Preparation of trifarotene and intermediates and polymorphs thereof

Abstract

To provide a method for preparing trifarotene, a new intermediate, and a new polymorph of trifarotene.SOLUTION: A process for the preparation of trifarotene, a compound of [Formula I], or a salt thereof, comprising hydrolyzing a compound of formula (V) to obtain the compound of [Formula I].SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure provides methods for the preparation of trifarotene. The present disclosure also provides The present invention provides novel intermediates in the described processes. Also, novel polymorphs of trifarotene are provided. is also provided. [Background technology]

[0002] 3''-(tert-butyl)-4'-(2- hydroxyethoxy)-4''-(pyrrolidin-1-yl)-[1,1':3',1'' -terphenyl]-4-carboxylic acid is a retinoic acid that inhibits the most common RAR found in the skin. It is a topical retinoid that can selectively target retinoid receptor (RAR) gamma. Loten is prescribed to treat acne vulgaris and was first approved in the United States in October 2019. For example, the current synthesis route for trifarotene, as described in WO2006 / 066978, , including some difficult steps, such as performing the reaction at -78°C; There are steps that use two separate protecting groups that must be hydrolyzed under different conditions, These can reduce workflow efficiency and overall yield. Summary of the Invention

[0003] In some embodiments, the present disclosure provides a compound of formula (I) [trifarotene] [ka] or a salt thereof, the method comprising: [ka] [In the formula, R 4is hydrogen, substituted or unsubstituted straight or branched C1-C8 alkanoyl substituted or unsubstituted straight-chain or branched C2-C8 alkenoyl groups, substituted or unsubstituted straight-chain or branched C2-C8 alkenoyl groups, or unsubstituted straight-chain or branched C2-C8 alkynoyl groups, substituted or unsubstituted cyclohexyl groups, chloroalkanoyl group, substituted or unsubstituted arylcarbonyl group, substituted or unsubstituted a heterocyclic carbonyl group, a substituted or unsubstituted heteroaryl carbonyl group, or a hetero Y is a C1-C8 alkanoyl group containing a nitrile (CN) or amide (C ONH2) to obtain a compound of Formula (I). So, R 4 is an acetyl group. In some embodiments, R 4 is hydrogen.

[0004] In some embodiments, the method comprises reacting a compound of formula (IV) [ka] [In the formula, R 3 is hydrogen, hydroxyl group, halogen, substituted or unsubstituted straight or branched chain Branched C1-C8 alkyl groups, substituted or unsubstituted straight or branched C2-C8 alkyl groups alkynyl groups, substituted or unsubstituted straight-chain or branched C2-C8 alkynyl groups, substituted or an unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted Substituted heterocycle, substituted or unsubstituted heteroaryl, or C1-C containing heteroatoms 8 alkyl group, and Y is a nitrile (CN) or an amide (CONH2) to give a compound of formula (V). In some embodiments, R 3 is methyl.

[0005] In some embodiments, the hydrolysis is carried out using a solvent such as water, methanol (MeOH), ethanol (EtO H), propanol (PrOH), isopropanol (IPA), or any of these In some embodiments, the reaction is carried out in the presence of a solvent comprising a mixture of water and ethanol. In some embodiments, the base includes sodium hydroxide (NaOH), potassium hydroxide, ammonium hydroxide (KOH), lithium hydroxide (LiOH), barium hydroxide (Ba(OH)2), or any mixture thereof.

[0006] In some embodiments, the compound of formula (IV) is present in a concentration of about 0.01 to about 0.5 mol / L (solvent ), preferably about 0.02 to about 0.2 mol / L (solvent), more preferably about 0.04 to about 0.08 mol / L (solvent). In some embodiments, the base is present in an amount of about 0. 1 to about 1 mol / L (solvent), preferably about 0.2 to about 0.8 mol / L (solvent), more preferably In some embodiments, the amount of the solvent is preferably about 0.3 to about 0.6 mol / L. The base is used in an amount of about 1 to about 10 molar equivalents relative to the compound of formula (IV), preferably the compound of formula (IV ) and more preferably about 2 to about 8 molar equivalents relative to the compound of formula (IV) It is present in an amount of about 3 to about 6 molar equivalents.

[0007] In some embodiments, the method comprises reacting a compound of formula (II) [ka] [In the formula, R 1 and R 2 are independently hydrogen or a straight or branched C1-C3 alkyl group. R 1 and R 2 may be the same or different, or R1 Oh BiR 2 together form pinacolate] with a compound of formula (III) [ka] [In the formula, R 3 is hydrogen, hydroxyl group, halogen, substituted or unsubstituted straight or branched chain Branched C1-C8 alkyl, substituted or unsubstituted straight or branched C2-C8 alkoxy alkynyl group, substituted or unsubstituted straight or branched C2-C8 alkynyl group, substituted or unsubstituted or unsubstituted cycloalkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted substituted heterocycle, substituted or unsubstituted heteroaryl, or C1-C8 containing heteroatoms is an alkyl group, X is a halogen or triflate, and Y is a nitrile or amide in the presence of a catalyst to obtain a compound of formula (IV), In some embodiments, R 3 is methyl and X is iodine.

[0008] In some embodiments, the reaction is carried out in a solvent such as toluene, dimethylformamide (DMF), dimethylformamide (DMF), Sulfoxide (DMSO), tetrahydrofuran (THF), dioxane, n-butanol (n-BuOH), isopropanol (IPA), dimethyl ether (DME), diethyl ether (DME), The reaction is carried out in the presence of a solvent comprising ethyl ether, or any mixture thereof. In an embodiment, the reaction is carried out using a mixture of K2CO3, CH3CO2K, K3PO4, KOtBu, Na2C O3, NaHCO3, NaOMe, Cs2CO 3、 Ag3PO4, Ag2O, Tl2CO 3, TlOEt, TlOH, t-BuNH2, KOH, NaOH, LiOH, Ba(OH )2, or a combination thereof.

[0009] 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 a metal. The catalyst was Pd(PPh3)2Cl2 [bis(triphenylphosphine)palladium(II ) dichloride], Pd(PPh3)4 [tetrakis(triphenylphosphine)palladium [Palladium(II) diacetate], 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 ) methanesulfonic acid], SPhos-Pd-G2 [chloro(2-dicyclohexylphosphite) 2-(2'-amino-1,1 '-biphenyl]palladium(II)], CATACXIUM® A Pd G 3(mesylate [di(1-adamantyl)-n-butylphosphine]-2-(2'-amino [(di(1-adamantyl) -butylphosphine)-2-(2'-amino-1,1'-biphenyl)palladium(II ) methanesulfonic acid), APhos Pd G3 (palladium G3-(4-(N,N-di methylamino)phenyl)di-tert-butylphosphine] or [4-(di-tert-butylphosphine) rt-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(I I) Chloride dimer (bis(allyl)dichlorodipalladium), or Pd(dppf) Cl2[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(I I) Pd catalyst.

[0010] In some embodiments, the compounds of Formula (II) and Formula (III) are mixed in a ratio of about 1:10 to about 10 :1, preferably about 1:5 to about 5:1, and more preferably about 1:1 molar ratio. In some embodiments, the compounds of Formula (II) and Formula (III) are independently from about 0.01 to about 0.15. About 1 mol / L (solvent), preferably about 0.05 to about 0.5 mol / L (solvent), It is preferably present in an amount of about 0.1 to about 0.4 mol / L (solvent).

[0011] In some embodiments, the catalyst is present in an amount of about 0. 0.01 to about 1 molar equivalent, preferably about 1 molar equivalent relative to the compound of formula (II) or (III) 0.002 to about 0.5 molar equivalents, more preferably a compound of formula (II) or (III) In some embodiments, the base is present in an amount of about 0.003 to about 0.1 molar equivalents relative to the total amount of the base. Preferably, the amount is about 0.1 to about 10 molar equivalents relative to the compound of formula (II) or (III). Preferably, the amount is about 1 to about 6 molar equivalents relative to the compound of formula (II) or (III), more preferably about 1 to about 6 molar equivalents relative to the compound of formula (II) or (III). Alternatively, it is present in an amount of about 2 to about 4 molar equivalents relative to the compound of formula (II) or formula (III).

[0012] In some embodiments, the present disclosure provides a compound of formula (I) [trifarotene] [ka] or a salt thereof, the method comprising: [ka] [In the formula, R 1 and R 2 are independently hydrogen or a straight or branched C1-C3 alkyl group. R 1 and R 2 may be the same or different, or R 1 Oh BiR 2 together form pinacolate] with a compound of formula (III) [ka] [In the formula, R 3 is a substituted or unsubstituted straight or branched C1-C8 alkyl, or an unsubstituted straight-chain or branched C2-C8 alkenyl group, a substituted or unsubstituted Straight-chain or branched C2-C8 alkynyl groups, substituted or unsubstituted cycloalkyl groups , a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted and X is a halogen atom. or triflate, and Y is a nitrile (CN) or an amide (CONH). in the presence of a catalyst to obtain a compound of formula (IV) [ka] [In the formula, R 3 is as defined above; and obtaining a compound of formula (IV) in the presence of a base to obtain trifarotene. 1 , R 2 , R 3 , R 4 , X, and Y, as well as various reactions and conditions, are further described herein. In some embodiments, R 3 is methyl, X is iodine, and Y is nitrile. In an embodiment of the present invention, R 3 is methyl and X is iodine.

[0013] In some embodiments, the present disclosure provides a compound of formula (III) [ka] [In the formula, R 3 is a substituted or unsubstituted straight or branched C1-C8 alkyl group; substituted or unsubstituted straight or branched C2-C8 alkenyl groups, substituted or unsubstituted a straight-chain or branched C2-C8 alkynyl group, a substituted or unsubstituted cycloalkyl a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic ring, a substituted or unsubstituted substituted heteroaryl or C1-C8 alkyl group containing a heteroatom; X is a halo wherein Y is a nitrile or a triflate, and Y is a nitrile or an amide. In embodiments, R 3 is methyl and X is iodine.

[0014] In some embodiments, the present disclosure provides a compound of formula (V) [ka] [In the formula, R 4 is hydrogen, substituted or unsubstituted straight or branched C1-C8 alkanoyl substituted or unsubstituted straight-chain or branched C2-C8 alkenoyl groups, substituted or unsubstituted straight-chain or branched C2-C8 alkenoyl groups, or unsubstituted straight-chain or branched C2-C8 alkynoyl groups, substituted or unsubstituted cyclohexyl groups, chloroalkanoyl group, substituted or unsubstituted arylcarbonyl group, substituted or unsubstituted a heterocyclic carbonyl group, a substituted or unsubstituted heteroaryl carbonyl group, or a hetero Y is a C1-C8 alkanoyl group containing a nitrile (CN) or amide (C (ONH2), and Y is a nitrile or an amide. , R 4 is hydrogen. In some embodiments, R 4 is acetyl.

[0015] In some embodiments, the present disclosure provides a compound of formula (I) [trifarotene-HCl] in the form and Form A polymorph, wherein Form A polymorph is present at 7.6°C, 11.5°C, 15.4°C, 21.1°C, and X-ray powder diffraction (XRPD) patterns with characteristic peaks at reflection angles 2θ of 23.2 degrees. In some embodiments, the Form A polymorph further exhibits 8.6, 9.0, 17. It shows peaks at 7 degrees, 18.3 degrees, 19.5 degrees, and 22.5 degrees.

[0016] In some embodiments, the present disclosure provides a compound of formula (I) [trifarotene-HCl] in the form and Form B polymorph is provided, the Form B polymorph being present at 12.6°C, 19.5°C, 19.8°C, 24.6°C, and an X-ray powder diffraction pattern with a characteristic peak at a reflection angle 2θ of 29.5 degrees. In some embodiments, the Form B polymorph may further comprise: 8.4°C, 12.0°C, 17.4°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18 Peaks are seen at 1.1 degrees, 23.2 degrees, 31.0 degrees, and 32.1 degrees.

[0017] In some embodiments, the present disclosure provides a compound of formula (I) [trifarotene-HCl] in the form and Form C polymorph, which has the following structural variations: 7.9°C, 15.6°C, 20.0°C, 23.6°C, and an X-ray powder diffraction pattern having a characteristic peak at a reflection angle 2θ of 27.8 degrees. In some embodiments, the Form C polymorph further comprises: 12.1°C, 16.4°C, 17.4°C, and and peaks at 28.8 degrees.

[0018] In some embodiments, the present disclosure provides the Form D polymorph of the compound of formula (I) [trifarotene]. The Form D polymorph provides reactions of 8.5°C, 16.2°C, 18.6°C, and 23.1°C. The compound exhibits an X-ray powder diffraction pattern having characteristic peaks at 2θ angles. The Form D polymorph additionally exhibits peaks at 12.2 degrees, 12.8 degrees, and 14.1 degrees.

[0019] In some embodiments, the present disclosure provides the Form E polymorph of the compound of formula (I) [trifarotene]. and Form E polymorphs have the following structural variations: 8.6°C, 12.8°C, 14.2°C, 17.9°C, and 2°C. The X-ray powder diffraction pattern shows a characteristic peak at a reflection angle 2θ of 4.0 degrees. In embodiments, the Form E polymorph is further characterized by the following: 10.6°C, 15.3°C, 16.3°C, 19.3°C. , and shows a peak at 22.0 degrees.

[0020] In some embodiments, the present disclosure provides the Form F polymorph of the compound of formula (I) [trifarotene]. and Form F polymorphs are available at 5.2°C, 6.3°C, 14.9°C, 18.0°C, and 19°C. The X-ray powder diffraction pattern shows a characteristic peak at a reflection angle 2θ of 0.1 degrees. In terms of form, the Form F polymorph further exhibits the following variations: 8.5°C, 15.6°C, 16.3°C, 18.5°C, and and peaks at 22.9 degrees.

[0021] In some embodiments, the present disclosure provides form G of the compound of formula (I) [trifarotene Na salt]. The polymorphs are provided, and the form G polymorph is 10.6, 11.5, 17.4, and 19. 1 shows an X-ray powder diffraction pattern with a characteristic peak at a reflection angle 2θ of 7 degrees. In the form G polymorph, the dimers of 8.9, 10.0, 14.7, and 16.2°C are further shown. The peak is shown in.

[0022] In some embodiments, the present disclosure provides a method for preparing trifarotene in accordance with the methods described herein. (b) adjusting the pH of trifarotene to a pH of about 2 to about 4 to provide trifarotene; (c) suspending the trifarotene salt in methyl ethyl ketone to obtain the trifarotene salt. , obtaining polymorphic form A of trifarotene-HCl, In some embodiments, the pH is adjusted using HCl. It will be adjusted.

[0023] In some embodiments, the present disclosure provides a method for preparing trifarotene in accordance with the methods described herein. (b) adjusting the pH of trifarotene to a pH of about 2 to about 4 to provide trifarotene; (c) obtaining a rotene salt, and (d) using acetonitrile, ethyl acetate, tetrahydrofuran, The trifarotene salt is suspended in a solvent containing 1-butanol, or the trifarotene salt is in methanol to obtain Form B polymorph of trifarotene. In some embodiments, a method for preparing the Form B polymorph of rotene-HCl is provided. The pH is adjusted using HCl.

[0024] In some embodiments, the present disclosure provides trifarotene according to the methods described herein. (b) adjusting the pH of the trifarotene to a pH of about 2 to about 4; (c) suspending the trifarotene salt in ethylene glycol to obtain the trifarotene salt; Form C polymorph of trifarotene-HCl, including obtaining Form C polymorph of trifarotene. Further provided are methods for preparing the soluble ... It will be adjusted.

[0025] In some embodiments, the present disclosure provides a method for preparing trifarotene in accordance with the methods described herein. and (b) adjusting the pH of the trifarotene to a pH of about 5 to about 6 to provide the trifarotene. Preparing Polymorph Form D of Trifarotene, Including Obtaining Polymorph Form D of Trifarotene In some embodiments, the pH is adjusted using HCl, acetic acid, sulfuric acid, lysine, or the like. Phosphoric acid, nitric acid, hydrobromic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid It is prepared with carboxylic acids, carboxylic acids, or any mixture thereof.

[0026] In some embodiments, the present disclosure provides a method for preparing trifarotene in accordance with the methods described herein. (b) adjusting the pH of trifarotene to a pH of about 5 to about 6 to provide trifarotene; (c) suspending the trifarotene salt in methanol to obtain a trifarotene salt; to prepare polymorphic form E of trifarotene, including obtaining polymorphic form E of trifarotene. The present invention further provides a method for

[0027] In some embodiments, the present disclosure provides a method for preparing trifarotene in accordance with the methods described herein. (b) adjusting the pH of trifarotene to a pH of about 5 to about 6 to provide trifarotene; (c) dissolving the trifarotene salt in isopropanol to obtain the trifarotene salt; Preparing Form F Polymorph of Trifarotene, Including Obtaining Form F Polymorph of Trifarotene The present invention further provides a method for

[0028] In some embodiments, the present disclosure provides a method for preparing trifarotene in accordance with the methods described herein. and (b) adjusting the pH of the trifarotene to a pH of about 9 to about 12, Form G polymorph of trifarotene sodium salt, including obtaining form G polymorph of trifarotene Further provided are methods for preparing the composition. In some embodiments, the pH is adjusted by adding sodium hydroxide. It is adjusted using the [Brief explanation of the drawings]

[0029] [Figure 1] FIG. 1 shows an X-ray powder diffraction (XRPD) spectrum of the trifarotene HCl salt described in embodiments herein.

[0030] [Figure 2] FIG. 2 shows the XRPD spectrum of the Form A polymorph of trifarotene-HCl described in embodiments herein.

[0031] [Figure 3] FIG. 3 shows the XRPD spectrum of the Form B polymorph of trifarotene-HCl described in embodiments herein.

[0032] [Figure 4] FIG. 4 shows the XRPD spectrum of the Form C polymorph of trifarotene-HCl described in embodiments herein.

[0033] [Figure 5] FIG. 5 shows the XRPD spectrum of the Form D polymorph of trifarotene described in embodiments herein.

[0034] [Figure 6]FIG. 6 shows the XRPD spectrum of the Form E polymorph of trifarotene described in embodiments herein.

[0035] [Figure 7] FIG. 7 shows the XRPD spectrum of the Form F polymorph of trifarotene described in embodiments herein.

[0036] [Figure 8] FIG. 8 shows the XRPD spectrum of the Form G polymorph of the trifarotene Na salt described in embodiments herein.

[0037] [Figure 9] FIG. 9 shows an exemplary method for the preparation of trifarotene [Formula (I)] as described in embodiments herein. DETAILED DESCRIPTION OF THE INVENTION

[0038] The present disclosure relates to a method for preparing trifarotene. The method provided herein is conditions (e.g., performed in extreme heat (e.g., >50°C) or cold (e.g., <-10°C)); Advantageously simplifies the preparation process by reducing or eliminating reaction steps that require do.

[0039] As used herein, "a" or "an" may mean one or more. As used herein, when used in conjunction with the word "comprises," the words "a" or "an" " can mean one or more. As used herein, "another" or "further" "To" can mean at least a second or more.

[0040] Throughout this application, the term "about" is used to indicate that a value accounts for the variation that exists between values ​​or test subjects. Used to indicate that the measurement includes the inherent variation in the error of the method / device used to Typically, the term "about" means approximately 1%, 2%, 3%, 4%, 5%, or 6%, depending on the context. %, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16 %, 17%, 18%, 19%, or 20%, or less, or more than In some embodiments, the term "variability" is used in context as used herein. Thus, one of ordinary skill in the art will understand the level of variability indicated by the term "about." It should also be understood that the use of the term "about" includes the specifically recited value. .

[0041] The use of the term "or" in the claims is intended to be an alternative only and not an "and / or" in this disclosure. Although definitions that refer to "or" are supported, they are not explicitly stated to refer only to alternatives. "and / or" means "and / or" unless and unless its alternatives are mutually exclusive It is used for.

[0042] As used herein, the terms "comprising" (and "including") Optional inclusions such as "comprise" and "comprises" variants or forms of "having" (and "ha" ve) and any variant or form of "to have" such as "has"; "Including" ("includes" and "including" "include" or any variant or form of "contain" "containing" ("contain" and "co" Any variant or form of containing (such as contains) is inclusive or on The present invention is open-ended and does not exclude additional, unrecited elements or method steps. Any embodiment discussed herein may be used in conjunction with any composition (e.g., formulation) of the present disclosure. It is further envisioned that the compositions of the present disclosure (e.g., formulation) can be used to achieve the methods of the present disclosure.

[0043] The term "for example" and its corresponding abbreviation "eg" (whether italicized or not) The use of any term (regardless of whether it is a Representative examples and examples of the present disclosure are not intended to be limited to the specific examples cited. and embodiments.

[0044] As used herein, "between" refers to a range that includes the ends of the range. For example, between x and The numbers between x and y explicitly include any numbers in the range between x and y, and between x and y.

[0045] Unless otherwise specified, used alone or in combination with other groups or atoms In this context, the term "alkyl" refers to saturated straight-chain or alkyl groups containing 1 to about 10 hydrogen-substituted carbon atoms. indicates a branched chain. Examples of alkyl groups include methyl, ethyl, propyl, and isopropyl. butyl, 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.

[0046] Unless otherwise specified, the term "alkenyl" refers to an alkyl group containing at least one double bond. refers to a partially unsaturated straight or branched chain containing from about 2 to about 10 hydrogen-substituted carbon atoms. Examples of alkenyl groups include vinyl, allyl, 2-methylprop-1-enyl, But-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, phenyl 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-methylpenta-1,3-dienyl hexenyl 1-enyl, hepten-1-yl, octen-1-yl, nonen-1-yl, decene- 1-yl, etc.

[0047] Unless otherwise specified, the term "alkynyl" refers to an alkynyl group containing at least one triple bond. refers to a partially unsaturated straight or branched chain containing from about 2 to about 10 hydrogen-substituted carbon atoms. Examples of the alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 2- Methylprop-1-ynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1,3-butynyl Diynyl, 3-methylbut-1-ynyl, 4-methylbut-ynyl, 4-methylbut-2 -ynyl, 2-methylbut-1-ynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl nyl, 4-pentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 3-methyl Pent-1-ynyl, 4-methylpent-2-ynyl, 4-methylpent-2-ynyl, 1-hexynyl, 1-heptynyl, 1-octynyl, 1-nonynyl, 1-decynyl, etc. Examples include:

[0048] Unless otherwise specified, the term "cycloalkyl" refers to a group containing from about 3 to about 10 carbon atoms. The term "saturated or unsaturated ring" refers to a ring containing carbon atoms, the carbon atoms of which may optionally be bonded to one or more of the same carbon atoms. one or different substituents, for example, 1 to 3, 1 to 6, 1 to 8, or 1 to 10 substituents; The cycloalkyl group may be substituted with a substituent. Examples of the cycloalkyl group include cyclopropyl. , cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, Cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl cyclooctenyl, cyclononyl, cyclodecyl, and the like.

[0049] Unless otherwise specified, the term "aryl" refers to a fully or partially saturated or unsaturated an aromatic monocyclic ring containing from about 5 to about 14 carbon atoms which may be optionally fused to a carbocyclic ring of The aryl group refers to a cyclic or bicyclic group. Examples of the aryl group include phenyl, naphthyl, indole, and the like. Examples include Nil.

[0050] Unless otherwise specified, the term "alkanoyl" refers to a carbonyl group attached to an alkyl group. The term "alkenoyl" refers to a carbonyl (C=O) group attached to an alkenyl group. The term "alkynoyl" refers to a carbonyl (C=O) group attached to an alkynyl group. The term "cycloalkyl" refers to a cycloalkyl group consisting of one or more rings of carbon atoms. "Cycloalkanoyl" refers to an alkane containing a cycloalkanoyl group attached to a cycloalkyl group. "Arylcarbonyl" refers to a carbonyl (C=O) group attached to an aryl group. Refers to carbonyl (C=O).

[0051] Unless otherwise specified, a "heterocycle" refers to a monocyclic ring containing from about 3 to about 10 carbon atoms. A non-aromatic hydrocarbon ring or bicyclic non-aromatic hydrocarbon containing from about 7 to about 14 carbon atoms. refers to a hydrocarbon ring system in which one or more carbon atoms within the hydrocarbon ring or ring system are bonded to one heteroatom. Examples of heterocyclic rings include, but are not limited to, azepan-1-yl , piperidinyl, for example piperidin-1-yl and piperidin-4-yl, piperadinyl Nyl, for example, N-piperazinyl and 1-alkylpiperazin-4-yl, morpholine -4-yl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydro thiazole, tetrahydrothiophene, sulfonyl, sulfonyl, oxazolinyl, Examples include isoxazolinyl, oxazolidinyl, and oxazolidinonyl. "Ring carbonyl" refers to a carbonyl (C=O) attached to a heterocyclic group.

[0052] Unless otherwise specified, "heteroaryl" refers to a group containing at least one heteroatom. Examples of heteroaryl groups include, but are not limited to, pyrrolidinyl ... aryl, 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 Lysinyl, pyrrolo(2,3-b)pyridinyl, pyrazolo(1,5-a)pyridinyl, 1, 2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, oxazolyl, iso Oxazolyl, 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, tetrahydrofuranyl Hydrothiophenyl, benzothiophenyl, benzisothiophenyl, pyridyl, piperidine Lysinyl, quinolinyl, isoquinolinyl, quinolizinyi, pyrazinyl, pyridazinyl, pyridazinyl, Rimidinyl, pyranyl, tetrahydropyranyl, 1,2,3-triazinyl, 1,2,4 -triazinyl, 1,3,5-triazinyl, chromenyl, morpholinyl, diazepinyl benzodiazepinyl, etc. "Heteroarylcarbonyl" refers to a heteroaryl Refers to a carbonyl (C=O) bonded to an aryl group.

[0053] In some embodiments, any of the carbon chain substituents described herein, e.g., alkyl, aralkyl ... Alkanoyl, alkenoyl, alkynoyl, alkanoyl, etc. include one or more alkyl groups in the carbon chain. a number of carbons may be replaced by one or more heteroatoms, i.e. atoms other than carbon or hydrogen, e.g. In some embodiments, the substituted aryl groups described herein are substituted with nitrogen, oxygen, sulfur, or phosphorus. The above-mentioned substituents include, for example, alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, and alkyl groups. Aryl group, heterocycle, heteroaryl, alkanoyl group, alkenoyl group, alkynoyl group , cycloalkanoyl group, arylcarbonyl group, heterocyclic carbonyl group, heteroaryl The term "substituted" refers to a group such as a hydroxyl group, a substituted or unsubstituted group, or a substituted or unsubstituted group. means replacing a hydrogen on a substituent with a different group, e.g., hydroxyl, halide, alkyl (e.g., For example, C 1-6 The term " refers to substitution with alkyl, alcohol, ketone, etc. "Unsubstituted" refers to the case where a substituent does not have a hydrogen replaced by a different group.

[0054] A "linear" molecule contains a single backbone. For example, a "linear C1-C n "There is one molecule It contains n carbon atoms, each bonded to its two neighboring atoms and two hydrogen atoms. bonded to only one carbon atom and three hydrogen atoms (terminal carbon, i.e. (Except those containing methyl groups.) A "branched" molecule contains a non-linear backbone, and the branches are located at one or more ends of the main backbone. may originate from multiple atoms. For example, a "branched C1-C n " The molecule is At least one of the hydrogen atoms bonded to at least one of the carbons is a substituent, e.g., alkyl Straight chain C1-C except substituted with groups n It comes from molecules.

[0055] Cyclic groups (e.g., cycloalkyl, aryl, heterocyclic, heteroaryl) described herein are Either of the cycloalkanes can be substituted or unsubstituted. For example, a substituted cycloalkane can have a ring-forming structure. Any of the atoms forming the alkyl group may have a substituent. The substituents may include any of the groups described herein. groups such as alkyl, alkenyl, alkynyl, and the like.

[0056] In some embodiments, the present disclosure provides a compound of formula (I) [trifarotene] [ka] or a salt thereof, the method comprising: [ka] [In the formula, R 4 is hydrogen, substituted or unsubstituted straight or branched C1-C8 alkanoyl substituted or unsubstituted straight-chain or branched C2-C8 alkenoyl groups, substituted or unsubstituted straight-chain or branched C2-C8 alkenoyl groups, or unsubstituted straight-chain or branched C2-C8 alkynoyl groups, substituted or unsubstituted cyclohexyl groups, chloroalkanoyl group, substituted or unsubstituted arylcarbonyl group, substituted or unsubstituted a heterocyclic carbonyl group, a substituted or unsubstituted heteroaryl carbonyl group, or a hetero Y is a C1-C8 alkanoyl group containing a nitrile (CN) or amide (C ONH2) to obtain a compound of formula (I).

[0057] In some embodiments, the compound of formula (I) is trifarotene. In some embodiments, the compound of formula (I) is trifarotene-HCl. ) is the sodium salt of trifarotene.

[0058] In some embodiments, R 4 is hydrogen. In embodiments, R 4 is an alkanoyl group In some embodiments, R 4 is a formyl group (—COH). In embodiments, R 4 Haa In some embodiments, the compound of formula (V) is selected from the group consisting of: Selected: [ka]

[0059] In some embodiments, Y is a nitrile. In some embodiments, Y is an amide. In some embodiments, R4 is hydrogen and Y is a nitrile or amide. In terms of form, R 4 is alkanoyl and Y is nitrile or amide. In this state, R 4 is formyl and Y is a nitrile or amide. , R 4 is acetyl and Y is a nitrile or amide.

[0060] In some embodiments, R 4 is alkenoyl and Y is nitrile or amide. In some embodiments, R 4 is alkynoyl and Y is nitrile or amide. In some embodiments, R 4 is a substituted cycloalkanoyl, and Y is a nitrile or amide. In some embodiments, R 4 is unsubstituted cycloalkanoyl, and Y is a nitrile or is an amide. In some embodiments, R 4 is a substituted arylcarbonyl group, and Y is nitro tolyl or amide. In some embodiments, R 4 is an unsubstituted arylcarbonyl group and Y is a nitrile or an amide. In some embodiments, R 4 is a substituted heterocycle is a carbonyl group and Y is a nitrile or an amide. 4 is not In some embodiments, the heterocyclic carbonyl group is a substituted heterocyclic carbonyl group, and Y is a nitrile or an amide. is R 4 is a substituted heteroarylcarbonyl group and Y is a nitrile or amide. In some embodiments, R 4 is an unsubstituted heteroarylcarbonyl group, and Y is a nitrile or or amide. In some embodiments, R 4C containing heteroatoms 1- C8 Arcanoy is a nitrile group, and Y is a nitrile or amide.

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

[0062] The term "hydrolyze" or variants thereof, such as "hydrolyze" or "hydrolyze" "Water" refers to the reaction product, typically as a hydroxyl (-OH) group, in which water is a reactant. The hydrolysis of a nitrile or amide gives a carboxylic acid (-COO In some embodiments, the hydrolysis can be carried out in the presence of water and a co-solvent to form H). Examples of co-solvents that can be used in combination with water for the hydrolysis reaction include, but are not limited to: However, alcohols such as methanol, ethanol, propanol, and isopropanol are not n-butanol, tert-butanol, sec-butanol, and isobutanol alcohol; methylene chloride; acetonitrile; ethyl acetate; and tetrahydrofuran 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 (MeOH), or the like. Ethyl alcohol (EtOH), propanol (PrOH), isopropanol (IPA), or In some embodiments, the hydrolysis is carried out using a mixture of water and ethanol. It is carried out in the presence of

[0063] In some embodiments, the hydrolysis is further carried out in the presence of an acid or a base. In embodiments, the acid is hydrochloric acid (HCl), sulfuric acid (H2SO4), nitric acid (HNO3), hydrobromic acid (H2SO4), Hydrochloric acid (HBr), hydroiodic acid (HI), perchloric acid (HClO4), chloric acid (HClO3 ), sulfurous acid (H2SO3), methanoic acid (HCO2H), phosphoric acid (H3PO4), nitrous acid ( HNO2), hydrofluoric acid (HF), or any mixture thereof. In this state, the base is sodium hydroxide (NaOH), potassium hydroxide (KOH), Lithium (LiOH), barium hydroxide (Ba(OH)2), or any mixture thereof Includes:

[0064] In some embodiments, R 4 is hydrogen and Y is hydrolyzed. Y is hydrolyzed to form a carboxylic acid. In some embodiments, R 4 is described in this specification. The carbonyl, together with the oxygen attached to it, is hydrolyzed to give the hydroxyl group. In some embodiments, R 4 and Y are hydrolyzed under the same reaction conditions. In some embodiments, R 4 and Y are simultaneously hydrolyzed.

[0065] In some embodiments, the compound of formula (V) is present in a concentration of about 0.1 to about 1 mol / L (solvent), about 0 Add 0.2 to 0.8 mol / L (solvent) or 0.3 to 0.5 mol / L (solvent). In some embodiments, the compound of formula (V) is present in a water splitting reaction at a concentration of 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 In some embodiments, the compound of formula (V) is present in the hydrolysis reaction at about 1 mol / L (solvent). The hydrolysis of the compound is carried out under acidic conditions. In some embodiments, the hydrolysis is carried out at a temperature of about 4 to 100°C. 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 In some embodiments, the hydrolysis reaction is carried out at a pH of about 4.5, about 4.6, or about 5.5. , 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, approximately 5.6, approximately 5.7, approximately 5.8, approximately 5.9, approximately 6, approximately 6.1, approximately 6.2, approximately 6. 3, about 6.4, or about 6.5.

[0066] In some embodiments, the present disclosure provides R 4 for preparing a compound of formula (V) wherein is hydrogen In some embodiments, the compound of formula (V) is a compound of formula (IV): [ka] [In the formula, R 3 is hydrogen, a hydroxyl group, a substituted or unsubstituted straight-chain or branched C1 -C8 alkyl group, substituted or unsubstituted straight-chain or branched C2-C8 alkenyl group , a substituted or unsubstituted straight-chain or branched C2-C8 alkynyl group, a substituted or unsubstituted Substituted cycloalkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclic groups ring, substituted or unsubstituted heteroaryl, or C1-C8 alkyl containing heteroatoms group, and Y is a nitrile (CN) or an amide (CONH2) in the presence of a base In some embodiments, the compound of formula (V) is prepared by hydrolysis of the compound of formula (V). The ester of the compound (IV) (-COOR 3 ) is hydrolyzed to form a hydroxyl group (-O In some embodiments, R of the compound of formula (V) forms 4 is hydrogen.

[0067] Y in compounds of formula (IV) is as defined herein for compounds of formula (V). In some embodiments, R 3 is hydrogen and Y is a nitrile or amide. In an embodiment of the present invention, R 3 is methyl and Y is a nitrile or an amide. In this state, R 3 is hydroxyl and Y is nitrile or amide. So, R 3 is methyl and Y is a nitrile.

[0068] In some embodiments, the hydrolysis of the compound of formula (IV) is carried out in the presence of water and a co-solvent. Exemplary co-solvents are provided herein. In some embodiments, a co-solvent of formula (IV) Hydrolysis of the compound can be achieved by using water, methanol (MeOH), ethanol (EtOH), propane, solvent containing ethanol (PrOH), isopropanol (IPA), or any mixture thereof In some embodiments, the solvent comprises water and ethanol.

[0069] In some embodiments, the hydrolysis of the compound of Formula (IV) is carried out in the presence of a base. Exemplary bases for the hydrolysis reaction are provided herein. In some embodiments, the base has the formula ( The bases for the hydrolysis of compounds IV) are sodium hydroxide (NaOH), potassium hydroxide, ammonium hydroxide (KOH), lithium hydroxide (LiOH), barium hydroxide (Ba(OH)2), or any mixture thereof.

[0070] In some embodiments, the compound of formula (IV) is present in a concentration of about 0.01 to about 0.5 mol / L (solvent ), about 0.02 to about 0.2 mol / L (solvent), about 0.03 to about 0.1 mol / L (solvent) ), about 0.04 to about 0.08 mol / L (solvent), or about 0.05 to about 0.07 mol / L (solvent) during the hydrolysis reaction. In some embodiments, the compound of formula (IV) ,approximately 0.01,approximately 0.02,approximately 0.03,approximately 0.04,approximately 0.05,approximately 0.06,approximately 0. 07, about 0.08, about 0.09, or about 0.1 mol / L (solvent) during the hydrolysis reaction In some embodiments, the base is present in an amount of about 1, about 2, about 3, or about 4 moles relative to the compound of Formula (IV). about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 molar equivalents added to the hydrolysis reaction In some embodiments, the base is about 0.1 to about 1 mol / L (solvent), about 0.2 to about 1 mol / L (solvent). About 0.8 mol / L (solvent), about 0.3 to about 0.6 mol / L (solvent), or about 0.4 It is added to the hydrolysis reaction at about 0.5 mol / L (solvent).

[0071] In some embodiments, the present disclosure further provides a method for preparing a compound of formula (IV). The method comprises providing a compound of formula (II) [ka] [In the formula, R 1 and R 2 are independently hydrogen, straight-chain or branched C1-C3 alkyl, or pinacolato, R 1 and R 2 can be the same or different? , or R 1 and R 2 together form pinacolate] with a compound of formula (III) [ka] [In the formula, R 3 is hydrogen, hydroxyl group, straight or branched C1-C8 alkyl, straight chain Or a branched C2-C8 alkenyl group, a straight-chain or branched C2-C8 alkynyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted aryl groups, or unsubstituted heterocycle, substituted or unsubstituted heteroaryl, or heteroatom-containing is a C1-C8 alkyl group, X is a halogen or a triflate, and Y is a nitrile or or an amide] in the presence of a catalyst to obtain a compound of formula (IV). include.

[0072] In some embodiments, R of the compound of formula (II) 1 and R 2 are independently hydrogen. In some embodiments, R of the compound of formula (II) 1 and R 2 are independently linear or In some embodiments, R of the compound of formula (II) is a branched C1-C3 alkyl group. 1 and R 2 combine to form pinacolate.

[0073] In some embodiments, the compound of Formula (II) is selected from: [ka]

[0074] R of the compound of formula (III) 3 and Y are defined above for compounds of formula (IV). In some embodiments, X in the compound of formula (III) is Suzuki. It is a leaving group in a coupling reaction. Examples of leaving groups in the Suzuki reaction are, for example, Liu et al.,Org Lett 7(6):1149-1151(2005);El- Berjawi 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, For example, fluorine, chlorine, bromine, or iodine. In some embodiments, X is a triflate. In some embodiments, R is a carboxylate (-OSO2CF3, also abbreviated as -OTf) group. 3 is hydrogen, Y is a nitrile or amide, and X is a halogen or triflate. In some embodiments, R 3 is methyl, Y is a nitrile or amide, and X is halogen or triflate. In some embodiments, R 3 is hydroxyl In some embodiments, Y is a nitrile or an amide, and X is a halogen or a triflate. In the embodiment, R 3 is methyl, Y is nitrile, and X is iodine.

[0075] In some embodiments, the compound of Formula (III) is selected from: [ka] TIFF2026016786000021.tif55153

[0076] In some embodiments, the reaction between the compound of Formula (II) and the compound of Formula (III) is toluene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran Hydrofuran (THF), dioxane, n-butanol (n-BuOH), isopropanol IPA, Ethanol (EtOH), Methanol (MeOH), Dimethyl Ether in the presence of a solvent containing (DME), diethyl ether, or any mixture thereof In some embodiments, the reaction between a compound of formula (II) and a compound of formula (III) is carried out using water as a solvent. In some embodiments, the reaction of a compound of formula (II) with a compound of formula (I The reaction between the compound II) and the compound II) is carried out in a solvent-free manner, for example, the reaction is microwave-assisted. (e.g., Nun et al., Synlett 11:1761-1764 (2 See 009).

[0077] In some embodiments, the reaction between the compound of Formula (II) and the compound of Formula (III) is Potassium carbonate (K2CO3), potassium acetate (CH3CO2K), potassium phosphate (K3P O4), potassium tert-butoxide (KOtBu), sodium carbonate (Na2CO3 ), sodium bicarbonate (NaHCO3), sodium methoxide (NaOMe), sodium Sodium tert-butoxide (NaOtBu), cesium carbonate (Cs2CO3), silver phosphate ( Ag3PO4), silver oxide (Ag2O), thallium carbonate (Tl2CO3), thallium ethoxylate Cid (TlOEt), tert-butylamine (t-BuNH2), potassium hydroxide (K OH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), barium hydroxide (Ba(OH)2), thallium hydroxide (TlOH), or a combination thereof It is carried out in the presence of

[0078] In some embodiments, for the reaction between a compound of formula (II) and a compound of formula (III): The catalysts are palladium (Pd), copper (Cu), nickel (Ni), iron (Fe), and zinc (Z). n), or rhodium (Rh). In some embodiments, the catalyst comprises a metal selected from 1 to 4. In some embodiments, the catalyst contains 6 atoms of the metal. In some embodiments, the catalyst contains 2 to 5 atoms of the metal. In embodiments, the catalyst comprises 2 to 4 atoms of metal. Palladium-catalyzed coupling reactions include those involving 3, 4, 5, or 6 atoms of metal. U.S. Patent Application Publication No. 2006 / 0264629 and U.S. Patent Application Publication No. 2010 / 0 No. 184739.

[0079] In some embodiments, the catalyst is a palladium catalyst. The catalyst was Pd(PPh3)2Cl2 [bis(triphenylphosphine)palladium(II ) dichloride], Pd(PPh3)4 [tetrakis(triphenylphosphine)palladium 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 ) methanesulfonic acid], SPhos-Pd-G2 [chloro(2-dicyclohexylphosphite) 2-(2'-amino-1,1 '-biphenyl]palladium(II)], CATACXIUM® A Pd G 3(mesylate [di(1-adamantyl)-n-butylphosphine]-2-(2'-amino bis(1-adamantyl)- (butylphosphine)-2-(2'-amino-1,1'-biphenyl)palladium(II) methanesulfonic acid), APhos Pd G3 (palladium G3-(4-(N,N-dimethyl (4-(di-tert-butylamino)phenyl)di-tert-butylphosphine] or [4-(di-tert-butylamino)phenyl)di-tert-butylphosphine] t-butylphosphino)-N,N-dimethylaniline-2(2'-aminobiphenyl)] Palladium(II) methanesulfonate, P(Cy3)Pd-G3 (Palladium G3-trimethylsilyl) Cyclohexylphosphine or [(tricyclohexylphosphine)-2-(2'- Aminobiphenyl)]palladium(II) methanesulfonate), allylpalladium(II) ) chloride dimer (bis(allyl)dichlorodipalladium), or Pd(dppf)C l2[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II )].

[0080] In some embodiments, the catalyst is a copper catalyst. In some embodiments, the copper catalyst is copper chloride ( I), [(o-(di-tert-butylphosphino)-N,N-dimethylaniline)iodide Copper chloride]2, [(o-(di-tert-butylphosphino)-N,N-dimethylaniline) copper fluoride]. In some embodiments, the catalyst is a nickel catalyst. Nickel catalysts are NiCl2, NiBr2, NiI2, G3DenP-Ni, (d ppf)Ni(cinnamyl)Cl, (PCy3)2NiCl2, or Ni(cod)2 Further exemplary catalysts are described, for example, in Tasker et al., Nature e 509(7500):299-309(2014);Yang et al.,An gew Chem Int Ed Engl 50(17):3904-3907(20 11);Barder et al., J Am Chem Soc 127(13): 4685-4696(2005);Bedford et al.,Chem Comm un(Camb)42:6430-6432(2009);and Catalysts Vol.9, ISSN 2073-4344(2019).

[0081] In some embodiments, the reaction between the compound of Formula (II) and the compound of Formula (III) is In some embodiments, the reaction is further carried out in the presence of a ligand, such as a phosphine ligand, In some embodiments, the ligand is PPh3, PCy 3, P(o-tolyl)3, P(i-Pr)3, P(O-Pr-i)3, n-BuP(1- Ad)2, P(t-Bu)2(p-NMe 2- Ph), dialkylbiaryl ligands (e.g. For example, Martin et al., Acc Chem Res 41:1461(20 08), bidentate phosphine ligands such as DPPF, DPPE, or DPPP, Rubene-type ligands (e.g., Kuwano et al., Org Lett 7:945 (2005)), olefinic ligands (e.g., Tao et al., J Or g Chem 69:4330 (2004)), amines, or imines (e.g., Tao et al., J Org Chem 69:4330 (2004) In some embodiments, the ligand and catalyst are present in the reaction as a preformed complex. For example, Pd(PPh3)4 is a palladium catalyst with a phosphine ligand. In some embodiments, the process for preparing the compound of formula (IV) includes the step of reacting a metal and and preparing a catalyst comprising the ligand.

[0082] In some embodiments, the reaction does not involve a catalyst. In some embodiments, the reaction does involve a ligand. Further exemplary reaction conditions are described, for example, in Suzuki, J. Organome tallic Chem 576:147-168(1999);Miyaura et al. al.,Chem Rev 95:2457-2483(1995);Chemler et al., Angew Chem Int Ed Engl 40:4544-4 568 (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 5:4219 3(2015).

[0083] In some embodiments, the compounds of Formula (II) and Formula (III) are mixed in a ratio of about 1:10, about 1: 5, approx. 1:4, approx. 1:3, approx. 1:2, approx. 1:1, approx. 1:0.75, approx. 1:0.5, approx. 1: 0.25, about 1:0.1, or about 1:0.05 molar ratio. In an embodiment, the compounds of formula (II) and (III) are present in a concentration of about 0.01 to about 1 mol / L (solvent). solvent), about 0.05 to about 0.5 mol / L (solvent), about 0.1 to about 0.4 mol / L (solvent) ), about 0.15 to about 0.35 mol / L (solvent), or about 0.2 to about 0.3 mol / L The amount of (solvent) is added.

[0084] In some embodiments, the catalyst is present in an amount of about 0 to about 0.05 wt. % of the compound of Formula (II) or Formula (III). 0.001 to approximately 1, approximately 0.002 to approximately 0.5, approximately 0.003 to approximately 0.1, approximately 0.004 to approximately 0.075, approx. 0.005 to approx. 0.05, approx. 0.006 to approx. 0.025, approx. 0.007 to It is added to the reaction in about 0.01, or about 0.008 to about 0.009 molar equivalents. In embodiments, the catalyst is present in an amount of about 0.001, Approximately 0.002, approximately 0.003, approximately 0.004, approximately 0.005, approximately 0.006, approximately 0.00 7, about 0.008, about 0.009, about 0.01, about 0.02, about 0.03, about 0.04, Approximately 0.05, approximately 0.06, approximately 0.07, approximately 0.08, approximately 0.09, approximately 0.1, approximately 0.2, about 0.3, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about 1 molar equivalent is added to the reaction.

[0085] In some embodiments, the base is about 0 to about 0.05 wt. % of the compound of Formula (II) or Formula (III). added to the reaction in an amount of about 0.1 to about 10, about 0.5 to about 8, about 1 to about 6, or about 2 to 4 molar equivalents. In some embodiments, the base is about 1000 ppm relative to the compound of Formula (II) or Formula (III). 0.1, approx. 0.5, approx. 1, approx. 1.5, approx. 2, approx. 2.5, approx. 3, approx. 3.5, approx. 4, approx. 4.5 , about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5 , or about 10 molar equivalents are added to the reaction.

[0086] In some embodiments, the present disclosure provides a compound of formula (I) [trifarotene] [ka] or a salt thereof, the method comprising: [ka] [In the formula, R 1 and R 2 are independently hydrogen or a straight or branched C1-C3 alkyl group. R 1 and R 2 may be the same or different, or R 1Oh BiR 2 together form pinacolate] with a compound of formula (III) [ka] [In the formula, R 3 is a substituted or unsubstituted straight or branched C1-C8 alkyl, or an unsubstituted straight-chain or branched C2-C8 alkenyl group, a substituted or unsubstituted Straight-chain or branched C2-C8 alkynyl groups, substituted or unsubstituted cycloalkyl groups , a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted and X is a halogen atom. or triflate, and Y is a nitrile (CN) or an amide (CONH). in the presence of a catalyst to obtain a compound of formula (IV) [ka] [In the formula, R 3 is as defined above; and obtaining a compound of formula (IV) in the presence of a base to obtain trifarotene. 1 , R 2 , R 3 , R 4 , X, and Y, as well as various reactions and conditions, are further described herein. In some embodiments, R 3 is methyl, X is iodine, and Y is nitrile.

[0087] An exemplary method for preparing trifarotene [formula (I)] as described in embodiments herein The method is shown in Figure 9.

[0088] In some embodiments, the present disclosure provides a compound of formula (II) [ka] [In the formula, R 1 and R 2 are independently hydrogen or a straight or branched C1-C3 alkyl group. R 1 and R 2 may be the same or different, or R 1 Oh BiR 2 which combine to form a pinacolate, the method comprising: [ka] -R in the presence of salt and catalyst 1 OBOR 2 A compound comprising: 1 and R 2 is the formula ( As defined above for compound II), In embodiments, the catalyst is a palladium catalyst. In some embodiments, the catalyst is P(tBu) 3. In some embodiments, the catalyst comprises Pd-162 ([P(tBu)3]Pd(chlorine). Pd-168 ([P(tBu)3] palladacycle), or Pd-21 6({Pd(μ-I)[P(t-Bu)3]}2). In some embodiments, the reaction is , about 15℃ to about 35℃, about 18℃ to about 32℃, about 20℃ to about 30℃, about 22℃ to about 28℃ or from about 24° C. to about 26° C. In some embodiments, the methods provided herein The process for preparing the compound of formula (II) is carried out at room temperature. For example, the reaction is carried out under harsh conditions (e.g., −78° C.), WO2006 / 06697 Compared to the method described in 8, the present method is significantly less complex and requires less preparation time. do.

[0089] In some embodiments, the present disclosure provides novel compounds. The novel compounds described herein are used to prepare trifarotene. The novel compounds described herein may advantageously simplify the process for preparing trifarotene.

[0090] In some embodiments, the present disclosure provides a compound of formula (III) [ka] [In the formula, R 3 is a substituted or unsubstituted straight or branched C1-C8 alkyl group; substituted or unsubstituted straight or branched C2-C8 alkenyl groups, substituted or unsubstituted a straight-chain or branched C2-C8 alkynyl group, a substituted or unsubstituted cycloalkyl a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic ring, a substituted or unsubstituted substituted heteroaryl or C1-C8 alkyl group containing a heteroatom; X is a halo R is a nitrile or triflate, and Y is a nitrile or amide. 3 , X and Y are further described herein.

[0091] In some embodiments, the compound of Formula (III) is selected from: [ka] TIFF2026016786000030.tif254166

[0092] In some embodiments, the compound of formula (III) is [ka] In the presence of a strong base, R 3CO2CH2Br, wherein X, Y, and R 3 is defined as above for compounds of formula (III). In an embodiment, the strong base is sodium hydride.

[0093] In some embodiments, the present disclosure provides a compound of formula (V) [ka] [In the formula, R 4 is hydrogen, substituted or unsubstituted straight or branched C1-C8 alkanoyl substituted or unsubstituted straight-chain or branched C2-C8 alkenoyl groups, substituted or unsubstituted straight-chain or branched C2-C8 alkenoyl groups, or unsubstituted straight-chain or branched C2-C8 alkynoyl groups, substituted or unsubstituted cyclohexyl groups, chloroalkanoyl group, substituted or unsubstituted arylcarbonyl group, substituted or unsubstituted a heterocyclic carbonyl group, a substituted or unsubstituted heteroaryl carbonyl group, or a hetero Y is a C1-C8 alkanoyl group containing a nitrile (CN) or amide (C ONH2)] to provide.

[0094] R 4 and Y are further described herein. In some embodiments, R 4 is hydrogen In some embodiments, R 4 is a substituted or unsubstituted straight or branched C1-C 8 Alkanoyl group, substituted or unsubstituted straight or branched C2-C8 alkenoyl a substituted or unsubstituted straight-chain or branched C2-C8 alkynoyl group, ... is an unsubstituted cycloalkanoyl group, a substituted or unsubstituted arylcarbonyl group, a substituted or unsubstituted arylcarbonyl group, or unsubstituted heterocyclic carbonyl group, substituted or unsubstituted heteroaryl carbonyl group or a C1-C8 alkanoyl group containing a heteroatom.

[0095] In some embodiments, R 4 is an unsubstituted straight-chain or branched C1-C8 alkanoyl unsubstituted linear or branched C2-C8 alkenoyl group, unsubstituted linear or branched C2-C8 alkenoyl group Branched C2-C8 alkynoyl groups, unsubstituted cycloalkanoyl groups, unsubstituted aryl groups a carbonyl group, an unsubstituted heterocyclic carbonyl group, an unsubstituted heteroaryl carbonyl group, or is a C1-C8 alkanoyl group containing a heteroatom.

[0096] In some embodiments, R 4 is an unsubstituted straight-chain or branched C1-C4 alkanoyl unsubstituted linear or branched C2-C4 alkenoyl group, unsubstituted linear or branched C2-C4 alkenoyl group Branched C2-C4 alkynoyl group or C1-C4 alkanoyl group containing a heteroatom be.

[0097] In some embodiments, R 4 is acetyl.

[0098] In some embodiments, the compound of Formula (V) is selected from: [ka]

[0099] In some embodiments, the present disclosure provides novel polymorphs of the compound trifarotene of formula (I). The novel polymorphs described herein provide improved trifarotene and its pharmaceutical properties. can be used to better characterize

[0100] In some embodiments, the present disclosure provides a compound of formula (I) [trifarotene-HCl] in the form and Form A polymorph, wherein Form A polymorph is present at 7.6°C, 11.5°C, 15.4°C, 21.1°C, and X-ray powder diffraction (XRPD) patterns with characteristic peaks at reflection angles 2θ of 23.2 degrees. In some embodiments, the Form A polymorph further exhibits 8.6, 9.0, 17. It exhibits peaks at 7 degrees, 18.3 degrees, 19.5 degrees, and 22.5 degrees. An exemplary XRPD spectrum of the form is shown in FIG.

[0101] In some embodiments, the present disclosure provides a method for preparing trifarotene in accordance with the methods described herein. (b) adjusting the pH of trifarotene to a pH of about 2 to about 4 to provide trifarotene; (c) suspending the trifarotene salt in methyl ethyl ketone to obtain the trifarotene salt. , obtaining polymorphic form A of trifarotene-HCl, Further provided are methods for preparing the formulations. In some embodiments, the pH is adjusted to the desired value as described herein. In some embodiments, the pH is adjusted using HCl. .

[0102] In some embodiments, the present disclosure provides a compound of formula (I) [trifarotene-HCl] in the form and Form B polymorph is provided, the Form B polymorph being present at 12.6°C, 19.5°C, 19.8°C, 24.6°C, and an X-ray powder diffraction pattern with a characteristic peak at a reflection angle 2θ of 29.5 degrees. In some embodiments, the Form B polymorph may further comprise: 8.4°C, 12.0°C, 17.4°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18 It exhibits peaks at 1.1, 23.2, 31.0, and 32.1 degrees. An exemplary XRPD spectrum is shown in FIG.

[0103] In some embodiments, the present disclosure provides a method for preparing trifarotene in accordance with the methods described herein. (b) adjusting the pH of trifarotene to a pH of about 2 to about 4 to provide trifarotene; (c) obtaining a rotene salt, and (d) using acetonitrile, ethyl acetate, tetrahydrofuran, The trifarotene salt is suspended in a solvent containing 1-butanol, or the trifarotene salt is in methanol to obtain Form B polymorph of trifarotene. Further provided is a method for preparing the Form B polymorph of rotene-HCl. In some embodiments, the pH is adjusted using an acid as described herein. It is adjusted with HCl.

[0104] In some embodiments, the present disclosure provides a compound of formula (I) [trifarotene-HCl] in the form and Form C polymorph, which has the following structural variations: 7.9°C, 15.6°C, 20.0°C, 23.6°C, and an X-ray powder diffraction pattern having a characteristic peak at a reflection angle 2θ of 27.8 degrees. In some embodiments, the Form C polymorph further comprises: 12.1°C, 16.4°C, 17.4°C, and An exemplary XRPD spectrum of the Form C polymorph is shown in Figure 4. vinegar.

[0105] In some embodiments, the present disclosure provides trifarotene according to the methods described herein. (b) adjusting the pH of the trifarotene to a pH of about 2 to about 4; (c) suspending the trifarotene salt in ethylene glycol to obtain the trifarotene salt; Form C polymorph of trifarotene-HCl, including obtaining Form C polymorph of trifarotene. Further provided are methods for preparing the composition. In some embodiments, the pH is adjusted to the desired pH as described herein. Adjusted with acid: In some embodiments, the pH is adjusted with HCl.

[0106] In some embodiments, the present disclosure provides the Form D polymorph of the compound of formula (I) [trifarotene]. The Form D polymorph provides reactions of 8.5°C, 16.2°C, 18.6°C, and 23.1°C. The compound exhibits an X-ray powder diffraction pattern having characteristic peaks at 2θ angles. The Form D polymorph additionally exhibits peaks at 12.2 degrees, 12.8 degrees, and 14.1 degrees. An exemplary XRPD spectrum of the Form D polymorph is shown in FIG.

[0107] In some embodiments, the present disclosure provides a method for preparing trifarotene in accordance with the methods described herein. and (b) adjusting the pH of the trifarotene to a pH of about 5 to about 6 to provide the trifarotene. Preparing Polymorph Form D of Trifarotene, Including Obtaining Polymorph Form D of Trifarotene In some embodiments, the pH is adjusted using an acid as described herein. In some embodiments, the pH is adjusted using HCl, acetic acid, sulfuric acid, phosphoric acid, nitric acid, or hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, or It may be prepared using any mixture of these.

[0108] In some embodiments, the present disclosure provides the Form E polymorph of the compound of formula (I) [trifarotene]. and Form E polymorphs have the following structural variations: 8.6°C, 12.8°C, 14.2°C, 17.9°C, and 2°C. The X-ray powder diffraction pattern shows a characteristic peak at a reflection angle 2θ of 4.0 degrees. In embodiments, the Form E polymorph is further characterized by the following: 10.6°C, 15.3°C, 16.3°C, 19.3°C. An exemplary XRPD spectrum of the Form E polymorph is shown in Figure 6, which shows peaks at 10.0°C, 11.0°C, and 22.0°C. Shown below.

[0109] In some embodiments, the present disclosure provides a method for preparing trifarotene in accordance with the methods described herein. (b) adjusting the pH of trifarotene to a pH of about 5 to about 6 to provide trifarotene; (c) suspending the trifarotene salt in methanol to obtain a trifarotene salt; to prepare polymorphic form E of trifarotene, including obtaining polymorphic form E of trifarotene. The present invention further provides a method for

[0110] In some embodiments, the present disclosure provides the Form F polymorph of the compound of formula (I) [trifarotene]. and Form F polymorphs are available at 5.2°C, 6.3°C, 14.9°C, 18.0°C, and 19°C. The X-ray powder diffraction pattern shows a characteristic peak at a reflection angle 2θ of 0.1 degrees. In terms of form, the Form F polymorph further exhibits the following variations: 8.5°C, 15.6°C, 16.3°C, 18.5°C, and An exemplary XRPD spectrum of the Form F polymorph is shown in Figure 7. vinegar.

[0111] In some embodiments, the present disclosure provides a method for preparing trifarotene in accordance with the methods described herein. (b) adjusting the pH of trifarotene to a pH of about 5 to about 6 to provide trifarotene; (c) dissolving the trifarotene salt in isopropanol to obtain the trifarotene salt; Preparing Form F Polymorph of Trifarotene, Including Obtaining Form F Polymorph of Trifarotene The present invention further provides a method for

[0112] In some embodiments, the present disclosure provides form G of the compound of formula (I) [trifarotene Na salt]. The polymorphs are provided, and the form G polymorph is 10.6, 11.5, 17.4, and 19. 1 shows an X-ray powder diffraction pattern with a characteristic peak at a reflection angle 2θ of 7 degrees. In the form G polymorph, the dimers of 8.9, 10.0, 14.7, and 16.2°C are further shown. An exemplary XRPD spectrum of the Form G polymorph is shown in FIG.

[0113] In some embodiments, the present disclosure provides a method for preparing trifarotene in accordance with the methods described herein. and (b) adjusting the pH of the trifarotene to a pH of about 9 to about 12, Form G polymorph of trifarotene sodium salt, including obtaining form G polymorph of trifarotene Further provided are methods for preparing the composition. In some embodiments, the pH is adjusted to the range described herein. In some embodiments, the pH is adjusted using sodium hydroxide. It will be adjusted.

[0114] All references cited herein, including patents, patent applications, articles, textbooks, etc., and the references cited therein, to the extent not already cited, are incorporated by reference in their entirety. No. 60 / 699,493, filed on Oct. 1, 2003, and incorporated herein by reference. [Example]

[0115] Example 1. 3"-(tert-butyl)-4'-(2-hydroxyethoxy)-4" -(Pyrrolidin-1-yl)-[1,1':3',1''-terphenyl]-4-carbo Synthesis of Trifarotene Phosphate - One-Step Hydrolysis A. 2-((3''-(tert-butyl)-4-cyano-4''-(pyrrolidine-1 -yl)-[1,1':3',1''-terphenyl]-4'-yl)oxy)ethyl acetate Preparation of tetrahydrofuran [formula IV(a)]

[0116] 100 g (0.3 mol) of (3-(tert-butyl)-4-(pyrrolidin-1-yl)- To the (phenyl)boronic acid [formula II] was added toluene (1450 mL) and 85 g (0.2 1 mol) of 2-((4'-cyano-3-iodo-[1,1'-biphenyl]-4-yl ) hydroxy) ethyl acetate [formula III] was added. 5M potassium carbonate (300 mL) was added. The reaction medium is stirred under nitrogen at 40° C. for 30 minutes. 0.87 g of Pd-100 (chloride) Palladium bis(triphenylphosphine) (0.0013 mol) was added under nitrogen, The reaction medium was heated to 85-90°C and stirred under reflux for 6 hours. The reaction was terminated by the addition of toluene. The phases were separated and the organic phase was filtered off. Toluene was distilled in vacuo to give an oil. A soluble residue was obtained.

[0117] The residue was suspended in heptane (3000 mL), stirred under reflux for 1 hour and filtered off hot. The mother liquor was further heated under reflux for 1 hour and then slowly cooled to room temperature. The precipitate was filtered off to give 2-( (3''-(tert-butyl)-4-cyano-4''-(pyrrolidin-1-yl)-[ 1,1':3',1''-terphenyl]-4'-yl)oxy) ethyl acetate [formula IV( a)] was further suspended in ethanol (150 ml) and heated under reflux for 2.5 hours. After heating, the mixture was cooled to room temperature. The precipitate was filtered off to give 50.0 g of 2-((3''-(ter t-butyl)-4-cyano-4'-(pyrrolidin-1-yl)-[1,1':3',1' Ethyl (4'-terphenyl)-4'-yloxy)acetate [formula IV(a)] was obtained as a white powder. The compound was obtained with an HPLC purity of 99.8% and a yield of 49%, with m / z 483.26. [ka]

[0118] B. 3''-(tert-butyl)-4'-(2-hydroxyethyl)-4 ... oxy)-4''-(pyrrolidin-1-yl)-[1,1':3',1''-terphenyl Synthesis of ]-4-carboxylic acid [trifarotene; Formula I]

[0119] 50g (0.104mol) of 2-((3''-(tert-butyl)-4-cyano- 4''-(pyrrolidin-1-yl)-[1,1':3',1''-terphenyl]-4' ethyl (-yl)oxy)acetate [formula IV(a)] in 5 M NaOH solution (100 mL) and and ethanol (200 mL) were added. The reaction medium was stirred under reflux for 15 hours. The mixture was cooled to 40°C, and water (400 mL) was added. HCl 32% (50 mL) was added dropwise. The pH was adjusted to 5.5. 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 was obtained, which was dissolved in ethanol (40 mL) and water ( The mixture was heated to 40°C for 5 hours and filtered to give 39.5 g of 3 ''-(tert-butyl)-4'-(2-hydroxyethoxy)-4''-(pyrrolidine) (1,1':3',1''-terphenyl)-4-carboxylic acid pure product [Triphenyl-1-yl]-[1,1':3',1''-terphenyl]-4-carboxylic acid pure product Rifarotene; Formula I] was obtained by HPLC with a purity of 99.9% and a yield of 74%, at m / z 460.24. Got it. [ka]

[0120] Example 2. 3"-(tert-butyl)-4'-(2-hydroxyethoxy)-4" -(Pyrrolidin-1-yl)-[1,1':3',1''-terphenyl]-4-carbo Synthesis of Trifarotene Phosphate - Two-Step Hydrolysis A. The compound of formula IV(a) was prepared according to Example 1.A.

[0121] B. 3'-(tert-butyl)-4'-(2-hydroxyethoxy)-4''-( Pyrrolidin-1-yl)-[1,1':3',1''-terphenyl]-4-carbonite Preparation of aryl [Formula V(a)]

[0122] 2.0 g (0.004 mol) of 2-((3''-(tert-butyl)-4-cyano -4''-(pyrrolidin-1-yl)-[1,1':3',1''-terphenyl]-4 Ethyl ('-yl)oxy)acetate [Formula IV(a)] was suspended in ethanol (60 mL). 2.9 g (0.021 mol) of potassium carbonate was added. The reaction medium was heated at 25°C for 2. Stir for 5 hours, then reflux for 2 hours and filter hot. Concentrate the solution to 20 mL and slowly add Cool to room temperature and stir for 15-18 hours to obtain a white precipitate, which is filtered off to give an off-white precipitate. A beige solid was obtained, 90.75% pure, in 97.2% yield (on a dry basis). The mixture was stirred in heptane (30 mL) under reflux for 15 to 18 hours, and then gradually cooled to 10 to 15°C. The mixture was gradually cooled. Stirring was continued for 1 hour. The resulting precipitate [Formula V(a)] was filtered off and A beige solid was obtained from white powder with a purity of 97.9% and a yield of 96%, m / z 441. Got it at 26. [ka]

[0123] C. 3''-(tert-butyl)-4'-(2-hydroxyethoxy)-4-hydroxybenzoate from Formula V(a) 4''-(pyrrolidin-1-yl)-[1,1':3',1''-terphenyl] Synthesis of 4-carboxylic acid [trifarotene; formula I]

[0124] 11.0 g (0.025 mol) of 3''-(tert-butyl)-4'-(2-hydroxybenzoate (4'-pyrrolidin-1-yl)-[1,1':3',1''-tetraethoxy]-4''-( ... [Diphenyl]-4-carbonitrile was dissolved in 0.5 M NaOH:EtOH solution (25:50 The suspension was heated under reflux for 18-22 hours, converting to a dark yellow solution. The reaction medium is cooled to room temperature, diluted with water (82 mL) and acidified to pH=4.7 with HCl 32%. The mixture was stirred at room temperature for 2 hours. The precipitate formed was filtered off and dissolved in a 20:80 mixture of ethanol and water. The mixture was washed with water and dried under vacuum at 45°C to give trifarotene (formula I) with a purity of 99.5%. It was obtained as a white powder with a zirconium ion concentration of 460.24. [ka]

[0125] Example 3.2-((4'-cyano-3-iodo-[1,1'-biphenyl]-4-yl) Preparation of ethyl hydroxyacetate [Formula III(a)] 180g (0.56mol) of 4'-hydroxy-3'-iodo-biphenyl-4-carboxylate To the carbonitrile, dimethylformamide (900 mL) and 247 g (1.8 mol) of potassium carbonate was added. The reaction medium was stirred for 30 minutes at 25°C. l) 2-Bromoethyl acetate was added, 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 reaction medium was cooled to 25°C. Precipitation The product was filtered to give 213.5 g of [Formula III(a)], yield 90.6%, HPLC purity 97%. % was obtained. [ka]

[0126] Example 4. 3-(tert-butyl)-4-(pyrrolidin-1-yl)phenyl)boron Preparation of the acid [formula II(a)] Under a nitrogen atmosphere, 40.0 g (0.14 mol) of 1-(4-bromo-2-tert-butyl) (phenyl)pyrrolidine, 34.8 g (0.355 mol) of anhydrous potassium acetate, 0. 15g (2.8 x 10 -4 mol) Pd-168, 400 mL of ethanol (EtOH ), and 120 mL of ethylene glycol were mixed together. 2 mol) of tetrahydroxyborane was added in portions with stirring. After 5 minutes, the temperature was 3 The temperature rose to 5-45°C. The reaction mixture was stirred at 40°C for 4-5 hours. A dark brown / gray suspension formed. A liquid formed. The reaction was stopped by adding 500 mL of water at a temperature below 25°C. The reaction mixture was stirred at 20-25°C for 2-3 hours. The solid was filtered off and washed with 500 mL of water. and purified to obtain 31.5 g of (3-(tert-butyl)-4-(pyrrolidin-1-yl)phenyl)- Nyl)boronic acid [Formula II(a)], 98.3% purity was obtained. [ka]

[0127] Example 5. 2-((3"-(tert-butyl)-4-cyano-4"-(pyrrolidine) -1-yl)-[1,1':3',1''-terphenyl]-4'-yl)oxy)acetic acid Alternative method for the preparation of ethyl [formula IV(a)] 247 g (0.015 mol) of (3-(tert-butyl)-4-(pyrrolidine-1 (-yl)phenyl)boronic acid in dimethylacetamide (1000 mL) and 100 g (0.25 mol) 2-((4'-cyano-3-iodo-[1,1'-biphenyl]- Ethyl (4-yloxy)acetate was added. 1.5 M tribasic potassium phosphate (500 ml L) was added. The reaction medium was stirred under nitrogen for 15 minutes. ) of palladium acetate was added under nitrogen and the reaction medium was stirred at 25° C. for 3 hours. The reaction was terminated by the addition of HCl. The precipitate was filtered off.

[0128] The solid was suspended in heptane (2500 mL), stirred under reflux for 1 hour and filtered off hot. The mother liquor was further heated under reflux for 1 hour and then slowly cooled to room temperature. The precipitate was filtered off to give 2-( (3''-(tert-butyl)-4-cyano-4''-(pyrrolidin-1-yl)-[ 1,1':3',1''-terphenyl]-4'-yl)oxy)ethyl acetate, was further suspended in ethanol (150 mL) and heated under reflux for 2.5 hours, then cooled to room temperature. The precipitate was filtered off to give 50.0 g of 2-((3''-(tert-butyl)-4 -Cyano-4''-(pyrrolidin-1-yl)-[1,1':3',1''-terfeni Ethyl [[(4'-yl)oxy]ethyl acetate] is obtained as a white powder with an HPLC purity of 99.6% and a yield of 54%, m / z 483.26. [ka]

[0129] Example 6. Preparation of Trifarotene HCl Salt 2-((3')) in a mixture of EtOH:20% aqueous NaOH (50 mL:25 mL) '-(tert-butyl)-4-cyano-4''-(pyrrolidin-1-yl)-[1,1 ethyl (3',1''-terphenyl)-4'-yloxyacetate (11 g) The reaction mixture was cooled to room temperature and acidified to pH 2 with HCl 32%. The mixture was stirred at room temperature for 2 hours, filtered, and the cake was diluted with EtOH:H2O 20:80 (1 The trifarotene HCl salt was dried under vacuum at 40-45°C and then washed with 1100 mL of water. 0.0 g of trifarotene HCl was obtained. The XRPD of the resulting sample is shown in Figure 1. .

[0130] Example 7. Preparation of Trifarotene HCl-Form B Polymorph A. Dissolve 150 mg of trifarotene HCl salt obtained in Example 6 in acetonitrile (5 mL). The mixture was suspended in HCl and shaken at 300 rpm at room temperature for 3 days. The product was filtered off and dried under ambient conditions. The resulting crystalline form is the Form B polymorph as determined by XRPD. The XRPD of the Form B polymorph is shown in Figure 3.

[0131] B. Dissolve 150 mg of trifarotene HCl salt obtained in Example 6 in ethyl acetate (5 mL). The product was suspended in HCl and shaken at 300 rpm for 3 days at room temperature. The product was filtered off and dried under ambient conditions. The resulting crystalline form is the Form B polymorph as determined by XRPD. do.

[0132] C. 150 mg of trifarotene HCl salt obtained in Example 6 was dissolved in tetrahydrofuran ( The product was suspended in 5 mL of ethanol and shaken at 300 rpm at room temperature for 3 days. The resulting crystalline form was Form B polymorph as determined by XRPD. It is a form.

[0133] D. Dissolve 150 mg of trifarotene HCl salt obtained in Example 6 in 1-butanol (5 ml) The product was suspended in 100 mL of ethanol and shaken at 300 rpm at room temperature for 3 days. The product was filtered off and stirred under ambient conditions. The resulting crystalline form is the Form B polymorph as determined by XRPD. is.

[0134] Example 8. Alternative Preparation of Trifarotene HCl-Form B Polymorph 1.5 g of trifarotene HCl salt obtained in Example 6 was dissolved in MeOH (33 m The cloudy solution was filtered through a glass filter. The solution was allowed to evaporate at room temperature for 3 days. made him do so.

[0135] The product was filtered off and washed with cold MeOH (3 mL) and dried under ambient conditions. The resulting crystalline form is the Form B polymorph as determined by XRPD.

[0136] Example 9. Preparation of Trifarotene HCl-Form A Polymorph 150 mg of trifarotene HCl salt obtained in Example 6 was dissolved in methyl ethyl ketone (5 ml) The product was suspended in 100 mL of ethanol and shaken at 300 rpm at room temperature for 3 days. The product was filtered off and stirred under ambient conditions. The resulting crystalline form is Form A polymorph as determined by XRPD. The XRPD of the Form A polymorph is shown in Figure 2.

[0137] Example 10. Preparation of Trifarotene HCl-Form C Polymorph 150 mg of trifarotene HCl salt obtained in Example 6 was dissolved in ethylene glycol (5 ml) The product was suspended in 100 mL of ethanol and shaken at 300 rpm at room temperature for 3 days. The product was filtered off and stirred under ambient conditions. The resulting crystalline form is the Form C polymorph as determined by XRPD. The XRPD of the Form C polymorph is shown in Figure 4.

[0138] Example 11. Preparation of Trifarotene - Form D Polymorph 2-((3')) in a mixture of EtOH:20% aqueous NaOH (22 mL:11 mL) '-(tert-butyl)-4-cyano-4''-(pyrrolidin-1-yl)-[1,1 ethyl acetate (3',1''-terphenyl)-4'-yloxy) (5 g) was added to reflux The reaction mixture was cooled to room temperature and acidified to pH 5.5 with HCl 32%. The mixture was stirred at room temperature for 2 hours, filtered, and the cake was washed with EtOH:H2O 20:80 ( The trifarotene was washed with 45 mL of water. The trifarotene was then dried under vacuum at 40-45°C for 12-48 hours (18 The resulting crystal form was X The XRPD of Form D polymorph is shown in Figure 5.

[0139] Example 12. Preparation of Trifarotene - Form E Polymorph 150 mg of trifarotene obtained in Example 11 was suspended in MeOH (5 mL). The mixture was shaken at 300 rpm at room temperature for 2 days. The product was filtered off and stored under ambient conditions for 2-6 days ( The resulting crystalline form was Form E as determined by XRPD. The XRPD of Form E polymorph is shown in Figure 6.

[0140] Example 13. Preparation of Trifarotene - Form F Polymorph 1.5 g of trifarotene obtained in Example 11 was dissolved in IPA (24 mL) under reflux. The cloudy solution was filtered through nylon filter paper. The solution was allowed to evaporate at room temperature for 3 days. The product was filtered off and washed with cold IPA (1.5 mL). The product was allowed to stand at ambient temperature for 2-6 days. The resulting crystalline form was determined by XRPD. The XRPD of Form F polymorph is shown in Figure 7.

[0141] Example 14. Preparation of Trifarotene - Form G Polymorph 4.59 g of trifarotene Form A obtained according to Example 9 was dissolved in MeOH:HO The solution was suspended in 400 mL of 1:1 HCl solution. The pH was adjusted to 11 with 0.1 N NaOH. The mixture was stirred at room temperature for 30 minutes, and the precipitate was filtered off. The cake was washed with water (20 The trifarotene sodium salt was washed with 1 mL of ethanol at 40-45°C under vacuum for 12-48 hours. The crystals were dried for 18 hours to give 4.3 g of trifarotene sodium salt. The form is the Form G polymorph as determined by XRPD. Shown in 8.

Claims

1. A process for the preparation of a compound of formula (I) [trifarotene] or a salt thereof, comprising: 【Chemistry 1】 Compound of formula (V) 【Chemistry 2】 [In the formula, R ４ is hydrogen, substituted or unsubstituted straight or branched chain C １ -C ８ Arcanoy a substituted or unsubstituted straight or branched C ２ -C ８ Alkenoyl groups, substituted or unsubstituted or unsubstituted straight-chain or branched C ２ -C ８ Alkynoyl groups, substituted or unsubstituted cyclohexyl groups chloroalkanoyl group, substituted or unsubstituted arylcarbonyl group, substituted or unsubstituted a heterocyclic carbonyl group, a substituted or unsubstituted heteroaryl carbonyl group, or a hetero C containing a B atom １ -C ８ is an alkanoyl group, Y is a nitrile (CN) or amide (CONH ２ ) to obtain said compound of formula (I).

2. R ４ The method of claim 1 , wherein is an acetyl group.

3. R ４ The method of claim 1 , wherein is hydrogen.

4. Compound of formula (IV) 【Transformation 3】 [In the formula, R ３ is hydrogen, a hydroxyl group, a halogen, a substituted or unsubstituted straight chain or Branched C １ -C ８ alkyl group, substituted or unsubstituted straight or branched C ２ -C ８ Alkenyl groups, substituted or unsubstituted straight or branched C ２ -C ８ Alkynyl group, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted aryl groups, Unsubstituted heterocycle, substituted or unsubstituted heteroaryl, or C containing a heteroatom １ - C ８ is an alkyl group, Y is a nitrile (CN) or amide (CONH ２ ) in the presence of a base to obtain said compound of formula (V), The method of claim 3 further comprising preparing the compound.

5. R ３ The method of claim 4 wherein is methyl.

6. The hydrolysis may be carried out using water, methanol (MeOH), ethanol (EtOH), propanoic acid, or the like. Solvents including PrOH, isopropanol (IPA), or any mixture thereof The method according to any one of claims 1 to 5, wherein the method is carried out in the presence of

7. The method of claim 6 , wherein the solvent comprises water and ethanol.

8. The base may be sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide, Lithium (LiOH), barium hydroxide (Ba(OH) ２ ), or any mixture thereof The method according to any one of claims 4 to 7, comprising:

9. The compound of formula (IV) is present in a concentration of about 0.01 to about 0.5 mol / L (solvent), preferably about 0.02 to about 0.2 mol / L (solvent), more preferably about 0.04 to about 0.08 mol 9. The method of claim 4, wherein the solvent is present in an amount of 1 / L (solvent).

10. The base is about 0.1 to about 1 mol / L (solvent), preferably about 0.2 to about 0.8 mol 1 / L of solvent, more preferably from about 0.3 to about 0.6 mol / L of solvent. The method according to any one of claims 4 to 9,

11. The base is present in an amount of about 1 to about 10 molar equivalents relative to the compound of formula (IV), preferably about 2 to about 8 molar equivalents relative to said compound of formula (IV), more preferably 11. The method of claim 10, wherein the compound is present in an amount of from about 3 to about 6 molar equivalents.

12. Compound of formula (II) 【Chemistry 4】 [In the formula, R １ and R ２ are independently hydrogen or a straight-chain or branched C １ -C ３ Archi R １ and R ２ may be the same or different, or R １ Oh BiR ２ together form pinacolate] Compound of formula (III) 【Transformation 5】 [In the formula, R ３ is hydrogen, hydroxyl group, halogen, substituted or unsubstituted straight or branched chain Branched C １ -C ８ Alkyl, substituted or unsubstituted straight or branched chain C ２ -C ８ Al phenyl group, substituted or unsubstituted straight or branched C ２ -C ８ Alkynyl groups, also substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted a substituted heterocycle, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heteroaryl containing a heteroatom; is unsubstituted C １ -C ８ is an alkyl group, X is a halogen or triflate; Y is a nitrile or an amide. in the presence of a catalyst to obtain the compound of formula (IV) The method of any one of claims 4 to 11, further comprising preparing the compound of formula 。

13. The R ３ 13. The method of claim 12, wherein is methyl and X is iodine.

14. The reaction is carried out in toluene, dimethylformamide (DMF), dimethyl sulfoxide (DMF), MSO), tetrahydrofuran (THF), dioxane, n-butanol (n-BuOH ), isopropanol (IPA), dimethyl ether (DME), diethyl ether, or 14. The method according to claim 12 or 13, wherein the reaction is carried out in the presence of a solvent comprising the reaction product or any mixture thereof. How to post.

15. 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, CS ２ CO ３、 Ag ３ PO ４ Ag ２ O, Tl ２ CO ３ T DAY、SYN、90 ２ 、HY、NYOY、HYH、MY(OY) ２ ま 15. The method according to claim 12, wherein the reaction is carried out in the presence of a base, including a base selected from the group consisting of methyl methyl ketone, ... The method described below.

16. 16. The method of claim 12, wherein the catalyst comprises a metal selected from Pd, Cu, or Ni.

10. The method according to any one of claims 1 to 9.

17. 17. The method of claim 16, wherein the catalyst comprises at least two atoms of the metal.

18. The catalyst is: Pd(PPh ３ ) ２ Cl ２ [Bis(triphenylphosphine)palladium(II) dichloride Lorido], Pd(PPh ３ ) ４ [tetrakis(triphenylphosphine)palladium(0)], Pd(OAc) ２ [palladium(II) diacetate], XPhos Pd-G3 [(2-dicyclohexylphosphino-2',4',6'-trimethylsilyl) 2-(2'-amino-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)-isopropyl-1,1'-biphenyl] ) ]palladium(II) methanesulfonate], SPhos-Pd-G2 [chloro(2-dicyclohexylphosphino-2',6'-di Methoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] pa radium (II)], CATACHIUM® A Pd-G3 [mesylate [(di(1-adamantine)] (2'-amino-1,1'-biphenyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]paradiphenyl (II), [(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, [4-(di-tert-butylphosphino)-N, N-dimethylaniline-2-(2'-aminobiphenyl)]palladium(II) methane sulfonic acid], P(Cy ３ ) Pd-G3[(tricyclohexylphosphine)-2-(2'-aminobiphenyl phenyl)]palladium(II) methanesulfonate], Allylpalladium(II) chloride dimer bis(allyl)dichlorodipalladium, teeth Pd(dppf)Cl ２ [1,1'-bis(diphenylphosphino)ferrocene]dichloro 17. The method of claim 16, wherein the Pd catalyst is selected from the group consisting of:

19. The compounds of formula (II) and formula (III) are mixed in a ratio of about 1:10 to about 10:1, preferably Claims 12 to 18 are present in a molar ratio of about 1:5 to about 5:1, more preferably about 1:

1.

10. The method according to any one of the preceding claims.

20. The compounds of formula (II) and formula (III) are independently from about 0.01 to about 1 mol / L (solvent), preferably about 0.05 to about 0.5 mol / L (solvent), more preferably about 0 20. The method of claim 12, wherein the solvent is present in an amount of 0.1 to about 0.4 mol / L of solvent. The method described.

21. The catalyst is from about 0.001 to about 1 with respect to the compound of formula (II) or formula (III). In molar equivalents, preferably about 0.00 with respect to said compound of formula (II) or formula (III). 2 to about 0.5 molar equivalents, more preferably the compound of formula (II) or formula (III) 21. Any one of claims 12 to 20, wherein the compound is present in an amount of from about 0.003 to about 0.1 molar equivalents relative to The method described below.

22. The base is in an amount of about 0.1 to about 10 moles per mole of the compound of formula (II) or (III). and preferably from about 1 to about 6 mole equivalents relative to said compound of formula (II) or formula (III). and more preferably about 2 to 1000 mg / kg of the compound of formula (II) or (III).

22. The method of any one of claims 15 to 21, wherein the compound is present in an amount of about 4 molar equivalents.

23. A process for the preparation of a compound of formula (I) [trifarotene] or a salt thereof, comprising: 【Transformation 6】 a) a compound of formula (II) 【Transformation 7】 [In the formula, R １ and R ２ are independently hydrogen or a straight-chain or branched C １ -C ３ Archi R １ and R ２ may be the same or different, or R １ Oh BiR ２ together form pinacolate] Compound of formula (III) 【Transformation 8】 [In the formula, R ３ is a substituted or unsubstituted straight or branched C １ -C ８ Alkyl, substituted Or unsubstituted linear or branched C ２ -C ８ Alkenyl groups, substituted or unsubstituted Linear or branched C ２ -C ８ Alkynyl groups, substituted or unsubstituted cycloalkyl groups , a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted Heteroaryl or substituted or unsubstituted C containing a heteroatom １ -C ８ Alkyl group and X is a halogen or triflate; Y is a nitrile (CN) or amide (CONH ２ ) in the presence of a catalyst to obtain a compound of formula (IV) 【Chemistry 9】 [In the formula, R ３ is as defined above, and b) hydrolyzing said compound of formula (IV) in the presence of a base to obtain trifarotene. and

24. R ３ 24. The method of claim 23, wherein X is methyl, X is iodine, and Y is nitrile. Law.

25. Formula (III) 【Chemistry 10】 [In the formula, R ３ is a substituted or unsubstituted straight or branched C １ -C ８ Alkyl group, Substituted or unsubstituted straight or branched C ２ -C ８ Alkenyl groups, substituted or unsubstituted Linear or branched C ２ -C ８ Alkynyl group, substituted or unsubstituted cycloalkyl a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic ring, a substituted or unsubstituted substituted heteroaryl or substituted or unsubstituted C containing a heteroatom １ -C ８ Alkyl It is the basis, X is a halogen or triflate; Y is a nitrile or an amide.

26. R ３ 26. The compound of claim 25, wherein is methyl and X is iodine.

27. Formula (V) 【Chemistry 11】 [In the formula, R ４ is hydrogen, substituted or unsubstituted straight or branched chain C １ -C ８ Arcanoy a substituted or unsubstituted straight or branched C ２ -C ８ Alkenoyl groups, substituted or unsubstituted or unsubstituted straight-chain or branched C ２ -C ８ Alkynoyl groups, substituted or unsubstituted cyclohexyl groups chloroalkanoyl group, substituted or unsubstituted arylcarbonyl group, substituted or unsubstituted a heterocyclic carbonyl group, a substituted or unsubstituted heteroaryl carbonyl group, or a hetero C containing a B atom １ -C ８ is an alkanoyl group, Y is a nitrile (CN) or amide (CONH ２ ) a compound.

28. R ４ 28. The compound of claim 27, wherein is hydrogen.

29. R ４ 28. The compound of claim 27, wherein is acetyl.

30. The reflection angles 2θ are 7.6 degrees, 11.5 degrees, 15.4 degrees, 21.1 degrees, and 23.2 degrees. The compound of formula (I) [trifarotene] exhibits an X-ray powder diffraction pattern with characteristic peaks. -HCl] as Form A polymorph.

31. Peaks at 8.6 degrees, 9.0 degrees, 17.7 degrees, 18.3 degrees, 19.5 degrees, and 22.5 degrees 31. The Form A polymorph of claim 30, further exhibiting a .

32. At reflection angles 2θ of 12.6 degrees, 19.5 degrees, 19.8 degrees, 24.6 degrees, and 29.5 degrees The compound of formula (I) [Trifarotene] exhibits an X-ray powder diffraction pattern with characteristic peaks. Form B polymorph of benzophenone-HCl].

33. 8.4 degrees, 12.0 degrees, 17.4 degrees, 21.1 degrees, 23.2 degrees, 31.0 degrees, and 3 33. The Form B polymorph of claim 32, further exhibiting a peak at 2.1 degrees.

34. The reflection angles 2θ are 7.9 degrees, 15.6 degrees, 20.0 degrees, 23.6 degrees, and 27.8 degrees. The compound of formula (I) [trifarotene] exhibits an X-ray powder diffraction pattern with characteristic peaks. -HCl] form C polymorph.

35. The claimed invention further shows peaks at 12.1 degrees, 16.4 degrees, 17.4 degrees, and 28.8 degrees.

35. The Form C polymorph of paragraph 34.

36. Characteristic peaks at reflection angles 2θ of 8.5 degrees, 16.2 degrees, 18.6 degrees, and 23.1 degrees Form D of the compound of formula (I) [trifarotene] exhibits an X-ray powder diffraction pattern having the formula Shape.

37. 37. The method of claim 36 further exhibiting peaks at 12.2 degrees, 12.8 degrees, and 14.1 degrees. Form D polymorph of .

38. The reflection angles 2θ are 8.6 degrees, 12.8 degrees, 14.2 degrees, 17.9 degrees, and 24.0 degrees. The compound of formula (I) [trifarotene] exhibits an X-ray powder diffraction pattern with characteristic peaks. ] Form E polymorph.

39. Peaks at 10.6°, 15.3°, 16.3°, 19.3°, and 22.0° 39. The Form E polymorph of claim 38, as shown in

40. Characterized by reflection angles 2θ of 5.2 degrees, 6.3 degrees, 14.9 degrees, 18.0 degrees, and 19.1 degrees The compound of formula (I) [trifarotene] exhibits an X-ray powder diffraction pattern with typical peaks. Form F polymorph of.

41. Further peaks at 8.5°, 15.6°, 16.3°, 18.5°, and 22.9° 41. The Form F polymorph of claim 40,

42. Characteristic peaks at reflection angles 2θ of 10.6 degrees, 11.5 degrees, 17.4 degrees, and 19.7 degrees The compound of formula (I) [trifarotene Na salt] exhibits an X-ray powder diffraction pattern having a Form G polymorphism.

43. Claim further showing peaks at 8.9 degrees, 10.0 degrees, 14.7 degrees, and 16.2 degrees.

42. The Form G polymorph according to claim 42.

44. a) providing trifarotene according to the method of any one of claims 1 to 24; thing, b) adjusting the pH of the trifarotene to a pH of about 2 to about 4 to obtain a trifarotene salt; and c) suspending the trifarotene salt in methyl ethyl ketone to obtain trifarotene Form A Method for preparing Form A polymorph of trifarotene-HCl, comprising obtaining the polymorph - Patent application 。

45. a) providing trifarotene according to the method of any one of claims 1 to 24; thing, b) adjusting the pH of the trifarotene to a pH of about 2 to about 4 to obtain a trifarotene salt; and c) dissolving the trifarotene salt in acetonitrile, ethyl acetate, tetrahydrofuran, 1 -butanol or suspending the trifarotene salt in methanol. of trifarotene-HCl, including dissolving to obtain the Form B polymorph of trifarotene. Process for preparing the Form B polymorph.

46. a) providing trifarotene according to the method of any one of claims 1 to 24; thing, b) adjusting the pH of the trifarotene to a pH of about 2 to about 4 to obtain a trifarotene salt; and c) suspending the trifarotene salt in ethylene glycol to form trifarotene Method for preparing Form C polymorph of trifarotene-HCl, comprising obtaining Form C polymorph Law.

47. 47. The method according to claim 44, wherein the pH is adjusted using hydrochloric acid (HCl). How to do it.

48. a) providing trifarotene according to the method of any one of claims 1 to 24; That, and b) adjusting the pH of the trifarotene to a pH of about 5 to about 6 to obtain the trifarotene form 1. A process for preparing the Form D polymorph of trifarotene, comprising obtaining the D polymorph.

49. The pH is determined by the addition of HCl, acetic acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, trifluoroacetic acid, p - Using acids including toluenesulfonic acid, methanesulfonic acid, or any mixture thereof 49. The method of claim 48, wherein the

50. a) providing trifarotene according to the method of any one of claims 1 to 24; thing, b) adjusting the pH of the trifarotene to a pH of about 5 to about 6 to obtain trifarotene. That, and c) suspending the trifarotene in methanol to obtain the Form E polymorph of trifarotene; 10. A process for preparing the Form E polymorph of trifarotene, comprising obtaining

51. a) providing trifarotene according to the method of any one of claims 1 to 24; thing, b) adjusting the pH of the trifarotene to a pH of about 5 to about 6 to obtain trifarotene. That, and c) dissolving the trifarotene in isopropanol to obtain Form F poly(trifarotene); 10. A process for preparing the Form F polymorph of trifarotene, comprising obtaining the form F.

52. a) providing trifarotene according to the method of any one of claims 1 to 24; That, and b) adjusting the pH of the trifarotene to a pH of about 9 to about 12 to obtain a trifarotene salt; Method for preparing polymorphic form G of trifarotene Na salt, including obtaining polymorphic form G method.

53. 53. The method of claim 52, wherein the pH is adjusted using sodium hydroxide.

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