1,1'-Carbonyldiimidazole → HCID 131730468, compound

HRID 1963565Notes

Reaction equation

HRID 1963565 reaction equation
[C:1]([OH:7])(=[O:6])[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(O)=O)[CH2:20][CH:19]1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=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]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:35])[F:37])[CH:29]=2)[CH2:20]1)=[O:7])[CH3:9].[CH2:43]([O:7][C:1](=[O:6])[CH2:2][C:3]([C@H:21]1[CH2:22][CH2:23][N:18]([C:16]([O:15][CH3:14])=[O:17])[C@@H:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[CH2:20]1)=[O:5])[CH3:44]

Participants

9

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 5360315Magnesium ChlorideHCID 667318321-(Methoxycarbonyl)-2-(3-(trifluoromethyl)benzyl)piperidine-4-carboxylic acid2×HCID 178461627HCID 178461627, compound

Product 2

HCID 131730467HCID 131730467, compoundYield 26%HCID 131730468HCID 131730468, compoundYield 35%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
50 °C

Procedure

Ethyl potassium malonate (3.42 g, 20.16 mmol) and MgCl2 (1.599 g, 16.80 mmol) were added to dry THF (50 ml). The reaction flask was stirred vigorously overnight at 50° C. (flask 1). 1-(Methoxycarbonyl)-2-(3-(trifluoromethyl)benzyl)piperidine-4-carboxylic acid (5.8 g, 16.80 mmol) (reference compound 48) and carbonyldiimidazole (4.09 g, 25.19 mmol) were added to dry THF (50 mL) at 5° C. and was stirred overnight at room temperature (flask 2). The contents of flask 2 was added to flask 1 at room temperature and stirred for 3 days. The reaction mixture was dissolved between water and diethyl ether. The organic phase was evaporated to remove most of the THF. Dissolved the crude between water and diethyl ether again. The organic phase was isolated, dried with Na2SO4, filtered through celite and the solvent was evaporated. Chromatography using the Biotage equipment. Gradient eluation using ethyl acetate-heptane, started 0-100 and ended 100-0. Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-(trifluoromethyl)benzyl)piperidine-1-carboxylate (1.8 g, 26%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-(trifluoromethyl)benzyl)piperidine-1-carboxylate (2.45 g, 35%) were isolated. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.20-1.32 (m, 3H), 1.63-1.99 (m, 4H), 2.67-2.86 (m, 2H), 2.92-3.12 (m, 2H), 3.47 (s, 2H), 3.59 (s, 3H), 3.89-4.00 (m, 1H), 4.09-4.29 (m, 3H), 7.32-7.51 (m, 4H). MS m/z 416 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.19-1.35 (m, 3H), 1.42-2.08 (m, 4H), 2.51-3.09 (m, 4H), 3.35-3.78 (m, 5H), 4.04-4.38 (m, 3H), 4.47-4.79 (m, 1H), 7.23-7.56 (m, 4H). MS m/z 416 (M+H)+

Workup

  1. stirringwas stirred overnight at room temperature (flask 2)
  2. additionThe contents of flask 2 was added to flask 1 at room temperature
  3. stirringstirred for 3 days
  4. customThe organic phase was evaporated
  5. customto remove most of the THF
  6. dissolutionDissolved the crude between water and diethyl ether again
  7. customThe organic phase was isolated
  8. dry with materialdried with Na2SO4
  9. filtrationfiltered through celite
  10. customthe solvent was evaporated

Sources & evidence

ORD record
ord-16661e058eac42b1ad581f25422ba5c1
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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