tert-Butyl piperazine-1-carboxylate → 4-[6-(4-Cyclohexyl-3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester

HRID 2100661Notes

Reaction equation

HRID 2100661 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:12]([C:22]([F:25])([F:24])[F:23])[CH:11]=2)=[N:6][CH:7]=1.[N:26]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=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].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.[Fe+2]>[C:35]([O:34][C:32]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)=[C:12]([C:22]([F:25])([F:24])[F:23])[CH:11]=3)=[CH:4][CH:3]=2)[CH2:28][CH2:27]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]

Participants

7

Reactant 3

HCID 143452tert-Butyl piperazine-1-carboxylateHCID 23676156Sodium t-butoxideHCID 688136965-Bromo-2-(4-cyclohexyl-3-trifluoromethyl-benzyloxy)-pyridine

Product 1

HCID 688120204-[6-(4-Cyclohexyl-3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 3

HCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

5-Bromo-2-(4-cyclohexyl-3-trifluoromethyl-benzyloxy)-pyridine (332 mg, 0.8 mmol), tert-butyl 1-piperazine-carboxylate (178 mg, 0.96 mmol), Pd(dppf)Cl2 (17.5 mg, 0.024 mmol), dppf (20 mg, 0.036 mmol) and sodium tert-butoxide (115 mg, 1.19 mmol) are mixed in toluene (2 mL). The mixture is purged with N2 (g), heated at 80° C. for 14 h, poured into saturated aqueous NaHCO3 and extracted with EtOAc. The combined extracts are washed with brine and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (180:25:1 hexanes/EtOAc/Et3N) to give 4-[6-(4-Cyclohexyl-3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester.

Workup

  1. customThe mixture is purged with N2 (g)
  2. additionpoured into saturated aqueous NaHCO3
  3. extractionextracted with EtOAc
  4. washThe combined extracts are washed with brine
  5. dry with materialdried over Na2SO4
  6. concentrationAfter concentration
  7. customthe residue is purified by silica gel chromatography (180:25:1 hexanes/EtOAc/Et3N)

Sources & evidence

ORD record
ord-bb25bb0d10bf4987a9cb2b94e14637d5
Source dataset
uspto-grants-2009_08
Patent number
US07572811B2

Reaction notes

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