Bromomethylcyclopropane → (3S,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one

HRID 931938Notes

Reaction equation

HRID 931938 reaction equation
[NH:1]1[C:5]([CH2:6][C@@H:7]2[CH2:12][C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C@@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[NH:9][C:8]2=[O:27])=[N:4][N:3]=[N:2]1.[CH3:28][C:29]([CH3:32])([O-])[CH3:30].[Na+].BrCC1CC1>CN(C=O)C>[NH:4]1[C:5]([CH2:6][C@@H:7]2[CH2:12][C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C@@H:10]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:9]([CH2:28][CH:29]3[CH2:32][CH2:30]3)[C:8]2=[O:27])=[N:1][N:2]=[N:3]1

Participants

5

Reactant 3

HCID 81503BromomethylcyclopropaneHCID 23676156Sodium t-butoxideHCID 178517874HCID 178517874, compound

Product 1

HCID 178516686(3S,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

A solution of (3S,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 60, Step A) (65 mg, 0.162 mmol) in DMF (1.6 mL) was cooled to 0° C. and sodium tert-butoxide (31.1 mg, 0.323 mmol) was added. The reaction mixture was stirred at 0° C. for ten minutes before adding (bromomethyl)cyclopropane (78 μL, 0.808 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hours, quenched with saturated ammonium chloride and diluted with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the organic layers were combined, washed with 1M LiCl, 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 20 minutes) to afford the title compound.

Workup

  1. temperatureThe reaction mixture was warmed to room temperature
  2. stirringstirred for 16 hours
  3. customquenched with saturated ammonium chloride
  4. additiondiluted with water and ethyl acetate
  5. extractionThe aqueous layer was extracted with ethyl acetate
  6. washwashed with 1M LiCl, sat. aq. NaCl solution
  7. dry with materialdried over sodium sulfate
  8. concentrationconcentrated under reduced pressure
  9. 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 20 minutes)

Sources & evidence

ORD record
ord-26aca1b6dc56430cafc9ab67a2192f90
Source dataset
uspto-grants-2016_03
Patent number
US09296736B2

Reaction notes

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