反应详情

Charge (1S,2S)-ethyl 2-((S)-1-phenylethylamino)cyclohexane carboxylate hydrochloride (10, 163.5 g, 0.524 mol, 1.0 equiv.) to a 2-L reactor containing 788 mL of 10% w/v sodium carbonate solution and 327 mL of heptanes at ambient temperature. Mix the contents rapidly at 18-25° C. for NLT 30 min. During this period, the solids were dissolved and agitation was stopped for NLT 10 min to form two clear layers. Separate the phases and retain both layers. Extract the lower aqueous layer twice with 327 mL of heptanes each. Combine all heptanes extracts and wash sequentially with 327 mL of tap water then 327 mL of 3.5 M aqueous sodium chloride solution. Dry the heptanes solution with anhydrous magnesium sulfate (13.5 g), filter and concentrate under vacuum to yield 148.9 g of (1S,2S)-ethyl 2-((S)-1-phenylethyl amino)cyclohexane carboxylate (>99% yield and contains residual heptanes) free base as an oil. Charge 1154 mL of tetrahydrofuran to the free base in a clean/dry 4 L reactor flask under nitrogen at ambient temperature, which is equipped with mechanical stirrer, thermocouple, and begin agitation. At ambient temperature, charge potassium borohydride (42.4 g, 0.786 mol, 1.5 mol equiv.) followed by lithium chloride (33.3 g, 0.785 mol, 1.5 mol equiv.) under nitrogen. The reaction mixture was heated to reflux (67° C.) with agitation and continue for NLT 12 h under nitrogen atmosphere. The mixture was cooled to below 22° C. temperature and charged 1734 mL of tap water over 20 min period using an addition funnel, while maintaining the temperature at NMT 27° C. The contents were mixed for an additional 30 min at ambient temperature and allowed the layers to separate. The upper organic layer was separated and concentrated using a rotary evaporator at NMT 50° C. temperature to yield crude product (11), as viscous oil. The lower aqueous layer was extracted three times with 327 mL of heptanes each. Combined the heptanes extracts were mixed with the concentrated viscous oil and wash the combined heptanes solution was sequentially washed with 327 mL of water and 327 mL of 3.5 M aqueous sodium chloride solution. The heptanes solution was dried with anhydrous magnesium sulfate (13.5 g), filtered and concentrated using vacuum at a temperature NMT 70° C. The resulting crude product was further dried using a high vacuum pump (−0.2 mmHg) for NLT 12 h period to afforded 120.9 g of (1S,2S)-2-[(S)-1-Phenylethylamino]cyclohexyl)methanol (11) as a viscous oil, which was carried to the next step without further purification. 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: 18.39 min, 98.66% (PA); LC-MS (m/z): 234.2 (M+H)+.

1. additioncontaining 788 mL of 10%
2. customat ambient temperature
3. additionMix the contents rapidly at 18-25° C. for NLT 30 min
4. waitDuring this period
5. dissolutionthe solids were dissolved
6. customwas stopped for NLT 10 min
7. customto form two clear layers
8. customSeparate the phases
9. extractionExtract the lower aqueous layer twice with 327 mL of heptanes each
10. washCombine all heptanes extracts and wash sequentially with 327 mL of tap water
11. dry with materialDry the heptanes solution with anhydrous magnesium sulfate (13.5 g)
12. filtrationfilter
13. concentrationconcentrate under vacuum