An improved process for the preparation of highly pure solifenacin succinate via resolution through diastereomeric crystallisation

Article abstract of DOI:10.1021/op500083y

An improved process for the preparation of solifenacin succinate (1) involving resolution through diastereomeric crystallization is described. (1S)-IQL derivative (5) is esterified to form (1S)-ethoxycarbonyl IQL derivative (6) which is condensed with (RS)-3-quinuclidinol (7) to form a solifenacin diastereomeric mixture (8); this is subjected to resolution through diastereomeric crystallization to produce solifenacin succinate (1), which is used for the treatment of an overactive bladder.

Full text of DOI:10.1021/op500083y

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Full Paper
AN IMPROVED PROCESS FOR THE PREPARATION OF
HIGHLY PURE SOLIFENACIN SUCCINATE VIA RESOLUTION
THROUGH DIASTEREOMERIC CRYSTALLISATION
Ganala Naga Trinadhachari, Anand Gopalkrishna Kamat, Venkata Balaji Boddu, K Joseph
Prabahar, Mohan Naidu Kolukuluru, Korupolu Raghu Babu, and Paul Douglas Sanasi
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/op500083y • Publication Date (Web): 27 Jun 2014
Downloaded from http://pubs.acs.org on July 1, 2014
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AN IMPROVED PROCESS FOR THE PREPARATION OF HIGHLY PURE
SOLIFENACIN SUCCINATE VIA RESOLUTION THROUGH DIASTEREOMERIC
CRYSTALLISATION
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Ganala Naga Trinadhacharia,b, Anand Gopalkrishna Kamata, Boddu Venkata Balajia,
Koilpillai Joseph Prabahara, Kolukuluru Mohan Naidua, Korupolu Raghu Babub, and
Paul Douglas Sanasi*b
aChemical Research and Development, APL Research Center, Aurobindo Pharma Ltd., Survey
No. 71 & 72, Indrakaran (V), Sangareddy (M), Medak Distꢀ502329, Andhra Pradesh, India and
bDepartment of Engineering Chemistry, A. U. College of Engineering, Andhra University,
Visakhapatnamꢀ530003, Andhra Pradesh, India.
KEYWORDS: Solifenacin succinate, (RS)ꢀ3ꢀQuinuclidinol, diastereomeric crystallisation.
ABSTRACT
An improved process for the preparation of solifenacin succinate (1) involving resolution through
diastereomeric crystallisation is described. (1S)ꢀIQL derivative (5) is esterified to form (1S)ꢀ
ethoxycarbonyl IQL derivative (6) which is condensed with (RS)ꢀ3ꢀQuinuclidinol (7) to form
solifenacin diastereomeric mixture (8), this is subjected to resolution through diastereomeric
crystallisation to produce solifenacin succinate (1), which is used for the treatment of overactive
bladder.
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INTRODUCTION
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Solifenacin (1) is a quinoline derivative which is chemically known as (1S)ꢀ3,4ꢀdihydroꢀ1ꢀ
phenylꢀ2ꢀ(1H)ꢀisoquinolinecarboxylic acid (3R)ꢀ1ꢀazabicyclo[2.2.2]octꢀ3ꢀyl ester. The chemical
structure of solifenacin succinate (1) is as represented in Figureꢀ1.
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3
6
7
N2
O
4'
R
S
1
5'
6'
CH2COOH
CH2COOH
3'
2'
.
O
N
1'
1
Figure-1. Structure of solifenacin succinate.
Molecular structure of solifenacin has two chiral centers and hence exists in two racemic pairs
(four stereoisomers) viz., [(1S,3’R)ꢀisomer, solifenacin] (1a), [(1S,3’S)ꢀisomer, diastereomer of
solifenacin] (
diastereomer of solifenacin] (
therapeutically active and approved isomer.
2), [(1R,3’S)ꢀisomer, enantiomer of solifenacin] (3), [(1R,3’R)ꢀisomer,
4
), (Figureꢀ2) 1
.
Solifenacin i. e., (1S,3’R)ꢀisomer (1a) is the
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N
O
S
R
N
O
S
S
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O
O
N
N
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1a
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[(1S,3'R)ꢀISOMER]
SOLIFENACIN
[(1S,3'S)ꢀISOMER]
DIASTEREOMER
OF SOLIFENACIN
N
O
R
S
N
O
R
R
O
O
N
N
3
4
[(1R,3'S)ꢀISOMER]
[(1R,3'R)ꢀISOMER]
ENANTIOMER
OF SOLIFENACIN
DIASTEREOMER
OF SOLIFENACIN
Figure-2. Structures of solifenacin stereoisomers.
Solifenacin is a potent muscarinic M3 receptor antagonist. Muscarinic receptors play an
important role in several major cholinergically mediated functions, including contractions of the
urinary bladder, gastrointestinal smooth muscle, saliva production, and iris sphincter function.
Solifenacin has great affinity for the M3 receptor than the other known muscarinic receptors.2ꢀ5
Solifenacin also shows a wide spectrum of bowel dysfunction through the blockade of M3
receptors, its therapeutic potential for treating irritable bowel syndrome (IBS).6 Solifenacin
succinate is commercially available and it has been approved for the treatment of overactive
bladder with symptoms of urinary urgency and urinary frequency.
Naito, R. et al. first designed and developed potent and more bladder selective muscarinic M3
receptor antagonist solifenacin (1
).7 Takuchi, M. et al. disclosed the synthesis of solifenacin and
its pharmaceutical acceptable salts.8 In general solifenacin has been prepared by two synthetic
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approaches: in the first one, (1S)ꢀ1ꢀphenylꢀ1,2,3,4ꢀtetrahydroisoquinolineꢀ2ꢀcarboxylic acid ethyl
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6
ester (6) was transesterified with pure (R)ꢀ3ꢀquinuclidinol to provide pure isomer solifenacin (1),
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the second approach involves the preparation of solifenacin as its diastereomeric mixture by the
transesterification of (1RS)ꢀ1ꢀphenylꢀ1,2,3,4ꢀtetrahydroisoquinolineꢀ2ꢀcarboxylic acid ethyl ester
with (R)ꢀ3ꢀquinuclidinol and this mixture was either resolved by chiral HPLC2 or through
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crystallisation9 to produce pure solifenacin (
1). The resolution process of (RS)ꢀ3ꢀquinuclidinol
(
7
) involves acetylation, resolution and deacetylation through hydrolysis to yield only 10% of
(R)ꢀ3ꢀquinuclidinol10 or asymmetric hydrogenation of (RS)ꢀ3ꢀquinuclidinol (
use of highly costly Ruthinium (II) complex11 or by means of enzymatic resolution process of
) to access pure isomer.12
7
) catalysed by the
acetylated (RS)ꢀ3ꢀquinuclidinol (
7
The present invention discloses an improved synthetic strategy for the preparation of solifenacin
succinate ( ) as depicted in scheme 1. The present authors selected less expensive racemic (RS)ꢀ
3ꢀquinuclidinol ( ) rather than the expensive pure isomer, (R)ꢀ3ꢀquinuclidinol as one of the key
1
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raw materials to develop the process for the preparation solifenacin succinate (
1).
RESULTS AND DISCUSSION
To carry out the synthesis of solifenacin succinate, (1S)ꢀIQL derivative (
ethyl chloroformate in presence of a base such as triethylamine. We studied the optimal quantity
of ethyl chloroformate for the condensation with (1S)ꢀIQL derivative ( ) in the presence of
triethylamine and found that 1.05 molar equivalents of ethyl chloroformate and triethylamine
w.r.t. (1S)ꢀIQL derivative ( ) are sufficient to achieve desired conversion consistently. We
5) is condensed with
5
5
carried out this reaction in different solvents like methylene chloride and toluene and found that
toluene is the suitable solvent for this reaction. Since toluene solution containing (1S)ꢀ
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ethoxycarbonyl IQL derivative (6) was obtained after aqueous workꢀup, it can be used as such in
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8
the subsequent stage. We also carried out this reaction at different temperatures and observed that
25ꢀ30°C is ideal temperature for this reaction.# After completion of the reaction, the reaction
mass is washed with water to remove the triethylamine hydrochloride byꢀproduct and the toluene
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solution containing (1S)ꢀethoxycarbonyl IQL derivative (
6
) is taken to the next stage as such
) to produce
without isolation for the condensation reaction with (RS)ꢀ3ꢀQuinuclidinol (
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solifenacin and its diastereomer (8).
#
We have observed that ethyl chloroformate addition was exothermic, therefore, we have started the addition of
ethyl chloroformate at low temperature ~5 °C and during the addition of ethyl chloroformate, the temperature
raises to 25ꢀ30 °C on its own due to exothermicity. Thereafter, the reaction mass is allowed to be stirred at the
same temperature which is an ideal temperature for this reaction to achieve desired conversion. It was also
observed that this reaction at higher temperature (35ꢀ40 °C) yielded lesser purity product and at lower temperature
(10ꢀ15°C) the reaction mass becomes a thick mass and further stirring was observed to be difficult.
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Scheme 1
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9
NH
S
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(1S)-IQL derivative
5
Ethyl chloroformate
N
OC2H5
S
O
(1S)-Ethoxycarbonyl IQL derivative
6
HO
N
(RS)-3-Quinuclidinol
7
N
O
R
S
N
O
S
S
+
O
O
N
N
(1S,3'R)-Isomer
Solifenacin
1a
(1S,3'S)-Isomer
Diastereomer of Solifenacin
2
Diastereomeric mixture of Solifenacin
8
Diastereomeric crystallisation
Succinic acid / Ethyl acetate
N
O
R
S
CH2COOH
CH2COOH
.
O
N
Solifenacin succinate
1
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It is known from the literature2 that (1S)ꢀethoxycarbonyl IQL derivative (
6) can be transesterified
5
6
7
8
with 3ꢀquinuclidinol in presence of a strong basic metal hydride such as sodium hydride or metal
alkoxides like sodium ethoxide in an organic solvent at elevated temperatures to obtain
solifenacin. We conducted our initial experiments by using sodium hydride as base in toluene at
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reflux temperature of 110ꢀ115°C. In this reaction, (1S)ꢀethoxycarbonyl IQL derivative (
reacted with (RS)ꢀ3ꢀQuinuclidinol ( ) in presence of sodium hydride base in toluene solvent at
reflux temperature to produce 1:1 mixture of solifenacin and its diastereomer ( ). It has been also
6) is
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8
observed that ethanol is formed as a byꢀproduct during this reaction and is required to be
removed from the reaction mass to facilitate the forward reaction to yield desired product.
Therefore, the byꢀproduct ethanol is azeotropically distilled out with toluene and an additional
amount of toluene is added simultaneously to maintain the volume of the reaction mass.
The progress of the reaction is monitored by HPLC. It was observed that in this
transesterification reaction the formation ~ 85% of desired product and one major impurity
around ~10ꢀ15% was formed and this impurity was identified as (1S)ꢀIQL derivative (
on its retention time and LCꢀMS. It is anticipated that (1S)ꢀIQL derivative ( ) could form during
reaction not only by the hydrolysis of (1S)ꢀethoxycarbonyl IQL derivative ( ) but also hydrolysis
of solifenacin and its diastereomer ( ). To optimize the conditions to control the formation of this
5) based
5
6
8
impurity, we carried out this reaction by using varying amount of sodium hydride base and the
results are summarized in Table 1.
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Table 1 Effect of sodium hydride base quantity on transesterification reaction.
5
6
7
Reaction monitoring dataa
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9
R
N
O
S
N
O
S
S
+
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O
O
N
S
OC2H5
NH
S
N
N
Quantity
of sodium
hydride used
O
(1S,3’R)ꢀisomer
(1S,3’S)ꢀisomer
(1a)
(2)
(1S)ꢀethoxycarbonyl
Diastereomeric mixture of
IQL derivative
IQL derivative
Solifenacin
(5)
(6)
14.76
(8)
57.17
1.00 m. eq.
0.50 m. eq.
0.20 m. eq.
25.30
16.89
10.68
2.06
5.88
79.93
81.49
aBy HPLC, by area normalization.
The results indicate that higher molar quantity of the base, sodium hydride facilitates the
formation of higher amount of undesired impurity (1S)ꢀIQL derivative ( ). It was also observed
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that the experiment which was performed by using 1.0 m. eq. of sodium hydride has resulted in
the isomerisation, leading to the formation of other undesired (1R,3S)ꢀisomer and (1R,3R)ꢀ
isomer of solifenacin ~ 6% by chiral HPLC analysis. It is reported13 that in this transesterification
reaction sodium ethoxide is generated inꢀsitu from reaction of sodium hydride with the byꢀ
product, ethanol. Therefore, it was concluded that 0.2 m. eq. of sodium hydride w.r.t. (1S)ꢀIQL
derivative (5) is sufficient to carry out this transesterification reaction.
Effect of temperature on this transesterification reaction was also studied at different
temperatures such as 80ꢀ85°C, 110ꢀ115°C and 120ꢀ125°C. oꢀXylene was used as the solvent
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where the condensation reaction was carried out at 120ꢀ125°C. It was observed that in case of
experiments with toluene at low temperature and with oꢀxylene at high temperature, the byꢀ
product ethanol could not be removed effectively and hence resulted in low conversion and lesser
amount of product formation. The reaction was very slow and the unreacted (1S)ꢀethoxycarbonyl
IQL derivative remained in higher amount. Therefore, the removal of ethanol byꢀproduct is
essential to move forward the reaction towards the formation of desired product. Therefore, 110ꢀ
115°C is the suitable temperature for this reaction to achieve the desired conversion. The
experimental results of the temperature study are tabulated in Table 2.
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Table 2 Effect of temperature on the transesterification reaction.
Reaction monitoring dataa
R
N
O
S
N
O
S
S
+
O
O
N
S
OC2H5
NH
S
N
N
Solvent
used for the
reaction
Reaction
Temperature
O
(1S,3’R)ꢀisomer (1S,3’S)ꢀisomer
(1a)
(2)
IQL
(1S)ꢀethoxycarbonyl
Diastereomeric mixture of
derivative
IQL derivative
Solifenacin
(5)
(6)
(8)
Toluene
Toluene
oꢀXylene
80ꢀ85°C
110ꢀ115°C
120ꢀ125°C
6.54
48.91
42.71
10.68
11.14
5.88
81.49
36.53
29.22
aBy HPLC, by area normalization.
Next we focused to study the effect of solvent quantity used in the reaction. We have carried out
this reaction by using 10, 7.5 and 4 volumes of toluene and observed that toluene quantity during
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transesterification reaction plays an important role. It was observed from these reactions that the
rate of the reaction is slower with higher volume of toluene and the rate of reaction is faster with
higher conversion when lesser volume of toluene is used. The results obtained from the effect of
reaction volume study are summarized in Table 3.
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Table 3 Effect of Toluene quantity on the transesterification reaction.
Reaction monitoring dataa
R
N
O
S
N
O
S
S
+
O
O
N
S
OC2H5
NH
S
N
N
Reaction
volume
Reaction
time
O
(1S,3’R)ꢀisomer
(1S,3’S)ꢀisomer
(1a)
(2)
IQL
(1S)ꢀethoxycarbonyl
Diastereomeric mixture of
derivative
IQL derivative
Solifenacin
(5)
(6)
(8)
81.49
10 times
7.5 times
4 times
42 h
42 h
20 h
10.68
5.88
5.88
2.94
10.68
3.97
81.49
92.68
aBy HPLC, by area normalization.
It was concluded that toluene solution of (1S)ꢀethoxycarbonyl IQL derivative (
obtained from stageꢀI reaction was concentrated to about four volumes w.r.t. (1S)ꢀIQL derivative
) and proceed for the transesterification reaction. We have also carried out this
6) product
(5
transesterification reaction by using 0.2 m. eq. of sodium ethoxide base and identical results were
obtained when sodium ethoxide base was used in place of sodium hydride.
After completion of the reaction, the mass was cooled and quenched with DM water and
subjected to acidꢀbase treatment. Thereafter, the product was extracted in ethyl acetate and the
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ethyl acetate solution containing solifenacin and its diastereomer was dehydrated and used as
such directly to produce solifenacin succinate by treating it with succinic acid through
diastereomeric crystallisation in the next stage.
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The next focus of our study was to resolve the solifenacin and its diastereomeric mixture by
resolution through diastereomeric crystallisation to obtain our target product solifenacin
succinate (1) in pure form. In general, the conventional diastereomeric resolution is carried out
by using a chiral resolving agent. It was reported in the literature that the diastereomeric mixture
of (1S,3’R)ꢀisomer and (1R,3’R)ꢀisomer was resolved through crystallisation using succinic acid
as achiral resolving agent.9 Even though solifenacin molecule can exist in four stereoisomers,
from our reaction only one diastereomeric pair is obtained. Since the product itself obtained as
diastereomeric pair and the diastereomeric resolution is carried out with a achiral resolving agent
by converting into its succinate salt through diastereomeric crystallisation.
To select the suitable solvent medium for this diastereomeric crystallisation, we have carried out
the experiments for preparation of solifenacin succinate by using 0.60 m. eq. of succinic acid in
solvents mixture comprising of 30%, 10%, 5%, 2.5% and 0% ethanol in ethyl acetate.
Solifenacin succinate crystallisation is induced by adding solifenacin succinate seed and stirring
at 25ꢀ30°C for about 15 h to complete the crystallisation process. Thereafter, the slurry mass was
heated to 70ꢀ75°C, stirred for about 2 h at the same temperature and then cooled to 25ꢀ30°C. The
product was filtered and washed with ethyl acetate. This solifenacin succinateꢀcrude product was
analysed by chiral HPLC and observed that the undesired (1S,3’S)ꢀisomer is < 6%. Therefore,
The obtained solifenacin succinateꢀcrude product was then purified from ethyl acetate by heating
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at 70ꢀ75°C, cooling to 25ꢀ30°C, filtration and washing with ethyl acetate to remove undesired
(1S,3S)ꢀisomer. The results of these experiments are summarized in Table 4.
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Table 4 Effect of solvent during resolution through diastereomeric crystallisation.
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% of Producta
Solifenacin succinateꢀcrude
Before EtOAc slurry wash
After EtOAc slurry wash
Quantity
of ethanol
in ethyl
Yield
(w/w
based on)
N
O
R
N
O
N
S
O
R
N
O
S
S
S
S
S
acetate
O
O
O
O
N
N
N
N
Solifenacin
(1S,3’S)ꢀisomer
Solifenacin
(1S,3’S)ꢀisomer
(1a)
(2)
(1a)
(2)
30% v/v
10% v/v
5% v/v
2.5% v/v
0%
96.00
93.83
94.13
95.62
94.30
4.00
6.17
5.87
4.38
5.70
99.60
99.40
99.23
99.39
99.45
0.40
0.60
0.77
0.61
0.55
36%
41%
49%
55%
65%
aChromatographic purity (by chiral HPLC, by area normalization).
Based on the experimental results, it was found that ethyl acetate is better solvent for resolution
of solifenacin succinate and further to obtain desired chiral purity of solifenacin succinate.
Finally, the above obtained solifenacin succinateꢀcrude was purified from 30% v/v ethanol in
ethyl acetate solvent mixture to obtain solifenacin succinate drug substance containing ≤ 0.10%
of (1S,3’S)ꢀisomer.
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We also studied the quantity of succinic acid required for this diastereomeric crystallisation by
using 0.50, 0.60 and 0.80 m. eq. of succinic acid and found that 0.50 molar equivalent resulted in
lower yield whereas 0.80 molar equivalent gave impure product contaminated with higher
amount of undesired (1S,3’S)ꢀisomer. Thus, it was concluded that 0.60 m. eq. of succinic acid is
suitable in order to obtain solifenacin succinate drug substance containing ≤ 0.10% of (1S,3’S)ꢀ
isomer. The results of these experiments are summarized in Table 5.
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Table 5 Effect of organic acid (succinic acid) quantity on the diastereomeric crystallisation.
Content of (1S,3’S)ꢀisomer a
Quantity of
Yield
(w/w based on)
Solifenacin succinateꢀcrude
succinic acid
used
Solifenacin
succinate pure
Before EtOAc
slurry wash
After EtOAc
slurry wash
0.50 m. eq.
0.60 m. eq.
0.80 m. eq.
4.25%
6.85%
33.82%
0.69%
0.51%
12.90%
0.10%
0.09%
2.27%
45%
57%
60%
aBy chiral HPLC, by area normalization.
We have analysed the samples of solifenacin succinateꢀcrude and solifenacin succinate for
succinic acid content and observed that it was between 24.17 to 24.52% w/w which is meeting to
the theoretical requirement of 24.58% w/w succinic acid.
Based on the experimental results, the final step of the process for the preparation solifenacin
was optimized as the diastereomeric crystallisation was carried out by using 0.60 m. eq. of
succinic acid w.r.t. (1S)ꢀIQL derivative (5) in ethyl acetate by addition of solifenacin succinate
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seed at 25ꢀ30°C. The crude product was purified first by slurrying in ethyl acetate and finally
purified by recrystallization from a mixture of ethyl acetate (70%) and ethanol (30%).§
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CONCLUSION
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An improved process for the preparation of solifenacin succinate (
optimized, involving the preparation of solifenacin and its diastereomer (
further, resolution through diastereomeric crystallisation to yield highly pure solifenacin
1
) was developed and
8
) intermediate and its
succinate (1
).14
§
Our aim is to obtain solifenacin undesired isomers <0.15% preferably < 0.10%. In this direction, it is
essential to control the undesired (1S,3’S)ꢀisomer before proceeding for final purification by crystallisation
from ethanol and ethyl acetate mixture. In order to achieve the suitable / desirable content of (1S,3’S)ꢀ
isomer in crude product with desired yield, slurry wash in ethyl acetate has been incorporated. To balance
the yield and to achieve the desired purity of product (API), it is required to carry out three unit operations.
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EXPERIMENTAL SECTION
5
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8
GENERAL: IQL derivative (5) and other reagents and solvents were obtained from commercial
suppliers and used without further purification. (RS)ꢀ3ꢀQuinuclidinol was prepared by keto
reduction of 3ꢀQuinuclidinone. Melting points were determined on a Polmon MP96 capillary
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1
melting point apparatus and are uncorrected. H and 13C NMR spectra were recorded on a
Brucker 300 MHz spectrometer in DMSOꢀd6, chemical shift data are reported in ppm from the
internal standard TMS. The reaction monitoring and chromatographic purity (area percentage)
was analyzed qualitatively by High Performance Liquid Chromatography (HPLC) on Shimadzu
VP series UV using Symmetry C18 column (250 mm X 4.6 mm, 5 µ). The chiral purity of
Solifenacin were analyzed on a Waters 2695 with 2996 PDA detector using Chiralpak IC (250
mm X 4.6 mm, 5 µ) column respectively High Resolution Mass spectra (HRMS) were taken on
Xevo G2 Q TOF HRMS instrument with electrospray ionization (positive) mode in units of mass
(m/z). The IR spectra were recorded on KBr pellets on PerkinꢀElmer FTIR (spectrum one)
spectrophotometer.
Preparation of compound (1S)-ethyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolincarboxylate
[(1S)-ethoxycarbonyl IQL derivative] (6). Ethyl chloroformate (109 g, 1.005 moles) was
slowly added to a mixture of (1S)ꢀ1ꢀphenylꢀ1,2,3,4ꢀtetrahydroisoquinoline (IQL derivative) (5,
200 g, 0.957 moles) in toluene (2000 mL) in presence of triethylamine (101.50 g, 1.005 moles) at
5ꢀ30°C over a period of 30 min. Thereafter the reaction mixture was stirred at 25ꢀ30°C for about
30 min. and the completion of the reaction was monitored by qualitative HPLC analysis. The
reaction mass was washed with water (2 x 600 mL) to obtain toluene solution (2000 mL)
containing (1S)ꢀethyl 1ꢀphenylꢀ1,2,3,4ꢀtetrahydroꢀ2ꢀisoquinolincarboxylate (6)
.
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Chromatographic purity: 99.32 % (by HPLC). IR (KBr) (cmꢀ1): 3511, 1694, 1600, 1493. HRMS:
m/z = 282.1487 [M + H] +. 1H NMR (DMSOꢀd6,): δ 1.20 (t, 3H), 2.81 (m, 2H), 3.28 & 3.86 (2m,
2H), 4.10 (m, 2H), 6.27 (m, 1H,), 7.13ꢀ7.33 (m, 9H).
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Preparation of (1S)-3,4-dihydro-1-phenyl-2-(1H)-isoquinolinecarboxylic acid (3RS) -1-
azabicyclo[2.2.2]oct-3-yl ester [(1S,3’R)- & (1S,3’S)-isomeric mixture] (diastereomeric
mixture of Solifenacin) (8). (RS)ꢀ3ꢀQuinuclidinol (7, 145.80 g 1.148 moles) was added to a
solution of (1S)ꢀethyl 1ꢀphenylꢀ1,2,3,4ꢀtetrahydroꢀ2ꢀisoquinolincarboxylate (6) in toluene (2000
mL, as obtained in StageꢀI) at 25ꢀ30°C under nitrogen atmosphere. The contents were heated to
108ꢀ112 °C and concentrated to collect ~1200 mL of distillate to remove traces of water present
in the reactants. Thereafter, the contents were cooled to 25ꢀ30°C and sodium hydride (60% w/w,
7.70g 0.1925 moles) was added to the reaction mixture and the reaction mass was stirred at
reflux for about 20 h. The byꢀproduct ethanol was removed azeotropically with toluene and fresh
toluene was added simultaneously to maintain the volume of the reaction mass. The completion
of the reaction was monitored by qualitative HPLC analysis. The reaction mass was cooled to 20ꢀ
25°C and DM water (800 mL) was added slowly at 20ꢀ30 °C. The reaction was stirred for about
20 min. and toluene layer was separated. DM water (700 mL) was added to the organic layer and
cooled to 5ꢀ10°C and pH was adjusted to 1.0±0.2 by using ~9% w/w aqueous hydrochloric acid
(350 mL). The aqueous layer was separated, cooled to 5ꢀ10°C and pH was adjusted to 7.0 to 7.5
by using 10% w/w aqueous sodium hydroxide solution (170 mL). Thereafter ethyl acetate (1600
mL) was added and the pH was further adjusted to 10.0±0.2 using 10% w/w aqueous sodium
hydroxide solution (170 mL). The mass was stirred at 25ꢀ30°C for 20 min. and separated the
upper organic layer. The organic layer was washed with DM water (400 mL) and then it was
treated with carbon (10 g) at 25ꢀ30°C for 30 min. The carbon was removed by filtration through
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hyflo and the residue was washed with ethyl acetate (400 mL) to obtain ethyl acetate solution
(2000 mL) of (1S)ꢀ3,4ꢀdihydroꢀ1ꢀphenylꢀ2ꢀ(1H)ꢀisoquinolinecarboxylic acid (3RS) ꢀ1ꢀ
azabicyclo[2.2.2]octꢀ3ꢀyl ester [(1S,3’R)ꢀ & (1S,3’S)ꢀisomeric mixture] (diastereomeric mixture
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of Solifenacin) (8).
Chiral purity : 51.14 % (by chiral HPLC). (1S, 3’S)ꢀDiastereomer content: 48.79% (by chiral
HPLC). IR (KBr) (cmꢀ1): 3363, 3026, 1693, 1582, 1493. HRMS: m/z = 363.2077 [M + H] . 1H
+
NMR(DMSOꢀd6): δ 1.47 & 1.56 (m, 4H), 1.91 (m, 1H), 2.60 & 2.68 (m, 4H), 2.86 (brs, 1H),
3.05 ꢀ 3.09 (m, 1H), 3.83 ꢀ 3.89 (m, 1H), 4.63 (brs, 2H), 6.25 (brs, 2H), 7.20 ꢀ 7.34 (m, 9H).
Preparation of (1S)-3,4-dihydro-1-phenyl-2-(1H)-isoquinolinecarboxylic acid (3RS) -1-
azabicyclo[2.2.2]oct-3-yl ester [(1S,3’R)- & (1S,3’S)-isomeric mixture] (diastereomeric
mixture of Solifenacin) (8). (RS)ꢀ3ꢀQuinuclidinol (
solution of (1S)ꢀethyl 1ꢀphenylꢀ1,2,3,4ꢀtetrahydroꢀ2ꢀisoquinolincarboxylate (6) in toluene (330
mL, as obtained in StageꢀI from 33g input of IQL derivative, ) at 25ꢀ30°C under nitrogen
7, 24.06 g 0.1894 moles) was added to a
5
atmosphere. The contents were heated to 108ꢀ112 °C and concentrated to collect ~198 mL of
distillate to remove traces of water present in the reactants. Thereafter, the contents were cooled
to 25ꢀ30°C and sodium ethoxide (2.15 g, 0.0316 moles) was added to the reaction mixture and
the reaction mass was stirred at reflux for about 20 h. The byꢀproduct ethanol was removed
azeotropically with toluene and fresh toluene was added simultaneously to maintain the volume
of the reaction mass. The completion of the reaction was monitored by qualitative HPLC
analysis. The reaction mass was cooled to 20ꢀ25°C and DM water (132 mL) was added slowly at
20ꢀ30 °C. The reaction was stirred for about 20 min. and toluene layer was separated. DM water
(115.5 mL) was added to the organic layer and cooled to 5ꢀ10°C and pH was adjusted to 1.0±0.2
by using ~9% w/w aqueous hydrochloric acid (57.8 mL). The aqueous layer was separated,
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cooled to 5ꢀ10°C and pH was adjusted to 7.0 to 7.5 by using 10% w/w aqueous sodium
hydroxide solution (28 mL). Thereafter ethyl acetate (264 mL) was added and the pH was
further adjusted to 10.0±0.2 using 10% w/w aqueous sodium hydroxide solution (28 mL). The
mass was stirred at 25ꢀ30°C for 20 min. and separated the upper organic layer. The organic layer
was washed with DM water (66 mL) and then it was treated with carbon (1.65 g) at 25ꢀ30°C for
30 min. The carbon was removed by filtration through hyflo and the residue was washed with
ethyl acetate (66 mL) to obtain ethyl acetate solution (330 mL) of (1S)ꢀ3,4ꢀdihydroꢀ1ꢀphenylꢀ2ꢀ
(1H)ꢀisoquinolinecarboxylic acid (3RS) ꢀ1ꢀazabicyclo[2.2.2]octꢀ3ꢀyl ester [(1S,3’R)ꢀ & (1S,3’S)ꢀ
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isomeric mixture] (diastereomeric mixture of Solifenacin) (8).
Chiral purity : 51.64 % (by chiral HPLC). (1S, 3’S)ꢀDiastereomer content: 48.24% (by chiral
HPLC).
Preparation of (1S)-3,4-dihydro-1-phenyl-2-(1H)-isoquinolinecarboxylic acid (3R)-1-
azabicyclo[2.2.2]oct-3-yl ester. succinate (Solifenacin succinate) (1). Ethyl acetate solution
(2000 mL) containing (1S)ꢀ3,4ꢀdihydroꢀ1ꢀphenylꢀ2ꢀ(1H)ꢀisoquinolinecarboxylic acid (3RS) ꢀ1ꢀ
azabicyclo[2.2.2]octꢀ3ꢀyl ester [(1S,3’R)ꢀ & (1S,3’S)ꢀisomeric mixture] (diastereomeric mixture
of Solifenacin) (8) (as obtained in StageꢀII) was dehydrated by azeotropic distillation to remove
~600 mL of distillate and cooled to 25ꢀ30°C. Added ethyl acetate (~600 mL, equal amount of
distillate collected). To this solution succinic acid (67.80 g 0.5746 moles) was added, followed
by Solifenacin succinate seed (1 g). The contents were stirred at 25ꢀ30°C for 8h. Thereafter, the
mass was heated to 75ꢀ80 °C and stirred at this temperature for 2h. The slurry was cooled to 25ꢀ
30°C and stirred at this temperature for 1h. The product was filtered and was washed with ethyl
acetate (400 mL).
Chromatographic purity: 98.75% (by HPLC). Chiral purity : 93.69 % (by chiral HPLC).
(1S, 3’S)ꢀDiastereomer content: 6.30 % (by chiral HPLC).
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Above filtered mass (250 g) was suspended ethyl acetate (2000 mL) at 25ꢀ30°C. The suspension
was heated to 75ꢀ80 °C and stirred at this temperature for 2h. Thereafter, the reaction mass was
cooled to 25ꢀ30 °C and stirred at this temperature for 1h. The product was filtered, washed with
ethyl acetate (240 mL) and then dried under reduced pressure at 50ꢀ55 °C to produce Solifenacin
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succinateꢀcrude (1) as cream color crystalline powder. (130 g, 65% w/w yield based on 5).
Chromatographic purity: 99.93 % (by HPLC). Chiral purity: 99.44 % (by chiral HPLC).
(1S, 3’S)ꢀDiastereomer content: 0.56% (by chiral HPLC).
Purification of (1S)-3,4-dihydro-1-phenyl-2-(1H)-isoquinolinecarboxylic acid (3R)-1-
azabicyclo[2.2.2]oct-3-yl ester. succinate (Solifenacin succinate) (1). Solifenacin succinate
(120 g) as obtained above was stirred in a mixture of ethanol (260 mL) and ethyl acetate (504
mL) at 60ꢀ65°C to obtain a clear solution. This was treated with carbon (6 g) at 60ꢀ65 °C for 30
min. Carbon was removed by filtration through hyflo at 60ꢀ65°C and the residue was washed
with preꢀheated 30% v/v ethanolꢀethyl acetate mixture (240 mL). The filtrate was slowly cooled
to 0ꢀ5°C and stirred at this temperature for 1h. Thereafter, the product was filtered, washed with
ethyl acetate (120 mL) and then dried under reduced pressure at 50ꢀ55 °C to produce pure
Solifenacin succinate (1) as white crystalline powder. (104.50 g, 87% w/w yield based on inꢀput).
Chromatographic purity: 99.94 % (by HPLC). Chiral purity: 99.94% (by chiral HPLC). (1S, 3’S)ꢀ
Diastereomer content: 0.06% (by chiral HPLC). Mp 145ꢀ146 °C. [α]D 25 (c=1, in Water): + 40.6°.
IR (KBr) (cmꢀ1): 3282, 3024, 3007, 2964, 2937, 2881, 2607, 1722, 1685, 1579, 1491, 1227, 761,
+
1
751. HRMS: m/z = 363.2071 [M + H] . H NMR (DMSOꢀd6): δ 1.50 ꢀ 1.81 (m, 4H), 2.07 (m,
1H), 2.36 (s, 4H), 2.56 ꢀ 3.30 (m, 8H), 3.41 & 3.85 (2m, 2H), 4.79 (m, 1H), 6.27 (brs, 1H), 7.20 ꢀ
13
7.32 (m, 9H), 11.79 (brs, 2H). C NMR (DMSOꢀd6): δ 18.3 (CH2), 22.3 (CH2), 24.6 (CH), 27.7
(CH2), 30.2 (2xCH2), 38.9 (CH2), 45.1 (CH2), 46.0 (CH2), 54.1 (CH2), 57.3, 70.2, 126.2 (CH),
127.1 (CH), 127.2 (2xCH), 128.1 (CH), 128.4 (2xCH), 128.7 (CH), 134.7, 135.4, 154.3, 174.5.
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AUTHOR INFORMATION
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*Corresponding Author Eꢀmail: pauldouglas12@gmail.com. Tel: +91ꢀ9347098430
ACKNOWLEDGEMENTS
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Authors are grateful to the management of Aurobindo Pharma Ltd., Hyderabad for the
permission to publish this work. Authors thank the entire Analytical Research Department for
their valuable analytical support to this work.
SUPPORTING INFORMATION
This information is available free of charge via the Internet at http://pubs.acs.org/.
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TABLE OF CONTENTS
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An Improved Process For The Preparation Of Highly Pure Solifenacin Succinate
Via Resolution Through Diastereomeric Crystallisation
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Ganala Naga Trinadhacharia,b, Anand Gopalkrishna Kamata, Boddu Venkata Balajia,
Koilpillai Joseph Prabahara, Kolukuluru Mohan Naidua, Korupolu Raghu Babub, and
Paul Douglas Sanasi*b
aChemical Research and Development, APL Research Center, Aurobindo Pharma Ltd., Survey No. 71 & 72,
b
Indrakaran (V), Sangareddy (M), Medak Dist-502329, Andhra Pradesh, India and Department of Engineering
Chemistry, A. U. College of Engineering, Andhra University, Visakhapatnam-530003, Andhra Pradesh, India.
Abstract
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CH COOH
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Solifenacin succinate
(1S)-IQL derivative
Diastereomeric mixture of Solifenacin
An improved process for the preparation of solifenacin succinate (1) involving resolution
through diastereomeric crystallisation is described. (1S)-IQL derivative (5) is esterified to form
(1S)-ethoxycarbonyl IQL derivative (6) which is condensed with (RS)-3-Quinuclidinol (7) to
form solifenacin diastereomeric mixture (8), this is subjected to resolution through
diastereomeric crystallisation to produce solifenacin succinate (1), which is used for the
treatment of overactive bladder.
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