Hydrochloric Acid → HCID 131730471, compound

HRID 1963571Notes

Reaction equation

HRID 1963571 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[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22])=[O:4].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:37]([O:39][C:40](=[O:45])[CH2:41][C:42]([O-:44])=[O:43])[CH3:38].[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>[CH2:37]([O:39][C:40](=[O:45])[CH2:41][C:42]([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:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:7]1)=[O:43])[CH3:38].[CH2:37]([O:39][C:40](=[O:45])[CH2:41][C:42]([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:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:7]1)=[O:44])[CH3:38]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 66732367HCID 66732367, compound2×

Product 2

HCID 131730470HCID 131730470, compoundYield 12%HCID 131730471HCID 131730471, compoundYield 37%

Reagents, catalysts & solvents 3

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

Procedure

1-(Methoxycarbonyl)-2-(2-(trifluoromethyl)benzyl)piperidine-4-carboxylic acid (4.718 g, 13.66 mmol) (reference compound 49) was dissolved in methyl THF (100 mL) and di(1H-imidazol-1-yl)methanone (3.32 g, 20.49 mmol) added. The suspension was stirred at room temperature under nitrogen overnight (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (4.19 g, 24.59 mmol) was suspended in methyl THF (100 mL) and magnesium chloride (2.342 g, 24.59 mmol) added. The suspension was stirred at 50° C. under nitrogen overnight using an oversized stirring bar (flask 2). The yellow suspension in flask 1 was now added to the white suspension in flask 2. The resulting white suspension was stirred under nitrogen at room temperature for 3 days. The mixture was acidified to pH 1 with 3.8 M HCl and MTBE and water added. The phases were separated and the organic phase washed with water and satd NaHCO3. Evaporated the solvents to yield a yellow oil. The diastereomers were separated in 2 runs on Biotage (20%=>50% EtOAc in heptane, 8 CV; Biotage® KP-SIL 340 g column). Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-(trifluoromethyl)-benzyl)piperidine-1-carboxylate (0.67 g, 12%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-(trifluoromethyl)benzyl)piperidine-1-carboxylate (2.11 g, 37%) were isolated as yellow oils. Cis-isomer: 1H NMR (600 MHz, cdcl3) δ 1.22 (t, 3H), 1.65-1.99 (m, 4H), 2.65-2.73 (m, 1H), 2.85-2.91 (m, 1H), 2.95-3.02 (m, 1H), 3.15 (ddd, 1H), 3.35 (s, 3H), 3.46 (s, 2H), 4.01 (dd, 1H), 4.12-4.19 (m, 2H), 4.23-4.33 (m, 1H), 7.20 (d, 1H), 7.27 (t, 1H), 7.41 (t, 1H), 7.60 (d, 1H). MS m/z 416 (M+H)+. Trans-isomer: 1H NMR (600 MHz, cdcl3) δ 1.13-1.27 (m, 3H), 1.41-1.97 (m, 5H), 2.79-3.67 (m, 8H), 4.01-4.33 (m, 3H), 4.64 (br. d, 1H), 7.07-7.50 (m, 3H), 7.53-7.62 (m, 1H). MS m/z 416 (M+H)+

Workup

  1. stirringThe suspension was stirred at 50° C. under nitrogen overnight
  2. additionThe yellow suspension in flask 1 was now added to the white suspension in flask 2
  3. stirringThe resulting white suspension was stirred under nitrogen at room temperature for 3 days
  4. additionadded
  5. customThe phases were separated
  6. washthe organic phase washed with water and satd NaHCO3
  7. customEvaporated the solvents
  8. customto yield a yellow oil
  9. customThe diastereomers were separated in 2

Sources & evidence

ORD record
ord-49c62b9a8a19485084068fa6a6a6ab98
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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