Pharmaceutical material, medicinal preparation and pharmaceutical composition that contain bempedoic acid

Abstract

To provide a pharmaceutical material that can be used for lowering low-density lipid cholesterol, treating primary hyperlipidemia, or preventing myocardial infarction.SOLUTION: A pharmaceutical material contains a crystalline form of a compound of formula (V) or a pharmaceutically acceptable salt thereof, where the content of the compound of formula (V) or pharmaceutically acceptable salt thereof is more than 98 wt.% based on the total weight of the pharmaceutical material.SELECTED DRAWING: None

Description

[Technical field]

[0001] cross reference This application is a continuation of U.S. patent application Ser. No. 62 / 864,873, filed June 21, 2019. No. 6,313,636, filed on Oct. 23, 2006, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] A robust, cost-effective and efficient method for producing pharma- ceutical active compounds in desired yields and purities. Development of an efficient production method for bempedoic acid (8-hydroxy- 2,2,14,14-tetramethylpentadecanedioic acid) is a multipotent steroid that can cause liver damage and cardiovascular disease. It is a compound that is being developed for the treatment of a variety of diseases. Process for synthesizing 2,2,14,14-tetramethylpentadecanedioic acid It is desirable to have a product that meets the requirements of regulatory agencies for the manufacture of commercial drug products. It has the required purity and impurity profile. Summary of the Invention

[0003] The present inventors have developed a method for efficiently producing high-purity bempedoic acid and a method for using bempedoic acid as a pharmaceutical ingredient. A highly pure and stable form of bempedoic acid suitable for use has been found. In one aspect, the present invention provides a method for preparing a compound of formula (V) or a pharma- ceutically acceptable salt thereof. This provides a method for The compound of formula (V) or a pharma- ceutically acceptable salt thereof may be of high purity. Thus, in certain embodiments, the present invention provides a compound of formula (V) or a pharma- ceutically acceptable salt thereof. The present invention provides a method for producing a pharmaceutical material comprising an acceptable salt of the pharmaceutical material, wherein the pharmaceutical material is More than 99.0% by weight of the compound of formula (V) or a pharma- ceutically acceptable salt thereof It contains salts that are

[0004] In various embodiments of the invention, the method generally comprises: (a) contacting ethyl isobutyrate with a substituted 5-chloropentane in the presence of a first base; , forming a compound of formula (I). TIFF2025032197000002.tif17160 The substituted 5-chloropentanes are 1-bromo-5-chloropentane and 1-iodo-5- chloropentane. (b) reacting a compound of formula (I) with a compound of formula [M] + [X] - to obtain a compound of formula (II) Form. TIFF2025032197000003.tif16160, [M] + Li + , Na + and K + [X] - is B r - and I - is selected from the group consisting of: (c) reacting a compound of formula (II) with toluenesulfonylmethylisocyanate in the presence of a second base; and contacting the first intermediate with an acid to form a compound of formula (IV). A compound is formed. (d) contacting the compound of formula (IV) with a reducing agent to form a second intermediate, and The intermediate is contacted with a hydrolysis base to form a compound of formula (V) or a pharma- ceutically acceptable salt thereof. Complete.

[0005] In certain embodiments of the invention, the method comprises: (a) 1-Bromo-5-chloropentane is reacted with riboflavin at a temperature in the range of about -20°C to about 0°C. about 1 to about 1.21 molar equivalents of ethyl isobutyrate in the presence of titanium diisopropylamide; upon contact to form a compound of formula (I). (b) A compound of formula (I) in 2-butanone at a temperature ranging from about 78° C. to about 82° C. Contact with about 1.1 molar equivalents of sodium iodide to form a compound of formula (IIa). JPEG2025032197000006.jpg17143(c) Compound of formula (IIa) is reacted with sodium tert-pentane in dimethylacetamide. in the presence of toluenesulfonylmethyl tungstate at a temperature ranging from about -20°C to about 10°C. and contacting the intermediate with an isocyanide to form an intermediate, said intermediate being heated to a temperature in the range of about -10°C to about 35°C. Upon contact with an acid at temperature, a compound of formula (IV) is formed. (d) contacting a compound of formula (IV) with about 0.35 molar equivalents of sodium borohydride; and contacting the second intermediate with sodium hydroxide in solution to form a compound of formula (V ) compound.

[0006] In certain embodiments of the invention, the method further comprises: (e) purifying the compound of formula (V) to produce a pharmaceutical material comprising a purified amount of the compound of formula (V). to provide. In certain embodiments of the invention, purifying the compound of formula (V) comprises: (f) adjusting the pH of the solution containing the compound of formula (V) to about 6; (g) extracting the compound of formula (V) from the solution using methyl tert-butyl ether; providing a methyl tert-butyl ether solution comprising a compound of formula (V), (h) Methyl tert-butyl ether solution of methyl tert-butyl ether with acetic acid ethyl to provide an ethyl acetate solution comprising a compound of formula (V), (i) filtering a solution of a compound of formula (V) in ethyl acetate through silica gel; (j) crystallizing the compound of formula (V) using ethyl acetate and water to obtain the compound of formula (V) providing a crystalline form; and (k) Recrystallizing the crystalline form of compound of formula (V) using ethyl acetate and water to purify it. The present invention provides a pharmaceutical material comprising an amount of a compound of formula (V).

[0007] In another aspect, the present invention provides highly purified or purified bempedoic acid or a pharma- ceutical acceptable salt thereof. For example, provided herein are compounds comprising the compound of formula (V) It is a pharmaceutical material or a pharma- ceutically acceptable salt thereof. TIFF2025032197000008.tif19160 The pharmaceutical material contains a compound of formula (V) in an amount of more than 99.0% by weight, based on the total weight of the pharmaceutical material. The present invention includes a compound or a pharma- ceutically acceptable salt thereof.

[0008] In various embodiments, the pharmaceutical material is a crystalline form of the compound of formula (V) or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical material comprises an amount of about 100 mg of the pharmaceutical material, based on the total weight of the pharmaceutical material. The composition contains more than 99.0% by weight of the compound of formula (V). In another aspect, the present invention provides a method for the preparation of a pharmaceutical composition comprising administering to a subject a pharmaceutical composition comprising: Pharmaceutical compositions or formulations that include pharma- ceutically acceptable salts are provided. For example, pharmaceutical compositions include The pharmaceutical material of the invention (e.g., a pharmaceutical material having a formula ( V) a pharmaceutical material comprising the compound or a pharma- ceutical acceptable salt thereof and In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of The pharmaceutical composition of the present invention may include the pharmaceutical material of the present invention and a pharma- ceutical acceptable excipient. In one embodiment, the pharmaceutical composition comprises a crystalline form of the compound of formula (V) or a pharma- ceutically acceptable salt thereof. and pharma- ceutically acceptable excipients.

[0009] Purified bempedoic acid or a pharma- ceutically acceptable salt thereof, bempedoic acid or a pharma- ceutically acceptable salt thereof The crystalline form of the salt is acceptable for the pharmaceutical material of the present invention (e.g., 90% or more based on the total weight of the pharmaceutical material). A pharmaceutical preparation comprising a compound of formula (V) or a pharma- ceutical acceptable salt thereof in an amount of more than 9.0% by weight. The compounds or pharmaceutical compositions of the present invention can be used to treat various conditions and diseases described herein. For example, the method of treatment can be used to inhibit adenosine triphosphate citrate lyase (ATC) L), inhibition of cholesterol synthesis and / or inhibition of fatty acid biosynthesis. In some embodiments, the condition or disease is hyperlipidemia, such as primary hyperlipidemia. This method may include treating hyperlipidemia, such as primary hyperlipidemia. In an embodiment, the disease may be a cardiovascular disease and the method includes treating the cardiovascular disease. In various embodiments, the method of treatment includes reducing low density lipid cholesterol (LDL-C ), non-high-density lipoprotein cholesterol (non-HDL-C), serum total cholesterol (TC), Improve or reduce apoB and / or high-sensitivity C-reactive protein (hsCRP) This may include: [Brief description of the drawings]

[0010] [Figure 1]1 is an exemplary reaction scheme of the present invention for synthesizing bempedoic acid (i.e., a compound of formula (V)) as described in Example 1, which involves the synthesis of a pharmaceutical material comprising greater than 99.0 wt. % of the compound of formula (V), based on the total weight of the pharmaceutical material. [Diagram 2] 1 is an exemplary 1H-NMR spectrum of the compound of formula (V). [Diagram 3] 1 is an exemplary 13C-NMR spectrum of the compound of formula (V). [Figure 4] 1 is an X-ray powder diffraction pattern of the compound of formula (V) in crystalline form as further described in Example 1. [Diagram 5] 1 is a differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curve overlay of the crystalline form of compound of formula (V), as further described in Example 1. [Figure 6] 1 is a water sorption isotherm of the compound of formula (V) in crystalline form. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Currently, bempedoic acid (including its pharma- ceutically acceptable salts) is available in high purity and / or ballast water. It has been found that benphene can be produced in large quantities. A crystalline form of the do acid or a pharma- ceutically acceptable salt thereof is provided. The process for preparing bempedoic acid described herein avoids the formation of impurities during the synthesis process that are difficult to remove. In some cases, high levels or amounts of bempedoic acid or a pharma- ceutical acceptable salt thereof may be achieved by controlling It is possible to provide a pharmaceutical material comprising: Furthermore, a pharmaceutical preparation containing bempedoic acid or a pharma- ceutical acceptable salt thereof in a highly pure crystalline form is provided. For example, the pharmaceutical material may be a crystalline form of bempedoic acid or a pharma- ceutically acceptable salt thereof. The pharmaceutical material is made up of more than 99.0% by weight of benzoyl perfluorooctanoic acid based on the total weight of the pharmaceutical material. When the pharmaceutical material comprises bempedoic acid or a pharma- ceutically acceptable salt thereof, the pharmaceutical material is bempedoic acid or can provide bempedoic acid in highly pure crystalline form of its pharmaceutical salts.

[0012] I. Definition To facilitate the understanding of this invention, several terms and phrases are defined below. Unless otherwise defined, all technical and scientific terms used herein are defined by the principles of the present invention. The term "term" has the same meaning as commonly understood by a person skilled in the art to which the present invention pertains. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The depicted chemical structures and formulas are constructed according to the standard rules of chemical valence known in the chemical arts. can be.

[0013] Throughout this specification, compositions and kits are referred to as having or including particular components. g) or when described as comprising, or when described as comprising, The method has, includes, or comprises certain steps. g) if described as consisting essentially of or consisting of the recited components, The compositions and kits of the present invention comprise: It is contemplated that the processes and methods of the present invention comprise The elements or components included in and / or listed in the list of elements or components in which the elements or components are listed In this application where it is said to be selected from a list of elements or components, the element or component refers to the recited elements. or the element or component may be any one of the elements or components listed. It is to be understood that the compound may be selected from the group consisting of one or more.

[0014] Additionally, elements and / or features of the compositions or methods described herein may be used interchangeably herein. Various modifications, whether express or implied, are intended to be included without departing from the spirit and scope of the present invention. It is understood that combinations of compounds may be used in a variety of ways. For example, In this case, the compound is not intended to be a part of the composition of the invention and / or the composition of the invention, unless otherwise understood from the context. In other words, within this application, Although the embodiments have been described and illustrated in a manner that allows for a clear and concise description and depiction of the application, The embodiments may be combined or separated in various ways without departing from the teachings and invention. It is intended and understood that the present invention may be practiced in various ways, for example as described and illustrated herein. All features shown are consistent with all aspects of the invention(s) described and illustrated herein. It will be appreciated that the present invention may be applicable to

[0015] The articles "a" and "an" are used in conjunction with the articles "a" and "an" unless the context is inappropriate. It is used in this disclosure to refer to one or more (ie, up to at least one) of a legal subject. By way of example, "an element" means one element or more than one element. do. The term "and / or" is used in this disclosure to mean "and" or "or" unless otherwise indicated. " is used to mean either " The phrase "at least one of" is used unless otherwise understood from context and usage. Each of the objects listed after this expression, and various combinations of two or more of the objects listed It is understood that the terms "and" and "combinations" individually include any combination of the terms "and" and "combinations" that relate to three or more enumerated items. The expressions "or" are understood to have the same meaning unless otherwise indicated from the context. stomach. "include", "includes", "includes "having", "has", "having "contain", "contains" or "includes" The use of the term "containing," including its grammatical equivalents, Generally, the invention should be understood as being open-ended and non-limiting, and for example, unless otherwise specified. Unless otherwise specified or understood from the context, no additional unrecited elements or steps are excluded. do not have.

[0016] When the term "about" is used before a quantitative value, the present invention encompasses, unless otherwise stated. As used herein, the term "about" includes the specific quantitative value itself. Unless otherwise specified or inferred from the context, refers to a variation of ±10% from the nominal value.

[0017] For example, where molecular weights are provided rather than absolute values ​​for polymers, the molecular weights are not necessarily specified. Unless otherwise specified or understood from the context, it should be understood to be an average molecular weight. . The order of steps or order for performing certain actions may be varied so long as the invention remains operable. It should be understood that the order in which two or more steps or actions are conducted is not critical. Good too.

[0018] At various places in the specification, variables or parameters are disclosed in groups or ranges. The description includes any and all individual subcombinations of the members of such groups and ranges. For example, the integers in the range of 0 to 40 are specifically intended to include 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 3 1, 32, 33, 34, 35, 36, 37, 38, 39, and 40 must be disclosed separately. In particular, the integers in the range of 1 to 20 are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 It is intended to be disclosed separately.

[0019] Any and all examples or exemplary language herein, such as "such as" The use of "including" or "including" is merely to better describe the invention. and is not intended to limit the scope of the invention unless otherwise stated in the claims. No language in this specification is deemed essential to the practice of the invention. should not be construed as indicating elements not included in the specification. As a general matter, compositions specifying percentages are on a weight basis unless otherwise noted. Furthermore, if a variable is not accompanied by a definition, then any previous definition of the variable controls.

[0020] As used herein, "pharmaceutically acceptable salts" refers to the compounds present in the present invention. The term "salt" refers to any salt of a compound having an acidic or basic group which is compatible with pharmaceutical administration. For example, one or both of the carboxylic acid groups of bempedoic acid may be converted to a pharma- ceutically acceptable salt. can be done. As known to those skilled in the art, a "salt" of a compound is a salt derived from an inorganic or organic acid or base. Examples of acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, and the like. acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid Acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, Examples of these include malonic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Other acids, such as oxalic acid, while not themselves pharma- ceutically acceptable, are not limited to the acids described herein. The compound is useful as an intermediate in obtaining the compounds described in the document and their pharma- ceutically acceptable acid addition salts. It can be used to prepare useful salts. Examples of bases include alkali metal (e.g., sodium and potassium) hydroxides, alkoxides, Potassium earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and W C 1~4 Formula NW4 is an alkyl + Examples of compounds include, but are not limited to,

[0021] Examples of salts include acetates, adipates, alginates, aspartates, and benzoates. Salt, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate Salt, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfone acid salt, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate , hexanoate, hydrochloride, hydrobromide, 2-hydroxyethanesulfonate, lactate, Maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, Salts, pamoates, pectinates, persulfates, phenylpropionates, picrates, picrates Valine, propionate, succinate, tartrate, thiocyanate, tosylate, Other examples of salts include, but are not limited to, Na + , K+ , Ca 2+ , NH4 + , and NW4 + (W is C 1~4 (which may be an alkyl group) and the anion of a compound of the present invention combined with an appropriate cation.

[0022] For therapeutic use, the salts of the compounds of the invention are considered to be pharma- ceutically acceptable. However, salts of acids and bases that are not pharma- ceutically acceptable are not included, e.g., in the synthesis of pharma- ceutically acceptable compounds. They may also be used in the preparation or purification of substances.

[0023] As used herein, a "pharmaceutical composition" or "pharmaceutical formulation" refers to a mixture of an active agent and an inactive or refers to the combination of an active agent with a carrier and the composition for use in in vivo or ex vivo diagnosis. Particularly suitable for diagnostic or therapeutic applications. As used herein, "pharmacologically acceptable" and "pharmacologically acceptable" refer to " refers to any substance that, when administered to animals or humans, is harmful, allergic or otherwise harmful. Refers to compounds, molecular entities, compositions, materials, and / or dosage forms that do not cause adverse reactions For human administration, the preparation meets FDA Office of Biologics standards. It should meet the sterility, pyrogenicity, and general safety and purity standards required by the "Pharmaceutically acceptable" and "pharmacologically acceptable" are defined as any term used by a federal or has been or may be approved by a state government regulatory agency or a corresponding agency in a country other than the United States. or to comply with the United States Pharmacopoeia or other commonly used standards for use in animals, and more particularly in humans. "Listed in a commonly recognized pharmacopoeia" can mean "listed in a commonly recognized pharmacopoeia."

[0024] As used herein, a "carrier" refers to bempedoic acid or a pharma- ceutically acceptable salt thereof. transport or transfer such medicines from one organ or part of the body to another Materials, compositions, such as liquid or solid fillers, diluents, excipients, solvents or encapsulating materials, involved in It refers to a composition or vehicle. As used herein, a "pharmaceutically acceptable excipient" refers to a vehicle that is suitable for administration of an active agent to a subject. and / or aid in absorption by the subject, and to administer the compound without causing significant adverse toxic effects to the patient. Pharmaceutically acceptable excipients refer to substances that can be included in the compositions of the invention. Examples include water, NaCl, normal saline (e.g., phosphate buffered saline), emulsions, etc. fusions (e.g., oil / water or water / oil emulsions), lactated Ringer's, regular sucrose , regular glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings , salt solutions (e.g. Ringer's solution), alcohol, oil, gelatin, carbohydrates (lactose, Amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinyl chloride Such preparations are sterile and, if necessary, Lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts affecting osmotic pressure, buffers, coloring agents, and / or may be mixed with adjuvants, such as aromatic substances, which do not deleteriously react with the compounds of the present invention. For examples of excipients, see Martin, Remington's Pharmac eutical Sciences,15th Ed.,Mack Publ.Co., See Easton, P.A. (1975).

[0025] As used herein, "treating" or "treatment" refers to the treatment of a condition, disease, disorder, etc. Any effect that results in improvement or amelioration of the symptoms thereof, such as alleviation, reduction, regulation, amelioration or elimination Treating includes curing, ameliorating, or at least partially reversing a disorder. In certain embodiments, treating can be curing a disease. That is the thing. As used herein, one or more of the symptom(s) (and the grammatical equivalents of this phrase) "Reduce" or "reduction" of refers to a decrease in the severity or frequency of a symptom(s), or a decrease in the severity or frequency of a symptom(s). This means the exclusion of several

[0026] As used herein, an "effective amount" or a "therapeutically effective amount" refers to an amount that is effective to achieve a beneficial or desired result. An effective amount refers to an amount of a compound (e.g., a compound of the present invention) sufficient to provide one or more The above dosages, applications or doses may be used, but are not limited to specific formulations or routes of administration. As used herein, the term "treat" refers to a condition, disease, Any effect that results in the improvement of a disorder or the like or the amelioration of its symptoms, such as alleviation, reduction, regulation, Includes improvement or elimination.

[0027] As used herein, "subject" and "patient" are used interchangeably and are intended to describe the methods of the present invention. The term "organism" refers to an organism that is treated by the methods and compositions of the present invention. Such organisms are preferably mammals, e.g. For example, a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human spirit. protozoa, e.g. monkeys, chimpanzees, baboons and rhesus monkeys), more preferably humans. be.

[0028] As used herein, the terms "disease," "disorder," "symptom," or "disease" are used interchangeably with "disease" in the context. may be used interchangeably unless otherwise fully operative or understood; Patients that can be treated with the compounds, pharmaceutical materials, pharmaceutical compositions or methods provided herein In some embodiments, the term "condition" refers to a condition or health state of a person or subject. The compounds and methods include, for example, administering a compound of formula (V) or a pharma- ceutically acceptable salt thereof This includes reducing or eliminating one or more symptoms of a disease, disorder or condition, or illness, by

[0029] As used herein, "administering" includes administering to a subject orally, as a suppository, Local contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or This refers to administration by subcutaneous administration, or by implantation of a sustained release device, such as a mini-osmotic pump. Any, including oral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal) Parenteral administration can be, for example, by intravenous, intramuscular, intraarterial, intradermal, or transdermal routes. Other modes of delivery include intravenous, intraperitoneal, intracerebroventricular, and intracranial. These include, but are not limited to, the use of intravenous injections, transdermal patches, etc. " refers to administering the compositions described herein in combination with one or more additional therapies (e.g., anti-cancer agents, chemotherapy The drug may be administered simultaneously with, immediately before, or immediately after the administration of a neurodegenerative disease treatment agent (a neuroprotective agent, or a neurodegenerative disease treatment agent). The compounds of the present invention can be administered alone or co-administered to a patient. Co-administration can refer to administration of the compounds individually or in combination (two or more compounds or drugs). The term "preparation" is intended to include simultaneous or sequential administration of the two agents. If necessary, they can be combined with other active substances (e.g., to reduce metabolic degradation). do.

[0030] As used herein, "liver disorder" generally refers to any disease, disorder, or condition that affects the liver. and / or symptoms, such as simple accumulation of fat in liver cells (steatosis), macrovesicular fatty changes, The disease can lead to a number of complications, including chronic, periportal and lobular inflammation (steatohepatitis), cirrhosis, fibrosis, liver cancer, and liver failure. These conditions can have a wide range of severity, including: As used herein, "fatty liver disease" ("FLD"), also known as "fatty liver," refers to , refers to a disease that leads to liver damage caused by abnormal fat accumulation in liver cells. FLD is a condition caused by excessive alcohol consumption and metabolic disorders (related to insulin resistance, obesity and hypertension). These can arise from many causes, including those related to As used herein, "nonalcoholic fatty liver disease" ("NAFLD") refers to A series of events resulting from the accumulation of fat in hepatocytes in individuals with no history of excessive alcohol consumption In its mildest form, NAFLD refers to hepatic steatosis. As used herein, "drug-induced liver disease" or "toxic liver damage" refers to the inability of an active agent to affect the liver. This refers to a disease or condition that causes organ damage. As used herein, "alcoholic liver disease," also known as "alcoholic liver injury," refers to The disease is a result of fatty accumulation in liver cells, which is at least partially caused by alcohol consumption. Examples include alcoholic simple fatty liver disease, alcohol-induced Alcoholic steatohepatitis (ASH) ), alcoholic liver fibrosis, alcoholic cirrhosis, and alcoholic fatty liver disease. These include, but are not limited to, alcoholic fatty liver disease. Steatohepatitis is a type of liver disease caused by alcohol. Also known as alcoholic fatty hepatitis, this condition includes alcoholic liver fibrosis.

[0031] As used herein, "fatty liver of pregnancy" refers to a life-threatening condition that can occur during pregnancy. This refers to possible acute fatty liver symptoms.

[0032] As used herein, "altering lipid metabolism" refers to at least one of the following: This refers to observable (measurable) changes in one area, including total blood lipid content, Blood HDL cholesterol, Blood LDL cholesterol, Blood VLDL cholesterol, Blood triglycerides, blood Lp(a), blood apo AI, blood apo E and blood non- Includes, but is not limited to, esterified fatty acids. As used herein, "altering glucose metabolism" refers to the alteration of glucose metabolism. This refers to an observable (measurable) change in at least one aspect, including total blood Glucose content, blood insulin, blood insulin to blood glucose ratio, insulin sensitivity These include, but are not limited to, oxygen consumption, and oxygen tolerance.

[0033] As used herein, "purified bempedoic acid" refers to bempedoic acid when isolated as a solid. , the pharmaceutical material is at least 95% by weight of 8-hydroxy-2-(2-methyl-1,2-dioxane) based on the total weight of the pharmaceutical material. ,2,14,14 tetramethylpentadecanedioic acid. In the form, purified bempedoic acid is a pharmaceutical material that, when isolated as a solid, At least 99.0% by weight of 8-hydroxy-2,2,14,14 based on the total weight of It means that it contains tetramethylpentadecanedioic acid. An acid is any acid that is pharma- ceutically acceptable unless otherwise specified or understood from the context. It may contain salt.

[0034] As used herein, a "substantially complete" reaction means that the reaction is greater than about 80% by weight. In certain embodiments, a substantially complete reaction means containing the desired product. %, or greater than about 90% by weight of the desired product. In certain embodiments, substantially complete The reaction contains greater than about 95% by weight of the desired product. In certain embodiments, substantially A complete reaction contains greater than about 97% by weight of the desired product. Unless otherwise stated, all X-ray powder diffraction (XRPD) patterns presented herein are , which corresponds to the XRPD pattern measured using a Cu Kα radiation source, and shows the crystalline form of Ben Pedoic acid is analyzed by XRPD at ambient temperature.

[0035] II. Crystalline forms of bempedoic acid A. Crystalline bempedoic acid In one aspect, the present invention provides 8-hydroxy-2,2,14,14-tetramethylpentadecamethylpentadecamethylphenyl ether. Crystalline forms of candiic acid, also referred to herein as "bempedoic acid" and / or of formula (V) are provided. Also known and referred to as compounds. TIFF2025032197000009.tif19160In certain embodiments, the crystalline form of the compound of formula (V) has the following diffraction angle (2θ): 10. 3±0.2, 10.4±0.2, 17.9±0.2, 18.8±0.2, 19.5±0. The compound may be characterized by an X-ray powder diffraction pattern including peaks at 20.7±0.2 and 20.7±0.2. In an embodiment, the crystalline form of the compound of formula (V) has the following diffraction angle (2θ): 10.3±0. 2, 10.4±0.2, 17.6±0.2, 17.9±0.2, 18.8±0.2, 19 .5±0.2, 19.7±0.2, 20.4±0.2, 20.7±0.2 and 22.6± It may be characterized by an X-ray powder diffraction pattern including a peak at 0.2.

[0036] In certain embodiments, the crystalline form of the compound of formula (V) has a diffraction angle 2θ as shown in Table 1. , optionally with the interplanar distance d (angstroms) and the relative intensity (percentage relative to the most intense peak) The compound is characterized by an X-ray powder diffraction pattern expressed in terms of [Table 1]

[0037] In certain embodiments, the crystalline form of the compound of formula (V) has substantially the same structure as shown in FIG. It is characterized by a 1-line powder diffraction pattern. In certain embodiments, the crystalline form of the compound of formula (V) exists in the monoclinic system and has a P21 / c In certain embodiments, the crystalline form of the compound of formula (V) has the crystalline space group shown in Table 2. The lattice structure is characterized by the following parameters:

[0038] [Table 2]

[0039] The crystalline forms of the compound of formula (V) may also be characterized by the onset melting point temperature. Thus, in certain embodiments, the compound of formula (V) in crystalline form is dissolved at about 82° C. to about 94° C. In certain embodiments, the melting point onset as determined by differential scanning calorimetry is in the range of The compound of formula (V) in crystalline form can be measured by differential scanning calorimetry in the range of about 90°C to about 94°C. In certain embodiments, the crystalline form of the compound of formula (V) has a melting point onset of about It has a melting point onset as determined by differential scanning calorimetry of 92° C. In certain embodiments, The crystalline form of the compound of formula (V) has a differential scanning calorimetry curve substantially similar to that shown in FIG. do.

[0040] The compound of formula (V) in crystalline form also exhibits a clear linear relationship to its mass gain / loss as a function of temperature. Thus, in certain embodiments, the crystalline form of formula (V) When heated to about 200°C, the compound has a molecular weight of about 0.1%, as determined by thermogravimetric analysis. In certain embodiments, the crystalline form of the compound of formula (V) is When heated to approximately 200°C, it loses mass of less than approximately 0.7% as determined by thermogravimetric analysis. In certain embodiments, the crystalline form of the compound of formula (V) is substantially similar to that shown in FIG. The thermogravimetric analysis curves are the same as those in Example 1. The compound of formula (V) in crystalline form can also be characterized by its water sorption properties. Thus, in certain embodiments, the compound of formula (V) in crystalline form has a dynamic water vapor sorption When determined by the above, it is about 0.01% to about 0.05% at a relative humidity of 80% and a temperature of 25°C. In certain embodiments, the crystalline form of the compound of formula (V) exhibits a dynamic water vapor absorption When determined by immersion, the mass change is approximately 0.03% at 80% relative humidity and 25°C. In certain embodiments, the crystalline form of the compound of formula (V) is as shown in FIG. 6. References herein to bempedoic acid or purified bempedoic acid, unless otherwise specified, is understood to include crystalline forms of bempedoic acid, unless otherwise understood from the context.

[0041] B. Bempedoic acid in crystalline salt form Additionally, it has been discovered that various crystalline salt forms of bempedoic acid can be prepared. In particular, the following counterions have produced crystalline salt forms of bempedoic acid: ammonium, sodium, Calcium (in two crystalline forms), lysine, diethylamine, ethylenediamine amine, piperazine, betaine, tromethamine and isonicotinamide.

[0042] (i) Bempedoic acid in the form of a crystalline betaine salt In certain embodiments, the crystalline salt form of bempedoic acid is a crystalline betaine salt of bempedoic acid. In certain embodiments, the crystalline betaine salt of bempedoic acid has the following diffraction angle (2θ): 6 .2±0.2°, 13.5±0.2°, 17.5±0.2°, 19.3±0.2° and 2 It may be characterized by an X-ray powder diffraction pattern including a peak at 5.6±0.2°. The crystalline betaine salt of bempedoic acid has the following diffraction angles (2θ): 6.2±0.2°, 1 3.5±0.2°, 16.1±0.2°, 17.5±0.2°, 19.3±0.2°, 1 X-ray powder diffraction including peaks at 9.9±0.2, 25.6±0.2° and 27.2±0.2° The fold pattern may be a feature. In certain embodiments, the crystalline betaine salt of bempedoic acid has a diffraction angle of 2 θ, optionally the interplanar distance d, and the relative intensity (expressed as a percentage relative to the most intense peak) The compound is characterized by an X-ray powder diffraction pattern expressed in terms of

[0043] [Table 3]

[0044] (ii) The crystalline calcium salt form of bempedoic acid In certain embodiments, the crystalline salt form of bempedoic acid is a crystalline calcium salt of bempedoic acid. In certain embodiments, the crystalline calcium salt of bempedoic acid has the following diffraction angles (2θ): : 4.9±0.2, 6.4±0.2, 9.1±0.2, 14.8±0.2, 19.7±0 It may be characterized by an X-ray powder diffraction pattern including peaks at 0.2 and 37.1±0.2°. In certain embodiments, the crystalline calcium salt of bempedoic acid has a diffraction angle of 1.0 nm to 1.5 nm as shown in Table 4. 2θ, optionally the interplanar distance d, and the relative intensity (expressed as a percentage of the most intense peak ) is characterized by an X-ray powder diffraction pattern expressed in [Table 4]

[0045] In certain embodiments, the crystalline calcium salt of bempedoic acid has the following diffraction angle (2θ): 6 Peaks of 0.0±0.2°, 6.8±0.2°, 8.5±0.2° and 9.8±0.2° In certain embodiments, the crystalline form of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising The calcium salt has the following diffraction angles (2θ): 6.0±0.2°, 6.8±0.2°, 8.5± Includes peaks at 0.2°, 9.8±0.2°, 17.1±0.2° and 19.0±0.2°. The compound may be characterized by an X-ray powder diffraction pattern including: In certain embodiments, the crystalline calcium salt of bempedoic acid has a diffraction angle of 1.0 nm to 1.5 nm as shown in Table 5. 2θ, optionally the interplanar distance d, and the relative intensity (expressed as a percentage of the most intense peak ) is characterized by an X-ray powder diffraction pattern expressed in [Table 5]

[0046] (iii) Bempedoic acid in the form of a crystalline diethylamine salt In certain embodiments, the crystalline salt form of bempedoic acid is crystalline diethylamine salt of bempedoic acid. In certain embodiments, the crystalline diethylamine salt of bempedoic acid has the following diffraction angles: (2θ): Peaks at 9.6±0.2°, 14.1±0.2°, and 19.8±0.2° In certain embodiments, the crystalline dimer of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising The ethylamine salt has the following diffraction angles (2θ): 9.6±0.2°, 14.1±0.2°, 1 7.8±0.2°, 19.8±0.2°, 22.6±0.2°, and 38.7±0.2° The compound may be characterized by an X-ray powder diffraction pattern including peaks of In certain embodiments, the crystalline diethylamine salt of bempedoic acid can be recovered as shown in Table 6. The diffraction angle 2θ, optionally the interplanar distance d, and the relative intensity (expressed as a percentage of the most intense peak) The compound is characterized by an X-ray powder diffraction pattern expressed in terms of [Table 6]

[0047] (iv) Bempedoic acid in the form of its crystalline ethylenediamine salt In certain embodiments, the crystalline salt form of bempedoic acid is a crystalline ethylenediamine salt of bempedoic acid. In certain embodiments, the crystalline ethylenediamine salt of bempedoic acid is Frequency angle (2θ): 6.8±0.2°, 10.8±0.2°, 16.2±0.2°, 18.3 It may be characterized by an X-ray powder diffraction pattern including peaks at 18.8±0.2° and 18.8±0.2°. In certain embodiments, the crystalline diethylamine salt of bempedoic acid has the following diffraction angles (2θ): :6.8±0.2°, 7.7±0.2°, 10.8±0.2°, 13.9±0.2°, 1 5.2±0.2°, 16.2±0.2°, 18.3±0.2°, 18.8±0.2°, 2 Characterized by an X-ray powder diffraction pattern including peaks at 1.4±0.2° and 22.3±0.2° possible. In certain embodiments, the crystalline ethylenediamine salt of bempedoic acid is as shown in Table 7: The diffraction angle 2θ, optionally the interplanar distance d, and the relative intensity (expressed as a percentage of the most intense peak) The compound is characterized by an X-ray powder diffraction pattern expressed in terms of [Table 7]

[0048] (v) Bempedoic acid in the form of a crystalline isonicotinamide salt In certain embodiments, the crystalline salt form of bempedoic acid is a crystalline isonicotinic acid salt of bempedoic acid. In certain embodiments, the crystalline isonicotinamide salt of bempedoic acid is Diffraction angles (2θ): 4.4±0.2°, 18.8±0.2°, 20.1±0.2° and 2 It may be characterized by an X-ray powder diffraction pattern including a peak at 4.5±0.2°. The crystalline isonicotinamide salt of bempedoic acid has the following diffraction angle (2θ): 4.4±0 .2°, 14.5±0.2°, 18.8±0.2°, 20.1±0.2°, 24.5±0 X-ray powder diffraction pattern including peaks at 26.2±0.2°, 26.2±0.2° and 29.5±0.2° The present invention may be characterized by the above. In certain embodiments, the crystalline isonicotinamide salt of bempedoic acid is as shown in Table 8. , the diffraction angle 2θ, optionally the interplanar distance d, and the relative intensity (as a percentage of the most intense peak) The compound is characterized by an X-ray powder diffraction pattern shown in Table 1 for a compound represented by the formula (I). [Table 8]

[0049] (vi) Bempedoic acid in the form of its crystalline potassium salt In a particular embodiment, the crystalline salt form of bempedoic acid is a crystalline potassium salt of bempedoic acid. In certain embodiments, the crystalline potassium salt of bempedoic acid has the following diffraction angle (2θ): 5 Peaks of .7±0.2°, 7.3±0.2°, 9.6±0.2° and 22.1±0.2° In certain embodiments, the crystalline form of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising: The potassium salt has the following diffraction angles (2θ): 5.7±0.2°, 7.3±0.2°, 9.6± Peaks of 0.2°, 16.0±0.2°, 22.1±0.2° and 23.0±0.2° The compound may be characterized by an X-ray powder diffraction pattern comprising: In certain embodiments, the crystalline potassium salt of bempedoic acid has a diffraction angle of 2 θ, optionally the interplanar distance d, and the relative intensity (expressed as a percentage relative to the most intense peak) The compound is characterized by an X-ray powder diffraction pattern expressed in terms of [Table 9]

[0050] (vii) Bempedoic acid in the form of a crystalline lysine salt In certain embodiments, the crystalline salt form of bempedoic acid is a crystalline lysine salt of bempedoic acid. In certain embodiments, the crystalline lysine salt of bempedoic acid has the following diffraction angle (2θ): 4.2 ±0.2°, 10.2±0.2°, 19.1±0.2°, 19.7±0.2° and 21. The compound may be characterized by an X-ray powder diffraction pattern including a peak at 9±0.2°. In certain embodiments, The crystalline lysine salt of bempedoic acid has the following diffraction angles (2θ): 4.2±0.2°, 10.2 ±0.2°, 13.5±0.2°, 14.2±0.2°, 16.0±0.2°, 19.1 X-ray powder diffraction pattern including peaks at 19.7±0.2°, 19.7±0.2°, and 21.9±0.2° It may feature turns. In certain embodiments, the crystalline lysine salt of bempedoic acid has a diffraction angle of 2 θ, optionally the interplanar distance d, and the relative intensity (expressed as a percentage relative to the most intense peak) The compound is characterized by an X-ray powder diffraction pattern expressed in terms of [Table 10]

[0051] (viii) Crystalline sodium salt form of bempedoic acid In certain embodiments, the crystalline salt form of bempedoic acid is a crystalline sodium salt of bempedoic acid. In certain embodiments, the crystalline sodium salt of bempedoic acid has the following diffraction angles (2θ): : 6.1±0.2°, 14.2±0.2°, 18.3±0.2° and 24.5±0.2° In certain embodiments, bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising the peaks: The crystalline sodium salt of has the following diffraction angles (2θ): 6.1±0.2°, 13.4±0.2° °, 14.2±0.2°, 16.6±0.2°, 18.3±0.2°, 19.1±0.2 It may be characterized by an X-ray powder diffraction pattern including peaks at 24.5±0.2° and 24.5±0.2°. In certain embodiments, the crystalline sodium salt of bempedoic acid has a diffraction pattern as shown in Table 11. angle 2θ, optionally the interplanar distance d, and the relative intensity (expressed as a percentage of the most intense peak It is characterized by an X-ray powder diffraction pattern expressed in terms of [Table 11]

[0052] (ix) Bempedoic acid in the form of a crystalline ammonium salt In certain embodiments, the crystalline salt form of bempedoic acid is a crystalline ammonium salt of bempedoic acid. In certain embodiments, the crystalline ammonium salt of bempedoic acid has the following diffraction angles (2 θ):6.9±0.2°, 7.1±0.2°, 14.3±0.2°, 16.0±0.2° The compound may be characterized by an X-ray powder diffraction pattern including peaks at 21.4±0.2° and 21.4±0.2°. In an embodiment, the crystalline ammonium salt of bempedoic acid has the following diffraction angle (2θ): 6.9±0 .2°, 7.1±0.2°, 9.3±0.2°, 14.3±0.2°, 16.0±0.2 °, 18.2±0.2°, 19.2±0.2°, 21.4±0.2° and 22.3±0. It may be characterized by an X-ray powder diffraction pattern including a peak at 2°. In certain embodiments, the crystalline ammonium salt of bempedoic acid is soluble in water as shown in Table 12. The diffraction angle 2θ, optionally the interplanar distance d, and the relative intensity (expressed as a percentage of the most intense peak) The compound is characterized by an X-ray powder diffraction pattern expressed in terms of [Table 12]

[0053] (x) Bempedoic acid in the form of a crystalline piperazine salt In certain embodiments, the crystalline salt form of bempedoic acid is a crystalline piperazine salt of bempedoic acid. In certain embodiments, the crystalline piperazine salt of bempedoic acid has the following diffraction angles (2θ): :6.7±0.2°, 8.7±0.2°, 10.7±0.2°, 15.7±0.2° and It may be characterized by an X-ray powder diffraction pattern including a peak at 16.0±0.2°. In this state, the crystalline piperazine salt of bempedoic acid has the following diffraction angle (2θ): 6.7±0.2° , 8.7±0.2°, 10.7±0.2°, 15.7±0.2°, 16.0±0.2°, X-ray powder containing peaks at 19.4±0.2°, 20.1±0.2° and 21.4±0.2° The diffraction pattern may be characterized. In certain embodiments, the crystalline piperazine salt of bempedoic acid has a diffraction gravitational coefficient of 1:1 as shown in Table 13. angle 2θ, optionally the interplanar distance d, and the relative intensity (expressed as a percentage of the most intense peak It is characterized by an X-ray powder diffraction pattern expressed in terms of [Table 13]

[0054] (xi) Bempedoic acid in the form of a crystalline tromethamine salt In certain embodiments, the crystalline salt form of bempedoic acid is a crystalline tromethamine salt of bempedoic acid. In certain embodiments, the crystalline tromethamine salt of bempedoic acid has the following diffraction angles (2 θ):6.6±0.2°, 18.2±0.2°, 18.6±0.2° and 19.8±0. In certain embodiments, the compound may be characterized by an X-ray powder diffraction pattern including a peak at 2°. The crystalline tromethamine salt of dodecyl sulfate has the following diffraction angles (2θ): 6.6±0.2°, 13.6± 0.2°, 18.2±0.2°, 18.6±0.2°, 19.8±0.2° and 26.5 It may be characterized by an X-ray powder diffraction pattern containing peaks at ±0.2°. In certain embodiments, the crystalline tromethamine salt of bempedoic acid is soluble in water as shown in Table 14. The diffraction angle 2θ, optionally the interplanar distance d, and the relative intensity (expressed as a percentage of the most intense peak) The compound is characterized by an X-ray powder diffraction pattern expressed in terms of [Table 14]

[0055] C. Co-crystalline forms of bempedoic acid It has further been found that specific co-crystalline forms of bempedoic acid can be prepared. The coformers formed cocrystals with bempedoic acid: palmitic acid and aspartame (2 (two crystal forms). (i) Cocrystal of bempedoic acid with aspartame In certain embodiments, the co-crystalline form of bempedoic acid is a co-crystalline form of bempedoic acid and aspartame. In certain embodiments, the co-crystalline form of bempedoic acid and aspartame is Lower diffraction angle (2θ): 7.6±0.2°, 8.6±0.2°, 17.3±0.2°, 18 The compound was characterized by an X-ray powder diffraction pattern including peaks at 0.4±0.2° and 25.1±0.2°. In certain embodiments, the co-crystalline form of bempedoic acid and aspartame has the following diffraction pattern: Angle (2θ): 7.6±0.2°, 8.6±0.2°, 14.4±0.2°, 17.3±0 Includes peaks at 0.2°, 18.4±0.2°, 25.1±0.2°, and 25.2±0.2° It may be characterized by X-ray powder diffraction pattern. In certain embodiments, the co-crystal form of bempedoic acid and aspartame is shown in Table 15. The diffraction angle 2θ, the interplanar distance d, and the relative intensity (percentage of the most intense peak) are The compound is characterized by an X-ray powder diffraction pattern which is expressed in terms of rheological constants (ratio expressed as a percentage). [Table 15]

[0056] In certain embodiments, the co-crystalline form of bempedoic acid and aspartame has the following diffraction angles ( 2θ):4.4±0.2°, 6.8±0.2°, 10.6±0.2°, 13.2±0.2 The compound may be characterized by an X-ray powder diffraction pattern including peaks at 18.4±0.2° and 18.4±0.2°. In an embodiment, the co-crystalline form of bempedoic acid and aspartame has the following diffraction angles (2θ): 4.4±0.2°, 5.6±0.2°, 6.8±0.2°, 10.6±0.2°, 12. 3±0.2°, 13.2±0.2°, 13.6±0.2°, 16.2±0.2°, 17. It can be characterized by an X-ray powder diffraction pattern including peaks at 6±0.2° and 18.4±0.2°. do. In certain embodiments, the co-crystal form of bempedoic acid and aspartame is shown in Table 16. The diffraction angle 2θ, the interplanar distance d, and the relative intensity (percentage of the most intense peak) are The compound is characterized by an X-ray powder diffraction pattern which is expressed in terms of rheological constants (ratio expressed as a percentage). [Table 16]

[0057] (ii) Cocrystal of bempedoic acid with palmitic acid In certain embodiments, the co-crystalline form of bempedoic acid is a co-crystalline form of bempedoic acid and palmitic acid. In certain embodiments, the co-crystalline form of bempedoic acid and palmitic acid is Diffraction angles (2θ): 4.3±0.2°, 6.3±0.2°, 8.5±0.2°, and 17 The compound may be characterized by an X-ray powder diffraction pattern including peaks at 0.0±0.2°. The co-crystal form of bempedoic acid and palmitic acid has the following diffraction angle (2θ): 4.3±0. 2°, 6.3±0.2°, 8.5±0.2°, 10.5±0.2°, 17.0±0.2° and 25.5±0.2°. In certain embodiments, the co-crystal forms of bempedoic acid and palmitic acid are shown in Table 17. As such, the diffraction angle 2θ, optionally the interplanar distance d, and the relative intensity (percentage of the most intense peak) The compound is characterized by an X-ray powder diffraction pattern expressed in terms of [Table 17]

[0058] III. Methods for Preparing Bempedoic Acid, Including Purified Bempedoic Acid As described herein, in one aspect, the present invention provides a compound of formula (V): 8-hydroxybenzoic acid A method for preparing hydroxy-2,2,14,14-tetramethylenepentadecanoic acid is provided. , the method includes making a pharma- ceutically acceptable salt thereof. TIFF2025032197000027.tif21160

[0059] It is to be understood that the methods of the present invention include preparing bempedoic acid. In one embodiment, the process for preparing bempedoic acid results in purified bempedoic acid, which is also A pharmaceutical material, i.e., a certain amount of bempedoic acid or a certain amount of the compound of formula (V), or a pharmaceutical These terms and expressions may be used herein with reference to pharmaceutical materials, including their physiologically acceptable salts. Words and phrases are used interchangeably herein unless otherwise stated or understood from context. It can be used in Noh. Thus, in various embodiments, a compound of formula (V) or a pharma- ceutically acceptable salt thereof is Methods are provided for preparing pharmaceutical materials that include the salts. TIFF2025032197000028.tif21160

[0060] In various embodiments, the method generally includes: (a) contacting ethyl isobutyrate with a substituted 5-chloropentane in the presence of a first base; , forming a compound of formula (I). TIFF2025032197000029.tif17151 Substituted 5-chloropentanes include 1-bromo-5-chloropentane and 1-iodo -5-chloropentane, and substituted 5-chloropentanes. The ethane is selected from the group consisting of 1-bromo-5-chloropentane. (b) reacting a compound of formula (I) with a compound of formula [M] + [X] - to obtain a compound of formula (II) Form. TIFF2025032197000030.tif19152[M] + Li + , Na + and K. + [X] - Br - Oh Bi I - is selected from the group consisting of: (c) reacting a compound of formula (II) with toluenesulfonylmethylisocyanate in the presence of a second base. an anide to form a first intermediate, and contacting the first intermediate with an acid to form a compound of formula (IV) Form a compound. (d) contacting the compound of formula (IV) with a reducing agent to form a second intermediate; is contacted with a hydrolysable base to form a compound of formula (V). In certain embodiments of the invention, the method further comprises: (e) purifying the compound of formula (V) to produce a pharmaceutical material comprising a purified amount of the compound of formula (V). to provide.

[0061] Synthesis of Compounds of Formula (I) - Step (a) In various embodiments, the synthesis of the compound of formula (I) generally comprises the steps of: , comprising contacting ethyl isobutyrate with a substituted 5-chloropentane. In certain embodiments, in step (a), a substituted ethyl isobutyrate is added in the presence of a first base. The contact with 5-chloropentane is carried out at a temperature of about -30°C to about 10°C, about -25°C to about 1 0℃, approx. -20℃~approx. 10℃, approx. -18℃~approx. 10℃, approx. -15℃~approx. 10℃, approx. -10 ℃ to about 10℃, about -5℃ to about 10℃, about 0℃ to about 10℃, about 5℃ to about 10℃, about -30℃ ~5℃, ~-30℃~0℃, ~-30℃~-5℃, ~-30℃~-10℃, ~ 30℃~approx. -15℃, approx. -30℃~approx. -18℃, approx. -30℃~approx. -20℃, approx. -30℃~ Approximately -25℃, Approximately -25℃ to Approximately 5℃, Approximately -25℃ to Approximately 0℃, Approximately -25℃ to Approximately -5℃, Approximately -2 5℃~approx. -10℃, approx. -25℃~approx. -15℃, approx. -25℃~approx. -18℃, approx. -25℃~approx. -20℃, approx. -20℃~approx. 5℃, approx. -20℃~approx. 0℃, approx. -20℃~approx. -5℃, approx. -20 ℃ to about -10℃, about -20℃ to about -15℃, about -20℃ to about -18℃, about -18℃ to about 5 ℃, about -18℃ to about 0℃, about -18℃ to about -5℃, about -18℃ to about -10℃, about -18℃ ~ about -15℃, about -15℃~about 5℃, about -15℃~about 0℃, about -15℃~about -5℃, about - 15℃~approx. -10℃, approx. -10℃~approx. 5℃, approx. -10℃~approx. 0℃, approx. -10℃~approx. -5℃ In certain embodiments, the reaction is carried out at a temperature ranging from about -5°C to about 5°C, or from about -5°C to about 0°C. In step (a), ethyl isobutyrate is reacted with a substituted 5-chloropentene in the presence of a first base. The contacting with the tan is carried out at a temperature ranging from about -20°C to about 0°C. In step (a), ethyl isobutyrate is reacted with a substituted 5-chlorophenyl ether in the presence of a first base. The contacting with pentane is carried out at a temperature ranging from about -18°C to about -5°C. In certain embodiments, in step (a), about 0.5% by weight, about 0.6% by weight, about 0. 7% by weight, approximately 0.8% by weight, approximately 0.9% by weight, approximately 1% by weight, approximately 1.1% by weight, approximately 1.2% by weight %, about 1.3%, about 1.4%, or about 1.5% by weight of substituted 5-chloropentaerythritol. The amine remains after forming the compound of formula (I). and less than about 1% by weight of substituted 5-chloropentane remains after forming the compound of formula (I). do. In certain embodiments, in step (a), ethyl isobutyrate versus substituted 5-chloropentane The molar ratio of is about 1:1, about 1.01:1, about 1.02:1, about 1.03:1, about 1.04 :1, approx. 1.05:1, approx. 1.06:1, approx. 1.07:1, approx. 1.08:1, approx. 1.09 :1, approx. 1.1:1, approx. 1.11:1, approx. 1.12:1, approx. 1.13:1, approx. 1.14: 1, approx. 1.15:1, approx. 1.16:1, approx. 1.17:1, approx. 1.18:1, approx. 1.19: 1, about 1.2:1, or about 1.21:1, including ranges between each of these ratios. In some embodiments, in step (a), ethyl isobutyrate versus a substituted 5-chloropentane The molar ratio of ethyl isobutyrate to substituted 5-chloroethyl ester is about 1.1:1. The molar ratio of tetrafluoroethylene is from about 1.1:1 to about 1.21:1.

[0062] In certain embodiments, in step (a), the substituted 5-chloropentane is used in an amount of about 1 molar equivalent. , about 1.01 molar equivalents, about 1.02 molar equivalents, about 1.03 molar equivalents, about 1.04 molar equivalents , about 1.05 molar equivalents, about 1.06 molar equivalents, about 1.07 molar equivalents, about 1.08 molar equivalents , about 1.09 molar equivalents, about 1.1 molar equivalents, about 1.11 molar equivalents, about 1.12 molar equivalents, about 1.13 molar equivalents, about 1.14 molar equivalents, about 1.15 molar equivalents, about 1.16 molar equivalents, about 1.17 molar equivalents, about 1.18 molar equivalents, about 1.19 molar equivalents, about 1.2 molar equivalents, or is contacted with ethyl isobutyrate present in an amount of about 1.21 molar equivalents. In step (a), the substituted 5-chloropentane is mixed with about 1.1 molar equivalents of ethyl isobutyrate. Contact the In certain embodiments, in step (a), ethyl isobutyrate and a substituted 5-chloropentaerythritol are Ethyl isobutyrate and substituted 5-chloropentane were contacted by adding ethanol to the reactor. In some embodiments, in step (a), ethyl isobutyrate is added. and adding the substituted 5-chloropentane to the reactor at a temperature of less than about 10° C., less than about 5° C., less than about Less than 0°C, less than about -5°C, less than about -10°C, less than about -15°C, less than about -20°C, less than about -25°C In some embodiments, step (a) is carried out at a temperature of less than about 100° C. or less than about −30° C. In the present invention, adding ethyl isobutyrate and substituted 5-chloropentane to a reactor is carried out in a reaction vessel at a rate of about 10 ℃, about 5℃, about 0℃, about -5℃, about -7℃, about -10℃, about -12℃, about -14℃, about - 16℃, about -18℃, about -20℃, about -22℃, about -24℃, about -26℃, about -28℃ or is carried out at a temperature of about -30° C. In some embodiments, in step (a), isobutyric acid is The addition of the ethyl acetate and the substituted 5-chloropentane to the reactor is carried out at a temperature of about -5°C. In some embodiments, in step (a), ethyl isobutyrate and a substituted 5-chloro The addition of the dipentane to the reactor is carried out at a temperature of about -12°C. In this embodiment, in step (a), ethyl isobutyrate and a substituted 5-chloropentane are added to a reactor. The addition is carried out at a temperature of about -18°C.

[0063] In certain embodiments, in step (a), ethyl isobutyrate and a substituted 5-chloropentaerythritol are The time for adding the amine to the reactor is about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 ... 0 minutes, about 50 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours. In certain embodiments, in step (a), ethyl isobutyrate and a substituted 5-chloropentaerythritol are The time for adding the amine to the reactor is about 10 minutes to about 60 minutes, about 20 minutes to about 60 minutes, about 30 minutes to about 60 minutes, 40 minutes to 60 minutes, 50 minutes to 60 minutes, 10 minutes to 50 minutes, 10 minutes to 50 minutes 40 minutes, 10 minutes to 30 minutes, 10 minutes to 20 minutes, 20 minutes to 50 minutes, 20 minutes to 50 minutes 40 minutes, 20 to 30 minutes, 30 to 50 minutes, 30 to 40 minutes, or 40 minutes ~About 50 minutes.

[0064] In certain embodiments, in step (a), ethyl isobutyrate and a substituted 5-chloropentaerythritol are The time for adding the amine to the reactor is about 1 hour to about 12 hours, about 2 hours to about 12 hours, about 3 hours ~12 hours, ~4 hours~12 hours, ~5 hours~12 hours, ~6 hours~12 hours, About 7 hours to about 12 hours, about 8 hours to about 12 hours, about 9 hours to about 12 hours, about 10 hours to about 12 hours, approx. 11 hours to approx. 12 hours, approx. 1 hour to approx. 11 hours, approx. 1 hour to approx. 10 hours, approx. 1 hour to about 9 hours, about 1 hour to about 8 hours, about 1 hour to about 7 hours, about 1 hour to about 6 hours, about 1 hour to about 5 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours, about 1 hour to about 2 hours, about 2 hours to 11 hours, 2 hours to 10 hours, 2 hours to 9 hours, 2 hours to 8 hours , about 2 hours to about 7 hours, about 2 hours to about 6 hours, about 2 hours to about 5 hours, about 2 hours to about 4 hours , about 2 hours to about 3 hours, about 3 hours to about 11 hours, about 3 hours to about 10 hours, about 3 hours to about 9 hours Time, about 3 hours to about 8 hours, about 3 hours to about 7 hours, about 3 hours to about 6 hours, about 3 hours to about 5 hours Time, about 3 hours to about 4 hours, about 4 hours to about 11 hours, about 4 hours to about 10 hours, about 4 hours or more About 9 hours, About 4 hours to about 8 hours, About 4 hours to about 7 hours, About 4 hours to about 6 hours, About 4 hours About 5 hours, About 5 hours to about 11 hours, About 5 hours to about 10 hours, About 5 hours to about 9 hours, About 5 hours 8 hours, 5 hours to 7 hours, 5 hours to 6 hours, 6 hours to 11 hours, 6 hours to 11 hours hours to about 10 hours, about 6 hours to about 9 hours, about 6 hours to about 8 hours, about 6 hours to about 7 hours, about 7 hours to 11 hours, 7 hours to 10 hours, 7 hours to 9 hours, 7 hours to 8 hours , about 8 hours to about 11 hours, about 8 hours to about 10 hours, about 8 hours to about 9 hours, about 9 hours to about 1 The time is 1 hour, about 9 hours to about 10 hours, or about 10 hours to about 11 hours. In some embodiments, ethyl isobutyrate and substituted 5-chloropentane are added to the reactor. In some embodiments, adding ethyl isobutyrate to the reactor simultaneously. This is done before the substituted 5-chloropentane is added to the reactor. In this case, adding ethyl isobutyrate to the reactor increases the amount of substituted 5-chloropentane added to the reactor. This is done after addition.

[0065] In certain embodiments, ethyl isobutyrate is reacted with substituted 5-chloropentane in the presence of a first base. In certain embodiments, in step (a), At the end of the reaction, the method includes quenching the reaction mixture with an acid. In the present embodiment, the acid is hydrochloric acid. In certain embodiments, ethyl isobutyrate and a substituted 5-chloropentane are represented by the compound of formula (I) In certain embodiments, the substituted 5-chloropentane is a starting material used in the preparation of the product. Purity is 99% or more and 99.1% or less when measured by gas chromatography (GC). Above, 99.2% or more, 99.3% or more, 99.4% or more, 99.5% or more, 99.6% or more or more, 99.7% or more, 99.8% or more, or 99.9% or more. In the present invention, the purity of the substituted 5-chloropentane is 99% or higher as measured by GC. In certain embodiments, the purity of the ethyl isobutyrate is measured by gas chromatography (GC). When specified, it is 99% or more, 99.1% or more, 99.2% or more, 99.3% or more, 99. 4% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or 9 In some embodiments, the purity of the ethyl isobutyrate is determined by GC. If so, the accuracy is 99.5% or more.

[0066] In certain embodiments, the concentration of ethanol present in the ethyl isobutyrate is determined by GC. If measured, 0.05% or less, 0.06% or less, 0.07% or less, 0.08% or less, 0.09% or less, 0.1% or less, 0.11% or less, 0.12% or less, 0.13% or less, 0 In some embodiments, the ethyl isobutyrate is 0.14% or less, or 0.15% or less. The concentration of ethanol present is less than 0.1% as measured by GC.

[0067] In certain embodiments, the substituted 5-chloropentane is 1-iodo-5-chloropentane. In certain embodiments, the substituted 5-chloropentane is 1-bromo-5-chloropentane. It is.

[0068] In certain embodiments, 1-iodo-5-chloropentane or 1-bromo-5-chloropentane The purity of ethane is 99% or more as measured by gas chromatography (GC). , 99.1% or more, 99.2% or more, 99.3% or more, 99.4% or more, 99.5% or more , 99.6% or more, 99.7% or more, 99.8% or more, or 99.9% or more. In certain embodiments, in step (a), the first base is lithium diisopropyl ether. amide, lithium bis(trimethylsilyl)amide, sodium hydride, sodium amide , lithium amide and lithium tetramethylpiperidide. In some embodiments, in step (a), the first base is lithium diisopropylamine. It is. In certain embodiments, the unreacted substituted 5-chloropentane remaining upon completion of step (a) is The amount of is less than 0.05%, less than 0.06%, less than 0.07% when measured by GC. Lower, 0.08% or less, 0.09% or less, 0.1% or less, 0.11% or less, 0.12% or less , 0.12% or less, 0.13% or less, 0.14% or less, 0.15% or less, 0.16% or less , 0.17% or less, 0.18% or less, 0.19% or less, or 0.2% or less. In this embodiment, the amount of unreacted substituted 5-chloropentane remaining upon completion of step (a) is , when measured by GC, 0.21% or less, 0.22% or less, 0.23% or less, .24% or less, 0.25% or less, 0.25% or less, 0.26% or less, 0.27% or less, 0 .28% or less, 0.29% or less, 0.3% or less, 0.31% or less, 0.32% or less, 0. 33% or less, 0.34% or less, 0.35% or less, 0.36% or less, 0.37% or less, 0. 38% or less, 0.39% or less, or 0.4% or less.

[0069] Synthesis of lithium diisopropylamide (first base for preparing the compound of formula (I)) Growth In various embodiments, the base used to prepare the compound of formula (I) is The synthesis of butyllithium diisopropylamide is generally carried out by reacting diisopropylamine with butyllithium The method includes contacting the TIFF2025032197000033.tif17160

[0070] In certain embodiments, the molar ratio of butyllithium to diisopropylamine is about 1:1. 04, approx. 1:1.05, approx. 1:1.06, approx. 1:1.07, approx. 1:1.08, approx. 1:1. 09, about 1:1.1, about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5 or about In some embodiments, the ratio of butyllithium to diisopropylamine is 1:1.6. The molar ratio is about 1:1.07. In some embodiments, the butyllithium to diisopropyl The molar ratio of propylamine is about 1:1.5. In certain embodiments, the molar ratio of butyllithium to diisopropylamine is about 1:1. 04~approx. 1:1.1, approx. 1:1.05~approx. 1:1.1, approx. 1:1.06~approx. 1:1.1, Approx. 1:1.07 to approx. 1:1.1, Approx. 1:1.08 to approx. 1:1.1, Approx. 1:1.09 to approx. :1, about 1:1.04~about 1:1.09, about 1:1.04~about 1:1.08, about 1:1. 04~approx. 1:1.07, approx. 1:1.04~approx. 1:1.06, approx. 1:1.04~approx. 1:1. 05, about 1:1.05 to about 1:1.09, about 1:1.05 to about 1:1.08, about 1:1. 05~approx. 1:1.07, approx. 1:1.05~approx. 1:1.06, approx. 1:1.06~approx. 1:1. 09, about 1:1.06 to about 1:1.08, about 1:1.06 to about 1:1.07, about 1:1. 1:07 to about 1:1.09, about 1:1.07 to about 1:1.08, or about 1:1.08 to about 1: In some embodiments, the molar ratio of butyllithium to diisopropylamine is 1.09. The ratio of the fluorine-containing gas to the fluorine-containing gas is about 1:1.06 to about 1:1.07.

[0071] In certain embodiments, the contacting of diisopropylamine with butyllithium is carried out at temperatures below 0° C. It is carried out at temperatures below -5°C, below -10°C, below -15°C or below -20°C. In one embodiment, the contacting of diisopropylamine with butyllithium is carried out at a temperature of −5° C. or less. It is held. In certain embodiments, contacting diisopropylamine with butyllithium comprises contacting diisopropylamine with tetrahydrofuran. It is carried out in THF. In certain embodiments, lithium diisopropylamide is reacted prior to step (a), e.g., It is prepared prior to contacting ethyl isobutyrate with 1-bromo-5-chloropentane. In certain embodiments, lithium diisopropylamide can be used, for example, by reacting ethyl isobutyrate with -bromo-5-chloropentane during step (a). In some embodiments, lithium diisopropylamide is prepared during step (a). When prepared in situ, substituted 5-chloropentane vs. ethyl isobutyrate vs. butyllithium vs. The molar ratio of diisopropylamine is about 1:1.1:1.2:1.26, about 1:1.1:1 .15:1.75, approx. 1:1.1:1.24:1.3, approx. 1:1.1:1.2:1.29 , about 1:1.1:1.2:1.28, or about 1:1-1.25:1.15-1.2:1. In some embodiments, lithium diisopropylamide is Substituted 5-chloropentane vs. ethyl isobutyrate vs. butyrate when prepared in situ during (a) The molar ratio of lithium to diisopropylamine is about 1:1.1:1.2:1.28. . In some embodiments, the substituted 5-chloropentane is 1-bromo-5-chloropentane. It is.

[0072] Synthesis of Compounds of Formula (II) - Step (b) In various embodiments, synthesis of a compound of formula (II) (wherein X is Br or I) Generally, a compound of formula (I) is reacted with a compound of formula [M] + [X] - The method includes contacting the compound with a salt of TIFF2025032197000034.tif16160

[0073] In certain embodiments, in step (b), the compound of formula (I) is reacted with a compound of formula [M] + [X] - of Contacting the salt with acetone, 2-butanone, methyl isobutyl ketone, THF and 3-pentanone, where M is selected from the group consisting of Li, Na, and K. and X is selected from the group consisting of Br and I. In certain embodiments, in step (b), the solvent contains less than about 3.5% by weight water, about 3% by weight water, % water by weight, less than about 2.5% water by weight, less than about 2% water by weight, less than about 1.5% water by weight , less than about 1% water by weight, or less than about 0.5% water by weight. In some embodiments, In step (b), the solvent contains less than about 3% water by weight. In certain embodiments, in step (b), the compound of formula (I) is reacted with a compound of formula [M] + [X] - of The contacting of the compound of formula (I) with the salt is carried out by subjecting the compound of formula (I) to about 1 molar equivalent, about 1.05 molar equivalents, about 1.1 molar equivalents, about 1.15 molar equivalents, about 1.2 molar equivalents or about 1.25 molar equivalents of the formula [M] + [X] - In particular, the method includes contacting the In certain embodiments, in step (b), the compound of formula (I) is reacted with a compound of formula [M] + [X] - Salt and The contacting comprises contacting the compound of formula (I) with about 1.1 moles of the compound of formula (I) Molar equivalent formula [M] + [X] - The method includes contacting the compound with a salt of

[0074] In certain embodiments, in step (b), the compound of formula (I) is reacted with a compound of formula [M] + [X] - of The contacting with the salt may be performed at about 75° C. to about 85° C., at about 76° C. to about 85° C., at about 77° C. to about 85° C. , about 78℃ to about 85℃, about 79℃ to about 85℃, about 80℃ to about 85℃, about 81℃ to about 85℃ , about 82℃ to about 85℃, about 83℃ to about 85℃, about 84℃ to about 85℃, about 75℃ to about 84℃ , about 75℃ to about 83℃, about 75℃ to about 82℃, about 75℃ to about 81℃, about 75℃ to about 80℃ , about 75℃ to about 79℃, about 75℃ to about 78℃, about 75℃ to about 77℃, about 75℃ to about 76℃ , about 76℃ to about 84℃, about 76℃ to about 83℃, about 76℃ to about 82℃, about 76℃ to about 81℃ , about 76℃ to about 80℃, about 76℃ to about 79℃, about 76℃ to about 78℃, about 76℃ to about 77℃ , about 77℃ to about 84℃, about 77℃ to about 83℃, about 77℃ to about 82℃, about 77℃ to about 81℃ , about 77℃ to about 80℃, about 77℃ to about 79℃, about 77℃ to about 78℃, about 78℃ to about 84℃ , about 78℃ to about 83℃, about 78℃ to about 82℃, about 78℃ to about 81℃, about 78℃ to about 80℃ , about 78℃ to about 79℃, about 79℃ to about 84℃, about 79℃ to about 83℃, about 79℃ to about 82℃ , about 79℃ to about 81℃, about 79℃ to about 80℃, about 80℃ to about 84℃, about 80℃ to about 83℃ , about 80℃ to about 82℃, about 80℃ to about 81℃, about 81℃ to about 84℃, about 81℃ to about 83℃ , about 81°C to about 82°C, about 82°C to about 84°C, about 82°C to about 83°C, or about 83°C to about 8 In some embodiments, step (b) is carried out at a temperature in the range of 4° C. The compound of formula [M] + [X] - The contacting with the salt is carried out at a temperature ranging from about 78° C. to about 82° C. It is performed at 300 degrees. In certain embodiments, in step (b), a compound of formula [M] + [X] - The salt is lithium bromide. (LiBr), lithium iodide (LiI), potassium bromide (KBr), potassium iodide ( Sodium iodide (NaI), sodium bromide (NaBr), and sodium iodide (NaI). In some embodiments, in step (b), a compound of formula [M] is selected. + [X] - The salt is It is sodium urate.

[0075] Synthesis of compounds of formula (IV) - step (c) In various embodiments, the synthesis of a compound of formula (IV) generally comprises the steps of: contacting the first intermediate with toluenesulfonylmethyl isocyanide in the presence of a second base to form a first intermediate The method includes forming a first intermediate and contacting the first intermediate with an acid. TIFF2025032197000035.tif18160

[0076] Synthesis of the first intermediate In various embodiments, the synthesis of the first intermediate generally comprises reacting a compound of formula (II) with a second intermediate. with toluenesulfonylmethyl isocyanide in the presence of a base of TIFF2025032197000036.tif39160

[0077] In certain embodiments, in step (c), the second base is sodium hydride, potassium hydroxide, sodium tert-butoxide and sodium tert-pentoxide. In some embodiments, in step (c), the second base is sodium tert-pentoxy It is. In certain embodiments, in step (c), the presence of sodium tert-pentoxide The compound of formula (II) is contacted with toluenesulfonylmethyl isocyanide under The formation of the intermediate body is performed at about -20°C to about 10°C, about -10°C to about 10°C, about 0°C to about 10°C, ℃, about -20℃ to about 0℃, about -20℃ to about -10℃, or about -10℃ to about 0℃ In certain embodiments, in step (c), sodium tert-pentanol is used. The compound of formula (II) is contacted with toluenesulfonylmethyl isocyanide in the presence of toluenesulfonylmethyl isocyanide. The reaction to form the first intermediate is carried out at a temperature ranging from about -20°C to about 10°C. In certain embodiments, in step (c), in the presence of sodium tert-pentoxide contacting the compound of formula (II) with toluenesulfonylmethyl isocyanide to produce a first intermediate The forming of is carried out at a temperature ranging from about -15°C to about 0°C.

[0078] In certain embodiments, in step (c), a compound of formula (II) is reacted in the presence of a second base. with toluenesulfonylmethyl isocyanide to form a first intermediate, The reaction is carried out at a temperature of about -20°C, about -15°C, about -10°C, about -5°C or about 0°C. In certain embodiments, in step (c), a compound of formula (II) is reacted with toluenesulfonyl The molar ratio of methyl isocyanide is about 1.7:1, about 1.8:1, about 1.9:1, about 2:1 , about 2.1:1, or about 2.2:1. In certain embodiments, in step (c), The molar ratio of the compound of formula (II) to toluenesulfonylmethyl isocyanide is about 1.9:1. be. In some embodiments, in step (c), the compound of formula (II) is reacted with toluenesulfonyl. The molar ratio of diphenylmethyl isocyanide to the second base is about 1.9:1.0:2.1. In some embodiments, in step (c), the compound of Formula (II) is reacted with toluenesulfonyl The molar ratio of methyl isocyanide to the second base is about 1.9:1.0:2.2. In some embodiments, in step (c), the compound of formula (II) is reacted with toluenesulfonyl. The molar ratio of nylmethyl isocyanide to sodium tert-pentoxide is approximately 1.9:1. In some embodiments, in step (c), the compound of formula (II) Molar ratio of toluenesulfonylmethyl isocyanide to sodium tert-pentoxide is approximately 1.9:1.0:2.2. In certain embodiments, in step (c), a compound of formula (II) and a toluenesulfonyl The contacting of methyl isocyanide is carried out in a solvent containing dimethylacetamide or dimethyl This is carried out in a solvent which is acetamide.

[0079] Synthesis of compounds of formula (IV) In various embodiments, the synthesis of a compound of formula (IV) generally comprises reacting a first intermediate with an acid. This includes contacting. TIFF2025032197000037.tif18160

[0080] In certain embodiments, in step (c), contacting the first intermediate with an acid comprises about -15℃ to about 35℃, about -10℃ to about 35℃, about -5℃ to about 35℃, about 0℃ to about 35℃, About 5℃ to about 35℃, about 10℃ to about 35℃, about 15℃ to about 35℃, about 20℃ to about 35℃, about 25℃~approx. 35℃, approx. 30℃~approx. 35℃, approx. -15℃~approx. 30℃, approx. -15℃~approx. 25℃ , about -15℃ to about 20℃, about -15℃ to about 15℃, about -15℃ to about 10℃, about -15℃ to About 5℃, about -15℃ to about 0℃, about -15℃ to about -5℃, about -15℃ to about -10℃, about -1 0℃~approx. 30℃, approx. -10℃~approx. 25℃, approx. -10℃~approx. 20℃, approx. -10℃~approx. 15℃ , about -10℃ to about 10℃, about -10℃ to about 5℃, about -10℃ to about 10℃, about -10℃ to about -5℃, approx. -5℃~approx. 30℃, approx. -5℃~approx. 25℃, approx. -5℃~approx. 20℃, approx. -5℃~approx. 15℃, approx. -5℃~approx. 10℃, approx. -5℃~approx. 5℃, approx. -5℃~approx. 0℃, approx. 0℃~approx. 30℃ , about 0℃ to about 25℃, about 0℃ to about 20℃, about 0℃ to about 15℃, about 0℃ to about 10℃, about 0℃ ~5℃, ~5℃~30℃, ~5℃~25℃, ~5℃~20℃, ~5℃~15℃ , about 5°C to about 10°C, about 10°C to about 30°C, about 10°C to about 25°C, about 10°C to about 20°C, About 10℃ to about 15℃, about 15℃ to about 30℃, about 15℃ to about 25℃, about 15℃ to about 20℃, The reaction is carried out at about 20°C to about 30°C, about 20°C to about 25°C, or about 25°C to about 30°C. In some embodiments, in step (c), contacting the first intermediate with an acid is at about -1 The reaction is carried out at a temperature ranging from 0° C. to about 35° C. In some embodiments, in step (c), The contacting of the first intermediate with the acid is carried out at a temperature ranging from about −15° C. to about 25° C. In some embodiments, in step (c), contacting the first intermediate with an acid The reaction is carried out at a temperature ranging from about 10°C to about 25°C. In certain embodiments, in step (c), the acid is hydrochloric acid.

[0081] Synthesis of Compounds of Formula (V) - Step (d) In various embodiments, the synthesis of a compound of formula (V) generally comprises reacting a compound of formula (IV) contacting the second intermediate with a reducing agent to form a second intermediate, and contacting the second intermediate with a hydrolyzable base. This includes contacting. TIFF2025032197000038.tif18160

[0082] Synthesis of the second intermediate In various embodiments, the synthesis of the second intermediate generally comprises reducing a compound of formula (IV) The method includes contacting the composition with an agent. TIFF2025032197000039.tif20160

[0083] In certain embodiments, in step (d), the reducing agent is sodium borohydride, cyano. Sodium borohydride, cerium borohydride, zinc borohydride and diisopropyl borohydride In some embodiments, the reducing agent is selected from the group consisting of water, butylaluminum, It is sodium borohydride. In certain embodiments, in step (d), the compound of formula (IV) is contacted with a reducing agent. This means that the compound of formula (IV) is mixed with about 0.25 moles of the compound of formula (IV) based on the molar amount of the compound of formula (IV). about 0.3 molar equivalents, about 0.35 molar equivalents, about 0.4 molar equivalents, about 0.45, about 0 0.5 molar equivalent, about 0.6 molar equivalent, about 0.7 molar equivalent, about 0.8 molar equivalent, about 0.9 molar equivalent equivalent, about 1.0 molar equivalent, about 1.1 molar equivalent, about 1.2 molar equivalent, about 1.3 molar equivalent, about In some embodiments, the reaction is carried out in a manner similar to that described above, but in which ... In an embodiment, in step (d), contacting the compound of formula (IV) with a reducing agent provides a compound of formula The compound of formula (IV) is reduced in an amount of about 0.35 molar equivalents based on the molar amount of the compound of formula (IV). The method includes contacting the composition with an agent.

[0084] In certain embodiments, in step (c), the compound of formula (IV) is contacted with a reducing agent. That is, about 5°C to about 30°C, about 10°C to about 30°C, about 15°C to about 30°C, about 20°C to about 3 0℃, about 25℃ to about 30℃, about 5℃ to about 25℃, about 5℃ to about 20℃, about 5℃ to about 15℃, About 5℃ to about 10℃, about 10℃ to about 25℃, about 10℃ to about 20℃, about 10℃ to about 15℃, about The reaction is carried out at a temperature ranging from 15°C to about 25°C, from about 15°C to about 20°C, or from about 20°C to about 25°C. do. In certain embodiments, in step (c), contacting the compound of formula (IV) with a reducing agent comprises: It is carried out at a temperature of about 5°C, about 10°C, about 15°C, about 20°C, about 25°C or about 30°C.

[0085] Synthesis of compounds of formula (V) In various embodiments, the synthesis of a compound of formula (V) generally comprises hydrolyzing a second intermediate. The method includes contacting the mixture with a decomposing base. TIFF2025032197000040.tif18160

[0086] In certain embodiments, in step (d), the concentration of the hydrolyzable base is about 20% weight / Weight, approx. 25% w / w, approx. 30% w / w, approx. 35% w / w, approx. 40% w / w by weight, about 45% wt / wt, about 50% wt / wt, about 55% wt / wt or about 60% wt In some embodiments, in step (d), the concentration of the hydrolyzable base is Approximately 50% weight / weight. In certain embodiments, in step (d), the second intermediate is contacted with a hydrolysis base to form Forming the compound of formula (V) is carried out in solution. In some embodiments, in step In (d), the method further comprises adjusting the pH of the solution containing the compound of formula (V) to about 3 to about 7. It further includes:

[0087] In certain embodiments, in step (d), the second intermediate is contacted with a hydrolyzable base. The temperature range is about 30℃ to about 60℃, about 35℃ to about 60℃, about 40℃ to about 60℃, and about 45℃ to about About 60℃, about 50℃~about 60℃, about 55℃~about 60℃, about 30℃~about 55℃, about 30℃~ About 50℃, about 30℃~about 45℃, about 30℃~about 40℃, about 30℃~about 35℃, about 35℃~ About 55℃, about 35℃~about 50℃, about 35℃~about 45℃, about 35℃~about 40℃, about 40℃~ About 55℃, about 40℃~about 50℃, about 40℃~about 45℃, about 45℃~about 55℃, about 45℃~ The reaction is carried out at a temperature of about 50°C or in the range of about 50°C to about 60°C.

[0088] In certain embodiments, in step (d), the second intermediate is contacted with a hydrolyzable base. The temperature can be about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C or about 60°C. In certain embodiments, in step (d), the reaction is carried out at a temperature of about 100° C. The contacting with the acidic base is carried out at a temperature of about 50°C. In certain embodiments, in step (d), the hydrolysis base is sodium hydroxide. In certain embodiments, in step (d), the compound of formula (IV) is contacted with a reducing agent to form forming a second intermediate and contacting the second intermediate with a hydrolysis base to form a compound of formula (V): The formation of the compound is carried out in a single reaction vessel.

[0089] In some embodiments of this aspect, the method comprises: (a) contacting ethyl isobutyrate with 1-bromo-5-chloropentane in the presence of a first base to form a compound of formula (I); (b) contacting a compound of formula (I) with sodium iodide to form a compound of formula (IIa) To achieve (c) reacting a compound of formula (IIa) with toluenesulfonylmethylisocyanate in the presence of a second base; an anide to form a first intermediate, and contacting the first intermediate with an acid to form a compound of formula (IV) forming a compound; TIFF2025032197000043.tif18160 and (d) contacting the compound of formula (IV) with a reducing agent to form a second intermediate; and contacting the intermediate of 2 with a hydrolysis base to form a compound of formula (V). In some embodiments of the invention, the method comprises the steps of: (e) purifying the compound of formula (V) to provide a pharmaceutical material comprising a purified amount of the compound of formula (V). This includes:

[0090] In some embodiments as described above, the same conditions as previously described (e.g., temperature ) amounts, ratios, equivalents, times, purities, and other parameters or variables may be equally applicable. For example, replace "substituted-5-chloropentane" with "1-bromo-5-chloropentane" In this case, "Formula [M] + [X] - "Salt" is replaced with "sodium iodide"; "M" is replaced with "Na" is replaced; "X" is replaced with "I"; "Compound of formula (IIa)" is replaced with "Compound of formula II "Compound of

[0091] Additionally, in certain embodiments, 1,5-dichloro in 1-bromo-5-chloropentane The concentration of pentane, as measured by GC, was 0.1%, 0.2%, 0.3%, or less. % or less, 0.4% or less, 0.5% or less, 0.6% or less, 0.7% or less, 0.8% or less, 0 0.9% or less, or 1% or less. In some embodiments, 1-bromo-5-chloropene The concentration of 1,5-dichloropentane in the ethane is less than 0.5% as determined by GC.

[0092] In certain embodiments, 1,5-dibromopentane in 1-bromo-5-chloropentane The concentration of is 0.05%, 0.1%, 0.15% or less when measured by GC. , 0.2% or less, 0.25% or less, 0.3% or less, 0.35% or less, 0.4% or less, 0. 45% or less, 0.5% or less, 0.6% or less, 0.7% or less, 0.8% or less, 0.9% or less or 1.0% or less. In some embodiments, in 1-bromo-5-chloropentane The concentration of 1,5-dibromopentane in the solution is less than 0.2% as determined by GC. In an embodiment, the concentration of 1,5-dibromopentane in 1-bromo-5-chloropentane is , measured by GC, is less than 1.0%.

[0093] In certain embodiments, the unreacted 1-bromo-5-chloro- The amount of pentane, as measured by GC, is 0.05%, 0.06%, or less. 07% or less, 0.08% or less, 0.09% or less, 0.1% or less, 0.11% or less, 0.1 2% or less, 0.12% or less, 0.13% or less, 0.14% or less, 0.15% or less, 0.1 6% or less, 0.17% or less, 0.18% or less, 0.19% or less or 0.2% or less. In some embodiments, any unreacted 1-bromo-5-chlorophenyl ether remaining upon completion of step (a) may be The amount of pentane, as measured by GC, is 0.21%, 0.22%, or less. .23% or less, 0.24% or less, 0.25% or less, 0.25% or less, 0.26% or less, 0 .27% or less, 0.28% or less, 0.29% or less, 0.3% or less, 0.31% or less, 0. 32% or less, 0.33% or less, 0.34% or less, 0.35% or less, 0.36% or less, 0. 37% or less, 0.38% or less, 0.39% or less, or 0.4% or less.

[0094] In certain embodiments, the method for preparing a compound of formula (V) comprises the steps of: (a) In the presence of lithium diisopropylamide, 1 at a temperature in the range of about -20°C to about 0°C 1.1 molar equivalents of ethyl isobutyrate to produce a compound of formula (I) forming a compound of formula I); (b) dissolving a compound of formula (I) in about 1% by mass in 2-butanone at a temperature in the range of about 78° C. to about 82° C. .1 molar equivalent of sodium iodide to form a compound of formula (IIa) , TIFF2025032197000045.tif15160(c) In dimethylacetamide, in the presence of sodium tert-pentoxide, ca. -2 Compound (IIa) is reacted with toluenesulfonylmethyl isopropanol at a temperature ranging from 0° C. to about 10° C. cyanide to form a first intermediate, at a temperature in the range of about -10°C to about 35°C. contacting the first intermediate with an acid to form a compound of formula (IV); TIFF2025032197000046.tif18160 and (d) contacting a compound of formula (IV) with about 0.35 molar equivalents of sodium borohydride; forming a second intermediate; and contacting the second intermediate with sodium hydroxide in solution. to form a compound of formula (V). In certain embodiments of the invention, the method comprises: (e) purifying the compound of formula (V) to provide a pharmaceutical material comprising a purified amount of the compound of formula (V). This includes:

[0095] In certain embodiments of the above, the amounts, ratios, and conditions (e.g., temperature) are the same as those previously described. , equivalents, time, purity, and other parameters or variables may be equally applicable, for example: When the "first base" is replaced with "lithium diisopropylamide", the "second base" Replace "sodium tert-pentoxide" with "reducing agent" and "sodium borohydride" with and replace "hydrolyzable base" with "sodium hydroxide."

[0096] Further, in certain embodiments, in step (a), lithium diisopropylamide Contacting ethyl isobutyrate with 1-bromo-5-chloropentane in the presence of 0℃~approx. 0℃, approx. -15℃~approx. 0℃, approx. -10℃~approx. 0℃, approx. -5℃~approx. 0℃, approx. -20 ℃ to about -5℃, about -20℃ to about -10℃, about -20℃ to about -15℃, about -15℃ to about -5 °C, about -15°C to about -10°C, or about -10°C to about -5°C. In certain embodiments, in step (b), the compound of formula (I) is contacted with sodium iodide. The contacting is performed at a temperature of about 78°C to about 82°C, about 78°C to about 80°C, or about 80°C to about 82°C. It is carried out at a range of temperatures.

[0097] In certain embodiments, in step (c), the compound of formula (IIa) is reacted with toluenesulfonyl The molar ratio of dimethyl isocyanide to sodium tert-pentoxide is approximately 1.9:1:2. .1.

[0098] Purification of compound of formula (V)--step (e) Various embodiments of the present invention include a method for producing a pharmaceutical material comprising a purified amount of a compound of formula (V). Including, TIFF2025032197000047.tif18160That is, the method may include purifying the compound of formula (V). In various embodiments, purifying the compound of formula (V) comprises eluting through silica gel. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is ethyl acetate. In certain embodiments, purifying the compound of formula (V) comprises crystallizing the compound of formula (V). to provide a compound of formula (V) in crystalline form. In certain embodiments, purifying the compound of formula (V) comprises purifying the compound of formula (V) with charcoal In some embodiments, the compound of formula (V) is Contacting the article with charcoal may be accomplished by reacting a compound of formula (V) with acetonitrile and activated charcoal (e.g. 5% (w / w) activated carbon).

[0099] In certain embodiments, purifying the compound of formula (V) comprises purifying the compound of formula (V) in crystalline form. and recrystallizing the product to provide a pharmaceutical material comprising a purified amount of the compound of formula (V). In various embodiments, purifying the compound of formula (V) comprises the steps of: (f) adjusting the pH of the solution containing the compound of formula (V) to about 5 to about 6; (g) Extracting the compound of formula (V) from solution using methyl tert-butyl ether providing a methyl tert-butyl ether solution comprising a compound of formula (V); (h) Methyl tert-butyl ether solution of methyl tert-butyl ether with acetic acid ethyl to provide an ethyl acetate solution comprising a compound of formula (V); (i) filtering a solution of a compound of formula (V) in ethyl acetate through silica gel; (j) crystallizing the compound of formula (V) using ethyl acetate and water to obtain a crystalline form of the formula ( V) providing a compound of formula (I); and (k) Recrystallizing the crystalline form of the compound of formula (V) using ethyl acetate and water to obtain a purified providing a pharmaceutical material comprising a prescribed amount of a compound of formula (V).

[0100] In certain embodiments, methyl tert-butyl ether is used in step (g). The compound of formula (V) can be extracted from the solution at about 5° C., about 10° C., about 15° C., about 20° C. , about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, or about 55°C or less In certain embodiments, in step (g), methyl tert-butyl ether is Extraction of the compound of formula (V) from solution using ether is carried out at a temperature of about 15° C. or less. In certain embodiments, in step (g), methyl tert-butyl ether is The extraction of the compound of formula (V) from the solution using is carried out at a temperature of about 50° C. or less.

[0101] In certain embodiments, in step (j), ethyl acetate and water are used to prepare a compound of formula (V): The compound may be crystallized at a temperature of about 60° C. to about −10° C., about 55° C. to about −10° C., about 50° C. ~ about -10℃, about 45℃~ about -10℃, about 40℃~ about -10℃, about 35℃~ about -10℃, About 30℃ to about -10℃, about 25℃ to about -10℃, about 20℃ to about -10℃, about 15℃ to about - 10℃, approx. 10℃~approx. -10℃, approx. 5℃~approx. -10℃, approx. 0℃~approx. -10℃, approx. -5℃~ Approximately -10℃, Approximately 60℃ to Approximately -5℃, Approximately 55℃ to Approximately -5℃, Approximately 50℃ to Approximately -5℃, Approximately 45℃ ~ about -5℃, about 40℃~ about -5℃, about 35℃~ about -5℃, about 30℃~ about -5℃, about 25℃ ~ about -5℃, about 20℃~ about -5℃, about 15℃~ about -5℃, about 10℃~ about -5℃, about 5℃~ Approximately -5℃, Approximately 0℃ to Approximately -5℃, Approximately 60℃ to Approximately 0℃, Approximately 55℃ to Approximately 0℃, Approximately 50℃ to Approximately 0℃ , about 45℃ to about 0℃, about 40℃ to about 0℃, about 35℃ to about 0℃, about 30℃ to about 0℃, about 25 ℃~approx. 0℃, approx. 20℃~approx. 0℃, approx. 15℃~approx. 0℃, approx. 10℃~approx. 0℃, approx. 5℃~approx. 0℃ , about 60°C to about 5°C, about 55°C to about 5°C, about 50°C to about 5°C, about 45°C to about 5°C, about 40 ℃~approx. 5℃, approx. 35℃~approx. 5℃, approx. 30℃~approx. 5℃, approx. 25℃~approx. 5℃, approx. 20℃~approx. 5 ℃, about 15℃ to about 5℃, about 10℃ to about 5℃, about 60℃ to about 10℃, about 55℃ to about 10℃, About 50℃ to about 10℃, about 45℃ to about 10℃, about 40℃ to about 10℃, about 35℃ to about 10℃, About 30℃ to about 10℃, about 25℃ to about 10℃, about 20℃ to about 10℃, about 15℃ to about 10℃, About 60℃ to about 15℃, about 55℃ to about 15℃, about 50℃ to about 15℃, about 45℃ to about 15℃, About 40℃ to about 15℃, about 35℃ to about 15℃, about 30℃ to about 15℃, about 25℃ to about 15℃, About 20℃ to about 15℃, about 60℃ to about 20℃, about 55℃ to about 20℃, about 50℃ to about 20℃, About 45℃ to about 20℃, about 40℃ to about 20℃, about 35℃ to about 20℃, about 30℃ to about 20℃, About 25℃ to about 20℃, about 60℃ to about 25℃, about 55℃ to about 25℃, about 50℃ to about 25℃, About 45℃ to about 25℃, about 40℃ to about 25℃, about 35℃ to about 25℃, about 30℃ to about 25℃, About 60℃ to about 30℃, about 55℃ to about 30℃, about 50℃ to about 30℃, about 45℃ to about 30℃, About 60℃ to about 35℃, about 55℃ to about 35℃, about 50℃ to about 35℃, about 45℃ to about 35℃, About 40℃ to about 35℃, about 60℃ to about 40℃, about 55℃ to about 40℃, about 50℃ to about 40℃, About 45℃ to about 40℃, about 60℃ to about 45℃, about 55℃ to about 45℃, about 50℃ to about 45℃, Over a temperature range of about 60°C to about 50°C, about 55°C to about 50°C, or about 60°C to about 55°C In certain embodiments, in step (j), ethyl acetate and water are used to prepare a compound of formula The crystallization of compound (V) can be carried out over a temperature range of about 50° C. to about −5° C. do.

[0102] In certain embodiments, in step (k), ethyl acetate and water are used to prepare a crystalline form of formula The compound (V) can be recrystallized at about 70° C. to about 5° C., about 65° C. to about 5° C., about 60° C. to about 70° C. ℃~approx. 5℃, approx. 55℃~approx. 5℃, approx. 50℃~approx. 5℃, approx. 45℃~approx. 5℃, approx. 40℃~approx. 5 ℃, about 35℃ to about 5℃, about 30℃ to about 5℃, about 25℃ to about 5℃, about 20℃ to about 5℃, about 1 5℃~approx. 5℃, approx. 10℃~approx. 5℃, approx. 70℃~approx. 10℃, approx. 65℃~approx. 10℃, approx. 60℃ ~10℃, ~55℃~10℃, ~50℃~10℃, ~45℃~10℃, ~40℃ ~10℃, ~35℃~10℃, ~30℃~10℃, ~25℃~10℃, ~20℃ ~10℃, ~15℃~10℃, ~70℃~15℃, ~65℃~15℃, ~60℃ ~15℃, ~55℃~15℃, ~50℃~15℃, ~45℃~15℃, ~40℃ ~15℃, ~35℃~15℃, ~30℃~15℃, ~25℃~15℃, ~20℃ ~15℃, ~70℃~20℃, ~65℃~20℃, ~60℃~20℃, ~55℃ ~20℃, ~50℃~20℃, ~45℃~20℃, ~40℃~20℃, ~35℃ ~20℃, ~30℃~20℃, ~25℃~20℃, ~70℃~25℃, ~65℃ ~25℃, ~60℃~25℃, ~55℃~25℃, ~50℃~25℃, ~45℃ ~25℃, ~40℃~25℃, ~35℃~25℃, ~30℃~25℃, ~70℃ ~30℃, ~65℃~30℃, ~60℃~30℃, ~55℃~30℃, ~50℃ ~30℃, ~45℃~30℃, ~40℃~30℃, ~35℃~30℃, ~70℃ ~35℃, ~65℃~35℃, ~60℃~35℃, ~55℃~35℃, ~50℃ ~35℃, ~45℃~35℃, ~40℃~35℃, ~70℃~40℃, ~65℃ ~40℃, ~60℃~40℃, ~55℃~40℃, ~50℃~40℃, ~45℃ ~40℃, ~70℃~45℃, ~65℃~45℃, ~60℃~45℃, ~55℃ ~45℃, ~50℃~45℃, ~70℃~50℃, ~65℃~50℃, ~60℃ ~50℃, ~55℃~50℃, ~70℃~55℃, ~65℃~55℃, ~60℃ Temperature of about 55°C, about 70°C to about 60°C, about 65°C to about 60°C, or about 70°C to about 65°C In certain embodiments, in step (k), ethyl acetate and water are The crystalline form of the compound of formula (V) can be recrystallized using a method comprising the steps of: This is done over a range of degrees.

[0103] In certain embodiments, purifying a compound of formula (V) comprises the steps of: (l) dissolving a compound of formula (V) in crystalline form in acetonitrile, thereby forming a solution; To accomplish; (m) contacting the solution with charcoal; (n) filtering the charcoal to obtain a purified solution comprising the compound of formula (V); and (o) crystallizing the compound of formula (V) from the purified solution to obtain a purified amount of the compound of formula (V). and providing a pharmaceutical material comprising the In various embodiments, steps (l) to (o) above may be carried out in the manner described above by carrying out steps (f) to (k). It should be understood that this may be performed later or without.

[0104] Crystallization of the compound of formula (V) In various embodiments, purifying the compound of formula (V) comprises removing a solvent or mixture of solvents. For example, crystallizing the compound of formula (V) from ethyl acetate and water.

[0105] In certain embodiments, the concentration of water in the mixture of solvents comprising ethyl acetate and water is about 0.5 %(w / w), approx. 0.6%(w / w), approx. 0.75%(w / w), approx. 0.9 % (wt / wt), approx. 1.05% (wt / wt), approx. 1.2% (wt / wt), approx. 1.3 5% (w / w), about 1.4% (w / w) or about 1.5% (w / w). In some embodiments, the concentration of water in the mixture of solvents comprising ethyl acetate and water is about 1. 05% (w / w).

[0106] In certain embodiments, the concentration of water in the mixture of solvents comprising ethyl acetate and water is about 0.5 % (weight / weight) ~ approx. 1.5% (weight / weight), approx. 0.5% (weight / weight) ~ approx. 1.4% (weight / weight), approx. 0.5% (weight / weight) ~ approx. 1.35% (weight / weight), approx. 0.5% (Weight / Weight) ~ Approx. 1.2% (Weight / Weight), Approx. 0.5% (Weight / Weight) ~ Approx. 1.05% (weight / weight), approx. 0.5% (weight / weight) ~ approx. 0.9% (weight / weight), approx. 0.5% ( Weight / Weight) ~ Approx. 0.75% (Weight / Weight), Approx. 0.5% (Weight / Weight) ~ Approx. 0.6% ( weight / weight), approx. 0.6% (weight / weight) to approx. 1.5% (weight / weight), approx. 0.6% (weight / weight), approx. (weight / weight) ~ approx. 1.4% (weight / weight), approx. 0.6% (weight / weight) ~ approx. 1.35% (weight / weight) amount / weight), approximately 0.6% (weight / weight) ~ approximately 1.2% (weight / weight), approximately 0.6% (weight / weight) ~ approx. 1.05% (weight / weight), approx. 0.6% (weight / weight) ~ approx. 0.9% (weight / weight), approx. 0.6% (wt / wt) ~ approx. 0.75% (wt / wt), approx. 0.75% (wt / wt), approx. (weight / weight) ~ approx. 1.5% (weight / weight), approx. 0.75% (weight / weight) ~ approx. 1.4% (weight / weight) amount / weight), approximately 0.75% (weight / weight) ~ approximately 1.35% (weight / weight), approximately 0.75% (weight / weight) ~ approx. 1.2% (weight / weight), approx. 0.75% (weight / weight) ~ approx. 1.05 % (weight / weight), approx. 0.75% (weight / weight) ~ approx. 0.9% (weight / weight), approx. 0.9 % (weight / weight) ~ approx. 1.5% (weight / weight), approx. 0.9% (weight / weight) ~ approx. 1.35 % (weight / weight), approx. 0.9% (weight / weight) ~ approx. 1.2% (weight / weight), approx. 0.9% (Weight / Weight) ~ Approx. 1.05% (Weight / Weight), Approx. 1.05% (Weight / Weight) ~ Approx. 1.5 % (wt / wt), approx. 1.05% (wt / wt) ~ approx. 1.35% (wt / wt), approx. 1. 05% (weight / weight) ~ approx. 1.2% (weight / weight), approx. 1.2% (weight / weight) ~ approx. 1. 5% (wt / wt), approx. 1.2% (wt / wt) ~ approx. 1.5% (wt / wt), approx. 1.2 % (wt / wt) to about 1.35% (wt / wt), or about 1.35% (wt / wt) to about 1.5% (w / w). In some embodiments, the solvent comprises ethyl acetate and water. The concentration of water in the mixture is about 0.6% (w / w) to about 1.4% (w / w). In some embodiments, the concentration of water in the mixture of solvents comprising ethyl acetate and water is about 0. It ranges from .75% (w / w) to about 1.35% (w / w).

[0107] In various embodiments, a compound of formula (V) is prepared by condensing a compound of formula (V) with ethyl acetate and water. Crystallizing the compound of formula V (1) heating the mixture to a first temperature (T 1 ) to the second temperature (T 2 ) by cooling to , T 1 is about 40°C to about 60°C, and T 2 The temperature is about 15° C. to about 30° C., and the mixture is heated for about 1 T at a rate of 0°C / hour to about 20°C / hour 1 From T 2 Cool to room temperature; (2) T 2 for at least 3 hours; (3) Add the mixture to T 2 to the third temperature (T 3 ) and T 3 is about -5 °C to about 10 °C, and the mixture is heated to T 2 From T 3 Ma and (4) T 3 for at least 3 hours; Thereby producing a crystalline form of the compound of formula (V).

[0108] In certain embodiments, in the crystallization step (1), T 1 is about 40℃ to about 60℃, about 4 5℃~60℃, 50℃~60℃, 55℃~60℃, 40℃~55℃, 4 0°C to about 50°C, about 40°C to about 45°C, about 45°C to about 55°C, about 45°C to about 50°C, or In some embodiments, in the crystallization step (1), T 1 In some embodiments, in the crystallization step (1), T 1 The temperature is about 45°C to about 55°C.

[0109] In certain embodiments, in the crystallization step (1), T 1 is about 40℃, about 45℃, about 5 In some embodiments, the crystallization temperature in the crystallization step (1) is about 0° C., about 55° C., or about 60° C. And T 1 is about 50°C. In certain embodiments, in the crystallization step (1), T 2 is about 15℃ to about 30℃, about 2 0°C to about 30°C, about 25°C to about 30°C, about 15°C to about 25°C, about 15°C to about 20°C, or In some embodiments, in the crystallization step (i), T 2 In some embodiments, in the crystallization step (1), T 2 The temperature is about 20°C to about 25°C.

[0110] In certain embodiments, in the crystallization step (1), T 2 is about 15℃, about 16℃, about 1 7℃, about 18℃, about 19℃, about 20℃, about 21℃, about 22℃, about 23℃, about 24℃, about 2 5°C, about 26°C, about 27°C, about 28°C, about 29°C, or about 30°C. In the crystallization step (1), T 2 is about 22°C. In a specific embodiment, in the crystallization step (1), the mixture is heated at about 10° C. / hour to about 20° C. / hour. ℃ / hour, about 12℃ / hour to about 20℃ / hour, about 14℃ / hour to about 20℃ / hour, about 16 ℃ / hour to about 20℃ / hour, about 18℃ / hour to about 20℃ / hour, about 10℃ / hour to about 18 ℃ / hour, about 10℃ / hour to about 16℃ / hour, about 10℃ / hour to about 14℃ / hour, about 10 ℃ / hour to about 12℃ / hour, about 12℃ / hour to about 18℃ / hour, about 12℃ / hour to about 16℃ / hour ℃ / hour, about 12℃ / hour to about 14℃ / hour, about 14℃ / hour to about 18℃ / hour, about 14 °C / hour to about 16 °C / hour, or about 16 °C / hour to about 18 °C / hour 1 ~T 2 Ma In some embodiments, the mixture is cooled at a rate of about 10° C. / hour to about 20° C. / hour. T in degrees 1 From T 2 In some embodiments, the mixture is cooled at about 10° C. / hour to about 10° C. / hour. T at a rate of about 12°C / hour 1 From T 2 The mixture is cooled to . In a particular embodiment, in the crystallization step (1), the mixture is heated at about 10° C. / hour for about 11 °C / hour, about 12 °C / hour, about 13 °C / hour, about 14 °C / hour, about 15 °C / hour, about 16 °C / hour, about 17 °C / hour, about 18 °C / hour, about 19 °C / hour, or about 20 °C / hour T in degrees 1 From T 2 In certain embodiments, in the crystallization step (1), the mixture is cooled to at a rate of about 11°C / hour. 1 From T 2 Cool to 35°C.

[0111] In certain embodiments, in the crystallization step (2), the mixture is subjected to T 2 At least 3 hours , at least 3.5 hours, at least 4 hours, at least 4.5 hours, at least 5 hours , at least 5.5 hours, at least 6 hours, at least 6.5 hours, at least 7 hours , at least 7.5 hours, at least 8 hours, at least 8.5 hours, at least 9 hours , at least 9.5 hours, or at least 10 hours. In the crystallization step (2), the mixture is subjected to T 2 Hold for at least 6 hours. In certain embodiments, in the crystallization step (2), the mixture is subjected to T 2 3 hours or less, 3.5 Hours or less, 4 hours or less, 4.5 hours or less, 5 hours or less, 5.5 hours or less, 6 hours or less, 6 .5 hours or less, 7 hours or less, 7.5 hours or less, 8 hours or less, 8.5 hours or less, 9 hours or less , 9.5 hours or less, 10 hours or less, 10.5 hours or less, 11 hours or less, 11.5 hours or less , 12 hours or less, 16 hours or less, 20 hours or less, or 24 hours or less. In an embodiment, in the crystallization step (2), the mixture is subjected to T 2 Hold for 6 hours or less.

[0112] In certain embodiments, in the crystallization step (3), T 3 is about -5℃ to about 10℃, about 0 °C to about 10 °C, about 5 °C to about 10 °C, about -5 °C to about 5 °C, about -5 °C to about 0 °C, or about 0 °C to In some embodiments, the T 3 The temperature ranges from about -5°C to about 10°C. In the embodiment, T 3 is about -5°C to about 5°C. In certain embodiments, in the crystallization step (3), T 3 is about -5℃, about 0℃, about 5℃ or about 10° C. In some embodiments, in the crystallization step (3), T 3 is about It is 0℃. In certain embodiments, in the crystallization step (3), the mixture is heated at about 5° C. / hour to about 15° C. / hour. / hour, about 7℃ / hour to about 15℃ / hour, about 9℃ / hour to about 15℃ / hour, about 11℃ / hour 10°C / hour to 15°C / hour, 13°C / hour to 15°C / hour, 5°C / hour to 13°C / hour , about 5°C / hour to about 11°C / hour, about 5°C / hour to about 9°C / hour, about 5°C / hour to about 7°C / hour, about 7℃ / hour to about 13℃ / hour, about 7℃ / hour to about 11℃ / hour, about 7℃ / hour about 9° C. / hour, about 9° C. / hour to about 13° C. / hour, about 9° C. / hour to about 11° C. / hour, or T at a rate of about 11℃ / hour to about 13℃ / hour 2 From T 3 In some embodiments, In the crystallization step (3), the mixture is heated to T at a rate of about 5° C. / hour to about 15° C. / hour. 2 From T 3 In some embodiments, in the crystallization step (3), the mixture is cooled to about T at a rate of 7℃ / hour to 13℃ / hour 2 From T 3 Cool to 35°C. In certain embodiments, in the crystallization step (3), the mixture is heated at about 5° C. / hour, about 6° C. / hour, time, about 7°C / hour, about 8°C / hour, about 9°C / hour, about 10°C / hour, about 11°C / hour, T at a rate of about 12° C. / hour, about 13° C. / hour, about 14° C. / hour, or about 15° C. / hour 2 mosquito et al. 3 In some embodiments, in the crystallization step (3), the mixture is cooled to about 1 T at a rate of 1°C / hour 2 From T 3 Cool to 35°C.

[0113] In certain embodiments, in the crystallization step (4), the mixture is subjected to T 3 At least 3 hours , at least 3.5 hours, at least 4 hours, at least 4.5 hours, at least 5 hours , at least 5.5 hours, at least 6 hours, at least 6.5 hours, at least 7 hours , at least 7.5 hours, at least 8 hours, at least 8.5 hours, at least 9 hours , at least 9.5 hours, or at least 10 hours. In the crystallization step (4), the mixture is subjected to T 3 Hold for at least 6 hours. In certain embodiments, in the crystallization step (4), the mixture is subjected to T 3 3 hours or less, 3.5 Hours or less, 4 hours or less, 4.5 hours or less, 5 hours or less, 5.5 hours or less, 6 hours or less, 6 .5 hours or less, 7 hours or less, 7.5 hours or less, 8 hours or less, 8.5 hours or less, 9 hours or less , 9.5 hours or less, 10 hours or less, 10.5 hours or less, 11 hours or less, 11.5 hours or less , 12 hours or less, 16 hours or less, 20 hours or less, or 24 hours or less. In an embodiment, in the crystallization step (4), the mixture is subjected to T 3 and hold for 10 hours or less.

[0114] In certain embodiments, a compound of formula (V) can be prepared from a mixture comprising a compound of formula (V), ethyl acetate, and water. In order to promote the crystallization of the compound of formula (V), a crystallization step (1), during crystallization step (1), during crystallization step (2), during crystallization step (3), the mixture during the crystallization step (4), during the crystallization step (5), or any combination thereof. The method further comprises seeding the crystals with an amount of a compound of formula (V) in crystalline form.

[0115] In certain embodiments, the amount of seeds added to the mixture is selected from the group consisting of 1,2-dichlorophenyl ether (1,2-dichlorophenyl ether) and 1,2-dichlorophenyl ether (1,2-dichlorophenyl ether). IV) about 0.001 kg / kg based on the weight of seeds per kilogram of compound g, approx. 0.0012kg / kg, approx. 0.0014kg / kg, approx. 0.0016kg / kg , about 0.0018 kg / kg or about 0.002 kg / kg. The amount of seeds added to the mixture is determined by the amount of one of the compounds of formula (IV) produced in step (c). Based on the weight of seeds per kilogram, this is approximately 0.0014 kg / kg.

[0116] In certain embodiments, the crystalline form of the compound of formula (V) that is added as a seed to the mixture is , e.g., X-ray powder diffraction pattern or peak(s), and / or crystalline form of bempedoic acid The compound of formula (V) in crystalline form is characterized herein by other characteristic properties of It can be a thing. In certain embodiments, a compound of formula (V) can be prepared from a mixture comprising a compound of formula (V), ethyl acetate, and water. Crystallizing the compound of formula (V) includes filtering the compound of formula (V). In certain embodiments, the filtration of the crystalline form of the compound of formula (V) is carried out at about -20°C to about 5°C, about -15℃~5℃, -10℃~5℃, -5℃~5℃, 0℃~5℃, -20℃ ℃ to about 0℃, about -20℃ to about -5℃, about -20℃ to about -10℃, about -20℃ to about -15℃ , about -15℃ to about 5℃, about -15℃ to about 0℃, about -15℃ to about -5℃, about -15℃ to about - 10℃, approx. -10℃~approx. 5℃, approx. -10℃~approx. 0℃, approx. -10℃~approx. -5℃, approx. -5℃~ The reaction is carried out at a temperature of about 5° C., about −5° C. to about 0° C., or about 0° C. to about 5° C. In some embodiments, the reaction is carried out at a temperature of about 5° C., about −5° C. to about 0° C., or about 0° C. to about 5° C. The filtration of the crystalline form of the compound of formula (V) is carried out at a temperature of about -20°C to about -5°C. In one embodiment, the filtration of the crystalline form of the compound of formula (V) is carried out at a temperature of about -5°C to about 5°C. .

[0117] In certain embodiments, the filtration of the crystalline form of the compound of formula (V) is carried out at about -20°C, about -15°C, , at a temperature of about -10°C, about -5°C, about 0°C, or about 5°C. Filtration of the crystalline form of compound (V) is carried out at a temperature of about -10°C, about -5°C, or about 0°C. In certain embodiments, the filtering further comprises washing. In certain embodiments, the washing comprises washing a fluorinated fluoride compound represented by formula (V): In some embodiments, the washing comprises washing the crystalline form of the compound of formula washing the crystalline form of compound (V) with ethyl acetate. In certain embodiments, the temperature of the solvent, e.g., ethyl acetate, is from about -20°C to about 10°C, about 10℃~approx. 10℃, approx. 0℃~approx. 10℃, approx. -20℃~approx. 0℃, approx. -20℃~approx. -10℃, or from about -10°C to about 0°C. In some embodiments, the temperature of the solvent is from about -10°C to It is about 10 degrees Celsius. In certain embodiments, the temperature of the solvent, e.g., ethyl acetate, is about -20°C, about -15°C, about The temperature is about -10°C, about -5°C, about 0°C, about 5°C, or about 10°C. In some embodiments, The temperature of the solvent is about 0°C.

[0118] In various embodiments, a compound of formula (V) is prepared by condensing a compound of formula (V) with ethyl acetate and water. Crystallizing the compound of formula V (1) heating the mixture to a first temperature (T 1 ) to the second temperature (T 2 ) by cooling to , T 1 is about 50°C, and T 2 is about 22° C., and the mixture is heated to T 1 From T 2 Cool to room temperature; (2) The compound of formula (V) is 2 for at least 6 hours; (3) The compound of formula (V) is 2 to the third temperature (T 3 ) is cooled to T 3but The temperature was about 0° C., and the mixture was heated to T 2 From T 3 cooling to (4) The compound of formula (V) is 3 and holding the temperature at 40° C. for at least 6 hours. Thereby producing a crystalline form of the compound of formula (V).

[0119] Conditions (e.g., temperature), time, and the like for crystallizing the compound of formula (V) described herein. Seeding, amounts, compounds, and other parameters and / or variables are Unless otherwise stated or understood from the context (e.g., a condition or parameter is not (outside the value or range in the crystallization process), immediately equivalent to the crystallization process described above It should be understood that this may be applicable.

[0120] In certain embodiments, crystals produced by any of the crystallization methods described herein are A compound of formula (V) of the form may be identified, for example, by an X-ray powder diffraction pattern or peak(s), and / or or other characteristic properties of the crystalline form of bempedoic acid as herein characterized. The compound of formula (V) may be in crystalline form.

[0121] In certain embodiments, a compound of formula (I) produced by any of the crystallization methods described herein is The purity of the crystalline form of the compound of formula (V) is, by weight, the percentage of the total weight of the crystalline form of the compound of formula (V). More than about 85%, more than about 90%, more than about 95%, more than about 96%, more than about 97%, more than about 98%, about 99% Very, more than about 99.1%, more than about 99.2%, more than about 99.3%, more than about 99.4%, about 99.5% Super, more than about 99.6%, more than about 99.7%, more than about 99.8%, more than about 99.85%, about 99.9 %, greater than about 99.95%, or greater than about 99.98%.

[0122] Recrystallization of the crystalline form of the compound of formula (V) In various embodiments, in step (e), the purification of the compound of formula (V) comprises purifying the compound in crystalline form. and preparing a pharmaceutical preparation comprising a purified amount of the compound of formula (V). Provide the materials.

[0123] In certain embodiments, one or more recrystallizations of the crystalline form of the compound of formula (V) include the following: (1) dissolving a crystalline compound of formula (V) in one or more solvents, thereby forming a mixture; To do; (2) heating the mixture to a first temperature (T 1 ) to the second temperature (T 2 ) by cooling to , T 1 is about 40°C to about 65°C, and T 2 is about 20°C to about 40°C, and the mixture is heated for about 3 T at a rate of about 11°C / hour to about 12°C / hour 1 From T 2 Cool to room temperature; (3) Add the mixture to T 2 for at least 0.5 hours; (4) T 2 to the third temperature (T 3 ) and T 3 About 30 °C to about 50 °C, and the mixture is heated to T 2 From T 3 Ma Heating at ; (5) T 3 for at least 0.5 hours; (6) Add the mixture to T 3 to the fourth temperature (T 4 ) to T 4 is about 2 5° C. to about 40° C., and the mixture is heated to T 3 From T 4 Cool until crisp; (7) Add the mixture to T 4 for at least 0.5 hours; (8) T 4 to the fifth temperature (T 5 ) to T 5 About - 10° C. to about 10° C., and the mixture is heated to T 4 From T 5 Approximately 3℃ / hour to approximately 11℃ / hour cooling at a rate; and (9) Add the mixture to T 5 and holding at for at least 0.5 hours; Thereby, a pharmaceutical material is produced which contains a purified amount of the compound of formula (V) in crystalline form.

[0124] In certain embodiments, in the recrystallization step (1), the one or more solvents are ethyl acetate and and water. In certain embodiments, the one or more solvents are ethyl acetate and water.

[0125] In certain embodiments, in the recrystallization step (1), the amount of ethyl acetate in the mixture is represented by the formula Approximately 2.5 kg of ethyl acetate per kilogram of crystalline compound (V). g / kg ~ approx. 3.3kg / kg, approx. 2.7kg / kg ~ approx. 3.3kg / kg, approx. 2.9k g / kg ~ approx. 3.3kg / kg, approx. 3.1kg / kg ~ approx. 3.3kg / kg, approx. 2.5k g / kg ~ approx. 3.1kg / kg, approx. 2.5kg / kg ~ approx. 2.9kg / kg, approx. 2.5k g / kg ~ approx. 2.7kg / kg, approx. 2.7kg / kg ~ approx. 3.1kg / kg, approx. 2.7k g / kg to about 2.9 kg / kg, or about 2.9 kg / kg to about 3.1 kg / kg. In some embodiments, in the recrystallization step (1), the amount of ethyl acetate in the mixture is Approximately 2.5 kg of ethyl acetate based on the weight of ethyl acetate per kilogram of the crystalline compound of formula (V). In some embodiments, the recrystallization step (1) is carried out at a concentration of from about 3.3 g / kg to about 3.3 g / kg. In the mixture, the amount of ethyl acetate is 100 mg of ethyl acetate per kilogram of the crystalline compound of formula (V). The amount is about 2.7 kg / kg to about 3.1 kg / kg based on the weight of ethyl acetate.

[0126] In certain embodiments, in the recrystallization step (1), the amount of ethyl acetate in the mixture is represented by the formula Approximately 2.5 kg, based on the weight of ethyl acetate per kilogram of crystalline compound (V). / kg, about 2.7kg / kg, about 2.9kg / kg, about 3.1kg / kg, or about 3.3 In some embodiments, in the recrystallization step (1), The amount of ethyl acetate is based on the weight of ethyl acetate per kilogram of the crystalline compound of formula (V). Based on this, it is approximately 2.9 kg / kg.

[0127] In certain embodiments, in the recrystallization step (2), T 1 is about 40℃ to about 65℃, about 45℃~65℃, 50℃~65℃, 55℃~65℃, 60℃~65℃, 40℃~60℃, 40℃~55℃, 40℃~50℃, 40℃~45℃, 45℃~60℃, 45℃~55℃, 45℃~50℃, 50℃~60℃, In some embodiments, the recrystallization temperature is from about 50° C. to about 55° C., or from about 55° C. to about 60° C. In step (2), T 1 In some embodiments, the recrystallization temperature is about 40° C. to about 65° C. In the crystallization step (2), T 1 The temperature is about 50°C to about 60°C. In certain embodiments, in the recrystallization step (2), T 1 is about 40℃, about 45℃, about The recrystallization temperature is about 50° C., about 55° C., about 60° C., or about 65° C. In some embodiments, the recrystallization temperature is about 50° C., about 55° C., about 60° C., or about 65° C. In step (2), T 1 is about 55°C. In certain embodiments, in the recrystallization step (2), T 2 is about 20℃ to about 40℃, about 25℃~about 40℃, about 30℃~about 40℃, about 35℃~about 40℃, about 20℃~about 35℃, about 20℃~about 30℃, about 20℃~about 25℃, about 25℃~about 35℃, about 25℃~about 30℃, or In a specific embodiment, in the recrystallization step (2), T 2 The temperature is about 25°C to about 35°C. In certain embodiments, in the recrystallization step (2), T 1 is about 20℃, about 25℃, about In some embodiments, the recrystallization temperature is about 30° C., about 35° C., or about 40° C. In T 1 is about 30°C.

[0128] In certain embodiments, in the recrystallization step (2), the mixture is heated at about 3° C. / hour to about 11° C. / hour. °C / hour, about 5 °C / hour to about 11 °C / hour, about 7 °C / hour to about 11 °C / hour, about 9 °C / hour 11℃ / hour, 3℃ / hour to 9℃ / hour, 3℃ / hour to 7℃ / hour, °C / hour to about 5 °C / hour, about 5 °C / hour to about 9 °C / hour, about 5 °C / hour to about 7 °C / hour, Or at a rate of about 7°C / hour to about 9°C / hour 1 From T 2 In some embodiments, In the recrystallization step (2), the mixture is heated to T at a rate of about 3° C. / hour to about 11° C. / hour. 1 From T 2 In some embodiments, in the recrystallization step (2), the mixture is cooled to at a rate of about 5°C / hour to about 7°C / hour. 1 From T2 Cool to 35°C. In certain embodiments, in the recrystallization step (2), the mixture is heated at about 3° C. / hour, about 4° C. / hour, / hour, about 5℃ / hour, about 6℃ / hour, about 7℃ / hour, about 8℃ / hour, about 9℃ / hour, about T at a rate of 10°C / hour or about 11°C / hour 1 From T 2 Some implementations In this embodiment, in the recrystallization step (2), the mixture is heated at about 5° C. / hour, about 6° C. / hour, or about 7° C. / hour. / time rate of T 1 From T 2 Cool to 35°C.

[0129] In certain embodiments, in the recrystallization step (3), the mixture is treated with T 2 At least 1 o'clock 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours 5.5 hours, 6 hours, 6.5 hours, at least 7 hours, at least 7.5 hours, at least at least 8 hours, at least 8.5 hours, at least 9 hours, at least 9.5 hours, or In some embodiments, in the recrystallization step (3), T the mixture 2 Hold for at least 2 hours. In certain embodiments, in the recrystallization step (3), the mixture is treated with T 2 1 hour or less, 1 .5 hours or less, 2 hours or less, 2.5 hours or less, 3 hours or less, 3.5 hours or less, 4 hours or less , 4.5 hours or less, 5 hours or less, 5.5 hours or less, 6 hours or less, 6.5 hours or less, 7 hours Less than, 7.5 hours or less, 8 hours or less, 8.5 hours or less, 9 hours or less, 9.5 hours or less, 1 0 hours or less, 10.5 hours or less, 11 hours or less, 11.5 hours or less, 12 hours or less, 16 In some embodiments, the recrystallization is performed for 1 hour or less, 20 hours or less, or 24 hours or less. In step (3), the mixture is 2 Hold for 2 hours or less.

[0130] In certain embodiments, in the recrystallization step (4), T 3 is about 30℃ to about 50℃, about 35℃~approx. 50℃, approx. 40℃~approx. 50℃, approx. 45℃~approx. 50℃, approx. 30℃~approx. 45℃, approx. 30℃~about 40℃, about 30℃~about 35℃, about 35℃~about 45℃, about 35℃~about 40℃, or In some embodiments, in the recrystallization step (4), T 3 In some embodiments, the temperature in the recrystallization step (4) is about 30° C. to about 50° C. T 3 The temperature is about 35°C to about 45°C. In certain embodiments, in the recrystallization step (4), T 3 is about 30℃, about 35℃, about In some embodiments, the recrystallization temperature is about 40° C., about 45° C., or about 50° C. In T 3 is about 40°C. In certain embodiments, in the recrystallization step (4), the mixture is heated at a rate of about 3° C. / hour to about 11° C. / hour. °C / hour, about 5 °C / hour to about 11 °C / hour, about 7 °C / hour to about 11 °C / hour, about 9 °C / hour 11℃ / hour, 3℃ / hour to 9℃ / hour, 3℃ / hour to 7℃ / hour, °C / hour to about 5 °C / hour, about 5 °C / hour to about 9 °C / hour, about 5 °C / hour to about 7 °C / hour, Or at a rate of about 7°C / hour to about 9°C / hour 2 From T 3 In some embodiments, In the recrystallization step (4), the mixture is heated to T at a rate of about 3° C. / hour to about 11° C. / hour. 2 From T 3 In some embodiments, in the recrystallization step (4), the mixture is heated to at a rate of about 5°C / hour to about 7°C / hour. 2 From T 3 Heat to .

[0131] In certain embodiments, in the recrystallization step (4), the mixture is heated at about 3° C. / hour, about 4° C. / hour, about 5℃ / hour, about 6℃ / hour, about 7℃ / hour, about 8℃ / hour, about 9℃ / hour, about T at a rate of 10°C / hour or about 11°C / hour 2 From T 3 Several implementations In one embodiment, in the recrystallization step (4), the mixture is heated at about 5° C. / hour, about 6° C. / hour, or about 7° C. / hour. / time rate of T 2 From T 3 Heat to . In certain embodiments, in the recrystallization step (5), the mixture is treated with T 3 At least 1 o'clock 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours 5.5 hours, 6 hours, 6.5 hours, at least 7 hours, at least 7.5 hours, at least at least 8 hours, at least 8.5 hours, at least 9 hours, at least 9.5 hours, or In some embodiments, in the recrystallization step (5), T the mixture 3 Hold for at least 1 hour. In certain embodiments, in the recrystallization step (5), the mixture is treated with T 3 1 hour or less, 1 .5 hours or less, 2 hours or less, 2.5 hours or less, 3 hours or less, 3.5 hours or less, 4 hours or less , 4.5 hours or less, 5 hours or less, 5.5 hours or less, 6 hours or less, 6.5 hours or less, 7 hours Less than, 7.5 hours or less, 8 hours or less, 8.5 hours or less, 9 hours or less, 9.5 hours or less, 1 0 hours or less, 10.5 hours or less, 11 hours or less, 11.5 hours or less, 12 hours or less, 16 hours or less, 20 hours or less, or 24 hours or less.

[0132] In certain embodiments, in the recrystallization step (6), T 4 is about 25℃ to about 40℃, about 30℃~about 40℃, about 35℃~about 40℃, about 25℃~about 35℃, about 25℃~about 30℃, or In some embodiments, in the recrystallization step (6), T 4 In some embodiments, the temperature in the recrystallization step (6) is about 25° C. to about 40° C. T 4 The temperature is about 30°C to about 40°C. In certain embodiments, in the recrystallization step (6), T 4 is about 25℃, about 30℃, about 35° C., or about 40° C. In some embodiments, in the recrystallization step (6), T 4 is about 35°C. In certain embodiments, in the recrystallization step (6), the mixture is heated at about 3° C. / hour to about 11° C. / hour. °C / hour, about 5 °C / hour to about 11 °C / hour, about 7 °C / hour to about 11 °C / hour, about 9 °C / hour 11℃ / hour, 3℃ / hour to 9℃ / hour, 3℃ / hour to 7℃ / hour, °C / hour to about 5 °C / hour, about 5 °C / hour to about 9 °C / hour, about 5 °C / hour to about 7 °C / hour, Or at a rate of about 7°C / hour to about 9°C / hour 3 From T 4 In some embodiments, In the recrystallization step (6), the mixture is heated to T at a rate of about 3° C. / hour to about 11° C. / hour. 3 From T 4 In some embodiments, in the recrystallization step (6), the mixture is cooled to at a rate of about 5°C / hour to about 7°C / hour. 3 From T 4 Cool to 35°C. In certain embodiments, in the recrystallization step (6), the mixture is heated at about 3° C. / hour, about 4° C. / hour, / hour, about 5℃ / hour, about 6℃ / hour, about 7℃ / hour, about 8℃ / hour, about 9℃ / hour, about T at a rate of 10°C / hour or about 11°C / hour 3 From T 4 Some implementations In one embodiment, in the recrystallization step (6), the mixture is heated at about 5° C. / hour, about 6° C. / hour, or about 7° C. / hour. / time rate of T 3 From T 4 Cool to 35°C.

[0133] In certain embodiments, in the recrystallization step (7), the mixture is treated with T 4 At least 1 o'clock 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours 5.5 hours, 6 hours, 6.5 hours, at least 7 hours, at least 7.5 hours, at least at least 8 hours, at least 8.5 hours, at least 9 hours, at least 9.5 hours, or In some embodiments, in the recrystallization step (7), T the mixture 4 Hold for at least 2 hours. In certain embodiments, in the recrystallization step (7), the mixture is treated with T 4 1 hour or less, 1 .5 hours or less, 2 hours or less, 2.5 hours or less, 3 hours or less, 3.5 hours or less, 4 hours or less , 4.5 hours or less, 5 hours or less, 5.5 hours or less, 6 hours or less, 6.5 hours or less, 7 hours Less than, 7.5 hours or less, 8 hours or less, 8.5 hours or less, 9 hours or less, 9.5 hours or less, 1 0 hours or less, 10.5 hours or less, 11 hours or less, 11.5 hours or less, 12 hours or less, 16 hours or less, 20 hours or less, or 24 hours or less.

[0134] In certain embodiments, in the recrystallization step (8), T 5 is about -10℃ to about 10℃, About -5℃ to about 10℃, about 0℃ to about 10℃, about 5℃ to about 10℃, about -10℃ to about 5℃, about - 10°C to about 0°C, about -10°C to about -5°C, about -5°C to about 5°C, about -5°C to about 0°C, or about In some embodiments, in the recrystallization step (8), T 5 is about In some embodiments, in the recrystallization step (8), T 5 is about 0℃ to about 10℃. In certain embodiments, in the recrystallization step (8), T 5 is about -10℃, about -5℃, The temperature is about 0° C., about 5° C., or about 10° C. In some embodiments, the recrystallization step (8) Hey, T 5 is about 5°C. In certain embodiments, in the recrystallization step (8), the mixture is heated at a temperature of about 3° C. / hour to about 11° C. / hour. °C / hour, about 5 °C / hour to about 11 °C / hour, about 7 °C / hour to about 11 °C / hour, about 9 °C / hour 11℃ / hour, 3℃ / hour to 9℃ / hour, 3℃ / hour to 7℃ / hour, °C / hour to about 5 °C / hour, about 5 °C / hour to about 9 °C / hour, about 5 °C / hour to about 7 °C / hour, Or at a rate of about 7°C / hour to about 9°C / hour 4 From T 5 In some embodiments, In the recrystallization step (8), the mixture is heated to T at a rate of about 3° C. / hour to about 11° C. / hour. 4 From T 5 In some embodiments, in the recrystallization step (8), the mixture is cooled to at a rate of about 5°C / hour to about 7°C / hour. 4 From T 5 Cool to 35°C. In certain embodiments, in the recrystallization step (8), the mixture is heated at about 3° C. / hour, about 4° C. / hour, / hour, about 5℃ / hour, about 6℃ / hour, about 7℃ / hour, about 8℃ / hour, about 9℃ / hour, about T at a rate of 10°C / hour or about 11°C / hour 4 From T 5 Some implementations In one embodiment, in the recrystallization step (8), the mixture is heated at about 5° C. / hour, about 6° C. / hour, or about 7° C. / hour. / time rate of T 4 From T 5 Cool to 35°C.

[0135] In certain embodiments, in the recrystallization step (9), the mixture is treated with T 5 At least 1 o'clock 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours 5.5 hours, 6 hours, 6.5 hours, at least 7 hours, at least 7.5 hours, at least at least 8 hours, at least 8.5 hours, at least 9 hours, at least 9.5 hours, or In some embodiments, in the recrystallization step (9), T the mixture 5 Hold for at least 4 hours. In certain embodiments, in the recrystallization step (9), the mixture is treated with T 5 1 hour or less, 1 .5 hours or less, 2 hours or less, 2.5 hours or less, 3 hours or less, 3.5 hours or less, 4 hours or less , 4.5 hours or less, 5 hours or less, 5.5 hours or less, 6 hours or less, 6.5 hours or less, 7 hours Less than, 7.5 hours or less, 8 hours or less, 8.5 hours or less, 9 hours or less, 9.5 hours or less, 1 0 hours or less, 10.5 hours or less, 11 hours or less, 11.5 hours or less, 12 hours or less, 16 hours or less, 20 hours or less, or 24 hours or less.

[0136] In certain embodiments, recrystallizing the compound of formula (V) provides a crystallization of the compound of formula (V). In order to promote crystallization, the recrystallization step (2) may be performed before or during the recrystallization step (2). During the recrystallization step (3), during the recrystallization step (4), during the recrystallization step (5), During the step (6), during the recrystallization step (7), during the recrystallization step (8), During step (9), or any combination thereof, the mixture is added with an amount of a compound represented by formula (V) The method further comprises seeding the compound in a crystalline form of Conditions (e.g., temperature), time, and the like for crystallizing the compound of formula (V) described herein. Seeding, amounts, compounds, and other parameters and / or variables are Unless otherwise indicated or understood from the context, or as described below, the compound of formula (V) It should be understood that it may be equally applicable to recrystallization.

[0137] For example, in certain embodiments, recrystallization of a compound of formula (V) provides a crystallization of the compound of formula (V). In certain embodiments, the filtration of the crystalline form of the compound of formula (V) comprises filtering the crystalline form of the compound of formula (V) at about - 20℃~approx. 15℃, approx. -15℃~approx. 15℃, approx. -10℃~approx. 15℃, approx. -5℃~approx. 15℃ , about 0℃ to about 15℃, about 5℃ to about 15℃, about 10℃ to about 15℃, about -20℃ to about 10℃, About -20℃ to about 5℃, about -20℃ to about 0℃, about -20℃ to about -5℃, about -20℃ to about -1 0℃, approx. -20℃ to approx. -15℃, approx. -15℃ to approx. 10℃, approx. -15℃ to approx. 5℃, approx. -15 ℃ to about 0℃, about -15℃ to about -5℃, about -15℃ to about -10℃, about -10℃ to about 10℃, Approximately -10℃ to approximately 5℃, approximately -10℃ to approximately 0℃, approximately -10℃ to approximately -5℃, approximately -5℃ to approximately 10℃ , about -5℃ to about 5℃, about -5℃ to about 0℃, about 0℃ to about 10℃, about 0℃ to about 5℃, or about 5 In some embodiments, the reaction is carried out at a temperature of from about 10° C. to about 10° C. In some embodiments, the crystalline form of the compound of formula (V) The filtration is carried out at a temperature of about 0°C to about 15°C.

[0138] In certain embodiments, the filtration of the crystalline form of the compound of formula (V) is carried out at about -20°C, about -15°C, The reaction is carried out at a temperature of about -10°C, about -5°C, about 0°C, about 5°C, about 10°C or about 15°C. In some embodiments, the filtration of the crystalline form of the compound of Formula (V) is carried out at about 0° C., about 5° C., about 10° C., or about 20° C. The reaction is carried out at a temperature of about 15° C. or about 20° C. In certain embodiments, the filtering further comprises washing. In certain embodiments, the washing comprises washing a fluorinated fluoride compound represented by formula (V): In some embodiments, the washing comprises washing the crystalline form of the compound of formula washing the crystalline form of compound (V) with acetonitrile.

[0139] In certain embodiments, recrystallizing the compound of formula (V) comprises centrifugation of the mixture. The method includes isolating the crystalline form of the compound of formula (V) from the product.

[0140] In certain embodiments, isolation of the crystalline form of the compound of formula (V) by centrifugation may further include washing. In certain embodiments, washing comprises washing the crystalline form of the compound of formula (V) with a solvent. In some embodiments, washing comprises removing the crystalline form of the compound of formula (V) from acetonite. This includes washing with a drill. In certain embodiments, the temperature of the solvent, e.g., acetonitrile, is from about -20°C to about 30°C; Approximately -10℃ to approximately 30℃, approximately 0℃ to approximately 30℃, approximately 10℃ to approximately 30℃, approximately -20℃ to approximately 20℃ , about -20℃ to about 10℃, about -20℃ to about 0℃, about -20℃ to about -10℃, about -10℃ to About 20℃, about -10℃ to about 10℃, about -10℃ to about 0℃, about 0℃ to about 20℃, about 0℃ to about 10° C., or from about 10° C. to about 20° C. In some embodiments, the temperature of the solvent is about 0℃ to approximately 30℃.

[0141] In certain embodiments, the temperature of the solvent, e.g., acetonitrile, is about -20°C, about -10°C, , about 0° C., about 10° C., about 20° C., or about 30° C. In some embodiments, the solvent The temperature is about 20°C. In certain embodiments, recrystallizing the compound of formula (V) comprises drying. In certain embodiments, drying comprises drying the compound of formula (V) in crystalline form at temperatures below about 85° C., below about 75° C. less than about 65°C, less than about 55°C, less than about 45°C, less than about 35°C, or less than about 25°C In some embodiments, the drying step comprises heating to a temperature of 100° C. to 50° C. ... In some embodiments, the drying step comprises heating the crystalline form to a temperature of less than about 85° C. The process includes heating a crystalline form of the compound of formula (V) to a temperature of less than about 45°C. In certain embodiments, one or more recrystallizations of the crystalline form of the compound of formula (V) may be performed. Including 3, 4, 5, 6, 7, 8, 9 or 10 recrystallizations.

[0142] In certain embodiments, one or more recrystallizations of the crystalline form of the compound of formula (V) are as follows: (1) dissolving the crystalline compound of formula (V) in one or more solvents including ethyl acetate and water; thereby forming a mixture; (2) heating the mixture to a first temperature (T 1 ) to the second temperature (T 2 ) by cooling to , T 1 is about 55°C, and T 2 is about 30° C., and the mixture is heated at about 5° C. / hour to about 7° C. / hour At a speed between T 1 From T 2 Cool to room temperature; (3) The compound of formula (V) is 2 for at least 2 hours; (4) T 2 to the third temperature (T 3 ) to T 3 is about 4 0° C., and the mixture is heated to T 2 From T 3 Heat until thing; (5) T 3 for at least 1 hour; (6) Add the mixture to T 3 to the fourth temperature (T 4 ) to T 4 is about 3 5° C., and the mixture is heated to T 3 From T 4 Cool until thing; (7) Add the mixture to T 4 for at least 2 hours; (8) T 4 to the fifth temperature (T 5 ) to T 5 is about 5 °C, and the mixture is heated to T 4 From T 5 Cool until and; (9) Add the mixture to T 5 and holding the temperature at 40° C. for at least 4 hours. Thereby, a pharmaceutical material is produced which contains a purified amount of the compound of formula (V) in crystalline form.

[0143] Conditions for crystallizing and / or recrystallizing the compounds of formula (V) described herein (e.g. (e.g., temperature), time, seeding, amount, compound, and other parameters and / or variables may be , unless otherwise stated or understood from the context (e.g., a condition or parameter , which is outside the value or range in the recrystallization process described immediately above), It should be understood that it may be equally applicable to crystallization processes.

[0144] In certain embodiments, a pharmaceutical agent produced by any of the crystallization methods described herein. The compound of formula (V) in crystalline form in a material may be identified, for example, by an X-ray powder diffraction pattern or peaks ( and / or other characteristic properties of the crystalline form of bempedoic acid, which are distinguished herein by The compound of formula (V) may be in a characterized crystalline form. In various embodiments, the purified amount of the compound of formula (V) in the pharmaceutical material is, by weight, More than 99.0%, more than about 99.1%, more than about 99.2%, more than about 99.3%, or more than about More than 99.4%, more than about 99.5%, more than about 99.6%, more than about 99.7%, more than about 99.8%, about More than 99.85%, more than about 99.9%, more than about 99.95%, or more than about 99.98%. In some embodiments, the purified amount of the compound of Formula (V) in the pharmaceutical material is about 100% by weight of the total pharmaceutical material. In some embodiments, the purified amount of the compound of formula (V) in the pharmaceutical material is greater than 99.0% by weight. In some embodiments, the pharmaceutical composition is greater than about 99.5% by weight of the total weight of the pharmaceutical material. The purified amount of the compound of formula (V) in the material is greater than about 99.7% by weight of the total weight of the pharmaceutical material. In some embodiments, the purified amount of the compound of formula (V) in the pharmaceutical material is about 100% by weight of the total pharmaceutical material. More than about 99.85% by weight.

[0145] In certain embodiments, a compound of formula (V) in crystalline form is provided to provide a recrystallized compound of formula (V). After recrystallizing the compound, the method includes contacting the recrystallized compound of formula (V) with charcoal; and filtering the charcoal to provide a pharmaceutical material containing a purified amount of the compound of formula (V). In some embodiments, contacting the compound of Formula (V) with charcoal comprises contacting the compound of Formula (V) with charcoal. with a solution containing acetonitrile and activated carbon (e.g., 5% (w / w) activated carbon). This includes making the person do so.

[0146] In certain embodiments, the methods described herein are used to prepare a batch of bempedoic acid. In certain embodiments, the methods described herein can be used to prepare batches of pharmaceutical material. The pharmaceutical composition may be used to prepare a pharmaceutical composition comprising a purified amount of a compound of formula (V). In one embodiment, the purified amount of the compound of formula (V) or a pharma- ceutically acceptable salt thereof is More than 99.0% by weight of the total weight of the material. In certain embodiments, the batches are about 1 kg, 2 kg, 3 kg, 4 kg, 5 kg, 10 kg, g, 20kg, 30kg, 40kg, 50kg, 60kg, 70kg, 80kg, 90k g, 100kg, 200kg, 300kg, 400kg, 500kg, 600kg, 70 The amount is 0kg, 800kg, 900kg or 1000kg.

[0147] IV. High Purity Compositions of Bempedoic Acid As described herein, in one aspect, the present invention provides a method for the preparation of bempedoic acid, e.g., in crystalline form. A pharmaceutical material is provided that includes bempedoic acid, or a pharma- ceutically acceptable salt thereof. In various embodiments, the pharmaceutical material generally comprises a compound of formula (V): or a pharma- ceutically acceptable salt thereof, wherein the pharmaceutical material is 99.0% by weight or more of the compound of formula (V) or a pharma- ceutically acceptable salt thereof. In some embodiments, the amount of the compound of formula (V) in the pharmaceutical material is, by weight, More than about 99.1%, more than about 99.2%, more than about 99.3%, more than about 99.4%, or more than about More than 99.5%, more than about 99.6%, more than about 99.7%, more than about 99.8%, more than about 99.85%, In some embodiments, the solubility is greater than about 99.9%, greater than about 99.95%, or greater than about 99.98%. In the present invention, the pharmaceutical material contains more than 99.5% by weight of formula (V) based on the total weight of the pharmaceutical material. In some embodiments, the pharmaceutical material comprises a compound of, based on the total weight of the pharmaceutical material: In some embodiments, the pharmaceutical composition comprises greater than 99.7% by weight of a compound of formula (V). The pharmaceutical composition contains more than 99.9% by weight of the compound of formula (V) based on the total weight of the pharmaceutical material. nothing.

[0148] In certain embodiments, the pharmaceutical material is eluted by high performance liquid chromatography (HPLC) assay. When determined by, based on the total weight of the pharmaceutical material (anhydrous, solvent-free system), about 98% to about It contains the compound of formula (V) in an amount of 102% by weight. In certain embodiments, the HPLC assay comprises one or more of the following: (i) Waters XBridge BEH C18 column (inner diameter 4.6 mm x 15 0 mm, 2.5 μm); (ii) a column temperature of about 40°C; (iii) a mobile phase containing about 0.05% phosphoric acid in water / acetonitrile (about 50:50) ; (iv) isocratic elution; (v) a flow rate of approximately 1.2 mL / min; (vi) ambient sample temperature; (vii) detection at 215 nm; and (viii) The retention time of the compound of formula (V) is about 4.6 minutes. In some embodiments, the HPLC assay comprises each of the above, i.e., (i) to (ii). viii). In certain embodiments, the compound of formula (V) in crystalline form can be identified, for example, by an X-ray powder diffraction pattern or The present invention is characterized by the peak(s) and / or other characteristic properties of the crystalline form of bempedoic acid. The compound of formula (V) may be in the crystalline form as characterized in the specification.

[0149] In certain embodiments, the pharmaceutical materials described herein comprise a compound of formula (VI): TIFF2025032197000049.tif18160 or a pharma- ceutically acceptable salt thereof. The acceptable salts are also referred to herein as "diol impurities." In certain embodiments, the amount of diol impurity in the drug substance is based on the total weight of the drug substance. Approximately 0.15%, approximately 0.125%, approximately 0.1%, approximately 0.075%, approximately 0.0 Less than 5%, about 0.025%, about 0.01%, about 0.001%, or about 0.0001% In some embodiments, the amount of diol impurity in the drug substance is based on the total weight of the drug substance. In some embodiments, the diol in the pharmaceutical material is less than about 1.25% by weight. The amount of impurities is less than about 0.15% by weight, based on the total weight of the pharmaceutical material. In embodiments, the amount of diol impurity in the pharmaceutical material is about 0.01 to about 0.01% by weight, based on the total weight of the pharmaceutical material. Less than .1% by weight. In certain embodiments, the pharmaceutical material comprises about 0.1 by weight based on the total weight of the pharmaceutical material. 5%, approx. 0.125%, approx. 0.1%, approx. 0.075%, approx. 0.05%, approx. 0.025%, About 0.01%, about 0.001%, or about 0.0001% or less of a compound of formula (VI) or In some embodiments, the pharmaceutical material comprises a total amount of the pharmaceutical material. On a weight basis, about 0.125% by weight or less of the compound of formula (VI) or a pharma- ceutical acceptable salt thereof In some embodiments, the pharmaceutical material comprises a total weight of the pharmaceutical material. and about 0.15% by weight or less of a compound of formula (VI) or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical material comprises about 0.1 weight percent, based on the total weight of the pharmaceutical material. The composition contains an amount of a compound of formula (VI) or a pharma- ceutically acceptable salt thereof in an amount of 0.5% or less. In certain embodiments, the amount of diol impurity in the drug substance is based on the total weight of the drug substance. and by weight, about 0.0001% to about 0.15%, about 0.001% to about 0.15%, about 0.01% to approx. 0.15%, approx. 0.025% to approx. 0.15%, approx. 0.05% to approx. 0.15 %, about 0.075% to about 0.15%, about 0.1% to about 0.15%, about 0.125% to about 0 .15%, approx. 0.01% to approx. 0.125%, approx. 0.01% to approx. 0.1%, approx. 0.01% to About 0.075%, about 0.01% to about 0.05%, about 0.01% to about 0.025%, about 0. 0.025% to 0.125%, 0.025% to 0.1%, 0.025% to 0.07 5%, approx. 0.025% to approx. 0.05%, approx. 0.05% to approx. 0.125%, approx. 0.05% to About 0.1%, about 0.05% to about 0.075%, about 0.075% to about 0.125%, about 0. In some embodiments, the concentration of the glycerol in the glycerol solution is from about 0.075% to about 0.1%, or from about 0.1% to about 0.125%. The amount of diol impurities in the pharmaceutical material is about 0.01% to 1.001% based on the total weight of the pharmaceutical material. In some embodiments, the amount of diol impurity in the drug substance is about 0.15% by weight. , about 0.01% to about 0.1% by weight, based on the total weight of the pharmaceutical material.

[0150] In certain embodiments, the pharmaceutical materials described herein comprise a compound of formula (VII): TIFF2025032197000050.tif18160 or a pharma- ceutically acceptable salt thereof. The acceptable salts are also referred to herein as "ketone impurities." In certain embodiments, the amount of ketone impurity in the pharmaceutical material is based on the total weight of the pharmaceutical material. , about 0.15%, about 0.125%, about 0.1%, about 0.075%, about 0.05% by weight %, about 0.025%, about 0.01%, about 0.001% or less than about 0.0001%. In certain embodiments, the amount of ketone impurity in the pharmaceutical material is, based on the total weight of the pharmaceutical material, In certain embodiments, the amount of ketone impurity in the pharmaceutical material is less than about 0.15% by weight. Less than about 0.05% by weight, based on the total weight of the pharmaceutical material. In certain embodiments, the pharmaceutical material comprises about 0.1 by weight based on the total weight of the pharmaceutical material. 5%, approx. 0.125%, approx. 0.1%, approx. 0.075%, approx. 0.05%, approx. 0.025%, About 0.01%, about 0.001%, or about 0.0001% or less of a compound of formula (VII) or In some embodiments, the pharmaceutical material is a pharmaceutical The compound of formula (VII) or its pharma- ceutical equivalents in an amount of about 0.15% by weight or less, based on the total weight. In some embodiments, the pharmaceutical material comprises a pharmaceutical agent having a total weight of about 1000 mg / kg, including acceptable salts thereof. In the case of a pharmaceutical composition comprising a compound of formula (VII) or a pharma- ceutically acceptable salt thereof, the compound may be present in an amount of about 0.05% by weight or less. Contains salt. In certain embodiments, the amount of ketone impurity in the pharmaceutical material is based on the total weight of the pharmaceutical material. , by weight, about 0.0001% to about 0.15%, about 0.001% to about 0.15%, about 0. 01% to approx. 0.15%, approx. 0.025% to approx. 0.15%, approx. 0.05% to approx. 0.15%, Approximately 0.075% to approximately 0.15%, approximately 0.1% to approximately 0.15%, approximately 0.125% to approximately 0.1 5%, about 0.01% to about 0.125%, about 0.01% to about 0.1%, about 0.01% to about 0 .075%, approx. 0.01% to approx. 0.05%, approx. 0.01% to approx. 0.025%, approx. 0.02 5% to approx. 0.125%, approx. 0.025% to approx. 0.1%, approx. 0.025% to approx. 0.075% , about 0.025% to about 0.05%, about 0.05% to about 0.125%, about 0.05% to about 0 .1%, about 0.05% to about 0.075%, about 0.075% to about 0.125%, about 0.07 In some embodiments, the concentration is from about 5% to about 0.1%, or from about 0.1% to about 0.125%. The amount of ketone impurities in the pharmaceutical material ranges from about 0.01% to about 0. 15% by weight. In some embodiments, the amount of ketone impurity in the pharmaceutical material is The amount is about 0.01% to about 0.05% by weight, based on the total weight of the material.

[0151] In certain embodiments, the pharmaceutical materials described herein comprise a compound of formula (VIII): TIFF2025032197000051.tif28160 or a pharma- ceutically acceptable salt thereof. Acceptable salts are also referred to herein as "acetone impurities." In certain embodiments, the amount of acetone impurity in the pharmaceutical material is based on the total weight of the pharmaceutical material. Approximately 0.15%, approximately 0.125%, approximately 0.1%, approximately 0.075%, approximately 0.0 Less than 5%, about 0.025%, about 0.01%, about 0.001%, or about 0.0001% . In certain embodiments, the pharmaceutical material comprises about 0.1 by weight based on the total weight of the pharmaceutical material. 5%, approx. 0.125%, approx. 0.1%, approx. 0.075%, approx. 0.05%, approx. 0.025%, About 0.01%, about 0.001%, or about 0.0001% or less of a compound of formula (VIII) includes pharma- ceutically acceptable salts thereof. In certain embodiments, the amount of acetone impurity in the pharmaceutical material is based on the total weight of the pharmaceutical material. About 0.0001% to about 0.15%, about 0.001% to about 0.15%, about 0 .01% to approx. 0.15%, approx. 0.025% to approx. 0.15%, approx. 0.05% to approx. 0.15% , about 0.075% to about 0.15%, about 0.1% to about 0.15%, about 0.125% to about 0. 15%, about 0.01% to about 0.125%, about 0.01% to about 0.1%, about 0.01% to about 0.075%, approx. 0.01% to approx. 0.05%, approx. 0.01% to approx. 0.025%, approx. 0.0 25% to approx. 0.125%, approx. 0.025% to approx. 0.1%, approx. 0.025% to approx. 0.075 %, about 0.025% to about 0.05%, about 0.05% to about 0.125%, about 0.05% to about 0.1%, approx. 0.05% to approx. 0.075%, approx. 0.075% to approx. 0.125%, approx. 0.0 75% to about 0.1%, or about 0.1% to about 0.125%.

[0152] In certain embodiments, the pharmaceutical materials described herein comprise a compound of formula (IX): TIFF2025032197000052.tif30160 or a pharma- ceutically acceptable salt thereof. Acceptable salts are also referred to herein as "dimeric impurities." In certain embodiments, the amount of dimeric impurity in the pharmaceutical material is based on the total weight of the pharmaceutical material. , about 0.15%, about 0.125%, about 0.1%, about 0.075%, about 0.05% by weight %, about 0.025%, about 0.01%, about 0.001% or less than about 0.0001%. In certain embodiments, the pharmaceutical material comprises about 0.1 by weight based on the total weight of the pharmaceutical material. 5%, approx. 0.125%, approx. 0.1%, approx. 0.075%, approx. 0.05%, approx. 0.025%, About 0.01%, about 0.001%, or about 0.0001% or less of a compound of formula (IX) or This includes pharma- ceutically acceptable salts of the formula: In certain embodiments, the amount of dimeric impurity in the pharmaceutical material is based on the total weight of the pharmaceutical material. , by weight, about 0.0001% to about 0.15%, about 0.005% to about 0.15%, about 0. 01% to approx. 0.15%, approx. 0.025% to approx. 0.15%, approx. 0.05% to approx. 0.15%, Approximately 0.075% to approximately 0.15%, approximately 0.1% to approximately 0.15%, approximately 0.125% to approximately 0.1 5%, about 0.01% to about 0.125%, about 0.01% to about 0.1%, about 0.01% to about 0 .075%, approx. 0.01% to approx. 0.05%, approx. 0.01% to approx. 0.025%, approx. 0.02 5% to approx. 0.125%, approx. 0.025% to approx. 0.1%, approx. 0.025% to approx. 0.075% , about 0.025% to about 0.05%, about 0.05% to about 0.125%, about 0.05% to about 0 .1%, about 0.05% to about 0.075%, about 0.075% to about 0.125%, about 0.07 5% to about 0.1%, or about 0.1% to about 0.125%.

[0153] In certain embodiments, the pharmaceutical materials described herein comprise a compound of formula (X): TIFF2025032197000053.tif29160 or a pharma- ceutically acceptable salt thereof. The resulting salt is also referred to herein as the "monoethyl ester impurity." In certain embodiments, the amount of monoethyl ester impurity in the pharmaceutical material is about 100% by weight of the total pharmaceutical material. Based on the amount, about 0.15%, about 0.125%, about 0.1%, about 0.075% by weight , about 0.05%, about 0.025%, about 0.01%, about 0.001%, or about 0.0001% is less than. In certain embodiments, the pharmaceutical material comprises about 0.1 by weight based on the total weight of the pharmaceutical material. 5%, approx. 0.125%, approx. 0.1%, approx. 0.075%, approx. 0.05%, approx. 0.025%, About 0.01%, about 0.001%, or about 0.0001% or less of a compound of formula (X) or its This includes pharma- ceutically acceptable salts. In certain embodiments, the amount of monoethyl ester impurity in the pharmaceutical material is about 100% by weight of the total pharmaceutical material. Based on the amount, from about 0.0001% to about 0.15%, from about 0.0005% to about 0. 15%, approx. 0.01% to approx. 0.15%, approx. 0.025% to approx. 0.15%, approx. 0.05% About 0.15%, about 0.075% to about 0.15%, about 0.1% to about 0.15%, about 0.12 5% to approx. 0.15%, approx. 0.01% to approx. 0.125%, approx. 0.01% to approx. 0.1%, approx. .01% to approx. 0.075%, approx. 0.01% to approx. 0.05%, approx. 0.01% to approx. 0.025 %, approx. 0.025% to approx. 0.125%, approx. 0.025% to approx. 0.1%, approx. 0.025% to Approximately 0.075%, approximately 0.025% to approximately 0.05%, approximately 0.05% to approximately 0.125%, approximately 0 .05% to approx. 0.1%, approx. 0.05% to approx. 0.075%, approx. 0.075% to approx. 0.125 %, about 0.075% to about 0.1%, or about 0.1% to about 0.125%.

[0154] In certain embodiments, the pharmaceutical material described herein is a compound of formula (XI) or a pharmaceutical The compound may include a physiologically acceptable salt. TIFF2025032197000054.tif28160 The compound of formula (XI) or a pharma- ceutically acceptable salt thereof is referred to herein as "diethyl ester." These are also called "ter impurities." In certain embodiments, the amount of diethyl ester impurity in the pharmaceutical material is about 100% by weight of the total pharmaceutical material. About 0.15%, about 0.125%, about 0.1%, about 0.075%, by weight based on About 0.05%, about 0.025%, about 0.01%, about 0.001% or less than about 0.0001% It is full. In certain embodiments, the pharmaceutical material comprises about 0.1 by weight based on the total weight of the pharmaceutical material. 5%, approx. 0.125%, approx. 0.1%, approx. 0.075%, approx. 0.05%, approx. 0.025%, About 0.01%, about 0.001%, or about 0.0001% or less of a compound of formula (XI) or This includes pharma- ceutically acceptable salts of the formula: In certain embodiments, the amount of diethyl ester impurity in the pharmaceutical material is about 100% by weight of the total pharmaceutical material. Based on the above, about 0.0001% to about 0.15%, about 0.0005% to about 0.1 5%, about 0.01% to about 0.15%, about 0.025% to about 0.15%, about 0.05% to about 0.15%, approx. 0.075% to approx. 0.15%, approx. 0.1% to approx. 0.15%, approx. 0.125 % to about 0.15%, about 0.01% to about 0.125%, about 0.01% to about 0.1%, about 0. 0.01% to approx. 0.075%, approx. 0.01% to approx. 0.05%, approx. 0.01% to approx. 0.025% , about 0.025% to about 0.125%, about 0.025% to about 0.1%, about 0.025% to about 0.075%, about 0.025% to about 0.05%, about 0.05% to about 0.125%, about 0. 05% to approx. 0.1%, approx. 0.05% to approx. 0.075%, approx. 0.075% to approx. 0.125% , about 0.075% to about 0.1%, or about 0.1% to about 0.125%.

[0155] In certain embodiments, the pharmaceutical materials described herein have a solubility in water as determined by HPLC. In some cases, impurities with relative retention times (RRT) of about 1.04 to about 1.05 may be included. In embodiments, the pharmaceutical materials described herein have a relative In certain embodiments, the impurity may have a retention time (RRT) of about 1.06 to about 1.08. The pharmaceutical materials described herein have a relative retention time ( In certain embodiments, the present invention may include impurities having a RRT of about 1.18 to about 1.20. The pharmaceutical materials described in have a relative retention time (RRT) as determined by HPLC: In certain embodiments, the pharmaceutical materials described herein may contain impurities of about 1.36. It may contain an impurity with an RRT of about 1.43 as determined by PLC. In some embodiments, the pharmaceutical materials described herein have a RR In certain embodiments, the present invention may include an impurity having a T of about 1.86. The pharmaceutical material contains a first impurity with an RRT of about 1.36 as determined by HPLC, and and a second impurity having an RRT of about 1.86. The RRT is based on the retention time of bempedoic acid, where the RRT of bempedoic acid is approximately 1.0 The value is 0. In certain embodiments, the pharmaceutical materials described herein contain one or more unspecified impurities. substances (e.g., impurities in pharmaceutical materials for which the chemical structure cannot be determined but the RRT is known) It may contain (pure).

[0156] In certain embodiments, the pharmaceutical material is eluted by high performance liquid chromatography (HPLC) assay. The present invention contains one or more impurities as described herein, as determined by In certain embodiments, the HPLC assay comprises one or more of the following: (i) Waters XBridge BEH C18 column (inner diameter 4.6 mm x 15 0 mm, 2.5 μm); (ii) a column temperature of about 40°C; (iii) a first mobile phase comprising about 0.05% formic acid in water; (iv) a second mobile phase comprising about 0.05% formic acid in acetonitrile; (v) a flow rate of approximately 1.2 mL / min; (vi) ambient sample temperature; and (vii) The retention time of the compound of formula (V) is about 15.2 minutes. In some embodiments, the HPLC assay comprises each of the above, i.e., (i) to (ii). vii).

[0157] In certain embodiments, the amount of one or more unspecified impurities in the pharmaceutical material is About 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.09%, about 0.10%, about 0.11%, about 0.12%, about 0.13%, about 0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, about 0.19%, about 04%, approximately 0.05%, approximately 0.06%, approximately 0.07%, approximately 0.08%, approximately 0.09%, or In some embodiments, one or more specified The amount of free impurities is less than about 0.05% by weight, based on the total weight of the pharmaceutical material. In certain embodiments, the amount of one or more unspecified impurities in the pharmaceutical material is Approximately 0.0001% to 0.1%, approximately 0.0005% to 1.0% by weight based on the total weight of the material Approximately 0.1%, approximately 0.001% to approximately 0.1%, approximately 0.005% to approximately 0.1%, approximately 0.01% ~0.1%, ~0.05%~0.1%, ~0.0001%~0.05%, ~0.0 0.001% to approx. 0.01%, approx. 0.0001% to approx. 0.005%, approx. 0.0001% to approx. 0 .001%, approx. 0.0001% to approx. 0.0005%, approx. 0.0005% to approx. 0.05%, About 0.0005% to about 0.01%, about 0.0005% to about 0.005%, about 0.0005 % to about 0.001%, about 0.001% to about 0.05%, about 0.001% to about 0.01%, About 0.001% to about 0.005%, about 0.005% to about 0.05%, about 0.005% to about In certain embodiments, the pharmaceutical material contains 0.01%, or about 0.01% to about 0.05%. The amount of one or more unspecified impurities is based on the total weight of the pharmaceutical material, on a weight basis. In certain embodiments, the pharmaceutical material may contain one or more of the following: The amount of unspecified impurities is approximately 0.05% by weight, based on the total weight of the pharmaceutical material. ~About 0.1%.

[0158] V. Pharmaceutical Compositions In another aspect, bempedoic acid or a medicament thereof as described and / or prepared herein. A pharmaceutical composition comprising a biologically acceptable salt thereof, which is free of impurities along with any pharmaceutical ingredient. Provided herein is a pharmaceutical composition comprising: The pharmaceutical composition may include a pharmaceutical material as described herein and a pharma- ceutical acceptable excipient. The material comprises greater than 99.0% of the compound of formula (V), or a pharma- ceutically acceptable salt thereof. It is possible.

[0159] In certain embodiments, the pharmaceutical composition is specially formulated for administration as a solid or liquid dosage form. In some embodiments, the pharmaceutical compositions described herein may be formulated into an oral dosage form. Examples of oral dosage forms include, but are not limited to, liquids, tablets, and the like. tablets, capsules, cachets, pills, emulsions, lozenges, solutions, suspensions, boluses , powder, elixir or drop, lozenge, mouthwash, granule, or tongue coating In some embodiments, the pharmaceutical composition described herein is administered in the form of a paste for application to the skin. The composition is formulated in a form suitable for parenteral administration. The pharmaceutical compositions described herein may be administered by subcutaneous, intramuscular, intravenous or epidural injection. Examples of dosage forms suitable for parenteral administration include sterile solutions or suspensions, or sustained release formulations. In some embodiments, the pharmaceutical compositions described herein include, but are not limited to, The product is formulated in a dosage form suitable for topical application. Examples of dosage forms suitable for topical administration include: Including but not limited to powders, sprays, ointments, pastes, creams, lotions, gels, solutions , patches, inhalants, or controlled release patches or sprays applied to the skin. In some embodiments, the pharmaceutical compositions described herein are suitable for vaginal or rectal administration. Examples of dosage forms suitable for vaginal or rectal administration include pessaries. In some embodiments, the composition may be a moisturizer, cream, or foam. The pharmaceutical compositions described herein may be administered in a dosage form suitable for sublingual, ophthalmic, transdermal or nasal administration. It is formulated.

[0160] In certain embodiments, the solid dosage forms described herein for use in oral administration contain pharmaceutical materials. It is prepared by mixing with one or more pharma- ceutically acceptable excipients. fillers or bulking agents, sweeteners, binders, humectants, disintegrants, preservatives, flavors, flavorings, oxidants Inhibitors, solution retarders, absorption enhancers, wetting agents, absorbents, lubricants, colorants, and controlled release agents. In some embodiments, the solid dosage form can be selected from the group consisting of a capsule, When in tablet or pill form, the pharmaceutical compositions described herein may also include a buffering agent. In embodiments, when the solid dosage form is a gelatin capsule, the pharmaceutical composition comprises lactose, milk, One or more excipients selected from sugars, high molecular weight polyethylene glycols, and combinations thereof The composition may further comprise an agent.

[0161] In certain embodiments, the pharmaceutical compositions of the present invention comprise a cyclodextrin, cellulose, lipopolysaccharide, or the like. one or more excipients selected from the group consisting of soluble soluble micelle-forming agents, and polymeric carriers. In some embodiments, the pharmaceutical compositions of the present invention may include an antibacterial agent, an antifungal agent, or Examples of antibacterial and antifungal agents include parabens, chlorobutanol, Examples of suitable phenols include, but are not limited to, phenol and sorbic acid. In accordance with the present invention, the pharmaceutical composition comprises an isotonicity agent. In certain embodiments, the dosage form of the present invention comprises a compound of formula (V) or a pharma- ceutically acceptable salt thereof. The compound may be formulated to provide slow or controlled release of the salt. For example, the compound may be formulated to provide sustained release of bempedoic acid. See PCT / US2019 / 018356, which discloses several formulations. In embodiments, the dosage forms of the present invention may be formulated for rapid release. In certain embodiments, the liquid dosage form of the pharmaceutical composition of the present invention comprises one or more of the following: an inactive Diluents, solubilizers and emulsifiers. In certain embodiments, the oral suspension of the pharmaceutical composition of the present invention comprises an ethoxylated isostearyl Alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulosic , aluminum metahydroxide, bentonite, agar and tragacanth, and their The mixture comprises one or more suspending agents.

[0162] In some embodiments, the ointments, pastes, creams and gels of the pharmaceutical compositions of the present invention are , and one or more excipients, the one or more excipients being animal fats, vegetable fats, oils, waxes, Paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, May contain silica, bentonite, silicic acid, talc, zinc oxide, or mixtures thereof. can.

[0163] In certain embodiments, powders and sprays of the pharmaceutical compositions of the present invention contain one or more excipients. and one or more excipients are lactose, talc, silicic acid, aluminum hydroxide, silicic acid In some embodiments, the composition may include calcium, polyamide powder, or a mixture thereof. In form, the spray of the present invention can contain a conventional propellant, which is Contains one or more chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons. In certain embodiments, the transdermal patch of the pharmaceutical composition of the present invention comprises a compound of formula (V) or its In some embodiments, the method provides for controlled delivery of a pharma- ceutically acceptable salt to the body. Also included within the scope of the present invention are ophthalmic formulations, eye ointments, powders, solutions and the like. In certain embodiments, the pharmaceutical compositions described herein may be administered in unit dosage form, It may be prepared by any method known in the art of pharmacy. The amount of the compound of formula (I) or a pharma- ceutically acceptable salt thereof will depend on the patient being treated and / or the particular may vary depending on the mode of administration.

[0164] In certain embodiments, the compound is combined with a pharma- ceutically acceptable carrier to produce a single dosage form. The amount of the compound of formula (V) or a pharma- ceutically acceptable salt thereof that can be administered is generally determined based on the therapeutic The amount of a compound of formula (V) or a pharma- ceutically acceptable salt thereof that produces a therapeutic effect. In various embodiments, bempedoic acid or a pharma- ceutically acceptable salt thereof, or a medicament according to the present invention Ming pharmaceutical materials are available in fixed dose formulations (e.g., U.S. Patent Application Publication No. 2018 / 0338922 (see WO 2018 / 218147 and WO 2018 / 218147). do.

[0165] VI. Methods of Treatment and Administration In various embodiments, the methods described herein, including pharmaceutical materials and / or pharmaceutical compositions, are provided herein. and / or the bempedoic acid or pharma- ceutically acceptable salts thereof prepared herein may be used to treat various diseases. The methods of treating a disease or disorder generally include the steps of: a purified amount of a compound of formula (V) or a pharma- ceutical acceptable salt thereof, This involves administering a therapeutically effective amount of a pharmaceutical material to treat a disease or disorder.

[0166] Examples of diseases and disorders include cardiovascular disease, atrial fibrillation, blood clotting, coronary heart disease, hypercoagulation, condition, ischemia, myocardial infarction, myopathy, myositis, pulmonary embolism, stroke, peripheral vascular disease, dyslipidemia disease, dyslipoproteinemia, glucose metabolism disorders, Alzheimer's disease, Parkinson's disease, Diabetic nephropathy, diabetic retinopathy, insulin resistance, metabolic syndrome disorders (e.g. For example, syndrome X, galactosemia, HIV infection, and peroxisome proliferator activation. Receptor-related disorders, sepsis, thrombotic disorders, obesity, pancreatitis, hypertension, renal disease, cancer, inflammation (e.g. , liver inflammation), inflammatory muscle diseases (e.g., polymyalgia rheumatica, polymyositis and fibromyalgia inflammation), impotence, gastrointestinal disorders, irritable bowel syndrome, inflammatory bowel disease, inflammatory disorders (e.g. Asthma, vasculitis, ulcerative colitis, Crohn's disease, Kawasaki disease, Wegener's granulomatosis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS) and autoimmune chronic hepatitis), joint Inflammation (e.g., rheumatoid arthritis, juvenile rheumatoid arthritis and osteoarthritis), osteoporosis, soft tissue Rheumatism (e.g. tendonitis), bursitis, autoimmune diseases (e.g. systemic lupus and erythematosus) erythematosus), scleroderma, ankylosing spondylitis, gout, pseudogout, non-insulin-dependent diabetes mellitus, Diabetes (e.g., type 2), polycystic ovarian disease, hyperlipidemia (e.g., primary hyperlipidemia, familial Hypercholesterolemia (FH), Frederickson II hypercholesterolemia Type a, hypercholesterolemia Frederickson type IIb, familial combined hyperlipidemia Fibrillation deficiency (FCH), lipoprotein lipase deficiency (e.g., hypertriglyceridemia, hypoalbuminemia, leucolipoproteinemia and hypercholesterolemia), diabetes-related lipoproteins Abnormalities, obesity-related lipoprotein abnormalities, and lipoprotein abnormalities associated with Alzheimer's disease In certain embodiments, the method includes the step of In some embodiments, the method includes treating and / or preventing hyperlipidemia, such as endogenous hyperlipidemia. The methods include treating and / or preventing cardiovascular disease.

[0167] In certain embodiments, the methods described and claimed herein, including pharmaceutical materials and / or pharmaceutical compositions, are provided herein. and / or the resulting bempedoic acid or pharma- ceutical acceptable salt thereof may have high levels of low density lipase. High levels of low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apolipoprotein B B), high levels of lipoprotein(a) (Lp(a)), high levels of very low density lipoprotein High levels of very low density lipoprotein (VLDL), high levels of non-high density lipoprotein cholesterol (non-HDL-C), of total serum cholesterol (TC) and high levels of high-sensitivity c-reactive protein (hsCRP) , high levels of fibrinogen, high levels of insulin, high levels of glucose, and low Treatment or prevention of one or more of the following: In other words, the method of the present invention can be used to lower LDL-C, apoB Lowering Lp(a) Lowering VLDL Lowering non-HDL -C reduction, TC reduction, and / or hsCRP reduction The method of the present invention may include inhibiting adenosine triphosphate citrate lyase (ACL). inhibiting cholesterol synthesis, and / or suppressing fatty acid biosynthesis. In some embodiments, a purified amount of a compound of formula (V) of the present invention or a pharmaceutical composition thereof may be used. The pharmaceutical composition or pharmaceutical material is a compound that is useful for treating heterozygous familial hypercholesterolemia. To lower LDL-C in adults with hypercalcemia or established atherosclerotic cardiovascular disease It may be used as an adjunct to dietary therapy and maximally tolerated statin therapy to reduce In some embodiments, a purified amount of a compound of formula (V) or a pharma- ceutically acceptable salt thereof is The salts, pharmaceutical compositions or pharmaceutical materials of the present invention are capable of providing non-insulin dependent metabolism without increasing weight gain. It may be used for the treatment of diabetes.

[0168] In certain embodiments, the methods and compositions described herein, including pharmaceutical materials and / or pharmaceutical compositions, are and / or the prepared bempedoic acid or a pharma- ceutically acceptable salt thereof may be used to treat aging, Alzheimer's, Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, glucose metabolism disorder, dyslipidemia , dyslipoproteinemia, increased bile production, hypertension, impotence, inflammation, insulin resistance Sex, biliary lipid clearance, regulation of C-reactive protein, obesity, biliary oxysterol clearance Pancreatitis, pancreatitis, pancreatitis, Kinson's disease, peroxisome proliferator-activated receptor-associated disorders, biliary phospholipid clearance, These include, but are not limited to, renal disease, rhabdomyolysis, sepsis, sleep apnea, syndrome X, and thrombotic disorders. The compounds may be used to treat or prevent a variety of diseases and conditions, including but not limited to:

[0169] In certain embodiments, the present invention relates to a method for treating steatohepatitis, alcoholic liver disease, fatty liver disease, and the like. er), liver steatosis, liver cirrhosis, liver fibrosis, and pregnancy Provided herein are methods for treating a liver disorder selected from the group consisting of acute fatty liver. In some embodiments, the disorder is steatohepatitis. In some embodiments, the steatohepatitis is non-alcoholic. In some embodiments, the disorder is alcoholic fatty liver disease. In some embodiments, the disorder is fatty liver. In some embodiments, the disorder is acute fatty liver disease during pregnancy. In some embodiments, the patient is an adult.

[0170] In certain embodiments, the present invention relates to a method for treating aging, Alzheimer's disease, cancer, cardiovascular disease, diabetic Nephropathy, diabetic retinopathy, glucose metabolism disorder, dyslipidemia, dyslipoproteinemia, increased bile production , Enhancement of reverse lipid transport, Hypertension, Impotence, Inflammation, Insulin resistance, Lipids in bile elimination, regulation of C-reactive protein, obesity, biliary oxysterol clearance, pancreatitis creatitis, pancreatitis, Parkinson's disease, Oxysome proliferator-activated receptor-associated disorders, biliary phospholipid clearance, renal disease, sepsis, For treating or preventing metabolic syndrome disorders (e.g., Syndrome X), or thrombotic disorders This provides a method for

[0171] In certain embodiments, the disorder is lipodystrophy, lysosomal acid lipase deficiency. and glycogen storage diseases. In some embodiments, the patient is an adult. In certain embodiments, the disorder is hepatitis C, infection with human immunodeficiency virus, α1- Antitrypsin deficiency, Bassen-Kornzweig syndrome, low beta lipoprotein from the group consisting of hepatitis, celiac disease, Wilson's disease, and Weber-Christian syndrome In some embodiments, the disorder is hepatitis B. In some embodiments, the disorder is hepatitis C. In some embodiments, the disorder is human immunodeficiency virus (HIV). In some embodiments, the disorder is an infection by alpha 1-antitrypsin deficiency. In some embodiments, the disorder is Bassen-Kornzweig syndrome. In some embodiments, the disorder is hypobetalipoproteinemia. In embodiments, the disorder is celiac disease or Wilson's disease. In some embodiments, the patient is an adult. do. In certain embodiments, the condition is toxic liver injury, total parenteral nutrition, severe surgical weight loss, In some embodiments, the condition is selected from the group consisting of environmental toxicity, malnutrition, and starvation. In some embodiments, the condition is toxic liver injury. In some embodiments, the condition is environmental toxicity. In some embodiments, the symptom is malnutrition or starvation. In some embodiments, the patient is an adult. .

[0172] In certain embodiments, the compound of formula (V) or its pharmaceutical equivalents is administered to prolong the effect of a drug. The acceptable salts can be administered by subcutaneous or intramuscular injection or by dissolving the drug in an oil vehicle. Alternatively, it may be administered by suspension. In certain embodiments, the compound of formula (V) or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition of the present invention is The actual dosage levels of the salts that can be administered will depend on the particular patient, composition, and / or agent used, without being toxic to the patient. and an amount of a compound of formula (V) or its analogues effective to achieve the desired therapeutic response for the mode of administration. The compound may be altered to obtain a pharma- ceutically acceptable salt thereof.

[0173] In certain embodiments, the selected dosage level depends on the route of administration, the time of administration, the specific The rate of excretion or metabolism of a particular compound, the rate and extent of absorption, the duration of treatment, the specific Other drugs, compounds and / or materials used in combination with the compound, the age of the patient being treated Age, sex, weight, symptoms, general health and previous medical history, and similar factors well known in the medical arts. The outcome depends on a variety of factors, including the cause. In certain embodiments, a physician or veterinarian of ordinary skill in the art will administer an effective amount of the pharmaceutical composition as needed. can be readily determined and formulated.

[0174] In certain embodiments, a suitable daily dose of a compound of formula (V) or a pharma- ceutically acceptable salt thereof is The dose corresponds to the minimum dose effective to produce a therapeutic effect. In this embodiment, the compound of formula (V) or a pharma- ceutically acceptable salt thereof is administered at a dose of about 0.01 mg / kg to In certain embodiments, the compound of formula (V) or a pharmaceutical composition thereof is administered at about 200 mg / kg. When a physiologically acceptable salt is co-administered with another therapeutic agent, an effective amount is the compound of formula (V) or may be less than when the pharma- ceutically acceptable salt is used alone.

[0175] In certain embodiments, the effective daily dose of the compound of formula (V) or a pharma- ceutically acceptable salt thereof is The amount may be administered as 2, 3, 4, 5, 6 or more subdoses. In some embodiments, two, three, four, five, six or more subdoses are optionally provided in unit dosage form. In some embodiments, the administrations are administered separately at appropriate intervals throughout the day. In some embodiments, the compound of formula (V) or a pharma- ceutically acceptable salt thereof is administered once. Acceptable salts are 1 day, 5 days, 10 days, 20 days, 30 days, 1 week, 2 weeks, 3 Weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months 1 year, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 2 years, 3 years, 4 In some embodiments, the compound of formula (V) is administered to the patient for a period of 1 year, 2 years, or 5 years. or a pharma- ceutically acceptable salt thereof is administered to the patient for the life of the patient.

[0176] VII. Combination Therapy In various embodiments, the pharmaceutical materials and pharmaceutical compositions of the present invention include those described herein. and / or the bempedoic acid or pharma- ceutically acceptable salt thereof prepared herein is useful in combination therapy In certain embodiments, the combination therapy may be a compound of formula (V) or a pharmaceutical composition thereof. In certain embodiments, the combination therapy comprises a purified a pharmaceutical material comprising a compound of formula (V) or a pharma- ceutically acceptable salt thereof, and a second therapeutic agent. Includes.

[0177] In some embodiments, the second therapeutic agent is lovastatin, a thiazolidinedione or fibrates, bile acid-binding resins, niacin, anti-obesity drugs, hormones, antivirals (e.g. For example, to treat the underlying hepatitis C infection that causes liver disease in patients), anti-cancer agents (e.g., to treat hepatocellular carcinoma or other cancers that cause liver disease or fatty liver); Antioxidants, drugs that reduce insulin resistance, or drugs that improve lipid metabolism (e.g., Treatment of hyperlipidemia), tyrophostin, sulfonylurea drugs, biguanides, α-glucose Syndase inhibitors, apolipoprotein AI agonists, apolipoprotein E, cardiovascular Drugs, HDL-raising drugs, HDL enhancers, or apolipoprotein AI, apolipoprotein Selected from the group including regulators of protein A-IV and / or apolipoprotein A genes In some embodiments, a purified amount of a compound of formula (V) or a pharma- ceutically acceptable salt thereof is The resulting salt, on a weight basis, is greater than 99.0% of the total weight of the pharmaceutical material.

[0178] In various embodiments, the second therapeutic agent may be a statin and / or ezetimibe. For example, U.S. Patent Application Publication No. 2018 / 0078518 (bempedoic acid and statins) Combination), No. 2018 / 0064671 and No. 2018 / 0338922 (BenPed and ezetimibe), WO 2018 / 218147 (combination of bempedoic acid and ezetimibe), and ezetimibe); and WO 2018 / 148417 (combination of bempedoic acid and ezetimibe) See also combination of antidepressants and statins.

[0179] In certain embodiments, a compound of formula (V) or a pharma- ceutically acceptable salt thereof and a second therapeutic agent are Administering a pharmaceutical material or composition of the present invention comprising a therapeutic agent provides a compound of formula (V) or Providing a beneficial effect from the synergy of a pharma- ceutically acceptable salt thereof with a second therapeutic agent. In some embodiments, the beneficial effect of the combination therapy is achieved by administering to a subject a compound of formula (V) or a pharmacokinetic or pharmacodynamic effect resulting from the combination of a medicament for which the compound is ... may include pharmacodynamic co-actions.

[0180] VIII. Kit In various embodiments, the present invention provides a method for treating a condition, disease, or disorder described herein. In some embodiments, the kit comprises: i) a kit for administering a therapeutic agent to a subject, e.g., a subject as described herein; and ii) a compound of formula (V) or a combination thereof for treating said condition, disease or disorder. A pharma- ceutically acceptable salt (e.g., a purified amount of a compound of formula (V) or a pharma- ceutically acceptable salt thereof) In some embodiments, the kit comprises a pharmaceutical composition for use in treating a condition, disease, or disorder, including a salt thereof. The compound of formula (V) or a pharma- ceutical acceptable salt thereof is It may contain one or more unit dosage forms.

[0181] Described herein is a method for making a compound of formula (V) or a pharma- ceutically acceptable salt thereof. , a compound of formula (V) or a pharma- ceutically acceptable salt thereof, e.g., a purified amount of a compound of formula (V) or a pharma- ceutically acceptable salt thereof, Aspects and embodiments of the present invention include compositions and kits that include pharma- ceutically acceptable salts. This patent application covers all combinations and permutations of the aspects and embodiments described herein. Specifically, the present invention relates to pharmaceutical materials, pharmaceutical compositions, methods of treating disorders or conditions, and The doses include those containing bempedoic acid or its pharmacopoeitic derivatives, as prepared by the methods described herein. It is understood that acceptable salts can be included and / or used. EXAMPLES

[0182] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthesis and analytical protocols described in this application are intended to provide a method for the preparation of compounds provided herein. These are provided to illustrate, but in no way limit the scope of, the pharmaceutical compositions and methods. should not be interpreted as

[0183] Example 1: Manufacturing process for preparing a pharmaceutical material containing a purified amount of the compound of formula (V) In this example, the synthesis of purified bempedoic acid refers to FIG. Step 1 - Preparation of Compounds of Formula (I) Preparation of lithium diisopropylamide (LDA) A reaction vessel was charged with diisopropylamine (317±3 kg, 1.1 equivalents) and tetrahydrofuran. Charge run (THF, 2,102±105 L) and then cool the mixture to below −10° C. Next, while maintaining the temperature at -10°C or less, n-butyl lithium (n-BuLi , 757±8 kg, 1.2 equivalents) was added over 1 hour. The feed line was THF. The addition was exothermic. Finally, the batch was then cooled to below -10°C with stirring. Cooled.

[0184] Alkylation Reaction Ethyl isobutyrate (317±3 kg, 1.1 equivalents) was heated at -10°C or lower (Figure 1) for at least 1 hour. The batch was stirred while maintaining the temperature below -10°C. Bromo-5-chloropentane (460±5 kg, 1.00 equivalent) was incubated at -10°C or below for 1 hour or The lines were rinsed with THF. The addition was exothermic. The reaction mixture was then The mixture was stirred at -10°C or below for 10 hours. This stage of the reaction was monitored by gas chromatography. - (1-bromo-5-chloropentane: <3% area) was used to confirm completion. The reaction mixture was then warmed to 0±5° C. and maintained at this temperature until the conversion was complete. The reaction was analyzed by gas chromatography (1-bromo-5-chloropentane: <0.5% area). ) to ensure it was complete.

[0185] Quenching and Phase Separation A 9% hydrochloric acid solution (HCl, 1337 ± 50 kg) was reacted while maintaining the temperature below 30°C. The reaction mixture was quenched by adding 100 mL of 10 ... The mixture was stirred at 0.5 °C or less for 15 minutes or more. The pH of the aqueous layer was measured (range: pH 6-10). The process was stopped and the layers were allowed to settle for at least 30 minutes. The lower aqueous phase was removed for disposal. Distillation and removal of THF The solvent was removed by distillation under reduced pressure below 40° C. to the desired volume of about 950 L.

[0186] The concentration of the compound of formula (I) was determined by gas chromatography (GC) (within the concentration range of The measurement was performed using the target compound: 57 to 62% by weight. To adjust the concentration within the target range, THF is added or further removed by distillation. Ta. The batch was then cooled to below 30° C. and the crude compound of formula (I) was concentrated by drumming. The process is repeated in the same manner to obtain a compound of formula (I). , a second batch was obtained.

[0187] Step 2 - Preparation of Compounds of Formula (II) Additional aqueous wash Two separate batches of the compound of formula (I) (57-62% w / w solution in THF) were While stirring, 5% HCl (1,767±79 kg) was added at 25°C or lower. The addition was exothermic. The mixture was stirred for 15 minutes more. Stirring was stopped and the phases were separated for 30 minutes. The lower aqueous phase was removed, leaving the compound of formula (I) / THF in the reactor. .

[0188] Iodide exchange reaction With stirring, methyl ethyl ketone (MEK, 4,384±227 L) and sodium iodide were added to the Sodium (NaI, 831 ± 9 kg, 1.16 equiv.) was charged (Figure 1). The batch was heated to reflux. After approximately 30 hours, the reaction was determined to be complete using GC (Eq. ( Compound I) <1.0% area). If the reaction is not complete, allow more time (expected reaction The mixture was then heated to about 20° C. for 25 to 35 hours, with NaI being added again as necessary. The mixture was cooled to .

[0189] Solvent exchange and aqueous workup The batch is concentrated by vacuum distillation below 60° C. until no more distillate is collected. The mixture was then cooled to 20±5°C and n-heptane (3,624±187 L) was added. Then, 5% sodium hydrogen sulfite solution (NaHSO3, 2,121±10 4 kg) was added and the mixture was stirred for at least 60 minutes. Stirring was stopped and the phases were allowed to settle for at least 60 minutes. The lower aqueous phase was removed for disposal. Water (1980±102 L) was added and the mixture was stirred. The phases were allowed to settle for at least 60 minutes and the lower aqueous phase was removed for disposal. An optional second water wash was performed if necessary.

[0190] final concentration The batch is concentrated using vacuum distillation below 50° C. until no more distillate is collected. The batch was then cooled to 20° C. and the compound of formula (II) was drummed and assayed. The expected yield range was 80-120% (wt / wt%). Ta.

[0191] Step 3 - Preparation of Compounds of Formula (IV) Preparation of sodium t-pentoxide / DMAc The following sequence of intermediates / compounds of formula (IV) is: 00 kg of compound of formula (II) / n-heptane, which is 665 k g represents the amount of the compound of formula (II) contained. N,N-Dimethylacetamide (DMAc, 1,476±37kg) and sodium t - A solution of pentoxide (271 ± 3 kg, 2.10 equivalents) was prepared in a vessel and almost all of the solid was dissolved in water. The mixture was stirred for about 30 minutes until everything was dissolved.

[0192] Preparation of the first intermediate Compound of formula (II) (700 kg, 1 equivalent), DMAc (1,272±27 kg) and TosMIC (219 ± 1 kg) was placed in a container (see Figure 1). The mixture was cooled to below -5°C. The solution was cooled and thoroughly stirred. Sodium t-pentoxide / DMAc mixture was added to the solution. The addition took approximately 1 hour at 5°C or less. The transfer line was rinsed with DMAc (181 ± 9 kg). The reaction was strongly exothermic. The reaction mixture was stirred below -5°C for at least 30 min. UV detection High performance liquid chromatography (HPLC-UV) using monoalkylated TosMIC ≦1% area and compound of formula (II) ≦1.4% area) to confirm that the conversion was complete. Based on the following instructions, if necessary, the reaction may be completed. ), TosMIC and an optional kicker charge of sodium t-pentoxide ( kicker charge) was used (Table 18): [Table 18]

[0193] Quenching and Phase Separation n-Heptane (2,407±120 L) and water (3,061±153 L) were placed in a separate reactor. The first intermediate reaction mixture was stirred at 0°C to 40°C (target 20°C) for 1 hour. The reaction was highly exothermic. The transfer line was flushed with n-heptane / water mixture. (470±24 L). The mixture was then stirred for at least 1 hour. The stirring was stopped and The mixture was allowed to stand for at least 1 hour. The lower aqueous phase was removed for disposal. 5% Sodium Chloride An aqueous solution (NaCl, 3,106 ± 147 kg) was added and the mixture was heated to approximately 20 °C (range: 0 °C The mixture was stirred at 40° C. for at least 1 hour at room temperature (−40° C.). The stirrer was stopped and the mixture was allowed to stand for at least 60 minutes. The lower aqueous phase was removed for disposal. The remaining solution of the first intermediate in n-heptane was added to another volume. Transferred to a container.

[0194] Reaction of compounds of formula (IV) Isopropyl acetate (IPAc, 451 ± 23 L) was added to the solution of the first intermediate in n-heptane. The mixture was cooled to -10±10°C. Concentrated H was added while maintaining the temperature at ≦25°C. Cl (115±2 kg) was added. The reaction was exothermic and the reaction mixture was stirred as needed. The mixture was heated to 20±5°C. During the heating period, the mixture was stirred for more than 30 minutes. Intermediate (≦2% area) was used to measure reaction conversion.

[0195] Quenching and Phase Separation In a separate container, add sodium hydroxide (NaOH) solution (50% wt / wt, 175 ± 2 kg g) was combined with water (1927±96 L). The resulting aqueous NaOH solution was added to the reaction mixture in an amount of about 2 The mixture was added at 0°C (range: 10°C to 40°C). The lines were rinsed with water. The mixture was stirred for more than 3 hours. The neutralization end point is pH 9 to 12. Stirring is stopped and the phase is allowed to stand for 60 minutes or more. The lower aqueous phase was removed for disposal. NaCl (55 ± 3 kg), water (1,572 ± 79 L) ) and 50% sodium hydroxide (4.6 ± 0.2 kg) in a separate container. and charged into the product mixture of the compound of formula (IV). 6 L) was applied and the mixture was stirred for at least 60 minutes. Stirring was stopped and the phases were allowed to settle for at least 60 minutes. The lower aqueous phase was removed for disposal.

[0196] concentrated The mixture was concentrated under vacuum at below 80° C. until no more distillate was collected. The distillation was monitored using a 250-mL 2-chloro-5-phenylenediamine (PHA) (>75% area of ​​compound of formula (IV)). The batch was cooled to about 20° C. The concentrate of the compound of formula (IV) was cooled and held until the second batch was prepared. The process for preparing the compound of formula V) was repeated in an identical manner to obtain a compound of formula V in n-heptane. A second batch of compound (IV) was obtained. The second batch was then transferred to the final distillation and packaging. The first batch was combined with the second batch (in n-heptane). The product was weighed and stored for assay. The expected yield range was 80-120% w / w.

[0197] Step 4 - Preparation of compound of formula (V) (crude bempedoic acid) Reaction 1 (Ketone reduction) Compound of formula (IV) (545±5 kg) and ethanol (EtOH, 1090±55 kg) g) was charged to the vessel. While maintaining the batch at 35°C or below, sodium borohydride ( NaBH4, 12 wt% in 40% NaOH, 155±2 kg, 0.35 equivalents) for about 2-3 The dosing line was filled with water (155±8 kg) and rinsed. After keeping at 25±10°C for at least 1 hour, the mixture was analyzed by HPLC-UV (Formula (IV) The conversion was measured using a compound of ≦0.5% area).

[0198] Reaction 2 (saponification) Aqueous NaOH solution (50% wt / wt, 435±4 kg) was added to the container at 50°C or less. The addition was exothermic. The dosing lines were rinsed with water (155±8 kg) and the reaction mixture was stirred for 5 min. The mixture was heated to 0±5° C. for at least 6 hours. The saponification was confirmed by HPLC-UV (monoester of compound (V) Water (1873 ± 94 kg) was added to the reaction mixture. The EtOH and water were vacuumed until the batch volume reached the target level (approximately 2184 L). The mixture was transferred to another reactor and the transfer line was filled with water (273±1 4kg) and rinsed.

[0199] pH adjustment, phase separation and extraction Methyl tert-butyl ether (MTBE, 1628±81 kg) was added and the batch The mixture was cooled to 10-15°C. Concentrated HCl (647±6 kg) was added slowly at 10-20°C. (The addition was exothermic) and the batch was stirred for an additional hour. A sample was taken for pH analysis. The pH was adjusted with HCl or NaOH as necessary (target pH range: 5-6). The formation of hydrogen gas was observed. Stirring was stopped and the phases were allowed to stand at 10-20°C for at least 60 minutes. The lower aqueous phase was removed for disposal. The batch was decanted and forward rinsed with MTBE. Using HPLC-UV (compound of formula (V): 17% to 20% by weight), MTBE The concentration of the compound of formula (V) in the solution was measured.

[0200] Step 5 - Purification of Compound of Formula (V) / Preparation of Compound of Formula (V) in Crystalline Form Silica gel preparation The diameter × height ratio of the silica gel plugs was varied from 1 × 1 to 1 × 3. Silica gel (6 0±2 kg) was placed in a filter, moistened with ethyl acetate (EtOAc), and then poured into a reactor. The silica gel bed was washed with EtOAc (1,173±5 9 kg) was preheated by recirculation at 50±5° C. Excess EtOAc was removed by distillation with V) Removed immediately prior to filtration of the batch of compound.

[0201] Solvent exchange to ethyl acetate The compound of formula (V) in MTBE was charged to the reactor. The batch was initially heated under vacuum at below 50°C. The mixture was concentrated to 30%-35% of the initial volume. EtOAc (2,002 ± 100 kg) was added. The batch was concentrated again to 30%-35% of the original volume. EtOAc (1601 ± 80k g) was charged and the distillation was repeated. EtOAc (1601 ± 80 kg) was charged and the batch The solvent exchange was measured by GC (MTBE 0.1% by weight or less). Additional EtOAc charges and distillation were added as necessary.

[0202] Silica gel filtration Once the solvent exchange was complete, the batch was warmed to 50±5° C. The batch was then transferred to a preheated silica gel column. Filter through a gel plug into another reactor. Add EtO to rinse the lines and silica gel. Ac (964±20 kg) was charged to the reactor and warmed to 50° C., followed by warm EtOAc. A portion of the mixture was transferred to a silica gel plug. Product loss due to retention on the silica gel filter was measured using HPLC (less than 0.5% by weight of compound of formula (V) in the eluent). If necessary, further washing with EtOAc was performed. Purification of Formula (V) in EtOAc The mixture is partially concentrated by distillation under vacuum at 50 to a final volume of approximately 1700 L. did.

[0203] Crystallization The temperature of the concentrated compound of formula (V) in EtOAc was adjusted to about 50±5° C. Water (24±1 kg), rinse the lines with EtOAc (74 ± 10 kg), and heat the solution at 50 ± 5 °C. The solution was then cooled at a rate of 14°C / hour and stirred slowly. The mixture was cooled to 22±5° C. while stirring, and then held at this temperature for 2 hours or more to initiate crystallization. Once the slurry was formed, the solution was stirred at about 20 to 25°C for 6 hours or more. The batch was cooled to 0±5°C using a cooling rate of 11°C / h and then incubated at this temperature for at least 6 hours. The mixture was stirred.

[0204] Isolation and Drying The crude crystalline form of the compound of formula (V) is isolated by centrifugation at 0±5° C. and then cooled to 0± Wash with EtOAc cooled at 5° C. Dry the wet cake under vacuum at up to 45° C. Drying was monitored by loss on drying (LOD) (LOD ≤ 0.5%). Optional in situ filtration For vessels designed with in situ filtration, the slurry is filtered at 0± Allow to stand at 5° C. for at least 1 hour. Filter the batch, leaving the wet cake in the reactor. tOAc (1,064±53 kg) was charged into a separate vessel, cooled to 0±5°C, and decanted. The mixture was then passed through a filter and transferred back into the reactor containing the wet cake. The batch was stirred for at least 1 hour. The slurry was then allowed to stand for at least 1 hour. The filtration was repeated. The slurry washing and filtration processes were performed simultaneously. Repeated three times in the same pattern.

[0205] Step 6 - Preparation of a pharmaceutical material comprising a purified amount of a compound of formula (V) Recrystallization (ethyl acetate / water) Following in situ filtration, the amount of compound of formula (V) in crystalline form produced in step 5 is In step 4, the compound of formula (IV) (charge amount: 545 kg) was converted 100% to the compound of formula (V). The estimates were based on the assumption that the population was converted into In the reactor, E was added until the volume reached the 1433 L mark (approximately 619 kg of EtOAc). tOAc is charged to a wet cake of the compound of formula (V) in crystalline form, and then all the solids are The suspension was heated to 55-60°C until the cations were dissolved. Water (16 ± 1 kg) was added to the clear solution. The batch was stirred at 55-70°C for at least 1 hour. The temperature was adjusted to 55±5°C, and then The batch was transferred to another reactor by polish filtration. Reactors, filters and lines was rinsed with EtOAc (162±12 kg). The temperature was adjusted to 55±5° C. Then The hot solution was cooled to 30±5° C. over 1 hour and stirred for 2 hours. The mixture was heated to 40±5°C over 1 hour and then maintained at 40±5°C for 1 hour or more. Then, cool the batch to 35±5°C over 1 hour and then heat at 35±5°C for 2 hours or more. The batch was then cooled to 5±5° C. over 5 hours and then heated at 5±5° C. for 4 hours. The resulting solid was isolated by centrifugation. The washing solvent was acetonitrile. The solution was diluted with ACN and stored at 20±10°C until use.

[0206] Isolation, drying, compound identification and IPC test of the compound of formula (V) The purified compound of formula (V) solid is collected by centrifugation and then cooled to 20±10° C. Wash with acetonitrile (2 × 2 kg / kg of compound of formula (V)) to remove all remaining mother liquor. The wet cake was dried in vacuum at below 45°C. Yield: 324.2 kg (84.9%) purified amount of a pharmaceutical material comprising the compound of formula (V).

[0207] The purified compound of formula (V) was dissolved in 10 mg / mL of CDCl3 and 5 By preparing a 0 mg / mL solution, 1 H- and 13 Prepared for C-NMR analysis Using an Inova 500MHz NMR spectrometer, 1 H- and 13 C-NMR The spectra were obtained to allow for better relative quantification of the integrals and that all signals were captured. To guarantee this, the window was extended from 5000 to 8000 Hz and the latency between acquisitions was increased to The reaction time was extended from 1 second to 25 seconds. 1 H- and 13 C-NMR spectrum 2(a) and 2(b), respectively, show the known 1 H- and 13 The C-NMR spectrum is consistent with that of the 1H-C NMR spectrum (Table 19). [Table 19] A sample of the purified compound of formula (V) is run in positive electrospray mode. Agilent coupled to a Thermo LTQ-XL electrospray mass spectrometer The analysis was performed on a 1100 HPLC. The capillary temperature was 200°C. The column was The mobile phase was X-Bridge C18, 4.6 x 75 mm, 2.5 μm. Mobile phase A was 0.05% formic acid and mobile phase B was 0.04% formic acid in acetonitrile. The experimental mass of compound V) was found to be 344.38 Da, which is 344.4 This is in good agreement with the calculated mass of bempedoic acid of 9 Da.

[0208] The expected yield range was 66-91%. Residual solvent was measured by GC (ACN ≤ 350 ppm). After drying was completed, a charged aerosol detector (CAD) was used to measure the drying time. Impurities were measured using HPLC (unknown impurities 0.08 wt% or less and known impurities If the impurity profile criteria are met, the product may be used as a final active pharmaceutical ingredient. If the impurity profile criteria are not met, the above Another recrystallization was performed as described above.

[0209] Using the HPLC assay described in Example 3, the purity of the purified compound of formula (V) was determined to be 99. It was determined to be 6% (w / w). X-ray powder diffraction (XRPD) data for the crystalline form of the compound of formula (V) was obtained from Pana Lytical X'Pert 3 Powder diffractometer (Cu, Kα radiation; X-ray tube settings -45kV, 40mA; Divergence slit-Fixed 1 / 8°; Scan mode-Continuous; Scan Range -3~40°(2θ); Scan step time -18.87 sec; Step size -0.0 A sample of the compound of formula (V) in crystalline form was collected using a Si The sample was placed on a zero background holder. The 2θ position was referenced to Panalytical Si. The XRPD pattern of the crystalline form of compound of formula (V) is shown in FIG. The tabulated characteristics of the XRPD pattern of FIG. 4 are shown in Table 20 below, which shows the diffraction angles The 2θ and relative intensities (expressed as a percentage relative to the most intense peak) are listed.

[0210] Differential scanning calorimetry (DSC) data for the crystalline form of compound of formula (V) is shown in Table 1. The data were collected using a Q2000 DSC instrument. The DSC instrument was run using an indium reference standard. A sample of the crystalline form of the compound of formula (V) was placed on a pressed aluminum plate. The sample was placed in a pull pan and heated from ambient temperature (approximately 25°C) to 300°C at a rate of 10°C / min. The DSC curve of the crystalline form of the compound of formula (V) is shown in FIG. The reaction showed an endothermic event with an onset of . Thermogravimetric analysis (TGA) data for the crystalline form of compound of formula (V) is reported by TA Discove The data were collected using a ry 550 TGA instrument. The TGA instrument was run using a nickel reference standard. A sample of the compound of formula (V) in crystalline form was placed in an open platinum sample pan and calibrated using the following method: The mixture was heated from about ambient temperature (about 25° C.) to about 315° C. at a rate of 10° C. / min. The TGA curve of the crystalline form of this compound is shown in Figure 6. The TGA curve shows negligible amounts of crystalline The weight loss was significant. [Table 20]

[0211] In addition, a single crystal of the crystalline form of the compound of formula (V) was analyzed by single crystal X-ray diffraction. The unit cell parameters of the crystalline forms of the compounds of the present invention, as well as the data collection and structure refinement methods, are described. These are shown in Tables 21 and 22, respectively. [Table 21] [Table 22] Atomic coordinates (×10 4 ) and isotropic displacement parameters (Å 2 ×10 3 ) are shown in Table 23 below. U(eq) is the orthogonalized U ij It is defined as one-third of the trace of a tensor. [Table 23]

[0212] Bond distances (Å) are shown in Table 24 below. [Table 24]

[0213] The bond angles (°) are shown in Table 25 below. [Table 25]

[0214] The twist angles (°) are shown in Table 26 below. [Table 26]

[0215] Anisotropic displacement parameter (Å 2 ) is shown in Table 27 below. The anisotropic displacement coefficient index is It can be expressed in the form: -2π 2 [h 2 a* 2 U 11 +…+2 hka*b* U 12 ]. [Table 27]

[0216] Hydrogen atom coordinates and isotropic atomic displacement parameters (Å 2 ) are shown in Table 28 below. [Table 28]

[0217] Selected hydrogen bond information (in Å and °) is shown in Table 29 below. [Table 29] Symmetry transformation used to generate equivalent atoms: #1 x, y-1, z #2-x+ 1, -y+2, -z+1 #3-x+1, y+1 / 2, -z+3 / 2

[0218] Example 2: Alternative manufacturing process for preparing a pharmaceutical material containing a purified amount of the compound of formula (V) vinegar Step 1 - Preparation of Compounds of Formula (I) Preparation of lithium diisopropylamide (LDA) The reaction vessel contained approximately 321 kg of diisopropylamine and approximately 1870 L of tetrahydrofuran. Lam (THF) was added and the mixture was then cooled to -18°C to -5°C. n-Butyl lithium (n-BuLi, heptane solution) was heated at -18℃ to -5℃. The batch was kept at -18°C to -5°C with stirring.

[0219] Alkylation Reaction Approximately 317 kg of ethyl isobutyrate was stored at the target temperature of -18℃ to -5℃. The LDA was added to the reactor containing the LDA over a period of 1 hour. The line was then drained to approximately 100 L. Rinse with THF. The batch was stirred while maintaining the temperature at -18°C to -5°C. Approximately 46 0 kg of 1-bromo-5-chloropentane was administered to the target at -18°C to -5°C for over 1 hour. The lines were then rinsed with approximately 100 L of THF. The reaction mixture was incubated at -18°C to -5°C. The mixture was stirred and then warmed to 0° C.±5° C. The reaction was analyzed by gas chromatography (GC) ( -Bromo-5-chloropentane: ≦0.4% area) to ensure completion Ta. Quenching and Phase Separation Approximately 1,337 kg of 9% aqueous hydrochloric acid (HCl) was reacted while maintaining the temperature below 30°C. After administration, the reaction mixture was incubated at 20°C ± 5°C for 15 minutes or more. The mixture was stirred overnight. The layers were allowed to settle. The pH of the aqueous layer was then measured (range: pH 6-10). If the pH range is not met, add additional sodium hydroxide (NaOH) or HCl. The lower aqueous phase was removed for disposal. Distillation and removal of THF The solvent was removed by distillation under reduced pressure below 40° C. to the desired volume of about 950 L. The crude compound of formula (I) concentrate is temporarily stored in the reaction vessel or dried until further processing. The compound of formula (II) was prepared by repeating the process for the compound of formula (I) in the same manner. This was repeated to obtain a second batch.

[0220] Step 2 - Preparation of Compounds of Formula (II) Additional aqueous wash Two separate batches of the compound of formula (I) in THF were added to the vessel. While stirring, about 1767 kg of 5% HCl aqueous solution was added at 20°C ± 5°C. The mixture was stirred for 15 minutes. The mixture was stirred for at least 1 hour. The stirring was stopped and the phases were allowed to settle. The lower aqueous phase was removed and the mixture of Formula (I) / THF of compound was left in the reactor. Iodide exchange reaction Approximately 4386 L of methyl-ethyl-ketone (MEK) and approximately 824 kg of sodium iodide The mixture was stirred and charged with NaI. The batch was heated to reflux. After approximately 30 hours, GC The reaction completion was determined using the ELISA (compound of formula (I) ≦3.0% area). If not, additional time may be allowed and additional NaI may be charged as needed. The mixture was cooled to about 20°C ± 10°C. Solvent exchange and aqueous workup The batch is concentrated by vacuum distillation below 60° C. until no more distillate is collected. Next, about 3000 L of n-heptane was added. About 2115 kg of 5% aqueous sulfurous acid solution was added. Prepare an aqueous sodium hydroxide solution (NaHSO3) and add the reaction mixture of the compound of formula (II) to the solution. Approximately 612 L of n-heptane rinse was added. The mixture was stirred at 20°C ± 5°C. Agitation was stopped and the phases were allowed to settle. The lower aqueous phase was removed for disposal. Approximately 1976 L of water is added, the mixture is stirred, the phases are allowed to settle, and the lower aqueous phase is then removed for disposal. The water wash was repeated once more. final concentration The batch is concentrated using vacuum distillation below 50° C. until no more distillate is collected. The compound of formula (II) was then drummed and sampled for intermediate testing. The expected yield range is 80% to 100%.

[0221] Step 3 - Preparation of Compounds of Formula (IV) Preparation of sodium t-pentoxide / DMAc The sequence of the first intermediate / compound of formula (IV) below is the reaction of 650 kg of compound of formula (II) The compound of formula (II) / heptane was assayed at 90.0% weight / weight, which represents the amount of the input. Based on an input of approximately 722 kg of tank. Approximately 1,450 kg of N,N-dimethylacetamide (DMAc) and approximately 267.3 kg of A solution of sodium t-pentoxide was prepared in a vessel and the mixture was stirred at below 30°C. Preparation of the first intermediate Compound of formula (II) in heptane (approximately 722 kg), DMAc (approximately 1259 kg) g) and TosMIC (approximately 213.8 kg) were placed in a vessel. The mixture was then added to a -1 The mixture was cooled to 5°C to 0°C and thoroughly stirred. The transfer line was filled with approximately 178 kg of DMAc. The reaction mixture was stirred at -15°C to 0°C. Monoalkylated TosMIC≦3.0% area and compound of formula (II)≦3.0% area The conversion was confirmed to be complete using high performance liquid chromatography (HPLC) with Based on the information provided in Table 30, additional steps were taken, if necessary, to ensure completion of the reaction. , a compound of formula (II), TosMIC, and an optional kicker of sodium t-pentoxide (Additional) inputs can be used. [Table 30] IPC = in-process control; TosMIC = p-toluenesulfonylmethyl isocyanide.

[0222] Quenching and Phase Separation About 2344 L of n-heptane and about 2993 L of water were charged into a separate reactor. The intermediate reaction mixture was transferred to a heptane / water mixture under temperature control at 0°C to 40°C (target 20°C). The transfer line was then rinsed with approximately 456 L of n-heptane. The mixture was heated to 0°C to 40°C. The mixture was stirred at 0.5° C. for 1-3 hours. The stirring was then stopped and the mixture was allowed to settle. The lower aqueous phase Approximately 3,036 kg of 5% sodium chloride solution (NaCl) was added. The mixture was stirred. The stirrer was then stopped and the mixture was allowed to settle. The lower aqueous phase was Removed for disposal.

[0223] Reaction of compounds of formula (IV) Add approximately 440 L of isopropyl acetate (IPAc) to the solution of the first intermediate in heptane. The mixture was then cooled to -15°C to 0°C. The mixture was then stirred at -15°C to 25°C. Then, concentrated HCl (about 112 kg) was added. The reaction mixture was heated at 10°C to 25°C as needed. Upon reaching 10°C to 25°C, the mixture was stirred for 30 to 60 minutes. UV was used to measure reaction conversion (area of ​​first intermediate ≦20%).

[0224] Quenching and Phase Separation In a separate container, add approximately 177 kg of NaOH (50% w / w) to approximately 1884 L of water. The resulting aqueous NaOH solution was then added to the reaction mixture at approximately 20°C (range: 10°C to The mixture was stirred. The pH is 9-12. Agitation is stopped and the phases are allowed to settle. The lower aqueous phase is removed for disposal. The solution contained approximately 54 kg of NaCl, approximately 1535 L of water, and approximately 4.5 kg of 50% NaOH. A dilute aqueous solution of the compound of formula (IV) was prepared in a separate vessel and added to the product mixture. Then, about 126 L of water rinse was applied. The mixture was stirred, the phases were allowed to settle, and the lower aqueous phase was Removed and discarded.

[0225] concentrated The mixture was concentrated under reduced pressure at below 80° C. to reduce the volume. The batch was then cooled to about 20° C. The concentrate of the compound of formula (IV) was cooled and held until the second batch was prepared. The process is repeated in the same manner to obtain the first compound of formula (IV) in heptane. The second batch (in heptane) was then added to the first batch for final distillation. The distillation was monitored using GC (75% by weight or more of the compound of formula (IV)). The product was packaged. The product was weighed and sampled for intermediate testing. The yield range is 85% to 105%.

[0226] Step 4 - Preparation of compound of formula (V) (crude bempedoic acid) Reaction 1 (Ketone reduction) Approximately 710 kg of the compound of formula (IV) and approximately 1420 kg of ethanol (EtOH) were Approximately 202 kg of sodium borohydride was added to the vessel while maintaining the batch at 25°C ± 10°C. Sodium (NaBH4, 12 wt% in 40% NaOH, approximately 0.35 equivalents) was then added. Then, the input line was rinsed with about 202 kg of water. After keeping the temperature at 25℃±5℃ for more than 1 hour, Conversion was monitored using HPLC-UV (compound of formula (IV)≦0.9% area).

[0227] Reaction 2 (saponification) Approximately 567 kg of NaOH solution (50% wt / wt) is charged at 15°C to 50°C. The lines are rinsed with approximately 202 kg of water and the reaction mixture is warmed to 50°C ± 5°C for not less than 6 hours. Saponification was performed using HPLC-UV (compound of formula (V) monoethyl ester ≦1.3% area). Approximately 2440 kg of water is charged to the reaction mixture. The batch volume reaches the target level ( Distill EtOH and water under vacuum and below 50° C. until a total volume of about 2845 L is reached.

[0228] pH adjustment, phase separation and extraction The mixture is diluted with approximately 356 L of water and then cooled to 200° C. while maintaining the batch at 15° C. to 50° C. 121 kg of methyl tert-butyl ether (MTBE) was added. The batch was heated to 10° C. Cooled to ~20° C. Concentrated HCl (about 912 kg) was added slowly at 10° C.-20° C. Samples were taken for pH analysis and pH was adjusted with HCl or NaOH as necessary. (Target pH range: 5.0-6.0). Stop stirring and allow the phases to settle. Discard the lower aqueous phase. The concentration of the compound of formula (V) in MTBE was measured using HPLC-UV. The batch was then transferred to a separate vessel and rinsed forward with approximately 629 kg of MTBE.

[0229] Step 5 - Purification of Compound of Formula (V) / Preparation of Compound of Formula (V) in Crystalline Form Silica gel preparation The diameter x height ratio of the silica gel plug can vary from 1 x 0.8 to 1 x 3. 78 kg of silica gel was placed in the filter. Approximately 1173 kg of EtOAc was added at 50°C ± 5 The silica gel bed was prepared by recirculating at 100° C. The excess EtOAc was removed by elution with a hexane-containing ... It was removed immediately prior to filtration of the batch compound.

[0230] Solvent exchange to ethyl acetate The compound of formula (V) in MTBE was concentrated under vacuum at below 50° C. to about 1148 L. 2608 kg of EtOAc was charged and then the batch was concentrated again to about 1148 L. 2086 kg of EtOAc was added and the distillation was repeated. EtOAc (approximately 2086 kg) The solvent exchange was performed by GC (MTBE 0.1% wt.). Additional EtOAc charges and distillations may be performed if necessary.

[0231] Silica gel filtration Once the solvent exchange was complete, the batch was heated to 45°C to 55°C. The batch was then placed in the preheating system. The solution was filtered through a silica gel plug into another reactor. To rinse the lines and silica gel, Approximately 521 kg of EtOAc was charged to the reactor and warmed to 50° C.±5° C., and then the warm Et The OAc was transferred through a silica gel plug. The purified compound of formula (V) was then dissolved in EtOAc. The product was partially concentrated by distillation under vacuum at 50° C. or less to a final volume of about 2321 L. It shrunk.

[0232] Crystallization The concentrated compound of formula (V) in EtOAc was adjusted to about 50° C.±5° C. About 31.3 kg of Water was added and the solution was maintained at 50°C ± 5°C for at least 1 hour. The mixture was cooled slowly to 22° C.±5° C. over a period of 1 hour to initiate crystallization of the compound of formula (V). The mixture was stirred at about 22°C ± 5°C for at least 6 hours, and then a slurry was confirmed to form. If no β-amino group is present, seeding can be performed at 20°C to 25°C with further stirring if necessary. The batch is then slowly cooled to 0°C ± 5°C over 2 hours and stirred for 6 hours at 0°C ± 5°C. The mixture was stirred for over an hour.

[0233] Optional in situ filtration For vessels designed with in situ filtration, the slurry is filtered at approximately 0. The batch was then filtered, leaving the wet cake in the reactor. 86 kg of EtOAc was charged into a separate container and cooled to 0°C ± 5°C. The batch was stirred at 0° C.±5° C. and then allowed to settle. The solids were filtered. The slurry washing and filtering process was repeated three times in the same manner.

[0234] Step 6 - Preparation of a pharmaceutical material comprising a purified amount of a compound of formula (V) Recrystallization (ethyl acetate / water) After in situ filtration, the amount of compound of formula (V) used to prepare the compound of formula (V) Based on a 100% conversion input of the compound of formula (IV) (710 kg), approximately 488 kg It is assumed that In the reactor, EtOAc was added to the solid compound of formula (V) until the volume reached the 1867 L mark. The mixture was then heated to 55°C to 60°C while stirring. 0.5 kg of water was added and the batch was stirred at 55°C-70°C for at least 1 hour. The batch was then transferred to another reactor by polish filtration. The filter and lines were rinsed with EtOAc. The temperature was then adjusted to 55°C ± 5°C. Then, cool the hot solution to 30°C ± 5°C over 2 hours, then incubate at 30°C ± 5°C for 2 hours. If no slurry is present, mix further at 30°C ± 5°C as necessary. The batch is then heated to 40°C ± 5°C for at least 1 hour and cooled to 40°C ± 5°C for 1 hour. The batch was then cooled to 35°C ± 5°C for at least 1 hour and then cooled to 35°C ± 5°C for at least 2 hours. The batch was then slowly cooled to 5°C ± 5°C over a period of 5 hours. The temperature was kept at 5°C ± 5°C for at least 4 hours.

[0235] Isolation, drying and IPC testing The resulting solid was isolated by centrifugation and washed with up to 2000 kg of acetonitrile. The wet cake was then dried under vacuum (jacket) at up to 45°C. The solvent was measured by GC (ACN≦410 ppm, EtOAc≦5000 ppm) to confirm completion of drying. The expected yield range is 66%-91%. The pharmaceutical material release specification criteria were met. If the release specifications of the drug product were not met, the product was processed as a finished drug product. A second recrystallization was carried out.

[0236] Optional second recrystallization (ethyl acetate / water) The following procedure is for the second recrystallization of compound of formula (V) in a batch size of about 430 kg. Please write: A solid (about 430 kg) of the compound of formula (V) is placed in a vessel, followed by EtOAc (about 123 The suspension was then heated to 55°C-60°C while stirring. About 18 kg of water was added, and the mixture was then stirred at 55°C to 70°C for at least 1 hour. The temperature was then adjusted to 55°C ± 5°C and the batch was polish filtered. The reactor, filter and lines were rinsed with EtOAc, then The temperature was then adjusted to 55°C ± 5°C. The hot solution was then cooled to 30°C ± 5°C over a period of 2 hours. Cool and then stir at 30°C ± 5°C for at least 2 hours. If no slurry is present, If desired, further mixing and seeding may be performed at 30°C ± 5°C. The batch is then heated to 40°C ± 5°C for 1 hour. The batch was then heated to 35°C ± 5°C for at least one hour and held at 40°C ± 5°C for at least one hour. The batch was then cooled for at least 1 hour and held at 35°C ± 5°C for at least 2 hours. The mixture was then slowly cooled to 5°C ± 5°C and held at 5°C ± 5°C for at least 4 hours.

[0237] Optional isolation, drying and IPC testing The resulting solid was isolated by centrifugation and washed with up to 2000 kg of acetonitrile. The wet cake was dried under vacuum at up to 45°C (jacket). The solvent was measured by GC (ACN≦410 ppm, EtOAc≦5000 ppm) to confirm completion of drying. The expected yield range is 75% to 100%. The impurity profile criteria were met. If so, the product is processed as a finished pharmaceutical material.

[0238] Example 3: Analytical method for determining the purity of the compound of formula (V) Determination of the amount of impurities The amount of impurities present in the purified form of the compound of formula (V) is determined by the gradient force ( dient capability, thermostat column compartment and charged aerosol detection The determination was carried out using a high performance liquid chromatograph equipped with a carbon-acid emission (CAD) detector. The amount of impurities in the purified form of the compound of formula (V) is between 0.05 and 0.50% weight / weight. It was determined that the amount was within the range. Column: Waters XBridge BEH C18 (inner diameter 4.6 mm x 150 m) m, 2.5μm) Mobile phase: A: 0.05% formic acid (HCOOH) in water (HO) Mobile phase: B: 0.05% HCOOH in acetonitrile (ACN) Sample temperature: ambient Column temperature: 40℃ Gradient (time: A:B): (0 min: 90:10; 8.5 min, 56:44; 20 min , 45:55;32 min, 5:95;36 min, 5:95). Flow rate: 1.2mL / min Retention time: ~15.2 minutes (purified form of bempedoic acid)

[0239] Determination of Purity of Compound of Formula (V) (Bempedoic Acid) The level of purity of the purified form of the compound of formula (V) was determined using a high performance liquid chromatography equipped with a UV detector. Determined using chromatography. The assay for the purified form of the compound of formula (V) was 98-102% (anhydrous, solvent-free). It was determined that the range of Column: Waters XBridge BEH C18 (inner diameter 4.6 mm x 150 m) m, 2.5μm) Mobile phase: A: 0.05% phosphoric acid in H2O (H3PO4):ACN (50:50) Sample temperature: ambient Column temperature: 40℃ Detection: 215nm Flow rate: 1.2mL / min Analysis time: 16 minutes. Gradient: Isocratic Retention time: ~4.6 minutes (purified form of bempedoic acid) Incorporation by Reference The entire disclosure of each patent document and scientific article referred to herein is hereby incorporated by reference for all purposes. Incorporated by. Equivalent The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. Therefore, the above-described embodiments should not be construed as limiting the invention described herein. The present invention is not to be construed as limiting the scope of the present invention, but should be considered in all respects as illustrative and illustrative. The scope of the present invention is defined by the appended claims, not the above description, and has the same meaning as the claims. All variations within taste and range are intended to be included.

Claims

1. A pharmaceutical material comprising a crystalline form of a compound of formula (V) or a pharma- ceutically acceptable salt thereof, said pharmaceutical material comprises a compound of formula (V) or a pharma- ceutically acceptable salt thereof in an amount of more than 98% by weight, based on the total weight of the pharmaceutical material; The pharmaceutical material comprises at least one of 0.001% to 0.15% by weight of a compound of formula (VI) or a pharma- ceutically acceptable salt thereof and 0.001% to 0.15% by weight of a compound of formula (VIII) or a pharma- ceutically acceptable salt thereof, based on the total weight of the pharmaceutical material.

2. 2. The pharmaceutical material of claim 1, wherein the crystalline form of the compound of formula (V) exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 10.4±0.2, 17.9±0.2, 18.8±0.2, 19.5±0.2 and 20.7±0.

2.

3. 3. The pharmaceutical material according to claim 1 or 2, wherein the crystalline form of the compound of formula (V) is characterized by an X-ray powder diffraction pattern substantially similar to that shown in Figure 4 below.

4. 4. The pharmaceutical material according to any one of claims 1 to 3, wherein the crystalline form of the compound of formula (V) has a melting point onset as determined by differential scanning calorimetry in the range of about 90°C to about 94°C.

5. 4. The pharmaceutical material according to any one of claims 1 to 3, wherein the crystalline form of the compound of formula (V) has a differential scanning calorimetry curve substantially similar to that shown in Figure 5 below.

6. 6. The pharmaceutical material according to any one of claims 1 to 5, wherein the pharmaceutical material comprises the compound of formula (V) in an amount of more than 99.0% by weight, based on the total weight of the pharmaceutical material.

7. 7. The pharmaceutical material according to any one of claims 1 to 6, comprising from 0.001% by weight to 0.15% by weight of the compound of formula (VI) or a pharma- ceutically acceptable salt thereof, based on the total weight of the pharmaceutical material.

8. 8. The pharmaceutical material according to any one of claims 1 to 7, wherein the pharmaceutical material comprises from 0.001% to 0.15% by weight of the compound of formula (VIII) or a pharma- ceutically acceptable salt thereof, based on the total weight of the pharmaceutical material.

9. Further, the present invention includes a compound of formula (VII) or a pharma- ceutically acceptable salt thereof:

9. The pharmaceutical material according to any one of claims 1 to 8, wherein the pharmaceutical material comprises not more than 0.15% by weight of the compound of formula (VII) or a pharma- ceutically acceptable salt thereof, based on the total weight of the pharmaceutical material.

10. 10. A pharmaceutical material according to any one of claims 1 to 9, comprising a compound of formula (V).

11. A pharmaceutical formulation comprising the pharmaceutical material according to any one of claims 1 to 10 and a pharma-ceutically acceptable excipient.

12. A pharmaceutical formulation comprising a compound of formula (V) and a pharma- ceutically acceptable excipient, The pharmaceutical preparation comprises a pharmaceutical material according to any one of claims 1 to 10.

13. A pharmaceutical composition for use in lowering low density lipoprotein cholesterol (LDL-C) in a patient comprising a therapeutically effective amount of the pharmaceutical material according to any one of claims 1 to 10 or the pharmaceutical formulation according to claim 11 or 12.

14. A pharmaceutical composition for use in treating primary hyperlipidemia in a patient, comprising a therapeutically effective amount of a pharmaceutical material according to any one of claims 1 to 10 or a pharmaceutical formulation according to claim 11 or 12.

15. A pharmaceutical composition for use in the prevention of myocardial infarction in a patient, comprising a therapeutically effective amount of a pharmaceutical material according to any one of claims 1 to 10 or a pharmaceutical formulation according to claim 11 or 12.

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