4-Chlorophenyl Isocyanate → HCID 73442922, compound

HRID 530587Notes

Reaction equation

HRID 530587 reaction equation
[F:1][C:2]([F:24])([F:23])[C@@H:3]([OH:22])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH2:6]1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1.[N-]=C=O>C1(C)C=CC=CC=1>[F:24][C:2]([F:1])([F:23])[C@@H:3]([O:22][C:33](=[O:34])[NH:32][C:29]1[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:20])([F:21])[F:19])[CH:12]=2)[CH2:6]1

Participants

5

Reactant 3

HCID 76934-Chlorophenyl Isocyanate2×HCID 105034IsocyanateHCID 117871761HCID 117871761, compound

Product 1

HCID 73442922HCID 73442922, compound

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

(S)-1,1,1-Trifluoro-3-((R)-2-(4-fluoro-3-(trifluoromethyl)phenyl)morpholino)propan-2-ol (427 mg, 1.18 mmol) was mixed with 1-chloro-4-isocyanatobenzene (180 mg, 1.17 mmol) in toluene (5 mL). The mixture was stirred at 90° C. for 2 h. TLC indicated still significant amount of the starting material. So a second batch of 1-chloro-4-isocyanatobenzene (180 mg, 1.17 mmol) was added and the mixture was further stirred at 95° C. for 2 h. TLC indicated still significant amount of starting material. A second batch of isocyanate was added and the mixture was stirred at 90° C. for 2 h. The mixture was concentrated and the residue was extracted with ethyl acetate and water, washed with sodium bicarbonate solution and brine, dried and concentrated. The residue was purified through ISCO flash column chromatography (ethyl acetate in hexanes 0% to 40% gradient in 16 min). The desired fraction was concentrated to give (4-chlorophenyl)-carbamic acid (S)-2,2,2-trifluoro-1-[(R)-2-(4-fluoro-3-trifluoromethyl-phenyl)-morpholin-4-ylmethyl]-ethyl ester a colorless oil, which was dissolved in ether and 1N HCl in ether (1 mL) was added. Solvent was evaporated and the residue was dissolved in ether. Hexane was added and solvents were evaporated to give a white solid 241 mg. LC/MS indicated 13% des-fluoro ((M+H)+=497 m/e) and 87% desired compound ((M+H)+=515 m/e).

Workup

  1. stirringthe mixture was further stirred at 95° C. for 2 h
  2. stirringthe mixture was stirred at 90° C. for 2 h
  3. concentrationThe mixture was concentrated
  4. extractionthe residue was extracted with ethyl acetate and water
  5. washwashed with sodium bicarbonate solution and brine
  6. customdried
  7. concentrationconcentrated
  8. customThe residue was purified through ISCO flash column chromatography (ethyl acetate in hexanes 0% to 40% gradient in 16 min)
  9. concentrationThe desired fraction was concentrated

Sources & evidence

ORD record
ord-5d97651dccce4cf896542482b0c4719e
Source dataset
uspto-grants-2016_05
Patent number
US09353096B2

Reaction notes

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