Potassium ethyl malonate → HCID 131730465, compound

HRID 1963557Notes

Reaction equation

HRID 1963557 reaction equation
[Cl-].[Mg+2].[Cl-].[CH2:4]([O:6][C:7](=[O:12])[CH2:8][C:9]([O-:11])=O)[CH3:5].[K+].[CH3:14][O:15][C:16]([N:18]1[CH2:23][CH2:22][C@H:21](C(O)=O)[CH2:20][C@@H: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]>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O>[CH2:4]([O:6][C:7](=[O:12])[CH2:8][C:9]([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:29]=[CH:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=2)[CH2:20]1)=[O:11])[CH3:5]

Participants

5

Reactant 3

HCID 3446434Potassium ethyl malonate2×HCID 5360315Magnesium Chloride2×HCID 66732120HCID 66732120, compound2×

Product 1

HCID 131730465HCID 131730465, compoundYield 88%

Reagents, catalysts & solvents 1

HCID 178479889HCID 178479889, compoundSolvent3×

Conditions

Temperature
50 °C

Procedure

Magnesium chloride (7.39 g, 77.58 mmol) and potassium 3-ethoxy-3-oxopropanoate (13.20 g, 77.58 mmol) were suspended in methyl THF (100 mL) under nitrogen and the resulting suspension heated to 50° C. while stirring with an oversized stirring bar for 4 h, then cooled to room temperature (flask 1). In a separate flask was added to cis-1-(methoxycarbonyl)-2-(4-(trifluoromethyl)benzyl)piperidine-4-carboxylic acid (14.1 g, 40.83 mmol) (reference compound 46) in methyl THF (100 mL) di(1H-imidazol-1-yl)methanone (10 g, 61.67 mmol) under nitrogen. The resulting mixture was stirred at room temperature for 4 h 30 min (flask 2). Then, the contents of flask 2 is transferred into flask 1 by transfer needle, washed with methyl THF (40 mL). The resulting suspension was stirred at room temperature for 19 h 30 min. Additional magnesium chloride (3.7 g, 38.86 mmol) and potassium 3-ethoxy-3-oxopropanoate (6.6 g, 38.78 mmol) in methyl THF (50 mL) were sonicated at 50° C. for 2 h 30 min, then added to the reaction mixture. Stirred at room temperature for 21 h. The reaction mixture was partitioned between 2 M HCl (ca. 150 mL) and MTBE. The phases were separated. The organic phase was washed with brine and satd NaHCO3, then dried over MgSO4 and evaporated. Crude cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (14.9 g, 88%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.21-1.30 (m, 3H), 1.63-2.04 (m, 4H), 2.67-2.86 (m, 2H), 2.93-3.09 (m, 2H), 3.46 (s, 2H), 3.60 (s, 3H), 3.85-3.98 (m, 1H), 4.11-4.26 (m, 3H), 7.30 (d, 2H), 7.53 (d, 2H). MS m/z 416 (M+H)+

Workup

  1. temperaturecooled to room temperature (flask 1)
  2. stirringThe resulting mixture was stirred at room temperature for 4 h 30 min (flask 2)
  3. customThen, the contents of flask 2 is transferred into flask
  4. wash1 by transfer needle, washed with methyl THF (40 mL)
  5. stirringThe resulting suspension was stirred at room temperature for 19 h 30 min
  6. additionadded to the reaction mixture
  7. stirringStirred at room temperature for 21 h
  8. customThe reaction mixture was partitioned between 2 M HCl (ca. 150 mL) and MTBE
  9. customThe phases were separated
  10. washThe organic phase was washed with brine
  11. dry with materialdried over MgSO4
  12. customevaporated

Sources & evidence

ORD record
ord-ae46768068f2429bbec1157a819617b0
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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