Synthesis of [35S]aryl sulfonyl chlorides from [ 35S]elemental sulfur

Article abstract of DOI:10.1002/jlcr.920

A new synthetic methodology that captures electrophilic ³⁵S ₈ with aryl Grignard reagents or lithiates provides entry to a wide variety of [³⁵S]aryl sulfonyl chlorides upon oxidation and chlorination. Copyright

Full text of DOI:10.1002/jlcr.920

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2005; 48: 275–283.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.920
Research Article
Synthesis of [35S]aryl sulfonyl chlorides from
[35S]elemental sulfur
Michael A. Wallace*, Conrad E. Raab, Dennis C. Dean and David G. Melillo
Department of Drug Metabolism, Merck Research Laboratories, 126 E. Lincoln Ave.,
Rahway, NJ 07065, USA
Summary
A new synthetic methodology that captures electrophilic 35S8 with aryl Grignard
reagents or lithiates provides entry to a wide variety of [35S]aryl sulfonyl chlorides
upon oxidation and chlorination. Copyright # 2005 John Wiley & Sons, Ltd.
Key Words: [35S]aryl sulfonyl chlorides; [35S]alkyl sulfonyl chlorides
Introduction
High specific activity [35S]methanesulfonamide1 and [35S]benzenesulfonamide2
radioligands are finding increased use as tools to study receptors in biological
systems. The coupling of amines with [35S]sulfonyl chlorides is generally a fast
and high-yielding procedure that can be adapted to a variety of substrates and
can provide radioligands that offer superior sensitivity and better resolution
for autoradiography when compared to tritiated and iodinated radioligands,
respectively.
While initial attempts to produce high specific activity [35S]benzenesulfonic
acid by [35S]sulfonation of benzene suffered from dilution of specific activity,
presumably due to ubiquitous sulfates in the reagents or vessels,
both [35S]methanesulfonate and [35S]benzenesulfonate are now commercially
available at high specific activities (800–1200 Ci/mmol).y Following a
simple one-step procedure using oxalyl chloride, the corresponding
[35S]sulfonyl chlorides are typically formed in over 90% radiochemical
yields.1,2
In order to support a discovery program at Merck, we needed to prepare
high specific activity [35S]aryl sulfonamide radioligands. Initially, we
*Correspondence to: M. A. Wallace, RY80R-104, P.O. Box 2000, Rahway, NJ 07065, USA.
E-mail: mike wallace@merck.com
y
[
35S]Benzenesulfonate and [35S]methanesulfonate are commercially available by custom synthesis from
Perkin-Elmer Life Sciences.
Copyright # 2005 John Wiley & Sons, Ltd.
Received 22 November 2004
Revised 30 November 2004
Accepted 1 December 2004

276
M. A. WALLACE ET AL.
considered [35S]sulfonation as an approach to making the desired [35S]aryl
sulfonates. However, the potential for deactivation of the aromatic ring by
substituents and poor regiocontrol, as well as the potential for dilution of
specific activity, made [35S]sulfonation a less attractive option. A new synthetic
methodology using [35S]elemental sulfur (S8) as a sulfur source was developed
to overcome these limitations and was further developed as a general method
to synthesize multisubstituted [35S]aryl sulfonic acids and their corresponding
[35S]sulfonyl chlorides.
Results and discussion
While high specific activity [35S]elemental sulfur has demonstrated
limited stability in storage, herein we report the trapping of aryl Grignard
reagents or lithiates3 with commercially available, electrophilic high
specific activity [35S]S8 to generate the corresponding [35S]thiol or [35S]poly-
thiane species. Subsequent oxidation with KNO3 and chlorination with
SO2Cl42 generated the [35S]aryl sulfonyl chlorides directly as shown in Scheme 1
below.
Using this procedure, a variety of multisubstituted aryl [35S]sulfonyl
chlorides were produced as highlighted in Table 1 below. While [35S]sulfona-
*
SH
*
X
SO2Cl
R
SO2Cl2, KNO3
CH2Cl2
1. Mg, or n-BuLi
2. [35S]S8
R
R
X = Br, I
R = H, Cl, di-Cl, CF3, CN
Scheme 1.
Table 1.
Starting halide
[35S]Sulfonyl chloride
Radiochemical
yield (%)
1-Bromo-3,4-dichlorobenzene
1-Bromo-2,4-dichlorobenzene
1-Iodo-3,5-dichlorobenzene
2-Bromonaphthylene
Bromobenzene
1-Iodo-3-trifluoromethylbenzene
3,4-Dichlorobenzenesulfonyl chloride
2,4-Dichlorobenzenesulfonyl chloride
3,5-Dichlorobenzenesulfonyl chloride
2-Naphthylenesulfonyl chloride
Benzenesulfonyl chloride
3-Trifluoromethylbenzene
sulfonyl chloride
3-Cyanobenzenesulfonyl chloride
n-Butanesulfonyl chloride
15b
25a
30a
16b
30b
14a
3-Iodobenzonitrile
n-Butyl bromide
27a
25a
a Crude [35S]sulfonyl chloride was hydrolyzed, purified, and reconstituted.
b Crude [35S]sulfonyl chloride used ‘as is’.
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 275–283

SYNTHESIS OF [35S]
277
tion of naphthylene gives a mixture of the 1 and 2 isomers (ratio 85/15),z the
2-isomer can be exclusively prepared by this new method from
2-bromonaphthylene. Deactivation of the aromatic ring by halogens, coupled
with poor regioselectivity reduces the utility of [35S]sulfonation of haloben-
zenes. Using standard lithium-halogen exchange or Grignard formation
procedures,5 followed by quenching with [35S8] and treatment with KNO3/
SO2Cl2, several [35S]dichlorobenzenesulfonyl chlorides were produced as single
regioisomers. In the synthesis of [35S]2,4-dichlorobenzenesulfonyl chloride,
lithium-halogen exchange on 1-bromo-2,4 dichlorobenzene was performed at
low temperature to avoid potential benzyne formation. In general, the
resulting [35S]sulfonyl chloride was used ‘as is’ or hydrolyzed to the
[35S]sulfonic acid, purified by reverse phase chromatography, and reconsti-
tuted to the [35S]sulfonyl chloride under standard conditions.1
We have also demonstrated the synthesis of an alkyl [35S]sulfonyl chloride
using this procedure, which provides an alternative to the Strecker synthesis of
[35S]alkylsulfonic acids. More specifically, [35S]n-butanesulfonyl chloride was
produced from n-butyl magnesium bromide (Scheme 2).
35S8]
SO2Cl2, KNO3
[
*
*
n-butylSO2Cl
n-butylSH
n-butylMgBr
CH2Cl2
Scheme 2.
While the overall yields to several of the [35S]aryl sulfonyl chlorides are
moderate, this methodology remains a useful one in that many of the desired
[35S]aryl sulfonyl chlorides cannot be obtained any other way. Derivatization
of the resulting [35S]sulfonyl chlorides with amines provided several
[35S]sulfonamide radioligands with specific activities in the range of 700–
1100 Ci/mmol indicating that no dilution had taken place (Scheme 3).
Experimental
Radioactivity measurements were carried out using Lumi-Scint Luminometer
LSC liquid scintillation spectrometer using Packard Ultima Gold as
scintillation medium. Analytical HPLC analyses were performed using a
Dupont Zorbax RX C8 column (4.6 mm ꢀ 25 cm or Dupont Zorbax RX C18
column (4.6 mm ꢀ 25 cm), 1 ml/min, Rainin UV-1 detector at 240 nm, Packard
Flo-1 Beta radioactivity monitor, Spectra-Physics SP8810 LC pump and
controller, and software run on an IBM computer. [35S]Elemental sulfur was
obtained from Perkin-Elmer. Mass spectra were performed on a Hewlett
Packard Series 1100 MSD mass spectrometer using an XDBC8 column with
z Personal communication from Perkin-Elmer regarding the initial [35S]isomeric ratio.
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 275–283

278
M. A. WALLACE ET AL.
HN
CH3
N
O
HN
O
OCH3
1
O
N
H
O
CH3
O
N
N
H
H
CH3
CH3
1. [35S]3,5-dichlorobenzenesulfonyl chloride
di-tert-butyl methyl pyridine, CH2Cl2
2 . LiOH, MeOH/THF/H2O
3 . HPLC purification
Cl
Cl
*
S
N
O2
2
CH3
N
O
HN
O
OH
O
N
H
O
CH3
O
N
N
* denotes 35S label
H
H
CH3
CH3
Scheme 3.
pH 3.5 formate buffer/acetonitrile gradient. The identities of the appropriate
labeled sulfonyl chlorides or sulfonic acids were established by HPLC
co-elution with authentic material or known derivatives.
[35S]3,4-Dichlorobenzenesulfonyl chloride
To a flame dried flask containing Mg (23mg, 0.95mmol) and a crystal of iodine
was added 1-iodo-3,4-dichlorobenzene (175 mg, 0.65mmol) in 500ml ether. The
Grignard reaction was initiated with heating to 358C for 30 min. After cooling
to room temperature, [35S]S8 (25mCi, stock solution in benzene) was added and
the mixture aged for 2 h. HPLC analysis (Zorbax RX C8, 50/50 A/B,
A=CH3CN, B=0.1% TFA, rt=16.3 min) showed the mixture contained many
radiochemical entities (presumably due to the polymeric nature of the S8).} The
} HPLC analysis does not always demonstrate the presence of free thiol due to the polymeric nature of
elemental sulfur. Reaction with KNO3/SO2Cl2 apparently breaks the polymer and leads to formation of the
free sulfonyl chloride.
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 275–283

SYNTHESIS OF [35S]
279
reaction was quenched with 1 ml of 1.0 N HCl, diluted with methylene chloride
(10 ml). The phases were separated and the organic phase dried over MgSO4
and filtered. A count of the solution indicated 7 mCi. The dichloromethane
solution was treated directly with KNO3 (10 mg) and SO2Cl2 (35 ml) and aged
16 h at room temperature. HPLC analysis (Zorbax RX C8, 50/50 A/B,
A=CH3CN, B=0.1% TFA, rt=16.3 min) showed formation of the desired
[35S]3,4-dichlorobenzenesulfonyl chloride in 40% radiochemical yield. The
organic phase was stirred vigorously with aqueous sodium bicarbonate
solution to hydrolyze the sulfonyl chloride and the phases separated. The
resulting aqueous phase was loaded on an Oasis HLB 1 g cartridge. Following
elution with 3 volumes of water, followed by 20/80 CH3CN/water afforded
4 mCi of 98% radiochemically pure [35S]3,4-dichlorobenzenesulfonic acid
HPLC analysis (Zorbax RX C8, 20/80 A/B, A=CH3CN, B=0.1% TFA,
rt=11.6 min). The aqueous phase was concentrated by a stream of N2 and the
resulting solid dried in vacuo for 1 h. The solids were slurried into methylene
chloride (5 ml) and 1 ml of DMF and 50 ml of oxalyl chloride were added. The
reaction mixture was aged at room temperature overnight, then quenched with
water (2 ꢀ 5 ml), washed with 10% aqueous sodium bicarbonate solution
(5 ml) and dried twice over MgSO4 to give 3.8 mCi of [35S]3,4-dichlorobenze-
nesulfonyl chloride.
[35S]2,4-Dichlorobenzenesulfonyl chloride
1-Bromo-2,4-dichlorobenzene (375 mg, 1.67 mmol) was dissolved in
THF (1 ml) and ether (2 ml). The mixture was cooled to ꢁ908C and n-BuLi
(1.04 ml, 1.6 M) was added over 10 min. A toluene solution of [35S]S8 (14 mCi)
was added over 10 min and the mixture aged for 15 min. The reaction
was warmed to ꢁ508C over 15 min then quenched with 1.0 N HCl (3 ml). The
aqueous phase was extracted with methylene chloride (2 ꢀ 4 ml) and
the combined organic phase dried over MgSO4. To the crude reaction mixture
was added KNO3 (40 mg) and SO2Cl2 (100 ml) and the solution aged for 4 h
at room temperature. To the mixture was added 100 ml of water and 50 ml of
pyridine to hydrolyze the sulfonyl chloride and the stirred mixture aged
overnight. The organic phase was extracted with water (1 ꢀ 8 ml) and the
resulting aqueous phase loaded on an Oasis HLB 1 g cartridge. After washing
with 3 volumes of water the [35S]acid was eluted with 20/80 CH3CN/water
to afford 3.6 mCi of 98% radiochemically pure [35S]2,4 dichlorobenzene
sulfonic acid HPLC analysis (Zorbax RX C8, 20/80 A/B, A=CH3CN,
B=0.1% TFA, rt=11.5 min). The aqueous phase was concentrated and the
resulting solid dried in vacuo for 1 h. The solids were slurried into methylene
chloride (5 ml) and 1 ml of DMF and 50 ml of oxalyl chloride were added. The
reaction mixture was aged at room temperature overnight, then quenched with
water (2 ꢀ 5 ml), washed with 10% aqueous sodium bicarbonate solution
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 275–283

280
M. A. WALLACE ET AL.
(5 ml) and dried twice over MgSO4 to give 3.5 mCi of [35S]2,4-dichlorobenzene
sulfonyl chloride.
[35S]3,5-Dichlorobenzenesulfonyl chloride
To a flame dried flask containing Mg (23 mg, 0.95 mmol) and a crystal of
iodine was added 1-iodo-3,5-dichlorobenzene (185 mg, 0.7 mmol) in
500 ml ether. The Grignard reaction was initiated with heating to 358C for
30 min. After cooling to room temperature, [35S]S8 (12 mCi, stock solution in
benzene) was added and the mixture aged for 2 h. The reaction was quenched
with 1 ml of 1.0 N HCl, diluted with methylene chloride (10 ml). The phases
were separated and the organic phase dried over MgSO4 and filtered. A count
of the solution indicated 7 mCi. The dichloromethane solution was treated
directly with KNO3 (10 mg) and SO2Cl2 (35 ml) and aged 16 h at room
temperature. HPLC analysis (Zorbax RX C8, 50/50 A/B, A=CH3CN,
B=0.1% TFA, rt=15.9 min) showed formation of the desired [35S]3,5-
dichlorobenzenesulfonyl chloride formation in 47% radiochemical yield. The
organic phase was stirred vigorously with aqueous sodium bicarbonate
solution to hydrolyze the sulfonyl chloride and the phases separated.
The resulting aqueous phase was loaded on an Oasis HLB 1 g cartridge.
Elution with 3 volumes of water, followed by 20/80 CH3CN/water afforded
4 mCi of 98% radiochemically pure [35S]3,5-dichlorobenzenesulfonic
acid. HPLC analysis (Zorbax RX C8, 20/80 A/B, A=CH3CN, B=0.1%
TFA, rt=11 min). The aqueous phase was concentrated by a stream of N2 and
the resulting solid dried in vacuo for 1 h. The solids were slurried into
methylene chloride (5 ml) and 1 ml of DMF and 50 ml of oxalyl chloride were
added. The reaction mixture was aged at room temperature overnight, then
quenched with water (2 ꢀ 5 ml), washed with 10% aqueous sodium
bicarbonate solution (5 ml) and dried twice over MgSO4 to give 3.8 mCi of
[35S]3,5-dichlorobenzenesulfonyl chloride.
[35S]2-Napthylenesulfonyl chloride
To a flame dried flask containing Mg (51 mg, 2.12 mmol) and a crystal of
iodine was added 2-bromonapthylene (250 mg, 1.2 mmol) in 2 ml of ether.
The Grignard reaction was initiated with heating to 358C for 30 min. After
cooling to room temperature, [35S]S8 (150 mCi, stock solution in benzene) was
added and the mixture aged for 2 h. The reaction was quenched with 2 ml of
aqueous ammonium chloride and diluted with methylene chloride (10 ml).
The phases were separated and the organic phase dried over MgSO4
and filtered. A count of the solution indicated 75 mCi. The dichloromethane
solution was treated directly with KNO3 (10 mg) and SO2Cl2 (75 ml) and
aged 16 h at room temperature. HPLC analysis (Zorbax RX C18, 30/70 A/B
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 275–283

SYNTHESIS OF [35S]
281
to 100 A over 20 min, A=CH3CN, B=0.1% TFA, rt=18 min) showed
formation of the desired [35S]2-naphthylenesulfonyl chloride in 47 (25 mCi)
radiochemical yield.
[35S]Benzenesulfonyl chloride
To a 08C solution of phenyl magnesium bromide in THF (1 ml, 1.0 M, 1 mmol)
under N2 was added [35S]S8 (stock solution in benzene, 50 ml, 2.2 mCi). The
mixture was aged 1 h at room temperature. HPLC analysis (Zorbax RX C18,
30/70 A/B to 100 A over 20 min, A=CH3CN, B=0.1% TFA, rt=14 min)
showed [35S]thiophenol formation in 50% radiochemical yield.4 The reaction
was quenched with 1 ml of 1.0 N HCl and diluted with methylene chloride
(5 ml). The phases were separated and the organic phase dried over MgSO4
and filtered. A count of the solution indicated 1.75 mCi. The dichloromethane
solution was treated directly with KNO3 (5 mg) and SO2Cl2 (25 ml) and aged
16 h at room temperature. HPLC analysis (Zorbax RX C18, 30/70 A/B to 100
A over 20 min, A=CH3CN, B=0.1% TFA, rt=13.2 min) indicated formation
of [35S]benzenesulfonyl chloride in 40% yield.
[35S]3-Trifluoromethylbenzenesulfonyl chloride
To a solution of 1-iodo-3-trifluoromethylbenzene (189 mg, 0.695 mmol)
in anhydrous THF (1.0 ml) was added n-BuLi (435 ml, 0.696 mmol) at ꢁ788C
under N2. After stirring at ꢁ788C for 30 min, 100 ml of the aryl lithiate solution
was added dropwise to a solution of [35S]S8 (100 mCi, stock solution in
toluene). The reaction mixture was allowed to warm to room temperature
and aged for 1 h, then cooled to 08C, and quenched with 1 ml of 1.0 N HCl.
The mixture was extracted with methylene chloride (4 ꢀ 2 ml) and the
combined organic phase dried over MgSO4 and filtered. The dichloromethane
solution was treated directly with KNO3 (25 mg) and SO2Cl2 (50 ml) and
aged 16 h at room temperature. The organic phase was stirred vigorously
with water and the phases separated the resulting aqueous phase was loaded
on an Oasis HLB 1 g cartridge. After washing with 3 volumes of water
the [35S]acid was eluted with 20/80 CH3CN/water to afford 14 mCi of
97% radiochemically pure [35S]3-trifluoromethylbenzene sulfonic acid.
HPLC analysis (Zorbax RX C8, 20/80 A/B, A=CH3CN, B=0.1% TFA,
rt=8 min). The aqueous phase was concentrated and the resulting solid
dried in vacuo for 1 h. The solids were slurried into methylene chloride (5 ml)
and 1 ml of DMF and 50 ml of oxalyl chloride were added. The reaction
mixture was aged at room temperature overnight, then quenched with water
(2 ꢀ 5 ml), washed with 10% aqueous sodium bicarbonate solution (5 ml) and
dried twice over MgSO4 to give 13.8 mCi of [35S]3-trifluromethylbenzenesul-
fonyl chloride.
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 275–283

282
M. A. WALLACE ET AL.
[35S]3-Cyanobenzenesulfonyl chloride
To a solution of 1-iodo-3-cyanobenzene (51 mg, 0.267 mmol) in anhydrous
THF (1.0 ml) was added n-BuLi (165 ml, 0.267 mmol) at ꢁ788C under N2.
After stirring at ꢁ788C for 30 min, 100 ml of the [35S]S8 (18 mCi) in toluene
(100 ml) was added dropwise to the anion solution. The reaction mixture was
quenched with 1 ml of saturated ammonium chloride at ꢁ788C. The mixture
was extracted with methylene chloride (4 ꢀ 2 ml) and the combined organic
phase dried over MgSO4 and filtered. The dichloromethane solution was
treated directly with KNO3 (25 mg) and SO2Cl2 (50 ml) and aged 16 h at room
temperature. To the organic phase was added 50 ml of pyridine and 100 ml of
water and stirred vigorously to hydrolyze the [35S]sulfonyl chloride. The
phases were separated and the resulting aqueous phase was loaded on an Oasis
HLB 1 g cartridge. After washing with 3 volumes of water the [35S]acid was
eluted with 20/80 CH3CN/water to afford 5 mCi of 97% radiochemically pure
[35S]3-cyanobenzenesulfonic acid. HPLC analysis (Zorbax RX C8, 20/80 A/B,
A=CH3CN, B=0.1% TFA, rt=12 min) The aqueous phase was concentrated
and the resulting solid dried in vacuo for 1 h. The solids were slurried into
methylene chloride (5 ml) and 1 ml of DMF and 50 ml of oxalyl chloride were
added. The reaction mixture was aged at room temperature overnight, then
quenched with water (2 ꢀ 5 ml), washed with 10% aqueous sodium
bicarbonate solution (5 ml) and dried twice over MgSO4 to give 4.8 mCi of
[35S]3-cyanobenzenesulfonyl chloride.
[35S]n-Butanesulfonyl chloride
To a solution of butyl magnesium bromide (1 ml, 2.0 M, 2 mmol) under N2 was
added [35S]S8 (stock solution in benzene, 75 ml, 3 mCi). The mixture was aged
1 h at room temperature. The reaction was quenched with 1 ml of 1.0 N HCl,
diluted with methylene chloride (5 ml). The phases were separated and the
organic phase dried over MgSO4 and filtered. A count of the solution indicated
1.4 mCi. The dichloromethane solution was treated directly with KNO3 (5 mg)
and SO2Cl2 (25 ml) and aged 16 h at room temperature. HPLC analysis
(Zorbax RX C18, 30/70 A/B to 100 A over 20 min, A=CH3CN, B=0.1%
TFA, rt=9 min) demonstrated [35S]butanesulfonyl chloride formation in 60%
radiochemical yield.
[35S]Sulfonamide 2
3.9 mg of amine 1 and 4 mg of di-tert-butylmethyl pyridine was dissolved in
20 ml of methylene chloride. [35S]3,5-Dichlorobenzenesulfonyl chloride in
methylene chloride (5.5 mCi) was concentrated by atmospheric distillation to a
volume of approximately 75 ml and added to the amine solution. The mixture
was aged at room temperature for 2 h, then quenched directly into methanol
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 275–283

SYNTHESIS OF [35S]
283
(1 ml), THF (1 ml) and water (1 ml). 5 mg of lithium hydroxide was added and
the mixture aged for 1 h at room temperature. HPLC analysis (Zorbax RX
C18, 50/50 A/B, A=CH3CN, B=0.1% TFA, rt=15 min) indicated the desired
[35S]sulfonamide 2 in 80% overall radiochemical yield. The crude tracer was
purified by preparative HPLC (Zorbax RX C18, 50/50 A/B, A=CH3CN,
B=0.1% TFA) to afford 3.45 mCi of pure [35S]sulfonamide 2. Mass spectral
analysis (MS m/e 817 [M+H]+ unlabeled, m/e 820 [M+H]+ labeled)
demonstrated the specific activity of [35S]sulfonamide 2 was 755 Ci/mmol.
Conclusion
A new synthetic methodology has been developed that captures electrophilic
35S8 with aryl or alkyl Grignard reagents or lithiates. The methodology
provides access to a wide variety of substituted [35S]aryl sulfonyl chlorides
upon oxidation and chlorination.}
Acknowledgements
The authors would like to acknowledge Herb Jenkins and Allen Jones for their
analytical work in determining the specific activity of several [35S]sulfonamides
derived from [35S]sulfonyl chlorides prepared as described.
References
1. Dean DC, Nargund R, Pong SS, Chaung L, Griffin P, Melillo D, Ellsworth R, Van
Der Ploeg L, Patchett A, Smith R. J Med Chem 1996; 39: 1767–1770; Kale T, Raab
C, Yu N, Dean D, Distefano M. J Am Chem Soc 2001; 123: 4373–4381; Kale T,
Raab C, Yu N, Aquino A, Dean D, Distefano M. J Label Compd Radiopharm
2003; 46: 29–54.
2. Pepinsky R, Mumford R, Chen L, Leone D, Amo S, Riper G, Whitty A, Dolinski
B, Lobb R, Dean D, Chang L, Raab C, Si Q, Hagmann W, Lingham R.
Biochemistry 2002; 41: 7125–7141; Egger L, Cao J, McCallum C, Kidambi U,
Riper G, McCauley E, Mumford R, Lanza T, Lin L, de Laszlo S, Young D, Yang
G, Dean D, Raab C, Wallace M, Jones A, Hagmann W, Schmidt J, Pepinsky R,
Scott D, Lee WC, Cornebise M, Detmers P. J Pharmacol Exp Ther 2003; 306:
903–913.
3. van Leusen AM, Hundscheid FJ, Tandon VK, Rouwette P. Tetrahedron 1987; 43:
5073–5088; Tercio J, Ferreria B, Catani V, Comasseto JV. Synthesis 1987; 2:
149–153.
4. Park YJ, Shin HH, Kim YH. Chem Lett 1992; 8: 1483–1486.
5. Mallon JM, Bebb RL. Chem Rev 1969; 69: 693–755.
} It has been discovered that the resulting aqueous waste from the oxidation/chlorination reaction gives off
volatile radioactivity and must be stored in a capped container to prevent contamination.
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 275–283