J. H. M. Lange et al. / Tetrahedron Letters 52 (2011) 1303–1305
1305
19. Foloppe, N.; Benwell, K.; Brooks, T. D.; Kennett, G.; Knight, A. R.; Misra, A.;
Monck, N. J. T. Bioorg. Med. Chem. Lett. 2009, 19, 4183–4190.
which can equilibrate with its tautomer 12 (Scheme 2). Subsequent
reaction of 11 with methyl iodide in methanol gave 13 in almost
quantitative yield (99%). Gratifyingly, no chromatographic purifi-
cation was required for these first two steps. The racemic target
compound 14 was obtained32 in 87% yield by the reaction of 13
with commercially available 4-chlorophenylsulfonamide in aceto-
nitrile. The overall yield of this reaction sequence was 78% which
is substantially higher than the original route20 (ꢀ60%). The
atom-efficiency of this novel route was 75% which is considerably
higher than those of the previously described routes. Analogously,
piperidine analogue 15 was prepared in 82% yield from 13 and
commercially available piperidine-1-sulfonamide. The resultant
overall yield in this sequence was 73% being much higher than
the original route21 (ꢀ45%).
20. Lange, J. H. M.; Coolen, H. K. A. C.; van Stuivenberg, H. H.; Dijksman, J. A. R.;
Herremans, A. H. J.; Ronken, E.; Keizer, H. G.; Tipker, K.; McCreary, A. C.;
Veerman, W.; Wals, H. C.; Stork, B.; Verveer, P. C.; den Hartog, A. P.; de Jong, N.
M. J.; Adolfs, T. J. P.; Hoogendoorn, J.; Kruse, C. G. J. Med. Chem. 2004, 47, 627–
643.
21. Lange, J. H. M.; van Stuivenberg, H. H.; Veerman, W.; Wals, H. C.; Stork, B.;
Coolen, H. K. A. C.; McCreary, A. C.; Adolfs, T. J. P.; Kruse, C. G. Bioorg. Med. Chem.
Lett. 2005, 15, 4794–4798.
22. Lange, J. H. M.; van der Neut, M. A. W.; den Hartog, A. P.; Wals, H. C.;
Hoogendoorn, J.; van Stuivenberg, H. H.; van Vliet, B. J.; Kruse, C. G. Bioorg. Med.
Chem. Lett. 2010, 20, 1752–1757.
23. Lange, J. H. M.; den Hartog, A. P.; van der Neut, M. A. W.; Kruse, C. G. Bioorg.
Med. Chem. Lett. 2009, 19, 5675–5678.
24. Lange, J. H. M.; Coolen, H. K. A. C.; van der Neut, M. A. W.; Borst, A. J. M.; Stork,
B.; Verveer, P. C.; Kruse, C. G. J. Med. Chem. 2010, 53, 1338–1346.
25. Trost, B. M. Science 1991, 254, 1471–1477.
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Li, C.; O’Connor, S. P.; Zhang, J.; Shi, M.; Bisaha, S. N.; Wang, Y.; Sitkoff, D.;
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Application of preparative chiral HPLC enabled the active 4S
enantiomers 1 and 2 to be obtained20,21 in multi-kilogram amounts
after scale-up.
A crucial step herein constituted racemisation of the corre-
sponding 4R enantiomers, which were also collected during the
preparative chiral HPLC procedure, under basic conditions and sub-
sequently recycling the respective racemates 14 and 15 in the chi-
ral HPLC separation process. It was found that treatment with 2 N
NaOH in ethanol at room temperature for 20 h resulted in clean
racemisation which is in line with the observed epimerization33
in structural analogues of 1 and 2.
In conclusion, a novel synthetic approach to the highly selective
and orally active cannabinoid CB1 receptor inverse agonist ibipina-
bant (1) and a structural analogue 2 is disclosed. This route com-
bines the use of inexpensive, commercially available reagents
and mild reaction conditions with a high degree of atom-efficiency.
It can be anticipated that the outlined synthetic methodology will
enable easy access to a wide variety of sulfonylguanidine deriva-
tives. Work in this area is currently in progress.
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32. Yields refer to isolated pure products unless otherwise noted and were not
optimized. Selected data for compounds 14 and 15. Synthesis of compound 14: A
Acknowledgements
mixture of
4 (30 g, 117 mmol), absolute EtOH (180 ml) and methyl
isothiocyanate (11.1 g, 152 mmol) was stirred under an N2 atmosphere at
reflux temperature for 3 h. The resulting solid was filtered off and washed with
EtOH (3 Â 70 ml) and dried under vacuum to give 11 as a white solid (35 g, 90%
Chris Kruse, Fabrice Guillier and Uwe Schön are gratefully
acknowledged for their helpful suggestions and Syncom BV (The
Netherlands) for synthetic support. Belal Shadid is thanked for
his contribution to the described racemisation procedure.
yield). Melting point: 181–183 °C. 1H NMR (400 MHz, CDCl3):
d 3.25 (d,
J = 5 Hz, 3H), 4.33–4.45 (m, 1H), 4.63–4.73 (m, 2H), 7.12–7.18 (m, 2H), 7.22–
7.36 (m, 5H), 7.44 (br s, 1H), 7.56 (d, J = 8.7 Hz, 2H). 13C NMR (100 MHz, CDCl3):
d 31.5, 50.6, 58.6, 127.2 (2C), 127.8, 128.5 (2C), 128.85, 128.88 (2C), 129.4 (2C),
136.2, 139.6, 155.9, 177.0. To a stirred solution of 11 (5 g, 15.2 mmol) in MeOH
(150 ml) was added MeI (9.5 ml, 152 mmol). The mixture was heated at 40 °C
(oil bath temperature) overnight under an N2 atmosphere. The solution was
concentrated in vacuum with an oil bath temperature below 45 °C. The residue
was dissolved in CH2Cl2 (300 ml) and washed with saturated aqueous NaHCO3
solution (70 ml) and brine (70 ml), dried over Na2SO4, filtered and
concentrated under vacuum to afford 13 (5.2 g, 99% yield) as a yellow solid.
1H NMR (400 MHz, CDCl3): d 2.64 (s, 3H), 3.25 (s, 3H), 3.88 (dd, J = 11 and
4.5 Hz, 1H), 4.37 (t, J = 11 Hz, 1H), 4.56 (dd, J = 11 and 4.5 Hz, 1H), 7.15–7.33
(m, 7H), 7.56 (d, J = 8.7 Hz, 2H). 13C NMR (100 MHz, CDCl3): d 16.7, 38.5, 49.8,
58.1, 127.2 (2C), 127.4, 127.7 (2C), 128.6 (2C), 129.1 (2C), 130.1, 134.7, 140.0,
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152.5, 154.1.
A stirred solution of 13 (4.00 g, 11.62 mmol) and 4-
chlorobenzenesulfonamide (2.34 g, 12.20 mmol) in MeCN (90 ml) was heated
at reflux temperature for 16 h. The resulting mixture was evaporated under
vacuum. The obtained crude residue was further purified by flash
chromatography
[silica
gel,
eluent
gradient:
petroleum
ether/
EtOAc = 90:10?60:40 (v/v/)] to afford 14 (4.93 g, 87% yield) as a solid. The
1H NMR spectrum and other analytical data of 14 were in accordance with
reported data.20 Synthesis of compound 15: A solution of 13 (5.0 g, 14.5 mmol)
and piperidine-1-sulfonamide (2.5 g, 15.23 mmol) in MeCN (110 ml) was
stirred at reflux temperature overnight. The resulting yellow solution was
evaporated under vacuum. Purification by column chromatography on alumina
(Act. III) eluting with an heptane/EtOAc gradient from 3:1 to 1:1 gave 15 (5.5 g,
82% yield, 99% HPLC purity) as a white solid. Compound 15 crystallized in the
test tubes upon collection from the column (heptane/EtOAc, 2:1). Melting
point: 175–177 °C. The 1H NMR spectrum and other analytical data of 15 were
in accordance with reported data.21
33. Donohue, S. R.; Pike, V. W.; Finnema, S. J.; Truong, P.; Andersson, J.; Gulyás, B.;
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