1,1'-Carbonyldiimidazole → cis-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate

HRID 1963473Notes

Reaction equation

HRID 1963473 reaction equation
[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11](O)=[O:12])[CH2:7][CH:6]1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1[CH3:24])=[O:4].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:37]([O:39][C:40](=[O:45])[CH2:41]C([O-])=O)[CH3:38].[K+].[Cl-].[Mg+2].[Cl-]>C1COCC1>[CH2:37]([O:39][C:40](=[O:45])[CH2:41][C:11]([C@H:8]1[CH2:9][CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[C@@H:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:15]=2[CH3:24])[CH2:7]1)=[O:12])[CH3:38]

Participants

6

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 667318401-(Methoxycarbonyl)-2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid2×

Product 1

HCID 131730430cis-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylateYield 67%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

1-(Methoxycarbonyl)-2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (7.79 g, 22.56 mmol) (reference compound 31) was dissolved in THF (60 mL) and then di(1H-imidazol-1-yl)methanone (5.49 g, 33.84 mmol) was added. The reaction was stirred overnight at room temperature (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (7.68 g, 45.12 mmol) and anhydrous magnesium chloride (4.30 g, 45.12 mmol) were suspended in THF (60.0 mL) and stirred at 50° C. under nitrogen overnight and then allowed to cool to room temperature (flask 2). The content of flask 1 was added to flask 2 and stirred under nitrogen for 48 h. The reaction was quenched by addition of 2 M HCl. The mixture was extracted three times with EtOAc, the combined organic phases were evaporated and purified by column chromatography on silica (100 g Biotage column with heptane/EtOAc 88/12-33/67 over 9 column volumes) to give cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (6.28 g, 67%). 1H NMR (400 MHz, cdcl3) δ 1.23-1.33 (m, 3H), 1.68-1.97 (m, 2H), 2.08-2.21 (m, 2H), 2.44 (s, 3H), 2.87-2.98 (m, 1H), 3.46 (s, 2H), 3.44-3.66 (m, 1H), 3.58 (s, 3H), 4.15-4.29 (m, 3H), 4.91-5.01 (m, 1H), 7.24-7.32 (m, 1H), 7.36-7.43 (m, 2H). MS m/z 416 (M+H)+

Workup

  1. stirringstirred at 50° C. under nitrogen overnight
  2. temperatureto cool to room temperature (flask 2)
  3. additionThe content of flask 1 was added to flask 2
  4. stirringstirred under nitrogen for 48 h
  5. customThe reaction was quenched by addition of 2 M HCl
  6. extractionThe mixture was extracted three times with EtOAc
  7. customthe combined organic phases were evaporated
  8. custompurified by column chromatography on silica (100 g Biotage column with heptane/EtOAc 88/12-33/67 over 9 column volumes)

Sources & evidence

ORD record
ord-a2db1f760ab84f95a5bd4f27531620cd
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

Loading…