US3201387A|1963-09-18|1965-08-17|Heidelberger Charles|5-trifluoromethyluracil, derivatives thereof, and processes for preparing the same|
    US3360523A|1964-06-17|1967-12-26|Du Pont|3, 5, 6-substituted hydrouracils|
    US3406023A|1966-10-31|1968-10-15|Du Pont|Herbicidal method|
    US3954758A|1970-05-27|1976-05-04|Pcr, Inc.|Process for fluorinating uracil and derivatives thereof|
    CH553195A|1971-03-19|1974-08-30|Sandoz Ag|PROCESS FOR PRODUCING NEW 2,6-DICHLORO BENZALDOXIMO ) -ETHER.|
    US3987045A|1971-05-03|1976-10-19|Basf Aktiengesellschaft|Disperse dyes based on isoindolene derivatives|
    US3954759A|1972-07-13|1976-05-04|Pcr, Inc.|Process for preparation of 6-substituted 5-fluorouracil derivatives|
    DE2401619C2|1974-01-14|1986-04-03|Kailash Kumar Prof. Dr. 2359 Lentföhrden Gauri|Fungistically active uracil derivatives and processes for their preparation|
    FR2298332B1|1975-01-22|1978-12-08|Asahi Chemical Ind|
    US4071519A|1975-11-05|1978-01-31|Mitsui Toatsu Chemicals, Incorporated|1-Carbamoyl-5-fluorouracil derivatives|
    US4080455A|1975-12-16|1978-03-21|Taisho Pharmaceutical Company Limited|5-Fluoropyrimidin-4-one compositions|JPS57179188A|1981-04-28|1982-11-04|Shionogi & Co Ltd|5-fluorouracil derivative|
    DK167280B1|1985-03-20|1993-10-04|Ciba Geigy Ag|3-ARYLURACIL DERIVATIVES, PROCEDURES FOR PREPARING THEREOF, WEED POLLUTANTS CONTAINING THESE DERIVATIVES AND THE USE OF THE DERIVATIVES FOR THE WEED PREVENTION|
    US4669081A|1986-02-04|1987-05-26|Raytheon Company|LSI fault insertion|
    US4904714A|1987-10-02|1990-02-27|Olin Corporation|Synthetic resin composition and its method of use|
    US4816585A|1987-03-05|1989-03-28|Olin Corporation|Tetraalkylpiperidinyl substituted uracil derivatives and their use as ultraviolet light stabilizers|
    US4920126A|1988-05-10|1990-04-24|Uniroyal Chemical Ltd/Uniroyal Chemical Ltee|Barbituric acid derivative and treatment of leukemia and tumors therewith|
    US5312919A|1992-06-12|1994-05-17|Baylor Research Institute|Photooxidation products and derivatives thereof of merocyanine-540, their preparation and uses|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP3665376A|JPS52118480A|1976-03-31|1976-03-31|Synthesis of uracil derivatives|
    JP12993276A|JPS6115070B2|1976-10-27|1976-10-27|
    JP14679576A|JPS5420507B2|1976-12-06|1976-12-06|
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