Triphosgene → HCID 57411181, compound

HRID 527714Notes

Reaction equation

HRID 527714 reaction equation
[CH3:1][C:2]1([CH3:33])[C:6]2[C:7]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH:19][C:20]([C@H:22]([NH:25][C:26](=[O:32])OC(C)(C)C)[CH2:23][CH3:24])=[O:21])=[CH:15][N:14]=3)=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][CH2:3]1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>Cl.C(O)(C)C.C(OCC)(=O)C>[CH2:23]([C@H:22]1[NH:25][C:26](=[O:32])[N:19]([C:16]2[CH:15]=[N:14][C:13]([O:12][C:7]3[C:6]4[C:2]([CH3:33])([CH3:1])[CH2:3][O:4][C:5]=4[C:10]([CH3:11])=[CH:9][CH:8]=3)=[N:18][CH:17]=2)[C:20]1=[O:21])[CH3:24]

Participants

6

Reactant 2

HCID 94429TriphosgeneHCID 86698457HCID 86698457, compound2×

Product 1

HCID 57411181HCID 57411181, compoundYield 89.6%

Reagents, catalysts & solvents 3

HCID 313Hydrochloric AcidSolventHCID 3776IsopropanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
35 °C

Procedure

1,1-dimethylethyl {(1R)-1-[({2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}amino)carbonyl]propyl}carbamate (Intermediate 191, 213 mg, 0.47 mmol) was dissolved in HCl 5-6 N in isopropanol (1 mL) and the resulting solution was heated to 35° C. for 30 minutes. The reaction mixture was then concentrated under vacuum, the residue diluted with ethyl acetate (50 mL) and an aqueous 5% solution of K2CO3 (30 mL). Two phases were separated and the organic layer was washed with an aqueous saturated solution of ammonium chloride (30 mL), dried over Na2SO4 and concentrated under vacuum. The resulting crude was dissolved in ethyl acetate (10 mL) and triethylamine was added (0.23 mL, 1.64 mmol). The reaction mixture was cooled to 0-5° C. and a solution of triphosgene (55 mg, 0.185 mmol) in ethyl acetate (5 mL) was added drop wise in 10 minutes. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with brine dried over Na2SO4 and concentrated under vacuum. The residue was purified purified by flash chromatography on silica gel using cyclohexane/ethyl acetate 50:50 as eluent affording the title compound (161 mg) as a white solid.

Workup

  1. concentrationThe reaction mixture was then concentrated under vacuum
  2. additionthe residue diluted with ethyl acetate (50 mL)
  3. customTwo phases were separated
  4. washthe organic layer was washed with an aqueous saturated solution of ammonium chloride (30 mL)
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated under vacuum
  7. dissolutionThe resulting crude was dissolved in ethyl acetate (10 mL)
  8. additiontriethylamine was added (0.23 mL, 1.64 mmol)
  9. temperatureThe reaction mixture was cooled to 0-5° C.
  10. customThe reaction was quenched with water (50 mL)
  11. extractionextracted with ethyl acetate (50 mL)
  12. washThe organic layer was washed with brine
  13. dry with materialdried over Na2SO4
  14. concentrationconcentrated under vacuum
  15. customThe residue was purified
  16. custompurified by flash chromatography on silica gel

Sources & evidence

ORD record
ord-f90d007d8f4a436d8807194dddccfe42
Source dataset
uspto-grants-2016_05
Patent number
US09346790B2

Reaction notes

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