反应详情

温度

0 °C

(S)-(1-Methylpiperidin-3-yl)methanol (1.50 g, 11.6 mmol; prepared according to Example 1 but starting from (S)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate) was dissolved in DCM (20 mL) and cooled to 0° C. NMM (1.30 mL, 12.2 mmol) and nitrophenyl chloroformate (2.46 g, 12.2 mmol) were added. The reaction mixture was stirred at 0° C. for 2 hours and then a solution of 4-(4-methylphenyl)piperazine dihydrochloride (1.88 g, 7.5 mmol) and DIPEA (3.70 mL, 22.1 mmol) in DMF (40 mL) was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (300 mL) and then washed sequentially with 1M aq Na2CO3 solution (5×200 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 85:15 mixture of DCM:MeOH) followed by reverse phase HPLC (Advanced Chromatography Technologies ACE-122-1030 RP silica 100×30 mm column, packed with Ace 5 C8 (5 μm), Pore Size 100 Å, 30 mL/min, gradient of CH3CN in water, with 0.1% TFA in each solvent, 8-38%). The residue was dissolved in DCM (70 mL) and stirred with solid K2CO3 for 20 min, filtered and concentrated in vacuo to give a yellow oil which was recrystallised from heptane/EtOAc to give [(3S)-1-methylpiperidin-3-yl]methyl 4-(4-methylphenyl)piperazine-1-carboxylate (521 mg, 13.5%) as a white solid.

1. stirringThe reaction mixture was stirred at room temperature for 2 hours
2. concentrationconcentrated in vacuo
3. dissolutionThe residue was dissolved in EtOAc (300 mL)
4. washwashed sequentially with 1M aq Na2CO3 solution (5×200 mL)
5. dry with materialdried (MgSO4)
6. concentrationconcentrated in vacuo
7. customThe residue was purified by normal phase column chromatography (
8. washeluting with DCM
9. additionfollowed by a 85:15 mixture of DCM
10. dissolutionThe residue was dissolved in DCM (70 mL)
11. stirringstirred with solid K2CO3 for 20 min
12. filtrationfiltered
13. concentrationconcentrated in vacuo
14. customto give a yellow oil which
15. customwas recrystallised from heptane/EtOAc