Synthesis of iminoguanidines

Abstract

Methods of synthesizing an imino compound by performing a condensation reaction of a multi-carbonyl compound with an amine in an aqueous medium. The amine may be a guanidine, such as aminoguanidine, or an amidine, such as an amino amidine. The imino compound may be an iminoguanidine compound, such as bis(imino)guanidine. Methods may produce a freebase or salt of the iminoguanidine.

Description

SYNTHESIS OF IMINOGUANIDINESINCORPORATED BY REFERENCE

[0001] A PCT Request Form is filed concurrently with this specification as part of the present application. Each application that the present application claims benefit of or priority to as identified in the concurrently filed PCT Request Form is incorporated by reference herein in their entireties and for all purposes.TECHNICAL FIELD

[0002] The present disclosure relates to the field of chemical synthesis, and more particularly to the synthesis of iminoguanidines, such as bis(imino)guanidines (BIGs).BACKGROUND

[0003] Capturing carbon dioxide (CO2) from the atmosphere is one approach to mitigating greenhouse gas emissions and slowing climate change. However, many technologies designed for CO2 capture from point sources of emissions, such as from flue gas of industrial facilities, are generally ineffective in capturing CO2 from the atmosphere due to the significantly lower CO2 concentrations and large volumes of atmospheric air required to process. In recent years, progress has been made in finding technologies better suited to capture CO2 directly from the atmosphere. Some of these direct air capture (DAC) systems use a solid sorbent where an active agent is attached to a substrate. These DAC systems typically employ a cyclic adsorptiondesorption process where, after the solid sorbent is saturated with CO2, it releases the CO2 using a humidity or thermal swing and is regenerated.

[0004] Other DAC systems use a liquid sorbent (sometimes referred to as a solvent) to capture CO2 from the atmosphere. An example of such a DAC system would be one where a fan is used to draw air across a high surface area packing that is wetted with a solution comprising the liquid sorbent. CO2 in the air reacts with the liquid sorbent to generate a CO2 rich solution. The rich solution is processed to regenerate a lean solution and to release a concentrated carbon stream, for example, CO, CO2 or other carbon products.SUMMARY

[0005] Provided herein are materials and methods for synthesizing BIGs, which may be used in recovering purified CO2 from an impure CO2 source such as air.

[0006] One general aspect includes a method for synthesizing BIGs by reacting an aminoguanidine compound with a multi-carbonyl compound in an aqueous medium to produce an iminoguanidine salt, and converting the iminoguanidine salt to an iminoguamdine freebase. Implementations may include one or more of the following features.

[0007] In some implementations, converting the iminoguanidme salt to the iminoguanidine freebase involves directly converting the iminoguanidme salt to the iminoguanidine freebase. This direct conversion may be performed in the presence of the aqueous medium without isolating the iminoguanidine salt. In some implementations, the direct conversion may be performed without washing and / or drying the iminoguanidine salt in solid form. In some implementations, the direct conversion may involve converting the iminoguanidine salt to the iminoguanidine freebase without generating an intermediate iminoguanidine salt prior to forming the iminoguanidine freebase. In some implementations, the direct conversion may involve converting the iminoguanidine salt to the iminoguanidine freebase without generating an iminoguanidme oxyanion salt prior to forming the iminoguanidine freebase.

[0008] In some implementations, the method for synthesizing BIGs involves, prior to converting the iminoguanidine salt to the iminoguanidine freebase, isolating the iminoguanidine salt from the aqueous medium and washing the iminoguanidine salt and / or drying the iminoguanidine salt in solid form.

[0009] In some implementations, converting the iminoguanidme salt to the iminoguanidine freebase involves reacting the iminoguamdine salt with an inorganic base that is water soluble. The inorganic base may be an alkali metal hydroxide, an alkaline earth metal hydroxide, or combinations thereof. Examples of the inorganic base include potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), or any combination thereof.

[0010] In various implementations, the iminoguanidine salt is insoluble in the aqueous medium.

[0011] In some implementations, converting the iminoguanidme salt to the iminoguanidine freebase involves converting the iminoguanidine salt to an iminoguanidine carbonate and / or an iminoguanidine bicarbonate, and thermally decomposing the iminoguanidme carbonate and / or the iminoguanidine bicarbonate to generate the iminoguanidine freebase.

[0012] In some implementations, the aminoguanidine compound is an aminoguanidine acid salt, such as aminoguanidine-HCl.

[0013] In some implementations, the multi-carbonyl compound is a dicarbonyl compound, such as a dialdehyde, a diketone, a mixed aldehyde-ketone, or any combination thereof. In some implementations, examples of the dicarbonyl compound include 2,6-pyridine dialdehyde, 2,6-diacetylpyridine, 1,3-diacetylbenzene, 1,3-diacetylpyridine, 1,3-indanedione, 1,4- diacetylbenzene, 1,2-diacetylbenzene, 2,3-butadione, 2,3-pentadione, 2,5 -hexanedione, 2,5- dicarboxaldehyde furan, or any combination thereof.

[0014] In some implementations, the iminoguanidine freebase is a bis(imino)guanidine freebase. In some implementations, the bis(imino)guanidine freebase may be a compound according to formula:where A is a central moiety comprising a single bond, a linear or branched hydrocarbon, and / or a cyclic group having at least one carbon ring atom, the cyclic group comprising a monocyclic ring moiety or a polycyclic ring moiety , and any one or more of the hydrogen atoms, whether the hydrogen atoms are shown or not shown in the formula, are replaceable with one or more Ci-C6alkyl groups,.

[0015] In some implementations, the central moiety A is or includes a saturated or unsaturated carbocyclic ring, a saturated or unsaturated heterocyclic ring. In some implementations, the cyclic group includes at least one five-membered, six-membered, or seven-membered ring.

[0016] In some implementations, one or both of the terminal carbons in imino groups linked to the central moiety A are bonded to an alkyl group or other substituents that are not part of the linkage with the central moiety A.

[0017] In some implementations, the iminoguanidine freebase is a tris(imino)guanidine freebase.

[0018] In some implementations, the method involves reacting the aminoguanidine compound with the multi-carbonyl compound in the aqueous medium and monitoring the formation of a mono(iminoguanidine) intermediate that is soluble in the aqueous medium.

[0019] In some implementations, the method involves, prior to reacting the aminoguanidine compound and the multi-carbonyl compound, purifying at least one of the aminoguanidine compound and the multi-carbonyl compound.

[0020] In some implementations, the aqueous medium includes one or more of: deionized water, a water miscible co-solvent, a catalyst for reacting the aminoguanidine compound with the multi -carbonyl compound. In some implementations, the catalyst may be hydrohalic acid or acetic acid.

[0021] In various implementations, the iminoguanidine freebase is substantially insoluble in the aqueous medium.

[0022] In some implementations, the method further involves purifying the iminoguanidine freebase. The purification of the iminoguanidine freebase may involve washing away one or more impurities that are soluble in the aqueous medium being derived from the aminoguanidine compound.

[0023] In some implementations, reacting the aminoguanidine compound and the multicarbonyl compound and converting the iminoguanidine salt to an iminoguanidine freebase is performed within a reaction vessel of one apparatus containing the aqueous medium. In some implementations, the apparatus is a stirred tank reactor. In some implementations, the reacting to form the iminoguanidine salt is performed continuously.

[0024] In some implementations, the method involves gradually adding at least one of the aminoguanidine compound and the multi-carbonyl compound to control the exotherm when reacting the aminoguanidine compound and the multi-carbonyl compound.

[0025] In some implementations, converting to form the iminoguanidine freebase is performed continuously.

[0026] Another general aspect includes a method for synthesizing BIGs by reacting an aminoguanidine compound with a multi-carbonyl compound in an aqueous medium to produce a first iminoguanidine salt, and converting the first iminoguanidine salt to an iminoguanidine carbonate and / or an iminoguanidine bicarbonate. Implementations may include one or more of the following features.

[0027] In some implementations, the aminoguanidine compound is aminoguanidine-HCl and the first iminoguanidine salt is an iminoguanidine-HCl.

[0028] In some implementations, converting the first iminoguanidine salt to the iminoguanidine carbonate and / or the iminoguanidine bicarbonate involves contacting the first iminoguanidine salt with a carbonate salt and / or a bicarbonate salt.

[0029] In some implementations, converting the first iminoguanidine salt to the iminoguanidine carbonate and / or the iminoguanidine bicarbonate involves directly converting the first iminoguanidine salt to the iminoguanidine carbonate and / or the iminoguanidine bicarbonate. This direct conversion may be performed in the presence of the aqueous medium without isolating the first iminoguanidine salt from the aqueous medium. In some implementations, the direct conversion may be performed without washing and / or drying the first iminoguanidine salt in solid form.

[0030] In some implementations, the method involves thermally decomposing the iminoguanidine carbonate and / or iminoguanidine bicarbonate to generate an iminoguanidine freebase.

[0031] In some implementations, the direct conversion may involve converting the iminoguanidine salt to the iminoguanidine freebase without generating an intermediate iminoguanidine salt prior to forming the iminoguanidme freebase. In some implementations, the direct conversion may involve converting the iminoguanidine salt to the iminoguanidine freebase without generating an iminoguanidine oxyanion salt prior to forming the iminoguanidine freebase.

[0032] Another general aspect includes a method for synthesizing BIGs by reacting an aminoguanidine freebase with a multi-carbonyl compound in an aqueous medium to produce an iminoguanidine freebase. In some implementations, reacting the aminoguanidine freebase with the multi-carbonyl compound does not involve production of an iminoguanidine salt.

[0033] In some implementations, the iminoguanidine freebase is a bis(imino)guanidine freebase or a tris(imino)guanidine freebase. In some implementations, the bis(imino)guanidine freebase may be a compound according to formula:where A is a central moiety having a single bond, a linear or branched hydrocarbon, and / or a cyclic group having at least one carbon ring atom, the cyclic group comprising a monocyclic ring moiety or a polycyclic ring moiety , and any one or more of the hydrogen atoms, whether the hydrogen atoms are shown or not shown in the formula, are replaceable with one or more Ci-Ce alkyd groups.

[0034] In some implementations, the central moiety A is or includes a saturated or unsaturated carbocyclic ring, a saturated or unsaturated heterocyclic ring. In some implementations, the cyclic group includes at least one five-membered, six-membered, or seven-membered ring.

[0035] In some implementations, one or both of the terminal carbons in imino groups linked to the central moiety A are bonded to an alkyl group or other substituents that are not part of the linkage with the central moiety A.

[0036] In some implementations, the aqueous medium includes one or more of: deionized water, a water miscible co-solvent, a catalyst for reacting the aminoguanidine freebase with the multi-carbonyl compound. In some implementations, the catalyst may be hydrohalic acid or acetic acid.

[0037] In various implementations, the iminoguanidine freebase is substantially insoluble in the aqueous medium and is present as a solid form when in the aqueous medium.

[0038] In some implementations, the method further involves purifying the iminoguanidine freebase solid. The purification of the iminoguanidine freebase solid may involve washing the iminoguanidine freebase solid to remove one or more impurities that are soluble in the aqueous medium, and the one or more impurities being derived from the aminoguanidine compound.

[0039] In some implementations, the method further comprises preparing the aminoguanidine freebase. In some implementations, preparing aminoguanidine freebase involves contacting an aminoguanidine salt with an ion exchange polymer. In some implementations, preparing aminoguanidine freebase involves reacting an aminoguanidine salt with a base. In some implementations, the base is a hydroxide such as sodium hydroxide (NaOH), potassium hydroxide (KOH), or lithium hydroxide (LiOH). In some implementations, the aminoguanidine salt is aminoguanidine-HCl.

[0040] In some implementations, reacting the aminoguanidine freebase with the multicarbonyl compound is performed before the ammoguanidine freebase decomposes substantially. In some implementations, reacting the aminoguanidine freebase and the multi-carbonyl compound is performed within, at most, about 10 minutes of preparing the aminoguanidine freebase.

[0041] Another general aspect includes a method, the method involves contacting an aminoguanidine compound with a multi-carbonyl compound in an aqueous medium to produce a mono(imino)guanidine compound, and reacting the mono(imino)guanidine compound with the aminoguanidine compound in the aqueous medium to produce a bis(imino)guanidine compound. The multi-carbonyl compound is insoluble in the aqueous medium, the mono(imino)guanidine compound is soluble in the aqueous medium, and the bis(imino)guanidine compound is insoluble in the aqueous medium. Implementations may include one or more of the following features.

[0042] In some implementations, the method involves monitoring the progress of production of bis(imino)guanidine compound by monitoring the presence of solids in the aqueous medium.

[0043] In some implementations, the process of the mono(imino)guanidine intermediate production, soluble in aqueous medium, is monitored by high-performance liquid chromatography (HPLC) with UV-VIS detection.

[0044] In some implementations, bis(imino)guanidine compound is diacetylbenzene bis(imino)guanidine or diacetyl bis(imino)guanidine.

[0045] In some implementations, the method further include purifying the bis(imino)guanidine compound by washing the bis(imino)guanidine compound, in solid form, to remove one or more impurities that are soluble in the aqueous medium, where the one or more impurities being derived from the aminoguanidine compound.

[0046] In various implementations, the method may include one or more of the features described earlier.BRIEF DESCRIPTION OF THE DRAWINGS

[0047] FIG. 1 is a schematic block flow diagram of a carbon capture system, such as a Direct Air Capture (DAC) system, including a gas-liquid contactor subsystem and a regeneration subsystem of the present disclosure.

[0048] FIG. 2 includes three chromatographs obtained by hydrophilic interaction liquid chromatography (HPLC in HILIC mode) showing progress of consumption of 1,3-diacetylbenzene (DAB) and aminoguanidine hydrochloride, and production of DAB- bis(imino)guanidine.

[0049] FIGS. 3 to 6 each illustrate a block flow diagram of a separate method for synthesizing BIGs in accordance with certain implementations.DETAILED DESCRIPTION

[0050] In the following descriptions, numerous specific details are set forth to provide a thorough understanding of the presented implementations. The disclosed implementations may be practiced without some or all these specific details. In other instances, well-known process operations have not been described in detail to not unnecessarily obscure the disclosed implementations. While the disclosed implementations will be described in conjunction with the specific implementations, it will be understood that it is not intended to limit the disclosed implementations.

[0051] As used herein, the term “sorbent” refers to an absorption compound that may be provided in solution, thereby forming an absorption solution or sorbent solution. The sorbent of the present disclosure may react with, complex with or otherwise facilitate absorption of carbon dioxide in solution. The sorbent of the present disclosure includes at least one amino acid, at least one amine or any combinations thereof. The term “sorbent” may refer to hindered and / or unhindered amines or amino acids that include at least one nitrogen. In some cases, the sorbent may be an amino acid or amine that is capable of complexing with carbon dioxide via a nitrogen atom to form a carbamate. In some cases, the “sorbent” may not be directly complexed with carbon dioxide. For example, a sorbent may facilitate the formation of carbonate ions and / or bicarbonate ions in a solution containing the sorbent.

[0052] As used herein, the term “freebase” refers to the neutral form of a molecule. In the context of iminoguanidines, the term “freebase” refers to the neutral form of an iminoguanidine. Examples of freebases of the present disclosure may include specific BIGs (e.g., glyoxal bis(imino)guanidine). Salts are generally not freebases. Hence, BIG salts such as BIG hydrochlorides, BIG carbonates, BIG bicarbonates, BIG sulfates, BIG nitrates, etc. are not freebases. However, an unprotonated BIG without an associated anion may be a freebase.

[0053] As used herein, the term “aqueous solution”, “aqueous medium” or “aqueous reaction media” refers to a liquid medium consisting of water or including water as in a mixture of water and a water-miscible organic solvent. For example, the aqueous solution can be a mixture ofwater and at most 10 vol% of a water-miscible organic solvent. Water in the aqueous solution is present in sufficient amount to ensure sol ubi 1 i ty of the reactants of the present disclosure, e.g., aminoguanidine-HCl, at the selected reaction temperature.

[0054] As used herein, “precipitation”, “reactive crystallization” and similar terms refer to any reaction or process condition that drives a component or reaction product species to come out of solution as a solid. The solid may be amorphous, crystalline, or some combination thereof. The solid may exhibit one or more amorphous or crystalline structures; e.g., it may have one or more distinct crystalline phases. In certain implementations, precipitation or reactive crystallization refers to a reaction involving one or more soluble reactant species in a solvent (as a solution) and that produces a reaction product species that comes out of solution as a solid. As an example of precipitation or reactive crystallization, cations derived from a bis(imino)guanidine freebase or salt react with at least one of carbonate anions or a bicarbonate anions in solution to produce an insoluble bis(imino)guanidine carbonate and / or bicarbonate salt that comes out of solution as a solid during the reaction.

[0055] As used herein, the term “insoluble” may encompass "sparingly soluble", i.e. being of negligible solubility in aqueous medium under the operational conditions disclosed herein, such that a dissolved amount of a compound is merely sufficient to produce a reactive concentration of dissolved species in solution. Insoluble compounds include compounds where the solubility product (Ksp) is low and the equilibrium concentration of dissolved ions remains very small, typically in the micromolar to low millimolar range.

[0056] As used herein, "soluble" may encompass "substantially soluble", i.e. being of significant solubility in an aqueous medium under the operational conditions disclosed herein, such that a dissolved amount of a compound is sufficient to produce a significant concentration of dissolved species in solution enabling consistent reactivity or analytical detectability in the intended applications disclosed herein. Soluble compounds include those with a solubility product (Ksp) or dissolution profile that allows for equilibrium concentrations typically in the millimolar range or higher.

[0057] As used herein a “source of impure carbon dioxide” has less than about 50 mol% CO2, or less than about 20 mol% CO2, or less than about 10 mol% CO2, or less than about 1 mol% CO2. In some implementations, the source of impure carbon dioxide is a gas phase mixture of carbon dioxide and one more other gaseous component. As examples, the source of impure carbon dioxide can be, for example, air, waste gas from an industrial or commercialprocess, flue gas from a power plant, exhaust from an engine, or sewage or landfill gas. The source of impure carbon dioxide of the present disclosure includes a dilute gas source. The dilute gas source can include the atmosphere (e.g., ambient or atmospheric air) or another fluid source that contains dilute concentrations of CO2. Dilute concentrations of CO2, for example in the atmosphere, are in the range of 400-420 parts per million (“ppm”) or approximately 0.04- 0.042% v / v, and less than 1% v / v. These dilute concentrations of CO2 are at least one order of magnitude lower than the concentration of CO2 in point-source emissions, such as flue gases, where point-source emissions can have concentrations of CO2 ranging from 1.5-15% v / v, or from 5-15% v / v depending on the source of emissions.

[0058] “ Carbon dioxide complexing agent” refers to any compound that can selectively complex with carbon dioxide either directly or via carbon dioxide-derived species. In complexed form, a carbon-dioxide complexing agent may form a salt, such as a carbonate or bicarbonate.

[0059] As used herein, the term “about” may include + / -10% of any recited value. As used herein, this term modifies any recited value, range of values, or endpoints of one or more ranges.Introduction and Context

[0060] Iminoguanidines, and bis(imino)guanidines (BIGs) more specifically, as disclosed herein and as synthesized as disclosed herein can be used in a carbon dioxide capture process including direct air capture (DAC) of carbon dioxide. As an example, a DAC process may employ an amine and / or amino acid as sorbent in a sorbent solution to capture carbon dioxide from the air and to form a carbon-loaded sorbent solution, and a carbon complexing agent to unload carbon dioxide from the carbon-loaded sorbent solution and to provide a concentrated source of carbon dioxide, which may be a sparingly soluble complex of carbon dioxide and the complexing agent. Iminoguanidines of the present disclosure are examples of carbon complexing agents. For example, at least one BIG complexing agent (BIG freebase and / or BIG acid salt of the present disclosure) may be used to regenerate the sorbent by unloading the carbon dioxide from the carbon-dioxide derived species of the carbon-loaded sorbent solution.

[0061] While some of the disclosure herein refers to DAC processes, which remove carbon dioxide from air, the associated processes, systems and apparatus of this disclosure apply more broadly to any carbon dioxide capture process that removes or captures carbon dioxide from a source of impure carbon dioxide to produce carbon dioxide-derived species.

[0062] In some implementations, a carbon dioxide capture process, e.g., a DAC process, may include the following operations performed in a carbon dioxide capture system, e.g. a DAC system 1 as shown in FIG. 1. First, a sorbent solution 6, such as an aqueous sorbent solution, comprising one or more sorbent compounds such as an amino acid and / or amine is flowed, e.g., pumped or flowed via gravity, through a gas-liquid contactor 10 where the sorbent solution 6 is brought into contact with a dilute gas source 2, such as atmospheric air or other dilute concentration source of carbon dioxide, that is flowed through the gas-liquid contactor 10 being part of a gas-liquid contactor subsystem 3. For example, carbon dioxide in the dilute gas source 2, such as atmospheric air, is dissolved in the sorbent solution 6 and interacts / reacts with the sorbent in the sorbent solution 6, thereby forming a carbon-loaded sorbent solution 8 comprising captured carbon dioxide in any of various forms comprising at least one of carbon dioxide and carbon dioxide-derived species, such as carbonate ions, bicarbonate ions and / or carbonates. Upon absorption of the CO2 from the dilute gas source 2 by the sorbent solution 6 in the gas-liquid contactor 10, the dilute gas source 2 becomes depleted in CO2 and is flowed out of the gas-liquid contactor 10 as a CCh-lean gas stream 4.

[0063] In some implementations, the DAC system 1 includes processing the carbon-loaded sorbent solution 8 to recover the captured CO2 and to regenerate the sorbent to be reused in the sorbent solution 6 during a regeneration stage of the DAC process. Still referring to FIG. 1, a regeneration subsystem 11 is in fluid communication with the gas-liquid contactor 10. In the regeneration subsystem 11, one or more steps are performed to achieve extraction of CO2 from the carbon-loaded sorbent solution 8 to form a regenerated sorbent solution 22, and a CO2 product stream 28. The regenerated sorbent solution 22 is flowed to the gas-liquid contactor 10 to be reused in capturing CO2 from the dilute gas source 2. Implementations of the regeneration subsystem 11 are described in greater detail below.

[0064] The present disclosure further includes method implementations in relation to the synthesis of a complexing agent 14 involved in the DAC system 1.

[0065] A condensation reaction is one in which water is formed as a co-product. An example condensation reaction is between a carbonyl and a primary amine to form an imine:A carbonyl compound A primary amine An imine

[0066] A condensation reaction is known to be reversible - the reverse reaction being known as hydrolysis - and so the overall reaction is usually written as if products and reactants are in equilibrium, the half-arrows indicating a forward and a reverse reaction:A carbonyl compound A primary amine

[0067] Le Chatelier’s Principle holds that this equilibrium can be shifted to the right by increasing the concentration of a component on the left or reducing the concentration of a component on the right. Because water is generated in condensation reactions, it is often necessary to remove the water as it is formed in order to shift the reaction to the right (forward reaction) and drive it to completion.

[0068] One known method by which this forward shifting is performed includes using a solvent that is immiscible with water (e.g., toluene) and collecting the water at reflux in a Dean- Stark trap. Another known method includes using a physical desiccant such as a molecular sieve. Yet another known method includes using a chemical desiccant, two examples of which are CaHz and acetone dimethylacetal.

[0069] Yet another known way to prevent (or at least minimize) the reverse reaction includes selecting a solvent in which the product has low to no solubility. If the product precipitates, it is no longer in intimate contact with water produced in the condensation reaction, so the hydrolysis reaction is inhibited.

[0070] Bis(iminoguanidine)s are made in a condensation reaction between a dicarbonyl compound (e.g., diacetyl) and an aminoguanidine compound (e.g., hydrochloride salt of aminoguanidine), as exemplified by the synthesis of DABIG-2HC1 according to the following condensation reaction:

[0071] Most known approaches to synthesizing bis(imino)guanidines have employed a nonaqueous solvent, such as ethanol or isopropyl alcohol. There is proposed herein a less expensive, less flammable, and less toxic reaction medium in which to synthesize bis(imino)guani dines.

[0072] The inventors have discovered that an aqueous medium may be employed as a substitute to non-aqueous solvents in many contexts for the synthesis of bis(imino)guani dines, and even for room temperature synthesis. When using an aqueous medium, the produced bis(imino)guanidine is more thermodynamically stable than the starting materials and the reverse reaction (within reason) is thus highly disfavored. Even using an aqueous medium as a solvent is not enough to shift the equilibrium to starting materials, at least not at ordinary temperatures.

[0073] Two observations support this. First, the reaction is very strongly exothermic. Second, and even more telling, is that a batch of DABIG-2HC1 made by a conventional isopropyl alcohol process contained a minor impurity visible by 1H-NMR that was to be removed. An extensive screening of organic solvents failed to identify a suitable recrystallization system. The inventors, upon selecting an aqueous medium as a recrystallization solvent, for example at 70°C, successfully and surprisingly achieved recrystallization by recovering a pure DABIG-2HC1 in high yield, with trivial losses that might be attributed to hydrolysis.

[0074] Thus, in the case of bis(imino)guani dines, Le Chatelier’s Principle can fail to predict the observed result. One explanation may be that the products lie in a deep thermodynamic well such that the reverse reaction is not competitive except at very high temperatures. Synthesis of iminoguanidine salt and freebase

[0075] As indicated, conventional syntheses of iminoguanidines, e.g., bis(imino)guanidines (BIGs), are performed in alcohols or solvent mixtures containing alcohols via a condensation reaction.

[0076] The present disclosure relates to iminoguanidines, and as examples bis(imino)guanidines and tris(imino)guanidines, and methods of preparing iminoguanidine freebases or salts in an aqueous solution, e.g., water. In some implementations, the method involves (i) reacting an aminoguanidine compound with a multi-carbonyl compound in an aqueous medium to produce an iminoguanidine salt. For example, the synthesis can terminate upon forming the iminoguanidine salt. In such implementations, examples of the iminoguanidine salt include iminoguanidine carbonates and iminoguanidine bicarbonates. In some implementations, the method further includes (ii) converting the iminoguanidine salt to an iminoguanidine freebase.

[0077] In some implementations, the aminoguanidine compound is aminoguanidine HC1. However, any other suitable aminoguanidine compound may be used for the condensation reaction. Additional details on aminoguanidine compounds are provided below.

[0078] In some implementations, the multi-carbonyl compound is a dicarbonyl compound such as a dialdehyde, a diketone, or a mixed aldehyde-ketone. Examples of dicarbonyl compounds includes, but are not limited to, 2,6-pyridine dialdehyde, 2,6-diacetylpyridine, 2,5- furan dicarboxaldehyde.

[0079] In some implementations, the iminoguanidine freebase or salt is a bis(imino)guanidine (BIG) or a tris(imino)guanidine (TRIG). In some implementations, the iminoguanidine freebase or salt is a BIG that includes a ring-containing moiety. Examples of BIGs with ring-containing moiety are provided herein.

[0080] In some implementations, the iminoguanidine freebase or salt is insoluble (i.e., sparingly soluble) in the aqueous medium.

[0081] In some implementations, the iminoguanidine salt is converted directly to the iminoguanidine freebase. Direct conversion refers herein to method implementations being rendered possible by the use of the aqueous medium, and including at least one of: conversion of a first iminoguanidine salt into an iminoguanidine freebase without producing any intermediate immoguanidine salt, conversion of an iminoguanidine salt into an iminoguanidine freebase by adding carbonate or bicarbonate ions to the aqueous medium without isolating the iminoguanidine salt, conversion of an aminoguanidine freebase into an iminoguanidme freebase upon contacting a multicarbonyl precursor in the aqueous medium, or converting an iminoguanidine salt into an iminoguanidine freebase in the aqueous medium having a purity of at least 99.5% without any washing and / or purifying step. For example, in some cases,iminoguanidine salt is not isolated from the aqueous medium prior to directly converting the iminoguanidine salt to iminoguanidine freebase. For example, the iminoguanidine salt is not washed and / or dried as a solid.

[0082] In some implementations, the iminoguanidine salt is not converted to a second iminoguanidine salt prior to forming the iminoguanidine freebase. In some implementations, the iminoguanidine freebase is formed without converting the iminoguanidine salt to an iminoguanidine oxyanion salt. For example, the iminoguanidine freebase may be formed without forming an iminoguanidine nitrate, an iminoguanidine sulfate, and / or an iminoguanidine carbonate.

[0083] In some implementations, direct conversion of an iminoguanidine salt to an iminoguanidine freebase is performed in the presence of an aqueous medium. In some implementations, direct conversion of an iminoguanidine salt to an iminoguanidine freebase involves reacting the iminoguanidine salt with an inorganic base. In various implementations, an advantage of an aqueous medium for performing direct conversion to an iminoguanidine freebase is that an inorganic base may be directly added, which may not be suitably soluble in a non-aqueous medium. In some implementations, the inorganic base is potassium hydroxide (KOH), sodium hydroxide (NaOH), and / or lithium hydroxide (LiOH). However, any other suitable inorganic base may be used additionally or alternatively to KOH, NaOH, and / or LiOH. In some implementations, the aqueous medium is or comprises deionized water.

[0084] In some implementations, an immoguanidine freebase or salt synthesis method as disclosed herein is performed in the presence of a catalyst. In some implementations, the aqueous medium includes a catalyst that accelerates the reaction between the aminoguanidine compound with the multi-carbonyl compound. Examples of a catalyst include but are not limited to, ahydrohahc acid (e.g., HC1) and acetic acid.

[0085] In some implementations, once formed, the iminoguanidine freebase or the iminoguanidine salt is purified and washed, removing one or more impurities that are soluble in the aqueous medium, which may have been present with the aminoguanidine compound (reactant). In some implementations, washing a precipitate of the iminoguanidine freebase removes any impurities and any unreacted aminoguanidine compound.

[0086] In some implementations, the disclosed operations of the method for preparing the iminoguanidine freebase or iminoguanidine salt are performed in a single apparatus. Theapparatus used for preparing the iminoguanidine freebase or iminoguanidine salt may include a stirred tank reactor.

[0087] In some implementations, an iminoguanidine freebase is prepared according to the following method. First, the method uses aminoguanidine freebase, rather than aminoguanidine HC1 or other aminoguanidine salt, as a reactant. The method reacts the aminoguanidine freebase with a multi-carbonyl compound in an aqueous medium to directly form the iminoguanidine freebase. There are many possible approaches to this direct synthesis method. Variations include the choices of an aminoguanidine freebase reactant, an iminoguanidme freebase product, an inorganic base, the aqueous medium composition, a catalyst, etc.

[0088] In some implementations, reacting the aminoguanidine freebase with the multicarbonyl compound is performed before the aminoguanidine freebase is substantially decomposed. It has been observed that aminoguanidine freebase is relatively unstable and decomposes when left standing, even in isolation. Therefore, in some implementations, the reaction between aminoguanidine freebase and the multi-carbonyl compound is performed within minutes, e.g., less than about ten minutes, of preparing the aminoguanidine freebase.

[0089] In some implementations, the method includes preparing an aminoguanidine freebase by contacting an aminoguanidine salt with an ion-exchange polymer. For example, aminoguanidine HC1 can be converted to its freebase by exposure to an anion exchange resin, either in bulk or in a column. When used, contacting a concentrated aqueous solution of aminoguanidine HC1 with a resin such as Amberlyst A26 (OH form) causes the initially neutral pH solution to become strongly alkaline, which indicates the presence of aminoguanidine freebase. The resulting aqueous solution containing aminoguanidine freebase may be substantially free of the salts that would have been formed by neutralization with an inorganic base. In some implementations, the aminoguanidine freebase condenses with a dicarbonyl compound or other multi-carbonyl compound, and the resulting BIG freebase is free of neutralization salts. As a result, the BIG freebase can be directly harvested by filtration. The approach incorporating the ion-exchange polymer may be beneficial since it can reduce the number of washes to remove impurities which may reduce the material needed or used and may be more cost-effective.

[0090] In some implementations, the aqueous solution of aminoguanidine freebase obtained from an ion exchange column may be too dilute to use directly in a condensation reaction witha multi -carbonyl compound. In such cases, the method may include concentrating the aqueous solution of aminoguanidine by removal of water, for example, using a rotary evaporator.

[0091] In some implementations, the aminoguanidine freebase or salt and / or the dicarbonyl compound may be too impure to use directly as reactant of the condensation reaction. The method of the present disclosure may include purifying at least one of the reactant.

[0092] In some implementations, the aminoguanidine freebase is prepared by reacting an aminoguanidine salt with a base, such as an inorganic base. In some implementations, the base used to prepare the aminoguanidine freebase is a hydroxide, such as sodium hydroxide, potassium hydroxide, and / or lithium hydroxide.

[0093] In some implementations, the reaction between the aminoguanidine freebase and the multi-carbonyl compound is performed without producing a substantial amount of iminoguanidine salt.

[0094] In some implementations, the aminoguanidine compound is an aminoguanidine salt, such as aminoguanidine-HCl. Any other suitable aminoguanidine compound such as an alkyl or aryl substituted aminoguanidine may be used.

[0095] In some implementations, the iminoguanidine freebase or iminoguanidine salt is a bis(imino)guanidine (BIG), or tris(imino)guanidine (TRIG). In some implementations, iminoguanidine freebase is a bis(imino)guanidine that includes a ring-containing moiety. Examples of BIGs with ring-containing moiety are provided herein.

[0096] In some implementations, the aqueous medium comprises deionized water.

[0097] In some implementations, the iminoguanidine freebase synthesis method discussed above (i.e., based on an aminoguanidine freebase) is performed in the presence of a catalyst. In such implementations, the aqueous medium may include a catalyst that accelerates the reaction between the aminoguanidine freebase with the multi-carbonyl compound. Examples of a catalyst include but are not limited to, a hydrohalic acid (e.g., hydrochloric acid) and acetic acid.

[0098] In some implementations, the iminoguanidine freebase or iminoguanidine salt is only sparingly soluble in the aqueous medium, thereby being referred to as a solid.

[0099] In some implementations, once formed, the iminoguanidine freebase solid or iminoguanidine salt solid is washed to remove any unreacted aminoguanidine compound.

[0100] In some implementations, once formed, the iminoguanidine freebase solid or iminoguanidine salt solid is purified, removing one or more impurities that are soluble in the aqueous medium, which may have been present with the reactant aminoguanidine compound. In some implementations, purification of the iminoguanidine freebase solid or iminoguanidme salt solid may include at least one of recrystallization in or washing with an aqueous medium to achieve a purity of at least 99.5% as measured with a HPLC system including a UV detector operating at a maximum absorbance wavelengthof the iminoguanidine freebase or iminoguanidine salt. For example, the aqueous medium can be water or a mixture comprising water and a water-miscible organic solvent being more volatile than water, such as methanol, ethanol, isopropyl alcohol (IP A) and analogs thereof. In some implementations, washing the iminoguanidine freebase solid or iminoguanidine salt solid removes any impurities and any unreacted aminoguanidine compound.

[0101] In some implementations, there is provided a method for prepanng an iminoguanidine freebase including the following operations / steps. First, an aminoguanidine compound is contacted with a multi-carbonyl compound in an aqueous medium, where the multi-carbonyl compound is insoluble, i.e., at most sparingly soluble, in the aqueous medium. Second, the aminoguanidine compound is allowed to react with the multi-carbonyl compound in the aqueous medium to produce a mono(imino)guanidine compound, where the mono(imino)guanidine compound is substantially soluble in the aqueous medium. Third, the mono(imino)guanidine compound is allowed to react with the aminoguanidine compound in the aqueous medium and produce a bis(imino)guanidine compound, where the bis(imino)guanidine compound is insoluble, i.e. at most sparingly soluble in the aqueous medium. In some implementations, the bis(imino)guanidine compound is a bis(imino)guanidine freebase. Lastly, the resulting bis(imino)guanidine compound is washed or otherwise purified to remove one or more impurities that are soluble in the aqueous medium and were present with the aminoguanidine compound.

[0102] In some implementations, the progress of the reaction (e.g., the production of monoiminoguanidine compound and / or the bis(imino)guanidine compound) is monitored by the presence of solids in the aqueous medium.

[0103] While much of the disclosure herein focuses on iminoguanidines, it should be understood that it extends to related imines formed by condensation reactions involving carbonyl-containing precursors. For example, the syntheses described herein can be extendedto iminoamidines and di-iminoguanidium compounds. See e.g., US Patent 11,001,554, issued May 11, 2021, which is incorporated herein by reference in its entirety.Bis (imino) guanidines Compounds

[0104] An iminoguanidine refers herein to an iminoguanidine compound that can be in neutral form (freebase) or in salt form.

[0105] In some implementations, the iminoguanidine may be a bis(imino)guanidine compound represented by the following formula (I).Formula (I)

[0106] The bis(imino)guanidine compound includes a central moiety (A) attached to two iminoguanidine or iminoguanidinium groups. Although formula (I) depicts a specific tautomeric arrangement, formula (I) is intended to include any other tautomer that can be derived from or mterconvert with the tautomer shown in formula (I). Formula (I) is also intended to include any regioisomers that may differ in the connection points of the two aminoguanidine or aminoguanidinium groups on the central moiety (A). In the event the structure according to formula (I) possesses one or more stereocenters, formula (I) is intended to include all resulting stereoisomers. The stereoisomer may include one or more enantiomers and / or diastereomers. Although formula (I) depicts a neutral molecule (freebase), iminoguanidines of the present disclosure are intended to also encompass salt forms of the formula (I), for example, as depicted by formula (II).

[0107] In some implementations, iminoguanidine salt may be a bis(imino)guanidine salt represented by the formula (II).Formula (II)

[0108] The salt forms may correspond to those that can be produced by the reaction of the neutral form of formula (I) with a mineral acid or alkyl halide, which results in protonation or alkylation of one or more of the shown amine or imine groups. Similarly to formula (I), formula (II) is intended to include all possible tautomers, regioisomers, and stereoisomers. Accordingly, the positive charge shown in formula (II) may be located on any of the other nitrogen atoms through tautomerization. As well as known in the case of tautomers, the positive charge is generally distributed among all atoms capable of holding a positive charge in the various tautomers. Likewise, a partial double bond character is generally present among all the bonds capable of engaging in double bonds in the various tautomers.

[0109] In formula (II), Xm' is an anionic species with a magnitude of charge m, where m is an integer of at least 1, and n is an integer of at least 1, provided that n x m=2. The anionic species may be any anionic species that, when complexed as a salt with the bis- aminoguanidinium portion shown in formula (II), can be exchanged for another anionic species desired to be removed from an aqueous solution. As the different anionic species have different dissociation constants, any anionic species may be useful in exchanging with another anionic species to be removed from an aqueous source. The anionic species may also represent a species that has been removed from an aqueous solution wherein the resulting salt of the removed anion and bis-aminoguanidinium portion shown in Formula (II) is valuable as a precursor for producing a neutral form of formula (II) or by exchanging with another anionic species that can be used to exchange with and remove another anionic species of interest. The anionic species (X”1') can be, for example, a halide, such as fluoride, chloride, bromide, or iodide. The anionic species can alternatively be a halide equivalent (or pseudohalide), such as methanesulfonate (mesylate), trifluoromethanesulfonate (triflate), tosylate, cyanate, thiocyanate, cyanide, or a sulfonamide anion, such as bis(trifhioromethane)sulfonamide (i.e., bistriflimide). The anionic species may alternatively be a borate anion, such as tetrafluoroborate, tetrakis(pentafluorophenyl)borate, or tetrakis[3,5- bis(trifluoromethyl)phenyl]borate. The anionic species may alternatively behexafluorophosphate (PFe ’ ). The anionic species may alternatively be hydroxide, or an alkoxide (e.g., methoxide or ethoxide). The anionic species may alternatively be a carboxylate species, such as formate, acetate, propionate, or glycolate. In other implementations, the anionic species (Xm_) can be an oxyanion. As used herein, the term “oxyanion” refers to an anion having at least three or four oxygen atoms, wherein the oxygen atoms are generally all n bound to a central element. Some examples of oxyanions include sulfate (e.g., SO4 ), nitrate (NO3 ’ ), chromate (e.g., CrO42" ), selenate (e.g., SeCL2" ), phosphate (e.g., PO43" ), arsenate (ASO43“ ), carbonate (CO32" ), bicarbonate (HCO3 ’ ), and perchlorate (CIO4 ’ ). The oxy anions provided above may or may not also include related derivatives. For example, unless otherwise stated, the term “sulfate” may also include thiosulfate (S2O32" ), bisulfate (HSO4 ’ ), and sulfite (SO32“ ). Similarly, the term “chromate” may also include CPO?2" (dichromate). Similarly, the term “phosphate” may also include hydrogenphosphate (HPO42“ ), dihydrogenphosphate (H2PO4 ’ ), pyrophosphate (P2O74" ), thiosphosphates (e.g., PO3S3 ’ or PO2S23“ ), and phosphite (e.g., PO33“ , HPO32" , or H2PO3 ’ ). The oxyanion may also be selected from among less common species, such as tungstate, vanadate, molybdate, tellurate, and stannate.

[0110] When Xm' is a carbonate or bicarbonate anion, m may be 1 for bicarbonate and 2 for carbonate, n is 0.5, 1, or 2. loin] Structures of formulae (I) and (II), include structures having one or more of the hydrogen atoms, whether the hydrogen atoms are shown or not shown in the formula, being replaced with one or more alkyl groups (e.g., Ci-Ce alkyl groups such as methyl groups) or other substituents, respectively. For example, one or both of the terminal carbon atoms in the imino groups linked to the central moiety (A) in formulae (I) and (II) may be bonded to an alkyl group (e.g., a Ci-Ce alkyl group such as a methyl group) or other substituent that is not part of the linkage with A. Examples include methyglyoxyl bis(imino)guanidine and diacetyl bis(imino)guanidine.

[0112] Referring to both formulae (I) and (II), central moiety (A) may be a single bond, or it may be a linear or branched hydrocarbon (e.g., a Ci-Ce alkyl, alkenyl, or alkynyl group), optionally substituted with alcohol, amine, and / or include one or more heteroatoms.

[0113] Refernng to both formulae (I) and (II), central moiety (A) may be a single bond, a linear or branched hydrocarbon, and / or a ring containing moiety. The ring-containing moiety(A) is or includes any cyclic group that includes at least one, two, three, or four carbon atoms. Since the cyclic group is attached to two iminoguanidine or iminoguanidinium groups, the cyclic group in the ring-contammg moiety (A) necessarily includes two sites engaged in bonds, either directly, or indirectly via a linker, to the iminoguanidine or iminoguanidinium groups. Typically, the two sites in the ring (A) linked, directly or indirectly, to the iminoguanidine or iminoguanidinium groups are ring carbon atoms. In some implementations, the ring-containing moiety is or includes a monocyclic ring, i.e., a single ring not bound or fused to another ring. In other implementations, the ring-containing moiety is or includes a ring system, wherein the term “ring system” refers to apolycyclic moiety (e.g., abicyclic or tricyclic moiety). The cyclic group can be polycyclic by either possessing a bond between at least two rings or a shared (i.e., fused) bond between at least two rings. The one or more rings in the ring-containing moiety is typically a five-membered, six-membered, or seven-membered ring.

[0114] In one set of implementations, the central moiety (A) is or includes a carbocyclic ring or ring system. The term “carbocyclic” indicates that the ring or ring system contains only carbon atoms. The carbocyclic ring or ring system can be saturated or unsaturated. Some examples of carbocyclic rings that are monocyclic and saturated include cyclopentyl, cyclohexyl, and cycloheptyl rings. Some examples of carbocyclic rings that are monocyclic and unsaturated (which may be aliphatic or aromatic) include cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and phenylene (benzene) rings. Some examples of carbocyclic rings that are polycyclic and saturated include decalin, norbomane, bi cyclohexane, and 1,2-di cyclohexylethane ring systems. Some examples of carbocyclic rings that are polycyclic and unsaturated include naphthalene, anthracene, phenanthrene, phenal ene, and indene ring systems.

[0115] In another set of implementations, the central moiety (A) is or includes a heterocyclic ring or ring system. The term “heterocyclic” indicates that the ring or ring system contains at least one ring heteroatom. As examples, the ring heteroatom may be selected from nitrogen, oxygen, and sulfur. The heterocyclic ring or ring system can be saturated or unsaturated. Some examples of heterocyclic saturated rings or ring systems include those containing at least one ring nitrogen atom (e.g., pyrrolidine, piperidine, piperazine, imidazolidine, azepane, and decahydroquinoline rings); those containing at least one ring oxygen atom (e.g., oxetane, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, and 1,3-dioxepane rings); those containing at least one ring sulfur atom (e.g., tetrahydrothiophene, tetrahydrothiopyran, 1,4- dithiane, 1,3-dithiane, and 1,3-dithiolane rings); those containing at least one ring oxygen atomand at least one ring nitrogen atom (e.g., morpholine and oxazolidine rings); and those containing at least one ring nitrogen atom and at least one nng sulfur atom (e.g., thiazolidine and thiamorpholine rings). Some examples of heterocyclic unsaturated rings or ring systems include those containing at least one ring nitrogen atom (e.g., pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, 1,3,5-triazine, azepine, diazepine, indole, purine, benzimidazole, indazole, 2,2'-bipyridine, quinoline, isoquinoline, phenanthroline, 1, 4,5,6- tetrahydropyrimidine, 1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydroquinoline, quinoxaline, quinazoline, pyridazine, cinnoline, and 1,8-naphthyridine rings); those containing at least one ring oxygen atom (e.g., furan, pyran, 1,4-dioxin, benzofuran, dibenzofuran, and dibenzodioxin); those containing at least one ring sulfur atom (e.g., thiophene, thianaphthene, benzothiophene, thiochroman, and thiochromene rings); those containing at least one ring oxygen atom and at least one ring nitrogen atom (e.g., oxazole, isoxazole, benzoxazole, benzisoxazole, oxazoline, 1,2,5-oxadiazole (furazan), and 1,3,4-oxadiazole rings); and those containing at least one ring nitrogen atom and at least one ring sulfur atom (e g., thiazole, isothiazole, benzothiazole, benzoisothiazole, thiazoline, and 1,3,4-thiadiazole rings).

[0116] Some examples of compounds according to formula (I) include the following.

[0117] Some examples of compounds according to Formula (II) include the following.

[0118] Any of the above exemplary compounds may also be converted to the respective neutral analogue according to Formula (I) by removal of the two protons located on positivelycharged amine groups. Moreover, in any of the above exemplary formulas, a hydrogen atom on a ring nitrogen atom may be replaced with a hydrocarbon group, such as a methyl, ethyl, n- propyl, isopropyl, in-butyl, isobutyl, sec-butyl, t-butyl, phenyl, or benzyl group. As also provided above, any one or more of the hydrogen atoms in any of the above exemplary structures, whether the hydrogen atoms are shown or not shown, may be replaced with one or more alkyl groups (e.g., methyl or other Ci-Ce alkyd groups), respectively.Tris(imino)guanidines

[0119] In some implementations, the iminoguanidine is a tris(imino)guanidine (TRIG). For example, the TRIG can be 1,3,5-benzene tris(imino)guanidine and 1,3,5-triacetylbenzene tris(imino)guanidine.Multi-carbonyl compound

[0120] The present disclosure includes the multi-carbonyl precursors required to synthesize each of the BIG structures, TRIG structures, and other iminoguanidine structures described herein. The multi-carbonyl precursors include multi-aldehydes, multi-ketones, aldehydes, ketones and any mixtures thereof. For example, the multi-carbonyl precursor can be a dicarbonyl precursor.

[0121] Examples of dicarbonyl precursors include: 2,6-pyridine dialdehyde, 2,6- diacetylpyridine, 1,3-diacetylbenzene; 1,3-diacetylpyndine, 1,3 -indanedi one. 1,4- diacetylbenzene, 1,2-diacetylbenzene, 2,3-butadione, 2,3-pentadione, 2,5-hexanedione, and 2,5-dicarboxaldehyde furan.Aqueous Synthesis Conditions

[0122] As indicated herein, aspects of this disclosure pertain to aqueous synthesis of iminoguanidines, such as bis(imino)guanidines (BIGs). Disclosed methods for synthesizing the BIGs can include application of the following synthesis conditions in an aqueous medium.

[0123] Regarding the pre-reaction handling of the dicarbonyl compound and the aminoguanidine compound precursors, in general, preprocessing in aqueous and non-aqueous media may be similar. For example, impurities in the aminoguanidine HC1 salt are generally soluble in an aqueous medium, which can simplify downstream separation and may permit working with less pure starting materials.

[0124] In certain implementations, a synthetic pathway includes pre-purification of the aminoguanidine HC1 salt (e.g., via washing with water or via recrystallization in hot water orin a mixture of hot water and a water-miscible organic solvent). In certain implementations, a synthetic pathway includes pre-punfication of the dicarbonyl compound.

[0125] It should be understood that combining and reacting BIG precursors (dicarbonyl and aminoguanidine compounds) in an aqueous reaction medium may introduce challenges. For example, dicarbonyl compounds are not necessarily fully or even moderately miscible with water or soluble in an aqueous medium. Thus, the starting mixtures may be heterogeneous. However, the inventors have found that the BIG synthesis reaction is thermodynamically favorable that even dicarbonyl compounds of limited solubility can be quickly consumed as they dissolve.

[0126] The aqueous reaction media (e.g., water) can, in some implementations, allow additional control of reaction conditions as the BIG synthesis runs to completion. As mentioned, the BIG synthesis pathway sometimes produces an intermediate being soluble in aqueous medium, such as a mono(imino)guanidine. This facilitates tracking the extent of reaction. The reaction may also be tracked with standard techniques such as a chromatography technique (e.g., TLC or HPLC), as exemplified below. Further, progressing through a soluble mono(imino)guanidine intermediate may also facilitate the synthesis of unsymmetrical (imino)guanidine compounds.

[0127] FIG. 2 includes chromatographs obtained by hydrophilic interaction liquid chromatography (HPLC in HILIC mode) and that can be used to follow the condensation reaction between 1,3-diacetylbenzene (DAB) and aminoguanidine hydrochloride. For example, the following experimental set up can be used to that effect:Chromatography system: Thermo Scientific UltiMate3000, UV / Vis @ 254nmColumn: Ascentis Express 90A (2.7pm) HILIC, 150mm x 3mmMobile phases: A = 90% acetonitrile + 10% water, 10 mM ammonium acetateB = 100% water, lOmM ammonium acetateFlow / Elution: Isocratic @ 0.5 mL / min, 65% A, 35% B.

[0128] Referring to FIG. 2, the top chromatogram shows the starting material, DAB at a retention time (RT) of about 1.3 min. As shown in the middle chromatogram, after addition of one equivalent of aminoguanidine hydrochloride, the starting material DAB has nearly been depleted and the first product, the monoadduct (RT ~2 min), and a small amount of the ultimate product, DAB-BIG, have been formed (RT ~4.9 mm). The ultimate product, DAB-BIG, is shown at the bottom chromatograph. The aminoguanidine compound is not shown in thechromatograms of FIG. 2. Detection of such aminoguanidine compound can be performed using the following techniques: UV / Vis and Charged Aerosol detectors.

[0129] Using an aqueous medium, a BIG freebase synthesis can directly convert a BIG salt (intermediate) to a BIG freebase, e.g., without first isolating the BIG salt. Such direct conversion may be accomplished in various ways.

[0130] In some implementations, the method of making a BIG freebase in an aqueous medium includes mixing the reaction product of the dicarbonyl and aminoguanidine salt with an aqueous medium-soluble carbonate (e.g., sodium carbonate). The mixture may form a slurry with the carbonate. For example, the process may react sodium carbonate with the just synthesized BIG-HC1 salt (first salt) to produce a second salt being a BIG-CO3 salt. This may be implemented as a slurry-to-slurry conversion. In some implementations, the method includes thermally decomposing the resulting BIG-CO3 to generate the BIG freebase in a high yield. In some optional implementations, any resulting impurities may be washed out.

[0131] In some other implementations, the method of making a BIG freebase in an aqueous medium includes mixing the reaction product of the dicarbonyl and aminoguanidine salt with a hydroxide, such as an inorganic hydroxide (e.g., NaOH, KOH, or LiOH) to directly neutralize the BIG salt into a BIG freebase within the aqueous medium. In some implementations, the method can be carried out as a one pot process in which a single apparatus and / or reaction medium is employed to both synthesize a BIG salt (e.g., a BIG HC1) and convert the salt to a BIG freebase in-situ.

[0132] Using an aqueous medium, a BIG freebase synthesis can also convert a BIG salt (intermediate) to a BIG freebase by first isolating the BIG salt. In some implementations, the method of making a BIG freebase in an aqueous medium includes isolating the reaction product (e.g., a BIG HC1 salt) of the dicarbonyl and aminoguanidine salt via precipitation or other process and then converting the isolated salt to a freebase.

[0133] There are various advantages to using an aqueous medium as a synthesis medium.

[0134] For example, downstream purification of BIG freebase may be simplified. In some examples, the intermediate (a mono-condensation product) is soluble, whereas the BIG-HC1 salt is insoluble, i. e. , at most sparingly soluble. This facilitates the purification of the desired product via filtration. This is not possible with organic solvents, as both the intermediate and final product are much less soluble in organic solvents. Further, using an aqueous mediumallows the process to employ a less pure starting aminoguanidine HC1 or other salt. Many impurities are soluble in an aqueous medium.

[0135] Relatedly, there can be certain challenges introduced by using an aqueous medium such as water as a solvent. One potential challenge occurs because some dicarbonyl precursors are only sparingly soluble, with such low solubilities that one might assume that no reaction meaningfully proceeds (or proceeds too slowly) in an aqueous solvent (due to inaccessibility of the precursor). However, the inventors have observed that reactions from starting materials that are only sparingly soluble (e.g., in some cases, at the level of about 5mg / 10mL) may still proceed. The thermodynamic favorability of the reaction can alleviate the concerns about low precursor solubility. The inventors have observed that the use of water as a solvent in an aqueous medium was ideal for a condensation reaction and did not lead to the reversibility of the reaction.

[0136] The aqueous syntheses disclosed herein use an aqueous medium may allow for, or facilitate, synthesis of BIG salts on an industrial scale. For example, method implementations described herein can directly produce an insoluble BIG salt in one step, as they avoid the need to convert a BIG-acid salt (e.g., BIG-HC1) to a BIG-oxyanion (e.g., SO4, CO3, orNOs) salt. In some implementations, the insoluble BIG salt is a BIG-HC1 salt. Examples of an insoluble BIG salts include diacetyl BIG (DABIG HC1), pyridine BIG (PyBIG HC1), diacetylbenzene BIG (DAB BIG HC1), diacet lpyridine BIG (DAP BIG HC1), m-benzene BIG (m-BBIG HC1). Acid salts of iminoguanidine of the present disclosure include, but not are limited to, a hydrochloric acid, a hydrobromic acid, a hydroiodic acid, a sulfuric acid, a nitric acid, a boric acid, an acetic acid, a phosphoric acid, a formic acid, a benzoic acid, a citric acid, a tartaric acid, an oxalic acid, a fumaric acid, a malonic acid, a succinic acid, a lactic acid of an iminoguanidine and analogs thereof as further defined, for example, by formula II of the present disclosure. Furthermore, method implementations described herein can also include directly producing a BIG freebase, e.g., without producing a prior BIG-HC1 salt (either intermediate or final compound).

[0137] In some implementations, non-HCl aminoguanidinium salts are used as precursors of the condensation reaction. In some implementations, the non-HCl aminoguanidinium salts may include, for example, aminoguanidinium carbonate, aminoguanidinium bicarbonate, aminoguanidinium sulfate or any combinations thereof.

[0138] In some implementations, an aminoguanidine freebase is used as a precursor of the condensation reaction. For example, the method can include producing the aminoguanidinefreebase precursor using aminoguanidine-HCl or other acid salt by neutralizing the aminoguanidine acid salt into the aminoguanidine freebase, e.g., by the addition of a base such as NaOH or by contact with an ion exchange material. Soon after production, such aminoguanidine freebase is contacted with a dicarbonyl compound to directly form a BIG freebase (i.e., without producing a prior BIG-HC1 salt).

[0139] Method implementations descnbed herein can also include producing a bis(imino) compound using a non-aminoguanidine precursor (i.e., a compound other than aminoguanidine) including, but not being limited to, e g., amino amidine, a substituted amino amidine, a substituted aminoguanidine or any combinations thereof. For example, the bis(imino) compound can be produced from aminoguanidine derivatives, such as alkyl or aryl substituted aminoguanidines.

[0140] In some implementations, the bis(imino)guanidine synthesized in the aqueous medium is methylglyoxal bis(imino)guanidine (MGBIG), benzene bis(imino)guanidine (BBIG), diacetyl benzene bis(imino)guanidine (DAB BIG), diacetyl-bis(imino)guanidine, diacetyl pyridine bis(imino)guanidine (DAP BIG), pyridine bis(imino)guanidine (PyBIG), glyoxyl bis(imino)guanidine (GBIG), furan bis(imino)guanidine (FU BIG), 1,3 -indanedi one bis(imino)guanidine (indane BIG), or 1,3-benzenedialdehyde bis(iminoguanidine) (BDA BIG).

[0141] Although certain implementations and advantages are discussed in relation to the synthesis of abis(imino)guanidine (BIG) using a di carbonyl compound, such implementations and advantages can apply, mutatis mutandis, to the synthesis of an unsymmetric imino compound in an aqueous medium. As an example, a multi-carbonyl precursor may separately react with two or more different nitrogen-containing reactants (e.g., at least one being an aminoguanidine). Thus, a central portion of the synthesized molecule derives from a multicarbonyl precursor. The different carbonyl groups on the multi-carbonyl precursor react, via a condensation reaction, with the nitrogen atoms of the nitrogen-containing reactants.Reaction Conditions

[0142] The reaction conditions of the BIG synthesis condensation reactions can vary. Some example parameters for the BIG synthesis in aqueous medium are presented below.

[0143] Solubility: Most reactants have some level of water solubility, and only a small level of solubility is required for the aqueous synthesis to proceed. For example, dicarbonyl precursors having a solubility of about 5mg / 10mL of water or greater may be adequate.

[0144] Temperature range: A reaction temperature may be from about 20°C to just below the boiling point of water (100°C). At high temperature in water, some level of hydrolysis may occur, during cooling recondensation. In some implementations, temperature may be from about 20°C to 70°C. In some implementations, temperature may be from about 20°C to 50°C.

[0145] Medium / solvent composition: In some implementations, the aqueous medium can consist of water. In some implementations, the aqueous medium comprises water. In some implementation, in addition to water, the aqueous medium can include water and another solvent or medium component. For example, the medium component can be a catalyst being added to the water in a small amount, particularly for aqueous medium of aromatic multicarbonyl precursors. The catalyst provides non-precipitating anions and may for example be an acid, which may be either organic or inorganic. Examples include a hydrohalic acid (e.g., HC1) or acetic acid. In some cases, an acid catalyst may be introduced with the aminoguanidinium salt (aminoguanidine HC1, for example).

[0146] “ One pot” synthesis: In some implementations, the method can include using the same apparatus to produce a BIG salt and then convert the BIG salt into a BIG freebase. Direct neutralization is possible in an aqueous synthesis (e.g., without isolating the BIG salt), which would not be readily possible in an alcoholic solvent. For example, BIG freebase can be synthesized in two steps, first with addition of 2 eq aminoguanidinium HC1 to a dicarbonyl precursor, and then with the addition of 2 eq NaOH or similar base in the same apparatus.

[0147] The reactional pathway can include formation of the monoadduct from the precursors, formation of the diadduct salt (e.g., diadduct-HCl salt) from the monoadduct, and then optional neutralization of the diadduct salt into a diadduct freebase.

[0148] In some implementations, the method can be implemented as an industrial scale process that may employ a batch or semi-batch reactor to produce the iminoguanidine (salt or freebase). In some implementations, the method can be implemented as an industrial scale process that may employ a continuous stir tank reactor (CSTR) or other continuous reactor to produce the iminoguanidine (salt or freebase) as a slurry. Optionally, the continuous reactor can be followed by a subsequent filtration unit operated either batchwise or continuously to recover the iminoguanidine (salt or freebase) from the slurry.

[0149] In some implementations, the process includes controlling a solids content of the slurry of iminoguanidine salt or freebase. For example, the process can include thickening the produced slurry during a highly intensified synthesis by exotherm control, optionally viainternal (direct) or external (indirect) cooling. Additionally or alternatively, the process can include gradually adding the precursors to control exotherm.Purification

[0150] In some implementations, the method can include punfication of at least one of the reactants and the produced iminoguanidine. Purification can include at least one of recrystallization in or washing with an aqueous purification medium to achieve a purity of at least 99.5% as measured with aHPLC system including a UV detector operating at a maximum absorbance wavelength / .n,ax of the compound to be detected for a given temperature. For example, the aqueous purification medium can be water or a mixture comprising water and a water-miscible organic solvent being more volatile than water, such as methanol, ethanol, isopropyl alcohol (IP A) and analogs thereof. For example, the aminoguanidine-HCl salt can be purified, before contacting the dicarbonyl precursor, by recrystallization in hot water. Purification can include other techniques. For example, the dicarbonyl precursor can be purified, before being contacted with the aminoguanidine-HCl salt, by distillation.Carbon dioxide capture process and system

[0151] In example implementations, the carbon dioxide capture system of the present disclosure, such as the DAC system 1, employs an iminoguanidine synthesized according to the methods described herein, as a complexing agent to capture large quantities of carbon dioxide.

[0152] Referring to FIG. 1, the sorbent solution 6 contacts the dilute gas source 2 in the at least one gas-liquid contactor 10 of the gas-liquid contactor subsystem 3 to form the carbon- loaded sorbent solution 8 comprising captured carbon dioxide in any of various forms such as carbonate ions, bicarbonate ions and / or carbonates. The carbon-loaded sorbent solution 8 can be referred to as a CCh-rich capture solution or a carbonate-rich capture solution. The composition of the carbon-loaded sorbent solution 8 can vary in accordance with several factors including the nature of the sorbent and the operational absorption conditions. Upon absorption of the CO2 from the dilute gas source 2 by the sorbent solution 6 in the gas-liquid contactor 10, the dilute gas source 2 becomes depleted in CO2 and is flowed out of the gas-liquid contactor 10 as the C Ch-lean gas stream 4. The CCh-lean gas stream 4 can contain compounds of the sorbent solution 6, and possibly also compounds of the carbon-loaded sorbent solution 8. The compounds of the sorbent solution 6 and possibly also of the carbon-loaded sorbent solution 8can be in liquid and / or vapor phase and can be present in the flow of the CCh-lean gas stream 4.

[0153] The gas-liquid contactor 10 may be of any suitable format. The sorbent solution 6 may be distributed on contacting surfaces, such as surfaces of a packing material, as uniformly as possible, e.g., in the form of a thin film liquid. The gas-liquid contactor 10 may exhibit a low pressure drop and efficient mass transfer. FIG. 1 is not to be interpreted as limiting the present disclosure to a cross-flow configuration contactor and encompasses any gas-liquid contactor 10 configurations where the sorbent solution 6 contacts a carbon dioxide containing feedstock, such as the dilute gas source 2. Reference is also made to carbon capture systems and gas-liquid contactor subsystems described in U.S. Patent No. 9,095,813, U.S. Patent No. 10,421,039, U.S. Patent No. 12,239,936, U.S. Patent Application No. 18 / 865,777, U.S. Patent Application No. 17 / 558,321, U.S. Patent No. 12,214,311, U.S. Patent Application No. 17 / 742,334, U.S. Patent Application No. 18 / 691,780, U.S. Patent Application No. 18 / 717,768, PCT Patent Application No. PCT / US2024 / 039378, PCT Patent Application No. PCT / US2024 / 060124, PCT Patent Application No. PCT / US2025 / 034032, PCT Patent Application No. PCT / US2025 / 031782, PCT Patent Application No. PCT / US2025 / 025246, PCT Patent Application No. PCT / US2025 / 042410, PCT Patent Application No. PCT / US2025 / 042381 and U.S. Provisional Patent Application No. 63 / 706,421, the entire contents of which are incorporated herein by reference.

[0154] In some implementations, and referring to FIG. 1, the process further includes processing the carbon-loaded sorbent solution 8 to recover the captured CO2 and to regenerate the sorbent to be reused in the sorbent solution 6 during a regeneration stage of the carbon dioxide capture system 1. For example, once the aqueous sorbent solution 6 is sufficiently loaded with CO2, in any of various forms (as CCh-derived species), the carbon-loaded sorbent solution 8 is pumped into a solids formation subsystem 12, e.g., comprising a crystallizer, to which the complexing agent 14 (e.g., a bis(imino)guanidine free base) is added, optionally in the form of crystals. The complexing agent 14 reacts with the carbon dioxide-derived species of the carbon-loaded sorbent solution 8 and forms a precipitate being a salt (e.g., carbonate and / or bicarbonate salt) with lower solubility than that of the (uncomplexed) complexing agent. The salt solids (e.g., a carbonate and / or bicarbonate salt) precipitate (e.g., crystallize) out of the carbon-loaded sorbent solution 8, thereby unloading the carbon dioxide content from the carbon-loaded sorbent solution 8 and forming a slurry 16 comprising the salt solids in theunloaded sorbent solution. The salt solids of the slurry 16 can be referred to as a CO2- complexed material.

[0155] In some implementations, and referring to FIG. 1, the DAC system 1 includes componentry for separating the slurry 16. For example, the DAC system 1 includes a solidliquid separation subsystem 18, e.g., comprising a filtration unit, to recover a solid material 20 comprising the salt solids (e.g., carbonate and / or bicarbonate salt) from the slurry 16, and the unloaded sorbent solution 22. The unloaded sorbent solution 22 comprises the sorbent being regenerated into its active form. In some implementations, the water content of the unloaded sorbent solution 22 can be reduced using an evaporator unit 30 to produce a regenerated sorbent solution 32 that may be redirected to form the aqueous sorbent solution 6 being flowed to the gas-liquid contactor 10 for reuse in capturing CO2 from air or other dilute gas source.

[0156] Referring to the example implementation of FIG. 1, the separated solid material 20 (e.g., carbonate material) is further treated in a CO2 recovery subsystem 24 to release gaseous carbon dioxide and regenerate the uncomplexed complexing agent 26 (e.g., solid BIG free base). Various techniques may be employed to release the carbon dioxide from the solid material 20 in the CO2 recovery subsystem 24. For example, the process can include heating the solid material 20 to about 40-160°C, e.g., between 80°C and 60°C, to release CO2 as part of the CO2 product stream 28 and to thermally regenerate the complexing agent for reuse in further carbon unloading cycles.

[0157] In some implementations, the CO2 capture process, such as that of the DAC system 1, is a continuous process. For example, the DAC system 1 may employ a continuous flow airliquid contactor as the gas-liquid contactor 10 and may continuously operate filtration of solid CO2-complexed material as the solid material 20 in the solid-liquid separation subsystem 18. For example, the DAC system 1 can comprise reusing at least one of the unloaded sorbent solution 22 (e.g., including an amino acid) and a regenerated CO2 complexing compound 26 (e.g., a guanidine derivative). For example, the DAC system 1 can comprise reusing both the unloaded sorbent solution 22 (e.g., including an amino acid) and the regenerated CO2 complexing compound 26 (e.g., a guanidine derivative).

[0158] In some implementations, because CO2 is recovered from the solid material 20 (e.g., complexed carbonate / bicarbonate forming a BIG carbonate material), the CO2 recovery stage / step in the CO2 recovery subsystem 24 may operate on a relatively small quantity (mass and volume) of solid material 20. This batch operation can minimize the consumption of energybecause, to the extent the carbon dioxide is present in a very high concentration in a low-mass vehicle, i.e. solid material 20 such as a BIG carbonate, energy is not wasted heating liquid that does not contain appreciable quantities of CO2.

[0159] Contrary to known processes involving high-temperature treatment of a carbon- loaded sorbent solution to release the CO2 therefrom, which sometimes degrades the sorbent (e.g., amine) by oxidation or thermal degradation, some implementations of the DAC system 1 of the present disclosure include a low-temperature CO2 release / recovery stage, which may be enabled by employing a guanidine derivative as the complexing agent.

[0160] FIG. 3 illustrates example operations in a method 300 for synthesizing BIGs. As shown, method 300 begins with operation 301 where aminoguanidine compound is reacted with a multi-carbonyl compound in an aqueous medium to produce an iminoguanidine salt. Following operation 301, operation 305 may be performed, where the iminoguanidine salt is converted into an iminoguanidine freebase. Optionally, operation 309 may be performed, where the iminoguanidine freebase may be purified.

[0161] In other implementations, a method 400 may be used to synthesize BIGs. As shown in FIG. 4, method 400 may begin with operation 401, where aminoguanidine compound is reacted with a multi-carbonyl compound in an aqueous medium to produce a first iminoguanidine salt. In operation 405, the first iminoguanidine salt is converted to an iminoguanidine carbonate and / or an iminoguanidine bicarbonate. In some implementations, optional operation 409 may be performed, where the iminoguanidine carbonate and / or the iminoguanidine bicarbonate is thermally decomposed to generate an iminoguanidine freebase.

[0162] In other implementations, a method 500 may be used to synthesize BIGs. As shown in FIG. 5, operation 503 may be performed where the aminoguanidine freebase is reacted with a multi-carbonyl compound in an aqueous medium to produce an iminoguanidine freebase. In some implementations, one or more of optional operations 501 and / or 507 may be performed. The optional operation 501 may be performed prior to operation 503, where the aminoguanidine freebase is first prepared. In some implementations, optional operation 507 may be performed where the iminoguanidine freebase is purified.

[0163] In other implementations, method 600 may be used to synthesize BIGs. As shown in FIG. 6, the method 600 may begin with operation 601, where an aminoguamdine compound is contacted with a multi-carbonyl compound in an aqueous medium to produce a mono(imino)guanidine compound. In operation 603, the mono(imino)guanidine compound isreacted with the aminoguanidine compound to produce bis(imino)guanidine compound. In some implementations, operation 607 may be performed, where the bis(imino)guanidme compound is purified iminoguanidine. Implementations of pertinent DAC process may be found in U.S. Patent No. 10,633,332, issued April 28, 2021, which is incorporated herein by reference in its entirety.EXPERIMENTAL RESULTS AND EXAMPLESExample 1: Aqueous synthesis of DA BIG

[0164] 175. 1 g of AG-HC1 (1.58 moles) and 600 mL of DI water were charged to a 2000 mL beaker. Dissolution of AG-HC1 is endothermic, so a slight heat was applied with a hotplate while stirring the mixture mechanically to keep the temperature close to ambient. Discontinued heating was performed after solids had dissolved. Addition of 63.1 g (0.73 moles) of diacetyl was begun when all solids dissolved. The solution was held at a temperature between about 20°C and about 25°C. Because the reaction is quite exothermic, an addition rate of the diacetyl was adjusted to allow the batch temperature to rise to no higher than about 65°C. The product began to precipitate within 5 minutes after start of diacetyl addition. At no time during the reaction was external heating required.

[0165] When addition of the diacetyl was complete, continued stirring was performed while the batch cooled to room temperature.

[0166] The product can be isolated by filtration, if desired. However, advantageously, neutralization, can be optionally carried out in the same pot without isolation.

[0167] 500g of formed DABIG-2HC1 (1.84 moles) was added to 2500 mL DI water at room temperature and stirred the slurry with a mechanical stirrer.

[0168] About 300g (3.75 moles) of a 50 wt% NaOH solution was weighted.

[0169] The weighted NaOH was added slowly and carefully, under a blanket of N2, to the slurry of DABIG-2HC1. Shortly after addition had begun, the batch was observed to sti ffen a bit, but continued addition of NaOH caused the slurry to thin out.

[0170] When pH was of at least 13 (about 270g of NaOH solution had been added), NaOH addition was discontinued and stirring was maintained for 15 min. pH again was checked again to ensure that pH was still of at least 13. If pH had drifted down, more NaOH would be added to bring the pH back to at least 13.

[0171] When the pH of at least 13 was steady for at least 15 minutes, the batch was filtered and sucked as dry as possible. Then, the recovered solids were washed to remove excess base and NaCl. The washed solids were filtered and sucked dry again. The pH of this first wash filtrate was about 12.

[0172] The filter cake was washed a second time with 2000 mL of cold DI water. The pH of the final wash filtrate was not above 10. Two washes have been found to be adequate for small lab batches, but much larger batches may require additional washing.

[0173] The final filter cake was tested for chloride. Precipitation of AgCl (with a solubility of 0.002g / L in neutral to acidic water) can reveal very low levels of chloride. A small sample (about 50 mg) of filter cake was dispersed in 1 mL DI water, the pH was brought down to 7 or lower with IN HO Ac until solids had mostly dissolved. The solution can be filtered through a glass wool plug if necessary' (e.g., if the solution is not clear enough). A few drops of aqueous AgNCh was added to the solution which was then well mixed. If all chloride has been removed, one should see no precipitate of AgCl. AgCl is soluble in water at high pH, so unless pH is adjusted down first, one might not see a precipitate even if trace chloride is present. If AgCl precipitates, or if the solution becomes hazy, the wash may be repeated until this test is negative.

[0174] The filter cake was air dried or vacuum dried (at 50°C or lower) to remove the bulk of water from the final product. Any suitable means of monitoring water loss to determine the endpoint can be used. Typical recovery is 83-85%.Example 2: Aqueous Synthesis of DAB-BIG-2HCI

[0175] To a 40 mL vial was charged 3.03g (27.4 mmol) of aminoguanidine-HCl, 15 mL DI water and a magnetic stir bar. Brief stirring gave a clear, colorless solution. To this was added 300 microliters of 3N HC1.

[0176] 1,3-Diacetylbenzene (2.10g, 12.9 mmol) was added to the vial containing the aminoguanidine-HCl solution. Within 3 minutes all solids had dissolved to give a clear, colorless solution. At the 7 minute mark, a white precipitate began to form. After 25 minutes the reaction mixture had become a thick paste and magnetic stirring was no longer possible. Another 15 mL DI water added to thin the paste and the vial was left stirring overnight. The reaction was carried out at 20°C.

[0177] After approximately 18 hours, the contents of the vial were found again to be a thick paste. The paste was transferred to centrifuge tubes with tared baskets and spun down (20 min @ 3500 rpm). The supernatant was decanted and saved.

[0178] The solids in the centrifuge tube were dispersed in 30 mL of ice-cold DI water, then transferred to centrifugal filters (VectraSpin 20, 0.45 micron polypropylene membrane) and spun down (20 min @ 3500 rpm). The filter cake was washed with 35 mL of ice-cold isopropyl alcohol, spun down again and dried. Recovered white solid weighed 4.01g, representing a yield of 89.1 % of theoretical.Example 3: Generalized Example of an Aqueous Synthesis Process

[0179] In a general example, a dicarbonyl precursor is combined with 2 equivalents of aminoguanidinium HC1 in a vessel and allowed to react in an aqueous medium to completion or near completion. The resulting bis(imino)guanidine HC1 forms a suspension or slurry. The reaction may be monitored using HPLC as described herein or a similar technique. Then, in the same vessel, the suspension or slurry is reacted with 2 equivalents NaOH or similar strong base. This produces a bis(imino)guanidine in the vessel. Finally, the bis(imino)guanidine freebase is isolated by solid liquid separation or similar technique.Aqueous Synthesis of DAB-BIG (Industrial)

[0180] In an example, 25,000 moles of aminoguanidine hydrochloride and 2,500 gallons of deionized water are charged into a 6,500 gallon stirred tank reactor equipped with internal cooling coils and stirred at a rate of 300 rpm. 11 ,500 moles of diacetyl are gradually added into the reactor at a rate of around 100 moles per minute, controlling both the rate of addition of diacetyl and the flow of cooling water through the internal cooling coils to maintain the internal reactor temperature below about 65C. Upon completion of the addition of diacetyl to the reactor, the reaction progress is monitored by HPLC. Upon the complete conversion of diacetyl to DABIG-2HC1 and the cooling of the internal reactor temperature to between about 25°C and 30°C, gradual addition of NaOH was performed with a 50 wt% NaOH aqueous solution at a rate of approximately 20 gallons per minute while monitoring the pH of the reaction. The rate of addition is slowed to 10 gallons per minute with the pH reaching about 12, and the addition is stopped when the pH is about 13. The mixture is filtered with a belt filter, and the solids of DABIG freebase are washed with DI water such that substantially no chloride containing salts are present in the solids. The solids of DABIG freebase are air dried.Example 4: Pre-purification of aminoguanidine-HCl

[0181] Aqueous solutions of commercial aminoguanidine-HCl can be slightly colored and hazy. The aqueous solution of aminoguanidine-HCl can be filtered to remove any haze before its use in the synthesis of an iminoguanidine, such as a bis(iminoguanidine). Filtration can remove insoluble foreign solids whose effect can be detrimental to a final performance of iminoguanidine production. Other impurities can be present in commercial aminoguanidine- HCl, typically detectable upon showing a green tint, which can be removed by recrystallization.

[0182] Aminoguanidine-HCl is soluble in aqueous media and only sparingly soluble in other solvents such that pure solvent are generally not useable for its recrystallization. However, the inventors have found herein that mixtures of water with water-miscible organic solvents - isopropyl alcohol, for example - can be effective recrystallization solvents.

[0183] An effective recrystallization solvent comprising, for example, 90 vol% IPA can be made by mixing 1800 mL IPA and 200 mL DI water. At a laboratory scale, 1400 mL of this recrystallization solvent is charged to a 2000 mL Erlenmeyer flask equipped with a large magnetic stir bar. The remaining 600 mL is placed in a refrigerator to be used later to coldrinse a recrystallized product.

[0184] The recrystallization solvent (1400 mL of 90% IPA) is heated to 75°C on a hotplatestirrer. As the solvent is heating up, 180g of crude (commercial) aminoguanidine-HCl was added batch-wise at a rate adapted to avoid interruption of the magnetic stirring. Addition of the recrystallization solvent could be continuous upon using mechanical stirring, and could be started before heating has begun.

[0185] The hazy, sometimes green-colored solution is hot-filtered through hardened Whatman #2 filter paper (a glass frit may be substituted if it has been pre-warmed to prevent premature crystallization). The batch is allowed to cool to room temperature to deposit the bulk of the recrystallized product, then refrigerated at +5°C for at least 4 hours to finish the recrystallization. The recrystallized product is collected by suction filtration and washed twice with the remainder of the recrystallization solvent (cold 90 vol% IPA) under a nitrogen atmosphere, then dried by standard methods. Maintaining a nitrogen atmosphere during crystal collection and until the crystals have warmed to room temperature can prevent some loss of yield because of water condensing on cold aminoguanidine-HCl crystals and partially dissolving them.

[0186] Although the foregoing implementations have been described in some detail for purposes of clarity of understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims. It should be noted that there aremany alternative ways of implementing the methods, processes, systems, and apparatus of the present disclosure. Accordingly, the present implementations are to be considered as illustrative and not restrictive, and the implementations are not to be limited to the details given herein.

Claims

1. CLAIMS1. A method comprising: reacting an aminoguanidine compound with a multi-carbonyl compound in an aqueous medium to produce an iminoguanidine salt; and converting the iminoguanidine salt to an iminoguanidine freebase.

2. The method of claim 1, wherein converting the iminoguanidine salt to the iminoguanidine freebase comprises directly converting the iminoguanidine salt to the iminoguanidine freebase.

3. The method of claim 2, wherein directly converting the iminoguanidine salt to the iminoguanidine freebase comprises performing the conversion in presence of the aqueous medium without isolating the iminoguanidine salt.

4. The method of claim 2 or 3, wherein directly converting the iminoguanidine salt to the iminoguanidine freebase comprises performing the conversion without washing and / or drying the iminoguanidine salt in solid form.

5. The method of any one of claims 2 to 4, wherein directly converting the iminoguanidine salt to the iminoguanidine freebase comprises converting the iminoguanidine salt to the iminoguanidine freebase without generating an intermediate iminoguanidine salt prior to forming the iminoguanidine freebase.

6. The method of any one of claims 2 to 5, wherein directly converting the iminoguanidine salt to the iminoguanidine freebase comprises converting the iminoguanidine salt to the iminoguanidine freebase without generating an iminoguanidine oxyanion salt prior to forming the iminoguanidine freebase.

7. The method of claim 1, comprising isolating the iminoguanidine salt from the aqueous medium and at least one of washing the iminoguanidine salt or drying the iminoguanidine salt in solid form prior to converting the iminoguanidine salt to the iminoguanidine freebase.

8. The method of any one of claims 1 to 7, wherein converting the iminoguanidine salt to an iminoguanidine freebase comprises reacting the iminoguanidine salt with an inorganic base that is soluble in the aqueous medium.

9. The method of claim 8, wherein the inorganic base is an alkali metal hydroxide, an alkaline earth metal hydroxide or a combination thereof.

10. The method of claim 8 or 9, wherein the inorganic base is KOH, NaOH, LiOH or any combinations thereof.

11. The method of any one of claims 1 to 10, wherein the iminoguanidine salt is insoluble in the aqueous medium.

12. The method of any one of claim 1 to 7, wherein converting the iminoguanidine salt to an iminoguanidine freebase compnses converting the iminoguanidine salt to an iminoguanidine carbonate and / or an iminoguanidine bicarbonate, and thermally decomposing the immoguanidine carbonate and / or an iminoguanidine bicarbonate to generate the iminoguanidine freebase.

13. The method of any one of claims 1 to 12, wherein the aminoguanidine compound is an aminoguanidine acid salt.

14. The method of claim 13, wherein the aminoguanidine acid salt is aminoguanidine-HCl.

15. The method of any one of claims 1 to 14, wherein the multi-carbonyl compound is a dicarbonyl compound comprising a dialdehyde, a diketone, a mixed aldehyde-ketone or any combination thereof.

16. The method of claim 14 or 15, wherein the dicarbonyl compound comprises 2,6-pyridine dialdehyde, 2,6-diacetylpyridine, 1,3 -diacetylbenzene; 1,3-diacetylpyndine, 1,3- indanedione. 1,4-diacetylbenzene, 1,2-diacetylbenzene, 2,3-butadione, 2,3-pentadione, 2, 5 -hexanedi one, 2,5-dicarboxaldehyde furan, or any combinations thereof.

17. The method of any one of claims 1 to 16, wherein the iminoguanidine freebase is a bis(imino)guanidine freebase.

18. The method of claim 17, wherein the bis(imino)guanidine freebase has the formula:wherein A is a central moiety comprising a single bond, a linear or branched hydrocarbon, and / or a cyclic group having at least one carbon atom, the cyclic group comprising a monocyclic ring moiety or a polycyclic ring moiety, and wherein any one or more of the hydrogen atoms, whether the hydrogen atoms are shown or not shown in the formula, are replaceable with one or more Ci-Cg alkyl groups.

19. The method of claim 18, wherein the central moiety A is or comprises a carbocyclic ring being saturated or unsaturated.

20. The method of claim 18, wherein the central moiety A is or comprises a heterocyclic ring being saturated or unsaturated.

21. The method of any one of claims 18 to 20, wherein the cyclic group comprises at least one ring being a five-membered, six-membered, or seven-membered ring.

22. The method of any one of claims 18 to 21, wherein one or both of terminal carbon atoms in imino groups linked to the central moiety A are bonded to an alkyl group or other substituent that is not part of the linkage with the central moiety A.

23. The method of any one of claims 1 to 16, wherein the iminoguanidine freebase is a tris(imino)guanidine freebase.

24. The method of any one of claims 1 to 23, wherein reacting the aminoguanidine compound with the multi-carbonyl compound in the aqueous medium comprises monitoring a formation of a mono(imino)guanidine intermediate being soluble in the aqueous medium.

25. The method of any one of claims 1 to 24, comprising purifying at least one of the aminoguanidine compound and the multi-carbonyl compound prior to reacting with one another.

26. . The method of any one of claims 1 to 25, wherein the aqueous medium comprises deionized water.

27. The method of any one of claims 1 to 26, wherein the aqueous medium comprises a water- miscible co-solvent.

28. . The method of any one of claims 1 to 27, wherein the aqueous medium comprises a catalyst for reacting the aminoguanidine compound with the multi-carbonyl compound.

29. The method of claim 28 wherein the catalyst comprises a hydrohalic acid or acetic acid.

30. The method of any one of claims 1 to 29, wherein the iminoguanidine freebase is insoluble in the aqueous medium.

31. The method of claim 30, further compnsing purifying the iminoguanidine freebase.

32. The method of claim 31 , wherein purifying the iminoguanidine freebase comprises washing away one or more impurities that are soluble in the aqueous medium.

33. The method of any one of claims 1 to 32, wherein the reacting and the converting operations are performed within a reacting vessel of one apparatus containing the aqueous medium.

34. . The method of claim 33, wherein the one apparatus comprises a stirred tank reactor.

35. The method of any one of claims 1 to 34, wherein the reacting to form the iminoguanidine salt is performed continuously.

36. The method of any one of claims 1 to 35, wherein the reacting to form the iminoguanidine salt comprises gradually adding at least one of the aminoguanidine compound and the multi-carbonyl compound to control an exotherm.

37. The method of any one of claims 1 to 36, wherein the converting to form the iminoguanidine freebase is performed continuously.

38. A method comprising: reacting an aminoguanidine compound with a multi-carbonyl compound in an aqueous medium to produce a first iminoguanidine salt; and converting the first iminoguanidine salt to an iminoguanidine carbonate and / or an iminoguanidine bicarbonate.

39. The method of claim 38, wherein the aminoguanidine compound is aminoguanidine HC1 and the first iminoguanidine salt is an iminoguanidine HC1.

40. The method of claim 38 or 39, wherein converting the first iminoguanidine salt to the iminoguanidine carbonate and / or the iminoguanidine bicarbonate comprises contacting the first iminoguanidine salt with at least one of a carbonate salt or a bicarbonate salt.

41. The method of any one of claims 38 to 40, wherein converting the first iminoguanidine salt to the iminoguanidine carbonate and / or the iminoguanidine bicarbonate comprises directly converting the iminoguanidine salt to the iminoguanidine carbonate and / or the iminoguanidine bicarbonate.

42. The method of claim 41, wherein directly converting the first iminoguanidine salt to the iminoguanidine carbonate and / or iminoguanidine bicarbonate comprises performing the conversion in presence of the aqueous medium without isolating the first iminoguanidme salt from the aqueous medium.

43. The method of claim 41 or 42, wherein directly converting the first iminoguanidine salt to the iminoguanidine carbonate and / or iminoguanidine bicarbonate comprises performing the conversion without washing and / or drying the first iminoguanidine salt in solid form.

44. The method of any one of claims 38 to 43, comprising thermally decomposing the iminoguanidine carbonate and / or iminoguanidine bicarbonate to generate an iminoguanidine freebase.

45. A method comprising: reacting an aminoguanidine freebase with a multi-carbonyl compound in an aqueous medium to produce an iminoguanidine freebase.

46. The method of claim 45, wherein reacting the aminoguanidine freebase with the multicarbonyl compound is performed without producing an iminoguanidine salt.

47. The method of claim 45 or 46, wherein the iminoguanidine freebase is a bis(imino)guanidine freebase or a tri s(imino)guani dine freebase.

48. The method of any one of claims 45 to 47, wherein the iminoguanidine freebase is a bis(imino)guanidine freebase having the formula:wherein A is a central moiety comprising a single bond, a linear or branched hydrocarbon, and / or a cyclic group having at least one carbon atom, the cyclic group comprising a monocyclic ring moiety or a polycyclic ring moiety, and wherein any one or more of the hydrogen atoms, whether the hydrogen atoms are shown or not shown in the formula, are replaceable with one or more Ci-Ce alkyl groups, respectively.

49. The method of claim 48, wherein the central moiety (A) is or comprises a carbocyclic ring being saturated or unsaturated.

50. The method of claim 48, wherein the central moiety (A) is or comprises a heterocyclic ring being saturated or unsaturated.

51. The method of any one of claims 48 to 50, wherein the cyclic group comprises at least one ring being a five-membered, six-membered, or seven-membered ring.

52. The method of any one of claims 48 to 51, wherein one or both of terminal carbon atoms in imino groups linked to central moiety A are bonded to an alkyl group or other substituent that is not part of the linkage with the central moiety A.

53. The method of any one of claims 45 to 52, wherein the aqueous medium comprises deionized water.

54. The method of any one of claims 45 to 53, wherein the aqueous medium comprises a water- miscible co-solvent.

55. The method of any one of claims 45 to 54, wherein the aqueous medium comprises a catalyst for reacting the aminoguanidine freebase with the multi-carbonyl compound.

56. The method of claim 55, wherein the catalyst comprises a hydrohalic acid or acetic acid.

57. The method of any one of claims 45 to 56, wherein the iminoguanidine freebase is insoluble in the aqueous medium and is present in the aqueous medium in solid form.

58. The method of claim 57, comprising purifying the iminoguanidine freebase solid.

59. The method of claim 57 or 58, comprising washing the iminoguanidine freebase solid to remove one or more impurities that are soluble in the aqueous medium, the one or more impurities being derived from the aminoguanidine compound60. The method of any one of claims 45 to 59, comprising preparing the aminoguanidine freebase.

61. The method of claim 60, wherein reacting the aminoguanidine freebase with the multicarbonyl compound is performed before the aminoguanidine freebase substantially decomposes.

62. The method of claim 60 or 61, wherein reacting the aminoguanidine freebase with the multi-carbonyl compound is performed within at most about 10 minutes of preparing the aminoguanidine freebase.

63. The method of any one of claims 60 to 62, wherein preparing the aminoguanidine freebase comprises contacting an aminoguanidine salt with an ion exchange polymer.

64. The method of any one of claims 60 to 62, wherein preparing the aminoguanidine freebase comprises reacting an aminoguanidine salt with a base.

65. The method of claim 64, wherein the base is a hydroxide.

66. The method of claim 65, wherein the hydroxide is NaOH, KOH, or LiOH.

67. The method of any one of claims 64 to 66, wherein the aminoguanidine salt is aminoguanidine HC1.

68. A method comprising: contacting an aminoguanidine compound with a multi-carbonyl compound in an aqueous medium to produce a mono(imino)guanidine compound, the multi-carbonyl compound being insoluble in the aqueous medium, and the mono(imino)guanidine compound being soluble in the aqueous medium; and reacting the mono(imino)guanidine compound with the aminoguanidine compound in the aqueous medium to produce a bis(immo)guanidine compound, the bis(imino)guanidine compound being insoluble in the aqueous medium.

69. The method of claim 68, comprising monitoring progress of production of the bis(imino)guanidine compound by monitoring the presence of solids in the aqueous medium.

70. The method of claim 68 or 69, comprising monitoring progress of production of the mono(imino)guanidine intermediate being soluble in the aqueous medium by HPLC with UV-Vis detection.

71. The method of any one of claims 68 to 70, wherein the bis(imino)guanidine compound is diacetylbenzene bis(imino)guanidine or di acety l bis(imino)guanidine.

72. The method of any one of claims 68 to 71, comprising purifying the bis(imino)guanidine compound by washing the bis(imino)guanidine compound in solid form to remove one more impurities that are soluble in the aqueous medium, the one or more impurities being derived from the aminoguanidine compound.

73. The method of any one of claims 68 to 72, comprising at least one feature as defined in any one of claims 1 to 44.

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