Compounds for the treatment of kinase-dependent disorders - Patents.com

Abstract

The present disclosure relates to a tyrosine kinase inhibitor of formula I and compound 1, or a pharma- ceutically acceptable salt thereof. The present disclosure further relates to a method for preparing a tyrosine kinase inhibitor of formula I and compound 1, or a pharma- ceutically acceptable salt thereof. In one aspect, the present disclosure provides a compound of formula I, or a pharma- ceutically acceptable salt thereof, containing 200 ppm or less of contaminants or degradants, wherein R 1 -COOH, -COO(C 1~6 alkyl), -C(O)-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, and R 2 Ha-OC 1~6 It is an alkyl.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Application No. 63 / 275,255, filed November 3, 2021, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to tyrosine kinase inhibitors of formula I and compound 1, or pharma- ceutically acceptable salts thereof, that are essentially free of impurities, contaminants, or degradants. The present disclosure further relates to methods for preparing c-Met inhibitors of formula I and compound 1, or pharma-ceutically acceptable salts thereof. [Background technology]

[0003] Protein tyrosine kinases are important regulatory signaling proteins that govern the growth and metastasis of cancer cells. Protein kinase signaling is of special relevance in the growth and proliferation of, for example, renal, gastric, head and neck, lung, breast, prostate, colon and hepatocellular carcinoma, as well as brain cancer cells.

[0004] Small molecule compounds that specifically inhibit, regulate, and / or modulate kinase (e.g., c-Met, VEGFR2, KDR, c-Kit, Axl, flt-3, and flt-4) signaling are desirable as a means to treat or prevent disease states associated with abnormal cell proliferation and angiogenesis. Tyrosine kinase inhibitors (TKIs) are playing an increasingly prominent role in the treatment of cancer and other diseases. Highly pure, uncontaminated TKIs are particularly desirable for use as anti-cancer drugs.

[0005] Impurities in drugs can include starting materials, intermediates, by-products, contaminants, degradation products, etc. Impurity levels in drugs must be minimized to acceptable safety limits to protect patients. Therefore, removal or reduction of impurities, especially genotoxic impurities, is crucial. According to the International Council for Harmonization Guidelines (ICH) S2(R1), genotoxic impurities are broadly defined as impurities that have been demonstrated to cause deleterious changes in genetic material, regardless of mechanism.

[0006] The present invention addresses the need to provide kinase inhibitors that are highly pure and have minimal amounts of impurities, including genotoxic contaminants, and by providing improved methods for making TKIs that minimize the formation of genotoxic contaminants, impurities, by-products, or degradants. Summary of the Invention [Means for solving the problem]

[0007] These and other needs are met in one embodiment by the compound of formula I: [ka] or a pharma- ceutical acceptable salt thereof, containing 200 ppm or less of contaminants or degradants, including genotoxic contaminants or degradants, wherein R 1 -COOH, -COO(C 1~6 alkyl), -C(O)-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 It is an alkyl.

[0008] Another embodiment is compound 1 [ka] or a pharma- ceutically acceptable salt thereof, containing 200 ppm or less of contaminants or degradants, including genotoxic contaminants or degradants.

[0009] Another aspect provides a pharmaceutical composition comprising a compound of formula I or Compound 1, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, the pharmaceutical composition containing 200 ppm or less of contaminants or degradants, including genotoxic contaminants or degradants.

[0010] Also disclosed are compounds of formula I and methods for making compound 1. Compounds of formula I and compound 1 are small molecule inhibitors of TAM receptor tyrosine kinases (e.g., Axl and Mer) for cancer treatment. Compound 1 and its preparation methods are disclosed in PCT Application No. PCT / US2019 / 015297, the entire contents of which are incorporated herein by reference. Compound 1 and its crystalline solid forms and crystalline salts are disclosed in PCT / US2019 / 065972, the entire contents of which are incorporated herein by reference. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] For purposes of the present invention, the chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 95th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry," 2nd Ed., Thomas Sorrell, University Science Books, Sausalito: 2006 and "March's Advanced Organic Chemistry", 7th Ed., Ed: Smith, M. B. and March, J., John Wiley & Sons, New York: 2013, the entire contents of which are incorporated herein by reference.

[0012] As used herein, the term "about" or "approximate" or "approximately" includes (and describes) embodiments that are directed to the value or parameter itself. In certain embodiments, the term "about" or "approximately" or "approximately" includes the stated amount ±10%. In other embodiments, the term "about", "approximately" or "approximately" includes the stated amount ±5%. In certain other embodiments, the term "about", "approximately" or "approximately" includes the stated amount ±1%.

[0013] As used herein, the term "slurry" refers to a mixture of solids suspended in a liquid. A slurry can be prepared by adding enough solids such that there are undissolved solids in a given solvent at ambient conditions. A slurry can be prepared by agitation (typically stirring or shaking) in a closed vial at a given temperature for an extended period of time. Typically, the solids are recovered after a given period of time using the methods described herein.

[0014] The expression "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, within the bounds of sound medical evaluation, and commensurate with a reasonable benefit-risk ratio.

[0015] As used herein, the term "catalytic amount" refers to an amount that is less than the stoichiometric equivalent of the limiting reagent. In some embodiments, the catalytic amount is much less than the stoichiometric equivalent of the limiting reagent, for example, 0-5 weight percent (wt%), 0-4 wt%, 0-3 wt%, 0-2 wt%, 0-1 wt%, 0-0.9 wt%, 0-0.8 wt%, 0-0.7 wt%, 0-0.6 wt%, 0-0.5 wt%, 0-0.4 wt%, 0-0.3 wt%, 0-0.2 wt%, 0-0.1 wt%, 0-0.05 wt%, and 0-0.01 wt% of the stoichiometric amount of the limiting reagent.

[0016] The phrase "essentially free" as used in the phrase "essentially free of contaminants, degradants, or impurities" means that the compounds or compositions disclosed herein are mixed with 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 3 ppm or less, 2.5 ppm or less, or 1 ppm or less of such contaminants, degradants, or impurities.

[0017] In general, the nomenclature used in this application is based on the nomenclature rules adopted by the International Union of Pure and Applied Chemistry (IUPAC). The chemical structures shown herein were prepared using CHEMDRAW®. Any open valency appearing on a carbon, oxygen, or nitrogen atom in the structures herein indicates the presence of a hydrogen atom.

[0018] Examples of pharma- ceutical acceptable excipients, diluents, fillers, binders, disintegrants, lubricants, and coatings can be found in references readily available to those skilled in the art (e.g., Handbook of Pharmaceutical Excipients, 9th Ed., 1999). th Ed., Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020; and Remington, The Science and Practice of Pharmacy, 23 rdThis is described in more detail in Ed., Adeboye Adejare, Philadelphia, PA.

[0019] The diluent can be any diluent known to those skilled in the art.In one embodiment, the diluent is an inorganic diluent, a polysaccharide, a monosaccharide, or a disaccharide, or a sugar alcohol.In another embodiment, the diluent comprises lactose, microcrystalline cellulose, starch, corn starch, croscarmellose sodium, or a mixture thereof.

[0020] The filler can be any filler known to those skilled in the art. Examples of fillers include lactose, microcrystalline cellulose, starch, corn starch, croscarmellose sodium, sucrose, calcium phosphate, maltodextrin, mannitol, inorganic salts, and mixtures thereof.

[0021] The binder can be any binder known to those skilled in the art. Suitable binders include sodium carboxymethylcellulose, polyvinylpyrrolidone (PVP), copovidone, polyvinylpyrrolidone-vinyl acetate (PVP / VA) copolymer, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, or mixtures thereof.

[0022] The disintegrant can be any disintegrant known to those skilled in the art. Suitable disintegrants include croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate, or mixtures thereof.

[0023] The flow agent can be any lubricant known to those skilled in the art.Suitable flow agents include starch, corn starch, silicon dioxide, colloidal silicon dioxide, or mixtures thereof.In another embodiment, the flow agent is silicon dioxide.

[0024] The lubricant can be any lubricant known to one of skill in the art, hi another embodiment, the lubricant is stearic acid or magnesium stearate.

[0025] Film coatings typically involve a mixture of pharma- ceutically acceptable excipients that are applied to compressed tablets, beads, granules, or particles of active ingredient that are compressed into a tablet. It is understood that the coating selected must be compatible with the active agent. It is further understood that one skilled in the art would know how to engineer the coating to achieve disintegration in the stomach by selecting the excipients that make up the coating, their type, and / or their thickness.

[0026] Suitable polymers for film coating are soluble at a pH of about 1.2 to about 5 and include, for example, hydroxypropyl methylcellulose (HPMC) alone and / or in combination with hydroxypropyl cellulose (HPC), carboxymethyl cellulose, methyl cellulose, ethyl cellulose, acrylic resins, and polyvinylpyrrolidone, and gelatin, or other commercially available film coating formulations (e.g., Dri-Klear® (Crompton & Knowles Corp, Mahwah, NJ) or Opadry® (Colorcon, West Point Pa.)).

[0027] The symbol "-" denotes a single bond and "=" denotes a double bond.

[0028] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0029] When a variable is generically defined with multiple possible substituents, each individual radical can be defined with or without a bond. For example, R z can be hydrogen, this is R z In the definition of, it can be shown as either "-H" or "H".

[0030] Embodiment In one embodiment, the disclosure provides a compound of formula I: [ka] or a pharma- ceutical acceptable salt thereof, containing 200 ppm or less of contaminants or degradants, wherein R 1 -COOH, -COO(C 1~6 alkyl), -C(O)-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 It is an alkyl.

[0031] In one embodiment, the disclosure provides a compound of formula I: [ka] or a pharma- ceutical acceptable salt thereof, containing 200 ppm or less of genotoxic contaminants or degradants, wherein R 1 -COOH, -COO(C 1~6 alkyl), -C(O)-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 It is an alkyl.

[0032] In one embodiment, the disclosure provides a compound of formula I: [ka] or a pharma- ceutical acceptable salt thereof, containing 100 ppm or less of contaminants or degradants, wherein R1 -CO-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 It is an alkyl.

[0033] In one embodiment, the disclosure provides a compound of formula I: [ka] or a pharma- ceutical acceptable salt thereof, containing 100 ppm or less of genotoxic contaminants or degradants, wherein R 1 -CO-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 It is an alkyl.

[0034] In some embodiments, the contaminants or degradants are 4-aminophenol, 4-fluoroaniline, [ka] or a mixture thereof.

[0035] Contaminants or degradants include genotoxic contaminants or degradants.

[0036] In some embodiments, the genotoxic contaminants or degradants are 4-aminophenol, 4-fluoroaniline, [ka] or a mixture thereof.

[0037] In some embodiments, the genotoxic contaminants or degradants are 4-aminophenol, 4-fluoroaniline, [ka] or a mixture thereof.

[0038] In one embodiment, the present disclosure provides a compound of formula I: [ka] or a pharma- ceutical acceptable salt thereof, containing 200 ppm or less of contaminants or degradants, wherein R 1 -COOH, -COO(C 1~6 alkyl), -C(O)-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 is alkyl, Contaminants or decomposition products include 4-aminophenol, 4-fluoroaniline, [ka] or a mixture thereof.

[0039] In one embodiment, the present disclosure provides a compound of formula I: [ka] or a pharma- ceutical acceptable salt thereof, containing 100 ppm or less of genotoxic contaminants or degradants, wherein R 1 -CO-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 is alkyl, Genotoxic contaminants or degradation products include 4-aminophenol, 4-fluoroaniline, [ka] or a mixture thereof.

[0040] In one embodiment, the disclosure provides a compound of formula I [ka] or a pharma- ceutical acceptable salt thereof, and one or more pharma- ceutical acceptable excipients, the pharmaceutical composition containing 200 ppm or less of contaminants or degradants, wherein the pharmaceutical composition comprises R 1 -COOH, -COO(C 1~6 alkyl), -C(O)-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 It is an alkyl.

[0041] In one embodiment, the present disclosure provides a compound of formula I [ka] or a pharma- ceutical acceptable salt thereof, and one or more pharma- ceutical acceptable excipients, the pharmaceutical composition containing 200 ppm or less of contaminants or degradants, wherein the pharmaceutical composition comprises R 1 -COOH, -COO(C 1~6 alkyl), -C(O)-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 is alkyl, Contaminants or decomposition products include 4-aminophenol, 4-fluoroaniline, [ka] or a mixture thereof.

[0042] In some embodiments, the one or more pharma- ceutical acceptable excipients include one or more fillers, one or more disintegrants, one or more glidants, and one or more lubricants.

[0043] In some embodiments, the one or more pharma- ceutical acceptable excipients include one or more diluents, one or more disintegrants, one or more glidants, one or more binders, and one or more lubricants.

[0044] In one embodiment, the pharmaceutical composition is a tablet.

[0045] In another embodiment, the pharmaceutical composition is a capsule.

[0046] In some embodiments, R1 is -COOH or -C(O)-NHMe.

[0047] In some embodiments, R 1 is -C(O)-NHMe.

[0048] In some embodiments, R 2 is -OMe.

[0049] In some embodiments, R 1 is -C(O)-NHMe, R 2 is -OMe.

[0050] In some embodiments, contaminants or degradants are 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 3 ppm or less, 2.5 ppm or less, or 1 ppm or less.

[0051] In some embodiments, genotoxic contaminants or degradants are 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 3 ppm or less, 2.5 ppm or less, or 1 ppm or less.

[0052] In some embodiments, genotoxic contaminants or degradants are 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, or 2.5 ppm or less, or 1 ppm or less.

[0053] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with no more than 200 ppm, no more than 100 ppm, no more than 75 ppm, no more than 50 ppm, no more than 25 ppm, no more than 20 ppm, no more than 15 ppm, no more than 13 ppm, no more than 10 ppm, no more than 5 ppm, no more than 2.5 ppm, or no more than 1 ppm of impurities, contaminants, or degradants.

[0054] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 2.5 ppm or less, or 1 ppm or less of impurities, contaminants, or degradants including 4-aminophenol, 4-fluoroaniline, (I-1), (I-2), or mixtures thereof.

[0055] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, or 2.5 ppm or less of 4-aminophenol.

[0056] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 2.5 ppm or less, or 1 ppm or less of 4-fluoroaniline.

[0057] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with no more than 100 ppm, no more than 75 ppm, no more than 50 ppm, no more than 25 ppm, no more than 20 ppm, no more than 15 ppm, no more than 13 ppm, no more than 10 ppm, no more than 5 ppm, no more than 2.5 ppm, or no more than 1 ppm of the compound of formula I-1.

[0058] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with no more than 100 ppm, no more than 75 ppm, no more than 50 ppm, no more than 25 ppm, no more than 20 ppm, no more than 15 ppm, no more than 13 ppm, no more than 10 ppm, no more than 5 ppm, or no more than 2.5 ppm of the compound of formula I-1.

[0059] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with no more than 100 ppm, no more than 75 ppm, no more than 50 ppm, no more than 25 ppm, no more than 20 ppm, no more than 15 ppm, no more than 13 ppm, no more than 10 ppm, no more than 5 ppm, or no more than 2.5 ppm of the compound of formula I-2.

[0060] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with at least two of 4-aminophenol, 4-fluoroaniline, (I-1), and (I-2), and the combined level of the at least two of 4-aminophenol, 4-fluoroaniline, (I-1), and (I-2) is 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 2.5 ppm or less, or 1 ppm or less.

[0061] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with at least three of 4-aminophenol, 4-fluoroaniline, (I-1), and (I-2), and the combined level of the at least three of 4-aminophenol, 4-fluoroaniline, (I-1), and (I-2) is 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 2.5 ppm or less, or 1 ppm or less.

[0062] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with 4-aminophenol, 4-fluoroaniline, (I-1), and (I-2), and the combined level of 4-aminophenol, 4-fluoroaniline, (I-1), and (I-2) is 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 2.5 ppm or less, or 1 ppm or less.

[0063] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with 4-fluoroaniline and a compound of formula I-2, and the combined level of 4-fluoroaniline and the compound of formula I-2 is 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, or 2.5 ppm or less.

[0064] In some embodiments, a compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with 4-aminophenol and a compound of formula I-2, and the combined level of 4-aminophenol and the compound of formula I-2 is 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 2.5 ppm or less, or 1 ppm or less.

[0065] In some embodiments, a compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with a compound of formula I-1 and a compound of formula I-2, and the combined level of the compounds of formula I-1 and formula I-2 is 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 2.5 ppm or less, or 1 ppm or less.

[0066] Another aspect of the present disclosure is compound 1 [ka] or a pharma- ceutical acceptable salt thereof, wherein the compound 1 or a pharma- ceutical acceptable salt thereof contains 200 ppm or less of contaminants or degradants.

[0067] Another aspect of the present disclosure is compound 1 [ka] or a pharma- ceutically acceptable salt thereof, wherein the compound 1 or a pharma- ceutically acceptable salt thereof contains 100 ppm or less of contaminants or degradants.

[0068] Another aspect of the present disclosure is compound 1 [ka] or a pharma- ceutically acceptable salt thereof, wherein the compound 1 or a pharma- ceutically acceptable salt thereof contains 200 ppm or less of genotoxic contaminants or degradants.

[0069] Another aspect of the present disclosure is compound 1 [ka] or a pharma- ceutically acceptable salt thereof, wherein the compound 1 or a pharma- ceutically acceptable salt thereof contains 100 ppm or less of genotoxic contaminants or degradants.

[0070] Another aspect of the disclosure provides a pharmaceutical composition comprising Compound 1, or a pharma- ceutical acceptable salt thereof, and one or more pharma- ceutical acceptable excipients, the pharmaceutical composition containing 200 ppm or less of contaminants or degradants.

[0071] In some embodiments, the one or more pharma- ceutical acceptable excipients include one or more fillers, one or more disintegrants, one or more glidants, and one or more lubricants.

[0072] In some embodiments, the one or more pharma- ceutical acceptable excipients include one or more diluents, one or more disintegrants, one or more glidants, one or more binders, and one or more lubricants.

[0073] In one embodiment, the pharmaceutical composition is a tablet.

[0074] In another embodiment, the pharmaceutical composition is a capsule.

[0075] In some embodiments, the contaminants or degradants are 4-aminophenol, 4-fluoroaniline, [ka] or a mixture thereof.

[0076] In some embodiments, the contaminants or degradants include genotoxic contaminants or degradants.

[0077] In some embodiments, the genotoxic contaminants or degradants are 4-aminophenol, 4-fluoroaniline, [ka] or a mixture thereof.

[0078] In some embodiments, the genotoxic contaminants or degradants include 4-aminophenol, 4-fluoroaniline, or a mixture thereof.

[0079] In some embodiments, the genotoxic contaminant or degradant comprises 4-fluoroaniline.

[0080] 4-Aminophenol, 4-fluoroaniline, compound a, and compound b are starting materials or intermediates used in the synthesis of compound 1 and its pharma- ceutical acceptable salts, or by-products or decomposition products generated during the process, or impurities from the starting materials. These compounds may also be undesirable genotoxic impurities in the final pharmaceutical product. It is therefore important to remove or minimize the levels of these or other genotoxic impurities. The presence of these impurities at low levels is difficult to avoid, as no other viable synthetic routes that do not contain these substances have been identified. The present disclosure provides improved manufacturing methods to ensure that the levels of these impurities are as low as reasonably possible.

[0081] In some embodiments, contaminants or degradants are 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 3 ppm or less, 2.5 ppm or less, or 1 ppm or less.

[0082] In some embodiments, genotoxic contaminants or degradants are 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 3 ppm or less, 2.5 ppm or less, or 1 ppm or less.

[0083] In some embodiments, the contaminants or degradants, or genotoxic contaminants or degradants, are between 200 ppm and 0.001 ppm, 100 ppm and 0.001 ppm, 75 ppm and 0.001 ppm, 50 ppm and 0.001 ppm, 25 ppm and 0.001 ppm, 20 ppm and 0.001 ppm, 15 ppm and 0.001 ppm, 13 ppm and 0.001 ppm, 10 ppm and 0.001 ppm, 5 ppm and 0.001 ppm, 3 ppm and 0.001 ppm, 2.5 ppm and 0.001 ppm, 2 ppm and 0.001 ppm, or 1 ppm and 0.001 ppm, inclusive.

[0084] In some embodiments, the contaminants or degradants, or genotoxic contaminants or degradants, are between 200 ppm and 0.01 ppm, 100 ppm and 0.01 ppm, 75 ppm and 0.01 ppm, 50 ppm and 0.01 ppm, 25 ppm and 0.01 ppm, 20 ppm and 0.01 ppm, 15 ppm and 0.01 ppm, 13 ppm and 0.01 ppm, 10 ppm and 0.01 ppm, 5 ppm and 0.01 ppm, 3 ppm and 0.01 ppm, 2.5 ppm and 0.01 ppm, 2 ppm and 0.01 ppm, or 1 ppm and 0.01 ppm, inclusive.

[0085] In some embodiments, the contaminants or degradants, or genotoxic contaminants or degradants, are between 200 ppm and 0.1 ppm, 100 ppm and 0.1 ppm, 75 ppm and 0.1 ppm, 50 ppm and 0.1 ppm, 25 ppm and 0.1 ppm, 20 ppm and 0.1 ppm, 15 ppm and 0.1 ppm, 13 ppm and 0.1 ppm, 10 ppm and 0.1 ppm, 5 ppm and 0.1 ppm, 3 ppm and 0.1 ppm, 2.5 ppm and 0.1 ppm, 2 ppm and 0.1 ppm, or 1 ppm and 0.1 ppm, inclusive.

[0086] In some embodiments, the pharma- ceutical acceptable salt is Compound 1 hemifumarate.

[0087] In some embodiments, Compound 1 free base or Compound 1 hemifumarate is mixed with no more than 200 ppm, no more than 100 ppm, no more than 75 ppm, no more than 50 ppm, no more than 25 ppm, no more than 20 ppm, no more than 15 ppm, no more than 13 ppm, no more than 10 ppm, no more than 5 ppm, no more than 2.5 ppm, or no more than 1 ppm of impurities, contaminants, or degradants.

[0088] In some embodiments, Compound 1 free base or Compound 1 hemifumarate is mixed with no more than 200 ppm, no more than 100 ppm, no more than 75 ppm, no more than 50 ppm, no more than 25 ppm, no more than 20 ppm, no more than 15 ppm, no more than 13 ppm, no more than 10 ppm, no more than 5 ppm, no more than 2.5 ppm, or no more than 1 ppm of genotoxic impurities, contaminants, or degradants.

[0089] In some embodiments, compound 1 free base or compound 1 hemifumarate is mixed with impurities, contaminants, or degradants including 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 2.5 ppm or less, or 1 ppm or less of 4-aminophenol, 4-fluoroaniline, compound a, compound b, or mixtures thereof.

[0090] In some embodiments, compound 1 free base or compound 1 hemifumarate is mixed with 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, or 2.5 ppm or less of 4-aminophenol, 4-fluoroaniline, compound a, compound b, or a mixture thereof.

[0091] In some embodiments, compound 1 free base or compound 1 hemifumarate is mixed with 200 ppm to 0.001 ppm, 100 ppm to 0.001 ppm, 75 ppm to 0.001 ppm, 50 ppm to 0.001 ppm, 25 ppm to 0.001 ppm, 20 ppm to 0.001 ppm, 15 ppm to 0.001 ppm, 13 ppm to 0.001 ppm, 10 ppm to 0.001 ppm, 5 ppm to 0.001 ppm, 3 ppm to 0.001 ppm, 2.5 ppm to 0.001 ppm, 2 ppm to 0.001 ppm, or 1 ppm to 0.001 ppm of 4-aminophenol, 4-fluoroaniline, compound a, compound b, or mixtures thereof, inclusive.

[0092] In some embodiments, compound 1 free base or compound 1 hemifumarate is mixed with 200 ppm to 0.01 ppm, 100 ppm to 0.01 ppm, 75 ppm to 0.01 ppm, 50 ppm to 0.01 ppm, 25 ppm to 0.01 ppm, 20 ppm to 0.01 ppm, 15 ppm to 0.01 ppm, 13 ppm to 0.01 ppm, 10 ppm to 0.01 ppm, 5 ppm to 0.01 ppm, 3 ppm to 0.01 ppm, 2.5 ppm to 0.01 ppm, 2 ppm to 0.01 ppm, or 1 ppm to 0.01 ppm of 4-aminophenol, 4-fluoroaniline, compound a, compound b, or mixtures thereof, inclusive.

[0093] In some embodiments, Compound 1 free base or Compound 1 hemifumarate is mixed with 200 ppm to 0.1 ppm, 100 ppm to 0.1 ppm, 75 ppm to 0.1 ppm, 50 ppm to 0.1 ppm, 25 ppm to 0.1 ppm, 20 ppm to 0.1 ppm, 15 ppm to 0.1 ppm, 13 ppm to 0.1 ppm, 10 ppm to 0.1 ppm, 5 ppm to 0.1 ppm, 3 ppm to 0.1 ppm, 2.5 ppm to 0.1 ppm, 2 ppm to 0.1 ppm, or 1 ppm to 0.1 ppm of 4-aminophenol, 4-fluoroaniline, Compound a, Compound b, or mixtures thereof, inclusive.

[0094] In some embodiments, the contaminant or genotoxic contaminant or degradant comprises 4-aminophenol.

[0095] In some embodiments, Compound 1 free base or Compound 1 hemifumarate is mixed with 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 3 ppm or less, 2.5 ppm or less, or 1 ppm or less of 4-aminophenol.

[0096] In some embodiments, Compound 1 free base or Compound 1 hemifumarate is mixed with 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, or 2.5 ppm or less of 4-aminophenol.

[0097] In some embodiments, the free base of Compound 1 is mixed with up to 15 ppm of 4-aminophenol.

[0098] In some embodiments, Compound 1 hemifumarate is mixed with 15 ppm or less of 4-aminophenol.

[0099] In some embodiments, the free base of Compound 1 is mixed with no more than 3 ppm of 4-aminophenol.

[0100] In some embodiments, Compound 1 hemifumarate is mixed with 3 ppm or less of 4-aminophenol.

[0101] In some embodiments, the contaminant or genotoxic contaminant or degradant comprises 4-fluoroaniline.

[0102] In some embodiments, Compound 1 free base or Compound 1 hemifumarate is mixed with 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, or 2.5 ppm or less, or 1 ppm or less of 4-fluoroaniline.

[0103] In some embodiments, the free base of Compound 1 is mixed with up to 15 ppm of 4-fluoroaniline.

[0104] In some embodiments, Compound 1 hemifumarate is mixed with no more than 15 ppm of 4-fluoroaniline.

[0105] In some embodiments, the free base of Compound 1 is mixed with 5 ppm or less of 4-fluoroaniline.

[0106] In some embodiments, Compound 1 hemifumarate is mixed with 5 ppm or less of 4-fluoroaniline.

[0107] In some embodiments, the free base of Compound 1 is mixed with no more than 3 ppm of 4-fluoroaniline.

[0108] In some embodiments, Compound 1 hemifumarate is mixed with no more than 3 ppm of 4-fluoroaniline.

[0109] In some embodiments, the free base of Compound 1 is mixed with 2 ppm or less of 4-fluoroaniline.

[0110] In some embodiments, Compound 1 hemifumarate is mixed with no more than 2 ppm of 4-fluoroaniline.

[0111] In some embodiments, the free base of Compound 1 is mixed with 1 ppm or less of 4-fluoroaniline.

[0112] In some embodiments, Compound 1 hemifumarate is mixed with 1 ppm or less of 4-fluoroaniline.

[0113] In some embodiments, the contaminant or contaminant or degradant comprises compound a.

[0114] In some embodiments, the genotoxic contaminant or degradant comprises compound a.

[0115] In some embodiments, compound 1 free base or compound 1 hemifumarate is mixed with 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 2.5 ppm or less, or 1 ppm or less of compound a.

[0116] In some embodiments, compound 1 free base or compound 1 hemifumarate is mixed with 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, or 2.5 ppm or less of compound a.

[0117] In some embodiments, compound 1 free base is mixed with up to 15 ppm of compound a.

[0118] In some embodiments, compound 1 hemifumarate is mixed with no more than 15 ppm of compound a.

[0119] In some embodiments, compound 1 free base is mixed with 5 ppm or less of compound a.

[0120] In some embodiments, compound 1 hemifumarate is mixed with no more than 5 ppm of compound a.

[0121] In some embodiments, compound 1 free base is mixed with no more than 4 ppm of compound a.

[0122] In some embodiments, compound 1 hemifumarate is mixed with no more than 4 ppm of compound a.

[0123] In some embodiments, compound 1 free base is mixed with no more than 3 ppm of compound a.

[0124] In some embodiments, compound 1 hemifumarate is mixed with no more than 3 ppm of compound a.

[0125] In some embodiments, the contaminant or genotoxic contaminant or degradant comprises compound b.

[0126] In some embodiments, compound 1 free base or compound 1 hemifumarate is mixed with 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 2.5 ppm or less, or 1 ppm or less of compound b.

[0127] In some embodiments, compound 1 free base or compound 1 hemifumarate is mixed with 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, or 2.5 ppm or less of compound b.

[0128] In some embodiments, compound 1 free base is mixed with up to 75 ppm of compound b.

[0129] In some embodiments, compound 1 hemifumarate is mixed with up to 75 ppm of compound b.

[0130] In some embodiments, compound 1 free base is mixed with up to 50 ppm of compound b.

[0131] In some embodiments, compound 1 hemifumarate is mixed with 50 ppm or less of compound b.

[0132] In some embodiments, compound 1 free base is mixed with up to 15 ppm of compound b.

[0133] In some embodiments, compound 1 hemifumarate is mixed with no more than 15 ppm of compound b.

[0134] In some embodiments, compound 1 free base is mixed with no more than 7 ppm of compound b.

[0135] In some embodiments, compound 1 hemifumarate is mixed with no more than 7 ppm of compound b.

[0136] In some embodiments, compound 1 free base or compound 1 hemifumarate is mixed with at least two of 4-aminophenol, 4-fluoroaniline, compound a, and compound b, and the combined level of at least two of 4-aminophenol, 4-fluoroaniline, compound a, and compound b is 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 2.5 ppm or less, or 1 ppm or less.

[0137] In some embodiments, compound 1 free base or compound 1 hemifumarate is mixed with compound a and compound b, and the combined level of compound a and compound b is 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 2.5 ppm or less, or 1 ppm or less. In some embodiments, the combined level of compound a and compound b is 100 ppm or less. In some embodiments, the combined level of compound a and compound b is 75 ppm or less. In some embodiments, the combined level of compound a and compound b is 50 ppm or less. In some embodiments, the combined level of compound a and compound b is 15 ppm or less.

[0138] In some embodiments, compound 1 free base or compound 1 hemifumarate is mixed with at least three of 4-aminophenol, 4-fluoroaniline, compound a, and compound b, and the combined level of the at least three of 4-aminophenol, 4-fluoroaniline, compound a, and compound b is 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 2.5 ppm or less, or 1 ppm or less.

[0139] In some embodiments, compound 1 free base or compound 1 hemifumarate is mixed with 4-aminophenol, compound a, and compound b, and the combined levels of 4-aminophenol, compound a, and compound b are 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 2.5 ppm or less, or 1 ppm or less. In some embodiments, the combined levels of 4-aminophenol, compound a, and compound b are 100 ppm or less. In some embodiments, the combined levels are 75 ppm or less. In some embodiments, the combined levels are 50 ppm or less. In some embodiments, the combined levels are 15 ppm or less.

[0140] In some embodiments, compound 1 free base or compound 1 hemifumarate is mixed with 4-fluoroaniline, compound a, and compound b, and the combined levels of 4-fluoroaniline, compound a, and compound b are 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 2.5 ppm or less, or 1 ppm or less. In some embodiments, the combined levels of 4-fluoroaniline, compound a, and compound b are 100 ppm or less. In some embodiments, the combined levels are 75 ppm or less. In some embodiments, the combined levels are 50 ppm or less. In some embodiments, the combined levels are 15 ppm or less.

[0141] In some embodiments, compound 1 free base or compound 1 hemifumarate is mixed with 4-aminophenol, 4-fluoroaniline, compound a, and compound b, and the combined levels of 4-aminophenol, 4-fluoroaniline, compound a, and compound b are 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, or 5 ppm or less. In some embodiments, the combined levels of 4-aminophenol, 4-fluoroaniline, compound a, and compound b are 100 ppm or less. In some embodiments, the combined levels are 75 ppm or less. In some embodiments, the combined levels are 50 ppm or less. In some embodiments, the combined levels are 15 ppm or less.

[0142] In some embodiments, the disclosure provides a pharmaceutical composition comprising compound 1 or compound 1 hemifumarate and one or more pharma- ceutically acceptable excipients, wherein the pharmaceutical composition contains 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 2.5 ppm or less, or 1 ppm or less of contaminants or degradants including 4-aminophenol, 4-fluoroaniline, compound a, compound b, or mixtures thereof.

[0143] In some embodiments, the pharmaceutical composition is selected from any one of the compositions in the table below. [Table 1]

[0144] In one embodiment, the disclosure provides a compound of formula I: [ka] or a pharma- ceutical acceptable salt thereof, containing 200 ppm or less of contaminants or degradants, wherein R 1 -COOH, -COO(C 1~6 alkyl), -C(O)-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 is alkyl, The compound of formula I is (b) reacting a compound of formula I-2 with a compound I-4 to obtain a compound of formula I [ka] The method comprises the steps of:

[0145] In one embodiment, the disclosure provides a compound of formula I: [ka] or a pharma- ceutical acceptable salt thereof, containing 100 ppm or less of genotoxic contaminants or degradants, wherein R 1 -CO-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 is alkyl, The compound of formula I is (b) reacting a compound of formula I-2 with a compound I-4 to obtain a compound of formula I [ka] The method comprises the steps of:

[0146] In one embodiment, the disclosure provides a compound of formula I: [ka] or a pharma- ceutical acceptable salt thereof, containing 200 ppm or less of contaminants or degradants, wherein R 1 -COOH, -COO(C 1~6 alkyl), -C(O)-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 is alkyl, The compound of formula I is (a) reacting a compound of formula I-1' with 4-aminophenol to obtain a compound of formula I-2 [ka] (b) reacting a compound of formula I-2 with a compound I-4 to obtain a compound of formula I [ka] and (c) optionally produced by a process comprising reacting a compound of formula I with an acid.

[0147] In one embodiment, the disclosure provides a compound of formula I: [ka] or a pharma- ceutical acceptable salt thereof, containing 100 ppm or less of genotoxic contaminants or degradants, wherein R 1 -CO-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 is alkyl, The compound of formula I is (a) reacting a compound of formula I-1' with 4-aminophenol to obtain a compound of formula I-2 [ka] (b) reacting a compound of formula I-2 with a compound I-4 to obtain a compound of formula I [ka] and (c) optionally produced by a process comprising reacting a compound of formula I with an acid.

[0148] In one embodiment, the disclosure provides a compound of formula I: [ka] or a pharma- ceutical acceptable salt thereof, containing 200 ppm or less of contaminants or degradants, wherein R 1 -COOH, -COO(C 1~6 alkyl), -C(O)-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 is alkyl, The compound of formula I is (b) reacting a compound of formula I-2 with a compound I-4 to obtain a compound of formula I [ka] and Contaminants or decomposition products include 4-aminophenol, 4-fluoroaniline, [ka] or a mixture thereof.

[0149] In one embodiment, the disclosure provides a compound of formula I: [ka] or a pharma- ceutical acceptable salt thereof, containing 100 ppm or less of genotoxic contaminants or degradants, wherein R 1 -CO-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 is alkyl, The compound of formula I is (b) reacting a compound of formula I-2 with a compound I-4 to obtain a compound of formula I [ka] and Genotoxic contaminants or degradation products include 4-aminophenol, 4-fluoroaniline, [ka] or a mixture thereof.

[0150] In one embodiment, the disclosure provides a compound of formula I: [ka] or a pharma- ceutical acceptable salt thereof, containing 200 ppm or less of contaminants or degradants, wherein R 1 -COOH, -COO(C 1~6 alkyl), -C(O)-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 is alkyl, The compound or salt of formula I is (a) reacting a compound of formula I-1' with 4-aminophenol to obtain a compound of formula I-2 [ka] (b) reacting a compound of formula I-2 with a compound I-4 to obtain a compound of formula I [ka] and (c) optionally produced by a process comprising reacting a compound of formula I with an acid; Contaminants or decomposition products include 4-aminophenol, 4-fluoroaniline, [ka] or a mixture thereof.

[0151] In one embodiment, the disclosure provides a compound of formula I: [ka] or a pharma- ceutical acceptable salt thereof, containing 100 ppm or less of genotoxic contaminants or degradants, wherein R 1 -CO-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 is alkyl, The compound or salt of formula I is (a) reacting a compound of formula I-1' with 4-aminophenol to obtain a compound of formula I-2 [ka] (b) reacting a compound of formula I-2 with a compound I-4 to obtain a compound of formula I [ka] and (c) optionally produced by a process comprising reacting a compound of formula I with an acid; Genotoxic contaminants or degradation products include 4-aminophenol, 4-fluoroaniline, [ka] or a mixture thereof.

[0152] In one embodiment, the disclosure provides a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, containing 200 ppm or less of contaminants or degradants, wherein R 1 -COOH, -COO(C 1~6 alkyl), -C(O)-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 is alkyl, The method comprises: (b) reacting a compound of formula I-2 with a compound I-4 to obtain a compound of formula I [ka] Includes.

[0153] In one embodiment, the disclosure provides a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, containing 100 ppm or less of contaminants or degradants, wherein R 1-CO-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 is alkyl, The method comprises: (b) reacting a compound of formula I-2 with a compound I-4 to obtain a compound of formula I [ka] Includes.

[0154] In one embodiment, the disclosure provides a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, containing 200 ppm or less of contaminants or degradants, wherein R 1 -COOH, -COO(C 1~6 alkyl), -C(O)-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 is alkyl, The method comprises: (a) reacting a compound of formula I-1' with 4-aminophenol to obtain a compound of formula I-2 [ka] (b) reacting a compound of formula I-2 with a compound I-4 to obtain a compound of formula I [ka] and (c) optionally reacting the compound of formula I with an acid.

[0155] In one embodiment, the disclosure provides a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, containing 100 ppm or less of contaminants or degradants, wherein R 1 -CO-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 is alkyl, The method comprises: (a) reacting a compound of formula I-1' with 4-aminophenol to obtain a compound of formula I-2 [ka] (b) reacting a compound of formula I-2 with a compound I-4 to obtain a compound of formula I [ka] and (c) optionally reacting the compound of formula I with an acid.

[0156] In some embodiments, the contaminants or degradants are 4-aminophenol, 4-fluoroaniline, [ka] or a mixture thereof.

[0157] In some embodiments, the genotoxic contaminants or degradants are 4-aminophenol, 4-fluoroaniline, [ka] or a mixture thereof.

[0158] In some embodiments, the present disclosure provides a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, containing 200 ppm or less of contaminants or degradants, wherein R 1 -COOH, -COO(C 1~6 alkyl), -C(O)-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 is alkyl, The method comprises: (b) reacting a compound of formula I-2 with a compound I-4 to obtain a compound of formula I [ka] Including, Genotoxic contaminants or degradation products include 4-aminophenol, 4-fluoroaniline, [ka] or a mixture thereof.

[0159] In some embodiments, the present disclosure provides a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, containing 200 ppm or less of contaminants or degradants, wherein R 1 -COOH, -COO(C 1~6 alkyl), -C(O)-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R2 Ha-OC 1~6 is alkyl, The method comprises: (a) reacting a compound of formula I-1' with 4-aminophenol to obtain a compound of formula I-2 [ka] (b) reacting a compound of formula I-2 with a compound I-4 to obtain a compound of formula I [ka] and (c) optionally reacting the compound of formula I with an acid; Genotoxic contaminants or degradation products include 4-aminophenol, 4-fluoroaniline, [ka] or a mixture thereof.

[0160] In some embodiments, the present disclosure provides a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, containing 100 ppm or less of genotoxic contaminants or degradants, wherein R 1 -CO-NH2, -C(O)-NH(C 1~6 alkyl), or -C(O)-N(C 1~6 alkyl)2, R 2 Ha-OC 1~6 is alkyl, The method comprises: (b) reacting a compound of formula I-2 with a compound I-4 to obtain a compound of formula I [ka] Including, Genotoxic contaminants or degradation products include 4-aminophenol, 4-fluoroaniline, [ka] or a mixture thereof.

[0161] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 2.5 ppm or less, or 1 ppm or less of impurities, contaminants, or degradants including 4-aminophenol, 4-fluoroaniline, (I-1), (I-2), or mixtures thereof.

[0162] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt is mixed with 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, or 2.5 ppm or less of 4-aminophenol, 4-fluoroaniline, compound I-1, compound I-2, or a mixture thereof.

[0163] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, or 2.5 ppm or less of 4-aminophenol.

[0164] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, or 2.5 ppm or less, or 1 ppm or less of 4-fluoroaniline.

[0165] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with no more than 100 ppm, no more than 75 ppm, no more than 50 ppm, no more than 25 ppm, no more than 20 ppm, no more than 15 ppm, no more than 13 ppm, no more than 10 ppm, no more than 5 ppm, or no more than 2.5 ppm of the compound of formula I-1.

[0166] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with no more than 100 ppm, no more than 75 ppm, no more than 50 ppm, no more than 25 ppm, no more than 20 ppm, no more than 15 ppm, no more than 13 ppm, no more than 10 ppm, no more than 5 ppm, or no more than 2.5 ppm of the compound of formula I-2.

[0167] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with 4-fluoroaniline and a compound of formula I-2, and the combined level of 4-fluoroaniline and the compound of formula I-2 is 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, or 2.5 ppm or less.

[0168] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with at least two of 4-aminophenol, 4-fluoroaniline, (I-1), and (I-2), and the combined level of the at least two of 4-aminophenol, 4-fluoroaniline, (I-1), and (I-2) is 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 2.5 ppm or less, or 1 ppm or less.

[0169] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with at least three of 4-aminophenol, 4-fluoroaniline, (I-1), and (I-2), and the combined level of the at least three of 4-aminophenol, 4-fluoroaniline, (I-1), and (I-2) is 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, or 2.5 ppm or less.

[0170] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is mixed with 4-aminophenol, 4-fluoroaniline, (I-1), and (I-2), and the combined level of at least four of 4-aminophenol, 4-fluoroaniline, (I-1), and (I-2) is 200 ppm or less, 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, or 5 ppm or less.

[0171] In some embodiments, R 1 is -C(O)-NHMe, R 2 is -OMe.

[0172] In some embodiments, step (a) is carried out in the presence of sodium tert-butoxide or sodium tert-pentoxide and N,N-dimethylacetamide (DMA) at a temperature ranging from about 100° C. to about 130° C. In some embodiments, the temperature ranges from about 100° C. to about 120° C. In some embodiments, the temperature ranges from about 110° C. to about 120° C. In some embodiments, the temperature ranges from about 120° C. to about 130° C.

[0173] In some embodiments, step (a) is carried out in the presence of sodium tert-butoxide or sodium tert-pentoxide and DMA at a temperature ranging from about 60° C. to about 90° C. In some embodiments, the temperature ranges from about 60° C. to about 80° C. In some embodiments, the temperature ranges from about 70° C. to about 80° C. In some embodiments, the temperature ranges from about 70° C. to about 90° C.

[0174] In some embodiments, step (a) is carried out in the presence of sodium tert-butoxide or sodium tert-pentoxide and DMA at a temperature ranging from about 40° C. to about 90° C. In some embodiments, the temperature ranges from about 50° C. to about 70° C. In some embodiments, the temperature ranges from about 50° C. to about 60° C.

[0175] In some embodiments, the compound of formula I-2 can be prepared by the following steps: Cooling the reaction; Adding water to the reaction mixture to obtain a solid; filtering the solids; washing the solid with water and DMA; and The solid is isolated by drying.

[0176] In some embodiments, step (b) includes reacting compound I-4 with a chlorinating agent to obtain 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride.

[0177] In some embodiments, the chlorinating agent is added to compound I-4 for 90 minutes or more.

[0178] In some embodiments, step (b) further comprises reacting the compound of formula I-2 with 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride at a temperature ranging from about 10° C. to about 30° C. In some embodiments, the temperature ranges from about 10° C. to about 20° C. In some embodiments, the temperature ranges from about 10° C. to about 15° C. In some embodiments, the temperature ranges from about 5° C. to about 15° C. In some embodiments, the temperature ranges from about 20° C. to about 30° C. In some embodiments, the temperature ranges from about 25° C. to about 30° C.

[0179] In some embodiments, the compound of formula I can be prepared by the following steps: adding water to the reaction mixture; Stirring the reaction mixture at about 15-25°C to obtain a solid. filtering the solids; washing the solid with water and tetrahydrofuran; and The solid is purified by drying.

[0180] In some embodiments, the compound of formula I is Cooling the reaction to about 15-25°C; Add water over a period of 2 hours or more. Aging the reaction mixture at about 15-25°C for at least 2 hours to obtain a crystalline slurry. filtering the crystal slurry; washing the crystals with water and tetrahydrofuran; Drying the crystals at a jacket temperature of 40° C. or less; and Compound I is purified by crystallization, which involves recrystallization in tetrahydrofuran and 95:5 (v / v) water:ethanol.

[0181] In some embodiments, the compound of formula I can be prepared by the following steps: Add water over an hour. Stir the reaction mixture at about 15 to 25° C. for at least 2 hours to obtain a solid. filtering the solids; washing the solid with water and tetrahydrofuran; and The solid is purified by drying.

[0182] In some embodiments, the compound of formula I is adding water to the organic phase of the reaction mixture after phase separation at about 55-60° C. to obtain a second mixture; seeding the second mixture with Compound 1; adding water to the seeded second mixture over a period of at least one hour to obtain a slurry; cooling the slurry to about 20-25°C and aging the slurry; filtering the slurry to obtain a solid; The solid is purified by steps including washing to obtain compound 1.

[0183] In some embodiments, step (c) comprises reacting the compound of formula I with fumaric acid in ethanol and water to produce the fumarate of the compound of formula I.

[0184] In some embodiments, the pharma- ceutically acceptable salt is Compound 1 hemifumarate.

[0185] In one embodiment, the present disclosure provides Compound 1: [ka] or a pharma- ceutically acceptable salt thereof, containing 200 ppm or less of contaminants or degradants, (b) Reacting compound b with compound I-4 to obtain compound 1 [ka] The compound is produced by a method comprising:

[0186] In one embodiment, the present disclosure provides Compound 1: [ka] or a pharma- ceutical acceptable salt thereof, containing 100 ppm or less of genotoxic contaminants or degradants, (b) Reacting compound b with compound I-4 to obtain compound 1 [ka] The method comprises the steps of:

[0187] In one embodiment, the present disclosure provides Compound 1: [ka] or a pharma- ceutically acceptable salt thereof, containing 200 ppm or less of contaminants or degradants, (a) Reacting compound b' with 4-aminophenol to obtain compound b [ka] (b) Reacting compound b with compound I-4 to obtain compound 1 [ka] and (c) Optionally, produced by a process comprising reacting compound 1 with an acid.

[0188] In one embodiment, the present disclosure provides Compound 1: [ka] or a pharma- ceutical acceptable salt thereof, containing 100 ppm or less of genotoxic contaminants or degradants, (a) Reacting compound b' with 4-aminophenol to obtain compound b [ka] (b) Reacting compound b with compound I-4 to obtain compound 1 [ka] and (c) Optionally, produced by a process comprising reacting compound 1 with an acid.

[0189] In one embodiment, the present disclosure provides Compound 1: [ka] or a pharma- ceutical acceptable salt thereof, containing 200 ppm or less of contaminants or degradants, the method comprising: (b) Reacting compound b with compound I-4 to obtain compound 1 [ka] Includes.

[0190] In one embodiment, the present disclosure provides Compound 1: [ka] or a pharma- ceutical acceptable salt thereof, the method comprising: (b) Reacting compound b with compound I-4 to obtain compound 1 [ka] Includes.

[0191] In one embodiment, the present disclosure provides Compound 1: [ka] or a pharma- ceutical acceptable salt thereof, containing 200 ppm or less of contaminants or degradants, the method comprising: (a) Reacting compound b' with 4-aminophenol to obtain compound b [ka] (b) Reacting compound b with compound I-4 to obtain compound 1 [ka] and (c) optionally, reacting compound 1 with an acid.

[0192] In one embodiment, the present disclosure provides Compound 1: [ka] or a pharma- ceutical acceptable salt thereof, the method comprising: (a) Reacting compound b' with 4-aminophenol to obtain compound b [ka] (b) Reacting compound b with compound I-4 to obtain compound 1 [ka] Includes. (c) optionally, reacting compound 1 with an acid.

[0193] In some embodiments, the contaminants or degradants are 4-aminophenol, 4-fluoroaniline, [ka] or a mixture thereof.

[0194] In some embodiments, the contaminants or degradants include genotoxic contaminants or degradants.

[0195] In some embodiments, the genotoxic contaminants or degradants are 4-aminophenol, 4-fluoroaniline, [ka] or a mixture thereof.

[0196] In some embodiments, the acid is fumaric acid.

[0197] In one embodiment, the present disclosure provides Compound 1: [ka] or a fumarate salt of Compound 1, the fumaric acid salt containing 200 ppm or less of contaminants or degradants, (a) Reacting compound b' with 4-aminophenol to obtain compound b [ka] (b) Reacting compound b with compound I-4 to obtain compound 1 [ka] and (c) optionally produced by a process comprising reacting compound 1 with fumaric acid; Contaminants or decomposition products include 4-aminophenol, 4-fluoroaniline, [ka] or a mixture thereof.

[0198] In one embodiment, the disclosure provides a method for making Compound 1 or a fumarate salt of Compound 1, the method comprising the steps of: (a) Reacting compound b' with 4-aminophenol to obtain compound b [ka] (b) Reacting compound b with compound I-4 to obtain compound 1 [ka] and (c) optionally reacting compound 1 with fumaric acid; Contaminants or decomposition products include 4-aminophenol, 4-fluoroaniline, [ka] or a mixture thereof.

[0199] In some embodiments, the acid is fumaric acid and the pharma- ceutically acceptable salt is Compound 1 hemifumarate.

[0200] In some embodiments, Compound 1 free base or Compound 1 hemifumarate is mixed with no more than 200 ppm, no more than 100 ppm, no more than 75 ppm, no more than 50 ppm, no more than 25 ppm, no more than 20 ppm, no more than 15 ppm, no more than 13 ppm, no more than 10 ppm, no more than 5 ppm, no more than 2.5 ppm, or no more than 1 ppm of impurities, contaminants, or degradants.

[0201] In some embodiments, compound 1 free base or compound 1 hemifumarate is mixed with less than 200 ppm, less than 100 ppm, less than 75 ppm, less than 50 ppm, less than 25 ppm, less than 20 ppm, less than 15 ppm, less than 13 ppm, less than 10 ppm, less than 5 ppm, less than 2.5 ppm, or less than 1 ppm of impurities, contaminants, or degradants including 4-aminophenol, 4-fluoroaniline, compounds a and b, or mixtures thereof.

[0202] In some embodiments, compound 1 or a salt thereof is mixed with 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, or 2.5 ppm or less, or 1 ppm or less of 4-aminophenol, 4-fluoroaniline, compound a, compound b, or a mixture thereof.

[0203] In some embodiments, the free base of Compound 1 is mixed with up to 15 ppm of 4-aminophenol.

[0204] In some embodiments, Compound 1 hemifumarate is mixed with up to 15 ppm of 4-aminophenol.

[0205] In some embodiments, the free base of Compound 1 is mixed with no more than 3 ppm of 4-aminophenol.

[0206] In some embodiments, Compound 1 hemifumarate is mixed with no more than 3 ppm of 4-aminophenol.

[0207] In some embodiments, the free base of Compound 1 is mixed with up to 15 ppm of 4-fluoroaniline.

[0208] In some embodiments, Compound 1 hemifumarate is mixed with no more than 15 ppm of 4-fluoroaniline.

[0209] In some embodiments, the free base of Compound 1 is mixed with 5 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less of 4-fluoroaniline.

[0210] In some embodiments, Compound 1 hemifumarate is mixed with no more than 5 ppm, no more than 3 ppm, no more than 2 ppm, or no more than 1 ppm of 4-fluoroaniline.

[0211] In some embodiments, compound 1 free base is mixed with up to 15 ppm of compound a.

[0212] In some embodiments, compound 1 hemifumarate is mixed with no more than 15 ppm of compound a.

[0213] In some embodiments, compound 1 free base is mixed with no more than 5 ppm, no more than 4 ppm, or no more than 3 pm of compound a.

[0214] In some embodiments, compound 1 hemifumarate is mixed with no more than 5 ppm, no more than 4 ppm, or no more than 3 pm of compound a.

[0215] In some embodiments, compound 1 or compound 1 hemifumarate is mixed with no more than 75 ppm, no more than 50 ppm, no more than 15 ppm, or no more than 10 pm of compound b.

[0216] In some embodiments, compound 1 free base is mixed with up to 75 ppm of compound b.

[0217] In some embodiments, compound 1 hemifumarate is mixed with up to 75 ppm of compound b.

[0218] In some embodiments, compound 1 free base is mixed with up to 50 ppm of compound b.

[0219] In some embodiments, compound 1 hemifumarate is mixed with 50 ppm or less of compound b.

[0220] In some embodiments, compound 1 free base is mixed with up to 15 ppm of compound b.

[0221] In some embodiments, compound 1 hemifumarate is mixed with no more than 15 ppm of compound b.

[0222] In some embodiments, compound 1 free base is mixed with no more than 7 ppm of compound b.

[0223] In some embodiments, compound 1 hemifumarate is mixed with no more than 7 ppm of compound b.

[0224] In some embodiments, step (a) is carried out in the presence of sodium tert-butoxide or sodium tert-pentoxide and DMA at a temperature ranging from about 40°C to about 90°C.

[0225] In some embodiments, step (a) is carried out in the presence of sodium tert-butoxide or sodium tert-pentoxide and DMA at a temperature ranging from about 60°C to about 90°C.

[0226] In one embodiment, step (a) is carried out at a temperature of 50 to 60°C.

[0227] In one embodiment, step (a) is carried out at a temperature of 75 to 80°C.

[0228] In one embodiment, step (a) is carried out at a temperature of 80 to 90°C.

[0229] In one embodiment, compound b is isolated by adding water to the reaction mixture and isolating the solid product.

[0230] In some embodiments, compound b is prepared by the steps of: Cooling the reaction to room temperature; Adding water to the reaction mixture to obtain a solid; filtering the solids; washing the solid with water and DMA; and Dry the solid at a temperature of about 40-60°C. It is isolated by

[0231] In some embodiments, step (b) comprises reacting compound I-4 with a chlorinating agent to obtain 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride (g). In one embodiment, the reaction is carried out at a temperature of 15° C. or less. In a further embodiment, the reaction is carried out at a temperature of 5-15° C. In a further embodiment, the reaction is carried out at a temperature of about 10-15° C. In a further embodiment, the reaction is carried out at a temperature of about 10-15° C. for 2-3 hours. In a further embodiment, the reaction is carried out at room temperature for 2-4 hours. It has been discovered that the formation of acid chloride (g) is rapid when carried out at room temperature, being complete after approximately 15 minutes. However, batch-to-batch inconsistencies have been observed at room temperature, with some batches containing higher levels of impurities than others. It has also been discovered that by running the reaction at 10-15° C., the formation of unwanted by-products is avoided. At 10-15°C the reaction was slower, typically taking 2-3 hours to complete, but impurity levels could be controlled and minimized, especially the level of 4-fluoroaniline in the final product was significantly reduced.

[0232] In another embodiment, the reaction with the chlorinating agent is carried out in the presence of a catalytic amount of dimethylformamide.

[0233] In one embodiment, step (b) is carried out in the presence of an organic solvent. In a further embodiment, the organic solvent is tetrahydrofuran.

[0234] In some embodiments, step (b) further comprises reacting compound b with compound I-4 at a temperature ranging from about 10° C. to about 30° C. In some embodiments, the temperature ranges from about 20° C. to about 25° C. In some embodiments, the temperature ranges from about 10° C. to about 15° C.

[0235] In one embodiment, compound b is contacted with compound g by adding a solution of compound g dissolved in a first solvent to a solution of compound b dissolved in a second solvent to create a reaction mixture.

[0236] In one embodiment, the first solvent is an organic solvent. In a further embodiment, the first solvent is a polar aprotic solvent. In a further embodiment, the first solvent is tetrahydrofuran.

[0237] In one embodiment, the second solvent is tetrahydrofuran:water in an approximate weight ratio of 2:1.

[0238] In one embodiment, compound g dissolved in a first solvent is added to a solution of compound b dissolved in a second solvent over a period of about 30 minutes to about 1 hour. In another embodiment, compound g dissolved in a first solvent is added to a solution of compound b dissolved in a second solvent over a period of 30 minutes or more.

[0239] In one embodiment, the temperature of the reaction mixture of compound g and compound b is maintained at about 20-27° C. In one embodiment, the reaction mixture is maintained at about 25-27° C. In one embodiment, the reaction mixture is maintained below about 27° C. In another embodiment, the reaction temperature is maintained at about 20-25° C. In another embodiment, the reaction temperature is maintained at about 10-15° C.

[0240] In another embodiment, the reaction mixture of compound g and compound b is heated to 35-40° C. and allowed to stand to separate into an organic phase and an aqueous phase.

[0241] In another embodiment, the reaction mixture is heated to 35-45° C. and allowed to settle and separate into organic and aqueous phases.

[0242] In one embodiment, the method further comprises discarding the aqueous phase, heating the organic phase to 45-50°C, and then filtering the organic phase at 45-50°C.

[0243] In one embodiment, the method further comprises discarding the aqueous phase, heating the organic phase to 55-60°C, and then filtering the organic phase at 55-60°C.

[0244] In one embodiment, the method further comprises discarding the aqueous phase and heating the organic phase to 55-60°C.

[0245] In one embodiment, the method further comprises discarding the aqueous phase and heating the organic phase to 35-45°C.

[0246] In another embodiment, the method further comprises cooling the organic phase to 20-25° C. and adding water to the organic phase to create a second mixture, wherein the volume of water added is about 1.5 to about 2.5 times the volume of the organic phase.

[0247] In another embodiment, the method further comprises adding water to the organic phase while maintaining the temperature at 50-55° C. to create a second mixture.

[0248] In another embodiment, the method further comprises adding water to the organic phase while maintaining the temperature at 55-60° C. to create a second mixture.

[0249] In another embodiment, the method further comprises adding water to the organic phase while maintaining a temperature of 35-45° C. to create a second mixture.

[0250] In one embodiment, the water is added to the organic phase over a period of at least 1 hour, hi another embodiment, the water is added to the organic phase over a period of approximately 4 to 4.5 hours.

[0251] In one embodiment, the second mixture is stirred for at least 12 hours, and compound 1 is a solid, which is collected, such as by filtration. In another embodiment, the second mixture is stirred for at least 2 hours, and the product is collected, such as by filtration. In one embodiment, the second mixture is stirred for at least 2 hours at a temperature of 35-45° C., and the crude product is collected, such as by filtration.

[0252] In one embodiment, the crude product is purified by polishing filtration and recrystallization.

[0253] In some embodiments, Compound 1 is prepared by the steps of: Add water over an hour. Stir the reaction mixture at about 15 to 25° C. for at least 2 hours to obtain a solid. filtering the solids; washing the solid with water and tetrahydrofuran; and Drying the solids It is refined by.

[0254] In some embodiments, Compound 1 is prepared by the steps of: adding water to the organic phase of the reaction mixture after phase separation at about 55-60° C. to obtain a second mixture; seeding the second mixture with Compound 1; adding water to the seeded second mixture over a period of at least one hour to obtain a slurry; cooling the slurry to about 20-25°C and aging the slurry; filtering the slurry to obtain a solid; The solid is washed with THF and water to give compound 1. It is refined by.

[0255] In some embodiments, step (c) comprises reacting compound 1 with fumaric acid in ethanol and water to produce compound 1 hemifumarate.

[0256] In one embodiment, step (c) is carried out in the presence of a solvent. In a further embodiment, the solvent is selected from water, an alcoholic solvent, THF, DMF, MEK, acetonitrile, 1,4-dioxane, and MTBE, or any combination thereof. In a further embodiment, the solvent is a mixture of water in an alcoholic solvent.

[0257] In one embodiment, the alcohol solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, pentanol, hexanol, heptanol, and octanol.

[0258] In a further embodiment, the solvent is a 20% solution of water in ethanol.

[0259] In a further embodiment, the solvent is a 5% solution of water in ethanol.

[0260] In one embodiment, the volume of a 20% solution of water in ethanol used in the reaction is about 2 to 3 times the weight of compound 1. In another embodiment, the volume (mL) of a 20% solution of water in ethanol used in the reaction is about 3 times the weight (grams) of compound 1.

[0261] In one embodiment, the amount of fumaric acid used is about 0.5-1.0 stoichiometric equivalents relative to compound 1. In another embodiment, the amount of fumaric acid used is about 0.75-1.0 stoichiometric equivalents relative to compound 1. In another embodiment, the amount of fumaric acid used is about 0.8-0.82 stoichiometric equivalents relative to compound 1.

[0262] In one embodiment, the reaction of compound 1 with fumaric acid is carried out by adding a mixture of fumaric acid dissolved in a 20% solution in water and ethanol at 45-50° C. to compound 1 to produce a reaction mixture.

[0263] In one embodiment, the volume (mL) of a 20% solution of water in ethanol used to dissolve fumaric acid is about 2 to 3 times the weight (grams) of compound 1. In another embodiment, the volume of a 20% solution of water in ethanol used to dissolve fumaric acid is about 2.2 to 2.8 times the weight of compound 1. In another embodiment, the volume of a 20% solution of water in ethanol used to dissolve fumaric acid is about 2.4 to 2.6 times the weight of compound 1.

[0264] In one embodiment, step (c) further comprises heating the reaction mixture to reflux temperature and stirring. In another embodiment, the refluxed reaction mixture is stirred for 4 to 6 hours. In one embodiment, step (c) further comprises cooling the reaction mixture and separating the solid product from the solvent. EXAMPLES

[0265] Preparation of Compound 1 Hemifumarate Example 1 [ka]

[0266] Synthesis of 4-chloro-7-methoxy-N-methylquinoline-6-carboxamide [ka] To a suspension of methyl 4-chloro-7-methoxyquinoline-6-carboxylate a' (2 g, 8 mmol) in THF (20 mL) was added methylamine in EtOH (33% w / w, 8 M, 20 mL, 160 mmol) and H2O (10 mL). The resulting mixture was stirred at room temperature. The mixture became a clear solution in about 10 min and remained a clear solution throughout the reaction. Stirring was continued until the starting material was completely consumed as evidenced by LCMS and HPLC. This took about 3 h. The mixture was then concentrated and the residue was slurried in 20 mL of water and filtered using a filter funnel. Some EtOAc was used to transfer the material from the flask to the filter funnel. The product was dried to give 4-chloro-7-methoxy-N-methylquinoline-6-carboxamide as a white solid (yield 1.8 g, 90%, HPLC purity >97%).

[0267] Synthesis of 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide [ka] A 5 L three-necked round bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer was charged with 4-chloro-7-methoxy-N-methylquinoline-6-carboxamide (b'; 300 g; 1 equiv.), 4-aminophenol (195.9 g; 1.5 equiv.), and DMA (1500 mL). The resulting solution was stirred at room temperature and a solution of sodium t-pentoxide (184.52 g; 1.4 equiv.) dissolved in anhydrous THF (313 mL) was added with stirring over a period of 5 minutes. The reaction mixture was then heated to 75-80°C and stirred for an additional 2-6 hours. The reaction mixture was then cooled to room temperature and charged with water (3 L) and stirred for at least an additional hour. The product was filtered and washed twice with 600 mL of 1:1 DMA / water, then once with 1200 mL of water. The product was transferred to a crystallizing dish and dried in a vacuum oven at 40-45°C for a minimum of 18 hours to give a light brown, glossy solid (370-377g; 96-97%).

[0268] Synthesis of 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride (Method 1) [ka] A 250 mL three-neck round bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer was charged with 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (I-4, 19.11 g; 1.3 equiv.), 75 mL of anhydrous THF, and 0.25 mL of DMF (catalyst). The mixture was stirred until all solids were dissolved, cooled to 5-10 °C, and charged with oxalyl chloride (7.13 mL; 1.28 equiv.). The resulting mixture was aged at 10-15 °C for 2-3 h, and IPC (in-process control) confirmed the completion of the reaction. Once the reaction was complete, the resulting product mixture was used in the next step without further purification. Synthesis of 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride (Method 2)

[0269] A 250 mL three-neck round bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer was charged with 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (I-4, 19.11 g; 1.3 equiv.), 75 mL of anhydrous THF, and 0.25 mL of DMF (catalyst). The mixture was stirred until all solids were dissolved, cooled to 5-15 °C, and then charged with oxalyl chloride (7.13 mL; 1.28 equiv.). The resulting mixture was allowed to warm to room temperature and then stirred for 2-4 h. The resulting product was used in the next step without further purification.

[0270] Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (1) (Method 1) [ka] A 500 mL three-neck round bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer was charged with 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide (b, 21.3 g; 1.0 equiv.), 210 mL of anhydrous THF, and a solution consisting of potassium carbonate (27.32 g; 3 equiv.) and 100 mL of water. The added aqueous K2CO3 solution was rinsed with an additional 6.4 mL of water. With vigorous stirring, the reaction mixture containing compound g from the previous example was transferred to this reaction mixture over a period of 30 minutes while maintaining an internal temperature of 20-25°C. The transfer apparatus was washed with 32 mL of anhydrous THF. The reaction mixture was stirred at ambient temperature for 0.5-1 hour. The resulting mixture was warmed to 35-40°C and the phases were allowed to separate. The lower aqueous layer was discarded and the upper organic phase was warmed to 55-60 °C, then polish filtered and washed with 21 mL of THF. The filtered organic phase was transferred to a 1 L three-neck round bottom flask equipped with a thermometer, nitrogen inlet, and mechanical stirring and charged with water at 55-60 °C. The resulting solution was seeded with compound 1 and added to the resulting seeded bed over 4-4.5 h while maintaining a temperature of 50-55 °C with water as the anti-solvent. The resulting slurry was cooled to 20-25 °C and aged for ≥2 h. The product was filtered, washed with water / THF, and dried.

[0271] Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (1) (Method 2) A 500 mL three-neck round bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer was charged with 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide (b, 21.3 g; 1.0 equiv.), 210 mL of anhydrous THF, and a solution consisting of potassium carbonate (27.32 g; 3 equiv.) and 100 mL of water. The added aqueous K2CO3 solution was rinsed with an additional 6.4 mL of water. With vigorous stirring, the reaction mixture containing compound g from the previous example was transferred to this reaction mixture over a period of 0.5-1 h while maintaining an internal temperature below 27 °C. The transfer apparatus was washed with 32 mL of anhydrous THF. The reaction mixture was stirred at ambient temperature for 0.5-1 h. The resulting mixture was warmed to 35-40 °C and the phases were allowed to separate. The lower aqueous layer was discarded and the upper organic phase was warmed to 45-50°C then filtered through a filter paper and rinsed with 21 mL of THF. The filtered organic phase was transferred to a 1 L three-neck round bottom flask equipped with a thermometer, nitrogen inlet, and mechanical stirring and charged with 694 mL of filtered water over a minimum of 1 h. The resulting mixture was stirred at 20-25°C for a minimum of 12 h and then the product was filtered and washed twice with 42 mL of a 2:1 water:THF mixture. The product was then dried on the filter paper at room temperature or in a vacuum oven at 40-45°C to give a white to beige solid (31.36 g; 90%).

[0272] Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide-1 / 2 fumaric acid (1 hemifumarate) (Method 1) [ka] A 2000 mL three-necked round-bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer was charged with fumaric acid (80 g; 0.82 equiv.) and 1.2 L of a 20% solution of water in ethanol. The mixture was heated to 45-50 °C and stirred until all solids were dissolved. A separate 3 L three-necked round-bottom flask equipped with a thermometer, nitrogen inlet, and mechanical stirrer was charged with N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (1, 500 g; 1.0 equiv.). The fumaric acid solution was clarified with filter paper at 40-45 °C and transferred to the flask containing compound 1 at 40-45 °C. The 2000 mL round-bottom flask was rinsed with 300 mL of a 20% solution of water in ethanol at 45-50 °C. The resulting mixture was heated to reflux (75-80°C) and stirred for 4-6 hours. The reaction mixture was then cooled to room temperature, the product was filtered, and the filter cake was washed twice with 300 mL of a 20% solution of water in ethanol. The product was then dried on the filter paper at room temperature or in a vacuum oven at 40-45°C to give a white to beige solid (472-474g; 97%).

[0273] Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide-1 / 2 fumaric acid (2 hemifumarate) (Method 1) Fumaric acid (2.68 g, 1 equiv.) and EtOH / acetone 1:1 (48 mL) were added to a 2-piece EasyMax® (EM) (Mettler, Toledo, OH, USA) reaction vessel and heated to a reaction temperature of 50° C. to dissolve all materials. In an adjacent EM pot, a 1-piece EM vessel containing compound 1 (12.0 g, 1 equiv.) was set to a jacket temperature of 50° C. The fumaric acid solution was transferred to the vessel containing compound 1. Seed was charged (2% seed, 0.244 g) and the vessel was heated to reflux (approximately 65° C.). After 1 h, 0.5 mL of the slurry was filtered, washed with EtOH (6×1.5 mL), and analyzed by HPLC to quantify fumaric acid content (result should be approximately 10%). The slurry was then cooled to 25° C. over 1 h and stirred for an additional 1 h. The solid was filtered, washed with 1:1 EtOH / acetone (2×3V) and dried under vacuum at 25° C. over the weekend. 1 H NMR 700 MHz (DMSO-d6) δ 1.473 (s, 4H), δ 4.009 (s, 3H), δ 2.839 (d, 3H), δ 2.840 (d, 3H), δ 6.450 (d, 1H), δ 6.632 (s, 2H), δ 6.635 (s, 2H), δ 7.137 (m, 2H), δ 7.244 (d, 2H), δ 7.494 (s, 1H), δ 7.642 (m, 2H), δ 7.776 (d, 2H), δ 8.361 (q, 1H), δ 8.618 (s, 1H), 8.615 (s, 1H), δ 8.638 (d, 1H), δ 10.070 (s, 1H), δ 10.216 (s, 1H), δ 13.164 (s, 1H). 19 F NMR 700 MHz (DMSO-d6; reference trifluorotoluene at -63.72 ppm) δ -121.460. 13C NMR 700 MHz (DMSO-d6) δ 15.46, δ 26.47, δ 31.60, δ 56.15, δ 102.91, δ 107.83, δ 114.55, δ 115.05 (d), δ 121.15, δ 122.23, δ 122.43 (d), δ 124.35, δ 125.24, δ 134.03, δ 135.22 (d), δ 136.73, δ 149.08, δ 151.46, δ 153.18, δ 157.94, δ 158.30 (d), δ 161.76, δ 164.89, δ 168.16, and δ 168.16. 15 N NMR 700 MHz (DMSO-d6) δ 106.25 ( 15 N), δ 127.79 ( 15 N), δ 128.86 ( 15 N), δ 166.04, δ 289.56 ( 15 N).

[0274] Preparation of Compound 1 Hemifumarate Example 2 Synthesis of 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide [ka] The reactor was charged with DMA (7.05 kg), 4-aminophenol (0.98 kg), and 4-chloro-7-methoxy-N-methylquinoline-6-carboxamide (b'; 1.5 kg). The batch was charged with 35% wt sodium t-pentoxide (2.635 kg) while stirring at room temperature. The reaction mixture was heated to 75-80°C for 1 hour and cooled to 40-45°C. At 40-45°C, water (15 kg) was charged to the reaction mixture. The batch was adjusted to 20-25°C and stirred for 1 hour. The product, compound b, was filtered and washed with a mixture of DMA:water (2.8:3 kg) and then with water (6 kg). The product was dried on the filter for 66 hours (shutdown point). This procedure yielded 1.785 kg of compound b (92% yield).

[0275] Synthesis of 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride [ka] The first reactor was charged with carboxylic acid I-4 (1.6 kg), DMF (0.02 kg), and THF (4.6 kg). The acid was dissolved and the solution was cooled to 5-10° C. Oxalyl chloride (0.898 kg) was added to the solution over 1.5 hours while maintaining the temperature below 20° C. The mixture was then warmed to 20-25° C. and kept stirring for 3 hours.

[0276] Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (1) [ka] (i) A second reactor was charged with compound b (1.759 kg) and THF (15.9 kg). To this mixture was added a solution of K2CO3 (2.29 kg) in water (8.4 L) and rinsed with water (0.5 kg). The contents of the first reactor were transferred to the second reactor over 40 minutes while maintaining the temperature in the second reactor at 20-25°C, and the first reactor was rinsed with THF (2.4 kg). The mixture was agitated at 20-25°C for 1 hour. The mixture in the second reactor was warmed to 35-40°C, the phases were separated, and the lower aqueous phase was discarded.

[0277] (ii) The organic phase was warmed to 55-60°C to dissolve the solids in the mixture. The batch was clarified and transferred to the first reactor and rinsed with THF (1.6 kg). Water (58 kg) was charged to the first reactor over 1 hour. The batch was then agitated at 20-25°C for 14 hours. The product was filtered, washed with a mixture of THF:water (2:4.7 kg) and dried on the filter for a total of about 70 hours. This procedure yielded 3.243 kg of compound 1 in 97.5% yield.

[0278] Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide-1 / 2 fumaric acid (1 hemifumarate) [ka] The third reactor was charged with fumaric acid (0.58 kg), EtOH (4.9 kg), and water (1.5 kg). The batch was heated to 45-50° C. to dissolve the solids. The fourth reactor was charged with free base Compound 1 (3.23 kg) and the jacket temperature was adjusted to approximately 50° C. The contents of the third reactor were charged to the fourth reactor and rinsed with a mixture of water:EtOH (0.4:1.2 kg). The resulting mixture was heated to 75-80° C. and agitated for 4 hours. The reaction was cooled to 45-50° C. and sampled for analysis. The mixture was further cooled to 20-25° C. and agitated for 1 hour. The product was filtered and washed with water:EtOH (0.8:2.4 kg). The product was dried on the filter for 48 hours. This procedure yielded 2.649 kg of Compound 1 hemifumarate (74% yield).

[0279] Preparation of Compound 1 Hemifumarate Example 3 Synthesis of 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide The procedure was carried out as described in Preparative Example 2.

[0280] Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (1) The procedure was similar to preparative example 2, except that the reaction temperature in the synthesis of compound g was controlled at about 10-15° C. instead of 20-25° C. The reaction temperature in step (i) of the synthesis of compound 1 was controlled at about 10-15° C. before warming to 35-40° C. This procedure afforded 2.571 kg of the free base compound 1 (94% yield when corrected for the presence of residual THF).

[0281] Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide-1 / 2 fumaric acid (1 hemifumarate) The procedure was carried out as described in Preparative Example 2 using 2.571 kg of free base Compound 1. The procedure yielded 2.304 kg of Compound 1 hemifumarate (88% yield).

[0282] Preparation of Compound 1 Hemifumarate Example 4 Synthesis of 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide The procedure was carried out as described in Preparative Example 2.

[0283] Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (1) Step (i) of this procedure was similar to step (i) of preparative example 2 using 1.5 kg of compound b, except that the reaction temperature in the synthesis of compound g was controlled at about 10-15° C. instead of 20-25° C. The reaction temperature in step (i) of the synthesis of compound 1 was controlled at about 10-15° C. before being warmed to 35-40° C.

[0284] In step (ii), the organic phase was warmed to 55-60° C. and water (9.7 kg) was charged over 0.5 hours. The mixture was seeded with solid Compound 1 (10 g) in water (0.1 kg) and stirred for 1 hour and 20 minutes. Additional water (26.7 kg) was introduced over 4 hours. The batch was cooled to 20-25° C. over 3 hours and stirred for 2.5 hours. The resulting product was filtered, washed with a mixture of THF (2.9 kg) and water (2.6 kg) and dried on the filter for 80 hours. This procedure yielded 2.054 kg of free base Compound 1 (84% yield).

[0285] Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide-1 / 2 fumaric acid (1 hemifumarate) The procedure was carried out as described in Preparative Example 2 using 1.1794 kg of free base Compound 1. 5% water in ethanol was used for the salt formation. The procedure yielded 1.806 kg of Compound 1 hemifumarate (92.4% yield).

[0286] Example of analysis: The compounds disclosed herein (including Compound 1), as well as impurities, contaminants, or degradants, were analyzed by analytical procedures including, but not limited to, the following methods.

[0287] Assay and Purity by High Performance Liquid Chromatography (UPLC)

[0288] An FTIR sample of compound 1 hemifumarate was prepared by mixing approximately 6-7 mg of sample with approximately 200 mg of potassium bromide and placing it in a sample cell holder. The spectrum was recorded from 650 to 3800 cm. -1 The identity of compound 1 hemifumarate was confirmed when the FTIR spectrum of the sample matched that of a reference standard.

[0289] Compound 1 hemifumarate assay and weight or area percent quantification of impurity levels were determined using a gradient reversed-phase UPLC method (Mobile Phase A: 15% acetonitrile / 85% ammonium acetate buffer, pH 8.0, Mobile Phase B: 80% acetonitrile / 20% ammonium acetate buffer, pH 8.0). UV detection was performed at 245 nm. Single-point external reference standards were used to quantitate weight percent assays (% w / w based on free base and salt). Area percent purity was quantified by normalization to total area.

[0290] Impurities by LC-MS

[0291] Impurities or contaminants were quantified using a gradient reversed-phase HPLC method coupled with QDa mass spectrometry (MS) detection. Impurity levels are calculated against external reference standards.

[0292] 4-Aminophenol by HPLC

[0293] The amount of 4-aminophenol in compound 1 hemifumarate was quantified using an ion exchange / reversed phase mixed mode HPLC method and UV detection at 192 nm. Mobile phase A was 30% acetonitrile / 70% water and 0.3% phosphoric acid, and mobile phase B was 2% phosphoric acid in 100% acetonitrile. The level of 4-aminophenol is calculated relative to the average response factor of three levels of external standard concentration (5, 10, 15 ppm).

[0294] Table 2 below shows the batch analysis of compound 1 hemifumarate. Table 2 shows that by lowering the reaction temperature from 20-25° C. to about 10-15° C. in the synthesis of compound g, the levels of 4-aminophenol and 4-fluoroaniline in compound 1 hemifumarate were significantly reduced. By seeding compound 1 and slowly adding water in step (ii) of the synthesis of compound 1, the level of 4-fluoroaniline in the final product was further reduced, resulting in compound 1 hemifumarate with minimal impurities. [Table 2]

[0295] Other embodiments The foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity and understanding. The invention has been described with reference to various specific and preferred embodiments and techniques. It should be understood, however, that many variations and modifications may be made while remaining within the spirit and scope of the invention. It will be apparent to those skilled in the art that changes and modifications may be practiced within the scope of the appended claims. It is therefore to be understood that the foregoing description is intended to be illustrative and not restrictive.

[0296] The scope of the invention should, therefore, be determined not with reference to the above description, but instead with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

1. Compound 1 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein said compound or a pharmaceutically acceptable salt thereof is mixed with 200 ppm or less of contaminants or degradants.

2. The contaminants or decomposition products are 4-aminophenol, 4-fluoroaniline, 【Chemistry 2】 or a mixture thereof.

3. 3. The compound of claim 2, wherein the contaminants or decomposition products are at or below 100 ppm, 75 ppm, 50 ppm, 25 ppm, 20 ppm, 15 ppm, 13 ppm, 10 ppm, 5 ppm, 3 ppm, 2.5 ppm, or 1 ppm.

4. The compound of any one of claims 1 to 3, wherein the pharmaceutically acceptable salt is Compound 1 hemifumarate.

5. 5. The compound of claim 4, wherein the Compound 1 or the Compound 1 hemifumarate is mixed with 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less of 4-fluoroaniline.

6. Compound 1: 【Transformation 5】 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition contains 200 ppm or less of contaminants or degradants.

7. 7. The pharmaceutical composition of claim 6, wherein the contaminants or degradants are at 100 ppm or less, 75 ppm or less, 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 2.5 ppm or less, or 1 ppm or less.

8. The contaminants or decomposition products are 4-aminophenol, 4-fluoroaniline, 【Transformation 6】 8. The pharmaceutical composition according to claim 6 or claim 7, comprising:

9. Compound 1: 【Transformation 7】 or a pharmaceutically acceptable salt thereof, wherein Compound 1 or said salt is mixed with 75 ppm or less of 4-fluoroaniline, said method comprising: (a) Reacting compound b' with 4-aminophenol to obtain compound b 【Transformation 8】 , and (b) Reacting compound b with compound I-4 to obtain compound 1 【Chemistry 9】 The method comprising:

10. The method of claim 9, wherein step (b) comprises reacting compound I-4 with a chlorinating agent to obtain 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride.

11. The method of claim 9 or claim 10, wherein compound 1 or the pharmaceutically acceptable salt thereof is mixed with 50 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 13 ppm or less, 10 ppm or less, 5 ppm or less, 2.5 ppm or less, or 1 ppm or less of 4-fluoroaniline.

12. The method of claim 11, wherein the pharmaceutically acceptable salt is compound 1 hemifumarate, and the compound 1 hemifumarate is mixed with 15 ppm or less of 4-fluoroaniline.

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