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

HRID 1888121노트

반응식

HRID 1888121 반응식
[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

참가 물질

6

반응물 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

생성물 1

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

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매

실험 절차

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)+.

후처리

  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.

출처 및 근거

ORD 기록
ord-90e9989e04c3421681bf3f6f133ca1bd
출처 데이터셋
uspto-grants-2013_08
특허 번호
US08501782B2

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