FLUORINE-CONTAINING PYRIMIDINE COMPOUND AND METHOD FOR PRODUCING SAME

Abstract

A fluorine-containing pyrimidine compound is provided represented by formula (1):

##STR00001##

wherein in the above formula (1), R represents a hydrocarbon group having 1 to 12 carbon atoms, B.sup.1 and B.sup.2 each independently represent a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, —C.sub.nF.sub.2n+1 where n is an integer of 1 to 10, a nitro group, a boronic acid group, —OA.sup.1, —SO.sub.mA.sup.1 where m is an integer of 0 to 3, —NA.sup.1A.sup.2, —COOA.sup.1 or —CONA.sup.1A.sup.2, W, X, Y and Z each independently represent CV or N, V represents a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, —C.sub.nF.sub.2n+1 where n is an integer of 1 to 10, a nitro group, a boronic acid group, —OA.sup.1, —SO.sub.mA.sup.1 where m is an integer of 0 to 3, —NA.sup.1A.sup.2, —COOA.sup.1 or —CONA.sup.1A.sup.2, and A.sup.1 and A.sup.2 each independently represent a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.

Claims

1. A fluorine-containing pyrimidine compound represented by the following formula (1): ##STR00014## wherein R represents a hydrocarbon group having 1 to 12 carbon atoms, B.sup.1 and B.sup.2 each independently represent a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, —C.sub.nF.sub.2n+1 where n is an integer of 1 to 10, a nitro group, a boronic acid group, —OA.sup.1, —SO.sub.mA.sup.1 where m is an integer of 0 to 3, NA.sup.1A.sup.2, —COOA.sup.1 or —CONA.sup.1A.sup.2, W, X, Y and Z each independently represent CV or N, V represents a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, —C.sub.nF.sub.2n+1 where n is an integer of 1 to 10, a nitro group, a boronic acid group, —OA.sup.1, —SO.sub.mA.sup.1 where m is an integer of 0 to 3, —NA.sup.1A.sup.2, —COOA.sup.1 or —CONA.sup.1A.sup.2, and A.sup.1 and A.sup.2 each independently represent a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.

2. The fluorine-containing pyrimidine compound according to claim 1, wherein R is an alkyl group having 1 to 10 carbon atoms.

3. A method for producing a fluorine-containing pyrimidine compound, comprising: a step of reacting a fluoroisobutylene derivative represented by the following formula (2) with a compound represented by the following formula (3) or a salt thereof to obtain a fluorine-containing pyrimidine compound of the following formula (1): ##STR00015## wherein R represents a hydrocarbon group having 1 to 12 carbon atoms, B.sup.1 and B.sup.2 each independently represent a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, —C.sub.nF.sub.2n+1 where n is an integer of 1 to 10, a nitro group, a boronic acid group, —OA.sup.1, —SO.sub.mA.sup.1 where m is an integer of 0 to 3, —NA.sup.1A.sup.2, —COOA.sup.1 or —CONA.sup.1A.sup.2, W, X, Y and Z each independently represent CV or N, V represents a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, —C.sub.nF.sub.2n+1 where n is an integer of 1 to 10, a nitro group, a boronic acid group, —OA.sup.1, —SO.sub.mA.sup.1 where m is an integer of 0 to 3, —NA.sup.1A.sup.2, —COOA.sup.1 or —CONA.sup.1A.sup.2, and A.sup.1 and A.sup.2 each independently represent a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.

4. A method for producing a fluorine-containing pyrimidine compound, comprising: a step of reacting a fluoroisobutane derivative represented by the following formula (4) with a compound represented by the following formula (3) or a salt thereof to obtain a fluorine-containing pyrimidine compound of the following formula (1): ##STR00016## wherein Q represents a halogen atom, —OA.sup.1, —SO.sub.mA.sup.1 where m is an integer of 0 to 3, or —NA.sup.1A.sup.2, R represents a hydrocarbon group having 1 to 12 carbon atoms, B.sup.1 and B.sup.2 each independently represent a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, —C.sub.nF.sub.2n+1 where n is an integer of 1 to 10, a nitro group, a boronic acid group, —OA.sup.1, —SO.sub.mA.sup.1 where m is an integer of 0 to 3, —NA.sup.1A.sup.2, —COOA.sup.1 or —CONA.sup.1A.sup.2, W, X, Y and Z each independently represent CV or N, V represents a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, —C.sub.nF.sub.2n+1 where n is an integer of 1 to 10, a nitro group, a boronic acid group, —OA.sup.1, —SO.sub.mA.sup.1 where m is an integer of 0 to 3, —NA.sup.1A.sup.2, —COOA.sup.1 or —CONA.sup.1A.sup.2, and A.sup.1 and A.sup.2 each independently represent a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.

5. The method for producing a fluorine-containing pyrimidine compound according to claim 3, wherein R is an alkyl group having 1 to 10 carbon atoms.

6. The method for producing a fluorine-containing pyrimidine compound according to claim 4, wherein R is an alkyl group having 1 to 10 carbon atoms.

Description

EXAMPLES

[0059] Hereinafter, Examples of the present disclosure will be described, but the present disclosure is not limited to these Examples as long as the gist of the present disclosure is not exceeded. Moreover, room temperature denotes a temperature within the range of 20° C. ±5° C. unless otherwise specified.

Example 1

Production of 6-fluoro-4-methoxy-2-(1-pyrazolyl)-5-(trifluoromethyl)pyrimidine

[0060] Under ice-water cooling, to 33 g of tetrahydrofuran were added 2 g (13.6 mmol) of 1-amidinopyrazole hydrochloride, 17.4 g (54.4 mmol) of potassium bis(trifluoromethanesulfonyl)imide and 3.3 g (15.6 mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-(trifluoromethyl)-1-propene. Subsequently, a mixed solution of 9.2 g (71 mmol) of diisopropylethylamine and 10 g of tetrahydrofuran was added dropwise such that the internal temperature did not exceed 10° C., and the temperature was raised to room temperature. After about 64 hours, tetrahydrofuran was distilled off under reduced pressure, and then the residue was dissolved in ethyl acetate followed by column purification to obtain 2.4 g of the compound represented by the following formula (5) (chemical formula: C.sub.9H.sub.6F.sub.4N.sub.4O, molecular weight: 262.17 g/mol). The isolated yield of the obtained compound was 67%.

##STR00010##

[0061] The analysis results were as follows.

Mass Spectrum (APCI, m/z): 262 ([M].sup.+)
.sup.1H-NMR (300 MHz, CDCl.sub.3) δ ppm: 8.52 (dd, 1H), 7.88 (d, 1H), 6.54 (m, 1H), 4.25 (s, 3H)
.sup.19F-NMR (300 MHz, C.sub.6F.sub.6) δ ppm: −58.51 (dd, 1F), −58.57 (d, 3F)

Example 2

Production of 6-fluoro-4-methoxy-2-(1-triazolyl)-5-(trifluoromethyl)pyrimidine

[0062] Under ice-water cooling, to 20 g of tetrahydrofuran were added 1 g (6.8 mmol) of 1-amidinotriazole hydrochloride, 8.7 g (27 mmol) of potassium bis(trifluoromethanesulfonyl)imide and 1.7 g (7.8 mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-(trifluoromethyl)-1-propene. Subsequently, a mixed solution of 4.6 g (35 mmol) of diisopropylethylamine and 10 g of tetrahydrofuran was added dropwise such that the internal temperature did not exceed 10° C., and the temperature was raised to room temperature. After about 16 hours, tetrahydrofuran was distilled off under reduced pressure, and then the residue was dissolved in ethyl acetate followed by column purification to obtain 70 mg of the compound represented by the following formula (6) (chemical formula: C.sub.8H.sub.5F.sub.4N.sub.5O, molecular weight: 263.16 g/mol). The isolated yield of the obtained compound was 4%.

##STR00011##

[0063] The analysis results were as follows.

Mass Spectrum (APCI, m/z): 263 ([M].sup.+)
.sup.1H-NMR (300 MHz, CDCl.sub.3) δ ppm: 9.19 (s, 1H), 8.20 (s, 1H), 4.29 (s, 3H)
.sup.19F-NMR (300 MHz, C.sub.6F.sub.6) δ ppm: −57.40 (dd, 1F), −58.86 (d, 3F)

Example 3

Production of 6-fluoro-4-methoxy-2-(1-pyrazolyl)-5-(trifluoromethyl) pyrimidine by Using 1,1,1,3,3-pentafluoro-3-methoxy-2-(trifluoromethyl)-propane Instead of 1,3,3,3-tetrafluoro-1-methoxy-2-(trifluoromethyl)-1-propene of Example 1

[0064] Under ice-water cooling, to 50 g of tetrahydrofuran were added 2 g (13.6 mmol) of 1-amidinopyrazole hydrochloride, 21.7 g (68.0 mmol) of potassium bis(trifluoromethanesulfonyl)imide and 3.6 g (15.6 mmol) of 1,1,1,3,3-pentafluoro-3-methoxy-2-(trifluoromethyl)-propane. Subsequently, a mixed solution of 11.4 g (88.4 mmol) of diisopropylethylamine and 10 g of tetrahydrofuran was added dropwise such that the internal temperature did not exceed 10° C., and the temperature was raised to room temperature. After about 16 hours, tetrahydrofuran was distilled off under reduced pressure, and then the residue was dissolved in ethyl acetate followed by column purification. The analysis results of the obtained compound were the same as those of the product of Example 1.

Example 4

Production of 6-fluoro-4-methoxy-2-(1-triazolyl)-5-(trifluoromethyl)pyrimidine by Using 1,1,1,3,3-pentafluoro-3-methoxy-2-(trifluoromethyl)-propane Instead of 1,3,3,3-tetrafluoro-1-methoxy-2-(trifluoromethyl)-1-propene of Example 2

[0065] Under ice-water cooling, to 50 g of tetrahydrofuran were added 2 g (13.6 mmol) of 1-amidinotriazole hydrochloride, 21.7 g (68.0 mmol) of potassium bis(trifluoromethanesulfonyl)imide and 3.6 g (15.6 mmol) of 1,1,1,3,3-pentafluoro-3-methoxy-2-(trifluoromethyl)-propane. Subsequently, a mixed solution of 11.4 g (88.4 mmol) of diisopropylethylamine and 10 g of tetrahydrofuran was added dropwise such that the internal temperature did not exceed 10° C., and the temperature was raised to room temperature. After about 16 hours, tetrahydrofuran was distilled off under reduced pressure, and then the residue was dissolved in ethyl acetate followed by column purification. The analysis results of the obtained compound were the same as those of the product of Example 2.

Example 5

Production of 6-fluoro-4-methoxy-2-(1-triazolyl)-5-(trifluoromethyl)pyrimidine by Using Sodium Tetraphenylborate Instead of Potassium bis(trifluoromethanesulfonyl)imide of Example 2

[0066] Under ice-water cooling, to 20 g of tetrahydrofuran were added 1 g (6.8 mmol) of 1-amidinotriazole hydrochloride, 9.2 g (27 mmol) of sodium tetraphenylborate and 1.7 g (7.8 mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-(trifluoromethyl)-1-propene. Subsequently, a mixed solution of 4.6 g (35 mmol) of diisopropylethylamine and 10 g of tetrahydrofuran was added dropwise such that the internal temperature did not exceed 10° C., and the temperature was raised to room temperature. After about 16 hours, tetrahydrofuran was distilled off under reduced pressure, and then the residue was dissolved in ethyl acetate followed by column purification. The analysis results of the obtained compound were the same as those of the product of Example 2.

[0067] In Examples 3 to 5, the isolated yields of the obtained compounds were not calculated, but in Examples 3 and 4, types and amounts of impurities are expected to be increased due to byproducts that can be generated in the course of producing 1,3,3,3-tetrafluoro-1-methoxy-2-(trifluoromethyl)-1-propene from 1,1,1,3,3-pentafluoro-3-methoxy-2-(trifluoromethyl)-propane in the reaction system. Therefore, the production methods of Examples 1 and 2 are conjectured to give high isolated yields of the obtained products as compared with the corresponding production methods of Examples 3 and 4. On the other hand, since in Example 5, the sodium salt that has a higher capacity of capturing fluoride ions than potassium, is used as the fluoride ion scavenger, the isolated yield of the obtained product is conjectured to be higher than that of the production method of Example 2.

Example 6

Production of 6-fluoro-2-(4-fluoro-1-pyrazolyl)-4-methoxy-5-(trifluoromethyl)pyrimidine

[0068] 0.5 g (3.0 mmol) of 4-fluoro-1H-pyrazol-1-carboxyimideamide hydrochloride was dissolved in 8 ml of tetrahydrofuran, to this were added 4.5 g (14.0 mmol) of potassium bis(trifluoromethanesulfonyl)imide, 0.8 g (3.8 mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-(trifluoromethyl)-1-propene and 2.1 g (16.2 mmol) of diisopropylethylamine, and the mixture was stirred at room temperature for 16.7 hours. After stirring, the reaction solution was purified by a column to obtain 0.2 g (0.9 mmol) of the compound represented by the following formula (7) (chemical formula: C.sub.9H.sub.5F.sub.5N.sub.4O, molecular weight: 280.16 g/mol). The isolated yield of the obtained compound was 28.0%.

##STR00012##

[0069] The analysis results were as follows.

Mass Spectrum (APCI, m/z): 280.9 ([M+H].sup.+)
.sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm: 8.35 (dd, J=4.0, 0.9 Hz, 1H), 7.79 (dd, J=4.3, 0.6 Hz, 1H), 4.24 (s, 3H)

Example 7

Production of 6-fluoro-4-methoxy-2-(3-methyl-1-pyrazolyl)-5-(trifluoromethyl)pyrimidine

[0070] 0.5 g (3.1 mmol) of 3-methyl-1H-pyrazol-1-carboxyimideamide hydrochloride was dissolved in 8.4 ml of tetrahydrofuran, to this were added 4.0 g (12.5 mmol) of potassium bis(trifluoromethanesulfonyl)imide, 0.8 g (3.8 mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-(trifluoromethyl)-1-propene and 2.1 g (16.2 mmol) of diisopropylethylamine, and the mixture was stirred at room temperature for 16.2 hours. After stirring, the reaction solution was purified by a column to obtain 0.6 g (2.1 mmol) of the compound represented by the following formula (8) (chemical formula: C.sub.10H.sub.8F.sub.4N.sub.4O, molecular weight: 276.19 g/mol). The isolated yield of the obtained compound was 67.0%.

##STR00013##

[0071] The analysis results were as follows.

Mass Spectrum (APCI, m/z): 277.1 ([M+H].sup.+)
.sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm: 8.40 (d, J=2.6 Hz, 1H), 6.35 (d, J=2.8Hz, 1H), 4.23 (s, 3H), 2.42 (s, 3H)

Test Example of Biological Activity

Evaluation Test for Rice Blast

[0072] 6-fluoro-4-methoxy-2-(1-pyrazolyl)-5-(trifluoromethyl)pyrimidine prepared in Example 1 was dissolved in acetone to prepare a solution having a concentration of 100,000 ppm. Next, to 1 ml of this acetone solution was added sterilized water up to 50 ml to prepare a test solution having a concentration of 2,000 ppm. 1,000 μl of the test solution having a concentration of 2,000 ppm was added dropwise to a separately fabricated oatmeal culture medium, and air-dried. Subsequently, a 4-mm rice blast disc was placed such that flora contacted a treated surface of the oatmeal culture medium. Then, the oatmeal culture medium was allowed to stand still in a thermostatic room at 25° C. for 6 days, and an elongation length of hyphae was then investigated. The results are shown in Table 1. The preventive value was calculated according to the following expression. In the following expression, “without treatment” means that 1 ml of acetone was diluted with sterilized water to 50 ml as a test solution, and the solution was added dropwise to the culture medium. In addition, “with treatment” means that a test solution that had been diluted and adjusted to a set concentration was added dropwise to the culture medium.

TABLE-US-00001 TABLE 1 Concentration of test solution (ppm) Preventive value 2000 100

Preventive value={(average of elongation lengths of hyphae without treatment−average of elongation lengths of hyphae with treatment)/average of elongation lengths of hyphae without treatment}×100   [Expression 1]

[0073] As shown in Table 1, the fluorine-containing pyrimidine compound of the present disclosure exhibits the control activity against the pathogens of rice blast, and is found to be effective as a compound exhibiting a biological activity.