Carbon Dioxide → 4-Ethoxy-N-(4-hydroxybutyl)benzamide

Temperature

-5 °C

A 22-L, 3-necked, round-bottom flask equipped with a mechanical stirrer, nitrogen bubbler, and a thermocouple probe, was charged with 1.16 kg of 4-ethoxybenzoic acid and 11 L of THF. A total of 1.403 kg (8.65 mole, 1.24 eq) of 1,1′-carbonyldiimidazole was added at ambient temperature in 4 portions (to control CO2 evolution) to attain a conversion of 98% to the activated acid. After the yellow solution was cooled to −5° C., a solution prepared from 684.5 g (7.68 mole, 1.10 eq) of 4-amino-1-butanol in 0.5 L of THF was added over a period of 50 min while maintaining a temperature of −7 to −3° C. The gummy mixture was allowed to warm to room temperature and stir overnight. The light-yellow solution was concentrated (45° C., 50 mbar) to 3.22 kg of an orange oil that was charged to an extractor along with 5.7 kg of 10% HCl and 6 L DCM. The aqueous phase was extracted with 3 L DCM. The DCM extracts were combined, washed with 5 L of 0.5 N HCl, washed with 5 L of saturated aq. NaHCO3, dried (MgSO4), filtered, concentrated (45° C., 25 mbar), and air dried to give 1.52 kg (91.9%) of crude product as a white solid. Impurities were removed by saponification. A 12-L, 3-necked, round-bottom flask equipped with a mechanical stirrer, nitrogen bubbler, and a thermocouple probe, was charged with 1.52 kg of crude product, 5.5 L of IPA and 156.5 g of 50% NaOH. The mixture was heated for 30 min at 55-78° C. After cooling to 37° C., the hazy solution was charged into an extractor along with 7.8 L of water and 17 L of DCM. After the phases were separated, the aqueous layer was is extracted with 6 L of DCM. The organic extracts were combined, washed with 7.8 L-of water, dried (MgSO4), filtered, concentrated (50° C., 25 mbar) and air dried to give 1.453 kg (87.7%) of N-(4-hydroxybutyl)-4-ethoxybenzamide (V-5) as a white lumpy solid.

1. additionwas added over a period of 50 min
2. temperaturewhile maintaining a temperature of −7 to −3° C
3. temperatureto warm to room temperature
4. concentrationThe light-yellow solution was concentrated (45° C., 50 mbar) to 3.22 kg of an orange oil that
5. additionwas charged to an extractor along with 5.7 kg of 10% HCl and 6 L DCM
6. extractionThe aqueous phase was extracted with 3 L DCM
7. washwashed with 5 L of 0.5 N HCl
8. washwashed with 5 L of saturated aq. NaHCO3
9. dry with materialdried (MgSO4)
10. filtrationfiltered
11. concentrationconcentrated (45° C., 25 mbar), and air
12. customdried
13. customto give 1.52 kg (91.9%) of crude product as a white solid
14. customImpurities were removed by saponification
15. customA 12-L, 3-necked, round-bottom flask equipped with a mechanical stirrer
16. additionnitrogen bubbler, and a thermocouple probe, was charged with 1.52 kg of crude product, 5.5 L of IPA and 156.5 g of 50% NaOH
17. temperatureThe mixture was heated for 30 min at 55-78° C
18. temperatureAfter cooling to 37° C.
19. additionthe hazy solution was charged into an extractor along with 7.8 L of water and 17 L of DCM
20. customAfter the phases were separated
21. extractionthe aqueous layer was is extracted with 6 L of DCM
22. washwashed with 7.8 L-of water
23. dry with materialdried (MgSO4)
24. filtrationfiltered
25. concentrationconcentrated (50° C., 25 mbar) and air
26. customdried

ORD record

ord-9b631a24e3ff4f5b8f626f94af56fa35

Source dataset

uspto-grants-2009_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07550469B2