* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
The product from Step A (8.0 g, 41.0 mmol) was stirred in H3PO4 (85percent, 50 ml) at room temperature for 30 minutes. The resulting cloudy mixture was diluted with water and extracted (4*) with diethyl ether. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent removed in vacuo. The crude material was purified by flash chromatography on silica gel (20:1 hexanes/ethyl acetate) to afford benzofuran methyl ester 3.87 g (53percent) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ7.99 (d, 1H, J=7.1 Hz), 7.68-7.74 (m, 2H), 7.32-7.38 (m, 2H), 3.99 (m, 3H); CI MS m/z=177 [C10H8O3+H]+.
Reference：
[1] Journal of Medicinal Chemistry, 1995, vol. 38, # 16, p. 3094 - 3105
[2] Patent: US2006/111385, 2006, A1, . Location in patent: Page/Page column 9; 16
2
[ 166599-85-5 ]
[ 166599-84-4 ]
Yield
Reaction Conditions
Operation in experiment
62%
Stage #1: for 5.46667 h; Heating / reflux Stage #2: With sodium hydroxide; water In toluene at 60℃; for 9 h; Stage #3: With hydrogenchloride In water at 2 - 14℃; for 14.5 h; Heating / reflux
A solution of Intermediate 10 in toluene (1 wt in 6.6 vol) was added to a refluxing mixture of p-toluenesulfonic acid (0.03 eq., 0.03 wt) in toluene (3.8 vol) over 43 minutes. The mixture was stirred under reflux for 33 minutes then solvent (1.1 vol) was withdrawn at 130 0C jacket temperature under slightly reduced pressure (1000- 880 mbar). The mixture was further stirred at reflux. 4.25 hours after the addition of Intermediate 10 the mixture was cooled to 25 0C. The mixture was filtered over silica gel (1.1 wt) that had been conditioned with toluene (4.1 vol). The silica plug was further washed with toluene (8.2 vol). The product containing fractions were combined (total volume 10.8 vol). Solvent (8.6 vol) was withdrawn at 80 0C jacket temperature under reduced pressure. Toluene (0.6 vol) and 1.0 M NaOH (1.5 eq., 7.7 vol) was added and the two-phase mixture was stirred at 60 0C for 9 hours. After cooling to 20 0C the phases were separated and 32percent HCI (1.7 vol) was added at 2- 14°C to the aqueous phase. After addition of 9.4 vol toluene the mixture was stirred under reflux for 14.5 hours. The suspension was cooled to 20 0C and THF (5.3 vol) was added. The phases were separated and the organic layer was washed two times with a mixture of 5.6 vol water and 0.6 vol THF. 10.3 vol of solvent was distilled off at 80 0C jacket temperature and reduced pressure before 3.2 vol toluene was added. The mixture was refluxed for 33 minutes (ambient pressure), cooled to 0 0C over 3 hours and stirred at that temperature for 2.5 days. The precipitate was filtered, dried for 2 hours in a stream of nitrogen and dried in a rotavap at 50 0C to give the title compound as an off-white solid. Yield (percent theory): 62percent
Reference：
[1] Patent: WO2009/34133, 2009, A1, . Location in patent: Page/Page column 18
[2] Journal of Medicinal Chemistry, 1995, vol. 38, # 16, p. 3094 - 3105
The product from Step A (8.0 g, 41.0 mmol) was stirred in H3PO4 (85%, 50 ml) at room temperature for 30 minutes. The resulting cloudy mixture was diluted with water and extracted (4*) with diethyl ether. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent removed in vacuo. The crude material was purified by flash chromatography on silica gel (20:1 hexanes/ethyl acetate) to afford benzofuran methyl ester 3.87 g (53%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) delta7.99 (d, 1H, J=7.1 Hz), 7.68-7.74 (m, 2H), 7.32-7.38 (m, 2H), 3.99 (m, 3H); CI MS m/z=177 [C10H8O3+H]+.
A solution of Intermediate 10 in toluene (1 wt in 6.6 vol) was added to a refluxing mixture of p-toluenesulfonic acid (0.03 eq., 0.03 wt) in toluene (3.8 vol) over 43 minutes. The mixture was stirred under reflux for 33 minutes then solvent (1.1 vol) was withdrawn at 130 0C jacket temperature under slightly reduced pressure (1000- 880 mbar). The mixture was further stirred at reflux. 4.25 hours after the addition of Intermediate 10 the mixture was cooled to 25 0C. The mixture was filtered over silica gel (1.1 wt) that had been conditioned with toluene (4.1 vol). The silica plug was further washed with toluene (8.2 vol). The product containing fractions were combined (total volume 10.8 vol). Solvent (8.6 vol) was withdrawn at 80 0C jacket temperature under reduced pressure. Toluene (0.6 vol) and 1.0 M NaOH (1.5 eq., 7.7 vol) was added and the two-phase mixture was stirred at 60 0C for 9 hours. After cooling to 20 0C the phases were separated and 32% HCI (1.7 vol) was added at 2- 14C to the aqueous phase. After addition of 9.4 vol toluene the mixture was stirred under reflux for 14.5 hours. The suspension was cooled to 20 0C and THF (5.3 vol) was added. The phases were separated and the organic layer was washed two times with a mixture of 5.6 vol water and 0.6 vol THF. 10.3 vol of solvent was distilled off at 80 0C jacket temperature and reduced pressure before 3.2 vol toluene was added. The mixture was refluxed for 33 minutes (ambient pressure), cooled to 0 0C over 3 hours and stirred at that temperature for 2.5 days. The precipitate was filtered, dried for 2 hours in a stream of nitrogen and dried in a rotavap at 50 0C to give the title compound as an off-white solid. Yield (% theory): 62%
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