N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine → 2-((S)-tetrahydrofuran-3-yloxy)-5-(5-fluoro-4-(octahydro-5,5-dimethylindolizin-7-ylamino)pyrimidin-2-ylamino)benzonitrile

HRID 633375노트

반응식

HRID 633375 반응식
Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:17][CH: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.[O:21]1[CH2:25][CH2:24][C@H:23]([O:26][C:27]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:28]=2[C:29]#[N:30])[CH2:22]1>CC(O)C>[NH3:3].[CH3:22][OH:21].[O:21]1[CH2:25][CH2:24][C@H:23]([O:26][C:27]2[CH:34]=[CH:33][C:32]([NH:35][C:2]3[N:7]=[C:6]([NH:8][CH:9]4[CH2:17][CH:16]5[N:12]([CH2:13][CH2:14][CH2:15]5)[C:11]([CH3:19])([CH3:18])[CH2:10]4)[C:5]([F:20])=[CH:4][N:3]=3)=[CH:31][C:28]=2[C:29]#[N:30])[CH2:22]1

참가 물질

5

반응물 2

HCID 86704443N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amineHCID 867044802-((S)-tetrahydrofuran-3-yloxy)-5-aminobenzonitrile

생성물 2

HCID 21705897Ammonia methanol수율 1%HCID 718114822-((S)-tetrahydrofuran-3-yloxy)-5-(5-fluoro-4-(octahydro-5,5-dimethylindolizin-7-ylamino)pyrimidin-2-ylamino)benzonitrile수율 188.4%

시약·촉매·용매 1

HCID 3776Isopropanol용매

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온도
70 °C

실험 절차

A mixture of N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (Racemic, single diastereomer; 200 mg, 0.669 mmol, 1 equiv), 2-((S)-tetrahydrofuran-3-yloxy)-5-aminobenzonitrile (191 mg, 0.937 mmol, 1.4 equiv), and PTSA monohydrate (127 mg, 0.669 mmol, 1 equiv) in IPA (7 ml) were heated to 70° C. for 3 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 (×2), 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 96:4 using 1% 2M NH3/MeOH increments to give compound 2-((S)-tetrahydrofuran-3-yloxy)-5-(5-fluoro-4-(octahydro-5,5-dimethylindolizin-7-ylamino)pyrimidin-2-ylamino)benzonitrile (Compound 60) (two diastereomers; 294 mg, 95%) as a solid.

후처리

  1. temperatureAfter cooling to ambient temperature
  2. concentrationthe crude mixture was concentrated to dryness
  3. customThe layers were separated
  4. washThe organic layer was washed with 1N NaOH (×2)
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated to dryness
  8. customThe crude product was purified by flash chromatography
  9. washeluted with DCM

출처 및 근거

ORD 기록
ord-ac23d502eaea4b5aad240ec31b67690f
출처 데이터셋
uspto-grants-2016_04
특허 번호
US09321763B2

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