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

Temperatur

35 °C

(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.

1. dissolutionto dissolve all solids
2. temperatureThe mixture was cooled to 10° C.
3. customresulting in an exotherm to 17° C
4. temperatureThe mixture was cooled to 6° C.
5. additionwas added over 28 min (constant jacket temperature of 6° C.) until the reaction mixture
6. temperatureThe mixture was heated to 15° C.
7. concentrationconcentrated to about 30% of the original volume under reduced pressure
8. customto give a 3 phase mixture, which
9. customwas re-evaporated
10. customthe mixture re-evaporated
11. customto give a suspension that
12. filtrationwas collected by filtration
13. customsucked dry on the filter
14. dry with materialThe damp product (16.27 g) was dried in a vacuum oven at 40° C.

ORD-Eintrag

ord-4d7019c9296348e18a8bb4b9f3aacd3a

Quelldatensatz

uspto-grants-2010_08

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07772403B2