Improved epoxidation methodology for synthesis of the highly selective β2-adrenoceptor antagonist ICI 118551 [erythro (±)-3-isopropylamino-1-(7-methylindan-4-yloxy)butan-2-ol]

Article abstract of DOI:10.1071/C98145

In this communication we describe a much improved methodology for the synthesis of the selective β₂-adrenoceptor antagonist ICI 118551 (1), a procedure which overcomes capricious fractional crystallization and epoxidation methodologies described for its original preparation. Our approach involving a bromohydrin precursor to the key epoxide intermediate (7) yielded an 85:15 mixture of the threo/erythro isomers of (7) which could be conveniently separated by flash chromatography on amine-pretreated silica. This new approach proved much more successful than attempts to separate the precursor alkene isomers (6) by fractional crystallization as described in the original patent literature. The product (1) obtained by using our methodology was found to have identical pharmacological properties to authentic ICI118551 when tested both in vitro and in vivo.

Full text of DOI:10.1071/C98145

C S I R O P U B L I S H I N G
Australian Journal
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Volume 52, 1999
© CSIRO Australia 1999
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Aust. J. Chem., 1999, 52, 153–155
.
Improved Epoxidation Methodology for Synthesis of
the Highly Selective 2-Adrenoceptor Antagonist
ICI 118551 [erythro ( )-3-Isopropylamino-1-
(7-methylindan-4-yloxy)butan-2-ol]
Graham G. Pegg,A,B Terry W. Badran,A Andrew J. Hoey,C
Cli ord M. JacksonA and Martin N. SillenceD
A
School of Chemical and Biomedical Sciences, Central Queensland University,
Rockhampton MC, Qld. 4072.
B
Author to whom correspondence should be addressed.
Department of Biology, University of Southern Queensland,
C
Toowoomba, Qld. 4350.
D
Department of Agriculture, Charles Sturt University,
Wagga Wagga, N.S.W. 2678.
In this communication we describe a much improved methodology for the synthesis of the selective
-
2
adrenoceptor antagonist ICI 118551 (1), a procedure which overcomes capricious fractional crystallization
and epoxidation methodologies described for its original preparation. Our approach involving
a bromohydrin precursor to the key epoxide intermediate (7) yielded an 85 : 15 mixture of the
threo/erythro isomers of (7) which could be conveniently separated by ash chromatography on
amine-pretreated silica. This new approach proved much more successful than attempts to separate the
precursor alkene isomers (6) by fractional crystallization as described in the original patent literature.
The product (1) obtained by using our methodology was found to have identical pharmacological
properties to authentic ICI 118551 when tested both in vitro and in vivo.
Introduction
(3), and this intermediate then subjected to Lewis
acid catalysed rearrangement to produce the indanone
derivative (4). The indanone carbonyl group of (4) is
then removed reductively, and the resultant indanol
(5) reacted with crotyl chloride to a ord the key
alkenyloxy intermediate (6).
Over the past decade, it has been recognized that
long-acting 2-adrenoceptor ( 2-AR) agonists such
as clenbuterol and cimaterol cause carcass reparti-
tioning e ects in animals and in humans, resulting
from concomitant increases in protein accretion and
lipolysis.1 Our group has undertaken a number of
Results and Discussion
studies aimed at determining the mechanisms of
-
2
Synthesis
agonist action in muscle,2
and to ascertain the
6
functional role of 3-adrenoceptors.7
In a recent
In our hands, the four-step conversion12,13 of (2)
into an 85 : 15 trans/cis mixture of (6) was achieved in
67% overall yield. While Hutton had reported that the
isomers of (6) could be separated by low-temperature
fractional crystallization,13 we found this approach
unsatisfactory. Instead we chose to epoxidize the
isomeric mixture and then to attempt separation of
the corresponding threo and erythro epoxides.
9
study we needed to e ect selective 2-AR block-
ade in cattle,10 which required prohibitively expensive
quantities of ICI 118551 [erythro ( )-3-isopropylamino-
1-(7-methylindan-4-yloxy)butan-2-ol] (1). Compound
(1) is the most selective 2-antagonist yet identi ed,
and has also attracted attention for its inverse-agonist
properties.11
Synthetic methodology for preparation of the target
compound (1) is reported in the patent literature,12
and an interesting anecdotal account of the problems
encountered in the industrial-scale preparation of the
drug has been provided by Hutton.13 The synthesis
(Fig. 1) commences with 6-methylcoumarin (2), which
is rst catalytically reduced to the chromen-2-one
Epoxidation of (6) using the peroxyimidate method-
ology described by Hutton13 proved capricious. The
patent report describes the in-situ preparation of the
peroxyimidate derived from acetonitrile and 50% H2O2
in the presence of potassium carbonate, although
no yield was reported for the 5-day reaction with
(6).12 For the industrial-scale synthesis of (1), the
Manuscript received 16 September 1998
᭧ CSIRO 1999
0004-9425/99/020153$ 05.00
10.1071/CH98145

154
Short Communications
corresponding benzonitrile peroxyimidate was found
to react more rapidly with (6); however, the large
amount of benzamide side product caused problems
in the clean-up of the nal product.13 In our hands,
neither m-chloroperbenzoic acid nor the peroxyimidate
approaches gave satisfactory results (typical yield 30%).
Biological Results
The a nity of (1) for 2-adrenoceptors was deter-
mined by using in-vitro organ bath techniques.
A
bovine tracheal strip maintained in oxygenated Tyrode’s
solution was rst contracted with carbachol, and then
relaxation of the tissue was achieved through increasing
concentrations of isoprenaline. Pre-incubation of the
tissue with either 0 1 or 1 0 M CGP 20712A did not
a ect the isoprenaline concentration–response curve sig-
ni cantly, indicating few functional 1-adrenoceptors
in the preparation. In contrast, a reference sample of
ICI 118551 (ICI Pharmaceuticals, Maccles eld, U.K.)
produced concentration-dependent rightward shifts of
the isoprenaline response curves, indicating that the
drug was antagonizing the 2-AR mediated relaxation
induced by isoprenaline. Schild plot analysis pro-
duced a pA2 value of 7 76 0 12 (mean s.e.m.) for
ICI 118551. Likewise, compound (1) synthesized by
the methodology described herein produced rightward
shifts of similar magnitudes, giving a pA2 value of
7 65 0 10, which was not signi cantly di erent to
that found for the reference ICI 118551 sample.
Conclusions
Our synthetic approach to the key threo epoxide
intermediate (7), via the bromohydrin, overcomes the
low yield/purity problems associated with the perox-
yimidate epoxidation methodology described for this
conversion in the patent literature.12 Moreover, we
have developed a convenient chromatographic method
for separating the required threo isomer of (7) from
the minor erythro isomer. This strategy provides an
alternative to separation of the precursor alkene isomers
(6) by low-temperature fractional crystallization.12 The
procedures described in this communication have been
used to prepare several 20-g batches of ICI 118551 (1)
in high purity.
Fig. 1. Synthetic route to ICI 118551.
After some experimentation, we found that the
required threo epoxide (7) could be obtained routinely
in 75% yield from isomeric (6) after a two-step process
and subsequent chromatographic puri cation. Hence
the 85 : 15 trans/cis mixture of (6) was reacted with
N -bromosuccinimide in a 1,2-dimethoxyethane/water
mixture to a ord the bromohydrin, which was then
treated with 1,8-diazabicyclo[5.4.0]undec-7-ene in 1,2-
dimethoxyethane solvent. The resultant 85 : 15 mix-
ture of threo and erythro epoxides (7) was then
subjected to ash chromatography on silica which had
been pretreated with 1% triethylamine in 1 : 20 ethyl
acetate–hexane. Base pre-treatment of the silica in this
manner prevented decomposition of the epoxide during
the chromatographic separation of the isomers. The
threo epoxide (7) was then reacted with isopropylamine
in methanol12,13 to yield the free base (1). The product
obtained was found to be spectroscopically identical
to an authentic sample of ICI 118551 (1).
Experimental
General
1H and 13C n.m.r. spectra of CDCl3 solutions of test com-
pounds were obtained by using a Bruker AMX-300 spectrometer.
Chemical shifts are quoted as values relative to tetramethylsi-
lane. Infrared spectra were recorded with a Perkin–Elmer 1600
Fourier-transform i.r. spectrophotometer. U.v. spectra were
obtained with a Varian DMS-100 spectrophotometer and rou-
tine mass spectra were obtained by using a Shimadzu QP2000
gas chromatography–mass spectrometer incorporating a direct
insertion probe. High-resolution mass spectrometry data were
kindly provided by Dr John MacLeod of the Research School
of Chemistry, Australian National University, Canberra, Aus-
tralia. Analytical thin-layer chromatography employed Merck
Kieselgel G 60F 254 plates. Pressure-assisted ash chromato-
graphy was conducted with Merck silica gel 60, 230–400 mesh.
Elemental analyses were performed either by the Canadian
Microanalytical Service, Delta, BC, Canada, or by the Microan-
alytical service at the Australian National University, Canberra,
Australia.

Short Communications
155
Preparation of 2-Methyl-3-(7-methylindan-4-yloxymethyl)oxiran
(7) by the N-Bromosuccinimide/1,8-Diazabicyclo[5.4.0]undec-
7-ene Methodology
and allowed to equilibrate for 60 min with regular replacement of
the Tyrode’s solution. Indomethacin (3 M) and corticosterone
(100 M) were added to block the uptake of isoprenaline. Next,
the preparations were contracted with 1 M carbachol until a
stable sub-maximal contraction was obtained (2 h). The 1- or
2-AR selective antagonists CGP 20712A and ICI 118551 were
added and allowed to equilibrate for 30 min before initiation
of relaxation. Isoprenaline was added cumulatively at 8-min
intervals when the e ect of the previous addition (8 min) had
reached equilibrium. This induced a concentration-dependent
relaxation from which pA2 values were determined by Schild
plot analysis.
Isomeric (6)12,13 (3 0 g, 14 9 mmol, obtained from 6-
methylcoumarin in 67% overall yield) was dissolved in 1,2-
dimethoxyethane (69 ml) and water (23 ml); N -bromosuccin-
imide (2 78 g, 15 6 mmol) was added, and the reaction mixture
was stirred in the dark for 24 h. Ether (150 ml) was then
added and, after partitioning, the ether layer was washed
with water (40 ml), dried and ltered. Concentration of the
ltrate under vacuum a orded a crude residue which was
then taken up in dry 1,2-dimethoxyethane (50 ml) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (2 28 g, 15 3 mmol) was added.
The reaction mixture was stirred under a nitrogen atmosphere
for 6 h. The reaction mixture was then poured into ether
(150 ml), washed with water, dried and ltered. Concentration
of the ltrate under vacuum and ash chromatography of the
residue on silica pretreated with 1% triethylamine in ethyl
acetate–hexane (1 : 20), a orded the crystalline epoxide as a
colourless solid (2 34 g, 73%), m.p. 61 0–61 5 . 1H n.m.r.
1 39, d, J 2 91 Hz, 3H; 2 10, quintet, J 7 47 Hz, 2H; 2 22,
s, 3H; 2 85, t, J 7 47 Hz, 2H; 2 93, t, J 7 47 Hz, 2H; 3 06,
m, 2H; 4 01, dd, J 5 10, 11 1 Hz, 1H; 4 17, dd, J 3 38,
11 1 Hz, 1H; 6 60, d, J 8 13 Hz, 1H; 6 92, d, J 8 13 Hz, 1H.
13C n.m.r. 17 29, 18 34, 24 47, 29 73, 31 90, 52 50, 57 33,
CGP 20712A (Ciba–Geigy, Basel, Switzerland) and
ICI 118551 (Imperial Chemical Industries, Cheshire, England)
were dissolved in dimethyl sulfoxide. Isoprenaline was obtained
from Sigma Chemical Company (Sigma, St Louis, MO).
Acknowledgments
We are grateful for nancial support of this work
from the Australian Research Council and from the Pri-
mary Industries Research Centre at Central Queensland
University.
68 39, 109 56, 126 47, 127 77, 131 80, 144 95, 153 14. I.r.
References
1
1
(Nujol) 1607, 1495, 1308, 1264, 1079, 868, 801 cm
. Mass
Yang, Y. T., and McElligott, M. A., Biochem. J., 1989,
261, 1.
Sillence, M. N., Pegg, G. G., and Lindsay, D. B., Arch.
Pharmacol., Naunyn-Schmiedeberg’s, 1991, 344, 442.
Sillence, M. N., Mathews, M. L., Spiers, W. G., Pegg,
G. G., and Lindsay, D. B., Arch. Pharmacol., Naunyn-
Schmiedeberg’s, 1991, 344, 449.
Pegg, G. G., Sillence, M. N., Sleeman, M. J., and Lindsay,
D. B., J. Labelled Compd Radiopharm., 1991, 29, 1337.
Moore, N. G., Pegg, G. G., and Sillence, M. N., Am. J.
Physiol.: Endocrinol. Metab., 1994, 267, E475.
Sillence, M. N., Hunter, R. A., Pegg, G. G., Brown, L.,
Mathews, M. L., Magner, T., Sleeman, M., and Lindsay,
D. B., J. Anim. Sci., 1993, 73, 2942.
Sillence, M. N., Moore, N. G., Pegg, G. G., and Lindsay,
D. B., Br. J. Pharmacol., 1993, 109, 1157.
Hoey, A. J., Jackson, C. M., Pegg, G. G., and Sillence, M.
N., Br. J. Pharmacol., 1996, 119, 564.
Hoey, A. J., Jackson, C. M., Pegg, G. G., and Sillence, M.
N., Br. J. Pharmacol., 1996, 119, 712.
Hoey, A. J., Mathews, M. L., Badran, T. W., Pegg, G. G.,
and Sillence, M. N., J. Anim. Sci., 1995, 73, 1754.
spectrum m/z 218 (17%), 148 (60), 133 (58), 91 (30), 57 (55),
43 (100) (Found: C, 76 9; H, 8 3. Calc. for C14H18O2: C,
77 0; H, 8 3%).
2
3
Synthesis of ICI 118551
This oxiran (7) was converted into the title compound (1)
by reaction with isopropylamine in methanol.12 The product
(1) was found to be spectroscopically identical to authentic
ICI 118551 obtained from ICI Pharmaceuticals, Maccles eld,
U.K.
4
5
6
Biological Testing
Bovine trachea were obtained within 30 min of death from
a slaughterhouse and transported to the laboratory in cold
aerated Tyrode’s solution (in mM: NaCl, 136 9; KCl, 5 4;
MgCl2.H2O, 1 05; NaH2PO4.2H2O, 0 42; NaHCO3, 22 6;
CaCl2.2H2O, 1 8; glucose, 5 5; ascorbic acid, 0 28). The
smooth muscle layer of the trachea was dissected free from the
cartilage and epithelial layer, and cut into strips approximately
2 mm wide and 6 mm long. A small stainless steel hook
was placed in one end to connect the tissue to the tissue
holder, and a silk thread connected the tissue at the other
end to a force transducer (Grass FT03, Quincy, MA, U.S.A.).
Force of contraction was recorded with a MacLab system (AD
Instruments, Cannon Hill, Australia) by a Macintosh LC 475
computer. The preparations were suspended under optimum
preload in 25-ml water-jacketed organ baths (35 0 5 ) in
Tyrode’s solution aerated with carbogen (95% O2, 5% CO2),
7
8
9
10
11
Bond, R. A., Le , P., Johnson, T. D., Milano, C. A.,
Rockman, H. A., McMinn, T. R., Apparsundaram, S.,
Hyek, M. F., Kenakin, T. P., Allen, L. F., and Lefkowitz,
R. J., Nature, 1995, 374, 272.
Tucker, H., Eur. Pat. Appl., 1979, No. 79300169.4 (Bulletin
79/17).
12
13
Hutton, J., Chem. Ind. (London), 1989, 134.