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With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide; at 80℃; for 2.0h;
A mixture of methyl 8-bromo-l,7-diazabicyclo[4.3.0]nona-2,4,6J8-tetraene-3-carboxylate (1.18 mmol, 300 mg), 2-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.76 mmol, 394 mg), Pd(dppf)Cl2*DCM (0.12 mmol, 96 mg) and K2CO3 (2.3 ml, 2M) in DMF (5 mL) was heated at 80 0C under an argon atmosphere for 2 h. The reaction mixture <n="62"/>was filtered and to the filtrate was added EtOAc and water. The layers were sepatrated, and the aqueous phase was extracted twice with EtOAc. The organic layers were combined, dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was dissolved in DMSO and was purified by preparative HPLC to give methyl 2-(6- fluoropyridin-3-yl)imidazo[2,l-f]pyridine-6-carboxylate as a light brown solid (38 mg); MS m/z (M+H) 272
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 80℃; for 1h;
A mixture of methyl delta-bromo-lJ-diazabicyclo^^.OJnona^^^jdelta-tetraene-S-carboxylate (0.39 mmol, 100 mg), (6-dimethylaminopyridin-3-yl)boronic acid (0.59 mmol, 98 mg), cesium carbonate (1.57 mmol, 510 mg) and Pd(dppf)Cl2*DCM ( 39 mumol, 32 mg) was <n="63"/>dissolved in DMF (3 ml). The mixture was stirred at 80 0C for 1 h and filtered. The filtrate lambdavas subjected to preparative HPLC to give 20 mg of the title compound as a white solid. IH NMR (400 MHz, DMSO-^6) delta ppm 9.24 (s, 1 H) 8.69 (d, J=2.02 Hz, 1 H) 8.38 (s, 1 H) 8.02 (dd, J=8.84, 2.27 Hz, 1 H) 7.61 (s, 2 H) 6.73 (d, J=8.84 Hz, 1 H) 3.89 (s, 3 H) 3.08 (s, 6 H); MS m/z (M+H) 297
The crude mixture above (1.45 g) and phosphorus oxybromide (1.75 g) was refluxed in 1,2-dichloroethane (30 mL) under an atmosphere of argon for 2h. Additional phosphorus oxybromide (7.3 g) was added and the reaction mixture was stirred under reflux for another 16 h before it was quenched by adding it to NaHCO3 (sat aq). The mixture was extracted with ethyl acetate, and the organic phase was dried (Na2SO4) and concentrated to give 1.06 g of crude title compound as a red solid. The crude material was purified by column chromatography (SiO2 (120 g); n-heptane/ethyl acetate 7/3) to give 0.77 g of the methyl 8-bromo-l, 7-diazabicyclo[4.3.0]nona-2,4,6,8-tetraene-3-carboxylate title. 1H NMR (DMSO-^6) delta 9.27 (s, 1 H), 8.24 (s, 1 H), 9.70 (dd5 IH), 7.62 (d, 1 H), 3.89 (s, 3 H). MS m/z (M+H) 254.9, 256.7.
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 80℃; for 1.0h;
A mixture of methyl S-bromo-lJ-diazabicyclo^.S.Ojnona^^ojS-tetraene-S-carboxylate (0.65 mmol, 165 mg), tert-but5d N-methyl-N-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl]carbamate (0.98 mmol, 312 mg), Pd(dprhof)Cl2*DCM (65 mumol, 53mg) and cesium carbonate (1.95 mmol, 656 mg) in DMF (5 mL) was heated at 80 CC under an argon atmosphere for 1 h. The reaction mixture was filtered and the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography (EtOAc / hep) to give 150 mg of methyl 2-[6-[methyl-[(2-methylpropan- 2-yl)oxycarbonyl]amino]pyridin-3-yl]imidazo[2,l-fJpyridine-6-carboxylate as a yellow solid. MS m/z (M+H) 383
(2-bromoimidazo[1,2-a]pyridin-6-yl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With diisobutylaluminium hydride; In tetrahydrofuran; at 0 - 20℃; for 1.0h;
Example 1 2-({ [2-(2-methylbiphenyl-3-yl)imidazo[l,2-a]pyridin-6-yl]methyl}amino)ethanol Step 1: (2-bromoimidazo[l, To a solution of methyl 2-bromoimidazo[l,2-a]pyridine-6-carboxylate (200 mg, 0.784 mmol) (ArkPharm, catAK-31669) in tetrahydrofuran (5.0 mL) at 0 C was added 1.0 M diisobutylaluminum hydride in tetrahydrofuran (862 mu, 0.862 mmol). The resulting mixture was sitrred at room temperature for 1 h then it was quenched with saturated NH4CI aqueous solution (1 mL), stirred for 1 h then filtered through celite. The organic layer was dried over Na2S04, filtered and concentrated. The residue was used for next step without further purification. LC-MS calculated for C8H8BrN20 (M+H)+: m/z = 227.0; found 227.2.
With lithium aluminium tetrahydride; In diethyl ether; at 0 - 20℃;
Methyl 2-bromoimidazo[1,2-ajpyridine-6-carboxylate (300 mg, 1.18 mmol) dissolved in diethyl ether (12 mL) and cooled to 0 C was treated with lithium aluminum hydride (46 mg, 1.21 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. Aftercooling to 0 C again, the reaction mixture was quenched by addition of sodium sulfate decahydrate. The mixture was stirred for 20 mm and filtered. The filtrate was concentrated to give (2-bromoimidazo[1,2- ajpyridin-6-yl)methanol.
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