Nitrogen → tert-Butyl 6-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

HRID 587113노트

반응식

HRID 587113 반응식
Br[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:20][C:9]3([CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]3)[CH2:8]2)[CH:6]=1.[Cl:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]([Cl:29])[C:23]=1[CH:30]([O:32][C:33]1[C:34]([NH2:48])=[N:35][CH:36]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:38]=1)[CH3:31].N#N.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[NH2:48][C:34]1[N:35]=[CH:36][C:37]([C:2]2[CH:3]=[N:4][N:5]([CH:7]3[CH2:20][C:9]4([CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]4)[CH2:8]3)[CH:6]=2)=[CH:38][C:33]=1[O:32][CH:30]([C:23]1[C:24]([Cl:29])=[CH:25][CH:26]=[C:27]([F:28])[C:22]=1[Cl:21])[CH3:31]

참가 물질

7

반응물 4

HCID 947Nitrogen2회HCID 10340Sodium CarbonateHCID 211113943-(1-(2,6-Dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amineHCID 71244309tert-butyl 6-(4-bromo-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

생성물 1

HCID 71240178tert-Butyl 6-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate수율 45%

시약·촉매·용매 2

HCID 178418476HCID 178418476, 화합물촉매HCID 80711,2-Dimethoxyethane용매

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온도
90 °C

실험 절차

tert-Butyl 6-(4-bromo-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (145 mg, 0.42 mmol) and (±)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (268 mg, 0.63 mmol) were added to a round bottom flask. It was vacuumed and refilled with N2 (3 times). DME (2.0 mL) and a solution of Na2CO3 (2.0 M, 1.0 mL) were sequentially added. It was vacuumed and refilled with N2 (3 times). Pd(PPh3)2Cl2 (14.7 mg, 0.021 mmol) was added. It was degassed again refilled with N2 (2 times). The mixture was stirred at 90° C. (heating bath) for 16 hrs. The reaction mixture was cooled to room temperature and H2O (30 mL) was added. The aqueous phase was extracted with EtOAc (30 mL) and DCM (3×30 mL). The combined organic phase was dried over anhydrous Na2SO4, concentrated by evaporation in vacuo to give black residue which was purified by CombiFlash (40 g silica gel column, Hexane/EtOAc) to afford (±)-tert-butyl 6-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (106 mg, 45%) as a off-white solid.

후처리

  1. customIt was degassed again
  2. additionrefilled with N2 (2 times)
  3. temperature(heating bath) for 16 hrs
  4. temperatureThe reaction mixture was cooled to room temperature
  5. additionH2O (30 mL) was added
  6. extractionThe aqueous phase was extracted with EtOAc (30 mL) and DCM (3×30 mL)
  7. dry with materialThe combined organic phase was dried over anhydrous Na2SO4
  8. concentrationconcentrated by evaporation in vacuo
  9. customto give black residue which
  10. customwas purified by CombiFlash (40 g silica gel column, Hexane/EtOAc)

출처 및 근거

ORD 기록
ord-a37fc8f051724aec9244c9a4b3868890
출처 데이터셋
uspto-grants-2016_01
특허 번호
US09226923B2

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