Hydrochloric Acid → (R)-benzyl 2-methylpiperazine-1-carboxylate

Temperature

0 °C

To a 0° C. solution of (R)-2-methylpiperazine (5.0 g, 50 mmol, 1.0 equiv) in dry DCM (200 mL) was added triethylamine (21 mL, 150 mmol, 3 equiv) by syringe. A solution of Boc2O (10.4 g, 47.4 mmol, 0.95 equiv) was then added as a solution in dry DCM (100 mL) over the course of an hour. After stirring for an addition 15 min at 0° C., the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then washed with aq. satd. NaHCO3 and brine. The resulting DCM solution was dried over sodium sulfate, filtered, and concentrated in vacuo, and used in the next step without further purification. The residue was dissolved in dry DCM (50 mL), and Et3N (21 mL, 150 mmol, 3 equiv) was added by syringe. To this room temperature solution was added CbzCl (8.4 mL, 60 mmol, 1.2 equiv) dropwise by syringe. After stirring at room temperature for 30 minutes, the mixture was quenched by the addition of aq. satd. NaHCO3. The solution was washed an additional time with aq. satd. NaHCO3, twice with aq. 1 N KHSO4, and twice with brine. The DCM layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in MeOH (100 mL), and HCl (4 N in dioxane, 150 mL, 600 mmol, 12 equiv) was added dropwise by syringe. After 2 h, the reaction mixture was concentrated in vacuo. To the resulting solid was added EtOAc and 1 N NaOH. The aqueous layer was extracted twice with EtOAc, and the organic layers were combined and washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide (R)-benzyl 2-methylpiperazine-1-carboxylate (5.3 g, 45%).

1. stirringthe reaction mixture was stirred at room temperature for 30 min
2. washThe reaction mixture was then washed with aq. satd
3. dry with materialThe resulting DCM solution was dried over sodium sulfate
4. filtrationfiltered
5. concentrationconcentrated in vacuo
6. customused in the next step without further purification
7. dissolutionThe residue was dissolved in dry DCM (50 mL)
8. stirringAfter stirring at room temperature for 30 minutes
9. customthe mixture was quenched by the addition of aq. satd
10. washThe solution was washed an additional time with aq. satd
11. dry with materialThe DCM layer was dried over sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated in vacuo
14. dissolutionThe resulting residue was dissolved in MeOH (100 mL)
15. waitAfter 2 h
16. concentrationthe reaction mixture was concentrated in vacuo
17. additionTo the resulting solid was added EtOAc and 1 N NaOH
18. extractionThe aqueous layer was extracted twice with EtOAc
19. washwashed with brine
20. dry with materialdried over sodium sulfate
21. filtrationfiltered
22. concentrationconcentrated in vacuo

ORD record

ord-7d4cc5e1c9a344488dfb47cf2fc45439

Source dataset

uspto-grants-2014_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08871768B2