反应详情

温度

-20 °C

Tert-butyl 8-trifluoromethyl-2,3,4,5-tetrahydro-[1,5]benzothiazepine-5-carboxylate may be prepared in the following manner: 102 ml of a 1.5 M solution of tert-butyllithium in pentane are added dropwise over 1 hour to a solution, kept at −70° C. under argon, of 20 g of tert-butyl 4-trifluoromethylphenylcarbamate in 250 ml of anhydrous tetrahydrofuran. The mixture is stirred for 4 hours at −20° C., cooled to around −60° C., supplemented with 2.5 g of sulphur and then stirred for 45 minutes at −20° C. The mixture is cooled to around −60° C., supplemented with 15.6 g of 1-chloro-3-iodopropane, and then stirred for 16 hours at a temperature close to 20° C., heated for 7 hours under reflux, and then at a temperature close to 20° C. for 48 hours. The mixture is hydrolysed with 200 ml of distilled water and extracted twice with 180 ml of ethyl acetate in total. The combined organic extracts are dried over magnesium sulphate and concentrated to dryness under reduced pressure (2 kPa). The product is chromatographed under nitrogen pressure (150 kPa) on 450 g of 20-45 μm silica gel contained in a column 6 cm in diameter, eluting with a mixture of cyclohexane and ethyl acetate (90-10 by volume). 13 g of tert-butyl 8-trifluoromethyl-[1,5]benzothiazepine-5-carboxylate are thus obtained in the form of a pale yellow oil [1H NMR spectrum in DMSO-d6, T=300K, δ in ppm (300 Mhz): 1.50 (9H, s, (CH3)3), 1.95 (2H, m, CH2), 3.05 (2H, t, J=6 Hz, SCH2), 3.70 (2H, t, J=6 Hz, CH2Cl), 7.60 (1H, dd, J=8 and 2 Hz, arom. CH), 7.75 (1H, d, J=2 Hz, arom. CH), 7.85 (1H, d, J=8 Hz, arom. CH), 8.60 (1H, s, NHCO)].

1. temperaturecooled to around −60° C.
2. stirringstirred for 45 minutes at −20° C
3. temperatureThe mixture is cooled to around −60° C.
4. stirringstirred for 16 hours at a temperature
5. customclose to 20° C.
6. temperatureheated for 7 hours
7. temperatureunder reflux
8. customat a temperature close to 20° C. for 48 hours
9. extractionextracted twice with 180 ml of ethyl acetate in total
10. dry with materialThe combined organic extracts are dried over magnesium sulphate
11. concentrationconcentrated to dryness under reduced pressure (2 kPa)
12. customThe product is chromatographed under nitrogen pressure (150 kPa) on 450 g of 20-45 μm silica gel
13. washeluting with a mixture of cyclohexane and ethyl acetate (90-10 by volume)