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4-Methylmorpholine → 4-[(3-Bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-[(1-oxo-2,4-hexadien-1-yl)amino]quinazoline

HRID 1023294
Notes
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Reaction equation

HRID 1023294 reaction equation
[C:1](O)(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][CH2:38][CH:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1)[N:31]=[CH:30][N:29]=[C:28]2[NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([Br:53])[CH:48]=1>O1CCCC1.N1C=CC=CC=1>[Br:53][C:49]1[CH:48]=[C:47]([NH:46][C:28]2[C:27]3[C:32](=[CH:33][C:34]([O:35][CH2:36][CH2:37][CH2:38][CH:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)=[C:25]([NH:24][C:1](=[O:7])[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6])[CH:26]=3)[N:31]=[CH:30][N:29]=2)[CH:52]=[CH:51][CH:50]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 643460Sorbic AcidHCID 111906016-Amino-4-[(3-bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]quinazoline

Product 1

HCID 537025584-[(3-Bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-[(1-oxo-2,4-hexadien-1-yl)amino]quinazoline

Reagents, catalysts & solvents

2
HCID 1049PyridineSolventHCID 8028TetrahydrofuranSolvent

Procedure

To 31 mg of sorbic acid in 1 ml of tetrahydrofuran are added 40 μl of isobutyl chloroformate followed by 45 μl of N-methylmorpholine whilst cooling with an ice bath. The white suspension is stirred for one minute, then a solution of 100 mg of 6-amino-4-[(3-bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]quinazoline in 1.5 ml of pyridine is added. The ice bath is removed and the reaction mixture is stirred overnight. For working up, it is poured onto 20 ml of ice water, stirred for 30 minutes and adjusted to pH 9-10 with a few drops of 2 N sodium hydroxide solution. The aqueous phase is extracted with methylene chloride, the combined organic phases are dried over sodium sulfate and concentrated by evaporation. The resin-like crude product is purified by chromatography over an aluminium oxide column (activity III) with methylene chloride/methanol (99.5:0.5). Yield: 62 mg (52% of theory); Rf value: 0.29 (aluminium oxide, activity III; methylene chloride/methanol=98:2); mass spectrum (EI): m/z=563, 565 [M]+.

Workup

  1. temperaturewhilst cooling with an ice bath
  2. customThe ice bath is removed
  3. stirringthe reaction mixture is stirred overnight
  4. additionit is poured onto 20 ml of ice water
  5. stirringstirred for 30 minutes
  6. extractionThe aqueous phase is extracted with methylene chloride
  7. dry with materialthe combined organic phases are dried over sodium sulfate
  8. concentrationconcentrated by evaporation
  9. customThe resin-like crude product is purified by chromatography over an aluminium oxide column (activity III) with methylene chloride/methanol (99.5:0.5)

Sources & evidence

ORD record
ord-04c9b8b8f214439f9d1842022ef96776
Source dataset
uspto-grants-2014_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08722694B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes