Hydrochloric Acid → 7-{3-[3-(tert-Butyldimethylsilanyloxy)propyl]isoxazol-5-yl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3-tert-butyl ester 9-(2,2,2-trichloro-1,1-dimethylethyl) ester

Temperature

80 °C

A mixture of compound C3 (1.03 g, 1.40 mmol) in EtOH (10 mL) and aq. 1M NaOH (10 mL) was stirred at 80° C. for 5 h. The mixture was allowed to cool to rt, and was then diluted with EtOAc. This mixture was acidified with aq. 1M HCl until a pH between 3 and 4 was obtained. The layers were separated, then the aq. phase was extracted with EtOAc (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The crude product was dissolved in DMF (20 mL). Imidazole (381 mg, 5.6 mmol) and TBDMS-Cl (527 mg, 3.5 mmol) were added. The mixture was stirred overnight. Aq. sat. NH4Cl was added and the resulting suspension was extracted with heptane (3×). The combined org. extracts were dried over MgSO4, filtered, and concentrated to yield a yellow oil. This crude product was dissolved in THF (15 mL), MeOH (5 mL) and H2O (5 mL), and K2CO3 (97 mg) was added. The mixture was stirred at rt for 2.5 h and was concentrated to half under reduced pressure. The residue was then diluted with Et2O to produce a clear yellow sol. This yellow sol. was washed with aq. sat. NH4Cl. The aq. phase was extracted with Et2O (2×), and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The crude title compound (950 mg, 95%) was used without further purification.

1. temperatureto cool to rt
2. customwas obtained
3. customThe layers were separated
4. extractionthe aq. phase was extracted with EtOAc (2×)
5. dry with materialextracts were dried over MgSO4
6. filtrationfiltered
7. customthe solvents were removed under reduced pressure
8. dissolutionThe crude product was dissolved in DMF (20 mL)
9. stirringThe mixture was stirred overnight
10. extractionthe resulting suspension was extracted with heptane (3×)
11. dry with materialextracts were dried over MgSO4
12. filtrationfiltered
13. concentrationconcentrated
14. customto yield a yellow oil
15. stirringThe mixture was stirred at rt for 2.5 h
16. concentrationwas concentrated to half under reduced pressure
17. additionThe residue was then diluted with Et2O
18. customto produce a clear yellow sol. This yellow sol.
19. washwas washed with aq. sat. NH4Cl
20. extractionThe aq. phase was extracted with Et2O (2×)
21. dry with materialextracts were dried over MgSO4
22. filtrationfiltered
23. customthe solvents were removed under reduced pressure
24. customThe crude title compound (950 mg, 95%) was used without further purification

ORD record

ord-fc18b00da5b7450aad84c4e6ff5e700d

Source dataset

uspto-grants-2012_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08138340B2