Triphosgene → HCID 53241010, compound

HRID 1023624Notes

Reaction equation

HRID 1023624 reaction equation
ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:15]=[N:16][C:17]([O:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([CH2:29][CH3:30])[CH:22]=2)=[N:18][CH:19]=1.Cl.[CH3:32][C:33]([C:36](OC)=[O:37])([CH3:35])[NH2:34].C[O-].[Na+]>CCOC(C)=O.CO>[CH3:32][C:33]1([CH3:35])[C:36](=[O:37])[N:13]([C:14]2[CH:15]=[N:16][C:17]([O:20][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([CH2:29][CH3:30])[CH:22]=3)=[N:18][CH:19]=2)[C:5](=[O:11])[NH:34]1

Participants

7

Reactant 4

HCID 94429TriphosgeneHCID 10942334Sodium MethoxideHCID 13258034Methyl 2-aminoisobutyrate hydrochloride2×HCID 67235928HCID 67235928, compound2×

Product 1

HCID 53241010HCID 53241010, compoundYield 46.8%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8857Ethyl AcetateSolvent3×

Conditions

Temperature
60 °C

Procedure

To a solution of triphosgene (20.8 mg, 0.07 mmol) in EtOAc (0.5 mL) at 0° C., a solution of 4-[(5-amino-2-pyrimidinyl)oxy]-2-ethylbenzonitrile (Intermediate 144, 35 mg)/TEA (0.037 mL, 0.27 mmol) in EtOAc (1.0 mL) was added dropwise under stirring. Then a solution of methyl 2-methylalaninate hydrochloride (Intermediate 107, 33.6 mg)/TEA (0.073 mL, 0.52 mmol) in 1.0 mL of EtOAc at 0° C. was slowly added and the reaction mixture was stirred at that temperature for 10 minutes. The mixture was quenched with an aqueous pH 3 buffer solution to pH 5-6 and extracted with EtOAc (three times). The collected organic were dried over Na2SO4, filtered and evaporated. The crude obtained was dissolved in MeOH (1.0 mL) and 3.0 mg (0.056 mmol) of sodium methoxide were added and the mixture was heated at 60° C. for 5 minutes. After cooling down to r.t., the mixture was evaporated, diluted with EtOAc and washed with NH4Cl (aqueous saturated solution) and the aqueous phase was extracted with EtOAc (three times). The collected organic were dried over Na2SO4, filtered and evaporated. The crude obtained was charged on a silica gel column and eluted with Cyclohexane/EtOAc (from 70:30 Cyclohexane/EtOAc to 60:40 in 20 CV, plateau at 60:40 in 20 CV) affording 11.5 mg of the title compound.

Workup

  1. stirringthe reaction mixture was stirred at that temperature for 10 minutes
  2. customThe mixture was quenched with an aqueous pH 3 buffer solution to pH 5-6
  3. extractionextracted with EtOAc (three times)
  4. dry with materialThe collected organic were dried over Na2SO4
  5. filtrationfiltered
  6. customevaporated
  7. customThe crude obtained
  8. temperatureAfter cooling down to r.t.
  9. customthe mixture was evaporated
  10. additiondiluted with EtOAc
  11. washwashed with NH4Cl (aqueous saturated solution)
  12. extractionthe aqueous phase was extracted with EtOAc (three times)
  13. dry with materialThe collected organic were dried over Na2SO4
  14. filtrationfiltered
  15. customevaporated
  16. customThe crude obtained
  17. additionwas charged on a silica gel column
  18. washeluted with Cyclohexane/EtOAc (from 70:30 Cyclohexane/EtOAc to 60:40 in 20 CV, plateau at 60:40 in 20 CV)

Sources & evidence

ORD record
ord-7e51be3a0e8c4bacba89fa2bc9cfa945
Source dataset
uspto-grants-2014_05
Patent number
US08722695B2

Reaction notes

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