Cesium carbonate → Ethyl 4-[[6-(4-Hydroxy-4-Methyl-1-Piperidyl)-3-Methyl-Pyridine-2-carbonyl]amino]-3,5-dimethyl-benzoate

HRID 239968Notes

Reaction equation

HRID 239968 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[C:21]([CH3:22])=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][C:12]=2[CH3:23])=[O:9])[C:5]([CH3:24])=[CH:4][CH:3]=1.[CH3:25][C:26]1([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[Cs+].[Cs+].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>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:32][C:26]1([CH3:25])[CH2:31][CH2:30][N:29]([C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[C:21]([CH3:22])=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][C:12]=3[CH3:23])=[O:9])[C:5]([CH3:24])=[CH:4][CH:3]=2)[CH2:28][CH2:27]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 156491744-Methylpiperidin-4-olHCID 86707305Ethyl 4-[(6-chloro-3-methyl-pyridine-2-carbonyl)amino]-3,5-dimethyl-benzoate

Product 1

HCID 86707351Ethyl 4-[[6-(4-Hydroxy-4-Methyl-1-Piperidyl)-3-Methyl-Pyridine-2-carbonyl]amino]-3,5-dimethyl-benzoateYield 80%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Procedure

To a solution of ethyl 4-[(6-chloro-3-methyl-pyridine-2-carbonyl)amino]-3,5-dimethyl-benzoate (275 mg, 792.93 mmoles), 4-methylpiperidin-4-ol (120 mg, 1.04 mmol) and Cs2CO3 (0.8 g, 2.46 mmol) in 1,4-dioxane (6 ml) is added Pd(OAc)2 (27 mg, 120.26 μmoles) followed by racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (54 mg, 86.72 moles). The reaction mixture is purged with nitrogen for 5 minutes and then heated to reflux. After 2 hours, the reaction is cooled to ambient temperature and diluted with ammonium chloride and extracted twice with EtOAc. The combined organic layers are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using 0-70% ethyl acetate in hexane to afford the title compound as a yellow oil (0.27 g, 80%). Mass spectrum (m/z): 426.2 (M+1).

Workup

  1. customThe reaction mixture is purged with nitrogen for 5 minutes
  2. temperatureheated to reflux
  3. additiondiluted with ammonium chloride
  4. extractionextracted twice with EtOAc
  5. dry with materialThe combined organic layers are dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe resulting residue is purified by flash chromatography (silica gel)

Sources & evidence

ORD record
ord-d7eec7774bdd4b89b8828fa6c93b3fa6
Source dataset
uspto-grants-2014_02
Patent number
US08642768B2

Reaction notes

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