| 97.2% |
|
Preparation of 2-amino-5-bromo-4-chlorophenol (19): To a suspension of <strong>[102170-53-6]4-bromo-3-chloro-6-methoxyaniline</strong> (18) (944 mg, 4 mmol) in 10 ml DCM was added 1 M BBr3 in DCM (8 ml, 8 mmol). The reaction mixture was stirred at r.t. for 2 h, which turned to a brown solution and back to a brown suspension. After quenched with aq. sodium bicarbonate solution, the mixture was extracted with EA. The org. phase was washed with brine, dried over sodium sulfate, concentrated to dryness to give 865 mg 19 as brown solid. Yield: 97.2%, purity >95%.Preparation of 6-bromo-5-chloro-2-methylbenzoxazole (20): A mixture of 2-amino-5-bromo-4-chlorophenol (19) (865 mg, 3.89 mmol), trifluoromethanesulfonic acid Ytterbium (III) salt (24 mg, 1% mol) and trimethyl orthoacetate (610 mul, 1.2 eq.) in 3 ml EtOH was heated at 90 C. for 1 h. After cooling down to r.t., off-white needles fell off, which were filtered, washed with MeOH, water and dried to give 791 mg title compound as off-white crystalline solid. Yield: 80.2%; purity >95%.Preparation of 2-(5-chloro-2-methylbenzoxzzol-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (21): A mixture of 6-bromo-5-chloro-2-methylbenzoxazole (20, 493 mg, 2 mmol), bis(pinacolato)diboron (1.01 g, 2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (1:1) (163 mg) and potassium acetate (588 mg) in 8 ml dioxane was heated under Ar for 20 h at 90 C. After EA/brine work-up, the org. phase was dried over sodium sulfate, concentrated and subjected to silica gel flash column purification to give 925 mg white solid, which was dissolved in 20 ml THF/MeOH/H2O (5:4:1) and stirred with 30 ml 1 M HCl at r.t. for 30 min. EA/brine work-up and followed by flash column to give 205 mg of 2-(5-chloro-2-methylbenzoxzzol-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (21) as white solid. Preparation of [5-(5-chloro-2-methylbenzoxazol-6-yl)selenophen-2yl]-N-(2-fluorophenyl)carboxamide (22): A mixture of (5-bromoselenophen-2-yl)-N-(2-fluorophenyl)carboxamide (4) (20 mg, 0.057 mmol), 2-(5-chloro-2-methylbenzoxazol-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (21) (20 mg, 1.2 eq), tetrakis(triphenylphosphine)-palladium(0) (Pd(Ph3P)4, 12 mg) and sodium carbonate (18 mg) in 0.5 ml DME, 0.5 ml EtOH and 0.25 ml water was heated under Ar in microwave reactor at 110 C. for 30 min. The reaction mixture was worked up with EA/brine. Org. phase was concentrated and then subjected to silica gel flash column chromatography to furnish 2.9 mg of [5-(5-chloro-2-methylbenzoxazol-6-yl)selenophen-2yl]-N-(2-fluorophenyl)carboxamide (22) as yellow solid (yield: 11.7%; purity 90%). |
| 89% |
With boron tribromide; In dichloromethane; at 0 - 20℃; for 15.0h; |
Intermediate 7: 2-Amino-5-bromo-4-chlorophenol 4-Bromo-5-chloro-2-methoxyaniline (Intermediate 6, 10g, 42.3 mmol) in DCM (200 mL) was cooled to 0 C. Boron tribromide (21 .2 g, 84.6 mmol) was added drop-wise over 30 min, the reaction mixture was stirred at 0 C for 1 h and then at room temperature for 14 h. The reaction mixture was poured into ice water, sodium hydrogen carbonate was added until pH >7 and aqueous layer was extracted with ethyl acetate (300 mL x 3). The organic phase was dried over magnesium sulphate and the solvent removed under vacuum to give 2-amino-5-bromo-4-chlorophenol as a red solid (8.4 g, 89%, used without further purification for the next step). LCMS (A): Rt 1.46 min, MH+ 222/224. |
| 220 g |
With boron tribromide; In dichloromethane; at 20℃; for 2.0h;Cooling with ice; |
To each of 2 ice/water cooled flasks, containing <strong>[102170-53-6]4-bromo-5-chloro-2-methoxyaniline</strong> (120 g, 507.42 mmol) in DCM (1000 mL) was added boron tribromide (382 g, 1522.26 mmol). After addition, the mixture was warmed to room temperature and stirred for 2 h. The reactionmixtures were poured into ice/water (2L), basified with solid sodium bicarbonate to pH 7 and extracted with ethyl acetate (l000mL x 6). The combined organics were dried over sodium sulphate and the solvent removed to give 2-amino-5-bromo-4-chlorophenol as a brown solid (220 g).LCMS: Rt 1.35 mi MH 222/224. |
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