Lithium diisopropylamide → HCID 67999885, compound

HRID 932189Notes

Reaction equation

HRID 932189 reaction equation
[CH2:1]([C@@:4]1([CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:5]1=[O:31])[CH:2]=[CH2:3].C([N-]C(C)C)(C)C.[Li+].[F:41][CH:42]([F:45])[CH2:43]I>C1COCC1>[CH2:1]([C@@:4]1([CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:43][CH:42]([F:45])[F:41])[C:5]1=[O:31])[CH:2]=[CH2:3]

Participants

5

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 38335651,1-Difluoro-2-iodoethaneHCID 58573766HCID 58573766, compound

Product 1

HCID 67999885HCID 67999885, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pyridin-2-ylmethyl)piperidin-2-one (705 mg, 1.515 mmol; Example 71, Step D) in inhibitor free THF (7 mL) under N2 at −78° C. was added lithium diisopropylamide (1.515 mL, 3.03 mmol) and the mixture was stirred for 30 min. 1,1-Difluoro-2-iodoethane (727 mg, 3.79 mmol; Oakwood) was added and the orange reaction mixture was stirred at −78° C. for 1 h. The reaction was warmed to rt overnight and quenched with 0.2 mL of MeOH, filtered and concentrated. The residue was purified by HPLC(C18 column, eluted with 10-95% CH3CN in water, with 0.1% TFA) to give (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-3,3-difluoro-1-(pyridin-2-yl)propyl)-3-methylpiperidin-2-one (HPLC retention time 7.38 min, Agilent Eclipse Plus C18 column, 0.1% TFA in CH3CN/H2O, gradient 70%-90% over 25 minutes) and (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-3,3-difluoro-1-(pyridin-2-yl)propyl)-3-methylpiperidin-2-one (HPLC retention time 7.94 min, Agilent Eclipse Plus C18 column (Agilent Technologies, Santa Clara, Calif.), 0.1% TFA in CH3CN/H2O, gradient 70%-90% over 25 minutes). Mass Spectrum (ESI) m/z=529 (M+1).

Workup

  1. stirringthe orange reaction mixture was stirred at −78° C. for 1 h
  2. customquenched with 0.2 mL of MeOH
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue was purified by HPLC(C18 column
  6. washeluted with 10-95% CH3CN in water, with 0.1% TFA)

Sources & evidence

ORD record
ord-11fbb7aa511e4a5ea06adc223d9058e9
Source dataset
uspto-grants-2016_03
Patent number
US09296736B2

Reaction notes

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