Phosgene → HCID 131733873, compound

HRID 708882Notes

Reaction equation

HRID 708882 reaction equation
[C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:55]([C:58]([CH3:61])([CH3:60])[CH3:59])(=[O:57])=[O:56])=[C:10]([CH2:12][N:13]([CH3:54])[C:14]([CH:16]([NH:28][C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[C:35]([N:39]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[N:34][CH:33]=[CH:32]3)[C:17]2[CH:22]=[CH:21][C:20]([C@@H:23]([CH3:26])[CH2:24][OH:25])=[C:19]([CH3:27])[CH:18]=2)=[O:15])[CH:11]=1>C(#N)C.C(Cl)Cl>[C:42]([O:41][C:40]([N:39]([C:35]1[C:36]2[C:31](=[CH:30][C:29]([NH:28][CH:16]3[C:14](=[O:15])[N:13]([CH3:54])[CH2:12][C:10]4[CH:11]=[C:6]([CH:7]=[CH:8][C:9]=4[S:55]([C:58]([CH3:61])([CH3:60])[CH3:59])(=[O:57])=[O:56])[NH:5][C:1](=[O:2])[O:25][CH2:24][C@H:23]([CH3:26])[C:20]4[CH:21]=[CH:22][C:17]3=[CH:18][C:19]=4[CH3:27])=[CH:38][CH:37]=2)[CH:32]=[CH:33][N:34]=1)[C:47](=[O:48])[O:49][C:50]([CH3:52])([CH3:53])[CH3:51])=[O:46])([CH3:43])([CH3:44])[CH3:45]

Participants

5

Reactant 2

HCID 6371PhosgeneHCID 118098756HCID 118098756, compound

Product 1

HCID 131733873HCID 131733873, compoundYield 24.46%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent2×

Procedure

Phosgene (201 mg, 0.406 mmol) was added dropwise to a solution of 22D (297 mg, 0.369 mmol) in acetonitrile (4 mL)/CH2Cl2 (4 mL) at 0° C. The bath was removed and the mixture was stirred at rt for 30 min. Ar was bubbled though the solution (10 min) to remove excess phosgene. The resulting solution was added to a solution of TEA (0.257 mL, 1.847 mmol) in CH2Cl2 (40 mL) at 40° C. over 5 h via a syringe pump. The reaction was stirred at rt overnight, quenched with H2O (1 mL) and MeOH (5 mL) and then concentrated. The crude product was purified by flash chromatography to give a mixture of diastereoisomers. The diastereomers were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm) to give 22E (75 mg, 0.090 mmol, 24.46% yield). MS (ESI) m/z: 830.8 (M+H)+.

Workup

  1. customThe bath was removed
  2. customAr was bubbled though the solution (10 min)
  3. customto remove excess phosgene
  4. stirringThe reaction was stirred at rt overnight
  5. customquenched with H2O (1 mL) and MeOH (5 mL)
  6. concentrationconcentrated
  7. customThe crude product was purified by flash chromatography
  8. customto give
  9. additiona mixture of diastereoisomers
  10. customThe diastereomers were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm)

Sources & evidence

ORD record
ord-94e5275c04cb4dbe98799570670d7381
Source dataset
uspto-grants-2015_11
Patent number
US09174974B2

Reaction notes

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