Phthalimide potassium salt → 2-(3-(5-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-1H-indazol-1-yl)propyl)isoindoline-1,3-dione

HRID 2390445Notes

Reaction equation

Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.[K]>CN(C=O)C.O>[O:30]=[C:15]1[CH:16]=[C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=2)[CH:18]=[CH:19][N:14]1[C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][CH2:3][CH2:2][N:35]1[C:31](=[O:41])[C:32]3[C:33](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:34]1=[O:36])[N:6]=[CH:7]2

Participants

Conditions

Temperature: 100 °C

Procedure

To a solution of 1-(1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (278 mg, 0.783 mmol) in DMSO (4.0 mL) was added 3-bromo-1-chloropropane (1.23 g, 7.83 mmol) and Cs2CO3 (765 mg, 2.35 mmol), and the reaction was stirred at ambient temperature for 18 h. The reaction was diluted with H2O (25 mL) and extracted with EtOAc (3×25 mL). The extracts were washed with brine (25 mL), dried over Na2SO4, and concentrated. Flash chromatography (silica gel, CH2Cl2/MeOH, 100:1) yielded 1-(1-(3-chloropropyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one. To a solution of 1-(1-(3-chloropropyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (84 g, 0.20 mmol) in DMF (1.5 mL) was added potassium phthalimide (41 mg, 0.22 mmol) and the reaction was heated to 100° C. for 4 h. The reaction was allowed to cool, diluted with H2O (20 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4, and concentrated. Flash chromatography (Biotage 25+M column, CH2Cl2/MeOH, 50:1 to 40:1) yielded 2-(3-(5-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-1H-indazol-1-yl)propyl)isoindoline-1,3-dione. 2-(3-(5-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-1H-indazol-1-yl)propyl)isoindoline-1,3-dione (73 mg, 0.13 mmol) was dissolved in ethanolamine (1.0 mL) and stirred at ambient temperature for 18 h. The reaction was concentrated. Flash column chromatography (Biotage 25+M column, CH2Cl2/MeOH/NH4OH, 30:1:0.1 to 10:1:0.2) yielded 1-(1-(3-aminopropyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one. 1-(1-(3-aminopropyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one was dissolved in CH2Cl2 (1.0 mL) and Et3N (30 μL, 0.22 mmol), and di-tert-butyl dicarbonate (26 mg, 0.12 mmol) were added. The resulting solution was stirred at ambient temperature for 18 h. The reaction was concentrated. Flash column chromatography (silica gel, CH2Cl2/MeOH, 40:1) afforded tert-butyl-3-(5-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-1H-indazol-1-yl)propylcarbamate. Tert-butyl-3-(5-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-1H-indazol-1-yl)propylcarbamate was dissolved in CH2Cl2 (1.0 mL) and TFA (25 μL, 0.33 mmol). The resulting solution was stirred at ambient temperature for 18 h. The reaction was diluted with CH2Cl2 (10 mL) and washed with saturated NaHCO3. The organic solution was dried over Na2SO4, filtered and concentrated. Flash column chromatography (silica gel, CH2Cl2/MeOH/NH4OH, 30:1:0.1 to 20:1:0.1) yielded the title compound (16 mg, 29%): 1H NMR (500 MHz, CDCl3) δ 8.03 (s, 1H), 7.77-7.74 (m, 5H), 7.58-7.44 (m, 3H), 6.92 (d, J=1.5 Hz, 1H), 6.53 (dd, J=7.5, 2.0 Hz, 1H), 4.54 (t, J=7.0 Hz, 2H), 2.70 (t, J=7.0 Hz, 2H), 2.10-2.04 (m, 2H).

Workup

temperatureto cool
extractionextracted with CH2Cl2 (3×25 mL)
washThe combined organic extracts were washed with brine (25 mL)
dry with materialdried over Na2SO4
concentrationconcentrated

Sources & evidence

ORD record: ord-8b77d3145c8442fd9dd105c38b947764
Source dataset: uspto-grants-2012_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08273770B2

Reaction notes

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