反应详情

温度

23 °C

To a solution of 2-(2,5-dichlorophenyl)piperazine (316 mg, 1.369 mmol, Ark Pharm, Libertyville, Ill.) in CH2Cl2 (7.0 mL) was added 2-thiophenesulfonyl chloride (250 mg, 1.369 mmol, Sigma-Aldrich, St. Louis, Mo.) and triethylamine (572 μL, 4.11 mmol). The reaction was stirred at 23° C. for 18 h, after which time the mixture was concentrated to dryness. To this intermediate was added 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (368.3 mg, 1.369 mmol, Example 27, step 1), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) (95.8 mg, 0.734 mmol, Strem Chemical Inc, Newburyport, Mass.) tris(dibenzylideneacetone)dipalladium (0) (62.7 mg, 0.068 mmol, Strem Chemical Inc, Newburyport, Mass.), 10 mL of toluene (9.78 mL) and sodium tert-butoxide (315.7 mg, 3.28 mmol). The reaction was heated to 90° C. and stirred for 20 h. After that time, the mixture was cooled to room temperature, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (50 g of silica, 10 to 40% EtOAc in hexanes) followed by reverse-phase preparative HPLC using a Phemomenex Gemini-NX C18 110 A column (150×30 mm), eluting with 0.1% TFA in CH3CN/H2O (10% to 90% over 16.5 min) to provide 2-(4-(2-(2,5-dichlorophenyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol as a mixture of 4 isomers.

1. concentrationafter which time the mixture was concentrated to dryness
2. temperatureThe reaction was heated to 90° C.
3. stirringstirred for 20 h
4. temperatureAfter that time, the mixture was cooled to room temperature
5. filtrationfiltered
6. concentrationconcentrated
7. customThe crude material was absorbed onto a plug of silica gel
8. custompurified by silica gel chromatography (50 g of silica, 10 to 40% EtOAc in hexanes)
9. washeluting with 0.1% TFA in CH3CN/H2O (10% to 90% over 16.5 min)