Preparation of a compound for the treatment of gout or hyperuricemia

Abstract

This invention describes the chemical intermediates used in the preparation and synthesis methods of compounds for treating gout or hyperuricemia.

Description

Preparation of compounds for the treatment of gout or hyperuricemia Hyperuricemia is caused by excessive production or insufficient secretion of uric acid and is considered a contributing factor to several diseases that significantly impair quality of life. For example, hyperuricemia is considered a contributing factor to the most common form of gouty arthritis, characterized by severe joint pain and tenderness caused by the accumulation of urate crystals. Identifying unmet medical needs regarding the effectiveness and reduced toxicity of gout / hyperuricemia medications in lowering serum uric acid (sUA) indicates a potentially beneficial effect on patients. This article describes a method for synthesizing 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- d 4) Methyl ketone (compound 1) or a pharmaceutically acceptable salt thereof. In one state, it is a sample for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7- d 4) Method for producing methyl ketone (compound 1): (Compound 1), the method comprises making a compound having the following structure: It is contacted 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, dimethyl sulfoxide, N-methyl-2-pyrrolidone, acetic acid, and combinations thereof. In some embodiments, the solvent is selected from methanol. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7- d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: Contact 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)Cl 2. PdCl 2. Pd(OAc) 2. Pd(Ph) 3P) 4. Pd 2(dba) 3 and Pd / C. In some embodiments, the palladium catalyst is Pd(dppf)Cl. 2. In some embodiments, the coordination system is selected from Ph 3P, BINAP, DPEphos, S-Phos, Xantphos, dtbpf, Mephos. In some embodiments, the solvent is selected from dimethyl sulfoxide, dimethylformamide, N-methyl-2-pyrrolidone, acetone, acetonitrile, cyclobutane, tetrahydrofuran, and toluene. In some embodiments, the solvent is dimethyl sulfoxide. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: With compounds having the following structures: Potassium phosphate is contacted in the presence of a solvent, followed by contact with 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 the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: Contact with sodium bicarbonate, potassium bromide, (2,2,6,6-tetramethylpiperidin-1-yl)oxide (TEMPO), and sodium hypochlorite. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: With compounds having the following structures: The base is contacted 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, dimethyl alkylene, and toluene. In some embodiments, the solvent is tetrahydrofuran. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: Contact 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 dimethylpyridine. In some embodiments, the base is pyridine. In some embodiments, the solvent is selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone. In some embodiments, the solvent is dichloromethane. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: Contact 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, dimethyl sulfoxide, and N-methyl-2-pyrrolidone. In some embodiments, the solvent is acetonitrile. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: Contact with sodium nitrite, potassium iodide, and toluenesulfonic acid. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: Contact with 10% platinum / carbon and deuterium oxide. This article further reveals a method for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7- d 4) A method for producing methyl ketone (compound 1), comprising: A) reacting a compound having the following structure: Reacts with 10% platinum / carbon and deuterium oxide to produce a compound having the following structure: B) Subsequently, the compound having the following structure is made: Reacts with sodium nitrite, potassium iodide, and toluenesulfonic acid to produce compounds with the following structures: C) To make the compound having the following structure: Reacts with 4-methoxybenzyl chloride and potassium carbonate to produce a compound having the following structure: D) To make the compound have the following structure: Reacts with benzoyl chloride and pyridine to produce compounds having the following structures: E) Subsequently, the compound having the following structure is made: Reaction with lithium diisopropylamide yields a compound having the following structure: F) Subsequently, the compound having the following structure is made: Reacts with sodium bicarbonate, potassium bromide, (2,2,6,6-tetramethylpiperidin-1-yl)oxide (TEMPO), and sodium hypochlorite to produce compounds having the following structures: G) Subsequently, the compound having the following structure is made: It reacts with potassium phosphate, followed by contact with trifluoroacetic acid to produce a compound having the following structure: H) Subsequently, the compound having the following structure was subjected to: With potassium carbonate and Pd(dppf)Cl 2. The reaction produces a compound having the following structure: I) Subsequently, the compound having the following structure is made: Reacts with cesium carbonate to produce compounds having the following structure: (Compound 1). This article further reveals a compound having a structure selected from the following: Or a medically acceptable salt thereof. References are included. All publications, patents and patent applications mentioned in this specification are incorporated herein by reference as if specifically and individually indicated that each individual publication, patent or patent application is incorporated by reference. Cross-reference This application claims the benefits of PCT / CN2021 / 143104, filed on December 30, 2021, which is incorporated herein by reference in its entirety. Large-scale manufacturing of clinically applicable drug candidates typically requires good operating practices. This article provides information on the manufacture of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7- d 4) Certain processes and methods for the preparation of methyl ketone (compound 1) or its pharmaceutically acceptable salts or eutectics. definition Unless otherwise stated, the following terms shall have the meanings specified below as used in the specification and the accompanying claims. Unless the context clearly requires otherwise, as used herein and in the claims of the appended patent application, the singular forms “a,” “an,” and “the” include a plurality of indicators. Thus, for example, reference to “a reagent” includes a plurality of such reagents, and reference to “the cell” includes reference to one or more cells (or a plurality of cells) and their equivalents. When the scope used herein refers to physical properties such as molecular weight or chemical properties such as chemical formula, it is intended to include all combinations and sub-combinations of the scope and specific embodiments herein. The term "approximately" when referring to a number or range of numbers means that the number or range of numbers mentioned is an approximation within experimental variability (or within statistical experimental error), and therefore the number or range of numbers varies between 1% and 15% of the stated number or range of numbers. The term "comprising" (and related terms such as "comprise / comprises" or "having" or "including") is not intended to exclude the following: in some other embodiments, such as any material composition, composition, method or process described herein or similar embodiments, "consist of" or "consist substantially of" the described features. The terms "individual" or "patient" encompass both mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammal class: humans, non-human primates such as chimpanzees and other ape and monkey species; livestock such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs; and the like. 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. As used herein, the terms "treatment / treating," "mitigation," or "relief" are used interchangeably. These terms refer to methods for achieving beneficial or desired outcomes, including but not limited to therapeutic and / or preventive benefits. "Therapeutic benefit" means the eradication or improvement of the underlying condition being treated. Furthermore, therapeutic benefit is achieved by eradicating or improving one or more physiological symptoms associated with the underlying condition, resulting in observed improvement in a patient, even though the patient still suffers from the underlying condition. Regarding preventive benefit, the composition is administered to a patient at risk of developing a specific disease or to a patient reported to have one or more physiological symptoms of a disease, even though the disease has been diagnosed. "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. The term "pharmaceutically acceptable salt" for any of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts for the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. "Pharmaceutical-acceptable acid addition salts" refers to salts that retain the biological effectiveness and properties of the free base, are biologically or otherwise desirable, and are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. It also includes salts formed from organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkyl acids, hydroxyalkyl acids, alkyl alkanoates, aromatic acids, aliphatic 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, and similar acids. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, octanoates, sebacic acid salts, transbutenedioic acid salts, maleic acid salts, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Salts of amino acids, such as arginine, gluconates, and galacturons, are also included (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 a free base with a sufficient amount of the desired acid to produce a salt. "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological efficacy and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by the addition reaction of an inorganic or organic base with a free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed from metals or amines, such as alkali metals 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, and similar salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, and procaine. N,N-Diphenylmethylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethyldiphenylamine, N-methyl-reduced glucosamine, glucosamine, methyl-reduced glucosamine, theobromine, purine, piperidine, piperidine N-ethylpiperidine, polyamine resins and the like. See Berge et al., above. As used herein, the term "medicine combination" means a product resulting from the mixing or combination of more than one active ingredient, including both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means the simultaneous administration of the active ingredient to a patient in a single entity or dose. The term "non-fixed combination" means the simultaneous, concurrent, or sequential administration of the active ingredient to a patient in a single entity without specific intervention time constraints, wherein such administration provides an effective amount of two compounds in the patient's body. The latter also applies to mixture therapies, such as the administration of three or more active ingredients. As used herein, the term "co-administration" or similar means to encompass the administration of a selected therapeutic agent to a single patient and is intended to include treatment regimens in which the agent is administered via the same or different routes of administration or at the same or different times. The term "activator" is used in this specification to refer to any molecular species that causes activation of the specified receptor, regardless of whether the species itself binds to the receptor or whether its metabolites bind to the receptor upon local administration. Thus, an activator may be a ligand of the receptor or an activator that can be metabolized into a ligand of the receptor, i.e., a metabolite formed in the tissue and which is the actual ligand. As used in this article, "antagonist" refers to a small molecule drug that binds to a nuclear hormone receptor and subsequently reduces the transcriptional activity induced by agonists of the nuclear hormone receptor. As used in this article, "activator" refers to a small molecule drug that binds to a nuclear hormone receptor and subsequently increases the transcriptional activity of the nuclear hormone receptor in the absence of a known activator. As used in this article, "reverse agonist" refers to a small molecule that binds to a nuclear hormone receptor and subsequently reduces the baseline level of transcriptional activity of the existing nuclear hormone receptor in the absence of a known agonist. As used herein, the term "regulation" means, directly or indirectly, interacting with a target protein to alter its activity, and by way of example only, includes inhibiting or limiting or reducing the activity of the target protein. As used herein, the term "modifier" refers to a compound that alters the activity of a target. For example, a modifier may cause an increase or decrease in the amount of a target activity compared to the amount of activity in the absence of a modifier. In some embodiments, the modifier is an inhibitor that reduces the amount of one or more of the target activities. In some embodiments, the inhibitor completely inhibits one or more of the target activities. compound In some embodiments, the compound used to treat gout or hyperuricemia as described herein is (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7- d 4) Methyl ketone (compound 1) or a pharmaceutically acceptable salt or cocrystal thereof. Compound 1 has the following structure: . In some embodiments, the initial substance used to synthesize compound 1 is In some embodiments, the intermediate in the synthesis of compound 1 is... In some embodiments, the intermediate in the synthesis of compound 1 is... In some embodiments, the starting material in the synthesis of compound 1 is... In some embodiments, the intermediate in the synthesis of compound 1 is... In some embodiments, the starting material in the synthesis of compound 1 is... In some embodiments, the intermediate in the synthesis of compound 1 is... In some embodiments, the intermediate in the synthesis of compound 1 is... In some embodiments, the intermediate in the synthesis of compound 1 is... In some embodiments, the intermediate in the synthesis of compound 1 is... In some embodiments, the intermediate in the synthesis of compound 1 is... In some embodiments, the intermediate in the synthesis of compound 1 is... In some embodiments, the intermediate in the synthesis of compound 1 is... In some embodiments, the intermediate in the synthesis of compound 1 is... In some embodiments, the intermediate in the synthesis of compound 1 is... In some embodiments, the intermediate in the synthesis of compound 1 is... In some embodiments, the intermediate in the synthesis of compound 1 is... . Other forms of compounds In some cases, the compounds described herein may exist as non-mirror image isomers, mirror image isomers, or other stereoisomers. The compounds presented herein include all non-mirror image isomers, mirror image isomers, and epiisomers, as well as suitable mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming non-mirror image isomers and by recrystallization or chromatography, or any combination thereof (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981, the contents of which are incorporated herein by reference). Stereoisomers may also be obtained by stereoselective synthesis. In some cases, compounds may exist as tautomers. All tautomers are included in the formulas described herein. Medically acceptable salt In some embodiments, the compounds described herein are present in their pharmaceutically acceptable salt form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering a pharmaceutically acceptable salt. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salt in the form of a pharmaceutical composition. In some embodiments, the compounds described herein have acidic or basic groups and thus react with a variety of inorganic or organic bases and any of inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, such salts are prepared in situ during the final isolation and purification of the compounds of the invention, or by reacting the purified compound in its free form with a suitable acid or base alone, and isolating the salts thus formed. In some embodiments, pharmaceutically acceptable salts of Compound 1 are acetates, benzoates, benzenesulfonates, hydrogen tartrates, carbonates, citrates, fumarates, gluconates, hydrobroms, hydrochlorides, maleates, methanesulfonates, nitrates, phosphates, salicylates, succinates, sulfates, or tartrates. In some embodiments, pharmaceutically acceptable salts of Compound 1 are monohydrochlorides. In other embodiments, pharmaceutically acceptable salts of Compound 1 are monohydrochlorides. solvates In some embodiments, the compounds described herein are present in the form of solvates. The present invention provides a method for treating a disease by administering such solvates. The present invention further provides a method for treating a disease by administering such solvates in the form of a pharmaceutical composition. The solvates contain stoichiometric or non-stoichiometric solvents and, in some embodiments, are formed during a crystallization process with a pharmaceutically acceptable solvent such as water, ethanol, and the like. When the solvent is water, a hydrate is formed; when the solvent is an alcohol, an alcoholic compound is formed. The solvates of the compounds described herein are preferably prepared or formed during the processes described herein. By way of example only, the hydrates of the compounds described herein are preferably prepared by recrystallization from an aqueous / organic solvent mixture using an organic solvent, including but not limited to dialkyl, tetrahydrofuran, or methanol. Furthermore, the compounds provided herein exist in both non-solvated and solvated forms. Generally, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the non-solvated form. Labeled compounds 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 in the form of a pharmaceutical composition. Therefore, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are the same as those listed herein, except that one or more atoms have undergone atomic substitutions with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively such as 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Compounds described herein containing the aforementioned isotopes and / or other isotopes of other atoms, and their pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives, are within the scope of this invention. Certain isotopically labeled compounds (e.g., those containing, but not limited to, other isotopes such as...) 3 H and 14 Compounds containing radioactive isotopes of C are suitable for the analysis of drug and / or substrate tissue distribution. Tritization (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, isotopes such as deuterium (i.e., 2 Heavy isotope substitution of deuterium (H) produces certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirement. Compared to compound 1 with naturally occurring deuterium, the increased deuterium content contributes to detectable kinetic isotope effects (KIEs) that can influence the pharmacokinetic, pharmacological, and / or toxicological parameters of compound 1. In some embodiments, the isotopically labeled compound or its pharmaceutically acceptable salt is prepared by any suitable method. In some embodiments, at least one hydrogen atom in compound 1 is replaced with deuterium. In some embodiments, the compounds described herein are labeled in other ways, including but not limited to using chromophores or fluorescent portions, bioluminescent labeling, or chemiluminescent labeling. Methods for preparation In some embodiments, the compounds described herein are synthesized using methods described in the chemical literature, or by a combination thereof. Furthermore, the solvents, temperatures, and other reaction conditions presented herein may vary. In other embodiments, the starting materials and reagents used to synthesize the compounds described herein are synthetic or derived from commercial sources, such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals) and Acros Organics. In other embodiments, the compounds described herein and other related compounds with different substituents are synthesized using the techniques and materials described herein and other techniques and materials recognized in the art, such as those described in the following: 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 Supplements (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*, 4th Edition (Wiley 1992); Carey and Sundberg's *Advanced Organic Chemistry*, 4th Edition, Volumes A and B (Plenum 2000, 2001); and Green and Wuts' *Protective Groups in Organic Synthesis*. 3rd edition, (Wiley 1999) (All disclosures herein are incorporated herein by reference). The general methods for preparing compounds disclosed herein may be derived from reactions, and these reactions may be modified by using appropriate reagents and conditions to incorporate various parts found in the formulas provided herein. In some embodiments, a method for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7- d 4) Method for producing methyl ketone (compound 1): This method involves making a compound having the following structure: It is contacted 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, dimethyl sulfoxide, 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 dimethyl sulfoxide. In some embodiments, the solvent is N-methyl-2-pyrrolidone. In some embodiments, the solvent is acetic acid. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising preparing a compound having the following structure: Contact 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 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 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 palladium catalyst is selected from Pd(dppf)Cl. 2. PdCl 2. Pd(OAc) 2. Pd(Ph) 3P) 4. Pd 2(dba) 3 and Pd / C. In some embodiments, the palladium catalyst is Pd(dppf)Cl. 2. In some embodiments, the palladium catalyst is PdCl. 2. In some embodiments, the palladium catalyst is Pd(OAc). 2. In some embodiments, the palladium catalyst is Pd(Ph 3P) 4. In some embodiments, the palladium catalyst is Pd. 2(dba) 3. In some embodiments, the palladium catalyst is Pd / C. In some embodiments, the coordination system is selected from Ph 3P, BINAP, DPEphos, S-Phos, Xantphos, dtbpf, and Mephos. In some embodiments, the ligand is Ph 3P. 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 dimethyl sulfoxide, dimethylformamide, N-methyl-2-pyrrolidone, acetone, acetonitrile, cyclobutane, tetrahydrofuran, and toluene. In some embodiments, the solvent is dimethyl sulfoxide. 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 cyclobutane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is toluene. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: Contact 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)Cl. 2. PdCl 2. Pd(OAc) 2. Pd(Ph) 3P) 4. Pd 2(dba) 3 and Pd / C. In some embodiments, the palladium catalyst is Pd(dppf)Cl. 2. In some embodiments, the palladium catalyst is PdCl. 2. In some embodiments, the palladium catalyst is Pd(OAc). 2. In some embodiments, the palladium catalyst is Pd(Ph 3P) 4. In some embodiments, the palladium catalyst is Pd. 2(dba) 3. In some embodiments, the palladium catalyst is Pd / C. In some embodiments, the coordination system is selected from Ph 3P, BINAP, DPEphos, S-Phos, Xantphos, dtbpf, and Mephos. In some embodiments, the ligand is Ph 3P. 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 dimethyl sulfoxide, dimethylformamide, N-methyl-2-pyrrolidone, acetone, acetonitrile, cyclobutane, tetrahydrofuran, and toluene. In some embodiments, the solvent is dimethyl sulfoxide. 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 cyclobutane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is toluene. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: With compounds having the following structures: Potassium phosphate is contacted in the presence of a solvent, followed by contact with 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. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: With compounds having the following structures: The solvent is contacted with 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. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: Contact with sodium bicarbonate, potassium bromide, (2,2,6,6-tetramethylpiperidin-1-yl)oxide (TEMPO), and sodium hypochlorite. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: Contact under Swern oxidation conditions. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: With MnO 2. Contact. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: Contact with sodium bicarbonate, potassium bromide, (2,2,6,6-tetramethylpiperidin-1-yl)oxide (TEMPO), and sodium hypochlorite. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: Contact under Sven oxidation conditions. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: With MnO 2. Contact. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: With compounds having the following structures: The base is contacted 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, dimethyl alkylene, and toluene. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is 2-methyltetrahydrofuran. In some embodiments, the solvent is dimethyl alkylene. In some embodiments, the solvent is toluene. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: With compounds having the following structures: The base is contacted 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, dimethyl alkylene, and toluene. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is 2-methyltetrahydrofuran. In some embodiments, the solvent is dimethyl alkylene. In some embodiments, the solvent is toluene. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: Contact 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 dimethylpyridine. 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 dimethylpyridine. In some embodiments, the solvent is selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, 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 dimethyl sulfoxide. In some embodiments, the solvent is N-methyl-2-pyrrolidone. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: Contact 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, dimethyl sulfoxide, 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 dimethyl sulfoxide. In some embodiments, the solvent is N-methyl-2-pyrrolidone. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: Contact 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, dimethyl sulfoxide, 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 dimethyl sulfoxide. In some embodiments, the solvent is N-methyl-2-pyrrolidone. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: Contact with sodium nitrite, potassium iodide, and toluenesulfonic acid. In the preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) In some embodiments of the method for producing methyl ketone (compound 1), the compound having the following structure: It is prepared by a method comprising making a compound having the following structure: Contact with 10% platinum / carbon and deuterium oxide. This article further reveals a method for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) A method for producing methyl ketone (compound 1), comprising: A) reacting a compound having the following structure: Reacts with 10% platinum / carbon and deuterium oxide to produce a compound having the following structure: B) Subsequently, the compound having the following structure is made: Reacts with sodium nitrite, potassium iodide, and toluenesulfonic acid to produce compounds with the following structures: C) To make the compound having the following structure: Reacts with 4-methoxybenzyl chloride and potassium carbonate to produce a compound having the following structure: D) To make the compound have the following structure: Reacts with benzoyl chloride and pyridine to produce compounds having the following structures: E) Subsequently, the compound having the following structure is made: Reaction with lithium diisopropylamide yields a compound having the following structure: F) Subsequently, the compound having the following structure is made: Reacts with sodium bicarbonate, potassium bromide, (2,2,6,6-tetramethylpiperidin-1-yl)oxide (TEMPO), and sodium hypochlorite to produce compounds having the following structures: G) Subsequently, the compound having the following structure is made: It reacts with potassium phosphate, followed by contact with trifluoroacetic acid to produce a compound having the following structure: H) Subsequently, the compound having the following structure was subjected to: With potassium carbonate and Pd(dppf)Cl 2. The reaction produces a compound having the following structure: I) Subsequently, the compound having the following structure is made: Reacts with cesium carbonate to produce compounds having the following structure: (Compound 1). This article further reveals a method for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4) A method for producing methyl ketone (compound 1), comprising: A) reacting a compound having the following structure: Reacts with 10% platinum / carbon and deuterium oxide to produce a compound having the following structure: B) Subsequently, the compound having the following structure is made: Reacts with sodium nitrite, potassium iodide, and toluenesulfonic acid to produce compounds with the following structures: C) To make the compound having the following structure: It reacts with benzoyl chloride and potassium carbonate to produce a compound having the following structure: D) To make the compound have the following structure: Reacts with benzoyl chloride and pyridine to produce compounds having the following structures: E) Subsequently, the compound having the following structure is made: Reaction with lithium diisopropylamide yields a compound having the following structure: F) Subsequently, the compound having the following structure was subjected to: Reacts with sodium bicarbonate, potassium bromide, (2,2,6,6-tetramethylpiperidin-1-yl)oxide (TEMPO), and sodium hypochlorite to produce compounds having the following structures: G) Subsequently, the compound having the following structure is made: Reacts with potassium phosphate to produce a compound having the following structure: H) Subsequently, the compound having the following structure was subjected to: With triethylamine and Pd(dppf)Cl 2. The reaction produces a compound having the following structure: I) Subsequently, the compound having the following structure is made: Reacts with cesium carbonate to produce compounds having the following structure: (Compound 1). Pharmaceutical Compositions and Administration Methods The administration of compound 1 described herein may take any pharmacological form, including therapeutically effective amounts of compound 1 alone or in combination with a pharmaceutically acceptable carrier. Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers (including excipients and adjuvants) that facilitate the processing of the active compound into a pharmaceutically usable formulation. Appropriate formulations depend on the chosen route of administration. Additional details regarding suitable excipients for the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th edition (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, 7th edition (Lippincott Williams & Wilkins 1999), all of which are incorporated herein by reference. 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. The pharmaceutical composition facilitates the administration of the compound to a living organism. When performing the treatment or method of use provided herein, a therapeutically effective amount of the compound described herein is administered in the pharmaceutical composition to a mammal suffering from the disease, condition, or illness to be treated. In some embodiments, the mammal is a human. The therapeutically effective amount can vary considerably depending on the severity of the disease, the individual's age and relative health status, 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 components of a mixture (such as in combination therapy). The pharmaceutical formulations described herein can be administered to individuals via a variety of routes of administration, including but not limited to oral, non-enteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration. Furthermore, the pharmaceutical compositions described herein, including compound 1, 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, instantaneous formulations, foaming formulations, lyophilized formulations, tablets, powders, pills, sugar-coated pills, capsules, delayed-release formulations, extended-release formulations, pulsatile-release formulations, multi-particle formulations, and mixtures of immediate-release and controlled-release formulations. In some embodiments, compound 1 is formulated as a tablet. In some embodiments, compound 1 is formulated as a capsule. In some embodiments, compound 1 is formulated as a suspension. 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 for reconstitution into a suspension. Pharmaceutical compositions including the compounds described herein can be manufactured in known ways, such as (by way of example only) by means of known mixing, dissolving, granulating, making sugar-coated pills, water milling, emulsifying, encapsulating, coating or compressing processes. The dosage is repeated based on the pharmacokinetic parameters of the visible dose formulation and the route of administration. For ease of administration and uniform dosage, unit dosage forms are particularly advantageous for preparing compositions. As used herein, a unit dosage form refers to a physically discrete unit suitable as a unit dose for a mammalian individual to be treated; each unit contains a predetermined amount of active compound, calculated to produce the desired therapeutic effect, associated with the desired pharmaceutical carrier. The specifications of the unit dosage form are determined by and directly depend on: (a) the unique characteristics of Compound 1 and the specific therapeutic effect to be achieved, and (b) the inherent limitations in the techniques for mixing this active compound for individual sensitivities. A specific dose can be easily calculated by someone generally skilled in the art, for example, based on the patient's approximate weight, body surface area, or volume of body space to be occupied. The dose will also be calculated depending on the chosen route of administration. Further modifications to the calculations necessary to determine the appropriate dose for treatment are typically made by someone skilled in the art. Accurate doses are determined in conjunction with standard dose-response studies. It should be understood that the actual amount of the composition administered will be determined by the physician based on relevant circumstances, including one or more conditions to be treated, the choice of the composition to be administered, the individual patient's age, weight and response, the severity of the patient's symptoms, and the chosen route of administration. Example All chemicals, reagents and solvents were purchased from commercial sources (where available) and used without further purification. Example 1 : synthesis (3,5- dibromo -4- Hydroxyphenyl )(2-(1- Hydroxyethyl ) Benzofuran -3- base -4,5,6,7- d 4) Methyl ketone ( compound 1) Step A process description: 1) In N 2nd General 1) Place AR01-1 (712 g, 1.0 eq.) and DCM (4300 mL) into a flask. 2) Cool to 0-10℃. 3) Incubate at 0-10℃... 4) Add AR01-2 (1570 g, 1.1 eq.) dropwise to the mixture. 5) Stir the mixture at 0-10℃ for 0.5 h. 6) Increase the temperature to 15-25℃. 7) Stir the mixture at 15-25℃ for 1 h. 8) Pour the reaction solution into ice water. 9) Slowly add HCl dropwise to the mixture while stirring. 10) Use NaHCO3. 3. Perform liquid separation and organic phase washing 10) with Na 2SO 4. Drying 11) Concentration under reduced pressure 12) Reduced pressure distillation to obtain a white solid AR01-3 (1595 g, 90.1%). 1 H NMR (400 MHz, DMSO) δ 7.98 (d, J = 7.8 Hz, 2H), 7.70 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.6 Hz, 2H), 5.73 - 5.53 (m, 1H), 3.61 (d, J = 1.6 Hz, 1H), 1.57 (d, J = 6.7 Hz, 3H). Step B process description: 1) Under N2, AR01-4 (2000 g, 1.0 eq.), K 2CO 3 (1185 g, 1.5 eq.), CH 1) Pour 3CN (13 L) into a 20 L flask. 2) Stir the mixture at 20-30℃ for 0.5 h. 3) ... 4) Add AR01-5 (1296 g, 1.5 eq.) dropwise to the mixture. 5) Add NaI to the flask. 6) Heat to 58-68℃. 7) Stir the mixture at 55-65℃ for 5 h. 8) Filter. 9) Concentrate the mixture under vacuum to obtain... AR01-69) Recrystallization yields a white solid. AR01-6 (1670 g, 77.3%). 1 H NMR (400 MHz, DMSO) δ 9.92 (s, 1H), 8.20 (s, 2H), 7.50 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 5.03 (s, 2H), 3.79 (s, 3H). Step C process description: 1) Under N2, 1) Add AR01-3 (727 g, 1.0 eq.) and THF (10 L) to a flask. 2) Cool to -70 to -60°C. 3) Add LDA (2.5 L) dropwise to the mixture. 4) Stir the mixture at -70 to -60°C for 30 min. 5) In N... 2. At -70→-60℃ 6) Add AR01-6 (1670 g, 1.0 eq.) and THF (3.4 L) to the mixture. 7) Stir the mixture at -70 to -60°C for 1.5 h. 8) Add AcOH (601 g) and NH4Cl aqueous solution. 9) Separate the aqueous layer. 2SO 4. Drying 10. Concentrating under reduced pressure 11. Purifying by column chromatography to obtain a yellow solid AR01-7 (4.1 kg, 65%). 1H NMR (400 MHz, DMSO) δ 7.99 (d, J = 7.4 Hz, 2H), 7.71 (s, 2H), 7.68 (d, J = 7.4 Hz, 1H), 7.55 (t, J = 7.4 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 6.97 (d, J = 7.9 Hz, 2H), 6.33 (s, 1H), 5.71 (d, J = 6.8 Hz, 1H), 4.89 (s, 2H), 3.77 (s, 3H), 1.59 (d, J = 6.5 Hz, 3H). Step D process description: 1) To AR01-7 (4100 g), DCM (24.6 mL), H 2O (16.4 L), KBr (85 g), NaHCO 3) Pour 600 g into a flask. 2) Cool to 0-5℃. 3) At 3℃, add Tempo (56 g) to the mixture. 4) Add NaOCl aqueous solution (7250 g) dropwise to the mixture at 0-5℃. 5) Separate the liquids. 6) Extract the aqueous phase with DCM. 7) Use saturated Na... 2S 2O 3. Aqueous solution and water washing of the organic layer 8) Na 2SO 4. Dry and concentrate under reduced pressure to obtain crude product. AR01-SM1. 9) From CH 3CN recrystallization yields a white solid. AR01-SM1 (2.5 kg, 61.2%). 1 H NMR (400 MHz, DMSO) δ 8.23 ​​(s, 2H), 8.08-8.02 (m, 2H), 7.72 (t, J=7.4Hz, 1H), 7.59 (t, J = 7.7 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.6Hz, 2H), 5.94 (q, J = 6.8 Hz, 1H), 5.02 (s, 2H), 3.78 (s, 3H), 1.74 (d, J = 6.8 Hz, 3H). Step E process description: 1) Add to a 2000 mL flask AR01-8 (30 g, 1.0 eq.), D 2O (600 mL) and 10% Pt / C (3 g) 2) with N 2. Degas the flask three times, and then use H... 2. Degas three times. 3. Heat the mixture to 120°C and stir at 120°C for 48 h. 4. Cool the mixture to 25-35°C and add EA (600 mL). 5. Filter and wash the liner with EA (60 mL). 6. Separate the two phases and extract the aqueous layer twice with EA (300 mL). 7. Concentrate the combined organic layers to 2-3 V under vacuum at 40-45°C. 8. Concentrate the mixture until no distillate is produced under vacuum at 40-45°C. 9. D 2O (600 mL) was added to the residue. 10) 10% Pt / C (3 g) was added and N was used. 2. Degas the flask three times, and then use H... 2. Degas three times. 11) Heat the mixture to 120°C and stir at 120°C for 24 h. 12) Cool the mixture to 25-35°C and add EA (600 mL). 13) Filter and wash the liner with EA (60 mL). 14) Separate the two phases and extract the aqueous layer twice with EA (300 mL). 15) Concentrate the combined organic layers to 2-3 V under vacuum at 40-45°C. 16) Adjust the temperature to 30-40°C and slowly add n-heptane (240 mL, 8 V). 17) Slowly cool the mixture to 0-5°C and stir at 0-5°C for 0.5-1 h. 18) Dry the moist product under vacuum at 40-45°C. 19) Obtain a bronze-colored solid. AR01-9 (25 g, 83.0% yield). 1 H NMR (400 MHz, DMSO) δ 9.36 (s, 1H), 6.74 (t, 1H), 6.72 (t, 1H), 6.62 (d, 1H), 6.60 (d, 1H). Step F process description: 1) Add to a 5000 mL flask AR01-9 (100.0 g, 1.0 eq.) and ACN (1000 mL), H2O (600 mL) were added. 2) TsOH (3.0 eq.) was added to the mixture and stirred for 0.5 h. 3) The mixture was cooled to 0-5℃ and then slowly added with NaNO3. 2(1.3 eq.) of H 4) Stir the mixture at 0-5℃ for 0.5-1 h. 5) Adjust the temperature to -5-0℃ and slowly add H containing KI (2.0 eq.) over 30 min. 6) Adjust the temperature to 0-30℃ and stir the mixture for 8-10 h. 7) Add saturated Na. 2SO 3) Stir the mixture in an aqueous solution at 0-15°C for 1 h. 8) Separate the mixture and extract it twice with EA (1000 mL). 9) Wash the organic layer with saturated NaCl solution (500 mL). 10) Filter the organic layer through a silica-lined filter. 11) Concentrate the combined organic layers to 2-3 V under vacuum at 35-45°C. 12) Add n-heptane (500 mL) to the mixture. 13) Concentrate the mixture to 2-3 V under vacuum at 35-45°C. 14) Add n-heptane (500 mL) to the mixture. 15) Slowly cool the mixture to -10-0°C and stir at -10-0°C for 0.5-1 h. 16) Filter and wash the wet filter cake with cooled n-heptane (1-2 V). 17) Dry the wet product under vacuum at 25-30°C. 18) Obtain the product. AR01-SM2 (110 g, 55.6% yield). 1 H NMR (400 MHz, DMSO) δ 10.26 (s, 1H), 7.66 (s, 1H), 7.19 (s, 1H), 6.89 (s, 1H), 6.59 (s, 1H). Step 1 process description: 1) Add to a 1 L three-necked flask AR01-SM1 (25.75 g, 1.0 eq.), potassium phosphate (4.8 g, 1.0 eq.), DCM (460 ml, 18 V) 2) AR01-SM2 (10.0 g, 1.0 eq.) and DCM (50 ml, 2 V) were added to a 100 ml constant pressure dropping funnel, and the internal temperature was lowered to 5 to 10 °C using a nitrogen protection system 3), and the mixture was added dropwise. 4) After the AR01-SM2 DCM solution temperature drops, maintain the internal temperature at 5 to 10°C and react for 2 hours. 5) Add TFA (25.65 g, 5.0 eq.) dropwise to the reaction solution to raise the internal temperature to 25 to 30°C and react for 2 hours. 6) Add NaHCO3... 3. Aqueous solution was slowly added dropwise to the reaction solution to adjust the pH to 7-8. Water (125 mL, 5 V) was added, and stirring was continued for 30 min. The layers were separated, and the aqueous phase was extracted with DCM (50 mL, 2 V). The organic phases were combined and washed four times with 125 mL of water. The mixture was dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure at 40 °C. Toluene (75 mL, 3 V) and n-heptane (26 mL, 1 V) crystals were added, and the mixture was stirred at room temperature for 2 h. After cooling to 0-5 °C, the mixture was filtered. The filter cake was washed once with toluene:n-heptane = 5:1 (2 V), and the solid was dried to constant weight at 50 °C by blowing air in. AR01-INT-1 (25.1 g, 82.5% yield). (C) 24 H 13 D 4Br 2IO 5) [M+H] + The calculated HPLC m / z values ​​were 675.5 and 677.4, while the experimental values ​​were also 675.5 and 677.4. 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.33 - 7.86 (m, 2H), 7.77 (s, 2H), 7.67 (t, J = 7.4 Hz, 1H), 7.54 (t, J = 7.7 Hz, 2H), 6.50 (q, J = 6.6 Hz, 1H), 5.74 (s, 1H), 1.79 (d, J = 6.6 Hz, 3H). Step 2 process description: 1) To AR01-INT-1 (20.0 g, 1.0 eq.), K 2CO 3(12.3 g, 3.0 eq.), Pd(dppf)Cl 2 (1.08 g, 0.05 eq.) and DMSO (400 mL, 20 V) were added to a 1 L three-necked flask. 2) The magnetic stirrer was turned on and stirred with N2. 2 permutations three times, and N is used 2. Protection 3) Maintain the internal temperature at 90-95℃ for 3 hours. 4) Cool the reaction solution to room temperature, add EA (400 mL, 20 V), mix thoroughly, and slowly add dropwise to the HCl aqueous solution and water (200 mL, 10 V). Adjust the pH to 2-3, continue stirring for 2 hours, filter (with diatomaceous earth lining), wash the filter cake with EA (80 mL, 4 V), separate the filtrate into layers, wash the aqueous phase with EA (80 mL, 4 V), combine the organic phases, wash with 100 mL of water four times, concentrate the organic phase to dryness at 45℃ under reduced pressure, add acetone (80 mL, 4 V), filter, wash the filter cake with ice-cold acetone (20 mL, 1 V), and dry the solid to constant weight at 50℃ under reduced pressure to obtain the desired product. AR01-INT-2 (12.1 g, 74.6% yield). (C) 24 H 12 D 4Br 2O 5) [MH] - The calculated HPLC m / z values ​​were 545.5 and 547.6, while the experimental values ​​were also 545.5 and 547.6. 1 H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 7.92 (s, 2H), 7.90 - 7.86 (m, 2H), 7.65 (dd, J = 10.6, 4.3 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H), 6.17 (q, J = 6.6 Hz, 1H), 1.78 (d, J = 6.7 Hz, 3H). Step 3 process description: 1) To AR01-INT-2 (14.31 g, 1.0 eq.) and MeOH (10 V) were loaded into the reactor. 2) Cs were loaded in batches at 28±5℃. 2CO 3 (25.5 g, 3.0 eq.) 3) Stir at 28±5℃ for at least 16 h. 4) Add purified water (280 mL, 20 V) to react at 25±5℃. 5) Adjust the pH to 2-3 with 12 N HCl aqueous solution at 25±5℃ and stir for at least 1 h. 6) Filter and wash twice with purified water (28 mL, 2 V). 7) Dissolve the filter cake with EA (215 mL, 15 V). 8) Add 1 N HCl solution (70 mL, 5 V) 9) Stir for at least 1 h and separate 10) Wash the organic phase once with 20% NaCl aqueous solution (70 mL, 5 V) 11) Concentrate to 2 V-3 V under vacuum at 40±5℃ and add EA (84 mL, 6 V) 12) Concentrate to 2 V-3 V under vacuum at 40±5℃ 13) Add EA (140 mL, 10 V), add activated carbon to increase the internal temperature to 50±5℃, stir for one hour, filter and wash the filter cake with EA (28 mL, 2 V) 14) Concentrate to 2 V-3 V under vacuum at 40±5℃ 15) Add n-heptane dropwise (140 mL, 10 V) and stir at 50±5℃ for at least 2 h 16) 17) Cool to 25±5℃ and stir for at least 12 h. 18) Filter and wash twice with n-heptane (14 mL, 1 V). 19) Dry under vacuum at 50±5℃ for at least 12 h to obtain a grayish-white solid. compound 1 (8.7 g, 81% yield). (C) 17 H 8D 4Br 2O 4) [M+H] + The calculated HPLC m / z values ​​were 425.3 and 427.3, while the experimental values ​​were also 425.3 and 427.3. 1 H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 7.95 (s, 2H), 5.59 (s, 1H), 4.86 (d, J = 6.6 Hz, 1H), 1.48 (d, J = 6.6 Hz, 3H). Example 2 : Substitute Synthesis (3,5- dibromo -4- Hydroxyphenyl )(2-(1- Hydroxyethyl ) Benzofuran -3- base -4,5,6,7- d 4) Methyl ketone ( compound 1) Complete steps A, E, F, and 3 as described in Example 1. Complete steps B, C, D, 1, and 2 as described below. Step B process description: 1) In N 2nd General AR01-4-1(2000 g, 1.0 eq.), K 2CO 3 (1185 g, 1.5 eq.), CH 1) Pour 3CN (13 L) into a 20 L flask. 2) Stir the mixture at 0-10℃ for 0.5 h. 3) ... AR01-2-1 (1511.9 g, 1.5 eq.) was added dropwise to the mixture. 4) The mixture was stirred at 0-10°C for 5 h. 5) Filtered. 6) The mixture was concentrated under vacuum to obtain... AR02-6-17) Recrystallization to obtain a white solid AR02-6-1 (2199.5 g, 80%). Step C process description: 1) In N 2nd General 1) Add AR01-3-1 (727 g, 1.0 eq.) and THF (10 L) to a flask. 2) Cool to -70 to -60°C. 3) Add LDA (2.5 L) dropwise to the mixture. 4) Stir the mixture at -70 to -60°C for 30 min. 5) In N... 2. At -70→-60℃ 6) Add AR02-6-1 (1595.2 g, 1.0 eq.) and THF (3.4 L) to the mixture. 7) Stir the mixture at -70 to -60°C for 1.5 h. 8) Add AcOH (601 g) and NH4+. 8) Separation of aqueous layer using 4Cl aqueous solution 9) Through Na 2SO 4. Drying 10. Concentrating under reduced pressure 11. Purifying by column chromatography to obtain a yellow solid AR02-7-1 (1.51 kg, 65%). (C) 25 H 18 Br 2O 5) [M-17] - The calculated values ​​of LCMS (254m, t=1.86min) are 539.3 and 541.3, respectively. The experimental values ​​are also 539.3 and 541.3. Step D process description: 1) To AR02-7-1(3984.5 g), DCM (24.6 L), H 2O (16.4 L), KBr (85 g), NaHCO 3) Pour 600 g into a flask. 2) Cool to 0-5℃. 3) At 3℃, add Tempo (56 g) to the mixture. 4) Add NaOCl aqueous solution (7250 g) dropwise to the mixture at 0-5℃. 5) Separate the liquids. 6) Extract the aqueous phase with DCM. 7) Use saturated Na... 2S 2O 3. Aqueous solution and water washing of the organic layer 8) Na 2SO 4. Dry and concentrate under reduced pressure to obtain crude product. AR02-SM1-1. 9) From CH 3CN recrystallization yields a white solid. AR02-SM1-1 (3.26 kg, 82%). 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). Step 1 process description: 1) Add to a 1 L three-necked flask AR02-SM1-1 (25.75 g, 1.0 eq.), potassium phosphate (4.9 g, 0.5 eq.), DCM (460 ml, 18 V) 2) AR02-SM2-1 (10.0 g, 1.0 eq.) and DCM (50 ml, 2 V) were added to a 100 ml constant pressure dropping funnel, and the internal temperature was lowered to 5 to 10 °C using a nitrogen protection system 3), and the mixture was added dropwise. 4) After the AR02-SM2-1 DCM solution drops, maintain the internal temperature at 5 to 10°C and react for 2 hours. 5) Add NaHCO3. 3. Aqueous solution was slowly added dropwise to the reaction solution to adjust the pH to 7-8. Water (125 mL, 5 V) was added, and stirring was continued for 30 min. The layers were separated, and the aqueous phase was extracted with DCM (50 mL, 2 V). The organic phases were combined and washed four times with 125 mL of water. The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure at 40 °C until dry. Toluene (75 mL, 3 V) and n-heptane (26 mL, 1 V) crystals were added, and the mixture was stirred at room temperature for 2 h. The mixture was then 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 dried to constant weight at 50 °C by blowing air in to obtain a yellow solid. AR02-INT-1-1 (32.5 g, 91%). Step 2 process description: 1) To AR02-INT-1-1(20.0 g, 1.0 eq.), n-Pr 3N (11.3 g, 3.0 eq.), Pd(dppf)Cl 2 (1.08 g, 0.05 eq.) and DMSO (400 ml, 20 V) were added to a 1 L three-necked flask. 2) The magnetic stirrer was turned on and stirred with N2. 2 permutations three times, and N is used 2. Protection 3) Maintain the internal temperature at 100-115℃ for 3 hours. 4) Cool the reaction solution to room temperature, add EA (400 mL, 20 V), mix thoroughly, and slowly add dropwise to the HCl aqueous solution and water (200 mL, 10 V). Adjust the pH to 2-3, continue stirring for 2 hours, filter (with diatomaceous earth lining), wash the filter cake with EA (80 mL, 4 V), separate the filtrate into layers, wash the aqueous phase with EA (80 mL, 4 V), combine the organic phases, wash with 100 mL of water four times, concentrate the organic phase to dryness at 45℃ under reduced pressure, add acetone (80 mL, 4 V), filter, wash the filter cake with ice-cold acetone (20 mL, 1 V), and dry the solid to constant weight at 50℃ under reduced pressure to obtain the desired product. AR01-INT-2-1. (C 24 H 12 D 4Br 2O 5) [MH] - The calculated values ​​of LCMS (254 nm, t=3.29 min) and m / z are 545.5 and 547.5, respectively, while the experimental values ​​are also 545.5 and 547.5. 1 H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 7.92 (s, 2H), 7.88 (dd, J= 8.3, 1.2 Hz, 2H), 7.69 - 7.62 (m, 1H), 7.50 (t, J = 7.8 Hz, 2H), 6.17 (q, J = 6.7 Hz, 1H), 1.78 (d, J = 6.7 Hz, 3H). Example 3 : compound 1 and benzbromarone (Benzbromarone) With humans URAT1 In vitro interaction study of ingested transporters Uptake experiments were performed using MDCKII cells that stably expressed the human URAT1 uptake transporter. Cells were incubated at 37±1℃ in a 95:5 air:CO2 atmosphere. The cells were cultured in an atmosphere of 2 and seeded onto standard 96-well tissue culture plates at the number of cells described in Table 1. surface 1 DMEM: Dulbecco's Modified Eagle's Medium; HBSS: Hank's Balanced Salt Solution; w / o: Not available Before the experiment, remove the culture medium and rinse the cells with 100 µL of Cl-free solution. - The sample was washed twice with HBSS. The intake assay was performed at 37±1℃ in 50 µL of Cl-free solution containing the probe receptor (20 µM uric acid) and the test substance (TA) or solvent at pH 7.4. - The test was performed using HBSS. The concentration of the organic solvent was equal in all wells and did not exceed 1% (v / v). The treatment group is shown in Table 2. surface 2 After the experiment, the cells were treated with 100 µL of Cl-free solution. - The sample was washed twice with ice-cold HBSS and then cleaved with 50 µL of 0.1 M NaOH. Mass transport of the radiolabeled probe was determined by measuring equal aliquots (35 µL) of the sample used for liquid scintillation counting. Results: Both test items (compound 1 and benzbromarone) were soluble in HBSS buffer at all test concentrations; the highest test concentration was 10 µM. Compound 1 inhibited URAT1-mediated uric acid polymerization by 100% at a concentration of 10 µM, with an IC50 concentration of [missing value]. 50 = 0.067 µM. Benzbromarone inhibited URAT1-mediated uric acid aggregation by 98% at a concentration of 10 µM, with an IC50 concentration of 0.067 µM. 50 = 0.196 µM. The examples and embodiments described herein are for illustrative purposes only, and in some embodiments, various modifications or variations will be included within the scope of the invention and the appended claims.

Claims

1. A method for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4) methyl ketone (compound 1):

1. The method comprises contacting a compound having the following structure with cesium carbonate in the presence of solvent 1; wherein solvent 1 is selected from methanol, ethanol, isopropanol, butanol, water, acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, acetic acid, and combinations thereof; wherein the compound having the following structure is prepared by a method comprising contacting the compound having the following structure with a base and a palladium catalyst in the presence of solvent 2.

2. The method of claim 1, wherein 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.

3. The method of claim 1, wherein the palladium catalyst is selected from Pd(dppf)Cl2, PdCl2, Pd(OAc)2, Pd(Ph3P)4, Pd2(dba)3 and Pd / C.

4. The method of claim 1, wherein the coordination system is selected from Ph3P, BINAP, DPEphos, S-Phos, Xantphos, dtbpf and Mephos.

5. The method of claim 1, wherein the solvent 2 is selected from dimethyl sulfoxide, dimethylformamide, N-methyl-2-pyrrolidone, acetone, acetonitrile, cyclobutane, tetrahydrofuran and toluene.

6. The method of claim 1, wherein the compound having the following structure is prepared by a method comprising contacting the compound having the following structure with a compound having the following structure and potassium phosphate in the presence of a solvent, followed by contacting with trifluoroacetic acid.

7. The method of claim 6, wherein the solvent is selected from dichloromethane, chloroform, acetonitrile, toluene, ethyl acetate and tetrahydrofuran.

8. The method of claim 6, wherein the compound having the following structure is prepared by a method comprising contacting the compound having the following structure with sodium bicarbonate, potassium bromide, (2,2,6,6-tetramethylpiperidin-1-yl)oxide (TEMPO) and sodium hypochlorite.

9. The method of claim 8, wherein the compound having the following structure is prepared by a method comprising contacting the compound having the following structure with a compound having the following structure and a base in the presence of a solvent.

10. The method of claim 9, wherein the base system is selected from lithium diisopropylamide, LiHMDS, NaHMDS, KHMDS, t-BuOK, t-BuONa, t-BuOLi and NaH.

11. The method of claim 9, wherein the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, diane and toluene.

12. The method of claim 9, wherein the compound having the following structure is prepared by a method comprising contacting the compound having the following structure with benzoyl chloride and a base in the presence of a solvent.

13. The method of claim 12, wherein 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 dimethylpyridine.

14. The method of claim 12, wherein the solvent is selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone.

15. The method of claim 9, wherein the compound having the following structure is prepared by a method comprising contacting the compound having the following structure with 4-methoxybenzyl chloride and a base in the presence of a solvent.

16. The method of claim 15, wherein the base is selected from potassium carbonate, sodium hydride, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine and pyridine.

17. The method of claim 15, wherein the solvent is selected from acetonitrile, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone.

18. The method of claim 6, wherein the compound having the following structure is prepared by a method comprising contacting the compound having the following structure with sodium nitrite, potassium iodide and toluenesulfonic acid.

19. The method of claim 18, wherein the compound having the following structure is prepared by a method comprising contacting the compound having the following structure with 10% platinum / carbon and deuterium oxide.

20. A method for preparing (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4) methyl ketone (compound 1), comprising: A) reacting a compound having the following structure with 10% platinum / carbon and deuterium oxide to produce a compound having the following structure: 20.B) The compound having the following structure is then reacted with sodium nitrite, potassium iodide, and toluenesulfonic acid to produce a compound having the following structure: 20.C) Reacting a compound having the following structure with 4-methoxybenzyl chloride and potassium carbonate to produce a compound having the following structure: 20.D) React the compound having the following structure with benzoyl chloride and pyridine to produce a compound having the following structure: 20.E) The compound having the following structure is then reacted with lithium diisopropylamide to produce a compound having the following structure: 20.F) The compound having the following structure is then reacted with sodium bicarbonate, potassium bromide, (2,2,6,6-tetramethylpiperidin-1-yl)oxide (TEMPO), and sodium hypochlorite to produce a compound having the following structure: 20.G) The compound having the following structure is then reacted with potassium phosphate, followed by contact with trifluoroacetic acid to produce a compound having the following structure: 20.H) Subsequently, the compound having the following structure is reacted with potassium carbonate and Pd(dppf)Cl2 to produce a compound having the following structure: 20.I) The compound having the following structure is then reacted with cesium carbonate to produce a compound having the following structure:

21. A compound having a structure selected from the following:

21. and; or its medically acceptable salt.