Ethyl 4-piperidinecarboxylate → 5-Chloro-2-[5-(4-ethoxycarbonyl-piperidin-1-yl)-2-fluoro-phenyl]-benzoimidazole-1-carboxylic acid tert-butyl ester

HRID 77083Notes

Reaction equation

HRID 77083 reaction equation
[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]1[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:19]=1[F:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(P(C(C)(C)C)C1C=CC=CC=1C1C(CCC)=CC(CCC)=CC=1CCC)(C)(C)C.CC(C)([O-])C.[Na+].[CH2:62]([O:64][C:65]([CH:67]1[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]1)=[O:66])[CH3:63]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]1[CH:23]=[C:22]([N:70]2[CH2:71][CH2:72][CH:67]([C:65]([O:64][CH2:62][CH3:63])=[O:66])[CH2:68][CH2:69]2)[CH:21]=[CH:20][C:19]=1[F:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 70770Ethyl 4-piperidinecarboxylateHCID 23676156Sodium t-butoxideHCID 66977490HCID 66977490, compoundHCID 67346612HCID 67346612, compound

Product 1

HCID 669776225-Chloro-2-[5-(4-ethoxycarbonyl-piperidin-1-yl)-2-fluoro-phenyl]-benzoimidazole-1-carboxylic acid tert-butyl esterYield 24%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
85 °C

Procedure

Method 10—Step a 2-(5-Bromo-2-fluoro-phenyl)-5-chloro-benzoimidazole-1-carboxylic acid tert-butyl ester (obtained as described in general method 7, step c) (1.06 g, 2.50 mmol), Pd2(dba)3 (0.36 g, 0.50 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-1-propyl-1,1′biphenyl (t-BuXphos) (0.32 g, 0.75 mmol) and sodium tert-butoxide (0.48 g, 5.00 mmol) were placed into a dried vial and few cycles of vacuum/nitrogen were performed. Then dry toluene (5 mL) and piperidine-4-carboxylic acid ethyl ester (0.50 mL, 3.25 mmol) were added, the reaction mixture was heated at 85° C. overnight, and washed with saturated Na2CO3 solution (3×5 mL) and water (3×3 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure, and the crude was purified by flash chromatography (eluent: gradient from EtOAc:cyclohexane/1:5 to 1:2) to obtain 0.30 g of the title compound (24%).

Workup

  1. washwashed with saturated Na2CO3 solution (3×5 mL) and water (3×3 mL)
  2. dry with materialThe organic layer was dried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated under reduced pressure
  5. customthe crude was purified by flash chromatography (eluent: gradient from EtOAc:cyclohexane/1:5 to 1:2)

Sources & evidence

ORD record
ord-6e776323228645cbaa3764533d6eb58a
Source dataset
uspto-grants-2014_09
Patent number
US08835648B2

Reaction notes

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