Phosphorus pentachloride → HCID 89813529, compound

Temperature

50 °C

To a 50 mL flask containing sodium 1,2,4-thiadiazol-5-ylsulfamate (Intermediate A, 96 mg, 0.472 mmol) and 10 mL of DCM was added PCl5 (Aldrich, St. Louis, Mo., 245 mg, 1.179 mmol). The resulting slurry was heated at 50° C. for 1.5 hours. LCMS showed conversion to the methyl sulfamate (following quench into methanol). The reaction was cooled to rt and was quenched with the addition of 5 drops of brine. The resulting slurry was stirred vigorously for 5 minutes before being filtered through a plug of diatomaceous earth, washing well with DCM. The mixture was concentrated under reduced pressure. The derived oil was taken up in 1 mL of DCM and was added to a solution of 5-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride (ASW Medchem, 50 mg, 0.236 mmol) and TEA (164 μl, 1.179 mmol) in 2 mL of DCM at 0° C. Another 0.164 mL of TEA was added and the reaction allowed to warm to room temperature where it was maintained for 2 hours. LCMS showed clean conversion to sulfonamide. The reaction was allowed to stir overnight before being diluted with saturated sodium bicarbonate (10 mL) and poured into a separatory funnel containing methylenechloride (10 mL). The layers were separated and the aqueous layer was extracted with methylenechloride (2×25 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under a vacuum to provide a yellow oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (12 g), 0-10% methanol in methylenechloride) to provide 5-bromo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide as an off white solid. [M+H]+=375.0 1H NMR (400 MHz, Acetone) δ ppm 8.28 (s, 1H), 7.96 (s, 1H), 7.45-7.50 (m, 1H), 7.09-7.20 (m, 2H), 4.32 (s, 2H), 3.48 (t, J=6.1 Hz, 2H), 2.86-2.92 (m, 2H)

1. temperatureThe reaction was cooled to rt
2. customwas quenched with the addition of 5 drops of brine
3. filtrationbefore being filtered through a plug of diatomaceous earth
4. washwashing well with DCM
5. concentrationThe mixture was concentrated under reduced pressure
6. temperatureto warm to room temperature where it
7. temperaturewas maintained for 2 hours
8. stirringto stir overnight
9. additionpoured into a separatory funnel
10. customThe layers were separated
11. extractionthe aqueous layer was extracted with methylenechloride (2×25 mL)
12. washThe combined organic layers were washed with brine
13. dry with materialdried over sodium sulfate
14. filtrationfiltered
15. concentrationconcentrated under a vacuum
16. customto provide a yellow oil that
17. customwas purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (12 g), 0-10% methanol in methylenechloride)

ORD record

ord-9a3278588c144f359d06c3c56b6af4db

Source dataset

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09051311B2