Phosgene → HCID 118101204, compound

HRID 708839Notes

Reaction equation

HRID 708839 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([F:58])[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](=[C:33]([F:35])[CH:34]=2)[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:59](Cl)(Cl)=[O:60]>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]=[C:4]([F:58])[C:5]=4[S:52]([CH:55]4[CH2:57][CH2:56]4)(=[O:53])=[O:54])[NH:1][C:59](=[O:60])[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][C:33]=2[F:35])[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 131733863HCID 131733863, compound

Product 1

HCID 118101204HCID 118101204, compoundYield 43%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of 11F (163 mg, 0.198 mmol) in acetonitrile (3 mL) and dichloromethane (6 mL) was cooled to 0° C. To this solution was added phosgene (20% in toluene) (0.108 mL, 0.218 mmol). The mixture was stirred at 0° C. for 5 min, and rt for 1 h. The mixture was bubbled with Ar for 10 min to remove excess phosgene. The resulting solution was added dropwise over 3 h via a syringe pump into a solution of TEA (0.276 mL, 1.978 mmol) in CH2Cl2 (260 mL) at rt. The solution was stirred for 16 h. Solvent was removed and the crude product was purified by flash chromatography to give a mixture of diastereoisomers (102 mg, 60.7% yield). The diastereoisomers were separated by a prep chiral HPLC equipped with an IA column to give 11G (43 mg, 0.051 mmol, 43.0% yield). MS (ESI) m/z: 850.1 [M+1]+.

Workup

  1. waitrt for 1 h
  2. customThe mixture was bubbled with Ar for 10 min
  3. customto remove excess phosgene
  4. stirringThe solution was stirred for 16 h
  5. customSolvent was removed
  6. customthe crude product was purified by flash chromatography
  7. customto give
  8. additiona mixture of diastereoisomers (102 mg, 60.7% yield)
  9. customThe diastereoisomers were separated by a prep chiral HPLC
  10. customequipped with an IA column

Sources & evidence

ORD record
ord-5ea9a1ccc2eb41b28af75f5d401356c5
Source dataset
uspto-grants-2015_11
Patent number
US09174974B2

Reaction notes

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