(2-Fluoro-4-methylphenyl)hydrazine hydrochloride → Methyl N-(4-{(1S)-1-[(R)-(4-chlorophenyl)(7-fluoro-5-methyl-1H-indol-3-yl)methyl]butyl}benzoyl)-beta-alaninate

HRID 919032Notes

Reaction equation

HRID 919032 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:28][CH:29]=O)[CH:9]([C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.Cl.[F:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1[NH:40]N>[Cl-].[Cl-].[Zn+2].C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:28]2[C:35]3[C:34](=[C:33]([F:32])[CH:38]=[C:37]([CH3:39])[CH:36]=3)[NH:40][CH:29]=2)[C@@H:9]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])=[CH:26][CH:27]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1

Participants

5

Reactant 2

HCID 53420391(2-Fluoro-4-methylphenyl)hydrazine hydrochlorideHCID 86619550Methyl N-{4-[2-(4-chlorophenyl)-4-oxo-1-propylbutyl]benzoyl}-beta-alaninate

Product 1

HCID 67016819Methyl N-(4-{(1S)-1-[(R)-(4-chlorophenyl)(7-fluoro-5-methyl-1H-indol-3-yl)methyl]butyl}benzoyl)-beta-alaninate

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 176Acetic AcidSolvent

Procedure

An acetic acid solution (10 ml) of methyl N-{4-[2-(4-chlorophenyl)-4-oxo-1-propylbutyl]benzoyl}-β-alaninate, INTERMEDIATE 4, (757 mg, 1.76 mmol), ZnCl2 (3.1M in AcOH, 1.7 ml, 5.27 mol) and 2-fluoro-4-methylphenylhydrazine hydrochloride (374 mg, 2.1 mmol) was heated at 80° C. for 45 minutes. The solution was concentrated and the residue partitioned between EtOAc and water. The organic phase was washed with water (2×), brine (2×) and dried over Na2SO4. The solution was filtered, concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. Data for the major diastereomer: 1H NMR (500 MHz, CD3CN): δ 9.11 (s, 1 H); 7.54 (d, J=8.2 Hz, 2 H); 7.48 (d, J=8.5 Hz, 2H); 7.38 (d, J=8.2 Hz, 2 H); 7.30 (d, J=8.4 Hz, 2 H); 7.15 (d, J=2.5 Hz, 1 H); 7.11 (s, 1 H); 7.02-6.97 (m, 1 H); 6.59 (d, J=12.3 Hz, 1 H); 4.49 (d, J=11.6 Hz, 1 H); 3.60 (s, 3H); 3.56-3.48 (m, 3 H); 2.52 (t, J=6.8 Hz, 2 H); 2.32 (s, 3 H); 1.49-1.35 (m, 2 H); 1.04-0.90 (m, 2 H); 0.69 (t, J=7.4 Hz, 3 H). LC1=3.94 min. (M+H)=535. Chiral LC1 (1% to 15% EtOH/heptane over 25 min,15% EtOH/heptane isocratic >25 min) retention time=28.38 minutes. The material also contains ca 2% by area of the enantiomer. Chiral LC1 (1% to 15% EtOH/heptane over 25 min,15% EtOH/heptane isocratic >25 min) retention time=26.88 minutes.

Workup

  1. concentrationThe solution was concentrated
  2. customthe residue partitioned between EtOAc and water
  3. washThe organic phase was washed with water (2×), brine (2×)
  4. dry with materialdried over Na2SO4
  5. filtrationThe solution was filtered
  6. concentrationconcentrated
  7. customthe residue purified by silica gel chromatography

Sources & evidence

ORD record
ord-23220e7fa3d34d919238d76b1e46438a
Source dataset
uspto-grants-2016_03
Patent number
US09272999B2

Reaction notes

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