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12.2 1-(3-Bromo-2-chlorophenyl)ethanone 0.5 g of compound obtained in stage 12.1 is placed in a round-bottomed flask and dissolved in 18 ml of tetrahydrofuran. The solution is cooled to 0 C. with an ice bath and 2.7 ml of a 3M solution of methylmagnesium bromide in ethyl ether (standardized beforehand at 2M) are added dropwise thereto. The mixture is left stirring at 0 C. for 1 h and then at ambient temperature for 2 hours. The reaction mixture is subsequently hydrolysed at 0 C. with water and a saturated ammonium chloride solution and then extracted with ethyl acetate. The organic phase is separated, washed with a saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. 0.380 g of compound is obtained. 1H NMR (d6-DMSO, δ in ppm): 2.6 (s, 3H); 7.4 (t, 1H); 7.65 (d, 1H); 7.95 (d, 1H).
In tetrahydrofuran; diethyl ether; at 0 - 20℃;
To a solution of 3-bromo-2-chloro-N-methoxy-N-methylbenzamide (0.71 mmol) in 7 mL THF was added a solution of MeMgBr (4.31 mmol, 3M solution in Et20) at 0C. The cooling bath was removed after 1 h and stirring was continued at RT overnight. The reaction was quenched with water and sat. aq. NH4CI solution under cooling. The mixture was extracted with EtOAc (3x), the combined organic layers were washed with brine, dried over MgS04 and concentrated in vacuo. Purification by CC (KP-SIL from Biotage) using Hept to Hept/EtOAc (85/15) gives the desired compound as colorless oil; LC-MS (C): tR = 0.84 min; 1H NMR ((CD3)2SO) δ: 7.91 (d, 1 H), 7.65 (d, 1 H), 7.39 (t, 1 H), 2.58 (s, 3H).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80℃; for 2.0h;Inert atmosphere;
12.3 1-[2-Chloro-3-[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-6-yl]phenyl]ethanone 380 mg of compound obtained in stage 12.2 are dissolved in 16 ml of toluene and 8 ml of ethanol and degassed under a stream of argon for 10 min. 113 mg of tetrakis(triphenylphosphine)palladium, 654 mg of 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-6-boronic acid (compound obtained according to the protocol described in Example 4.2) and 4.07 ml of a 2M sodium carbonate solution are subsequently added thereto. The reaction mixture is heated at 80 C. for 2 hours and then, after cooling to ambient temperature, concentrated under reduced pressure. The residue is taken up between water and ethyl acetate. The organic phase is separated by settling, washed twice with water and then twice with a saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel, elution being carried out with a dichloromethane/ethyl acetate mixture. The solid obtained is triturated from diisopropyl ether, collected by filtration and then dried in an oven under reduced pressure. 259 mg of compound are obtained. 1H NMR (d6-DMSO, δ in ppm): 2.65 (s, 3H); 7.35 (d, 1H); from 7.5 to 7.65 (m, 3H); 7.7 (m, 3H); 8.05 (d, 2H); 8.5 (s, 1H); 8.7 (s, 1H).
With thiophen-2-yl magnesium bromide; In tetrahydrofuran; diethyl ether;
A.1.6.2 Synthesis of 1-(3-bromo-2-chlorophenyl)ethanone To a solution of 3-bromo-2-chloro-N-methoxy-N-methylbenzamide (0.71 mmol) in 7 mL THF was added a solution of MeMgBr (4.31 mmol, 3M solution in Et2O) at 0 C. The cooling bath was removed after 1 h and stirring was continued at RT overnight. The reaction was quenched with water and sat. aq. NH4Cl solution under cooling. The mixture was extracted with EtOAc (3*), the combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by CC (KP-SIL from Biotage) using Hept to Hept/EtOAc (85/15) gives the desired compound as colorless oil; LC-MS (C): tR=0.84 min; 1H NMR ((CD3)2SO) δ: 7.91 (d, 1H), 7.65 (d, 1H), 7.39 (t, 1H), 2.58 (s, 3H).
2-bromo-1-(3-bromo-2-chlorophenyl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-Bromosuccinimide; toluene-4-sulfonic acid; In dichloromethane; at 90℃; for 2.0h;Inert atmosphere; Microwave irradiation;
1-(3-bromo-2-chlorophenyl)ethan-l-one (1 eq, 340 mg), NBS (1.05 eq, 272 mg) and pTsOH monohydrate (0.11 eq, 30 mg) were mixed with 12 mL dry DCM and reacted in the microwave (90 C, 80 min) and then again (90 C, 40 min). The mixture was diluted with DCM and washed with sat. bicarbonate solution, water and then brine. The combined aq. phases were backextrated into DCM, the combined organic layers dried over sodium sulfate, filtered and concentrated in vacuo to result in a crude yellow oil (460 mg). It was purified by silica column chromatography (50 g, EtOAc in Hept 0-30%). The target was obtained as a yellow oil (429 mg, ca. 80% pure, 75% yield). Confirmed by ' H-NMR.
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