Pyridine → [(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinic acid

Temperature

2.5 °C

A 1 L four-necked round-bottomed flask equipped with mechanical stirrer, addition funnel, condenser, and a thermocouple was charged with {(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinic acid ethyl ester (26.4 g, 0.056 mol), acetonitrile (200 mL) and pyridine (11.0 mL, 0.136 mol). To the resulting mixture was then added bromotrimethylsilane (15.5 mL, 0.117 mol), 15 minutes, while maintaining the temperature of the resulting mixture below about 30° C. The mixture was then stirred for an additional 15 minutes to yield a clear yellow solution, which was aged for about 2 hours. The resulting mixture was then cooled to about 0-5° C. To the mixture was then added concentrated sulfuric acid (5.4 mL) in water (90 mL), using vigorous agitation. To the resulting mixture was then added MTBE (150 mL) and the mixture aged with stirring until two homogeneous layers were obtained. The layers were separated and the organic layer was washed twice with water (45 mL) and then concentrated to yield a residue. The residue was digested with methanol (180 mL) under vigorous stirring. then concentrated to about 50% of its original volume under reduced pressure. The resulting slurry was cooled to about 0-5° C., then aged at this temperature for about 1 hours. The resulting solids were filtered, washed twice with cold methanol (18 mL), dried in a vacuum oven at 50° C., overnight, to yield the title compound as a white crystalline solid

1. customA 1 L four-necked round-bottomed flask equipped with mechanical stirrer, addition funnel, condenser
2. customto yield a clear yellow solution, which
3. waitwas aged for about 2 hours
4. stirringwith stirring until two homogeneous layers
5. customwere obtained
6. customThe layers were separated
7. washthe organic layer was washed twice with water (45 mL)
8. concentrationconcentrated
9. customto yield a residue
10. concentrationthen concentrated to about 50% of its original volume under reduced pressure
11. temperatureThe resulting slurry was cooled to about 0-5° C.
12. waitaged at this temperature for about 1 hours
13. filtrationThe resulting solids were filtered
14. washwashed twice with cold methanol (18 mL)
15. customdried in a vacuum oven at 50° C., overnight

ORD record

ord-30192975f7234e2b823bb7c360685973

Source dataset

uspto-grants-2013_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08378122B2