Phosgene → HCID 118098701, compound

HRID 708831Notes

Reaction equation

HRID 708831 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:52]([CH:55]([CH3:57])[CH3:56])(=[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]([CH3:57])[CH3:56])(=[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])([CH3:41])([CH3:39])[CH3:40]

Participants

5

Reactant 2

HCID 6371PhosgeneHCID 118098699HCID 118098699, compound

Product 1

HCID 118098701HCID 118098701, compoundYield 32.7%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 8C (228 mg, 0.282 mmol) in acetonitrile (10 mL) and dichloromethane (5 mL) at 0° C., was added phosgene solution (20% in toluene) (0.178 mL, 0.339 mmol) dropwise. The mixture was stirred at 0° C. for 20 min, then at rt for 15 min. The extra phosgene was removed by bubbling Ar though the reaction mixture (15 min). The resulting solution was added dropwise via syringe pump into a stirred solution of TEA (0.315 mL, 2.258 mmol) in dichloromethane (80 ml) at rt over 3.0 h. The reaction was quenched by 0.5 N HCl and extracted with CH2Cl2. The organic layer was collected, washed with water and dried over sodium sulfate, then concentrated. The crude product was purified by flash chromatography to give a mixture of diastereoisomers (235 mg). The diastereomers (165 mg) were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm) to give 8D (54 mg, 0.065 mmol, 32.7% yield). MS (ESI) m/z: 883 [M+1]+. 1H NMR (400 MHz, chloroform-d) δ ppm 1.26 (d, J=6.59 Hz, 3H) 1.28-1.37 (m, 21H) 1.42 (d, J=6.59 Hz, 3H) 2.09 (s, 3H) 3.27-3.42 (m, 5H) 3.90 (dd, J=10.77, 3.73 Hz, 1H) 4.30 (d, J=17.58 Hz, 1H) 4.63 (t, J=10.99 Hz, 1H) 5.43 (d, J=5.71 Hz, 1H) 5.68 (d, J=18.02 Hz, 1H) 6.36 (s, 1H) 6.55 (d, J=5.71 Hz, 1H) 6.75 (d, J=8.35 Hz, 1H) 6.86 (s, 1H) 7.01 (d, J=9.23 Hz, 1H) 7.04-7.12 (m, 2H) 7.45-7.54 (m, 2H) 7.61 (d, J=7.91 Hz, 1H) 7.77 (d, J=8.35 Hz, 1H) 8.03 (s, 1H). 19F NMR (376 MHz, chloroform-d) δ ppm −141.12 (br. s., 1F).

Workup

  1. waitat rt for 15 min
  2. customThe extra phosgene was removed
  3. customby bubbling Ar though the reaction mixture (15 min)
  4. customThe reaction was quenched by 0.5 N HCl
  5. extractionextracted with CH2Cl2
  6. customThe organic layer was collected
  7. washwashed with water
  8. dry with materialdried over sodium sulfate
  9. concentrationconcentrated
  10. customThe crude product was purified by flash chromatography
  11. customto give
  12. additiona mixture of diastereoisomers (235 mg)
  13. customThe diastereomers (165 mg) were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm)

Sources & evidence

ORD record
ord-4c6a61c05e834bc1962622a833791a3e
Source dataset
uspto-grants-2015_11
Patent number
US09174974B2

Reaction notes

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