Morpholine → N-{4-[(3-Bromo-4-fluorophenyl)amino]-3-cyano-7-methoxy-6-quinolinyl}-4-morpholino-2-butenamide

HRID 612111Notes

Reaction equation

HRID 612111 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][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][C:23]([C:31]#[N:32])=[C:22]2[NH:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[C:36]([Br:41])[CH:35]=1.C(N(CC)C(C)C)(C)C.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C1COCC1.C(Cl)Cl>[Br:41][C:36]1[CH:35]=[C:34]([NH:33][C:22]2[C:21]3[C:26](=[CH:27][C:28]([O:29][CH3:30])=[C:19]([NH:18][C:5](=[O:7])[CH:4]=[CH:3][CH2:2][N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)[CH:20]=3)[N:25]=[CH:24][C:23]=2[C:31]#[N:32])[CH:39]=[CH:38][C:37]=1[F:40]

Participants

10

Reactant 6

HCID 8083Morpholine2×HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 224666136-Amino-4-[(3-bromo-4-fluorophenyl)amino]-7-methoxy-3-quinolinecarbonitrileHCID 53861946Trimethylsilyl 4-bromobut-2-enoate

Product 1

HCID 53990663N-{4-[(3-Bromo-4-fluorophenyl)amino]-3-cyano-7-methoxy-6-quinolinyl}-4-morpholino-2-butenamideYield 25.7%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

Made 2.07 mmol of 5-bromo-but-2-enoyl chloride by mixing 363 μl (2.07 mmol) trimethylsilyl 4-bromo-but-2-enoate, 8 ml methylene chloride, 270 μl (3.10 mmol) oxalyl chloride and 2 drops of DMF. Removed solvent when bubbling subsided and dissolved in 10 ml THF. The acid chloride solution was added to a mixture of 800 mg A (2.07 mmol) 6-amino-4-[(3-bromo-4-fluorophenyl)amino]-7-methoxy-3-quinolinecarbonitrile, 50 ml THF, and 721 μl (4.14 mmol) N,N-diisopropylethylamine chilled to 0° C. under N2. At 1.5 hours added this mixture to a solution of 900 g (10.4 mmol) morpholine in 4.3 ml THF at 0° C. Warmed to 25° C. after complete addition, and at 2 hours added 900 μl more morpholine. At 3 hours, poured onto a mixture of ice and saturated sodium bicarbonate, extracted with ethyl acetate, dried with sodium sulfate, and reduced solvent to a small volume. Loaded compound onto a column of silica gel, eluted with 12% methanol/ethyl acetate, stripped solvent from desired fractions, and dried in vacuo, giving 287 mg of orange-brown solid: mass spectrum (electrospray m/e): M+H=539.9, 541.9.

Workup

  1. customRemoved solvent when bubbling
  2. dissolutiondissolved in 10 ml THF
  3. temperatureWarmed to 25° C.
  4. additionafter complete addition
  5. extractionextracted with ethyl acetate
  6. dry with materialdried with sodium sulfate
  7. washeluted with 12% methanol/ethyl acetate
  8. customdried in vacuo

Sources & evidence

ORD record
ord-5f814033a4df4fa5a61cbf3ece9e136a
Source dataset
uspto-grants-1999_12
Patent number
US06002008

Reaction notes

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