1,1'-Carbonyldiimidazole → HCID 66732608, compound

HRID 1963498Notes

Reaction equation

HRID 1963498 reaction equation
C[N:2]1[C:6]([CH:7]2[CH2:12][CH:11](C(OCC)=O)[CH2:10][CH2:9][N:8]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[N:5][N:4]=[N:3]1.N1(C(N2C=CN=C2)=O)C=CN=[CH:29]1.[CH2:40]([O:42][C:43](=[O:48])[CH2:44][C:45]([O-])=[O:46])[CH3:41].[K+].[Cl-].[Mg+2].[Cl-]>C1COCC1>[CH2:40]([O:42][C:43](=[O:48])[CH2:44][C:45]([CH:11]1[CH2:10][CH2:9][N:8]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH:7]([C:6]2[N:2]=[N:3][N:4]([CH3:29])[N:5]=2)[CH2:12]1)=[O:46])[CH3:41]

Participants

6

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 66734713HCID 66734713, compound2×

Product 1

HCID 66732608HCID 66732608, compoundYield 59%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

1-(Benzyloxycarbonyl)-2-(2-methyl-2H-tetrazol-5-yl)piperidine-4-carboxylic acid (0.828 g, 2.40 mmol) (reference compound 36) was dissolved in THF (7 mL) and then di(1H-imidazol-1-yl)methanone (0.583 g, 3.60 mmol) was added. The reaction was stirred overnight at room temperature (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (0.816 g, 4.80 mmol) and anhydrous magnesium chloride (0.457 g, 4.80 mmol) were suspended in THF (7.00 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 over the weekend (72 h). The reaction was quenched by addition of 2 M HCl. The mixture was extracted three times with EtOAc, the combined organic phase was evaporated and purified on a 50 g Biotage column with heptane/EtOAc 88/12-100/0 over 12 CV. Benzyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-methyl-2H-tetrazol-5-yl)piperidine-1-carboxylate (499 mg, 59%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.22-1.31 (m, 3H), 1.72-1.83 (m, 1H), 2.00-2.08 (m, 1H), 2.41 (dt, 1H), 2.70-2.78 (m, 1H), 2.88-2.95 (m, 1H), 3.35-3.63 (m, 3H), 3.99-4.07 (m, 1H), 4.12-4.20 (m, 2H), 4.28 (s, 3H), 5.11-5.21 (m, 2H), 5.59 (t, 1H), 7.27-7.40 (m, 5H). 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 over the weekend (72 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 phase was evaporated
  8. custompurified on a 50 g Biotage column with heptane/EtOAc 88/12-100/0 over 12 CV

Sources & evidence

ORD record
ord-e79aa7046e434b4fa5b284f2a2d92765
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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