Triethylamine → ethyl 2-(((1S,2S)-2-((methylsulfonyloxy)methyl)cyclohexyl)((S)-1-phenylethyl)amino)acetate

Participants

Reaction Conditions

Reaction Steps

A solution of 167.4 g of ethyl 2-(((1S,2S)-2-(hydroxymethyl)cyclohexyl)((S)-1-phenylethyl)amino)acetate (13, 0.524 mol, 1.0 equiv. based on HCl salt 10) dissolved in 685 mL of dichloromethane was added to a 2 L reactor, which is equipped with mechanical stirrer and thermocouple under nitrogen atmosphere. To this solution, 63.8 g of triethylamine (0.629 mol, 1.2 equiv.) was added and the mixture was cooled to less than 5° C. temperature. 66 g (0.576 mol, 1.1 equiv.) of methanesulfonyl chloride was added dropwise while maintaining the temperature below 10° C. and after the addition was complete, the mixture was stirred for an additional 30 min and then warmed to approximately 20° C. temperature under nitrogen atmosphere. The reaction mixture was stirred for NLT 1 h and quenched with 261 mL of ice-water at below 25° C. temperature and mixed for NLT 15 min. The lower organic layer was separated and the upper aqueous layer was extracted with 2×135 mL of dichloromethane. The combined organic layers were washed with 3×327 mL of water, dried using anhydrous magnesium sulfate (13.5 g), filtered and concentrated on a rotary evaporator under vacuum at NMT 60° C. temperature. The resulting crude product (viscous oil) was dried over night using a high vacuum pump to afford 204.7 g of ethyl 2-(((1S,2S)-2-((methylsulfonyloxy)methyl)cyclohexyl) ((S)-1-phenylethyl)amino) acetate (14) 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: 17.23 min; LC-MS (m/z): 398.2 (M+H)+.

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