Diethyl Ether → 8-fluoro-5-{[5-(methyloxy)-1-(1-methyl-L-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 1014454Notes

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.ClCCl.C(OCC)C>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: 90 °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-L-prolyl)-2,3-dihydro-1H-indol-6-amine (363 mg, 1.320 mmol) in 2,2,2-trifluoroethanol (50 ml) was maintained at 90° C. for 2 hours. The solution was cooled, poured into dichloromethane/saturated sodium bicarbonate, and the organic layer was taken to a residue under reduced pressure. Trituration with diethyl ether affords 8-fluoro-5-{[5-(methyloxy)-1-(1-methyl-L-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 (0.390 g, 0.572 mmol, 49.9%) as a pale yellow solid contaminated with 25% of the corresponding ring-openened trifluoroethyl ester. This mixture (0.390 g, 0.572 mmol) was directly dissolved in tetrahydrofuran (50 ml) and 2.0M MeNH2 in THF (2.86 ml, 5.72 mmol) was added. 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-L-prolyl)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide (0.096 g, 0.172 mmol, 30.0%) as a grey solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.27 (s, 1H), 10.14 (s, 1H), 8.69 (s, 1H), 8.55 (s, 1H), 8.35 (d, J=8.63 Hz, 1H), 7.55 (s, 1H), 7.26-7.38 (m, 1H), 6.92-6.99 (m, 2H), 6.83-6.92 (m, 1H), 6.28 (dd, J=3.31, 1.91 Hz, 1H), 4.07-4.30 (m, 2H), 3.77 (s, 3H), 3.18-3.27 (m, 1H), 3.07-3.16 (m, 2H), 2.93-3.04 (m, 1H), 2.80 (d, J=4.61 Hz, 3H), 2.26 (s, 3H), 2.11-2.21 (m, 1H), 1.77 (m, 4H). ESIMS (M+H)+=559.

Workup

temperatureThe solution was cooled

Sources & evidence

ORD record: ord-26167ed23e4e4b6bb130bd60516a3cbd
Source dataset: uspto-grants-2011_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07981903B2

Reaction notes

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