Preparation of compounds for the treatment of gout or hyperuricemia

Abstract

Described herein is the preparation of compounds for treating gout or hyperuricemia, as well as chemical intermediates used in the synthetic process.

Description

[Technical field]

[0001] cross reference This application claims the benefit of PCT / CN2021 / 143104, filed December 30, 2021, which is incorporated by reference in its entirety. [Background technology]

[0002] Hyperuricemia is thought to be a causative factor in several diseases caused by overproduction or underexcretion of uric acid, which significantly impairs quality of life. For example, hyperuricemia is thought to be a causative factor in gout, the most common form of inflammatory arthritis caused by the accumulation of uric acid crystals and characterized by severe pain and tenderness in the joints. Identifying gout / hyperuricemia drugs that are effective in lowering serum uric acid (sUA) and have low toxicity represents an unmet medical need that would beneficially impact patients. Summary of the Invention

[0003] Described herein is a process for the synthesis of a compound for the treatment of gout or hyperuricemia, wherein the compound is (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (Compound 1), or a pharma- ceutically acceptable salt thereof.

[0004] One embodiment is (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1).

[0005] [ka] A process for preparing

[0006] [ka] with cesium carbonate in the presence of a solvent. In some embodiments, the solvent is selected from methanol, ethanol, isopropanol, butanol, water, acetone, acetonitrile, dimethylformamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, acetic acid, and combinations thereof. In some embodiments, the solvent is selected from methanol.

[0007] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0008] [ka] A compound having the structure

[0009] [ka] The compound is prepared by a process comprising contacting a compound having the structure of: with a base and a palladium catalyst in the presence of a solvent. In some embodiments, the base is selected from potassium carbonate, silver carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, triethylamine, diisopropylethylamine, 1,8-diazabicyclo(5.4.0)undec-7-ene, and 1,4-diazabicyclo[2.2.2]octane. In some embodiments, the base is potassium carbonate. In some embodiments, the palladium catalyst is selected from Pd(dppf)Cl2, PdCl2, Pd(OAc)2, Pd(Ph3P)4, Pd2(dba)3, and Pd / C. In some embodiments, the palladium catalyst is Pd(dppf)Cl2. In some embodiments, the ligand is selected from Ph3P, BINAP, DPEphos, S-Phos, Xantphos, dtbpf, and Mephos. In some embodiments, the solvent is selected from dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone, acetone, acetonitrile, sulfolane, tetrahydrofuran, and toluene, hi some embodiments, the solvent is dimethylsulfoxide.

[0010] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0011] [ka] A compound having the structure

[0012] [ka] and a compound having the structure

[0013] [ka] and potassium phosphate in the presence of a solvent, followed by trifluoroacetic acid. In some embodiments, the solvent is selected from dichloromethane, chloroform, acetonitrile, toluene, ethyl acetate, and tetrahydrofuran. In some embodiments, the solvent is dichloromethane.

[0014] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0015] [ka] A compound having the structure

[0016] [ka] It is prepared by a process comprising contacting a compound having the structure: with sodium bicarbonate, potassium bromide, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), and sodium hypochlorite.

[0017] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0018] [ka] A compound having the structure

[0019] [ka] and a compound having the structure

[0020] [ka] and a base in the presence of a solvent. In some embodiments, the base is selected from lithium diisopropylamide, LiHMDS, NaHMDS, KHMDS, t-BuOK, t-BuONa, t-BuOLi, and NaH. In some embodiments, the base is lithium diisopropylamide. In some embodiments, the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, and toluene. In some embodiments, the solvent is tetrahydrofuran.

[0021] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0022] [ka] A compound having the structure

[0023] [ka] It is prepared by a process comprising contacting a compound having the structure of with benzoyl chloride and a base in the presence of a solvent. In some embodiments, the base is selected from pyridine, potassium carbonate, sodium hydroxide, triethylamine, diisopropylethylamine, 1,8-diazabicyclo(5.4.0)undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, and lutidine. In some embodiments, the base is pyridine. In some embodiments, the solvent is selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, and N-methyl-2-pyrrolidone. In some embodiments, the solvent is dichloromethane.

[0024] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0025] [ka] A compound having the structure

[0026] [ka] It is prepared by a process comprising contacting a compound having the structure of: with 4-methoxybenzyl chloride and a base in the presence of a solvent. In some embodiments, the base is selected from potassium carbonate, sodium hydride, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine, and pyridine. In some embodiments, the base is potassium carbonate. In some embodiments, the solvent is selected from acetonitrile, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, dimethylsulfoxide, and N-methyl-2-pyrrolidone. In some embodiments, the solvent is acetonitrile.

[0027] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0028] [ka] A compound having the structure

[0029] [ka] It is prepared by a process comprising contacting a compound having the structure: with sodium nitrite, potassium iodide, and toluenesulfonic acid.

[0030] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0031] [ka] A compound having the structure

[0032] [ka] It is prepared by a process comprising contacting a compound having the structure: with 10% platinum on carbon and deuterium oxide.

[0033] Further provided herein is a process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), comprising: A)

[0034] [ka] A compound having the structure of the formula (I) is reacted with 10% platinum on carbon and deuterium oxide,

[0035] [ka] producing a compound having the structure B) After that,

[0036] [ka] with sodium nitrite, potassium iodide, and toluenesulfonic acid to obtain

[0037] [ka] producing a compound having the structure C)

[0038] [ka] A compound having the structure:

[0039] [ka] producing a compound having the structure D)

[0040] [ka] With benzoyl chloride and pyridine,

[0041] [ka] producing a compound having the structure E) After that,

[0042] [ka] With lithium diisopropylamide,

[0043] [ka] producing a compound having the structure F) After that,

[0044] [ka] A compound having the structure of the formula (I) is reacted with sodium bicarbonate, potassium bromide, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), and sodium hypochlorite to obtain

[0045] [ka] producing a compound having the structure G) After that,

[0046] [ka] A compound having the structure: is reacted with potassium phosphate, and then contacted with trifluoroacetic acid,

[0047] [ka] producing a compound having the structure H) After that,

[0048] [ka] A compound having the structure of the formula (I) is reacted with potassium carbonate and Pd(dppf)Cl2 to form

[0049] [ka] producing a compound having the structure I) After that,

[0050] [ka] A compound having the structure of

[0051] [ka] and producing a compound having the structure:

[0052] Further, the present specification provides:

[0053] [ka] Disclosed are compounds having a structure selected from:

[0054] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0055] Good manufacturing practices are usually required for large-scale production of clinically useful drug candidates. Provided herein are certain processes and methods for producing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (Compound 1), or a pharma- ceutically acceptable salt or co-crystal thereof.

[0056] definition As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings indicated below.

[0057] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or cells), and equivalents thereof.

[0058] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formula, it is intended that all combinations and subcombinations of the ranges and specific embodiments within those ranges are included.

[0059] The term "about," when referring to a numerical value or numerical range, means that the stated numerical value or numerical range is an approximation within experimental error (or within statistical experimental error), and thus the numerical value or numerical range may vary from 1% to 15% of the stated numerical value or numerical range.

[0060] The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude other specific embodiments, such as embodiments of any composition of matter, composition, method, or process described herein, from "consisting of" or "consisting essentially of" the described features.

[0061] The term "subject" or "patient" encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any animal belonging to the Mammalian class, such as humans, non-human primates such as chimpanzees, and other ape and monkey species, livestock animals such as cows, horses, sheep, goats, and pigs, domestic animals such as rabbits, dogs, and cats, and laboratory animals including rodents such as rats, mice, and guinea pigs. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0062] As used herein, "treatment", "treating", "palliating" or "ameliorating" are used interchangeably herein. These terms refer to an approach to obtain a beneficial or desired outcome, including but not limited to therapeutic benefit and / or preventive benefit. "Therapeutic benefit" refers to the eradication or amelioration of the underlying disease being treated. Moreover, therapeutic benefit is achieved by eradication or amelioration of one or more of the physiological symptoms associated with the underlying disease, such that an improvement is observed in the patient, even though the patient still suffers from the underlying disease. For preventive benefit, the composition is administered to a patient who is at risk of developing a particular disease, or who reports one or more of the physiological symptoms of the disease, even though no diagnosis of the disease has been made.

[0063] "Pharmaceutically acceptable salt" includes both acid addition salt and base addition salt. Any one of the pharmaceutically acceptable salts of the compounds described herein is intended to include any pharmaceutically suitable salt form. The preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0064] "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed with organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic sulfonic acids, and aromatic sulfonic acids, including, for example, acetic acid, trifluoroacetic 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, salicylic acid, etc. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Additionally, salts of amino acids such as arginate, gluconate, and galacturonate are contemplated (see, for example, Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997). Acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt.

[0065] "Pharmaceutically acceptable base addition salt" refers to a salt that retains the biological effectiveness and properties of the free acid, which is not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals, or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, primary amines, secondary amines, tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, as well as basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0066] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combination of two or more active ingredients, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the active ingredients being administered to a patient simultaneously in the form of a single entity or single dosage form. The term "non-fixed combination" refers to the active ingredients being administered to a patient as separate entities simultaneously, together, or sequentially, without any specific time limit between them, such administration providing effective levels of the two compounds in the patient's body. Non-fixed combination also applies to cocktail therapy, for example, the administration of three or more active ingredients.

[0067] As used herein, terms such as "co-administration" are meant to encompass the administration of selected therapeutic agents to a single patient and are intended to include treatment regimens in which agents are administered by the same route of administration or by different routes of administration, or at the same time or at different times.

[0068] The term "activator" is used herein to denote any molecular species that, when locally administered, results in activation of the indicated receptor, regardless of whether the molecular species itself binds to the receptor or a metabolic product of the molecular species binds to the receptor. Thus, an activator can be a ligand for the receptor or an activator that is metabolized to a ligand for the receptor, i.e., a metabolite formed in the tissue that is the actual ligand.

[0069] As used herein, the term "antagonist" refers to a small molecule agent that binds to a nuclear hormone receptor and subsequently reduces agonist-induced transcriptional activity of the nuclear hormone receptor.

[0070] As used herein, the term "agonist" refers to a small molecule agent that binds to a nuclear hormone receptor and subsequently increases the transcriptional activity of the nuclear hormone receptor in the absence of a known agonist.

[0071] As used herein, the term "inverse agonist" refers to a small molecule drug that binds to a nuclear hormone receptor and subsequently reduces the basal level of nuclear hormone receptor transcriptional activity that is present in the absence of a known agonist.

[0072] As used herein, the term "modulate" means to interact directly or indirectly with a target protein to alter the activity of the target protein, including, by way of example only, inhibiting the activity of the target or limiting or reducing the activity of the target.

[0073] As used herein, the term "modulator" refers to a compound that changes the activity of a target. For example, a modulator can cause an increase or decrease in the magnitude of a particular activity of a target, compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor that reduces the magnitude of one or more activities of a target. In certain embodiments, an inhibitor completely prevents one or more activities of a target.

[0074] compound In some embodiments, the compound for treating gout or hyperuricemia described herein is (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (Compound 1), or a pharma- ceutically acceptable salt or co-crystal thereof. Compound 1 is

[0075] [ka] It has the structure:

[0076] In some embodiments, the starting material for synthesizing compound 1 is

[0077] [ka] In some embodiments, an intermediate in the synthesis of compound 1 is

[0078] [ka] In some embodiments, an intermediate in the synthesis of compound 1 is

[0079] [ka] In some embodiments, the starting material in the synthesis of compound 1 is

[0080] [ka] In some embodiments, an intermediate in the synthesis of compound 1 is

[0081] [ka] In some embodiments, the starting material in the synthesis of compound 1 is

[0082] [ka] In some embodiments, an intermediate in the synthesis of compound 1 is

[0083] [ka] In some embodiments, an intermediate in the synthesis of compound 1 is

[0084] [ka] In some embodiments, an intermediate in the synthesis of compound 1 is

[0085] [ka] In some embodiments, an intermediate in the synthesis of compound 1 is

[0086] [ka] In some embodiments, an intermediate in the synthesis of compound 1 is

[0087] [ka] In some embodiments, an intermediate in the synthesis of compound 1 is

[0088] [ka] In some embodiments, an intermediate in the synthesis of compound 1 is

[0089] [ka] In some embodiments, an intermediate in the synthesis of compound 1 is

[0090] [ka] In some embodiments, an intermediate in the synthesis of compound 1 is

[0091] [ka] In some embodiments, an intermediate in the synthesis of compound 1 is

[0092] [ka] In some embodiments, an intermediate in the synthesis of compound 1 is

[0093] [ka] It is.

[0094] Further forms of the compound The compounds described herein may exist as diastereomers, enantiomers, or other stereoisomeric forms, depending on the case. The compounds presented herein include all diastereoisomeric, enantiomeric, and epiisomeric forms, and the appropriate mixtures thereof. Separation of stereoisomers can be performed by chromatography, or by forming diastereoisomers and separating them by recrystallization, or by chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Reresolution", John Wiley And Sons, Inc., 1981, which are incorporated herein by reference for the purposes of this disclosure). Stereoisomers can also be obtained by stereoselective synthesis.

[0095] In some situations, compounds may exist as tautomers, and all tautomers are included within the formulae presented herein.

[0096] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts.In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts.In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0097] In some embodiments, the compounds described herein possess acidic or basic groups, which allow them to react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form pharma- ceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting the purified compound in its free form with the appropriate acid or base and isolating the salt thus formed.

[0098] In some embodiments, the pharma- ceutically acceptable salt of compound 1 is acetate, benzoate, besylate, bitartrate, carbonate, citrate, fumarate, gluconate, hydrobromide, hydrochloride, maleate, mesylate, nitrate, phosphate, salicylate, succinate, sulfate, or tartrate. In some embodiments, the pharma- ceutically acceptable salt of compound 1 is monohydrochloride. In further embodiments, the pharma- ceutically acceptable salt of compound 1 is monohydrochloride.

[0099] solvate In some embodiments, the compounds described herein exist as solvates. The present invention provides a method of treating a disease by administering such a solvate. The present invention further provides a method of treating a disease by administering such a solvate as a pharmaceutical composition.

[0100] Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments are formed during the process of crystallization with pharma- ceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the process described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from aqueous / organic solvent mixtures using organic solvents, including but not limited to dioxane, tetrahydrofuran, or methanol. Furthermore, the compounds provided herein exist in unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0101] labeled compound 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 disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to those listed herein except for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes incorporated in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chloride, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 The compounds described herein, and pharma- ceutically acceptable salts, esters, solvates, hydrates, or derivatives thereof, that contain the aforementioned isotopes and / or other isomers of other atoms are within the scope of the present invention. Certain isotopically labeled compounds, e.g., 3 H and 14 Compounds incorporating radioactive isotopes, such as C, are useful in drug and / or substrate tissue distribution assays. Tritium isotopes, i.e., 3 H and carbon-14, i.e. 14 C is particularly preferred because it is easy to prepare and detectable. In addition, deuterium, i.e. 2Substitution with heavy isotopes such as H provides certain therapeutic advantages due to greater metabolic stability, e.g., increased half-life in vivo, or reduced dose required. Increased levels of deuterium incorporation result in a detectable kinetic isotope effect (KIE) that can affect the pharmacokinetic, pharmacological, and / or toxicological parameters of compound 1 compared to compound 1 with naturally occurring levels of deuterium. In some embodiments, the isotopically labeled compound, or a pharmaceutically acceptable salt thereof, is prepared by any suitable method.

[0102] In some embodiments, at least one hydrogen in compound 1 is replaced with deuterium.

[0103] 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 labels, or chemiluminescent labels.

[0104] Preparation process In some embodiments, synthesis of the compounds described herein is accomplished using means described in the chemical literature, using methods described herein, or by a combination thereof. Additionally, solvents, temperatures, and other reaction conditions presented herein may be varied.

[0105] In other embodiments, the starting materials and reagents used in the synthesis of the compounds described herein are synthesized or obtained from commercial sources, including, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and AcrosOrganics. In further embodiments, the compounds described herein, and other related compounds having different substituents, can be synthesized and / or synthesized in accordance with the techniques and materials described herein, as well as in other publications, such as, for example, Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 th Ed., (Wiley 1992), Carey and Sundberg, Advanced Organic Chemistry 4 th Ed., Vols. A and B(Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3 rd Ed., (Wiley 1999), all of which are incorporated herein by reference for such disclosure. General methods for preparing compounds as disclosed herein can be derived from reactions which may be modified by using appropriate reagents and conditions for the introduction of various functional moieties found in the formulae as provided herein.

[0106] Some embodiments include 3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1).

[0107] [ka] A process for preparing

[0108] [ka] with cesium carbonate in the presence of a solvent. In some embodiments, the solvent is selected from methanol, ethanol, isopropanol, butanol, water, acetone, acetonitrile, dimethylformamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, acetic acid, and combinations thereof. In some embodiments, the solvent is methanol. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is isopropanol. In some embodiments, the solvent is butanol. In some embodiments, the solvent is water. In some embodiments, the solvent is acetone. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethylsulfoxide. In some embodiments, the solvent is N-methyl-2-pyrrolidone. In some embodiments, the solvent is acetic acid.

[0109] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0110] [ka] A compound having the structure

[0111]

change

[0112] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0113] [ka] A compound having the structure

[0114] [ka] with a base and a palladium catalyst in the presence of a solvent. In some embodiments, the base is selected from potassium carbonate, silver carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, triethylamine, diisopropylethylamine, 1,8-diazabicyclo(5.4.0)undec-7-ene, and 1,4-diazabicyclo[2.2.2]octane. In some embodiments, the base is triethylamine. In some embodiments, the base is potassium carbonate. In some embodiments, the base is silver carbonate. In some embodiments, the base is sodium carbonate. In some embodiments, the base is cesium carbonate. In some embodiments, the base is sodium bicarbonate. In some embodiments, the base is diisopropylethylamine. In some embodiments, the base is 1,8-diazabicyclo(5.4.0)undec-7-ene. In some embodiments, the base is 1,4-diazabicyclo[2.2.2]octane. In some embodiments, the palladium catalyst is selected from Pd(dppf)Cl2, PdCl2, Pd(OAc)2, Pd(Ph3P)4, Pd2(dba)3, and Pd / C. In some embodiments, the palladium catalyst is Pd(dppf)Cl2. In some embodiments, the palladium catalyst is PdCl2. In some embodiments, the palladium catalyst is Pd(OAc)2. In some embodiments, the palladium catalyst is Pd(Ph3P)4. In some embodiments, the palladium catalyst is Pd2(dba)3. In some embodiments, the palladium catalyst is Pd / C. In some embodiments, the ligand is selected from Ph3P, BINAP, DPEphos, S-Phos, Xantphos, dtbpf, and Mephos. In some embodiments, the ligand is Ph3P. In some embodiments, the ligand is BINAP. In some embodiments, the ligand is DPEphos. In some embodiments, the ligand is S-Phos. In some embodiments, the ligand is Xantphos. In some embodiments, the ligand is dtbpf. In some embodiments, the ligand is Mephos.In some embodiments, the solvent is selected from dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone, acetone, acetonitrile, sulfolane, tetrahydrofuran, and toluene. In some embodiments, the solvent is dimethylsulfoxide. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is N-methyl-2-pyrrolidone. In some embodiments, the solvent is acetone. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is sulfolane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is toluene.

[0115] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0116] [ka] A compound having the structure

[0117] [ka] and a compound having the structure

[0118] [ka] and potassium phosphate in the presence of a solvent, followed by trifluoroacetic acid. In some embodiments, the solvent is selected from dichloromethane, chloroform, acetonitrile, toluene, ethyl acetate, and tetrahydrofuran. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is chloroform. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is toluene. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is tetrahydrofuran.

[0119] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0120] [ka] A compound having the structure

[0121] [ka] and a compound having the structure

[0122] [ka] and potassium phosphate in the presence of a solvent. In some embodiments, the solvent is selected from dichloromethane, chloroform, acetonitrile, toluene, ethyl acetate, and tetrahydrofuran. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is chloroform. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is toluene. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is tetrahydrofuran.

[0123] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0124] [ka] A compound having the structure

[0125] [ka] It is prepared by a process comprising contacting a compound having the structure: with sodium bicarbonate, potassium bromide, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), and sodium hypochlorite.

[0126] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0127] [ka] A compound having the structure

[0128] [ka] The compound is prepared by a process comprising contacting under Swern oxidation conditions a compound having the structure:

[0129] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0130] [ka] A compound having the structure

[0131] [ka] It is prepared by a process comprising contacting a compound having the structure:

[0132] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0133] [ka] A compound having the structure

[0134] [ka] It is prepared by a process comprising contacting a compound having the structure: with sodium bicarbonate, potassium bromide, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), and sodium hypochlorite.

[0135] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0136] [ka] A compound having the structure

[0137] [ka] The compound is prepared by a process comprising contacting under Swern oxidation conditions a compound having the structure:

[0138] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0139] [ka] A compound having the structure

[0140] [ka] It is prepared by a process comprising contacting a compound having the structure:

[0141] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0142] [ka] A compound having the structure

[0143] [ka] and a compound having the structure

[0144] [ka] and a base in the presence of a solvent. In some embodiments, the base is selected from lithium diisopropylamide, LiHMDS, NaHMDS, KHMDS, t-BuOK, t-BuONa, t-BuOLi, and NaH. In some embodiments, the base is lithium diisopropylamide. In some embodiments, the base is LiHMDS. In some embodiments, the base is NaHMDS. In some embodiments, the base is KHMDS. In some embodiments, the base is t-BuOK. In some embodiments, the base is t-BuONa. In some embodiments, the base is t-BuOLi. In some embodiments, the base is NaH. In some embodiments, the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, and toluene. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is 2-methyltetrahydrofuran. In some embodiments, the solvent is dioxane. In some embodiments, the solvent is toluene.

[0145] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0146] [ka] A compound having the structure

[0147] [ka] and a compound having the structure

[0148] [ka] and a base in the presence of a solvent. In some embodiments, the base is selected from lithium diisopropylamide, LiHMDS, NaHMDS, KHMDS, t-BuOK, t-BuONa, t-BuOLi, and NaH. In some embodiments, the base is lithium diisopropylamide. In some embodiments, the base is LiHMDS. In some embodiments, the base is NaHMDS. In some embodiments, the base is KHMDS. In some embodiments, the base is t-BuOK. In some embodiments, the base is t-BuONa. In some embodiments, the base is t-BuOLi. In some embodiments, the base is NaH. In some embodiments, the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, and toluene. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is 2-methyltetrahydrofuran. In some embodiments, the solvent is dioxane. In some embodiments, the solvent is toluene.

[0149] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0150] [ka] A compound having the structure

[0151] [ka] with benzoyl chloride and a base in the presence of a solvent. In some embodiments, the base is selected from pyridine, potassium carbonate, sodium hydroxide, triethylamine, diisopropylethylamine, 1,8-diazabicyclo(5.4.0)undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, and lutidine. In some embodiments, the base is pyridine. In some embodiments, the base is potassium carbonate. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is triethylamine. In some embodiments, the base is diisopropylethylamine. In some embodiments, the base is 1,8-diazabicyclo(5.4.0)undec-7-ene. In some embodiments, the base is 1,4-diazabicyclo[2.2.2]octane. In some embodiments, the base is lutidine. In some embodiments, the solvent is selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, and N-methyl-2-pyrrolidone. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is 2-methyltetrahydrofuran. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethylsulfoxide. In some embodiments, the solvent is N-methyl-2-pyrrolidone.

[0152] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0153] [ka] A compound having the structure

[0154] [ka] The compound is prepared by a process comprising contacting a compound having the structure of: with 4-methoxybenzyl chloride and a base in the presence of a solvent. In some embodiments, the base is selected from potassium carbonate, sodium hydride, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine, and pyridine. In some embodiments, the base is potassium carbonate. In some embodiments, the base is sodium hydride. In some embodiments, the base is sodium carbonate. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments, the base is lithium hydroxide. In some embodiments, the base is triethylamine. In some embodiments, the base is diisopropylethylamine. In some embodiments, the base is pyridine. In some embodiments, the solvent is selected from acetonitrile, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, dimethylsulfoxide, and N-methyl-2-pyrrolidone. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is chloroform. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is 2-methyltetrahydrofuran. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethylsulfoxide. In some embodiments, the solvent is N-methyl-2-pyrrolidone.

[0155] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0156] [ka] A compound having the structure

[0157] [ka] The compound is prepared by a process comprising contacting a compound having the structure of: with benzoyl chloride and a base in the presence of a solvent. In some embodiments, the base is selected from potassium carbonate, sodium hydride, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine, and pyridine. In some embodiments, the base is potassium carbonate. In some embodiments, the base is sodium hydride. In some embodiments, the base is sodium carbonate. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments, the base is lithium hydroxide. In some embodiments, the base is triethylamine. In some embodiments, the base is diisopropylethylamine. In some embodiments, the base is pyridine. In some embodiments, the solvent is selected from acetonitrile, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, dimethylsulfoxide, and N-methyl-2-pyrrolidone. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is chloroform. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is 2-methyltetrahydrofuran. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethylsulfoxide. In some embodiments, the solvent is N-methyl-2-pyrrolidone.

[0158] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0159] [ka] A compound having the structure

[0160] [ka] It is prepared by a process comprising contacting a compound having the structure: with sodium nitrite, potassium iodide, and toluenesulfonic acid.

[0161] In some embodiments of the process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1),

[0162] [ka] A compound having the structure

[0163] [ka] It is prepared by a process comprising contacting a compound having the structure: with 10% platinum on carbon and deuterium oxide.

[0164] Further provided herein is a process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), comprising: A)

[0165] [ka] A compound having the structure of the formula (I) is reacted with 10% platinum on carbon and deuterium oxide,

[0166] [ka] producing a compound having the structure B) After that,

[0167] [ka] with sodium nitrite, potassium iodide, and toluenesulfonic acid to obtain

[0168] [ka] producing a compound having the structure C)

[0169] [ka] A compound having the structure:

[0170] [ka] producing a compound having the structure D)

[0171] [ka] With benzoyl chloride and pyridine,

[0172] [ka] producing a compound having the structure E) After that,

[0173] [ka] With lithium diisopropylamide,

[0174] [ka] producing a compound having the structure F) After that,

[0175] [ka] A compound having the structure of the formula (I) is reacted with sodium bicarbonate, potassium bromide, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), and sodium hypochlorite to obtain

[0176] [ka] producing a compound having the structure G) After that,

[0177] [ka] A compound having the structure: is reacted with potassium phosphate, and then contacted with trifluoroacetic acid,

[0178] [ka] producing a compound having the structure H) After that,

[0179] [ka] A compound having the structure of the formula (I) is reacted with potassium carbonate and Pd(dppf)Cl2 to form

[0180] [ka] producing a compound having the structure I) After that,

[0181] [ka] A compound having the structure of

[0182] [ka] and producing a compound having the structure:

[0183] Further provided herein is a process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), comprising: A)

[0184] [ka] A compound having the structure of the formula (I) is reacted with 10% platinum on carbon and deuterium oxide,

[0185] [ka] producing a compound having the structure B) After that,

[0186] [ka] with sodium nitrite, potassium iodide, and toluenesulfonic acid to obtain

[0187] [ka] producing a compound having the structure C)

[0188] [ka] A compound having the structure:

[0189] [ka] producing a compound having the structure D)

[0190] [ka] With benzoyl chloride and pyridine,

[0191] [ka] producing a compound having the structure E) After that,

[0192] [ka] With lithium diisopropylamide,

[0193] [ka] producing a compound having the structure F) After that,

[0194] [ka] A compound having the structure of the formula (I) is reacted with sodium bicarbonate, potassium bromide, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), and sodium hypochlorite to obtain

[0195] [ka] producing a compound having the structure G) After that,

[0196] [ka] A compound having the structure of

[0197] [ka] producing a compound having the structure H) After that,

[0198] [ka] A compound having the structure of the formula (I) is reacted with triethylamine and Pd(dppf)Cl2 to form

[0199] [ka] producing a compound having the structure I) After that,

[0200] [ka] A compound having the structure of

[0201] [ka] and producing a compound having the structure:

[0202] Pharmaceutical Compositions and Methods of Administration Administration of Compound 1 as described herein can be in any pharmacological form, such as a therapeutically effective amount of Compound 1 alone or in combination with a pharma- ceutically acceptable carrier.

[0203] Pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliary agents that facilitate the processing of active compounds into pharma-ceutically usable preparations.Suitable formulations vary according to the route of administration selected.More details about suitable excipients for pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams&Wilkins 1999), which are incorporated herein by reference for such disclosure.

[0204] As used herein, a pharmaceutical composition refers to a mixture of compound 1 described herein with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. A pharmaceutical composition facilitates administration of a compound to an organism. In practicing the treatment or use methods provided herein, a compound described herein is administered in a pharmaceutical composition in a therapeutically effective amount to a mammal having a disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. The therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. Compound 1 can be used alone or in combination with one or more therapeutic agents as a component of a mixture (as in a combination therapy).

[0205] The pharmaceutical formulations described herein can be administered to a subject by multiple routes of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. Furthermore, the pharmaceutical compositions described herein, including Compound 1 described herein, can be formulated into any suitable dosage form, including but not limited to aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, controlled release formulations, fast dissolving formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and immediate release and sustained release mixed formulations.

[0206] In some embodiments, compound 1 is formulated in a tablet dosage form. In some embodiments, compound 1 is formulated in a capsule dosage form. In some embodiments, compound 1 is formulated in a suspension dosage form. In some embodiments, compound 1 is formulated as a powder-in-capsule dosage form. In some embodiments, compound 1 is formulated as a powder-in-bottle dosage form for reconstitution as a suspension.

[0207] Pharmaceutical compositions containing the compounds described herein may be manufactured in a conventional manner, such as by way of example only, using conventional mixing, dissolving, granulating, dragee-making, granulating, emulsifying, encapsulating, entrapping, or compressing processes.

[0208] Dose administration can be repeated depending on the pharmacokinetic parameters of the dosage formulation and the route of administration used.

[0209] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate the composition in dosage unit forms. As used herein, dosage unit form refers to a physically discrete unit suitable as a single dose for the mammalian subject to be treated, with each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications of the dosage unit form are determined by and directly depend on (a) the specific characteristics of compound 1 and the particular therapeutic effect to be achieved, and (b) the inherent limitations of the technology of compounding such active compounds to treat hypersensitivity in an individual. The specific dosage can be easily calculated by those skilled in the art according to, for example, the approximate body weight or body surface area of ​​the patient, or the volume of body space occupied. The dosage is also calculated according to the specific route of administration selected. Further refinement of the calculations required to determine the appropriate dosage for treatment is routinely performed by those skilled in the art. The exact dosage is determined together with standard dose-response studies. It will be understood that the amount of composition actually administered will be determined by the practitioner in light of the relevant circumstances, including the disease or diseases to be treated, the choice of composition to be administered, the age, weight, and response of the particular patient, the severity of the patient's symptoms, and the selected route of administration. EXAMPLES

[0210] All chemicals, reagents, and solvents were purchased from commercial sources when available and used without further purification.

[0211] Example 1: Synthesis of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (Compound 1)

[0212] [ka] Process description for step A 1) AR01-1 (712 g, 1.0 equiv.) and DCM (4300 mL) were charged into a flask under N2. 2) Cooled to 0-10°C 3) AR01-2 (1570 g, 1.1 eq.) was charged dropwise to the mixture at 0-10° C. 4) The mixture was stirred at 0 to 10°C for 0.5 hours. 5) Heated to 15-25℃ 6) The mixture was stirred at 15-25°C for 1 hour. 7) Pour the reaction solution into ice water. 8) Slowly add HCl dropwise to the mixture and stir. 9) Liquid separation organic phase wash with NaHCO3 10) Dried with Na2SO4 11) Concentrated under reduced pressure 12) Distillation under reduced pressure gave AR01-3 (1595 g, 90.1%) as a white solid. 1 H NMR(400MHz,DMSO)δ7.98(d,J=7.8Hz,2H),7.70(t,J=7.4Hz,1H),7.56(t,J=7.6Hz,2H),5.73-5.53(m,1H),3.61(d,J=1.6Hz,1H),1.57(d,J=6.7Hz,3H).

[0213] Process description for step B 1) AR01-4 (2000 g, 1.0 equiv.), KCO (1185 g, 1.5 equiv.), and CHCN (13 L) were charged to a 20 L flask under N. 2) The mixture was stirred at 20-30°C for 0.5 hours. 3) AR01-5 (1296 g, 1.5 eq.) was charged dropwise to the mixture. 4) NaI was filled into the flask. 5) Heated to 58-68℃ 6) The mixture was stirred at 55-65°C for 5 hours. 7) Filtered 8) The mixture was concentrated in vacuo to give AR01-6. 9) Recrystallization afforded AR01-6 (1670 g, 77.3%) as a white solid. 1 H NMR(400MHz,DMSO)δ9.92(s,1H),8.20(s,2H),7.50(d,J=8.4Hz,2H),6.99(d,J=8.4Hz,2H),5.03(s,2H),3.79(s,3H).

[0214] Process description for step C 1) AR01-3 (727 g, 1.0 equiv.), THF (10 L) were charged into a flask under N2. 2) Cooled from -70 to -60℃ 3) LDA (2.5 L) was added dropwise to the mixture. 4) The mixture was stirred at -70 to -60°C for 30 minutes. 5) AR01-6 (1670 g, 1.0 equiv.), THF (3.4 L) was charged to the mixture under N at -70 → -60 °C. 6) The mixture was stirred at -70 to -60°C for 1.5 hours. 7) AcOH (601 g), NH4Cl aqueous solution was charged 8) The aqueous layer was separated. 9) Dried with Na2SO4 10) Concentrated under reduced pressure 11) Purification by column chromatography afforded AR01-7 (4.1 kg, 65%) as a yellow solid. 1 H NMR(400MHz,DMSO)δ7.99(d,J=7.4Hz,2H),7.71(s,2H),7.68(d,J=7.4Hz,1H),7.55(t,J=7.4Hz,2H),7.48(d,J=8.1 Hz,2H),6.97(d,J=7.9Hz,2H),6.33(s,1H),5.71(d,J=6.8Hz,1H),4.89(s,2H),3.77(s,3H),1.59(d,J=6.5Hz,3H).

[0215] Process description for step D 1) AR01-7 (4100 g), DCM (24.6 mL), HO (16.4 L), KBr (85 g), and NaHCO (600 g) were charged into a flask. 2) Cooled to 0-5°C 3) Charge the mixture with Tempo (56 g) at 3°C. 4) An aqueous solution of NaOCl (7250 g) was added dropwise to the mixture at 0-5°C. 5) Liquid separation was performed 6) The aqueous phase was extracted with DCM. 7) The organic layer was washed with saturated Na2S2O3 aqueous solution and water. 8) Dried over Na2SO4 and concentrated under reduced pressure to give crude AR01-SM1. 9) Recrystallization from CH3CN gave AR01-SM1 (2.5 kg, 61.2%) as a white solid. 1 H NMR(400MHz,DMSO)δ8.23(s,2H),8.08-8.02(m,2H),7.72(t,J=7.4Hz,1H),7.59(t,J=7.7Hz,2H),7.48(d,J =8.6Hz,2H),6.98(d,J=8.6Hz,2H),5.94(q,J=6.8Hz,1H),5.02(s,2H),3.78(s,3H),1.74(d,J=6.8Hz,3H).

[0216] Process description for step E 1) To a 2000 mL flask was added AR01-8 (30 g, 1.0 equiv.), DO (600 mL), and 10% Pt / C (3 g). 2) The flask was degassed 3 times with N2 and then 3 times with H2. 3) The mixture was heated to 120° C. and the mixture was stirred at 120° C. for 48 hours. 4) The mixture was cooled to 25-35°C and EA (600 mL) was added. 5) Filter and wash the pad with EA (60 mL) 6) The two phases were separated and the aqueous layer was extracted twice with EA (300 mL). 7) The combined organic layers were concentrated under vacuum at 40-45°C to 2-3V. 8) The mixture was concentrated under vacuum at 40-45°C until no more distillate was produced. 9) To the residue was added DO (600 mL). 10) 10% Pt / C (3 g) was added and the flask was degassed three times with N2 and then three times with H2. 11) The mixture was heated to 120° C. and the mixture was stirred at 120° C. for 24 hours. 12) The mixture was cooled to 25-35°C and EA (600 mL) was added. 13) Filter and wash the pad with EA (60 mL) 14) The two phases were separated and the aqueous layer was extracted twice with EA (300 mL). 15) The combined organic layers were concentrated under vacuum at 40-45°C to 2-3V. 16) The temperature was adjusted to 30-40°C and n-heptane (240 mL, 8 V) was slowly added. 17) The mixture was slowly cooled to 0-5°C and stirred at 0-5°C for 0.5-1 hour. 18) The wet product was dried under vacuum at 40-45°C. 19) AR01-9 (25 g, 83.0% yield) was obtained as a bronze solid. 1 H NMR(400MHz,DMSO)δ9.36(s,1H),6.74(t,1H),6.72(t,1H),6.62(d,1H),6.60(d,1H).

[0217] Process description for step F 1) To a 5000 mL flask was added AR01-9 (100.0 g, 1.0 equiv.), ACN (1000 mL), and HO (600 mL). 2) To the mixture was added TsOH (3.0 equiv.) and the mixture was stirred for 0.5 h. 3) The mixture was cooled to 0-5 °C, then a solution of NaNO2 (1.3 equiv.) in H2O (200 mL) was added slowly. 4) The mixture was stirred at 0 to 5°C for 0.5 to 1 hour. 5) The temperature was adjusted to -5 to 0°C, and a solution of KI (2.0 equiv.) in HO (200 mL) was added slowly over 30 min. 6) The temperature was adjusted to 0-30°C and the mixture was stirred for 8-10 hours. 7) A saturated aqueous solution of Na2SO3 was added, and the mixture was stirred at 0-15°C for 1 hour. 8) The mixture was separated and extracted twice with EA (1000 mL). 9) The organic layer was washed with saturated NaCl solution (500 mL). 10) The organic layer was filtered through a silicone pad. 11) The combined organic layers were concentrated under vacuum at 35-45°C to 2-3V. 12) N-heptane (500 mL) was added to the mixture. 13) The mixture was concentrated under vacuum at 35-45°C to 2-3V. 14) To the mixture was added n-heptane (500 mL). 15) The mixture was slowly cooled to -10 to 0°C and stirred at -10 to 0°C for 0.5 to 1 hour. 16) Filter and wash the wet cake with chilled n-heptane (1-2V). 17) The wet product was dried under vacuum at 25-30°C. 18) AR01-SM2 (110 g, yield 55.6%) was obtained. 1 H NMR(400MHz,DMSO)δ10.26(s,1H),7.66(s,1H),7.19(s,1H),6.89(s,1H),6.59(s,1H).

[0218] Step 1 Process Description 1) Into a 1 L three-neck flask was added AR01-SM1 (25.75 g, 1.0 eq.), potassium phosphate (4.8 g, 1.0 eq.), and DCM (460 ml, 18 V). 2) AR01-SM2 (10.0 g, 1.0 eq.) and DCM (50 ml, 2V) were added to a 100 mL constant pressure dropping funnel and the system was protected with nitrogen. 3) The internal temperature was lowered to 5-10°C, and a solution of AR01-SM2 in DCM was added dropwise. 4) After the dropwise addition, the internal temperature was maintained at 5 to 10°C and the reaction was carried out for 2 hours. 5) TFA (25.65 g, 5.0 equivalents) was added dropwise to the reaction solution, the internal temperature of the reaction solution was raised to 25-30°C, and the reaction was carried out for 2 hours. 6) NaHCO3 aqueous solution was slowly added dropwise to the reaction solution to adjust the pH to 7-8, water (125 mL, 5 V) was added, stirring was continued for 30 min, the layers were separated, the aqueous phase was extracted with DCM (50 mL, 2 V), the organic phases were combined, washed with 125 mL of water four times, dried over anhydrous magnesium sulfate, concentrated to dryness under reduced pressure at 40 °C, toluene (75 ml, 3 V), n-heptane (26 mL, 1 V) crystals were added, stirred at room temperature for 2 h, cooled to 0-5 °C, and filtered. The filter cake was washed once with toluene: n-heptane = 5:1 (2 V), and the solid was blown dry at 50 °C to constant weight to give AR01-INT-1 (25.1 g, 82.5% yield). HPLC m / z calculated (C 24 H 13 D4Br2IO5)[M+H] + 675.5,677.4, actual value 675.5,677.4. 1 H NMR(400MHz,DMSO)δ10.99(s,1H),8.33-7.86(m,2H),7.77(s,2H),7.67(t,J=7.4Hz, 1H),7.54(t,J=7.7Hz,2H),6.50(q,J=6.6Hz,1H),5.74(s,1H),1.79(d,J=6.6Hz,3H).

[0219] Step 2 Process Description 1) AR01-INT-1 (20.0 g, 1.0 equiv.), K2CO3 (12.3 g, 3.0 equiv.), Pd(dppf)Cl2 (1.08 g, 0.05 equiv.), and DMSO (400 mL, 20 mL) were added to a 1 L three-neck flask. 2) Place under magnetic stirring, flush with N2 three times, and protect with N2. 3) The internal temperature was controlled at 90-95°C and the reaction was carried out for 3 hours. 4) The reaction solution was cooled to room temperature, EA (400 mL, 20 V) was added, mixed well, and slowly added dropwise to aqueous HCl and water (200 mL, 10 V), adjusted to pH = 2-3, continued stirring for 2 h, filtered (adding diatomaceous earth), washed the filter cake with EA (80 mL, 4 V), the filtrate was layer separated, the aqueous phase was washed with EA (80 mL, 4 V), the organic phases were combined, washed four times with 100 mL of water, the organic phase was concentrated to dryness under reduced pressure at 45 ° C, acetone (80 mL, 4 V) was added, filtered, the filter cake was washed with ice acetone (20 mL, 1 V), and the solid was dried to constant weight under reduced pressure at 50 ° C to give AR01-INT-2 (12.1 g, 74.6% yield). HPLC m / z calculated (C 24 H 12 D4Br2O5)[MH] - 545.5,547.6, actual value 545.5,547.6. 1 H NMR(400MHz,DMSO)δ11.11(s,1H),7.92(s,2H),7.90-7.86(m,2H),7.65(dd,J=10. 6,4.3Hz,1H),7.49(t,J=7.8Hz,2H),6.17(q,J=6.6Hz,1H),1.78(d,J=6.7Hz,3H).

[0220] Process description for step 3 1) AR01-INT-2 (14.31 g, 1.0 equiv.) and MeOH (10 V) were charged to a reactor. 2) Cs2CO3 (25.5 g, 3.0 equiv.) was charged batchwise at 28±5° C. 3) Stir at 28±5°C for at least 16 hours. 4) Purified water (280 mL, 20 V) was charged to the reaction at 25±5° C. 5) The pH was adjusted to 2-3 using 12N HCl aqueous solution at 25±5°C. Stir for at least 1 hour. 6) Filter and wash twice with purified water (28 mL, 2 V) 7) The filter cake was dissolved with EA (215 mL, 15 V). 1N HCl solution (70 mL, 5 V) was charged. 8) Stir for at least 1 hour and separate. 9) The organic phase was washed once with 20% aqueous NaCl solution (70 mL, 5 V). 10) Concentrate to 2V-3V under vacuum at 40±5°C and fill with EA (84mL, 6V). 11) Concentrate to 2V-3V under vacuum at 40±5°C and fill with EA (84mL, 6V). 12) Concentrated to 2V~3V under vacuum at 40±5℃ 13) Charge EA (140 mL, 10 V), add activated charcoal, raise the internal temperature to 50±5° C., stir for 1 h, filter and wash the filter cake with EA (28 mL, 2 V). 14) Concentrated to 2V-3V under vacuum at 40±5℃ 15) n-Heptane (140 mL, 10 V) was added dropwise and stirred at 50±5° C. for at least 2 hours. 16) Cool to 25±5°C and stir for at least 12 hours. 17) Filtered and washed twice with n-heptane (14 mL, 1 V) 18) Drying under vacuum at 50±5° C. for at least 12 hours afforded compound 1 (8.7 g, 81% yield) as an off-white solid. HPLC m / z calculated (C 17 H8D4Br2O4) [M+H] + 425.3,427.3, actual value 425.3,427.3. 1 H NMR(400MHz,DMSO)δ11.08(s,1H),7.95(s,2H),5.59(s,1H),4.86(d,J=6.6Hz,1H),1.48(d,J=6.6Hz,3H).

[0221] Example 2: Alternative synthesis of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1)

[0222] [ka] Steps A, E, F, and 3 were completed as described in Example 1. Steps B, C, D, 1, and 2 were completed as described below.

[0223] Process description for step B 1) AR01-4-1 (2000 g, 1.0 equiv.), KCO (1185 g, 1.5 equiv.), and CHCN (13 L) were charged to a 20 L flask under N. 2) The mixture was stirred at 0 to 10°C for 0.5 hours. 3) AR01-2-1 (1511.9 g, 1.5 eq.) was charged dropwise to the mixture. 4) The mixture was stirred at 0 to 10°C for 5 hours. 5) Filtered 6) The mixture was concentrated in vacuo to give AR02-6-1. 7) Recrystallization afforded AR02-6-1 (2199.5 g, 80%) as a white solid.

[0224] Process description for step C 1) AR01-3-1 (727 g, 1.0 equiv.), THF (10 L) were charged into a flask under N2. 2) Cooled from -70 to -60℃ 3) LDA (2.5 L) was added dropwise to the mixture. 4) The mixture was stirred at -70 to -60°C for 30 minutes. 5) AR02-6-1 (1595.2 g, 1.0 equiv.), THF (3.4 L) was charged to the mixture under N at -70 → -60 °C. 6) The mixture was stirred at -70 to -60°C for 1.5 hours. 7) AcOH (601 g), NH4Cl aqueous solution was charged 8) The aqueous layer was separated. 9) Dried with Na2SO4 10) Concentrated under reduced pressure 11) Purification by column chromatography afforded AR02-7-1 (1.51 kg, 65%) as a yellow solid. LCMS (254 m, t = 1.86 min) calculated (C 25 H 18 Br2O5)[M-17] - =539.3,541.3, actual value 539.3,541.3.

[0225] Process description for step D 1) AR02-7-1 (3984.5 g), DCM (24.6 L), HO (16.4 L), KBr (85 g), and NaHCO (600 g) were charged into a flask. 2) Cooled to 0-5°C 3) Tempo (56 g) was charged into the mixture at 3° C. 4) An aqueous solution of NaOCl (7250 g) was added dropwise to the mixture at 0-5°C. 5) Liquid separation was performed 6) The aqueous phase was extracted with DCM. 7) The organic layer was washed with saturated Na2S2O3 aqueous solution and water. 8) Dried over Na2SO4 and concentrated under reduced pressure to give crude AR02-SM1-1. 9) Recrystallization from CH3CN gave AR02-SM1-1 (3.26 kg, 82%) as a white solid. 1H NMR (400 MHz,) δ 8.21-8.13 (m, 4H), 8.04 (dd, J = 8.3, 1.3 Hz, 2H), 7.83-7.49 (m, 8H), 5.96 (q, J = 6.8 Hz, 1H), 1.75 (d, J = 6.8 Hz, 3H).

[0226] Step 1 Process Description 1) Into a 1 L three-neck flask was added AR02-SM1-1 (25.75 g, 1.0 eq.), potassium phosphate (4.9 g, 0.5 eq.), and DCM (460 mL, 18 V). 2) AR02-SM2-1 (10.0 g, 1.0 equiv.) and DCM (50 mL, 2V) were added to a 100 mL constant pressure dropping funnel and the system was protected with nitrogen. 3) The internal temperature was lowered to 5-10°C, and a DCM solution of AR02-SM2-1 was added dropwise. 4) After the dropwise addition, the internal temperature was maintained at 5 to 10°C and the reaction was carried out for 2 hours. 5) Aqueous NaHCO3 solution was slowly added dropwise to the reaction solution to adjust the pH to 7-8, water (125 mL, 5 V) was added, stirring was continued for 30 min, the layers were separated, the aqueous phase was extracted with DCM (50 mL, 2 V), the organic phases were combined, washed with 125 mL of water four times, dried over anhydrous magnesium sulfate, concentrated to dryness under reduced pressure at 40 °C, toluene (75 mL, 3 V), n-heptane (26 mL, 1 V) crystals were added, stirred at room temperature for 2 h, cooled to 0-5 °C, and filtered. The filter cake was washed once with toluene: n-heptane = 5:1 (2 V), and the solid was blown dry at 50 °C to constant weight to give AR02-INT-1-1 (32.5 g, 91%) as a yellow solid.

[0227] Step 2 Process Description 1) AR02-INT-1-1 (20.0 g, 1.0 equiv.), n-PrN (11.3 g, 3.0 equiv.), Pd(dppf)Cl (1.08 g, 0.05 equiv.), and DMSO (400 ml, 20 V) were added to a 1 L three-neck flask. 2) Place under magnetic stirring, flush with N2 three times, and protect with N2. 3) The internal temperature was controlled at 100-115°C and the reaction was carried out for 3 hours. 4) The reaction solution was cooled to room temperature, EA (400 mL, 20 V) was added, mixed well, and slowly added dropwise to aqueous HCl and water (200 mL, 10 V), adjusted to pH=2-3, continued stirring for 2 h, filtered (adding diatomaceous earth), washed the filter cake with EA (80 mL, 4 V), the filtrate was layer separated, the aqueous phase was washed with EA (80 mL, 4 V), the organic phases were combined, washed 4 times with 100 mL of water, the organic phase was concentrated to dryness under reduced pressure at 45 °C, acetone (80 mL, 4 V) was added, filtered, the filter cake was washed with ice acetone (20 mL, 1 V), and the solid was dried to constant weight under reduced pressure at 50 °C to give AR01-INT-2-1. LCMS (254 nm, t=3.29 min) and calculated m / z (C 24 H 12 D4Br2O5)[MH] - =545.5,547.5, actual value 545.5,547.5. 1H NMR(400MHz,DMSO)δ11.11(s,1H),7.92(s,2H),7.88(dd,J=8.3,1.2Hz,2H),7.69 -7.62(m,1H),7.50(t,J=7.8Hz,2H),6.17(q,J=6.7Hz,1H),1.78(d,J=6.7Hz,3H).

[0228] Example 3: In vitro interaction study of compound 1 and benzbromarone with human URAT1 uptake transporter Uptake experiments were performed using MDCKII cells stably expressing the human URAT1 uptake transporter. Cells were cultured at 37±1°C in a 95:5 air:CO2 atmosphere and plated in standard 96-well tissue culture plates at cell numbers as listed in Table 1.

[0229] [Table 1]

[0230] Before the experiment, remove the medium and add Cl - The cells were washed twice with 100 μL of HBSS without Cl. The cells were then washed twice with 50 μL of HBSS (Cl) containing the probe substrate (20 μM uric acid) and the test substance (TA) or vehicle. - Uptake experiments were performed in 100 mM NaCl (pH 7.4, without HCl) at 37 ± 1 °C. Organic solvent concentrations were equal in all wells and did not exceed 1% (v / v).

[0231] Treatment groups are shown in Table 2.

[0232] [Table 2]

[0233] After the experiment, Cl - Cells were washed twice with 100 μL of ice-cold HBSS without HO and lysed with 50 μL of 0.1 M NaOH. Transport of radiolabeled probe substrate was determined by measuring an aliquot (35 μL) from each well by liquid scintillation counting.

[0234] Results: All test substances (compound 1 and benzbromarone) were dissolved in HBSS buffer at all concentrations tested, with the highest test concentration being 10 μM. Compound 1 inhibited URAT1-mediated uric acid accumulation by 100% at a concentration of 10 μM, with an IC 50 = 0.067 μM. At a concentration of 10 μM, benzbromarone inhibited URAT1-mediated uric acid accumulation by 98%, with an IC 50 =0.196 μM.

[0235] The examples and embodiments described herein are for illustrative purposes only, and in some embodiments, various modifications or variations are intended to be within the scope of the disclosure and the appended claims.

Claims

1. (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d ４ ) methanone (compound 1) 【Chemistry 1】 1. A process for preparing 【Chemistry 2】 with cesium carbonate in the presence of a solvent.

2. 2. The process of claim 1, wherein the solvent is selected from methanol, ethanol, isopropanol, butanol, water, acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, acetic acid, and combinations thereof. 【Request Item 3】 【Chemistry 3】 A compound having the structure 【Chemistry 4】 10. The process of claim 1, wherein the compound is prepared by a process comprising contacting a compound having the structure: with a base and a palladium catalyst in the presence of a solvent.

4. The base is selected from potassium carbonate, silver carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, triethylamine, diisopropylethylamine, 1,8-diazabicyclo(5.4.0)undec-7-ene, and 1,4-diazabicyclo[2.2.2]octane; the palladium catalyst is selected from Pd(dppf)Cl 2 , PdCl 2 , Pd(OAc) 2 , Pd(Ph 3 P) 4 , Pd 2 (dba) 3 , and Pd / C; and the ligand is selected from Ph 3 4. The process of claim 3, wherein the catalyst is selected from the group consisting of dimethyl sulfoxide, dimethylformamide, N-methyl-2-pyrrolidone, acetone, acetonitrile, sulfolane, tetrahydrofuran, and toluene. 【Request Item 5】 【Chemistry 5】 A compound having the structure 【Transformation 6】 and a compound having the structure 【Transformation 7】 and potassium phosphate in the presence of a solvent, followed by contacting with trifluoroacetic acid.

6. The process of claim 5, wherein the solvent is selected from dichloromethane, chloroform, acetonitrile, toluene, ethyl acetate, and tetrahydrofuran. [Request Item 7] [Transformation 8] A compound having the structure 【Chemistry 9】 with sodium bicarbonate, potassium bromide, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), and sodium hypochlorite. 【Request Item 8】 【Chemistry 10】 A compound having the structure 【Chemistry 11】 and a compound having the structure 【Chemistry 12】 8. The process of claim 7, wherein the compound is prepared by a process comprising contacting a compound having the structure:

9. The process of claim 8, wherein the base is selected from lithium diisopropylamide, LiHMDS, NaHMDS, KHMDS, t-BuOK, t-BuONa, t-BuOLi, and NaH, and the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, and toluene. 【Request Item 10】 【Chemistry 13】 A compound having the structure 【Chemistry 14】 9. The process of claim 8, wherein the compound is prepared by a process comprising contacting a compound having the structure: with benzoyl chloride and a base in the presence of a solvent.

11. The process of claim 10, wherein the base is selected from pyridine, potassium carbonate, sodium hydroxide, triethylamine, diisopropylethylamine, 1,8-diazabicyclo(5.4.0)undec-7-ene, and 1,4-diazabicyclo[2.2.2]octane, and lutidine, and the solvent is selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone. 【Request Item 12】 【Chemistry 15】 A compound having the structure 【Chemistry 16】 9. The process of claim 8, wherein the compound is prepared by a process comprising contacting a compound having the structure: with 4-methoxybenzyl chloride and a base in the presence of a solvent.

13. The process of claim 12, wherein the base is selected from potassium carbonate, sodium hydride, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine, and pyridine, and the solvent is selected from acetonitrile, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone. 【Request Item 14】 【Chemistry 17】 A compound having the structure [Chemistry 18] 6. The process of claim 5, wherein the compound is prepared by a process comprising contacting a compound having the structure: with sodium nitrite, potassium iodide, and toluene sulfonic acid. 【Request Item 15】 【Chemistry 19】 A compound having the structure 【Chemistry 20】 15. The process of claim 14, wherein the compound is prepared by a process comprising contacting a compound having the structure: with 10% platinum on carbon and deuterium oxide.

16. A process for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4 )methanone (compound 1), comprising: A) 【Chemistry 21】 with 10% platinum on carbon and deuterium oxide, 【Chemistry 22】 producing a compound having the structure B) After that, 【Chemistry 23】 with sodium nitrite, potassium iodide, and toluenesulfonic acid to obtain 【Chemistry 24】 producing a compound having the structure C) 【Chemistry 25】 with 4-methoxybenzyl chloride and potassium carbonate, 【Chemistry 26】 producing a compound having the structure D) 【Chemistry 27】 with benzoyl chloride and pyridine, 【Chemistry 28】 producing a compound having the structure E) After that, 【Chemistry 29】 and reacting a compound having the structure: with lithium diisopropylamide, 【Transformation 30】 producing a compound having the structure F) After that, 【Chemistry 31】 with sodium bicarbonate, potassium bromide, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), and sodium hypochlorite, 【Chemistry 32】 producing a compound having the structure G) After that, 【Transformation 33】 A compound having the structure: 【Transformation 34】 producing a compound having the structure H) After that, 【Chemistry 35】 with potassium carbonate and Pd(dppf)Cl 2 , 【Transformation 36】 producing a compound having the structure I) After that, 【Chemistry 37】 A compound having the structure of 【Transformation 38】 producing a compound having the structure The process includes: 【Request Item 17】 【Chemistry 39】 or a pharmaceutically acceptable salt thereof.

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