A NEW ISOTOPICALLY LABELLED ANTIFUNGAL AGENT 249
fractions were rotary evaporated to remove acetonitrile
and the product was extracted with dichloromethane
(2 ꢁ 30 mL). The combined extracts were washed with
saturated sodium chloride solution (30 mL) and dried
over sodium sulfate. Filtration gave a clear solution
(24 mCi) which was concentrated to a solid. This was
recrystallized from diisopropyl ether/pentane and
dried under vacuum to give a white solid (35.7 mg,
0.248 mmol, 22%). The specific activity was determined
as 367.4 mCi/mg, equivalent to 56 mCi/mmol, corre-
sponding to 13.88 mCi, The material was consistent
with an authentic sample provided by mass spectro-
metry, NMR spectroscopy and HPLC. HPLC (system 1):
tR ¼ 8:48 min, radiochemical purity 99.3%. 1H-NMR
(DMSO-d6, 400 MHz): d ¼ 9:22 (s, 1H), 7.78 (dd, 1H),
7.25 (dd, 1H), 7.19 (m, 1H) 4.98 (s, 2H). MS (EI): m/z
151/153 (Mꢀ1); specific activity 55 mCi/mmol.
Jt ¼ 8:6 Hz, Jd ¼ 3:3 Hz, 1H), 7.29 (dd, J ¼ 9:9 and
3.3 Hz, 1H), 7.59 (dd, J ¼ 9:0 and 5.1 Hz, 1H).
(2-Bromo-5-fluoro[a,a-2H2]benzyl)(methoxymethyl)
ether (11)
To a mixture of 2-bromo-5-fluoro[a,a-2H2]benzyl alco-
hol (10, 9.4 g, 45 mmol) and diisopropylethylamine
(12 mL, 67.5 mmol) in methylene chloride (150 mL)
was added dropwise chloromethyl methyl ether
(4.3 mL, 56.3 mmol) at 08C under a nitrogen atmo-
sphere. After being stirred overnight at room tempera-
ture, the mixture was washed with NaHCO3 solution,
dried, filtered and evaporated. The oil residue was
purified by flash column chromatography over silica gel
eluted with a mixed solvent of hexane and ethyl acetate
(5:1, v/v) to afford the title ether compound as a
colorless liquid (8.87 g, yield 78.5%). 1H NMR (DMSO-
d6, 300 MHz) d 3.30 (s, 3H), 4.71 (s, 2H), 7.13 (td,
Jt ¼ 8:7 Hz, Jd ¼ 3:3 Hz, 1H), 7.31 (dd, J ¼ 9:9 and
3.3 Hz, 1H), 7.64 (dd, J ¼ 9:0 and 5.4 Hz, 1H).
2-Bromo-5-fluorobenzoic acid methyl ester (9)
A solution of 2-bromo-5-fluorobenzoic acid (8, 10.29 g,
46.98 mmol) and 98% sulfuric acid (3 mL) in methanol
(150 mL) was stirred at room temperature over a
weekend and then refluxed for 24 h under nitrogen
atmosphere. The solution was concentrated to about
50 mL and then slowly added to a cold saturated
aqueous NaHCO3 solution (300 mL). Sodium chloride-
saturated water (200 mL) was added and the mixture
was extracted with ethyl acetate (2 ꢁ 200 mL), dried
over MgSO4, filtered and evaporated. The residue was
dissolved in hexane, dried again, filtered and evapo-
rated to give the title methyl ester as a colorless liquid
(10.42 g, yield 95%). 1H NMR (DMSO-d6, 300 MHz) d
3.85 (s, 3H), 7.39 (td, Jt ¼ 8:1 Hz, Jd ¼ 3:3 Hz, 1H), 7.62
(dd, J ¼ 9:3 and 3.3 Hz, 1H), 7.78 (dd, J ¼ 9:0 and
5.1 Hz, 1H).
[3,3-2H2]-5-Fluoro-1,3-dihydro-1-hydroxy-2,1-ben-
zoxaborole (12)
To
a
solution of (2-bromo-5-fluoro[a,a-2H2]benzyl)
(methoxymethyl) ether (11, 8.86 g, 35.3 mmol) in anhy-
drous THF (150 mL) was added dropwise tert-butyl
lithium (1.7 M solution in hexane, 25 mL, 42.5 mmol) at
ꢀ788C under nitrogen atmosphere. After being stirred
for 5–10 min at ꢀ788C, B(OMe)3 (3.93 mL, 35.3 mmol)
was added in one portion, and then the cooling bath
was removed. The reaction mixture was stirred for
30 min before the reaction flask was placed into a room
temperature water bath with additional 1.5 h stirring.
Hydrochloric acid (6 N, 16 mL) was added and THF was
removed by rotary evaporation. Methanol (125 mL) was
added to the acidic aqueous residue and the resulting
solution was stirred overnight at room temperature to
hydrolyze the methoxymethyl group. The solution was
evaporated to give a residue that was mixed with brine
and extracted with ethyl acetate. The residue after
evaporation was purified by flash column chromato-
graphy over silica gel eluted with a mixed solvent of
hexane and ethyl acetate (3:1, v/v) to produce a solid
(3.0 g) that was stirred in n-pentane (25 mL). Sonication
of the suspension and then filtration afforded the final
compound 1,3-dihydro-5-fluoro-1-hydroxy-[3,3-2H2]-
2,1-benzoxaborole as a white solid (2.29 g, yield 42%).
The 1H NMR data indicated the presence of 1.5 mol%
undeuteriated compound 1,3-dihydro-5-fluoro-1-hy-
droxy-2,1-benzoxaborole in the product. M.p. 120–
2-Bromo-5-fluoro[a,a-2H2]benzyl Alcohol (10)
To a solution of 2-bromo-5-fluorobenzoic acid methyl
ester (9, 10.4 g, 44.63 mmol) in anhydrous THF
(180 mL) was added dropwise lithium triethylborodeu-
teride (super deuteride, 1 M THF solution, 95 mL,
95 mmol) at 08C. The mixture was stirred overnight at
08C to room temperature, then recooled to 08C and 6 N
HCl (30 mL) was slowly added under nitrogen atmo-
sphere. Rotary evaporation gave a residue that was
mixed with brine and extracted with ethyl acetate. The
solution was dried over MgSO4, filtered and evaporated
to provide the title alcohol as a white solid (9.4 g, yield
100%). The 1H NMR data indicated the presence of
2.0 mol% non-deuteriated alcohol in the product. 1H
NMR (DMSO-d6, 300 MHz) d 5.54 (s, 1H), 7.07 (td,
1258C; 1H NMR (DMSO-d6, 300 MHz)
d 7.15 (td,
Jt ¼ 8:9 Hz, Jd ¼ 2:4 Hz, 1H), 7.23 (dd, J ¼ 9:6 and
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 245–250
DOI: 10.1002.jlcr
Baker, Stephen J.
