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

HRID 530600Notes

Reaction equation

HRID 530600 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH: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:5]=[CH:6][CH:7]=1.ClCCl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][C:26]=1[F:34]>CCOCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[O:9][CH2:10][CH2:11][N:12]([CH2:14][C@H:15]([O:20][C:32](=[O:33])[NH:31][C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[C:26]([F:34])[CH:27]=3)[C:16]([F:18])([F:19])[F:17])[CH2:13]2)[CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 6344DichloromethaneHCID 130033651-Chloro-2-fluoro-4-isocyanato-benzeneHCID 118276730(2S)-3-(2-(3-chlorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol

Product 1

HCID 73775589(4-chloro-3-fluoro-phenyl)-carbamic acid (S)-1-[(S)-2-(3-chlorophenyl)-morpholin-4-ylmethyl]-2,2,2-trifluoro-ethyl ester hydrochlorideYield 90%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Conditions

Temperature
50 °C

Procedure

In a 50 mL round-bottom flask, (2S)-3-(2-(3-chlorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol (218 mg, 704 μmol) was combined with dichloromethane (12 ml) to give a colorless solution. TEA (71.2 mg, 98.1 μl, 704 μmol) was added. 1-Chloro-2-fluoro-4-isocyanatobenzene (157 mg, 915 μmol) was added. The reaction mixture was heated to 50° C. and stirred for 3 h and filtered. The solid was washed with dichloromethane (2×). The combined filtrate and washes were concentrated to a reduced volume and loaded onto a silica column. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 20% EtOAc in hexanes). The fractions that contained product were re-purified by flash chromatography (silica gel, 40 g, 10% to 20% (2:1 dichlormethane:EtOAc) in hexanes). The fractions from the back peak were pooled and concentrated and the resulting colorless film was dissolved in 2:1 hexanes ether and treated with 1M HCl in ether (1 mL). The resulting sticky solid was concentrated in vacuo to afford the salt, which was foamed to a white solid with ether (120 mg). The foam was triturated with ether/hexanes to afford ca. 90% pure (4-chloro-3-fluoro-phenyl)-carbamic acid (S)-1-[(S)-2-(3-chlorophenyl)-morpholin-4-ylmethyl]-2,2,2-trifluoro-ethyl ester hydrochloride. LCMS: M+1=481;

Workup

  1. customto give a colorless solution
  2. filtrationfiltered
  3. washThe solid was washed with dichloromethane (2×)
  4. concentrationThe combined filtrate and washes were concentrated to a reduced volume
  5. customThe crude material was purified by flash chromatography (silica gel, 40 g, 0% to 20% EtOAc in hexanes)
  6. customwere re-purified by flash chromatography (silica gel, 40 g, 10% to 20% (2:1 dichlormethane:EtOAc) in hexanes)
  7. concentrationconcentrated
  8. dissolutionthe resulting colorless film was dissolved in 2:1 hexanes ether
  9. additiontreated with 1M HCl in ether (1 mL)
  10. concentrationThe resulting sticky solid was concentrated in vacuo
  11. customto afford the salt, which
  12. customThe foam was triturated with ether/hexanes

Sources & evidence

ORD record
ord-547122dc4f4c4e6cb7e2263dac3c86ae
Source dataset
uspto-grants-2016_05
Patent number
US09353096B2

Reaction notes

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