Hydrochloric Acid → HCID 131730388, compound

HRID 1963374Notes

Reaction equation

HRID 1963374 reaction equation
[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11](O)=[O:12])[CH2:7][CH:6]1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[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)[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.O.CC(OC)(C)C>[CH2:36]([O:38][C:39](=[O:44])[CH2:40][C:11]([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:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH2:7]1)=[O:12])[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:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH2:7]1)=[O:43])[CH3:37]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 66731634HCID 66731634, compound2×

Product 2

HCID 131730387HCID 131730387, compoundYield 9%HCID 131730388HCID 131730388, compoundYield 38%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 15413tert-Butyl methyl etherSolventHCID 178479889HCID 178479889, compoundSolvent2×

Procedure

1-(Methoxycarbonyl)-2-(3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (1.479 g, 4.46 mmol) (reference compound 12) was dissolved into methyl THF (50 mL), then di(1H-imidazol-1-yl)methanone (1.086 g, 6.70 mmol) was added. The mixture was stirred at room temperature under nitrogen for 3 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (1.368 g, 8.04 mmol) was suspended in methyl THF (50.0 mL), then magnesium chloride (0.765 g, 8.04 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 3 h using a large magnetic stirring bar (flask 2). The contents of flask 1 was transferred to flask 2. The resulting white suspension was stirred under nitrogen at room temperature overnight. The mixture was acidified to pH 1 with 3.8 M HCl, then MTBE (50 mL) and water (50 mL) were added. The phases were separated and the organic layer was washed with water, satd NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated leaving a slightly yellow oil. The residue was purified by automated column chromatography on Biotage (340 g) with a gradient of 20-55% EtOAc in n-heptane (8 CV) to yield trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-(trifluoromethyl)phenyl)-piperidine-1-carboxylate (157 mg, 9%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate (679 mg, 38%). Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.19-1.27 (m, 3H), 1.75-2.20 (m, 3H), 2.23-2.32 (m, 1H), 2.82-2.94 (m, 1H), 3.26-3.48 (m, 3H), 3.61 (s, 3H), 4.05-4.21 (m, 3H), 4.91-5.04 (m, 1H), 7.35-7.50 (m, 4H). MS m/z 402 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.16-1.32 (m, 3H), 1.46-2.09 (m, 4H), 2.48-2.90 (m, 2H), 3.40-3.50 (m, 2H), 3.75 (s, 3H), 4.02-4.42 (m, 3H), 5.65 (s, br., 1H), 7.36-7.56 (m, 4H). MS m/z 402 (M+H)+

Workup

  1. stirringThe suspension was stirred at 50° C. under nitrogen for 3 h
  2. customThe contents of flask 1 was transferred to flask
  3. stirringThe resulting white suspension was stirred under nitrogen at room temperature overnight
  4. customThe phases were separated
  5. washthe organic layer was washed with water
  6. dry with materialThe organic layer was dried over Na2SO4
  7. filtrationfiltered
  8. customevaporated
  9. customleaving a slightly yellow oil
  10. customThe residue was purified by automated column chromatography on Biotage (340 g) with a gradient of 20-55% EtOAc in n-heptane (8 CV)

Sources & evidence

ORD record
ord-08e43600533644c3b23aaeb7f1afbdf9
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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