Ammonium Chloride → 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

Temperature

15 °C

N-(2,4-Dimethoxybenzyl)-1,3,4-thiadiazol-2-amine (Preparation 248, 203.4 g, 0.809 moles) was dissolved in 2-methyltetrahydrofuran (1.63 L) and the yellow suspension was cooled to −38° C. to −45° C. Lithium bis(trimethylsilyl)amide (890 mL of 1 molar solution in tetrahydrofuran, 0.890 moles) was added slowly over 15 minutes keeping the temperature between −38° C. and −45° C. to give an orange suspension. This orange suspension was stirred at −38° C. to −45° C. for 45 minutes and then a solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride, (200 g, 0.809 moles) in 2-methyltetrahydrofuran (407 mL) was added slowly over 20 minutes keeping the temperature between −38° C. and −45° C. to give an orange suspension. The mixture was stirred whist warming to 15° C. over 1 hour. The reaction was quenched by adding a solution of ammonium chloride (203.4 g, 3.80 moles) in water (1.02 L) and stirred vigorously for 5 minutes. The stirring was stopped and the phases allowed to separate. The lower layer was removed and the organic layer was washed with water (813.6 mL). The organic layer was concentrated in vacuo to give an orange solid which was triturated with isopropyl acetate (1.22 L) to give the title compound as a yellow-orange solid (218.6 g).

1. temperaturethe yellow suspension was cooled to −38° C. to −45° C
2. customthe temperature between −38° C. and −45° C.
3. customto give an orange suspension
4. customthe temperature between −38° C. and −45° C.
5. customto give an orange suspension
6. stirringThe mixture was stirred whist
7. customThe reaction was quenched
8. stirringstirred vigorously for 5 minutes
9. customto separate
10. customThe lower layer was removed
11. washthe organic layer was washed with water (813.6 mL)
12. concentrationThe organic layer was concentrated in vacuo
13. customto give an orange solid which
14. customwas triturated with isopropyl acetate (1.22 L)

ORD record

ord-e9ef8fdc7ee343efa8059b5f3757afb2

Source dataset

uspto-grants-2013_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08541588B2