Phosgene → 1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(2-morpholin-4-yl-ethoxy)phenylamino]-pyrimidin-4-yl}-urea

HRID 409653Notes

Reaction equation

HRID 409653 reaction equation
C(Cl)(Cl)=O.[Cl:5][C:6]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([O:15][CH3:16])=[C:9]([Cl:17])[C:7]=1[NH2:8].[N-:18]=[C:19]=[O:20].[N:21]1([CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37]3[CH:42]=[C:41](N)[N:40]=[CH:39][N:38]=3)=[CH:32][CH:31]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])(O)=O.[Na+]>O1CCOCC1.CN1C(=O)CCC1.C(Cl)Cl>[Cl:5][C:6]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([O:15][CH3:16])=[C:9]([Cl:17])[C:7]=1[NH:8][C:19]([NH:18][C:41]1[CH:42]=[C:37]([NH:36][C:33]2[CH:34]=[CH:35][C:30]([O:29][CH2:28][CH2:27][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:31][CH:32]=2)[N:38]=[CH:39][N:40]=1)=[O:20]

Participants

9

Reactant 5

HCID 6371PhosgeneHCID 105034IsocyanateHCID 516892Sodium BicarbonateHCID 594862532,6-Dichloro-3,5-dimethoxyanilineHCID 59864576N-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrimidine-4,6-diamine

Product 1

HCID 236302781-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(2-morpholin-4-yl-ethoxy)phenylamino]-pyrimidin-4-yl}-urea

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 13387N-methyl-2-pyrrolidoneSolventHCID 312751,4-DioxaneSolvent

Procedure

Phosgene (20% in toluene, 0.8 mL, 1.58 mmol, 2.4 equiv) is added to a solution of 2,6-dichloro-3,5-dimethoxyaniline (175 mg, 0.79 mmol, 1.2 equiv) in dioxane (2.5 mL), under an argon atmosphere. The mixture is heated to reflux, stirred for 1 h, allowed to cool to RT, and concentrated in vacuo. The resulting isocyanate is added to a solution of N-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrimidine-4,6-diamine (208.5 mg, 0.66 mmol) in NMP (2 mL), at 75° C. and under an argon atmosphere. The reaction mixture is stirred at 75° C. for 2 h, allowed to cool to RT, and is then diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the crude product by silica gel column chromatography (DCM/MeOH+1% NH3aq, 96:4), followed by trituration of the resulting material in MeOH, affords the title compound as a white solid: ESI-MS: 562.9/564.9 [MH]+; tR=2.99 min (purity: 100%, system 1); TLC: Rf=0.36 (DCM/MeOH+1% NH3aq, 93:7).

Workup

  1. temperatureThe mixture is heated
  2. temperatureto reflux
  3. concentrationconcentrated in vacuo
  4. stirringThe reaction mixture is stirred at 75° C. for 2 h
  5. temperatureto cool to RT
  6. customThe aqueous layer is separated
  7. extractionextracted with DCM
  8. washThe organic phase is washed with brine
  9. dry with materialdried (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customPurification of the crude product by silica gel column chromatography (DCM/MeOH+1% NH3aq, 96:4)

Sources & evidence

ORD record
ord-043a0c6a124540bdb2566f4e5faa3739
Source dataset
uspto-grants-2014_06
Patent number
US08759517B2

Reaction notes

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