WO2024182418A1

WO2024182418A1 - Methods of preparing trifarotene

Info

Publication number: WO2024182418A1
Application number: PCT/US2024/017515
Authority: WO
Inventors: Ilana Ozer; Yulia KAFTANOV; Elliot Simhon; Andrey DUSHKIN; Shani SHEFFER DEE-NOOR; Hillel Pizem; Avi Avramoff
Original assignee: Taro Pharmaceutical Industries Ltd.; Taro Pharmaceuticals U.S.A., Inc.
Priority date: 2023-02-28
Filing date: 2024-02-27
Publication date: 2024-09-06

Abstract

The present disclosure provides a process for the preparation of Trifarotene. The disclosure also provides for intermediates in the process described herein. Also provided are methods of making polymorph Form E of Trifarotene.

Description

Methods of Preparing Trifarotene

FIELD OF THE INVENTION

[0001] The present disclosure relates to processes and intermediates for the synthesis of Trifarotene. Also provided is a novel polymorph of Trifarotene.

BACKGROUND

[0002] Retinoic acid receptor (RAR) selective compounds can treat acne, lamellar ichthyosis, photoaging and other diseases by modulating skin functions such as epidermal keratinization, differentiation, maturation, and proliferation. 3"-(tert-butyl)-4'-(2-hydroxyethoxy)- 4"-(pyrrolidin-l-yl)-[l,T:3',l"-terphenyl]-4-carboxylic acid, commonly known as Trifarotene, is a potent and selective agonist of RAR-y, the most common RAR found in the skin. Trifarotene is the latest fourth generation retinoid and was approved for the treatment of acne via topical administration by the Food and Drug Administration (FDA) in October 2019.

[0003] Current approaches for the synthesis of Trifarotene include several challenging steps and/or produce moderate to low yield Trifarotene. For example, described in WO 2006/066978, utilizes a reaction that is performed at -78°C and uses two separate protecting groups that must be hydrolyzed under different conditions. WO 2021/119351 uses a reaction in which all functional groups of the intermediates are hydrolyzed in one step. Multiple and complex reaction steps can decrease workflow efficiency and overall yield.

SUMMARY OF THE INVENTION

[0004] In some embodiments, the disclosure provides a process for the preparation of a compound of formula (I) [Trifarotene], or a salt thereof

comprising reacting a compound of formula (III)

HO

with a compound of formula (IV)

to obtain a compound of formula (V)

and hydrolyzing the compound of formula (V) to obtain the compound of formula (I), wherein R¹ and R² are independently hydrogen or a linear or branched C1-C3 alkyl, wherein R¹ and R² can be the same or different or R¹ and R² together form a pinacolate in the presence of a catalyst, wherein X is a halogen or triflate, and wherein Y is a nitrile (CN) or amide (CONH2).

[0005] In some embodiments, the disclosure provides a process for the preparation of a compound of formula (I) [Trifarotene], or a salt thereof

comprising hydrolyzing a compound of formula (II)

in the presence of a base, to obtain a compound of formula (III)

reacting the compound of formula (III) with a compound of formula (IV)

to obtain a compound of formula (V)

HO

and hydrolyzing the compound of formula (V) to obtain the compound of formula (I), wherein R¹ and R² are independently hydrogen or a linear or branched C1-C3 alkyl, wherein R¹ and R² can be the same or different; or R¹ and R² together form a pinacolate in the presence of a catalyst, wherein R³ is hydrogen, a substituted or unsubstituted linear or branched Ci-Cs alkyl, a substituted or unsubstituted linear or branched Ci-Cs alkenyl group, a substituted or unsubstituted linear or branched Ci-Cs 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 substituted or unsubstituted Ci-Cs alkyl group comprising a heteroatom, wherein X is a halogen or triflate, and wherein Y is a nitrile (CN) or amide (CONH2).

[0006] In some embodiments, the X is iodine.

[0007] In some embodiments, the hydrolysis is performed in the presence of a solvent comprising water, methanol (MeOH), ethanol (EtOH), propanol (PrOH), isopropanol (IP A), or any mixture thereof. In some embodiments, the solvent comprises water and ethanol.

[0008] In some embodiments, the reaction is performed in the presence of a solvent comprising toluene, Dimethylacetamide (DMA) dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dioxane, n-butanol (n-BuOH), isopropanol (IP A), dimethyl ether (DME), diethyl ether, or any mixture thereof.

[0009] In some embodiments, the reaction is performed in the presence of a base comprising K2CO3, CH3CO2K, K3PO4, KOtBu, Na₂CO₃, NaHCCh, NaOMe, CaCO₃, Li₂CO₃, CS2CO3, Ag₃PO₄, Ag₂O, T1₂CO₃, TIOEt, T1OH, t-BuNH₂, KOH, NaOH, LiOH, Ba(OH)₂, or combination thereof. [0010] 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(PPh3)2C12 [bis(triphenylphosphine)palladium(II) dichloride]; Pd(PPhs)4 [tetrakis(triphenylphosphine)palladium(0)]; Pd(OAc)2 [palladium(II) diacetate]; XPhos Pd-G3 [(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'- amino-l,r-biphenyl)]palladium(II) methanesulfonate]; SPhos-Pd-G2 [chloro(2- dicyclohexylphosphino-2',6'-dimethoxy-l,r-biphenyl)[2-(2'-amino-l,rbiphenyl)]palladium(II)]; CATACXIUM® A Pd G3 (mesylate[(di(l-adamantyl)-n-butylphosphine)-2-(2'-amino-l,l'- biphenyl)]palladium(II) or [(di(l-adamantyl)-butylphosphine)-2-(2'-amino-l, 1 biphenyl)]palladium(II) methanesulfonate); APhos Pd G3 (palladium G3-(4-(N,N- dimethylamino)phenyl)di-tert-butylphosphine] or [4-(di-tert-butylphosphino)-N,N- dimethylaniline-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate); P(Cys) Pd-G3 (palladium G3 -tri cyclohexylphosphine or [(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate); Allylpalladium(II) chloride dimer (bis(allyl)dichlorodipalladium); or Pd(dppf)C12 [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)].

[0011] In some embodiments, the compounds of formula (III) and formula (IV) are present in a molar ratio of about 1 :10 to about 10: 1, preferably about 1 :5 to about 5:1, more preferably about 1 : 1. In some embodiments, the compounds of formula (III) and formula (IV) are independently present in an amount of about 0.01 to about 1 mol/L (solvent), preferably about 0.05 to about 0.5 mol/L (solvent), more preferably about 0.1 to about 0.4 mol/L (solvent).

[0012] In some embodiments, the catalyst is present at about 0.001 to about 1 molar equivalents relative to the compounds of formula (III) or formula (IV), preferably about 0.002 to about 0.5 molar equivalents relative to the compounds of formula (III) or formula (IV), more preferably about 0.003 to about 0.1 molar equivalents relative to the compounds of formula (III) or formula (IV). In some embodiments, the base is present at about 0.1 to about 10 molar equivalents relative to the compounds of formula (III) or formula (IV), preferably about 1 to about 6 molar equivalents relative to the compounds of formula (III) or formula (IV), more preferably about 2 to about 4 molar equivalents relative to the compounds of formula (III) or formula (IV). [0013] In some embodiments, the pH is adjusted to about 3.4 to about 6.0 after hydrolyzing the compound of formula (V). In some embodiments, the pH is adjusted to about 4.0 to about 6.0 after hydrolyzing the compound of formula (V). In some embodiments, the pH is adjusted to about 4.5 to about 6.0 after hydrolyzing the compound of formula (V). In some embodiments, the pH is adjusted to about 5.0 to about 6.0 after hydrolyzing the compound of formula (V). In some embodiments, the pH is adjusted to 5.5 after hydrolyzing the compound of formula (V).

[0014] In some embodiments, the disclosure provides a compound of formula (III)

wherein X is a halogen or triflate, and wherein Y is a nitrile (CN) or amide (CONH2).

[0015] In some embodiments, the disclosure provides a process for the preparation of a compound of formula (III)

comprising hydrolyzing a compound of formula (II)

wherein R³ is hydrogen, a substituted or unsubstituted linear or branched Ci-Cs alkyl, a substituted or unsubstituted linear or branched Ci-Cs alkenyl group, a substituted or unsubstituted linear or branched Ci-Cs 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 substituted or unsubstituted Ci-Cs alkyl group comprising a heteroatom, wherein X is a halogen or triflate, and wherein Y is a nitrile (CN) or amide (CONH2) in the presence of a base.

[0016] In some embodiments, the process further comprises further comprising preparing a compound of formula (I) [Trifarotene], or a salt thereof

by reacting the compound of formula (ITT) with a compound of formula (IV)

to obtain a compound of formula (V)

wherein R¹ and R² are independently hydrogen or a linear or branched C1-C3 alkyl, wherein R¹ and R² can be the same or different; or R¹ and R² together form a pinacolate in the presence of a catalyst, wherein Y is a nitrile (CN) or amide (CONH2) and hydrolyzing the compound of formula (V) to obtain the compound of formula (I).

[0017] In some embodiments, the disclosure provides a Form E polymorph of Trifarotene, comprising providing Trifarotene according to a process described herein and suspending the Trifarotene in ethyl acetate to obtain a Form E polymorph of Trifarotene.

[0018] In some embodiments, 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 20 of 3.8±0.2, 7.4±0.2, 8.9±0.2, 10.9±0.2, 13.1±0.2, 14.6±0.2, 16.6±0.2, 18.2±0.2, 22.3±0.2, and 24.4±0.2 degrees. In some embodiments, any single impurity in the Form E polymorph is less than 0.15%.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIG. 1 shows an exemplary process for the preparation of Trifarotene [Formula (I)] as described in embodiments herein.

[0020] FIG. 2 is the XRD spectrum of Trifarotene polymorph Form E.

DETAILED DESCRIPTION OF THE INVENTION

[0021] 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. In some embodiments, the methods described herein provide for improved methods of making polymorph Form E of Trifarotene. In some embodiments, the methods described herein provide for Trifarotene of increased purity.

[0022] 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. [0023] 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 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% 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.

[0024] 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.”

[0025] 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 compound or method of making as described in the present disclosure. Furthermore, the compounds of the present disclosure can be used to achieve and optimize the methods of making of the present disclosure.

[0026] 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.

[0027] 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. [0028] 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 1 to about 10 hydrogen-substituted carbon atoms. Alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, 1 -methylpropyl, isobutyl, t-butyl, 2,2-dimethylbutyl, n-pentyl, 2-methylpentyl, 3- methylpentyl, 4-methylpentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. In some embodiments, the term “alkyl” is modified by the number of carbon atoms in the chain. For example, the term “C1-C3 alkyl” includes any alkyl group with 1 to 3 carbons.

[0029] Unless specified otherwise, the term “alkenyl” refers to a partially unsaturated (on in some embodiments, fully unsaturated) linear or branched chain including about 2 to about 10 hydrogen-substituted carbon atoms that contain at least one double bond. Alkenyl groups include, e.g., vinyl, allyl, 2-methylprop-l-enyl, but-l-enyl, but-2-enyl, but-3-enyl, buta-l,3-dienyl, penta- 1, 3-dienyl, penta-2, 4-dienyl, 2-methylbut-l-enyl, 2-methylpent-l-enyl, 4-methylpent-l-enyl, 4- methylpent-2-enyl, 2-methylpent-2-enyl, 4-methylpenta- 1,3-dienyl, hexen-l-yl, hepten-l-yl, octen-l-yl, nonen-l-yl, decen-l-yl, and the like.

[0030] Unless specified otherwise, the term “alkynyl” refers to a partially unsaturated linear or branched chain including about 2 to about 10 hydrogen-substituted carbon atoms that contains at least one triple bond. Alkynyl groups include, e.g., ethynyl, 1-propynyl, 2-propynyl, 2- methylprop-l-ynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1,3-butadiynyl, 3-methylbut-l-ynyl, 4- methylbut-ynyl, 4-methylbut-2-ynyl, 2-methylbut-l-ynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4- pentynyl, 1,3 -pentadiynyl, 1,4-pentadiynyl, 3 -methylpent- 1-ynyl, 4-methylpent-2-ynyl, 4- methylpent-2-ynyl, 1 -hexynyl, 1-heptynl, 1 -octynyl, 1-nonynyl, 1 -decynyl, and the like.

[0031] Unless specified otherwise, the term “cycloalkyl” refers to a saturated or unsaturated ring including about 3 to about 10 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.

[0032] Unless specified otherwise, the term “aryl” refers to an aromatic mono- or bicyclic group containing from about 5 to about 14 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.

[0033] Unless specified otherwise, a “heterocycle” refers to a monocyclic non-aromatic hydrocarbon ring containing about 3 to about 10 carbon atoms, or a bicyclic non-aromatic hydrocarbon ring system containing about 7 to about 14 carbon atoms, wherein one or more of the carbon atoms of the in the hydrocarbon ring or ring system is replaced by a heteroatom. Examples of heterocycles include but are not limited to azepan-l-yl, piperidinyl, e.g., piperidin-l-yl and piperidin-4-yl, piperazinyl, e.g., N-piperazinyl and l-alkylpiperazine-4-yl, morpholine-4-yl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiophen, sulfolanyl, sulfolenyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxazolidinon-yl. A “heterocycle carbonyl” refers to a carbonyl (C=O) attached to a heterocycle group. In some embodiments, the heteroatom is N, O, P or S. In some embodiments, the heteroatom is N or O.

[0034] 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(l,2-a)pyridinyl, indazolyl, purinyl, pyrrolo(2,3-c)pyridinyl, pyrrolo(3,2- c)pyridinyl, pyrrolo(2,3-b)pyridinyl, pyrazolo(l,5-a)pyridinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3- oxadiazolyl, thiazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3- thiadiazolyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, benzofuranyl, isobenzofuranyl, thiophenyl, dihydrothiophenyl, tetrahydrothiophenyl, benzothiophenyl, benzoisothiophenyl, pyridyl, piperidinyl, quinolinyl, isoquinolinyl, quinolizinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyranyl, tetrahydropyranyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, chromenyl, morpholinyl, diazepinyl, benzodiazepinyl, and the like. A “heteroaryl carbonyl” refers to a carbonyl (C=O) attached to a heteroaryl group.

[0035] 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., Ci-Ce alkyl), alcohol, ketone, and the like. The term “unsubstituted” refers where the substituent has not had a hydrogen substituted with a different group.

[0036] A “linear” molecule contains a single backbone. For example, a “linear Ci-C»” 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 Ci-C„” molecule is derived from a linear Ci-C„ 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.

[0037] 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.

[0038] In some embodiments, the present disclosure provides a process for the preparation of a compound of Formula (I) [Trifarotene], or a salt thereof

comprising reacting a compound of formula (III)

with a compound of formula (IV)

to obtain a compound of formula (V)

and hydrolyzing the compound of formula (V) to obtain the compound of formula (I), wherein R¹ and R² are independently hydrogen or a linear or branched C1-C3 alkyl, wherein Ri and R2 can be the same or different; or Ri and R2 together form a pinacolate in the presence of a catalyst, wherein X is a halogen or triflate, and wherein Y is a nitrile (CN) or amide (CONH2).

[0039] In some embodiments, the present disclosure provides a process for the preparation of a compound of formula (I) [Trifarotene], or a salt thereof

comprising hydrolyzing a compound of formula (II)

in the presence of a base, to obtain a compound of formula (III)

reacting the compound of formula (III) with a compound of formula (IV)

to obtain a compound of formula (V)

and hydrolyzing the compound of formula (V) to obtain the compound of formula (I), wherein R¹ and R² are independently hydrogen or a linear or branched C1-C3 alkyl, wherein R¹ and R² can be the same or different, or R¹ and R² together form a pinacolate in the presence of a catalyst, wherein R³ is a hydrogen, substituted or unsubstituted linear or branched Ci-Cs alkyl, a substituted or unsubstituted linear or branched Ci-Cs alkenyl group, a substituted or unsubstituted linear or branched Ci-Cs 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 substituted or unsubstituted Ci-Cs alkyl group comprising a heteroatom, wherein X is a halogen or triflate, and wherein Y is a nitrile (CN) or amide (CONH2). In some embodiments, R³ is hydrogen. In some embodiments, R³ is methyl.

[0040] 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.

[0041] In some embodiments, wherein the X is iodine. In some embodiments, Y is a nitrile. In some embodiments, Y is an amide.

[0042] In some embodiments, the methods provided herein advantageously simplify the preparation process or Trifarotene by reducing or eliminating reaction steps that require harsh conditions (e g., performed in extreme heat (e g., > 50°C) or cold (e g., < -10°C)).

[0043] 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. 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 solvent comprises water and ethanol. In some embodiments, the solvent comprises dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dioxane, n-butanol (n-BuOH), isopropanol (IP A), dimethyl ether (DME), diethyl ether, or any mixture thereof. 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 (IP A), or any mixture thereof. In some embodiments, the hydrolysis is performed in the presence of water and ethanol.

[0044] In some embodiments, hydrolysis is performed further in the presence of a base. In some embodiments, the base comprises potassium carbonate (K2CO3), potassium acetate (CH3CO2K), potassium phosphate (K3PO4), potassium tert-butoxide (KOtBu), sodium carbonate (Na2COs), sodium bicarbonate (NaHCCh), sodium methoxide (NaOMe), calcium carbonate (CaCCE), lithium carbonate (Li2COj), cesium carbonate (CS2CO3), silver phosphate (AgiPCh), silver oxide (Ag2O), thallium carbonate (TI2CO3), thallium ethoxide (TIOEt), thallium hydroxide (T1OH), tert-butyl amine (t-BuNH2), potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), barium hydroxide (Ba(OH)2), or any mixture thereof.

[0045] In some embodiments, the compound of Formula (V) is present in the hydrolysis reaction at about 0.1 to about 1 mol/L (solvent), about 0.2 to about 0.8 mol/L (solvent), or about 0.3 to about 0.5 mol/L (solvent). In some embodiments, the compound of Formula (V) is present in the hydrolysis reaction at about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about 1 mol/L (solvent). In some embodiments, the hydrolysis is performed at a pH of about 4 to about 6.5, about 4.2 to about 6.2 about 4.5 to about 6, about 4.7 to about 5.7, or about 5 to about 5.5. In some embodiments, the hydrolysis reaction is performed at pH about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6, about 6.1, about 6.2, about 6.3, about 6.4, or about 6.5.

[0046] In some embodiments, the catalyst for the reaction between the compounds of Formula (III) and Formula (IV) 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 at least two atoms of the metal. In some embodiments, the catalyst comprises 1 to 6 atoms of the metal. In some embodiments, the catalyst comprises 2 to 5 atoms of the metal. In some embodiments, the catalyst comprises 2 to 4 atoms of the metal. In some embodiments, the catalyst comprises 1, 2, 3, 4, 5, or 6 atoms of the metal. Palladium-catalyzed coupling reactions are further described, e.g., in US 2006/0264629 and US 2010/0184739.

[0047] In some embodiments, the catalyst is a palladium catalyst. In some embodiments, the palladium catalyst is Pd(PPh3)2C12 [bis(triphenylphosphine)palladium(II) dichloride]; Pd(PPh3)4 [tetrakis(triphenylphosphine)palladium(0)]; Pd(OAc)2 [palladium(II) diacetate]; XPhos Pd-G3 [(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,r-biphenyl)[2-(2'-amino-l,l'- biphenyl)]palladium(II) methanesulfonate]; SPhos-Pd-G2 [chloro(2-dicyclohexylphosphino-2',6'- dimethoxy-l,r-biphenyl)[2-(2'-amino-l,r-biphenyl)]palladium(II)]; CATACXIUM® A Pd G3 (mesylate[(di(l-adamantyl)-n-butylphosphine)-2-(2'-amino-l, 1 '-biphenyl)]palladium(II) or [(di( 1 -adamantyl)-butylphosphine)-2-(2'-amino- 1 , 1 '-biphenyl)]palladium(II) methanesulfonate); APhos Pd G3 (palladium G3-(4-(N,N-dimethylamino)phenyl)di-tert-butylphosphine] or [4-(di- tert-butylphosphino)-N,N-dimethylaniline-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate); P(Cy3) Pd-G3 (palladium G3-tricyclohexylphosphine or [(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate);

Allylpalladium(II) chloride dimer (bis(allyl)di chlorodipalladium); or Pd(dppf)C12 [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II)].

[0048] In some embodiments, the catalyst is a copper catalyst. In some embodiments, the copper catalyst is copper(I) chloride, [(o-(di-/c/7-butylphosphino)-,V,A'-dimethylaniline)copper iodide]2, [(< -(di-/c 7-butylphosphino)-A^f,/V-dimethylaniline)copper fluoride]2. In some embodiments, the catalyst is a nickel catalyst. In some embodiments, the nickel catalyst is NiCh, NiBr2, Nib, GjDenP-Ni, (dppf)Ni(cinnamyl)Cl, (PCya^NiCh, or Ni(cod)2. Further exemplary catalysts are provided in, e.g., Tasker et al., Nature 509(7500):299-309 (2014); Yang et al., Angew Chem Int Eld Engl 50(17):3904-3907 (2011); Barder et al., J Am Chem Soc 127(13):4685-4696 (2005); Bedford et al., Chem Commun (Camb) 42:6430-6432 (2009); and Catalysts vol. 9, ISSN 2073-4344 (2019). [0049] In some embodiments, the reaction between the compounds of Formula (III) and Formula (IV) 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 PPhs, PCys, P(o-tolyl)3, P(i-Pr)3, P(O-Pr-i)3, n-BuP(l-Ad)2, P(t-Bu)2(p-NMe2-Ph), a dialkylbiaryl ligand (e.g., as described in Martin et al., Acc Chem Res 41: 1461 (2008)), a bidentate phosphine ligand such as DPPF, DPPE or DPPP, a carbene-type ligand (e g., as described in Kuwano et al., Org Lett 7:945 (2005)), an olefin-type ligand (e.g., as described in Tao et al., J Org Chem 69:4330 (2004)), an amine, or imine (e.g., as described in Tao et al., J Org Chem 69:4330 (2004)). In some embodiments, the ligand and catalyst are provided in the reaction as a preformed complex. For example, Pd(PPh3)4 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.

[0050] 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., Suzuki, J Organometallic Chem 576: 147-168 (1999); Miyaura et al., Chem Rev 95:2457-2483 (1995); Chemler et al., Angew Chem Int Ed Engl 40:4544-4568 (2001); Franzen, Can J Chem 78:957-962 (2000); Suzuki, Proc Jpn Acad, Ser B. 80(8):359 (2004); and Paul et al., RSC Adv 5:42193 (2015).

[0051] In some embodiments, the compounds of formula (III) and formula (IV) are present in a molar ratio of about 1 : 10 to about 10: 1, about 1 :5 to about 5: 1, about 1 :3 to about 3:1, about 1 :2 to about 2:1, or about 1 : 1 when reacted together. In some embodiments, the compounds of formula (III) and formula (IV) are independently present in an amount of about 0.01 mol/L to about 1 mol/L (solvent), about 0.05 mol/L to about 0.5 mol/L (solvent), or about 0.1 mol/L to about 0.4 mol/L (solvent) when reacted together.

[0052] In some embodiments, the pH is reduced after the hydrolyzing of the compound of Formula (V). In some embodiments, the pH is reduced to about 4 to about 6.5, about 4.2 to about 6.2 about 4.5 to about 6, about 4.7 to about 5.7, or about 5 to about 5.5. In some embodiments, the hydrolysis reaction is performed at pH about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6, about 6.1, about 6.2, about 6.3, about 6.4, or about 6.5.

[0053] In some embodiments, the catalyst is present at about 0.001 to about 1 molar equivalents relative to the compounds of formula (III) or formula (IV), preferably about 0.002 to about 0.5 molar equivalents relative to the compounds of formula (III) or formula (IV), more preferably about 0.003 to about 0.1 molar equivalents relative to the compounds of formula (III) or formula (IV).

[0054] In some embodiments, the base is present at about 0.1 to about 10 molar equivalents relative to the compounds of formula (III) or formula (IV), preferably about 1 to about 6 molar equivalents relative to the compounds of formula (III) or formula (IV), more preferably about 2 to about 4 molar equivalents relative to the compounds of formula (III) or formula (IV).

[0055] In some embodiments, the disclosure provides a compound of formula (III)

[0056] In some embodiments, the present disclosure provides a process for the preparation of a compound of formula (III)

comprising hydrolyzing a compound of formula (II)

wherein R³ is hydrogen, a substituted or unsubstituted linear or branched Ci-Cg alkyl, a substituted or unsubstituted linear or branched Ci-Cs alkenyl group, a substituted or unsubstituted linear or branched Ci-Cs 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 substituted or unsubstituted Ci-Cs alkyl group comprising a heteroatom, wherein X is a halogen or tritiate, and wherein Y is a nitrile (CN) or amide (CONH2) in the presence of a base. In some embodiments, R³ is hydrogen. In some embodiments, R³ is methyl.

[0057] In some embodiments, the process for the preparation of a compound of formula (III) further comprises preparing a compound of formula (I) [Trifarotene], or a salt thereof

[0058]

by reacting the compound of formula (III) with a compound of formula (IV)

to obtain a compound of formula (V)

wherein R¹ and R² are independently hydrogen or a linear or branched C1-C3 alkyl, wherein R¹ and R² can be the same or different; or R¹ and R² together form a pinacolate in the presence of a catalyst, wherein Y is a nitrile (CN) or amide (CONH2), and hydrolyzing the compound of formula (V) to obtain the compound of formula (I). In some embodiments, the pH is adjusted to a pH of about 3.4 to about 6.0 after hydrolyzing the compound of formula (V).

[0059] In some embodiments, some embodiments, the compound of Formula (IV) is selected from the following:

[0060] In some embodiments, R³ and Y of the compound of Formula (II) are defined herein. In some embodiments, X of the compound of Formula (II) is a leaving group for a Suzuki coupling reaction. Examples of leaving groups for Suzuki reactions are further provided in, e g., Liu et al., Org Lett 7(6): 1149-1151 (2005); El-Beqawi et al., Dyes Pigments 159:551-556 (2018); Chemler et al., Angew Chem Int Ed 40:4544 (2001). In some embodiments, X is a halogen, e.g., fluorine, chlorine, bromine, or iodine. In some embodiments, X is a triflate (-OSO2CF3; also abbreviated as -OTf) group. In some embodiments, R³ is hydrogen, Y is a nitrile or amide, and X is a halogen or triflate. In some embodiments, R³ is methyl, Y is a nitrile or amide, and X is a halogen or triflate. In some embodiments, R³ is a hydrogen, Y is a nitrile or amide, and X is a halogen or triflate. In some embodiments, R³ is methyl, Y is a nitrile, and X is iodine.

[0061] In some embodiments, the compound of Formula (II) is selected from the following:

[0062] In some embodiments, the disclosure provides an improved process for making a novel polymorph of the compound of Formula (I), Trifarotene, wherein the polymorph has a higher purity level. In some embodiments, the novel polymorph Form E described herein can be used to provide a desired release property or other desired pharmaceutical properties or Trifarotene.

[0063] In some embodiments, the disclosure provides a process for preparing a Form E polymorph of Trifarotene-HCl, comprising: (a) providing Trifarotene according to a process described herein; (b) suspending the Trifarotene in ethyl acetate to obtain a Form E polymorph of Trifarotene. In some embodiments, any single impurity in the Form E polymorph is less than 0.15%. In some embodiments, the Form E polymorph shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 20 of3.8±0.2, 7.4±0.2, 8.9±0.2, 10.9±0.2, 13.1±0.2, 14.6±0.2, 16.6±0.2, 18.2±0.2, 22.3±0.2, and 24.4±0.2 degrees. [0064] All references cited herein, including patents, patent applications, papers, textbooks and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated herein by reference in their entirety.

EXAMPLES

Example 1. Synthesis of 3"-(tert-butyl)-4'-(2-hydroxyethoxy)-4"-(pyrrolidin-l-yl)-rLr:3' "- terphenyll-4-carboxylic acid [Trifarotenel

[0065] A. Preparation of 2-((4'-cyano-3-iodo-[l,l'-biphenyl]-4-yl)oxy)ethyl acetate

[Formula Ila]

[0066] 2-((4'-cyano-3-iodo-[l,l'-biphenyl]-4-yl)oxy)ethyl acetate was prepared according to methods disclosed in WO 2021/119351. To 180 g (0.56 mol) of 4'-hydroxy-3'-iodo-biphenyl-4- carbonitrile were added dimethylformamide (900 mL) and 247 g (1.8 mol) of potassium carbonate. The reaction medium was stirred at room temperature. 117 g (0.7 mol) of 2-bromoethyl acetate was added, and the reaction medium was heated to 60-65°C and stirred for 6 hours. The reaction was terminated by the addition of water (1800 mL). The precipitate was filtered off to afford 213.5 g of 2-((4'-cyano-3-iodo-[l,l'-biphenyl]-4-yl)oxy)ethyl acetate; 90.6% yield; HPLC purity 97%.

[0067] B. Conversion of 2-((4'-cyano-3-iodo-[l,l'-biphenyl]-4-yl)oxy)ethyl acetate [Formula Ila] to 2-((4'-cyano-3-iodo-[l,l'-biphenyl]-4-yl)oxy)ethanol [Formula III]

[0068] The 2-((4'-cyano-3-iodo-[l,l'-biphenyl]-4-yl)oxy)ethyl acetate was suspended in ethanol (1600 mL). Potassium carbonate (200 g) was added to the mixture. The mixture was heated for 3 to 4 hours. The reaction terminated by addition of water (100 mL) to precipitate the 2-((4'- cyano-3-iodo-[l,l'-biphenyl]-4-yl)oxy)ethanol. The solid was filtered off, washed with water and dried under vacuum.

[0069] C. Synthesis of 2-((3"-(tert-butyl)-4-cyano-4"-(pyrrolidin-l-yl)-[l,l':3',l''- terphenyl]-4'-yl)oxy) ethanol [Formula V]

[0070] 2-((4'-cyano-3-iodo-[l,l'-biphenyl]-4-yl)oxy)ethanol was dissolved in Dimethylacetamide (DMA) (2000 mL). 140 g of (3-(tert-butyl)-4-(pyrrolidin-l-yl)phenyl) boronic acid [Formula IV], which was prepared according to methods disclosed in Example 4 of WO 2021/119351), was added to the mixture. 35 g of tribasic potassium phosphate was added to the reaction mixture. The reaction medium was mixed at room temperature. The catalyst Pd(OAc)2 (4 g) was added to the reaction medium and stirred. . The reaction was terminated by the addition of water (500 mL). The precipitate was filtered off.

[0071] D. Synthesis of 3"-(tert-butyl)-4'-(2-hydroxyethoxy)-4"-(pyrrolidin-l-yl)-[l,l':3',l"- terphenyl]-4-carboxylic acid [Trifarotene; Formula I] from Formula V

[0072] 2-((3"-(tert-butyl)-4-cyano-4"-(pyrrolidin-l-yl)-[l,r:3',r'-terphenyl]-4'- yl)oxy)ethanol (Formula V) was suspended in ethanol (1100 mL) and water (600 mL) followed by a 50% sodium hydroxide solution (300 mL). The reaction medium was stirred under reflux. The reaction medium was acidified to pH 3.0 to 6.0 using HC1 32%. The white precipitate was filtered off to afford crude 3"-(tert-butyl)-4'-(2-hydroxyethoxy)-4"-(pyrrolidin-l-yl)-[l,l':3',l"- terphenyl]-4-carboxylic acid, which was suspended in ethyl acetate (1000 ml) followed by filtration of the product. The white wet solid of 3"-(tert-butyl)-4'-(2-hydroxyethoxy)-4"- (pyrrolidin-l-yl)-[l,r:3',l"-terphenyl]-4-carboxylic acid was suspended in water (4000 mL) and heated to 70 tolOO°C for 5 to 9 hours and filtered off. The white wet powder was then dried under vacuum to afford 120 g of 3"-(tert-butyl)-4'-(2-hydroxyethoxy)-4"-(pyrrolidin-l-yl)-[l,r:3',l"- terphenyl]-4-carboxylic acid pure [Trifarotene; Formula I], 2-((3"-(tert-butyl)-4-cyano-4"-

(pyrrolidin-l-yl)-[l,r:3',l"-terphenyl]-4'-yl)oxy) ethanol was analyzed by HPLC analytical method.

Example 2: Comparison of the methods of the present disclosure to previously described methods [0073] The total yield from the methods of the present disclosure were compared to the yield of a previously known method of making Trifarotene, as found in US 17/756,994. The previously known method combined a Trifarotene nitrile ether precursor (e.g., 4-((4-bromo-2-(tert- butyl)phenyl)amino)-4-oxobutanoic acid, “Trif-nitrile ether”), with a Trifarotene borate precursor (e.g., (3-(tert-butyl)-4-pyrrolidine-l-yl)phenyl)boronic acid, “Trif-Boronic”) to form a Trifarotene nitrile ester (referred to herein as “the Trif-nitrile ester pathway”). The present disclosure provides a new method of synthesis in which the Trifarotene nitrile ether precursor is first converted to a Trifarotene alcohol precursor (Formula III).

[0074] HPLC analysis was conducted on the samples using both the old pathway (the Trif- nitrile ester pathway) and the new pathway (Trif-alcohol ether pathway). A RP18 column, was used. Using gradient of water: 0.02M Ammonium acetate: acetonitrile, with a flow rate of 1.0 mL/min.

[0075] A comparison of the yields resulting from the two pathways is presented in Table 1.

Table 1

[0076] The data demonstrates that the Trif-alcohol ether pathway described herein results in a significant increase in yield relative to the previously used method, while maintaining good purity.

Example 3, Preparation of Trifarotene - Form E Polymorph and Its Analysis

[0077] 150 mg Trifarotene obtained in Example 1 was suspended in 5 mL of MeOH or

EtOAc and shaken at 300 rpm for 2 days at room temperature. The product was filtered off and dried under ambient conditions for 2-6 days (3 days). The resulting crystal form is the Form E polymorph as determined by XRPD and IR spectrum analysis.

[0078] An exemplary diffraction pattern of the Trifarotene Form E polymorph can be found in Figure 2. Table 2 lists the main X-Ray powder diffraction peaks. The XRD is accordance with what is described in US 17/756,994, incorporated herein in its entirety.

Table 2: X-Ray powder main diffraction peaks (°20) of Trifarotene

[0079] The samples were analyzed by HPLC analytical method described above. Table 3 shows the HPLC purity results of the Form E polymorph of Trifarotene.

Table 3

[0080] The purity level of Trifarotene Form E polymorphs (as determined by HPLC prepared in EtOAc 1 :10: 1 (samples 2, 3 and 4) was higher than the purity level observed for the Form E polymorphs prepared in MeOH 1 : 10: 1 (sample 1) and EtOH 1 : 10: 1 (sample 5, 6 and 7). See the Trifarotene peak at 30.2 min (bolded). These results indicate that the preparation of Trifarotene - Form E Polymorph using ethyl acetate provides Trifarotene with higher purity compared to the other solvents tested. Furthermore, all impurities in Trifarotene Form E Polymorph suspended in ethyl acetate are less than 0.15%.

Claims

WHAT IS CLAIMED IS:

1. A process for the preparation of a compound of formula (I) [Trifarotene], or a salt thereof

comprising a) reacting a compound of formula (III)

HO

with a compound of formula

to obtain a compound of formula (V)

and b) hydrolyzing the compound of formula (V) to obtain the compound of formula (I); wherein R¹ and R² are independently hydrogen or a linear or branched C1-C3 alkyl, wherein R¹ and R² can be the same or different; or R¹ and R² together form a pinacolate in the presence of a catalyst, wherein X is a halogen or triflate; and wherein Y is a nitrile (CN) or amide (CONH2).

2. A process for the preparation of a compound of formula (I) [Trifarotene], or a salt thereof

comprising a) hydrolyzing a compound of formula (II)

in the presence of a base, to obtain a compound of formula (III)

HO

(Hi); b) reacting the compound of formula compound of formula (IV) i ’

(IV) to obtain a compound of formula (V)

and c) hydrolyzing the compound of formula (V) to obtain the compound of formula (I); wherein R¹ and R² are independently hydrogen or a linear or branched C1-C3 alkyl, wherein R¹ and R² can be the same or different; or R¹ and R² together form a pinacolate in the presence of a catalyst, wherein R³ is hydrogen, a substituted or unsubstituted linear or branched Ci-Cs alkyl, a substituted or unsubstituted linear or branched Ci-Cs alkenyl group, a substituted or unsubstituted linear or branched Ci-Cs 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 substituted or unsubstituted Ci- Cs alkyl group comprising a heteroatom; wherein X is a halogen or triflate; and wherein Y is a nitrile (CN) or amide (CONH2).

3. The process according to claim 1 or 2, wherein the X is iodine.

4. The process according to any one of claims 1 to 3, wherein the hydrolysis is performed in the presence of a solvent comprising water, methanol (MeOH), ethanol (EtOH), propanol (PrOH), isopropanol (IP A), or any mixture thereof.

5. The process according to claim 4, wherein the solvent comprises water and ethanol.

6. The process according to any one of claims 1 to 5, wherein the reaction is performed in the presence of a solvent comprising toluene, Dimethylacetamide (DMA) dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dioxane, n-butanol (n-BuOH), isopropanol (IP A), dimethyl ether (DME), diethyl ether, or any mixture thereof.

7. The process according to any one of claims 1 to 6, wherein the reaction is performed in the presence of a base comprising K2CO3, CH3CO2K, K3PO4, KOtBu, Na2CO3, NaHCCh, NaOMe, CaCCk Li₂CO₃, CS2CO3, Ag₃PO4, Ag₂O, TI2CO3, TIOEt, T10H, t-BuNH₂, KOH, NaOH, LiOH, Ba(0H)2, or combination thereof.

8. The process according to any one of claims 1 to 7, wherein the catalyst comprises a metal selected from Pd, Cu, or Ni.

9. The process according to claim 8, wherein the catalyst comprises at least two atoms of the metal.

10. The process according to claim 8, wherein the catalyst is a Pd catalyst selected from:

(i) Pd(PPh3)2Ch [Bis(triphenylphosphine)palladium(II) dichloride];

(ii) Pd(PPh3)4 [Tetrakis(triphenylphosphine)palladium(0)];

(iii) Pd(OAc)2 [Palladium (II) diacetate];

(iv) XPhos Pd-G3 [(2-Dicyclohexylphosphino-2',4',6'-triisopropyl-l,T-biphenyl)[2- (2'-amino-l, 1 '-biphenyl)]palladium(II) Methanesulfonate];

(v) SPhos-Pd-G2 [Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-l,l'- biphenyl)[2-(2'-amino-l,T-biphenyl)]palladium(Il)];

(vi) CATACXIUM® A Pd-G3 [Mesylate[(di(l-adamantyl)-n-butylphosphine)-2-(2'- amino-1, 1 '-biphenyl)]palladium(II), [(Di(l-adamantyl)-butylphosphine)-2-(2'- amino-1, 1 '-biphenyl)]palladium(II) Methanesulfonate];

(vii) APhos-Pd-G3 [Palladium G3-(4-(N,N-Dimethylamino)phenyl)di-tert- butylphosphine, [4-(Di-tert-butylphosphino)-N,N-dimethylaniline-2-(2'- aminobiphenyl)]palladium(II) Methanesulfonate];

(viii) P(Cy3) Pd-G3 [(Tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II) Methanesulfonate];

(ix) Allylpalladium(II) chloride dimer Bis(allyl)dichlorodipalladium; or

(x) Pd(dppf)Ch [l,T-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)].

11. The process according to any one of claims 1 to 10, wherein the compounds of formula (III) and formula (IV) are present in a molar ratio of about 1 : 10 to about 10: 1, preferably about 1 : 5 to about 5: 1, more preferably about 1 : 1.

12. The process according to any one of claims 1 to 10, wherein the compounds of formula (III) and formula (IV) are independently present in an amount of about 0.01 to about 1 mol/L (solvent), preferably about 0.05 to about 0.5 mol/L (solvent), more preferably about 0.1 to about 0.4 mol/L (solvent).

13. The process according to any one of claims 1 to 12, wherein the catalyst is present at about 0.001 to about 1 molar equivalents relative to the compounds of formula (III) or formula (IV), preferably about 0.002 to about 0.5 molar equivalents relative to the compounds of formula (III) or formula (IV), more preferably about 0.003 to about 0.1 molar equivalents relative to the compounds of formula (III) or formula (IV).

14. The process according to claim 7 , wherein the base is present at about 0.1 to about 10 molar equivalents relative to the compounds of formula (III) or formula (IV), preferably about 1 to about 6 molar equivalents relative to the compounds of formula (III) or formula (IV), more preferably about 2 to about 4 molar equivalents relative to the compounds of formula (III) or formula (IV).

15. The process according to any one of claims 1 to 13, wherein the pH is reduced to about 3.4 to about 6.0 after hydrolyzing the compound of formula (V).

16. A compound of formula (III)

wherein X is a halogen or triflate; and wherein Y is a nitrile (CN) or amide (CONH2).

17. A process for the preparation of a compound of formula (III)

comprising hydrolyzing a compound of formula (II)

wherein R³ is hydrogen, a substituted or unsubstituted linear or branched C1-C8 alkyl, a substituted or unsubstituted linear or branched Ci-Cs alkenyl group, a substituted or unsubstituted linear or branched Ci-Cs 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 substituted or unsubstituted Ci- Cs alkyl group comprising a heteroatom; wherein X is a halogen or triflate; and wherein Y is a nitrile (CN) or amide (CONH2), in the presence of a base.

18. The process of claim 17, further comprising preparing a compound of formula (I) [Trifarotene], or a salt thereof

by reacting the compound of formula (III) with a compound of formula (IV)

to obtain a compound of formula (V)

wherein R¹ and R² are independently hydrogen or a linear or branched C1-C3 alkyl, wherein R¹ and R² can be the same or different; or R¹ and R² together form a pinacolate in the presence of a catalyst, wherein Y is a nitrile (CN) or amide (CONH2); and c) hydrolyzing the compound of formula (V) to obtain the compound of formula (I).

19. The method of claim 18, wherein the pH is adjusted to a pH of about 3.4 to about 6.0 after the hydrolysis of (c).

20. A process for preparing a Form E polymorph of Trifarotene, comprising: a) providing Trifarotene according to the process of any one of claims 1 to 19; b) suspending the Trifarotene in ethyl acetate to obtain a Form E polymorph of Trifarotene.

21. The process of claim 20, wherein any single impurity is less than 0.15%.

2. The process of claim 21, wherein an X-ray powder diffraction (XRPD) comprising three or more 29 values selected from 3.8±0.2, 7.4±0.2, 8.9±0.2, 10.9±0.2, 13.1±0.2, 14.6±0.2, 16.6±0.2, 18.2±0.2,

22.3±0.2, and 24.4±0.2.