Dichloromethane → (+/-)-trans-4-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexy]phenylacetamide Hydrochloride

Temperature

5 °C

To a solution of 4-trifluoromethylphenyl acetic acid (1.45 g, 7.08 mmol) in 10 mL of dry CH2Cl2 under a nitrogen atmosphere was added 1-hydroxybenzotrazole hydrate (HOBT) (0.95 g, 7.08 mmol) and stirred. The reaction mixture was cooled to 0→5° C. and added solid EDCI ([1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide HCl])(1.35 g, 7.08 mmol) and stirrat this temperature for 30 min. A solution (±) 3 (1.0 g, 5.48 mmol) in 10 mL of dry CH2Cl2 was added followed by N,N-diisopropylethylamine (Hunig's Base) (0.915 g, 7.08 mmol). The reaction mixture was stirred for 24 h while warming to the room temperature. The reaction mixture was then poured on to excess of ice-cold saturated aqueous NaHCO3 solution and stirred for 30 min. After dilution with CH2Cl2, the organic was separated washed with saturated salt solution, and dried over anhydrous Na2SO4. Removal of solvent gave a brown oil which was chromatogrphed on a silica gel column [solvent system: CH2Cl2: CH3OH: 28% NH4OH (99:1:2)] to give the desired product as free base. The hydrochloride salt was prepared from IM etherial HCl and recrystallzed from CH2Cl2: Et2O (1:1) to give (±) 5 g HCl as a cream colored solid, 0.68 g (30%); 213-215° C.; 1H NMR (200 MHz, CDCl3) δ1.02-1.47 (m, 4H), 1.52-2.22 (m, 8H), 2.75-2.90 (m, 2H), 2.94 (s, 3H), 3.07 (m, 1H), 3.37 (m, 1H), 3.62 (d, J=15.0 Hz, 1H), 3.77 (m, 1H), 4.17 (d, J=15.0 Hz, 1H), 4.57 (m, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H). Anal. Calcd for C20H27F3N2O.HCl.0.25H2O: C, 58.68; H, 7.02; N, 6.84. Found: C, 58.68; H, 6.84; N, 6.69.

1. stirringThe reaction mixture was stirred for 24 h
2. temperaturewhile warming to the room temperature
3. additionThe reaction mixture was then poured on to excess of ice-cold saturated aqueous NaHCO3 solution
4. stirringstirred for 30 min
5. customAfter dilution with CH2Cl2, the organic was separated
6. washwashed with saturated salt solution
7. dry with materialdried over anhydrous Na2SO4
8. customRemoval of solvent
9. customgave a brown oil which

ORD record

ord-e652c3bdd41d4e13bbeb16f65c688cda

Source dataset

uspto-grants-2002_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06476063B2