| 65% |
With potassium acetate In N,N-dimethyl-formamide at 80℃; for 8h; |
1
4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine: A 10 mL microwave reaction tube with septum closure was charged with 4-(4-bromo-3-fluorobenzyl)morpholine (405 mg, 1.48 mmol),Bis(pinacolato)diboron (516 mg, 2.03 mmol), Pd(dppf)Cl2.CH2Cl2 (62 mg, 0.076 mmol), potassium acetate (659 mg, 6.72 mmol), and DMF (3.6 mL). The vial was placed under nitrogen by evacuation/backfilling (5 cycles) and stirred at 80° C. for 8 hours. The reaction was cooled, diluted with ethyl acetate (25 mL) and filtered. The organics were washed with water (25 mL) and saturated sodium chloride (25 mL). The organic layer was then dried over MgSO4 and concentrated to a dark oil. The product was purified by silica gel chromatography eluting with 2% MeOH in CHCl3 to give 310 mg (65%) of an off-white solid. |
|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 120℃; for 0.5h; Microwave irradiation; |
7
To a solution of 4-(4-bromo-3-fluorobenzyl)morpholine (preparation 12) (445 mg, 1.62 mmol) in 1,4-dioxane (4 ml), bis(pinacolato)diboron (495 mg, 1.95 mmol), potassiumacetate (350 mg, 3.57 mmol) and [1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (59 mg, 0.081 mmol) were added and the mixture was heated under microwave irradiation at 120 °C for 30 minutes. The reaction mixture was concentrated in vacuo, diluted with dichloromethane (10 ml), washed with water (5 ml) and filtered through a phase separator. The filtrate was concentrated in vacuo to afford the boronic ester intermediate as determined by 1H NMR in CDCl3. The crude boronic ester was then dissolved in DMF (10 ml) and 2-chloro-6- fluoro-N-(2-(pyrrolidin-1-yl)ethyl)quinoline-4-carboxamide (preparation 4) (261 mg, 0.81mmol), potassium phosphate tribasic (344 mg, 1.62 mmol) in water (2 ml), bis(triphenylphosphine) palladium(ll) dichloride (71 mg, 0.062 mmol) were added. The reaction mixture was heated under microwave irradiation for 30 minutes at 12000. The reaction crude was filtered through a CeliteTM pad and washed with ethyl acetate (4 x 10 ml). The combined organic phases were washed with 5% lithium chloride aqueoussolution (3 x 10 ml), brine (10 ml), dried over magnesium sulphate and concentrated in vacuo. The mixture was purified by mass directed autoprep HPLC to afford the desired product as an off-white solid (193mg, 0.4Ommol, 25% yield over 2 steps). 1H NMR (500 MHz; CDCl3) δ 1.93 (brs, 4H), 2.49 (t, 4H, J = 4.4 Hz), 2.59 (brs, 4H), 2.78 (brs, 2H), 3.56 (5, 2H), 3.74 (t, 4H, J = 4.7 Hz), 3.78 (brs, 2H), 7.23-7.30 (m, 2H), 7.53 (ddd, 1H, J= 2.8 Hz, J= 8.1 Hz, J= 9.3 Hz), 8.02-8.08 (m, 3H), 8.19 (dd, 1H, J= 5.5 Hz, J= 9.3 Hz) ppm. Purity by LCMS (UV Chromatogram, 190-450 nm) 95 %, rt = 0.68 min m/z 481 (M+H)+ |
|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 120℃; for 0.5h; Microwave irradiation; |
7 6-fluoro-2-(2-fluoro-4-(morpholinomethyl)phenyl)-N-(2-(pyrrolidin-1-yl)ethyl)quinoline-4-carboxamide
Example 7 6-fluoro-2-(2-fluoro-4-(morpholinomethyl)phenyl)-N-(2-(pyrrolidin-1-yl)ethyl)quinoline-4-carboxamide To a solution of 4-(4-bromo-3-fluorobenzyl)morpholine (preparation 12) (445 mg, 1.62 mmol) in 1,4-dioxane (4 ml), bis(pinacolato)diboron (495 mg, 1.95 mmol), potassium acetate (350 mg, 3.57 mmol) and [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (59 mg, 0.081 mmol) were added and the mixture was heated under microwave irradiation at 120° C. for 30 minutes. The reaction mixture was concentrated in vacuo, diluted with dichloromethane (10 ml), washed with water (5 ml) and filtered through a phase separator. The filtrate was concentrated in vacuo to afford the boronic ester intermediate as determined by 1H NMR in CDCl3. The crude boronic ester was then dissolved in DMF (10 ml) and 2-chloro-6-fluoro-N-(2-(pyrrolidin-1-yl)ethyl)quinoline-4-carboxamide (preparation 4) (261 mg, 0.81 mmol), potassium phosphate tribasic (344 mg, 1.62 mmol) in water (2 ml), bis(triphenylphosphine) palladium(II) dichloride (71 mg, 0.062 mmol) were added. The reaction mixture was heated under microwave irradiation for 30 minutes at 120° C. The reaction crude was filtered through a Celite pad and washed with ethyl acetate (4*10 ml). The combined organic phases were washed with 5% lithium chloride aqueous solution (3*10 ml), brine (10 ml), dried over magnesium sulphate and concentrated in vacuo. The mixture was purified by mass directed autoprep HPLC to afford the desired product as an off-white solid (193 mg, 0.40 mmol, 25% yield over 2 steps). 1H NMR (500 MHz; CDCl3) δ 1.93 (brs, 4H), 2.49 (t, 4H, J=4.4 Hz), 2.59 (brs, 4H), 2.78 (brs, 2H), 3.56 (s, 2H), 3.74 (t, 4H, J=4.7 Hz), 3.78 (brs, 2H), 7.23-7.30 (m, 2H), 7.53 (ddd, 1H, J=2.8 Hz, J=8.1 Hz, J=9.3 Hz), 8.02-8.08 (m, 3H), 8.19 (dd, 1H, J=5.5 Hz, J=9.3 Hz) ppm. Purity by LCMS (UV Chromatogram, 190-450 nm) 95%, rt=0.68 min, m/z 481 (M+H)+ |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
Life Science
For Research Only
88K+ Compounds
Competitive Price
1-2 Day Shipping
