A practical and scaleable synthesis of A-224817.0, a novel nonsteroidal ligand for the glucocorticoid receptor

Article abstract of DOI:10.1021/jo0268613

A practical and scaleable synthesis of a novel nonsteroidal ligand for the glucocorticoid receptor A-224817.0 1A is described. The synthesis proceeds in seven steps starting from 1,3-dimethoxybenzene. The biaryl intermediate 5 was prepared by an optimized

Full text of DOI:10.1021/jo0268613

A P r a ctica l a n d Sca lea ble Syn th esis of A-224817.0, a Novel
Non ster oid a l Liga n d for th e Glu cocor ticoid Recep tor †
Yi-Yin Ku,* Tim Grieme, Prasad Raje, Padam Sharma, Howard E. Morton,
Mike Rozema, and Steve A. King
D-R450, Process Chemistry, Global Pharmaceutical, Research and Development, Abbott Laboratories,
North Chicago, Illinois 60064-4000
yiyin.ku@abbott.com
Received December 17, 2002
A practical and scaleable synthesis of a novel nonsteroidal ligand for the glucocorticoid receptor
A-224817.0 1A is described. The synthesis proceeds in seven steps starting from 1,3-dimethoxy-
benzene. The biaryl intermediate 5 was prepared by an optimized high-yielding and high-throughput
Negishi protocol. The quinoline core 8 was constructed by using a modified Skraup reaction. The
final product was obtained by a direct allylation reaction of lactol 10 with allyltrimethylsilane.
The process was accomplished efficiently to produce 1A in 25% overall yield and >99% purity with
simple and practical isolation and purification procedures.
1
0,11
In tr od u ction
A-240610.0 1B,
the S-enantiomer of A-224817.0
8
,9
1
A, has demonstrated equivalent antiinflammatory
1
Glucocorticoids therapy has been used for the treat-
ment of inflammatory diseases for more than forty years.
Synthetic glucocorticoids such as dexamethasone and
activity relative to prednisolone with an improved side
effect profile in vivo. To further evaluate its effectiveness,
an efficient process, which is suitable for large-scale
preparation, was required to prepare a larger quantity
of material to support initial biological studies. Thus, a
practical and scaleable seven-step chromatography-free
process was developed for the preparation of A-224817.0
2
prednisolone3 have been widely used in the clinical
treatment of chronic inflammatory diseases. It is also well
documented that corticosteroid antiinflammatory therapy
causes many undesirable side effects, such as glucocor-
ticoid-induced osteoporosis4 and glucose intolerance.5
These side effects occur because these glucocorticoids
have cross-reactivity with other steroid receptors.6,7
Medicinal chemistry research sought after a nonsteroidal
glucocorticoid receptor selective ligand that would imitate
natural glucocorticoids but differentiate from the meta-
1
A.
Resu lts a n d Discu ssion
Preparation of the biaryl compound 5 was initially
accomplished with a two-step process with an overall
yield of 58%, using a Suzuki protocol (Scheme 1) in
8
8
,9
12
bolic side effects.
which the isolated boronic acid 3 was coupled in the
(6) Weinberger, C.; Hollenberg, S. M.; Ong, E. S.; Harmon, J . M.;
Brower, S. T.; Cidlowski, J .; Thompson, E. B.; Rosenfeld, M. G.; Evans,
R. M. Science 1985, 228, 740-742.
(7) (a) Mulatero, P.; Veglio, F.; Pilon, C.; Rabbia, F.; Zocchi, C.;
Limone, P.; Boscaro, M.; Sonino, N.; Fallo, F. J . Clin. Endocrinol.
Metab. 1998, 83, 2573-2575. (b) Neef, G.; Beier, S.; Elger, W.;
Henderson, D.; Wiechert, R. Steroids 1984, 44, 349-372.
(8) Coughlan, M. J .; Kym, P. R.; Elmore, S. W.; Wang, A. X.; Luly,
J . R.; Wilcox, D.; Stashko, M.; Lin, C. W.; Miner, J .; Tyree, C.; Nakane,
M.; J acobson, P.; Lane, B. C. J . Med. Chem. 2001, 44, 2879-2885.
(9) Elmore, S. W.; Coughlan, M. J .; Anderson, D. D.; Pratt, J . K.;
Green, B. E.; Wang, A. X.; Stashko, M.; Lin, C. W.; Tyree, C. M.; Miner,
J . N.; J acobson, P. B.; Wilcox, D. M.; Lane, B. C. J . Med. Chem. 2001,
4
4, 4481-4491.
†
This article is dedicated to the memory of 100 year old Emeritus
Professor Y. H. Ku of the University of Pennsylvania, who passed away
on September 9, 2002.
(10) Coughlan, M. J .; Elmore, S. W.; Kort, M. E.; Kym, P. R.; Moore,
J . L.; Pratt, J . K.; Wang, A. X.; Edwards, J . P.; J ones, T. K. Patent
(PCT) WO99/41256.
(
1) Schimmer, B. P.; Parker, K. L. Goodman & Gilman’s The
(11) Ku, Y.; Grieme, T.; Raje, P.; Sharma, P.; King, S. A.; Morton,
H. E. J . Am. Chem. Soc. 2002, 124, 4282-4286.
Pharmacological Basis of Therapeutics, 9th ed.; Hardman, J . G.,
Limbird, L. E., Molinoff, P. B., Ruddon, R. W., Eds.; McGraw-Hill: New
York, 1996; pp 1459-1485.
(12) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995,
95, 2457-2483. (b) Suzuki, A. J . Organomet. Chem. 1999, 576, 147-
168. (c) Miyaura, N. In Advances in Metal-Organic Chemistry; Liebe-
skind, L. S., Ed.; J AI: London, UK, 1998; Vol. 6, pp 187-243. (d)
Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich,
F., Stang, P. J ., Eds.; Wiley-VCH: New York, 1998; Chapter 2. (e)
Stanforth, S. P. Tetrahedron 1998, 54, 263-303.
(
(
2) Cohen, E. M. Anal. Profiles Drug Subst. 1973, 2, 163-197.
3) Ali, S. L. Anal. Profiles Drug Subst. Excipients 1992, 21, 415-
5
00.
(
(
4) Gennari, C. Br. J . Rheumatol. 1993, 32, 11-14.
5) Anon. Nutr. Rev. 1976, 34, 185-187.
1
0.1021/jo0268613 CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/20/2003
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J . Org. Chem. 2003, 68, 3238-3240

Practical and Scaleable Synthesis of A-224817.0
SCHEME 1
SCHEME 3
SCHEME 2
the reaction solvent to NMP, the reaction concentration
was increased 10-fold. The reaction time was reduced
from 40 h to less than 2 h. Removal of Pd-catalyst could
then be carried out at room temperature. It was also
found that the filtered reaction mixture could be used
directly in the next step, thus, the isolation step was
eliminated. This modification improved the throughput
1
0-fold. In addition, the decomposition of the isolated
presence of Pd-catalyst with 2-bromo-5-nitrobenzoate 4
at 100 °C in DMF. The concerns with its low overall yield,
long processing time, and tedious isolation and purifica-
tion procedures have led to the development of a highly
efficient alternate Pd-catalyzed cross-coupling procedure
involving a Negishi protocol13 (Scheme 4). This procedure
involves lithiation of 1,3-dimethoxybenzene 2 with n-
BuLi at 0 °C in THF followed by transmetalation with
aminocoumarin 7 intermediate was avoided.
The Skraup reactions14 have been demonstrated as
efficient routes for assembling quinolines. The quinoline
core 8 was constructed by the modified Skraup reaction
with use of the published protocol15 with some variations
(Scheme 4). The reaction was performed in acetone/NMP
in the presence of iodine at high temperature (105 °C)
and pressure for 72 h. The presence of NMP allowed the
reaction to be carried out in higher concentration.
Initially, a tedious column chromatography that required
large volume of solvents8 was needed to purify the
quinoline core 8. It was observed that the desired product
was quite soluble in EtOAc/heptane, while the polymeric
byproducts were not. Thus an improved isolation and
purification procedure was developed involving an ex-
tractive workup procedure. The majority of the byprod-
ucts were removed with a liquid-liquid extraction of
ZnCl
was then coupled directly with 2-bromo-5-nitrobenzoate
in the presence of a palladium catalyst, dichlorobis-
triphenylphosphine)palladium, to produce the desired
2
to generate the organozinc derivative in situ. It
4
(
biaryl compound 5 in essentially quantitative conversion.
The reaction went to completion within 2 h and the
product precipitated out of the reaction mixture, which
simplified the isolation and purification. The desired
product was isolated in excellent yield (90%) and high
purity (99%) by a simple filtration.
2
EtOAc/heptane and H O followed by a filtration. The
The biaryl 5 was then treated with boron tribromide
in a two-step, one-pot protocol 8 in which cleavage of the
methoxy groups was followed by lactone formation to
yield nitrocoumarin 6 in 93% yield (Scheme 4). Initially,
the reduction of the nitrocoumarin 6 to the aminocou-
marin 7 was carried out by hydrogenation with palladium
on carbon in dioxane (Scheme 2). Although the reduction
worked well, large volumes of solvent and long reaction
times (over 40 h) were required due to the poor solubility
of the nitrocoumarin 6 in dioxane. A hot filtration of the
reaction mixture to remove palladium catalyst was also
necessary to prevent the product from precipitating out
of the solution. In addition, isolation of the product from
a water-dioxane suspension involved a slow filtration
during which some product degradation occurred. Fur-
thermore, dioxane as a solvent was not desirable due to
its hazardous nature. Solubility studies with a variety
of solvents revealed that the starting material, nitrocou-
marin 6, and product, aminocoumarin 7, were both highly
soluble in NMP (1-methyl-2-pyrrolidinone). By changing
purity of the isolated product could be further improved
by formation of an HCl salt. The quinoline core 8 was
methylated with dimethyl sulfate in the presence of
potassium tert-butoxide in THF to give the methylated
quinoline lactone 9 in 89% yield (Scheme 4). The lactone
9
was then reduced with DIBAL16 in toluene to produce
the lactol 10 in 79% yield.
The final product A-224817.0 1A was prepared initially
by a two-step reaction sequence8 from the lactol 10:
methylation of lactol 10 in methanol in the presence of
p-TsOH to produce the methyl lactol 11 and allylation
with allyltrimethylsilane (Scheme 3). This reaction se-
quence was demonstrated to work well although chro-
matographic purification of both methyl lactol 11 and the
final product 1A were required.
(
14) (a) Walter, H.; Sauter, H.; Winkler, T. Helv. Chim. Acta 1992,
5, 1274-1280. (b) Eisch, J . J .; Dluzniewski, T. J . Org. Chem. 1989,
54, 1269-1274. (c) Skraup, Z. H. Ber. Dtsch. Chem. Ges.1880, 13,
086-2087.
15) Edwards, J . P.; West, S. J .; Marschke, K. B.; Mais, D. E.;
7
2
(
Gottardis, M. M.; J ones, T. K. J . Med. Chem. 1998, 41, 303-310.
(16) (a) Yamamoto, H.; Maruoka, K. J . Am. Chem. Soc. 1981, 103,
4186-4194. (b) Greene, A. E.; LeDrian, C.; Crabbe, P. J . Am. Chem.
Soc. 1980, 102, 7583-7584.
(
13) (a) Negishi, E.; King, A. O.; Okukado, N. J . Org. Chem. 1977,
2, 1821-1823. (b) Stanforth, S. P. Tetrahedron 1998, 54, 263-303.
c) Miller, J . A.; Farrell, R. P. Tetrahedron Lett. 1998, 39, 6441-6444.
4
(
J . Org. Chem, Vol. 68, No. 8, 2003 3239

Ku et al.
SCHEME 4
It was then discovered that the lactol 10 could be
directly allylated with allyltrimethylsilane after being
purified by crystallization with EtOAc/heptane to produce
the final compound A-224817.0 1A in excellent yield
purity (>99%). The process is highlighted by the develop-
ment of a highly efficient Pd-catalyzed cross-coupling
reaction for the preparation of the biaryl intermediate 5
and a direct allylation procedure to allylation of lactol
10. In addition, the ability to obtain a crystalline solid
for A-224817.0 1A made the isolation and purification of
the final product simple and practical. This column
chromatograph-free process has addressed several con-
cerns related to the scale-up of chemical processes and
is amendable to the large-scale preparation of A-224817.0
1A.
(95%) and purity (96%). The reaction could be carried out
at 0 °C instead of -78 °C under 3-fold concentrated
conditions, using fewer equivalents of reagents (2 instead
of 4 equiv). Initially the final product 1A was isolated as
a foam; it was critical to obtain a crystalline solid for the
final product that would allow the isolation and purifica-
tion procedure to be more practical. After screening a
variety of solvent and solvent combinations, polar sol-
i
vents, such as EtOH or PrOH, were found to effectively
Ack n ow led gm en t. The authors would like to thank
Phil Kym, Steve Elmore, and Mike Coughlan of Medici-
nal Chemistry for their assistance and useful discus-
sions.
crystallize the final product. This made the isolation and
purification of the final product practical and efficient,
thus crude allylation product 1A could be further purified
to high purity (>99%) by simple crystallization and
filtration.
In summary, we have developed an efficient, practical,
and scaleable process for the synthesis of A-224817.0 1A
as a crystalline solid with an overall yield of 25% in high
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O0268613
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