1
274 P. M. GANNETT ET AL.
1
26.13 (t), 127.6, 129.1, 133.5, 135.4, 155.1, 175.5;
UV (MeOH) l nm (log (e)) 229 (4.63), 265 (3.56), 274
3.59); MS m/z (intensity) 220 (9), 219 (36), 218 (100),
17 (57), 216 (7) (Total D ¼ 2:95); ½aꢃD ¼ 66:1.
1.430 (3H, d, J ¼ 7:2 Hz), 3.809 (1H, q, J ¼ 7:2 Hz),
3.891 (3H, s), 7.137 (1H, dd, J ¼ 2:8, 8.9 Hz), 7.275
(1H, d, J ¼ 2:8 Hz), 7.392 (1H, dd, J ¼ 2:1, 8.5 Hz),
7.698 (1H, d, J ¼ 2:2 Hz), 7.760 (1H, d, J ¼ 8:5 Hz),
(
2
1
3
7
.789 (1H, d, J ¼ 8:9 Hz), 12.28, (1H, bs); C NMR
Methyl 2-(6-methoxy-2-naphthyl)propanoate (6a)
(dmso-d ) d ppm 18.4, 44.55, 55.12, 108.4, 118.7,
6
1
25.5, 126.3, 126.8, 128.4, 129.1, 133.2, 136.3,
To DMSO (3.0 mL) and crushed KOH pellets (0.318 g,
157.1, 175.5; UV (MeOH) l nm (log (e)) 232 (4.81), 261
(3.42), 271 (3.39); MS m/z (intensity) 231 (93), 217
(19), 180 (1 0 0).
5
1
.68 mmol) was added
a solution of 2 (0.32 g,
.44 mmol), and iodomethane (0.375 mL, 6 mmol) in
DMSO (2.25 mL), dropwise. The reaction mixture was
stirred at room temperature for 24 h and then concen-
trated to dryness in vacuo. The dried product was
dissolved in distilled water (20 mL), filtered and the
filter cake dissolved in CH Cl , dried (MgSO ), filtered,
2
2
-[6-(1,4,7- D )-2-naphthyl]propanoic acid (5a)
3
IR (KBr) cmꢀ1 2210, 2070; MS m/z (intensity) 234 (7),
33 (36), 232 (1 0 9), 231 (31), 230 (6) (2.91 D).
2
2
4
2
and concentrated in vacuo to give 6a (0.23 g, 69%). The
NMR of the proto material, 6a, is given here. For the
remaining isotopically labeled compounds (4a, 4b, 6b)
the proton, carbon, and UV data were identical to 6a
except as would be predicted based on the isotopic
2
2
3 3
2
-(6-[( D )methyloxy](1,4,7- D )-2-naphthylpropa-
noic acid (5b)
IR (KBr) cmꢀ 2230, 2215, 2070; MS m/z (intensity)
1
ꢀ1
substitution. IR (KBr) cm
1
2980, 1730, 1605, 1200;
2
37 (9), 236 (36), 235 (100), 234 (57), 233 (12) (6.01 D).
H NMR (dmso-d ) d ppm 1.465 (3H, d, J ¼ 7:5 Hz),
6
3
.584 (3H, s), 3.853 (3H, s), 3.911 (1H, q, J ¼ 7:5 Hz),
.143 (1H, dd, J ¼ 2:7, 9 Hz), 7.277 (1H, d, J ¼ 2:7 Hz),
.373 (1H, d, J ¼ 9 Hz), 7.696 (1H, J ¼ 1:8 Hz), 7.788
2
7
7
2
-(6-[( D )methyloxy]-2-naphthyl)propanoic acid (6c)
3
1
3
(
1H, d, J ¼ 9 Hz), 7.965 (1H, d, J ¼ 9 Hz); C NMR
dmso-d ) d ppm 19.13, 45.02, 52.46, 55.86, 106.4,
19.5, 126.3, 126.9, 127.7, 129.1, 129.8, 134.0,
36.4, 157.9, 175.1; UV (MeOH) l nm (log (e)) 231
IR (KBr) cmꢀ1 2230, 2215, 2070; MS m/z (intensity)
34 (4), 233 (26), 232 (100), 231 (14), 230 (6) (3.05 D).
(
6
2
1
1
Conclusions
(4,91), 261 (3.83), 272 (3.82).
The modification of the hydrogen–deuterium exchange
reagent reported here and originally developed by
Yavorsky and Gorin is more conveniently used and
yet as effective, though somewhat less reactive. While
the reaction conditions caused racemization, chiral
resolution resulted in optically pure deuterium-labeled
products. The methods described here can be
used to prepare naproxen labeled on the aromatic ring,
methoxy group or both and provide optically pure
products.
(
S)-(+)-2-(6-methoxy-2-naphthyl)propanoic acid (1)
Hydrolysis of 6a was achieved by heating 4 (200 mg,
.82 mmol) in 10% NaOH (7 mL) at reflux for 3 h and
0
then stirred at room temperature during which a
precipitate was formed. The entire mixture was acid-
ified with conc. HCl (3 mL, pH 1). The mixture was then
filtered and dried in vacuo to yield 5 (97%). The product
0
was treated with d-l-amino-1-(1 -naphthyl)-ethane
(
0.21 mg, 1.23 mmol) in boiling ethanol–acetone (9:1,
mL) and cooled. The precipitate was recrystallized
2
twice from methanol, acidified, extracted into CH Cl ,
5
Acknowledgements
2
We thank the National Institutes of Health for their
financial support of the work (GM063215 and
GM069753).
dried, filtered, and concentrated in vacuo. NMR analy-
sis in the presence of a-phenyethylamine indicated that
the product was enantiomerically pure. The NMR of the
proto material, 6a, is given here. For the remaining
isotopically labeled compounds the proton, carbon,
and UV data were identical to 6a except as would be
predicted based on the isotopic substitution. Conse-
quently, for the isotopically labeled compounds, only
the C–D absorptions observed in the IR and the mass
REFERENCES
1. Williams PA, Cosme J, Vinkovic DM, Ward A, Angove
HC, Day PJ, Vonrhein C, Tickle IJ, Jhoti H. Science
2004; 305: 683–686.
ꢀ
1
spectrometry data are reported. 1: IR (KBr) cm 2500–
2. Rettie A, Jones JP. Annu Rev Pharmacol Toxicol
2005; 45: 477–494.
1
3
500, 1715, 1600, 1230; H NMR (dmso-d ) d ppm
6
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 1272–1275
DOI: 10.1002.jlcr