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

HRID 530598Notes

Reaction equation

HRID 530598 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.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]>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:39](=[O:40])[NH:38][C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[C:33]([F:41])[CH:34]=3)[C:16]([F:18])([F:19])[F:17])[CH2:13]2)[CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 4

HCID 6344DichloromethaneHCID 8471TriethylamineHCID 130033651-Chloro-2-fluoro-4-isocyanato-benzeneHCID 118276730(2S)-3-(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 58.7%

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. triethylamine (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 gradient). The fractions that contained product were re-purified by flash chromatography (silica gel, 40 g, 10% to 20% (2:1 dichlormethane:EtOAc) in hexanes gradient). The front peak was collected and pooled and concentrated in vacuo. TLC corresponded to the free base of (4-chloro-3-fluoro-phenyl)-carbamic acid (S)-1-[(R)-2-(3-chlorophenyl)-morpholin-4-ylmethyl]-2,2,2-trifluoro-ethyl ester hydrochloride prepared in Example 6. 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 to give 107 mg of (4-chloro-3-fluoro-phenyl)-carbamic acid (S)-1-[(R)-2-(3-chlorophenyl)-morpholin-4-ylmethyl]-2,2,2-trifluoro-ethyl ester hydrochloride. LCMS: M+1=481; 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.83 (br. s., 1H) 3.03 (br. s., 1H) 3.16 (br. s., 1H) 3.48 (t, J=6.99 Hz, 1H) 3.68 (br. s., 2H) 4.21 (d, J=11.71 Hz, 1H) 4.52 (br. s., 1H) 5.61 (br. s., 1H) 5.71 (br. s., 1H) 7.17 (d, J=7.55 Hz, 1H) 7.29-7.45 (m, 5H) 7.50 (d, J=10.58 Hz, 1H) 8.83 (br. s., 1H).

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 gradient)
  6. customwere re-purified by flash chromatography (silica gel, 40 g, 10% to 20% (2:1 dichlormethane:EtOAc) in hexanes gradient)
  7. customThe front peak was collected
  8. concentrationconcentrated in vacuo
  9. dissolutionThe resulting colorless film was dissolved in 2:1 hexanes ether
  10. additiontreated with 1M HCl in ether (1 mL)
  11. concentrationThe resulting sticky solid was concentrated in vacuo
  12. customto afford the salt, which

Sources & evidence

ORD record
ord-b76dff50195a41a1936ebda15ee9a1d5
Source dataset
uspto-grants-2016_05
Patent number
US09353096B2

Reaction notes

Loading…