1-Methylpiperazine → 4-(4-Chloro-2-fluoroanilino)-6-methoxy-7-(3-(4-methylpiperazin-1-ylcarbonyl)propoxy)quinazoline

HRID 2227949Notes

Reaction equation

HRID 2227949 reaction equation
Cl.CN(C)CCCN=C=NCC.[C:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])=[N:25][CH:26]=[N:27]2)=[CH:22][C:21]=1[O:39][CH3:40])([OH:15])=O.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>CN(C)C1C=CN=CC=1.CN(C=O)C>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:24]2[C:23]3[C:28](=[CH:29][C:20]([O:19][CH2:18][CH2:17][CH2:16][C:13]([N:45]4[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]4)=[O:15])=[C:21]([O:39][CH3:40])[CH:22]=3)[N:27]=[CH:26][N:25]=2)=[C:32]([F:38])[CH:33]=1

Participants

6

Reactant 3

HCID 531671-MethylpiperazineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 224782937-(3-Carboxypropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline

Product 1

HCID 187534264-(4-Chloro-2-fluoroanilino)-6-methoxy-7-(3-(4-methylpiperazin-1-ylcarbonyl)propoxy)quinazolineYield 44%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent

Procedure

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (145 mg, 0.75 mmol) was added to a mixture of 7-(3-carboxypropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (250 mg, 0.62 mmol), (prepared as described for the starting material in Example 42), 1-methylpiperazine (0.21 ml, 2.32 mmol) and 4-dimethylaminopyridine (300 mg, 2.46 mol) in DMF (7.5 ml). The reaction mixture was stirred at ambient temperature for 24 hours and the volatiles were removed by evaporation. Water was added to the residue and the aqueous mixture was extracted with methylene chloride (3×30 ml). The combined organic extracts were washed with brine and the solvent was removed by evaporation. The residue was triturated with ether and the precipitate was collected by filtration. The solid was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (100/8/1). The purified product was triturated with ether collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(4-methylpiperazin-1-ylcarbonyl)propoxy)quinazoline (133 mg, 44%).

Workup

  1. custom(prepared
  2. customthe volatiles were removed by evaporation
  3. additionWater was added to the residue
  4. extractionthe aqueous mixture was extracted with methylene chloride (3×30 ml)
  5. washThe combined organic extracts were washed with brine
  6. customthe solvent was removed by evaporation
  7. customThe residue was triturated with ether
  8. filtrationthe precipitate was collected by filtration
  9. customThe solid was purified by column chromatography
  10. washeluting with methylene chloride/methanol/aqueous ammonia (100/8/1)
  11. customThe purified product was triturated with ether
  12. filtrationcollected by filtration
  13. customdried

Sources & evidence

ORD record
ord-d6535a5f423f4991b8402b6f4aea0248
Source dataset
uspto-grants-2002_07
Patent number
US06414148B1

Reaction notes

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