Phosgene → HCID 118098732, compound

HRID 708862Notes

Reaction equation

HRID 708862 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:53]([CH:56]2[CH2:58][CH2:57]2)(=[O:55])=[O:54])=[C:6]([CH2:8][N:9]([CH3:52])[C:10]([CH:12]([NH:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[C:33]([N:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[N:32][CH:31]=[CH:30]3)[C:13]2[CH:18]=[CH:17][C:16]([C@H:19]([CH2:23][OH:24])[CH:20]([F:22])[F:21])=[C:15]([CH3:25])[CH:14]=2)=[O:11])[CH:7]=1.[C:59](Cl)(Cl)=[O:60]>C(#N)C.ClCCl>[C:40]([O:39][C:38]([N:37]([C:33]1[C:34]2[C:29](=[CH:28][C:27]([NH:26][C@H:12]3[C:10](=[O:11])[N:9]([CH3:52])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[S:53]([CH:56]4[CH2:57][CH2:58]4)(=[O:54])=[O:55])[NH:1][C:59](=[O:60])[O:24][CH2:23][C@H:19]([CH:20]([F:21])[F:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:25])=[CH:36][CH:35]=2)[CH:30]=[CH:31][N:32]=1)[C:45](=[O:46])[O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:44])([CH3:43])([CH3:42])[CH3:41]

Participants

5

Reactant 2

HCID 6371PhosgeneHCID 118098733HCID 118098733, compound

Product 1

HCID 118098732HCID 118098732, compoundYield 48%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 16K (0.144 g, 0.175 mmol) in acetonitrile (5 mL) and dichloromethane (2.5 mL) at 0° C. was added phosgene solution (20% in toluene, 0.101 mL, 0.192 mmol) dropwise. The mixture was stirred at 0° C. for 30 min. Extra phosgene was removed by bubbling Ar for 20 min. The resulting solution was added dropwise via syringe pump into a solution of TEA (0.195 mL, 1.398 mmol) in dichloromethane (60 mL) at rt over 3.0 h. The reaction mixture was stirred at rt over night. The solvent was removed and the crude product was purified by flash chromatography (0-80% ethyl acetate/hexanes). The desired fractions were collected, concentrated to give a mixture of diastereoisomers (0.12 g, 0.141 mmol, 81% yield). The diastereoisomers were separated using a prep chiral HPLC equipped with a Whelko-01 column to give 16L (34 mg, 48% yield). MS (ESI) (m/z): 850.0 (M+H)+.

Workup

  1. customExtra phosgene was removed
  2. customby bubbling Ar for 20 min
  3. stirringThe reaction mixture was stirred at rt over night
  4. customThe solvent was removed
  5. customthe crude product was purified by flash chromatography (0-80% ethyl acetate/hexanes)
  6. customThe desired fractions were collected
  7. concentrationconcentrated
  8. customto give
  9. additiona mixture of diastereoisomers (0.12 g, 0.141 mmol, 81% yield)
  10. customThe diastereoisomers were separated
  11. customequipped with a Whelko-01 column

Sources & evidence

ORD record
ord-4632b09d36b94cc89fe723837124d24f
Source dataset
uspto-grants-2015_11
Patent number
US09174974B2

Reaction notes

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