1,1'-Carbonyldiimidazole → HCID 131730425, compound

HRID 1963461Notes

Reaction equation

HRID 1963461 reaction equation
[C:1]([OH:7])(=O)[CH2:2][C:3]([OH:5])=[O:4].[CH2:8]([K])[CH3:9].[Mg+2].[Cl-].[Cl-].[CH3:14][O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH:19]1[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[C:29]([CH3:37])[CH:28]=1)=[O:17].C(N1C=CN=C1)(N1[CH:44]=[CH:43]N=C1)=O>C(OCC)C.O.C1COCC1>[CH2:8]([O:5][C:3](=[O:4])[CH2:2][C:1]([C@@H:21]1[CH2:22][CH2:23][N:18]([C:16]([O:15][CH3:14])=[O:17])[C@@H:19]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[C:29]([CH3:37])[CH:28]=2)[CH2:20]1)=[O:7])[CH3:9].[CH2:43]([O:5][C:3](=[O:4])[CH2:2][C:24]([C@H:21]1[CH2:22][CH2:23][N:18]([C:16]([O:15][CH3:14])=[O:17])[C@@H:19]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[C:29]([CH3:37])[CH:28]=2)[CH2:20]1)=[O:26])[CH3:44]

Participants

9

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 5360315Magnesium ChlorideHCID 66731806HCID 66731806, compound2×HCID 178461627HCID 178461627, compound

Product 2

HCID 131730424HCID 131730424, compoundYield 22%HCID 131730425HCID 131730425, compoundYield 44%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
50 °C

Procedure

Ethyl potassium malonate (1.567 g, 9.21 mmol) and MgCl2 (0.731 g, 7.67 mmol) were added to dry THF (50 mL). The reaction flask was stirred vigorously for 4 h at 50° C. (flask 1). 1-(Methoxycarbonyl)-2-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (2.65 g, 7.67 mmol) (reference compound 29) and carbonyldiimidazole (1.867 g, 11.51 mmol) were added to dry THF (50 mL) at room temperature (flask 2). The contents of flask 2 was added to flask 1 and the resulting mixture stirred at room temperature overnight. The reaction mixture was dissolved between water and diethyl ether. The organic phase was isolated, dried with Na2SO4, filtered through celite and the solvent was evaporated. Chromatography using the Biotage equipment. Gradient eluation using ethylacetate-heptane, started 0-100 and ended 100-0. Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-methyl-4-(trifluoromethyl)phenyl)-piperidine-1-carboxylate (0.69 g, 22%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (1.40 g, 44%) were isolated. Cis-isomer: 1H NMR (600 MHz, cdcl3) δ 1.25 (t, 3H), 1.00-2.29 (m, 4H), 2.44 (s, 3H), 2.47-2.95 (m, 1H), 3.27-3.34 (m, 1H), 3.37-3.48 (m, 2H), 3.62 (s, 3H), 3.66-4.20 (m, 3H), 4.88-4.96 (m, 1H), 7.05-7.11 (m, 2H), 7.50-7.54 (m, 1H). Trans-isomer: 1H NMR (600 MHz, cdcl3) δ 1.22 (t, 3H), 1.47-2.03 (m, 4H), 2.47 (s, 3H), 2.49-2.89 (m, 2H), 3.40-3.47 (m, 2H), 3.74 (s, 3H), 4.15 (q, 2H), 4.11-4.36 (m, 1H), 5.37-5.75 (m, 1H), 7.06-7.13 (m, 2H), 7.57 (d, 1H).

Workup

  1. additionThe contents of flask 2 was added to flask 1
  2. stirringthe resulting mixture stirred at room temperature overnight
  3. customThe organic phase was isolated
  4. dry with materialdried with Na2SO4
  5. filtrationfiltered through celite
  6. customthe solvent was evaporated

Sources & evidence

ORD record
ord-9fccd16bf05c4045ba26dd7b5d64d201
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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