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

HRID 1963550Notes

Reaction equation

HRID 1963550 reaction equation
[Cl-].[Mg+2].[Cl-].[C:4]([OH:10])(=O)[CH2:5][C:6]([OH:8])=[O:7].[CH2:11]([K])[CH3:12].N1(C(N2C=CN=C2)=O)[CH:18]=[CH:17]N=C1.[F:26][C:27]1[CH:46]=[CH:45][CH:44]=[CH:43][C:28]=1[CH2:29][CH:30]1[CH2:35][CH:34]([C:36]([OH:38])=O)[CH2:33][CH2:32][N:31]1[C:39]([O:41][CH3:42])=[O:40]>C1COCC1>[CH2:11]([O:8][C:6](=[O:7])[CH2:5][C:4]([C@@H:34]1[CH2:33][CH2:32][N:31]([C:39]([O:41][CH3:42])=[O:40])[C@@H:30]([CH2:29][C:28]2[CH:43]=[CH:44][CH:45]=[CH:46][C:27]=2[F:26])[CH2:35]1)=[O:10])[CH3:12].[CH2:17]([O:8][C:6](=[O:7])[CH2:5][C:36]([C@H:34]1[CH2:33][CH2:32][N:31]([C:39]([O:41][CH3:42])=[O:40])[C@@H:30]([CH2:29][C:28]2[CH:43]=[CH:44][CH:45]=[CH:46][C:27]=2[F:26])[CH2:35]1)=[O:38])[CH3:18]

Participants

7

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 5360315Magnesium ChlorideHCID 667323532-(2-Fluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid2×HCID 178461627HCID 178461627, compound

Product 2

HCID 131730463trans-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluorobenzyl)piperidine-1-carboxylateYield 14%HCID 131730464cis-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluorobenzyl)piperidine-1-carboxylateYield 58%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
50 °C

Procedure

A suspension of magnesium chloride (2.60 g, 27.33 mmol) and ethyl potassium malonate (4.65 g, 27.33 mmol) in dry THF (80 mL) was stirred under nitrogen atmosphere at 50° C. for 2.5 h (flask 1). In another flask di(1H-imidazol-1-yl)methanone (3.69 g, 22.77 mmol) was added portionwise to a solution of 2-(2-fluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.483 g, 15.18 mmol) (reference compound 45) in dry THF (20 mL) at 0° C. under nitrogen atmosphere. The ice bath was removed and the solution was stirred for 2 h at room temperature (flask 2). The contents of flask 1 was added slowly to flask 2 and the resulting mixture was stirred for 19 h under nitrogen. The reaction mixture was concentrated and the residue was taken up in EtOAc and H2O. The aqueous phase was extracted once with EtOAc and the combined organic phases were washed with H2O, 10% Na2CO3 and then dried over Na2SO4. The compound was purified further via Biotage, 2 runs, SNAP 340 g KP-SIL, first 8:2 for 2 CV then linear gradient heptanes/ethyl acetate 8:2 to 3:7 over 7CV. Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluorobenzyl)piperidine-1-carboxylate (1.145 g, 14%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluorobenzyl)piperidine-1-carboxylate (3.19 g, 58%) were isolated. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.20-1.30 (m, 3H), 1.63-1.99 (m, 4H), 2.63-2.76 (m, 1H), 2.77-3.13 (m, 3H), 3.46 (s, 2H), 3.53 (s, 3H), 3.85-3.99 (m, 1H), 4.17 (q, 2H), 4.22-4.32 (m, 1H), 6.93-7.08 (m, 2H), 7.09-7.22 (m, 2H). MS m/z 366 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.19-1.32 (m, 3H), 1.39-1.99 (m, 4H), 2.52-3.12 (m, 4H), 3.37-3.71 (m, 5H), 4.18 (q, 2H), 4.02-4.32 (m, 1H), 4.48-4.71 (m, 1H), 6.94-7.24 (m, 4H). MS m/z 366 (M+H)+

Workup

  1. customThe ice bath was removed
  2. stirringthe solution was stirred for 2 h at room temperature (flask 2)
  3. additionThe contents of flask 1 was added slowly to flask 2
  4. stirringthe resulting mixture was stirred for 19 h under nitrogen
  5. concentrationThe reaction mixture was concentrated
  6. extractionThe aqueous phase was extracted once with EtOAc
  7. washthe combined organic phases were washed with H2O, 10% Na2CO3
  8. dry with materialdried over Na2SO4
  9. customThe compound was purified further via Biotage, 2 runs, SNAP 340 g KP-SIL, first 8:2 for 2 CV

Sources & evidence

ORD record
ord-8174ae5ed62f440f9e3064a6bffc4f6c
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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