Diisopropylethylamine → HCID 67024875, compound

HRID 488414Notes

Reaction equation

HRID 488414 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH:14]1[CH2:16][CH2:15]1)[N:8]=[CH:7][N:6]=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1.C(N(C(C)C)CC)(C)C.Br[CH2:36][CH:37]=[CH:38][C:39](Cl)=[O:40].[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43]>O1CCCC1.C(Cl)Cl.CN(C)C=O>[Cl:25][C:20]1[CH:19]=[C:18]([NH:17][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH2:13][CH:14]4[CH2:16][CH2:15]4)=[C:2]([NH:1][C:39](=[O:40])[CH:38]=[CH:37][CH2:36][N:52]4[CH2:51][CH2:50][N:49]([C:47]([O:46][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:48])[CH2:54][CH2:53]4)[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:23]=[CH:22][C:21]=1[F:24]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 143452tert-Butyl piperazine-1-carboxylateHCID 155418526-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopropylmethoxyquinazolineHCID 536352004-Bromo-but-2-enoyl chloride

Product 1

HCID 67024875HCID 67024875, compound

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

4.7 ml of oxalyl dichloride are added to a solution of 4.51 g 4-bromo-but-2-enoic acid in 100 ml of methylene chloride at room temperature. After addition of one drop of N,N-dimethyl-formamide, the reaction mixture is stirred for approximately 45 minutes until the gas evolution has ceased. The solvent is distilled off in vacuo to give the crude acid chloride. In the meantime, a mixture of 7.00 g 6-amino-4-[(3-chloro-4-fluoro-phenyl)amino]-7-cyclopropylmethoxy-quinazoline and 10.2 ml diisopropylethylamine in 250 ml tetrahydrofuran is cooled to 0° C. in an ice/water bath. The crude 4-bromo-but-2-enoic acid chloride is dissolved in 20 ml of methylene chloride and added dropwise to this mixture within 5 minutes. After stirring for 45 minutes at 0° C. and one hour at room temperature, 18.17 g of piperazine-1-carboxylic acid tert.butyl ester suspended in 5 ml of N,N-dimethyl-formamide are added. After stirring for 48 hours at room temperature, the solvent is distilled off in vacuo and the residue is partitioned between 100 ml of water and 200 ml of ethyl acetate. The aqueous layer is extracted with ethyl acetate, the combined organic layers are washed with concentrated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The crude product is purified by column chromatography on silica gel with ethyl acetate/methanol (15:1 to 9:1). Yield: 5.2 g (44% of theory), Rf value: 0.42 (silica gel, methylene chloride/methanol=9:1) Mass spectrum (ESI*): m/z=609, 611 [M−H]*

Workup

  1. additionadded dropwise to this mixture within 5 minutes
  2. additionare added
  3. stirringAfter stirring for 48 hours at room temperature
  4. distillationthe solvent is distilled off in vacuo
  5. customthe residue is partitioned between 100 ml of water and 200 ml of ethyl acetate
  6. extractionThe aqueous layer is extracted with ethyl acetate
  7. washthe combined organic layers are washed with concentrated aqueous sodium chloride solution
  8. dry with materialdried over magnesium sulfate
  9. concentrationconcentrated in vacuo
  10. customThe crude product is purified by column chromatography on silica gel with ethyl acetate/methanol (15:1 to 9:1)

Sources & evidence

ORD record
ord-0ce48420a6d04174bf49dce22aee3d10
Source dataset
uspto-grants-2005_12
Patent number
US06972288B1

Reaction notes

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