WO2019142205A1 - An improved process for preparation of quaternary pyridinium salts - Google Patents

An improved process for preparation of quaternary pyridinium salts Download PDF

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Publication number
WO2019142205A1
WO2019142205A1 PCT/IN2019/050013 IN2019050013W WO2019142205A1 WO 2019142205 A1 WO2019142205 A1 WO 2019142205A1 IN 2019050013 W IN2019050013 W IN 2019050013W WO 2019142205 A1 WO2019142205 A1 WO 2019142205A1
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Prior art keywords
preparation
formula
water
quaternary pyridinium
compound
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PCT/IN2019/050013
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French (fr)
Inventor
Jayeshkumar Mohanlal Pandya
Vinod Dilip PATIL
Snehal Chandreshbhai Devani
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Suyog Life Sciences Pvt. Ltd.
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Publication of WO2019142205A1 publication Critical patent/WO2019142205A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • C07D213/20—Quaternary compounds thereof

Definitions

  • the present invention relates to an improved process for preparing quaternary ammonium salts.
  • the present invention relates to an improved process for preparing hydrates of quaternary ammonium salts. More particularly, the present invention relates to an improved process for preparing Cetylpyridinium chloride monohydrate.
  • Quaternary ammonium salts are widely used salts in many fields such as pharmaceuticals, oral and personal care, cosmetics, cleaning agents, diagnostics etc. Many Quaternary ammonium salts are used in many industries as antimicrobial preservative, sanitizers, solubilizers etc.
  • cetylpyridinium chloride (CPC) is used as antimicrobial for medical devices, antibacterial agent in mouth-wash and toothpastes, anti-plaque agents in throat lozenges, periodontal agent in the dentistry, preservative in ophthalmic products, disinfectant, surface stabilizer, antiseptic OTC products etc.
  • J. Am. Chem. Soc, 1946, 68, 757 discloses Quaternary Ammonium Salts as Germicides and process for preparation thereof by reacting alkyl halide with 10 to 30% excess amount of pyridine at temperatures from 60 to l30°C for 8 to 16 hours to yields 95% quaternary pyridinium salt.
  • European Patent No. 1125927 discloses a process for the preparation of cetylpyridinium chloride (CPC) monohydrate by reacting cetyl chloride under pressure and by crystallization with methyl ethyl ketone followed by treatment with water to obtain CPC monohydrate.
  • Indian patent application No. 3661/DEL/2014 discloses similar process for the production of quaternary pyridinium salts in presence of catalyst followed by conversion to monohydrate salts by treatment with water.
  • the present invention takes advantage of in-situ production of hydrate and thus removing process steps for production of quaternary pyridinium salt hydrates thereby solves the problem in the art.
  • the invention provides single step process for preparation of quartemary pyridinium salt hydrates and is also industrially advantageous.
  • the main object of the invention is to provide an improved process for the preparation of quaternary pyridinium salts which provides the process for the preparation of compound of formula (I),
  • Another object of the invention is to provide an improved process for the preparation of quaternary pyridinium salts which provides the different processes for the preparation of cetylpyridinium chloride monohydrate of formula (la),
  • Still another object of the invention is to provide an improved process for the preparation of quaternary pyridinium salts which provides the different process for the preparation of laurylpyridinium chloride monohydrate of formula (Ha),
  • Yet another object of the invention is to provide an improved process for the preparation of quaternary pyridinium salts which is a single step process and is also industrially advantageous.
  • R represent a Hydrogen, C1-C5 alkyl, or Ci-Csalkoxy
  • X is any halogen
  • n is any integer from 1 to 20 and;
  • y is any integer from 0 to 5.
  • the inventors of the present invention have found that the preparation of quaternary pyridinium salts hydrate of the compound of formula (I) by the process of present invention is industrially advantageous as it requires few reaction steps compared to prior art.
  • the term "obtaining” means isolating compound of interest by the ways of filtration, filtration under vacuum, centrifugation, and decantation.
  • the product may be preceded for further steps with or without isolation and with or without drying in case of the product was isolated.
  • isolated or “isolation” refer to the subject compound as physically separated from the reaction mixture in which it is formed.
  • cooling means the reaction mixture is subjected to cooling at temperature from about Odegree C. to about 35. degree. C. In particular, from about 5. degree. C. to about 30.degree. C.
  • treating means stirring, slurring, mixing, keeping that at any temperature or conditions.
  • removing the solvents may include, for example, one or more of filtration, filtration under vacuum, centrifugation, decantation, distillation and distillation under vacuum.
  • hydrate refers to a combination of water with a compound of formula (I), wherein the water retains its molecular state as water and is either absorbed, adsorbed or contained within a crystal lattice of the substrate molecule of compound of formula (I) or compound of formula (la).
  • R represent a Hydrogen, C1-C5 alkyl, or Ci-Csalkoxy
  • X is any halogen
  • n is any integer from 1 to 20 and;
  • y is any integer from 0 to 5.
  • the compound of formula (II) is reacted with the compound of formula (III) in presence of water, optionally in presence of solvent to obtain compound of formula (I).
  • solvent comprises one or more of methanol, ethanol, n-proponal, isopropanol, n-butanol, iso-butanol, acetone, methyl isobutyl ketone, cyclohexanone, methyl ethyl ketone, ethyl aceate, propyl acetate, butyl acetate, methyl isobutyrate or mixtures thereof.
  • the compound of formula (I) prepared by the process of present invention can optionally be purified.
  • the process for preparation of quaternary pyridinium salt hydrate compound of formula (I) by reacting a compound of formula (II) with a compound of formula (III) in presence of water is one pot process preferably carried out in absence of any other solvent.
  • the process is carried out in the temperature range of 0 to 170 °C, preferably between 70-130 °C, more preferably at 80 to 110 °C.
  • the compound of formula (I) obtained by above process can be purified by re-crystallization from solvent.
  • the solvent comprises, one or more of methanol, ethanol, n-proponal, isopropanol, n-butanol, iso-butanol, acetone, methyl isobutyl ketone, cyclohexanone, methyl ethyl ketone, ethyl aceate, propyl acetate, butyl acetate, methyl isobutyrate or mixtures thereof.
  • pyridine is reacted with cetyl chloride in presence of water, optionally in presence of solvent to obtain cetylpyridinium chloride monohydrate.
  • solvent comprises one or more of methanol, ethanol, n-proponal, isopropanol, n-butanol, iso-butanol, acetone, methyl isobutyl ketone, cyclohexanone, methyl ethyl ketone, ethyl aceate, propyl acetate, butyl acetate, methyl isobutyrate or mixtures thereof.
  • the process for preparation of cetylpyridinium chloride hydrate of compound of formula (la) by reacting pyridine with cetyl chloride in presence of water is one pot process preferably carried out in absence of any other solvent.
  • the process is carried out in the temperature range of 0 to 170 °C, preferably between 70-130 °C, more preferably at 80 to 110 °C.
  • Cetyl chloride (1000 g), pyridine (1220 g) and water (410 g) were charged into a round bottom flask, heated to 95-102 °C and maintained for 30 hours. After the completion of reaction, the excess pyridine and water were distilled off. Reaction mass was cooled, filtered. The solids were refluxed in Acetone for 30 minutes followed by crystallization to obtain crystalline cetylpyridinium chloride monohydrate (1200 g) with purity of about99.5 by are percentage of HPLC purity. The product was confirmed by m.p. (80-84° C), mass spectroscopy, 'H NMR and 13 C NMR.
  • Cetyl bromide (150 g), pyridine (156 g) and water (53 g) were charged into a round bottom flask, heated to 95-102 °C and maintained for 30 hours. After the completion of reaction, the excess pyridine and water were distilled off. Reaction mass was cooled, filtered. The solids were refluxed in Acetone for 30 minutes followed by crystallization to obtain crystalline cetylpyridinium bromide mono hydrate (180 g) with assay of about 99 by are titrimetric analysis and moisture content. The product was confirmed by m.p. (67-73° C), mass spectroscopy.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

The present invention discloses a process for the production of quaternary pyridinium salts and hydrates thereof. In this process, Cetylpyridinium chloride monohydrate with high purity and yield is obtained by reacting Cetyl chloride, pyridine, and water and Laurylpyridinium chloride monohydrate with high purity and yield is obtained by reacting Lauryl chloride, pyridine, and water. The process disclosed herein is simple, cost-effective and eco-friendly and produces quaternary pyridinium salts and hydrates thereof having high purity and yield at industrial scale.

Description

TITLE OF THE INVENTION
An improved process for preparation of quaternary pyridinium salts
FIELD OF THE INVENTION
The present invention relates to an improved process for preparing quaternary ammonium salts. In particular, the present invention relates to an improved process for preparing hydrates of quaternary ammonium salts. More particularly, the present invention relates to an improved process for preparing Cetylpyridinium chloride monohydrate.
BACKGROUND OF THE INVENTION
Quaternary ammonium salts are widely used salts in many fields such as pharmaceuticals, oral and personal care, cosmetics, cleaning agents, diagnostics etc. Many Quaternary ammonium salts are used in many industries as antimicrobial preservative, sanitizers, solubilizers etc. In pharmaceuticals, cetylpyridinium chloride (CPC) is used as antimicrobial for medical devices, antibacterial agent in mouth-wash and toothpastes, anti-plaque agents in throat lozenges, periodontal agent in the dentistry, preservative in ophthalmic products, disinfectant, surface stabilizer, antiseptic OTC products etc.
J. Am. Chem. Soc, 1946, 68, 757 discloses Quaternary Ammonium Salts as Germicides and process for preparation thereof by reacting alkyl halide with 10 to 30% excess amount of pyridine at temperatures from 60 to l30°C for 8 to 16 hours to yields 95% quaternary pyridinium salt.
European Patent No. 1125927 discloses a process for the preparation of cetylpyridinium chloride (CPC) monohydrate by reacting cetyl chloride under pressure and by crystallization with methyl ethyl ketone followed by treatment with water to obtain CPC monohydrate. Indian patent application No. 3661/DEL/2014 discloses similar process for the production of quaternary pyridinium salts in presence of catalyst followed by conversion to monohydrate salts by treatment with water.
Therefore there is a need for industrially feasible process for preparation of quaternary pyridinium salt hydrates. The present invention takes advantage of in-situ production of hydrate and thus removing process steps for production of quaternary pyridinium salt hydrates thereby solves the problem in the art.
The invention provides single step process for preparation of quartemary pyridinium salt hydrates and is also industrially advantageous.
OBJECT OF THE INVENTION The main object of the invention is to provide an improved process for the preparation of quaternary pyridinium salts which provides the process for the preparation of compound of formula (I),
Figure imgf000004_0001
Another object of the invention is to provide an improved process for the preparation of quaternary pyridinium salts which provides the different processes for the preparation of cetylpyridinium chloride monohydrate of formula (la),
Figure imgf000004_0002
Still another object of the invention is to provide an improved process for the preparation of quaternary pyridinium salts which provides the different process for the preparation of laurylpyridinium chloride monohydrate of formula (Ha),
Figure imgf000004_0003
Yet another object of the invention is to provide an improved process for the preparation of quaternary pyridinium salts which is a single step process and is also industrially advantageous.
SUMMARY OF THE INVENTION
In one general aspect, there is provided process for preparation of compound of formula (I),
Figure imgf000005_0001
the process comprising:
a) reacting compound of formula (II) with compound of formula (III), in presence of water and optionally in presence of solvent to obtain compound of formula (I),
X - (CH2)n - CH3
Figure imgf000005_0002
(III) (P)
b) optionally, purifying the compound of formula (I);
wherein, R represent a Hydrogen, C1-C5 alkyl, or Ci-Csalkoxy;
X is any halogen,
n is any integer from 1 to 20 and;
y is any integer from 0 to 5.
In another general aspect, there is provided a process for preparation of cetylpyridinium chloride monohydrate of formula (la),
Figure imgf000006_0001
the process comprising:
a) reacting pyridine with cetyl chloride in presence of water
b) optionally purifying the cetylpyridinium chloride.
DETAILED DESCRIPTION OF THE INVENTION
The nature of the invention and the manner in which it is performed is clearly described in the specification. The invention has various components and they are clearly described in the following pages of the complete specification.
The inventors of the present invention have found that the preparation of quaternary pyridinium salts hydrate of the compound of formula (I) by the process of present invention is industrially advantageous as it requires few reaction steps compared to prior art. As used herein the term "obtaining" means isolating compound of interest by the ways of filtration, filtration under vacuum, centrifugation, and decantation. The product may be preceded for further steps with or without isolation and with or without drying in case of the product was isolated.
All ranges recited herein include the endpoints and the terms "about", "from", "to" be construed as modifying a value they are applied to such that it is not absolute and includes, to the very least, the degree of expected experimental error, limitation of method or instrument error for a given technique used to measure the value.
As used herein, unless indicated otherwise, the term "isolated" or "isolation" refer to the subject compound as physically separated from the reaction mixture in which it is formed.
The term "cooling" means the reaction mixture is subjected to cooling at temperature from about Odegree C. to about 35. degree. C. In particular, from about 5. degree. C. to about 30.degree. C.
The term "treating" means stirring, slurring, mixing, keeping that at any temperature or conditions. The term "removing the solvents" may include, for example, one or more of filtration, filtration under vacuum, centrifugation, decantation, distillation and distillation under vacuum. As used herein, the term “hydrate” refers to a combination of water with a compound of formula (I), wherein the water retains its molecular state as water and is either absorbed, adsorbed or contained within a crystal lattice of the substrate molecule of compound of formula (I) or compound of formula (la). In one general aspect, there is provided process for preparation compound of formula (I),
Figure imgf000008_0001
the process comprising:
a) reacting compound of formula (II) with compound of formula (III), in presence of water and optionally in presence of solvent to obtain compound of formula (I), X - (CH2)n - CH3
Figure imgf000009_0001
(III) (II)
b) optionally, purifying the compound of formula (I);
wherein,
R represent a Hydrogen, C1-C5 alkyl, or Ci-Csalkoxy;
X is any halogen,
n is any integer from 1 to 20 and;
y is any integer from 0 to 5.
In general, the compound of formula (II) is reacted with the compound of formula (III), in presence of water to obtain the compound of formula (I).
In general, the compound of formula (II) is reacted with the compound of formula (III) in presence of water, optionally in presence of solvent to obtain compound of formula (I). In general, solvent comprises one or more of methanol, ethanol, n-proponal, isopropanol, n-butanol, iso-butanol, acetone, methyl isobutyl ketone, cyclohexanone, methyl ethyl ketone, ethyl aceate, propyl acetate, butyl acetate, methyl isobutyrate or mixtures thereof. In general, the compound of formula (I) prepared by the process of present invention, can optionally be purified.
In general, the process for preparation of quaternary pyridinium salt hydrate compound of formula (I) by reacting a compound of formula (II) with a compound of formula (III) in presence of water, is one pot process preferably carried out in absence of any other solvent. The process is carried out in the temperature range of 0 to 170 °C, preferably between 70-130 °C, more preferably at 80 to 110 °C.
In general, the compound of formula (I) obtained by above process can be purified by re-crystallization from solvent. The solvent comprises, one or more of methanol, ethanol, n-proponal, isopropanol, n-butanol, iso-butanol, acetone, methyl isobutyl ketone, cyclohexanone, methyl ethyl ketone, ethyl aceate, propyl acetate, butyl acetate, methyl isobutyrate or mixtures thereof.
In another general aspect, there is provided a process for preparation of cetylpyridinium chloride monohydrate of formula (la),
Figure imgf000010_0001
the process comprising:
a) reacting pyridine with cetyl chloride in presence of water b) Optionally purifying the cetylpyridinium chloride.
In general, pyridine is reacted with cetyl chloride in presence of water, optionally in presence of solvent to obtain cetylpyridinium chloride monohydrate.
In general, solvent comprises one or more of methanol, ethanol, n-proponal, isopropanol, n-butanol, iso-butanol, acetone, methyl isobutyl ketone, cyclohexanone, methyl ethyl ketone, ethyl aceate, propyl acetate, butyl acetate, methyl isobutyrate or mixtures thereof.
In general, the process for preparation of cetylpyridinium chloride hydrate of compound of formula (la) by reacting pyridine with cetyl chloride in presence of water, is one pot process preferably carried out in absence of any other solvent. The process is carried out in the temperature range of 0 to 170 °C, preferably between 70-130 °C, more preferably at 80 to 110 °C.
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. Examples
Example 1 : Cetylpyridinium chloride monohydrate
Cetyl chloride (1000 g), pyridine (1220 g) and water (410 g) were charged into a round bottom flask, heated to 95-102 °C and maintained for 30 hours. After the completion of reaction, the excess pyridine and water were distilled off. Reaction mass was cooled, filtered. The solids were refluxed in Acetone for 30 minutes followed by crystallization to obtain crystalline cetylpyridinium chloride monohydrate (1200 g) with purity of about99.5 by are percentage of HPLC purity. The product was confirmed by m.p. (80-84° C), mass spectroscopy, 'H NMR and 13 C NMR.
Example 2: Laurylpyridinium chloride monohydrate
Lauryl chloride (1000 g), pyridine (1542 g) and water (527 g) were charged into a round bottom flask, heated to 95-102 °C and maintained for 30 hours. After the completion of reaction, the excess pyridine and water were distilled off. Reaction mass was cooled, filtered. The solids were refluxed in Acetone for 30 minutes followed by crystallization to obtain crystalline cetylpyridinium chloride monohydrate(l230 g) with purity of about 99.5 by area percentage of HPLC. The product was confirmed by m.p. (88-90° C), mass spectroscopy and 'H NMR and 13 C NMR.
Example 3: Cetylpyridinium bromide monohydrate
Cetyl bromide (150 g), pyridine (156 g) and water (53 g) were charged into a round bottom flask, heated to 95-102 °C and maintained for 30 hours. After the completion of reaction, the excess pyridine and water were distilled off. Reaction mass was cooled, filtered. The solids were refluxed in Acetone for 30 minutes followed by crystallization to obtain crystalline cetylpyridinium bromide mono hydrate (180 g) with assay of about 99 by are titrimetric analysis and moisture content. The product was confirmed by m.p. (67-73° C), mass spectroscopy.
Although the preferred embodiment as well as the construction and use have been specifically described, it should be understood that variations in the preferred embodiment could be achieved by a person skilled in the art without departing from the spirit of the invention. The invention has been described with reference to specific embodiments which are merely illustrative and not intended to limit the scope of the invention as defined in the claims.

Claims

We claim:
1. An improved process for preparation of quaternary pyridinium salts wherein the process for preparation of compound of formula (I),
Figure imgf000014_0001
comprises:
a) reacting compound of formula (II) with compound of formula (III), in presence of water and optionally in presence of solvent to obtain compound of formula (I);
Figure imgf000014_0002
(III) (II)
b) optionally, purifying the compound of formula (I);
wherein,
R represents a Hydrogen, C1-C5 alkyl, or Ci-Csalkoxy;
X is any halogen;
n is any integer from 1 to 20; and
y is any integer from 0 to 5.
2 The improved process for preparation of quaternary pyridinium salts as claimed in claim 1 wherein R is Hydrogen.
3. The improved process for preparation of quaternary pyridinium salts as claimed in claim 1 wherein X is Cl.
4. The improved process for preparation of quaternary pyridinium salts as claimed in claim 1 wherein n is 15.
5. The improved process for preparation of quaternary pyridinium salts as claimed in claim 1 wherein n is 11.
6 The improved process for preparation of quaternary pyridinium salts as claimed in claim 1 wherein the process for preparation of cetylpyridinium chloride monohydrate of formula (la),
Figure imgf000015_0001
comprises:
a) reacting pyridine with cetyl chloride in presence of water; and
b) optionally purifying the cetylpyridinium chloride monohydrate.
The improved process for preparation of quaternary pyridinium salts as claimed in claim 1 wherein the process for preparation of cetylpyridinium chloride monohydrate of formula (Ia),
Figure imgf000016_0001
compnses:
a) reacting pyridine with cetyl chloride in presence of water at about 95 to l02°C;
b) distilling off water and pyridine; and
c) purifying the cetylpyridinium chloride monohydrate of formula (la) with
Acetone.
8 The improved process for preparation of quaternary pyridinium salts as claimed in claim 1 wherein the process for preparation of laurylpyridinium chloride monohydrate of formula (Ila),
Figure imgf000016_0002
compnses:
a) reacting pyridine with lauryl chloride in presence of water; and b) optionally purifying the laurylpyridinium chloride monohydrate.
The improved process for preparation of quaternary pyridinium salts as claimed in claim 1 wherein the process for preparation of laurylpyridinium chloride monohydrate of formula (Ila),
Figure imgf000017_0001
compnses:
a) reacting pyridine with lauryl chloride in presence of water at about 95 to l02°C;
b) distilling off water and pyridine; and
c) purifying the laurylpyridinium chloride monohydrate of formula (Ila) with
Acetone.
PCT/IN2019/050013 2018-01-16 2019-01-08 An improved process for preparation of quaternary pyridinium salts WO2019142205A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102660919B1 (en) * 2023-11-06 2024-04-24 권영진 Wet tissue preservatives and wet tissues containing the same

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005254144A (en) * 2004-03-12 2005-09-22 Wako Pure Chem Ind Ltd Crystallization method for halogenated alkyl pyridinium salt

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005254144A (en) * 2004-03-12 2005-09-22 Wako Pure Chem Ind Ltd Crystallization method for halogenated alkyl pyridinium salt

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102660919B1 (en) * 2023-11-06 2024-04-24 권영진 Wet tissue preservatives and wet tissues containing the same

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