Process for the synthesis of monoesters of ethylenediaminetetraacetic acid

Abstract

A process for the synthesis of a compound of Formula (I) is provided. (I) wherein R is selected from the group consisting of alkyl, alkenyl, alkynyl, and steroidyl. The process comprises reacting a compound of Formula (IIa), Formula (IIb) or a mixture thereof with a compound of Formula R-X, to obtain a compound of Formula (IIIa), a compound of Formula (IIIb) or a mixture thereof, wherein A+ is a cesium cation, a quaternary ammonium cation or a quaternary phosphonium cation, and X is a leaving group; and reacting the compound of Formula (IIIa), compound of Formula (IIIb) or mixture thereof with an acid to obtain a reaction product which comprises the compound of Formula (I). (IIa) (IIb) (IIIa) (IIIb)

Description

PROCESS FOR THE SYNTHESIS OF MONOESTERS OF ETHYLENEDIAMINETETRAACETIC ACIDCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Application No. 63 / 602,499, titled “PROCESS FOR THE SYNTHESIS OF MONOESTERS OF ETHYLENEDIAMINETETRAACETIC ACID” filed on November 24, 2023, the entire disclosure of which is hereby incorporated by reference in its entirety.TECHNICAL FIELD

[0002] The technical field generally relates to the synthesis of alkylated chelators, and more particularly to the synthesis of monoesters of ethylenediaminetetraacetic acid.BACKGROUND

[0003] Ethylenediaminetetraacetic acid (EDTA) is one of the most widely used chelators. EDTA is generally used to bind cations such as iron and calcium cations and is known for forming water-soluble complexes even at neutral pH. EDTA can be used in various fields such as textiles and paper, food, water treatment, scrubbing, ion-exchange chromatography, medicine, household products, cleaning products, cosmetics and agriculture.

[0004] Mono-alkylated EDTA (or monoesters of EDTA) in which one carboxylic acid groups of the EDTA is alkylated (or esterified) with a long carbon chain maintain their chelating agent properties while gaining surfactant properties. Mono-alkylated EDTA compounds can for example be used as additives in biocide, pesticide and / or herbicide formulations.

[0005] Mono-alkylated EDTA can be prepared as a mixture with free EDTA and dialkylated EDTA by a method described in Takeshita et al.: Takeshita, T.; Wakebe, I.; Maeda, S. Synthesis of EDTA-Monoalkyl Ester Chelates and Evaluation of the Surface Active Properties, J. Am. Oil Chem. Soc., 1980, 430-434, which is hereby incorporated by reference in its entirety. However, this synthetic method has several shortcomingssuch as low yield in mono-alkylated EDTA, solvent (including pyridine and DMF) which are not preferable, for example because of accessibility, safety and / or environmental friendliness, and difficulty in scaling up. For example, isolation of EDTA anhydrides requires washing of filtered anhydrides with fresh acetic anhydride and dry diethyl ether, which is highly volatile and flammable, thus not appropriate and safe for a large-scale production. Further, DMF seems to be the best solvent to perform this synthesis, but it decomposes to dimethylamine, which contaminates the final ester product with EDTA amides, and the final filtration process produces tons of wastewater contaminated with DMF. Further, there currently is no known no good separation method that can be applied to recycle DMF for this process. Even if it could be recycled, it must be very dry to reuse for the mentioned reactions. Thus, long-term stable and safe production by this method, in part due to the environmental and safety concerns, is in question. Therefore, several challenges remain for the synthesis of mono-alkylated EDTA compounds.SUMMARY

[0006] Described herein is a process for the synthesis of a compound of Formula (I):wherein R is selected from the group consisting of alkyl, alkenyl, alkynyl, and steroidyl. The process includes reacting a compound of Formula (Ila), a compound of Formula (lib) or a mixture thereof with a compound of Formula R-X, to obtain a compound of Formula (Illa), a compound of Formula (I I lb) or a mixture thereof,(Illa) (lllb) wherein A+is a cesium cation, a quaternary ammonium cation or a quaternary phosphonium cation, and X is a leaving group. The process also comprises reacting the compound of Formula (Illa), the compound of Formula (II lb) or a mixture thereof with an acid to obtain a reaction product which includes the compound of Formula (I).

[0007] The process described herein can advantageously allow obtaining the monoester of Formula (I) (or mono-alkylated EDTA) as the major product, with minimal amounts of unreacted EDTA and minimal amounts of diester product (or di-alkylated EDTA) compared to other known synthesis methods such as the dianhydride method described in Takeshita et al. The process will be described in further detail herein below.

[0008] In Example 1 , a process for the synthesis of a compound of Formula (I):wherein R is selected from the group consisting of alkyl, alkenyl, alkynyl, and steroidyl, the process comprising: reacting a compound of Formula (Ila), a compound of Formula (lib) or a mixture thereof, with a compound of Formula R-X:to obtain a compound of Formula (Illa), a compound of Formula (lllb) or a mixture thereof:(Hla) (lllb) wherein A+is a cesium cation, a quaternary ammonium cation or a quaternary phosphonium cation, and X is a leaving group; and reacting the compound of Formula (Illa), the compound of Formula (lllb) or mixture thereof, with an acid to obtain a reaction product which comprises the compound of Formula (I).

[0009] In Example 2, the process of Example 1 , further comprising reacting ethylenediaminetetraacetic acid (EDTA) with a hydroxide salt of Formula A+HO’ to obtain the compound of Formula (Ila), compound of Formula (lib) or mixture thereof.

[0010] In Example 3, the process of Example 2, wherein reacting EDTA with the hydroxide salt is performed in methanol.

[0011] In Example 4, the process of Example 1 , further comprising reacting reacting ethylenediaminetetraacetic acid (EDTA) with a carbonate salt of Formula A2CO3 and heating to eliminate carbon dioxide, to obtain the compound of Formula (Ila), compound of Formula (lib) or mixture thereof.

[0012] In Example 5, the process of any one of Examples 1 to 4, wherein reacting the compound of Formula (Ila), compound of Formula (lib) or mixture thereof, with the compound of Formula R-X is performed in a solvent selected from the group consisting of methanol, ethanol, isopropanol, t-butanol, n-butanol, THF, dimethyl carbonate, acetone, ethyl acetate, DMF, DMSO, dioxane, NMP and mixtures thereof, provided that the solvent solubilizes the compound of Formula (Ila), the compound of Formula (lib) or mixture thereof, and provided that the solvent solubilizes the compound of Formula R-X.

[0013] In Example 6, the process of any one of Examples 1 to 5, wherein X is selected from the group consisting of Cl, Br, I, methylsulfate, methanesulfonate (OMs), trifluoromethanesulfonate (OTf) and 4-methylbenzenesulfonate (OTs).

[0014] In Example 7, the process of any one of Examples 1 to 5, wherein X is Br or I.

[0015] In Example 8, the process of any one of Examples 1 to 7, wherein R is unsubstituted or substituted with one or more aryl, -OH, -O-(Ci-C4)alkyl, -CF3 and -CN.

[0016] In Example 9, the process of any one of Examples 1 to 7, wherein R is unsubstituted.

[0017] In Example 10, the process of any one of Examples 1 to 9, wherein R is selected from the group consisting of C4-C24alkyl, C4-C24alkenyl, C4-C24alkynyl and steroidyl.

[0018] In Example 11 , the process of any one of Examples 1 to 9, wherein R is selected from the group consisting of Cs-Ci salky I , Cs-Cisalkenyl and Cs-Cisalkynyl.

[0019] In Example 12, the process of any one of Examples 1 to 9, wherein R is selected from the group consisting of Ci2-Ciealkyl, Ci2-Ciealkenyl and Ci2-Ciealkynyl.

[0020] In Example 13, the process of any one of Examples 1 to 12, wherein A+is selected from the group consisting of a cesium cation, a tetraalkyl ammonium, a trialkylbenzylammonium, a benzalkonium, a tetraalkyl phosphonium, a trialkylbenzylphosphonium, tetraphenyl phosphonium, benzyl triphenyl phosphonium and mixtures thereof.

[0021] In Example 14, the process of any one of Examples 1 to 12, wherein A+is selected from the group consisting of a tetraalkyl ammonium, a trialkylbenzylammonium, a benzalkonium, a tetraalkyl phosphonium and mixtures thereof.

[0022] In Example 15, the process of any one of Examples 1 to 12, wherein A+is selected from the group consisting of cetyltrimethylammonium, tetrabutylammonium, tetraethylammonium, tetramethylammonium and choline.

[0023] In Example 16, the process of any one of Examples 1 to 12, wherein A+is tetrabutylammonium or choline.

[0024] In Example 17, the process of any one of Examples 1 to 16, wherein the acid is selected from the group consisting of a carboxylic acid, a sulfonic acid, HCI, HBr, HI, sulfuric acid, nitric acid and perchloric acid.

[0025] In Example 18, the process of any one of Examples 1 to 16, wherein the acid is HCI.

[0026] In Example 19, the process of any one of Examples 1 to 18, wherein the compound of Formula (Ila), compound of Formula (lib) or mixture thereof; and the compound of Formula R-X are provided at a molar ratio Formula (I la) / (l lb) : RX of about 2 : 1.

[0027] In Example 20, the process of any one of Examples 1 to 5, further comprising: dissolving the reaction product in an acetate buffer; lowering the pH of the acetate buffer to obtain a precipitate; and recovering the precipitate which is the reaction product comprising the compound of Formula (I) at a higher purity.

[0028] In Example 21 , the process of Example 20, wherein the pH of the acetate buffer is lowered to between 2.3 and 3.8.

[0029] In Example 22, the process of any one of Examples 1 to 6, further comprising: heating a suspension of the reaction product in isopropanol to at least partially dissolve the reaction product, thereby obtaining a mixture; cooling the mixture, thereby obtaining a precipitate; and recovering the precipitate which is the reaction product comprising the compound of Formula (I) at a higher purity.

[0030] In Example 23, the process of Example 22, wherein heating the suspension comprises heating to a boiling point of the isopropanol, between about 5 and about 20 minutes.

[0031] In Example 24, the process of Example 22 or 23, wherein cooling the mixture comprises cooling the mixture to room temperature.BRIEF DESCRIPTION OF THE DRAWINGS

[0032] FIG. 1 illustrates the synthesis of mono- C16 EDTA ester using tetrabutylammonium hydroxide of Example 1.

[0033] FIG. 2 illustrates the synthesis of mono- C16 EDTA ester using choline hydroxide of Example 2.

[0034] FIG. 3 illustrates the synthesis of mono-C14 EDTA ester using choline hydroxide of Example 5.

[0035] FIG. 4 illustrates the synthesis of mono- C4 EDTA ester using tetrabutylammonium hydroxide of Example 6.

[0036] FIG. 5 illustrates the synthesis of EDTA C6 monoester from hexyl methanesulfonate of Example 7.

[0037] FIG. 6 illustrates the synthesis of EDTA C6 monoester from hexyl p- tolunenesulfonate of Example 8.

[0038] FIG. 7 illustrates the synthesis of EDTA C16 monoester using tetraethylammonium bicarbonate of Example 9.

[0039] FIG. 8 illustrates the synthesis of EDTA C14 monoester using cesium carbonate of Example 10.

[0040] FIG. 9 illustrates the synthesis of Mono cholesteryl EDTA.

[0041] While embodiments of the disclosed subject matter are amenable to various modifications and alternative forms, specific embodiments have been shown by way of example in the drawings and are described in detail below. The intention, however, is not to limit the subject matter to the particular embodiments described. On the contrary, the subject matter is intended to cover all modifications, equivalents, and alternatives falling within the ambit of the disclosure as defined by the appended claims.DETAILED DESCRIPTIONDefinitions

[0042] When a range of values is mentioned herein, the lower and upper limits of the range are, unless otherwise indicated, always included in the definition. When a range of values is mentioned in the present application, then all intermediate ranges and subranges, as well as individual values within the ranges, are intended to be included.

[0043] The chemical structures described herein are drawn according to conventional standards. Also, when an atom, such as a carbon atom as drawn, seems to include an incomplete valency, then the valency is assumed to be satisfied by one or more hydrogen atoms even if they are not necessarily explicitly drawn.

[0044] It is understood that all enantiomers, diastereomers, and racemic mixtures, tautomers, polymorphs, and pseudopolymorphs of compounds within the scope of the chemical formulae described herein, are embraced by the present description. All mixtures of such enantiomers and diastereomers are also within the scope of the present description.

[0045] It is understood that when referring to a chemical structure of EDTA or an EDTA derivative (i.e., an alkylated EDTA also referred to an EDTA ester - such as a monoester or a diester), it is understood that unless otherwise specified, a single drawn structure is meant to encompass all the equivalent EDTA structures where an acidic hydrogen is on a carboxylic acid group or on an amino group. For example, the EDTA structure drawn in the following manner:is meant to also encompass both of the following structures:Similarly, an EDTA salt structure drawn in the following manner:is meant to also encompass the following structure:Similarly, an EDTA monoester salt structure drawn in the following manner:is meant to also encompass the following structure:Similarly, an EDTA monoester structure drawn in the following manner:is meant to also encompass the following structures:

[0046] The term “approximately” or its equivalent term “about”, as used herein, mean around or in the region of. When the terms “approximately” or “about” are used in relation to a numerical value, it is understood to encompass a variation of 10% above and below the numerical value. These terms can also take into account the rounding of a number or the probability of random errors in experimental measurements, for instance, due to equipment limitations.

[0047] Throughout the following description when the article “a” or “an” is used to introduce an element, the article “a” or “an” does not have the meaning of “only one” and rather means “one or more” unless otherwise indicated. It is to be understood that where the specification states that a step, component, feature, or characteristic “may”, “might”, “can” or “could” be included, that particular component, feature or characteristic is not required to be included in all alternatives.

[0048] When trade names are used herein, it is intended to independently include the tradename product and the active ingredient(s) of the tradename product.

[0049] As used herein, the phrase “a compound of Formula (I)” means a compound of Formula (I) or a salt thereof. With respect to isolatable intermediates, the phrase “a compound of Formula (number)” means a compound of that formula and salts thereof.

[0050] The term “Alkyl”, as used herein, means a hydrocarbon containing primary, secondary, tertiary, or cyclic carbon atoms. The term “Cm-Cn alkyl” refers to an alkyl group having from the indicated “m” number of carbon atoms to the indicated “n” number of carbon atoms. Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CHs), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl ( / -Pr, / -propyl, -CH(CH3)2), 1 -butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1- propyl ( / -Bu, / -butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CHs)3), 1 -pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3),3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1 -butyl (-CH2CH2CH(CH3)2), 2-methyl-1 -butyl (-CH2CH(CH3)CH2CH3), 1 -hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2- pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3- pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, n-heptyl (-(CH2)6CH3), n-octyl (-(CH2)7CH3), n-nonyl (-(CH2)8CH3), n-decyl (-(CH2)9CH3), n-undecyl (-(CH2)IOCH3), n-dodecyl (-(CH2)nCH3), n-tridecyl (-(CH2)i2CHs), n-tetradecyl (-(CH2)i3CHs), n-pentadecyl (-(CH2)i4CHs), n- hexadecyl (-(CH2)ISCH3), n-heptadecyl (-(CH2)i6CHs), n-octadecyl (-(CH2)i7CHs), and other alkyl groups.

[0051] The term “Alkenyl”, as used herein, means a hydrocarbon containing primary, secondary, tertiary, or cyclic carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon sp2double bond. The term “Cm-Cn alkenyl” refers to an alkenyl group having from the indicated “m” number of carbon atoms to the indicated “n” number of carbon atoms. Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), 5-hexenyl (-CH2CH2CH2CH2CH-CH2) and 9-octadecenyl (-CH2-(CH2)7-CH=CH-(CH2)7-CH3). It is understood that the term “alkenyl” also includes terpenyl radicals. Terpenyl radicals are derived from terpenes which are of general formula (CsH8)n where n is 2, 3, 4 or more. As used herein, the terms “terpene” and “terpenyl” extend to compounds which are known as “terpenoids”, involving the loss or shift of a fragment, generally a methyl group. As a non-limiting example, sesquiterpenes (where n is 3) can contain 14 rather than 15 carbon atoms - and are then considered to be terpenoids (or more specifically sesquiterpenoids). Terpene or terpenyl radicals can be cyclic or acyclic. Non-limitingexamples of sub-classes of terpenes are carotenes or carotenoids, also referred to as tetraterpenes or tetraterpenoids.

[0052] The term “Alkynyl”, as used herein, means a hydrocarbon containing primary, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond. The term “Cm-Cnalkynyl” refers to an alkynyl group having from the indicated “m” number of carbon atoms to the indicated “n” number of carbon atoms. Examples of suitable alkynyl groups include, but are not limited to, acetylenic (-C=CH), propargyl (-Ch C^CH), and hexadecynyl (-(CH2)i4-C=CH).

[0053] The term “Alkoxy”, as used herein, is interchangeable with the term “O(Alkyl)”, in which an “Alkyl” group as defined above is attached to the parent molecule via an oxygen atom. For example, and without being limiting, the alkyl portion of an O(Alkyl) group can have 1 to 24 carbon atoms (i.e., Ci-C24alkyl), 4 to 18 carbon atoms (i.e., C4- C-isalkyl), 8 to 16 carbon atoms (i.e., Cs-C-iealkyl) or 12 to 16 carbon atoms (i.e., C12- Ciealkyl). Examples of suitable Alkoxy or O(Alkyl) groups include, but are not limited to, methoxy (-OCH3 or -OMe), ethoxy (-OCH2CH3 or -OEt) and t-butoxy (-O-C(CHs)3 or - OtBu). Similarly, “O(alkenyl)”, “O(alkynyl)”, and the corresponding substituted groups will be understood by a person skilled in the art.

[0054] The term “Acyl”, as used herein, is meant to encompass several functional moieties such as “C=O(Alkyl)”, “C=O(Alkenyl)”, “C=O(Alkynyl)” and their corresponding substituted groups, in which an “Alkyl”, “Alkenyl” and “Alkynyl” groups are as defined above and attached to an 0, N, S of a parent molecule via a C=O group. For example, and without being limiting, the alkyl portion of a C=O(Alkyl) group can have 1 to 24 carbon atoms (i.e., Ci-C24alkyl), 1 to 8 carbon atoms (i.e., C-i-Csalkyl), 1 to 6 carbon atoms (i.e., Ci-Cealkyl) or 1 to 4 carbon atoms (i.e., Ci-C4alkyl). Examples of suitable Acyl groups include, but are not limited to, formyl (i.e., a carboxyaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl. A person skilled in the art will understand that a corresponding definition applies for “C=O(Alkenyl)” and “C=O(Alkynyl)” moieties. In the present description, “C=O(Alkyl)”, “C=O(Alkenyl)”, “C=O(Alkynyl)” can also be written as “CO(Alkyl)”, “CO(Alkenyl) and “CO(Alkynyl)”, respectively. It is understoodthat the term “(Ci-C24)acyl, as used herein, refers to “C=O((Ci-C24)Alkyl), C=O(((Ci- C24)Alkenyl), or C=O(((Ci-C24)Alkynyl)”.

[0055] The term “Alkylene”, as used herein, means a saturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For example, and without being limiting, an alkylene group can have 1 to 24 carbon atoms, 1 to 18 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, 8 to 24 carbon atoms or 8 to 18 carbon atoms. Typical alkylene radicals include, but are not limited to, methylene (-CH2-), 1 ,1 -ethyl (-CH(CHs)-), 1 ,2- ethyl (-CH2CH2-), 1 ,1 -propyl (-CH(CH2CH3)-), 1 ,2-propyl (-CH2CH(CH3)-), 1 ,3-propyl (-CH2CH2CH2-) and 1 ,4-butyl (-CH2CH2CH2CH2-).

[0056] The term “Alkenylene”, as used herein, means an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. For example, and without being limiting, and alkenylene group can have 2 to 24 carbon atoms, 2 to 18 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, 8 to 24 carbon atoms, or 8 to 18 carbon atoms. Typical alkenylene radicals include, but are not limited to, 1 ,2-ethylene (-CH=CH-).

[0057] The term “Alkynylene”, as used herein, means an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. For example, and without being limiting, an alkynylene group can have 2 to 24 carbon atoms, 2 to 18 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms or 2 to 4 carbon atoms, 8 to 24 carbon atoms or 8 to 18 carbon atoms. Typical alkynylene radicals include, but are not limited to, acetylene (-C=C-), propargyl (-CH2C=C-), and 4-pentynyl (-CH2CH2CH2C=C-).

[0058] The term “Aryl”, as used herein, means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, and without being limiting, an aryl group can have 6 to 20carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, and biphenyl. It is understood that the term “aryl” encompasses polyaromatic radicals, such as naphtalenyl, biphenyl, fluorenyl, anthracenyl, phenanthrenyl, and phenalenyl. The polyaromatic radicals can be substituted or unsubstituted.

[0059] The term “Arylalkyl”, as used herein, means an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. For example, and without being limiting, the arylalkyl group can include 7 to 20 carbon atoms, e.g., the alkyl moiety is 1 to 6 carbon atoms, and the aryl moiety is 6 to 14 carbon atoms.

[0060] The term “Arylalkenyl”, as used herein, means an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, but also a sp2carbon atom, is replaced with an aryl radical. The aryl portion of the arylalkenyl can include, for example, any of the aryl groups described herein, and the alkenyl portion of the arylalkenyl can include, for example, any of the alkenyl groups described herein. The arylalkenyl group can include 8 to 20 carbon atoms, e.g., the alkenyl moiety is 2 to 6 carbon atoms, and the aryl moiety is 6 to 14 carbon atoms.

[0061] The term “Arylalkynyl”, as used herein, means an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, but also a sp carbon atom, is replaced with an aryl radical. The aryl portion of the arylalkynyl can include, for example, any of the aryl groups disclosed herein, and the alkynyl portion of the arylalkynyl can include, for example, any of the alkynyl groups disclosed herein. For example, and without being limiting, the arylalkynyl group can include 8 to 20 carbon atoms, e.g., the alkynyl moiety is 2 to 6 carbon atoms, and the aryl moiety is 6 to 14 carbon atoms.

[0062] The term “steroidyl group”, as used herein, refers to a steroid fused ring system which can be covalently bound to the EDTA derivative. Non-limiting examples of steroids include cholesterol, cholic acid, lanosterol and chenodeoxycholic acid.

[0063] The term “substituted”, as used herein in reference to alkyl, alkylene, alkoxy, alkenyl, alkynyl, alkenylene, aryl, alkynylene, etc., for example “substituted alkyl”, “substituted alkylene”, “substituted alkoxy” - “or substituted O(Alkyl)”, “substituted alkenyl”, “substituted alkynyl”, “substituted alkenylene”, “substituted aryl” and “substituted alkynylene”, unless otherwise indicated, means alkyl, alkylene, alkoxy, alkenyl, alkynyl, alkenylene, aryl and alkynylene, respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent.

[0064] Typical non-hydrogen substituents include, but are not limited to, -X, -RB, -O’, =0, -ORB, -SRB, -S’, -NRB2, Si(Rc)3, -N+RB3, -NRb-(Alk)-NRB2, -NRB-(Alk)-N+RB3, -NRB-(Alk)- ORB, -NRB-(Alk)-OP(=O)(ORB)(O’), -NRB-(Alk)-OP(=O)(ORB)2,-NRB-(Alk)-Si(Rc)3, -NRB-(Alk)-SRB, -O-(Alk)-NRB2, -O-(Alk)-N+RB3, -O-(Alk)-ORB, -O-(Alk)-OP(=O)(ORB)(O’),_-O-(Alk)-OP(=O)(ORB)2, -O-(Alk)-Si(Rc)3, -O-(Alk)-SRB, =NRB, -CX3, -CN, -OCN, -SON, -N=C=O, -NCS, -NO, -NO2, =N2, -N3, -NHC(=O)RB, -OC(=O)RB, -NHC(=O)NRB2, -S(=O)2-, -S(=O)2OH, -S(=O)2RB,-OS(=O)2ORB, -S(=O)2NRB2, -S(=O)RB, -OP(=O)(ORB)(O’),-OP(=O)(ORB)2, -P(=O)(ORB)2, -P(=O)(O2, -P(=O)(OH)2, -P(O)(ORB)(O’), -C(=O)RB, -C(=O)X, -C(S)RB, -C(O)ORB, -C(O)O-, -C(S)ORB, -C(O)SRB, -C(S)SRB, -C(O)NRB2, -C(S)NRB2or -C(=NRB)NRB2where each X is independently a halogen: F, Cl, Br, or I; each RBis independently H, alkyl, aryl, arylalkyl, a heterocycle, an alkyloxy group such as poly(ethyleneoxy), PEG or poly(methyleneoxy), or a protecting group; each Rcis independently alkyl, O(alkyl) or O(tri-substituted silyl); and each Aik is independently alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, or substituted alkynylene. Unless otherwise indicated, when the term “substituted” is used in conjunction with groups such as arylalkyl, which have two or more moieties capable of substitutions, the substituents can be attached to the aryl moiety, the alkyl moiety, or both.

[0065] Selected substituents of the compounds of the present description can be present to a recursive degree. In this context, “recursive substituent” means that a substituent can recite another instance of itself. Because of the recursive nature of such substituents, theoretically, a large number of compounds can be present in any given implementation. For example, Rxincludes a Rysubstituent. Rycan be R. R can be W3. W3can be W4and W4can be R or include substituents including Ry. A person skilled in the art of organic chemistry understands that the total number of such substituents is to be reasonably limited by the desired properties of the compound intended. Such properties include, by way of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, possibility of application in biocide compositions, surface tension, foamability, and practical properties such as ease of synthesis. Typically, each recursive substituent can independently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 11 , 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 , or 0, times in a given implementation. For example, each recursive substituent can independently occur 3 or fewer times in a given implementation. Recursive substituents are an intended aspect of the compounds of the present description. A person skilled in the art of organic chemistry understands the versatility of such substituents.

[0066] The term “optionally substituted”, as used herein in reference to a particular moiety of the compounds of the present description, means a moiety wherein all substituents are hydrogen or wherein one or more of the hydrogens of the moiety can be replaced by substituents such as those listed under the definition of the term “substituted” or as otherwise indicated.Process

[0067] Described herein is a process for the synthesis of a compound of Formula (I):wherein R is selected from the group consisting of alkyl, alkenyl, alkynyl, and steroidyl.The process includes reacting a compound of Formula (Ila), a compound of Formula (lib) or a mixture thereof with a compound of Formula R-X, to obtain a compound of Formula (Illa), a compound of Formula (I I lb) or a mixture thereof,(Illa) (lllb) wherein A+is a cesium cation, a quaternary ammonium cation or a quaternary phosphonium cation, and X is a leaving group. The process also comprises reacting thecompound of Formula (Illa), the compound of Formula (II lb) or a mixture thereof with an acid to obtain a reaction product which includes the compound of Formula (I).

[0068] In some implementations, the process can further include reacting EDTA with a hydroxide salt of Formula A+HO’ (or AOH) to obtain the compound of Formula (Ila), the compound of Formula (lib) or a mixture thereof, as follows:EDTA (Hb)

[0069] In some implementations, the cation A+is selected from the group consisting of a cesium cation, a tetraalkyl ammonium, a trialkylbenzylammonium, a benzalkonium, a tetraalkyl phosphonium, a trialkylbenzylphosphonium, tetraphenyl phosphonium, benzyl triphenyl phosphonium and mixtures thereof. In some implementations, A+is selected from the group consisting of a tetraalkyl ammonium, a trialkylbenzylammonium, a benzalkonium, a tetraalkyl phosphonium and mixtures thereof. For example, in some implementations, A+is selected from the group consisting of tetrabutylammonium, tetramethylammonium, tetraethyl ammonium (bicarbonate), choline, tetrabutylphosphonium hydroxide, and caesium carbonate. For example, in someimplementations, A+is selected from the group consisting of cetyltrimethylammonium, tetrabutylammonium, tetraethylammonium, tetramethylammonium and choline. In some implementations, A+is tetrabutylammonium or choline.

[0070] It is understood that the EDTA used as starting material can be any type of EDTA such as, without being limiting, H4EDTA, N32EDTA, Na2CaEDTA. If an EDTA salt is used, the EDTA salt can be acidified prior to being transformed into the compound of Formula (Ila), compound of Formula (lib) of a mixture thereof.

[0071] The reaction to obtain the compound of Formula (Ila), the compound of Formula (lib) or a mixture thereof from EDTA and AOH is performed in a solvent. Non-limiting examples of solvents which can be used include methanol, ethanol, isopropanol, n- butanol, t-butanol, THF and acetone.

[0072] 3 equivalents of AOH are typically used to obtain the compound of Formula (Ila). It is however understood that in some scenarios, AOH can be added in excess of 3 equivalents, and in such case a mixture of the compound of Formula (Ila) and compound of Formula (lib) can be obtained, or mostly the compound of Formula (lib) when 4 equivalents or more of AOH are used. AOH can be added to a solution of EDTA in the solvent, or a solution of AOH can be added to dry EDTA or to EDTA in the solvent.

[0073] The reaction of EDTA with a hydroxide salt of Formula A+HO’ (or AOH) to obtain the compound of Formula (Ila), compound of Formula (lib) or mixture thereof can be performed at room temperature, or between about 15 °C and about 35 °C, or between about 20 °C and about 30 °C. The reaction of EDTA with a hydroxide salt of Formula A+HO’ (or AOH) to obtain the compound of Formula (Ila), the compound of Formula (lib) or mixture thereof can be performed by at least one of magnetic agitation, mechanical agitation, sonication or any other known mixing technique.

[0074] Alternatively in some implementations, instead of reacting the EDTA with a hydroxide salt, the process can further include reacting EDTA with a carbonate salt ofFormula (A+)2-CO32’ (or A2CO3) to obtain the compound of Formula (Ila), the compound of Formula (lib) or a mixture thereof, as follows:

[0075] Alternatively in some implementations, instead of reacting the EDTA with a hydroxide salt or a carbonate salt, the process can further include reacting EDTA with a bicarbonate salt of Formula (A+) HCO3_(or AHCO3) to obtain the compound of Formula (Ila), the compound of Formula (lib).

[0076] In some implementations, the cation A+is selected from the group consisting of a cesium cation, a tetraalkyl ammonium, a trialkylbenzylammonium, a benzalkonium. In some implementations, A+is selected from the group consisting of a cesium cation, cetyltrimethylammonium, tetrabutylammonium, tetraethylammonium, tetramethylammonium and choline. In some implementations, A+is a cesium cation.

[0077] It is understood that the EDTA used as starting material can be any type of EDTA such as, without being limiting, H4EDTA, N32EDTA, Na2CaEDTA. If an EDTA salt isused, the EDTA salt can be acidified prior to being transformed into the compound of Formula (Ila), compound of Formula (lib) of a mixture thereof.

[0078] The reaction to obtain the compound of Formula (Ila), the compound of Formula (lib) or a mixture thereof from EDTA and A2CO3 is performed in a solvent. Non-limiting examples of solvents which can be used include methanol, ethanol, isopropanol and acetone.

[0079] 1.5 equivalents of A2CO3 are typically used to obtain the compound of Formula (Ila). It is however understood that in some scenarios, A2CO3 can be added in excess of 1.5 equivalents, and in such case a mixture of the compound of Formula (Ila) and compound of Formula (lib) can be obtained, or mostly the compound of Formula (lib) when 2 equivalents or more of A2CO3 are used. A2CO3 can be added to a solution of EDTA in the solvent, or a solution of A2CO3 can be added to dry EDTA or to EDTA in the solvent.

[0080] The reaction of EDTA with a carbonate salt of Formula A2CO3 to obtain the compound of Formula (Ila), compound of Formula (lib) or mixture thereof can be performed at room temperature, or between about 15 °C and about 35 °C, or between about 20 °C and about 30 °C. Heating the mixture can allow to convert the carbonate to carbon dioxide and water, to obtain the compound of Formula (Ila), compound of Formula (lib) or mixture thereof.

[0081] Reacting the compound of Formula (Ila), the compound of Formula (lib) or a mixture thereof with the compound of Formula R-X, as shown below to obtain the compound of Formula (Illa), compound of Formula (I I lb) or mixture thereof, can typically be performed in various solvents.(Ila) (Illa)(Hb) (lllb)

[0082] For example, and without being limiting, the solvent can be selected from the group consisting of methanol, ethanol, isopropanol, t-butanol, n-butanol, THF, dimethyl carbonate, acetone, ethyl acetate, DMF, DMSO, dioxane, NMP and mixtures thereof. It is understood that it is generally desirable that the solvent solubilizes at least in part the compound of Formula (Ila) and / or compound of Formula (lib), and the compound of Formula R-X. In some scenarios, the solvent completely solubilizes both the compound of Formula (Ila) and / or compound of Formula (lib), and the compound of Formula R-X. In some implementations, the solvent is isopropanol. In some implementations, the compound of Formula (Ila) and / or compound of Formula (lib), and the compound of Formula R-X are provided at a molar ratio Formula (lla) / (llb) : RX of between about 1 :1 and about 3: 1 , or of about 1 :1 , or of about 2:1.

[0083] It is understood that the leaving group X can be any suitable leaving group which, depending on the reaction conditions, will allow the reaction to proceed. Non-limiting examples of X include Cl, Br, I, methanesulfonate (OMs), trifluoromethanesulfonate (OTf), p-touenesulfonate, and 4-methylbenzenesulfonate (OTs). In some implementations, X is Br or I.

[0084] In some implementations, R is an unsubstituted or substituted alkyl, alkenyl, alkynyl, or steroidyl. Without being limiting, when R is substituted, R can for example be substituted with one or more aryl, -OH, -O-(Ci-C4)alkyl, -CFs and -CN. In some implementations, R is unsubstituted.

[0085] In some implementations, R is selected from the group consisting of C4-C24alkyl, C4-C24alkenyl, C4-C24alkynyl and steroidyl. In some implementations, R is selected from the group consisting of C4-C24alkyl, C4-C24alkenyl and C4-C24alkynyl. In some implementations, R is selected from the group consisting of Ce-C22alkyl, Ce-C22alkenyl and Ce-C22alkynyl. In some implementations, R is selected from the group consisting ofCs-C2oalkyl, Cs-C2oalkenyl and Cs-C2oalkynyl. In some implementations, R is selected from the group consisting of Cs-C-isalkyl, Cs-Cisalkenyl and Cs-Cisalkynyl. In some implementations, R is selected from the group consisting of Cio-Ciealkyl, Cio-Ciealkenyl and Cio-Ciealkynyl. In some implementations, R is selected from the group consisting of Ci2-Ciealkyl, Ci2-Ciealkenyl and Ci2-Ciealkynyl. In some implementations, R is C4-C24alkyl, Ce-C22alkyl, Cs-C2oalkyl, Cs-C-isalkyl or Cio-Ciealkyl.

[0086] In some implementations, the steroidyl group can be derived from cholesterol, cholic acid, lanosterol or chenodeoxycholic acid. In some implementations, the steroidyl group is:

[0087] As a non-limiting example, an EDTA derivative bearing a steroidyl group can be:

[0088] Reacting the compound of Formula (Illa), the compound of Formula (lllb) or a mixture thereof with an acid to obtain a reaction product which includes the compound of Formula (I) is shown below:(Hlb) (I)

[0089] The acid can be any suitable acid which has a pKa that allows the reaction to occur. Non-limiting examples of acids include organic acids or inorganic acids. Non- limiting examples of organic acids include carboxylic acids such as acetic acid, propionic acid, formic acid, maleic acid and succinic acid; and sulfonic acids such as methanesulfonic acid and toluenesulfonic acid. Non-limiting examples of inorganic acids include HCI, HBr, HI, sulfuric acid, nitric acid and perchloric acid. In some implementations, the acid is HCI.

[0090] It is understood that the expression “a reaction product which includes the compound of Formula (I)” means that the reaction product can, in some scenarios, include impurities such as unreacted EDTA and / or diester EDTA derivatives. Additional purification steps can be performed to lower the amount of the impurities in the reaction product.

[0091] In some implementations, the process can further include: dissolving the reaction product in an acidic buffer, such as an acetate buffer (e.g. a sodium acetate buffer); lowering the pH of the acetate buffer to obtain a precipitate; and recovering the precipitate which is the reaction product comprising the compound of Formula (I) in a higher purity. Generally, performing the “pH buffer” purification step allows to keep the unreacted EDTA in solution (and therefore eliminating most or all of the unreacted EDTA), and recovering the esterified EDTA compounds (monoester EDTA and diester EDTA) as the precipitate. In some implementations, the pH of the acetate buffer is lowered to between 2.3 and 3.8, for example by adding an acid such as HCI or any other suitable acid to lower the pH to the desired level. In some implementations, recovering the precipitate includes filtering the precipitate.

[0092] In some implementations, the process can further include a pseudorecrystallization step: heating a suspension of the reaction product in a solvent, such as isopropanol, to at least partially dissolve the reaction product and obtain a mixture; cooling the mixture to obtain a precipitate; and recovering the precipitate which is the reaction product comprising the compound of Formula (I) at a higher purity. Generally, performing the pseudo-recrystallization step allows to keep the diester EDTA derivative in solution while precipitating the monoester EDTA derivative. That is, the final has an improved monoester EDTA purity with a reduced amount of byproducts, free EDTA and / or EDTA diesters. In some implementations, the suspension comprises heating to a boiling point of the isopropanol solvent, for example between about 5 and about 20 minutes, prior to recovering the precipitate. In some implementations, cooling the mixture comprises cooling the mixture to room temperature, or between about 15°C and about 35°C, or between about 20°C and about 30°C. In some implementations, recovering the precipitate includes filtering the precipitate. This purification method can avoid use of extra organic solvents such as 1 ,4-dioxiane.

[0093] The current process uses direct conversion of EDTA to EDTA monoester using common chemicals such as KOH, choline chloride, methanol, isopropanol, alkyl bromides. In the current process, ionic organic soluble EDT complexes with bulky counter cations (A+) and can be dissolved in benign solvents such as ethanol,isopropanol and butanol. The current process avoids the conventional EDTA dianhydride pathway. Thus, the current process can avoid use of reactive, toxic (nongreen), and / or unsafe chemicals (such as DMF) and the anhydrous synthetic conditions of prior processing methods. Additionally, in some implementations, the solvents and / or EDTA of the current process can be recyclable.

[0094] The current process can result in a higher purity product than obtained through other processes. For example, the current process can eliminate possible amide formation which can occur from DMF decomposition.EXAMPLES

[0095] The following non-limiting examples are illustrative and should not be construed as further limiting the scope of the claims. These examples will be better understood in combination with the accompanying Figures.Materials• Choline chloride, >98%, Sigma-Aldrich™• Tetrabutylammonium hydroxide (37% or 1.2M in methanol), TCI• Tetraethylammonium bicarbonate (TEA bicarbonate) >95.0% (T), Sigma-Aldrich• Potassium hydroxide (KOH) (pellets), Assay min 85.0%, ACS grade, EMD™ (PX1480-1)• Methanol (MeOH), Assay >99.9%, Reagent ACS, ACP Chemicals• Ethylenediaminetetraacetic acid (H4EDTA or EDTA), 99%, powder, Alfa Aesar™• Whatman™ Qualitative filter paper No.1• 2-Propanol (isopropanol), suitable for HPLC, 99.9%, Sigma-Aldrich or Reagent grade, Caledon Laboratory Chemicals• 1 -Bromohexadecane, 97%, Sigma-Aldrich• Hexyl p-toluenesulfonate, >98.0%(GC), TCI• 1-lodobutane, 99%, contains copper as stabilizer, Sigma-Aldrich• Cholestery bromide, GLPBIO• Glacial acetic acid (AcOH), reagent acids, Caledon Laboratory Chemicals• Sodium acetate trihydrate, ACS grade, BioShop™ Canada Inc.• Sodium hydroxide (NaOH), Reagent grade, Caledon Laboratory Chemicals• Cesium carbonate, 99%, Oakwood chemical• Hydrochloric acid (concentrated HCI), Reagent, Assay 36.5-38.0% HCI, ACS grade, BioShop™ Canada Inc.• Sulfuric acid, Assay 95.8w / w%, certified ACS plus, Fisher Chemical• Sodium chloride, reagentplus, >99%, Sigma-Aldrich• Potassium iodide (KI), reagentplus, 99%, Sigma-Aldrich• Ethyl acetate, ACS reagent, >99.5%, Sigma-Aldrich• Dimethyl carbonate, reagentplus, 99%, Sigma-Aldrich• Tetrahydrofuran, >99.9%, anhydrous, inhibitor-free, Sigma-Aldrich• TLC Silica gel 60 F254 plates, Merck KGaA• Water by reverse osmosis (RO)• N2 99.5% by rotary screw air compressor (Atlas Copco; GA15) with a nitrogen generator (CGT model PMNG500ES membrane type)Instrumentation• Branson Bransonic™ MH Mechanical Bath 1800.• FiveEasyPlus™pH meter FEP20, Metler-Toledo AG Analytical. The pH meter was calibrated with fresh buffer reference standards pH 10.00±0.01 at 25°C, 4.00±0.01 at 25°C (VWR BDH Chemicals BDH 5072 and 5018) and pH 7.00±0.01 at 25°C (Supelco BX1632-1).• Heidolph Rotary Evaporator + Manual Vacuum Controller P / N: 591-26000-00-1 + Rotachill P / N: LM61 MX1 HD10C + Roravac P / N: 200136835 0218.• Fisherbrand™ Isotemp™ Hot Plate, 50°C to 350°C, Aluminum, Ceramic.• Bruker™ maXis4G micro Q-ToF mass spectrometer, with infusion autosampler. Injection speed 0.1 mL / min. Acquisition Parameter: Source Type ESI, Ion Polarity Negative, Set Nebulizer 0.3 Bar, Focus Not active, Set Capillary 3000 V, Set Dry Heater 180°C, Scan Begin 250 m / z, Set End Plate Offset -500 V, Set Dry Gas 4.0 l / min, Scan End 2700 m / z, Set Charging Voltage 2000 V, Set Divert Valve Waste, Set Corona 0 nA,Set APCI Heater 0 °C. All data were obtained at room temperature, sample was dissolved in MeOH at final concentration of about 10-20 pM• Bruker™ NEO 600 MHz NMR spectrometer equipped with a 5 mm Prodigy BBO(H, F) cold probe and SampleCasePlus autosampler, operating at 600.13 MHz for 1 H. All data were obtained at 298K and referenced either to residual protons in the deuterated solvent, or to TMS at 0.00 ppm.Example 1

[0096] Synthesis of mono- C16 EDTA ester using tetrabutylammonium hydroxide

[0097] The synthesis is illustrated in FIG. 1. EDTA 1 was mixed with 3 equivalents of tetrabutylammonium hydroxide (TBAOH) in methanol. EDTA 1 (1.000g, 3.422mmol) was weighed in a 100rriL 24 / 40 joint one-neck round bottom flask, added 37% [1.2M] TBAOH in methanol (8.55mL, 3 equivalents) and methanol (4-5mL), and the mixture was sonicated for 15-20 minutes at room temperature to obtain a clear solution. Methanol was stripped off by a rotary evaporator (50mbar at 20°C to begin and the temperature was gradually increased to 40 and 60°C) to obtain a cloudy viscous liquid 2TBA.

[0098] Isopropanol (1 OmL) was added, and the mixture was sonicated for 10 minutes to obtain a clear solution. 1 -Bromohexadecanol (one equivalent) was added. The flask was glass-stoppered, and the solution was stirred at 21 °C overnight (18-20 hours). The mixture became cloudy. The reaction was monitored by TLC (silica plate, solvent system: MeOH / EtOAc / AcOH=2 / 2 / 1 , spots were stained with 1 M H2SO4 and heat). The direct spot of the reaction mixture gave streaky spots, but with the time the polar spot increased obviously. Isopropanol was removed by a rotary evaporator (80mbar at 60°C) to obtain compound 3TBA-CI6. The residue was suspended in water (30mL). 37% HCI (2mL) was added, and the flask was swirled to obtain compound 4-Cie as a white precipitate which was filtered, washed with water, and air-dried in the fume hood. Dried mass of compound 4-Cie was about 1 ,68g.

[0099] The TLC analysis of this solid showed clear formation of the monoester as the major product. The NMR of this solid in DMSO-de supported the result of TLC. The peak positions were deduced from the literature values and compared with the anhydride synthetic method. The diesters were removed by washing the compound with organic solvents such as acetone, ethyl acetate, MeOH-chloroform mixture. Unreacted EDTA was removed by pH control in an acetate buffer, filtration, and washing with water.

[0100] The reaction was also successfully performed in aprotic solvents such as acetone and THF. The use of TBAOH allowed to produce the mono ester in a significant amount compared to the di-alkylated EDTA and unreacted EDTA.Example 2

[0101] Synthesis of mono- C16 EDTA ester using choline hydroxide.

[0102] The synthesis is illustrated in FIG. 2. EDTA 1 (1.000g, 3.422mmol) was weighed in a 10OmL 24 / 40 joint one-neck round bottom flask, added 0.893M choline hydroxide in methanol (11.5mL, 3 equivalents) and methanol (2-3mL), and the mixture was sonicated for 15 minutes at room temperature to obtain a clear solution. The methanol was stripped off by a rotary evaporator (50mbar at 20°C to begin and the temperature was gradually increased to 40 and 60°C) to obtain a clear viscous liquid 2choi.

[0103] Isopropanol (12mL) was added, and the mixture was sonicated for 10 minute to obtain a clear solution. 1 -Bromohexadecanol (835uL, 0.8 equivalents) was added. The flask was glass-stoppered, and the solution was stirred at 25°C for 4 days. The mixture became cloudy after 4-5 days of reaction. The reaction was monitored by TLC (silica plate, solvent system: MeOH / EtOAc / AcOH=2 / 2 / 1 , spots were stained with 1 M H2SO4 and heat). The direct spot of the reaction mixture gave streaky spots, but with the time the polar spot increased obviously. Isopropanol was removed by a rotary evaporator (80mbar at 60°C) to obtain compound 3choi-Ci6. The residue was suspended in water (30mL). The pH of the suspension was 8.55. 37% HCI (2mL) was added to adjust the pH to 2.98. The formed white precipitate was filtered, washed with water, and air-dried in the fume hood to obtain compound 4-Cie. Dried mass was about 1.3g. TLC analysisas well as NMR analysis of the product showed the monoester as the major product. Unreacted EDTA was removed by pH control in an acetate buffer, filtration, and washing with water.Example 3

[0104] Synthesis of mono-C16 EDTA ester using choline hydroxide, with EDTA:alkylbromide ratio of 2:1 to form less di-ester product.

[0105] H4EDTA (9.8636g, 0.033752mol) and 1.35M choline hydroxide in methanol (75.0mL, 0.101 mol) (prepared from choline chloride and KOH) was placed in a 250mL 24 / 40 one-neck round bottom flask. The mixture was stirred at room 70 °C under nitrogen for 5 minutes to obtain a clear solution. The temperature was increased to 100 °C and the methanol was distilled out under a stream of nitrogen. The temperature was further increased to 115 °C and the solution became thick and bubbly. When bubbling stopped and a viscous liquid was obtained, the temperature was set to 50 °C.

[0106] The liquid was dissolved in 2-propanol (98mL) and 1 -bromohexadecane (5.158mL, 0.01688mol) was added. The clear mixture was stirred at 50°C under nitrogen for 65.5 hours. 2-Propanol was removed under a reduced pressure (130- 50mbar at 60°C). The recovery percent for 2-propanol was 89% by mole.

[0107] The white solid residue was dissolved in RO water and diluted to 300mL. The pH was 6.90. To the stirring solution, 37% HCI (ca. 4.5mL) was added to adjust the pH to 2.87 and to obtain a white suspension. The precipitate was filtered off and washed with RO water (80mL). Sodium hydroxide (7.52g) and acetic acid (12.5mL) were dissolved in RO water (200mL) to form an acetate buffer solution. The filtered white solid was dispersed in this acetate buffer solution and heated at 60°C to dissolve. The solution was filtered to remove insoluble materials.

[0108] The filtrate was transferred to a 600mL beaker with the rinsing. The total volume was 350mL and the pH was 5.11. To the stirring solution, was 37% HCI (16 mL) added to set the pH 3.34. The suspension was digested at 60°C for 30 minutes. The precipitate was filtered while it was warm (-50° C) and the filtered white solid waswashed with RO water (150 mL). The filtered white solid was air-dried in the fume hood. The air-dried solid was boiled in methanol (200 mL) until chunks were broken into small particles. The suspension was cooled to room temperature. The product was filtered, and the beaker was rinsed with minimum amount of methanol. The product was dried under suction and air-dried overnight. The yield 7.01 g (80% by mole based on 1- bromohexadecane) .

[0109] ESI-MS (negative ion mode): m / z 515.32 ([M-1 H]; 100 %), 257.16 ([M-2H]2; 22), 553.26 ([M-2H+K]’, 22).

[0110] 1H NMR ((CD3)2SO, 600 MHz): d 0.853 (t, 3H, J = 6.9 Hz, -CH3), 1.292-1.235 (m, 26H, -OCH2CH2(CH2)I3CH3), 1.551 (quint, 2H, J = 6.9 Hz, -OCH2CH2(CH2)I3CH3), 2.751-2.741 (m, 4H, NCH2CH2N), 3.444 (bs, 4H, CH2CO2H ester-free side), 3.539 (bs, 2H, CH2CO2CI6H33), 4.011 (t, 2H, J = 6.6 Hz, -OCH2CH2(CH2)I3CH3), 12.262 (bs, 2.5H, CH2CO2H).Example 4

[0111] Purification of 4-Ci6 by pseudo-recrystallization in isopropanol.

[0112] Crude product 4-Ci6 (1.26g) was suspended in isopropanol (70mL) and chunks were pulverized with the help of a sonicator. The mixture was heated at 85°C for 10 minutes to partially dissolve the crude 4-Ci6. The mixture was cooled to room temperature, and a white solid was filtered. The flask was rinsed with isopropanol and the rinsing was poured onto the filtered material. The filtered powder was rinsed with isopropanol. The product was dried under suction. The yield was 880mg.1H-NMR showed that the diester impurities were reduced.

[0113] It was also shown that this purification process worked better when unreacted EDTA was first removed (e.g., by pH control in acetate buffer followed by filtration and washing), as unreacted EDTA cannot be dissolved in alcohols. Repeating this pseudo crystallization process yielded a pure monoester.Example 5

[0114] Synthesis of mono-C14 EDTA ester using choline hydroxide.

[0115] The synthesis is illustrated in FIG. 3. H4EDTA (1.000 g, 3.422 mmol) was placed in a 100rriL 24 / 40 one-neck round bottom flask. Choline hydroxide (0.982 M) (3 equivalents) in methanol (10.4 mL) prepared from choline chloride and KOH. The mixture was sonicated at room temperature for 20 minutes to obtain a clear solution. Methanol was stripped under reduced pressure (50 mbar). The bath temperature started at 20 °C and gradually increased to 60°C until viscous and slightly cloudy liquid 2choi was obtained and no more bubbling from the liquid was observed.

[0116] Isopropanol (10 mL) was added and sonicated for 15 minutes to obtain a clear solution. 1 -Bromotetradecane (510 pL, 0.5 equivalents) was added. The clear solution was stirred under nitrogen at 35 °C for 67.5 hours. Isopropanol was removed under reduced pressure (80 mbar) at 60 °C. The cloudy residue was dispersed in RO water (40 mL) at room temperature. The pH was set to 2.82 with concentrated HCI. The white precipitate was filtered and washed with RO water. The solid 3choi-Ci4 was roughly dried under suction to pack.

[0117] The white wet solid was transferred to a 250 mL beaker and dissolved in acetate buffer (NaOH 587 mg - AcOH 1.1 mL + 50 mL RO water) at 60 °C. The pH was adjusted to 2.5 (37.8 °C) with the acetate buffer and HCL. The beaker was covered with parafilm and left for 15 minutes. The supernatant was clear. It was filtered and washed with RO water (25 mL). The white solid residue on the filter was suction-dried and air-dried in the hood overnight. TLC and ESI (negative) showed EDTA C14 mono ester 4-Ci4 as a major product. The yield 0.7259g (86% by mole) with ~5% of diester. The product can be further purified using the pseudo-recrystallization method using methanol.

[0118] ESI-MS (negative ion mode): m / z 487.28 ([M-1 H]-, 100 %), 975.57 ([2M-1 H]’, 6).

[0119] 1H NMR ((CD3)2SO, 600 MHz): d 0.853 (t, 3H, J = 6.9 Hz, -CH3), 1.290-1.237 (m, 22H, -OCH2CH2(CH2)IICH3), 1.552 (quint, 2H, J = 6.9 Hz, -OCH2CH2(CH2)nCH3), 2.750(m, 4H, NCH2CH2N), 3.440 (bs, 2H, CH2CO2H), 3.449 (bs, 4H, CH2CO2H) 3.541 (bs, 2H, CH2CO2C14H29), 4.012 (t, 2H, J = 6.6 Hz, -OCH2CH2(CH2)nCH3), 12.244 (bs, 2H, CH2CO2H).

[0120] The reaction can be further purified using the pseudo-recrystallization method of Example 4 to lower the amount of di-ester present.Example 6

[0121] Synthesis of mono- C4 EDTA ester using tetrabutylammonium hydroxide.

[0122] The synthesis is illustrated in FIG. 4. H4EDTA (2.0001 g, 6.8437 mmol) and 37% TBAOH in MeOH (17.1 mL) were mixed and methanol (5 mL) was added. The mixture was sonicated for 30min to obtain a clear solution. Methanol was stripped by rotary evaporation. The cloudy viscous residue 2TBA W3S dissolved in acetone (20 mL).

[0123] lodobutane (390 pL, 3.42 mmol) was added. The flask was glass-stoppered and covered with aluminum foil. The mixture was stirred at room temperature for 20 hours and the reaction mixture was cloudy. The solvent was removed by a rotary evaporator at room temperature. RO water (30mL) was added to dissolve the residue. The mixture was kept in a fridge at 4°C for 30min and filtered to remove formed crystals.

[0124] 37% HCI (1.5mL) was added to adjust the pH to 1.73 (21 °C). After 30 minutes, the formed white precipitate was filtered. The filtrate was rotary evaporated to remove water by toluene azeotrope to obtain a viscous clear liquid. RO water was added, and slightly yellow precipitates were formed. The precipitates were filtered and washed with a small amount of water. The yellowish solid was dried under vacuum overnight.

[0125] The dried solid was dispersed in dichloromethane, sonicated, filtered with a 0.45um polyamide membrane filter, and washed with dichloromethane to obtain a white powder of EDTA C4 monoester. Yield: 0.2630g (22.06% mole yield based on iodobutane)

[0126] ESI-MS (negative ion mode): m / z 347.134 ([M-1 H]’, 100 %).

[0127] 1H NMR ((CD3)2SO, 600 MHz): d 0.883 (t, 3H, J = 7.2 Hz, -CH3), 1.320 (sextet, 2H, J = 7.8 Hz, -OCH2CH2CH2CH3), 1.547 (quint, 2H, J = 7.8 Hz, -OCH2CH2CH2CH3), 2.751 (m, 4H, NCH2CH2N), 3.440 (bs, 2H, CH2CO2H), 3.450 (bs, 4H, CH2CO2H), 3.544 (bs, 2H, CH2CO2C4H9), 4.027 (t, 2H, J = 6.6 Hz, -OCH2CH2CH2CH3), 12.248 (bs, 2.3H, CH2CO2H).Example 7

[0128] EDTA C6 monoester from hexyl methanesulfonate.

[0129] The synthesis is illustrated in FIG. 5. H4EDTA 1.000g (3.422 mmol) was added 1.2M tetrabutylammonium hydroxide (TBAOH) in methanol (8.55 mL) and methanol (4 mL). The mixture was sonicated for 25 minutes to obtain a clear solution. The solvent was removed by rotary evaporation (45 mbar, 20-40-60 °C).

[0130] The obtained cloudy IL was dissolved in tetrahydrofuran (THF) (10 mL) by sonication. Hexyl methanesulfonate (291 pL, 1.71 mmol) (EDTA: hexyl mathanesulfonate = 1 : 0.5 (molar)) was added to the cloudy solution. The flask was stoppered, and the mixture was stirred at room temperature for 48 hours. The solvent was removed, and water (10 mL) was added.

[0131] The solution was transferred to a 250mL beaker and rinsed with water. The total volume was 40 mL (The pH was 7.32 at 21.4 °C). The pH was lowered to 1.21 with concentrated HCI (1 mL). A white solid slowly precipitated out. The precipitate was filtered and dried under suction. The white solid was suspended in methanol (50 mL), sonicated to break chunks into small particles. The suspension was warmed in a 60 °C water bath for 30 minutes, and it was filtered while it is hot. The filtrate was rotary evaporated to obtain a white solid of EDTA C6 monoester. Yield: 0.3689 g (57% mole yield based on hexyl methanesulfonate).

[0132] ESI-MS (negative ion mode): m / z 375.19 ([M-1 Hp, 100 %), 459.29 ([M+C6HI2- 1 Hp, 4).

[0133] 1H NMR ((CD3)2SO, 600 MHz): d 0.859 (t, 3H, J = 6.9 Hz, -CH3), 1.236-1.320 (m, 6H, -OCH2CH2(CH2)3CH3), 1.555 (quint, 2H, J = 6.6 Hz, -OCH2CH2(CH2)3CH3), 2.751 (m, 4H, NCH2CH2N), 3.449 (bs, 6H, CH2CO2H), 3.539 (bs, 2H, CH2CO2C6HI3), 4.018 (t, 2H, J = 6.6 Hz, -OCH2CH2(CH2)3CH3), 12.238 (bs, ~2H, CH2CO2H).Example 8

[0134] EDTA C6 monoester from hexyl p-tolunenesulfonate.

[0135] The synthesis is illustrated in FIG. 6. The synthesis was carried out by the same procedure described for the synthesis of EDTA C6 monoester using hexyl methanesulfonate (Example 7, above) except for the starting material, hexyl p- toluenesulfonate (403 pL) was used in place of hexyl methanesulfonate. The yield of C6EDTA mono ester: 0.4647 g (72% molar yield based on p-toluenesulfonate).Example 9

[0136] EDTA C16 monoester using tetraethylammonium bicarbonate.

[0137] The synthesis is illustrated in FIG. 7. A mixture of H4EDTA (1.000 g, 3.422 mmol) and TEA bicarbonate (1.963 g, 10.265 mmol) was dissolved in MeOH (12 mL) with sonication and heating (60 °C) to obtain a clear solution. MeOH was removed to obtain a clear viscous liquid.

[0138] Isopropanol (10 mL) was added to dissolve the residue. 1 -Bromohexadecane (520 pL) was added, and the mixture was stirred at 50 °C for 22 hours. The solvent was removed (35 mbar, 40-60-80 °C) to obtain a sticky pale solid.

[0139] It was dissolved in RO water (50 mL), and NaCI (1.01 g) was dissolved. 37% HCI (~0.5 mL) was added to adjust the pH to 3.02, which caused the product to precipitate. The white precipitate was filtered and washed with RO water (50 mL). The filtered wet residue was dissolved in an acetate buffer solution (50 mL) (containing NaOH (661.7 mg) and AcOH (1.10 mL)) by heating at 60 °C. 37% HCI (-1.1 mL) was added to adjust the pH to 2.96. The white precipitate was filtered, washed with RO water, and dried under suction for about 1 hour.

[0140] The wet filtered residue was dispersed in methanol (30mL) and sonicated to make the solid chunks fine particles. The suspension was boiled for 5 minutes to partially dissolve the product mixture. It was cooled to room temperature and filtered. The flask and filtered product were rinsed with methanol. The obtained product was the pure C16 EDTA monoester. The molecule was identified by TLC and1H NMR. Yield 660mg (74% molar yield based on 1 -bromohexadecane).Example 10

[0141] EDTA C14 monoester using cesium carbonate.

[0142] The synthesis is illustrated in FIG. 8. A mixture of H4EDTA (1.001 g, 3.424 mmol) and CS2CO3 (2.237 g, 6.866 mmol) in methanol (20 mL) was sonicated at room temperature for 15 minutes to obtain a clear solution. Methanol was stripped by rotary evaporation (50 mbar, 20 to 40 °C) to obtain a foamy white solid.

[0143] The solid was dissolved in methanol (5 mL) and dimethyl carbonate (7 mL) was added. 1 -Bromotetradecane (510 pL) was added. The clear solution was stirred at 50 °C under nitrogen for 23 hours. Methanol was removed by rotary evaporator under reduced pressure. The white residue was dissolved in RO water (50 mL). NaCI (1.04g) was added and dissolved. The pH was adjusted to 2.59 with 37% HCI (0.75 mL).

[0144] The white precipitates were filtered and washed with RO water. The filtered white residue was dried under suction, and the wet product was dispersed in methanol (20 mL). The suspension was boiled for 5 minutes. After cooling down to room temperature, the product was filtered and washed with methanol. The product was identified by TLC and 1 H NMR. Yield: 92mg (2.7% molar yield based on 1 -bromotetradecane).Example 11

[0145] EDTA C8 monoester using TBAOH and 2-propanol.

[0146] A mixture of H4EDTA (1.0006 g, 3.4239 mmol), 37% TBAOH (8.50 mL) and methanol (4 mL) was sonicated for 20 minutes to obtain a clear solution. Methanol wasremoved under reduced pressure (50 mbar, 20-40-60 °C) to obtain a cloudy viscous liquid.

[0147] The viscous residue was dissolved in isopropanol (10 mL) and 1-bromooctane (300 pL, 1.7367 mmol) was added. The mixture (a clear solution) was stirred at 50 °C under nitrogen for 96 hours. Isopropanol was removed by rotary evaporator under reduced pressure. The viscous clear liquid was dissolved in RO water (10 mL). KI (1.705 g) was added and sonicated. It formed white crystals. It was filtered and washed with cold water to make the volume of the filtrate 75 mL. The pH of the filtrate was 7.65 (20.9 °C). NaCI (3 g) was dissolved, and the pH dropped to 7.15. The pH was adjusted to 2.82 (20.2 °C) with 37% HCI (~0.5mL) to cause precipitation of the product. The product was filtered, washed with water, air-dried, and washed with dichloromethane. Yield: 0.410g (58% molar yield).

[0148] ESI-MS (negative ion mode): m / z 403.1942 ([M-1 H]’, 100 %).

[0149] 1H NMR ((CD3)2SO, 600 MHz): d 0.857 (t, 3H, J = 7.2 Hz, -CH3), 1.286 (m, 10H,- OC 2CH2CH2CH2CH2CH2C 2C 3), 1.557 (m, 2H, -OCH2CH2CH2CH2CH2CH2CH2CH3), 2.756 (m, 4H, NCH2CH2N), 3.444 (bs, 2H, CH2CO2H), 3.457 (bs, 4H, CH2CO2H), 3.546 (bs, 2H, CH2CO2C4H9), 4.017 (t, 2H, J = 6.6 Hz, -OCH2CH2CH2CH2CH2CH2CH2CH3), 12.245 (bs, 2.7H, CH2CO2H).Example 12

[0150] Mono cholesteryl EDTA.

[0151] The synthesis is illustrated in FIG. 9. Ethylenediamine tetraacetic acid (H4EDTA) (1304 mg, 4.463 mmol) was added 37% tetrabutylammonium hydroxide (TBAOH) in methanol (14.5 mL) and dissolved at 60 °C in 5 minutes. Methanol was distilled out. Residual MeOH and water was boiled off at 105 °C under a gentle stream of nitrogen. Cholesteryl bromide (1003 mg, 2.228 mmol) and dry tetrahydrofuran (THF) (10 mL) was added, and the clear brown solution was stirred at 50 °C under nitrogen for 10 minutes and for 20 hours at 25 °C. THF was removed by rotary evaporator. The viscous brown residue was added water (100 mL) and sonicated to obtain an off-white suspension.The pH was adjusted to 4.85 with concentrated hydrochloric acid (0.75 ml_). The suspension was warmed at 60 °C for 15 minutes. The precipitate was filtered off. The filtrated was kept in the hood for 3 days and a white solid came out. The solid was dissolved in aqueous sodium bicarbonate and the formation of mono cholesteryl EDTA as a major product was confirmed by ESI.

[0152] ESI-MS (positive ion mode): m / z 661.2758 ([M+H]+, 1 (relative intensity)), 637.2590 (unknown, 0.46), 675.4057 (unknown, 0.27), 717.4477 (unknown, 0.22), 741.5390 (unknown, 0.10)

Claims

CLAIMS1 . A process for the synthesis of a compound of Formula (I):wherein R is selected from the group consisting of alkyl, alkenyl, alkynyl, and steroidyl, the process comprising: reacting a compound of Formula (Ila), a compound of Formula (lib) or a mixture thereof, with a compound of Formula R-X:to obtain a compound of Formula (Illa), a compound of Formula (lllb) or a mixture thereof:(Illa) (lllb)wherein A+is a cesium cation, a quaternary ammonium cation or a quaternary phosphonium cation, and X is a leaving group; and reacting the compound of Formula (Illa), the compound of Formula (lllb) or mixture thereof, with an acid to obtain a reaction product which comprises the compound of Formula (I).

2. The process of claim 1 , further comprising reacting ethylenediaminetetraacetic acid (EDTA) with a hydroxide salt of Formula A+HO_to obtain the compound of Formula (Ila), compound of Formula (lib) or mixture thereof.

3. The process of claim 2, wherein reacting EDTA with the hydroxide salt is performed in methanol.

4. The process of claim 1 , further comprising reacting ethylenediaminetetraacetic acid (EDTA) with a carbonate salt of Formula A2CO3 and heating to eliminate carbon dioxide, to obtain the compound of Formula (Ila), compound of Formula (lib) or mixture thereof.

5. The process of any one of claims 1 to 4, wherein reacting the compound of Formula (Ila), compound of Formula (lib) or mixture thereof, with the compound of Formula R-X is performed in a solvent selected from the group consisting of methanol, ethanol, isopropanol, t-butanol, n-butanol, THF, dimethyl carbonate, acetone, ethyl acetate, DMF, DMSO, dioxane, NMP and mixtures thereof, provided that the solvent solubilizes the compound of Formula (Ila), the compound of Formula (lib) or mixture thereof, and provided that the solvent solubilizes the compound of Formula R-X.

6. The process of any one of claims 1 to 5, wherein X is selected from the group consisting of Cl, Br, I, methylsulfate, methanesulfonate (OMs), trifluoromethanesulfonate (OTf) and 4-methylbenzenesulfonate (OTs).

7. The process of any one of claims 1 to 6, wherein R is substituted with one or more aryl, -OH, -O-(Ci-C4)alkyl, -CFs and -CN.

8. The process of any one of claims 1 to 6, wherein R is unsubstituted.

9. The process of any one of claims 1 to 8, wherein A+is selected from the group consisting of a cesium cation, a tetraalkyl ammonium, a trialkylbenzylammonium, a benzalkonium, a tetraalkyl phosphonium, a trialkylbenzylphosphonium, tetraphenyl phosphonium, benzyl triphenyl phosphonium and mixtures thereof.

10. The process of any one of claims 1 to 8, wherein A+is tetrabutylammonium or choline.

11. The process of any one of claims 1 to 10, wherein the acid is selected from the group consisting of a carboxylic acid, a sulfonic acid, HCI, HBr, HI, sulfuric acid, nitric acid and perchloric acid.

12. The process of any one of claims 1 to 11 , wherein the compound of Formula (Ila), compound of Formula (lib) or mixture thereof; and the compound of Formula R-X are provided at a molar ratio Formula (I la) / (l lb) : RX of about 2 : 1.

13. The process of any one of claims 1 to 5, further comprising: dissolving the reaction product in an acetate buffer; lowering the pH of the acetate buffer to obtain a precipitate; and recovering the precipitate which is the reaction product comprising the compound of Formula (I) at a higher purity.

14. The process of claim 13, wherein the pH of the acetate buffer is lowered to between 2.3 and 3.8.

15. The process of any one of claims 1 to 6, further comprising: heating a suspension of the reaction product in isopropanol to at least partially dissolve the reaction product, thereby obtaining a mixture; cooling the mixture, thereby obtaining a precipitate; andrecovering the precipitate which is the reaction product comprising the compound of Formula (I) at a higher purity.

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