J. Cossy, D. Belotti / Bioorg. Med. Chem. Lett. 11 (2001) 1989–1992
1991
Scheme 3. Synthesis of the pipecolic acid derivative.
Scheme 4. Synthesis of argatroban.
After removal of the tert-butoxycarbonyl group by
HCl/AcOEt at rt, in quantitative yield, compound 8 was
transformed to 9 by treatment with 3-methyl-8-quino-
3. (a) Topol, E. J.; Bonan, R.; Jewitt, D.; Sigwart, U.; Kak-
kar, V. V.; Rothman, M.; de Bono, D.; Fegurson, J.; Will-
erson, J. T.; Strony, J.; Ganz, P.; Cohen, M. D.; Raymond,
R.; Fox, I.; Maranganore, J.; Adelman, B. Circulation 1993,
87, 1622. (b) Cicala, C.; Bucci, M.; De Dominicis, G.; Har-
riot, P.; Sorrentino, L.; Cirino, G. Br. J. Pharmacol. 1999,
ꢂ
line sulfonyl chloride (Et N, CH Cl , 0 C; yield: 86%).
3
2
2
As expected, the hydrogenation of 9 on Pd/C (10% Pd/
C; H ; 1 atm; EtOH, AcOH; rt) effected the debenzyla-
2
1
26, 478.
. (a) Taparelli, C.; Metternich, R.; Ehrhardt, C.; Cook, N. S.
tion of the ester group, the cleavage of the nitro group
and the hydrogenation of the pyridine ring affording
argatroban monohydrate in 90% yield after recrystalli-
4
Trends Pharmacol. Sci. 1993, 14, 366. (b) No
¨
nalt, J.; Kvarnstrom, I.; Linschoten, M.; Musil, D.; Nystro
teberg, D.; Bra-
m,
¨
¨
zation from EtOH/H O, in a 65:35 ratio of the 21-(R)/
2
J.-E.; Zuccarello, G.; Samuelsson, B. J. Med. Chem. 2000, 43,
1705 and references cited therein.
5. Bush, L. R. Cadiosvasc. Drug Rev. 1991, 9, 247.
6. Okamoto, S.; Hijikata, A.; Kikumoto, R.; Tamao, Y.;
Ohkubo, K.; Tezuka, T.; Tonamura, S.; US Patent, 4,101,653,
1
3
ꢂ
25
2
0
1-(S) diastereomers (mp: 177–181 C, [a]D +78 (c 1,
1
2a,17
.2 N HCl)
(Scheme 4).
The synthesis of argatroban was achieved in seven steps
from (ꢀ)-4-methylpiperidine. This synthesis is shorter and
more efficient than the synthesis described previously due
to the separation of the diastereomers 7a and 7b and the
use of the (ꢀ)-trans-benzyl 4-methylpipecolic acid ester
instead of the trans-ethyl 4-methylpipecolic acid ester.
1
7
978.
. Brundish, D.; Bull, A.; Donovan, V.; Fullerton, D. J.;
Garman, S. M.; Hayler, J. F.; Janus, D.; Kane, P. D.;
McDonnell, M.; Smith, G. P.; Wakeford, R.; Walker,
C. V.; Howarth, G.; Hoyle, W.; Allen, M. C.; Ambler,
J.; Butler, K.; Talbot, M. D. J. Med. Chem. 1999, 42,
4
8
584.
. Kikumoto, R.; Tamao, Y.; Tezuka, T.; Tonamura, S.;
Hara, H.; Ninomiya, K.; Hijikata, A.; Okamoto, S. Biochem-
istry 1984, 23, 85.
References and Notes
9
. Shebuski, R. J. In Annual Reports in Medicinal Chemistry;
1
. Markwardt, F. Thromb. Haemost. 1991, 66, 141.
. (a) Vandenbos, A. A.; Deckers, J. W.; Heyndrickx, G. R.;
Bristol, J. A., Ed.; Academic: San Diego, 1999; Vol. 26, p 98.
10. Strupczewski, J. D.; Ellis, D. B.; Allen, R. C. In Annual
Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic:
San Diego, 1991; Vol. 26, p 299.
11. (a) Reviews: Taparelli, C.; Metternich, R.; Ehrhardt, C.;
Cook, N. S. Trends Pharmacol. Sci. 1993, 14, 366. (b) Jaku-
bowski, J. A.; Smith, G. F.; Sall, D. J. Annu. Rep. Med. Chem.
1992, 27, 99.
2
Laarman, G. J.; Suryapranata, H.; Zijlstra, F.; Close, P.; Rij-
nierse, J. J. M. M.; Buller, H. R.; Serruys, P. W. Circulation
1
Weber, P. C. Am. J. Physiol. 1995, 268, C36. (c) Albrightson,
C. R.; Pullen, M.; Wu, H.-L.; Dytko, G.; Hersh, L. B.; Nambi,
P. Mol. Pharmacol. 1995, 47, 1156.
993, 88, 2058. (b) Kruse, H.-J.; Mayerhofer, C.; Siess, W.;