Water → Tert-butyl (3-((5-fluoro-2-((4-(2-((2-methoxyethoxy)methoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)(methyl)carbamate

HRID 1482716Notes

Reaction equation

HRID 1482716 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=2)[C:5]([F:24])=[CH:4][N:3]=1.[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30][O:31][CH2:32][CH2:33][O:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1>[F:24][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([NH:39][C:38]2[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][O:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH3:25])=[CH:41][CH:40]=2)=[N:3][CH:4]=1

Participants

6

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 86724363Tert-butyl (3-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)(methyl)carbamateHCID 867243654-(2-((2-Methoxyethoxy)methoxy)ethoxy)aniline

Product 1

HCID 86724364Tert-butyl (3-((5-fluoro-2-((4-(2-((2-methoxyethoxy)methoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)(methyl)carbamateYield 57.5%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

In a 25 ml 3-Neck RBF, tert-butyl (3-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)(methyl)carbamate (0.88 g), 4-(2-((2-methoxyethoxy)methoxy)ethoxy)aniline (0.901 g), Cs2CO3 (1.21 g) and Xantphose (0.144 g) were added in degassed 1,4-dioxane (10 mL) and the reaction mixture was degassed under argon for 30 minutes. Palladium(II)acetate (0.055 g) was added to reaction mixture and again it was degassed for 30 minutes. The reaction mixture was heated to 80° C. and stirred for 3.5 h. The reaction was monitored on TLC using CHCl3:methanol (9.5:0.5) as mobile phase. After completion of the reaction, reaction mixture was allowed to cool at room temperature. The reaction mixture was poured into water and product was extracted with ethyl acetate (3×25 ml). Ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. Crude material was purified by using Combiflash chromatography. Product was eluted with 2% methanol in CHCl3 to give 0.8 g of tert-butyl (3-((5-fluoro-2-((4-(2-((2-methoxyethoxy)methoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)(methyl)carbamate. M+1=557.9.

Workup

  1. customthe reaction mixture was degassed under argon for 30 minutes
  2. additionPalladium(II)acetate (0.055 g) was added to reaction mixture and again it
  3. customwas degassed for 30 minutes
  4. customAfter completion of the reaction, reaction mixture
  5. temperatureto cool at room temperature
  6. extractionwas extracted with ethyl acetate (3×25 ml)
  7. washEthyl acetate layer was washed with brine solution
  8. dry with materialdried over sodium sulfate
  9. concentrationconcentrated under reduced pressure
  10. customCrude material was purified
  11. washProduct was eluted with 2% methanol in CHCl3

Sources & evidence

ORD record
ord-b7b6ec8d757747b88b92f8a0846cb530
Source dataset
uspto-grants-2016_08
Patent number
US09415049B2

Reaction notes

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