U.S. patent application number 09/779743 was filed with the patent office on 2001-08-30 for method for preparation of a quaternary ammonium salt.
This patent application is currently assigned to WAKO PURE CHEMICAL INDUSTRIES, LTD.. Invention is credited to Kimura, Takuhiro, Sano, Atsunori, Sano, Kimihiko, Urano, Yoji.
Application Number | 20010018526 09/779743 |
Document ID | / |
Family ID | 18558881 |
Filed Date | 2001-08-30 |
United States Patent
Application |
20010018526 |
Kind Code |
A1 |
Sano, Kimihiko ; et
al. |
August 30, 2001 |
Method for preparation of a quaternary ammonium salt
Abstract
The present invention provides a method for preparation of a
quaternary ammonium salt comprising reacting an alkyl halide with 2
equimolar amount or more per the alkyl halide of a pyridine
compound or an N-lower alkyl imidazole at 120.degree. C. to
350.degree.C., and a method for the continuous production of a
quatemary ammonium salt comprises introducing continuously an alkyl
halide and 2 equimolar amount or more per the alkyl halide of a
pyridine compound or an N-lower alkyl imidazole into a pipe reactor
from the one end thereof under heating at 120 to 350.degree. C. to
pass through the pipe reactor wherein a reaction is allowed to take
place, and taking out continuously the resulting quaternary
ammonium salt from the other end of the reactor.
Inventors: |
Sano, Kimihiko; (Saitama,
JP) ; Urano, Yoji; (Saitama, JP) ; Kimura,
Takuhiro; (Saitama, JP) ; Sano, Atsunori;
(Saitama, JP) |
Correspondence
Address: |
ARMSTRONG, WESTERMAN, HATTORI
McLELAND & NAUGHTON, LLP
Suite 1000
1725 K. Street, N.W.
Washington
DC
20006
US
|
Assignee: |
WAKO PURE CHEMICAL INDUSTRIES,
LTD.
Osaka
JP
|
Family ID: |
18558881 |
Appl. No.: |
09/779743 |
Filed: |
February 9, 2001 |
Current U.S.
Class: |
546/347 ;
548/335.1 |
Current CPC
Class: |
C07D 213/20 20130101;
C07D 249/08 20130101; C07D 231/12 20130101; C07D 233/56
20130101 |
Class at
Publication: |
546/347 ;
548/335.1 |
International
Class: |
C07D 233/54; C07D
213/02 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 14, 2000 |
JP |
2000-34564 |
Claims
What is claimed is:
1. A method for preparation of a quaternary ammonium salt, which
comprises reacting an alkyl halide with 2 equimolar amount or more
per the alkyl halide of a pyridine compound or an N-lower alkyl
imidazole at 120 to 350.degree. C.
2. A method according to claim 1, wherein the reaction temperature
is 140 to 300.degree. C.
3. A method according to claim 1, wherein the pyridine compound is
pyridine or a pyridine derivative having a lower alkyl group at
hydrogen atom(s) of the pyridine ring.
4. A method according to claim 1, wherein the N-lower alkyl
imidazole is N-methylimidazole.
5. A method according to claim 1, wherein the alkyl halide is a
cetyl halide.
6. A method according to claim 1, wherein the alkyl halide is cetyl
chloride and the pyridine compound or an N-lower alkyl imidazole is
pyridine.
7. A method for continuous production of a quaternary ammonium salt
comprises introducing continuously an alkyl halide and 2 equimolar
amount or more per the alkyl halide of a pyridine compound or an
N-lower alkyl imidazole into a pipe reactor from the one end
thereof under heating at 120 to 350.degree. C. to pass through the
reactor wherein a reaction is allowed to take place, and taking out
continuously the resulting quaternary ammonium salt from the other
end of the reactor.
8. A method according to claim 7, wherein the temperature is 140 to
300.degree. C.
9. A method according to claim 7, wherein the pyridine compound is
pyridine or a pyridine derivative having a lower alkyl group at
hydrogen atom(s) of the pyridine ring.
10. A method according to claim 7, wherein the N-lower alkyl
imidazole is N-methylimidazole.
11. A method according to claim 7, wherein the alkyl halide is a
cetyl halide.
12. A method according to claim 7, wherein the alkyl halide is
cetyl chloride and the pyridine compound or the N-lower alkyl
imidazole is pyridine.
13. A method according to claim 7, wherein an introduction speed of
the pyridine compound or the N-lower alkyl imidazole and the alkyl
halide and a volume of the reactor are adjusted in such a way that
the reaction is completed around the end position of the
reactor.
14. A method according to claim 13, wherein the alkyl halide is
cetyl chloride and the pyridine compound or the N-lower alkyl
imidazole is pyridine.
Description
BACKGROUND OF INVENTION
[0001] The present invention relates to a method for preparation of
a quaternary ammonium salt at high yield in a short reaction
time.
[0002] Quaternary ammonium salts have been a remarkably important
compound as starting materials for medicines and quasi-drugs and
cosmetics, phase-transfer catalysts, ionized solvents, etc. Among
the salts, quaternary pyridinium salts have recently be noticed
mainly as an antibacterial agent and have been thought to increase
its demand in future. However, it has been difficult to produce
those compounds in an industrial scale at high efficacy in a short
period of time. For instance, there has been disclosed a method
comprising reacting dodecyl chloride with pyridine at 100.degree.
C. for 24 hours in J. Chem. Soc., 682(1938) and a method comprising
reacting an alkyl halide with 10 to 30% excess amount of pyridine
at 60 to 130.degree. C. for 8 to 16 hours in J. Am. Chem. Soc. 68,
757-759(1946). However, in the former method, the reaction time is
long and further yield of the object compound, a quaternary
pyridinium salt, is such low as 1.7%, and in the latter method, the
yield is considerably such high as 95% but the reaction time is
remarkably long such as 8 to 16 hours, and therefore both methods
are not-satisfactory as a method for production of a quaternary
ammonium salt in an industrial scale.
[0003] There has been also disclosed a method comprising reacting
picoline, the methyl-substituted pyridine, with an alkyl halide
under refluxing for 12 hours to obtain a quaternary picolinium salt
in J. Heterocycl. Chem. 23(1)209-221(1986). However, the reaction
time is so long, and thus this method is not satisfactory as a
method for production of a quaternary picolinium salt in an
industrial scale.
[0004] On the other side, a quaternary imidazolinium salt as well
as a quaternary pyridinium salt have been thought to increase its
demand in future, and there has been disclosed a method comprising
reacting an alkyl halide with methyl imidazole under refluxing in
an organic solvent to obtain a quaternary imidazolinium salt in
Inorg. Chem. 35(5)1168-1178(1996). However, this method can not be
easily conducted because of using a organic solvent and the yield
is also low, and therefore this method is not satisfactory as a
method for production of a quaternary imidazolinium salt in an
industrial scale.
[0005] Furthermore, since a preparation for a quaternary ammonium
salt as mentioned above have been conducted by batch process, its
productivity is low and therefore those methods are not suitable
for production in an industrial scale.
SUMMARY OF INVENTION
[0006] The present invention has been accomplished under such
circumstances as above and its object is to provide a method for
preparation of a quaternary ammonium salt by reacting a pyridine
compound or an N-lower alkyl imidazole(hereinafter the pyridine
compound and the N-lower alkyl imidazole are, sometimes,
inclusively abbreviated as a heterocyclic compound of the present
invention) with an alkyl halide in an industrial scale at high
efficiency in a short reaction time.
[0007] The present invention relates to a method for preparation of
a quaternary ammonium salt comprising reacting an alkyl halide with
2 equimolar amount or more per the alkyl halide of a pyridine
compound or an N-lower alkyl imidazole at 120.degree. C. to
350.degree. C.
[0008] Further, the present invention relates to a method for the
continuous production of a quaternary ammonium salt comprises
introducing continuously an alkyl halide and 2 equimolar amount or
more per the alkyl halide of a heterocyclic compound of the present
invention into a pipe reactor from the one end thereof under
heating at 120 to 350.degree. C. to pass through the pipe reactor
wherein a reaction is allowed to take place, and taking out
continuously the resulting quaternary ammonium salt from the other
end of the reactor.
[0009] Namely, the present inventors have extensively conducted
study in order to fulfill the above object to arrive at the finding
that a quaternary ammonium salt can be produced effectively in a
short reaction time by reacting an alkyl halide with 2 equimolar
amount or more per the alkyl halide of a pyridine compound or an
N-lower alkyl imidazole at 120.degree. C. to 350.degree. C., and
the present invention has been completed on the basis of this
finding.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 shows the continuous reaction plant used in Example 4
and 5.
PREFERRED EMBODIMENTS OF INVENTION
[0011] The N-lower alkyl imidazole includes one in which a hydrogen
atom binding to a nitrogen atom is substituted by a lower alkyl
group having 1 to 4 carbon atoms such as a methyl group, an ethyl
group, an n-propyl group, an iso-propyl group, an n-butyl group, an
iso-butyl group, a tert-butyl group, a sec-butyl group etc., and is
specifically exemplified by N-methylimidazole, N-ethylimidazole,
N-n-propylimidazole, N-isopropylimidazole, N-n-butylimidazole,
N-iso-butylimidazole, N-tert-butylimidazole, N-sec-butylimidazole
etc., among which N-methylimidazole is preferable.
[0012] The pyridine compound of the present invention includes
pyridine or a pyridine derivative whose 1 to 3 hydrogen atoms are
substituted by a lower alkyl group having 1 to 4 carbon atoms
mentioned above, which is specifically exemplified by picoline,
dimethyl pyridine, trimethyl pyridine, ethyl pyridine, propyl
pyridine, butyl pyridine etc, among which pyridine and picoline are
preferable.
[0013] The alkyl halide of the present invention includes one shown
by the following general formula [1]
R.sub.1--Y [1]
[0014] (wherein R.sub.1 is an alkyl group and Y is a halogen
atom).
[0015] The alkyl group shown by R.sub.1 in the general formula [1]
may be straight chained or branched and includes one having
generally 1 to 30 carbon atoms, preferably 1 to 24 carbon atoms,
more preferably 3 to 24 carbon atoms, which is specifically
exemplified by a methyl group, an ethyl group, an n-propyl group,
an iso-propyl group, an n-butyl group, an iso-butyl group, a
sec-butyl group, a tert-butyl group, an n-pentyl group, an
isopentyl group, a sec-pentyl group, a tert-pentyl group, a
neopentyl group, an n-hexyl group, an isohexyl group, a
3-methylpentyl group, a 2-methylpentyl group, a 1-methylpentyl
group, a 1-ethylbutyl group, a 2-ethylbutyl group, a
1,2-dimethylbutyl group, a 2,3-dimethylbutyl group, an n-heptyl
group, an n-octyl group, an n-nonyl group, an n-decyl group, an
n-undecyl group, an n-dodecyl group, an n-tridecyl group, an
n-tetradecyl group, an n-pentadecyl group, an n-cetyl group, an
n-heptadecyl group, an n-octadecyl group, an n-nonadecyl group, an
n-icosyl group, an n-henicosyl group, an n-docosyl group, an
n-tricosyl group, an n-tetracosyl group, an n-pentacosyl group, an
n-hexacosyl group, an n-octacosyl group, an n-nonacosyl group, an
n-triacontyl group, etc.
[0016] The halogen atom shown by Y includes a fluorine atom, a
chlorine atom, an iodine atom, a bromine atom, etc.
[0017] The quaternary ammonium salt of the present invention can be
shown by the following general formula [2] or [3] 1
[0018] (wherein R.sub.2 is a lower alkyl group having 1 to 4 carbon
atoms mentioned above, R.sub.3 is a hydrogen atom or one to three
lower alkyl groups having 1 to 4 carbon atoms mentioned above and
R.sub.1 and Y have the same meaning as above).
[0019] Specific examples of the quaternary ammonium salts obtained
by reacting an alkyl halide with an N-lower alkyl imidazole are as
follows. 2
[0020] Specific examples of the quaternary ammonium salts obtained
by reacting an alkyl halide with a pyridine compound are as follows
including those of which 1 to 3 hydrogen atoms are substituted by a
lower alkyl group having 1 to 4 carbon atoms. 3
[0021] The preparation of the quaternary ammonium salt by the
present invention is realized, for instance, by reacting the alkyl
halide with 2 equimolar amount or more per the alkyl halide of the
heterocyclic compound of the present invention in an airtight
container such as autoclave at 120.degree. C. to 350.degree. C.,
among which the continuous preparation of a quaternary ammonium
salt using a pipe reactor is preferable, and may be conducted
concretely by a method mentioned below.
[0022] Namely, the alkyl halide and the heterocyclic compound of
the present invention are charged into a pipe reactor from the one
end thereof continuously, for instance, with a pump at the
introduction speed mentioned below and those compounds are passed
through the pipe reactor which is kept at the desired temperature,
wherein the reaction is allowed to take place continuously, and
then the reaction product produced in the reactor is taken out from
the other end of the reactor continuously. On conducting this
method, the pressure in the pipe reactor may be controlled by
installing a control valve equipped on the end of the pipe reactor.
Even when the pressure is increased too high, the reaction efficacy
is not increased, and thus the pressure may be adjusted to
generally 1 to 100 kg/cm.sup.2, preferably 2 to 20 kg/cm.sup.2,
more preferably 2 to 10 kg/cm.sup.2. The quaternary ammonium salt
taken from the pipe reactor may be subjected to the after-treatment
which has so far been conducted generally in this kind of technical
field, such as crystallization with a spray dryer or a film
evaporator.
[0023] The pipe reactor of the present invention includes those
having two openings at the both ends, which can be made into sealed
condition by closing the openings and is durable ever under high
temperature and high pressure, and among them, preferable ones are
those wherein heat is conducted up to the inner part by heating
from the outer side.
[0024] A typical example of the pipe reactor is one made of
stainless steal of which shape can be kept without deformation
under heating up to about 500.degree. C. under pressure up to about
100 kg/cm.sup.2.
[0025] The introduction speed of the compounds to be charged into
the reactor is adjusted on the basis of the inner volume of the
reactor and the time required for the objection reaction, and it is
preferably in proportion to the volume of the pipe reactor, namely
the introduction speed is adjusted to twice when the volume of the
pipe reactor is twice, for instance more concretely, the
introduction speed of those compounds is generally shown by the
following equations,
(p/q).ltoreq.r.ltoreq.[p/(q.times.10)]
[0026] (wherein, p(ml) is the volume of the reactor, q(min) is the
time required for the object reaction and r(ml/min) is the
introduction speed of the compounds.) preferably,
(p/q).ltoreq.r.ltoreq.[p/(q.times.2)]
[0027] particular preferably,
p/q=r
[0028] On setting forth the introduction speed of the compounds by
using the above equations, it is preferable that the volume of the
pipe reactor is adjusted according to the required amount of a
quaternary ammonium salt etc. and the time required for the
reaction is set forth according to the combination of the kinds of
starting materials (as mentioned below, it is generally 5 minutes
to 6 hours), and then the introduction speed is calculated by the
equations using thus determined values. The introduction speed
means the total amount of the alkyl halide and the heterocyclic
compound of the present invention to be introduced per unit of
time, and a ratio of these two compounds are such one as 2
equimolar amount or more per the alkyl halide of the heterocyclic
compound of the present invention per the alkyl halide. The alkyl
halide is mixed with 2 equimolar amount or more per the alkyl
halide of the heterocyclic compound of the present invention, and
then the mixture may be introduced into the pipe reactor at the
introduction speed adjusted as mentioned above. More particularly,
for instance, when the volume of the pipe reactor is set forth as
200 ml and the time required for the reaction is set forth as 15
minutes, then the introduction speed is calculated as 200 ml.div.15
min.apprxeq.13.3 ml/min, and on the basis of this value it can be
determined generally as 1.3 to 13.3 ml/min, preferably as 6.7 to
13.3 mil/min, still preferably as 13.3 ml/min.
[0029] An amount of the heterocyclic compound of the present
invention to be used is generally 2 equimolar amount or more per
the alkyl halide, whereupon the desired reaction can be completed
by adjusting the reaction temperature of 120.degree. C. to
350.degree. C., and preferably the amount is 2 to 20 equimolar
amount, more preferably it is 3 to 10 equimolar amount.
[0030] When an amount of the heterocyclic compound of the present
invention to be used is a theoretical amount or a slightly excess
amount to the alkyl halide, the reaction is not completed even
after a long reaction time.
[0031] The reaction temperature is generally 120.degree. C. to
350.degree. C., preferably 140 to 300.degree. C., more preferably
150 to 250.degree. C.
[0032] The preparation of the present invention may be conducted
under streams of an inert gas such as helium gas, nitrogen gas and
argon gas and, in this case, the reaction temperature may be
increased by elevating pressure of the inert gas in the reaction
system. Even when the pressure is increased too high, the reaction
efficacy is not increased, and thus the pressure may be adjusted to
generally 1 to 100 kg/cm.sup.2, preferably 2 to 20 kg/cm.sup.2,
more preferably 2 to 10 kg/cm.sup.2.
[0033] The reaction time is generally 5 minutes to 6 hours,
preferably 5 minutes to 2 hours, more preferably 5 to 30
minutes.
[0034] The after-treatment of the present invention may be
conducted according to the general method of after treatment in
this kind of technical field.
[0035] By using the method of the present invention, a quaternary
ammonium salt can be obtained effectively and easily in a short
reaction time even without setting severe reaction conditions.
[0036] The quaternary ammonium salt obtained by the method of the
present invention is useful as starting materials for medicines,
quasi-drugs, cosmetics, etc., phase-transfer catalysts, ionized
solvents, antibacterial agents, etc.
[0037] In the following, the present invention is explained in
details with reference to Examples, and the present invention is
not limited thereto by any means.
EXAMPLE
Example 1
[0038] Nitrogen gas was introduced in an autoclave charged with
115.1 g (0.44 mole) of n-cetyl chloride and 146.6 g (1.85 mole) of
pyridine to adjust the pressure in the autoclave to 2 kg/cm.sup.2,
followed by agitation at 180.degree. C. for 15 minutes to allow a
reaction to take place.
[0039] After the reaction, the reaction solution was dried under
reduced pressure to give powdery crystal.
[0040] The reaction solution after the reaction was analyzed by
HPLC to confirm the reaction rate to be 100%. To the obtained
powdery crystal was added 316 ml of methylethyl ketone, followed by
agitation at room temperature, and the resulting crystal was
recovered by filtration, washed with methylethyl ketone and dried
under reduced pressure to give 142.5 g of powdery crystal (yield
95%). The obtained crystal was determined as cetyl pyridinium
chloride by measuring the melting point and .sup.1HNMR
analysis.
[0041] Treatment of the obtained cetyl pyridinium chloride with
water easily gave n-cetyl pyridinium chloride monohydrate.
Example 2
[0042] The same process as in Example 1 except for agitation at
160.degree. C. for 30 minutes was conducted to give n-cetyl
pyridinium chloride. After the reaction, the reaction solution was
analyzed by HPLC to confirm the reaction rate to be 100%.
Control Example 1
[0043] 115.1 Grams (0.44 mole) of n-cetyl chloride and 146.6 g
(1.85 mole) of pyridine were subjected to a reaction under
refluxing at 96 to 100.degree. C. under nitrogen gas streams. The
reaction solution at 15 minutes after the start of the reaction was
analyzed by HPLC to find the reaction rate to be 3%.
Control Example 2
[0044] Nitrogen gas was introduced into an autoclave charged with
115.1 g (0.44 mole) of n-cetyl chloride and 38.4 g (0.44 mole) of
pyridine to adjust the pressure in the autoclave to 2 kg/cm.sup.2,
followed by agitation at 160.degree. C. for 4 hours to allow a
reaction to take place.
[0045] After the reaction, the reaction solution was analyzed by
HPLC to find the reaction rate to be 80%.
Example 3
[0046] Nitrogen gas was introduced into an autoclave charged with
40.8 g (0.44 mole) of n-butyl chloride and 146.6 g (1.85 mole) of
pyridine to adjust the pressure in the autoclave to 2 kg/cm.sup.2,
followed by agitation at 180.degree. C. for 15 minutes to allow a
reaction to take place. After the reaction, the reaction solution
was analyzed by HPLC to find the reaction rate to be 100%.
[0047] As clear from comparing Example 1, 2 and 3 on one hand with
Control Example 1 and 2 on the other hand, it is found that the
reaction rate can be increased and further the reaction time can
remarkably be shortened and thus the object quaternary ammonium
salt can be obtained effectively by adjusting the amount of
pyridine to be used to 2 equimolar amount or more per the alkyl
halide and conducting the reaction at 120.degree. C. to
350.degree.0 C.
Example 4
[0048] Using the continuous reaction plant equipped with the pipe
reactor of 200 ml as shown in the FIG. 1, n-cetyl chloride was
continuously introduced into the pipe reactor at 6.29 ml/min with
pump{circle over (1)} and at the same time pyridine was
continuously introduced into the pipe reactor at 7.04 mmin with
pump{circle over (2)} to adjust the inner pressure of the pipe
reactor to 5 kg/cm.sup.2 and the inner temperature to 180.degree.
C.
[0049] The reaction solution (261.7 g) taken from the end of
condenser was dried under reduced pressure with the spray dryer to
obtain 150 g of powdery crystal(yield 100%). Analysis of the
reaction solution by HPLC showed the reaction rate to be 100%.
After the same treatment of the above obtained powdery crystal as
in Example 1 gave 141.0 g of powdery crystal (yield 94%).
Example 5
[0050] The same process as in Example 4 except for using a film
evaporator in place of a spray dryer was conducted to give n-cetyl
pyridinium chloride. After the reaction, the reaction solution was
analyzed by HPLC to confirm the reaction rate to be 100%.
[0051] As clear from the result of Example 4 and 5, it is found
that quaternary pyridinium salt can be produced continuously by
using the plant equipped with the pipe reactor as shown in the FIG.
1 at the same high yield and high reaction rate as in Examples 1 to
3.
Example 6
[0052] Nitrogen gas was introduced into an autoclave charged with
95.9 g (0.70 mole) of n-butyl bromide and 241.4 g (2.94 mole) of
1-methyl imidazole to adjust the pressure in the autoclave to 2
kg/cm.sup.2, followed by agitation at 160.degree. C. for 30 minutes
to allow a reaction to take place. After the reaction, the reaction
solution was analyzed by NMR to find the reaction rate to be
100%.
Example 7
[0053] Nitrogen gas was introduced into an autoclave charged with
182.6 g (0.70 mole) of n-cetyl chloride and 241.4 g (2.94 mole) of
1-methyl imidazole to adjust the pressure in the autoclave to 2
kg/cm.sup.2, followed by agitation at 180.degree. C. for 30 minutes
to allow a reaction to take place. After the reaction, the reaction
solution was analyzed by NMR to find the reaction rate to be
100%.
Example 8
[0054] Nitrogen gas was introduced into an autoclave charged with
52.1 g (0.38 mole) of n-butyl bromide and 178.4 g (1.92 mole) of
4-picoline to adjust the pressure in the autoclave to 2
kg/cm.sup.2, followed by agitation at 160.degree. C. for 15 minutes
to allow a reaction to take place. After the reaction, the reaction
solution was analyzed by NMR to find the reaction rate to be
100%.
Example 9
[0055] Nitrogen gas was introduced into an autoclave charged with
100.0 g (0.38 mole) of n-cetyl chloride and 178.4 g (1.92 mole) of
4-picoline to adjust the pressure in the autoclave to 2
kg/cm.sup.2, followed by agitation at 180.degree. C. for 15 minutes
to allow a reaction to take place. After the reaction, the reaction
solution was analyzed by NMR to find the reaction rate to be
94%.
[0056] As clear from the result of Examples 6 to 9, it is found
that a quaternary ammonium salt derived from methyl imidazole or
picoline can be produced effectively in a short reaction time just
like as the quaternary pryridinium salt.
EFFECT OF INVENTION
[0057] The present invention is to provide a method for preparation
of a quaternary ammonium salt effectively in a short reaction time
by reacting an alkyl halide with a heterocyclic compound of the
present invention, and according to the method of the present
invention, all of problems found in known methods, namely
requirements for severe reaction conditions and complicated
reaction process steps and a poor reaction rate and a long reaction
time, can be solved. Further, the object quaternary ammonium salt
can continuously be produced by conducting the reaction in a pipe
reactor of the present invention, and thus the method of the
present invention is excellent also from industrial point of
view.
* * * * *