Methanol → HCID 76568123, compound

Temperature

140 °C

To a solution of 1-{3-bromo-2-fluoro-6-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenyl}-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 183c in toluene (30 mL) was added E/Z-6-chloro-3-(3-chlorobenzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.5 g, 1.28 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 140° C. for 45 min. After the solution was cooled to room temperature, methanol (10 mL) was added. The reaction mixture was filtered through a short pad of celite gel and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in dichloromethane (20 mL) and trifluoroactic acid (15 mL) was added. After the reaction mixture was stirred at room temperature for 1 h, the mixture was concentrated. The residue was partitioned between saturated NaHCO3 solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated. The residue was dissolved in tetrahydrofuran (10 mL) and tetrabutylammonium fluoride solution (1M in THF, 10 mL) was added. The reaction mixture was stirred at room temperature for 10 min, then poured into water and extracted with ethyl acetate. The combined organic layer was dried over MgSO4 and concentrated. The residue was purified by chromatography to give racemic (2′R,3R,4′S)-2′-[3-bromo-2-fluoro-6-(2-hydroxy-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 0.4 g, 65.6%).

1. temperatureAfter the solution was cooled to room temperature
2. filtrationThe reaction mixture was filtered through a short pad of celite gel
3. washwashed with ethyl acetate
4. concentrationThe filtrate was concentrated
5. dissolutionThe residue was dissolved in dichloromethane (20 mL)
6. additiontrifluoroactic acid (15 mL) was added
7. stirringAfter the reaction mixture was stirred at room temperature for 1 h
8. concentrationthe mixture was concentrated
9. customThe residue was partitioned between saturated NaHCO3 solution and ethyl acetate
10. extractionThe aqueous layer was extracted with ethyl acetate
11. dry with materialThe combined organic layer was dried over Na2SO4
12. concentrationconcentrated
13. dissolutionThe residue was dissolved in tetrahydrofuran (10 mL)
14. additiontetrabutylammonium fluoride solution (1M in THF, 10 mL) was added
15. stirringThe reaction mixture was stirred at room temperature for 10 min
16. additionpoured into water
17. extractionextracted with ethyl acetate
18. dry with materialThe combined organic layer was dried over MgSO4
19. concentrationconcentrated
20. customThe residue was purified by chromatography

ORD record

ord-c1c663f5e4704808b4c93a65cc137159

Source dataset

uspto-grants-2009_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07495007B2