Ethyl Acetate → 5'-(4-Iodo-3-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid ethyl ester

HRID 2190570Notes

Reaction equation

HRID 2190570 reaction equation
Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([CH3:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:19]1[CH2:29][CH2:28][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C.CCOC(C)=O>O1CCOCC1.O>[CH2:26]([O:25][C:23]([CH:22]1[CH2:28][CH2:29][N:19]([C:2]2[CH:18]=[CH:17][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:14]=[CH:13][C:12]([I:15])=[C:11]([CH3:16])[CH:10]=3)=[CH:4][N:3]=2)[CH2:20][CH2:21]1)=[O:24])[CH3:27]

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 70770Ethyl 4-piperidinecarboxylate2×HCID 81531DiisopropylethylamineHCID 593181386-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide

Product 1

HCID 593181915'-(4-Iodo-3-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid ethyl esterYield 45%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
115 °C

Procedure

A solution of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide (500 mg, 1.34 mmol), ethyl isonipecotate (250 mg, 1.61 mmol) and diisopropylethyl amine (0.7 mL, 4.02 mmol) in dioxane (15 mL) was heated at 80° C. in a sealed tube for 18.5 h then at 95° C. for 9 h and then at 115° C. for an additional 24 h. The reaction mixture was then cooled, another portion of ethyl isonipecotate (250 mg, 1.61 mmol) was added and the mixture was stirred at 115° C. for 8 h more. The mixture was then cooled and portioned between EtOAc and water. The EtOAc layer was dried over Na2SO4, filtered and concentrated. The residue was chromatographed with a silica gel column and 10-40% EtOAc in hexanes gradient to afford the product. (300 mg, Yield: 45%). HRMS m/z calcd for C21H24N3O3I [M+H]+: 494.0935. Found: 494.0937.

Workup

  1. waitat 115° C. for an additional 24 h
  2. temperatureThe reaction mixture was then cooled
  3. temperatureThe mixture was then cooled
  4. dry with materialThe EtOAc layer was dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was chromatographed with a silica gel column and 10-40% EtOAc in hexanes gradient
  8. customto afford the product

Sources & evidence

ORD record
ord-87ed9e38effb4639b238da95000b96a9
Source dataset
uspto-grants-2012_12
Patent number
US08324385B2

Reaction notes

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