Phosgene → HCID 23630305, compound

HRID 409658Notes

Reaction equation

HRID 409658 reaction equation
[C:1](Cl)(Cl)=[O:2].[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-]=C=O.[CH3:21][NH:22][C:23]1[CH:28]=[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)[CH:31]=2)[N:26]=[CH:25][N:24]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.C1(C)C=CC=CC=1.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:1](=[O:2])[N:22]([CH3:21])[C:23]1[CH:28]=[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][N:37]3[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]3)[CH:31]=2)[N:26]=[CH:25][N:24]=1

Participants

9

Reactant 5

HCID 6371PhosgeneHCID 105034IsocyanateHCID 516892Sodium BicarbonateHCID 594862532,6-Dichloro-3,5-dimethoxyanilineHCID 69180606N-methyl-N'-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidine-4,6-diamine

Product 1

HCID 23630305HCID 23630305, compound

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Procedure

Phosgene (20% in toluene, 1 mL, 2.0 mmol, 2.4 equiv) is added to a solution of 2,6-dichloro-3,5-dimethoxyaniline (221 mg, 1.0 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-methyl-N′-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidine-4,6-diamine (Step 2.1) (259 mg, 0.83 mmol) in toluene (5 mL), at reflux and under an argon atmosphere. The reaction mixture is stirred at reflux for 3 h, allowed to cool to RT, and 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, 95:5) affords the title compound as a yellow solid: ESI-MS: 560.0/562.0 [MH]+; tR=3.26 min (purity: 99%, system 1); TLC: Rf=0.37 (DCM/MeOH+1% NH3aq, 9:1).

Workup

  1. temperatureThe mixture is heated
  2. temperatureto reflux
  3. concentrationconcentrated in vacuo
  4. temperatureat reflux and under an argon atmosphere
  5. stirringThe reaction mixture is stirred
  6. temperatureat reflux for 3 h
  7. temperatureto cool to RT
  8. customThe aqueous layer is separated
  9. extractionextracted with DCM
  10. washThe organic phase is washed with brine
  11. dry with materialdried (Na2SO4)
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customPurification of the crude product by silica gel column chromatography (DCM/MeOH+1% NH3aq, 95:5)

Sources & evidence

ORD record
ord-2173d2858cb744b7af77bde3e1d1e8f4
Source dataset
uspto-grants-2014_06
Patent number
US08759517B2

Reaction notes

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