S-(-)-N-甲基2-哌啶甲酸

反应条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (S)-1-methyl-piperidine-2-carboxylic acid (250 mg, 1.74 mmol) and (5-fluoro-pyridin-2-yl)-hydrazine (244 mg, 1.92 mmol) in DCM (20 mL) was added HATU (790 mg, 2.09 mmol) and DIPEA (606 μL, 3.48 mmol) and the reaction stirred for 18 h. The reaction was then heated to 45° C. for 1 h then cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM to give the title compound (272 mg, 62%). LCMS (Method 4): Rt 0.87 min, m/z 253 [MH+]. then cooled partitioned between EtOAc and water The aqueous phase was extracted with EtOAc (×3) the combined organic layers were washed with brine dried (MgSO4) concentrated in vacuo The resultant residue was purified by FCC on silica

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

实验步骤: To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (250 mg, 1.96 mmol) in DMF (20.0 mL) was added (S)-1-methyl-piperidine-2-carboxylic acid (281 mg, 1.96 mmol), EDC (416 mg, 2.16 mmol) and HOBt.H2O (25.0 mg, 0.20 mmol). The reaction was stirred overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was taken up in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound (331 mg, 67%). LCMS (Method 1): Rt 0.35 min, m/z 253.2 [MH+]. then partitioned between EtOAc and water The aqueous layer was then extracted with EtOAc (3×) The combined organic layers were washed with brine dried (MgSO4) filtered evaporated in vacuo was washed with MeOH The product was eluted with 2M NH3 in MeOH concentration in vacuo gave residue

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

实验步骤: To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (250 mg, 1.96 mmol) in DMF (20.0 mL) was added (S)-1-methyl-piperidine-2-carboxylic acid (281 mg, 1.96 mmol), EDC (416 mg, 2.16 mmol) and HOBt.H2O (25.0 mg, 0.20 mmol). The reaction was stirred overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was taken up in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound (331 mg, 67%). LCMS (Method 1): Rt 0.35 min, m/z 253.2 [MH+]. then partitioned between EtOAc and water The aqueous layer was then extracted with EtOAc (3×) The combined organic layers were washed with brine dried (MgSO4) filtered evaporated in vacuo was washed with MeOH The product was eluted with 2M NH3 in MeOH concentration in vacuo gave residue

反应条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (S)-1-methyl-piperidine-2-carboxylic acid (250 mg, 1.74 mmol) and (5-fluoro-pyridin-2-yl)-hydrazine (244 mg, 1.92 mmol) in DCM (20 mL) was added HATU (790 mg, 2.09 mmol) and DIPEA (606 μL, 3.48 mmol) and the reaction stirred for 18 h. The reaction was then heated to 45° C. for 1 h then cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM to give the title compound (272 mg, 62%). LCMS (Method 4): Rt 0.87 min, m/z 253 [MH+]. then cooled partitioned between EtOAc and water The aqueous phase was extracted with EtOAc (×3) the combined organic layers were washed with brine dried (MgSO4) concentrated in vacuo The resultant residue was purified by FCC on silica

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

实验步骤: To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (250 mg, 1.96 mmol) in DMF (20.0 mL) was added (S)-1-methyl-piperidine-2-carboxylic acid (281 mg, 1.96 mmol), EDC (416 mg, 2.16 mmol) and HOBt.H2O (25.0 mg, 0.20 mmol). The reaction was stirred overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was taken up in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound (331 mg, 67%). LCMS (Method 1): Rt 0.35 min, m/z 253.2 [MH+]. then partitioned between EtOAc and water The aqueous layer was then extracted with EtOAc (3×) The combined organic layers were washed with brine dried (MgSO4) filtered evaporated in vacuo was washed with MeOH The product was eluted with 2M NH3 in MeOH concentration in vacuo gave residue

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

实验步骤: The reaction was carried out as in Example 2A(i) using 525 ml (358 g) of the same MoO3 on silica-alumina catalyst at a reaction temperature of 553° C. Thereafter, consecutive runs of 216 g of MPDA/hour, 216 g of water/hour and 210 L of nitrogen/hour (mole ratio N2 /MPDA=5) resulted in 0.1% net yield of MePip and 73% net yield of Beta in the first-hour run, 0.5% net yield of MePip and 99% net yield of Beta in the second hour, 0.7% net yield of MePip and 86% net yield of Beta in the third hour, 1.4% net yield of MePip and 81% net yield of Beta in the fourth hour, and 1.6% net yield of MePip and 81% net yield of Beta in the fifth hour. Conversions were 100% throughout the runs. These significantly selective and high yields of Beta were achieved without regeneration of the catalyst and with no indication of catalyst deactivation over time as has been common in this area. These superior results were also in contrast to those obtained using the same components, but at a temperature of 400° C. and with hydrogen in place of nitrogen. In those runs the initial net yield of Beta was 34%, but it decreased to 25% by the end of the first hour and no further runs were made as the trend was obvious toward decreasing and unacceptable yields without regeneration. The 73% net yield of Beta over the first hour of this high temperature run also compares favorably with Example 2 above in which a 43% net yield of Beta was observed over 30 minutes at 399° C. at a reaction temperature of 553° C

反应条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (S)-1-methyl-piperidine-2-carboxylic acid (250 mg, 1.74 mmol) and (5-fluoro-pyridin-2-yl)-hydrazine (244 mg, 1.92 mmol) in DCM (20 mL) was added HATU (790 mg, 2.09 mmol) and DIPEA (606 μL, 3.48 mmol) and the reaction stirred for 18 h. The reaction was then heated to 45° C. for 1 h then cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM to give the title compound (272 mg, 62%). LCMS (Method 4): Rt 0.87 min, m/z 253 [MH+]. then cooled partitioned between EtOAc and water The aqueous phase was extracted with EtOAc (×3) the combined organic layers were washed with brine dried (MgSO4) concentrated in vacuo The resultant residue was purified by FCC on silica

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

实验步骤: To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (250 mg, 1.96 mmol) in DMF (20.0 mL) was added (S)-1-methyl-piperidine-2-carboxylic acid (281 mg, 1.96 mmol), EDC (416 mg, 2.16 mmol) and HOBt.H2O (25.0 mg, 0.20 mmol). The reaction was stirred overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was taken up in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound (331 mg, 67%). LCMS (Method 1): Rt 0.35 min, m/z 253.2 [MH+]. then partitioned between EtOAc and water The aqueous layer was then extracted with EtOAc (3×) The combined organic layers were washed with brine dried (MgSO4) filtered evaporated in vacuo was washed with MeOH The product was eluted with 2M NH3 in MeOH concentration in vacuo gave residue