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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
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HRID 1028131 반응식
[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
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참가 물질

7

반응물 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 67236328HCID 67236328, 화합물2회HCID 71629906tert-Butyl 4-((2-chloropyrimidin-4-yl)oxy)piperidine-1-carboxylate

생성물 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

시약·촉매·용매 2

HCID 167845palladium(II) acetate촉매HCID 312751,4-Dioxane용매

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온도
100 °C

실험 절차

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=+++.

후처리

  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)

출처 및 근거

ORD 기록
ord-6ae9c9d0fe6a4a5793f75215c9848a69
출처 데이터셋
uspto-grants-2014_05
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US08735417B2

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