An Efficient Multigram Synthesis of the Potent Histamine H3 Antagonist GT-2331 and the Reassessment of the Absolute Configuration

Article abstract of DOI:10.1021/jo035264t

GT-2331 is a potent histamine H₃ antagonist which has entered clinical trials. Efficient multigram syntheses of this compound and its enantiomer are described. The literature reports that GT-2331 is the dextrorotatory (+), more potent, enantiom

Full text of DOI:10.1021/jo035264t

An Efficien t Mu ltigr a m Syn th esis of th e
P oten t Hista m in e H3 An ta gon ist GT-2331
a n d th e Rea ssessm en t of th e Absolu te
Con figu r a tion
Huaqing Liu,* Francis A. Kerdesky, Lawrence A. Black,
Michael Fitzgerald, Rodger Henry,
Timothy A. Esbenshade, Arthur A. Hancock, and
Youssef L. Bennani
F IGURE 1. Structures reported for GT-2331 and its enantio-
mer.
Neuroscience Research, Global Pharmaceutical Research
Division, Abbott Laboratories, 100 Abbott Park Road,
Abbott Park, Illinois 60064-6123
2331 in several steps. Recently, a kilogram-scale frac-
tional crystallization chiral separation utilizing chiral
R-methylbenzylamine has been described to prepare
intermediate 4.8
huaqing.liu@abbott.com
Received August 29, 2003
We encountered several problems with key steps of the
reported synthetic route describing the synthesis of GT-
2331 (Scheme 1). Several commercially available chiral
columns were tested, yet in our hands, none gave
sufficient separation of the enantiomers of the n-butyl
ester 3 to be practical for the preparation of multigram
quantities targeted. Also, despite several trials, the
alkylation of acetylene 5 with 3,3-dimethylbutyl iodide
gave less than a 10% yield, due to the propensity of the
acetylenyl anion to induce elimination of HI from the
alkyl iodide and generate 3,3-dimethylbut-1-ene. For
these reasons, an alternative synthesis of GT-2331 was
sought.
We began this approach by attempting to resolve the
acid 79 (Scheme 2), using the Oppolzer sultam as a chiral
auxiliary to form diastereomers (6a + 6b), which could
be separated by methods other than chiral chromatog-
raphy. The camphorsultam diastereomers 6a and 6b
have been reported to be separable with silica gel
chromatography.10 We were gratified to confirm that 6a
and 6b could be separated by flash chromatography on
Abstr a ct: GT-2331 is a potent histamine H3 antagonist
which has entered clinical trials. Efficient multigram syn-
theses of this compound and its enantiomer are described.
The literature reports that GT-2331 is the dextrorotatory
(+), more potent, enantiomer of 4-[2-(5,5-dimethylhex-1-
ynyl)cyclopropyl]-1H-imidazole with the absolute configu-
ration of (1R,2R)-1. However, we found that the dextroro-
tatory, more potent, enantiomer of 4-[2-(5,5-dimethylhex-1-
ynyl)cyclopropyl]-1H-imidazole has the (1S,2S) absolute
configuration. We suggest a reconsideration of the absolute
configuration of GT-2331.
The histamine H3 receptor, discovered 20 years ago,1
is a presynaptic autoreceptor2 that regulates the release
and synthesis of histamine. Recent data have shown that
this receptor also modulates the release of other neu-
rotransmitters, such as acetylcholine, dopamine, GABA,
glutamate, noradrenaline, and serotonin.3 Neurophar-
macological studies of the histaminergic system have
shown the potential for H3 antagonists as therapeutic
agents for disorders involving sleep, thermoregulation,
cognition, food intake, and memory formation.4
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B.; Esbenshade, T. A.; Bitner, R. S.; Nikkel, A. L.; Miller, T.; Kang, C.
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Since the discovery of H3 receptors, various laboratories
have developed potent and selective H3 antagonists.5 The
first such agent to enter clinic trials was GT-2331
(Cipralisant).6 Because researchers may need to test GT-
2331 as an experimental reference agent, we report an
efficient synthesis and also an important finding sug-
gesting that the absolute configuration assigned to the
compound in the literature7 be reconsidered (Figure 1).
The reported preparation for GT-2331 is shown in
Scheme 1. The synthesis used chiral column chromatog-
raphy to resolve the enantiomers of intermediate 3, of
which the (1R,2R) enantiomer was then converted to GT-
* Corresponding author.
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Shankley, N. P.; Young, J . M.; Schunack, W.; Levi, R.; Haas, H. L.
Pharmacol. Rev. 1997, 49, 253. (b) Leurs, R.; Smit, M. J .; Timmerman,
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10.1021/jo035264t CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/09/2003
192
J . Org. Chem. 2004, 69, 192-194

SCHEME 1. Liter a tu r e Rou te to GT-2331
SCHEME 2. Revised Syn th esis of En a n tiom er s of 4-[2-(5,5-Dim eth ylh ex-1-yn yl)cyclop r op yl]-1H-im id a zolea
a
Reagents and conditions: (a) (1S)-(-)-2,10-camphorsultam, DBU/CDI, 40 °C, 46% of single diastereomer after two columns; (b) DIBALH,
CH2Cl2, -78 °C, 3-5 h, 87%; (c) TMSC(Li)N2, THF, -78 to 0 °C, 5 h, 74%; (d) 1.1 equiv of n-BuLi, 1.1 equiv of TMEDA, 1.1 equiv of
HMPA, -20 °C, then, 3,3-dimethylbutyl triflate, -20 to 0 °C, 75%; (e) 2 N HCl, EtOH, 70 °C, 85%.
F IGURE 2. X-ray structure of compound 6b (1S,2S).
silica gel on a multigram scale with clean separation of
the diastereomers. The structure of 6b was confirmed by
X-ray crystallography to be (1S,2S) as shown in Figure
2. The separated diastereomers 6a and 6b of the cam-
phorsultam were efficiently reduced with DIBALH in one
step to give aldehydes 4a and 4b, respectively, in 88%
yield. Utilizing the Colvin rearrangment,11 aldehydes 4a
and 4b were treated with TMSC(Li)N2 to give acetylenes
5a and 5b in one step in 74% yield. We found that the
yield of the coupling reaction of acetylenes 5a and 5b
could be dramatically improved by the use of 3,3-
dimethylbutyl triflate as the reactive alkylating agent,
instead of 3,3-dimethylbutyl iodide, and by running the
reaction in the presence of 1.1 equiv of TMEDA and 1.1
equiv of HMPA. These conditions were able to greatly
reduce the amount of 3,3-dimethylbut-1-ene side product
and provided yields of 75%. After removal of the trityl
groups of 8a and 8b with HCl in ethanol, both enantio-
(9) Burger, A.; Burnabe, M.; Collins, P. W. J . Med. Chem. 1970, 13,
33.
(10) Khan, M. A.; Yates, S. L.; Tedford, C. E.; Kirschbaum, K.;
Philips, J . G. Bioorg. Med. Chem. Lett. 1997, 7, 3017.
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J . Org. Chem, Vol. 69, No. 1, 2004 193

TABLE 1. Ra d ioliga n d Bin d in g a n d Op tica l Rota tion
for En a n tiom er s 1 a n d 2
compd and
absolute
configuration (c, MeOH) affinity (nM)
[R]20
rat H3 binding
D
F IGURE 3. X-ray structure of the L-tartrate of compound 2
(1S,2S) and the D-tartrate of compound 1 (1R,2R).
lit.7 data
1 (1R,2R)
2 (1S,2S)
1 (1R,2R)
2 (1S,2S)
+140 (0.5)
-131 (0.83)
-247 (0.52)
+277 (0.5)
0.12
5.3
data from this report
3.2a
0.26a
mers of the target product GT-2331 were obtained as 1
(1R,2R) and 2 (1S,2S), respectively.
a
Average of >12 experiments.
The 1:1 D-tartaric acid salt of 1 (1R,2R) was prepared
in methanol, as was the 1:1 L-tartaric acid salt of 2
(1S,2S). Both salts were recrystallized from ethyl acetate/
methanol (1:1) to provide crystals suitable for X-ray
crystallographic analysis. The ORTEP diagrams of 1
(1R,2R) and 2 (1S,2S) are shown in Figure 3.
In summary, efficient syntheses of the enantiomers 1
and 2 have been demonstrated. By using the described
synthetic route, we synthesized 14 g of 2 in 38% overall
yield starting from 7. A discrepancy was found between
the physical properties and H3 receptor binding data for
compounds 1 and 2, compared to the values reported in
the literature. For these reasons, we suggest a reconsid-
eration of the literature reported assignment of the
absolute configuration of these compounds. In our work,
we find that the more potent enantiomer of 4-[2-(5,5-
dimethylhex-1-ynyl)cyclopropyl]-1H-imidazole is the (1S,
2S) enantiomer 2.
The histamine H3 receptor affinities were determined
in rat cortical membranes.12,13 The literature7 reports that
GT-2331 is the dextrorotatory, more potent, enantiomer
of 4-[2-(5,5-dimethylhex-1-ynyl)cyclopropyl]-1H-imidazole
and has the (1R,2R) absolute configuration of structure
1. In contrast to that report, we found that (1S,2S) enan-
tiomer 2 is the more potent enantiomer and its optical
rotation sign is dextrorotatory. The opposite enantiomer
1 (1R,2R) was found to have levorotatory optical rotation
and was 12-fold less potent than the (1S,2S) enantiomer
2 (Table 1). Interestingly, the rotation values we obtained
are approximately twice as large as the reported values.
Previous studies with H3 agonists possessing a cyclo-
propyl imidazole moiety lend additional support to our
finding that GT-2331 possesses (S,S) stereochemistry.
Two independent groups observed that the (S,S) enan-
tiomer of 1-(1H-imidazole-4-yl)-2-aminopropane was more
potent in binding to the H3 receptor than the (R,R) enan-
tiomer,14 which is in contrast to the work of Khan et al.10
Ack n ow led gm en t. We are grateful to Dr. Marlon
Cowart and Mr. Robert Altenbach for extensive editing
and advice on design of the manuscript. We thank Dr.
Perry Labib’s help for the large scale-up synthesis of
intermediate 7.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and copies of 1H NMR spectra for all the compounds.
X-ray crystallographic data for compounds 6b, 1, and 2. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O035264T
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