(S)-3,3,3-trifluoro-2-trimethylsilyloxy-2-methylpropanoyl chloride → (R)-N-(3-Acetamido-2-Chloro-4-{4-fluorophenylsulphanyl}phenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

HRID 2120354Notes

Reaction equation

HRID 2120354 reaction equation
[F:1][C:2]([F:14])([F:13])[C@@:3]([O:8][Si](C)(C)C)([CH3:7])[C:4](Cl)=[O:5].[C:15]([NH:18][C:19]1[C:20]([Cl:34])=[C:21]([CH:23]=[CH:24][C:25]=1[S:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[NH2:22])(=[O:17])[CH3:16]>C(Cl)Cl.C(N(CC)CC)C>[C:15]([NH:18][C:19]1[C:20]([Cl:34])=[C:21]([NH:22][C:4](=[O:5])[C@:3]([OH:8])([CH3:7])[C:2]([F:14])([F:13])[F:1])[CH:23]=[CH:24][C:25]=1[S:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)(=[O:17])[CH3:16]

Participants

5

Reactant 2

HCID 10586677(S)-3,3,3-trifluoro-2-trimethylsilyloxy-2-methylpropanoyl chloride2×HCID 234393893-Acetamido-2-chloro-4-(4-fluorophenylsulphanyl)aniline

Product 1

HCID 69882903(R)-N-(3-Acetamido-2-Chloro-4-{4-fluorophenylsulphanyl}phenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamideYield 57.9%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent3×HCID 8471TriethylamineSolvent2×

Procedure

A solution of (S)-3,3,3-trifluoro-2-(trimethylsilyloxy)-2-methylpropanoyl chloride (prepared from (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (Method 25) as described in J. Med. Chem., 1999, 42, 2741-2746) (1.179 g) in DCM (10 ml) was added dropwise to a stirred and ice-cooled suspension of 3-acetamido-2-chloro-4-(4-fluorophenylsulphanyl)aniline (Method 18) (1.315 g) in DCM (20 ml) and triethylamine (1.72 ml). The mixture was allowed to warm to ambient temperature overnight. More triethylamine (0.8 ml) followed by (S)-3,3,3-trifluoro-2-(trimethylsilyloxy)-2-methylpropanoyl chloride (0.6 g) in DCM (5 ml) was added. After a further 6 hours the mixture was concentrated by evaporation. MeOH (50 ml) and 2M aqueous HCl (5 ml) were added, the mixture was stirred overnight, and then diluted with water (20 ml). The MeOH was removed by evaporation and 2M aqueous HCl (30 ml) was added. The mixture was then extracted with ether (2×80 ml). The extracts were washed with brine then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a Biotage cartridge (40 g silica), eluting with 50% EtOAc/isohexane to give the title compound (1.104 g) as a foam. NMR: 1.6 (s, 3H), 2.05 (s, 3H), 7.0 (d, 1H), 7.26 (t, 2H), 7.38-7.48 (m, 2H), 7.8-7.9 (m, 2H), 9.76 (brs, 1H), 9.9 (brs, 1H); m/z: 449.

Workup

  1. temperatureice-cooled
  2. additionwas added
  3. concentrationAfter a further 6 hours the mixture was concentrated by evaporation
  4. additionMeOH (50 ml) and 2M aqueous HCl (5 ml) were added
  5. stirringthe mixture was stirred overnight
  6. additiondiluted with water (20 ml)
  7. customThe MeOH was removed by evaporation and 2M aqueous HCl (30 ml)
  8. additionwas added
  9. extractionThe mixture was then extracted with ether (2×80 ml)
  10. washThe extracts were washed with brine
  11. customthen dried
  12. customVolatile material was removed by evaporation
  13. customthe residue was purified by chromatography on a Biotage cartridge (40 g silica)
  14. washeluting with 50% EtOAc/isohexane

Sources & evidence

ORD record
ord-feb6a8fd24a346fe8a3d5a4a3c2cedf1
Source dataset
uspto-grants-2004_02
Patent number
US06689909B1

Reaction notes

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