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Formaldehyde → Narmafotinib

HRID 705748
Notes
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Reaction equation

HRID 705748 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=1.C=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:40])[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:35])([F:36])[F:37])=[CH:18][N:17]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 712FormaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 601619862-(2-(2-(2-((2-Methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide

Product 1

HCID 60162119NarmafotinibYield 95%

Reagents, catalysts & solvents 1

HCID 887Methanol
Solvent

Procedure

2-(2-(2-(2-((2-Methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (2) (2.249 g, 4.38 mmol) was dissolved in methanol (220 mL) and 37% formaldehyde solution (0.483 mL, 17.5 mmol) was added. After five minutes sodium tris(acetoxy)borohydride (4.641 g, 21.9 mmol) was added and stirring continued at room temperature for two hours. The volatiles were evaporated and the residue suspended in 5% aqueous sodium hydroxide (200 mL), The resuiting mixture was extracted with ethyl acetate (5×200 mL) then the combined organic phases were washed with brine (500 mL), dried over sodium sulfate and evaporated. The residue was evaporated from ether and the solvent traces removed under high vacuum to give the title compound (3) (2.196 g, 95% yield) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.85 (s, 1H), 7.28-7.22 (m, overlaps with CHCl3), 6.88 (dd. J=8.3, 18 Hz, 1H), 6.81 (d, J=1.8 Hz, 1H), 5.41 (s, 2H), 3.90 (s, 3H), 3.70 (s, 2H), 3.16-3.06 (m, 4H), 2.99 (d, J=12.1 Hz, 2H), 2.48 (tt, J=10.5, 5.9 Hz, 1H), 2.34 (s, 3H), 2.07 (td, J=11.1, 4.1 Hz, 2H), 1.89-1.77 (m, overlaps with water). LCMS Method C: rt 4.94 min; m/z 528.1 [M+H]+, 550.1 [M+Na]+; m/z 526.2 [M−H]−.

Workup

  1. customThe volatiles were evaporated
  2. extractionThe resuiting mixture was extracted with ethyl acetate (5×200 mL)
  3. washthe combined organic phases were washed with brine (500 mL)
  4. dry with materialdried over sodium sulfate
  5. customevaporated
  6. customThe residue was evaporated from ether
  7. customthe solvent traces removed under high vacuum

Sources & evidence

ORD record
ord-d122f75c97d442178e368f08201bdf2e
Source dataset
uspto-grants-2015_11
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09174946B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes