Water → (R)-3-chloro-N-[1-(4-chlorophenyl)ethyl]-3-methyl-1-(trifluoromethyl)cyclobutanecarboxamide

HRID 1841626Notes

Reaction equation

HRID 1841626 reaction equation
[Cl:1][C:2]1([CH3:13])[CH2:5][C:4]([C:9]([F:12])([F:11])[F:10])([C:6]([OH:8])=O)[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([CH3:29])[NH2:28])=[CH:23][CH:22]=1.O>S(Cl)(Cl)=O.O1CCOCC1.O>[Cl:1][C:2]1([CH3:13])[CH2:3][C:4]([C:9]([F:12])([F:11])[F:10])([C:6]([NH:28][C@@H:27]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=2)[CH3:29])=[O:8])[CH2:5]1

Participants

7

Reactant 4

HCID 962WaterHCID 10340Sodium CarbonateHCID 1715226(1R)-1-(4-chlorophenyl)ethan-1-amineHCID 109219311-(Trifluoromethyl)-3-chloro-3-methylcyclobutane-1-carboxylic acid

Product 1

HCID 23550325(R)-3-chloro-N-[1-(4-chlorophenyl)ethyl]-3-methyl-1-(trifluoromethyl)cyclobutanecarboxamide

Reagents, catalysts & solvents 2

HCID 24386Thionyl ChlorideSolventHCID 218864351,4-Dioxane--water (1/1)Solvent

Conditions

Temperature
0 °C

Procedure

A solution of 0.240 g (1.11 mmol) of 3-chloro-3-methyl-1-(trifluoromethyl)cyclobutane carboxylic acid (prepared according to the method described by H. K. Hall, Jr., E. P. Blanchard Jr. and E. L Martin in Macromolecules 4(2) 142-146 (1971)) in 5 mL thionyl chloride was heated at reflux for 1 h. Solvent was removed in vacuo. The residue was added to a solution of 0.176 g (1.66 mmol) sodium carbonate and 0.172 g (1.11 mmol) (R)-4-chloro-α-methylbenzenemethanamine in 6 mL of 1:1 dioxane-water, pre-cooled to 0° C. After stirring at room temperature overnight, the mixture was poured into 50 mL water and extracted two times with 50 mL ethyl acetate (EtOAc). Drying (magnesium sulfate) and removal of the solvent gave an oil which was chromatographed on silica gel, eluting with 25% hexane-dichloromethane, to afford 43 mg of the cis isomer of the title compound: mp 129-130° C., 1H NMR (CDCl3) δ1.49 (d, 3H), 1.69 (s, 3H), 2.86-2.95 (m, 2H), 2.98-3.05 (m, 2H), 5.05-5.12 (q, 1H), 5.86 (s, 1H), 7.20 (d, 2H), 7.32 (d, 2H), and 77 mg of the trans isomer of the title compound: mp 145-146 C, 1H NMR (CDCl3) 1.54 (d, 3H), 1.74 (s, 3H), 2.79-2.86 (m, 2H), 3.13 (d, 2H), 5.14 (q, 1H), 5.85 (s, 1H), 7.23 (d, 2H), 7.31 (d, 2H).

Workup

  1. temperatureat reflux for 1 h
  2. customSolvent was removed in vacuo
  3. extractionextracted two times with 50 mL ethyl acetate (EtOAc)
  4. customDrying
  5. custom(magnesium sulfate) and removal of the solvent
  6. customgave an oil which
  7. customwas chromatographed on silica gel
  8. washeluting with 25% hexane-dichloromethane

Sources & evidence

ORD record
ord-590c6092d6c248b9a4efbf023f4a261e
Source dataset
uspto-grants-2004_01
Patent number
US06683212B1

Reaction notes

Loading…