Nitrogen → 3-(3-chloro-4-((1-(4-chloro-3-fluorophenyl)-2-methylpropan-2-yl)amino)phenyl)-2,6-dimethylpyrimidin-4(3H)-one

HRID 56310Notes

Reaction equation

HRID 56310 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH3:21])([CH3:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1.C[Al](C)C.N#N.FC1C=C(C=CC=1)O[CH2:33][C:34]([NH:36]/[C:37](/[CH3:43])=[CH:38]\[C:39](OC)=[O:40])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:39](=[O:40])[CH:38]=[C:37]([CH3:43])[N:36]=[C:34]2[CH3:33])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH3:21])([CH3:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1

Participants

6

Reactant 4

HCID 947NitrogenHCID 16682925Trimethylaluminum2×HCID 90022556Methyl 3-(2-(3-fluorophenoxy)acetamido)crotonate2×HCID 1179660612-chloro-N1-(1-(4-chloro-3-fluorophenyl)-2-methylpropan-2-yl)benzene-1,4-diamine

Product 1

HCID 900223713-(3-chloro-4-((1-(4-chloro-3-fluorophenyl)-2-methylpropan-2-yl)amino)phenyl)-2,6-dimethylpyrimidin-4(3H)-oneYield 33.7%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent3×

Procedure

To a solution of 2-chloro-N1-(1-(4-chloro-3-fluorophenyl)-2-methylpropan-2-yl)benzene-1,4-diamine (408 mg, 1.25 mmol) in toluene (15 mL) was added trimethylaluminium (2.5 mL, 5.00 mmol, 2.0 M in toluene) dropwise under N2 and the mixture was stirred at rt for 30 min after addition was completed. A solution of (Z)-methyl 3-(2-(3-fluorophenoxy)acetamido)but-2-enoate (295 mg, 1.88 mmol) in toluene (5 mL) was added slowly and the resulting mixture was stirred at rt for 22 h. Trimethylaluminium (2.0 mL, 4.00 mmol, 2 M in toluene) was then added dropwise and the mixture was stirred at rt for 30 min. A solution of (Z)-methyl 3-(2-(3-fluorophenoxy)acetamido)but-2-enoate (295 mg, 1.88 mmol) in toluene (3 mL) was added and the mixture was stirred further for 18 h. The mixture was quenched with saturated NH4Cl aqueous solution (50 mL) and filtered and the organic phase was separated from the filtrate. The aqueous phase was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL×2), dried over anhydrous Na2SO4 (15 g) and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:3) to give the title compound as a yellow solid (183 mg, 33.7%). The compound was characterized by the following spectroscopic data:

Workup

  1. additionafter addition
  2. stirringthe resulting mixture was stirred at rt for 22 h
  3. stirringthe mixture was stirred at rt for 30 min
  4. stirringthe mixture was stirred further for 18 h
  5. customThe mixture was quenched with saturated NH4Cl aqueous solution (50 mL)
  6. filtrationfiltered
  7. customthe organic phase was separated from the filtrate
  8. extractionThe aqueous phase was extracted with EtOAc (30 mL×3)
  9. washThe combined organic layers were washed with brine (30 mL×2)
  10. dry with materialdried over anhydrous Na2SO4 (15 g)
  11. concentrationconcentrated in vacuo
  12. customThe residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:3)

Sources & evidence

ORD record
ord-038ed3ba5fb04478b5c5d615d9c72808
Source dataset
uspto-grants-2016_09
Patent number
US09434695B2

Reaction notes

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