Cesium fluoride → N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-2-(piperidin-1-yl)pyrimidin-4-amine

HRID 1621530Notes

Reaction equation

HRID 1621530 reaction equation
I[C:2]1[C:3]([NH:14][C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:23][C:24]1[N:29]=[C:28]([S:30][CH3:31])[N:27]=[C:26]([Sn](CCCC)(CCCC)CCCC)[N:25]=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>[CH3:22][O:21][C:18]1[N:17]=[CH:16][C:15]([NH:14][C:3]2[C:2]([C:26]3[N:25]=[C:24]([CH3:23])[N:29]=[C:28]([S:30][CH3:31])[N:27]=3)=[CH:7][N:6]=[C:5]([N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[N:4]=2)=[CH:20][CH:19]=1

Participants

8

Reactant 4

HCID 25953Cesium fluorideHCID 312751,4-DioxaneHCID 601547172-Methyl-4-(methylthio)-6-(tributylstannyl)-1,3,5-triazineHCID 666003625-iodo-N-(6-methoxypyridin-3-yl)-2-(piperidin-1-yl)pyrimidin-4-amine

Product 1

HCID 66611658N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-2-(piperidin-1-yl)pyrimidin-4-amineYield 21.7%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
140 °C

Procedure

A glass microwave reaction vessel was charged with 5-iodo-N-(6-methoxypyridin-3-yl)-2-(piperidin-1-yl)pyrimidin-4-amine (161 mg, 0.391 mmol), 2-methyl-4-(methylthio)-6-(tributylstannyl)-1,3,5-triazine (168 mg, 0.391 mmol), cesium fluoride (119 mg, 0.783 mmol), copper(I) iodide (15 mg, 0.078 mmol), tetrakis(triphenylphosphine)palladium(0) (45.2 mg, 0.039 mmol) and 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 EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an orange solid. The crude product was purified by silica gel chromatography eluting with 40% EtOAc/Hexanes to give N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-2-(piperidin-1-yl)pyrimidin-4-amine (36 mg, 0.085 mmol, 21.66% yield). 1H NMR (300 MHz, CDCl3) δ 11.61 (s, 1H); 9.41 (s, 1H); 7.99 (d, J=8.48 Hz, 1H); 6.77 (d, J=8.77 Hz, 1H); 3.95 (s, 3H); 3.78-3.91 (m, 4H); 2.59 (s, 3H); 2.56 (s, 3H); 1.56-1.78 (m, J=2.63 Hz, 6H). m/z (ESI, +ve ion) 425.0 (M+H)+.

Workup

  1. customA glass microwave reaction vessel
  2. extractionextracted with EtOAc (2×30 mL)
  3. extractionThe organic extract
  4. washwas washed with saturated NaCl (10 mL)
  5. dry with materialdried over Na2SO4
  6. filtrationThe solution was filtered
  7. concentrationconcentrated in vacuo
  8. customto give the crude material as an orange solid
  9. customThe crude product was purified by silica gel chromatography
  10. washeluting with 40% EtOAc/Hexanes

Sources & evidence

ORD record
ord-769624fa287647078e1648e83b5c4f08
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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