Ammonium Chloride → HCID 131730446, compound

HRID 1963513Notes

Reaction equation

HRID 1963513 reaction equation
[F:1][CH:2]([F:16])[CH:3]1[CH2:8][CH:7]([C:9]([OH:11])=O)[CH2:6][CH2:5][N:4]1[C:12]([O:14][CH3:15])=[O:13].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:29]([O:31][C:32](=[O:37])[CH2:33][C:34]([O-:36])=O)[CH3:30].[K+].[Cl-].[Mg+2].[Cl-].[NH4+].[Cl-]>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O.C(Cl)Cl>[F:16][CH:2]([F:1])[C@H:3]1[CH2:8][C@H:7]([C:9](=[O:11])[CH2:33][C:32]([O:31][CH2:29][CH3:30])=[O:37])[CH2:6][CH2:5][N:4]1[C:12]([O:14][CH3:15])=[O:13].[F:16][CH:2]([F:1])[C@H:3]1[CH2:8][C@@H:7]([C:34](=[O:36])[CH2:33][C:32]([O:31][CH2:29][CH3:30])=[O:37])[CH2:6][CH2:5][N:4]1[C:12]([O:14][CH3:15])=[O:13]

Participants

9

Reactant 5

HCID 25517Ammonium ChlorideHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonate2×HCID 5360315Magnesium Chloride2×HCID 59536568HCID 59536568, compound2×

Product 2

HCID 131730445HCID 131730445, compoundYield 7%HCID 131730446HCID 131730446, compoundYield 48%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 178479889HCID 178479889, compoundSolvent3×

Procedure

2-(Difluoromethyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (2.2 g, 9.27 mmol) (reference compound 39) was dissolved in methyl THF (60 mL) under nitrogen atmosphere and di(1H-imidazol-1-yl)methanone (2.256 g, 13.91 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 (2.84 g, 16.69 mmol) suspended in methyl THF (60 mL) and magnesium chloride (1.590 g, 16.69 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 22 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. In a separate flask potassium 3-ethoxy-3-oxopropanoate (0.71 g, 4.17 mmol) was suspended in methyl THF (30 mL) under nitrogen atmosphere and magnesium chloride (0.41 g, 4.31 mmol) was added. The suspension was stirred vigorously at 50° C. for 6 h. The suspension was added to the reaction mixture and stirring was continued at room temperature for 17 h. Satd NH4Cl and DCM were added and the phases were separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column. A gradient of 5:1 to 1:1 of EtOAc in heptane over 15 CV was used as mobile phase. Trans-methyl 2-(difluoromethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (203 mg, 7%) and cis-methyl 2-(difluoromethyl)-4-(3-ethoxy-3-oxopropanoyl)-piperidine-1-carboxylate (1.38 g, 48%) were isolated. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.29 (t, 3H), 1.47-2.09 (m, 4H), 2.70-2.83 (m, 1H), 3.05-3.18 (m, 1H), 3.51 (d, 2H), 3.73 (s, 3H), 3.91-4.02 (m, 1H), 4.20 (q, 2H), 4.11-4.30 (m, 1H), 5.91 (dt, 1H). MS m/z 308 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.28 (t, 3H), 1.39-2.32 (m, 4H), 2.88-3.23 (m, 2H), 3.51 (s, 2H), 3.73 (s, 3H), 4.20 (q, 2H), 4.11-4.70 (m, 2H), 5.88 (t, 1H). MS m/z 308 (M+H)+

Workup

  1. customIn a separate flask was
  2. stirringThe suspension was stirred at 50° C. under nitrogen for 22 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. stirringThe suspension was stirred vigorously at 50° C. for 6 h
  6. additionThe suspension was added to the reaction mixture
  7. stirringstirring
  8. waitwas continued at room temperature for 17 h
  9. customthe phases were separated
  10. extractionThe aqueous phase was extracted with DCM
  11. filtrationthe combined organic layers were filtered through a phase separator
  12. customevaporated
  13. customThe residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column

Sources & evidence

ORD record
ord-0bc0fbfd63b6414d86cd520f7b1871ab
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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