Toluene → 6-(1-Cyclopropylmethyl-piperidin-4-yloxy)-pyridin-2-ylamine

HRID 1822011Notes

Reaction equation

HRID 1822011 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]([CH2:15][CH:16]3[CH2:18][CH2:17]3)[CH2:11][CH2:10]2)[N:3]=1.C(=[NH:32])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C1COCC1.Cl.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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH:16]1([CH2:15][N:12]2[CH2:13][CH2:14][CH:9]([O:8][C:4]3[N:3]=[C:2]([NH2:32])[CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11]2)[CH2:18][CH2:17]1

Participants

9

Reactant 4

HCID 1140TolueneHCID 136809Benzophenone imineHCID 23676156Sodium t-butoxideHCID 578937202-Chloro-6-(1-cyclopropylmethyl-piperidin-4-yloxy)-pyridine

Product 1

HCID 578937436-(1-Cyclopropylmethyl-piperidin-4-yloxy)-pyridin-2-ylamineYield 70%

Reagents, catalysts & solvents 4

HCID 634876Binap, (A+-)-CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 313Hydrochloric AcidSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

Combine 2-chloro-6-(1-cyclopropylmethyl-piperidin-4-yloxy)-pyridine (preparation 56, 480 mg, 1.80 mmol), benzophenone imine (391 mg, 2.16 mmol), BINAP (67 mg, 0.11 mmol), pd2(dba)3 (33 mg, 0.036 mmol), sodium t-butoxide (242 mg, 2.52 mmol) and toluene (8 mL) and heat at 100° C. for 14 hr. Quench the reaction with saturated NaHCO3 solution, extract with ethyl acetate three times. Combine the organic layers, dry over Na2SO4, filter and concentrate under reduced pressure to give a residue. Dissolve the residue in THF (10 mL), add 5N HCl (1.0 mL) and stir for 30 min. Dilute the mixture with 0.1N HCl solution, extract twice with ethyl acetate-hexanes (1:2). Keep the aqueous layer and adjust pH>11 with 5N NaOH solution, extract with methylene dichloride three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 7% 2M NH3-methanol in methylene dichloride provides 310 mg (70%) of the title compound as a white solid: mass spectrum (ion spray): m/z=248.1 (M+1); 1H NMR (CDCl3, ppm): 7.23 (t, 1H), 5.95 (pseudo-t, 2H), 4.81 (m, 1H), 4.14 (s, br, 2H), 2.76 (m, 2H), 2.26 (m, 2H), 2.18 (d, 2H), 1.92 (m, 2H), 1.71 (m, 2H), 0.80 (m, 1H), 0.44 (m, 2H), 0.00 (m, 2H).

Workup

  1. customQuench
  2. customthe reaction with saturated NaHCO3 solution
  3. extractionextract with ethyl acetate three times
  4. dry with materialCombine the organic layers, dry over Na2SO4
  5. filtrationfilter
  6. concentrationconcentrate under reduced pressure
  7. customto give a residue
  8. extractionextract twice with ethyl acetate-hexanes (1:2)
  9. extractionextract with methylene dichloride three times
  10. dry with materialCombine the organic layers, dry over Na2SO4
  11. filtrationfilter
  12. concentrationconcentrate
  13. customto give a residue
  14. washChromatography (silica gel) eluting with 7% 2M NH3-methanol in methylene dichloride

Sources & evidence

ORD record
ord-a508220f18cc4738be1c38368711c8d2
Source dataset
uspto-grants-2009_10
Patent number
US07608629B2

Reaction notes

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