RU2840774C2 - Novel chemical method of producing 6-chloro-4-(4-fluoro-2-methylphenyl)pyridine-3-amine, key intermediate compound for production of nt-814 - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to the technology of producing 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-N,2-dimethylpropanamide (compound IX), which is an intermediate compound in the synthesis of drug 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl)hexahyd-ropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-3-pyridinyl}-N,2-dimethylpropanamide, as well as to novel intermediate compound (VII). Process for the preparation of compound (IX) involves reaction of 6-chloro-4-(4-fluoro-2-methylphenyl)pyridine-3-amine salt with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride in dichloromethane in the presence of an organic base at temperature of 0-5 °C to obtain compound (VII) and subsequent reaction of compound (VII) with methyl halide in presence of caesium carbonate.

EFFECT: obtaining compound (IX) using an improved method.

5 cl, 8 ex

Description

Field of technology to which the invention relates

The present invention relates to a new process for the preparation of Compound IX, which is useful for the manufacture of Compound A. The present invention also relates to Compound IX obtained by this process and its use for the manufacture of Compound A. The present invention also relates to new intermediates obtained by this process, including Compound III, Compound IV, salts of Compound V, Compound VII, and pharmaceutically acceptable salts thereof, and their use for the manufacture of Compound IX or Compound A.

Field of technology to which the invention relates

Compound A or its pharmaceutically acceptable salts were first disclosed in publication WO 2007/028654.

Compound A is also known in anhydrous crystalline form. Thus, Compound A in anhydrous crystalline form (e.g. anhydrous crystalline Form 1) is described in WO 2011/023733.

Compound A, including its anhydrous crystalline Form 1, or pharmaceutically acceptable salts thereof are useful, inter alia, for the treatment of diseases associated with sex hormones, including hot flashes, polycystic ovary syndrome (PCOS), endometriosis, heavy menstrual bleeding, uterine fibroids or adenomyosis. See International Patent Application Publication WO 2016/184829.

Methods for preparing Compound A or its pharmaceutically acceptable salts and its anhydrous crystalline Form 1 are disclosed in International Patent Application Publications WO 2007/028654 and WO 2011/023733, respectively. The methods allow for the preparation of Compound A or its anhydrous crystalline Form 1 by the reaction of Compound XI.

Methods for the preparation of Compound IX are disclosed in International Patent Application Publications WO 2005/002577, WO 2006/013050 and WO 2002/016324, and in European Patents EP 3067349 and EP 3141541. However, these methods are generally characterized by low yields and high costs, or are carried out using substances that are not commercially available, which, as a consequence, affects the overall cost of the synthesis of Compound A.

Thus, there is a need for an improved process for the preparation of Compound IX that is suitable for the preparation of Compound A. The present invention is directed to satisfying this need.

Brief summary of the invention

In some aspects, the present invention provides a method for producing Compound IX, which comprises one or more of the following steps:

(i) the reaction of Compound I with Compound II to form Compound III;

(ii) reaction of Compound III to form Compound IV;

(iii) reacting Compound IV to form Compound V or a pharmaceutically acceptable salt thereof;

(iv) reacting Compound V or a pharmaceutically acceptable salt thereof with Compound VI to form Compound VII; and

(v) reaction of Compound VII with Compound VIII to form Compound IX.

In some aspects, the present invention provides the use of Compound I, Compound III, Compound IV, Compound V, Compound VII, or pharmaceutically acceptable salts thereof for the manufacture of Compound IX.

In some aspects, the present invention provides an intermediate compound that is selected from Compound III, Compound IV, Compound VII, or salts thereof.

In one aspect, the present invention provides salts of Compound V.

In some aspects, the present invention provides Compound IX prepared by the process disclosed herein.

In some aspects, the present invention provides a method for producing Compound A, which comprises one or more of the following steps:

(vi) reacting Compound IX obtained by the process disclosed herein with Compound X to form Compound XI or a pharmaceutically acceptable salt thereof;

(vii) reacting Compound XI or a pharmaceutically acceptable salt thereof to form a pharmaceutically acceptable salt and/or solvate of Compound A;

(viii) reacting a pharmaceutically acceptable salt and/or solvate of Compound A to form Compound A (e.g., Form 1).

In some aspects, the present invention provides a method for producing Compound A that comprises one or more of steps (i)-(viii).

In some aspects, the present invention provides the use of Compound III, Compound IV, Compound V, Compound VII, or pharmaceutically acceptable salts thereof for the manufacture of Compound A.

In some aspects, the present invention provides the use of Compound IX, prepared by the process disclosed herein, for the manufacture of Compound A.

In some aspects, the present invention provides Compound A prepared by the method disclosed herein.

In some aspects, the present invention provides a pharmaceutical composition comprising Compound A prepared by the process disclosed herein and one or more pharmaceutically acceptable excipients, carriers and/or diluents.

In some aspects, the present invention provides a method of treating or preventing a disease associated with sex hormones, which comprises administering to a subject in need thereof Compound A obtained by the method disclosed herein, or a pharmaceutical composition thereof.

In some aspects, the present invention provides Compound A, prepared by the process disclosed herein, or a pharmaceutical composition thereof, for use in the treatment or prevention of a disease associated with sex hormones.

In some aspects, the present invention provides the use of Compound A obtained by the process disclosed herein for the manufacture of a medicament for use in the treatment or prevention of a disease associated with sex hormones.

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

In some aspects, the present invention provides Compound A, obtained by the process disclosed herein, or a pharmaceutical composition thereof, for use as a medicament.

In some aspects, the present invention provides the use of Compound A obtained by the process disclosed herein for the manufacture of a medicament for use in therapy.

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which the invention pertains. As used herein, the singular forms "a" and "an" also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the most suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned in this application are incorporated by reference. References cited herein are not considered prior art to the claimed invention. In the event of any conflict, the present invention, including definitions, will control. Furthermore, the materials, methods and examples are illustrative only and are not intended to limit the invention.

Other features and advantages of the invention will be apparent from the following detailed description and claims.

Detailed description of the invention

The present invention is based, among other things, on the discovery of a new and efficient method for producing Compound IX. The method can provide Compound IX with a quality suitable for producing Compound A (e.g., with high purity) and can be easily scaled up to an industrial scale.

Definitions

In the context of this application, "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 and has the chemical structure shown below.

In the context of this application, "Form 1" of Compound A refers to the anhydrous crystalline form of Compound A ("Form 1") having 2-theta angles 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, which correspond, respectively, to d-spacings of 20.4, 11.1, 9.0, 8.3, 8.2, 6.6, 6.3, and 5.9 angstroms (A).

In the context of this application, "Compound I" refers to 4-chloro-5-nitropyridin-2(1H)-one and has the chemical structure depicted below. It is to be understood that Compound I is commercially available, for example, from Leapchem, RennoTech Co., Ltd., Chemieliva Pharmaceutical Co., Ltd., or Alchem Pharmtech, Inc.

In the context of this application, "Compound II" refers to 4-fluoro-2-methylphenylboronic acid and has the chemical structure depicted below:

In the context of this application, "Compound III" refers to 4-(4-fluoro-2-methylphenyl)-5-nitropyridin-2(1H)-one and has the chemical structure depicted below:

In the context of this application, "Compound IV" refers to 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine and has the chemical structure depicted below:

In the context of this application, "Compound V" refers to 6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine and has the chemical structure depicted below:

In the context of this application, "Compound VI" refers to 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride and has the chemical structure depicted 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).

In the context of this application, "Compound VII" refers to 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methylpropanamide and has the chemical structure depicted below:

In the context of this application, "Compound VIII" refers to a methyl halide and has the chemical structure _CH3X , wherein X is a halogen. In some embodiments, X is Cl, I, Br, or I. In some embodiments, X is Cl, Br, or I. In some embodiments, Compound VIII is _CH3Cl , _CH3Br , or _CH3I . In some embodiments, Compound VIII is _CH3Cl , _CH3Br , or _CH3I .

In the context of this application, "Compound IX" refers to 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-N,2-dimethylpropanamide and has the chemical structure depicted below:

In the context of this application, "Compound X" refers to (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazino[2,1-c][1,4]oxazine, a compound having the chemical structure depicted below:

In the context of this application, "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 depicted below:

It is to be understood that the present disclosure includes the compounds of the present invention and any pharmaceutically acceptable salts and solvates thereof, as well as stereoisomers, mixtures of stereoisomers and polymorphs of all isomeric forms of said compounds.

In the context of this application, the term "salt" or "pharmaceutically acceptable salts" refers to any salt of a compound of the present invention prepared from an inorganic or organic acid. Suitable salts 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, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphoric, isothionic, mucinous, gentisic, isonicotinic, saccharic, glucuronic, pyrolysic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinic, alginic, galacturonic and arylsulfonic, such as benzenesulfonic and p-toluenesulfonic acids.

In the context of this application, the term "solvate" refers to solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to trap solvent molecules in a fixed molar ratio in the crystalline solid state, thereby forming a solvate. If the solvent is water, the resulting solvate is a hydrate; and if the solvent is an alcohol, the resulting solvate is an alkoxide. Hydrates are formed by the combination of one or more water molecules with one molecule of the substance, with the water retaining its molecular state as _H2O .

In the context of this application, the term "Compound A" includes, unless otherwise indicated, 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.

In the context of this application, the term "salt" of Compound V includes salts, solvates and hydrates of Compound V.

In the context of this application, the term "treatment" is intended to mean the management and care of a patient with the aim of alleviating, arresting, partially arresting or slowing the progression of the clinical manifestation of a disease, or curing the disease. The patient to be treated is preferably a mammal, in particular a human.

In the context of this application, the term "preventing" or "preventing" describes the reduction or elimination of the occurrence of symptoms or complications of such disease, condition or disorder.

In the context of this application, the term "hot flashes" is interchangeable with the term "hot flashes" and the term "vasomotor symptoms" and has the same meaning.

In the context of the present application, the term "comprising" includes the case of "consisting only of".

A description in this application of any aspect or aspect of the invention using terms such as "having", "including", or "comprising" in relation to an element or elements is intended to provide support for a similar aspect or aspect of the invention that "consists of", "essentially consists of", or "essentially includes" that particular element or elements, unless otherwise indicated or unless clearly contradicted by context (e.g., a disclosure of a composition described in this application containing a particular element should be understood as also describing a composition consisting of that element, unless otherwise indicated or unless clearly contradicted by context).

In the context of the present application, the term "room temperature" refers to a temperature range from about 15°C to about 25°C.

The use of singular and plural terms and similar designations in the context of the description of the invention, unless otherwise indicated or clearly contradicted by the context, shall be construed as covering both the singular and the plural. For example, the phrase "compound", unless otherwise indicated, shall be understood as referring to various "compounds" of the invention or a particular aspect described.

In this context, the term "purity" refers to the percentage of area corresponding to the product, as determined by a chromatographic method such as HPLC-MS or quantitative ¹ H NMR (where measurements are made relative to an internal reference standard).

In this context, the term "conversion" refers to the degree of conversion of the substrate in a given reaction.

As used herein, the term "pharmaceutical composition" means a formulation comprising 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 dosage form. The unit dosage form is any of a variety of forms including, for example, a capsule, an intravenous infusion bag, a tablet, a single-action pump on an aerosol inhaler, or a vial. The amount of the active component (e.g., a formulation of the disclosed compound or a salt, hydrate, solvate, or isomer thereof) in a single dose of the composition is an effective amount and varies according to the particular method of treatment in which the composition is used. One skilled in the art will recognize that routine variations in dosage may sometimes be necessary depending on the age and condition of the patient. In addition, the dosage will depend on the route of administration. The invention contemplates a variety of routes of administration, 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 compound 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 pharmaceutically acceptable carrier, and with any necessary preservatives, buffers, or propellants.

In the context of this application, the term "pharmaceutically acceptable" refers to those compounds, anions, cations, substances, compositions, carriers and/or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic reaction or other problems or complications commensurate with a reasonable benefit/risk ratio.

In the context of this application, the term "pharmaceutically acceptable excipient" means an excipient that is suitable for the preparation of a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as for pharmaceutical use in humans. "Pharmaceutically acceptable excipient" in the context of the description and claims includes both one and more than one such excipient.

In the context of this application, the term "subject" is interchangeable with the term "subject in need thereof", both of which refer to a subject having a disease or having an increased risk of developing a disease. "Subject" includes a mammal. A 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 also be a wild or domestic bird. In one embodiment, the mammal is a human. A subject in need thereof may be a subject who has previously been diagnosed with or identified as having an imprinting disorder. A subject in need thereof may also be a subject who has (e.g., suffers from) an imprinting disorder. Alternatively, a subject in need thereof may be a subject who has an increased risk of developing such a disorder compared to the general population (i.e., a subject who is predisposed to developing such a disorder compared to the general population). A subject in need thereof may have a refractory or resistant imprinting disorder (i.e., an imprinting disorder that does not or has not yet responded to treatment). The subject may be resistant at the start of treatment or may become resistant during treatment.

In the context of this application, the expressions "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", etc. are used interchangeably and all refer to a selection from the group consisting of A, B and/or C, i.e. one or more As, one or more Bs, one or more Cs, or any combination thereof, unless otherwise indicated.

All publications and patent documents cited in this application are herein incorporated by reference as if each such publication or document were specifically and individually indicated to be incorporated by reference. The citation of publications and patent documents is not intended to be an admission that they are prior art, nor does it constitute any admission of identical content or information. Now that the invention has been described in written form, those skilled in the art will recognize that the invention may be practiced in various ways and that the foregoing description and the following examples are intended to illustrate and not to limit the claims that follow.

Methods for obtaining Compound IX

The inventors of the present invention have discovered a new and efficient method for preparing Compound IX:

which includes one or more of the following stages:

(i) reaction of Compound I:

with Compound II:

in the presence of a palladium catalyst and a base to form Compound III:

(ii) reaction of Compound III with a chlorinating reagent to form Compound IV:

(iii) reduction of Compound IV by catalytic hydrogenation to form Compound V or a salt thereof

(iv) reaction of Compound V or its salt with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride (Compound VI) to form Compound VII:

And

(v) reaction of Compound VII with a methylating reagent (e.g., Compound VIII (e.g., _CH3Cl , _CH3Br , or _CH3I )) to form Compound IX.

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

In some embodiments, the method includes step (ii).

In some embodiments, the method includes step (iii).

In some embodiments, the method includes step (iv).

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

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

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

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

In some embodiments, the method comprises steps (i)-(v).

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

Scheme A,

where X is a halogen selected from chlorine, bromine or iodine.

In some embodiments, Compound IX, compared to known processes (e.g., the processes described in WO 2005/002577 and U.S. 2002/0022624), is formed in comparable or higher yield and with a high degree of purity.

It should be appreciated that the method disclosed in the present application provides, among other advantages, a Suzuki aryl coupling with commercially available Compound I, wherein the activated group for the aryl coupling (e.g., Cl) is already present in Compound I, thereby eliminating the need to carry out the iodination reaction according to the previously disclosed methods.

Stage (i)

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

In some embodiments, the palladium catalyst is a palladium(0) complex, such as tetrakis(triphenylphosphine)palladium.

In some embodiments, in step (i), the molar ratio between the palladium catalyst (e.g., palladium(0) complex) and Compound I is in the range of 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 tert-butoxide or potassium tert-butoxide.

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

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

Suitable solvents include a cyclic ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, or 1,4-dioxane), toluene, dimethylformamide, NMP, acetonitrile, or any mixture thereof.

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

In some embodiments, step (i) is carried out at a temperature in the range of from about 20°C to about 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 in the range of about 88°C to about 100°C.

Stage (ii)

In some embodiments, the chlorinating agent is _POCl3 .

In some embodiments, step (ii) is carried out 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 (e.g., tetrahydrofuran), a halohydrocarbon (e.g., dichloromethane), N,N-dimethylformamide, or dimethoxyethane, or any mixture thereof.

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

In some embodiments, step (ii) is carried out at a temperature in the range of from about 20°C to about 75°C.

Stage (iii)

Suitable hydrogenation catalysts include palladium or platinum on carbon.

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

In some embodiments, in step (iii), the weight ratio between the hydrogenation catalyst and Compound IV is in the range of from about 0.05 to about 0.5 (e.g., from about 0.2 to about 0.3).

In some embodiments, step (iii) is carried out 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 thereof.

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

In some embodiments, step (iii) is performed at about room temperature.

In some embodiments, in step (iii), Compound V is isolated.

The inventors have discovered a very convenient method for isolating Compound (V) with good purity and yield directly from the reaction mixture by reacting (V) with an acid, resulting in the formation of a salt of Compound (V).

Suitable salts of Compound V include the salt of maleic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, fumaric acid, salicylic acid, sulfuric acid, citric acid, lactic acid, mandelic acid, tartaric acid or methanesulfonic acid.

In some embodiments, in step (iii), the hydrochloride salt of Compound V is isolated.

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

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

In some embodiments, in step (iii), the acid is a 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 (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 water.

In some embodiments, in step (iii), the hydrochloride salt of Compound V is prepared 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 prepared by adding hydrogen chloride in 1,4-dioxane to the reaction mixture.

Stage (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).

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

In some embodiments, step (iv) is carried out at a temperature in the range of about 0°C to about 5°C.

In some embodiments, in step (iv), Compound VI is added to a mixture of Compound V or a pharmaceutically acceptable salt thereof and an organic base in a solvent.

In some embodiments, in step (iv), Compound V, Compound VI and the organic base are mixed in a solvent simultaneously.

In some embodiments, in step (iv), Compound VII is formed in high purity and is used in the next step without any further purification.

In some embodiments, in step (iv), Compound VI is added to a mixture of a pharmaceutically 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).

Stage (v)

In some embodiments, Compound VIII is _CH3Cl , _CH3Br , or _CH3I .

In some embodiments, in step (v), the methylating reagent is dimethyl sulfate.

In some embodiments, 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 tert-butoxide, or potassium tert-butoxide).

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

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

Methods for obtaining Compound A

In some aspects, the present invention provides a method for producing Compound A, which comprises one or more of the following steps:

(vi) reacting Compound IX obtained by the process disclosed herein with Compound X or a pharmaceutically acceptable salt thereof to form Compound XI or a pharmaceutically acceptable salt thereof;

(vii) reacting Compound XI or a pharmaceutically acceptable salt thereof to form a pharmaceutically acceptable salt and/or solvate of Compound A;

(viii) reacting a pharmaceutically acceptable salt and/or solvate of Compound A to form Compound A (e.g., Form 1).

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

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

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

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

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

In some aspects, the present invention provides a method for producing Compound A comprising one or more of steps (i)-(viii).

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

In some embodiments, the method includes step (ii).

In some embodiments, the method includes step (iii).

In some embodiments, the method includes step (iv).

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

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

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

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

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

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

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

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

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

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

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

In some aspects, the present invention provides the use of Compound III, Compound IV, Compound V, Compound VII, or pharmaceutically acceptable salts thereof for the manufacture of Compound A.

In some aspects, the present invention provides the use of Compound IX, prepared by the process disclosed herein, for the manufacture of Compound A.

In some aspects, the present invention provides Compound A prepared by the method disclosed herein.

In some embodiments, the method includes one or more of the steps shown in Scheme B.

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

Obtained Intermediates and Compounds

In some aspects, the present invention provides an intermediate compound that is selected from Compound I, Compound III, Compound IV, Compound VII or salts thereof, and a salt of Compound V.

In some embodiments, the intermediate compound is prepared by a method described herein.

In some embodiments, the intermediate compound is Compound III or a salt thereof.

In some embodiments, the intermediate compound is Compound III.

In some embodiments, the intermediate compound is Compound IV or a salt thereof.

In some embodiments, the intermediate compound 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 hydrochloride.

In some embodiments, the intermediate compound is Compound VII or a pharmaceutically acceptable salt thereof.

In some embodiments, the intermediate compound is Compound VII.

In some aspects, the present invention provides Compound IX prepared by the method disclosed herein.

In some aspects, the present invention provides Compound A prepared by the method disclosed herein.

Pharmaceutical compositions

In some aspects, the present invention provides a pharmaceutical composition comprising Compound A prepared by the process disclosed herein and one or more pharmaceutically acceptable excipients, carriers and/or diluents.

Pharmaceutical compositions containing Compound A are disclosed in WO 2016/184829, WO 2011/023733 and WO 2007/028654 and International Patent Application Publication WO 2019/175253.

It should be understood that pharmaceutical compositions may be included in a container, package or dispenser together with instructions for use.

Application of the obtained Compound A

In some aspects, the present invention provides a method of treating or preventing a disease associated with sex hormones, which comprises administering to a subject in need thereof Compound A obtained by the method disclosed herein, or a pharmaceutical composition thereof.

In some aspects, the present invention provides Compound A, obtained by the process disclosed herein, or a pharmaceutical composition thereof, for use in the treatment or prevention of a sex hormone-related disease in a subject in need thereof.

In some aspects, the present invention provides the use of Compound A obtained by the process disclosed herein for the manufacture of a medicament for use in the treatment or prevention of a sex hormone-related disease in a subject in need thereof.

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

In some embodiments, the subject in need thereof is a male.

In some embodiments, the subject in need thereof is a woman.

In some embodiments, the sex hormone-related disorder is endometriosis, puberty disorders, uterine fibroids, uterine fibroids, heavy menstrual bleeding, dysfunctional uterine bleeding, hormone-dependent malignancies (e.g., breast, endometrial, ovarian, or uterine cancer), hot flashes, hyperandrogenism, hirsutism, hypertrichosis, female androgenetic alopecia, androgen-dependent acne, seborrhea, virilization, polycystic ovary syndrome (PCOS), premenstrual dysphoric disorder (PMDD), HAIR-AN syndrome (hyperandrogenism, insulin resistance, and papillary pigmentary dystrophy), ovarian hyperthecosis (HAIR-AN with hyperplasia of luteinized thecal cells in the ovarian stroma), other manifestations of high concentrations of intraovarian androgens (eg, follicular maturation arrest, atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding, infertility) and androgen-producing tumor (virilizing tumor of the ovary or adrenal gland) or osteoporosis.

In some embodiments, the disorder associated with sex hormones is hidradenitis suppurativa or hot flashes. In some aspects, the present invention provides a method of treating or preventing a condition that includes administering to a subject in need thereof Compound A prepared by the method disclosed herein or a pharmaceutical composition thereof.

In some aspects, the present invention provides Compound A prepared by the process disclosed herein, or a pharmaceutical composition thereof, for use in the treatment or prevention of a condition in a subject in need thereof.

In some aspects, the present invention provides the use of Compound A obtained by the process disclosed herein for the manufacture of a medicament for use in the treatment or prevention of a sex hormone-related condition in a subject in need thereof.

In some embodiments, the condition is a symptom of perimenopause, menopause, or postmenopause selected from abnormal increase in excess body fat and/or excess body weight, diabetes, excessive fatigue, irritability, cognitive decline, hair loss, dry skin, insomnia, sleep disturbances and night awakenings, anxiety and depression, decreased libido, vaginal dryness and pain, loss of connective tissue and decreased muscle mass, loss of bone tissue, urinary symptoms - urgency and dysuria, hot flashes and night sweats.

In some embodiments, the 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, cyclofenil, tamoxifen, ormeloxifene, toremifene, raloxifene, lasofoxifene, and ospemifene; selective estrogen receptor disruptors (SERDs) such as fulvestrant, brilanestrant, and elacestrant; CYP17A1 inhibitors such as abiraterone, ketoconazole, and seviteronel; and combination androgen receptor blockers and CYP17A1 inhibitors such as galeterone.

In some embodiments, the symptom associated with andropause is selected from pathological increase in excess body fat and/or excess body weight, diabetes, excessive fatigue, irritability, decreased cognitive function, hair loss, dry skin, insomnia, sleep disturbances, nocturnal awakenings, anxiety and depression, decreased libido, loss of connective tissue and decreased muscle mass, urinary symptoms - urgency and dysuria, hot flashes and night sweats.

In some embodiments, the symptom associated with andropause may be caused by certain androgen deprivation therapies, such as 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 combined androgen receptor blockers and CYP17A1 inhibitors such as galeterone.

In some embodiments, the disease is a "leptin-related disease" selected from metabolic disorders such as diabetes, cardiovascular disease, obesity, overnutrition, hypertension, metabolic syndrome, and inflammatory disorders.

In some embodiments, the disease is a "weight-related disease" selected from a genetic predisposition to being overweight, obesity associated with metabolic disorders, or a condition in which weight loss can have a therapeutic effect.

In some embodiments, the disease is a "pregnancy disorder" selected from eclampsia, preeclampsia, gestational diabetes, high blood pressure, morning sickness and vomiting of pregnancy, hyperemesis gravidarum, miscarriage, pelvic girdle pain, and preterm labor.

All references, including publications, patent applications and patents, cited in this application are hereby incorporated by reference in their entirety and to the same extent as if each referenced document were individually and specifically indicated to be incorporated by reference and set forth in its entirety in this application (to the maximum extent permitted by law), notwithstanding any separately provided incorporation of specific documents made elsewhere herein.

It should be understood that the various aspects, embodiments, implementations and features of the disclosure mentioned in this application may be claimed individually or in any combination.

Embodiments according to the invention

Embodiments of the present invention are disclosed below. The first embodiment is designated E1, the second embodiment is designated E2, etc.

E1 Method for obtaining Compound IX:

which includes the following stage:

i) reaction of 4-chloro-5-nitropyridin-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 give 4-(4-fluoro-2-methylphenyl)-5-nitropyridin-2(1H)-one of structure (III):

E2 The method according to embodiment 1, wherein said 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 complex of palladium, preferably tetrakis(triphenylphosphine)palladium.

E3 The method according to any one of embodiments 1-2, wherein the ratio between said palladium complex and Compound I is in the range of about 0.05 to 0.10.

E4 The method according to any one of embodiments 1-3, wherein said base is selected from potassium carbonate, cesium carbonate, triethylamine, potassium phosphate, sodium tert-butoxide, potassium tert-butoxide or a mixture thereof, preferably potassium carbonate.

E5 The method according to any of embodiments 1-4, 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.

E6 The process according to any of embodiments 1-5, 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.

E7 The method according to any one of embodiments 1 to 6, wherein step i) comprises reacting 4-chloro-5-nitropyridin-2(1H)-one (Compound I) with 4-fluoro-2-methylphenylboronic acid (Compound II) to produce 4-(4-fluoro-2-methylphenyl)-5-nitropyridin-2(1H)-one (Compound III), catalyzed by tetrakis(triphenylphosphine)palladium(0) in the presence of potassium carbonate, wherein step I) is carried out in a solvent containing 1,4-dioxane and at a temperature of from 88 to 100°C.

E8 The method according to any one of embodiments 1-7, wherein step i) is followed by

ii) reaction of 4-(4-fluoro-2-methylphenyl)-5-nitropyridin-2(1H)-one (Compound III), obtained in step i), with POCl ₃ to give 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine (Compound IV).

E9 A process for the preparation of Compound IX, which comprises the following step: ii) reacting 4-(4-fluoro-2-methylphenyl)-5-nitropyridin-2(1H)-one (Compound III), obtained in step i), with POCl ₃ to obtain 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine (Compound IV).

E10 A process for the preparation of Compound IX, which comprises the following step: ii) reacting 4-(4-fluoro-2-methylphenyl)-5-nitropyridin-2(1H)-one (Compound III) with _POCl3 to give 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine (Compound IV).

E11 The process 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.

E12 The method according to any one of embodiments 8-11, wherein step ii) is carried out at a temperature in the range from 20° to 75°C.

E13 The method according to any of embodiments 8 to 12, wherein step ii) is followed by step iii) comprising 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 salts thereof.

E14 A process for preparing Compound IX, which comprises 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 its salts.

E15 A process for preparing Compound IX which comprises the following step: iii) 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)pyridin-3-amine (Compound V) or its salts.

E16 The process according to any one of embodiments 13-15, wherein said catalytic hydrogenation is carried out in the presence of catalysts selected from palladium or platinum on carbon, preferably platinum on carbon.

E17 The method according to any one of embodiments 13-16, wherein the platinum is present in an amount of from 0.05 to 0.5 mass, relative to Compound IV; preferably from 0.2 to 0.3 mass, relative to Compound IV.

E18 The process according to any of embodiments 13-17, wherein step (iii) is carried out in alcohols, ethers, esters, hydrocarbons or mixtures thereof, preferably in esters, and even more preferably in ethyl acetate.

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

E20 The method according to any one 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 method according to any one of embodiments 13-20, wherein a solution of Compound V is reacted with gaseous hydrogen chloride in aqueous solution or in dioxane, followed by treatment with acetonitrile to obtain Compound V as a hydrochloride salt.

E22 The method according to any one of embodiments 13 to 21, wherein step iii) is carried out followed by 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-methylpropanamide of formula (Compound VII).

E23 A process for the preparation of intermediate compound (IX), which comprises the following step: iv) reaction of 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-methylpropanamide of formula (Compound VII).

E24 A process for the preparation of intermediate compound (IX), which comprises the following step: iv) reaction of 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-methylpropanamide of formula (Compound VII).

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

E26 The method according to any one of embodiments 22-25, 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.

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

E28 The process according to any of embodiments 22 to 27, wherein step iv) is carried out followed by step v): reacting 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methylpropanamide (Compound VII), obtained in 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) reacting 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methylpropanamide (Compound VII) obtained in 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)pyridin-3-yl)-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) reacting 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-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)pyridin-3-yl)-N,2-dimethylpropanamide of formula (IX); wherein X is a halogen selected from chlorine, bromine or iodine.

E31 The method according to any of embodiments 28-30, wherein step v) is carried out in organic bases 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, potassium tert-butoxide or a mixture thereof.

E32 The method according to any of embodiments 28-31, wherein step v) is carried out in a solvent selected from DMF, acetonitrile or ethers.

E33 A process for the production of Compound IX, which comprises:

performing step i) according to any one of embodiments 1-7, followed by

performing step ii) according to any one of embodiments 8-12, followed by

performing step iii) according to any one of embodiments 13-21, followed by

performing step iv) according to any one of embodiments 22-27, followed by

performing step v) according to any one of embodiments 28-32.

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

E33 Use of Compound IX obtained by the method according to any one of embodiments 1-33 for the production of Compound A.

E36 Compound A obtained from Compound IX, wherein said Compound IX is obtained according to the method of any one of embodiments 1-33.

E37 A pharmaceutical composition comprising Compound A obtained from Compound IX, wherein said Compound IX is obtained according to the method of any one of embodiments 1-33.

E38 Compound A obtained from Compound IX, wherein said Compound IX is obtained according to the method of any embodiment 1-33, for use in the treatment of a disease associated with sex hormones or for 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 obtained according to the method of any one of embodiments 1-33, for use in the treatment of a sex hormone-related disease selected from 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 obtained according to the method of any one of embodiments 1-33, for use in the treatment of a condition or symptom associated with perimenopause, menopause or postmenopause, selected from pathological increase in excess body fat and/or excess body weight, diabetes, excessive fatigue, irritability, decreased cognitive function, hair loss, dry skin, insomnia, sleep disorders and night awakenings, anxiety and depression, decreased libido, vaginal dryness and pain, loss of connective tissue and decreased muscle mass, loss of bone tissue, urinary tract symptoms - urgency and dysuria, hot flashes and night sweats.

E41 Compound A obtained from Compound IX, wherein said Compound IX is obtained according to the process of any one of embodiments 1 to 33, for use in the treatment of a condition or symptom associated with menopause induced by certain chemotherapy therapies, 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, cyclofenil, 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 combination androgen receptor blockers and CYP17A1 inhibitors such as galeterone.

E42 Compound A obtained from Compound IX, wherein said Compound IX is obtained according to the method of any one of embodiments 1-33, 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, excessive fatigue, irritability, decreased cognitive function, hair loss, dry skin, insomnia, sleep disorders and night awakenings, anxiety and depression, decreased libido, loss of connective tissue and decreased muscle mass, urinary symptoms - urgency and dysuria, hot flashes and night sweats.

E43 Compound A prepared from Compound IX, wherein said Compound IX is prepared according to the process of any one of embodiments 1 to 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 combination androgen receptor blockers and CYP17A1 inhibitors such as galeterone.

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

E45 Compound A obtained from Compound IX, wherein said Compound IX is obtained according to the method of any one of embodiments 1-33, for use in the treatment of a "disease associated with excess body weight" selected from a genetic predisposition to excess body weight, obesity associated with metabolic disorders, or a condition in which weight loss can have a therapeutic effect.

E46 Compound A obtained from Compound IX, wherein said Compound IX is obtained according to the method of any one 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 and vomiting of pregnancy, hyperemesis gravidarum, miscarriage, pelvic girdle pain and preterm labor.

E47 A pharmaceutical composition comprising Compound A obtained from intermediate (IX), wherein said Compound IX is obtained according to the method of any embodiment 1-33, for use in the treatment of a disease associated with sex hormones or for 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 obtained according to the method of any embodiment 1-33, for use in the treatment of a disease associated with sex hormones.

E49 A pharmaceutical composition comprising Compound A obtained from Compound IX, wherein said Compound IX is obtained according to the method of any embodiment 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 obtained according to the method of any one of embodiments 1-33, for use in the treatment of a disease associated with sex hormones selected from 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 obtained according to the method of any of embodiments 1-33, and one or more pharmaceutically acceptable excipients, carriers and/or diluents.

E52 Compound III.

E53 Compound IV.

E54 Salts Compounds V.

E55 Compound VII.

E56 Use of a Compound of formula (III), (IV), (V) or (VII) for the preparation of Compound A.

Examples

The invention is illustrated by the following non-limiting examples. The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way.

In the procedures below, a reference to the description is usually given after each starting material. This is provided only as an aid to the skilled chemist. The starting material may not necessarily be obtained from the reaction mixture indicated.

In the context of the present application, the symbols and conventions used in the methods, diagrams and examples provided are consistent with those used in contemporary scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry.

In particular, the following abbreviations may be used in the examples and throughout the description text:

Unless otherwise stated, all temperatures are expressed in °C (degrees Celsius). All reactions, unless otherwise stated, were carried out under an inert atmosphere at room temperature.

In Examples, unless otherwise noted:

1H-qNMR

Quantitative NMR analysis was performed according to standard ¹ H NMR but using an internal standard to allow quantification of the product.

HPLC

Purity was determined using reversed-phase HPLC. The stationary phase C18 was used with an acidified aqueous mobile phase with an organic modifier - acetonitrile. Elution was carried out in a gradient mode.

Example 1

Preparation of 4-(4-fluoro-2-methylphenyl)-5-nitropyridin-2(1H)-one (Compound III)

A three-necked flask connected to a condenser and a 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, e.g., from Sigma Aldrich), potassium carbonate (92.6 g, 670 mmol), and 1,4-dioxane (480 mL). After evacuation and backfilling with nitrogen three times, tetrakis(triphenylphosphine)palladium(0) (12.9 g, 11.2 mmol) was added under nitrogen flow and the resulting mixture was stirred at moderate reflux (internal temperature 99 °C) for 18 h. 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 give the title compound as a dark yellow solid (78.0 g, 314 mmol, 141% yield w/w) with a purity of 60% according to ¹ H-qNMR. The compound was used in the next step without further purification. ¹ H NMR (d-DMSO) δ/ ppm 8.88 (s, 1H), 6.96~7.06 (m, 3H), .44 (s, 1 H), 2.03 (s, 3H, -CH ₃ ).

Example 2

Preparation of 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine (Compound IV)

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-necked flask under nitrogen. POCl ₃ (0.10 kg, 61 mL, 0.65 mol) was added dropwise (slightly exothermic reaction, temperature rose to 40 °C) followed by addition of 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 reaction, mixture was cooled in ice-water bath). The mixture was adjusted to neutral pH _with solid _Na2CO3 , 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 afford the title compound as _a brown solid (46.2 g, 173 mmol, 91% w/w yield) with 86% purity (HPLC). ¹ H NMR ( _CDCl3 ) δ/ ppm 9.05 (s, 1H), 7.34 (s, 1H), 6.97~7.08 (m, 3H), 2.13 (s, 3H, _-CH3 ).

Example 3

Preparation of 6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine hydrochloride (Compound V)

A Parr hydrogenation flask was charged with platinum on carbon (5.4 g, 5% w/w, 1.4 mmol). EtOAc (400 mL) was added under N ₂ flow 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 stirred with a mechanical stirrer at room temperature under 3 bar hydrogen pressure. After 48 h, additional platinum on carbon (2.7 g, 5% w/w, 0.7 mmol) was added because HPLC-MS showed no further reaction. The mixture was stirred under 3 bar H ₂ for 96 h, after which time HPLC-MS showed no progress in the conversion. Additional platinum on carbon (2.7 g, 5% w/w, 0.7 mmol) was added and the reaction mixture was stirred under 3.5 bar _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. 4 N 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 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% yield w/w) with a purity of 95.7% (HPLC). ¹ H NMR (d-DMSO) δ ppm 9.95 (s, 2H, -NH ₂ ), 8.54 (s, 1H), 7.23~7.43 (m, 3H), 7.13 (s, 1H), 2.15 (s, 3H, -CH ₃ ).

Example 4

Preparation of 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methylpropanamide (Compound VII)

Getting 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 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 solids (34.5 g, 106 mmol, 110% w/w yield). This material was used directly in the next step.

Example 3 (6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine hydrochloride (Compound V)) (27.0 g, 97.9 mmol) was added portionwise (mildly exothermic reaction) to a three-necked flask containing pyridine (139 g, 0.14 L, 1.76 mol) at 0 °C and under N ₂ . 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 layer was collected, washed with water and brine, dried over _Na2SO4 , filtered and concentrated in vacuo to give the title product as an orange oil that solidified on standing (52.5 g, 100 mmol, 102% _w /w yield), 93% pure (HPLC). The compound was used in the next step without further purification.

Getting 2

2-(3,5-Bis(trifluoromethyl)phenyl)-2-methylpropanoic acid (15.3 kg) and DCM (11.0 L/kg 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoic acid) were charged. After cooling to -5/5 °C, DMF (0.01 L/kg 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoic acid) was charged and oxalyl chloride (1.02 mol/mol) was added maintaining the temperature below 10 °C. The addition vessel was rinsed with DCM (1.0 L/kg 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 completion of the reaction, the reaction mixture was concentrated to a volume of 2.0 L/kg 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoic acid. Then DCM (2.0 L/kg 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoic acid) was added and a solution of 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride stored under N ₂ was used in the next step.

Example 3 (6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine hydrochloride (Compound V)) (11.9 kg) and DCM (2.7 L/kg Example 3) were charged. After cooling to -5/5 °C, pyridine (3.00 mol/mol Example 3) was added maintaining the temperature below 10 °C. Then a solution of 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride in DCM was added maintaining the temperature below 10 °C. The addition vessel was rinsed with DCM (0.3 L/kg Example 3). The reaction mixture was warmed to 20/25 °C and stirred for at least 18 h.

After completion of the reaction, the reaction mixture was cooled to 10°C and water (8.0 L/kg of Example 3 compound) 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 re-extracted with DCM (4.0 L/kg of Example 3 compound).

The combined organic layers were washed with water (2 × 5.0 L/kg of Example 3 compound) and concentrated in vacuo to a volume of 2.7 L/kg of Example 3 compound. Heptane (8.5 L/kg of Example 3 compound) was then added while maintaining the temperature at 35-45°C, and 2-(3,5-bis(trifluoromethyl)phenyl)-T-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methylpropanamide (0.005 w/w relative to Example 3 compound) was loaded as a seed.

The seed mixture was held for at least 1 h at 40°C and the resulting slurry was concentrated in vacuo to a volume of 10.0 L/kg of Example 3 compound. Additional heptane (2.0 L/kg of Example 3 compound) was added at 35/45°C. The slurry was cooled to 10/20°C over at least 2 h and held at 10/20°C for at least 2 h before proceeding to the centrifugation step.

The suspension was centrifuged and the sediment layer was washed with heptane (2.0 L/kg of Example 3 compound).

The wet product was dried in vacuo at a temperature not exceeding 45°C to give 19.9 kg of the title compound (yield=88.1%) with a purity of 99.87% as an off-white solid.

¹ H NMR (DMSO-d ₆ ): δ 8.99 (s, 1H), 8.36 (s, 1H), 7.98 (s, 1H), 7.74 (s, 2H), 7.43 (s, 1H), 7.00-6.95 (m, 2H), 6.90-6.85 (m, 1H), 1.98 (s, 3H), 1.44 (s, 6H).

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)

Getting 1

A three-necked flask connected to a nitrogen line was charged with the compound of 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, and methyl iodide (14 g, 6.3 mL, 0.10 mol) was added dropwise over 5 min. The resulting 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 Na ₂ SO ₄ , and filtered. The solvent was evaporated in vacuo, 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 pale brown solid was collected and dried in vacuo. The brown colour was removed by dissolving the product in EtOAc (200 mL) and filtering through a short pad of silica gel. 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 a purity of 96.7% (HPLC).

Getting 2

The compound of 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 _charged . 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 completion of the reaction, the reaction mixture was cooled to 10°C and water (12.0 L/kg of Example 4 compound) and ethyl acetate (12.0 L/kg of Example 4 compound) were added, maintaining the temperature below 20°C. After stirring for an additional 15 min 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 compound).

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

The suspension was centrifuged and the sediment layer was washed with heptane (2.0 L/kg of Example 4 compound).

The wet product was dried in vacuo at a temperature not exceeding 45°C to afford 14.2 kg of the title compound as a white solid (yield=69.4%) with a purity of 99.99%. ¹ H NMR (DMSO- _d6 ): 5 8.32 (s, 1H), 8.03 (s, 1H), 7.74 (brough s, 2H), 7.55 (s, 1H), 7.30-7.00 (brough +d, 3H), 2.90-2.40 (brough m, 3H), 2.15 (brough m, 3H), 1.70-1.20 (brough m, 6H).

Example 6

Method of obtaining N-(6-((7S.9aS)-7-((benzyloxy)methyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-4-( 4-fluoro-2-methylphenyl)pyridin-3-yl)-2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamide (Compound XI)

Getting 1

In a three-necked flask connected to a thermometer, condenser and nitrogen line was charged the compound of 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 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 through celite. The filtrate was collected, transferred to a separatory funnel, washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel to give the title compound as a brownish solid (610 mg, 0.8 mmol, yield 67% w/w).

Getting 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 of Example 5 from Preparation 2), toluene (20.0 L/kg of Example 5), and 1 N NaOH (20.0 L/kg of Example 5) were charged. 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 a volume of 8.0 L/kg Example 5 compound under vacuum, toluene (4.0 L/kg Example 5 compound) was added, and distilled again under vacuum to a volume of 8.0 L/kg Example 5 compound. A sample was collected for Karl Fischer titration (KF). If the KF met the requirements, additional toluene (8.0 L/kg Example 5 compound) was added. If not, toluene was added again (4.0 L/kg Example 5 compound) and the distillation step to a volume of 8.0 L/kg Example 5 compound was repeated.

Into another reactor were charged the compound of 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-tert-butylphosphine) (0.10 mol/mol of Example 5). A solution of (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazino[2,1-c][1,4]oxazine free base in toluene was charged and the transfer line was flushed with toluene (2.0 L/kg of Example 5). The reaction mixture was heated to 85°C and stirred for at least 4 h before sampling to determine the completion of the conversion.

The reaction mixture was cooled to 25 °C and charged with 20 wt % _NaHSO3 solution (8.7 L/kg of the compound of Example 5). The mixture was heated to 60 °C for at least 1 h and cooled again to 25 °C. After filtering the reaction mixture through K100 paper and washing the filter and transfer line with toluene (1.0 L/kg of the compound of Example 5), the layers were settled for at least 30 min at 25 °C and the lower aqueous layer was discarded. Through the organic layer, 5 wt % L-cysteine solution (10.0 kg/kg of the compound of Example 5) was charged. The mixture was heated to 60 °C for at least 1 h and cooled again to 25 °C. After filtering the reaction mixture through K100 paper and washing the filter and transfer line with toluene (1.0 L/kg of the compound of Example 5), 10 wt % HCl was added. % NaCl solution, the layers were stirred for at least 15 min and settled for at least 30 min at 25°C. Finally, the lower aqueous layer was discarded. 5 wt. % L-cysteine solution (10.0 kg/kg of the compound of Example 5) was loaded through the organic layer. The mixture was heated to 60°C for at least 1 h and cooled again to 25°C. After filtering the reaction mixture through K100 paper and washing the filter and the transfer line with toluene (1.0 l/kg of the compound of Example 5), 10 wt. % NaCl solution was added, the layers were stirred for at least 15 min and settled for at least 30 min at 25°C. Finally, the lower aqueous layer was discarded. The organic layer was washed with 5 wt. % _NaHCO3 solution and twice with 2 wt. % NaCl solution.

The resulting organic layer was concentrated to a volume of 4.0 L/kg of Example 5 under vacuum. Toluene (7.0 L/kg of Example 5) was charged and solution samples were collected for KF analysis.

After heating the reaction mixture to 40°C, 4 M HCl in dioxane (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 kept at 40°C for at least 30 min and concentrated to a volume of 10.0 L/kg of Example 5 in vacuo. Toluene (9.0 L/kg of Example 5) was charged and distilled again to a volume of 10.0 L/kg of Example 5. This last operation was repeated one more time and samples of the resulting solution were collected for gas chromatographic analysis.

The temperature of the reaction mixture was brought to 25°C and n-heptane (7.0 L/kg of Example 5 compound) was added, maintaining the internal temperature at 20/30°C. The suspension was maintained at 20/30°C for at least 4 h before proceeding to the centrifugation step.

The suspension was centrifuged and the sediment layer was washed with n-heptane (4.0 L/kg of Example 5 compound).

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

NMR spectrometer: Varian Agilent Mercury Vx 400 (16 scans, 6400 Hz, 25°C.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.66 (bd, 1H), 8.02 (s, 1H), 7.95 (s, 1H), 7.74 (bd, 2H), 7.36-6.93 (m, 8H), 6.83 (s, 1H), 4.97 (bd, 1H), 4.62 (m, 1H), 4.50 (d, 11.8 Hz, 1H), 4.44-4.10 (m, 7H), 4.08-3.69 (m, 3H), 3.60 (d, 12.8 Hz, 1H), 3.45 (d, 11.8 Hz, 1H), 3.30 (d, 9.7 Hz, 1H), 3.19 (t, 10.7 Hz, 1H), 3.05 (m, 1H), 2.30-1.90 (m, 4H), 1.57-1.12 (m, 6H).

Example 7

Monoisopropanol solvate of the salt - dihydrochloride 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 (Compound XII)

The compound of 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), 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 charged into a hydrogenation autoclave. 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) was weighed in isopropanol (20.4 L/kg of Example 6), loaded into the hydrogenation autoclave and rinsed with additional isopropanol (8.9 L/kg of Example 6). Hydrogenation conditions were created (2.00 barg, 50°C) and held until hydrogen consumption was complete.

After completion of the reaction, the reaction mixture was filtered through a Veladisc® filter holder equipped with a SUPRAdisc™ cartridge and washed with a mixture of isopropanol (9.0 L/kg of Example 6 compound) and water (1.0 L/kg of Example 6 compound).

The filtrate was concentrated in vacuo to a volume of 3.5 L/kg of Example 6 compound. Isopropanol (10.0 L/kg of Example 6 compound) was added and distilled again to a volume of 3.5 L/kg of Example 6 compound. Isopropanol (10.0 L/kg of Example 6 compound) was added and distilled again to a volume of 3.5 L/kg of Example 6 compound. Isopropanol (8.5 L/kg of Example 6 compound) was added and a sample was collected for KF analysis.

If the KF analysis was satisfactory, 4 M HCl in dioxane (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 reaction mixture was then cooled to 25°C over at least 60 min and isooctane (5.0 L/kg of Example 6) was added at 20/30°C over at least 30 min. The slurry was maintained at 25°C for at least 5 h before proceeding to the centrifugation step.

The suspension was centrifuged and the sediment layer was washed with a mixture of isopropanol (2.0 L/kg of the compound of Example 6) and isooctane (2.0 L/kg of the compound of Example 6).

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

NMR spectrometer: Varian Agilent Mercury V × 400 (16 scans, w.s. 6400 Hz, 25°C.

¹ H NMR (400 MHz, DMSO-d ₆ ): 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,1 H), 4.20 (t, 12.2 Hz, 1H), 4.07-3.90 (m, 3H), 3.84 (m, 1H), 3.77 (hept, 6.1 Hz, 1H), 3.64 (d, 12.6 Hz, 1H), 3.43 (m, 2H), 3.28 (m, 1H), 3.16 (m, 2H), sa. 2.58 (bd, 2H), 2.41-2.00 (m, 5H), 1.60-1.10 (m, 6H), 1.03 (d, 6.1 Hz, 6H).

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 as anhydrous crystalline form (Compound A)

The compound of 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 salt monoisopropanol solvate (Compound XII)) (3.4 kg), methyl tert-butyl ether (hereinafter, MTBE) (15.0 L/kg of the compound of Example 7) and 2.5 N NaOH (4.9 L/kg of the compound of Example 7) were charged, the mixture was heated to 40 °C and stirred for 10 - 30 min. The layers were settled for at least 30 min at 40 °C and the lower aqueous layer was discarded.

An aqueous 9 wt.% L-cysteine solution (5.0 L water/kg compound of Example 7+0.5 w/w L-cysteine relative to the compound of Example 7) was added through the organic layer and stirred at 40°C for at least 60 min. The layers were settled for at least 30 min at 40°C and the lower aqueous layer was discarded.

Water (5.0 L/kg of Example 7 compound) was added through the organic layer and the mixture was 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 compound) was added through the organic layer and the mixture was 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 a volume of 2.5 L/kg of Example 7 compound. Isooctane (8.3 L/kg of Example 7 compound) was added at 50/55°C for at least 1 h, and the solution was distilled under light vacuum to a volume of 4.0 L/kg of Example 7 compound. A sample was taken to monitor the removal of water and MTBE.

Isopropanol (0.8 l/kg of Example 7 compound) was added and the mixture was stirred at 65/75°C until completely dissolved. The solution was cooled to 45/55°C and filtered to remove any foreign matter. Isooctane (4.5 l/kg of Example 7 compound) was added and the reaction mixture was heated to 70°C for at least 30 min. 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)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-3-pyridinyl}-N,2-dimethylpropanamide (0.008% w/w relative to the compound of Example 7) in isooctane (0.07 l/kg of the compound of Example 7) and isopropanol (0.01 l/kg of the compound of Example 7). The seeded solution was maintained at 50°C for at least 3 h and additional isooctane (4.2 L/kg of Example 7) was added over at least 3 h maintaining the temperature at 50/55°C. The slurry was maintained at 50°C for at least 8 h, cooled to 0°C over at least 5 h and maintained for at least 3 h before proceeding to the centrifugation step.

The suspension was centrifuged and the sediment layer was washed with isooctane (2 × 3.3 L/kg of Example 7 compound).

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

NMR spectrometer: Varian Agilent Mercury V × 400 (16 scans, w.s. 6400 Hz, 25°C).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.02 (s, 1H), 7.85 (s, 1H), 7.74 (bd, 2H), 7.22-6.92 (m, 3H), 6.61 (s, 1H), 4.70 (m, 1H), 4.21 (bd, 1H), 4.09 (bd, 1H), 3.75 (m, 3H), 3.55 (td, 11.3 Hz, 2.2 Hz, 1H), 3.40 (bd, 1H), 3.15 (t, 10.5 Hz, 1H), 3.02 (d, 11.3 Hz, 1H), 2.63 (d, 11.3 Hz, 1H), ca. 2.5 (bd, 2H), 2.31-2.00 (m, 7H), 1.58-1.10 (m, 6H).

Claims (10)

1. Method for obtaining intermediate compound (IX), including the following stages: the reaction of 6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine salt (compound V) with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride (compound VI) in dichloromethane in the presence of an organic base and at a temperature of 0-5°C to obtain 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methylpropanamide (compound VII) and reaction of compound (VII) with a methyl halide of formula _CH3X (compound VIII) in the presence of cesium carbonate to obtain compound (IX), where X is a halogen selected from chlorine, bromine or iodine. 2. The method according to claim 1, wherein the stage of reaction of compound (V) with compound (VI) is carried out in the presence of an organic base selected from pyridine, triethylamine, N,N-diisopropylethylamine, 2,6-lutidine or a mixture thereof. 3. The method according to claim 1 or 2, wherein the step of reaction of compound (VII) with compound (VIII) in the presence of cesium carbonate is carried out in an organic base selected from pyridine, triethylamine, N,N-diisopropylethylamine, 2,6-lutidine, or in an inorganic base selected from potassium carbonate, cesium carbonate, potassium phosphate, sodium tert -butoxide, potassium tert -butoxide or a mixture thereof. 4. The method according to any one of claims 1 to 3, wherein the step of reaction of compound (VII) with compound (VIII) in the presence of cesium carbonate is carried out in a solvent selected from DMF, acetonitrile or ethers. 5. Compound of formula (VII)