METHODS OF MAKING BEMPEDOIC ACID AND COMPOSITIONS OF THE SAME

CROSS-REFERENCE

This application claims the benefit of and priority to U.S. Patent Application No. 62/864,873, filed on June 21, 2019, the entire contents of which are incorporated by reference herein.

BACKGROUND

The development of robust, cost-effective and efficient manufacturing methods for the production of pharmaceutically active compounds with desired yield and purity remains a significant challenge. Bempedoic acid (8-hydroxy -2, 2, 14, 14-tetramethylpentadecanedioic acid) is a compound under development for the treatment of a wide variety of diseases including liver disorders and cardiovascular disease. Accordingly, a process for synthesizing bempedoic acid (8-hydroxy -2, 2, 14, 14-tetramethylpentadecanedioic acid) is desired, whereby the product has purity and impurity profiles required by regulatory agencies for the production of a commercializable drug product.

SUMMARY

The inventors have discovered an efficient process for producing high purity bempedoic acid, as well as highly pure, stable forms of bempedoic acid suitable for use as an active pharmaceutical ingredient.

In one aspect, the invention provides methods of preparing a compound of formula (V):

or a pharmaceutically acceptable salt thereof. The compound of formula (V), or a

pharmaceutically acceptable salt thereof, can be of high purity. Accordingly, in certain embodiments, the invention provides methods of preparing a pharmaceutical material comprising a compound of formula (V), or a pharmaceutically acceptable salt thereof, where the pharmaceutical material includes the compound of formula (V), or a pharmaceutically acceptable salt thereof, in an amount greater than 99.0% by weight based on the total weight of the pharmaceutical material.

In various embodiments of the invention, the method generally comprises:

(a) contacting ethyl isobutyrate with a substituted 5-chloropentane in the presence of a first base to form a compound of formula (I):

wherein the substituted 5-chloropentane is selected from the group consisting of 1-bromo-5-chloropentane and l-iodo-5-chloropentane;

(b) contacting the compound of formula (I) with a salt of formula [M]+[X] to form a compound of formula (II):

wherein [M]+ is selected from the group consisting of Li+, Na+ and K+, wherein [X] is selected from the group consisting of Br and G;

(c) contacting the compound of formula (II) with toluenesulfonylmethyl 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):

(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.

In certain embodiments of the invention, the method comprises:

(a) contacting l-bromo-5-chloropentane with about 1 to about 1.21 molar equivalents of ethyl isobutyrate in the presence of lithium diisopropylamide at a temperature in the range of about -20 °C to about 0 °C to form a compound of formula (I):

(b) contacting the compound of formula (I) with about 1.1 molar equivalents of sodium iodide in 2-butanone at a temperature in the range of about 78 °C to about 82 °C to form a compound of formula (Ha):

(c) contacting the compound of formula (Ila) with toluenesulfonylmethyl isocyanide in the presence of sodium tert-pentoxide in dimethylacetamide at a temperature in the range of about -20 °C to about 10 °C to form an intermediate, and contacting the intermediate with an acid at a temperature in the range of about -10 °C to about 35 °C to form a compound of formula (IV):

(d) contacting the compound of formula (IV) with about 0.35 molar equivalents of sodium borohydride to form a second intermediate, and contacting the second intermediate with sodium hydroxide in a solution to form a compound of formula (V).

In certain embodiments of the invention, the method further comprises:

(e) purifying the compound of formula (V) to provide a pharmaceutical material comprising a purified amount of the compound of formula (V).

In certain embodiments of the invention, purifying the compound of formula (V) comprises:

(f) adjusting the pH of the solution comprising the compound of formula (V) to about 6;

(g) extracting the compound of formula (V) from the solution using methyl tert-butyl ether to provide a methyl tert-butyl ether solution comprising the compound of formula (V);

(h) exchanging the methyl tert-butyl ether of the methyl tert-butyl ether solution with ethyl acetate to provide an ethyl acetate solution comprising the compound of formula (V);

(i) filtering the ethyl acetate solution comprising the compound of formula (V) through silica gel;

(j) crystallizing the compound of formula (V) using ethyl acetate and water to provide a crystalline form of the compound of formula (V); and

(k) recrystallizing the crystalline form of the compound of formula (V) using ethyl acetate and water to provide a pharmaceutical material comprising a purified amount of the compound of formula (V).

In another aspect, the invention provides high purity or purified bempedoic acid, or a pharmaceutically acceptable salt thereof. For example, described herein are pharmaceutical materials comprising a compound of formula (V):

or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical material comprises the compound of formula (V), or a pharmaceutically acceptable salt thereof, in an amount greater than 99.0% by weight based on the total weight of the pharmaceutical material.

In various embodiments, the pharmaceutical material comprises a crystalline form of the compound of formula (V), or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical material comprises the compound of formula (V) in an amount greater than 99.0% by weight based on the total weight of the pharmaceutical material.

In another aspect, the invention provides pharmaceutical compositions or formulations including high purity bempedoic acid, or a pharmaceutically acceptable salt thereof, such as the pharmaceutical materials described herein. For example, a pharmaceutical composition can include a pharmaceutical material of the invention (e.g., a pharmaceutical material comprising the compound of formula (V), or a pharmaceutically acceptable salt thereof, in an amount greater than 99.0% by weight based on the total weight of the pharmaceutical material); and a pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition can include a therapeutically effective amount of a pharmaceutical material of the invention; and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises a crystalline form of the compound of formula (V), or a

pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Purified bempedoic acid, or a pharmaceutically acceptable salt thereof; a crystalline form of bempedoic acid, or a pharmaceutically acceptable salt thereof; a pharmaceutical material of the invention (e.g., a pharmaceutical material comprising the compound of formula (V), or a pharmaceutically acceptable salt thereof, in an amount greater than 99.0% by weight based on the total weight of the pharmaceutical material); or a pharmaceutical composition of the invention can be used in treating the various conditions and diseases described herein. For example, the methods of treatment can include inhibiting adenosine triphosphate citrate lyase (ACL), inhibiting cholesterol synthesis, and/or suppressing fatty acid biosynthesis. In some embodiments, the condition or disease can be hyperlipidemia such as primary hyperlipidemia and the methods include treating hyperlipidemia such as primary hyperlipidemia. In some embodiments, the disease can be cardiovascular disease and the methods include treating cardiovascular disease. In various embodiments, the methods of treatment can include improving or lowering low density lipid cholesterol (LDL-C), non-high density lipid cholesterol (non-HDL-C), total serum cholesterol (TC), apolipoprotein B (apoB), and/or high sensitivity C-reactive protein (hsCRP).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an exemplary reaction scheme of the invention for the synthesis of bempedoic acid (i.e., a compound of formula (V)) as described in Example 1, which reaction scheme includes the synthesis of a pharmaceutical material comprising the compound of formula (V) in an amount greater than 99.0% by weight based on the total weight of the pharmaceutical material.

FIG. 2 is an exemplary 1H-NMR spectrum of the compound of formula (V).

FIG. 3 is an exemplary 13C-NMR spectrum of the compound of formula (V).

FIG. 4 is an X-ray powder diffraction pattern of the crystalline form of the compound of formula (V), as further described in Example 1.

FIG. 5 is an overlay of differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curves of the crystalline form of the compound of formula (V), as further described in Example 1.

FIG. 6 is a water sorption isotherm of the crystalline form of the compound of formula (V).

DETAILED DESCRIPTION OF THE INVENTION

It has now been discovered that bempedoic acid, including pharmaceutically acceptable salts thereof, can be prepared with high purity and/or in bulk quantities. In various

embodiments, a crystalline form of bempedoic acid, or a pharmaceutically acceptable salt thereof, is provided.

The methods for preparing bempedoic acid described herein can provide a

pharmaceutical material containing a high level or amount of bempedoic acid, or a

pharmaceutically acceptable salt thereof, in part, due to the control of the formation of hard-to-remove impurities during the synthetic process.

In addition, a pharmaceutical material with a high purity crystalline form of bempedoic acid, or a pharmaceutically acceptable salt thereof, is provided, for example, where the pharmaceutical material comprises the crystalline form of bempedoic acid, or a

pharmaceutically acceptable salt thereof, and wherein the pharmaceutical material comprises

bemepedoic acid, or a pharmaceutically acceptable salt thereof, in an amount greater than 99.0% by weight based on the total weight of the pharmaceutical material.

I. DEFINITIONS

To facilitate an understanding of the present invention, a number of terms and phrases are defined below.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

Throughout the description, where compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

In the application, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.

Further, it should be understood that elements and/or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present invention, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various

embodiments of compositions of the present invention and/or in methods of the present invention, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and invention(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the invention(s) described and depicted herein.

The articles“a” and“an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article, unless the context is inappropriate. By way of example,“an element” means one element or more than one element.

The term“and/or” is used in this disclosure to mean either“and” or“or” unless indicated otherwise.

It should be understood that the expression“at least one of’ includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression“and/or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context.

The use of the term“include,”“includes,”“including,”“have,”“has,”“having,” “contain,”“contains,” or“containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.

Where the use of the term“about” is before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term“about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred from the context.

Where a molecular weight is provided and not an absolute value, for example, of a polymer, then the molecular weight should be understood to be an average molecule weight, unless otherwise stated or understood from the context.

It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present invention remain operable. Moreover, two or more steps or actions may be conducted simultaneously.

At various places in the present specification, variable or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 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, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

The use of any and all examples, or exemplary language herein, for example,“such as” or“including,” is intended merely to illustrate better the present invention and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present invention.

As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

As used herein,“pharmaceutically acceptable salt” refers to any salt of an acidic or a basic group that may be present in a compound of the present invention, which salt is compatible with pharmaceutical administration. For example, one or both of the carboxylic acid groups of bempedoic acid can be transformed to pharmaceutically acceptable salt(s).

As is known to those of skill in the art,“salts” of compounds may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acid. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

Examples of bases include, but are not limited to, alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and compounds of formula NW4+, wherein W is Ci-4 alkyl, and the like.

Examples of salts include, but are not limited, to acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate,

flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present invention compounded with a suitable cation such as Na+, K+, Ca2+, NH-f , and NWf (where W can be a Ci-4 alkyl group), and the like.

For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

As used herein,“pharmaceutical composition” or“pharmaceutical formulation” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

The phrases“pharmaceutically acceptable” and“pharmacologically acceptable,” as used herein, refer to compounds, molecular entities, compositions, materials, and/or dosage forms that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.“Pharmaceutically acceptable” and“pharmacologically acceptable” can mean approved or approvable by a regulatory agency of the federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

As used herein,“carrier” refers to a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent such as bempedoic acid, or a pharmaceutically acceptable salt thereof, from one organ, or portion of the body, to another organ, or portion of the body.

As used herein,“pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, such as a phosphate buffered saline solution, emulsions (e.g., such as an oil/water or water/oil emulsions), lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention. For examples of excipients, see Martin,

Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

As used herein,“treating” or“treatment” includes any effect, for example, lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof. Treating can be curing, improving, or at least partially ameliorating the disorder. In certain embodiments, treating is curing the disease.

As used herein,“reducing” or“reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).

As used herein,“effective amount” or“therapeutically-effective amount” refers to the amount of a compound (e.g., a compound of the present invention) sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term“treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the

improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

As used herein,“subject” and“patient” are used interchangeably and refer to an organism to be treated by the methods and compositions of the present invention. Such organisms are preferably a mammal (e.g., human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, and rhesus), and more preferably, a human.

As used herein,“disease,”“disorder,”“condition,” or“illness,” can be used

interchangeably unless otherwise underacted or understood from the context, refers to a state of being or health status of a patient or subject capable of being treated with a compound, pharmaceutical materials, pharmaceutical composition, or method provided herein. In some

embodiments, the compounds and methods described herein comprise reduction or elimination of one or more symptoms of the disease, disorder, or condition, or illness e.g., through administration of the compound of formula (V), or a pharmaceutically acceptable salt thereof.

As used herein,“administering” means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular,

intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini -osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By“co administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g., anti cancer agent, chemotherapeutic, or treatment for a neurodegenerative disease). The compound of the invention can be administered alone or can be co-administered to the patient. Co administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).

As used herein,“liver disorder” refers generally to a disease, a disorder, and/or a condition affecting the liver, and may have a wide range of severity encompassing, for example, simple accumulation of fat in the hepatocytes (steatosis), macrovescicular steatosis, periportal and lobular inflammation (steatohepatitis), cirrhosis, fibrosis, liver cancers, and liver failure.

As used herein,“fatty liver disease” (“FLD”), which is also called“fatty liver,” refers to a disease leading to liver injury caused by abnormal fat accumulation in liver cells. FLD may arise from a number of sources, including excessive alcohol consumption and metabolic disorders, such as those associated with insulin resistance, obesity, and hypertension.

As used herein,“non-alcoholic fatty liver disease” (“NAFLD”) refers to the spectrum of disorders resulting from an accumulation of fat in liver cells in individuals with no history of excessive alcohol consumption. In the mildest form, NAFLD refers to hepatic steatosis.

As used herein,“drug-induced liver disease” or“toxic liver injury” refers to a disease or a condition in which an active agent has caused injury to the liver.

As used herein,“alcoholic liver disease,” also called“alcoholic liver injury,” refers to a disease caused by fat accumulation in liver cells, caused at least in part by alcohol ingestion. Examples include, but are not limited to, diseases such as alcoholic simple fatty liver, alcoholic steatohepatitis (“ASH”), alcoholic hepatic fibrosis, alcoholic cirrhosis, alcoholic fatty liver disease, and the like. It should be noted that alcoholic steatohepatitis is also called alcoholic fatty hepatitis and includes alcoholic hepatic fibrosis.

As used herein,“fatty liver of pregnancy” refers to acute fatty liver conditions that can arise during pregnancy and can be life-threatening.

As used herein,“altering lipid metabolism” refers to an observable (measurable) change in at least one aspect of lipid metabolism, including but not limited to total blood lipid content, blood HDL cholesterol, blood LDL cholesterol, blood VLDL cholesterol, blood triglyceride, blood Lp(a), blood apo A-I, blood apo E and blood non-esterified fatty acids.

As used herein,“altering glucose metabolism” refers to an observable (measurable) change in at least one aspect of glucose metabolism, including but not limited to total blood glucose content, blood insulin, the blood insulin to blood glucose ratio, insulin sensitivity, and oxygen consumption.

As used herein,“purified bempedoic acid” means that, when isolated as a solid, a pharmaceutical material contains at least 95% by weight of 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid based on the total weight of the pharmaceutical material. In certain embodiments, purified bempedoic acid means that, when isolated as a solid, a pharmaceutical material contains at least 99.0% by weight of 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid based on the total weight of the pharmaceutical material. In addition, purified bempedoic acid can include a pharmaceutically acceptable salt thereof, unless stated otherwise or understood from the context.

As used herein, a reaction that is“substantially complete” means that the reaction contains more than about 80% by weight of the desired product. In certain embodiments, a substantially complete reaction contains more than about 90% by weight of the desired product. In certain embodiments, a substantially complete reaction contains more than about 95% by weight of the desired product. In certain embodiments, a substantially complete reaction

contains more than about 97% by weight of the desired product.

Unless stated otherwise, all X-ray powder diffraction (XRPD) patterns described herein correspond to XRPD patterns measured using a Cu Ka radiation source, and the crystalline forms of bempedoic acid are analyzed by XRPD at ambient temperature.

II. CRYSTALLINE FORMS OF BEMPEDOIC ACID

A. Crystalline Bempedoic Acid

In one aspect, the invention provides a crystalline form of 8-hydroxy-2,2, 14, 14-tetramethylpentadecanedioic acid, which is also known as and referred to herein as“bempedoic acid” and/or a compound of formula (V):

In certain embodiments, the crystalline form of the compound of formula (V) may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 10.3±0.2, 10.4±0.2, 17.9±0.2, 18.8±0.2, 19.5±0.2, and 20.7±0.2. In certain embodiments, the crystalline form of the compound of formula (V) may be

characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 10.3±0.2, 10.4±0.2, 17.6±0.2, 17.9±0.2, 18.8±0.2, 19.5±0.2, 19.7±0.2, 20.4±0.2, 20.7±0.2 and 22.6±0.2.

In certain embodiments, the crystalline form of the compound of formula (V) is characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q, and optionally inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 1.

Table 1 - X-ray Powder Diffraction Data of the Crystalline Form of the Compound of Formula (V)

In certain embodiments, the crystalline form of the compound of formula (V) is characterized by an X-ray powder diffraction pattern substantially the same as shown in FIG. 4.

In certain embodiments, the crystalline form of the compound of formula (V) exists in a monoclinic crystal system and has a P2i !c space group. In certain embodiments, the crystalline form of the compound of formula (V) is characterized by the crystallographic unit cell parameters as set forth in Table 2.

Table 2 - Unit Cell Parameters of the Crystalline Form of Compound of Formula (V)

The crystalline form of the compound of formula (V) may also be characterized according to the temperature of melting point onset. Accordingly, in certain embodiments, the crystalline form of the compound of formula (V) has a melting point onset as determined by differential scanning calorimetry in the range of from about 82 °C to about 94 °C. In certain embodiments, the crystalline form of the compound of formula (V) has a melting point onset as determined by differential scanning calorimetry in the range of about 90 °C to about 94 °C. In certain embodiments, the crystalline form of the compound of formula (V) has a melting point onset as determined by differential scanning calorimetry at about 92 °C. In certain

embodiments, the crystalline form of the compound of formula (V) has a differential scanning calorimetry curve substantially the same as shown in FIG. 5.

The crystalline form of the compound of formula (V) may also be characterized according to its mass gain/mass loss as a function of temperature. Accordingly, in certain embodiments, the crystalline form of the compound of formula (V) exhibits a reduction in mass, as determined by thermogravimetric analysis, of from about 0.1% to about 0.7% upon heating to about 200 °C. In certain embodiments, the crystalline form of the compound of formula (V) exhibits a reduction in mass, as determined by thermogravimetric analysis, of less than or equal to about 0.7% upon heating to about 200 °C. In certain embodiments, the crystalline form of the compound of formula (V) has a thermogravimetric analysis curve substantially the same as shown in FIG. 5.

The crystalline form of the compound of formula (V) may also be characterized according to its water sorption properties. Accordingly, in certain embodiments, the crystalline form of the compound of formula (V) exhibits a change in mass, as determined by dynamic vapor sorption, of from about 0.01% to about 0.05% at a relative humidity of 80% and a temperature of 25 °C. In certain embodiments, the crystalline form of the compound of formula (V) exhibits a change in mass, as determined by dynamic vapor sorption, of about 0.03% at a relative humidity of 80% and a temperature of 25 °C. In certain embodiments, the crystalline form of the compound of formula (V) has a water sorption isotherm, when measured at 25 °C, substantially the same as shown in FIG. 6.

It should be understood that reference herein to bempedoic acid or a purified bempedoic acid includes the crystalline form of bempedoic acid, unless otherwise stated or understood from the context.

B. Crystalline Salt Forms of Bempedoic Acid

In addition, it has been discovered that various crystalline salt forms of bempedoic acid can be prepared. In particular, the following counter ions produced crystalline salt forms of bempedoic acid: ammonium, sodium, potassium, calcium (two crystal forms), lysine, diethylamine, ethylenediamine, piperazine, betaine, tromethamine, and isonicotinamide.

(i) Crystalline Betaine Salt Form of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is a crystalline betaine salt of bempedoic acid. In certain embodiments, the crystalline betaine salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 6.2±0.2, 13.5±0.2, 17.5±0.2, 19.3±0.2, and 25.6±0.2.

In certain embodiments, the crystalline betaine salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 6.2±0.2, 13.5±0.2, 16.1±0.2, 17.5±0.2, 19.3±0.2, 19.9±0.2, 25.6±0.2, and 27.2±0.2.

In certain embodiments, the crystalline betaine salt of bempedoic acid is characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q, and optionally inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 3.

Table 3 - X-ray Powder Diffraction Data of the Crystalline Betaine Salt of Bempedoic Acid

(ii) Crystalline Calcium Salt Forms of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is a crystalline calcium salt of bempedoic acid. In certain embodiments, the crystalline calcium salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 4.9±0.2, 9.1±0.2, and 19.7±0.2. In certain

embodiments, the crystalline calcium salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 4.9±0.2, 6.4±0.2, 9.1±0.2, 14.8±0.2, 19.7±0.2, and 37.1±0.2.

In certain embodiments, the crystalline calcium salt of bempedoic acid is characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q, and optionally inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 4.

Table 4 - X-ray Powder Diffraction Data of the Crystalline Calcium Salt of Bempedoic Acid

In certain embodiments, the crystalline calcium salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 6.0±0.2, 6.8±0.2, 8.5±0.2, and 9.8±0.2. In certain embodiments, the crystalline calcium salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 6.0±0.2, 6.8±0.2, 8.5±0.2, 9.8±0.2, 17.1±0.2, and 19.0±0.2.

In certain embodiments, the crystalline calcium salt of bempedoic acid is characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q, and

optionally inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 5.

Table 5 - X-ray Powder Diffraction Data of the Crystalline Calcium Salt of Bempedoic Acid

(iii) Crystalline Diethylamine Salt Form of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is a crystalline diethylamine salt of bempedoic acid. In certain embodiments, the crystalline diethylamine salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 9.6±0.2, 14.1±0.2, and 19.8±0.2. In certain embodiments, the crystalline diethylamine salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 9.6±0.2, 14.1±0.2, 17.8±0.2, 19.8±0.2, 22.6±0.2, and 38.7±0.2.

In certain embodiments, the crystalline diethylamine salt of bempedoic acid is characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q, and optionally inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 6.

Table 6 - X-ray Powder Diffraction Data of the Crystalline Diethylamine Salt of

Bempedoic Acid

(iv) Crystalline Ethylenediamine Salt Form of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is a crystalline ethylenediamine salt of bempedoic acid. In certain embodiments, the crystalline

ethylenediamine salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 6.8±0.2, 10.8±0.2, 16.2±0.2, 18.3±0.2, and 18.8±0.2. In certain embodiments, the crystalline ethylenediamine salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 6.8±0.2, 7.7±0.2, 10.8±0.2, 13.9±0.2, 15.2±0.2, 16.2±0.2, 18.3±0.2, 18.8±0.2, 21.4±0.2, and 22.3±0.2.

In certain embodiments, the crystalline ethylenediamine salt of bempedoic acid is characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q, and optionally inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 7.

Table 7 - X-ray Powder Diffraction Data of the Crystalline Ethylenediamine Salt of Bempedoic Acid

(v) Crystalline Isonicotinamide Salt Form of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is a crystalline isonicotinamide salt of bempedoic acid. In certain embodiments, the crystalline

isonicotinamide salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 4.4±0.2, 18.8±0.2, 20.1±0.2, and 24.5±0.2. In certain embodiments, the crystalline isonicotinamide salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 4.4±0.2, 14.5±0.2, 18.8±0.2, 20.1±0.2, 24.5±0.2, 26.2±0.2, and 29.5±0.2.

In certain embodiments, the crystalline isonicotinamide salt of bempedoic acid is characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q, and optionally inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 8.

Table 8 - X-ray Powder Diffraction Data of the Crystalline Isonicotinamide Salt of Bempedoic Acid

(vi) Crystalline Potassium Salt Form of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is a crystalline potassium salt of bempedoic acid. In certain embodiments, the crystalline potassium salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 5.7±0.2, 7.3±0.2, 9.6±0.2, and 22.1±0.2. In certain embodiments, the crystalline potassium salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q):

5.7±0.2, 7.3±0.2, 9.6±0.2, 16.0±0.2, 22.1±0.2, and 23.0±0.2.

In certain embodiments, the crystalline potassium salt of bempedoic acid is

characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q, and optionally inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 9.

Table 9 - X-ray Powder Diffraction Data of the Crystalline Potassium Salt of Bempedoic Acid

(vii) Crystalline Lysine Salt Form of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is a crystalline lysine salt of bempedoic acid. In certain embodiments, the crystalline lysine salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 4.2±0.2, 10.2±0.2, 19.1±0.2, 19.7±0.2, and 21.9±0.2. In certain embodiments, the crystalline lysine salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 4.2±0.2, 10.2±0.2, 13.5±0.2, 14.2±0.2, 16.0±0.2, 19.1±0.2, 19.7±0.2, and 21.9±0.2.

In certain embodiments, the crystalline lysine salt of bempedoic acid is characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q, and optionally inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 10.

Table 10 - X-ray Powder Diffraction Data of the Crystalline Lysine Salt of Bempedoic Acid

(viii) Crystalline Sodium Salt Form of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is a crystalline sodium salt of bempedoic acid. In certain embodiments, the crystalline sodium salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 6.1±0.2, 14.2±0.2, 18.3±0.2, and 24.5±0.2. In certain embodiments, the crystalline sodium salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

In certain embodiments, the crystalline sodium salt of bempedoic acid is characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q, and optionally inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 11.

Table 11 - X-ray Powder Diffraction Data of the Crystalline Sodium Salt of Bempedoic Acid

(ix) Crystalline Ammonium Salt Form of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is a crystalline ammonium salt of bempedoic acid. In certain embodiments, the crystalline ammonium salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 6.9±0.2, 7.1±0.2, 14.3±0.2, 16.0±0.2, and 21.4±0.2. In certain embodiments, the crystalline ammonium salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 6.9±0.2, 7.1±0.2, 9.3±0.2, 14.3±0.2, 16.0±0.2, 18.2±0.2, 19.2±0.2, 21.4±0.2, and

22.3±0.2.

In certain embodiments, the crystalline ammonium salt of bempedoic acid is characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q, and optionally inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 12.

Table 12 - X-ray Powder Diffraction Data of the Crystalline Ammonium Salt of Bempedoic Acid

(x) Crystalline Piperazine Salt Form of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is a crystalline piperazine salt of bempedoic acid. In certain embodiments, the crystalline piperazine salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 6.7±0.2, 8.7±0.2, 10.7±0.2, 15.7±0.2, and 16.0±0.2. In certain embodiments, the crystalline piperazine salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 6.7±0.2, 8.7±0.2, 10.7±0.2, 15.7±0.2, 16.0±0.2, 19.4±0.2, 20.1±0.2, and 21.4±0.2.

In certain embodiments, the crystalline piperazine salt of bempedoic acid is

characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q, and optionally inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 13.

Table 13 - X-ray Powder Diffraction Data of the Crystalline Piperazine Salt of Bempedoic Acid

(xi) Crystalline Tromethamine Salt Form of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is a crystalline tromethamine salt of bempedoic acid. In certain embodiments, the crystalline tromethamine salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 6.6±0.2, 18.2±0.2, 18.6±0.2, and 19.8±0.2. In certain embodiments, the crystalline tromethamine salt of bempedoic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 6.6±0.2, 13.6±0.2, 18.2±0.2, 18.6±0.2, 19.8±0.2, and 26.5±0.2.

In certain embodiments, the crystalline tromethamine salt of bempedoic acid is characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q, and optionally inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 14.

Table 14 - X-ray Powder Diffraction Data of the Crystalline Tromethamine Salt of Bempedoic Acid

C. Co-crystal Forms of Bempedoic Acid

Moreover, it was discovered that certain co-crystal forms of bempedoic acid could be prepared. In particular, the following co-formers produced co-crystals with bempedoic acid: palmitic acid and aspartame (two crystal forms).

(i) Co-crystal of Bempedoic Acid and Aspartame

In certain embodiments, the co-crystal form of bempedoic acid is a co-crystal form of bempedoic acid and aspartame. In certain embodiments, the co-crystal form of bempedoic acid and aspartame may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 7.6±0.2, 8.6±0.2, 17.3±0.2, 18.4±0.2, and 25.1±0.2. In certain embodiments, the co-crystal form of bempedoic acid and aspartame may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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, 26.1.

In certain embodiments, the co-crystal form of bempedoic acid and aspartame is characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q, and optionally inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 15.

Table 15 - X-ray Powder Diffraction Data of the Co-crystal Form of Bempedoic Acid and Aspartame

In certain embodiments, the co-crystal form of bempedoic acid and aspartame may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 4.4±0.2, 6.8±0.2, 10.6±0.2, 13.2±0.2, and 18.4±0.2. In certain embodiments, the co-crystal form of bempedoic acid and aspartame may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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, 17.6±0.2, and 18.4±0.2.

In certain embodiments, the co-crystal form of bempedoic acid and aspartame is characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q, and optionally inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 16.

Table 16 - X-ray Powder Diffraction Data of the Co-crystal Form of Bempedoic Acid and Aspartame

(ii) Co-crystal of Bempedoic Acid and Palmitic Acid

In certain embodiments, the co-crystal form of bempedoic acid is a co-crystal form of bempedoic acid and palmitic acid. In certain embodiments, the co-crystal form of bempedoic acid and palmitic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 4.3±0.2, 6.3±0.2, 8.5±0.2, and 17.0±0.2. In certain embodiments, the co-crystal form of bempedoic acid and palmitic acid may be characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 4.3±0.2, 6.3±0.2, 8.5±0.2, 10.5±0.2, 17.0±0.2, and 25.5±0.2.

In certain embodiments, the co-crystal form of bempedoic acid and palmitic acid is characterized by the X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q, and optionally inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak) as set forth in Table 17.

Table 17 - X-ray Powder Diffraction Data of the Co-crystal Form of Bempedoic Acid and Palmitic Acid

III. METHODS OF PREPARING BEMPEDOIC ACID INCLUDING PURIFIED BEMPEDOIC ACID

As described herein, in one aspect, the invention provides methods of preparing 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid, which is a compound of formula (V):

which methods also include making a pharmaceutically acceptable salt thereof.

It should be understood that methods of the invention include preparing bempedoic acid. In certain embodiments, the methods of preparing bempedoic acid result in purified bempedoic acid, which also can be described herein with respect to a pharmaceutical material, i.e., a pharmaceutical material comprising an amount of bempedoic acid or an amount of a compound of formula (V), or a pharmaceutically acceptable salt thereof. These terms and phrases can be used interchangeably herein, unless otherwise stated or understood from the context.

Accordingly, in various embodiments, methods are provided for preparing a pharmaceutical material comprising a compound of formula (V):

or a pharmaceutically acceptable salt thereof.

In various embodiments, the methods generally include:

(a) contacting ethyl isobutyrate with a substituted 5-chloropentane in the presence of a first base to form a compound of formula (I):

wherein the substituted 5-chloropentane is selected from the group consisting of l-bromo-5-chloropentane and l-iodo-5-chloropentane;

(b) contacting the compound of formula (I) with a salt of formula [M]+[X] to form a compound of formula (II):

wherein [M]+ is selected from the group consisting of Li+, Na+ and K+, wherein [X] is selected from the group consisting of Br and G;

(c) contacting the compound of formula (II) with toluenesulfonylmethyl 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):

(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).

In certain embodiments of the invention, the method further comprises:

(e) purifying the compound of formula (V) to provide a pharmaceutical material comprising a purified amount of the compound of formula (V).

Synthesis of a Compound of Formula (I)— Step (a)

In various embodiments, synthesis of the compound of formula (I):

generally comprises contacting ethyl isobutyrate with a substituted 5-chloropentane in the presence of a first base.

In certain embodiments, in step (a), contacting ethyl isobutyrate with the substituted 5-chloropentane in the presence of a first base is conducted at a temperature in the range of from about -30 °C to about 10 °C, from about -25 °C to about 10 °C, from about -20 °C to about 10 °C, from about -18 °C to about 10 °C, from about -15 °C to about 10 °C, from about -10 °C to about 10 °C, 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 -30 °C to about 5 °C, from about -30 °C to about 0 °C, from about -30 °C to about -5 °C, from about -30 °C to about -10 °C, from about -30 °C to about -15 °C, from about -30 °C to about -18 °C, from about -30 °C to about -20 °C, from about -30 °C to about -25 °C, from about -25 °C to about 5 °C, from about -25 °C to about 0 °C, from about -25 °C to about -5 °C, from about -25 °C to about -10 °C, from about -25 °C to about -15 °C, from about -25 °C to about -18 °C, from about -25 °C to about -20 °C, from about -20 °C to about 5 °C, from about -20 °C to about 0 °C, from about -20 °C to about -5 °C, from about -20 °C to about -10 °C, from about -20 °C to about -15 °C, from about -20 °C to about -18 °C, from about -18 °C to about 5 °C, from about -18 °C to about 0 °C, from about -18 °C to about -5 °C, from about -18 °C to about -10 °C, from about -18 °C to about -15 °C, from about -15 °C to about 5 °C, from about -15 °C to about 0 °C, from about -15 °C to about -5 °C, from about -15 °C to about -10 °C, from about -10 °C to about 5 °C, from about -10 °C to about 0 °C, from about -10 °C to about -5 °C, from about -5 °C to about 5 °C, or from about -5 °C to about 0 °C. In certain embodiments, in step (a), contacting ethyl isobutyrate with the substituted 5-chloropentane in the presence of a first base is conducted at a temperature in the range of from about -20 °C to about 0 °C. In certain embodiments, in step (a), contacting ethyl isobutyrate with the substituted 5-chloropentane in the presence of a first base is conducted at a temperature in the range of from about -18 °C to about -5 °C.

In certain embodiments, in step (a), less than about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, about 1% by weight, about 1.1% by weight, about 1.2% by weight, about 1.3% by weight, about 1.4% by weight, or about 1.5% by weight of the substituted 5-chloropentane remains after forming the compound of formula (I). In some embodiments, in step (a), less than about 1% by weight of the substituted 5-chloropentane remains after forming the compound of formula (I).

In certain embodiments, in step (a), the molar ratio of ethyl isobutyrate to the substituted 5-chloropentane is about 1 : 1, about 1.01 : 1, about 1.02: 1, about 1.03 : 1, about 1.04: 1, about 1.05: 1, about 1.06: 1, about 1.07: 1, about 1.08: 1, about 1.09: 1, about 1.1 : 1, about 1.11 : 1, about 1.12: 1, about 1.13 : 1, about 1.14: 1, about 1.15: 1, about 1.16: 1, about 1.17: 1, about 1.18: 1, about 1.19: 1, about 1.2: 1, or about 1.21 : 1, including the ranges between each of these ratios. In some embodiments, in step (a), the molar ratio of ethyl isobutyrate to the substituted 5-chloropentane is about 1.1 : 1. In some embodiments, the molar ratio of ethyl isobutyrate to the substituted 5-chloropentane is from about 1.1 : 1 to about 1.21 : 1.

In certain embodiments, in step (a), the substituted 5-chloropentane is contacted ethyl isobutyrate, which is present in an amount of about 1 molar equivalent, about 1.01 molar equivalents, about 1.02 molar equivalents, about 1.03 molar equivalents, about 1.04 molar equivalents, about 1.05 molar equivalents, about 1.06 molar equivalents, about 1.07 molar

equivalents, about 1.08 molar equivalents, about 1.09 molar equivalents, about 1.1 molar equivalents, about 1.11 molar equivalents, about 1.12 molar equivalents, about 1.13 molar equivalents, about 1.14 molar equivalents, about 1.15 molar equivalents, about 1.16 molar equivalents, about 1.17 molar equivalents, about 1.18 molar equivalents, about 1.19 molar equivalents, about 1.2 molar equivalents, or about 1.21 molar equivalents. In some

embodiments, in step (a), the substituted 5-chloropentane is contacted with about 1.1 molar equivalents of ethyl isobutyrate.

In certain embodiments, in step (a), contacting ethyl isobutyrate and the substituted 5-chloropentane occurs by adding ethyl isobutyrate and the substituted 5-chloropentane to a reactor. In some embodiments, in step (a), adding ethyl isobutyrate and the substituted 5-chloropentane to the reactor occurs at a temperature of less than about 10 °C, less than about 5 °C, less than about 0 °C, less than about -5 °C, less than about -10 °C, less than about -15 °C, less than about -20 °C, less than about -25 °C, or less than about -30 °C. In some embodiments, in step (a), adding ethyl isobutyrate and the substituted 5-chloropentane to the reactor occurs at a temperature of about 10 °C, about 5 °C, about 0 °C, about -5 °C, about -7 °C, about -10 °C, about -12 °C, about -14 °C, about -16 °C, about -18 °C, about -20 °C, about -22 °C, about -24 °C, about -26 °C, about -28 °C, or about -30 °C. In some embodiments, in step (a), adding ethyl isobutyrate and the substituted 5-chloropentane to the reactor occurs at a temperature of about -5 °C. In some embodiments, in step (a), adding ethyl isobutyrate and the substituted 5-chloropentane to the reactor occurs at a temperature of about -12 °C. In some embodiments, in step (a), adding ethyl isobutyrate and the substituted 5-chloropentane to the reactor occurs at a temperature of about -18 °C.

In certain embodiments, in step (a), the time of adding ethyl isobutyrate and the substituted 5-chloropentane to the reactor is about 5 mins, about 10 mins, about 15 mins, about 20 mins, about 30 mins, about 40 mins, about 50 mins, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours.

In certain embodiments, in step (a), the time of adding ethyl isobutyrate and the substituted 5-chloropentane to the reactor is from about 10 mins to about 60 mins, from about 20 mins to about 60 mins, from about 30 mins to about 60 mins, from about 40 mins to about 60 mins, from about 50 mins to about 60 mins, from about 10 mins to about 50 mins, from about 10 mins to about 40 mins, from about 10 mins to about 30 mins, from about 10 mins to

about 20 mins, from about 20 mins to about 50 mins, from about 20 mins to about 40 mins, from about 20 mins to about 30 mins, from about 30 mins to about 50 mins, from about 30 mins to about 40 mins, or from about 40 mins to about 50 mins.

In certain embodiments, in step (a), the time of adding ethyl isobutyrate and the substituted 5-chloropentane to the reactor is from about 1 hour to about 12 hours, from about 2 hours to about 12 hours, from about 3 hours to about 12 hours, from about 4 hours to about 12 hours, from about 5 hours to about 12 hours, from about 6 hours to about 12 hours, from about 7 hours to about 12 hours, from about 8 hours to about 12 hours, from about 9 hours to about 12 hours, from about 10 hours to about 12 hours, from about 11 hours to about 12 hours, from about 1 hours to about 11 hours, from about 1 hours to about 10 hours, from about 1 hours to about 9 hours, from about 1 hours to about 8 hours, from about 1 hours to about 7 hours, from about 1 hours to about 6 hours, from about 1 hours to about 5 hours, from about 1 hours to about 4 hours, from about 1 hours to about 3 hours, from about 1 hours to about 2 hours, from about 2 hours to about 11 hours, from about 2 hours to about 10 hours, from about 2 hours to about 9 hours, from about 2 hours to about 8 hours, from about 2 hours to about 7 hours, from about 2 hours to about 6 hours, from about 2 hours to about 5 hours, from about 2 hours to about 4 hours, from about 2 hours to about 3 hours, from about 3 hours to about 11 hours, from about 3 hours to about 10 hours, from about 3 hours to about 9 hours, from about 3 hours to about 8 hours, from about 3 hours to about 7 hours, from about 3 hours to about 6 hours, from about 3 hours to about 5 hours, from about 3 hours to about 4 hours, from about 4 hours to about 11 hours, from about 4 hours to about 10 hours, from about 4 hours to about 9 hours, from about 4 hours to about 8 hours, from about 4 hours to about 7 hours, from about 4 hours to about 6 hours, from about 4 hours to about 5 hours, from about 5 hours to about 11 hours, from about 5 hours to about 10 hours, from about 5 hours to about 9 hours, from about 5 hours to about 8 hours, from about 5 hours to about 7 hours, from about 5 hours to about 6 hours, from about 6 hours to about 11 hours, from about 6 hours to about 10 hours, from about 6 hours to about 9 hours, from about 6 hours to about 8 hours, from about 6 hours to about 7 hours, from about 7 hours to about 11 hours, from about 7 hours to about 10 hours, from about 7 hours to about 9 hours, from about 7 hours to about 8 hours, from about 8 hours to about 11 hours, from about 8 hours to about 10 hours, from about 8 hours to about 9 hours, from about 9 hours to about 11 hours, from about 9 hours to about 10 hours, or from about 10 hours to about 11 hours.

In some embodiments, adding ethyl isobutyrate and the substituted 5-chloropentane to the reactor occurs simultaneously. In some embodiments, adding ethyl isobutyrate to the reactor occurs prior to adding the substituted 5-chloropentane to the reactor. In some embodiments, adding ethyl isobutyrate to the reactor occurs after adding the substituted 5-chloropentane to the reactor.

In certain embodiments, contacting ethyl isobutyrate with the substituted 5-chloropentane in the presence of a first base forms a reaction mixture. In certain embodiments, in step (a), at the end of the reaction, the methods include quenching the reaction mixture with an acid. In some embodiments, the acid is hydrochloric acid.

In certain embodiments, ethyl isobutyrate and the substituted 5-chloropentane are starting materials used in the production of the compound of formula (I). In certain

embodiments, the purity of the substituted 5-chloropentane is > 99%, > 99.1%, > 99.2%, > 99.3%, > 99.4%, > 99.5%, > 99.6%, > 99.7%, > 99.8%, or > 99.9%, as measured by gas chromatography (GC). In some embodiments, the purity of the substituted 5-chloropentane is > 99%, as measured by GC.

In certain embodiments, the purity of ethyl isobutyrate is > 99%, > 99.1%, > 99.2%, > 99.3%, > 99.4%, > 99.5%, > 99.6%, > 99.7%, > 99.8%, or > 99.9%, as measured by gas chromatography (GC). In some embodiments, the purity of ethyl isobutyrate is > 99.5%, as measured by GC.

In certain embodiments, the concentration of ethanol present in ethyl isobutyrate is < 0.05%, < 0.06%, < 0.07%, < 0.08%, < 0.09%, < 0.1%, < 0.11%, < 0.12%, < 0.13%, < 0.14%, or < 0.15%, as measured by GC. In some embodiments, the concentration of ethanol present in ethyl isobutyrate is < 0.1%, as measured by GC.

In certain embodiments, the substituted 5-chloropentane is l-iodo-5-chloropentane. In certain embodiments, the substituted 5-chloropentane is l-bromo-5-chloropentane.

In certain embodiments, the purity of l-iodo-5-chloropentane or l-bromo-5-chloropentane is > 99%, > 99.1%, > 99.2%, > 99.3%, > 99.4%, > 99.5%, > 99.6%, > 99.7%, > 99.8%, or > 99.9%, as measured by gas chromatography (GC).

In certain embodiments, in step (a), the first base is selected from the group consisting of lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium hydride, sodium amide, lithium amide, and lithium tetramethylpiperidide. In some embodiments, in step (a), the first base is lithium diisopropylamide.

In certain embodiments, the amount of unreacted substituted 5-chloropentane remaining upon completion of step (a) is < 0.05%, < 0.06%, < 0.07%, < 0.08%, < 0.09%, < 0.1%, < 0.11%, < 0.12%, < 0.12%, < 0.13%, < 0.14%, < 0.15%, < 0.16%, < 0.17%, < 0.18%, < 0.19%, or < 0.2%, as measured by GC. In some embodiments, the amount of unreacted substituted 5-chloropentane remaining upon completion of step (a) is < 0.21%, < 0.22%, < 0.23%, < 0.24%,

< 0.25%, < 0.25% ,< 0.26%, < 0.27%, < 0.28%, < 0.29%, < 0.3%, < 0.31%, < 0.32%, < 0.33%,

< 0.34%, < 0.35%, < 0.36%, < 0.37%, < 0.38%, < 0.39%, or < 0.4%, as measured by GC.

Synthesis of Lithium Diisopropylamide (A First Base for Makins the Compound of Formula

Oil

In various embodiments, the synthesis of lithium diisopropylamide, which is a base used for making the compound of formula (I):

generally comprises contacting diisopropylamine with butyllithium.

In certain embodiments, the molar ratio of butyllithium to diisopropylamine is about 1 : 1.04, about 1 : 1.05, about 1 : 1.06, about 1 : 1.07, about 1 : 1.08, about 1 : 1.09, about 1 : 1.1, about 1 : 1.2, about 1 : 1.3, about 1 : 1.4, about 1 : 1.5, or about 1 : 1.6. In some embodiments, the molar ratio of butyllithium to diisopropylamine is about 1 : 1.07. In some embodiments, the molar ratio of butyllithium to diisopropylamine is about 1 : 1.5.

In certain embodiments, the molar ratio of butyllithium to diisopropylamine is from about 1 : 1.04 to about 1 : 1.1, from about 1 : 1.05 to about 1 : 1.1, from about 1 : 1.06 to about 1 : 1.1, from about 1 : 1.07 to about 1 : 1.1, from about 1 : 1.08 to about 1 : 1.1, from about 1 : 1.09 to about 1 : 1, from about 1 : 1.04 to about 1 : 1.09, from about 1 : 1.04 to about 1 : 1.08, from about 1 : 1.04 to about 1 : 1.07, from about 1 : 1.04 to about 1 : 1.06, from about 1 : 1.04 to about 1 : 1.05, from about 1 : 1.05 to about 1 : 1.09, from about 1 : 1.05 to about 1 : 1.08, from about 1 : 1.05 to about 1 : 1.07, from about 1 : 1.05 to about 1 : 1.06, from about 1 : 1.06 to about 1 : 1.09, from about 1 : 1.06 to about 1 : 1.08, from about 1 : 1.06 to about 1 : 1.07, from about 1 : 1.07 to about 1 : 1.09, from about 1 : 1.07 to about 1 : 1.08, or from about 1 : 1.08 to about 1 : 1.09. In some embodiments, the molar ratio of butyllithium to diisopropylamine is from about 1 : 1.06 to about 1 : 1.07.

In certain embodiments, contacting diisopropylamine with butyllithium is conducted at a temperature of < 0 °C, < -5 °C, < -10 °C, < -15 °C, or < -20 °C. In some embodiments,

contacting diisopropylamine with butyllithium is conducted at a temperature of < -5 °C.

In certain embodiments, contacting diisopropylamine with butyllithium is conducted in tetrahydrofuran (THF).

In certain embodiments, lithium diisopropylamide is prepared before step (a), for example, before contacting ethyl isobutyrate with l-bromo-5-chloropentane.

In certain embodiments, lithium diisopropylamide is prepared in situ during step (a), for example, while contacting ethyl isobutyrate with l-bromo-5-chloropentane. In some embodiments, when lithium diisopropylamide is prepared in situ during step (a), the molar ratio of the substituted 5-chloropentane to ethyl isobutyrate to butyllithium to diisopropylamine is about 1 : 1.1 : 1.2: 1.26, about 1 : 1.1 : 1.15: 1.75, about 1 : 1.1 : 1.24: 1.3, about 1 : 1.1 : 1.2: 1.29, about 1 : 1.1 :1.2: 1.28, or about 1 : 1-1.25: 1.15-1.2: 1.25-1.75. In some embodiments, when lithium diisopropylamide is prepared in situ during step (a), the molar ratio of the substituted 5-chloropentane to ethyl isobutyrate to butyllithium to diisopropylamine is about 1 : 1.1 : 1.2: 1.28.

In some embodiments, the substituted 5-chloropentane is l-bromo-5-chloropentane. Synthesis of a Compound of Formula (II)— Step (b)

In various embodiments, the synthesis of a compound of formula (II):

wherein X is Br or I, generally comprises contacting the compound of formula (I) with a salt of formula [M]+[X] .

In certain embodiments, in step (b), contacting the compound of formula (I) with a salt of formula [M]+[X] , is conducted in a solvent comprising one or more of acetone, 2-butanone, methyl isobutyl ketone, THF and 3-pentanone, 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.

In certain embodiments, in step (b), the solvent comprises less than about 3.5% by weight water, less than about 3% by weight water, less than about 2.5% by weight water, less than about 2% by weight water, less than about 1.5% by weight water, less than about 1% by weight water, or less than about 0.5% by weight water. In some embodiments, in step (b), the solvent comprises less than less than about 3% by weight water.

In certain embodiments, in step (b), contacting the compound of formula (I) with the

salt of formula [M]+[X] comprises contacting the compound of formula (I) with about 1 molar equivalent, about 1.05 molar equivalents, about 1.1 molar equivalents, about 1.15 molar equivalents, about 1.2 molar equivalents, or about 1.25 molar equivalents of the salt of formula [M]+[X] based on the molar amount of the compound of formula (I). In certain embodiments, in step (b), contacting the compound of formula (I) with the salt of formula [M]+[X] comprises contacting the compound of formula (I) with about 1.1 molar equivalents of the salt of formula [M]+[X] based on the molar amount of the compound of formula (I).

In certain embodiments, in step (b), contacting the compound of formula (I) with the salt of formula [M]+[X] is conducted at a temperature in the range of from about 75 °C to about 85 °C, from about 76 °C to about 85 °C, from about 77 °C to about 85 °C, from about 78 °C to about 85 °C, from about 79 °C to about 85 °C, from about 80 °C to about 85 °C, from about 81 °C to about 85 °C, from about 82 °C to about 85 °C, from about 83 °C to about 85 °C, from about 84 °C to about 85 °C, from about 75 °C to about 84 °C, from about 75 °C to about 83 °C, from about 75 °C to about 82 °C, from about 75 °C to about 81 °C, from about 75 °C to about 80 °C, from about 75 °C to about 79 °C, from about 75 °C to about 78 °C, from about 75 °C to about 77 °C, from about 75 °C to about 76 °C, from about 76 °C to about 84 °C, from about 76 °C to about 83 °C, from about 76 °C to about 82 °C, from about 76 °C to about 81 °C, from about 76 °C to about 80 °C, from about 76 °C to about 79 °C, from about 76 °C to about 78 °C, from about 76 °C to about 77 °C, from about 77 °C to about 84 °C, from about 77 °C to about 83 °C, from about 77 °C to about 82 °C, from about 77 °C to about 81 °C, from about 77 °C to about 80 °C, from about 77 °C to about 79 °C, from about 77 °C to about 78 °C, from about 78 °C to about 84 °C, from about 78 °C to about 83 °C, from about 78 °C to about 82 °C, from about 78 °C to about 81 °C, from about 78 °C to about 80 °C, from about 78 °C to about 79 °C, from about 79 °C to about 84 °C, from about 79 °C to about 83 °C, from about 79 °C to about 82 °C, from about 79 °C to about 81 °C, from about 79 °C to about 80 °C, from about 80 °C to about 84 °C, from about 80 °C to about 83 °C, from about 80 °C to about 82 °C, from about 80 °C to about 81 °C, from about 81 °C to about 84 °C, from about 81 °C to about 83 °C, from about 81 °C to about 82 °C, from about 82 °C to about 84 °C, from about 82 °C to about 83 °C, or from about 83 °C to about 84 °C. In some embodiments, in step (b), contacting the compound of formula (I) with the salt of formula [M]+[X] is conducted at a temperature in the range of from about 78 °C to about 82 °C.

In certain embodiments, in step (b), the salt of formula [M]+[X] is selected from the group consisting of lithium bromide (LiBr), lithium iodide (Lil), potassium bromide (KBr), potassium iodide (KI), sodium bromide (NaBr) and sodium iodide (Nal). In some embodiments, in step (b), the salt of formula [M]+[X] is sodium iodide.

Synthesis of a Compound of Formula (IV)— Step (c)

In various embodiments, the synthesis of a compound of formula (IV):

generally comprises contacting the compound of formula (II) with toluenesulfonylmethyl isocyanide in the presence of a second base to form a first intermediate, and contacting the first intermediate with an acid.

Synthesis of the First Intermediate

In various embodiments, the synthesis of the first intermediate:

generally comprises contacting the compound of formula (II) with toluenesulfonylmethyl isocyanide in the presence of a second base.

In certain embodiments, in step (c), the second base is selected from sodium hydride, potassium tert-butoxide, and sodium tert-pentoxide. In some embodiments, in step (c), the second base is sodium tert-pentoxide.

In certain embodiments, in step (c), contacting the compound of formula (II) with toluenesulfonylmethyl isocyanide in the presence of sodium tert-pentoxide to form the first intermediate is conducted at a temperature in a range of from about -20 °C to about 10 °C, from about -10 °C to about 10 °C, from about 0 °C to about 10 °C, from about -20 °C to about 0 °C, from about -20 °C to about -10 °C, or from about -10 °C to about 0 °C. In certain embodiments, in step (c), contacting the compound of formula (II) with toluenesulfonylmethyl isocyanide in the presence of sodium tert-pentoxide to form the first intermediate is conducted at a temperature in a range of from about -20 °C to about 10 °C. In certain embodiments, in step

(c), contacting the compound of formula (II) with toluenesulfonylmethyl isocyanide in the presence of sodium tert-pentoxide to form the first intermediate is conducted at a temperature in a range of from about -15 °C to about 0 °C.

In certain embodiments, in step (c), contacting the compound of formula (II) with toluenesulfonylmethyl isocyanide in the presence of a second base to form the first

intermediate is conducted at a temperature of about -20 °C, about -15 °C, about -10 °C, about -5 °C, or about 0 °C.

In certain embodiments, in step (c), the molar ratio of the compound of formula (II) to toluenesulfonylmethyl isocyanide is about 1.7: 1, about 1.8: 1, about 1.9: 1, about 2: 1, about 2.1 : 1 , or about 2.2: 1. In certain embodiments, in step (c), the molar ratio of the compound of formula (II) to toluenesulfonylmethyl isocyanide is about 1.9: 1.

In some embodiments, in step (c), the molar ratio of the compound of formula (II) to toluenesulfonylmethyl isocyanide to the second base is about 1.9: 1.0:2.1. In some

embodiments, in step (c), the molar ratio of the compound of formula (II) to

toluenesulfonylmethyl isocyanide to the second base is about 1.9: 1.0:2.2.

In some embodiments, in step (c), the molar ratio of the compound of formula (II) to toluenesulfonylmethyl isocyanide to sodium tert-pentoxide is about 1.9: 1.0:2.1. In some embodiments, in step (c), the molar ratio of the compound of formula (II) to

toluenesulfonylmethyl isocyanide to sodium tert-pentoxide is about 1.9: 1.0:2.2.

In certain embodiments, in step (c), contacting the compound of formula (II) with toluenesulfonylmethyl isocyanide is conducted in a solvent comprising dimethylacetamide or that is dimethylacetamide.

Synthesis of a Compound of Formula (TV)

In various embodiments, the synthesis of a compound of formula (IV):

generally comprises contacting the first intermediate with an acid.

In certain embodiments, in step (c), contacting the first intermediate with an acid is conducted at a temperature in a range of from about -15 °C to about 35 °C, from about -10 °C to about 35 °C, from about -5 °C to about 35 °C, from about 0 °C to about 35 °C, from about 5 °C to about 35 °C, from about 10 °C to about 35 °C, from about 15 °C to about 35 °C, from about 20 °C to about 35 °C, from about 25 °C to about 35 °C, from about 30 °C to about 35 °C, from about -15 °C to about 30 °C, from about -15 °C to about 25 °C, from about -15 °C to about 20 °C, from about -15 °C to about 15 °C, from about -15 °C to about 10 °C, from about -15 °C to about 5 °C, from about -15 °C to about 0 °C, from about -15 °C to about -5 °C, from about -15 °C to about -10 °C, from about -10 °C to about 30 °C, from about -10 °C to about 25 °C, from about -10 °C to about 20 °C, from about -10 °C to about 15 °C, from about -10 °C to about 10 °C, from about -10 °C to about 5 °C, from about -10 °C to about 10 °C, from about -10 °C to about -5 °C, from about -5 °C to about 30 °C, from about -5 °C to about 25 °C, from about -5 °C to about 20 °C, from about -5 °C to about 15 °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, from about 0 °C to about 30 °C, from about 0 °C to about 25 °C, from about 0 °C to about 20 °C, from about 0 °C to about 15 °C, from about 0 °C to about 10 °C, from about 0 °C to about 5 °C, from about 5 °C to about 30 °C, from about 5 °C to about 25 °C, from about 5 °C to about 20 °C, from about 5 °C to about 15 °C, from about 5 °C to about 10 °C, from about 10 °C to about 30 °C, from about 10 °C to about 25 °C, from about 10 °C to about 20 °C, from about 10 °C to about 15 °C, from about 15 °C to about 30 °C, from about 15 °C to about 25 °C, from about 15 °C to about 20 °C, from about 20 °C to about 30 °C, from about 20 °C to about 25 °C, or from about 25 °C to about 30 °C. In some embodiments, in step (c), contacting the first intermediate with an acid is conducted at a temperature in a range of from about -10 °C to about 35 °C. In some embodiments, in step (c), contacting the first intermediate with an acid is conducted at a temperature in a range of from about -15 °C to about 25 °C. In some embodiments, in step (c), contacting the first intermediate with an acid is conducted at a temperature in a range of from about 10 °C to about 25 °C.

In certain embodiments, in step (c), the acid is hydrochloric acid.

Synthesis of a Compound of Formula ( V)— Step (d)

In various embodiments the synthesis of a compound of formula (V):

generally comprises contacting the compound of formula (IV) with a reducing agent to form a second intermediate, and contacting the second intermediate with a hydrolyzing base.

Synthesis of the Second Intermediate

In various embodiments, the synthesis of the second intermediate:

generally comprises contacting the compound of formula (IV) with a reducing agent.

In certain embodiments, in step (d), the reducing agent is selected from the group consisting of sodium borohydride, sodium cyanoborohydride, cerium borohydride, zinc borohydride and diisobutylaluminum hydride. In some embodiments, the reducing agent is sodium borohydride.

CLAIMS

We claim:

1. A method of preparing a compound of formula (V):

the method comprising:

(a) contacting ethyl isobutyrate with a substituted 5-chloropentane in the presence of a first base to form a compound of formula (I):

wherein the substituted 5-chloropentane is selected from the group consisting of 1-bromo-5-chloropentane and l-iodo-5-chloropentane;

(b) contacting the compound of formula (I) with a salt of formula [M]+[X]

to form a compound of formula (II):

wherein [M]+ is selected from the group consisting of Li+, Na+ and K+, and [X] is selected from the group consisting of Br and G;

(c) contacting the compound of formula (II) with toluenesulfonylmethyl 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):

(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).

2 The method of claim 1, wherein in step (a), the first base is selected from the group

consisting of lithium diisopropyl amide, lithium bis(trimethylsilyl)amide, sodium hydride, sodium amide, lithium amide, and lithium tetramethylpiperidide.

3. The method of claim 1 or 2, wherein in step (a), contacting ethyl isobutyrate with the substituted 5-chloropentane is conducted at a temperature in the range of about -20 °C to about 0 °C.

4. The method of any one of claims 1-3, wherein in step (a), less than about 1% by weight of the substituted 5-chloropentane remains after forming the compound of formula (I).

5. The method of any one of claims 1-4, wherein in step (a), the molar ratio of ethyl isobutyrate to the substituted 5-chloropentane is from about 1.1 : 1 to about 1.21 : 1.

6. The method of any one of claims 1-5, wherein in step (b), contacting the compound of formula (I) with the salt of formula [M]+[X] is conducted in a solvent comprising one or more of acetone, 2-butanone, methyl isobutyl ketone, and tetrahydrofuran, 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.

7. The method of claim 6, wherein in step (b), the solvent comprises less than about 3% by weight water.

8. The method of any one of claims 1-7, wherein in step (b), contacting the compound of formula (I) with the salt of formula [M]+[X] is conducted at a temperature in the range of about 78 °C to about 82 °C, 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.

9. The method of any one of claims 1-8, wherein in step (b), contacting the compound of formula (I) with the salt of formula [M]+[X] comprises contacting the compound of formula (I) with about 1.1 molar equivalents of the salt of formula [M]+[X] based on the molar amount of the compound of formula (I), 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.

10. The method of any one of claims 1-9, wherein in step (b), the salt of formula [M]+[X] is sodium iodide.

11. The method of any one of claims 1-10, wherein in step (c), the second base is selected from sodium hydride, potassium tert-butoxide, and sodium tert-pentoxide.

12. The method of any one of claims 1-11, wherein in step (c), contacting the compound of formula (II) with toluenesulfonylmethyl isocyanide in the presence of a second base to form the first intermediate is conducted at a temperature in a range of about -20 °C to about 10 °C.

13. The method of any one of claims 1-12, wherein in step (c), the molar ratio of the compound of formula (II) to toluenesulfonylmethyl isocyanide is about 1.9: 1.

14. The method of any one of claims 1-13, wherein in step (c), contacting the compound of formula (II) with toluenesulfonylmethyl isocyanide is conducted in dimethylacetamide.

15. The method of any one of claims 1-14, wherein in step (c), contacting the first intermediate with an acid is conducted at a temperature in a range of about -10 °C to about 35 °C.

16. The method of any one of claims 1-15, wherein in step (c), the acid is hydrochloric acid.

17. The method of any one of claims 1-16, wherein in step (d), the reducing agent is selected from the group consisting of sodium borohydride, sodium cyanoborohydride, cerium borohydride, zinc borohydride and diisobutylaluminum hydride.

18. The method of any one of claims 1-17, wherein in step (d), contacting the compound of formula (IV) with a reducing agent comprises contacting the compound of formula (IV) with about 0.35 molar equivalents of the reducing agent based on the molar amount of the compound of formula (IV).

19. The method of any one of claims 1-18, wherein in step (d), the hydrolyzing base is sodium hydroxide.

20. The method of any one of claims 1-19, wherein in step (d), contacting the second intermediate with a hydrolyzing base to form a compound of formula (V) is conducted in a solution; and the method further comprises adjusting the pH of the solution comprising the compound of formula (V) to between about 3 to about 7.

21. The method of any one of claims 1-20, wherein in step (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) is conducted in a single reaction vessel.

22. The method of any one of claims 1-21, further comprising:

(e) purifying the compound of formula (V) to provide a pharmaceutical material comprising a purified amount of the compound of formula (V).

23. The method of claim 22, wherein in step (e), purifying the compound of formula (V) comprises filtering the compound of formula (V) in a solvent through silica gel.

24. The method of claim 22 or 23, wherein in step (e), purifying the compound of formula (V) comprises crystallizing the compound of formula (V).

25. The method of any one of claims 22-24, wherein in step (e), purifying the compound of formula (V) comprises crystallizing the compound of formula (V) from a solvent, wherein the solvent comprises ethyl acetate.

26. The method of any one of claims 22-25, wherein in step (e), purifying the compound of formula (V) comprises crystallizing the compound of formula (V) from a mixture of solvents, wherein the mixture of solvents comprises ethyl acetate and water.

27. The method of any one of claims 22-26, wherein in step (e), purifying the compound of formula (V) comprises crystallizing the compound of formula (V) to provide a crystalline form of the compound of formula (V), and the method further comprises recrystallizing the crystalline form of the compound of formula (V).

28. The method of claim 27, wherein crystallizing the compound of formula (V) and recrystallizing the crystalline form of the compound of formula (V) comprise crystallizing the compound of formula (V) in a mixture of solvents comprising ethyl acetate and water, and recrystallizing the crystalline form of the compound of formula (V) in a mixture of solvents comprising ethyl acetate and water.

29. The method of any one of claims 22-28, further comprising purifying the compound of formula (V) by contacting the compound of formula (V) with charcoal and then filtering the charcoal.

30. The method of any one of claims 22-29, wherein the purified amount of the compound

of formula (V) is greater than 99.0% by weight of the total weight of the pharmaceutical material.

31. A method of preparing a compound of formula (V):

the method comprising:

(a) contacting l-bromo-5-chloropentane with about 1.1 molar equivalents of ethyl isobutyrate in the presence of lithium diisopropylamide at a temperature in the range of about -20 °C to about 0 °C to form a compound of formula (I):

(b) contacting the compound of formula (I) with about 1.1 molar equivalents of sodium iodide in 2-butanone at a temperature in the range of about 78 °C to about 82 °C to form a compound of formula (Ha):

(c) contacting the compound of formula (Ila) with toluenesulfonylmethyl isocyanide in the presence of sodium tert-pentoxide in dimethylacetamide at a temperature in the range of about -20 °C to about 10 °C to form a first intermediate, and contacting the first intermediate with an acid at a temperature in the range of about -10 °C to about 35 °C to form a compound of formula (IV):

(d) contacting the compound of formula (IV) with about 0.35 molar equivalents of sodium borohydride to form a second intermediate, and contacting the second intermediate with sodium hydroxide in a solution to form a compound of formula (V).

32. The method of claim 31, wherein in step (c), the molar ratio of the compound of formula (Ila) to toluenesulfonylmethyl isocyanide to sodium tert-pentoxide is about 1.9: 1 :2.1.

33. The method of claim 31 or 32, further comprising:

(f) adjusting the pH of the solution comprising the compound of formula (V) to about 5 to about 6;

(g) extracting the compound of formula (V) from the solution using methyl tert-butyl ether to provide a methyl tert-butyl ether solution comprising the compound of formula (V);

(h) exchanging the methyl tert-butyl ether of the methyl tert-butyl ether solution with ethyl acetate to provide an ethyl acetate solution comprising the compound of formula (V);

(i) filtering the ethyl acetate solution comprising the compound of formula (V) through silica gel;

(j) crystallizing the compound of formula (V) using ethyl acetate and water to provide a crystalline form of the compound of formula (V); and

(k) recrystallizing the crystalline form of the compound of formula (V) using ethyl acetate and water to provide a pharmaceutical material comprising a purified amount of the compound of formula (V).

34. The method of claim 33 wherein in step (g), extracting the compound of formula (V) from the solution using methyl tert-butyl ether is conducted at a temperature less than or equal to about 50 °C.

35. The method of claim 33 or 34, wherein in step (j), crystallizing the compound of formula (V) using ethyl acetate and water is conducted over a temperature range of about 50 °C to about -5 °C.

36. The method of any one of claims 33-35, wherein in step (k), recrystallizing the crystalline form of the compound of formula (V) using ethyl acetate and water is conducted over a temperature range of about 70 °C to about 5 °C.

37. The method of any one of claims 33-36, further comprising:

(l) dissolving the crystalline form of the compound of formula (V) in acetonitrile, thereby forming a solution;

(m) contacting the solution with charcoal;

(n) filtering the charcoal to provide a purified solution comprising the compound of formula (V); and

(o) crystallizing the compound of formula (V) from the purified solution to provide a pharmaceutical material comprising a purified amount of the compound of formula (V).

38. The method of any one of claims 33-37, wherein the purified amount of the compound of formula (V) is greater than 99.0% by weight of the total weight of the pharmaceutical material.

39. A pharmaceutical material comprising a crystalline form of the compound of formula

(V):

or a pharmaceutically acceptable salt thereof;

wherein the pharmaceutical material comprises the compound of formula (V), or a pharmaceutically acceptable salt thereof, in an amount greater than 99.0% by weight based on the total weight of the pharmaceutical material.

40. The pharmaceutical material of claim 39, wherein the crystalline form of the compound of formula (V) exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 10.3±0.2, 10.4±0.2, 17.9±0.2, 18.8±0.2, 19.5±0.2, and 20.7±0.2.

41. The pharmaceutical material of claim 39, wherein the crystalline form of the compound of formula (V) is characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q:

42. The pharmaceutical material of any one of claims 39-41, wherein the crystalline form of the compound of formula (V) exists in a monoclinic crystal system and has a P2i !c space group.

43. The pharmaceutical material of claim 42, wherein the crystalline form of the compound of formula (V) is characterized by the following crystallographic unit cell parameters:

44. The pharmaceutical material of any one of claims 39-43, wherein the crystalline form of the compound of formula (V) is characterized by an X-ray powder diffraction pattern substantially the same as shown in FIG. 4.

45. The pharmaceutical material of any one of claims 39-44, wherein the crystalline form of the compound of formula (V) has a melting point onset as determined by differential scanning calorimetry in the range of from about 90 °C to about 94 °C.

46. The pharmaceutical material of claim 45, wherein the crystalline form of the compound of formula (V) has a melting point onset as determined by differential scanning calorimetry at about 92 °C.

47. The pharmaceutical material of any one of claims 39-46, wherein the crystalline form of the compound of formula (V) has a differential scanning calorimetry curve substantially the same as shown in FIG. 5.

48. The pharmaceutical material of any one of claims 39-47, wherein the pharmaceutical material comprises the compound of formula (V) in an amount greater than 99.5% by weight based on the total weight of the pharmaceutical material.

49. The pharmaceutical material of any one of claims 39-48, wherein the pharmaceutical material comprises the compound of formula (V) in an amount greater than 99.7% by weight based on the total weight of the pharmaceutical material.

50. The pharmaceutical material of any one of claims 39-49, wherein the pharmaceutical material comprises the compound of formula (V) in an amount greater than 99.9% by weight based on the total weight of the pharmaceutical material.

51. The pharmaceutical material of any one of claims 39-50, wherein the pharmaceutical material comprises the compound of formula (V) in an amount of from about 98% to about 102% by weight based on the total weight of the pharmaceutical material, as determined by a high performance liquid chromatography (HPLC) assay.

52. The pharmaceutical material of claim 51, wherein the HPLC assay uses a Waters XBridge BEH C18 column (4.6 mm i.d. x 150 mm, 2.5 pm) at a temperature of about 40 °C, with isocratic elution of a mobile phase comprising about 0.05% phosphoric acid in

water/acetonitrile (about 50:50) at a flow rate of about 1.2 mL/minute, and detection at 215 nm, wherein the retention time of the compound of formula (V) is about 4.6 minutes.

53. The pharmaceutical material of any one of claims 39-52, further comprising a compound of formula (VI):

or a pharmaceutically acceptable salt thereof.

54. The pharmaceutical material of claim 53, wherein the pharmaceutical material comprises the compound of formula (IX), or a pharmaceutically acceptable salt thereof, in an amount no greater than about 0.15% by weight based on the total weight of the pharmaceutical material.

55. The pharmaceutical material of any one of claims 40-54, further comprising a compound of formula (VII):

or a pharmaceutically acceptable salt thereof.

56. The pharmaceutical material of claim 55, wherein the pharmaceutical material comprises the compound of formula (VII), or a pharmaceutically acceptable salt thereof, in an amount no greater than about 0.15% by weight based on the total weight of the pharmaceutical material.

57. The pharmaceutical material of any one of claims 39-56, further comprising less than or equal to 0.2% by weight of unknown impurities.

58. A pharmaceutical formulation comprising:

the pharmaceutical material of any one of claims 39-57; and

a pharmaceutically acceptable excipient.

59. A method of treating a disease or a condition as described herein, the method comprising administering to a patient a therapeutically-effective amount of the pharmaceutical material of any one of claims 39-57, or of the pharmaceutical formulation of claim 58.

60. The method of claim 59, wherein the disease or condition is primary hyperlipidemia.

61. A method of treating primary hyperlipidemia in a patient in need thereof, the method comprising administering to a patient a therapeutically-effective amount of the pharmaceutical material of any one of claims 39-57, or of the pharmaceutical formulation of claim 58.