Improved process for the preparation of tamsulosin hydrochloride

Article abstract of DOI:10.1080/00397910802519216

Ellman's sulfinamide reagent is used in asymmetric synthesis of Tamsulosin hydrochloride. The enantiomeric ratio achieved is 87:13. The crystallization of the same with dibenzoyl tartarate afforded the product 2 with 99.5% ee.

Full text of DOI:10.1080/00397910802519216

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Improved Process for the
Preparation of Tamsulosin
Hydrochloride
A. Veera Reddy a , S. Udaya Bhaskara Rao a , G.
Lakshmi Narasimha a & P. K. Dubey b
a Research and Development Laboratories, Suven
Life Sciences Ltd., Hyderabad, India
b Department of Chemistry, College of Engineering,
J. N. T. University, Hyderabad, India
Version of record first published: 19 Mar 2009.
To cite this article: A. Veera Reddy , S. Udaya Bhaskara Rao , G. Lakshmi
Narasimha & P. K. Dubey (2009): Improved Process for the Preparation of Tamsulosin
Hydrochloride, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 39:8, 1451-1456
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Synthetic Communications1, 39: 1451–1456, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802519216
Improved Process for the Preparation
of Tamsulosin Hydrochloride
A. Veera Reddy,1 S. Udaya Bhaskara Rao,1
G. Lakshmi Narasimha,1 and P. K. Dubey2
1Research and Development Laboratories, Suven Life Sciences Ltd.,
Hyderabad, India
2Department of Chemistry, College of Engineering, J. N. T. University,
Hyderabad, India
Abstract: Ellman’s sulfinamide reagent is used in asymmetric synthesis of
Tamsulosin hydrochloride. The enantiomeric ratio achieved is 87:13. The crystalli-
zation of the same with dibenzoyl tartarate afforded the product 2 with >99.5% ee.
Keywords: Dibenzoyl tartarate, hydrogenation, t-butyl sulfinamide (Ellman’s
sulfinamide)
INTRODUCTION
During the past two decades, many synthetic groups have been engaged
in the development of single enantiomeric drug targets that exhibit an
amine functionality at the chiral center.[1,2] In spite of the fact that these
chiral amines are regarded as an important class of compounds, their
practical synthesis poses significant challenges to organic chemists.
Tamsulosin (1), an antihypertensive drug also used in the treatment of
benign prostatic hyperplasia, was invented by Yamanouchi (now Astellas
Pharma) and codeveloped by Boehringer Ingelheim in the United States
and CSL Pharma in Australia.
Received August 3, 2008.
Address correspondence to A. Veera Reddy, Research and Development
Laboratories, Suven Life Sciences Ltd., 18, Phase III, Jeedimetla, Hyderabad
500 055, India. E-mail: reddyvenis@rediffmail.com
1451

1452
A. V. Reddy et al.
RESULTS AND DISCUSSION
The key intermediate in the preparation of Tamsulosin (1) is the amine (2),
an amphetamine derivative 3-(4-methoxy-3-sulfonamido-phenyl)-2-amino
propane or 1-methyl-2-(4-methoxy-3-sulfonamido phenyl) ethyl amine.
The known methods of synthesis for this amine are given in Scheme 1.
The innovator[3] prepared the amine (2) using asymmetric synthesis
with the help of (R)-phenyl ethylamine (3). The optical purity they
achieved is 94.5%, and they purified it four times to get the optical purity
of >99%. The Indian authors[4,5] used the conventional resolution
technology of the dl-amine (2) with (D)-tartaric acid. They also did the
purification two times to get the optically pure (>99%) amine (2).
During the past decade, Prof. Ellman developed the t-butyl
sulfinamide reagents (4) (both R=S isomers) as chiral reagents to prepare
a variety of amines.[6]
Because these reagents (R and S) have started to be available commer-
cially, we decided to study the preparation of amine (2) using this technology.
1-Phenyl (substituted) propan-2-one (5) is reacted with (R)-t-butyl
sulfinamide (4) as per Ellman’s procedure[7] to give the product with

Preparation of Tamsulosin Hydrochloride
1453
Scheme 1. Synthesis of 2 by resolution method.
87% optical purity (Scheme 2). Different reaction conditions, such as low
temperatures during condensation, and different reducing agents in next
step did not improve the optical ratio. The results are given in Table 1.
The results are similar with (S) isomer of (4). Simple crystallizations
of (2) as HCl or as a base did not improve the chirality further. Different
tartarate salts (see Table 2) were tried to prepare the amine (2) with high
optical purity. As reported, tartaric acid salt, did not give the best quality
even after two crystallizations (98.2% chiral purity). The ditoluoyl
tartarate also did not yield the correct quality of product in one crystal-
lization. Only with the dibenzoyl tartaric acid salt and two crystalliza-
tions was the optical purity improved to 99.55%. This amine 2 was
further converted to tamsulosin and confirmed in all respects.
In conclusion, we have demonstrated the t-butyl sulfinamide’s useful-
ness in producing tamsulosin hydrochloride with chiral purity >85%. The
chiral purity has been enhanced further to >99.5% with salt formation
and recrystallization.
EXPERIMENTAL
General Procedure for the Condensation of Ketone (5) with 4
(R)-t-Butyl sulfinamide (4) (1 equiv.) was added to a 0.5 M solution of
titanium tetraisopropoxide (2 equiv.) and 5-acetonyl-2-methoxybenzene
sulfonamide (5) (1.2 equiv.) in tetrahydrofuron (THF) under an N2
Scheme 2. Synthesis of 2 with (R)-t-butylsulfinamide.

1454
A. V. Reddy et al.
Table 1. Reduction of imine with different reducing agents
Entry Temperature Reducing agent Optical purity (%)
Comments
6
ꢁ48 ꢀC
ꢁ70 ꢀC
NaBH4
NaBH4
87
No improvement in
optical purity
Optical purity is low
No reaction
No reaction
No reaction
No reaction
6
6
6
6
6
87
—
—
—
—
55–60 ꢀC & rt Raney nickel
rt
NaBH (OAc)3
Vitride
DIBAL
ꢁ40 ꢀC
ꢁ40 ꢀC
atmosphere, and the flask was heated (65–75 ꢀC). Upon completion, as
determined by thin-layer chromatography (TLC), the mixture was cooled
to room temperature first and then to ꢁ48 ꢀC with a dry ice=acetone
bath. NaBH4 (4 equiv.) was added portionwise at ꢁ48 ꢀC, and the reac-
tion mixture was stirred at ꢁ48 ꢀC until the reduction was complete. Then
methanol was added dropwise until gas no longer evolved. The resulting
mixture was poured into an equal volume of brine with rapid stirring.
The resulting suspension was filtered through hyflo, and the bed washed
with ethyl acetate. The filtrate was extracted with ethyl acetate. The com-
bined organic portions were dried (Na2SO4), filtered, and concentrated to
obtain the crude product (2). The crude product thus obtained was
purified by making hydrochloride salt, followed by base preparation
using a known procedure.[3] Chiral ratio of the crude product is 85:15.
Preparation of Dibenzoyl-D-tartarate Salt of (R)-5-(2-Aminopropyl)-
2-Methoxybenzene Sulfonamide
(R)-5-(2-Aminopropyl)-2-methoxybenzene sulfonamide (25 g) was dis-
solved in a solvent mixture of alcohol (250 ml) and N,N-dimethyl
formamide (50 ml) with heating. Dibenzoyl-D-tartaric acid (40 g) was
added at 75–80 ꢀC, and the temperature was maintained for 6 h. The
crystals formed were collected by filtration and washed with alcohol,
Table 2. Resolution of 2 with different tartarate derivatives
Tartaric salt
Solvent mixture
HPLC chiral purity (%)
D-(–)-Tartaric acid
Di-p-toluoyl tartarate
Dibenzoyl-D-tartarate
MeOH–DMF (10:2)
Acetone–DMF (6:3)
Alcohol–DMF (10:2)
98.5
99.25
99.55

Preparation of Tamsulosin Hydrochloride
1455
affording dibenzoyl-D-tartarate salt of (R)-5-(2-aminopropyl)-2-methoxy-
benzene sulfonamide, dry weight: 26 g and HPLC chiral purity: 97–98%.
(Chiral purity was checked on a Daicel chiralpak AD–H, 250 ꢂ 4.6 mm
with eluent 1 ml diethyl amine in 1.0 L of ethanol and wavelength at
226 nm. Flow rate was 1.0 ml=min.)
Purification of Dibenzoyl-D-tartarate Salt of (R)-5-(2-aminopropyl)-
2-methoxybenzene Sulfonamide
A mixture of dibenzoyl-D-tartarate salt of (R)-5-(2-aminopropyl)-2-
methoxybenzene sulfonamide (26 g) and methanol (25 ml) was stirred
for 15 min to become a clear solution. Absolute alcohol (260 ml) was
added to the clear solution and heated to reflux temperature, which
was maintained for 1 h. The reaction mixture was cooled to 28–30 ꢀC,
filtered, and washed with alcohol. The solid was dried at 50–55 ꢀC to a
constant weight to give dibenzoyl-D-tartarate salt, dry weight: 24 g and
HPLC chiral purity: 99.5%.
(R)-5-(2-Aminopropyl)-2-methoxybenzenesulfonamide
K2CO3 (16 g) was added to dibenzoyl-D-tartarate salt of (R)-5-(2-amino-
propyl)-2-methoxybenzene sulfonamide (24 g) in water (72 ml). The
reaction mixture was stirred for 1 h at room temperature. The isolated
solid was filtered, washed with water, and dried at 60–65 ꢀC to a
constant weight to give pure (R)-5-(2-aminopropyl)-2-methoxy benzene
sulfonamide, dry weight: 8 g and HPLC chiral purity: 99.5%.
23
[a]D (C ¼ 1.07, methanol): ꢁ17.1 ꢀ (lit: ꢁ17.3ꢀ); melting point:
166–167 ꢀC.
ACKNOWLEDGMENTS
The authors thank Dr. Kumar P. (Suven, U.S.) for helpful discussions
and Suven Life Sciences Ltd. for excellent facilities to carry out this work.
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