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2-chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]pyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 100℃;Inert atmosphere; Microwave irradiation;
2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridin-4-amine (0631) To a solution of 2-chloro-4-iodo-5-methylpyridine (2.00 mmol) in 8 mL toluene is added <strong>[76697-50-2]1-amino-2-(isopropylsulphonyl)benzene</strong> (2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and cesium carbonate (2.20 mmol). The mixture is purged with nitrogen, and can be subjected to microwaves at 100° C. until formation of 2-chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]pyridin-4-amine. The reaction mixture can then be concentrated and purified by silica gel chromatography.
Stage #1: 2-chloro-4-iodo-5-methylpyridine With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate In tetrahydrofuran at 0℃; for 0.25h;
Stage #2: cyclohexylzinc(II) bromide In tetrahydrofuran at 5 - 20℃;
C
A 3 L 4-neck flask was equipped with a mechanical stirrer, an addition funnel, and a thermocouple, and was charged with 2-chloro-4-iodo-5-methylpyridine (30.0 g, 118.0 mmol, 1.0 equiv) in anhydrous tetrahydrofuran (237 mL). The solution was sparged with nitrogen for 15 minutes then cooled to 0° C. Then, 2-dicyclohexyl phosphino-2′,6′-dimethoxybi-phenyl (SPhos) (2.92 g, 7.1 mmol, 0.06 equiv) and palladium(II) acetate (0.8 g, 3.55 mmol, 0.03 equiv) were added. A 0.61 M solution of cyclohexylzinc(II) bromide in tetrahydrofuran (213.0 mL, 130 mmol, 1.1 equiv) was added drop-wise, maintaining the temperature below 5° C. When addition was completed, the reaction mixture was allowed to warm to room temperature and stirred overnight. Saturated aqueous sodium bicarbonate (200 mL) and ethyl acetate (200 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was chromatographed on silica gel (500 g), eluting with a gradient of 0-30% ethyl acetate in heptanes (1.0 L of solvent mixture for each 10% increase in polarity), to give 2-chloro-4-cyclohexyl-5-methylpyridine (18.0 g, 73% yield) as a yellow syrup.
With potassium phosphate monohydrate; palladium diacetate; XPhos In tetrahydrofuran at 20℃; Inert atmosphere;
1 Synthesis of 2-chloro-5-methyl-4-(2,4,5-trimethyl)pyridine
2-chloro-4-iodo-5-methylpyridine (12 g, 47.3 mmol), (2,4,5-trimethylphenyl)boronic acid (8.54 g, 52.1 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphane (0.677 g, 1.420 mmol), potassium phosphate tribasic monohydrate (32.7 g, 142 mmol), and THF (90 ml) were added to a 250 ml round bottom flask. Nitrogen was bubbled into the mixture and diacetoxypalladium (0.106 g, 0.473 mmol) was added. The mixture was stirred at room temperature overnight under nitrogen. The mixture was partitioned between water and ethyl acetate. The layers were separated and extracted the aqueous layer with ethyl acetate, The organic layers were washed with brine and dried over magnesium sulfate, filtered, then evaporated. Took up in DCM, purified using column chromatography eluting with 50-100% DCM/heptane and obtained 10.23 g (81% yield) of solid.
With (1,2-dimethoxyethane)dichloronickel(II); Ir(p-CF<SUB>3</SUB>-ppy)<SUB>3</SUB>; N-ethyl-N,N-diisopropylamine; 4,4'-di-tert-butyl-2,2'-bipyridine In dimethyl sulfoxide at 23℃; for 16h; Irradiation; Inert atmosphere;
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