Benzophenone imine → 4-[6-(Benzhydrylidene-amino)-pyridin-2-yloxy]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester

HRID 1822006Notes

Reaction equation

HRID 1822006 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](=[NH:36])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(C)([O-])C.[Na+]>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].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[NH3:8].[CH3:1][OH:5].[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:36]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 3

HCID 136809Benzophenone imineHCID 23676156Sodium t-butoxideHCID 767272004-(6-Chloro-pyridin-2-yloxy)-2-methyl-piperidine-1-carboxylic acid tert-butyl ester

Product 2

HCID 21705897Ammonia methanolHCID 767271984-[6-(Benzhydrylidene-amino)-pyridin-2-yloxy]-2-methyl-piperidine-1-carboxylic acid tert-butyl esterYield 94%

Reagents, catalysts & solvents 3

HCID 634876Binap, (A+-)-CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

Combine 4-(6-chloro-pyridin-2-yloxy)-2-methyl-piperidine-1-carboxylic acid tert-butyl ester cis isomer 1 (preparation 49, 4.50 g, 13.77 mmol), toluene (150 mL), benzhydrylideneamine (3.0 g, 16.52 mmol), sodium-t-butoxide (1.85 g, 19.28 mmol), and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.343 g, 0.55 mmol), stir and heat at 100° C. After 10 min., add tris(dibenzylideneacetone)-dipalladium(0) (0.252 g, 0.275 mmol), stir and heat at 100° C. After 3 hr., cool to ambient temperature. Partition between water (200 mL) and 4:1 hexane:ethyl acetate (200 mL). Separate the aqueous fraction and wash again with 4:1 hexane:ethyl acetate (200 mL). Dry the combined organic layers over sodium sulfate, filter and concentrate. Purify the residue by silica gel flash chromatography eluting with 9:1:0.2 hexane:ethyl acetate:2M ammonia/methanol to obtain the title compound (6.08 g, 94%). 1H NMR (CDCl3): 7.8 (d, 2H), 7.45 (m, 4H), 7.3 (m, 3H), 7.2 (m, 2H), 6.3 (dd, 2H), 5.1 (m, 1H), 4.2 (m, 1H), 3.8 (m, 1H), 3.2 (m, 1H), 1.6 (m, 4H), 1.5 (s, 9H), 1.2 (d, 3H).

Workup

  1. stirringstir
  2. temperatureheat at 100° C
  3. waitAfter 3 hr
  4. temperature, cool to ambient temperature
  5. customPartition between water (200 mL) and 4:1 hexane
  6. customSeparate the aqueous fraction
  7. washwash again with 4:1 hexane
  8. dry with materialDry the combined organic layers over sodium sulfate
  9. filtrationfilter
  10. concentrationconcentrate
  11. customPurify the residue by silica gel flash chromatography
  12. washeluting with 9:1:0.2 hexane

Sources & evidence

ORD record
ord-2d0a374e550f4444ad7e105ab528b1d4
Source dataset
uspto-grants-2009_10
Patent number
US07608629B2

Reaction notes

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