Pyridine → tert-Butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(3-hydroxy-3-methylbut-1-ynyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate

HRID 384710

반응식

HRID 384710 반응식
Cl[C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:5](I)=[CH:4][N:3]=1.C[Si](C)(C)[O:26][C:27]([CH3:31])([C:29]#[CH:30])[CH3:28].[N:34]1C=CC=C[CH:35]=1.[NH2:40][C:41]1[CH2:46][N:45](C#N)[CH:44]=[CH:43][N:42]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:35]([C:44]1[N:45]=[CH:46][C:41]([NH:40][C:2]2[CH:7]=[C:6]([NH:8][CH2:9][CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[C:5]([C:30]#[C:29][C:27]([OH:26])([CH3:31])[CH3:28])=[CH:4][N:3]=2)=[N:42][CH:43]=1)#[N:34]

참가 물질

10

반응물 6

HCID 1049PyridineHCID 10796Cesium carbonateHCID 87344((1,1-Dimethyl-2-propynyl)oxy)trimethylsilaneHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 59613389Tert-butyl 4-(((2-chloro-5-iodopyridin-4-yl)amino)methyl)piperidine-1-carboxylateHCID 866483902-Amino-4-cyanopyrazine

생성물 1

HCID 59613530tert-Butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(3-hydroxy-3-methylbut-1-ynyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate수율 30%

시약·촉매·용매 3

HCID 83717Copper iodide촉매HCID 178418476HCID 178418476, 화합물촉매2회HCID 312751,4-Dioxane용매

반응 조건

온도
150 °C

실험 절차

A solution of tert-butyl 4-((2-chloro-5-iodopyridin-4-ylamino)methyl)piperidine-1-carboxylate (Synthesis 170-B) (0.100 g, 0.22 mmol), dichlorobis(triphenylphosphine)-palladium (II) (0.009 g, 0.01 mmol), trimethyl(2-methylbut-3-yn-2-yloxy)silane (0.048 mL, 0.24 mmol) and copper iodide (0.002 g, 0.01 mmol) was heated under microwave irradiation for 5 min at 120° C. The crude mixture was concentrated in vacuo and filtered through a pad of silica, eluting with hexane/ethyl acetate (8/2), to give the crude product which was used without further purification. The crude pyridine (0.085 g, 0.163 mmol), 2-amino-4-cyanopyrazine (0.023 g, 0.195 mmol), Xantphos (0.015 g, 0.026 mmol), cesium carbonate (0.106 g, 0.326 mmol), dichlorobis(triphenylphosphine)-palladium (II) (0.012 g, 0.013 mmol) in dioxane (1.2 mL) were stirred at room temperature under nitrogen for 10 min, then heated under microwave irradiation for 60 min at 150° C. The reaction mixture was purified by ion exchange on SCX-II acidic resin (2 g), eluting with methanol/dichloromethane (1/1), then 2M ammonia-methanol. The basic fractions were combined and solvent was removed in vacuo. The crude product was purified by preparative thin layer chromatography, eluting with methanol/dichloromethane (1/19), to give the title compound as a yellow solid (0.024 g, 27%).

후처리

  1. concentrationThe crude mixture was concentrated in vacuo
  2. filtrationfiltered through a pad of silica
  3. washeluting with hexane/ethyl acetate (8/2)
  4. customto give the crude product which
  5. customwas used without further purification
  6. customThe reaction mixture was purified by ion exchange on SCX-II acidic resin (2 g)
  7. washeluting with methanol/dichloromethane (1/1)
  8. customsolvent was removed in vacuo
  9. customThe crude product was purified by preparative thin layer chromatography
  10. washeluting with methanol/dichloromethane (1/19)

출처 및 근거

ORD 기록
ord-8e9efce735a14276b1bfd105d8423015
출처 데이터셋
uspto-grants-2013_02
특허 번호
US08367658B2

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