Hydrochloric Acid → 7-{5-[2-(tert-Butyldimethylsilanyloxy)ethyl]-4-methylthiazol-2-yl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester

Temperature

80 °C

A mixture of compound C1 (8.37 g, 13.6 mmol) in EtOH (88 mL) and aq. 1M NaOH (88 mL) was stirred at 80° C. for 2 h. The mixture was allowed to cool to rt, and was then diluted with EtOAc (500 mL). This mixture was acidified with aq. 1M HCl (110 mL) until a pH between 3 and 4 was obtained. The layers were separated, then the aq. phase was extracted with EtOAc. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The crude product was dissolved in DMF (175 mL). Imidazole (5.43 g, 79.7 mmol)) and TBDMS-Cl (7.74 g, 51.3 mmol) were added. The mixture was stirred overnight. Aq. sat. NH4Cl (500 mL) was added and the resulting suspension was extracted with heptane (3×800 mL). The combined org. extracts were dried over MgSO4, filtered, and concentrated to yield a yellow oil. This crude product was dissolved in THF (130 mL), MeOH (44 mL) and H2O (44 mL), and K2CO3 (0.95 g) 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 (800 mL) to produce a clear yellow sol. This yellow sol. was washed with aq. sat. NH4Cl (500 mL). The aq. phase was extracted with Et2O (2×800 mL), and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The crude title product (10.5 g, quantitative yield) was used without further purification. LC-MS: tR=1.19 min, ES+: 624.27.

1. temperatureto cool to rt
2. customwas obtained
3. customThe layers were separated
4. extractionthe aq. phase was extracted with EtOAc
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 (175 mL)
9. stirringThe mixture was stirred overnight
10. extractionthe resulting suspension was extracted with heptane (3×800 mL)
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 (800 mL)
18. customto produce a clear yellow sol. This yellow sol.
19. washwas washed with aq. sat. NH4Cl (500 mL)
20. extractionThe aq. phase was extracted with Et2O (2×800 mL)
21. dry with materialextracts were dried over MgSO4
22. filtrationfiltered
23. customthe solvents were removed under reduced pressure

ORD record

ord-a07dacdc34e949dda08f269385f0ee0a

Source dataset

uspto-grants-2012_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08138340B2