U.S. patent application number 14/382529 was filed with the patent office on 2015-04-23 for process of preparing solifenacin or salt thereof, and novel intermediate used in the process.
This patent application is currently assigned to Kyung Dong Pharm. Co., Ltd.. The applicant listed for this patent is KYUNG DONG PHARM. CO., LTD.. Invention is credited to Byoung Suk Lee, Ki Young Lee, Sang Hoon Shin.
Application Number | 20150112072 14/382529 |
Document ID | / |
Family ID | 49260649 |
Filed Date | 2015-04-23 |
United States Patent
Application |
20150112072 |
Kind Code |
A1 |
Lee; Byoung Suk ; et
al. |
April 23, 2015 |
PROCESS OF PREPARING SOLIFENACIN OR SALT THEREOF, AND NOVEL
INTERMEDIATE USED IN THE PROCESS
Abstract
Disclosed herein is a method of preparing solifenacin or a salt
thereof, including the steps of: (a) reacting (R)-quinuclidinol
with bis(pentafluorophenyl)carbonate in an organic solvent to
prepare a solifenacin intermediate,
(3R)-1-azabicyclo[2,2,2]oct-3-yl pentafluorophenylcarbonate, and
(b) reacting the solifenacin intermediate with
(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline in an organic solvent
to prepare solifenacin. The method is advantageous in that
high-purity solifenacin or a salt thereof can be simply and
efficiently prepared with high yield using a novel
intermediate.
Inventors: |
Lee; Byoung Suk; (Seoul,
KR) ; Shin; Sang Hoon; (Gyeonggi-do, KR) ;
Lee; Ki Young; (Gyeonggi-do, KR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
KYUNG DONG PHARM. CO., LTD. |
Gyeonggi-do |
|
KR |
|
|
Assignee: |
Kyung Dong Pharm. Co., Ltd.
Gyeonggi-do
KR
|
Family ID: |
49260649 |
Appl. No.: |
14/382529 |
Filed: |
March 21, 2013 |
PCT Filed: |
March 21, 2013 |
PCT NO: |
PCT/KR2013/002358 |
371 Date: |
September 2, 2014 |
Current U.S.
Class: |
546/137 |
Current CPC
Class: |
C07D 453/02 20130101;
A61K 31/439 20130101; A61P 13/00 20180101; C07C 51/412 20130101;
C07C 51/412 20130101; C07C 55/10 20130101 |
Class at
Publication: |
546/137 |
International
Class: |
C07D 453/02 20060101
C07D453/02 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 28, 2012 |
KR |
10-2012-0031492 |
Claims
1. A method of preparing solifenacin or a salt thereof, comprising
the steps of: (a) reacting (R)-quinuclidinol of Formula (VI):
##STR00016## with bis(pentafluorophenyl)carbonate of Formula (VII):
##STR00017## in an organic solvent to prepare
(3R)-1-azabicyclo[2,2,2]oct-3-yl pentafluorophenylcarbonate of
Formula (IV): ##STR00018## and (b) reacting the
(3R)-1-azabicyclo[2,2,2]oct-3-yl pentafluorophenylcarbonate of
Formula (IV): ##STR00019## with
(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline of Formula (V):
##STR00020## in an organic solvent to prepare solifenacin of
Formula (II): ##STR00021## ##STR00022##
2. The method of claim 1, further comprising the step of converting
the solifenacin of Formula (II): ##STR00023## into solifenacin
succinate of Formula (I): ##STR00024##
3. The method of claim 1, wherein, in the step (a), an amount of 1
to 3 molar equivalents of bis(pentafluorophenyl)carbonate of
Formula (VII) per 1 molar equivalent of (R)-quinuclidinol of
Formula (VI) is used.
4. The method of claim 1, wherein, in the step (a) or (b), the
reaction is performed at a temperature of 10.degree. C. to
30.degree. C.
5. The method of claim 4, wherein, in the step (a) or (b), the
reaction is performed for 2 hours to 12 hours.
6. The method of claim 1, wherein, in the step (a) or (b), the
reaction is performed without using a base.
7. The method of claim 1, wherein, in the step (a) or (b), the
organic solvent is selected from the group consisting of toluene,
ethyl acetate, dichloromethane, acetone, isopropanol and mixtures
thereof.
8. The method of claim 1, wherein the step (b) is performed by an
in-situ reaction in which the
(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline of Formula (V) is
added dropwise without dissociating the
(3R)-1-azabicyclo[2,2,2]oct-3-yl pentafluorophenylcarbonate of
Formula (IV) prepared in the step (a).
9. The method of claim 2, wherein the step (c) is performed in the
presence of an organic solvent selected from the group consisting
of aliphatic alcohol, ketone, ester, aromatic hydrocarbon, polar
aliphatic hydrocarbon and mixtures thereof.
10. The method of claim 9, wherein, in the step (c), the organic
solvent is toluene, acetone or a mixture thereof.
11. A compound represented by Formula (IV): ##STR00025##
12. A method of preparing a compound of Formula (IV): ##STR00026##
comprising the step of reacting (R)-quinuclidinol of Formula (VI):
##STR00027## with bis(pentafluorophenyl)carbonate of Formula (VII):
##STR00028## in an organic solvent: ##STR00029##
Description
TECHNICAL FIELD
[0001] The present invention relates to a method of preparing
solifenacin or a salt thereof. More particularly, the present
invention relates to a method of preparing a novel solifenacin
intermediate and a method of preparing solifenacin or a salt
thereof using the intermediate.
BACKGROUND ART
[0002] Solifenacin succinate
((1S)-(3R)-1-azabicyclo[2,2,2]oct-3-yl-3,4-dihydro-1-phenyl-2(1H)-isoquin-
oline carboxylate succinate), represented by Formula (I) below, is
a competitive and selective M3 muscarine receptor antagonist, and
is known as a compound used to treat overactive bladder symptoms
such as urgent urinary incontinence, urinary urgency, urinary
frequency and the like.
##STR00001##
[0003] Conventional methods of preparing solifenacin or solifenacin
succinate are disclosed in U.S. Pat. No. 6,017,927, International
Patent Publication No. 2005/075474 (WO 2005/075474) and
International Patent Publication No. 2005/105795 (WO
2005/105795).
[0004] U.S. Pat. No. 6,017,927 discloses two synthesis pathways for
preparing solifenacin, synthesis pathway A and synthesis pathway B
represented by Reaction Formula 1 below.
##STR00002##
[0005] In the synthesis pathway A, the transesterification reaction
of a racemic mixture of 1-phenyl-1,2,3,4-tetrahydroisoquinoline
ethyl ester and quinuclidinol was conducted in a toluene suspension
under the presence of sodium hydride (NaH), and the obtained
mixture was refluxed and stirred. In this case, the obtained
diastereomeric mixture was optically separated by high performance
liquid chromatography (HPLC).
[0006] In the synthesis pathway B, quinuclidinyl chloroformate
mono-hydrochloride was reacted with
(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline in the presence of
sodium hydride (NaH) to synthesize solifenacin.
[0007] However, the method of preparing solifenacin using the
synthesis pathway A and synthesis pathway B is problematic in that
it requires high cost, its efficiency is not high due to
post-treatment processes, and it is not suitable for producing
solifenacin on an industrial scale.
[0008] Moreover, ethyl carboxylate used in the synthesis pathway A
produces ethanol as a by-product of a transesterification reaction.
In this case, since ethanol initiates a nucleophilic attack against
solifenacin in the presence of a base, in order to continue the
reaction, there is a problem in that ethanol must be separated from
a reaction system using an azeotrope with toluene or a method
related thereto, which is very industrially difficult. Further, the
synthesis pathway A is also problematic in that it is difficult to
obtain solifenacin having high optical purity because solifenacin
is racemized.
[0009] Further, in the synthesis pathway A and the synthesis
pathway B, the mixture was heated under reflux in order to
accelerate the reaction in the solifenacin synthesis process, and a
very strong base, such as sodium hydride (NaH), was used.
Therefore, there are problems in that it is not easy to control the
reaction and it is difficult to produce solifenacin on an
industrial scale.
[0010] International Patent Publication No. 2005/075474 (WO
2005/075474) discloses another synthesis pathway for preparing
solifenacin and solifenacin succinate, as represented by Reaction
Formula 2 below.
##STR00003##
[0011] However, as mentioned in U.S. Pat. No. 6,017,927, this
synthesis pathway of Reaction Formula 2 is also problematic in that
a reaction is performed using ethylchloroformate in the presence of
a base, and thus ethanol is produced in the second step of the
reaction as a by-product.
[0012] International Patent Publication No. 2005/105795 (WO
2005/105795) discloses another synthesis pathway for preparing
solifenacin, as represented by Reaction Formula 3 below.
##STR00004##
[0013] As shown in Reaction Formula 3 above, solifenacin is
prepared through an intermediate, which is formed from
(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline with a leaving group
(Lv) such as 1H-imidazole-1-yl, 2,5-dioxopyrrolidine-1-yloxy,
3-methyl-1H-imidazol-3-lium-1-yl or chloride and then conducted a
condensation reaction with (R)-quinuclidinol in a mixed solvent of
toluene and dimethylsulfoxide or in a single solvent of toluene by
refluxing and stirring in the presence of sodium hydride (NaH).
[0014] However, this synthesis pathway of Reaction Formula 3 is
also problematic in that it is not easy to control a reaction
process because a strong base such as sodium hydride (NaH) is used,
a purification process using chromatography is required and a
moisture-sensitive leaving group is used.
[0015] Accordingly, in order to solve the above-mentioned problems,
the present inventors have devised a high yield method of preparing
solifenacin or a salt thereof, in which high-purity solifenacin or
a salt thereof can be simply and efficiently prepared at room
temperature without using a base, and which can be industrially
used.
DISCLOSURE OF INVENTION
Technical Problem
[0016] An object of the present invention is to provide a method of
preparing high-purity solifenacin or a salt thereof with high
yield.
[0017] Another object of the present invention is to provide a
method of preparing solifenacin or a salt thereof in large amounts
by a simple process.
[0018] Still another object of the present invention is to provide
a novel intermediate used in the method and a method of preparing
the novel intermediate.
Solution to Problem
[0019] In order to accomplish the above objects, an aspect of the
present invention provides a method of preparing solifenacin or a
salt thereof, comprising the steps of: (a) reacting
(R)-quinuclidinol of Formula (VI) below with
bis(pentafluorophenyl)carbonate of Formula (VII) below in an
organic solvent to prepare (3R)-1-azabicyclo[2,2,2]oct-3-yl
pentafluorophenylcarbonate of Formula (IV) below; and (b) reacting
the (3R)-1-azabicyclo[2,2,2]oct-3-yl pentafluorophenylcarbonate of
Formula (IV) below with
(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline of Formula (V) below
in an organic solvent to prepare solifenacin of Formula (II)
below:
##STR00005##
[0020] Another aspect of the present invention provides a compound
represented by Formula (IV) below, which is used as an intermediate
for preparing solifenacin:
##STR00006##
[0021] Still another aspect of the present invention provides a
method of preparing a compound of Formula (IV) below, comprising
the step of reacting (R)-quinuclidinol of Formula (VI) below with
bis(pentafluorophenyl)carbonate of Formula (VII) below in an
organic solvent.
##STR00007##
Advantageous Effects of Invention
[0022] The present invention can provide a method of preparing high
purity solifenacin or a salt thereof with high yield.
[0023] Further, the present invention can provide a method of
preparing solifenacin or a salt thereof that can produce large
amounts by a simple process.
[0024] Further, the present invention can provide a novel
intermediate and a method of preparing the novel intermediate used
in the process.
BEST MODE FOR CARRYING OUT THE INVENTION
Method of Preparing Solifenacin or a Salt Thereof
[0025] The present invention provides a novel synthesis pathway for
preparing solifenacin or a salt thereof, represented by Reaction
Formula 4 below:
##STR00008##
[0026] As shown in Reaction Formula 4, the method of preparing
solifenacin or a salt thereof according to the present invention
includes the steps of: (a) preparing a solifenacin intermediate;
(b) preparing solifenacin using the intermediate; and (c)
converting the solifenacin into a solifenacin salt.
[0027] Hereinafter, the method of preparing solifenacin or a salt
thereof according to the present invention will be described in
detail with respect to each step.
Step (a): Preparation of Solifenacin Intermediate
[0028] The present invention provides a method of preparing
(3R)-1-azabicyclo[2,2,2]oct-3-yl pentafluorophenylcarbonate of
Formula (IV) below, which can be used as an intermediate for
preparing solifenacin or a salt thereof:
##STR00009##
[0029] The solifenacin intermediate is prepared by reacting
(R)-quinuclidinol of Formula (VI) below with
bis(pentafluorophenyl)carbonate of Formula (VII) below in an
organic solvent, as shown in Reaction Formula 5 below:
##STR00010##
##STR00011##
[0030] The bis(pentafluorophenyl)carbonate of Formula (VII) can be
used at an amount of 1 to 3 molar equivalent per 1 molar equivalent
of (R)-quinuclidinol of Formula (VI), preferably 1 to 1.5 molar
equivalent.
[0031] The organic solvent can be selected from the group including
of toluene, ethyl acetate, dichloromethane, acetone, isopropanol
and mixtures thereof. The organic solvent can be used at an amount
of 2 mL to 20 mL per 1 g of (R)-quinuclidinol of Formula (VI), and
preferably 5 ml to 15 mL.
[0032] The reaction of Reaction Formula 5 above may be performed at
-40.degree. C. to 100.degree. C., and preferably 10.degree. C. to
30.degree. C. Particularly, the reaction of Reaction Formula 5 may
be performed at room temperature, and thus this reaction can be
performed under moderate conditions without conducting an
additional process such as heating, cooling or the like.
[0033] It is preferred that the reaction of Reaction Formula 5 be
performed for 2 hours to 12 hours at the mentioned temperature.
[0034] Further, the reaction of Reaction Formula 5 may be performed
without using any base or catalyst even under the moderate
conditions.
[0035] Further, according to the reaction of Reaction Formula 5,
the solifenacin intermediate of Formula (IV) can be obtained with
high yield of more than 87% under the moderate reaction
conditions.
Step (b): Preparation of Solifenacin
[0036] The present invention provides a method of preparing
solifenacine by reacting the solifenacin intermediate of Formula
(IV) prepared in the step (a) with
(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline of Formula (V) below
in an organic solvent, as shown in Reaction Formula 6 below:
##STR00012##
##STR00013##
[0037] The reaction of Reaction Formula 6 above may be performed by
an in-situ reaction in which the
(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline of Formula (V) is
added dropwise without dissociating the
(3R)-1-azabicyclo[2,2,2]oct-3-yl pentafluorophenylcarbonate of
Formula (IV) prepared in the step (a).
[0038] The (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline of Formula
(V) can be used at an amount of 1 to 3 molar equivalent per 1 molar
equivalent of (3R)-1-azabicyclo[2,2,2]oct-3-yl
pentafluorophenylcarbonate of Formula (IV), preferably 1 to 1.5
molar equivalent.
[0039] The organic solvent, just like in the step (a), may be
selected from the group including of toluene, ethyl acetate,
dichloromethane, acetone, isopropanol and mixtures thereof.
Further, the organic solvent in the step (b) may be same with that
of in the step (a).
[0040] The reaction of Reaction Formula 6 above may be performed at
-40.degree. C. to 100.degree. C., and preferably, 10.degree. C. to
30.degree. C. Particularly, the reaction of Reaction Formula 6 may
be performed at room temperature, and thus this reaction can be
performed under moderate conditions without conducting an
additional process such as heating, cooling or the like.
[0041] It is preferred that the reaction of Reaction Formula 6 be
performed for 2 hours to 12 hours at the mentioned temperature.
[0042] Further, the reaction of Reaction Formula 6 may be performed
without using any base or catalyst even under the moderate
conditions.
[0043] After the reaction of Reaction Formula 6 is completed, the
solifenacin of Formula (II) can be obtained by the following
purification process. Specifically, water is added to the solution
obtained after the completion of the reaction of Reaction Formula
6, a strong acid such as hydrochloric acid is added dropwise into
the solution to adjust the pH of the solution to 1.about.2, an
organic layer is separated from the solution to remove
pentafluorophenol produced during the reaction, a base such as
ammonium hydroxide is further dripped into the solution to adjust
the pH of the solution to 9.about.10, the solution is extracted
with toluene, and then the extracted solution is concentrated,
thereby obtain oily solifenacin.
[0044] Further, according to the reaction of Reaction Formula 6,
the solifenacin of Formula (II) can be obtained with high yield of
more than 87% under the moderate reaction conditions.
Step (c): Preparation of a Salt of Solifenacin
[0045] The present invention provides a method of converting the
solifenacin of Formula (II) prepared in the step (b) into a salt
thereof.
[0046] The salt of solifenacin may be an acid addition salt
prepared by reacting the solifenacin of Formula (II) prepared in
the step (b) with an inorganic or organic acid in an organic
solvent.
[0047] The inorganic acid may be hydrochloric acid, hydrobromic
acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid
or the like. The organic acid may be formic acid, acetic acid,
propionic acid, oxalic acid, malonic acid, succinic acid, fumaric
acid, maleic acid, lactic acid, malic acid, citric acid, tartaric
acid, carbonic acid, picric acid, methanesulfonic acid,
ethanesulfonic acid, glutamic acid or the like. Preferably, the
organic acid may be succinic acid.
[0048] The pathway of preparing solifenacin succinate of Formula
(I), which is an acid addition salt of solefenacin, is represented
by Reaction Formula 7 below:
##STR00014##
[0049] Examples of the organic solvent used in the reaction of
Reaction Formula 7 may include: aliphatic alcohols, such as
ethanol, 1-butanol, isopropanol and the like; ketones, such as
acetone, methyl isobutyl ketone, and the like; esters, such as
ethyl acetate, n-butyl acetate, ethyl propionate, and the like;
aromatic hydrocarbons, such as tolune and the like; and polar
aliphatic hydrocarbons, such as n-hexane, heptane, and the like.
Preferably, acetone, toluene or a mixture thereof may be used as
the organic solvent.
[0050] The reaction of Reaction Formula 7 may be performed by
stirring the reaction mixture at 50.degree. C..about.65.degree. C.
for 20 minutes.about.1 hour and then further stirring the reaction
mixture at 10.degree. C..about.15.degree. C. for 1 hour.about.3
hours.
[0051] When the reaction is completed, the prepared solifenacin is
filtered, washed and then dried to obtain solifenacin
succinate.
[0052] The solifenacin succinate obtained in this way may be
crystalline solifenacin succinate, and this crystalline solifenacin
succinate has a melting point of 146.degree. C..about.148.degree.
C.
[0053] Further, according to the reaction of Reaction Formula 7,
the solifenacin succinate of Formula (I) can be obtained with high
yield of more than 78%.
[0054] Novel Solifenacin Intermediate and Preparation Method
Thereof
[0055] The present invention provides a novel intermediate
represented by Formula (IV) below, which can be used to prepare
solifenacin and a salt thereof, and a method of preparing the
intermediate:
##STR00015##
[0056] The method of preparing a solifenacin intermediate is the
same as the step (a) of the method of preparing solifenacin or a
salt thereof.
[0057] The solifenacin intermediate is a material which can be
simply and efficiently prepared at room temperature without using a
base by the step (a). Further, the solifenacin intermediate is used
as a reactant in the step (b), and can be easily converted into
solifenacin at room temperature without using a base.
[0058] The method of preparing solifenacin or a salt thereof using
a solifenacin intermediate is advantageous in that high-purity
solifenacin or a salt thereof can be prepared with high yield by a
simple process.
[0059] Therefore, the solifenacin intermediate of Formula (IV) can
be used to produce solifenacin or a salt thereof in large
amounts.
Mode for the Invention
[0060] Hereinafter, the present invention will be described in
detail with reference to the following Examples. These Examples are
set forth to illustrate the present invention, and the scope of the
present invention is not limited thereto.
Example 1
Preparation of Solifenacin Intermediate
[0061] 127.2 g (1.0 mol) of (R)-quinuclidinol was dissolved in 1270
mL of toluene and then stirred at 10.about.15.degree. C. for 20
minutes to obtain a reaction solution. Subsequently, 472.9 g (1.2
mol) of bis(pentafluorophenyl)carbonate was added to the reaction
solution to form a suspended reaction solution, and then the
suspended reaction solution was stirred at 10.about.15.degree. C.
for 7.about.8 hours. After confirming the completion of a reaction
using thin layer chromatography (TLC), the reaction solution was
concentrated under reduced pressure. Subsequently, 1270 mL water
was added to the reaction solution, and concentrated hydrochloric
acid was added dropwise into the reaction solution to adjust the pH
of the reaction solution to 1.about.2. Then, the reaction solution
was washed with 1270 mL of toluene to remove pentafluorophenol (a
by-product formed during the reaction) from the reaction product.
Then, an aqueous layer was extracted from the reaction solution
using 1270 mL of dichloromethane, 1270 mL of water was added to the
reaction solution, and then the pH of the reaction solution was
adjusted to 9.about.10 using ammonium hydroxide. Then, an organic
layer was separated from the reaction solution. Finally, the
reaction solution was washed with 1270 mL of water, dried with
MgSO.sub.4 and then concentrated under reduced pressure to obtain
304.9 g (90.4%) of (3R)-1-azabicyclo[2,2,2]oct-3-yl
pentafluorophenylcarbonate.
[0062] .sup.1H NMR (MeOD, 400 MHz): 1.79-1.89 (m, 2H,
--CH--CH.sub.2), 1.97-2.12 (m, 2H, --CH--CH.sub.2), 2.30-2.40 (m,
1H, --O--CH--CH), 3.18-3.30 (m, 6H,
N--CH.sub.2--CH.sub.2,N--CH.sub.2--CH.sub.2,N--CH.sub.2--CH.sub.2),
3.59-3.75 (m, 1H, --O--CH--CH.sub.2)
[0063] Elementary analysis of C.sub.14H.sub.12F.sub.5NO.sub.3
[0064] Theoretical value: C, 49.8; H, 3.6; N, 4.1
[0065] Experimental value: C, 49.1; H, 4.4; N, 3.8
Example 2
Preparation of Solifenacin Intermediate
[0066] 127.2 g (1.0 mol) of (R)-quinuclidinol was dissolved in 1270
mL of dichloromethane and then stirred at 25.about.30.degree. C.
for 20 minutes to obtain a reaction solution. Subsequently, 472.9 g
(1.2 mol) of bis(pentafluorophenyl)carbonate was added to the
reaction solution to form a suspended reaction solution, and then
the suspended reaction solution was stirred at 25.about.30.degree.
C. for 3.about.4 hours. After confirming the completion of a
reaction using thin layer chromatography (TLC), the reaction
solution was concentrated under reduced pressure. Subsequently,
1270 mL water was added to the reaction solution, and concentrated
hydrochloric acid was added dropwise into the reaction solution to
adjust the pH of the reaction solution to 1.about.2. Then, the
reaction solution was washed with 1270 mL of toluene to remove
pentafluorophenol (a by-product formed during the reaction) from
the reaction product. Then, an aqueous layer was extracted from the
reaction solution using 1270 mL of dichloromethane, 1270 mL of
water was added to the reaction solution, and then the pH of the
reaction solution was adjusted to 9.about.10 using ammonium
hydroxide. Then, an organic layer was separated from the reaction
solution. Finally, the reaction solution was washed with 1270 mL of
water, dried with MgSO.sub.4 and then concentrated under reduced
pressure to obtain 300.8 g (89.2%) of
(3R)-1-azabicyclo[2,2,2]oct-3-yl pentafluorophenylcarbonate.
[0067] Here, elementary analysis and spectral data are the same as
those of Example 1.
Example 3
Preparation of Solifenacin Intermediate
[0068] 127.2 g (1.0 mol) of (R)-quinuclidinol was dissolved in 1270
mL of ethyl acetate and then stirred at 25.about.30.degree. C. for
20 minutes to obtain a reaction solution. Subsequently, 472.9 g
(1.2 mol) of bis(pentafluorophenyl)carbonate was added to the
reaction solution to form a suspended reaction solution, and then
the suspended reaction solution was stirred at 25.about.30.degree.
C. for 3.about.4 hours. After confirming the completion of a
reaction using thin layer chromatography (TLC), the reaction
solution was concentrated under reduced pressure. Subsequently,
1270 mL water was added to the reaction solution, and concentrated
hydrochloric acid was added dropwise into the reaction solution to
adjust the pH of the reaction solution to 1.about.2. Then, the
reaction solution was washed with 1270 mL of toluene to remove
pentafluorophenol (a by-product formed during the reaction) from
the reaction product. Then, an aqueous layer was extracted from the
reaction solution using 1270 mL of dichloromethane, 1270 mL of
water was added to the reaction solution, and then the pH of the
reaction solution was adjusted to 9.about.10 using ammonium
hydroxide. Then, an organic layer was separated from the reaction
solution. Finally, the reaction solution was washed with 1270 mL of
water, dried with MgSO.sub.4 and then concentrated under reduced
pressure to obtain 298.1 g (88.4%) of
(3R)-1-azabicyclo[2,2,2]oct-3-yl pentafluorophenylcarbonate.
[0069] Here, elementary analysis and spectral data are the same as
those of Example 1.
Example 4
Preparation of Solifenacin Intermediate
[0070] 127.2 g (1.0 mol) of (R)-quinuclidinol was dissolved in 1270
mL of isopropanol and then stirred at 10.about.15.degree. C. for 20
minutes to obtain a reaction solution. Subsequently, 472.9 g (1.2
mol) of bis(pentafluorophenyl)carbonate was added to the reaction
solution to form a suspended reaction solution, and then the
suspended reaction solution was stirred at 10.about.15.degree. C.
for 10.about.12 hours. After confirming the completion of a
reaction using thin layer chromatography (TLC), the reaction
solution was concentrated under reduced pressure. Subsequently,
1270 mL water was added to the reaction solution, and concentrated
hydrochloric acid was added dropwise into the reaction solution to
adjust the pH of the reaction solution to 1.about.2. Then, the
reaction solution was washed with 1270 mL of toluene to remove
pentafluorophenol (a by-product formed during the reaction) from
the reaction product. Then, an aqueous layer was extracted from the
reaction solution using 1270 mL of dichloromethane, 1270 mL of
water was added to the reaction solution, and then the pH of the
reaction solution was adjusted to 9.about.10 using ammonium
hydroxide. Then, an organic layer was separated from the reaction
solution. Finally, the reaction solution was washed with 1270 mL of
water, dried with MgSO.sub.4 and then concentrated under reduced
pressure to obtain 295.4 g (87.6%) of
(3R)-1-azabicyclo[2,2,2]oct-3-yl pentafluorophenylcarbonate.
[0071] Here, elementary analysis and spectral data are the same as
those of Example 1.
Example 5
Preparation of Solifenacin
[0072] 337.2 g (1.0 mol) of the (3R)-1-azabicyclo[2,2,2]oct-3-yl
pentafluorophenylcarbonate prepared in Example 1 was dissolved in
337 mL of toluene to obtain a reaction solution. Subsequently,
209.3 g (1.0 mol) of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline
was added to the reaction solution, and then stirred at
10.about.15.degree. C. for 9.about.10 hours. After confirming the
completion of a reaction using high performance liquid
chromatography (HPLC), the reaction solution was concentrated under
reduced pressure. Subsequently, 1400 mL water was added to the
reaction solution, and concentrated hydrochloric acid was added
dropwise into the reaction solution to adjust the pH of the
reaction solution to 1.about.2. Then, the reaction solution was
washed with 1400 mL of toluene to remove pentafluorophenol (a
by-product formed during the reaction) from the reaction product.
Then, an aqueous layer was extracted from the reaction solution
using 1400 mL of dichloromethane, and then the reaction solution
was concentrated under reduced pressure. Then, 1270 mL of water was
added to the reaction solution, the pH of the reaction solution was
adjusted to 9.about.10 using ammonium hydroxide, and then an
aqueous layer was further extracted from the reaction solution
using 1270 mL of toluene. Then, an organic layer was separated from
the reaction solution. Finally, the reaction solution was washed
with 1400 mL of water, dried with MgSO.sub.4 and then concentrated
under reduced pressure to obtain 329.8 g (91.0%) of
solifenacin.
[0073] .sup.1H NMR (MeOD, 400 MHz): 1.89-2.21 (m, 4H,
--CH--CH.sub.2,--CH--CH.sub.2), 2.34 (m, 1H, --CH--CH--CH.sub.2),
2.75-3.10 (m, 3H, --N--CH.sub.2--CH.sub.2--CH,
--N--CH.sub.2--CH.sub.2--CH), 3.17-3.40 (m, 5H,
--N--CH.sub.2--CH.sub.2--CH, --N--CH.sub.2--CH.sub.2,
--N--CH.sub.2--CH.sub.2), 3.60-3.63 (m, 2H,
--N--CH.sub.2--CH.sub.2--CH), 3.93 (m, 1H,
--N--CH.sub.2--CH.sub.2--CH), 5.03 (m, 1H, --O--CH--CH), 6.22-6.35
(m, 1H, --N--CH--CH), 7.08-7.28 (m, 9H, aromatic H)
Example 6
Preparation of Solifenacin
[0074] 337.2 g (1.0 mol) of the (3R)-1-azabicyclo[2,2,2]oct-3-yl
pentafluorophenylcarbonate prepared in Example 2 was dissolved in
337 mL of toluene to obtain a reaction solution. Subsequently,
209.3 g (1.0 mol) of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline
was added to the reaction solution, and then stirred at
25.about.30.degree. C. for 4.about.5 hours. After confirming the
completion of a reaction using high performance liquid
chromatography (HPLC), the reaction solution was concentrated under
reduced pressure. Subsequently, 1400 mL water was added to the
reaction solution, and concentrated hydrochloric acid was added
dropwise into the reaction solution to adjust the pH of the
reaction solution to 1.about.2. Then, the reaction solution was
washed with 1400 mL of toluene to remove pentafluorophenol (a
by-product formed during the reaction) from the reaction product.
Then, an aqueous layer was extracted from the reaction solution
using 1400 mL of dichloromethane, and then the reaction solution
was concentrated under reduced pressure. Then, 1270 mL of water was
added to the reaction solution, the pH of the reaction solution was
adjusted to 9.about.10 using ammonium hydroxide, and then an
aqueous layer was further extracted from the reaction solution
using 1270 mL of toluene. Then, an organic layer was separated from
the reaction solution. Finally, the reaction solution was washed
with 1400 mL of water, dried with MgSO.sub.4 and then concentrated
under reduced pressure to obtain 320.4 g (88.4%) of
solifenacin.
[0075] Here, spectral data are the same as those of Example 5.
Example 7
Preparation of Solifenacin
[0076] 337.2 g (1.0 mol) of the (3R)-1-azabicyclo[2,2,2]oct-3-yl
pentafluorophenylcarbonate prepared in Example 1 was dissolved in
337 mL of dichloromethane to obtain a reaction solution.
Subsequently, 209.3 g (1.0 mol) of
(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline was added to the
reaction solution, and then stirred at 25.about.30.degree. C. for
4.about.5 hours. After confirming the completion of a reaction
using high performance liquid chromatography (HPLC), the reaction
solution was concentrated under reduced pressure. Subsequently,
1400 mL water was added to the reaction solution, and concentrated
hydrochloric acid was added dropwise into the reaction solution to
adjust the pH of the reaction solution to 1.about.2. Then, the
reaction solution was washed with 1400 mL of toluene to remove
pentafluorophenol (a by-product formed during the reaction) from
the reaction product. Then, an aqueous layer was extracted from the
reaction solution using 1400 mL of dichloromethane, and then the
reaction solution was concentrated under reduced pressure. Then,
1270 mL of water was added to the reaction solution, the pH of the
reaction solution was adjusted to 9.about.10 using ammonium
hydroxide, and then an aqueous layer was further extracted from the
reaction solution using 1270 mL of toluene. Then, an organic layer
was separated from the reaction solution. Finally, the reaction
solution was washed with 1400 mL of water, dried with MgSO.sub.4
and then concentrated under reduced pressure to obtain 318.2 g
(87.8%) of solifenacin.
[0077] Here, spectral data are the same as those of Example 5.
Example 8
Preparation of Solifenacin
[0078] 337.2 g (1.0 mol) of the (3R)-1-azabicyclo[2,2,2]oct-3-yl
pentafluorophenylcarbonate prepared in Example 1 was dissolved in
337 mL of acetone to obtain a reaction solution. Subsequently,
209.3 g (1.0 mol) of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline
was added to the reaction solution, and then stirred at
25.about.30.degree. C. for 4.about.5 hours. After confirming the
completion of a reaction using high performance liquid
chromatography (HPLC), the reaction solution was concentrated under
reduced pressure. Subsequently, 1400 mL water was added to the
reaction solution, and concentrated hydrochloric acid was added
dropwise into the reaction solution to adjust the pH of the
reaction solution to 1.about.2. Then, the reaction solution was
washed with 1400 mL of toluene to remove pentafluorophenol (a
by-product formed during the reaction) from the reaction product.
Then, an aqueous layer was extracted from the reaction solution
using 1400 mL of dichloromethane, and then the reaction solution
was concentrated under reduced pressure. Then, 1270 mL of water was
added to the reaction solution, the pH of the reaction solution was
adjusted to 9.about.10 using ammonium hydroxide, and then an
aqueous layer was further extracted from the reaction solution
using 1270 mL of toluene. Then, an organic layer was separated from
the reaction solution. Finally, the reaction solution was washed
with 1400 mL of water, dried with MgSO.sub.4 and then concentrated
under reduced pressure to obtain 320.4 g (88.4%) of
solifenacin.
[0079] Here, spectral data are the same as those of Example 5.
Example 9
Preparation of Solifenacin
[0080] 337.2 g (1.0 mol) of the (3R)-1-azabicyclo[2,2,2]oct-3-yl
pentafluorophenylcarbonate prepared in Example 1 was dissolved in
337 mL of isopropanol to obtain a reaction solution. Subsequently,
209.3 g (1.0 mol) of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline
was added to the reaction solution, and then stirred at
10.about.15.degree. C. for 9.about.11 hours. After confirming the
completion of a reaction using high performance liquid
chromatography (HPLC), the reaction solution was concentrated under
reduced pressure. Subsequently, 1400 mL water was added to the
reaction solution, and concentrated hydrochloric acid was added
dropwise into the reaction solution to adjust the pH of the
reaction solution to 1.about.2. Then, the reaction solution was
washed with 1400 mL of toluene to remove pentafluorophenol (a
by-product formed during the reaction) from the reaction product.
Then, an aqueous layer was extracted from the reaction solution
using 1400 mL of dichloromethane, and then the reaction solution
was concentrated under reduced pressure. Then, 1270 mL of water was
added to the reaction solution, the pH of the reaction solution was
adjusted to 9.about.10 using ammonium hydroxide, and then an
aqueous layer was further extracted from the reaction solution
using 1270 mL of toluene. Then, an organic layer was separated from
the reaction solution. Finally, the reaction solution was washed
with 1400 mL of water, dried with MgSO.sub.4 and then concentrated
under reduced pressure to obtain 326.9 g (90.2%) of
solifenacin.
[0081] Here, spectral data are the same as those of Example 5.
Example 10
Preparation of Solifenacin
[0082] 337.2 g (1.0 mol) of the (3R)-1-azabicyclo[2,2,2]oct-3-yl
pentafluorophenylcarbonate prepared in Example 1 was dissolved in
337 mL of ethyl acetate to obtain a reaction solution.
Subsequently, 209.3 g (1.0 mol) of
(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline was added to the
reaction solution, and then stirred at 25.about.30.degree. C. for
4.about.5 hours. After confirming the completion of a reaction
using high performance liquid chromatography (HPLC), the reaction
solution was concentrated under reduced pressure. Subsequently,
1400 mL water was added to the reaction solution, and concentrated
hydrochloric acid was added dropwise into the reaction solution to
adjust the pH of the reaction solution to 1.about.2. Then, the
reaction solution was washed with 1400 mL of toluene to remove
pentafluorophenol (a by-product formed during the reaction) from
the reaction product. Then, an aqueous layer was extracted from the
reaction solution using 1400 mL of dichloromethane, and then the
reaction solution was concentrated under reduced pressure. Then,
1270 mL of water was added to the reaction solution, the pH of the
reaction solution was adjusted to 9.about.10 using ammonium
hydroxide, and then an aqueous layer was further extracted from the
reaction solution using 1270 mL of toluene. Then, an organic layer
was separated from the reaction solution. Finally, the reaction
solution was washed with 1400 mL of water, dried with MgSO.sub.4
and then concentrated under reduced pressure to obtain 220.4 g
(88.4%) of solifenacin.
[0083] Here, spectral data are the same as those of Example 5
Example 11
Preparation of Solifenacin Succinate
[0084] 127.2 g (1.0 mol) of (R)-quinuclidinol was dissolved in 1270
mL of toluene and then stirred at 25.about.30.degree. C. for 20
minutes to obtain a reaction solution. Subsequently, 472.9 g (1.2
mol) of bis(pentafluorophenyl)carbonate was added to the reaction
solution to form a suspended reaction solution, and then the
suspended reaction solution was stirred at 25.about.30.degree. C.
for 3.about.4 hours. After confirming the completion of a reaction
using thin layer chromatography (TLC), 209.3 g (1.0 mol) of
(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline was added to the
reaction solution, and then stirred at 25.about.30.degree. C. for
4.about.5 hours. After confirming the completion of a reaction
using high performance liquid chromatography (HPLC), the reaction
solution was concentrated under reduced pressure. Subsequently,
1270 mL water was added to the reaction solution, and concentrated
hydrochloric acid was added dropwise into the reaction solution to
adjust the pH of the reaction solution to 1.about.2. Then, the
reaction solution was washed with 1270 mL of toluene to remove
pentafluorophenol (a by-product formed during the reaction) from
the reaction product. Then, an aqueous layer was extracted from the
reaction solution using 1270 mL of dichloromethane, and then the
reaction solution was concentrated under reduced pressure. Then,
1270 mL of water was added to the reaction solution, the pH of the
reaction solution was adjusted to 9.about.10 using ammonium
hydroxide, and then an aqueous layer was further extracted from the
reaction solution using 1270 mL of toluene. Subsequently, 1270 mL
of acetone and 118.1 g (1.0 mol) of succinic acid were added to the
reaction solution, stirred at 55.about.60.degree. C. for 30
minutes, further stirred at 10.about.15.degree. C. for 2 hours, and
then filtered to obtain a reaction product. Finally, the reaction
product was washed with 640 mL of toluene and 640 mL of acetone,
and then dried in vacuum at 40.degree. C. to obtain 390.2 g (81.2%)
of solifenacin succinate.
[0085] HPLC content: 99.9%, optical purity: 99.95%
[0086] Melting point: 146.about.148.degree. C.
[0087] .sup.1H NMR (MeOD, 400 MHz): 1.89-2.21 (m, 4H,
--CH--CH.sub.2, --CH--CH.sub.2), 2.34 (m, 1H, --CH--CH--CH.sub.2),
2.49 (s, 4H, --O--CO--CH.sub.2--CH.sub.2--), 2.75-3.10 (m, 3H,
--N--CH.sub.2--CH.sub.2--CH, --N--CH.sub.2--CH.sub.2--CH),
3.17-3.40 (m, 5H, --N--CH.sub.2--CH.sub.2--CH.sub.2,
--N--CH.sub.2--CH.sub.2, --N--CH.sub.2--CH.sub.2), 3.60-3.63 (m,
2H, --N--CH.sub.2--CH.sub.2--CH), 3.93 (m, 1H,
--N--CH.sub.2--CH.sub.2--CH), 5.03 (m, 1H, --O--CH--CH), 6.22-6.35
(m, 1H, --N--CH--CH), 7.08-7.28 (m, 9H, aromatic H)
[0088] Elementary analysis of C.sub.27H.sub.32N.sub.2O.sub.6
[0089] Theoretical value: C, 67.4; H, 6.7; N, 5.8
[0090] Experimental value: C, 66.7; H, 6.7; N, 5.8
Example 12
Preparation of Solifenacin Succinate
[0091] 127.2 g (1.0 mol) of (R)-quinuclidinol was dissolved in 1270
mL of dichloromethane and then stirred at 25.about.30.degree. C.
for 20 minutes to obtain a reaction solution. Subsequently, 472.9 g
(1.2 mol) of bis(pentafluorophenyl)carbonate was added to the
reaction solution to form a suspended reaction solution, and then
the suspended reaction solution was stirred at 25.about.30.degree.
C. for 3.about.4 hours. After confirming the completion of a
reaction using thin layer chromatography (TLC), 209.3 g (1.0 mol)
of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline was added to the
reaction solution, and then stirred at 25.about.30.degree. C. for
4.about.5 hours. After confirming the completion of a reaction
using high performance liquid chromatography (HPLC), the reaction
solution was concentrated under reduced pressure. Subsequently,
1270 mL water was added to the reaction solution, and concentrated
hydrochloric acid was added dropwise into the reaction solution to
adjust the pH of the reaction solution to 1.about.2. Then, the
reaction solution was washed with 1270 mL of toluene to remove
pentafluorophenol (a by-product formed during the reaction) from
the reaction product. Then, an aqueous layer was extracted from the
reaction solution using 1270 mL of dichloromethane, and then the
reaction solution was concentrated under reduced pressure. Then,
1270 mL of water was added to the reaction solution, the pH of the
reaction solution was adjusted to 9.about.10 using ammonium
hydroxide, and then an aqueous layer was further extracted from the
reaction solution using 1270 mL of toluene. Subsequently, 1270 mL
of acetone and 118.1 g (1.0 mol) of succinic acid were added to the
reaction solution, stirred at 55.about.60.degree. C. for 30
minutes, further stirred at 10.about.15.degree. C. for 2 hours, and
then filtered to obtain a reaction product. Finally, the reaction
product was washed with 640 mL of toluene and 640 mL of acetone,
and then dried in vacuum at 40.degree. C. to obtain 381.5 g (79.4%)
of solifenacin succinate.
[0092] HPLC content: 99.9%,
[0093] Optical purity: 99.95%
[0094] Here, melting point, elementary analysis and spectral data
are the same as those of Example 11.
Example 13
Preparation of Solifenacin Succinate
[0095] 127.2 g (1.0 mol) of (R)-quinuclidinol was dissolved in 1270
mL of dichloromethane and then stirred at 25.about.30.degree. C.
for 20 minutes to obtain a reaction solution. Subsequently, 472.9 g
(1.2 mol) of bis(pentafluorophenyl)carbonate was added to the
reaction solution to form a suspended reaction solution, and then
the suspended reaction solution was stirred at 25.about.30.degree.
C. for 3.about.4 hours. After confirming the completion of a
reaction using thin layer chromatography (TLC), the reaction
solution was concentrated under reduced pressure.
[0096] Subsequently, oily matter obtained by adding 1270 mL of
acetone to the reaction solution was dissolved, and then 209.3 g
(1.0 mol) of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline was added
to the reaction solution and stirred at 25.about.30.degree. C. for
4.about.5 hours. After confirming the completion of a reaction
using high performance liquid chromatography (HPLC), the reaction
solution was concentrated under reduced pressure. Subsequently,
1270 mL water was added to the reaction solution, and concentrated
hydrochloric acid was added dropwise into the reaction solution to
adjust the pH of the reaction solution to 1.about.2. Then, the
reaction solution was washed with 1270 mL of toluene to remove
pentafluorophenol (a by-product formed during the reaction) from
the reaction product. Then, an aqueous layer was extracted from the
reaction solution using 1270 mL of dichloromethane, and then the
reaction solution was concentrated under reduced pressure. Then,
1270 mL of water was added to the reaction solution, the pH of the
reaction solution was adjusted to 9.about.10 using ammonium
hydroxide, and then an aqueous layer was further extracted from the
reaction solution using 1270 mL of toluene. Subsequently, 1270 mL
of acetone and 118.1 g (1.0 mol) of succinic acid were added to the
reaction solution, stirred at 55.about.60.degree. C. for 30
minutes, further stirred at 10.about.15.degree. C. for 2 hours, and
then filtered to obtain a reaction product. Finally, the reaction
product was washed with 640 mL of toluene and 640 mL of acetone,
and then dried in vacuum at 40.degree. C. to obtain 377.2 g (78.5%)
of solifenacin succinate.
[0097] HPLC content: 99.9%,
[0098] Optical purity: 99.95%
[0099] Here, melting point, elementary analysis and spectral data
are the same as those of Example 11.
Example 14
Preparation of Solifenacin Succinate
[0100] 127.2 g (1.0 mol) of (R)-quinuclidinol was dissolved in 1270
mL of dichloromethane and then stirred at 25.about.30.degree. C.
for 20 minutes to obtain a reaction solution. Subsequently, 472.9 g
(1.2 mol) of bis(pentafluorophenyl)carbonate was added to the
reaction solution to form a suspended reaction solution, and then
the suspended reaction solution was stirred at 25.about.30.degree.
C. for 3.about.4 hours. After confirming the completion of a
reaction using thin layer chromatography (TLC), the reaction
solution was concentrated under reduced pressure. Subsequently,
oily matter obtained by adding 1270 mL of isopropanol to the
reaction solution was dissolved, and then 209.3 g (1.0 mol) of
(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline was added to the
reaction solution and stirred at 25.about.30.degree. C. for
4.about.5 hours. After confirming the completion of a reaction
using high performance liquid chromatography (HPLC), the reaction
solution was concentrated under reduced pressure. Subsequently,
1270 mL water was added to the reaction solution, and concentrated
hydrochloric acid was added dropwise into the reaction solution to
adjust the pH of the reaction solution to 1.about.2. Then, the
reaction solution was washed with 1270 mL of toluene to remove
pentafluorophenol (a by-product formed during the reaction) from
the reaction product. Then, an aqueous layer was extracted from the
reaction solution using 1270 mL of dichloromethane, and then the
reaction solution was concentrated under reduced pressure. Then,
1270 mL of water was added to the reaction solution, the pH of the
reaction solution was adjusted to 9.about.10 using ammonium
hydroxide, and then an aqueous layer was further extracted from the
reaction solution using 1270 mL of toluene. Subsequently, 1270 mL
of acetone and 118.1 g (1.0 mol) of succinic acid were added to the
reaction solution, stirred at 55.about.60.degree. C. for 30
minutes, further stirred at 10.about.15.degree. C. for 2 hours, and
then filtered to obtain a reaction product. Finally, the reaction
product was washed with 640 mL of toluene and 640 mL of acetone,
and then dried in vacuum at 40.degree. C. to obtain 386.4 g (80.4%)
of solifenacin succinate.
[0101] HPLC content: 99.9%,
[0102] Optical purity: 99.95%
[0103] Here, melting point, elementary analysis and spectral data
are the same as those of Example 11.
Example 15
Preparation of Solifenacin Succinate
[0104] 127.2 g (1.0 mol) of (R)-quinuclidinol was dissolved in 1270
mL of dichloromethane and then stirred at 25.about.30.degree. C.
for 20 minutes to obtain a reaction solution. Subsequently, 472.9 g
(1.2 mol) of bis(pentafluorophenyl)carbonate was added to the
reaction solution to form a suspended reaction solution, and then
the suspended reaction solution was stirred at 25.about.30.degree.
C. for 3.about.4 hours. After confirming the completion of a
reaction using thin layer chromatography (TLC), the reaction
solution was concentrated under reduced pressure. Subsequently,
oily matter obtained by adding 1270 mL of ethyl acetate to the
reaction solution was dissolved, and then 209.3 g (1.0 mol) of
(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline was added to the
reaction solution and stirred at 25.about.30.degree. C. for
4.about.5 hours. After confirming the completion of a reaction
using high performance liquid chromatography (HPLC), the reaction
solution was concentrated under reduced pressure. Subsequently,
1270 mL water was added to the reaction solution, and concentrated
hydrochloric acid was added dropwise into the reaction solution to
adjust the pH of the reaction solution to 1.about.2. Then, the
reaction solution was washed with 1270 mL of toluene to remove
pentafluorophenol (a by-product formed during the reaction) from
the reaction product. Then, an aqueous layer was extracted from the
reaction solution using 1270 mL of dichloromethane, and then the
reaction solution was concentrated under reduced pressure. Then,
1270 mL of water was added to the reaction solution, the pH of the
reaction solution was adjusted to 9.about.10 using ammonium
hydroxide, and then an aqueous layer was further extracted from the
reaction solution using 1270 mL of toluene. Subsequently, 1270 mL
of acetone and 118.1 g (1.0 mol) of succinic acid were added to the
reaction solution, stirred at 55.about.60.degree. C. for 30
minutes, further stirred at 10.about.15.degree. C. for 2 hours, and
then filtered to obtain a reaction product. Finally, the reaction
product was washed with 640 mL of toluene and 640 mL of acetone,
and then dried in vacuum at 40.degree. C. to obtain 384.9 g (80.1%)
of solifenacin succinate.
[0105] HPLC content: 99.9%,
[0106] Optical purity: 99.95%
[0107] Here, melting point, elementary analysis and spectral data
are the same as those of Example 11.
[0108] Although the preferred embodiments of the present invention
have been disclosed for illustrative purposes, those skilled in the
art will appreciate that various modifications, additions and
substitutions are possible, without departing from the scope and
spirit of the invention as disclosed in the accompanying
claims.
* * * * *