Reduction of ethyl benzoylacetate and selective protection of 2-(3-hydroxy-1-pheny|propyl)4-methylphenol: A new and facile synthesis of tolterodine

Article abstract of DOI:10.1021/op7001134

A new and facile synthesis of tolterodine using ethyl benzoylacetate as the starting material was developed. Reduction using sodium borohydride in methanol followed by Friedel-Crafts alkylation utilizing FeCl₃ ·6H₂O as catalyst lead to the known 2-(3-hydroxyl- phenylpropyl)-4-methylphenol intermediate. Consecutive protection of phenolic OH withp-toluenesulfonyl chloride via two-phase reaction and conversion of aliphatic OH using p-nitrobenzenesulfonyl chloride facilitates direct substitution of duesopropylamine. After simultaneous deprotection of the tosyl group, optically pure (R)-tolterodine·L-tartrate was obtained by resolution using L-tartaric acid with 99.99% purity.

Full text of DOI:10.1021/op7001134

Organic Process Research & Development 2007, 11, 918–921
Reduction of Ethyl Benzoylacetate and Selective Protection of
2-(3-Hydroxy-1-phenylpropyl)-4-methylphenol: A New and Facile Synthesis of
Tolterodine
Kathlia A. De Castro,† Jungnam Ko,‡ Daejong Park,‡ Sungdae Park,‡ and Hakjune Rhee*,†
Department of Chemistry and Applied Chemistry, Hanyang UniVersity, Ansan Sa 1-Dong 1271, Kyunggi-Do 426-791, Korea,
and R & D Center, Estech Pharma Co., Ansan Mokrae-Dong 445-1, Kyunggi-Do 425-100, Korea
Abstract:
longer reaction times and inert conditions. Others utilize harsh
conditions and hazardous chemicals. Some make use of shorter
routes but have lower yield or enantioselectivity, whereas other
routes require tedious workup. A number of published proce-
dures utilized asymmetric reactions and employed chiral
auxiliaries10,11 or expensive metal catalyst such as rhodium.12,13
However, the use of transition metal catalyst or other chiral
auxiliaries make the process unsuitable for industrial scale as a
result of the cost incurred. Thus, looking for a cheaper and
economical process well suited for industrial production is still
necessary.
A new and facile synthesis of tolterodine using ethyl benzoylacetate
as the starting material was developed. Reduction using sodium
borohydride in methanol followed by Friedel–Crafts alkylation
utilizing FeCl3 ·6H2O as catalyst lead to the known 2-(3-hydroxy-
1-phenylpropyl)-4-methylphenol intermediate. Consecutive protec-
tion of phenolic OH with p-toluenesulfonyl chloride via two-phase
reaction and conversion of aliphatic OH using p-nitrobenzene-
sulfonyl chloride facilitates direct substitution of diisopropylamine.
After simultaneous deprotection of the tosyl group, optically pure
(R)-tolterodine ·L-tartrate was obtained by resolution using L-
tartaric acid with 99.99% purity.
We report herein a new and facile synthesis of tolterodine
utilizing ethyl benzoylacetate, a relatively cheap starting material.
Results and Discussion
Introduction
Our strategy (Scheme 1) took advantage of known chemistry
such as reduction and Friedel–Crafts alkylation. Ethyl benzoyl-
acetate (1), a relatively cheap reagent, was used as the starting
material. Reduction of 1 to the corresponding 1-phenylpropane-
1,3-diol (2) was carried out at various conditions (Table 1). At
first, we attempted to use calcium borohydride for the reduction;
however, such condition required a longer time for in situ
preparation of calcium borohydride and reflux condition for the
reduction per se. In our quest to find a milder condition, we
considered using NaBH4 in THF or MeOH as solvent instead
of just additive,14 as some literature reported, under reflux
condition. Surprisingly the reaction proceeds excellently using
NaBH4 in MeOH at room temperature with 98% yield in a
shorter time (Table 1, entry 10). The mechanism behind such
observation is still under study. As shown in Table 1, the use
of 3 or 4 molar equiv of NaBH4 shows no significant difference
in terms of yield. Thus, we recommend using 3 molar equiv.
We believe that this finding is a new and better condition
especially for industrial scale.
Tolterodine is the first muscarinic receptor antagonist specif-
ically developed to treat overactive bladder. Overactive bladder
results from the uncontrolled spontaneous activity of the bladder
muscle (detrusor) during the filling phase, leading to the
symptoms of urinary urgency and increased frequency of
micturition with or without incontinence.1 Clinical studies
showed that it is equipotent with oxybutynin but possesses fewer
side effects, especially on salivary glands.2,3 This makes
tolterodine the drug of choice by most patients for treatment of
overactive bladder. In view of this, research to improve the
known synthetic routes or to develop new routes has never
stopped. There are various approaches published and patented,
and most of them involved formation of hydrocoumarin4–7 as
intermediate, which was mostly synthesized from the coupling
of p-cresol and trans-cinnamic acid. Others used hydrocoumarin
also to produce intermediate 2-(3-hydroxy-1-phenylpropyl)-4-
methylphenol (3).8,9 Some of these routes are long and employ
* To
whom
correspondence
should
be
addressed.
E-mail:
hrhee@hanyang.ac.kr.
Friedel–Crafts alkylation of alcohols using FeCl3 ·6H2O was
recently reported,15 and this technique with little modification
was used to facilitate the carbon–carbon bond formation to get
2-(3-hydroxy-1-phenylpropyl)-4-methylphenol (3). An excess
† Hanyang University.
‡ Estech Pharma Co.
(1) Kaur, K.; Aeron, S.; Bruhaspathy, M.; Shetty, S. J.; Gupta, S.; Hegde,
L. H.; Silamkoti, A. D. V.; Mehta, A.; Chugh, A.; Gupta, J. B.; Sarma,
P. K. S.; Kumar, N. Bioorg. Med. Chem. Lett. 2005, 15, 2093.
(2) Nilvebrant, L. Life Sci. 2001, 68, 2549.
(3) Chancellor, M. B.; Appell, R. A.; Sathyan, G.; Gupta, S. K. Clin.
Ther. 2001, 23, 753.
(10) Anderson, P. G.; Schink, H. E.; Osterlund, K. J. Org. Chem. 1998,
63, 8067.
(4) Gage, J. R.; Cabaj, J. E. WO Patent 199829402, 1998.
(5) Kumar, Y.; Prasad, M.; Misra, S. WO Patent 2003014060, 2003.
(6) Kankan, R. N.; Rao, D. R. WO Patent 2005061432, 2005.
(7) Venkataraman, S.; Mathad, V. T.; Reddy, K. S.; Srinivasan, N.; Reddy,
C. R.; Arunagiri, M.; Kumari, R. L. US Patent 20060094904, 2006.
(8) Toplak, T. WO Patent 2006066931, 2006.
(11) Hedberg, C.; Anderson, P. G. AdV. Synth. Catal. 2005, 347, 662.
(12) Botteghi, C.; Corrias, T.; Marchetti, M.; Paganelli, S.; Piccolo, O. Org.
Proc. Res. DeV. 2002, 6, 379.
(13) Colombo, L.; Rossi, R.; Castaldi, G.; Allegrini, P. CA Patent 2 502
640, 2005.
(14) Soai, K.; Oyamada, H. Synthesis 1984, 7, 605.
(15) Iovel, I.; Mertins, K.; Kischel, J.; Zapf, A.; Beller, M. Angew. Chem.,
Int. Ed. 2005, 44, 3913.
(9) Turchetta, S.; Ciambecchini, U.; Massardo, P. U.S. Patent 20060079716,
2006.
918
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Vol. 11, No. 5, 2007 / Organic Process Research & Development
10.1021/op7001134 CCC: $37.00
2007 American Chemical Society
Published on Web 08/17/2007

Scheme 1a
a Reagents and conditions: (a) NaBH4, MeOH, rt, 30 min (98%); (b) p-cresol, FeCl3 · 6H2O, CH2Cl2, reflux, 1 d (70%); (c) (1) TsCl, NaOH, H2O, CH2Cl2, 40 °C,
1 h, (2) NsCl, NEt3, 0 °C, 2 h (88%); (d) (1) NHPri2, CH3CN, reflux, 12 h, (2) NaOH, MeOH, reflux, 4 h, (3) HCl, CH2Cl2, rt, 1 h (77%); (e) (1) NaOH, Na2CO3,
CH2Cl2, rt, 1 h. (2) L-tartaric acid, MeOH, acetone, reflux, 1 h (88%).
Table 1. Reduction of ethyl benzoylacetate (1)
reaction condition
entry
reducing agent
molar equiv
solvent
time (h)
temp
reflux
yield (%)
a
1
2
3
4
5
6
7
8
9
10
Ca(BH4)2
2.0
2.0
2.0
2.0
3.0
3.0
3.0
3.0
4.0
3.0
dry THF
THF
72
24
30
91
52
2
71
32
66
69
78
91
92
93
99
98
a
Ca(BH4)2
reflux
reflux (inert)
reflux
reflux
reflux
reflux
reflux
rt
b
Ca(BH4)2
Ca(BH4)2
dry THF
dry THF
dry THF
MeOH
MeOH
MeOH
MeOH
MeOH
c
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
3
4
1
0.50
rt
a Prepared in situ, stirred for 24 h at rt. b Prepared in situ, stirred for 1 h at reflux condition. c Prepared in situ, stirred for 48 h at rt.
amount of p-cresol (4.0 equiv) and only 0.05 equiv of
FeCl3 ·6H2O catalyst in dichloromethane solvent were necessary
to effect the reaction.
(20–30%) and mostly starting material. Diisopropylamine
substitution did not proceed well, presumably because the tosyl
unit is not good enough as a leaving group. A new protecting
group and at the same time a better leaving group is needed;
hence we considered p-nitrobenzenesulfonyl chloride (nosyl
chloride, NsCl). As far as we know, nobody has tried to use
this moiety before. Initially, we did simultaneous protection and
substitution of the two OH groups using triethylamine in
dichloromethane. We failed to achieve complete conversion
because the aliphatic OH is more nucleophilic than the phenolic
OH. It is therefore necessary to change the phenolic OH into
phenoxide ion. To facilitate such transformation, we did
nosylation in a stepwise manner. First, one nosyl unit was added
using 1 M NaOH as base in dichloromethane via a two-phase
reaction. This makes nosylation at the phenolic OH. Then,
another nosyl unit was added to convert finally the aliphatic
OH. This stepwise procedure leads to an 87% yield of 2-(3-
(4-nitrobenzenesulfonyloxy)-1-phenylpropyl)-4-methylphenyl
p-nitrobenzenesulfonate (4b). The protection and conversion of
the two OH groups proceeded easily, and diisopropylamine
undergoes substitution smoothly. This shows that the nosyl unit
is really a better leaving group. However, nosyl chloride is
The next step is believed to be a major breakthrough in the
protection and deprotection technique, as well as in the direct
substitution of diisopropylamine employed in the synthesis of
tolterodine. In most cases, a methyl, benzyl, or p-toluenesulfonyl
(tosyl) unit is usually used to protect the phenolic OH, while a
tosyl unit is used to convert the alcoholic OH into a better
leaving group using an organic base simultaneously.5–8 How-
ever, such technique necessitates a longer reaction time (hours
or even days) under pressurized and high temperature conditions
to facilitate substitution of diisopropylamine. In some cases,
an additional step is required to convert the tosyl moiety into a
much better leaving group such as iodide,8 but still, doing so
requires the same drastic conditions mentioned above. With
these scenarios at hand, a more appropriate condition fitted for
industrial scale is essential. At first, we tried to use tosyl chloride
for protection and conversion of phenolic and aliphatic OH,
respectively, followed by direct substitution of diisopropylamine,
as done in the literature. However, contrary to the published
results, we obtained a very poor yield of substitution product
Vol. 11, No. 5, 2007 / Organic Process Research & Development
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somewhat more expensive than tosyl chloride. Therefore, we
considered protecting the phenolic OH with tosyl chloride
instead of nosyl chloride for economic consideration and
converting the aliphatic OH using nosyl chloride consecutively
in the same manner aforementioned. The idea materialized
easily to give 2-(3-(4-nitrobenzenesulfonyloxy)-1-phenylprop-
yl)-4-methylphenyl p-toluenesulfonate (4c). It gave the same
yield as that when using nosyl chloride for both OH groups.
Simultaneous diisopropylamine substitution and deprotection
of the phenolic OH were carried out without difficulty, and the
following treatment with hydrochloric acid produced tolterod-
ine ·
HCl salt (5) in 77% isolated yield. Finally, the racemic salt
formed was resolved using L-tartaric acid in hot methanol to
produce optically pure (R)-tolterodine·L-tartarate (6) in 88%
yield with 99.99% chemical purity based on the established and
validated HPLC method.16
and the organic layer was extracted using ethyl acetate (20 mL
as many times as necessary). The mixture was further purified
using silica gel column chromatography with hexane/ethyl
acetate (2:1, v/v) eluent system to give compound 217 in 98%
yield (2.98 g) as a pale yellow oil. 1H NMR (300 MHz, CDCl3):
δ 7.30 (m, 5H), 4.94 (dd, J ) 8.3, 6.0 Hz, 1H), 3.84 (m, 2H),
3.23 (s, 1H), 2.79 (s, 1H), 1.95 (m, 2H). 1H NMR (300 MHz,
CDCl3) upon D2O exchange: 7.31 (m, 5H), 4.94 (dd, J ) 8.5,
4.1 Hz, 1H), 4.79 (br s, 2H), 3.83 (t, J ) 5.5 Hz, 1H), 1.96 (m,
2H). 13C NMR (75 MHz, CDCl3): δ 144.5, 128.7, 127.8, 125.9,
74.2, 61.4, 40.6.
2-(3-Hydroxy-1-phenylpropyl)-4-methylphenol (3). 1-Phe-
nylpropane-1,3-diol (2) (1.48 g, 9.72 mmol) was dissolved in
CH2Cl2 (10 mL). p-Cresol (4.07 mL, 38.88 mmol) and
FeCl3 ·6H2O (0.13 g, 0.48 mmol) were added to the solution.
The resulting mixture was stirred and heated at reflux for 1
day. The reaction progress was monitored via TLC (hexane/
ethyl acetate ) 2:1, v/v). Upon completion, the mixture was
cooled down to room temperature and quenched with water
(10 mL). The product was extracted using CH2Cl2 (20 mL) as
many times as necessary. The organic layer was dried using
anhydrous MgSO4, and the solvent was evaporated under
reduced pressure and further dried using vacuum. The crude
product was purified using silica gel column chromatography
with hexane/ethyl acetate (2:1, v/v) eluent system to give
compound 38 in 70% yield (1.64 g) as a white crystalline
powder. 1H NMR (500 MHz, CDCl3): δ 7.32 (d, J ) 4.0 Hz,
4H), 7.23 (m, 1H), 6.88 (dd, J ) 8.3, 1.8 Hz, 1H), 6.79 (d, J
) 2.0 Hz, 1H), 6.73 (d, J ) 8.0 Hz, 1H), 4.58 (dd, J ) 10.3,
5.8 Hz, 1H), 3.77 (m, 1H), 3.55 (m, 1H), 2.39 (m, 1H), 2.17
(m, 4H). 13C NMR (75 MHz, CDCl3): δ 151.7, 144.3, 130.6,
130.5, 129.4, 128.7, 128.5, 128.2, 126.5, 116.2, 60.9, 38.6, 37.1,
21.0.
2-(3-(4-Nitrobenzenesulfonyloxy)-1-phenylpropyl)-4-meth-
ylphenyl p-Nitrobenzenesulfonate (4b). 2-(3-Hydroxy-1-
phenylpropyl)-4-methylphenol (3) (10.0 g, 41.27 mmol) and
p-nitobenzenesulfonyl chloride (9.60 g, 43.33 mmol) were
dissolved in CH2Cl2 (100 mL) at room temperature. Aqueous
NaOH (1.0 M, 83 mL) was added to the mixture, which was
stirred at 0–5 °C. The reaction was monitored by TLC. Upon
completion, the organic layer was separated and washed with
water (50 mL each time) until the pH of the aqueous layer was
approximately 6–7. The organic layer was collected and dried
with anhydrous MgSO4. p-Nitrobenzenesulfonyl chloride (10.06
g, 45.40 mmol) was then added to the dried organic layer, and
the mixture was stirred at 0–5 °C. Then triethylamine (8.35 g,
82.54 mmol) was added slowly using a dropping funnel. The
resulting mixture was stirred for 2 h at room temperature.
Afterwards, the mixture was washed with water (50 mL) twice.
The organic layer was collected and dried with anhydrous
MgSO4. The filtrate was concentrated to half its original volume
under reduced pressure, and the product was recrystallized using
acetone (75 mL). The resulting solid was filtered and vacuum
dried at 60 °C to give compound 4b in 87% yield (21.99 g) as
a white powder. Mp: 115–118 °C. 1H NMR (300 MHz, CDCl3):
δ 8.34 (m, 3H), 8.05 (m, 3H), 7.18 (m, 2H), 6.95 (m, 4H),
4.31 (t, J ) 7.5 Hz, 1H), 4.03 (m, 2H), 2.37 (m, 1H), 2.27 (s,
Conclusion
In conclusion, we have developed a new route for tolterodine
utilizing available chemistry. The reduction of ethyl benzoyl-
acetate using NaBH4 in MeOH at room temperature is very
practical. The successive selective protection and conversion
of the two OH groups using tosyl and nosyl chloride, respec-
tively, via a two-phase reaction is a new idea. It is believed
that this route is practical for industrial purposes because ethyl
benzoylacetate is a relatively cheap starting material and each
step employs mild reaction conditions coupled with cheap
reagents and easy handling.
Experimental Section
General Methods. 1H and 13C NMR spectra were obtained
using a Varian 300-MR spectrometer (300 or 500 MHz) in
CDCl3 or DMSO solvents. The chemical shifts were reported
in δ ppm relative to TMS. The FT-IR spectra were recorded in
the solid state as KBr pellets on a Varian FTS 1000 FT-IR
spectrometer. HRMS were obtained on a JMS 700 spectrometer.
The purity of the final product was checked using chiral AGP
column (100 mm × 2.0 mm, 5 µm, Chromtech Co.). Flash
column chromatography was performed using Merck silica gel
60 (230–400 mesh). Analytical thin layer chromatography
(TLC) was conducted on E. Merck 60 F254 aluminum-backed
silica gel plates. Developed plates were visualized with UV light
or with a 2.0% phosphomolybdic acid staining solution.
Uncorrected melting points were determined with a Gallenkamp
melting point apparatus.
1-Phenylpropane-1,3-diol (2). Ethyl benzoylacetate (1)
(3.44 mL, 19.99 mmol) was dissolved in MeOH (40 mL), and
sodium borohydride (2.27 g, 59.97 mmol) was added slowly
to the mixture at room temperature. The mixture was stirred
until the reaction was complete based on TLC monitoring
(hexane/ethyl acetate ) 2:1, v/v). After completion (30 min),
all of the MeOH was evaporated, and ethyl acetate was added
(20 mL). The mixture was shaken with brine solution (20 mL),
(16) Kumar, Y. R.; Ramulu, G.; Vevakanand, V. V.; Vaidyanathan, G.;
Srinivas, K.; Kumar, M. K.; Mukkanti, K.; Reddy, M. S.; Venkatra-
man, S.; Suryanarayana, M. V. J. Pharm. Biomed. Anal. 2004, 35,
1279.
(17) Chenevert, R.; Fortier, G.; Rhlid, R. B. Tetrahedron 1992, 48, 6769.
920
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Vol. 11, No. 5, 2007 / Organic Process Research & Development

3H). 13C NMR (75 MHz, CDCl3): δ 151.2, 150.9, 145.2, 141.4,
141.3, 140.9, 138.1, 135.6, 130.0, 129.5, 129.5, 129.0, 128.0,
127.2, 124.8, 124.7, 121.7, 69.6, 40.7, 39.4, 34.3, 21.4. IR (KBr,
cm-1): 1536, 1492 (NO2), 1371, 1313 (NO2, SdO), 1182
(SdO), 1095 (S–O); HRMS m/z calcd for C28H24N2O10S2 + H
613.0951, found 613.0955.
added, and the reaction was extracted with CH2Cl2 (75 mL).
The extract was washed with brine solution, and aqueous HCl
solution (1.88 mL of concentrated HCl in 5.64 mL of H2O)
was added to the organic layer. The mixture was stirred for
1 h, and the resulting solid was filtered and washed with CH2Cl2
(20 mL). The solid was dried under vacuum at 60 °C to give
tolterodine·HCl salt (5)18 in 77% yield (9.59 g) as a white
powder. 1H NMR (300 MHz, CD3OD): δ 7.25 (m, 5H); 6.94
(br s, 1H), 6.85 (dd, J ) 8.3, 1.9 Hz, 1H), 6.70 (dd, J ) 8.3,
1.4 Hz, 1H), 4.38 (t, J ) 7.7 Hz, 1H), 3.64 (m, 2H), 3.01 (t, J
2-(3-(4-Nitrobenzenesulfonyloxy)-1-phenylpropyl)-4-meth-
ylphenyl p-Toluenesulfonate (4c). 2-(3-Hydroxy-1-phenyl-
propyl)-4-methylphenol (3) (100.0 g, 412.69 mmol) and p-tol-
uenesulfonyl chloride (78.68 g, 412.69 mmol) were dissolved
in CH2Cl2 (500 mL) at room temperature. Next, 50% aqueous
NaOH (40 mL) was added, and the mixture was heated for 1 h
at 40 °C. The reaction mixture was cooled down to room
temperature, and the organic layer was separated. The organic
layer was washed with 1.0 M HCl (250 mL) and with water
(250 mL) twice. The organic layer was collected, dried with
anhydrous MgSO4 and filtered. p-Nitrobenzenesulfonyl chloride
(96.03 g, 433.31 mmol) was then added to the dried organic
layer at room temperature. The mixture was cooled down to 0
°C, and triethylamine was added dropwise. The resulting
mixture was stirred for 2 h at 0 °C. The mixture was washed
with 1.0 M HCl (250 mL) and with water (250 mL) twice.
The organic layer was collected and dried with anhydrous
MgSO4. The filtrate was concentrated to half its original volume
under reduced pressure, and the product was recrystallized using
n-hexane (750 mL). The resulting solid was filtered and vacuum
dried at 60 °C to give compound 4c in 88% yield (211.24 g)
as a dirty white powder. Mp: 128–130 °C. 1H NMR (300 MHz,
CDCl3): δ 8.32 (m, 2H), 8.05 (m, 2H), 7.78 (d, J ) 8.3 Hz,
2H), 7.36 (d, J ) 8.0 Hz, 2H), 7.16 (m, 3H), 6.99 (dd, J ) 8.0,
2.2 Hz, 2H), 6.88 (m, 2H), 6.81 (d, J ) 8.3 Hz, 1H), 4.31 (dd,
J ) 8.8, 6.9 Hz, 1H), 4.04 (m, 2H), 2.48 (s, 3H), 2.34 (m, 2H),
2.23(s, 3H). 13C NMR (75 MHz, CDCl3): δ 150.8, 145.9, 145.4,
141.5, 141.2, 137.5, 136.4, 133.0, 130.3, 129.6, 129.0, 128.9,
128.7, 128.6, 128.1, 127.1, 124.7, 122.1, 69.9, 39.5, 33.9, 22.1,
21.4. IR (KBr, cm-1): 1534, 1491 (NO2), 1350, 1311 (NO2,
SdO), 1184 (SdO), 1091 (S–O). HRMS m/z calcd for
C29H27NO8S2 + H 582.1256, found 582.1251.
) 8.7 Hz, 2H), 2.50 (m, 2H), 2.18 (s, 3H), 1.27 (m, 12H). 13
C
NMR (75 MHz, CD3OD): δ 152.5, 143.4, 129.2, 128.7, 128.5,
128.4, 128.0, 126.4, 115.0, 55.2, 41.9, 32.7, 19.6, 17.7, 15.9.
(R)-Tolterodine-L-tartarate (6). Tolterodine·HCl salt (5)
(14.56 g, 40.23 mmol), CH2Cl2 (73 mL), and H2O (73 mL)
were mixed. Aqueous NaOH solution (50%, 1.09 g, 27.31
mmol) and Na2CO3 (1.46 g, 13.74 mmol) were added to the
mixture, which was stirred for 1 h. The organic layer was
extracted and washed with H2O (73 mL). The solution was dried
under reduced pressure, and the residue was dissolved in acetone
(80 mL) and warmed to 60–70 °C. The dissolved L-tartaric acid
(6.64 g, 44.26 mmol) in hot MeOH (41 mL) was added at 60–70
°C, and the resulting mixture was heated at reflux for 1 h. The
reaction mixture was cooled down to 0 °C and was held at that
temperature for 1 h. The resulting solid was filtered and dried
under vacuum at 60 °C to give optically pure (R)-toltero-
dine ·L-tartarate in 88% yield with 99.99% chemical purity (8.42
g) as a white crystalline powder. The purity of the product was
checked using a chiral AGP column (100 mm × 2.0 mm, 5
µm, Chromtech Co.) based on the known validated procedure.16
1H NMR (300 MHz, DMSO): δ 7.29 (m, 5H), 7.16 (m, 1H),
7.03 (d, J ) 1.7 Hz, 1H), 6.80 (dd, J ) 8.0, 1.4 Hz, 1H), 6.69
(d, J ) 8.0 Hz, 1H), 4.29 (t, J ) 7.6 Hz, 1H), 4.03 (s, 2H),
3.46 (m, 2H), 2.75 (m, 3H), 2.37 (m, 2H), 2.16 (s, 3H), 1.12
(d, J ) 6.3 Hz, 12H). 13C NMR (75 MHz, DMSO): δ 175.0,
153.1, 144.7, 130.2, 128.9, 128.5, 128.2, 128.0, 126.7, 115.8,
72.6, 53.4, 45.9, 41.5, 33.0, 21.0, 18.5.
Acknowledgment
Tolterodine·HCl Salt (5). Diisopropylamine (34.79 g,
343.84 mmol) was added to 2-(3-(4-nitrobenzenesulfonyloxy)-
1-phenylpropyl)-4-methylphenyl p-toluenesulfonate (4c) (40.00
g, 34.38 mmol) in acetonitrile (50 mL). The reaction mixture
was heated at reflux for 12 h and dried under reduced pressure.
The residue was dissolved in MeOH (80 mL), and then aqueous
NaOH (6.88 g in 35 mL of H2O) was added to the mixture.
The reaction mixture was heated at reflux for 4 h and then
concentrated under reduced pressure. Water (250 mL) was
K.A.De C. acknowledges financial support from the Korean
Ministry of Education through the second stage of the BK21
project for Hanyang University graduate program.
Supporting Information Available
1H and 13C spectra for compounds 2–6 and HRMS and IR
spectra for compounds 4b and 4c. This material is available
free of charge via the Internet at http://pubs.acs.org.
(18) Srinivas, K.; Srinivasan, N.; Reddy, K. S.; Ramakrishna, M.; Reddy,
C. R.; Arunagiri, M.; Kumari, R. L.; Venkatarman, S.; Mathad, V. T.
Org. Proc. Res. DeV. 2005, 9, 314.
Received for review May 23, 2007.
OP7001134
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