Methyl 3-cyclohexyl-1H-indole-6-carboxylate → 1H-indole-6-carboxylic acid

Temperature

2.5 °C

Freshly recrystallized pyridinium tribromide (recrystallization from hot AcOH (5 mL per 1 g), rinsed with cold AcOH and dried under high vacuum over KOH) was added in portions (over 10 min.) to a stirring solution of methyl 3-cyclohexyl-1H-indole-6-carboxylate (60 g, 233 mmol) (prepared using procedures describe in WO2004/065367) in CHCl3/THF (1:1, 1.25 L) at 2° C. The reaction solution was stirred at 0-5° C. for 2.5 h, and washed with sat. aq. NaHSO3 (1 L), 1 N HCl (1 L) and brine (1 L). The organic layer was dried (MgSO4) and concentrated. The resulting red oil was diluted with Et2O and concentrated. The resulting pink solid was dissolved into Et2O (200 mL) treated with hexanes (300 mL) and partially concentrated. The solids were collected by filtration and rinsed with hexanes. The mother liquor was concentrated to dryness and the procedure repeated. The solids were combined to yield 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-, methyl ester (64 g, 190 mmol, 82%) as a fluffy pink solid, which was used without further purification. 1HNMR (300 MHz, CDCl3) δ 8.47 (br s, 1H), 8.03 (d, J=1.4 Hz, 1H), 7.74 (dd, J=1.4, 8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 3.92 (s, 3H), 2.82 (tt, J=3.7, 11.7 Hz, 1H), 1.98-1.72 (m, 7H), 1.50-1.27 (m, 3H). 13CNMR (75 MHz, CDCl3) δ 168.2, 135.6, 130.2, 123.1, 120.8, 120.3, 118.7, 112.8, 110.7, 52.1, 37.0, 32.2(2), 27.0(2), 26.1. LCMS: m/e 334 (M−H)−, ret time 3.34 min, column A, 4 minute gradient.

1. washwashed with sat. aq. NaHSO3 (1 L), 1 N HCl (1 L) and brine (1 L)
2. dry with materialThe organic layer was dried (MgSO4)
3. concentrationconcentrated
4. additionThe resulting red oil was diluted with Et2O
5. concentrationconcentrated
6. dissolutionThe resulting pink solid was dissolved into Et2O (200 mL)
7. additiontreated with hexanes (300 mL)
8. concentrationpartially concentrated
9. filtrationThe solids were collected by filtration
10. washrinsed with hexanes
11. concentrationThe mother liquor was concentrated to dryness

ORD record

ord-4550918e8f8743b093477a22ed9e343b

Source dataset

uspto-grants-2009_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07541352B2