Synthesis of acyl[35S]sulfonamides: Coupling of high specific activity [35S]methane sulfonamide with acids and acid chlorides

Article abstract of DOI:10.1002/jlcr.2974

Direct coupling of high specific activity [³⁵S] methanesulfonamide, generated from [³⁵S]methanesulfonyl chloride and ammonia, with acids and acid chlorides afforded the corresponding [ ³⁵S]acyl sulfonamides in excellent yi

Full text of DOI:10.1002/jlcr.2974

Note
Received 24 July 2012,
Revised 14 August 2012,
Accepted 21 September 2012
Published online 23 October 2012 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.2974
Synthesis of acyl[35S]sulfonamides: Coupling
of high specific activity [35S]methane
sulfonamide with acids and acid chlorides
*
Michael Wallace, Alban J. Allentoff, and Samuel Bonacorsi, Jr.
Direct coupling of high specific activity [35S]methanesulfonamide, generated from [35S]methanesulfonyl chloride and ammonia,
with acids and acid chlorides afforded the corresponding [35S]acyl sulfonamides in excellent yields. Examples of high specific
activity [35S]acyl sulfonamides were prepared containing functionality that can be further elaborated through carbon–carbon
or carbon–nitrogen bond forming reactions.
Keywords: [35S]methanesulfonamide; [35S]methanesulfonyl chloride; acyl sulfonamide
flow rate 5 mL/min). LC/MS analyses were performed on a Finningan LXQ mass
spectrometer. NMR spectra were recorded on Bruker Avance II 300 MHz
Introduction
Radioligands labeled with high specific activity sulfur (greater spectrometer. Liquid scintillation counting was performed on a Perkin-Elmer
Tri-Carb Model 2900Tr. [35S]Methanesulfonyl chloride was prepared from
than 750 Ci/mmol) have proven to be very useful tools in biological
reaction of oxalyl chloride with commercially available [35S]methanesulfonate
applications, such as receptor binding and receptor occupancy, and
according to the published procedure.2
offer advantages over 3H or 125I labeled radioligands.1 Although the
preparation of several high specific activity [35S]sulfonamides2 and
Synthesis of [35S]methanesulfonamide
[
35S]sulfones3 have been reported, we sought to expand the
potential functionality of sulfur-35 labeled biologically relevant A methylene chloride stock solution of [35S]methanesulfonyl chloride
(2.0 mCi/mL, 2 mL) was distilled at atmospheric pressure (68 ꢁC) by using
molecules to include acyl sulfonamide containing radioligands.
a water cooled short-path distillation apparatus with 2-inch vigreux column
Acyl sulfonamides can be formed by reaction of an amide with
to a volume of approximately 200 uL. The concentrated solution was added
methanesulfonyl chloride; however, the rigorous reaction conditions
(NaH, refluxing conditions, and long reaction times) precludes this
by syringe to 250uL of saturated ammonia/methylene chloride,† and the
mixture stirred for 1.5h at room temperature. The reaction mixture was
methodology from being adapted to sulfur-35 syntheses.4 Reports
concentrated by nitrogen stream to approximately 100 uL (1.85 mCi) and
have also shown that methanesulfonamide can generally be
aliquoted as needed.
coupled with acids and acid chlorides by using EDC, DCC, and DMAP
to form acyl sulfonamides in good yields.5 Herein, we report the
synthesis of high specific activity [35S]acyl sulfonamides through
the coupling of high specific activity [35S]methanesulfonamide
with representative acids and acid chlorides.
Synthesis of 4-iodo-N-(methyl[35S]sulfonyl)benzamide (representative
procedure of coupling of acid with [35S]methanesulfonamide)
4-Iodobenzoic acid (3mg, 0.012 mmol), EDC (3mg, 0.016 mmol), and DMAP
(4 mg, 0.033 mmol) were combined in methylene chloride (200 uL).
[
35S]methanesulfonamide (1.85 mCi) in methylene chloride (100 uL)
was added, and the mixture stirred overnight at room temperature.
HPLC analysis showed 85% radiochemical conversion to the desired
[
Experimental
35S]acyl sulfonamide. The mixture was diluted with methanol and
General experimental procedure
water and purified by semi-preparative HPLC (method A) to afford
All reagents and solvents used were of ACS grade or higher and used
without further purification. [35S]Methanesulfonate (1400Ci/mmol) was
purchased from Perkin-Elmer. All unlabeled compounds were prepared
and structurally identified by NMR and LC/MS analysis. Reactions were
monitored by HPLC with comparisons made with authentic unlabeled
materials. Final labeled compounds were identified by co-elution with
authentic unlabeled compounds. Radiochemical purities were determined
by HPLC (Rainin Model SD-200, Varian PDA-2 detector, and a Beta-Ram
detector (IN/US Systems Inc.)) using the method as described. (Luna C18(2)
4.6 ꢀ 150 column; mobile phase A = 0.1% TFA in water, B=CH3CN;
gradient 30–100% B over 20 min.) Semi-preparative chromatography
was performed using Rainin Model SD-200 pumps, Rainin UV detector:
254 nm, and Zorbax SB-C8 9.4 ꢀ 250 mm column. General purification
method A (A = 0.1% TFA in water, B=CH3CN; gradient 20–80% B over 45 min;
Radiochemistry, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ
08543, USA
*Correspondence to: Michael Wallace, Radiochemistry, Bristol-Myers Squibb
Company, P.O. Box 4000, Princeton, NJ 08543, USA.
E-mail: Michael.Wallace@BMS.com
† It is important to use ammonia/methylene chloride solution as ammonia/diox-
ane or ammonia/THF led to significant hydrolysis of the [35S]methanesulfonyl
chloride during [35S]methanesulfonamide formation. Any remaining excess
ammonia may react to form unlabeled primary amide, which is easily separable
by preparative HPLC.
J. Label Compd. Radiopharm 2012, 55 474–476
Copyright © 2012 John Wiley & Sons, Ltd.

M. Wallace et al.
Table 1. Syntheses of [35S]acyl sulfonamides
Radiochemical yield (%)*
85, 72
CH3½35Sꢂ SO2ΝΗ2
DMAP;EDC
X = OH, CI
78, 72
CH3½35Sꢂ SO2ΝΗ2
DMAP;EDC
R = I, OCH3
CH3½35Sꢂ SO2ΝΗ2
DMAP;EDC
78
75
CH3½35Sꢂ SO2ΝΗ2
DMAP;EDC
*Isolated radio chemical yields
1.56 mCi (78% isolated radiochemical yield) of 4-iodo-N-(methyl[35S]
sulfonyl)benzamide.
the yields of [35S]acyl sulfonamides in all cases were high for
both aryl and aliphatic acid derivatives. Additionally, [35S]acyl
sulfonamides were formed containing bromide, iodide, and
methoxy (a latent potential triflate group),3 which allow further
functionalization through Pd catalyzed carbon–carbon or carbon–
nitrogen couplings. A halogenated nicotinic acid derivative was
also formed in high yield (entry 3). Isolation of the [35S]acyl
sulfonamides from the reaction mixtures by semi-preparative
HPLC was straightforward and afforded clean [35S]products
with greater than 98% radiochemical purity.
Synthesis of N-(methyl[35S]sulfonyl)benzamide (representative procedure
of coupling of acid chloride with [35S]methanesulfonamide)
Benzoyl chloride (3.5mg, 0.025mmol) and Hunig’s base (8uL, 0.045mmol)
were combined in methylene chloride (200uL). [35S]methanesulfonamide
(2mCi) in methylene chloride (100uL) was added, and the mixture stirred
overnight at room temperature. HPLC analysis showed 87% radiochemical
conversion to the desired [35S]acyl sulfonamide. The mixture was diluted
with methanol and water and purified by semi-preparative HPLC
(method A) to afford 1.45 mCi (72% isolated radiochemical yield) of N-
(methyl[35S]sulfonyl)benzamide.
Conclusion
Results and discussion
We have developed a synthetic methodology that provides facile
access to high specific activity [35S]acyl methanesulfonamides
for biological applications by direct coupling of aryl and aliphatic
carboxylic acids and acid chlorides to [35S]methanesulfonamide
under mild conditions. These coupling reactions are high yielding,
robust, and tolerant of functionality. This flexibility allows
further elaboration to tailor the radioligand to suit the needs
of the biological study.
High specific activity [35S]methanesulfonamide was prepared in
excellent yields from [35S]methanesulfonyl chloride by quench-
ing the sulfonyl chloride with a saturated ammonia/methylene
chloride solution. Following concentration, which removed
excess ammonia, a stock solution of the [35S]methanesulfonamide
in methylene chloride was generated. Subsequent coupling of the
[35S]methanesulfonamide with aromatic and aliphatic acids or
acid chlorides proceeded smoothly and efficiently using EDC
and DMAP or Hunig’s base, respectively, in methylene chloride,
affording the corresponding [35S]acyl sulfonamides in high
Conflict of Interest
yields. A summary of our results (Table 1) demonstrates that The authors did not report any conflict of interest.
J. Label Compd. Radiopharm 2012, 55 474–476
Copyright © 2012 John Wiley & Sons, Ltd.
www.jlcr.org

M. Wallace et al.
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