5-chloro-1-[(dimethylamino)acetyl]-2,3-dihydro-1H-indol-6-amine → 5-{[5-chloro-1-(N,N-dimethylglycyl)-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

HRID 1014459Notes

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.[Cl:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][C:41]=1[NH2:42])[N:38]([C:43](=[O:48])[CH2:44][N:45]([CH3:47])[CH3:46])[CH2:37][CH2:36]2>O1CCCC1>[Cl:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][C:41]=1[NH:42][C:3]1[N:16]3[C:7](=[N:8][C:9]4[C:14]([C:15]3=[O:17])=[C:13]([F:18])[CH:12]=[CH:11][CH:10]=4)[C:6]3[CH:19]=[CH:20][N:21]([S:22]([C:25]4[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=4)(=[O:23])=[O:24])[C:5]=3[N:4]=1)[N:38]([C:43](=[O:48])[CH2:44][N:45]([CH3:46])[CH3:47])[CH2:37][CH2:36]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 (0.550 g, 1.147 mmol) and 5-chloro-1-[(dimethylamino)acetyl]-2,3-dihydro-1H-indol-6-amine (0.291 g, 1.147 mmol) in tetrahydrofuran (20 ml) was maintained at 80° C. in a pressure vessel for 16 hours. The vessel was cooled, THF removed under reduced pressure, and the solids were partitioned between methylene chloride/trifluoroethanol/saturated sodium bicarbonate. The organic layer was taken to a residue under reduced pressure and triturated with diethyl ether to afford 5-{[5-chloro-1-(N,N-dimethylglycyl)-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 (0.550 g, 0.833 mmol, 72.6%) as a reasonably pure (ca 70-80%) green solid. A solution of 5-{[5-chloro-1-(N,N-dimethylglycyl)-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 (0.550 g, 0.833 mmol) and 2.0M methyl amine/THF (2.500 ml, 5.00 mmol) in tetrahydrofuran (20 ml) was stirred at room temperature for 5 hours. The reaction was stripped directly onto celite and purified by column chromatography to afford the intermediate tosylate as a yellow foam. This intermediate was dissolved in 1,4-dioxane (8 ml) and added to a microwave vial with 2.0N NaOH (aq) (8 ml). Microwave heating at 120° C. for 12 minutes was followed by cooling, dilution with ethyl acetate/saturated sodium bicarbonate/THF and the resulting organic layer was dried over sodium sulfate, filtered, stripped onto celite, and purified by column chromatography to afford 2-[(2-{[5-chloro-1-(N,N-dimethylglycyl)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (0.068 g) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.31 (s, 1H), 10.19 (s, 1H), 8.52 (s, 1H), 8.39 (s, 1H), 8.32 (d, J=8.63 Hz, 1H), 8.15 (s, 1H), 7.33 (s, 1H), 7.20-7.30 (m, 1H), 6.92-6.97 (m, J=3.01 Hz, 1H), 6.83-6.92 (m, 1H), 6.26 (dd, J=3.41, 1.81 Hz, 1H), 4.21 (t, J=8.43 Hz, 2H), 3.20 (s, 2H), 3.09-3.17 (m, 2H), 2.80 (d, J=4.61 Hz, 3H), 2.24 (s, 6H). ESIMS (M+H)+=537.

Workup

temperatureThe vessel was cooled
customTHF removed under reduced pressure
customthe solids were partitioned between methylene chloride/trifluoroethanol/saturated sodium bicarbonate
customtriturated with diethyl ether

Sources & evidence

ORD record: ord-966f4f09e07d434fa01bc1a15e24f3f0
Source dataset: uspto-grants-2011_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07981903B2

Reaction notes

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