Piperidine → 1-(5-Tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(piperidin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea

HRID 631328노트

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HRID 631328 반응식
[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:37]5[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]

참가 물질

6

반응물 3

HCID 8082PiperidineHCID 81531DiisopropylethylamineHCID 668760471-(5-tert-Butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea

생성물 1

HCID 582679641-(5-Tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(piperidin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea수율 17.1%

시약·촉매·용매 2

HCID 67553Tetrabutylammonium Iodide촉매HCID 6228Dimethylformamide용매

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온도
60 °C

실험 절차

To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 79A (225 mg, 0.426 mmol) in DMF (3 mL) was added piperidine (0.126 mL, 1.278 mmol) followed by diisopropyl ethylamine (0.222 mL, 1.278 mmol) and tetrabutyl ammonium iodide (157.35 mg, 0.426 mmol). The reaction mixture was heated at 60° C. for 2 days. Formation of product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (using phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(piperidin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea (42 mg, 17%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.20 (s, 1H), 8.65 (s, 1H), 7.85 (s, 1H), 7.60-7.22 (m, 5H), 6.45 (s, 1H), 4.30 (m, 2H), 3.95 (s, 3H), 2.85-2.30 (m, 6H), 1.70-1.30 (m, 6H), 1.25 (s, 9H); LC-MS (ESI) m/z 577 (M+H)+.

후처리

  1. customThe crude reaction mixture
  2. customwas purified by preparative HPLC (
  3. washeluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN)

출처 및 근거

ORD 기록
ord-c27c8f771b6d43b7a76e7327cbd5da77
출처 데이터셋
uspto-grants-2016_04
특허 번호
US09320739B2

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