Diphosgene → HCID 57582930, compound

HRID 227159Notes

Reaction equation

HRID 227159 reaction equation
[NH2:1][C@H:2]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33](=[O:49])[N:34]([CH2:42][CH2:43][O:44][Si](C)(C)C)[CH2:35][CH2:36][O:37][Si](C)(C)C)=[CH:27][CH:26]=1)[C:3]([NH:5][C@H:6]([C:15]1[NH:19][C:18]2[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:17]=2[N:16]=1)[C@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:4].[O:50]=[C:51](Cl)OC(Cl)(Cl)Cl>>[OH:37][CH2:36][CH2:35][N:34]([CH2:42][CH2:43][OH:44])[C:33](=[O:49])[CH2:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C@@H:2]2[C:3](=[O:4])[N:5]([C@H:6]([C:15]3[NH:19][C:18]4[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:17]=4[N:16]=3)[C@H:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:8])[C:51](=[O:50])[NH:1]2)=[CH:26][CH:27]=1

Participants

3

Reactant 2

HCID 10426DiphosgeneHCID 66815277HCID 66815277, compound

Product 1

HCID 57582930HCID 57582930, compoundYield 27.7%

Procedure

After cyclization of (R)-2-amino-2-(4-{[bis-(2-trimethylsilanyloxy-ethyl)-carbamoyl]-methoxy}-phenyl)-N-[(1S,2S)-1-(6-iodo-1H-benzoimidazol-2-yl)-2-phenyl-propyl]-acetamide with diphosgene was complete and the reaction mixture had been partitioned between ethyl acetate and ice/water (as described in example 1, step 1-G) 1N aqueous hydrochloric acid (20 mL) was added to the ethyl acetate extracts and the mixture was stirred at ambient temperature for 15 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL) and washed with brine (50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by gradient flash chromatography using silica gel eluted with from 0 to 10% v/v methanol in dichloromethane. The product containing fractions were combined and concentrated to give a solid which was triturated with a 1:1 v/v mixture of dichloromethane/ether (1 mL). The suspension was stirred for 1 hour then filtered and dried to give N,N-bis-(2-hydroxy-ethyl)-2-(4-{(R)-1-[(1S,2S)-1-(6-iodo-1H-benzoimidazol-2-yl)-2-phenyl-propyl]-2,5-dioxo-imidazolidin-4-yl}-phenoxy)-acetamide (30 mg, 27.7%).

Workup

  1. customthe reaction mixture had been partitioned between ethyl acetate and ice/water (as described in example 1, step 1-G) 1N aqueous hydrochloric acid (20 mL)
  2. additionwas added to the ethyl acetate extracts
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted with ethyl acetate (2×50 mL)
  5. washwashed with brine (50 mL)
  6. dry with materialThe combined organic layers were dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude product was purified by gradient flash chromatography
  10. washeluted with from 0 to 10% v/v methanol in dichloromethane
  11. additionThe product containing fractions
  12. concentrationconcentrated
  13. customto give a solid which
  14. customwas triturated with a 1:1 v/v mixture of dichloromethane/ether (1 mL)
  15. stirringThe suspension was stirred for 1 hour
  16. filtrationthen filtered
  17. customdried

Sources & evidence

ORD record
ord-fb6d91d9d08b43c3bf547ddaae170ead
Source dataset
uspto-grants-2009_07
Patent number
US07557221B2

Reaction notes

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