Ethyl oxoacetate → Ethyl 4-(3-(benzyloxycarbonylamino)-2-fluorophenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxylate

Temperature

125 °C

To a light homogeneous, orange solution of benzyl 3-(2-amino-1-(6-(2-methoxyethoxy)-1H-indol-3-yl)ethyl)-2-fluorophenylcarbamate (3.5215 g, 7.37 mmol) and ethyl 2-oxoacetate (2.92 mL, 14.75 mmol) (50% in toluene) under nitrogen was added 4N HCl/1,4-dioxane (2.212 mL, 8.85 mmol); reaction turned dark burgundy. The reaction was stirred overnight, concentrated in vacuo, dissolved in EtOAc (50 mL) and saturated aqueous NaHCO3 (20 mL). After separation of the layers, the aqueous layer was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine (30 mL), dried over MgSO4, and concentrated in vacuo to give crude product which was used in subsequent step. This was added to 10% Pd/C (1.569 g, 1.474 mmol) in p-xylene (211 mL), and the solution was heated at 125° C. After 3.5 hr, the reaction was cooled to room temperature, filtered through a pad of CELITE®, and the insolubles were rinsed with EtOAc (250 mL). The filtrate was washed with brine (75 mL), and the layers were separated. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 220 g column eluting with 5-40% EtOAc/CH2Cl2. Appropriate fractions (20-25% elution) were collected and concentrated in vacuo to give the desired product (0.811 g, 1.381 mmol, 18.7% yield) as a light orange solid.

1. customreaction
2. concentrationconcentrated in vacuo
3. dissolutiondissolved in EtOAc (50 mL)
4. customAfter separation of the layers
5. extractionthe aqueous layer was extracted with EtOAc (3×50 mL)
6. washwashed with brine (30 mL)
7. dry with materialdried over MgSO4
8. concentrationconcentrated in vacuo
9. customto give crude product which
10. waitAfter 3.5 hr
11. temperaturethe reaction was cooled to room temperature
12. filtrationfiltered through a pad of CELITE®
13. washthe insolubles were rinsed with EtOAc (250 mL)
14. washThe filtrate was washed with brine (75 mL)
15. customthe layers were separated
16. dry with materialThe organic layer was dried over MgSO4
17. filtrationfiltered
18. concentrationconcentrated in vacuo
19. customto give a residue which
20. customwas purified by flash chromatography
21. washeluting with 5-40% EtOAc/CH2Cl2
22. washAppropriate fractions (20-25% elution)
23. customwere collected
24. concentrationconcentrated in vacuo

ORD record

ord-ac00d39c1c004d1bbeb38c64ac1d7a0a

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08685969B2