tert-butyl 4-bromopiperidine-1-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2.2 g (19.3 mmol) Potassium thioacetate and 2.65 g (10 mmol) 4-Bromo-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 50 ml of DMF and stirred at 100° C. for 4 h. The mixture was taken up in ethyl acetate and washed with brine. The organic phases were dried over Sodium sulfate and evaporated. Purification over silica gel (10% to 20% ethyl acetate in heptane) gave 2.15 g of the expected compound. washed with brine The organic phases were dried over Sodium sulfate evaporated Purification over silica gel (10% to 20% ethyl acetate in heptane)

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 6.9 g (0.02 mol) of 4-bromo-piperidine-1-carboxylic acid tert-butyl ester in DMF (18 mL) are added 5.25 g (0.012 mmol) potassium thioacetate, followed by a catalytic amount of NaI (0.35 g, 10 mol %) at room temperature. After complete addition, the reaction is heated to 50° C. for 20 h. The reaction mixture is partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer is dried over Na2SO4, filtered and the solvent is removed under reduced pressure to afford 5.41 g of 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester as a brown oil. Yield: 81%; ES-MS: m/z 245 [M+H—CH3], 160 [M+H—C5H9O2]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.37-1.64 (11H, m), 1.78-1.99 (2H, m), 2.25-2.35 (3H, m), 3.06 (2H, ddd, J=13.63, 10.43, 3.05 Hz), 3.61 (1H, tt, J=10.28, 4.04 Hz), 3.76-3.96 (2H, m) After complete addition The reaction mixture is partitioned between ethyl acetate (100 mL) and water (100 mL) The organic layer is dried over Na2SO4 filtered the solvent is removed under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 45.3 g (172 mmol) of 4-bromo-1-(tert-butoxycarbonyl)piperidine in 750 mL of DMF was added 22.3 g (343 mmol) of sodium azide and 2.5 g (17 mmol) of sodium iodide. The reaction was stirred at RT for 24 h and then at 60° C. for 4 h. The mixture was poured into water containing 20 mL of sodium bicarbonate and extracted twice with 1:1 ether/hexane. The organic layers were each washed with a portion of water and brine, dried over sodium sulfate, combined and concentrated. The residue was purified by flash column chromatography, eluting with 5-10% ethyl acetate in hexane, to afford 39 g of title compound having a trace of elimination byproduct. 1H NMR (400 MHz, CDCl3): δ 3.78 (m, 2H), 3.55 (m, 1H), 3.07 (m, 2H), 1.85 (m, 2H), 1.52 (m, 2H), 1.43 (s, 9H). at 60° C. for 4 h extracted twice with 1:1 ether/hexane each washed with a portion of water and brine dried over sodium sulfate concentrated The residue was purified by flash column chromatography eluting with 5-10% ethyl acetate in hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 45.3 g (172 mmol) of 4-bromo-1-t-butoxycarbonylpiperidine in 750 mL of DMF was added 22.3 g (343 mmol) of sodium azide and 2.5 g (17 mmol) of sodium iodide. The reaction was stirred at rt for 24 h and then at 60° C. for 4 h. The mixture was poured into water containing 20 mL of sodium bicarbonate and extracted twice with 1:1 ether:hexanes. The organic layers were each washed with a portion of water and brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FCC eluting with 5 -10% ethyl acetate/hexanes to afford 39 g of title compound having a trace of elimination biproduct. 1H NMR (400 MHz, CDCl3): δ 1.43 (s,9H), 1.52 (m, 2H), 1.85 (m, 2H), 3.07 (m, 2H), 3.55 (m, 1H), 3.78 (m, 2H). at 60° C. for 4 h extracted twice with 1:1 ether each washed with a portion of water and brine dried over sodium sulfate concentrated The residue was purified by FCC eluting with 5 -10% ethyl acetate/hexanes

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A pressure tube was charged with 2-(5-difluoromethoxy-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (180 mg, 0.34 mmol), tert-butyl 4-bromopiperidine-1-carboxylate (179 mg, 0.68 mmol), cesium carbonate (332 mg, 1.02 mmol) and DMF (1.5 ml). The tube was flushed with argon, sealed and stirred at 100° C. in an oil bath overnight. The reaction was cooled to room temperature and additional tert-butyl 4-bromopiperidine-1-carboxylate (179 mg, 0.68 mmol) and cesium carbonate (332 mg, 1.02 mmol) were added. The tube was again flushed with argon, sealed and stirred at 100° C. in an oil bath for 6 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 25 g silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc) to afford 197 mg (81%) of 4-{3-[7-tert-butylcarbamoyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-5-difluoromethoxy-indazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester as an off-white solid. The tube was flushed with argon sealed The reaction was cooled to room temperature The tube was again flushed with argon sealed stirred at 100° C. in an oil bath for 6 h The reaction mixture was cooled to room temperature quenched with water extracted with diethyl ether (2×) The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate filtered concentrated The residue was chromatographed over 25 g silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc)

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A pressure tube was charged with 2-(5-difluoromethoxy-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (180 mg, 0.34 mmol), tert-butyl 4-bromopiperidine-1-carboxylate (179 mg, 0.68 mmol), cesium carbonate (332 mg, 1.02 mmol) and DMF (1.5 ml). The tube was flushed with argon, sealed and stirred at 100° C. in an oil bath overnight. The reaction was cooled to room temperature and additional tert-butyl 4-bromopiperidine-1-carboxylate (179 mg, 0.68 mmol) and cesium carbonate (332 mg, 1.02 mmol) were added. The tube was again flushed with argon, sealed and stirred at 100° C. in an oil bath for 6 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 25 g silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc) to afford 197 mg (81%) of 4-{3-[7-tert-butylcarbamoyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-5-difluoromethoxy-indazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester as an off-white solid. The tube was flushed with argon sealed The reaction was cooled to room temperature The tube was again flushed with argon sealed stirred at 100° C. in an oil bath for 6 h The reaction mixture was cooled to room temperature quenched with water extracted with diethyl ether (2×) The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate filtered concentrated The residue was chromatographed over 25 g silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc)

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A microwave vial was charged with 2-(6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (182 mg, 0.44 mmol), tert-butyl 4-bromopiperidine-1-carboxylate (234 mg, 0.89 mmol), cesium carbonate (432 mg, 1.33 mmol) and DMF (2 ml). The vial was flushed with argon, sealed, and heated in a microwave reactor at 100° C. for 2 h. The reaction was quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc to give 108 mg (41%) of 4-{6-fluoro-3-[7-formyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-indazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester as a light brown solid. The vial was flushed with argon sealed The reaction was quenched with water extracted with diethyl ether (2×) The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate filtered concentrated The residue was chromatographed over silica gel with EtOAc/hexanes (gradient

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A microwave vial was charged with 2-(6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (182 mg, 0.44 mmol), tert-butyl 4-bromopiperidine-1-carboxylate (234 mg, 0.89 mmol), cesium carbonate (432 mg, 1.33 mmol) and DMF (2 ml). The vial was flushed with argon, sealed, and heated in a microwave reactor at 100° C. for 2 h. The reaction was quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc to give 108 mg (41%) of 4-{6-fluoro-3-[7-formyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-indazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester as a light brown solid. The vial was flushed with argon sealed The reaction was quenched with water extracted with diethyl ether (2×) The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate filtered concentrated The residue was chromatographed over silica gel with EtOAc/hexanes (gradient

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 45.3 g (172 mmol) of 4-bromo-1-(tert-butoxycarbonyl)piperidine in 750 mL of DMF was added 22.3 g (343 mmol) of sodium azide and 2.5 g (17 mmol) of sodium iodide. The reaction was stirred at RT for 24 h and then at 60° C. for 4 h. The mixture was poured into water containing 20 mL of sodium bicarbonate and extracted twice with 1:1 ether/hexane. The organic layers were each washed with a portion of water and brine, dried over sodium sulfate, combined and concentrated. The residue was purified by flash column chromatography, eluting with 5-10% ethyl acetate in hexane, to afford 39 g of title compound having a trace of elimination byproduct. 1H NMR (400 MHz, CDCl3): δ3.78 (m, 2H), 3.55 (m, 1H), 3.07 (m, 2H), 1.85 (m, 2H), 1.52 (m, 2H), 1.43 (s, 9H). at 60° C. for 4 h extracted twice with 1:1 ether/hexane each washed with a portion of water and brine dried over sodium sulfate concentrated The residue was purified by flash column chromatography eluting with 5-10% ethyl acetate in hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 45.3 g (172 mmol) of 4-bromo-1-t-butoxycarbonylpiperidine in 750 mL of DMF was added 22.3 g (343 mmol) of sodium azide and 2.5 g (17 mmol) of sodium iodide. The reaction was stirred at rt for 24 h and then at 60° C. for 4 h. The mixture was poured into water containing 20 mL of sodium bicarbonate and extracted twice with 1:1 ether:hexanes. The organic layers were each washed with a portion of water and brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC eluting with 5-10% ethyl acetate in hexanes to afford 39 g of title compound having a trace of elimination byproduct. at 60° C. for 4 h extracted twice with 1:1 ether each washed with a portion of water and brine dried over sodium sulfate concentrated The residue was purified by FC eluting with 5-10% ethyl acetate in hexanes

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 45.3 g (172 mmol) of 4-bromo-1-t-butoxycarbonylpiperidine in 750 mL of DMF was added 22.3 g (343 mmol) of sodium azide and 2.5 g (17 mmol) of sodium iodide. The reaction was stirred at rt for 24 h and then at 60° C. for 4 h. The mixture was poured into water containing 20 mL of sodium bicarbonate and extracted twice with 1:1 ether:hexanes. The organic layers were each washed with a portion of water and brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC eluting with 5-10% ethyl acetate in hexanes to afford 39 g of title compound having a trace of elimination byproduct. at 60° C. for 4 h extracted twice with 1:1 ether each washed with a portion of water and brine dried over sodium sulfate concentrated The residue was purified by FC eluting with 5-10% ethyl acetate in hexanes