Morpholine → N-{4-[(3-Bromo-4-fluorophenyl)amino]-3-cyano-6-quinolinyl}-4-morpholino-2-butenamide

HRID 612110Notes

Reaction equation

HRID 612110 reaction equation
Br[CH2:2][CH:3]=[CH:4][C:5]([O:7][Si](C)(C)C)=O.C(Cl)(=O)C(Cl)=O.[NH2:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][C:23]([C:29]#[N:30])=[C:22]2[NH:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([Br:39])[CH:33]=1.C(N(CC)C(C)C)(C)C.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>CN(C=O)C.C1COCC1.C(Cl)Cl>[Br:39][C:34]1[CH:33]=[C:32]([NH:31][C:22]2[C:21]3[C:26](=[CH:27][CH:28]=[C:19]([NH:18][C:5](=[O:7])[CH:4]=[CH:3][CH2:2][N:49]4[CH2:54][CH2:53][O:52][CH2:51][CH2:50]4)[CH:20]=3)[N:25]=[CH:24][C:23]=2[C:29]#[N:30])[CH:37]=[CH:36][C:35]=1[F:38]

Participants

9

Reactant 5

HCID 8083MorpholineHCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 224666726-Amino-4-[(3-bromo-4-fluorophenyl)amino]-3-quinolinecarbonitrileHCID 53861946Trimethylsilyl 4-bromobut-2-enoate

Product 1

HCID 54318491N-{4-[(3-Bromo-4-fluorophenyl)amino]-3-cyano-6-quinolinyl}-4-morpholino-2-butenamideYield 32.1%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

Made 2.25 mmol of 5-bromo-but-2-enoyl chloride by mixing 386 μl (2.25 mmol) trimethylsilyl 4-bromo-but-2-enoate, 10 ml methylene chloride, 294 μl (3.38 mmol) oxalyl chloride, and 2 drops of DMF. After bubbling had subsided, removed solvent and dissolved in 10 ml THF. This solution was added to a mixture of 800 mg (2.25 mmol) 6-amino-4-[(3-bromo-4-fluorophenyl)amino]-3-quinolinecarbonitrile, 50 ml THF, and 392 μl (2.25 mmol) N,N-diisopropylethylamine chilled to 0° C. under N2. At 1 hour, added the mixture dropwise to a solution of 1 ml (11.2 mmol) morpholine in 4.5 ml THF chilled to 0° C. After complete addition, removed the ice bath, and at 2 hours poured onto a mixture of ice and saturated sodium bicarbonate. Extracted with ethyl acetate, dried organic layer with sodium sulfate and reduced solvent to a small volume. Loaded onto a column of silica gel, eluted with 12% methanol/ethyl acetate, stripped solvent from desired fractions and dried in vacuo, giving 369 mg of yellow solid: mass spectrum (electrospray m/e): M+H=509.9, 511.9.

Workup

  1. customAfter bubbling
  2. customremoved solvent
  3. dissolutiondissolved in 10 ml THF
  4. temperaturechilled to 0° C
  5. additionAfter complete addition
  6. customremoved the ice bath
  7. additionat 2 hours poured onto a mixture of ice and saturated sodium bicarbonate
  8. extractionExtracted with ethyl acetate, dried organic layer with sodium sulfate
  9. washeluted with 12% methanol/ethyl acetate
  10. customdried in vacuo

Sources & evidence

ORD record
ord-98d9cdbd19ec483993a5fae55efabb0f
Source dataset
uspto-grants-1999_12
Patent number
US06002008

Reaction notes

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