NEW CHEMICAL PROCESS FOR THE PREPARATION OF 6-CHLORO-4-(4-FLUORO-2-METHYLPHENYL)PYRIDIN-3-AMINE, A KEY INTERMEDIARY OF NT-814

Abstract

The invention relates to a new process for the production of 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 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

NEW CHEMICAL PROCESS FOR THE PREPARATION OF 6-CHLORO^4-(4FLUORO-2-METHYLPHENYL)PYRIDIN-3-AMINE, A KEY INTERMEDIARY OF NT-814 FIELD OF INVENTION. The present invention relates to a novel process for producing Compound IX, which is useful in the manufacture of Compound A. The present invention also relates to the preparation of Compound IX by the process, and to uses of said compound in the manufacture of Compound A. The present invention further relates to novel intermediates prepared by the process, including Compound III, Compound IV, salts of Compound V, Compound VII and their pharmaceutically acceptable salts, and their uses in the manufacture of Compound IX or Compound A. BACKGROUND OF THE INVENTION. Compound A or its pharmaceutically acceptable salts were first described in WO 2007 / 028654. Compound A is also known in anhydrous crystalline form. Therefore, Compound A as anhydrous crystalline form (e.g., Anhydrous Crystalline Form 1) is described in document WO2011 / 023733. Compound A or its pharmaceutically acceptable salts, including its anhydrous crystalline Form 1, are useful, inter alia, in the treatment of sex hormone disorders, including hot flashes, polycystic ovary syndrome (PCOS), endometriosis, heavy menstrual bleeding, uterine fibroids, or adenomyosis. See International Patent Publication No. WO2016 / 184829. The methods for preparing Compound A or its pharmaceutically acceptable salts, and its anhydrous crystalline Form 1, are described in International Patent Publications Nos. WO2007 / 028654 and WO2011 / 023733, respectively. The methods produce Compound A or its anhydrous crystalline Form 1 by reaction with Compound XI. The methods for preparing Compound IX are described in International Patent Publications Nos. WO2005 / 002577, WO2006 / 013050 and WO2002 / 016324, and in European Patents Nos. EP3067349 and EP3141541. However, these methods generally have low yield and high cost, or use materials that are not commercially available, with a consequent impact on the overall cost of the synthesis of Compound A. j Qocnn / zznz / E / YiAi Therefore, there is a need to develop an improved process for preparing Compound IX, which is useful for producing Compound A. The present invention addresses this need. SUMMARY OF THE INVENTION. In some respects, the present invention provides a method for preparing Compound IX, comprising one or more of the following steps: (i) react Compound I with Compound II to form Compound III; (i) react Compound III to form Compound IV; (iii) react Compound IV to form Compound V or one of its pharmaceutically acceptable salts; (iv) reacting Compound V or its pharmaceutically acceptable salt with Compound VI to form Compound Vil; and (v) reacting Compound Vil with Compound VIII to form Compound IX. In some respects, the present invention provides for the use of Compound I, Compound III, Compound IV, Compound V, Compound VII, or one of their pharmaceutically acceptable salts, in the preparation of Compound IX. In some respects, the present invention provides a selected intermediate of Compound III, Compound IV, Compound VII, or their salts. In some respects, the present invention provides salts of Compound V. In some respects, the present invention provides Compound IX, prepared by a method described herein. In some respects, the present invention provides a method for preparing Compound A, comprising one or more of the following steps: (vi) reacting Compound IX, prepared by a method described herein, with Compound X to form Compound XI or one of its pharmaceutically acceptable salts; (vile) react Compound XI or its pharmaceutically acceptable salt to form a pharmaceutically acceptable salt and / or solvate of Compound A; (viii) reacting the pharmaceutically acceptable salt and / or solvate of Compound A to form Compound A (e.g., Form 1). i Qocnn / zznz / E / YiAi In some respects, the present invention provides a method for preparing Compound A, comprising one or more of the steps ()-(viii). In some respects, the present invention provides for the use of Compound III, Compound IV, Compound V, Compound VII, or one of their pharmaceutically acceptable salts, in the preparation of Compound A. In some respects, the present invention provides for the use of Compound IX prepared by a method described herein, in the preparation of Compound A. In some respects, the present invention provides Compound A prepared by a method described herein. In some respects, the present invention provides a pharmaceutical composition comprising Compound A prepared by a method described herein and one or more pharmaceutically acceptable excipients, carriers and / or diluents. In some respects, the present invention provides a method of treating or preventing a sex hormone disorder, comprising administering to the subject in need Compound A prepared by a method described herein or a pharmaceutical composition of said compound. In some respects, the present invention provides Compound A prepared by a method described herein, or a pharmaceutical composition of said compound, for use in the treatment or prevention of a sex hormone disorder. In some respects, the present invention provides for the use of Compound A prepared by a method described herein in the manufacture of a medicament for use in the treatment or prevention of a sex hormone disease. In some respects, the present invention provides a method of treating or preventing a condition, comprising administering to the subject in need Compound A prepared by a method described herein or a pharmaceutical composition of said compound. In some respects, the present invention provides Compound A prepared by a method described herein, or a pharmaceutical composition of said compound, for use as a medicament. i oocnn / zznz / E / YiAi In some respects, the present invention provides for the use of Compound A prepared by a method described herein in the preparation of a medicament for use in therapy. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which this invention pertains. In the specification, singular forms also include the plural, unless the context clearly indicates otherwise. Although methods and materials similar to or equivalent to those described herein may be used in the implementation 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 as prior art to the claimed invention. In case of conflict, this specification, including the definitions, shall prevail.Furthermore, the materials, methods, and examples are for illustrative purposes only and are not intended to be limiting. Other features and advantages of the invention will become evident from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION. The present invention is based, inter alia, on the discovery of a novel and efficient process for the preparation of Compound IX. The process can produce Compound IX with a quality suitable for the production of Compound A (e.g., with high purity), and can be easily scaled up to an industrial scale. Definitions. As used herein, “Compound A” refers to 2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl)hexahydrophorazino[2,1-c][1,4]oxazin-8(1 H)I]-3-pyridiniI}—N,2-dimethylpropanamide, and has the chemical structure represented below. j Qocnn / zznz / E / YiAi i Qocnn / zznz / E / YiAi (Compound A). As used in this descriptive memorandum, “Form 1” of Compound A refers to the anhydrous crystalline form of Compound A (“Form 1”) having 2 theta angles occurring at 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 respectively to spacing of 20.4, 11.1, 9.0, 8.3, 8.2, 6.6, 6.3 and 5.9 Angstroms (Å). As used in this specification, “Compound I” refers to 4-chloro-5-nitropiridine-2(1H)-one, and has the chemical structure shown below. Compound I is understood to be commercially available from, for example, Leapchem, RennoTech Co., Ltd., Chemieliva Pharmaceutical Co., Ltd., or Alchem ​​Pharmtech, Inc. (Compound I). As used in this descriptive report, “Compound II” refers to 4-fluoro-2-methylpheniBoronic acid, and has the chemical structure represented below: B(OH)2 (Compound II). As used in this descriptive report, “Compound III” refers to 4-(4-fluoro-2-methylphenyl)-5-nitropiridine-2(1H)-one and has the chemical structure represented below: i Qocnn / zznz / E / YiAi (Compound III). As used in this descriptive report, “Compound IV” refers to 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine, and has the chemical structure represented below: (Compound IV). As used in this descriptive report, “Compound V” refers to 6-chloro-4-(4-fluoro-2-methylphenyl)pridine-3-amine and has the chemical structure represented below: (Compound V). As used in this specification, “Compound VI” refers to 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride, and has the chemical structure shown below. Compound VI and methods for its preparation are described in U.S. Application Publication No. 2015 / 0011510, and in the Journal of Organic Chemistry, 71(5), 2000-2008 (2006). cf3cAJX (Compound VI). As used in this descriptive report, “Compound VII” refers to 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)propidine-3-1)-2-methylpropanamide and has the chemical structure represented below: F (Vile Compound). i Qocnn / zznz / E / YiAi As used in this descriptive report, “Compound VIII” refers to methyl halide and has the chemical structure CH3X, where X is a halogen. In some embodiments, X is Cl, I, Br, or I. In some embodiments, Compound VIII is CH3Cl, CH3Br, or CH3I. In some embodiments, Compound VIII is CH3Cl, CH3Br, or CH3L As used in this descriptive report, “Compound IX” refers to 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)propidine-3-1)-N,2-dimethylpropanamide and has the chemical structure represented below: cf3F(Compound IX). As used in this descriptive report, “Compound X” refers to (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazine[2,1-c][1,4]oxazine, a compound having the chemical structure represented below: to I,NH (Compound X). As used in this descriptive report, “Compound XI” refers to N-(6-((7S,9aS)7-((benzyloxy)methyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1 H)-yl)-4-(4-fluoro-2-methylphenyl)pyridine-3-yl)-2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamide, a compound having the chemical structure represented below: O N j ci Ν Ν o -J i Qocnn / zznz / Ε / γΐΛΐF(Compound XI). It should be understood that this disclosure includes the compounds of the present invention and any pharmaceutically acceptable salts and solvates of said compounds, and includes stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of said compounds. As used herein, the term pharmaceutically acceptable salt or salts refers to any salt of a compound according to the present invention prepared from an organic or inorganic acid.Suitable or pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric, and sulfuric acids, and with organic acids such as tartaric, acetic, trifluoroacetic, citric, melic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isotionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinil, alginic, galacturonic, and arylsulfonic acids. for example, benzenesulfonic acid and p-toluenesulfonic acid. As used in this document, the term solvate refers to solvent additions that contain either stoichiometric or nonstoichiometric amounts of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is an alcohol, the solvate formed is an alkoxide. Hydrates are formed by the combination of one or more water molecules with a molecule of the substance in which the water retains its molecular state as H₂O. As used herein, the term Compound A is intended to include, unless otherwise stated herein, any form of Compound A, such as the free base and pharmaceutically acceptable salts. The free base and pharmaceutically acceptable salts include anhydrous forms and solvated forms such as hydrates. Anhydrous forms and solvates include amorphous and crystalline forms. As used in this document, the term salt of Compound V is intended to include salts, solvates, and hydrates of Compound V. As used herein, treatment or treat is intended to indicate the approach to and care of a patient for the purpose of relieving, halting, partially halting, or delaying the progression of the clinical manifestation of the disease, or curing the disease. The patient to be treated is preferably a mammal, in particular, a human being. As used in this document, the term prevent or prevention describes the reduction or elimination of the occurrence of symptoms or complications of such disease, condition, or disorder. As used in this document, the term hot flashes is used interchangeably with the term heat and with the term vasomotor symptoms, and is intended to have the same meaning. As used in this document, the term comprising includes the case that consists only of. The description herein of any aspect or feature of the invention using terms such as comprising, having, including, or containing with reference to one or more elements is intended to provide support for a similar aspect or feature of the invention that consists of, essentially consists of, or substantially comprises those particular one or more elements, unless otherwise indicated or clearly contradicted by the context (e.g., a composition described herein comprising a particular element should also be understood as describing a composition consisting of that element, unless otherwise indicated or clearly contradicted by the context). As used in this document, the term ambient temperature refers to a range of temperatures from about 15°C to about 25°C. The use of the terms "a" and "an" and "the" and similar references in the context of the description of the invention should be interpreted to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context. For example, the phrase "the compound" should be understood as referring to various compounds of the invention or particular aspect described, unless otherwise indicated. In the present context, the term purity indicates the percentage by area of ​​the product determined by a chromatographic method, such as HPLC-MS or by quantitative 1H NMR (measured against an internal reference standard). i Qocnn / zznz / E / YiAi In the present context, the term conversion indicates the degree of transformation of a substrate in a given reaction. As used herein, the term pharmaceutical composition is a formulation containing the compounds of the present invention in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is in bulk or unit-dose form. The unit-dose form is any of a variety of forms, including, for example, a capsule, an intravenous bag, a tablet, a single pump in an aerosol inhaler, or a vial. The amount of active ingredient (for example, a formulation of the described compound or a salt, hydrate, solvate, or isomer thereof) in a unit dose of composition is an effective amount and varies according to the particular treatment involved. A person skilled in the art will appreciate that routine dosage adjustments are sometimes necessary, based on the patient's age and condition. The dosage will also depend on the route of administration.A number of routes of administration are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, and similar routes. Dosage forms for topical or transdermal administration of a compound of this 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 pharmaceutically acceptable carrier and any required preservative, buffer, or propellant. As used in this document, the term pharmaceutically acceptable refers to those compounds, anions, cations, materials, compositions, carriers and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problem or complication, consistent with a reasonable benefit / risk ratio. As used herein, the term pharmaceutically acceptable excipient means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. A pharmaceutically acceptable excipient as used in the specification and claims includes one or more of such excipients. As used in this document, the term subject is interchangeable with the term subject in need, both of which refer to a subject who has a disease or who is at increased risk of developing the disease. A subject includes a mammal. The mammal may be, for example, a human being or an appropriate non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. The subject may also be a bird. In one embodiment, the mammal is a human being. A subject in need may be one who has been previously diagnosed or identified with an imprinting disorder. A subject in need may also be one who has (for example, suffers from) an imprinting disorder.Alternatively, an individual in need may be someone at higher risk of developing such a disorder relative to the general population (i.e., an individual predisposed to developing such a disorder relative to the general population). An individual in need may have a resistant or refractory imprinting disorder (i.e., an imprinting disorder that does not respond or has not yet responded to treatment). The individual may be resistant at the start of treatment, or may become resistant during treatment. As used herein, the expressions one or more of A, B or C, one or more A, B and C, one or more of A, B and C, one or more 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 interchangeably, and all refer to a selection from a group consisting of A, B and / or C, i.e., one or more A, one or more B, one or more C, or any combination thereof, unless otherwise stated. All publications and patent documents cited herein are incorporated herein by reference, as if each such publication or document were specifically and individually indicated for incorporation herein by reference. The citation of publications and patent documents is not intended as an admission that any of them constitutes prior art, nor does it constitute an admission as to their content or date. The invention having now been described in writing, those skilled in the art will recognize that the invention can be implemented in a variety of embodiments, and that the foregoing description and the examples that follow are intended to illustrate, not to limit, the claims that follow. Methods of preparing compound IX. The inventors of the present invention have found a new and efficient process for preparing Compound IX: i Qocnn / zznz / E / YiAi i oocnn / zznz / E / YiAi which comprises one or more of the following steps: (i) react Compound I: with Compound II: B(OH)2 Me in the presence of a palladium catalyst and a base to form Compound III: H NO2 react Compound III with a chlorinating agent to form Compound IV: Cl no2(IV); (iii) reduction of Compound IV by catalytic hydrogenation to form Compound V or one of its salts Qocnn / zznz / E / YiAi F (V). (iv) reacting Compound V or one of its salts with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride (Compound VI) to form Compound VII: and (v) react Compound Vil with a methylating agent (for example, Compound VIII (for example, CH3CI, CHsBr, or CH3I)) to form Compound IX. In some embodiments, the method comprises step (i). In some embodiments, the method comprises step (i). In some embodiments, the method comprises step (iii). In some embodiments, the method includes step (iv). In some embodiments, the method comprises step (v). In some embodiments, the method comprises two or more of the steps ()-(v). In some embodiments, the method comprises three or more of the steps (i)—(v). In some embodiments, the method comprises four or more of the steps ()(v). In some embodiments, the method comprises steps (i)—(v). In some embodiments, the method comprises one or more of the steps shown in the Scheme A. i Qocnn / zznz / E / YiAi Scheme A where X is a halogen selected from chlorine, bromine, or iodine. In some embodiments, Compound IX is formed with comparable or superior yield compared to known methods (e.g., the methods described in documents WO2005 / 002577 and US 2002 / 0022624), and with a high degree of purity. It is understood that the method described in this document provides, among other advantages, the Suzuki aryl coupling in the commercially available Compound I, wherein the activated group for aryl coupling (e.g., Cl) is already present in Compound I, thereby relieving the need for iodination reaction in the previously described methods. Step (i). Suitable palladium catalysts for Suzuki coupling include palladium acetate, tetrakis(triphenylphosphine) palladium, bis(triphenylphosphine) palladium dichloride, or [1,1bis(diphenylphosphine)ferrocene] palladium dichloride. In some embodiments, the palladium catalyst is a palladium(O) complex, for example, tetrakis(triphenylphosphine) palladium. In some embodiments, in step (i), the molar ratio between the palladium catalyst (e.g., palladium complex (0)) and Compound I varies from about 0.05 to about 0.20 (e.g., from about 0.05 to about 0.10). Suitable bases in step (i) include potassium carbonate, cesium carbonate, triethylamine, potassium phosphate, sodium t-butoxide, or potassium t-butoxide. In some embodiments, in step (i), the base is potassium carbonate. In some embodiments, step (i) is performed in the presence of a solvent (e.g., an organic solvent). Suitable solvents include a cyclic ether (e.g., tetrahydrofuran, 2-methyl tetrahydrofuran or 1,4-dioxane), toluene, dimethylformamide, NMP, acetonitrile or any of their mixtures. In some embodiments, in step (i), the solvent is 1,4-dioxane. In some embodiments, step (i) is performed at a temperature ranging from around 20°C to around 100°C. 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), and at a temperature ranging from about 88°C to about 100°C. Step (ii). In some embodiments, the chlorinating agent is POCh. In some embodiments, step (ii) is performed in the presence of a solvent (e.g., an organic solvent). In some embodiments, in step (ii), the solvent is an aprotic solvent. In some embodiments, in step (ii), the solvent is an ether (for example, tetrahydrofuran), a halohydrocarbon (for example, dichloromethane), N,N-dimethylformamide or dimethoxyethane, or any mixture of the above. i Qocnn / zznz / E / YiAi In some embodiments, in step (i), the solvent is N,N-dimethylformamide, dimethoxyethane, or a mixture of the above. In some embodiments, step (i) is performed at a temperature ranging from around 20°C to around 75°C. Step (iii). Suitable hydrogenation catalysts include palladium or platinum on carbon. In some embodiments, in step (iii), the hydrogenation catalyst is preferably platinum over carbon. In some embodiments, in step (iii), the weight ratio between the hydrogenation catalyst and Compound IV varies from about 0.05 to about 0.5 (e.g., from about 0.2 to about 0.3). In some embodiments, step (iii) is performed in the presence of a solvent. In some embodiments, in step (III), the solvent is an alcohol, an ether, an ester, a hydrocarbon, or any mixture of the above. In some embodiments, in step (iii), the solvent is an ester (e.g., ethyl acetate). In some embodiments, step (iii) is performed at around room temperature. In some embodiments, in step (iii), Compound V is isolated. The inventors have found a very convenient method for isolating Compound (V) with good purity and yield by reacting (V) with an acid to form a salt of Compound (V) directly from the reaction mixture. Suitable salts of Compound V include a maleic salt, a hydrochloric salt, a hydrobromic salt, a phosphoric salt, an acetic salt, a fumaric salt, a salicylic salt, a sulfate salt, a citric salt, a lactic salt, a mandelic salt, a tartaric salt, or a methanesulfonic salt. In some embodiments, in step (iii), a hydrochloride salt is isolated from Compound V. In some embodiments, in step (iii), the hydrochloride salt of Compound V is isolated with a purity of at least about 97.5% and with a yield of at least about 72%. i Qocnn / zznz / E / YiAi Suitable acids include hydrohalic acid, maleic acid, phosphoric acid, acetic acid, fumaric acid, salicylic acid, sulfate acid, citric acid, lactic acid, mandelic acid, tartaric acid, or methanesulfonic acid. In some embodiments, in step (i¡¡), the acid is hydrohalic acid (e.g., hydrogen chloride, hydrogen bromide, or hydrogen iodide). In some embodiments, in step (iii), the acid is hydrogen chloride. In some embodiments, in step (iii), hydrogen chloride is added as hydrogen chloride gas. In some embodiments, in step (i¡¡), 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. In some embodiments, in step (i¡¡), the hydrochloride salt of Compound V is obtained by adding an aqueous solution of hydrogen chloride to the reaction mixture, followed by the addition of an aprotic solvent (e.g., acetonitrile). In some embodiments, in step (iii), the hydrochloride salt of Compound V is obtained by adding hydrogen chloride to the reaction mixture in 1,4-dioxane. Step (iv). In some embodiments, step (iv) is performed in the presence of an organic base (e.g., pyridine, triethylamine, diisopropylamine, N,N-diisopropylethylamine or 2,6-lutidine). In some embodiments, step (iv) is performed in the presence of a solvent (e.g., dichloromethane). In some embodiments, step (iv) is performed at a temperature ranging from about 0°C to about 5°C. In some embodiments, in step (iv), Compound VI is added to the mixture of Compound V or its pharmaceutically acceptable salt and the organic base in the solvent. In some embodiments, in step (iv), Compound V, Compound VI and the organic compound are mixed simultaneously in the solvent. In some embodiments, in step (iv), Compound Vile is formed with a high degree of purity and is used in the next step without any further purification. i oocnn / zznz / E / YiAi In some embodiments, in step (iv), Compound VI is added to a mixture of the pharmaceutically acceptable salt of Compound V (e.g., the hydrochloride salt of Compound V) and the organic base (e.g., pyridine) in the solvent (e.g., dichloromethane). Step (v). In some embodiments, Compound VIII is CH3Cl, CH3Br, or CH3L In some embodiments, in step (v), the methylating agent is dimethyl sulfate. In some forms of realization, step (v) is performed in the presence of a base. In some embodiments, in step (v), the base is an organic base (e.g., pyridine, triethylamine, diisopropylamine, N,N-diisopropylethylamine or 2,6-lutidine). 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). In some embodiments, in step (v), the base is cesium carbonate. In some embodiments, step (v) is performed in the presence of a solvent (e.g., DMF, acetonitrile, or an ether). Methods of preparing compound A. In some respects, the present invention provides a method for preparing Compound A, comprising one or more of the following steps: (vi) reacting Compound IX, prepared by a method described herein, with Compound X or its pharmaceutically acceptable salts to form Compound XI or one of its pharmaceutically acceptable salts; (vile) react Compound XI or its pharmaceutically acceptable salt to form a pharmaceutically acceptable salt and / or solvate of Compound A; (viii) reacting the pharmaceutically acceptable salt and / or solvate of Compound A to form Compound A (e.g., Form 1). In some embodiments, the method comprises step (vi). In some forms of implementation, the method comprises the (vile) step. In some embodiments, the method comprises step (viii). In some embodiments, the method comprises two or more of the steps (vi)— (viü). i Qocnn / zznz / E / YiAi In some forms of implementation, the method comprises steps (vi)—(viii). In some respects, the present invention provides a method for preparing Compound A, comprising one or more of steps (i)-(viii). i Qocnn / zznz / E / YiAi In some embodiments, the method comprises In some embodiments, the method comprises In some embodiments, the method comprises In some embodiments, the method comprises In some embodiments, the method comprises In some embodiments, the method comprises In some embodiments, the method comprises In some embodiments, the method comprises step (i). step (i). step (v). step (v). step (vi). step (vii). step (viii). In some embodiments, the method comprises two or more of the steps (i)—(viii). In some embodiments, the method comprises three or more of the steps (i)—(viii). In some embodiments, the method comprises four or more of the steps ()(viii). In some forms of implementation, the method comprises five or more of the steps ()(viii). In some embodiments, the method comprises six or more of the steps (i)—(viii). In some forms of implementation, the method comprises seven or more of the steps ()(viii). In some embodiments, the method comprises steps (i)-(viii). In some respects, the present invention provides for the use of Compound III, Compound IV, Compound V, Compound VII, or one of their pharmaceutically acceptable salts, in the preparation of Compound A. In some respects, the present invention provides for the use of Compound IX prepared by a method described herein in the preparation of Compound A. In some respects, the present invention provides Compound A prepared by a method described herein. In some embodiments, the method comprises one or more of the steps shown in Scheme B. In some embodiments, the method comprises one or more of the steps shown in Scheme A or Scheme B. / Qocnn / zznz / E / YiAi Scheme B 1. H2, Pd / C, isopropanol 2. HCl, isopropanol Prepared Intermediates and Compounds. 1. NaOH, MTBE 2. IPA In some respects, the present invention provides a selected intermediate of Compound I, Compound III, Compound IV, Compound VII, or their salts, and a salt of Compound V. In some embodiments, the intermediary is prepared by a method described in this document. In some embodiments, the intermediate is Compound III or one of its salts. In some forms of realization, the intermediary is Compound III. In some embodiments, the intermediate is Compound IV or one of its salts. In some forms of realization, the intermediary is Compound IV. 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. In some embodiments, the intermediate is Compound Vil or a pharmaceutically acceptable salt thereof. In some forms of realization, the intermediary is the Vile Compound. In some respects, the present invention provides Compound IX prepared by a method described herein. In some respects, the present invention provides Compound A prepared by a method described herein. Pharmaceutical compositions. In some respects, the present invention provides a pharmaceutical composition comprising Compound A prepared by a method described herein and one or more pharmaceutically acceptable excipients, carriers and / or diluents. The pharmaceutical compositions comprising Compound A are described in documents WO2016 / 184829, WO2011 / 023733 and WO2007 / 028654, and International Patent Publication WO2019 / 175253. It should be understood that pharmaceutical compositions may be included in a container, package or dispenser, along with instructions for administration. Uses of the prepared Compound A. In some respects, the present invention provides a method of treating or preventing a sex hormone disorder, comprising administering to the subject in need Compound A prepared by a method described herein or a pharmaceutical composition of said compound. In some respects, the present invention provides Compound A prepared by a method described herein, or a pharmaceutical composition of said compound, for use in the treatment or prevention of a sex hormone disorder in a subject who needs it. In some respects, the present invention provides for the use of Compound A prepared by a method described herein in the manufacture of a medicament for use in the treatment or prevention of a sex hormone disorder in a subject who needs it. In some forms of realization, sex hormone disease is benign prostatic hyperplasia (BPH), metastatic prostatic carcinoma, testicular cancer, breast cancer, androgen-dependent acne, seborrhea, hypertrichosis, male pattern baldness, or precocious puberty in children. In some forms of realization, the subject who needs it is a man. In some forms of implementation, the subject who needs it is a woman. In some manifestations, sex hormone disease includes endometriosis, abnormal puberty, uterine fibroids, uterine fibroid tumor, heavy menstrual bleeding, dysfunctional uterine bleeding, hormone-dependent cancers (e.g., breast, endometrium, ovary, or uterus), hot flashes, hyperandrogenism, hirsutism, hypertrichosis, female androgen alopecia, androgen-dependent acne, seborrhea, virilization, polycystic ovary syndrome (PCOS), premenstrual dysphoric disorder (PMDD), HAIR-AN syndrome (hyperandrogenism, insulin resistance, and acanthosis nigricans), ovarian hyperthecosis (HAIR-AN with hyperplasia of luteinized theca cells in the ovarian stroma), and other manifestations of high intraovarian androgen concentrations (e.g., arrest of follicular maturation, atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding,infertility) and androgen-producing tumor (virilizing ovarian or adrenal tumor) or osteoporosis. In some embodiments, the sex hormone disorder is hidradenitis suppurativa or hot flashes. In some respects, the present invention provides a method for treating or preventing such a condition, comprising administering to a subject in need Compound A prepared by a method described herein or a pharmaceutical composition thereof. In some respects, the present invention provides Compound A prepared by a method described herein, or a pharmaceutical composition thereof, for use in the treatment or prevention of a condition in a subject in need. In some respects, the present invention provides for the use of Compound A prepared by a method described herein in the manufacture of a medicament for use in the treatment or prevention of a sexual condition in a subject who needs it. i oocnn / zznz / E / YiAi In some manifestations, the condition is a symptom of perimenopause, menopause, or postmenopause selected from a pathological gain of excess body fat and / or excess body weight, diabetes, fatigue, irritability, cognitive impairment, hair loss, dry skin, insomnia, sleep disorders and night awakenings, anxiety and depression, decreased sexual desire, vaginal dryness and pain, loss of connective tissue and reduction of muscle mass, loss of bone mass, urinary urgency and dysuria, hot flashes, and night sweats. In some embodiments, a symptom of menopause in women can be caused by 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); selective estrogen receptor modulators (SERMs) such as bazedoxifene, clomiphene, cyclophenyl, 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 seviteronel;and androgen receptor blockers and CYP17A1 inhibitors combined, such as galeterone.; In some forms of realization, a symptom associated with andropause is selected from a pathological increase in excess body fat and / or excess body weight, diabetes, fatigue, irritability, cognitive impairment, hair loss, dry skin, insomnia, sleep disturbances, night awakenings, anxiety and depression, decreased sexual desire, loss of connective tissue and reduction of muscle mass, urinary urgency symptoms and dysuria, hot flashes and night sweats. In some forms of implementation, a symptom of andropause can be caused by certain androgen deprivation therapies, e.g., 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, and nilutamide; CYP17A1 inhibitors such as abiraterone, ketoconazole, and seviteronel; and combined androgen receptor blockers and CYP17A1 inhibitors, such as galeterone. i Qocnn / zznz / E / YiAi In some embodiments, the disease is a leptin-related illness selected from metabolic disorders such as diabetes, cardiovascular disease, obesity, overeating, hypertension, metabolic syndrome, and inflammatory disorders. In some embodiments, the disease is a weight-related illness selected from a genetic sensitivity to excess body weight, obesity associated with metabolic disorders, or a condition for which a decrease in body weight would be of therapeutic benefit. In some forms of realization, the disease is a selected pregnancy disorder from eclampsia, preeclampsia, gestational diabetes mellitus, high blood pressure, morning sickness, hyperemesis gravidarum, spontaneous abortion, pelvic girdle pain, and premature delivery. All references, including publications, patent applications, and patents, cited in this document are incorporated herein by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and set forth in full in this document (to the maximum extent permitted by law), irrespective of any separate incorporation of particular documents made elsewhere in this memorandum. It should be understood that the various aspects, forms of realization, implementations, and characteristics of disclosure mentioned in this document may be claimed separately, or in any combination. Forms of embodiment according to the invention. The following describes embodiments of the invention. The first embodiment is designated as E1, the second embodiment as E2, and so on. E1 A process for the preparation of Compound IX: i Qocnn / zznz / E / YiAi where said process comprises the following step i) reaction of 4-chloro-5-nitropiridin-2(1H)-one (Compound I) with 4-fluoro-2-methylphenylboronic acid (Compound II) catalyzed by a palladium complex in the presence of a base to obtain 4-(4-fluoro-2-methylphenyl)-5-nitropiridin-2(1H)-one of structure (III): H O^N ^Y^no2F(III). E2 The process according to embodiment 1, wherein said palladium complex is selected from palladium acetate, tetrakis(triphenylphosphine) palladium, bis(triphenylphosphine) palladium(II) dichloride, and [1,1bis(diphenylphosphine)ferrocene] palladium(II) dichloride, phosphine palladium complex, preferably tetrakis(triphenylphosphine) palladium. E3 The process according to any of embodiments 1-2, wherein the ratio between said palladium complex and Compound I varies from about 0.05 to 0.10. E4 The process according to any of embodiments 1-3, wherein said base is selected from potassium carbonate, cesium carbonate, triethylamine, potassium phosphate, sodium t-butoxide, potassium t-butoxide, or one of their mixtures, preferably potassium carbonate. E5 The process according to any of embodiments 1-4, wherein step i) takes place at a temperature in the range of 20° to 100°C, preferably in the range of 88-100°C. E6 The process according to any of embodiments 1-5, wherein step i) takes place in an organic solvent selected from acyclic and cyclic ethers, toluene, dimethylformamide, NMP, acetonitrile or mixtures thereof; preferably in dioxane. E7 The process according to any of embodiments 1-6, wherein step i) comprises the reaction of 4-chloro-5-nitropiridin-2(1H)-one (Compound I) with 4-fluoro-2-methylphenylboronic acid (Compound II) to obtain 4-(4-fluoro-2-methylphenyl)-5-nitropiridin-2(1H)-one (Compound III); catalyzed by tetrakis(triphenylphosphine)palladium(O) in the presence of potassium carbonate, wherein step i) takes place in a solvent comprising 1,4-dioxane and at a temperature of 88-100°C. E8 The process according to any of embodiments 1-7, wherein step i) is followed by: i Qocnn / zznz / E / YiAi i) the reaction of 4-(4-fluoro-2-methylphenyl)-5-nitropiridine-2(1 H)-one (Compound III) obtained in step i) with POCI3 to obtain 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropiridine (Compound IV). E9 A process for the preparation of Compound IX, wherein said process comprises the following step: ii) the reaction of 4—(4—fluoro—2—methylphenyl)—5—nitropiridine—2(1 H)-one (Compound III) obtained in step i) with POCh to obtain 2-chloro-4-(4-fluoro-2-methylphenyl)—5—nitropiridine (Compound IV). E10 A process for the preparation of Compound IX, wherein said process comprises the following step: ii) the reaction of 4-(4-fluoro-2-methylphenyl)-5-nitropiridine-2(1 H)-one (Compound III) with POCl3 to obtain 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropiridine (Compound IV). E11 The process according to any of embodiments 8-10, wherein step ii) takes place in a solvent comprising tetrahydrofuran, a halohydrocarbon, for example dichloromethane, N,N-dimethylformamide or dimethoxyethane, preferably N,N-dimethylformamide or dimethoxyethane or mixtures thereof. E12 The process according to any of embodiments 8-11, wherein step i) takes place at a temperature in the range of 20° to 75°C. E13 The process according to any of embodiments 8-12, wherein step i) is followed by step i) comprising the reduction of said 2-chloro-1-(4-fluoro-2-methylphenyl)-5-nitropyridine Compound (IV) by catalytic hydrogenation to obtain 6-chloro-4-(4-fluoro-2-methylphenyl)pyridine-3-amine of formula (Compound V) or its salts. E14 A process for the preparation of Compound IX, wherein said process comprises the following step (ii), the reduction of 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)pyridine-3-amine of formula (Compound V) or its salts. E15 A process for the preparation of Compound IX, wherein said process comprises the following step (ii), the reduction of 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine (Compound IV) by catalytic hydrogenation to obtain 6-chloro-4-(4-fluoro-2-methylphenyl)pyridine-3-amine (Compound V) or its salts. E16 The process according to any of embodiments 13-15, wherein said catalytic hydrogenation is carried out in the presence of a catalyst selected from palladium or platinum on carbon, preferably platinum on carbon. Qocnn / zznz / E / YiAi E17 The process according to any of embodiments 13-16, wherein platinum is present in an amount of 0.05 to 0.5 by weight relative to Compound IV; preferably 0.2 to 0.3 by weight relative to Compound IV. E18 The process according to any of embodiments 13-17, wherein step (iii) takes place in alcohols, ethers, esters, hydrocarbons or mixtures thereof, preferably in esters, and even more preferably in ethyl acetate. E19 The process according to any of embodiments 13-18, wherein step (iii) takes place at room temperature. E20 The process according to any of embodiments 13-19, wherein the salts of Compound V are selected from maleate, hydrochloride, hydrobromide, phosphate, acetate, fumarate, salicylate, sulfate, citrate, lactate, mandelate, tartrate or methanesulfonate, preferably hydrochloride. E21 The process according to any of embodiments 13-20, 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 a hydrochloride salt. E22 The process according to any of embodiments 13-21, wherein step iii) is followed by iv): the reaction of 6-chloro-4-(4-fluoro-2-methylphenyl)pridin-3-amine or one of its salts 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)pridin-3-1)-2-methylpropanamide of formula (Compound VII). E23 A process for the preparation of intermediate (IX), wherein said process comprises the following step: iv): the reaction of 6-chloro-4-(4-fluoro-2-methylphenyl)pridin-3-amino or one of its salts (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)pridin-3-yl)-2-methylpropanamide of formula (Compound VII). E24 A process for the preparation of intermediate (IX), wherein said process comprises the following step: iv): the reaction of 6-chloro-4-(4-fluoro-2-methylphenyl)pyridine-3-amino one of its salts (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)pyridine-3-1)-2-methylpropanamide of formula (Compound VII). E25 The process according to any of embodiments 22-24, wherein step iv) takes place in dichloromethane in the presence of an organic base. i Qocnn / zznz / E / YiAi E26 The process according to any of embodiments 22-25, wherein step iv) takes place in the presence of an organic base selected from pyridine, triethylamine, diisopropylamine, N,N-diisopropylethylamine, 2,6-lutidine or one of their mixtures. E27 The process according to any of embodiments 22-26, wherein step iv) takes place at a temperature of 0-5°C. E28 The process according to any of embodiments 22-27, wherein step iv) is followed by v): ​​the reaction of 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4(4-fluoro-2-methylphenyl)pridin-3-yl)-2-methylpropanamide (VII) obtained by step iv) with a methyl halide of formula CH3X (VIII) in the presence of cesium carbonate, to obtain Compound IX); wherein X is a halogen selected from chlorine, bromine, or iodine. E29 A process comprising the following step v): the reaction of 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pridin-3-1)-2-methylpropanamide (Compound VII) obtained by step iv) 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)pridin-3-1)-N,2-dimethylpropanamide of formula (IX); wherein X is a halogen selected from chlorine, bromine, or iodine. E30 A process comprising the following step v): the reaction of 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pridin-3-1)-2-methylpropanamide (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)pridin-3-1)-N,2-dimethylpropanamide of formula (IX); wherein X is a halogen selected from chlorine, bromine, or iodine. E31 The process according to any of embodiments 28-30, wherein step v) takes place on an organic base selected from pyridine, triethylamine, diisopropylamine, N,N-diisopropylethylamine, 2,6-lutidine, or on an organic base selected from potassium carbonate, cesium carbonate, potassium phosphate, t-sodium butoxide, t-potassium butoxide or one of their mixtures. E32 The process according to any of embodiments 28-31, wherein step v) takes place in a solvent selected from DMF, acetonitrile or ethers. E33 Process for the preparation of Compound IX, wherein said process comprises: Qocnn / zznz / E / YiAi perform step i) according to any of the embodiment forms 1-7, followed by performing step ii) according to any of the embodiment forms 8-12, followed by performing step iii) according to any of the embodiment forms 13-21, followed by performing step iv) according to any of the embodiment forms 22-27, followed by performing step v) according to any of the embodiment forms 28-32. E34 Compound IX obtained from the process in accordance with any of embodiments 1-33. E35 The use of Compound IX obtained from the process in accordance with any of embodiments 1-33 for the preparation of Compound A. E36 Compound A obtained from Compound IX, wherein said Compound IX is prepared according to the process of any of embodiments 1-33. E37 A pharmaceutical composition comprising Compound A obtained from Compound IX, wherein said Compound IX is prepared according to the process of any of embodiments 1-33. E38 Compound A obtained from Compound IX, wherein said Compound IX is prepared according to the process of any of embodiments 1-33, for use in the treatment of diseases of the sex hormones or in the treatment or prevention of a condition or symptom associated with perimenopause, menopause, or postmenopause. E39 Compound A obtained from Compound IX, wherein said Compound IX is prepared according to the process of any of embodiments 1-33, for use in the treatment of selected sex hormone disorders of hot flashes, polycystic ovary syndrome (PCOS), endometriosis, heavy menstrual bleeding, adenomyosis or uterine fibroids. E40 Compound A obtained from Compound IX, wherein said Compound IX is prepared according to the process of any of embodiments 1-33, for use in the treatment of a condition or symptom associated with perimenopause, menopause or postmenopause selected from a pathological increase in excess body fat and / or excess body weight, diabetes, fatigue, irritability, cognitive impairment, hair loss, dry skin, insomnia, sleep disorders and night awakenings, anxiety and depression, decreased sexual desire, vaginal dryness and pain, loss of connective tissue and reduction of muscle mass, loss of bone mass, urinary urgency and dysuria, hot flashes and night sweats. i Qocnn / zznz / E / YiAi E41 Compound A obtained from Compound IX, wherein said Compound IX is prepared according to the process of any of embodiments 1-33, for use in the treatment of a condition or symptom associated with menopause caused by 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); selective estrogen receptor modulators (SERMs) such as bazedoxifene, clomiphene, cyclofenium, 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 seviteronel; and antrogen receptor blockers and combined CYP17A1 inhibitors, such as galeterone. E42 Compound A obtained from Compound IX, wherein said Compound IX is prepared according to the process of any of embodiments 1-33, for use in the treatment of a condition or symptom associated with andropause selected from a pathological increase in excess body fat and / or excess body weight, diabetes, fatigue, irritability, cognitive impairment, hair loss, dry skin, insomnia, sleep disorders and night awakenings, anxiety and depression, decreased sexual desire, loss of connective tissue and reduction of muscle mass, urinary urgency and dysuria, hot flashes and night sweats. E43 Compound A obtained from Compound IX, wherein said Compound IX is prepared according to the process of any of embodiments 1-33, for use in the treatment of a condition or symptom 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 androgen receptor blockers and CYP17A1 inhibitors combined, such as galeterone. E44 Compound A obtained from Compound IX, wherein said Compound IX is prepared according to the process of any of embodiments 1-33, 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 disorders. E45. Compound A obtained from Compound IX, wherein said Compound IX is prepared according to the process of any of embodiments 1-33, for use in the treatment of a 'weight-related disease' selected from a genetic sensitivity to excess body weight, obesity associated with metabolic disorders, or a condition for which a decrease in body weight would be of therapeutic benefit. E46 Compound A obtained from Compound IX, wherein said Compound IX is prepared according to the process of any of embodiments 1-33, for use in the treatment of a “pregnancy disorder selected from eclampsia, preeclampsia, gestational diabetes mellitus, high blood pressure, morning sickness, hyperemesis gravidarum, miscarriage, pelvic girdle pain and premature labor. E47 A pharmaceutical composition comprising Compound A obtained from intermediate (IX), wherein said Compound IX is prepared according to the process of any of embodiments 1-33, for use in the treatment of sex hormone disorders or in the treatment or prevention of a condition or symptom associated with perimenopause, menopause, or postmenopause. E48 A pharmaceutical composition comprising Compound A obtained from Compound IX, wherein said Compound IX is prepared according to the process of any of embodiments 1-33, for use in the treatment of sex hormone disorders. E49 A pharmaceutical composition comprising Compound A obtained from Compound IX, wherein said Compound IX is prepared according to the process of any of embodiments 1-33, for use in the treatment of a condition or symptom associated with perimenopause, menopause or postmenopause. E50 A pharmaceutical composition comprising Compound A obtained from Compound IX, wherein said Compound IX is prepared according to the process of any of embodiments 1-33, for use in the treatment of selected sex hormone disorders of hot flashes, polycystic ovary syndrome (PCOS), endometriosis, heavy menstrual bleeding, adenomyosis or uterine fibroids. E51 A pharmaceutical composition comprising Compound A obtained from Compound IX, wherein said Compound IX is prepared according to the process of any of embodiments 1-33 and one or more of a pharmaceutically acceptable excipient, carrier and / or diluent. i Qocnn / zznz / E / YiAi E52 Compound III. E53 Compound IV. E54 Salts of Compound V. E55 Vile Compound E56 Use of a compound of formula (III), (IV), (V) or (Vil) in the preparation of Compound A. Examples. The invention will be illustrated by the following non-limiting examples. The following examples are for illustrative purposes only and are not intended to limit the scope of the invention in any way. In the procedures that follow, a reference to a description is typically provided after each starting material. This is provided simply as an aid to the expert chemist. The starting material may not necessarily have been prepared from the batch mentioned. As used in this document, the symbols and conventions used in these processes, diagrams, and examples are consistent with those used in contemporary scientific literature, e.g., the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, the following abbreviations may be used in the examples and throughout the descriptive report: j Qocnn / zznz / E / YiAi g (grams); mg (milligrams); L (liters); mL (milliliters); M (molar); mM (millimolar); kg (kilogram); mol (moles); w / w (weight / weight); MS (mass spectrometry); mmol (millimoles); TA or ta (room temperature); min (minutes); h hrs (hours); NMP (N-methyl-2-pyrrolidone) THF (tetrahydrofuran); DMSO (dimethyl sulfoxide); EtOAc (ethyl acetate); i Qocnn / zznz / E / YiAi DME (1,2-dimethoxyethane); DCM (dichloromethane); DMF (A / ,A / -dimethylformamide) MS (mass spectrometry); HPLC (high-performance liquid chromatography). Unless otherwise stated, all temperatures are expressed in °C (degrees Celsius). All reactions are conducted under an inert atmosphere at room temperature, unless otherwise noted. In the Examples, unless otherwise stated: 1H-QRMN. Quantitative NMR was conducted according to the 1H NMR standard, but using an internal standard to allow product assay estimation. HPLC. Purity is determined by reversed-phase HPLC. A C18 stationary phase is used with an aqueous mobile phase acidified with an organic acetonitrile modifier. Elution is performed in gradient mode. Example 1. Preparation of 4—(4—fluoro—2—methylphenyl)—5—nitropiridine—2(1 H)—one (Compound III). A three-necked flask, connected to a condenser and a vacuum / nitrogen line, was charged with 4-chloro-5-nitropiridine-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, e.g., from Sigma Aldrich), potassium carbonate (92.6 g, 670 mmol), and 1,4-dioxane (480 mL). After evacuating and refilling with nitrogen three times, tetrakis(triphenylphosphine)palladium(O)₂ (12.9 g, 11.2 mmol) was added under a stream of nitrogen, and the resulting mixture was stirred under gentle reflux (99 °C internal temperature) 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 x 200 mL), the filtrate was collected, concentrated in vacuo, and dried to obtain the title compound as a dark yellow solid (78.0 g, 314 mmol).Yield 141% w / w) with a purity of 60% according to 1H-QNMR. The compound was used for the next stage without further purification. 1H NMR (d-DMSO) δ / ppm 8.88 (s, 1H), 6.96-7.06 (m, 3H), 0.44 (s, 1H), 2.03 (s, 3H, -CH3). Example 2. Preparation of 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropiridine (Compound IV). CI^N Ύ X ^^NO2 F 4-(4-fluoro-2-methylphenyl)-5-nitropiridine-2(1 / - / )-one (78.0 g, 60% w / w, 0.19 mol) was suspended in DME (600 mL) in a three-necked flask under nitrogen. POCh (0.10 kg, 61 mL, 0.65 mol) was added dropwise (slightly exothermic reaction, 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 slowly poured into water (600 mL) (exothermic peak, cooled with an ice-water bath). The pH was neutralized with solid Na2Cl3, the mixture was transferred to a separatory funnel and extracted with EtOAc (2 x 600 mL). The organic layer was collected, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to obtain the title compound as a brown solid (46.2 g, 173 mmol, 91% w / w yield) with 86% purity (HPLC).1H NMR (CDCI3) 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). Example 3. Preparation of 6-chloro-4-(4-fluoro-2-mephilphenyl)pyridin-3-am¡ne hydrochloride (Compound V). j oocnn / zznz / E / YiAi A flask for the Parr hydrogenation 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 the Parr apparatus and mechanically stirred at room temperature under 300 kPa (3 bar) of hydrogen. After 48 h, more platinum on carbon (2.7 g, 5% w / w, 0.7 mmol) was added because HPLC-MS showed that the reaction was no longer proceeding. The mixture was stirred under 300 kPa (3 bar) of H2 for 96 h when HPLC-MS showed no further progress in this conversion. An additional amount of platinum on carbon (2.7 g, 5% w / w, 0.7 mmol) was added, and the reaction was stirred under 350 kPa (3.5 bar) of H₂ for 24 h. The reaction mixture was filtered over Celite and concentrated in a vacuum. The crude product was dissolved in EtOAc (200 mL), and the resulting solution was cooled to 0°C.A 4 N solution of HCl in dioxane (55 mL, 220 mmol) was added slowly, and the solution was stirred at room temperature for 18 h. The mixture was concentrated in a vacuum, 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 obtain the title compound as a whitish 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 Η, -NH2), 8.54 (s, 1 H), 7.23-7.43 (m, 3 H), 7.13 (s, 1 H), 2.15 (s, 3 H,-CH3). Example 4. Preparation of 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridine-3-1)-2-methylpropanamide (Compound VII). F j Qocnn / zznz / E / YiAi Preparation 1. A three-necked 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 using 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 under vacuum to obtain 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride in the form of a pale yellow oil containing some solid particles (34.5 g, 106 mmol, Yield 110% w / w). This material was used directly in the next step. In Example 3, 6-chloro-4-(4-fluoro-2-methylphenyl)pyridine-3-amine hydrochloride (Compound V) (27.0 g, 97.9 mmol) was added in portions (slightly exothermic) to a three-necked flask containing pyridine (139 g, 0.14 L, 1.76 mol) at 0 °C and under N2. A suspension of 2-(3,5-bis(thiofluoromethyl)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 of each) and transferred to a separatory funnel. The organic layer was collected, washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title product in the form of an orange oil, which solidified upon standing (52.5 g, 100 mmol, 102% w / w yield) with 93% purity (HPLC). The compound was used for the next stage without further purification. 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 sC, 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, keeping the temperature below 10 sC. 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 h. After the reaction was completed, the reaction mixture was concentrated to 2.0 µL / 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. Example 3, (6-chloro-4-(4-fluoro-2-methylphenyl)pyridine-3-amine hydrochloride (Compound V)) (11.9 kg), and DCM (2.7 L / kg of Example 3) were loaded. After cooling to 5-5°C, pyridine (3.00 mol / mol of Example 3) was added, maintaining the temperature below 10°C. Then, 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride solution was added to DCM, maintaining 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 at least 18 h. After the reaction was complete, the reaction mixture was cooled to 10°C, and water (8.0 L / kg of Example 3) was added, maintaining 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 extracted again with DCM (4.0 L / kg of Example 3). i Qocnn / zznz / E / γΐΛΐ The combined organic layers were washed with water (2 x 5.0 L / kg of Example 3) and concentrated under vacuum to 2.7 L / kg of Example 3. Heptane (8.5 L / kg of Example 3) was then added while maintaining the temperature at 35-452C, and 2—(3,5—bis(trifluoromethyl)phenyl)—N—(6—chloro-4-(4-fluoro-2-methylphenyl)pridin-3-yl)-2-methylpropanamide (0.005 w / w of Example 3) was loaded for seeding. The seeded mixture was aged for not less than 1 h at 402°C, and the resulting suspension was concentrated under vacuum to 10.0 U / kg of Example 3. An additional amount of heptane (2.0 L / kg of Example 3) was added at 35 / 45°C. The suspension was cooled to 10 / 20°C in not less than 2 h and held at 10 / 20°C for not less than 2 h before proceeding with the centrifugation step. The suspension was centrifuged, and the cake was washed with heptane (2.0 L / kg of Example 3). The wet product was vacuum dried at no more than 45SC to obtain 19.9 kg of the title compound (Yield = 88.1%) with 99.87% purity in the form of a whitish solid. 1H NMR (DMSO-cfe): 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). Example 5. Preparation of 2-(3,5-bis(trifluoromethyl)phenyl)-A / -(6-chloro-4-(4-fluoro-2-methylphenyl)pyridine-S-iD-A / ^-dimethylpropanamide (Compound IX). i oocnn / zznz / E / YiAi F Preparation 1. A three-necked flask, connected to a nitrogen line, was charged with Example 4, Preparation 1 (52.0 g, 95%, 95 mmol), DMF (300 mL), and cesium carbonate (62 g, 0.19 mol). The resulting mixture was cooled to 0 °C before adding methyl iodide (14.3 g, 6.3 mL, 0.10 mol) dropwise for 5 minutes. The mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was poured into water (600 mL) and extracted with EtOAc (2 x 600 mL). The organic layer was collected, washed successively with water and brine, dried over Na₂SO₄, and filtered. The solvent was evaporated under vacuum, and the residue was dried to a dark brown solid. The solid was suspended in heptane (500 mL) and stirred for 30 min. The suspension was filtered, the pale brown solid was collected and dried under vacuum. The brown color was removed by dissolving the product in EtOAc (200 mL) and filtering over a short silica pad.The filtrate was collected and concentrated under vacuum to obtain the title product in the form of a pale yellow solid (34.1 g, 64 mmol, Yield 67% w / w) with 96.7% purity (HPLC). Preparation 2. Example 4, (2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methylpropanamide (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 loaded. After cooling to 5 / 5 °C, methyl iodide (1.10 mol / mol of Example 4) was added, maintaining the temperature below 10 °C. The addition vessel was rinsed with DMF (0.8 L / kg of Example 4). The reaction mixture was heated to 20 / 25 °C and stirred for at least 18 h. After the reaction was complete, 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, maintaining the temperature below 20°C. After stirring for a further 15 minutes at 20-25°C, the layers separated, and the aqueous layer was re-extracted with ethyl acetate (12.0 L / kg of Example 4). The combined organic layers were washed with water (12.0 L / kg of Example 4) and 20 wt% NaCl solution (5.0 kg / kg of Example 4). After vacuum distillation (2.0 µkg of Example 4), heptane (9.0 L / kg of Example 4) was added at 35–45°C. The suspension was stirred at 40°C for at least 2 h, cooled to 10–20°C in at least 2 h, and aged at 10–20°C for at least 2 h before centrifugation. The suspension was centrifuged, and the cake was washed with heptane (2.0 L / kg of Example 4). The wet product was vacuum dried at NMT 45SC to obtain 14.2 kg of the title compound as a white solid (yield = 69.4%) with 99.99% purity.1H NMR (DMSO-O6 δ 8.32 (s, 1 H), 8.03 (s, 1 H), 7.74 (broad s, 2 H), 7.55 (s, 1 H), 7.30-7.00 (broad + d, 3 H), 2.90-2.40 (broad m, 3 H), 2.15 (broad m, 3 H), 1.70-1.20 (broad m, 6 H). Example 6. Method of preparation of N-(6-((7S,9aS)-7-((benzyloxy)methyl)hexahydropyrazino[2,1c][1,41oxazin-8(1 H)-¡I)-4-(4-fluoro-2-methylpheniDpyridin-3-¡I)-2-(3,5-bis(trifluoromethyl)phenyl)- N,2-dimethylpropanamide (Compound XI). oocnn / zznz / E / YiAi Ox2HCI F j Qocnn / zznz / E / YiAi Preparation 1. A three-necked flask connected to a thermometer, a condenser, and nitrogen, was charged with Example 5, (2-(3,5-bis(trifluoromethyl)phenyl)-LZ-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridine-3-l)- / V,2-dimethylpropanamide (Compound IX)) (643 mg, 1.21 mmol), sodium fer-butoxide (218 mg, 2.66 mmol) and Bis(tri-tert-butylphosphine)palladium(O) (0.16 mmol, 62 mg). A solution of (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazino[2,1-c][1,4]oxazine (380 mg, 1.45 mmol) in toluene was added, and the reaction mixture was stirred at 85°C for 18 h. The mixture was cooled and filtered over Celite. The filtrate was collected, transferred to a separatory funnel, washed with water and brine, dried over Na₂S₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound as a brown solid (610 mg, 0.8 mmol, 67% w / w yield). Preparation 2, (7S,9aS)-7-((benzylox¡)met¡l)octah¡drop¡razino[2,1-c][1,4]oxaz¡ne. A solution of the dioxalate salt of (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazine[2,1-c][1,4]oxazine (1.26 mol / mol of Example 5 from Preparation 2), toluene (20.0 L / kg of Example 5), and 1N NaOH (20.0 L / kg of Example 5) were loaded. The mixture was heated to 75°C and stirred for at least 5 min. The layers were allowed to settle for at least 30 min, and the lower aqueous layer was discarded. The organic layer was cooled to 25°C, and water (10.0 L / kg of Example 5) was added. The mixture was stirred for at least 10 min, the layers were allowed to settle for at least 15 min, and the lower aqueous layer was discarded. The organic layer was concentrated to 8.0 L / kg of Example 5 under vacuum, toluene (4.0 L / kg of Example 5) was added, and the mixture was redistilled under vacuum to 8.0 L / kg of Example 5. A sample was taken for Karl Fischer (KF) determination. If the KF was successful, additional toluene (8.0 L / kg of Example 5) was added. Otherwise, toluene (4.0 L / kg of Example 5) was added again, and the distillation step was repeated at 8.0 L / kg of Example 5. In another reactor, Example 5, (2-(3,5-bis(trifluoromethyl)phenyl)- / V-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridine-3-I)-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-1-butylphosphine) (0.10 mol / mol of Example 5) were charged. (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazino[2,1c][1,4]oxazine free base / toluene solution was charged, and the transfer line was rinsed with toluene (2.0 L / kg of Example 5)). The reaction mixture was heated to 852C and stirred for no less than 4 h before sampling for reaction completion. The reaction mixture was cooled to 25°C, and charged with 20 wt% NaHSOg solution (8.7 L / kg of Example 5). The mixture was heated to 60°C for not less than 1 minute and then cooled again to 25°C. After filtering the batch through K100 filter paper, the filter and transfer line were washed with toluene (1.0 L / kg of Example 5). The layers were allowed to settle for at least 30 min at 25°C, and the lower aqueous layer was discarded. A 5 wt% LC-steine ​​solution (10.0 kg / kg of Example 5) was added to the organic layer. The mixture was heated to 60°C for at least 1 min and then cooled to 25°C. After filtering the batch through K100 filter paper and washing the filter and transfer line with toluene (1.0 L / kg of Example 5), a 10 wt% NaCl solution was added. The layers were stirred for at least 15 min and allowed to settle for at least 30 min at 25°C. Finally, the lower aqueous layer was discarded.A 5 wt% L-cysteine ​​solution (10.0 kg / kg of Example 5) was added to the organic layer. The mixture was heated to 60°C for at least 1 minute and then cooled to 25°C. After filtering the batch through K100 filter paper and washing the filter and transfer line with toluene (1.0 L / kg of Example 5), a 10 wt% NaCl solution was added. The layers were stirred for at least 15 minutes and allowed to settle for at least 30 minutes at 25°C. Finally, the lower aqueous layer was discarded. The organic layer was washed with a 5 wt% NaHCO3 solution and twice with a 2 wt% NaCl solution. The resulting organic layer was concentrated to 4.0 L / kg of Example 5 under vacuum. Toluene (7.0 L / kg of Example 5) was added, and the solution was sampled for KF analysis. After heating the batch to 40°C, a 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 maintained at 40°C for at least 30 min and concentrated to 10.0 L / kg of Example 5 under vacuum. Toluene (9.0 L / kg of Example 5) was added, and the solution was redistilled to 10.0 L / kg of Example 5. This last operation was repeated once more, and the resulting solution was sampled for gas chromatography analysis. The batch temperature was adjusted to 25°C, and n-heptane (7.0 L / kg of Example 5) was added, maintaining the internal temperature at 20 / 30°C. The suspension was maintained at 20 / 30°C for no less than 4 h before proceeding with the centrifugation step. The suspension was centrifuged, and the cake was washed with n-heptane (4.0 L / kg of Example 5). The wet product was vacuum dried at 35SC to obtain 4.4 kg of title compound (yield = 88.2%) with 97.4% purity in the form of a light brown solid. i oocnn / zznz / E / YiAi NMR spectrometer: Varian Agilent Mercury Vx 400 (16 scans, sw 6400 Hz, 25 °C. 1H 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, 17 H), 4.62 (m, 1 H), 4.50 (d, 11.8 Hz, 1 H), 4.444.10 (m, 7 H), 4.08-3.69 (m, 3 H), 3.60 (d, 12.8 Hz, 1 H), 3.45 (d, 11.8 Hz, 3.97 Hz), 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). Example 7. 2-[3,5-B¡s(trifluorometh¡l)phen¡l1-N-{4-(4-fluoro-2-methylphen¡l)-6-[(7S,9aS)-7-(h¡drox¡methyl)hex¡droD¡raz¡no[2,1-c][1,4-8(1)oxazine] H)—ill—3—pyridinyl}—N,2—dimethylpropanamide, dichlorhydrate salt, mono-isopropanol solvate (Compound XII). i Qocnn / zznz / E / YiAi Example 6, (N-(6-((7S,9aS)-7-((benzyloxy)methyl)hexahydropyrazino[2,1-c][1,4]oxazin8(1 H)-1)-4-(4-fluoro-2-methylphenyl)pyridin-3-II)-2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamide (Compound XI)) (4.4 kg), Norit DARCO G60 activated carbon (0.10 kg / kg of Example 6), isopropanol (22.9 L / kg of Example 6), water (2.5 L / kg of Example 6), and 35 wt% HCl (4.0 mol / mol of Example 6) were loaded into the hydrogenator. The mixture was heated to 50°C and stirred for at least 30 min. Then, Pd / C 10% (0.20 kg / kg of Example 6) in isopropanol (20.4 Ukg of Example 6) was loaded into the hydrogenator and rinsed with more isopropanol (8.9 Ukg of Example 6). The hydrogenation conditions were established (2.00 BarG, 50sC) and maintained until no further hydrogen consumption was observed. Once the reaction was complete, the batch was filtered through a Veladisc® filter box 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). 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. If the KF analysis passed the specification criteria, 4M dioxane / HCl (2.00 mol / mol of Example 6) was added at 20 / 30°C, and the mixture was heated to 65°C for at least 30 min. The batch was then cooled to 25°C in at least 60 min, and isooctane (5.0 L / kg of Example 6) was added at 20 / 30°C in at least 30 min. The suspension was held at 25°C for at least 5 h before proceeding to the centrifugation step. The suspension was centrifuged, and the cake was washed with a mixture of isopropanol (2.0 L / kg Example 6) and isooctane (2.0 L / kg of Example 6). The wet product was vacuum dried at 35SC to obtain 3.5 kg of the title compound (yield = 82.1%) with 99.3% purity in the form of a beige solid. NMR Spectrometer: Vahan Agilent Mercury Vx 400 (16 sweeps, sw 6400 Hz, 25°C. 1H NMR (400 MHz, DMSO-d6): δ 11.34 (bd, 1 H), 8.02 (s, 1 H), 7.96 (bd s, 1 H), 7.227.00 (m, 3 H), 6.91 (s, 1 H), 4.68 (bd s, 1 H), 4.49 (bd, 1 H), 4.20 (t, 12.2 Hz, 1 H), 4.07-3.90 (m, 3 H), 3.84 (m, 1 H), 3.77 (hept„ 6.1 Hz, 1 H), 3.64 (d, 12.6 Hz, 1 H), 3.43 (m, 2 H), 3.28 (m, 1). Η), 3.16 (m, 2 Η), ca, 2.58 (bd, 2 H), 2.41–2.00 (m, 5 H), 1.60–1.10 (m, 6 H), 1.03 (d, 6.1 Hz, 6 H). Example 8. 2-[3,5-B¡s(trifluoromethyl)phenyl-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-(hydrox¡methyl)hexahydropyraz¡nof2,1-c][1,41oxazin-8(1). H)-¡l1-3-Diridinyl}-N,2-d¡methylproDan¡de as Anhydrous Crystalline Form (Compound A). o F j oocnn / zznz / E / YiAi 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(1 H)-1I]-3-pyridinyl}-N,2-dimethylpropanamide, dihydrochloride salt, monoisopropanol solvate (Compound XII)) (3.4 kg), methyl-1-butyl ether (hereafter MTBE) (15.0 µkg of Example 7) and 2.5N NaOH (4.9 L / kg of Example 7), were loaded, heated to 40°C and stirred for 10 to 30 min. The layers were allowed to settle for not less than 30 min at 40°C, and the lower aqueous layer was discarded. A 9 wt% aqueous solution of L-cysteine ​​(5.0 L water per kg of Example 7 + 0.5 w / w L-cysteine ​​per Example 7) was added to the organic layer and stirred at 40°C for not less than 60 min. The layers were allowed to settle for not less than 30 min at 40°C, and the lower aqueous layer was discarded. Water (5.0 L / kg of Example 7) was added to the organic layer and stirred at 40°C for at least 15 min. The layers were allowed to settle for at least 60 min at 40°C, and the lower aqueous layer was discarded. Water (5.0 L / kg of Example 7) was added to the organic layer and stirred at 40°C for at least 15 min. The layers were allowed to settle for at least 60 min at 40°C, and the lower aqueous layer was discarded. 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 for not less than 1 h, and the solution was distilled under light vacuum to 4.0 L / kg of Example 7. A sample was taken for monitoring MTBE removal and water. 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 any extraneous material. Isooctane (4.5 L / kg of Example 7) was added, and the batch was heated to 70°C for at least 30 minutes. The solution was cooled to 50°C and seeded with a suspension of 2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl)hexahydrophorazine[2,1c][1,4]oxazin-8(1H)-1I]-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 not less than 3 h, and additional isooctane (4.2 L / kg of Example 7) was added over not less than 3 h, maintaining the temperature at 50 / 55°C. The suspension was kept at 50°C for no less than 8 h, cooled to 02°C in no less than 5 h and aged for no less than 3 h before proceeding to the centrifugation stage. The suspension was centrifuged, and the cake was washed with isooctane (2 x 3.3 L / kg of Example 7). The wet product was vacuum dried at 50°C to obtain 2.34 kg of title compound (yield = 82.7%). This product was sieved to remove lumps to obtain 2.26 kg of title compound with 99.8% purity in the form of a white powder. NMR Spectrometer: Varian Agilent Mercury Vx 400 (16 sweeps, sw 6400 Hz, 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, 2H), 2.31-2.00 (m, 7 H), 1.58-1.10 (m, 6 H).

Claims

1. A process for the preparation of Compound (IX), cf3 Cl Xjói F (IX) wherein said process comprises the following step i) reaction of 4-chloro-5-nitropiridin-2(1H)-one with 4-fluoro-2-methylphenyl boronic acid, catalyzed by a palladium complex in the presence of a base, to obtain 4-(4-fluoro-2-methylphenyl)-5-nitropiridin-2(1 H)-one (III): HO^NF (III).

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

3. The process according to claim 1 or 2, wherein step i) is followed by i) the reaction of 4-(4-fluoro-2-methylphenyl)-5-nitropiridine-2(1 H)-one (III) obtained in step i) with POCh to obtain 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropiridine (IV): XX γνο2 F (iv).

4. The process according to claim 3, wherein step i) is followed by iii) the reduction of said 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropidine (IV) by catalytic hydrogenation to obtain 6-chloro-4-(4-fluoro-2-methylphenyl)pridine3-amine of formula (V) or its salts: CI^.N. I Ί Xj F (V), wherein • said catalytic hydrogenation is carried out in the presence of catalysts selected from palladium or platinum on carbon and • the salts of Compound (IV) are selected from maleate, hydrochloride, hydrobromide, phosphate, acetate, fumarate, salicylate, sulfate, citrate, lactate, mandelate, tartrate or methanesulfonate, preferably hydrochloride.

5. The process according to claim 4, wherein step (iv) is followed by the step of: (iv) the reaction of 6-chloro-4-(4-fluoro-2-methylphenyl)pridin-3-amine or one of its salts (V) obtained in step (iii) with 2-(3,5-bis(trifluoromethyl)phenyl)2-methylpropanoyl chloride (VI) to obtain 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pridin-3-yl)-2-methylpropanamide of formula (VIi): / Qocnn / zznz / E / YiAi F (vii), wherein step (iv) takes place in dichloromethane in the presence of an organic base, selected from pyridine, triethylamine, diisopropylamine, N,Ndiisopropylethyl lamine, 2,6-lutidine or one of its mixtures, at a temperature of 05°C.

6. The process according to claim 5, wherein step iv) is followed by step v) the reaction of 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridine-3-1)-2-methylpropanamide (VII) obtained by step iv) with a methyl halide of formula CH3X (VIII), wherein X is a halogen selected from chlorine, bromine, or iodine, in the presence of cesium carbonate to obtain Compound (IX), wherein step v) takes place in an organic base selected from pyridine, triethylamine, diisopropylamine, N,N-diisopropylethylamine, 2,6-lutidine, or in an inorganic base selected from potassium carbonate, cesium carbonate, potassium phosphate, sodium tert-butoxide, tert-butoxide of potassium or one of its mixtures.

7. The process for the preparation of intermediate (IX), according to any of claims 1-6, wherein said process comprises the following steps: i) reaction of 4-chloro-5-nitropiridine-2(1H)-one (I) with 4-fluoro-2-methylphenyl boronic acid (II), catalyzed by a palladium complex in the presence of a base to obtain 4-(4-fluoro-2-methylphenyl)-5-nitropiridine-2(1H)-one of structure (III): HO^N γ^NO2 F (ni); followed by i) the reaction of 4-(4-fluoro-2-methylphenyl)-5-nitropiridine-2(1H)-one (III) obtained in step i) with POCh to obtain 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropiridine (IV): i Qocnn / zznz / E / YiAi F (IV); followed by iii) reduction of 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine (IV) by catalytic hydrogenation to obtain 6-chloro-4-(4-fluoro-2-methylphenyl)pyridine-3-amine of formula (V) or its salts: followed by iv) the reaction of 6-chloro-4-(4-fluoro-2-methylphenyl)pyridine-3-amine or one of its salts (V) obtained in step iii) with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl (VI) to obtain 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridine-3-yl)-2-methylpropanamide of formula (VII):

8. followed by (v) the reaction of 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridine-3-yl)-2-methylpropanamide (VII) with a methyl halide of formula CH3X (VIII) in the presence of cesium carbonate to obtain Compound (IX). Use of Compound (IX) obtained from the process according to any one of claims 1 to 7 in the preparation of 2-(3,5-bis(trifluoromethyl)phenyl)- / V-(4-(4-fluoro-2-methylphenyl)-6-((7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,1c][1,4]oxazin-8(1 / - / )-yl)pyridine-3-yl)-1 / ,2-dimethylpropanamide (Compound A):

9.

10. Compound A as defined in claim 8, for use in the treatment of selected sex hormone disorders of hot flashes, polycystic ovary syndrome (PCOS), endometriosis,Heavy menstrual bleeding, adenomyosis, or uterine fibroids. A salt of the intermediate compound (V):

11. F (V), wherein the salts are selected from maleate, hydrochloride, hydrobromide, phosphate, acetate, fumarate, salicylate, sulfate, citrate, lactate, mandelate, tartrate, or methanesulfonate. An intermediate compound of formula (Vil):,