Purification method for naproxen and pregabalin 1-(acyloxy)-alkylcarbamate drug conjugates

Abstract

Described herein is a method for purifying the conjugate (S)-3-((((S)-1-((S)-2-(6-methoxynaphthalen-2-yl)propanoyloxy)ethoxy)carbonyl-amino)methyl)-5-methylhexanoic acid.

Description

[Technical Field]

[0001] cross reference This patent application claims the benefit of International Patent Application PCT / CN2022 / 134094, filed November 24, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Several treatments involving the administration of single drugs are currently recommended for the relief of pain, including neurological pain. Single doses of narcotic analgesics, gamma (γ)-aminobutyric acid (GABA) analogs such as gabapentin, pregabalin, and baclofen, antidepressants, and nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to exhibit pain-relieving properties in clinical settings and in various animal models. Summary of the Invention

[0003] Described herein is a purification method for obtaining Compound 1 from a mother liquor, comprising the steps of:

[0004] [ka] A purification method is disclosed that includes a salt formation step that includes contacting a mother liquor containing:

[0005] In some embodiments of the purification method, the amine is N-methylbenzylamine.

[0006] In some embodiments of the purification method, the salt formed in the salt-forming step is

[0007] [ka] is.

[0008] In some embodiments of the purification method, the method comprises:

[0009] [ka] with an acid to obtain Compound 1.

[0010] In some embodiments of the purification method, the acid is KHSO4.

[0011] In some embodiments of the purification method, Compound 1 is crystalline.

[0012] In some embodiments of the purification method, crystalline Compound 1 is characterized by X-ray powder diffraction (XRPD) peaks at 9.0±0.1°2θ, 10.3±0.1°2θ, 13.8±0.1°2θ, and 15.7±0.1°2θ.

[0013] In some embodiments of the purification method, crystalline Compound 1 is characterized by having at least one additional X-ray powder diffraction (XRPD) peak at 16.3±0.1°2θ, 19.8±0.1°2θ, 21.9±0.1°2θ, 22.7±0.1°2θ, and 24.1±0.1°2θ.

[0014] In some embodiments of the purification method, crystalline Compound 1 is characterized by X-ray powder diffraction (XRPD) peaks at 8.1±0.1°2θ, 9.0±0.1°2θ, 10.3±0.1°2θ, 13.8±0.1°2θ, 15.7±0.1°2θ, 16.3±0.1°2θ, 19.8±0.1°2θ, 21.9±0.1°2θ, 22.7±0.1°2θ, and 24.1±0.1°2θ.

[0015] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is between about 70 / 30 and about 90 / 10.

[0016] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is between about 75 / 25 and about 90 / 10.

[0017] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is between about 80 / 20 and about 90 / 10.

[0018] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is about 85 / 15.

[0019] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is about 84 / 16.

[0020] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is about 83 / 17.

[0021] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is about 82 / 18.

[0022] In some embodiments of the purification method, the mother liquor is obtained from a process for preparing compound 2.

[0023] In some embodiments, the method for preparing compound 2 comprises:

[0024] [ka] of

[0025] [ka] Contact with

[0026] [ka] The method includes the step of obtaining:

[0027] In some embodiments, the method for preparing compound 2 comprises contacting compound C with naproxen.

[0028] [ka] The method further comprises the step of obtaining:

[0029] In some embodiments, the method for preparing compound 2 includes contacting intermediate B with pregabalin to form

[0030] [ka] The method further comprises the step of obtaining:

[0031] In some embodiments, the method for preparing compound 2 further comprises resolving intermediate C to obtain compound 2 and a mother liquor.

[0032] In some embodiments, the resolution of intermediate C is carried out with isopropanol and heptane.

[0033] Also in this specification:

[0034] [ka] Also disclosed is a compound wherein:

[0035] Also provided herein is a method of treating osteoarthritis of the knee in a subject in need thereof, comprising:

[0036] [ka] or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0037] In some embodiments of the method of treating osteoarthritis of the knee, Compound 1 or a pharmaceutically acceptable salt thereof is administered locally to the knee. [Brief explanation of the drawings]

[0038] [Figure 1] FIG. 1 is an X-ray powder diffraction pattern of a crystalline form of Compound 1. DETAILED DESCRIPTION OF THE INVENTION

[0039] Several treatments involving the administration of single drugs are currently recommended for the relief of pain, including neurological pain. Single doses of narcotic analgesics, gamma (γ)-aminobutyric acid (GABA) analogs such as gabapentin, pregabalin, and baclofen, antidepressants, and nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to exhibit pain-relieving properties in clinical settings and in various animal models.

[0040] Despite the benefits of current single-drug pain relief regimens, these regimens have drawbacks. One area of ​​concern relates to the incidence of undesirable side effects caused by many of the pain treatment regimens available today. Narcotic analgesics such as morphine are rarely prescribed for chronic pain due to their well-known addictive effects, as well as central nervous system (CNS) and gastrointestinal side effects caused by single doses of the analgesic.

[0041] Another concern about current pain treatment regimens is their effectiveness.Many of the single active ingredients, such as antidepressants or GABA analogues, that are adopted in current pain relief regimens cannot achieve adequate pain relief, even at the maximum approved therapeutic dose for certain severe pain conditions.Increasing drug doses may not achieve adequate pain relief, and may also increase undesirable side effects such as cognitive impairment, dizziness, somnolence, nausea and constipation.

[0042] Additionally, other concerns about GABA analogs and many narcotic analgesics relate to their less than favorable pharmacokinetic and physiological properties. Many orally administered opioid molecules are extensively metabolized by the gastrointestinal tract before reaching the systemic circulation. The rapid systemic clearance and saturable absorption of some GABA analogs limit these drugs from achieving their full potential in the treatment of pain and other CNS disorders. These suboptimal properties often result in suboptimal efficacy and undesirable side effects for patients.

[0043] Sustained-release formulations are a conventional method for addressing the problem of rapid systemic clearance, as is well known to those skilled in the art (e.g., "Remington's Pharmaceutical Sciences," Philadelphia College of Pharmacy and Science, 17th ed., 1985). GABA analogs such as baclofen, gabapentin, and pregabalin are not absorbed by the large intestine. Rather, these compounds are typically absorbed in the small intestine by the neutral amino transport system (Jezyk et al., Pharm. Res., 1999, 16, 519-526). Rapid passage through conventional ducts has prevented successful application of sustained-release techniques to these GABA analogs.

[0044] Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for pain management, often as first-line therapy. Naproxen, approved by the FDA in 1976 and available over-the-counter in 1994, is one of the most commonly used NSAIDs for managing both acute and chronic pain. Oral use of NSAIDs such as naproxen, which result in systemic exposure, is generally well tolerated but is often associated with serious gastrointestinal (GI) side effects, such as ulcers or bleeding (Aleve USPI ref, Kyremateng 2019, Solomon 2017).

[0045] In light of these concerns, there is a clear need for improved pain regimens that provide improved therapeutic benefit (i.e., reduced pain severity and / or frequency) and / or reduce the incidence of undesirable side effects caused by many of the current regimens. Additionally, improving the pharmacokinetic profiles of GABA analogs would also lead to more tailored dosing regimens tailored to patient needs. Furthermore, local administration of NSAIDs via naproxen would eliminate gastrointestinal (GI) and systemic exposure, improving overall safety.

[0046] Naproxen is a commercially available product for the treatment of various types of pain (due to rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, tendonitis, bursitis, and acute gout), while pregabalin is marketed for the treatment of neuropathic pain, neuralgia, and fibromyalgia. Naproxen was first approved by the United States (US) Food and Drug Administration (FDA) in 1976 and approved as an over-the-counter (OTC) medication in 1994. Pregabalin was first approved by the US FDA in 2004 and has been available in generic form since 2018. Topical formulations of naproxen, designed to deliver naproxen locally, have been developed to reduce side effects and improve patient compliance (Patwardhan et al., 2017). A 10% w / v topical formulation of naproxen gel has been approved in several European countries (Momendol Gel). Similarly, various formulation development studies have been completed for pregabalin, and controlled transdermal alternatives to the traditional oral route have been developed to minimize its CNS side effects (Arafa and Ayoub 2017, Arafa and Ayoub 2017, Bhatia et al. 2012). Avoiding or minimizing the central nervous system (CNS)-mediated side effects of orally administered pregabalin may be a useful treatment option (Fukasawa et al. 2014). However, due to the hydrophilic chemical properties that make local delivery of pregabalin very difficult, topical pregabalin products are unlikely to be available on the market.

[0047] A multidisciplinary approach to pain treatment is recommended to minimize the adverse effects of individual medications and target different mechanisms of pain, including nociceptive, inflammatory, and neuropathic pain (Finnerup 2019; American Pain Society monograph on pain; Hsu et al. 2019). The use of such an approach may result in better efficacy and lower opioid use in pain management for both acute and chronic pain syndromes. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in pain management, often as first-line therapy. Naproxen, approved by the FDA in 1976 and available over-the-counter in 1994, is one of the most commonly used NSAIDs in the management of both acute and chronic pain. The addition of pregabalin, a drug known to target neuropathic pain, to NSAIDs can result in improved pain control in both acute pain (Wang et al., 2010, bunionectomy model) and chronic pain (Sofat et al., 2017 - wrist osteoarthritis; Derry et al., 2017 - acute and chronic neuropathic pain; Lambrechts et al., 2013 - chronic post-thoracotomy pain).

[0048] (S)-3-(((((S)-1-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid is a drug conjugate of pregabalin and naproxen. This drug conjugate is being developed for the management of both acute and chronic pain syndromes. Preclinical animal models have shown improved efficacy against pain and inflammation with the drug conjugate compared to naproxen alone. Topical (S)-3-(((((S)-1-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid fulfills an unmet clinical need for improved management of both acute and chronic pain and is expected to reduce the need for opioids. Pure (S)-3-(((((S)-1-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid is required.

[0049] definition Unless otherwise defined, 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.

[0050] As used in this specification and claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise.

[0051] "Drug conjugate" refers to a biologically active drug linked by a chemical linker having a labile chemical bond. Typically, the linker will be attached to the drug via a bond that is cleaved in vivo by enzymatic or non-enzymatic means.

[0052] "Solvate" refers to a compound (e.g., a compound described herein or a pharmaceutically acceptable salt thereof) that is physically associated with one or more molecules of a pharmaceutically acceptable solvent.

[0053] "Crystalline form" and "polymorph" may be used interchangeably herein and are meant to include all crystalline and amorphous forms of a compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a specific crystalline or amorphous form is referenced. The compounds of the present invention include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms, as well as mixtures thereof.

[0054] If the composition exists as a mixture of polymorphs, the proportion of each polymorphic component may be determined by one or more techniques well known in the art, including, but not limited to, solid state NMR, IR, and XRPD.

[0055] compound 1 Compound 1 is (S)-3-(((((S)-1-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid.

[0056] [ka]

[0057] In some embodiments, compound 1 has faster enzymatic cleavage than compound 2. In some embodiments, compound 1 has better local penetration than compound 2.

[0058] compound 2 Compound 2 is (S)-3-(((((R)-1-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid.

[0059] [ka]

[0060] compound 3 Compound 3 is the N-methylbenzylamine salt of (S)-3-(((((S)-1-(((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)ethoxy)carbonyl)amino)methyl)-5-methylhexanoic acid.

[0061] [ka]

[0062] Crystalline form of Compound 1 The crystalline form may be characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot stage microscopy, and spectroscopy (e.g., Raman, solid state nuclear magnetic resonance (ssNMR), and infrared (IR)).

[0063] XRPD Crystalline forms can be characterized by X-ray powder diffraction patterns (XRPD). The relative intensities of XRPD peaks can vary depending on particle size, sample preparation technique, sample mounting procedure, and the particular instrument utilized. Additionally, instrument variation and other factors can affect 2-theta values. Therefore, XRPD peak assignments can vary by plus or minus about 0.3 degrees. In some embodiments, the crystals have an X-ray powder diffraction pattern substantially similar to that shown in FIG. 1.

[0064] DSC Crystalline forms can also be identified by their characteristic differential scanning calorimetry (DSC) traces. With DSC, the observed temperatures are known to depend on the rate of temperature change as well as the sample preparation technique and the particular instrument used. Thus, values ​​reported herein relating to DSC thermograms can vary by plus or minus about 4°C.

[0065] TGA The crystalline forms of the present invention may also exhibit thermal behavior that differs from that of amorphous materials or other polymorphic forms. Thermal behavior can be measured in the laboratory by thermogravimetric analysis (TGA), which can be used to distinguish some polymorphic forms from other polymorphic forms. In one embodiment, the crystalline forms can be characterized by thermogravimetric analysis.

[0066] Disclosed herein are crystalline forms of Compound 1.

[0067] In some embodiments, crystalline Compound 1 is characterized by X-ray powder diffraction (XRPD) peaks at 9.0±0.1 degrees 2θ, 10.3±0.1 degrees 2θ, 13.8±0.1 degrees 2θ, and 15.7±0.1 degrees 2θ.

[0068] In some embodiments, crystalline Compound 1 is characterized by having at least one additional X-ray powder diffraction (XRPD) peak at 16.3±0.1°2θ, 19.8±0.1°2θ, 21.9±0.1°2θ, 22.7±0.1°2θ, and 24.1±0.1°2θ.

[0069] In some embodiments, crystalline Compound 1 is characterized by X-ray powder diffraction (XRPD) peaks at 8.1±0.1°2θ, 9.0±0.1°2θ, 10.3±0.1°2θ, 13.8±0.1°2θ, 15.7±0.1°2θ, 16.3±0.1°2θ, 19.8±0.1°2θ, 21.9±0.1°2θ, 22.7±0.1°2θ, and 24.1±0.1°2θ.

[0070] Purification method Described herein is a purification method for obtaining Compound 1 from a mother liquor, comprising the steps of:

[0071] [ka] A purification method is disclosed that includes a salt formation step that includes contacting a mother liquor containing:

[0072] In some embodiments of the purification method, the amine is a chiral amine. In some embodiments of the purification method, the amine is an achiral amine.

[0073] In some embodiments of the purification method, the amine is an arylalkylamine. In some embodiments of the purification method, the amine is an n-alkylarylalkylamine.

[0074] In some embodiments of the purification method, the amine is S-α-phenylethylamine, R-α-phenylethylamine, L-phenylalaninol, quinine, 1-(naphthalen-1-yl)ethan-1-amine, or N-methylbenzylamine. In some embodiments of the purification method, the amine is S-α-phenylethylamine or R-α-phenylethylamine. In some embodiments of the purification method, the amine is S-α-phenylethylamine. In some embodiments of the purification method, the amine is R-α-phenylethylamine. In some embodiments of the purification method, the amine is N-methylbenzylamine.

[0075] In some embodiments of the purification method, the salt formed in the salt-forming step is

[0076] [ka] is.

[0077] In some embodiments of the purification method, the salt formed in the salt-forming step is

[0078] [ka] is.

[0079] In some embodiments of the purification method, the salt formed in the salt-forming step is

[0080] [ka] is.

[0081] In some embodiments of the purification method, the salt formed in the salt-forming step is

[0082] [ka] is.

[0083] In some embodiments of the purification method, the method comprises:

[0084] [ka] with an acid to obtain Compound 1.

[0085] In some embodiments of the purification method, the method comprises:

[0086] [ka] with an acid to obtain Compound 1.

[0087] In some embodiments of the purification method, the method comprises:

[0088] [ka] with an acid to obtain Compound 1.

[0089] In some embodiments of the purification method, the method comprises:

[0090] [ka] with an acid to obtain Compound 1.

[0091] In some embodiments of the purification method, the acid is KHSO. In some embodiments of the purification method, the acid is HCl. In some embodiments of the purification method, the acid is acetic acid. In some embodiments of the purification method, the acid is sulfuric acid.

[0092] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is between about 70 / 30 and about 90 / 10.

[0093] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is between about 75 / 25 and about 90 / 10.

[0094] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is between about 80 / 20 and about 90 / 10.

[0095] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is between about 70 / 30 and about 85 / 15.

[0096] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is between about 75 / 25 and about 80 / 20.

[0097] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is about 90 / 10.

[0098] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is about 89 / 11.

[0099] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is about 88 / 12.

[0100] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is about 87 / 13.

[0101] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is about 86 / 14.

[0102] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is about 85 / 15.

[0103] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is about 84 / 16.

[0104] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is about 83 / 17.

[0105] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is about 82 / 18.

[0106] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is about 81 / 19.

[0107] In some embodiments of the purification method, the weight ratio of compound 1 / compound 2 in the mother liquor is about 80 / 20.

[0108] In some embodiments of the purification method, the mother liquor is obtained from a process for preparing compound 2.

[0109] In some embodiments of the method for preparing compound 2, the method comprises:

[0110] [ka] of

[0111] [ka] Contact with

[0112] [ka] The method includes the step of obtaining:

[0113] In some embodiments of the method for preparing compound 2, the method includes contacting compound C with naproxen to form

[0114] [ka] The method further comprises the step of obtaining:

[0115] In some embodiments of the method for preparing compound 2, the method comprises contacting intermediate B with pregabalin to obtain

[0116] [ka] The method further comprises the step of obtaining:

[0117] In some embodiments of the method for preparing compound 2, the method further comprises the step of resolving intermediate C to obtain compound 2 and a mother liquor.

[0118] In some embodiments of the process for preparing compound 2, the resolution of intermediate C is carried out with isopropanol and heptane.

[0119] Also in this specification:

[0120] [ka] Also disclosed is a compound wherein:

[0121] Also in this specification:

[0122] [ka] Also disclosed is a compound wherein:

[0123] Also in this specification:

[0124] [ka] Also disclosed is a compound wherein:

[0125] Also in this specification:

[0126] [ka] Also disclosed is a compound wherein:

[0127] Treatment method Provided herein is a method of treating osteoarthritis in a subject in need thereof, comprising:

[0128] [ka] or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0129] Provided herein is a method of treating osteoarthritis of the knee in a subject in need thereof, comprising:

[0130] [ka] or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0131] In some embodiments of the method of treating osteoarthritis of the knee, Compound 1 or a pharmaceutically acceptable salt thereof is administered locally to the knee.

[0132] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims and their equivalents be covered thereby. [Example]

[0133] The following examples describe in detail the preparation of Compound 1 and Compound 2, as well as salts of Compound 1. It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of the invention.

[0134] Example 1: Exemplary Salt Formation Conditions

[0135] [Table 1-1]

[0136] [Table 1-2]

[0137] [Table 1-3]

[0138] [Table 1-4]

[0139] [Table 1-5]

[0140] Example 2: Exemplary Salt Breaking Conditions

[0141] [Table 2-1]

[0142] [Table 2-2]

[0143] [Table 2-3]

[0144] [Table 2-4]

[0145] [Table 2-5]

[0146] [Table 2-6]

[0147] [Table 2-7]

[0148] [Table 2-8]

[0149] Example 3: Final Process Description

[0150] [ka]

[0151] The reactor was evacuated to below -0.08 MPa and then expanded to atmospheric pressure three times with nitrogen. NaHCO3 (2.0 equivalents) was dissolved in purified water (10 V). 2-Fluorophenol (1.0 equivalents) was added to the system. The temperature was lowered to 2±3°C, and 1-chloroethyl chloroformate (1.3 equivalents) was added dropwise to the system. After the dropwise addition, the temperature was raised to 15±5°C. n-Heptane (10 V) was added to the system, and the temperature was maintained at 25±5°C. The resulting mixture was stirred for at least 20 minutes. The mixture was then allowed to stand for at least 30 minutes, separated, and the organic phase was separated. The organic phase was washed twice with purified water (5 V) and once with a 10% NaCl (wt%) aqueous solution (5 V). The organic phase was concentrated to 4-5 V (in vacuo, system temperature below 50°C, jacket temperature below 60°C). Toluene (10 V) was added to the system, and the mixture was concentrated to 4-5 V (in vacuo, system temperature below 50 °C, jacket temperature below 60 °C). This process was repeated twice. Intermediate A was placed in a high-density polyethylene keg or a 304 stainless steel storage tank, weighed, and stored at room temperature.

[0152] [ka]

[0153] The reactor was evacuated to -0.08 MPa or less and then expanded to atmospheric pressure three times with nitrogen. Naproxen (2.0 equivalents) and Intermediate A (1.0 equivalent) were dispersed in toluene (5.0 V). Cuprous oxide (0.8 equivalents) was added to the system. The temperature was increased to 115±5°C. After reacting at 115±5°C for at least 8.0 hours, the reaction mixture was cooled to 60±5°C. Samples were taken for HPLC monitoring of the area % of Intermediate A below 2.5%. If the area % of Intermediate A was greater than 2.5%, the temperature was increased to 115±5°C for at least 1.0 hour of reaction, then cooled to 60±5°C, and samples were taken and HPLC monitoring was performed until the area % of Intermediate A was below 2.5%. When the area % of intermediate A was 2.5% or less, the temperature was decreased to 50±5°C, and MTBE (10.0V) was added to reactor A at 50±5°C, followed by continued temperature decrease to 25±5°C. The reaction mixture was filtered. The filter cake was washed twice with MTBE (0.5V). The filtrate was transferred to a new reactor. Purified water (10.0V) was added to the reactor, and the mixture was cooled to 0±5°C.

[0154] Ammonium hydroxide (15 wt%) (1.0-2.0 V) was slowly added to the reactor to adjust the pH to 9-11. The organic phase was separated and collected. The organic phase was washed once with an aqueous solution of ammonium hydroxide (0.5 wt%) (10.0 V). The organic phase was washed once with an aqueous solution of NaCl (10 wt%) (10.0 V). The organic phase was concentrated under vacuum below 50°C until the volume of the system reached 2.5-3.0 volumes. MeCN (10.0 V) was added to the reactor. The mixture was concentrated under vacuum below 50°C until the volume of the mixture reached 2.5-3.0 volumes. This process was repeated until the peak area ratio of toluene in the system was 10% or less. A sample was taken for HPLC analysis to determine the purity of Intermediate B. Specification: Intermediate B area % is 85.0% or more. Intermediate B in MeCN was packaged in a high-density polyethylene keg or a 304 stainless steel storage tank and stored at room temperature under nitrogen protection.

[0155] [ka]

[0156] The reactor was evacuated to below -0.08 MPa and then backfilled with nitrogen to atmospheric pressure three times. Intermediate B (1.0 equivalent) in ACN (1.5 V) and MTBE (2.0 V) was added. Purified water (2.0 V) was added to the system, followed by pregabalin (2.0 equivalents). The temperature was lowered to 15±5°C. TEA (2.0 equivalents) was added dropwise at 15±5°C, and then the temperature was raised to 25±3°C. The reaction proceeded at 25±3°C for at least 4 hours until the area percentage of intermediate B was 0.5% or less. The temperature was lowered to 5±5°C. A 10 wt% aqueous solution of KHSO4 (approximately 10-11 V) was added dropwise to the reactor at 5±5°C, and the pH was adjusted to 3-5. MTBE (5.0 V) was added to the system. The organic phase was separated and recovered. The organic phase was washed once with purified water (5.0 V). The organic phase was washed once with a 20 wt% NaCl aqueous solution (5.0 V). The organic phase was filtered through a microporous filter and then concentrated under vacuum at 45°C or less until the temperature reached 2.5-3.0 V. i-PrOH (5.0 V) was added to the reactor through a microporous filter, and the reaction mixture was concentrated under vacuum at 45°C or less until the temperature reached 2.5-3.0 V. This process was repeated until the total area ratio of MTBE and MeCN in the system was 5% or less. The reaction mixture was heated to 40-45°C and stirred until dissolved. Heptane (6.8 V) was added to the reactor at 40-45°C.

[0157] After stirring at 40-45°C for 1.0-1.5 hours, the mixture was cooled to 25±3°C, then stirred at 25±3°C for 15-16 hours, and then cooled to 10-15°C. The temperature was maintained at 10-15°C and the mixture was stirred for 1.0-1.5 hours. The reaction mixture was filtered. The resulting filter cake was washed twice with heptane (0.5V). The filter cake is Compound 2. The filtrate, containing some remaining Compound 2 and Compound 1, was collected and concentrated under vacuum at less than 45°C until the residual volume was 3-4V. This process was repeated three times. The mixture, containing some remaining Compound 2 and Compound 1, was transferred to a high-density polyethylene drum and stored at 10-30°C.

[0158] [ka]

[0159] The reactor was evacuated to -0.08 MPa or less and then backfilled with nitrogen to atmospheric pressure three times. A mixture containing some remaining compound 2 and compound 1 (1.0 equivalent) from step 4 and ethyl acetate (10 V) was added to the reactor and stirred. N-methylbenzylamine (1.0 equivalent) was added to the reactor at 25±5°C. The resulting mixture was stirred at 25±5°C for at least 4 hours. The mixture was filtered, and the filter cake was washed twice with ethyl acetate (2 V). The filter cake was dried under vacuum at 45°C for at least 12 hours. Compound 3 was recovered, packaged in a double low-density polyethylene bag, sealed with a cable tie, placed in a fiber drum, and stored at room temperature.

[0160] [ka]

[0161] The reactor was evacuated to below -0.08 MPa and then expanded to atmospheric pressure three times with nitrogen. Compound 3 (1.0 equivalent) and ethyl acetate (10 V) were added to the reactor. The temperature was raised to 45 ± 5 °C, and the reaction mixture was stirred at 45 ± 5 °C for at least 4 hours. The mixture was then cooled to 25 ± 5 °C and filtered. The filter cake was washed twice with ethyl acetate (2 V). The product was sampled and analyzed by HPLC. The criteria were as follows: area % of Compound 1 in the salt of Compound 1 was 97.0% or more, 2-fluorophenol was 0.2% or less, naproxen was 0.5% or less, Compound 2 was 2.0% or less, and unidentified single impurities were 0.10% or less. If these criteria were not met, the hot slurry procedure was repeated. If the criteria were met, the filter cake was dried under vacuum at 45 °C for at least 12 hours. Pure Compound 3 was packaged in a double low-density polyethylene bag, sealed with a cable tie, and stored at room temperature.

[0162] [ka]

[0163] The reactor was evacuated to below -0.08 MPa and then expanded to atmospheric pressure three times with nitrogen. Purified water (5 V) and KHSO4 (1.2 equiv.) were added to the reactor and stirred until completely dissolved. Ethyl acetate (5 V) and pure compound 3 (1.0 equiv.) were added, and the temperature was adjusted to 25 ± 5 °C. The mixture was stirred at 25 ± 5 °C for at least 2 hours. The mixture was then allowed to settle for at least 30 minutes. The organic phase was separated and washed once with purified water (5 V) and then once with 15% aqueous NaCl (5 V). This washing process was repeated until the N-methylbenzylamine content was 0.1% or less. The organic phase was concentrated under vacuum at below 40 °C until the volume was reduced to 3-4 volumes. Ethyl acetate (5 V) was added to the reactor, and the mixture was concentrated under vacuum at below 40 °C until the volume was reduced to 3-4 volumes. This process was repeated until the KF content was 0.5% or less. The reaction mixture was filtered through an activated carbon filter cartridge to remove all color, then through a microporous filter before being transferred to the reactor. The temperature was maintained at 25±5°C. n-Heptane (5V) was added to the reaction mixture. Seeds were added to the reaction mixture (0.5%, w / w) and stirred for 0.5-1.0 hours. n-Heptane (5V) was added dropwise to the system at 25±5°C and then stirred for at least 4 hours. The reaction mixture was cooled to 5±5°C and maintained at that temperature for at least 1 hour. The mixture was centrifuged, and the resulting filter cake was washed twice with n-heptane (2V). A sample was taken and analyzed by HPLC. The purity criteria were as follows: area % of compound 1 was ≥ 98.0%, N-methylbenzylamine was ≤ 0.1%, naproxen was ≤ 0.5%, compound 2 was ≤ 1.0%, unidentified impurities were ≤ 0.10%, and total impurities were ≤ 2.0%. The cake was dried under vacuum at 40°C for at least 15 hours. Residual solvent criteria were as follows: 2-propanol <5000 ppm, acetonitrile <410 ppm, tert-butyl methyl ether <5000 ppm, n-heptane <5000 ppm, toluene <890 ppm, and ethyl acetate <5000 ppm. Compound 1 was packaged in a double low-density polyethylene bag under nitrogen protection, sealed with cable ties, and stored at room temperature in a tightly closed container.

Claims

1. A purification method for obtaining Compound 1 from a mother liquor, comprising: 【Chemistry 1】 a salt formation step comprising contacting said mother liquor containing:

2. 2. The purification method of claim 1, wherein the amine is N-methylbenzylamine.

3. The salt formed in the salt-forming step is 【Chemistry 2】 The purification method according to claim 1 or 2, 【Request Item 4】 【Chemistry 3】 4. The method of claim 3, further comprising a salt destruction step comprising contacting the compound with an acid to obtain compound 1.

5. The acid is KHSO ４ The purification method according to claim 4, wherein

6. The purification method according to any one of claims 1 to 5, wherein Compound 1 is crystalline.

7. 7. The purification method of claim 6, wherein the crystalline Compound 1 has X-ray powder diffraction (XRPD) peaks at 9.0±0.1°2θ, 10.3±0.1°2θ, 13.8±0.1°2θ, and 15.7±0.1°2θ.

8. 8. The purification method of claim 7, wherein crystalline Compound 1 has at least one additional X-ray powder diffraction (XRPD) peak at 16.3±0.1°2θ, 19.8±0.1°2θ, 21.9±0.1°2θ, 22.7±0.1°2θ, and 24.1±0.1°2θ.

9. 7. The purification method of claim 6, wherein the crystalline Compound 1 has X-ray powder diffraction (XRPD) peaks at 8.1±0.1°2θ, 9.0±0.1°2θ, 10.3±0.1°2θ, 13.8±0.1°2θ, 15.7±0.1°2θ, 16.3±0.1°2θ, 19.8±0.1°2θ, 21.9±0.1°2θ, 22.7±0.1°2θ, and 24.1±0.1°2θ.

10. 8. The purification method according to any one of claims 1 to 7, wherein the weight ratio of compound 1 / compound 2 in the mother liquor is between about 70 / 30 and about 90 / 10.

11. 8. The purification method according to any one of claims 1 to 7, wherein the weight ratio of compound 1 / compound 2 in the mother liquor is between about 75 / 25 and about 90 / 10.

12. 8. The purification method according to any one of claims 1 to 7, wherein the weight ratio of compound 1 / compound 2 in the mother liquor is between about 80 / 20 and about 90 / 10.

13. The purification method according to any one of claims 1 to 7, wherein the weight ratio of compound 1 / compound 2 in the mother liquor is about 85 / 15.

14. The purification method according to any one of claims 1 to 7, wherein the weight ratio of compound 1 / compound 2 in the mother liquor is about 84 / 16.

15. The purification method according to any one of claims 1 to 7, wherein the weight ratio of compound 1 / compound 2 in the mother liquor is about 83 / 17.

16. The purification method according to any one of claims 1 to 7, wherein the weight ratio of compound 1 / compound 2 in the mother liquor is about 82 / 18.

17. The purification method according to any one of claims 1 to 13, wherein the mother liquor is obtained from a process for preparing compound 2.

18. The method for preparing compound 2 comprises: 【Chemistry 4】 of 【Transformation 5】 Contact with 【Transformation 6】 18. The method of claim 17, comprising obtaining

19. The method for preparing compound 2 comprises contacting compound C with naproxen 【Transformation 7】 20. The method of claim 18, further comprising obtaining

20. The method for preparing compound 2 comprises contacting intermediate B with pregabalin 【Transformation 8】 20. The method of claim 19, further comprising obtaining

21. 21. The purification method of claim 20, wherein the method for preparing compound 2 further comprises decomposing intermediate C to obtain compound 2 and the mother liquor.

22. 22. The purification method of claim 21, wherein the decomposition of intermediate C is carried out using isopropanol and heptane. 【Request Item 23】 【Chemistry 9】 A compound which is

24. 1. A method of treating osteoarthritis of the knee in a subject in need thereof, comprising: 【Chemistry 10】 or a pharmaceutically acceptable salt thereof to said subject in need thereof.

25. 25. The method of claim 24, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered locally to the knee.

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