J.-Q. Wang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4102–4106
4105
4
. McKillop, D.; Hutchinson, M.; Partridge, E. A.; Bushby,
N.; Cooper, C. M. F.; Clarkson-Jones, J. A.; Herron, W.;
Swaisland, H. C. Xenobiotica 2004, 34, 917.
CH
2
Cl), 2.48 (t, J = 7.35 Hz, 2H, NCH
2
CH
2
CH
2
Cl), 2.44
(t, J = 4.42 Hz, 4H, NCH
2H, CH CH CH ).
2 2
CH O), 1.94 (q, J = 7.36 Hz,
2
2
2
5
6
7
8
9
. Mulholland, G. K.; Zheng, Q.-H.; Winkle, W. L.; Carlson,
K. A. J. Nucl. Med. 1997, 38(Suppl. 5), 141.
. Mulholland, G. K.; Winkle, W.; Mock, B. H.; Sledge, G.
W. J. Nucl. Med. 1995, 36(Suppl. 5), 71.
. Seimbille, Y.; Phelps, M. E.; Czernin, J.; Silverman, D. H.
S. J. Labelled Compd. Radiopharm. 2005, 48, 829.
. Gilday, J. P.; Moody, D. PCT Int. Appl. WO 2004/024703
A1, 2004.
. Gungor, T.; Chen, Y.; Golla, R.; Ma, Z.; Corte, J. R.;
Northrop, J. P.; Bin, B.; Dickson, J. K.; Stouch, T.; Zhou,
R.; Johnson, S. E.; Seethala, R.; Feyen, J. H. M. J. Med.
Chem. 2006, 49, 2440.
(c) Compound 3. A mixture of 3-hydroxy-4-methoxybenz-
aldehyde (10 g, 65.72 mmol), sodium formate (8.94 g,
131.45 mmol), and formic acid (48 mL) was heated to
85 ꢁC. To the above mixture was added hydroxylamine
sulfate (6.47 g, 39.42 mmol) in six equal portions at 30 min
intervals, and the mixture was heated at 85 ꢁC for 5 h. The
reaction was cooled to room temperature and poured to a
solution of sodium chloride (40 g) in water (200 mL). The
resultant solid was collected by filtration, washed with
water, and dried to give an off-white solid 3 (8.62 g, 88%).
1
H NMR (300 MHz, DMSO-d ): d 9.78 (s, 1H, OH), 7.24
6
(dd, J = 2.21 Hz, J = 8.09 Hz, 1H, Ph-H), 7.00–7.13 (m,
2H, Ph-H), 3.83 (s, 3H, OCH
1
2
1
1
1
0. Mock, B. H.; Mulholland, G. K.; Vavrek, M. T. Nucl.
Med. Biol. 1999, 26(4), 467.
1. Zheng, Q.-H.; Mock, B. H. Biomed. Chromatogr. 2005, 19,
3
).
(d) Compound 4. A mixture of compound 3 (8 g,
53.64 mmol), K CO (13 g, 94.07 mmol), compound 2
2
3
671.
2. Mock, B. H.; Glick-Wilson, B. E.; Zheng, Q.-H.; DeGra-
do, T. R. J. Labelled Compd. Radiopharm. 2005, 48(Suppl.
(9.54 g, 58.30 mmol), and DMF (50 mL) was heated to
85 ꢁC for 10 h. Solvent was removed under vacuum to
leave a residue which was partitioned between tert-butyl
methyl ether and water. The organic phase was dried over
1
), S224.
3. Experimental details and characterization data.
a) General. All commercial reagents and solvents were
used without further purification unless otherwise speci-
fied. CH OTf was made according to a literature proce-
1
MgSO
(14.07 g, 95%). H NMR (300 MHz, DMSO-d
7.43 (m, 2H, Ph-H), 7.09 (d, J = 8.82 Hz, 1H, Ph-H), 4.03
(t, J = 5.88 Hz, 2H, OCH CH CH N), 3.82 (s, 3H,
OCH ), 3.55 (t, J = 5.88 Hz, 4H, NCH CH O), 2.10–
), 1.85 (q, J = 6.62 Hz, 2H,
4
and evaporated to give a very viscous liquid 4
1
(
6
): d 7.33–
3
2
2
2
1
0 1
dure.
3
H NMR spectra were recorded on a Bruker QE
00 NMR spectrometer using tetramethylsilane (TMS) as
3
2
2
2.43 (m, 6H, NCH
2
an internal standard. Chemical shift data for the proton
resonances were reported in parts per million (d) relative
to internal standard TMS (d 0.0). Low resolution mass
spectra were obtained using a Bruker Biflex III MALDI-
Tof mass spectrometer, and high resolution mass mea-
surements were obtained using a Kratos MS80 mass
spectrometer, in the Department of Chemistry at Indiana
University. Chromatographic solvent proportions are
expressed on a volume:volume basis. Thin-layer chroma-
CH CH CH ).
2
2
2
(e) Compound 5. To a 250 mL two-necked flask were
added compound (10 g, 36.19 mmol) and HOAc
(25 mL). The mixture of H SO (70%, 25 mL) and
HNO3 (70%, 5 mL) was cooled to room temperature,
then was added slowly to the above solution under ice/
water. The mixture was slowly warmed to room temper-
ature and stirred for 50 h. After addition of water
(200 mL), the mixture was basified to pH 11 by addition
of 50% NaOH aqueous solution. A large amount of yellow
solid formed. CH
dissolved the solid. The aqueous phase was further
extracted with CH Cl . The combined organic phase was
washed with water, dried over MgSO , and evaporated to
4
2
4
tography was run using Analtech silica gel GF uniplates
(
2
5 · 10 cm ). Plates were visualized by UV light. Normal
2 2
Cl was added to the mixture, which
phase flash chromatography was carried out on EM
Science silica gel 60 (230–400 mesh) with a forced flow of
the indicated solvent system in the proportions described
below. All moisture-sensitive reactions were performed
under a positive pressure of nitrogen maintained by a
direct line from a nitrogen source. Analytical HPLC was
performed using a Prodigy (Phenomenex) 5 lm C18
2
2
4
give a yellow solid. The solid was recrystallized in EtOAc
to give a pure yellow solid 5 (11.07 g, 95%), R = 0.44 (20:1
f
1
/MeOH). H NMR (300 MHz, DMSO-d
CH
2
Cl
2
6
): d 7.84
(s, 1H, Ph-H), 7.69 (s, 1H, Ph-H), 4.22 (t, J = 5.88 Hz, 2H,
OCH CH CH N), 3.96 (s, 3H, OCH3), 3.56 (t,
column, 4.6 · 250 mm; 3:1:3 CH CN/MeOH/20 mM, pH
3
2
2
2
ꢀ
6
1
.7, KHPO4 (buffer solution) mobile phase, flow rate
.5 mL/min, and UV (254 nm) and c-ray (NaI) flow
J = 4.42 Hz, 4H, NCH CH O), 2.27–2.44 (m, 6H,
2 2
NCH ), 1.90 (q, J = 6.62 Hz, 2H, CH CH CH ).
2 2 2 2
detectors. Semi-preparative HPLC was performed using
a Prodigy (Phenomenex) 5 lm C-18 column, 10 · 250 mm;
(f) Compound 6. To a 250 mL two-necked flask were
added compound 5 (5 g, 15.56 mmol), sodium dithionite
(8.34 g), and water (80 mL). The mixture was stirred at
room temperature for 2 h and the heated to 50 ꢁC
overnight. After the mixture was heated to 70 ꢁC,
concentrated HCl (37%, 25 mL) was added slowly in a
period of 2 h. Heating was continued for another 1 h. The
mixture was cooled to room temperature and basified with
50% NaOH aqueous solution to pH 11. The mixture was
extracted with CH Cl three times to give a residue, which
ꢀ
3
:1:3 CH
3
CN/MeOH/20 mM, pH 6.7, KHPO
mobile
4
phase, 5.0 mL/min flow rate, UV (254 nm) and c-ray (NaI)
flow detectors. Sterile vented Millex-GS 0.22 lm filter unit
was obtained from Millipore Corporation, Bedford, MA.
(
b) Compound 2. 1-Bromo-3-chloropropane (6 mL,
0.98 mmol) was added slowly to a hot solution of
morpholine (12 mL, 137.74 mmol) in toluene (40 mL) at
0 ꢁC. The reaction mixture soon became cloudy, and it
6
8
2
2
was stirred at 80 ꢁC for 24 h. After cooling to room
temperature, more toluene (20 mL) was added to dilute
the mixture, and then aqueous HCl (18%, 14 mL) was
added. The aqueous layer was separated and basified with
was subject to silica gel chromatography eluted with 30:1
CH Cl /MeOH to give a very viscous liquid 6 (3.38 g,
2
2
1
H
75%), R = 0.25 (30:1 CH Cl /MeOH).
NMR
): d 6.88 (s, 1H, Ph-H), 6.38 (s, 1H,
), 3.84 (t, J = 6.62 Hz, 2H,
N), 3.72 (s, 3H, OCH ), 3.55 (t,
J = 4.41 Hz, 4H, NCH CH O), 2.26–2.40 (m, 6H,
f
2
2
(300 MHz, DMSO-d
6
5
0% NaOH solution to pH 11, extracted twice using
toluene, and the organic layer was dried over MgSO and
Ph-H), 5.63 (s, 2H, NH
OCH CH CH
2
4
2
2
2
3
evaporated to give a liquid residue. The crude product was
subject to vacuum distillation to give a colorless liquid 2
2
2
2 2 2 2
NCH ), 1.77 (q, J = 6.62 Hz, 2H, OCH CH CH N).
(g) Compound 7. Compound 6 (3.38 g, 11.60 mmol) and
tert-amyl alcohol (30 mL) were added to a 250 mL
1
7.33 g, 73%). H NMR (300 MHz, CDCl
(
J = 4.41 Hz, 4H, OCH CH N), 3.61 (t, J = 6.62 Hz, 2H,
3
): d 3.71 (t,
2
2