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

HRID 409653ノート

反応式

HRID 409653 の反応式
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]

参加物

9

反応物 5

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

生成物 1

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

試薬・触媒・溶媒 3

HCID 6344Dichloromethane溶媒HCID 13387N-methyl-2-pyrrolidone溶媒HCID 312751,4-Dioxane溶媒

実験手順

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).

後処理

  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)

出典と根拠

ORDレコード
ord-043a0c6a124540bdb2566f4e5faa3739
出典データセット
uspto-grants-2014_06
特許番号
US08759517B2

反応ノート

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