Oxalyl chloride → 4-(3-{4-[(tert-Butoxycarbonyl-cyclopropyl-amino)-methyl]-piperidin-1-yl}-3-oxo-propyl)-3-methyl-benzoic Acid Methyl Ester

HRID 220934Notes

Reaction equation

HRID 220934 reaction equation
C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([OH:20])=O)=[C:12]([CH3:21])[CH:11]=1.CCN(C(C)C)C(C)C.[C:32]([O:36][C:37](=[O:49])[N:38]([CH:46]1[CH2:48][CH2:47]1)[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)([CH3:35])([CH3:34])[CH3:33]>ClCCl.CN(C=O)C>[CH3:7][O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([N:43]2[CH2:42][CH2:41][CH:40]([CH2:39][N:38]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:49])[CH:46]3[CH2:48][CH2:47]3)[CH2:45][CH2:44]2)=[O:20])=[C:12]([CH3:21])[CH:11]=1

Participants

7

Reactant 4

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 57555260Methyl 4-(2-carboxyethyl)-3-methylbenzoateHCID 57555340tert-butyl N-cyclopropyl-N-[(piperidin-4-yl)methyl]carbamate

Product 1

HCID 575553004-(3-{4-[(tert-Butoxycarbonyl-cyclopropyl-amino)-methyl]-piperidin-1-yl}-3-oxo-propyl)-3-methyl-benzoic Acid Methyl EsterYield 43%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent3×

Procedure

Oxalyl chloride (1.26 ml, 14.4 mmol) was added to a solution of 4-(2-carboxy-ethyl)-3-methyl-benzoic acid methyl ester from Example E30.3 (1.60 g, 7.2 mmol) in dichloromethane (50 ml) and few drops of DMF. The mixture was stirred for 1 h at room temperature, concentrated in vacuo and azeotroped with toluene. The residue was dissolved in dichloromethane (50 ml) and DIEA (2.5 ml, 14.4 mmol) and cyclopropyl-piperidin-4-ylmethyl-carbamic acid tert-butyl ester from Example E38 (1.83 g, 7.2 mmol) in dichloromethane (5 ml) was added. The mixture was stirred for 2 h at room temperature, diluted with dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% EtOAc:50% cyclohexane) to yield the title compound (1.42 g, 43%).

Workup

  1. concentrationconcentrated in vacuo
  2. customazeotroped with toluene
  3. dissolutionThe residue was dissolved in dichloromethane (50 ml)
  4. stirringThe mixture was stirred for 2 h at room temperature
  5. washwashed with saturated NaHCO3
  6. dry with materialbrine, dried
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by flash chromatography on silica gel (eluant; 50% EtOAc:50% cyclohexane)

Sources & evidence

ORD record
ord-6231eb3bb4b54ac4b5512b27118739ff
Source dataset
uspto-grants-2012_06
Patent number
US08202858B2

Reaction notes

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