Cesium carbonate → 5-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)nicotinonitrile

HRID 930320노트

반응식

HRID 930320 반응식
Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[N:28][CH:29]=1)#[N:23].C(=O)([O-])[O-].[Cs+].[Cs+].C(C1C=NC=C(B2OC(C)(C)C(C)(C)O2)C=1)#N>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:16])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([C:26]3[CH:27]=[N:28][CH:29]=[C:24]([CH:25]=3)[C:22]#[N:23])[CH:3]=[CH:4][C:5]=2[F:21])([CH2:19][F:20])[N:9]=1

참가 물질

8

반응물 4

HCID 10796Cesium carbonateHCID 164142165-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrileHCID 450795765-Cyanopyridine-3-boronic acidHCID 86732143(4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine

생성물 1

HCID 867321495-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)nicotinonitrile수율 65.9%

시약·촉매·용매 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)촉매2회HCID 962Water용매HCID 8028Tetrahydrofuran용매

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온도
80 °C

실험 절차

In a microwave vial a mixture of (4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (8a, 110 mg, 0.295 mmol), 5-cyano-3-pyridinyl boronic acid (43.6 mg, 0.295 mmol), and cesium carbonate (384 mg, 1.179 mmol) in THF (2.0 mL) and water (983 μL) was purged with argon for 5 min. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (12.04 mg, 0.015 mmol) was added and the tube was sealed and the mixture was heated at 80° C. overnight. Additional 3-cyanopyridine-5-boronic acid pinacol ester (67.8 mg, 0.295 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (12.04 mg, 0.015 mmol) were added. The reaction mixture was stirred at 80° C. for another 6 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water and brine. The aqueous layer was back extracted with EtOAc (2×) and the combined organics was washed with brine, dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 0% EtOAc in hexane, to provide 5-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)nicotinonitrile (77 mg, 0.194 mmol, 65.9% yield) as off-white solid. MS m/z=397 [M]+. Calculated for C18H13F5N4O: 396.31.

후처리

  1. customwas purged with argon for 5 min
  2. customthe tube was sealed
  3. temperatureAfter cooling to room temperature
  4. customthe reaction mixture was partitioned between EtOAc and water and brine
  5. extractionThe aqueous layer was back extracted with EtOAc (2×)
  6. washthe combined organics was washed with brine
  7. dry with materialdried (Na2SO4)
  8. concentrationconcentrated
  9. customThe crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g)
  10. washeluting with a gradient of 0% to 0% EtOAc in hexane

출처 및 근거

ORD 기록
ord-9ae78750ce2943f89baa59d61f8379cc
출처 데이터셋
uspto-grants-2016_03
특허 번호
US09296734B2

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