Novel synthesis of isoxazoline indolizine amides for potential application to tropical diseases

Article abstract of DOI:10.1016/j.tetlet.2014.02.003

Synthetically challenging isoxazoline indolizine amide compounds were designed and prepared for potential application to tropical diseases. Indolizine core structures were synthesized strategically as common intermediates for efficient derivatization. The

Full text of DOI:10.1016/j.tetlet.2014.02.003

Tetrahedron Letters 55 (2014) 1936–1938
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel synthesis of isoxazoline indolizine amides for potential
application to tropical diseases
a
a
b
c
d
Yong-Kang Zhang a, , Jacob J. Plattner , Yasheen Zhou , Musheng Xu , Jianxin Cao , Qingquan Wu
⇑
a Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA
b WuXi AppTec (Tianjin) Co., Ltd, 111 Huanghai Road, 4th Avenue TEDA, Tianjin 300457, China
c Shanghai ChemPartner, 998 Ha-lei Road, Zhangjiang High-tech Park, Pudong New Area, Shanghai 201203, China
d Shanghai Medicilon, Inc., 585 Chuanda Road, Zhangjiang High-tech Park, Pudong New Area, Shanghai 201200, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthetically challenging isoxazoline indolizine amide compounds were designed and prepared for
potential application to tropical diseases. Indolizine core structures were synthesized strategically as
common intermediates for efficient derivatization. The chemistry for the syntheses of 8-(5-(3,5-dichloro-
phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)
indolizine-5-carboxamide (3) and 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-
3-yl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-indolizine-8-carboxamide (4) is described in this
Letter.
Received 30 December 2013
Revised 28 January 2014
Accepted 3 February 2014
Available online 8 February 2014
Keywords:
Synthesis
Isoxazoline
Indolizine
Ó 2014 Elsevier Ltd. All rights reserved.
Parasiticide
Tropical diseases
Introduction
O
N
O
O
N
O
F3C
F3C
Cl
Cl
HN
CF3
HN
CF3
Tropical neglected diseases have drawn increasing attention in
recent years from academic institutions, non-profit organizations,
pharmaceutical industry, and government agencies. Such attention
from various parties provides strong support to the enrichment of
future new treatments for tropical neglected diseases. Anacor is
interested in research in this field and has active research pro-
grams of neglected diseases. One of the strategies used for discov-
ering new treatments for human neglected diseases is to research
established animal drugs as a starting point for improvement.
Albendazole, as an example, was first discovered at an animal
health laboratory in 1970s and now has application in humans
for the treatment of worm infestations.1 It was rationalized that
a long acting animal ectoparasiticide may interrupt the transmis-
sion between vectors, such as mosquitoes and flies, and humans
with potential application for human use.
NH
NH
O
O
Cl
1
Cl
2
Figure 1. Chemical structures of typical isoxazoline compounds.
indolizine scaffold to replace the lipophilic moiety of methylphenyl
in 1 and naphthyl in 2. These synthetically challenging compounds
were prepared by first building indolizine core structures
(synthons 5–8 in Fig. 2) as common intermediates for efficient
derivatization for the structure-activity relationship study on the
structure variation of the left side isoxazoline and right side
amide.3 These synthons are functionalized with the acetyl or
aldehyde group on the left side for assembling an isoxazoline ring
and with the carboxylic ester group on the right side for building
an amide moiety. Herein, the chemistry for the syntheses of 3
and 4 is described in this article.
Isoxazoline compounds as a new class of ectoparasiticide agents
have recently been discovered and drawn broad attention.2 Struc-
tures of two efficacious isoxazoline compounds (1 and 2) are
shown as examples in Figure 1.
Results and discussion
During our research program, isoxazoline indolizine amide
target compounds (3 and 4 in Fig. 2) were designed to use the
As shown in Scheme 1, the acetyl indolizine intermediate 5 was
used as key intermediate to synthesize target compound 3. The
chemistry started with the substitution reaction of pyrrole 9 with
the lactone, 5-methyldihydrofuran-2(3H)-one, to give compound
⇑
Corresponding author. Tel.: +1 650 543 7513; fax: +1 650 543 7660.
E-mail address: yzhang@anacor.com (Y.-K. Zhang).
http://dx.doi.org/10.1016/j.tetlet.2014.02.003
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

Y.-K. Zhang et al. / Tetrahedron Letters 55 (2014) 1936–1938
1937
O
N
O
O
R
F3C
COOEt
Cl
Cl
N
N
HN
CF3
NH
O
Cl
3
Synthons for target
[R = Me (5) or H (6)]
3
O
N
O
F3C
O
COOMe
N
HN
CF3
N
R
NH
O
Cl
4
Synthons for target 4
[(R = Me (7) or H (8)]
Figure 2. Structures of two isoxazoline indolizine amide target compounds and their synthons for chemistry plan.
1.KH, DMF,
MeI, K2CO3
DMF, rt, 16h
BBr3
DCM
H
N
rt, 1h, N2
O
O
O
O
N
N
N
2.
0 oC, 10 min
Y 44%
O
O
Y 31%
OH
2 steps
10
11
9
12
160 oC, 4h
Br
-
1. KMnO4, H2O,
Br
O
DBU, THF
rt, 3h
t-BuOH, 70 oC, 16h
PhMe3N+Br3
Br O
O
O
O
HO
N
OEt
2. SOCl2, EtOH
reflux, 5h, Y 30%
THF, rt, 3h
Y 51%
N
OEt
N
OEt
13
14
15
Bu3Sn OEt
H2/Pd/C
Tf2O, Et3N
O
EtO
O
O
DCM, 0 oC, 2h
K2CO3
TfO
1,4-dioxane
LiBr, Pd(dppf)Cl2
reflux, 16h, N2
HO
N
OEt
N
OEt
OEt
N
Y 41%
EtOAc
rt, 4h
3 steps
17
18
16
O
O
Cl
O
CF3
aq HCl,
O
OH
O
Ac2O, Et3N
rt, 3h
F3C
acetone, rt, 2h
Cl
N
OEt
N
OEt
Y 63%
Y 44%
Et3N, toluene
60 oC, 24h
Cl
2 steps
2 steps
5
19
Cl
O
O
O
O
N
H2N
F3C
1. NH2OH, NaOH
THF, H2O
OEt
F3C
N
O
OEt
OH
N
HATU, DIPEA
DMF, rt, 16h
Y 84%
2. aq HCl
Y 87%
Cl
Cl
21
Cl
20
Cl
O
N
O
O
N
O
1. LiOH
F3C
H2N
CF3
HN
F3C
N
THF/H2O
HN
N
O
3
2. aq HCl
Y 95%
O
EtO
HATU, DIPEA
DMF, rt, 16h
Y 27%
Cl
HO
Cl
22
Cl
23
Cl
Scheme 1. Synthesis of isoxazoline indolizine amide compound 3.
10.4 It was then esterified and cyclized to provide the fused
compound 12, of which the methyl group was oxidized and then
esterified to generate compound 13. Compound 13 was bromi-
nated using phenyltrimethylammonium tribromide (PTT) to afford
the bisbromo intermediate 14, which was de-acidified and debro-
minated stepwise to yield the hydroxyl indolizine ester 16. The
hydroxyl group was then triflated and coupled with tributyl(1-eth-
oxyvinyl)stannane to give the ethoxyvinyl compound 18. Removal
of the ethyl group in 18 by aqueous hydrochloric acid provided the
key indolizine intermediate 5. Addition of 5 to 1-(3,5-dichloro-
phenyl)-2,2,2-trifluoroethanone and then dehydration generated
compound 20, which was treated with hydroxylamine under basic
condition to give the isoxazoline indolizine acid 21. It reacted
with ethyl glycine to form the amide 22 and then hydrolyzed to
give 23. This acid went through amide formation to afford the final
compound 3.
Similarly the chemistry for the synthesis of isoxazoline indoli-
zine amide compound 4 is shown in Scheme 2. In this case, the
aldehyde indolizine 8 was used as a key intermediate to test a
different synthetic methodology for isoxazoline ring formation.
Starting from compound 17, the ester group was reduced to the
hydroxylmethyl group to afford compound 24. The triflate group

1938
Y.-K. Zhang et al. / Tetrahedron Letters 55 (2014) 1936–1938
CO (50 psi),
O
NaBH4
O
Et3N, MeOH
OTf
MeOH
OTf
Pd(dppf)Cl2
EtO
N
N
HO
HO
N
OMe
50 oC, 2h
Y 57%, 2 steps
rt, 16h
17
24
25
Cl
CF3
O
O
MnO2
HO
N
H
O
NH2OH HCl
NaOAc
DCM
Cl
H
N
OMe
N
OMe
rt, 16h
Y 45%
DIB, THF
68 oC, 2h
Y 7%, 2 steps
THF/H2O
rt, 2h
8
26
O
N
O
N
O
O
F3C
F3C
N
OMe
NaOH, THF-H2O
rt, 3h, Y 34%
N
OH
Cl
Cl
27
Cl
28
Cl
O
N
H
N
O
F3C
CF3
H2N
HCl
Cl
O
N
HN
CF3
NH
HATU, Et3N, DMF
rt, 16h, Y 34%
O
Cl
4
Scheme 2. Synthesis of isoxazoline indolizine amide compound 4.
in 24 was converted to methoxycarbonyl of 25 by reacting with
Supplementary data
carbon monoxide in methanol in the presence of a catalyst, 1,10-
bis(diphenylphosphino)ferrocene-palladium(II)dichloride.
The
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.02.
003.
hydroxylmethyl group of 25 was oxidized to aldehyde and then re-
acted with hydroxylamine to give the oxime intermediate 26. It
was oxidized with diacetate iodobenzene (DIB) and then went
through an addition-cyclization reaction with 1,3-dichloro-5-
(3,3,3-trifluoroprop-1-en-2-yl)benzene to form the isoxazoline
indolizine ester 27. The ester was hydrolyzed to the carboxylic acid
28 and then reacted with 2-amino-N-(2,2,2-trifluoroethyl)acetam-
ide to form the final amide 4.
References and notes
1. Theodorides, V. J.; Gyurik, R. J.; Kingsbury, W. D.; Parish, R. C. Experientia 1976,
32, 702–703.
2. (a) Ozoe, Y.; Asahi, M.; Ozoe, F.; Nakahira, K.; Mit, T. Biochem. Biophys. Res.
Commun. 2010, 391, 744–749; (b) Mita, T.; Maeda, K.; Komoda, M.; Ikeda, E.;
Toyama, K.-I.; Iwasa, M., US patent 7,947,715.; (c) Lahm, G. P.; Shoop, W. L.; Xu,
M., WO2007079162.
3. Through very different synthetic methods, isoxazoline indolizine compounds
were reported on June 23, 2011 in WO2011075591, which coincidentally
overlapped with our project.
4. Amos, R. I. J.; Gourlay, B. S.; Molesworth, P. P.; Smith, J. A.; Sprod, O. R.
Tetrahedron 2005, 61, 8226–8230.
The experimental procedures for the preparation of compounds
3 and 4 are described in the Supporting information.
In summary, new synthetic methods for the preparation of two
isoxazoline indolizine amide compounds 3 and 4 have been estab-
lished. These compounds are being tested to evaluate their biolog-
ical activities. The biological results may be disclosed in the future
publication.