Diphosgene → (S)-2-{(R)-4-[4-(2-tert-butoxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-4,4-dimethyl-pentanoic acid (2-fluoro-4-iodo-phenyl)-amide

HRID 1433777Notes

Reaction equation

HRID 1433777 reaction equation
[O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.C1(C)C=CC=CC=1.O1CCCC1.[F:21][C:22]1[CH:27]=[C:26]([I:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30](=[O:56])[C@@H:31]([NH:37][C:38](=[O:55])[C@H:39]([NH2:54])[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[CH:42][CH:41]=1)[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34].C(N(CC)C(C)C)(C)C>O1CCCC1.O>[F:21][C:22]1[CH:27]=[C:26]([I:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30](=[O:56])[C@@H:31]([N:37]1[C:38](=[O:55])[C@@H:39]([C:40]2[CH:41]=[CH:42][C:43]([O:46][CH2:47][CH2:48][O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[CH:44][CH:45]=2)[NH:54][C:2]1=[O:1])[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34]

Participants

7

Reactant 4

HCID 10426DiphosgeneHCID 81531DiisopropylethylamineHCID 22635083Tetrahydrofuran tolueneHCID 69304181(S)-2-{(R)-2-amino-2-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetylamino-}4,4-dimethyl-pentanoic acid(2-fluoro-4-iodo-phenyl)-amide

Product 1

HCID 69303691(S)-2-{(R)-4-[4-(2-tert-butoxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-4,4-dimethyl-pentanoic acid (2-fluoro-4-iodo-phenyl)-amideYield 135.7%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of diphosgene (41 μL, 0.34 mmol) in 1:1 v/v toluene/tetrahydrofuran (18 mL total) at −35° C. under an atmosphere of dry argon was added a solution of (S)-2-{(R)-2-amino-2-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetylamino}4,4-dimethyl-pentanoic acid (2-fluoro-4-iodo-phenyl)-amide (300 mg, 0.49 mmol) and N,N-diisopropylethylamine (260 μL, 1.47 mmol) in tetrahydrofuran (9 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 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 to give (S)-2-{(R)-4-[4-(2-tert-butoxyethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}4,4-dimethylpentanoic acid (2-fluoro-4-iodo-phenyl)-amide as yellow sticky solid (295 mg, 95%) which was used in the subsequent step without further purification.

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. washwashed 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

Sources & evidence

ORD record
ord-2f50b68118034fc0b20553dc269e17bf
Source dataset
uspto-grants-2009_11
Patent number
US07612212B2

Reaction notes

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