Hydrochloric Acid → racemic N-cyclohexyl-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide

To 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoic acid (0.10 g, 0.43 mmol), HBTU (0.19 g, 0.51 mmol), and HOBt (0.072 g, 0.53 mmol) was added DMF (1 mL) and Hünig's base (0.18 mL, 1.0 mmol). The acid was activated by stirring at room temperature for 5 min. To the activated ester was added N-cyclopropylcyclohexylamine (0.13 g, 0.86 mmol). The reaction mixture was stirred for 1 h, poured into H2O (7 mL), acidified with 5 N HCl and extracted with CH2Cl2 (2 mL). The organic extracts were washed with 1 N NaOH (4 mL), dried with Na2SO4, and removed in vacuo. Silica gel chromatography (gradient 20 to 30% ethyl acetate in hexanes) afforded racemic N-cyclohexyl-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide. Chiral HPLC (Chiracel AD-H, isocratic 10% IPA in hexanes) afforded the early eluting R- and late eluting S-isomers,35 mg and 37 mg, respectively. S-isomer: 1H NMR (500 MHz, CDCl3) δ 0.40-0.50 (m, 2H), 0.51-0.61 (m, 2H), 1.12-1.25 (m, 1H), 1.33-1.45 (m, 2H), 1.67-1.75 (m, 2H), 1.79-1.90 (m, 7H), 1.91-2.00 (m, 1H), 2.53-2.6 (m, 1H), 2.83 (s, 1H), 4.03-4.15 (bs, 1H), 7.47 (d, J=9 Hz, 2H), 7.58 (d, J=9 Hz, 2H).

1. stirringThe reaction mixture was stirred for 1 h
2. extractionextracted with CH2Cl2 (2 mL)
3. washThe organic extracts were washed with 1 N NaOH (4 mL)
4. dry with materialdried with Na2SO4
5. customremoved in vacuo

ORD record

ord-55edbc34a029449892aab47b349e5070

Source dataset

uspto-grants-2009_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07605289B2