Methylamine → HCID 178485520, compound

HRID 1014526Notes

Reaction equation

HRID 1014526 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.[NH2:32][C:33]1[CH:42]=[C:41]2[C:36]([C:37]([CH3:45])([CH3:44])[CH2:38][C:39](=[O:43])[NH:40]2)=[CH:35][C:34]=1[O:46][CH3:47].[CH3:48][NH2:49].C[O-].[Na+]>O1CCCC1.C(=O)(O)[O-].[Na+].O>[CH3:45][C:37]1([CH3:44])[C:36]2[C:41](=[CH:42][C:33]([NH:32][C:3]3[NH:4][C:5]4=[N:21][CH:20]=[CH:19][C:6]4=[C:7]([NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:18])[C:14]=4[C:15]([NH:49][CH3:48])=[O:17])[N:16]=3)=[C:34]([O:46][CH3:47])[CH:35]=2)[NH:40][C:39](=[O:43])[CH2:38]1

Participants

8

Reactant 4

HCID 6329MethylamineHCID 10942334Sodium MethoxideHCID 59441929HCID 59441929, compoundHCID 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 178485520HCID 178485520, compoundYield 47.6%

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (0.20 g, 0.41 mmol) and 7-amino-4,4-dimethyl-6-(methyloxy)-3,4-dihydro-2(1H)-quinolinone (0.10 g, 0.45 mmol) was taken in tetrahydrofuran (7.0 mL) and refluxed for 3 h. The reaction was cooled, diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate, filtered, concentrated, diluted with tetrahydrofuran (10 mL) and treated with excess methyl amine (10 mL, 20 mmol, 2M in THF). The reaction was stirred for 16 h and then heated in a sealed tube at 50° C. for another 6 h. The reaction was cooled, diluted with water, and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated. The crude material was dissolved in tetrahydrofuran (5.0 mL), diluted with methanol (5.0 mL) and treated with sodium methoxide (700 mg, 28.5 mmol) and stirred at 50° C. for 3 h. The reaction was cooled, diluted with water, and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, and purified by flash silica gel column chromatography (dichloromethane to 8:1:1 mixture of dichloromethane:methanol:2M ammonia in methanol) to provide 2-[(2-{[4,4-dimethyl-6-(methyloxy)-2-oxo-1,2,3,4-tetrahydro-7-quinolinyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (0.100 g, 0.195 mmol, 43% over 3 steps).

Workup

  1. temperaturerefluxed for 3 h
  2. temperatureThe reaction was cooled
  3. extractionextracted with dichloromethane
  4. customThe organic layer was separated
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. additiondiluted with tetrahydrofuran (10 mL)
  9. temperatureThe reaction was cooled
  10. extractionextracted with ethyl acetate
  11. customThe organic layer was separated
  12. dry with materialdried over sodium sulfate
  13. concentrationconcentrated
  14. dissolutionThe crude material was dissolved in tetrahydrofuran (5.0 mL)
  15. additiondiluted with methanol (5.0 mL)
  16. stirringstirred at 50° C. for 3 h
  17. temperatureThe reaction was cooled
  18. extractionextracted with ethyl acetate
  19. customThe organic layer was separated
  20. dry with materialdried over sodium sulfate
  21. custompurified by flash silica gel column chromatography (dichloromethane to 8:1:1 mixture of dichloromethane:methanol:2M ammonia in methanol)

Sources & evidence

ORD record
ord-3cd83c39921e475d880ff83bfcd7dd46
Source dataset
uspto-grants-2011_07
Patent number
US07981903B2

Reaction notes

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