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

HRID 1812234Notes

Reaction equation

HRID 1812234 reaction equation
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

Participants

8

Reactant 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

Product 1

HCID 866470665-chloro-N-(5-fluoro-6-methoxypyridin-3-yl)-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-amineYield 69.2%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
140 °C

Procedure

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)+.

Workup

  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

Sources & evidence

ORD record
ord-afe1b2ad1ad6422b8d2ee8e98f8c8e78
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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