Ethanethiol → Phenylacetic Acid

To a solution of methyl 3-aminophenylacetate (102 g, 0.62 mole) in 1N HCl (1600 ml) cooled in an ice bath was added NaNO2 (42.7 g, 0.62 mole) portionwise and the solution stirred for 20 minutes. A solution of potassium ethanethiolate was prepared by adding ethanethiol (202 ml, 2.73 mole) dropwise over 10 minutes to a solution of 87.5% KOH (159 g, 2.48 mole) in water (1.2 l) at 0° C. The diazonium salt solution was then added via cannula to the solution of potassium ethanethiolate and the reaction mixture was stirred 30 minutes in an ice bath. Diethyl ether (~1.5 l) was added and the mixture was stirred 1.5 hours at room temperature. The ether layer was separated, the aqueous phase further extracted with diethyl ether (3×700 ml), and the combined ether solutions concentrated. The residue was eluted from silica gel with ethyl acetate:hexane (1:14) to give a mixture of methyl 3-ethylthiophenylacetate 1H NMR (DMSO-d6, 200 MHz) δ: 1.21 (t, J=7 Hz, 3H, ethyl CH3), 2.95 CH2), 3.60 (s, 3H, OCH3), 3.65 (s, 2H, ArCH2), 7.02-7.44 (m, Ar), and methyl phenylacetate (85.9 g). The esters (84 g) were hydrolyzed in a solution of methanol (500 ml) and 6.25N NaOH(100 ml) stirred overnight at room temperature. The solution was concentrated in vacuo to remove the methanol, the remaining solution acidified with concentrated HCl and the resulting solid was extracted into diethyl ether. The ether solution was washed with brine (3×100 ml), dried (Na2SO4) and concentrated. Vacuum distillation (0.5 mm Hg) gave a distillate (100°-115° C.) of phenylacetic acid and a residue of 3-ethylthiophenylacetic acid. The residue in the flask solidified upon cooling to give 3-ethylthiophenylacetic acid (49.8 g). Mp=49°-51° C. 1H NMR (DMSO-d6, 200 MHz) δ: 1.21 (t, J=7 Hz, 3H, CH3), 2.95 (q, J=7 Hz, 2H, SCH2), 3.54 (s, 2H, ArCH), 7.01-7.28 (m, 4H, Ar), 12.33 (br s, 1H, CO2H). Mass spectrum (CI-CH4): 197 (M+1, 100%).

1. stirringthe reaction mixture was stirred 30 minutes in an ice bath
2. stirringthe mixture was stirred 1.5 hours at room temperature
3. customThe ether layer was separated
4. extractionthe aqueous phase further extracted with diethyl ether (3×700 ml)
5. concentrationthe combined ether solutions concentrated
6. washThe residue was eluted from silica gel with ethyl acetate:hexane (1:14)
7. customto give
8. stirringstirred overnight at room temperature
9. concentrationThe solution was concentrated in vacuo
10. customto remove the methanol
11. extractionthe resulting solid was extracted into diethyl ether
12. washThe ether solution was washed with brine (3×100 ml)
13. dry with materialdried (Na2SO4)
14. concentrationconcentrated
15. distillationVacuum distillation (0.5 mm Hg)

ORD record

ord-40c734056c204795906bba355b878bfc

Source dataset

uspto-grants-1997_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05661155