1-Chloro-2-fluoro-4-isocyanato-benzene → (4-Chloro-3-fluorophenyl)-carbamic acid (S)-2,2,2-trifluoro-1-[(S)-2-(6-trifluoromethyl-pyridin-3-yl)-morpholin-4-ylmethyl]-ethyl ester hydrochloride

HRID 530619Notes

Reaction equation

HRID 530619 reaction equation
[F:1][C:2]([F:23])([F:22])[C@@H:3]([OH:21])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH:7]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[CH2:6]1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][C:26]=1[F:34]>ClCCl>[ClH:24].[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])=[C:26]([F:34])[CH:27]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][C@@H:7]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=2)[CH2:6]1

Participants

4

Reactant 2

HCID 130033651-Chloro-2-fluoro-4-isocyanato-benzeneHCID 118276764(2S)-1,1,1-trifluoro-3-(2-(6-(trifluoromethyl)pyridin-3-yl)morpholino)propan-2-ol

Product 1

HCID 73775718(4-Chloro-3-fluorophenyl)-carbamic acid (S)-2,2,2-trifluoro-1-[(S)-2-(6-trifluoromethyl-pyridin-3-yl)-morpholin-4-ylmethyl]-ethyl ester hydrochloride

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
50 °C

Procedure

In a 25 mL round-bottom flask, (2S)-1,1,1-trifluoro-3-(2-(6-(trifluoromethyl)pyridin-3-yl)morpholino)propan-2-ol (384 mg, 1.12 mmol) was combined with dichloromethane (12 ml) to give a colorless solution. TEA (113 mg, 155 μl, 1.12 mmol) was added. 1-chloro-2-fluoro-4-isocyanatobenzene (211 mg, 1.23 mmol) was added. The reaction mixture was warmed at 50° C. overnight. Reaction was complete by LCMS. Two major close-running spots of similar intensity could be seen by TLC (silica 25% EtOAc in hexanes eluent), a front-running spot and a later-running spot. The crude material was purified by flash chromatography (silica gel, 80 g, 5% to 20% EtOAc in hexanes). Mixed fractions were purified by flash chromatography (silica gel, 80 g, 5% to 20% EtOAc in hexanes). Fractions from both columns that contained pure later-running product were concentrated, dissolved in ether and treated with 1M HCl in ether to form the HCl salt. The resultant salt formed a gummy solid, which was scraped on the sides of the flask to form an off-white solid. This solid was filtered and washed with ether. A portion of the product was lost during the transfer. The resultant solid was placed on the pump to afford (4-chloro-3-fluorophenyl)-carbamic acid (S)-2,2,2-trifluoro-1-[(S)-2-(6-trifluoromethyl-pyridin-3-yl)-morpholin-4-ylmethyl]-ethyl ester hydrochloride (60 mg) as an off-white solid. (M+H)+=516 m/e.

Workup

  1. customto give a colorless solution
  2. customReaction
  3. customTwo major close-running spots of similar intensity
  4. customThe crude material was purified by flash chromatography (silica gel, 80 g, 5% to 20% EtOAc in hexanes)
  5. customMixed fractions were purified by flash chromatography (silica gel, 80 g, 5% to 20% EtOAc in hexanes)
  6. concentrationwere concentrated
  7. dissolutiondissolved in ether
  8. additiontreated with 1M HCl in ether

Sources & evidence

ORD record
ord-6684d802aa254d75bb1954cbce7a3fd1
Source dataset
uspto-grants-2016_05
Patent number
US09353096B2

Reaction notes

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