Reaction #502108

Reaction equation

(2S)-2-(6-methoxy(2-naphthyl))propanoic acid

2,2′-thiodiethanol

1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride

ether hexane

→

title compound

Yield 81.5%

2-(2-Hydroxyethylthio)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

Yield 81.5%

Solvents

dichloromethane

Conditions

Workup

1. 1
   OtherThe reaction mixture was partitioned between CH2Cl2 and water
2. 2
   Washthe water layer was washed with more CH2Cl2
3. 3
   WashThe combined organic layer was washed with water, 0.1 N HCl, water, brine
4. 4
   Dryingdried over magnesium sulfate
5. 5
   ConcentrationThe solution was concentrated under vacuum
6. 6
   Otherthe residue was purified via column chromatography, 5% ethyl acetate/dichloromethane
7. 7
   Otherthe solvent evaporated

Procedure

To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 15.0 g, 65 mmol), 2,2′-thiodiethanol (40 g, 325 mmol) and N,N-dimethylaminopyridine (DMAP, 1.59 g, 13 mmol) in dichloromethane (400 mL) at room temperature was added 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC, 14.98g, 78 mmol) as a solid, in portions. After stirring for 3 hours at room temperature, TLC analysis indicated the reaction was complete. The reaction mixture was partitioned between CH2Cl2 and water, and the water layer was washed with more CH2Cl2. The combined organic layer was washed with water, 0.1 N HCl, water, brine, and dried over magnesium sulfate. The solution was concentrated under vacuum, and the residue was purified via column chromatography, 5% ethyl acetate/dichloromethane. The appropriate fractions were combined, and the solvent evaporated. Trituration of the residue with ether/hexane gave the title compound as a white solid (17.72 g, 81% yield). Mp 58-61° C. 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=8.6 Hz, 2H), 7.67 (d, J=0.9 Hz, 1H), 7.40 (dd, J=1.7, 8.5 Hz, 1H), 7.14 (dd, J=2.5, 8.8 Hz, 1H), 7.11 (d, J=2.5 Hz, 1H), 4.24 (t, J=6.7 Hz, 2H), 3.86 (q, J=7.2 Hz, 1H), 3.60 (app q, J=6.0 Hz, 2H), 2.69 (t, J=6.6 Hz, 2H), 2.61 (t, J=5.9 Hz, 2H), 2.00 (t, J=6.2 Hz, 1H), 1.59 (d, J=7.2 Hz, 3H). Mass spectrum (API-TIS) m/z 352 (MNH4+); Anal. calcd. for C18H22O4S: C, 64.65; H, 6.63; S, 9.59; Found: C, 64.62; H, 6.59; S, 9.47.

Source