Preparation of tazarotene, its intermediates and polymorphs

Abstract

The present disclosure provides methods for preparing tretinoin. The present disclosure also provides novel intermediates in the methods described herein. Also provided are novel polymorphs of tretinoin.

Description

Technical Field

[0001] The present disclosure provides methods for preparing tazarotene. The present disclosure also provides novel intermediates in the methods described herein. Also provided are novel polymorphs of tazarotene. Background Art

[0002] 3''-(tert-Butyl)-4'-(2-hydroxyethoxy)-4''-(pyrrolidin-1-yl)-[1,1':3',1''-terphenyl]-4-carboxylic acid, commonly known as tazarotene, is a topical retinoid that can selectively target retinoic acid receptor (RAR) γ, which is the most common RAR found in the skin. Tazarotene is prescribed for the treatment of acne vulgaris and was first approved in the United States in October 2019. The current synthetic route for tazarotene, as described in, for example, WO 2006 / 066978, includes several challenging steps, such as performing reactions at -78 °C and using two separate protecting groups that must be hydrolyzed under different conditions, which can reduce workflow efficiency and overall yield. Summary of the Invention

[0003] In some embodiments, the present disclosure provides a method for preparing a compound of formula (I) [tazarotene] or a salt thereof,

[0004]

[0005] which comprises hydrolyzing a compound of formula (V),

[0006]

[0007] wherein R 4 is hydrogen, a substituted or unsubstituted linear or branched C1-C8 alkanoyl, a substituted or unsubstituted linear or branched C1-C8 alkenoyl, a substituted or unsubstituted linear or branched C1-C8 alkynoyl, a substituted or unsubstituted cycloalkanoyl, a substituted or unsubstituted arylcarbonyl, a substituted or unsubstituted heterocyclocarbonyl, a substituted or unsubstituted heteroarylcarbonyl, or a C1-C8 alkanoyl containing a heteroatom; and wherein Y is nitrile (CN) or amide (CONH2); to obtain a compound of formula (I). In some embodiments, R 4 is acetyl. In some embodiments, R 4 is hydrogen.

[0008] In some embodiments, the method further comprises preparing the compound of formula (V) by hydrolyzing a compound of formula (IV) in the presence of a base,

[0009]

[0010] wherein R 3is hydrogen, a hydroxyl group, a halogen, a substituted or unsubstituted linear or branched C1-C8 alkyl group, a substituted or unsubstituted linear or branched C1-C8 alkenyl group, a substituted or unsubstituted linear or branched C1-C8 alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heteroaryl group, or a C1-C8 alkyl group containing a heteroatom; and wherein Y is nitrile (CN) or amide (CONH2); to obtain a compound of formula (V). In some embodiments, R 3 is methyl.

[0011] In some embodiments, the hydrolysis is carried out in the presence of a solvent comprising water, methanol (MeOH), ethanol (EtOH), propanol (PrOH), isopropanol (IPA) or any mixture thereof. In some embodiments, the solvent comprises water and ethanol. In some embodiments, the base comprises sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), barium hydroxide (Ba(OH)2) or any mixture thereof.

[0012] In some embodiments, the compound of formula (IV) is present in an amount 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 about 0.3 to about 0.6 mol / L (solvent). In some embodiments, 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 the compound of formula (IV), more preferably about 3 to about 6 molar equivalents relative to the compound of formula (IV).

[0013] In some embodiments, the method further comprises preparing the compound of formula (IV) by: in the presence of a catalyst, reacting a compound of formula (II)

[0014]

[0015] wherein, R 1 and R 2 are independently hydrogen or a linear or branched C1-C3 alkyl group, wherein R 1 and R 2 may be the same or different; or R 1 and R 2 together form a pinacol ester, and reacting with a compound of formula (III)

[0016]

[0017] wherein, R3 is hydrogen, hydroxy, halogen, substituted or unsubstituted linear or branched C1-C8 alkyl, substituted or unsubstituted linear or branched C1-C8 alkenyl, substituted or unsubstituted linear or branched C1-C8 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl, or C1-C8 alkyl containing a heteroatom; wherein X is halogen or trifluoromethanesulfonate; and wherein Y is nitrile or amide; to obtain a compound of formula (IV). In some embodiments, R 3 is methyl and X is iodine.

[0018] In some embodiments, the reaction is carried out in the presence of a solvent comprising toluene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dioxane, n-butanol (n-BuOH), isopropanol (IPA), dimethyl ether (DME), diethyl ether or any mixture thereof. In some embodiments, the reaction is carried out in the presence of a base comprising K2CO3, CH3CO2K, K3PO4, KOtBu, Na2CO3, NaHCO3, NaOMe, Cs2CO3, Ag3PO4, Ag2O, Tl2CO3, TlOEt, TlOH, t-BuNH2, KOH, NaOH, LiOH, Ba(OH)2 or a combination thereof.

[0019] In some embodiments, the catalyst comprises a metal selected from Pd, Cu or Ni. In some embodiments, the catalyst comprises at least two metal atoms. In some embodiments, the catalyst is a Pd catalyst selected from: Pd(PPh3)2Cl2 [bis(triphenylphosphine)palladium(II) dichloride]; Pd(PPh3)4 [tetrakis(triphenylphosphine)palladium(0)]; Pd(OAc)2 [palladium(II) diacetate]; XPhos Pd-G3 [(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate]; SPhos-Pd-G2 [chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)]; A Pd G3 (mesylate [(bis(1 - adamantyl)-n - butylphosphine)-2-(2'-amino - 1,1'-biphenyl)]palladium(II) or [(bis(1 - adamantyl)-butylphosphine)-2-(2'-amino - 1,1'-biphenyl)]palladium(II) mesylate); APhos Pd G3 (palladium G3-(4-(N,N - dimethylamino)phenyl)di - tert - butylphosphine] or [4-(di - tert - butylphosphine)-N,N - dimethylaniline - 2-(2'-aminobiphenyl)]palladium(II) mesylate); P(Cy3)Pd - G3 (palladium G3 - tricyclohexylphosphine or [(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II) mesylate); allyl palladium(II) chloride dimer (bis(allyl)dichlorodipalladium); or Pd(dppf)Cl2 [1,1′ - bis(diphenylphosphino)ferrocene]dichloropalladium(II)].

[0020] In some embodiments, the compounds of formula (II) and formula (III) are present in a molar ratio of about 1:10 to about 10:1, preferably about 1:5 to about 5:1, more preferably about 1:1. In some embodiments, the compounds of formula (II) and formula (III) independently are present in an amount of about 0.01 to about 1 mol / L (solvent), preferably about 0.05 to about 0.5 mol / L (solvent), more preferably about 0.1 to about 0.4 mol / L (solvent).

[0021] In some embodiments, the catalyst is present in an amount of about 0.001 to about 1 molar equivalent relative to the compound of formula (II) or formula (III), preferably about 0.002 to about 0.5 molar equivalent relative to the compound of formula (II) or formula (III), more preferably about 0.003 to about 0.1 molar equivalent relative to the compound of formula (II) or formula (III). In some embodiments, the base is present in an amount of about 0.1 to about 10 molar equivalents relative to the compound of formula (II) or formula (III), preferably about 1 to about 6 molar equivalents relative to the compound of formula (II) or formula (III), more preferably about 2 to about 4 molar equivalents relative to the compound of formula (II) or formula (III).

[0022] In some embodiments, the present disclosure provides a method for preparing a compound of formula (I) [tazarotene] or a salt thereof,

[0023]

[0024] which comprises, in the presence of a catalyst, reacting a compound of formula (II)

[0025]

[0026] wherein, R 1 and R 2Independently hydrogen or a linear or branched C1-C3 alkyl group, wherein R 1 and R 2 may be the same or different; or R 1 and R 2 together form a pinacol ester and react with a compound of formula (III)

[0027]

[0028] wherein R 3 is a substituted or unsubstituted linear or branched C1-C8 alkyl group, a substituted or unsubstituted linear or branched C1-C8 alkenyl group, a substituted or unsubstituted linear or branched C1-C8 alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heteroaryl group, or a C1-C8 alkyl group containing a heteroatom; wherein X is a halogen or trifluoromethanesulfonate; and wherein Y is a nitrile (CN) or an amide (CONH2); to obtain a compound of formula (IV),

[0029]

[0030] wherein R 3 is as defined above; and in the presence of a base, hydrolyze the compound of formula (IV) to obtain tazarotene. R 1 、R 2 、R 3 、R 4 、X and Y, and the various reactions and conditions are further described herein. In some embodiments, R 3 is methyl, X is iodine, and Y is a nitrile. In some embodiments, R 3 is methyl and X is iodine.

[0031] In some embodiments, the present disclosure provides a compound of formula (III),

[0032]

[0033] wherein R 3 is a substituted or unsubstituted linear or branched C1-C8 alkyl group, a substituted or unsubstituted linear or branched C1-C8 alkenyl group, a substituted or unsubstituted linear or branched C1-C8 alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heteroaryl group, or a C1-C8 alkyl group containing a heteroatom; wherein X is a halogen or trifluoromethanesulfonate; and wherein Y is a nitrile or an amide. In some embodiments, R 3 is methyl and X is iodine.

[0034] In some embodiments, the present disclosure provides a compound of formula (V),

[0035]

[0036] wherein R 4 is hydrogen, a substituted or unsubstituted linear or branched C1-C8 alkanoyl, a substituted or unsubstituted linear or branched C1-C8 alkenoyl, a substituted or unsubstituted linear or branched C1-C8 alkynoyl, a substituted or unsubstituted cycloalkanoyl, a substituted or unsubstituted arylcarbonyl, a substituted or unsubstituted heterocyclocarbonyl, a substituted or unsubstituted heteroarylcarbonyl, or a C1-C8 alkanoyl containing a heteroatom; and wherein Y is nitrile (CN) or amide (CONH2); and wherein Y is nitrile or amide. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is acetyl.

[0037] In some embodiments, the present disclosure provides an A polymorph of the compound of formula (I) [tazarotene-HCl], wherein the A polymorph exhibits an X-ray powder diffraction (XRPD) pattern having characteristic peaks at reflection angles 2θ of 7.6, 11.5, 15.4, 21.1, and 23.2 degrees. In some embodiments, the A polymorph further exhibits peaks at 8.6, 9.0, 17.7, 18.3, 19.5, and 22.5 degrees.

[0038] In some embodiments, the present disclosure provides a B polymorph of the compound of formula (I) [tazarotene-HCl], wherein the B polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks at reflection angles 2θ of 12.6, 19.5, 19.8, 24.6, and 29.5 degrees. In some embodiments, the B polymorph further exhibits peaks at 8.4, 12.0, 17.4, 21.1, 23.2, 31.0, and 32.1 degrees.

[0039] In some embodiments, the present disclosure provides a C polymorph of the compound of formula (I) [tazarotene-HCl], wherein the C polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks at reflection angles 2θ of 7.9, 15.6, 20.0, 23.6, and 27.8 degrees. In some embodiments, the C polymorph further exhibits peaks at 12.1, 16.4, 17.4, and 28.8 degrees.

[0040] In some embodiments, the present disclosure provides a D polymorph of the compound of formula (I) [tazarotene], wherein the D polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks at reflection angles 2θ of 8.5, 16.2, 18.6, and 23.1 degrees. In some embodiments, the D polymorph further exhibits peaks at 12.2, 12.8, and 14.1 degrees.

[0041] In some embodiments, the present disclosure provides an E-polymorph of a compound of formula (I) [tazarotene], wherein the E-polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks at reflection angles 2θ of 8.6, 12.8, 14.2, 17.9 and 24.0 degrees. In some embodiments, the E-polymorph further exhibits peaks at 10.6, 15.3, 16.3, 19.3 and 22.0 degrees.

[0042] In some embodiments, the present disclosure provides an F-polymorph of a compound of formula (I) [tazarotene], wherein the F-polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks at reflection angles 2θ of 5.2, 6.3, 14.9, 18.0 and 19.1 degrees. In some embodiments, the F-polymorph further exhibits peaks at 8.5, 15.6, 16.3, 18.5 and 22.9 degrees.

[0043] In some embodiments, the present disclosure provides a G-polymorph of a compound of formula (I) [tazarotene Na salt], wherein the G-polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks at reflection angles 2θ of 10.6, 11.5, 17.4 and 19.7 degrees. In some embodiments, the G-polymorph further exhibits peaks at 8.9, 10.0, 14.7 and 16.2 degrees.

[0044] In some embodiments, the present disclosure provides a method for preparing the A-polymorph of tazarotene-HCl, which comprises: (a) providing tazarotene according to the method described herein; (b) adjusting the pH of tazarotene to a pH of about 2 to about 4 to obtain a tazarotene salt; and (c) suspending the tazarotene salt in methyl ethyl ketone to obtain the A-polymorph of tazarotene. In some embodiments, HCl is used to adjust the pH.

[0045] In some embodiments, the present disclosure provides a method for preparing the B-polymorph of tazarotene-HCl, which comprises: (a) providing tazarotene according to the method described herein; (b) adjusting the pH of tazarotene to a pH of about 2 to about 4 to obtain a tazarotene salt; and (c) suspending the tazarotene salt in a solvent comprising acetonitrile, ethyl acetate, tetrahydrofuran, 1-butanol; or dissolving the tazarotene salt in methanol to obtain the B-polymorph of tazarotene. In some embodiments, HCl is used to adjust the pH.

[0046] In some embodiments, the present disclosure also provides a method for preparing the C polymorph of tretinoin-HCl, which includes: providing tretinoin according to the method described herein; (b) adjusting the pH of tretinoin to a pH of about 2 to about 4 to obtain a tretinoin salt; and (c) suspending the tretinoin salt in ethylene glycol to obtain the C polymorph of tretinoin. In some embodiments, HCl is used to adjust the pH.

[0047] In some embodiments, the present disclosure also provides a method for preparing the D polymorph of tretinoin, which includes: (a) providing tretinoin according to the method described herein; and (b) adjusting the pH of tretinoin to a pH of about 5 to about 6 to obtain the D polymorph of tretinoin. In some embodiments, HCl, acetic acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, or any mixture thereof is used to adjust the pH.

[0048] In some embodiments, the present disclosure also provides a method for preparing the E polymorph of tretinoin, which includes: (a) providing tretinoin according to the method described herein; (b) adjusting the pH of tretinoin to a pH of about 5 to about 6 to obtain a tretinoin salt; and (c) suspending the tretinoin salt in methanol to obtain the E polymorph of tretinoin.

[0049] In some embodiments, the present disclosure also provides a method for preparing the F polymorph of tretinoin, which includes: (a) providing tretinoin according to the method described herein; (b) adjusting the pH of tretinoin to a pH of about 5 to about 6 to obtain a tretinoin salt; and (c) dissolving the tretinoin salt in isopropanol to obtain the F polymorph of tretinoin.

[0050] In some embodiments, the present disclosure also provides a method for preparing the G polymorph of tretinoin Na salt, which includes: (a) providing tretinoin according to the method described herein; and (b) adjusting the pH of tretinoin to a pH of about 9 to about 12 to obtain the G polymorph of tretinoin. In some embodiments, sodium hydroxide is used to adjust the pH. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 The X-ray powder diffraction (XRPD) spectrum of tretinoin HCl salt as described in the examples herein is shown.

[0052] Figure 2 The XRPD spectrum of tretinoin-HCl, A polymorph as described in the examples herein is shown.

[0053] Figure 3Displays the XRPD spectrum of tretinoin-HCl, Form B polymorph as described in the examples herein.

[0054] Figure 4 Displays the XRPD spectrum of tretinoin-HCl, Form C polymorph as described in the examples herein.

[0055] Figure 5 Displays the XRPD spectrum of tretinoin, Form D polymorph as described in the examples herein.

[0056] Figure 6 Displays the XRPD spectrum of tretinoin, Form E polymorph as described in the examples herein.

[0057] Figure 7 Displays the XRPD spectrum of tretinoin, Form F polymorph as described in the examples herein.

[0058] Figure 8 Displays the XRPD spectrum of tretinoin Na salt, Form G polymorph as described in the examples herein.

[0059] Figure 9 Is an exemplary method for preparing tretinoin [Formula (I)] as described in the examples herein. Detailed Description

[0060] The present disclosure relates to methods for preparing tretinoin. The methods provided herein advantageously simplify the preparation process by reducing or eliminating reaction steps that require harsh conditions (e.g., carried out at extremely high temperatures (e.g., >50 °C) or extremely low temperatures (e.g., < -10 °C)).

[0061] As used herein, "a" or "an" can mean one or more. As used herein, when used in conjunction with the word "comprising", the word "a" or "an" can mean one or more. As used herein, "another" or "further" can mean at least a second or more.

[0062] Throughout this application, the term "about" is used to indicate that a value includes the inherent error variations of the method / device used to determine that value, or the variations present in the subject under study. Generally, depending on the circumstances, the term "about" is intended to cover variability of approximately or less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% or higher. In some embodiments, due to the context in which it is used herein, those skilled 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" also includes the specifically recited value.

[0063] The term "or" as used in the claims is intended to mean "and / or" unless explicitly indicated to refer only to alternatives or the alternatives are mutually exclusive, although the present disclosure supports definitions that refer only to alternatives as well as "and / or".

[0064] As used herein, the terms "comprising" (and any variations or forms thereof, such as "comprise" and "comprises"), "having" (and any variations or forms thereof, such as "have" and "has"), "including" (and any variations or forms thereof, such as "includes" and "include"), or "containing" (and any variations or forms thereof, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in this specification may be implemented with respect to any composition (e.g., formulation) or method of the present disclosure. Additionally, the compositions (e.g., formulations) of the present disclosure may be used to implement the methods of the present disclosure.

[0065] The use of the term "for example" and its corresponding abbreviation "e.g." (whether italicized or not) means that the particular terms recited are representative examples and embodiments of the present disclosure, and unless otherwise expressly stated, the representative examples and embodiments are not intended to be limited to the specific examples mentioned or cited.

[0066] As used herein, "between" is a range that includes the endpoints of the range. For example, a number between x and y expressly includes the numbers x and y, and any number that falls within x and y.

[0067] Unless otherwise specified, when used alone or in combination with other groups or atoms, the term "alkyl" refers to a saturated straight-chain or branched chain including from 1 to about 10 hydrogen-substituted carbon atoms. Alkyl includes, for example, methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, isobutyl, tert-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.

[0068] Unless otherwise specified, the term "alkenyl" refers to a partially unsaturated straight or branched chain containing from about 2 to about 10 hydrogen-substituted carbon atoms and having at least one double bond. Alkenyl includes, for example, vinyl, allyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, penta-1,3-dienyl, penta-2,4-dienyl, 2-methylbut-1-enyl, 2-methylpent-1-enyl, 4-methylpent-1-enyl, 4-methylpent-2-enyl, 2-methylpent-2-enyl, 4-methylpenta-1,3-dienyl, hex-1-enyl, hept-1-enyl, oct-1-enyl, non-1-enyl, dec-1-enyl, and the like.

[0069] Unless otherwise specified, the term "alkynyl" refers to a partially unsaturated straight or branched chain containing from about 2 to about 10 hydrogen-substituted carbon atoms and having at least one triple bond. Alkynyl includes, for example, ethynyl, 1-propynyl, 2-propynyl, 2-methylprop-1-ynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1,3-butadiynyl, 3-methylbut-1-ynyl, 4-methylbutynyl, 4-methylbut-2-ynyl, 2-methylbut-1-ynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 3-methylpent-1-ynyl, 4-methylpent-2-ynyl, 4-methylpent-2-ynyl, 1-hexynyl, 1-heptynyl, 1-octynyl, 1-nonynyl, 1-decynyl, and the like.

[0070] Unless otherwise specified, the term "cycloalkyl" refers to a saturated or unsaturated ring containing from about 3 to about 10 carbon atoms, which may optionally be substituted by one or more identical or different substituents, such as one to three, one to six, one to eight, or one to ten substituents. Cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononyl, cyclodecyl, and the like.

[0071] Unless otherwise specified, the term "aryl" refers to an aromatic monocyclic or bicyclic group containing from about 5 to about 14 carbon atoms, which may optionally be fused to a fully or partially saturated or unsaturated carbocyclic ring. Aryl includes, for example, phenyl, naphthyl, indanyl, and the like.

[0072] Unless otherwise specified, the term "alkanoyl" refers to a carbonyl group (C=O) bonded to an alkyl group. The term "enoyl" refers to a carbonyl group (C=O) bonded to an alkenyl group. The term "alkynoyl" refers to a carbonyl group (C=O) bonded to an alkynyl group. The term "cycloalkyl" refers to an alkane containing one or more carbon atom rings. "Cycloalkanoyl" refers to a carbonyl group (C=O) bonded to a cycloalkyl group. "Arylcarbonyl" refers to a carbonyl group (C=O) bonded to an aryl group.

[0073] Unless otherwise specified, "heterocycle" refers to a monocyclic non-aromatic hydrocarbon ring containing about 3 to about 10 carbon atoms, or a bicyclic non-aromatic hydrocarbon ring system containing about 7 to about 14 carbon atoms, wherein one or more carbon atoms in the hydrocarbon ring or ring system are replaced by a heteroatom. Examples of heterocycles include, but are not limited to, azepan-1-yl, piperidinyl such as piperidin-1-yl and piperidin-4-yl, piperazinyl such as N-piperazinyl and 1-alkylpiperazin-4-yl, morpholin-4-yl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiophene, sulfolanyl, sulfolenyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxazolidinonyl. "Heterocyclic carbonyl" refers to a carbonyl (C=O) bonded to a heterocyclic group.

[0074] Unless otherwise specified, "heteroaryl" refers to an aromatic compound containing at least one heteroatom. Examples of heteroaryls include, but are not limited to, pyrrolyl, dihydropyrrolyl, pyrrolidinyl, indolyl, isoindolyl, indolizinyl, imidazolyl, pyrazolyl, benzimidazolyl, imidazo(1,2-a)pyridinyl, indazolyl, purinyl, pyrrolo(2,3-c)pyridinyl, pyrrolo(3,2-c)pyridinyl, pyrrolo(2,3-b)pyridinyl, pyrazolo(1,5-a)pyridinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, thiazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, furyl, dihydrofuryl, tetrahydrofuryl, benzofuryl, isobenzofuryl, thienyl, dihydrothienyl, tetrahydrothienyl, benzothienyl, benzisothienyl, pyridinyl, piperidinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyranyl, tetrahydropyranyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, chromenyl, morpholinyl, diazepinyl, benzodiazepinyl, and the like. "Heteroaryl carbonyl" refers to a carbonyl (C=O) bonded to a heteroaryl group.

[0075] In some embodiments, any carbon chain substituents described herein, such as alkyl, alkanoyl, enoyl, alkynoyl, etc., may have one or more carbons in the carbon chain replaced by one or more heteroatoms, which are atoms other than carbon or hydrogen, such as nitrogen, oxygen, sulfur, phosphorus. In some embodiments, the substituents described herein, such as alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, alkanoyl, enoyl, alkynoyl, cycloalkanoyl, arylcarbonyl, heterocyclocarbonyl, heteroarylcarbonyl, etc. may be "substituted or unsubstituted". The term "substituted" means that the hydrogen on the substituent is replaced by a different group, such as a hydroxyl group, a halide, an alkyl (e.g., C 1-6 alkyl), an alcohol, a ketone, etc. The term "unsubstituted" means that the substituent does not have hydrogen replaced by a different group.

[0076] A "linear" molecule contains a single backbone. For example, a "linear C1-C n " molecule includes from one to n number of carbon atoms, where each carbon atom is bonded to its two neighbors and two hydrogen atoms (except for the terminal carbons that are bonded to only one carbon atom and three hydrogen atoms). A "branched" molecule contains a non-linear backbone, where the branches can sprout from one or more atoms of the backbone. For example, a "branched C1-C n " molecule is derived from a linear C1-C n molecule, except that at least one hydrogen atom bonded to at least one carbon is replaced by a substituent such as an alkyl group.

[0077] Any cyclic group described herein (e.g., cycloalkyl, aryl, heterocycle, heteroaryl) may be substituted or unsubstituted. For example, a substituted cycloalkane may have a substituent at any atom forming the ring. The substituents may include any group described herein, such as alkyl, alkenyl, alkynyl, etc.

[0078] In some embodiments, the present disclosure provides a method for preparing a compound [tazarotene] of formula (I) or a salt thereof,

[0079]

[0080] which comprises hydrolyzing a compound of formula (V),

[0081]

[0082] wherein, R 4is hydrogen, a substituted or unsubstituted linear or branched C1-C8 alkanoyl, a substituted or unsubstituted linear or branched C1-C8 alkenoyl, a substituted or unsubstituted linear or branched C1-C8 alkynoyl, a substituted or unsubstituted cycloalkanoyl, a substituted or unsubstituted arylcarbonyl, a substituted or unsubstituted heterocyclocarbonyl, a substituted or unsubstituted heteroarylcarbonyl, or a C1-C8 alkanoyl containing a heteroatom; and wherein Y is nitrile (CN) or amide (CONH2); to obtain a compound of formula (I).

[0083] In some embodiments, the compound of formula (I) is tazarotene. In some embodiments, the compound of formula (I) is tazarotene-HCl. In some embodiments, the compound of formula (I) is the Na salt of tazarotene.

[0084] In some embodiments, R 4 is hydrogen. In an embodiment, R 4 is alkanoyl. In some embodiments, R 4 is formyl (-COH). In an embodiment, R 4 is acetyl (-COCH3). In some embodiments, the compound of formula (V) is selected from the following:

[0085]

[0086] In some embodiments, Y is nitrile. In some embodiments, Y is amide. In some embodiments, R 4 is hydrogen, and Y is nitrile or amide. In some embodiments, R 4 is alkanoyl, and Y is nitrile or amide. In some embodiments, R 4 is formyl, and Y is nitrile or amide. In some embodiments, R 4 is acetyl, and Y is nitrile or amide.

[0087] 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 nitrile or amide. In some embodiments, R 4 is an unsubstituted cycloalkanoyl, and Y is nitrile or amide. In some embodiments, R 4 is a substituted arylcarbonyl, and Y is nitrile or amide. In some embodiments, R 4 is an unsubstituted arylcarbonyl, and Y is nitrile or amide. In some embodiments, R 4 is a substituted heterocyclocarbonyl, and Y is nitrile or amide. In some embodiments, R 4is an unsubstituted heterocyclic carbonyl, and Y is a nitrile or an amide. In some embodiments, R 4 is a substituted heteroaryl carbonyl, and Y is a nitrile or an amide. In some embodiments, R 4 is an unsubstituted heteroaryl carbonyl, and Y is a nitrile or an amide. In some embodiments, R 4 is a C1-C8 alkanoyl containing a heteroatom, and Y is a nitrile or an amide.

[0088] In some embodiments, the compounds of formula (V) are selected from the following:

[0089]

[0090]

[0091] The term "hydrolysis" or variants thereof such as "hydrolyze" or "hydrolyzing" refers to a reaction in which water is a reactant and typically becomes part of the reaction product as a hydroxy (-OH) group. Hydrolysis of a nitrile or an amide can form a carboxylic acid (-COOH). In some embodiments, hydrolysis is carried out in the presence of water and a co-solvent. Examples of co-solvents that can be used with water for the hydrolysis reaction include but are not limited to alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, sec-butanol, and isobutanol; dichloromethane; acetonitrile; ethyl acetate; and tetrahydrofuran (THF). In some embodiments, hydrolysis is carried out in the presence of water and an alcohol. In some embodiments, the alcohol is methanol (MeOH), ethanol (EtOH), propanol (PrOH), isopropanol (IPA), or any mixture thereof. In some embodiments, hydrolysis is carried out in the presence of water and ethanol.

[0092] In some embodiments, hydrolysis is further carried out in the presence of an acid or a base. In some embodiments, the acid comprises hydrochloric acid (HCl), sulfuric acid (H2SO4), nitric acid (HNO3), hydrobromic acid (HBr), hydroiodic acid (HI), perchloric acid (HClO4), chloric acid (HClO3), sulfurous acid (H2SO3), formic acid (HCO2H), phosphoric acid (H3PO4), nitrous acid (HNO2), hydrofluoric acid (HF), or any mixture thereof. In some embodiments, the base comprises sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), barium hydroxide (Ba(OH)2), or any mixture thereof.

[0093] In some embodiments, R 4 is hydrogen, and Y is hydrolyzed. In some embodiments, Y is hydrolyzed to form a carboxylic acid. In some embodiments, R 4Contains a carbonyl as described herein, and the carbonyl, together with the attached oxygen, is hydrolyzed to form a hydroxyl group. In some embodiments, R 4 and Y are capable of being hydrolyzed under the same reaction conditions. In some embodiments, R 4 and Y are hydrolyzed simultaneously.

[0094] In some embodiments, the compound of formula (V) is present in the hydrolysis reaction at about 0.1 to about 1 mol / L (solvent), about 0.2 to about 0.8 mol / L (solvent), or about 0.3 to about 0.5 mol / L (solvent). In some embodiments, the compound of formula (V) is present in the hydrolysis reaction at about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about 1 mol / L (solvent). In some embodiments, the hydrolysis of the compound of formula (V) is carried out under acidic conditions. In some embodiments, the hydrolysis is carried out at a pH of about 4 to about 6.5, about 4.2 to about 6.2, about 4.5 to about 6, about 4.7 to about 5.7, or about 5 to about 5.5. In some embodiments, the hydrolysis reaction is carried out at a pH of about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6, about 6.1, about 6.2, about 6.3, about 6.4, or about 6.5.

[0095] In some embodiments, the present disclosure provides a method for preparing a compound of formula (V) in which R 4 is hydrogen. In some embodiments, the compound of formula (V) is prepared by hydrolyzing a compound of formula (IV) in the presence of a base,

[0096]

[0097] wherein, R 3 is hydrogen, hydroxyl, substituted or unsubstituted linear or branched C1-C8 alkyl, substituted or unsubstituted linear or branched C1-C8 alkenyl, substituted or unsubstituted linear or branched C1-C8 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl, or C1-C8 alkyl containing a heteroatom; and wherein Y is nitrile (CN) or amide (CONH2); to obtain a compound of formula (V). In some embodiments, the ester (-COOR 3 ) of the compound of formula (IV) is hydrolyzed to form a hydroxyl group (-OH). In some embodiments, R 4 of the compound of formula (V) is hydrogen.

[0098] Y in the compound of formula (IV) is as defined herein for the compound of formula (V). In some embodiments, R 3 is hydrogen and Y is nitrile or amide. In some embodiments, R 3 is methyl and Y is nitrile or amide. In some embodiments, R 3 is hydroxyl and Y is nitrile or amide. In some embodiments, R 3 is methyl and Y is nitrile.

[0099] 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, the hydrolysis of the compound of formula (IV) is carried out in a solvent comprising water, methanol (MeOH), ethanol (EtOH), propanol (PrOH), isopropanol (IPA), or any mixture thereof. In some embodiments, the solvent comprises water and ethanol.

[0100] 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 for hydrolyzing the compound of formula (IV) comprises sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), barium hydroxide (Ba(OH)₂), or any mixture thereof.

[0101] In some embodiments, the compound of formula (IV) is present in the hydrolysis reaction at 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). In some embodiments, the compound of formula (IV) is present in the hydrolysis reaction at about 0.01, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, or about 0.1 mol / L (solvent). In some embodiments, the base is added to the hydrolysis reaction at about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 molar equivalents relative to the compound of formula (IV). In some embodiments, the base is added to the hydrolysis reaction at about 0.1 to about 1 mol / L (solvent), about 0.2 to about 0.8 mol / L (solvent), about 0.3 to about 0.6 mol / L (solvent), or about 0.4 to about 0.5 mol / L (solvent).

[0102] In some embodiments, the present invention also provides a method for preparing the compound of formula (IV), which comprises reacting the compound of formula (II) with the compound of formula (III) in the presence of a catalyst,

[0103]

[0104] Wherein, R 1 and R 2 are independently hydrogen, linear or branched C1-C3 alkyl or pinacol ester, and wherein R 1 and R 2 can be the same or different, or R 1 and R 2 together form a pinacol ester,

[0105]

[0106] Wherein, R 3 is hydrogen, hydroxyl, linear or branched C1-C8 alkyl, linear or branched C1-C8 alkenyl, linear or branched C1-C8 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl, or C1-C8 alkyl containing a heteroatom; wherein X is halogen or trifluoromethanesulfonate; and wherein Y is nitrile or amide to obtain a compound of formula (IV).

[0107] In some embodiments, R 1 and R 2 of the compound of formula (II) are independently hydrogen. In some embodiments, R 1 and R 2 of the compound of formula (II) are independently linear or branched C1-C3 alkyl. In some embodiments, R 1 and R 2 of the compound of formula (II) together form a pinacol ester.

[0108] In some embodiments, the compound of formula (II) is selected from the following:

[0109]

[0110] R 3X and Y are as defined above for the compounds of formula (IV). In some embodiments, X of the compound of formula (III) is a leaving group for the Suzuki coupling reaction. Examples of leaving groups for the Suzuki reaction are further provided in, for example, Liu et al., Org Lett 7(6):1149-1151 (2005); El-Berjawi et al., Dyes Pigments 159:551-556 (2018); Chemler et al., Angew Chem Int Ed 40:4544 (2001). In some embodiments, X is a halogen, such as fluorine, chlorine, bromine or iodine. In some embodiments, X is a trifluoromethanesulfonate (-OSO2CF3; also abbreviated as -OTf) group. In some embodiments, R 3 is hydrogen, Y is nitrile or amide, and X is halogen or trifluoromethanesulfonate. In some embodiments, R 3 is methyl, Y is nitrile or amide, and X is halogen or trifluoromethanesulfonate. In some embodiments, R 3 is hydroxyl, Y is nitrile or amide, and X is halogen or trifluoromethanesulfonate. In some embodiments, R 3 is methyl, Y is nitrile, and X is iodine.

[0111] In some embodiments, the compounds of formula (III) are selected from the following:

[0112]

[0113]

[0114] In some embodiments, the reaction between the compounds of formula (II) and formula (III) is carried out in the presence of a solvent comprising toluene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dioxane, n-butanol (n-BuOH), isopropanol (IPA), ethanol (EtOH), methanol (MeOH), dimethyl ether (DME), diethyl ether or any mixture thereof. In some embodiments, the reaction between the compounds of formula (II) and formula (III) is carried out using water as the solvent. In some embodiments, the reaction between the compounds of formula (II) and formula (III) is carried out in a solvent-free manner, for example, the reaction is microwave-assisted (see, for example, Nun et al., Synlett 11:1761-1764 (2009)).

[0115] In some embodiments, the reaction between the compounds of formula (II) and formula (III) is carried out in the presence of a base, said base comprising potassium carbonate (K2CO3), potassium acetate (CH3CO2K), potassium phosphate (K3PO4), potassium tert-butoxide (KOtBu), sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), sodium methoxide (NaOMe), sodium tert-butoxide (NaOtBu), cesium carbonate (Cs2CO3), silver phosphate (Ag3PO4), silver oxide (Ag2O), thallium carbonate (Tl2CO3), thallium ethoxide (TlOEt), tert-butylamine (t-BuNH2), potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), barium hydroxide (Ba(OH)2), thallium hydroxide (TlOH) or a combination thereof.

[0116] In some embodiments, the catalyst for the reaction between the compounds of formula (II) and formula (III) comprises a metal selected from palladium (Pd), copper (Cu), nickel (Ni), iron (Fe), zinc (Zn) or rhodium (Rh). In some embodiments, the catalyst comprises a metal selected from Pd, Cu or Ni. In some embodiments, the catalyst comprises 1 to 6 metal atoms. In some embodiments, the catalyst comprises 2 to 5 metal atoms. In some embodiments, the catalyst comprises 2 to 4 metal atoms. In some embodiments, the catalyst comprises 1, 2, 3, 4, 5 or 6 metal atoms. Palladium-catalyzed coupling reactions are further described, for example, in US 2006 / 0264629 and US2010 / 0184739.

[0117] In some embodiments, the catalyst is a palladium catalyst. In some embodiments, the palladium catalyst is Pd(PPh3)2Cl2 [bis(triphenylphosphine)palladium(II) dichloride]; Pd(PPh3)4 [tetrakis(triphenylphosphine)palladium(0)]; Pd(OAc)2 [palladium(II) diacetate]; XPhos Pd-G3 [(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate]; SPhos-Pd-G2 [chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)]; A Pd G3 (palladium(II) bis(1-adamantyl)-n-butylphosphine-2-(2'-aminobiphenyl) methanesulfonate or palladium(II) bis(1-adamantyl)butylphosphine-2-(2'-aminobiphenyl) methanesulfonate); APhos Pd G3 (palladium G3-(4-(N,N-dimethylamino)phenyl)di-tert-butylphosphine] or [4-(di-tert-butylphosphino)-N,N-dimethylaniline-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate); P(Cy3)Pd-G3 (palladium G3-tricyclohexylphosphine or [(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate); allyl palladium(II) chloride dimer (bis(allyl)dichlorodipalladium); or Pd(dppf)Cl2 [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)].

[0118] In some embodiments, the catalyst is a copper catalyst. In some embodiments, the copper catalyst is copper(I) chloride, [(o-(di-tert-butylphosphino)-N,N-dimethylaniline)copper(I) iodide]2, [(o-(di-tert-butylphosphino)-N,N-dimethylaniline)copper(I) fluoride]2. In some embodiments, the catalyst is a nickel catalyst. In some embodiments, the nickel catalyst is NiCl2, NiBr2, NiI2, G3DenP-Ni, (dppf)Ni(cinnamyl)Cl, (PCy3)2NiCl2 or Ni(cod)2. Further exemplary catalysts are provided, for example, in: Tasker et al., Nature 509(7500):299-309 (2014); Yang et al., Angew Chem Int Ed Engl 50(17):3904-3907 (2011); Barder et al., J Am Chem Soc 127(13):4685-4696 (2005); Bedford et al., Chem Commun (Camb) 42:6430-6432 (2009); and Catalysts Volume 9, ISSN 2073-4344 (2019).

[0119] In some embodiments, the reaction between the compounds of formula (II) and formula (III) is further carried out in the presence of a ligand. In some embodiments, the ligand is a phosphine ligand, a carbon ligand or a nitrogen ligand. In some embodiments, the ligand is PPh3, PCy3, P(o-tolyl)3, P(i-Pr)3, P(O-Pr-i)3, n-BuP(1-Ad)2, P(t-Bu)2(p-NMe2-Ph), a diarylalkyl ligand (e.g., as described by Martin et al., Acc Chem Res 41:1461 (2008)), a bidentate phosphine ligand such as DPPF, DPPE or DPPP, a carbene-type ligand (e.g., as described by Kuwano et al., Org Lett 7:945 (2005)), an olefin-type ligand (e.g., as described by Tao et al., J Org Chem 69:4330 (2004)), an amine or an imine (e.g., as described by Tao et al., J Org Chem 69:4330 (2004)). In some embodiments, the ligand and the catalyst are provided as a preformed complex in the reaction. For example, Pd(PPh3)4 comprises both a palladium catalyst and a phosphine ligand. In some embodiments, the method for preparing the compound of formula (IV) includes preparing a catalyst comprising a metal and a ligand.

[0120] In some embodiments, the reaction does not include a catalyst. In some embodiments, the reaction does not include a ligand. Further exemplary reaction conditions are discussed, for example, in: Suzuki, J Organometallic Chem 576:147-168 (1999); Miyaura et al., Chem Rev 95:2457-2483 (1995); Chemler et al., Angew Chem Int Ed Engl 40:4544-4568 (2001); Franzén, Can J Chem 78:957-962 (2000); Suzuki, Proc Jpn Acad, Ser B. 80(8):359 (2004); and Paul et al., RSC Adv 5:42193 (2015).

[0121] In some embodiments, the compounds of formula (II) and formula (III) are added to the reaction in a molar ratio of about 1:10, about 1:5, about 1:4, about 1:3, about 1:2, about 1:1, about 1:0.75, about 1:0.5, about 1:0.25, about 1:0.1 or about 1:0.05. In some embodiments, the compounds of formula (II) and (III) are added in an amount of about 0.01 to about 1 mol / L (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 (solvent).

[0122] In some embodiments, the catalyst is added to the reaction in an amount of about 0.001 to about 1, about 0.002 to about 0.5, about 0.003 to about 0.1, about 0.004 to about 0.075, about 0.005 to about 0.05, about 0.006 to about 0.025, about 0.007 to about 0.01, or about 0.008 to about 0.009 molar equivalents relative to the compound of formula (II) or formula (III). In some embodiments, the catalyst is added to the reaction in an amount of about 0.001, about 0.002, about 0.003, about 0.004, about 0.005, about 0.006, about 0.007, about 0.008, about 0.009, about 0.01, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.1, about 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 relative to the compound of formula (II) or formula (III).

[0123] In some embodiments, the base is 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 about 4 molar equivalents relative to the compound of formula (II) or formula (III). In some embodiments, the base is added to the reaction in an amount of about 0.1, about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 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 relative to the compound of formula (II) or formula (III).

[0124] In some embodiments, the present disclosure provides a method for preparing a compound of formula (I) [tazarotene] or a salt thereof,

[0125]

[0126] which comprises, in the presence of a catalyst, reacting a compound of formula (II)

[0127]

[0128] wherein R 1 and R 2 are independently hydrogen or a linear or branched C1-C3 alkyl group, wherein R 1 and R 2 may be the same or different; or R 1 and R 2 together form a pinacol ester and react with a compound of formula (III)

[0129]

[0130] wherein R 3 is a substituted or unsubstituted linear or branched C1-C8 alkyl group, a substituted or unsubstituted linear or branched C1-C8 alkenyl group, a substituted or unsubstituted linear or branched C1-C8 alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heteroaryl group, or a C1-C8 alkyl group containing a heteroatom; wherein X is a halogen or trifluoromethanesulfonate; and wherein Y is a nitrile (CN) or an amide (CONH2); to obtain a compound of formula (IV),

[0131]

[0132] wherein R 3 is as defined above; and in the presence of a base, hydrolyze the compound of formula (IV) to obtain tretinoin. R 1 , R 2 , R 3 , R 4 , X and Y, and the various reactions and conditions are further described herein. In some embodiments, R 3 is methyl, X is iodine, and Y is a nitrile.

[0133] An exemplary method for preparing tretinoin [formula (I)] as described in the examples herein is shown in Figure 9 .

[0134] In some embodiments, the present disclosure provides a method for preparing a compound of formula (II),

[0135]

[0136] wherein R 1 and R 2 are independently hydrogen or a linear or branched C1-C3 alkyl group, wherein R 1 and R 2 may be the same or different; or R 1 and R 2Together form a pinacol ester, the method comprising

[0137]

[0138] reacting a compound comprising -R 1 OBOR 2 - in the presence of a salt and a catalyst, wherein R 1 and R 2 are as defined above for the compounds of formula (II). In some embodiments, the catalyst is a palladium catalyst. In some embodiments, the catalyst comprises P(tBu)3. In some embodiments, the catalyst is Pd-162 ([P(tBu)3]Pd(crotyl)Cl), Pd-168 ([P(tBu)3]palladacycle), or Pd-216 ({Pd(μ-I)[P(t-Bu)3]}2). In some embodiments, the reaction is carried out at about 15 °C to about 35 °C, about 18 °C to about 32 °C, about 20 °C to about 30 °C, about 22 °C to about 28 °C, or about 24 °C to about 26 °C. In some embodiments, the method for preparing the compounds of formula (II) provided herein is carried out at room temperature. When compared with previously described methods, for example, methods carried out under harsh conditions (e.g., at -78 °C) as described in WO 2006 / 066978, the present method greatly reduces complexity and shortens the preparation time.

[0139] In some embodiments, the present disclosure provides novel compounds. In some embodiments, the novel compounds described herein are used to prepare tretinoin. The novel compounds provided herein can advantageously simplify the preparation method of tretinoin.

[0140] In some embodiments, the present disclosure provides a compound of formula (III),

[0141]

[0142] wherein R 3 is a substituted or unsubstituted linear or branched C1-C8 alkyl, substituted or unsubstituted linear or branched C1-C8 alkenyl, substituted or unsubstituted linear or branched C1-C8 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl, or a C1-C8 alkyl containing a heteroatom; wherein X is a halogen or trifluoromethanesulfonate; and wherein Y is a nitrile or an amide. R 3 , X and Y are further described herein.

[0143] In some embodiments, the compounds of formula (III) are selected from the following:

[0144]

[0145]

[0146] In some embodiments, the compound of formula (III) is prepared by reacting the following with R

[0147]

[0148] with R 3 CO2CH2Br, wherein X, Y and R 3 are as defined above for the compound of formula (III). In some embodiments, the strong base is sodium hydride.

[0149] In some embodiments, the present disclosure provides a compound of formula (V),

[0150]

[0151] wherein R 4 is hydrogen, a substituted or unsubstituted linear or branched C1-C8 alkanoyl, a substituted or unsubstituted linear or branched C1-C8 alkenoyl, a substituted or unsubstituted linear or branched C1-C8 alkynoyl, a substituted or unsubstituted cycloalkanoyl, a substituted or unsubstituted arylcarbonyl, a substituted or unsubstituted heterocyclic carbonyl, a substituted or unsubstituted heteroarylcarbonyl, or a C1-C8 alkanoyl containing a heteroatom; and wherein Y is nitrile (CN) or amide (CONH2).

[0152] 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 linear or branched C1-C8 alkanoyl, a substituted or unsubstituted linear or branched C1-C8 alkenoyl, a substituted or unsubstituted linear or branched C1-C8 alkynoyl, a substituted or unsubstituted cycloalkanoyl, a substituted or unsubstituted arylcarbonyl, a substituted or unsubstituted heterocyclic carbonyl, a substituted or unsubstituted heteroarylcarbonyl, or a C1-C8 alkanoyl containing a heteroatom.

[0153] In some embodiments, R 4 is an unsubstituted linear or branched C1-C8 alkanoyl, an unsubstituted linear or branched C1-C8 alkenoyl, an unsubstituted linear or branched C1-C8 alkynoyl, an unsubstituted cycloalkanoyl, an unsubstituted arylcarbonyl, an unsubstituted heterocyclic carbonyl, an unsubstituted heteroarylcarbonyl, or a C1-C8 alkanoyl containing a heteroatom.

[0154] In some embodiments, R 4is an unsubstituted linear or branched C1-C4 alkanoyl, unsubstituted linear or branched C1-C4 alkenoyl, unsubstituted linear or branched C1-C4 alkynoyl, or a C1-C4 alkanoyl containing a heteroatom.

[0155] In some embodiments, R 4 is acetyl.

[0156] In some embodiments, the compounds of formula (V) are selected from the following:

[0157]

[0158] In some embodiments, the present disclosure provides a compound of formula (I), a novel polymorph of tretinoin. The novel polymorphs described herein can be used to better characterize tretinoin and its pharmaceutical properties.

[0159] In some embodiments, the present disclosure provides a polymorph of type A of the compound [tretinoin-HCl] of formula (I), wherein the polymorph of type A shows an X-ray powder diffraction (XRPD) pattern having characteristic peaks at reflection angles 2θ of 7.6, 11.5, 15.4, 21.1, and 23.2 degrees. In some embodiments, the polymorph of type A further shows peaks at 8.6, 9.0, 17.7, 18.3, 19.5, and 22.5 degrees. An exemplary XRPD spectrum of the polymorph of type A is shown in Figure 2 .

[0160] In some embodiments, the present disclosure also provides a method for preparing the polymorph of type A of tretinoin-HCl, which includes: (a) providing tretinoin according to the method described herein; (b) adjusting the pH of tretinoin to a pH of about 2 to about 4 to obtain a tretinoin salt; and (c) suspending the tretinoin salt in methyl ethyl ketone to obtain the polymorph of type A of tretinoin. In some embodiments, the pH is adjusted using an acid described herein. In some embodiments, the pH is adjusted using HCl.

[0161] In some embodiments, the present disclosure provides a polymorph of type B of the compound [tretinoin-HCl] of formula (I), wherein the polymorph of type B shows an X-ray powder diffraction pattern having characteristic peaks at reflection angles 2θ of 12.6, 19.5, 19.8, 24.6, and 29.5 degrees. In some embodiments, the polymorph of type B further shows peaks at 8.4, 12.0, 17.4, 21.1, 23.2, 31.0, and 32.1 degrees. An exemplary XRPD spectrum of the polymorph of type B is shown in Figure 3 .

[0162] In some embodiments, the present disclosure also provides a method for preparing the polymorphic form B of tretinoin-HCl, which includes: (a) providing tretinoin according to the method described herein; (b) adjusting the pH of tretinoin to a pH of about 2 to about 4 to obtain a tretinoin salt; and (c) suspending the tretinoin salt in a solvent comprising acetonitrile, ethyl acetate, tetrahydrofuran, 1-butanol; or dissolving the tretinoin salt in methanol to obtain the polymorphic form B of tretinoin. In some embodiments, the pH is adjusted using the acid described herein. In some embodiments, the pH is adjusted using HCl.

[0163] In some embodiments, the present disclosure provides a polymorphic form C of the compound of formula (I) [tretinoin-HCl], wherein the polymorphic form C exhibits an X-ray powder diffraction pattern having characteristic peaks at reflection angles 2θ of 7.9, 15.6, 20.0, 23.6 and 27.8 degrees. In some embodiments, the polymorphic form C further exhibits peaks at 12.1, 16.4, 17.4 and 28.8 degrees. An exemplary XRPD spectrum of the polymorphic form C is shown in Figure 4 In.

[0164] In some embodiments, the present disclosure also provides a method for preparing the polymorphic form C of tretinoin-HCl, which includes: providing tretinoin according to the method described herein; (b) adjusting the pH of tretinoin to a pH of about 2 to about 4 to obtain a tretinoin salt; and (c) suspending the tretinoin salt in ethylene glycol to obtain the polymorphic form C of tretinoin. In some embodiments, the pH is adjusted using the acid described herein. In some embodiments, the pH is adjusted using HCl.

[0165] In some embodiments, the present disclosure provides a polymorphic form D of the compound of formula (I) [tretinoin], wherein the polymorphic form D exhibits an X-ray powder diffraction pattern having characteristic peaks at reflection angles 2θ of 8.5, 16.2, 18.6 and 23.1 degrees. In some embodiments, the polymorphic form D further exhibits peaks at 12.2, 12.8 and 14.1 degrees. An exemplary XRPD spectrum of the polymorphic form D is shown in Figure 5 In.

[0166] In some embodiments, the present disclosure also provides a method for preparing the polymorphic form D of tretinoin, which includes: (a) providing tretinoin according to the method described herein; and (b) adjusting the pH of tretinoin to a pH of about 5 to about 6 to obtain the polymorphic form D of tretinoin. In some embodiments, the pH is adjusted using the acid described herein. In some embodiments, HCl, acetic acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid or any mixture thereof is used to adjust the pH.

[0167] In some embodiments, the present disclosure provides an E polymorph of a compound of formula (I) [tazarotene], wherein the E polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks at reflection angles 2θ of 8.6, 12.8, 14.2, 17.9 and 24.0 degrees. In some embodiments, the E polymorph further exhibits peaks at 10.6, 15.3, 16.3, 19.3 and 22.0 degrees. An exemplary XRPD spectrum of the E polymorph is shown in Figure 6 in.

[0168] In some embodiments, the present disclosure also provides a method for preparing the E polymorph of tazarotene, which comprises: (a) providing tazarotene according to the method described herein; (b) adjusting the pH of tazarotene to a pH of about 5 to about 6 to obtain a tazarotene salt; and (c) suspending the tazarotene salt in methanol to obtain the E polymorph of tazarotene.

[0169] In some embodiments, the present disclosure provides an F polymorph of a compound of formula (I) [tazarotene], wherein the F polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks at reflection angles 2θ of 5.2, 6.3, 14.9, 18.0 and 19.1 degrees. In some embodiments, the F polymorph further exhibits peaks at 8.5, 15.6, 16.3, 18.5 and 22.9 degrees. An exemplary XRPD spectrum of the F polymorph is shown in Figure 7 in.

[0170] In some embodiments, the present disclosure also provides a method for preparing the F polymorph of tazarotene, which comprises: (a) providing tazarotene according to the method described herein; (b) adjusting the pH of tazarotene to a pH of about 5 to about 6 to obtain a tazarotene salt; and (c) dissolving the tazarotene salt in isopropanol to obtain the F polymorph of tazarotene.

[0171] In some embodiments, the present disclosure provides a G polymorph of a compound of formula (I) [tazarotene Na salt], wherein the G polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks at reflection angles 2θ of 10.6, 11.5, 17.4 and 19.7 degrees. In some embodiments, the G polymorph further exhibits peaks at 8.9, 10.0, 14.7 and 16.2 degrees. An exemplary XRPD spectrum of the G polymorph is shown in Figure 8 in.

[0172] In some embodiments, the present disclosure also provides a method for preparing the G polymorph of tazarotene Na salt, which comprises: (a) providing tazarotene according to the methods described herein; and (b) adjusting the pH of tazarotene to a pH of about 9 to about 12 to obtain the G polymorph of tazarotene. In some embodiments, the pH is adjusted using a base described herein. In some embodiments, the pH is adjusted using sodium hydroxide.

[0173] All references cited herein, including patents, patent applications, papers, textbooks, etc., and references cited therein, are hereby incorporated by reference in their entirety to the extent that they have not been previously cited.

[0174] Examples

[0175] Example 1. Synthesis of 3”-(tert-butyl)-4'-(2-hydroxyethoxy)-4”-(pyrrolidin-1-yl)-[1,1':3',1”-ter biphenyl]-4-carboxylic acid [tazarotene] - one-step hydrolysis

[0176] A. Preparation of 2-((3”-(tert-Butyl)-4-cyano-4”-(pyrrolidin-1-yl)-[1,1':3',1”-terphenyl]-4'-yl)oxy)ethyl acetate [Formula IV(a)]

[0177] To 100 g (0.3 mol) of (3-(tert-butyl)-4-(pyrrolidin-1-yl)phenyl)boronic acid [Formula II], toluene (1450 mL) and 85 g (0.21 mol) of 2-((4'-cyano-3-iodo-[1,1'-biphenyl]-4-yl)oxy)ethyl acetate [Formula III] were added. 5 M potassium carbonate (300 mL) was added. The reaction medium was stirred at 40 °C under nitrogen for 30 minutes. 0.87 g of Pd-100 (palladium chloride bis(triphenylphosphine)) (0.0013 mol) was added under nitrogen, and the reaction medium was heated to 85 - 90 °C and stirred under reflux for 6 hours. The reaction was terminated by adding water (625 mL). The phases were separated. The organic phase was filtered off. Toluene was distilled off in vacuo to obtain an oily residue.

[0178] The residue was suspended in heptane (3000 mL), stirred for 1 hour under reflux and filtered while hot. The mother liquor was further heated under reflux for 1 hour and gradually cooled to room temperature. The precipitate was filtered off to obtain ethyl 2-((3”-(tert-butyl)-4-cyano-4”-(pyrrolidin-1-yl)-[1,1':3',1”-terphenyl]-4'-yl)oxy)acetate [Formula IV(a)], which 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 obtain 50.0 g of ethyl 2-((3”-(tert-butyl)-4-cyano-4”-(pyrrolidin-1-yl)-[1,1':3',1”-terphenyl]-4'-yl)oxy)acetate [Formula IV(a)] as a white powder, with HPLC purity of 99.8%; yield 49%; m / z 483.26.

[0179]

[0180] B. Synthesis of 3”-(tert-butyl)-4'-(2-hydroxyethoxy)-4”-(pyrrolidin-1-yl)-[1,1':3',1”-terphenyl]-4-carboxylic acid [tazarotene; Formula I] from Formula IV(a)

[0181] To 50 g (0.104 mol) of ethyl 2-((3”-(tert-butyl)-4-cyano-4”-(pyrrolidin-1-yl)-[1,1':3',1”-terphenyl]-4'-yl)oxy)acetate [Formula IV(a)] was added 5 M NaOH solution (100 mL) and ethanol (200 mL). The reaction medium was stirred under reflux for 15 hours. The reaction medium was cooled to 40 °C and water (400 mL) was added. 32% HCl (50 mL) was added dropwise to pH 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, which was suspended in ethanol (40 ml) and water (40 ml). The mixture was heated to 40 °C for 5 hours and filtered off to obtain 39.5 g of pure 3”-(tert-butyl)-4'-(2-hydroxyethoxy)-4”-(pyrrolidin-1-yl)-[1,1':3',1”-terphenyl]-4-carboxylic acid [tazarotene; Formula I], with HPLC purity of 99.9%; yield 74%; m / z 460.24.

[0182]

[0183] Example 2. Synthesis of 3”-(tert-butyl)-4'-(2-hydroxyethoxy)-4”-(pyrrolidin-1-yl)-[1,1':3',1”-ter biphenyl]-4-carboxylic acid [tazarotene] - two-step hydrolysis

[0184] A. Prepare the compound of formula IV(a) according to Example 1.A.

[0185] B. Preparation of 3”-(tert-butyl)-4'-(2-hydroxyethoxy)-4”-(pyrrolidin-1-yl)-[1,1':3',1”-terphenyl]-4-carbonitrile [Formula V(a)]

[0186] Suspend 2.0 g (0.004 mol) of 2-((3”-(tert-butyl)-4-cyano-4”-(pyrrolidin-1-yl)-[1,1':3',1”-terphenyl]-4'-yl)oxy)ethyl acetate [Formula IV(a)] in ethanol (60 ml). Add 2.9 g (0.021 mol) of potassium carbonate. Stir the reaction medium at 25 °C for 2.5 hours, then reflux for two hours and filter while hot. Concentrate the solution to 20 mL, gradually cool to room temperature and stir for 15 - 18 hours to obtain a white precipitate, which is filtered out to obtain an off-white to beige solid; purity 90.75%; yield 97.2% (on a dry weight basis). Stir the product in heptane (30 mL) at reflux for 15 - 18 hours, then gradually cool to 10 - 15 °C. Continue stirring for 1 hour. Filter out the obtained precipitate [Formula V(a)] to obtain an off-white to light beige solid, with purity 97.9%; yield 96%; m / z 441.26.

[0187]

[0188] C. Synthesis of 3”-(tert-butyl)-4'-(2-hydroxyethoxy)-4”-(pyrrolidin-1-yl)-[1,1':3',1”-terphenyl]-4-carboxylic acid [tazarotene; Formula I] from Formula V(a)

[0189] Suspend 11.0 g (0.025 mol) of 3”-(tert-butyl)-4'-(2-hydroxyethoxy)-4”-(pyrrolidin-1-yl)-[1,1':3',1”-terphenyl]-4-carbonitrile in 0.5 M NaOH:EtOH solution (25:50 mL). Reflux the suspension under heating for 18 - 22 hours and it turns into a dark yellow solution. Cool the reaction medium to room temperature, dilute with water (82 mL), acidify to pH = 4.7 with 32% HCl, and stir at room temperature for 2 hours. Filter out the formed precipitate, wash with a 20:80 mixture of ethanol:water, and dry in vacuo at 45 °C to obtain tazarotene [Formula I] as a white powder, with purity 99.5%; m / z 460.24.

[0190]

[0191] Example 3. Preparation of 2-((4'-cyano-3-iodo-[1,1'-biphenyl]-4-yl)oxy)ethyl acetate [Formula III(a)] Preparation

[0192] To 180 g (0.56 mol) of 4'-hydroxy-3'-iodo-biphenyl-4-carbonitrile, dimethylformamide (900 mL) and 247 g (1.8 mol) of potassium carbonate were added. The reaction medium was stirred at 25 °C for 30 minutes. 117 g (0.7 mol) of 2-bromoethyl acetate was added, and the reaction medium was heated to 60 - 65 °C and stirred for 6 hours. The reaction was terminated by adding water (1800 mL). The reaction medium was cooled to 25 °C. The precipitate was filtered off to give 213.5 g of [Formula III(a)]; 90.6% yield; HPLC purity 97%.

[0193]

[0194] Example 4. Preparation of (3-(tert-butyl)-4-(pyrrolidin-1-yl)phenyl)boronic acid [Formula II(a)]

[0195] 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, 0.15 g (2.8×10 -4 mol) of Pd-168, 400 mL of ethanol (EtOH) and 120 mL of ethylene glycol were mixed together. 25.5 g (0.282 mol) of tetrahydroxyborane was added all at once with stirring. After 5 minutes, the temperature was raised to 35 - 45 °C. The reaction mixture was stirred at 40 °C for 4 - 5 hours. A dark brown / grey suspension was formed. The reaction was terminated 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 to give 31.5 g of (3-(tert-butyl)-4-(pyrrolidin-1-yl)phenyl)boronic acid [Formula II(a)]; purity 98.3%.

[0196]

[0197] Example 5. Alternative method for the preparation of 2-((3”-(tert-butyl)-4-cyano-4”-(pyrrolidin-1-yl)-[1,1':3', 1”-terphenyl]-4'-yl)oxy)ethyl acetate [Formula IV(a)]

[0198] To 247 g (0.015 mol) of (3-(tert-butyl)-4-(pyrrolidin-1-yl)phenyl)boronic acid, dimethylacetamide (1000 mL) and 100 g (0.25 mol) of 2-((4'-cyano-3-iodo-[1,1'-biphenyl]-4-yl)oxy)ethyl acetate were added. 1.5 M tripotassium phosphate (500 mL) was added. The reaction medium was stirred under nitrogen for 15 minutes. 1.66 g (0.0074 mol) of palladium acetate was added under nitrogen, and the reaction medium was stirred at 25 °C for 3 hours. The reaction was terminated by adding water (500 mL). The precipitate was filtered off.

[0199] The solid was suspended in heptane (2500 mL), stirred under reflux for 1 h and filtered hot. The mother liquor was further heated under reflux for 1 h and gradually cooled to room temperature. The precipitate was filtered off to obtain 2-((3”-(tert-butyl)-4-cyano-4”-(pyrrolidin-1-yl)-[1,1':3',1”-terphenyl]-4'-yl)oxy)ethyl acetate, which was further suspended in ethanol (150 mL) and refluxed under heating for 2.5 h, then cooled to room temperature. The precipitate was filtered off to obtain 50.0 g of 2-((3”-(tert-butyl)-4-cyano-4”-(pyrrolidin-1-yl)-[1,1':3',1”-terphenyl]-4'-yl)oxy)ethyl acetate as a white powder, having an HPLC purity of 99.6%; yield 54%; m / z 483.26.

[0200]

[0201] Example 6. Preparation of tazarotene HCl salt

[0202] 2-((3”-(tert-butyl)-4-cyano-4”-(pyrrolidin-1-yl)-[1,1':3',1”-terphenyl]-4'-yl)oxy)ethyl acetate (11 g) in a mixture of EtOH: 20% aqueous NaOH solution (50 mL: 25 mL) was refluxed under heating for 18 h. The reaction mixture was cooled to room temperature and acidified to pH 2 with 32% HCl. The mixture was stirred at room temperature for 2 h, filtered, and the filter cake was washed with EtOH:H2O 20:80 (100 mL). Tazarotene HCl salt was dried under vacuum at 40 - 45 °C to obtain 11.0 g of tazarotene HCl. The XRPD of the obtained sample is shown in Figure 1 in.

[0203] Example 7. Preparation of tazarotene HCl - Form B polymorph

[0204] A. 150 mg of tazarotene HCl salt obtained in Example 6 was suspended in acetonitrile (5 mL) and shaken at 300 rpm at room temperature for 3 days. The product was filtered off and dried under ambient conditions. The obtained crystal form was the B polymorph as determined by XRPD. The XRPD of the B polymorph is shown in Figure 3 in.

[0205] B. 150 mg of tazarotene HCl salt obtained in Example 6 was suspended in ethyl acetate (5 mL) and shaken at 300 rpm at room temperature for 3 days. The product was filtered off and dried under ambient conditions. The obtained crystal form was the B polymorph as determined by XRPD.

[0206] C. Suspend 150 mg of tretinoin HCl salt obtained in Example 6 in tetrahydrofuran (5 mL) and shake at 300 rpm at room temperature for 3 days. Filter the product and dry it under ambient conditions. As determined by XRPD, the resulting crystal form is polymorph B.

[0207] D. Suspend 150 mg of tretinoin HCl salt obtained in Example 6 in 1-butanol (5 mL) and shake at 300 rpm at room temperature for 3 days. Filter the product and dry it under ambient conditions. As determined by XRPD, the resulting crystal form is polymorph B.

[0208] Example 8. Alternative preparation of tazarotene HCl - Form B polymorph

[0209] Dissolve 1.5 g of tretinoin HCl salt obtained in Example 6 in MeOH (33 mL) under reflux. Filter the turbid solution through a glass filter paper. Let the solution stand at room temperature to evaporate for 3 days.

[0210] Filter the product and wash it with cold MeOH (3 mL). Dry the product under ambient conditions. As determined by XRPD, the resulting crystal form is polymorph B.

[0211] Example 9. Preparation of tazarotene HCl - Form A polymorph

[0212] Suspend 150 mg of tretinoin HCl salt obtained in Example 6 in methyl ethyl ketone (5 mL) and shake at 300 rpm at room temperature for 3 days. Filter the product and dry it under ambient conditions. As determined by XRPD, the resulting crystal form is polymorph A. The XRPD of polymorph A is shown in Figure 2 in.

[0213] Example 10. Preparation of tazarotene HCl - Form C polymorph

[0214] Suspend 150 mg of tretinoin HCl salt obtained in Example 6 in ethylene glycol (5 mL) and shake at 300 rpm at room temperature for 3 days. Filter the product and dry it under ambient conditions. As determined by XRPD, the resulting crystal form is polymorph C. The XRPD of polymorph C is shown in Figure 4 in.

[0215] Example 11. Preparation of tazarotene - Form D polymorph

[0216] 2-((3”-(tert-Butyl)-4-cyano-4”-(pyrrolidin-1-yl)-[1,1':3',1”-terphenyl]-4'-yl)oxy)ethyl acetate (5 g) in a mixture of EtOH:20% aqueous NaOH (22 mL:11 mL) was refluxed for 18 h under heating. The reaction mixture was cooled to room temperature and acidified to pH 5.5 with 32% HCl. The mixture was stirred at room temperature for 2 h, filtered, and the filter cake was washed with EtOH:H2O 20:80 (45 mL). Tretinoin was dried under vacuum at 40 - 45 °C for 12 - 48 h (18 h) to give 4.6 g of tretinoin. The obtained crystal form was the D polymorph as determined by XRPD. The XRPD of the D polymorph is shown in Figure 5 in.

[0217] Example 12. Preparation of tazarotene - Form E polymorph

[0218] 150 mg of tretinoin obtained in Example 11 was suspended in MeOH (5 mL) and shaken at 300 rpm at room temperature for 2 days. The product was filtered and dried under ambient conditions for 2 - 6 days (3 days). The obtained crystal form was the E polymorph as determined by XRPD. The XRPD of the E polymorph is shown in Figure 6 in.

[0219] Example 13. Preparation of tazarotene - Form F polymorph

[0220] 1.5 g of tretinoin obtained in Example 11 was dissolved in IPA (24 mL) under reflux. The turbid solution was filtered through a nylon filter paper. The solution was left to evaporate at room temperature for 3 days. The product was filtered and washed with cold IPA (1.5 mL). The product was dried under ambient conditions for 2 - 6 days (3 days). The obtained crystal form was the F polymorph as determined by XRPD. The XRPD of the F polymorph is shown in Figure 7 in.

[0221] Example 14. Preparation of tazarotene - Form G polymorph

[0222] 4.59 g of tretinoin A type obtained according to Example 9 was suspended in MeOH:H2O 1:1 (400 mL). 0.1 N NaOH was added dropwise with pH control until pH 11.5. The mixture was stirred at room temperature for 30 min and the precipitate was filtered out. The filter cake was washed with water (20 mL). Tretinoin sodium salt was dried under vacuum at 40 - 45 °C for 12 - 48 h (18 h) to give 4.3 g of tretinoin sodium salt. The obtained crystal form was the G polymorph as determined by XRPD. The XRPD of the G polymorph is shown in Figure 8 in.

Claims

1. A method for preparing a compound of formula (I) [tazarotene] or a salt thereof, It includes: hydrolyzing a compound of formula (V) in the presence of a solvent comprising water, methanol, ethanol, propanol, isopropanol or a mixture thereof, wherein, R 4 is hydrogen, a substituted or unsubstituted linear or branched C1-C8 alkanoyl group, a substituted or unsubstituted linear or branched C2-C8 alkenoyl group, a substituted or unsubstituted linear or branched C2-C8 alkynoyl group, a substituted or unsubstituted cycloalkanoyl group, a substituted or unsubstituted arylcarbonyl group, a substituted or unsubstituted heterocyclocarbonyl group, a substituted or unsubstituted heteroarylcarbonyl group, or a C1-C8 alkanoyl group containing a heteroatom; and wherein Y is -CN or -CONH2; to obtain a compound of formula (I).

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

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

4. The method according to claim 3, which further comprises preparing a compound of formula (V) by hydrolyzing a compound of formula (IV) in the presence of a base, Among them, R 3 is hydrogen, hydroxy, halogen, substituted or unsubstituted linear or branched C1-C8 alkyl, substituted or unsubstituted linear or branched C2-C8 alkenyl, substituted or unsubstituted linear or branched C2-C8 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl, or C1-C8 alkyl containing a heteroatom; and wherein Y is -CN or -CONH2; to obtain a compound of formula (V).

5. The method according to claim 4, wherein R 3 is methyl.

6. The method according to any one of claims 1 - 5, wherein the solvent comprises water and ethanol.

7. The method according to claim 4, wherein the base comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide or any mixture thereof.

8. The method according to claim 4, wherein the compound of formula (IV) is present in an amount of 0.01 to 0.5 mol / L of the solvent.

9. The method according to claim 4, wherein the base is present in an amount of 0.1 to 1 mol / L of the solvent.

10. The method according to claim 9, wherein the base is present in an amount of 1 to 10 molar equivalents relative to the compound of formula (IV).

11. The method according to claim 4, which further comprises preparing a compound of formula (IV) by reacting a compound of formula (II) Among them, R 1 and R 2 are independently hydrogen or a linear or branched C1-C3 alkyl group, where R 1 and R 2 may be the same or different; or R 1 and R 2 together form a pinacol ester, with a compound of formula (III) in the presence of a catalyst, Wherein, R 3 is hydrogen, hydroxyl, halogen, substituted or unsubstituted linear or branched C1-C8 alkyl, substituted or unsubstituted linear or branched C2-C8 alkenyl, substituted or unsubstituted linear or branched C2-C8 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl, or substituted or unsubstituted C1-C8 alkyl containing a heteroatom; wherein X is halogen or trifluoromethanesulfonate; and wherein Y is -CN or -CONH2, to obtain a compound of formula (IV).

12. The method according to claim 11, wherein said R 3 is methyl and X is iodine.

13. The method according to claim 11, wherein the reaction is carried out in the presence of a solvent comprising toluene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dioxane, n - butanol (n - BuOH), isopropanol (IPA), dimethyl ether (DME), diethyl ether or any mixture thereof.

14. The method according to claim 11, wherein the reaction for preparing the compound of formula (IV) from the compound of formula (II) and the compound of formula (III) is carried out in the presence of a base comprising K2CO3, CH3CO2K, K3PO4, KOtBu, Na2CO3, NaHCO3, NaOMe, Cs2CO3, Ag3PO4, Ag2O, Tl2CO3, TlOEt, TlOH, t - BuNH2, KOH, NaOH, LiOH, Ba(OH)2 or a combination thereof.

15. The method according to claim 11, wherein the catalyst comprises a metal selected from Pd, Cu or Ni.

16. The method according to claim 15, wherein the catalyst comprises at least two metal atoms.

17. The method according to claim 15, wherein the catalyst is a Pd catalyst selected from the following: Pd(PPh3)2Cl2 [bis(triphenylphosphine)palladium(II) dichloride]; Pd(PPh3)4 [tetrakis(triphenylphosphine)palladium(0)]; Pd(OAc)2 [palladium(II) diacetate]; XPhos Pd-G3 [(2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-aminobiphenyl)]palladium(II) methanesulfonate]; SPhos-Pd-G2 [Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-aminobiphenyl)]palladium(II)]; Pd G3 [Methanesulfonate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II), [(di(1-adamantyl)-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate]; APhos Pd G3 [Palladium G3-(4-(N,N-dimethylamino)phenyl)di-tert-butylphosphine, [4-(di-tert-butylphosphino)-N,N-dimethylaniline-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate]; P(Cy3)Pd-G3 [(Tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate]; Allylpalladium(II) chloride dimer (Bis(allyl)dichlorodipalladium); or Pd(dppf)Cl2 [1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium(II)].

18. The method according to claim 11, wherein the compounds of formula (II) and formula (III) are present in a molar ratio of 1:10 to 10:

1.

19. The method according to claim 11, wherein the compounds of formula (II) and formula (III) are independently present in an amount of 0.01 to 1 mol / L of solvent.

20. The method according to claim 11, wherein the catalyst is present in an amount of 0.001 to 1 molar equivalent relative to the compound of formula (II) or formula (III).

21. The method according to claim 14, wherein the base is present in an amount of 0.1 to 10 molar equivalents relative to the compound of formula (II) or formula (III).

22. A compound of formula (V), wherein R 4 is hydrogen, a substituted or unsubstituted linear or branched C1-C8 alkanoyl group, a substituted or unsubstituted linear or branched C2-C8 alkenoyl group, a substituted or unsubstituted linear or branched C2-C8 alkynoyl group, a substituted or unsubstituted cycloalkanoyl group, a substituted or unsubstituted arylcarbonyl group, a substituted or unsubstituted heterocyclocarbonyl group, a substituted or unsubstituted heteroarylcarbonyl group, or a C1-C8 alkanoyl group containing a heteroatom; and wherein Y is -CN or -CONH2.

23. The compound according to claim 22, wherein R 4 is hydrogen.

24. The compound according to claim 22, wherein R 4 is an acetyl group.

25. A method for preparing the A polymorph of tretinoin-HCl, comprising: a) Providing tretinoin according to the method of any one of claims 1 to 21; b) Adjusting the pH of tretinoin to a pH of 2 to 4 to obtain a tretinoin salt; and c) Suspending the tretinoin salt in methyl ethyl ketone to obtain the A polymorph of tretinoin, which shows an X-ray powder diffraction pattern having characteristic peaks at reflection angles 2θ of 7.6, 11.5, 15.4, 21.1 and 23.2 degrees.

26. A method for preparing the B polymorph of tretinoin-HCl, comprising: a) Providing tretinoin according to the method of any one of claims 1 to 21; b) Adjusting the pH of tretinoin to a pH of 2 to 4 to obtain a tretinoin salt; and c) Suspending the tretinoin salt in a solvent comprising acetonitrile, ethyl acetate, tetrahydrofuran, 1-butanol; or dissolving the tretinoin salt in methanol to obtain the B polymorph of tretinoin, which shows an X-ray powder diffraction pattern having characteristic peaks at reflection angles 2θ of 12.6, 19.5, 19.8, 24.6 and 29.5 degrees.

27. A method for preparing the C polymorph of tretinoin-HCl, which comprises: a) providing tretinoin according to the method of any one of claims 1 to 21; b) adjusting the pH of tretinoin to a pH of 2 to 4 to obtain a tretinoin salt; and c) suspending the tretinoin salt in ethylene glycol to obtain the C polymorph of tretinoin, which shows an X-ray powder diffraction pattern having characteristic peaks at reflection angles 2θ of 7.9, 15.6, 20.0, 23.6 and 27.8 degrees.

28. The method according to any one of claims 25 to 27, wherein the pH is adjusted using hydrochloric acid (HCl).

29. A method for preparing the D polymorph of tretinoin, which comprises: a) providing tretinoin according to the method of any one of claims 1 to 21; and b) adjusting the pH of tretinoin to a pH of 5 to 6 to obtain the D polymorph of tretinoin, which shows an X-ray powder diffraction pattern having characteristic peaks at reflection angles 2θ of 8.5, 16.2, 18.6 and 23.1 degrees.

30. The method according to claim 29, wherein the pH is adjusted using an acid, the acid comprising HCl, acetic acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid or any mixture thereof.

31. A method for preparing the E polymorph of tretinoin, which comprises: a) providing tretinoin according to the method of any one of claims 1 to 21; b) adjusting the pH of tretinoin to a pH of 5 to 6 to obtain tretinoin; and c) suspending tretinoin in methanol to obtain the E polymorph of tretinoin, which shows an X-ray powder diffraction pattern having characteristic peaks at reflection angles 2θ of 8.6, 12.8, 14.2, 17.9 and 24.0 degrees.

32. A method for preparing the F polymorph of tretinoin, which comprises: a) providing tretinoin according to the method of any one of claims 1 to 21; b) adjusting the pH of tretinoin to a pH of 5 to 6 to obtain tretinoin; and c) dissolving tretinoin in isopropanol to obtain the F polymorph of tretinoin, which shows an X-ray powder diffraction pattern having characteristic peaks at reflection angles 2θ of 5.2, 6.3, 14.9, 18.0 and 19.1 degrees.

33. A method for preparing the G polymorph of the Na salt of tretinoin, which comprises: a) providing tretinoin according to the method of any one of claims 1 to 21; and b) adjusting the pH of tretinoin to a pH of 9 to 12 to obtain the G polymorph of the tretinoin salt, which shows an X-ray powder diffraction pattern having characteristic peaks at reflection angles 2θ of 10.6, 11.5, 17.4 and 19.7 degrees.

34. The method according to claim 33, wherein the pH is adjusted using sodium hydroxide.

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