Synthesis
The general procedure for the synthesis of (R)-4-benzyl-5-oxo-3-morpholinecarboxylic acid from (R)-2-(benzylamino)-3-hydroxypropanoic acid and chloroacetyl chloride was as follows: a 300-gallon Hastelloy reactor was charged with N-benzyl-D-serine (50.0 kg), followed by tetrahydrofuran (THF, 271.2 kg). The resulting solution was cooled to 0 °C and an aqueous solution (152.5 L) of potassium carbonate (53.1 kg) was added all at once while the temperature was controlled between -5 °C and 5 °C. The temperature was readjusted to 0 °C, followed by the addition of chloroacetyl chloride (40.2 kg) in batches over a period of 1 hour, ensuring that the temperature did not exceed 4 °C. The reaction mixture was stirred at 0-4 °C for 30 min and then another portion of chloroacetyl chloride (4.4 kg) was added in one go. Stirring was continued at 0-4°C for 30 minutes. A 50% aqueous sodium hydroxide solution (82.0 kg) was slowly added over 50 min while keeping the reaction temperature below 10 °C until the final pH reached 13-13.5. After addition, the solution was cooled to 3-5 °C and stirred at this temperature for 4 h. The reaction was then completed by HPLC. After confirming the completion of the reaction by HPLC, the mixture was warmed to 20-22°C, heptane (75.0 kg) was added and stirred vigorously. The basic aqueous layer was separated and collected, and after removing the heptane, the aqueous layer was re-poured into the reactor. The basic aqueous solution was again washed with heptane (107.8 kg) and then cooled to 30°C. Finally, 12N HCl (193.8 kg) was added in batches over a period of 1-1.5 hours for acidification.
References
[1] Patent: WO2011/23733, 2011, A1. Location in patent: Page/Page column 19-20
[2] Patent: WO2009/61879, 2009, A1. Location in patent: Page/Page column 85
[3] Patent: WO2013/82388, 2013, A1. Location in patent: Page/Page column 74-75
[4] Patent: US2008/300242, 2008, A1. Location in patent: Page/Page column 93
[5] Patent: WO2008/47109, 2008, A1. Location in patent: Page/Page column 40
