Phosgene → HCID 131733860, compound

HRID 708819Notes

Reaction equation

HRID 708819 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:52]([CH2:55][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:57](Cl)(Cl)=[O:58]>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]([CH2:55][CH3:56])(=[O:54])=[O:53])[NH:1][C:57](=[O:58])[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 118098690HCID 118098690, compound

Product 1

HCID 131733860HCID 131733860, compoundYield 63.9%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 3D (303 mg, 0.382 mmol) in acetonitrile (7 mL) and dichloromethane (4 mL) at 0° C., was added phosgene solution (20% in toluene) (0.241 mL, 0.458 mmol) dropwise. The mixture was stirred at 0° C. for 40 min, then at rt for 10 min while extra phosgene was removed by bubbling Ar. The resulting solution was added dropwise via syringe pump into a solution of TEA (0.426 mL, 3.05 mmol) in dichloromethane (120 mL) at rt over 3.0 h. The solution was stirred at rt for additional 45 min. Solvent was removed and the crude was purified by prep HPLC to give a mixture of diastereoisomer (237 mg). The diastereoisomers were separated by chiral HPLC ((R,R)-Whelk-01 250×21.1 mm column) to give 3E (100 mg, 63.9% yield). MS (ESI) m/z: 820 [M+1]+; 1H NMR (400 MHz, chloroform-d) δ ppm 1.29-1.41 (m, 24H) 2.21 (s, 3H) 3.18-3.33 (m, 2H) 3.33-3.39 (m, 3H) 3.38-3.48 (m, 1H) 3.95 (dd, J=10.77, 4.17 Hz, 1H) 4.28 (d, J=17.58 Hz, 1H) 4.67 (t, J=11.21 Hz, 1H) 5.43 (d, J=5.71 Hz, 1H) 5.65 (d, J=17.58 Hz, 1H) 6.39-6.48 (m, 2H) 6.63 (s, 1H) 6.76 (d, J=8.35 Hz, 1H) 6.85 (s, 1H) 7.03 (d, J=9.23 Hz, 1H) 7.08 (s, 1H) 7.50 (d, J=7.91 Hz, 1H) 7.56-7.65 (m, 2H) 7.85 (d, J=8.35 Hz, 1H) 8.05 (s, 1H). 19F NMR (376 MHz, chloroform-d) δ ppm −141.30 (br. s., 1F).

Workup

  1. customat rt for 10 min while extra phosgene was removed
  2. customby bubbling Ar
  3. stirringThe solution was stirred at rt for additional 45 min
  4. customSolvent was removed
  5. customthe crude was purified by prep HPLC
  6. customto give
  7. additiona mixture of diastereoisomer (237 mg)
  8. customThe diastereoisomers were separated by chiral HPLC ((R,R)-Whelk-01 250×21.1 mm column)

Sources & evidence

ORD record
ord-2b8b3c5ee0f5468ab9598ac7cfe4152f
Source dataset
uspto-grants-2015_11
Patent number
US09174974B2

Reaction notes

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