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

HRID 530618Notes

Reaction equation

HRID 530618 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.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][C:33]=1[F:41]>ClCCl>[F:23][C:2]([F:1])([F:22])[C@@H:3]([O:21][C:39](=[O:40])[NH:38][C:35]1[CH:36]=[CH:37][C:32]([Cl:31])=[C:33]([F:41])[CH:34]=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

5

Reactant 3

HCID 8471TriethylamineHCID 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 73775311(4-Chloro-3-fluorophenyl)-carbamic acid (S)-2,2,2-trifluoro-1-[(R)-2-(6-trifluoromethyl-pyridin-3-yl)-morpholin-4-ylmethyl]-ethyl ester

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. Triethylamine (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 gradient). Mixed fractions were purified by flash chromatography (silica gel, 80 g, 5% to 20% EtOAc in hexanes gradient). Fractions from both columns that contained pure front-running product were concentrated, dissolved in ether and treated with 1M HCl in ether to form the HCl salt. The salt came out as a sticky semisolid, which turned yellow. The resulting residue was taken up in dichloromethane and free-based by washing with saturated NaHCO3. The aqueous phase was extracted 3 times with dichloromethane. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 20% to 30% EtOAc in hexanes gradient) to afford (4-chloro-3-fluorophenyl)-carbamic acid (S)-2,2,2-trifluoro-1-[(R)-2-(6-trifluoromethyl-pyridin-3-yl)-morpholin-4-ylmethyl]-ethyl ester (146 mg) as a white foam. (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 gradient)
  5. customMixed fractions were purified by flash chromatography (silica gel, 80 g, 5% to 20% EtOAc in hexanes gradient)
  6. concentrationwere concentrated
  7. dissolutiondissolved in ether
  8. additiontreated with 1M HCl in ether

Sources & evidence

ORD record
ord-d3361e5529e84c52bae652116f61c2ad
Source dataset
uspto-grants-2016_05
Patent number
US09353096B2

Reaction notes

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