An efficient synthesis of racemic tolterodine

Article abstract of DOI:10.14233/ajchem.2014.15708

The efficient and cost effective of the synthesis of (±)-tolterodine (1), a precursor of (+)-(R)-tolterodine was efficiently performed from 6-methyl-4-chroman-2-one (2) via 4 steps in high yield. This process is suitable for large-scale commercial production by avoiding hazardous reagents and high pressure of hydrogen gas.

Full text of DOI:10.14233/ajchem.2014.15708

Asian Journal of Chemistry; Vol. 26, No. 9 (2014), 2813-2814
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.15708
NOTE
An Efficient Synthesis of Racemic Tolterodine
*
K. SUDARSHAN RAO, K. NAGESWARA RAO, P. MURALIKRISHNA and A. JAYASHREE
Department of Chemistry, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad-500 085, India
Corresponding author: E-mail: muralikp999@gmail.com
Received: 30 April 2013; Accepted: 20 August 2013;
*
Published online: 28 April 2014;
AJC-15124
The efficient and cost effective of the synthesis of (±)-tolterodine (1), a precursor of (+)-(R)-tolterodine was efficiently performed from
-methyl-4-chroman-2-one (2) via 4 steps in high yield. This process is suitable for large-scale commercial production by avoiding
6
hazardous reagents and high pressure of hydrogen gas.
Keywords: Cost effective, Synthesis, Tolterodine.
1
3
Tolterodine, in particular (+)-(R)-tolterodine L-tartrate
2.36 (m, 1H), 2.17 (s, 3H), 2.15 (m, 1H); C NMR (100 MHz,
CDCl ) δ 151.4, 144.0, 130.5, 130.2, 129.1, 128.4, 128.2,
(
Detrol®), is a new and potent competitive muscarinic receptor
3
1
antagonist and is used to treat urinary incontinence . The drug
acts on M and M subtypes of muscarinic receptors whereas
other antimuscarinic treatment for overactive bladder only acts
127.9, 126.3, 116.0, 60.7, 38.7, 37.0, 20.7.
2-(3-Methanesulfonyloxy-1-phenyl-propyl)-4-methyl-
2
3
phenyl methanesulfonate (4): To a solution of diol 3 (18.3 g,
2
-5
on M
3
receptors making them more selective . Nonetheless,
75.6 mmol) in CH
2
Cl (300 mL) was added triethylamine (26.4
2
tolterodine has fewer side effects than other antimuscarinics
because tolterodine targets the bladder more than other areas
of the body . This means that fewer drugs need to be given
mL, 2.5 equiv.) and methanesulfonyl chloride (12.9 mL, 2.2
equiv.) at 0 ºC. After stirring at room temperature for 1 h, the
resulting mixture was washed with water (100 mL) and dried
6
daily (due to efficient targeting of the bladder) and so there
are fewer side effects. Therefore, some different approaches
have been published for racemic and asymmetric synthesis of
tolterodine . In the case of racemic tolterodine, a classical
resolution by the formation of diastereomeric salt using L-
over MgSO
4
and concentrated in vacuo to provide 4 (29.7 g,
1
99 %) as a brown oil: H NMR (400 MHz, CDCl
(m, 7H), 7.12 (d, J = 1.9 Hz, 1H), 7.05 (dd, J = 8.3, 1.8 Hz,
1H), 4.56 (t, J = 7.8 Hz, 1H), 4.21-4.16 (m, 2H), 3.01 (s, 3H),
3
) δ 7.32-7.22
7
-14
13
2.93 (s, 3H), 2.47 (m, 2H), 2.33 (s, 3H); C NMR (100 MHz,
CDCl ) δ 145.0, 141.8, 137.4, 135.7, 129.2, 128.8, 128.7,
(
+)-tartaric acid is used to achieve pure (R)-tolterodine and
the racemization of (S)-tolterodine.
-(3-Hydroxy-1-phenylpropyl)-4-methylphenol (3): To
3
128.1, 127.0, 121.6, 68.0, 39.8, 37.9, 37.3, 34.3, 21.2.
2
2-(3-N,N-Diisopropylamino-1-phenylpropyl)-4-
methylphenyl methanesulfonate (5): A reaction mixture of
4 (29.7 g, 74.5 mmol) and potassium iodide (18.6 g, 111.8
mmol, 1.5 equiv.) in acetonitrile (500 mL) was heated at reflux
for 6 h. The reaction mixture was cooled to room temperature
and treated with N,N-diisopropylamine (109.7 mL, 782.6
mmol, 10.5 equiv.). The resulting mixture was further stirred
at reflux for 24 h.After cooling to room temperature, the organic
solvent was removed under reduced pressure. The residue was
extracted with ethyl acetate. The combined organic extract was
a solution of 6-methyl-4-chroman-2-one (2, 37.5 g, 0.16
Scheme-I. mol) in tetrahydrofuran (500 mL), was slowly added
lithium borohydride (3.60 g, 0.16 mol) at 0 ºC. The reaction
mixture was stirred at room temperature for 24 h, cooled to 0
°C and quenched with water (50 mL).After removal of solvent,
the resulting residue was adjusted to pH 1-1.5 with water (150
mL) and concentrated hydrochloric acid (20 mL). The mixture
was extracted with ethyl acetate. The extract was washed with
water, dried over MgSO
as a white solid (35.4 g, 93 %): m.p. 111-113 ºC; H NMR
400 MHz, CDCl ) δ 7.29-7.18 (m, 5H), 6.84 (dd, J = 8.1, 1.9
Hz, 1H), 6.76 (d, J = 1.7 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H),
.56 (m, 1H), 3.82 (br S, 2H), 3.72 (m, 1H), 3.52 (m, 1H),
4
and concentrated in vacuo to afford
1
3
washed with water, dried over MgSO
in vacuo to afford 5 (30.0 g, 99 %) as yellowish oil: H NMR
(400 MHz, CDCl ) δ 7.30-7.22 (m, 6H), 7.14 (m, 1H), 6.99
(dd, J = 8.4, 1.9 Hz, 1H), 4.35 (t, J = 7.5 Hz, 1H), 3.00-2.93
4
and concentrated
1
(
3
3
4

2
814 Rao et al.
Asian J. Chem.
O
1
44.7, 132.2, 129.2, 128.7, 128.5, 128.3, 127.8, 126.1, 117.9,
OH
OH
48.5, 42.6, 39.7, 33.4, 20.8, 19.9, 19.5.
O
The synthetic route to (±)-tolterodine (1) proposed by us
is depicted in Scheme-I. Commercially available 6-methyl-4-
chroman-2-one (2) as a starting material was reduced with
a
LiBH
4
to afford a diol 3 in 93 % yield, which was treated with
SO Cl in the presence of triethylamine to
2
.2 equiv of CH
3
2
3
2
give a dimesylated compound 4 in quantitative yield.A solution
of compound 4 in acetonitrile was treated with 1.5 equiv of
KI followed by an addition of 10.5 equiv of N,N-diisopropyl-
amine to provide mono-mesylated amine 5 in quantitative
N
OMs
OMs
OMs
yield. Finally, hydrolysis of 5 with NaOH in MeOH-H O
2
b
c
provided (±)-tolterodine (1) in quantitative yield.
In summary, the synthesis of (±)-tolterodine (1), a precursor
of (+)-(R)-tolterodine, was efficiently performed from 6-methyl-
4
-chroman-2-one (2) via 4 steps in high yield. This process is
4
5
suitable for large-scale commercial production by avoiding
hazardous reagents and high pressure of hydrogen gas.
N
Conclusion
OH
In summary, we have developed a method for prepare
±)-tolterodine and to controlled impurities, this process is
d
(
suitable for large-scale commercial production by avoiding
hazardous reagents and high pressure of hydrogen gas.
ACKNOWLEDGEMENTS
1
The authors express their thanks to colleagues in the
Jawaharlal Nehru Technological University, for providing
analytical and spectral data.
Scheme-I: Synthesis of racemic tolterodine; Reagents and reaction
conditions: (a) LiBH (1.0 equiv), THF, 0 ºC to room tempe-
rature, overnight, 93 %; (b) CH SO Cl (2.2 equiv), TEA (2.5
equiv), CH Cl , 0 ºC to room temperature, 1 h, 99 %; (c) KI
1.5 equiv), CH CN, reflux, 6 h and then N,N-diisopropylamine
10.5 equiv), room temperature to 70 ºC, 24 h, 99 %; (d) NaOH
5.0 equiv), MeOH/H O (2:1), 85 ºC, 10 h, 99 %
4
3
2
2
2
(
(
(
3
REFERENCES
2
1
2
3
.
.
.
U. Jonas, K. Höfner, H. Madersbacher and T.H. Holmdahl, World J.
Urol., 15, 144 (1997).
P.G. Gillberg, S. Sundquist and L. Nilvebrant, Eur. J. Pharmacol., 349,
285 (1998).
(
m, 2H), 2.77 (s, 3H), 2.39-2.33 (m, 2H), 2.30 (s, 3H), 2.15-
13
2
.09 (m, 2H), 0.93-0.91 (m, 12H). C NMR (100 MHz, CDCl )
3
T. Yamanishi, C.R. Chapple and R. Chess-Williams, World J. Urol.,
δ: 145.6, 143.9, 137.2, 136.9, 129.4, 128.5, 128.2, 128.1, 126.3,
21.5, 120.9, 48.8, 43.7, 41.9, 37.7, 37.4, 37.3, 20.8, 20.6.
±)-Tolterodine: 2-[3-(N,N-diisopropylamino)-1-
phenylpropyl]- 4-methylphenol (1): To a solution of 5 (51.74
g, 0.13 mol) in mixture of CH OH and H O (2:1, 500 mL)
was added sodium hydroxide (25.6 g, 0.64 mol, 5.0 equiv.).
The reaction mixture was heated at 85 ºC for 10 h and cooled
to room temperature. The volume of reaction mixture was
reduced to 1/3 under reduced pressure. The reaction mixture
was adjusted to pH 8 with concentrated hydrochloric acid and
extracted with ethyl acetate. The organic layer was dried over
1
9, 299 (2001).
1
4. D.J. Sellers, T. Yamanishi, C.R. Chapple, C. Couldwell, K. Yasuda and
R. Chess-Williams, J. Autonom. Pharmacol., 20, 171 (2000).
(
5
6
7
8
.
.
.
.
H. Hirose, I. Aoki, T. Kimura, T. Fujikawa, T. Numazawa, K. Sasaki,
M. Nishikibe and K. Noguchi, Eur. J. Pharmacol., 452, 245 (2002).
L. Nilvebrant, K.E. Andersson, P.G. Gillberg, M. Stahl and B. Sparf,
Eur. J. Pharmacol., 327, 195 (1997).
3
2
P.G. Andersson, H.E. Schink and K.J. Österlund, Org. Chem., 63, 8067
(
1998).
J.E. Cabaj and J.R. Gage, Process to Prepare Tolterodine, US Patent
,922,914 (1999).
5
9. C. Botteghi, T. Corrias, M. Marchetti, S. Paganelli and O. Piccolo,
Org. Process Res. Dev., 6, 379 (2002).
1
1
0. C. Selenski and T.R.R. Pettus, J. Org. Chem., 69, 9196 (2004).
1. L. Colombo, R. Rossi, G. Castaldi, P. Allegrini and S.P.A. Dipharma,
Italian Patent MI2004A000616 (2004); Canadian Patent CA 2502640,
(2005); European Patent EP1584621 (2005).
MgSO
0.0 g, 99 %) as oil. H NMR (400 MHz, CDCl
m, 5H), 6.81-6.78 (m, 2H), 6.60 (m, 1H), 4.47 (dd, J = 11.1,
4
and concentrated in vacuo to give (±)-tolterodine (1,
1
4
(
3
) δ 7.32-7.18
1
1
1
2. C. Hedberg and P.G. Andersson, Adv. Synth. Catal., 347, 662 (2005).
3. G. Chen, N. Tokunaga and T. Hayashi, Org. Lett., 7, 2285 (2005).
4. F. Ulgheri, M. Marchetti and O.J. Piccolo, Org. Chem., 72, 6056 (2007).
4
2
.18 Hz, 1H), 3.25-3.18 (m, 2H), 2.69 (m, 1H), 2.38-2.36 (m,
H), 2.12 (m, 1H), 2.11 (s, 3H), 1.11 (d, J = 6.7 Hz, 6H), 1.06
13
(
d, J = 6.7 Hz, 6H); C NMR (100 MHz, CDCl ) δ: 153.1,
3