Hydrochloric Acid → HCID 131730411, compound

HRID 1963432Notes

Reaction equation

HRID 1963432 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12][CH2:11][N:10]2[C:18]([O:20][CH3:21])=[O:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:34]([O:36][C:37](=[O:42])[CH2:38][C:39]([O-:41])=O)[CH3:35].[K+].[Cl-].[Mg+2].[Cl-].Cl>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O.O>[Cl:8][C:6]1[CH:5]=[C:4]([C@H:9]2[CH2:14][C@H:13]([C:15](=[O:17])[CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:42])[CH2:12][CH2:11][N:10]2[C:18]([O:20][CH3:21])=[O:19])[CH:3]=[C:2]([Cl:1])[CH:7]=1.[Cl:8][C:6]1[CH:5]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([C:39](=[O:41])[CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:42])[CH2:12][CH2:11][N:10]2[C:18]([O:20][CH3:21])=[O:19])[CH:3]=[C:2]([Cl:1])[CH:7]=1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 66731516HCID 66731516, compound2×

Product 2

HCID 131730410HCID 131730410, compoundYield 11%HCID 131730411HCID 131730411, compoundYield 64%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 178479889HCID 178479889, compoundSolvent3×

Procedure

2-(3,5-Dichlorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.6 g, 13.85 mmol) (reference compound 24) was dissolved in methyl THF (69.2 mL) and di(1H-imidazol-1-yl)methanone (3.37 g, 20.77 mmol) added. The suspension was stirred at room temperature overnight under nitrogen (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (4.24 g, 24.93 mmol) was suspended in methyl THF (69.2 mL) and magnesium chloride (2.373 g, 24.93 mmol) added. The suspension was stirred at 50° C. overnight under nitrogen (flask 2). The white suspension in flask 2 was then added to the brown suspension in flask 1. The resulting suspension was stirred at room temperature for 40 h. The mixture was acidified to pH 1 with 3 M HCl. Water and methyl THF were added. The phases were separated, the organic layer washed with water, satd NaHCO3, brine, dried over MgSO4, filtered and evaporated. Purified by flash chromatography using 20% EtOAc in heptane ->50% EtOAc over 10 CV, 3 CV at 50%. Trans-methyl 2-(3,5-dichlorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.6 g, 11%) and cis-methyl 2-(3,5-dichlorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (3.57 g, 64%) were isolated. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.22-1.32 (m, 3H), 1.79-1.94 (m, 2H), 2.03-2.17 (m, 1H), 2.20-2.29 (m, 1H), 2.82-2.93 (m, 1H), 3.24-3.34 (m, 1H), 3.46 (d, 2H), 3.64-3.68 (m, 3H), 4.10-4.23 (m, 3H), 4.83-4.92 (m, 1H), 7.06-7.09 (m, 2H), 7.22-7.25 (m, 1H). MS m/z 402 (M+H)+. Trans-isomer: MS m/z 402 (M+H)+

Workup

  1. stirringThe suspension was stirred at 50° C. overnight under nitrogen (flask 2)
  2. additionThe white suspension in flask 2 was then added to the brown suspension in flask 1
  3. stirringThe resulting suspension was stirred at room temperature for 40 h
  4. customThe phases were separated
  5. washthe organic layer washed with water
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. customevaporated
  9. customPurified by flash chromatography

Sources & evidence

ORD record
ord-6866ea471ef14674bebfd12be51fc6af
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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