Abstract: The C-H arylation of indoles holds the promise to shorten synthetic routes in the production of pharmaceuticals. However, late-stage C-H activation reactions often rely on the presence of protecting groups or stoichiometric metal additives. The regiospecific C-H arylation of a highly functionalized azepino[5,3,4-cd]indole scaffold lacking directing groups via Pd(II) and Cu(II) co-catalysis is reported. The direct C-H coupling was demonstrated in the convergent synthesis of rucaparib, an FDA approved anticancer drug.
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Stage #1: at 20℃; for 46 h; Stage #2: With sodium hydroxide In water at 0 - 35℃;
Example 13 Synthesis of 8-Fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (15) Lactam 14 (14.42 g, 0.038 mol) was dissolved in hydrobromic acid in acetic acid (30percent-32percent, 140 ml). The reaction solution was stirred for 46 hours at room temperature in a 500 ml flask that was connected to an ethanolamine scrubber system. HPLC analysis indicated the completion of the reaction. Ice (30 g) was added to the reaction solution followed by addition of aqueous NaOH (327 ml, 10 M, 3.27 mol) while the temperature was maintained between 25° C. and 35° C. When addition of NaOH was complete, the pH was 10. The resulting solid was collected by filtration, washed with water (2*50 ml). The filter cake was then suspended in water (125 ml) and stirred for 2 hours. The solid was collected by filtration, washed with water (2*25 ml) and dried to afford 10.76 g of product (88percent yield). 1H NMR (300 MHz, DMSO-d6) δ 2.577(s, 3H), 3.053(m, 2H), 3.406(m, 2H), 4.159(s, 2H), 7.36(dd, 1H, J=2.4 Hz and J=9.3 Hz), 7.44(dd, 1H, J=2.4 Hz and J=11.1 Hz), 7.63(d, 2H, J=8.1 Hz), 7.70(d, 2H, J=8.1 Hz), 8.265(t, 1H, J=5.7 Hz), 11.77(s, 1H). Exact mass calculated for C19H19FN3O: 324.1512. Found: 324.1497.
With bis(acetato)bis(triphenylphosphine)palladium(0); sodium carbonate In methanol; water at 60℃; for 4 h; Inert atmosphere
2-Bromo-8-fluoro-4,5-dihydro-lH-azepino[5,4,3-cd]indol-6(3H)-one (10 g; 35.3 mmol), prepared according to process described in Example 3, sodium carbonate (3.74 g; 35.3 mmol), bis(triphenylphosphine)palladium(II) diacetate (0.529 g; 0.71 mmol) and (4-((methylamino)methyl)phenyl)boronic acid solution (75 ml; 45.9 mmol), prepared according to process described in Example 2, are charged into a three-necked round bottom flask, followed by inertisation with nitrogen. A previously degassed mixture of methanol (130 mL) and water (40 mL) is added and the reaction mixture is stirred at 60°C for 4 hours. The reaction mixture is cooled to ambient temperature followed by addition of activated carbon. The mixture is stirred at ambient temperature for one hour, heated to 50 °C, stirred for another hour and then filtered through a layer of celite. The solution of 8-fluoro-2-(4- ((methylamino)methyl)phenyl)-4,5-dihydro-lH-azepino[5,4,3-cd]indol-6(3H)-one is concentrated to about 110 mL, heated to 40°C followed by dropwise addition of water (40 mL). Reaction mixture is cooled to ambient temperature and stirred for 17 hours at ambient temperature and additional one hour at 0-5°C. Solid is filtered off, washed with water and dried in vacuum oven at 50°C for 5 hours. Crude material (9.5 g) is suspended in methanol (95mL) at reflux temperature and stirred for 20 minutes. Suspension is than cooled down and stirred for 17 hours at ambient temperature and 1.5 hour at 0-5°C. Crystals are filtered off, washed with methanol and dried in vacuum oven at 50°C for 4 hours to obtain 6.82 g of Rucaparib base.
Reference：
[1] ACS Chemical Neuroscience, 2018, vol. 9, # 6, p. 1259 - 1263
4
[ 773059-19-1 ]
[ 283173-50-2 ]
Reference：
[1] Organic Process Research and Development, 2012, vol. 16, # 12, p. 1897 - 1904
5
[ 283173-84-2 ]
[ 283172-68-9 ]
[ 283173-50-2 ]
Reference：
[1] Patent: US6495541, 2002, B1,
6
[ 1408282-26-7 ]
[ 283173-50-2 ]
Reference：
[1] Organic Process Research and Development, 2012, vol. 16, # 12, p. 1897 - 1904
[2] Organic Process Research and Development, 2012, vol. 16, # 12, p. 1897 - 1904
[3] ACS Chemical Neuroscience, 2018, vol. 9, # 6, p. 1259 - 1263
[4] Patent: WO2018/140377, 2018, A1,
7
[ 283173-80-8 ]
[ 283173-50-2 ]
Reference：
[1] Organic Process Research and Development, 2012, vol. 16, # 12, p. 1897 - 1904
[2] Organic Process Research and Development, 2012, vol. 16, # 12, p. 1897 - 1904
[3] ACS Chemical Neuroscience, 2018, vol. 9, # 6, p. 1259 - 1263
8
[ 399-51-9 ]
[ 283173-50-2 ]
Reference：
[1] ACS Chemical Neuroscience, 2018, vol. 9, # 6, p. 1259 - 1263
9
[ 141071-78-5 ]
[ 283173-50-2 ]
Reference：
[1] ACS Chemical Neuroscience, 2018, vol. 9, # 6, p. 1259 - 1263
10
[ 283173-84-2 ]
[ 283173-50-2 ]
Reference：
[1] Organic Process Research and Development, 2012, vol. 16, # 12, p. 1897 - 1904
[2] Organic Process Research and Development, 2012, vol. 16, # 12, p. 1897 - 1904
11
[ 1408282-25-6 ]
[ 283173-50-2 ]
Reference：
[1] Organic Process Research and Development, 2012, vol. 16, # 12, p. 1897 - 1904
[2] Organic Process Research and Development, 2012, vol. 16, # 12, p. 1897 - 1904
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