KR820001543B1 - Process for preparation of fluorouracil derivatives - Google Patents

Abstract

Title compds. (I; R1 = lower alkyl; R4-CO- is residue of carboxylic acid; R2, R3 = phenyl, alkylidene, cycloalkylidene), having antivirus activity, were prepd. by reacting compd. (II) with compd. (III). Thus, anhydrous acetic acid 2.55 g and pyridine 10 ml were added in the soln. of acetone 6 ml and methyl-5-fluoro-6-hydroxy-1,2,3,4,5,6-hexa hydro-2,4-dioxopyrimidine-5-carboxylate 4.12 g, stirred for 12 hr and then cyclohexanone oxime 2.26 g was added. The reaction mixt. was stirred at room temp. for 2 hr and reacted at 65≰C for 3 hr to give methyl-5-fluoro-6-cyclohexylidene aminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylic acid 4.0 g.

Description

Preparation of Fluorouracil Derivatives

The present invention is a structural formula,

It relates to a new compound of.

는 R₂와 R₃중의 적어도 하나가 페닐에 의하거나, S, N 혹은 O를 포함하는 페닐이나 5혹은 6원 방향족환 및 수소에 의해서 선택적으로 치환될 수 있는 저급 알킬기인 알킬리덴기를 나타내거나, 혹은 벤젠환이 선택적으로 축합될 수 있는 탄소원자 6이하의 사이클로 알킬리덴기를 나타낸다.Where R ₁ represents a lower alkyl group

Denotes an alkylidene group wherein at least one of R ₂ and R ₃ is phenyl, or a lower alkyl group which may be optionally substituted by phenyl containing S, N or O or by a 5 or 6 membered aromatic ring and hydrogen; or Or a cycloalkylidene group having up to 6 carbon atoms to which the benzene ring can be optionally condensed.

의 화합물로서 대응되는 6-아실록시 화합물을 반응시켜서 제조된다.These compounds have structural formulas

It is manufactured by making the corresponding 6-acyloxy compound react as a compound of.

The novel compounds of the present invention have an antiviral action and are useful for prolonging the survival of bile cancer animals.

The present invention relates to an ideal fluoro uracil derivative. More specifically, the present invention relates to a fluorine uracil derivative having a fluorine atom and an ester group at the 5 position of the uracil ring and an alkylidene or cycloalkylidene aminooxy group at the 6 position.

Fluorine uracil derivatives according to the present invention are useful compounds that prolong the lifespan of anti-cancer animals and have antiviral action. That is, it is an object of the present invention to provide a fluoro uracil derivative and a method for preparing the substance.

Other objects will be apparent from the detailed description that follows.

The present invention is directly connected to the compound of the following structural formula.

은 R₂와 R₃중의 하나가 적어도 페닐에 의하거나, S, N 혹은 O를 포함하는 페닐이나 5혹은 6원 방향족환 및 수소에 의해 선택적으로 치환될 수 있는 저급알킬인 알킬리덴기를 나타내거나 혹은 벤젠환이 선택적으로 축합될 수 있는 탄소원자 6이하의 사이클로알킬리덴기를 나타낸다.R ₁ here represents a lower alkyl group,

Is an alkylidene group, at least one of R ₂ and R ₃ being at least phenyl, or a lower alkyl which may be optionally substituted by phenyl containing S, N or O or by a 5 or 6 membered aromatic ring and hydrogen; or A benzene ring represents a cycloalkylidene group having 6 or less carbon atoms which can be optionally condensed.

Lower alkyl groups R ₁ , R ₂ and R ₃ may be the same or different and may, for example, have up to 4 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, etc.) It may be an alkyl group.

Furthermore, the alkyl groups R ₂ and R ₃ may each have more than four to six carbon atoms (eg pentyl, isopentyl, hexyl). As such alkyl groups R ₂ and R ₃ may each be substituted with phenyl (eg benzyl or phenethyl).

The 5 or 6 membered aromatic S-, N-, O-other ring represented by R ₂ or R ₃ may be, for example, furyl thienyl or pyridyl.

로 표시한 탄수소 6이하의 사이클로알킬리딘기의 예로서는 사이클로헥실리딘, 사이클로펜틸리딘과 사이클로부틸리딘을 들수 있고, 또 벤젠환은, 예컨데 인다닐리덴, 벤조사이클로 헥시리덴이나, 플루오레닐리덴기를 형성하는 사이클로알킬리덴기와 같은 것에 축합될 수도 있다.

Examples of the cycloalkylidine group having 6 or less carbon atoms represented by the above include cyclohexylidene, cyclopentylidene, and cyclobutylidene. The benzene ring is, for example, indanilide, benzocyclohexilidene, or fluorine. It may also be condensed to something like a cycloalkylidene group forming a nilidene group.

Compound (I) according to the invention can be prepared, for example, by the following process. That is,

Wherein R ₁ is as defined above and R ₄ -Co- is a carboxylic acid residue (acyl group).

Can be prepared by reacting with a compound wherein R ₂ and R ₃ are each as previously defined.

Examples of R ₄ include lower alkyl such as methyl and ethyl, and mono-, di- and tri-halogenated lower alkyl groups (eg, mono-, di- and tri-methyl chloride, methyl trifluoride) and phenyl.

Based on compound (II), compound (III) can be used in the range of 1 to about 2 times the molar equivalent. The reaction is carried out at a suitable temperature in the range of about 100 ° C. under cooling. The reaction is carried out with ketones (e.g. acetone or methyl ethyl ketone), esters (e.g. ethyl acetate or butyl acetate), ethyl (e.g. tetrahydrofuran, dioxane or 1,2-dimethoxyethane) or dimethylformamide. It may be carried out as a suitable solvent or as a suitable mixture of such solvents.

Sometimes it is more advantageous that the reaction is carried out in the presence of a catalyst such as tertiary amines (for example pyridine, pyrroline, driethylamine or dimethylaniline).

Compound (I) prepared by the above method can be isolated and purified by known processes such as concentration, solvent extraction, chromatography and recrystallization.

Compound (I) may have several stereoisomers such as geometric isomers and optical isomers due to the presence of absent carbon atoms and alkylidene aminooxy groups at the 5- and 6- positions.

It will be appreciated that all such individual isomers as well as mixtures thereof are included within the scope of the present invention.

Compound (II) is for example a structural formula,

Compounds wherein R ₁ is as defined above can be produced by fluorination in the presence of R ₁ -COOH. Fluorination can be carried out as a fluorinating agent.

Examples of the fluorinating agent include fluoro sfurhypofluorite (for example, pentafluoro spurfluorite) and lower fluorinated alkylhypofluorite containing 1 to 6 carbon atoms (for example, trifluoromethyl hypofluorite, perfluorinated propyl). Hypofluorite, perfluorinated isopropyl hypofluorite, perfluorinated tertiary fluoride hypofluorite, monochloride hexafluoropropyl hypofluorite and perfluorinated tertiary pentyl hypofluorite) and difluorooxy-compounds (e.g., 1,2-difluorooxy difluoroethane and difluorooxy difluoromethane). Fluorine molecules can equally be used.

When a gaseous fluorinating agent, ie, a fluorine molecule is used as an example, it is preferable to generate bubbles through the reaction system after dilution with an inert gas such as nitrogen or argon gas.

Fluorinating agents are desired for fluorine gas and trifluoromethylhypofluorite.

Based on compound (IV), the fluorinating agent may be used in a ratio of 1 to 10 moles, preferably about 1.2 to 2.5 moles. The reaction temperature is selected from the range of about 78 ° C to + 40 ° C, which is suitably about -20 ° C to + 30 ° C.

Compound (II) thus prepared can be easily separated from the reaction mixture by a conventionally known process. What is desired is, for example, evaporating the solvent under reduced pressure.

Such a reaction mixture may be directly reacted with compound (II) in order to obtain compound (I) without separating compound (II).

Starting compound (II) also undergoes a fluorination step of compound (IV) in the presence of water,

(R ₁ is as defined above), and acylation of compound (V) as an acylating agent which is a reactive derivative in the carboxyl group in R ₄ -COOH.

The fluorination reaction of compound (IV) in the presence of water can be carried out by the same method of fluorination of compound (IV) in the presence of R ₄ -COOH described above.

Acylation of compound (V) can be performed using a well-known process. For example, compound (V) can be a halogenated compound (e.g. chlorine or bromine) or carboxylic acid R ₄ -in the presence of an organic salt (e.g. It can be acylated as an acid anhydride of COOH.

Compound (II) thus obtained may be reacted with compound (III) without the need for separation. Of course, the compound (II) may be separated in advance by a conventionally known process (eg, removal of the solvent by distillation, recrystallization, chromatography, or the like).

Compound (I) according to the present invention effectively inhibits the proliferation of tumor cells.

For example, cultured cell lines include KB-cells (cultured cells derived from human basal cancer), C-34 cells (cultured cell lines of fibroblastic tumors of virally infected mice in vitro) and AC-cells. It is derived from various tumor cells such as (brain tumor proliferation cells of rats).

Moreover, compound (I) has a prolonged lifespan effect in rats with leukemia (9388, L-1210). The compound (I) according to the invention is thus of remarkable value.

Compound (I) according to the present invention is effective in inhibiting the growth of various tumor cells and prolonging the lifespan of living mammals with leukemia in mammals (eg, rats, mice, humans).

The inventive compound (I) may be administered alone or in a single dosage form such as carriers, excipients, diluents, such as powders, granules, dry syrups, tablets, capsules, suppositories, injections, etc. It may be formed into oral or parenteral administration. Appropriate dosage depends on factors such as animal type, disease management, symptoms and route of administration, but in most cases it is administered in the range of about 25-800 mg / kg body weight per day and the upper limit is usually about 400 mg / kg body weight More generally, about 200 mg / kg body weight may be administered, but there may be cases where it is advantageous to be out of this range.

Life-long Effects of Mice with Leukemia L-1210

1) test process

Survival by implanting 1 × 10 ⁵ tumor cells into the abdominal cavity of ⁵ BDF ₁ (C57BL / 6 × DBA / 2) mice in group 1 and administering the drug intraperitoneally or orally 1-9 times The days were measured.

The results are expressed as the ratio of median (T) to median (C) of the days of survival of control animals (T / C%).

2) test result

Example 1

4.12 g (20 mmol) of methyl 5-fluor-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylic acid in 6 ml acetone It dissolved and added 2.55 g (25 mmol) acetic anhydride and 10 ml pyridine under ice-cooling.

The reaction was carried out with stirring overnight at room temperature.

2.26 g (20 mmol) cyclohexane oxime was added to the reaction mixture.

The mixture was stirred at room temperature for 2 hours and then proceeded with reaction at 65 ° C for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure and the residue was subjected to silica gel column chromatography (developing solvent system; chloroform / acetone = 85 / 15V / V).

4.0 g of methyl 5-fluoro-6-cyclohexylidinaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxo-pyrimidine-5-car by the above process I got the main acid. Melting Point 171-175 ° C. (Decomposition) ”(Recrystallized from Acetone-Chloroform-hexane)

NMR (in DMSO-d ₆ ) δ: 1.66 (6H, broad singlet), 1.9-2.6 (4H, broad two peaks), 3.82 (3H, s), 5.38 (1H, dxd; D ₂ O with d, J = 1 Hz), 8.97 (1H, broad), 11.07 (1H, broad)

Elemental analysis: using C ₁₂ H ₁₆ FN ₃ O ₅ ,

Calculated value: C, 47.84; H, 5. 35; N, 13.95

Found: C, 47.82; H, 5. 37; N, 13.87

Example 2

8.80 g (40 mmol) of ethyl 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carbon in 10 ml of acetone The acid salt was dissolved and 5.10 g (50 mmol) acetic anhydride and 10 ml pyridine were added under ice cooling. The compound was reacted overnight at room temperature.

(A sample of the reaction compound was taken, and the solvent was distilled off under reduced pressure, and the NMR spectrum of the reaction residue was measured, and ethyl 6-acetoxy-5-fluor-1,2,3,4,5,6-hexahydro- was contained therein. It was confirmed that 2,4-dioxo pyrimidine-5-carbonate was produced.

NMR spectrum (in DMSC-d ₆ ) δ: (Hazardous peaks in residual acetic acid, pyridine, etc.) ), 6.28 (1 H, q, slightly broad), 9.19 (1 H, broad), 11.04 (-1 H, broad)).

4.52 g (40 mmol) of cyclohexanone oxime was added to the reaction mixture together with 10 ml of pyridine. The mixture was heated at 60 ° C. for one hour. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvents: chloroform / acetone = 87.5 / 12.5, V / V).

By the above process, ethyl 5-fluoro-6-cyclohexylidene aminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxo pyrimidine-5-carboxylic acid salt was obtained. . Melting point 185-187 ° C. (decomposition) (recrystallized from acetone-chloroform-hexane).

NMR (in DMSO-d ₆ ) δ: 1.25 (3H, t, J = 7 Hz), 1.56 (6H, broad singlet), 1.9-2.6 (4H, broad two peaks), 4.32 (2H, q, J = 7 Hz) , 5.43 (1H, dxd, J _HF = 1 Hz, J _HH = 5 Hz), 8.98 (1H, broad), 11.07 (1H, broad).

Elemental Analysis: For C ₁₃ H ₁₈ FN ₃ O ₅ ,

Calculated value: C, 49.52; H, 5.75; N, 13.33

Found: C, 49.61; H, 5.69; N, 13.31

Example 3

The process of Example 2 was repeated except that 9.04 g (80 mmol) was used instead of 4.52 g (40 mmol) of cyclohexane oxime used in the process of Example 2. In this process, 10.5 g of ethyl 5-fluoro-6-cyclohexylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-garborate Got it.

Example 4

28.80 g (40 mmol) ethyl 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylic acid, 5.10 g A solution prepared of (50 mmol) acetic anhydride, 20 ml pyridine and 10 ml acetone was left overnight at room temperature, and then 4.38 g (60 mmol) of acetosim was added and reacted at 50-60 ° C. for 3 hours. This reaction mixture was purified by the process as described in Example 1.

7.40 g of ethyl 5-fluoro-6-isopropylidene aminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylic acid by the above process Got. Melting point 173-178 ° C. (decomposition) (recrystallized from acetone-chloroform-hexane)

NMR (in DMSO-d ₆ ) δ: 1.20 (3H, t J = 7 Hz), 1.75 (3H, s), 1.77 (3H, s), 4.28 (2H, q, J = 7 Hz), 5.42 (1H, dxd , J _HF = 1 Hz, J _HH = 5 Hz), 8.92 (1H, broad), 11.02 (1H, broad).

Elemental Analysis: C ₁₀ H ₁₄ FN ₃ O ₅

Calculated value: C, 43.64; H, 5.13; N, 15.27

Found: C, 43.63; H, 5.09; N, 15.21

Example 5

6.60 g (30 mmol) ethyl 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate, 3.27 acetic anhydride After the solution prepared with g (32 mmol), 10 ml of pyridine, and 10 ml of acetone was left overnight at room temperature, 5.22 g (35 mmol) of phenyl acetosim was added, and it heated at 50-60 degreeC for 2 hours.

The reaction product was purified according to the method of Example 1 and 7.02 g of ethyl 5-fluoro-6-phenylisopropylidene aminooxy-1,2,3,4,5,6-hexahydro-2,4 -Dioxopyrimidine-5-carboxylic acid salt was obtained. Melting point 135-139 ° C. (crystallized from acetone-chloroform-hexane).

NMR (in DMSO-D ₆ ) δ: 1.23 (3H, t, J = 7 Hz), 1.67 (3H, s), 3.37 (2H, S), 4.30 (2H, q, J = 7 Hz), 5.50 (1H, dxd, J _HF = 0.5 Hz, J _HH = 5 Hz), 9.03 (1H, broad), 11.15 (1H, broad).

Elemental Analysis: For C ₁₆ H ₁₈ FN ₃ O ₅ ,

Calculated values: C, 54.70; H, 5. 16; N, 11.96

Found: C, 54.54; H, 4.95; N, 11.86

Example 6

Ethyl 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylic acid 6.60 g (30 mmol) acetic anhydride 3.27 g (32 mmol), 10 ml of pyridine and ml of acetone were left overnight at room temperature, and then 7.40 g (35 mmol) of benzyl phenylketoxim was added thereto, followed by heating at 60 ° C. for 3 hours. The reaction mixture was purified in the same manner as in Example 1, in which 7.40 g of ethyl 5-fluoro-6- (α, -diphenyl) ethylideneaminooxy-1,23,4,5,6- Hexahydro-2,4-dioxopyrimidine-5-carboxylic acid salt was obtained.

Melting point 173-175 ° C. (recrystallized from acetone-chloroform-hexane)

NMR (in DMSO-d ₆ ) δ: 1.22 (3H, t, J = 7 Hz), 4.15 (2H, s), 4.30 (2H, q, J = 7 Hz), 5.76 (1H, ca, d, J = 5 Hz ), 9.08 (1 H, broad), 11.20 (1 H, broad).

Elemental Analysis: About C21H20FN3O5

Calc .: C, 61.01; H, 4.88; N, 10.16

Found: C, 60.90; H, 4.70; N, 10.03

Example 7

6.60 g (30 mmol) ethyl 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylic acid, 3.27 acetic anhydride The prepared solution of g (32 mmol), 10 ml of pyridine and 10 ml of acetone was left overnight at room temperature, and then 5.15 g (35 mmol) of 1-indacin oxime was added and reacted at 60 ° C for 3 hours. The reaction mixture was purified in the same manner as in Example 1 and 3.38 g of ethyl 5-fluoro-6- (1-indanylidene) aminooxy-1,2,3,4,5,6-hexahydro -2,4-dioxopyrimidine-5-carboxylic acid salt was obtained.

Melting point 190-193 ° C. (decomposition) (recrystallized from acetone-chloroform-hexane).

NMR (in DMSO-d ₆ ) δ: 1.23 (3H, t, J = 7 Hz), 2.56-3, 10 (4H, broad m), 4.30 (2H, q, J = 7 Hz), 5.75 (1H, dxd, J _HF = 0.5 Hz, J _HH = 5 Hz), 7.40 (4H, broad), 9.00 (1H, broad), 11.10 (1H, broad)

Elemental Analysis: For C ₁₆ H ₁₆ FN ₃ O ₅ H ₂ O,

Calculated value: C, 52.32; H, 4.94; N, 11.44

Found: C, 52.70; H, 4. 34; N, 11.33

Example 8

Ethyl 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxo pyrimidine-5-carboxylate 8.80 g (40 mmol), acetic anhydride 4.60 The solution prepared with g (45 mmol), 10 ml of pyridine, and 10 ml of acetone was left overnight at room temperature, and then 8.46 g (60 mmol) of methyl 2-thienyl ketoxim was added and reacted at 60 ° C for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure and the residue was purified in the same manner as in Example 1.

6.68 g of ethyl 5-fluoro-6- (α-2-thianyl) ethylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimi by the above process Dean-5-carboxylic acid was obtained. Melting point 201-204 ° C. (decomposition) (recrystallized from acetone-chloroform-hexane)

NMR (in DMSO-d ₆ ) δ: 1.20 (3H, t, J = 7 Hz), 2.20 (3H, s), 4.31 (2H, q, J = 7 Hz), 5.62 (1H, d, J = 5 Hz, D s) ₂ O was added to, 7.0-7.8 (3H, m), 9.00 (1H, broad), 11.17 (1H, broad).

Elemental Analysis: About C ₁₃ H ₁₄ FN ₃ O ₅ S

Calculated value: C, 45.48; H, 4.11; N, 12.24

Found: C, 45.33; H, 4.04; N, 12.22

Example 9

Ethyl 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5- carbonate 4.62 g (21 mmol), acetic anhydride 2.25 g, a solution prepared with 10 ml of pyridine and 10 ml of acetone were left overnight at room temperature, and then 3.3 g (24.2 mmol) of methyl 4-pyridylketoxim was added and reacted for 3 hours in a water bath at about 90 ° C. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified in the same manner as in Example 1. 6.1 g of ethyl 5-fluoro-6- (α-4-pyridyl) ethylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimi by the above process Obtained Dean-5-Carbonate.

NMR (in DMSO-d ₆ ) δ: 1.20 (3H, t, J = 7 Hz), 2.16 (3H, s), 4.30 (2H, q, J = 7 Hz), 5.75 (1H, dxd, J _HF = 0.5 Hz , J _HH = 5 Hz), 7.50-8.55 (4H, m), 9.10 (1H, broad), 11.27 (1H, broad).

Example 10

5.5 g of ethyl 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate, 12.5 ml of pyridine and 6.5 ml of acetone It is dissolved in a mixed solution of, 3.2 g of acetic anhydride is added and stirred overnight at room temperature. Subsequently, 3.9 g of benzaldoxim and 6.6 ml of pyridine were added and reacted at room temperature for 1 hour and at 50 ° C for 2 hours. Then, the reaction mixture was concentrated, dissolved in about 100 ml of ethyl acetate, washed with water, and concentrated to dryness to obtain a pale yellow oily substance. This oily product was subjected to silica gel column chromatography (developing solvent: benzene: acetone = 10: 1) to give ethyl 5-fluoro-6-benzylideneaminooxy-1,2,3,4,5 in a white crystalline powder. 2.1 g of, 6-hexahydro-2,4-dioxopyrimidine-5-carboxylic acid salts were obtained. Melting Point 198-199 ℃ (Decomposition)

NMR spectrum (in DMSO-d ₆ ) δ: 1.24 (3H, t, J = 7 Hz), 4.34 (2H, qua., J = 7 Hz), 5.64 (1H, dxd, J = 1 Hz, 4 Hz), 7.36-7.80 (5H, m), 8.40 (1H, s), 9.03 (1H, broad), 11.15 (1H, broad).

Elemental Analysis: For C ₁₄ H ₁₄ FN ₃ O ₅ ,

Calculated value: C, 52.02; H, 4. 37; N, 13.00

Found: C, 52.18; H, 4. 21; N, 13.12

Example 11

15% fluorine-nitrogen (V / V) in a solution of 1.84 g (10 mmol) of ethyl 1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylic acid dissolved in 200 ml of acetic acid Of mixed gas was passed through the solution at a temperature of 20 ° C-25 ° C to form bubbles. After passing 1.5 molar equivalents of fluorine, the mixture was stirred at the same temperature for 1 hour. Acetic acid is distilled off under reduced pressure, residual solvent is removed in vacuo, and 3.0 g of crude ethyl 5-fluoro-6-acetoxy-1,2,3,4,5,6-tetrahydro-2,4 -Dioxopyrimidine-5-carbonate was obtained as a viscous oily substance.

NMR spectrum (in DMSP-d ₆ ) δ: (other than peak derived from acetic acid) 1.24 (3H, t, J = 7 Hz), 2.11 (3H, s), 4.35 (2H, q, J = 7 Hz), 6.21 (1H, dxd, J = 5Hz and 2Hz, with D ₂ O added d, J = 2Hz), 9.13 (1H, broad), 11.3 (1H, broad).

The oily substance was dissolved in a small amount of acetone, and a solution in which 2.26 g (20 mmol) of cyclohexanone oxime was mixed in 5 ml of pyridine was added, stirred at room temperature for 1 hour, and then heated to 60 ° C for 1 hour.

The reaction mixture was concentrated under reduced pressure, and the residue was analyzed by chromatography as in Example 2. 2.6 g of ethyl 5-fluoro-6-cyclohexylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylic acid in the process Got.

The following compound (I) can be prepared by the same method as described in the foregoing description and the examples.

Ethyl 5-fluoro-6-isobutylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylic acid.

Ethyl 5-fluoro-6- (α-methyl) butylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylic acid salt.

Ethyl 5-fluoro-6- (α-methyl) propylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylic acid salt.

Ethyl 5-fluoro-6- (α-methyl) pentylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-diocopyrimidine-5-carboxylic acid.

Example 12

Ethyl 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylic acid salt (6.60 g, 30 mmol), acetic anhydride (3.27g, 32mmol), pyridine (10ml) and acetone (10ml) were mixed to prevent overnight at room temperature (18-23 ℃).

To this mixture is added cyclobutanone oxime (3.82 g, 45 mmol) and pyridine (5 ml) heated at 60 ° C. for 2 hours.

The volatiles were then removed under reduced pressure and the residue was chromatographed on a silica gel column with chloroform / acetone = 85/15 (V / V) to give 4.78 g of ethyl 5-fluoro-6-cyclobutylideneaminooxy-1. , 2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylic acid salt was obtained. Melting point 188-189 ° C. (recrystallized from acetone-chloroform-hexane)

NMR spectrum (in DMSO-d ₆ ) δ: 1.18 (3H, t, J = 7 Hz), 1.7-2.3 (2H, m), 2.5-3.1 (4H, m), 4.25 (2H, q, J = 7 Hz) , 5.32 (1H, dxd, J = 1 Hz and 5 Hz; add D ₂ O, d, J = 1 Hz), 8.90 (1H, broad), 11.00 (1H, broad)

Elemental Analysis: About C ₁₁ H ₁₄ FN ₃ O ₅

Calculated value: C, 46.00; H, 4.91; N, 14.63

Found: C, 45.85; H, 4.80; N, 14.85

Example 13

By the same process as in Example 2 or 12, the following compounds are prepared from the corresponding starting materials.

(A) ethyl 5-fluoro-6-cyclopentylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylic acid salt. Melting point 170-171 ° C. (crystallized from acetone-chloroform-hexane).

NMR spectrum (in DMSO-d ₆ ) δ: 1.20 (3H, t, J = 7 Hz), 1.5-2.1 (4H, m), 2.1-2.7 (4H, m), 4.27 (2H, q, J = 7 Hz) , 5.36 (1H, dxd, J = 5Hz and 1Hz, was added the _{d 2 O d, J = 1Hz} ), 8.90 (1H, broad), 11.00 (1H, broad).

Elemental Analysis: For C ₁₂ H ₁₆ FN ₃ O ₅

Calculated value: C, 47.85; H, 5. 35; N, 13.95

Found: C, 47.72; H, 5. 18; N, 14.06

(Ii) ethyl 5-fluoro-6- [α- (2-furyl) ethylidene] aminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5 -Carbonates. Melting point 196-197 ° C. (recrystallized from acetone-chloroform-hexane)

NMR spectrum (in DMSO-d ₆ ) δ: 1.22 (3H, t, J = 7 Hz), 2.06 (3H, s), 4.30 (2H, q, J = 7 Hz), 5.60 (1H, dxd, J = 1 Hz and 5 Hz; after adding D ₂ O, d, J = 1 Hz, 6.57 (1H, dxd, J = 1 Hz and 3 Hz), 6.82 (1H, d, J = 3 Hz), 7.77 (1H, aJ = 1 Hz), 9.07 (1H, broad), 11.13 (1H, broad).

Elemental Analysis: For C ₁₃ H ₁₄ FN ₃ O ₆

Calculated value: C, 47.71; H, 4.31; N, 12.84

Found: C, 47.54; H, 4. 15; N, 12.91

(C) ethyl 6-ethylideneaminooxy-5-fluoro-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylic acid (approximately the same amount of E And a mixture of Z isomers). Melting point 128-129 ℃

NMR spectrum (in DMSO-d ₆ ) δ: 1.18 (3H, t, J = 7 Hz), 1.70 and 1.73 (total 3H, d + d, J = 5.5 Hz), 4.28 (2H, q, J = 7 Hz), 5.41 (1H, m), 7.01 and 7.52 (total 1H, q + q, J = 5 Hz), 8.93 (1H, broad), 11.02 (1H, broad).

Elemental Analysis: For C ₉ H ₁₂ FN ₃ O ₅

Calculated value: C, 41.38; H, 4.63; N, 16.09

Found: C, 41.38; H, 4.57; N, 16.08

(D) ethyl 5-fluoro-6-α, α-diphenylmethylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carbon Acid salts. Melting point 184-185 ℃

NMR spectrum (in DMSO-d ₆ ) δ: 1.22 (3H, t, J = 7 Hz), 4.28 (2H, q, J = 7 Hz), 5.58 (1H, d, J = 4.5 Hz), 7.33 (10H, broad ), 9.35 (1H, broad), 11.53 (1H, broad)

Elemental Analysis: For C ₂₀ H ₁₈ FN ₃ O ₅

Calculated value: C, 60.15; H, 4.54; N, 10.52

Found: C, 60.00; H, 4. 43; N, 10.63

(E) ethyl 5-fluoro-6-α, α-diisobutylmethylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxo pyrimidine-5-car Phosphate. Melting point 145-146 ℃

NMR spectrum (in DMSO-d ₆ ) δ: 0.83 (12H, broad, d, H = 5 Hz), 1.24 (3H, t, J = 7 Hz), 1.67-2.0 (6H, m), 4.28 (2H, q, J = 7 Hz), 5.38 (1H, d × d, J = 4.5 Hz and 1 Hz), 8.83 (1H, broad), 10.97 (1H, broad).

Elemental Analysis: For C ₁₆ H ₂₆ FN ₃ O ₅

Calculated values: C, 53.47; H, 7. 29; N, 11.69

Found: C, 53.61; H, 7.39; N, 11.47

(F) ethyl 5-fluoro-6- (E) -hexylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylic acid . Melting point 128-129 ℃

NMR spectrum (in DMSO-d ₆ ) δ: 0.6-1.75 (12H, m), 1.83-2.38 (2H, m), 4.26 (2H, q, J = 7 Hz), 5.34 (1H, d × d, J = 5 Hz and 1 Hz), 7.46 (1H, t, J = 5.5 Hz), 8.83 (1H, broad), 10.75 (1H, broad)

Elemental Analysis: For C ₁₈ H ₂₀ FN ₂ O ₅

Calculated Value: C, 49.21; H, 6. 35; N, 13.24

Found: C, 49.17; H, 6. 37; N, 13.23

Ethyl 5-fluoro-6- (Z) -hexylideneaminooxy-1,2,3,4,5,6-hexahydro-2,6-dioxopyrimidine-5-carboxylic acid .

NMR spectrum (in DMSO-d ₆ ) δ: E- except for the signal at δ 7.46 (1 H, t) replaced by δ 6.89 (1 H, t, J = 5.5 Hz) for the latter compound It is usually easy to overlap with the signal of the isomer.

Example 14

Gas mixture of fluorine / nitrogen = 1/3 (v / v) in a suspension of 100 ml of acetic acid and 5.0 g of ethyl 1,2,3,4-tetrahydro 2,4-dioxopyrimidine-5-carboxylic acid salt Passed with sufficient stirring at 18-25 ° C. until UV-absorption at 270 mm due to the starting pyrimidine disappeared. About 1.55 molar equivalents of fluorine were consumed. The solvent was then separated under reduced pressure to give a white solid. It was crushed with toluene, collected by filtration and dried in vacuo to give 4.9 g of ethyl 6-acetoxy-5-fluoro-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine. A white crystalline solid of -5- carbonate was obtained. Melting point 128-135 ℃

NMR spectrum (in DMSO-d ₆ ) δ: 1.25 (3H, t, J = 7 Hz), 2.11 (3H, s), 4.32 (2H, q, J = 7 Hz), 6.19 (1H, d × d, J = 2 Hz and 5.5 Hz), 9.13 (1H, broad), 11.33 (1H, broad).

2.62 g of this 6-acetoxy compound was dissolved in a mixture of 2.5 ml of acetone and 5 ml of pyridine. 4.529 g of cyclohexanone oxime was added to the solution and heated at 60 ° C. for 1 hour. The solvent was distilled off under reduced pressure, and the residue was subjected to chromatography on silica gel containing chloroform acetone = 87.5 / 12.5 (v / v) to give 2.65 g of ethyl 6-cyclohexylidene-aminooxy-5-fluoro-1 , 2,3,4,5,6-hexacarboxylic acid salt was obtained.

Reference Example 1

15.04 g (80 mmol) of methyl 1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylate monohydrate is deposited in 400 ml of mole and stirred vigorously at room temperature. Here, a mixed gas of fluorine: nitrogen = 1: 3 (v / v) was allowed to pass through at a flow rate of about 45 ml per minute for 6.6 hours while occasionally cooling with water so that the reaction temperature did not exceed 28 ° C.

Subsequently, 15.6 g of calcium carbonate was added to neutralize the hydrogen fluoride while the reaction mixture was cooled, followed by 5.2 g of sodium hydrogen sulfite. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure and dried in vacuo to give 23.7 g of powder. 500 ml of acetone was added to the powder, the insoluble substance was filtered off, and the acetone was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent: acetone / chloroform = 1/3 (v / v) 13.0 g of methyl 5-fluoro-6-hydroxy-1,2,3,4,5,6- Hexahydro-2,4-dioxopyrimidine-5-carboxylic acid salt was obtained.

NMR spectrum (in DMSO-d ₆ ) δ: 3.80 (3H, s), 4.90 (1H, m: d after heavy water addition, J _HF = 4Hz), 7.13 (1H, d, J = 5Hz), 8.53 (1H, broad), 10.85 (1 H, broad).

Elemental Analysis: For C ₆ H ₇ FN ₂ O ₅

Calculated value: C, 34.96; H, 3. 42; N, 13.59

Found: C, 35.07; H, 3.41; N, 13.58

Reference Example 2

920 mg of ethyl 1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylic acid salt was suspended in 200 ml of water and vigorously stirred at room temperature to remove fluorine gas (25v / v%) and nitrogen. The mixed gas is passed through this suspension to generate bubbles. During the reaction, the raw material is dissolved to form a homogeneous solution. When 2.6 molar equivalents of the mixed gas was injected, the ultraviolet absorption spectra of the reaction mixture were measured.

The reaction ends after confirming that there are no traces of unreacted raw materials.

The reaction mixture was stirred for a while, such as 1.10 g of calcium carbonate, and the insolubles were filtered out. The filtrate was concentrated to dryness under reduced pressure to give a white solid residue. The solid product was suspended in 50 ml of acetone, the insoluble material was filtered off, and the acetone solution was subjected to eluca gel chromatography (chloroform containing developer: 1.5 v / v%). The oil of the desired compound was concentrated under reduced pressure to give a white solid. This was recrystallized from methanol-chloroform-hexane to give ethyl 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylic acid salt. 561 mg of colorless columnar crystals are obtained. Melting Point 163-165 ℃

NMR spectrum (in DMSO-d ₆ ) δ: 1.22 (3H, t, J = 7 Hz), 4.28 (2H, q, J = 7 Hz), 4.93 (1H, d × d, J _HF = 3 Hz, J = 5 Hz, D, J _HF = 3Hz), 6.3 (1H, broad), 8.48 (1H, broad), 10.80 (1H, broad) after heavy water addition.

Elemental Analysis: For C ₇ H ₉ FN ₂ O ₅

Calculated value: C, 38.19; H, 4. 12; N, 12.73

Found: C, 37.90; H, 3.94; N, 12.87

Reference Example 3

850 mg (5.0 mmol) of methyl 1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylic acid salt are dissolved in 200 ml of acetic acid and 10% fluorine and nitrogen (v / v) Of mixed gas was bubbled through the solution at 18-19 ° C. After passing through 23.2 mmol of fluorine, the solvent was distilled off under reduced pressure, and the residue was dissolved in a mixed solution of 5 ml of acetone and 20 ml of benzene, and the solution was passed through a column of silica gel (10 g), and benzene / acetone = Elution was at 4/1 (v / v). The eluate (about 150 ml) was concentrated to dryness under reduced pressure and 1.00 g of methyl-6-acetoxy-5-fluoro-1,2,3,4,5,6-hexahydro-2,4-dioxopy in this process A pale yellow solid of limidine-5-carbonate was obtained.

NMR spectrum (in DMSO-d ₆ ) δ: 2.08 (3H, s), 3.83 (3H, s), 6.23 (1H, d × d, J = 6 Hz and 2 Hz); After heavy water addition, d, J = 2Hz), 9.10 (1H, 1broad), 11.33 (1H, broad)

Claims (1)

constitutional formula

Compound of the structural formula

Reacts with phosphorus compounds

Method for preparing a compound of. Wherein R ₁ is a lower alkyl group, R ₄ -CO- is a carboxylic acid residue,

At least one of R ₂ and R ₃ is phenyl, an phenyl ring having S, N or O, or an alkylidene group or a benzene ring which is a lower alkyl group optionally substituted with hydrogen with a 5 or 6 membered aromatic ring including the same; To cycloalkylidene groups having up to 6 carbon atoms which can be tackified.)