Hydrochloric Acid → 4-Methoxyphthalic acid

To a solution of 4-hydroxyphthalic acid (0.25 g, 1.37 mmol) in anhydrous N,N-dimethylformamide (3 ml) under nitrogen was added sodium hydride (0.22 g, 5.48 mmol). The solution was stirred for 5 minutes and then methyl iodide (0.68 ml) was added and continued stirring for 3 hours. Several drops of water were added to quench the reaction and the mixture was concentrated in vacuo. The crude material was partitioned between ethyl acetate (40 ml) and water (10 ml). The layers were separated and the organic layer washed with brine (2×10 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The resulting oil was dissolved in methanol (8 ml) and 1N sodium hydroxide (4 ml) was added. The reaction was stirred at ambient temperature for 24 hours, after which LC-MS indicated only partial hydrolysis. The material was reconstituted in methanol (5 ml) and treated with of sodium hydroxide (0.12 g, 3.0 mmol) dissolved in water (1 ml). The reaction mixture was stirred for 48 hours, at which time a precipitate had formed. The mixture was acidified with 6 N hydrochloric acid until pH=1, causing the solution to become homogeneous. The reaction was concentrated in vacuo and the residue partitioned between ethyl acetate (30 ml) and 0.5N hydrochloric acid (10 ml). The layers were separated and the organic layer concentrated in vacuo to give 100 mg (51%) of 4-methoxy-phthalic acid as a solid.

1. stirringcontinued stirring for 3 hours
2. customto quench
3. customthe reaction
4. concentrationthe mixture was concentrated in vacuo
5. customThe crude material was partitioned between ethyl acetate (40 ml) and water (10 ml)
6. customThe layers were separated
7. washthe organic layer washed with brine (2×10 ml)
8. dry with materialdried (Na2SO4)
9. filtrationfiltered
10. customthe solvent evaporated in vacuo
11. dissolutionThe resulting oil was dissolved in methanol (8 ml)
12. addition1N sodium hydroxide (4 ml) was added
13. stirringThe reaction was stirred at ambient temperature for 24 hours
14. customhydrolysis
15. stirringThe reaction mixture was stirred for 48 hours, at which time a precipitate
16. customhad formed
17. concentrationThe reaction was concentrated in vacuo
18. customthe residue partitioned between ethyl acetate (30 ml) and 0.5N hydrochloric acid (10 ml)
19. customThe layers were separated
20. concentrationthe organic layer concentrated in vacuo

ORD record

ord-561bdf09f5174de7bd21098166a01a5b

Source dataset

uspto-grants-2006_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07019026B1