Hydrochloric Acid → HCID 131730497, compound

HRID 1963639Notes

Reaction equation

HRID 1963639 reaction equation
[Cl-].[Mg+2].[Cl-].[CH2:4]([O:6][C:7](=[O:12])[CH2:8][C:9]([O-:11])=[O:10])[CH3:5].[K+].[F:14][C:15]1[CH:16]=[C:17]([CH:32]=[CH:33][C:34]=1[C:35]([F:38])([F:37])[F:36])[CH2:18][CH:19]1[CH2:24][CH:23](C(O)=O)[CH2:22][CH2:21][N:20]1[C:28]([O:30][CH3:31])=[O:29].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.CC(OC)(C)C>[CH2:4]([O:6][C:7](=[O:12])[CH2:8][C:9]([C@@H:23]1[CH2:22][CH2:21][N:20]([C:28]([O:30][CH3:31])=[O:29])[C@@H:19]([CH2:18][C:17]2[CH:32]=[CH:33][C:34]([C:35]([F:38])([F:36])[F:37])=[C:15]([F:14])[CH:16]=2)[CH2:24]1)=[O:11])[CH3:5].[CH2:4]([O:6][C:7](=[O:12])[CH2:8][C:9]([C@H:23]1[CH2:22][CH2:21][N:20]([C:28]([O:30][CH3:31])=[O:29])[C@@H:19]([CH2:18][C:17]2[CH:32]=[CH:33][C:34]([C:35]([F:38])([F:37])[F:36])=[C:15]([F:14])[CH:16]=2)[CH2:24]1)=[O:10])[CH3:5]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 667322622-(3-Fluoro-4-(trifluoromethyl)benzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid2×

Product 2

HCID 131730496HCID 131730496, compoundYield 10%HCID 131730497HCID 131730497, compoundYield 45%

Reagents, catalysts & solvents 2

HCID 15413tert-Butyl methyl etherSolventHCID 178479889HCID 178479889, compoundSolvent2×

Conditions

Temperature
50 °C

Procedure

Magnesium chloride (3.25 g, 34.13 mmol) and potassium 3-ethoxy-3-oxopropanoate (5.82 g, 34.19 mmol) were suspended under a nitrogen atmosphere in methyl THF (100 mL) and stirred with an oversized stirring bar at 50° C. for 18 h, then cooled to room temperature (flask 1). To a suspension of 2-(3-fluoro-4-(trifluoromethyl)benzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (6.56 g, 18.06 mmol) (reference compound 59) in methyl THF (100 mL) was added di(1H-imidazol-1-yl)methanone (4.77 g, 29.42 mmol) under nitrogen. The resulting mixture was stirred at room temperature for 2 h (flask 2). 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. 200 mL) and the resulting biphasic mixture stirred vigorously for 30 min. MTBE was added and the phases separated. The organic phase was washed with water, satd NaHCO3 and water, then dried over MgSO4 and evaporated. The residue was purified via Biotage (Biotage® KP-SIL 340 g column, 1 CV 20% EtOAc in heptanes, then 20%=>60% over 7 CV). Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (0.794 g, 10%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-4-(trifluoromethyl)-benzyl)piperidine-1-carboxylate (3.57 g, 45%) were isolated as pale yellow oils. Cis-isomer: MS m/z 434 (M+H)+. Trans-isomer: MS m/z 434 (M+H)+

Workup

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

Sources & evidence

ORD record
ord-12cfe625515a4e4d8430c5af93c9065d
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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