(S)-N-BOC-2-哌啶甲醇

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

实验步骤: A 4M HCl solution in dioxane (30 mL) was added to (S)-2-Hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (5.12 g, 23.78 mmol). The mixture was stirred at rt for 3 h. The solvent was removed in vacuo to yield the title product as a hydrochloride salt (3.43 g, 95%). The solvent was removed in vacuo

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

实验步骤: A 4M HCl solution in dioxane (30 mL) was added to (S)-2-Hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (5.12 g, 23.78 mmol). The mixture was stirred at rt for 3 h. The solvent was removed in vacuo to yield the title product as a hydrochloride salt (3.43 g, 95%). The solvent was removed in vacuo

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Bromo-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridine (702 mg, 2.32 mmol, from Example 21a), tert-butyl (2S)-2-(hydroxymethyl)piperidine-1-carboxylate (500 mg, 2.32 mmol), Pd(OAc)2 (26 mg, 0.116 mmol), 2-(di-t-butylphosphino)biphenyl (42 mg, 0.139 mmol) and Cs2(CO3) (1.51 g, 4.64 mmol) were mixed in toluene (20 ml). The reaction was stirred under an N2 atmosphere and heated to 100° C. on an oil bath for 24 h. The solvent was evaporated in vacuo and the residue separated between EtOAc (250 ml) and water (250 ml). The organic phase washed with water (250 ml) and the combined aqueous phases were extracted with EtOAc (250 ml). The combined EtOAc phases were dried over Na2SO4 (s), filtered and evaporated in vacuo. Purification by silica gel flash chromatography using a 40+M Biotage column with a gradient of 5-20% EtOAc in heptane yielded the title compound as a colorless oil. Yield: 729 mg (72%). 1H NMR (400 MHz, CDCl3) δ 7.43 (t, 1H, J=7.8 Hz), 6.91 (d, 1H, J=7.3 Hz), 6.44 (d, 1H, J=8.2 Hz), 4.57 (s, 2H), 4.48 (m, 1H), 4.25 (d, 2H, J=7.4 Hz), 3.91 (d, 1H, J=11.6 Hz), 2.76 (dt, 1H, J=13.3 Hz, J=2.0 Hz), 1.69 (d, 1H, J=12.0 Hz), 1.57-1.37 (m, 5H), 1.27 (s, 9H), 0.84 (s, 9H), 0.00 (s, 6H). The solvent was evaporated in vacuo the residue separated between EtOAc (250 ml) and water (250 ml) The organic phase washed with water (250 ml) the combined aqueous phases were extracted with EtOAc (250 ml) The combined EtOAc phases were dried over Na2SO4 (s) filtered evaporated in vacuo Purification by silica gel flash chromatography

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Bromo-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridine (702 mg, 2.32 mmol, from Example 21a), tert-butyl (2S)-2-(hydroxymethyl)piperidine-1-carboxylate (500 mg, 2.32 mmol), Pd(OAc)2 (26 mg, 0.116 mmol), 2-(di-t-butylphosphino)biphenyl (42 mg, 0.139 mmol) and Cs2(CO3) (1.51 g, 4.64 mmol) were mixed in toluene (20 ml). The reaction was stirred under an N2 atmosphere and heated to 100° C. on an oil bath for 24 h. The solvent was evaporated in vacuo and the residue separated between EtOAc (250 ml) and water (250 ml). The organic phase washed with water (250 ml) and the combined aqueous phases were extracted with EtOAc (250 ml). The combined EtOAc phases were dried over Na2SO4 (s), filtered and evaporated in vacuo. Purification by silica gel flash chromatography using a 40+M Biotage column with a gradient of 5-20% EtOAc in heptane yielded the title compound as a colorless oil. Yield: 729 mg (72%). 1H NMR (400 MHz, CDCl3) δ 7.43 (t, 1H, J=7.8 Hz), 6.91 (d, 1H, J=7.3 Hz), 6.44 (d, 1H, J=8.2 Hz), 4.57 (s, 2H), 4.48 (m, 1H), 4.25 (d, 2H, J=7.4 Hz), 3.91 (d, 1H, J=11.6 Hz), 2.76 (dt, 1H, J=13.3 Hz, J=2.0 Hz), 1.69 (d, 1H, J=12.0 Hz), 1.57-1.37 (m, 5H), 1.27 (s, 9H), 0.84 (s, 9H), 0.00 (s, 6H). The solvent was evaporated in vacuo the residue separated between EtOAc (250 ml) and water (250 ml) The organic phase washed with water (250 ml) the combined aqueous phases were extracted with EtOAc (250 ml) The combined EtOAc phases were dried over Na2SO4 (s) filtered evaporated in vacuo Purification by silica gel flash chromatography

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Bromo-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridine (702 mg, 2.32 mmol, from Example 21a), tert-butyl (2S)-2-(hydroxymethyl)piperidine-1-carboxylate (500 mg, 2.32 mmol), Pd(OAc)2 (26 mg, 0.116 mmol), 2-(di-t-butylphosphino)biphenyl (42 mg, 0.139 mmol) and Cs2(CO3) (1.51 g, 4.64 mmol) were mixed in toluene (20 ml). The reaction was stirred under an N2 atmosphere and heated to 100° C. on an oil bath for 24 h. The solvent was evaporated in vacuo and the residue separated between EtOAc (250 ml) and water (250 ml). The organic phase washed with water (250 ml) and the combined aqueous phases were extracted with EtOAc (250 ml). The combined EtOAc phases were dried over Na2SO4 (s), filtered and evaporated in vacuo. Purification by silica gel flash chromatography using a 40+M Biotage column with a gradient of 5-20% EtOAc in heptane yielded the title compound as a colorless oil. Yield: 729 mg (72%). 1H NMR (400 MHz, CDCl3) δ 7.43 (t, 1H, J=7.8 Hz), 6.91 (d, 1H, J=7.3 Hz), 6.44 (d, 1H, J=8.2 Hz), 4.57 (s, 2H), 4.48 (m, 1H), 4.25 (d, 2H, J=7.4 Hz), 3.91 (d, 1H, J=11.6 Hz), 2.76 (dt, 1H, J=13.3 Hz, J=2.0 Hz), 1.69 (d, 1H, J=12.0 Hz), 1.57-1.37 (m, 5H), 1.27 (s, 9H), 0.84 (s, 9H), 0.00 (s, 6H). The solvent was evaporated in vacuo the residue separated between EtOAc (250 ml) and water (250 ml) The organic phase washed with water (250 ml) the combined aqueous phases were extracted with EtOAc (250 ml) The combined EtOAc phases were dried over Na2SO4 (s) filtered evaporated in vacuo Purification by silica gel flash chromatography

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

实验步骤: A 4M HCl solution in dioxane (30 mL) was added to (S)-2-Hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (5.12 g, 23.78 mmol). The mixture was stirred at rt for 3 h. The solvent was removed in vacuo to yield the title product as a hydrochloride salt (3.43 g, 95%). The solvent was removed in vacuo

反应条件: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (S)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5 g, 21.8 mmol) in anhydrous THF (32 mL) at 0-5° C. was added borane-tetrahydrofuran complex (1M solution in THF) (3.6 g, 41.84 mmol) over a period of 15 min. The mixture was stirred at 0-5° C. for 2 h and then at rt for 2 h. The mixture was added over a period of 10 min to cold water (75 mL) and extracted with EtOAc (300 mL). The aqueous layer was re-extracted with EtOAc (2×150 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated to obtain the title product as a colorless oil (4.72 g). at rt for 2 h extracted with EtOAc (300 mL) The aqueous layer was re-extracted with EtOAc (2×150 mL) dried over anhydrous Na2SO4 concentrated

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

实验步骤: A 4M HCl solution in dioxane (30 mL) was added to (S)-2-Hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (5.12 g, 23.78 mmol). The mixture was stirred at rt for 3 h. The solvent was removed in vacuo to yield the title product as a hydrochloride salt (3.43 g, 95%). The solvent was removed in vacuo