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was stirred in the ice bath for another hour then at room temperature
overnight. The solution was concentrated in vacuo and the residue was stirred
in 100 ml of 5% EtOAc in hexanes for 90 min. The white precipitate was
filtered and rinsed with 5% EtOAc in hexanes. The combined filtrates were
concentrated and the residue was purified by chromatography (SiO2, hexanes).
The desired fractions were pooled and concentrated, and the residue was
further dried in vacuo to give the product 5-[14C] (236 mg, 0.91 mmol, 51.9%)
as a colorless viscous oil. It was co-eluted with a non-labeled reference on TLC
(SiO2, hexanes). Proton-NMR of non-labeled product: (CDCl3, ppm) 7.4 (m,
5 H), 7.15 (d, 1 H), 7.0 (t, 1 H), 6.85 (t, 1 H), 6.65 (d, 1 H), 5.42 (m, 1 H), 3.85
(m, 1 H), 3.65 (m, 1 H), 2.55 (m, 1 H), 2.3 (M, 1 H), 2.35 (s, 3 H).
Synthesis of (R)-N-methyl-3-[2-methylphenoxy]-benzenepropanamine-[3-14C]-
hydrochloride, LY139603-[14C]
A solution of chloride 5 (236 mg, 0.91 mmol) in 50 ml of acetone was refluxed
with 5 g of NaI over the weekend (about 68 h). The solution was concentrated
and the residue, as a light yellow solid, was dissolved in 20 ml of water and
20 ml of hexanes. The organic layer was separated, washed with water
(25 ml ꢀ 3), and concentrated to give a colorless oil. HPLC (Zorbax ODS,
3 ꢀ 250 mm, 30:70 H2O/CH3CN, 0.8 ml/min, UV at 220 nm) indicated less
than 0.5% of chloride 5 remained. The colorless oil was dissolved in 15 ml of
THF and stirred with 5 ml of 40% aqueous CH3NH2 at room temperature
overnight (about 20 h). TLC indicated that iodide was consumed. The solution
was concentrated, the aqueous residue was added to 25 ml of EtOAc, and the
solution was washed with water. Removal of solvent and chromatography
(SiO2, 100:10:1 CH2Cl2/MeOH/NH4OH) gave the product (free base of
LY139603-[14C], co-eluted with non-labeled reference) as a colorless viscous oil
(222 mg, 0.87 mmol). Proton-NMR of non-labeled product (CDCl3, ppm) 7.35
(m, 5 H), 7.15 (d, 1 H), 7.0 (t, 1 H), 6.82 (t, 1 H), 6.65 (d, 1 H), 5.35 (m, 1 H),
2.6–3.2 (m, 2 H), 2.45 (s, 3 H), 2.37 (s, 3 H), 2.3–2.5 (m, 2 H). This free base was
dissolved in 30 ml of CH2Cl2, to which a solution of 0.5 ml of 12 N HCl in 2 ml
of MeOH was added with stirring, and the solution was then concentrated.
The residue was added to 20 ml of anhydrous EtOH and concentrated again to
remove the residual water. The residue was dissolved in 2 ml of anhydrous
EtOH, diluted with 20 ml of ether, and stirred at room temperature for 30 min.
The white precipitate was filtered off, washed with ether, and dried in vacuo to
give the final product LY139603-[14C] as a white hydrochloride salt (217 mg,
0.74 mmol, 82% from chloride 5). Radiochemical purity: 99% by radio-HPLC
and TLC. Specific activity=60.94 mCi/mg, The white salt was mixed with
400 mg of LY139603, dissolved in CH2Cl2, and concentrated to give a white
salt. Recrystalization from EtOH and ether gave the product LY139603-[14C]
as a white crystalline solid (502 mg, 1.72 mmol). MS: M+H=256/258.
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 615–625