4,5,6-TRIFLUOROPYRIMIDINE

Preparation of 4, 5, 6-trifluoropyrimidine; 7160 ml of sulpholane and 3876 g of KF were initially charged in an autoclave and stirred at 150° C. for 1 h. Subsequently, the mixture was dried by distilling off 700 ml of sulpholane under reduced pressure. The mixture was then cooled to 90° C. and aerated with nitrogen, and a solution, heated to 45° C., of 3122 g of 4, 5, 6-trichloropyrimidine and 2386 g of dry sulpholane was pumped in. Afterwards, 166 g of CNC catalyst and 20.5 g of nitrobenzene were added rapidly and the vessel was sealed. The mixture was heated to 200° C. with stirring for 5 h and subsequently to 220° C. for 11 h. During the reaction, a maximum total pressure of 6.5 bar arose. The mixture was cooled to 40° C. with stirring and decompressed slowly into an ice-cooled receiver. The internal temperature was increased slowly to 150° C. and the product was distilled off initially at standard pressure, later under reduced pressure. After redistillation of the crude product, 1540 g of 4, 5, 6-trifluoropyrimidine (66percent of theory) were obtained as a colourless liquid.Into a 500 mL flask equipped with a reflux condenser, 75 g of sulfolane was charged and the inner temperature thereof was adjusted at 140° C. To this, the solution obtained by dissolving 17.8 g of potassium fluoride, which was the same as used in Example 1, in 209 g of methanol was added dropwise together with removing distilled methanol out the system. The addition of all amount of the methanol solution of potassium fluoride dropwise was finished and methanol was hardly distilled out at all, and then, the concentration was further conducted at 160° C. at 2.7 kPa to obtain a potassium fluoride dispersion essentially consisting of potassium fluoride and sulfolane.To a 120 mL autoclave, 10.3 g of 4, 5, 6-trichloropyrimidine was charged. The above-mentioned potassium fluoride dispersion was added thereto and the autoclave was sealed. After the inner pressure thereof was adjusted to 0.5 MPa at room temperature using nitrogen, the reaction was conducted at an inner temperature of 220° C. for 10 hours. The inner pressure after completion of the reaction was 0.82 MPa at 220° C. The reaction mixture was cooled to room temperature and the supernatant solution was analyzed with gas chromatography internal standard method (internal standard: methyl isobutyl ketone). The yield of 4, 5, 6-trifluoropyrimidine was 50percent and the yield of 4, 6-difluoro-5-chloropyrimidine was 26percent.4, 5, 6-Trifluoro-pyrimidine (0.27 g, 2.0 mmol) and N-[[4-(trifluoromethyl)phenyl]methyl]cyclopropanamine (0.43 g, 2.0 mmol) were dissolved in dry DMSO (4 mL) and DIPEA (0.7 mL, 4.0 mmol) was added. The reaction was stirred at room temperature overnight, poured into 3M aq. calcium chloride, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash CC (eluent: DCM/MeOH, on silica gel)yielding N-cyclopropyl-5 , 6-difluoro-N- [ [4-(trifluoromethyl)phenyl]methyl]pyrimidin-4- amine (0.50 g, 76% yield).Step 1: 1-(5, 6-Difluoropyrimidin-4-yl)-1H-pyrazole-3-amine (via route A-1) 1H-Pyrazole-3-amine (1.25 g) was initially charged in acetonitrile (75 ml), Into a 500 mL flask equipped with a reflux condenser, 75 g of sulfolane was charged and the inner temperature thereof was adjusted at 140 C. To this, the solution obtained by dissolving 17.8 g of potassium fluoride, which was the same as used in Example 1, in 209 g of methanol was added dropwise together with removing distilled methanol out the system. The addition of all amount of the methanol solution of potassium fluoride dropwise was finished and methanol was hardly distilled out at all, and then, the concentration was further conducted at 160 C. at 2.7 kPa to obtain a potassium fluoride dispersion essentially consisting of potassium fluoride and sulfolane.To a 120 mL autoclave, 10.3 g of 4, 5, 6-trichloropyrimidine was charged. The above-mentioned potassium fluoride dispersion was added thereto and the autoclave was sealed. After the inner pressure thereof was adjusted to 0.5 MPa at room temperature using nitrogen, the reaction was conducted at an inner temperature of 220 C. for 10 hours. The inner pressure after completion of the reaction was 0.82 MPa at 220 C. The reaction mixture was cooled to room temperature and the supernatant solution was analyzed with gas chromatography internal standard method (internal standard: methyl isobutyl ketone). The yield of II. Process Part 2 [00260] Process Part 2 E) (Process part 1 and Process Steps 9 and 10) Using the Compound (I-1g) Obtained in Process Step 8 According to Process Part 1 D) With Addition of Acetone as Carbonyl Compound Process Step 9 N-Methyl-2-[2-(5, 6-difluoro-pyrimidin-4-yloxy)-phenyl]-2-methoxyiminoacetamide (Example XIII-1g) (cf. Example (IV-1) From WO9821189, Page 25) 6 g (0.0280 mol) of N-methyl-2-(2-hydroxyphenyl)-2-methoxyiminoacetamide (Example I-1g from process step 1; HPLC: 43.7% N-methyl-E-2-(2-hydroxyphenyl)-2-methoxyimino-acetamide of log p=0.98 and 53.5% N-methyl-Z-2-(2-hydroxyphenyl)-2-methoxyiminoacetamide of log p=1.29) are dissolved in 80 ml of acetonitrile.. The solution is cooled to 0 C., 4.7 g (0.034 mol) of potassium carbonate are added and the mixture is stirred for another 30 minutes. 3.8 g (0.0283 mol) of In this exemplification, to a 50 mL round bottom flask fitted with a stirbar and charged with 7 (280 mg, 2.1 mmol) in n-BuOH cooled to 0 C. was added N, N-diisopropylethylamine (DIEA) (1 mL, 6.3 mmol) and 4. The reaction was stirred at 0 C. for 1 hr. The reaction mixture was allowed to warm to room temperature and evaporated in vacuo and purified on a plug of SiO2. A white solid 8 was recovered (640 mg, 83% yield) which was taken on without further purification.Example (IV-1) Process e) At 20 C., initially 0.7 g (5.1 mmol) of Example 1-3; 0.5 g of Example 1-1; EPO 0.5 gof 0.5 gof 4, 5, 6-trifluoropyrimidine, 0.31 gof 2-butyn-l-ol and 0.62 ml of N, N-diisopropylethylamine were added to 1 ml of hexane, then the mixture was stirred at room temperature for1 hour. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.55 g of4-(2-butynyloxy) -5, 6-difluoropyrimidine0.5gof To a mixture obtained by adding 110.0 g of To a mixture obtained by adding 110.0 g of STR11 3.6 g (0.12 mol) of sodium hydride (80% in paraffin oil) are added in portions at 0 C. to a mixture of 16.1 g (0.12 mol) of a) 13.4 parts of