Methylamine → 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methylamide

HRID 216468

반응식

HRID 216468 반응식
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:20]([OH:22])=O)=[CH:11][C:12]3[N:16](C)[CH:15]=[N:14][C:13]=3[C:18]=2[F:19])=[C:4]([Cl:23])[CH:3]=1.C1C=CC2N(O)N=[N:30][C:28]=2C=1.C(N(CC)CC)C.CN.CCN=C=NCCCN(C)C>CN(C)C=O.C(OCC)(=O)C.O>[CH3:28][NH:30][C:20]([C:10]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[Cl:23])=[C:18]([F:19])[C:13]2[N:14]=[CH:15][NH:16][C:12]=2[CH:11]=1)=[O:22]

참가 물질

9

반응물 5

HCID 6329MethylamineHCID 8471TriethylamineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 16092137AZ-133266637

생성물 1

HCID 113954076-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methylamide수율 43%

시약·촉매·용매 3

HCID 962Water용매HCID 6228Dimethylformamide용매HCID 8857Ethyl Acetate용매

실험 절차

6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid 10c (0.029 g, 0.076 mmol) is dissolved in N,N-dimethylformamide (1.1 mL). HOBT (0.016 g, 0.10 mmol), triethylamine (0.028 mL, 0.20 mmol), methylamine (0.059 mL, 0.12 mmol, 2 M solution in tetrahydrofuran), and EDCI (0.019 g, 0.10 mmol) are added consecutively to the reaction mixture at room temperature. The solution is stirred at room temperature for 16 hours under N2. The reaction mixture is poured into a separatory funnel and diluted with ethyl acetate and water and the layers separated. The ethyl acetate layer is washed successively with aqueous saturated NH4Cl (2×), brine (1×), aqueous saturated sodium bicarbonate (2×), water (1×), and brine (1×), dried (MgSO4) and concentrated under reduced pressure. The resulting solid is purified by FCC (eluting with 19:1 methylene chloride:methanol) to yield 0.013 g (42%) of the pure desired product. MS APCI (+) m/z 397, 399 (M+, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (broad s, 1H), 8.69 (m, 1H), 8.41 (s, 1H), 7.76 (s, 1H), 7.63 (d, 1H), 7.30 (dd, 1H), 6.50 (dd, 1H), 2.76 and 2.75 (s and s, 3H total, amide rotamers). 19F NMR (376 MHz, DMSO-d6) −132.69 (s).

후처리

  1. additionThe reaction mixture is poured into a separatory funnel
  2. customthe layers separated
  3. washThe ethyl acetate layer is washed successively with aqueous saturated NH4Cl (2×), brine (1×), aqueous saturated sodium bicarbonate (2×), water (1×), and brine (1×)
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated under reduced pressure
  6. customThe resulting solid is purified by FCC (eluting with 19:1 methylene chloride:methanol)

출처 및 근거

ORD 기록
ord-4ea53be6329143b98e316154be8b3679
출처 데이터셋
uspto-grants-2012_06
특허 번호
US08193229B2

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