Acetic Acid → HCID 66876498, compound

HRID 1917808Notes

Reaction equation

HRID 1917808 reaction equation
[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH:35]5[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C=O.[C:43](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(OCC)(=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH:35]5[CH2:40][CH2:39][N:38]([CH3:43])[CH2:37][CH2:36]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 712FormaldehydeHCID 14798Sodium HydroxideHCID 5049666Sodium triacetoxyborohydrideHCID 66876208HCID 66876208, compound

Product 1

HCID 66876498HCID 66876498, compoundYield 68%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 1-(3-tert-butylisoxazol-5-yl)-3-(3-(6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-yloxy)phenyl)urea (82.5 mg, 0.15 mmol) in 1,2-dichloroethane/N,N′-dimethylacetamide (1.3 mL, 3:1) was added 37% formaldehyde (24 mL, 0.3 mmol) and acetic acid (10 μL, 0.18 mmol). The mixture was stirred at room temperature for 20 minutes. Sodium triacetoxyborohydride (48 mg, 0.23 mmol) was added in portions and the resulting mixture stirred at room temperature for 2 h. Ethyl acetate and 1N sodium hydroxide were added to the mixture, the organic layer was separated and the water phase extracted three times. The organics were combined, dried (MgSO4) and concentrated under reduced pressure. The crude material was purified by preparative HPLC (Phenomenex phenylhexyl reverse phase column) to afford 1-(3-tert-butylisoxazol-5-yl)-3-(3-(6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-yloxy)phenyl)urea (57 mg, 68%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.75 (bs, 1H), 9.21 (bs, 1H), 8.55 (s, 1H), 7.57 (d, 2H), 7.37-7.26 (m, 3H), 6.96 (d, 1H), 6.47 (s, 1H), 4.07-3.99 (m, 5H), 2.83-2.79 (m. 2H), 2.17 (s, 3H), 1.93-1.76 (m, 5H), 1.39-1.35 (m, 2H), 1.27 (s, 9H); LC-MS (ESI) m/z 561 (M+H)+.

Workup

  1. stirringthe resulting mixture stirred at room temperature for 2 h
  2. customthe organic layer was separated
  3. extractionthe water phase extracted three times
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated under reduced pressure
  6. customThe crude material was purified by preparative HPLC (Phenomenex phenylhexyl reverse phase column)

Sources & evidence

ORD record
ord-7b7febf87c084323bedcbecba956ee1a
Source dataset
uspto-grants-2013_12
Patent number
US08618289B2

Reaction notes

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