Enantioselective synthesis of (-)-(R) Silodosin by ultrasound-assisted diastereomeric crystallization

Article abstract of DOI:10.1016/j.tet.2013.01.061

Enantioselective synthesis of clinically approved drug - Silodosin for the treatment of benign prostatic hyperplasia from the commercially available compounds 1-acetyl-5-(2-aminopropyl) indoline-7-carbonitrile A and 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate C is explored. Key step in the synthesis is chiral resolution of intermediate 1, which was achieved by a simple diastereomeric crystallization using (S)-(+)-mandelic acid assisted by ultrasonication. The present synthetic strategy has lesser number of steps and is vastly improved the overall yield in this short route towards target compound - Silodosin.

Full text of DOI:10.1016/j.tet.2013.01.061

Tetrahedron 69 (2013) 2834e2843
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective synthesis of (ꢀ)-(R) Silodosin by ultrasound-
assisted diastereomeric crystallization
,
Indrajeet J. Barve a, Li-Hsun Chen a, Patrick C.P. Wei b, Jui-Te Hung b, Chung-Ming Sun a
*
a Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300-10, Taiwan, ROC
b Formosa Laboratories, Inc. 36 Hoping Street, Taoyuan 338-42, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantioselective synthesis of clinically approved drugdSilodosin for the treatment of benign prostatic hy-
perplasia from the commercially available compounds 1-acetyl-5-(2-aminopropyl) indoline-7-carbonitrile
A and 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate C is explored. Key step in the synthe-
sis is chiral resolution of intermediate 1, which was achieved by a simple diastereomeric crystallization using
(S)-(þ)-mandelic acid assisted by ultrasonication. The present synthetic strategy has lesser number of steps
and is vastly improved the overall yield in this short route towards target compounddSilodosin.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 2 November 2012
Received in revised form 13 January 2013
Accepted 21 January 2013
Available online 1 February 2013
1. Introduction
coupling of single enantiomer of compound I with 2-(2-(2,2,2-
trifluoroethoxy)phenoxy)ethyl methanesulfonate and subsequent
Silodosin is a medication for the treatment of problems associ-
ated with human prostrate. It is a a1a-adrenoceptor (AR) antagonist
that selectively binds to a1a-AR, which is present in the prostate
and bladder neck situated at the lower urinary tract.1,2
deacetylation, partial hydrolysis afforded Silodosin. In another re-
ported patent (Scheme 2), synthesis started from coupling of either
A and B or A0 and B0. After several steps compound II obtained, which
was resolved by diastereomeric crystallization using (þ) mandelic
acid at the penultimate step. The cleavage of Boc group at the final
step gave Silodosin. The main drawbacks of the reported synthetic
routes contain greater numberof steps tocause a drastic reduction in
the overall yield of the final compound. Hence it is of great interest
and challenge to upgrade the current route with an aim to improve
reaction efficiency and enhance overall yield in the synthesis.
Reterosynthetic analysis for the synthesis of Silodosin is outlined
in Scheme 3. It is recognized that the crucial step in the synthesis
is the NeC bond formation between 5-(2-aminopropyl)-1-(3-
hydroxypropyl) indoline-7-carboxamide B and suitably protected
This high selectivity for a1a-AR is due to the inhibition of sym-
pathetic nerve stimulation and relaxation of smooth muscle tone of
the lower urinary tract tissues, resulting in reduction of the
symptoms of benign prostatic hyperplasia (BPH).3 Clinical data
suggested that Silodosin showed significant improvement in lower
urinary tract symptoms associated with BPH, as well as the quality
of life.4e6 There are no reported synthetic methods for Silodosin in
the literature and the existing strategy was patented.7e9
b-trifluoromethyl diethyl catechol derivative C. From the analysis of
patented procedures, we speculated that -trifluoromethyl diethyl
b
catechol derivative with mesylate as a leaving group would be more
facile for nucleophilic substitution. Introduction of the amide and
the 3-hydroxy n-propyl side chain is predicted by the functional
group transformation from the corresponding precursor 3. It is ap-
parent that the attachment of the catechol moiety can be introduced
at any stage in the sequence of proposed reaction scheme. However,
during the present route it is planned to use this combination of
A and C in the first coupling step.
One of the reported patent synthesis (Scheme 1) started from
benzoic acid. After several functional group transformations,
racemic amine I was obtained. The racemate I resolved by di-
astereomeric crystallization using
tained compound I was purified by column chromatography. The
L
-(þ)-tartaric acid and the so ob-
2. Results and discussion
Our synthetic endeavour towards Silodosin began with a cou-
* Corresponding author. E-mail addresses: cmsun@mail.nctu.edu.tw, chung-
mingsun@gmail.com (C.-M. Sun).
pling reaction of commercially available A and C (Scheme 12).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.061

I.J. Barve et al. / Tetrahedron 69 (2013) 2834e2843
2835
Scheme 1. Reported route for Silodosin.8
Condensation of the racemic amine A and catechol mesylate C in
the presence of triethylamine in refluxing ethanol failed to give any
desired product 1. Starting materials A and C were recovered in this
case. An attempt to couple A with C in the presence of NaHCO3 in
refluxing acetonitrile for 36h, provided compound 1 in only 32% yield
along with unreacted starting materials. Refluxing of the reaction for
prolonged time (48 h) did not improve the yield. A better protocol for
the coupling reaction of compounds A and C was designed as follows.
Variety of solvents (polar protic and polar aprotic) with trie-
thylamine and sodium bi carbonate were investigated, but no
substantial improvement was observed in terms of isolated yield
(Table 1, entries 2e4). A stronger inorganic base is used in order to
drive the reaction for completion.
yield (10%). The incompleteness of the diastereomeric salt 2 for-
mation of 1 and (S)-(þ) mandelic acid in refluxing methanol was
the main reason associated with the yield loss of 3. Prolong heating
(24 h) did not result in the complete transformation of 1 into di-
astereomeric salt 2. After cooling of the reaction mixture, (S)-(þ)
mandelic acid with little amount of diastereomeric salt 2 crystal-
lized out to leave most of compound 1 in methanol. Another major
problem with this protocol was nature of the diastereomeric salt.
The diastereomeric salt 2 was obtained as a sticky solid (Scheme 6).
These drawbacks of the refluxing condition for the chiral resolution
of 1 made us to search a more efficient technique. Application of
ultrasound to crystallization can enhance chiral amplification,
resulting in rapid crystallization process and enrichment of the
single enantiomer.13 Accordingly, a solution of racemic compound 1
and (S)-(þ) mandelic acid in methanol was sonicated for 30 min.
The crystallized solid diastereomeric salt was filtered off, and
treated with aqueous solution of base. Extraction of aqueous layer
afforded 3 in 34% yield (Scheme 12). Threefold increase in the yield
during resolution under ultrasound radiation was achieved in the
key step. The purity of the single enantiomer 3 was confirmed by
chiral HPLC, optical rotation and 1H NMR. The chiral amplification
during crystallization of the diastereomers is due to the influence of
ultrasound waves on the physicochemical phenomena of crystal-
lization. The crystallization process composed of two events: nu-
cleation and crystal growth.14 In the nucleation stage, the dissolved
solute molecules start to accumulate into clusters and reach to
a critical size to form nuclei. The application of ultrasound energy to
crystallization significantly reduces the induction time of nucle-
ation.15 When ultrasonic energy passes through a solution, it cre-
ates the cycle of compression and expansion to produce bubbles.
The collapse of the bubbles provides energy, which promotes the
rapid cluster formation of diastereomeric salt.16 In our case, the
(R,S) diastereomeric salt 2 formed had less solubility in methanol,
hence it was crystallized out leaving 30 in the solution (Scheme 7).
The use of K2CO3 in refluxing ethanol or isopropyl alcohol or
tert-butyl alcohol or acetonitrile for the coupling reaction of com-
pounds A and C resulted in deacetylated compound 9 (Scheme 5).
The deacetylation was observed due to the trace amount of water
present in the solvent.
Nevertheless, all efforts in optimizing this step could not improve
the yield beyond 58%. Eventually, we found that addition of KI in
stoichiometric amount facilitated the coupling reaction to afford the
crucial intermediate 1 in 93% yield (Scheme 4).10 Dry acetonitrile
was then used to avoid the formation of deacetylated product 9. It is
likely that mesylate group of C was replaced in situ by iodide, which
proved to be a better leaving group to deliver 1 in an excellent yield
over that of the reported yield (65%) in the patented procedure.8,9
Next step was the chiral resolution of the racemic compound 1,
which was achieved by crystallization of the diastereomers by
treating 1 with (S)-(þ) mandelic acid.11,12 A refluxed solution of 1
and (S)-(þ) mandelic acid in methanol was allowed to stand at
room temperature.
The diastereomeric salt 2 obtained after cooling at room tem-
perature was filtered off and treated with aqueous solution of
a base. The extraction of an aqueous layer yielded 3 in very low

2836
I.J. Barve et al. / Tetrahedron 69 (2013) 2834e2843
Scheme 2. Reported route for Silodosin.9
The amino function in 3 was converted to N-Boc by treating with
product 10 was detected in 30% yield via dehydration of the 3-
hydroxypropyl side chain of 7, which decreased the yield of 14
(Scheme 10).
di-tert-butyl dicarbonate and triethylamine to afford 4 in 90% yield.
In the next step, to keep Boc group intact, acidic condition was
avoided for the deacetylation of compound 4.
In the final step, the partial hydrolysis of nitrile group of 14 was
accomplished by a mixture of 30% hydrogen peroxide and NaOH to
furnish target compoundeSilodosin in 67% yield (Scheme 11).
In short, an attempt for the introduction of 3-hydroxypropyl
side chain in 5 using benzyl 3-bromopropyl ether as an alkylating
reagent suffered from many drawbacks. Firstly, this approach in-
volved the debenzylation using expensive palladium reagents.8
Secondly, formation of unwanted byproduct at the penultimate
step resulted in significant drop in the yield of Silodosin.
In order to achieve simple, efficient and metal free synthetic se-
quence, attempts were initiated to search for alternate alkylating
reagent. From the literature search it was found that introduction
of the 3-hydroxypropyl side chain would be promising if 3-
bromopropan-1-ol was used.17,18 For the sake of ease in handling
the reaction steps, it was decided to protect the bare hydroxyl group
by tert-butyl dicarbonate.
As the hydrolysis of acetyl group was observed when K2CO3 in
refluxing solvents was applied for the condensation (Scheme 5), it
was speculated that deacetylation of 4 could be smoothly accom-
plished by same condition. Accordingly, selective N-deacetylation
of 4 was achieved by K2CO3 in aqueous ethanol to afford 5 in 98%
yield. This mild alkaline condition ensured that the N-Boc group
was remained intact (Scheme 8). Initially, we attempted to in-
troduce the 3-hydroxypropyl side chain in 5 by commercially
available benzyl 3-bromopropyl ether.
Thus, compound 5 was alkylated with benzyl 3-bromopropyl
ether and strong base to afford 6 in 65% yield. The subsequent
debenzylation of 6 in the presence of H2 gas and Pd/C provided 7 in
quantitative yield (Scheme 9).
Moving to the next step, deprotection of Boc group of 7
under TFA conditions provided 14 in 67% yield. Formation of side

I.J. Barve et al. / Tetrahedron 69 (2013) 2834e2843
2837
Scheme 3. Retrosynthetic analysis of Silodosin.
Table 1
NMR spectrum, characteristic up-field signals due to tert-butyl
protons were absent, which indicated removal of both the Boc-
groups attached to N and O simultaneously. The product corre-
sponded to 14 was obtained in quantitative yield.
Thus, in this N-alkylation, additional step required for Boc
deprotection was escaped, which has greatly contributed to the
success of this new synthetic route. Such N,O-Boc in situ double
deprotections are first observed in our study. Consequently, the
desired compound 14 was directly isolated in good yield. Final step
in this synthesis required partial hydrolysis of nitrile group of 14
into amide, which was achieved by a mixture of 30% hydrogen
peroxide and base in methanol to afford Silodosin in an excellent
yield.
Optimization of the coupling reaction of compounds A and C
Entry
Base
Additive
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
TEA
d
d
d
d
KI
d
d
d
d
KI
EtOH
EtOH
IPA
ACN
DMF
EtOH
IPA
TBA
ACN
ACN
36
36
16
16
16
16
16
16
16
16
No reaction
NaHCO3
NaHCO3
NaHCO3
NaHCO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
46
42
32
46
44
38
58
52
93
10
Scheme 4. Coupling reaction of A and C.
Scheme 5. Coupling reaction of A and C using K2CO3 in polar protic and aprotic solvents.
Thus, a new O-Boc-protected 3-bromopropan-1-ol 12 was syn-
thesized during the present work for the purpose of introducing 3-
hydroxypropyl side chain at the indole nitrogen. Attempted alkyl-
ation of compound 5 with 3-bromopropyl tert-butyl carbonate 12
in the presence of NaH in dry acetonitrile was the most surprising
step in this route (Scheme 12). The expected bis Boc-protected
compound 13 due to N-alkylation was not observed. In the 1H
3. Conclusion
In conclusion, a short and efficient protocol for the synthesis of
Silodosin has been accomplished. The title compound was syn-
thesized in enantiomerically pure form in only six steps from
commercially available compounds in an overall yield of 15%. The
unique feature of this synthetic sequence is the use of simple and

2838
I.J. Barve et al. / Tetrahedron 69 (2013) 2834e2843
Scheme 6. Chiral resolution of racemic compound 1.
Scheme 7. Resolution of racemic compound 1.

I.J. Barve et al. / Tetrahedron 69 (2013) 2834e2843
2839
Scheme 8. Boc protection and deacetylation of 3.
Scheme 9. Alkylation and debenzylation of 5.
Scheme 10. Deprotection of the Boc group of 7.

2840
I.J. Barve et al. / Tetrahedron 69 (2013) 2834e2843
Scheme 11. Partial hydrolysis of nitrile group of 14.
effective ultrasound radiation to assist diastereomeric crystalliza-
afford 4 (3.17 g, 90%). 1H NMR (300 MHz, CDCl3)
d 7.30e7.08 (m,
tion to achieve the chiral resolution of racemic compound 1.
2H), 7.05e6.79 (m, 4H), 4.34 (q, J¼8.4 Hz, 2H), 4.08e3.93 (m, 5H),
3.47e3.37 (m, 2H), 3.07e2.82 (m, 3H), 2.65 (dd, J¼13.8, 6.6 Hz, 1H),
2.25 (s, 3H), 1.40 (s, 9H), 1.24 (d, J¼6.8 Hz, 3H); 13C NMR (75 MHz,
4. General experimental procedures
CDCl3)
d 168.7, 155.8, 155.3, 149.5e147.4 (m), 141.8, 136.5, 135.6,
132.8, 130.3, 125.7, 124.2 (d, J¼6.2 Hz), 122.0e121.4 (m), 117.9, 117.0,
114.3, 113.8, 102.3 (d, J¼15.9 Hz), 80.3, 68.2 (d, J¼12.3 Hz), 67.7 (d,
J¼10.2 Hz), 55.3, 54.7, 50.3, 44.6, 40.5 (d, J¼42 Hz), 28.8 (d,
4.1. 1-Acetyl-5-(2-((2-(2-(2,2,2-trifluoroethoxy)phenoxy)
ethyl)amino)propyl)indoline-7-carbonitrile (1)
J¼6.0 Hz), 24.0, 19.4, 18.6; MS (EIþ) m/z: 584.2 (MþNa)þ; IR (cmꢀ1
,
To a mixture of amine A (20 g, 82.7 mmol) and mesylate C (20 g,
63.63 mmol) in dry acetonitrile (300 mL) were added K2CO3 (26.3 g,
190.9 mmol) and KI (3.16 g, 19.09 mmol), and the reaction mixture
was refluxed for 16 h. The solvent was evaporated in vacuo. The
residue was diluted with water (500 mL) and extracted with ethyl
acetate (3ꢁ100 mL). The combined organic layers were dried over
MgSO4, and concentrated in vacuo. The crude product was purified
by flash chromatography (10e15% methanol in dichloromethane)
to afford racemic compound 1 (24 g, 93%), which was further
subjected for the chiral resolution.
25
neat): 2971, 2931, 2201, 1679; [
a]
ꢀ46.26 (c 0.01, MeOH).
D
4.4. (R)-tert-Butyl(1-(7-cyanoindolin-5-yl)propan-2-yl)(2-(2-
(2,2,2-trifluoroethoxy)phenoxy)ethyl)carbamate (5)
To a stirred solution of 4 (3 g, 5.34 mmol) in ethanol/water
(50:50 mL) was added K2CO3 (14.7 g, 106.8 mmol) and the reaction
mixture was refluxed for 6 h. The solvent was evaporated in vacuo.
The residue was diluted with water (100 mL) and extracted with
ethyl acetate (3ꢁ50 mL). The combined organic layers were dried
over MgSO4, and concentrated in vacuo. The crude product was
purified by flash chromatography (5e10% methanol in dichloro-
4.2. (R)-(L)-1-Acetyl-5-(2-((2-(2-(2,2,2-trifluoroethoxy) phe-
noxy) ethyl) amino) propyl) indoline-7-carbonitrile (3)
methane) to afford 5 (2.76 g, 98%). 1H NMR (300 MHz, CDCl3)
d 7.11
(s, 2H), 7.08e6.97 (m, 4H), 4.37 (q, J¼8.4 Hz, 2H), 4.19e3.98 (m, 3H),
3.66 (t, J¼8.4 Hz, 2H), 3.53e3.33 (m, 2H), 3.01 (t, J¼8.5 Hz, 2H), 2.81
(m, 1H), 2.57 (dd, J¼13.8, 6.6 Hz, 1H), 1.43 (s, 9H), 1.25 (d, J¼6.9 Hz,
To a stirred solution of 1 (20 g, 43.33 mmol) in methanol (300 mL)
was added (S)-(þ) mandelic acid (6.59 g, 43.3 mmol) and the re-
action mixture was sonicated for 30 min. The precipitated solid was
filtered, washed with diethyl ether/methanol (100:100 mL) and
dried. To a mixture of ethyl acetate (200 mL) and 10% NaHCO3
(200 mL) was added this solid, and the mixture was stirred at room
temperature for 1 h. The mixture was extracted with ethyl acetate
(2ꢁ100 mL). The combined organic layers were washed with 10%
NaHCO3 (100 mL), dried over MgSO4 and concentrated in vacuo to
3H); 13C NMR (75 MHz, CDCl3)
d
155.9, 155.3, 153.5 (d, J¼13.4 Hz),
149.7e147.4 (m), 131.2, 130.3, 129.7 (d, J¼13.8 Hz), 124.3, 122.0,
121.8e121.4 (m), 118.2, 117.3, 114.1 (d, J¼34.5 Hz), 90.5, 80.2, 68.2 (d,
J¼8.3 Hz), 67.7 (d, J¼8.0 Hz), 67.3, 55.4, 54.7, 47.4, 44.3, 40.5 (d,
J¼39 Hz), 29.4, 28.8, 19.4, 18.6; MS (EIþ) m/z: 542.2 (MþNa)þ; IR
(cmꢀ1, neat): 3351, 2973, 2933, 2877, 2213,1685; [
MeOH).
a
]
25 ꢀ56.2 (c 0.01,
D
give 3 (7.8 g, 34%). 1H NMR (300 MHz, CDCl3)
d 7.30 (s, 1H), 7.27 (s,
1H), 7.07e6.87 (m, 4H), 4.33 (q, J¼8.4 Hz, 2H), 4.13e3.06 (m, 4H),
3.14e2.92 (m, 5H), 2.74 (dd, J¼13.5, 6.2 Hz, 1H), 2.54 (dd, J¼6.99,
13.5 Hz, 1H), 2.28 (s, 3H), 1.04 (d, J¼6.2 Hz, 3H); 13C NMR (75 MHz,
4.5. (R)-tert-Butyl(1-(1-(3-(benzyloxy)propyl)-7-cyanoindo-
lin-5-yl)propan-2-yl)(2-(2-(2,2,2-trifluoroethoxy)phenoxy)
ethyl)carbamate (6)
CDCl3)
d
168.8, 149.7, 148.7, 147.4 (d, J¼11.8 Hz), 141.7, 136.3, 135.9,
132.9, 130.5, 125.7, 124.4, 124.1, 122.4, 121.8, 118.0 (d, J¼15.0 Hz),
116.7, 114.7 (d, J¼16.9 Hz), 102.1, 68.9 (d, J¼17.0 Hz), 68.3, 67.8 (d,
J¼9.7 Hz), 67.1 (d, J¼13.7 Hz), 54.5, 50.3, 46.3, 42.5, 37.7, 28.7, 23.9,
19.9; MS (EIþ) m/z: 462.5 (MþH)þ; IR (cmꢀ1, neat): 2962, 2931, 2223,
To a stirred solution of 5 (2.7 g, 5.19 mmol) in acetonitrile
(100 mL) was added NaH (0.24 g, 10.3 mmol) at 0 ꢂC. After stirring
for 30 min at the same temperature, benzyl 3-bromopropyl ether
(1.0 mL, 5.71 mmol) was added and the reaction mixture was
stirred at room temperature for 16 h. The solvent was evaporated in
vacuo. The residue was diluted with water (100 mL) and extracted
with ethyl acetate (3ꢁ50 mL). The combined organic layers were
dried over MgSO4 and concentrated in vacuo. The crude product
was purified by flash chromatography (10e15% ethyl acetate in
hexanes) to afford 6 (2.36 g, 65%). 1H NMR (300 MHz, CDCl3)
1675; [
a]
25 ꢀ21.9 (c 0.01, MeOH); enantiomeric excess¼100% ee.
D
4.3. (R)-tert-Butyl(1-(1-acetyl-7-cyanoindolin-5-yl)propan-2-
yl)(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)carbamate (4)
To a stirred solution of 3 (2.7 g, 5.85 mmol) in dichloromethane
(50 mL) were added triethylamine (2.44 mL, 17.55 mmol) and di-
tert-butyl dicarbonate (1.66 g, 7.60 mmol) at 0 ꢂC and the reaction
mixture was stirred for 30 min. Further it was stirred at room
temperature for 16 h. The solvent was evaporated in vacuo. The
residue was diluted with water (50 mL) and extracted with ethyl
acetate (3ꢁ50 mL). The combined organic layers were dried over
MgSO4, and concentrated in vacuo. The crude product was purified
by flash chromatography (3e5% methanol in dichloromethane) to
d
7.39e7.25 (m, 5H), 7.10e6.87 (m, 6H), 4.54 (s, 2H), 4.38 (q,
J¼8.3 Hz, 2H), 4.25e3.84 (m, 3H), 3.76e3.59 (m, 4H), 3.58e3.35 (m,
4H), 2.90 (t, J¼8.6 Hz, 2H), 2.86e2.66 (m, 1H), 2.55 (dd, J¼13.8,
6.6 Hz, 1H), 1.99 (p, J¼6.5 Hz, 2H), 1.45 (s, 9H), 1.26 (d, J¼6.9 Hz, 3H);
13C NMR (75 MHz, CDCl3)
d 155.9, 155.3, 151.9, 149.7, 147.3, 138.7,
133.0, 131.7, 129.8, 128.7, 128.0 (d, J¼10.3 Hz), 125.7, 124.3, 121.8 (d,
J¼31.2 Hz), 121.4, 119.9, 117.4, 114.4, 113.9, 87.9, 80.2, 73.4, 68.7,

I.J. Barve et al. / Tetrahedron 69 (2013) 2834e2843
2841
Scheme 12. An initially attempted and modified synthetic route for the synthesis of Silodosin.

2842
I.J. Barve et al. / Tetrahedron 69 (2013) 2834e2843
68.4e67.4 (m), 67.3, 54.5, 53.6, 45.6, 44.1, 40.5, 40.0, 28.8, 28.2, 27.7,
19.4, 18.6; MS (ESIþ) m/z: 668.5 (MþH)þ; IR (cmꢀ1, neat): 2967,
2931, 2863, 2211, 1683, 1284, 1251, 1162, 1122.
(0.46 g, 69%). 1H NMR (300 MHz, CDCl3)
d 7.05e6.89 (m, 6H), 4.31
(q, J¼8.4 Hz, 2H), 4.08 (dt, J¼6.0, 4.2 Hz, 2H), 3.74 (td, J¼5.7, 2.7 Hz,
1H), 3.65e3.47 (m, 5H), 3.07e2.85 (m, 6H), 2.63 (dd, J¼13.6, 6.4 Hz,
1H), 2.45 (dd, J¼13.6, 7.0 Hz, 1H), 2.07 (m, 1H), 1.82 (m, 1H), 1.05 (d,
4.6. (R)-tert-Butyl(1-(7-cyano-1-(3-hydroxypropyl)indolin-5-
yl)propan-2-yl)(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)
carbamate (7)
J¼6.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 154.1, 150.0, 147.7, 132.6,
130.3, 130.0, 124.5, 121.9 (d, J¼16.6 Hz), 118.3 (d, J¼10.1 Hz), 114.9,
109.9, 90.1, 70.0, 69.2e68.4 (m), 68.1, 67.6, 62.0, 61.5, 54.7, 47.4, 46.6,
42.9, 30.9, 29.4, 20.3 (d, J¼7.3 Hz); MS (EIþ) m/z: 478.3 (MþHþ); IR
25
To the stirred solution of 6 (2.2 g, 3.29 mmol) in methanol
(100 mL) was added 10% Pd/C (1.1 g, 10.3 mmol) and the reaction
mixture was stirred at room temperature under H2 balloon pres-
sure for 1 h. The reaction mixture was filtered over a pad of Celite.
The filtrate was concentrated in vacuo to afford 7 (1.52 g, 97%). 1H
(cmꢀ1, neat): 3330, 3193, 3073, 2929, 2854, 2360, 2333, 1662; [
a]
D
ꢀ30.4 (c 0.01, MeOH).
4.9. (R)-tert-Butyl(1-(1-allyl-7-cyanoindolin-5-yl)propan-2-
yl)(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)carbamate (10)
NMR (300 MHz, CDCl3)
d
7.04e6.89 (m, 6H), 4.37 (q, J¼8.3 Hz, 2H),
4.17e3.91 (m, 3H), 3.80 (t, J¼6.0 Hz, 2H), 3.66 (t, J¼7.3 Hz, 2H), 3.57
(t, J¼8.6 Hz, 2H), 3.45 (dd, J¼23.0, 7.2 Hz, 2H), 2.93 (t, J¼8.6 Hz, 2H),
2.83e2.70 (m, 1H), 2.55 (dd, J¼13.9, 6.7 Hz, 1H), 1.92 (p, J¼7.0 Hz,
2H), 1.44 (s, 9H), 1.25 (d, J¼7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3)
Dehydrated compound 10 was formed as a side product as per
Scheme 7.
1H NMR (300 MHz, CDCl3)
d
7.13e6.71 (m, 6H), 5.89 (ddt, J¼17.2,
10.2, 5.8 Hz, 1H), 5.33e5.06 (m, 2H), 4.37 (q, J¼8.4 Hz, 2H),
4.25e4.10 (m, 2H), 4.08e3.83 (m, 2H), 3.59e3.46 (m, 2H),
3.46e3.27 (m, 2H), 2.98e2.87 (m, 2H), 2.84 (m, 2H), 2.55 (dd,
J¼13.8, 6.7 Hz, 1H), 1.44 (s, 9H), 1.24 (t, J¼6.0 Hz, 3H); 13C NMR
d
155.9, 152.1, 149.6, 133.0, 131.6, 130.0, 128.5, 124.3, 121.8 (d,
J¼31.1 Hz), 121.4, 120.2, 117.3, 114.4, 113.9, 88.0, 80.3, 68.3, 67.8 (t,
J¼35.1 Hz), 60.7, 54.4, 53.7, 45.9, 44.4, 40.5, 40.0, 30.8, 28.8, 27.6,
19.4, 18.62; MS (ESIþ) m/z: 578.4 (MþH)þ; IR (cmꢀ1, neat):
3457e3388, 2971, 2933, 2211, 1677, 1251, 1162.
(75 MHz, CDCl3)
d 155.5, 154.9, 151.1, 149.3, 146.9, 132.7 (d,
J¼16.5 Hz), 131.3, 129.6, 128.2, 123.9, 117.8, 117.0, 102.3, 88.2, 68.3,
67.9 (d, J¼10.4 Hz), 67.7, 67.4 (d, J¼11.0 Hz), 67.2, 66.9, 54.8, 52.6,
50.3, 43.8, 40.1, 39.6, 28.4, 28.3, 27.1, 19.0, 18.2; MS (EIþ) m/z: 560.4
(MþH)þ IR (cmꢀ1, neat): 2975, 2933, 2210, 1687, 1502, 1166, 748.
4.7. 5-(2-((2-(2-(2,2,2-Trifluoroethoxy)phenoxy)ethyl)amino)
propyl)indoline-7-carbonitrile (9)
To a mixture of amine A (0.46 g, 1.9 mmol) and mesylate C (0.5 g,
1.59 mmol) in acetonitrile (50 mL) was added K2CO3 (0.65 g,
4.77 mmol) and the reaction mixture was refluxed for 16 h. The
solvent was evaporated in vacuo. The residue was diluted with water
(20 mL) and extracted with ethyl acetate (3ꢁ20 mL). The combined
organic layers were dried over MgSO4, and concentrated in vacuo.
The crude product was purified by flash chromatography (10e15%
methanol in dichloromethane) to afford compound 9 (0.201 g, 52%).
4.10. (R)-1-(3-Hydroxypropyl)-5-(2-((2-(2-(2,2,2-trifluoroe-
thoxy)phenoxy)ethyl)amino)propyl)indoline-7-carboxamide
(Silodosin)
(A) To a stirred solution of 14 (1.5 g, 3.14 mmol) in methanol was
added NaOH (0.16 g, 4.71 mmol) and the reaction mixture was stir-
red at room temperature for 30 min. To the above reaction mixture
was added 30% H2O2 (0.11 mL, 4.71 mmol) and the reaction mixture
was stirred at room temperature for 8 h. The solvent was evaporated
in vacuo. The reaction mixture was neutralized by 1 N HCl (50 mL)
and extracted with ethyl acetate (3ꢁ75 mL). The combined organic
layers were dried over MgSO4, and concentrated in vacuo. The crude
product was purified by flash chromatography (10e15% methanol in
dichloromethane) to afford Silodosin (1.48 g, 95%).
(B) To a stirred solution of 14 (1.4 g, 3.13 mmol) in methanol was
added NaOH (0.1 g, 4.7 mmol) and the reaction mixture was stirred
at room temperature for 30 min. To the above reaction mixture was
added 30% H2O2 (0.10 mL, 4.7 mmol) and the reaction mixture was
stirred at room temperature for 8 h. The solvent was evaporated in
vacuo. The reaction mixture was neutralized by 1 N HCl (40 mL) and
extracted with ethyl acetate (3ꢁ75 mL). The combined organic
layers were dried over MgSO4, and concentrated in vacuo. The
crude product was purified by flash chromatography (10e15%
methanol in dichloromethane) to afford Silodosin (0.96 g, 67%). 1H
1H NMR (300 MHz, CDCl3)
d
6.94 (m, 6H), 4.36 (q, J¼8.4 Hz, 2H),
4.20e3.98 (m, 2H), 3.64 (t, J¼8.5 Hz, 2H), 3.16e2.92 (m, 4H), 2.64 (dd,
J¼13.6, 6.3 Hz, 1H), 2.57e2.32 (m, 2H), 1.06 (d, J¼6.2 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d 154.14,149.99,147.74,131.23,130.36,129.66,
129.24,124.59,122.11,118.57e117.87 (m),115.37,114.93, 90.12, 71.34,
69.04, 68.58, 68.11, 67.66, 61.35, 54.73, 47.43, 46.55, 42.87, 29.46,
22.37, 20.19; MS (EIþ) m/z: 420.2 (MþHþ); IR (cmꢀ1, neat):
3420e3210, 3037, 2958, 2935, 2875, 2211, 1500, 750.
4.8. (R)-1-(3-Hydroxypropyl)-5-(2-((2-(2-(2,2,2-trifluoroethoxy)
phenoxy)ethyl)amino)propyl)indoline-7-carbonitrile (14)
(A) To a stirred solution of 5 (2.5 g, 4.81 mmol) in dry acetonitrile
(75 mL) was added NaH (0.57 g, 24.05 mmol) at 0 ꢂC. After stirring
for 30 min at the same temperature, 3-bromopropyl tert-butyl
carbonate 12 (1.38 g, 5.77 mmol) was added and the reaction
mixture was refluxed for 4 h. The solvent was evaporated in vacuo.
The residue was diluted with water (100 mL) and extracted with
ethyl acetate (3ꢁ50 mL). The combined organic layers were washed
with satd solution of NaHSO3 (20 g in 100 mL), dried over MgSO4
and concentrated in vacuo. The crude product was purified by flash
chromatography (8e15% methanol in dichloromethane) to afford
14 (1.78 g, 78%).
(B) To a stirred solution of 7 (0.8 g, 1.38 mmol) in dichloro-
methane (50 mL) was added TFA (0.31 mL, 4.15 mmol) at 0 ꢂC and
the reaction mixture was stirred at room temperature for 8 h. The
solvent was evaporated in vacuo. The residue was neutralized by
satd NaHCO3 (100 mL) and extracted with ethyl acetate (3ꢁ25 mL).
The combined organic layers were dried over MgSO4, and con-
centrated in vacuo. The crude product was purified by flash chro-
matography (8e15% methanol in dichloromethane) to afford 14
NMR (300 MHz, CDCl3)
d 7.13 (s, 1H), 7.08e6.82 (m, 5H), 4.27
(q, J¼8.4 Hz, 2H), 4.08e4.03 (m, 2H), 3.65 (t, J¼5.6 Hz, 2H), 3.33
(t, J¼8.4 Hz, 3H), 3.14e2.87 (m, 6H), 2.67 (dd, J¼13.6, 6.3 Hz, 1H),
2.48 (dd, J¼13.5, 6.9 Hz, 1H), 1.74e1.70 (m, 2H), 1.04 (d, J¼6.2 Hz,
3H); 13C NMR (75 MHz, CDCl3)
d 172.1, 150.2, 149.8, 147.6, 134.2,
130.3, 128.4 (d, J¼17.1 Hz), 125.7, 124.6, 121.9, 118.6, 118.2, 115.0,
68.9, 68.5, 68.0, 59.7, 54.9, 53.9, 51.1, 46.3, 42.7, 31.3, 28.6, 20.0; MS
(EIþ) m/z: 496.5 (MþH)þ; IR (cmꢀ1, neat): 3355, 3193, 3072, 2929,
25
2854, 1660. [
a]
ꢀ10.02 (c 0.01, MeOH).
D
Acknowledgements
The authors thank the Formosa Laboratories, Inc. for major fi-
nancial support. The authors thank the National Science Council of
Taiwan for the financial assistance. This work is particularly

I.J. Barve et al. / Tetrahedron 69 (2013) 2834e2843
2843
6. Sountoulides, P.; Dijk, M.; Wijkstra, H.; Rosette, J.; Michel, M. World J. Urol. 2010,
28, 3e8.
supported by ‘Center for Bioinformatics Research of Aiming for the
Top University Program’ of the National Chiao Tung University and
Ministry of Education, Taiwan, ROC.
7. Joshi, S.; Bhuta, S.; Talukdar, S.; Sawant, S.; Venkataraman, D.; Pise, A.; Metkar, S.;
Chavan, D.; Luthra, P. K. Process for the Preparation of Indoline Derivatives and
Their Intermediates Thereof. PCT WO 2011/030356 A2, March 17, 2011.
8. Kitazawa, M.; Ban, M.; Okazaki, K.; Ozawa, M.; Yazaki, T.; Yamagishi, R. 1,5,7-
Trisubstituted Indoline Compounds and Salts Thereof. U.S. Patent 5,387,603,
February 7, 1995.
Supplementary data
Analytical data (1H NMR, 13C NMR, LRMS, IR, HPLC) of all in-
termediates and Silodosin. Supplementary data associated with
this article can be found in the online version, at http://dx.doi.org/
10.1016/j.tet.2013.01.061.
9. Gidwani, R. M.; Kolhatkar, M. V. Process for Preparing an Intermediate for
Silodosin. PCT WO 2011/124704 A1, October 13, 2011.
10. Maloney, D.; Hecht, S. Org. Lett. 2005, 7, 4297e4300.
11. Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Kebeler, M.; Sturmer, R.; Zelinski, T.
€
Angew. Chem., Int. Ed. 2004, 43, 788e824.
12. Hirayama, Y.; Ikunaka, M.; Matsumoto, J. Org. Process Res. Dev. 2005, 9, 30e38.
13. Medina, D.; Gedanken, A.; Mastai, Y. Chem.dEur. J. 2011, 17, 11139e11142.
14. Sayan, P.; Sargut, S.; Kiran, B. Ultrason. Sonochem. 2011, 18, 795e800.
15. Amara, N.; Ratsimba, B.; Wilhelm, A.; Delmas, H. Ultrason. Sonochem. 2001, 8,
265e270.
16. Ruecroft, G.; Hipkiss, D.; Ly, T.; Maxted, N.; Cains, P. W. Org. Process Res. Dev.
2005, 9, 923e932.
17. Lowdon, I. Manufacture of Rimcazole. PCT WO 2008/040950 A1, April 10, 2008.
18. Jin, H.; Xu, Y.; Shen, Z.; Zou, D.; Wang, D.; Zhang, W.; Fan, X.; Zhou, Q.
Macromolecules 2010, 43, 8468e8478.
References and notes
1. Shibata, K.; Foglar, R.; Horie, K.; Obika, K.; Sakamoto, A.; Ogawa, S.; Tsujimoto, G.
Mol. Pharmacol. 1995, 48, 250e258.
2. Murata, S.; Taniguchi, T.; Muramatsu, I. Br. J. Pharmacol. 1999, 127, 19e26.
ꢀ
3. Rossi, M.; Roumeguere, T. Drug Des. Devel. Ther. 2010, 4, 291e297.
4. Watanabe, M.; Yamanishi, T.; Mizuno, T.; Tatsumiya, K.; Masuda, A.; Honda, M.;
Uchiyama, T.; Sakakibara, R.; Yoshida, K. LUTS 2010, 2, 31e36.
5. Montorsi, F. Eur. Urol. Suppl. 2010, 9, 491e495.