U.S. patent application number 10/867350 was filed with the patent office on 2004-11-18 for production method of citalopram, intermediate therefor and production method of the intermediate.
This patent application is currently assigned to Sumika Fine Chemicals Co., Ltd.. Invention is credited to Gao, Wei-Guo, Igi, Masami, Ikemoto, Tetsuya.
Application Number | 20040230066 10/867350 |
Document ID | / |
Family ID | 26585589 |
Filed Date | 2004-11-18 |
United States Patent
Application |
20040230066 |
Kind Code |
A1 |
Ikemoto, Tetsuya ; et
al. |
November 18, 2004 |
Production method of citalopram, intermediate therefor and
production method of the intermediate
Abstract
Citalopram can be industrially and economically produced and at
a high yield by reacting a compound of the following formula [VI]
with 3-(dimethylamino)propyl chloride in the presence of at least
one of N,N,N',N'-tetramethylethylenediamine and
1,3-dimethyl-2-imidazolidinone and a condensing agent. The compound
of the following formula [III], which is a key compound for the
production of citalopram, can be easily produced by subjecting the
compound of the following formula [II] to reduction and
cyclization. 1
Inventors: |
Ikemoto, Tetsuya;
(Osaka-shi, JP) ; Gao, Wei-Guo; (Osaka-shi,
JP) ; Igi, Masami; (Osaka-shi, JP) |
Correspondence
Address: |
LEYDIG VOIT & MAYER, LTD
TWO PRUDENTIAL PLAZA, SUITE 4900
180 NORTH STETSON AVENUE
CHICAGO
IL
60601-6780
US
|
Assignee: |
Sumika Fine Chemicals Co.,
Ltd.
1-21, Utajima 3-chome, Nishiyodogawa-ku
Osaka-shi
JP
555-0021
|
Family ID: |
26585589 |
Appl. No.: |
10/867350 |
Filed: |
June 14, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10867350 |
Jun 14, 2004 |
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10086076 |
Feb 28, 2002 |
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10086076 |
Feb 28, 2002 |
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09654768 |
Sep 5, 2000 |
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6433196 |
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Current U.S.
Class: |
549/479 ;
562/412; 568/809 |
Current CPC
Class: |
C07C 51/265 20130101;
C07C 33/46 20130101; C07C 51/373 20130101; C07D 307/87 20130101;
C07C 29/40 20130101; C07C 33/46 20130101; C07C 51/265 20130101;
C07C 65/34 20130101; C07C 65/34 20130101; C07C 29/40 20130101; C07C
51/373 20130101 |
Class at
Publication: |
549/479 ;
562/412; 568/809 |
International
Class: |
C07C 051/16; C07D
307/02; C07C 033/36 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 17, 2000 |
JP |
39936/2000 |
Mar 9, 2000 |
JP |
65527/2000 |
Claims
1. A compound of the formula [I] 11
2. A production method of a compound of the formula [I] 12which
comprises converting 4-bromofluorobenzene to
4-fluorophenylmagnesium bromide, and reacting the
4-fluorophenylmagnesium bromide with 2,4-dimethylbenzaldehyd-
e.
3. A production method of a compound of the formula [II] 13which
comprises oxidizing a compound of the formula [I] 14
4. A production method of 1,3-dimethyl-4-(4'-fluorobenzoyl)benzene,
which comprises subjecting m-xylene as a starting material and
solvent to Friedel-Crafts reaction with 4-fluorobenzoyl halide.
5. A production method of a compound of the formula [II] 15which
comprises subjecting m-xylene as a starting material and solvent to
Friedel-Crafts reaction with 4-fluorobenzoyl halide to give
1,3-dimethyl-4-(4'-fluoroben- zoyl)benzene and oxidizing said
1,3-dimethyl-4-(4'-fluorobenzoyl)benzene.
6. A production method of a compound of the formula [II] 16which
comprises subjecting 2,4-dimethylbenzoyl halide to Friedel-Crafts
reaction with fluorobenzene to give
1,3-dimethyl-4-(4'-fluorobenzoyl)benzene and oxidizing said
1,3-dimethyl-4-(4'-fluorobenzoyl)benzene.
7. A production method of a compound of the formula [II] 17which
comprises subjecting trimellitic anhydride to Friedel-Crafts
reaction with fluorobenzene in a dichloro-substituted or
trichloro-substituted benzene solvent.
8.-20. (Canceled)
Description
TECHNICAL FIELD OF THE INVENTION
[0001] The present invention relates to a production method of
citalopram useful as an antidepressant, a synthetic intermediate
therefor and a production method of the intermediate.
BACKGROUND OF THE INVENTION
[0002] Citalopram having the formula [A] 2
[0003] is useful as an antidepressant. As a production method of
citalopram, there is known a method comprising the use of a
5-phthalancarbonitrile compound of the formula [VI] 3
[0004] hereinafter to be also referred to as compound [VI]. For
example, compound [VI] is reacted with 3-(dimethylamino)propyl
halide in the presence of a condensing agent (JP-B-61-35986). In
this publication, sodium hydride is used as a condensing agent.
According to this method, citalopram is obtained at a low yield,
and therefore, this method is not necessarily a preferable one.
Moreover, this publication does not teach how to increase the
yield, not to mention the use of a different additive besides the
condensing agent to improve the yield.
[0005] As a different production method of citalopram, there is
reported reaction of compound [VI] with 3-(dimethylamino)propyl
halide under basic conditions (WO98/19511). In this publication,
lithium diisopropylamide obtained from n-butyllithium and
diisopropylamine is used as a base. While the yield is improved,
expensive n-butyllithium is necessary and a reaction at a very low
temperature (Example, from -50.degree. C. to -40.degree. C.) is
required, which makes the method industrially unpreferable. This
publication does not teach an economical base that permits reaction
in a typical temperature range, or industrial and economical
production of citalopram at a high yield under basic conditions
wherein specific bases are combined.
[0006] It is therefore an object of the present invention to
provide an economical and industrially advantageous production
method of citalopram, which affords production of citalopram at
high yields.
[0007] Another object of the present invention is to provide a
novel production method of a compound represented by the
formula
[0008] to be mentioned later.
SUMMARY OF THE INVENTION
[0009] For this purpose, the method described in JP-B-61-35986
utilizing a condensing agent has been improved. According to the
present invention, a method comprising adding, besides a condensing
agent, at least one of N,N,N',N'-tetramethylethylenediamine and
1,3-dimethyl-2-imidazolidinone is suggested.
[0010] The present inventors have already reported (JP application
No. 11-311703) a method based on a completely new strategy for the
safe production of a 5-phthalancarbonitrile compound, which method
imposes a small environmental burden and utilizes a compound of the
formula [III] 4
[0011] also referred to as compound [III]. They have now found that
the compound [III], a key compound in this production method, can
be produced easily from a compound of the formula [II] 5
[0012] also referred to as compound [II], as a starting material.
They have also found that compound [II] can be produced safely and
with less burden on the environment by the independent use of
1,3-dimethyl-4-(4'-fluorobenzoyl)benzene (hereinafter to be also
referred to as compound [I']), trimellitic anhydride or a novel
compound of the formula [I] 6
[0013] hereinafter to be referred to as compound [I], as the
starting material. In addition, the present invention provides
novel production methods of these starting materials.
[0014] Accordingly, the present invention relates to the following
reactions.
[0015] Conversion of 4-bromofluorobenzene to
4-fluorophenylmagnesium bromide, and reaction thereof with
2,4-dimethylbenzaldehyde to give compound [I].
[0016] Friedel-Crafts reaction of 4-fluorobenzoyl halide using
m-xylene as a starting material and solvent to give compound
[I'].
[0017] The following respective reactions (1) to (4) to give
compound [II].
[0018] (1) Oxidation of compound [I].
[0019] (2) Friedel-Crafts reaction of 4-fluorobenzoyl halide using
m-xylene as a starting material and solvent to give compound [I'],
which is then subjected to oxidation.
[0020] (3) Friedel-Crafts reaction of 2,4-dimethylbenzoyl halide
with fluorobenzene to give compound [I'], which is then subjected
to oxidation.
[0021] (4) Friedel-Crafts reaction of trimellitic anhydride with
fluorobenzene in a dichloro-substituted or trichloro-substituted
benzene solvent.
[0022] The following respective reactions (1) and (2) to give
compound [III].
[0023] (1) Reduction and cyclization of compound [II].
[0024] (2) Friedel-Crafts reaction of trimellitic anhydride with
fluorobenzene to give a mixture of compound [II], an isomer
thereof, and a compound of the formula [IV] 7
[0025] hereinafter to be also referred to as compound [IV], which
mixture is then subjected to reduction and cyclization, and then
isolation.
[0026] Oxidation of compound [III] using manganese dioxide to give
a compound of the formula [V] 8
[0027] hereinafter to be also referred to as compound [V].
[0028] A reaction of compound [VI] with 3-(dimethylamino)propyl
chloride in the presence of at least one of
N,N,N',N'-tetramethylethylenediamine and
1,3-dimethyl-2-imidazolidinone and a condensing agent to give
citalopram.
DETAILED DESCRIPTION OF THE INVENTION
[0029] The present invention is explained in detail in the
following. In the present invention, by the reaction time is meant
the period of time from the addition of all the reagents necessary
for the reaction to the completion of the reaction.
Production Method of Compound [I]
[0030] The compound [I] is novel and can be produced by, for
example, a Grignard reaction of 2,4-dimethylbenzaldehyde with a
Grignard reagent of 4-bromofluorobenzene. To be specific, a
Grignard reagent of 4-bromofluorobenzene is prepared in a reaction
solvent, to which is added, preferably by dropwise addition,
2,4-dimethylbenzaldehyde to give compound [I]. The order of
addition of the reaction reagents is subject to no particular
limitation.
[0031] Production of the Grignard reagent of 4-bromofluorobenzene
follows a conventional method, which includes, for example,
dispersing metal magnesium in an organic solvent and dropwise
addition of 4-bromofluorobenzene thereto generally at a temperature
of from -30.degree. C. to 100.degree. C., preferably 15.degree.
C.-70.degree. C. The amount of the metal magnesium to be used is
that necessary for conversion of 4-bromofluorobenzene to a Grignard
reagent, which is, for example, generally 0.9 mol-2 mol, preferably
0.95 mol-1.3 mol, per 1 mol of 4-bromofluorobenzene.
[0032] 2,4-Dimethylbenzaldehyde is used in an amount of generally
0.5 mol-2 mol, preferably 0.8 mol-1.2 mol, per 1 mol of
4-bromofluorobenzene.
[0033] The reaction solvent in this reaction is subject to no
particular limitation as long as it does not interfere with the
Grignard reaction. A solvent which can be used for the preparation
of a Grignard reagent can be applied to the Grignard reaction
without isolation after preparation of the Grignard reagent,
thereby preferably making the reaction step simple. Preferable
solvent may be, for example, ether solvent (e.g., diethyl ether,
diisopropyl ether, dibutyl ether, dipentyl ether, dihexyl ether,
t-butyl methyl ether, ethylene glycol dimethyl ether, diethylene
glycol dimethyl ether, triethylene glycol dimethyl ether,
tetraethylene glycol dimethyl ether, tetrahydrofuran (THF),
1,4-dioxane, 1,3-dioxolan etc.) and the like, with more preference
given to THF, diethyl ether, ethylene glycol dimethyl ether and
diethylene glycol dimethyl ether. The amount of the reaction
solvent to be used in this reaction is generally 1 L-30 L,
preferably 2 L-20 L, per 1 kg of 4-bromofluorobenzene.
[0034] The temperature of this reaction is generally from
-30.degree. C. to 100.degree. C., preferably from -10.degree. C. to
50.degree. C., and the reaction time is generally 5 min-6 hr,
preferably 10 min-3 hr.
[0035] After inactivation of the Grignard reagent by the addition
of water etc. to the reaction mixture, compound [I] can be isolated
by a conventional method (e.g., extraction). After the isolation,
it can be purified by a conventional method. Alternatively, it can
be used in the next reaction without purification.
[0036] The compound [I] of the present invention may be present as
an optically active compound or racemate due to an asymmetric
carbon to which hydroxyl group is bonded. The racemate can be
resolved into each optically active compound by a known method
production method of compound [I'] using m-xylene as starting
material
[0037] Method 1 (m-xylene as a starting material and solvent)
[0038] As taught in U.S. Pat. No. 3,835,167, compound [I'] can be
produced by Friedel-Crafts reaction of m-xylene with
4-fluorobenzoyl chloride. In this publication, dichloromethane is
used as a solvent, which is unpreferable from the aspect of the
influence on the environment. According to the present invention, a
production method of compound [I'] at a high yield, which comprises
the use of m-xylene as a starting material and solvent, is
provided. That is, 4-fluorobenzoyl halide is subjected to
Friedel-Crafts reaction using m-xylene as a starting material and
solvent to give compound [I'] at a high yield, which route is
desirable for the environment.
[0039] To be specific, Lewis acid or Bronsted acid is dispersed in
m-xylene, and 4-fluorobenzoyl halide is added, preferably by
dropwise addition, or Lewis acid or Bronsted acid is added,
preferably by dropwise addition, to a solution of 4-fluorobenzoyl
halide in m-xylene to give compound [I'] at a high yield.
[0040] The halide moiety of 4-fluorobenzoyl halide in Method 1 is
subject to no particular limitation, and is exemplified by fluorine
atom, chlorine atom, bromine atom and iodine atom, with preference
given to chlorine atom.
[0041] In Method 1, the amount of m-xylene used as a starting
material and solvent is generally 3 L-30 L, preferably 5 L-15 L,
per 1 kg of 4-fluorobenzoyl halide.
[0042] The Lewis acid used in Method 1 is subject to no particular
limitation as long as it is generally used for Friedel-Crafts
reaction, and is exemplified by aluminum chloride, aluminum
bromide, zinc fluoride, zinc chloride, zinc bromide, zinc iodide,
boron trifluoride, boron trichloride, silicon tetrachloride,
titanium tetrachloride and the like, with particular preference
given to aluminum chloride in view of the quick reaction it
affords. The amount of Lewis acid to be used is generally 2 mol-6
mol, preferably 3 mol-4 mol, per 1 mol of 4-fluorobenzoyl
halide.
[0043] The Bronsted acid used in Method 1 is subject to no
particular limitation as long as it is generally used for
Friedel-Crafts reaction, and is exemplified by hydrogen fluoride,
sulfuric acid, polyphosphoric acid, trifluoromethanesulfonic acid
and the like, with preference given to trifluoromethanesulfonic
acid. The amount of the Bronsted acid to be used is generally
0.0001 mol-1 mol, preferably 0.01 mol-0.2 mol, per 1 mol of
4-fluorobenzoyl halide.
[0044] In Method 1, the reaction temperature is generally from
-20.degree. C. to 120.degree. C., preferably 10.degree.
C.-50.degree. C., and the reaction time is generally 0.5 hr-15 hr,
preferably 2 hr-8 hr.
[0045] The compound [I'] can be isolated and purified by a
conventional method. For example, the reaction mixture is poured
into hydrochloric acid and the organic layer obtained by separation
is washed with water or aqueous alkali solution. The solvent is
evaporated to isolate compound [I']. The isolated product can be
further purified by a conventional method, or may be used in the
next reaction without purification. By this method, an isomer of
compound [I'], 1,4-dimethyl-2-(4'-fluorobenzoyl)benz- ene, is
concurrently obtained, but can be easily separated by a
conventional method such as recrystallization. The compound [I']
may be subjected to the next reaction without separation of the
isomer.
[0046] Method 2 (Friedel-Crafts reaction of 2,4-dimethylbenzoyl
halide with fluorobenzene)
[0047] The compound [I'] can be also produced by Friedel-Crafts
reaction of 2,4-dimethylbenzoyl halide with fluorobenzene in a
reaction solvent. The reaction solvent may be fluorobenzene (Method
2-1) or a solvent generally used for Friedel-Crafts reaction
(Method 2-2). Specifically, in the case of Method 2-1, Lewis acid
or Bronsted acid is dispersed in fluorobenzene and
2,4-dimethylbenzoyl halide is added, preferably added dropwise, or
Lewis acid or Bronsted acid is added to a mixture of fluorobenzene
and 2,4-dimethylbenzoyl halide, and in the case of Method 2-2,
fluorobenzene is diluted in a solvent generally used for
Friedel-Crafts reaction, Lewis acid or Bronsted acid is dispersed
in this solution, and 2,4-dimethylbenzoyl halide is added,
preferably added dropwise, or fluorobenzene and 2,4-dimethylbenzoyl
halide are added to a solvent generally used for Friedel-Crafts
reaction for dissolution and Lewis acid or Bronsted acid is added,
to give compound [I'] at a high yield.
[0048] The amount of fluorobenzene to be used in Method 2-1 is
generally 2 L-20 L, preferably 4 L-10 L, per 1 kg of
2,4-dimethylbenzoyl halide.
[0049] The amount of fluorobenzene to be used in Method 2-2 is
generally 1 mol-5 mol, preferably 1 mol-3 mol, per 1 mol of
2,4-dimethylbenzoyl halide.
[0050] The solvent generally used for Friedel-Crafts reaction in
Method 2-2 is exemplified by methylene chloride,
1,2-dichloroethane, nitrobenzene, carbon disulfide and the like,
with preference given to dichloro-substituted benzene and
trichloro-substituted benzene from the aspect of the environment,
with particular preference given to 1,2-dichlorobenzene. The amount
of the reaction solvent to be used is generally 1 L-20 L,
preferably 5 L-15 L, per 1 kg of 2,4-dimethylbenzoyl halide.
[0051] The Lewis acid to be used in Method 2-1 and Method 2-2 is
subject to no particular limitation as long as it is generally used
for Friedel-Crafts reaction, and is exemplified by aluminum
chloride, aluminum bromide, zinc fluoride, zinc chloride, zinc
bromide, zinc iodide, boron trifluoride, boron trichloride, silicon
tetrachloride, titanium tetrachloride and the like, with preference
given to aluminum chloride in view of the quick reaction it
provides. The amount of the Lewis acid to be used is generally 0.8
mol-3 mol, preferably 1 mol-1.5 mol, per 1 mol of
2,4-dimethylbenzoyl halide.
[0052] The Bronsted acid used in Method 2-1 and Method 2-2 is
subject to no particular limitation as long as it is generally used
for Friedel-Crafts reaction, and is exemplified by hydrogen
fluoride, sulfuric acid, polyphosphoric acid,
trifluoromethanesulfonic acid and the like, with preference given
to trifluoromethanesulfonic acid. The amount of the Bronsted acid
to be used is generally 0.0001 mol-1 mol, preferably 0.01 mol-0.5
mol, per 1 mol of 2,4-dimethylbenzoyl halide.
[0053] In Method 2-1 and Method 2-2, the reaction temperature is
generally from -20.degree. C. to 100.degree. C., preferably
0.degree. C-90.degree. C., and the reaction time is generally 0.5
hr-10 hr, preferably 1 hr-4 hr.
[0054] The compound [I'] can be isolated and purified by a
conventional method. For example, the reaction mixture is poured
into hydrochloric acid and the organic layer obtained by separation
is washed with water or aqueous alkali solution. The solvent is
evaporated to isolate compound [I'].
Production Method of Compound [II]
[0055] Method A (production method of compound [II] from compound
[I] as starting material)
[0056] The compound [II] can be obtained by oxidation of novel
compound [I]. The oxidation of compound [I] is performed using, for
example, an oxidizing agent. To be specific, a solution of compound
[I] and a solution or dispersion of the oxidizing agent are mixed
and stirred to give compound [II]. The solvent for these solution
and dispersion is exemplified by the following reaction
solvents.
[0057] As regards Method A, the oxidizing agent is subject to no
particular limitation as long as it allows oxidation of methyl and
hydroxyl into carboxyl and carbonyl, respectively. Examples of the
oxidizing agent include permanganate, dichromate and the like.
Considering the influence on the environment and toxicity,
permanganate (e.g., potassium permanganate and the like) is
preferable. While permanganate used for oxidation reaction causes
side production of manganese dioxide, manganese dioxide can be used
as an oxidizing agent for synthesis of compound [V] from compound
[III] to be mentioned later. Therefore, manganese dioxide is
preferably used because it does not need to be wasted and can
reduce the production cost. The amount of the oxidizing agent to be
used in Method A is generally 3 mol-15 mol, preferably 4.6 mol-10
mol, more preferably 6 mol-7.5 mol, per 1 mol of compound [I].
[0058] In Method A, the reaction solvent is subject to no
particular limitation as long as it is hardly oxidized by the
oxidizing agent to be used for the oxidation reaction. Examples
thereof include water, t-butyl alcohol, t-amyl alcohol, acetone,
ethyl methyl ketone, isobutyl methyl ketone, methylene chloride,
chloroform, 1,2-dichloroethane, benzene, monochlorobenzene,
1,2-dichlorobenzene, acetic acid, propionic acid, butyric acid and
the like, and mixed solvents thereof, with preference given to
water, t-butyl alcohol, a mixed solvent of water and t-butyl
alcohol, t-amyl alcohol, a mixed solvent of water and t-amyl
alcohol, acetone and a mixed solvent of water and acetone. The
amount of the solvent to be used is generally 5 L-50 L, preferably
8 L-24 L, per 1 kg of compound [I].
[0059] In Method A, the reaction temperature is generally 0.degree.
C.-120.degree. C., preferably 50-100.degree. C., and the reaction
time is generally 0.5 hr-12 hr, preferably 2 hr-8 hr.
[0060] The compound [II] can be isolated by a conventional method.
For example, the reaction mixture is filtrated to remove insoluble
matter (inclusive of manganese dioxide), a typical inorganic acid
(e.g., hydrochloric acid, sulfuric acid etc.) is added and the
precipitated compound [II] is collected by filtration. After the
isolation, it is further purified by a conventional method.
Alternatively, it can be used in the next reaction without
purification.
[0061] Method B (production method of compound [II] using compound
[I'] as starting material)
[0062] The compound [II] can be also obtained by oxidation of
compound [I'], wherein the oxidation can be performed by the use of
an oxidizing agent. In Method B, the amount of the oxidizing agent
to be used is generally 2.5 mol-14 mol, preferably 4 mol-9 mol,
more preferably 5.5 mol-7 mol, per 1 mol of compound [I'], and the
amount of the solvent to be used is generally 5 L-50 L, preferably
8 L-24 L, per 1 kg of compound [I']. Other factors such as reaction
conditions, isolation conditions and the like are the same as those
employed for the oxidation reaction in the above-mentioned Method
A. The isolated product can be purified by a conventional method.
Alternatively, it can be used in the next reaction without
purification.
[0063] Method C (production method of compound [II] using
trimellitic anhydride as starting material)
[0064] U.S. Pat. No. 3,835,167 teaches Friedel-Crafts reaction of
trimellitic anhydride and benzene. According to the method
disclosed in this publication, nitrobenzene is used as a solvent,
which is unpreferable from the aspect of the environment. According
to the present invention, the reaction in this publication is
carried out using fluorobenzene instead of benzene and under the
same conditions or at a higher temperature, whereby the progress of
the Friedel-Crafts reaction is mostly prevented (see Comparative
Example 1). The present inventors have studied a solvent that
allows smooth progress of the Friedel-Crafts reaction of
trimellitic anhydride and fluorobenzene, and that is
environmentally preferable, and found dichloro-substituted benzene
and trichloro-substituted benzene to be most suitable. That is,
trimellitic anhydride and fluorobenzene are subjected to
Friedel-Crafts reaction in a dichloro-substituted or
trichloro-substituted benzene solvent to give compound [II]
environmentally preferably and smoothly.
[0065] To be specific, trimellitic anhydride and fluorobenzene are
dispersed in a reaction solvent, Lewis acid or Bronsted acid is
added and the mixture is stirred to give compound [II].
[0066] In Method C, the amount of fluorobenzene to be used is
generally 1 mol-10 mol, preferably 1.2 mol-3 mol, per 1 mol of
trimellitic anhydride.
[0067] The reaction solvent in Method C, dichloro-substituted or
trichloro-substituted benzene, may be, for example,
1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,2,4-trichlorobenzene,
1,2,3-trichlorobenzene and the like, with particular preference
given to 1,2-dichlorobenzene because it produces compound [II]
relatively highly selectively. These solvents may be used alone or
in combination. The amount of the reaction solvent to be used is
generally 5 L-40 L, preferably 10 L-25 L, per 1 kg of trimellitic
anhydride. Other than the above-mentioned solvents, certain
solvents can accelerate the reaction in Method C. Examples thereof
include methylene chloride, 1,2-dichloroethane, nitrobenzene,
carbon disulfide and the like, with preference given to methylene
chloride and 1,2-dichloroethane. The amount of the solvent to be
used is 4 L-40 L, preferably 8 L-25 L, per 1 kg of trimellitic
anhydride.
[0068] In Method C, the Lewis acid is subject to no particular
limitation as long as it is used for Friedel-Crafts reaction.
Examples thereof include aluminum chloride, aluminum bromide, zinc
fluoride, zinc chloride, zinc bromide, zinc iodide, boron
trifluoride, boron trichloride, silicon tetrachloride, titanium
tetrachloride and the like, with particular preference given to
aluminum chloride in view of the quick reaction it provides. The
amount of the Lewis acid to be used is generally 2.5 mol-5 mol,
preferably 3 mol-3.5 mol, per 1 mol of trimellitic anhydride.
[0069] The Bronsted acid used in Method C is subject to no
particular limitation as long as it is generally used for
Friedel-Crafts reaction, and is exemplified by hydrogen fluoride,
sulfuric acid, polyphosphoric acid, trifluoromethanesulfonic acid
and the like, with preference given to trifluoromethanesulfonic
acid. The amount of the Bronsted acid to be used is 0.0001 mol-1
mol, preferably 0.01 mol-0.2 mol, per 1 mol of trimellitic
anhydride.
[0070] In Method C, the reaction temperature is generally
40.degree. C.-150.degree. C., preferably 70.degree. C.-120.degree.
C., and the reaction time is generally 0.5 hr-16 hr, preferably 2
hr-9 hr.
[0071] In Method C, compound [II] is obtained as a mixture with its
isomer, compound [IV]. This mixture can be easily separated from
the reaction mixture according to a conventional method. For
example, the reaction mixture is poured into an acidic aqueous
solution such as aqueous hydrochloric acid solution, aqueous
sulfuric acid solution and the like and partitioned to separate an
organic layer, which is, after extraction with an aqueous alkali
solution, neutralized with an acidic aqueous solution to separate
the mixture. The compound [II] and compound [IV] can be separated
by recrystallization and the like. The mixture can be used in the
next reaction without separation of compound [II] from compound
[IV]. The mixture and compound [II] can be used in the next
reaction without purification.
Production Method of Compound [III]
[0072] The compound [III] has been disclosed in JP Application No.
11-311703 by the present inventors as an important intermediate for
efficient synthesis of compound [VI] which is a citalopram
precursor. The present inventors have studied a method for
producing compound [III] by a new route and found compound [II] to
be a precursor of compound [III], as well as a simple and easy
production method of compound [III] from compound [II]. That is,
compound [III] can be easily obtained by reduction and cyclization
of compound [II]. The order of the reduction and cyclization is
subject to no particular limitation. Cyclization after reduction of
compound [II], or cyclization after partial reduction (reduction of
ketone) of compound [II], followed by reduction may be employed.
Cyclization after reduction is preferable because it requires a
short reaction step. The starting material compound [II] can be
used as a mixture with an isomer, compound [IV], for the production
of compound [III]. When the mixture of compound [II] and compound
[IV] is subjected to reduction and cyclization, compound [III] is
obtained along with the isomer of compound [III]. When compared
with the yield of compound [III] when it is obtained by isolation
followed by reduction and cyclization, the yield is higher by the
former route. Therefore, isolation not in the stage of compound
[II] but in the stage of compound [III] is efficient and
preferable.
[0073] The compound obtained by reduction of compound [II] is
represented by the formula [VII] 9
[0074] hereinafter to be also referred to as compound [VII]. When
cyclization is conducted after partial reduction of compound [II],
and further reduction is applied, various intermediates are
present, such as a compound of the formula 10
[0075] and the like. The production of compound [III] from compound
[II] in the present invention consists of two steps of (1)
reduction and (2) cyclization.
[0076] When cyclization follows reduction, the reaction conditions
of (1) may lead to the simultaneous production of compound [VII]
and compound [III], in which case (2) can be omitted depending on
the proportion of compound [III] produced.
[0077] The following explains a method for producing compound [III]
by cyclization after reduction of compound [II].
[0078] The conditions of (1) are as follows.
[0079] The compound [II] can be reduced in the same manner as in
the generally known reduction of carboxylic acid into alcohol by
the use of a reducing agent. To be specific, a reducing agent is
dispersed in a reaction solvent, and compound [II] is added to the
dispersion, preferably by dropwise addition to give compound [VII].
This reduction is preferably conducted using a suitable catalyst in
addition to the reducing agent. The catalyst is preferably added
after the addition of a reducing agent and compound [II].
[0080] The reducing agent in (1) is subject to no particular
limitation as long as it is generally used for the conversion of
carboxylic acid to alcohol. Examples thereof include sodium
borohydride, lithium aluminum hydride, sodium
bis(2-methoxyethoxy)aluminum hydride, borane-THF complex,
borane-dimethyl sulfide complex and the like, with preference given
to sodium borohydride. The amount of the reducing agent to be used
is generally 1.25 mol-7.5 mol, preferably 2.5 mol-5 mol, per 1 mol
of compound [II].
[0081] The catalyst in (1) is exemplified by inorganic acid (e.g.,
hydrochloric acid, sulfuric acid, phosphoric acid, boric acid,
nitric acid etc.), organic acid (e.g., methanesulfonic acid,
trifluoromethanesulfonic acid, p-toluenesulfonic acid,
benzenesulfonic acid etc.), Lewis acid (e.g., boron trifluoride,
boron trichloride, boron tribromide, zinc fluoride, zinc chloride,
zinc bromide, zinc iodide, aluminum fluoride, aluminum chloride,
aluminum bromide, magnesium fluoride, magnesium chloride, magnesium
bromide, magnesium iodide, silicon tetrachloride, titanium
tetrachloride etc.), dialkyl sulfate (e.g., dimethyl sulfate,
diethyl sulfate etc.) and the like, with preference given to Lewis
acid and dialkyl sulfate in view of an increased yield and
selectivity, with more preference given to sulfuric acid, boron
trifluoride, dimethyl sulfate and diethyl sulfate for higher yield.
The amount of the catalyst to be used is generally 1.25 mol-7 mol,
preferably 2 mol-6 mol, per 1 mol of compound [II].
[0082] The reaction solvent in (1) is subject to no particular
limitation as long as it hardly shows reaction under the conditions
of reduction. Preferred are ether solvents. Examples of the ether
solvent include diethyl ether, diisopropyl ether, dibutyl ether,
dipentyl ether, dihexyl ether, t-butyl methyl ether, ethylene
glycol dimethyl ether, diethylene glycol dimethyl ether,
triethylene glycol dimethyl ether, tetraethylene glycol dimethyl
ether, tetrahydrofuran (THF), 1,4-dioxane, 1,3-dioxolan and the
like, with preference given to THF, diethyl ether, ethylene glycol
dimethyl ether, diethylene glycol dimethyl ether, t-butyl methyl
ether, dibutyl ether and the like, and with particular preference
given to THF, t-butyl methyl ether, dibutyl ether, ethylene glycol
dimethyl ether and diethylene glycol dimethyl ether. The amount of
the reaction solvent to be used is generally 1 L-40 L, preferably 5
L-20 L, per 1 kg of compound [II].
[0083] In (1), trialkyl borate (e.g., trimethyl borate, triethyl
borate, tripropyl borate, tributyl borate etc.) is preferably used
to prevent gelation of the reaction mixture. The amount of trialkyl
borate to be used is preferably 0.1 mol-3 mol, more preferably 0.1
mol-0.5 mol, per 1 mol of compound [II].
[0084] In (1), the reaction temperature is generally from
-20.degree. C. to 120.degree. C., preferably 25.degree.
C.-75.degree. C., and the reaction time is generally 0.5 hr-10 hr,
preferably 2 hr-7 hr.
[0085] The compound [VII] can be isolated and purified by a
conventional method. For example, water is added to the obtained
reaction mixture, and the mixture is cooled to allow crystal
precipitation. The reaction mixture containing compound [VII] can
be used in the next reaction as it is without isolation of compound
[VII]. Alternatively, a reaction mixture wherein the reducing agent
has been inactivated with water can be used in the reaction.
[0086] The following explains (2).
[0087] Cyclization of compound [VII] is conducted via dehydration
reaction by applying a heat. In this case, for acceleration of the
dehydration reaction, further addition of an acid catalyst is
preferable. To be specific, for example, an acid catalyst is added
to the reaction mixture obtained in (1) or a mixture of the
reaction solvent and compound [VII], to give compound [III].
[0088] The acid catalyst in (2) is exemplified by inorganic acid
(e.g., hydrochloric acid, sulfuric acid, phosphoric acid,
polyphosphoric acid, boric acid, nitric acid etc.), organic acid
(e.g., acetic acid, propionic acid, trifluoroacetic acid,
methanesulfonic acid, trifluoromethanesulfoni- c acid,
p-toluenesulfonic acid, benzenesulfonic acid, benzoic acid etc.),
Lewis acid (e.g., boron trifluoride, boron trichloride, boron
tribromide, zinc fluoride, zinc chloride, zinc bromide, zinc
iodide, aluminum fluoride, aluminum chloride, aluminum bromide,
magnesium fluoride, magnesium chloride, magnesium bromide,
magnesium iodide, silicon tetrachloride, titanium tetrachloride and
the like) and the like, with preference given to inorganic acid,
particularly preferably hydrochloric acid, sulfuric acid and
phosphoric acid. The amount of the acid catalyst to be used is
generally 0.01 kg-50 kg, preferably 0.1 kg-5 kg, per 1 kg of
compound [II] which is a starting material in (1).
[0089] The cyclization reaction tends to proceed easily by the
addition of the above-mentioned acid catalyst. The use of the
above-mentioned acid catalyst in (1) often advances not only the
reduction reaction but also cyclization reaction. Thus, the use in
(1) of an excess acid catalyst mentioned above enables synthesis of
compound [III] in one pot. In this case, the amount of catalyst to
be used in (1) is generally 2 mol-30 mol, preferably 3 mol-15 mol,
per 1 mol of compound [II] which is a starting material in (1).
[0090] The solvent in (2) is subject to no particular limitation as
long as it does not interfere with the reaction. Preferred are the
solvents used in (1), and a mixed solvent of the solvent used in
(1) and water. The use of such solvents is preferable because the
obtained reaction mixture can be applied to the step of (2) after
the completion of the reaction of (1) without isolation of compound
[VII] from the reaction mixture, and the reaction mixture
containing water to inactivate the reducing agent after the
completion of the reaction of (1) can be applied as it is to the
step of (2), which means that the isolation and purification of
compound [VII] can be omitted. When water is added to inactivate
the reducing agent, only the solvent used for the reaction mixture
of (1) can be evaporated to leave only water, which is subjected to
the cyclization reaction, or a suitable solvent other than the
solvent used in (1) may be added to the above-mentioned mixture
containing only water. Examples of the suitable solvent other than
the solvent used in (1) is subject to no particular limitation.
Examples thereof include hydrocarbon solvents (e.g., toluene,
xylene, mesitylene, hexane, heptane, octane etc.) and the like. The
amount thereof is generally 0.5 L-20 L, preferably 3 L-10 L, per 1
kg of compound [II] which is a starting material in (1).
[0091] In (2), the reaction time is generally 0.5 hr-15 hr,
preferably 1 hr-7 hr, and the reaction temperature is generally
10.degree. C.-100.degree. C., preferably 20.degree. C.-70.degree.
C.
[0092] The compound [III] can be isolated by a conventional method,
for example, by adding water to the reaction mixture, cooling the
mixture and collecting the resulting crystals. After the isolation,
compound [III] can be further purified by a conventional method.
Alternatively, it can be used in the next reaction without
purification.
[0093] A method comprising cyclization after partial reduction of
compound [II] and further reduction, is performed in the same
manner as in the above-mentioned method by the use of reaction
reagents (e.g., reducing agent) generally used for desired partial
reduction and cyclization.
Production Method of Compound [V]
[0094] The compound [V] is useful as an intermediate for the
efficient synthesis of compound [VI] which is a precursor of
citalopram. The method for efficient synthesis of compound [V] is
important because it eventually contributes greatly to the
efficient synthesis of citalopram. It is known that compound [V]
can be obtained by oxidation using compound [III] as an oxidizing
agent (JP application No. 11-311703). The positions of compound
[III] that are easily oxidized are 5-position hydroxymethyl of
1,3-dihydroisobenzofuran ring, and the 1-position and 3-position
carbons. Therefore, oxidation of compound [III] may result in the
oxidation of the 1-position and 3-position carbons besides the
5-position hydroxymethyl. After intensive studies, the present
inventors have found that the use of manganese dioxide as an
oxidizing agent results in the production of compound [V] at a high
yield almost without any side reaction (oxidation of the 1-position
and 3-position carbons). That is, by the use of manganese dioxide
as an oxidizing agent for the oxidation of compound [III], compound
[V] can be obtained at a high yield. To be specific, compound [III]
is dissolved or dispersed in a suitable solvent and manganese
dioxide is added to give compound
[0095] The order of addition and the like are subject to no
particular limitation.
[0096] The amount of the manganese dioxide to be used for this
reaction is generally 1 kg-20 kg, preferably 3 kg-10 kg, per 1 kg
of compound [III].
[0097] The solvent to be used for this reaction is subject to no
particular limitation as long as it is not easily subject to
oxidation, and is exemplified by ethers (e.g., diethyl ether,
diisopropyl ether, dibutyl ether, dipentyl ether, dihexyl ether,
t-butyl methyl ether, ethylene glycol dimethyl ether, diethylene
glycol dimethyl ether, triethylene glycol dimethyl ether,
tetraethylene glycol dimethyl ether, tetrahydrofuran (THF),
1,4-dioxane, 1,3-dioxolan etc.), ketones (e.g., acetone, methyl
ethyl ketone, methyl isobutyl ketone, 2-pentanone, 3-pentanone,
cyclopentanone, cyclohexanone etc.), esters (e.g., ethyl acetate,
propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate,
amyl acetate, isoamyl acetate, benzyl acetate, phenyl acetate,
methyl propionate, ethyl propionate, propyl propionate, isopropyl
propionate, butyl propionate, isobutyl propionate, amyl propionate,
isoamyl propionate, benzyl propionate, phenyl propionate, methyl
butyrate, ethyl butyrate, propyl butyrate, isopropyl butyrate,
butyl butyrate, isobutyl butyrate, amyl butyrate, isoamyl butyrate,
benzyl butyrate, phenyl butyrate etc.), lactones (e.g.,
.gamma.-butyrolactone etc.), carbonates (e.g., dimethyl carbonate,
diethyl carbonate, ethylene carbonate etc.), aromatic hydrocarbons
(e.g., benzene, toluene, xylene, mesitylene, ethylbenzene,
t-butylbenzene etc.), aliphatic hydrocarbons (e.g., pentane,
hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane,
decane, undecane, dodecane, petroleum ether etc.), halogen
substituted aromatic hydrocarbons (e.g., monochlorobenzene,
1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,2,4-trichlorobenzene,
1,2,3-trichlorobenzene etc.), halogen substituted aliphatic
hydrocarbons (e.g., dichloromethane, chloroform,
1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,1-trichloroethane,
1-chloropropane, 2-chloropropane etc.), amide solvents (e.g.,
N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone
etc.), sulfur-containing solvents (e.g., dimethyl sulfoxide,
sulforane etc.), and the like. Of these, particularly preferable
solvents are t-butyl methyl ether, ethylene glycol dimethyl ether,
diethylene glycol dimethyl ether, toluene, xylene, mesitylene,
dichloromethane and monochlorobenzene. The amount of the solvent to
be used is generally 3 L-50 L, preferably 5 L-20 L, per 1 kg of
compound [III].
[0098] In this reaction, the reaction temperature is generally from
-10.degree. C. to 100.degree. C., preferably 10.degree.
C.-60.degree. C., and the reaction time is generally 0.1 hr-24 hr,
preferably 0.5 hr-5 hr.
[0099] The compound [V] can be isolated by a conventional method
comprising, for example, filtration of the reaction mixture, and
evaporation of the solvent from the obtained filtrate. After
filtration of the reaction mixture, it can be used in the next
reaction without evaporation of the solvent from the resulting
filtrate. The waste manganese compound thus filtered off can be
reprocessed and recycled for use as permanganate or manganese
dioxide by a conventional method, which is environmentally
preferable.
Production Method of Compound [VI]
[0100] The compound [VI] is a useful intermediate as a precursor of
citalopram. The compound [VI] can be obtained by successive
oxidation, oximation (condensation with hydroxylamine or a mineral
acid salt thereof) and dehydration of compound [III] as a starting
compound. When the following solvents are used, the series of
reactions (oxidation, oximation and dehydration reaction) can be
conducted in a single solvent and compound [VI] can be produced
easily and efficiently because evaporation of the solvent can be
omitted. To be specific, compound [III] and an oxidizing agent are
added to the following solvent to allow oxidation reaction. After
the completion of the oxidation reaction, the oxidizing agent is
filtered off and hydroxylamine or a mineral acid salt thereof is
added to the resulting filtrate to allow oximation reaction.
Finally, a dehydrating agent is added to the obtained reaction
mixture for a dehydration reaction to give compound [VI].
[0101] The solvent usable for oxidation, oximation and dehydration
reaction is subject to no particular limitation as long as it does
not interfere with each reaction and is exemplified by ethers
(e.g., dibutyl ether, dipentyl ether, dihexyl ether, diethylene
glycol dimethyl ether, triethylene glycol dimethyl ether,
tetraethylene glycol dimethyl ether etc.), ketones (e.g.,
cyclopentanone, cyclohexanone etc.), esters (e.g., amyl acetate,
isoamyl acetate, benzyl acetate, phenyl acetate, butyl propionate,
isobutyl propionate, amyl propionate, isoamyl propionate, benzyl
propionate, phenyl propionate, butyl butyrate, isobutyl butyrate,
amyl butyrate, isoamyl butyrate, benzyl butyrate, phenyl butyrate
etc.), lactones (e.g., .gamma.-butyrolactone etc.), carbonates
(e.g., diethyl carbonate, ethylene carbonate etc.), aromatic
hydrocarbons (e.g., xylene, mesitylene, ethylbenzene,
t-butylbenzene, toluene etc.), halogen substituted aromatic
hydrocarbons (e.g., monochlorobenzene, 1,2-dichlorobenzene,
1,3-dichlorobenzene, 1,2,4-trichlorobenzene, 1,2,3-trichlorobenzene
etc.), amide solvents (e.g., N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidone etc.), sulfur-containing
solvents (e.g., dimethyl sulfoxide, sulforane etc.), and the like.
Of these, particularly preferable solvents are diethylene glycol
dimethyl ether, xylene, mesitylene, toluene, t-butylbenzene and
monochlorobenzene. The amount of the solvent to be used is
generally 3 L-50 L, preferably 5 L-20 L, per 1 kg of compound
[III], the starting material.
[0102] The following explains the oxidation reaction of compound
[III].
[0103] The compound [III] can be oxidized in completely the same
manner as in the above-mentioned "Production method of compound
[V]" except the solvent is other than those mentioned above. The
compound [V] obtained by oxidation of compound [III] can be used in
the next oximation reaction without isolation from the reaction
mixture. Note that the oxidizing agent should be removed from the
reaction mixture according to a conventional method.
[0104] The following explains the oximation reaction.
[0105] The compound [V] can be converted to an oxime by, for
example, oximation reaction with hydroxylamine or a mineral acid
salt thereof. To be specific, for example, the oxidizing agent is
filtered off from the reaction mixture after oxidation, and
hydroxylamine or a mineral acid salt thereof is added to give the
oxime.
[0106] Examples of hydroxylamine mineral acid salt include salts of
hydroxylamine with hydrochloric acid, sulfuric acid, phosphoric
acid, nitric acid and the like, with preference given to
hydroxylamine hydrochloride and hydroxylamine sulfate.
[0107] The amount of hydroxylamine or a mineral acid salt thereof
to be used for oximation is generally 1 mol-5 mol, preferably 1
mol-2 mol, per 1 mol of compound [III] used in the oxidation
step.
[0108] When a hydroxylamine mineral acid salt is used, a suitable
base is preferably added in 1 mol-5 mol per 1 mol of hydroxylamine
mineral acid salt. The base is added, preferably dropwise, together
with hydroxylamine mineral acid salt or after the addition thereof.
The base is subject to no particular limitation as long as it shows
less influence on cyano group. Examples thereof include organic
base (e.g., triethylamine, tributylamine, dimethylaniline,
pyridine, sodium methoxide, sodium ethoxide, sodium t-butoxide,
potassium t-butoxide etc.), inorganic base (e.g., sodium carbonate,
sodium hydrogencarbonate, sodium hydroxide, potassium carbonate,
potassium hydrogencarbonate, potassium hydroxide etc.) and the
like, with preference given to triethylamine.
[0109] The reaction temperature of the oximation reaction is
generally 20.degree. C.-120.degree. C., preferably 40.degree.
C.-100.degree. C., and the reaction time is generally 10 min-4 hr,
preferably 30 min-2 hr.
[0110] The oxime obtained from compound [III] can be subjected to
dehydration reaction without isolation from the reaction
mixture.
[0111] The following explains dehydration reaction.
[0112] The oxime obtained by oximation reaction can be dehydrated
by the use of a dehydration agent. For example, a dehydration agent
is added to the reaction mixture after the oximation reaction to
give compound [VI].
[0113] Examples of the dehydration agent to be used for this
dehydration step include anhydride (e.g., acetic anhydride,
phthalic anhydride etc.), phosphorus oxychloride, methanesulfonyl
chloride, p-toluenesulfonyl chloride and the like, with particular
preference given to acetic anhydride in view of the environment and
yield. The amount of the dehydration agent to be used is generally
1 mol-10 mol, preferably 2 mol-5 mol, per 1 mol of oxime.
[0114] In the dehydration reaction, the reaction temperature is
generally 60.degree. C.-160.degree. C., preferably 120.degree.
C.-150.degree. C., more preferably 125.degree. C.-150.degree. C.,
and the reaction time is generally 0.5 hr-8 hr, preferably 1.5 hr-6
hr.
[0115] The compound [VI] can be isolated by subjecting the reaction
mixture to a conventional method (e.g., neutralization, extraction,
crystallization and the like).
Production Method of Citalopram
[0116] Citalopram can be obtained at a high yield by reacting
compound [VI] with 3-(dimethylamino)propyl chloride together with a
condensing agent and in the presence of at least one of
N,N,N',N'-tetramethylethylen- ediamine and
1,3-dimethyl-2-imidazolidinone. To be specific, compound [VI],
3-(dimethylamino)propyl chloride, a condensing agent, and at least
one of N,N,N',N'-tetramethylethylenediamine and
1,3-dimethyl-2-imidazolid- inone are mixed in a suitable solvent,
and the mixture is heated where necessary for the progress of the
reaction to give citalopram. The order of addition is subject to no
particular limitation. For example, compound [VI] is added to the
reaction solvent, and a condensing agent and
3-(dimethylamino)propyl chloride are successively added.
Alternatively, compound [VI] and 3-(dimethylamino)propyl chloride
are added to the reaction solvent, and a condensing agent is added,
or a condensing agent is added to the reaction solvent, and
compound [VI] and 3-(dimethylamino)propyl chloride are successively
added or added by mixture. In this case,
N,N,N',N'-tetramethylethylenediamine and
1,3-dimethyl-2-imidazolidinone can be added at any stage, but they
are preferably divided and added before and after the addition of
the condensing agent for easy progress of the reaction. To be
specific, compound [VI] is added to the reaction solvent and
3-(dimethylamino)propyl chloride,
N,N,N',N'-tetramethylethylenediamine (or
1,3-dimethyl-2-imidazolidinone), condensing agent and
N,N,N',N'-tetramethylethylenediamine (or
1,3-dimethyl-2-imidazolidinone) are successively added. The
reagents used in the present invention can be added as they are or
added after dilution with a reaction solvent or a different solvent
that does not interfere with the reaction (e.g., triethylamine,
pyridine, N,N-dimethylaniline and the like).
[0117] In the present invention, a quaternary ammonium salt (e.g.,
tetra n-butylammonium halide, benzyltrialkylammonium halide and the
like) is added to the reaction system to carry out the reaction
without elevating the reaction temperature too high. The amount of
the quaternary ammonium salt to be added is preferably 0.001
mol-0.1 mol, more preferably 0.01 mol-0.05 mol, per 1 mol of
compound [VI].
[0118] The amount of 3-(dimethylamino)propyl chloride to be added
is preferably 1 mol-3 mol, more preferably 1 mol-1.5 mol, per 1 mol
of compound [VI]. When the 3-(dimethylamino)propyl chloride is in
the form of a hydrochloride, it is preferably prepared into a free
form by neutralization, and used for the reaction of the present
invention.
[0119] The amount of N,N,N',N'-tetramethylethylenediamine to be
added is preferably 0.1 mol-10 mol, more preferably 0.2 mol-4 mol,
per 1 mol of compound [VI].
[0120] The amount of 1,3-dimethyl-2-imidazolidinone to be added is
preferably 1 mol-50 mol, more preferably 3 mol-30 mol, per 1 mol of
compound [VI].
[0121] The condensing agent used for the production of citalopram
is subject to no particular limitation as long as it is generally
used as a condensing agent. Examples thereof include sodium
hydride, potassium hydride, calcium hydride, potassium hydroxide,
sodium hydroxide, potassium carbonate, sodium carbonate, potassium
t-butoxide, sodium t-butoxide, sodium methoxide, sodium ethoxide,
potassium methoxide, potassium ethoxide, lithium diisopropylamide,
lithium hexamethyldisiladide and the like, with preference given to
sodium hydride and potassium t-butoxide, with more preference given
to sodium hydride. The amount of the condensing agent to be used is
generally 0.9 mol-3 mol, preferably 1 mol-1.5 mol, per 1 mol of
compound [VI].
[0122] The reaction solvent to be used for the production of
citalopram is, for example, dimethyl sulfoxide, sulfolane,
N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran
(THF), 1,4-dioxane, 1,3-dioxolan, dimethoxyethane, diethylene
glycol dimethyl ether, t-butyl methyl ether, diethyl ether,
diisopropyl ether, dibutyl ether, anisole, benzene, toluene,
xylene, mesitylene, cyclohexane, heptane, hexane, liquid paraffin
and the like, with preference given to dimethyl sulfoxide,
sulforane, N,N-dimethylformamide, N,N-dimethylacetamide, THF,
1,3-dioxolan, dimethoxyethane, diethylene glycol dimethyl ether,
toluene, xylene, t-butyl methyl ether and liquid paraffin, which
may be used alone or in combination. In addition,
N,N,N',N'-tetramethylethylenediamine and
1,3-dimethyl-2-imidazolidinone may be used as a reaction solvent.
The reaction solvent in the present invention is particularly
preferably a mixed solvent of toluene and
N,N,N',N'-tetramethylethylenediamine or
1,3-dimethyl-2-imidazolidinone for a higher yield.
[0123] The amount of the reaction solvent to be used for the
production of citalopram varies depending on the kind of the
reaction solvent, reaction conditions and the like. It is generally
preferably 1 L-100 L, more preferably 3 L-30 L, per 1 kg of
compound [VI].
[0124] The reaction temperature for the production of citalopram is
generally from -70.degree. C. to 150.degree. C., preferably
20.degree. C.-90.degree. C., more preferably 40.degree.
C.-70.degree. C. The reaction time is subject to no particular
limitation, and is generally 30 min-15 hr, preferably 2 hr-8
hr.
[0125] Citalopram can be isolated and purified generally by a
post-treatment and separation. For example, the reaction mixture is
poured into ice water and extracted with an organic solvent. The
obtained organic layer is extracted with an aqueous acid solution,
neutralized and extracted again with an organic solvent, which is
followed by evaporation of the solvent to isolate citalopram. Where
necessary, a conventional method is used for the purification.
[0126] The present invention is explained in detail by referring to
illustrative examples. The present invention is not limited by
these examples in any way.
EXAMPLE 1
Synthesis of (2,4-dimethylphenyl)-(4'-fluorophenyl)methanol
(compound [I])
[0127] Under a nitrogen atmosphere, turnings of magnesium (16.8 g)
were dispersed in THF (116 ml), and iodine (0.1 g) was added. Under
a nitrogen atmosphere, a solution of 4-bromofluorobenzene (116 g)
in THF (201 ml) was added dropwise at 15-40.degree. C., and the
mixture was stirred at 20-40.degree. C. for 2 hr. The obtained
mixture with a Grignard reagent was cooled and thereto was added
dropwise a solution of 2,4-dimethylbenzaldehyde (81 g) in THF (81
ml) at 0-20.degree. C. After the dropwise addition, the reaction
mixture was stirred at 0-20.degree. C. for 2 hr. A saturated
aqueous ammonium chloride solution was added to stop the reaction.
The reaction mixture was partitioned and the obtained organic layer
was retained. The aqueous layer was extracted with toluene and
combined with the organic layer obtained earlier, and washed with
saturated brine. The solvent was evaporated from the organic layer
under reduced pressure to give
(2,4-dimethylphenyl)-(4'-fluorophenyl)methanol (139.2 g, 100%) as a
colorless oil.
[0128] .sup.1H-NMR(CDCl.sub.3, 400 MHz) .delta.=2.05(1H, d, J=4
Hz), 2.21(3H, s), 2.31(3H, s), 5.96(1H, d, J=4 Hz), 6.98(1H, s),
7.00(2H, t, J=9 Hz), 7.05(1H, d, J=8 Hz), 7.29(2H, dd, J=9 Hz, J=5
Hz), 7.33(1H, d, J=8 Hz) ppm.
EXAMPLE 2
Synthesis of (2,4-dimethylphenyl)-(4'-fluorophenyl)methanol
(compound [I])
[0129] Under a nitrogen atmosphere, turnings of magnesium (16.8 g)
were dispersed in THF (54 ml), and iodine (0.1 g) was added. Under
a nitrogen atmosphere, a solution of 4-bromofluorobenzene (116 g)
in THF (201 ml) was added dropwise at 15-40.degree. C., and the
mixture was stirred at 20-40.degree. C. for 2 hr. The obtained
mixture with a Grignard reagent was cooled and thereto was added
dropwise a solution of 2,4-dimethylbenzaldehyde (81 g) in THF (81
ml) at 0-20.degree. C. After the dropwise addition, the reaction
mixture was stirred at 0-20.degree. C. for 2 hr. A saturated
aqueous ammonium chloride solution was added to stop the reaction.
The reaction mixture was partitioned and the obtained organic layer
was washed with saturated brine. The solvent was evaporated from
the organic layer under reduced pressure to give
(2,4-dimethylphenyl)-(4'-fluorophenyl)methanol (139.2 g, 100%) as a
colorless oil. The obtained colorless oil was measured for
.sup.1H-NMR and found to be the same as in Example 1.
EXAMPLE 3
Synthesis of (2,4-dimethylphenyl)-(4'-fluorophenyl)methanol
(compound [I])
[0130] Under a nitrogen atmosphere, turnings of magnesium (16.8 g)
were dispersed in THF (46 ml), and iodine (0.1 g) was added. Then,
4-bromofluorobenzene (2.1 g) was added dropwise. After confirmation
of the start of the reaction, THF (242 ml) was flown in.
4-Bromofluorobenzene (113.9 g) was added dropwise at
31.8-48.9.degree. C., and the mixture was stirred at 38-40.degree.
C. for 2 hr. The obtained mixture with a Grignard reagent was
cooled and thereto was added dropwise 2,4-dimethylbenzaldehyde (81
g) at 5-29.9.degree. C. After the dropwise addition, the reaction
mixture was stirred at 21.3-28.3.degree. C. for 1.5 hr. A saturated
aqueous ammonium chloride solution was added to stop the reaction.
The reaction mixture was partitioned and the obtained organic layer
was washed with saturated brine. The solvent was evaporated from
the organic layer under reduced pressure to give
(2,4-dimethylphenyl)-(4'-fluorophenyl)methanol (139.2 g, 100%) as a
colorless oil. The obtained colorless oil was measured for
.sup.1H-NMR and found to be the same as in Example 1.
EXAMPLE 4
Synthesis of 4-(4'-fluorobenzoyl)isophthalic acid (compound
[II])
[0131] To (2,4-dimethylphenyl)-(4'-fluorophenyl)methanol (121 g)
were added t-butyl alcohol (723 ml) and water (1090 ml) and the
mixture was heated to 50.degree. C. Potassium permanganate (582 g)
was added at 50-75.degree. C. over 6 hr. The reaction mixture was
stirred at 70-85.degree. C. for 3 hr and most of t-butyl alcohol
was evaporated under reduced pressure. The by-produced manganese
dioxide was filtered off and the obtained filtrate was neutralized
with 6N hydrochloric acid. The generated crystals were collected by
filtration and dried to give nearly pure
4-(4'-fluorobenzoyl)isophthalic acid (114.2 g, 75%) as white
crystals.
[0132] .sup.1H-NMR(DMSO-d.sub.6, 400 MHz) .delta.=7.31(2H, t, J=9
Hz), 7.55(1H, d, J=8 Hz), 7.70(2H, dd, J=9 Hz, J=5 Hz), 8.23(1H,
dd, J=8 Hz, J=2 Hz), 8.51(1H, d, J=2 Hz), 13.52(2H, br) ppm.
EXAMPLE 5
Synthesis of 4-(4'-fluorobenzoyl)isophthalic acid (compound
[II])
[0133] To (2,4-dimethylphenyl)-(4'-fluorophenyl)methanol (121 g)
were added t-butyl alcohol (703 ml) and water (578 ml) and the
mixture was heated to 70.degree. C. Potassium permanganate (548 g)
was added at 70-80.degree. C. over 32 hr. The reaction mixture was
stirred at 70-85.degree. C. for 3 hr and most of t-butyl alcohol
was evaporated under reduced pressure. The by-produced manganese
dioxide was filtered off and the obtained filtrate was neutralized
with 6N hydrochloric acid. The generated crystals were collected by
filtration and dried to give nearly pure
4-(4'-fluorobenzoyl)isophthalic acid (108.1 g, 71.4%) as white
crystals. The obtained white crystals were measured for .sup.1H-NMR
and found to be the same as in Example 4.
EXAMPLE 6
Synthesis of 4-(4'-fluorobenzoyl)isophthalic acid (compound
[II])
[0134] To (2,4-dimethylphenyl)-(4'-fluorophenyl)methanol (121 g)
were added a 87% aqueous solution (847 ml) of t-butyl alcohol and
water (580.8 ml) and the mixture was heated to 69.9.degree. C.
Potassium permanganate (582 g) was added at 70.0-80.2.degree. C.
over 31 hr 20 min. The reaction mixture was stirred at
70-85.degree. C. for 3 hr and most of t-butyl alcohol was
evaporated under reduced pressure. The by-produced manganese
dioxide was filtered off and the obtained filtrate was neutralized
with 6N hydrochloric acid. The generated crystals were collected by
filtration and dried to give nearly pure
4-(.sup.4'-fluorobenzoyl)isophthalic acid (108.4 g, 71.5%) as white
crystals. The obtained white crystals were measured for .sup.1H-NMR
and found to be the same as in Example 4.
EXAMPLE 7
Synthesis of 1,3-dimethyl-4-(4'-fluorobenzoyl)benzene (compound
[I'])
[0135] To a suspension of anhydrous aluminum chloride (19.5 g)
dispersed in m-xylene (150 ml) was added dropwise 4-fluorobenzoyl
chloride (21.1 g) under ice-cooling. The mixture was stirred at
0-10.degree. C. for 3 hr and poured into 6N hydrochloric acid. The
reaction mixture was partitioned and the obtained organic layer was
washed successively with water, 10% aqueous sodium hydroxide
solution and water. The solvent was evaporated to give a 96:4
mixture (30.2 g, 99%) of 1,3-dimethyl-4-(4'-fluorobenzoyl)benzene
and 1,3-dimethyl-2-(4'-fluoroben- zoyl)benzene as pale-yellow oil.
1,3-Dimethyl-4-(4'-fluorobenzoyl)benzene
[0136] .sup.1H-NMR(CDCl.sub.3, 400 MHz) .delta.=2.32(3H, s),
2.38(3H, s), 7.05(1H, d, J=8 Hz), 7.11(2H, dd, J=9 Hz, J=7 Hz),
7.21(1H, d, J=8 Hz), 7.82(2H, dd, J=9 Hz, J=5ppm.
EXAMPLE 8
Synthesis of 1,3-dimethyl-4-(4'-fluorobenzoyl)benzene (compound
[I'])
[0137] To a suspension of anhydrous aluminum chloride (16.2 g)
dispersed in 1,2-dichlorobenzene (150 ml) was added fluorobenzene
(13 g), and thereto was added dropwise 2,4-dimethylbenzoyl chloride
(17.0 g) at 0-20.degree. C. The mixture was stirred at
10-30.degree. C. for 1 hr and heated to 80.degree. C. The mixture
was stirred for 1 hr, cooled again and poured into 6N hydrochloric
acid. The reaction mixture was diluted with a great excess toluene
and partitioned. The obtained organic layer was washed successively
with 5% aqueous sodium hydroxide solution and water, and the
solvent was evaporated under reduced pressure. The residue was
purified by silica gel column chromatography using
cyclohexane-ethyl acetate as eluent to give nearly pure
1,3-dimethyl-4-(4'-fluorobenzoyl)be- nzene (19.4 g, 85%) as
pale-yellow oil. The spectrum data of this oil were the same as
those confirmed in Example 7.
EXAMPLE 9
Synthesis of 4-(4'-fluorobenzoyl)isophthalic acid (compound
[II])
[0138] Potassium permanganate (45 g) was dispersed in 25w % aqueous
t-butyl alcohol solution (110 g) and heated to 65.degree. C.
Thereto was added dropwise a t-butyl alcohol (28 ml) solution of a
96:4 mixture, synthesized in Example 7, (10 g) of
1,3-dimethyl-4-(4'-fluorobenzoyl)benz- ene and
1,3-dimethyl-2-(4'-fluorobenzoyl)benzene. After the dropwise
addition, the mixture was reacted at 80-85.degree. C. for 3 hr and
most of t-butyl alcohol was evaporated under reduced pressure. The
by-produced manganese dioxide was filtered off. The obtained
filtrate was neutralized with 6N hydrochloric acid and the
generated crystals were collected by filtration and dried to give
nearly pure 4-(4'-fluorobenzoyl)isophthalic acid (9.9 g, 78%) as
white crystals. The spectrum data of the crystals were the same as
those in Example 4.
EXAMPLE 10
Synthesis of 4-(4'-fluorobenzoyl)isophthalic acid (compound
[II])
[0139] Trimellitic anhydride (20 g) and fluorobenzene (18.5 g) were
dispersed in 1,2-dichlorobenzene (200 ml) and thereto was added
anhydrous aluminum chloride (42 g). The mixture was stirred at
70-90.degree. C. for 4 hr. The reaction mixture was poured into 4N
hydrochloric acid (400 ml) and extracted with methyl isobutyl
ketone (400 ml). The organic layer was extracted with 5% aqueous
sodium hydroxide solution (240 g) and the aqueous layer was
neutralized with 6N hydrochloric acid (64 g). The resulting
crystals were collected by filtration, washed with water and dried
to give a 7:3 mixture (22.4 g, 0.75%) of
4-(4'-fluorobenzoyl)-isoph- thalic acid and
2-(4'-fluorobenzoyl)terephthalic acid as white crystals.
[0140] The obtained mixture was recrystallized from methanol-water
(8:5) to give nearly pure 4-(4'-fluorobenzoyl)isophthalic acid (6.8
g). The spectrum data of the crystals were the same as those in
Example 4.
EXAMPLE 11
Synthesis of 4-(4'-fluorobenzoyl)isophthalic acid (compound
[II])
[0141] Trimellitic anhydride (20 g) and fluorobenzene (20 g) were
dispersed in 1,2,4-trichlorobenzene (150 ml) and anhydrous aluminum
chloride (42 g) was added. The mixture was stirred at 70-90.degree.
C. for 8 hr. The reaction mixture was poured into 4N hydrochloric
acid (300 ml) in an ice bath, and the mixture was stirred at
50.degree. C. for 3 hr and cooled. The resulting crystals were
thoroughly washed with water, collected by filtration and dried to
give a 65:35 mixture (19.1 g, 64%) of
4-(4'-fluorobenzoyl)-isophthalic acid and
2-(4'-fluorobenzoyl)terephth- alic acid as white crystals.
[0142] 4-(4'-Fluorobenzoyl)isophthalic acid
[0143] .sup.1H-NMR(DMSO-d.sub.6, 400 MHz) .delta.=7.31(2H, t, J=9
Hz), 7.55(1H, d, J=8 Hz), 7.70(2H, dd, J=9 Hz, J=5 Hz), 8.23(1H,
dd, J=8 Hz, J=2 Hz), 8.51(1H, d, J=2 Hz), 13.52(2H, br) ppm.
[0144] 2-(4'-Fluorobenzoyl)terephthalic acid
[0145] .sup.1H-NMR(DMSO-d.sub.6, 400 MHz) .delta.=7.32(2H, t, J=9
Hz), 7.71(2H, dd, J=9 Hz, J=5 Hz), 7.87(1H, d, J=2 Hz), 8.09(1H, d,
J=8 Hz), 8.17(1H, dd, J=8 Hz, J=2 Hz), 13.52(2H, br) ppm.
Comparative Example 1
Synthesis of 4-(4'-fluorobenzoyl)isophthalic acid (compound
[II])
[0146] Trimellitic anhydride (20 g) and fluorobenzene (20 g) were
dispersed in nitrobenzene (200 ml) and anhydrous aluminum chloride
(45 g) was added. The mixture was stirred at 70-90.degree. C. for 6
hr. The reaction mixture was analyzed by HPLC, and as a result,
4-(4'-fluorobenzoyl)isophthalic acid was found to have been
generated by 4%. The mixture was further stirred at 110-120.degree.
C. for 6 hr, but only the by-product (other than isomer) increased
and the production rate of 4-(4'-fluorobenzoyl)isophthalic acid
showed a propensity toward decrease.
EXAMPLE 12
Synthesis of
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (compound
[III])
[0147] To a suspension of sodium borohydride (2.5 g) dispersed in
diethylene glycol dimethyl ether (40 ml) was added dropwise a
solution of a 7:3 mixture, obtained in Example 10, (5.8 g) of
4-(4'-fluorobenzoyl)iso- phthalic acid and
2-(4'-fluorobenzoyl)-terephthalic acid in diethylene glycol
dimethyl ether (29 ml) at 20-25.degree. C., and the mixture was
stirred for 10 min. Thereto was added dropwise boron
trifluoride-THF complex (10.9 g) at 20-45.degree. C., and the
mixture was heated at 40-50.degree. C. for 2 hr. After hydrolysis
with water (50 ml) in an ice bath, 85% phosphoric acid (50 ml) was
added, and the mixture was stirred at 60.degree. C. for 5 hr. Water
(200 ml) was added and the mixture was cooled. The generated
crystals were collected by filtration, washed with water and dried
to give crude 1-(4'-fluorophenyl)-1,3-dihydroisobenzofura-
n-5-ylmethanol (3.23 g). This was recrystallized twice from toluene
to give nearly pure
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethano- l (2.10
g, 43%).
[0148] melting point 101-104.degree. C.
[0149] IR(KBr) .nu.=3214(br), 2848(w), 1606(s), 1511(s), 1225(s),
1157(m), 1135(m), 1046(s), 1015(s), 824(s), 810(s),
783(m)cm.sup.-1
[0150] .sup.1H-NMR(CDCl.sub.3, 400 MHz) .delta.=4.72(2H, s),
5.19(1H, d, J=12 Hz), 5.31(1H, d, J=12 Hz), 6.14(1H, s), 6.98(1H,
d, J=8 Hz), 7.03(2H, t, J=9 Hz), 7.24(1H, d, J=8 Hz), 7.29(2H, dd,
J=9 Hz, J=6 Hz), 7.32(1H, s) ppm.
EXAMPLE 13
Synthesis of
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (compound
[III])
[0151] To a suspension of sodium borohydride (14.6 g) dispersed in
THF (120 ml) was added dropwise at 20-30.degree. C. a solution of a
7:3 mixture (24.0 g), obtained in the same manner as in Example 10,
of 4-(4'-fluorobenzoyl) isophthalic acid and
2-(4'-fluorobenzoyl)terephthali- c acid in THF (240 ml). The
mixture was heated to 55.degree. C. and thereto was added dropwise
dimethyl sulfate (47.0 g) at 55-65.degree. C. After the dropwise
addition, the mixture was refluxed for 5 hr, and hydrolyzed with
water (72 ml) in an ice bath. THF was evaporated under reduced
pressure. To the residue was added 85% phosphoric acid (48 g) and
the mixture was stirred at 60.degree. C. for 5 hr. Water (72 ml)
was added and the mixture was cooled. The generated crystals were
collected by filtration, washed with water and dried to give crude
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (15.1 g).
This was recrystallized twice from toluene to give nearly pure
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (8.2 g,
40%). The various spectrum data of the crystals were the same as
those obtained in Example 12.
EXAMPLE 14
Synthesis of
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (compound
[III])
[0152] To a suspension of sodium borohydride (15.0 g) dispersed in
THF (130 ml) was added dropwise at 20-30.degree. C. a solution of
4-(4'-fluorobenzoyl)isophthalic acid (26.0 g) synthesized in
Example 4 in THF (260 ml) and the mixture was heated to 55.degree.
C. Dimethyl sulfate (51.0 g) was added dropwise at 55-65.degree. C.
After the dropwise addition, the mixture was refluxed for 5 hr, and
hydrolyzed with water (130 ml) in an ice bath. THF was evaporated
under reduced pressure. To the residue was added 85% phosphoric
acid (52 g) and the mixture was stirred at 60.degree. C. for 5 hr.
Water (390 ml) was added and the mixture was cooled. The generated
crystals were collected by filtration, washed with water and dried
to give crude 1-(4'-fluorophenyl)-1,3-dihydro-
isobenzofuran-5-ylmethanol (20.4 g). This was recrystallized from a
mixed solvent of ethyl acetate and heptane (2:3) to give nearly
pure 1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol
(18.9 g, 86%). The various spectrum data of the crystals were the
same as those obtained in Example 12.
EXAMPLE 15
Synthesis of
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (compound
[III])
[0153] To a suspension of sodium borohydride (43.5 g) dispersed in
THF (327 ml) was added trimethyl borate (9.1 g) and added dropwise
at 20-30.degree. C. a solution of 4-(4'-fluorobenzoyl)isophthalic
acid (100.5 g) synthesized in Example 4 in THF (313 ml), and the
mixture was heated to 35.degree. C. A boron trifluoride-THF complex
(181.7 g) was added dropwise at 35-42.degree. C. After the dropwise
addition, the mixture was heated at 40-50.degree. C. for 7 hr, and
hydrolyzed with water (101 ml) in an ice bath. THF was evaporated
under reduced pressure. To the residue was added 30% sulfuric acid
(110 g) and the mixture was stirred at 60.degree. C. for 5 hr. A
25% aqueous solution of sodium hydroxide (200 g) was added and the
mixture was extracted with hot toluene (450 ml) at 70.degree. C.
The hot toluene layer was washed with warm water (70.degree. C., 60
ml), heptane (450 ml) was added and the mixture was cooled. The
precipitated crystals were collected by filtration and dried to
give 1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran- -5-ylmethanol
(69.0 g, 81%). The various spectrum data of the crystals were the
same as those obtained in Example 12.
EXAMPLE 16
Synthesis of
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (compound
[III])
[0154] To a suspension of lithium aluminum hydride (1.0 g)
dispersed in THF (10 ml) was added dropwise at room temperature a
solution of 4-(4'-fluorobenzoyl)isophthalic acid (3.0 g) in THF (30
ml), and the mixture was stirred for 10 hr. To the reduced reaction
mixture was added 10% hydrochloric acid (10 ml) and the mixture was
passed through celite. THF was evaporated under reduced pressure,
and 85% phosphoric acid (10 g) was added. The mixture was stirred
at 60.degree. C. for 5 hr. To the reaction mixture was added water
(50 ml) and the resulting crystals were collected by filtration and
dried. The objective compound was separated by silica gel column
chromatography to give 1-(4'-fluorophenyl)-1,3-dihyd-
roisobenzofuran-5-ylmethanol (0.21 g, 8%). The various spectrum
data of the crystals were the same as those obtained in Example
12.
EXAMPLE 17
Synthesis of
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (compound
[III])
[0155] Sodium borohydride (40.3 kg) was added to THF (280.3 kg)
under a nitrogen atmosphere. Trimethyl borate (8.4 kg) was added
dropwise at 20-30.degree. C. and a solution of
4-(4'-fluorobenzoyl)-isophthalic acid (93.1 kg) produced in the
same manner as in Example 4 in THF (280.3 kg) was added dropwise at
20-30.degree. C. A boron trifluoride-THF complex (173.3 kg, boron
trifluoride:45 wt %) was added dropwise at 35-42.degree. C. and the
mixture was reacted at 38-42.degree. C. for 3 hr and then at
48-50.degree. C. for 4 hr. The reaction mixture was cooled to
0-5.degree. C. and water (93.6 kg) was added dropwise at
0-25.degree. C. The mixture was heated to 50-55.degree. C. and warm
water (372 kg, 40-50.degree. C.) was flown in. The mixture was
heated to 50-85.degree. C. and the solvent (637 kg) was evaporated
at normal pressure. The reaction mixture was cooled to about
57.degree. C. and 30% sulfuric acid (102 kg) was flown in at
55-60.degree. C. The reaction mixture was stirred at 60-65.degree.
C. for 3 hr 50 min. By confirmation by HPLC, the triol compound
(compound [VII]) was contained by 0.1%. A 25% aqueous solution
(186.6 kg) of sodium hydroxide was added dropwise at 20-40.degree.
C. and toluene (363 kg) was added. The mixture was heated at
75-80.degree. C., extracted and stood for separation. The organic
layer was washed with warm water (280 kg, 70-80.degree. C.) and
stood for separation. Warm water (55.6 kg, 70-80.degree. C.) was
added to the organic layer and the mixture was cooled to
25-30.degree. C. Heptane (284 kg) was flown in at 25-30.degree. C.
and the mixture was aged for 1 hr, heated once to 40-42.degree. C.,
cooled to 0-5.degree. C. over 5 hr and aged for 1 hr. The crystals
were collected by filtration and washed with a mixture cooled to
0-5.degree. C. containing toluene (40.7 kg) and heptane (31.5 kg).
The crystals were dried under reduced pressure at about 45.degree.
C. for 15 hr and at 60-70.degree. C. for 12 hr to give
1-(4'-fluorophenyl)-1,3-dihydroisobenz- ofuran-5-ylmethanol (64.5
kg, yield 81.8%). Various spectrum data of the crystals were the
same as those obtained in Example 12.
EXAMPLE 18
Synthesis of
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde
(compound [V])
[0156] 1-(4'-Fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol
(299.3 g) and manganese dioxide (2.25 kg, type HMH, manufactured by
Toso) were dispersed in t-butyl methyl ether (3.4 L) and the
mixture was stirred at 10-30.degree. C. for 6 hr. The reaction
mixture was filtered and washed with t-butyl methyl ether (0.9 L).
The solvent was evaporated under reduced pressure to give nearly
pure 1-(4'-fluorophenyl)-1,3-dihydroisobe- nzofuran-5-carbaldehyde
(258.2 g, 87%) as pale-yellow white crystals.
[0157] .sup.1H-NMR(CDCl.sub.3, 400 MHz) .delta.=5.25(1H, d, J=13
Hz), 5.38(1H, d, J=13 Hz), 6.18(1H, s), 7.06(2H, t, J=9 Hz),
7.16(1H, d, J=8 Hz), 7.30(2H, dd, J=9 Hz, J=5 Hz), 7.71(1H, d, J=8
Hz), 7.83(1H, s), 10.03(1H, s) ppm.
EXAMPLE 19
Synthesis of
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde
(compound [V])
[0158] 1-(4'-Fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol
(66.0 g) was dispersed in toluene (660 ml) and manganese dioxide
(594 g, type HMH, manufactured by Toso) was added over 1 hr at
15-30.degree. C. The mixture was stirred at 20-30.degree. C. for 1
hr. The reaction mixture was filtered and washed with toluene (330
ml). The solvent was evaporated under reduced pressure to give
nearly pure 1-(4'-fluorophenyl)-1,3-dihydr-
oisobenzofuran-5-carbaldehyde (57.6 g, 88%) as pale-yellow white
crystals various spectrum data of the crystals were the same as
those obtained in Example 18.
EXAMPLE 20
Synthesis of
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde
(compound [V])
[0159] 1-(4'-Fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol
(60.5 kg) produced in Example 17 was added to toluene (520.9 kg)
and manganese dioxide (544.8 kg, type HMH, manufactured by Toso)
divided in three portions was added at 10-30.degree. C. over 3 hr.
The mixture was stirred at 23-27.degree. C. for 1 hr, and the
starting material was confirmed by HPLC to be 0.03%. Thereto were
added Hyflo Super-Cel.RTM. (18.2 kg, Celite Co.) and anhydrous
magnesium sulfate (30.2 kg). The mixture was cooled to about
10.degree. C. over 2 hr and stirred at 2-10.degree. C. for 40 min.
The mixture was filtrated and the residue (waste manganese) was
washed with toluene (284 kg). As a result of the analysis,
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde (60 kg,
yield about 100%) was contained in the solution (917 kg). The
crystals obtained by partial concentration of the solution showed
the same physical properties as in Example 18.
EXAMPLE 21
Synthesis of
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile.
(compound [VI])
[0160] 1-(4'-Fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol
(50.0 g) and manganese dioxide (200 g, type HMH, manufactured by
Toso) were dispersed in xylene (400 ml) and the mixture was stirred
at 25-45.degree. C. for 6 hr. The reaction mixture was filtered,
and hydroxylamine hydrochloride (14.1 g) and triethylamine (20.5 g)
were added. The mixture was stirred at 70-75.degree. C. for 1 hr
and acetic anhydride (75.3 g) was added. The mixture was stirred at
130-140.degree. C. for 6 hr and water (180 ml) was added to the
reaction mixture. Thereto was added 10% aqueous sodium hydroxide
solution (100 g) and the mixture was partitioned. The solvent was
evaporated under reduced pressure, and xylene (44 ml) and heptane
(71 ml) were added at 60.degree. C. The mixture was cooled to room
temperature and the resulting crystals were collected by filtration
and dried to give 1-(4'-fluorophenyl)-1,3-dihydro-
isobenzofuran-5-carbonitrile (35.8 g, 73%) as pale-yellow
crystals.
[0161] melting point 96-98.degree. C.
[0162] IR(KBr) .nu.=3050(w), 2867(m), 2228(s), 1603(s), 1510(s),
1224(s), 1157(m), 1048(s), 1031(s), 832(s)cm.sup.-1
[0163] .sup.1H-NMR(CDCl.sub.3, 400 MHz) .delta.=5.21(1H, d, J=13
Hz), 5.34(1H, d, J=13 Hz), 6.16(1H, s), 7.06(2H, t, J=9 Hz),
7.10(1H, d, J=8 Hz), 7.27(2H, dd, J=9 Hz, J=5 Hz), 7.55(1H, d, J=8
Hz), 7.60(1H, s) ppm.
EXAMPLE 22
Synthesis of
citalopram(1-(3-(dimethylamino)propyl)-1-(4'-fluorophenyl)-1,-
3-dihydroisobenzofuran-5-carbonitrile)
[0164] 60% Sodium hydride (0.96 g) was dispersed in THF (20 ml),
and to this suspension was added dropwise a solution of
1-(4'-fluorophenyl)-1,3-- dihydroisobenzofuran-5-carbonitrile (5.0
g) in THF (10 ml) at 40-50.degree. C. under a nitrogen atmosphere.
Thereto was added tetra n-butylammonium bromide (0.2 g), and a
solution of 3-(dimethylamino)propyl chloride (3.4 g) in t-butyl
methyl ether (18 ml) was added dropwise, which was followed by
stirring for 10 min. Further, 1,3-dimethyl-2-imidazolidinone (26.1
g, 25 ml) was added and the mixture was stirred at 61-64.degree. C.
for 6 hr. The reaction mixture was poured into ice water (83 ml)
and extracted 3 times with toluene (33 ml). The organic layer was
extracted 3 times with 20% aqueous acetic acid (41 ml), and the
obtained aqueous layer was neutralized with 25% aqueous sodium
hydroxide solution (120 g) and extracted 3 times with toluene (40
ml). The obtained organic layer was washed with water, and the
solvent was evaporated to give
1-(3-(dimethylamino)propyl)-1-(4'-fluorophenyl)-1,3-di-
hydroisobenzofuran-5-carbonitrile (citalopram base) as a viscous
oil (5.36 g, yield 79.1%).
[0165] .sup.1H-NMR(CDCl.sub.3, 400 MHz) .delta.=1.26-1.52(2H, m),
2.11-2.26(4H, m), 2.13(6H, s), 5.15(1H, d, J=13 Hz), 5.19(1H, d,
J=13 Hz), 7.00(2H, t, J=9 Hz), 7.39(1H, d, J=8 Hz), 7.43(2H, dd,
J=9 Hz, J=5 Hz), 7.50(1H, s), 7.59(1H, d, J=8 Hz) ppm.
[0166] This oil was converted to hydrobromide by a conventional
method and the obtained crystals had a melting point of
184-186.degree. C.
[0167] HPLC retention time and measurement conditions
[0168] Retention time; 10.5 min
[0169] Column; manufactured by GL Sciences, Inertsil(trademark)
[0170] ODS-2 4.6 mm.times.150 mm
[0171] Buffer solution; 0.01% aqueous trifluoroacetic acid
solution
[0172] Mobile phase; acetonitrile:buffer solution=2:8-7:3, linear
gradient is applied over 40 min
[0173] Flow rate; 1 ml/min
EXAMPLE 23
Synthesis of Citalopram
[0174] By the same reaction and post-treatment as in Example 22
except that N,N,N',N'-tetramethylethylenediamine (4.86 g) and
N,N-dimethyl formamide (25 ml) were successively added instead of
1,3-dimethyl-2-imidazolidinone (26.1 g, 25 ml),
1-(3-(dimethylamino)-prop-
yl)-1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile
(citalopram base) was obtained as a viscous oil (5.13 g, yield
75.7%). Hydrobromide thereof showed the same HPLC retention time
and melting point as obtained in Example 22.
EXAMPLE 24
Synthesis of Citalopram
[0175] 60% Sodium hydride (0.58 g) was dispersed in THF (12 ml),
and to this suspension was added dropwise a solution of
1-(4'-fluorophenyl)-1,3-- dihydroisobenzofuran-5-carbonitrile (3.0
g) in THF (6 ml) at 40-50.degree. C. under a nitrogen atmosphere.
Thereto was added tetra n-butylammonium bromide (0.12 g), and a
solution of 3-(dimethylamino)propyl chloride (2.0 g) in t-butyl
methyl ether (12 ml) was added dropwise, which was followed by
stirring for 10 min. Further, N,N,N',N'-tetramethylethylenediamine
(0.73 g) and N,N-dimethylformamide (14.2 g, 15 ml) were added and
the mixture was stirred at 61-64.degree. C. for 7 hr. The reaction
mixture was treated in the same manner as in Example 22 to give
1-(3-(dimethylamino)propyl)-1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran--
5-carbonitrile (citalopram base) as a viscous oil (3.14 g, yield
77.2%). Hydrobromide thereof showed the same HPLC retention time
and melting point as obtained in Example 22.
EXAMPLE 25
Synthesis of Citalopram
[0176] By the same reaction and post-treatment as in Example 24
except that 1,3-dimethyl-2-imidazolidinone (6.3 g, 6 ml) and
N,N-dimethylformamide (8.5 g, 9 ml) were added instead of
N,N,N',N'-tetramethylethylenediamine (0.73 g) and
N,N-dimethylformamide (15 ml),
1-(3-(dimethylamino)propyl)-1-(4'-fluorophenyl)-1,3-dihydroisobe-
nzofuran-5-carbonitrile (citalopram base) was obtained as a viscous
oil (2.88 g, yield 70.7%). Hydrobromide thereof showed the same
HPLC retention time and melting point as obtained in Example
22.
Comparative Example 2
Synthesis of Citalopram
[0177] In the same manner as in Example 22 except that the mixture
was stirred as it was at 61-64.degree. C. for 6 hr without adding
1,3-dimethyl-2-imidazolidinone (26.1 g, 25 ml), the reaction was
carried out. As a result, the reaction hardly proceeded.
Comparative Example 3
Synthesis of Citalopram
[0178] By the same reaction and post-treatment as in Example 22
except that N,N-dimethylformamide (23.6 g, 25 ml) was added instead
of 1,3-dimethyl-2-imidazolidinone (26.1 g, 25 ml) and the mixture
was stirred at 61-64.degree. C. for 7 hr,
1-(3-(dimethylamino)-propyl)-1-(4'--
fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (citalopram
base) was obtained as a viscous oil (4.12 g, yield 60.8%).
EXAMPLE 26
Synthesis of Citalopram
[0179] 60% Sodium hydride (0.58 g) was dispersed in toluene (12
ml), and to this suspension was added dropwise a solution of
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (3.0 g)
in THF (6 ml) at 40-50.degree. C. under a nitrogen atmosphere.
Thereto was added tetra n-butylammonium bromide (0.12 g), and a
solution of 3-(dimethylamino)propyl chloride (2.0 g) in toluene (12
ml) was added dropwise, which was followed by stirring for 10 min.
Further, N,N,N',N'-tetramethylethylenediamine (2.92 g) and dimethyl
sulfoxide (15 ml) were added and the mixture was-stirred at
61-64.degree. C. for 7 hr. The reaction mixture was treated in the
same manner as in Example 22 to give
1-(3-(dimethylamino)propyl)-1-(4'-fluorophenyl)-1,3-dihydroisobenzof-
uran-5-carbonitrile (citalopram base) as a viscous oil (2.79 g,
yield 68.6%). Hydrobromide thereof showed the same HPLC retention
time and melting point as obtained in Example 22.
EXAMPLE 27
Synthesis of Citalopram
[0180] Under nitrogen atmosphere, to a solution of
1-(4'-fluorophenyl)-1,3- -dihydroisobenzofuran-5-carbonitrile (3.0
g) in N,N-dimethylformamide (15 ml) were added tetra
n-butylammonium bromide (0.12 g) and
N,N,N',N'-tetramethylethylenediamine (2.92 g). Thereto was added
dropwise a solution of 3-(dimethylamino)propyl chloride (2.0 g) in
toluene (12 ml), and then a suspension of 60% sodium hydride (0.58
g) and liquid paraffin (1.5 ml) over 1.5 hr. The mixture was
stirred at 61-64.degree. C. for 7 hr. The reaction mixture was
treated in the same manner as in Example 22 to give
1-(3-(dimethylamino)propyl)-1-(4'-fluorophenyl)-1,3-di-
hydroisobenzofuran-5-carbonitrile (citalopram base) as a viscous
oil (2.69 g, yield 66.1%). Hydrobromide thereof showed the same
HPLC retention time and melting point as obtained in Example
22.
EXAMPLE 28
Synthesis of Citalopram
[0181] By the same reaction and post-treatment as in Example 27
except that dimethyl sulfoxide (15 ml) was used instead of
N,N-dimethylformamide (15 ml),
1-(3-(dimethylamino)propyl)-1-(4'-fluorophenyl)-1,3-dihydroisobe-
nzofuran-5-carbonitrile (citalopram base) was obtained as a viscous
oil (2.68 g, yield 65.9%). Hydrobromide thereof showed the same
HPLC retention time and melting point as obtained in Example
22.
EXAMPLE 29
Synthesis of Citalopram
[0182] Under a nitrogen atmosphere, to a solution of
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (9.00
g) in 1,3-dimethyl-2-imidazolidinone (54 ml) was added 60% sodium
hydride (1.73 g) at room temperature. 3-(dimethylamino)propyl
chloride hydrochloride (8.02 g) was neutralized with 10% aqueous
sodium hydroxide solution (39 g) and extracted twice with toluene
(13.5 ml). A toluene solution of 3-(dimethylamino)propyl chloride
(about 6.1 g) obtained by dehydrating the extract with potassium
carbonate and molecular sieves 3A was added dropwise to the
above-mentioned red brown 1,3-dimethyl-2-imidazolidinone solution
at room temperature under a nitrogen atmosphere. Tetra
n-butylammonium bromide (0.36 g) and
N,N,N',N'-tetramethylethylenediamine (4.37 g) were added and the
mixture was stirred at 60-62.degree. C. for 5 hr. The reaction
mixture was poured into ice water (149 ml) and extracted 3 times
with toluene (54 ml). The organic layer was extracted 3 times with
20% aqueous acetic acid solution (71 ml). The obtained aqueous
layer was neutralized with 25% aqueous sodium hydroxide solution
(210 g) and extracted 3 times with toluene (54 ml). The obtained
organic layer was washed with water, and potassium carbonate (3.6
g) and silica gel (1.8 g) were added. The mixture was thoroughly
stirred and filtered. The solvent was evaporated under reduced
pressure to give 1-(3-(dimethylamino)propyl)-
-1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile
(citalopram base) as a viscous oil (10.50 g, yield 86.0%).
Hydrobromide thereof showed the same HPLC retention time and
melting point as obtained in Example 22.
EXAMPLE 30
Synthesis of Citalopram
[0183] Sodium hydroxide (19.6 kg) was added to water (134 kg) for
dissolution, and a 65.6% aqueous solution (60.7 kg) of
3-(dimethylamino)propyl chloride hydrochloride was added dropwise
at 20-25.degree. C. Toluene (58.2 kg) was added and the mixture was
stirred and left standing to allow separation. Toluene (58.2 kg)
was added to the aqueous layer and the mixture was stirred, which
was followed by standing to allow separation. The organic layers
were combined and powdery anhydrous potassium carbonate (9 kg) and
molecular sieves 4A (1.7 kg) were added, which was followed by
stirring for 1 hr. The mixture was filtrated and the residue was
washed with toluene (27 kg) to give a solution of
3-(dimethylamino)propyl chloride in toluene.
[0184] A solution (639.9 kg, corresponding to
1-(4'-fluorophenyl)-1,3-dihy- droisobenzofuran-5-carbonitrile, 44.8
kg) of 1-(4'-fluorophenyl)-1,3-dihyd-
roisobenzofuran-5-carbonitrile in toluene obtained in the same
manner as in Example 21 was concentrated under reduced pressure at
30-50.degree. C. and toluene (539 kg) was evaporated. To the
residue was added toluene (27 kg) and a solution of
3-(dimethylamino)propyl chloride prepared in advance in toluene was
flown in, which was followed by the addition of
1,3-dimethyl-2-imidazolidinone (10 kg). Sodium hydride (64.8%, 9.1
kg) was added at 25-30.degree. C. and
1,3-dimethyl-2-imidazolidinone (183 kg) was added dropwise at
25-60.degree. C. over 4 hr 20 min. The mixture was reacted at
60-63.degree. C. for 6 hr and cooled to about 10.degree. C. The
reaction mixture was analyzed by HPLC. As a result, the residual
rate of 1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile
was 0.1%.
[0185] The reaction mixture was added dropwise to water (806 kg) at
about 5.degree. C., and toluene (233.5 kg) was added. After
stirring and extraction, the mixture was left standing to allow
separation. Toluene (233.5 kg) was added to the aqueous layer and
the mixture was stirred and extracted, which was followed by
separation. The extracted organic layers were combined and stirred
and extracted with a 5% aqueous solution (179 kg) of hydrochloric
acid, which was followed by separation. The organic layer was again
extracted with a 5% aqueous solution (179 kg) of hydrochloric acid
and partitioned. The aqueous layers extracted with hydrochloric
acid were combined. To the combined aqueous layer was added toluene
(234 kg), and a 25% aqueous solution (89.6 kg) of sodium hydroxide
was added dropwise at 25-35.degree. C. to give an alkaline
solution. The solution was stirred and extracted, which was stood
to allow separation. The aqueous layer was again extracted with
toluene (156.3 kg) and the organic layers were combined. The
organic layer was washed three times with water (268.7 kg). The
organic layer was dehydrated with powdery anhydrous potassium
carbonate (17.9 kg), silica gel (Merk 9385, 6.7 kg) was added, and
the mixture was stirred for 1 hr. The mixture was filtrated and the
residue was washed with toluene (39.1 kg). Toluene was evaporated
under reduced pressure at 40-65.degree. C. The amount of the
evaporated toluene was 425 kg. Acetone (35.5 kg) was added to the
residue for dissolution to give a solution of citalopram in
acetone. In the liquid amount (114.3 kg), citalopram base was
contained by 52.96 kg (yield 87.2%). The HPLC retention time of
hydrobromide of the crystals obtained by partial evaporation of
acetone was the same as those in Example 22.
Reference Example 1
Synthesis of
1-(3-(dimethylamino)propyl)-1-(4'-fluorophenyl)-1,3-dihydrois-
obenzofuran-5-carbonitrile hydrobromide
[0186] A solution (94.1 kg including citalopram 51.8 kg) of
citalopram in acetone produced in Example 30 was added to acetone
(163.4 kg) and hydrogen bromide (13.2 kg) was blown in over 3 hr at
25-35.degree. C. After aging for 3 hr, the mixture was cooled to
about 5.degree. C. and aged at 0-5.degree. C. for three more hours.
The crystals were collected by filtration and washed with acetone
(40.9 kg) cooled to 0-5.degree. C. The crystals were dried under
reduced pressure at 30-50.degree. C. to give citalopram
hydrobromide (54.9 kg, yield 83.7%).
[0187] Melting point:180-183.degree. C.
[0188] Tapped density: 0.29 kg/L by standing, 0.32 kg/L by
processing
Reference Example 2
Synthesis of
1-(3-(dimethylamino)propyl)-1-(4'-fluorophenyl)-1,3-dihydrois-
obenzofuran-5-carbonitrile (citalopram base)
[0189] To a suspension of 60% sodium hydride (4.2 g) dispersed in
THF (135 ml) was added dropwise at 40-50.degree. C. a solution of
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (21.6
g) in THF (40 ml). The mixture was stirred at the same temperature
for 30 min and a solution of 3-dimethylaminopropyl chloride (14.4
g) in t-butyl methyl ether (60 ml) was added dropwise. The mixture
was stirred for 10 min and dimethyl sulfoxide (135 ml) was added
dropwise. The mixture was stirred at 60-70.degree. C. for 5 hr. The
reaction mixture was poured into ice water (800 ml) and extracted 3
times with toluene (250 ml). The organic layer was extracted twice
with 20% aqueous acetic acid solution (250 ml). The aqueous layer
was neutralized, extracted twice with toluene (250 ml) and washed
with water. The solvent was evaporated to give
1-(3-(dimethylamino)propyl)-1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran--
5-carbonitrile (citalopram base) as a viscous oil (17.9 g,
61.1%).
[0190] .sup.1H-NMR(CDCl.sub.3, 400 MHz) .delta.=1.26-1.52(2H, m),
2.11-2.26(4H, m), 2.13(6H, s), 5.15(1H, d, J=13 Hz), 5.19(1H, d,
J=13 Hz), 7.00(2H, t, J=9 Hz), 7.39(1H, d, J=8 Hz), 7.43(2H, dd,
J=9 Hz, J=5 Hz), 7.50(1H, s), 7.59(1H, d, J=8 Hz) ppm.
[0191] This oil was converted to hydrobromide by a conventional
method and the obtained crystals had a melting point of
184-186.degree. C.
[0192] As described in the foregoing, the production method of the
present invention enables industrial and economical production of
citalopram useful as an antidepressant, at a high yield. The new
production method of compound [III], which is a key compound for
the synthesis of citalopram, can widen the possibility of the
synthesis of compound [III].
[0193] This application is based on patent application Nos.
039936/2000 and 065527/2000 filed in Japan, the contents of which
are hereby incorporated by reference.
* * * * *