Diisopropylethylamine → (4-chloro-3-fluoro-phenyl)-carbamic acid (S)-1-[(R)-2-(4-chloro-3-fluoro-phenyl)-morpholin-4-ylmethyl]-2,2,2-trifluoro-ethyl ester hydrochloride

HRID 530593Notes

Reaction equation

HRID 530593 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][N:12]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][O:9]2)=[CH:4][C:3]=1[F:21].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][C:24]=1[F:32].CCN(C(C)C)C(C)C>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:9][CH2:10][CH2:11][N:12]([CH2:14][C@H:15]([O:20][C:30](=[O:31])[NH:29][C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([F:32])[CH:25]=3)[C:16]([F:17])([F:18])[F:19])[CH2:13]2)=[CH:4][C:3]=1[F:21]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 130033651-Chloro-2-fluoro-4-isocyanato-benzeneHCID 117871400(S)-3-((R)-2-(4-chloro-3-fluorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol

Product 1

HCID 73775583(4-chloro-3-fluoro-phenyl)-carbamic acid (S)-1-[(R)-2-(4-chloro-3-fluoro-phenyl)-morpholin-4-ylmethyl]-2,2,2-trifluoro-ethyl ester hydrochlorideYield 119.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
60 °C

Procedure

(S)-3-((R)-2-(4-chloro-3-fluorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol (338 mg, 1.03 mmol) was combined with 1-chloro-2-fluoro-4-isocyanatobenzene (212 mg, 1.24 mmol) in 4 mL of dichloromethane. DIPEA (160 mg, 1.24 mmol) was added. The reaction tube was sealed and reaction mixture stirred at 60° C. for 5 h. TLC indicated complete consumption of the starting material. The mixture was evaporated and the residue was extracted with ether/hexanes (1:2 ratio) and water. The organic layer was washed with brine and dried. Solvents were evaporated and the residue was purified by ISCO flash column chromatography (0% to 25% ethyl acetate in hexanes gradient). The desired fraction was concentrated and dissolved in ether/hexanes (1:2 ratio) and treated with 1N HCl in ether. Solvents were evaporated the residue was triturated with ether/hexanes (1:2 ratio) and the clear top layer solution was decanted. The resultant white solid residue was dried under heated vacuum to provide (4-chloro-3-fluoro-phenyl)-carbamic acid (S)-1-[(R)-2-(4-chloro-3-fluoro-phenyl)-morpholin-4-ylmethyl]-2,2,2-trifluoro-ethyl ester hydrochloride as a white solid (330 mg). (M+H)+=499 m/e.

Workup

  1. customThe reaction tube was sealed
  2. customreaction mixture
  3. customconsumption of the starting material
  4. customThe mixture was evaporated
  5. extractionthe residue was extracted with ether/hexanes (1:2 ratio) and water
  6. washThe organic layer was washed with brine
  7. customdried
  8. customSolvents were evaporated
  9. customthe residue was purified by ISCO flash column chromatography (0% to 25% ethyl acetate in hexanes gradient)
  10. concentrationThe desired fraction was concentrated
  11. dissolutiondissolved in ether/hexanes (1:2 ratio)
  12. additiontreated with 1N HCl in ether
  13. customSolvents were evaporated the residue
  14. customwas triturated with ether/hexanes (1:2 ratio)
  15. customthe clear top layer solution was decanted
  16. customThe resultant white solid residue was dried
  17. temperatureunder heated vacuum

Sources & evidence

ORD record
ord-2129cd4130ca4c58b803d4c78da35ec5
Source dataset
uspto-grants-2016_05
Patent number
US09353096B2

Reaction notes

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