Lithium Hexamethyldisilazide → 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Temperatur

-78 °C

N-(2,4-Dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (Preparation 18, 42.8 g, 170 mmol) was dissolved in anhydrous THF (600 mL) and stirred under a nitrogen atmosphere at −78° C. A 1M solution of LiHMDS in THF (238 mL, 238 mmol) was added dropwise over 30 minutes maintaining the temperature between −65° C. and −70° C. The reaction mixture was left at −78° C. for 5 minutes, then allowed to warm to −10° C. over 1.5 hours. Upon reaching −10° C., the brown reaction mixture was cooled to −78° C. again, and a solution of 3-cyano-4-fluorobenzene sulfonyl chloride (48.6 g, 221 mmol) in THF (200 mL) was added dropwise over 30 minutes maintaining the temperature between −65° C. and −70° C. The brown solution was allowed to warm gradually to ambient temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with a saturated ammonium chloride solution, and extracting with further ethyl acetate. The combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford a brown residue. The residue was purified by silica gel column chromatography (10%-30% ethyl acetate in heptane gradient elution) to afford the title compound as a white solid (52.3 g, 71%).

1. temperaturemaintaining the temperature between −65° C. and −70° C
2. temperatureto warm to −10° C. over 1.5 hours
3. customUpon reaching −10° C.
4. temperaturethe brown reaction mixture was cooled to −78° C. again
5. temperaturemaintaining the temperature between −65° C. and −70° C
6. temperatureto warm gradually to ambient temperature
7. stirringstirred overnight
8. washwashed with a saturated ammonium chloride solution
9. extractionextracting with further ethyl acetate
10. dry with materialThe combined organics were dried over MgSO4
11. filtrationfiltered
12. concentrationconcentrated in vacuo
13. customto afford a brown residue
14. customThe residue was purified by silica gel column chromatography (10%-30% ethyl acetate in heptane gradient elution)

ORD-Eintrag

ord-3668af3c47694a34a552556dad9e70d9

Quelldatensatz

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09096558B2