SU847917A3 - Method of preparing uracyl derivatives - Google Patents

Abstract

PURPOSE:Fluoropyrimidine derivatives of formula I(X is O, NH;R1 is OH or SH, etherified or not etherified, amino which may be substituted;R2 and R3 are H, lower alkyl, 2-tetrahydrofuryl, Y is esterified or amidated carboxyl, CN), e.g. methyl-5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5c arboxylate.

Description

(54) METHOD FOR OBTAINING URACIL DERIVATIVES

This invention relates to the synthesis of new uracil derivatives that can be used in medicine.

A known method for producing esters by reacting alcohols with the corresponding alcohols, fl acids.

The purpose of the invention is the synthesis of new biologically active derivatives of uracil.

The goal is achieved by the method of obtaining uracil derivatives of the general formula

Hn o

but)

1 JL

I 7

H

group-CN or -SOOU,

where U Y, alkyl, R C cd-alkoxy, C, 1st - alkylthio, cyclohexyloxy, 2,2,2-trifluoroethoxy, benzyloxy, allyloxy, propargyloxy, phenoxy, phenylthio or naphthylthio group.

The method is that the compounds of the formula

HK-v;

(

n

where u has the indicated values

R is hydroxyl, C., -aliphatic acyloxy or C., is an alkoxy group,

subjected to interaction with the compound of the formula

R N.

15

where R has the indicated values, at a temperature of 0-150 ° C.

The compounds of formula I have the ability to prolong the life of animals

20 sufferers of carcinoma, and / or have antiviral activity.

The compounds of formula 1 contain asymmetric carbon monoxide 1 at the 5- and 6- positions; there may be two isomers containing a hydrogen atom in the cis or trans configuration with respect to the fluorine atom at the 5- position and, with respect to each isomer, there may be d30 or t-form optical isomers.

Therefore, the compounds of formula 1 include each of the isomers and a mixture consisting of at least two types of zomers. The compound of formula 1 can be obtained by conducting a reaction between a compound of formula II with an alcohol, or a thiol of formula R N. This reaction is known as nucleophilic substitution, and the nucleophilic reagent R H can be selected from a wide range of compounds with an active hydrogen atom.

Said esterification or thioetherification reaction can be successfully carried out on an acid analyzer (e.g., inorganic and organic strong acids, such as hydrochloride chloride, anhydrous hydrogen fluoride, concentrated sulfuric acid, methanesulfonic acid, paratoluene sulfonic acid, trifluoroacetic acid, etc., acid L). such as boron trifluoride, zinc chloride, titanium chloride, etc.,).

Esterification and thioetherification can be carried out in the presence of a solvent. The solvent may be alcohol or thiol, which are used as esterification or thioetherification agents, although other solvents may be used, such as halogenated hydrocarbons (e.g. diethyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane), aromatic hydrocarbons (eg benzene, toluene, xylene, chlorophenol), etc.

An etherification reaction or a thioetherification reaction can be successfully carried out by removing a by-product such as water, alcohol, and the like. using conventional methods or agents such as azeotropic distillation, silica gel, molecular sieve, sodium sulphate and magnesium sulphate.

It should be borne in mind that during the esterification reaction, if the Y symbol is an esterified carboxyl group, a transesterification reaction can occur at the place of the Y symbol, and if the Y symbol is a cyano group, it can become an esterified carboxyl group.

After the reaction is completed, the resulting compound of Formula 1 can be isolated and purified to separate from the reaction mixture by known methods. For example, the solvent can be distilled off under reduced pressure to isolate the target compound and

the latter can be purified by recrystallization or chromatography.

The starting compounds of formula II can be prepared, for example, by fluorinating a compound of formula III in the presence of water, alcohol or carboxylic acid.

 ll

(R11) 0 # kjjx,

H

where Y means COOU, where Y is alcohol or CN.

5 Compounds of formula 1 not only have a potent inhibitory ability against the growth and multiplication of tumor cells, for example, KB cell groups (cultured cells,

0 derived from human carcinoma or nasopharynx), C-34 cell groups (mouse kidney fibroblast cells) and AC cell groups (rat astrocytoma cells), but also have

5 life-prolonging effect on mice with leukemia (P-388, Z-1210). These compounds inhibit the growth and reproduction of various tumor cells in mammals (such as

j. rats, mice and humans), and also have a prolonged lifespan effect on mammals suffering from leukemia. The compounds of formula 1 can be administered orally or non-orally, since they are made in the form of preparations containing a pharmaceutically acceptable carrier, diluent or excipient that are prepared using the methods 1 — tablets, powders, granules, anhydrous syrups,

0 capsules, suppositories and injections. Depending on the type of animal, the disease and its symptoms,. individual compound, route of administration, etc., dosage usually

5 is selected in the range of about 25,800 mg / kg of body weight per day. Although the upper limit is about 400 mg / kg body weight, in many cases it is preferable to have a dose of about

200 mg / kg body weight and there are cases where it is desirable to use a higher or lower dose. Compounds of formula 1, enter the blood in a sufficiently high concentration that is maintained for an extended period of time.

The method for determining the prolonging

0 life is influenced by P-388 leukemia in KMs. .

0.1 ml of diluted ascithin fluid containing cells is implanted into BDF mice weighing 185–25 g. The test compound suspension is administered intraperitoneally. At a constant rate to a volume of OPT ml / 10 g body weight 2, the results are recorded according to T / C %, calculated on the basis of the average duration of the animals treated and control animals. The results of the experiments: Compound Dose (mg / T / C kg / day) Methyl 5-fluoro-6-methoxy-1, 2,3,4,5,6-hexahydro-2, 4-β-monoxyl pyrimidine 200 243 -5 -carboxylic acid 100 217. .50 208 b-ethoxy-5-fluoro-1 ethyl ester, 2,3,4,5,6-hex200 160 sagidro-2,4-diox100 143 sapyrimidine-car50 130 bonoic acid Inhibiting effect on the proliferation of tumor cells. Test method: 1. Inhibition of cell proliferation HF. 2x10 cells are suspended in 1 ml of Minimum Essential Medium Inl (MEM) + 10% fetal calf serum (MEM10 Fes) and plated in a steel dish (1.8 cm in diameter) with a round lid (1.5 cm in diameter). On the first day after seeding, three samples (per group of test cells) were taken and transferred to a glass dish (4.5 cm in diameter) with 5 ml of MEM 10 FCS and from different concentrations of the test compound. On the fourth day after seeding, determine the number of cells per cap (3 samples for each concentration level) with a Coulter counter. The results are expressed by the concentration of the drug substance, in which the cell number is 50% (EDdd) of the average number of cells in the control experiment (without the drug substance), which on the fourth day is taken as 100%. 2. Inhibit the induction of cell proliferation in C 34 cells that are enclosed with VAH3. cells are suspended in 1 m MEM (Eagle) + 10% fetal calf serum (MEM 10 Fes) and sown in a glass dish (1.8 s in diameter, with a round lid (1.5 cm in diameter). On the second day after sowing, Infection (37 ° C, 120 mi (imitation infection or viral infection) in the case of the latter, 100-200 PFV is injected into the cell). After this operation, one group for testing (3 portions) is selected and transferred to a glass ( with a diameter of 4.5 cm) with 5 ml of MEM -2 FCS in hygd of the tested concentrations of the drug substance. On the sixth day after seeding, using a counter K Ulter counts the number of cells per sample. For each experimental group, the difference for all members between virus-infected cells (y) and virus-generated parodies (M) is calculated. The results are expressed as the drug concentration giving (Y-M) a value of 50%. (U) with respect to the control group (non-medicated), which is taken as 100%. 3. Inhibition of cell proliferation of Ac. 1 10 AS cells (2 ml of MEM Needles with 10% fetal calf serum) are seeded into Falcon's cup (inner diameter 3.5 cm). After 24 hours, they were replaced with the aid of the aforementioned cultivation period containing different concentrations of the drug substance. The number of cells is determined on the third day after changing the medium. The pharmacological effect is defined as U, le. carcinogenic matter, accounting for 50% of the counted cells for the group receiving the medicinal substance, as compared with the group for which the number of cells considered control is 100%. I Experimental Results: Compound. Inhibition of growth- (gamma / ta cells / ml) Methyl 5-fluoro-6-methoxy-1, 2,3,4, 5, b7 hexahydro-2, 4-dioxoKB 3 AC 0.12 pyrimidine-5C34, infi-carboxylic acid, VAUZ 0.023 5-fluoro-b-ethoxy-1 ethyl ester, 2,3,4,5,6-hexahydro-KB 2,8 -2,4-dioxopyr-C34, imidine-carbono- VAPA 0.023 ficirovanic acid; Example 1. A gaseous mixture of fluorine (15 vol% by volume) and nitrogen, containing 5 mol equivalents of fluorine, is fed into the suspension 2.04 g of steyl 1,2,3,4-tetrahydro-2,4- dioxoirimidine-5-carboxylate in 200 ml of acetic acid for 8.5 hr. Filtration of the substance was filtered to 89%. unreacted starting material, and the filtrate is concentrated under reduced pressure. The residue is dissolved in 10 ml of ethanol and heated at reflux overnight. The solvent is distilled off, and the residue is chromatographed on silica gel (solvent: chloroform-ethyl acetate 1: 1 (v / v) to isolate 54 mg of stearyl 5-fluoro-b-ethoxy-1, 2,3,4,5, b -hexahydro-2,4-dioxypyrimidine-5-carboxylate, mp 104-106 0 {recrystallized from xyuroform-hexane). NMR spectrum (DMSO-c36) f: 0.6-1.8, (38H, m), 3.3-3.93 (2H, m), 2-934, 42 (2H, m), 4 , 82 (IH, m), after adding deuterium oxide, d, j 2HZ). 8.70, 10.83 (each IH, wide). Calculated: C 62.34, H 9.62, N 5.82. . C25 Hj) 5 FN ,, 05-1 / 2 HjO Found: C 62.52, H 9.45, N 5.85. Example 2. B200 ml of absolute methanol dissolved 8, O g (38.8 millimoles) methyl 5-fluoro-6.-Hydroxy-1,2,3,4,5,6-Hexahydro-2,4-dioxopyrimidine The 5-carboxylate and, while cooling on ice, dry hydrogen chloride gas is supplied until approximately 14 g of hydrogen chloride is absorbed. The reaction mixture is left to stand at about overnight, and then it is concentrated to dryness under reduced pressure. The solid obtained is chromatographed on a silica gel column (solvent acetone-chloroform 1: 4 (volume / volume gives 7.64 g of colorless crystals. Based on thin layers, the chromatographic mobility in the thin layer and the IR and NMR spectra are determined in an authentic manner) methyl 5-fluoro-6-methoxy-1,2,3, 5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate Example 3. 1.03 g methyl 5-fluoro is dissolved in 30 ml of anhydrous dioxane -6-hydroxy-1,2,3,4,5,6-hex-sagidro-2,4-dioxopyrimidine-5-carb oxylate with the subsequent addition of 1.0 g of cyclohexanol. Then I serve A sufficient amount of hydrogen chloride and the Harpe reaction mixture are heated under reflux for 2 hours. The reaction mixture is concentrated to dryness and benzene-p-1, san mixture is added to the concentrate. The resulting precipitate is isolated by filtration and placed on a silica gel column (solvent: benzene-acetone, h 3: 1) (volume / volume) to obtain 0.71 g of methyl 5-fluoro-6-cyclohexyloxy-1,2,3,4,5,6-hexahydro-2, 4-dioxopyr-imidine-5- carboxylate. Melting point 196-197 ° C. NMR spectrum (DMSO-d) (f: 0.9-2.0 (OH, broad, m), 3.60 (IH, m), 3.83 (3H, s), 4.97 (IH, d l d, j - 5HZ, j 2HZ), 8.8 (IH, wide), 11.00 (IH, wide). Calculated: C 50.00, H 5.94, N 9.72, Ci2 HIT Found : C 49.94, H 5.83, N 9.78. Example 4. 0.52 g of methyl 5-fluoro-b-hydroxy-1,2,3,4,5,6 is dissolved in 10 ml of anhydrous dioxane. -hexahydro-2, 4-dioxopyrimidine-5-carboxylate, followed by the addition of 0.65 g of p-octyl alcohol, 15 ml of p-toluene sulfonic acid and 0.5 g of anhydrous magnesium sulfate. The mixture is heated with stirring under reflux for 4 hours. The reaction mixture is filtered and concentrated. Benzene is added to the residue, and then hexane, and the resulting precipitate is isolated by filtration. The filtrate is chromatographed on a silica gel column (solvent: benzene-acetone 3: 1) to give 0.65 g of methyl 5-fluoro-6-p-Oxtiloxy-1, 2, 4, 4 , 5,6-hexahydro-2, 4-dioxopyrimidine-5-carboxylate as a white powder. Melting point 147-148 C. NMR spectrum (DMSO-dd,) cf: 0.9 (34, wide), 1.3 (12H, wide, s) 3.6 (2H, wide). 3.82 ZN, s), 4.82 (1H, d X d, j 5HZ, j 2HZ), 8.9 (IH, wide), 11.0 (IH, wide). Calculated: C 52.82, H 7.27, N 8.80. m Found: C, H 7.27, N 8.71. Example 5. In 400 ml of acetic acid, 2.1 g of 1,2,3,4-tetrahydro-2,4-dioxypyrimidine-5-carboxamide is suspended, and with intensive stirring 1.5 mol of equilibrium of fluorine gas, previously diluted with a nine-fold volume, are fed nitrogen gas for 6 hours at room temperature. The reaction mixture is then concentrated to isolate the crude product b-acetoxy-5-fluoro-1, 2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxamide. NMR spectrum (OMSO - dj,) cG: 2.10 (3N, s), 6.12 (1H, wide, d, j 5HZ), 8.0 (IH, wide), 8.2 (IH, wide ), 9.1 (IH, wide), 11.1 (IH, wide). This crude 6-acetoxy compound is dissolved in 100 ml of ethanol and the solution is heated under reflux for 2 hours and then cooled. The resulting crystals are collected by filtration, and the filtrate is concentrated to obtain the next portion of crystals, which are collected by filtration. Both crystalline products are mixed and recrystallized from ethanol to obtain 1.7 g, 5-FLUORO-6-ETOXI-1,2,3,4,5, b-hexahydro-2, 4-dioxopyrimidine-5-carboxid, as colorless prisms. Melting point 224-226 ° C (with decomposition). NMR spectrum (DMSO - d) (f: 0.901, 32 (4.5H, m), 3.30-3.88 (ZN, m), 4.78 (IH, wide d, j), 7.84 (IH, wide), 8.06 (IH, wide), 8.75 (IH, wide), 10.55 (IH, wide). Calculated: C 39.67, H 5.41, N, 17.35. ftt.Ott 1/2 Found: C 39.44, H 5.37, N 17.37. Example 6. 1.03 g (5 ml of mlyl) methyl-5-fluoro-6-hydroxy- is dissolved in 15 ml of dimethoxyethane 1,2,3,4 5,6-hexahydro-2,4-dioxypyrimidine-5-carboxylate. To this solution was added 1.03 g (10 millimole) of benzyl alcohol and a catalytic amount of methanesulfonic acid. The mixture was heated under reflux for 2 h. The reaction mixture is concentrated under reduced pressure and about The stack is cleaned in a manner analogous to that described in Example 27, yielding 0.80 g of methyl 6-benzo ILOXI-5-Fluoro-1,2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine-5- carboxylate lat. Melting point 173-174 ° C (recrystallized from mixture: acetone-chloroform). NMR spectrum (DMSO - d) cf: 4.68 (2H, s), 3.80 (3N, s), 4.98 (1H, d Kd), 7.34 (5H, wide, s), 9.00 (1H, wide), 11.08 (1H, wide),, Calculated: C 52.71, H 4.42, N 9.46. CiiH, 3 FN, i05 Found: C 52.50 ,, H 4.28, N 9.35 Example 7. VOm of ethanol, containing 20% hydrogen chloride, is dissolved in 0.30 g of 5-fluoro-6-hydroxy-1 , 2,3,4,5,6-hexahydro-2,4-dioxoprimidine-5-carbonitrile, followed by the addition of 1.0 g of silica gel for chromatography. The mixture is stirred at room temperature for 20 hours. The reaction mixture is evaporated to dryness under reduced pressure and subjected to chromatography on silica gel (solvent: chloroform, ethanol 12: 1), with a release of 0.27 g of ethyl 5-fluoro-6-ethoxy-1,2, 3,4,5,6-hexa hydro-2,4-dioxopyrimidine-5-carboxylate. Example 8. A solution containing 3.30 g (15 mmol) ethyl 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine-5-carboxylate, 2.05 g (15.5 millimoles), benzyl mercaptan, a catalytic amount of methanesulfonic acid and 20 ml of dimethoxyethane is heated under reflux for 1 hour. The reaction mixture is then purified as in Example 27 to give 2.23 g of ethyl 6-benzylthio-5-fluoro- 1, 2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine-5-carboxylate. Melting point 149-150 ° C (recrystallized from a mixture: chloroform-n-hexane). NMR spectrum (OMSO - dft): 1.16 (3N, t, j 7HZ), 3.96 (2H, s), 4.25 (2H, g, j 7HZ), 5.02 (IH, d X d, after adding deuterium oxide, d, 7HZ), 7.30 (5H, s), 8.85 (IH, wide), 11.18 (IH, wide). Calculated: C 51.53, H 4.63, N 8.58, F 5.82, C | AH, 5 Found: C 51.51, H 4.47, N 8.73, F 5.84. Example.9. 50 ml pressure resistant stainless steel reactor. 3.30 g (15 millimole) of ethyl 5-fluoro-6-6-oxy-1, 2,3,4,5,6-hexahydro-2,4-dioxypyrimidine-5-carboxylate, 1.33 g (18 mmol) are charged allyl mercaptan, a catalytic amount of methanesulfonic acid and 20 ml of dimethoxyethane and heated on an oil bath at 80-90 s for 1 h with magnetic stirring of the contents. The contents were concentrated under reduced pressure and the residue was purified as in Example 2 to give 1.28 g of ethyl 6-allylthio-5-fluoro-1,2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine- 5-carboxylate. Melting point: 122-123 ° C (recrystallized from a mixture: chloroform-n-hexane). NMR spectrum (OHSO - d,) (: 1.20 (3N, t, j 7HZ), 3.36 (2H, 2 peaks), 4.30 (2H, g, j 7HZ), 4.75-6 , 20 (2H, m), 8.77 (IH, wide), 11.15 (IH, wide). Calculated from 43.47, H 4.7.4, N 10.14 F 6.88. C oHiifNaO (A) Found C 43.52, H 4.44, N 10.12, F 6.90 Example 10 A solution containing 3.30 g (15 mmol) ethyl 5-fluoro-6-hydroxy-1, 2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine-5-carboxylate, 2.40 g (15 mmol) of 2-naphthalenethiol, a catalytic amount of methanesulfonic acid and 25 ml of dimethoxyethane, under reflux for 1 h , and the reaction product is purified in the same manner as in Example 27 to obtain 1.71 g of e. 5-fluoro-6- (L-naphthylthio-1, 2,3,4,5,6-ge Sagidro-2, 4-dioxopyrimidine-5-carboxylate, Melting point: 198-201 C (recrystallized from mixture: acetone chloroform-n-hexane). NMR spectrum (DMSO-d) cp .: 1.16 (G, t, j 7HZ), 4.27 (2H, g, j 7HZ), 5.55 (IH, z, j IfHZ, after adding deuterium oxide, d, JHF), 7.1-8.2 (7H, m), 8.90 (IH, wide), 11.18 (IH, wide). C 56.35, H 4.41, N 7.73, F 5.24, C „FN, Found C 56.38, H 4.06, N 8.01, F 5.07. Synthesis Example 1. In 750 ml of anhydrous dimethylformamide, 156 g of 1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carbamate acid are suspended, and to this suspension, while stirring, 238 g of thionyl chloride is added at a temperature not exceeding for 1 hour and 10 minutes, then the resulting reaction mixture is heated at 45-50 seconds for 1 hour and at 50-60 ° C for another 1 hour. The .CMeqb is then allowed 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 under reduced pressure. In this way, 210 g of 1,2,3,4-tetrahydro-2, 4-dioxopyrimidine-5-carbonyl chloride dimethylformamide of the semi-acidic complex are obtained in the form of a white powder. Melting point (with decomposition). C, 36.14; H, 3.98; N, 15.80. GsH-to CtNjOi,. 1/2 NS I Found C 36.04, H 3.73, N 15.82 NMR spectrum (OMSO - and ,,) cG: 2.7 (ZN, s), 2.87 (ZN, s), 7.88 (1H, s 8.18 (1H, wide), 11.77-12.2 (1H, wide), 13.4 (1H, wide). Reference Example 2. Synthesis of esters 1,2,3 , 4-tetrahydro-2,4-dioxopyrimidine-5 carboxylic acid 13.3 g of 1,2,3,4-tetrahydro-2, 4 - dioxopyrimidine-4-carbonyl chloride: dimethylformag are suspended in 50-100 ml of anhydrous toluene Add a half-acid chloride complex followed by the addition of 1.1 mol equivalents of the corresponding alcohol or phenol. The mixture is heated under reflux for 20 minutes. After cooling, the precipitate is heated. is isolated by filtration, washed with a solvent such as toluene or ether, and -g is dried and the resulting ester of 1,2,3,4-tetrahydro-2,4-dioxopyrim din-5-carboxylic acid is obtained. thus, the product is sufficiently pure so that it can be used directly as the source material in the following procedural substances. You can specify examples of new complex methods that can be obtained by the method. The general formula is Example 3. In 20 ml of toluene suspended 6.0 g of 1,2,3,4-hydroxy-2, 4-dioxopyrimidine-5-acid, followed by 7 ml of piperidine. When boiling and heating with additional drops of 4 ml of oxychloride, the phospho mixture is heated under reflux for 30 minutes. After the denu day, toluene / a of the ostape is discharged with 50 ml of water. Received by

the crystalline precipitate is isolated by filtration and recrystallized from 50 ml of water to obtain 2.3 g of N- (1,2,3,4-tetrahydro-2, 4-dioxopyrimidine-5-carbonyl) -piperidine, in the form of white flakes. Melting point 294-295 0 (with decomposition).

Reference examples 4-6. In a manner similar to that described, the following compounds were prepared.

 (1, 2, 3,4-Tetrahydro-2, 4-dioxopyrimidine-5-carbonyl) -morpholine, melting point 306-3070 ° C (with decomposition), white microscopic crystals ..

1,2,3,4-Tetrahydro-2,4-dioxopyrimidine-5- (N, N-diethyl) -carboxamide, melting point 248-249 ° C (with decomposition), pale yellow prisms.

1,2,3,4-Tetrahydro-2,4-dioxopyrimidine-5- (N-phenyl) -carboxamide, melting point, 359-360 ° C (with decomposition), pale yellow powder.

Reference Example 7. A mixture of 5 g of methyl 1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylate, 50 ml of DMF (dimethylformamide) and 20 ml of benzylamine are heated for 7 hours and then the reaction mixture is kong center under reduced pressure. Water was added to the residue, and the solid precipitate was isolated by filtration, then washed with ethanol, to give 2.2 g of 1,2,3,4-tetrahydro-2, 4-dioxopyrimidine-5- (N-benzyl) -carboxamide, as white flakes. Point-melting 321-322 ° C (with decomposition).

Reference Example 8. 1.3 g of 1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carbonitrile are suspended in 7 ml of acetic acid, 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 for 2 days. 20 g of le is added to the white with the mud of the reaction mixture; water and the precipitate is isolated by filtration, rinsed with water and then dried to obtain 1.2 g of 1,2, 3,4-tetrahydro-2,4-dioxopyr-imidine-5- (N-tertiary butyl) -carboxamide, as a white powder. Melting point Zyu-ZI C (with decomposition).

Reference Example 9. 15.6 N-methyl urea, 30.1 g of a formic ethyl ethyl ortho ester and 27.1 g of dimethyl malonate are loaded into a 200 ml glass reaction vessel and the mixture is heated with vigorous stirring in an oil bath at 135 ° C. M-Methyl Urea dissolves to give a homogeneous solution. After some time, colorless flakes fall out. The resulting ethanol is distilled off in about 50 minutes. After cooling, the crystals are isolated by filtration, washed with ethanol and then hexane. The NMR spectrum of this product confirms that it is N, N-bis- (methylcarbamoyl) -formamidine. Exit 4.9 g

NMR spectrum (DMSO - d6) cr: 2.67 (6H, d, j 5HZ), 7.20 (2H, wide 8.73 (1H, s), 9.80 (1H, wide)).

An additional portion of colorless crystals is obtained from the mother liquor. These crystals are subjected to chromatography on a silica gel column, providing 6.5 g of colorless needles of dimethyl N- (N-methylcarbamoyl) -aminomethylenemalonate. . NMR spectrum {OMSO - dt) f 2.73 ZN, d, j 4.5HZ), 3.67 (ZN, s), 3.72 (ZN, s), 7.97 (IH, wide), 8j50 (IH, d, j I2HZ), 10.73 (IH, d, j 12HZ).

Reference Example 10. 11.35 g of dimethyl N -. (N-methylcarbamoyl) -aminome -, tylenmalonate are suspended in 120 ml of methanol, followed by the addition of 15 ml of 28% sodium methylate solution. This mixture is stirred for some time at room temperature. After dissolving the starting material to form a homogeneous solution, the mixture is heated under reflux for 20 minutes. As a result of heating to reflux, ogsshok drops out. After cooling, 80 ml of 1N is added. hydrochloric acid to acidify the mixture, and the precipitate is converted to crystals. After cooling on ice, the crystals are separated by filtration, washed with water and then with acetone and dried in air to obtain 6.59 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. Melting point 262-264 ° C.

Example 11. 8.80 g of ethyl 5-fluoro-b-hydroxy-1, 2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine-5-carboxylate is dissolved in 50 ml of dimethoxyethane, followed by the addition of 6, 0 g of 2,2,2-trifluoroethanol and a catalytic amount of methanesulfonic acid. The mixture was heated under reflux for 1.5 hours. The solvent was distilled off under reduced pressure and the residue was worked up as in Example 2 to give 1.54 g of ethyl 5-fluoro-6- (2,2,2-trifluoroethyloxy) -1, 2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate as a white powder. mp 166-173 ° C.

NMR spectrum (OMSO - d.) CG: 1.22 (3N, t, j, 7HZ), 4.27 (2H, a. J - 9HZ), 4.30 (2H, d, -j 7HZ.) , 5.15 (1H, d) id, after adding deuterium oxide d, j 2HZ), 8.35 (IH, wide), 10.53 (IH, wide). Example 12. A solution containing 10.30 g (50 mmol) methyl 5-fluoro-b-hydroxy-1,2,3,4,5,6-hexahyd, po-2,4-dioxopyrimidine-5-car6 oxyl, 4 6 g of ethanol, 0.3 f of methanesulphonic acid and 50 ml of dimethoxyethane are heated under reflux for 3 hours. The reaction mixture is concentrated to dryness under reduced pressure. The concentrate is subjected to chromatography on a silica gel column (solvent: acetone-chloroform 1.4 (v / v), vadel 8.0 g of methyl 5-FLUORO-6-ETOXY-1,2,3,4,5,6-hexahydro 2, 4-dioxopyrimidine-5-carboxylate, melting point 185-187 ° C (recrystallized from mixture :: acetone chloroform-hexane). NMR spectrum (DMSO - d) sec: 1.10 (MH, t, J 7HZ), 3.3-4.0 (2H, t), 3.78 (3N, s), 4.82 (1H, dxd, after adding deuterium oxide, d, j. 2HZ), 8.93 (IH, wide ), 11.07 (IH, broad). Calculated from C 41.03, H 4.73, N 11.96. CgH. Found C 40.75, H 4.55, N 11.68 Example 13. Solution 17, 6 g (80 millimole) ethyl 5-fluoro-6-hydroxy -1,2,3,4,5,6-hexahydro-2,4-wild sopirimidine-5-carboxylate, 4.8 g of methanol, methanesulfonic acid and 100 1,2-dimethoxyethane are heated under reflux for 3 h. The reaction mixture is purified as in example 2 to give 15.6 g of these 5-fluoro-6 -methyxy-1,2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine-5-carboxylate. Melting point 135-137 ° C (recrystallized from acetone-chloroform-hexane). NMR spectrum (d (j) f: 1.18 (3N, t, j - 7HZ), 3.30 (3N, s), 4.24 2H, g, j 7H2), 4.70 (IH, dxd , after adding deuterium oxide, d, J 2HZ), 8.93 (IH, wide 11.02 (IH, wide). Calculated from C 41.03, H 4.73, N 11.96. CgH ,, FNaOs Found From 41.06, H 4.58 ,, N 11.95 Example 14. 2.35 g of acetic anhydride, 2.05 g of pyridine and 10 acetone are added to 4.40 g (20 mmol) of ethyl 5-fluoro-6 -oxy-1,2,3, 4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate. The mixture is left to stand at room temperature overnight, and then after adding 10 ml of isopropanol and 10 ml pyridine is heated under reflux for 1 hour. After distilling the volatile fraction The residue was purified as in Example 2 to give 3.7 g of ethyl 5-fluoro-6-isopropoxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxyl Melting point 21618 ° C (recrystallized from tetone-chloroform-hexane). NMR spectrum (OMSO - df) cf: 1.07 (6H, d, J 6HZ), 1.16 (3N, t, j 7HZ ), 3.82 (IH, g, J 6HZ), 4.25 (2H, g, j 7HZ), 4.83 (IH, dxd, after adding oxide. Deuterium d, J 2HZ), 8.83 (IH , wide), 11.00 (IH, wide). C, 45.80; H, 5.77; N, 10.68. C oH 5PN2 ° 5 Found C 45.79, H 5.74, N 10.72. Example 15. A solution of 6.18 g (30 millimole) methyl 5-fluoro-6-hydroxy-1, 2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate, 2.96 g butyl alcohol, a catalytic amount of methanesulfonic acid and 40 ml of 1,2-dimethoxyethane is heated. under reflux for 1.5 hours. The reaction mixture is purified as in Example 23, yielding 4.86 g of methyl 5-fluoro-6-butoxy-1,2,3,4,5,6-hexahydro-2 , 4-dioxopyrimidine-5-carboxylate. Melting point 140141 ° C (recrystallized from mixture: acetone-chloroform-hexane). NMR spectrum (OMSO - d) sJ: 0.61, 8 (7H, t), 3.56 (2H, t), 3, (3N, s), 4.82 (1H, dy: d, after adding deuterium oxides, d, j 2HZ), 8.80 (IH, wide), 10.97 (IH, wide). C 45.80, H 5.77, N 10.68, CioH-isFNaOs calculated. C 45.83, H 5.59, N 10.57. Example 16. 9.90 g of ethyl 5-fluoro-6-hydroxy-1, 2,3,4,5,6-hexahydro-2,5-dioxopyrimidine-4-carboxylate are dissolved in 50 ml of acetone and the solution is stirred under continuous mixing. 5.2 ml of acetic anhydride and 9.0 ml of pyridine and are added. the mixture is left to stand overnight, and then, after adding 10 ml of butanol, it is distilled under atmospheric pressure to remove acetone from the reaction mixture. A pale yellow product is obtained, which is dissolved in benzene and subjected to chromatography on a silica gel column (150 g solvent: chloroform-benzene 6: 1 (v / v), a white solid is isolated from the fractions rich in the desired compound. The solid is recrystallized from acetone -chloroform-hexane to obtain 4.88 g of ethyl 5-fluoro-6-butoxy-1,2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine-5-carboxylate, as colorless needles. Melting point 141-142c. NMR spectrum (DMSO - db) c: 0.87 (ZN, t), 1.22 ZN, t, J r 7HZ), 1.45) (4H, m), 3.60 (2H , .m), 4.30 (2H, g, j 7HZ), 4.78 (IH, d X d, 2HZ, j 5HZ, after d add:

neither deuterium oxide, d, JHFC 8.87 (1H, wide), 10.98 (1H, wide).

C, 47.82; H, 6.20; N, 10.14.

C ,, n,.

Found C 47.52, H 6.22, N 10.11

Example 17. A solution of 8.80 g (40 mmol) of ethyl 5-fluoro-6-hydroxy-1, 2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate, 4.44 g of isobutyl alcohol, 0.3 g of methanesulfonic acid and 20 ml of 1,2-dimethoxyethane is heated under reflux for 1.5 hours. The reaction mixture is then purified in the same manner as in Example 2 to give 6.44 g of ethyl 5-fluor-6 β-isobutoxy-1,2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine-5-carboxylate.

Melting point ia7-188 G (recrystallized from acetone / chloroform-hexane).

NMR spectrum (DMSO - d) sJ: 0.78 (6H, d, j 7HZ), 1.15 (3N, t, j 7HZ), 1.4-2.0 (IH, t), 3.30 (2H, d, j 7HZ), 4.25 (2H, g. J 7HZ). 4.77 (IH, after adding hydroxy deuterium, d, j 2HZ), 8.88 (IH, wide), 11.00 (IH, wide).

C, 47.82; H, 6.20; N, 10.14.

C-, 1 FNnOg.

Found C 47.53, H 6.20, N 10.04

Example 18. A solution of 8.80 g (40 mmol) ethyl 5-fluoro-6-hydroxy-1, 2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate, 4.44 g sec - butyl. alcohol, 0.3 methanesulphonic acid and 20 ml of 1,2-dimethoxyethane is heated under reflux for .2.5 hours. Then the reaction mixture is purified in the same way as in Example 2 to obtain 5.58 g of ethyl 5-fluoro- 6-sec-betoxy-1,2,3, 4,5,6-hexahydro-2,4, dioxopyrimidine-5-carboxylate. The point of management is 192-194 ° C (recrystallized from acetone-chloroform-hexane).

NMR spectrum (OMSO - d (,) cf: 0.51, 6 (IH, m), 3.35-3.90 (IH, m), 4.25 (2H, g, j 7HZ) -, 4 , 82 (IH, d X d, after adding deuterium oxide, d, j 2HZ), 8.83 (IK, wide 11.00 (IH, wide).

C 47.82, H 6.20, and 10.14.

11 L1 9.b

Found C 47.88, H 6.30, N 10.19

Example 19. In a solution of 4.40 X20 millimoles) ethyl 5-fluoro-6-hydroxy-1, 2,3,4,5,6 hexahydro-2,4-dioxopyrimidine-5-carboxylate, 2.70 g of benzyl alcohol and 30 ml of 1,2-dimethoxyethane serves dry hydrogen chloride gas until about 3.4 g of hydrogen chloride is absorbed. The mixture is left to stand at room temperature.

overnight and then volatile substances are distilled off under reduced pressure. The residue was purified in the same manner as in Example 2 to obtain 3.20 g of ethyl 5-fluoro-6-benzyloxy-1,2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine-5-carboxylate. Melting point 132133 ° C (recrystallized from acetone chloroform-hexane).

NMR spectrum (DMSO - df,) (f 1.18 (3N, t, j 7HZ), 4.26 (2H, g, j - 7HZ), 4.65 (2H, broad, s), 4.97 (IH, dx d, after adding deuterium oxide, d, j 2HZ), 7.33 (5H, wide, s), 9.05 (IH, wide), 11.10 (IH, wide).

C, 54.19; H, 4.87; N, 9.03.

C N ,, 05.

Found, C 54.19, H 4.84, N 9.08.

Example 20 2.35 g of acetic anhydride, 3 g of pyridine and 10 ml of acetone are added to 4.40 g (20 millimoles) of ethyl 5-fluoro-b-oxy-1, 2,3,4,5,6 -hexahydro-2,4-dioxopyrimidine-5-carboxylate and the mixture left to stand at room temperature overnight. The volatiles are distilled off and 2.82 g of phenol, 20 ml of pyridine and 10 ml of 1,2- are added to the residue. dimethoxyethane. The mixture is heated for 1 hour, then the volatiles are distilled off from the mixture under reduced pressure and the residue is purified. In the same manner as in Example 2, 2.0 g of ethyl 5-fluoro-6-phenoxy-1, 2, 2, 4 are obtained. , 5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate. Melting point 164-167 ° C (recrystallized from acetone-chloroform-hexane).

NMR spectrum (OMSO - d (,) (f: 1.21 (3N, t, j 7HZ), 4.28 (2H, g, j 7HZ), 5.74 (IH, d xd, after adding deuterium oxide , d, j 2HZ). 6.8-7.5 (5H, m), 9.30 (IH, wide), 11.33 (IH, wide).

C, 52.71; H, 4.42; N, 9.46.

., H., iFN., 05.

Found C, 52.14; H, 4.30; N, 9.87.

Example 21. A solution of 8.24 g (40 mmol) methyl 5-fluoro-6-C) Xi-1, 2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate, 4,5 g of butylmercaptan, a catalytic amount of methanesulfonic acid and 25 ml of 1,2-dimethoxyethane is heated under reflux for 3 hours. The reaction mixture is purified in the same manner as in Example 2 to obtain 8.3 g of methyl 5-fluoro-6-bu: Ilthio - 1,2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine-5-carboxylate.

Melting point 123-125 ° C (recrystallized from acetone-chloroform-hexane).

. NMR spectrum (OMSO - d): 0.80 (3N, t, i 7HZ), 1.0-1.8 (4H, m).

2.66 (2H, t, j - 7HZ), 3.76 (3N, s), 5.08 (IH dA d, after adding deuterium oxide, d, J 7.5 HZ), 8.75 (IH, wide ), 11.13 (IH, wide),

C, 43.16; H, 5.43; N, 10.07.

Was passed

Found C 43.21, H 5.24, N 10.02. Example 22. 2.35 g of acetic anhydride, 2.05 g of pyridine and 10 m of acetone are added to 4.40 g (20 mil of dimole) ethyl 5-fluoro-6-hydroxy-1,2,3, 4,5 , b-hexahydro-2,4-dioxopyrimidine-5-carboxylate. The mixture is left to stand at room temperature overnight, and then, after adding 3.3 g of thiophenol and 5 g of pyridine, the reaction is carried out at 1 , 5 h. Volatiles are distilled off under reduced pressure and the residue is purified in the same manner as in Example 2 to obtain 4.82 g of ethyl 5-fluoro 6-phenylthio-1, 2, 3.4, 5, 6-hexahydrog 2, 4 Di6 xopyrimidine-5-carboxylate, Mp 164-166, (recrystallization ano from acetone-chloroform-hexane).

NMR spectrum (DMSO - d (,) cG t 1.18. (3N, t, j 7HZ), 4.28 (2H, g, j 7H2), 5.37 (IH, t, after adding deuterium oxide, d, j 3HZ), 7.40 (5H, wide), 8.87 (IH, wide), 11.13 (IH, wide). Calculated from 49.99, H 4.20, N 8.9.7,

C H iFNaO / S

Founding C 49.55, H 3.98, N 9.09. Example 23, V400ML of acetic acid are 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 (15:85 (volume / volume). When about 1.5 molar equivalents of fluorine are applied to the substrate, the reaction mixture is evaporated to dryness, ethanol (70 ml) is added to the residue and the mixture is heated under reflux for 2 hours and then evaporated to dryness again. The resulting syrup is subjected to chromatography on a silica gel column (solvent; benzene-acetone 4: 1 (v / v), aggregate 1.54 g of 5-fluoro-6-ethoxy-1,2, 3,4,576-hexahydro-2, 4-dioxopyrimidine-5-carbonitrile, in the form of white crystals.

Melting point 195-19 ° C.

NMR spectrum (DMSO - dfe) cya: 1.07 (3N, t, j 7HZ), 3.64 2H, g X d, j. 7HZ and J 2HZ), 5.42 (lH, dxd, j - and j - 2HZ), 9.38 (IH, wide), 11.59 (IH, wide).

C, 41.80; H, 4.01; N, 20.89. -,

C HftFNi O / x.

Found C 41.44, H 3.95, N 20.70

EXAMPLE 24 10.0 g of ethyl 5-fluoro-6-hydroxy-2,4-dioxo-1, 2,3,4,5,6-hexahydropyrimidine-5-carboxylate is dissolved in 200 ml of anhydrous dioxane. To this mixture, 11.8 g of octyl alcohol, 0.3 g of p-toluenesulfonic acid and 3.0 g of anhydrous magnesium sulfate are added. The mixture is heated under reflux with stirring. The reaction mixture is evaporated to dryness under reduced pressure. Hexane was added to this residue and the resulting precipitate was filtered by filtration. The filtrate is chromatographed on a silica gel column (solvent: chloroform-acetone 95: 5 5 (v / v)) to obtain 8.4 g of a white crystalline powder. The powder is recrystallized twice from ethyl acetate-hexane to give 6.37 g of ethyl 5-FTOR-6- AXTILOXY-2,4-dioxo-1,2,3,4,5,6-hexahydropyrimidine 5-carboxylate, as a white powder.

Melting point 123-124- C.

NMR (sos), cf: 0.88-1.17 5 (MN, t), 1.20-1.98 T15H, t), 3.603, 93 (2H, t), 4.48 ( 28 / g, j 7HZ), 5.11 (IH, d xd, j 5HZ, J 2HZ, after adding deuterium oxide, d, j ZHZ), 7.82 (IH, wide), 9.38 (IH, wide ).

C, 54.21; H, 7.58; N, 8.43.

 H25.FN20S.

Found C, 54.32; H, 7.73; N, 8.39.

Example 25. A mixture of 72.8 g

ethyl 5-fluoro-6-oxI-1,2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine-5-carboxylate, 52.0 g of octyl alcohol, 700 ml of toluene and 7.0 g of methanesulfonic acid Heated under reflux in an oil bath maintained at 140 ° C. In this case, the water formed during the reaction is removed as an azeotrope from the reaction mixture5. si Heating is stopped after an hour and the reactants are allowed to cool, and some precipitate is filtered off. The filtrate is chromatographed on a silica gel column (400 g, solvent:

l Chloroform: methanol 100: 1 (v / v). From the fraction rich in the desired compound, 96.8 g of crude ethyl 5-fluoro-b-octyl-hydroxy-1, 2,3,4,5,6-hexahydro-2,4-dioxo-pyrimidine are obtained after evaporation of the solvent 5-carboxylate (mixture

cis and trans compounds), in the form of a white solid. The solid is recrystallized twice from ethanol-hexane to give 40.2 g

0 ethyl 5-fluoro-1-6-octyloxy-1,2,3,4, 5,6-gexahydro-2,4-dioxopyrimidine-5-carboxylate as colorless .gl. Based on the results of thin layer chromatography and NMR; this

5 product is completely identical with the image

com, synthesized by another method, melting point 126-127 C.

NMR spectrum (COCI ,,) (f: 0.90 (MN, t), 1.28 (.15H, broad), 3.72 (2H, t), 4.38 (2H, d, j 7HZ) , 5.12 (1H, wide, after adding deuterium oxide, d, j 2HZ), 8.22 (IH, wide), 9.90 (IH, wide).

C, 54.20; H, 7.58; N, 8.43.

S-15 chk

Found C, 54.40; H, 7.79; N, 8.32. The mother liquor from recrystallization is chromatographed on a silica gel column (300 g solvent: chloroform-benzene 4: 1, then 7: 1 (v / v), and then chloroform-methanol 20: 1 (v / v), to obtain fractions g-5- 1-6-compounds {10.7 g), mixtures (4.3 g), g-5-t-6-r-5-c-6 compounds, and G-5-C-6 compounds (3.0 g) . The product from the last fraction is recrystallized to obtain 0.5 g of methyl 15-fluoro-s-6-octyloxy-1,2,3,, 6-hexahydro-2, 4-dioxopyrimidine-g-5-carboxylate as colorless prisms. Melting point 148-149s.

NMR spectrum (CDCl2,) cf: 0.90 (3N, m), 1.28 (15H, broad), 3.73 (2H, t), 4.42 (2H, d, j 7HZ), 5, 13 (1H, wide, d, j 11HZ), after adding deuterium, 9 JHF 11HZ), 7.63 (IH, wide,), 9.75 (1H, wide).

 Calculated: C54.20, H 7.58, N 8.43.

 HngFNuOs

Found C 54.43, H 8.19, N 8.45.

Example 26. Mix 11.2 g of ethyl 5-fluoro-6-hydroxy-1, .2 3,4, 5, 6-hexahydro-2, 4-dioxopyrimidine-5-carboxylate, 4.2 g of butanol, 2.7 g of methanesulfonic acid, 100 ml of dioxane and 5.0 g of molecular sieves (3A), and the mixture is heated with stirring in an oil bath maintained at 60-70 ° C for one hour. The reaction mixture is allowed to cool and then insoluble materials are filtered out. The filtrate is concentrated under reduced pressure and the yellow oily residue is dissolved in 400 ml of chloroform. The solution is washed with an aqueous solution of sodium bicarbonate to remove the acid. The chloroform solution was dried over anhydrous magnesium sulphate and concentrated under reduced pressure to give 10.1 g of a white solid. From the NMR spectrum and from thin layer chromatography on silica gel, a white solid was identified as ethyl 6-butoxy-5-fluoro-1, 2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate.

Example 27. Through a suspension of 70 g of 1,2,3,4-tetra- ethyl ether

hydro-2,4-dioxopyrimidine-5-carboxylic acid in 1 liter of acetic acid passes a gaseous mixture of fluorine and nitrogen (1: 9, volume / volume), with vigorous stirring at e temperature of about 20-30 s until absorption in ultraviolet region at 270 nm, due to the original pyrimidine does not disappear. Thereafter, the solvent was removed under reduced pressure to obtain a white solid, which was dissolved in ethyl acetate. This solution in ethyl acetate is washed with water and the solvent is distilled off. The remaining solid is collected by filtration, washed with ethyl acetate and dried in vacuo to give 50 g of 6-acetoxy-5-fluoro-1, 2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine-5-carbono ethyl ester acid in the form of white crystals melting at 134-136 ° C. The NMR spectrum (in dimethyl sulfoxide, df, d parts-on 10 - 1.25 (3N, three, plet, j 7HZ), 2.11 (3N, singlet ) ,.

5 4.32 (2H, quadruplet, j 7HZ), 6.19 (1H, doublet X doublet, j 2 2HZ and 6HZ), 9.13 (1H, wide band), 11.33 (1H, wide band). This is a 6-acetoxy compound (26.2 g)

Q is dissolved in a mixture of 18 ml of ethanol and 16 ml of pyridine and the solution is heated in a water bath maintained at 60-70 ° C for 3 hours. The reaction mixture is poured into 300 ml of water and,

 after stirring, the precipitate formed is collected by filtration and washed with water. The crude product thus obtained is recrystallized from ethanol / WW (about 1: 1, volume) and after

0 of this ethanol / hexane (approximately 1: 3, v / v) to obtain 13.7 g of ethyl 6-ethoxy-5-fluoro-1, 2,3,4,5,6-hexahydro-2,4-dioxopyrimidine -5-carboxylic acid 5 g. Example 28. Ethyl ether

6-acetoxy-1,2,3,4,5,6-hexahydro-2, 4-dioxopyrimidine-5-carboxylic acid (26.2 g), butanol (19.0 ml)

Q and pyridine (16 ml) are mixed and reacted as described in the previous example. The reaction mixture is treated as in Example 27 to obtain 18.2 g of 6-butoxy-5-fluoro-1,2,2,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylic acid ethyl ester.

Example 29. A solution of ethyl 5-fluorop-6-etoxy-J, 2,3,4,5,6-hexahydro-2, 4-dioxypyrimidine-5-carboxy0 lat (7.21 g) and methanesulfonic acid (1.0 ml ) in 250 ml of butanol, dried over the molecular sieves FOR, heated in an oil bath for 30 minutes at a temperature maintained within 140-145 ° C. In time

heat is removed by distillation with about 70 ml of butanol and ethyl ether. The reaction mixture is concentrated under reduced pressure to give a colorless syrup, which is dissolved in 300 ml of ethyl acetate. The solution is successively washed with an aqueous solution of sodium bicarbonate and water and dried over anhydrous sodium sulfate.

The solvents are removed under reduced pressure to obtain 7.8 g of a solid, which is crystallized from an ethanol-hexane mixture, to obtain 6.1 g of ethyl 5-fluoro-b-butoxy-1, 2,3,4,5, b-hexahydro -2,4-dioxypyrim din-5-carboxylate.

Claims (2)

1. Veigaid-Hilgetag Experimental methods in organic chemistry. M., Himi, 1963, p. 329-351. 2. Jeran R.T. et al., Protocols for the selection of chemical agents and natural products against tumors in animals and other biological systems. Cancer Chemotherapy Report, 1972, 3, (Part 3), p. 7