Bagley et al.
JOCArticle
SCHEME 1. Disconnective Strategy for the Synthesis of
VX-745
automated for analogue production. Thus the unusual cen-
tral heterocyclic motif would be prepared by heteroannula-
tion of a (phenylthio)pyridazine, prepared ultimately from
3
,6-dichloropyridazine (2) by an Ullmann-type coupling
with 2,4-difluorothiophenol that was facilitated by micro-
wave irradiation.
Results and Discussion
FIGURE 1. Sample P38R MAPK inhibitors.
Although microwave irradiation has received increasing
attention in recent years as a valuable alternative to the use
of conductive heating for accelerating transformations, in
synthetic chemistry, medicinal chemistry, and the bios-
specificity to SB203580, in particular with regard to its
1
inhibition of the stress-activated JNK kinases.
In 1999 Vertex Pharmaceuticals released the structure of a
new clinical candidate, VX-745 (1), that functioned by ATP
competitive inhibition of p38R MAPK. This compound
displayed potent activity, clinical efficacy, and an exquisite
selectivity profile, effective at 5.0 nM concentration with
4,15
2
0
ciences, it was surprising to find that very few of the many
21
methods available for the synthesis of diaryl sulfides by
1
6
2
2
SNAr or Ullmann-type coupling with copper or palladium
catalysts had been investigated under microwave-assisted
23
1
000-fold selectivity over closely related kinases, including
conditions, despite the great synthetic versatility and
ERK1, JNK1-3, and MK2. This profile, in particular the
high selectivity for p38 MAPKs over JNKs, made the eva-
luation of VX-745 (1) in WS cells compelling, and so we set
out to realize the synthesis of this inhibitor to facilitate its
(
20) (a) Caddick, S.; Fitzmaurice, R. Tetrahedron 2009, 65, 3325.
(b) Kappe, C. O. Chem. Soc. Rev. 2008, 37, 1127. (c) Collins, J. M.;
Leadbeater, N. E. Org. Biomol. Chem. 2007, 5, 1141. (d) Nilsson, P.;
Olofsson, K.; Larhed, M. Top. Curr. Chem. 2006, 266, 103. (e) Wannberg,
J.; Ersmark, K.; Larhed, M. Top. Curr. Chem. 2006, 266, 167. (f) Kappe,
C. O.; Dallinger, D. Nat. Rev. Drug Discovery 2006, 5, 51. (g) Adam, D.
Nature 2003, 421, 571. (h) In Microwaves in Organic Synthesis; Loupy, A.;
Wiley-VCH: Weinheim, 2002. (i) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43,
6250. (j) Hayes, B. L. Aldrichimica Acta 2004, 37, 66. (k) Kuhnert, N. Angew.
Chem., Int. Ed. 2002, 41, 1863. (l) Lidstr €o m, P.; Tierney, J.; Wathey, B.; Westman,
J. Tetrahedron 2001, 57, 9225. (m) Loupy, A.; Petit, A.; Hamelin, J.; Texier-
Boullet, F.; Jacquault, P.; Math ꢀe , D. Synthesis 1998, 1213. (n) Gabriel, C.; Gabriel,
S.; Grant, E. H.; Halstead, B. S. J.; Mingos, D. M. P. Chem. Soc. Rev. 1998, 27,
1
7,18
biological study. Our approach
mido[1,6-b]pyridazinone motif was mindful of the limita-
(Scheme 1) to the pyri-
1
6
tions recorded in the original release, later shown to be
poorly reproducible and low-yielding in further applications
in both academic and industrial laboratories, in particular
19
regarding the formation of the S-heteroaryl bond. In addres-
sing these difficulties, it was hoped that new general micro-
wave-mediated methods, in particular for sulfide formation,
could be realized that were rapid, efficient, and readily
2
13. (o) Galema, S. A. Chem. Soc. Rev. 1997, 26, 233. (p) Caddick, S.
Tetrahedron 1995, 51, 10403. (q) Strauss, C. R.; Trainor, R. W. Aust. J. Chem.
995, 48, 1665.
21) Reported methods for arylsulfide formation by Ullmann-type coup-
ling or S Ar methodology include: (a) Kwong, F. Y.; Buchwald, S. L. Org.
1
(
N
(
14) Godl, K.; Daub, H. Cell Cycle 2004, 3, 393.
Lett. 2002, 4, 3517. (b) Hickman, R. J. S.; Christie, B. J.; Guy, R. W.; White,
T. J. Aust. J. Chem. 1985, 38, 899. (c) Li, G. Y.; Zheng, G.; Noonan, A. F.
J. Org. Chem. 2001, 66, 8677. (d) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40,
1513. (e) Schopfer, U.; Schlapbach, A. Tetrahedron 2001, 57, 3069.
(f) Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1995, 36, 4133.
(g) Zheng, N.; McWilliams, J. C.; Fleitz, F. J.; Armstrong, J. D. III; Volante,
R. P. J. Org. Chem. 1998, 63, 9606. (h) Kosugi, M.; Ogata, T.; Terada, M.;
Sano, H.; Migita, T. Bull. Chem. Soc. Jpn. 1985, 58, 3657. (i) Migita, T.;
Shimizu, T.; Asami, Y.; Shiobara, J.; Kato, Y.; Kosugi, M. Bull. Chem. Soc.
Jpn. 1980, 53, 1385. (j) Kalinin, A. V.; Bower, J. F.; Riebel, P.; Snieckus, V.
J. Org. Chem. 1999, 64, 2986. (k) Itoh, T.; Mase, T. Org. Lett. 2004, 6, 4587.
(l) Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett. 2002, 4, 2803.
(m) Varala, R.; Ramu, E.; Mujahid Alam, M.; Adapa, S. R. Chem. Lett.
2004, 33, 1614. (n) Carril, M.; SanMartin, R.; Dominguez, E.; Tellitu, I.
Chem.-Eur. J. 2007, 13, 5100. (o) Kondo, T.; Shimizu, T. Chem. Rev. 2000,
100, 3205. (p) Lindley, J. Tetrahedron 1984, 40, 1433. (q) Fernandez-
Rodriguez, M. A.; Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128,
2180. (r) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. (s) Buranaprasertsuk,
P.; Chang, J. W. W.; Chavasiri, W.; Chan, P. W. H. Tetrahedron Lett. 2008,
49, 2023. (t) Ranu, B. C.; Saha, A.; Jana, R. Adv. Synth. Catal. 2007, 349,
2690.
(15) Regan, J.; Breitfelder, S.; Cirillo, P.; Glimore, T.; Graham, A. G.;
Hickey, E.; Klaus, B.; Madwed, J.; Moriak, M.; Moss, N.; Pargellis, C.; Pav,
S.; Proto, A.; Swinamer, A.; Tong, L.; Torcellini, C. J. Med. Chem. 2002, 45,
2
994.
16) (a) Bemis, G. W.; Salituro, F. G.; Duffy, J. P.; Cochran, J. E.; Harrington,
E. M.; Murcko, M. A.; Wilson, K. P.; Su, M.; Galullo, V. P. Intl. Patent WO 98/
7098, 1998; Chem. Abstr. 1998, 129, 81749. (b) Bemis, G. W.; Salituro, F. G.;
Duffy, J. P.; Harrington, E. M. U.S. Patent 6,147,080, 2000; Chem. Abstr. 2000,
(
2
1
9
(
33, 350242. (c) Natarajan, S. R.; Doherty, J. B. Curr. Top. Med. Chem 2005, 5,
87. (d) Lee, M. R.; Dominguez, C. Curr. Med. Chem. 2005, 12, 2979.
e) Haddad, J. J. Curr. Opin. Invest. Drugs 2001, 2, 1070.
(
Bagley, M. C.; Davis, T.; Dix, M. C.; Rokicki, M. J.; Kipling, D. Bioorg.
Med. Chem. Lett. 2007, 17, 5107.
(
forming procedure, see: Bagley, M. C.; Dix, M. C.; Fusillo, V. Tetrahedron
Lett. 2009, 50, 3661.
(19) (a) Treu, M.; Jordis, U.; Lee, V. J. Molecules 2001, 6, 959.
b) Natarajan, S. R.; Wisnoski, D. D.; Singh, S. B.; Stelmach, J. E.; O’Neill,
E. A.; Schwartz, C. D.; Thompson, C. M.; Fitzgerald, C. E.; O’Keefe, S. J.;
Kumar, S.; Hop, C. E. C. A.; Zaller, D. M.; Schmatz, D. M.; Doherty, J. B.
Bioorg. Med. Chem. Lett. 2003, 13, 273.
17) For a preliminary communication of our synthesis of VX-745, see:
18) For preliminary communication and optimization of the C-S bond-
(
(22) Thomas, A. W.; Ley, S. V. Angew. Chem., Int. Ed. 2003, 42, 5400.
(23) Tiecco, M. Synthesis 1988, 749.
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