A novel chemical method for preparing 6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine, a key intermediate of NT-814

Abstract

The present invention relates to a novel method for producing the compound 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-N,2-dimethylpropanamide (Compound IX), which is useful in the preparation of the compound 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-3-pyridinyl}-N,2-dimethylpropanamide (Compound A).

Description

[Technical field]

[0001] The present invention relates to a novel process for producing compound IX, which is useful in the preparation of compound A. The present invention also relates to compound IX prepared by this process, and its use in the preparation of compound A. The present invention also relates to novel intermediates prepared by this process, including compound III, compound IV, salts of compound V, compound VII, and pharma- ceutically acceptable salts thereof, and their use in the preparation of compound IX or compound A. [Background technology]

[0002] Compound A, or a pharma- ceutically acceptable salt thereof, was first disclosed in WO 2007 / 028654.

[0003] Compound A is also known in anhydrous crystalline form. Thus, Compound A as an anhydrous crystalline form (e.g., anhydrous crystalline form 1) is described in WO 2011 / 023733.

[0004] Compound A or its pharma- ceutically acceptable salts, including anhydrous crystalline form 1, are useful for the treatment of sex hormone disorders, including, inter alia, hot flashes, polycystic ovary syndrome (PCOS), endometriosis, heavy menstrual bleeding, uterine fibroids or adenomyosis. See WO 2016 / 184829.

[0005] Methods for preparing Compound A or a pharma- ceutically acceptable salt thereof, and its anhydrous crystalline form 1 are disclosed in WO 2007 / 028654 and WO 2011 / 023733, respectively. These methods produce Compound A or its anhydrous crystalline form 1 by reaction of Compound XI.

[0006] Methods for preparing compound IX are disclosed in WO 2005 / 002577, WO 2006 / 013050, and WO 2002 / 016324, as well as EP 3067349 and EP 3141541. However, these methods generally have low yields and use high cost or non-commercially available materials, thereby affecting the overall cost of synthesizing compound A.

[0007] Thus, there is a need for improved methods for preparing compound IX, which is useful for producing compound A. The present invention addresses this need. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2007 / 028654 Brochure [Patent Document 2] International Publication No. 2011 / 023733 Brochure [Patent Document 3] International Publication No. 2016 / 184829 Brochure [Patent Document 4] International Publication No. 2005 / 002577 Brochure [Patent Document 5] International Publication No. 2006 / 013050 Brochure [Patent Document 6] International Publication No. 2002 / 016324 Brochure [Patent Document 7] European Patent No. 3067349 [Patent Document 8] European Patent No. 3141541 Summary of the Invention [Means for solving the problem]

[0009] In some aspects, the present invention provides a method for producing a method for the treatment of a disease comprising the steps of: (i) reacting compound I with compound II to form compound III; (ii) reacting compound III to form compound IV; (iii) reacting compound IV to form compound V, or a pharma- ceutically acceptable salt thereof; (iv) reacting compound V, or a pharma- ceutically acceptable salt thereof, with compound VI to form compound VII; and (v) reacting compound VII with compound VIII to form compound IX The present invention provides a method for preparing compound IX, comprising one or more of:

[0010] In some aspects, the present invention provides the use of Compound I, Compound III, Compound IV, Compound V, Compound VII, or a pharma- ceutically acceptable salt thereof in the manufacture of Compound IX.

[0011] In some aspects, the present invention provides an intermediate selected from Compound III, Compound IV, Compound VII, or a salt thereof.

[0012] In some embodiments, the present invention provides a salt of compound V.

[0013] In some aspects, the invention provides compound IX prepared by the methods disclosed herein.

[0014] In some aspects, the present invention provides a method for producing a method for the treatment of a disease comprising the steps of: (vi) reacting compound IX, prepared by the methods disclosed herein, with compound X to form compound XI or a pharma- ceutically acceptable salt thereof; (vii) reacting compound XI, or a pharma- ceutically acceptable salt thereof, to form a pharma- ceutically acceptable salt and / or solvate of compound A; (viii) reacting a pharma- ceutically acceptable salt and / or solvate of Compound A to form Compound A (e.g., Form 1). The present invention provides a method for preparing compound A, the method comprising one or more of:

[0015] In some aspects, the present invention provides a method of preparing compound A, comprising one or more of steps (i)-(viii).

[0016] In some aspects, the present invention provides the use of Compound III, Compound IV, Compound V, Compound VII, or a pharma- ceutically acceptable salt thereof in the manufacture of Compound A.

[0017] In some aspects, the present invention provides the use of compound IX, prepared by the methods disclosed herein, in the manufacture of compound A.

[0018] In some aspects, the present invention provides compound A prepared by the methods disclosed herein.

[0019] In some aspects, the present invention provides pharmaceutical compositions comprising Compound A prepared by the methods disclosed herein and one or more pharma- ceutically acceptable excipients, carriers, and / or diluents.

[0020] In some aspects, the present invention provides a method for treating or preventing a sex hormone disorder, comprising administering to a subject in need thereof compound A or a pharmaceutical composition thereof prepared by the methods disclosed herein.

[0021] In some aspects, the present invention provides Compound A, prepared by the methods disclosed herein, or a pharmaceutical composition thereof, for use in treating or preventing sex hormone disorders.

[0022] In some aspects, the present invention provides the use of Compound A, prepared by the methods disclosed herein, in the manufacture of a medicament for use in treating or preventing a sex hormone disorder.

[0023] In some aspects, the present invention provides a method of treating or preventing a condition, comprising administering to a subject in need thereof Compound A or a pharmaceutical composition thereof prepared by the methods disclosed herein.

[0024] In some aspects, the present invention provides compound A, prepared by the methods disclosed herein, or a pharmaceutical composition thereof, for use as a medicament.

[0025] In some aspects, the present invention provides the use of Compound A, prepared by the methods disclosed herein, in the manufacture of a medicament for use in therapy.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In this specification, the singular form includes the plural form unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. References cited herein are not admitted to be prior art to the claimed invention. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0027] Other features and advantages of the invention will become apparent from the following detailed description, and from the claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] The present invention is based inter alia on the discovery of a novel and efficient method for preparing compound IX, which can produce compound IX in a quality (e.g., high purity) suitable for the manufacture of compound A and can be readily scalable on an industrial scale.

[0029] definition As used herein, "Compound A" refers to 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-3-pyridinyl}-N,2-dimethylpropanamide, having the chemical structure shown below. [ka] (Compound A).

[0030] As used herein, "Form 1" of Compound A refers to an anhydrous crystalline form of Compound A ("Form 1") occurring at 2θ angles of 4.3±0.1, 7.9±0.1, 9.8±0.1, 10.7±0.1, 10.8±0.1, 13.3±0.1, 14.0±0.1, 15.1±0.1 degrees, corresponding to d-spacings of 20.4, 11.1, 9.0, 8.3, 8.2, 6.6, 6.3, and 5.9 angstroms (Å), respectively.

[0031] As used herein, "Compound I" refers to 4-chloro-5-nitropyridin-2(1H)-one, which has the chemical structure shown below. It is understood that Compound I is commercially available, for example, from Leapchem, RennoTech Co., Ltd., Chemieliva Pharmaceutical Co., Ltd., or Alchem ​​Pharmtech, Inc. [ka] (Compound I).

[0032] As used herein, "compound II" refers to 4-fluoro-2-methylphenylboronic acid, which has the chemical structure shown below: [ka] (Compound II).

[0033] As used herein, "compound III" refers to 4-(4-fluoro-2-methylphenyl)-5-nitropyridin-2(1H)-one, which has the chemical structure shown below: [ka] (Compound III).

[0034] As used herein, "compound IV" refers to 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine, having the chemical structure shown below: [ka] (Compound IV).

[0035] As used herein, "Compound V" refers to 6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine, which has the chemical structure shown below: [ka] (Compound V).

[0036] As used herein, "Compound VI" refers to 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride, which has the chemical structure shown below. Compound VI and methods for its preparation are described in U.S. Patent Application Publication No. 2015 / 0011510, and Journal of Organic Chemistry, 71(5), 2000-2008(2006). [ka] (Compound VI).

[0037] As used herein, "Compound VII" refers to 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methyl-propanamide, having the chemical structure shown below: [ka] (Compound VII).

[0038] As used herein, "compound VIII" refers to a methyl halide and has the chemical structure CHX, where X is a halogen. In some embodiments, X is Cl, l, Br, or I. In some embodiments, X is Cl, Br, or I. In some embodiments, compound VIII is CHCl, CHBr, or CHI. In some embodiments, compound VIII is CHCl, CHBr, or CHI.

[0039] As used herein, "compound IX" refers to 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-N,2-dimethylpropanamide, having the chemical structure shown below: [ka] (Compound IX).

[0040] As used herein, "compound X" refers to (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazino[2,1-c][1,4]oxazine, a compound having the chemical structure shown below: [ka] (Compound X).

[0041] As used herein, "compound XI" refers to N-(6-((7S,9aS)-7-((benzyloxy)methyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamide, a compound having the chemical structure shown below: [ka] (Compound XI).

[0042] The present disclosure includes the compounds of the present invention and their pharma- ceutically acceptable salts and solvates, and is understood to include stereoisomers, mixtures of stereoisomers, and all isomeric polymorphs of said compounds.

[0043] As used herein, the term "salt" or "pharmaceutically acceptable salt" refers to any salt of the compound according to the invention prepared from an inorganic or organic acid. Suitable salts or pharmaceutically acceptable salts of the compound of the invention include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, as well as acid addition salts formed with tartaric acid, acetic acid, trifluoroacetic acid, citric acid, malic acid, lactic acid, fumaric acid, benzoic acid, formic acid, propionic acid, glycolic acid, gluconic acid, maleic acid, succinic acid, camphorsulfuric acid, isethionic acid, mucic acid, gentisic acid, isonicotinic acid, glycer ... These include the acid addition salts formed with organic acids such as saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic, and arylsulfonic acids, e.g., benzenesulfonic and p-toluenesulfonic acids.

[0044] As used herein, the term "solvate" refers to a solvent addition form that contains a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state to form solvates. When the solvent is water, the solvate formed is a hydrate. When the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is formed by the combination of one or more water molecules with one molecule of a substance, where the water retains its molecular state as H2O.

[0045] As used herein, the term "Compound A" is intended to include any form of Compound A, such as free base and pharma- ceutically acceptable salts, unless otherwise specified herein. Free base and pharma-ceutically acceptable salts include anhydrous forms and solvated forms, such as hydrates. Anhydrous forms and solvates include amorphous and crystalline forms.

[0046] As used herein, the term "salts" of Compound V is intended to include salts, solvates and hydrates of Compound V.

[0047] As used herein, "treatment" or "treating" is intended to refer to the management and care of the patient with the purpose of alleviating, arresting, partially arresting or slowing the progression of the clinical symptoms of the disease or curing the disease. The patient to be treated is preferably a mammal, in particular a human.

[0048] As used herein, the term "prevention" or "preventing" describes the reduction or elimination of the onset of symptoms or complications of such a disease, condition or disorder.

[0049] As used herein, the term "hot flushes" is intended to be interchangeable and have the same meaning as the terms "hot flashes" and "vasomotor symptoms."

[0050] In this specification, the term "comprise" includes the case where "consist only of".

[0051] A description herein of one or more embodiments of the invention using terms such as "comprising," "having," "including," or "containing" in reference to one or more elements is intended to provide support for similar embodiments or embodiments of the invention that "consist," "consist essentially of," or "substantially comprise" that particular element or elements, unless otherwise indicated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood to also describe a composition consisting of that element, unless otherwise indicated or clearly contradicted by context).

[0052] As used herein, the term "room temperature" refers to a temperature range from about 15°C to about 25°C.

[0053] Use of the terms "a," "an," and "the," and similar reference words in the context of describing the present invention should be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. For example, the phrase "compounds" is understood to refer to various "compounds" of the present invention or specific described embodiments, unless otherwise indicated.

[0054] In the present context, the term "purity" refers to the area ratio of the product as determined by chromatographic methods such as HPLC-MS or by quantitative 1H NMR (measured against an internal standard).

[0055] In the present context, the term "conversion" refers to the degree of conversion of a substrate in a reaction.

[0056] As used herein, the term "pharmaceutical composition" refers to a formulation containing the compound of the present invention in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump of an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of the disclosed compound or its salt, hydrate, solvate, or isomer) in a unit dose composition is an effective amount and varies depending on the particular treatment involved. Those skilled in the art will understand that it may be necessary to routinely vary the dosage depending on the age and condition of the patient. The dosage also depends on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharma- ceutical acceptable carrier, and any preservatives, buffers, or propellants that are required.

[0057] As used herein, the term "pharmacologically acceptable" refers to compounds, anions, cations, materials, compositions, carriers, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0058] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and useful in preparing pharmaceutical compositions, including excipients that are acceptable for human pharmaceutical use as well as for veterinary use. As used in the specification and claims, "a pharmaceutically acceptable excipient" includes both one and more than one such excipient.

[0059] As used herein, the term "subject" is interchangeable with the term "subject in need thereof," both of which refer to a subject having a disease or at high risk of developing a disease. "Subject" includes mammals. The mammal may be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. The subject may be a bird or poultry. In one embodiment, the mammal is a human. The subject in need thereof may be one who has previously been diagnosed or identified as having an imprinting disorder. The subject in need thereof may be a subject who has an imprinting disorder (e.g., suffers from an imprinting disorder). Alternatively, the subject in need thereof may be one who is at high risk of developing such a disorder compared to the population as a whole (i.e., a subject who is predisposed to developing such a disorder compared to the population as a whole). The subject in need thereof may have a refractory or resistant imprinting disorder (i.e., an imprinting disorder that does not respond or has not yet responded to treatment). Subjects may develop resistance at the start of treatment or may develop resistance during treatment.

[0060] As used herein, phrases such as "one or more of A, B, or C," "one or more of A, B, or C," "one or more of A, B, and C," "one or more of A, B, and C," "selected from the group consisting of A, B, and C," "selected from A, B, and C," and the like are used synonymously and, unless otherwise specified, all refer to a selection from the group consisting of A, B, and / or C, i.e., a selection from one or more A, one or more B, one or more C, or any combination thereof.

[0061] All publications and patent documents cited in this specification are incorporated by reference as if each such publication or document was specifically and individually indicated to be incorporated by reference. Citation of publications and patent documents is not an admission that any is pertinent prior art, nor does it constitute an admission as to its contents or date. Although the invention has been described in writing herein, those skilled in the art will recognize that the invention can be practiced in a variety of embodiments, and that the foregoing description and the following examples are intended to be illustrative, and not limiting, of the scope of the claims which follow.

[0062] Method for preparing compound IX The present inventors have discovered that compound IX: [ka] The present inventors have discovered a novel and efficient method for preparing (i) Compound I: [ka] to compound II: [ka] in the presence of a palladium catalyst and a base to obtain compound III: [ka] forming a (ii) reacting compound III with a chlorinating agent to form compound IV: [ka] forming a (iii) reducing compound IV by catalytic hydrogenation to compound V [ka] or a salt thereof; (iv) reacting compound V or a salt thereof with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride (compound VI) to obtain compound VII: [ka] forming a and (v) reacting compound VII with a methylating agent (e.g., compound VIII (e.g., CH3Cl, CH3Br, or CH3I)) to form compound IX. Contains one or more of the following:

[0063] In some embodiments, the method comprises step (i).

[0064] In some embodiments, the method comprises step (ii).

[0065] In some embodiments, the method comprises step (iii).

[0066] In some embodiments, the method comprises step (iv).

[0067] In some embodiments, the method includes step (v).

[0068] In some embodiments, the method comprises two or more of steps (i)-(v).

[0069] In some embodiments, the method comprises three or more of steps (i)-(v).

[0070] In some embodiments, the method comprises four or more of steps (i)-(v).

[0071] In some embodiments, the method comprises steps (i) through (v).

[0072] In some embodiments, the method includes one or more steps shown in Scheme A.

[0073] [ka] Scheme A wherein X is a halogen selected from chlorine, bromine or iodine.

[0074] In some embodiments, compound IX is formed in comparable or better yields and with high purity compared to known methods (e.g., methods described in WO 2005 / 002577 and U.S. Patent Application Publication No. 2002 / 0022624).

[0075] It will be appreciated that the methods disclosed herein provide, among other advantages, Suzuki aryl coupling on commercially available compound I, alleviating the need for an iodination reaction in previously disclosed methods, since an activated group (e.g., Cl) for aryl coupling is already present on compound I.

[0076] Step (i) Suitable palladium catalysts for the Suzuki coupling include palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, or [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.

[0077] In some embodiments, the palladium catalyst is a palladium(0) complex, for example, tetrakis(triphenylphosphine)palladium.

[0078] In some embodiments, in step (i), the molar ratio of the palladium catalyst (e.g., palladium(0) complex) to compound I ranges from about 0.05 to about 0.20 (e.g., from about 0.05 to about 0.10).

[0079] Suitable bases for step (i) include potassium carbonate, caesium carbonate, triethylamine, potassium phosphate, sodium t-butoxide, or potassium t-butoxide.

[0080] In some embodiments, in step (i), the base is potassium carbonate.

[0081] In some embodiments, step (i) is carried out in the presence of a solvent (e.g., an organic solvent).

[0082] Suitable solvents include cyclic ethers (eg, tetrahydrofuran, 2-methyltetrahydrofuran, or 1,4-dioxane), toluene, dimethylformamide, NMP, acetonitrile, or mixtures thereof.

[0083] In some embodiments, in step (i), the solvent is in 1,4-dioxane.

[0084] In some embodiments, step (i) is carried out at a temperature of about 20°C to about 100°C.

[0085] In some embodiments, step (i) is carried out in the presence of a palladium catalyst (e.g., tetrakis(triphenylphosphine)palladium), a base (e.g., potassium carbonate), and a solvent (e.g., 1,4-dioxane) at a temperature of about 88° C. to about 100° C.

[0086] Step (ii) In some embodiments, the chlorinating agent is POCl.

[0087] In some embodiments, step (ii) is carried out in the presence of a solvent (eg, an organic solvent).

[0088] In some embodiments, in step (ii), the solvent is an aprotic solvent.

[0089] In some embodiments, in step (ii), the solvent is an ether (e.g., tetrahydrofuran), a halohydrocarbon (e.g., dichloromethane), N,N-dimethylformamide, or dimethoxyethane, or a mixture thereof.

[0090] In some embodiments, in step (ii), the solvent is N,N-dimethylformamide, dimethoxyethane, or a mixture thereof.

[0091] In some embodiments, step (ii) is carried out at a temperature of about 20°C to about 75°C.

[0092] Step (iii) Suitable hydrogenation catalysts include palladium on carbon or platinum on carbon.

[0093] In some embodiments, in step (iii), the hydrogenation catalyst is preferably platinum on carbon.

[0094] In some embodiments, in step (iii), the weight ratio of the hydrogenation catalyst to compound IV ranges from about 0.05 to about 0.5 (eg, from about 0.2 to about 0.3).

[0095] In some embodiments, step (iii) is carried out in the presence of a solvent.

[0096] In some embodiments, in step (iii), the solvent is an alcohol, an ether, an ester, a hydrocarbon, or a mixture thereof.

[0097] In some embodiments, in step (iii), the solvent is an ester (e.g., ethyl acetate).

[0098] In some embodiments, step (iii) is carried out at about room temperature.

[0099] In some embodiments, in step (iii), compound V is isolated.

[0100] The present inventors have found a very convenient method to isolate compound (V) in good purity and yield by reacting (V) with an acid to form a salt of compound (V) directly from the reaction mixture.

[0101] Suitable salts of Compound V include the maleate, hydrochloride, hydrobromide, phosphate, acetate, fumarate, salicylate, sulfate, citrate, lactate, mandelate, tartrate, or methanesulfonate salts.

[0102] In some embodiments, in step (iii), the hydrochloride salt of compound V is isolated.

[0103] In some embodiments, in step (iii), the hydrochloride salt of compound V is isolated in a purity of at least about 97.5% and in a yield of at least about 72%.

[0104] Suitable acids include hydrohalic, maleic, phosphoric, acetic, fumaric, salicylic, sulfuric, citric, lactic, mandelic, tartaric, or methanesulfonic acid.

[0105] In some embodiments, in step (iii), the acid is a hydrohalic acid (e.g., hydrogen chloride, hydrogen bromide, or hydrogen iodide).

[0106] In some embodiments, in step (iii), the acid is hydrogen chloride.

[0107] In some embodiments, in step (iii), hydrogen chloride is added as hydrogen chloride gas.

[0108] In some embodiments, in step (iii), hydrogen chloride is dissolved in an organic solvent (e.g., an alcohol (e.g., methanol, ethanol, propanol, isopropanol, or butanol), or an ether (e.g., 1,4-dioxane)), or hydrogen chloride is dissolved in an aqueous solution.

[0109] In some embodiments, in step (iii), the hydrochloride salt of compound V is obtained by adding an aqueous solution of hydrogen chloride to the reaction mixture, followed by addition of an aprotic solvent (eg, acetonitrile).

[0110] In some embodiments, in step (iii), the hydrochloride salt of compound V is obtained by adding hydrogen chloride in 1,4-dioxane to the reaction mixture.

[0111] Step (iv) In some embodiments, step (iv) is carried out in the presence of an organic base (e.g., pyridine, triethylamine, diisopropylamine, N,N-diisopropylethylamine, or 2,6-lutidine).

[0112] In some embodiments, step (iv) is carried out in the presence of a solvent (e.g., dichloromethane).

[0113] In some embodiments, step (iv) is carried out at a temperature of about 0°C to about 5°C.

[0114] In some embodiments, in step (iv), compound VI is added to a mixture of compound V or a pharma- ceutically acceptable salt thereof and an organic base in a solvent.

[0115] In some embodiments, in step (iv), compound V, compound VI, and the organic are mixed simultaneously in a solvent.

[0116] In some embodiments, in step (iv), compound VII is formed in high purity and is used in the next step without further purification.

[0117] In some embodiments, in step (iv), compound VI is added to a mixture of a pharma- ceutically acceptable salt of compound V (e.g., the hydrochloride salt of compound V) and an organic base (e.g., pyridine) in a solvent (e.g., dichloromethane).

[0118] Step (v) In some embodiments, compound VIII is CH3Cl, CH3Br, or CH3I.

[0119] In some embodiments, in step (v), the methylating agent is dimethyl sulfate.

[0120] In some embodiments, step (v) is carried out in the presence of a base.

[0121] In some embodiments, in step (v), the base is an organic base (e.g., pyridine, triethylamine, diisopropylamine, N,N-diisopropylethylamine, or 2,6-lutidine).

[0122] In some embodiments, in step (v), the base is an inorganic base (e.g., potassium carbonate, cesium carbonate, potassium phosphate, sodium t-butoxide, or potassium t-butoxide).

[0123] In some embodiments, in step (v), the base is cesium carbonate.

[0124] In some embodiments, step (v) is carried out in the presence of a solvent (e.g., DMF, acetonitrile, or ether).

[0125] Method for preparing compound A In some aspects, the present invention provides a method for producing a method for the treatment of a disease comprising the steps of: (vi) reacting compound IX, prepared by the methods disclosed herein, with compound X, or a pharma- ceutically acceptable salt thereof, to form compound XI, or a pharma- ceutically acceptable salt thereof; (vii) reacting compound XI, or a pharma- ceutically acceptable salt thereof, to form a pharma- ceutically acceptable salt and / or solvate of compound A; (viii) reacting a pharma- ceutically acceptable salt and / or solvate of Compound A to form Compound A (e.g., Form 1). The present invention provides a method for preparing compound A, the method comprising one or more of:

[0126] In some embodiments, the method includes step (vi).

[0127] In some embodiments, the method includes step (vii).

[0128] In some embodiments, the method includes step (viii).

[0129] In some embodiments, the method comprises two or more of steps (vi)-(viii).

[0130] In some embodiments, the method comprises steps (vi)-(viii).

[0131] In some aspects, the present invention provides a method of preparing compound A, comprising one or more of steps (i)-(viii).

[0132] In some embodiments, the method comprises step (i).

[0133] In some embodiments, the method comprises step (ii).

[0134] In some embodiments, the method comprises step (iii).

[0135] In some embodiments, the method comprises step (iv).

[0136] In some embodiments, the method includes step (v).

[0137] In some embodiments, the method includes step (vi).

[0138] In some embodiments, the method includes step (vii).

[0139] In some embodiments, the method includes step (viii).

[0140] In some embodiments, the method comprises two or more of steps (i)-(viii).

[0141] In some embodiments, the method comprises three or more of steps (i)-(viii).

[0142] In some embodiments, the method comprises four or more of steps (i)-(viii).

[0143] In some embodiments, the method comprises five or more of steps (i)-(viii).

[0144] In some embodiments, the method comprises six or more of steps (i)-(viii).

[0145] In some embodiments, the method comprises seven or more of steps (i)-(viii).

[0146] In some embodiments, the method comprises steps (i)-(viii).

[0147] In some aspects, the present invention provides the use of Compound III, Compound IV, Compound V, Compound VII, or a pharma- ceutically acceptable salt thereof in the manufacture of Compound A.

[0148] In some aspects, the present invention provides the use of compound IX, prepared by the methods disclosed herein, in the manufacture of compound A.

[0149] In some aspects, the present invention provides compound A prepared by the methods disclosed herein.

[0150] In some embodiments, the method comprises one or more steps shown in Scheme B.

[0151] In some embodiments, the method includes one or more steps shown in Scheme A or Scheme B.

[0152] Scheme B [ka]

[0153] Prepared intermediates and compounds. In some embodiments, the present invention provides an intermediate selected from Compound I, Compound III, Compound IV, Compound VII, or a salt thereof, and a salt of Compound V.

[0154] In some embodiments, the intermediate is prepared by a method described herein.

[0155] In some embodiments, the intermediate is compound III or a salt thereof.

[0156] In some embodiments, the intermediate is compound III.

[0157] In some embodiments, the intermediate is compound IV or a salt thereof.

[0158] In some embodiments, the intermediate is compound IV.

[0159] In some embodiments, the intermediate is a salt of compound V, preferably a salt selected from the group consisting of maleate, malate, hydrochloride, hydrobromide, phosphate, acetate, fumarate, salicylate, sulfate, hydrogen sulfate, citrate, lactate, mandelate, tartrate, tosylate, besylate, and methanesulfonate, in some embodiments the salt of compound V is the hydrochloride salt.

[0160] In some embodiments, the intermediate is compound VII or a pharma- ceutically acceptable salt thereof.

[0161] In some embodiments, the intermediate is compound VII.

[0162] In some aspects, the invention provides compound IX prepared by the methods disclosed herein.

[0163] In some aspects, the present invention provides compound A prepared by the methods disclosed herein.

[0164] Pharmaceutical Compositions In some aspects, the present invention provides pharmaceutical compositions comprising Compound A prepared by the methods disclosed herein and one or more pharma- ceutically acceptable excipients, carriers, and / or diluents.

[0165] Pharmaceutical compositions comprising Compound A are disclosed in WO 2016 / 184829, WO 2011 / 023733, and WO 2007 / 028654, and WO 2019 / 175253.

[0166] It will be appreciated that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0167] Use of prepared compound A In some aspects, the present invention provides a method for treating or preventing a sex hormone disorder, comprising administering to a subject in need thereof compound A or a pharmaceutical composition thereof prepared by the methods disclosed herein.

[0168] In some aspects, the present invention provides Compound A, or a pharmaceutical composition thereof, prepared by the methods disclosed herein, for use in treating or preventing a sex hormone disorder in a subject in need thereof.

[0169] In some aspects, the present invention provides the use of Compound A, prepared by the methods disclosed herein, in the manufacture of a medicament for use in treating or preventing a sex hormone disorder in a subject in need thereof.

[0170] In some embodiments, the sex hormone disorder is benign prostatic hyperplasia (BPH), metastatic prostate cancer, testicular cancer, breast cancer, androgen-dependent acne, seborrhea, hirsutism, male pattern baldness, or precocious puberty in boys.

[0171] In some embodiments, the subject in need thereof is male.

[0172] In some embodiments, the subject in need thereof is female.

[0173] In some embodiments, the sex hormone disorder is endometriosis, pubertal abnormalities, uterine fibroids, uterine fibroids, heavy menstrual bleeding, menstrual bleeding disorders, hormone-dependent cancers such as (breast cancer, endometrial cancer, ovarian cancer, or uterine cancer), hot flashes, hyperandrogenism, hirsutism, hirsutism, female androgenetic alopecia, androgen-dependent acne, seborrhea, virilization, polycystic ovarian syndrome (PCOS), premenstrual dysphoric disorder (PMDD), HAIR-AN syndrome (hyperandrogenism, insulin resistance, and acanthosis nigricans), ovarian theca cell hyperplasia (HAIR-AN with hyperplasia of luteinized theca cells in the ovarian stroma), other conditions of high ovarian androgen levels (e.g., arrested follicular maturation, atresia, anovulation, dysmenorrhea, menstrual bleeding disorders, infertility), and androgen-producing tumors (virilized ovarian or adrenal tumors), or osteoporosis.

[0174] In some embodiments, the sex hormone disorder is hidradenitis suppurativa or hot flashes. In some aspects, the present invention provides a method for treating or preventing a condition, comprising administering to a subject in need thereof compound A or a pharmaceutical composition thereof prepared by the method disclosed herein.

[0175] In some aspects, the present invention provides Compound A, or a pharmaceutical composition thereof, prepared by the methods disclosed herein, for use in treating or preventing a condition in a subject in need thereof.

[0176] In some aspects, the present invention provides the use of Compound A, prepared by the methods disclosed herein, in the manufacture of a medicament for use in treating or preventing a sexual condition in a subject in need thereof.

[0177] In some embodiments, the condition is a perimenopausal, menopausal, or postmenopausal symptom selected from pathological gain of excess body fat and / or excess weight, diabetes, fatigue, irritability, cognitive decline, hair loss, dry skin, insomnia, sleep disorders and nighttime awakenings, anxiety and depression, decreased sexual desire, vaginal dryness and soreness, loss of connective tissue and muscle mass, bone loss, urinary urgency and dysuria symptoms, hot flashes, and night sweats.

[0178] In some embodiments, the symptoms of menopause in women can be treated with certain types of chemotherapy, for example, aromatase inhibitors such as anastrozole, exemestane, letrozole, and testolactone; gonadotropin releasing hormone receptor agonists such as leuprolide, buserelin, histrelin, goserelin, deslorelin, nafarelin, and triptorelin; gonadotropin releasing hormone receptor antagonists such as ASP1701, elagolix, relugolix, and linzagolix (OBE2109); bazedoxifene, clomiphene, This can be caused by selective estrogen receptor modulators (SERMs) such as cyclophenylsulfonylurea, tamoxifen, ormeloxifene, toremifene, raloxifene, lasofoxifene, and ospemifene; selective estrogen receptor degraders (SERDs) such as fulvestrant, brilanestrant, and elacestrant; CYP17A1 inhibitors such as abiraterone, ketoconazole, and ceviteronel; and the combined use of androgen receptor blockers and CYP17A1 inhibitors such as galeterone.

[0179] In some embodiments, the symptoms associated with andropause are selected from pathological gain of excess body fat and / or excess weight, diabetes, fatigue, irritability, cognitive decline, hair loss, dry skin, insomnia, sleep disorders, nighttime awakenings, anxiety and depression, decreased sexual desire, loss of connective tissue and reduced muscle mass, urinary urgency and symptoms of dysuria, hot flashes and night sweats.

[0180] In some embodiments, symptoms of andropause may be caused by certain androgen deprivation therapies, for example, gonadotropin-releasing hormone receptor agonists such as leuprolide, buserelin, histrelin, goserelin, deslorelin, nafarelin, and triptorelin; gonadotropin-releasing hormone receptor antagonists such as ASP1701, elagolix, relugolix, and linzagolix (OBE2109); antiandrogens (androgen receptor blockers) such as cyproterone acetate, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, nilutamide; CYP17A1 inhibitors such as abiraterone, ketoconazole, and seviteronel; and combinations of androgen receptor blockers and CYP17A1 inhibitors such as galeterone.

[0181] In some embodiments, the disease is a "leptin-related disease" selected from metabolic diseases such as diabetes, cardiovascular disease, obesity, overeating, hypertension, metabolic syndrome, and inflammatory diseases.

[0182] In some embodiments, the disease is a "weight-related disease" selected from a genetic susceptibility to being overweight, obesity associated with a metabolic disorder, or a condition in which weight loss would be of therapeutic benefit.

[0183] In some embodiments, the disease is a "pregnancy disorder" selected from eclampsia, pre-eclampsia, gestational diabetes, hypertension, morning sickness, hyperemesis gravidarum, miscarriage, pelvic girdle pain, and premature birth.

[0184] All references cited in this specification, including publications, patent applications, and patents, are incorporated by reference in their entirety to the same extent as if fully set forth herein (to the fullest extent permitted by law), notwithstanding any incorporation of particular documents individually made elsewhere in this specification, as if each reference was individually and specifically indicated to be incorporated by reference.

[0185] It will of course be understood that the various aspects, embodiments, implementations, and features of the disclosure mentioned herein may be claimed separately or in any combination.

[0186] Embodiments according to the present invention Hereinafter, embodiments of the present invention will be disclosed, the first embodiment being denoted as E1, the second embodiment being denoted as E2, and so on.

[0187] E1 Compound IX: [ka] 1. A method for preparing a compound comprising: The method comprises the following steps: i) reacting 4-chloro-5-nitropyridin-2(1H)-one (compound I) with 4-fluoro-2-methylphenylboronic acid (compound II) in the presence of a base, catalyzed by a palladium complex, to form 4-(4-fluoro-2-methylphenyl)-5-nitropyridin-2(1H)-one of structure (III): [ka] This includes obtaining

[0188] E2 The process according to embodiment 1, wherein the palladium complex is selected from palladium acetate, tetrakis(triphenylphosphine)palladium(palladum), bis(triphenylphosphine)palladium(II) dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride, phosphine palladium complexes, preferably tetrakis(triphenylphosphine)palladium.

[0189] E3. The method of any one of embodiments 1-2, wherein the ratio of the palladium complex to compound I is in the range of about 0.05 to 0.10.

[0190] E4. The method according to any one of the preceding embodiments, wherein the base is selected from potassium carbonate, cesium carbonate, triethylamine, potassium phosphate, sodium t-butoxide, potassium t-butoxide or mixtures thereof, preferably potassium carbonate.

[0191] E5. The method according to any one of the preceding embodiments, wherein step i) is carried out at a temperature in the range of 20 to 100°C, preferably in the range of 88 to 100°C.

[0192] E6. The method according to any one of the preceding embodiments, wherein step i) is carried out in an organic solvent selected from acyclic and cyclic ethers, toluene, dimethylformamide, NMP, acetonitrile or mixtures thereof; preferably in dioxane.

[0193] E7. The method according to any one of the preceding embodiments, wherein step i) comprises reacting 4-chloro-5-nitropyridin-2(1H)-one (compound I) with 4-fluoro-2-methylphenylboronic acid (compound II) to obtain 4-(4-fluoro-2-methylphenyl)-5-nitropyridin-2(1H)-one (compound III); the reaction is catalyzed by tetrakis(triphenylphosphine)palladium(0) in the presence of potassium carbonate, in a solvent comprising 1,4-dioxane, at a temperature of 88-100° C.

[0194] E8 After step i), The method according to any one of the preceding embodiments, wherein i) the 4-(4-fluoro-2-methylphenyl)-5-nitropyridin-2(1H)-one (compound III) obtained in step i) is reacted with POCl3 to obtain 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine (compound IV).

[0195] E9 A method for preparing compound IX, said method comprising the following step: ii) reacting 4-(4-fluoro-2-methylphenyl)-5-nitropyridine-2(1H)-one (compound III) obtained in step i) with POCl3 to obtain 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine (compound IV).

[0196] E10 A method for preparing compound IX, said method comprising the following step: ii) reacting 4-(4-fluoro-2-methylphenyl)-5-nitropyridine-2(1H)-one (compound III) with POCl3 to obtain 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine (compound IV).

[0197] The method according to any one of embodiments 8 to 10, wherein step ii) is carried out in a solvent comprising tetrahydrofuran, a halohydrocarbon, such as dichloromethane, N,N-dimethylformamide or dimethoxyethane, preferably in N,N-dimethylformamide or dimethoxyethane or a mixture thereof.

[0198] The method according to any one of embodiments 8 to 11, wherein step ii) is carried out at a temperature in the range of 20 to 75°C.

[0199] E13. The method according to any one of embodiments 8 to 12, wherein step ii) is followed by step iii) which comprises reducing said 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine compound (IV) by catalytic hydrogenation to obtain 6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine of formula (compound V) or a salt thereof.

[0200] E14 A method for preparing compound IX, said method comprising the following step iii) reducing 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine (compound IV) obtained in step (iii) by catalytic hydrogenation to obtain 6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine of formula (compound V) or a salt thereof.

[0201] E15 A method for preparing compound IX, said method comprising the following step iii): reducing 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine (compound IV) by catalytic hydrogenation to obtain 6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine (compound V) or a salt thereof.

[0202] E16 The method according to any one of embodiments 13 to 15, wherein the catalytic hydrogenation is carried out in the presence of a catalyst selected from palladium on carbon or platinum on carbon, preferably platinum on carbon.

[0203] E17. The method according to any one of embodiments 13-16, wherein platinum is present in an amount of 0.05 to 0.5 weight percent relative to compound IV; preferably 0.2 to 0.3 weight percent relative to compound IV.

[0204] E18. The method according to any one of embodiments 13 to 17, wherein step (iii) is carried out in an alcohol, an ether, an ester, a hydrocarbon or a mixture thereof, preferably in an ester, even more preferably in ethyl acetate.

[0205] E19. The method of any one of embodiments 13-18, wherein step (iii) is carried out at room temperature.

[0206] E20 The method according to any one of embodiments 13 to 19, wherein the salt of compound V is selected from the group consisting of maleate, hydrochloride, hydrobromide, phosphate, acetate, fumarate, salicylate, sulfate, citrate, lactate, mandelate, tartrate and methanesulfonate, preferably hydrochloride.

[0207] E21 The method according to any one of embodiments 13 to 20, wherein a solution of compound V is reacted with hydrogen chloride gas in aqueous solution or in dioxane, followed by treatment with acetonitrile to obtain compound V as the hydrochloride salt.

[0208] E22 The method according to any one of embodiments 13 to 21, wherein step iii) is followed by a step iv): reacting compound V of 6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine or its salt obtained in step iii) with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride (compound VI) to obtain 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methyl-propanamide of formula (compound VII).

[0209] E23 A process for preparing intermediate (IX), said process comprising the following step: iv): reacting 6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine or a salt thereof (compound V) obtained in step iii) with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride (compound VI) to obtain 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methyl-propanamide of formula (compound VII).

[0210] E24 A method for preparing intermediate (IX), said method comprising the following step: iv): reacting 6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine or a salt thereof (compound V) with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride (compound VI) to obtain 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methyl-propanamide of formula (compound VII).

[0211] E25. The method of any one of embodiments 22-24, wherein step iv) is carried out in dichloromethane in the presence of an organic base.

[0212] E26. The method according to any one of embodiments 22 to 25, wherein step iv) is carried out in the presence of an organic base selected from pyridine, triethylamine, diisopropylamine, N,N-diisopropylethylamine, 2,6-lutidine or a mixture thereof.

[0213] E27. The method according to any one of embodiments 22-26, wherein step iv) is carried out at a temperature of 0-5°C.

[0214] E28 The method according to any one of embodiments 22 to 27, wherein step iv) is followed by a step v): reacting 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methyl-propanamide (VII) obtained in step iv) with a methyl halide of formula CH3X (VIII) in the presence of cesium carbonate to obtain compound IX), where X is a halogen selected from chlorine, bromide or iodine.

[0215] E29 A process comprising the next step v): reacting 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methyl-propanamide (compound VII) obtained in step iv) with a methyl halide of formula CH3X (VIII) in the presence of caesium carbonate to obtain 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-N,2-dimethylpropanamide of formula (IX), where X is a halogen selected from chlorine, bromide or iodine.

[0216] E30. A process comprising the following step v): reacting 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methyl-propanamide (compound VII) with a methyl halide of formula CH3X (VIII) in the presence of cesium carbonate to obtain 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-N,2-dimethylpropanamide of formula (IX), where X is a halogen selected from chlorine, bromide or iodine.

[0217] E31 The method according to any one of embodiments 28 to 30, wherein step v) is carried out in an organic base selected from pyridine, triethylamine, diisopropylamine, N,N-diisopropylethylamine, 2,6-lutidine, or selected from potassium carbonate, cesium carbonate, potassium phosphate, sodium t-butoxide, potassium t-butoxide, or a mixture thereof.

[0218] E32. The method of any one of embodiments 28-31, wherein step v) is carried out in a solvent selected from DMF, acetonitrile or ether.

[0219] E33 A method for preparing a compound IX, said method comprising the steps of: Carrying out step i) according to any one of embodiments 1 to 7, followed by Implementing step ii) according to any one of embodiments 8 to 12, followed by Carrying out step iii) according to any one of embodiments 13 to 21, followed by Step iv) according to any one of embodiments 22 to 27 is carried out, followed by Carrying out step v) according to any one of embodiments 28 to 32. The method includes:

[0220] E34. Compound IX obtained by the method according to any one of embodiments 1 to 33.

[0221] E35. Use of compound IX obtained from the method according to any one of embodiments 1 to 33 for the preparation of compound A.

[0222] E36 Compound A obtained from compound IX, wherein said compound IX is prepared according to the method of any one of embodiments 1 to 33.

[0223] E37 A pharmaceutical composition comprising a compound A obtained from compound IX, said compound IX being prepared according to the method of any one of embodiments 1 to 33.

[0224] E38. A compound A obtained from compound IX, wherein said compound IX is prepared according to the method of any one of embodiments 1 to 33, for use in the treatment of a sex hormone disorder or in the treatment or prevention of a condition or symptom associated with perimenopause, menopause or postmenopause.

[0225] E39 Compound A obtained from compound IX for use in the treatment of sex hormone disorders selected from hot flashes, polycystic ovary syndrome (PCOS), endometriosis, heavy menstrual bleeding, adenomyosis or uterine fibroids, wherein said compound IX is prepared according to the method of any one of embodiments 1 to 33.

[0226] E40 A compound A derived from compound IX for use in the treatment of a condition or symptom associated with perimenopause, menopause or postmenopause selected from pathological gain of excess body fat and / or excess weight, diabetes, fatigue, irritability, cognitive decline, hair loss, dry skin, insomnia, sleep disorders and nighttime awakenings, anxiety and depression, decreased sexual desire, vaginal dryness and pain, loss of connective tissue and reduced muscle mass, bone loss, urinary urgency and dysuria symptoms, hot flashes, and night sweats, wherein said compound IX is prepared according to the method of any one of embodiments 1-33.

[0227] E41 Certain types of chemotherapy, for example aromatase inhibitors such as anastrozole, exemestane, letrozole and testolactone; gonadotropin releasing hormone receptor agonists such as leuprolide, buserelin, histrelin, goserelin, deslorelin, nafarelin and triptorelin; gonadotropin releasing hormone receptor antagonists such as ASP1701, elagolix, relugolix and linzagolix (OBE2109); bazedoxifene, clomiphene, cyclophenyl, tamoxifene ... Selective estrogen receptor modulators (SERMs), such as xifene, ormeloxifene, toremifene, raloxifene, lasofoxifene and ospemifene; selective estrogen receptor degraders (SERDs), such as fulvestrant, brilanestrant and elacestrant; CYP17A1 inhibitors, such as abiraterone, ketoconazole and seviteronel; and compound A derived from compound IX for use in the treatment of conditions or symptoms associated with menopause caused by a combination of an androgen receptor blocker and a CYP17A1 inhibitor, such as galeterone.

[0228] E42 A compound A derived from compound IX for use in the treatment of a condition or symptom associated with andropause selected from pathological increase in excess body fat and / or excess body weight, diabetes, fatigue, irritability, cognitive decline, hair loss, dry skin, insomnia, sleep disorders and nighttime awakenings, anxiety and depression, decreased sexual desire, loss of connective tissue and reduced muscle mass, symptoms of urinary urgency and dysuria, hot flashes and night sweats, wherein said compound IX is prepared according to the method of any one of embodiments 1-33.

[0229] E43 Compound A obtained from compound IX for use in the treatment of conditions or symptoms associated with andropause caused by certain androgen deprivation therapies, for example gonadotropin releasing hormone receptor agonists such as leuprolide, buserelin, histrelin, goserelin, deslorelin, nafarelin and triptorelin; gonadotropin releasing hormone receptor antagonists such as ASP1701, elagolix, relugolix and linzagolix (OBE2109); antiandrogens (androgen receptor blockers) such as cyproterone acetate, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, nilutamide; CYP17A1 inhibitors such as abiraterone, ketoconazole and seviteronel; and combinations of androgen receptor blockers and CYP17A1 inhibitors such as galeterone, wherein said compound IX is prepared according to the method of any one of embodiments 1 to 33.

[0230] E44. Compound A obtained from compound IX for use in the treatment of a "leptin-related disease" selected from metabolic disorders such as diabetes, cardiovascular disease, obesity, overeating, hypertension, metabolic syndrome and inflammatory diseases, wherein said compound IX is prepared according to the method of any one of embodiments 1 to 33.

[0231] E45. A compound A obtained from compound IX, wherein said compound IX is prepared according to the method of any one of embodiments 1 to 33, for use in the treatment of a "weight-related disorder" selected from a genetic susceptibility to excess weight, obesity associated with a metabolic disorder, or a condition in which a reduction in body weight would be of therapeutic benefit.

[0232] E46 Compound A obtained from compound IX for use in the treatment of a "pregnancy disorder" selected from eclampsia, pre-eclampsia, gestational diabetes, hypertension, morning sickness, hyperemesis gravidarum, miscarriage, pelvic girdle pain, and premature birth, wherein said compound IX is prepared according to the method of any one of embodiments 1 to 33.

[0233] E47 A pharmaceutical composition comprising compound A obtained from intermediate (IX), for use in the treatment of sex hormone disorders or in the treatment or prevention of conditions or symptoms associated with peri-, menopausal or post-menopause, wherein said compound IX is prepared according to the method of any one of embodiments 1 to 33.

[0234] E48 A pharmaceutical composition comprising a compound A obtained from compound IX, for use in the treatment of sex hormone disorders, wherein said compound IX is prepared according to the method of any one of embodiments 1 to 33.

[0235] E49 A pharmaceutical composition comprising a compound A obtained from compound IX, wherein said compound IX is prepared according to the method of any one of embodiments 1 to 33, for use in treating a condition or symptom associated with peri-menopause, menopause or post-menopause.

[0236] E50 A pharmaceutical composition comprising compound A obtained from compound IX, wherein said compound IX is prepared according to the method of any one of embodiments 1 to 33, for use in the treatment of a sex hormone disorder selected from hot flashes, polycystic ovary syndrome (PCOS), endometriosis, heavy menstrual bleeding, adenomyosis or uterine fibroids.

[0237] E51 A pharmaceutical composition comprising a compound A obtained from compound IX, said compound IX being prepared according to the method of any one of embodiments 1 to 33, and one or more pharma- ceutically acceptable excipients, carriers, and / or diluents.

[0238] E52 Compound III.

[0239] E53 Compound IV.

[0240] E54 Salt of compound V.

[0241] E55 Compound VII.

[0242] E56 Use of a compound of formula (III), (IV), (V) or (VII) in the preparation of compound A.

[0243] Working Example The present invention is illustrated by the following non-limiting examples, which are for illustrative purposes only and are not intended to limit the scope of the present invention in any way.

[0244] In the following procedures, after each starting material, a reference to an explanation is usually provided. This is provided merely to assist the skilled chemist. The starting material may not necessarily have been prepared from the batch referred to.

[0245] The symbols and conventions used in the methods, schemes, and examples herein are consistent with those used in the contemporary scientific literature, e.g., the Journal of the American Chemical Society or the Journal of Biological Chemistry.

[0246] Specifically, the following abbreviations may be used in the examples and throughout the specification: g(grams); mg(milligrams); L(Liter);mL(Milliliter); M (mol); mM (millimol); kg (kilogram) mol (mole) w / w (weight / weight) MS (mass spectrometry); mmol (millimol); RT (room temperature); min(minutes); h or hrs(hours); NMP (N-methyl-2-pyrrolidone) THF (tetrahydrofuran); DMSO (Dimethylsulfoxide); EtOAc (Ethyl acetate); DME (1,2-dimethoxyethane); DCM (dichloromethane); DMF (N,N-dimethylformamide) MS (mass spectrometry); HPLC (High Performance Liquid Chromatography); All temperatures are in °C (Celsius) unless otherwise noted. All reactions were conducted under an inert atmosphere at room temperature unless otherwise noted.

[0247] Unless otherwise stated, in the examples: 1H-QNMR Quantitative NMR was performed by standard 1H NMR but utilized an internal standard to allow extrapolation of product assays. HPLC Purity is determined by reversed-phase HPLC. A C18 stationary phase is used with an acidified aqueous mobile phase containing acetonitrile organic modifier. Elution is performed in gradient mode.

[0248] Example 1 Preparation of 4-(4-fluoro-2-methylphenyl)-5-nitropyridin-2(1H)-one (Compound III) [ka] A three-neck flask connected to a condenser and vacuum / nitrogen line was charged with 4-chloro-5-nitropyridin-2(1H)-one (39.0 g, 223 mmol, commercially available from Leapchem), (4-fluoro-2-methylphenyl)boronic acid (39.6 g, 257 mmol; commercially available, for example, from Sigma Aldrich), potassium carbonate (92.6 g, 670 mmol) and 1,4-dioxane (480 mL). After evacuating and backfilling with nitrogen three times, tetrakis(triphenylphosphine)palladium(0) (12.9 g, 11.2 mmol) was added under a stream of nitrogen and the resulting mixture was stirred at gentle reflux (internal temperature 99 °C) for 18 h. The reaction mixture was cooled to room temperature and filtered. The precipitate was washed with dioxane (300 mL) and the filtrate was discarded. The precipitate was then washed with MeOH (2×200 mL) and the filtrate was collected, concentrated in vacuo and dried to give the title compound as a dark yellow solid (78.0 g, 314 mmol, 141% yield w / w). 1 The purity by H-QNMR was 60%. This compound was used in the next step without further purification. 1H NMR (d-DMSO) δ / ppm 8.88(s,1 H), 6.96-7.06(m,3 H), .44(s,1 H), 2.03(s,3 H,-CH3).

[0249] Example 2 Preparation of 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine (Compound IV) [ka] 4-(4-Fluoro-2-methylphenyl)-5-nitropyridin-2(1H)-one (78.0 g, 60% w / w, 0.19 mol) was suspended in DME (600 mL) in a three-neck flask under nitrogen. POCl3 (0.10 kg, 61 mL, 0.65 mol) was added dropwise (the reaction was slightly exothermic and the temperature rose to 40° C.), followed by DMF (14 g, 15 mL, 0.19 mol). The resulting mixture was stirred at 70° C. (internal temperature) for 18 h. The reaction mixture was cooled to room temperature and water (600 mL) was slowly poured in (exothermic, cooled in an ice-water bath). The pH was neutralized with solid Na2CO3, and the mixture was transferred to a separatory funnel and extracted with EtOAc (2×600 mL). The organic layer was collected, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a brown solid (46.2 g, 173 mmol, 91% w / w yield) in 86% purity (HPLC). 1H NMR (CDCl3) δ / ppm 9.05 (s, 1 H), 7.34 (s, 1 H), 6.97-7.08 (m, 3 H), 2.13 (s, 3 H, -CH3);

[0250] Example 3 Preparation of 6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine hydrochloride (Compound V) [ka] A flask for hydrogenation Parr apparatus was charged with platinum on carbon (5.4 g, 5% w / w, 1.4 mmol). EtOAc (400 mL) was added under a stream of N2, followed by 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine (23.0 g, 80% w / w, 69 mmol). The flask was transferred to a Parr apparatus and mechanically stirred at room temperature under 3 bar of hydrogen. After 48 h, HPLC-MS showed that the reaction had not progressed further, so more platinum on carbon (2.7 g, 5% w / w, 0.7 mmol) was added. The mixture was stirred under 3 bar of H2 for 96 h, but HPLC-MS showed no progress in the conversion. More platinum on carbon (2.7 g, 5% w / w, 0.7 mmol) was added and the reaction was stirred under 3.5 bar of H2 for 24 h. The reaction mixture was filtered through Celite and concentrated in vacuo. The crude product was dissolved in EtOAc (200 mL) and the resulting solution was cooled to 0 °C. A 4N solution of HCl in dioxane (55 mL, 220 mmol) was slowly added and the solution was stirred at room temperature for 18 h. The mixture was concentrated in vacuo and the resulting brown solid was suspended in acetonitrile (220 mL). The suspension was heated to reflux with stirring. After cooling to room temperature, the solid was collected by filtration and dried to give the title compound as an off-white solid (13.6 g, 49.7 mmol, 72% w / w yield) with 95.7% purity (HPLC). 1H NMR (d-DMSO) δ / ppm 9.95 (s, 2 H, -NH2), 8.54 (s, 1 H), 7.23-7.43 (m, 3 H), 7.13 (s, 1 H), 2.15 (s, 3 H, -CH3);

[0251] Example 4 Preparation of 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methyl-propanamide (Compound VII) [ka]

[0252] Preparation 1 A three-neck flask connected to a nitrogen line was charged with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoic acid (30.56 g, 95% w / w, 96.7 mmol) and DCM (400 mL). The solution was cooled to 0° C. in an ice-water bath. Oxalyl chloride (13.5 g, 9.31 mL, 106 mmol) was added slowly, followed by DMF (1.41 g, 1.5 mL, 19.3 mmol), and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo to give 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride as a pale yellow oil containing some solid particles (34.5 g, 106 mmol, 110% w / w yield). This material was used as is in the next step.

[0253] Example 3 (6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine hydrochloride (compound V)) (27.0 g, 97.9 mmol) was added in small portions (slightly exothermic) to a three-neck flask containing pyridine (139 g, 0.14 L, 1.76 mol) at 0° C. and under N2. A suspension of 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride (34.5 g, 95%, 103 mmol) in DCM (20 mL) was added dropwise at 0° C. and the resulting mixture was stirred at room temperature for 18 h. The mixture was diluted with EtOAc / water (700 mL each) and transferred to a separatory funnel. The organic layers were collected, washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as an orange oil that solidified upon standing (52.5 g, 100 mmol, 102% w / w yield) with 93% purity (HPLC), which was used in the next step without further purification.

[0254] Preparation 2 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoic acid (15.3 kg) and DCM (11.0 L / kg of 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoic acid) were charged. After cooling to -5 / 5°C, DMF (0.01 L / kg of 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoic acid) was charged and oxalyl chloride (1.02 mol / mol) was added while keeping the temperature below 10°C. The addition vessel used was rinsed with DCM (1.0 L / kg of 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoic acid) and the reaction mixture was warmed to 20 / 25°C and stirred for at least 2 hours.

[0255] After the reaction was complete, the reaction mixture was concentrated to 2.0 L / kg of 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoic acid. Then, DCM (2.0 L / kg of 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoic acid) was added and the 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride solution stored under N2 was used in the next step.

[0256] Example 3 (6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine hydrochloride (Compound V)) (11.9 kg) and DCM (2.7 L / kg of Example 3) were charged. After cooling to -5 / 5°C, pyridine (3.00 mol / mol of Example 3) was added while keeping the temperature below 10°C. A solution of 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride in DCM was then added while keeping the temperature below 10°C. The addition vessel was rinsed with DCM (0.3 L / kg of Example 3). The reaction mixture was warmed to 20 / 25°C and stirred for not less than 18 hours.

[0257] After completion of the reaction, the reaction mixture was cooled to 10° C. and water (8.0 L / kg of Example 3) was added while keeping the temperature below 20° C. After stirring for an additional 30 min at 20 / 25° C., the layers were separated and the aqueous layer was re-extracted with DCM (4.0 L / kg of Example 3).

[0258] The combined organic layers were washed with water (2 x 5.0 L / kg of Example 3) and concentrated in vacuo to 2.7 L / kg of Example 3. Heptane (8.5 L / kg of Example 3) was then added while maintaining the temperature at 35-45°C, and 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methyl-propanamide (0.005 w / w of Example 3) was charged for seeding.

[0259] The seeded mixture was aged at 40° C. for >1 hour and the resulting slurry was vacuum concentrated to 10.0 L / kg of Example 3. Additional heptane (2.0 L / kg of Example 3) was added at 35 / 45° C. The slurry was cooled to 10 / 20° C. over >2 hours and held at 10 / 20° C. for >2 hours before proceeding with the centrifugation step.

[0260] The slurry was centrifuged and the cake was washed with heptane (2.0 L / kg of Example 3).

[0261] The wet product was dried under vacuum below 45° C. to give 19.9 kg of the title compound (yield=88.1%) with 99.87% purity as an off-white solid. 1 H NMR(DMSO-d6):δ 8.99(s,1 H),8.36(s,1 H),7.98(s,1 H),7.74(s,2 H),7.43(s,1 H),7.00-6.95(m,2H),6.90-6.85(m,1 H),1.98(s,3H),1.44(s,6H).

[0262] Example 5 Preparation of 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-N,2-dimethylpropanamide (Compound IX) [ka]

[0263] Preparation 1 A three-neck flask connected to a nitrogen line was charged with Preparation 1 of Example 4 (52.0 g, 95%, 95 mmol), DMF (300 mL), and cesium carbonate (62 g, 0.19 mol). The mixture was cooled to 0° C., and then methyl iodide (14 g, 6.3 mL, 0.10 mol) was added dropwise over 5 min. The mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was poured into water (600 mL) and extracted with EtOAc (2×600 mL). The organic layer was collected, washed successively with water and brine, dried over Na2SO4, and filtered. The solvent was evaporated in vacuum, and the residue was dried to give a dark brown solid. The solid was suspended in heptane (500 mL) and stirred for 30 min. The suspension was filtered, and the light brown solid was collected and dried in vacuum. The brown color was removed by dissolving the product in EtOAc (200 mL) and filtering through a short pad of silica. The filtrate was collected and concentrated in vacuo to give the title product as a pale yellow solid (34.1 g, 64 mmol, 67% yield w / w) with 96.7% purity (HPLC).

[0264] Preparation 2 Example 4 (2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methyl-propanamide (Compound VII)) from Preparation 2 (19.9 kg), Cs2CO3 (1.19 kg / kg of Example 4) and DMF (5.0 L / kg of Example 4) were charged. After cooling to -5 / 5°C, methyl iodide (1.10 mol / mol of Example 4) was added while keeping the temperature below 10°C. The addition vessel was rinsed with DMF (0.8 L / kg of Example 4). The reaction mixture was warmed to 20 / 25°C and stirred for 18 hours or more.

[0265] After the reaction was completed, the reaction mixture was cooled to 10° C. and water (12.0 L / kg of Example 4) and ethyl acetate (12.0 L / kg of Example 4) were added while keeping the temperature below 20° C. After stirring for an additional 15 minutes at 20 / 25° C., the layers were separated and the aqueous layer was re-extracted with ethyl acetate (12.0 L / kg of Example 4).

[0266] The combined organic layers were washed with water (12.0 L / kg of Example 4) and a 20 wt% solution of NaCl (5.0 kg / kg of Example 4). After distillation under vacuum (2.0 L / kg of Example 4), heptane (9.0 L / kg of Example 4) was added at 35 / 45° C. The slurry was stirred at 40° C. for ≥2 h, cooled to ≥10 / 20° C. over ≥2 h, and aged at ≥10 / 20° C. for ≥2 h before proceeding with centrifugation.

[0267] The slurry was centrifuged and the cake was washed with heptane (2.0 L / kg of Example 4).

[0268] The wet product was dried under vacuum below 45° C. to give 14.2 kg of the title compound as a white solid (yield=69.4%) with a purity of 99.99%. 1 H NMR(DMSO-d6δ 8.32(s,1H), 8.03(s,1H), 7.74(broad s,2 H), 7.55(s,1H), 7.30-7.00(broad+d,3H), 2.90-2.40(broad m,3H), 2.15(broad m,3H), 1.70-1.20(broad m,6H).

[0269] Example 6 Process for the preparation of N-(6-((7S,9aS)-7-((benzyloxy)methyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamide (Compound XI) [ka]

[0270] Preparation 1 A three-neck flask connected to a thermometer, condenser and nitrogen was charged with Example 5 (2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-N,2-dimethylpropanamide (Compound IX)) (643 mg, 1.21 mmol), sodium tert-butoxide (218 mg, 2.66 mmol) and bis(tri-tert-butylphosphine)palladium(0) (0.16 mmol, 62 mg). A toluene solution of (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazino[2,1-c][1,4]oxazine (380 mg, 1.45 mmol) was added and the reaction mixture was stirred at 85° C. for 18 hours. The mixture was cooled and filtered through Celite. The mixture was cooled and filtered through Celite. The filtrate was collected, transferred to a separatory funnel, washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a brownish solid (610 mg, 0.8 mmol, 67% w / w yield).

[0271] Preparation 2 (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazino[2,1-c][1,4]oxazine A solution of (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazino[2,1-c][1,4]oxazine dioxalate salt (1.26 mol / mol Example 5 from Preparation 2), toluene (20.0 L / kg Example 5) and NaOH 1N (20.0 L / kg Example 5) was charged. The mixture was heated to 75° C. and stirred for 5 min. The layers were allowed to settle for 30 min. and the bottom aqueous layer was discarded. The organic layer was cooled to 25° C. and water (10.0 L / kg Example 5) was added. The mixture was stirred for 10 min., the layers were allowed to settle for 15 min. and the bottom aqueous layer was discarded.

[0272] The organic layer was concentrated under vacuum to 8.0 L / kg of Example 5, toluene (4.0 L / kg of Example 5) was added, and distilled again under vacuum to 8.0 L / kg of Example 5. A sample was taken for Karl Fischer (KF) measurement. If the KF passed, additional toluene (8.0 L / kg of Example 5) was added. If it did not pass, toluene was added again (4.0 L / kg of Example 5) and the distillation step was repeated to 8.0 L / kg of Example 5.

[0273] In a separate reactor, Example 5 (2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-N,2-dimethylpropanamide (Compound IX)) from Preparation 2 (3.2 kg), sodium tert-butoxide (1.75 mol / mol of Example 5) and palladium bis(tri-t-butylphosphine) (0.10 mol / mol of Example 5) were charged. The (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazino[2,1-c][1,4]oxazine free base / toluene solution was charged and the transfer lines were rinsed with toluene (2.0 L / kg of Example 5). The reaction mixture was heated to 85° C. and stirred for 4+ hours before being sampled to confirm completion of the reaction.

[0274] The reaction mixture was cooled to 25°C and loaded with a 20 wt% solution of NaHSO3 (8.7 L / kg of Example 5). The mixture was heated to 60°C for 1 hour or more and cooled again to 25°C. The batch was filtered through K100 paper, the filter and transfer lines were washed with toluene (1.0 L / kg of Example 5), the layers were allowed to settle at 25°C for 30 minutes or more and the bottom aqueous layer was discarded. A 5 wt% solution of L-cysteine ​​(10.0 kg / kg of Example 5) was loaded above the organic layer. The mixture was heated to 60°C for 1 hour or more and cooled again to 25°C. The batch was filtered through K100 paper, the filter and transfer lines were washed with toluene (1.0 L / kg of Example 5), the layers were allowed to settle at 25°C for 30 minutes or more and the bottom aqueous layer was discarded. A 5 wt% L-cysteine ​​solution (10.0 kg / kg of Example 5) was loaded on top of the organic layer. The mixture was heated to 60°C for not less than 1 hour and cooled again to 25°C. The batch was filtered through K100 paper, the filter and transfer lines were washed with toluene (1.0 L / kg of Example 5), then a 10 wt% NaCl solution was added and the layers were stirred for not less than 15 minutes and allowed to settle at 25°C for not less than 30 minutes. Finally, the bottom aqueous layer was discarded. The organic layer was washed with a 5 wt% solution of NaHCO3 and twice with a 2 wt% solution of NaCl.

[0275] The resulting organic layer was concentrated under vacuum to 4.0 L / kg of Example 5. Toluene (7.0 L / kg of Example 5) was charged and the solution was taken for KF analysis.

[0276] The batch was heated to 40° C., then 4M HCl / dioxane solution (1.03 kg / kg of Example 5) and toluene (9.0 L / kg of Example 5) were added at 35 / 45° C. The solution was held at 40° C. for ≥30 minutes and concentrated under vacuum to 10.0 L / kg of Example 5. Toluene (9.0 L / kg of Example 5) was charged and distilled again to 10.0 L / kg of Example 5. This last operation was repeated one more time and the resulting solution was taken for gas chromatography analysis.

[0277] The batch temperature was adjusted to 25° C. and n-heptane (7.0 L / kg of Example 5) was added while maintaining the internal temperature at 20 / 30° C. The slurry was held at 20 / 30° C. for ≥4 hours before proceeding with the centrifugation step.

[0278] The slurry was centrifuged and the cake was washed with n-heptane (4.0 L / kg of Example 5).

[0279] The wet product was dried under vacuum at 35° C. to give 4.4 kg of the title compound (yield=88.2%) as a light brown solid with a purity of 97.4%.

[0280] NMR spectrometer: Varian Agilent Mercury Vx 400 (16 scans, sw 6400Hz, 25°C). 1 H NMR(400 MHz,DMSO-d6):δ 11.66(bd,1 H),8.02(s,1 H),7.95(s,1 H),7.74(bd,2 H),7.36-6.93(m,8 H),6.83(s,1 H),4.97(bd,1 H),4.62(m,1 H),4.50(d,11.8 Hz,1 H),4.44-4.10(m,7 H),4.08-3.69(m,3 H),3.60(d,12.8 Hz,1 H),3.45(d,11.8 Hz,1 H),3.30(d,9.7 Hz,1 H),3.19(t,10.7 Hz,1 H),3.05(m,1 H),2.30-1.90(m,4 H), 1.57-1.12(m,6 H).

[0281] Example 7 2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-3-pyridinyl}-N,2-dimethylpropanamide dihydrochloride mono-isopropanol solvate (Compound XII) [ka] Example 6 (N-(6-((7S,9aS)-7-((benzyloxy)methyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamide (Compound XI)) (4.4 kg), activated carbon Norit DARCO G60 (0.10 kg / kg of Example 6), isopropanol (22.9 L / kg of Example 6), water (2.5 L / kg of Example 6) and HCl 35 wt % (4.0 mol / mol of Example 6) were loaded into a hydrogenation apparatus. The mixture was heated to 50° C. and stirred for 30 min or more. Pd / C 10% (0.20 kg / kg of Example 6) was slurred in isopropanol (20.4 L / kg of Example 6) and loaded into the hydrogenator, rinsing with additional isopropanol (8.9 L / kg of Example 6). Hydrogenation conditions were set (2.00 BarG, 50° C.) and maintained until no hydrogen consumption was observed.

[0282] Upon reaction completion, the batch was filtered through a Veladisc® filter housing fitted with a SUPRAdisc™ cartridge and washed with a mixture of isopropanol (9.0 L / kg of Example 6) and water (1.0 L / kg of Example 6).

[0283] The filtrate was concentrated under vacuum to 3.5 L / kg of Example 6. Isopropanol (10.0 L / kg of Example 6) was added and distilled again to 3.5 L / kg of Example 6. Isopropanol (10.0 L / kg of Example 6) was added and distilled again to 3.5 L / kg of Example 6. Isopropanol (8.5 L / kg of Example 6) was added and a sample was taken for KF analysis.

[0284] If the KF analysis passed the specification criteria, dioxane / HCl 4M (2.00 mol / mol of Example 6) was added at 20 / 30° C. and the mixture was heated to 65° C. over 30 minutes. The batch was then cooled to 25° C. over 60 minutes and isooctane (5.0 L / kg of Example 6) was added over 30 minutes at 20 / 30° C. The slurry was held at 25° C. for over 5 hours before proceeding with the centrifugation step.

[0285] The slurry was centrifuged and the cake was washed with a mixture of isopropanol (2.0 L / kg of Example 6) and isooctane (2.0 L / kg of Example 6).

[0286] The wet product was dried under vacuum at 35° C. to give 3.5 kg of the title compound (yield=82.1%) as a beige solid with a purity of 99.3%.

[0287] NMR spectrometer: Varian Agilent Mercury Vx 400 (16 scans, sw 6400Hz, 25°C). 1 H NMR (400MHz, DMSO-d6): δ 11.34(bd,1H), 8.02(s,1H), 7.96(bd s,1H), 7.22-7.00(m,3H), 6.91(s,1H), 4.68(bd s,1H), 4.49(bd,1H), 4.20(t,12.2Hz,1H), 4.07-3.90(m,3H), 3.84(m,1H), 3.77(hept.,6.1Hz,1H), 3.64(d,12.6Hz, 1H), 3.43(m,2H), 3.28(m,1H), 3.16(m,2H), approximately 2.58(bd,2H), 2.41-2.00(m,5H), 1.60-1.10(m,6H), 1.03(d,6.1Hz,6H).

[0288] Example 8 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-3-pyridinyl}-N,2-dimethylpropanamide (Compound A) in anhydrous crystalline form. [ka] Example 7 (2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-3-pyridinyl}-N,2-dimethylpropanamide dihydrochloride mono-isopropanol solvate (Compound XII)) (3.4 kg), methyl-t-butyl ether (hereafter MTBE) (15.0 L / kg of Example 7) and NaOH 2.5N (4.9 L / kg of Example 7) were charged, heated to 40°C and stirred for 10-30 min. The layers were allowed to settle at 40°C for 30 min or more and the bottom aqueous layer was discarded.

[0289] A 9 wt % solution of L-cysteine ​​in water (5.0 L water per kg of Example 7 + 0.5 w / w L-cysteine ​​per Example 7) was added to the top of the organic layer and stirred for >60 min at 40° C. The layers were allowed to settle for >30 min at 40° C. and the bottom aqueous layer was discarded.

[0290] Water (5.0 L / kg of Example 7) was added on top of the organic layer and stirred for >15 min at 40° C. The layers were allowed to settle for >60 min at 40° C. and the bottom aqueous layer was discarded.

[0291] Water (5.0 L / kg of Example 7) was added on top of the organic layer and stirred for >15 min at 40° C. The layers were allowed to settle for >60 min at 40° C. and the bottom aqueous layer was discarded.

[0292] The organic layer was concentrated at atmospheric pressure to 2.5 L / kg of Example 7. Isooctane (8.3 L / kg of Example 7) was added at 50 / 55° C. over 1 h and the solution was distilled under light vacuum to 4.0 L / kg of Example 7. Samples were taken to control the removal of water and MTBE.

[0293] Isopropanol (0.8 L / kg of Example 7) was added and stirred at 65 / 75° C. until completely dissolved. The solution was cooled to 45 / 55° C. and filtered to remove extraneous material. Isooctane (4.5 L / kg of Example 7) was added and the batch was heated to 70° C. for 30 minutes or more. The solution was cooled to 50° C. and seeded with a slurry of 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-3-pyridinyl}-N,2-dimethylpropanamide (0.008% w / w of Example 7) in isooctane (0.07 L / kg of Example 7) and isopropanol (0.01 L / kg of Example 7). The seeds were aged at 50° C. for >3 hours and additional isooctane (4.2 L / kg of Example 7) was added over >3 hours while maintaining the temperature at 50 / 55° C. The slurry was held at 50° C. for >8 hours, cooled to 0° C. over >5 hours and aged >3 hours before proceeding with the centrifugation step.

[0294] The slurry was centrifuged and the cake was washed with isooctane (2×3.3 L / kg of Example 7).

[0295] The wet product was dried under vacuum at 50° C. to give 2.34 kg of the title compound (yield=82.7%). The product was sieved to remove lumps to give 2.26 kg of the title compound as a white powder with a purity of 99.8%.

[0296] NMR spectrometer: Varian Agilent Mercury Vx 400 (16 scans, sw 6400Hz, 25°C). 1H NMR(400 MHz,DMSO-d6):δ 8.02(s,1 H),7.85(s,1 H),7.74(bd,2 H),7.22-6.92(m,3 H),6.61(s,1 H),4.70(m,1 H),4.21(bd,1 H),4.09(bd,1 H),3.75(m,3 H),3.55(td,11.3 Hz,2.2 Hz,1 H),3.40(bd,1 H),3.15(t,10.5 Hz,1 H),3.02(d,11.3 Hz,1 H),2.63(d,11.3 Hz,1 H),ca.2.5(bd,2 H),2.31-2.00(m,7 H),1.58-1.10(m,6 H).

Claims

1. Compound (IX): 【Chemical 1】 1. A method for preparing a compound comprising: The method comprises the following step: i) reacting 4-chloro-5-nitropyridin-2(1H)-one with 4-fluoro-2-methylphenylboronic acid in the presence of a base, catalyzed by a palladium complex, to form 4-(4-fluoro-2-methylphenyl)-5-nitropyridin-2(1H)-one (III): 【Chemistry 2】 The method includes the step of obtaining

2. the palladium complex is selected from palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, a phosphine palladium complex; the base is selected from potassium carbonate, cesium carbonate, triethylamine, potassium phosphate, sodium t-butoxide, potassium t-butoxide, or mixtures thereof; The process according to claim 1, wherein step i) is carried out in an organic solvent selected from acyclic and cyclic ethers, toluene, dimethylformamide, N-methyl-2-pyrrolidone, acetonitrile or mixtures thereof.

3. After step i), ii) 4-(4-fluoro-2-methylphenyl)-5-nitropyridin-2(1H)-one (III) obtained in step i) was treated with POCl 3 and reacting with 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine (IV): 【Chemistry 3】 The method of claim 1 or 2, followed by a step of obtaining:

4. After step ii) iii) reducing the 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine (IV) by catalytic hydrogenation to give 6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine of formula (V): 【Chemistry 4】 or a salt thereof, the catalytic hydrogenation is carried out in the presence of a catalyst selected from palladium on carbon or platinum on carbon; the salt of compound (V) is selected from maleate, hydrochloride, hydrobromide, phosphate, acetate, fumarate, salicylate, sulfate, citrate, lactate, mandelate, tartrate, and methanesulfonate; The method of claim 3.

5. After step iii), iv) reacting 6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine or its salt (V) obtained in step iii) with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride (VI) to give 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methyl-propanamide of formula (VII): 【Chemistry 5】 This is followed by the step of obtaining step iv) is carried out in the presence of an organic base selected from pyridine, triethylamine, diisopropylamine, N,N-diisopropylethylamine, 2,6-lutidine or mixtures thereof, in dichloromethane at a temperature of 0-5°C; The method of claim 4.

6. After step iv), v) followed by a step of reacting 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methyl-propanamide (VII) obtained in step iv) with a methyl halide of formula CHX (VIII), where X is a halogen selected from chlorine, bromine or iodine, in the presence of cesium carbonate to obtain compound (IX), 6. The process of claim 5, wherein step v) is carried out in the presence of an organic base selected from pyridine, triethylamine, diisopropylamine, N,N-diisopropylethylamine, 2,6-lutidine, or an inorganic base selected from potassium carbonate, cesium carbonate, potassium phosphate, sodium t-butoxide, potassium t-butoxide, or a mixture thereof.

7. 7. A process for preparing intermediate (IX) according to any one of claims 1 to 6, said process comprising the steps: i) reacting 4-chloro-5-nitropyridin-2(1H)-one (I) with 4-fluoro-2-methylphenylboronic acid (II) in the presence of a base, catalyzed by a palladium complex, to give 4-(4-fluoro-2-methylphenyl)-5-nitropyridin-2(1H)-one of structure (III): 【Chemistry 6】 followed by ii) 4-(4-fluoro-2-methylphenyl)-5-nitropyridin-2(1H)-one (III) obtained in step i) was treated with POCl 3 to give 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine (IV): 【Chemistry 7】 followed by iii) reducing 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine (IV) by catalytic hydrogenation to give 6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine of formula (V) or a salt thereof: 【Chemistry 8】 followed by iv) reacting 6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine or its salt (V) obtained in step iii) with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride (VI) to give 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methyl-propanamide of formula (VII): 【Chemistry 9】 followed by v) reacting 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methyl-propanamide (VII) with a methyl halide of formula CHX (VIII) in the presence of cesium carbonate to obtain compound (IX); A method comprising:

8. Salt of compound (V): 【Chemistry 10】 A salt of compound (V), wherein the salt is selected from maleate, hydrochloride, hydrobromide, phosphate, acetate, fumarate, salicylate, sulfate, citrate, lactate, mandelate, tartrate, or methanesulfonate.

9. Compound of formula (VII): 【Chemistry 11】 。

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