First asymmetric synthesis of Silodosin through catalytic hydrogenation by using Ir-SIPHOX catalysts

Article abstract of DOI:10.1016/j.tetlet.2013.01.003

An asymmetric synthesis of Silodosin was accomplished in high yield via catalytic hydrogenation of α,β-unsaturated carboxylic acid derivatives by using chiral catalyst Ir-SIPHOX, followed by Curtius rearrangement. Copyright

Full text of DOI:10.1016/j.tetlet.2013.01.003

Tetrahedron Letters 54 (2013) 1449–1451
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
First asymmetric synthesis of Silodosin through catalytic hydrogenation
by using Ir-SIPHOX catalysts
Pu-Cha Yan a, Xian-Yi Zhang a, Xiao-Wei Hu a, Bin Zhang a, Xiang-Dong Zhang a, Michael Zhao a,
b,
Da-Qing Che a, Yuan-Qiang Li a, , Qi-Lin Zhou
⇑
⇑
a Zhejiang Jiuzhou Pharmaceutical Co. Ltd, Waisha Road 99, Jiaojiang, Taizhou, Zhejiang 318000, PR China
b Institute and State Key laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An asymmetric synthesis of Silodosin was accomplished in high yield via catalytic hydrogenation of
Received 8 November 2012
Revised 31 December 2012
Accepted 4 January 2013
Available online 10 January 2013
a
,b-unsaturated carboxylic acid derivatives by using chiral catalyst Ir-SIPHOX, followed by Curtius
rearrangement.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Silodosin
Asymmetric hydrogenation
Ir-SIPHOX catalyst
a,b-Unsaturated carboxylic acid
Introduction
amine derivatives.5,6 However, the efficiency, enantioselectivity,
and atom-economy of all those approaches are low. Therefore,
more efficient, economically, and environmentally benign route,
Benign prostatic hyperplasia (BPH) is a common disorder in
middle-aged and elderly men which produces bladder outlet
obstruction, followed by voiding dysfunction characterized by uri-
nary frequency, nocturia, urgency, poor steam, and hesitancy in
initiation of micturition. Functional response of the human pros-
tate is predominantly mediated through
ability of 1-adrenoceptor antagonists to improve the symptoms
of BHP was first demonstrated by Caine et al., and their use in
the treatment of therapy is now widely accepted.1
1-Blockers
1-adrenoceptor antagonists) are a well-established and effective
a1-adrenoceptors. The
a
H
N
O
OCH2CF3
a
N
(a
CO2NH2
treatment for BPH-related lower urinary tract symptoms and are
HO
generally a first-line therapy for BPH management.2
Silodosin (RapafloÒ) was developed by Kissei and Daiichi, and
was approved by the FDA in 2008. The drug works as a selective
Silodosin
a
1-adrenergic receptor antagonist developed for the treatment of
the signs and symptoms of BHP.3 Its chemical structure is known
as (R)-1-(3-hydroxypropyl)-5-[2-[[2-[2-(2,2,2-trifluoro-ethoxy)
phenoxy]-ethyl]amino]propyl]-indoline-7-carboxamide (Fig. 1).
The synthesis of Silodosin is relatively complex, which involves
multistep synthesis. The most challenging part is to construct a
chiral center bearing an amino group in the molecule. The general
approaches up to date are chiral resolution of the racemic amine 24
and reductive amination of the adduct from ketone and chiral
NH2
X
O
N
+
OCH2CF3
CN
HO
3a
) X = Br
2
3b
) X = OTs
⇑
Corresponding authors.
E-mail address: yqli@zbjz.cn (Y.-Q. Li).
Figure 1. Retrosynthesis of Silodosin.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.003

1450
P.-C. Yan et al. / Tetrahedron Letters 54 (2013) 1449–1451
COOH
COOH
which can be used for large scale manufacture of Silodosin, is
highly desired.
H2, Cat.
MeOH
N
N
It is well known that the catalytic asymmetric hydrogenation is
one of the elegant and powerful methods for the preparation of
optical active compounds in atom-economic way, and has been
widely used in industry. A number of efficient chiral catalysts
including Ru catalysts and Rh catalysts have been reported for
Br
Br
10
a,b-unsaturated carboxylic acid 9.
BnO
BnO
9
Scheme 2. Asymmetric hydrogenation of
the asymmetric hydrogenation of
a,b-unsaturated carboxylic acid
to produce optical chiral carboxylic acids.7
+
+
+
The chiral Ir catalysts, which are very efficient in the hydroge-
nations of unfunctionalized olefins, imines, and heteroaromatic
compounds,8 however, were rarely used in the hydrogenation of
unsaturated carboxylic acids9 until a novel class of chiral spiro irid-
ium/phosphine–oxazoline complexes (Ir-SIPHOX) was developed
by Zhou and co-workers.10 The Ir-SIPHOX catalysts have been
proved to be highly efficient for the asymmetric hydrogenation
O
O
O
Bn
Bn
N
N
N
-
-
-
BArF
BArF
BArF
Ir
Ir
Ir
P
P
P
DTB
DTB
DTB
DTB
DTB
DTB
(Ra,R)-1a
(Ra)-1b
(Ra,S)-1a
Figure 2. Ir-SIPHOX catalysts.
of
a-alkyl a,b-unsaturated carboxylic acids (ee up to 99.4%, TON
up to 10,000),11
a
-aryloxy and a-alkoxy a,b-unsaturated carbox-
ylic acids (ee up to 99.8%, TON up to 10,000)12 under mild condi-
tions. Herein, we report the first asymmetric synthesis of
Silodosin by using Ir-SIPHOX-catalyzed asymmetric hydrogenation
Table 1
Asymmetric hydrogenation of (E)-3-(1-(3-(benzyloxy)propyl)-7-bromoindolin-5-yl)-
2-methylacrylic acid: optimization of reaction conditionsa
of
Synthesis
The synthesis of
Scheme 1. The N-alkylation of indoline (4) with 1-chloro
benzyloxypropane produced compound 5 in 95% yield. Formyla-
tion of 5 by Vilsmeier–Haack reaction gave aldehyde 6 in 90% yield.
Bromination of 6 with bromine afforded regioselectively 7 as the
only product in 97% yield. Reaction of 7 with Wittig reagent
a,b-unsaturated carboxylic acid as the key technology.
Entry
Catalyst
S/C
Additive
Time
(h)
Convb
(%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
(Ra,R)-1a
(Ra,R)-1a
(Ra,S)-1a
(Ra)-1b
(Ra,R)-1a
(Ra)-1b
(Ra)-1b
(Ra)-1b
(Ra)-1b
(Ra)-1b
(Ra)-1b
(Ra)-1b
(Ra)-1b
(Ra)-1b
400
400
400
None
24
2
24
2
24
5
9
24
24
48
20
20
50
50
18
100
12
100
45
100
100
90
92
1 equiv of NEt3
1 equiv of NEt3
1 equiv of NEt3
1 equiv of NEt3
1 equiv of NEt3
2 equiv of NEt3
2 equiv of NEt3
98
n.d.d
98
a,b-unsaturated carboxylic acid 9 is shown in
400
1000
1000
2000
4000
4000
4000
4000
4000
6000
6000
n.d.d
98
98
97
i
2 equiv of Pr2NEt
72
97
1 equiv of CsCO3
3 equiv of NEt3
5 equiv of NEt3
3 equiv of NEt3
5 equiv of NEt3
57
96
Ph3P@C(Me)CO2Et provided
ester 8, followed by hydrolysis with sodium hydroxide in methanol
to give ,b-unsaturated carboxylic acid 9 in 86% yield.
The asymmetric hydrogenation of ,b-unsaturated carboxylic
a,b-unsaturated carboxylic acid ethyl
100
100
100
100
97
97
97
97
a
a
acid 9 (Scheme 2) was investigated by using Ir-SIPHOX catalysts.
Three of Ir-SIPHOX catalysts ( Fig. 2) were compared as they
showed high reactivity and high enantioselectivity in the asym-
a
b
c
Reaction conditions: [substrate] = 0.5 M in MeOH, PH2 = 8–10 atm, 70 °C.
Determined by 1H NMR analysis.
Determined by HPLC analysis with a chiral column (see Supplementary data).
n.d. = not determined.
metric hydrogenation of
a
,b-unsaturated carboxylic acids.11,12
d
The reaction was initially performed at a substrate to catalyst mole
ratio (S/C) of 400 in MeOH under 8 atm of H2 at 70 °C for 24 h
(Table 1). With catalyst (Ra,R)-1a, the hydrogenation product (10)
was obtained in 92% ee, but with only 18% conversion (entry 1).
With an addition of 1.0 equiv of triethylamine the reaction rate
and enantioselectivity were significantly improved (complete con-
version within 2 h in 98% ee) (entry 2). The low efficiency of the
catalyst (Ra,S)-1a (entry 3) revealed that it has mis-matched con-
figurations. In the presence of NEt3, the catalyst (Ra)-1b which
has no substituent on the oxazoline ring gave a result similar to
that of (Ra,R)-1a (entry 4). When the reaction was performed at a
lower catalyst loading, the catalyst (Ra)-1b showed much higher
efficiency than catalyst (Ra,R)-1a, giving a full conversion and high
CHO
CHO
c)
b)
a)
N
N
H
N
N
Br
BnO
BnO
BnO
6
4
5
7
COOEt
COOH
d)
e)
N
N
Br
Br
BnO
BnO
8
9
Scheme 1. Synthesis of
a,b-unsaturated carboxylic acid (9). Reaction conditions: (a) BnOCH2CH2CH2Cl, DIPEA, NaI, DMF, 100 °C, 3.5 h, 95%; (b) POCl3, DMF, 35 °C, 3 h, 90%; (c)
Br2, CH2Cl2, 0 °C, 2.5 h, 97%; (d) Ph3P@C(Me)CO2Et, toluene, 16 h, 100 °C; (e) NaOH, MeOH, 40 °C, 3 h, 86% (two steps).

P.-C. Yan et al. / Tetrahedron Letters 54 (2013) 1449–1451
1451
COOH
NHCbz
NHCbz
b)
a)
c)
N
N
N
CN
Br
Br
BnO
BnO
BnO
10
11
12
Boc
N
Boc
e)
d)
N
Silodosin
O
O
OCH2CF3
OCH2CF3
N
N
CONH2
CN
BnO
BnO
13
14
Scheme 3. Synthesis route of Silodosin from chiral acid 10. Reaction conditions: (a) Diphenylphosphoryl azide (DPPA), DIPEA, PhCH2OH, 70 °C, 10 h, 76%; (b) CuCN, DMF,
120 °C, 20 h, 88%; (c) (i) H2, Pd/C, MeOH, rt, 3 h; (ii) 3b, toluene, reflux, 18 h; (iii) Boc2O, NaHCO3, 1,4-dioxane, rt, 2 h, 72% (for three steps); (d) H2O2, 5 N NaOH, DMSO, rt, 12 h,
83%; (e) H2, Pd/C, 6 N HCl, MeOH, 90%.
enantioselectivity (98%, ee) within 9 h at S/C = 2000 (entries 5–7).
Further investigation indicated that in the presence of 3–5 equiv
of NEt3, the catalyst (Ra)-1b allowed the reaction to be performed
at a very low catalyst loading (S/C = 6000) without compromising
the enantioselectivity (entries 13 and 14), albeit the reaction needs
a longer time. Compared with NEt3, other additives such as iPr2NEt
and Cs2CO3 gave lower conversion (entries 9 and 10). It is worthy
mentioning that bromine on the aromatic ring of 9 was tolerated
under hydrogenation conditions, and the product (10) was isolated
in almost quantitative yield. A reasonable explanation raised by
References and notes
1. Caine, M.; Pfau, A.; Perlberg, S. Br. J. Urol. 1976, 48, 255–263.
2. Noguchi, Y.; Ohtake, A.; Suzuk, M.; Sasamata, M. Eur. J. Pharm. 2008, 580,
256–261.
3. (a) Kitazawa, M.; Ban, M.; Okazaki, K.; Ozawa, M.; Yazaki, T.; Yamagishi, R, U.S.
Patent 5,387,603.; (b) Lepor, H.; Hill, L. A. Pharmacotherapy 2010, 30,
1303–1312; (c) Michel, M. C. Eur. Urol. Suppl. 2010, 9, 486–490.
4. (a) Kamijo, T.; Yamaguchi, T.; Teranishi, H. JP Patent 200,11,99,956.; (b)
Yamaguchi, T.; Tsuchiya, I.; Kikuchi, K. WO 2006,46,499.; (c) Wang, X.; Wang,
X.; Wang, Z.; Sui, Q.; Shi, H. CN 101585798A.
5. Kamijo, T.; Yamaguchi, T.; Teranishi, H.; Tsuchiya, I. JP 200199956A.
6. (a) Yamaguchi, T.; Takeuchi, H.; Shiobara, H.; JP Patent 200,22,65,444.; (b) Luo,
X.; Chen, G.; Zhang, H. Chin. Chem. Lett. 2008, 19, 59–60.
Yamamoto et al. is that the
a,b-unsaturated carboxylate anion
7. For Ru catalysts, see: (a) Ohta, T.; Takaya, H.; Kitamura, M.; Nagai, K.; Noyori, R.
J. Org. Chem. 1987, 52, 3176–3178; (b) Uemura, T.; Zhang, X.; Matsumura, K.;
Sayo, N.; Kumobayashi, H.; Ohta, T.; Nozaki, K.; Takaya, H. J. Org. Chem. 1996,
61, 5510–5516; (c) Benincori, T.; Cesarotti, E.; Piccolo, O.; Sannicolò, F. J. Org.
Chem. 2000, 65, 2043–2047; (d) Pai, C.-C.; Lin, C.-W.; Lin, C.-C.; Chen, C.-C.;
Chan, A. S. C.; Wong, W. T. J. Am. Chem. Soc. 2000, 122, 11513–11514; (e)
Maligres, P. E.; Krska, S. W.; Humphrey, G. R. Org. Lett. 2004, 6, 3147–3150; (f)
Cheng, X.; Zhang, Q.; Xie, J.-H.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed.
2005, 44, 1118–1121; (g) Cheng, X.; Xie, J.-H.; Li, S.; Zhou, Q.-L. Adv. Synth. Catal.
2006, 348, 1271–1276; (h) Qiu, L.; Li, Y.-M.; Kwong, F. Y.; Yu, W.-Y.; Fan, Q.-H.;
Chan, A. S. C. Adv. Synth. Catal. 2007, 349, 517–520; For Rh catalysts, see: (i)
Yamada, I.; Yamaguchi, M.; Yamagishi, T. Tetrahedron: Asymmetry 1996, 7,
3339–3342; (j) Houpis, I. N.; Patterson, L. E.; Alt, C. A.; Rizzo, J. R.; Zhang, T. Y.;
Haurez, M. Org. Lett. 2005, 7, 1947–1950; (k) Co, T. T.; Shim, S. C.; Cho, C. S.;
Kim, T.-J.; Kang, S. O.; Han, W.-S.; Ko, J.; Kim, C.-K. Organometallics 2005, 24,
4824–4831; (l) Hoen, R.; Boogers, J. A. F.; Bernsmann, H.; Minnaard, A. J.;
Meetsma, A.; Tiemersma-Wegman, T. D.; de Vries, A. H. M.; de Vries, J. G.;
Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44, 4209–4212; (m) Chen, W.;
McCormack, P. J.; Mohammed, K.; Mbafor, W.; Roberts, S. M.; Whittall, J. Angew.
Chem., Int. Ed. 2007, 46, 4141–4144.
formed with the addition of tertiary amine is more strongly che-
lated to the transition-metal center than the acid itself, resulting
in higher reactivity and enantioselectivity.13
With chiral intermediate 10 in hand, the synthesis of Silodosin
was accomplished according to the route shown in Scheme 3.14
Curtius rearrangement of 10, followed by trapping the intermedi-
ary isocyanate with benzyl alcohol gave the amine 11 in 76%
yield with 97.8% ee without loss of the enantiomeric purity. Cyna-
tion of 11 by coupling with CuCN in DMF afforded cyanide com-
pound 12 in 85% yield. After deprotection of the Cbz group of 12
and coupling with 3b, followed by protection of amino group
with Boc, 13 was isolated in 90% yield in three steps. Oxidative
hydrolysis of 13 provided amide 14 in 83% yield. Deprotection
of Boc and benzyl groups simultaneously of 14 by hydrogenation
with Pd/C in the presence of acid gave Silodosin in 90% yield
(Scheme 3).
8. (a) Blaser, H.-U. Adv. Synth. Catal. 2002, 344, 17–31; (b) Roseblade, S. J.; Pfaltz, A.
Acc. Chem. Res. 2007, 40, 1402–1411; (c) Zhou, Y.-G. Acc. Chem. Res. 2007, 40,
1357–1366.
9. Scrivanti, A.; Bovo, S.; Ciappa, A.; Matteoli, U. Tetrahedron Lett. 2006, 47,
9261–9265.
In summary, we have accomplished the asymmetric synthesis
of Silodosin with high efficiency and high enantioselectivity by a
new approach. The key step of the synthesis is the asymmetric
hydrogenation of
by using the novel Ir-SIPHOX catalysts.
a
,b-unsaturated carboxylic acid intermediate 9
10. Zhu, S.-F.; Xie, J.-B.; Zhang, Y.-Z.; Li, S.; Zhou, Q.-L. J. Am. Chem. Soc. 2006, 128,
12886–12891.
11. Li, S.; Zhu, S.-F.; Zhang, C.-M.; Song, S.; Zhou, Q.-L. J. Am. Chem. Soc. 2008, 130,
8584–8585.
12. Li, S.; Zhu, S.-F.; Xie, J.-H.; Song, S.; Zhang, C.-M.; Zhou, Q.-L. J. Am. Chem. Soc.
2010, 132, 1172–1179.
Supplementary data
13. Yamamoto, K.; Ikeda, K.; Yin, L. L. J. Organomet. Chem. 1989, 370, 319–332.
14. (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94, 6203–6205;
(b) Carda, M.; Gonzalez, F.; Sanchez, R.; Marco, J. A. Tetrahedron: Asymmetry
2002, 13, 1005–1010; (c) Kim, S.; Ko, H.; Kim, E.; Kim, D. Org. Lett. 2002, 4,
1343–1345.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
01.003.