4-Fluorobenzylamine → HCID 178486487, compound

HRID 1014485Notes

Reaction equation

HRID 1014485 reaction equation
[CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:29]4[C:20](=[N:21][C:22]5[C:27]([C:28]4=[O:30])=[C:26]([F:31])[CH:25]=[C:24]([F:32])[CH:23]=5)[C:19]4[CH:33]=[CH:34][N:35](S(C5C=CC(C)=CC=5)(=O)=O)[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[F:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][NH2:57])=[CH:52][CH:51]=1>C1COCC1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[NH:17][C:18]4=[N:35][CH:34]=[CH:33][C:19]4=[C:20]([NH:21][C:22]4[CH:23]=[C:24]([F:32])[CH:25]=[C:26]([F:31])[C:27]=4[C:28]([NH:57][CH2:56][C:53]4[CH:54]=[CH:55][C:50]([F:49])=[CH:51][CH:52]=4)=[O:30])[N:29]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]

Participants

5

Reactant 2

HCID 673264-FluorobenzylamineHCID 673166665-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8,10-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2',3':4,5]pyrimido[6,1-b]quinazolin-7(3H)-one

Product 1

HCID 178486487HCID 178486487, compoundYield 23.4%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

To a solution of 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8,10-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (300 mg, 0.445 mmol) in THF (5 mL) was added [(4-fluorophenyl)methyl]amine (1.01 mL, 8.89 mmol). The resulting mixture was let stir at rt for 16 h at which time it was diluted with ethyl acetate and washed with a saturated ammonium chloride solution, a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure and purified via SiO2. This lead to a yellow solid containing 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,6-difluoro-N-[(4-fluorophenyl)methyl]benzamide. This crude material was dissolved in 1,4-dioxane (5 mL) and transferred to a 20 ml microwave vessel. A solution of 2 M NaOH (5 ml) was added and reaction heated in microwave at 120° C. for 8 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a 10% ammonium chloride solution, saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a yellow solid which was purified via chromatography on SiO2 to afford 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4,6-difluoro-N-[(4-fluorophenyl)methyl]benzamide (67 mg, 0.104 mmol) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 6 H), 3.06-3.18 (m, 4 H), 3.76 (s, 3 H), 4.16 (t, J=8.29 Hz, 2 H), 4.51 (d, J=5.86 Hz, 2 H), 6.17 (d, J=1.19 Hz, 1 H), 6.81-7.01 (m, 3 H), 7.13 (t, J=8.84 Hz, 2 H), 7.38 (dd, J=8.29, 5.72 Hz, 2 H), 7.78 (s, 1 H), 8.43 (d, J=11.90 Hz, 1 H), 8.51 (s, 1 H), 9.14-9.25 (m, 1 H), 10.38 (s, 1 H), 11.32 (br. s., 1 H). (ESIMS (M+H)+=645)

Workup

  1. washwashed with a saturated ammonium chloride solution
  2. dry with materialOrganics were dried over sodium sulfate and solvents
  3. customremoved under reduced pressure
  4. custompurified via SiO2
  5. additionThis lead to a yellow solid containing 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,6-difluoro-N-[(4-fluorophenyl)methyl]benzamide
  6. dissolutionThis crude material was dissolved in 1,4-dioxane (5 mL)
  7. customtransferred to a 20 ml microwave vessel
  8. additionA solution of 2 M NaOH (5 ml) was added
  9. customreaction
  10. temperatureheated in microwave at 120° C. for 8 minutes
  11. customResulting brown solution
  12. washwashed with a 10% ammonium chloride solution, saturated sodium bicarbonate solution, water
  13. dry with materialOrganics were dried over sodium sulfate and solvents
  14. customremoved under reduced pressure
  15. customto afford a yellow solid which
  16. customwas purified via chromatography on SiO2

Sources & evidence

ORD record
ord-7311157a0dc84b6db15d0cabb5ede350
Source dataset
uspto-grants-2011_07
Patent number
US07981903B2

Reaction notes

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