Towards the synthesis of osteoclast inhibitor SB-242784

Article abstract of DOI:10.1016/S0040-4039(03)00544-6

Osteoclast inhibitor SB-242784 (1) was prepared from pivotal indol intermediate 4. A 'Stille' cross coupling of organotin 2c with bromo acrylate 11 afforded diene 12 which was also obtained via a reduction-isomerization process of enyne 16. Bromoamide 3 was prepared from the corresponding acid 7 which was readily obtained from bromopyruvic acid.

Full text of DOI:10.1016/S0040-4039(03)00544-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3081–3084
Towards the synthesis of osteoclast inhibitor SB-242784
Jose J. Conde,* Michael McGuire and Michael Wallace
Department of Synthetic Chemistry, GlaxoSmithKline Pharmaceuticals, 709 Swedeland, PO Box 1539, King of Prussia,
PA 19406, USA
Received 21 November 2002; revised 21 February 2003; accepted 24 February 2003
Abstract—Osteoclast inhibitor SB-242784 (1) was prepared from pivotal indol intermediate 4. A ‘Stille’ cross coupling of
organotin 2c with bromo acrylate 11 afforded diene 12 which was also obtained via a reduction–isomerization process of enyne
16. Bromoamide 3 was prepared from the corresponding acid 7 which was readily obtained from bromopyruvic acid. © 2003
Elsevier Science Ltd. All rights reserved.
SB-242784 (Scheme 1) has been reported to be a poten-
tial osteoclast inhibitor of the vacuolar H+-ATPase for
the treatment of osteoporosis. Although an alternative
approach was demonstrated in our labs featuring a
‘three-component’ palladium-catalyzed process, it was
neither cost effective nor suitable for large scale
preparation.1
We needed a low cost and reliable synthesis by which
SB-242784 could be prepared on large scale. Herein we
report a highly efficient process for the preparation of
this novel osteoclast inhibitor. For the synthesis of 1 we
envisioned the assembling of 2 and 3 via a cross-cou-
pling process (Scheme 1), where 2 would come from
alkyne 4 which in turn could be prepared from the nitro
Scheme 1.
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00544-6

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10
compound 5 as a result of a reductive cyclization.
Alkylation of 6 with the corresponding alkyne would
afford 5. On the other hand, amide 3 (Scheme 2) could
potentially come from 7 which can be obtained from
bromopyruvic acid (9).
alkyne 4 to (Bu3Sn)BuCuCNLi2 which afforded 2c in
90% yield (Scheme 3).
On the other hand halide 3 was obtained via a ketaliza-
tion–dehydration process in acidic media (Scheme 4) in
60% overall yield. Subsequent hydrolysis of 11 followed
by reaction with amine 86 via the mixed anhydride
intermediate afforded 3.
Thus commercially available dichlorophenyl acetic acid
(Scheme 3), was nitrated under standard conditions2
and then converted into the corresponding acid chlo-
ride.3 The reaction of this acid chloride with bis-
Subsequent reaction of 2c with ester 11 under the
conditions shown in Scheme 5, yielded the desired diene
12 in 80%. When amide 3 was used instead, SB-242784
was obtained in poorer yield (40%).
trimethylsilylacetylene4 in the presence of
a
stoichiometric amount of AlCl3 afforded 5 which was
used as crude in the next step.
Reduction of the nitro group of 55 followed by basic
work-up gave pivotal intermediate 4 in >55% overall
yield from 6. We then thought of using intermediate 2
where M=AlLn or BLn capable to undergo cross-cou-
pling processes with halide 3. The synthesis of 2 pre-
sented more problems than expected since several
attempts to prepare various organoboron derivatives7
2a or organoalanes 2b failed. We then decided to
prepare the corresponding organotin, as the plan was to
perform a ‘Stille’8 cross-coupling reaction with bromide
3. Different conditions reported in the literature9 for
the synthesis of tributyltin species were evalutated. In
our case the best conditions to prepare 2c, was exposing
Although this process was scaled up and proven to be
reliable, we had to somehow eliminate the Bu3SnBr
produced in the reaction. Despite our efforts to remove
organotin in final drug substance, the levels remained
unacceptable. An alternative (Scheme 6) solution to this
problem, was the attempted coupling of 14 under Heck
conditions11 with the corresponding acrylates 15a12 or
15b.13 Unfortunately, none of the desired products were
obtained.
Based on these results, we abandoned this strategy,
however we still wanted to utilize 4 as it is stable and
easy to prepare. Assessing other possibilities, we real-
Scheme 2.
Scheme 3. Reagents and conditions: (a) HNO3, H2SO4, 0°C to r.t., 70%; (b) SOCl2, reflux, 2 h; (c) bis-TMS-acetylene, AlCl3,
CH2Cl2, 0°C; (d) Fe, AcOH, 95oC; (e) NaOH (1N), MeOH, 55% yield from 6; (f) DIBALH or BLn.

J. J. Conde et al. / Tetrahedron Letters 44 (2003) 3081–3084
3083
Scheme 4. Reagents and conditions: (a) HC(OMe)3, H2SO4, MeOH, 82%; (b) pTsOH, 200°C, 86%; (c) LiOH, MeOH, 77.5%; (d)
ClCO2Et, 8, Et3N, CH2Cl2, 5°C to r.t., 71%.
Scheme 5. Reagents and conditions: (a) 3, Pd(PPh3)4, THF, 60°C, 40%; (b) 11, Pd(PPh3)4, THF, 60°C, 80%.
Scheme 6. Reagents and conditions: (a) NaOH (1N), MeOH, r.t., 60%; (b) NaI, TFA, CH2Cl2, r.t., 68%; (c) Fe, AcOH, 60°C, 70%.
obtain 12 via an isomerization process of the unwanted
Z,Z isomer. For that, enyne 16 (Scheme 7) was reduced
via a Lindlar catalyzed hydrogenation obtaining as
expected a Z,Z:E,Z mixture (60:1).17 The catalyst was
removed by filtration and the filtrate directly treated
with catalytic amount of iodine in refluxing toluene
which gave 12 as the sole compound in 66% overall
yield from 16. Subsequent hydrolysis of the ester group
ized that we could prepare enyne 16 by the Sonogashira
reaction between bromoester 11 and 4 (Scheme 7) and
then selectively reduce the triple bond to afford diene
12 with the desired E,Z configuration.14 Accordingly 4
was treated with bromoester 11 in the presence of Pd(0)
to afford 1615 in good yield. 16 was exposed to CrSO4
16
which unfortunately afforded 12 in only 20% yield after
6 days. We then pursued another alternative hoping to
Scheme 7. Reagents and conditions: (a) Pd(PPh3)4, CuI, Et3N, DMF, 75%; (b) CrSO4, DMF, 6 days, 20%; (c) H2, Lindlar, 60 psi;
(d) I2, toluene, reflux, 16 h, 66% from 16; (e) LiOH, MeOH; (f) 8, EDCI, HOBt, CH2Cl2, 60% from 12.

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followed by coupling with amine 8, afforded SB-242784
(1) in 60% yield (2-steps).
Org. Chem. 1986, 51, 4514; (d) Lane, C.; Kabalka, G.
Tetrahedron 1976, 32, 981.
8. (a) Laporte, E.; Lesheski, L.; Kiely, J. Tetrahedron Lett.
1990, 31, 1837; (b) Stille, J. Angew. Chem., Int. Ed. Engl.
1986, 25, 508.
9. (a) Seitz, D.; Lee, S. Tetrahedron Lett. 1981, 22, 4909; (b)
Corey, E.; Suggs, J. J. Org. Chem. 1975, 40, 2554.
10. (a) Betzer, J.; Ardisson, J.; Lallemand, J.; Pancrazi, A.
Tetrahedron Lett. 1997, 38, 2279; (b) Lipshutz, B.;
Ellsworth, E.; Dimock, S.; Renter, D. Tetrahedron Lett.
1989, 30, 2065.
In conclusion we have described a covergent synthesis
of osteoclast inhibitor SB 242784 by using pivotal
intermediate 4 as template. From 4 it was possible to
obtain diene 12 by a cross-coupling process as well as
by the reduction–isomerization of the Z,Z:E,Z mixture.
11. (a) Jeffery, T. Tetrahedron Lett. 1985, 26, 2667; (b) Dieck,
H.; Heck, R. J. Am. Chem. Soc. 1974, 96, 1133; (c) Heck,
R.; Nolley, J. J. Org. Chem. 1972, 37, 2320.
12. 15a was prepared from pyruvic acid following the same
conditions shown in Scheme 4.
13. For the synthesis of 15b see also Scheme 4.
14. (a) Miossec, B.; Danion-Bougot, R.; Danion, D. Synthe-
sis 1994, 1171; (b) Ratovelomanana, V.; Linstrumelle, G.
Tetrahedron Lett. 1981, 22, 315; (c) Sonogashira, K.;
Tohda, V.; Hagihara, N. Tetrahedron Lett. 1975, 16,
4467.
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