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Glycolic Acid → 2-hydroxy-N-methyl-N-(2-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}ethyl)acetamide

HRID 1864352
Notes
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Reaction equation

HRID 1864352 reaction equation
[CH3:1][NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[C:19]([CH3:31])[CH:18]=1)=[N:9][CH:10]=[N:11]2.[C:32]([OH:36])(=O)[CH2:33][OH:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[OH:34][CH2:33][C:32]([N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[C:19]([CH3:31])[CH:18]=1)=[N:9][CH:10]=[N:11]2)=[O:36]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 757Glycolic AcidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 690582265-[2-(Methylamino)ethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine

Product 1

HCID 112252522-hydroxy-N-methyl-N-(2-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}ethyl)acetamideYield 60.3%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Procedure

5-[2-(Methylamino)ethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (32 mg, 0.077 mmol) and glycolic acid (6 mg, 0.085 mmol) were dissolved in DMA (10 ml). HATU (32 mg, 0.085 mmol) was added, and the mixture was stirred at ambient temperature for 16 hours. The mixture was concentrated in vacuo, and the residue purified by reverse-phase HPLC, eluting with 5 to 50% acetonitrile in H2O containing 0.2% TFA. The appropriate fraction was evaporated, and the residue dissolved in methanol/DCM (1:1, 25 ml). The mixture was neutralised by stirring overnight with tetraalkylammonium carbonate, polymer bound. The mixture was filtered, and the filtrate was evaporated. Crystallisation from ethyl acetate/iso-hexane gave 2-hydroxy-N-methyl-N-(2-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}ethyl)acetamide as a white crystalline solid (22 mg, 60%); NMR Spectrum (DMSO-d6, 400 MHz, 373K) 2.26 (s, 3H), 2.48 (s, 3H), 3.02 (s, 3H), 3.95 (t, 2H), 4.02-4.11 (m-3H), 4.55 (t, 2H), 6.96 (d, 1H), 7.20 (d, 1H), 7.23 (m, 2H), 7.38 (d, 1H), 7.65 (dd, 1H), 7.70 (d, 1H), 7.73 (dd, 1H), 8.20 (m, 1H), 8.49 (s, 1H), 9.77 (s, 1H); Mass spectrum MH+ 473.9

Workup

  1. concentrationThe mixture was concentrated in vacuo
  2. customthe residue purified by reverse-phase HPLC
  3. washeluting with 5 to 50% acetonitrile in H2O containing 0.2% TFA
  4. customThe appropriate fraction was evaporated
  5. dissolutionthe residue dissolved in methanol/DCM (1:1, 25 ml)
  6. stirringby stirring overnight with tetraalkylammonium carbonate, polymer
  7. filtrationThe mixture was filtered
  8. customthe filtrate was evaporated
  9. customCrystallisation from ethyl acetate/iso-hexane

Sources & evidence

ORD record
ord-7c90c72ddf4143be9e1f668a6f58058d
Source dataset
uspto-grants-2009_12
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07625908B2

Reaction notes

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