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
(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
Vol. 11, No. 5, 2007 / Organic Process Research & Development
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