Ammonia → 5-Bromo-3-(1,1-dioxido-4-thiepanyl)-1H-indole-7-carboxamide

Temperature

85 °C

To a solution of 1-(1,1-dimethylethyl) 7-ethyl 5-bromo-3-(1,1-dioxido-4-thiepanyl)-1H-indole-1,7-dicarboxylate (273 mg, 0.53 mmol) in methanol (3 mL) and water (1.6 mL) was added 6 M aqueous sodium hydroxide (1 mL). The mixture was heated to 85° C. for 2 h, after which time a clear yellow solution was obtained. The mixture was cooled to rt, concentrated to remove most of the methanol, and acidified with 6M aqueous hydrochloric acid until a pH=1 was obtained (pH paper). The product formed a gummy solid. The mixture was then concentrated to dryness. A light yellow gummy residue was obtained, which was used in the amide formation step as is. 5-bromo-3-(1,1-dioxido-4-thiepanyl)-1H-indole-7-carboxylic acid (prepared above) was diluted in N,N-dimethylformamide (1 mL) in a 20 mL microwave vial. EDCl hydrochloride (275 mg, 275 mg, 1.43 mmol, 2.7 eq), HOBt hydrate (81 mg, 0.6 mmol, 1.1 eq), and NH3 (0.5 M in dioxane, Aldrich, 8 mL) were added. The mixture was heated in a Biotage microwave oven at 10° C. for 20 minutes under regular absorption. The crude reaction mixture was diluted in ethyl acetate and washed with water. The aqueous layer was washed three times with ethyl acetate (30 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuum oven. The crude brown oil was purified by Isco Combiflash, 40 gram column, eluting with 0-20% methanol in dichloromethane. The title compound was obtained as a yellow tarry residue (198 mg, 97% combined yield for both steps).

1. customafter which time a clear yellow solution was obtained
2. temperatureThe mixture was cooled to rt
3. concentrationconcentrated
4. customto remove most of the methanol
5. customwas obtained (pH paper)
6. customThe product formed a gummy solid
7. concentrationThe mixture was then concentrated to dryness
8. customA light yellow gummy residue was obtained
9. temperatureThe mixture was heated in a Biotage microwave oven at 10° C. for 20 minutes under regular absorption
10. customThe crude reaction mixture
11. washwashed with water
12. washThe aqueous layer was washed three times with ethyl acetate (30 mL)
13. dry with materialThe combined organics were dried over sodium sulfate
14. filtrationfiltered
15. concentrationconcentrated in vacuum oven
16. customThe crude brown oil was purified by Isco Combiflash, 40 gram column
17. washeluting with 0-20% methanol in dichloromethane

ORD record

ord-3b3132f3d60647e9bd7717788a012bbe

Source dataset

uspto-grants-2011_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08071584B2