Sodium bicarbonate methylene chloride → 8-fluoro-5-{[5-(methyloxy)-1-(1-methyl-D-prolyl)-2,3-dihydro-1H-indol-6-yl]amino}-3-[(4-methylphenyl)sulfonyl]pyrrolo[2',3':4,5]pyrimido[6,1-b]quinazolin-7(3H)-one

HRID 1014455Notes

Reaction equation

Cl.Cl[C:3]1[N:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]2=[O:17])=[C:13]([F:18])[CH:12]=[CH:11][CH:10]=3)[C:6]2[CH:19]=[CH:20][N:21]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:5]=2[N:4]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][C:42]=1[NH2:43])[N:39]([C:44](=[O:51])[C@H:45]1[CH2:49][CH2:48][CH2:47][N:46]1[CH3:50])[CH2:38][CH2:37]2.C(=O)(O)[O-].[Na+].ClCCl>FC(F)(F)CO>[F:18][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[C:15](=[O:17])[N:16]1[C:3]([NH:43][C:42]3[CH:41]=[C:40]4[C:36]([CH2:37][CH2:38][N:39]4[C:44](=[O:51])[C@H:45]4[CH2:49][CH2:48][CH2:47][N:46]4[CH3:50])=[CH:35][C:34]=3[O:33][CH3:32])=[N:4][C:5]3[N:21]([S:22]([C:25]4[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=4)(=[O:23])=[O:24])[CH:20]=[CH:19][C:6]=3[C:7]1=[N:8]2

Participants

Conditions

Temperature: 80 °C

Procedure

A suspension of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (550 mg, 1.147 mmol) and 5-(methyloxy)-1-(1-methyl-D-prolyl)-2,3-dihydro-1H-indol-6-amine (363 mg, 1.320 mmol) in 2,2,2-trifluoroethanol (50 ml) was maintained at 80° C. for 2 hours. The solution was cooled, poured into saturated sodium bicarbonate/dichloromethane, and the organic layer was taken to a residue under reduced pressure. The residue was triturated with diethyl ether to afford 8-fluoro-5-{[5-(methyloxy)-1-(1-methyl-D-prolyl)-2,3-dihydro-1H-indol-6-yl]amino}-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (425 mg, 0.623 mmol, 54.3%) as a pale yellow solid. To a solution of 8-fluoro-5-{[5-(methyloxy)-1-(1-methyl-D-prolyl)-2,3-dihydro-1H-indol-6-yl]amino}-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (425 mg, 0.623 mmol) in tetrahydrofuran (50 ml) was added 2.0M MeNH2 in THF (3.12 ml, 6.23 mmol) and the resulting solution was stirred at room temperature for 6 hours. The reaction was diluted with ethyl acetate, washed with saturated sodium bicarbonate (aq) and the organic layer was dried over sodium sulfate, filtered, and taken to a residue under reduced pressure. The residue was dissolved in 1,4-dioxane (8 ml)/2.0 N NaOH (aq) (8 ml) and maintained at 120° C. under microwave heating for 12 minutes. The vial was cooled and its contents were dilulted with THF/EtOAc/saturated sodium chloride (aq). The organic layer was dried over sodium sulfate, filtered, stripped onto celite, and purified by column chromatography to afford 2-fluoro-N-methyl-6-[(2-{[5-(methyloxy)-1-(1-methyl-D-prolyl)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide (0.205 g, 0.367 mmol, 58.9%)as a grey solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.27 (s, 1H), 10.15 (s, 1H), 8.69 (s, 1H), 8.55 (s, 1H), 8.35 (d, J=8.43 Hz, 1H), 7.55 (s, 1H), 7.22-7.38 (m, 1H), 6.92-6.97 (m, 2H), 6.88 (t, J=9.30 Hz, 1H), 6.28 (dd, J=3.51, 1.91 Hz, 1H), 4.08-4.26 (m, 2H), 3.78 (s, 3H), 3.17-3.23 (m, 1H), 3.12 (t, J=7.62 Hz, 2H), 2.93-3.04 (m, 1H), 2.80 (d, J=4.21 Hz, 3H), 2.26 (s, 3H), 2.11-2.22 (m, 1H), 1.70-1.85 (m, 4H). ESIMS (M+H)+=559.

Workup

temperatureThe solution was cooled
customThe residue was triturated with diethyl ether

Sources & evidence

ORD record: ord-950dfc015b6546adb61d00fe776c43d7
Source dataset: uspto-grants-2011_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07981903B2

Reaction notes

Loading…