p-Toluenesulfonic acid → 8-((5-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-6-fluoropyridin-3-yl)amino)-5-fluoro-1,7-naphthyridine-3-carbonitrile

HRID 930305ノート

反応式

HRID 930305 の反応式
[NH2:1][C:2]1[O:3][C@H:4]([C:26]([F:29])([F:28])[F:27])[CH2:5][C@:6]([C:9]2[CH:10]=[C:11]([NH:16]C(=O)C3C=CC(Cl)=CN=3)[CH:12]=[N:13][C:14]=2[F:15])([CH3:8])[N:7]=1.Cl[C:31]1[N:32]=[CH:33][C:34]([F:43])=[C:35]2[C:40]=1[N:39]=[CH:38][C:37]([C:41]#[N:42])=[CH:36]2.CC1C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[NH2:1][C:2]1[O:3][C@H:4]([C:26]([F:27])([F:29])[F:28])[CH2:5][C@:6]([C:9]2[CH:10]=[C:11]([NH:16][C:31]3[N:32]=[CH:33][C:34]([F:43])=[C:35]4[C:40]=3[N:39]=[CH:38][C:37]([C:41]#[N:42])=[CH:36]4)[CH:12]=[N:13][C:14]=2[F:15])([CH3:8])[N:7]=1

参加物

5

反応物 3

HCID 6101p-Toluenesulfonic acidHCID 78321763N-(5-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-6-fluoropyridin-3-yl)-5-chloropicolinamideHCID 867158748-Chloro-5-fluoro-1,7-naphthyridine-3-carbonitrile2 回

生成物 1

HCID 867321348-((5-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-6-fluoropyridin-3-yl)amino)-5-fluoro-1,7-naphthyridine-3-carbonitrile収率 45%

試薬・触媒・溶媒 1

HCID 3776Isopropanol溶媒

反応条件

温度
100 °C

実験手順

To a solution of (4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (6a, 0.076 g, 0.260 mmol) and 8-chloro-5-fluoro-1,7-naphthyridine-3-carbonitrile (intermediate 17, 0.065 g, 0.312 mmol) in 2-propanol (2.6 ml) was added 4-methylbenzene sulfonic acid (monohydrate, Fluka, 0.099 g, 0.520 mmol). The reaction mixture was heated to 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between DCM and aqueous saturated sodium bicarbonate. The aqueous layer was backextracted with DCM. The combined organic extracts were washed with brine and dried over sodium sulfate. The filtrate was concentrated and the residue was purified by reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 20 min. The product containing fractions were combined and neutralized with aqueous sodium bicarbonate solution. The free-based product was extracted with DCM. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford the title compound (0.054 g, 0.117 mmol, 44.8% yield) as yellow solid. MS m/z=464.0 [M+H]+. Calculated for C20H14F5N7O: 463.4

後処理

  1. temperatureThe reaction mixture was cooled to room temperature
  2. concentrationconcentrated under reduced pressure
  3. customThe residue was partitioned between DCM and aqueous saturated sodium bicarbonate
  4. washThe combined organic extracts were washed with brine
  5. dry with materialdried over sodium sulfate
  6. concentrationThe filtrate was concentrated
  7. customthe residue was purified by reversed-phase preparative HPLC
  8. customover 20 min
  9. additionThe product containing fractions
  10. extractionThe free-based product was extracted with DCM
  11. dry with materialThe organic phase was dried over MgSO4
  12. customthe solvent was removed under reduced pressure

出典と根拠

ORDレコード
ord-ec3dc04e55d344e5ae58be43d2e15d12
出典データセット
uspto-grants-2016_03
特許番号
US09296734B2

反応ノート

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