An improved, scalable, and impurity-free process for tolterodine tartrate

Article abstract of DOI:10.1021/op050024w

Tolterodine tartrate is an anticholinergic muscle relaxant used to treat urinary frequency, urinary urgency, and incontinence in people with unstable bladders. An improved, cost-effective, and impurity-free process for tolterodine tartrate suitable for la

Full text of DOI:10.1021/op050024w

Organic Process Research & Development 2005, 9, 314−318
Communications to the Editor
An Improved, Scalable, and Impurity-Free Process for Tolterodine Tartrate†
Keesari Srinivas, Neti Srinivasan, Kikkuru Srirami Reddy, Muddasani Ramakrishna, Chinta Raveendra Reddy,
Muthulingam Arunagiri, Routhu Lalitha Kumari, Sundaram Venkataraman, and Vijayavitthal T. Mathad*
Department of Research and DeVelopment, Integrated Product DeVelopment, Dr. Reddy’s Laboratories Ltd., Unit-III,
Plot No. 116, S.V. Co-Op. Ind. Estate, Bollaram, Jinnaram, Medak District 502-325, Andhra Pradesh, India
Abstract:
process less viable for commercial production and in
producing the regulatory quality product.
Tolterodine tartrate is an anticholinergic muscle relaxant used
to treat urinary frequency, urinary urgency, and incontinence
in people with unstable bladders. An improved, cost-effective,
and impurity-free process for tolterodine tartrate suitable for
large-scale commercial production is described here by ad-
dressing various scale-up and impurity issues.
The other processes4 reported in the literature either use
hazardous reagents such as diisobutylaluminum hydride
(DIBAL) or end up with high production costs. Herein we
report an improved route, which is cost-effective, scalable,
plant friendly, and impurity free, which has been ac-
complished by modifying the original synthetic route.
Introduction
Results and Discussion
Tolterodine tartrate (9) is a competitive muscarine receptor
antagonist used in the treatment of urinary bladder disorders
such as urinary urge incontinence.1 Tolterodine tartrate acts
by relaxing the smooth muscle tissue in the wall of the
bladder by blocking cholinergic receptors.2 The first reported
synthetic route3 (Scheme 1) involved acid-catalyzed con-
densation of cinnamic acid 1, and 4-methyl phenol 2 in neat
sulfuric acid to afford lactone 3, followed by opening of 3
with potassium carbonate in the presence of methyl iodide
in refluxing acetone and methanol to give corresponding
methyl ester 4. Reduction of methyl ester 4 with lithium
aluminum hydride in diethyl ether yielded the corresponding
alcohol 5, which on tosylation followed by condensation of
obtained tosyl derivative 6 with diisopropylamine in hot
acetonitrile gave tertiary amine 7. Reaction of 7 with boron
tribromide in dichloromethane offered hydroxy compound
8, which upon resolution with L-(+)-tartaric acid yielded
tolterodine tartrate (9) in overall yield of around 5.5% with
several impurities. This process suffers from several draw-
backs, such as prolonged reaction time for diisopropylamine
condensation (4-6 days) and deprotection of methyl group
(2-3 days), usage of hazardous reagents such as lithium
aluminum hydride and boron tribromide and unacceptable
process solvents such as diethyl ether, pyridine, chloroform,
etc. The major disadvantage of this process is the poor yield
of the active pharmaceutical ingredient (API) along with the
formation of many unwanted impurities, which make this
In our approach (Scheme 2) we had explored the original
route, and we were clear about the disadvantages of the route.
Hence, our approach also started with acid-catalyzed con-
densation of the same starting materials, 1 and 2, to obtain
the intermediate 35 with quantitative yield in pilot plant by
eliminating the emulsion problem during the work-up process
which involves the separation of the sulfuric acid layer before
pH adjustments. Hydrolysis of the lactone ring in 3 with
potassium carbonate in acetone and methanol as a solvent
system followed by benzyl bromide addition to the reaction
mass yielded benzyl derivative 10 with 96% yield and
99.50% purity by HPLC.
As we experienced the problem in the deprotection of
the methyl group in the original route (Scheme 1), this small
change to benzylation in the modified route (Scheme 2)
avoided the usage of the hazardous reagent boron tribromide
for the deprotection of the methyl group in the later stage.
Also, instead of prolonged reaction time (2-3 days) for
deprotection, it took around 4-5 h of reaction time with
inexpensive Raney nickel6-catalyzed debenzylation. (Scheme
2). This change also benefited us by increasing the yield in
the subsequent stages. Reduction of 10 was tried with
different reducing agents such as DIBAL and sodium bis(2-
methoxyethoxy)aluminum hydride (Vitride)7 in different
solvents such as tetrahydrofuran (THF), cyclohexane, dichlo-
romethane, and toluene under different reaction conditions.
(4) (a) Gage, J. R.; Portage, M.; Cabaj, J. E. U.S. Patent 5,922,914, 1999. (b)
Botteghi, C.; Corrias, T.; Marchetti, M.; Paganelli, S.; Picollo, O. Org.
Process Res. DeV. 2002, 6, 379-383. (c) Anderson, P. G.; Hans E. Schink,
H. E.; Osterlund, K. J. Org. Chem. 1998, 63, 8067-8070. (d) Andersson,
P. G.; Hedberg, C. PCT WO 01/49649 A1, 2001.
(5) Manimaran, T.; Rama Krishnan, V. T. Ind. J. Chem. 1979, 18 B, 324-330.
(6) Raney nickel grade CAT-39 was used for reduction purposes.
(7) Commercially available reagent sodium bis(2-methoxyethoxy)aluminum
hydride (Vitride) (65% wt/wt in toluene) is used for this reaction. Procured
from Chematek S.P.A. CHEMICAL PRODUCTS, Italy.
† DRL-IPD Communication number: 007.
* To whom correspondence should be addressed. E-mail: vijayavitthalm@
drreddys.com. Telephone: 91 9392481740. Fax: 918458 279619.
(1) Jonas, U.; Hoefner, K.; Madersbacher, H.; Holmdahl, T. H. World J. Urol.
1997, 15, 144-151.
(2) Nilvebrant, L.; Andersson, K.-E.; Gillberg, P.-G.; Stahl, M.; Sparf, B. Eur.
J. Pharmacol. 1997, 327, 195-207.
(3) Jonsson, N. A.; Sparf, B. A.; Mikiver, L.; Moses, P.; Nilverbrant, L.; Glas,
G. U.S. Patent 5,382,600, 1995.
314
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10.1021/op050024w CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/23/2005

Scheme 1. Synthetic scheme of tolterodine tartaratea
a Reagents and conditions: a) H2SO4/120-125 °C. b) MeI/K2CO3, acetone, methanol/reflux. c) LAH/dry ether/25-35 °C. d) p-Toluene sulfonyl chloride/pyridine,
chloroform/-10 to -15 °C. e) Diisopropylamine/acetonitrile/80-85 °C/4-6 days. f) BBR3/20-25 °C/2-3 days, g) L-(+)-tartaric acid/ethanol.
Scheme 2. Modified synthetic scheme of tolterodine tartratea
a Reagents and conditions: a) H2SO4/120-125 °C. b) Benzyl bromide/K2CO3/acetone, methanol/reflux. c) Vitride/THF /25-35 °C. d) p-Toluene sufonyl chloride
/N-ethyldiisopropylamine/dichloromethane/25-35 °C. e) Diisopropylamine/acetonitrile/110-115 °C/12-14 h. f) H2/Raney Ni/methanol/25-35 °C g) L-(+)-tartaric
acid/acetonitrile/methanol.
The reduction was smooth and robust when we employed
Vitride in THF at an addition temperature below 40 °C and
yielded about 97.8% of alcohol 11 with 99.19% purity by
HPLC. The temperature of the Vitride addition was opti-
mized between -30 and +40 °C as it is an exothermic
reaction, and addition at below +40 °C is found to be
suitable, which is achieved in the plant by controlled addition.
This reaction is instantaneous and does not require further
maintenance. The byproduct of Vitride, 2-methoxy ethanol,
which was formed in the reaction, was completely removed
by employing excess water washings in the work-up as it is
water-soluble; the absence of this byproduct in the API was
confirmed in the organic volatile impurity (OVI) test by GC.
Tosylation of alcohol 11 with p-toluene sulfonyl chloride in
dichloromethane in the presence of N-ethyldiisopropylamine
as a base afforded the compound 12 in 99% yield with
98.96% purity by HPLC. Condensation of 12 with diiso-
propylamine in acetonitrile in an autoclave8 at 110-115 °C
under in-built pressure of 2.5-3.0 kg/cm2 for 10-12 h
yielded the product 13 in 95% yield with 95% purity by
HPLC. This optimized process enabled us to finish the total
reaction in 10-12 h instead of the 4-6 days for completion
as mentioned in the original route. During the optimization
of this stage, to avoid the pressure reaction, we have explored
the reactions with different bases such as potassium carbon-
ate, sodium hydroxide, potassium tertiary butoxide, and
sodium carbonate in solvents such as toluene, acetone, 1,4-
dioxane, acetonitrile, cyclohexane, DMF, DMSO, and dif-
ferent solvent mixture combinations at their reflux temper-
ature. In all the cases either the reaction did not proceed to
completion, or the product is impure. On the other hand, to
reduce the time of the reaction further, an experiment was
conducted by applying high pressure with nitrogen, wherein
the purity of the product was reduced and complete conver-
sion was not achieved. However, the major yield improve-
ment in this stage was achieved during the work-up
procedure. Out of several solvents tried for the isolation of
13, toluene was found to be an apt solvent to enhance the
yield to 95% from 75%. As expected, this step was critical
with respect to impurities, and two critical impurities of this
stage, monomer 14 and dimer 15, were isolated and
characterized and subsequently synthesized as shown in
Scheme 3. The formation of impurities 14 and 15 are due to
decomposition of the diisopropylamine under the reaction
conditions as we are using the pure diisopropylamine with
(8) A 50-L stainless steel autoclave, anchor-type agitator, designed for pressures
of 12.0-14.0 kg/cm2, manufactured by Chemec Equipment Pvt. Ltd.,
Mumbai, India, was used for the reaction.
Vol. 9, No. 3, 2005 / Organic Process Research & Development
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315

Scheme 3. Synthetic scheme of tolterodine impurities
Table 1. Solubility chart of impurities in various solvents and different pH ranges
solventsa
pH (acetone)b
cmpd
MeOH
acetone
DCM
ACN
EtOAc
below 1.0
1.0-2.0
2.0-3.0
3.0-4.0
8
14
15
16
17
18
++++
++++
++++
++++
++++
++++
+
++
+
+
-
+
+
+
+
+
-
+
+
+
+
+
-
+
-
-
+
-
-
-
-
-
-
-
++
+++
++++
+++
+++
++
+
++
++++
+++
+++
++
++
+++
+++
++++
++++
+++
++++
+++
a Notations used in case of solvents; + ) very slightly soluble, ++ ) slightly soluble, +++ ) sparingly soluble, and ++++ ) soluble. b Notations used in case
of pH: + ) soluble, and - ) insoluble.
Table 2. Content of impurities in the tolterodine tartrate (9)
99.77% (by GC) containing 0.01% of isopropylamine in it.9
Catalytic hydrogenation of 13 using Raney nickel at 25-35
content of other impuritiesa
expt.
no
purity by
HPLC (9) (%)
°C for 4-5 h in methanol afforded the desired debenzylated
compound 8 in 94% yield with 99% purity by HPLC. The
impurities described in the previous step were also sequen-
tially converted to deprotected impurities, viz., 16, 17, and
18 (Scheme 3), respectively. Removal of the impurities 14
and 15 could not be achieved efficiently in 13; however,
after deprotection of 13 to its corresponding hydroxyl
compound 8, all the protected and corresponding deprotected
impurities were removed efficiently by exploiting solubility
differences of their hydrochloride salts.
Hydrochloride salts of compounds 14, 15, 16, 17, and 18
are highly soluble in acid at a pH range between 1 and 2,
whereas 8 is did not. Thus, during the work-up of 8 the pH
of the reaction mass was adjusted to between 1 and 2, where
all these impurities were washed out in the filtrates, and the
thus-obtained tolterodine is substantially free of these impuri-
ties. The solubility10 of the impurities 14-18 and 8 in
different organic solvents and at different pH ranges in
acetone is shown in Table 1.
14
15
16
17
18
01
02
03
99.98
99.98
99.89
ND
ND
ND
ND
ND
ND
ND
0.007
ND
ND
ND
0.006
ND
ND
ND
a ND) not detected.
validated HPLC method. Thus, our process produces toltero-
dine tartrate with overall yield of around 30%. The final
process has been validated in the laboratory, and the results
of the batches have been reported in Table 2 along with the
content of impurities in it.
Conclusion
In conclusion, we have provided an improved, cost-
effective, and industrially feasible manufacturing process for
(10) The solubility of each compound has been measured in AR&D as per the
method of analysis (generally following USP general guidelines for solubility
measurement). Solubility has been measured according to the data below
in the case of solvents, whereas the solubility of the compounds in case of
pH was measured by taking 1 g of each sample in 30 mL of acetone followed
by adjusting the pH to the required range. Solubility differences were
basically identified by adjusting the pH of the reaction mass (experimental
procedure for 8) to different pH ranges followed by filtration, drying, and
HPLC analysis to see the presence of these impurities in the samples at set
pH during optimization.
Further, the racemic tolterodine hydrochloride 8 was
hydrolyzed in the presence of base and was subsequently
resolved with L-(+)-tartaric acid in the acetonitrile and
methanol mixture to get the 100% optically pure tolterodine
tartrate (9) with 80% yield (with respect to the required
isomer) with 99.99% of chemical purity by established and
(9) Alkylamines Chemicals Ltd., Maharashtra, India, supplied diisopropylamine,
which is 99.77% pure.
316
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Vol. 9, No. 3, 2005 / Organic Process Research & Development

tolterodine tartrate that is substantially free from potential
impurities and meets the regulatory norms in terms of quality.
128.6, 132.9, 153.5; MS m/z 332; Anal. Calcd for C23H24O2
: C, 83.10; H, 7.28; O, 9.63. Found: C, 83.08; H, 7.27; O,
9.61
Experimental Section
3-(2-Benzyloxy-5-methylphenyl)-3-phenylpropyl-p-tolu-
ene Sulphonate (12). To a mixture of 11 (9.13 kg, 27.50
mol), dichloromethane (27.4 L), and N-ethyl diisopropyl-
-amine (11.5 L, 66.01 mol) was added a solution of
p-toluenesulphonyl chloride (6.3 kg, 33.07 mol) in dichlo-
romethane (19 L) slowly, and the contents were stirred at
25-35 °C for about 10-12 h. Hydrochloric acid (1 N, 34.6
L) was added slowly to the above mass and stirred for half
an hour before the separation of the organic layer. The
organic layer was further washed with water (2 × 35 L) and
distilled under reduced pressure to give 12 as syrup, which
is directly used in the next step. Yield: 13.28 kg (99%); 1H
NMR (200 MHz, CDCl3): δ 2.15 (s, 3H), 2.30 (me, 2H),
2.35 (se, 3H), 3.90 (t, J ) 9.6, 3.2, 2H), 4.40 (t, J ) 16.0,
8.0, 1H), 4.90 (s, 2H), 6.60-7.80 (m, Ar-H, 17H); 13C NMR
(200 MHz, DMSO): δ 20.2, 20.8, 33.1, 38.9, 68.9,69.4,127.4,
129.3, 137.2, 143.1, 153.4; MS m/z 486; Anal. Calcd for
C30H30O4 S: C, 74.05; H, 6.21; O, 13.15; S, 6.59. Found:
C, 74.02; H, 6.20; O, 13.13; S, 6.56
1
The H and 13C NMR spectra were recorded in CDCl3
and DMSO, using a Varian Gemini 200 MHz FT NMR
spectrometer; the chemical shifts are reported in δ ppm
relative to TMS. The subscript “e” along with multiplicity
denotes the merging of the peak with other peaks. The FT-
IR spectra were recorded in the solid state as KBr dispersion
using Perkin-Elmer 1650 FT-IR spectrophotometer. The mass
spectrum (70 eV) was recorded on HP-5989A LC-MS
spectrometer. The CHN analysis was carried out on a Perkin-
Elmer model 2400S analyzer. The melting points were
determined by using the capillary method on POLMON
(model MP-96) melting point apparatus. The solvents and
reagents were used without further purification.
Methyl-3-(2-benzyloxy-5-methylphenyl)-3-phenylpro-
pionate (10). A mixture of 6-methyl-4 phenyl-3, 4-dihydro-
coumarin (3, 7.0 kg, 29.41 mol), benzyl bromide (3.85 L,
32.37 mol), potassium carbonate (5.32 kg, 38.55 mol),
acetone (21 L), and methanol (21 L) was heated to reflux
temperature for about 3 h. Solvent was distilled off from
the reaction mass under reduced pressure, and 70 L of water
was added to the crude and stirred for 15 min for dissolution.
Reaction mass was extracted with ethyl acetate (35 and 7
L). The combined organic layers were washed with water
(2 × 35L), and the solvent was distilled off under reduced
pressure. Acetone (35 L) was added to the crude at 50-55
°C, and the solution was stirred at 0-5 °C for about 2 h.
The solid was filtered, washed with acetone (7 L), and dried
at 50-55 °C for about 2 h under reduced pressure to give
compound 10 as a white crystalline powder. Yield: 10.2 kg
(96%); mp: 73-75 °C; 1H NMR (200 MHz, CDCl3): δ 2.25
(s, 3H), 3.05 (d, J ) 3.4, 2H), 3.50 (s, 3H), 4.95 (te, 1H),
4.95 (se, 2H), 6.60-7.40 (m, Ar-H, 13H); 13C NMR (200
MHz, DMSO): δ 20.2, 38.8, 39.7, 51.1, 69.4, 126.0, 127.5,
128.4, 131.6, 143.1, 153.2, 171.7; MS m/z 360; Anal. Calcd
for C24H24O3 : C, 79.97; H, 6.71; O, 13.32. Found: C, 79.95;
H, 6.70; O, 13.31.
N,N-Diisopropyl- 3-(2-benzyloxy-5-methylphenyl)-3-
phenylpropylamine (13). A mixture of 12 (6.0 kg, 12.34
mol), acetonitrile (23 L), and diisopropylamine (6.6 L, 47.18
mol) was heated in an autoclave at 110-115 °C with inbuilt
pressure 2.0-3.0 kg/cm2 for about 12-14 h. The reaction
mass was distilled off at 80-85 °C under reduced pressure,
and toluene (23 L) was added to the crude. The above organic
layer was washed with hydrochloric acid (0.5 N, 14.2 L),
then sodium hydroxide solution (2.5%, 9.5 L). followed by
water (2 × 23 L). The mixture was then distilled off under
reduced pressure to give compound 13 as syrup, which is
directly used in the next step. Yield: 4.9 kg (95%); 1H NMR
(200 MHz, CDCl3): δ 0.90 (br d, 12H), 2.30 (me, 2H), 2.30
(se, 3H), 2.98 (t, J ) 13.0, 6.8, 2H), 3.10 (m, 2H), 4.40 (t,
J ) 15.0, 7.6, 1H), 5.00 (s, 2H), 6.70-7.50 (m, Ar-H, 13H);
13C NMR (200 MHz, CDCl3): δ 20.5, 36.7, 41.3, 43.7, 48.4,
69.8, 111.5, 127.1, 128.1, 129.4, 133.4, 144.9, 153.7; MS
m/z 415; Anal. Calcd for C29H37NO: C, 83.81; H, 8.97; N,
3.37; O, 3.85. Found: C, 83.80; H, 8.95; N, 3.35; O, 3.83
N,N-Diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phen-
ylpropylamine Hydrochloride (8). To the solution of 13
(4.9 kg, 11.80 mol) in methanol (18.8 L) placed in an
autoclave was added Raney nickel (0.97 kg) with water (1.67
L) and maintained under hydrogen pressure at 5.0-5.5 kg/
cm2 at 25-35 °C for about 4-5 h. The reaction mass was
filtered after cooling to 25-30 °C, and the filter cake was
washed with methanol (7.5 L). The pH of the filtrate was
adjusted to 1.0-2.0 with concentrated hydrochloric acid (5.2
L) and stirred for 20 min. The solvent was distilled off under
reduced pressure, and the obtained crude was crystallized
from acetone (18.8 L). The crystalline solid obtained was
filtered, washed with chilled acetone (7.5 L), and dried at
60-65 °C for 2-3 h to get the desired compound 8 as a
white crystalline powder. Yield: 4.05 kg (94%); mp: 212-
3-(2-Benzyloxy-5-methylphenyl)-3-phenylpropanol (11).
To a stirred solution of 10 (10.2 kg, 28.33mol) in dry THF
(20.5 L) was slowly added Vitride, (10.62 L, 35.37 mol, 65%
wt/wt in toluene) at below 40 °C and stirred for about 20-
25 min. The reaction mixture was quenched by slowly adding
a solution of hydrochloric acid (6 N, 41 L) and extracted
with toluene (41 L); the toluene layer was separated, and
the aqueous layer was further extracted with toluene (10.2
L). The combined toluene layers were washed with water
(51 L), followed by a solution of sodium carbonate (30%,
9.3 L), and finally with water (51 L). The organic layer was
distilled off, hexane (41 L) was added to the resultant crude
at 40 °C and stirred for 2 h at 40 °C and 1 h at 25-30 °C.
The solid obtained was filtered and washed with hexane (10
L), and the solid was dried at 25-30 °C under reduced
pressure for 2-3 h to give compound 11 as a crystalline
1
powder. Yield: 9.13 kg (97%); mp: 65-67 °C; H NMR
1
216 °C; H NMR (200 MHz, CDCl3): δ 1.10 (br d, 12H),
(200 MHz, CDCl3): δ 1.60 (s, 1H), 2.25 (s, 3H), 2.30 (q, J
) 10.4, 3.2, 2H), 3.50 (s, 2H), 4.65 (t, J ) 16.2, 8.4, 1H),
5.05 (s, 2H), 6.70-7.50 (m, Ar-H, 13H); 13C NMR (200
MHz, DMSO): δ 20.4, 37.7, 39.2, 59.7, 69.4, 127.3, 128.1,
2.10 (s, 3H), 2.40 (br q, 2H), 2.70 (br t, 2H), 3.25 (m, 2H),
4.30 (t, J ) 15.0, 7.6, 1H), 5.30 (s, 1H), 6.40-7.40 (m, Ar-
H, 8H); 13C NMR (200 MHz, CDCl3): δ 19.3, 19.7, 20.6,
Vol. 9, No. 3, 2005 / Organic Process Research & Development
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317

33.2, 39.4, 42.3, 48.2, 117.8, 125.9, 128.1, 129.0, 144.5,
152.9; MS m/z 325.
144.9, 153.7; MS m/z 687; Anal. Calcd for C49H53NO2 : C,
85.55; H, 7.77; N, 2.04; O, 4.65. Found: C, 85.52; H, 7.75;
N, 2.01; O, 4.63.
N-Isopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl-
propylamine (14). The mixture of 12 (60.0 g, 0.123 mol),
isopropylamine (53 mL, 0.622 mol), and acetonitrile (300
mL) was stirred at 35-40 °C for 12 h. The reaction mass
was distilled off completely, and the obtained residue was
crystallized from ethyl acetate (150 mL) to give 14 as a white
crystalline powder. Yield: 40.0 g (86%); mp: 137-139
N-(3-(2-(Benzyloxy)-5-methylphenyl)-3-phenylpropyl)-
N-isopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpro-
pan-1-amine (17). A mixture of 16 (15.8 g, 0.055 mol (135
mL) and the intermediate (12) (27.0 g, 0.055 mol) in DMF
was heated in an autoclave at 60-70 °C under 3.0 kg/cm2
of nitrogen pressure for 16 h. The reaction mass was cooled
to 25-35 °C, decomposed with water (135 mL), and
extracted with toluene (135 mL). The toluene layer was
washed with hydrochloric acid (1 N, 150 mL), then sodium
hydroxide solution (10%, 54 mL) followed by water (135
mL). The organic layer was distilled off completely to obtain
1
°C: H NMR (200 MHz, CDCl3): δ 1.30 (de, 6H), 2.18 (s,
3H), 2.51 (q, J ) 23.4, 7.6, 2H), 3.18 (t, J ) 12.8, 6.4, 2H),
4.11 (m, 1H), 4.38 (t, J ) 15.8, 8.0, 1H), 5.00 (s, 2H), 6.70-
7.40 (m, Ar-H, 13H), 8.7 (s, 1H); 13C NMR (200 MHz,
DMSO): δ 19.1, 20.6, 31.6, 41.4, 44.8, 51.6, 69.8, 116.3,
127.1, 128.7, 128.8, 129.2, 137.2, 144.2, 152.4; MS m/z 373;
Anal. Calcd for C26H31NO: C, 83.60; H, 8.37; N, 3.75; O,
4.28. Found: C, 83.58; H, 8.34; N, 3.74; O, 4.26
1
crude 17 as syrup. Yield: 27 g (81.40%); H NMR (200
MHz, DMSO): δ 1.10 (d, J ) 5.6, 3H), 1.15 (d, J ) 6.2,3H),
2.10 (s, 6H), 2.30 (t, J ) 3.2, 3.4, 4H), 2.80 (br q, 4H), 3.55
(m, 1H), 4.30 (br t, 2H), 5.05 (s, 2H), 6.60-7.10 (m, Ar-
H, 21H), 7.40 (s, 1H); 13C NMR (200 MHz, DMSO): δ
16.3, 20.2, 28.5, 40.7, 47.9, 53.7, 69.8,127.6, 128.1, 143,152;
MS m/z 597; Anal. Calcd for C42H47NO2 : C, 84.38; H, 7.92;
N, 2.34; O, 5.35. Found: C, 84.36; H, 7.90; N, 2.31; O, 5.32
Bis{4-methyl-2-(3-phenylpropyl)phenol} (18). To a
mixture of 17 (25.0 g, 0.041 mol) in methanol (125 mL)
was added 5.0 g of Raney nickel with the reaction mass
maintained under 3.0 kg/cm2 of hydrogen pressure at 25-
35 °C for 5 h. Reaction mass was filtered over hyflow, the
filter cake was washed with methanol (25 mL), and the
filtrate was evaporated completely under vacuum to obtain
the residue, which was crystallized from hexanes (125 mL)
to give 18 as a crystalline solid. Yield: 15 g (70.65%); mp:
152-155 °C; 1H NMR (200 MHz, DMSO): δ 1.10 (d, J )
6.8, 3H), 1.20 (d, J ) 6.7, 3H), 2.05 (s, 6H), 2.30 (br t, 4H),
2.85 (br q, 4H), 3.35 (m, 1H), 4.30 (t, J ) 15.0, 8.0, 2H),
6.60-7.10 (m, Ar-H, 16 H), 7.40 (s, 2H); 13C NMR (200
MHz, DMSO): δ 16.3, 20.2, 28.5, 40.7, 47.9, 53.7, 115.1,
127.6, 128.1, 143.9, 152.3; MS m/z 507; Anal. Calcd for
C35H41NO2 : C, 82.80; H, 8.14; N, 2.76; O, 6.30. Found: C,
82.78; H, 8.11; N, 2.74; O, 6.28.
N-Isopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl-
propylamine (16). To a solution of 14 (40.0 g, 0.10 mol) in
methanol (200 mL) in an autoclave was added Raney nickel
(8.0 g), and the reaction was maintained at 25-30 °C under
hydrogen pressure of 3.5 kg/cm2 for 4-5 h. The reaction
mass was filtered through hyflow, the filter cake was washed
with 40 mL of methanol, and the filtrates were distilled off
1
completely to give 16 as syrup. Yield: 27.2 g (89%); H
NMR (200 MHz, DMSO): δ 1.15 (de, 6H), 2.18 (s, 3H),
2.5 (br t, 2H), 3.0 (m, 2H), 3.45 (m, 1H), 4.28 (t, J ) 15.2,
7.6, 1H), 6.70-7.40 (m, Ar-H, 8H), 8.3 (s, 1H), 9.2 (s, 1H);
13C NMR (200 MHz, DMSO): δ 19.2, 20.6, 31.6, 41.4, 44.8,
51.6, 116.3, 127.1, 128.7, 128.8, 129.2, 130.3, 144.2, 152.4;
MS m/z 283; Anal. Calcd for C19H25NO; C, 80.52; H, 8.89;
N, 4.94; O, 5.65. Found: C, 80.49; H, 8.87; N, 4.91; O,
5.63.
3-(2-(Benzyloxy)-5-methylphenyl)-N-(3-(2-(benzyloxy)-
5-methylphenyl)-3-phenylpropyl)-N-isopropyl-3-phenyl-
propan-1-amine (15). A mixture of intermediate 12 (27.0
g, 0.055 mol) and 14 (20.8 g, 0.055 mol) in DMSO (135
mL) was heated at 60-70 °C for 18 h. The reaction mass
was cooled to 25-35 °C, decomposed with water (135 mL),
and extracted with toluene (135 mL). The toluene layer was
washed with hydrochloric acid (1 N, 150 mL), then sodium
hydroxide solution (10%, 54 mL), followed by water (135
mL). The organic layer was distilled off completely to obtain
Acknowledgment
We thank the management of R&D-IPDO, Dr. Reddys
Laboratories Ltd., for supporting this work. Cooperation from
the colleagues from analytical research development is highly
appreciated.
1
15 as syrup. Yield: 29 g (75%); H NMR (200 MHz,
CDCl3): δ 0.97 (d, J ) 6.8, 3H), 1.10 (d, J ) 7.4, 3H),
2.10 (s, 6H), 2.40 (te, 4H), 2.70 (me, 4H), 2.98 (me, 2H),
3.50 (me, 1H), 4.39 (t, J ) 15.0, 8.0, 2H), 5.00 (s, 2H), 6.60-
7.10 (m, Ar-H, 26 H); 13C NMR (200 MHz, DMSO): δ
20.5, 36.7, 41.3, 43.7, 48.4, 69.8, 111.5, 128.1, 129.4, 133.4,
Received for review February 22, 2005.
OP050024W
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Vol. 9, No. 3, 2005 / Organic Process Research & Development