Oxalyl chloride → HCID 11218252, compound

Temperature

50 °C

A solution of 2-chloro-4,5-difluoro-benzoic acid (15.0 kg, 99 wgt % purity, 77.1 moles, 1.00 eq) and dimethylformamide (0.2 kg, 2.73 moles, 0.04 eq) in toluene (75.9 kg) was treated with oxalyl chloride (19.8 kg, 156.0 moles, 2.02 eq) while maintaining the temperature at <25° C. over 2 hours. The mixture was heated to 50° C. and held 1 hour. At this point, HPLC indicated reaction completion. Remaining oxalyl chloride was removed by distillation, the pot temperature rising from 85 to 110° C. reflecting the removal of the lower boiling oxalyl chloride until only toluene was distilling. The cooled reaction mass (<25° C.) was transferred to another vessel that contained 25 weight % sodium methoxide in methanol (50.5 kg, 233.7 moles, 3.03 eq) in methanol (90.0 kg). The mixture was stirred overnight at 25° C. and monitored by HPLC. The methanol was removed by distillation at 50° C./150 mmHg vacuum while the volume was maintained by the addition of toluene (total of 184.6 kg added). The distillation was continued until the methanol content by GC was 1.16 v/v %. The resulting solution was washed sequentially (each first stirred for 15 minutes) with water (150.0 kg), 1.6 weight % hydrochloric acid (37.0 kg), aqueous sodium bicarbonate (1.85 kg sodium bicarbonate in 33.15 kg water), and water (35.0 kg). The washed solution was filtered through a 0.2 micron cartridge filter and the volume reduced by half by distillation at 50° C./150 mmHg vacuum. The mixture was heated to 80° C. to redissolve the solids that had appeared and heptane (68.0 kg) was added while maintaining the temperature at 70° C. The slurry was cooled to 5° C. and held overnight. The crystals were collected by filtration, washed with heptane (34.0 kg) and dried at 50° C./50 mmHg to yield 14.4 kg (85% yield) of pure 2-chloro-5-fluoro-4-methoxy-benzoic acid methyl ester product.

1. temperaturewhile maintaining the temperature at <25° C. over 2 hours
2. customreaction completion
3. customRemaining oxalyl chloride was removed by distillation
4. customrising from 85 to 110° C.
5. customthe removal of the
6. distillationwas distilling
7. customThe cooled reaction mass (<25° C.)
8. customwas transferred to another vessel
9. customThe methanol was removed by distillation at 50° C./150 mmHg vacuum while the volume
10. temperaturewas maintained by the addition of toluene (total of 184.6 kg added)
11. distillationThe distillation
12. washThe resulting solution was washed sequentially (
13. stirringeach first stirred for 15 minutes) with water (150.0 kg), 1.6 weight % hydrochloric acid (37.0 kg), aqueous sodium bicarbonate (1.85 kg sodium bicarbonate in 33.15 kg water), and water (35.0 kg)
14. filtrationThe washed solution was filtered through a 0.2 micron cartridge
15. filtrationfilter
16. distillationthe volume reduced by half by distillation at 50° C./150 mmHg vacuum
17. temperatureThe mixture was heated to 80° C.
18. dissolutionto redissolve the solids that
19. additionheptane (68.0 kg) was added
20. temperaturewhile maintaining the temperature at 70° C
21. temperatureThe slurry was cooled to 5° C.
22. waitheld overnight
23. filtrationThe crystals were collected by filtration
24. washwashed with heptane (34.0 kg)
25. customdried at 50° C./50 mmHg

ORD record

ord-88b6e3d4da2447b5b187df349919791f

Source dataset

uspto-grants-2008_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07442792B2