(4-甲基苯基)甲基 (3S,4R)-4-(氨基甲基)-3-氟哌啶-1-羧酸乙酯

反应条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Two sealed tubes were each charged with a mixture of crude (±)-cis-4-methylbenzyl 4-(aminomethyl)-3-fluoropiperidine-1-carboxylate (Step 6, 3.7 g, 13.2 mmol) and 2-chloropyrimidine (1.51 g, 13.2 mmol) in n-butanol/diisopropyl-ethylamine (1:1, 13 mL). The tubes were sealed and the mixtures heated to 140° C. and stirred for 2 h. After cooling to RT, the reaction mixtures were combined and diluted with EtOAc and sat NaHCO3. The layers were separated and the organic was washed with H2O and brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (gradient elution: 1:1 hexanes:EtOAc to EtOAc) gave racemic cis-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate (6.9 g, 65% yield, 3 steps) as a white solid. The tubes were sealed After cooling to RT the reaction mixtures The layers were separated the organic was washed with H2O and brine dried over Na2SO4 filtered concentrated Purification by silica gel chromatography (gradient elution: 1:1 hexanes:EtOAc to EtOAc)

反应条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Two sealed tubes were each charged with a mixture of crude (±)-cis-4-methylbenzyl 4-(aminomethyl)-3-fluoropiperidine-1-carboxylate (Step 6, 3.7 g, 13.2 mmol) and 2-chloropyrimidine (1.51 g, 13.2 mmol) in n-butanol/diisopropyl-ethylamine (1:1, 13 mL). The tubes were sealed and the mixtures heated to 140° C. and stirred for 2 h. After cooling to RT, the reaction mixtures were combined and diluted with EtOAc and sat NaHCO3. The layers were separated and the organic was washed with H2O and brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (gradient elution: 1:1 hexanes:EtOAc to EtOAc) gave racemic cis-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate (6.9 g, 65% yield, 3 steps) as a white solid. The tubes were sealed After cooling to RT the reaction mixtures The layers were separated the organic was washed with H2O and brine dried over Na2SO4 filtered concentrated Purification by silica gel chromatography (gradient elution: 1:1 hexanes:EtOAc to EtOAc)

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of crude acid (±)-((cis)-3-fluoro-1-{[(4-methylbenzyl)oxy]carbonyl}piperidin-4-yl)acetic acid (9.1 g, 29.4 mmol) in toluene (80 mL) was added triethylamine (10.2 mL, 73.5 mmol) and diphenylphosphoryl azide (9.52 mL, 44.1 mmol). The reaction mixture was heated to 70° C. and stirred for 20 min. A mixture of dioxane (80 mL) and 1 M NaOH (80 mL) was added and the reaction mixture was cooled to RT. The reaction mixture was concentrated to remove the dioxane and extracted with EtOAc three times, dried over Na2SO4, filtered and concentrated. The residue was suspended in CH2Cl2, stirred for 30 min, and the white preciptate filtered off. The filtrate was concentrated to give crude product (7.5 g) as a yellow oil, used directly in the next step. An analytical sample was purified by silica gel chromatography (gradient elution: CH2Cl2 to 80:20:2 CH2Cl2:MeOH:NH4OH) for characterization: was added the reaction mixture was cooled to RT The reaction mixture was concentrated to remove the dioxane extracted with EtOAc three times dried over Na2SO4 filtered concentrated stirred for 30 min the white preciptate filtered off The filtrate was concentrated

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of crude acid (±)-((cis)-3-fluoro-1-{[(4-methylbenzyl)oxy]carbonyl}piperidin-4-yl)acetic acid (9.1 g, 29.4 mmol) in toluene (80 mL) was added triethylamine (10.2 mL, 73.5 mmol) and diphenylphosphoryl azide (9.52 mL, 44.1 mmol). The reaction mixture was heated to 70° C. and stirred for 20 min. A mixture of dioxane (80 mL) and 1 M NaOH (80 mL) was added and the reaction mixture was cooled to RT. The reaction mixture was concentrated to remove the dioxane and extracted with EtOAc three times, dried over Na2SO4, filtered and concentrated. The residue was suspended in CH2Cl2, stirred for 30 min, and the white preciptate filtered off. The filtrate was concentrated to give crude product (7.5 g) as a yellow oil, used directly in the next step. An analytical sample was purified by silica gel chromatography (gradient elution: CH2Cl2 to 80:20:2 CH2Cl2:MeOH:NH4OH) for characterization: was added the reaction mixture was cooled to RT The reaction mixture was concentrated to remove the dioxane extracted with EtOAc three times dried over Na2SO4 filtered concentrated stirred for 30 min the white preciptate filtered off The filtrate was concentrated

反应条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Two sealed tubes were each charged with a mixture of crude (±)-cis-4-methylbenzyl 4-(aminomethyl)-3-fluoropiperidine-1-carboxylate (Step 6, 3.7 g, 13.2 mmol) and 2-chloropyrimidine (1.51 g, 13.2 mmol) in n-butanol/diisopropyl-ethylamine (1:1, 13 mL). The tubes were sealed and the mixtures heated to 140° C. and stirred for 2 h. After cooling to RT, the reaction mixtures were combined and diluted with EtOAc and sat NaHCO3. The layers were separated and the organic was washed with H2O and brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (gradient elution: 1:1 hexanes:EtOAc to EtOAc) gave racemic cis-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate (6.9 g, 65% yield, 3 steps) as a white solid. The tubes were sealed After cooling to RT the reaction mixtures The layers were separated the organic was washed with H2O and brine dried over Na2SO4 filtered concentrated Purification by silica gel chromatography (gradient elution: 1:1 hexanes:EtOAc to EtOAc)

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of crude acid (±)-((cis)-3-fluoro-1-{[(4-methylbenzyl)oxy]carbonyl}piperidin-4-yl)acetic acid (9.1 g, 29.4 mmol) in toluene (80 mL) was added triethylamine (10.2 mL, 73.5 mmol) and diphenylphosphoryl azide (9.52 mL, 44.1 mmol). The reaction mixture was heated to 70° C. and stirred for 20 min. A mixture of dioxane (80 mL) and 1 M NaOH (80 mL) was added and the reaction mixture was cooled to RT. The reaction mixture was concentrated to remove the dioxane and extracted with EtOAc three times, dried over Na2SO4, filtered and concentrated. The residue was suspended in CH2Cl2, stirred for 30 min, and the white preciptate filtered off. The filtrate was concentrated to give crude product (7.5 g) as a yellow oil, used directly in the next step. An analytical sample was purified by silica gel chromatography (gradient elution: CH2Cl2 to 80:20:2 CH2Cl2:MeOH:NH4OH) for characterization: was added the reaction mixture was cooled to RT The reaction mixture was concentrated to remove the dioxane extracted with EtOAc three times dried over Na2SO4 filtered concentrated stirred for 30 min the white preciptate filtered off The filtrate was concentrated