4-Bromo-3,5-dimethylpyridine → 8-(cyclopropylmethoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

HRID 1095771노트

반응식

HRID 1095771 반응식
Br[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH3:9].[CH:10]1([CH2:13][O:14][C:15]2[C:16]([O:35][CH3:36])=[CH:17][CH:18]=[C:19]3[C:24]=2[NH:23][C:22](=[O:25])[CH:21]=[C:20]3[NH:26]C2C(Cl)=CN=CC=2Cl)[CH2:12][CH2:11]1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH:10]1([CH2:13][O:14][C:15]2[C:16]([O:35][CH3:36])=[CH:17][CH:18]=[C:19]3[C:24]=2[NH:23][C:22](=[O:25])[CH:21]=[C:20]3[NH:26][C:2]2[C:7]([CH3:8])=[CH:6][N:5]=[CH:4][C:3]=2[CH3:9])[CH2:11][CH2:12]1

참가 물질

6

반응물 3

HCID 223232464-Bromo-3,5-dimethylpyridineHCID 23676156Sodium t-butoxideHCID 248519118-(Cyclopropylmethoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

생성물 1

HCID 236492908-(cyclopropylmethoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

시약·촉매·용매 2

HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 1140Toluene용매

반응 조건

온도
110 °C

실험 절차

A solution of 4-bromo-3,5-dimethylpyridine (1.16 g, 6.21 mmol) and degassed toluene (5 mL) was added to a mixture of 4-amino-8-(cyclopropylmethoxy)-7-methoxyquinolin-2(1H)-one (1.94 g, 7.45 mmol, intermediate for Example 3), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), (0.28 g, 0.31 mmol), 2,2-dicyclohexylphosphorane triisopropylbiphenyl (0.59 g, 1.24 mmol), sodium tert-butoxide (1.20 g, 12.4 mmol), and degassed toluene (20 mL) under N2. The mixture was heated at 110° C. for 2 h, allowed to cool to room temperature, sonicated until the solids broke up, and then filtered through Celite with ethyl acetate (500 mL). The filtrate was concentrated, purified by silica gel chromatography (0→8% methanol/dichloromethane), and then re-purified by reverse-phase HPLC (25→100% acetonitrile/H2O) to give 8-(cyclopropylmethoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one: 1H NMR (400 MHz, DMSO-d6): δ 9.64 (s, 1H), 8.43 (s, 1H), 8.42 (s, 2H), 7.89 (d, 1H), 7.03 (d, 1H), 4.54 (s, 1H), 3.91 (s, 3H), 3.85 (d, 2H), 2.15 (s, 6H), 1.28 (m, 1H), 0.47 (m, 2H), 0.28 (m, 2H); MS (ESI): 365.8.

후처리

  1. customdegassed toluene (20 mL) under N2
  2. temperatureto cool to room temperature
  3. customsonicated until the solids
  4. filtrationfiltered through Celite with ethyl acetate (500 mL)
  5. concentrationThe filtrate was concentrated
  6. custompurified by silica gel chromatography (0→8% methanol/dichloromethane)
  7. customre-purified by reverse-phase HPLC (25→100% acetonitrile/H2O)

출처 및 근거

ORD 기록
ord-1b9ca662985849afa2be363c23d93d77
출처 데이터셋
uspto-grants-2012_03
특허 번호
US08138205B2

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