Methyl iodide → HCID 131731102, compound

To a solution of 1-(benzyloxycarbonyl)-4-piperidinone (20.0 g, 85.80 mmol) in Et2O (200 mL) at 0° C. was added boron trifluoride etherate (12.0 mL, 94.40 mmol) followed by the addition of ethyl diazoacetate (11.7 mL, 94.40 mmol) maintaining the temperature below 7° C. The reaction mixture was stirred for 1 hr, quenched with a 2 M aqueous solution of sodium carbonate (150 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) gave a light yellow oil. This oil (10 g, 31.30 mmol) was dissolved in DMF (75 mL) at 0° C. and sodium hydride (60% dispersion in mineral oil, 1.38 g, 34.50 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 1 hr before iodomethane (2.15 mL, 34.50 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 18 hr. The mixture was diluted with Et2O (100 mL) and quenched with water (100 mL). The aqueous layer was extracted with Et2O (3×75 mL) and the combined organic layers were washed with water (2×100 mL) and brine (2×100 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (50% Et2O/isohexane) gave a light yellow oil. A portion of this oil (0.90 g, 2.70 mmol) was dissolved in MeOH (4 mL) and added to a stirred suspension of NaBH4 (0.12 g, 3.24 mmol) in MeOH (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 hr, before being quenched with a 1 M aqueous solution of HCl (5 mL). The aqueous layer was extracted with DCM (3×10 mL) and the combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (25-100% EtOAc/isohexane) gave O1-benzyl O4-ethyl 5-hydroxy-4-methyl-azepane-1,4-dicarboxylate as a colourless oil (480 mg, 1% over three steps). 1H NMR (400 MHz, CDCl3) δ 7.37-7.28 (m, 5H), 5.17-5.10 (m, 2H), 4.20-4.07 (m, 2H), 3.78-3.20 (m, 7H), 2.32-2.24 (m, 1H), 2.07-1.86 (m, 3H), 1.73-1.62 (m, 1H), 1.30-1.19 (m, 3H). Exchangeable OH not observed.

1. temperaturemaintaining the temperature below 7° C
2. customquenched with a 2 M aqueous solution of sodium carbonate (150 mL)
3. extractionextracted with EtOAc (3×150 mL)
4. dry with materialThe combined organic layers were dried over MgSO4
5. concentrationconcentrated under reduced pressure
6. customPurification via silica gel column chromatography (0-50% EtOAc/isohexane)
7. customgave a light yellow oil
8. additionwas added
9. stirringstirred for 18 hr
10. customquenched with water (100 mL)
11. extractionThe aqueous layer was extracted with Et2O (3×75 mL)
12. washthe combined organic layers were washed with water (2×100 mL) and brine (2×100 mL)
13. customseparated
14. dry with materialdried over MgSO4
15. concentrationconcentrated under reduced pressure
16. customPurification via silica gel column chromatography (50% Et2O/isohexane)
17. customgave a light yellow oil
18. stirringThe reaction mixture was stirred at 0° C. for 3 hr
19. custombefore being quenched with a 1 M aqueous solution of HCl (5 mL)
20. extractionThe aqueous layer was extracted with DCM (3×10 mL)
21. customthe combined organic layers were passed through a phase separation cartridge
22. concentrationconcentrated under reduced pressure
23. customPurification via silica gel column chromatography (25-100% EtOAc/isohexane)

ORD record

ord-059bbce485db46e89d679d3183eeae7c

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08614206B2