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Cesium carbonate → Tert-butyl 4-{[2-({3-methyl-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]oxy}piperidine-1-carboxylate

HRID 1028131
ノート
印刷プレビュー

反応式

HRID 1028131 の反応式
[NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([N:14]3[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]3)=[N:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:29]1[N:34]=[C:33]([O:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)[CH:32]=[CH:31][N:30]=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)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:8][C:6]1[CH:7]=[C:2]([NH:1][C:29]2[N:34]=[C:33]([O:35][CH:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]3)[CH:32]=[CH:31][N:30]=2)[CH:3]=[C:4]([C:9]2[S:13][C:12]([N:14]3[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]3)=[N:11][CH:10]=2)[CH:5]=1
参加物反応条件実験手順後処理出典と根拠反応ノート

参加物

7

反応物 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 67236328HCID 67236328、化合物2 回HCID 71629906tert-Butyl 4-((2-chloropyrimidin-4-yl)oxy)piperidine-1-carboxylate

生成物 1

HCID 71074837Tert-butyl 4-{[2-({3-methyl-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]oxy}piperidine-1-carboxylate

試薬・触媒・溶媒 2

HCID 167845palladium(II) acetate触媒HCID 312751,4-Dioxane溶媒

反応条件

温度
100 °C

実験手順

To 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (Intermediate XX, 59 mg, 0.19 mmol) in a scintillation vial was added dioxane (0.97 ml), cesium carbonate (126 mg, 0.39 mmol), and tert-butyl 4-[(2-chloropyrimidin-4-yl)oxy]piperidine-1-carboxylate (67 mg, 0.21 mmol). The system was purged and flushed with argon (3×) before adding XantPhos (17 mg, 0.029 mmol) and palladium(II) acetate (5 mg, 0.021 mmol). The system was purged and flushed with argon (3×) before sealing the system and heating to 100° C. overnight. The reaction was cooled to room temperature, filtered through celite and diluted with water. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. Purification via reverse phase chromatography (10-80% acetonitrile in water, linear gradient) provided tert-butyl 4-{[2-({3-methyl-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]oxy}piperidine-1-carboxylate. This material was treated with 2 ml of 1:1 trifluoroacetic acid:dichloromethane solution for 1 hr. The reaction was concentrated to dryness and purified by reverse phase chromatography (5-60% acetonitrile in water) to provide 16 mg (0.027 mmol, 14% yield) of 4-[5-(3-methyl-5-{[4-(piperidin-4-yloxy)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one as the TFA salt. MS APCI: [M+H]+ m/z 480.2. 1H NMR (500 MHz, dmso) δ 9.70-9.49 (m, 1H), 8.72-8.37 (m, 2H), 8.34-8.08 (m, 1H), 7.70-7.61 (m, 1H), 7.61-7.54 (m, 1H), 7.54-7.47 (m, 1H), 7.41-7.33 (m, 1H), 6.96-6.91 (m, 1H), 6.41-6.13 (m, 1H), 5.42-5.15 (m, 1H), 4.17 (s, 2H), 3.96-3.65 (m, 2H), 3.36-3.14 (m, 2H), 3.14-2.93 (m, 2H), 2.27 (s, 3H), 2.22-2.07 (m, 2H), 2.01-1.84 (m, 2H), 1.84-1.63 (m, 2H), 1.21-1.01 (m, 2H). TFA salt proton was visible. rhSyk=+++.

後処理

  1. customThe system was purged
  2. customflushed with argon (3×)
  3. customThe system was purged
  4. customflushed with argon (3×)
  5. temperatureThe reaction was cooled to room temperature
  6. filtrationfiltered through celite
  7. additiondiluted with water
  8. customThe organic layer was separated
  9. dry with materialdried over sodium sulfate
  10. concentrationconcentrated under reduced pressure
  11. customPurification via reverse phase chromatography (10-80% acetonitrile in water, linear gradient)

出典と根拠

ORDレコード
ord-6ae9c9d0fe6a4a5793f75215c9848a69
出典データセット
uspto-grants-2014_05
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US08735417B2

反応ノート

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