Cesium fluoride → 5-chloro-N-(5-fluoro-6-methoxypyridin-3-yl)-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-amine

HRID 1621826Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1621826
Br[C:2]1[C:3]([NH:9][C:10]2[CH:11]=[N:12][C:13]([O:17][CH3:18])=[C:14]([F:16])[CH:15]=2)=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:19][C:20]1[N:25]=[C:24]([S:26][CH3:27])[CH:23]=[C:22]([Sn](CCCC)(CCCC)CCCC)[N:21]=1.[F-].[Cs+]>O1CCOCC1.O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:6]1[N:7]=[C:2]([C:22]2[CH:23]=[C:24]([S:26][CH3:27])[N:25]=[C:20]([CH3:19])[N:21]=2)[C:3]([NH:9][C:10]2[CH:11]=[N:12][C:13]([O:17][CH3:18])=[C:14]([F:16])[CH:15]=2)=[N:4][CH:5]=1

Komponenten

8

Edukt 3

HCID 25953Cesium fluorideHCID 595482802-Methyl-4-(methylthio)-6-(tributylstannyl)pyrimidineHCID 866470653-bromo-5-chloro-N-(5-fluoro-6-methoxypyridin-3-yl)pyrazin-2-amine

Produkt 1

HCID 866470665-chloro-N-(5-fluoro-6-methoxypyridin-3-yl)-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-amineAusbeute 69,2 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)KatalysatorHCID 178418397HCID 178418397, VerbindungKatalysatorHCID 962WaterLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
140 °C

Versuchsvorschrift

A glass microwave reaction vessel was charged with 3-bromo-5-chloro-N-(5-fluoro-6-methoxypyridin-3-yl)pyrazin-2-amine (216 mg, 0.648 mmol,), 2-methyl-4-(methylthio)-6-(tributylstannyl)pyrimidine (334 mg, 0.777 mmol), copper (I) iodide (25 mg, 0.130 mmol, Aldrich, St. Louis, Mo.), cesium fluoride (197 mg, 1.295 mmol, Alfa Aesar) and tetrakis(triphenylphosphine)palladium (74.8 mg, 0.065 mmol, Strem) in dioxane (3 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 30 min. The reaction mixture was diluted with water (5 mL) and extracted with CH2Cl2 (2×30 mL). The combined organic extracts were washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was purified by silica gel chromatography, eluting with 5% EtOAc/CH2Cl2 to give 5-chloro-N-(5-fluoro-6-methoxypyridin-3-yl)-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-amine (176 mg, 0.448 mmol, 69.2% yield). 1H NMR (300 MHz, CDCl3) δ 2.63 (s, 3H) 2.79 (s, 3H) 4.04 (s, 3H) 8.01-8.29 (m, 4H) 12.45 (s, 1H). m/z (ESI, +ve ion) 393.0 (M+H)+.

Aufarbeitung

  1. customA glass microwave reaction vessel
  2. extractionextracted with CH2Cl2 (2×30 mL)
  3. washThe combined organic extracts were washed with saturated NaCl (5 mL)
  4. dry with materialdried over Na2SO4
  5. filtrationThe solution was filtered
  6. concentrationconcentrated in vacuo
  7. customto give the crude material as a yellow solid
  8. customThe crude product was purified by silica gel chromatography
  9. washeluting with 5% EtOAc/CH2Cl2

Quellen und Nachweise

ORD-Eintrag
ord-7cf778fd20434d6bb297d7397f8452ee
Quelldatensatz
uspto-grants-2014_07
Patentnummer
US08772480B2

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