Methylamine → HCID 178485537, compound

HRID 1014479Notes

Reaction equation

HRID 1014479 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(C3C=CC(C)=CC=3)(=O)=O)[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:48])[CH2:45][O:46][CH3:47])[CH2:38][CH2:37]2.[CH3:49][NH2:50].[OH-].[K+].[OH-].[Na+]>C1COCC1.CCOC(C)=O>[F:18][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:8][C:7]2[N:16]=[C:3]([NH:43][C:42]3[CH:41]=[C:40]4[C:36]([CH2:37][CH2:38][N:39]4[C:44](=[O:48])[CH2:45][O:46][CH3:47])=[CH:35][C:34]=3[O:33][CH3:32])[NH:4][C:5]3=[N:21][CH:20]=[CH:19][C:6]=23)[C:14]=1[C:15]([NH:50][CH3:49])=[O:17]

Participants

8

Reactant 5

HCID 6329MethylamineHCID 14797Potassium HydroxideHCID 14798Sodium HydroxideHCID 594417515-(methyloxy)-1-[(methyloxy)acetyl]-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

Product 1

HCID 178485537HCID 178485537, compoundYield 26.7%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

A thick white slurry of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (400 mg, 0.835 mmol) and 5-(methyloxy)-1-[(methyloxy)acetyl]-2,3-dihydro-1H-indol-6-amine (197 mg, 0.835 mmol) in THF (15 mL) was heated at 80° C. After 17 h a methylamine solution (2 N in THF, 4.17 mL, 8.35 mmol) was added. The reaction mixture was maintained at rt for 22 h, then filtered, the solid washed with THF. The filtrate was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2. The crude product was dissolved in dioxane (15 mL) and a 1N KOH solution (4.38 mL, 4.38 mmol), then heated at 80° C. After 3 h the reaction mixture was allowed to cool somewhat, diluted with EtOAc (100 mL) and a 2N NaOH solution (50 mL). The organic layer was washed with a 2N NaOH solution (2×50 mL), concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 2-fluoro-N-methyl-6-{[2-({5-(methyloxy)-1-[(methyloxy)acetyl]-2,3-dihydro-1H-indol-6-yl}amino)-1H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}benzamide as a yellow solid (116 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.80 (d, J=4.39 Hz, 3H), 3.13 (t, J=8.24 Hz, 2H), 3.79 (s, 3H), 4.04 (t, J=8.24 Hz, 2H), 4.17 (s, 2H), 6.25-6.34 (m, 1H), 6.84-7.04 (m, 3H), 7.27-7.40 (m, 1H), 7.58 (s, 1H), 8.35 (d, J=8.24 Hz, 1H), 8.50-8.61 (m, 1H), 8.68 (s, 1H), 10.16 (s, 1H), 11.30 (s, 1H), a Me-O signal with 3 protons is missing, may overlap with water peak in sample; ESIMS (M+H)+=520.16.

Workup

  1. filtrationfiltered
  2. washthe solid washed with THF
  3. concentrationThe filtrate was concentrated onto Celite
  4. custompurified by silica gel chromatography
  5. dissolutionThe crude product was dissolved in dioxane (15 mL)
  6. temperatureto cool somewhat
  7. washThe organic layer was washed with a 2N NaOH solution (2×50 mL)
  8. concentrationconcentrated onto Celite
  9. custompurified by silica gel chromatography

Sources & evidence

ORD record
ord-19a65f1ababd48c191e45c09934fc921
Source dataset
uspto-grants-2011_07
Patent number
US07981903B2

Reaction notes

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