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 1014454노트

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HRID 1014454 반응식
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

참가 물질

6

반응물 4

HCID 3283Diethyl EtherHCID 6344DichloromethaneHCID 673161895-(methyloxy)-1-(1-methyl-L-prolyl)-2,3-dihydro-1H-indol-6-amineHCID 673162535-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2',3':4,5]pyrimido[6,1-b]quinazolin-7(3H)-one HCl salt

생성물 1

HCID 673170068-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)-one수율 49.9%

시약·촉매·용매 1

HCID 64092,2,2-Trifluoroethanol용매

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온도
90 °C

실험 절차

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.

후처리

  1. temperatureThe solution was cooled

출처 및 근거

ORD 기록
ord-26167ed23e4e4b6bb130bd60516a3cbd
출처 데이터셋
uspto-grants-2011_07
특허 번호
US07981903B2

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