Cesium carbonate → N4-(2,2-dimethyl-3,4-dihydro-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-(isoquinolin-7-yl)-2,4-pyrimidinediamine

HRID 1916047노트

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HRID 1916047 반응식
Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:13][C:14]([CH3:21])([CH3:20])[C:15](=[O:19])[NH:16][C:17]=3[N:18]=2)[C:5]([F:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][N:30]=[CH:31]2)=[CH:26][CH:25]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CN1C(=O)CCC1.C(Cl)Cl.CO.CC(C)=O.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:20][C:14]1([CH3:21])[O:13][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[C:5]([F:22])=[CH:4][N:3]=[C:2]([NH:23][C:24]4[CH:33]=[C:32]5[C:27]([CH:28]=[CH:29][N:30]=[CH:31]5)=[CH:26][CH:25]=4)[N:7]=3)=[N:18][C:17]=2[NH:16][C:15]1=[O:19]

참가 물질

10

반응물 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 14660277Isoquinolin-7-amineHCID 575629316-((2-Chloro-5-fluoro-4-pyrimidinyl)amino)-2,2-dimethyl-2H-pyrido(3,2-b)-1,4-oxazin-3(4H)-one

생성물 1

HCID 53477410N4-(2,2-dimethyl-3,4-dihydro-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-(isoquinolin-7-yl)-2,4-pyrimidinediamine수율 15.5%

시약·촉매·용매 5

HCID 167845palladium(II) acetate촉매HCID 13387N-methyl-2-pyrrolidone용매HCID 312751,4-Dioxane용매HCID 21226129Dichloromethane methanol용매HCID 21894497Aceton-methanol용매

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온도
100 °C

실험 절차

A mixture of 1.6 g 2-chloro-5-fluoro-N4-[2,2-dimethyl-3,4-dihydro-3-oxo-pyrido[3,2-b][1,4]oxazin-6-yl]-4-pyrimidineamine, 800 mg of 7-aminoisoquinoline, 320 mg of palladium acetate, 320 mg of rac-Binap and 3.68 g cesium carbonate in 32 mL of 1,4-dioxane and 8 mL of NMP was heated at reflux at 100° C. overnight under argon. The reaction was cooled, diluted with CH2Cl2/MeOH and filtered. The filtrate was diluted with water and the organic phase evaporated to give the crude product which was dissolved in acetone/MeOH and evaporated onto silica gel. The material was purified by flash chromatography eluting isocratically with CH2Cl2/2 N ammonia solution in MeOH 15:1 to yield 330 mg of the title compound. 1H NMR (DMSO-d6): δ 8.91 (s, 1H), 8.48 (s, 1H), 8.28 (d, 1H), J=5.4 Hz), 8.16 (d, 1H, J=2.1 Hz), 7.82 (m, 2H), 7.68 (d, 1H, J=6 Hz), 7.51 (d, 1H, J=8.1 Hz), 7.30 (d, 1H, J=8.4 Hz), 1.43 (s, 6H); LCMS: purity: 99%; MS (m/e): 432 (MH+)

후처리

  1. temperaturewas heated
  2. temperatureThe reaction was cooled
  3. filtrationfiltered
  4. additionThe filtrate was diluted with water
  5. customthe organic phase evaporated
  6. customto give the crude product which
  7. customevaporated onto silica gel
  8. customThe material was purified by flash chromatography
  9. washeluting isocratically with CH2Cl2/2 N ammonia solution in MeOH 15:1

출처 및 근거

ORD 기록
ord-f56aea9faf844889a5042e37635c5de8
출처 데이터셋
uspto-grants-2013_12
특허 번호
US08618095B2

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