Efficient and single pot process for the preparation of enantiomerically pure solifenacin succinate, an antimuscarinic agent

Article abstract of DOI:10.1007/s00706-011-0610-7

The development of an efficient and economic one-pot process, in which the configuration of the chiral centers of the starting materials is retained, for the preparation of highly pure solifenacin succinate, an antimuscarinic agent, is presented in this communication. The earlier reported processes suffer from the drawbacks of racemization and low yields due to the use of strong base, higher temperatures, and longer reaction times. The present work circumvents these issues by activating (3R)-quinuclidin-3-ol into a mixed active carbonate derivative by treating it with bis(4-nitrophenyl)carbonate. The subsequent reaction of the active carbonate with an enantiomerically pure amine without using any base at ambient temperature provided enantiomerically pure solifenacin with an overall yield of 90%. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-011-0610-7

Monatsh Chem (2011) 142:1181–1186
DOI 10.1007/s00706-011-0610-7
ORIGINAL PAPER
Efficient and single pot process for the preparation
of enantiomerically pure solifenacin succinate,
an antimuscarinic agent
•
Navnath C. Niphade Kunal M. Jagtap
•
•
Anil C. Mali Pavankumar V. Solanki
•
•
Madhukar N. Jachak Vijayavitthal T. Mathad
Received: 4 June 2010 / Accepted: 5 August 2011 / Published online: 27 August 2011
Ó Springer-Verlag 2011
Abstract The development of an efficient and economic
one-pot process, in which the configuration of the chiral
centers of the starting materials is retained, for the prepa-
ration of highly pure solifenacin succinate, an antimu-
scarinic agent, is presented in this communication. The
earlier reported processes suffer from the drawbacks of
racemization and low yields due to the use of strong base,
higher temperatures, and longer reaction times. The present
work circumvents these issues by activating (3R)-quinu-
clidin-3-ol into a mixed active carbonate derivative by
treating it with bis(4-nitrophenyl)carbonate. The sub-
sequent reaction of the active carbonate with an
enantiomerically pure amine without using any base at
ambient temperature provided enantiomerically pure soli-
fenacin with an overall yield of 90%.
(solifenacin succinate, 1) is a well-known urinary anti-
spasmodic drug, acting as a selective antagonist to the
M(3) receptor. This drug is used for the treatment of
patients with overactive bladder, such as urinary urgency,
urinary incontinence, and high urinary frequency, and
marketed under the brand name of VesicareTM with a dose
of 5–10 mg once daily [1–5]. The first reported synthesis
for the preparation of solifenacin (6) by Makoto and
co-workers [6, 7] used a convergent approach (Scheme 1,
path A) that involved the reaction of (1S)-1-phenyl-
1,2,3,4-tetrahydroisoquinoline (5) with ethyl chloroformate
in dichloromethane to give ethyl (1S)-1-phenyl-3,4-dihy-
droisoquinoline-2(1H)-carboxylate (7). Transesterification
of 7 with 2 in the presence of sodium hydride in toluene at
140 °C for 48 h with continuous removal of ethanol
formed during the reaction, followed by usual work-up and
column chromatography purification provided solifenacin
6 in 12.3% yield. The second approach reported by the
same authors [7] involved conversion of 2 to its quinuc-
lidinyl chloroformate monohydrochloride derivative 8,
followed by portionwise addition of the chloroformate 8 to
a solution of 5 in pyridine at 80 °C (Scheme 1, path B).
Improved processes reported by others [8, 9] follow the
same approach (Scheme 1, path A) but do not overcome
the problems associated with this approach. One more
process reported (Scheme 1, path C) for 6 is similar to
path A but using different leaving groups such as
1H-imidazol-1-yl, 2,5-dioxopyrrolidine-1-yloxy, 3-methyl-
1H-imidazol-3-ium-1-yl, chloro, trichloromethyl, and halo-
alkyl [10–12].
Keywords Solifenacin ꢀ Antimuscarinic agent ꢀ
Bis(4-nitrophenyl)carbonate ꢀ One-pot synthesis
Introduction
(3R)-1-Azabicyclo[2.2.2]oct-3-yl (1S)-3,4-dihydro-1-phe-
nyl-2(1H)-isoquinolinecarboxylate as its succinate salt
N. C. Niphade ꢀ K. M. Jagtap ꢀ A. C. Mali ꢀ
P. V. Solanki ꢀ V. T. Mathad (&)
Department of Process Research and Development,
Megafine Pharma (P) Ltd, 201 Lakhmapur, Dindori,
Nashik 422 202, Maharashtra, India
Recently, Jordi et al. [13] have reported the synthesis of
a carbamate intermediate by reacting 1,10-carbonyl-
bis(1,2,4-triazole) and (3R)-quinuclidin-3-ol (2) in iso-
propyl acetate in the presence of triethylamine at reflux
temperature for 4–5 h, which was subsequently converted
e-mail: drvtmathad@yahoo.co.in; vt.mathad@megafine.in
M. N. Jachak
Department of Chemistry, Organic Chemistry Research Center,
KRT Arts, B.H. Commerce and A.M. Science College,
Gangapur Road, Nashik 422 002, India
123

1182
N. C. Niphade et al.
Scheme 1
O
O
.HCl
O
H
N
Cl
N
OEt
N
8
Cl
OEt
Path A
O
Path B
5
7
HO
Path C
NaH
N
O
2
N
O
N
Lv
2
N
O
O
NaH
O
N
N
6
9
6
into solifenacin by reacting with amine 5 with an overall
yield of 63%.
solifenacin succinate (1) with 72% yield, 99.94% chemical
purity, and 99.9% enantiomeric purity by HPLC.
Reported routes have several drawbacks such as (1) use
of hazardous, lachrymatory, and pyrophoric reagents like
NaH (path A), metal alkoxides, ethyl chloroformate, and
Lewis acids (path C), (2) use of strong bases at higher
temperatures for transesterification leads to racemization
and thus fails to provide enantiomerically pure solifenacin,
(3) ethylcarboxylate derivative 7 produces ethanol as a by-
product (path A) that hinders the nucleophilic attack of 2 in
the presence of a base, (4) use of column chromatography
for the purification of 6, which is expensive and industrially
not feasible, (5) the reaction requires longer time for the
completion and hence turnaround time of batch in pro-
duction makes it less attractive, (6) use of moisture
sensitive and expensive leaving groups (Lv) in path C
along with the use of sodium hydride is industrially not
feasible, (7) use of carcinogenic pyridine as a reaction
medium (path C) is not safe, and (8) the additional step of
converting 2 to its chloroformate derivative 8 makes the
process (path C) lengthy and uneconomical.
Results and discussion
Synthesis of solifenacin succinate (1) as per Scheme 2,
path A
Synthesis of solifenacin (6) via formation of active
carbonate 4
In our approach, we identified bis(4-nitrophenyl)carbonate
(3) as a suitable reagent to prepare the mixed active car-
bonate 4 as designed in Scheme 2, path A. Synthesis of 4
was explored by reacting 2 with 3 in various solvents
(toluene, tetrahydrofuran, dimethylformamide, pyridine,
dichloromethane, and acetonitrile) at different temperatures
with and without the use of bases.
During feasibility studies, dimethylformamide was
found to be a highly suitable solvent for this reaction
without base, but the removal of DMF was an issue for
isolation of 4 as it has to be distilled at higher temperature.
However, we have isolated 4 as oil by conducting the
reaction in tetrahydrofuran in the presence of pyridine or
triethylamine as a base to explore further. With isolated 4
in hand, we have explored the synthesis of solifenacin by
treating 4 with isoquinoline 5 in various solvents at dif-
ferent temperatures. Fortunately, the reaction of 4 with 5
went for completion in DMF in the absence of base at
25–30 °C. Meanwhile, we have also noticed that the iso-
lated 4 is unstable, moisture sensitive, and converted back
to compound 2 if exposed to air. Contrarily, it was found
Here, we report an efficient and economic one-pot
process, which retains the configuration of the chiral cen-
ters of the starting materials, for the large-scale preparation
of compound 1 (Scheme 2, path A) by surmounting the
aforementioned challenges. The process involves the acti-
vation of alcohol 2 by treating with 3 in DMF at ambient
temperature to form the mixed active carbonate (3R)-1-
azabicyclo[2.2.2]oct-3-yl 4-nitrophenyl carbonate (4),
which is then treated in situ with 5 to give solifenacin (6)
with 90% yield and 98% purity by HPLC. Solifenacin is
further treated with succinic acid in acetone to obtain
123

Efficient and single pot process for the preparation of solifenacin succinate
1183
Scheme 2
O
O
O
O N
NO
2
2
3
Path B
Path A
HO
DMF
RT
NH
DMF
RT
N
5
2
O
O
N
O
O
O N
N
2
O
4
NO
2
10
1. Compound 5/ DMF/ RT
2. HCl/ DIPE/ DCM
3. NH4OH/ Toluene
Compound 2
Base
DMF
Heating
N
O
N
O
O
O
N
N
6
6
Acetone
Succinic acid
Acetone
Succinic acid
Solifenacin Succinate ( 1)
stable as a solution in DMF at ambient temperature. Thus,
we have telescoped both the reactions in a single pot using
DMF as a solvent.
solution to remove the traces of p-nitrophenol followed by
water, and concentrated to yield solifenacin as syrup with
90% yield and 99.8% chemical purity by HPLC.
The optimized process involves stirring 2 and 3 in DMF
at 25–30 °C for 2–3 h followed by adding compound 5 to
the reaction mixture and stirring the contents for 3 h at
25–30 °C. After completion of the reaction (detected by
HPLC), the mass is diluted with water, adjusted to pH 1–2
using conc. hydrochloric acid, and extracted with diiso-
propylether (DIPE) to remove the by-product p-nitrophenol
exclusively into the organic layer. The solifenacin hydro-
chloride present in the acidic aqueous layer was extracted
into dichloromethane leaving behind the un-reacted com-
pounds and by-products 2, 5, and 10 in the aqueous layer.
The dichloromethane layer was then concentrated to yield
Preparation of solifenacin succinate (1)
Solifenacin (6) obtained was dissolved in acetone, treated
with succinic acid, and the mass was heated to 50–55 °C
for 30 min. The suspension was cooled to 5–10 °C, solid
crystals obtained were filtered and dried under vacuum to
yield solifenacin succinate (1) with 99.94% chemical purity
by HPLC and 99.9% enantiomeric purity by chiral HPLC.
Analytical results of the samples at various stations of
work-up during the process development to monitor the
elimination of impurities in few laboratory batches (entries
1–3) and a scale-up batch at 5.0 kg level (entry 4) are given
in Table 1.
a
thick syrup containing solifenacin hydrochloride
(SOL-HCl) with 98.0% purity by HPLC. The obtained
residue was dissolved in water, adjusted pH to 9–10 with
ammonium hydroxide solution, and extracted with toluene.
The toluene layer was washed with 5% sodium hydroxide
The chiral purity of the obtained product 1 is measured
by chiral HPLC and the results are shown in Table 2
(entries 1–3: laboratory batches; and entry 4: scale-up
batch) indicating retaining the chiral centers during the
123

1184
N. C. Niphade et al.
Table 1 Monitoring of
impurities by HPLC in
downstream process
Sample. no. Sample
station
Impurities and their content by HPLC/%
Comp. 5 p-Nitrophenol Comp. 10 Unknown
(RRT 0.42) (RRT 0.54) (RRT 1.95) imp
Comp. 1
(RRT 1.0)
(for HPLC
analysis)
(RRT 1.14)
1
2
3
4
MDC layer (SOL-HCl) 3.15
0.5
0.02
0.01
ND
0.08
ND
ND
0.09
ND
ND
0.08
ND
ND
0.09
0.10
0.04
0.05
0.04
0.04
0.09
0.05
0.05
0.03
0.03
0.03
96.26
99.76
99.94
95.68
99.86
99.94
96.0
Solifenacin base
0.03
ND
ND
ND
1.02
ND
ND
0.85
ND
ND
2.2
Solifenacin succinate
MDC layer (SOL-HCl) 3.47
Solifenacin base
0.01
ND
Solifenacin succinate
MDC layer (SOL-HCl) 3.30
Solifenacin base
0.01
ND
99.85
99.93
96.65
99.85
99.95
Solifenacin succinate
MDC layer (SOL-HCl) 0.81
Solifenacin base
0.04
ND
ND
ND
Solifenacin succinate
Compound 5
(R)-5
Compound 2
Compound 2
(RS)-2
Solifenacin6 [(SR)-isomer]
(RR)-isomer
Table 2 Chiral purity of 1 for laboratory and scale-up batches
+
+
+
+
+
Batch no.
(RR)-isomer
(RS)-isomer
(SS)-isomer
Compound 5
(SR) + (SS) pair
1
2
3
4
\0.03
\0.03
\0.03
\0.03
\0.03
\0.03
\0.03
\0.03
\0.03
\0.03
\0.03
\0.03
(R)-5
(RS)-2
(RS)-2
(RR) + (RS) pair
(RS)-5
(RR), (RS), (SR), (SS) mixture
Fig. 1 Strategy to prepare different isomers for analytical method
development
0.03% is the LOQ value for all the diastereomers of solifenacin
succinate
Recovery of p-nitrophenol
During the optimization, we have explored different sol-
vents such as methyl t-butyl ether (MTBE), n-heptane,
hexane, and cyclohexane to extract the impurities, spe-
cifically p-nitrophenol to avoid the use of diisopropylether
(DIPE). Unfortunately, DIPE was found to be highly
specific and efficient in extracting these impurities from
the reaction mixture. The huge quantity requirement of
other solvents (almost 70–80 parts per part of 2) dis-
couraged us to select them as large amount of effluent in
the mind. In contrast, 20–30 volumes of DIPE were suf-
ficient to extract these impurities specifically without any
trace of impurities left in the reaction mixture and hence
was opted. The careful concentration of the extracted
DIPE layer under nitrogen atmosphere provided p-nitro-
phenol quantitatively, which can be recycled further for
preparing compound 3.
developed process due to prevention of the use of any
bases at higher reaction temperature and longer reaction
time.
All stereoisomers of solifenacin (6) were synthesized
and provided for the method development to the Analytical
Research and Development Department. The (RR) isomer
was synthesized by treating 4 with (1R)-1-phenyl-1,2,3,4-
tetrahydroisoquinoline [(R)-5, synthesized by resolving
(RS)-1-phenyl-1,2,3,4-tetrahydroisoquinoline using D-(?)-
tartaric acid in methanol) following the procedure descri-
bed in the ‘‘Experimental’’ section for 6 as a brown oil,
whereas (SS) and (RS) isomers were provided as (SR)–(SS)
and (RR)–(RS) mixtures, respectively. The (SR)–(SS) and
(RR)–(RS) pairs were synthesized by treating racemic
quinuclidin-3-ol [(RS)-2] with bis(4-nitrophenyl)carbonate
to obtain the corresponding carbonate derivative, which
was subsequently reacted with (1R)-1-phenyl-1,2,3,4-tet-
rahydroisoquinoline [(R)-5] and (1S)-1-phenyl-1,2,3,4-
tetrahydroisoquinoline (5), respectively (Fig. 1). We
adopted this strategy as (3S)-quinuclidin-3-ol was not
available. The resolution experiments to obtain (3S)-
quinuclidin-3-ol are under progress.
Synthesis of solifenacin succinate (1) as per Scheme 2,
path B
Alternatively, by changing the reaction sequence amine 5
was reacted with 3 in toluene at 25–30 °C to obtain the
carbamate derivative 10 with 83.6% yield after usual
123

Efficient and single pot process for the preparation of solifenacin succinate
1185
work-up as a crystalline solid. The trans esterification
reaction of 10 with 2 conducted without a base was found to
be unsuccessful, but the reaction was progressed when a
strong base like NaH was used with toluene as a reaction
medium at 110 °C with a yield of 40% with few potential
impurities. Although the process (Scheme 2, path B) is
successful in preparing solifenacin succinate, it was found
to be inferior over path A in the following aspects: (1) the
overall yield of the process is 40%, (2) a strong base like
NaH at higher temperature was essential to carry out the
trans esterification, (3) it produces several process-related
impurities, and (4) the enantiomeric purity of the product
was much lower and it requires multiple purifications to
achieve the desired quality.
mobile phase A comprising 0.025 M K2HPO4 in water (pH
adjusted to 4.5 with orthophosphoric acid); mobile phase B
comprising acetonitrile/methanol/water in the ratio
40:40:20 v/v/v; gradient elution: t/%B: 0/45, 30/85, 50/85,
53/45, 60/45; flow rate 1.0 cm3/min; column temperature
40 °C; wavelength 220 nm. Isomeric impurities of soli-
fenacin succinate (1) were estimated by NP-HPLC analysis
developed at Megafine using Chiralpak-IC, 250 mm 9
4.6 mm ID column; mobile phase comprising n-hexane/
ethanol/isopropyl alcohol/diethylamine (60:15:25:0.1, v/v/
v/v); flow rate 1.0 cm3/min; column temperature 30 °C;
wavelength 220 nm.
Solifenacin succinate (1)
To a stirred solution of 100 g (3R)-quinuclidin-3-ol (2,
0.78 mol) in 400 cm3 dimethylformamide was added
285.04 g bis-(4-nitrophenyl)carbonate (3, 0.93 mol) with
stirring at 25–30 °C under nitrogen atmosphere. The
stirring was maintained at 25–30 °C for 2–3 h. After
reaction completion (by TLC, mobile phase: dichloro-
methane/methanol/ammonia = 8.0:2.0:0.5 cm3) 171.44 g
(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (5, 0.82 mol)
was added to the resultant brown-colored reaction solution
and further stirred at 25–30 °C for 3–4 h. After completion
of the reaction (by HPLC), the reaction mixture was diluted
with 1,000 cm3 water and the pH of the solution was
adjusted to 1–2 using concentrated hydrochloric acid. The
resulting reaction mass was extracted with diisopropylether
(1,000 cm3 9 2) to separate the p-nitrophenol. The aque-
ous layer was then mixed with 1,000 cm3 dichloromethane,
the contents were stirred, and the dichloromethane layer
was separated. The aqueous layer was re-extracted with
1,000 cm3 dichloromethane and combined with the main
layer. The combined dichloromethane layer was distilled
off completely to obtain the residue. The residue was
dissolved in 1,000 cm3 water and 1,000 cm3 toluene and
the pH of the biphasic mixture was adjusted to 9–10 using
ammonium hydroxide. The toluene layer was separated and
the aqueous layer was re-extracted with 1,000 cm3 toluene.
The combined toluene layer was washed with 1,000 cm3
water, treated with 0.5% sodium hydroxide solution
(1000 cm3 9 2) and further washed with 1,000 cm3 water
and 1,000 cm3 brine solution. The toluene layer was
distilled off completely to obtain the residue, which was
dissolved in 1,600 cm3 acetone, decolorized with activated
charcoal, and treated with 88.0 g succinic acid (0.74 mol).
The contents were heated at 50–55 °C for 30 min, cooled
to 5–10 °C, and maintained for 60 min. The crystalline
solid obtained was filtered and dried under vacuum
(870–930 mbar) to afford pure solifenacin succinate as
white crystalline solid. Yield: 272 g (72%, calculated
starting from (3R)-quinuclidin-3-ol); chemical purity by
HPLC: 99.94%; enantiomeric purity by HPLC: 99.99%.
Conclusions
An efficient and single-pot process for the preparation of
enantiomerically pure solifenacin succinate (1) via the
formation of active carbonate derivative 4 is reported.
The established process does not require any base and
higher temperatures either for the formation of active
carbonate 4 or solifenacin (6). The total time cycle to
finish a batch is around 45–50 h, thus making the process
suitable for commercial production with efficient turn-
around time. The developed process was successfully
implemented in the plant level with high production
throughput.
Experimental
The 1H NMR (400 MHz) and 13C NMR (100 MHz)
spectra were recorded on a Varian Gemini 400 MHz FT
NMR spectrometer. Chemical shifts are reported in d units
in ppm from the internal standard tetramethylsilane (TMS).
The solvent for NMR spectra was DMSO-d6 unless
otherwise stated. Infrared spectra were taken on a Perkin
Elmer Spectrum 100 in potassium bromide pellets unless
otherwise stated. High-resolution mass spectra were
obtained with a Mat 112 Varian Mat Bremen (70 eV) mass
spectrometer. All reactions were monitored by thin layer
chromatography (TLC) carried out on 0.2-mm silica gel
60F254 (Merck) plates using UV light (254 and 366 nm) or
high performance liquid chromatography (HPLC) on Agi-
lent Technologies 1200 series for detection. Common
reagent-grade chemicals are either commercially available
and were used without further purification or were prepared
by standard literature procedures.
Related substances of solifenacin succinate (1) were
estimated by gradient HPLC analysis developed at Mega-
fine using an Inertsil ODS 3 V, 250 9 4.6 mm ID column;
123

1186
N. C. Niphade et al.
Acknowledgments Authors thank the management of Megafine
Pharma (P) Ltd. for the permission to publish this work. Authors also
thank the Analytical Research and Development Department for their
valuable contribution to this work.
The spectral data of compound 1 prepared by our process
were found to agree with the reported data [6].
4-Nitrophenyl (1S)-1-phenyl-3,4-dihydroisoquinoline-
2(1H)-carboxylate (10)
To a stirred solution of 20.0 g (1S)-1-phenyl-1,2,3,4-
tetrahydroisoquinoline (5, 0.095 mol) in 50 cm3 dimethyl-
formamide was added 30.55 g bis(4-nitrophenyl)carbonate
(3, 0.1 mol) with stirring at 25–30 °C under nitrogen
atmosphere. The stirring was maintained at 25–30 °C for
2–3 h. After reaction completion (by TLC, mobile phase:
dichloromethane/methanol/ammonia = 8.0:2.0:0.5 cm3),
the reaction mixture was diluted with 100 cm3 water and
the pH of the solution was adjusted to 9–10 using
ammonium hydroxide. The resulting reaction mass was
extracted with toluene (100 cm3 9 2), the combined
toluene layer was washed with water (50 cm3 9 2),
treated with 0.5% sodium hydroxide solution (50 cm3 9
2), and further washed with 50 cm3 water. The toluene
layer was distilled off completely to obtain the residue,
which was stirred in 100 cm3 n-heptane for 25–30 min at
5–10 °C. The crystalline solid obtained was filtered and
dried under vacuum (870–930 mbar) to afford pure
compound 10. Yield: 30.0 g (83.6%); chemical purity
by HPLC: 99.00%. The spectral data of compound 10
were found to agree with the reported data [14].
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