Method for preparing trifarotene

Abstract

The present disclosure provides processes for the preparation of trifarotene. The present disclosure also provides intermediates in the processes described herein. Also provided is a method for making polymorphic Form E of trifarotene.

Description

[Technical Field]

[0001] The present disclosure relates to processes and intermediates for the synthesis of trifarotene. Also provided are novel polymorphs of trifarotene. [Background technology]

[0002] Retinoic acid receptor (RAR)-selective compounds can treat acne, lamellar ichthyosis, photoaging, and other diseases by regulating skin functions such as epidermal keratinization, differentiation, maturation, and proliferation. 3'-(tert-butyl)-4'-(2-hydroxyethoxy)-4'-(pyrrolidin-1-yl)-[1,1':3',1'-terphenyl]-4-carboxylic acid, commonly known as trifarotene, is a potent and selective agonist of RAR-γ, the most common RAR found in skin. Trifarotene is the latest fourth-generation retinoid and was approved by the U.S. Food and Drug Administration (FDA) in October 2019 for the treatment of acne via topical administration.

[0003] Current approaches to the synthesis of trifarotene involve several difficult steps and / or produce trifarotene in moderate to low yields. For example, WO 2006 / 066978 describes a reaction performed at -78°C and employs two separate protecting groups that must be hydrolyzed under different conditions. WO 2021 / 119351 employs a reaction in which all functional groups of an intermediate are hydrolyzed in a single step. Multiple complex reaction steps can reduce the efficiency and overall yield of the workflow. Summary of the Invention

[0004] In some embodiments, the present disclosure provides a process for the preparation of a compound of formula (I) [trifarotene] or a salt thereof, comprising: [ka] The compound of formula (III) [ka] by reacting with a compound of formula (IV) [ka] Obtaining a compound of formula (V), [ka] hydrolyzing the compound of formula (V) to obtain a compound of formula (I), wherein R 1 and R 2 are independently hydrogen or linear or branched C1-C3 alkyl, and R 1 and R 2 may be the same or different, or R 1 and R 2 together form a pinacolate in the presence of a catalyst, where X is a halogen or a triflate, and Y is a nitrile (CN) or an amide (CONH).

[0005] In some embodiments, the present disclosure provides a process for the preparation of a compound of formula (I) [trifarotene] or a salt thereof, comprising: [ka] The compound of formula (II) [ka] hydrolysis in the presence of a base to obtain a compound of formula (III); [ka] Reacting a compound of formula (III) with a compound of formula (IV) [ka] Obtaining a compound of formula (V), [ka] hydrolyzing the compound of formula (V) to obtain a compound of formula (I), wherein R 1 and R 2 are independently hydrogen or linear or branched C1-C3 alkyl, and R 1 and R 2 may be the same or different, or R 1 and R 2 together to form pinacolate in the presence of a catalyst, R 3 is hydrogen, a substituted or unsubstituted linear or branched C1-C8 alkyl, a substituted or unsubstituted linear or branched C1-C8 alkenyl group, a substituted or unsubstituted linear or branched C1-C8 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 C1-C8 alkyl group containing a heteroatom; X is a halogen or triflate; and Y is a nitrile (CN) or an amide (CONH2).

[0006] In some embodiments, X is iodine.

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

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

[0009] In some embodiments, the reaction is carried out using K2CO3, CH3CO2K, K3PO4, KOtBu, Na2CO3, NaHCO3, NaOMe, CaCO 3、 It is carried out in the presence of a base including Li2CO3, Cs2CO3, Ag3PO4, Ag2O, Tl2CO3, TlOEt, TlOH, t-BuNH2, KOH, NaOH, LiOH, Ba(OH)2, or a combination thereof.

[0010] In some embodiments, the catalyst comprises a metal selected from Pd, Cu, or Ni, hi some embodiments, the catalyst comprises at least two atoms of the metal. In some embodiments, the catalyst is selected from the group consisting of Pd(PPh3)2Cl2 [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-1,1'biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate], SPhos-Pd-G2 [chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'biphenyl)]palladium(II)], CATACXIUM® A Pd G3 ([(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) mesylate or [(di(1-adamantyl)-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate), APhos Pd The Pd catalyst is selected from 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)dichlorodipalladium), or Pd(dppf)Cl2[1,1'-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, and 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 of solvent, preferably about 0.05 to about 0.5 mol / L of solvent, and more preferably about 0.1 to about 0.4 mol / L of solvent.

[0012] In some embodiments, the catalyst is present in about 0.001 to about 1 molar equivalent relative to the compound of Formula (III) or Formula (IV), preferably about 0.002 to about 0.5 molar equivalent relative to the compound of Formula (III) or Formula (IV), more preferably about 0.003 to about 0.1 molar equivalent relative to the compound of Formula (III) or Formula (IV). In some embodiments, the base is present in about 0.1 to about 10 molar equivalents relative to the compound of Formula (III) or Formula (IV), preferably about 1 to about 6 molar equivalents relative to the compound of Formula (III) or Formula (IV), more preferably about 2 to about 4 molar equivalents relative to the compound 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 present disclosure provides a compound of formula (III): [ka] where X is a halogen or triflate and Y is a nitrile (CN) or amide (CONH2).

[0015] In some embodiments, the present disclosure provides a process for the preparation of a compound of formula (III): [ka] A compound of formula (II), [ka] In the formula, R 3 is hydrogen, a substituted or unsubstituted linear or branched C1-C8 alkyl, a substituted or unsubstituted linear or branched C1-C8 alkenyl group, a substituted or unsubstituted linear or branched C1-C8 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 C1-C8 alkyl group containing a heteroatom; X is a halogen or triflate; and Y is a nitrile (CN) or an amide (CONH2), in the presence of a base.

[0016] In some embodiments, the process comprises: [ka] Reacting a compound of formula (III) with a compound of formula (IV) [ka] A compound of formula (V): [ka] In the formula, R 1 and R 2 but, are independently hydrogen or straight-chain or branched C1-C3 alkyl, and R 1 and R 2 may be the same or different, or R 1 and R 2together to form a pinacolate in the presence of a catalyst to obtain a compound of formula (V), wherein Y is a nitrile (CN) or an amide (CONH), and hydrolyzing the compound of formula (V) to obtain a compound of formula (I), [trifarotene] or a salt thereof.

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

[0018] In some embodiments, the disclosure provides Form E polymorph of compound (I) of formula [trifarotene], wherein Form E polymorph exhibits an X-ray powder diffraction pattern with characteristic peaks at reflection angles 2θ 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, the content of any single impurity in Form E polymorph is less than 0.15%. [Brief explanation of the drawings]

[0019] [Figure 1] 1 illustrates an exemplary process for the preparation of trifarotene [Formula (I)] as described in embodiments herein. [Figure 2] 1 is an XRD spectrum of trifarotene polymorph form E. DETAILED DESCRIPTION OF THE INVENTION

[0020] 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 improved methods for making polymorphic Form E of trifarotene. In some embodiments, the methods described herein provide increased purity of trifarotene.

[0021] As used herein, "a" or "an" may mean one or more. As used herein, when used in conjunction with the term "comprising," the terms "a" or "an" may mean one or more. As used herein, "another" or "further" may mean at least a second or more.

[0022] Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for the method / device used to determine the value or the variation that exists among study subjects. Typically, the term "about" is intended to encompass approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%, or less, or more, depending on the context. In some embodiments, one of ordinary skill in the art will understand the level of variability implied by the term "about" due to the context in which it is used herein. It should also be understood that the use of the term "about" also includes the specifically recited value.

[0023] Although the use of the term "or" in the claims is used to mean "and / or" unless expressly indicated to refer to alternatives only or unless the alternatives are mutually exclusive, the present disclosure supports a definition that refers to alternatives only and "and / or."

[0024] As used herein, the terms "comprising" (and any variation or form of "comprising," such as "comprise" and "comprises"), "having" (and any variation or form of "having," such as "have" and "has"), or "containing" (and any variation 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 herein can be implemented with respect to any compound or method of making 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.

[0025] The term "for example" and its corresponding abbreviation "eg" (whether italicized or not) mean that the specific terms listed are representative examples and embodiments of the present disclosure that are not intended to be limited to the specific examples referenced or cited, unless expressly stated otherwise.

[0026] As used herein, "between" refers to a range that includes the endpoints of the range. For example, a number between x and y explicitly includes the numbers x and y, as well as any numbers subsumed between x and y.

[0027] Unless otherwise specified, the term "alkyl," used alone or in combination with other groups or atoms, refers to a saturated, straight- or branched-chain group containing 1 to about 10 hydrogen-substituted carbon atoms. Alkyl groups include, for example, 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 having 1 to 3 carbons.

[0028] Unless otherwise specified, the term "alkenyl" refers to a partially unsaturated (or in some embodiments fully unsaturated) straight or branched chain containing from about 2 to about 10 hydrogen-substituted carbon atoms including at least one double bond. Alkenyl groups include, for example, vinyl, allyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, penta-1,3-dienyl, penta-2,4-dienyl, 2-methylbut-1-enyl, 2-methylpent-1-enyl, 4-methylpent-1-enyl, 4-methylpent-2-enyl, 2-methylpent-2-enyl, 4-methylpent-1,3-dienyl, hexen-1-yl, hepten-1-yl, octen-1-yl, nonen-1-yl, decen-1-yl, and the like.

[0029] Unless otherwise specified, the term "alkynyl" refers to a partially unsaturated straight or branched chain containing about 2 to about 10 hydrogen-substituted carbon atoms containing at least one triple bond. Alkyl groups include, for example, ethynyl, 1-propynyl, 2-propynyl, 2-methylprop-1-ynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1,3-butadiynyl, 3-methylbut-1-ynyl, 4-methylbut-ynyl, 4-methylbut-2-ynyl, 2-methylbut-1-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-heptynyl, 1-octynyl, 1-nonynyl, 1-decynyl, and the like.

[0030] Unless otherwise specified, the term "cycloalkyl" refers to a saturated or unsaturated ring containing about 3 to about 10 carbon atoms, which can be optionally substituted with one or more of the same or different substituents, for example, 1 to 3, 1 to 6, 1 to 8, or 1 to 10 substituents. Cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononyl, cyclodecyl, and the like.

[0031] Unless otherwise specified, the term "aryl" refers to an aromatic monocyclic or bicyclic group containing from about 5 to about 14 carbon atoms, which may be optionally fused with a fully or partially saturated or unsaturated carbocyclic ring. Aryl groups include, for example, phenyl, naphthyl, indanyl, and the like.

[0032] Unless otherwise specified, "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 in the hydrocarbon ring or ring system are replaced by a heteroatom. Examples of heterocycles include, but are not limited to, azepan-1-yl, piperidinyl, e.g., piperidin-1-yl and piperidin-4-yl, piperazinyl, e.g., N-piperazinyl and 1-alkylpiperazin-4-yl, morpholin-4-yl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiophene, sulfonyl, sulfonyl, oxazolinyl, isoxazolinyl, oxazolidinyl, and oxazolidinonyl. "Heterocyclecarbonyl" refers to a carbonyl (C=O) bonded to a heterocycle group. In some embodiments, the heteroatom is N, O, P, or S. In some embodiments, the heteroatom is N or O.

[0033] Unless otherwise specified, "heteroaryl" refers to an aromatic compound containing at least one heteroatom. Examples of heteroaryl groups include pyrrolyl, dihydropyrrolyl, pyrrolidinyl, indolyl, isoindolyl, indolizinyl, imidazolyl, pyrazolyl, benzimidazolyl, imidazo(1,2-a)pyridinyl, indazolyl, purinyl, pyrrolo(2,3-c)pyridinyl, pyrrolo(3,2-c)pyridinyl, pyrrolo(2,3-b)pyridinyl, pyrazolo(1,5-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- Examples of heteroarylcarbonyl include, but are not limited to, thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, benzofuranyl, isobenzofuranyl, thiophenyl, dihydrothiophenyl, tetrahydrothiophenyl, benzothiophenyl, benzisothiophenyl, 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. "Heteroarylcarbonyl" refers to a carbonyl (C=O) attached to a heteroaryl group.

[0034] In some embodiments, any of the carbon chain substituents described herein, e.g., alkyl, alkanoyl, alkenoyl, alkynoyl, alkanoyl, etc., can have one or more heteroatoms, i.e., one or more of the carbons in the carbon chain replaced by one or more atoms other than carbon or hydrogen, e.g., nitrogen, oxygen, sulfur, phosphorus. In some embodiments, the substituents described herein, e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, alkanoyl, alkenoyl, alkynoyl, cycloalkanoyl, arylcarbonyl, heterocyclecarbonyl, heteroarylcarbonyl, etc., can be "substituted or unsubstituted." The term "substituted" refers to the substitution of different groups, e.g., hydroxyl, halide, alkyl (e.g., C 1~ C6 alkyl), alcohol, ketone, etc. The term "unsubstituted" refers to the absence of a substituent replacing a hydrogen with a different group.

[0035] A "linear" molecule contains a single backbone. For example, a "linear C1-C n A "branched" molecule contains 1 to n carbon atoms, each carbon atom bonded to its two neighbors and two hydrogen atoms (except for the terminal carbon atom, which is bonded to only one carbon atom and three hydrogen atoms). A "branched" molecule contains a non-linear backbone, and the branching can occur from one or more atoms of the main backbone. For example, a "branched C1-C n The molecule is a straight-chain C1-C2 carbon atom, except that at least one of the hydrogen atoms bonded to at least one of the carbon atoms is replaced with a substituent, e.g., an alkyl group. n It comes from molecules.

[0036] 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 a substituent on any of the atoms that form the ring. The substituent can include any of the groups described herein, such as alkyl, alkenyl, alkynyl, etc.

[0037] In some embodiments, the present disclosure provides a process for the preparation of a compound of formula (I) [trifarotene] or a salt thereof, comprising: [ka] The compound of formula (III) [ka] by reacting with a compound of formula (IV) [ka] Obtaining a compound of formula (V), [ka] hydrolyzing the compound of formula (V) to obtain a compound of formula (I), wherein R 1 and R 2 are independently hydrogen or a straight chain or branched C1-C3 alkyl, R1 and R2 can be the same or different, or R1 and R2 together form a pinacolate in the presence of a catalyst, X is a halogen or a triflate, and Y is a nitrile (CN) or an amide (CONH2).

[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: [ka] The compound of formula (II) [ka] hydrolysis in the presence of a base to obtain a compound of formula (III); [ka] Reacting a compound of formula (III) with a compound of formula (IV) [ka] Obtaining a compound of formula (V), [ka] hydrolyzing the compound of formula (V) to obtain a compound of formula (I), wherein R 1 and R 2 are independently hydrogen or linear or branched C1-C3 alkyl, and R 1 and R 2 may be the same or different, or R 1 and R 2 together to form pinacolate in the presence of a catalyst, R 3 is hydrogen, a substituted or unsubstituted linear or branched C1-C8 alkyl, a substituted or unsubstituted linear or branched C1-C8 alkenyl group, a substituted or unsubstituted linear or branched C1-C8 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 C1-C8 alkyl group containing a heteroatom; X is a halogen or triflate; and Y is a nitrile (CN) or an amide (CONH). 3 is hydrogen. In some embodiments, R 3 is methyl.

[0039] 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 trifarotene Na salt.

[0040] In some embodiments, X is iodine. In some embodiments, Y is a nitrile. In some embodiments, Y is an amide.

[0041] 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., carried out in extreme heat (e.g., >50°C) or extreme cold (e.g., <-10°C)).

[0042] The term "hydrolysis" or variants thereof, such as "hydrolyze" or "hydrolyzing," refers to a reaction in which water is a reactant and typically becomes part of the reaction product as a hydroxyl (-OH) group. In some embodiments, the hydrolysis is carried out in the presence of water and a co-solvent. Examples of co-solvents that can be used with water for the hydrolysis reaction include, but are not limited to, alcohols such as 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 (IPA), dimethyl ether (DME), diethyl ether, or any mixture thereof. In some embodiments, the hydrolysis is carried out 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 carried out in the presence of water and ethanol.

[0043] In some embodiments, the hydrolysis is further carried out in the presence of a base. In some embodiments, the base is selected from the group consisting of potassium carbonate (K2CO3), potassium acetate (CH3CO2K), potassium phosphate (K3PO4), potassium tert-butoxide (KOtBu), sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), sodium methoxide (NaOMe), calcium carbonate (CaCO3), lithium carbonate (Li2CO3), cesium carbonate (Cs2CO3), silver phosphate (Ag3PO4), silver oxide (Ag2O), thallium carbonate (Tl2CO3), thallium ethoxide (TlOEt), thallium hydroxide (TlOH), tert-butylamine (t-BuNH2), potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), barium hydroxide (Ba(OH) 2) , or any mixture thereof.

[0044] In some embodiments, the compound of Formula (V) is present in the hydrolysis reaction at about 0.1 to about 1 mol / L of solvent, about 0.2 to about 0.8 mol / L of solvent, or about 0.3 to about 0.5 mol / L of 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 of solvent. In some embodiments, the hydrolysis is carried out 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 carried out at a pH of 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.

[0045] In some embodiments, the catalyst for the reaction between a compound of Formula (III) and a compound of 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, for example, in US 2006 / 0264629 and US 2010 / 0184739.

[0046] In some embodiments, the catalyst is a palladium catalyst. In some embodiments, the catalyst is selected from the group consisting of Pd(PPh3)2Cl2 [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-1,1'biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate], SPhos-Pd-G2 [chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'biphenyl)]palladium(II)], CATACXIUM® A Pd G3 ([(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) mesylate 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)dichlorodipalladium), or Pd(dppf)Cl2[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)].

[0047] 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]2, [(o-(di-tert-butylphosphino)-N,N-dimethylaniline)copper iodide]2, In some embodiments, the catalyst is a nickel catalyst. In some embodiments, the nickel catalyst is NiCl, NiBr, NiI, G3DenP-Ni, (dppf)Ni(cinnamyl)Cl, (PCy3)2NiCl2, or Ni(cod)2. Further exemplary catalysts are provided, for example, in Tasker et al., Nature 509(7500):299-309 (2014), Yang et al., Angew Chem Int Ed 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).

[0048] In some embodiments, the reaction between the compound of Formula (III) and the compound of Formula (IV) is further carried out in the presence of a ligand, hi some embodiments, the ligand is a phosphine ligand, a carbon ligand, or a nitrogen ligand. In some embodiments, the ligand is PPh3, PCy3, P(o-tolyl)3, P(i-Pr)3, P(O-Pr-i)3, n-BuP(1-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 an 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 contains both a palladium catalyst and a phosphine ligand. In some embodiments, the process for preparing a compound of Formula (IV) includes preparing a catalyst containing a metal and a ligand.

[0049] 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, for example, in 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).

[0050] In some embodiments, the compounds of Formula (III) and Formula (IV), when reacted together, 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. In some embodiments, the compounds of Formula (III) and Formula (IV), when reacted together, are independently present in an amount of about 0.01 mol / L to about 1 mol / L of solvent, about 0.05 mol / L to about 0.5 mol / L of solvent, or about 0.1 mol / L to about 0.4 mol / L of solvent.

[0051] In some embodiments, the pH is reduced after hydrolysis 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 carried out at a pH of 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.

[0052] In some embodiments, the catalyst is present in an amount of from about 0.001 to about 1 molar equivalent relative to the compound of Formula (III) or Formula (IV), preferably from about 0.002 to about 0.5 molar equivalent relative to the compound of Formula (III) or Formula (IV), and more preferably from about 0.003 to about 0.1 molar equivalent relative to the compound of Formula (III) or Formula (IV).

[0053] In some embodiments, the base is present in about 0.1 to about 10 molar equivalents relative to the compound of Formula (III) or Formula (IV), preferably about 1 to about 6 molar equivalents relative to the compound of Formula (III) or Formula (IV), and more preferably about 2 to about 4 molar equivalents relative to the compound of Formula (III) or Formula (IV).

[0054] In some embodiments, the present disclosure provides a compound of formula (III): [ka] where X is a halogen or triflate and Y is a nitrile (CN) or amide (CONH2).

[0055] In some embodiments, the present disclosure provides a process for the preparation of a compound of formula (III): [ka] A compound of formula (II), [ka] In the formula, R 3 is hydrogen, a substituted or unsubstituted linear or branched C1-C8 alkyl, a substituted or unsubstituted linear or branched C1-C8 alkenyl group, a substituted or unsubstituted linear or branched C1-C8 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 C1-C8 alkyl group containing a heteroatom, X is a halogen or triflate, and Y is a nitrile (CN) or an amide (CONH). 3 is hydrogen. In some embodiments, R 3 is methyl.

[0056] In some embodiments, the process for the preparation of a compound of formula (III) comprises:

[0057] [ka] Reacting a compound of formula (III) with a compound of formula (IV) [ka] A compound of formula (V): [ka] In the formula, R 1 and R 2 are independently hydrogen or linear or branched C1-C3 alkyl, and R 1 and R 2 may be the same or different, or R 1 and R 2 and Y are reacted with each other to form a pinacolate in the presence of a catalyst to obtain a compound of formula (V), wherein Y is a nitrile (CN) or an amide (CONH), and hydrolyzing the compound of formula (V) to obtain a 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).

[0058] In some embodiments, the compound of formula (IV) is selected from: [ka]

[0059] In some embodiments, R of the compound of formula (II) 3 and Y are defined herein. In some embodiments, X in the compound of Formula (II) is a leaving group for Suzuki coupling reactions. Examples of leaving groups for Suzuki reactions are further provided in, for example, Liu et al., Org Lett 7(6):1149-1151 (2005), El-Berjawi et al., Dyes Pigments 159:551-556 (2018), and Chemler et al., Angew Chem Int Ed 40:4544 (2001). In some embodiments, X is a halogen, such as fluorine, chlorine, bromine, or iodine. In some embodiments, X is a triflate (-OSO2CF3, also abbreviated as -OTf) group. In some embodiments, R 3 is hydrogen, Y is a nitrile or amide, and X is a halogen or triflate. 3is methyl, Y is nitrile or amide, and X is halogen or triflate. 3 is hydrogen, Y is a nitrile or amide, and X is a halogen or triflate. 3 is methyl, Y is nitrile, and X is iodine.

[0060] In some embodiments, the compound of formula (II) is selected from the following: [ka] [ka]

[0061] In some embodiments, the present disclosure provides improved processes for making novel polymorphs of the compound of formula (I), trifarotene, wherein the polymorphs have higher purity levels. In some embodiments, the novel polymorph Form E described herein can be used to provide desired release characteristics or other desired pharmaceutical properties of trifarotene.

[0062] In some embodiments, the present disclosure provides a process for preparing Form E polymorph of trifarotene-HCl, comprising: (a) providing trifarotene according to the processes described herein; and (b) suspending trifarotene in ethyl acetate to obtain Form E polymorph of trifarotene. In some embodiments, the Form E polymorph contains less than 0.15% of any single impurity. In some embodiments, Form E polymorph exhibits an X-ray powder diffraction pattern with characteristic peaks at reflection angles 2θ 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.

[0063] All references cited herein, including patents, patent applications, articles, textbooks, etc., and references cited therein, to the extent they have not already been cited, are incorporated herein by reference in their entirety. [Example]

[0064] Example 1. Synthesis of 3″-(tert-butyl)-4′-(2-hydroxyethoxy)-4″-(pyrrolidin-1-yl)-[1,1′:3′,1″-terphenyl]-4-carboxylic acid [trifarotene] A. Preparation of 2-((4′-cyano-3-iodo-[1,1′-biphenyl]-4-yl)oxy)ethyl acetate [Formula IIa] [ka]

[0065] 2-((4'-cyano-3-iodo-[1,1'-biphenyl]-4-yl)oxy)ethyl acetate was prepared according to the method disclosed in WO 2021 / 119351. 180 g (0.56 mol) of 4'-hydroxy-3'-iodo-biphenyl-4-carbonitrile were mixed with 900 mL of dimethylformamide and 247 g (1.8 mol) of potassium carbonate. The reaction mixture was stirred at room temperature. 117 g (0.7 mol) of 2-bromoethyl acetate were added, and the mixture 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, yielding 213.5 g of 2-((4'-cyano-3-iodo-[1,1'-biphenyl]-4-yl)oxy)ethyl acetate. 90.6% yield, 97% HPLC purity.

[0066] B. Conversion of 2-((4'-cyano-3-iodo-[1,1'-biphenyl]-4-yl)oxy)ethyl acetate [Formula IIa] to 2-((4'-cyano-3-iodo-[1,1'-biphenyl]-4-yl)oxy)ethanol [Formula III] [ka]

[0067] 2-((4'-cyano-3-iodo-[1,1'-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 3-4 hours. The reaction was quenched by the addition of water (100 mL) to precipitate 2-((4'-cyano-3-iodo-[1,1'-biphenyl]-4-yl)oxy)ethanol. The solid was filtered off, washed with water, and dried under vacuum.

[0068] C. Synthesis of 2-((3''-(tert-butyl)-4-cyano-4''-(pyrrolidin-1-yl)-[1,1':3',1''-terphenyl]-4'-yl)oxy)ethanol [Formula V] [ka]

[0069] 2-((4'-cyano-3-iodo-[1,1'-biphenyl]-4-yl)oxy)ethanol was dissolved in dimethylacetamide (DMA) (2000 mL). 140 g of (3-(tert-butyl)-4-(pyrrolidin-1-yl)phenyl)boronic acid [formula IV] (prepared according to the method disclosed in Example 4 of WO2021 / 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.

[0070] D. Synthesis of 3″-(tert-butyl)-4′-(2-hydroxyethoxy)-4″-(pyrrolidin-1-yl)-[1,1′:3′,1″-terphenyl]-4-carboxylic acid [trifarotene, Formula I] from Formula V

[0071] 2-((3"-(tert-butyl)-4-cyano-4"-(pyrrolidin-1-yl)-[1,1':3',1"-terphenyl]-4'-yl)oxy)ethanol (formula V) was suspended in ethanol (1100 mL) and water (600 mL), followed by 50% sodium hydroxide solution (300 mL). The reaction medium was stirred under reflux. The reaction medium was acidified to pH 3.0-6.0 using 32% HCl. The white precipitate was filtered off to obtain crude 3"-(tert-butyl)-4'-(2-hydroxyethoxy)-4"-(pyrrolidin-1-yl)-[1,1':3',1"-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-1-yl)-[1,1':3',1''-terphenyl]-4-carboxylic acid was suspended in water (4000 mL), heated to 70-100 °C for 5-9 hours, and filtered off. The white, wet powder was then dried under vacuum to give 120 g of pure 3''-(tert-butyl)-4'-(2-hydroxyethoxy)-4''-(pyrrolidin-1-yl)-[1,1':3',1'-terphenyl]-4-carboxylic acid [trifarotene, Formula I]. 2-((3''-(tert-butyl)-4-cyano-4''-(pyrrolidin-1-yl)-[1,1':3',1''-terphenyl]-4'-yl)oxy)ethanol was analyzed by HPLC analytical method.

[0072] Example 2: Comparison of the disclosed method with previously described methods The overall yield from the disclosed method was compared to the yield of a known method for making trifarotene found in U.S. Pat. No. 17 / 756,994. The 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-pyrrolidin-1-yl)phenyl)boronic acid, "trif-boronic acid") to form a trifarotene nitrile ester (referred to herein as the "trif-nitrile ester route"). 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).

[0073] HPLC analysis was performed on samples using both the old route (trif-nitrile ester route) and the new route (trif-alcohol ether route). An RP18 column was used. A gradient of water:0.02 M ammonium acetate:acetonitrile was used with a flow rate of 1.0 mL / min.

[0074] A comparison of the yields resulting from the two routes is presented in Table 1. [Table 1]

[0075] The data demonstrate that the trif-alcohol ether route described herein provides a significant increase in yield over previously used methods while maintaining good purity.

[0076] Example 3 Preparation of Trifarotene - Form E Polymorph and Its Analysis 150 mg of trifarotene obtained in Example 1 was suspended in 5 mL of MeOH or EtOAc and shaken at 300 rpm at room temperature for 2 days. The product was filtered and dried under ambient conditions for 2 to 6 days (3 days). The resulting crystalline form is Form E polymorph as determined by XRPD and IR spectral analysis.

[0077] An exemplary diffraction pattern for trifarotene Form E polymorph can be found in Figure 2. Table 2 lists the major X-ray powder diffraction peaks. XRD was performed according to that described in US 17 / 756,994, which is incorporated herein in its entirety. [Table 2]

[0078] The samples were analyzed by the HPLC analytical method described above. Table 3 shows the HPLC purity results for the Form E polymorph of trifarotene. [Table 3]

[0079] The purity level of trifarotene Form E polymorph (determined by HPLC prepared in EtOAc 1:10:1 (Samples 2, 3, and 4)) was higher than that observed for Form E polymorph prepared in MeOH 1:10:1 (Sample 1) and EtOH 1:10:1 (Samples 5, 6, and 7). See the trifarotene peak at 30.2 minutes (bold). These results indicate that 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

1. A process for the preparation of a compound of formula (I) [trifarotene] or a salt thereof, comprising: 【Chemistry 1】 a) reacting a compound of formula (III) with 【Chemistry 2】 by reacting with a compound of formula (IV) 【Transformation 3】 Obtaining a compound of formula (V), 【Chemistry 4】 b) hydrolyzing the compound of formula (V) to obtain the compound of formula (I), In the formula, R １ and R ２ are independently hydrogen or linear or branched C １ ~C ３ alkyl, and R １ and R ２ may be the same or different, or R １ and R ２ together to form pinacolate in the presence of a catalyst, X is halogen or triflate; Y is a nitrile (CN) or an amide (CONH ２ ) is a process.

2. A process for the preparation of a compound of formula (I) [trifarotene] or a salt thereof, comprising: 【Transformation 5】 a) reacting a compound of formula (II) with 【Transformation 6】 hydrolysis in the presence of a base to obtain a compound of formula (III); 【Transformation 7】 b) reacting said compound of formula (III) with a compound of formula (IV), 【Transformation 8】 Obtaining a compound of formula (V), 【Chemistry 9】 c) hydrolyzing the compound of formula (V) to obtain the compound of formula (I), In the formula, R １ and R ２ are independently hydrogen or linear or branched C １ ~C ３ alkyl, and R １ and R ２ may be the same or different, or R １ and R ２ together to form pinacolate in the presence of a catalyst, R ３ is hydrogen, substituted or unsubstituted straight-chain or branched C １ ~C ８ Alkyl, substituted or unsubstituted straight or branched chain C １ ~C ８ Alkenyl group, substituted or unsubstituted straight or branched C １ ~C ８ an 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 C containing a heteroatom １ ~C ８ is an alkyl group, X is halogen or triflate; Y is a nitrile (CN) or an amide (CONH ２ ) is a process.

3. 3. The process of claim 1 or 2, wherein X is iodine.

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

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

6. 6. The process of any one of claims 1 to 5, wherein the reaction is carried out in the presence of a solvent comprising toluene, dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), dioxane, n-butanol (n-BuOH), isopropanol (IPA), dimethyl ether (DME), diethyl ether, or any mixture thereof.

7. The reaction is ２ CO ３ , C.H. ３ CO ２ K.K. ３ P.O. ４ , KOtBu, Na ２ CO ３ , NaHCO ３ , NaOMe, CaCO ３、 Li ２ CO ３ , Cs ２ CO ３ , Ag ３ P.O. ４ , Ag ２ O, Tl ２ CO ３ , TlOEt, TlOH, t-BuNH ２ , KOH, NaOH, LiOH, Ba(OH) ２ 7. The process of any one of claims 1 to 6, carried out in the presence of a base comprising:

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

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

10. The catalyst is (i) Pd(PPh ３ ) ２ Cl ２ [bis(triphenylphosphine)palladium(II) dichloride], (ii) Pd(PPh ３ ) ４ [tetrakis(triphenylphosphine)palladium(0)], (iii) Pd(OAc) ２ [palladium(II) diacetate], (iv) XPhos Pd-G3 [(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate], (v) SPhos-Pd-G2 [chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)], (vi) CATACHIUM® A Pd-G3 [mesylate [(di(1-adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II), [(di(1-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(Cy ３ ) Pd-G3 [(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate], (ix) allylpalladium(II) chloride dimer bis(allyl)dichlorodipalladium, or (x)Pd(dppf)Cl ２ The process of claim 8, wherein the Pd catalyst is selected from [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)].

11. 11. The process of 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. 11. The process of 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 of solvent, preferably about 0.05 to about 0.5 mol / L of solvent, more preferably about 0.1 to about 0.4 mol / L of solvent.

13. 13. The process of any one of claims 1 to 12, wherein the catalyst is present in an amount of from about 0.001 to about 1 molar equivalent relative to the compound of formula (III) or formula (IV), preferably from about 0.002 to about 0.5 molar equivalent relative to the compound of formula (III) or formula (IV), more preferably from about 0.003 to about 0.1 molar equivalent relative to the compound of formula (III) or formula (IV).

14. 8. The process of claim 7, wherein the base is present in an amount of from about 0.1 to about 10 molar equivalents relative to the compound of formula (III) or formula (IV), preferably from about 1 to about 6 molar equivalents relative to the compound of formula (III) or formula (IV), and more preferably from about 2 to about 4 molar equivalents relative to the compound of formula (III) or formula (IV).

15. 14. The process of 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, 【Chemistry 10】 wherein X is a halogen or a triflate; Y is a nitrile (CN) or an amide (CONH ２ ) a compound.

17. A process for the preparation of a compound of formula (III) comprising 【Chemistry 11】 A compound of formula (II) 【Chemistry 12】 In the formula, R ３ is hydrogen, substituted or unsubstituted straight-chain or branched C １ -C8 alkyl, substituted or unsubstituted straight or branched C １ ~C ８ Alkenyl group, substituted or unsubstituted straight or branched C １ ~C ８ an 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 C containing a heteroatom １ ~C ８ is an alkyl group, X is halogen or triflate; Y is a nitrile (CN) or an amide (CONH ２ ) A process comprising hydrolyzing a compound of formula (II) in the presence of a base. 【Request Item 18】 【Chemistry 13】 reacting said compound of formula (III) with a compound of formula (IV) 【Chemistry 14】 A compound of formula (V) 【Chemistry 15】 In the formula, R １ and R ２ are independently hydrogen or linear or branched C １ ~C ３ alkyl, and R １ and R ２ are or can be the same as, or R １ and R ２ together to form pinacolate in the presence of a catalyst, Y is a nitrile (CN) or an amide (CONH ２ and obtaining a compound of formula (V), 18. The process of claim 17, further comprising preparing the compound of formula (I) [trifarotene] or a salt thereof by: c) hydrolyzing the compound of formula (V) to obtain the compound of formula (I).

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

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

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

22. 22. The process of claim 21, wherein the X-ray powder diffraction (XRPD) comprises three or more 2-theta 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.

Images