3-Fluoroaniline → 2-{3-[(7-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide

HRID 749163Notes

Reaction equation

HRID 749163 reaction equation
[C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[CH:32]=[C:31]([CH2:33][C:34]([OH:36])=O)[NH:30][N:29]=4)=[N:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:37][CH3:38])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43].Cl.CN(C)CCCN=C=NCC.OC1C=CC=C[N+]=1[O-]>CN(C)C=O.ClCCl>[C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[CH:32]=[C:31]([CH2:33][C:34]([NH:43][C:42]5[CH:44]=[CH:45][CH:46]=[C:40]([F:39])[CH:41]=5)=[O:36])[NH:30][N:29]=4)=[N:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:37][CH3:38])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 4

HCID 97423-FluoroanilineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 68990806{3-[(7-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetic acidHCID 178526252HCID 178526252, compound

Product 1

HCID 689939892-{3-[(7-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamideYield 65.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

{3-[(7-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetic acid (210 mg, 0.4 mmol) in dimethylformamide (2.1 ml) was reacted with 3-fluoroaniline (58 mg, 0.52 mmol) in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (107 mg, 0.56 mmol) and 2-hydroxypyridine-1-oxide (53 mg, 0.48 mmol) at 55° C. for 1.5 hours. The reaction mixture was cooled, diluted with dichloromethane (7 ml) and purified by chromatography on silica gel. Elution with dichloromethane:methanol (9:1) and increased polarity to dichloromethane:methanol:ammonia (9:1:0.1) yielded 2-{3-[(7-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide (162 mg, 65% yield) as a light pink solid:

Workup

  1. temperatureThe reaction mixture was cooled
  2. custompurified by chromatography on silica gel
  3. washElution with dichloromethane:methanol (9:1)
  4. temperatureincreased polarity to dichloromethane:methanol:ammonia (9:1:0.1)

Sources & evidence

ORD record
ord-1cd7159baf754a19a77e9be56dd3f2b3
Source dataset
uspto-grants-2008_07
Patent number
US07402585B2

Reaction notes

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