4-(2-((甲磺酰基)氧基)乙基)哌啶-1-羧酸叔丁酯

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The reaction was prepared in 2 batches, with both batches purified together. The amounts of reactants and product reflect the sum of both batches. To 1,1-dimethylethyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate (172 g, 750 mmol) in DCM (4 L) was added TEA (304 g, 1.50 mol). The mixture was cooled 0° C. and methanesulfonyl chloride (190 g, 827 mmol) was added dropwise. The reaction mixture was stirred at rt for 2 h. The reaction was determined to be complete by TLC. The reaction was diluted with DCM and washed with saturated Na2CO3 and the aqueous layer was separated. The organic layer was dried (Na2SO4), and rotovapped down to provide the title compound of Step B (280 g, 911 mmol, 61%). 1H NMR (400 MHz, CDCl3) δ 0.95-1.15 (m, 2H), 1.38 (s, 9H), 1.47-1.68 (m, 5H), 2.53-2.70 (m, 2H), 2.94 (s, 3H), 3.95-4.10 (m, 2H), 4.21 (t, J=8.8 Hz, 2H). The reaction was prepared in 2 batches, with both batches purified together washed with saturated Na2CO3 the aqueous layer was separated The organic layer was dried (Na2SO4)

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: Methanesulfonyl chloride (4.0 mL, 52 mmol) was added slowly to a 0° C. solution of 1-t-butyloxycarbonyl-4-hydroxyethylpiperidine (10.0 g, 43.7 mmol) and diisopropylethylamine (7.3 mL, 52 mmol) in dichloromethane (100 mL) with stirring under a nitrogen atmosphere. After 24 hours at room temperature, the mixture was extracted with water (4×100 mL), dried (MgSO4), filtered, and concentrated in vacuo to yield a clear oil which crystallized upon standing. Mp:60°-63° C. MSCI:252(MH+, base). 1H NMR(300 MHz, CDCl3 /TMS, δ): 4.3(br t,2H), 4.1(br d,2H), 3.0(S,3H), 2.7(br t,2H), 1.7-1.1(m,16H). the mixture was extracted with water (4×100 mL) dried (MgSO4) filtered concentrated in vacuo to yield a clear oil which crystallized

反应条件: temp:37.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Combine tert-butyl 4-(2-methylsulfonyloxyethyl)piperidine-1-carboxylate (5.26 kg, 17.1 mol), ethyl cyanoacetate (7 kg, 62 mol), 21% sodium ethoxide in EtOH (8.25 L, 24.75 mol) and EtOH (35 L) in a 50 L reactor under a nitrogen atmosphere. Heat the mixture at 35-40° C. for 18 h at which time NMR analysis shows 20% of the mesylate remaining Continue heating the mixture at 35-40° C. for 24 h at which time NMR analysis shows only a small amount of mesylate. Slowly cool the reaction to RT and add glacial acetic acid (1422 mL, 22.68 mol) over 30 min. Concentrate the mixture using vacuum distillation and then partition between water (25 L) and EtOAc (35 L). Separate the layers and extract the aqueous phase with EtOAc (10 L). Combine the organic portions, wash with brine (15 L), and concentrate to a red oil. Purify the oil using silica gel chromatography (75 kg silica gel, 65-250 mesh), eluting with hexane (40 L) and then 20% EtOAc/hexane to provide a fraction (7.8 kg) that is 30% ethyl cyanoacetate/70% desired product. Concentrate the material by wipe film distillation at 100° C. and 210 mtorr vacuum, collecting the non-volatile fraction to provide the title compound (4.54 kg, 82%). heating the mixture at 35-40° C. for 24 h at which time NMR analysis Slowly cool the reaction to RT Concentrate the mixture vacuum distillation partition between water (25 L) and EtOAc (35 L) Separate the layers extract the aqueous phase with EtOAc (10 L) Combine the organic portions, wash with brine (15 L) concentrate to a red oil Purify the oil eluting with hexane (40 L) 20% EtOAc/hexane to provide a fraction (7.8 kg) that

反应条件: temp:37.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Combine tert-butyl 4-(2-methylsulfonyloxyethyl)piperidine-1-carboxylate (5.26 kg, 17.1 mol), ethyl cyanoacetate (7 kg, 62 mol), 21% sodium ethoxide in EtOH (8.25 L, 24.75 mol) and EtOH (35 L) in a 50 L reactor under a nitrogen atmosphere. Heat the mixture at 35-40° C. for 18 h at which time NMR analysis shows 20% of the mesylate remaining Continue heating the mixture at 35-40° C. for 24 h at which time NMR analysis shows only a small amount of mesylate. Slowly cool the reaction to RT and add glacial acetic acid (1422 mL, 22.68 mol) over 30 min. Concentrate the mixture using vacuum distillation and then partition between water (25 L) and EtOAc (35 L). Separate the layers and extract the aqueous phase with EtOAc (10 L). Combine the organic portions, wash with brine (15 L), and concentrate to a red oil. Purify the oil using silica gel chromatography (75 kg silica gel, 65-250 mesh), eluting with hexane (40 L) and then 20% EtOAc/hexane to provide a fraction (7.8 kg) that is 30% ethyl cyanoacetate/70% desired product. Concentrate the material by wipe film distillation at 100° C. and 210 mtorr vacuum, collecting the non-volatile fraction to provide the title compound (4.54 kg, 82%). heating the mixture at 35-40° C. for 24 h at which time NMR analysis Slowly cool the reaction to RT Concentrate the mixture vacuum distillation partition between water (25 L) and EtOAc (35 L) Separate the layers extract the aqueous phase with EtOAc (10 L) Combine the organic portions, wash with brine (15 L) concentrate to a red oil Purify the oil eluting with hexane (40 L) 20% EtOAc/hexane to provide a fraction (7.8 kg) that

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Combine tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (4.720 kg, 20.6 mol) with DCM (40 L) and TEA (3020 mL, 21.63 mol) in a 50 L reactor under a nitrogen atmosphere. Cool the solution to about 0° C. and slowly add methane sulfonyl chloride (2.478 kg, 21.63 mol) in DCM (5 L) while keeping the reaction temperature below 10° C. After the addition is complete stir the mixture for 18 h at 15° C. at which time TLC (1:1, hexane:EtOAc) shows no starting material remaining Wash the mixture with water (30 L) and allow the phases to separate. Concentrate the organic phase to a solid. Slurry the solid in MTBE (6 L), collect by filtration, and dry in a vacuum oven at 50° C. to provide the title compound as a white solid (5.67 kg, 91%). the reaction temperature below 10° C After the addition remaining Wash the mixture with water (30 L) to separate Concentrate the organic phase to a solid collect by filtration dry in a vacuum oven at 50° C.

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The reaction was prepared in 2 batches, with both batches purified together. The amounts of reactants and product reflect the sum of both batches. To 1,1-dimethylethyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate (172 g, 750 mmol) in DCM (4 L) was added TEA (304 g, 1.50 mol). The mixture was cooled 0° C. and methanesulfonyl chloride (190 g, 827 mmol) was added dropwise. The reaction mixture was stirred at rt for 2 h. The reaction was determined to be complete by TLC. The reaction was diluted with DCM and washed with saturated Na2CO3 and the aqueous layer was separated. The organic layer was dried (Na2SO4), and rotovapped down to provide the title compound of Step B (280 g, 911 mmol, 61%). 1H NMR (400 MHz, CDCl3) δ 0.95-1.15 (m, 2H), 1.38 (s, 9H), 1.47-1.68 (m, 5H), 2.53-2.70 (m, 2H), 2.94 (s, 3H), 3.95-4.10 (m, 2H), 4.21 (t, J=8.8 Hz, 2H). The reaction was prepared in 2 batches, with both batches purified together washed with saturated Na2CO3 the aqueous layer was separated The organic layer was dried (Na2SO4)

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The reaction was prepared in 2 batches, with both batches purified together. The amounts of reactants and product reflect the sum of both batches. To 1,1-dimethylethyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate (172 g, 750 mmol) in DCM (4 L) was added TEA (304 g, 1.50 mol). The mixture was cooled 0° C. and methanesulfonyl chloride (190 g, 827 mmol) was added dropwise. The reaction mixture was stirred at rt for 2 h. The reaction was determined to be complete by TLC. The reaction was diluted with DCM and washed with saturated Na2CO3 and the aqueous layer was separated. The organic layer was dried (Na2SO4), and rotovapped down to provide the title compound of Step B (280 g, 911 mmol, 61%). 1H NMR (400 MHz, CDCl3) δ 0.95-1.15 (m, 2H), 1.38 (s, 9H), 1.47-1.68 (m, 5H), 2.53-2.70 (m, 2H), 2.94 (s, 3H), 3.95-4.10 (m, 2H), 4.21 (t, J=8.8 Hz, 2H). The reaction was prepared in 2 batches, with both batches purified together washed with saturated Na2CO3 the aqueous layer was separated The organic layer was dried (Na2SO4)

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

实验步骤: A solution of 4-(2-hydroxyethyl)-piperidine-1-carboxylic acid tert-butyl ester (Aldrich, 0.50 g, 2.2 mmol), triethylamine (0.91 mL, 6.5 mmol), and methanesulfonyl chloride (0.25 mL, 3.3 mmol) in 10 mL THF were processed as described in Example 1C to give the crude title compound which was used directly in the next reaction.

反应条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: t-BuOK (45 mg, 401 μmol) and 4-(2-methanesulfonyloxyethyl)piperidine-1-carboxylic acid tert-butyl ester (134 mg, 436 μmol) were added to a stirred solution of furo[3,2-c]pyridin-2-ylmethanol (Preparation 4, 50 mg, 336 μmol) in anhydrous THF (5 mL). The reaction was heated under reflux for 6 h, before being cooled to 20° C. and quenched with saturated aqueous NH4Cl. The mixture was extracted twice with EtOAc, then the combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by column chromatography (EtOAc-MeOH, 1:0 to 50:1) to furnish the title compound: RT=2.86 min; m/z (ES+)=361.3 [M+H]+. The reaction was heated under reflux for 6 h quenched with saturated aqueous NH4Cl The mixture was extracted twice with EtOAc the combined organic extracts were washed with brine dried (MgSO4) filtered concentrated The residue was purified by column chromatography (EtOAc-MeOH, 1:0 to 50:1)