Cesium fluoride → 1-(5-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-YL)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-YL)ethanone

HRID 1812208Notes

Reaction equation

HRID 1812208 reaction equation
Cl[C:2]1[CH:3]=[C:4]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:16][CH3:17])=[C:13]([F:15])[CH:14]=2)=[N:6][CH:7]=1.[F-].[Cs+].[O:46]1CCO[CH2:48][CH2:47]1.C([Sn](CCCC)(CCCC)C(OCC)=C)CCC>CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:25]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:20]2[N:21]=[C:22]([CH3:24])[N:23]=[C:18]([C:4]3[CH:3]=[C:2]([C:47](=[O:46])[CH3:48])[CH:7]=[N:6][C:5]=3[NH:8][C:9]3[CH:10]=[N:11][C:12]([O:16][CH3:17])=[C:13]([F:15])[CH:14]=3)[N:19]=2)=[CH:28][CH:29]=1

Participants

6

Reactant 4

HCID 25953Cesium fluorideHCID 312751,4-DioxaneHCID 619414Stannane, tributyl(1-ethoxyethenyl)-HCID 666111934-(5-chloro-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

Product 1

HCID 666002411-(5-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-YL)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-YL)ethanone

Reagents, catalysts & solvents 1

HCID 86647063palladium(II) acetate 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenylCatalyst

Conditions

Temperature
110 °C

Procedure

A stirred mixture of 4-(5-chloro-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 313, Step 2; 0.6020 g, 1.000 mmol), X-Phos-Pd(OAc)2 re-milled mix (1:1, 0.070 g, 0.100 mmol), and cesium fluoride (0.129 mL, 3.50 mmol) in 1,4-dioxane (5.00 mL, 58.5 mmol) was treated with tributyl(1-ethoxyvinyl)stannane (0.507 mL, 1.500 mmol) under nitrogen. The mixture was sealed and heated at 110° C. for 16 h. The reaction mixture was then cooled to room temperature and passed through a short plug of Celite® (diatomaceous earth). The filter cake was washed with EtOAc (3×20 mL) and the combined filtrates were concentrated in vacuo. The residue was loaded onto a short column of silica gel, tin byproducts were eluted with DCM, and the desired product was then eluted with 5% MeOH/DCM to give a mixture of desired product and a small amount of dechlorinated product. Chromatographic purification of this mixture (silica gel, 0% to 30% EtOAc/hexanes) gave 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (0.482 g, 0.791 mmol, 79% yield) as a light yellow solid. m/z (ESI, positive ion) 610 (M+H)+.

Workup

  1. customre-milled
  2. customThe mixture was sealed
  3. temperatureThe reaction mixture was then cooled to room temperature
  4. washThe filter cake was washed with EtOAc (3×20 mL)
  5. concentrationthe combined filtrates were concentrated in vacuo
  6. washwere eluted with DCM
  7. washthe desired product was then eluted with 5% MeOH/DCM
  8. customto give

Sources & evidence

ORD record
ord-f9d38114d36544799f4600a134f6fca8
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

Loading…