Hydrochloric Acid → HCID 131730474, compound

HRID 1963578Notes

Reaction equation

HRID 1963578 reaction equation
[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=O)[CH2:7][CH:6]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)=[O:4].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:38]([O:40][C:41](=[O:46])[CH2:42][C:43]([O-:45])=O)[CH3:39].[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.CCCCCCC.CCOC(C)=O.O.CC(OC)(C)C>[CH2:38]([O:40][C:41](=[O:46])[CH2:42][C:11]([C@@H:8]1[CH2:9][CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[C@@H:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=2)[CH2:7]1)=[O:13])[CH3:39].[CH2:38]([O:40][C:41](=[O:46])[CH2:42][C:43]([C@H:8]1[CH2:9][CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[C@@H:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=2)[CH2:7]1)=[O:45])[CH3:39]

Participants

12

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 66732042HCID 66732042, compound2×

Product 2

HCID 131730473HCID 131730473, compoundYield 12.1%HCID 131730474HCID 131730474, compoundYield 43.8%

Reagents, catalysts & solvents 5

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent2×HCID 8900HeptaneSolvent2×HCID 15413tert-Butyl methyl etherSolventHCID 178479889HCID 178479889, compoundSolvent2×

Procedure

1-(Methoxycarbonyl)-2-(4-(trifluoromethoxy)benzyl)piperidine-4-carboxylic acid (4.7 g, 13.01 mmol) (reference compound 50) was dissolved into methyl THF (150 mL), then di(1H-imidazol-1-yl)methanone (3.16 g, 19.51 mmol) was added in one portion. The mixture was stirred at room temperature under nitrogen for 3 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (3.99 g, 23.41 mmol) was suspended in methyl THF (150 mL) then magnesium chloride (2.229 g, 23.41 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 3 h using a large magnetic stirring bar (flask 2). After 3 h, the contents of flask 1 was transferred into flask 2. The resulting yellow suspension was stirred under nitrogen at room temperature overnight. The mixture was acidified to pH 1 with 3.8 M HCl, then MTBE (100 mL) and water (100 mL) was 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 product was flashed on Biotage (340 g) with a gradient of 20-60% EtOAc in n-heptane (8 CV). The column was conditioned at 20% EtOAc in -n-heptane (1 CV). Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethoxy)benzyl)piperidine-1-carboxylate (679 mg, 12.1%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethoxy)benzyl)piperidine-1-carboxylate (2.457 g, 43.8%) were isolated. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.19-1.32 (m, 3H), 1.64-1.98 (m, 4H), 2.67-2.78 (m, 2H), 2.86-3.11 (m, 2H), 3.47 (s, 2H), 3.59 (s, 3H), 3.87-3.98 (m, 1H), 4.07-4.23 (m, 3H), 7.09-7.16 (m, 2H), 7.16-7.23 (m, 2H). MS m/z 432 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.20-1.31 (m, 3H), 1.38-2.03 (m, 4H), 2.66-3.08 (m, 4H), 3.32-3.75 (m, 5H), 3.97-4.36 (m, 3H), 4.40-4.77 (m, 1H), 7.10-7.32 (m, 4H). MS m/z 432 (M+H)+

Workup

  1. stirringThe suspension was stirred at 50° C. under nitrogen for 3 h
  2. waitAfter 3 h
  3. customthe contents of flask 1 was transferred into flask
  4. stirringThe resulting yellow suspension was stirred under nitrogen at room temperature overnight
  5. customThe phases were separated
  6. washthe organic layer was washed with water
  7. dry with materialThe organic layer was dried over Na2SO4
  8. filtrationfiltered
  9. customevaporated
  10. customleaving a slightly yellow oil

Sources & evidence

ORD record
ord-820a7a728e844bc4ae078578eb6665c6
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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