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

HRID 1502466Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1502466
[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]

Komponenten

7

Edukt 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

Produkt 1

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

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)KatalysatorHCID 6342AcetonitrileLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
130 °C

Versuchsvorschrift

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.

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-302e7fbc50694b66ab3fdaf6ff7b5a02
Quelldatensatz
uspto-grants-2015_12
Patentnummer
US09206175B2

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