Hydrochloric Acid → HCID 131730395, compound

HRID 1963394Notes

Reaction equation

HRID 1963394 reaction equation
[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8](C(O)=O)[CH2:7][CH:6]1[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)=[O:4].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:36]([O:38][C:39](=[O:44])[CH2:40][C:41]([O-:43])=[O:42])[CH3:37].[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.CC1OCCC1.O1CCOCC1>[CH2:36]([O:38][C:39](=[O:44])[CH2:40][C:41]([C@H:8]1[CH2:9][CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[C@@H:6]([C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=2)[CH2:7]1)=[O:42])[CH3:37].[CH2:36]([O:38][C:39](=[O:44])[CH2:40][C:41]([C@@H:8]1[CH2:9][CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[C@@H:6]([C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=2)[CH2:7]1)=[O:43])[CH3:37]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonate2×HCID 5360315Magnesium Chloride2×HCID 66731694HCID 66731694, compound

Product 2

HCID 131730395HCID 131730395, compoundYield 47.1%HCID 131730396HCID 131730396, compoundYield 8.81%

Reagents, catalysts & solvents 3

HCID 73012-MethyltetrahydrofuranSolventHCID 312751,4-DioxaneSolventHCID 178479889HCID 178479889, compoundSolvent3×

Procedure

1-(Methoxycarbonyl)-2-(4-(methylsulfonyl)phenyl)piperidine-4-carboxylic acid (4.756 g, 13.93 mmol) was dissolved in methyl THF (70 mL) and di(1H-imidazol-1-yl)methanone (3.39 g, 20.90 mmol) added. A thick white precipitate was formed. methyl THF (70.0 mL) was added and the suspension stirred under nitrogen at room temperature for 6 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (4.74 g, 27.86 mmol) was suspended in methyl THF (70.0 mL) and magnesium chloride (2.65 g, 27.86 mmol) added. Heated at 50° C. under nitrogen for 6 h (flask 2). The white suspension in flask 2 was then added to the thick white suspension in flask 1. The suspension was stirred at room temperature for 16 h. The temperature was increased to 50° C. for 6 h. More of potassium 3-ethoxy-3-oxopropanoate (4.74 g, 27.86 mmol) and magnesium chloride (2.65 g, 27.86 mmol) in MeTHF (15 mL) was added along with dioxane (60 mL). The reaction was stirred at 50° C. for 18 h. The reaction mixture was acidified to pH 1 with 3 M HCl. The organic phase was washed with water (2×400 mL), satd NaHCO3 (400 mL), brine (400 mL), dried with Na2SO4, filtered and evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. A gradient from 50% EtOAc in heptane over 2 CV followed by 50% to 80% of EtOAc in heptane over 10 CV was used as mobile phase. Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(methylsulfonyl)phenyl)piperidine-1-carboxylate (2.70 g, 47.1%) and trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(methylsulfonyl)phenyl)-piperidine-1-carboxylate (0.505 g, 8.81%) were isolated. Cis-isomer: NMR: 1H NMR (600 MHz, CDCl3) δ 1.25 (t, 3H), 1.80-1.95 (m, 2H), 2.04-2.16 (m, 1H), 2.23-2.32 (m, 1H), 2.84-2.95 (m, 1H), 3.02 (s, 3H), 3.29-3.38 (m, 1H), 3.38-3.48 (m, 2H), 3.63 (s, 3H), 4.10-4.21 (m, 3H), 4.95-5.04 (m, 1H), 7.40 (d, 2H), 7.88 (d, 2H). MS m/z 410 (M−H)−. Trans-isomer: 1H NMR (600 MHz, cdcl3) δ 1.23 (t, 3H), 1.12-2.26 (m, 3H), 2.51-2.62 (m, 2H), 2.83 (td, 1H), 3.04 (s, 3H), 3.40-3.48 (s, 2H), 3.75 (s, 3H), 4.07-4.38 (m, 1H), 4.15 (q, 2H), 5.49-5.77 (m, 1H), 7.41 (d, 2H), 7.93 (d, 2H). MS m/z 412 (M+H)+

Workup

  1. customA thick white precipitate was formed
  2. temperatureHeated at 50° C. under nitrogen for 6 h (flask 2)
  3. additionThe white suspension in flask 2 was then added to the thick white suspension in flask 1
  4. stirringThe suspension was stirred at room temperature for 16 h
  5. temperatureThe temperature was increased to 50° C. for 6 h
  6. stirringThe reaction was stirred at 50° C. for 18 h
  7. washThe organic phase was washed with water (2×400 mL), satd NaHCO3 (400 mL), brine (400 mL)
  8. dry with materialdried with Na2SO4
  9. filtrationfiltered
  10. customevaporated in vacuo
  11. customThe residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column

Sources & evidence

ORD record
ord-2ae59591cd474fb08c7f00f9eb11e4d8
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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