Carbon Dioxide → (5-Chloro-1-benzothiophen-3-yl)[ethoxy(methyl)phosphoryl]acetic acid

Temperature

-20 °C

To a dry 4N 300 ml flask equipped with magnetic stirrer, nitrogen inlet, temperature probe and addition port was added ethyl (5-chlorobenzo[b]thiophen-3-yl)methyl(methyl)phosphinate (12.7, 43.99 mmol) and dry THF (15 mL) under nitrogen. The resulting solution was cooled to −20° C. To the mixture was then added a 40% (2.2 M) NaHMDS solution in THF (25 mL), maintaining the temperature below 10° C. Following the base addition, CO2 was bubbled cautiously until no exotherm was observed, while maintaining the temperature of the reaction mixture below 15° C. The resulting mixture was then degassed with nitrogen and NaHMDS (10 mL) was added, followed by additional CO2 bubbling. The addition of NaHMDS ad CO2 was repeated 3 more times. The resulting solution was cooled to 0° C. and MTBE (80 mL) was added. To the resulting mixture was then added, slowly, 2N HCl (20 mL), followed by 6N HCl (40 mL), at which point the pH of the mixture was measured to be about 2. Throughout the addition of the acid, the temperature of the mixture was maintained between 0 and 15° C. Initial precipitation was observed upon acidification, while on completion of the acid addition, the mixture resolved in two clear layers. The layers were split, and the organic layer evaporated to yield an oil. The oil was digested overnight with MTBE (20 mL) to yield the title compound as a filterable solid.

1. customTo a dry 4N 300 ml flask equipped with magnetic stirrer, nitrogen inlet
2. additiontemperature probe and addition port
3. temperaturemaintaining the temperature below 10° C
4. customwas bubbled cautiously until no exotherm
5. temperaturewhile maintaining the temperature of the reaction mixture below 15° C
6. customThe resulting mixture was then degassed with nitrogen and NaHMDS (10 mL)
7. additionwas added
8. additionThe addition of NaHMDS ad CO2
9. temperatureThe resulting solution was cooled to 0° C.
10. additionMTBE (80 mL) was added
11. additionTo the resulting mixture was then added
12. additionThroughout the addition of the acid
13. temperaturethe temperature of the mixture was maintained between 0 and 15° C
14. customInitial precipitation
15. additionwas observed upon acidification, while on completion of the acid addition
16. customThe layers were split
17. customthe organic layer evaporated
18. customto yield an oil

ORD record

ord-155ed65f4f70492ea26e02fbe42fb525

Source dataset

uspto-grants-2013_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08378122B2