Citric Acid → 4-(3-Carboxy-propyl)-3-methyl-benzoic Acid Methyl Ester

4-(2-Carboxy-ethyl)-3-methyl-benzoic acid methyl ester from Example E30.3 (500 mg, 2.25 mmol) was dissolved in dry dichloromethane (10 ml) and a few drops of DMF. Oxalyl chloride (0.393 ml, 4.5 mmol) was added dropwise and the mixture was stirred for 1 h at room temperature. Solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in acetonitrile (20 ml) and cooled to 0° C. A solution of 2M (trimethyl-silyl)diazomethane in hexanes (2.25 ml, 4.5 mmol) was added dropwise and the reaction mixture was stirred for 5 h at 0° C. then 20 h at room temperature. Ethyl acetate then 10% citric acid solution were added and the layers were partitioned. The organic layer was washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% ethyl acetate:50% cyclohexane). The product obtained was dissolved in a mixture of acetonitrile and water. A solution of silver benzo-ate (103 mg, 0.45 mmol) in triethylamine (1.25 ml, 9 mmol) was added gradually while the mixture was sonicated in an ultrasound bath. After 30 min at room temperature, solvents were removed in vacuo. Ethyl acetate and 10% aqueous citric acid solution were added and the layers were partitioned. The organic layer was washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% EtOAc:50% cyclohexane) to yield the title compound (378 mg, 71%).

1. customSolvents were removed in vacuo
2. customazeotroped with toluene
3. dissolutionThe residue was redissolved in acetonitrile (20 ml)
4. temperaturecooled to 0° C
5. stirringthe reaction mixture was stirred for 5 h at 0° C.
6. custom20 h
7. customat room temperature
8. customthe layers were partitioned
9. washThe organic layer was washed with saturated NaHCO3
10. dry with materialbrine, dried
11. concentrationconcentrated in vacuo
12. customThe residue was purified by flash chromatography on silica gel (eluant; 50% ethyl acetate:50% cyclohexane)
13. customThe product obtained
14. customwas sonicated in an ultrasound bath
15. waitAfter 30 min at room temperature
16. customsolvents were removed in vacuo
17. additionEthyl acetate and 10% aqueous citric acid solution were added
18. customthe layers were partitioned
19. washThe organic layer was washed with brine
20. customdried
21. concentrationconcentrated in vacuo
22. customThe residue was purified by flash chromatography on silica gel (eluant; 50% EtOAc:50% cyclohexane)

ORD-Eintrag

ord-f7dc7f2504dd4c7cb6461b75e397a5e4

Quelldatensatz

uspto-grants-2012_06

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08202858B2