4-Methylmorpholine → 3-(2,6-Difluorophenyl)-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-1-(4-methylphenyl)-1H indazole-6-carboxamide

HRID 1047632Notes

Reaction equation

HRID 1047632 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:20])=O)=[CH:15][CH:16]=2)[N:11]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[N:10]=1.Cl.Cl.[CH3:30][C:31]1[N:35]=[C:34]([C@H:36]([NH2:38])[CH3:37])[O:33][N:32]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([NH:38][C@@H:36]([C:34]3[O:33][N:32]=[C:31]([CH3:30])[N:35]=3)[CH3:37])=[O:20])=[CH:15][CH:16]=2)[N:11]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[N:10]=1

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 66661491(R)-1-(3-Methyl-1,2,4-oxadiazol-5-yl)ethanamine dihydrochlorideHCID 666616413-(2,6-Difluorophenyl)-1-(4-methylphenyl)-1H-indazole-6-carboxylic acid

Product 1

HCID 469459763-(2,6-Difluorophenyl)-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-1-(4-methylphenyl)-1H indazole-6-carboxamideYield 58.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

3-(2,6-Difluorophenyl)-1-(4-methylphenyl)-1H-indazole-6-carboxylic acid (30.0 mg, 0.040 mmol, with 6 equivalents of sodium chloride), (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine bis-hydrochloride (12.5 mg, 0.062 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16.2 mg, 0.085 mmol), 1-hydroxy-7-azabenzotriazole (3.4 mg, 0.025 mmol), and N-methylmorpholine (20 μl, 0.182 mmol) were dissolved in N,N-dimethylformamide (500 μl) at 25° C. The reaction mixture was heated to 50° C. and allowed to stir for 30 min. The reaction was stopped and quenched by addition of water (ca 0.1 mL) and trifluoroacetic acid (ca 0.1 mL). The crude reaction mixture was purified directly by preparative HPLC (Reverse phase (C-18)), eluting with acetonitrile/water+0.1% trifluoroacetic acid (5-95%), to afford the title compound (16.3 mg, 0.023 mmol, 58.2% yield) as a white solid. HRMS [M+1]=474.1739. 1H NMR (400 MHz, CDCl3): δ 8.29 (s, 1H); 7.77 (d, J=8.6 Hz, 1H); 7.66 (d, J=8.2 Hz, 2H); 7.61 (dd, J=8.5, 1.4 Hz, 1H); 7.48-7.40 (m, 1H); 7.38 (d, J=8.1 Hz, 2H); 7.10 (m, 2H); 6.79 (d, J=7.7 Hz, 1H); 5.62 (m, 1H); 2.46 (s, 3H); 2.41 (s, 3H); 1.73 (d, J=7.1 Hz, 3H).

Workup

  1. customquenched by addition of water (ca 0.1 mL) and trifluoroacetic acid (ca 0.1 mL)
  2. customThe crude reaction mixture
  3. customwas purified directly by preparative HPLC (Reverse phase (C-18))
  4. washeluting with acetonitrile/water+0.1% trifluoroacetic acid (5-95%)

Sources & evidence

ORD record
ord-148c8c748a18493d917594c2559098b2
Source dataset
uspto-grants-2013_10
Patent number
US08569512B2

Reaction notes

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