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

HRID 1963439Notes

Reaction equation

HRID 1963439 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[CH:13]1[CH2:18][CH:17]([C:19]([OH:21])=O)[CH2:16][CH2:15][N:14]1[C:22]([O:24][CH3:25])=[O:23].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.C(Cl)Cl>[CH2:38]([O:40][C:41](=[O:46])[CH2:42][C:19]([C@H:17]1[CH2:16][CH2:15][N:14]([C:22]([O:24][CH3:25])=[O:23])[C@@H:13]([C:3]2[CH:4]=[CH:5][C:6]([O:8][C:9]([F:12])([F:10])[F:11])=[CH:7][C:2]=2[F:1])[CH2:18]1)=[O:21])[CH3:39].[CH2:38]([O:40][C:41](=[O:46])[CH2:42][C:43]([C@@H:17]1[CH2:16][CH2:15][N:14]([C:22]([O:24][CH3:25])=[O:23])[C@@H:13]([C:3]2[CH:4]=[CH:5][C:6]([O:8][C:9]([F:12])([F:10])[F:11])=[CH:7][C:2]=2[F:1])[CH2:18]1)=[O:45])[CH3:39]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 66731655HCID 66731655, compound2×

Product 2

HCID 131730413cis-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)piperidine-1-carboxylateYield 70.9%HCID 131730414trans-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)piperidine-1-carboxylateYield 8.66%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 178479889HCID 178479889, compoundSolvent2×

Procedure

2-(2-Fluoro-4-(trifluoromethoxy)phenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.07 g, 11.14 mmol) (reference compound 25) was dissolved in methyl THF (100 mL) under nitrogen atmosphere and di(1H-imidazol-1-yl)methanone (2.71 g, 16.71 mmol) was added. The suspension was stirred at room temperature for 5 h (flask 1). In a separate flask was potassium 3-ethoxy-3-oxopropanoate (3.41 g, 20.06 mmol) suspended in methyl THF (50 mL) and magnesium chloride (1.910 g, 20.06 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 15 h using an oversized stirring bar (flask 2). The contents of flask 1 was added to flask 2 and the resulting white suspension was stirred at room temperature for 20 h. 0.1 M HCl and DCM were added and the phases separated. The aqueous phase was extracted with DCM, the combined organic layers filtered through a phase separator and evaporated. The residue was purified via Biotage (gradient 3:1->1:1 heptane:EtOAc, Biotage® KP-SIL 340 g column, 10 CV). Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (3.44 g, 70.9%) and trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (0.420 g, 8.66%) were isolated as colorless oils. Cis-isomer: 1H NMR (600 MHz, cdcl3) δ 1.23-1.28 (m, 3H), 1.77-1.96 (m, 2H), 2.03-2.14 (m, 1H), 2.24-2.31 (m, 1H), 2.84-2.93 (m, 1H), 3.32-3.48 (m, 3H), 3.57-3.65 (m, 3H), 4.08-4.20 (m, 3H), 5.03-5.12 (m, 1H), 6.89-6.98 (m, 2H), 7.13-7.21 (m, 1H). MS m/z 436 (M+H)+. Trans-isomer: 1H NMR (600 MHz, cdcl3) δ 1.16-1.28 (m, 3H), 1.62 (dq, 1H), 1.85-2.00 (m, 2H), 2.37-2.60 (m, 2H), 3.12 (dt, 1H), 3.43 (s, 2H), 3.68 (s, br., 3H), 4.08-4.20 (m, 2H), 4.25 (s, br., 1H), 5.68 (s, br., 1H), 6.92-7.01 (m, 2H), 7.13 (t, 1H). MS m/z 436 (M+H)+

Workup

  1. customIn a separate flask was
  2. stirringThe suspension was stirred at 50° C. under nitrogen for 15 h
  3. additionThe contents of flask 1 was added to flask 2
  4. stirringthe resulting white suspension was stirred at room temperature for 20 h
  5. customthe phases separated
  6. extractionThe aqueous phase was extracted with DCM
  7. filtrationthe combined organic layers filtered through a phase separator
  8. customevaporated
  9. customThe residue was purified via Biotage (gradient 3:1->1:1 heptane:EtOAc, Biotage® KP-SIL 340 g column, 10 CV)

Sources & evidence

ORD record
ord-a5a7a455455140f580ba990302a557bd
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

Loading…