1,1'-Carbonyldiimidazole → HCID 131730441, compound

HRID 1963502Notes

Reaction equation

HRID 1963502 reaction equation
[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH:12]1[C:20]1[N:24]([CH3:25])[N:23]=[N:22][N:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:38]([O:40][C:41](=[O:46])[CH2:42]C([O-])=O)[CH3:39].[K+].[Cl-].[Mg+2].[Cl-]>C1COCC1>[CH2:38]([O:40][C:41](=[O:46])[CH2:42][C:17]([C@H:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C@@H:12]([C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)[CH2:13]1)=[O:19])[CH3:39]

Participants

6

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 66734697HCID 66734697, compound2×

Product 1

HCID 131730441HCID 131730441, compoundYield 81.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

1-(Benzyloxycarbonyl)-2-(1-methyl-1H-tetrazol-5-yl)piperidine-4-carboxylic acid (0.495 g, 1.43 mmol) (reference compound 37) was dissolved in THF (4 mL) and then di(1H-imidazol-1-yl)methanone (0.349 g, 2.15 mmol) was added. The reaction was stirred overnight at room temperature (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (0.488 g, 2.87 mmol) and anhydrous magnesium chloride (0.273 g, 2.87 mmol) were suspended in THF (4.00 mL) and stirred at 50° C. under nitrogen overnight and then allowed to cool to room temperature (flask 2). The contents 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. Cis-benzyl 4-(3-ethoxy-3-oxopropanoyl)-2-(1-methyl-1H-tetrazol-5-yl)piperidine-1-carboxylate (482 mg, 81%) was isolated. 1H NMR (600 MHz, cdcl3) δ 1.25 (t, 3H), 1.89-1.97 (m, 1H), 2.05-2.12 (m, 1H), 2.28-2.34 (m, 1H), 2.59-2.66 (m, 1H), 2.93 (p, 1H), 3.35-3.41 (m, 1H), 3.62 (dd, 2H), 3.85-3.98 (m, 4H), 4.16 (q, 2H), 5.09 (q, 2H), 5.36-5.42 (m, 1H), 7.21-7.37 (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 contents 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-7f6d819369744d7c8846226aff982b87
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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