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 1047632노트

반응식

HRID 1047632 반응식
[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

참가 물질

7

반응물 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

생성물 1

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

시약·촉매·용매 1

HCID 6228Dimethylformamide용매

반응 조건

온도
50 °C

실험 절차

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).

후처리

  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%)

출처 및 근거

ORD 기록
ord-148c8c748a18493d917594c2559098b2
출처 데이터셋
uspto-grants-2013_10
특허 번호
US08569512B2

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