The synthesis of [carboxamido-14C]SAR240550, [carboxamido- 14C]Iniparib, via monocarboxylation of 1,4-diiodobenzene

Article abstract of DOI:10.1002/jlcr.2983

1,4-Diiodobenzene was monolithiated with n-butyllithium and subsequently carboxylated with ¹⁴CO₂ in 86% yield. The resulting [carboxyl-¹⁴C]-4-iodobenzoic acid was used in the synthesis of [carboxamido-¹⁴C]SAR240

Full text of DOI:10.1002/jlcr.2983

Note
Received 10 September 2012,
Accepted 16 October 2012
Published online 27 November 2012 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.2983
The synthesis of [carboxamido-14C]SAR240550,
[carboxamido-14C]Iniparib, via monocarboxylation
of 1,4-diiodobenzene
†
†
†
*
Thomas J. Gregson, Andrew D. Kohler, and Daniel W. Spurr
1,4-Diiodobenzene was monolithiated with n-butyllithium and subsequently carboxylated with 14CO2 in 86% yield. The resulting
[carboxyl-14C]-4-iodobenzoic acid was used in the synthesis of [carboxamido-14C]SAR240550, [carboxamido-14C]Iniparib.
1,4-diiodobenzene at À78 ꢀC with one equivalent of n-butyllithium
Introduction
and subsequent quenching with 0.9 equivalents of 14CO2
generated from barium [14C]carbonate afforded [carboxyl-14C]-4-
Iniparib (SAR240550, 4-iodo-3-nitrobenzamide) is a novel investi-
gational agent for the treatment of various cancers.1 The poten-
iodobenzoic acid in 86% radiochemical yield. In comparison with
tial chemotherapeutic activity of this compound has long been
the previously described labelled syntheses, this is both the most
recognised.2 To enable ADME (absorption, distribution, metabo-
direct and the highest yielding method. The remainder of the
lism and elimination) and human studies, [carboxamido-14C]
SAR240550 (1) was required. As initial metabolic studies had
indicated that the amide carbon was metabolically stable, we
decided that labelling in that position would be appropriate.
The key labelled intermediate, [carboxyl-14C]-4-iodobenzoic acid
(2), has previously been accessed by a number of means; (1) cyana-
tion of 4-nitrobenzenediazonium salt, reduction and subsequent
Sandmeyer reaction (75%);3 (2) Rosenmund–von Braun monocyana-
tion of 1,4-diiodobenzene followed by hydrolysis (<60%);4 or (3) via
1-bromo-4-trimethylsilylbenzene with a lithium–bromide exchange
quenched by 14CO2 and then replacement of the silyl group with
iodine using iodine monochloride (80%).5 Other nonlabelled
methods have been described, which appeared to be applicable
to radiosynthesis and these include organozinc preparations
from diiodobenzene,6 copper-catalysed carboxylations of 4-
iodophenylboronic esters7 and isopropylmagnesium chloride reac-
tions on fluorinated analogues.8 However, direct monolithiation of
diiodobenzene and CO2 quench has not previously been reported.
Although it has been suggested that such an approach might be
difficult,9 the formation and use of 4-iodophenylithium from 1,4-
diiodobenzene and its reaction with electrophiles has been widely
examined.10 In a number of cases, concerns over the potential issues
synthesis of [carboxamido-14C]SAR240550 (1) required two simple
steps; a nitration, which was achieved in 89% yield with a mixture
of concentrated nitric and sulfuric acids affording the nitroaromatic
(3), formation of the acyl chloride using thionyl chloride and
subsequent amination using ammonium hydroxide in 60% yield.
Thus, [carboxamido-14C]SAR240550 (1), [carboxamido-14C]Iniparib,
was prepared rapidly and in 46% radiochemical yield and in doing
so, we have demonstrated that [carboxyl-14C]-4-iodobenzoic acid
can be successfully prepared by the lithium–halogen exchange
of 1,4-diiodobenzene and subsequent quenching with 14CO2.
Experimental
Barium [14C]carbonate was purchased from GE Healthcare. All steps
were carried out at low specific activity prior to being repeated at high
specific activity. High specific activity materials were characterised by
comparative TLC (to known standards) and 1H-NMR. Merck silica gel 60
F254 TLC plates (Merck KGaA, Darmstadt, Germany) were analysed by
electronic autoradiography using a Packard A202401 model Instantima-
ger (Packard Instrument Company, Meriden, Connecticut, USA) (since
integrated into PerkinElmer, Waltham, Massachusetts, USA). Activities
were determined by liquid scintillation analysis using a Packard Tri-Carb
of disproportionation of 4-iodophenylithium to starting material 1900TR (Packard Instrument Company, Meriden, Connecticut, USA) (since
integrated into PerkinElmer, Waltham, Massachusetts, USA). 1H-NMR data
and dilithiobenzene or reaction of the butyliodide to form 4-iodobu-
tylbenzene were raised.10a-b Such side reactions have been observed
were recorded on a Bruker DRX 500 NMR instrument (Bruker Biospin
Corporation, Billerica, Massachusetts, USA).
when reaction times were extended due to large scale, or when
temperatures were raised for the subsequent reaction. Notably,
the formation of 4-bromophenylithium from 1,4-dibromobenzene
is well-established11 and this has been used as an intermediate to
synthesise 4-bromobenzoic acid.12 With this precedent in mind,
we decided that the lithium exchange and subsequent carboxyla-
Sanofi-Aventis, Isotope Chemistry and Metabolite Synthesis, Willowburn Ave.,
Alnwick, Northumberland NE66 2JH, UK
tion reaction on 1,4-diiodobenzene was worthy of re-examination.
*Correspondence to: Thomas J. Gregson, Covance Laboratories, Willowburn
Avenue, Alnwick, Northumberland, NE66 2JH, UK.
E-mail: tom.gregson@covance.com
Results and discussion
The preparation of [carboxamido-14C]SAR240550 (1) is outlined
in Scheme 1. Reaction of tetrahydrofuran solution of 2JH, UK.
† Covance Laboratories, Willowburn Avenue, Alnwick, Northumberland, NE66
a
J. Label Compd. Radiopharm 2012, 55 497–498
Copyright © 2012 John Wiley & Sons, Ltd.

T. J. Gregson et al.
[Carboxamido-14C]-4-iodo-3-nitrobenzamide (1)
[Carboxyl-14C]-4-iodo-3-nitrobenzoic acid (3) (1860 MBq, 0.86 mmole) was
partially dissolved in toluene (1.10 mL). N,N-Dimethylformamide was
then added and the vessel was put under an atmosphere of nitrogen.
Thionyl chloride (0.13 mL) was added to the reaction flask, which caused
dissolution of the yellow solid. The reaction was heated to 96 ꢀC for 2 h.
The reaction was then allowed to cool and the solvent and thionyl
chloride were removed under vacuum. The acyl chloride thus produced
was dissolved in tetrahydrofuran (0.6 mL) and this was then added, over
1 min, to a stirred solution of ammonium hydroxide (25–30% as NH3,
2.38 mL). The reaction was allowed to stir for 1 h 15 min under nitrogen
before being diluted with ethyl acetate (7 mL). The phases were
separated and the aqueous layer was extracted with ethyl acetate
(4 Â 8 mL). The organic phases were combined and chromatographed
on silica gel, using ethyl acetate as eluant. This yielded [carboxami-
do-14C]-4-iodo-3-nitrobenzamide (1) (1124 MBq, 0.52 mmole, 60% radio-
chemical yield) as a yellow solid. dH(DMSO-d6) 7.72 (1H, broad s), 7.84
(1H, dd, J 2.0, 8.5), 8.22 (1H, d, J 8.5), 8.25 (1H, broad s), 8.34 (1H, d, J 2.0).
Scheme 1. Synthesis of [carboxamido-14C]SAR240550.
Acknowledgements
[Carboxyl-14C]-4-iodobenzoic acid (2)
The authors wish to thank Dr. S. J. Byard for the NMR spectra and
Dr. G. J. Ellames for the assistance in editing the manuscript.
(The preparation was performed on a glass manifold attached to a high-
vacuum pump). To a solution of 1,4-diiodobenzene (468 mg, 1.42 mmole)
in tetrahydrofuran (3.5 mL) at À78 ꢀC, n-butyllithium solution (2.5 M in
hexanes, 570 mL, 1.42 mmole) was added dropwise. This afforded a
yellow suspension that was stirred at À78 ꢀC for 1 h 20 min before freez-
ing with liquid nitrogen. In a separate flask containing concentrated sul-
furic acid (6 mL), barium [14C]carbonate (2696 MBq, 248 mg, 1.24 mmole)
was introduced very slowly using a solid-addition tube. The [14C]carbon
dioxide thus produced was transferred to the frozen reaction mixture
that was then sealed, taken to À78 ꢀC and stirred for 3 h. The reaction
mixture was then refrozen with liquid nitrogen and the vacuum was
replaced with a flow of nitrogen. Aqueous ammonium chloride solution
(2 M, 1.5 mL, 3 mmole) was added and the mixture was allowed to room
temperature and stirred overnight under nitrogen. Aqueous sodium
hydroxide solution (0.5 M, 20 mL) was added and the layers were
separated. The organic phase was extracted with further aqueous sodium
hydroxide (0.5 M, 20 mL). The aqueous layers were combined and
aqueous hydrochloric acid (1 M, 25 mL) was added to afford a thick, white
precipitate that was stirred for 10 min. Ethyl acetate (2 Â 50 mL) was
then used to extract the aqueous phase. Combined extractions were
dried over anhydrous sodium sulfate, filtered and evaporated to afford
Conflict of Interest
The authors did not report any conflict of interest.
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[Carboxyl-14C]-4-iodo-3-nitrobenzoic acid (3)
Concentrated sulfuric acid (1.15 mL) was added to [carboxyl-14C]-4-iodo-
benzoic acid (2) (2269 MBq, 1.04 mmole) affording a red suspension. A
mixture of concentrated sulfuric acid with concentrated nitric acid
(0.5 mL, 1:2 vol) was then added and the mixture was stirred under nitro-
gen. A yellow solution was formed with a white solid adhering to the
sides of the flask. By manipulation of the flask, the majority of the solid
was moved into solution and was stirred overnight. Cold water (5 ꢀC,
12 mL) was added to the reaction mixture producing a yellow precipitate.
Ethyl acetate (12 mL) was then added which dissolved the precipitate,
and the phases were separated. The aqueous layer was further extracted
with ethyl acetate (30 mL), and the combined organics were dried over
anhydrous magnesium sulfate, filtered and evaporated to afford a yellow
solid. This was purified by column chromatography on silica gel eluting
rapidly with 7% methanol, 1% acetic acid in dichloromethane to afford
[carboxyl-14C]-4-iodo-3-nitrobenzoic acid (3) as a fine, yellow powder
(2028 MBq, 0.93 mmole, 89% radiochemical yield). dH(DMSO-d6) 7.85
(1H, dd, J 2.0, 8.0), 8.23 (1H, d, J 8.0), 8.31 (1H, d, J 2.0).
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Copyright © 2012 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2012, 55 497–498