Diisopropylethylamine → N-(4-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-4-oxobutan-2-yl)benzamide

HRID 1888121Notes

Reaction equation

HRID 1888121 reaction equation
[C:1]([NH:9][CH:10]([CH3:16])[CH:11]([CH3:15])[C:12]([OH:14])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C@@:24]2([OH:32])[CH2:29][CH2:28][NH:27][CH2:26][C:25]2([CH3:31])[CH3:30])=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C1COCC1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C@@:24]2([OH:32])[CH2:29][CH2:28][N:27]([C:12](=[O:14])[CH:11]([CH3:15])[CH:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH3:16])[CH2:26][C:25]2([CH3:30])[CH3:31])=[CH:20][CH:19]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 138635073-Benzamido-2-methylbutanoic acidHCID 18437142(S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol

Product 1

HCID 59444196N-(4-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-4-oxobutan-2-yl)benzamideYield 35.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To 3-benzamido-2-methylbutanoic acid (0.055 g, 0.249 mmol) in THF (2 mL) are sequentially added (S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (WO 04/043965, 0.060 g, 0.249 mmol), N,N-diisopropylethylamine (0.087 mL, 0.497 mmol) and BOP (0.110 g, 0.249 mmol) at RT. The reaction mixture was stirred at RT for 70 h, and concentrated. The oily residue was dissolved in MeOH (2.0 mL) and subjected to preparative HPLC (Phenomex S10 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA). Two fractions (diastereomer A and B) are collected and individually processed by concentrating and partitioning between dichloromethane (10 mL) and sat. aq. NaHCO3 (10 mL). The dichloromethane layer was dried over sodium sulfate and concentrated to yield: Diastereomer A: (0.042 g, 0.089 mmol, 35.9% yield) as a foamy solid. Retention time=3.23 min (YMC S5 Combi ODS 4.6×50 mm; 4 min. gradient; solvent A=10% MeOH, 90% H2O, 0.2% H3PO4, solvent B=90% MeOH, 10% H2O, 0.2% H3PO4. MS (ESI) m/z 443.11 (M+H)+; and Diastereomer B: (0.03 g, 0.064 mmol, 25.9% yield) as a foamy solid. Retention time=3.42 min (YMC S5 Combi ODS 4.6×50 mm; 4 min. gradient; solvent A=10% MeOH, 90% H2O, 0.2% H3PO4, solvent B=90% MeOH, 10% H2O, 0.2% H3PO4. MS (ESI) m/z 443.12 (M+H)+.

Workup

  1. customat RT
  2. concentrationconcentrated
  3. dissolutionThe oily residue was dissolved in MeOH (2.0 mL)
  4. customsubjected to preparative HPLC (Phenomex S10 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA)
  5. customTwo fractions (diastereomer A and B) are collected
  6. concentrationby concentrating
  7. custompartitioning between dichloromethane (10 mL) and sat. aq. NaHCO3 (10 mL)
  8. dry with materialThe dichloromethane layer was dried over sodium sulfate
  9. concentrationconcentrated to yield
  10. custom4 min.
  11. custom4 min.

Sources & evidence

ORD record
ord-90e9989e04c3421681bf3f6f133ca1bd
Source dataset
uspto-grants-2013_08
Patent number
US08501782B2

Reaction notes

Loading…