Sodium Carbonate → (1S,2S)-2-fluoro-N-(7-(5-fluoro-2-(hydroxymethyl)-4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide

HRID 468949노트

반응식

HRID 468949 반응식
[F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]([NH:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13](B1OC(C)(C)C(C)(C)O1)[CH:12]=2)=[O:6].Br[C:28]1[C:29]([CH2:36][OH:37])=[N:30][CH:31]=[C:32]([F:35])[C:33]=1[CH3:34].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]([NH:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:28]1[C:29]([CH2:36][OH:37])=[N:30][CH:31]=[C:32]([F:35])[C:33]=1[CH3:34])[CH:12]=2)=[O:6]

참가 물질

7

반응물 3

HCID 10340Sodium CarbonateHCID 67974745(3-Bromo-5-fluoro-4-methyl-2-pyridyl)methanolHCID 71115194(1S,2S)-2-fluoro-N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-yl)cyclopropanecarboxamide

생성물 1

HCID 71115258(1S,2S)-2-fluoro-N-(7-(5-fluoro-2-(hydroxymethyl)-4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide수율 11%

시약·촉매·용매 3

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)촉매HCID 6342Acetonitrile용매HCID 8857Ethyl Acetate용매

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온도
130 °C

실험 절차

A mixture of (1S,2S)-2-fluoro-N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-yl)cyclopropanecarboxamide (230 mg, 0.648 mmol), (3-bromo-5-fluoro-4-methyl-2-pyridyl)methanol (143 mg, 0.648 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (46 mg, 0.065 mmol) and saturated aqueous sodium carbonate solution (0.3 mL) in acetonitrile (3 mL) was heated under microwave irradiation (Biotage) at 130° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (15 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water w/0.1% NH4OH, 14 min). Desired fractions were combined and evaporated in vacuo to afford the title compound as an off-white solid (26 mg, 11%). 1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 9.16 (s, 1H), 8.54 (s, 2H), 7.99 (m, 2H), 7.59 (d, J=8.4 Hz, 1H), 5.08-4.81 (m, 2H), 4.24 (s, 2H), 2.34-2.22 (m, 1H), 2.00 (s, 3H), 1.70 (m, 1H), 1.20 (m, 1H). LCMS (Method E): RT=6.66 min, M+H+=370.0.

후처리

  1. washwashed with water (15 mL)
  2. customThe organic layer was separated
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customto provide a residue that
  7. customwas purified by reverse phase HPLC (5-85% acetonitrile in water w/0.1% NH4OH, 14 min)
  8. customevaporated in vacuo

출처 및 근거

ORD 기록
ord-fd0cbd16bba8425ca48e2ee2af557753
출처 데이터셋
uspto-grants-2014_01
특허 번호
US08623889B2

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