Triethylamine → (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(1-methyl-2-oxoazepan-3-yl)-1H-indazole-6-carboxamide

HRID 912456노트

반응식

HRID 912456 반응식
Cl.[NH2:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=[O:11].C(N(CC)CC)C.O=C1CCC(=O)N1[C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:44]([O-])=[O:45])=[C:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=3[F:43])[CH:33]=2)[N:28]([CH2:47][CH:48]([CH3:50])[CH3:49])[N:27]=1>CN(C)C=O.C(OCC)(=O)C>[F:43][C:37]1[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:36]=1[O:35][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][C:31]=1[C:44]([NH:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=[O:11])=[O:45])[N:28]([CH2:47][CH:48]([CH3:50])[CH3:49])[N:27]=[CH:26]2

참가 물질

6

반응물 3

HCID 8471TriethylamineHCID 67416248(3S)-3-amino-1-methylazepan-2-one hydrochlorideHCID 866310512,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate

생성물 1

HCID 24864925(S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(1-methyl-2-oxoazepan-3-yl)-1H-indazole-6-carboxamide수율 78%

시약·촉매·용매 2

HCID 6228Dimethylformamide용매HCID 8857Ethyl Acetate용매

실험 절차

(S)-3-Amino-1-methylazepan-2-one hydrochloride (0.112 g, 0.627 mmol) was dissolved in triethylamine (0.238 mL, 1.71 mmol) and N,N-dimethylformamide (3 mL). To this was added 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (prepared according to Example 16, Step A; 253 mg, 0.570 mmol), and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude reaction mixture was purified by flash chromatography on a silica gel column, eluting with 60% ethyl acetate/hexanes to yield pure (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(1-methyl-2-oxoazepan-3-yl)-1H-indazole-6-carboxamide (If) (208 mg, 78%). Mass spec: 471 (M+1). 1H NMR (CDCl3) δ 9.15 (br, 1H), 8.32 (s, 1H), 7.85 (s, 1H), 7.21 (m, 1H), 6.99 (m, 2H), 6.92 (m, 1H), 4.91 (ddd, 1H), 4.21 (d, 2H), 3.67 (dd, 1H), 3.22 (dd, 1H), 3.04 (s, 3H), 2.35 (m, 1H), 2.21 (m, 1H), 2.05-1.81 (m, 3H), 1.54 (m, 1H), 1.45 (m, 1H), 0.92 (d, 6H).

후처리

  1. washwashed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and brine
  2. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe crude reaction mixture
  6. customwas purified by flash chromatography on a silica gel column
  7. washeluting with 60% ethyl acetate/hexanes

출처 및 근거

ORD 기록
ord-4893f8fbb51d40d09cd68e7bb434e3c8
출처 데이터셋
uspto-grants-2011_09
특허 번호
US08026233B2

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