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

HRID 1621832Notes

Reaction equation

HRID 1621832 reaction equation
Br[C:2]1[C:3]([NH:9][C:10]2[CH:11]=[N:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.[F-].[Cs+].[CH3:20][C:21]1[N:26]=[C:25]([S:27][CH3:28])[CH:24]=[C:23]([Sn](CCCC)(CCCC)CCCC)[N:22]=1>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:23]2[CH:24]=[C:25]([S:27][CH3:28])[N:26]=[C:21]([CH3:20])[N:22]=2)[C:3]([NH:9][C:10]2[CH:11]=[N:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[N:4][CH:5]=1

Participants

8

Reactant 3

HCID 25953Cesium fluorideHCID 595482802-Methyl-4-(methylthio)-6-(tributylstannyl)pyrimidineHCID 866470673-bromo-5-chloro-N-(6-methoxypyridin-3-yl)pyrazin-2-amine

Product 1

HCID 866470685-chloro-N-(6-methoxypyridin-3-yl)-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-amineYield 73%

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-(6-methoxypyridin-3-yl)pyrazin-2-amine (83 mg, 0.263 mmol), copper (I) iodide (10 mg, 0.053 mmol, Aldrich), cesium fluoride (80 mg, 0.526 mmol, Alfa Aesar), tetrakis(triphenylphosphine)palladium(0) (30.4 mg, 0.026 mmol) and 2-methyl-4-(methylthio)-6-(tributylstannyl)pyrimidine (113 mg, 0.263 mmol) in dioxane (2 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 (10 mL) and extracted with CH2Cl2 (2×30 mL). The combined organic extracts were washed with saturated NaCl (10 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 10% EtOAc/hexanes to give 5-chloro-N-(6-methoxypyridin-3-yl)-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-amine (72 mg, 0.192 mmol, 73.0% yield). 1H NMR (300 MHz, CDCl3) δ 2.63 (s, 3H) 2.78 (s, 3H) 3.95 (s, 3H) 6.79 (d, J=8.77 Hz, 1H) 8.01 (dd, J=8.70, 2.12 Hz, 1H) 8.17 (d, J=5.55 Hz, 2H) 8.39 (s, 1H) 12.21 (s, 1H). m/z (ESI, +ve ion) 375.0 (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 (10 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 10% EtOAc/hexanes

Sources & evidence

ORD record
ord-04e2f6b9266347b1afa355021448cffb
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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