Phosgene → HCID 131733868, compound

HRID 708871Notes

Reaction equation

HRID 708871 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][CH:34]=2)[C:31]([N:35]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N:30][CH:29]=[C:28]3[F:50])[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:38]([O:37][C:36]([N:35]([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])=[CH:34][CH:33]=2)[C:28]([F:50])=[CH:29][N:30]=1)[C:43](=[O:44])[O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:42])([CH3:40])([CH3:39])[CH3:41]

Participants

5

Reactant 2

HCID 6371PhosgeneHCID 131733869HCID 131733869, compound

Product 1

HCID 131733868HCID 131733868, compoundYield 34.5%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent3×

Conditions

Temperature
0 °C

Procedure

To a solution of 19A (135 mg, 0.168 mmol) in acetonitrile (6 mL) and dichloromethane (3 mL) at 0° C., was added phosgene solution (20% in toluene, 0.106 mL, 0.201 mmol) dropwise. The mixture was stirred at 0° C. for 40 min, then at rt for 10 min. Extra phosgene was removed by bubbling Ar for 20 min. The crude was redissolved in acetonitrile (1.0 mL) and dichloromethane (1.0 mL), and was added dropwise via syringe pump into a solution of TEA (0.187 mL, 1.340 mmol) in dichloromethane (60 mL) at rt over 3.0 h. The solution was stirred at rt over night. The solvent was removed and the crude residue was purified using a prep HPLC equipped with a C18 PHENOMENEX® Luna Axia column (30 mm×75 cm, 5μ). The desired fractions were collected and concentrated to give a mixture of diastereoisomers (114 mg). The diastereoisomers were separated by a prep chiral HPLC [(R,R)-Whelk-01 250×21.1 mm column] to give 19B (48 mg, 0.058 mmol, 34.4% yield). MS (ESI) m/z: 832.6 (M+H)+.

Workup

  1. waitat rt for 10 min
  2. customExtra phosgene was removed
  3. customby bubbling Ar for 20 min
  4. dissolutionThe crude was redissolved in acetonitrile (1.0 mL)
  5. stirringThe solution was stirred at rt over night
  6. customThe solvent was removed
  7. customthe crude residue was purified
  8. customequipped with a C18 PHENOMENEX® Luna Axia column (30 mm×75 cm, 5μ)
  9. customThe desired fractions were collected
  10. concentrationconcentrated
  11. customto give
  12. additiona mixture of diastereoisomers (114 mg)
  13. customThe diastereoisomers were separated by a prep chiral HPLC [(R,R)-Whelk-01 250×21.1 mm column]

Sources & evidence

ORD record
ord-39bc7675cad5429e9ccc55c99f8eff26
Source dataset
uspto-grants-2015_11
Patent number
US09174974B2

Reaction notes

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