반응 #474447

반응 방정식

EDCl hydrochloride

HOBt hydrate

NH3

1-(1,1-dimethylethyl) 7-ethyl 5-bromo-3-(1,1-dioxido-4-thiepanyl)-1H-indole-1,7-dicarboxylate

sodium hydroxide

5-bromo-3-(1,1-dioxido-4-thiepanyl)-1H-indole-7-carboxylic acid

→

title compound

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

용매

ethyl acetate

methanol

water

N,N-dimethylformamide

반응 조건

후처리

1. 1
   기타after which time a clear yellow solution was obtained
2. 2
   온도The mixture was cooled to rt
3. 3
   농축concentrated
4. 4
   기타to remove most of the methanol
5. 5
   기타was obtained (pH paper)
6. 6
   기타The product formed a gummy solid
7. 7
   농축The mixture was then concentrated to dryness
8. 8
   기타A light yellow gummy residue was obtained
9. 9
   온도The mixture was heated in a Biotage microwave oven at 10° C. for 20 minutes under regular absorption
10. 10
    기타The crude reaction mixture
11. 11
    세척washed with water
12. 12
    세척The aqueous layer was washed three times with ethyl acetate (30 mL)
13. 13
    건조The combined organics were dried over sodium sulfate
14. 14
    여과filtered
15. 15
    농축concentrated in vacuum oven
16. 16
    기타The crude brown oil was purified by Isco Combiflash, 40 gram column
17. 17
    세척eluting with 0-20% methanol in dichloromethane

실험 절차

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).

출처