4-Methylmorpholine → HCID 86589102, compound

Temperature

25 °C

A three-necked round bottom flask equipped with a thermocouple, a nitrogen inlet, and a mechanical stirrer was charged with (R)-3-[N-(1-hydroxymethyl-2-phenylethyl)amino]methyl]-4-nitrobenzenecarbonitrile (25 g, 0.08 moles), THF (20 ml), and N-methyl morpholine (NMM) (17.8 mL, 2.0 eq). To this mixture was added N,O-bis(trimethylsilyl)acetamide (BSA) (15 mL, 0.75 eq). The reaction mixture was stirred for 30–45 min at a temperature of 20 to 30° C.; then, a solution of 2-thienylsulfonyl chloride (23.0 g, 1.5 eq) in THF (5 mL) was added with stirring while holding the reaction mixture in the same temperature range for 8 h to 16 h until the reaction was judged to be sufficiently complete by HPLC analysis. THF (200 mL), MTBE (200 mL), and water (80 mL) were added sequentially and the reaction mixture was stirred for 10–15 min before separating the phases. The organic phase was washed with water and any remaining THF solvent was exchanged for methanol through repeatedly removing portions of the THF by distillation at ambient pressure and adding fresh methanol. The cycles were reiterated until the volume of the solution was approximately 125 mL and the solvent exchange was judged to be sufficiently complete by HPLC analysis. The reaction product was crystallized by cooling the methanol solution to 20–25° C. and stirring for at least 2 h. The crystals were removed by filtration, washed with cold methanol, and dried in a vacuum oven (25 inches at 40° to 50° C.) to yield (R)-N-[5-cyano-2-nitrophenyl) methyl]-N-[(1-hydroxymethyl)-2-phenylethyl]thiophene-2-sulfonamide (30.4 g, 83.0% yield).

1. customA three-necked round bottom flask equipped with a thermocouple, a nitrogen inlet, and a mechanical stirrer
2. stirringwith stirring
3. customfor 8 h to 16 h
4. stirringthe reaction mixture was stirred for 10–15 min
5. custombefore separating the phases
6. washThe organic phase was washed with water
7. distillationany remaining THF solvent was exchanged for methanol through repeatedly removing portions of the THF by distillation at ambient pressure
8. additionadding fresh methanol
9. customThe reaction product was crystallized
10. temperatureby cooling the methanol solution to 20–25° C.
11. stirringstirring for at least 2 h
12. customThe crystals were removed by filtration
13. washwashed with cold methanol
14. customdried in a vacuum oven (25 inches at 40° to 50° C.)

ORD record

ord-1c5a13dd0dcf440dbcd2da5397634bd9

Source dataset

uspto-grants-2006_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07074921B2