FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. Title of the Invention
A PROCESS FOR THE SYNTHESIS OF QUATERNARY AMMONIUM COMPOUNDS
2. Applicant(s)
Name Nationality Address
GHARDA CHEMICALS LIMITED Indian R & D CENTER, B-27, MIDC PHASE-I, DOMBIVILI (E), DIST.THANE-421203, MAHARASHTRA, INDIA
3. Preamble to the description
The following specification particularly describes the invention and the manner in which it is to be performed

FIELD
The present disclosure relates to a process for the synthesis of quaternary ammonium compounds.
BACKGROUND
The background information herein below relates to the present disclosure but is not necessarily prior art.
The use of quaternary ammonium compounds as antiseptics and disinfectants is well known in the art. Many quaternary ammonium compounds have been synthesized that are not only antibacterial, but also possess antifungal and antiviral capabilities. Coating of quaternary ammonium compounds/ moieties onto various surfaces, represents one of the most promising strategies for the preparation of antimicrobial/antiviral materials.
However, the widespread and injudicious use of antibiotics and disinfectants has induced the emergence of new strains of antimicrobial-resistant microorganisms, leading to dramatically increased difficulties in the antimicrobial issue. With the unceasing emergence of new strains of global infectious pathogens in recent years, there is an urgent demand for exploring more efficient, broad-spectrum and long-lasting antimicrobial agents.
Therefore, there felt a need to provide a process for the synthesis of quaternary ammonium compounds that mitigates the drawbacks mentioned herein above.
OBJECTS
Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows:

An object of the present disclosure is to ameliorate one or more problems of the prior art or to at least provide a useful alternative.
Another object of the present disclosure is to provide a process for the synthesis of quaternary ammonium compounds that are useful as antiviral and antimicrobial agent.
Yet another object of the present disclosure is to provide a process for the synthesis of quaternary ammonium compounds that can be easily coated on different surfaces to impart protection from viruses.
Still another object of the present disclosure is to provide a process for the synthesis of quaternary ammonium compounds that possess comparatively high level of antimicrobial activity against a broad spectrum of microorganisms including viruses.
Another object of the present disclosure is to provide a process for the synthesis of quaternary ammonium compounds that are safe, cost effective.
Other objects and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.
SUMMARY
The present disclosure relates to a process for the synthesis of a quaternary
ammonium compound. The process comprising reacting 4-hydroxy benzophenone
with 1,6-dibromohexane by using a base in a first fluid medium at a first
predetermined temperature for a first predetermined time period to obtain 4-((6-
bromohexyl)oxy)phenyl(phenyl) methanone. Separately, 2-bromo-N-decyl
acetamide is reacted with dimethyl amine in a second fluid medium at a second
predetermined temperature for a second predetermined time period to obtain N-
decyl-2-(dimethylamino)acetamide. 4-((6-bromohexyl)oxy)phenyl(phenyl)
methanone so obtained is reacted with N-decyl-2-(dimethylamino)acetamide in a

third fluid medium for a third predetermined temperature for a third predetermined time period to obtain the quaternary ammonium compound.
DETAILED DESCRIPTION
Embodiments are provided so as to thoroughly and fully convey the scope of the present disclosure to the person skilled in the art. Numerous details are set forth, relating to specific components, and methods, to provide a complete understanding of embodiments of the present disclosure. It will be apparent to the person skilled in the art that the details provided in the embodiments should not be construed to limit the scope of the present disclosure. In some embodiments, well-known processes, well-known apparatus structures, and well-known techniques are not described in detail.
The terminology used, in the present disclosure, is only for the purpose of explaining a particular embodiment and such terminology shall not be considered to limit the scope of the present disclosure. As used in the present disclosure, the forms "a,” "an," and "the" may be intended to include the plural forms as well, unless the context clearly suggests otherwise. The terms "comprises," "comprising," “including,” and “having,” are open ended transitional phrases and therefore specify the presence of stated features, integers, steps, operations, elements, modules, units and/or components, but do not forbid the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. The particular order of steps disclosed in the method and process of the present disclosure is not to be construed as necessarily requiring their performance as described or illustrated. It is also to be understood that additional or alternative steps may be employed.
As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed elements.
The terms first, second, third, etc., should not be construed to limit the scope of the present disclosure as the aforementioned terms may be only used to

distinguish one element, component, region, layer or section from another component, region, layer or section. Terms such as first, second, third etc., when used herein do not imply a specific sequence or order unless clearly suggested by the present disclosure
Use of antibiotics and disinfectants has induced the emergence of new strains of antimicrobial-resistant microorganisms, leading to dramatically increased difficulties in the antimicrobial issue. With the unceasing emergence of new strains of global infectious pathogens in recent years, there is an urgent demand for exploring more efficient, broad-spectrum and long-lasting antimicrobial agents. Quaternary ammonium compounds can also act as an antimicrobial agent, however, the existing process for the preparation of the same have drawbacks.
The present disclosure provides a process for the synthesis of quaternary ammonium compounds that possess antimicrobial activity and antiviral activity.
The process for the synthesis of a quaternary ammonium compound comprises the following steps:
(i) reacting 4-hydroxy benzophenone with 1,6-dibromohexane by using a
base in a first fluid medium at a first predetermined temperature for a
first predetermined time period to obtain 4-((6-
bromohexyl)oxy)phenyl(phenyl) methanone;
(ii) separately, reacting 2-bromo-N-decyl acetamide with dimethyl amine in
a second fluid medium at a second predetermined temperature for a
second predetermined time period to obtain N-decyl-2-
(dimethylamino)acetamide; and
(iii) reacting 4-((6-bromohexyl)oxy)phenyl(phenyl) methanone obtained in step (i) with N-decyl-2-(dimethylamino)acetamide obtained in step (ii) in a third fluid medium for a third predetermined temperature for a third

predetermined time period to obtain the quaternary ammonium compound.
The process for the synthesis of a quaternary ammonium compound is described in detail as given below:
Step 1: Synthesis of 4-((6-bromohexyl)oxy)phenyl(phenyl) methanone:
In the first step, 4-hydroxy benzophenone is reacted with 1,6-dibromohexane by using a base in a first fluid medium at a first predetermined temperature for a first predetermined time period to obtain 4-((6-bromohexyl)oxy)phenyl(phenyl) methanone.
The schematic representation of the synthesis of 4-((6-
bromohexyl)oxy)phenyl(phenyl) methanone is given in Scheme 1 below:

In accordance with the embodiments of the present disclosure, a mixture of 4-hydroxy benzophenone, 1,6-dibromohexane, a base and a first fluid medium is stirred at a first predetermined temperature under nitrogen atmosphere for a first predetermined time period to obtain a reaction mixture. The reaction mixture is cooled to a temperature in the range of 5°C to 25°C and after workup a crude 4-((6-bromohexyl)oxy)phenyl(phenyl) methanone is obtained. The crude 4-((6-bromohexyl)oxy)phenyl(phenyl) methanone has HPLC purity of 95% and dimer impurity, 1,6-Bis(4-benzoylphenoxy)hexane, less than 3.0%. In an embodiment, the crude product is purified on a silica gel column by using 20:1 hexane: ethyl acetate mixture to remove the dimer impurity. Solid white product, 4-((6-

bromohexyl)oxy)phenyl(phenyl) methanone obtained after column
chromatography has HPLC purity of > 99 %.
In accordance with the present disclosure, the base is selected from potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate. In an exemplary embodiment, the base is potassium carbonate.
In accordance with of the present disclosure, the first fluid medium is selected from dry dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP) and acetonitrile (ACN). In an exemplary embodiment, the first fluid medium is dry dimethyl formamide (DMF).
In accordance with the present disclosure, the first predetermined temperature is in the range of 20 °C to 40 °C. In an exemplary embodiment, the first predetermined temperature is 25 °C (room temperature).
In accordance with the present disclosure, the first predetermined time period is in the range of 2 to 20 hours. In an exemplary embodiment, the first predetermined time period is 18 hours.
In accordance with the present disclosure, a molar ratio of 4-hydroxy benzophenone to 1,6-dibromohexane is in the range of 1:1.5 to 1:10. In an exemplary embodiment, the molar ratio of 4-hydroxy benzophenone to 1,6-dibromohexane is 1:3.
Step 2: Synthesis of N-decyl-2-(dimethylamino) acetamide:
Separately, 2-bromo-N-decyl acetamide is reacted with dimethyl amine in a second fluid medium at a second predetermined temperature and for a second predetermined time period to obtain N-decyl-2-(dimethylamino) acetamide.
The schematic representation of the synthesis of N-decyl-2-(dimethylamino) acetamide is given in Scheme 2 below:


In accordance with the present disclosure, a mixture of 2-bromo-N-decyl acetamide, dimethyl amine and a second fluid medium is stirred at a second predetermined temperature for a second predetermined time period to obtain N-decyl-2(dimethylamino) acetamide.
In accordance with the present disclosure, the second fluid medium is selected from ethanol, methanol, propanol and butanol. In an exemplary embodiment of the present disclosure, the second fluid medium is ethanol.
In accordance with the present disclosure, the second predetermined temperature is in the range of 30°C to 70°C. In an exemplary embodiment of the present disclosure, the second predetermined temperature is 50°C.
In accordance with the present disclosure, the second predetermined time period is in the range of 2 to 6 hours. In an embodiment of the present disclosure, the time period is 4 hours.
In accordance with the present disclosure, a molar ratio of 2-bromo-N-decyl-acetamide to dimethyl amine is in the range of 1:5 to 1:10. In an exemplary embodiment of the present disclosure, the molar ratio of 2-bromo-N-decyl-acetamide to dimethyl amine is 1:6.
Step 3: Synthesis of Quaternary ammonium compound, 6-(4-
benzoylphenoxy)-N-(2-(decylamino)-2-oxoethyl)-N,N-dimethylhexan-1-ammonium bromide:
4-((6-bromohexyl)oxy)phenyl(phenyl) methanone obtained in step 1 is reacted with N-decyl-2-(dimethylamino)acetamide obtained in step 2 in a third fluid medium for a third predetermined temperature and for a third predetermined time period to obtain the quaternary ammonium compound.

The schematic representation of the synthesis of N-decyl-2-(dimethylamino) acetamide is given in Scheme 3 below.

In accordance with the embodiments of the present disclosure, the third fluid medium is selected from acetonitrile, tetrahydro furan (THF), xylene, toluene, chloroform and ethyl acetate. In an exemplary embodiment of the present disclosure, the third fluid medium is acetonitrile.
In accordance with the present disclosure, the third predetermined temperature is in the range of 50 °C to 90 °C. In an embodiment, the third predetermined temperature is 80°C.
In accordance with the present disclosure, the third predetermined time period is in the range of 20 to 40 hours. In an embodiment, the third predetermined time period is 32 hours.
In accordance with the present disclosure, a molar ratio of N-decyl-2-(dimethylamino)-acetamide to 4-[(6-bromo-hexyl)oxy]-benzophenone is in the range of as 1:0.5 to 1:1. In an exemplary embodiment of the present disclosure,

the molar ratio of N-decyl-2-(dimethylamino)-acetamide to 4-[(6-bromo-hexyl)oxy]-benzophenone is 1:0.95.
In accordance with the embodiments of the present disclosure, quaternary ammonium compound has a purity greater than 95% and a yield in the range of 75 to 95%.
In accordance with the embodiments of the present disclosure, the quaternary ammonium compound can be covalently coated onto different surfaces such as cotton, polyurethane, polyvinyl chloride, polypropylene, polystyrene, and the like. The surfaces coated with the quaternary ammonium compounds are highly efficient against different kinds of drug resistance bacteria, fungi, and viruses.
In an embodiment, the quaternary ammonium compound (antiviral agent) of the
present disclosure is used with other adjuvants in personal
protective equipments (PPE) for example face masks, face shield, gloves and the like by covalently coating onto different surfaces such as cotton, polyurethane, polyvinyl chloride, polypropylene, polystyrene, and the like.
The foregoing description of the embodiments has been provided for purposes of illustration and not intended to limit the scope of the present disclosure. Individual components of a particular embodiment are generally not limited to that particular embodiment, but, are interchangeable. Such variations are not to be regarded as a departure from the present disclosure, and all such modifications are considered to be within the scope of the present disclosure.
EXPERIMENTAL DETAILS:
Experiment 1: Synthesis of Quaternary ammonium compound in accordance with the present disclosure
Step (i): Synthesis of (4-((6-bromohexyl)oxy)phenyl)(phenyl)methanone

4-Hydroxy benzophenone (1 mole), 1,6-dibromohexane (3 moles/moles (m/m)), potassium carbonate (1.5 m/m) and dry dimethylformamide (DMF) (1000 ml/m) were added in a reactor/round bottom flask and stirred at 25 °C under nitrogen atmosphere for 18 hours to obtain a reaction mixture. Reaction was monitored by HPLC for absence of starting material 4-hydroxybenzophenone. After completion of reaction, the reaction mixture was cooled to 10 °C and filtered off inorganics along with major dimer impurity, 1,6-Bis (4-benzoylphenoxy) hexane to obtain a clear filtrate and residue.
The clear filtrate was poured into ice-water and extracted with ethylenedichloride
(EDC) (2 times extraction). The ethylenedichloride (EDC) (organic layer)
containing the product was separated and combined. The so obtained EDC was
washed with water to remove DMF, if any and EDC layer was obtained. The EDC
was concentrated to obtain a crude mass of product ((4-((6-
bromohexyl)oxy)phenyl)(phenyl)methanone). The crude product was separated from the crude mass.
The so obtained product was 70 % with HPLC purity >95 % and impurity (dimer) < 3.0 %. The so obtained product was further purified on a silica gel column by using 20:1 hexane: ethyl acetate mixture to remove dimer and to obtain solid white product ((4-((6-bromohexyl)oxy)phenyl)(phenyl)methanone) having HPLC purity > 99 %, having melting point 52 °C.
Other experiments were conducted similarly using different molar ratio of 1,6-dibromo hexane (1,6-DBH) with respect to 4-hydroxy-benzophenone. The results are represented in the table below:

Sr. No. molar ratio 1,6-DBH : 4-hydroxy-benzophenone HPLC area ratio product : dimer
1. 1:1.5 67:33
2. 1:2 74:26
3. 1:3 88:12

4. 1:10 95:5
To obtain the desired compound i.e., 4-((6-bromohexyl)oxy)phenyl) (phenyl)methanone, use of excess of 1,6-DBH is required, so that only one -Br group of 1,6-DBH is reacted with -OH group of benzophenone compound. On the contrary, when 1:1 molar ratio of benzophenone compound to 1,6-DBH is used, both the -Br groups of 1,6-DBH get reacted and majorly dimer compound will be formed.
From the above Table, it is observed that, when 1:3 molar ratio of benzophenone compound to 1,6-DBH was used, the product to dimer ratio obtained is 88:12, which is feasible. However, when 1:10 molar ratio of benzophenone compound to 1,6-DBH was used, the product to dimer ratio obtained was 95:5,, Although, the product formation is more, the use of 1,6-DBH is much more excess which is not feasible.
Step (ii): Synthesis of N-decyl-2-(dimethylamino)-acetamide
Into a clean and dry reactor 40 gms of 2-bromo-N-decyl-acetamide (0.143 moles) 390 ml of ethanol and 104 ml of 8.6 N aq. dimethyl amine solution were charged to obtain a mixture. The mixture was stirrer at 50 °C for 4 hours to obtain a product mixture. Ethanol was distilled out under vacuum from the product mixture and residual mass was extracted in DCM, washed with water and concentrated to get 34 gms of N-decyl-2-(dimethylamino)-acetamide having 99 % purity by GC analysis.
Step (iii): Synthesis of Quaternary ammonium compound, 6-(4-benzoylphenoxy)-N-(2-(decylamino)-2-oxoethyl)-N,N-dimethylhexan-1-ammonium bromide
Into a clean and dry reactor, 5 gms of N-decyl-2-(dimethylamino)-acetamide (0.02 moles) in 62 ml of acetonitrile and 6.9 gms of 4-[(6-bromo-hexyl)oxy]-benzophenone (0.019 mole) were charged to obtain a mixture in the form of a clear solution. The mixture (in the form of clear solution) was heated at 80 °C for

32 hours and acetonitrile was distilled out to get a crude product containing light brown solids (12 gms). HPLC analysis shows 90% product (6-(4-benzoylphenoxy)-N-(2-(decylamino)-2-oxoethyl)-N,N-dimethylhexan-1-ammonium bromide). The crude product was crystallized by using ethyl acetate to get 97% pure quaternary ammonium compound (6-(4-benzoylphenoxy)-N-(2-(decylamino)-2-oxoethyl)-N,N-dimethylhexan-1 -ammonium bromide) as off white solids.
TECHNICAL ADVANCEMENTS
The present disclosure described herein above has several technical advantages including, but not limited to, the realization of,
- a quaternary ammonium compound obtained by the process of the present disclosure, is cost effective and non-toxic to mammals; and
- a simple process for the synthesis of a quaternary ammonium compound.
Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising, will be understood to imply the inclusion of a stated element, integer or step,” or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the invention to achieve one or more of the desired objects or results. While certain embodiments of the inventions have been described, these embodiments have been presented by way of example only, and are not intended to limit the scope of the inventions. Variations or modifications to the formulation of this invention, within the scope of the invention, may occur to those skilled in the art upon reviewing the disclosure herein. Such variations or modifications are well within the spirit of this invention.

The numerical values given for various physical parameters, dimensions and quantities are only approximate values and it is envisaged that the values higher than the numerical value assigned to the physical parameters, dimensions and quantities fall within the scope of the invention unless there is a statement in the specification to the contrary.
While considerable emphasis has been placed herein on the specific features of the preferred embodiment, it will be appreciated that many additional features can be added and that many changes can be made in the preferred embodiment without departing from the principles of the disclosure. These and other changes in the preferred embodiment of the disclosure will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation.

WE CLAIM:
1. A process for the synthesis of a quaternary ammonium compound, said
process comprising the following steps:
(iv) reacting 4-hydroxy benzophenone with 1,6-dibromohexane by using a base in a first fluid medium at a first predetermined temperature for a first predetermined time period to obtain 4-((6-bromohexyl)oxy)phenyl(phenyl) methanone;
(v) separately reacting 2-bromo-N-decyl acetamide with dimethyl amine in a second fluid medium at a second predetermined temperature for a second predetermined time period to obtain N-decyl-2-(dimethylamino)acetamide; and
(vi) reacting 4-((6-bromohexyl)oxy)phenyl(phenyl) methanone
obtained in step (i) with N-decyl-2-(dimethylamino)acetamide obtained in step (ii) in a third fluid medium for a third predetermined temperature for a third predetermined time period to obtain the quaternary ammonium compound.
2. The process as claimed in claim 1, wherein said base is selected from potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate.
3. The process as claimed in claim 1, wherein said first fluid medium is selected from dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP) and acetonitrile (ACN).
4. The process as claimed in claim 1, wherein said first predetermined temperature is in the range of 20 °C to 40 °C.

5. The process as claimed in claim 1, wherein said first predetermined time period is in the range of 2 to 20 hours.
6. The process as claimed in claim 1, wherein a molar ratio of 4-hydroxy benzophenone to 1,6-dibromohexane is in the range of 1:2 to 1:10.
7. The process as claimed in claim 1, wherein said second fluid medium is
selected from ethanol, methanol, propanol and butanol.
8. The process as claimed in claim 1, wherein said second predetermined temperature is in the range of 30°C to 70°C.
9. The process as claimed in claim 1, wherein said second predetermined time period is in the range of 2 to 6 hours.
10. The process as claimed in claim 1, wherein a molar ratio of 2-bromo-N-decyl-acetamide to dimethyl amine is in the range of 1:5 to 1:10
11. The process as claimed in claim 1, wherein said third fluid medium is selected from acetonitrile, tetrahydro furan (THF), xylene, toluene, chloroform and ethyl acetate.
12. The process as claimed in claim 1, wherein said third predetermined temperature is in the range of 50 °C to 90°C.
13. The process as claimed in claim 1, wherein said third predetermined time period is in the range of 10 to 20 hours.
14. The process as claimed in claim 1, wherein a molar ratio of N-decyl-2-(dimethylamino)-acetamide to 4-[(6-bromo-hexyl)oxy]-benzophenone is in the range of as 1:0.5 to 1:1.
15. The process as claimed in claim 1, wherein said quaternary ammonium compound is 6-(4-benzophenoxy)-N-(2-(decylamino)-2-oxoethyl)-N,N-dimethylhexane-1-ammonium bromide.

16. The process as claimed in claim 1, wherein said quaternary ammonium compound has a purity greater than 95% and a yield in the range of 75 to 95%.