Methylamine → HCID 178485519, compound

HRID 1014525Notes

Reaction equation

HRID 1014525 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][N:33]([CH2:35][C:36]([N:38]1[C:47]2[C:42](=[CH:43][C:44]([O:49][CH3:50])=[C:45]([NH2:48])[CH:46]=2)[C:41]([CH3:52])([CH3:51])[CH2:40][CH2:39]1)=[O:37])[CH3:34].[CH3:53][NH2:54].C[O-].[Na+]>FC(F)(F)CO.C(=O)(O)[O-].[Na+].O>[CH3:34][N:33]([CH3:32])[CH2:35][C:36]([N:38]1[C:47]2[C:42](=[CH:43][C:44]([O:49][CH3:50])=[C:45]([NH:48][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:54][CH3:53])=[O:17])[N:16]=3)[CH:46]=2)[C:41]([CH3:52])([CH3:51])[CH2:40][CH2:39]1)=[O:37]

Participants

8

Reactant 4

HCID 6329MethylamineHCID 10942334Sodium MethoxideHCID 59441954HCID 59441954, 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 178485519HCID 178485519, compoundYield 41.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 64092,2,2-TrifluoroethanolSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
90 °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 (0.27 g, 0.54 mmol) and 1-[(dimethylamino)acetyl]-4,4-dimethyl-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinamine (0.18 g, 0.60 mmol) was taken in 2,2,2-trifluoroethanol (20 mL) and heated at 90° C. 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 at 50° C. in a sealed vial. The reaction was cooled and partitioned between water and ethyl acetate. Brine was added to assist in the separation of layers. The organic layer was separated, dried over sodium sulfate, and concentrated. The crude material was dissolved in tetrahydrofuran (10 mL), diluted with methanol (10 mL) and treated with sodium methoxide (250 mg, 4.63 mmol) and stirred at 70° 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:methano1:2M ammonia in methanol) to provide 2-[(2-{[1-(N,N-dimethylglycyl)-4,4-dimethyl-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (0.128 g, 0.223 mmol, 36% over 3 steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 6 H), 1.67-1.77 (m, 2 H), 2.11 (bs, 6 H), 2.78 (d, J=4.4 Hz, 3 H), 3.27 (s, 2 H), 3.75 (t, J=6.0 Hz, 2 H), 3.88 (s, 3 H), 6.29-6.34 (m, 1 H), 6.92-7.02 (s, 3 H), 7.37-7.45 (m, 1 H), 7.51 (s, 1 H), 8.18-8.27 (m, 1 H), 8.38 (s, 1 H), 8.52-8.58 (m, 1 H), 10.10 (s, 1 H), 11.39 (bs, 1 H); ESIMS (M+H)+=575.

Workup

  1. temperatureThe reaction was cooled
  2. extractionextracted with dichloromethane
  3. customThe organic layer was separated
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. additiondiluted with tetrahydrofuran (10 mL)
  8. temperatureThe reaction was cooled
  9. custompartitioned between water and ethyl acetate
  10. additionBrine was added
  11. customto assist in the separation of layers
  12. customThe organic layer was separated
  13. dry with materialdried over sodium sulfate
  14. concentrationconcentrated
  15. dissolutionThe crude material was dissolved in tetrahydrofuran (10 mL)
  16. additiondiluted with methanol (10 mL)
  17. stirringstirred at 70° C. for 3 h
  18. temperatureThe reaction was cooled
  19. extractionextracted with ethyl acetate
  20. customThe organic layer was separated
  21. dry with materialdried over sodium sulfate
  22. custompurified by flash silica gel column chromatography (dichloromethane to 8:1:1 mixture of dichloromethane:methano1:2M ammonia in methanol)

Sources & evidence

ORD record
ord-df6642a2421d4a10b72b9b216979e8b3
Source dataset
uspto-grants-2011_07
Patent number
US07981903B2

Reaction notes

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