p-Toluenesulfonic acid monohydrate → HCID 178429880, compound

HRID 1921143Notes

Reaction equation

HRID 1921143 reaction equation
[CH3:1][CH:2]1[C:7](=O)[CH:6]2[CH2:9][CH2:10][N:3]1[CH2:4][CH2:5]2.[C:11]1([C:17]2[N:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[N:3]2[CH2:10][CH2:9][CH:6](/[C:7]/1=[N:23]/[C:20]1[CH:21]=[N:22][C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:18][CH:19]=1)[CH2:5][CH2:4]2

Participants

5

Reactant 3

HCID 521998p-Toluenesulfonic acid monohydrateHCID 27628776-Phenylpyridin-3-amineHCID 123816982-Methyl-1-azabicyclo(2.2.2)octan-3-one

Product 1

HCID 178429880HCID 178429880, compound

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

A solution of 2-methyl-1-aza-bicyclo[2.2.2]octan-3-one (1.33 g, 9.5 mmol), 6-phenyl-pyridin-3-ylamine (1.25 g, 7.3 mmol) and p-toluene sulfonic acid monohydrate (139 mg, 0.73 mmol) in toluene (40 ml) is heated under reflux for 18 hours using a Dean-Stark apparatus. The toluene is evaporated and the residue is dissolved in ethyl acetate and washed with brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and evaporated to dryness, and the residual oil purified by silica gel column chromatography (eluent: EtOAc: CH3OH:NH4OH; 9:1:0.1) to afford [2-Methyl-1-aza-bicyclo[2.2.2]oct-(3Z)-ylidene]-(6-phenyl-pyridin-3-yl)-amine. A solution of LiAlH4 (1.03 ml, 1 M) in THF is added to a solution of [2-Methyl-1-aza-bicyclo[2.2.2]oct-(3Z)-ylidene]-(6-phenyl-pyridin-3-yl)-amine (300 mg, 1.02 mmol) in THF (10 ml). The resulting mixture is stirred at room temperature for 18 hours and then quenched with a saturated aqueous solution of sodium sulfate (1 ml). The solvents are removed by evaporation and the residue is redissolved in ethyl acetate and filtered. The filtrate is evaporated and purified by silica gel column chromatography (eluent: EtOAc: CH3OH: NH4OH; 8.5:1.5:0.1) to afford Rac.-trans-2-Methyl-1-aza-bicyclo[2.2.2]oct-3-yl)-(6-phenyl-pyridin-3-yl)-amine. MS (ES+): m/e=294.4 (MH+); preparative enantiomer separation (column: Chiralpak AD-H 10 um; (4.6×250 mm), eluent: n-hexane : EtOH 50:50, flow: 1.0 ml/min, detector: UV 210 nm): peak 1: 6.29 min; peak 2: 20.16 min.

Workup

  1. temperatureunder reflux for 18 hours
  2. customThe toluene is evaporated
  3. dissolutionthe residue is dissolved in ethyl acetate
  4. washwashed with brine
  5. dry with materialThe organic layer is dried over anhydrous magnesium sulfate
  6. filtrationfiltered
  7. customevaporated to dryness
  8. customthe residual oil purified by silica gel column chromatography (eluent: EtOAc: CH3OH:NH4OH; 9:1:0.1)

Sources & evidence

ORD record
ord-7bb558f63d2e4392bcaa358995138a1e
Source dataset
uspto-grants-2012_05
Patent number
US08173667B2

Reaction notes

Loading…