Phosgene → HCID 118098763, compound

HRID 708893Notes

Reaction equation

HRID 708893 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:52]([CH:55]2[CH2:57][CH2:56]2)(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][C:34]=2[F:35])[C:31]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:30][CH:29]=[CH:28]3)[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:58](Cl)(Cl)=[O:59]>C(#N)C.ClCCl>[C:39]([O:38][C:37]([N:36]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[S:52]([CH:55]4[CH2:56][CH2:57]4)(=[O:54])=[O:53])[NH:1][C:58](=[O:59])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:23])=[C:34]([F:35])[CH:33]=2)[CH:28]=[CH:29][N:30]=1)[C:44](=[O:45])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:43])([CH3:41])([CH3:40])[CH3:42]

Participants

5

Reactant 2

HCID 6371PhosgeneHCID 118098762HCID 118098762, compound

Product 1

HCID 118098763HCID 118098763, compoundYield 42.9%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 26A (80 mg, 0.099 mmol) in acetonitrile (6 mL) and dichloromethane (3 mL) at 0° C., was added phosgene solution (20% in toluene, 0.063 mL, 0.119 mmol) dropwise. The mixture was stirred at 0° C. for 40 min, then at rt for 30 min. Extra phosgene was removed by bubbling Ar though the reaction mixture (30 min). The mixture was added dropwise via syringe pump into a solution of TEA (0.111 mL, 0.794 mmol) in dichloromethane (40 ml) at rt over 3.0 h. The solution was stirred at rt overnight, quenched with 0.5 N HCl, extracted with CH2Cl2. The organic layer was washed with water and dried over sodium sulfate, then concentrated. The crude residue was purified by flash chromatography (30-100% EtOAc/hexanes) to give a mixture of diastereoisomers (70 mg, 0.084 mmol, 85% yield). The diastereomers were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm) to give 26B (30 mg, 0.036 mmol, 42.9% yield). MS (ESI) m/z: [M+1]+. 19F NMR (376 MHz, CDCl3) d ppm −128.71 (s, 1F).

Workup

  1. waitat rt for 30 min
  2. customExtra phosgene was removed
  3. customby bubbling Ar though the reaction mixture (30 min)
  4. stirringThe solution was stirred at rt overnight
  5. customquenched with 0.5 N HCl
  6. extractionextracted with CH2Cl2
  7. washThe organic layer was washed with water
  8. dry with materialdried over sodium sulfate
  9. concentrationconcentrated
  10. customThe crude residue was purified by flash chromatography (30-100% EtOAc/hexanes)
  11. customto give
  12. additiona mixture of diastereoisomers (70 mg, 0.084 mmol, 85% yield)
  13. customThe diastereomers were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm)

Sources & evidence

ORD record
ord-01cd5e95e1e6481ba89becaf498a1263
Source dataset
uspto-grants-2015_11
Patent number
US09174974B2

Reaction notes

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