Ethyl bromoacetate → Ethyl 2-(((1S,2S)-2-(hydroxymethyl)cyclohexyl)((S)-1-phenylethyl)amino)acetate

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Reaction Steps

A solution of (1S,2S)-2-[(S)-1-phenylethylamino]cyclohexyl)methanol (11, 120.9 g, 0.524 mol, 1.0 equiv. based on HCl salt 10) dissolved in acetonitrile (610 mL) was charged to a 2 L reactor, which is equipped with mechanical stirrer and thermocouple under nitrogen atmosphere. To this solution, ethyl bromoacetate (12, 104.9 g, 0.628 mol, 1.2 equiv.) and anhydrous sodium bicarbonate (57.2 g, 0.681 mol, 1.3 equiv.) were added sequentially with agitation. The contents were heated to reflux temperature for NLT 18 h with vigorous agitation under nitrogen atmosphere. Acetonitrile was distilled out under vacuum to about 300 mL volume and the mixture was cooled to less than 30° C. temperature and diluted with 327 ml, of heptanes and 423 mL of water. The contents were mixed for NLT 15 min and allowed settle to form two layers. The bottom aqueous layer was separated and further extracted with 2×327 mL of heptanes. The two heptanes extracts were combined with the organic layer in the reactor and washed sequentially with 1×327 mL of water and 1×327 mL 3.5 M aqueous sodium chloride solution. The heptanes solution was dried using anhydrous magnesium sulfate (13.5 g), filtered and concentrated under vacuum at NMT 60° C. temperature. The crude product was further dried under vacuum to afford 171.4 g of ethyl 2-(((1S,2S)-2-(hydroxymethyl)cyclohexyl)((S)-1-phenylethyl)amino) acetate (13) as 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: 23.62 min; LC-MS (m/z): 320.2 (M+H)+.

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