Triethylamine → 4-{7-[3-(4-Methyl-piperazin-1-yl)-propylamino]-quinazolin-4-yl}-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide

HRID 657256Notes

Reaction equation

HRID 657256 reaction equation
[NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.CCN(CC)CC.C(O[C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[C:41]3[C:36](=[CH:37][C:38](F)=[CH:39][CH:40]=3)[N:35]=[CH:34][N:33]=2)[CH2:28][CH2:27]1)=[O:25])(C)(C)C.[N+](C1C=CC(OC(=O)[NH:54][C:55]2[CH:60]=[CH:59][C:58]([O:61][CH:62]([CH3:64])[CH3:63])=[CH:57][CH:56]=2)=CC=1)([O-])=O>CN(C=O)C.O>[CH:62]([O:61][C:58]1[CH:59]=[CH:60][C:55]([NH:54][C:24]([N:26]2[CH2:27][CH2:28][CH:29]([C:32]3[C:41]4[C:36](=[CH:37][C:38]([NH:1][CH2:2][CH2:3][CH2:4][N:5]5[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]5)=[CH:39][CH:40]=4)[N:35]=[CH:34][N:33]=3)[CH2:30][CH2:31]2)=[O:25])=[CH:56][CH:57]=1)([CH3:64])[CH3:63]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 783281-(3-Aminopropyl)-4-methylpiperazineHCID 58769998(4-Isopropoxy-phenyl)-carbamic acid 4-nitrophenyl esterHCID 595517364-(7-Fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 587706844-{7-[3-(4-Methyl-piperazin-1-yl)-propylamino]-quinazolin-4-yl}-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
130 °C

Procedure

A mixture of 4-(3-aminopropyl)-1-methylpiperazine (0.1 mmol), Et3N (0.1 mmol) and 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.1 mmol), prepared as described in Example 65b, in DMF (1 mL) was stirred at 130° C. for 3 h. It was then diluted with water and extracted with EtOAc. The combined extracts were washed with water, brine, dried (anhydrous MgSO4), filtered and concentrated in vacuo. The crude product was then treated with 3M HCl/MeOH (2 mL) and stirred at rt for 2 h, then concentrated in vacuo. The crude residue was dissolved in a mixture of DCM:MeOH (1:1; 2 mL) and neutralized with excess Et3N and treated with (4-isopropoxy-phenyl)-carbamic acid 4-nitrophenyl ester (0.11 mmol), which was prepared as described in Example 1a, at rt for 1 h. It was then concentrated in vacuo and the crude product was dissolved in DCM and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was then purified by Preparative TLC (silica gel; DCM:MeOH, 9:1) to obtain 3.2 mg (6% overall yield over the three steps) of the title compound. 1H-NMR (300 MHz, CDCl3): 8.97 (s, 1H), 7.88 (d, 1H), 7.28-7.22 (m, 3H), 6.97-6.81 (m, 4H), 6.33 (s, 1H), 4.53-4.43 (m, 1H), 4.30-4.20 (d, 2H), 3.66-3.32 (m, 2H), 3.11 (t, 2H), 2.85-2.55 (m, 8H), 2.43 (s, 4H), 2.20-1.85 (m, 8H), 1.31 (d, 6H). LC/MS (ESI): 546.2 (MH)+.

Workup

  1. customprepared
  2. extractionextracted with EtOAc
  3. washThe combined extracts were washed with water, brine
  4. dry with materialdried (anhydrous MgSO4)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. additionThe crude product was then treated with 3M HCl/MeOH (2 mL)
  8. stirringstirred at rt for 2 h
  9. concentrationconcentrated in vacuo
  10. dissolutionThe crude residue was dissolved in a mixture of DCM:MeOH (1:1; 2 mL)
  11. customwas prepared
  12. waitas described in Example 1a, at rt for 1 h
  13. concentrationIt was then concentrated in vacuo
  14. dissolutionthe crude product was dissolved in DCM
  15. washwashed with water, brine
  16. dry with materialdried over anhydrous MgSO4
  17. filtrationfiltered
  18. concentrationconcentrated in vacuo
  19. customThe crude product was then purified by Preparative TLC (silica gel; DCM:MeOH, 9:1)
  20. customto obtain 3.2 mg (6%

Sources & evidence

ORD record
ord-7af084e44d23469994d30e9a95818030
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Reaction notes

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