Isopropanol → 5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-2-(4-isopropylpiperazin-1-yl)benzonitrile

HRID 633451노트

반응식

HRID 633451 반응식
Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([N:30]2[CH2:35][CH2:34][N:33]([CH:36]([CH3:38])[CH3:37])[CH2:32][CH2:31]2)=[C:26]([CH:29]=1)[C:27]#[N:28].C[CH:40]([OH:42])C>>[NH3:3].[CH3:40][OH:42].[CH3:18][C:11]1([CH3:19])[CH2:10][C@H:9]([NH:8][C:6]2[C:5]([F:20])=[CH:4][N:3]=[C:2]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([N:30]4[CH2:35][CH2:34][N:33]([CH:36]([CH3:38])[CH3:37])[CH2:32][CH2:31]4)=[C:26]([CH:29]=3)[C:27]#[N:28])[N:7]=2)[CH2:17][C@H:16]2[N:12]1[CH2:13][CH2:14][CH2:15]2

참가 물질

5

반응물 3

HCID 3776IsopropanolHCID 612969195-Amino-2-(4-isopropylpiperazin-1-yl)benzonitrileHCID 86704490(7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-5,5-dimethyloctahydroindolizin-7-amine

생성물 2

HCID 21705897Ammonia methanol수율 1%HCID 867045405-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-2-(4-isopropylpiperazin-1-yl)benzonitrile수율 71%

실험 절차

A mixture of (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (163 mg, 0.546 mmol, 1.0 equiv), 5-amino-2-(4-isopropylpiperazin-1-yl)benzonitrile (200 mg, 0.819 mmol, 1.5 equiv), and PTSA monohydrate (208 mg, 1.09 mmol, 2.0 equiv) in IPA (5 mL) was heated to reflux for 2 days. After cooling to ambient temperature, the crude mixture was concentrated to dryness and taken in water, EtOAc, and 1N NaOH. The layers were separated. The organic layer was washed with 1N NaOH 1×, dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by flash chromatography and eluted with DCM:2M NH3/MeOH=100:0 to 95:5 using 1% 2M NH3/MeOH increments to give Compound 138 (195 mg, 71% yield) as a solid.

후처리

  1. temperaturewas heated
  2. temperatureto reflux for 2 days
  3. concentrationthe crude mixture was concentrated to dryness
  4. customThe layers were separated
  5. washThe organic layer was washed with 1N NaOH 1×
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated to dryness
  9. customThe crude product was purified by flash chromatography
  10. washeluted with DCM

출처 및 근거

ORD 기록
ord-d8c98ba4ec104a079b04b571468b3b11
출처 데이터셋
uspto-grants-2016_04
특허 번호
US09321763B2

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