P-Xylene → ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylate

Temperature

120 °C

To a homogeneous, colorless solution of benzyl 3-(2-amino-1-(6-(2-methoxyethoxy)-1H-indol-3-yl)propyl)-2-methylphenylcarbamate (1.3975 g, 2.87 mmol) in dioxane (Volume: 143 ml) under nitrogen were added 50% ethyl 2-oxoacetate/toluene (1.136 ml, 5.73 mmol) and 4 N hydrochloric acid/1,4-dioxane (1.433 ml, 5.73 mmol). After stirring overnight, the reaction was concentrated in vacuo, dissolved in EtOAc (75 mL) and saturated aqueous NaHCO3 (30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2×75 mL). the organic layers were combined, dried over MgSO4, filtered and concentrated in vacuo to give crude cyclized product as a burgundy oil which was used in the next step. p-Xylene (Volume: 82 ml) and 10% palladium on carbon (0.916 g, 0.861 mmol) were added, and the reaction was heated at 120° C. After 3 h, the reaction was cooled to room temperature, diluted with EtOAc (200 mL) and filtered through a wad of CELITE®. The filtrate was concentrated in vacuo, dissolved in EtOAc (125 mL) and washed with water (25 mL). The layers were separated, and the organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using an ISCO 80 g column eluting with 20-75% EtOAc/hexane. Appropriate fractions were collected and concentrated in vacuo to give ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylate (0.6232 g, 1.098 mmol, 38.3% yield) as a tan solid, LC/MS (M+H)=568.24.

1. concentrationthe reaction was concentrated in vacuo
2. dissolutiondissolved in EtOAc (75 mL)
3. customThe layers were separated
4. extractionthe aqueous layer was extracted with EtOAc (2×75 mL)
5. dry with materialdried over MgSO4
6. filtrationfiltered
7. concentrationconcentrated in vacuo
8. customto give crude cyclized product as a burgundy oil which
9. waitAfter 3 h
10. temperaturethe reaction was cooled to room temperature
11. filtrationfiltered through a wad of CELITE®
12. concentrationThe filtrate was concentrated in vacuo
13. dissolutiondissolved in EtOAc (125 mL)
14. washwashed with water (25 mL)
15. customThe layers were separated
16. dry with materialthe organic layer was dried over MgSO4
17. filtrationfiltered
18. concentrationconcentrated in vacuo
19. customThe residue was purified by flash chromatography
20. washeluting with 20-75% EtOAc/hexane
21. customAppropriate fractions were collected
22. concentrationconcentrated in vacuo

ORD record

ord-28518019d6314036ab84d2bad0cdb183

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08685969B2