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

HRID 530596Notes

Reaction equation

HRID 530596 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([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:5]=[CH:6][CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[F:31]>C(#N)C>[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:29](=[O:30])[NH:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([F:31])[CH:24]=3)[C:16]([F:18])([F:19])[F:17])[CH2:13]2)[CH:5]=[CH:6][CH:7]=1

Participants

4

Reactant 2

HCID 130033651-Chloro-2-fluoro-4-isocyanato-benzeneHCID 117872579(S)-3-((R)-2-(3-chlorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol

Product 1

HCID 73775585(4-chloro-3-fluoro-phenyl)-carbamic acid (S)-1-[(R)-2-(3-chlorophenyl)-morpholin-4-ylmethyl]-2,2,2-trifluoro-ethyl ester hydrochlorideYield 112.7%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

(S)-3-((R)-2-(3-chlorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol (59.5 mg, 192 μmol), TEA (26.8 μL, 192 μmol) and 1-chloro-2-fluoro-4-isocyanatobenzene (32.9 mg, 192 μmol) were combined in 2 mL of acetonitrile and stirred at room temperature overnight. The solution was purified by reverse phase column chromatography (50-100% acetonitrile in water). The desired fractions were pooled, treated with 5 drops of conc. HCl and the solution lyophilized to afford (4-chloro-3-fluoro-phenyl)-carbamic acid (S)-1-[(R)-2-(3-chlorophenyl)-morpholin-4-ylmethyl]-2,2,2-trifluoro-ethyl ester hydrochloride (56 mg, 56%) as a white solid. (M+H)+=481 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.81 (t, J=11.14 Hz, 1H) 3.00 (t, J=10.39 Hz, 1H) 3.16 (d, J=13.22 Hz, 1H) 3.44 (d, J=11.71 Hz, 1H) 3.56-3.79 (m, 2H) 4.20 (dd, J=13.22, 3.02 Hz, 1H) 4.36-4.59 (m, 1H) 5.55 (d, J=9.82 Hz, 1H) 5.70 (d, J=3.02 Hz, 1H) 7.17 (d, J=8.69 Hz, 1H) 7.29-7.44 (m, 5H) 7.50 (dd, J=10.77, 2.08 Hz, 1H) 8.82 (br. s., 1H).

Workup

  1. customThe solution was purified by reverse phase column chromatography (50-100% acetonitrile in water)
  2. additiontreated with 5 drops of conc. HCl

Sources & evidence

ORD record
ord-5406a32832294fa68840c7e2c722c49d
Source dataset
uspto-grants-2016_05
Patent number
US09353096B2

Reaction notes

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