U.S. patent application number 09/981919 was filed with the patent office on 2002-03-21 for process for preparing pyridinemethanol compounds.
This patent application is currently assigned to Sumika Fine Chemicals Co., Ltd.. Invention is credited to Iishi, Eiichi, Yoshikawa, Kanami.
Application Number | 20020035255 09/981919 |
Document ID | / |
Family ID | 18431365 |
Filed Date | 2002-03-21 |
United States Patent
Application |
20020035255 |
Kind Code |
A1 |
Iishi, Eiichi ; et
al. |
March 21, 2002 |
Process for preparing pyridinemethanol compounds
Abstract
A pyridinemethanol compound is an important intermediate for a
mirtazapine which is useful as an antidepressant. The
pyridinemethanol compound is obtained by reducing potassium
pyridinecarboxylate represented by the formula (I): 1 with a metal
hydride.
Inventors: |
Iishi, Eiichi; (Osaka,
JP) ; Yoshikawa, Kanami; (Nara, JP) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Assignee: |
Sumika Fine Chemicals Co.,
Ltd.
|
Family ID: |
18431365 |
Appl. No.: |
09/981919 |
Filed: |
October 19, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09981919 |
Oct 19, 2001 |
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09706803 |
Nov 7, 2000 |
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09706803 |
Nov 7, 2000 |
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PCT/JP00/05384 |
Aug 11, 2000 |
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Current U.S.
Class: |
544/360 |
Current CPC
Class: |
C07D 401/04 20130101;
A61P 25/24 20180101 |
Class at
Publication: |
544/360 |
International
Class: |
C07D 43/04 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 13, 1999 |
JP |
11-353514 |
Claims
What is claimed is:
1. A process for preparing a pyridinemethanol compound represented
by the formula (II): 10comprising reducing potassium
pyridinecarboxylate represented by the formula (I): 11with a metal
hydride.
2. The process according to claim 1, wherein said potassium
pyridinecarboxylate represented by the formula (I) is prepared by
reacting a pyridinecarbonitrile compound represented by the formula
(III): 12or a salt thereof with potassium hydroxide in butanol.
3. A process for preparing mirtazapine comprising adding a
pyridinemethanol compound represented by the formula (II): 13to
sulfuric acid.
4. The process according to claim 3, wherein the pyridinemethanol
compound represented by the formula (II) is added in divided
portions to sulfuric acid.
5. The process according to claim 3 or 4, wherein the formed
mirtazapine is crystallized with toluene and heptane.
Description
[0001] This application is a continuation-in-part application of
PCT/JP00/05384, the entire contents of which are incorporated
herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to a pyridinemethanol
compound. More specifically, the present invention relates to a
process capable of simply and industrially preparing a
pyridinemethanol compound, which is an important intermediate for
mirtazapine which is useful as an antidepressant, and a process for
preparing mirtazapine using the pyridinemethanol compound.
[0004] 2. Discussion of the Related Art
[0005] Conventionally, as a process for preparing a
pyridinemethanol compound represented by the formula (II): 2
[0006] there has been proposed a process comprising reducing a
pyridinecarboxylic acid represented by the formula (IV): 3
[0007] using lithium aluminum hydride (U.S. Pat. No.
4,062,848).
[0008] However, there are some defects in this process that the
process is not economical because it is required to use an
expensive reagent lithium aluminum hydride in a large amount as
much as 8 times equivalent based on pyridinecarboxylic acid.
[0009] Also, in this process, pyridinecarboxylic acid is obtained
by dissolving a pyridinecarbonitrile compound in ethanol,
hydrolyzing the pyridinecarbonitrile compound with potassium
hydroxide under reflux for 24 hours, and thereafter adding an acid
thereto to liberate pyridinecarboxylic acid.
[0010] However, there are some defects in this process that its
production efficiency is poor because the hydrolysis requires a
long period of time and there is a necessity to liberate the
resulting pyridinecarboxylic acid.
[0011] In addition, conventionally, as a process for preparing
mirtazapine, there has been known a process as disclosed in U.S.
Pat. No. 4,062,848.
[0012] However, there are some defects in the process that stirring
is difficult because concentrated sulfuric acid is added in a thin
stream to the pyridinemethanol compound, so that the reaction
control would be difficult, and that a large amount of an aqueous
ammonia is required in order to make the reaction mixture alkaline
with the aqueous ammonia. In addition, there are some defects in
the process that even the impurities are extracted because the
reaction product is extracted with chloroform, and that mirtazapine
having a high purity cannot be obtained because crystallization is
inhibited during the crystallization from an ether.
[0013] The present invention has been accomplished in view of the
prior art described above. An object of the present invention is to
provide a process capable of economically and efficiently preparing
a pyridinemethanol compound.
[0014] Another object of the present invention is to provide a
process capable of efficiently preparing mirtazapine from the
above-mentioned pyridinemethanol compound on an industrial scale,
to give mirtazapine having a high purity.
[0015] These and other objects of the present invention will be
apparent from the following description.
SUMMARY OF THE INVENTION
[0016] According to the present invention; there are provided:
[0017] (1) a process for preparing a pyridinemethanol compound
represented by the formula (II): 4
[0018] comprising reducing potassium pyridinecarboxylate
represented by the formula (I): 5
[0019] with a metal hydride; and
[0020] (2) a process for preparing mirtazapine comprising adding a
pyridinemethanol compound represented by the formula (II): 6
[0021] to sulfuric acid.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 is a microphotograph of
2-(4-methyl-2-phenylpiperazin-1-yl) pyridine-3 -methanol obtained
in Example 4.
[0023] FIG. 2 is a microphotograph of
2-(4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol obtained in
Comparative Example 1.
DETAILED DESCRIPTION OF THE INVENTION
[0024] The potassium pyridinecarboxylate represented by the formula
(I): 7
[0025] can be easily prepared by using a pyridinecarbonitrile
compound represented by the formula (III): 8
[0026] or a salt thereof as a starting material, and reacting the
pyridinecarbonitrile compound or a salt thereof with potassium
hydroxide in butanol.
[0027] As described above, one of the great features of the present
invention resides in that the pyridinecarbonitrile compound or a
salt thereof is reacted with potassium hydroxide in butanol.
[0028] Conventionally, there is exhibited an especially remarkably
excellent effect that the reaction time can be surprisingly
shortened for about not less than 15 hours when both of the
compounds are reacted in butanol, while a reaction time of 24 hours
or so is required when ethanol is used.
[0029] Furthermore, there is exhibited an especially remarkably
excellent effect that potassium pyridinecarboxylate formed by the
reaction of the pyridinecarbonitrile compound or a salt thereof
with potassium hydroxide can be easily and efficiently extracted
from the reaction solution because butanol is used in the present
invention.
[0030] The pyridinecarbonitrile compound is concretely
2-(4-methyl-2-phenylpiperazin-1-yl) pyridine-3-carbonitrile. As the
salt of the pyridinecarbonitrile compound, there can be cited, for
instance, oxalates, hydrochlorides, methanesulfonates, and the like
of 2-(4-methyl-2-phenylpiperazin- 1 -yl) pyridine-3
-carbonitrile.
[0031] As the butanol, there can be cited, for instance, 1-butanol,
isobutanol, sec-butanol, and mixed solvents thereof. Among these
butanols, 1-butanol is preferable. The amount of the butanol is not
limited to specified ones. It is preferable that the amount is
usually 300 to 800 parts by weight or so, preferably 400 to 600
parts by weight or so based on 100 parts by weight of the
pyridinecarbonitrile compound or a salt thereof, from the
viewpoints of shortening the reaction time and improving the volume
efficiency.
[0032] As the form of potassium hydroxide, there can be usually
cited flaky, granular, and the like. Among them, flaky is
preferable from the viewpoint of solubility.
[0033] It is preferable that the amount of potassium hydroxide is
usually 7 to 14 moles, preferably 8 to 12 moles per one mole of the
pyridinecarbonitrile compound, from the viewpoint of shortening the
reaction time. When the salt of the pyridinecarbonitrile compound
is used, it is preferable that potassium hydroxide is further added
in an amount required for neutralization because potassium
hydroxide is consumed during the neutralization of the salt.
[0034] It is preferable that the reaction temperature of the
pyridinecarbonitrile compound or a salt thereof with potassium
hydroxide is usually 120.degree. to 145.degree. C., preferably
120.degree. to 140.degree. C., more preferably 130.degree. to
140.degree. C., from the viewpoint of shortening the reaction time.
As described above, as to the temperature of the reaction of the
pyridinecarbonitirle compound or a salt thereof with potassium
hydroxide, butanol does not boil even at a temperature of not lower
than the boiling point of the butanol (e.g. boiling point of
1-butanol: about 118.degree. C.) under atmospheric pressure, since
potassium hydroxide is used. Therefore, the reaction of both
compounds can be efficiently carried out.
[0035] It is preferable that the reaction is carried out, for
instance, in an atmosphere of an inert gas such as nitrogen gas or
argon gas, from the viewpoint of preventing coloration of the
resulting potassium pyridinecarboxylate represented by the formula
(I).
[0036] The period of time required for the reaction of the
pyridinecarbonitrile compound or a salt thereof with potassium
hydroxide cannot be absolutely determined, because it differs
depending upon the reaction temperature of both compounds. The
period of time is usually 5 to 10 hours or so.
[0037] The termination of the reaction can be confirmed by the
disappearance of the starting materials using, for instance,
high-performance liquid chromatography (hereinafter referred to as
"HPLC") or the like.
[0038] The thus obtained potassium pyridinecarboxylate represented
by the formula (I) is specifically potassium
2-(4-methyl-2-phenylpiperazin-1-yl) pyridine-3-carboxylate.
[0039] Next, potassium hydroxide in the reaction solution can be
removed by adding water to the reaction solution, and allowing the
reaction solution to separate into an organic layer and an aqueous
layer, thereby transferring the potassium hydroxide contained in
the reaction solution to the aqueous layer.
[0040] The amount of water used in the separation is not limited to
specified ones. It is preferable that the amount of water is
usually 400 to 600 parts by weight or so based on 100 parts by
weight of the pyridinecarbonitrile compound or a salt thereof, from
the viewpoints of improving separability and volume efficiency.
[0041] It is preferable that the temperature during the separation
is 30.degree. to 60.degree. C., from the viewpoints of preventing
precipitation of alkalis and improving extraction efficiency.
[0042] The potassium pyridinecarboxylate can be collected by
further extracting the aqueous layer with a butanol after the
separation, allowing to separate into a butanol layer and an
aqueous layer, and transferring the potassium pyridinecarboxylate
existing in the aqueous layer to the butanol layer.
[0043] Next, the above-mentioned organic layer and butanol layer
can be combined, and the butanol and water can be distilled away
from the resulting liquid mixture to concentrate the liquid
mixture.
[0044] The butanol and water can be distilled away under reduced
pressure. It is preferable that the pressure during the
distillation is usually 1 to 20 kPa, from the viewpoint of
increasing the rate for distillation. In addition, it is desired
that the temperature during the distillation of the butanol and
water is usually 30 to 80.degree. C., preferably 40.degree. to
60.degree. C., from the viewpoint of increasing the rate for
distillation.
[0045] The amount of the butanol and water distilled away is not
limited to specified ones. It is preferable that the amount is
usually 400 to 900 parts by weight, preferably 600 to 900 parts by
weight based on 100 parts by weight of the pyridinecarbonitrile
compound or a salt thereof, from the viewpoint of sufficiently
distilling away water.
[0046] Next, in order to further distill away moisture and the
butanol remaining in the above-mentioned liquid mixture, it is
preferable that the liquid mixture is mixed with a hydrocarbon, and
the resulting reaction solution is heated to azeotropically distill
away the butanol and water.
[0047] As the hydrocarbon, there can be cited, for instance,
toluene, xylene, benzene, and the like. Among them, xylene is
preferable.
[0048] The amount of the hydrocarbon differs depending upon the
amount of the butanol and water contained in the mixed solution. It
is desired that the amount is usually 100 to 600 parts by weight,
preferably 200 to 300 parts by weight based on 100 parts by weight
of the pyridinecarbonitrile compound or a salt thereof, from the
viewpoint of efficiently azeotropically distilling away.
[0049] It is desired that the temperature during the azeotropic
distillation usually satisfies the internal temperature of
110.degree. to 130.degree. C., preferably 120.degree. to
130.degree. C., from the viewpoint of efficiently azeotropically
distilling away.
[0050] It is preferable that the azeotropic distillation is carried
out until the water content in the mixed solution attains to not
more than 1% by weight, preferably not more than 0.5% by weight,
when determined by Karl-Fischer method, from the viewpoint of
efficiently progressing the subsequent reduction reaction step.
[0051] Since the hydrocarbon and the butanol are contained in the
solution after the azeotropic distillation, it is preferable to
distill away these solvents. The above distillation can be carried
out by heating the reaction solution. In this case, it is desired
that the heating temperature usually satisfies the internal
temperature of 130.degree. to 140.degree. C., preferably
135.degree. to 140.degree. C., from the viewpoint of sufficiently
distilling away the hydrocarbon and the butanol.
[0052] It is preferable that the amount of the hydrocarbon
distilled away is usually 65 to 90% by weight or so, preferably 80
to 90% by weight or so of the amount of the hydrocarbon used, from
the viewpoint of sufficiently distilling away the butanol.
[0053] The resulting potassium pyridinecarboxylate may be isolated.
It is preferable that a one-pot reaction of directly reducing a
concentrate is carried out. The pyridinemethanol compound
represented by the formula (II): 9
[0054] can be prepared by reducing potassium pyridinecarboxylate
with a metal hydride.
[0055] One of the great features of the present invention resides
in that potassium pyridinecarboxylate is reduced with a metal
hydride. The potassium pyridinecarboxylate has an excellent
characteristic that it easily dissolves in an ether solvent such as
tetrahydrofuran (hereinafter referred to as THF) which is used
during the reduction. Therefore, the amount of the metal hydride
which is used during reduction can be decreased, and at the same
time the potassium pyridinecarboxylate can be easily reduced with
the metal hydride.
[0056] During the reduction of the potassium pyridinecarboxylate
with the metal hydride, the solution from which the hydrocarbon is
distilled away obtained as mentioned above can be directly used.
When the above solution is used, the pyridinemethanol compound can
be directly and efficiently obtained without the isolation of the
potassium pyridinecarboxylate.
[0057] In addition, in the present invention, there is employed not
a conventional process of reducing the pyridinecarboxylic acid with
lithium aluminum hydride, but a process of reducing the potassium
pyridinecarboxylate with the metal hydride. In the case where this
process is employed, there is taken in an excellent effect that the
amount of the metal hydride can be remarkably decreased. As the
metal hydride, there can be cited lithium aluminum hydride,
bis(2-methoxyethoxy)aluminum sodium hydride, diisobutylaluminum
hydride, and the like. Among them, lithium aluminum hydride can be
favorably used.
[0058] During the reduction of the potassium pyridinecarboxylate
with the metal hydride, there can be used a solution or suspension
in which the metal hydride is previously dissolved or suspended in
an organic solvent. As the organic solvent, there can be cited THF,
diethyl ether, and the like. Among them, THF can be favorably used,
from the viewpoint of easy handling.
[0059] In addition, when using a solution in which the
above-mentioned hydrocarbon is distilled away, in order to
efficiently reduce the potassium pyridinecarboxylate contained in
the solution, it is preferable that the solution is previously
diluted with the above-mentioned organic solvent. Among the
above-mentioned organic solvents, THE can be favorably used.
[0060] It is desired that the total used amount of the organic
solvents is usually 500 to 1200 parts by weight or so, preferably
700 to 900 parts by weight based on 100 parts by weight of the
potassium pyridinecarboxylate, from the viewpoint of accelerating
the reduction reaction.
[0061] In addition, it is preferable that the amount of the metal
hydride is usually 2.5 to 5 moles, preferably 3 to 4 moles per one
mole of the potassium pyridinecarboxylate, from the viewpoint of
accelerating the reduction reaction.
[0062] It is preferable that the atmosphere during the reduction of
the potassium pyridinecarboxylate is an inert gas atmosphere. As
the inert gas, there can be cited, for instance, nitrogen gas,
argon gas, and the like. Among them, nitrogen gas is
preferable.
[0063] The reduction of the potassium pyridinecarboxylate can be
easily carried out by, for instance, adding in a thin stream a
dilute solution prepared by diluting with an organic solvent the
above-mentioned solution in which the hydrocarbon is distilled
away, to a solution or suspension prepared by dissolving or
suspending a metal hydride in an organic solvent. During the
reduction, it is preferable that each of the liquid temperatures of
the solution and suspension, prepared by dissolving or suspending a
metal hydride in an organic solvent, and the dilute solution is
10.degree. to 50.degree. C., preferably 15.degree. to 35.degree.
C., from the viewpoint of efficiently progressing the reduction
reaction.
[0064] The period of time required for the reduction reaction of
the potassium pyridinecarboxylate cannot be absolutely determined
because the period of time differs depending upon the amount of the
potassium pyridinecarboxylate, the reaction temperature, and the
like. The period of time is usually 1 to 6 hours or so.
[0065] The termination of the reaction can be confined by the
disappearance of the potassium pyridinecarboxylate by, for
instance, HPLC, or the like.
[0066] After the termination of the reaction, it is preferable that
water is added in a thin stream to the reaction solution. It is
desired that the amount of water is 90 to 110 parts by weight,
preferably 95 to 100 parts by weight based on 100 parts by weight
of the metal hydride. Since the reaction solution generates heat
during the addition of water, it is preferable that the addition of
water is carried out so that the liquid temperature of the reaction
solution can be 0.degree. to 20.degree. C.
[0067] Next, an aqueous alkali is added in a thin stream to the
reaction solution. As the alkali usable for the aqueous alkali,
there can be cited alkali metal hydroxides such as sodium hydroxide
and potassium hydroxide. Among them, sodium hydroxide is
preferable. When the aqueous sodium hydroxide is used as an aqueous
alkali, it is preferable that the concentration of sodium hydroxide
is usually 20 to 25% by weight or so. It is desired that the amount
of sodium hydroxide is usually 0.1 to 0.25 moles, preferably 0.15
to 0.2 moles per one mole of the metal hydride.
[0068] During the addition of the aqueous alkali in a thin stream,
it is desired that the liquid temperature of the reaction solution
is 0.degree. to 30.degree. C., preferably 0.degree. to 15.degree.
C.
[0069] Next, in order to improve the slurry property of this
reaction solution, it is preferable to add water thereto. It is
desired that the amount of water is 200 to 500 parts by weight,
preferably 250 to 400 parts by weight based on 100 parts by weight
of the metal hydride. In addition, it is desired that the
temperature during addition of water in a thin stream is 0.degree.
to 30.degree. C., preferably 0.degree. to 20.degree. C.
[0070] In order to improve the filterability of a metal hydroxide
formed from the metal hydride by hydrolysis, it is desired that the
reaction solution is aged at 15.degree. to 30.degree. C. for 30
minutes to 4 hours, preferably at 20.degree. to 25.degree. C. for 1
to 2 hours.
[0071] Next, the reaction solution is filtered to collect the metal
hydroxide by filtration. It is preferable that the liquid
temperature of the reaction solution during the filtration is
15.degree. to 25.degree. C.
[0072] Since the desired compound, pyridinemethanol compound
represented by the formula (II) remains in the collected metal
hydroxide, it is preferable that the metal hydroxide is washed with
a solvent such as THF. The amount of the solvent is not limited to
specified ones. It is desired that the amount of the solvent is
usually 500 to 3000 parts by weight, preferably 1000 to 2000 parts
by weight based on 100 parts by weight of the metal hydride.
[0073] Next, THF and water are distilled away from the filtrate
solution under atmospheric pressure until its internal temperature
attains to about 110.degree. C. It is preferable that its
distillation amount is 60 to 90% by weight, preferably 65 to 80% by
weight of the amount of the THF used in dissolving and reducing the
potassium pyridinecarboxylate used.
[0074] Next, the pyridinemethanol compound is crystallized. It is
preferable that the crystallization is carried out by adding
heptane in a thin stream to a solution after distillation. The
amount of heptane is not limited to specified ones, which may be
usually the amount that can sufficiently crystallize the
pyridinemethanol compound. It is desired that the amount of heptane
is usually 50 to 300 parts by weight, preferably 90 to 200 parts by
weight based on 100 parts by weight of the potassium
pyridinecarboxylate. It is desired that the temperature during the
addition of heptane in a thin stream is 40.degree. to 90.degree.
C., preferably 50.degree. to 70.degree. C. The period of time for
the addition in a thin stream may depend upon the amount of the
starting materials. The period of time is usually 1 to 2 hours.
[0075] In addition, during the crystallization, seed crystals may
be added. The seed crystals may be added at the beginning of the
addition of heptane in a thin stream or in the course of addition
in a thin stream. It is preferable that the seed crystals are added
at the beginning of the addition of heptane in a thin stream. The
amount of the seed crystals is not limited to specified ones. It is
preferable that the amount is usually 0.5 to 5% by weight or so of
the potassium pyridinecarboxylate. The temperature during the
addition of the seed crystals may be 50.degree. to 65.degree. C. or
so.
[0076] After the termination of the addition of heptane in a thin
stream, it is preferable that aging of the slurry mixture is
carried out with cooling. It is preferable that the aging with
cooling is carried out at 0.degree. to 5.degree. C. for 30 minutes
to 2 hours.
[0077] Thereafter, the slurry mixture is filtered, and the residue
is washed. The filtration temperature may be 0.degree. to 5.degree.
C. Washing can be carried out by using a mixed solvent prepared by
mixing an equal volume of toluene and heptane, and cooling to
0.degree. to 5.degree. C. The amount of the mixed solvent is not
limited to specified ones. It is preferable that the amount is
usually 100 to 150 parts by volume based on 100 parts by weight of
the potassium pyridinecarboxylate.
[0078] It is preferable that the pyridinemethanol compound is
usually dried at 50 to 60.degree. C. under reduced pressure of 0.6
to 14 kPa.
[0079] The pyridinemethanol compound has a rod-like crystal form as
shown in FIG. 1, and an average particle diameter is 75 to 90
.mu.m. Therefore, the pyridinemethanol compound has a desired
crystal form, from the viewpoints of filtration, drying, and the
like.
[0080] In addition, in the present invention, mirtazapine can be
prepared by using the pyridinemethanol compound. More specifically,
mirtazapine can be prepared by adding the pyridinemethanol compound
to sulfuric acid.
[0081] It is preferable that the atmosphere during the addition of
the pyridinemethanol compound to sulfuric acid is, for instance, an
atmosphere of an inert gas such as nitrogen gas or argon gas.
[0082] As sulfuric acid, there can be favorably used a concentrated
sulfuric acid of which concentration is 97 to 99%. It is desired
that the temperature of sulfuric acid during the addition of the
pyridinemethanol compound is 0.degree. to 40.degree. C., preferably
50 to 35.degree. C., from the viewpoints of suppressing heat
generation and suppressing the formation of impurities in a tarred
state.
[0083] When the pyridinemethanol compound is added to sulfuric
acid, it is preferable that the pyridinemethanol compound is added
in divided portions to sulfuric acid, from the viewpoint of
efficiently progressing the reaction. For instance, it is
preferable that the pyridinemethanol compound is added in 5 to 20
divided portions to sulfuric acid.
[0084] It is desired that the amount of sulfuric acid is usually
300 to 400 parts by weight, preferably 350 to 400 parts by weight
based on 100 parts by weight of the pyridinemethanol compound.
[0085] After the addition of the pyridinemethanol compound to
sulfuric acid, it is preferable that the mixture is stirred at a
temperature of 30 to 40.degree. C. or so for 7 to 10 hours or so,
in order to accelerate the reaction.
[0086] Thus, the pyridinemethanol compound is subjected to
dehydration and ring closure, and the end point of the ring closure
reaction can be confirmed by HPLC.
[0087] Next, it is preferable to add water to the resulting
reaction solution by means such as addition of water in a thin
stream, in order to decrease the concentration of sulfuric acid. It
is preferable that the amount of water is 100 to 200 parts by
weight or so based on 100 parts by weight of the reaction solution,
from the viewpoint of operability. In addition, it is preferable
that the liquid temperature of the reaction solution during the
addition of water is 0.degree. to 30.degree. C. or so, from the
viewpoints of suppressing heat generation and suppressing formation
of impurities (tarred product).
[0088] Next, it is preferable that an aqueous alkali is added to
the reaction solution for the purpose of neutralization. As the
alkali, there can be cited, for instance, sodium hydroxide,
potassium hydroxide, sodium carbonate, and the like. Among them,
sodium hydroxide is preferable. It is desired that the
concentration of the alkali hydroxide in the aqueous alkali is 20
to 25% by weight, from the viewpoint of operability. It is desired
that the amount of the aqueous alkali hydroxide is 50 to 250 parts
by weight, preferably 80 to 110 parts by weight based on 100 parts
by weight of the reaction solution.
[0089] After the addition of the aqueous alkali hydroxide, it is
desired that the pH of its solution is adjusted to 1 to 3,
preferably to 1 to 2, in order not to precipitate crystals. The
adjustment of the pH can be carried out by, for instance, adding
sodium hydroxide or the like to the solution.
[0090] After the adjustment of the pH, it is preferable that
decolorizing carbon is added to its solution for decolorizing the
solution.
[0091] Next, mirtazapine can be extracted by filtering this
solution, and adding toluene to the filtrate as occasion
demands.
[0092] It is desired that the amount of toluene is 100 to 400 parts
by weight, preferably 200 to 300 parts by weight based on 100 parts
by weight of the pyridinemethanol compound, from the viewpoint of
increasing yields. After the addition of toluene, it is preferable
that an alkali is added to the mixture at a temperature of
20.degree. to 50.degree. C. to adjust its pH of 8 to 12 in order to
completely end the neutralization. As the alkali, there can be
cited, for instance, an aqueous sodium hydroxide and the like.
[0093] Next, it is preferable that this solution is heated to a
temperature of 75.degree. to 80.degree. C. in order to dissolve the
crystals, thereby improving separability.
[0094] When this solution is allowed to stand, the mixture is
separated into two layers. Among them, heptane is added to the
organic layer in order to crystallize mirtazapine. It is desired
that the temperature during the addition of heptane is 40.degree.
to 70.degree. C., preferably 50.degree. to 60.degree. C., from the
viewpoint of improving filterability. It is desired that the amount
of heptane is 50 to 200 parts by weight, preferably 70 to 100 parts
by weight based on 100 parts by weight of toluene, from the
viewpoint of increasing yields. In addition, during the addition of
heptane, it is preferable that the heptane is added in a thin
stream. It is desired that its addition in a thin stream is carried
out over a period of 1 to 4 hours, preferably 1 to 2 hours.
[0095] Next, it is preferable that the resulting solution is
gradually cooled to a temperature of 0 to 5.degree. C. over a
period of 1 to 5 hours, preferably 2 to 3 hours, in order to form a
uniform crystal and to increase yields.
[0096] Thus, the mirtazapine can be crystallized, and the crystals
may be washed with a mixed solvent, prepared by, for instance,
mixing toluene with heptane, and cooling the mixture to 0.degree.
to 5.degree. C. In this case, the ratio of toluene to heptane may
be 70 to 100 parts by weight of heptane or so based on 100 parts by
weight of toluene.
[0097] Next, the crystals may be dried under reduced pressure at a
temperature of 50.degree. to 60.degree. C. or so as occasion
demands.
[0098] Thus, mirtazapine can be obtained.
EXAMPLES
[0099] Next, the present invention will be described more
specifically on the basis of the examples, without intending to
limit the present invention thereto.
Example 1
[0100] To 162 g of 1-butanol were added 60.93 g of potassium
hydroxide and 40 g (0.1086 moles) of
2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-carb- onitrile
oxalate, and the resulting mixture was heated at 125 to 135.degree.
C. As a result, it was confirmed by HPLC that the raw material
2-(4-methyl-2-phenylpiperazin-1-yl) pyridine-3-carbonitrile oxalate
disappeared after about 7 hours passed from the addition.
[0101] Two-hundred grams of water was added to the reaction
solution obtained above, and the mixture was allowed to separate
into two layers at 40 to 50.degree. C. The aqueous layer was
further extracted with 34 g of 1-butanol. The butanol layers were
combined together, and its pressure was reduced to 2.6 to 13 kPa.
Thereafter, the mixture was concentrated at 40.degree. to
60.degree. C., to distill off 204 g of the solvent.
[0102] Next, 86 g of xylene was added to the resulting solution,
and the mixture was subjected to azeotropic dehydration at an
internal temperature of 125.degree. to 135.degree. C. When the
water content of the mixture was reduced to 0.487% by weight
(determined by Karl-Fischer method), the mixture was concentrated
at 135.degree. to 140.degree. C. under atmospheric pressure, to
distill off 74 g of xylene and water.
[0103] There could be confined that the resulting compound was
potassium 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-carboxylate
from the finding that the retention time in HPLC and the infrared
absorption spectrum (hereinafter referred as "IR") of the resulting
compound were identical to those of separately prepared potassium
2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-carboxylate. NMR and
IR of the resulting potassium 2-(4-methyl-2-phenylpiperazin-l-yl)
pyridine-3-carboxylate are as follows.
[0104] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta.=2.00 (br, 1H),
2.10 (s, 3H), 2.32 (br, 1H), 2.53 (br, 1H), 2.85 -2.87 (m, 1H),
3.25 -3.33 (m, 2H), 3.65 (br, 1H), 5.65 (br, 1H), 6.39 (br, 1H),
6.78 -7.52 (m, 5H), 8.09 (br, 1H) ppm IR (KBr) v =1571, 1453, 1432,
1397, 1374, 759, 705 cm.sup.-1
Reference Example
[0105] Potassium
2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-carboxylate obtained
in Example 1 was formed into a free acid with hydrochloric acid, to
give 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-carboxylic
acid.
[0106] NMR and IR of the resulting
2-(4-methyl-2-phenylpiperazin-1-yl) pyridine-3-carboxylic acid are
as follows.
[0107] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta.=2.47 (s, 3H), 2.60
-2.66 (m, 2H), 3.1 -3.156 (m, 3H), 3.486 -3.49 (m, 1H), 4.81 -4.848
(d, 2H), 7.1 -7.266 (m, 6H), 8.318 -8.342 (m, 1H), 8.514 -8.531 (m,
1H) ppm IR (KBr) v =1571, 1456, 1429, 1386, 1136, 769 cm.sup.-1
Example 2
[0108] Eighty-nine grams of THF was added to the reaction solution
obtained in Example 1, to give a THF solution.
[0109] The THF solution was added in a thin stream to a solution
prepared by dissolving 12.5 g of lithium aluminum hydride in 234 g
of THF at 20.degree. to 30.degree. C. over 30 minutes, and the
mixture was stirred at the same temperature for 3 hours and 30
minutes.
[0110] The disappearance of potassium
2-(4-methyl-2-phenylpiperazin-1-yl) pyridine-3-carboxylate was
confirmed by HPLC, and 12.2 g of water was added in a tin stream
thereto at 20.degree. to 30.degree. C. To the mixture were added
12.2 g of a 20% by weight aqueous sodium hydroxide and subsequently
38 g of water, and the mixture was heated for 1 hour.
[0111] The precipitated crystals were filtered, washed with 45 g of
THF, and 375 g of THF was distilled off under atmospheric
pressure.
[0112] Forty-two grams of heptane was added in a tin stream to the
distilled residue at 48.degree. to 49.degree. C. over 30 minutes
with stirring. The mixture was stirred at 0.degree. to 5.degree. C.
for one hour, filtered at the same temperature, washed with a mixed
solution of 43 g of toluene and 34 g of heptane, and dried, to give
a compound as crystals (yield: 70.78%). There could be confirmed
that the resulting compound was
2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol (21.78 g)
from the finding that the above compound had the following physical
properties:
[0113] Melting point: 124.degree. to 126.degree. C.
[0114] .sup.1H-NMR (.delta.:ppm): 8.16 (d, 1H, 2-H: pyridine), 7.36
(d, 1H, 4-H: pyridine), 7.29 (d, 2H, 2-H: phenyl), 7.13 (t, 2H,
3-H: phenyl), 7.07 (d, 1H, 4-H: phenyl), 6.88 (dd, 1H, 3-H:
pyridine), 5.3 (br, 1H, OH), 4.86, 4.60 (d, 2H, CH.sub.2---OH),
4.70 (dd, 1H, 2-H: piperazine), 3.18 (m, 2H, piperazine), 2.96 (m,
2H, piperazine), 2.46 (m, 1H, piperazine), 2.34 (m, 1H,
piperazine), 2.37 (s, 1H, N-CH.sub.3)
Example 3
[0115] To 822 kg of 1-butanol was added 309.5 kg of potassium
hydroxide flake to dissolve, and 202.9 kg of
2-(4-methyl-2-phenylpiperazin-1-yl)pyr- idine-3-carbonitrile
oxalate was added thereto at 30.degree. to 50.degree. C. in divided
portions. The mixture was heated to 130.degree. to 140.degree. C.,
and stirred at the same temperature for 9 hours. The end point of
the reaction was confirmed by HPLC, and thereafter the mixture was
cooled to about 50.degree. C., and 1014 kg of water was introduced
thereinto. The mixture was stirred at 42.degree. to 45.degree. C.,
and the mixture was allowed to stand to separate into two
layers.
[0116] To the aqueous layer was added 823.5 kg of 1-butanol at 40
to 47.degree. C. with stirring, and the mixture was allowed to
stand to separate into two layers. The organic layers were
combined, and concentrated under reduced pressure until not less
than 95% of 1-butanol used was distilled off. Thereafter, 436.9 kg
of xylene was added to the concentrate, and the mixture was
subjected to azeotropic dehydration at an internal temperature of
120.degree. to 122.degree. C. until its water content attained to
not more than 1%. Further, the mixture was heated at atmospheric
pressure to distill off 328 kg of a distillation fraction
containing xylene. Thereto was added 430.6 kg of THF, to give a THF
solution of potassium 2-(4-methyl-2-phenylpiperazin-1-yl)
pyridine-3-carboxylate. Its water content was 179.5 ppm.
Example 4
[0117] To 889.15 kg of THF was added 65.6 kg of lithium aluminum
hydride under nitrogen atmosphere, and the resulting solution was
stirred for 2 hours. To this solution was added in a thin stream
the THF solution of potassium
2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-carboxylate obtained
in Example 3 at 20.degree. to 25.degree. C. A vessel in which the
potassium salt solution had been placed was washed with 21.4 kg of
THF, and the resulting washing liquid was added to the reaction
solution. The mixture was stirred at 23.degree. to 25.degree. C.
for 3 hours. Thereafter, 62.6 kg of water was added in a thin
stream thereto at 1.degree. to 15.degree. C., and 50.2 kg of a 25%
by weight aqueous sodium hydroxide was added in a thin stream to
the mixture at 4.degree. to 15.degree. C., and further 188.3 kg of
water was added in a thin stream to the mixture at 10.degree. to
20.degree. C. The mixture was stirred at 20.degree. to 25.degree.
C. For 70 minutes, and thereafter filtered, and aluminum hydroxide
formed by hydrolysis of lithium aluminum hydride was washed with
903.5 kg of THF.
[0118] Under atmospheric pressure, 2535 L of THF was distilled off
at an internal temperature up to 110.degree. C., and 50 g of seed
crystals of 2-(4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol
were added to the concentrate, and the mixture was stirred for 30
minutes. Thereto was added in a thin stream 215 kg of heptane at
50.degree. to 65.degree. C., and the mixture was cooled to
0.degree. to 5.degree. C., and aged for 1 hour. The mixture was
filtered, and the crystals were washed with a solution prepared by
mixing 110.5 kg of toluene with 87.1 kg of heptane and cooling the
mixture to 0.degree. to 5.degree. C. The washed crystals were dried
at 50.degree. to 60.degree. C., to give 124 kg of
2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3 -methanol. Its yield
[yield based on
2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-carbonitrile oxalate]
was 79.4%, and the HPLC purity was 99.7%.
[0119] The physical properties of the resulting
2-(4-methyl-2-phenylpipera- zin-1-yl) pyridine-3-methanol are as
follows.
[0120] Melting point: 120.6.degree. to 121.6.degree. C.
[0121] IR(KBr)v=1573, 1429, 1128, 1036, 757.8, 701 cm.sup.-1
[0122] In addition, the microphotograph of the resulting
2-(4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol is shown in
FIG. 1.
Comparative Example 1
[0123] In 150 mL of THF was dissolved 10.2 g of
2-(4-methyl-2-phenylpipera- zin-1-yl) pyridine-3-carboxylic acid
under nitrogen atmosphere. To 300 mL of THF was added 10.2 g of
lithium aluminum hydride, and the above THF solution was added in a
thin stream to the mixture over 50 minutes under reflux. After
refluxing the mixture for 4 hours, the mixture was cooled to
0.degree. to 5.degree. C., and 40.5 mL of water was gradually added
in a thin stream thereto. Aluminum hydroxide was separated
therefrom by filtration, and the filtrate was concentrated with an
evaporator. The residue was allowed to recrystallize from an ether,
to give 8.6 g of
2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol. Its yield
was 98%.
[0124] The microphotograph of the resulting
2-(4-methyl-2-phenylpiperazin-- 1-yl) pyridine-3-methanol is shown
in FIG. 2.
Example 5
[0125] To 442.6 kg of 98% concentrated sulfuric acid was added in
divided portions 123 kg of
2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol over 3 hours
at 5.degree. to 32.degree. C. under nitrogen atmosphere, and the
mixture was stirred at 30.degree. to 40.degree. C. for 7 hours. The
disappearance of the starting materials was confirmed by HPLC, and
the resulting reaction solution was added in a thin stream to 885
kg of water at 0.degree. to 30.degree. C. The vessel in which the
reaction solution had been placed was washed with 55 kg of sulfuric
acid, and the resulting washing liquid was added to the hydrolyzed
solution.
[0126] To the hydrolyzed solution was added in a thin stream 1285 g
of a 25% aqueous sodium hydroxide at a temperature of 0.degree. to
30.degree. C. to adjust its pH to 1 to 2. To the resulting solution
was added 6 kg of decolorizing carbon, and the mixture was stirred
and filtered. The decolorizing carbon was washed with 118 kg of
water. To the filtrate was added 159.1 kg of toluene, and the
mixture was stirred at 20.degree. to 30.degree. C. For 15 minutes
and allowed to stand to separate into two layers.
[0127] To the aqueous layer was added 159.1 kg of toluene, and
450.3 kg of a 25% aqueous sodium hydroxide was added to the mixture
at 20.degree. to 50.degree. C. to adjust its pH to 11. The solution
was heated to 75.degree. to 80.degree. C., and stirred for 15
minutes. The solution was allowed to stand for 90 minutes to
separate into two layers. To the organic layer was added in a thin
stream 126 kg of heptane at 50.degree. to 60.degree. C. over 65
minutes. The mixture was cooled to 0.degree. to 5.degree. C. over 3
hours and 40 minutes, and filtered. The resulting crystals were
washed with a solution prepared by mixing 122.3 kg of toluene with
97 kg of heptane and cooling the mixture to 0.degree. to 5.degree.
C. The crystals were dried at 50.degree. to 60.degree. C. under
reduced pressure, to give 103.2 kg of mirtazapine. Its yield was
86.7%, and the HPLC purity was 99.8%.
Comparative Example 2
[0128] To 28 g of
2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol was added in
a thin stream 100.8 g of 98% concentrated sulfuric acid at room
temperature (25.degree. to 30.degree. C.) under nitrogen
atmosphere. During the course of reaction, stirring became
difficult, and the mixture partially heated up to near 50.degree.
C. The mixture was stirred at 30.degree. to 40.degree. C. For 2
hours. Since 8% of the intermediate still remained according to
HPLC, the mixture was stirred for additional 6 hours. To the
reaction solution was added 240 g of ice. As a result, the mixture
heated up violently. Thereto was added 161 g of concentrated
aqueous ammonia to make the solution alkaline (pH 9).
[0129] The solution was extracted with 200 mL of chloroform. The
organic layer was dried over anhydrous magnesium sulfate, and
concentrated with an evaporator. An ether was added to an oily
residue with stirring to solidify the oily residue. The mixture was
filtered. The residue was dried, and the solid products were
recrystallized from petroleum ether 40 -60. However, the resulting
solid products were pale yellow crystals having poor crystallinity
and being in a state where the oil was partially solidified.
[0130] The crystals were filtered and dried, to give 20.1 g of pale
yellow mirtazapine. Its yield was 76.6%, and the HPLC purity was
98.3%.
[0131] According to the process of the present invention, the
pyridinemethanol compound represented by the formula (II) can be
economically and efficiently prepared in a short period of time
from the potassium pyridinecarboxylate represented by the formula
(I). Also, according to the process of the present invention, the
pyridinemethanol compound can be efficiently prepared in a short
period of time from the pyridinecarbonitrile compound represented
by the formula (I) or a salt thereof.
[0132] In addition, the mirtazapine can be favorably prepared form
the pyridinemethanol compound.
[0133] Equivalent
[0134] Those skilled in the art will recognize, or be able to
ascertain using simple routine experimentation, many equivalents to
the specific embodiments of the invention described in the present
specification. Such equivalents are intended to be encompassed in
the scope of the present invention as recited in the following
claims.
* * * * *