Formaldehyde → HCID 58318671, compound

HRID 1027932Notes

Reaction equation

HRID 1027932 reaction equation
[Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([O:19][C@@H:20]4[CH2:25][CH2:24][NH:23][C@H:22]([C:26]([O:28][CH3:29])=[O:27])[CH2:21]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl.O>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([O:19][C@@H:20]4[CH2:25][CH2:24][N:23]([CH3:35])[C@H:22]([C:26]([O:28][CH3:29])=[O:27])[CH2:21]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 58318662HCID 58318662, compound

Product 1

HCID 58318671HCID 58318671, compoundYield 70%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 21922555Acetic acid methylene chlorideSolvent

Procedure

Methyl (2S,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxylate (13) (0.35 g, 0.76 mmol) was dissolved in a solution of 15% Acetic acid/methylene chloride (6.1 ml). To this was then added powdered 4A° molecular sieves (0.63 g) and the resulting suspension stirred for 5 minutes. 37% formaldehyde in water (0.56 ml) was added drop-wise and the mixture stirred a further 2 minutes. Sodium triacetoxyborohydride (0.29 g) was added in one portion. The reaction mixture was stirred a further 2 hours at room temperature, filtered and evaporated. The residues were partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The combined organics were washed with brine, dried over MgSO4, filtered and evaporated. The crudes were purified by column chromatography on SiO2 eluting with increasingly polar mixtures of DCM/methanol (100/0-95/5). The fractions containing the desired product were combined and evaporated to give methyl (2S,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-1-methylpiperidine-2-carboxylate (14) as a foam (252 mg, 70%): 1H NMR Spectrum: (DMSO-d6) δ1.72-1.78 (2H, m), 2.05-2.35 (6H, m), 2.95-3.04 (2H, m), 3.63 (3H, s), 3.94 (3H, s), 4.51-4.59 (1H, m), 7.23 (1H, s), 7.29-7.31 (1H, m), 7.49-7.56 (2H, m), 7.84 (1H, s), 8.39 (1H, s), 9.55 (1H, s); Mass Spectrum: (M+H)+ 475.

Workup

  1. additionTo this was then added
  2. stirringthe mixture stirred a further 2 minutes
  3. stirringThe reaction mixture was stirred a further 2 hours at room temperature
  4. filtrationfiltered
  5. customevaporated
  6. customThe residues were partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution
  7. washThe combined organics were washed with brine
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. customevaporated
  11. customThe crudes were purified by column chromatography on SiO2 eluting
  12. temperaturewith increasingly polar mixtures of DCM/methanol (100/0-95/5)
  13. additionThe fractions containing the desired product
  14. customevaporated

Sources & evidence

ORD record
ord-dec6ff94498e4f81892ecc43fcb78cd9
Source dataset
uspto-grants-2014_05
Patent number
US08735410B2

Reaction notes

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