1-Methylpiperazine → 4-[7-(4-Methyl-piperazin-1-yl)-quinazolin-4-yl]-piperidine-1-carboxylic acid (4-morpholin-4-yl-phenyl)-amide

HRID 657264Notes

Reaction equation

HRID 657264 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(O[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:30]3[C:25](=[CH:26][C:27](F)=[CH:28][CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=[O:14])(C)(C)C.Cl.[N+](C1C=CC(OC(=O)[NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[CH:47][CH:46]=2)=CC=1)([O-])=O>CS(C)=O.O>[N:51]1([C:48]2[CH:47]=[CH:46][C:45]([NH:44][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([C:21]4[C:30]5[C:25](=[CH:26][C:27]([N:5]6[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]6)=[CH:28][CH:29]=5)[N:24]=[CH:23][N:22]=4)[CH2:19][CH2:20]3)=[O:14])=[CH:50][CH:49]=2)[CH2:52][CH2:53][O:54][CH2:55][CH2:56]1

Participants

6

Reactant 3

HCID 531671-MethylpiperazineHCID 595517364-(7-Fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl esterHCID 68947764(4-Morpholin-4-yl-phenyl)-carbamic acid 4-nitrophenyl ester hydrochloride

Product 1

HCID 587706464-[7-(4-Methyl-piperazin-1-yl)-quinazolin-4-yl]-piperidine-1-carboxylic acid (4-morpholin-4-yl-phenyl)-amideYield 21.3%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 1-methylpiperazine (0.11 mmol) and 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.05 mmol), prepared as described in Example 65, in DMSO (1 mL) was stirred at 120° C. for 1 h. It was then diluted with water and extracted with DCM. 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 and 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-morpholin-4-yl-phenyl)-carbamic acid 4-nitrophenyl ester hydrochloride (0.06 mmol), as prepared by the method outlined in Example 66a, at rt overnight. It was then concentrated in vacuo and the crude product was dissolved in DCM and washed with water thrice, then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was then purified by Preparative TLC (silica gel; DCM:MeOH:NH4OH, 90:9:1) to obtain 5.5 mg (21%) of the title compound. 1H-NMR (300 MHz, CDCl3): 9.04 (s, 1H), 7.98 (d, 1H), 7.36-7.18 (m, 4H), 6.88 (d, 2H), 6.32 (s, 1H), 4.25 (m, 2H), 3.89-3.83 (m, 4H), 3.69-3.55 (m, 1H), 3.53-3.43 (m, 4H), 3.19-3.04 (m, 6H), 2.66-2.58 (m, 4H), 2.39 (s, 3H), 2.20-1.90 (m, 4H). LC/MS (ESI): 516.1 (MH)+.

Workup

  1. customprepared
  2. extractionextracted with DCM
  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. customas prepared by the method
  12. waitoutlined in Example 66a, at rt overnight
  13. concentrationIt was then concentrated in vacuo
  14. dissolutionthe crude product was dissolved in DCM
  15. washwashed with water thrice
  16. washwashed with brine
  17. dry with materialdried over anhydrous MgSO4
  18. filtrationfiltered
  19. concentrationconcentrated in vacuo
  20. customThe crude product was then purified by Preparative TLC (silica gel; DCM:MeOH:NH4OH, 90:9:1)

Sources & evidence

ORD record
ord-9d9c66f70f3a4352954304cfe8de3381
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Reaction notes

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