Catalytic asymmetric total synthesis of the muscarinic receptor antagonist (R)-tolterodine

Article abstract of DOI:10.1002/adsc.200404234

A convenient and high yielding method for the preparation of (R)-tolterodine, utilizing a catalytic asymmetric Me-CBS reduction was developed. Highly enantioenriched (A)-6-methyl-4-phenyl-3,4-dihydrochromen-2-one (94% ee) was recrystallized to yield practically enantiopure material (ee >99%) and converted to (R)-tolterodine in a four-step procedure. The configuration of the crucial stereocenter was preserved during the synthesis and the obtained product was identified by chiral HPLC to be the (R)-tolterodine enantiomer.

Full text of DOI:10.1002/adsc.200404234

FULL PAPERS
Catalytic Asymmetric Total Synthesis of the Muscarinic Receptor
Antagonist (R)-Tolterodine
Christian Hedberg, Pher G. Andersson*
Department of Organic Chemistry, Uppsala University, Box 599, SE-751 24 Uppsala, Sweden
Fax: (þ46)-18-471-3818, e-mail: phera@kemi.uu.se
Received: July 22, 2004; Revised: February 7, 2005; Accepted: February 14, 2005
Abstract: A convenient and high yielding method for was preserved during the synthesis and the obtained
the preparation of (R)-tolterodine, utilizing a catalytic product was identified by chiral HPLC to be the
asymmetric Me-CBS reduction was developed. High- (R)-tolterodine enantiomer.
ly enantioenriched (R)-6-methyl-4-phenyl-3,4-dihy-
drochromen-2-one (94% ee) was recrystallized to
yield practically enantiopure material (ee >99%) Keywords: asymmetric synthesis; Me-CBS catalyst;
and converted to (R)-tolterodine in a four-step proce- sigmatropic rearrangement; tolterodine; total syn-
dure. The configuration of the crucial stereocenter thesis
Introduction
Results and Discussion
(R)-Tolterodine (Figure 1) is the first muscarinic recep- We were interested in developing a catalytic asymmetric
tor antagonist that has been specifically developed for route to (R)-tolterodine. Retrosynthetic analysis of tol-
treatment of an overactive bladder.[1] Tolterodine is terodine suggests that the corresponding dihydrocou-
non-selective with respect to the muscarinic M1-M5 re- marin is a suitable key intermediate for a catalytic asym-
ceptor subtypes, but has a greater effect on the bladder metric synthesis. The most interesting approach would
than on the salivary glands in vivo, in both animal and be an asymmetric hydrogenation of coumarin 12, direct-
humans.[2] (R)-Tolterodine (Detrolꢀ) is equipotent to ly leading to the desired dihydrochromen-2-one 7.[7]
oxybutynin, but shows less impact on saliva output However, this pathway to tolterodine was abandoned
than the latter, suggesting that tolterodine may give because of difficulties of preparing coumarin 12 from
rise to fewer side effects related to decreased saliva pro- simple starting materials by Pechmann condensation.[8]
duction compared to oxybutynin.[3] (R)-Tolterodine can Some years ago, Clark et al. reported a novel enantiose-
today be regarded as the drug of choice to treat overac- lective synthesis of highly enantioenriched 3-arylinda-
tive bladders in most patient groups.[4]
nones via three consecutive, base-induced [1,5]-suprafa-
An earlier reported asymmetric total synthesis of tol- cial sigmatropic rearrangements of the corresponding 3-
terodine was carried out using an oxazolidinone as a chi- arylindenol, easily available by catalytic asymmetric
ral auxiliary.[5] This approach led directly to the desired methyloxazaborolidine (Me-CBS) reduction of the in-
b,b’-diaryl-substituted propionic acid. Attempts to de- denone.[9] By adopting this approach, we would be
sign a catalytic asymmetric synthesis of (R)-tolterodine able to access the dihydrochromen-2-one 7 via a Baey-
have been reported recently in the literature, utilizing an er–Villiger oxidation (Scheme 1).
asymmetric hydroformylation as a key step.[6] However,
The synthesis of 7 starts with the condensation of 2’-
despite good yields, low enantioselectivity was reported. bromo-4’-methylacetophenone with benzaldehyde to
give the suitable brominated chalcone in high yield. Pal-
ladium-catalyzed Heck cyclization gives the corre-
sponding indenone in good yield.[10] Enantioselective re-
duction of the indenone was performed by slow addition
(1.5 h) of 4 to a solution of the (S)-Me-CBS catalyst
(5 mol %) and BH3 ·THF (1.05 equivs.) in THF at ꢀ
208C. Fast quenching of the reaction mixture at com-
plete conversion was crucial to achieve high enantiose-
lectivity. Because the indenone 4 is bright yellow, and
the indenol 5 colorless, the progress of the reaction could
Figure 1.
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DOI: 10.1002/adsc.200404234
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Asymmetric Total Synthesis of (R)-Tolterodine
FULL PAPERS
Scheme 1.
Scheme 3.
crystallization of 7 gave, in principle, enantiopure mate-
rial in 86% isolated yield (Scheme 2).
To complete the synthesis of (R)-tolterodine, dihydro-
chromen-2-one 7 was treated with MeOH/K2CO3 fol-
lowed by BnBr in acetone to give the corresponding
2’-O-benzylated methyl ester 8a, together with the ben-
zyl ester 8b as an inseparable mixture. Direct reduction
of the mixture gave alcohol 9, which was converted to
the p-nitrophenylsulfonyl ester 10, which in turn was
treated with (i-Pr)2NH to give 11.[13] Debenzylation by
hydrogenolysis of the benzyl ether gave (R)-tolterodine
1 in 30% overall yield starting from acetophenone 2.
Scheme 2.
Conclusion
easily be monitored. Prolonged reaction times, even at
low temperature, led to partial racemization of the prod-
uct. In the next step the resulting indenol (97% ee) was
treated with base (Et3N/DABCO) in THF at reflux for
3 h, which furnished the desired indanone with almost
complete retention of chirality (94% ee) in 90% yield.
Baeyer–Villiger oxidations of 3-arylindanones have
been reported in the literature previously.[11] To our sur-
prise, commercial 60% m-CPBA did not transform inda-
none 6 to the corresponding dihydrochromen-2-one 7.
By changing to pure m-CPBA,[12] a catalytic amount of
TsOH·H2O (20 mol %) and 4 ꢂ molecular sieves a
quantitative conversion and a high yield were obtained
after 38 h at 48C. Only a trace amount of the other oxi-
In conclusion, we have developed an efficient catalytic
asymmetric total synthesis of (R)-tolterodine in high
overall yield from commercially available starting mate-
rials. The desired compound is produced in 10 steps with
an overall yield of 30% and ee of 99%.[14]
Experimental Section
(E)-1-(2-Bromo-4-methylphenyl)-3-phenylprop-2-en-
1-one (3)
To a solution of 2’-bromo-4’-methylacetophenone[15] (7.20 g,
dation regioisomer could be observed by LC-MS. Re- 34.0 mmol) and benzaldehyde (3.65 g, 34.0 mmol) in dry
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FULL PAPERS
MeOH (50 mL), freshly prepared CH3ONa (35.7 mmol) in dry
MeOH (30 mL) was added at 08C. The resulting mixture was
stirred at 08C for 5 h and warmed to room temperature over-
night. HCl (10%, 10 mL) was added slowly and the mixture
was evaporated to near dryness under reduced pressure. The
residue was suspended in saturated NaHCO3 (50 mL) and ex-
tracted with Et2O (3ꢁ150 mL). The organic layer was washed
with brine and dried over MgSO4. Purification was done by
flash chromatography eluting with Et2O:pentane (5:95) gave
3 as a yellow oil; yield: 10.1 g (95%). Rf ¼0.66 (Et2O:pentane,
1H NMR: d¼2.25 (s, 3H), 6.96 (d, J¼10.2 Hz, 1H), 7.15 (d,
J¼10.2 Hz, 1H), 7.05 (dd, J1 ¼7.6 Hz, J2 ¼2.6 Hz, 1H), 7.24
(m, 3H), 7.34 (m, 2H), 7.40 (m, 3H); 13C NMR: d¼21.4,
112.5, 117.3, 122.5, 122.8, 123.7, 124.9, 128.4, 132.2, 133.6,
133.9, 143.6, 145.3, 186.6; MS (EI 70 eV): m/z (rel. in-
tensity)¼301(100) [Mþ], 221 (50), 193 (62), 178 (84), 77 (44);
anal. calcd. for C16H19BrO: C 63.81, H 4.35; found: C 63.85, H
4.20.
6.43 (d J¼2 Hz, 1H), 7.18 (d, J¼8 Hz, 1H), 7.27 (s, 1H), 7.47
(m, 4H), 7.59 (m, 2H); 13C NMR: d¼21.6, 76.2, 121.6, 123.6,
126.9, 127.6, 128.2, 128.6, 134.1, 134.9, 138.2, 142.1, 143.7,
145.6; MS (EI 70 eV): m/z (rel. intensity)¼222 (100) [Mþ],
207 (71), 178 (66), 144 (42), 116 (23); anal. calcd. for C16H14O:
C 86.45, H 6.35; found: C 86.36, H 6.29.
(R)-5-Methyl-3-phenyl-2,3-dihydroinden-1-one (6)
20:80); IR (neat): n¼2359, 2341, 1649, 1603, 1268, 766 cmꢀ1
;
Indenol 5 (0.75 g, 3.41 mmol) and DABCO (0.19 g, 1.71 mmol)
were dissolved in dry THF:Et3N (20:1 by volume, 15 mL) and
refluxed until TLC indicated complete disappearance of 5
(3 h). The reaction mixture was evaporated to dryness. Flash
chromatography (EtOAc:pentane, 5:95) gave 6; yield:
0.690 g (92%); mp 92–948C. Rf ¼0.62 (EtOAc:pentane,
20:80); ChiralCel OD-H, 0.5 mL minꢀ1, hexane/i-PrOH, 95/
5: (R)-isomer 19.12 min, (S)-isomer 22.33 min, 94% ee; IR
1
(neat): n¼3027, 2361, 1710, 1605, 1280, 1238, 1040 cmꢀ1; H
NMR: d¼2.39 (s, 3H), 2.69 (dd, J1 ¼3.0 Hz, J2 ¼19.2 Hz,
1H), 3.23 (dd, J1 ¼8.0 Hz, J2 ¼19.2 Hz, 1H), 4.53 (q, J¼4 Hz,
1H), 7.07 (s, 1H), 7.14 (d, J¼8.4 Hz, 1H), 7.15 (s, 1H), 7.26
(m, 2H), 7.33 (m, 2H), 7.72 (d, J¼7.6 Hz, 1H); 13C NMR: d¼
22.1, 44.3, 46.9, 123.2, 126.9, 127.0, 127.6, 128.9, 134.5, 143.8,
146.3, 158.4, 205.5; MS (EI 70 eV): m/z (rel intensity)¼222
(100) [Mþ], 207 (55), 194 (19), 178 (60), 144 (10); calcd. for
C16H14O: C 86.45, H 6.35; found: C 86.22, H 6.18.
5-Methyl-3-phenyl-1H-inden-1-one (4)
To a suspension of anhydrous K2CO3 (9.76 g, 70.6 mmol) in dry
DMF (100 mL), 3 (8.40 g, 28.3 mmol) was added and the mix-
ture was de-aerated by five freeze-thaw pump cycles. PPh3
(0.73 g, 2.83 mmol) was added followed by PdCl2 (0.20 g,
1.13 mmol). The mixture was heated at 1208C until an NMR
sample indicated the disappearance of the starting material
(5 h). The mixture was reduced to half its volume under re-
duced pressure and poured on ice/water (200 mL). Extractive
work-up with CH2Cl2 (3ꢁ100 mL) was followed by flash chro-
matography eluting with Et2O:pentane (5:95) to afford 4 as a
yellow oil that solidifies upon standing; yield: 4.2 g (72%).
Rf ¼0.62 (Et2O:pentane, 20:80); IR (neat): n¼1704, 1606,
(R)-6-Methyl-4-phenyl-3,4-dihydrochromen-2-one (7)
Indanone 6 (0.400 g, 1.8 mmol) and 98% mCPBA (0.485 g,
2.8 mmol) were suspended in dry CH2Cl2 (6 mL) at 08C fol-
lowed by addition of TsOH·H2O (0.034 g, 0.18 mmol). The re-
action mixture was kept at 48C for 48 h, then diluted with
CH2Cl2 (10 mL), filtered and washed with saturated Na2SO3
(2ꢁ10 mL), saturated NaHCO3 and brine. Flash chromatogra-
phy eluting with EtOAc:pentane (10:90) gave 7; yield: 0.390 g
(92%). Rf ¼0.83 (EtOAc:pentane, 20:80); ChiralCel OD-H,
0.5 mL minꢀ1 hexane/i-PrOH, 95/5: minor (S)-isomer
15.18 min, major (R)-isomer 17.42 min, 94% ee. Recrystalliza-
tion from TBME/hexane gave 7 in 89% recovery and 99% ee;
mp 84–868C, [a]2D5: þ368 (c 1.0, CH2Cl2); IR (neat): n¼2900,
2360, 1769, 1495, 1208, 1145 cmꢀ1; 1H NMR: d¼2.28 (s, 3H),
3.05 (m, 1H), 4.32 (t, J¼6.8 Hz, 1H), 6.98 (s, 1H), 7.04 (d, J¼
8.4 Hz, 1H), 7.11 (dd, J1 ¼2.0 Hz, J2 ¼8.4 Hz, 1H), 7.18 (d,
J¼8.4 Hz, 1H), 7.19 (s, 1H), 7.33 (m, 3H); 13C NMR: d¼20.7,
37.1, 40.7, 116.8, 125.3, 127.5, 127.6, 128.6, 129.1, 129.3, 134.3,
140.5, 149.6, 167.8; MS (EI 70 eV): m/z (rel. intensity)¼238
(55) [Mþ], 220 (57), 195 (100), 181(10), 165 (12), 152 (9);
anal. calcd. for C16H14O2: C 80.65, H 5.92; found: C 80.60, H
5.81.
1
1355, 1101, 815, 743 cmꢀ1; H NMR: d¼2.40 (s, 3H), 5.99 (s,
1H), 7.11 (d, J¼7.2 Hz, 1H), 7.18 (s, 1H), 7.43 (d, J¼7.6 Hz,
1H), 7.53 (m, 3H), 7.66 (m, 2H); 13C NMR: d¼22.1, 122.7,
122.9, 123.5, 127.4, 128.6, 128.9, 129.2, 129.9, 130.3, 133.2,
143.7, 144.4, 162.4; MS (direct inlet EI 70 eV): m/z (rel. in-
tensity)¼220 (100) [Mþ], 205 (75), 191 (51), 177 (10), 165
(15); anal. calcd. for C16H12O: C 87.25, H 5.49; found: C 87.30,
H 5.30.
(R)-5-Methyl-3-phenyl-1H-inden-1-ol (5)
Commercial (S)-Me CBS catalyst (0.22 mL, 1 M in toluene,
0.22 mmol) was mixed under argon in dry THF (5 mL). After
cooling to ꢀ208C, 2 M BH3 ·THF (5.0 mmol, 2.5 mL) in
THF was added and the mixture stirred for 10 min. Indenone
4 (1.00 g, 4.54 mmol) was added as a solution in THF (2 mL)
over 2 h via a syringe pump. The reaction was followed by
TLC. Then, MeOH (17 mmol, 0.6 mL) was added at 08C and
the mixture was evaporated to dryness. Flash chromatography
eluting with EtOAc:pentane (10:90) gave 5 as a white solid;
yield: 0.96 g (95%). An analytical sample, recrystallized from
hexanes/TBME (5:1) had mp. 76–788C. Rf ¼0.35 (EtOAc:
pentane, 20:80); ChiralCel OD-H, 0.5 mL minꢀ1, hexane/i-
PrOH, 95/5: (R)-isomer 24.53 min, (S)-isomer 27.22 min,
(R)-3-[2-(Benzyloxy)-5-methylphenyl]-3-
phenylpropan-1-ol (9)
Compound 7 (0.35 g, 1.46 mmol) was dissolved in dry MeOH
(10 mL) and anhydrous K2CO3 (1.01 g, 7.4 mmol) added. The
mixture was refluxed until a TLC sample showed disappear-
ance of 7. The reaction mixture was evaporated to near dryness
and the residue suspended in dry acetone (10 mL), benzyl bro-
mide (0.75 g, 4.38 mmol) was added, followed by NaI (0.233 g,
1
97% ee; IR (neat): n¼3300, 1605, 1446, 949, 813 cmꢀ1; H
NMR: d¼1.40 (s, 1H), 2.40 (s, 3H), 5.27 (d, J¼8 Hz, 1H),
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1.46 mmol). The mixture was heated at 408C for 36 h and
evaporated to dryness under reduced pressure. The residue
was then portioned between CH2Cl2 (20 mL) and H2O
(20 mL). The organic layer was separated and the aqueous
phase was extracted CH2Cl2 (2ꢁ20 mL). The combined organ-
ic extracts were washed with brine and dried (MgSO4) and
evaporated under reduced pressure to give a 3:1 mixture of
(R)-methyl 3-(2-(benzyloxy)-5-methylphenyl)-3-phenylpropa-
noate (8a) and (R)-benzyl 3-(2-(benzyloxy)-5-methylphenyl)-
3-phenylpropanoate (8b) as a colourless oil.
at 608C under argon until the TLC indicated complete con-
sumption of 7 (ca. 48 h). The reaction mixture was evaporated
to dryness and the residue portioned between CH2Cl2 (20 mL)
and 2 N NaOH (10 mL). The organic phase was washed with
brine and dried over anhydrous K2CO3. Flash chromatography
afforded 11 as a colorless oil; yield: 0.265 g (81%). [a]2D5: þ528
(c 1.04, CH2Cl2); IR ( neat): n¼3028, 2964, 2928, 2868, 1499,
1
1238, 1026 cmꢀ1; H NMR: d¼0.97 (d, J¼6.6 Hz 12H), 2.22
(m, 2H), 2.32 (s, 3H), 2.41 (m, 2H), 3.02 (sept, J¼6.6 Hz,
2H), 4.46 (t, J¼7.7 Hz, 1H), 5.01 (m, 2H), 6.79 (d, J¼8.2 Hz,
1H), 6.96 (dd, J1 ¼1.7 Hz, J2 ¼8.2 Hz, 1H), 7.17–7.40 (m,
11H); 13C NMR: d¼20.47, 20.54, 20.73, 36.83, 41.54, 44.12,
48.88, 70.12, 111.79, 125.58, 127.14, 127.29, 127.57, 127.95,
128.26, 128.30, 128.34,128.45, 129.77, 133.55, 137.46, 145.04,
153.91; MS (EI 70 eV): m/z (rel. intensity)¼416 (18) [Mþ],
223 (19), 167 (41), 91 (100); anal. calcd. for C29H37NO: C
83.81, H 8.97, N 3.85; found: C 83.92, H 9.07, N 3.80.
The crude ester mixture was dissolved in dry THF (10 mL)
and added dropwise to a slurry of LiAlH4 (0.074 g, 2.0 mmol)
in dry THF (10 mL) at 08C. After stirring for 4 h at 08C,
quenching, filtration and evaporation followed by flash chro-
matography (EtOAc:pentane, 20:80) afforded 9 as a colorless
oil; yield: 0.422 (87% over two steps). [a]2D5: þ448 (c 2.0,
CH2Cl2); IR (neat): n¼3368, 3061, 3028, 2937, 1499, 1453,
1239, 1025 cmꢀ1
;
1H NMR: d¼2.26 (s, 3H), 2.20–2.36 (m
2H), 3.58 (m, 2H), 4.64 (t, J¼9 Hz, 1H), 5.04 (q, J¼11.7 Hz,
2H), 6.83 (d, J¼8.2 Hz, 1H), 6.96 (dd, J1 ¼8.2 Hz, J2 ¼2.2 Hz
1H), 7.00 (d, J¼2.2 Hz, 1H), 7.16–7.40 (m, 10H); 13C NMR:
d¼20.67, 37.58, 39.26, 60.98, 64.99, 70.47, 112.11, 125.79,
126.81, 127.37, 127.45, 127.76, 128.08, 128.10, 128.36,
128.39,128.71, 130.18, 132.86, 136.99, 140.86, 144.46, 153.82;
MS (EI 70 eV): m/z (rel. intensity)¼331(100) [Mþ], 299 (12),
285 (21), 223 (11), 165 (28); anal. calcd. for C23H24O2: C 83.10,
H 7.28; found: C 83.22, H 7.26.
(R)-2-[3-(Diisopropylamino)-1-phenylpropyl]-4-
methylphenol, (R)-Tolterodine (1)
A solution of 11 (0.215 g, 0.52 mmol) in dry methanol (2 mL)
was added to a slurry of Pd/C (10%; 0.050 g) in dry methanol
(5 mL). The resulting mixture was debenzylated overnight at
room temperature and 1 atm of H2. Filtration and evaporation
gave 1; yield: 0.164 g (97%). The absolute configuration was de-
termined by HPLC on a chiral column by comparing retention
times with a sample of enantiopure (R)-tolterodine reference
standard. By the same method the ee was determined to be
99%; ChiralCel OD-H, 0.5 mL minꢀ1, hexane/i-PrOH, 95/5:
minor (S)-isomer 21.33 min, major (R)-isomer 24.12 min.
[a]2D5: þ728 (c 1.0, CH2Cl2); 1H NMR: d¼7.35–7.15 (m, 5 H),
6.84 (dd, J¼8, 2 Hz, 1H), 6.79 (d, J¼8 Hz, 1H), 6.54 (d, J¼
2 Hz, 1H), 4.47 (dd, J¼10, 3.5 Hz, 1H), 3.21 (m, 2H), 2.70
(m, 1H), 2.35 (m, 2H), 2.10 (s and m, 4 H), 1.10 (m, 12 H, 4ꢁ
Me); 13C NMR: d¼153.18, 144.77, 132.40, 129.35, 128.62,
128.49, 128.25, 127.70, 126.09, 118.12, 47.88, 42.13, 39.37,
33.38, 20.72, 19.94, 19.59.
(R)-3-[2-(Benzyloxy)-5-methylphenyl]-3-phenylpropyl
4-Nitrobenzenesulfonate (10)
To a solution of 9 (0.380 g, 1.1 mmol) in dry CH2Cl2 (5 mL),
Et3N (0.35 g, 3.3 mmol) and DMAP (0.013 g, 0.11 mmol)
were added. The resulting mixture was cooled to 08C and p-ni-
trophenylsulfonyl chloride (0.266 g, 1.2 mmol) was added por-
tionwise under vigorous stirring. The reaction was stirred
30 min at 08C then left at room temperature until TLC indicat-
ed complete conversion (6 h). The reaction mixture was dilut-
ed with CH2Cl2 (10 mL) and washed with brine, dried (MgSO4)
and evaporated. Flash chromatography (pentane:EtOAc,
80:20) afforded 10 as a light yellow oil; yield: 0.490 g (83%).
[a]2D5: þ44.28 (c 2.05, CH2Cl2); IR (neat): n¼3400, 2924,
References and Notes
1
1532, 1350, 1185, 920, 736 cmꢀ1; H NMR: d¼2.41 (s, 3H),
[1] L. Nilvebrant, Reviews in Contemporary Pharmacothera-
py 2000, 11, 13.
[2] L. Nilvebrant, K. E. Andersson, P. G. Gillberg, M. Stahl,
B. Sparf, Eur. J. Pharmacol. 1997, 327, 195.
[3] M. B. Chancellor, R. A. Appell, G. Sathyan, S. K. Gupta,
Clin. Ther. 2001, 23, 753.
[4] L. Nilvebrant, Life Sci. 2001, 68, 2549; J. Wefer, M. C.
Truss, U. Jonas, World J. Urol. 2001, 19, 312.
[5] P. G. Andersson, H. E. Schink, K. ꢃsterlund, J. Org.
Chem. 1998, 63, 8067.
2.47 (m, 2H), 4.16 (m, 2H) 4.52 (t, J¼8 Hz, 1H), 4.99 (app. q,
J¼11.7 Hz, 2H), 6.82 (d, J¼9 Hz, 1H), 6.98 (s, 1H), 7.01 (s,
1H), 7.13–7.45 (m, 10H), 7.93 (m, 2H), 8.21 (m, 2H); 13C
NMR: d¼20.52, 29.54, 33.31, 39.33, 70.00, 70.10, 111.92,
124.04, 126.11, 127.24, 127.71, 127.80, 128.04, 128.11, 128.15,
128.33, 128.81, 128.85, 129.85, 131.13, 136.90, 141.34, 142.65,
150.26, 153.65; MS (EI 70 eV): m/z (rel. intensity)¼517 (5)
[Mþ], 404 (11), 314 (25), 224 (100), 91 (28); anal. calcd. for
C29H27NO6S: C 67.29, H 5.26, N 2.71; found: C 67.35, H 5.31,
N 2.79.
[6] C. Botteghi, T. Corrias, M. Marchetti, S. Paganelli, O.
Piccolo, Org. Process Res. Dev. 2002, 6, 379.
[7] M. A. McGuire, S. C. Shilcrat, E. Sorensen, Tetrahedron
Lett. 1999, 40, 3293.
[8] S. Sethna, R. Phadke, Org. React. 1953, VII, 1.
[9] W. M. Clark, A. M. Tickner-Eldridge, G. K. Huang, L. N.
Pridgen, M. A. Olsen, R. J. Mills, I. Lantos, N. H. Baine,
J. Am. Chem. Soc. 1998, 120, 4550.
(R)-3-[2-(Benzyloxy)-5-methylphenyl]-N,N-
diisopropyl-3-phenylpropan-1-amine (11)
Toa solution of 10 (0.41 g, 0.79 mmol) in dry MeCN (5 mL), an-
hydrous K2CO3 (0.53 g, 3.9 mmol) was added followed by (i-
Pr)2NH (0.240 g, 2.4 mmol). The resulting mixture was stirred
Adv. Synth. Catal. 2005, 347, 662–666
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Christian Hedberg, Pher G. Andersson
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[10] For general considerations on palladium-catalyzed in-
denone synthesis, see: a) R. C. Larock, M. J. Doty, S.
Cacchi, J. Org. Chem. 1993, 58, 4579; b) for specific syn-
thesis of 2H-indenones, see ref.[7]
[11] M. R. Shukla, K. J. Padiya, P. N. Patil, M. M. Salunkhe,
Indian J. Chem. (B) 1999, 38, 372.
[12] 98% by weight by iodometric titration.
[13] A similar approach to racemic tolterodine has been re-
ported; see: N. A. Jonsson, B. A. Sparf, L. Mikiver, P.
Moses, L. Nilvebrant, G. Glas, (Pharmacia & Upjohn
Co.), European Patent EP 0325571, 1989.
[14] This work has been reported in a patent, see: P. G. An-
dersson, C. Hedberg, (Pharmacia) WO 01049649, 2001.
[15] Prepared according to the literature procedure, see: J. S.
Swenton, K. Carpenter, Y. Chen, M. L. Kerns, W. Gary,
J. Org. Chem. 1993, 58, 3308; analytical data consistent
with those previously reported, see: D. M. McKinnon,
A. Abouzeid, J. Heterocycl. Chem. 1991, 28, 347.
666
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Adv. Synth. Catal. 2005, 347, 662–666