(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one → HCID 178517874, compound

HRID 931937Notes

Reaction equation

HRID 931937 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.Cl[CH2:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1>C1COCC1>[NH:30]1[C:29]([CH2:28][C@@H:10]2[CH2:9][C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[NH:12][C:11]2=[O:21])=[N:33][N:32]=[N:31]1

Participants

5

Reactant 3

HCID 58573791(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-oneHCID 178418339ButyllithiumHCID 178478452HCID 178478452, compound

Product 1

HCID 178517874HCID 178517874, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A 100 mL round-bottomed flask was placed under vacuum and heated with a heat gun to ensure dryness. The flask was allowed to cool to room temperature and a solution of 500 mg (1.56 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1, Step E) in THF (12 mL) under argon was added and cooled to 0° C. Butyllithium (1.6M in hexanes, 2440 μL, 3.90 mmol) was added followed by 5-chloromethyl-1H-tetrazole (185 mg, 1.561 mmol) and the reaction mixture was stirred for 15 minutes at 0° C. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The aqueous layer was acidified with 1M HCl. The aqueous layer was extracted with ethyl acetate (2×30 mL) and the combined organic layers were washed with sat. aq. NaCl solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by reversed phase preparatory HPLC (column: Gemini-NX C18 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN +0.1% TFA in water +0.1% TFA, over 25 minutes) to afford the title compound.

Workup

  1. customA 100 mL round-bottomed flask was placed under vacuum
  2. temperatureheated with a heat gun
  3. temperaturecooled to 0° C
  4. customThe reaction was quenched with saturated ammonium chloride solution
  5. extractionextracted with ethyl acetate
  6. extractionThe aqueous layer was extracted with ethyl acetate (2×30 mL)
  7. washthe combined organic layers were washed with sat. aq. NaCl solution
  8. dry with materialdried over sodium sulfate
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was purified by reversed phase preparatory HPLC (column: Gemini-NX C18 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN +0.1% TFA in water +0.1% TFA, over 25 minutes)

Sources & evidence

ORD record
ord-31357ac876d845d8a63364d535586fc2
Source dataset
uspto-grants-2016_03
Patent number
US09296736B2

Reaction notes

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