Formic Acid → 5-Phenyl-6-chloro-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine

HRID 2305125Notes

Reaction equation

HRID 2305125 reaction equation
[C:1]1([C:7]2[CH:8]=[C:9]([O:14][CH2:15][C@@H:16]3[CH2:19][CH2:18][NH:17]3)[CH:10]=[N:11][C:12]=2[Cl:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[CH:22](O)=O.[BH3-]C#N.[Na+]>CCO.O.C([O-])([O-])=O.[K+].[K+]>[C:1]1([C:7]2[CH:8]=[C:9]([O:14][CH2:15][C@@H:16]3[CH2:19][CH2:18][N:17]3[CH3:22])[CH:10]=[N:11][C:12]=2[Cl:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1

Participants

8

Reactant 4

HCID 284Formic AcidHCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 98397025-phenyl-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine

Product 1

HCID 228726365-Phenyl-6-chloro-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 962WaterSolventHCID 11430Potassium CarbonateSolvent

Procedure

To 5-phenyl-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine from Example 67 (100 mg, 0.36 mmol) in EtOH (3 mL) was added formalin (37%, 0.5 mL) and formic acid (0.25 mL), and the pH was adjusted to 6. Then NaCNBH3 (70 mg) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and saturated with K2CO3. The mixture was extracted with CHCl3. The solvent was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with CH2Cl2:MeOH 10:1 to afford the free base of the title compound. MS (CI/NH3) m/z 289 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 2.05-2.14 (m, 2H), 2.40 (s, 3H), 2.32-2.44 (m, 1H), 3.34-3.51 (m, 2H), 4.44 (d, J=7.5 Hz, 2H), 7.26 (d, J=3 Hz, 1H), 8.09 (d, J=3Hz, 1H). The salt was prepared by treatment with HCl in Et2O, as described above, to give the title compound. mp 187-188° C. MS (CI/NH3) m/z 289 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 2.60-2.71 (m, 2H), 2.99 (s, 3H), 3.94-4.12 (m, 1H), 4.18-4/33 (m, 1H), 4.47-4.55 (m, 3H), 7.57 (m, 5H), 7.60 (d, J=3.0 Hz, 1H), 8.18 (d, J=3.0 Hz, 1H). Anal. Calcd for C16H17N2OCl.HCl.0.5 H2O: C, 57.50; H, 5.73; N, 8.38. Found: C, 57.38; H, 5.53; N, 8.35. [α]25D=+15° (c 0.11, MeOH).

Workup

  1. extractionThe mixture was extracted with CHCl3
  2. dry with materialThe solvent was dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue was chromatographed on a silica gel column
  6. washeluting with CH2Cl2:MeOH 10:1

Sources & evidence

ORD record
ord-f045f533b3a94e4ea588f7b5476e77b2
Source dataset
uspto-grants-2002_08
Patent number
US06437138B1

Reaction notes

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