Method for producing bempedoic acid and composition thereof

Abstract

This invention provides a method for efficiently producing high-purity bempedoic acid. [Solution] A method for producing bempedoic acid represented by formula (V), comprising: (a) contacting ethyl isobutyrate with substituted 5-chloropentane in the presence of a first base to form 7-chloro-2,2-dimethylheptanoic acid; (b) further contacting with an alkali metal salt to form bromine or an iodide salt; (c) contacting with toluenesulfonylmethyl isocyanide in the presence of a second base to form a first intermediate, contacting the first intermediate with an acid to form a compound of formula (IV); and (d) contacting the compound of formula (IV) with a reducing agent to form a second intermediate, and contacting the second intermediate with a hydrolyzing base to form a compound of formula (V). JPEG2026102795000073.jpg18160 JPEG2026102795000074.jpg19160

Description

[Technical Field]

[0001] cross reference This application is U.S. Patent Application No. 62 / 864,873, filed on June 21, 2019. The interests and priority of the party are asserted, and the entirety of its contents is incorporated herein by reference. [Background technology]

[0002] A robust, cost-effective, and efficient method for producing pharmaceutically active compounds in desired yield and purity. Developing efficient manufacturing methods remains a major challenge. (8-hydroxy- 2,2,14,14-tetramethylpentadecanedioate is used in many cases, including liver damage and cardiovascular disease. It is a compound being developed for the treatment of a wide variety of diseases. Therefore, bempedoic acid (8-Hydro) Process for synthesizing Roxy-2,2,14,14-tetramethylpentadecanedioate This is desirable, and thereby the product must not be required by regulatory authorities for the manufacture of commercially available drug products. It possesses the required purity and impurity profiles. [Overview of the Initiative]

[0003] The present inventors have developed a method for efficiently producing high-purity bempedoic acid, and a pharmaceutical active pharmaceutical ingredient. We have found a highly pure and stable form of bempedoic acid suitable for use. In one embodiment, the present invention provides for the production of a compound of formula (V) or a pharmaceutically acceptable salt thereof. To provide a method. The compound of formula (V) or its pharmaceutically acceptable salt can be made highly pure. Therefore, in certain embodiments, the present invention relates to a compound of formula (V) or a pharmaceutically acceptable compound of the same formula. The present invention provides a method for producing a pharmaceutical material containing a salt that is to be used. Here, the pharmaceutical material is the total amount of the pharmaceutical material. Contains an amount of a compound of formula (V) or a pharmaceutically acceptable salt thereof that exceeds 99.0% by weight, based on weight.

[0004] In various embodiments of the present invention, the method generally includes the following. (a) Contacting ethyl isobutyrate with substituted 5-chloropentane in the presence of a first base to form a compound of formula (I). TIFF2026102795000003.tif17160 The substituted 5-chloropentane is selected from the group consisting of 1-bromo-5-chloropentane and 1-iodo-5- chloropentane. (b) Contacting the compound of formula (I) with a salt of formula [M] [X] - to form a compound of formula (II) . TIFF2026102795000004.tif16160 wherein [M] + is selected from the group consisting of Li + , Na + and K + , and [X] - is selected from the group consisting of B r - and I - . (c) Contacting the compound of formula (II) with tosylmethyl isocyanide in the presence of a second base to form a first intermediate, and contacting the first intermediate with an acid to form a compound of formula (IV) . TIFF2026102795000005.tif18160 (d) Contacting the compound of formula (IV) with a reducing agent to form a second intermediate, and contacting the second intermediate with a hydrolyzing base to form a compound of formula (V) or a pharmaceutically acceptable salt thereof .

[0005] In certain embodiments of the present invention, the method includes the following. ​​​(a) 1-Bromo-5-chloropentane is heated at a temperature range of approximately -20°C to approximately 0°C. In the presence of thium diisopropylamide, about 1 to about 1.21 molar equivalents of ethyl isobutyrate and The compound of formula (I) is formed by bringing the materials into contact. JPEG2026102795000006.jpg17151(b) Compound of formula (I) in 2-butanone at a temperature in the range of approximately 78°C to approximately 82°C. It is brought into contact with approximately 1.1 molar equivalents of sodium iodide to form the compound of formula (IIa). JPEG2026102795000007.jpg17143(c) Compound of formula (IIa) in sodium tert-pentamine in dimethylacetamide In the presence of a tooxide, at temperatures ranging from approximately -20°C to approximately 10°C, toluenesulfonylmethyl An intermediate is formed by contact with an isocyanide, and this intermediate is heated in a temperature range of approximately -10°C to approximately 35°C. The compound of formula (IV) is formed by contact with an acid at a certain temperature. TIFF2026102795000008.tif18160(d) The compound of formula (IV) is brought into contact with approximately 0.35 molar equivalents of sodium borohydride. A second intermediate is formed, and the second intermediate is brought into contact with sodium hydroxide in solution to obtain formula (V It forms a compound of ).

[0006] In certain embodiments of the present invention, the method further includes the following: (e) Purify the compound of formula (V) to obtain a pharmaceutical material containing the purified amount of the compound of formula (V). To provide. In certain embodiments of the present invention, the purification of the compound of formula (V) includes the following: (f) Adjust the pH of the solution containing the compound of formula (V) to approximately 6. (g) Extract the compound of formula (V) from the solution using methyl tert-butyl ether. We provide a methyl tert-butyl ether solution containing the compound of formula (V), (h) Remove the methyl tert-butyl ether from the methyl tert-butyl ether solutionacetic acid solution. By replacing ethyl acetate, an ethyl acetate solution containing the compound of formula (V) is provided. (i) Filter an ethyl acetate solution containing compound (V) through silica gel, (j) The compound of formula (V) is crystallized using ethyl acetate and water. Provides a crystal form, and (k) The crystalline form of the compound of formula (V) was recrystallized using ethyl acetate and water, and purified. The present invention provides a pharmaceutical material containing a compound of formula (V) in a specified quantity.

[0007] In another aspect, the present invention relates to highly purified or refined bempedoic acid or its pharmaceutically acceptable Provides a suitable salt. For example, described herein includes a compound of formula (V). It is a pharmaceutical material or a pharmaceutically acceptable salt thereof. TIFF2026102795000009.tif19160 Pharmaceutical materials are calculated using formula (V) in amounts greater than 99.0% by weight, based on the total weight of the pharmaceutical materials. Contains compounds or pharmaceutically acceptable salts thereof.

[0008] In various embodiments, the pharmaceutical material is the crystalline form of the compound of formula (V) or its pharmaceutically acceptable form. Contains a salt. In some embodiments, the pharmaceutical material is based on the total weight of the pharmaceutical material. It contains more than 99.0% by weight of the compound of formula (V). In another aspect, the present invention relates to high-purity bempedoic acid or the pharmaceutical material described herein. The present invention provides a pharmaceutical composition or preparation containing a pharmaceutically acceptable salt. For example, the pharmaceutical composition is The pharmaceutical material of the invention (for example, the formula for an amount greater than 99.0% by weight based on the total weight of the pharmaceutical material) Pharmaceutical materials containing compounds of V) or pharmaceutically acceptable salts thereof and pharmaceutically acceptable It may contain excipients. In some embodiments, the pharmaceutical composition may contain a therapeutically effective amount. The present invention may include pharmaceutical materials and pharmaceutically acceptable excipients. In this state, the pharmaceutical composition is the crystalline form of the compound of formula (V) or a pharmaceutically acceptable salt thereof. It contains pharmaceutically acceptable excipients.

[0009] Purified bempedoic acid or its pharmaceutically acceptable salt, bempedoic acid or its pharmaceutically acceptable The acceptable crystalline form of the salt, the pharmaceutical material of the present invention (for example, based on the total weight of the pharmaceutical material, 9 A pharmaceutical product containing a compound of formula (V) or a pharmaceutically acceptable salt thereof in an amount exceeding 9.0% by weight. The materials or pharmaceutical compositions of the present invention may be used to treat the various conditions and diseases described herein. It can be used. For example, the treatment method is adenosine triphosphate citrate lyase (AC This includes inhibition of L), inhibition of cholesterol synthesis and / or suppression of fatty acid biosynthesis. Yes, it is possible. In some embodiments, the symptoms or disease are hyperlipidemia such as primary hyperlipidemia. This method may include treating hyperlipidemia such as primary hyperlipidemia. In terms of treatment form, the disease may be a cardiovascular disease, and this method is for treating cardiovascular diseases. Includes. In various embodiments, the treatment method includes low-density lipid cholesterol (LDL-C). ), non-high-density lipid cholesterol (non-HDL-C), serum total cholesterol (TC), A Improves or reduces polypoprotein B (apoB) and / or high-sensitivity C-reactive protein (hsCRP). It can include doing. [Brief explanation of the drawing]

[0010] [Figure 1]This is an exemplary reaction scheme of the present invention for synthesizing the bempedoic acid (i.e., the compound of formula (V)) described in Example 1, which involves the synthesis of a pharmaceutical material containing more than 99.0% by weight of the compound of formula (V) based on the total weight of the pharmaceutical material. [Figure 2] This is an example of the 1H-NMR spectrum of the compound of formula (V). [Figure 3] This is an example of the 13C-NMR spectrum of the compound of formula (V). [Figure 4] This is the X-ray powder diffraction pattern of the compound of formula (V) in the crystalline form further described in Example 1. [Figure 5] This is a superposition of differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curves of the compound of formula (V) in the crystalline form further described in Example 1. [Figure 6] This is a water sorption isotherm for the compound of the crystalline form (V). [Modes for carrying out the invention]

[0011] Currently, bempedoic acid (including its pharmaceutically acceptable salts) is available in high purity and / or as a balsamic acid. It has been found that it can be manufactured in large quantities. In various embodiments, bemp A crystalline form of a chlorophobic acid or a pharmaceutically acceptable salt thereof is provided. The method for producing bempedoic acid described herein is for the formation of impurities that are difficult to remove during the synthesis process. Through control, some high levels or amounts of bempedoic acid or its pharmaceutically acceptable salts can be controlled. It is possible to provide pharmaceutical materials that include these materials. Furthermore, pharmaceutical materials containing high-purity crystalline bempedoic acid or a pharmaceutically acceptable salt thereof. A material is provided, for example, a pharmaceutical material such as crystalline bempedoic acid or a pharmaceutically acceptable salt thereof. It consists of, and the pharmaceutical material contains an amount of benzoin that exceeds 99.0% by weight based on the total weight of the pharmaceutical material. If the pharmaceutical material consists of bempedoic acid or a pharmaceutically acceptable salt thereof, then the pharmaceutical material is bempedoic acid or This can provide bempedoic acid in its highly pure crystalline form as a pharmaceutical salt.

[0012] I. Definition To facilitate understanding of the present invention, several terms and phrases are defined below. Unless otherwise defined, all technical and scientific terms used herein are as defined herein. This specification has the same meaning as it is generally understood by those skilled in the art in which the term "Mei" belongs. The abbreviations used in this document have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas described are constructed according to the standard rules of chemical valence known in the field of chemistry. It can be done.

[0013] Throughout this specification, compositions and kits that have certain components include (including g) If described as including or encompassing, or process and method The law includes, or comprises a specific process. g) If described as, furthermore, essentially consisting of or otherwise derived from the listed components. The present invention includes compositions and kits which essentially consist of the listed processing steps, or The present invention is intended to include a process and method comprising the above. The elements or components included in the list of elements or components that are enumerated and / or the elements that are enumerated In this application, an element or component is said to be selected from a list of components, and the elements or components are listed elements. It may be any one of the components, or an element or component may be two of the listed elements or components. Please understand that a selection can be made from a group consisting of one or more elements.

[0014] Furthermore, the elements and / or features of the compositions or methods described herein are as follows: Whether explicit or implicit, without departing from the spirit and scope of the present invention, various It should be understood that they can be combined in different ways. For example, mention a specific compound. In that case, the compound is, unless otherwise understood from the context, the composition and / or the present invention. It can be used in various embodiments of the method. In other words, within this application, The embodiments have been described and illustrated in a manner that enables accurate and concise descriptions and illustrations of their uses. Without departing from these teachings and the present invention, embodiments may be combined or separated in various ways. It will be intended and understood that this is possible, for example, as described and illustrated in this specification. All features shown herein are applicable to all aspects of the invention(s) described and illustrated herein. It will be understood that this may be applicable.

[0015] The articles "a" and "an" are used in sentences unless the context is inappropriate. The terms used in this disclosure refer to one or more (i.e., at least one) legal subjects. For example, "an element" means one element or two or more elements. do. The term "and / or" in this disclosure, unless otherwise indicated, means "and" or "or" It is used to mean either of the following: The expression "at least one of ~" is not understood unless specifically from the context and usage. , each of the objects listed after this expression, and various pairs of two or more of the listed objects Please understand that this includes combinations individually. "and" refers to three or more listed items. The expression "or" is understood to have the same meaning unless specifically indicated by the context. stomach. "include", "includes", "include (includ (ing) '', have '', have '', have )", "contain", "contains", or "contains The use of the term "contains" includes its grammatical equivalent. Generally, it should be understood as unrestricted and indefinite, for example, unless otherwise specified. Unless otherwise stated or understood from the context, any further elements or processes not listed are excluded. do not have.

[0016] When the term "approximately" is used before a quantitative value, the present invention, unless otherwise specified, This also includes specific quantitative values ​​themselves. Where used herein, the term "about" indicates otherwise. Unless otherwise specified or inferred from the context, this refers to a variation of ±10% from the nominal value.

[0017] For example, if the molecular weight of a polymer is provided rather than its absolute value, that molecular weight is not specifically stated. Unless otherwise specified or understood from the context, it should be understood as the average molecular weight. . As long as the present invention remains operational, the sequence of steps or the sequence for performing a particular operation Please understand that this is not important. Furthermore, if two or more processes or actions are performed simultaneously That's good too.

[0018] In various parts of this specification, variables or parameters are disclosed in groups or scopes. The description is of any individual partial combination of members of such groups and scopes. It is specifically intended to include the following. For example, integers in the range of 0 to 40 are specifically 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 Disclose items 1, 32, 33, 34, 35, 36, 37, 38, 39, and 40 individually. This is intended to be an integer in the range of 1 to 20, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 individually It is intended to be disclosed separately.

[0019] Any example or exemplary language used herein, such as "etc." The use of ")" or "including" is merely to better describe the present invention. This is intended to be, and unless otherwise stated in the claims, it does not limit the scope of the invention. No. Any language in this specification is used in the claims that are essential to the practice of the present invention. It should not be interpreted as indicating elements that are not present. As a general rule, compositions specifying percentages are based on weight unless otherwise specified. It is quasi. Furthermore, if a variable has no definition, its previous definition takes precedence.

[0020] As used herein, “pharmaceutically acceptable salt” means present in the compound of the present invention. This refers to any salt of an acidic or basic group that can be used, and that salt is suitable for pharmaceutical administration. The method involves converting one or both of the carboxylic acid groups of bempedoic acid into a pharmaceutically acceptable salt. It is possible. As is known to those skilled in the art, "salts" of compounds are derived from inorganic or organic acids and bases. It is possible. Examples of acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, and maleic acid. Inic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfone Acids, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, Examples include malonic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid, but these This specification is not limited to other acids. Other acids such as oxalic acid may not be pharmaceutically acceptable in themselves, but this specification The compounds described in the book and intermediates used in obtaining their pharmaceutically acceptable acid addition salts are It can be used in the preparation of various types of salt. Examples of bases include alkali metal hydroxides (e.g., sodium and potassium), Potassium earth metals (e.g., magnesium and calcium) hydroxides, ammonia, and W C 1~4 Formula NW4 is an alkyl group. + Examples of such compounds include, but are not limited to, those listed above.

[0021] Examples of salts include acetate, adipine, alginate, aspartate, and benzoic acid. Salts, benzenesulfonates, bisulfates, butyrates, citrates, camphorates, camphor sulfonic acid Salt, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfone Salts, fumarates, flucoheptanates, glycerophosphates, hemisulfates, heptanes hexanoate, hydrochloride, hydrobromide, 2-hydroxyethanesulfonate, lactate, Maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, sulfate Pectinate, persulfate, phenylpropionate, picric acid, Valate, propionate, succinate, tartrate, thiocyanate, tosylate, u Examples include ndecanate, but are not limited to cholera. Other examples of salts include Na + , K+ Ca 2+ NH4 + , and NW4 + (W is C 1~4 Suitable (possibly an alkyl group) etc. Examples include anions of the compound of the present invention combined with a specific cation.

[0022] For therapeutic use, salts of the compounds of the present invention are considered pharmaceutically acceptable. However, However, pharmaceutically unacceptable acid and base salts are, for example, pharmaceutically acceptable compounds It can also be used in the preparation or purification of substances.

[0023] As used herein, "pharmaceutical composition" or "pharmaceutical preparation" refers to an activator and an inert or This refers to a combination with an active carrier, and the composition is used in vivo or ex vivo in the diagnosis of To make it particularly suitable for discontinuation or therapeutic use. As used herein, "pharmaceutically acceptable" and "pharmacologically acceptable" The phrase "if administered to animals or humans as necessary, it may be harmful, allergenic, or otherwise harmful." This refers to compounds, molecular entities, compositions, materials, and / or dosage forms that do not cause undesirable reactions. For human administration, the preparation must comply with FDA Office of Biologics standards. Therefore, it must meet the required standards of sterility, pyrogenity, and general safety and purity. Therefore, "pharmaceutically acceptable" and "pharmacologically acceptable" are defined by the federal government or It has been approved or may be approved by a state government regulatory agency or a corresponding agency in a country other than the United States. For use in animals, or more specifically in humans, the United States Pharmacopeia or other general guidelines. This could mean that it is listed in the recognized pharmacopoeia.

[0024] As used herein, “carrier” means bempedoic acid or a pharmaceutically acceptable salt thereof. Transporting or delivering pharmaceuticals such as the above from one organ or part of the body to another organ or part of the body. Materials and components involved in the process, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. It refers to a finished product or vehicle. As used herein, “pharmaceutically acceptable excipients” means the administration of an activator to a subject. It assists in the administration and / or absorption by the subject, without causing significant adverse toxic effects in the patient. This refers to a substance that can be included in the composition of the invention. A non-limiting list of pharmaceutically acceptable excipients. Examples include water, NaCl, regular physiological saline (such as phosphate-buffered saline), and emulsion. (e.g., oil / water or water / oil emulsion), lactated Ringer's solution, regular sucrose , regular glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings , salt solution (e.g., Ringer's solution), alcohol, oil, gelatin, carbohydrates (lactose, Amylose or starch, etc.), fatty acid esters, hydroxymethylcellulose, polyvinyl Examples include lupyrolidine and colorants. Such preparations are sterilized and, if necessary, Lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffering agents, colorants, and / or can be mixed with auxiliary agents such as aromatic substances that do not react harmfully with the compound of the present invention. For examples of excipients, see Martin, Remington's Pharmac. eutical Sciences,15th Ed.,Mack Publ.Co., See Easton, PA (1975).

[0025] As used herein, “to treat” or “treatment” means treating symptoms, diseases, disorders, etc. Any effect that brings about improvement or relief of the symptoms, such as reduction, decrease, regulation, improvement or elimination. This includes removal. To treat means to cure, improve, or at least partially treat a disorder. It may be possible to improve the condition. In certain embodiments, treating the condition may cure the disease. That is the case. As used herein, one or more symptoms (and the grammatical equivalent of this phrase) The "decrease" or "decrease" refers to a decrease in the severity or frequency of symptoms (multiple symptoms), or a decrease in the severity or frequency of symptoms (multiple symptoms). It means the exclusion of (multiple) elements.

[0026] As used herein, “effective dose” or “therapeutic effective dose” means “effective dose” or “therapeutic effective dose” to mean “effective or desired result.” This refers to the amount of compound (e.g., the compound of the present invention) sufficient to produce the desired result. The effective amount is one dose. It can be administered by dosing, applying, or using the above dosages, and is limited to specific formulations or routes of administration. It is not intended to mean that. As used herein, the term "treat" means symptoms, disease. any effect that brings about improvement of a disorder or other condition or improvement of its symptoms, for example, reduction, decrease, regulation, This includes improvement or elimination.

[0027] As used herein, "subject" and "patient" are interchangeable, and in accordance with the present invention... This refers to an organism treated by the law and composition. Such organism is preferably a mammal (for example) Humans, mice, rats, guinea pigs, dogs, cats, horses, cows, pigs, or non-human spirits. Long-tailed primates (e.g., monkeys, chimpanzees, baboons and rhesus macaques), more preferably humans be.

[0028] As used herein, “disease,” “disorder,” “symptom,” or “illness” are used in context. It can be used interchangeably unless other things do not work or are not understood. Patients that can be treated with the compounds, pharmaceutical materials, pharmaceutical compositions, or methods provided herein Refers to the state or health condition of a person or subject. In some embodiments, as described herein The compounds and methods include, for example, the administration of a compound of formula (V) or a pharmaceutically acceptable salt thereof. This includes the reduction or elimination of a disease, disorder, or symptom, or one or more symptoms of a disease, by means of.

[0029] As used herein, “administer” means oral administration to a subject, administration as a suppository, Local contact, intravenous, parenteral, intraperitoneal, intramuscular, intrafocal, intrathecal, intracranial, nasal cavity or This refers to subcutaneous administration or implantation of a sustained-release device, such as a mini osmotic pump. Administration is non-epileptic. Any method including the mouth and transmucosa (e.g., buccal, sublingual, palate, gums, nose, vagina, rectum, or percutaneous). This is done via the following routes. Parenteral administration includes, for example, intravenous, intramuscular, intra-arterial, intradermal, and dermal. This includes the lower, intraperitoneal, ventricular, and intracranial regions. Other delivery methods include liposomal formulations and intracellular delivery. This includes, but is not limited to, intravascular infusion and transdermal patch use. "The composition described herein is used in conjunction with one or more additional treatments (e.g., anticancer agents, chemotherapy)." It can be administered simultaneously with, immediately before, or immediately after the administration of a drug or treatment for neurodegenerative disease. This means that the compounds of the present invention can be administered alone or simultaneously to patients. It is possible to administer the compounds individually or in combination (two or more compounds or drugs). This means administering the drugs simultaneously or sequentially. Therefore, the preparation may be used as needed. Furthermore, it can be combined with other active substances (for example, to reduce metabolic breakdown). ru.

[0030] As used herein, “liver impairment” generally refers to a disease or disorder that affects the liver. And / or symptoms, such as simple accumulation of fat in liver cells (steatosis), macrodrip steatosis. This includes inflammation of the periportal vein and lobules (steatohepatitis), cirrhosis, fibrosis, liver cancer, and liver failure. It may have a wide range of severity levels. As used herein, “fatty liver disease” ("FLD") is also known as “fatty liver.” This refers to a disease that leads to liver damage caused by abnormal fat accumulation in liver cells. FLD is associated with excessive alcohol consumption and metabolic disorders (insulin resistance, obesity, and hypertension). It can result from many causes, including related factors. As used herein, “non-alcoholic fatty liver disease” (“NAFLD”) means A series of events resulting from the accumulation of fat in liver cells in individuals without a history of excessive alcohol consumption. It refers to a disorder. In its mildest form, NAFLD refers to hepatic steatohepatia. As used herein, “drug-induced liver disease” or “toxic liver injury” means that the activating agent is used in the liver. This refers to a disease or condition that causes damage to an organ. As used herein, "alcoholic liver disease" is also referred to as "alcoholic liver disease." "Disorder" is a condition in which fat accumulates in liver cells, at least partially caused by alcohol consumption. This refers to diseases caused by the accumulation of alcohol. Examples include alcoholic simple fatty liver disease, alcoholic simple fatty liver disease. Alcoholic steatohepatitis (ASH) ), diseases such as alcoholic liver fibrosis, alcoholic cirrhosis, and alcoholic fatty liver disease These are some examples, but are not limited to them. Alcoholic steatohepatitis steatohepatitis is alcoholic fatty liver disease. Also known as fatty hepatitis, it includes alcoholic liver fibrosis.

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

[0032] As used herein, “altering lipid metabolism” means at least one aspect of lipid metabolism. In one aspect, this refers to an observable (measurable) change, which includes 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- This includes, but is not limited to, esterified fatty acids. As used herein, “altering glucose metabolism” means altering 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 This includes, but is not limited to, receptivity and oxygen consumption.

[0033] As used herein, “purified bempedoic acid” refers to the solid when isolated. The pharmaceutical material contains at least 95% by weight of 8-hydroxy-2 based on the total weight of the pharmaceutical material. This means it contains 2,14,14-tetramethylpentadecanedioic acid. Specific implementation In terms of form, when purified bempedoic acid is isolated as a solid, the pharmaceutical material is a pharmaceutical material Based on the total weight, at least 99.0% by weight of 8-hydroxy-2,2,14,14 This means it contains tetramethylpentadecanedioic acid. Furthermore, purified benped Acids are pharmaceutically acceptable unless otherwise specified or understood from the context. It can contain salt.

[0034] As used herein, a “substantially completed” reaction is one in which the reaction exceeds approximately 80% by weight. This means that the desired product is contained. In certain embodiments, the reaction is substantially complete. , containing more than approximately 90% by weight of the desired product. In certain embodiments, substantially complete The reaction contains more than approximately 95% by weight of the desired product. In certain embodiments, substantially A complete reaction will result in a product containing over 97% by weight of the desired product. Unless otherwise specified, all X-ray powder diffraction (XRPD) patterns described herein are Corresponding to the XRPD pattern measured using a Cu Kα radiation source, the crystalline form of Ben Pedonic acid is analyzed by XRPD at ambient temperature.

[0035] II. Crystalline form of bempedoic acid A. Crystalline bempedoic acid In one embodiment, the present invention relates to 8-hydroxy-2,2,14,14-tetramethylpentade This provides a crystalline form of candioic acid, which is referred to herein as "bempedoic acid" and / or formula (V). It is also known and mentioned as a compound. In a particular embodiment, the crystalline form of the compound of formula (V) is as follows: diffraction angle (2θ): 10. 3±0.2, 10.4±0.2, 17.9±0.2, 18.8±0.2, 19.5±0. The X-ray powder diffraction pattern may be characterized by peaks 2 and 20.7±0.2. In this embodiment, the crystalline form of the compound of formula (V) is given by 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 0.5±0.2, 19.7±0.2, 20.4±0.2, 20.7±0.2, and 22.6± The X-ray powder diffraction pattern may be characterized by a peak at 0.2.

[0036] In certain embodiments, the crystalline form of the compound of formula (V) is as shown in Table 1, with a diffraction angle of 2θ. , arbitrarily, the inter-plane distance d (angstroms) and relative intensity (percentage relative to the strongest peak) It is characterized by an X-ray powder diffraction pattern represented with respect to (represented as). [Table 1]

[0037] In certain embodiments, the crystalline form of the compound of formula (V) is substantially the same as that shown in Figure 4. It is characterized by a linear powder diffraction pattern. In certain embodiments, the crystalline form of the compound of formula (V) exists in a monoclinic system, and P21 / c It has a space group. In certain embodiments, the crystalline form of the compound of formula (V) is the crystal shown in Table 2. It is characterized by scientific unit cell parameters.

[0038] [Table 2]

[0039] The crystalline form of the compound of formula (V) can also be characterized by its melting point onset temperature. Therefore, in certain embodiments, the compound of formula (V) in crystalline form is at approximately 82°C to approximately 94°C. It has a melting point onset determined by differential scanning calorimetry in the range of . In certain embodiments, The compound with crystalline form of formula (V) was determined by differential scanning calorimetry in the range of approximately 90°C to 94°C. It has a determined melting point onset. In certain embodiments, the compound of formula (V) in crystalline form is about It has a melting point onset determined by differential scanning calorimetry at 92°C. In certain embodiments, The crystalline form of the compound of formula (V) has substantially the same differential scanning calorimetry curve as shown in Figure 5. do.

[0040] Compounds of the crystalline form of formula (V) also exhibit a mass increase / decrease as a function of temperature. The properties can also be determined in this way. Therefore, in a particular embodiment, the formula (V) of the crystal form When the compound is heated to approximately 200°C, it is determined by thermogravimetric analysis to be approximately 0.1%. It exhibits a mass loss of approximately 0.7%. In certain embodiments, the crystalline form of the compound of formula (V) is When heated to approximately 200°C, the mass loss is approximately 0.7% or less, as determined by thermogravimetric analysis. It shows a small amount. In certain embodiments, the crystalline form of the compound of formula (V) is substantially the same as that shown in Figure 5. They have the same thermogravimetric analysis curve. Compounds of the crystalline form of formula (V) can also be characterized by their water sorption properties. Therefore, in certain embodiments, the compound of formula (V) in crystalline form is used for dynamic water vapor adsorption. When determined by [the relevant factor], the humidity is approximately 0.01% to 0.05% at a relative humidity of 80% and a temperature of 25°C. This shows the mass change. In a particular embodiment, the compound of formula (V) in crystalline form is a dynamic water vapor absorber. When determined by the garment, a mass change of approximately 0.03% occurs at a relative humidity of 80% and a temperature of 25°C. As shown. In a particular embodiment, the crystalline form of the compound of formula (V) is as shown in Figure 25°C. It has substantially the same hydrosomatic isotherms as shown in 6. References to bempedoic acid or purified bempedoic acid in this specification, unless otherwise specified, Unless otherwise understood from the context, please understand that this includes bempedoic acid in crystalline form.

[0041] B. Benpedoic acid in crystalline salt form Furthermore, it was discovered that bempedoic acid can be prepared in various crystalline salt forms. In particular, the following counterions produced crystalline salt forms of bempedoic acid: ammonium, sodium Potassium, calcium (two crystalline forms), lysine, diethylamine, ethylenediamine Min, piperazine, betaine, tromethamine, and isonicotinamide.

[0042] (i) bempedoic acid in crystalline betaine form In certain embodiments, the crystalline salt form of bempedoic acid is the crystalline betaine salt of bempedoic acid. In certain embodiments, the crystalline betaine salt of bempedoic acid exhibits the following diffraction angle (2θ): 6 0.2±0.2°, 13.5±0.2°, 17.5±0.2°, 19.3±0.2° and 2 The X-ray powder diffraction pattern may be characterized by a peak of 5.6±0.2°. Specific Embodiments The crystalline betaine salt of bempedoic acid has the following diffraction angle (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 radio waves containing peaks at 9.9±0.2°, 25.6±0.2°, and 27.2±0.2° It can be characterized by its folding pattern. In certain embodiments, the crystalline betaine salt of bempedoic acid has a diffraction angle of 2, as shown in Table 3. θ, arbitrarily, inter-plane distance d, and relative intensity (expressed as a percentage relative to the strongest peak) It is characterized by an X-ray powder diffraction pattern represented in relation to [the specified value].

[0043] [Table 3]

[0044] (ii) Crystalline calcium salt form of bempedoic acid In certain embodiments, the crystalline salt form of bempedoic acid is the crystalline calcium salt of bempedoic acid. Yes. In certain embodiments, the crystalline calcium salt of bempedoic acid has the following diffraction angle (2θ) : 4.9±0.2, 6.4±0.2, 9.1±0.2, 14.8±0.2, 19.7±0 The X-ray powder diffraction pattern may be characterized by peaks at 0.2 and 37.1±0.2°. In certain embodiments, the crystalline calcium salt of bempedoic acid has a diffraction angle as shown in Table 4. 2θ, arbitrarily the inter-plane distance d, and relative intensity (expressed as a percentage relative to the strongest peak) It is characterized by an X-ray powder diffraction pattern represented in relation to ). [Table 4]

[0045] In certain embodiments, the crystalline calcium salt of bempedoic acid has the following diffraction angle (2θ): 6 Peaks at 0.0±0.2°, 6.8±0.2°, 8.5±0.2°, and 9.8±0.2° It may be characterized by the X-ray powder diffraction pattern including bempedoic acid. In certain embodiments, the crystalline form of bempedoic acid Calcium salts exhibit 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°. It may be characterized by an X-ray powder diffraction pattern. In certain embodiments, the crystalline calcium salt of bempedoic acid has a diffraction angle as shown in Table 5. 2θ, arbitrarily the inter-plane distance d, and relative intensity (expressed as a percentage relative to the strongest peak) It is characterized by an X-ray powder diffraction pattern represented in relation to ). [Table 5]

[0046] (iii) bempedoic acid in crystalline diethylamine salt form In certain embodiments, the crystalline salt form of bempedoic acid is crystalline diethylamine of bempedoic acid. It is a salt. 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° It may be characterized by the X-ray powder diffraction pattern containing bempedoic acid. In certain embodiments, the crystalline ion of bempedoic acid Ethylamine salts exhibit 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 X-ray powder diffraction pattern may be characterized by a peak containing . In certain embodiments, the crystalline diethylamine salt of bempedoic acid is used as shown in Table 6. Let's take 2θ, the inter-plane distance d arbitrarily, and the relative intensity (expressed as a percentage relative to the strongest peak). It is characterized by an X-ray powder diffraction pattern represented by ( ). [Table 6]

[0047] (iv) Bempedoic acid in crystalline ethylenediamine salt form In certain embodiments, the crystalline salt form of bempedoic acid is crystalline ethylenediamine of bempedoic acid. It is a salt. In certain embodiments, the crystalline ethylenediamine salt of bempedoic acid is as follows: Angle (2θ): 6.8±0.2°, 10.8±0.2°, 16.2±0.2°, 18.3 The X-ray powder diffraction pattern may be characterized by peaks at ±0.2° and 18.8±0.2°. In certain embodiments, the crystalline diethylamine salt of bempedoic acid has the following diffraction angle (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 It is characterized by an X-ray powder diffraction pattern containing peaks at 1.4±0.2° and 22.3±0.2°. It is possible. In certain embodiments, the crystalline ethylenediamine salt of bempedoic acid is as shown in Table 7, Diffraction angle 2θ, arbitrary interplane distance d, and relative intensity (expressed as a percentage relative to the strongest peak). It is characterized by an X-ray powder diffraction pattern represented in relation to (the given). [Table 7]

[0048] (v) Bempedoic acid in crystalline isonicotinamide form In certain embodiments, the crystalline salt form of bempedoic acid is the crystalline isonicotinic acid of bempedoic acid. It is a mid salt. In certain embodiments, the crystalline isonicotinamide salt of bempedoic acid is as follows: Diffraction angles (2θ): 4.4±0.2°, 18.8±0.2°, 20.1±0.2° and 2 The X-ray powder diffraction pattern may be characterized by a peak of 4.5 ± 0.2°. Specific Embodiments The crystalline isonicotinamide salt of bempedoic acid has the following diffraction angle (2θ): 4.4±0 0.2°, 14.5±0.2°, 18.8±0.2°, 20.1±0.2°, 24.5±0 X-ray powder diffraction pattern containing peaks at 0.2°, 26.2±0.2°, and 29.5±0.2°. It can be characterized by [something]. In certain embodiments, the crystalline isonicotinamide salt of bempedoic acid is as shown in Table 8. , diffraction angle 2θ, arbitrary interplane distance d, and relative intensity (as a percentage relative to the strongest peak) It is characterized by an X-ray powder diffraction pattern represented with respect to (represented). [Table 8]

[0049] (vi) bempedoic acid in crystalline potassium salt form In certain embodiments, the crystalline salt form of bempedoic acid is the crystalline potassium salt of bempedoic acid. In certain embodiments, the crystalline potassium salt of bempedoic acid has the following diffraction angle (2θ): 5 Peaks at 0.7±0.2°, 7.3±0.2°, 9.6±0.2°, and 22.1±0.2° The X-ray powder diffraction pattern may be characterized by including the crystallinity of bempedoic acid. In certain embodiments, the crystallinity of bempedoic acid The diffraction angles (2θ) of potassium salts are as follows: 5.7±0.2°, 7.3±0.2°, 9.6± Peaks at 0.2°, 16.0±0.2°, 22.1±0.2°, and 23.0±0.2° The X-ray powder diffraction pattern may be characterized by its content. In certain embodiments, the crystalline potassium salt of bempedoic acid has a diffraction angle of 2, as shown in Table 9. θ, arbitrarily, inter-plane distance d, and relative intensity (expressed as a percentage relative to the strongest peak) It is characterized by an X-ray powder diffraction pattern represented in relation to [the specified value]. [Table 9]

[0050] (vii) Bempedoic acid in crystalline lysine salt form In certain embodiments, the crystalline salt form of bempedoic acid is the 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 X-ray powder diffraction pattern may be characterized by a peak of 9±0.2°. In certain embodiments, The crystalline lysine salt of bempedoic acid exhibits 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 An X-ray powder diffraction pattern including peaks of ±0.2°, 19.7 ± 0.2°, and 21.9 ± 0.2° may be characteristic. In certain embodiments, the crystalline lysine salt of bendophedic acid, as shown in Table 10, has a diffraction angle of 2 θ, optionally an interplanar distance d, and a relative intensity (expressed as a percentage relative to the strongest peak) is characterized by an X-ray powder diffraction pattern represented with respect to.

Table 10

[0051] (viii) Crystalline sodium salt form of bendophedic acid In certain embodiments, the crystalline salt form of bendophedic acid is the crystalline sodium salt of bendophedic acid There is. In certain embodiments, the crystalline sodium salt of bendophedic acid has the following diffraction angles (2θ) : 6.1 ± 0.2°, 14.2 ± 0.2°, 18.3 ± 0.2°, and 24.5 ± 0.2° An X-ray powder diffraction pattern including peaks may be characteristic. In certain embodiments, bendophedic acid The crystalline sodium salt 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 ° and 24.5 ± 0.2° may be characterized by an X-ray powder diffraction pattern including peaks. In certain embodiments, the crystalline sodium salt of bendophedic acid, as shown in Table 11, has a diffraction angle 2θ, optionally an interplanar distance d, and a relative intensity (expressed as a percentage relative to the strongest peak) is characterized by an X-ray powder diffraction pattern represented with respect to.

Table 11

[0052] (ix) Bendophedic acid in crystalline ammonium salt form In certain embodiments, the crystalline salt form of bempedoic acid is the crystalline ammonium salt of bempedoic acid. In certain embodiments, the crystalline ammonium salt of bempedoic acid has the following diffraction angle (2 θ):6.9±0.2°, 7.1±0.2°, 14.3±0.2°, 16.0±0.2° It may also be characterized by an X-ray powder diffraction pattern including a peak of 21.4 ± 0.2°. In the application form, the crystalline ammonium salt of bempedoic acid exhibits the following diffraction angle (2θ): 6.9±0 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. The X-ray powder diffraction pattern may be characterized by a peak at 2°. In certain embodiments, the crystalline ammonium salt of bempedoic acid is used as shown in Table 12. Let's take 2θ, the inter-plane distance d arbitrarily, and the relative intensity (expressed as a percentage relative to the strongest peak). It is characterized by an X-ray powder diffraction pattern represented by ( ). [Table 12]

[0053] (x) Benpedoic acid in crystalline piperazine salt form In certain embodiments, the crystalline salt form of bempedoic acid is a crystalline piperazine salt of bempedoic acid. Yes. In certain embodiments, 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° and It may be characterized by an X-ray powder diffraction pattern containing a peak of 16.0 ± 0.2°. Specific implementation In this state, the crystalline piperazine salt of bempedoic acid exhibits 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 final diffraction pattern may be a distinguishing feature. In certain embodiments, the crystalline piperazine salt of bempedoic acid diffracts as shown in Table 13. Angle 2θ, arbitrary inter-plane distance d, and relative intensity (expressed as a percentage relative to the strongest peak) It is characterized by an X-ray powder diffraction pattern represented by ( ). [Table 13]

[0054] (xi) Bempedoic acid in crystalline tromethamine salt form In certain embodiments, the crystalline salt form of bempedoic acid is the crystalline tromethamine salt of bempedoic acid. In certain embodiments, the crystalline trometamic salt of bempedoic acid has the following diffraction angle (2 θ): 6.6±0.2°, 18.2±0.2°, 18.6±0.2°, and 19.8±0. The X-ray powder diffraction pattern may be characterized by a peak of 2°. In certain embodiments, BEMPE The crystalline tromethamine salt of the acid exhibits 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 The X-ray powder diffraction pattern may be characterized by a peak of ±0.2°. In certain embodiments, the crystalline tromethamine salt of bempedoic acid is used as shown in Table 14. Let's take 2θ, the inter-plane distance d arbitrarily, and the relative intensity (expressed as a percentage relative to the strongest peak). It is characterized by an X-ray powder diffraction pattern represented by ( ). [Table 14]

[0055] C. Cocrystal morphology of bempedoic acid Furthermore, it has been found that a co-crystalline form of vemurafenib can be prepared. In particular, the following coformers formed co-crystals with vemurafenib: palmitic acid and aspartame (2 crystal forms). (i) Co-crystal of vemurafenib and aspartame In certain embodiments, the co-crystalline form of vemurafenib is the co-crystal form of vemurafenib and aspartame. In certain embodiments, the co-crystalline form of vemurafenib and aspartame has the following diffraction angles (2θ): 7.6 ± 0.2°, 8.6 ± 0.2°, 17.3 ± 0.2°, 18 .4 ± 0.2° and 25.1 ± 0.2° and is characterized by an X-ray powder diffraction pattern including peaks therebetween. In certain embodiments, the co-crystalline form of vemurafenib and aspartame has the following diffraction angles (2θ): 7.6 ± 0.2°, 8.6 ± 0.2°, 14.4 ± 0.2°, 17.3 ± 0 .2°, 18.4 ± 0.2°, 25.1 ± 0.2°, 25.2 ± 0.2° and may be characterized by an X-ray powder diffraction pattern including peaks therebetween. In certain embodiments, the co-crystalline form of vemurafenib and aspartame is characterized by an X-ray powder diffraction pattern represented with respect to diffraction angle 2θ, optionally interplanar distance d, and relative intensity (expressed as a percentage with respect to the strongest peak) as shown in Table 15. In certain embodiments, the co-crystalline form of vemurafenib and aspartame is characterized by an X-ray powder diffraction pattern including peaks at the following diffraction angles ( 2θ): 4.4 ± 0.2°, 6.8 ± 0.2°, 10.6 ± 0.2°, 13.2 ± 0.2 ° and 18.4 ± 0.2° and may be characterized by an X-ray powder diffraction pattern including peaks therebetween. In certain

Table 15

[0056] In certain embodiments, the co-crystalline form of vemurafenib and aspartame has the following diffraction angles ([[]] 2θ): 4.4 ± 0.2°, 6.8 ± 0.2°, 10.6 ± 0.2°, 13.2 ± 0.2 ° and 18.4 ± 0.2° and may be characterized by an X-ray powder diffraction pattern including peaks therebetween. In certain In this embodiment, the cocrystal morphology of bempedoic acid and aspartame is as follows, with the diffraction angle (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. The X-ray powder diffraction pattern may be characterized by peaks at 6±0.2° and 18.4±0.2°. ru. In certain embodiments, the cocrystal morphology of bempedoic acid and aspartame is shown in Table 16. As such, the diffraction angle is 2θ, the interplane distance is arbitrarily d, and the relative intensity is a percentage of the strongest peak. It is characterized by an X-ray powder diffraction pattern expressed in terms of a ratio. [Table 16]

[0057] (ii) Cocrystal of bempedoic acid and palmitic acid In certain embodiments, the cocrystal form of bempedoic acid is a cocrystal of bempedoic acid and palmitic acid. This is the crystalline form. In a particular embodiment, the cocrystal form of bempedoic acid and palmitic acid is as follows: Diffraction angles (2θ): 4.3±0.2°, 6.3±0.2°, 8.5±0.2°, and 17 The X-ray powder diffraction pattern may be characterized by a peak of 0.0 ± 0.2°. In certain embodiments, The cocrystal morphology of bempedoic acid and palmitic acid is as follows: diffraction angle (2θ): 4.3±0. 2°, 6.3±0.2°, 8.5±0.2°, 10.5±0.2°, 17.0±0.2° It may also be characterized by an X-ray powder diffraction pattern including a peak at 25.5 ± 0.2°. In certain embodiments, the cocrystal morphology of bempedoic acid and palmitic acid is shown in Table 17. Thus, the diffraction angle is 2θ, the interplane distance is arbitrarily d, and the relative intensity is the percentage relative to the strongest peak. It is characterized by an X-ray powder diffraction pattern represented with respect to (represented as). [Table 17]

[0058] III. Method for preparing bempedoic acid, including purified bempedoic acid As described herein, in one embodiment, the present invention relates to a compound of formula (V) 8-H This provides a method for preparing droxy-2,2,14,14-tetramethylenepentadecanoic acid. The method includes preparing a pharmaceutically acceptable salt thereof. TIFF2026102795000028.tif21160

[0059] It should be understood that the method of the present invention involves the preparation of bempedoic acid. Specific implementations In this state, the method for preparing bempedoic acid yields purified bempedoic acid, and these also produce A medicinal material, that is, a certain amount of bempedoic acid or a certain amount of a compound of formula (V), or the drug Pharmaceutical materials containing scientifically acceptable salts may be described herein. These terms and Unless otherwise specified or understood from the context, the terms and phrases are interchangeable in this specification. It can be used in Noh theater. Therefore, in various embodiments, the compound of formula (V) or its pharmaceutically acceptable may A method for producing pharmaceutical materials containing salts is provided. TIFF2026102795000029.tif21160

[0060] In various embodiments, this method generally includes the following: (a) Contact ethyl isobutyrate with substituted 5-chloropentane in the presence of the first base. , it forms the compound of formula (I). TIFF2026102795000030.tif17151 Substituted 5-chloropentane is 1-bromo-5-chloropentane and 1-iodine Selected from the group consisting of -5-chloropentane, and substituted with 5-chloropentane Tan is selected from the group consisting of 1-bromo-5-chloropentane. (b) Compound of formula (I) [M] + [X] - When brought into contact with the salt of formula (II), the compound of formula (II) It forms. TIFF2026102795000031.tif19152[M] + is Li + kaNa + and K + Selected from the group consisting of [X] - Br - Oh I - It is selected from the group consisting of the following. (c) The compound of formula (II) is subjected to toluenesulfonylmethylisoside in the presence of a second base. The first intermediate is formed by contact with an anido, and the first intermediate is brought into contact with an acid to form equation (IV). It forms a compound. TIFF2026102795000032.tif18160(d) The compound of formula (IV) is brought into contact with a reducing agent to form a second intermediate, and the second intermediate The compound of formula (V) is formed by contacting it with a hydrolyzable base. In certain embodiments of the present invention, the method further includes the following: (e) Purify the compound of formula (V) to obtain a pharmaceutical material containing the purified amount of the compound of formula (V). To provide.

[0061] Synthesis of the compound of formula (I) - Step (a) In various embodiments, the synthesis of the compound of formula (I) is generally carried out in the presence of a first base. This includes contacting ethyl isobutyrate with substituted 5-chloropentane. TIFF2026102795000033.tif21141 In a particular embodiment, in step (a), ethyl isobutyrate is used in the presence of a first base. Contact with 5-chloropentane is possible at temperatures of approximately -30°C to 10°C and approximately -25°C to 1°C. 0℃, approximately -20℃ to approximately 10℃, approximately -18℃ to approximately 10℃, approximately -15℃ to approximately 10℃, approximately -10 °C to approximately 10°C, approximately -5°C to approximately 10°C, approximately 0°C to approximately 10°C, approximately 5°C to approximately 10°C, approximately -30°C ~5℃, approx. -30℃~approx. 0℃, approx. -30℃~approx. -5℃, approx. -30℃~approx. -10℃, approx. - 30℃ to approximately -15℃, approximately -30℃ to approximately -18℃, approximately -30℃ to approximately -20℃, approximately -30℃ to Approximately -25°C, approximately -25°C to approximately 5°C, approximately -25°C to approximately 0°C, approximately -25°C to approximately -5°C, approximately -2 5℃ to approximately -10℃, approximately -25℃ to approximately -15℃, approximately -25℃ to approximately -18℃, approximately -25℃ to approximately -20℃, approximately -20℃ to approximately 5℃, approximately -20℃ to approximately 0℃, approximately -20℃ to approximately -5℃, approximately -20 ℃ to approximately -10℃, approximately -20℃ to approximately -15℃, approximately -20℃ to approximately -18℃, approximately -18℃ to approximately 5 °C, approximately -18°C to approximately 0°C, approximately -18°C to approximately -5°C, approximately -18°C to approximately -10°C, approximately -18°C ~approximately -15℃, approximately -15℃ to approximately 5℃, approximately -15℃ to approximately 0℃, approximately -15℃ to approximately -5℃, approximately - 15℃ to approximately -10℃, approximately -10℃ to approximately 5℃, approximately -10℃ to approximately 0℃, approximately -10℃ to approximately -5℃ The process is carried out at temperatures in the range of approximately -5°C to approximately 5°C, or approximately -5°C to approximately 0°C. In certain embodiments, In step (a), ethyl isobutyrate is substituted with 5-chloropene in the presence of a first base. Contact with the tan is performed at a temperature range of approximately -20°C to approximately 0°C. (Specific Embodiments) Then, in step (a), ethyl isobutyrate is substituted with 5-chloropeptide in the presence of the first base. Contact with tannins is performed at temperatures ranging from approximately -18°C to approximately -5°C. In a particular embodiment, in step (a), about 0.5% by weight, about 0.6% by weight, and 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 Substituted 5-chloropenta% by weight, approximately 1.3% by weight, approximately 1.4% by weight, or less than approximately 1.5% by weight The compound of formula (I) remains after it has formed. In some embodiments, step (a) After forming the compound of formula (I), less than 1% by weight of substituted 5-chloropentane remains. ru. In a particular embodiment, in step (a), ethyl isobutyrate substituted 5-chloropentane The molar ratios are approximately 1:1, 1.01:1, 1.02:1, 1.03:1, and 1.04. :1, approximately 1.05:1, approximately 1.06:1, approximately 1.07:1, approximately 1.08:1, approximately 1.09 :1, approximately 1.1:1, approximately 1.11:1, approximately 1.12:1, approximately 1.13:1, approximately 1.14: 1, approximately 1.15:1, approximately 1.16:1, approximately 1.17:1, approximately 1.18:1, approximately 1.19: 1, approximately 1.2:1, or approximately 1.21:1, and including the range between each of these ratios. In some embodiments, in step (a), ethyl isobutyrate is substituted for 5-chloropentane The molar ratio is approximately 1.1:1. In some embodiments, ethyl isobutyrate is substituted with 5- The molar ratio of lolopentane is approximately 1.1:1 to 1.21:1.

[0062] In a particular embodiment, in step (a), about 1 molar equivalent of substituted 5-chloropentane is added. Approximately 1.01 molar equivalents, approximately 1.02 molar equivalents, approximately 1.03 molar equivalents, approximately 1.04 molar equivalents Approximately 1.05 molar equivalents, approximately 1.06 molar equivalents, approximately 1.07 molar equivalents, approximately 1.08 molar equivalents Approximately 1.09 molar equivalents, approximately 1.1 molar equivalents, approximately 1.11 molar equivalents, approximately 1.12 molar equivalents, Approximately 1.13 molar equivalents, approximately 1.14 molar equivalents, approximately 1.15 molar equivalents, approximately 1.16 molar equivalents, Approximately 1.17 molar equivalents, approximately 1.18 molar equivalents, approximately 1.19 molar equivalents, approximately 1.2 molar equivalents, and It is brought into contact with ethyl isobutyrate, which is present in an amount of approximately 1.21 molar equivalents. Several embodiments Then, in step (a), about 1.1 molar equivalents of substituted 5-chloropentane are added to ethinobutyrate. Make contact with Ru. In a particular embodiment, in step (a), ethyl isobutyrate and substituted 5-chloropenta By adding n to the reactor, ethyl isobutyrate and substituted 5-chloropentane are brought into contact. This is carried out. In some embodiments, in step (a), ethyl isobutyrate is used. And adding substituted 5-chloropentane to the reactor is below approximately 10°C, below approximately 5°C, approximately Below 0°C, below approximately -5°C, below approximately -10°C, below approximately -15°C, below approximately -20°C, approximately -25°C The process is carried out at a temperature below ℃ or below approximately -30℃. In some embodiments, step (a) In this process, adding ethyl isobutyrate and substituted 5-chloropentane to the reactor is approximately 10 °C, approximately 5°C, approximately 0°C, approximately -5°C, approximately -7°C, approximately -10°C, approximately -12°C, approximately -14°C, approximately - 16℃, about -18℃, about -20℃, about -22℃, about -24℃, about -26℃, about -28℃ or This is carried out at a temperature of approximately -30°C. In some embodiments, in step (a), iso-bacteria The addition of ethyl acid and substituted 5-chloropentane to the reactor is carried out at a temperature of approximately -5°C. In some embodiments, in step (a), ethyl isobutyrate and substituted 5-chloromethyl The addition of lopentane to the reactor is carried out at a temperature of approximately -12°C. Several implementations In this process, in step (a), ethyl isobutyrate and substituted 5-chloropentane are added to the reactor. The addition process is carried out at a temperature of approximately -18°C.

[0063] In a particular embodiment, in step (a), ethyl isobutyrate and substituted 5-chloropenta The time for adding the ions to the reactor is approximately 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, and 4 minutes. 0 minutes, approximately 50 minutes, approximately 1 hour, approximately 2 hours, approximately 3 hours, approximately 4 hours, approximately 5 hours, approximately 6 hours, approximately 7 The duration is approximately 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours. In a particular embodiment, in step (a), ethyl isobutyrate and substituted 5-chloropenta The time for adding the substance to the reactor is approximately 10 to 60 minutes, 20 to 60 minutes, and 30 minutes to 60 minutes. 60 minutes, approximately 40 minutes to approximately 60 minutes, approximately 50 minutes to approximately 60 minutes, approximately 10 minutes to approximately 50 minutes, approximately 10 minutes to approximately 40 minutes, approximately 10 minutes to approximately 30 minutes, approximately 10 minutes to approximately 20 minutes, approximately 20 minutes to approximately 50 minutes, approximately 20 minutes to approximately 40 minutes, approximately 20-30 minutes, approximately 30-50 minutes, approximately 30-40 minutes, or approximately 40 minutes It takes approximately 50 minutes.

[0064] In a particular embodiment, in step (a), ethyl isobutyrate and substituted 5-chloropenta The time for adding the substance to the reactor is approximately 1 hour to 12 hours, approximately 2 hours to 12 hours, and approximately 3 hours. ~12 hours, approximately 4 hours to approximately 12 hours, approximately 5 hours to approximately 12 hours, approximately 6 hours to approximately 12 hours, Approximately 7 hours to 12 hours, approximately 8 hours to 12 hours, approximately 9 hours to 12 hours, approximately 10 hours to 12 hours, approximately 11 hours to approximately 12 hours, approximately 1 hour to approximately 11 hours, approximately 1 hour to approximately 10 hours, approximately 1 hour to approximately 9 hours, approximately 1 hour to approximately 8 hours, approximately 1 hour to approximately 7 hours, approximately 1 hour to approximately 6 hours, approximately 1 hour to approximately 5 hours, approximately 1 hour to approximately 4 hours, approximately 1 hour to approximately 3 hours, approximately 1 hour to approximately 2 hours, approximately 2 hours to approximately 11 hours, approximately 2 hours to approximately 10 hours, approximately 2 hours to approximately 9 hours, approximately 2 hours to approximately 8 hours Approximately 2 to 7 hours, approximately 2 to 6 hours, approximately 2 to 5 hours, approximately 2 to 4 hours Approximately 2 to 3 hours, approximately 3 to 11 hours, approximately 3 to 10 hours, approximately 3 to 9 hours Duration: Approximately 3 to 8 hours, approximately 3 to 7 hours, approximately 3 to 6 hours, approximately 3 to 5 hours Duration: Approximately 3 hours to 4 hours, approximately 4 hours to 11 hours, approximately 4 hours to 10 hours, approximately 4 hours to Approximately 9 hours, approximately 4 to 8 hours, approximately 4 to 7 hours, approximately 4 to 6 hours, approximately 4 hours Approximately 5 hours, approximately 5 hours to approximately 11 hours, approximately 5 hours to approximately 10 hours, approximately 5 hours to approximately 9 hours, approximately 5 hours Between approximately 8 hours, approximately 5 hours to approximately 7 hours, approximately 5 hours to approximately 6 hours, approximately 6 hours to approximately 11 hours, approximately 6 Hours: Approximately 10 hours, approximately 6 to 9 hours, approximately 6 to 8 hours, approximately 6 to 7 hours, approximately 7 hours to approximately 11 hours, approximately 7 hours to approximately 10 hours, approximately 7 hours to approximately 9 hours, approximately 7 hours to approximately 8 hours Approximately 8 to 11 hours, approximately 8 to 10 hours, approximately 8 to 9 hours, approximately 9 hours to 1 It can be 1 hour, approximately 9 to 10 hours, or approximately 10 to 11 hours. In some embodiments, ethyl isobutyrate and substituted 5-chloropentane are added to the reactor. The process is carried out simultaneously. In some embodiments, ethyl isobutyrate is added to the reactor. This is done before adding the substituted 5-chloropentane to the reactor. Several implementations In this state, adding ethyl isobutyrate to the reactor is equivalent to adding substituted 5-chloropentane to the reactor. This is done after the additive has been added.

[0065] In certain embodiments, ethyl isobutyrate is substituted for 5-chloropentane in the presence of a first base. When brought into contact with, a reaction mixture is formed. In a particular embodiment, in step (a), At the end of the reaction, the method includes quenching the reaction mixture with an acid. Several implementations In this case, the acid is hydrochloric acid. In certain embodiments, ethyl isobutyrate and substituted 5-chloropentane are compounded by formula (I). It is a starting material used in the manufacture of a product. In certain embodiments, substituted 5-chloropentane When purity is measured by gas chromatography (GC), it must be 99% or higher, or 99.1% or lower. Above, 99.2% or more, 99.3% or more, 99.4% or more, 99.5% or more, 99.6% or more The percentages are 99.7% or higher, 99.8% or higher, or 99.9% or higher. (Several embodiments) Therefore, the purity of substituted 5-chloropentane is 99% or higher when measured by GC. In certain embodiments, the purity of ethyl isobutyrate is measured by gas chromatography (GC). If specified, the percentages are 99% or higher, 99.1% or higher, 99.2% or higher, 99.3% or higher, and 99%. 4% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or 9 It is 9.9% or higher. In some embodiments, the purity of ethyl isobutyrate is measured by GC. In that case, the probability is over 99.5%.

[0066] In certain embodiments, the concentration of ethanol present in ethyl isobutyrate is determined by GC. If measured, the values ​​should be 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 The amount is 0.14% or less, or 0.15% or less. In some embodiments, ethyl isobutyrate is used The concentration of ethanol present, as measured by GC, is 0.1% or less.

[0067] In certain embodiments, the substituted 5-chloropentane is 1-iodo-5-chloropentane. Yes. 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 tannate is 99% or higher when measured by gas chromatography (GC). 99.1% or higher, 99.2% or higher, 99.3% or higher, 99.4% or higher, 99.5% or higher 99.6% or higher, 99.7% or higher, 99.8% or higher, or 99.9% or higher. In a particular embodiment, in step (a), the first base is lithium diisopropyl alcohol. Mid, lithium bis(trimethylsilyl)amide, sodium hydride, sodium amide Selected from the group consisting of lithium amide and lithium tetramethylpiperidide. In one embodiment, in step (a), the first base is lithium diisopropylamine. It is Do. In certain embodiments, unreacted substituted 5-chloropentane remains at the completion of step (a). The amount, when measured by GC, is 0.05% or less, 0.06% or less, and 0.07% or less. 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 at the completion of step (a) is When measured by GC, 0.21% or less, 0.22% or less, 0.23% 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. It is 38% or less, 0.39% or less, or 0.4% or less.

[0069] Lithium diisopropylamide (the first base for producing the compound of formula (I)) Growth In various embodiments, the base used to produce the compound of formula (I) is ri The synthesis of thium diisopropylamide generally involves converting diisopropylamine to butyllithium. This includes bringing it into contact with. TIFF2026102795000034.tif17160

[0070] In certain embodiments, the molar ratio of butyllithium to diisopropylamine is approximately 1:1. 04, approximately 1:1.05, approximately 1:1.06, approximately 1:1.07, approximately 1:1.08, approximately 1:1. 09, approximately 1:1.1, approximately 1:1.2, approximately 1:1.3, approximately 1:1.4, approximately 1:1.5 or approximately The ratio is 1:1.6. In some embodiments, butyllithium to diisopropylamine The molar ratio is approximately 1:1.07. In some embodiments, butyllithium to diisopropyl alcohol is used. The molar ratio of ropylamine is approximately 1:1.5. In certain embodiments, the molar ratio of butyllithium to diisopropylamine is approximately 1:1. 04~approx. 1:1.1, approx. 1:1.05~approx. 1:1.1, approx. 1:1.06~approx. 1:1.1, Approximately 1:1.07 to approximately 1:1.1, approximately 1:1.08 to approximately 1:1.1, approximately 1:1.09 to approximately 1 :1, approximately 1:1.04 to approximately 1:1.09, approximately 1:1.04 to approximately 1:1.08, approximately 1:1. 04~approximately 1:1.07, approximately 1:1.04~approximately 1:1.06, approximately 1:1.04~approximately 1:1. 05, approximately 1:1.05 to 1:1.09, approximately 1:1.05 to 1:1.08, approximately 1:1. 05 to approximately 1:1.07, approximately 1:1.05 to approximately 1:1.06, approximately 1:1.06 to approximately 1:1. 09, approximately 1:1.06 to 1:1.08, approximately 1:1.06 to 1:1.07, approximately 1:1. 07~approximately 1:1.09, approximately 1:1.07~approximately 1:1.08, or approximately 1:1.08~approximately 1: The ratio is 1.09. In some embodiments, butyllithium versus diisopropylamine is used. The ratio is approximately 1:1.06 to 1:1.07.

[0071] In certain embodiments, contact between diisopropylamine and butyllithium occurs at temperatures below 0°C. The tests are conducted at temperatures below -5°C, below -10°C, below -15°C, or below -20°C. In this embodiment, the contact between diisopropylamine and butyllithium occurs at a temperature of -5°C or lower. It will be held at [location]. In certain embodiments, contact between diisopropylamine and butyllithium is tetrahydro It will be held in Lofran (THF). In certain embodiments, lithium diisopropylamide is added before step (a), for example, It is prepared before contacting ethyl isobutyrate with 1-bromo-5-chloropentane. In certain embodiments, lithium diisopropylamide is, for example, ethyl isobutyrate 1 - While in contact with bromo-5-chloropentane, adjust in situ during step (a). It is manufactured. In some embodiments, lithium diisopropylamide is produced during step (a) When prepared in situ, substituted 5-chloropentane vs ethyl isobutyrate vs butyllithium The molar ratio of diisopropylamine is approximately 1:1.1:1.2:1.26 and approximately 1:1.1:1 0.15:1.75, approximately 1:1.1:1.24:1.3, approximately 1:1.1:1.2:1.29 Approximately 1:1.1:1.2:1.28, or approximately 1:1~1.25:1.15~1.2:1. The value is 25 to 1.75. In some embodiments, lithium diisopropylamide is used in the process. If prepared in situ during (a), substituted 5-chloropentane vs ethyl isobutyrate vs butyrate The molar ratio of lithium to diisopropylamine is approximately 1:1.1:1.2:1.28. . In some embodiments, the substituted 5-chloropentane is 1-bromo-5-chloropentane It is.

[0072] Synthesis of the compound of formula (II) - Step (b) Synthesis of the compound of formula (II) (wherein X is Br or I) in various embodiments Generally, compounds of formula (I) are given formula [M] + [X] - This includes contacting with the salt. TIFF2026102795000035.tif16160

[0073] In a particular embodiment, in step (b), the compound of formula (I) is added to formula [M] + [X] - of Contact with salts is possible with acetone, 2-butanone, methyl isobutyl ketone, THF and The test is carried out in a solvent containing one or more 3-pentanones, where M is composed of Li, Na, and K. X is selected from the group consisting of Br and I. In certain embodiments, in step (b), the solvent is less than about 3.5% by weight of water, about 3 times Water less than 1% by weight, water less than approximately 2.5% by weight, water less than approximately 2% by weight, water less than approximately 1.5% by weight , containing less than 1% by weight of water, or less than 0.5% by weight of water. In some embodiments, In step (b), the solvent contains less than approximately 3% by weight of water. In a particular embodiment, in step (b), the compound of formula (I) is added to formula [M] + [X] - of Contact with salt reduces the compound of formula (I) by approximately the amount of the compound of formula (I) 1 molar equivalent, approximately 1.05 molar equivalent, approximately 1.1 molar equivalent, approximately 1.15 molar equivalent, approximately 1.2 molar equivalent Formula for molar equivalent, or approximately 1.25 molar equivalent [M] + [X] - This includes contacting with salt. In a specific embodiment, in step (b), the compound of formula (I) is converted to formula [M] + [X] - salt and Contacting the compound of formula (I) results in approximately 1.1 based on the molar amount of the compound of formula (I). Molar equivalent formula [M] + [X] - This includes contacting with the salt.

[0074] In a particular embodiment, in step (b), the compound of formula (I) is added to formula [M] + [X] - of Contact with salt occurs at approximately 75°C to 85°C, 76°C to 85°C, and 77°C to 85°C. Approximately 78°C to 85°C, approximately 79°C to 85°C, approximately 80°C to 85°C, approximately 81°C to 85°C Approximately 82°C to 85°C, approximately 83°C to 85°C, approximately 84°C to 85°C, approximately 75°C to 84°C Approximately 75°C to 83°C, approximately 75°C to 82°C, approximately 75°C to 81°C, approximately 75°C to 80°C Approximately 75°C to 79°C, approximately 75°C to 78°C, approximately 75°C to 77°C, approximately 75°C to 76°C Approximately 76°C to 84°C, approximately 76°C to 83°C, approximately 76°C to 82°C, approximately 76°C to 81°C Approximately 76°C to 80°C, approximately 76°C to 79°C, approximately 76°C to 78°C, approximately 76°C to 77°C Approximately 77°C to 84°C, approximately 77°C to 83°C, approximately 77°C to 82°C, approximately 77°C to 81°C Approximately 77°C to 80°C, approximately 77°C to 79°C, approximately 77°C to 78°C, approximately 78°C to 84°C Approximately 78°C to 83°C, approximately 78°C to 82°C, approximately 78°C to 81°C, approximately 78°C to 80°C Approximately 78°C to 79°C, approximately 79°C to 84°C, approximately 79°C to 83°C, approximately 79°C to 82°C Approximately 79°C to 81°C, approximately 79°C to 80°C, approximately 80°C to 84°C, approximately 80°C to 83°C Approximately 80°C to 82°C, approximately 80°C to 81°C, approximately 81°C to 84°C, approximately 81°C to 83°C Approximately 81°C to 82°C, approximately 82°C to 84°C, approximately 82°C to 83°C, or approximately 83°C to 8 The process is carried out at temperatures in the range of 4°C. In some embodiments, in step (b), formula (I) The compound is given by formula [M] + [X] - Contact with salt is possible at temperatures in the range of approximately 78°C to 82°C. It will be done in stages. In a particular embodiment, in step (b), formula [M] + [X] - The salt is lithium bromide. (LiBr), lithium iodide (LiI), potassium bromide (KBr), potassium iodide ( Select from the group consisting of KI, sodium bromide (NaBr), and sodium iodide (NaI). Selected. In some embodiments, in step (b), formula [M] + [X] - The salt is It is sodium oxide.

[0075] Synthesis of the compound of formula (IV) - step (c) In various embodiments, the synthesis of the compound of formula (IV) is generally performed by synthesizing the compound of formula (II). The first intermediate is produced by contacting it with toluenesulfonylmethyl isocyanide in the presence of a second base. This includes forming a body and contacting the first intermediate with an acid. TIFF2026102795000036.tif18160

[0076] Synthesis of the first intermediate In various embodiments, the synthesis of the first intermediate generally involves the compound of formula (II) being converted to the second intermediate. This involves contacting toluenesulfonylmethyl isocyanide in the presence of a base. TIFF2026102795000037.tif39160

[0077] In certain embodiments, in step (c), the second base is sodium hydride, potassium Selected from tert-butoxide and sodium tert-pentoxide. In that embodiment, in step (c), the second base is sodium tert-pentoxy It is Do. In certain embodiments, in step (c), the presence of sodium tert-pentoxide Below, the compound of formula (II) is brought into contact with toluenesulfonylmethyl isocyanide in the first medium Interbody formation occurs at approximately -20°C to 10°C, approximately -10°C to 10°C, and approximately 0°C to 10°C. Temperatures in the range of °C, approximately -20°C to approximately 0°C, approximately -20°C to approximately -10°C, or approximately -10°C to approximately 0°C. The process is carried out at a certain degree. In a particular embodiment, in step (c), sodium tert-pent The compound of formula (II) was contacted with toluenesulfonylmethyl isocyanide in the presence of oxide. The formation of the first intermediate is carried out at temperatures in the range of approximately -20°C to approximately 10°C. In a specific embodiment, in step (c), in the presence of sodium tert-pentoxide The compound of formula (II) is contacted with toluenesulfonylmethyl isocyanide to obtain the first intermediate. The formation of this material takes place at temperatures ranging from approximately -15°C to approximately 0°C.

[0078] In a particular embodiment, in step (c), the compound of formula (II) is formed in the presence of a second base. Contacting with toluenesulfonylmethyl isocyanide to form the first intermediate is The process is carried out at temperatures of approximately -20°C, -15°C, -10°C, -5°C, or 0°C. In a particular embodiment, in step (c), the compound of formula (II) versus toluenesulfonyl The molar ratios of methyl isocyanide are approximately 1.7:1, 1.8:1, 1.9:1, and 2:1. , approximately 2.1:1, or approximately 2.2:1. In certain embodiments, in step (c), The molar ratio of the compound in formula (II) to toluenesulfonylmethyl isocyanide is approximately 1.9:1. be. In some embodiments, in step (c), the compound of formula (II) is compared with toluene sulfo The molar ratio of nylmethyl isocyanide to the second base is approximately 1.9:1.0:2.1. In some embodiments, in step (c), the compound of formula (II) is mixed with toluenesulfonyl The molar ratio of methyl isocyanide to the second base is approximately 1.9:1.0:2.2. In some embodiments, in step (c), the compound of formula (II) is compared with toluene sulfo The molar ratio of nylmethyl isocyanide to sodium tert-pentoxide is approximately 1.9:1. The ratio is 0:2.1. In some embodiments, in step (c), the compound of formula (II) is used. Molar ratio of toluenesulfonylmethyl isocyanide to sodium tert-pentoxide The ratio is approximately 1.9:1.0:2.2. In a particular embodiment, in step (c), the compound of formula (II) and toluenesulfonyl Contacting methyl isocyanide with a solvent containing dimethylacetamide or dimethyl The procedure is carried out in a solvent that is acetamide.

[0079] Synthesis of the compound of formula (IV) In various embodiments, the synthesis of the compound of formula (IV) generally involves a first intermediate being combined with an acid. This includes making contact. TIFF2026102795000038.tif18160

[0080] In a particular embodiment, in step (c), contacting the first intermediate with the acid is approximately -15℃ to approximately 35℃, approximately -10℃ to approximately 35℃, approximately -5℃ to approximately 35℃, approximately 0℃ to approximately 35℃, Approximately 5°C to 35°C, approximately 10°C to 35°C, approximately 15°C to 35°C, approximately 20°C to 35°C, approximately 25℃ to approximately 35℃, approximately 30℃ to approximately 35℃, approximately -15℃ to approximately 30℃, approximately -15℃ to approximately 25℃ Approximately -15°C to 20°C, approximately -15°C to 15°C, approximately -15°C to 10°C, approximately -15°C to Approximately 5°C, approximately -15°C to approximately 0°C, approximately -15°C to approximately -5°C, approximately -15°C to approximately -10°C, approximately -1 0°C to approximately 30°C, approximately -10°C to approximately 25°C, approximately -10°C to approximately 20°C, approximately -10°C to approximately 15°C Approximately -10°C to 10°C, approximately -10°C to 5°C, approximately -10°C to 10°C, approximately -10°C to 5°C -5°C, approximately -5°C to approximately 30°C, approximately -5°C to approximately 25°C, approximately -5°C to approximately 20°C, approximately -5°C to approximately 15℃, approximately -5℃ to approximately 10℃, approximately -5℃ to approximately 5℃, approximately -5℃ to approximately 0℃, approximately 0℃ to approximately 30℃ Approximately 0°C to 25°C, approximately 0°C to 20°C, approximately 0°C to 15°C, approximately 0°C to 10°C, approximately 0°C ~5℃, 5℃~30℃, 5℃~25℃, 5℃~20℃, 5℃~15℃ Approximately 5°C to 10°C, approximately 10°C to 30°C, approximately 10°C to 25°C, approximately 10°C to 20°C. Approximately 10°C to 15°C, approximately 15°C to 30°C, approximately 15°C to 25°C, approximately 15°C to 20°C, It is performed at approximately 20°C to 30°C, approximately 20°C to 25°C, or approximately 25°C to 30°C. How many In that embodiment, in step (c), contact of the first intermediate with the acid is approximately -1 The process is carried out at a temperature in the range of 0°C to approximately 35°C. In some embodiments, step (c) The contact of the first intermediate with the acid is carried out at a temperature in the range of approximately -15°C to approximately 25°C. In some embodiments, in step (c), the first intermediate is brought into contact with the acid. The process is carried out at temperatures ranging from approximately 10°C to 25°C. In certain embodiments, in step (c), the acid is hydrochloric acid.

[0081] Synthesis of the compound of formula (V) - step (d) In various embodiments, the synthesis of the compound of formula (V) is generally performed by using the compound of formula (IV). The process involves contacting the intermediate with a reducing agent to form a second intermediate, and then using the second intermediate as a hydrolyzable base. This includes making contact. TIFF2026102795000039.tif18160

[0082] Synthesis of the second intermediate In various embodiments, the synthesis of the second intermediate generally involves reducing the compound of formula (IV). This includes contact with the agent. TIFF2026102795000040.tif20160

[0083] In a particular embodiment, in step (d), the reducing agent is sodium borohydride, shea Sodium borohydride, cerium borohydride, zinc borohydride, and diisohydride Selected from the group consisting of butylaluminum. In some embodiments, the reducing agent is water It is sodium borohydride. In a particular embodiment, in step (d), the compound of formula (IV) is brought into contact with a reducing agent. This means that the compound of formula (IV) is approximately 0.25 molars based on the molar amount of the compound of formula (IV). 0.3 molar equivalents, approximately 0.35 molar equivalents, approximately 0.45 molar equivalents, approximately 0.0 0.5 mole equivalent, approximately 0.6 mole equivalent, approximately 0.7 mole equivalent, approximately 0.8 mole equivalent, approximately 0.9 moles Equivalent, approximately 1.0 mole equivalent, approximately 1.1 mole equivalent, approximately 1.2 mole equivalent, approximately 1.3 mole equivalent, approximately This involves contacting the product with 1.4 molar equivalents, or about 1.5 molar equivalents, of a reducing agent. In the application method, in step (d), contacting the compound of formula (IV) with the reducing agent is, The compound of formula (IV) is reduced to approximately 0.35 molar equivalents based on the molar amount of the compound of formula (IV). This includes contact with the agent.

[0084] In a particular embodiment, in step (c), the compound of formula (IV) is brought into contact with a reducing agent. This means that the temperature ranges are approximately 5°C to 30°C, 10°C to 30°C, 15°C to 30°C, and 20°C to 30°C. 0℃, approximately 25℃ to approximately 30℃, approximately 5℃ to approximately 25℃, approximately 5℃ to approximately 20℃, approximately 5℃ to approximately 15℃, Approximately 5°C to 10°C, approximately 10°C to 25°C, approximately 10°C to 20°C, approximately 10°C to 15°C, approximately The process is carried out at temperatures ranging from 15°C to approximately 25°C, approximately 15°C to approximately 20°C, or approximately 20°C to approximately 25°C. ru. In a particular embodiment, in step (c), contact between the compound of formula (IV) and the reducing agent is performed. The process is carried out at temperatures of approximately 5°C, 10°C, 15°C, 20°C, 25°C, or 30°C.

[0085] Synthesis of the compound of formula (V) In various embodiments, the synthesis of the compound of formula (V) generally involves adding water to the second intermediate. This includes contact with a desolvable base. TIFF2026102795000041.tif18160

[0086] In a particular embodiment, in step (d), the concentration of the hydrolyzable base is about 20% by weight / Weight, approx. 25% w / w, approx. 30% w / w, approx. 35% w / w, approx. 40% w / w Weight, approximately 45% weight / weight, approximately 50% weight / weight, approximately 55% weight / weight, or approximately 60% weight / weight. In some embodiments, in step (d), the concentration of the hydrolyzable base is It is approximately 50% weight / weight. In a particular embodiment, in step (d), the second intermediate is brought into contact with the hydrolyzing base. The formation of the compound of formula (V) is carried out in solution. In some embodiments, the process (d) In this method, the pH of the solution containing the compound of formula (V) is adjusted to approximately 3 to approximately 7. This further includes the following.

[0087] In a particular embodiment, in step (d), the second intermediate is brought into contact with a hydrolyzable base. This is because the temperature ranges are approximately 30°C to 60°C, 35°C to 60°C, 40°C to 60°C, and 45°C to 60°C. Approximately 60°C, approximately 50°C to approximately 60°C, approximately 55°C to approximately 60°C, approximately 30°C to approximately 55°C, approximately 30°C to Approximately 50°C, approximately 30°C to 45°C, approximately 30°C to 40°C, approximately 30°C to 35°C, approximately 35°C to Approximately 55°C, approximately 35°C to approximately 50°C, approximately 35°C to approximately 45°C, approximately 35°C to approximately 40°C, approximately 40°C to Approximately 55°C, approximately 40°C to approximately 50°C, approximately 40°C to approximately 45°C, approximately 45°C to approximately 55°C, approximately 45°C to The process is carried out at a temperature of approximately 50°C, or in the range of approximately 50°C to 60°C.

[0088] In a particular embodiment, in step (d), the second intermediate is brought into contact with a hydrolyzable base. This can be done at approximately 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, or 60°C. This is carried out at a temperature. In a particular embodiment, in step (d), a second intermediate is hydrolyzed. The contact of the base is carried out at a temperature of approximately 50°C. In certain embodiments, in step (d), the hydrolyzable base is sodium hydroxide. In a particular embodiment, in step (d), the compound of formula (IV) is brought into contact with a reducing agent. To form a second intermediate, and to contact the second intermediate with a hydrolyzable base to produce formula (V) The formation of the compound is carried out in a single reaction vessel.

[0089] In some embodiments of this model, the method is as follows: (a) Contact ethyl isobutyrate with 1-bromo-5-chloropentane in the presence of the first base. To form the compound of formula (I), TIFF2026102795000042.tif15160(b) The compound of formula (I) is brought into contact with sodium iodide to form the compound of formula (IIa) To make it happen TIFF2026102795000043.tif16160(c) In the presence of a second base, the compound of formula (IIa) is converted to toluenesulfonylmethylisothio The first intermediate is formed by contact with an anido, and the first intermediate is brought into contact with an acid to form equation (IV). To form a compound, TIFF2026102795000044.tif18160 and (d) Contacting the compound of formula (IV) with a reducing agent to form a second intermediate, and The process involves contacting the intermediate of 2 with a hydrolyzing base to form the compound of formula (V). In some embodiments of the present invention, the method is as follows: (e) Purify the compound of formula (V) to provide a pharmaceutical material containing a purified amount of the compound of formula (V). This includes doing so.

[0090] In some of the embodiments described above, the same conditions as previously described (for example, temperature) The quantity, ratio, equivalent, time, purity, and other parameters or variables of ) may be equally applicable. For example, replace "substituted-5-chloropentane" with "1-bromo-5-chloropentane". When changing, use the formula [M] + [X] - Replace "salt" with "sodium iodide" and "M" Replace with "Na"; replace "X" with "I"; change "compound of formula (IIa)" to "formula II Replace it with "compound of".

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

[0092] In certain embodiments, 1,5-dibromopentane in 1-bromo-5-chloropentane The concentrations, when measured by GC, are 0.05% or less, 0.1% or less, and 0.15% or less. , 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 less than 1.0%. In some embodiments, in 1-bromo-5-chloropentane The concentration of 1,5-dibromopentane is less than 0.2% as measured by GC. In this embodiment, the concentration of 1,5-dibromopentane in 1-bromo-5-chloropentane is The concentration measured by GC is less than 1.0%.

[0093] In certain embodiments, unreacted 1-bromo-5-chloromolecular The amount of pentane, when measured by GC, is 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, 0.1 2% or less, 0.12% or less, 0.13% or less, 0.14% or less, 0.15% or less, 0.1 It is 6% or less, 0.17% or less, 0.18% or less, 0.19% or less, or 0.2% or less. In some embodiments, unreacted 1-bromo-5-chloromide remains at the completion of step (a). The amount of lopentane, when measured by GC, is 0.21% or less, 0.22% or less, 0 .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. It is 37% or less, 0.38% or less, 0.39% or less, or 0.4% or less.

[0094] In a particular embodiment, the method for preparing the compound of formula (V) is as follows: (a) In the presence of lithium diisopropylamide, at a temperature in the range of approximately -20°C to approximately 0°C Bromo-5-chloropentane is brought into contact with approximately 1.1 molar equivalents of ethyl isobutyrate, and the formula ( I) To form the compound, TIFF2026102795000045.tif15160(b) At a temperature in the range of approximately 78°C to approximately 82°C, the compound of formula (I) is dissolved in approximately 1% of 2-butanone. Contact with 1 molar equivalent of sodium iodide to form the compound of formula (IIa). , TIFF2026102795000046.tif15160(c) Approximately -2 in dimethylacetamide in the presence of sodium tert-pentoxide At temperatures ranging from 0°C to approximately 10°C, the compound of formula (IIa) is dissolved in toluenesulfonylmethyliso By contacting with cyanide, a first intermediate is formed, and at a temperature in the range of approximately -10°C to approximately 35°C... The first intermediate is brought into contact with an acid to form the compound of formula (IV). TIFF2026102795000047.tif18160 and (d) Contact the compound of formula (IV) with approximately 0.35 molar equivalents of sodium borohydride. To form a second intermediate, and to contact the second intermediate with sodium hydroxide in solution. This includes causing the compound of formula (V) to form. In a particular embodiment of the present invention, the method is: (e) Purify the compound of formula (V) to provide a pharmaceutical material containing a purified amount of the compound of formula (V). This includes doing so.

[0095] In the specific embodiments described above, the quantities and ratios of the same conditions (e.g., temperature) previously described are used. Equivalents, time, purity, and other parameters or variables may be equally applicable, for example, When replacing "the first base" with "lithium diisopropylamide", the "second base" Replace with "sodium tert-pentoxide" and "reducing agent" with "sodium borohydride" Replace "lium" with "hydrolyzable base" and "sodium hydroxide".

[0096] Furthermore, in certain embodiments, in step (a), lithium diisopropylamide Contacting ethyl isobutyrate with 1-bromo-5-chloropentane in the presence of approximately -2 0°C to approximately 0°C, approximately -15°C to approximately 0°C, approximately -10°C to approximately 0°C, approximately -5°C to approximately 0°C, approximately -20°C ℃ to approximately -5℃, approximately -20℃ to approximately -10℃, approximately -20℃ to approximately -15℃, approximately -15℃ to approximately -5 The process is carried out at temperatures in the range of approximately -15°C to -10°C, or approximately -10°C to -5°C. In a particular embodiment, in step (b), the compound of formula (I) is brought into contact with sodium iodide. Contact is permitted at temperatures of approximately 78°C to 82°C, approximately 78°C to 80°C, or approximately 80°C to 82°C. It is performed at a range of temperatures.

[0097] In a particular embodiment, in step (c), the compound of formula (IIa) is compared with toluene sulfonyl The molar ratio of methyl isocyanide to sodium tert-pentoxide is approximately 1.9:1:2 It is 0.1.

[0098] Purification of the compound of formula (V) - step (e) Various embodiments of the present invention are methods for producing pharmaceutical materials containing a purified amount of the compound of formula (V). Includes, TIFF2026102795000048.tif18160 That is, the method may include purifying the compound of formula (V). In various embodiments, the compound of formula (V) is purified by dissolving it through silica gel. The process involves filtering the compound of formula (V) in a medium. In some embodiments, the solvent is acetate. It contains chill. In some embodiments, the solvent is ethyl acetate. In certain embodiments, purifying the compound of formula (V) involves crystallizing the compound of formula (V). This includes providing a compound of formula (V) in crystalline form. In certain embodiments, the purification of the compound of formula (V) is performed by using charcoal and This includes contacting the charcoal and then filtering it. In some embodiments, the compound of formula (V) Contacting a substance with charcoal allows the compound of formula (V) to react with acetonitrile and activated carbon (for example). This includes contacting the solution with a 5% (by weight / by weight) activated carbon solution.

[0099] In certain embodiments, the purification of the compound of formula (V) is performed to obtain the crystalline form of the compound of formula (V). The present invention includes recrystallizing a substance to provide a pharmaceutical material containing a purified amount of the compound of formula (V). In various embodiments, the purification of the compound of formula (V) is performed as follows: (f) Adjust the pH of the solution containing the compound of formula (V) to approximately 5 to 6; (g) Extract the compound of formula (V) from the solution using methyl tert-butyl ether. To provide a methyl tert-butyl ether solution containing the compound of formula (V); (h) Remove the methyl tert-butyl ether from the methyl tert-butyl ether solutionacetic acid solution. To provide an ethyl acetate solution containing the compound of formula (V) by replacing ethyl acetate; (i) Filter an ethyl acetate solution containing the compound of formula (V) through silica gel; (j) Using ethyl acetate and water, the compound of formula (V) is crystallized to obtain the crystalline form of formula ( To provide a compound of V); and (k) Recrystallize the compound of formula (V) in crystalline form using ethyl acetate and water. The invention includes providing a pharmaceutical material containing a compound of formula (V) for production.

[0100] In certain embodiments, step (g) uses methyl tert-butyl ether. Extracting the compound of formula (V) from the solution can be done at approximately 5°C, 10°C, 15°C, and 20°C. Approximately 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, or below 55°C. This is carried out at a temperature. In a particular embodiment, in step (g), methyl tert-butyl ester is used. Extraction of the compound of formula (V) from a solution using a ether can be performed at temperatures below approximately 15°C. In a particular embodiment, in step (g), methyl tert-butyl ether is used. Extraction of the compound of formula (V) from the solution using this method is performed at a temperature of approximately 50°C or lower.

[0101] In a particular embodiment, in step (j), ethyl acetate and water are used to make formula (V) The crystallization of compounds occurs at approximately 60°C to -10°C, approximately 55°C to -10°C, and approximately 50°C. ~approximately -10℃, approximately 45℃~approximately -10℃, approximately 40℃~approximately -10℃, approximately 35℃~approximately -10℃, Approximately 30°C to approximately -10°C, approximately 25°C to approximately -10°C, approximately 20°C to approximately -10°C, approximately 15°C to approximately - 10℃, approximately 10℃ to approximately -10℃, approximately 5℃ to approximately -10℃, approximately 0℃ to approximately -10℃, approximately -5℃ to Approximately -10°C, approximately 60°C to approximately -5°C, approximately 55°C to approximately -5°C, approximately 50°C to approximately -5°C, approximately 45°C ~approximately -5°C, approximately 40°C to approximately -5°C, approximately 35°C to approximately -5°C, approximately 30°C to approximately -5°C, approximately 25°C ~approximately -5°C, approximately 20°C~approximately -5°C, approximately 15°C~approximately -5°C, approximately 10°C~approximately -5°C, approximately 5°C~ Approximately -5°C, approximately 0°C to approximately -5°C, approximately 60°C to approximately 0°C, approximately 55°C to approximately 0°C, approximately 50°C to approximately 0°C Approximately 45°C to 0°C, approximately 40°C to 0°C, approximately 35°C to 0°C, approximately 30°C to 0°C, approximately 25 ℃ to approximately 0℃, approximately 20℃ to approximately 0℃, approximately 15℃ to approximately 0℃, approximately 10℃ to approximately 0℃, approximately 5℃ to approximately 0℃ Approximately 60°C to 5°C, approximately 55°C to 5°C, approximately 50°C to 5°C, approximately 45°C to 5°C, approximately 40 ℃ to approximately 5℃, approximately 35℃ to approximately 5℃, approximately 30℃ to approximately 5℃, approximately 25℃ to approximately 5℃, approximately 20℃ to approximately 5℃ ℃, approximately 15℃ to approximately 5℃, approximately 10℃ to approximately 5℃, approximately 60℃ to approximately 10℃, approximately 55℃ to approximately 10℃, Approximately 50°C to 10°C, approximately 45°C to 10°C, approximately 40°C to 10°C, approximately 35°C to 10°C. Approximately 30°C to 10°C, approximately 25°C to 10°C, approximately 20°C to 10°C, approximately 15°C to 10°C. Approximately 60°C to 15°C, approximately 55°C to 15°C, approximately 50°C to 15°C, approximately 45°C to 15°C. Approximately 40°C to 15°C, approximately 35°C to 15°C, approximately 30°C to 15°C, approximately 25°C to 15°C. Approximately 20°C to 15°C, approximately 60°C to 20°C, approximately 55°C to 20°C, approximately 50°C to 20°C. Approximately 45°C to 20°C, approximately 40°C to 20°C, approximately 35°C to 20°C, approximately 30°C to 20°C, Approximately 25°C to 20°C, approximately 60°C to 25°C, approximately 55°C to 25°C, approximately 50°C to 25°C. Approximately 45°C to 25°C, approximately 40°C to 25°C, approximately 35°C to 25°C, approximately 30°C to 25°C, Approximately 60°C to 30°C, approximately 55°C to 30°C, approximately 50°C to 30°C, approximately 45°C to 30°C, Approximately 60°C to 35°C, approximately 55°C to 35°C, approximately 50°C to 35°C, approximately 45°C to 35°C, Approximately 40°C to 35°C, approximately 60°C to 40°C, approximately 55°C to 40°C, approximately 50°C to 40°C, Approximately 45°C to 40°C, approximately 60°C to 45°C, approximately 55°C to 45°C, approximately 50°C to 45°C. Over a temperature range of approximately 60°C to 50°C, approximately 55°C to 50°C, or approximately 60°C to 55°C This is carried out. In a particular embodiment, in step (j), ethyl acetate and water are used to form the formula The crystallization of compound (V) is carried out over a temperature range of approximately 50°C to approximately -5°C. ru.

[0102] In a particular embodiment, in step (k), ethyl acetate and water are used to form the crystalline form of formula Recrystallizing compound (V) can be done at approximately 70°C to 5°C, approximately 65°C to 5°C, and approximately 60°C. ℃~approx. 5℃, approx. 55℃~approx. 5℃, approx. 50℃~approx. 5℃, approx. 45℃~approx. 5℃, approx. 40℃~approx. 5℃ °C, approximately 35°C to approximately 5°C, approximately 30°C to approximately 5°C, approximately 25°C to approximately 5°C, approximately 20°C to approximately 5°C, approximately 1 5°C to approximately 5°C, approximately 10°C to approximately 5°C, approximately 70°C to approximately 10°C, approximately 65°C to approximately 10°C, approximately 60°C ~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℃ Temperatures of approximately 55°C, 70°C to 60°C, 65°C to 60°C, or 70°C to 65°C. The process is carried out over a range. In a particular embodiment, in step (k), ethyl acetate and water Recrystallizing the crystalline form of the compound of formula (V) using a temperature of approximately 70°C to 5°C is possible. It is performed over a range of degrees.

[0103] In certain embodiments, the purification of the compound of formula (V) is performed as follows: (l) Dissolve the compound of formula (V) in crystalline form in acetonitrile, thereby forming the solution To accomplish; (m) Bring the solution into contact with charcoal; (n) Filter the charcoal to obtain a purified solution containing the compound of formula (V); and (o) Crystallize the compound of formula (V) from the purified solution, and obtain the purified amount of the compound of formula (V) This includes providing pharmaceutical materials. In various embodiments, steps (l) to (o) above are performed, followed by steps (f) to (k). Please understand that it can be done later or without taking the necessary steps.

[0104] Crystallization of the compound of formula (V) In various embodiments, the purification of the compound of formula (V) is performed using a solvent or a mixture of solvents. This includes, for example, crystallizing a compound of formula (V) from ethyl acetate and water.

[0105] In certain embodiments, the concentration of water in the solvent mixture containing 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 It is 5% (weight / weight), approximately 1.4% (weight / weight), or approximately 1.5% (weight / weight). In some embodiments, the concentration of water in the solvent mixture containing ethyl acetate and water is about 1. It is 0.5% (weight / weight).

[0106] In certain embodiments, the concentration of water in a solvent mixture containing 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), approximately 0.5% (weight / weight) ~ approximately 0.9% (weight / weight), approximately 0.5% ( Weight / Weight) ~ Approx. 0.75% (Weight / Weight), Approx. 0.5% (Weight / Weight) ~ Approx. 0.6% ( Weight / Weight), approx. 0.6% (Weight / Weight) ~ Approx. 1.5% (Weight / Weight), Approx. 0.6% (Weight / Weight), Approx. amount / 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% (w / w) ~ approx. 0.75% (w / w), 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 %(weight / weight) ~ approximately 1.35%(weight / weight), or approximately 1.35%(weight / weight) ~ approximately The concentration is 1.5% (by weight). In some embodiments, the solvent includes ethyl acetate and water. The concentration of water in the mixture is approximately 0.6% (weight / weight) to approximately 1.4% (weight / weight). In some embodiments, the concentration of water in a solvent mixture containing ethyl acetate and water is about 0 It is approximately 0.75% (weight / weight) to 1.35% (weight / weight).

[0107] In various embodiments, a mixture containing a compound of formula (V), ethyl acetate and water is obtained from formula ( Crystallizing compound V) is (1) The mixture is heated to a first temperature (T 1 ) from the second temperature (T 2 ) means cooling to that extent , T 1 The temperature range is approximately 40°C to 60°C, 2 The temperature is approximately 15°C to 30°C, and the mixture is approximately 1 At a rate of 0°C / hour to approximately 20°C / hour, T 1 From T 2 To cool down; (2) T 2 Hold for at least 3 hours; (3) Add the mixture to T 2 From the third temperature (T 3 ) may need to be cooled down to T 3 approximately -5 The temperature is approximately 10°C, and the mixture is heated at a rate of approximately 5°C / hour to approximately 15°C / hour. 2 From T 3 Ma To cool with; and (4) T 3 Hold for at least 3 hours; This generates the crystalline form of the compound of formula (V).

[0108] In a particular embodiment, in the crystallization step (1), T 1 It is approximately 40°C to 60°C, approximately 4 5℃ to approximately 60℃, approximately 50℃ to approximately 60℃, approximately 55℃ to approximately 60℃, approximately 40℃ to approximately 55℃, approximately 4 0°C to approximately 50°C, approximately 40°C to approximately 45°C, approximately 45°C to approximately 55°C, approximately 45°C to approximately 50°C, or The temperature is approximately 50°C to 55°C. In some embodiments, in the crystallization step (1), T 1 The temperature is approximately 40°C to approximately 60°C. In some embodiments, in the crystallization step (1), T 1 The temperature ranges from approximately 45°C to 55°C.

[0109] In a particular embodiment, in the crystallization step (1), T 1 It is approximately 40°C, approximately 45°C, and approximately 5 The temperature is 0°C, approximately 55°C, or approximately 60°C. In some embodiments, the crystallization step (1) T 1 The temperature is approximately 50°C. In a particular embodiment, in the crystallization step (1), T 2 It is approximately 15℃ to approximately 30℃, approximately 2 0°C to approximately 30°C, approximately 25°C to approximately 30°C, approximately 15°C to approximately 25°C, approximately 15°C to approximately 20°C, or The temperature is approximately 20°C to 25°C. In some embodiments, in the crystallization step (i), T 2 The temperature range is approximately 15°C to approximately 30°C. In some embodiments, in the crystallization step (1), T 2 The temperature is approximately 20°C to 25°C.

[0110] In a particular embodiment, in the crystallization step (1), T 2 It is approximately 15℃, approximately 16℃, approximately 1 7℃, approximately 18℃, approximately 19℃, approximately 20℃, approximately 21℃, approximately 22℃, approximately 23℃, approximately 24℃, approximately 2 These are 5°C, approximately 26°C, approximately 27°C, approximately 28°C, approximately 29°C, or approximately 30°C. Several implementations In terms of morphology, in the crystallization process (1), T 2 The temperature is approximately 22°C. In a particular embodiment, in the crystallization step (1), the mixture is heated at approximately 10°C / hour to approximately 20°C / hour. °C / hour, approximately 12°C / hour to approximately 20°C / hour, approximately 14°C / hour to approximately 20°C / hour, approximately 16 °C / hour ~ approximately 20°C / hour, approximately 18°C / hour ~ approximately 20°C / hour, approximately 10°C / hour ~ approximately 18 °C / hour, approximately 10°C / hour to approximately 16°C / hour, approximately 10°C / hour to approximately 14°C / hour, approximately 10 °C / hour ~ approximately 12°C / hour, approximately 12°C / hour ~ approximately 18°C / hour, approximately 12°C / hour ~ approximately 16 °C / hour, approximately 12°C / hour to approximately 14°C / hour, approximately 14°C / hour to approximately 18°C / hour, approximately 14 At a rate of ℃ / hour to approximately 16℃ / hour, or approximately 16℃ / hour to approximately 18℃ / hour, T 1 ~T 2 Ma Cooling is performed at a rate of approximately 10°C / hour to approximately 20°C / hour. In some embodiments, the mixture is cooled at a rate of approximately 10°C / hour to approximately 20°C / hour. T 1 From T 2 It is cooled to about 10°C / hour. In some embodiments, the mixture is cooled to about 10°C / hour. At a rate of approximately 12°C / hour, T 1 From T 2 It is cooled. In a particular embodiment, in the crystallization step (1), the mixture is heated at approximately 10°C / hour for approximately 11 °C / hour, approximately 12°C / hour, approximately 13°C / hour, approximately 14°C / hour, approximately 15°C / hour, approximately 16 Temperatures per hour, approximately 17°C / hour, approximately 18°C / hour, approximately 19°C / hour, or approximately 20°C / hour T 1 From T 2 Cool to a certain degree. In a particular embodiment, in the crystallization step (1), the mixture At a rate of approximately 11°C / hour, T 1 From T 2 Cool it down.

[0111] In a particular embodiment, in the crystallization step (2), the mixture is 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 , hold for at least 7.5 hours, at least 8 hours, at least 8.5 hours, at least 9 hours , hold for at least 9.5 hours, or at least 10 hours. In some embodiments, in crystallization step (2), hold the mixture at T 2 for at least 6 hours. In certain embodiments, in crystallization step (2), hold the mixture at T 2 for 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 some embodiments, in crystallization step (2), hold the mixture at T 2 for 6 hours or less.

[0112] In certain embodiments, in crystallization step (3), T 3 is from about -5°C to about 10°C, from about 0 °C to about 10°C, from about 5°C to about 10°C, from about -5°C to about 5°C, from about -5°C to about 0°C, or from about 0°C to about 5°C. In some embodiments, T 3 is from about -5°C to about 10°C. In some embodiments, T 3 is from about -5°C to about 5°C. In certain embodiments, in crystallization step (3), T 3 is about -5°C, about 0°C, about 5°C , or about 10°C. In some embodiments, in crystallization step (3), T 3 is about 0°C. In certain embodiments, in crystallization step (3), heat the mixture at a rate of about 5°C / hour to about 15°C / hour, about 7°C / hour to about 15°C / hour, about 9°C / hour to about 15°C / hour, about 11°C / hour Between about 15 °C / hour, about 13 °C / hour to about 15 °C / hour, about 5 °C / hour to about 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 °C / hour to about 13 °C / hour, about 7 °C / hour to about 11 °C / hour, about 7 °C / hour ~ about 9 °C / hour, about 9 °C / hour to about 13 °C / hour, about 9 °C / hour to about 11 °C / hour, or at a rate of about 11 °C / hour to about 13 °C / hour from T 2 to T 3 is cooled. In some embodiments in the crystallization step (3), the mixture is cooled from T 2 to T 3 at a rate of about 5 °C / hour to about 15 °C / hour. In some embodiments, in the crystallization step (3), the mixture is about cooled from T to T at a rate of 7 °C / hour to about 13 °C / hour 2 from T 3 to T. In certain embodiments, in the crystallization step (3), the mixture is at about 5 °C / hour, about 6 °C / hour, about 7 °C / hour, about 8 °C / hour, about 9 °C / hour, about 10 °C / hour, about 11 °C / hour, about 12 °C / hour, about 13 °C / hour, about 14 °C / hour, or about 15 °C / hour from T 2 or from T 3 to T. In some embodiments, in the crystallization step (3), the mixture is about 1 cooled from T to T at a rate of 11 °C / hour 2 from T 3 to T.

[0113] In certain embodiments, in the crystallization step (4), the mixture is at T 3 for 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 , hold for at least 9.5 hours, or at least 10 hours. In some embodiments, In the crystallization step (4), the mixture is T 3 Hold for at least 6 hours. In a particular embodiment, in the crystallization step (4), the mixture is T 3 Under 3 hours, 3.5 Less than 4 hours, 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 Hold for 12 hours or less, 16 hours or less, 20 hours or less, or 24 hours or less. In the application method, in the crystallization step (4), the mixture is T 3 Keep it for 10 hours or less.

[0114] In certain embodiments, a mixture comprising the compound of formula (V), ethyl acetate, and water is obtained from formula (V) Crystallizing the compound of formula (V) is necessary to promote the crystallization of the compound of formula (V) through the crystallization process. Before (1), during crystallization step (1), during crystallization step (2), during crystallization step (3) In between, during the crystallization step (4), or in any combination thereof, the mixture or The further method includes seeding with a certain amount of the compound of formula (V) in crystalline form.

[0115] In a particular embodiment, the amount of seed added to the mixture is the amount of the formula produced in step (c) ( Based on the weight of seeds per kilogram of compound IV), approximately 0.001 kg / k g, approx. 0.0012kg / kg, approx. 0.0014kg / kg, approx. 0.0016kg / kg This is approximately 0.0018 kg / kg or approximately 0.002 kg / kg. In some embodiments, The amount of seed added to the mixture is 1 part of the compound of formula (IV) produced in step (c). Based on the weight of the seeds per kilogram, it is approximately 0.0014 kg / kg.

[0116] In certain embodiments, the compound of formula (V) in crystalline form is added to the mixture as a seed. For example, the X-ray powder diffraction pattern or peak(s), and / or the crystalline form of bempedoic acid. The crystalline form of the compound of formula (V) as characterized herein by other characteristic properties It can be an object. In certain embodiments, a mixture comprising the compound of formula (V), ethyl acetate, and water is obtained from formula (V) Crystallizing the compound involves filtering the compound of formula (V). In certain embodiments, the crystalline form of the compound of formula (V) is filtered at approximately -20°C to approximately 5°C, approximately -15℃ to approximately 5℃, approximately -10℃ to approximately 5℃, approximately -5℃ to approximately 5℃, approximately 0℃ to approximately 5℃, approximately -20 ℃ to approximately 0℃, approximately -20℃ to approximately -5℃, approximately -20℃ to approximately -10℃, approximately -20℃ to approximately -15℃ Approximately -15°C to approximately 5°C, approximately -15°C to approximately 0°C, approximately -15°C to approximately -5°C, approximately -15°C to approximately - 10℃, approximately -10℃ to approximately 5℃, approximately -10℃ to approximately 0℃, approximately -10℃ to approximately -5℃, approximately -5℃ to The process is carried out at a temperature of approximately 5°C, approximately -5°C to approximately 0°C, or approximately 0°C to approximately 5°C. In some embodiments, The crystalline form of the compound of formula (V) is filtered at a temperature of approximately -20°C to approximately -5°C. In this embodiment, the crystalline form of the compound of formula (V) is filtered at a temperature of approximately -5°C to approximately 5°C. .

[0117] In certain embodiments, the crystalline form of the compound of formula (V) is filtered at approximately -20°C and approximately -15°C. The process is carried out at temperatures of approximately -10°C, approximately -5°C, approximately 0°C, or approximately 5°C. In some embodiments, the formula is used. The crystalline form of compound (V) is filtered at temperatures of approximately -10°C, approximately -5°C, or approximately 0°C. In certain embodiments, filtration further includes washing. In certain embodiments, washing is performed using formula (V) This involves washing the crystalline form of the compound with a solvent. In some embodiments, the washing is performed using the formula This includes washing the crystalline form of compound (V) with ethyl acetate. In certain embodiments, the temperature of the solvent, for example, ethyl acetate, is about -20°C to about 10°C, about - 10℃ to approximately 10℃, approximately 0℃ to approximately 10℃, approximately -20℃ to approximately 0℃, approximately -20℃ to approximately -10℃, Or it is about -10°C to about 0°C. In some embodiments, the solvent temperature is about -10°C to It is approximately 10°C. In certain embodiments, the temperature of the solvent, for example, ethyl acetate, is about -20°C, about -15°C, about These are -10°C, approximately -5°C, approximately 0°C, approximately 5°C, or approximately 10°C. In some embodiments, The solvent temperature is approximately 0°C.

[0118] In various embodiments, a mixture containing a compound of formula (V), ethyl acetate and water is obtained from formula ( Crystallizing compound V) is (1) The mixture is heated to a first temperature (T 1 ) from the second temperature (T 2 ) means cooling to that extent , T 1 The temperature is approximately 50°C, 2 The temperature is approximately 22°C, and the mixture is heated at a rate of approximately 11°C / hour. 1 From T 2 To cool down; (2) Compound (V) of formula T 2 Hold for at least 6 hours; (3) Compound (V) of formula T 2 From the third temperature (T 3 ) is cooled to T 3but The temperature is approximately 0°C, and the mixture is heated at a rate of approximately 11°C / hour. 2 From T 3 To cool to; and (4) Compound of formula (V) T 3 This includes holding it for at least 6 hours, This generates the crystalline form of the compound of formula (V).

[0119] Conditions (e.g., temperature), time, for crystallizing the compound of formula (V) described herein. Seeding, quantity, compound, and other parameters and / or variables are as specified unless otherwise stated. or unless understood from the context (for example, the condition or parameter is as explained above). If the value is outside the range of the crystallization process, it immediately becomes equivalent to the crystallization process described above. Please understand that it may be applicable.

[0120] In certain embodiments, crystals produced by any of the crystallization methods described herein Compounds of form (V) are, for example, X-ray powder diffraction patterns or peaks(s), and / Or, as characterized herein by other characteristic properties of bempedoic acid in its crystalline form. It may be a compound with the crystalline form of formula (V).

[0121] In certain embodiments, the formula produced by any of the crystallization methods described herein is The purity of the crystalline form of compound (V) is determined by weight, based on the total weight of the crystalline form of compound (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 It is greater than %, approximately greater than 99.95%, or approximately greater than 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) is performed in crystalline form. A pharmaceutical product comprising one or more recrystallizations of the compound of formula (V) and a purified amount of the compound of formula (V). We provide the materials.

[0123] In certain embodiments, one or more recrystallizations of the crystalline form of the compound of formula (V) are as follows: (1) Dissolve the crystalline compound of formula (V) in one or more solvents to form a mixture. To do; (2) The mixture is heated to a first temperature (T 1 ) from the second temperature (T 2 ) means cooling to that extent , T 1 The temperature range is approximately 40°C to 65°C, 2 The temperature is approximately 20°C to 40°C, and the mixture is heated for approximately 3 At a rate of approximately 11°C / hour, T 1 From T 2 To cool down; (3) Add the mixture to T 2 Hold for at least 0.5 hours; (4) T 2 From the third temperature (T 3 ) may be heated to this extent, T 3 about 30 The temperature is between ℃ and approximately 50℃, and the mixture is heated at a rate of approximately 3℃ / hour to approximately 11℃ / hour. 2 From T 3 Ma To heat; (5) Add the mixture to T 3 Hold for at least 0.5 hours; (6) T 3 From the fourth temperature (T 4 ) means cooling down to T 4 about 2 The temperature range is 5°C to approximately 40°C, and the mixture is heated at a rate of approximately 3°C / hour to approximately 11°C / hour. 3 From T 4 Cool to this extent; (7) Add the mixture to T 4 Hold for at least 0.5 hours; (8) T 4 From the 5th temperature (T 5 ) means cooling down to T 5 Approximately - The temperature is 10°C to approximately 10°C, and the mixture is T 4 From T 5 From approximately 3°C / hour to approximately 11°C / hour Cooling at a rate; and (9) Add the mixture to T 5 This includes holding it for at least 0.5 hours, This process produces a pharmaceutical material containing the compound of formula (V) in a purified crystalline form.

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

[0125] In a particular embodiment, in the recrystallization step (1), the amount of ethyl acetate in the mixture is given by formula Based on the weight of ethyl acetate per kilogram of the crystalline compound (V), approximately 2.5k 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 The concentration is approximately g / kg to 2.9 kg / kg, or approximately 2.9 kg / kg to 3.1 kg / kg. In some embodiments, in the recrystallization step (1), the amount of ethyl acetate in the mixture is Based on the weight of ethyl acetate per kilogram of the crystalline compound of formula (V), approximately 2.5k The concentration is approximately g / kg to 3.3 kg / kg. In some embodiments, the recrystallization step (1) In this mixture, the amount of ethyl acetate is equal to the amount of acetic acid per kilogram of the crystalline compound of formula (V). Based on the weight of ethyl acid, the concentration is approximately 2.7 kg / kg to 3.1 kg / kg.

[0126] In a particular embodiment, in the recrystallization step (1), the amount of ethyl acetate in the mixture is given by formula Based on the weight of ethyl acetate per kilogram of the crystalline compound (V), approximately 2.5 kg / kg, approximately 2.7kg / kg, approximately 2.9kg / kg, approximately 3.1kg / kg, or approximately 3.3 It is kg / kg. In some embodiments, in the recrystallization step (1), the mixture The amount of ethyl acetate is based on the weight of ethyl acetate per kilogram of the crystalline compound of formula (V). Therefore, it is approximately 2.9 kg / kg.

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

[0128] In certain embodiments, in the recrystallization step (2), the mixture is heated to approximately 3°C / hour to approximately 11°C / hour. °C / hour, approximately 5°C / hour to approximately 11°C / hour, approximately 7°C / hour to approximately 11°C / hour, approximately 9°C / hour Interval ~ approx. 11°C / hour, approx. 3°C / hour ~ approx. 9°C / hour, approx. 3°C / hour ~ approx. 7°C / hour, approx. 3 °C / hour ~ approximately 5°C / hour, approximately 5°C / hour ~ approximately 9°C / hour, approximately 5°C / hour ~ approximately 7°C / hour, Or at a rate of approximately 7°C / hour to approximately 9°C / hour 1 From T 2 To cool. Several embodiments Then, in the recrystallization step (2), the mixture is heated at a rate of approximately 3°C / hour to approximately 11°C / hour. 1 From T 2 Cool to the desired temperature. In some embodiments, in the recrystallization step (2), the mixture At a rate of approximately 5°C / hour to approximately 7°C / hour, T 1 From T2 Cool it down. In a particular embodiment, in the recrystallization step (2), the mixture is heated at approximately 3°C / hour and approximately 4°C. / hour, approximately 5°C / hour, approximately 6°C / hour, approximately 7°C / hour, approximately 8°C / hour, approximately 9°C / hour, approximately At a rate of 10°C / hour, or approximately 11°C / hour, T 1 From T 2 To cool. Several implementations In this state, in the recrystallization step (2), the mixture is heated at approximately 5°C / hour, approximately 6°C / hour, or approximately 7°C. / time at a speed of T 1 From T 2 Cool it down.

[0129] In a particular embodiment, in the recrystallization step (3), the mixture is T 2 at least 1 o'clock Intervals: 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours Interval, 5.5 hours, 6 hours, 6.5 hours, at least 7 hours, at least 7.5 hours, less At least 8 hours, at least 8.5 hours, at least 9 hours, at least 9.5 hours, or Hold for at least 10 hours. In some embodiments, in the recrystallization step (3), T the mixture 2 Hold for at least 2 hours. In a particular embodiment, in the recrystallization step (3), the mixture is T 2 Less than 1 hour, 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 Hold for less than 20 hours, less than 24 hours, or less. In some embodiments, recrystallization In step (3), the mixture is T 2 Keep it for 2 hours or less.

[0130] In a particular embodiment, in the recrystallization step (4), T 3 It is approximately 30℃ to approximately 50℃, 35℃ to approximately 50℃, approximately 40℃ to approximately 50℃, approximately 45℃ to approximately 50℃, approximately 30℃ to approximately 45℃, approximately 30℃~about 40℃, about 30℃~about 35℃, about 35℃~about 45℃, about 35℃~about 40℃, or The temperature is approximately 40°C to approximately 45°C. In some embodiments, in the recrystallization step (4), T 3 The temperature is approximately 30°C to approximately 50°C. In some embodiments, the recrystallization step (4) is performed T 3 The temperature is approximately 35°C to 45°C. In a particular embodiment, in the recrystallization step (4), T 3 It is approximately 30℃, approximately 35℃, approximately The temperature is 40°C, approximately 45°C, or approximately 50°C. In some embodiments, a recrystallization step (4) In T 3 The temperature is approximately 40°C. In certain embodiments, in the recrystallization step (4), the mixture is heated to approximately 3°C / hour to approximately 11°C / hour. °C / hour, approximately 5°C / hour to approximately 11°C / hour, approximately 7°C / hour to approximately 11°C / hour, approximately 9°C / hour Interval ~ approx. 11°C / hour, approx. 3°C / hour ~ approx. 9°C / hour, approx. 3°C / hour ~ approx. 7°C / hour, approx. 3 °C / hour ~ approximately 5°C / hour, approximately 5°C / hour ~ approximately 9°C / hour, approximately 5°C / hour ~ approximately 7°C / hour, Or at a rate of approximately 7°C / hour to approximately 9°C / hour 2 From T 3 Heat to a certain extent. Several embodiments Then, in the recrystallization step (4), the mixture is heated at a rate of approximately 3°C / hour to approximately 11°C / hour. 2 From T 3 Heat to the following. In some embodiments, in the recrystallization step (4), the mixture At a rate of approximately 5°C / hour to approximately 7°C / hour, T 2 From T 3 Heat it up.

[0131] In a particular embodiment, in the recrystallization step (4), the mixture is heated at approximately 3°C / hour and approximately 4°C. / hour, approximately 5°C / hour, approximately 6°C / hour, approximately 7°C / hour, approximately 8°C / hour, approximately 9°C / hour, approximately At a rate of 10°C / hour, or approximately 11°C / hour, T 2 From T 3 To heat. Several implementation forms In this state, in the recrystallization step (4), the mixture is heated at approximately 5°C / hour, approximately 6°C / hour, or approximately 7°C. / time at a speed of T 2 From T 3 Heat it up. In a particular embodiment, in the recrystallization step (5), the mixture is T 3 at least 1 o'clock Intervals: 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours Interval, 5.5 hours, 6 hours, 6.5 hours, at least 7 hours, at least 7.5 hours, less At least 8 hours, at least 8.5 hours, at least 9 hours, at least 9.5 hours, or Hold for at least 10 hours. In some embodiments, in the recrystallization step (5), T the mixture 3 Hold for at least one hour. In a particular embodiment, in the recrystallization step (5), the mixture is T 3 Less than 1 hour, 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 Hold for less than 20 hours, less than 24 hours, or less than 24 hours.

[0132] In a particular embodiment, in the recrystallization step (6), T 4 It is approximately 25℃ to approximately 40℃, 30℃~about 40℃, about 35℃~about 40℃, about 25℃~about 35℃, about 25℃~about 30℃, or The temperature is approximately 30°C to approximately 35°C. In some embodiments, in the recrystallization step (6), T 4 The temperature range is approximately 25°C to 40°C. In some embodiments, the recrystallization step (6) is performed T 4 The temperature is approximately 30°C to 40°C. In a particular embodiment, in the recrystallization step (6), T 4 It is approximately 25℃, approximately 30℃, approximately The temperature is 35°C or approximately 40°C. In some embodiments, in the recrystallization step (6), T 4 The temperature is approximately 35°C. In certain embodiments, in the recrystallization step (6), the mixture is heated to approximately 3°C / hour to approximately 11°C / hour. °C / hour, approximately 5°C / hour to approximately 11°C / hour, approximately 7°C / hour to approximately 11°C / hour, approximately 9°C / hour Interval ~ approx. 11°C / hour, approx. 3°C / hour ~ approx. 9°C / hour, approx. 3°C / hour ~ approx. 7°C / hour, approx. 3 °C / hour ~ approximately 5°C / hour, approximately 5°C / hour ~ approximately 9°C / hour, approximately 5°C / hour ~ approximately 7°C / hour, Or at a rate of approximately 7°C / hour to approximately 9°C / hour 3 From T 4 To cool. Several embodiments Then, in the recrystallization step (6), the mixture is heated at a rate of approximately 3°C / hour to approximately 11°C / hour. 3 From T 4 Cool to the desired temperature. In some embodiments, in the recrystallization step (6), the mixture At a rate of approximately 5°C / hour to approximately 7°C / hour, T 3 From T 4 Cool it down. In a particular embodiment, in the recrystallization step (6), the mixture is heated at approximately 3°C / hour and approximately 4°C. / hour, approximately 5°C / hour, approximately 6°C / hour, approximately 7°C / hour, approximately 8°C / hour, approximately 9°C / hour, approximately At a rate of 10°C / hour, or approximately 11°C / hour, T 3 From T 4 To cool. Several implementations In this state, in the recrystallization step (6), the mixture is heated at approximately 5°C / hour, approximately 6°C / hour, or approximately 7°C. / time at a speed of T 3 From T 4 Cool it down.

[0133] In a particular embodiment, in the recrystallization step (7), the mixture is T 4 at least 1 o'clock Intervals: 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours Interval, 5.5 hours, 6 hours, 6.5 hours, at least 7 hours, at least 7.5 hours, less At least 8 hours, at least 8.5 hours, at least 9 hours, at least 9.5 hours, or Hold for at least 10 hours. In some embodiments, in the recrystallization step (7), T the mixture 4 Hold for at least 2 hours. In a particular embodiment, in the recrystallization step (7), the mixture is T 4 Less than 1 hour, 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 Hold for less than 20 hours, less than 24 hours, or less than 24 hours.

[0134] In a particular embodiment, in the recrystallization step (8), T 5 It is approximately -10℃ to approximately 10℃. Approximately -5°C to approximately 10°C, approximately 0°C to approximately 10°C, approximately 5°C to approximately 10°C, approximately -10°C to approximately 5°C, approximately - 10℃ to approximately 0℃, approximately -10℃ to approximately -5℃, approximately -5℃ to approximately 5℃, approximately -5℃ to approximately 0℃, or approximately The temperature range is 0°C to approximately 5°C. In some embodiments, in the recrystallization step (8), T 5 Approximately The temperature range is -10°C to approximately 10°C. In some embodiments, in the recrystallization step (8), T 5 The temperature range is approximately 0°C to 10°C. In a particular embodiment, in the recrystallization step (8), T 5 It is approximately -10℃, approximately -5℃, The temperature is approximately 0°C, approximately 5°C, or approximately 10°C. In some embodiments, the recrystallization step (8) T 5 The temperature is approximately 5°C. In certain embodiments, in the recrystallization step (8), the mixture is heated to approximately 3°C / hour to approximately 11°C / hour. °C / hour, approximately 5°C / hour to approximately 11°C / hour, approximately 7°C / hour to approximately 11°C / hour, approximately 9°C / hour Interval ~ approx. 11°C / hour, approx. 3°C / hour ~ approx. 9°C / hour, approx. 3°C / hour ~ approx. 7°C / hour, approx. 3 °C / hour ~ approximately 5°C / hour, approximately 5°C / hour ~ approximately 9°C / hour, approximately 5°C / hour ~ approximately 7°C / hour, Or at a rate of approximately 7°C / hour to approximately 9°C / hour 4 From T 5 To cool. Several embodiments Then, in the recrystallization step (8), the mixture is heated at a rate of approximately 3°C / hour to approximately 11°C / hour. 4 From T 5 Cool to the desired temperature. In some embodiments, in the recrystallization step (8), the mixture At a rate of approximately 5°C / hour to approximately 7°C / hour, T 4 From T 5 Cool it down. In a particular embodiment, in the recrystallization step (8), the mixture is heated at approximately 3°C / hour and approximately 4°C. / hour, approximately 5°C / hour, approximately 6°C / hour, approximately 7°C / hour, approximately 8°C / hour, approximately 9°C / hour, approximately At a rate of 10°C / hour, or approximately 11°C / hour, T 4 From T 5 To cool. Several implementations In this state, in the recrystallization step (8), the mixture is heated at approximately 5°C / hour, approximately 6°C / hour, or approximately 7°C. / time at a speed of T 4 From T 5 Cool it down.

[0135] In a particular embodiment, in the recrystallization step (9), the mixture is T 5 at least 1 o'clock Intervals: 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours Interval, 5.5 hours, 6 hours, 6.5 hours, at least 7 hours, at least 7.5 hours, less At least 8 hours, at least 8.5 hours, at least 9 hours, at least 9.5 hours, or Hold for at least 10 hours. In some embodiments, in the recrystallization step (9), T the mixture 5 Hold for at least 4 hours. In a particular embodiment, in the recrystallization step (9), the mixture is T 5 Less than 1 hour, 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 Hold for less than 20 hours, less than 24 hours, or less than 24 hours.

[0136] In certain embodiments, recrystallizing the compound of formula (V) is performed on the compound of formula (V). To promote crystallization, before the recrystallization step (2), and during the recrystallization step (2), During the chemical process (3), during the recrystallization process (4), during the recrystallization process (5), recrystallization During process (6), during recrystallization process (7), during recrystallization process (8), recrystallization process During step (9), or in any combination thereof, a certain amount of formula (V) of the mixture This further includes seeding with the crystalline form of the compound. Conditions (e.g., temperature), time, for crystallizing the compound of formula (V) described herein. Seeding, quantity, compound, and other parameters and / or variables are as specified unless otherwise stated. Unless otherwise understood from the context, or as described below, the compound of formula (V) It should be understood that this may be equally applicable to recrystallization.

[0137] For example, in a particular embodiment, the recrystallization of the compound of formula (V) is performed on the compound of formula (V). This includes filtration of the crystalline form. In certain embodiments, filtration of the crystalline form of the compound of formula (V) is about - 20℃ to approximately 15℃, approximately -15℃ to approximately 15℃, approximately -10℃ to approximately 15℃, approximately -5℃ to approximately 15℃ Approximately 0°C to 15°C, approximately 5°C to 15°C, approximately 10°C to 15°C, approximately -20°C to 10°C. Approximately -20°C to approximately 5°C, approximately -20°C to approximately 0°C, approximately -20°C to approximately -5°C, approximately -20°C to approximately -1°C 0℃, approximately -20℃ to approximately -15℃, approximately -15℃ to approximately 10℃, approximately -15℃ to approximately 5℃, approximately -15 ℃ to approximately 0℃, approximately -15℃ to approximately -5℃, approximately -15℃ to approximately -10℃, approximately -10℃ to approximately 10℃, Approximately -10°C to 5°C, approximately -10°C to 0°C, approximately -10°C to -5°C, approximately -5°C to 10°C Approximately -5°C to 5°C, approximately -5°C to 0°C, approximately 0°C to 10°C, approximately 0°C to 5°C, or approximately 5 The process is carried out at a temperature of ℃ to approximately 10℃. In some embodiments, the crystalline form of the compound of formula (V) is used. The filtration is carried out at a temperature of approximately 0°C to 15°C.

[0138] In certain embodiments, filtration of the crystalline form of the compound of formula (V) is performed at approximately -20°C and approximately -15°C. The process is carried out at temperatures of approximately -10°C, -5°C, 0°C, 5°C, 10°C, or 15°C. In some embodiments, the filtration of the crystalline form of the compound of formula (V) is performed at approximately 0°C, approximately 5°C, and approximately 10°C. It is carried out at a temperature of ℃ or approximately 15℃. In certain embodiments, filtration further includes washing. In certain embodiments, washing is performed using formula (V) This involves washing the crystalline form of the compound with a solvent. In some embodiments, the washing is performed using the formula This includes washing the crystalline form of compound (V) with acetonitrile.

[0139] In certain embodiments, the recrystallization of the compound of formula (V) is performed by mixing by centrifugation. This includes isolating the crystalline form of the compound of formula (V) from a substance.

[0140] In certain embodiments, isolation of the crystalline form of the compound of formula (V) by centrifugation is further washed. It is included in. In certain embodiments, washing involves washing the crystalline form of the compound of formula (V) with a solvent. This includes. In some embodiments, washing is performed to remove the crystalline form of the compound of formula (V) from the acetonite. This includes washing with a lil. In certain embodiments, the temperature of the solvent, for example, acetonitrile, is approximately -20°C to approximately 30°C. Approximately -10°C to 30°C, approximately 0°C to 30°C, approximately 10°C to 30°C, approximately -20°C to 20°C Approximately -20°C to approximately 10°C, approximately -20°C to approximately 0°C, approximately -20°C to approximately -10°C, approximately -10°C to Approximately 20°C, approximately -10°C to approximately 10°C, approximately -10°C to approximately 0°C, approximately 0°C to approximately 20°C, approximately 0°C to approximately The temperature is 10°C, or approximately 10°C to approximately 20°C. In some embodiments, the solvent temperature is approximately 1 The temperature range is from 0°C to approximately 30°C.

[0141] In certain embodiments, the temperature of the solvent, for example, acetonitrile, is approximately -20°C, approximately -10°C. The temperature is approximately 0°C, approximately 10°C, approximately 20°C, or approximately 30°C. In some embodiments, the solvent The temperature is approximately 20°C. In certain embodiments, recrystallization of the compound of formula (V) includes drying. In certain embodiments, drying is performed at temperatures below approximately 85°C and approximately 75°C for compounds of formula (V) in crystalline form. Below approximately 65°C, below approximately 55°C, below approximately 45°C, below approximately 35°C, or below approximately 25°C This includes heating to a temperature. In some embodiments, the drying step involves the compound of formula (V). This includes heating the crystalline form to a temperature of less than approximately 85°C. In some embodiments, the drying process The process involves heating the crystalline form of the compound of formula (V) to a temperature of less than approximately 45°C. In certain embodiments, one or more recrystallizations of the crystalline form of the compound of formula (V) are performed as follows: This includes 3, 4, 5, 6, 7, 8, 9, or 10 recrystallization steps.

[0142] In certain embodiments, one or more recrystallizations of the crystalline form of the compound of formula (V) are as follows: (1) Dissolve the crystalline compound of formula (V) in one or more solvents containing ethyl acetate and water, To form a mixture thereafter; (2) The mixture is heated to a first temperature (T 1 ) from the second temperature (T 2 ) means cooling to that extent , T 1 The temperature is approximately 55°C, 2 The temperature is approximately 30°C, and the mixture is cooled at approximately 5°C / hour to approximately 7°C / hour. At a speed of T 1 From T 2 To cool down; (3) Compound (V) of formula T 2 Hold for at least 2 hours; (4) T 2 From the third temperature (T 3 ) means heating until T 3 about 4 The temperature is 0°C, and the mixture is heated at a rate of approximately 5°C / hour to approximately 7°C / hour. 2 From T 3 Heat until thing; (5) Add the mixture to T 3 Hold for at least one hour; (6) T 3 From the fourth temperature (T 4 ) means cooling down to T 4 approximately 3 The temperature is 5°C, and the mixture is heated at a rate of approximately 5°C / hour to approximately 7°C / hour. 3 From T 4 Cool until thing; (7) Add the mixture to T 4 Hold for at least 2 hours; (8) T 4 From the 5th temperature (T 5 ) means cooling down to T 5 about 5 The temperature is °C, and the mixture is heated at a rate of approximately 5°C / hour to approximately 7°C / hour. 4 From T 5 Cool it down to and; (9) Add the mixture to T 5 This includes holding it for at least 4 hours, This process produces a pharmaceutical material containing the compound of formula (V) in a purified crystalline form.

[0143] Conditions for crystallizing and / or recrystallizing the compound of formula (V) described herein (e.g.) If, then, temperature, time, seeding, quantity, compound, and other parameters and / or variables are Unless otherwise specified or understood from the context (for example, conditions or parameters are (, if the value is outside the range in the recrystallization process described above), immediately re... It should be understood that this may be equally applicable to the crystallization process.

[0144] In certain embodiments, pharmaceuticals produced by any of the crystallization methods described herein Compounds of formula (V) in the material have a crystalline form, for example, that can be identified by their X-ray powder diffraction pattern or peaks (multiple peaks). (possible), and / or other characteristic properties of bempedoic acid in crystalline form as described herein. It may be a compound of formula (V) with a crystalline form that determines its properties. In various embodiments, the purified amount of the compound of formula (V) in the pharmaceutical material is, by weight, Over 99.0% of the total weight of the medicinal materials, approximately over 99.1%, approximately over 99.2%, approximately over 99.3%, approximately 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 It is over 99.85%, approximately over 99.9%, approximately over 99.95%, or approximately over 99.98%. In some embodiments, the purified amount of the compound of formula (V) in the pharmaceutical material is equal to the total weight of the pharmaceutical material. It is more than 99.0% by weight. In some embodiments, the amount of purified material in the pharmaceutical material is expressed in formula (V) The compound is more than 99.5% by weight of the total weight of the pharmaceutical material. In some embodiments, the pharmaceutical The amount of the compound of formula (V) in the purified material is over 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 equal to the total weight of the pharmaceutical material. This is over 99.85% by weight.

[0145] In certain embodiments, the compound of formula (V) in a crystalline form provides a recrystallized compound of formula (V). After recrystallizing the material, the method involves contacting the recrystallized compound of formula (V) with charcoal, and The process involves 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 is performed on the compound of formula (V). Contact with a solution containing acetonitrile and activated carbon (e.g., 5% (by weight / by weight) activated carbon). This includes causing someone to do something.

[0146] In certain embodiments, batches of bempedoic acid are prepared using the method described herein. It is possible to prepare a batch of pharmaceutical materials using the method described herein. In certain embodiments, the method described herein is used to prepare a batch of pharmaceutical materials. It can be used to manufacture pharmaceutical materials containing the compound of formula (V) in a purified amount. In this embodiment, the purified amount of the compound of formula (V) or a pharmaceutically acceptable salt thereof is a pharmaceutical material. It exceeds 99.0% of the total weight of the ingredients. In certain embodiments, batches are approximately 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 quantity is 0 kg, 800 kg, 900 kg, or 1000 kg.

[0147] IV. High-purity compositions of bempedoic acid As described herein, in one embodiment, the present invention relates to bempedoic acid, for example, in crystalline form. The present invention provides a pharmaceutical material containing bempedoic acid or a pharmaceutically acceptable salt thereof. In various embodiments, the pharmaceutical material is generally a compound of formula (V): TIFF2026102795000049.tif18160 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical material is based on the total weight of the pharmaceutical material. It contains more than 99.0% by weight of the compound of formula (V) or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of compound of formula (V) in the pharmaceutical material is, on a weight basis, the pharmaceutical Approximately 99.1% or more of the total weight of the materials, approximately 99.2% or more, approximately 99.3% or more, approximately 99.4% or more More than 99.5%, more than about 99.6%, more than about 99.7%, more than about 99.8%, more than about 99.85%, This is approximately over 99.9%, approximately over 99.95%, or approximately over 99.98%. (Several embodiments) Therefore, the amount of pharmaceutical material exceeding 99.5% by weight is calculated using formula (V) based on the total weight of the pharmaceutical material. It contains the compound. In some embodiments, the pharmaceutical material is based on the total weight of the pharmaceutical material. It contains more than 99.7% by weight of the compound of formula (V). In some embodiments, it is a pharmaceutical material. The material contains more than 99.9% by weight of the compound of formula (V) based on the total weight of the pharmaceutical materials. nothing.

[0148] In certain embodiments, pharmaceutical materials are subjected to high-performance liquid chromatography (HPLC) assays. When determined by, based on the total weight of the pharmaceutical material (anhydrous solvent-free system), approximately 98% to approximately It contains 102% by weight of the compound of formula (V). In certain embodiments, the HPLC assay includes one or more of the following: (i) Waters XBridge BEH C18 column (4.6mm inner diameter x 15 0 mm, 2.5 μm); (ii) Column temperature of approximately 40°C; (iii) Mobile phase containing approximately 0.05% phosphoric acid in water / acetonitrile (approximately 50:50) ; (iv) isocratic elution; (v) Flow rate of approximately 1.2 mL / min; (vi) Sample temperature at ambient temperature; (vii) Detection at 215nm; and (viii) The retention time of the compound of formula (V) is approximately 4.6 minutes. In some embodiments, the HPLC assay is performed according to each of the above, i.e., (i)~( Includes (viii) In certain embodiments, the crystalline form of the compound of formula (V) is, for example, an X-ray powder diffraction pattern or The peak(s) and / or other characteristic properties of bempedoic acid in its crystalline form are evident. It may be a compound of formula (V) in which the crystalline form is characterized in detail.

[0149] In certain embodiments, the pharmaceutical material described herein is a compound of formula (VI): May contain TIFF2026102795000050.tif18160 or a pharmaceutically acceptable salt thereof. Compound of formula (VI) or a pharmaceutically acceptable salt thereof Tolerable salts are also referred to as "diol impurities" in this specification. In certain embodiments, the amount of diol impurities in the pharmaceutical material is based on the total weight of the pharmaceutical material. Based on weight, approximately 0.15%, 0.125%, 0.1%, 0.075%, and 0.0 5%, approximately 0.025%, approximately 0.01%, approximately 0.001%, or less than approximately 0.0001% In some embodiments, the amount of diol impurities in the pharmaceutical material is based on the total weight of the pharmaceutical material. Therefore, it is less than approximately 1.25% by weight. In some embodiments, diols in pharmaceutical materials The amount of impurities is less than approximately 0.15% by weight, based on the total weight of the pharmaceutical material. In this embodiment, the amount of diol impurities in the pharmaceutical material is approximately 0 based on the total weight of the pharmaceutical material. It is less than 0.1% by weight. In certain embodiments, the pharmaceutical material is approximately 0.1 by weight, based on the total weight of the pharmaceutical material. 5%, approximately 0.125%, approximately 0.1%, approximately 0.075%, approximately 0.05%, approximately 0.025%, Compounds of formula (VI) or less in amounts of approximately 0.01%, approximately 0.001%, or approximately 0.0001% or less. It contains a pharmaceutically acceptable salt of the pharmaceutical material. In some embodiments, the pharmaceutical material is the total of the pharmaceutical material. Based on weight, an amount of the compound of formula (VI) or its pharmaceutically acceptable substance of a certain type of compound of the same type in an amount of approximately 0.125% by weight or less. Contains a tolerable salt. In some embodiments, the pharmaceutical material is based on the total weight of the pharmaceutical material. Then, an amount of approximately 0.15% by weight or less of the compound of formula (VI) or a pharmaceutically acceptable salt thereof is used. Includes. In some embodiments, the pharmaceutical material is approximately 0.1 times the total weight of the pharmaceutical material. It contains an amount of the compound of formula (VI) or a pharmaceutically acceptable salt thereof in an amount of % or less. In certain embodiments, the amount of diol impurities in the pharmaceutical material is based on the total weight of the pharmaceutical material. Based on weight, approximately 0.0001% to approximately 0.15%, approximately 0.001% to approximately 0.15%, approximately 0.01% to approximately 0.15%, approximately 0.025% to approximately 0.15%, approximately 0.05% to approximately 0.15 %, approximately 0.075% to approximately 0.15%, approximately 0.1% to approximately 0.15%, approximately 0.125% to approximately 0 0.15%, approximately 0.01% to approximately 0.125%, approximately 0.01% to approximately 0.1%, approximately 0.01% Approximately 0.075%, approximately 0.01% to approximately 0.05%, approximately 0.01% to approximately 0.025%, approximately 0. 0.25% to approximately 0.125%, approximately 0.025% to approximately 0.1%, approximately 0.025% to approximately 0.07% 5%, approximately 0.025%~, approximately 0.05%, approximately 0.05%, approximately 0.125%, approximately 0.05%~ Approximately 0.1%, approximately 0.05% to approximately 0.075%, approximately 0.075% to approximately 0.125%, approximately 0. It is approximately 0.75% to 0.1%, or approximately 0.1% to 0.125%. In some embodiments, The amount of diol impurities in pharmaceutical materials is approximately 0.01% based on the total weight of the pharmaceutical materials. It is approximately 0.15% by weight. In some embodiments, the amount of diol impurities in the pharmaceutical material is Based on the total weight of the pharmaceutical materials, this is approximately 0.01% to approximately 0.1% by weight.

[0150] In certain embodiments, the pharmaceutical material described herein is a compound of formula (VII): May contain TIFF2026102795000051.tif18160 or a pharmaceutically acceptable salt thereof. Compound of formula (VII) or pharmaceutically acceptable thereof Acceptable salts are also referred to as "ketone impurities" in this specification. In certain embodiments, the amount of ketone impurities in the pharmaceutical material is based on the total weight of the pharmaceutical material. Based on weight, approximately 0.15%, 0.125%, 0.1%, 0.075%, and 0.05%. This is approximately 0.025%, approximately 0.01%, approximately 0.001%, or less than approximately 0.0001%. In certain embodiments, the amount of ketone impurities in the pharmaceutical material is determined based on the total weight of the pharmaceutical material. It is less than approximately 0.15% by weight. In certain embodiments, the amount of ketone impurities in the pharmaceutical material is Based on the total weight of the pharmaceutical materials, it is less than approximately 0.05% by weight. In certain embodiments, the pharmaceutical material is approximately 0.1 by weight, based on the total weight of the pharmaceutical material. 5%, approximately 0.125%, approximately 0.1%, approximately 0.075%, approximately 0.05%, approximately 0.025%, Compounds of formula (VII) in amounts of approximately 0.01%, approximately 0.001%, or approximately 0.0001% or less. It contains a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical material is a pharmaceutical material Based on the total weight, an amount of formula (VII) or its pharmaceutically acceptable amount of approximately 0.15% by weight or less. Contains acceptable salts. In some embodiments, the pharmaceutical material is based on the total weight of the pharmaceutical material. Furthermore, a compound of formula (VII) or its pharmaceutically acceptable amount in an amount of approximately 0.05% by weight or less. Contains salt. In certain embodiments, the amount of ketone impurities in the pharmaceutical material is based on the total weight of the pharmaceutical material. Based on weight, approximately 0.0001% to 0.15%, approximately 0.001% to 0.15%, and approximately 0. 0.01% to approximately 0.15%, approximately 0.025% to approximately 0.15%, approximately 0.05% to approximately 0.15%, Approximately 0.075% to approximately 0.15%, approximately 0.1% to approximately 0.15%, approximately 0.125% to approximately 0.1 5%, approximately 0.01% to approximately 0.125%, approximately 0.01% to approximately 0.1%, approximately 0.01% to approximately 0 0.075%, approximately 0.01% to approximately 0.05%, approximately 0.01% to approximately 0.025%, approximately 0.02 5% to approximately 0.125%, approximately 0.025% to approximately 0.1%, approximately 0.025% to approximately 0.075% Approximately 0.025% to approximately 0.05%, approximately 0.05% to approximately 0.125%, approximately 0.05% to approximately 0 0.1%, approximately 0.05% to approximately 0.075%, approximately 0.075% to approximately 0.125%, approximately 0.07 It is 5% to about 0.1%, or about 0.1% to about 0.125%. In some embodiments, The amount of ketone impurities in pharmaceutical materials is approximately 0.01% to 0% based on the total weight of the pharmaceutical material. It is 15% by weight. In some embodiments, the amount of ketone impurities in the pharmaceutical material is Based on the total weight of the ingredients, this is approximately 0.01% to 0.05% by weight.

[0151] In certain embodiments, the pharmaceutical material described herein is a compound of formula (VIII): May contain TIFF2026102795000052.tif28160 or a pharmaceutically acceptable salt thereof. Compound of formula (VIII) or its pharmaceutically acceptable Salts that may be tolerated are also referred to herein as "acetone impurities." In certain embodiments, the amount of acetone impurities in the pharmaceutical material is based on the total weight of the pharmaceutical material. Based on weight, approximately 0.15%, 0.125%, 0.1%, 0.075%, and 0.0 5%, approximately 0.025%, approximately 0.01%, approximately 0.001%, or less than approximately 0.0001% . In certain embodiments, the pharmaceutical material is approximately 0.1 by weight, based on the total weight of the pharmaceutical material. 5%, approximately 0.125%, approximately 0.1%, approximately 0.075%, approximately 0.05%, approximately 0.025%, Compounds of formula (VIII) in amounts of approximately 0.01%, approximately 0.001%, or approximately 0.0001% or less. It contains its pharmaceutically acceptable salt. In certain embodiments, the amount of acetone impurities in the pharmaceutical material is based on the total weight of the pharmaceutical material. Based on weight, approximately 0.0001% to approximately 0.15%, approximately 0.001% to approximately 0.15%, approximately 0 0.01% to approximately 0.15%, approximately 0.025% to approximately 0.15%, approximately 0.05% to approximately 0.15% Approximately 0.075% to 0.15%, approximately 0.1% to 0.15%, and approximately 0.125% to 0. 15%, approximately 0.01% to approximately 0.125%, approximately 0.01% to approximately 0.1%, approximately 0.01% to approximately 0.075%, approximately 0.01% to approximately 0.05%, approximately 0.01% to approximately 0.025%, approximately 0.0 25% to approximately 0.125%, approximately 0.025% to approximately 0.1%, approximately 0.025% to approximately 0.075% %, approximately 0.025% to approximately 0.05%, approximately 0.05% to approximately 0.125%, approximately 0.05% to approximately 0.1%, approximately 0.05% to approximately 0.075%, approximately 0.075% to approximately 0.125%, approximately 0.0 It is between 75% and approximately 0.1%, or between approximately 0.1% and approximately 0.125%.

[0152] In certain embodiments, the pharmaceutical material described herein is a compound of formula (IX): May contain TIFF2026102795000053.tif30160 or a pharmaceutically acceptable salt thereof. Compound of formula (IX) or a pharmaceutically acceptable salt thereof Tolerable salts are also referred to as "dimeric impurities" in this specification. In certain embodiments, the amount of dimeric impurities in the pharmaceutical material is based on the total weight of the pharmaceutical material. Based on weight, approximately 0.15%, 0.125%, 0.1%, 0.075%, and 0.05%. This is approximately 0.025%, approximately 0.01%, approximately 0.001%, or less than approximately 0.0001%. In certain embodiments, the pharmaceutical material is approximately 0.1 by weight, based on the total weight of the pharmaceutical material. 5%, approximately 0.125%, approximately 0.1%, approximately 0.075%, approximately 0.05%, approximately 0.025%, Compounds of formula (IX) or less in amounts of approximately 0.01%, approximately 0.001%, or approximately 0.0001% or less. Contains pharmaceutically acceptable salts of [the substance]. In certain embodiments, the amount of dimeric impurities in the pharmaceutical material is based on the total weight of the pharmaceutical material. Based on weight, approximately 0.0001% to 0.15%, approximately 0.005% to 0.15%, and approximately 0. 0.01% to approximately 0.15%, approximately 0.025% to approximately 0.15%, approximately 0.05% to approximately 0.15%, Approximately 0.075% to approximately 0.15%, approximately 0.1% to approximately 0.15%, approximately 0.125% to approximately 0.1 5%, approximately 0.01% to approximately 0.125%, approximately 0.01% to approximately 0.1%, approximately 0.01% to approximately 0 0.075%, approximately 0.01% to approximately 0.05%, approximately 0.01% to approximately 0.025%, approximately 0.02 5% to approximately 0.125%, approximately 0.025% to approximately 0.1%, approximately 0.025% to approximately 0.075% Approximately 0.025% to approximately 0.05%, approximately 0.05% to approximately 0.125%, approximately 0.05% to approximately 0 0.1%, approximately 0.05% to approximately 0.075%, approximately 0.075% to approximately 0.125%, approximately 0.07 It is between 5% and approximately 0.1%, or between approximately 0.1% and approximately 0.125%.

[0153] In certain embodiments, the pharmaceutical material described herein is a compound of formula (X): May contain TIFF2026102795000054.tif29160 or a pharmaceutically acceptable salt thereof. Compound of formula (X) or a pharmaceutically acceptable salt thereof The salts that may result are also referred to herein as "monoethyl ester impurities." In certain embodiments, the amount of monoethyl ester impurities in the pharmaceutical material is equal to the total weight of the pharmaceutical material. Based on quantity, approximately 0.15%, 0.125%, 0.1%, and 0.075% by weight. Approximately 0.05%, approximately 0.025%, approximately 0.01%, approximately 0.001%, or approximately 0.0001% It is less than. In certain embodiments, the pharmaceutical material is approximately 0.1 by weight, based on the total weight of the pharmaceutical material. 5%, approximately 0.125%, approximately 0.1%, approximately 0.075%, approximately 0.05%, approximately 0.025%, A compound of formula (X) or less in an amount of approximately 0.01%, approximately 0.001%, or approximately 0.0001% or less. Contains pharmaceutically acceptable salts. In certain embodiments, the amount of monoethyl ester impurities in the pharmaceutical material is equal to the total weight of the pharmaceutical material. Based on quantity, approximately 0.0001% to 0.15% and approximately 0.0005% to 0.0% by weight. 15%, approximately 0.01% to approximately 0.15%, approximately 0.025%, approximately 0.15%, approximately 0.05% Approximately 0.15%, approximately 0.075% to approximately 0.15%, approximately 0.1% to approximately 0.15%, approximately 0.12 5% to approximately 0.15%, approximately 0.01% to approximately 0.125%, approximately 0.01% to approximately 0.1%, approximately 0 0.01% to approximately 0.075%, approximately 0.01% to approximately 0.05%, approximately 0.01% to approximately 0.025% %, approximately 0.025% to approximately 0.125%, approximately 0.025% to approximately 0.1%, approximately 0.025% Approximately 0.075%, approximately 0.025% to approximately 0.05%, approximately 0.05% to approximately 0.125%, approximately 0 0.05% to approximately 0.1%, approximately 0.05% to approximately 0.075%, approximately 0.075% to approximately 0.125% This is approximately 0.075% to 0.1%, or approximately 0.1% to 0.125%.

[0154] In certain embodiments, the pharmaceutical material described herein is a compound of formula (XI) or its pharmaceutical It may contain salts that are generally acceptable. TIFF2026102795000055.tif28160 Compounds of formula (XI) or pharmaceutically acceptable salts thereof are referred to herein as "diethyl E It is also called "terneal impurity." In certain embodiments, the amount of diethyl ester impurities in the pharmaceutical material is equal to the total weight of the pharmaceutical material. Based on weight, approximately 0.15%, approximately 0.125%, approximately 0.1%, and approximately 0.075%. Approximately 0.05%, approximately 0.025%, approximately 0.01%, approximately 0.001%, or approximately 0.0001% It is full. In certain embodiments, the pharmaceutical material is approximately 0.1 by weight, based on the total weight of the pharmaceutical material. 5%, approximately 0.125%, approximately 0.1%, approximately 0.075%, approximately 0.05%, approximately 0.025%, Compounds of formula (XI) or less in amounts of approximately 0.01%, approximately 0.001%, or approximately 0.0001% or less. Contains pharmaceutically acceptable salts of [the substance]. In certain embodiments, the amount of diethyl ester impurities in the pharmaceutical material is equal to the total weight of the pharmaceutical material. Based on this, approximately 0.0001% to approximately 0.15% and approximately 0.0005% to approximately 0.1% by weight. 5%, approximately 0.01% to approximately 0.15%, approximately 0.025% to approximately 0.15%, approximately 0.05% to approximately 0.15%, approximately 0.075% to approximately 0.15%, approximately 0.1% to approximately 0.15%, approximately 0.125 %~approximately 0.15%, approximately 0.01%~approximately 0.125%, approximately 0.01%~approximately 0.1%, approximately 0. 0.01% to approximately 0.075%, approximately 0.01% to approximately 0.05%, approximately 0.01% to approximately 0.025% Approximately 0.025% to approximately 0.125%, approximately 0.025% to approximately 0.1%, approximately 0.025% to approximately 0.075%, approximately 0.025% to approximately 0.05%, approximately 0.05% to approximately 0.125%, approximately 0. 0.5% to approximately 0.1%, approximately 0.05% to approximately 0.075%, approximately 0.075% to approximately 0.125% It is approximately 0.075% to 0.1%, or approximately 0.1% to 0.125%.

[0155] In certain embodiments, the pharmaceutical materials described herein are determined by HPLC. In some cases, impurities with a relative retention time (RRT) of approximately 1.04 to 1.05 may be present. In the application form, the pharmaceutical materials described herein are relative when determined by HPLC. The product may contain impurities with a retention time (RRT) of approximately 1.06 to 1.08. In certain embodiments, The pharmaceutical materials described herein have a relative retention time (determined by HPLC). The RRT may contain impurities of about 1.18 to about 1.20. In certain embodiments, as specified herein. The pharmaceutical materials listed have a relative retention time (RRT) determined by HPLC. It may contain impurities of approximately 1.36. In certain embodiments, the pharmaceutical material described herein is H When determined by PLC, RRT can contain approximately 1.43 impurities. In the embodiments thereof, the pharmaceutical material described herein is determined by HPLC, RR T may contain impurities of approximately 1.86. In certain embodiments, as described herein When the pharmaceutical material is determined by HPLC, the RRT is approximately 1.36 for the first impurity and The RRT may contain a second impurity of about 1.86. In certain embodiments, the impurity The RRT of bempedoic acid is based on the retention time of bempedoic acid, where the RRT of bempedoic acid is approximately 1.0 It is 0. In certain embodiments, the pharmaceutical materials described herein include one or more unspecified impurities. (For example, in pharmaceutical materials where the chemical structure cannot be determined but the RRT is known) It may include (pure substances).

[0156] In certain embodiments, pharmaceutical materials are subjected to high-performance liquid chromatography (HPLC) assays. If determined by the foregoing, it may include one or more impurities as described herein. In certain embodiments, the HPLC assay includes one or more of the following: (i) Waters XBridge BEH C18 column (4.6mm inner diameter x 15 0 mm, 2.5 μm); (ii) Column temperature of approximately 40°C; (iii) A first mobile phase containing approximately 0.05% formic acid in water; (iv) A second mobile phase containing approximately 0.05% formic acid in acetonitrile; (v) Flow rate of approximately 1.2 mL / min; (vi) Sample temperature at ambient temperature; and (vii) The retention time of the compound of formula (V) is approximately 15.2 minutes. In some embodiments, the HPLC assay is performed according to each of the above, i.e., (i)~( Includes vii).

[0157] In certain embodiments, the amount of one or more unspecified impurities in the pharmaceutical material is the amount of the pharmaceutical material Based on the total weight of the ingredients, the percentages are approximately 0.01%, 0.02%, 0.03%, and 0% by weight. 04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, or It is less than approximately 0.1%. In some embodiments, one or more specified in the pharmaceutical material The amount of impurities present is less than approximately 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 the amount of the pharmaceutical material Based on the total weight of the ingredients, approximately 0.0001% to 0.1%, and approximately 0.0005% by weight. Approximately 0.1%, approximately 0.001% to approximately 0.1%, approximately 0.005% to approximately 0.1%, approximately 0.01% ~approximately 0.1%, approximately 0.05%~approximately 0.1%, approximately 0.0001%~approximately 0.05%, approximately 0.0 0.001% to approximately 0.01%, approximately 0.0001% to approximately 0.005%, approximately 0.0001% to approximately 0 0.001%, approximately 0.0001% to approximately 0.0005%, approximately 0.0005% to approximately 0.05%, Approximately 0.0005% to approximately 0.01%, approximately 0.0005% to approximately 0.005%, approximately 0.0005 %~approximately 0.001%, approximately 0.001%~approximately 0.05%, approximately 0.001%~approximately 0.01%, Approximately 0.001% to approximately 0.005%, approximately 0.005% to approximately 0.05%, approximately 0.005% to approximately The concentration is 0.01%, or approximately 0.01% to approximately 0.05%. In certain embodiments, the concentration is in the pharmaceutical material. The amount of one or more unspecified impurities is determined by weight, based on the total weight of the pharmaceutical material. It is approximately 0.0001% to approximately 0.1%. In certain embodiments, one or more of the pharmaceutical materials are used. The amount of unspecified impurities is approximately 0.05% by weight, based on the total weight of the pharmaceutical material. It is approximately 0.1%.

[0158] V. Pharmaceutical Compositions In another embodiment, bempedoic acid or the drug thereof as described and / or prepared herein. A pharmaceutical composition containing a scientifically acceptable salt, wherein any impurity is present alongside any of the pharmaceutical materials. Pharmaceutical compositions containing the above are provided herein. In various embodiments, the pharmaceutical compositions are generally This includes pharmaceutical materials described herein and pharmaceutically acceptable excipients. For example, pharmaceutical The material contains more than 99.0% of the compound of formula (V), or a pharmaceutically acceptable salt thereof. It is possible.

[0159] In certain embodiments, the pharmaceutical composition is specially prepared for administration in solid or liquid dosage form. It may be formulated into an oral dosage form. In some embodiments, the pharmaceutical compositions described herein are in oral dosage form. It is formulated for administration as an oral medication. Examples of oral dosage forms include, but are not limited to, liquids and tablets. Preparations, capsules, cachet preparations, pills, emulsions, lozenges, solutions, suspensions, boluses Powder, elixir or lozenge, lozenge, mouthwash, granules, or applied to the tongue. Examples include pastes for application. In some embodiments, the pharmaceuticals described herein The composition is formulated into a dosage form suitable for parenteral administration. In some embodiments, The pharmaceutical compositions described in the detailed document are 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. However, it is not limited to these. In some embodiments, the pharmaceutical composition described herein may be The substance is formulated into a dosage form suitable for topical application. Examples of dosage forms suitable for topical administration include: Not limited to, but including powders, sprays, ointments, pastes, creams, lotions, gels, and solutions. Examples include 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. It is formulated in various dosage forms. Examples of dosage forms suitable for vaginal or rectal administration include pessaries. Examples include, but are not limited to, creams or foams. In some embodiments... The pharmaceutical compositions described herein are in dosage forms suitable for sublingual, ocular, transdermal, or nasal administration. It is formulated into a pharmaceutical product.

[0160] In certain embodiments, the solid dosage forms described herein used for oral administration contain pharmaceutical materials. Prepared by mixing with one or more pharmaceutically acceptable excipients. Pharmaceutical excipients These include fillers or bulking agents, sweeteners, binders, humectants, disintegrants, preservatives, fragrances, flavorings, and oxidation agents. Inhibitors, solution retarders, absorption enhancers, wetting agents, absorbents, lubricants, colorants, and controlled release agents. It can be selected from the following group. In some embodiments, the solid dosage form is a capsule. When in the form of tablets or pills, the pharmaceutical compositions described herein may also include buffering agents. In the embodiment, when the solid dosage form is a gelatin capsule, the pharmaceutical composition is lactose, milk One or more excipients selected from sugars, high molecular weight polyethylene glycols, and combinations thereof. It may further contain other agents.

[0161] In certain embodiments, the pharmaceutical composition of the present invention comprises cyclodextrin, cellulose, and lipo One or more excipients selected from the group consisting of soms, micellars, and polymer carriers May include. In some embodiments, the pharmaceutical composition of the present invention may include an antibacterial agent, an antifungal agent, or the like. This includes combinations of these. Examples of antibacterial and antifungal agents include parabens, chlorobutanol, Examples include, but are not limited to, phenol and sorbic acid. The pharmaceutical composition of the present invention contains an isotonic agent. In certain embodiments, the dosage form of the present invention may be a compound of formula (V) or a pharmaceutically acceptable compound thereof. The salt can be formulated to provide sustained or controlled release. For example, the sustained release of bempedoic acid Please refer to PCT / US2019 / 018356, which discloses the formulations. In embodiments, the dosage form 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 includes one or more of the following: inert Diluents, solubilizers, and emulsifiers. In certain embodiments, the oral suspension of the pharmaceutical composition of the present invention is ethoxylated isostearyl Alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose Ace, aluminum metahydroxide, bentonite, agar and tragacanth, and their It contains one or more suspending agents, including a mixture.

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

[0163] In certain embodiments, the powder and spray of the pharmaceutical composition of the present invention contain one or more excipients. Contains, and one or more excipients: lactose, talc, silicic acid, aluminum hydroxide, silicic acid It may contain calcium, polyamide powder, or mixtures thereof. In form, the spray of the present invention may contain a conventional propellant, and the conventional propellant is Contains one or more chlorofluoro hydrocarbons and volatile unsubstituted hydrocarbons. In certain embodiments, the transdermal patch of the pharmaceutical composition of the present invention is a compound of formula (V) or the same It provides controlled delivery of pharmaceutically acceptable salts to the body. In some embodiments, Ophthalmic preparations, eye ointments, powders, solutions, etc., are also included within the scope of the present invention. In certain embodiments, the pharmaceutical compositions described herein may be administered in unit dosage forms. It may be prepared by any method known in the field of pharmacy. Formula (V) present in a single dosage form. The amount of the compound or its pharmaceutically acceptable salt is the amount of the patient being treated and / or specific It may vary depending on the administration method.

[0164] In certain embodiments, it is combined with a pharmaceutically acceptable carrier to produce a single dosage form. The amount of compound of formula (V) or its pharmaceutically acceptable salt that can be used is generally, This is the amount of the compound of formula (V) that produces a therapeutic effect, or a pharmaceutically acceptable salt thereof. In various embodiments, bempedoic acid or a pharmaceutically acceptable salt thereof, or the present invention The pharmaceutical materials of Ming include fixed-dose formulations (for example, U.S. Patent Application Publication No. 2018 / 0338922). It can be prepared as (see publication number and International Publication No. 2018 / 218147). ru.

[0165] VI. Methods of Treatment and Administration In various embodiments, the materials and / or pharmaceutical compositions described herein include pharmaceutical materials and / or pharmaceutical compositions. / or bempedoic acid or a pharmaceutically acceptable salt thereof prepared herein is used for various diseases It may be used for the treatment or prevention of diseases or disorders. Methods for treating diseases or disorders are generally... For patients requiring this, a purified amount of the compound of formula (V) or a pharmaceutically acceptable salt thereof is provided. This includes administering a therapeutically effective amount of pharmaceutical material to treat a disease or disorder.

[0166] Examples of diseases and disorders include cardiovascular disease, atrial fibrillation, blood coagulation, coronary heart disease, and hypercoagulation. Condition, ischemia, myocardial infarction, myopathy, myositis, pulmonary embolism, stroke, peripheral vascular disease, dyslipidemia Symptoms, dyslipoproteinemia, glucose metabolism disorders, Alzheimer's disease, Parkinson's disease, Diabetic nephropathy, diabetic retinopathy, insulin resistance, metabolic syndrome disorders (examples) For example, Syndrome X), galactosemia, HIV infection, peroxisome proliferator activation Receptor-related disorders, sepsis, thrombotic disorders, obesity, pancreatitis, hypertension, kidney disease, cancer, inflammation (for example) , liver inflammation), inflammatory muscle diseases (e.g., polymyalgia rheumatica, polymyositis and fibrous muscle disease) Inflammation), impotence, gastrointestinal disorders, irritable bowel syndrome, inflammatory bowel disease, inflammatory disorders (for example, Asthma, vasculitis, ulcerative colitis, Crohn's disease, Kawasaki disease, Wegener's granulomatous disease (RA), systemic (SLE, multiple sclerosis (MS), and autoimmune chronic hepatitis), joint Inflammation (e.g., rheumatoid arthritis, juvenile rheumatoid arthritis, and osteoarthritis), osteoporosis, soft tissue Synovial rheumatoid arthritis (e.g., tendinitis), bursitis, autoimmune diseases (e.g., systemic lupus and erythema infectiosum). Thematosus, scleroderma, ankylosing spondylitis, gout, pseudogout, non-insulin-dependent diabetes mellitus, glucose Diabetic urinary tract disease (e.g., type 2), polycystic ovary disease, hyperlipidemia (e.g., primary hyperlipidemia, familial hyperlipidemia) Hypercholesterolemia (FH), Frederickson II Type A hypercholesterolemia, Frederickson IIb familial combined hyperlipidemia (FCH)), lipoprotein lipase deficiency (e.g., hypertriglyceridemia, hypotrichosis) Lipoproteins associated with diabetes (lipoproteinemia and hypercholesterolemia), Abnormalities, obesity-related lipoprotein abnormalities, and lipoproteins associated with Alzheimer's disease Examples include, but are not limited to, quality abnormalities. In certain embodiments, the above method is This includes treating and / or preventing hyperlipidemia, such as autosomal hyperlipidemia. In some embodiments, The above methods include treating and / or preventing cardiovascular disease.

[0167] In certain embodiments, this includes pharmaceutical materials and / or pharmaceutical compositions as described herein. The bempedoic acid and / or the pharmaceutically acceptable salts thereof produced may contain high levels of low-density ri. High levels of apolipoprotein B (apolipoprotein B) B) High levels of lipoprotein (a) (Lp(a)), high levels of ultra-low density lipoprotein High levels of non-high-density lipid cholesterol (VLDL), high levels of non-HDL-C Total serum cholesterol (TC), high levels of highly sensitive 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 levels of high-density lipoprotein cholesterol (HDL-C) It can be used for the following. In other words, the method of the present invention reduces LDL-C, apoB To reduce Lp(a), reduce VLDL, non-HDL - To lower C, to lower TC, and / or to lower hsCRP The present invention may include the following. The method of the present invention inhibits adenosine triphosphate citrate lyase (ACL). to inhibit cholesterol synthesis and / or suppress fatty acid biosynthesis May include. In some embodiments, a purified amount of the compound of formula (V) of the present invention or the drug thereof. A scientifically acceptable salt, pharmaceutical composition, or pharmaceutical material is heterozygous familial hypercholesterol In adults with cholesterolemia or established atherosclerotic cardiovascular disease, lowering LDL-C levels It can be used as an adjunct to dietary therapy for purgatives and statin therapy that is tolerated to the greatest extent possible. In some embodiments, a purified amount of the compound of formula (V) or its pharmaceutically acceptable Salt, the pharmaceutical composition or pharmaceutical material of the present invention, does not increase weight gain and is non-insulin dependent. It can be used to treat diabetes.

[0168] In certain embodiments, the pharmaceutical materials and / or pharmaceutical compositions described herein are included. / or the bempedoic acid produced or its pharmaceutically acceptable salts are associated with aging, Alzheimer's disease. Illness, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, glucose metabolism disorders, dyslipidemia Heterolipoproteinemia, increased bile production, hypertension, impotence, inflammation, insulin resistance Sex, lipid removal from bile, regulation of C-reactive proteins, obesity, oxysterol removal from bile Pancreatitis, pancreatitis, per Kinson's disease, peroxisome proliferator-activated receptor-related disorders, phospholipid removal from bile, This includes kidney disease, rhabdomyolysis, sepsis, sleep apnea, syndrome X, and thrombotic disorders. It can be used for the treatment or prevention of a variety of diseases and symptoms, not limited to those mentioned above.

[0169] In certain embodiments, fatty liver disease, alcoholic liver disease, and fatty liver disease are referred to as "fatty liver disease." er), fatty liver (liver steatosis), cirrhosis, hepatic fibrosis, and during pregnancy Methods for treating liver disorders selected from the group consisting of acute fatty liver are provided herein. In some embodiments, the disorder is fatty liver disease. This is non-alcoholic steatohepatitis. In some embodiments, steatohepatitis is non-alcoholic. It is alcoholic fatty liver disease. In some embodiments, the disorder is alcoholic liver disease. In some embodiments, the disorder is fatty liver. The condition is fatty liver, cirrhosis, or hepatic fibrosis. In some embodiments, the disorder is acute fatty liver during pregnancy. The liver is crucial. In some embodiments, the patient is an adult.

[0170] In certain embodiments, the present invention relates to aging, Alzheimer's disease, cancer, cardiovascular disease, and diabetes. Nephropathy, diabetic retinopathy, impaired glucose metabolism, dyslipidemia, dyslipoproteinemia, increased bile production Increased reverse lipid transport, hypertension, impotence, inflammation, insulin resistance, and lipids in bile. Elimination, regulation of C-reactive protein, obesity, removal of oxysterols from bile, pancreatitis (pan creatitis, pancreatitis, Parkinson's disease, Per Oxisomal proliferator-activated receptor-related disorders, phospholipid removal from bile, renal disease, sepsis, To treat or prevent metabolic syndrome disorders (e.g., syndrome X) or thrombotic disorders. To provide a method.

[0171] In certain embodiments, the disorder is lipodystrophy, lysosomal acid lipase deficiency. The patient is selected from the group consisting of and glycogen storage diseases. In some embodiments, the patient is an adult. In certain embodiments, the disorder is hepatitis C, infection caused by human immunodeficiency virus, α1- Antitrypsin deficiency, Bassen-Kornzweig syndrome, low beta-lipoprotein A group consisting of celiac disease, Wilson's disease, and Weber-Christian syndrome. Selected from. In some embodiments, the ailment is hepatitis B. In this case, the disorder is hepatitis C. In some embodiments, the disorder is human immunodeficiency virus. The infection is caused by alpha-1 antitrypsin deficiency. In some embodiments, the disorder is due to alpha-1 antitrypsin deficiency. It is a disorder. In some embodiments, the disorder is Bassen-Kornzweig syndrome. In some embodiments, the impairment is hypobetalipoproteinemia. In the application, the disorder is celiac disease or Wilson's disease. In some embodiments, the disorder The harm is Weber-Christian syndrome. In some embodiments, the patient is an adult. ru. In certain embodiments, symptoms include toxic liver injury, complete parenteral nutrition, severe surgical weight loss, The group is selected from environmental toxicity, malnutrition, and starvation. In some embodiments, symptoms This is toxic liver injury. In some embodiments, symptoms include complete parenteral nutrition or severe extracorporeal venous effusion. This is a toxic effect. In some embodiments, the symptoms are environmental toxicity. In terms of form, the symptoms are malnutrition or starvation. In some embodiments, the patient is an adult. .

[0172] In certain embodiments, to extend the effect of the drug, a compound of formula (V) or its pharmaceutically appropriate The acceptable salts are administered by subcutaneous or intramuscular injection, or by dissolving the drug in an oily vehicle. Alternatively, it may be administered by suspension. In certain embodiments, a compound of formula (V) in the pharmaceutical composition of the present invention or a pharmaceutically acceptable compound thereof The actual dosage levels of the salt that may be used are determined by the specific patient, composition, and whether they are toxic to the patient. and a compound of formula (V) or a quantity effective to achieve the desired therapeutic response for the mode of administration. It can be modified to obtain a pharmaceutically acceptable salt.

[0173] In certain embodiments, the selected dose level is determined by the route of administration, the time of administration, and the specific method used. The rate of excretion or metabolism of a specific compound, the rate and degree of absorption, the duration of treatment, and the specific compound used. Other drugs, compounds, and / or materials used in combination with the compound, and the age of the patient being treated. Age, sex, weight, symptoms, overall health status and previous medical history, as well as similar requirements known in the medical field. It depends on various factors, including the causal factors. In certain embodiments, a physician or veterinarian skilled in the art may, as necessary, provide an effective amount of the pharmaceutical composition. It can be easily determined and prescribed.

[0174] In certain embodiments, a suitable day of the compound of formula (V) or a pharmaceutically acceptable salt thereof. The dosage is the minimum amount effective to produce a therapeutic effect. In this state, the compound of formula (V) or its pharmaceutically acceptable salt is approximately 0.01 mg / kg~ It is administered at approximately 200 mg / kg. In certain embodiments, the compound of formula (V) or its pharmaceutical When a suitably tolerable salt is administered concurrently with another therapeutic agent, the effective dose is the compound of formula (V) or The amount of pharmaceutically acceptable salt may be less than when it is used alone.

[0175] In certain embodiments, the effective daily supply of the compound of formula (V) or a pharmaceutically acceptable salt thereof is The dose may be administered as a subdose of 2, 3, 4, 5, 6 or more. Specific implementations In this state, two, three, four, five, six or more subdoses may be arbitrarily administered in unit dosage form. They are administered separately at appropriate intervals throughout the day. In some embodiments, the administration is done over the course of a day. This is a single dose. In some embodiments, a compound of formula (V) or a pharmaceutically acceptable compound thereof is used. The acceptable salt levels are for 1 day, 5 days, 10 days, 20 days, 30 days, 1 week, 2 weeks, and 3 days. Weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months Interval, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 2 years, 3 years, 4 It is administered to the patient over a period of one or five years. In some embodiments, the compound of formula (V) Alternatively, a pharmaceutically acceptable salt thereof may be administered to the patient for the duration of the patient's life.

[0176] VII. Combination Therapy In various embodiments, the pharmaceutical materials and pharmaceutical compositions of the present invention are included in the descriptions herein. and / or bempedoic acid or a pharmaceutically acceptable salt thereof prepared herein may be used in combination therapy. It may be part of the law. In certain embodiments, combination therapy may involve a compound of formula (V) or its pharmaceuticals. The combination therapy comprises a generally acceptable salt and a second therapeutic agent. In certain embodiments, the combination therapy is purified A pharmaceutical material comprising a compound of formula (V) or a pharmaceutically acceptable salt thereof, and a second therapeutic agent This includes.

[0177] In some embodiments, the second therapeutic agent is lovastatin, thiazolidinedione, or Examples include fibrates, bile acid binding resins, niacin, anti-obesity drugs, hormones, and antiviral drugs. For example, to treat the underlying hepatitis C infection that causes liver disease in patients, anti-cancer drugs Drugs (for example, 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 (for example, Treatment of hyperlipidemia), thyrophostine, sulfonylurea drugs, biguanides, alpha-gluco Sidase inhibitors, apolipoprotein AI agonists, apolipoprotein E, cardiovascular Drugs, HDL-raising drugs, HDL enhancers, or apolipoprotein AI, apolipo Select from the group that includes regulatory factors for proteins A-IV and / or apolipoprotein genes. In some embodiments, a purified amount of the compound of formula (V) or its pharmaceutically acceptable equivalent is obtained. The salt obtained, by weight, exceeds 99.0% of the total weight of the pharmaceutical materials.

[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) (Combination of acid and ezetimibe), International Publication No. 2018 / 218147 (Bempedo acid and ezetimibe) Combinations with thymib); and International Publication No. 2018 / 148417 (bempedoic acid and ezethibe). See the combination of buprofen and statins.

[0179] In certain embodiments, a compound of formula (V) or a pharmaceutically acceptable salt thereof, and a second therapeutic Administering the pharmaceutical material or pharmaceutical composition of the present invention, which includes a therapeutic agent, is equivalent to administering a compound of formula (V) or To provide beneficial effects from the synergistic action of the pharmaceutically acceptable salt and the second therapeutic agent. This is intended. In some embodiments, the beneficial effect of combination therapy is due to the compound of formula (V). Or the pharmacokinetic or This may include pharmacodynamic synergies.

[0180] VIII. Kit In various embodiments, the present invention treats the symptoms, diseases, or disorders described herein. A kit is provided for this purpose. In some embodiments, the kit is i) as described herein, for example. Instructions for treating the symptoms, diseases or disorders listed, and ii) the compound of formula (V) or its pharmaceutically acceptable salts (e.g., purified amounts of the compound of formula (V) or its pharmaceutically acceptable salts) The kit includes pharmaceutical materials (containing salts obtained). In some embodiments, the kit is used to treat symptoms, diseases, or disorders. It contains an effective amount of the compound of formula (V) or a pharmaceutically acceptable salt thereof to treat the harm. It may contain one or more unit dosage forms.

[0181] This specification describes a method for producing a compound of formula (V) or a pharmaceutically acceptable salt thereof. , the compound of formula (V) or a pharmaceutically acceptable salt thereof, for example, a purified amount of the compound of formula (V) A method using the substance or a pharmaceutically acceptable salt thereof, the purified amount of the compound of formula (V) or its Multiple embodiments and embodiments of the present invention, including compositions and kits containing pharmaceutically acceptable salts. This patent application includes all combinations of the embodiments and configurations described herein. This specifically includes pharmaceutical materials, pharmaceutical compositions, methods for treating disorders or symptoms, and The net is made by the method described herein, using bempedoic acid or its pharmaceutically appropriate Please understand that it may contain and / or may be used salts that are acceptable. [Examples]

[0182] To allow for a more complete understanding of the inventions described herein, the following examples are provided. The synthesis and analysis protocols described in this application apply to the compounds provided herein. Provided to describe pharmaceutical compositions and methods, and not to limit their scope. It should not be interpreted in that way.

[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 is shown in Figure 1. Step 1 - Preparation of the compound of formula (I) Preparation of lithium diisopropylamide (LDA) Diisopropylamine (317 ± 3 kg, 1.1 equivalents) and tetrahydrof Add ran (THF, 2,102±105L), then cool the mixture to below -10°C. Next, while maintaining the temperature below -10°C, n-butyllithium (n-BuLi 757±8kg (1.2 equivalents) was added over a period of more than one hour. The input line was THF. The addition was exothermic. Finally, the batch was then stirred and cooled to below -10°C. It was cooled.

[0184] Alkylation reaction Ethyl isobutyrate (317 ± 3 kg, 1.1 equivalents) is incubated at -10°C or below (Figure 1) for at least 1 hour. It was added to the reactor. The batch was stirred while maintaining the temperature below -10°C. 1-B Romo-5-chloropentane (460±5 kg, 1.00 equivalent) at -10°C or below for 1 hour It was poured over the top and added. The line was rinsed with THF. The addition was exothermic. Next, the reaction mixture The mixture was stirred at -10°C or below for more than 10 hours. This stage of the reaction was observed using gas chromatography. - Confirm that it is complete using (1-bromo-5-chloropentane: <3% area). Next, the reaction mixture was heated to 0±5℃ and maintained at this temperature until the conversion was complete. The reaction was observed by gas chromatography (1-bromo-5-chloropentane: <0.5% area). I confirmed that it was complete using ).

[0185] Quenching and phase separation While maintaining the temperature below 30°C, a 9% hydrochloric acid solution (HCl, 1337±50 kg) is reacted. The reaction was quenched by adding the solution to the reaction mixture over a period of more than one hour. After administration, the reaction mixture was 30 The mixture was stirred at temperatures below ℃ for at least 15 minutes. The pH of the aqueous layer was measured (range: pH 6-10). Stirrer The system was stopped, and the layers were allowed to stand for at least 30 minutes. The lower aqueous phase was removed for disposal. Distillation and THF removal The solvent was removed by distillation under reduced pressure and at a temperature below 40°C to a desired volume of approximately 950 L.

[0186] The concentration of the compound in formula (I) is determined by gas chromatography (GC) within the concentration range of formula (I). The measurement was performed using the target compound (57-62% by weight). If necessary, the compound of formula (I) was used. To adjust the concentration within the target range, THF is added or further removed by distillation. Ta. Next, the batch was cooled to below 30°C, and the concentrate of the crude compound of formula (I) was drummed. (drummed). Repeat the process to obtain the compound of formula (I) in the same manner. Then, we obtained the second batch.

[0187] Step 2 - Preparation of the compound of formula (II) Additional water-based cleaning Two individual batches of the compound of formula (I) (57-62% wt / mW solution in THF) It was poured into a container. While stirring, 5% HCl (1,767±79 kg) was added at a temperature of 25°C or below. The addition was exothermic. The mixture was stirred for more than 15 minutes. Stirring was stopped, and the phase was 30 The mixture was allowed to stand for at least 1 minute. The lower aqueous phase was removed, leaving the compound of formula (I) / THF in the reactor. .

[0188] Iodide exchange reaction While stirring, add methyl ethyl ketone (MEK, 4,384±227L) and sodium iodide. A solution of sodium (NaI, 831±9 kg, 1.16 equivalents) was added (Figure 1). The batch was heated and returned to the boiler. The mixture was run at 75-80°C. After approximately 30 hours, the completion of the reaction was measured using GC (Equation ( I) Compound <1.0% area). If the reaction is not complete, allow more time (expected reaction). Time: 25-35 hours), NaI was added again as needed. Then the mixture was cooled to approximately 20°C. It was cooled down.

[0189] Solvent exchange and aqueous workup The batch is concentrated by vacuum distillation at a temperature below 60°C until no further distillate can be recovered. Next, the mixture was cooled to 20±5℃, and n-heptane (3,624±187L) was added. It was added. Next, a 5% sodium bisulfite aqueous solution (NaHSO3, 2,121±10 Add 4 kg of the mixture and stir for at least 60 minutes. Stop stirring and allow the phase to stand for at least 60 minutes. The lower aqueous phase was removed for disposal. Water (1980±102L) was added, and the mixture was mixed. The mixture was stirred for more than 60 minutes. The phase was allowed to stand for more than 60 minutes, and the lower aqueous phase was removed for disposal. A second rinse was performed as needed.

[0190] final concentration The batch is concentrated by vacuum distillation at a temperature below 50°C until no further distillate can be recovered. Next, the batch was cooled to 20°C, and the compound of formula (II) was drummed and assayed. Samples were taken for analysis. The expected yield range was 80-120% (weight / weight%). Ta.

[0191] Step 3 - Preparation of the compound of formula (IV) Preparation of sodium t-pentoxide / DMAc The sequence of the intermediate / compound in formula (IV) below yielded 7 in a 94.9% weight / weight assay. This is based on the amount of compound (II) / n-heptane added in 00 kg, which is 665k This represents the amount of compound (II) containing g added. N,N-dimethylacetamide (DMAc, 1,476±37 kg) and sodium t -A solution of pentoxide (271 ± 3 kg, 2.10 equivalents) was prepared in a container, and the solid was almost 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. In contrast, it was thoroughly stirred. To this solution, the sodium t-pentoxide / DMAc mixture was added. The substance was added over approximately one hour at a temperature below 5°C. The transfer line was rinsed with DMAc (181±9kg). The reaction was strongly exothermic. The reaction mixture was stirred at -5°C or below for at least 30 minutes. Ultraviolet detection. High-performance liquid chromatography (HPLC-UV) using monoalkylated TosMIC The conversion was confirmed using the area of ​​≤1% and the area of ​​the compound of formula (II) ≤1.4%. Confirmed. Based on the following instructions, to ensure the completion of the reaction, use formula (II) as needed. ) compounds, TosMIC and sodium t-pentoxide, any kicker charge ( Using kicker charge (Table 18): [Table 18]

[0193] Quenching and phase separation n-heptane (2,407±120 L) and water (3,061±153 L) are added to a separate reactor. The first intermediate reaction mixture was added under temperature control from 0°C to 40°C (target 20°C). - The mixture was transferred to a heptane / water mixture. The reaction was strongly exothermic. The transfer line was then changed to n-heptane. Rinse with (470±24L). Then, stir the mixture for more than 1 hour. Stop stirring, The mixture was allowed to stand for more than one hour. The lower aqueous phase was removed for disposal. 5% sodium chloride Add an aqueous solution (NaCl, 3,106±147 kg) and mix at approximately 20°C (range: 0°C). The mixture was stirred at ~40°C for at least one hour. 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 separated into another container. I transferred it to a bowl.

[0194] Reaction of the compound of formula (IV) Isopropyl acetate (IPAc, 451±23L) is dissolved in n-heptane to form the first intermediate. The solution was added, and the mixture was cooled to -10±10°C. While maintaining the temperature at ≤25°C, concentrated H Cl (115 ± 2 kg) was added. The reaction product is exothermic, and the reaction mixture should be adjusted as needed. The mixture was heated to 20±5℃. During the heating period, the mixture was stirred for at least 30 minutes. HPLC-UV ( The reaction conversion was measured using an intermediate (≤2% area).

[0195] Quenching and phase separation In a separate container, sodium hydroxide (NaOH) solution (50% wt / kg, 175±2kJ) g) was combined with water (1927±96L). The resulting NaOH aqueous solution was added to the reaction mixture for about 2 minutes. The mixture was added at 0°C (range: 10°C to 40°C). The line was rinsed with water. The mixture was left for at least 3 hours. The mixture was stirred. The neutralization endpoint is pH 9-12. Stirring was stopped, and the phase was allowed to stand for at least 60 minutes. The lower aqueous phase was removed for disposal. (NaCl (55±3kg), Water (1,572±79L)) ) and a diluted aqueous solution containing 50% sodium hydroxide (4.6±0.2 kg) in a separate container Prepared and packed into a mixture of products of the compound of formula (IV). Rinsing with water (128± Apply 6L of solution and stir the mixture for at least 60 minutes. Stop stirring and allow the phase to stand for at least 60 minutes. The lower aqueous phase was removed for disposal.

[0196] concentrated The mixture was concentrated under vacuum at a temperature below 80°C until no further distillate could be recovered. Distillation was monitored using C (compound of formula (IV) ≥ 75% area). The batch was brought to approximately 20°C. The concentrate of compound (IV) was cooled and held until the second batch was prepared. The process for preparing compound V) is repeated in the same manner to obtain the formula in n-heptane. A second batch of compound (IV) was obtained. Then, for final distillation and packaging, the second batch The first batch was combined with thio (in n-heptane). The product was weighed and used for the assay. Samples were taken. The expected yield range was 80–120% by weight.

[0197] Step 4 - Preparation of compound (crude bempedoic acid) of formula (V) Reaction 1 (Ketone Reduction) Compound of formula (IV) (545±5 kg) and ethanol (EtOH, 1090±55 kg) g) was placed in a container. While maintaining the batch below 35°C, sodium borohydride ( (NaBH4, 12% by weight in 40% NaOH, 155±2kg, 0.35 equivalents) approximately 2-3 The substance was added over a period of time (Figure 1). The addition was exothermic. The input line was filled with water (155±8 Rinsed (kg). After holding at 25±10℃ for more than 1 hour, HPLC-UV (formula (IV)) The conversion was measured using the compound (≤0.5% area).

[0198] Reaction 2 (Saponification) A sodium oxide solution (50% wt / kg, 435±4kg) was placed in a container at a temperature of 50°C or below. The addition was exothermic. The input line was rinsed with water (155±8kg), and the reaction mixture was 5 The mixture was heated to 0±5℃ for more than 6 hours. Saponification was performed using HPLC-UV (compound monoester of formula (V)). Measurements were taken using a tergency (≤0.5% area). Water (1873 ± 94 kg) was added to the reaction mixture. Added. Vacuum the EtOH and water until the batch volume reaches the target level (approximately 2184L). The mixture was distilled below 50°C. The mixture was transferred to another reactor, and the transfer line was connected to water (273±1 I rinsed it (4kg).

[0199] pH adjustment, phase separation and extraction Add methyl tert-butyl ether (MTBE, 1628±81 kg) and batch The mixture was cooled to 10-15°C. Concentrated HCl (647±6 kg) was slowly added at 10-20°C. (The addition was exothermic), and the batch was stirred for more than 1 hour. The sample was then subjected to pH analysis. The sample was collected and the pH was adjusted with HCl or NaOH as needed (target pH range: 5-6). The formation of hydrogen gas was observed. Stirring was stopped, and the phase was allowed to stand at 10-20°C for 60 minutes or more. The lower aqueous phase was removed for disposal. The batch was transferred to another container and rinsed forward with MTBE. Yes. Using HPLC-UV (compound of formula (V): 17%~20% by weight), MTBE The concentration of the compound in formula (V) was measured.

[0200] Step 5 - Purification of compound (V) / Preparation of compound (V) in crystalline form Silica gel preparation The ratio of diameter to height of the silica gel plug varied from 1x1 to 1x3. Silica gel (6 (0±2 kg) is placed in a filter, moistened with ethyl acetate (siRNA), and then placed in a reactor. It was added to the mixture and then discharged into the filter. The silica gel bedding was treated with dimethyl(1,173±5 The system was preheated by recirculating 9 kg of water at 50 ± 5°C. Excess dimethyl was removed using the formula ( V) Removed immediately before filtration of the batch of compounds.

[0201] Solvent exchange to ethyl acetate The compound of formula (V) in MTBE was added to the reactor. The batch was incubated under vacuum at a temperature below 50°C. The solution was concentrated to 30% to 35% of its original volume. Filtrate (2,002 ± 100 kg) was added. The batch was then concentrated again to 30% to 35% of the initial volume. Filtrate (1601±80kJ) g) was added and distillation was repeated. HCl (1601 ± 80 kg) was added and batch The following samples were taken. Solvent exchange was measured by GC (MTBE ≤ 0.1% by weight). Additional phytochemicals were added and distillation was performed as needed.

[0202] Silica gel filtration After the solvent exchange was complete, the batch was heated to 50±5°C. Then, the batch was placed in a preheated silica gel. The mixture was filtered through a gel plug into another reactor. EtO2 was used to rinse the lines and silica gel. Ac (964 ± 20 kg) was added to the reactor and heated to 50°C, and then heated acet A portion of the product was transferred to a silica gel plug. Loss of product due to retention on the silica gel filter. This was measured using HPLC (for compounds of formula (V) at a concentration of 0.5% by weight or less in the eluent). Further washing with siRNA was performed as needed. Purification of formula (V) in siRNA. The mixture is partially concentrated to a final volume of approximately 1700L by distillation under vacuum at a temperature of 50°C or less. did.

[0203] crystallization The temperature of the concentrated compound of formula (V) in ԅ was adjusted to approximately 50±5°C. Water (24±1 Add (kg), rinse the line with HCl (74±10kg), and leave the solution at 50±5℃. The solution was maintained for more than one hour. Then, the solution was slowly stirred using a cooling rate of 14°C / hour. The mixture was then cooled to 22±5℃, and subsequently held at this temperature for more than 2 hours to initiate crystallization. Once slurry formation was confirmed, the solution was stirred at approximately 20-25°C for at least 6 hours. Then, The switch was cooled to 0±5°C using a cooling rate of 11°C / hour, and then cooled at this temperature for 6 hours. Stirred from above.

[0204] Isolation and drying The crude crystalline form of the compound of formula (V) was isolated by centrifugation at 0±5°C, and then 0± Washed with à cooled to 5°C. The wet cake was dried under vacuum at a temperature below 45°C. Drying was monitored by loss on drying (LOD) (LOD ≤ 0.5%). Any in situ filtration For containers designed using in situ filtration, the slurry should be 0± The mixture was allowed to stand at 5°C for at least one hour. The batch was filtered, leaving the wet cake in the reactor. E tOAc (1,064±53 kg) was placed in a separate container and cooled to 0±5°C, and then decanted. The mixture was passed through a filter and returned to the reactor containing the moist cake. The batch was stirred for at least one hour. Next, it was left to stand for more than an hour. Filtration was repeated. The slurry washing and filtration processes were the same. The first pattern was repeated three times.

[0205] Step 6 - Preparation of pharmaceutical material containing the compound of formula (V) in purified amount Recrystallization (ethyl acetate / water) Following in situ filtration, the amount of the compound of formula (V) in crystalline form produced in step 5 is... In step 4, the compound of formula (IV) (filling amount - 545 kg) is 100% converted to the compound of formula (V). This was estimated based on the assumption that it had been replaced (Figure 1). In the reactor, until the volume reaches the 1433L mark (approximately 619 kg of RINKAN) E tOAc was added to a wet cake of the compound of formula (V) in its crystalline form, and then all solids were added. The suspension was heated to 55-60°C until it dissolved. Water (16±1 kg) was added to the clear solution. The batch was then stirred at 55-70°C for at least 1 hour. The temperature was adjusted to 55±5°C, and then The batch was then transferred to another reactor by polish filtration. Reactor, filter and line It was rinsed with ԅ(162±12kg). The temperature was adjusted to 55±5℃. Then, The hot solution was cooled to 30±5°C over more than one hour, and then stirred for more than two hours. Then, batch It was heated to 40±5℃ over a period of more than one hour, and then maintained at 40±5℃ for more than one hour. Next, the batch is cooled to 35±5°C over a period of more than one hour, and then left at 35±5°C for more than two hours. The temperature was maintained. Next, the batch was cooled to 5±5°C over a period of 5 hours or more, and then cooled to 5±5°C for 4 hours. The mixture was maintained for more than 1 hour. The resulting solid was isolated by centrifugation. The washing solvent was acetonitrile. It is an ACN (Acrylic Acid) and was stored at 20±10℃ for use.

[0206] Isolation, drying, identification, and IPC testing of the compound of formula (V). The purified solid of the compound of formula (V) was recovered by centrifugation, and then at 20±10℃ Wash with acetonitrile (compound of formula (V) at 2 × 2 kg / kg) to remove all residual mother liquor. The [unclear] was removed. The wet cake was dried in a vacuum at a temperature below 45°C. Yield: 324.2 kg A pharmaceutical material containing the compound of formula (V) in a purified amount (84.9%).

[0207] The purified compound of formula (V) was added in 10 mg / mL and 5 mg of the purified compound of formula (V) in CDCl3. By preparing a 0 mg / mL solution, 1 H- and 13 Prepared for CNMR analysis. Using an Inova 500MHz NMR spectrometer, 1 H- and 13 C-NMR We obtained the vector. Better relative quantification of the integral, and all signals were captured. To ensure this, the window was extended from 5000 to 8000Hz, and the waiting time between acquisitions was reduced. The time was extended from 1 second to 25 seconds. The compound of formula (V) obtained 1 H- and 13 C-NMR Spectroscopy The culls (Figures 2(a) and 2(b) respectively) are known bempedoic acid 1 H- and 13 The 1C-NMR spectrum matches (Table 19). [Table 19] Perform the purified compound sample of formula (V) in positive electrospray mode. Agilent Thermo LTQ-XL Mass Spectrometer connected to an electrospray The assay was performed using HPLC with a capillary temperature of 200°C. The column was Wa The ters X-Bridge C18 was 4.6 × 75 mm and 2.5 μm in size. Mobile phase: A was 0.05% formic acid, and mobile phase B was 0.04% formic acid in acetonitrile. Formula ( The experimental mass of compound V) was found to be 344.38 Da, which is 344.4 This closely matches the calculated mass of bempedoic acid at 9Da.

[0208] The expected yield range was 66-91%. Residual solvent was measured by GC (ACN ≤ 350 ppm). The area was then checked, and the completion of drying was confirmed. Once drying was complete, electrostatic aerosol detection (CAD) was used. Impurities were measured using HPLC (unknown impurities less than 0.08% by weight and known impurities). (Impact 0.13% by weight or less). If the impurity profile meets the criteria, the product is used for the final active ingredient. It was processed as a drug ingredient (API). If the impurity profile does not meet the standards, the above applies. We performed a different recrystallization process on the sea urchin.

[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% (weight / weight). X-ray powder diffraction (XRPD) data for the compound with crystalline form formula (V) were obtained from Pana. Lytical X'Pert 3 Powder diffractometer (Cu, Kα radiation; X-ray tube setting) -45kV, 40mA; Divergence slit - fixed 1 / 8°; Scan mode - continuous; Scan Range -3~40°(2θ); Scan step time -18.87 seconds; Step size -0.0 The samples were collected using 131°(2θ). Samples of the compound of the crystalline form of formula (V) were taken from Si It was placed in a zero-background holder. The 2θ position is referenced to Panalytical Si. Calibrated against a standard disk. Figure 4 shows the XRPD pattern of the crystalline form of the compound of formula (V). The characteristics of the XRPD pattern in Figure 4 are shown in Table 20 below, and this table shows the diffraction angle. List the values ​​for 2θ and relative intensity (expressed as a percentage relative to the strongest peak).

[0210] Differential scanning calorimetry (DSC) data for the compound of crystalline form formula (V) are obtained from TA The data was collected using a Q2000 DSC instrument. The DSC instrument used an indium reference standard. The following calibration was performed: A sample of the compound in the crystalline form of formula (V) was pressed into an aluminum saturator. It was placed in a pull-pan and heated from ambient temperature (approximately 25°C) to 300°C at a rate of 10°C / minute. The DSC curve of the crystalline form of the compound of formula (V) is shown in Figure 5. The DSC curve is approximately 92.4°C. This shows an endothermic event with a starting value of . Thermogravimetric analysis (TGA) data of the compound with crystalline form formula (V) can be obtained using TA Discove. The data was collected using a RY 550 TGA instrument. The TGA instrument used a nickel reference standard. The calibration was performed by placing a sample of the compound with crystalline form formula (V) into an open platinum sample pan. The temperature was heated from approximately ambient temperature (approximately 25°C) to approximately 315°C at a rate of 10°C / min. Equation (V) The TGA curves of the crystalline form of the compound are shown in Figure 6. The TGA curves are negligible before decomposition occurs. It showed the weight loss that can be reduced. [Table 20]

[0211] Furthermore, the single crystal of the compound of formula (V) was analyzed by single-crystal X-ray diffraction. The unit cell parameters of the crystalline form of the compound, as well as the data acquisition and structural refinement methods, These are shown in Tables 21 and 22. [Table 21] [Table 22] Atomic coordinates (×10 4 ) and isotropic displacement parameter (Å 2 ×10 3 ) are shown in Table 23 below. U(eq) is the orthogonalized U ij It is defined as 1 / 3 of the trace of a tensor. [Table 23]

[0212] The 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 angles of twist (°) are shown in Table 26 below. [Table 26]

[0215] Anisotropic displacement parameter (Å 2 The following Table 27 shows the anisotropic displacement coefficient index. 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] The selected hydrogen bond information (Å and °) is shown in Table 29 below. [Table 29] Symmetry transformations 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 the compound of formula (I) Preparation of lithium diisopropylamide (LDA) In the reaction vessel, add approximately 321 kg of diisopropylamine and approximately 1870 L of tetrahydrof Lan (THF) was added, and then the mixture was cooled to -18°C to -5°C. Approximately 794 kg n-butyllithium (n-BuLi, heptane solution) is maintained at a temperature of -18°C to -5°C. The mixture was added slowly while holding it. The batch was kept at -18°C to -5°C while being stirred.

[0219] Alkylation reaction Approximately 317 kg of ethyl isobutyrate was processed while controlling the temperature between -18°C and -5°C to reach the target temperature. It was added to the reactor containing LDA over a period of more than one hour. Then, the line was opened to approximately 100 L Rinsed with THF. The batch was agitated while maintaining the temperature at -18°C to -5°C. Approximately 46 Administer 0 kg of 1-bromo-5-chloropentane to the target at -18°C to -5°C for more than 1 hour. Next, the line was rinsed with approximately 100 L of THF. The reaction mixture was then cooled at -18°C to -5°C. The mixture was stirred and then heated to 0°C ± 5°C. The reaction was then analyzed by gas chromatography (GC) (1 - Bromo-5-chloropentane: (≤0.4% area) confirm that completion is complete. Ta. Quenching and phase separation While maintaining the temperature below 30°C, approximately 1337 kg of 9% hydrochloric acid solution (HCl) was reacted. The mixture was added to quench the reaction. After administration, the reaction mixture was left at 20°C ± 5°C for 15 minutes. The mixture was stirred. The layers were allowed to stand. Next, the pH of the aqueous layer was measured (range: pH 6-10). If the pH range is not met, add additional sodium hydroxide (NaOH) or HCl. This is acceptable. The lower aqueous phase was removed for disposal. Distillation and THF removal The solvent was removed by distillation under reduced pressure and at a temperature below 40°C to a desired volume of approximately 950 L. The crude compound concentrate of formula (I) is temporarily stored in the reaction vessel, or until the process is complete. The compound of formula (II) was prepared by mixing. The compound of formula (I) was repeated in the same manner. We returned and obtained a second batch.

[0220] Step 2 - Preparation of the compound of formula (II) Additional water-based cleaning Two separate batches of the compound of formula (I) in THF were placed in a container. Then, they were stirred. However, approximately 1767 kg of 5% HCl aqueous solution was added at 20°C ± 5°C. The mixture was left for 15 minutes. The mixture was stirred for more than 1 hour. Stirring was stopped and the phase was allowed to stand. The lower aqueous phase was removed, and the mixture was converted to formula (I) / THF. The compound was left in the reactor. Iodide exchange reaction Approximately 4386 L of methyl ethyl ketone (MEK) and approximately 824 kg of sodium iodide NaI was added while stirring. The batch was heated under reflux. After approximately 30 hours, GC The completion of the reaction was measured using (compound of formula (I) ≤ 3.0% area). If not, additional time may be allowed and additional NaI may be packed as needed. Then, The mixture was cooled to approximately 20°C ± 10°C. Solvent exchange and aqueous workup The batch is concentrated by vacuum distillation at a temperature below 60°C until no further distillate can be recovered. Next, approximately 3000 liters of n-heptane were added. Approximately 2115 kg of 5% sulfur dioxide. Prepare an aqueous sodium chloride solution (NaHSO3) and add the reaction mixture of the compound of formula (II). Approximately 612 L of n-heptane rinse solution was added. The mixture was stirred at 20°C ± 5°C. The stirring was stopped, and the phase was allowed to stand. The lower aqueous phase was removed for disposal. Approximately 1976L Add water, stir the mixture, let the phase stand, then remove the lower aqueous phase for disposal. Okay. I repeated the water rinse once more. final concentration The batch is concentrated by vacuum distillation at a temperature below 50°C until no further distillate can be recovered. Next, the compound of formula (II) was drummed and sampled for intermediate testing. The expected yield range is 80% to 100%.

[0221] Step 3 - Preparation of the compound of formula (IV) Preparation of sodium t-pentoxide / DMAc The sequence of the first intermediate / compound in formula (IV) below is the same as that of 650 kg of compound (II). In a 90.0% weight / weight assay representing the amount of input contained, the compound / hept of formula (II) Based on an input volume of approximately 722 kg of tanks. Approximately 1450 kg of N,N-dimethylacetamide (DMAc) and approximately 267.3 kg A solution of sodium t-pentoxide was prepared in a container, and the mixture was stirred at a temperature of 30°C or below. 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 container. Then the mixture was mixed -1 The mixture was cooled to 5°C to 0°C and thoroughly stirred. Sodium t-pentoxy was added to this solution. The DMAc mixture was added at -15°C to 0°C. The transfer line was then filled with approximately 178 kg of DMAc. Rinse. Stir the reaction mixture at -15°C to 0°C. Ultraviolet detection (HPLC-UV) 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). Based on the information shown in Table 30, take as necessary to ensure the reaction is completed. , compound of formula (II), TosMIC, and any chuck of sodium t-pentoxide - (Additional) input can be used. [Table 30] IPC = In-Process Control; TosMIC = p-toluenesulfonylmethyl isocyanide.

[0222] Quenching and phase separation Approximately 2344 L of n-heptane and approximately 2993 L of water were added to another reactor. The intercellular reaction mixture is transferred to the heptane / water mixture under temperature control from 0°C to 40°C (target 20°C). Next, the transfer line was rinsed with approximately 456 L of n-heptane. The mixture was then heated at 0°C to 40°C. The mixture was stirred for 1 to 3 hours between °C. Then, stirring was stopped and the mixture was allowed to stand. The aqueous phase below. It was removed for disposal. Approximately 3036 kg of approximately 5% sodium chloride solution (NaCl) was added. The mixture was then stirred. Next, the stirrer was stopped and the mixture was allowed to stand. The lower aqueous phase It was removed for disposal.

[0223] Reaction of the compound of formula (IV) Approximately 440 L of isopropyl acetate (IPAc) was added to the solution of the first intermediate in heptane. The mixture was then cooled to -15°C to 0°C. Next, the temperature was maintained at -15°C to 25°C. Then, concentrated HCl (approximately 112 kg) was added. The reaction mixture was then heated at 10°C to 25°C as needed. The mixture was heated. Once it reached 10°C to 25°C, it was stirred for 30 to 60 minutes. HPLC- The reaction conversion was measured using UV light (area of ​​the first intermediate ≤20%).

[0224] Quenching and phase separation In a separate container, add approximately 177 kg of NaOH (50% wt / g) to approximately 1884 L of water. Then, the resulting NaOH aqueous solution was added to the reaction mixture at approximately 20°C (range: 10°C~). The mixture was added at 40°C. The line was rinsed with approximately 124 L of water. The mixture was stirred. Neutralization endpoint. The pH is 9-12. Stirring was stopped and the phase was allowed to stand. The lower aqueous phase was removed for disposal. It contained approximately 54 kg of NaCl, approximately 1535 L of water, and approximately 4.5 kg of 50% NaOH. A diluted aqueous solution was prepared in a separate container and added to the compound product mixture of formula (IV). Then, approximately 126 L of water rinse solution was applied. The mixture was stirred, the phase was allowed to stand, and the lower aqueous phase was... It was removed and discarded.

[0225] concentrated The mixture was concentrated under reduced pressure at a temperature below 80°C to reduce its volume. The batch was then returned to approximately 20°C. The concentrate of compound (IV) was cooled and held until the second batch was prepared. The compounding process in V) is repeated in the same manner to obtain compound (IV) of formula in heptane. Two batches were obtained. Next, for the final distillation, the second batch (in heptane) was added to the first batch. It was combined with Chi. Distillation was monitored using GC (75% or more by weight of compound (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 (crude bempedoic acid) of formula (V) Reaction 1 (Ketone Reduction) Approximately 710 kg of the compound of formula (IV) and approximately 1420 kg of ethanol (EtOH) were used. It was placed in a container. While maintaining the batch at 25°C ± 10°C, approximately 202 kg of sodium borohydride was added. I added sodium (NaBH4, 12% by weight in 40% NaOH, approximately 0.35 equivalents). Next Then, the input line was rinsed with approximately 202 kg of water. After being kept at 25°C ± 5°C for more than 1 hour, The conversion was measured using HPLC-UV (compound of formula (IV) ≤ 0.9% area).

[0227] Reaction 2 (Saponification) Add approximately 567 kg of NaOH solution (50% by weight) at 15°C to 50°C. Rinse the line with approximately 202 kg of water, and heat the reaction mixture at 50°C ± 5°C for at least 6 hours. Saponification was performed using HPLC-UV (compound (V) monoethyl ester ≤1.3% area). Then measure. Add approximately 2440 kg of water to the reaction mixture. Batch volume reaches target level ( Distill the EtOH and water under vacuum and at a temperature below 50°C until the volume reaches approximately 2845L.

[0228] pH adjustment, phase separation and extraction Dilute the mixture with approximately 356 L of water, then ferment the batch while maintaining the temperature between 15°C and 50°C for 2 121 kg of methyl tert-butyl ether (MTBE) was added. The batch was stored at 10°C. The mixture was cooled to ~20°C. Concentrated HCl (approximately 912 kg) was slowly added at 10°C to 20°C. Samples were taken for pH analysis, and the pH was adjusted with HCl or NaOH as needed. (Target pH range: 5.0~6.0). Stirring was stopped and the phase was allowed to stand. The lower aqueous phase was discarded. It was removed for this reason. The concentration of the compound of formula (V) in MTBE was measured using HPLC-UV. The batch was then transferred to another container and rinsed forward with approximately 629 kg of MTBE.

[0229] Step 5 - Purification of compound (V) / Preparation of compound (V) in crystalline form Silica gel preparation The diameter × height ratio of the silica gel plug can vary from 1 × 0.8 to 1 × 3. 78 kg of silica gel was placed in the filter. Approximately 1173 kg of ethyl acetate was added at 50°C ± 5°C. A silica gel bed was prepared by recirculating it at °C. Excess SiO was removed using formula (V) It was removed immediately before filtration of the batch of compounds.

[0230] Solvent exchange to ethyl acetate The compound of formula (V) in MTBE was concentrated under vacuum to approximately 1148 L at a temperature below 50°C. 2608 kg of siRNA was added, and then the batch was concentrated again to approximately 1148 L. 2086 kg of butyl phosphate was added, and distillation was repeated. butyl phosphate (approximately 2086 kg) The solvent was added, and then the batch was sampled. Solvent exchange was performed using GC (MTBE 0.1% The measurement was performed at a volume less than or equal to the specified amount. Additional phosphate addition and distillation may be performed as needed.

[0231] Silica gel filtration After the solvent exchange was complete, the batch was heated to 45°C to 55°C. Then, the batch was preheated. The silica gel was filtered through a silica gel plug into another reactor. To rinse the lines and silica gel, Approximately 521 kg of  was added to the reactor and heated to 50°C ± 5°C, and then heated Et OAc was transferred through a silica gel plug. Then, the phosphate of formula (V) in the phosphate mixture was purified. The compound is partially concentrated to a final volume of approximately 2321 L by distillation under vacuum at a temperature below 50°C. It shrunk.

[0232] crystallization The concentrated compound of formula (V) in ԅ was adjusted to approximately 50°C ± 5°C. Approximately 31.3 kg Water was added, and the solution was maintained at 50°C ± 5°C for more than 1 hour. Then, the solution was stirred while 2 The mixture was slowly cooled to 22°C ± 5°C over a period of time, and the crystallization of compound (V) was initiated. The mixture was stirred at approximately 22°C ± 5°C for more than 6 hours, and then slurry formation was confirmed. If not present, you can further stir and seed at 20°C to 25°C as needed. Good. Next, slowly cool the batch to 0°C ± 5°C over more than 2 hours, and then 6 Stirred for more than an hour.

[0233] Any in situ filtration For containers designed using in situ filtration, the slurry is approximately 0 It was allowed to stand at °C. Next, the batch was filtered, leaving the wet cake in the reactor. Approximately 13 86 kg of alkyl alkyl group was placed in a separate container and cooled to 0°C ± 5°C, resulting in a wet cake. The mixture was transferred to a reactor. The batch was stirred at 0°C ± 5°C and then allowed to stand. The solid was filtered. The slurry washing and filtration process was repeated three times in the same manner.

[0234] Step 6 - Preparation of pharmaceutical material containing the compound of formula (V) in purified amount Recrystallization (ethyl acetate / water) After in-situ filtration, the amount of compound (V) used to prepare compound (V) Based on the 100% conversion input amount (710 kg) of the compound of formula (IV), approximately 488 kg It is assumed that this is the case. In the reactor, SiO is converted to solid formula (V) until the volume reaches the mark of 1867 L. The mixture was then heated to 55°C-60°C while stirring. 0.5 kg of water was added, and the batch was stirred at 55°C to 70°C for at least 1 hour. Confirmation of solution formation. This was done. Next, the batch was transferred to another reactor by polish filtration. Reactor, phi The luthier and lines were rinsed with ¼. Then the temperature was adjusted to 55°C ± 5°C. Next Then, the hot solution is cooled to 30°C ± 5°C over a period of 2 hours or more, and then left at 30°C ± 5°C for 2 hours. The mixture was then stirred. If no slurry was present, it was stirred further at 30°C ± 5°C as needed before spreading. You may soak it. Then, heat the batch at 40°C ± 5°C for at least 1 hour, and then at 40°C ± 5°C for 1 hour. The batch was held for more than 1 hour. Then, the batch was cooled to 35°C±5°C for more than 1 hour, and then refrigerated at 35°C±5°C for 2 hours. The batch was held for more than 1 hour. Then, the batch was slowly cooled to 5°C ± 5°C over a period of more than 5 hours. It was kept at 5°C ± 5°C for more than 4 hours.

[0235] Isolation, drying, and IPC testing The obtained solid was isolated by centrifugation and washed with acetonitrile in a quantity of 2000 kg or less. Next, the wet cake was dried under vacuum at a temperature of 45°C or lower (jacket). Residual dissolved The solution was measured by GC (ACN ≤ 410 ppm, HCl ≤ 5000 ppm) and drying was completed. Confirmed. The expected yield range is 66% to 91%. The pharmaceutical material release specifications are met. If so, the product was treated as a final pharmaceutical material. If the release specifications for the pharmaceutical material are not met. Then, a second recrystallization was performed.

[0236] Any second recrystallization (ethyl acetate / water) The following procedure describes the second recrystallization of the compound of formula (V) in a batch size of approximately 430 kg. Write it down. A solid (approximately 430 kg) of the compound of formula (V) was placed in a container, followed by phenyl(approximately 123) 8 kg was added. Next, the suspension was heated to 55°C to 60°C while stirring. Approximately 18 kg of water was added, and the mixture was then stirred at 55°C to 70°C for at least one hour. Solution form The condition was confirmed. Next, the temperature was adjusted to 55°C ± 5°C, and the batch was subjected to polish filtration. Then it was transferred to another reactor. The reactor, filter and lines were rinsed with ¼, and then The temperature was then adjusted to 55°C ± 5°C. Next, the hot solution was heated for more than 2 hours until it reached 30°C ± 5°C. Cooling was followed by stirring at 30°C ± 5°C for at least 2 hours. If slurry is not present, as needed... Depending on the circumstances, the mixture may be further stirred and sown at 30°C ± 5°C. Then, the batch is heated to 40°C ± 5°C. The batch was heated for more than 1 hour and held at 40°C ± 5°C for more than 1 hour. Then the batch was cooled to 35°C ± 5°C. The batch was cooled for more than 1 hour and then kept at 35°C ± 5°C for more than 2 hours. Next, the batch was left to cool for more than 5 hours. It was then slowly cooled to 5°C ± 5°C and held at 5°C ± 5°C for more than 4 hours.

[0237] Optional isolation, drying, and IPC testing The obtained solid was isolated by centrifugation and washed with acetonitrile in a quantity of 2000 kg or less. The wet cake was dried under vacuum at a temperature of 45°C or lower (jacket). Then, the residual solvent... The solution was measured by GC (ACN ≤ 410 ppm, HCl ≤ 5000 ppm) and drying was completed. Confirmed. The expected yield range is 75% to 100%. The impurity profile criteria are met. If this occurs, the product is processed as a final pharmaceutical ingredient.

[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 (gra (Dient capability), thermostat column compartment and charged aerosol detection The determination was made using a high-performance liquid chromatograph equipped with a CAD detector. The amount of impurities in the purified form of the compound of formula (V) is 0.05–0.50% by weight / kg It was determined that the amount was within the acceptable range. Column: Waters XBridge BEH C18 (4.6mm inner diameter x 150m) (m, 2.5μm) Mobile phase: A: 0.05% formic acid (HCOOH)(H2O) in water 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 mins, 5:95; 36 mins, 5:95). Flow rate: 1.2mL / min Retention time: ~15.2 minutes (purified form of bempedoic acid)

[0239] Determination of the purity of compound (bempedoic acid) of formula (V) The level of purity of the purified form of the compound of formula (V) is measured using a high-performance liquid detector equipped with a UV detector. The determination was made using chromatography. Assays for the purified form of the compound of formula (V) are performed at 98-102% (anhydrous solvent-free). It was determined that it falls within the scope of the system. Column: Waters XBridge BEH C18 (4.6mm inner diameter x 150m) (m, 2.5μm) Mobile phase: A: 0.05% phosphoric acid (H3PO4) in H2O: ACN (50:50) Sample temperature: Ambient Column temperature: 40℃ Detection: 215nm Flow rate: 1.2mL / min Analysis time: 16 minutes. Gradient: constant composition Retention time: ~4.6 minutes (purified form of bempedoic acid) Embedding by reference The full disclosures of each patent document and scientific paper referenced herein are to be used for any purpose. It is incorporated by [the method described]. Equal portions This invention may be embodied in other specific forms without departing from its spirit or essential features. This may also be done. Therefore, the embodiments described above do not limit the invention described herein. It should be considered exemplary in all respects, and therefore the scope of the present invention is This is indicated by the attached claims, not by the above description, and is equivalent to the claims. All changes in taste and range are intended to be included.

Claims

[Claim 1] A method for producing the compound of formula (V), (a) Ethyl isobutyrate is contacted with substituted 5-chloropentane in the presence of a first base to form the compound of formula (I), The substituted 5-chloropentane is selected from the group consisting of 1-bromo-5-chloropentane and 1-iodo-5-chloropentane. (b) Compound of formula (I) ＋ [X] － By contacting it with the salt of, a compound of formula (II) is formed, (wherein, [M] ＋ is selected from the group consisting of Li ＋ , Na ＋ and K ＋ , and [X] － is selected from the group consisting of Br － and I － .) (c) In the presence of a second base, the compound of formula (II) is contacted with toluenesulfonylmethyl isocyanide to form a first intermediate, and the first intermediate is contacted with an acid to form the compound of formula (IV). (d) A method for producing the compound of formula (V), comprising contacting the compound of formula (IV) with a reducing agent to form a second intermediate, and contacting the second intermediate with a hydrolyzing base to form the compound of formula (V).

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