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

HRID 1963411Notes

Reaction equation

HRID 1963411 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([OH:16])=O)[CH2:11][CH2:10][N:9]2[C:17]([O:19][CH3:20])=[O:18])=[C:4]([F:21])[CH:3]=1.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.CCCCCCC.CCOC(C)=O.O.CC(OC)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([C:14](=[O:16])[CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:42])[CH2:11][CH2:10][N:9]2[C:17]([O:19][CH3:20])=[O:18])=[C:4]([F:21])[CH:3]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:39](=[O:41])[CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:42])[CH2:11][CH2:10][N:9]2[C:17]([O:19][CH3:20])=[O:18])=[C:4]([F:21])[CH:3]=1

Participants

12

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 66732454HCID 66732454, compound2×

Product 2

HCID 131730403trans-Methyl 2-(4-chloro-2-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylateYield 6%HCID 131730404cis-Methyl 2-(4-chloro-2-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylateYield 29%

Reagents, catalysts & solvents 5

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent3×HCID 8900HeptaneSolvent3×HCID 15413tert-Butyl methyl etherSolventHCID 178479889HCID 178479889, compoundSolvent2×

Procedure

2-(4-Chloro-2-fluorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (6.49 g, 20.56 mmol) (reference compound 20) was dissolved in methyl THF (250 mL), then di(1H-imidazol-1-yl)methanone (5.00 g, 30.83 mmol) was added. The mixture was stirred at room temperature under nitrogen for 3 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (6.30 g, 37.00 mmol) was suspended in methyl THF (250 mL), then magnesium chloride (3.52 g, 37.00 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 3 h using a large magnetic stirring bar (flask 2). After the 3 h, the contents of flask 1 was transferred into flask 2. The resulting white suspension was stirred under nitrogen at room temperature overnight. The mixture was acidified to pH 1 with 3.8 M HCl, then MTBE (50 mL) and water (50 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 1 CV 20% EtOAc in heptane followed by 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 2-(4-chloro-2-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.5 g, 6%) and cis-methyl 2-(4-chloro-2-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.31 g, 29%) were isolated. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.27 (t, 3H), 1.79-1.99 (m, 2H), 2.03-2.21 (m, 1H), 2.23-2.32 (m, 1H), 2.84-2.95 (m, 1H), 3.33-3.51 (m, 3H), 3.62 (s, 3H), 4.12-4.23 (m, 3H), 4.98-5.21 (m, 1H), 6.98-7.24 (m, 3H). MS m/z 386 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.22 (t, 3H), 1.57-1.69 (m, 1H), 1.86-2.01 (m, 2H), 2.36-2.62 (m, 2H), 3.07-3.18 (m, 1H), 3.44 (s, 2H), 3.70 (s, 3H), 4.10-4.21 (m, 2H), 4.32 (br, 1H), 5.67 (br, 1H), 7.02-7.14 (m, 3H). MS m/z 386 (M+H)+

Workup

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

Sources & evidence

ORD record
ord-9b109b4afbf8430cae8fddf15e6ff3dd
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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