反应详情

To a solution of 4-[6-(4-Cyclohexyl-3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (155 mg, 0.398 mmol) in DCM (2 mL) is added trifluoroacetic acid (TFA) (4 mL). The reaction mixture is stirred at room temperature for 30 minutes and evaporated to dryness. The residue obtained is mixed with tert-butyl acrylate (76 mg, 0.6 mmol) and DIEA (193 mg, 1.49 mmol) in MeOH (4 mL) and the mixture is heated in a microwave oven at 90° C. for 30 minutes. The reaction mixture is poured into saturated aqueous NaHCO3 and extracted with EtOAc. The combined extracts are washed with brine and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (150:50:1 hexanes/EtOAc/Et3N) to give 3-{4-[6-(4-Cyclohexyl-3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-piperazin-1-yl}-propionic acid tert-butyl ester. This material is dissolved in DCM/TFA (1:1 v/v, 2 mL), and the solution is stirred at room temperature for 1 hour. After concentration, the crude product is purified by preparative RP LC-MS to give 3-{4-[6-(4-Cyclohexyl-3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-piperazin-1-yl}-propionic acid. 1H NMR (CD3OD): 1.28-1.85 (10H), 2.88 (t, J=6.2 Hz, 2H), 2.90 (m, 1H), 3.15-3.85 (8H), 3.69 (t, J=6.2 Hz, 2H), 5.42 (s, 2H), 7.38 (br, 1H), 7.57 (d, J=7 Hz, 1H), 7.65 (d, J=7 Hz, 1H), 7.71 (s, 1H), 7.91 (s, 1H), 8.05 (br, 1H); ESI-MS m/z 492.2 (MH+).

1. customevaporated to dryness
2. customThe residue obtained
3. temperaturethe mixture is heated in a microwave oven at 90° C. for 30 minutes
4. extractionextracted with EtOAc
5. washThe combined extracts are washed with brine
6. dry with materialdried over Na2SO4
7. concentrationAfter concentration
8. customthe residue is purified by silica gel chromatography (150:50:1 hexanes/EtOAc/Et3N)