Hydrochloric Acid → HCID 131730382, compound

HRID 1963363Notes

Reaction equation

HRID 1963363 reaction equation
[F: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])=[CH:4][CH:3]=1.N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:33]([O:35][C:36](=[O:41])[CH2:37][C:38]([O-:40])=O)[CH3:34].[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>[CH2:33]([O:35][C:36](=[O:41])[CH2:37][C:14]([C@@H:12]1[CH2:11][CH2:10][N:9]([C:17]([O:19][CH3:20])=[O:18])[C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:13]1)=[O:16])[CH3:34].[CH2:33]([O:35][C:36](=[O:41])[CH2:37][C:38]([C@H:12]1[CH2:11][CH2:10][N:9]([C:17]([O:19][CH3:20])=[O:18])[C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:13]1)=[O:40])[CH3:34]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 66732276HCID 66732276, compound2×

Product 2

HCID 131730381HCID 131730381, compoundYield 12%HCID 131730382HCID 131730382, compoundYield 62%

Reagents, catalysts & solvents 3

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

Procedure

2-(4-fluorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (8.4 g, 29.86 mmol) (reference compound 10) was dissolved in methyl THF (120 mL) and di(1H-imidazol-1-yl)methanone (7.26 g, 44.80 mmol) added. The suspension was stirred at room temperature under nitrogen for 2 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (9.15 g, 53.75 mmol) was suspended in methyl THF (120 mL) and magnesium chloride (5.12 g, 53.75 mmol) added. The suspension was stirred at 50° C. under nitrogen for 3 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 M HCl (50 mL) and MTBE (200 mL) and water (70 mL) were added. The phases were separated and the organic phase extracted with water (30 mL), satd NaHCO3 (30 mL) and water (30 mL), dried over anhydrous Na2SO4 and evaporated. The diastereoisomers were separated on Biotage (20%=>55% EtOAc in heptane, 8 CV; Biotage® KP-SIL 340 g column) to yield trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorophenyl)piperidine-1-carboxylate (1.26 g, 12%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorophenyl)piperidine-1-carboxylate (6.58 g, 62%) as colorless oils. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.27 (t, 3H), 1.83-2.14 (m, 3H), 2.27 (ddd, 1H), 2.80-2.93 (m, 1H), 3.26-3.50 (m, 3H), 3.64 (s, 3H), 4.10-4.22 (m, 3H), 4.93-5.01 (m, 1H), 6.95-7.05 (m, 2H), 7.14-7.22 (m, 2H). MS m/z 352 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.18-1.33 (m, 3H), 1.50-1.89 (m, 2H), 1.90-2.02 (m, 1H), 2.47-2.59 (m, 1H), 2.59-2.72 (m, 1H), 2.79-2.91 (m, 1H), 3.47 (s, 2H), 3.76 (s, 3H), 4.08-4.30 (m, 3H), 5.50-5.69 (s, br., 1H), 6.98-7.10 (m, 2H), 7.10-7.23 (m, 2H). MS m/z 350 (M−H)−

Workup

  1. stirringThe suspension was stirred at 50° C. under nitrogen for 3 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. additionwere added
  5. customThe phases were separated
  6. extractionthe organic phase extracted with water (30 mL), satd NaHCO3 (30 mL) and water (30 mL)
  7. dry with materialdried over anhydrous Na2SO4
  8. customevaporated
  9. customThe diastereoisomers were separated on Biotage (20%=>55% EtOAc in heptane, 8 CV; Biotage® KP-SIL 340 g column)

Sources & evidence

ORD record
ord-913b05d27dc847168d82a72771c77717
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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