Synthesis method of cucurbituril compound

Abstract

The disclosure herein relates, inter alia, to cucurbituril compounds of the invention and novel processes for preparing them using glycoluril compounds of formula (II), glycoluril compounds of formula (II '), glycoluril diethers of formula (III), glycoluril dimers of formula (IV), glycoluril tetramer compounds of formula (V), and sodium 4, 4'-(1, 4-phenylene bis (oxy)) bis (butane-1-sulfonate, the process results in a significant increase in purity and yield of intermediates and end products.

Description

[0001] This application was made with government support under Grant No. U01 DA053054 awarded by the National Institutes of Health. The government has certain rights in the application. TECHNICAL FIELD

[0002] The disclosure herein relates, inter alia, to cucurbituril compounds and methods of making cucurbituril compounds. BACKGROUND

[0003] Cucurbiturils are a class of macrocyclic compounds based on oligomers of glycoluril, its analogs and derivatives. Cucurbiturils can be used to form complexes with other molecules and can be used as chelating agents. This property makes cucurbiturils attractive candidates for sequestering and removing chemical agents such as toxins and pollutants.

[0004] Cucurbiturils represent a promising technology for reversing methamphetamine intoxication and / or overdose. There is an urgent need to develop a safe and fast-acting reversal agent for methamphetamine. Meth is the fastest growing drug of abuse in the United States, with over 200,000 emergency room (ER) visits per year, a four-fold increase in deaths since 2015 (9356 deaths in 2017 alone), and no current treatment available for meth intoxication. Meth induces excessive, rapid, and sustained (serum half-life t 1 / 2 ~10 hours) stimulation of the sympathetic nervous system, which is the cause of a recognizable adrenergic intoxication syndrome that includes behavioral (psychomotor agitation) and physiological (tachycardia, hypertension, mydriasis, and diaphoresis) symptoms. Meth intoxication can lead to cardiovascular and other complications; 20% of ER emergencies require hospitalization. The current standard of care for meth intoxication is to treat only the symptoms. A meth reversal agent that normalizes the behavioral and physiological symptoms would minimize complications, improve patient outcomes, and reduce mortality. SUMMARY

[0005] Provided herein, inter alia, are methods of making cucurbituril compounds that can be adapted for large-scale synthesis and that can significantly improve the purity and yield of intermediates and final products.

[0006] In one aspect, the disclosure provides a method of making a compound of Formula I:

[0007]

[0008] or a pharmaceutically acceptable salt thereof,

[0009] wherein:

[0010] each R 1A and R 1Dindependently selected from hydrogen, halogen, -OH, C1-C6alkyl, 2 to 6 membered heteroalkyl, C3-C6cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-(CH2) n1 S(O) v1 X 1 , -O-(CH2) n1 CO2X 1 and -O-(CH2) n1 PO v1 X 1 ;

[0011] each R 1B and R 1C are independently selected from hydrogen, halogen, -OH, C1-C6alkyl, 2 to 6 membered heteroalkyl, C3-C6cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-(CH2) n1 S(O) v1 X 1 , -O-(CH2) n1 CO2X 1 and -O-(CH2) n1 PO v1 X 1 ; or

[0012] Additionally or alternatively, two R 1A , R 1B , R 1C and R 1D attached to the same phenyl ring at adjacent positions, together with the atoms to which they are attached, join to form a fused C6-C 12 aryl, 5 to 12 membered heteroaryl or 5 to 7 membered heterocycle, optionally substituted with 1 to 3 substituents independently selected from halogen, -OH, -NH2, substituted or unsubstituted C1-C6alkyl or substituted or unsubstituted 2 to 6 membered heteroalkyl;

[0013] each R 3A and R 3B are independently selected from hydrogen, halogen, -OH, C1-C6alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl;

[0014] each R 4A and R 4B are independently selected from hydrogen, halogen, -OH, C1-C6alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl;

[0015] each n1 is independently selected from 0 to 5;

[0016] each v1 is independently selected from 2 or 3; and

[0017] each X 1are independently selected from the group consisting of H, -OH, C1-C6 alkyl, alkali metal cation, and quaternary ammonium cation.

[0018] Methods of making compounds of Formula I include one or more of the following steps:

[0019] (i) contacting a compound of Formula II:

[0020]

[0021] with paraformaldehyde in the presence of an acid to give a compound of Formula III:

[0022]

[0023] (ii) contacting a compound of Formula II’:

[0024]

[0025] with paraformaldehyde and an acid, wherein the paraformaldehyde is added to the compound of Formula II’ over a period of at least about 1 hour, and wherein the reaction is maintained at a temperature above 55 °C to give a compound of Formula IV:

[0026]

[0027] (iii) contacting a compound of Formula III:

[0028]

[0029] with a compound of Formula IV in the presence of (a) one or more acids having a pKa less than about 1 and optionally (b) one or more polar aprotic solvents and / or additional acid solvents,

[0030] to give a compound of Formula V:

[0031]

[0032] and isolating the compound of Formula V;

[0033] (iv) contacting a compound of Formula V and a compound of Formula VI:

[0034]

[0035] in the presence of a solvent comprising one or more acids having a pKa less than about 1 and an acid anhydride to give a compound of Formula I.

[0036] In several embodiments, the reaction of step (i) is maintained at a temperature above about 35 °C.

[0037] In several embodiments, in the reaction of step (ii), the paraformaldehyde is added in four or more portions with at least about 10 minutes between portions.

[0038] In several embodiments, the reaction of step (ii) is maintained at a temperature above 65 °C.

[0039] In several embodiments, the reaction mixture of step (ii) is not solidified during the course of the reaction.

[0040] In several embodiments, the method further comprises a step of isolating the compound of Formula IV in step (ii) comprising contacting the reaction mixture with water, heating to a temperature of at least about 70 °C, cooling to a temperature of less than about 30 °C, and centrifuging or filtering the reaction mixture.

[0041] In several embodiments, the reaction temperature of step (iii) is maintained at equal to or above about 55 °C.

[0042] In several embodiments, the solvent of step (iii) comprises an acid selected from the group consisting of trifluoroacetic acid, phosphoric acid, sulfuric acid, HC1, HBr, HCIO4, HNO3, triflic acid, methanesulfonic acid, toluenesulfonic acid, Eaton’s reagent, and combinations thereof.

[0043] In several embodiments, the polar aprotic solvent of step (iii) comprises dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran (THF), dioxane, sulfolane, acetone, N,N'-dimethylpropyleneurea (DMPU), diglyme, hexamethylphosphoramide (HMPA), or combinations thereof.

[0044] In several embodiments, the acid of step (iii) is trifluoroacetic acid (TFA), which can also be the solvent.

[0045] In several embodiments, the method further comprises a step of isolating the compound of Formula V comprising adding additional TFA to the reaction mixture after the reaction is complete; precipitating the compound of Formula V; and filtering the mixture comprising the compound of Formula V.

[0046] In several embodiments, the step of precipitating the compound of Formula V comprises adding an anti-solvent for the compound of Formula V. The anti-solvent can comprise methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran (THF), dioxane, brine, or combinations thereof.

[0047] In several embodiments, in step (iii) or (iv), the one or more acids having a pKa less than about 1, respectively, include trifluoroacetic acid, Eaton’s reagent, methanesulfonic acid (MeSO3H), toluenesulfonic acid (TsOH), trifluoromethanesulfonic acid, phosphoric acid, sulfuric acid, camphorsulfonic acid (CSA), ethanesulfonic acid (EtSO3H), HC1, HBr, HCIO4, HNO3, or combinations thereof.

[0048] In several embodiments, each R 1A and R 1D is -O-(CH2) n1 S(O) v1 X 1 , -O-(CH2) n1 CO2X 1 or -O-(CH2) n1 PO v1 X 1 .

[0049] In several embodiments, R 1B and R 1C are hydrogen.

[0050] In several embodiments, X 1 is H or an alkali metal cation.

[0051] In several embodiments, each R 3A and R 3B is independently C1-C3 alkyl.

[0052] In several embodiments, R 4A and R 4B are hydrogen.

[0053] In another aspect, the present disclosure provides a method of preparing a compound of Formula VI-A:

[0054]

[0055] wherein:

[0056] X is selected from the group consisting of H, an alkali metal cation, and a quaternary ammonium cation.

[0057] The method comprises the steps of:

[0058] (i) reacting a hydroquinone having the formula

[0059]

[0060] and a sultolane having the formula

[0061]

[0062] in the presence of about 2.0 to 2.5 equivalents of a base and a solvent comprising one or more of water, a polar aprotic solvent, and combinations thereof.

[0063] In several embodiments, the base is present in about 2.2 to 2.4 equivalents.

[0064] In several embodiments, the base can include alkali metal hydroxides such as LiOH, NaOH, and KOH; alkali metal carbonates such as Na2C03or K2C03. Alternatively or additionally, the base can include non-nucleophilic organic bases such as diisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the like.

[0065] In several embodiments, the lactone is added over a period of longer than about 2 hours.

[0066] In several embodiments, the lactone is added in two or more portions separated by at least one hour.

[0067] In several embodiments, the reaction mixture is cooled to less than about 10 °C prior to each addition of lactone.

[0068] In several embodiments, the method further comprises the step of adding a base to the reaction, the amount of base being equal to or greater than the amount of lactone.

[0069] In several embodiments, the base is added in two or more portions separated by at least one hour.

[0070] In another aspect, the present disclosure provides a method of making a compound of Formula I-A

[0071]

[0072] wherein

[0073] X is selected from the group consisting of H, an alkali metal cation, and a quaternary ammonium cation, and combinations thereof.

[0074] The method comprises the steps of:

[0075] (i) contacting a hydroquinone of the formula

[0076]

[0077] and a lactone of the formula

[0078]

[0079] in the presence of about 2.0 to 2.5 equivalents of a base and a solvent comprising one or more of water, a polar aprotic solvent, and combinations thereof, to yield a compound of Formula VI-A:

[0080]

[0081] (ii) isolating the compound of Formula VI-A; and

[0082] (iii) contacting the compound of Formula VI-A and the compound of Formula V-A:

[0083]

[0084] to obtain a compound of Formula I-A.

[0085] In several embodiments, the base of step (i) is present in about 2.2 to 2.4 equivalents.

[0086] In several embodiments, the base of step (i) comprises an alkali metal hydroxide.

[0087] In several embodiments, the sultone of step (i) is added over a period of longer than about 2 hours.

[0088] In several embodiments, the sultone is added in two or more portions with at least one hour between portions.

[0089] In several embodiments, the reaction mixture of step (i) is cooled to less than about 10 °C prior to each addition of sultone.

[0090] In several embodiments, the method further comprises the step of adding a base to the reaction, the amount of base being equal to or greater than the amount of sultone.

[0091] In several embodiments, the base is added in two or more portions with at least one hour between portions.

[0092] Other aspects are disclosed infra. BRIEF DESCRIPTION OF DRAWINGS

[0093] Figure 1 An exemplary synthesis of compound CS-1103 according to exemplary embodiments is shown.

[0094] Figure 2 An exemplary synthesis of compound CS-1105 according to exemplary embodiments is shown. DETAILED DESCRIPTION

[0095] Provided herein, inter alia, are cucurbituril compounds and methods of making cucurbiturils. The synthetic processes in the methods described herein provide one or more of the following advantages: improved yield and purity of key intermediates and final product, in-process controls to prevent formation of sulfonate esters and other impurities, and improved purification processes allowing key intermediate steps to be performed on a large scale.

[0096] Definitions

[0097] As used herein, the abbreviations have their usual meanings in the chemical and biological arts. The chemical structures and formulas given herein are constructed according to standard rules of chemical valence.

[0098] The term "alkyl" refers to a saturated aliphatic group, including straight-chain alkyl and branched-chain alkyl groups. Alkyl groups can include a specified number of carbons (e.g., C1-C10 10 means one to ten carbons). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0099] The term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon group having at least one carbon-carbon double bond and including straight-chain and branched-chain alkenyl groups. Examples of alkenyl groups (e.g., "C2-C6 alkenyl") include ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like. When a compound of the disclosure contains an alkenyl group, the compound can exist as an E type, a Z type, or as any mixture thereof.

[0100] The term "alkynyl" refers to a straight-chain or branched-chain hydrocarbon group having at least one carbon-carbon triple bond and including straight-chain and branched-chain alkynyl groups. Examples of alkenyl groups (e.g., "C2-C6 alkynyl") include ethynyl, propynyl, and the like.

[0101] The term "cycloalkyl" refers to a saturated carbocyclic group having 3 to 9 carbons in the ring and including monocyclic, bicyclic, or polycyclic cycloalkyl ring systems. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings. In several embodiments, the bridged monocyclic ring contains a monocyclic cycloalkyl ring in which two non-adjacent carbon atoms of the monocyclic ring are connected by an alkylene bridge (i.e., a (CH2) w group, where w is 1, 2, or 3) between three additional carbon atoms. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane.

[0102] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise indicated, a stable straight or branched chain or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. The heteroatom(s) (e.g., N, S, Si, or P) can be placed at any interior position of the heteroalkyl group or at the position on the heteroalkyl group connecting to the rest of the molecule. Examples include, but are not limited to: -O-C1-C6 alkyl, -O-C2-C6 alkenyl, -O-C2-C6 alkynyl, -S-C1-C6 alkyl, -S-C2-C6 alkenyl, -S-C2-C6 alkynyl, -NH-C1-C6 alkyl, -NH-C2-C6 alkenyl, -NH-C2-C6 alkynyl, -N-(C1-C6 alkyl)2, -S(O)-C1-C6 alkyl, -S(O)-C2-C6 alkenyl, -S(O)-C2-C6 alkynyl, -S(O)2-C1-C6 alkyl, -S(O)2-C2-C6 alkenyl, -S(O)2-C2-C6 alkynyl, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-S-C1-C6 alkyl, -C1-C6 alkyl-NH-C1-C6 alkyl, -C1-C6 alkyl-N-(C1-C6 alkyl)2, -C1-C6 alkyl-S(O)-C1-C6 alkyl, -C1-C6 alkyl-S(O)2-C1-C6 alkyl, and more particularly including, but not limited to: —CH2—O—CH3, —CH2—NH—CH3, —CH2—CH2—N(CH3)—CH3, —CH2—S—CH3, —S(O)—CH3, —CH2—S(O)2—CH3, —Si(CH3)3, —O—CH3, or —O—CH2—CH3. Up to two or three heteroatoms can be consecutive, such as in —CH2—NH—OCH3and —CH2—O—Si(CH3)3. The term "heteroalkenyl," by itself or in combination with another term, means a heteroalkyl group, as described herein, including at least one carbon-carbon double bond. The term "heteroalkynyl," by itself or in combination with another term, means a heteroalkyl group, as described herein, including at least one carbon-carbon triple bond.

[0103] The term "cycloalkenyl" as used herein is a monocyclic, bicyclic, or polycyclic cycloalkenyl ring system. In several embodiments, the monocyclic cycloalkenyl ring system is a cyclic hydrocarbon group containing 3 to 9 carbon atoms, wherein such group is unsaturated (i.e., contains at least one ring carbon-carbon double bond), but is not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In several embodiments, the bicyclic cycloalkenyl ring is a bridged or fused bicyclic ring.

[0104] The term "heterocycle," "heterocyclyl," or "heterocyclic" as used herein means a monocyclic, bicyclic, or polycyclic ring. A monocyclic heterocycle is a 3, 4, 5, 6, 7, or 8 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, S, Si, and P, wherein the ring is saturated or unsaturated, but not aromatic. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepinyl, aziridinyl, diazepinyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl (thiomorpholine sulfone), thiofuranyl, and trithianyl. Representative examples of bicyclic heterocycles include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothiophen-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. The heterocycle is attached to the parent molecular moiety through any carbon atom or any nitrogen atom within the monocyclic or bicyclic ring system.

[0105] The term "aryl" as used herein includes 5- and 6-membered monocyclic aromatic groups, which can include zero to four heteroatoms, such as benzene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure can also be referred to as "aryl heterocycles," "heteroaromatic," or "heteroaryl." The term "aryl" also includes 7- to 14-membered polycyclic ring systems having two or more cyclic rings wherein two or more carbons are shared by two adjacent rings (the rings are "fused"), wherein at least one of the rings is aromatic (including heteroaryl), such as, for example, the other cyclic rings can be fused cycloalkyl, cycloalkenyl, aryl, heteroaryl, and / or heterocyclyl groups. Monocyclic heteroaryls can have 1 to 3 ring heteroatoms, and fused polycyclic heteroaryls can have 1 to 5 ring heteroatoms, wherein the ring heteroatoms are selected from N, O, and S.

[0106] The term "alkylene," by itself or as part of another substituent, means, unless otherwise indicated, a divalent radical derived from an alkyl group, exemplified by, but not limited to, -CH2CH2CH2CH2-. Generally, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those having 10 or fewer carbon atoms being preferred herein. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene, generally having eight or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise indicated, a divalent radical derived from an alkene.

[0107] It will be understood that "substituted," "to substitute" or "substituted by" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. Exemplary substituents, as used herein, mean a group selected from the group consisting of: oxo, halogen, — CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SCH3, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF3, -OCCl3, — OCBr3, — OCl3, — OCHF2, — OCHCl2, — OCHBr2, — OCHI2, — OCH2F, — OCH2Cl, — OCH2Br, — OCH2I, alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6-C10 aryl, C6-C8 aryl, or C6-C4 aryl), or heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and these alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups can be optionally substituted by at least one substituent. For example, in the cucurbituril compounds disclosed herein, each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, and heterocycle can be optionally substituted by 1 to 4 substituents selected from the aforementioned substituents. 10 aryl, C 10 aryl, or phenyl) or heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and these alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups can be optionally substituted by at least one substituent. For example, in the cucurbituril compounds disclosed herein, each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, and heterocycle can be optionally substituted by 1 to 4 substituents selected from the aforementioned substituents.

[0108] The term "sultone," as used herein, refers to a cyclic ester including a hydroxysulfonic acid (e.g., ). Exemplary sultones can be represented as wherein preferably, n is 1 to 3.

[0109] As used herein, a quaternary ammonium cation has the structure + N(R)4, where each R is independently selected from alkyl, cycloalkyl, aryl, aralkyl, and heteroaryl, each of which can be optionally substituted. A quaternary ammonium cation may, for example, have the structure + N(C 1- 6alkyl)4, where the C 1-6 alkyl groups are each independently selected.

[0110] Eaton’s reagent is a solution of phosphorus pentoxide in methanesulfonic acid. The weight % of phosphorus pentoxide in methanesulfonic acid can be from about 7% to about 15%, for example 7.5% or 10%.

[0111] The term “one” as used herein means one or more. The phrase “substituted” as used herein means that the specified group can be substituted with one or more of any or all of the specified substituents. For example, in the case of a group such as alkyl or heteroaryl “substituted with unsubstituted C1-C6alkyl or unsubstituted 2 to 20 membered heteroalkyl,” the group can contain one or more unsubstituted C1-C6alkyl groups and / or one or more unsubstituted 2 to 20 membered heteroalkyl groups. 20 alkyl groups and / or one or more unsubstituted 2 to 20 membered heteroalkyl groups. 20 alkyl groups and / or one or more unsubstituted 2 to 20 membered heteroalkyl groups.

[0112] Certain compounds provided in the present disclosure can exist in particular geometric or stereoisomeric forms. The present disclosure encompasses all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms can be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are included in the present disclosure.

[0113] The term "pharmaceutically acceptable salt" means a relatively non-toxic, inorganic and organic acid addition salt of a compound disclosed herein and a salt of an inorganic and organic base addition salt of a compound disclosed herein. When a compound of the present application contains a relatively acidic functionality, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base to provide the appropriate salt. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When a compound of the present application contains a relatively basic functionality, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid to provide the appropriate salt. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids, and the like, as well as salts derived from relatively nontoxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, etc.

[0114] Compounds

[0115] Provided herein are cucurbituril compounds that can be obtained or are obtainable by one or more synthesis steps described herein.

[0116] In one aspect, the cucurbituril compound has the structure of Formula I:

[0117]

[0118] or a pharmaceutically acceptable salt thereof,

[0119] wherein:

[0120] each R 1A and R 1D is independently selected from hydrogen, halogen, -OH, C1-C6alkyl, 2 to 6 membered heteroalkyl, C3-C6cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-(CH2) n1 S(O) v1 X 1 , -O-(CH2) n1 CO2X 1 , and -O-(CH2) n1 PO v1 X 1 ;

[0121] each R 1B and R 1Cindependently selected from hydrogen, halogen, -OH, C1-C6alkyl, 2 to 6 membered heteroalkyl, C3-C6cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-(CH2) n1 S(O) v1 X 1 , -O-(CH2) n1 CO2X 1 and -O-(CH2) n1 PO v1 X 1 ; or

[0122] Additionally or alternatively, two R 1A , R 1B , R 1C and R 1D , when attached to adjacent positions of the same phenyl ring, together with the atoms to which they are attached join to form a fused C6-C 12 aryl, 5 to 12 membered heteroaryl or 5 to 7 membered heterocycle, optionally substituted with 1 to 3 substituents independently selected from halogen, -OH, -NH2, substituted or unsubstituted C1-C6alkyl or substituted or unsubstituted 2 to 6 membered heteroalkyl;

[0123] each R 3A and R 3B is independently selected from hydrogen, halogen, -OH, C1-C6alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl;

[0124] each R 4A and R 4B is independently selected from hydrogen, halogen, -OH, C1-C6alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl;

[0125] each n1 is independently selected from 0 to 5;

[0126] each v1 is independently selected from 2 or 3; and

[0127] each X 1 is independently selected from H, -OH, C1-C6alkyl, an alkali metal cation and a quaternary ammonium cation.

[0128] In several embodiments, R 1B is hydrogen, halogen, -OH, C1-C6alkyl, 2 to 6 membered heteroalkyl, C3-C6cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl or 5 to 6 membered heteroaryl. In several embodiments, R 1B is hydrogen, halogen, -OH or C1-C6alkyl, and in particular R 1B is hydrogen or halogen.

[0129] In several embodiments, R 1Cis hydrogen, halogen, -OH, C1-C6alkyl, 2 to 6 membered heteroalkyl, C3-C6cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, or 5 to 6 membered heteroaryl. In several embodiments, R 1C is hydrogen, halogen, -OH, or C1-C6alkyl, and in particular, R 1C is hydrogen or halogen.

[0130] In several embodiments, R 1B and R 1C are hydrogen.

[0131] Additionally or alternatively, R 1A and R 1B together with the atom to which they are attached join to form a C6-C 12 aryl or 5 to 12 membered heteroaryl. In several embodiments, R 1A and R 1B together with the atom to which they are attached join to form a phenyl. In several embodiments, R 1A and R 1B together with the atom to which they are attached join to form a naphthyl. In several embodiments, R 1A and R 1B together with the atom to which they are attached join to form a pyridyl.

[0132] In several embodiments, R 1B and R 1C together with the atom to which they are attached join to form a C6-C 12 aryl or 5 to 12 membered heteroaryl. In several embodiments, R 1B and R 1C together with the atom to which they are attached join to form a phenyl. In several embodiments, R 1B and R 1C together with the atom to which they are attached join to form a naphthyl. In several embodiments, R 1B and R 1C together with the atom to which they are attached join to form a pyridyl.

[0133] In several embodiments, R 1C and R 1D together with the atom to which they are attached join to form a C6-C 12 aryl or 5 to 12 membered heteroaryl. In several embodiments, R 1C and R 1Dtogether with the atom to which they are attached form phenyl. In several embodiments, R 1C and R 1D together with the atom to which they are attached form naphthyl. In several embodiments, R 1C and R 1D together with the atom to which they are attached form pyridyl.

[0134] In several embodiments, R 1A , R 1B , R 1C and R 1D together with the atom to which they are attached form C6-C 12 aryl or 5- to 12-membered heteroaryl can be substituted with one or more substituents, for example, halogen, -OH, -NH2, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted 2- to 6-membered heteroalkyl.

[0135] In several embodiments, R 3A is hydrogen or substituted or unsubstituted C1-C3alkyl. In several embodiments, R 3A is C1-C3alkyl, and in particular, methyl.

[0136] In several embodiments, R 3B is hydrogen or substituted or unsubstituted C1-C3alkyl. In several embodiments, R 3B is C1-C3alkyl, and in particular, methyl.

[0137] In several embodiments, R 3A and R 3B are both hydrogen. Alternatively, R 3A and R 3B may both be methyl. In several embodiments, one of R 3A and R 3B is hydrogen and the other is methyl.

[0138] In several embodiments, R 4A is hydrogen or substituted or unsubstituted C1-C3alkyl. In several embodiments, R 4A is C1-C3alkyl, and in particular, methyl. In several embodiments, R 4A is H.

[0139] In several embodiments, R 4B is hydrogen or substituted or unsubstituted C1-C3alkyl. In several embodiments, R 4B is C1-C3alkyl, and in particular, methyl. In several embodiments, R 4B is hydrogen.

[0140] In several embodiments, each R 4A and R 4B is hydrogen. Alternatively, each R 4A and R 4B may be methyl. In several embodiments, one of R 4A and R 4B is hydrogen, and the other is methyl.

[0141] In several embodiments, each R 3A and R 3B is independently C1-C3 alkyl, and R 4A and R 4B is hydrogen, and in particular, each R 3A and R 3B is methyl, and each R 4A and R 4B is hydrogen.

[0142] In another aspect, a cucurbituril compound, which can be obtained or obtainable by one or more synthetic steps described herein, has the structure of Formula (I-a):

[0143]

[0144] or a pharmaceutically acceptable salt thereof. R 1A , R 1D , R 3A , R 3B , R 4A , and R 4B are as described herein.

[0145] In several embodiments, R 3A is hydrogen or substituted or unsubstituted C1-C3 alkyl. In several embodiments, R 3A is C1-C3 alkyl, and in particular, methyl.

[0146] In several embodiments, R 3B is hydrogen or substituted or unsubstituted C1-C3 alkyl. In several embodiments, R 3B is C1-C3 alkyl, and in particular, methyl.

[0147] In several embodiments, R 3A and R 3B are each hydrogen. Alternatively, R 3A and R 3B may each be methyl. In several embodiments, one of R 3A and R 3B is hydrogen, and the other is methyl.

[0148] In several embodiments, R 4Ais hydrogen or substituted or unsubstituted C1-C3 alkyl. In several embodiments, R 4A is C1-C3 alkyl, and in particular methyl. In several embodiments, R 4A is H.

[0149] In several embodiments, R 4B is hydrogen or substituted or unsubstituted C1-C3 alkyl. In several embodiments, R 4B is C1-C3 alkyl, and in particular methyl. In several embodiments, R 4B is hydrogen.

[0150] In several embodiments, each R 4A and R 4B is hydrogen. Alternatively, each R 4A and R 4B may be methyl. In several embodiments, one of R 4A and R 4B is hydrogen, and the other is methyl.

[0151] In several embodiments, each R 3A and R 3B is independently C1-C3 alkyl, and R 4A and R 4B is hydrogen, and in particular, each R 3A and R 3B is methyl, and each R 4A and R 4B is hydrogen.

[0152] In several embodiments, each R 1A and R 1D is neutral. In several embodiments, each R 1A and R 1D is in ionic salt form.

[0153] In several embodiments, R 1A is -O-(CH2) n1 S(O) v1 X 1 In several embodiments, R 1A is -O-(CH2) n1 CO2X 1 In several embodiments, R 1A is -O-(CH2) n1 PO v1 X 1In several embodiments, each n1 is 0. In several embodiments, each n1 is 1. In several embodiments, each n1 is 2. In several embodiments, each n1 is 3. In several embodiments, each n1 is 4. In several embodiments, each n1 is 5. In several embodiments, each v1 is 2. In several embodiments, each v1 is 3.

[0154] In several embodiments, R 1D is -O-(CH2) n1 S(O) v1 X 1 In several embodiments, R 1D is -O-(CH2) n1 CO2X 1 In several embodiments, R 1D is -O-(CH2) n1 PO v1 X 1 In several embodiments, each n1 is 0. In several embodiments, each n1 is 1. In several embodiments, each n1 is 2. In several embodiments, each n1 is 3. In several embodiments, each n1 is 4. In several embodiments, each n1 is 5. In several embodiments, each v1 is 2. In several embodiments, each v1 is 3.

[0155] In several embodiments, R 1A and R 1D connected to the same phenyl ring can be the same or different. In several embodiments, R 1A and R 1A connected to different phenyl rings can be the same or different. In several embodiments, R 1D and R 1D connected to different phenyl rings can be the same or different.

[0156] In several embodiments, each R 1A and R 1D connected to the same phenyl ring are independently -O-(CH2) n1 S(O) v1 X 1 In several embodiments, each R 1A and R 1A connected to different phenyl rings are independently -O-(CH2) n1 S(O) v1 X 1 In several embodiments, each R 1D and R 1D connected to different phenyl rings are independently -O-(CH2) n1S(O) v1 X 1 .

[0157] In another aspect, a cucurbituril compound that can be obtained or obtained by one or more synthetic steps described herein has the structure of Formula (I-b):

[0158]

[0159] or a pharmaceutically acceptable salt thereof. R 1A and R 1D as described herein.

[0160] In several embodiments, each R 1A and R 1D is neutral. In several embodiments, each R 1A and R 1D is in ionic salt form.

[0161] In several embodiments, R 1A is -O-(CH2) n1 S(O) v1 X 1 In several embodiments, R 1A is -O-(CH2) n1 CO2X 1 In several embodiments, R 1A is -O-(CH2) n1 PO v1 X 1 In several embodiments, each n1 is 0. In several embodiments, each n1 is 1. In several embodiments, each n1 is 2. In several embodiments, each n1 is 3. In several embodiments, each n1 is 4. In several embodiments, each n1 is 5. In several embodiments, each v1 is 2. In several embodiments, each v1 is 3.

[0162] In several embodiments, R 1D is -O-(CH2) n1 S(O) v1 X 1 In several embodiments, R 1D is -O-(CH2) n1 CO2X 1 In several embodiments, R 1D is -O-(CH2) n1 PO v1 X 1In several embodiments, each n1 is 0. In several embodiments, each n1 is 1. In several embodiments, each n1 is 2. In several embodiments, each n1 is 3. In several embodiments, each n1 is 4. In several embodiments, each n1 is 5. In several embodiments, each v1 is 2. In several embodiments, each v1 is 3.

[0163] In several embodiments, each R 1A and R 1D may be the same or different. In several embodiments, each R 1A and R 1A may be the same or different. In several embodiments, each R 1D and R 1D may be the same or different.

[0164] In several embodiments, each R 1A and R 1D are independently -O-(CH2) n1 S(O) v1 X 1 In several embodiments, each R 1A is independently -O-(CH2) n1 S(O) v1 X 1 In several embodiments, each R 1D is independently -O-(CH2) n1 S(O) v1 X 1 .

[0165] In another aspect, a cucurbituril compound that can be obtained or obtained by one or more synthesis steps described herein has the structure of Formula (I-c):

[0166]

[0167] or a pharmaceutically acceptable salt thereof. X 1 and n1 are as described herein.

[0168] In several embodiments, each X 1 is the same or different. In several embodiments, each X 1independently H, -OH, C1-C6alkyl, an alkali metal cation, or a quaternary ammonium cation. In embodiments, each n1is 0 to 5. In embodiments, each n1is 1 to 5. In embodiments, each n1is 2 to 5. In embodiments, each n1is 3 to 5. In embodiments, each n1is 4 or 5.

[0169] In another aspect, a cucurbituril compound that can be obtained or obtained by one or more synthetic steps described herein has the structure of Formula (I-A),

[0170]

[0171] or a pharmaceutically acceptable salt thereof. Each X is independently H, an alkali metal cation (e.g., Li + , Na + , K + , or Cs + ), an ammonium cation, or a combination thereof.

[0172] In another aspect, a cucurbituril compound that can be obtained or obtained by one or more synthetic steps described herein has the structure of Formula (I-d),

[0173]

[0174] or a pharmaceutically acceptable salt thereof. R 1A , R 1D , R 3A , R 3B , R 4A , and R 4B are as described herein.

[0175] In embodiments, R 3A is hydrogen or substituted or unsubstituted C1-C3alkyl. In embodiments, R 3A is C1-C3alkyl, and in particular methyl.

[0176] In embodiments, R 3B is hydrogen or substituted or unsubstituted C1-C3alkyl. In embodiments, R 3B is C1-C3alkyl, and in particular methyl.

[0177] In embodiments, R 3A and R 3B are each hydrogen. Alternatively, R 3A and R 3B may each be methyl. In embodiments, one of R 3A and R 3B is hydrogen and the other is methyl.

[0178] In several embodiments, R 4A is hydrogen or substituted or unsubstituted C1-C3alkyl. In several embodiments, R 4A is C1-C3alkyl, and in particular methyl. In several embodiments, R 4A is H.

[0179] In several embodiments, R 4B is hydrogen or substituted or unsubstituted C1-C3alkyl. In several embodiments, R 4B is C1-C3alkyl, and in particular methyl. In several embodiments, R 4B is hydrogen.

[0180] In several embodiments, each R 4A and R 4B is hydrogen. Alternatively, each R 4A and R 4B may be methyl. In several embodiments, one of R 4A and R 4B is hydrogen, and the other is methyl.

[0181] In several embodiments, each R 3A and R 3B is independently C1-C3alkyl, and R 4A and R 4B is hydrogen, and in particular, each R 3A and R 3B is methyl, and each R 4A and R 4B is hydrogen.

[0182] In several embodiments, each R 1A and R 1D is neutral. In several embodiments, each R 1A and R 1D is in ionic salt form.

[0183] In several embodiments, R 1A is -O-(CH2) n1 S(O) v1 X 1 . In several embodiments, R 1A is -O-(CH2) n1 CO2X 1 . In several embodiments, R 1A is -O-(CH2) n1 PO v1 X 1In several embodiments, each n1 is 0. In several embodiments, each n1 is 1. In several embodiments, each n1 is 2. In several embodiments, each n1 is 3. In several embodiments, each n1 is 4. In several embodiments, each n1 is 5. In several embodiments, each v1 is 2. In several embodiments, each v1 is 3.

[0184] In several embodiments, R 1D is -O-(CH2) n1 S(O) v1 X 1 In several embodiments, R 1D is -O-(CH2) n1 CO2X 1 In several embodiments, R 1D is -O-(CH2) n1 PO v1 X 1 In several embodiments, each n1 is 0. In several embodiments, each n1 is 1. In several embodiments, each n1 is 2. In several embodiments, each n1 is 3. In several embodiments, each n1 is 4. In several embodiments, each n1 is 5. In several embodiments, each v1 is 2. In several embodiments, each v1 is 3.

[0185] In several embodiments, R 1A and R 1D connected to the same phenyl ring can be the same or different. In several embodiments, R 1A and R 1A connected to different phenyl rings can be the same or different. In several embodiments, R 1D and R 1D connected to different phenyl rings can be the same or different.

[0186] In several embodiments, each R 1A and R 1D connected to the same phenyl ring is independently -O-(CH2) n1 S(O) v1 X 1 In several embodiments, each R 1A and R 1A connected to different phenyl rings is independently -O-(CH2) n1 S(O) v1 X 1 In several embodiments, each R 1D and R 1D connected to different phenyl rings is independently -O-(CH2) n1S(O) v1 X 1 .

[0187] In another aspect, a cucurbituril compound that can be obtained or obtained by one or more synthetic steps described herein has the structure of Formula (X),

[0188]

[0189] or a pharmaceutically acceptable salt thereof.

[0190] In several embodiments, each R 1A and R 1D is neutral. In several embodiments, each R 1A and R 1D is in ionic salt form.

[0191] In several embodiments, R 1A is -O-(CH2) n1 S(O) v1 X 1 In several embodiments, R 1A is -O-(CH2) n1 CO2X 1 In several embodiments, R 1A is -O-(CH2) n1 PO v1 X 1 In several embodiments, each n1 is 0. In several embodiments, each n1 is 1. In several embodiments, each n1 is 2. In several embodiments, each n1 is 3. In several embodiments, each n1 is 4. In several embodiments, each n1 is 5. In several embodiments, each v1 is 2. In several embodiments, each v1 is 3.

[0192] In several embodiments, R 1D is -O-(CH2) n1 S(O) v1 X 1 In several embodiments, R 1D is -O-(CH2) n1 CO2X 1 In several embodiments, R 1D is -O-(CH2) n1 PO v1 X 1In several embodiments, each n1 is 0. In several embodiments, each n1 is 1. In several embodiments, each n1 is 2. In several embodiments, each n1 is 3. In several embodiments, each n1 is 4. In several embodiments, each n1 is 5. In several embodiments, each v1 is 2. In several embodiments, each v1 is 3.

[0193] In several embodiments, each R 1A and R 1D may be the same or different. In several embodiments, each R 1A and R 1A may be the same or different. In several embodiments, each R 1D and R 1D may be the same or different.

[0194] In several embodiments, each R 1A and R 1D are independently -O-(CH2) n1 S(O) v1 X 1 In several embodiments, each R 1A is independently -O-(CH2) n1 S(O) v1 X 1 In several embodiments, each R 1D is independently -O-(CH2) n1 S(O) v1 X 1 .

[0195] Synthesis

[0196] Provided herein are methods of making the cucurbituril compounds described herein (i.e., compounds of Formula I, la, lb, Ic, I-A, I-D, X). The methods can include the use of one or more compounds having Formula (II), (II'), (III), (IV), (V), (VI), or (VI'). Also, provided herein are methods of making compounds having Formula (I-A), and the methods can include the use of one or more compounds having Formula (II-A), (II'-A), (III-A), (IV-A), (V-A), or (VI-A).

[0197] In several embodiments, the methods include Scheme 2 below.

[0198] Scheme 2

[0199]

[0200] where R 3A and R 3B As described herein. In several embodiments, R 3A and R 3B It is C 1-3 Alkyl, or R 3A and R 3B It's methyl.

[0201] The reaction according to Scheme 2 involves treating a glycoluril compound having Formula II with paraformaldehyde in the presence of an acid to obtain a glycoluril bisether of Formula III. The paraformaldehyde is added in a molar excess relative to the glycoluril compound. The ratio of paraformaldehyde to glycoluril compound can be from about 3 equivalents to about 8 equivalents or from about 4 equivalents to about 6 equivalents.

[0202] The paraformaldehyde used in Scheme 2 is a polyoxymethylene, which is a polymerization product of formaldehyde, and its typical degree of polymerization can be 8 to 100 units. The paraformaldehyde can be provided in the form of a solid or a solution, in particular in the form of an aqueous solution.

[0203] Paraformaldehyde can be added to the mixture of the glycoluril compound, acid, and solvent in the reaction vessel. Prior to adding the paraformaldehyde to the reaction mixture, the temperature of the mixture is brought to at least 35° C. The temperature of the reaction mixture is maintained at or above 35° C. for the duration of the addition, and can thereafter be maintained at or above 35° C., or increased, for example, to 45° C. or above, or to 50° C. or above, which increase can be temporary, or maintained at or above the remainder of the reaction, or even decreased from the temperature at the time of addition, as long as the reaction temperature remains at or above about 35° C.

[0204] The temperature of the reaction of Scheme 2 can be maintained above about 35° C., or above about 36° C., or above about 37° C., or above about 38° C., or above about 39° C., or above about 40° C., or above about 41° C., or above about 42° C., or above about 43° C., or above about 44° C., or above about 45° C. The temperature of the reaction of Scheme 2 can be maintained in the range of about 35 to 55° C., or about 35 to 50° C., or about 35 to 40° C., or at about 35° C.

[0205] Heating the reaction mixture during the addition of paraformaldehyde results in a significantly increased yield of the glycoluril bisether of Formula III. In several embodiments, the yield of the glycoluril bisether of Formula III is greater than about 70%.

[0206] The acid used in the reaction mixture is a strong acid. In several embodiments, the acid in the reaction of Scheme 2 can have a pKa of less than about 2.5 or a pKa of less than about 2.0 or a pKa of less than about 1.5 or a pKa of less than about 1 or a pKa of less than about 0.9 or a pKa of less than about 0.8 or a pKa of less than about 0.7 or a pKa of less than about 0.6 or a pKa of less than about 0.5. In several embodiments, the acid in the reaction of Scheme 2 can have a pKa of less than about 0.9.

[0207] The acid in the reaction of Scheme 2 can include, but is not limited to, HF, HC1, HBr, HCIO4, HNO3, H2SO4, H3PO4, a sulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid, Eaton’s reagent, trifluoroacetic acid, or combinations thereof. In several embodiments, the acid in the reaction of Scheme 2 includes HF, HC1, or HBr, and in particular, the acid is HC1. The molar concentration of the acid used in this reaction can range from about 5 to about 10 M, from about 6 to about 9 M, or from about 7 to about 9 M.

[0208] In several embodiments, the method includes the following Scheme 3.

[0209] Scheme 3

[0210]

[0211] wherein R 4A and R 4B are as described herein. In several embodiments, R 4A and R 4B are hydrogen.

[0212] The reaction according to Scheme 3 involves treating a glycoluril compound having Formula II’ with paraformaldehyde in the presence of an acid to give a glycoluril dimer of Formula IV. The solvent can be selected from water, an alcohol such as methanol, ethanol, and isopropanol, dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile, N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran (THF), dioxane, sulfolane, acetone, N,N’-dimethylpropyleneurea (DMPU), diglyme, hexamethylphosphoramide (HMPA), or combinations thereof. In several embodiments, the solvent is water, or a combination of water and another solvent.

[0213] The paraformaldehyde is added in about the same or similar amount as the glycoluril compound. The ratio of paraformaldehyde to glycoluril compound can be about 0.5 equivalents to about 1.5 equivalents or about 0.8 equivalents to about 1.2 equivalents. The paraformaldehyde can be about 1.0 equivalents relative to the glycoluril compound.

[0214] According to Scheme 3, the reaction mixture in Scheme 3 does not solidify during the course of the reaction. For example, the reaction mixture does not form a gel during the reaction or upon quenching of the reaction. Maintaining stoichiometry as the reaction proceeds can be important for the selective production of the dimer of Formula IV without gelling of the reaction mixture. The paraformaldehyde as used in Scheme 3 can be provided as a solid or in solution, particularly aqueous solution. The paraformaldehyde is added to the reaction vessel containing the compound of Formula (II’) and the acid over an extended period of time, for example dropwise or in portions.

[0215] Maintaining careful stoichiometry as the reaction proceeds can be important for the selective production of the glycoluril dimer of Formula IV. While it was expected that slow addition of paraformaldehyde to the reaction mixture can disrupt the reaction stoichiometry, the inventors have found that the yield and purity of the glycoluril dimer of Formula IV is consistently unchanged or improved. In addition, slow addition of paraformaldehyde to the reaction mixture reduces or prevents gelling of the reaction mixture. The reaction proceeds more completely and workup is greatly improved, making the reaction useful on a commercial scale.

[0216] The paraformaldehyde can be added to the compound of Formula II’ in more than 4 portions, for example in 4-10 portions or 5-8 portions. The paraformaldehyde can be added to the compound of Formula II’ in 4 portions, 5 portions, 6 portions, 7 portions, or 8 portions or more. For example, the paraformaldehyde is added in four or more portions spaced at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes apart. In embodiments, the paraformaldehyde is added in six or more portions spaced at least about 30 minutes apart.

[0217] Alternatively, the paraformaldehyde is added to the compound of Formula II’ over a period of at least about 45 minutes or at least about 1 hour, at least about 1.5 hours, at least about 2 hours, at least about 2.5 hours, at least about 3 hours, at least about 3.5 hours, at least about 4 hours, at least about 4.5 hours, or at least about 5 hours, wherein the addition is continuous (i.e., from the first addition to the last addition) over the time period, for example by continuous addition or dropwise addition, or in multiple portions over the time period.

[0218] The acid used in the reaction mixture of Scheme 3 is a strong acid. In embodiments, the acid in the reaction of Scheme 3 can have a pKa of less than about 2.5 or a pKa of less than about 2.0 or a pKa of less than about 1.5 or a pKa of less than about 1 or a pKa of less than about 0.9 or a pKa of less than about 0.8 or a pKa of less than about 0.7 or a pKa of less than about 0.6 or a pKa of less than about 0.5. In embodiments, the acid in the reaction of Scheme 3 can have a pKa of less than about 0.9.

[0219] The acid in the reaction of Scheme 3 can include, but is not limited to, HF, HC1, HBr, HCIO4, HNO3, H2SO4, H3PO4, a sulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid, Eaton’s reagent, trifluoroacetic acid, or combinations thereof. In several embodiments, the acid in the reaction of Scheme 3 includes HF, HC1, or HBr, and in particular, the acid is HC1. The molarity of the acid used in this reaction can range from about 5 to about 10 M, from about 6 to about 9 M, or from about 7 to about 9 M.

[0220] During the synthesis of the glycoluril dimer compound (IV) or (IV-A), additional improvements were realized by optimizing the reaction temperature to about 55 °C or greater than 55 °C, significantly improving purity and yield. The temperature of the reaction vessel was increased before, during, and after the addition of paraformaldehyde to the reaction according to Scheme 3. The temperature of the reaction vessel after the addition of paraformaldehyde was maintained at a temperature of greater than 50 °C, greater than 51 °C, greater than 52 °C, greater than 53 °C, greater than 54 °C, greater than 55 °C, greater than 56 °C, greater than 57 °C, greater than 58 °C, greater than 59 °C, greater than 60 °C, greater than 61 °C, greater than 62 °C, greater than 63 °C, greater than 64 °C, greater than 65 °C, greater than 66 °C, greater than 67 °C, greater than 68 °C, greater than 69 °C, or greater than 70 °C.

[0221] While heating the reaction of Scheme 3 can promote side reactions including oligomerization and polymerization, thereby reducing the yield of the glycoluril dimer of Formula IV, the inventors have discovered that conducting the reaction at elevated temperatures promotes an increase in the yield and purity of the reaction product.

[0222] The method can further include a step of isolating the glycoluril dimer compound of Formula IV. For example, the isolation can include recrystallization, precipitation, aggregation, centrifugation, filtration, or combinations thereof. The isolation process can include contacting the reaction mixture with water, heating to a temperature of at least about 70 °C, cooling to a temperature of less than about 30 °C, and isolating the solid, for example, by filtering or centrifuging the reaction mixture.

[0223] After adding or contacting the water with the reaction mixture, the reaction mixture is heated to a temperature of at least about 70 °C, at least about 71 °C, at least about 72 °C, at least about 73 °C, at least about 74 °C, at least about 75 °C, at least about 76 °C, at least about 77 °C, at least about 78 °C, at least about 79 °C, or at least about 80 °C. The reaction vessel can be set at a temperature of at least about 70 °C, at least about 71 °C, at least about 72 °C, at least about 73 °C, at least about 74 °C, at least about 75 °C, at least about 76 °C, at least about 77 °C, at least about 78 °C, at least about 79 °C, or at least about 80 °C while the reaction mixture is stirred for about 1 to 5 days, or about 2 to 5 days, or about 3 days.

[0224] After heating the reaction mixture and water, the temperature of the reaction mixture is cooled to less than about 30 °C, less than about 29 °C, less than about 28 °C, less than about 27 °C, less than about 26 °C, less than about 25 °C, less than about 24 °C, less than about 23 °C, less than about 22 °C, less than about 21 °C, or less than about 20 °C.

[0225] In certain embodiments, the compound of Formula IV in solid form (e.g., precipitate, granules, or powder) can be collected by centrifugation of the reaction mixture. Alternatively, the compound of Formula IV in solid form (e.g., precipitate, granules, or powder) can be collected by filtration. In large scale synthesis, post-reaction precipitation conditions can be important to improve the production yield and purity of the reaction in Scheme 3. Precipitation can include the addition of various solvents (e.g., water or aqueous solutions, or mixtures of polar solvents), followed by removal of the solids, e.g., by filtration.

[0226] Isaacs and co-workers disclose the synthesis of glycoluril dimer 3 in “Acyclic cucurbit[n]uril molecular containers enhance the solubility and bioactivity of poorly soluble pharmaceuticals”, Nature Chem 4, 503-510 (2012). However, this procedure does not suggest a method to reduce solidification of the reaction mixture, which the inventors have found makes purification and isolation of dimethyl glycoluril 3 very complex. In addition, the reported method is carried out at low temperature, which the inventors have determined is detrimental to the yield and purity of the glycoluril dimer. Furthermore, the inventors have found that the method of direct crystallization of the crude material as reported in the prior literature reduces the purity of the final product.

[0227] In several embodiments, the method comprises the following Scheme 4.

[0228] Scheme 4

[0229]

[0230] wherein R 4A and R 4B as described herein.

[0231] The reaction according to Scheme 4 involves condensation of glycoluril bisether of Formula III and glycoluril dimer of Formula IV to give glycoluril tetramer of Formula V. The reaction in Scheme 4 is carried out in the presence of (a) one or more acids having a pKa less than about 1, and optionally (b) one or more polar aprotic solvents and / or additional acid solvents.

[0232] In particular, the reaction solvent includes TFA, which can be present as the only solvent, or can be combined with one or more polar aprotic solvents, combined with one or more strong acids (e.g., Eaton’s reagent). The use of TFA without MeSO3H or Eaton’s reagent typically results in a very slow and inefficient reaction. Most non-acidic solvents do not completely dissolve the reagents and products, or are not compatible with the strongly acidic components.

[0233] In certain embodiments, the solid form of the glycoluril bisether of Formula III can be dispersed in a solvent component and added to a reaction vessel containing the glycoluril dimer. Further, the reaction as described in Scheme 4 can require less catalytic acid by using TFA. In certain embodiments, about 10 equivalents or more of Eaton’s reagent (as one or more acids) can still be added to promote an increase in the rate of reaction.

[0234] The one or more acids used in the reaction mixture of Scheme 3 are strong acids. In several embodiments, the strong acid in the reaction of Scheme 4 can have a pKa of less than about 1 or less than about 0.5 or less than about 0 or less than about -1. The reaction mixture can include an additional acidic solvent. The additional acidic solvent in the reaction of Scheme 4 can have a pKa of between about 3 to about 0, or can have a pKa of less than about 2.5, less than about 2.0, less than about 1.5, less than about 1, less than about 0.5.

[0235] The one or more strong acids in the reaction of Scheme 4 can include, but are not limited to, Eaton’s reagent, MeSO3H, toluenesulfonic acid, H2SO4, triflic acid, phosphoric acid, sulfuric acid, CSA, EtSO3H, HC1, HBr, HCIO4, HNO3, or combinations thereof. In several embodiments, the acid includes methanesulfonic acid. In several embodiments, the acid in the reaction includes Eaton’s reagent, which is a combination of methanesulfonic acid and phosphorus pentoxide, for example, including about 10 wt% phosphorus pentoxide in the methanesulfonic acid. In several embodiments, at least about 8 equivalents of the strong acid are used, and in particular, at least about 10 equivalents of the strong acid are used.

[0236] The solvent in the reaction of Scheme 4 can include an additional acid, including, but not limited to, trifluoroacetic acid (TFA), acetic acid, phosphoric acid, polyphosphoric acid (PPA), or combinations thereof. In certain embodiments, the additional acid is TFA.

[0237] In several embodiments, the ratio between the one or more strong acids in the solvent and the additional acid can range from about 1 : 1 to 20: 1, about 1 : 1 to 19: 1, about 1 : 1 to 18: 1, about 1 : 1 to 17: 1, about 1 : 1 to 16: 1, about 1 : 1 to 15: 1, or about 1 : 1 to 14: 1, about 1 : 1 to 13: 1, about 1 : 1 to 12: 1, about 1 : 1 to 11 : 1, about 1 : 1 to 10: 1, about 1 : 1 to 9: 1, about 1 : 1 to 8: 1, about 1 : 1 to 7: 1, about 1 : 1 to 6: 1, about 1 : 1 to 5: 1, about 1 : 1 to 4: 1, about 1 : 1 to 3: 1, or about 1 : 1 to 2: 1.

[0238] In addition, the ratio between the one or more strong acids in the solvent and the additional acid is about 20 to 1, about 19 to 1, about 18 to 1, about 17 to 1, about 16 to 1, about 15 to 1, about 14 to 1, about 13 to 1, about 12 to 1, about 11 to 1, about 10 to 1, about 9 to 1, about 8 to 1, about 7 to 1, about 6 to 1, about 5 to 1, about 4 to 1, about 3 to 1, about 2 to 1, or about 1 to 1.

[0239] The reaction of Scheme 4 optionally includes one or more polar aprotic solvents in the reaction of Scheme 4, including but not limited to DMF, DMSO, acetonitrile, DMA, NMP, THF, dioxane, sulfolane, acetone, DMPU, diglyme, HMPA, or combinations thereof.

[0240] In several embodiments, TFA is used as the solvent and about 10 equivalents of a strong acid (one or more acids with a pKa less than 1, such as Eaton’s Reagent) in the reaction of Scheme 4.

[0241] During the reaction of Scheme 4, the temperature of the reaction vessel can be increased due to the less reactive solvent and acid mixture by using TFA as the solvent. The reaction temperature is maintained at a temperature of greater than 55 °C, greater than 56 °C, greater than 57 °C, greater than 58 °C, greater than 59 °C, greater than 60 °C, greater than 61 °C, greater than 62 °C, greater than 63 °C, greater than 64 °C, greater than 65 °C, greater than 66 °C, greater than 67 °C, greater than 68 °C. In several embodiments, the temperature of the reaction vessel is maintained at a temperature of greater than 69 °C or greater than 70 °C. In certain embodiments, the reaction temperature is maintained at a temperature of about 55 °C.

[0242] The use of these conditions can significantly improve production yields, particularly in large scale reactions (e.g., kg scale reactions).

[0243] After the reaction is complete, the remaining acid (e.g., MeSO3H, etc.) can be removed by filtration and washing to quench, followed by drying the crude solid. A single filtration / recrystallization step can not be sufficient to remove impurities including excess glycoluril bisether.

[0244] Further, at the completion of the reaction, additional acid, such as TFA, can be added to the reaction, which can improve precipitation and improve purification and / or yield in large scale reactions. At the end of the reaction of Scheme 4, the compound of Formula V can be isolated by the following steps: adding additional acid, such as TFA, to the reaction mixture after the completion of the reaction; precipitating the compound of Formula V, for example, by adding an anti-solvent, such as water; and collecting the mixture comprising the compound of Formula V, for example, by filtration.

[0245] The precipitation of the compound of Formula V includes the step of adding an anti-solvent of the compound of Formula V. In certain embodiments, the anti-solvent includes, but is not limited to, water, methanol, ethanol, isopropanol, acetone, acetonitrile, THF, dioxane, and combinations thereof.

[0246] In several embodiments, the compound of Formula V in solid form (e.g., precipitate, granules, or powder) can be collected by centrifugation of the mixture. Alternatively, the compound of Formula V in solid form (e.g., precipitate, granules, or powder) can be collected by filtration. In several embodiments, the obtained compound can be washed with water and / or acetone.

[0247] Isaacs and co-workers reported the synthesis of the glycolaldehyde tetramer compound 5 (Nature Chem 4, 503-510 (2012)), in which the researchers found a lower yield (36%). Additionally, the reported purification process of the crude product with direct recrystallization with TFA after water wash resulted in a lower purity product. Other methods of forming this compound have been published (see, e.g., Org. Chem. Front., 2019, 1555), however we have found that the procedure is not feasible at large scale due to the small particle size of the product that penetrates the filter centrifuge. Furthermore, we saw an improvement in purity when decreasing the concentration of the Eaton’s reagent, as well as waste handling and cost benefits associated with using less strong acid.

[0248] In one aspect, a method of making a compound of Formula I includes the following Scheme 1.

[0249] Scheme 1

[0250]

[0251] R 1A , R 1B , R 1C , R 1D , R 3A , R 3B , R 4A and R 4B as described herein.

[0252] The reaction according to Scheme 1 involves the condensation of a glycoluril tetramer of Formula V with a compound of Formula VI. The reaction in Scheme 1 is conducted in the presence of a solvent system comprising (i) one or more acids having a pKa less than about 1 and (ii) an acid anhydride.

[0253] In several embodiments, the one or more acids having a pKa less than about 1 comprise trifluoroacetic acid, Eaton’s reagent, methanesulfonic acid (MeSO3H), toluenesulfonic acid (TsOH), trifluoromethanesulfonic acid, phosphoric acid, sulfuric acid, camphorsulfonic acid (CSA), ethanesulfonic acid (EtSO3H), or combinations thereof. In several embodiments, the one or more acids having a pKa less than about 1 comprise trifluoroacetic acid.

[0254] The use of an acid anhydride as a co-solvent greatly improves the reaction rate and overall yield of the reaction, e.g., overall yield (66%). The acid anhydride can be an organic acid anhydride in which the acyl group of the acid anhydride is derived from a carboxylic acid, a sulfonic acid, a phosphonic acid, or a combination. The acid anhydride can be selected from the group consisting of compounds having the general structure R’-C(=O)-O-C(=O)-R”, wherein R’ and R” can be the same or different and are independently selected from alkyl, aryl, heteroalkyl, or can be taken together to form a heterocyclic ring, each of which can be substituted with halo, alkyl, trihaloalkyl, and the like. In certain embodiments, the acid anhydride can be selected from, but not limited to, acetic anhydride, trifluoroacetic anhydride, butyric anhydride, propionic anhydride, trifluoromethanesulfonic anhydride, succinic anhydride, maleic anhydride, or combinations thereof. The acid anhydride can be acetic anhydride, trifluoroacetic anhydride, or combinations thereof.

[0255] The amount of acid anhydride in the reaction can range from about 0.01% (i.e., acid anhydride volume / total solvent volume x 100) by volume of solvent up to the concentration at which the acid anhydride is no longer soluble in the reaction solvent. The acid anhydride can be present at about 0.01% to about 60% by volume of solvent or about 0.3% to about 55% by volume of solvent or about 1% to about 55% by volume of solvent or about 2% to about 50% by volume of solvent; or about 1% to about 45% by volume of solvent or about 2% to about 40% by volume of solvent.

[0256] The reaction in Scheme 1 can benefit from avoiding the use of an inappropriately large excess of compound VI, thereby making the overall synthesis more efficient and economical. The reaction in Scheme 1 can use about 4 equivalents or less of compound of Formula VI or about 3 equivalents or less of compound of Formula VI. In several embodiments, the reaction of Scheme 1 uses about 2 equivalents to about 5 equivalents of compound of Formula VI or about 2.5 equivalents to about 4.5 equivalents of compound of Formula VI or about 2.5 equivalents to about 4 equivalents of compound of Formula VI.

[0257] An anti-solvent (e.g., a polar solvent) can be used to precipitate the product obtained after this reaction, particularly in large scale synthesis. Exemplary anti-solvents can include acetone, brine, ethanol, methanol, halogenated water, or combinations thereof.

[0258] Synthesis of cucurbituril compounds has been reported (see, e.g., Org. Biomol. Chem., 2014, 12, 2413-2422; WO2012 / 051407). However, these procedures report low yields (e.g., 40% vs. 67%) and do not use an anhydride as a co-solvent, which we have found improves the rate of reaction in this synthesis. In addition, we have seen that reactions employing anhydride-free conditions are incomplete, which results in lower purity and yield of the final product.

[0259] In an aspect, a method of making a compound of Formula (I-A) comprises the following Scheme 5.

[0260] Scheme 5

[0261]

[0262] X is as described herein.

[0263] The reaction according to Scheme 5 comprises contacting a compound of Formula VI-A and a compound of Formula V-A according to the conditions discussed above for Scheme 1.

[0264] In an aspect, a method of making a compound of Formula (I-B) comprises the following Scheme 6.

[0265] Scheme 6

[0266]

[0267] X is as described herein.

[0268] In several embodiments, the method comprises contacting a compound of Formula VI-B and a compound of Formula V-A according to the conditions discussed above for Scheme 1.

[0269] In several embodiments, the method comprises the following Scheme 7, which produces a compound of Formula VI-A.

[0270] Scheme 7

[0271]

[0272] X is as described herein.

[0273] The reaction in Scheme 7 is performed in the presence of a base and a solvent, which includes one or more of water, a polar aprotic solvent, and combinations thereof.

[0274] Rather than adding a base in an aqueous basic solution or as a solvent, the base can be added as a salt or in solid form. Thus, there can be a molar equivalent reduction of base in the reaction mixture, e.g., the base is present in about 1.5 to 3.0 equivalents, about 2.0 to 2.5 equivalents, about 2.2 to 2.4 equivalents, about 2.0 equivalents, about 2.1 equivalents, or particularly about 2.2 equivalents, about 2.3 equivalents, about 2.4 equivalents, or about 2.5 equivalents. The base includes, but is not limited to, an alkali metal hydroxide (e.g., NaOH, LiOH, or KOH) or a quaternary ammonium hydroxide.

[0275] The amount of base, such as NaOH, in this reaction can provide higher yields and purity of the compound of Formula (VI-A). While it is known that lactones hydrolyze in the presence of a base, it was not known that the rate of lactone hydrolysis competes with the alkylation of the hydroquinone with the lactone. For example, conventionally, a large excess of NaOH (2.5 M) can be used as a co-solvent in such reactions, however, the excess NaOH also reacts with the 1,3-propane lactone, resulting in incomplete reactions and loss of yield.

[0276] The lactone can be added over an extended period of time, e.g., dropwise or in several portions. In several embodiments, in the reaction of Scheme 6, the lactone is added over a period of longer than about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, or about 5 hours. Alternatively, the lactone is added in two portions, three portions, four portions, or more, with at least about 30 minutes or at least about 1 hour between portions. In several embodiments, the lactone is added in four portions or more, with at least about 1 hour, at least about 1.5 hours, at least about 2 hours, at least about 2.5 hours, or at least about 3 hours between portions.

[0277] The reaction further comprises a hydroquinone. Alternatively, the reaction can use 1,4-dihydroxynaphthalene.

[0278] The reaction vessel containing the hydroquinone, base, and solvent is cooled to less than about 10 °C, less than about 9 °C, less than about 8 °C, less than about 7 °C, less than about 6 °C, less than about 5 °C, prior to the addition of the lactone, or prior to each addition of the lactone when the lactone is added in portions or batches.

[0279] The amount of base in the reaction is equal to or greater than the amount of the sultolane. In certain embodiments, the amount of base in the reaction is between 1 and 10 equivalents of the sultolane, for example, 2 equivalents, 3 equivalents, 4 equivalents, 5 equivalents, 6 equivalents, 7 equivalents, 8 equivalents, 9 equivalents, or 10 equivalents of the sultolane. Further, the base can be added over an extended period of time, for example, dropwise or in several portions. In certain embodiments, the base is added over a period of longer than about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, or about 5 hours. Alternatively, the base is added in two portions, three portions, four portions, or more portions, with at least about 1 hour, at least about 1.5 hours, at least about 2 hours, at least about 2.5 hours, or at least about 3 hours between portions.

[0280] The synthesis of aromatic side wall compounds VI-A or VI B has been reported (see, e.g., Ma, D, et al. Nature Chem 4, 503-510 (2012); WO 2012 / 051407). However, the method disclosed herein achieves an improved yield (90% vs. 81%) through this step. Further, the method disclosed herein allows for a reduction in reaction time (e.g., from 12 h to 2 h). Also, when employing the procedure disclosed herein, a reduced level of mono-substituted impurities is observed.

[0281] In several embodiments, the method comprises the following Scheme 8, which produces a compound of Formula VI-B. X is as described herein. In several embodiments, the reaction in Scheme 8 can be performed according to the conditions provided above in Scheme 7.

[0282] Scheme 8

[0283]

[0284] In several embodiments, the method comprises the following Scheme 9.

[0285] Scheme 9

[0286]

[0287] In several embodiments, the reaction in Scheme 9 can be performed according to the conditions provided above for Scheme 4.

[0288] In several embodiments, the method comprises the following Scheme 10.

[0289] Scheme 10

[0290]

[0291] In several embodiments, the reaction in Scheme 10 can be performed according to the conditions provided above in Scheme 2.

[0292] In several embodiments, the method comprises Scheme 11 below.

[0293] Scheme 11

[0294]

[0295] In several embodiments, the reactions in Scheme 11 can be performed according to the conditions in Scheme 3 as described above.

[0296] Exemplary syntheses of a compound of Formula I-A (e.g., CS-1103) and a compound of Formula I-B (e.g., CS-1105) are shown in Figure 1 and Figure 2 respectively.

[0297] Among other things, in Scheme 4, the reaction includes the use of trifluoroacetic acid (TFA) as the solvent and 10 equivalents of a strong acid (e.g., Eaton’s reagent, H2SO4, MsOH, TsOH, or camphorsulfonic acid) to facilitate the reaction. This significantly reduces the amount of excess sulfonic acid used compared to what has been reported. This method also results in higher yields of the compound of Formula V or V-A and, unexpectedly, results in larger particles in the crude material, which can be effectively filtered on a large scale. These advantages are unexpected benefits that result from converting the solvent component in Scheme 4 to a combination of TFA and a strong acid (e.g., Eaton’s reagent, H2SO4, methanesulfonic acid, toluenesulfonic acid, or camphorsulfonic acid, etc.). Attempts to use TFA as the single solvent and catalyst without the addition of a sulfonic acid were found to be less efficient. Further, the reduced viscosity of the reaction mixture of Scheme 4 is an unexpected benefit of changing the reaction conditions. As a result, there is no need to conduct extensive optimization efforts while providing higher yields and purity. Further, the reaction mixture contains a lower concentration of the strong acid or Eaton’s reagent, which makes the reaction conditions safer and more easily disposed of. For example, the workup process of the reaction is easier with a weaker acid, and the reaction mixture becomes less viscous, which makes the reaction process easier to scale up to large volumes.

[0298] According to certain embodiments, the reactions in Scheme 7 or 8 reduce the amount of NaOH in this reaction, which can provide higher yields and purity of the compound of Formula (VI-A) or (VI-B). While it is known that the sultone hydrolyzes in the presence of base, it was not suggested in the related art to find that the rate of reaction of sultone hydrolysis competes with the alkylation of the hydroquinone with the sultone. Conventionally, a large excess of NaOH (2.5 M) is used in this reaction, however, the excess NaOH also reacts with the 1,3 propane sultone, resulting in incomplete reaction and loss of yield.

[0299] Further, according to certain embodiments of Scheme 3, by optimizing the reaction temperature at about 55 °C or above 55 °C, the present disclosure provides additional improvements during the synthesis of compound (IV) or (IV-A), significantly improving the purity and yield.

[0300] According to certain embodiments, in Scheme 1, the present disclosure provides the benefit of avoiding the use of excess compound VI or VI-A, making the overall synthesis more efficient and economical.

[0301] Examples

[0302] Comparative Example A

[0303] Glycoluril dimer [3]: Glycoluril (250 g, 1.76 mol) and paraformaldehyde (52.5 g, 1.76 mol) powders (no solvent) were stirred together in a Nalgene beaker at room temperature with a metal spatula until well mixed (~5 min). Aqueous HC1 (8 M, 350 mL) was slowly poured into the beaker while the mixture was manually stirred using a metal spatula. After ~90 seconds of stirring, a rubbery white solid formed in the beaker. Heat was generated inside the flask during this step (the beaker felt warm to the touch, but the temperature was not measured). Immediately the white solid was broken into smaller pieces with a metal spatula and the pieces and a magnetic stir bar were added to a round bottom flask. The mixture was stirred at 50 °C for 1 h. Any large pieces of solid were further broken up using a metal spatula. The residue along the sides of the flask was also scraped into the mixture. This well dispersed slurry was returned to the oil bath and stirred at 50 °C for 2 days.

[0304] The reaction mixture was then cooled to room temperature (RT) and filtered by vacuum filtration using Whatman 1 filter paper. Once mostly dry, the white semi-solid (glue-like) was transferred to a conical flask and stirred with 250 mL of water. The mixture was stirred at RT overnight (until the chunks broke up into small particles). The slurry was filtered by vacuum filtration (Whatman 1 filter paper) and left to dry on the filter paper (several hours) before being transferred to the next step. If the product is transferred before it is completely dry, the filter paper will stick to the product during the transfer and end up in the round bottom (RB) flask. The crude solid (~300 g) was transferred to a beaker and 4 x 100 mL aliquots of TFA were added. After each aliquot, the TFA / crude slurry was added to a 1 L RB flask. The mixture was stirred at 75 °C for 2 h, then cooled to RT and stirred at RT overnight. The mixture was filtered by vacuum filtration using Whatman 1 filter paper and dried on the filter funnel for 1 day. The solid was dried until it could be transferred to a round bottom flask. To remove the residual TFA, the dried solid was stirred with EtOH (600 mL) at 80 °C overnight.

[0305] The slurry was allowed to cool to RT, filtered by vacuum filtration using Whatman 1 filter paper, and the solids were dried on the filter funnel for 1 day. The white solid was broken up with a spatula and transferred to an RB flask, then dried under high vacuum until a constant weight was achieved (1 day). The resulting product was a white solid (119.7 g, 44%). The product was analyzed using 1 H and 13 C NMR, melting point, and IR were analyzed. The spectral data were consistent with those reported in the literature (Huang, W.-H.; Zavalij, P. Y.; Isaacs, L. J. Am. Chem. Soc. 2008, 130, 8446-8454).

[0306] Comparative Example B

[0307] Glycoluril tetramer building block [5]: Glycoluril dimer (13.1 g, 33.13 mmol) was dissolved in Eaton’s reagent (7.7% P2O5 in MeSO3H, 95 mL) and the solution was heated to 50 °C under nitrogen. After 30 minutes, with good magnetic stirring, most of the solid dissolved. Dimethylglycoluril bisether (4, 47.5 g, 186.4 mmol) was added in one portion and the powder was manually stirred into the solution using a spatula.

[0308] The reaction mixture was stirred at 50 °C for 3 h. During the 3 hours, the reaction mixture viscosity increased, so it was important to ensure stirring was maintained. At 3 hours, the red solution was poured into 850 mL of water and another 100 mL (total 950 mL) was used to wash the interior of the flask into the total volume. The mixture was stirred at 25 °C for 10 minutes, then transferred to four 1 L centrifuge bottles and centrifuged (3000 RPM, 2500 G, 10 minutes), and the supernatant was decanted.

[0309] To each centrifuge bottle, water was added (150 mL each), and the bottles were re-centrifuged and decanted (3000 RPM, 2500 G, 10 minutes) twice until the decanted solvent was no longer pink. After decanting, the centrifuge tubes were stored overnight at -4 °C. The solids were dried by transferring them to a round bottom flask and placing them on high vacuum or a rotary evaporator. The dried solids were then dissolved in TFA (96 mL total, 24 mL per centrifuge bottle), and the bottles were vortexed or sonicated to facilitate dissolution. To the TFA solution in each bottle, 150 mL of water was added, causing a white precipitate to form. The samples were vortexed, then centrifuged (3000 rpm, 2500 G, 10 minutes) and decanted. The solids were then washed with water (600 mL per bottle), vortexed or sonicated to break up the precipitate, and centrifuged (4000 rpm, 4400 G, 10 minutes). The solids were then washed with acetone twice (2x) (300 mL per tube), vortexed, and centrifuged (3800 rpm, 4000 G, 10 minutes). The precipitates were stored overnight at -4 °C. A second round of TFA / water / acetone washes removed colored impurities that were not visible on NMR. It was not clear how much impurity was removed compared to product.

[0310] The precipitates from each bottle were collected in a round bottom flask, and the centrifuge tubes were rinsed with EtOH in order to transfer all product to the flask. The EtOH was removed using rotary evaporation, and the final product was dried under high vacuum. The combined sample was purified again by dissolving all solids in TFA (48 mL). The product dissolved in TFA was then added in equal portions to six 50 mL falcon tubes (8 mL per centrifuge tube). The falcon tubes were filled with water to a total of 50 mL, and centrifuged (3800 RPM, 2300 G, 10 minutes) and decanted. The falcon tubes were then filled with water to the 25 mL mark, centrifuged (3800 RPM, 2300 G, 10 minutes) and decanted. The solids were then washed by adding acetone to the centrifuge tubes twice to the 25 mL mark, centrifuging (3800 RPM, 2300 G, 10 minutes) and decanting the tubes. The solids were transferred to a round bottom flask and dried using high vacuum until a constant weight was achieved. The final product was a white powder (12.1 g, 47% yield).

[0311] Using 1 H and 13 C NMR, melting point, and IR were analyzed.

[0312] Comparative Example C

[0313] Aromatic sidewall building blocks [8]: A solution of hydroquinone (72.7 g, 0.66 mol) in aqueous NaOH (2.5 M, 1.0 L) was treated with a solution of 1,3-propane sultone (200 g, 1.64 mol) in 1,4-dioxane (1.0 L). The mixture was stirred at RT for 12 h.

[0314] The solution was then poured into acetone (4.0 L) to precipitate a reddish solid. This solid was collected via vacuum filtration (Whatman 1 filter paper) funnel and rinsed with 100 mL of other acetone when the solid was still in the Buchner funnel. The solid was transferred to a round-bottomed flask, which was vacuum-dried overnight. The solid was recrystallized from a mixed solvent of water and EtOH to obtain the product, which was beige crystals (195 g, 74%). Note: 100 g of the crude material was dissolved in 500 mL of water, followed by addition of 1.0 L of EtOH. The mixture was heated to dissolve all solids, and if necessary, other H o ​​was added to promote this process. The mixture was then cooled to RT. The recrystallized product was then collected by filtration.

[0315] use 1 H and 13 Analyses were performed by C NMR, melting point and IR.

[0316] Comparative Example D

[0317] CS-1103 Synthesis: A solution of methyl tetramer (5) (20.0 g, 25.6 mmol) was formed in TFA / Ac2O (v / v = 1:1, 200 mL). [8](C6H4(OCH2CH2CH2SO3Na)2, 39.6 g, 102.4 mmol) was added to the solution under stirring. The mixture was stirred and heated at 70°C for 3 h.

[0318] The reaction mixture was poured into a conical flask while stirring with MeOH (1.0 L). The solids were collected by filtration (Whatman 1 filter paper) and dried under high vacuum. Upon drying, the solids (59.8 g) were dissolved in water (150 mL), stirred at room temperature, precipitated using acetone (300 mL), and filtered using vacuum filtration. Upon drying, the material was again dissolved in water (150 mL) and precipitated using acetone (300 mL), which resulted in the collection of 48.4 g of crude material. This material was dissolved in water (60 mL), stirred at room temperature, and precipitated using acetone (60 mL). The mixture was then cooled to 0 °C overnight and filtered using vacuum filtration (Whatman 1 filter paper). The resulting solids (~23.5 g) were dissolved in water (94 mL) to a concentration of 250 mg / mL. This solution was filtered using Whatman 1 filter paper and the filtrate was adjusted to pH = 7 by the addition of 1 M aqueous NaOH solution (~150 μί). The filtrate was concentrated by rotary evaporation and the solids were further dried under high vacuum to yield CS-1103 (23.4 g, 60%) as a light yellow powder. This powder was 93-95% pure by HPLC-UV / Vis analysis.

[0319] Re-crystallization

[0320] The light yellow powder CS-1103 (1.0 g) was suspended in deionized water (1.4 mL). The mixture was heated to reflux while stirring. When the compound was completely dissolved (~10 minutes), the mixture was removed from the heating device and slowly cooled to room temperature over two hours. As the solution cooled, crystals began to form. The solution containing the crystals was further cooled to 4 °C overnight. The resulting crystals were filtered and washed with ice-cold deionized water. Approximately 400 mg (40%) of product was recovered as colorless crystals (>98% pure by HPLC UV-Vis analysis).

[0321] Example 1: Synthesis of CS-1103

[0322] Step 1: Synthesis of [2] dimethyl glycoluril

[0323]

[0324] A solution of urea (1510 g, 25.1 mol) in HCl (0.3 M, 3.7 L) was treated with 2,3-butanedione (660 g, 7.7 mol). The solution was stirred at RT for 12 h. The reaction mixture was filtered and the solids were washed with water (3.5 L x 2) and then with ethanol (2.0 L) to give 2 as a white solid (1168 g, 86%).

[0325] Step 2: Synthesis of [4] dimethyl glycoluril diether

[0326]

[0327] A reactor was charged with 7.5 kg of water and 66.86 kg of 31.5% HC1 and the reactor temperature was set to 35 °C. Dimethyl glycoluril wet cake (19.54 kg, 114.8 mol) was added to the reactor followed by the addition of paraformaldehyde (15.67 kg, 522.3 mol, 4.5 equiv) and rinsed with water. The reaction mixture was set to a temperature of 50 °C and then cooled to a temperature of 35 °C. The reaction mixture was stirred for 24 hours and then cooled to a temperature of 25 °C. Water (120.5 L) was added for quenching and the resulting mixture was stirred at a temperature of 25 °C for 6 h and filtered. The filtered mixture was washed with water (4 x 46.0 L), filtered and washed with acetone (0-2 x 27.6 L). The mixture was dried and recovered to 19.5 kg of glycoluril bisether with a yield of 72%.

[0328] Step 3: Synthesis of [8] aromatic sidewalls

[0329]

[0330] A reaction vessel was charged with hydroquinone (7.0 kg, 63.6 mol), water 48.7 kg, 20% NaOH (28.98 kg, 144.9 mol NaOH, 2.3 equiv) and 12.34 kg of water. The reaction mixture was cooled to a temperature of 5 °C. A 20% solution of 1,3-propane sultone in dioxane (77.73 kg, 127 mol) and 2.0 equiv of sultone was added and the reaction temperature was set to a temperature of 25 °C and the reaction mixture was stirred for 2 hours. After the reaction, the mixture was cooled to a temperature of 5 °C.

[0331] A 20% solution of 1,3-propane sultone in dioxane (19.41 kg, 31.8 mol, 0.5 equivalent) was added to the reaction product, heated to 25°C and stirred for 2 hours. Optionally, a 20% solution of 1,3-propane sultone in dioxane (19.41 kg, 31.8 mol, 0.5 equivalent) was added and stirred for 2 hours. The reaction product was cooled to 5°C, a 20% aqueous solution of NaOH (13.04 kg, 65.2 mmol, 1.0 equivalent) was added, and the reactants were heated to 25°C and stirred for 2.5 hours. The reaction mixture was centrifuged, washed with acetone (2×53 L), and dissolved in water (35 kg). Additional EtOH (70 L) was added and heated to reflux for 2 hours. The mixture was cooled to 25°C, then centrifuged and washed with acetone (2×53 L). Recrystallization was optionally repeated. The washed mixture was dried under vacuum at 50° C., and 22.7 kg of compound 8 (90%) was recovered.

[0332] Step 4: [3] Synthesis of glycoluril dimer

[0333]

[0334] Water (8.8 kg), 31.5% HCl (35.8 kg), and 29.29 kg glycoluril (206.1 mol) were charged to a reaction vessel and the reaction vessel was set to a temperature of 50°C. Paraformaldehyde (6.08 kg, 202.7 mol, 1.0 equivalent) was added to the reaction vessel in 6 batches, the reaction temperature was set to 70°C, and the reaction mixture was stirred for 3 days. The reaction mixture was diluted with 29.4 kg of water, transferred to another container containing 119.4 kg of water, and the container was set to a temperature of 80°C, and the reaction mixture was stirred for 2 hours. The reaction was cooled to a temperature of 25°C, and the reaction mixture was centrifuged, washed with water (2 x 115 L) and acetone 1 x (73 L), and dried under vacuum at a temperature of 50°C. 16.5 kg of glycoluril dimer 3 (52%) was recovered.

[0335] Step 5: [5] Synthesis of glycoluril tetramer

[0336]

[0337] 5.21 (20.5 mol) kg of dimer 3, 15.04 kg of bis-ether 4 (59.2 mol, 2.8 equiv), 41.78 kg TFA were charged to a reaction vessel, the reaction temperature was set to a temperature of 55 °C and stirred for 90 minutes until all solids were dissolved, and the temperature was set to a temperature of 40 °C. Eaton’s reagent (19.31 kg) was added to the reaction vessel and the temperature was set to 55 °C for 4 hours and then to 40 °C. The reaction mixture was transferred to a vessel containing 148.4 kg water, the temperature was set to 25 °C and stirred for 30 minutes. The reaction mixture was centrifuged, washed with water (2 x 26.1 L) and then with acetone (2 x 25.5 L), transferred to a vacuum oven and then dried at a temperature of 50 °C.

[0338] The dried material was dissolved in TFA (117.6 kg) and stirred at a temperature of 35 °C until dissolved, then water 83.66 kg was added. The mixture was centrifuged, washed with water (1 x 87.5 L) and then with acetone (1 x 88.2 L). Water (43 kg) was added to the mixture to create a slurry and this was centrifuged, washed with water (116 kg) and then with acetone (117 L). A slurry was created by adding 88 L of acetone and the slurry was stirred, centrifuged, washed with acetone (117 L) and dried under vacuum at a temperature of 50 °C. The reaction product 5 (15.0 kg) was recovered (51%).

[0339] Step 6: Synthesis of CS-1103

[0340]

[0341] A reaction vessel was charged with 23.85 kg of acetic anhydride, 26.81 kg of TFA, compound 8 (10.23 kg, 25.7 mol, 4 eq) and tetramer 5 (4.99 kg). The reaction mixture was stirred at a temperature of 70 °C for 3 hours and cooled to a temperature of 35 °C. Then, the reaction mixture was added to another vessel containing 80 kg of MeOH and the mixture was stirred at a temperature of 0 °C for 30 minutes, centrifuged and washed with MeOH (31.2 kg x 2). The resulting product was dissolved in 37.5 kg of water at a temperature of 50 °C, then 60 kg of acetone was added to precipitate the product. The product was centrifuged, washed with acetone (1 x 30.65 kg), dissolved in 38.5 kg of water at a temperature of 50 °C. Acetone (59.24 kg) was added to precipitate the product and the mixture was centrifuged, washed with acetone (1 x 30.39 kg), dissolved in 27.5 kg of water at a temperature of 50 °C. 30 kg of EtOH was added to the product mixture, stirred at a temperature of 15 °C for 1 hour, centrifuged, washed with EtOH (1 x 29.56 kg), dissolved in 30.22 kg of water at a temperature of 50 °C. 2% NaOH was further added until the pH reached about 10.0 and the reaction mixture was filtered, washed with 47.27 kg of EtOH, precipitated, centrifuged and dried in a vacuum oven at a temperature of 50 °C. 11.8 kg (67%) of CS-1103 was recovered.

[0342] Example 2: Synthesis of CS-1105

[0343] The synthesis scheme of CS-1105 is shown in Figure 2

[0344]

[0345] ​Dissolve 1,4-hydroxynaphthalene (30 g, 187.3 mmol) in aqueous NaOH (18.6 g, 0.47 mol in 250 mL of H2O). In a separate flask, dissolve 1,3-propane sultone (57.2 g, 0.47 mol) in dioxane. Add the solution containing 1,3-propane sultone in dioxane to the aqueous 1,4-dihydroxynaphthalene solution. Stir the reaction mixture at room temperature for 18 h. Add an additional 25 g (0.20 mol) of 1,3-propane sultone in 75 mL of dioxane to the reaction mixture. Stir the reaction mixture at room temperature for 2 h. Add a solution containing 10 g of NaOH (0.25 mol) in 50 mL of H2O to the reaction mixture to hydrolyze excess sultone. Stir the reaction mixture at room temperature for 2 h and pour into 1 L of acetone. Filter the resulting precipitate and dry under high vacuum. Redissolve the precipitate in H2O (150 mL) and precipitate with 1.2 L of acetone. Filter the resulting precipitate and dry under high vacuum to give compound 9 as an off-white solid (77.0 g, 92%).

[0346]

[0347] To a solution of glycoluril tetramer (30.00 g, 38.4 mmol) in TFA / Ac2O (1:1, 250 mL) was added aromatic side wall 9 (68.2 g, 154 mmol). The mixture was stirred, heated at 70 °C for 3 h and poured into MeOH (1.5 L). The resulting suspension was stirred for 10 min and the precipitated solid was collected via filtration. The solid was recrystallized from a mixture of water and acetone (1:2 v / v, 750 mL, the crude material was first dissolved in water and then acetone was added and the product precipitated from the solution) and then the crude product was recrystallized from a mixed solvent of water (200 mL) and EtOH (200 mL) (the solid was first heated to dissolve in water and then EtOH was added and the mixture was cooled to 4 °C). The solid was dissolved in water (1.05 L) and insoluble impurities were removed by filtration. The filtrate was adjusted to pH = 7 by the addition of 1 M aqueous NaOH solution. The solvent was removed and the solid was further dried under high vacuum to give CS-1105 as an off-white solid (43.8 g, 69%).

[0348] Example 3

[0349]

[0350] The effect of varying the amount of acetic anhydride in the above reaction was investigated. Table 1 provides the conditions used for this study.

[0351] Table 1

[0352]

[0353] The solvent (i.e., TFA, acetic anhydride, MeSO3H), compound 8, and tetramer compound 5 were charged into an 8 mL reaction vessel. The reaction mixture was stirred at a temperature of 70 °C for 4 hours. A 10 μL sample was removed from each reaction and added to 1 mL of DMSO and the relative product purity was determined by HPLC. Each of reactions A through E showed good relative purity, with reactions B through E showing improved relative purity.

[0354] Example 4

[0355]

[0356] The effect of varying the amount of trifluoroacetic anhydride (TFAA) in the above reaction was investigated. Table 2 provides the conditions used for this study.

[0357] Table 2

[0358]

[0359] The solvent (i.e., TFA, acetic anhydride, TFAA), compound 8, and tetramer compound 5 were charged into an 8 mL reaction vessel according to the parameters in Table 2. The reaction mixture was stirred at a temperature of 70 °C for a total of 4 hours. A 10 μL sample was removed from each reaction and added to 1 mL of DMSO and the relative product purity was determined by HPLC. Each of reactions A through E showed good relative purity, with reactions C and D showing improved relative purity. Reactions E through H showed decreased relative purity.

[0360] Example 5

[0361]

[0362] The effect of varying the reaction temperature in the above reaction was investigated. Table 3 provides the conditions used for this study.

[0363] Table 3

[0364]

[0365] The solvent (i.e., TFA, acetic anhydride), compound 8, and tetramer compound 5 were charged into an 8 mL reaction vessel. The reaction mixture was stirred at the temperatures indicated in Table 3 for 4 hours. A 10 μL sample was removed from each reaction and added to 990 mL of DMSO and the relative product purity was determined by HPLC. Each reaction showed decreased relative product purity compared to reactions run at 70 °C.

[0366] Example 6

[0367]

[0368]

[0369] The solvent (i.e., TFA, acetic anhydride), compound 8, and tetramer compound 5 were charged into 4 mL reaction vessels. The reaction mixtures were stirred at 70 °C for 4 hours. A 10 μΐ^sample from each reaction was taken and added to 990 μΐ^of DMSO and the relative product purity was determined by HPLC. Each of reactions A to E showed good relative purity, with reactions c to E showing improved relative purity.

Claims

1. A method of preparing a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein: each R is independently selected from hydrogen, halogen, -OH, C1-C6alkyl, 2 to 6 membered heteroalkyl, C3-C6cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-(CH2) 1A and R 1D is independently selected from hydrogen, halogen, -OH, C1-C6alkyl, 2 to 6 membered heteroalkyl, C3-C6cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-(CH2) n1 S(O) v1 X 1 , -O-(CH2) n1 CO2X 1 , -O-(CH2) n1 PO v1 X 1 ; each R is independently selected from hydrogen, halogen, -OH, C1-C6alkyl, 2 to 6 membered heteroalkyl, C3-C6cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-(CH2) 1B and R 1C is independently selected from hydrogen, halogen, -OH, C1-C6alkyl, 2 to 6 membered heteroalkyl, C3-C6cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-(CH2) n1 S(O) v1 X 1 , -O-(CH2) n1 CO2X 1 , -O-(CH2) n1 PO v1 X 1 ; or, Additionally or alternatively, two R 1A , R 1B , R 1C and R 1D , together with the atoms to which they are attached, join to form a fused C6-C 12 aryl, 5- to 12-membered heteroaryl, or 5- to 7-membered heterocyclo, optionally substituted with 1 to 3 substituents independently selected from halogen, -OH, -NH2, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted 2- to 6-membered heteroalkyl Each R 3A and R 3B independently selected from hydrogen, halogen, -OH, C1-C6 alkyl, phenyl, substituted phenyl, and 2- to 6-membered heteroalkyl; Each R 4A and R 4B independently selected from hydrogen, halogen, -OH, C1-C6 alkyl, phenyl, substituted phenyl, and 2- to 6-membered heteroalkyl; each n1 is independently selected from 0 to 5; each v1 is independently selected from 2 or 3; and Each X 1 Independently selected from H, -OH, C1-C6 alkyl, alkali metal cation and quaternary ammonium cation; the method comprises: (i) contacting a compound of Formula II with paraformaldehyde in the presence of an acid to give a compound of Formula III (ii) contacting a compound of Formula II’ with paraformaldehyde and an acid, wherein the paraformaldehyde is added to the compound of Formula II’ over a period of at least about 1 hour, and wherein the reaction is maintained at a temperature higher than 55 °C to give a compound of Formula IV (iii) contacting a compound of Formula III with a compound of Formula IV in the presence of (a) one or more acids having a pKa less than about 1 and optionally (b) one or more polar aprotic solvents and / or additional acid solvents, to give a compound of Formula V: and isolating the compound of Formula V; (iv) contacting a compound of Formula V with a compound of Formula VI in the presence of a solvent comprising one or more acids having a pKa less than about 1 and an acid anhydride to give a compound of Formula I.

2. The method of claim 1, wherein the reaction of step (i) is maintained at a temperature higher than about 35 °C.

3. The method of claim 1 or claim 2, wherein in the reaction of step (ii), the paraformaldehyde is added in four or more portions at intervals of at least about 10 minutes or at least about 15 minutes or at least about 20 minutes or at least about 25 minutes or at least about 30 minutes.

4. The method of claim 3, wherein in the reaction of step (ii), the paraformaldehyde is added in six or more portions to the compound of Formula II’ at intervals of at least about 30 minutes.

5. The method of claim 1 or claim 2, wherein in the reaction of step (ii), the paraformaldehyde is added continuously or dropwise over a period of at least about 45 minutes or at least about 1 hour, at least about 1.5 hours, at least about 2 hours, at least about 2.5 hours, at least about 3 hours, at least about 3.5 hours, at least about 4 hours, at least about 4.5 hours, or at least about 5 hours.

6. The method of any one of claims 1 to 5, wherein the reaction of step (ii) is maintained at a temperature higher than 65 °C.

7. The method of any one of claims 1 to 6, wherein in the reaction of step (ii), the acid has a pKa less than about 2.5 or a pKa less than about 2.0 or a pKa less than about 1.5 or a pKa less than about 1 or a pKa less than about 0.9 or a pKa less than about 0.8 or a pKa less than about 0.7 or a pKa less than about 0.6 or a pKa less than about 0.

5. In embodiments, the acid in the reaction of Scheme 3 can have a pKa less than about 0.

9.

8. The method of any one of claims 1 to 7, wherein in the reaction of step (ii), the acid is selected from the group consisting of HF, HC1, HBr, HCIO4, HNO3, H2SO4, H3PO4, a sulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid, Eaton’s reagent, trifluoroacetic acid, or combinations thereof.

9. The method of any one of claims 1 to 7, wherein in the reaction of step (ii), the acid is HC1.

10. The method of any one of claims 1 to 9, wherein the reaction mixture of step (ii) is not solidified during the course of the reaction.

11. The method of any one of claims 1 to 10, wherein the method further comprises a step of isolating the compound of Formula IV in step (ii) comprising contacting the reaction mixture with water, heating to a temperature of at least about 70 °C, cooling to a temperature of less than about 30 °C, and centrifuging or filtering the reaction mixture.

12. The method of any one of claims 1 to 11, wherein the reaction temperature of step (iii) is maintained at about 55 °C or greater than about 55 °C.

13. The method of any one of claims 1 to 12, wherein the solvent of step (iii) comprises an acid selected from the group consisting of trifluoroacetic acid, phosphoric acid, sulfuric acid, HC1, HBr, HCIO4, HNO3, trifluoromethanesulfonic acid, methanesulfonic acid, toluenesulfonic acid, Eaton’s reagent, and combinations thereof.

14. The method of any one of claims 1 to 13, wherein the polar aprotic solvent of step (iii) comprises DMF, DMSO, acetonitrile, DMA, NMP, THF, dioxane, sulfolane, acetone, DMPU, diglyme, HMPA, or combinations thereof.

15. The method of any one of claims 1 to 14, wherein step (iii) comprises a solvent comprising trifluoroacetic acid.

16. The method of any one of claims 1 to 15, wherein the method further comprises a step of isolating the compound of Formula V, the step of isolating comprising: adding additional TFA to the reaction mixture after the reaction is complete; precipitating the compound of Formula V; and filtering the mixture comprising the compound of Formula V.

17. The method of claim 16, wherein the step of precipitating the compound of Formula V comprises adding an anti-solvent for the compound of Formula V, and the anti-solvent comprises methanol, ethanol, isopropanol, acetone, acetonitrile, THF, dioxane, or combinations thereof.

18. The method of any one of claims 1 to 17, wherein in step (iii) or (iv), the acid or acids having a pKa of less than about 1 comprises methanesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, phosphoric acid, sulfuric acid, camphorsulfonic acid, ethanesulfonic acid, HC1, HBr, HCIO4, HNO3, or combinations thereof.

19. The method of any one of claims 1 to 18, wherein the acid anhydride of step (iv) comprises acetic anhydride, trifluoroacetic anhydride, butyric anhydride, propionic anhydride, trifluoromethanesulfonic anhydride, succinic anhydride, maleic anhydride, or combinations thereof.

20. The method of claim 19, wherein the acid anhydride of step (iv) comprises acetic anhydride, trifluoroacetic anhydride, or a combination thereof.

21. The method of any one of claims 1 to 20, wherein the acid anhydride concentration is about 0.01% to about 60% by volume of solvent or about 0.3% to about 55% by volume of solvent or about 1% to about 55% by volume of solvent or about 2% to about 50% by volume of solvent; or about 1% to about 45% by volume of solvent or about 2% to about 40% by volume of solvent.

22. The method of any one of claims 1 to 21, wherein: each R 1A and R 1D is independently selected from the group consisting of -O-(CH2) n1 S(O) v1 X 1 , -O-(CH2) n1 CO2X 1 and -O-(CH2) n1 PO v1 X 1 ; R 1B and R 1C is hydrogen; and X 1 is H or an alkali metal cation.

23. The method of any one of claims 1 to 22, wherein: each R is independently H, C1-C3alkyl, or C1-C3haloalkyl; 3A and R is independently C1-C3alkyl, and 3B is independently C1-C3alkyl, and R 4A and R 4B is hydrogen.

24. A method of preparing a compound of Formula IV: the method comprising: (i) contacting a compound of Formula II’ with paraformaldehyde and an acid, wherein the paraformaldehyde is added to the compound of Formula II’ over a period of at least about 1 hour, wherein the reaction is maintained at a temperature above 55 °C; and (ii) optionally isolating the compound of Formula IV.

25. The method of claim 24, wherein the paraformaldehyde is added in four or more portions at intervals of at least about 10 minutes.

26. The method of claim 25, wherein the paraformaldehyde is added in four or more portions at intervals of at least about 15 minutes or at least about 20 minutes or at least about 25 minutes or at least about 30 minutes.

27. The method of claim 26, wherein the paraformaldehyde is added in six or more portions at intervals of at least about 30 minutes.

28. The method of claim 24, wherein the paraformaldehyde is added continuously or dropwise over a period of at least about 45 minutes or at least about 1 hour, at least about 1.5 hours, at least about 2 hours, at least about 2.5 hours, at least about 3 hours, at least about 3.5 hours, at least about 4 hours, at least about 4.5 hours, or at least about 5 hours.

29. The method of any one of claims 24 to 29, wherein the reaction is maintained at a temperature above 65 °C.

30. The method of any one of claims 24 to 29, wherein the reaction mixture does not solidify during the course of the reaction.

31. The method of any one of claims 24 to 30, wherein isolating the compound of Formula IV comprises (i) contacting the reaction mixture with water, (ii) heating to a temperature of at least about 70 °C, (iii) cooling to a temperature of less than about 30 °C, and (iv) centrifuging or filtering the reaction mixture.

32. The method of any one of claims 24 to 31, wherein R 4A and R 4B are hydrogen.

33. A method of preparing a compound of Formula I wherein: each R is independently selected from hydrogen, halogen, -OH, C1-C6alkyl, 2 to 6 membered heteroalkyl, C3-C6cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-(CH2) 1A and R 1D is independently selected from hydrogen, halogen, -OH, C1-C6alkyl, 2 to 6 membered heteroalkyl, C3-C6cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-(CH2) n1 S(O) v1 X 1 , -O-(CH2) n1 CO2X 1 and -O-(CH2) n1 PO v1 X 1 ; Each R 1B and R 1C independently selected from hydrogen, halogen, -OH, C1-C6 alkyl, 2- to 6-membered heteroalkyl, C3-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -O-(CH2) n1 S(O) v1 X 1 、-O-(CH2) n1 CO2X 1 and -O-(CH2) n1 PO v1 X 1 ;or Additionally or alternatively, two R 1A , R 1B , R 1C and R 1D , together with the atoms to which they are attached, join to form a fused C6-C 12 aryl, 5- to 12-membered heteroaryl, or 5- to 7-membered heterocyclo, optionally substituted with 1 to 3 substituents independently selected from halogen, -OH, -NH2, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted 2- to 6-membered heteroalkyl; Each R 3A and R 3B independently selected from hydrogen, halogen, -OH, C1-C6 alkyl, phenyl, substituted phenyl, and 2- to 6-membered heteroalkyl; Each R 4A and R 4B independently selected from hydrogen, halogen, -OH, C1-C6 alkyl, phenyl, substituted phenyl, and 2- to 6-membered heteroalkyl; each n1 is independently selected from 0 to 5; each v1 is independently selected from 2 or 3; and Each X 1 Independently selected from H, -OH, C1-C6 alkyl, alkali metal cation and quaternary ammonium cation; the method comprising: (i) contacting a compound of Formula II’ with paraformaldehyde and an acid, wherein the paraformaldehyde is added to the compound of Formula III over a period of at least about 1 hour, wherein the reaction is maintained at a temperature above 55 °C, to give a compound of Formula IV: (ii) optionally isolating the compound of Formula IV; and (iii) converting the compound of Formula IV to the compound of Formula I.

34. The method of claim 33, wherein the paraformaldehyde is added in four or more portions at intervals of at least about 10 minutes.

35. The method of claim 34, wherein the paraformaldehyde is added in four or more portions at intervals of at least about 15 minutes or at least about 20 minutes or at least about 25 minutes or at least about 30 minutes.

36. The method of claim 35, wherein the paraformaldehyde is added in six or more portions at intervals of at least about 30 minutes.

37. The method of claim 33, wherein the paraformaldehyde is added continuously or dropwise over a period of at least about 45 minutes or at least about 1 hour, at least about 1.5 hours, at least about 2 hours, at least about 2.5 hours, at least about 3 hours, at least about 3.5 hours, at least about 4 hours, at least about 4.5 hours, or at least about 5 hours.

38. The method of any one of claims 33 to 37, wherein the reaction is maintained at a temperature above 65 °C.

39. The method of any one of claims 33 to 38, wherein the reaction mixture does not solidify during the course of the reaction.

40. The method of any one of claims 33 to 39, wherein isolating the compound of Formula IV comprises (i) contacting the reaction mixture with water, (ii) heating to a temperature of at least about 70 °C, (iii) cooling to a temperature of less than about 30 °C, and (iv) centrifuging or filtering the reaction mixture.

34. The method of claim 33, wherein the paraformaldehyde is added in four or more portions with at least about 10 minutes between portions.

35. The method of claim 34, wherein the paraformaldehyde is added in four or more portions with at least about 15 minutes, or at least about 20 minutes, or at least about 25 minutes, or at least about 30 minutes between portions.

36. The method of claim 35, wherein the paraformaldehyde is added in six or more portions with at least about 30 minutes between portions.

37. The method of claim 33, wherein the paraformaldehyde is added continuously or dropwise over a period of at least about 45 minutes, or at least about 1 hour, at least about 1.5 hours, at least about 2 hours, at least about 2.5 hours, at least about 3 hours, at least about 3.5 hours, at least about 4 hours, at least about 4.5 hours, or at least about 5 hours.

38. The method of any one of claims 33 to 37, wherein the reaction is maintained at a temperature above 65 °C.

39. The method of any one of claims 33 to 38, wherein the reaction mixture does not solidify during the course of the reaction.

40. The method of any one of claims 33 to 39, wherein isolating the compound of Formula IV comprises (i) contacting the reaction mixture with water, (ii) heating to a temperature of at least about 70 °C, (iii) cooling to a temperature of less than about 30 °C, and (iv) centrifuging or filtering the reaction mixture.

41. The method of any one of claims 33 to 40, wherein: each R 1A and R 1D is independently selected from the group consisting of -O-(CH2) n1 S(O) v1 X 1 , -O-(CH2) n1 CO2X 1 and -O-(CH2) n1 PO v1 X 1 ; R 1B and R 1C is hydrogen; and X 1 is H or an alkali metal cation.

42. The method of any one of claims 33 to 41, wherein: Each R 3A and R 3B are independently C1-C3 alkyl, and R 4A and R 4B is hydrogen.

43. A method of making a compound of Formula V: each R 3A , R 3B , R 4A , and R 4B is independently hydrogen, halogen, -OH, Ci-C6alkyl, 2 to 6 membered heteroalkyl, the method comprising: (i) contacting a compound of Formula IV with a compound of Formula III in the presence of (a) one or more acids having a pKa of less than about 1 and optionally (b) one or more polar aprotic solvents and / or additional acid solvents; and (ii) isolating the compound of Formula V.

44. The method of claim 43, wherein the reaction temperature is maintained at about 55 °C or above about 55 °C.

45. The method of claim 43 or 44, wherein the acid is selected from the group consisting of trifluoroacetic acid, phosphoric acid, sulfuric acid, HC1, HBr, HCIO4, HNO3, triflic acid, or combinations thereof.

46. The method of any one of claims 43 to 45, wherein the solvent comprises an acid selected from the group consisting of trifluoroacetic acid, phosphoric acid, sulfuric acid, HC1, HBr, HCIO4, HNO3, triflic acid, methanesulfonic acid, toluenesulfonic acid, Eaton’s reagent, and combinations thereof.

47. The method of any one of claims 43 to 46, wherein the polar aprotic solvent comprises DMF, DMSO, acetonitrile, DMA, NMP, THF, dioxane, sulfolane, acetone, DMPU, diglyme, HMPA, or combinations thereof.

48. The method of any one of claims 43 to 47, comprising a solvent comprising trifluoroacetic acid.

49. The method of any one of claims 43-48, wherein the method further comprises: (ii) adding additional TFA to the reaction mixture after the reaction is complete; (iii) precipitating the compound of Formula V; and (iv) filtering the mixture comprising the compound of Formula V.

50. The method of claim 49, wherein precipitating the compound of Formula V comprises adding an anti-solvent for the compound of Formula V, and the anti-solvent comprises ethanol, brine, MeOH, acetone, iPA, THF, or a combination thereof.

51. The method of any one of claims 43-50, wherein: each R 3A and R 3B independently is C1-C3alkyl, and R 4A and R 4B is hydrogen.

52. A method of making a compound of Formula I wherein: each R is independently selected from hydrogen, halogen, -OH, C1-C6alkyl, 2 to 6 membered heteroalkyl, C3-C6cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-(CH2) 1A and R 1D is independently selected from hydrogen, halogen, -OH, C1-C6alkyl, 2 to 6 membered heteroalkyl, C3-C6cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-(CH2) n1 S(O) v1 X 1 , -O-(CH2) n1 CO2X 1 , -O-(CH2) n1 PO v1 X 1 ; each R is independently selected from hydrogen, halogen, -OH, C1-C6alkyl, 2 to 6 membered heteroalkyl, C3-C6cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-(CH2) 1B and R 1C is independently selected from hydrogen, halogen, -OH, C1-C6alkyl, 2 to 6 membered heteroalkyl, C3-C6cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-(CH2) n1 S(O) v1 X 1 , -O-(CH2) n1 CO2X 1 , -O-(CH2) n1 PO v1 X 1 ; or Additionally or alternatively, two R 1A , R 1B , R 1C and R 1D , together with the atoms to which they are attached, join to form a fused C6-C 12 aryl, 5- to 12-membered heteroaryl, or 5- to 7-membered heterocyclo, optionally substituted with 1 to 3 substituents independently selected from halogen, -OH, -NH2, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted 2- to 6-membered heteroalkyl; Each R 3A and R 3B independently selected from hydrogen, halogen, -OH, C1-C6 alkyl, phenyl, substituted phenyl, and 2- to 6-membered heteroalkyl; Each R 4A and R 4B independently selected from hydrogen, halogen, -OH, C1-C6 alkyl, phenyl, substituted phenyl, and 2- to 6-membered heteroalkyl; each n1 is independently selected from 0-5; each v1 is independently selected from 2 or 3; and Each X 1 Independently selected from H, -OH, C1-C6 alkyl, alkali metal cation and quaternary ammonium cation; the method comprises: (i) making an intermediate of Formula V comprising contacting a compound of Formula IV and a compound of Formula III in the presence of (a) one or more acids having a pKa less than about 1 and optionally (b) one or more polar aprotic solvents and / or additional acid solvent; (ii) isolating the compound of Formula V; and (iii) converting the compound of Formula V to the compound of Formula I.

53. The method of claim 52, wherein each R 1A and R 1D is -0-(CH2)3-S03Na.

54. The method of claim 52 or 53, wherein the reaction temperature of step (i) is maintained at about 55 °C or greater than about 55 °C.

55. The method of claim 52 or 54, wherein the acid is selected from the group consisting of trifluoroacetic acid, phosphoric acid, sulfuric acid, HC1, HBr, HCIO4, HNO3, triflic acid, or a combination thereof.

56. The method of any one of claims 52-55, wherein the solvent comprises an acid selected from the group consisting of trifluoroacetic acid, phosphoric acid, sulfuric acid, HC1, HBr, HCIO4, HNO3, triflic acid, methanesulfonic acid, toluenesulfonic acid, Eaton’s reagent, and combinations thereof.

57. The method of any one of claims 52-56, wherein the polar aprotic solvent comprises DMF, DMSO, acetonitrile, DMA, NMP, THF, dioxane, sulfolane, acetone, DMPU, diglyme, HMPA, or a combination thereof.

58. The method of any one of claims 52-57, comprising a solvent comprising trifluoroacetic acid.

59. The method of any one of claims 52-58, further comprising adding TFA to the reaction mixture after the reaction is complete, precipitating the compound of Formula V, and isolating the compound of Formula V, comprising filtering.

60. The method of claim 59, wherein precipitating the compound of Formula V comprises adding an anti-solvent for the compound of Formula V selected from the group consisting of ethanol, brine, MeOH, acetone, iPA, THF, or a combination thereof.

61. The method of any one of claims 52-60, wherein: each R 1A and R 1D is independently selected from the group consisting of -O-(CH2) n1 S(O) v1 X 1 , -O-(CH2) n1 CO2X 1 and -O-(CH2) n1 PO v1 X 1 ; R 1B and R 1C is hydrogen; and X 1 is H or an alkali metal cation.

62. The method of any one of claims 52-61, wherein: each R is independently H, C1-C3alkyl, or C1-C3haloalkyl; 3A and R is independently C1-C3alkyl, and 3B is independently C1-C3alkyl, and R 4A and R 4B is hydrogen.

63. A method of making a compound of Formula VI-A: wherein: X is selected from H and an alkali metal cation; the method comprises: (i) contacting a hydroquinone of the formula and a sultolane of the formula in the presence of (a) one or more acids having a pKa less than about 1 and optionally (b) one or more polar aprotic solvents and / or additional acid solvent; in the presence of about 2.0 to 2.5 equivalents of a base and a solvent comprising one or more of water, a polar aprotic solvent, and combinations thereof.

64. The process of claim 63, wherein the base is present in about 2.2 to 2.4 equivalents.

65. The process of claim 63 or 64, wherein the base comprises an alkali metal hydroxide.

66. The process of any one of claims 63 to 65, wherein the sultone is added over a period of longer than about 2 hours.

67. The process of claim 66, wherein the sultone is added in two or more portions at least one hour apart.

68. The process of any one of claims 63 to 67, wherein the reaction mixture is cooled to less than about 10 °C prior to each addition of the sultone.

69. The process of any one of claims 63 to 68, further comprising adding a base to the reaction in an amount equal to or greater than the amount of the sultone.

70. The process of claim 69, wherein the base is added in two or more portions at least one hour apart.

71. A process of making a compound of Formula I-A wherein X is selected from H and an alkali metal cation; the process comprising: (i) contacting a hydroquinone of the formula and a sultone of the formula in the presence of about 2.0 to 2.5 equivalents of a base and a solvent comprising one or more of water, a polar aprotic solvent, and combinations thereof, to give a compound of Formula VI-A: (ii) isolating the compound of Formula VI-A; and (iii) contacting the compound of Formula VI-A and a compound of Formula V-A to give a compound of Formula I-A.

72. The process of claim 71, wherein the base of step (i) is present in about 2.2 to 2.4 equivalents.

73. The process of claim 71 or 72, wherein the base of step (i) comprises an alkali metal hydroxide.

74. The process of any one of claims 71 to 73, wherein the sultone of step (i) is added over a period of longer than about 2 hours.

75. The process of claim 74, wherein the sultone is added in two or more portions at least one hour apart.

76. The process of any one of claims 71 to 75, wherein the reaction mixture of step (i) is cooled to less than about 10 °C prior to each addition of the sultone.

77. The process of any one of claims 71 to 76, further comprising adding a base to the reaction in an amount equal to or greater than the amount of the sultone.

78. The process of claim 77, wherein the base is added in two or more portions at least one hour apart.

79. A process of making a compound of Formula I wherein: each R is independently selected from hydrogen, halogen, -OH, C1-C6alkyl, 2 to 6 membered heteroalkyl, C3-C6cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-(CH2) 1A and R 1D is independently selected from hydrogen, halogen, -OH, C1-C6alkyl, 2 to 6 membered heteroalkyl, C3-C6cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-(CH2) n1 S(O) v1 X 1 , -O-(CH2) n1 CO2X 1 and -O-(CH2) n1 PO v1 X 1 ; each R is independently selected from hydrogen, halogen, -OH, C1-C6alkyl, 2 to 6 membered heteroalkyl, C3-C6cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-(CH2) 1B and R 1C is independently selected from hydrogen, halogen, -OH, C1-C6alkyl, 2 to 6 membered heteroalkyl, C3-C6cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-(CH2) n1 S(O) v1 X 1 , -O-(CH2) n1 CO2X 1 , -O-(CH2) n1 PO v1 X 1 ; or Additionally or alternatively, two R 1A , R 1B , R 1C and R 1D , together with the atoms to which they are attached, join to form a fused C6-C 12 aryl, 5- to 12-membered heteroaryl, or 5- to 7-membered heterocyclo, optionally substituted with 1 to 3 substituents independently selected from halogen, -OH, -NH2, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted 2- to 6-membered heteroalkyl; Each R 3A and R 3B independently selected from hydrogen, halogen, -OH, C1-C6 alkyl, phenyl, substituted phenyl, and 2- to 6-membered heteroalkyl; Each R 4A and R 4B independently selected from hydrogen, halogen, -OH, C1-C6 alkyl, phenyl, substituted phenyl, and 2- to 6-membered heteroalkyl; each n1 is independently selected from 0 to 5; each v1 is independently selected from 2 or 3; and Each X 1 Independently selected from H, -OH, C1-C6 alkyl, alkali metal cation and quaternary ammonium cation; the process comprising: contacting a compound of Formula V and a compound of Formula VI: in the presence of a solvent comprising one or more acids having a pKa of less than about 1 and an acid anhydride, to give a compound of Formula I.

80. The process of claim 79, wherein: each R 1A and R 1D is independently selected from the group consisting of -O-(CH2) n1 S(O) v1 X 1 , -O-(CH2) n1 CO2X 1 and -O-(CH2) n1 PO v1 X 1 ; R 1B and R 1C is hydrogen; and X 1 is H or an alkali metal cation.

81. The method of claim 79 or 80, wherein: each R 3A and R 3B independently is C1-C3alkyl, and R 4A and R 4B is hydrogen.

82. The method of claim 79 or 81, wherein: each R 3A and R 3B is methyl, R 4A and R 4B is hydrogen, and R 1A and R 1D is -O-(CH2) n1 S(O) v1 X 1 . Each n1 is 3; Each v1 is 3; and Each X 1 are independently selected from H or an alkali metal cation.

83. The method of any one of claims 79 to 82, wherein the anhydride is selected from compounds having the structure R'-C(=O)-OC(=O)-R" wherein R' and R" may be the same or different and are independently selected from alkyl, aryl, heteroalkyl, or may be taken together to form a heterocyclic ring, each of which may be optionally substituted with one or more halo, alkyl, or trihaloalkyl groups.

84. The method of any one of claims 79 to 82, wherein the anhydride is selected from acetic anhydride, trifluoroacetic anhydride, butyric anhydride, propionic anhydride, trifluoromethanesulfonic anhydride, succinic anhydride, maleic anhydride, or a combination thereof.

85. The method of any one of claims 79 to 82, wherein the anhydride is selected from acetic anhydride, trifluoroacetic anhydride, or a combination thereof.

86. The method of any one of claims 79 to 85, wherein the anhydride concentration is from about 0.01% to about 60% by volume of the solvent, or from about 0.3% to about 55% by volume of the solvent, or from about 1% to about 55% by volume of the solvent, or from about 2% to about 50% by volume of the solvent; or from about 1% to about 45% by volume of the solvent, or from about 2% to about 40% by volume of the solvent.

87. The method of any one of claims 79 to 86, wherein the reaction employs about 4 equivalents or less of the compound of Formula VI or about 3 equivalents or less of the compound of Formula VI.

88. The method of any one of claims 79 to 86, wherein the reaction employs about 2 to about 5 equivalents of the compound of Formula VI, or about 2.5 to about 4.5 equivalents of the compound of Formula VI, or about 2.5 to about 4 equivalents of the compound of Formula VI.

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