Formaldehyde → HCID 11518493, compound

HRID 1027917Notes

Reaction equation

HRID 1027917 reaction equation
C=O.[Cl:3][C:4]1[C:5]([F:34])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:32][CH3:33])=[C:18]([O:21][C@H:22]4[CH2:27][CH2:26][NH:25][C@H:24]([C:28]([NH:30][CH3:31])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O.C(Cl)Cl>[Cl:3][C:4]1[C:5]([F:34])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:32][CH3:33])=[C:18]([O:21][C@H:22]4[CH2:27][CH2:26][N:25]([CH3:35])[C@H:24]([C:28]([NH:30][CH3:31])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1

Participants

7

Reactant 4

HCID 712FormaldehydeHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydride2×HCID 67238726(2S,4S)-4-[[4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]oxy]-N-methyl-2-piperidinecarboxamide

Product 1

HCID 11518493HCID 11518493, compoundYield 65%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 21922555Acetic acid methylene chlorideSolvent

Procedure

Molecular sieves (5 g) followed by aqueous formaldehyde (10 ml) were added to a stirred solution of (2S,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-methylpiperidine-2-carboxamide (3.0 g, 6.52 mmol) in DCM-AcOH (100:10 ml) at room temperature. The reaction mixture was stirred for 1-2 minutes before solid sodium triacetoxyborohydride (2.77 g, 13.1 mmol) was added portionwise over 5 minutes. The reaction was essentially complete after all the sodium triacetoxyborohydride reducing agent had been added. DCM was added (100 ml) and the reaction was carefully neutralised with saturated aqueous NaHCO3(aq). The organic extract was washed with brine, dried (MgSO4) and concentrated to a yellow foam. The residue was purified by flash chromatography (silica gel, DCM-NH3/MeOH 2%) to give the title product as a white solid (2 g, 65%): 1H NMR Spectrum: (DMSO d6) 1.85-1.96 (m, 3H), 2.07 (m, 1H), 2.15 (s, 3H), 2.45-2.50 (m, 1H), 2.59 (d, 3H), 2.71 (m, 1H), 2.84 (m, 1H), 3.96 (s, 3H), 4.81 (m, 1H), 7.23 (s, 1H), 7.28 (t, 1H), 7.47-7.53 (m, 2H), 7.81 (s, 2H), 8.37 (s, 1H), 9.59 (s, 1H); Mass Spectrum: (M+H)+ 474.1.

Workup

  1. additionwas added portionwise over 5 minutes
  2. additionhad been added
  3. extractionThe organic extract
  4. washwas washed with brine
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated to a yellow foam
  7. customThe residue was purified by flash chromatography (silica gel, DCM-NH3/MeOH 2%)

Sources & evidence

ORD record
ord-63f9c243d27141cc82e2bf34938d0765
Source dataset
uspto-grants-2014_05
Patent number
US08735410B2

Reaction notes

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