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

HRID 2427801Notes

Reaction equation

HRID 2427801 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.CC(C1NC(=O)C(CCSC)NC(=O)C(NC(C(NC(C(NC(C(NC(C(N)CC(O)=O)=O)C(O)C)=O)CCSC)=O)CCCNC(N)=N)=O)CSSCC(C(NC(C(NC(C(NC(C(O)=O)C(C)C)=O)CCC(O)=O)=O)CC2C3C(=CC=CC=3)NC=2)=O)NC(=O)C2N(CCC2)C(=O)C(CCCNC(N)=N)NC(=O)C(CC2C=CC(O)=CC=2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CNC1=O)C.Cl.[F:176][C:177]1[CH:182]=[C:181]([CH3:183])[CH:180]=[CH:179][C:178]=1[NH:184]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:179]3[C:178](=[C:177]([F:176])[CH:182]=[C:181]([CH3:183])[CH:180]=3)[NH:184][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

6

Reactant 3

HCID 16167454Melanin-concentrating hormoneHCID 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

Conditions

Temperature
80 °C

Procedure

An acetic acid solution (10 ml) of methyl N-{4-[2-(4-chlorophenyl)-4-oxo-1-propylbutyl]benzoyl}-β-alaninate, prepared from INTERMEDIATE 2 as described in EXAMPLE 1, (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) were 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, 1H); 7.54 (d, J=8.2 Hz, 2H); 7.48 (d, J=8.5 Hz, 2H); 7.38 (d, J=8.2 Hz, 2H); 7.30 (d, J=8.4 Hz, 2H); 7.15 (d, J=2.5 Hz, 1H); 7.11 (s, 1H); 7.02-6.97 (m, 1H); 6.59 (d, J=12.3 Hz, 1H); 4.49 (d, J=11.6 Hz, 1H); 3.60 (s, 3H); 3.56-3.48 (m, 3H); 2.52 (t, J=6.8 Hz, 2H); 2.32 (s, 3H); 1.49-1.35 (m, 2H); 1.04-0.90 (m, 2H); 0.69 (t, J=7.4 Hz, 3H). 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-60bffa33d0ee42789e01e9cc65053943
Source dataset
uspto-grants-2011_06
Patent number
US07968589B2

Reaction notes

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