BR112017023742B1 - IMPROVED PROCESS FOR THE PREPARATION OF IMIDAZOLINIUM AMPHIPHILIC COMPOUNDS - Google Patents

Abstract

IMPROVED PROCESS FOR THE PREPARATION OF IMIDAZOLINIUM AMPHIPHILIC COMPOUNDS. The present invention generally relates to an improved process for the preparation of amphiphilic imidazolinium compounds such as 1-[2-(9(Z)-octadecenoyloxy)ethyl]-2-(8(Z)-heptadecenyl)- 3-(2-hydroxyethyl)imidazolinium (DOTIM). In particular, the invention relates to processes for synthesizing such compounds that avoid the need for toxic reagents, are more economical, and result in less waste than conventional methods. DOTIM and similar compounds can be formulated into cationic liposomes, which are useful as chemical vectors for nucleic acid delivery in gene therapy.

Description

FIELD OF THE INVENTION

[0001] The present invention generally relates to an improved process for the preparation of amphiphilic imidazolinium compounds, such as 1-[2-(9(Z)-octadecenoyloxy)ethyl]-2-(8(Z)- heptadecenyl)-3-(2-hydroxyethyl)imidazolinium (DOTIM). DOTIM and similar compounds can be formulated into cationic liposomes, which are useful as chemical vectors for nucleic acid delivery in gene therapy.

BACKGROUND OF THE INVENTION

[0002] Gene therapy uses nucleic acids as a treatment for genetic deficiencies and a wide variety of acquired diseases and includes large DNA molecules (plasmid DNA; pDNA) but also small DNA molecules (oligonucleotides; ODN) and RNA molecules ( ribozymes, siRNA and mRNA). The success of gene therapy is largely dependent on the development of gene delivery vectors, which may be a viral vector or a non-viral vector, such as a chemical carrier or delivery of naked DNA by physical methods. Non-viral vectors have many advantages over viral ones, including simple large-scale production, lack of immunogenicity, and low toxicity.

[0003] Cationic lipids capable of forming positively charged liposomes are one of the most widely used viral vectors for gene delivery (Zhi et al., Bioconjugate Chemistry, 2013, 24: 478519). Cationic lipids are amphiphilic molecules and are generally made up of a hydrophobic domain (e.g. aliphatic chains, steroid rings), a hydrophilic head group (e.g. amines, quaternary ammonium salts, guanidiniums, heterocycles), and a linking group ( eg, ether, ester, carbamate, or amide bond) that connects the two domains. The hydrophilic head group allows for the condensation of nucleic acids through electrostatic interactions with the phosphate groups of negatively charged genes, and further controls transfection efficiency. Cationic lipids are usually formulated as cationic liposomes with a co-lipid-like neutral dioleoyl phosphatidyl ethanolamine such as (DOPE) or cholesterol to enhance transfection. When mixed with negatively charged DNA, positively charged liposomes spontaneously form uniquely packed structures called lipoplexes.

[0004] Solodin et al reported the use of cationic imidazolinium lipids as synthetic carriers for delivering genes into cells (Solodin et al., Biochemistry, 1995, 34(41): 13537-13544). These lipids included 1-[2-(9(Z)-octadecenoyloxy)ethyl]-2-(8(Z)-heptadecenyl)-3-(2-hydroxyethyl)imidazolinium chloride (DOTIM), and its 1 - [2-(hexadecanoyloxy)ethyl]-2-pentadecyl-3-(2-hydroxyethyl)imidazolinium (DPTIM) and 1-[2-(tetradecanoyloxy)ethyl]-2-tridecyl-3-(2-hydroxyethyl) chloride - imidazolinium (DMTIM). DOTIM was found to be the most effective of the three compounds for both in vitro transfection and in vivo gene delivery. The structures of DMTIM, DPTIM and DOTIM are as follows:

[0005] Methods for preparing aliphatic imidazolinium compounds starting with the multifunctional compound N,N1-bis(2-hydroxyethyl) ethylenediamine have been described in US Patent Nos. 5,705,655 (Heath), 5,830,878 (Gorman) , and 8,044,215 (Yu). However, these prior processes suffer from several disadvantages. For example, to acylate the primary hydroxyl groups without concomitant acylation of the more nucleophilic secondary amines, the latter are protected with tert-butyloxycarbonyl groups. These protecting groups are commonly and herein referred to as "BOC" groups. This step requires the di-tert-butyl dicarbonate reagent, which is an expensive and toxic compound. Furthermore, the BOC protecting groups have to be removed by acid hydrolysis in a subsequent step, which results in an additional amount of organic and aqueous residues.

[0006] Furthermore, the acylation processes of this Boc-protected intermediate require the use of acid halides in the presence of a base (eg, triethylamine), or reaction with a carboxylic acid in the presence of N,N'-dicyclo- hexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP). The need for triethylamine or DMAP in the acylation reactions results in additional waste and costs. Furthermore, the DCC/DMAP procedure results in the formation of dicyclohexylurea (DCU) as a by-product, and generally requires purification of the formed ester which can be labor intensive.

[0007] There is a need, therefore, for improved methods for the preparation and purification of DOTIM and other amphiphilic imidazolinium compounds. In particular, there is a need for such processes that are easily scalable, low cost, environmentally friendly, and capable of consistently producing highly pure compounds.

SUMMARY OF THE INVENTION

[0008] Briefly, therefore, the present invention relates to improved processes for the preparation of amphiphilic imidazolinium compounds, including 1-[2-(9(Z)-octadecenoyloxy)ethyl]-2-(8(Z) -heptadecenyl)-3-(2-hydroxyethyl)imidazolinium (DOTIM).

[0009] In various embodiments, the present invention is directed to a process for preparing an amphiphilic imidazolinium compound of Formula (I) wherein R is a straight-chain, aliphatic, saturated or unsaturated hydrocarbon group of 11 to 29 carbon atoms. The process comprises reacting a compound of Formula (II) with a hydrogen halide (HX) to provide a compound of Formula (III) where X is Cl, Br or I. The compound of Formula (III) is reacted with a carboxylic acid halide [RC(O)Y], wherein Y is selected from the group consisting of Cl, Br, Fel, or a carboxylic acid anhydride [RC ( O)OC(O)R2] , wherein R is as defined above for Formula (I) and R2 is a straight or branched, aliphatic, saturated or unsaturated hydrocarbyl group of 1 to 29 carbon atoms, to provide a compound of Formula (IV). The compound of Formula (IV) is heated to provide a compound of Formula (I).

[0010] In various other embodiments, the present invention is directed to a process for preparing a compound of Formula (I) wherein R is a straight-chain, aliphatic, saturated or unsaturated hydrocarbon group of 11 to 29 carbon atoms. The process comprises heating a compound of Formula (IV) in a reaction mixture comprising an organic solvent and a base to provide the compound of Formula (I), wherein R is as defined above and X is Cl, Br or I .

[0011] Other objects and features will be partly apparent and partly pointed out below.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES

[0012] The present invention generally relates to processes for the preparation of amphiphilic imidazolinium compounds which provide advantages over the prior art. For example, the process avoids the use of BOC protecting groups and the need for a base during the acylation process, thus reducing process cost, toxicity issues and the amount of residues generated.

[0013] In particular, the present invention provides processes for the preparation of amphiphilic imidazolinium compounds of Formula (I): wherein R is a straight-chain, aliphatic, saturated or unsaturated hydrocarbyl group of 11 to 29 carbon atoms, or of 12 to 25 carbon atoms. When unsaturated, the R group can have one or more ethylenically unsaturated bonds.

[0014] Illustrative R groups, along with the carbonyl group to which they are attached (i.e., RC(O)-) include oleoyl, lauroyl, myristoyl, palmitoyl, stearoyl, linoleoyl, eicosanoyl, tricosanoyl, and nonacosanoyl (derived from fatty acids corresponding name: oleic, lauric, myristic, etc.). When system names are given for the individual R groups, the corresponding name of the hydrocarbyl group derived from oleic acid is cis-8-heptadecenyl; of lauryl acid is undecyl; of myristic acid is tridecyl; of palmitic acid is pentadecyl; of stearic acid is heptadecyl; of linoleic acid is cis,cis-8,11-heptadecidienyl; of eicosanoic acid is nonadecyl; of tricosanoic acid is dicosanyl; of triacontanoic acid is nonacosanyl. A particularly preferred compound of Formula (I) is 1-[2-(9(Z)-octadecenoyloxy-ethyl]-2-[8(Z)-heptadecenyl]-3-hydroxyethyl-imidazolinium chloride (DOTIM):

[0015] The imidazolinium compounds of the present invention do not have a pharmaceutically acceptable anion increase. Typically, the imidazolinium salt formed according to the present processes is a chloride salt. However, the anion can be exchanged to produce a salt with a different anion. For example, the imidazolinium chloride salt can be dissolved in an appropriate solvent and washed with a solution containing the desired anion. Although chloride is the preferred anion, bromide and other physiologically acceptable anions, including acetate, succinate, and citrate, are also acceptable.

[0016] According to the present invention, the general process for the preparation of an amphiphilic imidazolinium compound of formula (I) is as follows:

[0017] Formula (IVa) and formula (IVb) defined above as the product of Step 2 are generally referred to in the present invention (including in the appended claims) as Formula (IV).

Step 1: Protection of secondary amino groups

[0018] The first step in the process is the preparation of a hydrohalide salt of N,N'-bis(2-hydroxyethyl)ethylenediamine (Formula (III)). This is obtained by reacting N,N'-bis(2-hydroxyethyl) ethylenediamine (Formula (II)) with a hydrogen halide (HX) in a reaction mixture, typically including a suitable solvent, where X is Cl, Br or I. In various preferred embodiments, the hydrogen halide is hydrogen chloride (where X is Cl) or hydrogen bromide (where X is Br). In several particularly preferred embodiments, the hydrogen halide is hydrogen bromide. Generally, the hydrogen halide is introduced into a reaction mixture comprising N,N'-bis(2-hydroxyethyl)ethylenediamine. This can be achieved, for example, by introducing hydrogen halide as a gas into the reaction mixture, which is typically in the form of a solution of N,N'-bis(2-hydroxyethyl)ethylenediamine dissolved in an organic solvent. Alternatively, a solution of the hydrogen halide in an organic solvent (eg non-aqueous HBr in acetic acid, or HCl solution in methanol, ethanol, dioxane or diethyl ether) can be added to the reaction mixture. The introduction of hydrogen halide into the reaction mixture in the liquid phase is generally preferred.

[0019] Suitable organic solvents for preparing the hydrohalide salt of Formula (III) include, but are not limited to, C2-C6 carboxylic acids; C2-C6 nitriles; C1-Ce alcohols; C2-C10 ethers; C3-C6 alkyl acetates; C3-C10 ketones; C5-C8 aliphatic hydrocarbons; chlorinated Cj-Ce hydrocarbons; C3-C8 alkyl carbonates; sulfolane; dimethyl sulfoxide; toluene; chlorobenzene; as well as mono- or polyphasic mixtures thereof.

[0020] Specific examples of such solvents include, but are not limited to, acetic acid, propionic acid, acetonitrile, propionitrile, methanol, ethanol, isopropanol, tert-butanol, diethyl ether, tetrahydrofuran, dioxane, methyl tert-butyl ether , 1,2-dimethoxyethane, methyl acetate, ethyl acetate, tert-butyl acetate, acetone, methyl ethyl ketone, hexane, heptane, cyclohexane, dichloromethane, chloroform, 1,2-dichloroethane, propylene carbonate, sulfolane , dimethyl sulfoxide, toluene, chlorobenzene and combinations thereof. Preferably, the solvent is selected from the group consisting of acetic acid, methanol, ethanol, isopropanol, ethyl acetate and combinations thereof.

[0021] The reaction to form the hydrohalide salt of Formula (III) is typically conducted at a temperature of about 0 °C to about 60 °C, and more typically, at a temperature of about 10 °C C to about 30°C, for example, by controlled addition of the hydrogen halide to the reaction mixture.

[0022] Typically, the starting material is converted to a hydrohalide salt of Formula (III) over a reaction time of about 10 to about 120 minutes, and till Lc r dd uc \j d <,cLCa. uc VJ U HLIIIULOS ãpkjS the addition of the reagent.

[0023] The compound of Formula (III), in the form of a hydrohalide salt, easily forms a precipitate in the reaction mixture and can be isolated by filtration. The recovered product is typically washed and dried under vacuum.

Step 2: Acylation of primary hydroxyl groups

With the secondary amino groups of N,N'-bis(2-hydroxyethyl)ethylenediamine protected as the halide salt, the primary hydroxyl groups of the compound of Formula (III) are acylated to produce the diester.

[0025] The acylating agent may be an activated carboxylic acid derivative, such as a carboxylic acid halide (RC(O)Y) or carboxylic acid anhydride (RC(O)OC(O)R2), where R is as defined above for Formula (I) and R2 is a straight or branched chain, aliphatic, saturated or unsaturated hydrocarbon group of 1 to 29 carbon atoms, or 12 to 25 carbon atoms. In carboxylic acid anhydride, R and R2 can be the same (i.e., a symmetrical carboxylic acid anhydride). However, R and R2 are typically not the same. Typically, R2 represents a straight or branched chain C1-C10 aliphatic hydrocarbon, and more typically, R2 is a branched C3-C10 aliphatic hydrocarbon. It is currently believed that sterically hindered or branched R2 groups (eg, tert-butyl or isopropyl) lead to the desired product, minimizing the formation of unwanted mixed product esters. In the carboxylic acid halide, Y is typically selected from the group consisting of Cl, Br, Fel. More typically, Y is Cl or Br. Y may be identical to the counterion, X, of the compound of Formula (III), but this need not be. Carboxylic acid chlorides are generally preferred over bromides, fluorides and iodides as well as carboxylic acid anhydrides as the acylating agent because of their lower cost and ready availability. For the preparation of DOTIM, the carboxylic acid halide is preferably oleic acid chloride.

[0026] Carboxylic acid halide acylating agents are commercially available. However, it has been found that higher yields of the compound of Formula (IV) can be obtained when the carboxylic acid halide is prepared at the same time as or immediately prior to its use in the process of the present invention. A suitable process for preparing a carboxylic acid halide (oleic acid chloride) acylating agent is set forth in Example 2.

[0027] For hydrobromide salts of Formula (III), reaction with a carboxylic acid bromide or carboxylic acid anhydride yields the compound of Formula (IVa) shown above. Likewise, for hydrochloride salts of formula (III), reaction with a carboxylic acid chloride or acid anhydride yields a compound of formula (IVb).

[0028] For the acylation step, the hydrohalide salt of N,N'-bis(2-hydroxyethyl) ethylenediamine (Formula (III)) is diluted in an organic solvent followed by addition of the carboxylic acid acylating agent activated. Suitable organic solvents for the acylation step include, but are not limited to, C2-C6 nitriles; C2C10 ethers; C3-C6 alkyl acetates; C3-C10 ketones; C5-C8 aliphatic hydrocarbons; chlorinated C1-C6 hydrocarbons; C3-C8 alkyl carbonates; sulfolane; dimethyl sulfoxide; toluene; chlorobenzene; as well as their mono- or polyphasic mixtures.

[0029] Specific examples of such solvents include, but are not limited to, acetonitrile, propionitrile, diethyl ether, tetrahydrofuran, dioxane, methyl tert-butyl ether, 1,2-dimethoxyethane, methyl acetate, ethyl acetate, acetate tert-butyl acetone, methyl ethyl ketone, hexane, heptane, cyclohexane, dichloromethane, chloroform, 1,2-dichloroethane, propylene carbonate, sulfolane, dimethyl sulfoxide, toluene and chlorobenzene. Preferably, the solvent is selected from acetonitrile, propionitrile, dichloromethane, chloroform, tetrahydrofuran and combinations thereof.

[0030] The acylation is generally conducted at a temperature of from about 0 °C to about 120 °C, more typically from about 20 °C to about 100 °C, and even more typically from about 40 °C C to about 80°C.

[0031] The acylation reaction is typically carried out over a period of time from about 1 to about 12 hours, more typically from about 2 to about 6 hours.

[0032] When the acylating agent is a carboxylic acid halide, hydrogen halide gas is evolved during the course of the reaction and can be absorbed using a gas scrubber. When the acylating agent is a carboxylic acid anhydride, the by-product carboxylic acid is produced and retained in the organic solvent.

[0033] The acylation of N,N'-bis(2-hydroxyethyl)ethylenediamine hydrohalide salt (Formula (III)) proceeds smoothly, and provides the requisite diester of Formula (IV) in high yield. Upon completion of the reaction, the reaction mixture is typically cooled to a temperature of about 20°C to about 40°C and may be diluted with acetone to improve filtration of the formed precipitate. The precipitated product of Formula (IV) is then easily recovered, the filtrate is washed and the recovered solid is dried under vacuum.

[0034] In contrast to the acylation processes described in the prior art, no addition of base is required for this transformation. Furthermore, the acylation step of the present process is typically conducted in the absence of any acid catalyst. In particular, this step does not use acid catalysts, such as p-toluenesulfonic acid, benzenesulfonic acid, sulfoacetic acid, phosphorous acid and phosphorus trichloride.

[0035] In several preferred embodiments, X in Formula III is Br and the hydrobromide salt of N,N'-bis(2-hydroxyethyl)ethylenediamine (Formula (III)) is reacted with a carboxylic acid halide (e.g., chloride of oleic acid). This reaction was observed to readily form a compound of formula (IVb). When the symbol X in formula III is Cl, the hydrochloride salt of N,N'-bis(2-hydroxyethyl)ethylenediamine (Formula (III)) with a carboxylic acid halide (eg oleic acid chloride). Based on its solubility, however, it may be necessary to dissolve N,N'-bis(2-hydroxyethyl)ethylenediamine chloride salt in a highly polar solvent, such as, for example, sulfolane, dimethylformamide (DMF), and dimethylacetamide (DMAC). This procedure is generally less desired because of the additional processing required and added costs.

Conversion of hydrohalide salt IVa to hydrochloride salt IVb

[0036] Since chloride is the counterion in the final product of Formula (I), an additional washing step is required where the compound of Formula (IV) is a hydrohalide salt other than the hydrochloride salt (e.g. , where the compound of Formula (III) is reacted with a carboxylic acid halide RC(O)Y, where Y is not Cl). However, when the hydrochloride salt (IVb) is prepared from a compound of Formula (III), washing is unnecessary.

[0037] For any necessary washing step, the compound of Formula (IVa) is dissolved in a suitable solvent and washed with a concentrated aqueous solution of sodium chloride. Often multiple washes are used, for example 2 or more washes may be used. This anion exchange wash is normally conducted at a temperature of from about 0°C to about 60°C, more typically from about 10°C to about 30°C, and even more typically from about 15°C to about 25°C. After separation of the final aqueous sodium chloride layer (brine), the organic phase is concentrated to obtain the desired hydrochloride salt of Formula (IVb).

[0038] Suitable solvents for the anion exchange step include, but are not limited to, C∑-Cθ nitriles; C2-C10 ethers; C3-C6 alkyl acetates; C3-C10 ketones; C5-C8 aliphatic hydrocarbons; chlorinated Cy-Cε hydrocarbons; toluene; chlorobenzene; as well as their monoor polyphasic mixtures.

[0039] Specific examples of such solvents include, but are not limited to, acetonitrile, propionitrile, diethyl ether, tetrahydrofuran, dioxane, methyl tert-butyl ether, 1,2-dimethoxyethane, methyl acetate, ethyl acetate, acetate of tert-butyl, acetone, methyl ethyl ketone, hexane, heptane, cyclohexane, dichloromethane, chloroform, 1,2-dichloroethane, toluene, chlorobenzene and mixtures thereof. Preferably, the solvent is selected from dichloromethane, chloroform, 1,2-dichloroethane, methyl acetate, ethyl acetate, toluene and combinations thereof.

Step 3: Rearrangement reaction

[0040] To effect the rearrangement reaction, the compound of Formula (IVb) is dissolved in a reaction mixture comprising a suitable solvent and this reaction mixture is heated and stirred whereby migration of the acyl group followed by condensation takes place, the which results in the formation of the imidazolinium compound of Formula (I).

[0041] Suitable solvents for the rearrangement reaction include, but are not limited to, C2-C6 nitriles; Ci-Ce alcohols; C2-C10 ethers; C3-C6 alkyl acetates; C3-C10 ketones; C5-C8 aliphatic hydrocarbons; golden Ci-Cβ hydrocarbons; C3-C8 alkyl carbonates; sulfolane; dimethyl sulfoxide; toluene; chlorobenzene; as well as their mono- or polyphasic mixtures.

[0042] Specific examples of such solvents include, but are not limited to, acetonitrile, propionitrile, methanol, ethanol, isopropanol, tert-butanol, diethyl ether, tetrahydrofuran, dioxane, methyl tert-butyl ether, 1,2-dimethoxyethane , methyl acetate, ethyl acetate, tert-butyl acetate, acetone, methyl ethyl ketone, hexane, heptane, cyclohexane, dichloromethane, chloroform, 1,2-dichloroethane, propylene carbonate, sulfolane, dimethyl sulfoxide, toluene , chlorobenzene and mixtures thereof.

[0043] In certain embodiments, the solvent is a mixture of a chlorinated hydrocarbon and an alcohol, such as, for example, a mixture of chloroform and methanol. In such cases, the weight ratio of chloroform to methanol is typically from about 4:1 to about 10:1, or from about 6:1 to about 8:1. Additionally or alternatively, the volumetric ratio of chloroform to methanol is typically from about 2:1 to about 6:1, or from about 3:1 to about 5:1.

[0044] In certain embodiments, along with the solvent or solvent mixture, the reaction mixture further includes a base. In some embodiments a weak base is used. Suitable weak bases include, but are not limited to, sodium bicarbonate (sodium hydrogencarbonate), potassium bicarbonate (potassium hydrogencarbonate), potassium dihydrogenphosphate (monopotassium phosphate), dipotassium hydrogenphosphate (dipotassium phosphate), tertiary amines and mixtures thereof.

[0045] Generally, the base is incorporated in a molar ratio to the compound of Formula (IVb) of from about 0.25:1 to about 1.75:1 or from about 0.8:1 to about 1 ,5:1. In certain embodiments, the base is incorporated in a molar ratio to the compound of Formula (IVb) from about 1:1 to about 1:5:1, or from about 1:1 to about 1.2:1 (for example, about 1.1:1).

[0046] In addition to the solvent mixture or organic solvent, and an optional base, a drying agent can be added to the reaction mixture before heating. Suitable drying agents include, for example, molecular sieves (for example those having a pore size of 2Å to 5Å), calcium chloride, magnesium sulfate and sodium sulfate. In particular suitable drying agents include molecular sieves (for example those having a pore size of 2Å to 5Å or about 3Å) and magnesium sulfate. Activated charcoal is also a suitable drying agent. The amount of drying agent is not strictly critical, but should be sufficient to absorb the water formed during the rearrangement/condensation reaction.

[0047] The reaction mixture is typically conducted at a temperature of from about 20°C to about 100°C, more typically from about 40°C to about 80°C, and even more typically from about 50°C to about 70°C.

[0048] The rearrangement step is typically conducted over a period of time from about 2 to about 48 hours, more typically from about 12 to about 36 hours. While such lengths of time are acceptable, in certain embodiments when a base is incorporated into the reaction mixture, the rearrangement reaction proceeds at a faster rate. In such embodiments, the rearrangement step is conducted over a time period of from about 2 to about 12 hours, or from about 4 to about 10 hours, or from about 5 hours, or from about 6 hours.

[0049] After the reaction mixture is cooled or allowed to cool to room temperature, the mixture is filtered to remove a fraction of solids and provides a filtrate containing the imidazolinium compound of Formula (I). The filtrate is concentrated to obtain a crude product, typically as a waxy solid. The crude product can be purified by suitable methods known in the art, including, for example, solvent washing, by recrystallization, or even by a suitable chromatographic method.

[0050] Preferred purification/product recovery protocols include treating the crude product filtrate with acetone, followed by filtration and concentration to recover the desired solid product. Another preferred product recovery/purification protocol involves filtration using a silica column and dichloromethane or chloroform. Notably, these preferred product recovery/product purification protocols are chromatographic methods and, therefore, much simpler and more suitable for use on a commercial scale than the chromatography-based recovery methods conventionally used in the art. Advantageously, product recovery/purification protocols used in the present methods that are not chromatographic provide product purities in excess of 95% or greater (e.g., in excess of 97%).

[0051] Generally, the rearrangement step provides the compound of Formula (I) in a yield (based on the compound of Formula (IVb)) of at least about 70%, at least about 75%, at least about of 80%, at least about 85%, at least about 90%, or at least about 95% (e.g., about 97% or greater).

[0052] Having described the invention in detail, it will be evident that modifications and variations are possible without departing from the scope of the invention defined in the appended claims.

EXAMPLES

[0053] The following non-limiting examples are provided to further illustrate the present invention.

Example 1: Synthesis of N,N'-bis(2-hydroxyethyl)ethane-1,2-diaminonium dibromide

[0054] N,N'-Bis(2-hydroxyethyl) ethylenediamine (20 g, 0.135 mol) was dissolved in 100 ml of acetic acid (exothermic). After cooling this solution to approximately 20°C, hydrobromic acid (0.283 mol; 50.3 ml, 33% solution in acetic acid) was slowly added to the reaction mixture over 45 minutes so that the temperature of the reaction mixture did not exceed 30 °C. A white precipitate formed during the addition of hydrobromic acid to the reaction mixture. After complete addition, the reaction mixture was stirred for 30 minutes, followed by filtration of the precipitate. The precipitate was then washed with acetonitrile (2 x 25 ml) and dried at 30 °C under vacuum (5 mbar) to yield 40.58 g (0.131 mol, 97% yield) of N,N' dibromide -bis(2-hydroxyethyl)ethane-1,2-diaminium as a white solid. The structure of the product was confirmed by NMR spectroscopy: 1H-NMR (DMSO-de, 400 MHz) δ = 8.62 (4H, bs), 5.34 (2H, bs), 3.67 (4H, bs ), 3.29 (4H, bs), and 3.07 (4H, bs) ppm.

Example 2: Synthesis of N,N'-bis{2-[(9Z)-octadec-9-enoyloxy]ethyl}ethane-1,2-diaminonium dibromide

[0055] N,N'-Bis{2-[(9Z)-octadec-9-enoyloxy]ethyl}ethane-1,2-diaminium dibromide was prepared by acylation of N,N'-Bis(2- hydroxyethyl)ethane-1,2-diaminium with freshly prepared oleic acid chloride.

[0056] Oleic acid chloride was prepared by dissolving oleic acid (9.0 g, 0.0319 mol, 99% purity) in 20 ml of dichloromethane, followed by addition of oxalyl chloride (8.08 g, 0.064 mol ) at 20 °C. After the addition, the reaction mixture was stirred for 60 minutes. The dichloromethane and excess oxalyl chloride were evaporated at 30 °C under vacuum (750 mbar, gradually to 50 mbar) to yield 9.5 g (0.0315 mol, 99% yield) of oleic acid chloride as a colorless oil. The structure of the product was confirmed by NMR spectroscopy: 1H-NMR (DMSO-d3, 400 MHz) δ = 5.34 (2H, m), 2.88 (2H, t), 2.01 (4H, m) , 1.71 (2H, m), 1.31 (20H, m), and 0.88 (3H, t) ppm.

[0057] N,N-Bis(2-hydroxyethyl)ethane-1,2-diaminium dibromide (25 g, 0.0806 mol), prepared as described in Example 1 was added at 20 °C in 200 ml of acetonitrile, to provide a white mud. After heating to approximately 82 °C, freshly prepared oleic acid chloride (72.8 g, 0.242 mol) was added to the reaction mixture over 1 hour, followed by further stirring at about 82 °C for 3 hours. During this time, gaseous hydrogen chloride evolved from the reaction mixture, which was absorbed into a gas scrubber. After cooling to 40 °C, the reaction mixture was diluted with 150 ml of acetone to improve the filtration performance of the formed precipitate. At 20°C, the aqueous slurry was filtered and washed consecutively with acetone (1 x 20 ml), water (1 x 40 ml) and acetone (2 x 25 ml). The remaining solid was dried at 40 °C under vacuum (5 mbar) to obtain 54.1 g (0.0645 mol, 80% yield) of N,N'-bis(2-[(9Z)- octadec-9-enoyloxy]ethyl}ethane-1,2-diamino as an off-white solid. The bromide/chloride ratio in the product was found to be 18:1 as determined by ion chromatography. The structure of the product was confirmed by NMR spectroscopy: 1 H-NMR (DMSO-d3, 400 MHz) δ = 9.50 (4H, bs), 5.34 (4H, m), 4.52 (4H, m) , 3.81 (4H, bs), 3.45 (4H, bs), 2.47 (4H, m), 2.00 (8H, m), 1.62 (4H, m), 1.29 ( 40H, m), and 0.88 (6H, m) ppm.

Example 3: Synthesis of N,N'-bis{2-[(9Z)-octadec-9-enoyloxy]ethyl}ethane-1,2-diaminonium dichloride

[0058] N,N'-Bis{2-[(9Z)-octadec-9-enoyloxy]ethyl}ethane-1,2-diaminium dibromide (42 g, 0.050 mol) was dissolved in chloroform (500 ml). To this solution at 20°C were added 250 ml of water and 500 ml of brine. The reaction mixture was stirred for one hour and then the organic layer was separated from the aqueous layer. Prior centrifugation (at 3000 to 5000 RPM) of the reaction mixture typically produced better phase separation. The organic layer was treated again (2x) with brine in the same way. Finally, the organic layer was washed with water, dried with 2 g of calcium chloride, and concentrated at 40 °C under vacuum (500 mbar, gradually to 20 mbar), to yield 31.9 g (0.0425 mol, 85 %) of N,N'-bis{2-[(9Z)-octadec-9-enoyloxy]ethyl}ethane-1,2-diaminium dichloride as an off-white solid. The structure of the product was confirmed by NMR spectroscopy: 1H-NMR (DMSO-d3, 400 MHz) δ = 10.10 (4H, bs), 5.35 (4H, m), 4.49 (4H, m) , 3.69 (4H, bs), 3.38 (4H, m), 2.45 (4H, m), 1.99 (8H, m), 1.61 (4H, m), 1.29 ( 40H, m), and 0.88 (6H, m) ppm.

[0059] The bromide/chloride ratio of the product obtained after the third wash with concentrated aqueous sodium chloride solution was found to be 1:180.

Example 4: Synthesis of 1-[2-(9(Z)-octadecenoyloxy)ethyl]-2-(8(Z)heptadecenyl)-3-(2-hydroxyethyl)imidazolinium chloride

[0060] N,N'-Bis(2-[(9Z)-octadec-9-enoyloxy]ethyl)ethane-1,2-diamine dichloride (20 g, 0.0266 mol) was dissolved in a mixture of chloroform (160ml) and methanol (40ml), then to this mixture was added 3Å molecular sieves (5g). The reaction mixture was heated to approximately 54°C and stirred for 24 hours. The reaction mixture was then cooled to room temperature and filtered to remove solids. The filtrate was concentrated in vacuo (500 mbar, gradually to 5 mbar) at 40°C to yield a yellowish waxy solid. The product was treated with 30 ml of acetone and stirred for 30 minutes at 40°C. The resulting aqueous slurry was filtered, and the filtrate was concentrated again under vacuum to afford 14.4 g (0.0207 mol, 78% yield) of 1-[2-(9(Z)-octadecenoyloxy)ethyl] chloride -2-(8(Z)-heptadecenyl 1)-3-(2-hydroxyethyl)imidazolinium, as a colorless, waxy solid. The structure of the product was confirmed by NMR spectroscopy: 1H-NMR (DMSO-dj, 400 MHz) δ = 6.12 (1H, bs), 5.34 (4H, m), 4.34 (2H, m) , 4.09 (4H, s), 3.87 (2H, m), 3.77 (2H, m), 3.52 (2H, m), 2.78 (2H, m), 2.32 ( 2H, m), 2.00 (8H, m), 1.59 (4H, m), 1.30 (40H, m), and 0.88 (6H, m) ppm.

Example 5: Synthesis of (1-[2-(9(Z)-octadecenoyloxy)ethyl]-2-(8(Z)-heptadecenyl)-3-(2-hydroxyethyl)imidazolinium chloride) with addition of base

[0061] N,N'-Bis{2-[(9Z)-octadec-5-enoyloxy]ethyl] ethan-1,2-diaminium dichloride (140 g, 0.186 mol) and sodium bicarbonate (sodium hydrogencarbonate) (15.68g, 0.205 mol) were suspended in a mixture of chloroform (1120 ml) and methanol (280 ml) at 20°C. The reaction mixture was heated to approximately 50-52°C and stirred for 5 hours. The mixture was then concentrated in vacuo (40°C; 150 mbar) to remove solvents and give a residue (196 g). The crude product residue was dissolved in acetone (1120ml) and activated charcoal (28g, having been dried at 120°C) was then added and the suspension stirred for 30 minutes at room temperature. The resulting aqueous slurry was filtered, and the filter cake was washed with acetone (150 ml). The combined pale yellow filtrate was concentrated under vacuum (40 °C; 4 mbar) to provide 120.3 g (0.173 mol, 92.7% yield) of (1-[2-(9(Z)-octadecenoyloxy chloride) )ethyl]-2-(8(Z)-heptadecenyl)-3-(2-hydroxyethyl)imidazolinium).

MODALITIES

[0062] For further illustration, additional non-limiting embodiments of the present invention are presented below.

[0063] Modality Al is a process for preparing a compound of Formula (I) wherein R is a straight chain, aliphatic, saturated or unsaturated hydrocarbyl group of 11 to 29 carbon atoms, the process comprising: reacting a compound of Formula (II) with a hydrogen halide (HX) to provide a compound of Formula (II) Formula (III), wherein X is Cl, Br or I; reacting a compound of Formula (III) with a carboxylic acid halide [RC(O)Y], wherein Y is selected from the group consisting of Cl, Br, Fel, or a carboxylic acid anhydride [RC(0 ) OC(O)R2] , above for Formula (I) and R2 is a straight or branched chain, aliphatic, saturated or unsaturated hydrocarbyl group of 1 to 29 carbon atoms, to provide a compound of Formula (IV); It is heat the compound of formula (IV) to provide a compound of formula (I).

[0064| Embodiment A2 is the process of Embodiment Al, wherein, when the compound of Formula (III) is reacted with a carboxylic acid halide [RC(0)Y], and X is not Cl, a compound of Formula (IVa) is provided, the process further comprising washing the compound of formula (IVa) with an aqueous solution of chloride compound of formula (IVb).

[0065] Embodiment A3 is the process of Embodiment Al, in which, when the compound of Formula (III) is reacted with a carboxylic acid anhydride [RC(O)OC(O)R2], or a carboxylic acid halide [RC(O)Y] and X = Cl, a compound of formula (IVb) is provided.

[0066] Embodiment A4 is the process of Embodiment A2 or A3, wherein the compound of Formula (III) is reacted with a carboxylic acid halide or carboxylic acid anhydride in the absence of an acid catalyst.

[0067] Embodiment A5 is the process of Embodiment A2 or A3, in which the compound of Formula (III) is reacted with a carboxylic acid halide or carboxylic acid anhydride in the absence of an acid catalyst selected from the group consisting of into p-toluenesulfonic acid, benzenesulfonic acid, sulfoacetic acid, a phosphorus acid and phosphorus trichloride.

[0068] Embodiment A6 is the process of any of Embodiments A1 to A5, in which the compound of Formula (II) is reacted with hydrogen halide (HX) in a reaction mixture that further comprises an organic solvent.

[0069] The A7 embodiment is the process of the A6 embodiment, in which the organic solvent is selected from C2-C6 carboxylic acids, C2-C6 nitriles, C1-Cθ alcohols, C2-C10 ethers, C3-C6 alkyl acetates, ketones C3-C10, C5-C8 aliphatic hydrocarbons, chlorinated C1-Cβ hydrocarbons, C3-C8 alkyl carbonates, sulfolane, dimethyl sulfoxide, toluene, chlorobenzene and combinations thereof.

[0070] Modality A8 is the process of modality Al, in which the organic solvent is selected from the group consisting of acetic acid, propionic acid, acetonitrile, propionitrile, methanol, ethanol, isopropanol, tert-butanol, diethyl ether, tetrahydrofuran, dioxane, methyl tert-butyl ether, dimethoxyethane, methyl acetate, ethyl acetate, tert-butyl acetate, acetone, methyl ethyl ketone, hexane, heptane, cyclohexane, dichloromethane, chloroform, dichloroethane, carbonate propylene, sulfolane, dimethyl sulfoxide, toluene, chlorobenzene and combinations thereof.

[0071] The A9 embodiment is the process of the A8 embodiment, in which the organic solvent is selected from the group consisting of acetic acid, methanol, ethanol, isopropanol, ethyl acetate and combinations thereof.

[0072] The AIO embodiment is the process of any of the embodiments A1 to A9, in which the compound of Formula (II) is reacted with a hydrogen halide at a temperature of about 0 °C to about 60 °C.

[0073] The All mode is the process of the AIO mode, where the temperature is from about 10 °C to about 30 °C.

[0074] The A12 embodiment is the process of any of the A1 to All embodiments, in which R2 is a straight or branched chain C1-C10 aliphatic hydrocarbon.

[0075] The A13 embodiment is the process of any of the Al to All embodiments, in which R2 is a branched aliphatic C3-C10 hydrocarbon group.

[0076] Embodiment A14 is the process of any one of Embodiments A1 to A13, in which the compound of Formula (III) is reacted with a carboxylic acid halide [RC(O)Y], in which R is a hydrocarbyl group C11-C29 straight chain, and Y is Cl or Br.

[0077] The A15 modality is the process of the A14 modality in which R is a C12-C25 straight-chain, aliphatic, saturated or unsaturated hydrocarbyl group.

[0078] The A16 embodiment is the process of the A14 embodiment, in which the carboxylic acid halide is oleic acid chloride.

[0079] Embodiment A17 is the process of any one of Embodiments A1 to A13, in which the compound of Formula (III) is reacted with a carboxylic acid anhydride [RC(0)C(0)R2], wherein R is a straight chain, aliphatic, saturated or unsaturated C11-C29 hydrocarbyl group and R2 is a straight or branched chain C1-C10 aliphatic hydrocarbon.

[0080] The A18 modality is the process of the A17 modality, in which R is a C12-C25 straight-chain saturated or unsaturated hydrocarbyl group.

[0081] Embodiment A19 is the process of any one of Embodiments A1 to A18, in which the compound of Formula (III) is reacted with a carboxylic acid anhydride [RC(0)OC(0)R2], or a halide of carboxylic acid [RC(O)Yj in a reaction mixture further comprising an organic solvent.

|0082] Embodiment A20 is the process of Embodiment A19, wherein the organic solvent is selected from the group consisting of C2-C6 nitriles, C2-C10 ethers, C3-C6 alkyl acetates, C3-C10 ketones, hydrocarbons C5-C8 aliphatics, chlorinated C1-C6 hydrocarbons, C3-C8 alkyl carbonates, sulfolane, dimethyl sulfoxide, toluene, chlorobenzene and combinations thereof.

[0083] Embodiment A21 is the process of embodiment A20, wherein the organic solvent is selected from the group consisting of acetonitrile, propionitrile, diethyl ether, tetrahydrofuran, dioxane, methyl tert-butyl ether, dimethoxyethane, acetate methyl acetate, tert-butyl acetate, acetone, methyl ethyl ketone, hexanp, heptane, cyclohexane, dichloromethane, chloroform, dichloroethane, propylene carbonate, sulfolane, dimethyl sulfoxide, toluene, dichlorobenzene and combinations thereof .

[0084] Embodiment A22 is the process of embodiment A21, wherein the organic solvent comprises acetonitrile, propionitrile, dichloromethane, chloroform, tetrahydrofuran and combinations thereof.

[0085] Embodiment A23 is the process of any one of Embodiments A1 to A22, wherein the compound of Formula (III) is reacted with a carboxylic acid anhydride or a carboxylic acid halide at a temperature of about 0 °C at about 120°C.

[0086] Mode A24 is the process of mode A23, where the temperature is from about 20 °C to about 120 °C.

[0087] Mode A25 is the process of mode A24, where the temperature is from about 40 °C to about 85 °C.

[0088] Embodiment A26 is the process of any one of Embodiments A2 to A25, in which a compound of Formula (IVa) is contacted with an aqueous solution of sodium chloride to provide the compound of Formula (IVb).

[0089] Embodiment A27 is the process of embodiment A26, in which the compound of Formula (IVa) is brought into contact with aqueous sodium chloride solution in a reaction mixture further comprising an organic solvent.

[0090] The A28 embodiment is the process of the A27 embodiment, in which the organic solvent is selected from the group consisting of C2-C6 nitriles, C2-C10 ethers, C3-C6 alkyl acetates, C3-C10 ketones, hydrocarbons C5-C8 aliphatics, chlorinated C1-Ce hydrocarbons, toluene, chlorobenzene and combinations thereof.

[0091] Embodiment A29 is the process of embodiment A28, in which the organic solvent is selected from the group consisting of acetonitrile, propionitrile, diethyl ether, tetrahydrofuran, dioxane, methyl tert-butyl ether, acetone, methyl ethyl ketone, hexane, heptane, cyclohexane, dichloromethane, chloroform, dichloroethane, toluene, chlorobenzene and combinations thereof.

[0092] Embodiment A30 is the process of embodiment A29, wherein the organic solvent comprises dichloromethane, chloroform, 1,2-dichloroethane, methyl acetate, ethyl acetate, toluene and combinations thereof.

[0093] Embodiment A31 is the process of any one of Embodiments A27 to A30, in which the compound of Formula (IVa) is brought into contact with an aqueous solution of sodium chloride at a temperature of about 0 °C to about 60 °C.

[0094] Mode A32 is the process of mode A31, where the temperature is from about 10 °C to about 30 °C.

[0095] Embodiment A33 is the process of any one of Embodiments A2 to A32, wherein the compound of Formula (IVb) is heated in a reaction mixture comprising the compound of Formula (IVb) and an organic solvent.

[0096] The A34 embodiment is the process of the A33 embodiment, in which the organic solvent is selected from the group consisting of C2-C6 nitriles, C1-Cε alcohols, C2-C10 ethers, C3-C6 alkyl acetates, ketones C3-C10, aliphatic Cs-Cs hydrocarbons, chlorinated Cs-C6 hydrocarbons, C3-C8 alkyl carbonates, sulfolane, dimethyl sulfoxide, toluene, chlorobenzene and combinations thereof.

[0097] The A35 mode is the process of the A34 mode, in which. the organic solvent is selected from the group consisting of acetonitrile, propionitrile, methanol, ethanol, isopropanol, tert-butanol, diethyl ether, tetrahydrofuran, dioxane, methyl tert-butyl ether, dimethoxyethane, methyl acetate, ethyl acetate , tert-butyl acetate, acetone, methyl ethyl ketone, hexane, heptane, cyclohexane, dichloromethane, chloroform, dichloroethane, propylene carbonate, sulfolane, dimethyl sulfoxide, toluene, chlorobenzene and combinations thereof.

[0098] Modality A36 is the process of modality A35, organic solvent comprises chloroform and methanol.

[0099] Embodiment A37 is the process of any one of Embodiments A33 to A36 wherein the reaction mixture comprising the compound of Formula (IVb) further comprises a base.

[00100] The A38 modality is the process of the A37 modality, in which the base is a weak base.

[00101] The A39 modality is the process of the A38 modality, in which the base is sodium bicarbonate, potassium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, a tertiary amine, or a mixture thereof.

[00102] Embodiment A40 is the process of any one of Embodiments A33 to A39, in which the reaction mixture comprising the compound of Formula (IVb) and an organic solvent further comprises a drying agent selected from the group consisting of on molecular sieves, calcium chloride, magnesium sulfate, sodium sulfate, activated carbon, or a combination thereof.

[00103] Embodiment A41 is the process of any one of Embodiments A33 to A40, in which the reaction mixture comprising the compound of Formula (IVb) and an organic solvent is heated to a temperature of about 20 °C to about 100 °C.

[00104] Embodiment A42 is the process of embodiment A41, in which the reaction mixture comprising the compound of Formula (IVb) and an organic solvent is heated to a temperature of about 40 °C to about 80 °C.

[00105} Embodiment A43 is the process of embodiment A42, in which the reaction mixture comprising the compound of Formula (IVb) and an organic solvent is heated to a temperature of about 50 °C to about 70 °C.

[00106] Embodiment A44 is the process of any one of Embodiments A1 to A43, in which heating the compound of Formula (IV) forms a product mixture comprising the compound of Formula (I) and the process further comprises filtering the mixture of product to form a solid fraction and a filtrate comprising the compound of Formula (I).

[00107] Embodiment A45 is the process of embodiment A44, in which the compound of Formula (I) is recovered from the filtrate of the product mixture, and purified by solvent washing, by recrystallization, or by a chromatographic method.

[00108] Embodiment A46 is the process of embodiment A44, in which the filtrate of the product mixture is washed with a solvent to form an aqueous slurry, and the product compound of Formula (I) is recovered from the aqueous slurry by filtration, the product having a purity of at least 95%.

[00109] Embodiment A47 is the process of embodiment A44, in which the product mixture filtrate is passed through a silica column and the product compound of Formula (I) is recovered, the product having a purity of at least 95%.

[00110] Embodiment A48 is the process of any one of Embodiments A1 to A47, in which the compound of Formula (I) is 1-[2-(9(Z)-octadecenoyloxy)ethyl]-2-(8) chloride (Z)-heptadecenyl)-3-(2-hydroxyethyl)imidazolinium (DOTIM):

[00111] The BI modality is a process for the preparation of a compound of Formula (I) wherein R is a straight-chain, aliphatic, saturated or unsaturated hydrocarbyl group of 11 to 29 carbon atoms, the process comprising: heating a compound of Formula (IV) in a reaction mixture comprising an organic solvent and a base to provide the compound of Formula (I) wherein R is as defined above by Formula (I) and X is Cl, Br or I.

[00112] Embodiment B2 is the process of embodiment B1 which further comprises washing a compound of Formula (IVa) in which X is not Cl with an aqueous solution of sodium chloride to provide a compound of Formula (IVb), and the reaction mixture comprises a compound of Formula (IVb).

[00113] The B3 modality is the process of the BI or B2 modality, in which the base is a weak base.

[00114] Modality B4 is the process of any of the embodiments Bl to B3, in which the base is sodium bicarbonate, potassium bicarbonate, potassium dihydrogenphosphate, dipotassium hydrogenphosphate, a tertiary amine, or a mixture thereof .

[00115] When introducing the elements of the present invention or the preferred embodiments thereof, the articles "a", "an", "the, the" and the term "said" are intended to mean that there are one or more of the elements. The terms "comprising", "including" and "having" are intended to mean that there may be additional elements other than the listed elements.

[00116] In view of the above, it will be seen that the various objects of the invention are obtained and other advantageous results are achieved.

[00117] As various changes could be made to the foregoing compositions and processes without departing from the scope of the invention, it is intended that all matter contained in the above description and provided herein shall be construed as illustrative and not in a limiting sense.

Claims (22)

1. Process for the preparation of a compound of Formula (I) wherein R is a straight-chain, aliphatic, saturated or unsaturated hydrocarbyl group of 11 to 29 carbon atoms, the process being characterized by comprising: reacting a compound of Formula (II) with a hydrogen halide (HX) to provide a compound of Formula (III), wherein X is Cl, Br or I; reacting the compound of Formula (III) with a carboxylic acid halide [RC(O)Y], wherein R is as defined above for Formula (I) and Y is selected from the group consisting of Cl, Br, F and I, or a carboxylic acid anhydride [RC(O)OC(O)R2], wherein R is as defined above for Formula (I) and R2 is a straight or branched chain, aliphatic, saturated hydrocarbyl group or unsaturated of 1 to 29 carbon atoms, to provide a compound of Formula (IV); It is heating the compound of formula (IV) to provide a compound of formula (I) wherein the compound of Formula (III) is reacted with a carboxylic acid halide [RC(O)Y], and X is not Cl, a compound of Formula (IVa) is provided, the process further comprising washing the compound of Formula (IVa) with an aqueous sodium chloride solution to provide a compound of formula (IVb) or when the compound of Formula (III) is reacted with the carboxylic acid anhydride [RC(O)OC(O)R2], or a carboxylic acid halide [RC(O)Y] and X = Cl, a compound of formula (IVb) is provided. 2. Process according to claim 1, characterized in that the compound of Formula (III) is reacted with the carboxylic acid halide or the carboxylic acid anhydride in the absence of an acid catalyst. 3. Process according to claim 1, characterized in that the compound of Formula (III) is reacted with the carboxylic acid halide or the carboxylic acid anhydride in the absence of an acid catalyst selected from the group consisting in p-toluenesulfonic acid, benzenesulfonic acid, sulfoacetic acid, a phosphorus acid and phosphorus trichloride. 4. Process according to claim 1, characterized in that the compound of Formula (II) is reacted with the hydrogen halide (HX) in a reaction mixture further comprising an organic solvent selected from the group consisting of acids C2-C6 carboxylics, C2-C6 nitriles, C1-C6 alcohols, C2-C10 ethers, C3C6 alkyl acetates, C3-C10 ketones, C5-C8 aliphatic hydrocarbons, chlorinated C1-C6 hydrocarbons, C3-C8 alkyl carbonates, sulfolane , dimethyl sulfoxide, toluene, chlorobenzene and combinations thereof. 5. Process according to claim 1, characterized in that the compound of Formula (II) is reacted with a hydrogen halide (HX) at a temperature of about 0°C to about 60°C. 6. Process according to claim 1, characterized by the fact that R2 is an aliphatic hydrocarbyl C1-C10 straight or branched chain. 7. Process according to claim 1, characterized in that the compound of Formula (III) is reacted with the carboxylic acid halide [RC(O)Y], where R is a C11-C29 hydrocarbyl group of straight chain, and Y is Cl or Br. 8. Process according to claim 1, characterized in that the compound of Formula (III) is reacted with the carboxylic acid anhydride [RC(O)C(O)R2], where R is a hydrocarbyl group C11-C29 straight-chain, aliphatic, saturated or unsaturated and R2 is a straight-chain or branched C1-C10 aliphatic hydrocarbyl group. 9. Process according to claim 1, characterized in that the compound of Formula (III) is reacted with the carboxylic acid anhydride [RC(O)OC(O)R2], or the carboxylic acid halide [ RC(O)Y] in a reaction mixture further comprising an organic solvent selected from the group consisting of C2-C6 nitriles, C2-C10 ethers, C3-C6 alkyl acetates, C3-C10 ketones, C5-C5- C8 aliphatics, C1-C6 chlorinated hydrocarbons, C3-C8 alkyl carbonates, sulfolane, dimethyl sulfoxide, toluene, chlorobenzene and combinations thereof. 10. Process according to claim 1, characterized in that the compound of Formula (III) is reacted with the carboxylic acid anhydride or the carboxylic acid halide at a temperature of about 0 °C to about 120°C. 11. Process according to claim 1, characterized in that a compound of Formula (IVa), in which X is not Cl, is placed in contact with an aqueous solution of sodium chloride to provide the compound of Formula ( IVb). 12. Process according to claim 11, characterized in that the compound of Formula (IV) is placed in contact with the aqueous solution of sodium chloride in a reaction mixture further comprising an organic solvent selected from the group consisting of C2-C6 nitriles, C2-C10 ethers, C3-C6 alkyl acetates, C3-C10 ketones, C5-C8 aliphatic hydrocarbons, chlorinated C1-C6 hydrocarbons, toluene, chlorobenzene, and combinations thereof. 13. Process according to claim 12, characterized in that the compound of Formula (IV) is placed in contact with an aqueous solution of sodium chloride at a temperature of about 0°C to about 60°C . 14. Process according to claim 2, characterized in that the compound of Formula (IVb) is heated in a reaction mixture comprising the compound of Formula (IVb) and an organic solvent selected from the group consisting of C2C6 nitriles, C1-C6 alcohols, C2-C10 ethers, C3-C6 alkyl acetates, C3-C10 ketones, C5-C8 aliphatic hydrocarbons, chlorinated C1-C6 hydrocarbons, C3-C8 alkyl carbonates, sulfolane, dimethyl sulfoxide, toluene, chlorobenzene and combinations thereof. 15. Process according to claim 14, characterized in that the reaction mixture comprising the compound of Formula (IVb) further comprises a weak base selected from the group consisting of sodium bicarbonate, potassium bicarbonate, di - potassium hydrogen phosphate, dipotassium hydrogen phosphate, a tertiary amine, or a mixture thereof. 16. Process according to claim 14, characterized in that the reaction mixture comprising the compound of general formula (IVb) and an organic solvent further comprises a drying agent selected from the group consisting of molecular sieves, calcium chloride, magnesium sulfate, sodium sulfate, activated carbon, or a combination thereof. 17. Process according to claim 14, characterized in that the reaction mixture comprising the compound of Formula (IVb) and the organic solvent is heated to a temperature of 20°C to 100°C. 18. Process according to claim 1, characterized in that heating the compound of Formula (IV) forms a product mixture comprising the compound of Formula (I) and the process further comprises filtering the product mixture to form a solid fraction and a filtrate comprising the compound of Formula (I). 19. Process according to claim 18, characterized in that the compound of Formula (I) is recovered from the product mixture filtrate, and purified by solvent washing, by recrystallization, or by a chromatographic method. 20. Process according to claim 1, characterized in that the compound of Formula (I) is 1-[2-(9(Z)-octadecenoyloxy)ethyl]-2-(8(Z)- heptadecenyl)-3-(2-hydroxyethyl)imidazolinium (DOTIM): 21. Process for the preparation of a compound of Formula (I) wherein R is a straight-chain, aliphatic, saturated or unsaturated hydrocarbyl group of 11 to 29 carbon atoms, the process characterized by comprising: heating a compound of Formula (IV) in a reaction mixture comprising an organic solvent and a base to provide the compound of Formula (I) wherein R is as defined above by Formula (I) and X is Cl, Br or I further comprising washing a compound of Formula (IVa) wherein X is not Cl with an aqueous sodium chloride solution to provide a compound of Formula (IVb), and the reaction mixture comprises a compound of Formula (IVb) 22. Process according to claim 21, characterized in that the base is a weak base selected from sodium bicarbonate, potassium bicarbonate, potassium dihydrogenphosphate, dipotassium hydrogenphosphate, a tertiary amine, or a mixture of the same.