Hydrochloric Acid → 1-Methyl-3-(1-methylethyl)-5-(methyloxy)-1H-indole-7-carboxylic acid

Temperatur

120 °C

To methyl 5-bromo-1-methyl-3-(1-methylethyl)-1H-indole-7-carboxylate (620 mg, 2 mmol) and Copper(I)iodide (476 mg, 2.500 mmol) was added N-Methyl-2-pyrrolidone (NMP) (4 mL). To the mixture was added dropwise a solution of sodium methoxide (in methanol) (1802 mg, 8.34 mmol) with stirring over a 5 min period, during which time contents turned dark green. The reaction was heated to 120° C., upon which the contents were nearly black colored. The black colored mixture was stirred at 120° C. After 1 h 45 min, the dark reddish brown colored contents were removed from heating and allowed to cool. Upon reaching 80° C., water (150 uL) was added and the reaction mixture was allowed to cool to room temperature with stirring overnight. The reaction contents were then acidified with 1N HCl (8 mL), upon which the contents became a brown suspension. The mixture was diluted with water (8 mL), and lightened a bit. Next added EtOAc (10 mL), and the contents become a biphasic mixture. The contents were filtered through Celite, and the filter cake was washed with EtOAc. The filtrate was poured into a separatory funnel, and the organic phase was separated and set aside. The aq. phase was extracted with EtOAc (2×10 mL), and combined with the previously saved organic layer. The combined organic layers were washed with brine (10 mL), dried (MgSO4), filtered, and concentrated under vacuum. Purification by silica gel chromatography (gradient: 10 to 50% EtOAc in hexanes) gave the title compound as a cream colored solid (80 mg, 16%). Note: Some material loss occurred during purification due to a collection malfunction. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (d, J=6.82 Hz, 6H), 3.08-3.16 (m, 1H), 3.74 (s, 3H), 3.80 (s, 3H), 7.09 (s, 2H), 7.21 (s, 1H), 12.9-13.1 (br s, 1H). MS(ES) [M+H]+ 248.2.

1. stirringThe black colored mixture was stirred at 120° C
2. waitAfter 1 h 45 min
3. customthe dark reddish brown colored contents were removed
4. temperaturefrom heating
5. temperatureto cool
6. customUpon reaching 80° C.
7. additionwater (150 uL) was added
8. temperatureto cool to room temperature
9. stirringwith stirring overnight
10. customThe reaction contents
11. filtrationThe contents were filtered through Celite
12. washthe filter cake was washed with EtOAc
13. additionThe filtrate was poured into a separatory funnel
14. customthe organic phase was separated
15. extractionThe aq. phase was extracted with EtOAc (2×10 mL)
16. washThe combined organic layers were washed with brine (10 mL)
17. dry with materialdried (MgSO4)
18. filtrationfiltered
19. concentrationconcentrated under vacuum
20. customPurification by silica gel chromatography (gradient: 10 to 50% EtOAc in hexanes)

ORD-Eintrag

ord-a9ef1743d7cb4ff6b4f0e93b1fe046c4

Quelldatensatz

uspto-grants-2014_07

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08765792B2