Patent Description:
<NUM>"-(tert-butyl)-<NUM>'-(<NUM>-hydroxyethoxy)-<NUM>"-(pyrrolidin-<NUM>-yl)-[<NUM>,<NUM>':<NUM>',<NUM>"-terphenyl]-<NUM>-carboxylic acid, commonly known as Trifarotene, is a topical retinoid that can selectively target retinoic acid receptor (RAR) gamma, the most common RAR found in the skin. Trifarotene is prescribed for treatment of acne vulgaris and was first approved in the United States in October <NUM>. Current synthetic routes for Trifarotene, e.g., described in <CIT>, include several challenging steps, e.g., performing a reaction at -<NUM> and using two separate protecting groups that must be hydrolyzed under different conditions, which can decrease workflow efficiency and overall yield.

The subject matter for which protection is sought is as defined by the claims. Any reference to a "disclosure" or an "embodiment" not falling within the scope of the claims is present for explanatory purposes only and does not form part of the invention. In some embodiments, the disclosure provides a process for the preparation of a compound of Formula (I) [Trifarotene], or a salt thereof
<CHM>
comprising hydrolyzing a compound of Formula (V)
<CHM>
wherein R<NUM> is hydrogen, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkanoyl group, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkenoyl group, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkynoyl group, a substituted or unsubstituted cycloalkanoyl group, a substituted or unsubstituted aryl carbonyl group, a substituted or unsubstituted heterocyle carbonyl group, a substituted or unsubstituted heteroaryl carbonyl group, or a C<NUM>-C<NUM> alkanoyl group comprising a heteroatom; and wherein Y is a nitrile (CN) or amide (CONH<NUM>); to obtain the compound of Formula (I). In some embodiments, R<NUM> is an acetyl group. In some embodiments, R<NUM> is hydrogen.

In some embodiments, the process further comprises preparing the compound of formula (V) by hydrolyzing a compound of Formula (IV)
<CHM>
in the presence of a base, wherein R<NUM> is hydrogen, a hydroxyl group, a halogen, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkyl group, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkenyl group, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heteroaryl, or a C<NUM>-C<NUM> alkyl group comprising a heteroatom; and wherein Y is a nitrile (CN) or amide (CONH<NUM>); to obtain the compound of formula (V). In some embodiments, R<NUM> is methyl.

In some embodiments, the hydrolysis is performed in the presence of a solvent comprising water, methanol (MeOH), ethanol (EtOH), propanol (PrOH), isopropanol (IPA), or any mixture thereof. In some embodiments, the solvent comprises water and ethanol. In some embodiments, the base comprises sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), barium hydroxide (Ba(OH)<NUM>), or any mixture thereof.

In some embodiments, the compound of formula (IV) is present in an amount of about <NUM> to about <NUM> mol/L (solvent), preferably about <NUM> to about <NUM> mol/L (solvent), more preferably about <NUM> to about <NUM> mol/L (solvent). In some embodiments, the base is present in an amount of about <NUM> to about <NUM> mol/L (solvent), preferably about <NUM> to about <NUM> mol/L (solvent), more preferably about <NUM> to about <NUM> mol/L (solvent). In some embodiments, the base is present at about <NUM> to about <NUM> molar equivalents relative to the compound of formula (IV), preferably about <NUM> to about <NUM> molar equivalents relative to the compound of formula (IV), more preferably about <NUM> to about <NUM> molar equivalents relative to the compound of formula (IV).

In some embodiments, the process further comprises preparing the compound of formula (IV) by reacting a compound of formula (II)
<CHM>
wherein R<NUM> and R<NUM> are independently hydrogen or a linear or branched C<NUM>-C<NUM> alkyl, wherein R<NUM> and R<NUM> can be the same or different; or R<NUM> and R<NUM> together form a pinacolate, with a compound of formula (III)
<CHM>
in the presence of a catalyst, wherein R<NUM> is hydrogen, a hydroxyl group, a halogen, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkyl, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkenyl group, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heteroaryl, or a C<NUM>-C<NUM> alkyl group comprising a heteroatom; wherein X is a halogen or triflate; and wherein Y is a nitrile or amide, to obtain the compound of formula (IV). In some embodiments, the R<NUM> is methyl and X is iodine.

In some embodiments, the reaction is performed in the presence of a solvent comprising toluene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dioxane, n-butanol (n-BuOH), isopropanol (IPA), dimethyl ether (DME), diethyl ether, or any mixture thereof. In some embodiments, the reaction is performed in the presence of a base comprising K<NUM>CO<NUM>, CH<NUM>CO<NUM>K, K<NUM>PO<NUM>, KOtBu, Na<NUM>CO<NUM>, NaHCO<NUM>, NaOMe, Cs<NUM>CO<NUM>, Ag<NUM>PO<NUM>, Ag<NUM>O, Tl<NUM>CO<NUM>, TlOEt, TlOH, t-BuNH<NUM>, KOH, NaOH, LiOH, Ba(OH)<NUM>, or combination thereof.

In some embodiments, the catalyst comprises a metal selected from Pd, Cu, or Ni. In some embodiments, the catalyst comprises at least two atoms of the metal. In some embodiments, the catalyst is a Pd catalyst selected from Pd(PPh<NUM>)<NUM>Cl<NUM> [bis(triphenylphosphine)palladium(II) dichloride]; Pd(PPh<NUM>)<NUM> [tetrakis(triphenylphosphine)palladium(<NUM>)]; Pd(OAc)<NUM> [palladium(II) diacetate]; XPhos Pd-G3 [(<NUM>-dicyclohexylphosphino-<NUM>',<NUM>',<NUM>'-triisopropyl-<NUM>,<NUM>'-biphenyl)[<NUM>-(<NUM>'-amino-<NUM>,<NUM>'-biphenyl)]palladium(II) methanesulfonate]; SPhos-Pd-G2 [chloro(<NUM>-dicyclohexylphosphino-<NUM>',<NUM>'-dimethoxy-<NUM>,<NUM>'-biphenyl)[<NUM>-(<NUM>'-amino-<NUM>,<NUM>'-biphenyl)]palladium(II)]; CATACXIUM® A Pd G3 (mesylate[(di(<NUM>-adamantyl)-n-butylphosphine)-<NUM>-(<NUM>'-amino-<NUM>,<NUM>'-biphenyl)]palladium(II) or [(di(<NUM>-adamantyl)-butylphosphine)-<NUM>-(<NUM>'-amino-<NUM>,<NUM>'-biphenyl)]palladium(II) methanesulfonate); APhos Pd G3 (palladium G3-(<NUM>-(N,N-dimethylamino)phenyl)di-tert-butylphosphine] or [<NUM>-(di-tert-butylphosphino)-N,N-dimethylaniline-<NUM>-(<NUM>'-aminobiphenyl)]palladium(II) methanesulfonate); P(Cy<NUM>) Pd-G3 (palladium G3-tricyclohexylphosphine or [(tricyclohexylphosphine)-<NUM>-(<NUM>'-aminobiphenyl)]palladium(II) methanesulfonate); Allylpalladium(II) chloride dimer (bis(allyl)dichlorodipalladium); or Pd(dppf)Cl<NUM> [<NUM>,<NUM>'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)].

In some embodiments, the compounds of formula (II) and formula (III) are present in a molar ratio of about <NUM>:<NUM> to about <NUM>:<NUM>, preferably about <NUM>:<NUM> to about <NUM>:<NUM>, more preferably about <NUM>:<NUM>. In some embodiments, the compounds of formula (II) and formula (III) are independently present in an amount of about <NUM> to about <NUM> mol/L (solvent), preferably about <NUM> to about <NUM> mol/L (solvent), more preferably about <NUM> to about <NUM> mol/L (solvent).

In some embodiments, the catalyst is present at about <NUM> to about <NUM> molar equivalents relative to the compounds of formula (II) or formula (III), preferably about <NUM> to about <NUM> molar equivalents relative to the compounds of formula (II) or formula (III), more preferably about <NUM> to about <NUM> molar equivalents relative to the compounds of formula (II) or formula (III). In some embodiments, the base is present at about <NUM> to about <NUM> molar equivalents relative to the compounds of formula (II) or formula (III), preferably about <NUM> to about <NUM> molar equivalents relative to the compounds of formula (II) or formula (III), more preferably about <NUM> to about <NUM> molar equivalents relative to the compounds of formula (II) or formula (III).

In some embodiments, the present disclosure provides a process for the preparation of a compound of formula (I) [Trifarotene], or a salt thereof
<CHM>
comprising reacting a compound of formula (II)
<CHM>
wherein R<NUM> and R<NUM> are independently hydrogen or a linear or branched C<NUM>-C<NUM> alkyl, wherein R<NUM> and R<NUM> can be the same or different; or R<NUM> and R<NUM> together form a pinacolate, with a compound of formula (III)
<CHM>
wherein R<NUM> is a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkyl, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkenyl group, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heteroaryl, or a C<NUM>-C<NUM> alkyl group comprising a heteroatom; wherein X is a halogen or triflate; and wherein Y is a nitrile (CN) or amide (CONH<NUM>), in the presence of a catalyst, to obtain a compound of formula (IV)
<CHM>
wherein R<NUM> is as defined above; and hydrolyzing the compound of formula (IV) in the presence of a base, to obtain Trifarotene. R<NUM>, R<NUM>, R<NUM>, R<NUM>, X, and Y, and the various reactions and conditions are further described herein. In some embodiments, R<NUM> is methyl, X is iodine, and Y is nitrile. In some embodiments, R<NUM> is methyl and X is iodine.

In some embodiments, the present disclosure provides a compound of Formula (V)
<CHM>
wherein R<NUM> is hydrogen, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkanoyl group, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkenoyl group, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkynoyl group, a substituted or unsubstituted cycloalkanoyl group, a substituted or unsubstituted aryl carbonyl group, a substitute or unsubstituted heterocyle carbonyl group, a substituted or unsubstituted heteroaryl carbonyl group, or a C<NUM>-C<NUM> alkanoyl group comprising a heteroatom; and wherein Y is a nitrile (CN) or amide (CONH<NUM>); and wherein Y is nitrile or amide. In some embodiments, R<NUM> is hydrogen. In some embodiments, R<NUM> is acetyl.

The disclosure provides a Form E polymorph of the compound of Formula (I) [Trifarotene], wherein the Form E polymorph shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle <NUM> of <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> degrees. The Form E polymorph further shows peaks at <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> degrees.

In some embodiments, the disclosure further provides a process for preparing a Form E polymorph of Trifarotene, comprising: (a) providing trifarotene according to a process described herein; (b) adjusting pH of the trifarotene to a pH of about <NUM> to about <NUM>, to obtain a trifarotene salt; and (c) suspending the trifarotene salt in methanol, to obtain a Form E polymorph of trifarotene wherein the Form E polymorph shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2θ of <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> degrees.

The present disclosure relates to methods for the preparation of Trifarotene. The methods provided herein advantageously simplify the preparation process by reducing or eliminating reaction steps that require harsh conditions (e.g., performed in extreme heat (e.g., > <NUM>) or cold (e.g., < -<NUM>)).

As used herein, "a" or "an" may mean one or more. As used herein, when used in conjunction with the word "comprising," the words "a" or "an" may mean one or more than one. As used herein, "another" or "a further" may mean at least a second or more.

Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for the method/device being employed to determine the value, or the variation that exists among the study subjects. Typically, the term "about" is meant to encompass approximately or less than <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>% or <NUM>% or higher variability, depending on the situation. In some embodiments, one of skill in the art will understand the level of variability indicated by the term "about," due to the context in which it is used herein. It should also be understood that use of the term "about" also includes the specifically recited value.

The use of the term "or" in the claims is used to mean "and/or," unless explicitly indicated to refer only to alternatives or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and/or.

As used herein, the terms "comprising" (and any variant or form of comprising, such as "comprise" and "comprises"), "having" (and any variant or form of having, such as "have" and "has"), "including" (and any variant or form of including, such as "includes" and "include") or "containing" (and any variant or form of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any composition (e.g., formulation) or method of the present disclosure. Furthermore, compositions (e.g., formulations) of the present disclosure can be used to achieve methods of the present disclosure.

The use of the term "for example" and its corresponding abbreviation "e.g." (whether italicized or not) means that the specific terms recited are representative examples and embodiments of the disclosure that are not intended to be limited to the specific examples referenced or cited unless explicitly stated otherwise.

As used herein, "between" is a range inclusive of the ends of the range. For example, a number between x and y explicitly includes the numbers x and y, and any numbers that fall within x and y.

Unless specified otherwise, the term "alkyl," when used alone or in combination with other groups or atoms, refers to a saturated linear or branched chain including <NUM> to about <NUM> hydrogen-substituted carbon atoms. Alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, <NUM>-methylpropyl, isobutyl, t-butyl, <NUM>,<NUM>-dimethylbutyl, n-pentyl, <NUM>-methylpentyl, <NUM>-methylpentyl, <NUM>-methylpentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

Unless specified otherwise, the term "alkenyl" refers to a partially unsaturated linear or branched chain including about <NUM> to about <NUM> hydrogen-substituted carbon atoms that contain at least one double bond. Alkenyl groups include, e.g., vinyl, allyl, <NUM>-methylprop-<NUM>-enyl, but-<NUM>-enyl, but-<NUM>-enyl, but-<NUM>-enyl, buta-<NUM>,<NUM>-dienyl, penta-<NUM>,<NUM>-dienyl, penta-<NUM>,<NUM>-dienyl, <NUM>-methylbut-<NUM>-enyl, <NUM>-methylpent-<NUM>-enyl, <NUM>-methylpent-<NUM>-enyl, <NUM>-methylpent-<NUM>-enyl, <NUM>-methylpent-<NUM>-enyl, <NUM>-methylpenta-<NUM>,<NUM>-dienyl, hexen-<NUM>-yl, hepten-<NUM>-yl, octen-<NUM>-yl, nonen-<NUM>-yl, decen-<NUM>-yl, and the like.

Unless specified otherwise, the term "alkynyl" refers to a partially unsaturated linear or branched chain including about <NUM> to about <NUM> hydrogen-substituted carbon atoms that contains at least one triple bond. Alkynyl groups include, e.g., ethynyl, <NUM>-propynyl, <NUM>-propynyl, <NUM>-methylprop-<NUM>-ynyl, <NUM>-butynyl, <NUM>-butynyl, <NUM>-butynyl, <NUM>,<NUM>-butadiynyl, <NUM>-methylbut-<NUM>-ynyl, <NUM>-methylbut-ynyl, <NUM>-methylbut-<NUM>-ynyl, <NUM>-methylbut-<NUM>-ynyl, <NUM>-pentynyl, <NUM>-pentynyl, <NUM>-pentynyl, <NUM>-pentynyl, <NUM>,<NUM>-pentadiynyl, <NUM>,<NUM>-pentadiynyl, <NUM>-methylpent-<NUM>-ynyl, <NUM>-methylpent-<NUM>-ynyl, <NUM>-methylpent-<NUM>-ynyl, <NUM>-hexynyl, <NUM>-heptynl, <NUM>-octynyl, <NUM>-nonynyl, <NUM>-decynyl, and the like.

Unless specified otherwise, the term "cycloalkyl" refers to a saturated or unsaturated ring including about <NUM> to about <NUM> carbon atoms, that may optionally be substituted with one or more identical or different substituents, e.g., one to three, one to six, one to eight, or one to ten substituents. Cycloalkyl groups include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononyl, cyclodecyl, and the like.

Unless specified otherwise, the term "aryl" refers to an aromatic mono- or bicyclic group containing from about <NUM> to about <NUM> carbon atoms that may be optionally fused with a fully or partially saturated or unsaturated carbocyclic ring. Aryl groups include, e.g., phenyl, naphthyl, indanyl, and the like.

Unless specified otherwise, the term "alkanoyl" refers to a carbonyl (C=O) group bonded to an alkyl group. The term "alkenoyl" refers to a carbonyl (C=O) group bonded to an alkenyl group. The term "alkynoyl" refers to a carbonyl (C=O) group bonded to an alkynyl group. The term "cycloalkyl" refers to an alkane containing one or more rings of carbon atoms. A "cycloalkanoyl" refers to a carbonyl (C=O) group bonded to a cycloalkyl group. An "aryl carbonyl" refers to a carbonyl (C=O) bonded to an aryl group.

Unless specified otherwise, a "heterocycle" refers to a monocyclic non-aromatic hydrocarbon ring containing about <NUM> to about <NUM> carbon atoms, or a bicyclic non-aromatic hydrocarbon ring system containing about <NUM> to about <NUM> carbon atoms, wherein one or more of the carbon atoms of the in the hydrocarbon ring or ring system is replaced by a one heteroatom. Examples of heterocycles include but are not limited to azepan-<NUM>-yl, piperidinyl, e.g., piperidin-<NUM>-yl and piperidin-<NUM>-yl, piperazinyl, e.g., N-piperazinyl and <NUM>-alkylpiperazine-<NUM>-yl, morpholine-<NUM>-yl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiophen, sulfolanyl, sulfolenyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxazolidinon-yl. A "heterocycle carbonyl" refers to a carbonyl (C=O) bonded to a heterocycle group.

Unless specified otherwise, a "heteroaryl" refers to an aromatic compound containing at least one heteroatom. Examples of heteroaryl groups include but are not limited to pyrrolyl, dihydropyrrolyl, pyrrolidinyl, indolyl, isoindolyl, indolizinyl, imidazolyl, pyrazolyl, benzimidazolyl, imidazo(<NUM>,<NUM>-a)pyridinyl, indazolyl, purinyl, pyrrolo(<NUM>,<NUM>-c)pyridinyl, pyrrolo(<NUM>,<NUM>-c)pyridinyl, pyrrolo(<NUM>,<NUM>-b)pyridinyl, pyrazolo(<NUM>,<NUM>-a)pyridinyl, <NUM>,<NUM>,<NUM>-triazolyl, <NUM>,<NUM>,<NUM>-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, <NUM>,<NUM>,<NUM>-oxadiazolyl, <NUM>,<NUM>,<NUM>-oxadiazolyl, <NUM>,<NUM>,<NUM>-oxadiazolyl, <NUM>,<NUM>,<NUM>-oxadiazolyl, thiazolyl, isothiazolyl, <NUM>,<NUM>,<NUM>-thiadiazolyl, <NUM>,<NUM>,<NUM>-thiadiazolyl, <NUM>,<NUM>,<NUM>-thiadiazolyl, <NUM>,<NUM>,<NUM>-thiadiazolyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, benzofuranyl, isobenzofuranyl, thiophenyl, dihydrothiophenyl, tetrahydrothiophenyl, benzothiophenyl, benzoisothiophenyl, pyridyl, piperidinyl, quinolinyl, isoquinolinyl, quinolizinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyranyl, tetrahydropyranyl, <NUM>,<NUM>,<NUM>-triazinyl, <NUM>,<NUM>,<NUM>-triazinyl, <NUM>,<NUM>,<NUM>-triazinyl, chromenyl, morpholinyl, diazepinyl, benzodiazepinyl, and the like. A "heteroaryl carbonyl" refers to a carbonyl (C=O) bonded to a heteroaryl group.

In some embodiments, any of the carbon chain substituents described herein, e.g., alkyl, alkanoyl, alkenoyl, alkynoyl, alkanoyl, etc., can have one or more of the carbons in the carbon chain replaced by one or more heteroatoms, i.e., an atom other than a carbon or hydrogen, e.g., nitrogen, oxygen, sulfur, phosphorus. In some embodiments, the substituents described herein, e.g., alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heterocycle, heteroaryl, alkanoyl group, alkenoyl group, alkynoyl group, cycloalkanoyl group, aryl carbonyl group, heterocyle carbonyl group, heteroaryl carbonyl group, etc., can be "substituted or unsubstituted. " The term "substituted" refers to the substitution of a hydrogen on the substituent with a different group, e.g., a hydroxyl, halide, alkyl (e.g., C<NUM>-<NUM> alkyl), alcohol, ketone, and the like. The term "unsubstituted" refers where the substituent has not had a hydrogen substituted with a different group.

A "linear" molecule contains a single backbone. For example, a "linear C<NUM>-Cn" molecule includes one to n number of carbon atoms, wherein each carbon atom is bound to its two neighbors and to two hydrogen atoms (with the exception of the terminal carbons, which are bound to only one carbon atom and three hydrogen atoms). A "branched" molecule contains a nonlinear backbone, wherein branches can sprout from one or more atoms of the main backbone. For example, a "branched C<NUM>-Cn" molecule is derived from a linear C<NUM>-Cn molecule, except that at least one of the hydrogen atoms bound to at least one of the carbons is replaced with a substituent, e.g., an alkyl group.

Any of the cyclic groups described herein (e.g., cycloalkyl, aryl, heterocycle, heteroaryl) can be substituted or unsubstituted. For example, a substituted cycloalkane can have substituents at any of the atoms forming the ring. Substituents can include any of the groups described herein, e.g., alkyl, alkenyl, alkynyl, etc..

In some embodiments, the present disclosure provides a process for the preparation of a compound of Formula (I) [Trifarotene], or a salt thereof
<CHM>
comprising hydrolyzing a compound of Formula (V)
<CHM>
wherein R<NUM> is hydrogen, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkanoyl group, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkenoyl group, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkynoyl group, a substituted or unsubstituted cycloalkanoyl group, a substituted or unsubstituted aryl carbonyl group, a substituted or unsubstituted heterocyle carbonyl group, a substituted or unsubstituted heteroaryl carbonyl group, or a C<NUM>-C<NUM> alkanoyl group comprising a heteroatom; and wherein Y is a nitrile (CN) or amide (CONH<NUM>); to obtain the compound of Formula (I).

In some embodiments, the compound of Formula (I) is Trifarotene. In some embodiments, the compound of Formula (I) is Trifarotene-HCl. In some embodiments, the compound of Formula (I) is a Trifarotene Na salt.

In some embodiments, R<NUM> is hydrogen. In embodiments, R<NUM> is an alkanoyl group. In some embodiments, R<NUM> is a formyl group (-COH). In embodiments, R<NUM> is an acetyl group (-COCH<NUM>). In some embodiments, the compound of Formula (V) is selected from the following:
<CHM>.

In some embodiments, Y is a nitrile. In some embodiments, Y is an amide. In some embodiments, R<NUM> is hydrogen, and Y is a nitrile or amide. In some embodiments, R<NUM> is an alkanoyl, and Y is a nitrile or amide. In some embodiments, R<NUM> is formyl, and Y is a nitrile or amide. In some embodiments, R<NUM> is acetyl, and Y is a nitrile or amide.

In some embodiments, R<NUM> is an alkenoyl, and Y is a nitrile or amide. In some embodiments, R<NUM> is an alkynoyl, and Y is a nitrile or amide. In some embodiments, R<NUM> is a substituted cycloalkanoyl, and Y is a nitrile or amide. In some embodiments, R<NUM> is an unsubstituted cycloalkanoyl, and Y is a nitrile or amide. In some embodiments, R<NUM> is a substituted aryl carbonyl group, and Y is a nitrile or amide. In some embodiments, R<NUM> is an unsubstituted aryl carbonyl group, and Y is a nitrile or amide. In some embodiments, R<NUM> is a substituted heterocyle carbonyl group, and Y is a nitrile or amide. In some embodiments, R<NUM> is an unsubstituted heterocyle carbonyl group, and Y is a nitrile or amide. In some embodiments, R<NUM> is a substituted heteroaryl carbonyl group, and Y is a nitrile or amide. In some embodiments, R<NUM> is an unsubstituted heteroaryl carbonyl group, and Y is a nitrile or amide. In some embodiments, R<NUM> is a C<NUM>-C<NUM> alkanoyl group comprising a heteroatom, and Y is a nitrile or amide.

In some embodiments, the compound of Formula (V) is selected from the following:
<CHM>
<CHM>.

The term "hydrolysis" or variants thereof such as "hydrolyze" or "hydrolyzing," refers to a reaction in which water is a reactant and becomes part of the reaction product, typically as a hydroxyl (-OH) group. Hydrolysis of nitriles or amides can form a carboxylic acid (-COOH). In some embodiments, hydrolysis is performed in the presence of water and a co-solvent. Examples of co-solvents that can be used with water for hydrolysis reactions include but are not limited to alcohols, e.g., methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, sec-butanol, and isobutyl alcohol; methylene chloride; acetonitrile; ethyl acetate; and tetrahydrofuran (THF). In some embodiments, the hydrolysis is performed in the presence of water and an alcohol. In some embodiments, the alcohol is methanol (MeOH), ethanol (EtOH), propanol (PrOH), isopropanol (IPA), or any mixture thereof. In some embodiments, the hydrolysis is performed in the presence of water and ethanol.

In some embodiments, hydrolysis is performed further in the presence of an acid or a base. In some embodiments, the acid comprises hydrochloric acid (HCl), sulfuric acid (H<NUM>SO<NUM>), nitric acid (HNO<NUM>), hydrobromic acid (HBr), hydroiodic acid (HI), perchloric acid (HClO<NUM>), chloric acid (HClO<NUM>), sulfurous acid (H<NUM>SO<NUM>), methanoic acid (HCO<NUM>H), phosphoric acid (H<NUM>PO<NUM>), nitrous acid (HNO<NUM>), hydrofluoric acid (HF), or any mixture thereof. In some embodiments, the base comprises sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), barium hydroxide (Ba(OH)<NUM>), or any mixture thereof.

In some embodiments, R<NUM> is hydrogen, and Y is hydrolyzed. In some embodiments, Y is hydrolyzed to form a carboxylic acid. In some embodiments, R<NUM> comprises a carbonyl as described herein, and the carbonyl together with the oxygen attached thereto are hydrolyzed to generate a hydroxyl group. In some embodiments, R<NUM> and Y are capable of being hydrolyzed under the same reaction conditions. In some embodiments, R<NUM> and Y are hydrolyzed simultaneously.

In some embodiments, the compound of Formula (V) is present in the hydrolysis reaction at about <NUM> to about <NUM> mol/L (solvent), about <NUM> to about <NUM> mol/L (solvent), or about <NUM> to about <NUM> mol/L (solvent). In some embodiments, the compound of Formula (V) is present in the hydrolysis reaction at about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, or about <NUM> mol/L (solvent). In some embodiments, the hydrolysis of the compound of Formula (V) is performed in an acidic condition. In some embodiments, the hydrolysis is performed at a pH of about <NUM> to about <NUM>, about <NUM> to about <NUM> about <NUM> to about <NUM>, about <NUM> to about <NUM>, or about <NUM> to about <NUM>. In some embodiments, the hydrolysis reaction is performed at pH about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, or about <NUM>.

In some embodiments, the disclosure provides a process for preparing the compound of Formula (V) wherein R<NUM> is hydrogen. In some embodiments, the compound of Formula (V) is prepared by hydrolyzing a compound of Formula (IV)
<CHM>
in the presence of a base, wherein R<NUM> is hydrogen, a hydroxyl group, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkyl group, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkenyl group, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heteroaryl, or a C<NUM>-C<NUM> alkyl group comprising a heteroatom; and wherein Y is a nitrile (CN) or amide (CONH<NUM>); to obtain the compound of Formula (V). In some embodiments, the ester (-COOR<NUM>) of the compound of Formula (IV) is hydrolyzed to form a hydroxyl group (-OH). In some embodiments, R<NUM> of the compound of Formula (V) is hydrogen.

Y in the compound of Formula (IV) is as defined herein for the compound of Formula (V). In some embodiments, R<NUM> is hydrogen, and Y is a nitrile or amide. In some embodiments, R<NUM> is methyl, and Y is a nitrile or amide. In some embodiments, R<NUM> is hydroxyl, and Y is a nitrile or amide. In some embodiments, R<NUM> is methyl, and Y is a nitrile.

In some embodiments, the hydrolysis of the compound of Formula (IV) is performed in the presence of water and a co-solvent. Exemplary co-solvents are provided herein. In some embodiments, the hydrolysis of the compound of Formula (IV) is performed in a solvent comprising water, methanol (MeOH), ethanol (EtOH), propanol (PrOH), isopropanol (IPA), or any mixture thereof. In some embodiments, the solvent comprises water and ethanol.

In some embodiments, the hydrolysis of the compound of Formula (IV) is performed in the presence of a base. Exemplary bases for hydrolysis reactions are provided herein. In some embodiments, the base for the hydrolysis of the compound of Formula (IV) comprises sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), barium hydroxide (Ba(OH)<NUM>), or any mixture thereof.

In some embodiments, the compound of Formula (IV) is present in the hydrolysis reaction at about <NUM> to about <NUM> mol/L (solvent), about <NUM> to about <NUM> mol/L (solvent), about <NUM> to about <NUM> mol/L (solvent), about <NUM> to about <NUM> mol/L (solvent), or about <NUM> to about <NUM> mol/L (solvent). In some embodiments, the compound of Formula (IV) is present in the hydrolysis reaction at about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, or about <NUM> mol/L (solvent). In some embodiments, the base is added to the hydrolysis reaction at about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, or about <NUM> molar equivalents relative to the compound of Formula (IV). In some embodiments, the base is added to the hydrolysis reaction at about <NUM> to about <NUM> mol/L (solvent), about <NUM> to about <NUM> mol/L (solvent), about <NUM> to about <NUM> mol/L (solvent), or about <NUM> to about <NUM> mol/L (solvent).

In some embodiments, the disclosure further provides a process for preparing the compound of Formula (IV), comprising reacting a compound of Formula (II)
<CHM>
wherein R<NUM> and R<NUM> are independently hydrogen, a linear or branched C<NUM>-C<NUM> alkyl, or a pinacolate, and wherein R<NUM> and R<NUM> can be the same or different, or R<NUM> and R<NUM> together form a pinacolate, with a compound of Formula (III)
<CHM>
in the presence of a catalyst, wherein R<NUM> is hydrogen, a hydroxyl group, a linear or branched C<NUM>-C<NUM> alkyl, a linear or branched C<NUM>-C<NUM> alkenyl group, a linear or branched C<NUM>-C<NUM> alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heteroaryl, or a C<NUM>-C<NUM> alkyl group comprising a heteroatom; wherein X is a halogen or triflate; and wherein Y is a nitrile or amide, to obtain the compound of Formula (IV).

In some embodiments, R<NUM> and R<NUM> of the compound of Formula (II) are independently hydrogen. In some embodiments, R<NUM> and R<NUM> of the compound of Formula (II) are independently a linear or branched C<NUM>-C<NUM> alkyl group. In some embodiments, R<NUM> and R<NUM> of the compound of Formula (II) together form a pinacolate.

In some embodiments, the compound of Formula (II) is selected from the following:
<CHM>.

R<NUM> and Y of the compound of Formula (III) are defined as above for the compound of Formula (IV). In some embodiments, X of the compound of Formula (III) is a leaving group for a Suzuki coupling reaction. Examples of leaving groups for Suzuki reactions are further provided in, e.g., <NPL>); <NPL>); <NPL>). In some embodiments, X is a halogen, e.g., fluorine, chlorine, bromine, or iodine. In some embodiments, X is a triflate (-OSO<NUM>CF<NUM>; also abbreviated as -OTf) group. In some embodiments, R<NUM> is hydrogen, Y is a nitrile or amide, and X is a halogen or triflate. In some embodiments, R<NUM> is methyl, Y is a nitrile or amide, and X is a halogen or triflate. In some embodiments, R<NUM> is a hydroxyl, Y is a nitrile or amide, and X is a halogen or triflate. In some embodiments, R<NUM> is methyl, Y is a nitrile, and X is iodine.

In some embodiments, the compound of Formula (III) is selected from the following:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>.

In some embodiments, the reaction between the compounds of Formula (II) and Formula (III) is performed in the presence of a solvent comprising toluene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dioxane, n-butanol (n-BuOH), isopropanol (IPA), ethanol (EtOH), methanol (MeOH), dimethyl ether (DME), diethyl ether, or any mixture thereof. In some embodiments, the reaction between the compounds of Formula (II) and Formula (III) is performed using water as solvent. In some embodiments, the reaction between the compounds of Formula (II) and Formula (III) is performed in a solvent-free manner, e.g., the reaction is microwave-assisted (see, e.g., <NPL>)).

In some embodiments, the reaction between the compounds of Formula (II) and Formula (III) is performed in the presence of a base comprising potassium carbonate (K<NUM>CO<NUM>), potassium acetate (CH<NUM>CO<NUM>K), potassium phosphate (K<NUM>PO<NUM>), potassium tert-butoxide (KOtBu), sodium carbonate (Na<NUM>CO<NUM>), sodium bicarbonate (NaHCO<NUM>), sodium methoxide (NaOMe), sodium tert-butoxide (NaOtBu) cesium carbonate (Cs<NUM>CO<NUM>), silver phosphate (Ag<NUM>PO<NUM>), silver oxide (Ag<NUM>O), thallium carbonate (Tl<NUM>CO<NUM>), thallium ethoxide (TlOEt), tert-butylamine (t-BuNH<NUM>), potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), barium hydroxide (Ba(OH)<NUM>), thallium hydroxide (TIOH), or combination thereof.

In some embodiments, the catalyst for the reaction between the compounds of Formula (II) and Formula (III) comprises a metal selected from palladium (Pd), copper (Cu), nickel (Ni), iron (Fe), zinc (Zn), or rhodium (Rh). In some embodiments, the catalyst comprises a metal selected from Pd, Cu, or Ni. In some embodiments, the catalyst comprises <NUM> to <NUM> atoms of the metal. In some embodiments, the catalyst comprises <NUM> to <NUM> atoms of the metal. In some embodiments, the catalyst comprises <NUM> to <NUM> atoms of the metal. In some embodiments, the catalyst comprises <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> atoms of the metal. Palladium-catalyzed coupling reactions are further described, e.g., in <CIT> and <CIT>.

In some embodiments, the catalyst is a palladium catalyst. In some embodiments, the palladium catalyst is Pd(PPh<NUM>)<NUM>Cl<NUM> [bis(triphenylphosphine)palladium(II) dichloride]; Pd(PPh<NUM>)<NUM> [tetrakis(triphenylphosphine)palladium(<NUM>)]; Pd(OAc)<NUM> [palladium(II) diacetate]; XPhos Pd-G3 [(<NUM>-dicyclohexylphosphino-<NUM>',<NUM>',<NUM>'-triisopropyl-<NUM>,<NUM>'-biphenyl)[<NUM>-(<NUM>'-amino-<NUM>,<NUM>'-biphenyl)]palladium(II) methanesulfonate]; SPhos-Pd-G2 [chloro(<NUM>-dicyclohexylphosphino-<NUM>',<NUM>'-dimethoxy-<NUM>,<NUM>'-biphenyl)[<NUM>-(<NUM>'-amino-<NUM>,<NUM>'-biphenyl)]palladium(II)]; CATACXIUM® A Pd G3 (mesylate[(di(<NUM>-adamantyl)-n-butylphosphine)-<NUM>-(<NUM>'-amino-<NUM>,<NUM>'-biphenyl)]palladium(II) or [(di(<NUM>-adamantyl)-butylphosphine)-<NUM>-(<NUM>'-amino-<NUM>,<NUM>'-biphenyl)]palladium(II) methanesulfonate); APhos Pd G3 (palladium G3-(<NUM>-(N,N-dimethylamino)phenyl)di-tert-butylphosphine] or [<NUM>-(di-tert-butylphosphino)-N,N-dimethylaniline-<NUM>-(<NUM>'-aminobiphenyl)]palladium(II) methanesulfonate); P(Cy<NUM>) Pd-G3 (palladium G3-tricyclohexylphosphine or [(tricyclohexylphosphine)-<NUM>-(<NUM>'-aminobiphenyl)]palladium(II) methanesulfonate); Allylpalladium(II) chloride dimer (bis(allyl)dichlorodipalladium); or Pd(dppf)Cl<NUM> [<NUM>,<NUM>'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)].

In some embodiments, the catalyst is a copper catalyst. In some embodiments, the copper catalyst is copper(I) chloride, [(o-(di-tert-butylphosphino)-N,N-dimethylaniline)copper iodide]<NUM>, [(o-(di-tert-butylphosphino)-N,N-dimethylaniline)copper fluoride]<NUM>. In some embodiments, the catalyst is a nickel catalyst. In some embodiments, the nickel catalyst is NiCl<NUM>, NiBr<NUM>, NiI<NUM>, G<NUM>DenP-Ni, (dppf)Ni(cinnamyl)Cl, (PCy<NUM>)<NUM>NiCl<NUM>, or Ni(cod)<NUM>. Further exemplary catalysts are provided in, e.g., <NPL>); <NPL>); <NPL>); <NPL>); and <NPL>).

In some embodiments, the reaction between the compounds of Formula (II) and Formula (III) is performed further in the presence of a ligand. In some embodiments, the ligand is a phosphine ligand, a carbon ligand, or a nitrogen ligand. In some embodiments, the ligand is PPh<NUM>, PCy<NUM>, P(o-tolyl)<NUM>, P(i-Pr)<NUM>, P(O-Pr-i)<NUM>, n-BuP(<NUM>-Ad)<NUM>, P(t-Bu)<NUM>(p-NMe<NUM>-Ph), a dialkylbiaryl ligand (e.g., as described in <NPL>)), a bidentate phosphine ligand such as DPPF, DPPE or DPPP, a carbene-type ligand (e.g., as described in <NPL>)), an olefin-type ligand (e.g., as described in <NPL>)), an amine, or imine (e.g., as described in <NPL>)). In some embodiments, the ligand and catalyst are provided in the reaction as a preformed complex. For example, Pd(PPh<NUM>)<NUM> includes both a palladium catalyst and phosphine ligand. In some embodiments, the process for preparing a compound of Formula (IV) comprises preparing a catalyst comprising a metal and a ligand.

In some embodiments, the reaction does not include a catalyst. In some embodiments, the reaction does not include a ligand. Further exemplary reaction conditions are discussed in, e.g., <NPL>); <NPL>); <NPL>); <NPL>); <NPL>); and <NPL>).

In some embodiments, the compounds of Formula (II) and Formula (III) are added to the reaction at a molar ratio of about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, or about <NUM>:<NUM>. In some embodiments, the compounds of Formula (II) and (III) are added an amount of about <NUM> to about <NUM> mol/L (solvent), about <NUM> to about <NUM> mol/L (solvent), about <NUM> to about <NUM> mol/L (solvent), about <NUM> to about <NUM> mol/L (solvent), or about <NUM> to about <NUM> mol/L (solvent).

In some embodiments, the catalyst is added to the reaction at about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, or about <NUM> to about <NUM> molar equivalents relative to the compounds of Formula (II) or Formula (III). In some embodiments, the catalyst is added to the reaction at about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, or about <NUM> molar equivalents relative to the compounds of Formula (II) or Formula (III).

In some embodiments, the base is added to the reaction at a about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, or about <NUM> to about <NUM> molar equivalents relative to the compounds of Formula (II) or Formula (III). In some embodiments, the base is added to the reaction at about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, or about <NUM> molar equivalents relative to the compounds of Formula (II) or Formula (III).

In some embodiments, the disclosure provides a process for the preparation of a compound of formula (I) [Trifarotene], or a salt thereof
<CHM>
comprising reacting a compound of formula (II)
<CHM>
wherein R<NUM> and R<NUM> are independently hydrogen or a linear or branched C<NUM>-C<NUM> alkyl, wherein R<NUM> and R<NUM> can be the same or different; or R<NUM> and R<NUM> together form a pinacolate, with a compound of formula (III)
<CHM>
wherein R<NUM> is a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkyl, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkenyl group, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heteroaryl, or a C<NUM>-C<NUM> alkyl group comprising a heteroatom; wherein X is a halogen or triflate; and wherein Y is a nitrile (CN) or amide (CONH<NUM>), in the presence of a catalyst, to obtain a compound of formula (IV)
<CHM>
wherein R<NUM> is as defined above; and hydrolyzing the compound of formula (IV) in the presence of a base, to obtain Trifarotene. R<NUM>, R<NUM>, R<NUM>, R<NUM>, X, and Y, and the various reactions and conditions are further described herein. In some embodiments, R<NUM> is methyl, X is iodine, and Y is nitrile.

An exemplary process for the preparation of Trifarotene [Formula (I)] as described in embodiments herein is shown in <FIG>.

In some embodiments, the disclosure provides a process for preparing a compound of Formula (II)
<CHM>
wherein R<NUM> and R<NUM> are independently hydrogen or a linear or branched C<NUM>-C<NUM> alkyl, wherein R<NUM> and R<NUM> can be the same or different; or R<NUM> and R<NUM> together form a pinacolate, comprising reacting
<CHM>
with a compound comprising -R<NUM>OBOR<NUM>- in the presence of a salt and a catalyst, wherein R<NUM> and R<NUM> are defined as above for the compound of Formula (II). In some embodiments, the catalyst is a palladium catalyst. In some embodiments, the catalyst comprises P(tBu)<NUM>. In some embodiments, the catalyst is Pd-<NUM> ([P(tBu)<NUM>] Pd(crotyl)Cl), Pd-<NUM> ([P(tBu)<NUM>] Palladacycle), or Pd-<NUM> ({Pd(µ-I) [P(t-Bu)<NUM>]}<NUM>). In some embodiments, the reaction is performed at about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, or about <NUM> to about <NUM>. In some embodiments, the process for preparing the compound of Formula (II) provided herein is performed at room temperature. When compared with previously described methods, e.g., as described in <CIT>, which perform the reaction under harsh conditions (e.g., at -<NUM>), the present process greatly reduces the complexity and shortens preparation time.

In some embodiments, the present disclosure provides novel compounds. In some embodiments, the novel compounds described herein are used in the preparation of Trifarotene. The novel compounds provided herein can advantageously simplify the Trifarotene preparation process.

In some embodiments, the disclosure provides a compound of Formula (V)
<CHM>
wherein R<NUM> is hydrogen, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkanoyl group, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkenoyl group, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkynoyl group, a substituted or unsubstituted cycloalkanoyl group, a substituted or unsubstituted aryl carbonyl group, a substitute or unsubstituted heterocyle carbonyl group, a substituted or unsubstituted heteroaryl carbonyl group, or a C<NUM>-C<NUM> alkanoyl group comprising a heteroatom; and wherein Y is a nitrile (CN) or amide (CONH<NUM>).

R<NUM> and Y are further described herein. In some embodiments, R<NUM> is hydrogen. In some embodiments, R<NUM> is a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkanoyl group, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkenoyl group, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkynoyl group, a substituted or unsubstituted cycloalkanoyl group, a substituted or unsubstituted aryl carbonyl group, a substitute or unsubstituted heterocyle carbonyl group, a substituted or unsubstituted heteroaryl carbonyl group, or a C<NUM>-C<NUM> alkanoyl group comprising a heteroatom.

In some embodiments, R<NUM> is a unsubstituted linear or branched C<NUM>-C<NUM> alkanoyl group, a unsubstituted linear or branched C<NUM>-C<NUM> alkenoyl group, a unsubstituted linear or branched C<NUM>-C<NUM> alkynoyl group, a unsubstituted cycloalkanoyl group, a unsubstituted aryl carbonyl group, a unsubstituted heterocyle carbonyl group, a unsubstituted heteroaryl carbonyl group, or a C<NUM>-C<NUM> alkanoyl group comprising a heteroatom.

In some embodiments, R<NUM> is a unsubstituted linear or branched C<NUM>-C<NUM> alkanoyl group, a unsubstituted linear or branched C<NUM>-C<NUM> alkenoyl group, a unsubstituted linear or branched C<NUM>-C<NUM> alkynoyl group, or a C<NUM>-C<NUM> alkanoyl group comprising a heteroatom.

In some embodiments, the disclosure provides novel polymorphs of the compound of Formula (I), Trifarotene. The novel polymorphs described herein can be used to better characterize Trifarotene and its pharmaceutical properties.

The disclosure provides a Form E polymorph of the compound of Formula (I) [Trifarotene], wherein the Form E polymorph shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2θ of <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> degrees. In some embodiments, the Form E polymorph further shows peaks at <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> degrees. An exemplary XRPD spectra for the Form E polymorph is shown in <FIG>.

To <NUM> (<NUM> mol) of (<NUM>-(tert-butyl)-<NUM>-(pyrrolidin-<NUM>-yl)phenyl) boronic acid [Formula II] were added Toluene (<NUM>) and <NUM> (<NUM> mol) of <NUM>-((<NUM>'-cyano-<NUM>-iodo-[<NUM>,<NUM>'-biphenyl]-<NUM>-yl)oxy)ethyl Acetate [Formula III]. <NUM> potassium carbonate (<NUM>) was added. The reaction medium is stirred at <NUM> for <NUM> minutes under nitrogen. <NUM> of Pd-<NUM> (Palladium chloride bis(triphenylphosphine) (<NUM> mol) was added under nitrogen, and the reaction medium was heated to <NUM>-<NUM> and stirred under reflux for <NUM> hours. The reaction was terminated by the addition of water (<NUM>). Phases were separated. The organic phase was filtered off. Toluene was distilled off in vacuum to afford oily residue.

The residue was suspended in heptane (<NUM>) and stirred under reflux for <NUM> hour and hot filtered off. The mother liquor was further heated under reflux for <NUM> hour and cooled gradually to room temperature. The precipitate was filtered off to afford <NUM>-((<NUM>"-(tert-butyl)-<NUM>-cyano-<NUM>"-(pyrrolidin-<NUM>-yl)-[<NUM>,<NUM>':<NUM>',<NUM>"-terphenyl]-<NUM>'-yl)oxy)ethyl acetate [Formula IV(a)] which was further suspended in ethanol (<NUM>) and heated under reflux for <NUM> hours followed by cooling to room temperature. The precipitate was filtered off to afford <NUM> of <NUM>-((<NUM>"-(tert-butyl)-<NUM>-cyano-<NUM>"-(pyrrolidin-<NUM>-yl)-[<NUM>,<NUM>':<NUM>',<NUM>"-terphenyl]-<NUM>'-yl)oxy)ethyl acetate [Formula IV(a)] as a white powder with HPLC purity <NUM>%; yield <NUM>%; m/z <NUM>.

To <NUM> (<NUM> mol) of <NUM>-((<NUM>"-(tert-butyl)-<NUM>-cyano-<NUM>"-(pyrrolidin-<NUM>-yl)-[<NUM>,<NUM>':<NUM>',<NUM>"-terphenyl]-<NUM>'-yl)oxy)ethyl acetate [Formula IV(a)] were added <NUM> NaOH solution (<NUM>) and ethanol (<NUM>). The reaction medium was stirred under reflux for <NUM> hours. The reaction medium was cooled to <NUM>, and water (<NUM>) was added. HCl <NUM>% (<NUM>) was added dropwise to pH <NUM>. The white precipitate was filtered off to afford crude <NUM>"-(tert-butyl)-<NUM>'-(<NUM>-hydroxyethoxy)-<NUM>"-(pyrrolidin-<NUM>-yl)-[<NUM>,<NUM>':<NUM>',<NUM>"-terphenyl]-<NUM>-carboxylic acid, which was suspended in ethanol (<NUM>) and water (<NUM>). The mixture was heated to <NUM> for <NUM> hours and filtered off to afford <NUM> <NUM>"-(tert-butyl)-<NUM>'-(<NUM>-hydroxyethoxy)-<NUM>"-(pyrrolidin-<NUM>-yl)-[<NUM>,<NUM>':<NUM>',<NUM>"-terphenyl]-<NUM>-carboxylic acid pure [Trifarotene; Formula I] with HPLC purity <NUM>%; yield <NUM>%; m/z <NUM>.

<NUM> (<NUM> mol) of <NUM>-((<NUM>"-(tert-butyl)-<NUM>-cyano-<NUM>"-(pyrrolidin-<NUM>-yl)-[<NUM>,<NUM>':<NUM>',<NUM>"-terphenyl]-<NUM>'-yl)oxy)ethyl acetate [Formula IV(a)] was suspended in ethanol (<NUM>). <NUM> (<NUM> mol) of potassium carbonate was added. The reaction medium is stirred at <NUM> for <NUM> hours, followed by reflux for two hours and filtered hot. The solution was concentrated to <NUM>, cooled gradually to room temperature and stirred for <NUM>-<NUM> hours to afford white precipitate that was filtered off to obtain an off-white to beige solid; purity <NUM>%; yield <NUM>% (based on dry). The product was stirred under reflux in heptane (<NUM>) for <NUM>-<NUM> hours, then gradually cooled to <NUM>-<NUM>. Stirring was continued for <NUM> hour. The obtained precipitate [Formula V(a)] was filtered off to afford an off-white to slightly beige solid with purity <NUM>%; yield <NUM>%; m/z <NUM>.

<NUM> (<NUM> mol) of <NUM>"-(tert-butyl)-<NUM>'-(<NUM>-hydroxyethoxy)-<NUM>"-(pyrrolidin-<NUM>-yl)-[<NUM>,<NUM>':<NUM>',<NUM>"-terphenyl]-<NUM>-carbonitrile was suspended in <NUM> NaOH:EtOH solution (<NUM>:<NUM>). The suspension was heated under reflux for <NUM>-<NUM> hours and converted into a dark yellow solution. The reaction medium was cooled to room temperature, diluted with water (<NUM>), acidified with HCl <NUM>% to pH=<NUM> and stirred at room temperature for <NUM> hours. The formed precipitate was filtered off, washed with an ethanol:water <NUM>:<NUM> mixture, and dried under vacuum at <NUM> to afford a Trifarotene [Formula I] as a white powder with purity <NUM>%; m/z <NUM>.

To <NUM> (<NUM> mol) of <NUM>'-hydroxy-<NUM>'-iodo-biphenyl-<NUM>-carbonitrile were added dimethylformamide (<NUM>) and <NUM> (<NUM> mol) of potassium carbonate. The reaction medium was stirred at <NUM> for <NUM>. <NUM> (<NUM> mol) of <NUM>-bromoethyl acetate was added, and the reaction medium was heated to <NUM>-<NUM> and stirred for <NUM> hours. The reaction was terminated by the addition of water (<NUM>). The reaction medium was cooled to <NUM>. The precipitate was filtered off to afford <NUM> of [Formula III(a)]; <NUM>% yield; HPLC purity <NUM>%.

<NUM> (<NUM> mol) of <NUM>-(<NUM>-bromo-2tert-butyl) phenyl)pyrrolidine, <NUM> (<NUM> mol) of potassium acetate anhydrous, <NUM> (<NUM>×<NUM>-<NUM> mol) of Pd-<NUM>, <NUM> ethanol (EtOH) and <NUM> ethylene glycol under nitrogen atmosphere were mixed together. <NUM> (<NUM> mol) of tetrahydroxyborane was added with agitation in one portion. After <NUM> minutes, the temperature rose up to <NUM>-<NUM>. Reaction mixture was stirred at <NUM> for <NUM>-<NUM> hours. A dark brown/grey suspension formed. The reaction was terminated by adding <NUM> water at temperature below <NUM>. The reaction mixture was stirred at <NUM>-<NUM> for <NUM>-<NUM> hours. The solid was filtered off and washed with <NUM> water to afford <NUM> of (<NUM>-(tert-butyl)-<NUM>-(pyrrolidin-<NUM>-yl)phenyl) boronic acid [Formula II(a)]; purity <NUM>%.

To <NUM> (<NUM> mol) of (<NUM>-(tert-butyl)-<NUM>-(pyrrolidin-<NUM>-yl)phenyl) boronic acid were added dimethylacetamide (<NUM>) and <NUM> (<NUM> mol) of <NUM>-((<NUM>'-cyano-<NUM>-iodo-[<NUM>,<NUM>'-biphenyl]-<NUM>-yl)oxy)ethyl acetate. <NUM> potassium phosphate tribasic (<NUM>) was added. The reaction medium is stirred for <NUM> minutes under nitrogen. <NUM> (<NUM> mol) of palladium acetate was added under nitrogen, and the reaction medium was stirred for <NUM> hours at <NUM>. The reaction was terminated by the addition of water (<NUM>). The precipitate was filtered off.

The solid was suspended in heptane (<NUM>) and stirred under reflux for <NUM> hour and hot filtered off. The mother liquor was further heated under reflux for <NUM> hour and cooled gradually to room temperature. The precipitate was filtered off to afford <NUM>-((<NUM>"-(tert-butyl)-<NUM>-cyano-<NUM>"-(pyrrolidin-<NUM>-yl)-[<NUM>,<NUM>':<NUM>',<NUM>"-terphenyl]-<NUM>'-yl)oxy)ethyl acetate, which was further suspended in ethanol (<NUM>) and heated under reflux for <NUM> hours followed by cooling to room temperature. The precipitate was filtered off to afford <NUM> of <NUM>-((<NUM>"-(tert-butyl)-<NUM>-cyano-<NUM>"-(pyrrolidin-<NUM>-yl)-[<NUM>,<NUM>':<NUM>',<NUM>"-terphenyl]-<NUM>'-yl)oxy)ethyl acetate as a white powder with HPLC purity <NUM>%; yield <NUM>%; m/z <NUM>.

<NUM>-((<NUM>"-(tert-butyl)-<NUM>-cyano-<NUM>"-(pyrrolidin-<NUM>-yl)-[<NUM>,<NUM>':<NUM>',<NUM>"-terphenyl]-<NUM>'-yl)oxy)ethyl acetate (<NUM>) in a mixture of EtOH:<NUM>% NaOH aq. solution (<NUM>:<NUM>) was heated under reflux for <NUM> hours. The reaction mixture was cooled to room temperature and acidified to pH <NUM> with HCl <NUM>%. The mixture was stirred at room temperature for <NUM> hours, filtered off, and the cake was washed with EtOH:H<NUM>O <NUM>:<NUM> (<NUM>). Trifarotene HCl salt was dried under vacuum at <NUM>-<NUM> to afford <NUM> of Trifarotene HCl. The XRPD of the resulting sample is shown in <FIG>.

<NUM> Trifarotene HCl salt obtained in Example <NUM> was dissolved under reflux in MeOH (<NUM>). The turbid solution was filtered off through glass filter paper. The solution was left for evaporation at room temperature for <NUM> days.

The product was filtered off and washed with cold MeOH (<NUM>). The product was dried under ambient conditions. The resulting crystal form is the Form B polymorph as determined by XRPD.

<NUM> Trifarotene HCl salt obtained in Example <NUM> was suspended in methyl ethyl ketone (<NUM>) and shaken at <NUM> rpm for <NUM> days at room temperature. The product was filtered off and dried under ambient conditions. The resulting crystal form is the Form A polymorph as determined by XRPD. The XRPD of a Form A polymorph is shown in <FIG>.

<NUM> Trifarotene HCl salt obtained in Example <NUM> was suspended in ethylene glycol (<NUM>) and shaken at <NUM> rpm for <NUM> days at room temperature. The product was filtered off and dried under ambient conditions. The resulting crystal form is the Form C polymorph as determined by XRPD. The XRPD of a Form C polymorph is shown in <FIG>.

<NUM>-((<NUM>"-(tert-butyl)-<NUM>-cyano-<NUM>"-(pyrrolidin-<NUM>-yl)-[<NUM>,<NUM>':<NUM>',<NUM>"-terphenyl]-<NUM>'-yl)oxy)ethyl acetate (<NUM>) in a mixture of EtOH:<NUM>% NaOH aq. solution (<NUM>:<NUM>) was heated under reflux for <NUM> hours. The reaction mixture was cooled to room temperature and acidified to pH <NUM> with HCl <NUM>%. The mixture was stirred at room temperature for <NUM> hours, filtered off, and the cake was washed with EtOH:H<NUM>O <NUM>:<NUM> (<NUM>). Trifarotene was dried under vacuum at <NUM>-<NUM> for <NUM>-<NUM> hours (<NUM> hours) to afford <NUM> of Trifarotene. The resulting crystal form is the Form D polymorph as determined by XRPD. The XRPD of the Form D polymorph is shown in <FIG>.

<NUM> Trifarotene obtained in Example <NUM> was suspended in MeOH (<NUM>) and shaken at <NUM> rpm for <NUM> days at room temperature. The product was filtered off and dried under ambient conditions for <NUM>-<NUM> days (<NUM> days). The resulting crystal form is the Form E polymorph as determined by XRPD. The XRPD of the Form E polymorph is shown in <FIG>.

<NUM> Trifarotene obtained in Example <NUM> was dissolved under reflux in IPA (<NUM>). The turbid solution was filtered off through nylon filter paper. The solution was left for evaporation at room temperature for <NUM> days. The product was filtered off and washed with cold IPA (<NUM>). The product was dried under ambient conditions for <NUM>-<NUM> days (<NUM> days). The resulting crystal form is the Form F polymorph as determined by XRPD. The XRPD of the Form F polymorph is shown in <FIG>.

<NUM> of Trifarotene Form A obtained according to Example <NUM> was suspended in MeOH:H<NUM>O <NUM>:<NUM> (<NUM>). <NUM> N NaOH was added dropwise with pH control, up to pH <NUM>. The mixture was stirred at room temperature for <NUM> minutes, and the precipitate was filtered off. The cake was washed with water (<NUM>). Trifarotene sodium salt was dried under vacuum at <NUM>-<NUM> for <NUM>-<NUM> hours (<NUM> hours) to afford <NUM> of Trifarotene sodium salt. The resulting crystal form is the Form G polymorph as determined by XRPD. The XRPD of the Form G polymorph is shown in <FIG>.

<NUM>-((<NUM>"-(tert-butyl)-<NUM>-cyano-<NUM>"-(pyrrolidin-<NUM>-yl)-[<NUM>,<NUM>':<NUM>',<NUM>"-terphenyl]-<NUM>'-yl)oxy)ethyl acetate (<NUM>) in a mixture of EtOH:<NUM>% NaOH aq. solution (<NUM>:<NUM>) was heated under reflux for <NUM> hours. The reaction mixture was cooled to room temperature and acidified to pH <NUM> with HCl <NUM>%. The mixture was stirred at room temperature for <NUM> hours, filtered off, and the cake was washed with EtOH:H2O <NUM>:<NUM> (<NUM>). Trifarotene was dried under vacuum at <NUM>-<NUM> for <NUM>-<NUM> hours (<NUM> hours) to afford <NUM> of Trifarotene. The resulting crystal form is the Form D polymorph as determined by XRPD. The XRPD of the Form D polymorph is shown in <FIG>.

Claim 1:
A process for the preparation of a compound of formula (I) [Trifarotene], or a salt thereof
<CHM>
comprising hydrolyzing a compound of formula (V)
<CHM>
wherein R<NUM> is hydrogen, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkanoyl group, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkenoyl group, a substituted or unsubstituted linear or branched C<NUM>-C<NUM> alkynoyl group, a substituted or unsubstituted cycloalkanoyl group, a substituted or unsubstituted aryl carbonyl group, a substituted or unsubstituted heterocyle carbonyl group, a substituted or unsubstituted heteroaryl carbonyl group, or a C<NUM>-C<NUM> alkanoyl group comprising a heteroatom; and
wherein Y is a nitrile (CN) or amide (CONH<NUM>);
to obtain the compound of formula (I).