Method for synthesizing cucurbituril compounds

Abstract

The disclosure herein relates, inter alia, to inventive cucurbituril compounds and glycoluril compounds having formula (II), glycoluril compounds having formula (II'), glycoluril bisethers of formula (III), glycoluril dimers of formula (IV), glycoluril tetramer compounds of formula (V), and novel methods for their preparation using sodium 4,4'-(1,4-phenylenebis(oxy))bis(butane-1-sulfonate), which result in significantly improved purity and yields of intermediates and final products.

Description

[Technical Field]

[0001] This invention was made with United States government support under Grant No. U01DA053054 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0002] The disclosure herein relates, inter alia, to cucurbituril compounds and methods for preparing the same. [Background technology]

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

[0004] Cucurbiturils represent a promising technology for reversing methamphetamine addiction and / or overdose. Safe, fast-acting reversals of methamphetamine are urgently needed. Methamphetamine (meth) is the fastest-growing drug of addiction in the United States, representing over 200,000 emergency room (ER) visits annually, and deaths have increased fourfold since 2015 (9,356 deaths in 2017 alone), yet there are no current medications available to treat meth poisoning. Methamphetamine induces excessive, rapid, and sustained (serum half-life t) activation of the sympathetic nervous system, resulting in a recognizable adrenergic intoxication syndrome consisting of both behavioral (psychomotor agitation) and physiological (tachycardia, hypertension, mydriasis, and diaphoresis) components. 1 / 2Methamphetamine addiction causes stimulation (lasting approximately 10 hours). Methamphetamine addiction can lead to cardiovascular and other complications, and 20% of emergency department visits require hospitalization. The current standard of care for methamphetamine addiction is to treat only the symptoms. A reversal agent for methamphetamine that normalizes both behavioral and physiological components would minimize complications, improve patient outcomes, and reduce mortality. Summary of the Invention

[0005] Specifically provided herein are methods for preparing cucurbituril compounds that are suitable for large-scale synthesis and that result in significantly improved purity and yields of intermediates and final products. Provided herein are methods for preparing cucurbituril compounds that are suitable for large-scale synthesis and that result in significantly improved purity and yields of intermediates and final products.

[0006] In one aspect, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, comprising: During the ceremony, Each R 1A and R 1D are independently 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 is selected from Each R 1B and R 1Care independently 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 Selected from, or Additionally or alternatively, two R attached to adjacent positions on the same phenyl ring 1A , R 1B , R 1C and R 1D But they bond together with the atoms to which they are attached to form a fused C6-C 12 forming an aryl, a 5- to 12-membered heteroaryl, or a 5- to 7-membered heterocycle, which is optionally substituted with 1 to 3 substituents independently selected from halogen, —OH, —NH, substituted or unsubstituted C-C alkyl, or substituted or unsubstituted 2- to 6-membered heteroalkyl; Each R 3A and R 3B is independently selected from hydrogen, halogen, —OH, C1-C6 alkyl, phenyl, substituted phenyl, and 2- to 6-membered heteroalkyl; Each R 4A and R 4B is 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; each X 1 are independently selected from H, —OH, C1-C6 alkyl, alkali metal cations, and quaternary ammonium cations.

[0007] A method for preparing a compound of formula I comprises one or more of the following steps: (i) Formula II: [ka] with paraformaldehyde in the presence of an acid to produce a compound having formula III: [ka] to obtain (ii) Formula II': [ka] 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 the reaction is maintained at a temperature above 55°C, to produce a compound of formula IV [ka] providing a compound having the formula: (iii) Formula III: [ka] with a compound having Formula IV 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 acidic solvents; Formula V [ka] providing a compound having the formula: and isolating the compound of formula V; (iv) a compound having formula V and a compound having formula VI: [ka] with one or more acids having a pKa of less than about 1 in the presence of a solvent comprising an anhydride to obtain a compound having formula I.

[0008] In embodiments, the reaction in step (i) is maintained at a temperature greater than about 35°C.

[0009] In an embodiment, in the reaction of step (ii), paraformaldehyde is added in four or more portions spaced at least about 10 minutes apart.

[0010] In an embodiment, the reaction in step (ii) is maintained at a temperature greater than 65°C.

[0011] In an embodiment, the reaction mixture of step (ii) does not solidify during the reaction process.

[0012] In embodiments, the method further comprises isolating the compound of formula IV in step (ii), which comprises 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.

[0013] In an embodiment, the reaction temperature in step (iii) is maintained at a temperature above about 55°C.

[0014] In embodiments, the solvent in step (iii) comprises an acid selected from the group consisting of trifluoroacetic acid, phosphoric acid, sulfuric acid, HCl, HBr, HClO, HNO, trifluoromethanesulfonic acid, methanesulfonic acid, toluenesulfonic acid, Eaton's reagent, and combinations thereof.

[0015] In embodiments, the polar aprotic solvent in 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 a combination thereof.

[0016] In embodiments, the acid in step (iii) is trifluoroacetic acid (TFA), which may also be the solvent.

[0017] In some embodiments, the method further comprises isolating the compound of formula V, which comprises adding additional TFA to the reaction mixture after completion of the reaction, precipitating the compound of formula V, and filtering the mixture containing the compound of formula V.

[0018] In embodiments, the step of precipitating the compound of Formula V includes adding an anti-solvent for the compound of Formula V. The anti-solvent may include methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, tetrahydrofuran (THF), dioxane, brine, or a combination thereof.

[0019] In embodiments, in step (iii) or (iv), respectively, the one or more acids having a pKa of 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), HCl, HBr, HClO4, HNO3, or a combination thereof.

[0020] In embodiments, each R 1A and R 1D But -O-(CH2) n1 S(O) v1 X 1 , -O-(CH2) n1 CO2X 1 , or -O-(CH2) n1 PO v1 X 1 is.

[0021] In embodiments, R 1B and R 1C is hydrogen.

[0022] In embodiments, X 1 is H or an alkali metal cation.

[0023] In embodiments, each R 3A and R 3Bare independently C1-C3 alkyl.

[0024] In embodiments, R 4A and R 4B is hydrogen.

[0025] In another aspect, the present disclosure provides compounds of formula VI-A: [ka] The present invention provides a method for the preparation of a compound of formula: X is selected from H, an alkali metal cation, and a quaternary ammonium cation.

[0026] The method comprises: (i) the following formula: [ka] and hydroquinone having the following formula: [ka] 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.

[0027] In embodiments, the base is present in about 2.2 to 2.4 equivalents.

[0028] In embodiments, the base may include alkali metal hydroxides such as LiOH, NaOH, and KOH, alkali metal carbonates such as Na2CO3 or K2CO3, Alternatively or additionally, the base may include a non-nucleophilic organic base such as diisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the like.

[0029] In embodiments, the sultone is added over a period of greater than about 2 hours.

[0030] In an embodiment, the sultone is added in two or more portions separated by at least one hour.

[0031] In embodiments, the reaction mixture is cooled to below about 10° C. before each addition of sultone.

[0032] In embodiments, the method further comprises adding a base to the reaction in an amount equivalent to or greater than the amount of sultone.

[0033] In an embodiment, the base is added in two or more portions spaced at least one hour apart.

[0034] In another aspect, the present disclosure provides a compound of formula IA [ka] The present invention provides a method for the preparation of a compound having the formula: X is selected from H, alkali metal cations, and quaternary ammonium cations, and combinations thereof.

[0035] The method comprises: (i) the following formula: [ka] and hydroquinone having the following formula: [ka] 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 produce a sultone having the following formula VI-A: [ka] providing a compound having the formula: (ii) isolating the compound of formula VI-A, and (iii) Reacting a compound of formula VI-A with a compound of formula VA: [ka] to obtain a compound having formula IA.

[0036] In an embodiment, the base in step (i) is present in about 2.2 to 2.4 equivalents.

[0037] In an embodiment, the base in step (ii) comprises an alkali metal hydroxide.

[0038] In an embodiment, the sultone in step (i) is added over a period of greater than about 2 hours.

[0039] In an embodiment, the sultone is added in two or more portions separated by at least one hour.

[0040] In an embodiment, the reaction mixture of step (i) is cooled to below about 10° C. before each addition of sultone.

[0041] In embodiments, the method further comprises adding a base to the reaction in an amount equivalent to or greater than the amount of sultone.

[0042] In an embodiment, the base is added in two or more portions spaced at least one hour apart.

[0043] Other aspects are disclosed below. [Brief explanation of the drawings]

[0044] [Figure 1] 1 shows an exemplary synthesis of compound CS-1103, according to an exemplary embodiment. [Figure 2] 1 shows an exemplary synthesis of compound CS-1105, according to an exemplary embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0045] Among other things, provided herein are methods for producing cucurbituril compounds and cucurbiturils. The synthetic processes described herein offer one or more of the following advantages: improved yields and purity of key intermediates and final products, in-process controls in place to prevent the formation of sulfonate esters and other impurities, and improved purification processes that allow key intermediate steps to be performed at scale.

[0046] definition The abbreviations used herein have their conventional meanings within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to standard rules of chemical valency known in the chemical arts.

[0047] The term "alkyl" refers to the radical of a saturated aliphatic group, including straight-chain and branched-chain alkyl groups. An alkyl may contain a specified number of carbon atoms (e.g., C-C 10 means 1 to 10 carbons.) Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0048] The term "alkenyl" refers to a linear or branched hydrocarbyl group having at least one carbon-carbon double bond, including straight-chain and branched alkenyl groups. Examples of alkenyl groups (e.g., "C2-C6 alkenyl") include vinyl, 1-propenyl, 2-propenyl, 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 present disclosure contains an alkenyl group, the compound can exist as an E-form, a Z-form, or any mixture thereof.

[0049] The term "alkynyl" refers to a linear or branched hydrocarbyl group having at least one carbon-carbon triple bond, including straight-chain and branched alkynyl groups. Examples of alkenyl groups (e.g., "C2-C6 alkynyl") include ethynyl, propynyl, and the like.

[0050] The term "cycloalkyl" refers to a saturated carbocyclic group having 3-9 carbons in the ring and including monocyclic, bicyclic, or polycyclic cycloalkyl ring systems. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. A bicyclic cycloalkyl ring system is a bridged monocyclic ring or a fused bicyclic ring. In embodiments, a bridged monocyclic ring contains a monocyclic cycloalkyl ring in which two non-adjacent carbon atoms of the monocyclic ring are joined by an alkylene bridge of 1-3 additional carbon atoms (i.e., (CH) where w is 1, 2, or 3). w 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.

[0051] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise specified, stable linear or branched chains, or combinations thereof, containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), wherein the nitrogen and sulfur atoms can be optionally oxidized and the nitrogen heteroatom can be optionally 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 at which the alkyl group is attached to the remainder of the molecule. Examples include: -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 -CH2-O-CH3, -CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH3, Examples include, but are not limited to, -S(O)-CH, -CH-S(O)-CH, -Si(CH), -O-CH, or -O-CH-CH. Up to two or three heteroatoms may be consecutive, such as, for example, -CH-NH-OCH and -CH-O-Si(CH). The term "heteroalkenyl," by itself or in combination with another term, means, unless otherwise specified, a heteroalkyl containing at least one carbon-carbon double bond. The term "heteroalkynyl," by itself or in combination with another term, means, unless otherwise specified, a heteroalkyl containing at least one carbon-carbon triple bond.

[0052] As used herein, the term "cycloalkenyl" refers to a monocyclic, bicyclic, or polycyclic cycloalkenyl ring system. In embodiments, a monocyclic cycloalkenyl ring system is a cyclic hydrocarbon group containing 3-9 carbon atoms, and such group is unsaturated (i.e., contains at least one cyclic carbon-carbon double bond), but is not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, a bicyclic cycloalkenyl ring is a bridged or fused bicyclic ring.

[0053] As used herein, the term "heterocycle," "heterocyclyl," or "heterocyclic" refers to a monocyclic, bicyclic, or polycyclic heterocycle. 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, where the ring is saturated or unsaturated but not aromatic. Representative examples of monocyclic heterocycles include azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidin ... Representative examples of heterocyclic rings include, but are not limited to, thiazolinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholine sulfone), thiopyranyl, 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-dihydrobenzothien-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 contained within the monocyclic or bicyclic ring system.

[0054] As used herein, the term "aryl" includes 5- and 6-membered monocyclic aromatic groups that can contain zero to four heteroatoms, such as benzene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Aryl groups having heteroatoms within the ring structure may also be referred to as "aryl heterocycles," "heteroaromatics," or "heteroaryls." The term "aryl" also includes 7- to 14-membered polycyclic ring systems having two or more cyclic rings in which two or more carbons are shared by two adjacent rings (the rings are "fused rings"), where at least one of the rings is aromatic (including heteroaryl), and where, for example, the other cyclic rings can be fused cycloalkyl, cycloalkenyl, aryl, heteroaryl, and / or heterocyclic groups. Monocyclic heteroaryl groups can have 1 to 3 ring heteroatoms, and fused polycyclic heteroaryl groups can have 1 to 5 ring heteroatoms, the ring heteroatoms being selected from N, O and S.

[0055] The term "alkylene," by itself or as part of another substituent, means, unless otherwise specified, a divalent radical derived from alkyl, including, but not limited to, -CH2CH2CH2CH2. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having 8 or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise specified, a divalent radical derived from an alkene.

[0056] It will be understood that "substituted," "substituted," or "substituted with" includes the implicit proviso that such substitution is consistent with the permissible valence of the substituted atom and substituent, and that the substitution results in a stable compound, e.g., one that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, etc. Exemplary substituents used herein include oxo, halogen, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SCH, -SO, -SO, -SO, -NH, -NHNH, -ONH, -NHC(O)NHNH, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF3, -OCCl3, -OCBr3, -OCI3, -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-C 10 Aryl, C 10 The alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, 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 can be optionally substituted with 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 with 1 to 4 substituents selected from the aforementioned substituents.

[0057] The term "sultone" refers to a cyclic ester containing a hydroxysulfonic acid (e.g., [ka] ) Exemplary sultones are: [ka] In the formula, n is preferably 1 to 3.

[0058] As used herein, a quaternary ammonium cation has the structure + N(R)4, where each R is selected from alkyl, cycloalkyl, aryl, aralkyl, and heteroaryl, each of which can be optionally substituted. Quaternary ammonium cations can have, for example, the structure + N(C 1-6 alkyl)4, wherein C attached to the nitrogen 1-6 Each of the alkyl groups is independently selected.

[0059] Eaton's reagent is a solution of diphosphorus pentoxide in methanesulfonic acid. The wt% of diphosphorus pentoxide in methanesulfonic acid can be about 7% to about 15%, for example, 7.5% or 10%.

[0060] The terms "a" or "an," as used herein, mean one or more. Additionally, the phrase "substituted with [n]," as used herein, means that the particular group can be substituted with one or more of any or all of the specified substituents. For example, when a group such as an alkyl or heteroaryl group is "unsubstituted C1-C 20 When "substituted with alkyl, or unsubstituted 2-20 membered heteroalkyl," the group is also substituted with one or more unsubstituted C1-C 20 It may contain alkyl, and / or one or more unsubstituted 2-20 membered heteroalkyl.

[0061] Certain compounds provided in the present disclosure may exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds as being within the scope of the present invention, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included in the present invention.

[0062] The term "pharmaceutically acceptable salts" refers to relatively non-toxic inorganic and organic acid addition salts of the compounds disclosed herein, as well as inorganic and organic base addition salts of the compounds disclosed herein. When the compounds of the present invention contain a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When the compounds of the present invention contain a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic, or phosphorous acids, and the like, as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic acid, and the like.

[0063] compound Provided herein are cucurbituril compounds that may be obtained or obtainable by one or more of the synthetic steps described herein.

[0064] In one embodiment, the cucurbituril compound has Formula I: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Each R 1A and R 1D are independently 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 is selected from Each R 1B and R 1C are independently 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 Selected from, or Additionally or alternatively, two R attached to adjacent positions on the same phenyl ring 1A , R 1B , R 1C and R 1D However, they bond together with the atoms to which they are attached, forming condensed C6 to C 12forming an aryl, a 5- to 12-membered heteroaryl, or a 5- to 7-membered heterocycle, which is optionally substituted with 1 to 3 substituents independently selected from halogen, —OH, —NH, substituted or unsubstituted C-C alkyl, or substituted or unsubstituted 2- to 6-membered heteroalkyl; Each R 3A and R 3B is independently selected from hydrogen, halogen, —OH, C1-C6 alkyl, phenyl, substituted phenyl, and 2- to 6-membered heteroalkyl; Each R 4A and R 4B is 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; each X 1 are independently selected from H, —OH, C1-C6 alkyl, alkali metal cations, and quaternary ammonium cations.

[0065] In embodiments, R 1B is hydrogen, halogen, —OH, C1-C6 alkyl, 2- to 6-membered heteroalkyl, C3-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl. 1B is hydrogen, halogen, —OH, or C1-C6 alkyl, and in particular R 1B is hydrogen or halogen.

[0066] In embodiments, R 1C is hydrogen, halogen, —OH, C1-C6 alkyl, 2- to 6-membered heteroalkyl, C3-C6 cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl. 1C is hydrogen, halogen, —OH, or C1-C6 alkyl, and in particular R 1C is hydrogen or halogen.

[0067] In embodiments, R1B and R 1C is hydrogen.

[0068] Additionally or alternatively, R attached to the same phenyl ring 1A and R 1B is bonded to the atom that is bonded to it, C6-C 12 In embodiments, R 2 and R 3 attached to the same phenyl ring may form a 5- to 12-membered aryl or a 5- to 12-membered heteroaryl. 1A and R 1B are bonded together with the atoms to which they are bonded to form a phenyl. In embodiments, R 1A and R 1B are bonded together with the atoms to which they are attached to form naphthyl. In embodiments, R 1A and R 1B joins with the atom to which it is attached to form pyridyl.

[0069] In embodiments, R 1B and R 1C together with the atoms bonded to them, forming a bond between C6 and C 12 In one embodiment, R 1 and R 2 are bonded to the same phenyl ring to form a 5- to 12-membered aryl or 5- to 12-membered heteroaryl. 1B and R 1C are bonded together with the atoms to which they are bonded to form a phenyl. In embodiments, R 1B and R 1C are bonded together with the atoms to which they are attached to form naphthyl. In embodiments, R 1B and R 1C are bonded together with the atoms to which they are attached to form pyridyl.

[0070] In embodiments, R 1C and R 1D are bonded together with the atoms attached to them to form C6-C 12In one embodiment, R 1 and R 2 are bonded to the same phenyl ring to form a 5- to 12-membered aryl or 5- to 12-membered heteroaryl. 1C and R 1D are bonded together with the atoms to which they are bonded to form a phenyl. In embodiments, R 1C and R 1D are bonded together with the atoms to which they are attached to form naphthyl. In embodiments, R 1C and R 1D are bonded together with the atoms to which they are attached to form pyridyl.

[0071] In embodiments, R 1A , R 1B , R 1C , and R 1D C6-C formed by two of 12 The aryl or 5- to 12-membered heteroaryl may be substituted with one or more substituents, such as halogen, -OH, -NH2, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted 2- to 6-membered heteroalkyl.

[0072] In embodiments, R 3A is hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R 3A is C1-C3 alkyl, especially methyl.

[0073] In embodiments, R 3B is hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R 3B is C1-C3 alkyl, especially methyl.

[0074] In embodiments, R 3A and R 3B are both hydrogen, or R 3A and R 3B and may both be methyl. In embodiments, R 3A and R 3B One of them is hydrogen and the other is methyl.

[0075] In embodiments, R 4A is hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R 4A is C1-C3 alkyl, particularly methyl. In an embodiment, R 4A is H.

[0076] In embodiments, R 4B is hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R 4B is C1-C3 alkyl, particularly methyl. In an embodiment, R 4B is hydrogen.

[0077] In embodiments, each R 4A and R 4B is hydrogen. Alternatively, each R 4A and R 4B may be methyl. In embodiments, R 4A and R 4B One of them is hydrogen and the other is methyl.

[0078] In embodiments, each R 3A and R 3B are 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.

[0079] In another aspect, the cucurbituril compound that may be obtained or obtainable by one or more of the synthetic steps described herein has the formula (Ia): [ka] R has the structure: 1A , R 1D , R 3A , R 3B , R4A , and R 4B is as described herein.

[0080] In embodiments, R 3A is hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R 3A is C1-C3 alkyl, especially methyl.

[0081] In embodiments, R 3B is hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R 3B is C1-C3 alkyl, especially methyl.

[0082] In embodiments, R 3A and R 3B are both hydrogen, or R 3A and R 3B and may both be methyl. In embodiments, R 3A and R 3B One of them is hydrogen and the other is methyl.

[0083] In embodiments, R 4A is hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R 4A is C1-C3 alkyl, particularly methyl. In an embodiment, R 4A is H.

[0084] In embodiments, R 4B is hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R 4B is C1-C3 alkyl, particularly methyl. In an embodiment, R 4B is hydrogen.

[0085] In embodiments, each R 4A and R 4B is hydrogen. Alternatively, each R 4A and R 4B may be methyl. In embodiments, R 4A and R 4BOne of them is hydrogen and the other is methyl.

[0086] In embodiments, each R 3A and R 3B are 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.

[0087] In embodiments, each R 1A and R 1D is neutral. In embodiments, each R 1A and R 1D is in ionic salt form.

[0088] In embodiments, R 1A is -O-(CH2) n1 S(O) v1 X 1 In an embodiment, R 1A is -O-(CH2) n1 CO2X 1 In an embodiment, R 1A is -O-(CH2) n1 PO v1 X 1 In an embodiment, each n1 is 0. In an embodiment, each n1 is 1. In an embodiment, each n1 is 2. In an embodiment, each n1 is 3. In an embodiment, each n1 is 4. In an embodiment, each n1 is 5. In an embodiment, each n1 is 5. In an embodiment, each v1 is 2. In an embodiment, each v1 is 3.

[0089] In embodiments, R 1D is -O-(CH2) n1 S(O) v1 X 1 In an embodiment, R 1D is -O-(CH2) n1 CO2X 1 In an embodiment, R 1D is -O-(CH2)n1 PO v1 X 1 In an embodiment, each n1 is 0. In an embodiment, each n1 is 1. In an embodiment, each n1 is 2. In an embodiment, each n1 is 3. In an embodiment, each n1 is 4. In an embodiment, each n1 is 5. In an embodiment, each n1 is 5. In an embodiment, each v1 is 2. In an embodiment, each v1 is 3.

[0090] In embodiments, R 1A and R 1D In embodiments, R attached to different phenyl rings may be the same or different. 1A and R 1A In embodiments, R attached to the same phenyl ring may be the same or different. 1D and R 1D may be the same or different.

[0091] In embodiments, each R attached to the same phenyl ring 1A and R 1D are independently -O-(CH2) n1 S(O) v1 X 1 In embodiments, each R attached to the same phenyl ring is 1A and R 1A are independently -O-(CH2) n1 S(O) v1 X 1 In embodiments, each R attached to a different phenyl ring 1D and R 1D are independently -O-(CH2) n1 S(O) v1 X 1 is.

[0092] In another aspect, the cucurbituril compound that may be obtained or obtainable by one or more of the synthetic steps described herein has the formula (Ib): [ka] R has the structure: 1A and R 1D is as described herein.

[0093] In embodiments, each R 1A and R 1D is neutral. In embodiments, each R 1A and R 1D is in ionic salt form.

[0094] In embodiments, R 1A is -O-(CH2) n1 S(O) v1 X 1 In an embodiment, R 1A is -O-(CH2) n1 CO2X 1 In an embodiment, R 1A is -O-(CH2) n1 PO v1 X 1 In an embodiment, each n1 is 0. In an embodiment, each n1 is 1. In an embodiment, each n1 is 2. In an embodiment, each n1 is 3. In an embodiment, each n1 is 4. In an embodiment, each n1 is 5. In an embodiment, each n1 is 5. In an embodiment, each v1 is 2. In an embodiment, each v1 is 3.

[0095] In embodiments, R 1D is -O-(CH2) n1 S(O) v1 X 1 In an embodiment, R 1D is -O-(CH2) n1 CO2X 1 In an embodiment, R 1D is -O-(CH2) n1 PO v1 X 1In an embodiment, each n1 is 0. In an embodiment, each n1 is 1. In an embodiment, each n1 is 2. In an embodiment, each n1 is 3. In an embodiment, each n1 is 4. In an embodiment, each n1 is 5. In an embodiment, each n1 is 5. In an embodiment, each v1 is 2. In an embodiment, each v1 is 3.

[0096] In embodiments, R 1A and R 1D In embodiments, R attached to different phenyl rings may be the same or different. 1A and R 1A In embodiments, R attached to the same phenyl ring may be the same or different. 1D and R 1D may be the same or different.

[0097] In an embodiment, each of the R1A and R 1D are independently -O-(CH2) n1 S(O) v1 X 1 In embodiments, each R attached to the same phenyl ring is different. 1A are independently -O-(CH2) n1 S(O) v1 X 1 In embodiments, each R attached to a different phenyl ring 1D are independently -O-(CH2) n1 S(O) v1 X 1 is.

[0098] In another aspect, the cucurbituril compound that may be obtained or obtainable by one or more of the synthetic steps described herein has the formula (Ic): [ka] or a pharmaceutically acceptable salt thereof. 1 and n1 are as described herein.

[0099] In an embodiment, each X 1 are the same or different. In an embodiment, each X 1 are independently H, —OH, C1-C6 alkyl, an alkali metal cation, or a quaternary ammonium cation. In embodiments, each n1 is 0 to 5. In embodiments, each n1 is 1 to 5. In embodiments, each n1 is 2 to 5. In embodiments, each n1 is 3 to 5. In embodiments, each n1 is 4 or 5.

[0100] In another aspect, the cucurbituril compound that may be obtained or obtainable by one or more of the synthetic steps described herein has the formula (IA): [ka] or a pharmaceutically acceptable salt thereof. Each X is independently H, an alkali metal cation (e.g., Li + , Na + , K. + , or Cs + ), ammonium cation, or a combination thereof.

[0101] In another aspect, the cucurbituril compound that may be obtained or obtainable by one or more of the synthetic steps described herein has the formula (Id): [ka] R has the structure: 1A , R 1D , R 3A , R 3B , R 4A , and R 4B is as described herein.

[0102] In embodiments, R 3A is hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R 3A is C1-C3 alkyl, especially methyl.

[0103] In embodiments, R 3B is hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R 3B is C1-C3 alkyl, especially methyl.

[0104] In embodiments, R 3A and R 3B are both hydrogen, or R 3A and R 3B and may both be methyl. In embodiments, R 3A and R 3B One of them is hydrogen and the other is methyl.

[0105] In embodiments, R 4A is hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R 4A is C1-C3 alkyl, particularly methyl. In an embodiment, R 4A is H.

[0106] In embodiments, R 4B is hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R 4B is C1-C3 alkyl, particularly methyl. In an embodiment, R 4B is hydrogen.

[0107] In embodiments, each R 4A and R 4B is hydrogen. Alternatively, each R 4A and R 4B may be methyl. In embodiments, R 4A and R 4B One of them is hydrogen and the other is methyl.

[0108] In embodiments, each R 3A and R 3B are independently C1-C3 alkyl, and R 4A and R 4B is hydrogen, and in particular, each R 3A and R 3Bis methyl, and each R 4A and R 4B is hydrogen.

[0109] In embodiments, each R 1A and R 1D is neutral. In embodiments, each R 1A and R 1D is in ionic salt form.

[0110] In embodiments, R 1A is -O-(CH2) n1 S(O) v1 X 1 In an embodiment, R 1A is -O-(CH2) n1 CO2X 1 In an embodiment, R 1A is -O-(CH2) n1 PO v1 X 1 In an embodiment, each n1 is 0. In an embodiment, each n1 is 1. In an embodiment, each n1 is 2. In an embodiment, each n1 is 3. In an embodiment, each n1 is 4. In an embodiment, each n1 is 5. In an embodiment, each n1 is 5. In an embodiment, each v1 is 2. In an embodiment, each v1 is 3.

[0111] In embodiments, R 1D is -O-(CH2) n1 S(O) v1 X 1 In an embodiment, R 1D is -O-(CH2) n1 CO2X 1 In an embodiment, R 1D is -O-(CH2) n1 PO v1 X 1 In an embodiment, each n1 is 0. In an embodiment, each n1 is 1. In an embodiment, each n1 is 2. In an embodiment, each n1 is 3. In an embodiment, each n1 is 4. In an embodiment, each n1 is 5. In an embodiment, each n1 is 5. In an embodiment, each v1 is 2. In an embodiment, each v1 is 3.

[0112] In embodiments, R 1A and R 1D In embodiments, R attached to different phenyl rings may be the same or different. 1A and R 1A In embodiments, R attached to the same phenyl ring may be the same or different. 1D and R 1D may be the same or different.

[0113] In embodiments, each R attached to the same phenyl ring 1A and R 1D are independently -O-(CH2) n1 S(O) v1 X 1 In embodiments, each R attached to the same phenyl ring is 1A and R 1A are independently -O-(CH2) n1 S(O) v1 X 1 In embodiments, each R attached to a different phenyl ring 1D and R 1D are independently -O-(CH2) n1 S(O) v1 X 1 is.

[0114] In another aspect, the cucurbituril compound that may be obtained or obtainable by one or more of the synthetic steps described herein has the formula (X): [ka] or a pharmaceutically acceptable salt thereof.

[0115] In embodiments, each R 1A and R 1D is neutral. In embodiments, each R 1A and R 1D is in ionic salt form.

[0116] In embodiments, R 1Ais -O-(CH2) n1 S(O) v1 X 1 In an embodiment, R 1A is -O-(CH2) n1 CO2X 1 In an embodiment, R 1A is -O-(CH2) n1 PO v1 X 1 In an embodiment, each n1 is 0. In an embodiment, each n1 is 1. In an embodiment, each n1 is 2. In an embodiment, each n1 is 3. In an embodiment, each n1 is 4. In an embodiment, each n1 is 5. In an embodiment, each n1 is 5. In an embodiment, each v1 is 2. In an embodiment, each v1 is 3.

[0117] In embodiments, R 1D is -O-(CH2) n1 S(O) v1 X 1 In an embodiment, R 1D is -O-(CH2) n1 CO2X 1 In an embodiment, R 1D is -O-(CH2) n1 PO v1 X 1 In an embodiment, each n1 is 0. In an embodiment, each n1 is 1. In an embodiment, each n1 is 2. In an embodiment, each n1 is 3. In an embodiment, each n1 is 4. In an embodiment, each n1 is 5. In an embodiment, each n1 is 5. In an embodiment, each v1 is 2. In an embodiment, each v1 is 3.

[0118] In embodiments, R 1A and R 1D In embodiments, R attached to different phenyl rings may be the same or different. 1A and R 1A In embodiments, R attached to the same phenyl ring may be the same or different. 1D and R 1D may be the same or different.

[0119] In embodiments, each R attached to the same phenyl ring 1A and R 1D are independently -O-(CH2) n1 S(O) v1 X 1 In embodiments, each R attached to the same phenyl ring is different. 1A are independently -O-(CH2) n1 S(O) v1 X 1 In embodiments, each R attached to a different phenyl ring 1D are independently -O-(CH2) n1 S(O) v1 X 1 is.

[0120] synthesis Provided herein are methods for preparing the cucurbituril compounds described herein (i.e., compounds of Formula I, Ia, Ib, Ic, IA, ID, and X). The methods may include using one or more compounds having formula (II), (II'), (III), (IV), (V), (VI), or (VI'). Also provided herein are methods for preparing compounds having formula (IA), which may include using one or more compounds having formula (II-A), (II'-A), (III-A), (IV-A), (VA), or (VI-A).

[0121] In an embodiment, the method comprises Scheme 2 below. Scheme 2 [ka] In the formula, R 3A and R 3B is as described herein. In embodiments, R 3A and R 3B is C 1-3 alkyl or R 3A and R 3B is methyl.

[0122] The reaction according to Scheme 2 involves treating a glycoluril compound having Formula II with paraformaldehyde in the presence of an acid to give a glycoluril bisether of Formula III. The paraformaldehyde is added in 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.

[0123] The paraformaldehyde used in Scheme 2 is a polyoxymethylene, a polymerization product of formaldehyde, which may have a typical degree of polymerization of 8 to 100 units. Paraformaldehyde may be supplied as a solid or as a solution, particularly an aqueous solution.

[0124] Paraformaldehyde may be added to a mixture of glycoluril compound, acid, and solvent in a reaction vessel. Before adding 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 35°C or higher during the addition, after which the temperature can be maintained or increased, for example, to 45°C or higher or 50°C or higher; this increase can be temporary, or can be maintained for the remainder of the reaction period, or even reduced from the addition temperature, as long as the reaction temperature remains at about 35°C or higher.

[0125] The reaction of Scheme 2 may be maintained at a temperature greater than about 35° C., or greater than about 36° C., or greater than about 37° C., or greater than about 38° C., or greater than about 39° C., or greater than about 40° C., or greater than about 41° C., or greater than about 42° C., or greater than about 43° C., or greater than about 44° C., or greater than about 45° C. The reaction of Scheme 2 may be maintained at a temperature in the range of about 35-55° C., or about 35-50° C., or about 35-40° C., or about 35° C.

[0126] Heating the reaction mixture during the addition of paraformaldehyde results in a significantly improved yield of the glycoluril bis-ether of Formula III. In embodiments, the yield of glycoluril bis-ether of Formula III is greater than about 70%.

[0127] The acid used in the reaction mixture is a strong acid. In an embodiment, the acid in the reaction of Scheme 2 has a pKa of less than about 2.5, or less than about 2.0, or less than about 1.5, or less than about 1, or less than about 0.9, or less than about 0.8, or less than about 0.7, or less than about 0.6, or less than about 0.5. In an embodiment, the acid in the reaction of Scheme 2 may have a pKa of less than about 0.9.

[0128] The acid in the reaction of Scheme 2 can include, but is not limited to, HF, HCl, HBr, HClO, HNO, HSO, HPO, a sulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or toluenesulfonic acid, Eaton's reagent, trifluoroacetic acid, or a combination thereof. In embodiments, the acid in the reaction of Scheme 2 includes HF, HCl, or HBr, and in particular, the acid is HCl. 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.

[0129] In an embodiment, the method comprises Scheme 3 below. Scheme 3 [ka] In the formula, R 4A and R 4B is as described herein. In embodiments, R 4A and R 4B is hydrogen.

[0130] The reaction according to Scheme 3 involves treating a glycoluril compound having Formula II with paraformaldehyde in the presence of an acid to obtain a glycoluril dimer of Formula IV. The solvent may be selected from water, alcohols such as methanol, ethanol, and isopropanol, 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 a combination thereof. In an embodiment, the solvent is water or water combined with another solvent.

[0131] The paraformaldehyde is added in an amount approximately equal to or similar to 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 ratio of paraformaldehyde to glycoluril compound can be about 1.0 equivalent.

[0132] According to Scheme 3, the reaction mixture of Scheme 3 does not solidify during the reaction process. For example, the reaction mixture does not form a gel during the reaction or after the reaction is quenched. Maintaining stoichiometry as the reaction proceeds may be important to selectively produce the dimer of Formula IV without causing gelation of the reaction mixture. The paraformaldehyde used in Scheme 3 can be provided as a solid or as a solution, particularly an aqueous solution. The paraformaldehyde is added to a reaction vessel containing the compound of Formula (II') and the acid over an extended period of time, for example, dropwise or in several portions.

[0133] Maintaining careful stoichiometry as the reaction proceeds is important to selectively produce the glycoluril dimer of Formula IV. While gradual addition of paraformaldehyde to the reaction mixture might be expected to disrupt the stoichiometry of the reaction, the inventors have found that the yield and purity of the glycoluril dimer of Formula IV are consistent or improved. Furthermore, slow addition of paraformaldehyde to the reaction mixture reduced or prevented the occurrence of gelation in the reaction mixture. The reaction proceeded more completely, significantly improving the work process and allowing the reaction to be used on a commercial scale.

[0134] Paraformaldehyde may be added to the compound of Formula II' in more than four portions, for example, 4 to 10 portions, or 5 to 8 portions. Paraformaldehyde may be added to the compound of Formula II' in 4, 5, 6, 7, or 8 or more portions. For example, paraformaldehyde is added in 4 or more portions spaced at intervals of at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, or at least about 30 minutes. In embodiments, paraformaldehyde is added in 6 or more portions spaced at intervals of at least about 30 minutes.

[0135] Alternatively, paraformaldehyde is added to the compound of Formula II' over a period of at least about 45 minutes, 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, and the addition is continuous over that period (i.e., from the first addition to the last addition), e.g., continuous or dropwise addition, or multiple additions.

[0136] The acid used in the reaction mixture is a strong acid. In embodiments, the acid in the reaction of Scheme 3 has a pKa of less than about 2.5, or less than about 2.0, or less than about 1.5, or less than about 1, or less than about 0.9, or less than about 0.8, or less than about 0.7, or less than about 0.6, or less than about 0.5. In embodiments, the acid in the reaction of Scheme 3 may have a pKa of less than about 0.9.

[0137] The acid in the reaction of Scheme 3 can include, but is not limited to, HF, HCl, HBr, HClO, HNO, HSO, HPO, a sulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or toluenesulfonic acid, Eaton's reagent, trifluoroacetic acid, or a combination thereof. In embodiments, the acid in the reaction of Scheme 3 includes HF, HCl, or HBr, and in particular, the acid is HCl. 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.

[0138] In the synthesis of glycoluril dimer compound (IV) or (IV-A), an additional improvement is achieved by optimizing the reaction temperature to about 55°C or higher, which significantly improves purity and yield. The temperature of the reaction vessel is increased before, during, and after the addition of paraformaldehyde to the reaction according to Scheme 3. After the addition of paraformaldehyde, the reaction vessel temperature is maintained at a temperature 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.

[0139] Heating the reaction in Scheme 3 can promote side reactions such as oligomerization and polymerization, potentially reducing the yield of glycoluril dimer of Formula IV; however, the inventors have discovered that conducting the reaction at elevated temperatures improves the yield and purity of the reaction product.

[0140] This method can further include isolating the glycoluril dimer compound of formula IV. For example, the isolation can include recrystallization, precipitation, flocculation, centrifugation, filtration, or a combination 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 below about 30°C, and isolating the solid by, for example, filtering or centrifuging the reaction mixture.

[0141] After adding or contacting water with the reaction mixture, the reaction mixture is heated to at least about 70° C., at least about 71° C., at least about 72° C., at least about 73° C., at least 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 is set to at least about 70° C., at least about 71° C., at least about 72° C., at least about 73° C., at least 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 stirring the reaction mixture for about 1 to 5 days, or about 2 to 5 days, or about 3 days.

[0142] After the reaction mixture and water are heated, 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.

[0143] In certain embodiments, the compound of Formula IV in solid form (e.g., precipitate, particles, or powder) may be collected by centrifuging the reaction mixture. Alternatively, the compound of Formula IV in solid form (e.g., precipitate, particles, or powder) may be collected by filtration. In large-scale synthesis, post-reaction precipitation conditions may be important to improve yield and purity in the reaction of Scheme 3. Precipitation may involve adding various solvents (e.g., water or aqueous solutions, or mixed polar solvents) and then removing the solids, for example, by filtration.

[0144] The synthesis of glycoluril dimer 3 was disclosed by Isaacs and coworkers 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 did not suggest a method for reducing solidification of the reaction mixture, which the present inventors found to significantly complicate the purification and isolation of dimethylglycoluril 3. Furthermore, the reported method was performed at low temperatures, which the present inventors determined to be detrimental to the yield and purity of the glycoluril dimer. Furthermore, the present inventors found that the process of directly crystallizing the crude material, as reported in previous literature, resulted in a decrease in the purity of the final product.

[0145] In an embodiment, the method comprises Scheme 4 below. Scheme 4 [ka] In the formula, R 4A and R 4B is as described herein.

[0146] The reaction according to Scheme 4 involves condensing a glycoluril bisether of formula III with a glycoluril dimer of formula IV to give a glycol tetramer of formula V. The reaction of Scheme 4 is carried out 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 acidic solvents.

[0147] In particular, reaction solvents include TFA, which may be present as the sole solvent or in combination with one or more strong acids (e.g., Eaton's reagent) and one or more polar aprotic solvents. The use of TFA without MeSO3H or Eaton's reagent typically results in a very slow and ineffective reaction. Most non-acidic solvents are unable to completely dissolve the reagents and products or are incompatible with the strongly acidic components.

[0148] In certain embodiments, a solid form of the glycoluril bisether of Formula III may be dispersed in a solvent and added to a reaction vessel containing the glycoluril dimer. Furthermore, the reaction described in Scheme 4 can be performed using TFA to reduce the amount of catalytic acid required. In certain embodiments, one or more acids such as Eaton's reagent may be added in an amount of about 10 equivalents or more to facilitate an increase in the reaction rate.

[0149] The one or more acids used in the reaction mixture of Scheme 3 are strong acids. In 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 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 1, or less than about 0.5.

[0150] 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, trifluoromethanesulfonic acid, phosphoric acid, sulfuric acid, CSA, EtSO3H, HCl, HBr, HClO4, HNO3, or combinations thereof. In embodiments, the acid comprises methanesulfonic acid. In embodiments, the acid in the reaction comprises Eaton's reagent, which is a combination of methanesulfonic acid and phosphorus pentoxide, for example, about 10 wt% phosphorus pentoxide in methanesulfonic acid. In embodiments, at least about 8 equivalents of strong acid are used, and particularly, at least about 10 equivalents of strong acid are used.

[0151] The solvent in the reaction of Scheme 4 can include, but is not limited to, an additional acid, including trifluoroacetic acid (TFA), acetic acid, phosphoric acid, polyphosphoric acid (PPA), or a combination thereof. In certain embodiments, the additional acid is TFA.

[0152] In embodiments, the ratio of the one or more strong acids to the additional acid in the solvent may 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.

[0153] Additionally, the ratio of the one or more strong acids to the additional acid in the solvent is about 20:1, about 19:1, about 18:1, about 17:1, about 16:1, about 15:1, about 15:1, about 14:1, about 13:1, about 12:1, about 11:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, or about 1:1.

[0154] 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, diglymes, HMPA, or combinations thereof.

[0155] In embodiments, in the reaction of Scheme 4, TFA is used as the solvent and about 10 equivalents of a strong acid (one or more acids with a pKa less than 1, eg, Eaton's reagent) is used.

[0156] The use of TFA as a solvent during the reaction of Scheme 4 allows for an increase in the temperature of the reaction vessel due to the use of less of a reactive solvent and acid mixture. The reaction temperature is maintained at a temperature 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, or greater than 68°C. In embodiments, the reaction vessel temperature is maintained at a temperature greater than 69°C or greater than 70°C. In certain embodiments, the reaction temperature is maintained at a temperature of about 55°C.

[0157] Using these conditions, product yields can be significantly improved, especially in large scale reactions (eg, kg scale reactions).

[0158] After the reaction is complete, the residual acid (e.g., MeSO3H, etc.) can be removed by filtration and washing, followed by quenching, and the crude solid can be dried. A single filtration / recrystallization step may not be sufficient to remove impurities, including excess glycoluril bisether.

[0159] Additionally, when the reaction is complete, additional acid such as TFA can be added to the reaction, which can improve precipitation in large-scale reactions and improve purification and / or yield. At the end of the reaction of Scheme 4, the compound of formula V can be isolated by adding additional acid such as TFA to the reaction mixture after the reaction is complete, precipitating the compound of formula V by adding an anti-solvent such as water, and collecting the mixture containing the compound of formula V, for example, by filtration.

[0160] Precipitating the compound of formula V includes adding an anti-solvent for the compound of formula V. In certain embodiments, the anti-solvent includes, but is not limited to, water, methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, THF, dioxane, and combinations thereof.

[0161] In embodiments, the compound of formula V in solid form (e.g., precipitate, particles, or powder) may be collected by centrifuging the mixture. Alternatively, the compound of formula V in solid form (e.g., precipitate, particles, or powder) may be collected by filtration. In embodiments, the resulting compound may be washed with water and / or acetone.

[0162] The synthesis of glycoluril tetramer compound 5 was reported by Isaacs and coworkers (Nature Chem 4, 503-510 (2012)), who found a lower yield (36%). Furthermore, the reported purification process, which involved directly recrystallizing the crude product in TFA followed by washing with water, was found to yield a lower purity product. Other methods for forming this compound have been published (see, for example, Org. Chem. Front., 2019, 1555); however, the inventors found that these methods were difficult to implement on a large scale due to the small size of the product particles, which would pass through a filter centrifuge. Furthermore, reducing the concentration of Eaton's reagent resulted in improved purity, along with the waste disposal and cost benefits associated with using a weaker acid.

[0163] In one embodiment, a method for preparing a compound of formula I comprises Scheme 1 below. Scheme 1 [ka] R 1A , R 1B , R 1C , R 1D , R 3A , R 3B , R 4A , and R 4B is as described herein.

[0164] The reaction according to Scheme 1 involves the condensation of a glycol tetramer of formula V with a compound of formula VI. The reaction of Scheme 1 is carried out in the presence of a solvent system comprising (i) one or more acids having a pKa of less than about 1, and (ii) an anhydride.

[0165] In embodiments, the one or more acids having a pKa of less than about 1 include trifluoroacetic acid, Eaton's reagent, methanesulfonic acid (MeSO3H), toluenesulfonic acid (TsOH), trifluoromethanesulfonic acid, phosphoric acid, sulfuric acid, camphorsulfonic acid (CSA), ethanesulfonic acid (EtSO3H), or a combination thereof. In embodiments, the one or more acids having a pKa of less than about 1 include trifluoroacetic acid.

[0166] The use of an anhydride as a co-solvent significantly increases the reaction rate and overall yield of the reaction, e.g., the overall yield (66%). The anhydride can be an organic acid anhydride, where the acyl group of the anhydride is derived from a carboxylic acid, a sulfonic acid, a phosphonic acid, or a combination. The anhydride can be an organic acid anhydride, where the acyl group of the anhydride is derived from a carboxylic acid, a sulfonic acid, a phosphonic acid, or a combination thereof. The anhydride can be selected from compounds having the general structural formula R'-C(=O)-OC(=O)-R'', where R' and R'' can be the same or different and independently selected from alkyl, aryl, heteroalkyl, or can join to form a heterocycle, each of which can be substituted with halo, alkyl, trihaloalkyl, etc. In certain embodiments, the anhydride is selected from, but is not limited to, acetic anhydride, trifluoroacetic anhydride, butyric anhydride, propionic anhydride, trifluoromethanesulfonic anhydride, succinic anhydride, maleic anhydride, or a combination thereof. The anhydride can be acetic anhydride, trifluoroacetic anhydride, or a combination thereof.

[0167] The amount of anhydride in the reaction can range from about 0.01% of the solvent (i.e., volume of anhydride / volume of total solvent × 100) to a concentration where the anhydride is no longer soluble in the reaction solvent. The anhydride may be present in a range of about 0.01% to about 60% by volume of solvent, or about 0.3% to about 55%, or about 1% to about 55%, or about 2% to about 50% by volume of solvent. Alternatively, the anhydride may be present in a range of about 1% to about 45%, or about 2% to about 40% by volume of solvent.

[0168] The reaction of Scheme 1 can benefit from avoiding the use of excessive amounts of compound VI, making the overall synthesis more efficient and economical. The reaction of Scheme 1 can use about 4 equivalents or less of the compound of Formula VI, or about 3 equivalents or less of the compound of Formula VI. In embodiments, the reaction of Scheme 1 uses about 2 equivalents to about 5 equivalents of the compound of Formula VI, or about 2.5 equivalents to about 4.5 equivalents of the compound of Formula VI, or about 2.5 equivalents to about 4 equivalents of the compound of Formula VI.

[0169] The product obtained after this reaction can be precipitated using an anti-solvent (e.g., a polar solvent), especially in large-scale synthesis. Exemplary anti-solvents can include acetone, brine, ethanol, methanol, brine, or combinations thereof.

[0170] The synthesis of cucurbituril compounds has been reported (see, e.g., Org. Biomol. Chem., 2014, 12, 2413-2422; WO2012 / 051407). However, the procedure resulted in lower yields (e.g., 40% vs. 67%) and did not use an acid anhydride as a cosolvent, which the inventors found improved reaction rates in this synthesis. Furthermore, the inventors observed incomplete reactions using anhydride-free conditions, leading to reduced purity and yield of the final product.

[0171] In one aspect, a method for preparing a compound of formula (IA) comprises Scheme 5 below. Scheme 5 [ka] X is as described herein.

[0172] The reaction according to Scheme 5 involves contacting a compound of formula VI-A with a compound having formula VA according to the conditions discussed above for Scheme 1.

[0173] In one aspect, a method for preparing a compound of formula (IB) comprises Scheme 6 below. Scheme 6 [ka] X is as described herein.

[0174] In embodiments, the method comprises contacting a compound of formula VI-B with a compound having formula VA according to the conditions discussed above for Scheme 1.

[0175] In an embodiment, the method comprises the following Scheme 7 for producing a compound of formula VI-A: Scheme 7 [ka] X is as described herein.

[0176] The reaction of Scheme 7 is carried out in the presence of a base and a solvent comprising one or more of water, a polar aprotic solvent, and combinations thereof.

[0177] Instead of adding the base in aqueous basic solution or as a solvent, the base may be added in salt or solid form. As a result, reduced molar equivalents of base may be present in the reaction mixture, for example, when 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, particularly about 2.2 equivalents, about 2.3 equivalents, about 2.4 equivalents, or about 2.5 equivalents. Bases include, but are not limited to, alkali metal hydroxides (e.g., NaOH, LiOH, or KOH) and quaternary ammonium hydroxides.

[0178] The amount of base, such as NaOH, used in this reaction can provide a higher yield and purity for the compound of formula (VI-A). Although it is known that sultone hydrolyzes in the presence of a base, there is no known evidence that the reaction rate of sultone hydrolysis competes with the alkylation of hydroquinone with sultone. For example, in the past, a large excess of NaOH (2.5 M) could be used in such a reaction, but the excess NaOH also reacts with 1,3-propane sultone, causing an incomplete reaction and a reduced yield.

[0179] The sultone may be added over an extended period of time, for example, dropwise or in portions. In an embodiment, in the reaction of Scheme 6, the sultone is added over a period of more 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 sultone is added in two, three, four, or more portions spaced at intervals of at least about 30 minutes, or at least about 1 hour. In an embodiment, the sultone is added in four or more portions spaced at intervals of 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.

[0180] The reactants further include hydroquinone. Alternatively, the reaction can use 1,4-dihydroxynaphthalene.

[0181] 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, or less than about 5°C before adding the sultone, or before each addition of the sultone if the sultone is added in portions or in portions.

[0182] The base in the reaction is present in an amount equivalent to or greater than the amount of sultone. In certain embodiments, the base in the reaction is present in an amount of 1 to 10 equivalents of sultone, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 equivalents. Furthermore, the sultone may be added over an extended period of time, e.g., dropwise or in several portions. In certain embodiments, the base is added over a period of more 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, three, four, or more portions spaced at intervals of 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.

[0183] The synthesis of aromatic sidewall compounds VI-A or VIB has been reported (see, for example, Ma, D. et al. Nature Chem 4, 503-510 (2012); WO2012 / 051407). However, the process disclosed herein provides improved yields over this step (90% compared to 81%). Furthermore, the process disclosed herein allows for a reduction in reaction time (e.g., from 12 hours to 2 hours). Also, a reduction in the amount of monosubstituted impurities is observed when using the procedures described herein.

[0184] In embodiments, the method includes the following Scheme 8 for producing a compound of formula VI-B: X is as described herein. In embodiments, the reaction of Scheme 8 may be carried out according to the conditions of Scheme 7, as described above. Scheme 8 [ka]

[0185] In an embodiment, the method comprises Scheme 9 below. Scheme 9 [ka]

[0186] In embodiments, the reaction of Scheme 9 may be carried out according to the conditions of Scheme 4 as described above.

[0187] In an embodiment, the method comprises the following Scheme 10: Scheme 10 [ka]

[0188] In embodiments, the reaction of Scheme 10 may be carried out according to the conditions of Scheme 2 as described above.

[0189] In an embodiment, the method comprises the following Scheme 11: Scheme 11 [ka]

[0190] In embodiments, the reaction of Scheme 11 may be carried out according to the conditions of Scheme 3 as described above.

[0191] Exemplary synthetic methods for compound IA (eg, CS-1103) and compound IB (eg, CS-1105) are shown in Figures 1 and 2, respectively.

[0192] Notably, in Scheme 4, the reaction involves 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 promote reactivity. This significantly reduces the amount of excess sulfonic acid used compared to previously reported methods. This process also results in higher yields of compounds of formula V or VA and, unexpectedly, produces larger particles in the crude material, which can be effectively filtered on scale. These advantages are unexpected benefits of switching the solvent component of Scheme 4 to TFA in combination with a strong acid (e.g., Eaton's reagent, H2SO4, methanesulfonic acid, toluenesulfonic acid, or camphorsulfonic acid). Attempts to use TFA as the sole solvent and catalyst without the addition of sulfonic acid proved ineffective. Furthermore, the reduction in viscosity of the reaction mixture in Scheme 4 was a surprising benefit of modifying the reaction conditions. As a result, yields and purity can be improved while eliminating significant optimization efforts. Furthermore, the reaction mixture contains a low concentration of strong acid or Eaton's reagent, allowing for safer reaction conditions and easier waste disposal. For example, the work-up process of the reaction is facilitated by using a weak acid, and the viscosity of the reaction mixture is reduced, making it easier to scale up the reaction process to a large scale.

[0193] According to certain embodiments, in the reaction of Scheme 7 or 8, reducing the amount of NaOH in the reaction can provide a high yield and purity of the compound of Formula (VI-A) or (VI-B). Although it is known that sultone hydrolyzes in the presence of a base, the related art has not suggested that the reaction rate of sultone hydrolysis competes with the alkylation of sultone with hydroquinone. Conventionally, a large amount of NaOH (2.5 M) is used in such a reaction, but excess NaOH also reacts with 1,3 propane sultone, leading to an incomplete reaction and loss of yield.

[0194] Furthermore, according to certain embodiments, Scheme 3, the present disclosure provides further improvements during the synthesis of compound (IV) or (IV-A), with significantly improved purity and yield, by optimizing the reaction temperature at about 55° C. or higher.

[0195] According to certain embodiments, in Scheme 1, the present disclosure provides the advantage of avoiding the use of excess compound VI or VI-A, making the overall synthesis more efficient and economical. [Example]

[0196] Comparative Example A Glycoluril dimer [3]: Glycoluril (250 g, 1.76 mol) and paraformaldehyde (52.5 g, 1.76 mol) powders (solvent-free) were stirred together at room temperature in a Nalgene beaker using a metal spatula until well mixed (approximately 5 min). An aqueous solution of HCl (8 M, 350 mL) was slowly poured into the beaker while the metal spatula was used to manually stir the mixture. After approximately 90 seconds of stirring, a gummy white solid formed in the beaker. Heat was generated in the flask during this step (the beaker was warm to the touch, but the temperature was not measured). The white solid was immediately broken into small pieces with the 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 clumps were further broken up using the metal spatula. Any residue along the sides of the flask was also scraped into the mixture. The well-dispersed slurry was returned to the oil bath and stirred at 50°C for 2 days.

[0197] The reaction mixture was then cooled to room temperature (RT) and filtered by vacuum filtration using Whatman No. 1 filter paper. Once nearly dry, the white semi-solid (glue-like) was transferred to an Erlenmeyer flask and stirred with 250 mL of water. The mixture was stirred overnight at room temperature (until clumps broke down into small particles). The slurry was filtered by vacuum filtration (Whatman No. 1 filter paper) and allowed to dry on the filter paper (several hours) before being transferred to the next step. If the product was transferred before it was completely dry, the filter paper would adhere to the product during transfer, resulting in pellets. The crude solid (approximately 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 hours, then cooled to room temperature and stirred overnight at room temperature. The mixture was filtered by vacuum filtration using Whatman 1 filter paper and allowed to dry in the filter funnel for 1 day. The solid was allowed to dry until it could be transferred to a round-bottom flask. To remove residual TFA, the dried solid was stirred with ethanol (600 mL) at 80 °C overnight.

[0198] The slurry was cooled to room temperature and filtered by vacuum filtration using Whatman 1 filter paper, and the solid was dried in the filter funnel for 1 day. The white solid was broken up with a spatula, transferred to an RB flask, and then dried under high vacuum until a constant weight was reached (1 day). The resulting product was a white solid (119.7 g, 44%). 1 H and 13 Analysis was performed using C NMR, melting point, and IR. Spectroscopic data are consistent with those reported in the literature (Huang, W.-H.; Zavalij, P.Y.; Isaacs, L.J. Am. Chem. Soc. 2008, 130, 8446-8454).

[0199] Comparative Example B Glycoluril tetramer building block [5]: Glycoluril dimer (13.1 g, 33.13 mmol) was dissolved in Eaton's reagent (7.7% PO in MeSOH, 95 mL), and the solution was heated to 50 °C under nitrogen. After 30 min, with good magnetic stirring, the solid was mostly dissolved. Dimethylglycoluril bisether (4, 47.5 g, 186.4 mmol) was added in one portion, and the powder was manually stirred into solution using a spatula.

[0200] The reaction mixture was stirred at 50°C for 3 hours. It was important to ensure that stirring was maintained as the reaction mixture increased in viscosity over the course of 3 hours. After 3 hours, the red solution was poured into 850 mL of water, and an additional 100 mL (950 mL total) was used to rinse the inside of the flask to the full volume. The mixture was stirred at 25°C for 10 minutes, then transferred to four 1 L centrifuge bottles, centrifuged (3000 RPM, 2500G, 10 minutes), and the supernatant was decanted.

[0201] Water was added to each centrifuge bottle (150 mL each), and the bottles were centrifuged again and decanted two more times (3000 RPM, 2500 G, 10 min) until the decanted solvent was no longer pink. After decanting, the centrifuge tubes were kept overnight at -4 °C for storage. The solids were dried by transferring them into a round-bottom flask and placed on a high vacuum or rotary evaporator. The dried solids were then dissolved in TFA (96 mL total, 24 mL in each centrifuge bottle), and the bottles were vortexed or sonicated to facilitate dissolution. Addition of 150 mL of water to each bottle to the TFA solution resulted in the formation of a white precipitate. The samples were vortexed, then centrifuged (3000 rpm, 2500 G, 10 min), and decanted. The solids were then washed with water (600 mL each), vortexed or sonicated to break up the pellet, and centrifuged (4000 rpm, 4400 G, 10 min). The solid was then washed twice (2x) with acetone (300 mL per tube), vortexed, and centrifuged (3800 rpm, 4000 g, 10 min). The precipitate was kept at -4°C overnight. A second TFA / water / acetone wash removes a colored impurity that is not visible by NMR. It is unclear how much of the impurity has been removed compared to the product.

[0202] The precipitate from each bottle was collected in a round-bottom flask, and the centrifuge tube was rinsed with EtOH to transfer all the product to the flask. The EtOH was removed using rotary evaporation, and the final product was dried under high vacuum. To repurify the combined sample, all solids were dissolved in TFA (48 mL). The dissolved product in TFA was then added equally (8 mL per centrifuge tube) to six 50 mL Falcon tubes. The Falcon tubes were filled with water to a total volume of 50 mL, 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. Next, acetone was added to the centrifuge tubes twice to the 25 mL mark, and the tubes were centrifuged (3800 RPM, 2300 G, 10 minutes) and decanted to wash the solids. The solid was transferred to a round-bottom flask and dried to constant weight using high vacuum. The final product was a white powder (12.1 g, 47% yield).

[0203] 1 H and 13 Analysis was carried out using C NMR, melting point, and IR.

[0204] Comparative Example C Aromatic sidewall building block [8]: A solution of hydroquinone (72.7 g, 0.66 mol) in aqueous sodium hydroxide (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 room temperature for 12 hours.

[0205] The solution was then poured into acetone (4.0 L), precipitating a reddish solid. The solid was collected by vacuum filtration (Whatman 1 filter paper) funnel, and the solid was retained in the Buchner funnel and rinsed with 100 mL of additional acetone. The solid was transferred to a round-bottom flask, where it was dried under vacuum overnight. The solid was recrystallized from a mixed solvent of water and EtOH to yield the product (195 g, 74%) as beige crystals. Note: 100 g of crude material was dissolved in 500 mL of water, then 1.0 L of EtOH was added. The mixture was heated to dissolve all the solid, and additional HO was added as needed to expedite this process. The mixture was then cooled to room temperature. The recrystallized product was then collected by filtration.

[0206] 1 H and 13 Analysis was carried out using C NMR, melting point, and IR.

[0207] Comparative Example D Synthesis of CS-1103: A solution of methyl tetramer (5) (20.0 g, 25.6 mmol) was prepared in TFA / AcO (v / v = 1:1, 200 mL). To this solution was added [8] (C6H4(OCH2CH2CH2SO3Na)2, 39.6 g, 102.4 mmol) with stirring. The mixture was stirred and heated at 70 °C for 3 h.

[0208] While the reaction mixture was still hot, MeOH (1.0 L) was poured into an Erlenmeyer flask with stirring. The solid was collected by filtration (Whatman 1 filter paper) and dried under high vacuum. After drying, the solid (59.8 g) was dissolved in water (150 mL), stirred at room temperature, precipitated with acetone (300 mL), and filtered using vacuum filtration. After drying, the material was redissolved in water (150 mL) and precipitated with acetone (300 mL), collecting 48.4 g of crude material. This material was dissolved in water (60 mL), stirred at room temperature, and precipitated with acetone (60 mL). The mixture was then cooled to 0 °C overnight and filtered using vacuum filtration (Whatman 1 filter paper). The resulting solid (approximately 23.5 g) was dissolved in water (94 mL) to a concentration of 250 mg / mL. The solution was filtered using Whatman 1 filter paper, and the filtrate was adjusted to pH 7 with the addition of 1 M aqueous NaOH (approximately 150 μL). The filtrate was concentrated by rotary evaporation, and the solid was further dried under high vacuum to give CS-1103 (23.4 g, 60%) as a pale yellow powder. The powder was 93-95% pure by HPLC-UV / Vis analysis.

[0209] recrystallization

[0210] Pale yellow powder CS-1103 (1.0 g) was suspended in deionized water (1.4 mL). The mixture was heated to reflux with stirring. Once the compound was completely dissolved (approximately 10 minutes), the mixture was removed from the heat and allowed to cool slowly to room temperature over 2 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 the product was recovered as colorless crystals (>98% purity by HPLC UV-Vis analysis).

[0211] Example 1: Synthesis of CS-1103 Step 1: [2] Synthesis of Dimethylglycoluril [ka]

[0212] 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 room temperature for 12 h. The reaction mixture was filtered, and the solid was washed with water (3.5 L × 2) and then with ethanol (2.0 L) to give 2 as a white solid (1168 g, 86%).

[0213] Step 2: [4] Synthesis of dimethylglycoluril bisether [ka]

[0214] 7.5 kg of water and 66.86 kg of 31.5% HCl were charged to the reactor, 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 paraformaldehyde (15.67 kg, 522.3 mol, 4.5 equivalents), followed by a water rinse. 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 hours 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 19.5 kg of glycoluril bis ether was recovered in a 72% yield.

[0215] Step 3: [8] Synthesis of aromatic sidewalls [ka]

[0216] Hydroquinone (7.0 kg, 63.6 mol), 48.7 kg of water, 20% NaOH (28.98 kg, 144.9 mol NaOH, 2.3 equivalents), and 12.34 kg of water were charged to a reaction vessel. The reaction mixture was cooled to a temperature of 5°C. 20% 1,3-propane sultone in dioxane (77.73 kg, 127 mol, and 2.0 equivalents of sultone) was added, and then the reaction temperature was set to 25°C and the reaction mixture was stirred for 2 hours. After the reaction, the mixture was cooled to a temperature of 5°C.

[0217] 20% 1,3-propane sultone in dioxane (19.41 kg, 31.8 mol, 0.5 eq) was added to the reaction mixture, which was heated to 25° C. and stirred for 2 hours. Optionally, 20% 1,3-propane sultone in dioxane (19.41 kg, 31.8 mol, 0.5 eq) was added and stirred for 2 hours. The reaction mixture was cooled to 5° C., and 20% NaOH in water (13.04 kg, 65.2 mmol, 1.0 eq) was added. The reaction mixture was 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). The recrystallization was optionally repeated. The washed mixture was dried under vacuum at a temperature of 50° C., and 22.7 kg of compound 8 was recovered (90%).

[0218] Step 4: [3] Synthesis of glycoluril dimer [ka]

[0219] Water (8.8 kg), 31.5% HCl (35.8 kg), and 29.29 kg of glycoluril (206.1 mol) were charged to a reaction vessel, which was then set to a temperature of 50°C. Paraformaldehyde (6.08 kg, 202.7 mol, 1.0 equivalent) was added to the reaction vessel in six portions, 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 and transferred to a vessel containing 119.4 kg of water. The vessel was set to a temperature of 80°C, and the reaction mixture was stirred for 2 hours. The reaction mixture was cooled to a temperature of 25°C, and the reaction mixture was centrifuged, washed with water (2 x 115 L) and acetone (73 L), and dried under vacuum at 50°C. 16.5 kg of glycoluril dimer 3 was recovered (52%).

[0220] Step 5: [5] Synthesis of glycoluril tetramer [ka]

[0221] 5.21 (20.5 mol) kg of dimer 3, 15.04 kg of bisether 4 (59.2 mol, 2.8 equiv.), and 41.78 kg of TFA were charged to a reaction vessel, the reaction temperature was set to 55°C, and stirring was continued for 90 minutes until all solids were dissolved, after which the temperature was set to 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 of water, set to 25°C, and stirred for 30 minutes. The reaction mixture was centrifuged, washed with water (2 x 26.1 L), then acetone (2 x 25.5 L), transferred to a vacuum oven, and then dried at 50°C.

[0222] The dried material was dissolved in TFA (117.6 kg) and stirred at a temperature of 35° C. until dissolved, after which 83.66 kg of water was added. The mixture was centrifuged and washed with water (1×87.5 L) and then acetone (1×88.2 L). Water (43 kg) was added to the mixture to form a slurry, which was centrifuged and washed with water (116 kg) and then acetone (117 L). A slurry was formed 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. Reaction product 5 (15.0 kg) was recovered (51%).

[0223] Step 6: Synthesis of CS-1103 [ka]

[0224] 23.85 kg of acetic anhydride, 26.81 kg of TFA, compound 8 (10.23 kg, 25.7 mol, 4 equivalents), and tetramer 5 (4.99 kg) were charged into a reaction vessel. The reaction mixture was stirred at 70 °C for 3 hours and cooled to 35 °C. The reaction mixture was then added to another vessel containing 80 kg of MeOH, and the mixture was stirred at 0 °C for 30 minutes, centrifuged, and washed with MeOH (31.2 kg × 2). The resulting product was dissolved in 37.5 kg of water at 50 °C, and then 60 kg of acetone was added to precipitate the product. The product was centrifuged, washed with acetone (1 × 30.65 kg), and dissolved in 38.5 kg of water at 50 °C. Acetone (59.24 kg) was added to precipitate the product, and the mixture was centrifuged, washed with acetone (1 × 30.39 kg), and dissolved in 27.5 kg of water at 50 °C. 30 kg of EtOH was added to the resulting mixture, stirred at 15° C. for 1 hour, centrifuged, washed with EtOH (1×29.56 kg), and dissolved in 30.22 kg of water at 50° C. 2% NaOH was further added until the pH reached approximately 10.0, and the reaction mixture was filtered, precipitated with 47.27 kg of EtOH, centrifuged, and dried in a vacuum oven at 50° C. 11.8 kg (67%) of CS-1103 was recovered.

[0225] Example 2: Synthesis of CS-1105 The synthetic scheme of CS-1105 is shown in Figure 2. [ka]

[0226] 1,4-Hydroxynaphthalene (30 g, 187.3 mmol) was dissolved in aqueous NaOH (18.6 g, 0.47 mol, 250 mL HO). In a separate flask, 1,3-propane sultone (57.2 g, 0.47 mol) was dissolved in dioxane. A solution containing 1,3-propane sultone in dioxane was added to the aqueous solution of 1,4-dihydroxynaphthalene. The reaction mixture was stirred at room temperature for 18 hours. An additional 25 g (0.20 mol) of 1,3-propane sultone in dioxane (75 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. A solution containing 10 g of NaOH (0.25 mol) in 50 mL of HO was added to the reaction mixture to hydrolyze the excess sultone. The reaction mixture was stirred at room temperature for 2 hours and poured into 1 L of acetone. The resulting precipitate was filtered and dried under high vacuum. The precipitate was redissolved in HO (150 mL) and precipitated with 1.2 L of acetone. The resulting precipitate was filtered and dried under high vacuum to give compound 9 as an off-white solid (77.0 g, 92%). [ka]

[0227] Aromatic sidewall 9 (68.2 g, 154 mmol) was added to a solution of methyl glycoluril tetramer (30.00 g, 38.4 mmol) in TFA / AcO (1:1, 250 mL). The mixture was stirred and 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 by filtration. The solid was recrystallized from a mixture of water and acetone (1:2, v / v, 750 mL) (the crude product was first dissolved in water, then acetone was added, and the product precipitated from the solution). The crude product was then recrystallized from a mixture of water (200 mL) and ethanol (200 mL) (the solid was first dissolved in water by heating, then EtOH was added, and the mixture was cooled to 4 °C). The solid was dissolved in water (1.05 L) and filtered to remove insoluble impurities. The filtrate was adjusted to pH = 7 by adding 1 M aqueous NaOH solution. The solvent was removed and the solid was then further dried under high vacuum to give CS-1105 as an off-white solid (43.8 g, 69%).

[0228] Example 3 [ka] The effect of varying the amount of acetic anhydride in the above reaction was examined. Table 1 provides the conditions used in this study. [Table 1]

[0229] The solvents (i.e., TFA, acetic anhydride, MeSO3H), compound 8, and tetrameric 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 mL sample from each reaction was removed and added to 1 mL of DMSO, and the relative product purity was determined by HPLC. Reactions A through E each showed good relative purity, with reactions B through E showing improved relative purity.

[0230] Example 4 [ka] The effect of varying the amount of trifluoroacetic anhydride (TFAA) in the above reaction was examined. Table 2 provides the conditions used in this study. [Table 2]

[0231] The solvent (i.e., TFA, acetic anhydride, TFAA), compound 8, and tetrameric compound 5 were charged to an 8 mL reaction vessel according to the parameters in Table 2. The reaction mixture was stirred for a total of 4 hours at a temperature of 70 °C. A 10 μL sample from each reaction was removed and added to 1 mL of DMSO, and the relative product purity was determined by HPLC. Reactions A through E each showed good relative purity, while reactions C and D showed improved relative purity. Reactions E through H showed decreased relative purity.

[0232] Example 5 [ka] The effect of varying the reaction temperature on the above reaction was examined. Table 3 provides the conditions used in this study. [Table 3]

[0233] Solvents (i.e., TFA, acetic anhydride), compound 8, and tetrameric compound 5 were charged to an 8 mL reaction vessel. The reaction mixture was stirred for 4 hours at the temperature shown in Table 3. A 10 μL sample from each reaction was removed and added to 990 mL of DMSO, and the relative product purity was determined by HPLC. Each reaction showed a decrease in relative product purity compared to reactions performed at 70 °C.

[0234] Example 6 [ka] [Table 4]

[0235] Solvents (i.e., TFA, acetic anhydride), compound 8, and tetrameric compound 5 were charged to a 4 mL reaction vessel. The reaction mixture was stirred at 70 °C for 4 hours. A 10 μL sample from each reaction was removed and added to 990 μL of DMSO, and the relative product purity was determined by HPLC. Reactions A through E each showed good relative purity, with reactions C through E showing improved relative purity.

Claims

1. Formula I 【Chemical 1】 or a pharmaceutically acceptable salt thereof, comprising: During the ceremony, Each R １Ａ and R １Ｄ are independently hydrogen, halogen, —OH, C １ -C ６ Alkyl, 2- to 6-membered heteroalkyl, C ３ -C ６ cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -O-(CH ２ ) ｎ１ S (O) ｖ１ X １ , —O—(CH ２ ) ｎ１ CO ２ X １ , and —O—(CH ２ ) ｎ１ P.O. ｖ１ X １ is selected from Each R １Ｂ and R １Ｃ are independently hydrogen, halogen, —OH, C １ -C ６ Alkyl, 2- to 6-membered heteroalkyl, C ３ -C ６ Cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, —O—(CH ２ ) ｎ１ S (O) ｖ１ X １ , —O—(CH ２ ) ｎ１ CO ２ X １ , and —O—(CH ２ ) ｎ１ P.O. ｖ１ X １ Selected from, or Additionally or alternatively, two R １Ａ , R １Ｂ , R １Ｃ and R １Ｄ are bonded together with the atoms to which they are attached to form a fused C ６ ~C １２ aryl, 5- to 12-membered heteroaryl, or 5- to 7-membered heterocyclic ring, which are independently selected from halogen, —OH, —NH ２ , substituted or unsubstituted C １ -C ６ optionally substituted with 1 to 3 substituents selected from alkyl, or substituted or unsubstituted 2- to 6-membered heteroalkyl; Each R ３Ａ and R ３Ｂ are independently hydrogen, halogen, —OH, C １ -C ６ selected from alkyl, phenyl, substituted phenyl, and 2- to 6-membered heteroalkyl; Each R ４Ａ and R ４Ｂ are independently hydrogen, halogen, —OH, C １ -C ６ selected from 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; Each X １ are independently H, —OH, C １ -C ６ selected from alkyl, alkali metal cations, and quaternary ammonium cations; The method comprises: (i) Formula II 【Chemistry 2】 with paraformaldehyde in the presence of an acid to produce a compound of formula III 【Chemistry 3】 providing a compound having the formula: (ii) Formula II' 【Chemistry 4】 contacting a compound having 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 the reaction is maintained at a temperature above 55°C, to produce a compound having formula IV 【Chemistry 5】 providing a compound having the formula: (iii) Formula III 【Chemistry 6】 with a compound having Formula IV 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 acidic solvents; Formula V: 【Chemistry 7】 providing a compound having the formula: and isolating said compound of formula V. (iv) a compound having the formula V and a compound having the formula VI 【Chemistry 8】 with one or more acids having a pKa of less than about 1 in the presence of a solvent comprising an anhydride to provide a compound having formula I.

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

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

5. 3. The method of claim 1 or 2, wherein in the reacting of step (ii), the paraformaldehyde is added by continuous or dropwise addition over a period of at least about 45 minutes, or at least about 1 hour, at least about 1.5 periods, 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. 6. The method of any one of claims 1 to 5, wherein the reaction of step (ii) is maintained at a temperature above 65°C.

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

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

9.

8. In the reaction of step (ii), the acid is HF, HCl, HBr, HClO ４ , HNO ３ , H ２ SO ４ , H ３ P.O. ４ 8. The method of any one of claims 1 to 7, wherein the reactant is selected from a sulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or toluenesulfonic acid, Eaton's reagent, trifluoroacetic acid, or a combination thereof.

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

10. The method of any one of claims 1 to 9, wherein the reaction mixture of step (ii) does not solidify during the reaction process.

11. 11. The method of any one of claims 1 to 10, wherein the method further comprises isolating the compound of formula IV of 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. 12. The method of any one of claims 1 to 11, wherein the reaction temperature in step (iii) is maintained at about 55°C or higher.

13. The solvent in step (iii) is selected from the group consisting of trifluoroacetic acid, phosphoric acid, sulfuric acid, HCl, HBr, HClO ４ , HNO ３ 13. The method of any one of claims 1 to 12, comprising an acid selected from the group consisting of trifluoromethanesulfonic acid, methanesulfonic acid, toluenesulfonic acid, Eaton's reagent, and combinations thereof.

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

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

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

17. 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, wherein the anti-solvent comprises methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, THF, dioxane, or a combination thereof.

18. In step (iii) or (iv), the one or more acids having a pKa of less than about 1 are selected from the group consisting of methanesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, phosphoric acid, sulfuric acid, camphorsulfonic acid, ethanesulfonic acid, HCl, HBr, HClO ４ , HNO ３ or a combination thereof.

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

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

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

22. Each R １Ａ and R １Ｄ are independently —O—(CH ２ ) ｎ１ S (O) ｖ１ X １ , —O—(CH ２ ) ｎ１ CO ２ X １ , and —O—(CH ２ ) ｎ１ P.O. ｖ１ X １ is selected from R １Ｂ and R １Ｃ is hydrogen, and X １ The method of any one of claims 1 to 21, wherein is H or an alkali metal cation.

23. Each R ３Ａ and R ３Ｂ However, independently C １ -C ３ is alkyl, R ４Ａ and R ４Ｂ The method of any one of claims 1 to 22, wherein is hydrogen.

24. Formula IV 【Chemistry 9】 1. A method for the preparation of a compound having the formula: The method comprises: (i) Formula II' 【Chemistry 10】 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 the reaction is maintained at a temperature above 55°C; and (ii) optionally isolating said compound of formula IV.

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

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

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

28. 25. The method of claim 24, wherein the paraformaldehyde is added by continuous or dropwise addition over a period of at least about 45 minutes, or at least about 1 hour, at least about 1.5 periods, 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. 30. The method of any one of claims 24 to 29, wherein the reaction is maintained at a temperature above 65°C.

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

31. 31. The method of any one of claims 24-30, 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. R ４Ａ and R ４Ｂ The method of any one of claims 24 to 31, wherein is hydrogen.

33. Formula I 【Chemistry 11】 1. A method for the preparation of a compound having the formula: During the ceremony, Each R １Ａ and R １Ｄ are independently hydrogen, halogen, —OH, C １ -C ６ Alkyl, 2- to 6-membered heteroalkyl, C ３ -C ６ cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -O-(CH ２ ) ｎ１ S (O) ｖ１ X １ , —O—(CH ２ ) ｎ１ CO ２ X １ , and —O—(CH ２ ) ｎ１ P.O. ｖ１ X １ is selected from Each R １Ｂ and R １Ｃ are independently hydrogen, halogen, —OH, C １ -C ６ Alkyl, 2- to 6-membered heteroalkyl, C ３ -C ６ Cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, —O—(CH ２ ) ｎ１ S (O) ｖ１ X １ , —O—(CH ２ ) ｎ１ CO ２ X １ , and —O—(CH ２ ) ｎ１ P.O. ｖ１ X １ Selected from, or Additionally or alternatively, two R １Ａ , R １Ｂ , R １Ｃ and R １Ｄ are bonded together with the atoms to which they are attached to form a fused C ６ ~C １２ aryl, 5- to 12-membered heteroaryl, or 5- to 7-membered heterocyclic ring, which are independently selected from halogen, —OH, —NH ２ , substituted or unsubstituted C １ -C ６ optionally substituted with 1 to 3 substituents selected from alkyl, or substituted or unsubstituted 2- to 6-membered heteroalkyl; Each R ３Ａ and R ３Ｂ are independently hydrogen, halogen, —OH, C １ -C ６ selected from alkyl, phenyl, substituted phenyl, and 2- to 6-membered heteroalkyl; Each R ４Ａ and R ４Ｂ are independently hydrogen, halogen, —OH, C １ -C ６ selected from 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; Each X １ are independently H, —OH, C １ -C ６ selected from alkyl, alkali metal cations, and quaternary ammonium cations; The method comprises: (i) Formula II' 【Chemistry 12】 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, and the reaction is maintained at a temperature above 55° C. to produce a compound of formula IV: 【Chemistry 13】 providing a compound having the formula: (ii) optionally isolating said compound of formula IV; and (iii) converting said compound of formula IV to said compound of formula I.

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

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

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

37. 34. The method of claim 33, wherein the paraformaldehyde is added by continuous or dropwise addition over a period of at least about 45 minutes, or at least about 1 hour, at least about 1.5 periods, 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. 38. The method of any one of claims 33 to 37, wherein the reaction is maintained at a temperature above 65°C.

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

40. 40. The method of any one of claims 33-39, 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. Each R １Ａ and R １Ｄ are independently —O—(CH ２ ) ｎ１ S (O) ｖ１ X １ , —O—(CH ２ ) ｎ１ CO ２ X １ , and —O—(CH ２ ) ｎ１ P.O. ｖ１ X １ is selected from R １Ｂ and R １Ｃ is hydrogen, and X １ The method of any one of claims 33 to 40, wherein is H or an alkali metal cation.

42. Each R ３Ａ and R ３Ｂ However, independently C １ -C ３ is alkyl, and R ４Ａ and R ４Ｂ The method of any one of claims 33 to 41, wherein is hydrogen.

43. Formula V: 【Chemistry 14】 wherein each R ３Ａ and R ３Ｂ , R ４Ａ , and R ４Ｂ are independently hydrogen, halogen, —OH, C １ -C ６ alkyl, 2- to 6-membered heteroalkyl; The method comprises: (i) Formula IV 【Chemistry 15】 and a compound having formula III 【Chemistry 16】 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 acidic solvents; (ii) isolating said compound of formula V.

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

45. The acid may be trifluoroacetic acid, phosphoric acid, sulfuric acid, HCl, HBr, HClO ４ , HNO ３ 45. The method of claim 43 or 44, wherein the carboxylic acid is selected from the group consisting of: , trifluoromethanesulfonic acid, or a combination thereof.

46. The solvent may be trifluoroacetic acid, phosphoric acid, sulfuric acid, HCl, HBr, HClO ４ , HNO ３ 46. ​​The method of any one of claims 43 to 45, comprising an acid selected from the group consisting of trifluoromethanesulfonic acid, methanesulfonic acid, toluenesulfonic acid, Eaton's reagent, and combinations thereof.

47. 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 a combination thereof.

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

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

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

51. Each R ３Ａ and R ３Ｂ However, independently C １ -C ３ is alkyl, R ４Ａ and R ４Ｂ The method of any one of claims 43 to 50, wherein is hydrogen.

52. Formula I 【Chemistry 17】 1. A method for the preparation of a compound having the formula: During the ceremony, Each R １Ａ and R １Ｄ are independently hydrogen, halogen, —OH, C １ -C ６ Alkyl, 2- to 6-membered heteroalkyl, C ３ -C ６ cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -O-(CH ２ ) ｎ１ S (O) ｖ１ X １ , —O—(CH ２ ) ｎ１ CO ２ X １ , and —O—(CH ２ ) ｎ１ P.O. ｖ１ X １ is selected from Each R １Ｂ and R １Ｃ are independently hydrogen, halogen, —OH, C １ -C ６ Alkyl, 2- to 6-membered heteroalkyl, C ３ -C ６ Cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, —O—(CH ２ ) ｎ１ S (O) ｖ１ X １ , —O—(CH ２ ) ｎ１ CO ２ X １ , and —O—(CH ２ ) ｎ１ P.O. ｖ１ X １ Selected from, or Additionally or alternatively, two R １Ａ , R １Ｂ , R １Ｃ and R １Ｄ are bonded together with the atoms to which they are attached to form a fused C ６ ~C １２ aryl, 5- to 12-membered heteroaryl, or 5- to 7-membered heterocyclic ring, which are independently selected from halogen, —OH, —NH ２ , substituted or unsubstituted C １ -C ６ optionally substituted with 1 to 3 substituents selected from alkyl, or substituted or unsubstituted 2- to 6-membered heteroalkyl; Each R ３Ａ and R ３Ｂ are independently hydrogen, halogen, —OH, C １ -C ６ selected from alkyl, phenyl, substituted phenyl, and 2- to 6-membered heteroalkyl; Each R ４Ａ and R ４Ｂ are independently hydrogen, halogen, —OH, C １ -C ６ selected from 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; Each X １ are independently H, —OH, C １ -C ６ selected from alkyl, alkali metal cations, and quaternary ammonium cations; The method comprises: 【Chemistry 18】 and a compound having formula III 【Chemistry 19】 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 acidic solvents. 【Chemistry 20】 preparing an intermediate having the formula: (ii) isolating the compound of formula V; and (iii) converting said compound of formula V to said compound of formula I.

53. Each R １Ａ and R １Ｄ But -O-(CH ２ ) ３ -SO ３ 53. The method of claim 52, wherein the cation is Na.

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

55. The acid may be trifluoroacetic acid, phosphoric acid, sulfuric acid, HCl, HBr, HClO ４ , HNO ３ 45. The method of claim 43 or 44, wherein the hydroxybenzoate is selected from the group consisting of: a hydroxybenzoate, a trifluoroacid, or a combination thereof.

56. The solvent may be trifluoroacetic acid, phosphoric acid, sulfuric acid, HCl, HBr, HClO ４ , HNO ３ 56. The method of any one of claims 52 to 55, comprising an acid selected from the group consisting of trifluoromethanesulfonic acid, methanesulfonic acid, toluenesulfonic acid, Eaton's reagent, and combinations thereof.

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

59. 59. The method of any one of claims 52-58, further comprising adding TFA to the reaction mixture after completion of the reaction, precipitating the compound of formula V, and isolating the compound of formula V comprising filtration.

60. 60. The method of claim 59, wherein the precipitation of the compound of formula V comprises the addition of 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. Each R １Ａ and R １Ｄ are independently —O—(CH ２ ) ｎ１ S (O) ｖ１ X １ , —O—(CH ２ ) ｎ１ CO ２ X １ , and —O—(CH ２ ) ｎ１ P.O. ｖ１ X １ is selected from R １Ｂ and R １Ｃ is hydrogen, and X １ The method of any one of claims 52 to 60, wherein is H or an alkali metal cation.

62. Each R ３Ａ and R ３Ｂ But independently, C １ -C ３ is alkyl, and R ４Ａ and R ４Ｂ The method of any one of claims 52 to 61, wherein is hydrogen.

63. Formula VI-A: 【Chemical formula 21】 1. A process for the preparation of a compound of formula (I), comprising: During the ceremony, X is selected from H and an alkali metal cation; The method comprises: (i) a compound of the formula: 【Chemical 22】 and hydroquinone having the formula 【Chemical 23】 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. 64. The method of claim 63, wherein the base is present in about 2.2 to 2.4 equivalents.

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

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

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

68. 68. The method of any one of claims 63 to 67, wherein the reaction mixture is cooled to below about 10°C before each addition of the sultone.

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

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

71. Formula IA 【Chemistry 24】 1. A process for the preparation of a compound having the formula: X is selected from H and an alkali metal cation; The method comprises: (i) a compound of the formula: 【Chemistry 25】 and hydroquinone having the formula 【Chemical 26】 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 produce VI-A: 【Chemical 27】 providing a compound having the formula: (ii) isolating the compound of formula VI-A, and (iii) combining a compound of formula VI-A with a compound of formula VA: 【Chemical 28】 to provide a compound having formula IA.

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

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

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

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

76. 76. The method of any one of claims 71 to 75, wherein the reaction mixture is cooled to below about 10°C before each addition of the sultone.

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

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

79. Formula I ​ 1. A method for the preparation of a compound having the formula: During the ceremony, Each R １Ａ and R １Ｄ are independently hydrogen, halogen, —OH, C １ -C ６ Alkyl, 2- to 6-membered heteroalkyl, C ３ -C ６ cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -O-(CH ２ ) ｎ１ S (O) ｖ１ X １ , —O—(CH ２ ) ｎ１ CO ２ X １ , and —O—(CH ２ ) ｎ１ P.O. ｖ１ X １ is selected from Each R １Ｂ and R １Ｃ are independently hydrogen, halogen, —OH, C １ -C ６ Alkyl, 2- to 6-membered heteroalkyl, C ３ -C ６ Cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, —O—(CH ２ ) ｎ１ S (O) ｖ１ X １ , —O—(CH ２ ) ｎ１ CO ２ X １ , and —O—(CH ２ ) ｎ１ P.O. ｖ１ X １ Selected from, or Additionally or alternatively, two R １Ａ , R １Ｂ , R １Ｃ and R １Ｄ are bonded together with the atoms to which they are attached to form a fused C ６ ~C １２ aryl, 5- to 12-membered heteroaryl, or 5- to 7-membered heterocyclic ring, which are independently selected from halogen, —OH, —NH ２ , substituted or unsubstituted C １ -C ６ optionally substituted with 1 to 3 substituents selected from alkyl, or substituted or unsubstituted 2- to 6-membered heteroalkyl; Each R ３Ａ and R ３Ｂ are independently hydrogen, halogen, —OH, C １ -C ６ selected from alkyl, phenyl, substituted phenyl, and 2- to 6-membered heteroalkyl; Each R ４Ａ and R ４Ｂ are independently hydrogen, halogen, —OH, C １ -C ６ selected from 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; Each X １ are independently H, —OH, C １ -C ６ selected from alkyl, alkali metal cations, and quaternary ammonium cations; The method comprises: Formula V 【Chemistry 30】 and a compound having formula VI: 【Chemical 31】 contacting a compound having the formula:

80. Each R １Ａ and R １Ｄ are independently —O—(CH ２ ) ｎ１ S (O) ｖ１ X １ , —O—(CH ２ ) ｎ１ CO ２ X １ , and —O—(CH ２ ) ｎ１ P.O. ｖ１ X １ is selected from R １Ｂ and R １Ｃ is hydrogen, and X １ 80. The method of claim 79, wherein is H or an alkali metal cation.

81. Each R ３Ａ and R ３Ｂ But independently, C １ -C ３ is alkyl, and R ４Ａ and R ４Ｂ 81. The method of claim 79 or 80, wherein is hydrogen.

82. Each R ３Ａ and R ３Ｂ is methyl, R ４Ａ and R ４Ｂ is hydrogen, R １Ａ and R １Ｄ But -O-(CH ２ ) ｎ１ S (O) ｖ１ X １ and each n1 is 3; Each v1 is 3, and Each X １ 82. The method of claim 79 or 81, wherein is independently selected from H or an alkali metal cation.

83. The anhydride is R'-C(=O)-OC(=O)-R''; wherein R' and RR'' may be the same or different and are independently selected from alkyl, aryl, heteroalkyl, or may be joined together to form a heterocycle, each of which may be optionally substituted with one or more halo, alkyl, or trihaloalkyl.

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

85. 83. 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. 86. The method of any one of claims 79 to 85, wherein the concentration of the anhydride 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 reaction 87. The method of any one of claims 79 to 86, wherein no more than about 4 equivalents of the compound of formula VI, or no more than about 3 equivalents of the compound of formula VI, is used.

88. The reaction 87. The method of any one of claims 79 to 86, wherein about 2 equivalents to about 5 equivalents of the compound of formula VI, or about 2.5 equivalents to about 4.5 equivalents of the compound of formula VI, or about 2.5 equivalents to about 4 equivalents of the compound of formula VI are used.

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