Phosgene → HCID 118098681, compound

HRID 708809Notes

Reaction equation

HRID 708809 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:51])=[C:6]([CH2:8][N:9]([CH3:50])[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]=[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:52](Cl)(Cl)=[O:53]>C(#N)C.ClCCl.CN1C(=O)N(C)CCC1>[Br:51][C:5]1[CH:4]=[CH:3][C:2]2=[CH:7][C:6]=1[CH2:8][N:9]([CH3:50])[C:10](=[O:11])[C@H:12]([NH:24][C:25]1[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=1)[C:31]([N:35]([C:36]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:42])[C:43](=[O:44])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[N:30][CH:29]=[CH:28]3)[C:13]1[CH:14]=[C:15]([CH3:23])[C:16]([C@@H:19]([CH3:22])[CH2:20][O:21][C:52](=[O:53])[NH:1]2)=[CH:17][CH:18]=1

Participants

6

Reactant 2

HCID 6371PhosgeneHCID 118098680HCID 118098680, compound

Product 1

HCID 118098681HCID 118098681, compoundYield 33%

Reagents, catalysts & solvents 3

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent2×HCID 816462(1H)-Pyrimidinone, tetrahydro-1,3-dimethyl-Solvent

Conditions

Temperature
0 °C

Procedure

A solution of 1A (1.173 g, 1.538 mmol) in acetonitrile (8 mL), dichloromethane (8 mL) and DMPU (0.6 mL) was cooled to 0° C. To this solution was added phosgene (20% in toluene, 0.837 mL, 1.692 mmol). The mixture was stirred at 0° C. for 15 min. and then 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 (2.144 mL, 15.38 mmol) in dichloromethane (400 mL) at 40° C. The yellow solution was stirred for an additional 30 min. Reaction mixture was concentrated, suspended in EtOAc (250 mL), washed with water (2×200 mL), brine (1×100 ml) and dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified by Isco: (40 g) 50-100% EtOAc/hexanes. Fractions were combined and concentrated under reduced pressure to give product as a mixture of diastereomers. The diastereoisomers were separated by chiral HPLC (Chiral OD 10 um 4.6×250 mm; sol. A heptane; sol. B 50% MeOH-50% EtOH) to give 1B (0.200 g, 0.254 mmol, 33.0% yield): MS (ESI) m/z: 788.1 [M+1]+; Purity 95%; 1H NMR: (400 MHz, CD3OD) δ ppm 8.04 (1H, d, J=5.50 Hz), 7.68 (1H, d, J=6.05 Hz), 7.60 (1H, d, J=9.34 Hz), 7.51 (1H, d, J=6.05 Hz), 7.46 (1H, d, J=7.70 Hz), 7.40 (1H, d, J=8.24 Hz), 7.27 (1H, dd, J=8.79, 2.20 Hz), 7.22 (1H, s), 6.87 (1H, d, J=2.20 Hz), 6.63 (1H, dd, J=8.52, 2.47 Hz), 5.99 (1H, d, J=2.20 Hz), 5.71 (1H, s), 5.35 (1H, d, J=17.04 Hz), 4.65 (1H, t, J=11.27 Hz), 3.95 (1H, dd, J=10.99, 4.40 Hz), 3.65 (1H, s), 3.44-3.53 (1H, m), 3.34 (3H, s), 2.31 (3H, s), 1.31 (3H, d, J=7.15 Hz), 1.27 (18H, s).

Workup

  1. custombubbled with Ar for 10 min
  2. customto remove excess phosgene
  3. stirringThe yellow solution was stirred for an additional 30 min
  4. customReaction mixture
  5. concentrationwas concentrated
  6. washwashed with water (2×200 mL), brine (1×100 ml)
  7. dry with materialdried (Na2SO4)
  8. customEtOAc was removed under reduced pressure
  9. customthe residue was purified by Isco
  10. concentrationconcentrated under reduced pressure
  11. customto give product
  12. additionas a mixture of diastereomers
  13. customThe diastereoisomers were separated by chiral HPLC (Chiral OD 10 um 4.6×250 mm; sol. A heptane; sol. B 50% MeOH-50% EtOH)

Sources & evidence

ORD record
ord-7d245ba2f46b4fb6b75c495c0228c2a0
Source dataset
uspto-grants-2015_11
Patent number
US09174974B2

Reaction notes

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