Benzophenone imine → tert-Butyl 4-(5-aminopyridin-2-yl)piperidine-1-carboxylate

HRID 1748595Notes

Reaction equation

HRID 1748595 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C(O[Na])(C)(C)C.C(=[NH:69])(C1C=CC=CC=1)C1C=CC=CC=1.O.NO.C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+].C(OC(N1CC=C(C2C=CC(N)=CN=2)CC1)=O)(C)(C)C.C(OC(N1CC=C(C2C=CC(N(C3C=CC=CC=3)C3C=CC=CC=3)=CN=2)CC1)=O)(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:69])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

14

Reactant 9

HCID 136809Benzophenone imineHCID 516892Sodium Bicarbonate2×HCID 517045Sodium Acetate2×HCID 2734941(1,1'-Binaphthalen)-2-yldi-tert-butylphosphineHCID 22235265HCID 22235265, compound2×HCID 59529301HCID 59529301, compoundHCID 66864301HCID 66864301, compoundHCID 86692548HCID 86692548, compoundHCID 178418730sodium 2-methylpropan-2-olate

Product 1

HCID 59128562tert-Butyl 4-(5-aminopyridin-2-yl)piperidine-1-carboxylate

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 702EthanolSolvent2×HCID 962WaterSolvent2×HCID 1140TolueneSolvent

Conditions

Temperature
120 °C

Procedure

To a suspension of 4-(5-bromopyridin-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (6.45 g), palladium(II) acetate (533 mg), (±)-2-(di-tert-butylphosphino)-1,1′-binaphthyl (1.48 g), and tert-butoxysodium (2.74 g) in toluene (47 ml) was added benzophenone imine (3.35 ml), stirred at 120° C. for 3 hours, then ethanol (50 ml), water (50 ml), hydroxylamine monohydrate (5.28 g), and sodium acetate (9.35 g) were added thereto at room temperature, and stirred at room temperature for 2.5 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The obtained residue was purified with basic silica gel chromatography (n-hexane/ethyl acetate) to give a mixture of 4-(5-aminopyridin-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester and 4-(5-diphenylaminopyridin-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester. To the obtained mixture were added ethanol (100 ml), water (50 ml), hydroxylamine monohydrate (2.64 g), and sodium acetate (4.67 g), and stirred at room temperature for 6.5 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The obtained residue was purified with basic silica gel chromatography (n-hexane/ethyl acetate). To the obtained oil were added 1,4-dioxane (15 ml) and 10% palladium carbon (containing about 50% water, 1.7 g), stirred at room temperature for 3.5 hours under hydrogen atmosphere, and then stirred at 40° C. for 12 hours. The reaction solution was filtered through Celite, then the solvent was evaporated in vacuo, and the obtained residue was purified with basic silica gel chromatography (chloroform/methanol) to give 4-(5-aminopyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (2.8 g) as a yellow oil.

Workup

  1. stirringat room temperature, and stirred at room temperature for 2.5 hours
  2. extractionextracted with ethyl acetate
  3. dry with materialthe organic layer was dried over anhydrous sodium sulfate
  4. customthe solvent was evaporated in vacuo
  5. customThe obtained residue was purified with basic silica gel chromatography (n-hexane/ethyl acetate)
  6. customto give
  7. stirringstirred at room temperature for 6.5 hours
  8. extractionextracted with ethyl acetate
  9. dry with materialdried over anhydrous sodium sulfate
  10. customthe solvent was evaporated in vacuo
  11. customThe obtained residue was purified with basic silica gel chromatography (n-hexane/ethyl acetate)
  12. additionTo the obtained oil were added 1,4-dioxane (15 ml) and 10% palladium carbon (containing about 50% water, 1.7 g)
  13. stirringstirred at room temperature for 3.5 hours under hydrogen atmosphere
  14. stirringstirred at 40° C. for 12 hours
  15. filtrationThe reaction solution was filtered through Celite
  16. customthe solvent was evaporated in vacuo
  17. customthe obtained residue was purified with basic silica gel chromatography (chloroform/methanol)

Sources & evidence

ORD record
ord-126df071fe3e49fba57c49dda787d85f
Source dataset
uspto-grants-2015_10
Patent number
US09150555B2

Reaction notes

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