叔-丁基4-碘哌啶-1-羧酸盐

反应条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Zinc powder (10.50 g, 160.60 mmol) was added to 2M hydrochloric acid (25 mL) and the resulting suspension was stirred for 20 minutes. It was then filtered and washed with water (10 mL), ethanol (10 mL), diethyl ether (10 mL) and dried in a vacuum oven for 24 hours. The dried zinc was suspended in N,N-dimethylformamide (50 mL) and 1,2-dibromoethane (277 μL, 3.21 mmol) was added. The resulting suspension was warmed to 65° C. for 5 minutes and then allowed to cool to room temperature, after which time trimethylsilyl chloride (406 μL, 3.2 mmol) was added. The reaction was stirred at room temperature for 45 minutes and then a solution of tert-butyl 4-iodopiperidine-1-carboxylate (Synlett, 4, 379, 1998) (10 g, 32.1 mmol) and hydroquinone (177 mg, 0.05 mmol) in N,N-dimethylformamide (50 mL) was slowly added, followed by warming to 150° C. for 30 minutes. 2-bromopyridine (3.06 mL, 32.10 mmol) in N,N-dimethylformamide (20 mL) was then added, followed by 5 mol % of Pd2(dba)3 (1.44 g, 1.57 mmol), 10 mol % P-(2-furyl)3 (747 mg, 3.22 mmol) and the reaction was heated at 65° C. for 24 hours. The reaction mixture was filtered through Celite® and diluted with water (500 mL). It was then extracted with diethyl ether (2×250 ml). The organic layers were combined and washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the crude residue. Purification by column chromatography on silica gel using diethyl ether:pentane (50:50-100:0) as eluent afforded the product as a yellow oil, 1.9 g (23%). It was then filtered washed with water (10 mL), ethanol (10 mL), diethyl ether (10 mL) dried in a vacuum oven for 24 hours to cool to room temperature The reaction was stirred at room temperature for 45 minutes by warming to 150° C. for 30 minutes the reaction was heated at 65° C. for 24 hours The reaction mixture was filtered through Celite® diluted with water (500 mL) It was then extracted with diethyl ether (2×250 ml) washed with brine dried over magnesium sulfate concentrated in vacuo to give the crude residue Purification by column chromatography on silica gel

反应条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Zinc powder (10.50 g, 160.60 mmol) was added to 2M hydrochloric acid (25 mL) and the resulting suspension was stirred for 20 minutes. It was then filtered and washed with water (10 mL), ethanol (10 mL), diethyl ether (10 mL) and dried in a vacuum oven for 24 hours. The dried zinc was suspended in N,N-dimethylformamide (50 mL) and 1,2-dibromoethane (277 μL, 3.21 mmol) was added. The resulting suspension was warmed to 65° C. for 5 minutes and then allowed to cool to room temperature, after which time trimethylsilyl chloride (406 μL, 3.2 mmol) was added. The reaction was stirred at room temperature for 45 minutes and then a solution of tert-butyl 4-iodopiperidine-1-carboxylate (Synlett, 4, 379, 1998) (10 g, 32.1 mmol) and hydroquinone (177 mg, 0.05 mmol) in N,N-dimethylformamide (50 mL) was slowly added, followed by warming to 150° C. for 30 minutes. 2-bromopyridine (3.06 mL, 32.10 mmol) in N,N-dimethylformamide (20 mL) was then added, followed by 5 mol % of Pd2(dba)3 (1.44 g, 1.57 mmol), 10 mol % P-(2-furyl)3 (747 mg, 3.22 mmol) and the reaction was heated at 65° C. for 24 hours. The reaction mixture was filtered through Celite® and diluted with water (500 mL). It was then extracted with diethyl ether (2×250 ml). The organic layers were combined and washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the crude residue. Purification by column chromatography on silica gel using diethyl ether:pentane (50:50-100:0) as eluent afforded the product as a yellow oil, 1.9 g (23%). It was then filtered washed with water (10 mL), ethanol (10 mL), diethyl ether (10 mL) dried in a vacuum oven for 24 hours to cool to room temperature The reaction was stirred at room temperature for 45 minutes by warming to 150° C. for 30 minutes the reaction was heated at 65° C. for 24 hours The reaction mixture was filtered through Celite® diluted with water (500 mL) It was then extracted with diethyl ether (2×250 ml) washed with brine dried over magnesium sulfate concentrated in vacuo to give the crude residue Purification by column chromatography on silica gel

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of trimethylchlorosilane and 1,2-dibromoethane (7:5 v/v, 0.125 ml) was added dropwise (keeping the T° C. below 50° C.) to a suspension of zinc powder (422 mg) in dimethylacetamide (3 ml). The mixture was stirred 20 min at room temperature then a solution of 1-(t-butoxycarbonyl)-4-iodo-piperidine (1.62 g, prepared in 2 steps from 1-(t-butoxycarbonyl)-piperidin-4-one according to J. Org. Chem. 2004, 5120) in dimethylacetamide (3 ml) was added dropwise over 5 min (slightly exothermic). The resulting mixture was stirred at room temperature for 30 min then cannulated into a mixture of 2,5-dichloro-3-aminopyridine (603 mg), copper(I) iodide (42 mg) and PdCl2(dppf) (91 mg) in dimethylacetamide (5 ml). The resulting mixture was stirred at 80° C. for 3 hours, cooled to room temperature, poured into water, extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (ethyl acetate:cyclohexane 3:7) to afford 3-amino-5-chloro-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (535 mg) as a yellow solid. 1H NMR (400 MHz, CDCl3) 1.4 (s, 9H), 1.8 (m, 4H), 2.6 (m, 1H), 2.8 (m, 2H), 3.7 (br s, 2H), 4.2 (m, 2H), 6.9 (s, 1H), 7.9 (s, 1H). was added dropwise ( The resulting mixture was stirred at room temperature for 30 min The resulting mixture was stirred at 80° C. for 3 hours cooled to room temperature extracted with ethyl acetate dried over sodium sulfate concentrated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of trimethylchlorosilane and 1,2-dibromoethane (7:5 v/v, 0.125 ml) was added dropwise (keeping the T° C. below 50° C.) to a suspension of zinc powder (422 mg) in dimethylacetamide (3 ml). The mixture was stirred 20 min at room temperature then a solution of 1-(t-butoxycarbonyl)-4-iodo-piperidine (1.62 g, prepared in 2 steps from 1-(t-butoxycarbonyl)-piperidin-4-one according to J. Org. Chem. 2004, 5120) in dimethylacetamide (3 ml) was added dropwise over 5 min (slightly exothermic). The resulting mixture was stirred at room temperature for 30 min then cannulated into a mixture of 2,5-dichloro-3-aminopyridine (603 mg), copper(I) iodide (42 mg) and PdCl2(dppf) (91 mg) in dimethylacetamide (5 ml). The resulting mixture was stirred at 80° C. for 3 hours, cooled to room temperature, poured into water, extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (ethyl acetate:cyclohexane 3:7) to afford 3-amino-5-chloro-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (535 mg) as a yellow solid. 1H NMR (400 MHz, CDCl3) 1.4 (s, 9H), 1.8 (m, 4H), 2.6 (m, 1H), 2.8 (m, 2H), 3.7 (br s, 2H), 4.2 (m, 2H), 6.9 (s, 1H), 7.9 (s, 1H). was added dropwise ( The resulting mixture was stirred at room temperature for 30 min The resulting mixture was stirred at 80° C. for 3 hours cooled to room temperature extracted with ethyl acetate dried over sodium sulfate concentrated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Under a nitrogen atmosphere, zinc dust (4.06 g, 62.1 mmol) was suspended in N,N-dimethylacetamide (5 mL) and a mixture of trimethylsilylchloride (0.946 mL, 7.30 mmol) and 1,2-dibromoethane (0.636 mL, 7.30 mmol) was added cautiously over 10 min. After stirring for a further 15 min, a solution of N-(tert-butoxycarbonyl)-4-iodopiperidine (16.74 g, 51.11 mmol) in N,N-dimethylacetamide (20 mL) was added over 30 min and stirring was continued for an additional 30 min. In the open atmosphere, this mixture was filtered through Celite as quickly as possible, rinsing with a small amount of N,N-dimethylacetamide. The resulting yellow solution was injected into a separately prepared, nitrogen flushed suspension of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.35 g, 1.83 mmol), copper(I) iodide (695 mg, 3.65 mmol) and 2,6-dichloro-4-iodopyridine (10.0 g, 36.5 mmol) in N,N-dimethylacetamide (30 mL) and this mixture was stirred at 80° C. for 16.5 hr. After cooling to rt, the mixture was diluted with EtOAc and water and partitioned. Filtration through Celite was necessary to break the emulsion, following which, the organics were washed with water and then dried over MgSO4. After being freed of volatiles, the resultant residue was purified by flash column chromatography (100:0-70:30 heptanes/EtOAc) to afford tert-butyl 4-(2,6-dichloro-4-pyridyl)piperidine-1-carboxylate as a white solid (7.49 g, 62%); 1H NMR (400 MHz, CDCl3) δ 7.11 (s, 2H), 4.19 (m, 2H), 2.78 (m, 2H), 2.71 (m, 1H), 1.81 (m, 2H), 1.65 (m, 2H), 1.48 (s, 9H). was added cautiously over 10 min stirring was continued for an additional 30 min In the open atmosphere, this mixture was filtered through Celite as quickly as possible, rinsing with a small amount of N,N-dimethylacetamide a separately prepared nitrogen flushed this mixture was stirred at 80° C. for 16.5 hr partitioned Filtration through Celite the organics were washed with water dried over MgSO4 the resultant residue was purified by flash column chromatography (100:0-70:30 heptanes/EtOAc)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Under a nitrogen atmosphere, zinc dust (4.06 g, 62.1 mmol) was suspended in N,N-dimethylacetamide (5 mL) and a mixture of trimethylsilylchloride (0.946 mL, 7.30 mmol) and 1,2-dibromoethane (0.636 mL, 7.30 mmol) was added cautiously over 10 min. After stirring for a further 15 min, a solution of N-(tert-butoxycarbonyl)-4-iodopiperidine (16.74 g, 51.11 mmol) in N,N-dimethylacetamide (20 mL) was added over 30 min and stirring was continued for an additional 30 min. In the open atmosphere, this mixture was filtered through Celite as quickly as possible, rinsing with a small amount of N,N-dimethylacetamide. The resulting yellow solution was injected into a separately prepared, nitrogen flushed suspension of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.35 g, 1.83 mmol), copper(I) iodide (695 mg, 3.65 mmol) and 2,6-dichloro-4-iodopyridine (10.0 g, 36.5 mmol) in N,N-dimethylacetamide (30 mL) and this mixture was stirred at 80° C. for 16.5 hr. After cooling to rt, the mixture was diluted with EtOAc and water and partitioned. Filtration through Celite was necessary to break the emulsion, following which, the organics were washed with water and then dried over MgSO4. After being freed of volatiles, the resultant residue was purified by flash column chromatography (100:0-70:30 heptanes/EtOAc) to afford tert-butyl 4-(2,6-dichloro-4-pyridyl)piperidine-1-carboxylate as a white solid (7.49 g, 62%); 1H NMR (400 MHz, CDCl3) δ 7.11 (s, 2H), 4.19 (m, 2H), 2.78 (m, 2H), 2.71 (m, 1H), 1.81 (m, 2H), 1.65 (m, 2H), 1.48 (s, 9H). was added cautiously over 10 min stirring was continued for an additional 30 min In the open atmosphere, this mixture was filtered through Celite as quickly as possible, rinsing with a small amount of N,N-dimethylacetamide a separately prepared nitrogen flushed this mixture was stirred at 80° C. for 16.5 hr partitioned Filtration through Celite the organics were washed with water dried over MgSO4 the resultant residue was purified by flash column chromatography (100:0-70:30 heptanes/EtOAc)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of trimethylchlorosilane and 1,2-dibromoethane (7:5 v/v, 0.125 ml) was added dropwise (keeping the T° C. below 50° C.) to a suspension of zinc powder (422 mg) in dimethylacetamide (3 ml). The mixture was stirred 20 min at room temperature then a solution of 1-(t-butoxycarbonyl)-4-iodo-piperidine (1.62 g, prepared in 2 steps from 1-(t-butoxycarbonyl)-piperidin-4-one according to J. Org. Chem. 2004, 5120) in dimethylacetamide (3 ml) was added dropwise over 5 min (slightly exothermic). The resulting mixture was stirred at room temperature for 30 min then cannulated into a mixture of 2,5-dichloro-3-aminopyridine (603 mg), copper(I) iodide (42 mg) and PdCl2(dppf) (91 mg) in dimethylacetamide (5 ml). The resulting mixture was stirred at 80° C. for 3 hours, cooled to room temperature, poured into water, extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (ethyl acetate:cyclohexane 3:7) to afford 3-amino-5-chloro-3′,6′-dihydro-2′H-[2,4]bipyridinyl-1′-carboxylic acid tert-butyl ester (535 mg) as a yellow solid. 1H NMR (400 MHz, CDCl3) 1.4 (s, 9H), 1.8 (m, 4H), 2.6 (m, 1H), 2.8 (m, 2H), 3.7 (br s, 2H), 4.2 (m, 2H), 6.9 (s, 1H), 7.9 (s, 1H). was added dropwise ( The resulting mixture was stirred at room temperature for 30 min The resulting mixture was stirred at 80° C. for 3 hours cooled to room temperature extracted with ethyl acetate dried over sodium sulfate concentrated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of trimethylchlorosilane and 1,2-dibromoethane (7:5 v/v, 0.125 ml) was added dropwise (keeping the T° C. below 50° C.) to a suspension of zinc powder (422 mg) in dimethylacetamide (3 ml). The mixture was stirred 20 min at room temperature then a solution of 1-(t-butoxycarbonyl)-4-iodo-piperidine (1.62 g, prepared in 2 steps from 1-(t-butoxycarbonyl)-piperidin-4-one according to J. Org. Chem. 2004, 5120) in dimethylacetamide (3 ml) was added dropwise over 5 min (slightly exothermic). The resulting mixture was stirred at room temperature for 30 min then cannulated into a mixture of 2,5-dichloro-3-aminopyridine (603 mg), copper(I) iodide (42 mg) and PdCl2(dppf) (91 mg) in dimethylacetamide (5 ml). The resulting mixture was stirred at 80° C. for 3 hours, cooled to room temperature, poured into water, extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (ethyl acetate:cyclohexane 3:7) to afford 3-amino-5-chloro-3′,6′-dihydro-2′H-[2,4]bipyridinyl-1′-carboxylic acid tert-butyl ester (535 mg) as a yellow solid. 1H NMR (400 MHz, CDCl3) 1.4 (s, 9H), 1.8 (m, 4H), 2.6 (m, 1H), 2.8 (m, 2H), 3.7 (br s, 2H), 4.2 (m, 2H), 6.9 (s, 1H), 7.9 (s, 1H). was added dropwise ( The resulting mixture was stirred at room temperature for 30 min The resulting mixture was stirred at 80° C. for 3 hours cooled to room temperature extracted with ethyl acetate dried over sodium sulfate concentrated in vacuo

反应条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 0.16 ml of 1,2-dibromoethane is added at ambient temperature, under argon, to a suspension of 1.35 g of powdered zinc in 10 ml of tetrahydrofuran. The mixture is heated for 5 minutes at 65° C., then brought to ambient temperature, and 0.23 ml of trimethylsilyl is then added. After stirring the mixture for 30 minutes, a solution of 4.5 g of the compound obtained in Step 2 in 8 ml of tetrahydrofuran is slowly added, and then after 45 minutes a solution, prepared ex situ 10 minutes beforehand, of 0.2 g of Pd2(dba)3 and 0.2 g of P(2-furyl)3 in 5 ml of tetrahydrofuran is added by cannulation under argon and, finally, 5.5 g of 1-benzyl-4-bromo-1H-pyrrolo[3,2-c]pyridine in 30 ml of a 1/1 tetrahydrofuran/dimethylamine mixture are added. The reaction mixture is heated at 65° C. for 16 hours and then, after return to ambient temperature, filtered and concentrated in vacuo. Chromatography on silica gel (cyclohexane/ethyl acetate: 50150) enables the expected product to be isolated. brought to ambient temperature 0.23 ml of trimethylsilyl is then added after 45 minutes a solution prepared ex situ 10 minutes is added by cannulation under argon The reaction mixture is heated at 65° C. for 16 hours after return to ambient temperature, filtered concentrated in vacuo to be isolated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 86 g of iodine are added at ambient temperature to a suspension of 89 g of triphenylphosphine and 22 g of imidazole in 800 ml of acetonitrile. The reaction is exothermic. After return to ambient temperature, 45.9 g of the product obtained in Step 1 in 250 ml of acetonitrile are added in the course of 30 minutes. After 18 hours' stirring at ambient temperature, the reaction mixture is filtered and rinsed with 200 ml of acetonitrile and the resulting filtrate is concentrated in vacuo. The residue obtained is stirred in 250 ml of diethyl ether for 1 hour and the precipitate is filtered off. After concentration of the filtrate in vacuo, chromatography on silica gel (dichloromethane/ethyl acetate: 90/10) enables the expected product to be isolated. the reaction mixture is filtered rinsed with 200 ml of acetonitrile the resulting filtrate is concentrated in vacuo The residue obtained the precipitate is filtered off to be isolated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: This compound was synthesized from 6-bromonicotinonitrile and tert-butyl 4-iodopiperidine-1-carboxylate as described for example 49 step 1 (150 mg, yield 27%). 1H NMR (400 MHz, CDCl3) δ 8.82 (d, J=2.0 Hz, 1H), 7.91 (dd, J=8.2 Hz, 2.1 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 4.28 (m, 2H), 2.97-2.81 (m, 3H), 1.91 (m, 2H), 1.78-1.67 (m, 2H), 1.48 (s, 9H). MS (ESI) m/z: Calculated for C16H21N3O2: 287.16. found: 188.2 (M+H-Boc)+

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: This compound was synthesized from 6-bromonicotinonitrile and tert-butyl 4-iodopiperidine-1-carboxylate as described for example 49 step 1 (150 mg, yield 27%). 1H NMR (400 MHz, CDCl3) δ 8.82 (d, J=2.0 Hz, 1H), 7.91 (dd, J=8.2 Hz, 2.1 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 4.28 (m, 2H), 2.97-2.81 (m, 3H), 1.91 (m, 2H), 1.78-1.67 (m, 2H), 1.48 (s, 9H). MS (ESI) m/z: Calculated for C16H21N3O2: 287.16. found: 188.2 (M+H-Boc)+