1-[(dimethylamino)acetyl]-3,3-dimethyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine → 5-{[1-(N, N-dimethylglycyl)-3,3-dimethyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2',3':4,5]pyrimido[6,1-b]quinazolin-7(3H)-one
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][N:33]([CH2:35][C:36]([N:38]1[C:46]2[C:41](=[CH:42][C:43]([O:48][CH3:49])=[C:44]([NH2:47])[CH:45]=2)[C:40]([CH3:51])([CH3:50])[CH2:39]1)=[O:37])[CH3:34]>C1COCC1>[CH3:32][N:33]([CH3:34])[CH2:35][C:36]([N:38]1[C:46]2[C:41](=[CH:42][C:43]([O:48][CH3:49])=[C:44]([NH:47][C:3]3[N:16]4[C:7](=[N:8][C:9]5[C:14]([C:15]4=[O:17])=[C:13]([F:18])[CH:12]=[CH:11][CH:10]=5)[C:6]4[CH:19]=[CH:20][N:21]([S:22]([C:25]5[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=5)(=[O:24])=[O:23])[C:5]=4[N:4]=3)[CH:45]=2)[C:40]([CH3:50])([CH3:51])[CH2:39]1)=[O:37]Participants
Reactant 2
Product 1
Reagents, catalysts & solvents 1
Procedure
A solution of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (500 mg, 1.043 mmol) and 1-[(dimethylamino)acetyl]-3,3-dimethyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (333 mg, 1.200 mmol) in THF (8 ml) was warmed to 75° C. in a sealed pressure vial for 16 hours. The solution was concentrated under reduced pressure, suspended in dichloromethane, and washed with saturated sodium bicarbonate. The organic layer was taken to a residue under reduced pressure and triturated with diethyl ether to afford 5-{[1-(N, N-dimethylglycyl)-3,3-dimethyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (0.472 g, 0.690 mmol, 66.2%) as a pale greenish yellow solid. A solution of 5-{[1-(N,N-dimethylglycyl)-3,3-dimethyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8′-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (0.472 g, 0.690 mmol) and 2.0M methyl amine in THF (2.76 ml, 5.52 mmol) in THF (40 ml) was stirred for 3 hours at room temperature. The reaction was poured into saturated sodium bicarbonate and diluted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, redissolved in 1,4-dioxane (8 ml) and added to a microwave-safe vial with 2.0N NaOH (aq) (8 ml). The contents were warmed to 120° C. under microwave irradiation with rapid stirring for 12 minutes, cooled to room temperature, and poured into THF/ethyl acetate/saturated/sodium bicarbonate (aq). The organic layer was dried over sodium sulfate, filtered, stripped onto celite, and purified by column chromatography to afford 2-[(2-{[1-(N,N-dimethylglycyl)-3,3-dimethyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (0.202 g, 0.360 mmol, 52.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.26 (s, 1H), 10.14 (s, 1H), 8.56 (s, 1H), 8.54 (d, J=4.61 Hz, 1H), 8.34 (d, J=8.43 Hz, 1H), 7.58 (s, 1H), 7.25-7.35 (m, 1H), 6.93-7.00 (m, 2H), 6.85-6.93 (m, 1H), 6.21-6.32 (m, 1H), 3.93 (s, 2H), 3.79 (s, 3H), 3.17 (s, 2H), 2.79 (d, J=4.41 Hz, 3H), 2.24 (s, 6H), 1.32 (s, 6H). ESIMS (M+H)+=561.
Workup
- concentrationThe solution was concentrated under reduced pressure
- washwashed with saturated sodium bicarbonate
- customtriturated with diethyl ether
Sources & evidence
- ORD record
- ord-dfe327f80d7c416cbfe4caa2373ecd75
- Source dataset
- uspto-grants-2011_07
- Patent number
- US07981903B2
Reaction notes
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