* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
1 kg N-Bn-pyrrolidine (21) from previous step (synthesis 43) (4414 mmol, 1 equiv.) was dissolved in 10 L methanol and hydrogenated at atmospheric pressure over 101 g Pd/C (95 mmol Pd, 0.02 equiv., 10% Degussa E101 N/D). After completion of the reaction, the catalyst was filtered and the solution was concentrated to ca 10 L. 2 L methanol were added and distilled at constant volume. A solution of 1.025 kg Boc20 (4603 mmol, 1.05 equiv) in 2.4 L methanol was added over 40 min keeping the temperature between 20-30C. After completion of the reaction (GC IPC), the reaction mixture was concentrated under reduced pressure (50C, 300 to 17 mbar) to give 998 g of (22) as a yellow oil. 4 L toluene was added and the solution was washed with 1.6 L of 0.5 M HClaq and 1.6 L of 5% NaHC03 aq. The organic phase was dried over Na2S04 and concentrated under reduced pressure (80 to 16 mbar, 50C) to give 975 g of crude product (22) as orange oil (98.6a% GC, 3.2% residual toluene).
Synthesis 44: 1 kg N-Bn-pyrrolidine (21) from previous step (synthesis 43) (4414 mmol, 1 equiv.) was dissolved in 10 L methanol and hydrogenated at atmospheric pressure over 101 g Pd/C (95 mmol Pd, 0.02 equiv., 10% Degussa E101 N/D). After completion of the reaction, the catalyst was filtered and the solution was concentrated to ca 10 L. 2 L methanol were added and distilled at constant volume. A solution of 1.025 kg Boc2O (4603 mmol, 1.05 equiv) in 2.4 L methanol was added over 40 min keeping the temperature between 20-30 C. After completion of the reaction (GC IPC), the reaction mixture was concentrated under reduced pressure (50 C., 300 to 17 mbar) to give 998 g of ( 22) as a yellow oil. 4 L toluene was added and the solution was washed with 1.6 L of 0.5 M HClaq and 1.6 L of 5% NaHCO3 aq. The organic phase was dried over Na2SO4 and concentrated under reduced pressure (80 to 16 mbar, 50 C.) to give 975 g of crude product ( 22) as orange oil (98.6a % GC, 3.2% residual toluene).
[0165] To a stirred solution of the benzyl amine (32) (10 g, 1 equiv.) in dichloroethane (220 mL) was added, dropwise, 1-chloroethylchloroformate (5.91 mL, 1.2 equiv.). The reaction was stirred at rt for 30 min followed by concentration of the mixture under reduced pressure. The residue was dissolved in MeOH (100 mL), refluxed for 20 min and then concentrated under reduced pressure. The residue was then dissolved in CHCl3 (80 mL) and Et3N (19.1 mL, 3 equiv.) and cooled to 0 C. To this mixture was added Boc2O (9.95 g, 1 equiv.) in CHCl3 (20 mL) and the reaction was stirred at rt for 16 h. This mixture was then concentrated under reduced pressure, dissolved in EtOAc and washed with 10% citric acid, H2O and brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution: 20% EtOAc in hexane to 33% EtOAc in hexane) to afford the Boc-protected amine. To a solution of the Boc-protected amine (2.29 g, 1 equiv.) in MeOH (24 mL) was added 1 N NaOH (12 mL, 1.2 equiv.). The mixture was stirred at rt for 3 days and then concentrated under reduced pressure. The residue was poured into a solution of 1 N HCl (10 mL) and 10% citric acid (20 mL). The mixture was extracted with EtOAc (3×) and the combined organic extracts were washed with H2O and brine, dried (MgSO4) and concentrated under reduced pressure to yield the acid (33).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
120K+ Compounds
Competitive Price
1-2 Day Shipping
