Hydrochloric Acid → HCID 131730421, compound

HRID 1963456Notes

Reaction equation

HRID 1963456 reaction equation
[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:14][CH:13]([C:15](O)=[O:16])[CH2:12][CH2:11][N:10]2[C:18]([O:20][CH3:21])=[O:19])=[CH:4][C:3]=1[F:22].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:35]([O:37][C:38](=[O:43])[CH2:39][C:40]([O-:42])=O)[CH3:36].[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>[Cl:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([C@H:9]2[CH2:14][C@@H:13]([C:15](=[O:16])[CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:43])[CH2:12][CH2:11][N:10]2[C:18]([O:20][CH3:21])=[O:19])=[CH:6][C:7]=1[F:8].[Cl:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([C@H:9]2[CH2:14][C@H:13]([C:40](=[O:42])[CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:43])[CH2:12][CH2:11][N:10]2[C:18]([O:20][CH3:21])=[O:19])=[CH:6][C:7]=1[F:8]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonate2×HCID 5360315Magnesium Chloride2×HCID 66731660HCID 66731660, compound2×

Product 2

HCID 131730421HCID 131730421, compoundYield 74.8%HCID 131730422HCID 131730422, compoundYield 9.19%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 178479889HCID 178479889, compoundSolvent3×

Procedure

2-(4-Chloro-3,5-difluorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (1.6 g, 4.79 mmol) (reference compound 28) was dissolved in methyl THF (30 mL) under nitrogen atmosphere and di(1H-imidazol-1-yl)methanone (1.166 g, 7.19 mmol) was added. The suspension was stirred at room temperature for 3 h (flask 1). In a separate flask was potassium 3-ethoxy-3-oxopropanoate (1.469 g, 8.63 mmol) suspended in methyl THF (15 mL) and magnesium chloride (0.822 g, 8.63 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 7 h using an oversized stirring bar (flask 2). To flask 2 the contents of flask 1 was added and the resulting white suspension was stirred at room temperature for 20 h. In a separate flask was potassium 3-ethoxy-3-oxopropanoate (0.734 g, 4.32 mmol) suspended in methyl THF (15 mL) and magnesium chloride (0.411 g, 4.32 mmol) was added. The suspension was stirred at 50° C. for 5 h and then added to the reaction mixture. The mixture was stirred at room temperature for 15 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 by column chromatography on silica (2:1 heptane:EtOAc, Biotage® KP-SIL 340 g column, 10 CV). Cis-methyl 2-(4-chloro-3,5-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.448 g, 74.8%) and trans-methyl 2-(4-chloro-3,5-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.178 g, 9.19%) were isolated as colorless oils. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.23-1.32 (m, 3H), 1.74-2.19 (m, 3H), 2.20-2.30 (m, 1H), 2.82-2.92 (m, 1H), 3.23-3.34 (m, 1H), 3.46 (s, 2H), 3.63-3.69 (m, 3H), 4.04-4.23 (m, 3H), 4.84-4.95 (m, 1H), 6.81-6.90 (m, 2H). MS m/z 404 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.20-1.33 (m, 3H), 1.48-1.92 (m, 2H), 1.92-2.04 (m, 1H), 2.36-2.51 (m, 1H), 2.54-2.70 (m, 1H), 2.82 (dt, 1H), 3.47 (d, 2H), 3.73 (s, 3H), 4.08-4.45 (m, 3H), 5.56 (s, br., 1H), 6.86 (d, 2H). MS m/z 404 (M+H)+

Workup

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

Sources & evidence

ORD record
ord-58ab648196244745abe46c4b70d01b0f
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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