Hydrochloric Acid → tert-butyl [(2S)-2-{[4-bromo-2-(hydroxymethyl)thiophen-3-yl]oxy}propyl]carbamate

Temperature

50 °C

To a solution of methyl 4-bromo-3-{(1S)-2-[(tert-butoxycarbonyl)amino]-1-methylethoxy}thiophene-2-carboxylate (15.36 g) in THF-MeOH (5:1, 180 mL) was added 8 N aqueous sodium hydroxide solution (7.5 mL) at room temperature, and the mixture was stirred at 50° C. for 1 hr. The reaction solution was cooled to room temperature, neutralized with 6 N hydrochloric acid (10 mL), and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution (250 ml) of the residue in THF were added isobutyl chloroformate (5.6 mL) and triethylamine (6.5 ml), and the mixture was stirred at room temperature for 30 min. The reaction solution was filtered, a solution (10 ml) of sodium borohydride (4.42 g) in water was added to the filtrate, and the mixture was stirred at room temperature for 30 min. Saturated aqueous ammonium solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 10→25% ethyl acetate/hexane) to give the title compound (12.82 g, 90%) as a colorless oil.

1. temperatureThe reaction solution was cooled to room temperature
2. extractionextracted with ethyl acetate
3. washThe extract was washed with water and saturated brine
4. dry with materialdried over magnesium sulfate
5. customthe solvent was evaporated under reduced pressure
6. additionTo a solution (250 ml) of the residue in THF were added isobutyl chloroformate (5.6 mL) and triethylamine (6.5 ml)
7. stirringthe mixture was stirred at room temperature for 30 min
8. filtrationThe reaction solution was filtered
9. additiona solution (10 ml) of sodium borohydride (4.42 g) in water was added to the filtrate
10. stirringthe mixture was stirred at room temperature for 30 min
11. additionSaturated aqueous ammonium solution was added to the reaction solution
12. extractionthe mixture was extracted with ethyl acetate
13. washThe extract was washed with water and saturated brine
14. dry with materialdried over magnesium sulfate
15. customthe solvent was evaporated under reduced pressure
16. customThe residue was purified by silica gel column chromatography (solvent gradient; 10→25% ethyl acetate/hexane)

ORD record

ord-2bee2ee6b65748bab8dc1f21d91e02ad

Source dataset

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08916549B2