Acetic Anhydride → 4-Acetoxy-1-(4-acetylamino-phenoxy)-isoquinoline-3-carboxylic acid butyl ester

Temperature

0 °C

4-hydroxy-1-phenoxy-isoquinoline-3-carboxylic acid butyl ester (261 mg, 0.77 mmol; see Example D-20 d) was dissolved in conc. H2SO4 (4 ml) at ambient temperature. The solution was cooled to 0° C. and KNO3 (79 mg, 0.77 mmol) was added slowly with stirring. The mixture was stirred at 0° C. for 2 h before it was poured into ice water (100 ml) with stirring. The mixture was extracted with EtOAc (3×30 ml). The combined organic phases were washed with aqueous NaHCO3 solution and brine, dried, and concentrated in vacuo. The residue was dissolved in a mixture of EtOAc (20 ml) and MeOH (10 ml). Sodium acetate (70 mg, 0.85 mmol) and Pd/C (75 mg, 10 wt. % Pd) were added and the mixture was stirred under a H2-atmosphere (1 atm) at ambient temperature for 24 h. The mixture was then filtered through a pad of celite. Celite and filter cake were washed with hot MeOH (3×4 ml) and the combined organic phases were concentrated in vacuo. 150 mg of the resulting residue (total: 380 mg) were dissolved in EtOAc (8 ml). Triethylamine (325 μl, 2.3 mmol) was added and the solution was cooled to 0° C. Then acetic anhydride (110 μl, 1.15 mmol) was added slowly with vigorous stirring. The mixture was allowed to warm up to ambient temperature over night and was then stirred for another 20 h at ambient temperature. Subsequently, EtOAc (50 ml) was added. The mixture was washed with aqueous NaHCO3 solution and brine, dried, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using CH2Cl2:MeOH=100:1 to 100:3 as the eluent to give 150 mg of 4-Acetoxy-1-(4-acetylamino-phenoxy)-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=437.11.

1. stirringThe mixture was stirred at 0° C. for 2 h before it
2. stirringwith stirring
3. extractionThe mixture was extracted with EtOAc (3×30 ml)
4. washThe combined organic phases were washed with aqueous NaHCO3 solution and brine
5. customdried
6. concentrationconcentrated in vacuo
7. dissolutionThe residue was dissolved in a mixture of EtOAc (20 ml) and MeOH (10 ml)
8. stirringthe mixture was stirred under a H2-atmosphere (1 atm) at ambient temperature for 24 h
9. filtrationThe mixture was then filtered through a pad of celite
10. filtrationCelite and filter cake
11. washwere washed with hot MeOH (3×4 ml)
12. concentrationthe combined organic phases were concentrated in vacuo
13. dissolution150 mg of the resulting residue (total: 380 mg) were dissolved in EtOAc (8 ml)
14. temperaturethe solution was cooled to 0° C
15. temperatureto warm up to ambient temperature over night
16. stirringwas then stirred for another 20 h at ambient temperature
17. washThe mixture was washed with aqueous NaHCO3 solution and brine
18. customdried
19. concentrationconcentrated in vacuo
20. customThe residue was purified by flash column chromatography on silica gel

ORD record

ord-e766c3e405164e048e10e9324441f439

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09339527B2