Hydrochloric Acid → cis-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)phenyl)-piperidine-1-carboxylate

HRID 1963381Notes

Reaction equation

HRID 1963381 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]([C:20]([F:23])([F:22])[F: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.O.CC(OC)(C)C>[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][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=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]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)[CH2:7]1)=[O:43])[CH3:37]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 667324851-(Methoxycarbonyl)-2-(4-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid2×

Product 2

HCID 131730390trans-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylateYield 7%HCID 131730391cis-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)phenyl)-piperidine-1-carboxylateYield 52%

Reagents, catalysts & solvents 3

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

Procedure

1-(Methoxycarbonyl)-2-(4-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (5.629 g, 16.99 mmol) (reference compound 13) was dissolved in methyl THF (120 mL) and di(1H-imidazol-1-yl)methanone (4.13 g, 25.49 mmol) added. The suspension was stirred at room temperature under nitrogen for 3 h 45 min (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (5.21 g, 30.58 mmol) was suspended in methyl THF (120 mL) and magnesium chloride (2.91 g, 30.58 mmol) added. The suspension was stirred at 50° C. under nitrogen for 3.5 h using an oversized stirring bar (flask 2). The beige suspension in flask 1 was now added to the white suspension in flask 2. The resulting beige suspension was stirred under nitrogen at room temperature for 23 h. 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 extracted with water, satd NaHCO3 and water. The organic layer was evaporated and traces of water were azeotropically removed by MeCN to yield a brown oil. The diastereoisomers were separated in 2 runs on Biotage (20%=>55% EtOAc in heptane, 8 CV; Biotage® KP-SIL 340 g column). Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (0.474 g, 7%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)phenyl)-piperidine-1-carboxylate (3.532 g, 52%) were isolated as colorless oils. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.26 (t, 3H), 1.72-2.22 (m, 3H), 2.29 (ddd, 1H), 2.83-2.96 (m, 1H), 3.29-3.49 (m, 3H), 3.64 (s, 3H), 4.07-4.23 (m, 3H), 4.92-5.06 (m, 1H), 7.32 (d, 2H), 7.58 (d, 2H). MS m/z 402 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.13-1.26 (m, 3H), 1.43-1.60 (m, 1H), 1.64-1.85 (m, 1H), 1.95 (dt, 1H), 2.44-2.61 (m, 2H), 2.73-2.85 (m, 1H), 3.39 (s, 2H), 3.70 (s, 3H), 3.99-4.36 (m, 3H), 5.59 (br. s, 1H), 7.28 (d, 2H), 7.56 (d, 2H). MS m/z 402 (M+H)+

Workup

  1. stirringThe suspension was stirred at 50° C. under nitrogen for 3.5 h
  2. additionThe beige suspension in flask 1 was now added to the white suspension in flask 2
  3. stirringThe resulting beige suspension was stirred under nitrogen at room temperature for 23 h
  4. additionadded
  5. customThe phases were separated
  6. extractionthe organic phase extracted with water
  7. customThe organic layer was evaporated
  8. customtraces of water were azeotropically removed by MeCN
  9. customto yield a brown oil
  10. customThe diastereoisomers were separated in 2

Sources & evidence

ORD record
ord-459f9a21ef69425994321489f1e87fd8
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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