4-Methylmorpholine → 2-(4-Methyl-1,4-diazepan-1-yl)ethyl 4-(4-methylphenyl)piperazine-1-carboxylate

Temperatur

0 °C

2-(4-methylhomopiperazin-1-yl)ethanol from the previous step (2.77 g, 17.5 mmol) was dissolved in DCM (25 mL) and cooled to 0° C. NMM (2.00 mL, 18.4 mmol) and p-nitrophenyl chloroformate (3.71 g, 18.4 mmol) were added. The reaction mixture was stirred at 0° C. for 30 minutes and then at room temperature for 2 hours. A solution of 4-(4-methylphenyl)piperazine dihydrochloride (2.84 g, 11.4 mmol) and DIPEA (5.50 mL, 33.3 mmol) in DMF (40 mL) was then added. The reaction mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The residue was dissolved in EtOAc (300 mL) and then washed sequentially with 1 M 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 actonitrile in water, with 0.1% trifluoroacetic acid in each solvent, 8-38%). The resulting residue was dissolved in DCM (50 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give 2-(4-methyl-1,4-diazepan-1-yl)ethyl 4-(4-methylphenyl)piperazine-1-carboxylate (184 mg, 3.0%) as a pale yellow oil.

1. waitat room temperature for 2 hours
2. stirringThe reaction mixture was stirred at room temperature for 3 h
3. concentrationconcentrated in vacuo
4. dissolutionThe residue was dissolved in EtOAc (300 mL)
5. washwashed sequentially with 1 M aq Na2CO3 solution (5×200 mL)
6. dry with materialdried (MgSO4)
7. concentrationconcentrated in vacuo
8. customThe residue was purified by normal phase column chromatography (
9. washeluting with DCM
10. additionfollowed by a 85:15 mixture of DCM
11. dissolutionThe resulting residue was dissolved in DCM (50 mL)
12. stirringstirred with solid K2CO3 for 20 minutes
13. filtrationfiltered
14. concentrationconcentrated in vacuo

ORD-Eintrag

ord-8b6d08937b4544338ab319452703a2fd

Quelldatensatz

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08093248B2