Dichloromethane → 4-Hydroxy-4-(4-pyrimidin-2-ylphenyl)-piperidine-1-carboxylic acid tert-butyl ester

HRID 1038062Notes

Reaction equation

HRID 1038062 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[K+].[K+].Br[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(OCC)(=O)C.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([C:15]2[CH:20]=[CH:19][C:18]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

10

Reactant 5

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 783452-BromopyrimidineHCID 517044Potassium AcetateHCID 183795571-Boc-4-(4-bromo-phenyl)-piperidin-4-ol

Product 1

HCID 589464254-Hydroxy-4-(4-pyrimidin-2-ylphenyl)-piperidine-1-carboxylic acid tert-butyl esterYield 80%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (800 mg, 2.25 mmol), bis(pinacolate)diboron (856 mg, 3.37 mmol), PdCl2(dppf).CH2Cl2 (184 mg, 0.23 mmol), potassium acetate (660 mg, 6.74 mmol) were weighted into a sealed-tube. Methyl sulfoxide (20 ml) was added and the mixture was purged with nitrogen for 20 min before it was heated at 100° C. for 2 hr under nitrogen. The mixture was cooled to r.t. Potassium carbonate (1.55, 11.2 mmol), 2-bromopyrimidine (429 mg, 2.70 mmol) and water (10 ml) were added. The mixture was again purged with nitrogen for 20 min. Palladium tetrakistriphenylphosphine (260 mg, 0.23 mmol) was added and the final mixture was stirred at 100° C. for a further 2 hr. After being cooled to r.t., ethyl acetate and water were added. The mixture was filtered through a pad of Celite. Layers were separated and the organic layer was washed with water (×2). The combined aqueous layers were extracted with ethyl acetate (×1). The combined organic layers were dried (MgSO4) and filtered. Solvents were removed in vacuum and column chromatography [ethyl acetate-hexane, 1:1 (v/v)] gave 4-hydroxy-4-(4-pyrimidin-2-ylphenyl)-piperidine-1-carboxylic acid tert-butyl ester (639 mg, 80%) as colorless oil.

Workup

  1. customthe mixture was purged with nitrogen for 20 min before it
  2. temperatureThe mixture was cooled to r.t
  3. customThe mixture was again purged with nitrogen for 20 min
  4. temperatureAfter being cooled to r.t.
  5. filtrationThe mixture was filtered through a pad of Celite
  6. customLayers were separated
  7. washthe organic layer was washed with water (×2)
  8. extractionThe combined aqueous layers were extracted with ethyl acetate (×1)
  9. dry with materialThe combined organic layers were dried (MgSO4)
  10. filtrationfiltered
  11. customSolvents were removed in vacuum and column chromatography [ethyl acetate-hexane, 1:1 (v/v)]

Sources & evidence

ORD record
ord-ebf33b36049a4b89809ade8120dca9f2
Source dataset
uspto-grants-2013_10
Patent number
US08546404B2

Reaction notes

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