Thiophene-3-carboxylic acid → HCID 57697743, compound

Temperature

0 °C

A 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, addition funnel and a condenser with nitrogen inlet-outlet is charged with thiophen-3-carboxylic acid (448.2 g) and tetrahydrofuran (4.7 L) and stirred to dissolution. The solution is cooled to 0° C. and diisopropylamine (245 mL) is added over 5 min. Then, a 1.6M solution of butyl lithium in hexane (4.8 L) is added over 2.5 hours while maintaining the internal temperature at 0° C. The mixture is stirred for an additional hour before being cooled to −65° C. Then 7-Chloro-2-ethoxy-benzo[d][1,3]oxazin-4-one (830 g), dissolved in tetrahydrofuran (1.7 L) is added over 1 hour. The mixture is stirred at −65° C. for 1 hour, then warmed to 0° C. over 40 min and stirred for 30 min. Then water (4 L) is added over 10 min letting the temperature be raised to 20° C. The mixture is stirred at this temperature for 16 hours before being concentrated under reduced pressure to remove the organic solvents. To the residue ethanol (11 L) and lithium hydroxide (295.5 g) are added. The mixture is heated to 60° C. over 45 min, stirred at this temperature for 3 hours, then the temperature is raised to 75° C. over 10 min and hydrochloric acid (2 L, 37% m/m) is added over 10 min under gentle reflux. The mixture is stirred for an hour at 60-65° C. The suspension is then cooled to room temperature and the solid is collected, washed 5 times with water (4.2 L total), ethanol (5 L total) and dried under vacuum (60° C., 50 mbar) to yield the title compound with a melting point of >280° C.

1. customA 4-necked, round-bottomed flask, equipped with a mechanical stirrer
2. additiondigital thermometer, addition funnel and a condenser with nitrogen inlet-outlet
3. temperaturewhile maintaining the internal temperature at 0° C
4. stirringThe mixture is stirred for an additional hour
5. temperaturebefore being cooled to −65° C
6. additionis added over 1 hour
7. stirringThe mixture is stirred at −65° C. for 1 hour
8. temperaturewarmed to 0° C. over 40 min
9. stirringstirred for 30 min
10. temperaturebe raised to 20° C
11. stirringThe mixture is stirred at this temperature for 16 hours
12. concentrationbefore being concentrated under reduced pressure
13. customto remove the organic solvents
14. additionTo the residue ethanol (11 L) and lithium hydroxide (295.5 g) are added
15. temperatureThe mixture is heated to 60° C. over 45 min
16. stirringstirred at this temperature for 3 hours
17. temperaturethe temperature is raised to 75° C. over 10 min
18. additionhydrochloric acid (2 L, 37% m/m) is added over 10 min under gentle reflux
19. stirringThe mixture is stirred for an hour at 60-65° C
20. temperatureThe suspension is then cooled to room temperature
21. customthe solid is collected
22. washwashed 5 times with water (4.2 L total), ethanol (5 L total)
23. customdried under vacuum (60° C., 50 mbar)

ORD record

ord-e6ad894d56674a0f8f670102834fae89

Source dataset

uspto-grants-2012_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08258128B2