Iodoethane → 2-ETHYL-3-METHOXYBENZOIC ACID

Temperature

-65 °C

A 5 L, 4-necked round-bottom flask equipped with addition funnel, overhead stirring, and nitrogen purge was dried and charged with 128 g (623 mmoles) of 2-(3-methoxyphenyl)-5,5-dimethyloxazoline in 2.5 L of tetrahydrofuran. The mixture was cooled to -65° C. in a dry ice/isopropanol bath, and 450 mL of 1.6N n-butyl lithium was added slowly. After complete addition, the mixture was stirred for 1.5 hours at -45° to -30° C. After cooling to -45° C., ethyl iodide was added (80 mL, 1 mole). The temperature was maintained at -45° C. for 20 minutes, the mixture was allowed to warm to room temperature and was stirred overnight. Saturated ammonium chloride was added with ice cooling, and the mixture extracted several times with ether. The organic extracts were combined, dried over sodium sulfate, and solvent was removed in vacuo to give an oily solid. The solid was dissolved in 1 L of 6N hydrochloric acid in 3:1 water:methanol and heated at reflux for 15 hours. The hydrolysis was monitored by 1H NMR and shown to be about 75% complete. Additional acid was added (200 mL of 6N hydrochloric acid in 3:1 water:methanol), and the mixture was heated again at reflux for 8 hours. The mixture was cooled on ice, solids were collected, and dissolved in 10% aq. sodium hydroxide/methylene chloride. The aqueous layer was removed, acidified, and filtered to yield a tan solid which was air-dried at room temperature (53 g). An additional 23 g of product was obtained by further acidic hydrolysis of the methylene chloride extract. The melting point of the desired acid was 100°-101° C.

1. customA 5 L, 4-necked round-bottom flask equipped with addition funnel
2. customnitrogen purge
3. customwas dried
4. additionAfter complete addition
5. stirringthe mixture was stirred for 1.5 hours at -45° to -30° C
6. temperatureAfter cooling to -45° C.
7. temperatureThe temperature was maintained at -45° C. for 20 minutes
8. temperatureto warm to room temperature
9. stirringwas stirred overnight
10. extractionthe mixture extracted several times with ether
11. dry with materialdried over sodium sulfate, and solvent
12. customwas removed in vacuo
13. customto give an oily solid
14. temperatureat reflux for 15 hours
15. temperaturethe mixture was heated again
16. temperatureat reflux for 8 hours
17. temperatureThe mixture was cooled on ice, solids
18. customwere collected
19. dissolutiondissolved in 10% aq. sodium hydroxide/methylene chloride
20. customThe aqueous layer was removed
21. filtrationfiltered
22. customto yield a tan solid which
23. customwas air-dried at room temperature (53 g)

ORD record

ord-de00066a73fb41adb60de7197e12c816

Source dataset

uspto-grants-1996_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05530028