4-Chlorophenyl Isocyanate → HCID 117886091, compound

HRID 530613Notes

Reaction equation

HRID 530613 reaction equation
[F:1][C:2]([F:23])([F:22])[C@@H:3]([OH:21])[CH2:4][N:5]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH2:6]1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(#N)C>[F:23][C:2]([F:1])([F:22])[C@@H:3]([O:21][C:32](=[O:33])[NH:31][C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1)[CH2:4][N:5]1[CH2:10][CH2:9][S:8](=[O:11])(=[O:12])[C@H:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH2:6]1

Participants

4

Reactant 2

HCID 76934-Chlorophenyl Isocyanate3×HCID 118276756HCID 118276756, compound

Product 1

HCID 117886091HCID 117886091, compoundYield 13.7%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
85 °C

Procedure

In a 25 mL round-bottom flask, (S)-1,1,1-trifluoro-3-[2-(3-methoxyphenyl)-1,1-dioxo-1λ6-thiomorpholin-4-yl]-propan-2-ol (234 mg, 662 μmol) was combined with acetonitrile (5.00 ml) to give a colorless solution. 1-chloro-4-isocyanatobenzene (102 mg, 662 μmol) was added. The reaction mixture was warmed at 85° C. for 3 h, resulting in only a trace of product. Heating was continued at reflux overnight. The reaction was 50% complete by LCMS. An additional 60 mg of 1-chloro-4-isocyanatobenzene was added and the reaction mixture was heated at reflux for overnight. Reaction was not complete. Another 50 mg starting 1-chloro-4-isocyanatobenzene was added and the reaction mixture was stirred at reflux for 10 h. Reaction was complete by LCMS. The reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 5% to 30% EtOAc in hexanes gradient). The front end fractions of the product peak that was isolated from the column, that contained mostly one pure epimer (as determined by LCMS) were pooled to afford (4-chlorophenyl)-carbamic acid (S)-2,2,2-trifluoro-1-[(R)-2-(3-methoxyphenyl)-1,1-dioxo-1λ6-thiomorpholin-4-ylmethyl]-ethyl ester (46 mg) as a white foam. The absolute configuration was assigned based on analogy to Examples 1, 2, 11 and 12. (M+H)+=507 m/e.

Workup

  1. customto give a colorless solution
  2. customresulting in only a trace of product
  3. temperatureHeating
  4. temperatureat reflux overnight
  5. temperaturethe reaction mixture was heated
  6. temperatureat reflux for overnight
  7. customReaction
  8. additionwas added
  9. temperatureat reflux for 10 h
  10. customReaction
  11. concentrationThe reaction mixture was concentrated in vacuo
  12. customThe crude material was purified by flash chromatography (silica gel, 40 g, 5% to 30% EtOAc in hexanes gradient)
  13. customThe front end fractions of the product peak that was isolated from the column, that

Sources & evidence

ORD record
ord-cd987c8251ff4f0283a347dae622a8c0
Source dataset
uspto-grants-2016_05
Patent number
US09353096B2

Reaction notes

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