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With sodium azide; In N,N-dimethyl-formamide; at 90℃;
Step 5: 4- (4- (1- (2-Chloro-4- (trifluoromethyl) phenyl) ethyl) -1H-1, 2, 3-triazol-1-yl) -6-methoxy-2-methylpyrimidine.To a solution of <strong>[89466-39-7]4-chloro-6-methoxy-2-methylpyrimidine</strong> (400 mg, 2.52 mmol) in DMF (4 ml) was added sodium azide (246 mg, 3.78 mmol) at 90 . The reaction solution was stirred at 90 overnight. The reaction was cooled, diluted with water (10 mL) , and extracted with ethyl acetate (3 x10 mL) . The combined organic extracts were washed with brine (2x10 mL) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. to give 4-azido-6-methoxy-2-methylpyrimidine which was used without further purification.[0438]To a solution of 1- (but-3-yn-2-yl) -2-chloro-4- (trifluoromethyl) benzene (21.13 mg, 0.091 mmol) in DMF (1 ml) , Water (0.5 ml) was added copper (II) sulfate pentahydrate (4.54 mg, 0.018 mmol) , sodium ascorbate (7.20 mg, 0.036 mmol) , and 4-azido-6-methoxy-2-methylpyrimidine (50 mg, 0.303 mmol) at RT. The reaction solution was stirred at 85 for 3 h. The reaction mixture was cooled, diluted with water (10 mL) and extracted with ethyl acetate (3 x10 mL) . The combined organic extracts were washed with brine (2 x15 mL) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (12 ethyl acetate in petroleum ether) to furnish the title compound as a solid. MS 398.1 (M+1) .
1-(1-(6-methoxy-2-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 70℃; for 4h;
To a solution of 4-chloro-6-methoxy-2-methylpyrimidine (1.60 g, 10.1 mmol) and l -(H- pyrazol-4-yl)ethanone (1.11 g, 10.1 mmol) in DMF (15.0 mL) was added Cs2C03 (9.86 g, 30.2 mmol) at RT. The reaction solution was stirred at 70 C for 4 h. The resulting mixture was diluted with brine (60 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic extracts were dried with anhydrous Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure. The crude title compound was obtained as a solid and used in the next step without further purification. MS = 233.1 (M+l).
With tris-(dibenzylideneacetone)dipalladium(0); N,N-dimethyl acetamide; zinc; tert-butyl XPhos; at 20 - 90℃; for 1.5h;Inert atmosphere;
Dicyanozinc (0.267 g, 2.270 mmol)and zinc (0.049 g, 0.757 mmol) were added to a stirred solution of <strong>[89466-39-7]4-chloro-6-methoxy-2-methylpyrimidine</strong> (0.600 g, 3.78 mmol) in DMA (2.5 mL) at RT. To the mixture were added di-tertbutyl(2?,4?,6?-triisopropyl-[1,1?-biphenylj-2-yl)phosphine (0.321 g, 0.757 mmol) and Pd2(dba)3 (0.173 g, 0.189 mmol). The reaction mixture was degassed with nitrogen 3 times and stirred under nitrogen atmosphere for 30 minutes at RT, then stirred for another 1 h at 90 C. The reaction mixture wascooled, diluted with brine (10 mL) and extracted with ethyl acetate (5 x 6 mL). The combined organic extracts were dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-15% ethyl acetate in petroleum ether) to furnish the title compound as a solid. MS = 150.4 (+ESI).
4-methoxy-2-methyl-6-(trimethylstannyl)pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 100℃; for 1.0h;Inert atmosphere;
1,1,1 ,2,2,2-Hexamethyl-distannane (620 mg, 1.892 mmol) and tetrakis(triphenylphosphine)palladium (219 mg, 0.189 mmol)were added to a solution of <strong>[89466-39-7]4-chloro-6-methoxy-2-methylpyrimidine</strong> (300 mg, 1.892 mmol) in 1,4-dioxane (3 mL). The reaction mixture was degassed with nitrogen 3 times and stirred for 1 h at 100C under and atmosphere of nitrogen. The reaction mixture was used in the next step directly without further purification. MS = 285.0/287.0/289.0 (+ESI).
4-methoxy-2-methyl-6-(2-methylphenyl)pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; isopropyl alcohol; at 83℃; for 18.0h;Inert atmosphere; Sealed tube;
General procedure: To a degassed solution of4,6-dichloropyrimidine (200 mg, 1.0 equiv) and arylboronic acid (1.0 equiv) in iPrOH (4 mL) in a 20 mLmicrowave vial was added an aqueous solution of 2M Na2CO3 (2.5 equiv) and Pd(PPh3)4 (5.0 mol%)under an argon atmosphere and the resulting heterogeneous solution was further degassed for 10 min. Thevial was sealed and placed in an oil bath at 83 oC and the reaction mixture was refluxed for 18 h, cooled,diluted with H2O (20 mL) and the whole was extracted with EtOAc (3 X 30 mL). The combined organicextract was washed with brine, dried (Na2SO4), and evaporated under reduced pressure give an oil whichwas purified by gradient column chromatography on silica gel using EtOAc/hexanes as eluent to affordcompounds 9a-j.
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