* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
To a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 mL) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 mL, 312 mmol). The resulting mixture was stirred at 500C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 mL) and water (300 mL). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, by using 10:1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93percent): 1H NMR (400 MHz, CDCI3) δ ppm 8.60 (d, J = 1.60 Hz, 1 H), 8.01 (d, J = 8.40 Hz, 1 H), 7.75 (dd, J = 8.40, 2.40 Hz, 1 H), 3.92 (s, 3 H).
93%
at 50℃; for 24 h;
Intermediate 1 : methyl δ-chloro^-pyridinecarboxylate To a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 ml.) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 ml_, 312 mmol). The resulting mixture was stirred at 500C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 ml.) and water (300 ml_). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, by using 10:1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93percent): 1H NMR (400 MHz, CDCI3) δ ppm 8.60 (d, J = 1.60 Hz, 1 H), 8.01 (d, J = 8.40 Hz, 1 H), 7.75 (dd, J = 8.40, 2.40 Hz, 1 H), 3.92 (s, 3H).
93%
at 50℃; for 24 h;
Intermediate 1 : methyl δ-chloro^-pyridinecarboxylate To a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 ml.) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 ml_, 312 mmol). The resulting mixture was stirred at 500C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 ml.) and water (300 ml_). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, by using 10:1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93percent): 1H NMR (400 MHz, CDCI3) δ ppm 8.60 (d, J = 1.60 Hz, 1 H), 8.01 (d, J = 8.40 Hz, 1 H), 7.75 (dd, J = 8.40, 2.40 Hz, 1 H), 3.92 (s, 3H).
93%
at 50℃; for 24 h;
Intermediate 1 : methyl δ-chloro^-pyridinecarboxylate To a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 ml.) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 ml_, 312 mmol). The resulting mixture was stirred at 500C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 ml.) and water (300 ml_). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, by using 10:1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93percent): 1H NMR (400 MHz, CDCI3) δ ppm 8.60 (d, J = 1.60 Hz, 1 H), 8.01 (d, J = 8.40 Hz, 1 H), 7.75 (dd, J = 8.40, 2.40 Hz, 1 H), 3.92 (s, 3H).
93%
at 50℃; for 24 h;
Intermediate 1 : methyl δ-chloro^-pyridinecarboxylateTo a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 ml.) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 ml_, 312 mmol). The resulting mixture was stirred at 500C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 ml.) and water (300 ml_). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, by using 10:1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93percent): 1H NMR (400 MHz, CDCI3) δ ppm 8.60 (d, J = 1.60 Hz, 1 H), 8.01 (d, J = 8.40 Hz, 1 H), 7.75 (dd, J = 8.40, 2.40 Hz, 1 H), 3.92 (s, 3H).
93%
at 50℃; for 24 h;
I. methyl 5-chloro-2-pyridinecarboxylate To a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 mL) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 mL, 312 mmol). The resulting mixture was stirred at 50°C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 mL) and water (300 mL). The combined organic layers were dried (Na2SC>4) and evaporated. Flash chromatography of the residue over silica gel, by using 10: 1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93percent yield): 1H NMR (400 MHz, CDC13) δ ppm 8.60 (d, J = 1.60 Hz, 1H), 8.01 (d, J= 8.40 Ηζ,ΙΗ), 7.75 (dd, J = 8.40, 2.40 Hz, 1H), 3.92 (s, 3H).
To a cooled (00C) solution of methyl δ-chloro^-pyridinecarboxylate (43 g, 251 mmol) in methanol (400 ml_) was added NaBH4 (28.7 g, 754 mmol) in small portions over approximately 30 min. After addition, the reaction mixture was stirred at room temperature for 2 h, at which time TLC analysis showed the completion of the reaction. The reaction mixture was then concentrated under reduced pressure, and the residue was adjusted to pH 1 by adding 1 N HCI. The resulting solution was extracted with EtOAc (3 X 300 ml_). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel using 10:1 petroleum ether/EtOAc as eluent provided the title compound (36 g, 99percent): 1H NMR (400 MHz, CDCI3) δ ppm 8.44 (d, J = 1 .60 Hz, 1 H), 7.62 (dd, J = 8.40, 2.40 Hz, 1 H), 7.25 (d, J = 8.40 Hz, 1 H), 4.69 (s, 2 H), 3.83 (s, 1 H).
99%
at 0 - 20℃; for 2.5 h;
Intermediate 2: (5-chloro-2-pyridinyl)methanol To a cooled (00C) solution of methyl 5-chloro-2-pyridinecarboxylate (43 g, 251 mmol) in methanol (400 ml.) was added NaBH4 (28.7 g, 754 mmol) in small portions over approximately 30 min. After addition, the reaction mixture was stirred at room temperature for 2 h, at which time TLC analysis showed the completion of the reaction. The reaction mixture was then concentrated under reduced pressure, and the residue was adjusted to pH 1 by adding 1N HCI. The resulting solution was extracted with EtOAc (3 X 300 ml_). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel using 10:1 petroleum ether/EtOAc as eluent provided the title compound (36 g, 99percent): 1H NMR (400 MHz, CDCI3) δ ppm 8.44 (d, J = 1.60 Hz, 1 H), 7.62 (dd, J = 8.40, 2.40 Hz, 1 H), 7.25 (d, J = 8.40 Hz, 1 H), 4.69 (s, 2 H), 3.83 (s, 1 H).
99%
at 0 - 20℃; for 2.5 h;
Intermediate 2: (5-chloro-2-pyridinyl)methanol To a cooled (00C) solution of methyl 5-chloro-2-pyridinecarboxylate (43 g, 251 mmol) in methanol (400 ml.) was added NaBH4 (28.7 g, 754 mmol) in small portions over approximately 30 min. After addition, the reaction mixture was stirred at room temperature for 2 h, at which time TLC analysis showed the completion of the reaction. The reaction mixture was then concentrated under reduced pressure, and the residue was adjusted to pH 1 by adding 1N HCI. The resulting solution was extracted with EtOAc (3 X 300 ml_). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel using 10:1 petroleum ether/EtOAc as eluent provided the title compound (36 g, 99percent): 1H NMR (400 MHz, CDCI3) δ ppm 8.44 (d, J = 1.60 Hz, 1 H), 7.62 (dd, J = 8.40, 2.40 Hz, 1 H), 7.25 (d, J = 8.40 Hz, 1 H), 4.69 (s, 2 H), 3.83 (s, 1 H).
99%
at 0 - 20℃; for 2.5 h;
Intermediate 2: (5-chloro-2-pyridinyl)methanol To a cooled (00C) solution of methyl 5-chloro-2-pyridinecarboxylate (43 g, 251 mmol) in methanol (400 ml.) was added NaBH4 (28.7 g, 754 mmol) in small portions over approximately 30 min. After addition, the reaction mixture was stirred at room temperature for 2 h, at which time TLC analysis showed the completion of the reaction. The reaction mixture was then concentrated under reduced pressure, and the residue was adjusted to pH 1 by adding 1N HCI. The resulting solution was extracted with EtOAc (3 X 300 ml_). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel using 10:1 petroleum ether/EtOAc as eluent provided the title compound (36 g, 99percent): 1H NMR (400 MHz, CDCI3) δ ppm 8.44 (d, J = 1.60 Hz, 1 H), 7.62 (dd, J = 8.40, 2.40 Hz, 1 H), 7.25 (d, J = 8.40 Hz, 1 H), 4.69 (s, 2 H), 3.83 (s, 1 H).
99%
at 0 - 20℃; for 2.5 h;
Intermediate 2: (5-chloro-2-pyridinyl)methanolTo a cooled (00C) solution of methyl δ-chloro^-pyridinecarboxylate (43 g, 251 mmol) in methanol (400 ml.) was added NaBH4 (28.7 g, 754 mmol) in small portions over approximately 30 min. After addition, the reaction mixture was stirred at room temperature for 2 h, at which time TLC analysis showed the completion of the reaction. The reaction mixture was then concentrated under reduced pressure, and the residue was adjusted to pH 1 by adding 1 NHCI. The resulting solution was extracted with EtOAc (3 X 300 ml_). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel using 10:1 petroleum ether/EtOAc as eluent provided the title compound (36 g, 99percent): 1H NMR (400 MHz, CDCI3) δ ppm 8.44 (d, J = 1.60 Hz, 1 H), 7.62 (dd, J = 8.40, 2.40 Hz, 1 H), 7.25 (d, J = 8.40 Hz, 1 H), 4.69 (s, 2 H), 3.83 (s, 1 H).
99%
at 0 - 20℃; for 2.5 h;
II. (5-chloro-2-pyridinyl)methanol To a cooled (0°C) solution of methyl 5-chloro-2-pyridinecarboxylate (43 g, 251 mmol) in methanol (400 mL) was added NaB (28.7 g, 754 mmol) in small portions over approximately 30 min. After addition, the reaction mixture was stirred at room temperature for 2 h, at which time TLC analysis showed the completion of the reaction. The reaction mixture was then concentrated under reduced pressure, and the residue was adjusted to pH 1 by adding IN HC1. The resulting solution was extracted with EtOAc (3 X 300 mL). The combined organic layers were dried (Na2SC>4) and evaporated. Flash chromatography of the residue over silica gel using 10: 1 petroleum ether/EtOAc as eluent provided the title compound (36 g, 99percent yield): FontWeight="Bold" FontSize="10" H NMR (400 MHz, CDC13) δ ppm 8.44 (d, J = 1.60 Hz, 1H), 7.62 (dd, J = 8.40, 2.40 Hz, 1H), 7.25 (d, J = 8.40 Hz, 1H), 4.69 (s, 2 H), 3.83 (s, 1Η).
95%
at 20℃; for 4 h;
5-chloro-2(chloromethyl)pyridine; [00372] To a 0 °C solution of 5-chloropicolinic acid (3.00 g, 19.0 mmol) indichloromethane (20 mL) was added sulfurous dichloride (2.78 mL, 38.1 mmol), after which the reaction was warmed to room temperature and stirred at that temperature for 4 hours. The reaction was then concentrated to dryness, then reconstituted in dichloromethane (5 mL). Methanol (10 mL) was added to the reaction mixture, and the reaction was allowed to stir at room temperature for 12 hours, after which it was then diluted with water, extracted with ethyl acetate (3 x 50 mL), washed with water, then washed with saturated sodium bicarbonate solution, dried (magnesium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography (ISCO 80g) using 0 to 80percent ethyl acetate in hexanes to afford methyl 5-chloropicolinate was as an off-white solid (2.75 g, 15.2 mmol, 80percent yield ).[00373] To a 0 °C solution of methyl 5-chloropicolinate (2.70 g, 15.7 mmol) in methanol (50 mL) was added sodium borohydride (1.79 g, 47.2 mmol), after which the reaction was warmed to room temperature and stirred at that temperature for 4 hours. The reaction mixture was then concentrated to a residue which was treated with 1M hydrochloric acid solution (15 mL), extracted with ethyl acetate (3 x 100 mL), washed with water, then washed with saturated sodium bicarbonate solution, dried (magnesium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography (ISCO 80g) using 0 to 60percent ethyl acetate in hexanes to afford (5-chloropyridin-2-yl)methanol was as an off-white solid (2.15 g, 14.9 mmol, 95percent yield).[00374] To a 0 °C solution of (5-chloropyridin-2-yl)methanol (2.10 g, 14.6 mmol) in dichloromethane (10 mL) was added sulfurous dichloride (1.60 mL, 21.9 mmol) followed by N,N-dimethylformamide (50 μ), after which the reaction was warmed to room temperature and stirred at that temperature for 4 hours. The reaction mixture was then concentrated to a residue which was reconstituted in water (15 mL), ethyl acetate (15 mL), and saturated sodium bicarbonate solution (15 mL). The organic layers were separated and washed with saturated sodium chloride solution, dried (magnesium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography (ISCO 40g) using 0 to 50percent ethyl acetate in hexanes to afford 5-chloro-2(chloromethyl)pyridine as an light brown oil (2.11 g, 13.0 mmol, 89percent yield).
95%
With sodium tetrahydroborate In methanol at 20℃; for 1 h;
A solution of methyl 5-chloropicolinate (2 g, 1 1 .7 mmol) in MeOH (20 ml) and sodium borohydride (0.89 g, 23.3 mmol) was stirred at rt for 1 h. After reaction was completed, solvent was evaporated. Distilled water was added and the aqueous layer was extracted with dichloromethane (3 x 30 ml). The combined organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford 1 .6 g (95percent yield) of (5- Chloropyridin-2-yl) methanol as colourless liquid.1H NMR (400 MHz, CDCI3): δ ppm 3.29 (br s, 1 H), 4.75 (br s, 2H), 7.25 (1 H, merged with CDCI3), 7.67 (d, J = 7.0 Hz, 1 H), 8.52 (s, 1 H).LC-MS: m/z 144.0 (M+H)+.
5-chloro-2(chloromethyl)pyridine; [00372] To a 0 C solution of 5-chloropicolinic acid (3.00 g, 19.0 mmol) indichloromethane (20 mL) was added sulfurous dichloride (2.78 mL, 38.1 mmol), after which the reaction was warmed to room temperature and stirred at that temperature for 4 hours. The reaction was then concentrated to dryness, then reconstituted in dichloromethane (5 mL). Methanol (10 mL) was added to the reaction mixture, and the reaction was allowed to stir at room temperature for 12 hours, after which it was then diluted with water, extracted with ethyl acetate (3 x 50 mL), washed with water, then washed with saturated sodium bicarbonate solution, dried (magnesium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography (ISCO 80g) using 0 to 80% ethyl acetate in hexanes to afford methyl 5-chloropicolinate was as an off-white solid (2.75 g, 15.2 mmol, 80% yield ).[00373] To a 0 C solution of methyl 5-chloropicolinate (2.70 g, 15.7 mmol) in methanol (50 mL) was added sodium borohydride (1.79 g, 47.2 mmol), after which the reaction was warmed to room temperature and stirred at that temperature for 4 hours. The reaction mixture was then concentrated to a residue which was treated with 1M hydrochloric acid solution (15 mL), extracted with ethyl acetate (3 x 100 mL), washed with water, then washed with saturated sodium bicarbonate solution, dried (magnesium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography (ISCO 80g) using 0 to 60% ethyl acetate in hexanes to afford (5-chloropyridin-2-yl)methanol was as an off-white solid (2.15 g, 14.9 mmol, 95% yield).[00374] To a 0 C solution of (5-chloropyridin-2-yl)methanol (2.10 g, 14.6 mmol) in dichloromethane (10 mL) was added sulfurous dichloride (1.60 mL, 21.9 mmol) followed by N,N-dimethylformamide (50 mu), after which the reaction was warmed to room temperature and stirred at that temperature for 4 hours. The reaction mixture was then concentrated to a residue which was reconstituted in water (15 mL), ethyl acetate (15 mL), and saturated sodium bicarbonate solution (15 mL). The organic layers were separated and washed with saturated sodium chloride solution, dried (magnesium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography (ISCO 40g) using 0 to 50% ethyl acetate in hexanes to afford 5-chloro-2(chloromethyl)pyridine as an light brown oil (2.11 g, 13.0 mmol, 89% yield).
In methanol; palladium-dichloro-bis(triphenylphosphine); triethylamine;
Example 15 The carbonylation of 5.0 g (33.8 mmol) of 2,5-dichloropyridine in 50 ml of methanol/triethylamine 1:1 in the presence of 0.47 g of palladium dichloro-bis(triphenylphosphine) at 110 is carried out in a manner analogous to Example 1. Working-up of the crude product as in Example 1 yields 2.86 g (49%) of crude methyl 5-chloropyridine-2-carboxylate which, by crystallization from hexane, yields pure methyl 5-chloropyridine-2-carboxylate in the form of white crystals, m.p. 83-86.
A. Preparation of methyl 5-chloropicolinate A mixture of 5-chloropicolinonitrile (4 g, 28.87 mmol), concentrated aq. HCl (10 mL) and concentrated H2SO4 (5 mL) in methanol (30 mL) was stirred at reflux for 35 h under argon. The reaction mixture was concentrated and then carefully diluted with water (50 mL). The pH was adjusted to 6-7 with 20% aqueous NaOH solution. The product was extracted with EtOAc (3*20 mL). The combined organic phase was washed with brine, dried (MgSO4), filtered and concentrated under vacuum to obtain 4.9 g of the title compound as a white solid. HPLC/MS: retention time=1.977 min, [M+H]+=172.
Preparation of Reagent 5-chloro-2-(chloromethyl)pyridine; A. Preparation of methyl 5-chloropicolinate; A mixture of 5-chloropicolinonitrile (4 g, 28.87 mmol), concentrated aq. HCl (10 mL) and concentrated H2SO4 (5 mL) in methanol (30 mL) was stirred at reflux for 35 h under argon. The reaction mixture was concentrated and then carefully diluted with water (50 mL). The pH was adjusted to 6-7 with 20% aqueous NaOH solution. The product was extracted with EtOAc (3×20 mL). The combined organic phase was washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated under vacuum to obtain 4.9 g of the title compound as a white solid. HPLC/MS: retention time=1.977 min, [M+H]30 =172.
Diflouroethanol (2.38g, 29.1mmol) was added to a solution of potassium tert-butoxide (3.26g, 29.1mmol) in THF at 0 0C. The reaction mixture was stirred for 15 minutes and then methyl-5-chloropyridine-2-carboxylate (5.Og, 29.1mmol) was added and the reaction mixture stirred at ambient temperature for 4 hr. The reaction mixture was concentrated, the residue partitioned between water (50 mL) and ethyl acetate (50 mL) and the aqueous layer was extracted by ethyl acetate (2x50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by column chromatography eluting with 30% ethyl acetate in hexane to yield 3.9 g (62%) of the intermediate ester.
With triethylamine;palladium diacetate; 1,1'-bis(diphenylphosphino)ferrocene; at 50℃; under 775.743 Torr; for 24h;
To a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 mL) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 mL, 312 mmol). The resulting mixture was stirred at 500C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 mL) and water (300 mL). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, by using 10:1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93%): 1H NMR (400 MHz, CDCI3) delta ppm 8.60 (d, J = 1.60 Hz, 1 H), 8.01 (d, J = 8.40 Hz, 1 H), 7.75 (dd, J = 8.40, 2.40 Hz, 1 H), 3.92 (s, 3 H).
93%
With triethylamine;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; at 50℃; under 775.743 Torr; for 24h;
Intermediate 1 : methyl delta-chloro^-pyridinecarboxylate To a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 ml.) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 ml_, 312 mmol). The resulting mixture was stirred at 500C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 ml.) and water (300 ml_). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, by using 10:1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93%): 1H NMR (400 MHz, CDCI3) delta ppm 8.60 (d, J = 1.60 Hz, 1 H), 8.01 (d, J = 8.40 Hz, 1 H), 7.75 (dd, J = 8.40, 2.40 Hz, 1 H), 3.92 (s, 3H).
93%
With triethylamine;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; at 50℃; under 775.743 Torr; for 24h;
Intermediate 1 : methyl delta-chloro^-pyridinecarboxylate To a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 ml.) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 ml_, 312 mmol). The resulting mixture was stirred at 500C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 ml.) and water (300 ml_). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, by using 10:1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93%): 1H NMR (400 MHz, CDCI3) delta ppm 8.60 (d, J = 1.60 Hz, 1 H), 8.01 (d, J = 8.40 Hz, 1 H), 7.75 (dd, J = 8.40, 2.40 Hz, 1 H), 3.92 (s, 3H).
93%
With triethylamine;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; at 50℃; under 775.743 Torr; for 24h;
Intermediate 1 : methyl delta-chloro^-pyridinecarboxylate To a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 ml.) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 ml_, 312 mmol). The resulting mixture was stirred at 500C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 ml.) and water (300 ml_). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, by using 10:1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93%): 1H NMR (400 MHz, CDCI3) delta ppm 8.60 (d, J = 1.60 Hz, 1 H), 8.01 (d, J = 8.40 Hz, 1 H), 7.75 (dd, J = 8.40, 2.40 Hz, 1 H), 3.92 (s, 3H).
93%
With triethylamine;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; at 50℃; under 775.743 Torr; for 24h;
Intermediate 1 : methyl delta-chloro^-pyridinecarboxylateTo a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 ml.) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 ml_, 312 mmol). The resulting mixture was stirred at 500C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 ml.) and water (300 ml_). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, by using 10:1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93%): 1H NMR (400 MHz, CDCI3) delta ppm 8.60 (d, J = 1.60 Hz, 1 H), 8.01 (d, J = 8.40 Hz, 1 H), 7.75 (dd, J = 8.40, 2.40 Hz, 1 H), 3.92 (s, 3H).
93%
With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; triethylamine; at 50℃; under 775.743 Torr; for 24h;
I. methyl 5-chloro-2-pyridinecarboxylate To a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 mL) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 mL, 312 mmol). The resulting mixture was stirred at 50C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 mL) and water (300 mL). The combined organic layers were dried (Na2SC>4) and evaporated. Flash chromatography of the residue over silica gel, by using 10: 1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93% yield): 1H NMR (400 MHz, CDC13) delta ppm 8.60 (d, J = 1.60 Hz, 1H), 8.01 (d, J= 8.40 Etazeta,IotaEta), 7.75 (dd, J = 8.40, 2.40 Hz, 1H), 3.92 (s, 3H).
With potassium carbonate; In N,N-dimethyl-formamide; at 105℃; for 20h;
A mixture of S-chloro-pyridine^-carboxylic acid methyl ester (1.37 g), 3-trifluoromethyl- lH-pyrazole (1.63 g) and powdered K2CO3 (1.67 g) in DMF (20 ml) was heated to 1050C for 20 h. The mixture was evaporated and the residue partitioned between water and dichloromethane, the organic layer was washed with water, dried and evaporated. The residue was chromatographed on silica using n-heptane/ethyl acetate (gradient from 3:1 to 1 :1) to give 5-(3- trifluoromethyl-pyrazol-l-yl)-pyridine-2-carboxylic acid methyl ester (70 mg) as a colorless solid. MS (ESI): m/z = 272.1 [M+H]+.
4-[(5-chloropyridin-2-yl)methoxy]-1-{6-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylmethyl]-3,4-dihydronaphthalen-2-yl}pyridin-2(1H)-one tris(trifluoroacetate)[ No CAS ]
1-{2-[{(1S,4S)-2-[(tert-butyl)oxy]carbonyl}-2,5-diazabicyclo[2.2.1]heptan-5-yl}methyl]-7,8-dihydronaphthalen-6-yl}-4-[(5-chloro-2-pyridinyl)methyl]oxy}-2(1H)-pyridinone[ No CAS ]
1-{2-[{(3S)-[{(4-[(tert-butyl)oxy]carbonyl}morpholin-3-yl)methyl}amino]methyl]-7,8-dihydronaphthalen-6-yl}-4-[(5-chloro-2-pyridinyl)methyl]oxy}-2(1H)-pyridinone[ No CAS ]
4-[(5-chloropyridin-2-yl)methoxy]-1-[6-({methyl[(3S)-morpholin-3-ylmethyl]amino}methyl)-3,4-dihydronaphthalen-2-yl]pyridin-2(1H)-one tris(trifluoroacetate)[ No CAS ]
1-{2-[{(3S,4S)-3-hydroxy-4-[methyl[(benzyl)oxy]carbonyl]amino}pyrrolidin-1-yl}methyl]-7,8-dihydronaphthalen-6-yl}-4-[(5-chloro-2-pyridinyl)methyl]oxy}-2(1H)-pyridinone[ No CAS ]
1-{2-[{(35,45)-3-hydroxy-4-{methylamino}pyrrolidin-1-yl}methyl]-7,8-dihydronaphthalen-6-yl}-4-[(5-chloro-2-pyridinyl)methyl]oxy}-2(1H)-pyridinone[ No CAS ]
4-[(5-chloropyridin-2-yl)methoxy]-1-(6-[(3S,4S)-3-(dimethylamino)-4-hydroxypyrrolidin-1-yl]methyl}-3,4-dihydronaphthalen-2-yl)pyridin-2(1H)-one[ No CAS ]
2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)-phenol[ No CAS ]
methyl 5-{2-methoxy-5-[methyl(2-methylquinazolin-4-yl)amino]phenoxy}pyridine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; dimethylaminoacetic acid; caesium carbonate; In 1,4-dioxane; at 80℃; for 24h;Inert atmosphere;
To the reaction flask was added 1 mmol of compound F40,N, N-dimethylglycine,Copper iodide,Cs2CO3,Dioxane and 2 mmol of methyl p-bromobenzoate,Nitrogen under the protection of heating to 80 C reaction 24h,After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1: Light yellow oily liquid target products.
With copper(l) iodide; dimethylaminoacetic acid; caesium carbonate; In 1,4-dioxane; at 80℃; for 24h;Inert atmosphere;
1 mmol of the compound F40, N,N-dimethylglycine, cuprous iodide, Cs2CO3, 1,4-dioxane and 2 mmol <strong>[132308-19-1]methyl 5-chloropyridine-2-carboxylate</strong> were added into a reaction flask successively, and then heated to 80 C. under nitrogen atmosphere and allowed for reaction for 24 hours. Water was added after the reaction was complete, followed by extraction with ethyl acetate. The organic phases were combined and then dried over anhydrous sodium sulfate, followed by concentration under elevated pressure and then purification by silica gel column (the eluant was petroleum ether: ethyl acetate=1:1) to give a pale yellow oily liquid target product.
3-(methyl(2-methylquinazolin-4-yl)amino)phenol[ No CAS ]
Methyl 5-(3-(methyl(2-methyl-4-quinazolinyl)amino) phenoxy) pyridinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; dimethylaminoacetic acid; caesium carbonate; In 1,4-dioxane; at 80℃; for 24h;Inert atmosphere;
To the reaction flask were added 1 mmol of compound F55, N, N-dimethylglycine, cuprous iodide, Cs2CO3, 1, 4-Dioxane and 2 mmol of <strong>[132308-19-1]5-chloropyridine-2-carboxylic acid methyl ester</strong>, heating under nitrogen to 80 C for 24 h,Water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a silica gel column(Eluent: petroleum ether: ethyl acetate = 1: 1) to give the title product as a pale yellow oily liquid.
With copper(l) iodide; dimethylaminoacetic acid; caesium carbonate; In 1,4-dioxane; at 80℃; for 24h;Inert atmosphere;
1 mmol of the compound F55, N,N-dimethylglycine, cuprous iodide, Cs2CO3, 1,4-dioxane and 2 mmol <strong>[132308-19-1]methyl 5-chloropyridine-2-carboxylate</strong> were added into a reaction flask successively, and then heated to 80 C. under nitrogen atmosphere and allowed for reaction for 24 hours. Water was added after the reaction was complete, followed by extraction with ethyl acetate. The organic phases were combined and then dried over anhydrous sodium sulfate, followed by concentration under elevated pressure and then purification by silica gel column (the eluant was petroleum ether:ethyl acetate=1:1) to give a pale yellow oily liquid target product.
N-(4-hydroxyphenyl)-N,2-dimethylquinazolin-4-amine[ No CAS ]
[ 132308-19-1 ]
methyl 5-{4-[methyl(2-methylquinazolin-4-yl)amino]phenoxy}pyridine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; dimethylaminoacetic acid; caesium carbonate; In 1,4-dioxane; at 80℃; for 24h;Inert atmosphere;
To the reaction flask was added 1 mmol of compound F5,N, N-dimethylglycine,Copper iodide,Cs2CO3,1,4-dioxane and2 mmol of <strong>[132308-19-1]methyl 5-chloropyridine-2-carboxylate</strong>,Nitrogen under the protection of heating to 80 C reaction 24h,After the reaction was complete,Extracted with ethyl acetate,The organic phases were combined and dried over anhydrous sodium sulfate; after concentration under pressure,And then purified on a silica gel column (eluent petroleum ether: ethyl acetate = 1: 1)To give the object product as a pale yellow oily liquid.
With copper(l) iodide; dimethylaminoacetic acid; caesium carbonate; In 1,4-dioxane; at 80℃; for 24h;Inert atmosphere;
1 mmol of the compound F5, N,N-dimethylglycine, cuprous iodide, Cs2CO3, 1,4-dioxane and 2 mmol <strong>[132308-19-1]methyl 5-chloropyridine-2-carboxylate</strong> were added into a reaction flask successively and then heated to 80 C. under nitrogen atmosphere and allowed for reaction for 24 hours. Water was added after the reaction was complete, followed by extraction with ethyl acetate. The organic phases were combined and then dried over anhydrous sodium sulfate, followed by concentration under elevated pressure and then purification by silica gel column (the eluant was petroleum ether: ethyl acetate=1:1) to give a pale yellow oily liquid target product.
methyl 5-(4-(methyl(4-quinazolinyl)amino)phenoxy) pyridinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;Inert atmosphere;
To the reaction flask was added 1 mmol of compound F18,2 mmol Cs2CO3,1 ml of DMF and 2 mmol of <strong>[132308-19-1]methyl 5-chloropyridine-2-carboxylate</strong>,Nitrogen heated to 80 C environment reaction 2h,After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1: Light yellow oily liquid target products.
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;Inert atmosphere;
1 mmol of the compound F18, 2 mmol Cs2CO3, 1 ml DMF and 2 mmol <strong>[132308-19-1]methyl 5-chloropyridine-2-carboxylate</strong> were added into a reaction flask successively, and then heated to 80 C. under nitrogen atmosphere and allowed for reaction for 2 hours. Water was added after the reaction was complete, followed by extraction with ethyl acetate. The organic phases were combined and then dried over anhydrous sodium sulfate, followed by concentration under elevated pressure and then purification by silica gel column (the eluant was petroleum ether:ethyl acetate=1:1) to give a pale yellow oily liquid target product.
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃;
Step 1: K2CO3 (13.8 g, 0.1 mol) was added into a solution of compound 252-1 (8.6 g, 50 mmol) and 252-2 (5 g, 50 mmol) in DMF (50 mL), then the mixture was stirred at 120C overnight. The mixture was cooled and poured into H2O. The precipitate was collected after filtration, washed with H2O and methanol to deliver 6-(3-oxopiperazin-1-yl)nicotinic acid methyl ester (8.5 g, yield 72.6%) as yellow solid. MS ESI calcd for C11H13N3O3 [M+H]+ 236, found 236.
With potassium carbonate; In N,N-dimethyl-formamide; at 26℃; for 12h;
To a solution of 5-chloropicolinic acid (1 g, 6.34 mmol, commercial source: Combi-Bloc s) in Lambda/,/V-dimethylformamide (10 mL), potassium carbonate (1.75 g, 12.6 mmol) was added followed by methyl iodide (0.8 mL, 12.6 mmol) at 26 C. The reaction mixture was stirred for 12 h at the same temperature. On completion, the reaction mixture was quenched with ice cold water (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with water (2x100 mL) and brine solution (100 mL). The organic layer was dried over anhydrous Na2S04, filtered and the filtrate was concentrated under reduced pressure to afford methyl 5-chloropicolinate (1 .2 g) as a brown liquid.1H NMR (400 MHz, DMSO-de) delta 8.77 (dd, J = 2.4, 0.7 Hz, 1 H), 8.14 (dd, J = 8.4, 2.4 Hz, 1 H), 8.07 (dd, J = 8.4, 0.7 Hz, 1 H), 3.89 (s, 3H). MS m/z [M+H]+= 172.25. The compound was used for next step without any further purification.