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

HRID 1963544Notes

Reaction equation

HRID 1963544 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9][CH2:8][N:7]1[C:15]([O:17][CH3:18])=[O:16].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:34]([O:36][C:37](=[O:42])[CH2:38][C:39]([O-:41])=O)[CH3:35].[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.CC(OC)(C)C>[CH2:34]([O:36][C:37](=[O:42])[CH2:38][C:12]([C@@H:10]1[CH2:9][CH2:8][N:7]([C:15]([O:17][CH3:18])=[O:16])[C@@H:6]([CH2:5][C:4]2[CH:19]=[CH:20][CH:21]=[C:2]([F:1])[CH:3]=2)[CH2:11]1)=[O:14])[CH3:35].[CH2:34]([O:36][C:37](=[O:42])[CH2:38][C:39]([C@H:10]1[CH2:9][CH2:8][N:7]([C:15]([O:17][CH3:18])=[O:16])[C@@H:6]([CH2:5][C:4]2[CH:19]=[CH:20][CH:21]=[C:2]([F:1])[CH:3]=2)[CH2:11]1)=[O:41])[CH3:35]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 667325072-(3-Fluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid2×

Product 2

HCID 131730460trans-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluorobenzyl)piperidine-1-carboxylateYield 18%HCID 131730461cis-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluorobenzyl)piperidine-1-carboxylateYield 49%

Reagents, catalysts & solvents 2

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

Procedure

2-(3-Fluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (7.112 g, 24.08 mmol) (reference compound 44) was dissolved in methyl THF (150 mL) and di(1H-imidazol-1-yl)methanone (5.86 g, 36.13 mmol) added. The suspension was stirred at room temperature under nitrogen for 3.5 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (7.38 g, 43.35 mmol) was suspended in methyl THF (150 mL) and magnesium chloride (4.13 g, 43.35 mmol) added. The suspension was stirred at 50° C. under nitrogen for 3 h (flask 2). The orange suspension in flask 1 was now added to the white suspension in flask 2. The resulting yellow 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 added. The phases were separated and the organic phase extracted with water, satd NaHCO3 and water. Evaporated the solvents to yield an orange oil. 42% of the oil was purified on Biotage (20%=>50% EtOAc in heptane, 6 CV+50%, 4 CV; Biotage® KP-SIL 340 g column) to yield trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluorobenzyl)piperidine-1-carboxylate (664 mg, 18%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluorobenzyl)piperidine-1-carboxylate (1.8 g, 49%). Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.20 (t, 3H), 1.56-1.93 (m, 4H), 2.62-2.73 (m, 2H), 2.83-3.03 (m, 2H), 3.41 (s, 2H), 3.59 (s, 3H), 3.83-3.93 (m, 1H), 4.07-4.20 (m, 3H), 6.82-6.93 (m, 3H), 7.15-7.22 (m, 1H). MS m/z 366 (M+H)+. Trans-isomer: MS m/z 366 (M+H)+

Workup

  1. stirringThe suspension was stirred at 50° C. under nitrogen for 3 h (flask 2)
  2. additionThe orange suspension in flask 1 was now added to the white suspension in flask 2
  3. stirringThe resulting yellow suspension was stirred under nitrogen at room temperature for 3 days
  4. additionadded
  5. customThe phases were separated
  6. extractionthe organic phase extracted with water
  7. customEvaporated the solvents
  8. customto yield an orange oil
  9. custom42% of the oil was purified on Biotage (20%=>50% EtOAc in heptane, 6 CV+50%, 4 CV; Biotage® KP-SIL 340 g column)

Sources & evidence

ORD record
ord-7fe32b5c8f0349659822d055b90e65b4
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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