反应详情

温度

3.5 °C

Isobutyric acid (1.86 L, 1.762 Kg, 20.0 mol, 20.0 equiv.) was added to a 4 L reactor under nitrogen and cooled to 2-5° C. temperature. Sodium borohydride (113.49 g, 3.0 mol, 3.0 mole equiv.) is added with agitation between 0-10° C. in NLT 2 h. The mixture warmed to 18° C. temperature and mixed for an additional NLT 15 min. The solution was cooled to −5° C. to −8° C. then the toluene solution containing the (S)-ethyl 2-(1-phenylethylamino)cyclohex-1-enecarboxylate (8, 273.37 g, 1.0 mol, 1.0 equiv.) was added over 50 min while maintaining the temperature at 0±2° C. The contents were mixed for 2 h and 40 min and quenched by the slow addition of 1 L of 4N hydrochloric acid while maintaining the temperature below 10° C. To this mixture, 2.1 L of 25 w/w % sodium hydroxide solution was added while maintaining the temperature at 5-20° C. The phases were allowed to settle and the upper layer organic was separated. The lower aqueous layer was extracted with of toluene (2×680 mL). The combined organic layers were washed sequentially with water (2×680 mL) and 3.5 M aqueous sodium chloride solution (2×680 mL). The toluene solution was then dried using anhydrous magnesium sulfate (30 g), filtered and concentrated under vacuum to afford 298.1 g of crude (1R,2S)-Ethyl 2-((S)-1-phenylethylamino)cyclohexanecarboxylate (9) free base, as an oil. The crude product was dissolved in 1.1 L of ethyl acetate in a 2 L reactor flask and cooled to −0.5° C. temperature. To this mixture, 247 mL of 30 wt. % hydrogen bromide in propionic acid was added with agitation over 1 h and 20 min, while maintaining the temperature at 0±2° C. The contents were stirred for an additional 1 h at 0° C. and the crystalline product was filtered and washed twice with 300 mL of cold (0° C.) ethyl acetate. The wet cake was dried at 45° C. temperature under vacuum for 5 h to afford 302.3 g of the desired (1R,2S)-Ethyl 2-((S)-1-phenylethylamino)cyclohexanecarboxylate hydrobromide salt (9). The dried hydrobromide salt (9,) and 2.47 L of acetonitrile was added to a 3 L reactor flask under nitrogen then heated to reflux at approximately 81-82° C. temperature. After the solids were dissolved, the clear solution was gradually cooled to 0° C. over 3 h period and held for 30 min at 0±2° C. temperature. The solids were filtered and washed with 200 mL of cold (0° C.) acetonitrile. The wet cake was dried at 40-45° C. temperature under vacuum for 18 h to afford 246.2 g of the purified (1R,2S)-Ethyl 2-((S)-1-phenylethylamino)cyclohexanecarboxylate hydrobromide salt in 69.1% yield, as a white powder. Analytical HPLC (Daicel Chiralpack AD-RH column, Size: 150×4.6 mm); 0.02 M Ammonium acetate buffer (pH: 7.7-7.8): Acetonitrile/50:50, 0.3 mL/min, Wave length: 220 nm, Column oven temperature: 55° C., Rt: 16.14 min, 99.75% (PA); 1H NMR (D2O, 400 MHz): δ 7.56-7.50 (m, 5H), 4.62 (q, 1H, J=10.4, 6.8 Hz), 4.39-4.31 (m, 1H), 4.30-4.22 (m, 1H), 3.27-3.15 (m, 2H), 2.26-2.19 (m, 1H), 1.81-1.64 (m, 3H), 1.70 (d, 3H, J=6.8 Hz), 1.57-1.39 (m, 2H), 1.33 (t, 3 H, J=7.2 Hz), 1.30-1.18 (2H); LC-MS (m/z): 276.2 (M+H)+.

1. temperatureThe mixture warmed to 18° C. temperature
2. additionmixed for an additional NLT 15 min
3. temperatureThe solution was cooled to −5° C. to −8° C.
4. additionwas added over 50 min
5. temperaturewhile maintaining the temperature at 0±2° C
6. additionThe contents were mixed for 2 h and 40 min
7. customquenched by the slow addition of 1 L of 4N hydrochloric acid
8. temperaturewhile maintaining the temperature below 10° C
9. additionTo this mixture, 2.1 L of 25 w/w % sodium hydroxide solution was added
10. temperaturewhile maintaining the temperature at 5-20° C
11. customthe upper layer organic was separated
12. extractionThe lower aqueous layer was extracted with of toluene (2×680 mL)
13. washThe combined organic layers were washed sequentially with water (2×680 mL) and 3.5 M aqueous sodium chloride solution (2×680 mL)
14. dry with materialThe toluene solution was then dried
15. filtrationfiltered
16. concentrationconcentrated under vacuum