Process for polyethylene glycol synthesis

Abstract

The present disclosure relates to a method for synthesizing polyethylene glycol (PEG) derivatives.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 705,400, filed October 9, 2024, and U.S. Provisional Application No. 63 / 595,477, filed November 2, 2023, which are incorporated herein by reference in their entirety. Technical Field

[0003] This article discloses a method for preparing polyethylene glycol derivatives. Background Technology

[0004] Polyethylene glycol ('PEG') is a petroleum-derived polyether compound with a wide range of applications from medicine to biology. In medicinal chemistry, PEG is often used as a linker to connect heterobifunctional compounds with two different units. Given that PEG is a symmetrical compound, selective functionalization of the opposite PEG with alcohols remains challenging. Impurities such as bifunctionalized PEG often lead to poor downstream yields due to the multiple synthetic steps involved. Therefore, obtaining pure PEG analogs suitable for process-level and / or large-scale synthesis remains a significant challenge.

[0005] This disclosure relates to a method for synthesizing polyethylene glycol (PEG) derivatives. Summary of the Invention

[0006] This article provides a method for synthesizing (II) polyethylene glycol derivatives, or their salts, solvates, hydrates, or metal ion complexes thereof:

[0007] Equation (II),

[0008] Including intermediate C: (C)

[0009] Mix with intermediate D: (D),

[0010] in:

[0011] n is an integer from 1 to 21;

[0012] m is an integer from 0 to 6; and

[0013] x is n + (m + 3).

[0014] In some embodiments, intermediate C: (C) is derived from intermediate B: (B) Synthesized by oxidation reaction.

[0015] In some embodiments, intermediate D: (D) is from Synthesized via nucleophilic substitution reaction.

[0016] In some embodiments, the method further includes the synthesis of a compound of formula (IV) or a salt thereof:

[0017] Formula (IV),

[0018] Where Z is the counter ion;

[0019] It includes the following steps: making compound (II): (II) Reaction with phthalimide, triphenylphosphine (PPh3), and diisopropyl azodicarbonate (DIAD) to obtain compound (V): (V); and

[0020] The compound of formula (V) was treated with hydrazine to obtain the compound of formula (IV).

[0021] In some embodiments, the method further includes the synthesis of a compound of formula (VI), a salt thereof, or a metal ion complex thereof:

[0022] Formula (VI),

[0023] Where M is one or more metal ions;

[0024] It includes the step of reacting the compound of formula (IV) with a metal salt.

[0025] On the other hand, this article provides a compound having the following structure:

[0026] or its salts, solvates or hydrates, or metal ion complexes thereof, wherein x is 4 to 30, obtained by the methods described herein.

[0027] On the other hand, this article provides a compound having the following structure:

[0028] It, or its salts, solvates or hydrates, or metal ion complexes thereof, obtained by the methods described herein.

[0029] On the other hand, this article provides a compound having the following structure:

[0030] It, or its salts, solvates or hydrates, or metal ion complexes thereof, obtained by the methods described herein.

[0031] On the other hand, this article provides a compound having the following structure:

[0032] It, or its salts, solvates or hydrates, or metal ion complexes thereof, obtained by the methods described herein.

[0033] On the other hand, this article provides a compound having the following structure:

[0034]

[0035] Its solvates or hydrates, or its metal ion complexes, are obtained by the methods described herein.

[0036] On the other hand, this article provides a compound having the following structure:

[0037]

[0038] Its solvates or hydrates, or its metal ion complexes, are obtained by the methods described herein.

[0039] On the other hand, this document provides a composition comprising:

[0040] The composition contains less than about 10% impurities, as demonstrated by HPLC, or its salts, solvates or hydrates, or metal ion complexes thereof, wherein x is 4 to 30.

[0041] On the other hand, this document provides a composition comprising:

[0042] The composition contains less than about 10% impurities, as demonstrated by HPLC, or its salts, solvates or hydrates, or metal ion complexes thereof.

[0043] On the other hand, this article provides a compound having the following structure:

[0044]

[0045] Its solvates or hydrates, or its metal ion complexes, are obtained by the methods described herein.

[0046] On the other hand, this document provides a composition comprising:

[0047] Or its salts, solvates or hydrates, or metal ion complexes thereof, wherein the composition contains less than about 10% impurities, as demonstrated by HPLC.

[0048] On the other hand, this document provides a composition comprising:

[0049] Or its salts, solvates or hydrates, or metal ion complexes thereof, wherein the composition contains less than about 10% impurities, as demonstrated by HPLC.

[0050] On the other hand, this document provides a composition comprising:

[0051] Or its salts, solvates or hydrates, or metal ion complexes thereof, wherein the composition contains less than about 10% impurities, as demonstrated by HPLC.

[0052] On the other hand, this paper provides a metal ion complex having the following structure:

[0053]

[0054] Where n is 1 to 21 and M is one or more metal ions.

[0055] On the other hand, this paper provides a metal ion complex having the following structure:

[0056]

[0057] Where x is 4 to 30 and M is one or more metal ions.

[0058] On the other hand, this paper provides a metal ion complex having the following structure:

[0059]

[0060] Where x is 4 to 30 and M is one or more metal ions.

[0061] On the other hand, this paper provides a metal ion complex having the following structure:

[0062] ,

[0063] ,

[0064] ,

[0065] ,

[0066] or

[0067] ,

[0068] M can be one or more metal ions.

[0069] On the other hand, this paper provides a metal ion complex having the following structure:

[0070] ,

[0071] ,

[0072] ,

[0073] or

[0074] ,

[0075] M can be one or more metal ions.

[0076] In some embodiments, the metal ion is selected from iron, magnesium, calcium, barium, cobalt, nickel, copper, zinc, aluminum, manganese, and indium. In some embodiments, the metal ion is magnesium, calcium, or manganese. In some embodiments, the metal ion is magnesium. In some embodiments, the metal ion is calcium. In some embodiments, the metal ion is manganese.

[0077] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. However, it should be understood that although the detailed description and specific examples represent particular embodiments, they are given by way of illustration only, as various variations and modifications within the spirit and scope of this disclosure will become apparent to those skilled in the art based on this detailed description. Attached Figure Description

[0078] Various aspects of this disclosure are set forth in the appended claims. A better understanding of the features and advantages of this disclosure will be obtained by referring to the following detailed description of exemplary embodiments in which the principles of this disclosure are utilized in the following drawings.

[0079] Figure 1 The MicroED structure of the calcium-containing PEG-8-NHC metal ion complex is shown. The top figure shows the symmetry unit of the PEG-8-NHC crystal structure. The bottom figure shows a schematic diagram of the molecular structure of PEG-8-NHC.

[0080] Figure 2 The MicroED structure of the CPD-18 calcium metal ion complex is shown. The top figure shows the structural model superimposed on the electrostatic potential diagram. The middle figure shows the structure determined by MicroED. The bottom figure shows a schematic diagram of the molecular structure of the calcium-CPD-18 complex.

[0081] Incorporated by reference

[0082] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent, as specifically and individually indicated that each individual publication, patent, or patent application is incorporated by reference. In the event of any conflict between a publication or patent or patent application incorporated by reference and the disclosure contained herein, this specification is intended to substitute for and / or give precedence to any such conflicting material. Detailed Implementation

[0083] This article provides methods for preparing polyethylene glycol derivatives and compositions comprising said polyethylene glycol derivatives.

[0084] Synthesis of compound (I)

[0085] In one aspect, this article provides a method for synthesizing compounds of formula (I), or salts, solvates or hydrates thereof, or metal ion complexes thereof:

[0086] Formula (I),

[0087] Including intermediate C: (C) and

[0088] Intermediate D1 (D1) Mix

[0089] in:

[0090] R is an aryl group that is optionally substituted or an alkyl group that is optionally substituted;

[0091] n is an integer from 1 to 21;

[0092] m is an integer from 0 to 6; and

[0093] x ranges from 4 to 30.

[0094] In some embodiments, R is an optionally substituted C1-C6 alkyl group, optionally substituted with one, two, three or more substituents selected from alkyl, alkoxy, cyano, halogen and nitro groups. In some embodiments, R is an optionally substituted C1-C4 alkyl group. In some embodiments, R is an optionally substituted C1-C3 alkyl group. In some embodiments, R is methyl or ethyl. In some embodiments, R is ethyl. In some embodiments, R is methyl.

[0095] In some embodiments, R is an optionally substituted aryl group. In some embodiments, the aryl group is a phenyl group, which is optionally substituted with one, two, three or more substituents selected from alkyl, alkoxy, cyano, halogen and nitro groups. In some embodiments, R is a nitro-substituted phenyl group.

[0096] In some embodiments, the compound of formula (I) has the structure of formula (II), or a salt, solvate, or hydrate thereof, or a metal ion complex thereof. In some embodiments, the compound of formula (I) has the structure of formula (III), or a salt, solvate, or hydrate thereof, or a metal ion complex thereof.

[0097] In one aspect, this article provides a method for synthesizing compounds of formula (II), or their salts, solvates or hydrates, or their metal ion complexes:

[0098] Equation (II),

[0099] Including intermediate C: (C) and

[0100] Intermediate D (D) Mixing,

[0101] in:

[0102] n is an integer from 1 to 21;

[0103] m is an integer from 0 to 6; and

[0104] x is n + (m + 3).

[0105] In one aspect, this article provides a method for synthesizing compounds of formula (III), or their salts, solvates or hydrates, or their metal ion complexes:

[0106] Equation (III),

[0107] Including intermediate C: (C) and

[0108] Intermediate E (E) Mixing,

[0109] in:

[0110] n is an integer from 1 to 21;

[0111] m is an integer from 0 to 6; and

[0112] x is n + (m + 3). In some embodiments, the method includes (i) a first step and (ii) a second step.

[0113] In some embodiments, step (i) further includes purification of the metal ion complex. In some embodiments, step (ii) further includes purification of the metal ion complex.

[0114] First step (i)

[0115] In some embodiments, the first step includes mixing intermediate C and intermediate D1, intermediate D, or intermediate E in a first solvent in the presence of a base. In some embodiments, the first step includes mixing intermediate C and intermediate D1 in a first solvent in the presence of a base. In some embodiments, the first step includes mixing intermediate C and intermediate D in a first solvent in the presence of a base. In some embodiments, the first step includes mixing intermediate C and intermediate E in a first solvent in the presence of a base.

[0116] In some embodiments, the alkali is added to the first solvent in batches.

[0117] In some embodiments, the alkali includes a metal salt.

[0118] In some embodiments, the base is selected from sodium tert-butoxide (NaOtBu), potassium tert-butoxide (KOtBu), lithium tert-butoxide (LiOtBu), sodium hydride (NaH), potassium hydride (KH), methyllithium (MeLi), butyllithium (BuLi), hexyllithium (HxLi), lithium diisopropylamine (LDA), sodium bis(trimethylsilyl)amino (NaHMDS), potassium bis(trimethylsilyl)amino (KHMDS), lithium bis(trimethylsilyl)amino (LiHMDS), and lithium tetramethylpiperidine (LiTMP), or combinations thereof. In some embodiments, the base is selected from sodium tert-butoxide (NaOtBu), potassium tert-butoxide (KOtBu), and lithium tert-butoxide (LiOtBu). In some embodiments, the base is solid sodium tert-butoxide (NaOtBu). In some embodiments, the base is potassium tert-butoxide (KOtBu). In some embodiments, the base is lithium tert-butoxide (LiOtBu).

[0119] In some embodiments, the first solvent is selected from toluene, ethyl acetate, dichloromethane, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, isopropyl acetate, dimethylacetamide, and NMP, or combinations thereof. In some embodiments, the first solvent is selected from tetrahydrofuran and methyltetrahydrofuran, or combinations thereof.

[0120] In some embodiments, 0.8 to 3.0 equivalents of base are present in the first solvent. In some embodiments, 1.0 to 2.5 equivalents of base are present in the first solvent. In some embodiments, 1.0 to 2.0 equivalents of base are present in the first solvent. In some embodiments, 1.0 to 1.5 equivalents of base are present in the first solvent.

[0121] In some embodiments, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 equivalents of base are present in the first solvent. In some embodiments, 1.0 equivalent of base is present in the first solvent. In some embodiments, 1.1 equivalent of base is present in the first solvent. In some embodiments, 1.2 equivalent of base is present in the first solvent. In some embodiments, 1.3 equivalent of base is present in the first solvent. In some embodiments, 1.4 equivalent of base is present in the first solvent. In some embodiments, 1.5 equivalent of base is present in the first solvent.

[0122] In some embodiments, the first solvent is adjusted to a temperature of approximately -10°C to approximately 40°C before the addition of the alkali. In some embodiments, the first solvent is adjusted to a temperature of approximately -10°C to approximately 30°C before the addition of the alkali. In some embodiments, the first solvent is adjusted to a temperature of approximately -10°C to approximately 20°C before the addition of the alkali. In some embodiments, the first solvent is adjusted to a temperature of approximately -10°C to approximately 15°C before the addition of the alkali. In some embodiments, the first solvent is adjusted to a temperature of approximately -10°C to approximately 10°C before the addition of the alkali. In some embodiments, the first solvent is adjusted to a temperature of approximately -5°C to approximately 5°C before the addition of the alkali.

[0123] Step 2 (ii)

[0124] In some embodiments, the second step includes mixing the product from step (i) in a second solvent in the presence of an acid. In some embodiments, the product from step (i) is a compound of formula (I), a salt thereof, a solvate or hydrate thereof, or a metal ion complex thereof. In some embodiments, the product from step (i) is a compound of formula (II), a salt thereof, a solvate or hydrate thereof, or a metal ion complex thereof. In some embodiments, the product from step (i) is a compound of formula (III), a salt thereof, a solvate or hydrate thereof, or a metal ion complex thereof.

[0125] In some embodiments, the acid is added to the second solvent.

[0126] In some embodiments, the acid is selected from sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, acetic acid, and formic acid. In some embodiments, the acid is sulfuric acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the acid is phosphoric acid. In some embodiments, the acid is nitric acid. In some embodiments, the acid is acetic acid. In some embodiments, the acid is formic acid.

[0127] In some embodiments, the second solvent is selected from toluene, ethyl acetate, dichloromethane, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, dimethylacetamide, and NMP, or combinations thereof. In some embodiments, the second solvent is selected from tetrahydrofuran and methyltetrahydrofuran, or combinations thereof. In some embodiments, the second solvent is tetrahydrofuran. In some embodiments, the second solvent is methyltetrahydrofuran.

[0128] In some embodiments, the second solvent is adjusted to a temperature of about 50°C to about 90°C after the acid is added. In some embodiments, the second solvent is adjusted to a temperature of about 60°C to about 85°C after the acid is added. In some embodiments, the second solvent is adjusted to a temperature of about 70°C to about 80°C after the acid is added.

[0129] In some embodiments, the second solvent further comprises water as a co-solvent.

[0130] In some embodiments, steps (i) and (ii) are repeated. In some embodiments, these steps are repeated until the desired compound linker length is obtained. In some embodiments, steps (i) and (ii) are repeated 1 to 20 times. In some embodiments, steps (i) and (ii) are repeated 1 to 18 times. In some embodiments, steps (i) and (ii) are repeated 1 to 15 times. In some embodiments, steps (i) and (ii) are repeated 1 to 12 times. In some embodiments, steps (i) and (ii) are repeated 1 to 10 times. In some embodiments, steps (i) and (ii) are repeated 1 to 8 times. In some embodiments, steps (i) and (ii) are repeated 1 to 6 times. In some embodiments, steps (i) and (ii) are repeated 1 to 5 times. In some embodiments, steps (i) and (ii) are repeated 10 times. In some embodiments, steps (i) and (ii) are repeated 9 times. In some embodiments, steps (i) and (ii) are repeated 8 times. In some embodiments, steps (i) and (ii) are repeated 7 times. In some embodiments, steps (i) and (ii) are repeated 6 times. In some embodiments, steps (i) and (ii) are repeated 5 times. In some embodiments, steps (i) and (ii) are repeated 4 times. In some embodiments, steps (i) and (ii) are repeated 3 times. In some embodiments, steps (i) and (ii) are repeated 2 times. In some embodiments, steps (i) and (ii) are repeated once.

[0131] In some embodiments, the method is carried out in a single reactor.

[0132] In some embodiments, the method further includes purifying a compound of formula (I), (II), or (III), wherein the purification includes forming a complex with a metal ion and then filtering.

[0133] In some embodiments, the metal ion is calcium, magnesium, or manganese. In some embodiments, the metal ion is magnesium or manganese. In some embodiments, the metal ion is calcium. In some embodiments, the metal ion is magnesium. In some embodiments, the metal ion is manganese.

[0134] In some embodiments, the yield of compound (I), (II), or (III) is at least 20%. In some embodiments, the yield of compound (I), (II), or (III) is at least 30%. In some embodiments, the yield of compound (I), (II), or (III) is at least 40%. In some embodiments, the yield of compound (I), (II), or (III) is at least 45%. In some embodiments, the yield of compound (I), (II), or (III) is at least 50%. In some embodiments, the yield of compound (I), (II), or (III) is at least 55%. In some embodiments, the yield of compound (I), (II), or (III) is at least 60%. In some embodiments, the yield of compound (I), (II), or (III) is at least 65%. In some embodiments, the yield of compound (I), (II), or (III) is at least 70%. In some embodiments, the yield of compound (I), (II), or (III) is at least 75%. In some embodiments, the yield of compound (I), (II), or (III) is at least 80%. In some embodiments, the yield of compounds of formula (I), (II), or (III) is at least 85%. In some embodiments, the yield of compounds of formula (I), (II), or (III) is at least 90%.

[0135] In some embodiments, the purity of the compound of formula (I), (II), or (III) is at least 95.0%. In some embodiments, the purity of the compound of formula (I), (II), or (III) is at least 96.0%. In some embodiments, the purity of the compound of formula (I), (II), or (III) is at least 97.0%. In some embodiments, the purity of the compound of formula (I), (II), or (III) is at least 98.0%. In some embodiments, the purity of the compound of formula (I), (II), or (III) is at least 99.0%. In some embodiments, the purity of the compound of formula (I), (II), or (III) is at least 99.9%.

[0136] In some embodiments, the content of impurities of formula (I), (II), or (III) is less than about 2%, as determined by HPLC. In some embodiments, the content of impurities of formula (I), (II), or (III) is less than about 1.5%, as determined by HPLC. In some embodiments, the content of impurities of formula (I), (II), or (III) is less than about 1%, as determined by HPLC. In some embodiments, the content of impurities of formula (I), (II), or (III) is less than about 0.8%, as determined by HPLC. In some embodiments, the content of impurities of formula (I), (II), or (III) is less than about 0.5%, as determined by HPLC. In some embodiments, the content of impurities of formula (I), (II), or (III) is less than about 0.2%, as determined by HPLC. In some embodiments, the content of impurities of formula (I), (II), or (III) is less than about 0.1%, as determined by HPLC.

[0137] In some embodiments, the impurities are selected from:

[0138] , and , or a combination thereof.

[0139] In some embodiments, the impurity is: In some embodiments, the impurity is: In some embodiments, the impurity is: .

[0140] In some embodiments, the method further includes the synthesis of a compound of formula (IV) or a salt thereof:

[0141] Formula (IV),

[0142] Where Z is the counter ion;

[0143] It includes the following steps: making compound (II): (II)

[0144] The compound is reacted with phthalimide, triphenylphosphine (PPh3), and diisopropyl azodicarbonate (DIAD) to obtain compound (V): (V); and

[0145] The compound of formula (V) was treated with hydrazine to obtain the compound of formula (IV).

[0146] In some embodiments, Z is selected from Cl-, Br-, and SO4. -2 CO3 -2 Or PO4 -3The counter ion. In some embodiments, Z is Cl-. In some embodiments, Z is Br-. In some embodiments, Z is SO4. -2 .

[0147] In some embodiments, the purity of compound (IV) is at least 80.0%. In some embodiments, the purity of compound (IV) is at least 85.0%. In some embodiments, the purity of compound (IV) is at least 90.0%. In some embodiments, the purity of formula (IV) is at least 95.0%. In some embodiments, the purity of formula (IV) is at least 96.0%. In some embodiments, the purity of formula (IV) is at least 97.0%. In some embodiments, the purity of formula (IV) is at least 98.0%. In some embodiments, the purity of formula (IV) is at least 99.0%.

[0148] In some embodiments, the method further includes the synthesis of a compound of formula (VI), a salt thereof, or a metal ion complex thereof:

[0149] Formula (VI),

[0150] Where M is one or more metal ions;

[0151] It includes the step of reacting the compound of formula (IV) with a metal salt.

[0152] In some embodiments, the method of synthesizing the compound of formula (VI) includes a solvent selected from toluene, ethyl acetate, dichloromethane, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, isopropyl acetate, dimethylacetamide, toluene, and NMP, or combinations thereof. In some embodiments, the solvent is dichloromethane, tetrahydrofuran, methyltetrahydrofuran, or toluene, or combinations thereof. In some embodiments, the solvent is dichloromethane or toluene, or combinations thereof.

[0153] In some embodiments, the formation of compound (VI) is a purification step. In some embodiments, the purity of compound (VI) is greater than that of compound (VI).

[0154] In some embodiments, the purity of compound (VI) is at least 90.0%. In some embodiments, the purity of compound (VI) is at least 95.0%. In some embodiments, the purity of compound (VI) is at least 96.0%. In some embodiments, the purity of compound (VI) is at least 97.0%. In some embodiments, the purity of compound (VI) is at least 98.0%. In some embodiments, the purity of compound (VI) is at least 99.0%.

[0155] In some embodiments, the content of impurity (VI) is less than about 2%, as determined by HPLC. In some embodiments, the content of impurity (VI) is less than about 1.5%, as determined by HPLC. In some embodiments, the content of impurity (VI) is less than about 1%, as determined by HPLC. In some embodiments, the content of impurity (VI) is less than about 0.8%, as determined by HPLC. In some embodiments, the content of impurity (VI) is less than about 0.5%, as determined by HPLC. In some embodiments, the content of impurity (VI) is less than about 0.2%, as determined by HPLC. In some embodiments, the content of impurity (VI) is less than about 0.1%, as determined by HPLC.

[0156] In some embodiments, the metal ions form a metal complex. In some embodiments, the metal ions are selected from iron, magnesium, calcium, barium, cobalt, nickel, copper, zinc, aluminum, manganese, and indium. In some embodiments, the metal ion is magnesium, calcium, or manganese. In some embodiments, the metal ion is magnesium. In some embodiments, the metal ion is manganese. In some embodiments, the metal ion is calcium.

[0157] Synthesis of intermediate C

[0158] In some embodiments, intermediate C, or its salt, solvate, hydrate, or metal ion complex:

[0159] (C) is synthesized from intermediate B through an oxidation reaction:

[0160] (B)

[0161] In some embodiments, the oxidation reaction includes mixing intermediate B in a solvent in the presence of an oxidant.

[0162] In some embodiments, the oxidant is selected from potassium persulfate (oxone), hydrogen peroxide (H2O2), m-chloroperoxybenzoic acid (mCPBA), titanium dioxide and tert-butyl hydroperoxide (TiO2 / TBHP), osmium tetroxide, sodium periodate, ruthenium tetroxide, ruthenium(III) chloride (RuCl3), hydrate, sodium hypochlorite (NaOCl), and sodium periodate (NaIO4), or combinations thereof. In some embodiments, the oxidant is RuCl3 hydrate, or RuCl3 hydrate and NaIO4. In some embodiments, the oxidant is RuCl3 hydrate. In some embodiments, the oxidant is RuCl3 hydrate and NaIO4. In some embodiments, the oxidant is NaIO4.

[0163] In some embodiments, the oxidizing solvent is selected from dichloromethane, dichloroethane, acetonitrile, water, tetrahydrofuran, methyltetrahydrofuran, dimethyl sulfoxide, dimethylformamide, acetone, nitrobenzene, and dichlorobenzene, or combinations thereof. In some embodiments, the oxidizing solvent is selected from dichloromethane, acetonitrile, and water, or combinations thereof. In some embodiments, the oxidizing solvent is dichloromethane. In some embodiments, the oxidizing solvent is acetonitrile.

[0164] In some embodiments, intermediate C is purified by precipitation with heptane and filtration.

[0165] In some embodiments, the purity of intermediate C is at least 80.0%. In some embodiments, the purity of intermediate C is at least 85.0%. In some embodiments, the purity of intermediate C is at least 90.0%. In some embodiments, the purity of intermediate C is at least 95.0%. In some embodiments, the purity of intermediate C is at least 96.0%. In some embodiments, the purity of intermediate C is at least 97.0%. In some embodiments, the purity of intermediate C is at least 98.0%. In some embodiments, the purity of intermediate C is at least 99.0%.

[0166] In some embodiments, the content of intermediate C impurity is less than about 5%, as determined by HPLC. In some embodiments, the content of intermediate C impurity is less than about 4%, as determined by HPLC. In some embodiments, the content of intermediate C impurity is less than about 3%, as determined by HPLC. In some embodiments, the content of intermediate C impurity is less than about 2%, as determined by HPLC. In some embodiments, the content of intermediate C impurity is less than about 1%, as determined by HPLC.

[0167] In some embodiments, intermediate C impurity is selected from:

[0168] and , or a combination thereof.

[0169] In some embodiments, intermediate C impurity is In some embodiments, intermediate C impurity is a dimer of intermediate C. In some embodiments, intermediate C impurity is... .

[0170] Synthesis of intermediate B

[0171] In some embodiments, intermediate B, or its salt, solvate, hydrate, or metal ion complex:

[0172] (B) is derived from intermediate diol A: (A) Synthesized by cyclization reaction, wherein y is 3 to 10.

[0173] In some embodiments, the cyclization reaction includes mixing intermediate diol A in a third solvent in the presence of a third base and thionyl chloride.

[0174] In some embodiments, the third base is selected from triethylamine, diisopropylethylamine, pyridine, DMAP, DABCO, and DBU. In some embodiments, the third base is triethylamine. In some embodiments, the third base is diisopropylethylamine. In some embodiments, the third base is pyridine. In some embodiments, the third base is DMAP. In some embodiments, the third base is DABCO. In some embodiments, the third base is DBU.

[0175] In some embodiments, the third solvent is selected from toluene, ethyl acetate, dichloromethane, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, dimethylacetamide, and NMP, or combinations thereof. In some embodiments, the third solvent is selected from dichloromethane, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, dichloroethane, dichlorobenzene, cyclopentyl methyl ether, and methyl tert-butyl ether. In some embodiments, the third solvent is methyltetrahydrofuran. In some embodiments, the third solvent is tetrahydrofuran. In some embodiments, the third solvent is acetonitrile. In some embodiments, the third solvent is dichloromethane.

[0176] Synthesis of intermediate D

[0177] In some embodiments, intermediate D, or its salt, solvate, hydrate, or metal ion complex:

[0178] (D) is from Synthesized via nucleophilic substitution reaction.

[0179] In some embodiments, the nucleophilic substitution reaction includes, in the presence of a fourth base, Mix in a fourth solvent.

[0180] In some embodiments, the fourth solvent is selected from toluene, ethyl acetate, dichloromethane, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, dimethylacetamide, and NMP, or combinations thereof. In some embodiments, the fourth solvent is selected from dimethylformamide, DMA, NMP, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, dioxane, DME, and DMSO. In some embodiments, the fourth solvent is selected from acetonitrile, tetrahydrofuran, and methyltetrahydrofuran, or combinations thereof. In some embodiments, the fourth solvent is tetrahydrofuran. In some embodiments, the fourth solvent is methyltetrahydrofuran. In some embodiments, the fourth solvent is acetonitrile.

[0181] In some embodiments, the fourth base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, DBU, DIPEA, triethylamine, or pyridine. In some embodiments, the fourth base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and cesium carbonate. In some embodiments, the fourth base is sodium carbonate. In some embodiments, the fourth base is potassium carbonate. In some embodiments, the fourth base is sodium bicarbonate. In some embodiments, the fourth base is potassium bicarbonate. In some embodiments, the fourth base is cesium carbonate. In some embodiments, the fourth base is DBU. In some embodiments, the fourth base is DIPEA. In some embodiments, the fourth base is triethylamine. In some embodiments, the fourth base is pyridine.

[0182] In some embodiments, the method further includes purifying intermediate D, wherein the purification includes forming a complex with a metal ion and then filtering.

[0183] In some embodiments, the metal ion is calcium, magnesium, or manganese. In some embodiments, the metal ion is magnesium or manganese. In some embodiments, the metal ion is calcium. In some embodiments, the metal ion is magnesium. In some embodiments, the metal ion is manganese.

[0184] In some embodiments, purification further includes a solvent selected from ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, toluene, ACE, dichloromethane, ethanol, isopropanol, MTBE, and DME. In some embodiments, purification further includes a solvent selected from ethanol and tetrahydrofuran. In some embodiments, purification further includes ethanol. In some embodiments, purification further includes tetrahydrofuran.

[0185] In some embodiments, the purity of intermediate D is greater than 80.0%. In some embodiments, the purity of intermediate D is greater than 85.0%. In some embodiments, the purity of intermediate D is greater than 90.0%. In some embodiments, the purity of intermediate D is greater than 95.0%. In some embodiments, the purity of intermediate D is greater than 96.0%. In some embodiments, the purity of intermediate D is greater than 97.0%. In some embodiments, the purity of intermediate D is greater than 98.0%. In some embodiments, the purity of intermediate D is greater than 99.0%. In some embodiments, the purity of intermediate D is greater than 99.9%.

[0186] In some embodiments, the content of intermediate D impurity is less than about 5%, as determined by HPLC. In some embodiments, the content of intermediate D impurity is less than about 4%, as determined by HPLC. In some embodiments, the content of intermediate D impurity is less than about 3%, as determined by HPLC. In some embodiments, the content of intermediate D impurity is less than about 2%, as determined by HPLC. In some embodiments, the content of intermediate D impurity is less than about 1%, as determined by HPLC. In some embodiments, the content of intermediate D impurity is less than about 0.5%, as determined by HPLC. In some embodiments, the content of intermediate D impurity is less than about 0.1%, as determined by HPLC.

[0187] In some embodiments, intermediate D impurity is selected from:

[0188] , and , or a combination thereof.

[0189] In some embodiments, intermediate D impurity is selected from: In some embodiments, intermediate D impurity is selected from: In some embodiments, intermediate D impurity is selected from: .

[0190] In some embodiments, the polyethylene derivative of formula (II) has the structure of formula (IIa), (IIb) or (IIc), or a salt, solvate or hydrate thereof, or a metal ion complex thereof:

[0191] Formula (IIa), Formula (IIb), or

[0192] Equation (IIc).

[0193] In some embodiments, n is 1 to 21, 1 to 20, 1 to 19, 1 to 18, 1 to 17, 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2, or any integer thereof. In some embodiments, n is 1 to 21. In some embodiments, n is 1 to 20. In some embodiments, n is 1 to 19. In some embodiments, n is 1 to 18. In some embodiments, n is 1 to 17. In some embodiments, n is 1 to 16. In some embodiments, n is 1 to 15. In some embodiments, n is 1 to 14. In some embodiments, n is 1 to 13. In some embodiments, n is 1 to 12. In some embodiments, n is 1 to 11. In some embodiments, n is 1 to 10. In some embodiments, n is 1 to 9. In some embodiments, n is 1 to 8. In some embodiments, n is 1 to 7. In some embodiments, n is 1 to 6. In some embodiments, n is 1 to 5. In some embodiments, n is 1 to 4. In some embodiments, n is 1 to 3. In some embodiments, n is 1 to 2. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21. In some embodiments, n is 21. In some embodiments, n is 20. In some embodiments, n is 19. In some embodiments, n is 18. In some embodiments, n is 17. In some embodiments, n is 16. In some embodiments, n is 15. In some embodiments, n is 14. In some embodiments, n is 13. In some embodiments, n is 12. In some embodiments, n is 11. In some embodiments, n is 10. In some embodiments, n is 9. In some embodiments, n is 8. In some embodiments, n is 7. In some embodiments, n is 6. In some embodiments, n is 5. In some embodiments, n is 4. In some embodiments, n is 3. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1.

[0194] In some embodiments, m is 0 to 6, 0 to 5, 0 to 4, 0 to 3, 0 to 2, or 0 to 1, or any integer thereof. In some embodiments, m is 0 to 6. In some embodiments, m is 0 to 5. In some embodiments, m is 0 to 4. In some embodiments, m is 0 to 3. In some embodiments, m is 0 to 2. In some embodiments, m is 0 to 1. In some embodiments, m is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, m is 6. In some embodiments, m is 5. In some embodiments, m is 4. In some embodiments, m is 3. In some embodiments, m is 2. In some embodiments, m is 1. In some embodiments, m is 0.

[0195] In some embodiments, x is 1 to 30, 1 to 29, 1 to 28, 1 to 27, 1 to 26, 1 to 25, 1 to 24, 1 to 23, 1 to 22, 1 to 21, 1 to 20, 1 to 19, 1 to 18, 1 to 17, 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2, or any integer thereof. In some embodiments, x is 1 to 30. In some embodiments, x is 1 to 29. In some embodiments, x is 1 to 28. In some embodiments, x is 1 to 27. In some embodiments, x is 1 to 26. In some embodiments, x is 1 to 25. In some embodiments, x is 1 to 24. In some embodiments, x is 1 to 23. In some embodiments, x is 1 to 22. In some embodiments, x is 1 to 21. In some embodiments, x is 1 to 20. In some embodiments, x is 1 to 19. In some embodiments, x is 1 to 18. In some embodiments, x is 1 to 17. In some embodiments, x is 1 to 16. In some embodiments, x is 1 to 15. In some embodiments, x is 1 to 14. In some embodiments, x is 1 to 13. In some embodiments, x is 1 to 12. In some embodiments, x is 1 to 11. In some embodiments, x is 1 to 10. In some embodiments, x is 1 to 9. In some embodiments, x is 1 to 8. In some embodiments, x is 1 to 7. In some embodiments, x is 1 to 6. In some embodiments, x is 1 to 5. In some embodiments, x is 1 to 4. In some embodiments, x is 1 to 3. In some embodiments, x is 1 to 2. In some embodiments, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In some embodiments, x is 30. In some embodiments, x is 29. In some embodiments, x is 28. In some embodiments, x is 27. In some embodiments, x is 26. In some embodiments, x is 25. In some embodiments, x is 24. In some embodiments, x is 23. In some embodiments, x is 22. In some embodiments, x is 21. In some embodiments, x is 20. In some embodiments, x is 19. In some embodiments, x is 18. In some embodiments, x is 17. In some embodiments, x is 16. In some embodiments, x is 15. In some embodiments, x is 14. In some embodiments, x is 13. In some embodiments, x is 12. In some embodiments, x is 11. In some embodiments, x is 10. In some embodiments, x is 9. In some embodiments, x is 8. In some embodiments, x is 7. In some embodiments, x is 6.In some embodiments, x is 5. In some embodiments, x is 4. In some embodiments, x is 3. In some embodiments, x is 2. In some embodiments, x is 1.

[0196] In some embodiments, n is 1 to 6; and m is 1 to 4. In some embodiments, n is 4; and m is 0.

[0197] In some embodiments, n is 4; m is 0; and x is 7. In some embodiments, n is 5; m is 1; and x is 9. In some embodiments, n is 9; m is 1; and x is 13. In some embodiments, n is 9; m is 0; and x is 12. In some embodiments, n is 13; m is 1; and x is 17.

[0198] In some embodiments, y is 3 to 10. In some embodiments, y is 3 to 9. In some embodiments, y is 3 to 8. In some embodiments, y is 3 to 7. In some embodiments, y is 10. In some embodiments, y is 9. In some embodiments, y is 8. In some embodiments, y is 7. In some embodiments, y is 6. In some embodiments, y is 5. In some embodiments, y is 4. In some embodiments, y is 3.

[0199] On the other hand, this paper provides a method for synthesis:

[0200] ,

[0201] A method comprising mixing compounds having the following structures: (or salts, solvates, hydrates, or metal ion complexes thereof)

[0202] With compounds having the following structures:

[0203] .

[0204] In some embodiments, the method includes a first step and a second step, wherein the first step includes sodium tert-butoxide and the second step includes sulfuric acid.

[0205] In some embodiments, The substance, or its salt, solvate, or hydrate, or its metal ion complex, is synthesized by a two-step method comprising:

[0206] Step (i): Cyclization in the presence of thionyl chloride to form ;as well as

[0207] Step (ii): Oxidation in the presence of RuCl3 hydrate to form .

[0208] In some embodiments, compounds

[0209] The substance, or its salt, solvate, or hydrate, or its metal ion complex, is synthesized by a one-step method comprising:

[0210] Step (i): Mixing in the presence of K2CO3 and to form .

[0211] In some embodiments, compounds

[0212] It is purified by a purification method that involves forming a metal ion complex with manganese ions, followed by filtration.

[0213] On the other hand, this article provides a compound having the structure of formula (II), or a salt, solvate, or hydrate thereof, or a metal ion complex thereof:

[0214] Where x ranges from 4 to 30.

[0215] It is obtained through the method described in this article.

[0216] On the other hand, this article provides a compound having the structure of formula (VI), or a salt thereof, or a metal ion complex thereof:

[0217] Where x is 4 to 30 and M is one or more metal ions,

[0218] It is obtained through the method described in this article.

[0219] In some embodiments, x is 5, 9, 12, 13, 17, 21, 25, or 30.

[0220] On the other hand, this article provides a compound having the following structure:

[0221]

[0222] It is obtained through the method described in this article.

[0223] On the other hand, this article provides a compound having the following structure:

[0224]

[0225] It is obtained through the method described in this article.

[0226] On the other hand, this article provides a compound having the following structure:

[0227]

[0228] It is obtained through the method described in this article.

[0229] On the other hand, this article provides a compound having the following structure:

[0230]

[0231] It is obtained through the method described in this article.

[0232] On the other hand, this article provides a compound having the following structure:

[0233]

[0234] It is obtained through the method described in this article.

[0235] On the other hand, this article provides a compound having the following structure:

[0236]

[0237] It is obtained through the method described in this article.

[0238] Composition and metal ion complex

[0239] On the other hand, this document provides a composition comprising:

[0240] Where x ranges from 4 to 30.

[0241] Or its salts, solvates or hydrates, or metal ion complexes thereof, wherein the composition contains less than about 10% impurities, as determined by HPLC.

[0242] In some embodiments, x is 5, 9, 12, 13, 17, 21, 25, or 30.

[0243] On the other hand, this document provides a composition comprising:

[0244] ,

[0245] Or its salts, solvates or hydrates, or metal ion complexes thereof, wherein the composition contains less than about 10% impurities, as determined by HPLC.

[0246] On the other hand, this document provides a composition comprising:

[0247] The composition contains less than about 10% impurities, as demonstrated by HPLC.

[0248] On the other hand, this document provides a composition comprising:

[0249] Or its salts, solvates or hydrates, or metal ion complexes thereof, wherein the composition contains less than about 10% impurities, as demonstrated by HPLC.

[0250] On the other hand, this document provides a composition comprising:

[0251] Or its salts, solvates or hydrates, or metal ion complexes thereof, wherein the composition contains less than about 10% impurities, as demonstrated by HPLC.

[0252] On the other hand, this document provides a composition comprising:

[0253] The composition contains less than about 10% impurities, as demonstrated by HPLC.

[0254] On the other hand, this document provides a composition comprising:

[0255] ,

[0256] Or its salts, solvates or hydrates, or metal ion complexes thereof, wherein the composition contains less than about 10% impurities, as demonstrated by HPLC.

[0257] In some embodiments, the composition contains less than about 9% impurities. In some embodiments, the composition contains less than about 8% impurities. In some embodiments, the composition contains less than about 7% impurities. In some embodiments, the composition contains less than about 6% impurities. In some embodiments, the composition contains less than about 5% impurities. In some embodiments, the composition contains less than about 4% impurities. In some embodiments, the composition contains less than about 3% impurities. In some embodiments, the composition contains less than about 2% impurities. In some embodiments, the composition contains less than about 1% impurities. In some embodiments, the composition contains less than about 0.5% impurities.

[0258] In some embodiments, the impurities are selected from:

[0259] , , and , or a combination thereof.

[0260] In some embodiments, the impurity is: In some embodiments, the impurity is: In some embodiments, the impurity is: In some embodiments, the impurity is: In some embodiments, the impurity is: .

[0261] On the other hand, this paper provides a metal ion complex having the following structure:

[0262]

[0263] in:

[0264] M is one or more metal ions; and

[0265] n is between 1 and 21.

[0266] On the other hand, this paper provides a metal ion complex having the following structure:

[0267]

[0268] in:

[0269] M is one or more metal ions; and

[0270] x ranges from 4 to 30.

[0271] On the other hand, this paper provides a metal ion complex having the following structure:

[0272]

[0273] in:

[0274] M is one or more metal ions; and

[0275] x ranges from 4 to 30.

[0276] On the other hand, this paper provides a metal ion complex having the following structure:

[0277]

[0278] M can be one or more metal ions.

[0279] On the other hand, this paper provides a metal ion complex having the following structure:

[0280]

[0281] M can be one or more metal ions.

[0282] On the other hand, this paper provides a metal ion complex having the following structure:

[0283]

[0284] M can be one or more metal ions.

[0285] On the other hand, this paper provides a metal ion complex having the following structure:

[0286]

[0287] M can be one or more metal ions.

[0288] On the other hand, this paper provides a metal ion complex having the following structure:

[0289]

[0290] M can be one or more metal ions.

[0291] On the other hand, this paper provides a metal ion complex having the following structure:

[0292] ,

[0293] M can be one or more metal ions.

[0294] On the other hand, this paper provides a metal ion complex having the following structure:

[0295] ,

[0296] M can be one or more metal ions.

[0297] On the other hand, this paper provides a metal ion complex having the following structure:

[0298] ,

[0299] M can be one or more metal ions.

[0300] On the other hand, this paper provides a metal ion complex having the following structure:

[0301] ,

[0302] M can be one or more metal ions.

[0303] On the other hand, this paper provides a metal ion complex having the following structure:

[0304] ,

[0305] M can be one or more metal ions.

[0306] On the other hand, this paper provides a metal ion complex having the following structure:

[0307] ,

[0308] M can be one or more metal ions.

[0309] In some embodiments, the metal ions form a metal complex. In some embodiments, the metal ions are selected from iron, magnesium, calcium, barium, cobalt, nickel, copper, zinc, aluminum, manganese, and indium. In some embodiments, the metal ion is magnesium, calcium, or manganese. In some embodiments, the metal ion is magnesium. In some embodiments, the metal ion is calcium. In some embodiments, the metal ion is manganese.

[0310] In some embodiments, the purity of the metal ion complex is greater than 98.0%, greater than 99.0%, or greater than 99.9%. In some embodiments, the purity of the metal ion complex is greater than 98.0%. In some embodiments, the purity of the metal ion complex is greater than 99.0%. In some embodiments, the purity of the metal ion complex is greater than 99.9%.

[0311] In some embodiments, n is 1 to 21, 1 to 20, 1 to 19, 1 to 18, 1 to 17, 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2, or any integer thereof. In some embodiments, n is 1 to 21. In some embodiments, n is 1 to 20. In some embodiments, n is 1 to 19. In some embodiments, n is 1 to 18. In some embodiments, n is 1 to 17. In some embodiments, n is 1 to 16. In some embodiments, n is 1 to 15. In some embodiments, n is 1 to 14. In some embodiments, n is 1 to 13. In some embodiments, n is 1 to 12. In some embodiments, n is 1 to 11. In some embodiments, n is 1 to 10. In some embodiments, n is 1 to 9. In some embodiments, n is 1 to 8. In some embodiments, n is 1 to 7. In some embodiments, n is 1 to 6. In some embodiments, n is 1 to 5. In some embodiments, n is 1 to 4. In some embodiments, n is 1 to 3. In some embodiments, n is 1 to 2. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21. In some embodiments, n is 21. In some embodiments, n is 20. In some embodiments, n is 19. In some embodiments, n is 18. In some embodiments, n is 17. In some embodiments, n is 16. In some embodiments, n is 15. In some embodiments, n is 14. In some embodiments, n is 13. In some embodiments, n is 12. In some embodiments, n is 11. In some embodiments, n is 10. In some embodiments, n is 9. In some embodiments, n is 8. In some embodiments, n is 7. In some embodiments, n is 6. In some embodiments, n is 5. In some embodiments, n is 4. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1.

[0312] In some embodiments, x is 1 to 30, 1 to 29, 1 to 28, 1 to 27, 1 to 26, 1 to 25, 1 to 24, 1 to 23, 1 to 22, 1 to 21, 1 to 20, 1 to 19, 1 to 18, 1 to 17, 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2, or any integer thereof. In some embodiments, x is 1 to 30. In some embodiments, x is 1 to 29. In some embodiments, x is 1 to 28. In some embodiments, x is 1 to 27. In some embodiments, x is 1 to 26. In some embodiments, x is 1 to 25. In some embodiments, x is 1 to 24. In some embodiments, x is 1 to 23. In some embodiments, x is 1 to 22. In some embodiments, x is 1 to 21. In some embodiments, x is 1 to 20. In some embodiments, x is 1 to 19. In some embodiments, x is 1 to 18. In some embodiments, x is 1 to 17. In some embodiments, x is 1 to 16. In some embodiments, x is 1 to 15. In some embodiments, x is 1 to 14. In some embodiments, x is 1 to 13. In some embodiments, x is 1 to 12. In some embodiments, x is 1 to 11. In some embodiments, x is 1 to 10. In some embodiments, x is 1 to 9. In some embodiments, x is 1 to 8. In some embodiments, x is 1 to 7. In some embodiments, x is 1 to 6. In some embodiments, x is 1 to 5. In some embodiments, x is 1 to 4. In some embodiments, x is 1 to 3. In some embodiments, x is 1 to 2. In some embodiments, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In some embodiments, x is 30. In some embodiments, x is 29. In some embodiments, x is 28. In some embodiments, x is 27. In some embodiments, x is 26. In some embodiments, x is 25. In some embodiments, x is 24. In some embodiments, x is 23. In some embodiments, x is 22. In some embodiments, x is 21. In some embodiments, x is 20. In some embodiments, x is 19. In some embodiments, x is 18. In some embodiments, x is 17. In some embodiments, x is 16. In some embodiments, x is 15. In some embodiments, x is 14. In some embodiments, x is 13. In some embodiments, x is 12. In some embodiments, x is 11. In some embodiments, x is 10. In some embodiments, x is 9. In some embodiments, x is 8. In some embodiments, x is 7. In some embodiments, x is 6.In some embodiments, x is 5. In some embodiments, x is 4. In some embodiments, x is 3. In some embodiments, x is 2. In some embodiments, x is 1.

[0313] The number of metal ion atoms (M) is related to the number of oxygen atoms in the compound that can coordinate with the metal ion to form a metal ion complex. In some embodiments, the metal ion complex comprises one or more metal ions. In some embodiments, the metal ion complex comprises 1, 2, 3, 4, or 5 metal ions. In some embodiments, the metal ion complex comprises 1 or 2 metal ions. In some embodiments, the metal ion complex comprises 1 metal ion. In some embodiments, the metal ion complex comprises 2 metal ions. In some embodiments, the metal ion complex comprises 3 metal ions.

[0314] Further forms of the compound

[0315] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, engegen (E) and zusammen (Z) isomers, and suitable mixtures thereof. In some cases, the compounds described herein have one or more chiral centers, and each center exists in an R or S configuration. The compounds presented herein include all diastereomers, enantiomers, and epiomers, and corresponding mixtures thereof. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers obtained by a single preparation step, combination, or interconversion can be used in the applications described herein. In some embodiments, the compounds described herein are prepared as separate stereoisomers by reacting a racemic mixture of compounds with an optically active resolving agent to form a pair of diastereomers, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, diastereomers are separated by chiral chromatography.

[0316] In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those listed herein, except that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, such as... 2 H (D), 3 H, 13 C 14 C l5 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes of the compounds described herein containing the aforementioned isotopes and / or other atoms, as well as their pharmaceutical salts, solvates, or stereoisomers, are within the scope of this invention. Certain isotope-labeled compounds, such as those doped with radioactive isotopes such as... 3 H and 14 Compounds of C can be used in drug and / or substrate tissue distribution assays. Tritiumization (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability.

[0317] In some embodiments, the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% on a molar basis. In some embodiments, one or more of the substituents disclosed herein contain a percentage of deuterium higher than the natural abundance of deuterium. In some embodiments, in one or more of the substituents disclosed herein, one or more 1 H is replaced by one or more deuterium atoms.

[0318] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labeling, or chemiluminescent labeling.

[0319] In some embodiments, the compounds described herein are present as their pharmaceutical salts. In some embodiments, the methods disclosed herein include methods of treating a disease by applying such pharmaceutical salts. In some embodiments, the methods disclosed herein include methods of treating a disease by applying such pharmaceutical salts as a pharmaceutical composition.

[0320] In some embodiments, the compounds described herein have acidic or basic groups and thus react with a number of inorganic or organic bases and any of inorganic and organic acids to form pharmaceutical salts. In some embodiments, these salts are prepared in situ during the final separation and purification of the compounds disclosed herein, or their solvates or stereoisomers, or by reacting the purified compounds in their free form alone with a suitable acid or base and separating the resulting salts.

[0321] Examples of medicinal salts include those prepared by reacting the compounds described herein with minerals, organic acids, or inorganic bases. Such salts include acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, bisulfates, bisulfites, bromides, butyrates, 1,4-dibutyric acid, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, digluconate, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucono-heptanoates, glycerophosphates, glycolates, hemisulfates, heptanates, hexyne-1,6-dicitates, hydroxybenzoates, γ-hydroxybutyrates, hydrochlorides, hydrobromides, hydroiodates, 2-hydroxyethanesulfonates, iodides, isobutyrates, lactates, maleates, malonates, methanesulfonates, and mandelates. Metaphosphates, methanesulfonates, methoxybenzoates, methyl benzoate, monohydrogen phosphates, 1-naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, palmitates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, neopentanoates, propionates, pyrosulfates, pyrophosphates, valproate, phthalates, phenylacetates, phenylbutyrates, propanesulfonates, salicylates, succinates, sulfates, sulfites, succinates, octanoates, sebacic acid salts, sulfonates, tartrates, thiocyanates, toluenesulfonates, undecanoates, and xylenesulfonates.

[0322] Furthermore, the compounds described herein can be prepared into pharmaceutically acceptable salts by reacting their free base form with pharmaceutically acceptable inorganic or organic acids, including but not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, and benzoic acid. 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-en-1-carboxylic acid, glucoheponic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid. In some embodiments, other acids (such as oxalic acid), although not pharmaceutically useful themselves, are used to prepare salts that can be used as intermediates to obtain the compounds disclosed herein, their solvates or stereoisomers, and their pharmaceutically useful acid addition salts.

[0323] In some embodiments, those compounds comprising free acid groups described herein react with suitable bases (such as hydroxides, carbonates, bicarbonates, sulfates) of pharmaceutical metal cations, with ammonia, or with pharmaceutical organic primary, secondary, tertiary, or quaternary amines. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium salts, as well as aluminum salts. Exemplary examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2SO4. + (C1-C4 alkyl)4, etc.

[0324] Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It should be understood that the compounds described herein may also include quaternization of any basic nitrogen-containing group they contain. In some embodiments, such quaternization yields water- or oil-soluble or dispersible products.

[0325] In some embodiments, the compounds described herein are present as solvates. In some embodiments, this disclosure provides a method of treating a disease by applying a compound in such solvate form. In some embodiments, this disclosure provides a method of treating a disease by applying a composition comprising a compound in such solvate form. The solvate contains a stoichiometric or non-stoichiometric amount of solvent and, in some embodiments, is formed during a crystallization process using a pharmaceutical solvent.

[0326] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. A tautomer is a compound capable of interconverting through the migration of hydrogen atoms (accompanied by the conversion of single bonds and adjacent double bonds). In the possible bond arrangements of tautomers, a chemical equilibrium of tautomers will exist. All tautomer forms of the compounds disclosed herein are envisioned. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0327] definition

[0328] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0329] Unless the context otherwise requires, throughout the specification and the appended claims, the word “comprise” and its variations, such as “comprises” and “comprising”, should be interpreted in an open, inclusive sense, meaning “including, but not limited to”. Furthermore, the subheadings provided herein are for convenience only and do not define the scope or meaning of the claimed invention.

[0330] It should be noted that, unless the context clearly indicates otherwise, the singular forms “a / an” and “the” as used in this specification and the appended claims include the plural referent. It should also be noted that the term “or” is generally used to mean “and / or” unless the context clearly indicates otherwise.

[0331] When a range of values ​​is published and the notation "from n1... to n2" or "between n1... and n2" is used, where n1 and n2 are numbers, the notation is intended to include both the numbers themselves and the range between them, unless otherwise stated. This range can be integers between the endpoints or consecutive and include the endpoints. For example, a range of "2 to 6 carbons" is intended to include two, three, four, five, and six carbons, since carbon appears in integer units. In contrast, a range of "1 to 3 µM (micromolars)" is intended to include 1 µM, 3 µM, and any significant numbers in between (e.g., 1.255 µM, 2.1 µM, 2.9999 µM, etc.).

[0332] Unless otherwise stated, the following terms as used herein have the following meanings:

[0333] "Oxytochemical" refers to the compound oxygen (O).

[0334] "Carboxyl group" refers to -COOH.

[0335] "Cyano" refers to -CN.

[0336] "Alkyl" refers to a straight-chain or branched saturated hydrocarbon monoradical having one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups (such as heptyl and octyl). Whenever it appears herein, numerical ranges such as “C1-C6 alkyl” or “C1-6 alkyl” mean that the alkyl group can consist of 1, 2, 3, 4, 5, or 6 carbon atoms; however, the definition of this invention also covers the use of the term “alkyl” where no numerical range is specified. In some embodiments, alkyl is C1-C6. 10 Alkyl group. In some embodiments, the alkyl group is C1-C6 alkyl. In some embodiments, the alkyl group is C1-C5 alkyl. In some embodiments, the alkyl group is C1-C4 alkyl. In some embodiments, the alkyl group is C1-C3 alkyl. Unless otherwise expressly stated in the specification, the alkyl group may optionally be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl group may optionally be substituted with oxo, halogen, -CN, -C(O)OH, -C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl group may optionally be substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl group may optionally be substituted with halogen.

[0337] "Alkenyl" refers to a linear or branched hydrocarbon monoradical having one or more carbon-carbon double bonds and having two to ten carbon atoms, more preferably two to six carbon atoms. This group may be cis or trans conformation with respect to one or more double bonds and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever it appears herein, numerical ranges such as "C2-C6 alkenyl" or "C2-6 alkenyl" mean that the alkenyl group may consist of 2, 3, 4, 5, or 6 carbon atoms; however, the definition of this invention also covers the occurrence of the term "alkenyl" where no numerical range is specified. Unless otherwise expressly stated in the specification, the alkenyl group may optionally be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl group may optionally be substituted with oxo, halogen, -CN, -C(O)OH, -C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl group may optionally be substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl group may optionally be substituted with halogen.

[0338] "Alynyl" refers to a single radical of a straight-chain or branched hydrocarbon having one or more carbon-carbon triple bonds and having two to ten carbon atoms, more preferably two to six carbon atoms. Examples include, but are not limited to, acetylenyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Whenever it appears herein, numerical ranges such as "C2-C6 alkynyl" or "C2-C6 alkynyl" mean that the alkynyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but the definition of this invention also covers the occurrence of the term "alkynyl" without a specified numerical range. Unless otherwise expressly stated in the specification, the alkynyl group may optionally be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl group is optionally substituted with an oxo group, a halogen group, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl group is optionally substituted with a halogen group, -CN, -OH, or -OMe. In some embodiments, the alkynyl group is optionally substituted with a halogen group.

[0339] "alkylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise expressly stated in the specification, the alkylene group may optionally be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkylene group is optionally substituted with oxo, halogen, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene group is optionally substituted with halogen.

[0340] "Alkoxy" refers to the formula -OR a free radicals, of which R a It is an alkyl radical as defined herein. Unless otherwise expressly stated in the specification, the alkoxy group may optionally be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy group is optionally substituted with halogen, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy group is optionally substituted with halogen.

[0341] "Aryl" refers to a free radical derived from an aromatic monocyclic or polycyclic aromatic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. An aromatic monocyclic or polycyclic aromatic hydrocarbon ring system may contain only hydrogen and carbon, and from five to eighteen carbon atoms, wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic delocalized (4n+2) π–electron system according to Hückel's theory. Ring systems that derive aryl groups include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetrahydronaphthalene, and naphthalene. Aryl free radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused ring systems (where the aryl group is bonded to the aromatic ring atom when fused with a cycloalkyl or heterocyclic alkyl ring) or bridging ring systems. In some embodiments, the aryl group is a 6-membered to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from anthracene, naphthalene, phenanthrene, anthracene, azurite, benzene, phenanthrene, fluorene, as-dicyclopentanobenzene, s-dicyclopentanobenzene, indane, indene, naphthalene, uranium, phenanthrene, phenanthrene, pyrene, and biphenylene oxide. Unless otherwise expressly stated in the specification, the aryl group may optionally be substituted with, for example, halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxyl groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, etc. In some embodiments, the aryl group is optionally substituted with halogens, methyl groups, ethyl groups, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl group is optionally substituted with halogens, methyl groups, ethyl groups, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl group is optionally replaced by a halogen.

[0342] "Carbocyclic ring" refers to a saturated, unsaturated, or aromatic ring in which every atom of the ring is carbon. Carbocyclic rings can include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridging rings. Each ring of a bicyclic carbocyclic ring can be selected from saturated, unsaturated, and aromatic rings. Aromatic rings, such as phenyl, can be fused with saturated or unsaturated rings (e.g., cyclohexane, cyclopentane, or cyclohexene). Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of a carbocyclic ring when valence permits. Exemplary carbocyclic rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless otherwise expressly stated in the specification, the carbocyclic ring may optionally be substituted.

[0343] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbon ring, which may include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl is bonded by non-aromatic ring atoms), spirocyclic, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having three to fifteen carbon atoms (e.g., C3-C15). 15 Fully saturated cycloalkyl or C3-C 15Cycloalkenyl), three to ten carbon atoms (e.g., C3-C) 10 Fully saturated cycloalkyl or C3-C 10 Cycloalkyl groups are 3- to 10-membered fully saturated cycloalkyl groups or 3- to 6-membered cycloalkenyl groups. In some embodiments, the cycloalkyl group is a 5- to 6-membered fully saturated cycloalkyl group or a 5- to 6-membered cycloalkenyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornel, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, as well as 7,7-dimethyl-bicyclo[2.2.1]heptane. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise expressly stated in the specification, cycloalkyl groups may optionally be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxyl, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, etc. In some embodiments, the cycloalkyl group is optionally substituted with an oxo, halogen, methyl, ethyl, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl group is optionally substituted with an oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted with a halogen.

[0344] "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused or bridging ring systems, preferably having three to twelve carbon atoms and containing at least one double bond. In some embodiments, the cycloalkenyl group contains three to ten carbon atoms. In other embodiments, the cycloalkenyl group contains five to seven carbon atoms. The cycloalkenyl group can be attached to the rest of the molecule via a single bond. Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0345] "Halo" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0346] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl radical as defined above, substituted with one or more halogen radicals, such as trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical may optionally be further substituted. Examples of halogen-substituted alkanes (“haloalkanes”) include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), dihalomethanes and trihalomethanes (e.g., chloroform, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combination of alkanes (or substituted alkanes) with halogens (e.g., Cl, Br, F, I, etc.). When the alkyl group is substituted by more than one halogen radical, each halogen can be chosen independently, for example, 1-chloro,2-fluoroethane.

[0347] "Fluoroalkyl" refers to an alkyl radical as defined above that has been substituted by one or more fluorine radicals, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc.

[0348] "Hydroxyalkyl" refers to an alkyl radical as defined above, which is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0349] "Aminoalkyl" refers to an alkyl radical as defined above, which is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is, for example, aminomethyl.

[0350] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl group are selected from atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof). The heteroalkyl group is attached to the remainder of the molecule at the carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group consists of 1 to 6 carbon atoms and one or more atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof), wherein the heteroalkyl group is attached to the remainder of the molecule at the carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise expressly stated in the specification, heteroalkyl groups are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl groups are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyl groups are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyl groups are optionally substituted with halogens.

[0351] "Heterocyclic alkyl" refers to a 3- to 24-membered partially or fully saturated cyclic radical comprising 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocyclic alkyl is fully saturated. In some embodiments, the heterocyclic alkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocyclic alkyl comprises one to three nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises one or two nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises one nitrogen atom. In some embodiments, the heterocyclic alkyl comprises one nitrogen atom and one oxygen atom. Unless otherwise expressly stated in the specification, the heterocyclic alkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or heteroaryl ring, the heterocyclic alkyl is bonded by non-aromatic ring atoms), spirocyclic, or bridging ring systems; and the nitrogen, carbon, or sulfur atom in the heterocyclic alkyl radical may optionally be oxidized; the nitrogen atom may optionally be quaternized. Representative heterocyclic alkyl groups include, but are not limited to, heterocyclic alkyl groups having two to fifteen carbon atoms (e.g., C2-C). 15 Fully saturated heterocyclic alkyl or C2-C 15 Heterocyclic alkenyl groups, two to ten carbon atoms (e.g., C2-C)10 Fully saturated heterocyclic alkyl or C2-C 10The following are considered as separate categories: fully saturated heterocyclic alkenyl groups, two to eight carbon atoms (e.g., C2-C8 fully saturated heterocyclic alkyl groups or C2-C8 heterocyclic alkenyl groups), two to seven carbon atoms (e.g., C2-C7 fully saturated heterocyclic alkyl groups or C2-C7 heterocyclic alkenyl groups), two to six carbon atoms (e.g., C2-C6 fully saturated heterocyclic alkyl groups or C2-C6 heterocyclic alkenyl groups), two to five carbon atoms (e.g., C2-C5 fully saturated heterocyclic alkyl groups or C2-C5 heterocyclic alkenyl groups), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocyclic alkyl groups or C2-C4 heterocyclic alkenyl groups). Examples of such heterocyclic alkyl radicals include, but are not limited to, aziridinyl, aziridine, oxacyclobutane, dioxopentyl, thienyl[1,3]dithienyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, oxazolyl, piperidinyl, piperazine, 4-piperidinoneyl, pyrrolyl, and pyrazolyl. The terms heterocyclic alkyl include quininecycloalkyl, thiazolylalkyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxacyclopenten-4-yl, and 2-oxo-1,3-dioxacyclopenten-4-yl. The term heterocyclic alkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the ring of a heterocyclic alkyl group has 2 to 10 carbon atoms. It should be understood that when referring to the number of carbon atoms in a heterocyclic alkyl group, the number of carbon atoms in the heterocyclic alkyl group is different from the total number of atoms (including heteroatoms) constituting the heterocyclic alkyl group (i.e., the skeletal atoms of the heterocyclic alkyl ring). In some embodiments, the heterocyclic alkyl group is a fully saturated heterocyclic alkyl group consisting of 3 to 8 members. In some embodiments, the heterocyclic alkyl group is a fully saturated heterocyclic alkyl group consisting of 3 to 7 members. In some embodiments, the heterocyclic alkyl group is a fully saturated heterocyclic alkyl group consisting of 3 to 6 members. In some embodiments, the heterocyclic alkyl group is a fully saturated heterocyclic alkyl group consisting of 4 to 6 members. In some embodiments, the heterocyclic alkyl group is a fully saturated heterocyclic alkyl group consisting of 5 to 6 members. In some embodiments, the heterocyclic alkyl group is a 3 to 8 member. In some embodiments, the heterocyclic alkyl group is a 3 to 7 member. In some embodiments, the heterocyclic alkyl group is a 3 to 6 member. In some embodiments, the heterocyclic alkyl group is a 4 to 6 member. In some embodiments, the heterocyclic alkyl group is a 5 to 6 member. Unless otherwise expressly stated in the specification, the heterocyclic alkyl group may optionally be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, etc., as described below.In some embodiments, the heterocyclic alkyl group is optionally substituted with an oxo group, a halogen, a methyl group, an ethyl group, a -CN group, a -C(O)OH group, a C(O)OMe group, a -CF3 group, a -OH group, a -OMe group, a -NH2 group, or a -NO2 group. In some embodiments, the heterocyclic alkyl group is optionally substituted with a halogen, a methyl group, an ethyl group, a -CN group, a -CF3 group, a -OH group, or a -OMe group. In some embodiments, the heterocyclic alkyl group is optionally substituted with a halogen.

[0352] "Heteroaryl" refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl radical comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl radical comprises one to three nitrogen atoms. In some embodiments, the heteroaryl radical comprises one or two nitrogen atoms. In some embodiments, the heteroaryl radical comprises one nitrogen atom. The heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the heteroaryl radical is bonded through aromatic ring atoms) or bridging ring system; and the nitrogen, carbon, or sulfur atom in the heteroaryl radical may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl radical is a 5- to 10-membered heteroaryl radical. In some embodiments, the heteroaryl radical is a 5- to 6-membered heteroaryl radical. In some embodiments, the heteroaryl radical is a 6-membered heteroaryl radical. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, acrylonitrile, acrylonitrile, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxacycloheptyl, 1,4-benzodioxyl, benzonaphthuryl, benzooxazolyl, benzodioxacyclopentenyl, benzodioxinyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothiopheneyl (benzophenylthio), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenyl, dibenzofuranyl, dibenzophenylthio, furanyl, furanoneyl, isothiazyl Azolyl, imidazolyl, indazole, indolyl, isoindolyl, indololinyl, isoindololinyl, isoquinolinyl, inazinyl, isoxazolyl, naphridinyl, oxadiazolyl, 2-oxoachexenyl, oxazolyl, ethylene oxide, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and phenylthio (i.e., thiophene). Unless otherwise expressly stated in the specification, heteroaryl groups may optionally be substituted with, for example, halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxyl groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, etc. In some embodiments, heteroaryl groups may optionally be substituted with halogens, methyl groups, ethyl groups, -CN groups, -C(O)OH groups, C(O)OMe groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, or -NO2 groups.In some embodiments, the heteroaryl group is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl group is optionally substituted with a halogen.

[0353] The term "joint" or "oligomeric backbone" refers to a chain with at least 10 consecutive atoms. In some embodiments, the joint contains no more than 20 non-hydrogen atoms. The terms "joint" and "oligomeric backbone" are used interchangeably. In some embodiments, the joint contains no more than 40 non-hydrogen atoms. In some embodiments, the joint contains no more than 60 non-hydrogen atoms. In some embodiments, the joint contains atoms selected from C, H, N, O, and S. In some embodiments, each non-hydrogen atom is chemically bonded to two adjacent atoms in the joint, or to one adjacent atom in the joint and the end of the joint. In some embodiments, the joint forms an amide bond with at least one of the two other groups to which it is attached. In some embodiments, the joint forms an ester or ether bond with at least one of the two other groups to which it is attached. In some embodiments, the joint forms a thio bond or a thioether bond with at least one of the two other groups to which it is attached. In some embodiments, the joint forms a direct carbon-carbon bond with at least one of the two other groups to which it is attached. In some embodiments, the joint forms an amine or amide bond with at least one of the two other groups to which it is attached. In some embodiments, the joint comprises a –(CH2OCH2)- unit. In some embodiments, the connector comprises –(CH(CH3)OCH2)- units. In some embodiments, the connector comprises –(CH2NR)- units. N CH2) unit, where R N = C 1-4 Alkyl group. In some embodiments, the connector comprises an arylene, cycloalkyl, or heteroalkylene moiety.

[0354] The term "bond" refers to a covalent bond between two atoms or two parts (when the atoms bonded by a bond are considered part of a larger substructure). Unless otherwise specified, a bond can be a single, double, or triple bond. The dashed line between two atoms in a molecular diagram indicates whether another bond may be present at that location.

[0355] As used herein, “optionally substituted” means that the substituted group is derived from an unsubstituted parent group, wherein one or more hydrogen atoms have been exchanged for another atom or group. Unless otherwise specified, when a group is considered “substituted” or “optionally substituted,” it means that the group is substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocycloyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclo-C1-C6-alkyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), and C3-C7-carbocyclo-C1-C6-alkyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and...). C1-C6 haloalkoxy substituted), 3- to 10-membered heterocyclic groups (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3- to 10-membered heterocyclic -C1-C6-alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally) The group is substituted with halogenated, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy groups; 5- to 10-membered heteroaryl groups (optionally substituted with halogenated, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy groups); 5- to 10-membered heteroaryl (C1-C6)alkyl groups (optionally substituted with halogenated, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy groups); halogenated, cyano, hydroxyl, C1-C6 alkoxy, and C1-C6 alkoxy (C1-C6). Alkyl (i.e., ether), aryloxy, thioalkyl (mercapto), halo(C1-C6)alkyl (e.g., –CF3), halo(C1-C6)alkyl (e.g., –OCF3), C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfinamide, N-sulfinamide, C-carboxyl, O-carboxyl, acyl, cyanate, isocyanate, thiocyanate, isothiocyanate, sulfinyl, sulfonyl, and oxo (=O). When a group is described as “optionally substituted,” the group may be substituted with the substituents described above.

[0356] When optional substituents are involved, the term "one or more" means that the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

[0357] The term "salt" or "pharmaceutical salt" refers to a salt derived from a variety of organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and specifically, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0358] As used herein, the phrase “pharmaceutical” refers to compounds, materials, compositions, and / or dosage forms that are suitable for contact with human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications, and in proportion to a reasonable benefit / risk ratio.

[0359] As used herein, the phrase “medicinal excipient” or “medicinal carrier” refers to a pharmaceutically acceptable material, composition, or medium, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and harmless to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; and (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, and corn oil. (10) Soybean oil; (11) Diols, such as propylene glycol; (12) Polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (13) Esters, such as ethyl oleate and ethyl laurate; (14) Agar; (15) Buffers, such as magnesium hydroxide and aluminum hydroxide; (16) Alginate; (17) Apyrogen-free water; (18) Isotonic saline; (19) Ringer's solution; (20) Ethanol; (21) Phosphate buffer; and (22) Other non-toxic and compatible substances used in pharmaceutical formulations.

[0360] "Effective dose" or "therapeutic effective dose" refers to the amount of a compound administered to a mammalian subject as a single dose or as part of a series of doses that is effective in producing the desired therapeutic effect.

[0361] Example

[0362] The following examples are given to illustrate various embodiments of the invention and are not intended to limit the invention in any way. These examples and the methods described herein represent preferred embodiments and are exemplary, and are not intended to limit the scope of the invention. Variations and other uses covered within the spirit of the invention as defined by the claims will be apparent to those skilled in the art.

[0363] Compound Synthesis

[0364] The synthetic chemical transformations and methods that can be used to synthesize the compounds described herein are known in the art and include, for example, those described in the following literature: R. Larock, Comprehensive Organic Transformations (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2nd edition (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0365] abbreviation

[0366] Ac2O = acetic anhydride; AcCl = acetyl chloride; AcOH = acetic acid; ACE = acetone; AIBN = azobisisobutyronitrile; aq. = aqueous solution; AY = yield determination; Boc = tert-butoxycarbonyl; Boc2O = ditert-butyl dicarbonate; CD3OD = deuterated methanol; CDCl3 = deuterated chloroform; DABCO = (1,4-diazabicyclo[2.2.2]octane); DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM = dichloromethane; DEAD = diethyl azodicarbonate; DIBAL-H = diisobutylaluminum hydride; DIEA = DIPEA = N,N-diisopropylethylamine; DMAc = N,N-dimethylacetamide; DMAB = dimethylamineborane; DMAP = 4-dimethylaminopyridine; DME = dimethoxyethane; DMF = N,N-dimethylformamide; DMSO-d6 = deuterated dimethyl sulfoxide; DMSO = dimethyl sulfoxide; DPPA = diphenylphosphoazide; EA = EtOAc = ethyl acetate; EDC.HCl = EDCI.HCl = 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et2O = diethyl ether; EtOH = ethanol; h = hours; HATU = 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylammonium bromide hexafluorophosphate methylamine; HMDS = hexamethyldisilazane; HOBT = HOBt = 1-hydroxybenzotriazole; IMP = impurity; IPAc = isopropyl acetate; i-PrOH = isopropanol; KHMDS = bis(trimethylsilyl)aminopotassium; KOH = potassium hydroxide; LAH = lithium aluminum hydride; LCAP = liquid chromatography area purity; LiHMDS = bis(trimethylsilyl)aminolithium; LiOtBu = t-BuOLi = lithium tert-butoxide; mCBPA = m-chloroperoxybenzoic acid; MeCN = ACN = acetonitrile; MeOH = Methanol; MeTHF = 2-MeTHF = 2-methyltetrahydrofuran; MsCl = methanesulfonyl chloride; MTBE = methyl tert-butyl ether; Mol Wt = molar weight; n-BuLi = n-butyllithium; NaHMDS = sodium bis(trimethylsilyl)amino; NaIO4 = sodium periodate; NaOMe = sodium methoxide; NaOtBu = t-BuONa = sodium tert-butoxide; NBS = N-bromosuccinimide; NCS = N-chlorosuccinimide; NMI = 1-methyl-1H-imidazolium; NMM = N-methylmorpholine; NMP = N-methyl-2-pyrrolidone; P = product; PE = petroleum ether; PG = protecting group; HPLC = high performance liquid chromatography; PyBop = (benzotriazol-1-yloxy)hexafluorophosphate tripyrrolidinephosphonium; Pyr = pyridine; Q NMR = Quantitative NMR analysis; RT = rt = room temperature; sat. = saturated; ss = saturated solution; SM = starting material; t-BuOH = tert-butanol; TBAB = tetrabutylammonium bromide; TBS = TBDMS = tert-butyldimethylsilyl; TBSCl = TBDMSCl = tert-butyldimethylchlorosilane; TBHP = tert-butylhydrogen peroxide; TCHF = N'-tetramethylammonium hexafluorophosphate; TEA = Et3N = triethylamine; TFA = trifluoroacetic acid; TFAA = trifluoroacetic anhydride; THF = tetrahydrofuran; Tol = toluene; TPPO = tetraphenylphosphine oxide; TsCl = toluenesulfonyl chloride; V = vol = volume.

[0367] Analytical methods

[0368] NMR spectroscopy: 1 H and13 C ( 1 H-decoupled) NMR spectral data were obtained on a Bruker BioSpin GmbH 300 MHz (1H 300 MHz) microscope equipped with either a Z116098-0773 (PA BBO 400S1BBF-HD-05-Z-SP) or a Z825501-0039 (PA BBI 300S1 H-BB-D-05 Z) probe. 13 Acquired at 75 MHz (C). Chemical shifts are reported in parts per million (ppm), and coupling constants (J) are given in Hertz. In CDCl3 and referenced residual CHCl3 (δ 7.26 1H; 77.16 1H). 13 C) In DMSO-d6 and with reference to residual DMSO (δ 2.50) 1 H; 39.52 13 C) Record all data. Multiplicity is represented by singlet (s), doublet (d), doublet of doublet (dd), doublet of doublet (ddd), triplet (t), apparent triplet (app. t), doublet of triplet (dt), quartet (q), doublet of quartet (dq), triplet of quintet (tquin.), and multiplicity (m). Broad peaks are represented by (br).

[0369] QNMR for reaction solutions

[0370] The formula is as follows:

[0371]

[0372] Wt Std = Weight of internal standard (mg)

[0373] N[H] Std = Theoretical [H] value of CH group at a specific position in the internal standard

[0374] M Spl = Molecular weight of the sample

[0375] n[H] Spl = Actual [H] value of CH at a specific location in the sample

[0376] Wt Spl = Sample weight (mg)

[0377] n[H] Std = The actual [H] value of CH at a specific location in the internal standard

[0378] M Std = Molecular weight of internal standard

[0379] N[H] Spl = Theoretical [H] value of CH groups at specific locations in the sample

[0380] P = Purity of the internal standard

[0381] mass spectrometry HRMS data was obtained through two methods.

[0382] Method A A Q-TOF mass spectrometer (Agilent 1290UPLC with 6546 Q-TOF) was used in positive ion mode, with m / z ranging from 100 to 3200, and locked mass number correction was employed according to the manufacturer's instructions.

[0383] System: MPA: H2O containing 0.1% FA; and MPB: MeCN containing 0.1% FA.

[0384] Capillary voltage (kV): 4.0; Gas temperature (°C): 300; Dry gas (L / min): 5; Sheath gas (L / min): 11; Fragmentation voltage (V): 150; Interface type: ESI, positive ion; Analyzer mode: Sensitivity; Scan range: 100 to 3200 m / z.

[0385] Method B An ESI-TOF mass spectrometer (Agilent 1290UPLC with 6230 TOF) was used in positive ion mode, with m / z ranging from 50 to 1600, and locked mass number correction was employed according to the manufacturer's instructions.

[0386] System: MPA: H2O containing 0.04% NH4HO; and MPB: MeCN:MeOH = 1:1

[0387] Capillary voltage (kV): 4.0; Gas temperature (°C): 350; Dry gas (L / min): 5; Sheath gas (L / min): 10; Fragmentation voltage (V): 200; Interface type: ESI, positive ion; Analyzer mode: Sensitivity; Scan range: 50 to 1600 m / z.

[0388] Ion chromatography:Instrument: ICS-6000, Detection: Suppressed conductivity, Anion self-regenerating suppressor: ADRS 600, Acquisition rate: 5.0 Hz, Cell temperature: 35.0℃, Suppressor: External mode, Suppressor current: External mode, Suppressor current: 75mA, Column temperature: 30.0℃, Flow rate: 1.0 mL / min, Run time: 7 min, Injection volume: 25 µL, Column: AS18 4*250 mm, Guard column: AG18 4*50 mm, Eluent: Water containing 30 mM KOH.

[0389] MicroED: Polarizing microscope: Axio Scope 5 POL (Ziess), CryoEM: Talos F200C (200kV, Thermo Fisher Scientific), detector: Ceta-D (CMOS, Thermo Fisher Scientific), data acquisition software: EPU-D (version 1.4.0.125REL, Thermo Fisher Scientific), CryoEM grid: Holey Carbon EM grid (200-mesh copper grid R2 / 2, QUANTIFOIL), low-temperature sample holder: Type 698 (Gatan). Grid loading conditions: low-temperature transfer. Resolution: 0.90 Å. Unit cells (a, b, c, in Å; α, β, γ, in degrees): 13.39(3), 11.48(1), 13.75(2), 90, 97.16(16), 90; and space group: P2. 1 / c (Number 14).

[0390] Synthesis of polyethylene glycol derivatives

[0391] Example 1. Synthesis of first-generation PEG derivatives

[0392] Option 1. The route for the first-generation PEG connector

[0393]

[0394] The first-generation synthetic route for the PEG-8 linker consisted of 10 linear steps, resulting in an overall yield of 4.6% due to the low selectivity of step 5, toluenesulfonation. The intermediates and the Boc-protected final product were difficult to purify due to poor crystallinity. Furthermore, the synthesis used hazardous and / or expensive reagents such as NaH and Ag₂O. Therefore, this route was not suitable for process scale-up. A new route was subsequently developed.

[0395] Example 2: Synthesis of 1,3,6,9,12-pentaoxa-2-thiacyclotetradecane 2,2-dioxide (CPD-103)

[0396] Scheme 2. Steps a and b for the synthesis of CPD-103.

[0397]

[0398] Tetraethylene glycol is a key raw material for the synthesis of the intermediate 1,3,6,9,12-pentaoxa-2-thienocyclic tetradecane 2,2-dioxide (CPD-103). It is typically contaminated by n-PEG-OH (n = 1, 2, 3, 5, 6…) analogues, which will generate potential impurities in downstream chemistry. Tetraethylene glycol is purified using a short distillation route prior to step a.

[0399] Step a: Under nitrogen atmosphere and at ambient temperature, add dichloromethane (10.00 g / L) to a 3000 L reactor. V, V = L / kg (relative to limiting reagent)), and stirring at 25°C. Tetraethylene glycol (45.0 kg, 1.0 eq.) and N,N-diisopropylethylamine (143.5 kg, 4.8 eq.) were added at 25°C. The temperature was adjusted to 0°C, and a solution of thionyl chloride (55.3 kg, 2.0 eq.) in dichloromethane (5 V) was added over 12 hours. The reaction mixture was stirred at 0°C for 1 hour.

[0400] Under nitrogen atmosphere, deionized water (10 V) was added and the reaction mixture was stirred at 0 °C for 30 min. The temperature was adjusted to 25 °C, and the reaction mixture was stirred for another 30 min. The organic layer was separated and washed with 5% citric acid aqueous solution (10 V), followed by washing with 10% brine (10 V). The organic matter was separated and transferred to a 500 L reactor under nitrogen atmosphere, then concentrated under vacuum to obtain a volume of 2 V to 4 V. Acetonitrile (5 V) was added, and the volume was reduced under vacuum to approximately 2 V to 4 V. Next, deionized water (4 V to 8 V, to make the mixture CH3CN:H2O = 1:2) was added, and the mixture was stirred at 25 °C for 30 min. The mixture was pressure filtered through diatomaceous earth (22.50 kg), and the filter cake was washed with CH3CN:water = 1:2 (3 V). The resulting filtrate was collected and washed with n-heptane (2 x 10 V) at 25 °C. The resulting MeCN / water layer (430.2 kg) containing the desired product was used for the next step without further purification.

[0401] 1¹H NMR (300 MHz, chloroform-d): δ 4.35 (ddd, J = 10.7, 5.8, 4.6 Hz, 2H), 4.10 (dt, J = 11.1, 4.8 Hz, 2H), 3.85 – 3.64 (m, 12H).

[0402] 13 C NMR (75 MHz, chloroform-d): δ 70.68, 70.46, 69.47, 61.74.

[0403] HRMS (m / z): [M + H] + C8H 17 The calculated value of O6S is 241.0746, and the measured value is 241.0750.

[0404] Step b: Under nitrogen atmosphere, acetonitrile / water (430.2 kg) containing 1,3,6,9,12-pentaoxa-2-thiacyclotetradecane 2-oxide (CPD-102) was added to a 3000 L reactor, and dichloromethane (154.3 kg, 4 V) was added at 25 °C with stirring. Next, ruthenium(III) chloride hydrate (292.5 g, 0.01 eq.) was added at 25 °C, followed by sodium periodate (60.0 kg, 2.3 eq.) in portions at 30 °C. The reaction mixture was stirred for 4 h. After the intermediate CPD-102 was consumed (as monitored by GC), the temperature was adjusted to 25 °C and the reaction mixture was stirred for another 30 min.

[0405] The crude product was filtered through diatomaceous earth (14.8 kg, 0.5 w / w), and the filter cake was washed with dichloromethane (397.2 kg, 10 V). The resulting filtrate was further filtered through a filter element (0.45 μm), and the organic matter was separated and washed with 5% sodium bisulfite solution (156.2 kg, 5 V). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (195.1 kg, 5 V). The combined organic matter was concentrated to 2 V to 4 V under vacuum, ethyl acetate (5 V) was added, and the resulting mixture was concentrated to 2 V to 4 V. This process was repeated once.

[0406] The crude product was diluted with n-heptane (4 V) and purified by passing through a silica gel stopper (2.4 w / w, 70.0 kg, 100-200 mesh), followed by elution with 230.0 kg ethyl acetate:n-heptane = 1:2, 1538.6 kg ethyl acetate:n-heptane = 2:3, and 180 kg ethyl acetate, respectively. The combined fractions containing the product were concentrated under reduced pressure and milled in 5% ethyl acetate / n-heptane. The solid was dried under vacuum at 30 °C for 12 h to give 18.3 kg of the desired product as a grayish-white solid. [2-step yield 31%]

[0407] 1 ¹H NMR (300 MHz, chloroform-d): δ 4.52 – 4.44 (m, 4H), 3.90 – 3.81 (m, 4H), 3.71 – 3.62 (m, 8H).

[0408] 13 C NMR (75 MHz, chloroform-d): δ 72.21, 70.68, 70.61, 68.41.

[0409] HRMS (m / z): [M + H] + C8H 17 O7S calculated value = 257.0695, measured value 257.0697.

[0410] Key impurity in step b: triethylene glycol analogue of CPD-103

[0411] The main impurities include dimer byproducts, which can be removed by silica gel column purification in downstream processes.

[0412] Table 1. Identification of impurities in step b

[0413]

[0414] Example 3. Second-generation synthesis of 4-(4-nitrophenoxy)-3,6,9,12-tetraoxotetradecane-1-ol (CPD-18) Route 1

[0415] Option 3. Step 1 of Route 1.

[0416]

[0417] Step 1: Add 290.0 g (1.0 eq.) of 4-fluoronitrobenzene and 556.0 g (2.0 eq.) of K2CO3 to ethylene glycol (2.9 L, 10 V) at ambient temperature. Stir the mixture at 70 °C for 3 hours.

[0418] The reaction mixture was poured into ice water (8.7 L, 30 V) over 1 hour, and the resulting mixture was slurried at 25 °C for 2 hours. The mixture was then filtered, and the solids were washed with H₂O (1.4 L, 5 V). The filter cake was dissolved in dichloromethane (5.8 L, 20 V), and the organic phase was separated and concentrated (approximately 2.17 L, 7.5 V). With stirring, n-heptane (2.9 L, 10 V) was added at 25 °C over 0.5 hours. The mixture was slurried for 1 hour, filtered, and dried at 40 °C to give 297.0 g (yield: 79%) of the product as a white solid. The formation of a dimer impurity (CPD-181A) was observed and removed in subsequent steps.

[0419] Option 4. Steps 2 and 3 of Route 1.

[0420]

[0421] Step 2: Under N2, with stirring, 1,3,6,9,12-pentaoxa-2-thiacyclotetradecane 2,2-dioxide (CPD-103) (250 g, 1.0 eq.) and 2-(4-nitrophenoxy)ethanol-1-ol (CPD-181) (232.5 g, 1.3 eq.) were added to THF (1.2 L, 5 V). Tertiary-BuONa (731.0 mL, 1.5 eq., 2 M, in THF) was added over 4 hours at 10°C to 20°C. The mixture was stirred at 10°C to 20°C for 1 hour, and the consumption of the CPD-103 starting material was monitored by TLC. After the reaction was complete, H2O (1.5 L, 6 V) was added at 10°C to 20°C, and the solution was concentrated.

[0422] Step 3: Wash the mixture with dichloromethane (3 x 1.2 L, 3 x 5 V) and 20% H2SO4 aqueous solution (0.2 eq.). Add 2-Me-THF (1.5 L, 6 V) and 20% H2SO4 (125.0 mL, 0.5 V) to the aqueous layer and stir the mixture at 70-75°C for 2 hours. (The reaction was monitored by HPLC; CPD-18S < 1%). Cool the mixture to ambient temperature and separate the layers. Extract the aqueous phase with 2-Me-THF (2.5 L, 10 V). Wash the combined organic phases with 10% K2CO3 (2 x 2.5 L, 2 x 10 V) and 20% NaCl solution (1.2 L, 5 V), then concentrate to obtain crude CPD-18.

[0423] Purification: MgCl2 (613.0 g, 5.0 eq. wt) was added to crude CPD-18 (250.0 g, 1.0 eq.) dissolved in THF (2.5 L, 10 V) at 15 °C to 20 °C, and the slurry was stirred at 25 °C for 18 h. Next, the slurry was diluted with MTBE (2.5 L, 10 V) and stirred at 25 °C for 1 h. The reaction mixture was filtered, and the resulting solid was washed with a 1:1 mixture of THF:MTBE (1.2 L, 5 V) and dried at 40 °C for 3 to 6 h (purity of CPD-18 Mg complex as determined by HPLC: 99.82%).

[0424] The CPD-18-Mg complex (860 g) was dissolved in ice water (2.5 L, 10 vol) and extracted with dichloromethane (2.5 L, 10 V). The organic layer was concentrated and dried under vacuum at 40 °C to obtain CPD-18 (228.0 g, 65% yield in two steps).

[0425] Example 4. Second-generation synthesis of 4-(4-nitrophenoxy)-3,6,9,12-tetraoxatetradecane-1-ol (CPD-18) Route 2.

[0426] Option 5. Step 1 of Route 2.

[0427]

[0428] Step 1: 4-Fluoronitrobenzene (16.5 kg, 1.0 eq.) and K₂CO₃ (32.3 kg, 2.0 eq.) were added to acetonitrile (130.3 kg, 10 V) containing PEG-5 (33.6 kg, 1.2 eq.), and the mixture was heated to 80 °C and stirred for 12 hours. The mixture was filtered and washed with acetonitrile (39.6 kg, 3 V). The filtrate was diluted with n-heptane (57.0 kg, 5 V) and concentrated to 2 V to 3 V under reduced pressure. The solvent was changed to n-heptane by adding n-heptane (5 V), and then concentrated to 2 V to 3 V under reduced pressure. H₂O (329.5 kg, 20 V) was then added, and the mixture was stirred at 25 °C for 2 hours. The mixture was filtered, and the solid (CPD-18A) was washed with H₂O (33.0 kg, 2 V). Sodium chloride (66.0 kg, 4 w / w) was added, and the filtrate was extracted twice with 1:1 MTBE:IPAc (61.3 kg / 72.2 kg, 5 V / 5 V) and concentrated under reduced pressure. The solution was then further concentrated by adding ethanol (10... The solvent was changed to ethanol, and then concentrated to 2 V to 3 V (twice) under reduced pressure at 40 °C to obtain the crude product.

[0429] Purification: Crude CPD-18 was dissolved in ethanol (10 V) and anhydrous MnCl2 (25.8 kg, 2.5 eq.) was added. The mixture was stirred at ambient temperature for 30 min. The mixture was inoculated with pure CPD-18-Mn complex (147.0 g, 0.5% w / w) and stirred at 20 °C for 6 h. The mixture was filtered, and the solid was washed with ethanol (23.2 kg, 1 V) to obtain CPD-18 (purity 99.6% as determined by HPLC).

[0430] The resulting mixture was diluted with ethanol (140.0 kg, 6 V) and anhydrous MnCl2 (20.55 kg, 2.00 eq.) was added, followed by ethanol (46.1 kg, 2 V) as a flushing solution at the feed port. The mixture was stirred at 80 °C for 1 hour to obtain a clear solution, which was then slowly cooled to 25 °C over 6 hours. The mixture was then stirred again at 20 °C for 6 hours. The mixture was filtered, and the solid (CPD-18 complex, 100% purity as determined by HPLC) was washed with ethanol (23.2 kg, 1 V) and added to H2O (294.5 kg, 10 V), followed by dichloromethane (390.0 kg, 10 V). The resulting mixture was stirred for 30 min and filtered. The filtrate was collected, and the layers were separated. The aqueous layer was extracted with dichloromethane (372.3 kg, 10 V), and the combined organic layers were washed with water (146.0 kg, 5 V) and filtered. The solvent was changed to THF by adding THF (264.6 kg, 10 V), and the mixture was concentrated to 2 V to 4 V under reduced pressure at 40 °C to obtain the desired product (61.5 kg THF solution containing 25.6 kg CPD-18, yield 60.7%), which was used in the next step without further purification.

[0431] CPD-18 Mn complex

[0432] HRMS (m / z): [M + Na] + C 16 H 25 The calculated value of NNaO8 is 382.1478, and the measured value is 382.1459.

[0433] Ion chromatography: 14% by weight Cl - (1.0 eq.Cl - ).

[0434] CPD-18 Ca complex

[0435] HRMS (m / z): [M + Na] + C 16 H 25 Calculated value of CaCl2O8, measured value 470.35.

[0436] Such as the structure determined by MicroED Figure 2 As shown.

[0437] CPD-18

[0438] 1 ¹H NMR (300 MHz, chloroform-d): δ 8.23 ​​– 8.14 (m, 2H), 7.04 – 6.95 (m, 2H), 4.29 – 4.20 (m, 2H), 3.94 – 3.87 (m, 2H), 3.76 – 3.64 (m, ¹³H), 3.62 – 3.57 (m, 2H), 3.06 (s, 2H).

[0439] 13 C NMR (75 MHz, chloroform-d) δ: 163.87, 141.51, 125.82, 114.62, 72.59, 70.83, 70.53, 70.50, 70.46, 70.19, 69.31, 68.14, 61.60.

[0440] HRMS (m / z): [M + Na] + C 16 H 25 The calculated value of NNaO8 is 382.1478, and the measured value is 382.1400.

[0441] CPD-18 was successfully synthesized via the CPD-18S intermediate (Example 3) and purified by MnCl2 complexation to obtain CPD-18 with >99% purity.

[0442] The updated CPD-18 synthesis via PEG-5-OH (Example 4) is more cost-effective because the CPD-103 starting material is not involved in the process, and the synthesis of CPD-18 requires only a single step. Purification via MnCl2 complexation removes a higher range of PEG analog impurities more effectively than MgCl2 complexation.

[0443] (4-Nitrophenoxy)-3,6,9,12-Tetraoxatetradecane-1-ol (CMP-18) impurity

[0444] The three most important impurities shown in Table 2 (CPD-182, CPD-183, and CPD-184) are caused by poor-quality PEG-5 (which contains trace amounts of PEG-2, PEG-3, and PEG-4).

[0445] The corresponding impurities were synthesized and identified by HPLC using RRT (valley relative retention time) to monitor impurity trends.

[0446] Table 2. Process Impurities in CPD-18

[0447]

[0448] Example 5. Screening for purification of (4-nitrophenoxy)-3,6,9,12-tetraoxatetradecane-1- via metal complexation Metal salts and solvents of alcohol (CPD-18)

[0449] Option 6. Metal complex

[0450]

[0451] The experiment was conducted by mixing 0.1 g of (4-nitrophenoxy)-3,6,9,12-tetraoxatetradecane-1-ol (CPD-18, CPD-18-4:18 = 1.9:93.9) with 5 equivalents of XCl2 in 1 mL (10 V) solvent for 18 hours. The mixture was filtered, and the purity of the filter cake and the loss of the determined yield (AY) of CPD-18 in the mother liquor were assessed. The results are listed in Table 3.

[0452] Table 3. Screening of metal chloride salts for complexation with CPD-18

[0453]

[0454] LCAP: Liquid Chromatography Area Purity

[0455] AY: Determining yield

[0456] The experiment was conducted by slurrying 0.1 g of the CPD-18 complex with 5 equivalents of CaCl2 in 1 mL (10 V) solvent for 2 days. The mixture was filtered, and the purity of the filter cake and the loss of CPD-18 yield (AY) in the mother liquor were assessed. The results are shown in Table 4.

[0457] Table 4. Screening of solvents for CPD-18 Ca complex

[0458]

[0459] LCAP: Liquid Chromatography Area Purity

[0460] AY: Determining yield

[0461] The experiment was conducted by slurrying 0.1 g of the CPD-18 complex with 5 equivalents of MnCl2 in 1 mL (10 V) solvent for 2 days. The mixture was filtered, and the purity of the filter cake and the loss of CPD-18 yield (AY) in the mother liquor were assessed. The results are listed in Table 5.

[0462] Table 5. Screening of solvents for CPD-18 Mn complexes

[0463]

[0464] LCAP: Liquid Chromatography Area Purity

[0465] AY: Determining yield

[0466] The experiment was conducted by mixing 0.1 g of CPD-18 with different equivalents of MnCl2 in 1 mL (10 V) EtOH or THF for 18 h. The mixture was filtered, and the purity of the filter cake and the loss of the determined yield (AY) of CPD-18 in the mother liquor were assessed. The results are listed in Table 6.

[0467] Table 6. Screening of MnCl2 equivalents in EtOH and THF

[0468]

[0469] LCAP: Liquid Chromatography Area Purity

[0470] AY: Determining yield

[0471] Example 6.26-(4-nitrophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosane-1-ol (CPD- Synthesis of 110)

[0472] Solution 7. Steps 4 and 5.

[0473]

[0474] Step 1: Under nitrogen atmosphere, at 25°C, 21.0 kg (1.0 eq.) of THF containing 14-(4-nitrophenoxy)-3,6,9,12-tetraoxatetradecane-1-ol (CPD-18) was added to 18.1 kg (1.2 eq.) of 1,3,6,9,12-pentaoxa-2-thiebelcycle tetradecane 2,2-dioxide (CPD-103). The reaction mixture was cooled to 0°C, and tertiary-BuONa (6.1 kg) was added in portions. The resulting mixture was stirred at 25°C for 5 hours, then cooled to -5°C to 0°C. Water (210 L, 10 V) was added, and the mixture was stirred at 0°C to 5°C for 30 min. The mixture was washed with isopropyl acetate (3 x 178.8 kg, 3 x 10 V) and further washed with 2-Me-THF (2 x 180.7 kg, 2 x 10 V). The aqueous layer containing the product proceeded to the next step of the reaction without further purification.

[0475] Step 2: Add 2-Me-THF (91.0 kg, 5 V) to the aqueous solution of crude CPD-109. Cool the reaction to 15°C and add H2SO4 (19.3 kg, 0.5 V). Heat the resulting mixture to 70°C and stir for 2 hours. Cool the reaction to 25°C, add methyl tert-butyl ether (78.0 kg, 5 V), and stir the resulting mixture for 30 min. Separate the layers, and wash the aqueous phase twice with a 1:1 mixture of 2-Me-THF / methyl tert-butyl ether (90.7 kg / 78.0 kg, 5 V / 5 V), then extract with dichloromethane (279.5 kg, 10 V). Wash the organic phase with an 8% (w / w) aqueous solution of sodium bicarbonate (228.8 kg, 10 V), then with a 10% (w / w) aqueous solution of NaCl (233.8 kg, 10 V). The organic layer was filtered and concentrated to dryness below 40°C to obtain CPD-110 (18.9 kg, purity 99.9% by HPLC, yield 59.6%), which was a viscous oil.

[0476] 1 ¹H NMR (300 MHz, chloroform-d): δ 8.27 – 8.12 (m, 2H), 7.08 – 6.94 (m, 2H), 4.24 (dd, J = 5.7, 3.8 Hz, 2H), 3.90 (dd, J = 5.7, 3.8 Hz, 2H), 3.75 – 3.56 (m, 32H), 2.91 (s, 1H).

[0477] 13C NMR (75 MHz, chloroform-d): δ 163.87, 141.50, 125.81, 114.59, 72.52, 70.86, 70.57, 70.51, 70.28, 69.33, 68.20, 61.62.

[0478] HRMS (m / z): [M + H] + C 24 H 41 NNaO 12 Calculated value = 558.2526, measured value = 558.2428.

[0479] Example 7. Optimization of ring-opening of 1,3,6,9,12-pentaoxa-2-thionetradecane 2,2-dioxide (CPD-103)

[0480] Different solvent combinations with tert-BuONa and tert-BuOLi were screened, and the results were monitored by HPLC. The results are listed in Table 7. Impurities (CPD-187S and CPD-188S) are listed below.

[0481]

[0482] Table 7. Screening of Alkali and Solvent Combinations

[0483]

[0484] Dissolve the alkali in 10 V solvent and add it to the mixture within 2 hours.

[0485] SM: Starting material

[0486] P: Product

[0487] Different equivalents of tert-BuONa were screened, and the reaction was monitored by HPLC. The results are listed in Table 8.

[0488] Table 8. Base equivalents used for ring-opening of CPD-103.

[0489]

[0490] LCAP: Liquid Chromatography Area Purity

[0491] P: Product

[0492] SM: Starting material

[0493] Different equivalents of CPD-103 were explored using tertiary base-BuONa, and the reaction was monitored by HPLC. The results are listed in Table 9.

[0494] Table 9. CPD-103 equivalents used in the study for open-loop applications

[0495]

[0496] LCAP: Liquid Chromatography Area Purity

[0497] P: Product

[0498] SM: Starting material

[0499] Example 8. Screening for purification of 26-(4-nitrophenoxy)-3,6,9,12,15,18,21,24- via metal complexation Metal salts and solvents of octaoxahexadecane-1-ol (CPD-110)

[0500] The experiment was conducted by mixing 0.1 g of crude CPD-110 with 5 equivalents of XCl2 in 1 mL (10 V) solvent for 18 hours. The mixture was filtered, and the purity of the filter cake and the loss of the determined yield (AY) of CPD-110 in the mother liquor were assessed. The results are listed in Table 10.

[0501]

[0502] Table 10. Screening of metal chloride salts for complexation with CPD-110

[0503]

[0504] CaCl2 equivalent screening: The experiment was conducted by mixing 0.1 g CPD-110 (purity of 98.5% as determined by HPLC) with different equivalents of CaCl2 in 1 mL (10 V) solvent for 18 hours. The mixture was then filtered, and the purity of the filter cake and the loss of CPD-110 content in the mother liquor were tested. The results are listed in Table 11.

[0505] Table 11. Equivalent of CaCl2 for screening

[0506]

[0507] Solvent screening: The experiment was conducted by mixing 0.1 g of CPD-110 (purity of 99.54% as determined by HPLC) with 2.5 equivalents of CaCl2 in 1 mL (10 V) of solvent for 18 hours. The mixture was then filtered, and the purity of the filter cake and the loss of CPD-110 in the mother liquor were tested. The results are listed in Table 12.

[0508] Table 12. Solvent Screening

[0509]

[0510] LCAP: Liquid Chromatography Area Purity

[0511] 26-(4-nitrophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosane-1-ol CaCl2 complex (CPD-110 CaCl2 complex)

[0512] 1 H NMR (300 MHz, DMSO-d6): δ 8.28 – 8.15 (m, 2H), 7.28 – 7.14 (m, 2H), 4.90 (t, J = 5.3 Hz, 1H), 4.35 – 4.21 (m, 2H), 3.87 – 3.75 (m, 2H), 3.68 –3.40 (m, 32H).

[0513] 13 C NMR (75 MHz, DMSO-d6): δ 164.28, 141.15, 126.29, 115.59, 72.71,70.36, 70.21, 70.18, 69.03, 68.75, 60.44.

[0514] HRMS (m / z): [M + Na] + C 24 H 41 NNaO 12 Calculated value = 558.2526, measured value = 558.2437.

[0515] Ion chromatography: 20% by weight Cl - (1.2 eq. Cl - ).

[0516] 26-(4-Nitrophenoxy)-3,6,9,12,15,18,21,24-Octaoxahexacosane-1-ol (CPD-110) impurity

[0517] All possible PEG analog impurities (such as CPD-186, CPD-187, CPD-188, CPD-110-OAc, and CPD-110 dimer impurities) were synthesized, and the reaction characteristics were monitored by HPLC. Examples are shown in Table 13.

[0518] Table 13. Process Impurities in CPD-110

[0519]

[0520] Example 9. 2-(26-(4-nitrophenoxy)-3,6,9,12,15,18,21,24-octaoxahexadecyl)isoin Synthesis of Dolline-1,3-dione (CPD-110-NH3)

[0521] Scheme 8. Synthesis of PEG-8-NHC

[0522]

[0523] 26-(4-nitrophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosane-1-ol (100 g, 187 mmol, 1 eq.) was dissolved in THF (1000 mL, 10 V). PhtNH (33.0 g, 224 mmol, 1.2 eq.) and PPh3 (98.0 g, 373 mmol, 2 eq.) were added, and the resulting mixture was cooled to 5 ± 5 °C. DIAD (75.5 g, 373 mmol, 2 eq.) was added dropwise, and the resulting mixture was stirred at 5 ± 5 °C for 1 h. A 20 wt% NaCl aqueous solution (5 V) was added to the reaction mixture at 5 ± 5 °C, and the mixture was stirred at 20 ± 5 °C for 15 min. The organic layer was separated and concentrated under reduced pressure to obtain the desired product (375 g, crude product, assuming 100% yield), which was a yellow semi-solid.

[0524] 1 H NMR (300 MHz, DMSO-d6) δ 8.19 (d, J = 9.3 Hz, 2H), 7.92 – 7.79 (m,4H), 7.16 (d, J = 9.3 Hz, 2H), 4.31 – 4.20 (m, 2H), 3.82 – 3.70 (m, 4H), 3.67– 3.38 (m, 30H).

[0525] 13 C NMR (101 MHz, DMSO-d6) δ 168.22, 164.32, 141.27, 134.89, 132.00,126.29, 123.49, 115.50, 70.43, 70.25, 70.21, 70.17, 70.10, 69.94, 69.08, 68.71, 67.40, 37.57.

[0526] HRMS (m / z): [M+H] + C 32 H 45 N2O 13 The calculated value is 665.2916, and the measured value is 665.3439.

[0527] 26-(4-Nitrophenoxy)-3,6,9,12,15,18,21,24-octaoxahexadecane-1-ammonium chloride

[0528] 2-(26-(4-nitrophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosyl)isoindoline-1,3-dione (375 g, 144 mmol, crude, 1 eq.) was dissolved in ethanol (620 mL, 5 V). Hydrazine hydrate (35.1 g, 433 mmol, 3 eq. 80% aqueous solution) was added at 20 ± 5 °C, and the resulting mixture was warmed to 45 °C. The reaction mixture was stirred at 45 °C for 14 hours and then cooled to 25 ± 5 °C. 2-Methyltetrahydrofuran (10 V) was added, and the mixture was stirred at 25 ± 5 °C for 30 minutes. The solid was filtered off and washed with 2-methyltetrahydrofuran (5.00 V). The filtrate was concentrated to remove EtOH. The residue was slurried with 2-methyltetrahydrofuran (10 V) and 1 M HCl (10 V) at 25 ± 5 °C for 15 min. The solid was filtered off. The aqueous phase was washed with EA (10 V x 7) to obtain 675 g of aqueous phase. 225 g of NaCl was added to the aqueous phase, and the mixture was stirred to obtain a clear solution. The solution was extracted with DCM (10 V). The DCM solution was washed with a 25 wt% NaCl aqueous solution (10 V). The organic phase was concentrated to 1 V to 2 V to obtain the desired product (110 g), which was a yellow DCM solution. This DCM solution was used for the next step without further purification.

[0529] 1 H NMR (300 MHz, DMSO-d6) δ 8.20 (dd, J = 10.0, 2.9 Hz, 5H), 7.18 (d,J = 9.3 Hz, 2H), 4.35 – 4.19 (m, 2H), 3.81 – 3.77 (m, 2H), 3.66 – 3.48 (m,30H), 2.95 (q, J = 5.6 Hz, 2H).

[0530] 13 C NMR (101 MHz, DMSO-d6) δ 164.33, 141.27, 126.32, 115.55, 70.42,70.26, 70.23, 70.21, 70.10, 70.08, 69.08, 68.73, 67.04, 66.82, 38.88.

[0531] HRMS (m / z): [M+H] + C 24 H 43 N2O 11Calculated value: 535.2867; Measured value: 535.2931.

[0532] 26-(4-Nitrophenoxy)-3,6,9,12,15,18,21,24-Octaoxahexadecane-1-ammonium chloride calcium chloride complex (PEG-8-NHC)

[0533] 26-(4-nitrophenoxy)-3,6,9,12,15,18,21,24-octaoxahexadecane-1-ammonium chloride (110 g, 150 mmol, 1 eq., DCM solution containing 80 g of free base) was added to DCM (1 L). CaCl2 (41.5 g, 374 mmol, 2.5 eq.) was added, and the resulting mixture was stirred at 20 ± 5 °C for 18 h. Toluene (1 L) was added dropwise over 1 h, and the resulting mixture was stirred at 20 ± 5 °C for 2 h. The mixture was filtered, and the filter cake was washed under nitrogen with DCM:toluene = 1:1 (10 V). The filter cake was dried under vacuum at 40 ± 5 °C for 18 h to give PEG-8-NHC (133 g), a white solid. (Yield: 76% by 3 steps, Purity: 99.5%, Ca...) 2+ 10.4%, Cl - 22.8%, the structure was confirmed by MicroED, such as Figure 1 As shown.

[0534] 1 H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 3H), 8.21 (d, J = 9.2 Hz, 2H), 7.21 (d, J = 9.2 Hz, 2H), 4.33 – 4.21 (m, 2H), 3.84 – 3.75 (m, 2H), 3.68 (t,J = 5.6 Hz, 2H), 3.62 – 3.51 (m, 28H), 2.90 (t,J = 5.6 Hz, 2H).

[0535] 13 C NMR (101 MHz, DMSO-d6) δ 164.43, 141.33, 126.44, 115.74, 70.50, 70.31, 70.18, 70.15, 69.18, 68.89, 67.04, 38.82.

[0536] HRMS (m / z): [M+H] + C 24 H 43 N2O11 Calculated value: 535.2867; Measured value: 535.2926.

[0537] Example 10. Synthesis of 2,5,8,11,14,17,20,23,26,29-decaoxatricarboxane-31-ol

[0538] Option 9.

[0539]

[0540] Hexaethylene glycol monomethyl ether (45.0 g, 152 mmol, 1.0 eq.) was dissolved in THF (405 mL, 9 V). 1,3,6,9,12-pentaoxa-2λ6-thiecyclotetradecane-2,2-dione (46.7 g, 182 mmol, 1.2 eq.) was added to the mixture at 20 ± 5 °C. t-BuONa (21.9 g, 228 mmol, 1.5 eq.) was added in portions to the mixture at 20 ± 5 °C. The resulting reaction mixture was stirred at 20 ± 5 °C for 1 h. H₂O (225 mL, 5 V) was added to the mixture to quench the reaction. The quenched mixture was concentrated to remove THF. The residue was washed three times with 2-MeTHF (225 mL, 5 V). 2-MeTHF (225 mL, 5 V) and H₂SO₄ (45 mL, 1 V) were added to the aqueous phase at 20 ± 5 °C. The resulting mixture was heated to 80 ± 5 °C and stirred at 80 ± 5 °C for 4 h. The reaction mixture was cooled to 20 ± 5 °C and separated. The aqueous phase was extracted three times with DCM (450 mL, 10 V). The combined organic phases were washed successively with saturated NaHCO₃ solution (450 mL, 10 V) and saturated NaCl solution (450 mL, 10 V). The organic phase was concentrated under reduced pressure (P < -0.085 MPa) to give 62 g of product (85% yield) as a yellow oil.

[0541] 1 ¹H NMR (400 MHz, chloroform-d): δ 3.75 – 3.57 (m, 38H), 3.55 (dd, J = 6.0, 3.3Hz, 2H), 3.38 (s, 3H), 3.18 (d, J = 2.3 Hz, 3H, OH+H₂O).

[0542] 13 C NMR (101 MHz, chloroform-d): δ 72.67, 71.83, 70.49, 70.45, 70.41, 70.39, 70.13, 61.49, 61.47, 58.92.

[0543] HRMS (m / z): [M + H] + C 21 H 45 O 11 Calculated value: 473.2956; Measured value: 473.3014.

[0544] Example 11. Synthesis of polyethylene glycol (PEG) derivatives

[0545] The following PEG-derived compounds were prepared from Examples 1 to 8.

[0546] 35-(4-Nitrophenoxy)-3,6,9,12,15,18,21,24,27,30,33-Undecanotaxentapentadecan-1-ol (CPD-0150)

[0547]

[0548] 1 ¹H NMR (300 MHz, chloroform-d): δ 8.19 (dd, J = 8.7, 1.5 Hz, 2H), 7.05 – 6.93 (m, 2H), 4.31 – 4.19 (m, 2H), 3.90 (dd, J = 5.6, 3.9 Hz, 2H), 3.82 – 3.44 (m, 43H), 2.98 (s, 2H).

[0549] 13 C NMR (75 MHz, chloroform-d): δ 163.86, 141.48, 125.80, 114.59, 72.56, 70.84, 70.55, 70.49, 70.24, 69.31, 68.19, 61.58.

[0550] HRMS (m / z): [M + H] + C 30 H 54 NO 15 The calculated value is 668.3493, and the measured value is 668.3487.

[0551] 38-(4-Nitrophenoxy)-3,6,9,12,15,18,21,24,27,30,33,36-Dodecaoxaoctacosan-1-ol (CPD-0120)

[0552]

[0553] 1¹H NMR (300 MHz, chloroform-d): δ 8.27 – 8.13 (m, 2H), 7.07 – 6.91 (m, 2H), 4.23 (dd, J = 5.7, 3.7 Hz, 2H), 3.90 (dd, J = 5.6, 3.8 Hz, 2H), 3.81 – 3.36 (m, 47H), 2.95 (s, 2H).

[0554] 13 C NMR (75 MHz, chloroform-d): δ 163.87, 141.52, 125.82, 114.60, 72.56, 70.87, 70.58, 70.52, 70.25, 69.34, 68.20, 61.62.

[0555] HRMS (m / z): [M + H] + C 32 H 58 NO 16 Calculated value = 712.3756, measured value = 712.3732.

[0556] 47-(4-Nitrophenoxy)-3,6,9,12,15,18,21,24,27,30,33,36,39,42,45-pentadecaoxaheptadecane-1-ol (CPD-0160)

[0557]

[0558] 1 ¹H NMR (300 MHz, chloroform-d): δ 8.25 – 8.11 (m, 2H), 7.06 – 6.90 (m, 2H), 4.29 – 4.17 (m, 2H), 3.97 – 3.85 (m, 2H), 3.81 – 3.58 (m, 59H), 2.86 (s, 2H).

[0559] 13 C NMR (75 MHz, chloroform-d): δ 163.86, 141.54, 125.84, 114.60, 72.59, 70.88, 70.59, 70.52, 70.25, 69.35, 68.20, 61.63.

[0560] HRMS (m / z): [M + H] + C 38 H 70 NO19 Calculated value = 844.4542, measured value = 844.4532.

[0561] 50-(4-Nitrophenoxy)-3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48-Hexadecoxapentadecane-1-ol (CPD-0130)

[0562]

[0563] 1 ¹H NMR (300 MHz, chloroform-d): δ 8.28 – 8.13 (m, 2H), 7.08 – 6.91 (m, 2H), 4.32 – 4.19 (m, 2H), 3.94 – 3.86 (m, 2H), 3.77 – 3.57 (m, 63H), 2.82 (s, 2H).

[0564] 13 C NMR (75 MHz, chloroform-d): δ 163.87, 141.54, 125.84, 114.60, 72.54, 70.89, 70.60, 70.53, 70.30, 69.35, 68.21, 61.66.

[0565] HRMS (m / z): [M + H] + C 40 H 74 NO 20 Calculated value = 888.4804, measured value = 888.4788.

[0566] The development of synthetic routes has many advantages. Specifically, the total number of synthetic steps is reduced from 10 to 4, and the overall yield is increased.

[0567] While preferred embodiments of the invention have been shown and described herein, it will be clear to those skilled in the art that such embodiments are provided by way of example only. Many variations, modifications, and substitutions will now be apparent to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein can be used to practice the invention. The following claims are intended to define the scope of the invention and are thereby intended to cover the methods and structures within the scope of these claims and their equivalents.

Claims

1. A method for synthesizing a compound of formula (I), or a salt, solvate, or hydrate thereof, or a metal ion complex thereof: Equation (I), Including intermediate C: (C) Mix with intermediate D1: (D1) in: R is a phenyl group that is optionally substituted or a C1-C6 alkyl group that is optionally substituted; n is an integer from 1 to 21; m is an integer from 0 to 6; and x ranges from 4 to 30.

2. A method for synthesizing a compound of formula (II), or a salt, solvate, or hydrate thereof, or a metal ion complex thereof: Equation (II), Including intermediate C: (C) Mix with intermediate D: (D) in: n is an integer from 1 to 21 m is an integer from 0 to 6; and x is n + (m + 3).

3. The method according to claim 2, wherein the method comprises (i) a first step and (ii) a second step.

4. The method of claim 3, wherein the first step comprises mixing intermediate C and intermediate D in a first solvent in the presence of a base.

5. The method according to claim 4, wherein the alkali comprises a metal salt.

6. The method according to claim 4 or 5, wherein the base is selected from sodium tert-butoxide (NaOtBu), potassium tert-butoxide (KOtBu), lithium tert-butoxide (LiOtBu), sodium hydride (NaH), potassium hydride (KH), methyllithium (MeLi), butyllithium (BuLi), hexyllithium (HxLi), lithium diisopropylamine (LDA), sodium bis(trimethylsilyl)amino (NaHMDS), potassium bis(trimethylsilyl)amino (KHMDS), lithium bis(trimethylsilyl)amino (LiHMDS), and lithium tetramethylpiperidine (LiTMP), or combinations thereof.

7. The method according to any one of claims 4 to 6, wherein the base is selected from sodium tert-butoxide (NaOtBu), potassium tert-butoxide (KOtBu), and lithium tert-butoxide (LiOtBu).

8. The method according to any one of claims 4 to 7, wherein the base is solid sodium tert-butoxide (NaOtBu).

9. The method according to any one of claims 4 to 8, wherein 0.8 to 3.0 equivalents of the base are present in the first solvent.

10. The method according to any one of claims 4 to 9, wherein 1.0 to 1.5 equivalents of the base are present in the first solvent.

11. The method according to any one of claims 4 to 10, wherein 1.1 equivalents of the base are present in the first solvent.

12. The method according to any one of claims 4 to 11, wherein the base is added to the first solvent in batches.

13. The method according to any one of claims 4 to 12, wherein the first solvent is adjusted to a temperature of about -10°C to about 40°C before the alkali is added.

14. The method according to any one of claims 4 to 13, wherein the first solvent is adjusted to a temperature of about -10°C to about 15°C before the alkali is added.

15. The method according to any one of claims 4 to 14, wherein the first solvent is adjusted to a temperature of about -5°C to about 5°C before the alkali is added.

16. The method according to any one of claims 4 to 15, wherein the first solvent is selected from toluene, ethyl acetate, dichloromethane, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, methyl tert-butyl ether, isopropyl acetate, dimethylacetamide, NMP, cyclopentyl methyl ether and diphenyl ether, or combinations thereof.

17. The method according to any one of claims 4 to 16, wherein the first solvent is selected from tetrahydrofuran and methyltetrahydrofuran, or combinations thereof.

18. The method of claim 3, wherein the second step comprises mixing the product from step (i) in a second solvent in the presence of an acid.

19. The method of claim 18, wherein the acid is added to the second solvent.

20. The method according to claim 18 or 19, wherein the acid is selected from sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, acetic acid, and formic acid.

21. The method according to any one of claims 18 to 20, wherein the acid is sulfuric acid.

22. The method according to any one of claims 19 to 21, wherein the second solvent is adjusted to a temperature of about 50°C to about 90°C after the acid is added.

23. The method according to any one of claims 19 to 22, wherein the second solvent is adjusted to a temperature of about 70°C to about 80°C after the acid is added.

24. The method according to any one of claims 18 to 23, wherein the second solvent is selected from toluene, ethyl acetate, dichloromethane, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, methyl tert-butyl ether, isopropyl acetate, dimethylacetamide, NMP, cyclopentyl methyl ether and diphenyl ether, or combinations thereof.

25. The method according to any one of claims 18 to 24, wherein the second solvent is selected from tetrahydrofuran and methyltetrahydrofuran, or combinations thereof.

26. The method according to any one of claims 18 to 25, wherein the second solvent is methyltetrahydrofuran.

27. The method according to any one of claims 18 to 26, wherein the second solvent further comprises water as a co-solvent.

28. The method according to any one of claims 1 to 27, wherein steps (i) and (ii) are repeated 1 to 20 times.

29. The method according to any one of claims 1 to 28, wherein the method is carried out in a single reactor.

30. The method according to any one of claims 1 to 29, wherein the method further comprises purification by metal ion complexation.

31. The method according to claim 30, wherein the metal ion is calcium, magnesium or manganese.

32. The method according to claim 31, wherein the metal ion is calcium.

33. The method according to any one of claims 1 to 32, wherein the yield of the compound of formula (I) or (II) is at least 20%.

34. The method according to any one of claims 1 to 32, wherein the yield of the compound of formula (I) or (II) is at least 40%.

35. The method according to any one of claims 1 to 32, wherein the yield of the compound of formula (I) or (II) is at least 60%.

36. The method according to any one of claims 1 to 32, wherein the purity of the compound of formula (I) or (II) is at least 95.0%.

37. The method according to any one of claims 1 to 32, wherein the purity of the compound of formula (I) or (II) is at least 99.0%.

38. The method according to any one of claims 1 to 32, wherein the purity of the compound of formula (I) or (II) is at least 99.9%.

39. The method according to any one of claims 1 to 38, wherein the content of impurity of formula (I) or (II) is less than about 2%, as determined by HPLC.

40. The method according to any one of claims 1 to 38, wherein the content of the impurity of formula (I) or (II) is less than about 1%, as determined by HPLC.

41. The method according to any one of claims 1 to 38, wherein the content of the impurity of formula (I) or (II) is less than about 0.2%, as determined by HPLC.

42. The method according to any one of claims 39 to 41, wherein the impurity is selected from: , and , or combinations thereof.

43. The method according to any one of claims 1 to 42, wherein intermediate C, or its salt, solvate, hydrate, or metal ion complex thereof: (C) is synthesized from intermediate B through an oxidation reaction: (B)。 44. The method of claim 43, wherein the oxidation reaction comprises mixing intermediate B in a solvent in the presence of an oxidant.

45. The method according to claim 44, wherein the oxidant is selected from potassium persulfate, H2O2, mCPBA, TiO2 / TBHP, osmium tetroxide, sodium periodate, ruthenium tetroxide, RuCl3 hydrate, NaOCl and NaIO4, or combinations thereof.

46. ​​The method according to claim 44 or 45, wherein the oxidant is RuCl3 hydrate or RuCl3 hydrate and NaIO4.

47. The method according to any one of claims 43 to 46, wherein the oxidizing solvent is selected from dichloromethane, dichloroethane, acetonitrile, water, tetrahydrofuran, methyltetrahydrofuran, dimethyl sulfoxide, dimethylformamide, acetone, nitrobenzene, dichlorobenzene, isopropyl acetate, dimethylacetamide, NMP, cyclopentyl methyl ether and diphenyl ether, or combinations thereof.

48. The method according to any one of claims 43 to 46, wherein the oxidizing solvent is selected from dichloromethane, acetonitrile, and water, or combinations thereof.

49. The method according to any one of claims 43 to 48, wherein intermediate C is purified by precipitation with heptane and filtration.

50. The method according to any one of claims 43 to 49, wherein the purity of intermediate C is at least 90.0%.

51. The method according to any one of claims 43 to 49, wherein the purity of intermediate C is at least 95.0%.

52. The method according to any one of claims 43 to 49, wherein the purity of intermediate C is at least 98.0%.

53. The method according to any one of claims 43 to 52, wherein the content of intermediate C impurity is less than about 4%, as determined by HPLC.

54. The method according to any one of claims 43 to 52, wherein the content of intermediate C impurity is less than about 2%, as determined by HPLC.

55. The method according to any one of claims 43 to 52, wherein the content of intermediate C impurity is less than about 1%, as determined by HPLC.

56. The method according to any one of claims 53 to 55, wherein the intermediate C impurity is selected from... and , or combinations thereof.

57. The method according to any one of claims 43 to 56, wherein intermediate B: (B) is synthesized from intermediate diol A via a cyclization reaction: (A), where y is between 3 and 10.

58. The method of claim 57, wherein the cyclization reaction comprises mixing intermediate diol A in a third solvent in the presence of a third base and thionyl chloride.

59. The method according to claim 58, wherein the third base is selected from triethylamine, diisopropylethylamine, pyridine, DMAP, DABCO, and DBU.

60. The method according to claim 58 or 59, wherein the third base is diisopropylethylamine.

61. The method according to any one of claims 57 to 60, wherein the third solvent is selected from dichloromethane, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, dichloroethane, dichlorobenzene, cyclopentyl methyl ether, methyl tert-butyl ether, isopropyl acetate, dimethylacetamide, NMP, cyclopentyl methyl ether, and diphenyl ether.

62. The method according to any one of claims 57 to 60, wherein the third solvent is dichloromethane.

63. The method according to any one of claims 2 to 62, wherein intermediate D, or a salt, solvate, hydrate, or metal ion complex thereof, is: (D) is from Synthesized via nucleophilic substitution reaction.

64. The method of claim 63, wherein the nucleophilic substitution reaction comprises, in the presence of a fourth base, Mix in a fourth solvent.

65. The method of claim 64, wherein the fourth solvent is selected from dimethylformamide, dimethylamide, NMP, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, dioxane, DME, and dimethyl sulfoxide.

66. The method according to claim 64 or 65, wherein the fourth solvent is acetonitrile.

67. The method according to any one of claims 64 to 66, wherein the fourth base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, DBU, DIPEA, triethylamine, or pyridine.

68. The method according to any one of claims 64 to 66, wherein the fourth base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and cesium carbonate.

69. The method according to any one of claims 64 to 68, wherein the method further comprises purifying intermediate D by metal ion complexation.

70. The method of claim 69, wherein the metal ion is calcium, magnesium or manganese.

71. The method according to claim 69, wherein the metal ion is manganese.

72. The method according to any one of claims 69 to 71, wherein the purification further comprises a solvent selected from ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, toluene, ACE, dichloromethane, ethanol, isopropanol, MTBE and DME.

73. The method according to any one of claims 69 to 71, wherein the purification further comprises a solvent selected from ethanol and tetrahydrofuran.

74. The method according to any one of claims 63 to 73, wherein the purity of intermediate D is higher than 98.0%.

75. The method according to any one of claims 63 to 73, wherein the purity of intermediate D is higher than 99.0%.

76. The method according to any one of claims 63 to 73, wherein the purity of intermediate D is higher than 99.9%.

77. The method according to any one of claims 63 to 76, wherein the content of intermediate D impurity is less than about 1%, as determined by HPLC.

78. The method according to any one of claims 63 to 76, wherein the content of intermediate D impurity is less than about 0.1%, as determined by HPLC.

79. The method according to any one of claims 63 to 78, wherein the intermediate D impurity is selected from... , and , or combinations thereof.

80. The method according to any one of claims 1 to 79, wherein n is 5 and m is 1.

81. The method according to any one of claims 57 to 80, wherein y is 4.

82. The method according to any one of claims 1 to 81, wherein the method further comprises the synthesis of a compound of formula (IV) or a salt thereof: Formula (IV), Where Z is the counter ion; It includes the following steps: Make compound (II) (II) Reacts with phthalimide, triphenylphosphine (PPh3), and diisopropyl azodicarbonate (DIAD) to obtain compound (V): (V); and The compound of formula (V) was treated with hydrazine to obtain the compound of formula (IV).

83. The method according to any one of claims 1 to 82, wherein the method further comprises the synthesis of a compound of formula (VI), a salt thereof, or a metal ion complex thereof: Expression (VI) Where M is one or more metal ions; It includes the step of reacting the compound of formula (IV) with a metal salt.

84. A composition comprising: ， Or its salts, solvates or hydrates, or metal ion complexes thereof, wherein x is 4 to 30, and wherein said composition contains less than about 10% impurities, as determined by HPLC.

85. The composition according to claim 84, wherein x is 5, 9, 12, 13, 17, 21 or 25.

86. A composition comprising: The composition contains less than about 10% impurities, as determined by HPLC, or its salts, solvates or hydrates, or metal ions thereof.

87. A composition comprising: Or its salts, solvates or hydrates, or metal ion complexes thereof, wherein the composition contains less than about 10% impurities, as determined by HPLC.

88. A composition comprising: Or its salts, solvates or hydrates, or metal ion complexes thereof, wherein the composition contains less than about 10% impurities, as determined by HPLC.

89. A composition comprising: Or its salts, solvates or hydrates, or metal ion complexes thereof, wherein the composition contains less than about 10% impurities, as determined by HPLC.

90. A composition comprising: Or its salts, solvates or hydrates, or metal ion complexes thereof, wherein the composition contains less than about 10% impurities, as determined by HPLC.

91. The composition according to any one of claims 84 to 90, wherein the composition contains less than about 5% of the impurities.

92. The composition according to any one of claims 84 to 90, wherein the composition contains less than about 1% of the impurity.

93. The composition according to any one of claims 84 to 90, wherein the impurity is selected from: , , and , or combinations thereof.

94. A compound having the structure of formula (II), or a salt, solvate, hydrate, or metal ion complex thereof: Where x ranges from 4 to 30. It is obtained by the method according to any one of claims 1 to 83.

95. The compound, or salt, solvate, or hydrate, or metal ion complex thereof, according to claim 94, wherein x is 5, 9, 12, 13, 17, 21, or 25.

96. The compound according to claim 94 or 95, wherein the compound is ， ， ， or 。 97. A metal ion complex having the following structure: Where x is 4 to 30 and M is one or more metal ions.

98. The metal ion complex according to claim 97, wherein x is 5, 9, 12, 13, 17, 21 or 25.

99. A metal ion complex having the following structure: ， ， ， or ， Where M is one or more metal ions.

100. The metal ion complex according to claims 97 to 99, wherein the metal ion is selected from iron, magnesium, calcium, barium, cobalt, nickel, copper, zinc, aluminum, manganese and indium.

101. The metal ion complex according to claim 100, wherein the metal ion is calcium.

102. A metal ion complex having the following structure: Where n is 1 to 21 and M is one or more metal ions.

103. A metal ion complex having the following structure: ， Where M is one or more metal ions.

104. The metal ion complex according to claim 102 or 103, wherein the metal ion is selected from iron, magnesium, calcium, barium, cobalt, nickel, copper, zinc, aluminum, manganese and indium.

105. The metal ion complex according to claim 104, wherein the metal ion is manganese.

106. A metal ion complex having the following structure: Where x is 4 to 30 and M is one or more metal ions.

107. A metal ion complex having the following structure: ， ， ， or ， Where M is one or more metal ions.

108. The metal ion complex according to claim 106 or 107, wherein the metal ion is selected from iron, magnesium, calcium, barium, cobalt, nickel, copper, zinc, aluminum, manganese and indium.

109. The metal ion complex according to claim 108, wherein the metal ion is calcium.

110. The metal ion complex according to any one of claims 97 to 109, wherein the purity of the metal ion complex is higher than 98.0%, 99.0% or 99.9%.

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