Methylamine → HCID 178485530, compound

HRID 1014456Notes

Reaction equation

HRID 1014456 reaction equation
[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:49])[N:5]1[C:15]([NH:16][C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][CH2:22][N:23]4[C:26](=[O:33])[C@H:27]4[CH2:31][CH2:30][CH2:29][N:28]4[CH3:32])=[CH:19][C:18]=3[O:34][CH3:35])=[N:14][C:13]3[N:36](S(C4C=CC(C)=CC=4)(=O)=O)[CH:37]=[CH:38][C:12]=3[C:6]1=[N:7]2.[CH3:50][NH2:51]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:7][C:6]2[N:5]=[C:15]([NH:16][C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][CH2:22][N:23]4[C:26](=[O:33])[C@H:27]4[CH2:31][CH2:30][CH2:29][N:28]4[CH3:32])=[CH:19][C:18]=3[O:34][CH3:35])[NH:14][C:13]3=[N:36][CH:37]=[CH:38][C:12]=23)[C:3]=1[C:4]([NH:51][CH3:50])=[O:49]

Participants

5

Reactant 2

HCID 6329MethylamineHCID 673159178-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

Product 1

HCID 178485530HCID 178485530, compoundYield 58.9%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

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

  1. washwashed with saturated sodium bicarbonate (aq)
  2. dry with materialthe organic layer was dried over sodium sulfate
  3. filtrationfiltered
  4. dissolutionThe residue was dissolved in 1,4-dioxane (8 ml)/2.0 N NaOH (aq) (8 ml)
  5. temperaturemaintained at 120° C. under microwave
  6. temperatureheating for 12 minutes
  7. temperatureThe vial was cooled
  8. dry with materialThe organic layer was dried over sodium sulfate
  9. filtrationfiltered
  10. custompurified by column chromatography

Sources & evidence

ORD record
ord-c00fb7c7281142d88fe2169408326680
Source dataset
uspto-grants-2011_07
Patent number
US07981903B2

Reaction notes

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