Benzophenone imine → 6-(1-Methyl-piperidin-4-yloxy)-pyridin-2-ylamine

HRID 1822005Notes

Reaction equation

HRID 1822005 reaction equation
Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:3]=1.CC(C)([O-])C.[Na+].C(=[NH:35])(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:15][N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:4]2[N:3]=[C:2]([NH2:35])[CH:7]=[CH:6][CH:5]=2)[CH2:10][CH2:11]1

Participants

6

Reactant 3

HCID 136809Benzophenone imineHCID 135639172-Chloro-6-(1-methyl-piperidin-4-yloxy)-pyridineHCID 23676156Sodium t-butoxide

Product 1

HCID 187718666-(1-Methyl-piperidin-4-yloxy)-pyridin-2-ylamineYield 99%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

Combine 2-chloro-6-(1-methyl-piperidin-4-yloxy)-pyridine (preparation 46, 7.0 g, 31.0 mmol), Pd2(dba)3 (1.41 g, 1.5 mmol), (±)-BINAP (1.92 g, 3.0 mmol), sodium tert-butoxide (4.15 g, 43.0 mmol), and benzophenone imine (6.9 mL, 37.0 mmol), heat at 80° C. in 200 mL of toluene. After 18 hr., cool the reaction to room temperature, and partition between ethylacetate and water. Extract with ethylacetate (1×), and methylene dichloride (2×), combine organics and dry over MgSO4, and concentrate. Dissolve residue in of 1:1 1 N aqueous HCl/THF (200 mL), stir at room temperature. After 2 hr., adjust aqueous layer to pH>10 with 5 N NaOH. Partition between ethylacetate and water, extract aqueous layer with ethylacetate (1×) and methylene dichloride three times. Combine organics, dry over MgSO4, concentrate, and further purify by chromatography (silica gel, eluting with 0-20% 2 M NH3 in methanol/ethylacetate), to obtain the title compound (6.3 g, 99% yield). Mass spectrum (ion spray): m/z=208.1 (M+1); Anal calcd for C11H17N3O.HCl.0.85H2O: Theory: C, 51.00; H, 7.67; N, 16.22. Found: C, 50.72; H, 7.27; N, 16.22.

Workup

  1. temperature, cool
  2. customthe reaction to room temperature
  3. custompartition between ethylacetate and water
  4. extractionExtract with ethylacetate (1×), and methylene dichloride (2×)
  5. dry with materialdry over MgSO4
  6. concentrationconcentrate
  7. waitAfter 2 hr
  8. customPartition between ethylacetate and water
  9. extractionextract aqueous layer with ethylacetate (1×) and methylene dichloride three times
  10. dry with materialCombine organics, dry over MgSO4
  11. concentrationconcentrate
  12. customfurther purify by chromatography (silica gel, eluting with 0-20% 2 M NH3 in methanol/ethylacetate)

Sources & evidence

ORD record
ord-117bb2ddc79b478ca4a3d22ac2ff29b4
Source dataset
uspto-grants-2009_10
Patent number
US07608629B2

Reaction notes

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