Cesium carbonate → Methyl 3-[[6-(4-hydroxy-4-methyl-1-piperidyl)-3-methyl-pyridine-2-carbonyl]amino]-2,4-dimethyl-benzoate

HRID 239971Notes

Reaction equation

HRID 239971 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[C:12]([CH3:22])=[C:13]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:14]([O:16][CH3:17])=[O:15])=[O:9])[C:5]([CH3:23])=[CH:4][CH:3]=1.[CH3:24][C:25]1([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]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:31][C:25]1([CH3:24])[CH2:30][CH2:29][N:28]([C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[C:12]([CH3:22])=[C:13]([CH:18]=[CH:19][C:20]=3[CH3:21])[C:14]([O:16][CH3:17])=[O:15])=[O:9])[C:5]([CH3:23])=[CH:4][CH:3]=2)[CH2:27][CH2:26]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 156491744-Methylpiperidin-4-olHCID 86707343Methyl 3-[(6-chloro-3-methyl-pyridine-2-carbonyl)amino]-2,4-dimethyl-benzoate

Product 1

HCID 86707354Methyl 3-[[6-(4-hydroxy-4-methyl-1-piperidyl)-3-methyl-pyridine-2-carbonyl]amino]-2,4-dimethyl-benzoateYield 69%

Reagents, catalysts & solvents 2

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

Procedure

To a solution of methyl 3-[(6-chloro-3-methyl-pyridine-2-carbonyl)amino]-2,4-dimethyl-benzoate (315 mg, 946.55 mmoles), 4-methylpiperidin-4-ol (130 mg, 1.13 mmol) and Cs2CO3 (0.9 g, 2.76 mmol) in 1,4-dioxane (7 ml) is added Pd(OAc)2 (25 mg, 89.93 moles) followed by racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (56 mg, 89.93 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 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 0-100% ethyl acetate in hexane to afford the title compound as a brown solid (0.27 g, 69%). Mass spectrum (m/z): 412.2 (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 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-fd8cb64bb64a483e82718b229cf74e8b
Source dataset
uspto-grants-2014_02
Patent number
US08642768B2

Reaction notes

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