Acetic Acid → (4S)-(4-methyl-2,5-dioxoimidazolidin-4-yl)methanesulphonyl chloride

Participants

Reaction Conditions

Reaction Steps

(5S)-5-[(Tert-butylthio)methyl]-5-methylimidazolidine-2,4-dione (WO 03/106689) (1.00 eq, 56.9 mmol, 12.3 g) was charged to a 250 mL jacketed vessel followed by acetic acid (1.72 mol, 98.4 mL, 103 g) and water (683 mmol, 12.3 mL, 12.3 g). The resulting mixture was stirred at 300 rpm and heated to 35° C. to dissolve all solids. The mixture was cooled to 10° C. and a solution of hydrogen peroxide, 11.68M, 35% w/w in water (56.9 mmol, 4.87 mL, 5.53 g) was charged as one portion, resulting in an exotherm to 17° C. Analysis of the reaction mixture by hplc 48 min after the addition of peroxide revealed conversion to a diastereoisomeric mixture of sulfoxides along with 4.6 area % of starting material remaining. The mixture was cooled to 6° C., stirred at 400 rpm and chlorine gas (159 mmol, 3.57 L at STP, 2.80 eq) was added over 28 min (constant jacket temperature of 6° C.) until the reaction mixture turned green and a sharp decrease in temperature of the reaction mixture was noted. HPLC analysis of the mixture at this point revealed complete conversion of the sulfoxide intermediates to the required sulfonyl chloride. The mixture was heated to 15° C., discharged from the vessel and concentrated to about 30% of the original volume under reduced pressure. Toluene (577 mmol, 61.5 mL, 53.2 g) was then charged to give a 3 phase mixture, which was re-evaporated. Further toluene (798 mmol, 85.0 mL, 73.5 g) was added and the mixture re-evaporated. Iso-hexane (464 mmol, 61.5 mL, 40.0 g) was then added to the sticky residue to give a suspension that was collected by filtration, washed with iso-hexane (371 mmol, 49.2 mL, 32.0 g) and sucked dry on the filter. The damp product (16.27 g) was dried in a vacuum oven at 40° C. to give [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride as a white crystalline solid (0.868 eq, 49.4 mmol, 11.2 g) in 87% yield.

Provenance & Evidence