Diphosgene → HCID 86603395, compound

HRID 32835Notes

Reaction equation

HRID 32835 reaction equation
[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:41])[C@@H:12]([NH:21][C:22](=[O:40])[CH:23]([NH:32][C:33](OC(C)(C)C)=[O:34])[C:24]2[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=2)[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].C(N(C(C)C)CC)(C)C.O=C(Cl)OC(Cl)(Cl)Cl>FC(F)(F)C(O)=O.ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:41])[C@@H:12]([N:21]2[C:22](=[O:40])[CH:23]([C:24]3[CH:25]=[CH:26][C:27]([S:30][CH3:31])=[CH:28][CH:29]=3)[NH:32][C:33]2=[O:34])[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]

Participants

6

Reactant 3

HCID 10426DiphosgeneHCID 81531DiisopropylethylamineHCID 866033942-{(2S,3S)-2-[2-tert-butoxycarbonylamino-2-(4-methylsulfanyl-phenyl)-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester

Product 1

HCID 86603395HCID 86603395, compound

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent3×HCID 6422Trifluoroacetic acidSolvent

Procedure

2-{(2S,3S)-2-[2-tert-Butoxycarbonylamino-2-(4-methylsulfanyl-phenyl)-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (110 mg, 0.18 mmol) was dissolved at 0° C. in a 30% solution of trifluoroacetic acid in dichloromethane. After 2.5 hours the reaction mixture was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The aqueous layer was adjusted to pH=8 by the addition of solid sodium bicarbonate and then extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to an off white solid. The solid was dissolved in a solution of diisopropyl ethyl amine (0.16 mL, 0.92 mmol) in dichloromethane (5 mL) and the resulting solution was added in a dropwise manner to a 0° C. mixture of diphosgene (16 μL, 0.13 mmol) in dichloromethane (5 mL). The mixture was stirred for 20 minutes and then partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, filtered and concentrated to the crude product. After purification by chromatography over silica gel gradient eluted up to 3:2 ethyl acetate/hexanes and precipitation of the material obtained from chromatography from dichloromethane with excess hexanes, 2-{(2S,3S)-2-[4-(4-methylsulfanyl-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester, was isolated as a white amorphous solid (45 mg, 46%).

Workup

  1. customAfter 2.5 hours the reaction mixture was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate
  2. additionThe aqueous layer was adjusted to pH=8 by the addition of solid sodium bicarbonate
  3. extractionextracted twice with ethyl acetate
  4. dry with materialThe combined organic layers were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated to an off white solid
  7. additionthe resulting solution was added in a dropwise manner to a 0° C.
  8. custompartitioned between dichloromethane and water
  9. dry with materialThe organic layer was dried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated to the crude product
  12. customAfter purification by chromatography over silica gel gradient
  13. washeluted up to 3:2 ethyl acetate/hexanes and precipitation of the material

Sources & evidence

ORD record
ord-f12a3dc562ea44deb950e211fb79614d
Source dataset
uspto-grants-2008_09
Patent number
US07427635B2

Reaction notes

Loading…