1,2-Dichloroethane → 3-{6-[(4-methylpiperazin-1-yl)carbonyl]-1H-indol-2-yl}quinolin-2(1H)-one

Temperature

50 °C

A solution of 1-tert-butyl 6-methyl 2-(trimethylstannyl)-1H-indole-1,6-dicarboxylate (1-6, 3.56 g, 8.12 mmol, 2.00 equiv) in dioxane (15 ml) was added in two equal portions over 2 hours to a solution of 3-iodo-1H-quinolin-2-one (5—5, 1.10 g, 4.06 mmol, 1 equiv), copper iodide (77 mg, 0.41 mmol, 0.10 equiv), and Pd(PPh3)4 (234 mg, 0.202 mmol, 0.050 equiv) at 90° C. The reaction mixture was then stirred for 24 hours, then partitioned between EtOAc (3×150 mL) and a 3:1 mixture of aqueous saturated NaHCO3 solution and brine (300 mL). The combined organic layers were washed with brine (250 mL), dried over sodium sulfate and concentrated. A solution of the residue in t-BuOH (50 mL) was treated with NaOH (1N, 4.06 mL, 4.06 mmol, 1 equiv) and heated to 50° C. for 24 hours. The solvent was removed in vacuo, and residue was partitioned between ether (50 mL) and aqueous NaHCO3 solution (50 mL). The aqueous layer was acidified to pH 6 with aqueous 1N HCl solution, then extracted with EtOAc (3×130 mL). The combined organic layers were dried over Na2SO4 concentrated. A solution of the residue (primarily 2-(2-oxo-1,2-dihydroquinolin-3-yl)-1H-indole-6-carboxylic acid, 30 mg), N-methylpiperazine (10 μL, 0.12 mmol, 1.2 equiv), EDC (23 mg, 0.12 mmol, 1.2 equiv), HOAt (16 mg, 0.12 mmol, 1.2 equiv), and triethylamine (30 μL, 0.25 mmol, 2.5 equiv) in DMF (10 mL) was stirred for 24 hours at ambient temperature. The reaction mixture was partitioned between EtOAc (3×60 mL) and water (100 mL), and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residual brown oil was purified via reverse phase LC (H2O/CH3CN gradient with 0.1% TFA present) to provide 3-{6-[(4-methylpiperazin-1-yl)carbonyl]-1H-indol-2-yl}quinolin-2(1H)-one (1-7). 1H NMR (300 MHz, DMSO) δ 12.25 (s, 1H), 11.86 (s, 1H), 8.63 (s, 1H), 7.77 (d, 1H, J=7.9 Hz), 7.69 (s, 1H), 7.64 (d, 1H, J=8.2 Hz), 7.56 (t, 1H, J=7.6 Hz), 7.38 (m, 2H), 7.27 (t, 1H, J=7.3 Hz), 7.13 (d, 1H, J=8.5 Hz), 4.30 (br s, 2H), 3.35 (br s, 4H), 3.17 (br s, 2H), 2.84 (br s, 3H).

1. custompartitioned between EtOAc (3×150 mL)
2. additiona 3:1 mixture of aqueous saturated NaHCO3 solution and brine (300 mL)
3. washThe combined organic layers were washed with brine (250 mL)
4. dry with materialdried over sodium sulfate
5. concentrationconcentrated
6. customThe solvent was removed in vacuo, and residue
7. customwas partitioned between ether (50 mL) and aqueous NaHCO3 solution (50 mL)
8. extractionextracted with EtOAc (3×130 mL)
9. dry with materialThe combined organic layers were dried over Na2SO4
10. concentrationconcentrated
11. customThe reaction mixture was partitioned between EtOAc (3×60 mL) and water (100 mL)
12. dry with materialthe combined organic layers were dried over Na2SO4
13. filtrationfiltered
14. concentrationconcentrated
15. customThe residual brown oil was purified via reverse phase LC (H2O/CH3CN gradient with 0.1% TFA present)

ORD record

ord-f4fc35bb9742458cb4443a9904c77623

Source dataset

uspto-grants-2005_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06927293B2