Diphosgene → HCID 16722197, compound

HRID 1433747Notes

Reaction equation

HRID 1433747 reaction equation
[O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.C1(C)C=CC=CC=1.O1CCCC1.[NH2:21][C@H:22]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)[C:23]([NH:25][C@@H:26]([C@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:38])[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=1)=[O:28])=[O:24].C(N(CC)C(C)C)(C)C>O1CCCC1.O>[Br:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27](=[O:28])[C@@H:26]([N:25]2[C:23](=[O:24])[C@@H:22]([C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=3)[NH:21][C:2]2=[O:1])[C@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])=[CH:31][CH:32]=1

Participants

7

Reactant 4

HCID 10426DiphosgeneHCID 81531DiisopropylethylamineHCID 22635083Tetrahydrofuran tolueneHCID 69008784HCID 69008784, compound

Product 1

HCID 16722197HCID 16722197, compoundYield 98%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of diphosgene (20 μL, 0.17 mmol) in 1:1 v/v toluene/tetrahydrofuran (16 mL total) at −35° C. under an atmosphere of dry argon was added a solution of (2S,3S)-2-[(R)-2-amino-2-(4-methoxy-phenyl)-acetylamino]-N-(4-bromo-phenyl)-3-phenyl-butyramide (120 mg, 0.24 mmol) and N,N-diisopropylethylamine (210 μL, 1.2 mmol) in tetrahydrofuran (8 mL) dropwise with stirring over 10 minutes. After an additional 45 minutes ice was added and the reaction mixture stirred vigorously and warmed to ambient temperature. The reaction mixture was poured into water, extracted with ethyl acetate (twice) and the combined organic layers were washed sequentially with water (twice), 0.1 M aqueous hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel eluted with 2:1 v/v hexanes/ethyl acetate. The isolated product was dissolved in a small volume of dichloromethane and then precipitated by dropwise addition to a vigorously stirred large volume of petroleum ether. The precipitated solid was isolated by filtration and dried in vacuo to give (2S,3S)—N-(4-bromo-phenyl)-2-[(R)-4-(4-methoxy-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-phenyl-butyramide as a colorless solid (87 mg, 69%).

Workup

  1. additionAfter an additional 45 minutes ice was added
  2. stirringthe reaction mixture stirred vigorously
  3. extractionextracted with ethyl acetate (twice) and the combined organic layers
  4. washwere washed sequentially with water (twice), 0.1 M aqueous hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and brine
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude product was purified by chromatography over silica gel
  9. washeluted with 2:1 v/v hexanes/ethyl acetate
  10. dissolutionThe isolated product was dissolved in a small volume of dichloromethane
  11. customprecipitated by dropwise addition to a vigorously stirred large volume of petroleum ether
  12. customThe precipitated solid was isolated by filtration
  13. customdried in vacuo

Sources & evidence

ORD record
ord-f3b0915d207f4cc38d08e28b64187a97
Source dataset
uspto-grants-2009_11
Patent number
US07612212B2

Reaction notes

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