Phosgene → HCID 118101218, compound

HRID 708905Notes

Reaction equation

HRID 708905 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](=[CH:33][C:34]=2[F:35])[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[CH2:56][CH2:57]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])=[C:34]([F:35])[CH:33]=2)[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 118098772HCID 118098772, compound

Product 1

HCID 118101218HCID 118101218, compoundYield 46.3%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of 29A (133 mg, 0.161 mmol) in acetonitrile (3 mL) and dichloromethane (6 mL) was cooled to 0° C. To this solution was added phosgene (20% in toluene, 0.088 mL, 0.178 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 (0.225 mL, 1.614 mmol) in CH2Cl2 (260 mL). The solution was stirred for 16 h, concentrated and purified by flash chromatography to give a mixture of diastereoisomers (96 mg, 0.113 mmol, 70.0% yield). The diastereoisomers were separated by a prep chiral HPLC equipped with a IA column to give 29B (44 mg, 0.052 mmol, 46.3% yield). MS (ESI) m/z: 850.2 [M+1]+. 1H NMR (500 MHz, methanol-d4) δ ppm 8.09 (1H, d, J=5.8 Hz), 7.77 (1H, d, J=7.7 Hz), 7.53 (1H, d, J=6.1 Hz), 7.50 (1H, d, J=8.0 Hz), 7.42 (1H, d, J=11.8 Hz), 7.00-7.09 (2H, m), 6.61 (2H, dd, J=12.1, 1.9 Hz), 6.24 (1H, s), 5.76 (1H, d, J=17.9 Hz), 5.72 (1H, t, J=2.9 Hz), 4.62 (1H, t, J=11.1 Hz), 4.21 (1H, d, J=17.9 Hz), 3.96 (1H, dd, J=10.6, 4.3 Hz), 3.47 (1H, ddd, J=11.4, 7.0, 4.4 Hz), 3.32-3.38 (3H, m), 2.97 (1H, dd, J=4.8, 3.2 Hz), 2.22-2.33 (3H, m), 1.25-1.37 (24H, m), 1.03-1.13 (2H, m).

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. concentrationconcentrated
  6. custompurified by flash chromatography
  7. customto give
  8. additiona mixture of diastereoisomers (96 mg, 0.113 mmol, 70.0% yield)
  9. customThe diastereoisomers were separated by a prep chiral HPLC
  10. customequipped with a IA column

Sources & evidence

ORD record
ord-b697d75e50ba458397c4cd87300d9ffb
Source dataset
uspto-grants-2015_11
Patent number
US09174974B2

Reaction notes

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