Improved Preparation of Silodosin

Full text of DOI:10.1080/00304948.2019.1600127

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: 0030-4948 (Print) 1945-5453 (Online) Journal homepage: https://www.tandfonline.com/loi/uopp20
Improved Preparation of Silodosin
Hui Liu, Fei Lv & Yuan Liu
To cite this article: Hui Liu, Fei Lv & Yuan Liu (2019) Improved Preparation of Silodosin, Organic
Preparations and Procedures International, 51:3, 287-293, DOI: 10.1080/00304948.2019.1600127
To link to this article: https://doi.org/10.1080/00304948.2019.1600127
Published online: 08 May 2019.
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Organic Preparations and Procedures International, 51:287–293, 2019
# 2019 Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2019.1600127
OPPI BRIEF
Improved Preparation of Silodosin
Hui Liu,1
Fei Lv,2 and Yuan Liu2
1Key Laboratory for Green Chemical Process of Ministry of Education,
School of Chemical Engineering & Pharmacy, Wuhan Institute of
Technology, 693 Xiongchu Avenue, Wuhan 430073, P. R. China
2Department of Process Research and Development, Wuhan Synchallenge
Unipharm Inc., 666 Hi-tech Avenue, Wuhan 430075, P. R. China
Silodosin is a novel selective a1A-adrenoceptor (AR) antagonist developed by Kissei
Pharmaceutical Co. in Japan. It is indicated for the treatment of the signs and symptoms
of benign prostatic hyperplasia (BPH).1 Common signs and symptoms associated with
BPH are related to bladder outlet obstruction, which is caused by the increase of
smooth muscle tone in the prostate and bladder neck. Due to its high selectivity for the
a1a receptor to a1b receptor, silodosin causes relaxation of the smooth muscle resulting
in improvement of BPH symptoms while minimizing the effect on blood pressure.2–3
In the preparation of silodosin using the patented route (Scheme 1),4 four important
impurities were observed: IM-A and IM-B are starting materials for the synthesis of
SI-III, IM-C is the disubstituted by-product from SI-III, and IM-D is the S-enantiomer
of silodosin (Figure 1). It is necessary to control the formation of these impurities and
the subsequent impurities they become in downstream chemical steps.5–8 In the present
work, the preparation of silodosin was optimized to ensure high quality, aiming at the
effective control of the process-related impurities and degradation products.
In the formation of SI-III, the substitution of SI-II was conducted in tert-butanol
with sodium carbonate under reflux.4 During the course of the reaction, SI-II was sub-
stituted with IM-A to afford SI-III and the disubstituted product IM-C. An excess of
IM-A was used to achieve completion, resulting in the formation of SI-III with a high
level of IM-C, which was difficult to remove by crystallization. With the addition of an
acid, however, the secondary amine SI-III precipitated in the form of a salt, and the ter-
tiary amine IM-C still remained dissolved in the solution. By use of this concept, a var-
iety of inorganic and organic acids were screened in the present work to maximize the
yield of precipitate and to reduce the level of impurity IM-C below the acceptable
threshold limit (Table 1).4,9,10 In the patented route, SI-IV was obtained as its oxalate
salt to be isolated from the mixture. Instead, we found that the combination of L-tartaric
acid and isopropanol was the most effective combination for the formation of salt and
Received September 23, 2017; in final form November 3, 2018.
Address correspondence to Hui Liu, Key Laboratory for Green Chemical Process of Ministry of
Education, School of Chemical Engineering & Pharmacy, Wuhan Institute of Technology, 693
Xiongchu Avenue, Wuhan, 430073, P. R. China. E-mail: witty_lau@hotmail.com
Color versions of one or more of the figures in the article can be found online at www.tandfon-
line.com/uopp.
287

288
Liu et al.
O
O
OMs
CF3
H
N
NH2
OH
NH2
NaOH
oxalic acid
O
N
N
N
O
O
Na2CO3
HO
OH
CF3
O
O
O
N
N
N
O
OH
O
O
O
SI-I
SI-II
SI-III
H
N
H
N
H
N
O
O
O
H2O2
NaOH
O
N
O
N
N
O
NaOH
O
CF3
O
CF3
NH2
HO
CF3
HO
HO
OH
N
O
N
O
O
SI-IV
SI-V
Silodosin
Scheme 1. The patented synthetic route of silodosin.4
NH2
O
O
S
O
N
O
O
CF3
O
N
IM-A
O
IM-B
F3C
O
O
N
O
H
N
N
O
O
CF3
N
O
O
N
O
CF3
NH2
O
HO
IM-C
IM-D
Figure 1. Process-related impurities of silodosin.
Table 1
Effect of Acid and Solvent on the Content of IM-C
Entry
Acid
Solvent
Yield
Content of IM-C
ꢀ
1
2
3
4
5
6
7
8
9
HCl
H2SO4
malonic acid
succinic acid
oxalic acid
isopropanol
isopropanol
isopropanol
isopropanol
isopropanol
ethyl acetate
isopropanol
acetonitrile
ethyl acetate
-
-
-
-
-
-
-
-
ꢀ
ꢀ
ꢀ
73.4%
1.62%
-
0.15%
0.13%
0.09%
ꢀ
oxalic acid
-
L-tartaric acid
L-tartaric acid
L-tartaric acid
67.2%
66.5%
34.4%
ꢀNo precipitation.

Silodosin
289
Table 2
Effect of Stoichiometric Ratio on the Yield of Silodosin
equivalents
of NaOH
equivalents
of H2O2
Entry
reaction time
Yield
ꢀ
1
2
3
4
5
6
1.0
1.2
1.0
1.1
1.2
1.2
5
5
5.5
5.5
5.5
6
-
-
27 h
-
52.3%
-
68.8%
82.7%
75.4%
ꢀ
15 h
10 h
9 h
ꢀReaction was not completed.
removal of impurity. The stoichiometric ratio of base was also investigated to minimize
the disubstituted impurity IM-C, and 0.6 equiv. of sodium carbonate was sufficient to
complete the reaction in high conversion. Under the optimal conditions, the tartrate salt
of SI-III was isolated in a yield of 67.2% with the level of IM-C not more than 0.10%.
Moreover, the optical purity of SI-III was further enhanced by the formation of the tar-
trate salt.
Silodosin has one chiral center and is used as the single R-enantiomer.11 Control of
the optical isomer (S-isomer) IM-D is a major concern. The input material impacts the
quality of the finished product, so the optical purity used needed to be at least 98.0%.
We studied the effect of reaction temperature and base concentration on the content of
IM-D. It was found by HPLC analysis that no inversion was detected in the finished
product, and epimerization of silodosin did not occur under our reaction conditions (see
Experimental Section).
Optimization of Preparation of Silodosin
The hydrolysis of SI-V was conducted in DMSO with sodium hydroxide in the pres-
ence of hydrogen peroxide at 10-15 ꢁC. It was found that the stoichiometric ratio played
a vital role in the hydrolysis reaction. The reaction was too slow to be completed
(Table 2) when 1 equiv. of sodium hydroxide and 5 equiv. of hydrogen peroxide were
used. And the formation of degradation products was observed with an excess of
sodium hydroxide and hydrogen peroxide. Silodosin was not stable under either alkaline
or oxidizing conditions. Monitoring by HPLC, the best result was obtained by using 1.2
equiv. of sodium hydroxide and 5.5 equiv. of hydrogen peroxide with respect to inter-
mediate SI-V. The aqueous solutions of sodium hydroxide and hydrogen peroxide were
added dropwise at the same time, at such a rate that they were consumed together.
Following that, an aqueous solution of sodium dithionite or sodium sulfite was used to
remove the excess hydrogen peroxide in the workup. The formation of degradation
products was suppressed while high conversion was achieved.
Silodosin has been reported to be sensitive to both artificial light and to sunlight,
and the content of the active pharmaceutical ingredient diminished over time.12 The
drug is supplied in the form of capsules or tablets containing titanium dioxide for light-
shielding. In the present work, photo-degradation studies were conducted as per ICH
guidelines.5 After exposure to light, the level of the degradation product was found to
vary from 0.36% to 1.90%, well above the mandated threshold limits (Figure 2).

290
Liu et al.
Manual Acquisition
UV_VIS_2
WVL:235 nm
Manual Acquisition
UV_VIS_2
WVL:235 nm
2,500
2,000
1,500
1,000
500
800
mAU
mAU
silodosin
silodosin
625
500
375
250
125
photodegradaꢀon
product
min
17.6
min
-100
0.0
-200
0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
2.0
4.0
6.0
8.0
10.0
12.0
15.3
Retention Time [min]
Retention Time [min]
Figure 2. HPLC chromatograms of silodosin before (left) and after (right) radiation.
sl #723 RT: 8.61 AV:
1 NL: 1.97E5
sl #800 RT: 9.45 AV:
1 NL: 7.85E6
F: ITMS
+
c
ESIsid=35.00 Full ms [50.00-2000.00]
494.34
F: ITMS
+
c
ESIsid=35.00 Full ms [50.00-2000.00]
496.69
100
100
95
90
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
95
90
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
480.66
259.25
261.74
516.29
538.37
991.03
1012.96
1000
m/z
462.63
518.31
149.16
200
477.53
245.93
450.52
1622.27 1722.38
1522.28
355.25
1922.45
2000
1484.53
1400
684.25
987.06
1000
1322.36
1222.30
1200
1977.42
2000
0
0
400
600
800
1400
1600
1800
200
400
600
800
1200
1600
1800
m/z
Figure 3. LC-MS spectra of silodosin (upper) and its photodegraded product (below).
H
N
O
CH
Fragmentation
N
O
N
CF3
O
O
NH2
NH2
HO
HO
IM-E
m/z 494 [M+H]+
m/z 259 [M+H]+
H
N
O
CH
Fragmentation
N
O
N
CF3
O
O
NH2
NH2
HO
HO
Silodosin
m/z 496 [M+H]+
m/z 261 [M+H]+
Figure 4. MS fragmentation of photo-degradation impurity and silodosin.

Silodosin
291
The sample was subjected to LC-MS to identify the molecular weight of the photo-
degradation product, and the results revealed that its mass is 494 ([M þ H]þ), which
corresponds to the dehydrogenation product of silodosin (Figure 3). From fragmenta-
tion studies, the precursor ion at m/z 494 transits to the ion at m/z 259. In contrast, the
precursor ion at m/z 496 of silodosin transits to the ion at m/z 261. This is indicative of
the resilience of the N-ethylidene-2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethanamine moi-
ety, suggesting that dehydrogenation occurs at the 1-(3-hydroxypropyl)-5-methylindo-
line-7-carboxamide moiety of the drug (Figure 4). According to in vivo studies, IM-E
is also the metabolite of silodosin in human plasma.13 The metabolism is mediated by
CYP3A4 and inhibited significantly by ketoconazole.
In conclusion, parameters such as salt formation, optical purity, and stoichiometric
ratios of reagents have been optimized for the preparation of silodosin. The modified
route was efficient for the control of the process-related impurities and degradation
products. In addition, the significant photo-degradation product was identified to be the
same as the metabolite of silodosin.
Experimental Section
General
The starting materials SI-I and IM-A were prepared by using literature procedures.14
All reagents and solvents were purchased from commercial suppliers and used without
further purification. NMR spectra were recorded on an Agilent 400 MHz spectrometer
in the indicated solvents. Chemical shifts are expressed in parts per million (d) using
residual solvent protons as internal standards. The LC-MS was conducted on a Thermo
Scientific LTQ XL instrument. The reverse phase HPLC analysis was carried out on a
Dionex Ultimate 3000 using a column (Hypersil BDS C18, 4.6 ꢂ 250 mm, 5 lm) at
35 ꢁC. Mobile phase: A mixture of acetonitrile and water containing 0.1% triethylamine
in gradient elution mode with flow rate 1.0 mL/min. HPLC analysis for the enantiomers
of silodosin was carried out on a Dionex Ultimate 3000 instrument using a column
(Chiralpak IA, 4.6 ꢂ 250 mm, 5 lm) at 35 ꢁC. Mobile phase: A mixture of hexane and
ethanol (80:20) containing 0.1% ethanolamine with flow rate 0.5 mL/min.
Synthesis of Compound SI-III and SI-IV
To a slurry of SI-I (769 g, 1.50 mol) as the tartrate salt (e.e. 98.3%) in dichloromethane
(2 L) was added dropwise an aqueous solution of sodium hydroxide (5 N, 126 g,
3.15 mol) at 10 ꢁC, all in a round bottom flask (5 L). The reaction mixture was stirred
until the pH was 11. The organic layer was separated and the aqueous layer was
extracted with dichloromethane twice (500 ml ꢂ 2). The combined organic layer was
washed with water to neutrality, dried over sodium sulfate and filtered. The filtrate was
concentrated under reduced pressure to give the SI-II (531 g, 97.5%, HPLC 98.2%) as
a light yellow oil.
To a solution of SI-II (531 g, 1.46 mol) as the free base in tert-butanol (2.5 L) was
added IM-A (528 g, 1.68 mol) and sodium carbonate (92.9 g, 0.876 mol), all in a round
bottom flask (5 L). The reaction mixture was heated under reflux until TLC (dichloro-
methane/methanol, 20/1) showed the reaction to be complete. After cooling, the mixture
was extracted with ethyl acetate twice (2 L ꢂ 2). The combined organic layer was

292
Liu et al.
washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated
under reduced pressure and iso-propanol (4 L) was added. To the solution was added an
aqueous solution of L-tartaric acid (329 g, 2.19 mol) with stirring for 2 h at room tem-
perature. The precipitate was collected and washed with iso-propanol/water (100 ml/
100 ml) twice and recrystallized from iso-propanol/water (2.6 L/1.3 L) to give SI-IV tar-
trate (717 g, 67.2%, HPLC 98.5%) as a white solid. SI-III (free base): 1H NMR
(400 MHz, CDCl3): d 1.01 (d, 3H), 2.07 (t, 2H), 2.40 (m, 1H), 2.56 (m, 2H), 2.63 (m,
2H), 2.97 (m, 2H), 3.49 (t, 2H), 3.67 (t, 2H), 4.03 (m, 2H), 4.30 (m, 2H), 4.39 (t, 2H),
6.81-6.96 (m, 6H), 7.36 (m, 2H), 7.47 (m, 1H), 7.91 (m, 2H), 8.01 (d, 2H). The mother
liquor was purified by column chromatograph to give the IM-C as a yellow oil.15 IM-
1
C: H NMR (400 MHz, CDCl3): d 1.03 (d, 3H), 2.13-2.38 (m, 5H), 2.82 (t, 2H), 3.03
(m, 4H), 3.51 (t, 2H), 3.72 (t, 2H), 4.00 (m, 4H), 4.35 (q, 4H), 4.48 (t, 2H), 6.88-7.04
(m, 12H), 7.45 (m, 2H), 7.55 (m, 1H), 8.08 (d, 2H). These NMR data agreed with the
literature values.
Synthesis of Compound SI-V and Silodosin
To a solution of SI-IV (717 g, 0.98 mol) as the tartrate salt in methanol (2.5 L) was
added dropwise an aqueous solution of sodium hydroxide (5 N, 126 g, 3.14 mol), all in
a round bottom flask (5 L). The reaction mixture was stirred at room temperature until
TLC (dichloromethane/methanol, 5/1) showed the reaction to be complete. After filtra-
tion, the filtrate was concentrated under reduced pressure to 800 ml, then extracted with
ethyl acetate twice (1.5 L ꢂ 2). The combined organic layer was washed with water and
brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under
reduced pressure to give the crude SI-V (459 g, 98.1%, HPLC 95.6%) as a yellow oil.
To a solution of SI-V (459 g, 0.96 mol) as free base in DMSO (2.5 L) was added
dropwise 30% hydrogen peroxide (180 g, 5.28 mol) and 5 N sodium hydroxide (46.1 g,
1.15 mol) at the same time and rate, all in a round bottom flask (5 L). The reaction tem-
perature was kept at 10-15 ꢁC with stirring. After the completion of reaction by TLC
(dichloromethane/methanol, 5/1), the mixture was transferred to a cold solution of
sodium sulfite (215 g, 1.70 mol) in water (5 L). After quenching, the mixture was
extracted with ethyl acetate twice (2 L ꢂ 2). The combined organic layer was washed
with saturated sodium bicarbonate and brine, dried over sodium sulfate, and filtered.
The filtrate was concentrated under reduced pressure to give the crude silodosin
(393 g, 82.7%).
Purification of Silodosin
The crude silodosin (393 g, 0.79 mol) was dissolved in ethyl acetate (1 L) and heated to
reflux in a round bottom flask (2 L). The solution was cooled to room temperature. The
precipitate was filtered and washed with ethyl acetate. The filter cake was dried under
vacuum to give the pure silodosin (348 g, 88.5%, HPLC 99.2%, e.e. 98.6%) as a white
1
powder. H NMR (400 MHz, CDCl3): d 1.06 (d, 3H), 1.79 (t, 2H), 2.48-2.71 (m, 2H),
2.89-3.04 (m, 5H), 3.17 (t, 2H), 3.39 (t, 2H), 3.74 (m, 2H), 4.08 (m, 2H), 4.29 (q, 2H),
6.34 (s, 1H), 6.75 (s, 1H), 6.90 (t, 2H), 6.97-7.06 (m, 3H), 7.16 (s, 1H). MS (ESI, m/z):
496 (M þ Hþ).
Spectroscopic and HPLC data are available from the authors upon request.

Silodosin
293
Acknowledgment
We are grateful to Wuhan Institute of Technology Scientific Research Fund (No.
K201831) for financial support.
ORCID
Hui Liu
http://orcid.org/0000-0001-5140-7618
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