Chloroacetyl chloride → (R)-4-Benzyl-5-oxo-3-morpholinecarboxylic Acid

Participants

Reaction Conditions

Reaction Steps

A 300 gallon hastelloy reactor was charged with N-benzyl-D-serine (50.0 kg) followed by the addition of tetrahydrofuran (THF, 271.2 kg). This solution was then cooled to 0° C. and a potassium carbonate (53.1 kg) solution in water (152.5 L) was added in one portion while maintain the temperature between −5° C. and 5° C. The temperature was adjusted back to 0° C. and then chloroacetyl chloride (40.2 kg) was added portion wise over 1 h while keeping the temperature below 4° C. The mixture was stirred for 30 min between 0-4° C. and another portion of chloroacetyl chloride (4.4 kg) was added in one portion. Stirring was continued for and additional 30 min at 0-4° C. A 50% aqueous sodium hydroxide (82.0 kg) solution was added over 50 min while keeping the reaction temperature below 10° C. A final pH endpoint of 13-13.5 should be obtained. After the addition is complete, the solution was cooled to 3-5° C. and stirred at this temperature for 4 h. After determining the reaction was complete (HPLC), it was warmed to 20-22° C. and heptane (75.0 kg) was added and vigorously stirred. The basic aqueous layer was collected, the heptane was removed, and the aqueous layer was placed back into the reactor. The basic aqueous solution was washed once again with heptane (107.8 kg) and placed back into the reactor where it was cooled to 3° C. and then adjusted down to <pH 2.0 by portion wise addition of 12N HCl (193.8 kg) over 1-1.5 h, while keeping the temperature <6° C. After the acid addition was complete, the white solid suspension was cooled to 3-5° C., stirred for an additional 2 h, and then filtered. The cake was then rinsed with cold (3-5° C.) water (50.0 L), pulled dry, and then placed under vacuum at 55-60° C. until the LOD is <0.6% giving the title compound (54.9 kg, 91.2% yield) as a white solid. 1H NMR (DMSO-d6) δ 7.37-7.24 (m, 5H), 5.25 (d, J=15.4 Hz, 1H), 4.17 (m, 2H), 4.12 (m 1H), 3.94 (dd, J=5.6, 3.2 Hz, 1H), 3.92 (dd, J=16.8, 3.2 Hz, 1H), 3.82 (d, J=15.4 Hz, 1H).

Provenance & Evidence