Hydrochloric Acid → trans-Methyl 2-(4-tert-butylphenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate

HRID 1963391Notes

Reaction equation

HRID 1963391 reaction equation
[Cl-].[Mg+2].[Cl-].[CH2:4]([O:6][C:7](=[O:12])[CH2:8][C:9]([O-:11])=O)[CH3:5].[K+].[C:14]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH:28](C(O)=O)[CH2:27][CH2:26][N:25]2[C:33]([O:35][CH3:36])=[O:34])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].N1(C(N2C=CN=C2)=O)C=CN=C1.Cl>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([C@H:24]2[CH2:29][C@H:28]([C:9](=[O:11])[CH2:8][C:7]([O:6][CH2:4][CH3:5])=[O:12])[CH2:27][CH2:26][N:25]2[C:33]([O:35][CH3:36])=[O:34])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 667319312-(4-tert-Butylphenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid2×

Product 1

HCID 131730393trans-Methyl 2-(4-tert-butylphenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylateYield 9.4%

Reagents, catalysts & solvents 1

HCID 178479889HCID 178479889, compoundSolvent2×

Conditions

Temperature
50 °C

Procedure

Magnesium chloride (5.38 g, 56.51 mmol) and potassium 3-ethoxy-3-oxopropanoate (9.62 g, 56.51 mmol) were suspended in methyl THF (100 mL) and heated to 50° C. under nitrogen for 18 h using an oversized stirring bar, then cooled to room temperature (flask 1). In a separate flask was to a suspension of 2-(4-tert-butylphenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (9.5 g, 29.74 mmol) (reference compound 15) in methyl THF (100 mL) added di(1H-imidazol-1-yl)methanone (7.23 g, 44.62 mmol) under nitrogen. The resulting mixture was stirred at room temperature for 4 h (flask 2). Then, the contents of flask 2 is transferred into flask 1 by transfer needle. Wash with methyl THF (30 mL). Resulting suspension stirred at room temperature for 18 h. 3.8 M HCl was added (ca. 150 mL) and the resulting biphasic mixture stirred vigorously for 2 h. The phases were separated. The organic phase was washed with water, satd NaHCO3 and brine, then dried over MgSO4 and evaporated. The residue was purified via Biotage in two equal portions (Biotage® KP-SIL 340 g column, 1 CV 20% EtOAc in heptanes, then 20%=>60% over 7 CV). Trans-methyl 2-(4-tert-butylphenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.09 g, 9.4%) was isolated as a pale yellow oil. 1H NMR (400 MHz, cdcl3) δ 1.22-1.31 (m, 3H), 1.31 (s, 9H), 1.50-1.99 (m, 4H), 2.50-2.96 (m, 2H), 3.47 (s, 2H), 3.74 (s, 3H), 4.08-4.23 (m, 3H), 5.46-5.71 (m, 1H), 7.09-7.16 (m, 2H), 7.34-7.40 (m, 2H).

Workup

  1. temperaturecooled to room temperature (flask 1)
  2. customThen, the contents of flask 2 is transferred into flask
  3. washWash with methyl THF (30 mL)
  4. customResulting suspension
  5. stirringstirred at room temperature for 18 h
  6. stirringthe resulting biphasic mixture stirred vigorously for 2 h
  7. customThe phases were separated
  8. washThe organic phase was washed with water
  9. dry with materialdried over MgSO4
  10. customevaporated
  11. customThe residue was purified via Biotage in two equal portions (Biotage® KP-SIL 340 g column, 1 CV 20% EtOAc in heptanes

Sources & evidence

ORD record
ord-e1270fe95bab40c3ab3b05b94e9cfedd
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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