Field of the Invention
This invention, in general, relates to an improved process for the production of quatern'ary
ammonium compounds. More particularly, the present invention provides an improved one
pot, cost effective and eco-friendly process for large scale industrial production of quaternary
pyridinium salts of formula (I) and their hydrates with high yield and purity.
Background of the Invention
Quaternary ammonium salts have been remarkably important as starting materials for
medicines and quasi-drugs and cosmetics, phase-transfer catalysts, ionized solvents etc.
Among the salts, quaternary pyridinium salts have been found to be useful mainly as an
antibacterial agent thereby indicating an increase in their demand.
Pyridinium salts (CI2 and CI6) are used as solubilizers for water insoluble compounds in
analytical chemistry. A compound with a CI6 side chain on the pyridinium ring (cetyl
pyridinium, CP) is being used for the protection of the poultry against bacterial
contamination. CP is also being added to chewing gums as anti-plaque agents. The same
application is also possible in the dentistry. The surface activity of CP predicted its ability to
form the micelles which is being used for the removal of the pollutants (e.g. arsenic,
perchlorate) from the ground water and also for the removal of the heavy metals from
solutions. Pyridinium detergents are being used as carriers for improving adsorption of the
oligonucleotides at the phospholipid membrane. The pyridinium analogues with the alkyl
chains longer than Clo are known as nicotinic receptor antagonists. Pyridinium salts bearing
shorter alkyl chains are useful as cholinesterase inhibitors.
In the prior. art various methods are reported for the preparation of quaternary pyridinium
salts. Knight et a1 in J . Chem. Soc., 1938, 682 reported a method for preparing dodecyl
pyridinium chloride by reacting dodecyl chloride with pyridine at 100°C for 24 hours, but the
yield is very low 1.7%.
Shelton et a1 in J . Am. Chem. Soc., 1946, 68, 757 reported a method involving the reaction
of an alkyl halide with 10 to 30% excess amount of pyridine at temperatures from
60 to 130 "C for 8 to 16 hours to afford 95% quaternary pyridinium salt. In this method rate
of reaction is increased by using the excess of amine. Also for getting pure product one or
two crystallization are done after the completion of reaction:
Barni et a1 in J. Het. Chem., 1986, 23, 209 reported the reaction of 4-methyl pyridine with
cetyl iodide under refluxing for 6 hours to obtain 4-methyl cetyl pyridinium iodide with 75%
yield.
Polish Patent No. PL 149740 discloses a method for the purification of cetyl pyridinium
chloride (CPC). The process involves condensation of cetyl chloride with dehydrated and
purified pyridine at 110 OC for 80 hours. The purification of CPC obtained involves
dissolving the crude CPC into ethanol, charcoalizing for about 4-6 hours, cooling and left to
.settle for 12 hours. The solution obtained is filtered and greenish yellow CPC obtained is
extracted with acetone, filtered and dried to get pure'product. Long reaction times along with
tedious purification steps make this method commercially unviable.
EP Patent No. 1125927 discloses a method for the preparation of cetyl pyridinium chloride
monohydrate. The process involves reacting cetyl chloride (0.44 mole) with 1.8 mole of
pyridine under nitrogen atmosphere in an autoclave at 2 kg/cm2 of pressure followed by
agitation at 180' ". The product is crystallized with methyl ethyl ketone to obtain powdery
crystal of CPC which was treated with waterto obtain CPC monohydrate.
US Patent No.5041664 discloses a continuous process for preparing
dimethylcocoalkylbenzylamrnoniurn chloride which comprises reacting benzyl mine with
dirnethylcocoalkylmine, over alumina in the presence of isopropanol at a temperature of
120 OC and at a pressure of 1000 psi. High temperature and pressure reaction conditions
make the process commercially unviable.
Marek et a1 in Molecules, 2010, 15, 1967 reported the preparation of pyridinium salts
differing in the alkyl chains (C8 to C20) by refluxing a mixture of pyridine and alkyl halide in
dry ethanol for 40 hours. The solution is evaporated under reduced pressure and the crude
oily product crystallized from ether. Satisfactory purity is obtained after one or several
crystallizations from ether suspensions. The compounds with C18 to C20 alkyl chains are
contaminated with starting material and hence crystallized from acetone,
Chinese Patent Application No. CN 103539727A discloses preparation of CPC via
condensation of cetyl chloride and pyridine at 100- 125 "C for 10- 14 hours. After completion
of the reaction, pyridine is recycled via depressurization, and an alcohol solvent and active .
carbon are added for decolouring to obtain crude CPC which is subjected to two
purifications. The first purification is done with a mixture of acetone and water followed with
the second purification with a mixture of alcohol and water.. Thus, this process is
cumbersome as involve several steps.
f
Thus, the processes disclosed in the prior art involve multiple steps for purification which
results in increase in number of operations and reduced yield, consequently making the
process costly,and uneconomical. Further, the processes disclosed in the prior art can be used
for producing small batches of the desired products in low yield, hence making the processes
unsuitable for large-scale production.
In view of the increasing demand for producing quaternary pyridinium salts and hydrates
thereof, of high yield and purity, it is therefore desirable to develop a commercially and
economically viable process for industrial manufacturing of quaternary pyridinium salts and
,
hydrates thereof with high yield and purity which can address the above mentioned problems
associated with the known processes.
Summarv of the Invention
It is a principal object of the present invention to provide a process for producing quaternary
pyridinium salts and hydrates thereof at industrial scale, wherein the process enables single
I
pot production of the compounds.
It is another object of the invention to provide a cost effective and commercially viable
process for producing quaternary pyridinium salts and hydrates thereof at industrial scale,
wherein the process provides product with desired purity, involving simple isolation steps,
avoiding multi stage operations for purification.
It is another object of the present invention to provide an ecofriendly and carbon efficient
.process for producing quaternary pyridinium salts and hydrates thereof at industrial scale,
wherein the process enables production of highly pure quaternary pyridinium salts at
industrial scale with minimum generation of effluents.
4
In accordance with object of the present invention, there is provided a large scale industrial
process for the production of quaternary pyridinium salts of formula (I) and hydrates thereof,
wherein the process comprises:
Formula (I)
i) reacting pyridine compound of formula (11) with alkyl halide of formula (111) in the
presence of a catalyst to obtain quaternary pyridinium salt of formula (I),
Formula (11) Formula (111)
ii) optionally, converting the quaternary pyridinium salt of formula (I) to its hydrate.
wherein,
R represents a hydrogen atom, an optionally substituted CI-C5 alkyl group or an optionally
substituted C1-C5 alkoxyl group.
More specifically, R can be a hydrogen atom, a straight chain or branched CI-C5 alkyl, such
as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl,
sec-pentyl, tert-pentyl, and the likes; a hydroxy CI-C5 alkyl, such as hydroxymethyl,
1 -hydroxyethyl, 2-hydroxyethyl, 1 -hydroxyprbpyl, 2-hydroxypropyl, 3-hydroxyprop~l,
1 -hydroxyisopropyl, 1 -hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl and the likes; an
optionally-substituted CI-C5 alkoxyl, such as methoxy, ethoxy, propoxy, trifluoromethoxy
and the likes;
R' is selected from C 2-C20 alkyl group;
5
___~R~1 FXI~~d~-~,~~~t~-IIIBB66~421-P P1P .]Br-:B-L~pZ3L-_~- d- d- - - -----
n is any integer from 1 1 - 1 9;
X is halogen selected from chloro, bromo, fluoro and iodo.
In accordance with another object of the present invention, there is provided a large scale
industrial process for producing quaternary pyridinium salts of formula (I) and hydrates
thereof, wherein the process comprises reacting pyridine compound of formula (11) with alkyl
halide of formula (111) in the presence of catalyst, wherein the catalyst is selected from the
group consisting of acid, arnine and their salts, chelating agent, and mixtures thereof.
In accordance with yet another object of the present invention there is provided a large scale
industrial process for producing quaternary pyridinium salts of formula (I) and hydrates
thereof, wherein the reaction is performed in the temperature range of 0-1 75 "C.
Detailed Description of the Invention
While this specification concludes with claims particularly pointing out and distinctly
claiming that, which is regarded as the invention, it is anticipated that the invention can be
more readily understood through reading the following detailed description of the invention
and study of the included examples.
The present invention, in general, relates to a large scale industrial process for producing
quaternary pyridinium salts and hydrates thereof. More particularly, the present invention
provides a cost effective, ecofriendly and less capital intensive large scale industrial process
for producing quaternary pyridiniurn salts and hydrates thereof with high yield and purity.
The present invention involves with a'large scale industrial process for producing quaternary
pyridinium salts and hydrates thereof, which is easy to operate, involving less operational
steps and minimum effluent load generation thereby making the process commercially viable.
It has been observed during the preparation of quaternary pyridinium salts and hydrates of the
present invention that for reducing reaction time, if the temperature of the reaction is
increased then the color of the product deviates from white. Alternatively, if the temperature
is reduced then the rate of reaction becomes slow thereby resulting in incomplete reaction.
However, by using the catalyst of the present invention, the temperature required for
condensation of pyridine compounds with alky halide is reduced and conversion is also
complete resulting in the formation of product with desired purity.
According to the present invention, the process for the production of quaternary pyridinium
salts of formula (I) and hydrates thereof comprises of reacting pyridine compound of formula
(11) with alkyl halide'of formula (111) in. the presence of a catalyst to form quaternary
pyridinium salt of formula (I) and optionally, converting the quaternary pyridinium salt of
formula (I) to its hydrate.
Formula (I) Formula (11) Formula (111)
wherein R, R', n and X are the same as defined earlier.
According to the present invention, the process for the production of hydrates of quaternary
pyridinium salts of formula (I) is one pot process.
According to the present invention, the catalyst is selected from the group consisting of acid,
arnine and their salts, chelating agent andlor mixtures thereof. The amount of acid, amine,
chelating agent in the chelating agent can vary in the range of 0-100% by weight of the
catalyst.
The acid used as catalyst in the present invention, is selected from the group consisting of
organic acid, inorganic acid and mixtures thereof. The acid used as catalyst herein is
selected from the group consisting of acetic acid, formic acid, oxalic acid, benzoic acid,
hydrochloric acid, sulfuric acid, phosphoric acid and mixtures thereof.
The arnine used as catalyst in the present invention, is selected from the group consisting of
organic amine, inorganic arnine, their salts and mixtures thereof. The amine used as catalyst
herein is selected from the group consisting of N-methyl morphline, isopropyl ethyl amine,
propyl ethyl amine, triethylamine, trimethylamine, ethanolamine, chloramines, piperidine,
pyridine, their salts and mixtures thereof.
According to the. present invention, the chelating agent used as catalyst herein is selected
fiom the group consisting of ethylenediaminetetraacetic acid (EDTA),
! N,N-bis(carboxymethy1)glycine (NDTA) diethylenetriarninepentaacetic acid (DTPA), ~ nitrilotriacetic (NTA) acid, 2,3-dimercapto-1 -propano1 (dimercaprol), porphine and mixtures
1 thereof.
1 According to the present invention, the reaction of pyridine compound of formula (11) with
1 alkyl halide of formula (111) is carried out in the temperature range of 0 to 175 "C, preferably
I
I
between 75-1 50 "C. The process is carried out in the absence of solvent.
, According to the present invention, the step of converting the quaternary pyridinium salt of
formula (I) to its hydrate is carried out optionally in the presence of solvent. The solvent used
is selected from the group consisting of aliphatic alcohol such as methanol, ethanol,
n-proponal, isopropanol, n-butanol, iso-butanol; ketone such as acetone, methyl isobutyl
ketone, cyclohexanone, methyl ethyl ketone; ester such as ethyl aceate, propyl acetate, butyl
acetate, methyl isobutyrate and mixtures thereof.
According to the present invention, the solvent used in the isolation is recovered and reused.
Isolation of compound of formula (I) and hydrates thereof can be carried out by the
techniques known in the art such as filtration, centrifugation, nutch filtration etc.
The present invention is further illustrated below with reference to the following examples
without intending to limit the scope of the invention in any manner.
Example -1
Synthesis of cetyl pyridinium chloride: '
Cetyl chloride (100 g), pyridine (250 g) and catalyst (2 .g containing the mixture of EDTA,
N-methyl morpholine, N,N-bis(carboxymethyl)glycine and phosphoric acid) were charged I
into a round bottom flask, heated to 90-100 "C and maintained for 6-8 hours. After the I
complet'ion of reaction, the mass was cooled, filtered and washed with ethyl acetate to get I
. *
crystalline cetyl.pyridinium chloride (126.5 g) with 99.5% purity. The product was confirmed
by m.p., mass spectroscopy and 'H NMR and I3c NMR.
Example -2
Synthesis of cetyl pyridinium chloride monohydrate:
Cetyl chloride (100 g), pyridine (300 g) and catalyst (2 g containing the mixture of isopropyl
ethyl amine, N-methyl morpholine, oxalic acid and sulfuric acid) were charged into a round
bottom flask, heated to 90-100 "C and maintained for 6-8 hours. After. the completion of
reaction, the mass was cooled, filtered and the cake was charged to a mixture of methyl
isobutyl ketone (200 g) and water (7 g). Mass was agitated to get crystalline cetyl pyridinium
chloride monohydrate (120 g), with 99.6% purity. The solvent and unreacted pyridine was
recovered and reused in next batch. The product was confirmed by m.p., mass spectroscopy
and 'H NMR and 13c NMR.
Example -3
Synthesis of cetyl pyridinium chloride:
Cetyl chloride (10 kg), recovered pyridine (28 kg) and catalyst (0.2 kg containing the mixture
of formic acid, propyl ethyl amine, N,N-bis(carboxymethy1)glycine and hydrochloric acid)
were charged into a round bottom flask, heated to 90-100 "C and maintained for 6-8 hours.
After the completion of reaction, the mass was cooled, filtered and the product obtained was
washed with recovered methyl isobutyl ketone to get crystalline cetyl pyridinium chloride
(12.6 'kg) with 99.5% purity. The product was confirmed by mass spectroscopy and 'H NMR
and I3c NMR. I
Example -4
Synthesis. of 1 -hexadecyl-2-methyl pyridinium chloride:
Cetyl chloride (100 g), 2-methyl pyridine (250 g) and catalyst (2.0 g containing the mixture
of triethyl amine, EDTA, benzoic acid, sulfuric acid and formic acid) were charged into a
round bottom flask, heated to 120-135 "C and maintained for 25-30 hours. After the
completion of reaction, the mass was cooled, filtered and the product obtained was washed
with ethyl acetate to get crystalline 1-hexadecyl-2-methyl pyridinium chloride (120 g) with
99.2% purity. The product was confirmed by mass spectroscopy and 'H NMR and I3c NMR.
Example -5
Synthesis of 1-hexadecyl-3-methyl pyridinium chloride:
Cetyl chloride (100 g), 3-methyl pyridine (250 g) and catalyst (2.0 g containing the mixture
of formic acid, propyl ethyl amine, N,N-bis(carboxyrnethy1)glycine zind hydrochloric acid)
were charged into a round bottom flask, heated to 130-140 "C and maintained for 15-16
hours. After the completion of reaction, the mass was cooled, filtered and the product
obtained was washed with ethyl acetate to get crystalline 1-hexadecyl-3-methyl, pyridinium
chloride (122 g) with 99.8% purity. The product was confirmed by mass spectroscopy and
'H NMR and I3c NMR.
Example -6
Synthesis of 1 -hexadecyl-4-methyl pyridinium chloride:
Cetyl chloride (100 g), 4-methyl pyridine (250 g) and catalyst (2.0 g containing the mixture
of EDTA, N-methyl morpholine, N,N-bis(carboxymethyl)glycine and phosphoric acid) were
charged into a round bottom flask, heated to 135-145 "C and maintained for 8- 10 hours. After
the completion of reaction, the mass was cooled, filtered and the product obtained was
washed with ethyl acetate to get crystalline 1-hexadecyl-4-methyl pyridiniurn chloride (1 18g)
with 99.0% purity. The product was confirmed by mass spectroscopy and 'H NMR and
I3c NMR.

We claim:
1. A process for the production of quaternary pyridinium salts of formula (I) and hydrates
thereof, wherein the process comprises:
i) reacting pyridine compound of formula (11) with alkyl halide of formula (111) in the
presence of a catalyst to form quaternary pyridinium salt of formula (I),
ii) optionally, convetiing the quaternary pyridinium salt of formula (I) to its hydrate.
wherein,
R represents a hydrogen atom, an optionally substituted C1-C5 alkyl group or an optionally
substituted C1-C5 alkoxyl group.
More specifically, R can be a hydrogen atom, a straight chain or branched C1-C5 alkyl, such
as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl,
sec-pentyl, tert-pentyl, and the likes; a hydroxy CI-C5 alkyl, such as hydroxymethyl,
- 1 -hydroxyethyl, 2-hydroxyethyl, 1 -hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl,
1 -hydroxyisopropyl, 1 -hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl 'and the likes; an
optionally-substituted C1-G alkoxyl, such as methoxy, ethoxy, propoxy, trifluoromethoxy
and the likes;
R' is selected from C12-C20al kyl group
n is any integer from 1 1 - 19
X is halogen atom selected from chloro, bromo, fluoro and iodo group
2. The process as claimed in claim 1, wherein the catalyst is selected from the group
consisting of acid, mine and their salts, chelating agent andlor mixtures thereof.
3. The process as claimed in claim 2, wherein the catalyst is selected from the group
consisting of organic acid, inorganic acid and mixtures thereof.
4. The process as claimed in claim 1 and 2, wherein the catalyst is selected from the group
consisting of acetic acid, formic acid, oxalic acid, benzoic acid, hydrochloric acid, sulfuric
acid, phosphoric acid and mixtures thereof.
5. 'The process as claimed in claim 2, wherein the catalyst is selected from the group
consisting of organic amine, inorganic amine, their salts and mixtures thereof.
6. The process as claimed in claim 1 and 2, wherein the mine is selected from the group
consisting of N-methyl morphline, isopropyl ethyl amine, propyl ethyl amine, triethylarnine,
trimethylamine, ethanolamine, chloramines, piperidine, pyridine, their salts and mixtures
thereof.
7. The process as claimed in claim 1 and 2, wherein the chelating agent is selected from the
group consisting of ethylenediaminetetraacetic acid, N,N-bis(carboxyrnethyl)glycine,
diethylenetriaminepentaacetic acid, nitrilotriacetic acid, 2,3-dimercapto- 1 -propano1 and
mixtures thereof.
8. The process as claimed in claim 1, wherein the reaction is carried out in the temperature
range of 0-1 75 "C.
9. The process as claimed in claim 8, wherein the reaction is carried out in the temperature
range of 75- 150 "C.
10. The process as claimed in claim 1, wherein the step (ii) is'carried out optionally in the
presence of solvent selected from the group consisting of aliphatic alcohol, ketone, ester and
mixtures thereof.