[U-14C]-and [13C6]-1,3-dibromobenzene; Useful precursors with a rare substitution pattern in the synthesis of isotopologs

Article abstract of DOI:10.1002/jlcr.1886

A four-step procedure for the preparation of [U-¹⁴C]-1,3- dibromobenzene and [¹³C₆]-1,3-dibromobenzene, from the corresponding bromobenzene, has been developed in a 30% yield. The products were isolated in a high specific activity, 2.6 GBq/mmol, and highest possible ¹³C incorporation. Copyright

Full text of DOI:10.1002/jlcr.1886

Research Article
Received 22 December 2010,
Revised 21 January 2011,
Accepted 7 March 2011
Published online 25 April 2011 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.1886
[U-14C]- and [13C6]-1,3-dibromobenzene;
useful precursors with a rare substitution
pattern in the synthesis of isotopologs
Ã
Jonas Malmquist
A four-step procedure for the preparation of [U-14C]-1,3-dibromobenzene and [13C6]-1,3-dibromobenzene, from the
corresponding bromobenzene, has been developed in a 30% yield. The products were isolated in a high specific activity,
2.6 GBq/mmol, and highest possible 13C incorporation.
Keywords: isotopically labelled synthesis; C-14; C-13; 1,3-dibromobenzene; 13C; 14C; m-dibromobenzene; stable labelled synthesis
½
13C6ꢀNitrobromobenzene
Introduction
[13C6]Nitrobromobenzene was prepared as for [U-14C]nitro-
bromobenzene with similar yield. 13C NMR (125.7 MHz, DMSO-
d6) d ppm 146.8 (t), 134.7 (t), 132.8 (t), 129.3 (t), 112.8 (t). GC-MS
m/z 207, 209 (Mꢁ).
Isotopologs of 1,3-dibromobenzene1 have been scarcely used
over the years for the preparation of isotopically modified
substances with a meta substitution pattern. To be able to
prepare isotopologs of a candidate drug, a method was
developed for the preparation of [U-14C]- and [13C6]-1,3-
dibromobenzene from [U-14C]bromobenzene and [13C6]bromo-
benzene, respectively.
½U-14CꢀBromoaniline hydrochloride (4)
[U-14C]Nitrobromobenzene, 3, (891 mg, 2.08 mmol) was mixed
with tin(II) chloride dihydrate (1.4 mg, 6.2 mmol) in ethyl acetate
(5 mL). The mixture was heated to 781C under nitrogen. Two
extra portions of tin(II) chloride dihydrate (470 mg, 2.1 mmol)
were added to complete the reduction. The reaction was
concentrated. The residue was slurried in dichloromethane and
filtered through silica (5 g), eluting with dichloromethane
and dichloromethane/methanol 10/1. Hydrogen chloride in
diethyl ether (8.33 mL, 8.33 mmol) was added. The mixture
was concentrated to give [U-14C]bromoaniline hydrochloride, 4,
(765 mg, ꢂ100%). GC-MS m/z 169, 173, 175, 177, 179 (Mꢁ).
Experimental
General methods
All solvents used were analytical grade and commercially
available. Anhydrous solvents were routinely used for reactions.
Reactions were typically run under an inert atmosphere of
nitrogen or argon. 1H spectra were recorded on a Bruker
1
DRX600 NMR Spectrometer, H spectra were referenced to TMS
which was set to 0 ppm. Mass spectra were recorded on a gas
chromatograph coupled mass spectrometer with electron
impact ionization. Liquid scintillation analysis was performed on
½
13C6ꢀBromoaniline hydrochloride
a PACKARD TRI-CARB 2900TR. Thin layer chromatography (TLC) [13C6]Bromoaniline hydrochloride was prepared as for [U-14C]
was performed on Merck TLC-plates (Silica gel 60 F254) and bromoaniline hydrochloride with a similar yield. GC-MS m/z 177,
UV-light (254nm) visualized the spots. Flash column chromato- 179 (Mꢁ).
graphy was performed on a RedisepTM prepacked column.
½U-14CꢀDibromoaniline hydrochloride (5) and ½U-14Cꢀtribromo-
aniline hydrochloride (6)
½U-14CꢀNitrobromobenzene (3)
[U-14C]Bromoaniline hydrochloride, 4, (458mg, 2.08mmol) was
made basic with sodium hydroxide (10%, 4 mL) and was extracted
[U-14C]Bromobenzene, 2, (483 mg, 2.86 mmol, 7.4 GBq,
2.6GBq/mmol) was mixed with nitric acid (2.2mL, 31mmol) and
was cooled to 01C. Sulfuric acid (150mL, 2.8 mmol) was added,
carefully, dropwise at 01C four times, subsequently. The reaction
mixture was taken slowly to 211C. The reaction mixture was
quenched with ice (10 g) and was extracted with diethyl ether, in
three portions. The ethereal phase was dried over sodium sulfate,
filtered and concentrated to give the title compound (891 mg,
73%). GC-MS m/z 201, 203, 205, 207, 209 (Mꢁ).
AstraZeneca, Research & Development | Innovative Medicines, Isotope Chemistry,
Screening and Profiling Global DMPK IM, So¨derta¨lje, SE-151 85, Sweden
*Correspondence to: Jonas Malmquist, AstraZeneca, Research & Development |
Innovative Medicines, Isotope Chemistry, Screening and Profiling Global DMPK
IM, So¨derta¨lje SE-151 85, Sweden.
E-mail: jonas.malmquist@astrazeneca.com
J. Label Compd. Radiopharm 2011, 54 408–410
Copyright r 2011 John Wiley & Sons, Ltd.

J. Malmquist
Br
Br
Br
14C
Br
14C
Br
14C
14C
NO2
NH2
14CH 14CH
14CH 14CH
14C
14C
14C
14CH
14CH
i
ii
14CH 14CH
14CH 14CH
14C
14CH 14CH
14C
14CH 14CH
14CH
14CH 14CH
14CH
14CH 14CH
14CH
NO2
NH2
mix
mix
2
3
4
Scheme 1. (i) HNO3/H2SO4, (ii) SnCl2.
Br
Br
Br
14C
14C
14C
NH2
14CH 14CH
14C 14CH
14CH 14CH
14CH 14C
i
4
14C
14C
14CH 14C
14CH
Br
14C
NH2
Br
14C
NH2
Br
Br
mix
5
6
ii
ii
Br
Br
14C
14C
14CH 14CH
14CH 14CH
14C 14C
14CH 14C
14CH
Br
Br
14CH
Br
1
7
Scheme 2. (i) HMTAB, (ii) H3PO2, NaNO2, Cu2O.
with dichloromethane (10 mL) in four portions (phase separation
[13C6]Tribromoaniline hydrochloride was isolated with
a
by centrifuge). The organic phase was washed with water (3 mL) similar yield. GC-MS m/z 333, 335, 337, 339 (Mꢁ).
in three portions, was dried over sodium sulfate and was filtered.
2
HMTAB (478mg, 1.0 mmol) was added portionwise (10 in all)
until bromination was complete. The reaction mixture was filtered
½U-14Cꢀ-1,3-Dibromobenzene (1)
[U-14C]Dibromoaniline hydrochloride, 5, (332mg, 1.11mmol) was
dissolved in hypophosphorous acid (4.46 mL, 44mmol) and was
cooled to 01C. Sodium nitrite (191mg, 2.77mmol), dissolved in
water (1mL), was added. Dichloromethane (5mL) and then
copper(I) oxide (3mg, 0.02 mmol) were added at 01C. After 4 h the
organic phase was separated and the water phase was extracted
with dichloromethane (2 ꢃ 2 mL). The combined organic phase
was dried over sodium sulfate, was filtered and concentrated. The
product was bulb-to-bulb distilled at 60–701C at 0.8 mbar on a
kugelrohr apparatus to give 2.22 GBq [U-14C]-1,3-dibromobenzene,
1, (213 mg, 77%, S.A. 2.6GBq/mmol). 1H NMR (600 MHz, DMSO-d6)
d ppm 7.31 (t, J = 8.04Hz, 1H) 7.62 (dd, J = 7.97, 1.85Hz, 2H) 7.85
(m, 1H). GC-MS m/z 234, 236, 238, 240, 242, 244 (Mꢁ).
through silica (4 g) and was eluted with dichloromethane and
dichloromethane/methanol 10/1. The eluate was carefully con-
centrated with a stream of nitrogen. The distillate was trapped in
a dry-ice/ethanol cooled collector. The residue was chromato-
graphed on silica (12 g) using heptane to heptane/ethyl acetate
4/1 (Rfꢂ0.3) as eluent. Pooled fractions were mixed with
hydrogen chloride in dioxane (0.52mL, 2.1 mmol). The mixture
was concentrated to give [U-14C]Dibromoaniline hydrochloride, 5,
(332mg, 53%). GC-MS m/z 253–269 (Mꢁ).
Fractions containing [U-14C]tribromoaniline were pooled and
hydrogen chloride in dioxane (0.52 mL, 2.1 mmol) was added.
The mixture was concentrated to give [U-14C]tribromoaniline
hydrochloride, 6, (175 mg, 22%). GC-MS m/z 327, 329, 331, 333,
335, 337 (Mꢁ).
½
13C6ꢀ-1,3-Dibromobenzene
½
13C6ꢀDibromoaniline hydrochloride and ½13C6ꢀtribromoaniline
hydrochloride
[13C6]-1,3-Dibromobenzene was prepared as for [U-14C]-1,3-
dibromobenzene with a similar yield. 1H NMR (600 MHz,
DMSO-d6) d 7.43 (m, 1H), 7.72 (m, 1H), 7.92 (m, 1H) ppm. 13C
NMR (126 MHz, DMSO-d6) d ppm 122.5 (m), 130.4 (m), 132.2 (m),
133.4 (m). GC-MS m/z 241, 243, 245 (Mꢁ).
[13C6]Dibromoaniline hydrochloride was prepared as for
[U-14C]dibromoaniline hydrochloride with a similar yield. GC-
MS m/z 255, 257, 259 (Mꢁ).
J. Label Compd. Radiopharm 2011, 54 408–410
Copyright r 2011 John Wiley & Sons, Ltd.
www.jlcr.org

J. Malmquist
prepared in the same way from [13C6]bromobenzene with a
similar total yield.
Results and discussions
[U-14C]-1,3-Dibromobenzene 1 was used for the preparation
of [U-14C]-labeled candidate drug, placing the label in the core
of the structure. 2,4,6-Tribromoaniline 6 could be used for the
preparation of 1,3,5-tribromobenzene,3 7, analogous to that
above.
By the nitration of bromobenzene 2 (Scheme 1), a mixture of
nitro-bromobenzenes 3 was obtained. The mixture 3 was
reduced with tin(II) chloride dihydrate in ethyl acetate to give
the corresponding mixture of bromoanilines 4. The mixture 4
was brominated with a bromine complex of hexamethylene
tetraamine (HMTAB) (Scheme 2).2 In order to a minimize
dibromination, the reagent was added in small portions until
the bromination was complete. A 2 to 1 mixture of di- and
tribrominated aniline, 5 and 6, was obtained, which could be
separated chromatographically on silica. The products were
isolated as hydrochloride salts to avoid evaporation in work-up
and to have the material prepared for the diazotisative
deamination. The dibromoaniline hydrochloride mixture 5 was
dissolved in hypophosphorous acid and was diazotized with
sodium nitrite. Following the addition of copper(I) oxide, the 1,3-
dibromobenzene was extracted into dichloromethane upon
formation. [U-14C]-1,3-Dibromobenzene 1 was isolated by a final
distillation, in 30% yield from [U-14C]bromobenzene 2, with
retained specific activity, i.e. 2.6 GBq/mmol.
Conclusions
A good yielding method for the preparation of [U-14C]-1,3-
dibromobenzene 1, with high specific activity, and [13C6]-1,3-
dibromobenzene has been developed.
References
[1] Griess, Jahresbericht ueber die Fortschritte der Chemie
und Verwandter Theile Anderer Wissenschaften, 1867, 609,
536.
[2] M. M. Heravi, N. Abdolhosseini, H. A. Oskooie, Tetrahedron Lett.
2005, 46, 8959–8963.
[3] Stueber, Chem. Ber. 1871, 4, 961.
2,4,6-Tribromoaniline 6 was prepared in a similar way as for
[U-14C]-1,3-dibromobenzene 1. [13C6]-1,3-Dibromobenzene was
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J. Label Compd. Radiopharm 2011, 54 408–410