1,1'-Carbonyldiimidazole → HCID 131730466, compound

HRID 1963560Notes

Reaction equation

HRID 1963560 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(O)=O)[CH2:20][CH:19]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)=[O:17].C(N1C=CN=C1)(N1C=CN=C1)=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][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:30][CH:29]=2)[CH2:20]1)=[O:7])[CH3:9]

Participants

6

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 5360315Magnesium ChlorideHCID 66731937HCID 66731937, compound2×HCID 178461627HCID 178461627, compound

Product 1

HCID 131730466HCID 131730466, compoundYield 43%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
50 °C

Procedure

Ethyl potassium malonate (1.065 g, 6.26 mmol) and MgCl2 (0.496 g, 5.21 mmol) were added to dry THF (50 mL). The reaction mixture was stirred vigorously for 4 h at 50° C. (flask 1). 1-(Methoxycarbonyl)-2-(4-(trifluoromethyl)benzyl)piperidine-4-carboxylic acid (1.8 g, 5.21 mmol) (reference compound 47) and carbonyldiimidazole (1.268 g, 7.82 mmol) were added to dry THF (50 ml) at 5° C. (flask 2). The contents of flask 2 was added to flask 1 and the resulting suspension was stirred at room temperature overnight. THF was evaporated and the reaction mixture was partitioned 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 15-85 and ended 40-60. Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (0.93 g, 42.9%) was isolated. 1H NMR (600 MHz, cdcl3) δ 1.20-1.29 (m, 3H), 1.46-1.99 (m, 4H), 2.74-3.04 (m, 4H), 3.34-3.70 (m, 5H), 4.01-4.32 (m, 3H), 4.60 (d, 1H), 7.22-7.38 (m, 2H), 7.51-7.56 (m, 2H). MS m/z 416 (M+H)+

Workup

  1. additionThe contents of flask 2 was added to flask 1
  2. stirringthe resulting suspension was stirred at room temperature overnight
  3. customTHF was evaporated
  4. customthe reaction mixture was partitioned between water and diethyl ether
  5. customThe organic phase was isolated
  6. dry with materialdried with Na2SO4
  7. filtrationfiltered through celite
  8. customthe solvent was evaporated

Sources & evidence

ORD record
ord-f7106dacd50e42c99b3a85b3adb349df
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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