Toluene → 6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-ol

HRID 1614993Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1614993
Br[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](=[O:12])([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.[CH3:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1>O.C(O)C>[N:7]1[CH:2]=[CH:3][CH:4]=[C:5]([O:8][C:27]2[CH2:26][CH2:9][O:12][N:23]=2)[CH:6]=1.[CH3:22][N:23]1[CH:27]=[C:26]([C:2]2[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH:25]=[N:24]1

Komponenten

8

Edukt 4

HCID 1140TolueneHCID 10340Sodium CarbonateHCID 27628652-Bromo-5-hydroxypyridineHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Produkt 2

HCID 581263636-(1-methyl-1H-pyrazol-4-yl)pyridin-3-olHCID 668185323-(Pyridin-3-yloxy)-4,5-dihydroisoxazole

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 702EthanolLösungsmittelHCID 962WaterLösungsmittel

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole III-70a and III-70b were prepared in 2 steps according to the following procedures: 6-bromopyridin-3-ol (1.0 equiv) and sodium carbonate (10.0 equiv) are added to a microwave vial. Toluene, ethanol, and water (0.16 M, 2:2:1 v/v) are added followed by 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 equiv). The mixture is purged with argon for 15 min followed by the addition of palladium tetrakis (4 mol %). The reaction tube is then covered with aluminum foil and heated to 80° C. in an oil bath for 17 h. After cooling the reaction was transferred to a separatory funnel with excess water and ethyl acetate. The organic layer was then washed with water (1×), saturated ammonium chloride (1×) and brine (1×). The aqueous layers were combined and washed with ethyl acetate (1×). The organic layers were then combined, dried over sodium sulfate, concentrated and purified using flash silica gel chromatography (gradient methanol/methylene chloride) to provide 6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-ol III-69 as a white solid. This compound is then reacted with racemic 3-bromo-4,5-dihydroisoxazole III-66 using Method 5 to provide the desired racemic compound III-70. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=430.0 m/z. Activity: A

Aufarbeitung

  1. customThe mixture is purged with argon for 15 min
  2. additionfollowed by the addition of palladium tetrakis (4 mol %)
  3. temperatureAfter cooling the reaction
  4. customwas transferred to a separatory funnel with excess water and ethyl acetate
  5. washThe organic layer was then washed with water (1×), saturated ammonium chloride (1×) and brine (1×)
  6. washwashed with ethyl acetate (1×)
  7. dry with materialdried over sodium sulfate
  8. concentrationconcentrated
  9. custompurified

Quellen und Nachweise

ORD-Eintrag
ord-d629c8f4c3314e208054b17e0e5a3ffe
Quelldatensatz
uspto-grants-2014_07
Patentnummer
US08765735B2

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