Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/402—1-aryl substituted, e.g. piretanide
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• the present disclosure provides a process for the preparation of Trifarotene.
• the disclosure also provides novel intermediates in the process described herein. Also provided are novel polymorphs of Trifarotene.
• Trifarotene is a topical retinoid that can selectively target retinoic acid receptor (RAR) gamma, the most common RAR found in the skin. Trifarotene is prescribed for treatment of acne vulgaris and was first approved in the United States in October 2019.
• RAR retinoic acid receptor
• the disclosure provides a process for the preparation of a compound of Formula (I) [Trifarotene], or a salt thereof comprising hydrolyzing a compound of Formula (V) wherein R 4 is hydrogen, a substituted or unsubstituted linear or branched Ci-Cx alkanoyl group, a substituted or unsubstituted linear or branched Ci-Cs alkenoyl group, a substituted or unsubstituted linear or branched Ci-Cs alkynoyl group, a substituted or unsubstituted cycloalkanoyl group, a substituted or unsubstituted aryl carbonyl group, a substituted or unsubstituted heterocyle carbonyl group, a substituted or unsubstituted heteroaryl carbonyl group, or a Ci-Cs alkanoyl group comprising a heteroatom; and wherein Y is a nitrile (CN)
• the process further comprises preparing the compound of formula (V) by hydrolyzing a compound of Formula (IV) in the presence of a base, wherein R 3 is hydrogen, a hydroxyl group, a halogen, a substituted or unsubstituted linear or branched Ci-Cs alkyl group, a substituted or unsubstituted linear or branched Ci-Cs alkenyl group, a substituted or unsubstituted linear or branched C i-Cx alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heteroaryl, or a Ci-Cs alkyl group comprising a heteroatom; and wherein Y is a nitrile (CN) or amide (CONH2); to obtain the compound of formula (V) by hydrolyzing a compound
• R 3 is methyl.
• the hydrolysis is performed in the presence of a solvent comprising water, methanol (MeOH), ethanol (EtOH), propanol (PrOH), isopropanol (IP A), or any mixture thereof.
• the solvent comprises water and ethanol.
• the base comprises sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), barium hydroxide (Ba(OH)2), or any mixture thereof.
• 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).
• 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).
• the base is present at 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).
• the process further comprises preparing the compound of formula (IV) by reacting a compound of formula (II) wherein R 1 and R 2 are independently hydrogen or a linear or branched C1-C3 alkyl, wherein R 1 and R 2 can be the same or different; or R 1 and R 2 together form a pinacolate, with a compound of formula (III)
• the R 3 is methyl and X is iodine.
• the reaction is performed in the presence of a solvent comprising toluene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dioxane, n-butanol (n-BuOH), isopropanol (IP A), dimethyl ether (DME), diethyl ether, or any mixture thereof.
• a solvent comprising toluene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dioxane, n-butanol (n-BuOH), isopropanol (IP A), dimethyl ether (DME), diethyl ether, or any mixture thereof.
• the reaction is performed in the presence of a base comprising K2CO3, CH3CO2K, K3PO4, KOtBu, Na 2 C0 3 , NaHCCh, NaOMe, CS2CO3, Ag 3 P0 4 , Ag 2 0, TI2CO3, TIOEt, TIOH, t-BuNEb, KOH, NaOH, LiOH, Ba(OH) 2 , or combination thereof.
• a base comprising K2CO3, CH3CO2K, K3PO4, KOtBu, Na 2 C0 3 , NaHCCh, NaOMe, CS2CO3, Ag 3 P0 4 , Ag 2 0, TI2CO3, TIOEt, TIOH, t-BuNEb, KOH, NaOH, LiOH, Ba(OH) 2 , or combination thereof.
• the catalyst comprises a metal selected from Pd, Cu, or Ni. In some embodiments, the catalyst comprises at least two atoms of the metal. In some embodiments, the catalyst is a Pd catalyst selected from Pd(PPh 3 )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-l,l'-biphenyl)[2-(2'- amino-l,l'-biphenyl)]palladium(II) methanesulfonate]; SPhos-Pd-G2 [chloro(2- dicyclohexylphosphino
• 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) are independently present in an amount of about 0.01 to about 1 mol/L (solvent), preferably about 0.05 to about 0.5 mol/L (solvent), more preferably about 0.1 to about 0.4 mol/L (solvent).
• the catalyst is present at about 0.001 to about 1 molar equivalents relative to the compounds of formula (II) or formula (III), preferably about 0.002 to about 0.5 molar equivalents relative to the compounds of formula (II) or formula (III), more preferably about 0.003 to about 0.1 molar equivalents relative to the compounds of formula (II) or formula (III).
• the base is present at about 0.1 to about 10 molar equivalents relative to the compounds of formula (II) or formula (III), preferably about 1 to about 6 molar equivalents relative to the compounds of formula (II) or formula (III), more preferably about 2 to about 4 molar equivalents relative to the compounds of formula (II) or formula (III).
• the present disclosure provides a process for the preparation of a compound of formula (I) [Trifarotene], or a salt thereof comprising reacting a compound of formula (II) wherein R 1 and R 2 are independently hydrogen or a linear or branched C1-C3 alkyl, wherein R 1 and R 2 can be the same or different; or R 1 and R 2 together form a pinacolate, with a compound of formula (III) wherein R 3 is a substituted or unsubstituted linear or branched Ci-Cs alkyl, a substituted or unsubstituted linear or branched Ci-Cs alkenyl group, a substituted or unsubstituted linear or branched Ci-Cs alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or un
• R 1 , R 2 , R 3 , R 4 , X, and Y and the various reactions and conditions are further described herein.
• R 3 is methyl, X is iodine, and Y is nitrile.
• R 3 is methyl and X is iodine.
• the present disclosure provides a compound of Formula (III) wherein R 3 is a substituted or unsubstituted linear or branched Ci-Cs alkyl group, substituted or unsubstituted linear or branched Ci-Cs alkenyl group, substituted or unsubstituted linear or branched Ci-Cs alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heteroaryl, or a Ci-Cs alkyl group comprising a heteroatom; wherein X is a halogen or triflate; and wherein Y is a nitrile or amide.
• R 3 is methyl and X is iodine.
• the present disclosure provides a compound of Formula (V) wherein R 4 is hydrogen, a substituted or unsubstituted linear or branched Ci-Cs alkanoyl group, a substituted or unsubstituted linear or branched Ci-Cs alkenoyl group, a substituted or unsubstituted linear or branched Ci-Cs alkynoyl group, a substituted or unsubstituted cycloalkanoyl group, a substituted or unsubstituted aryl carbonyl group, a substitute or unsubstituted heterocyle carbonyl group, a substituted or unsubstituted heteroaryl carbonyl group, or a Ci-Cs alkanoyl group comprising a heteroatom; and wherein Y is a nitrile (CN) or amide (CONH2); and wherein Y is nitrile or amide.
• R 4 is hydrogen.
• the disclosure provides a Form A polymorph of the compound of Formula (I) [Trifarotene-HCl], wherein the Form A polymorph shows an X-ray powder diffraction (XRPD) pattern having characteristic peaks at reflection angle 2Q of 7.6, 11.5, 15.4, 21.1, and 23.2 degrees.
• the Form A polymorph further shows peaks at peaks at 8.6, 9.0, 17.7, 18.3, 19.5, and 22.5 degrees.
• the disclosure provides a Form B polymorph of the compound of Formula (I) [Trifarotene - HC1], wherein the Form B polymorph shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Q of 12.6, 19.5, 19.8, 24.6, and 29.5 degrees.
• the Form B polymorph further shows peaks at 8.4, 12.0, 17.4, 21.1, 23.2, 31.0, and 32.1 degrees.
• the disclosure provides a Form C polymorph of the compound of Formula (I) [Trifarotene-HCl], wherein the Form C polymorph shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Q of 7.9, 15.6, 20.0, 23.6, and 27.8 degrees. In some embodiments, the Form C polymorph further shows peaks at 12.1, 16.4, 17.4, and 28.8 degrees.
• the disclosure provides a Form D polymorph of the compound of Formula (I) [Trifarotene], wherein the Form D polymorph shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Q of 8.5, 16.2, 18.6, and 23.1 degrees. In some embodiments, the Form D polymorph further shows peaks at 12.2, 12.8, and 14.1 degrees.
• the disclosure provides a Form E polymorph of the compound of Formula (I) [Trifarotene], wherein the Form E polymorph shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Q of 8.6, 12.8, 14.2, 17.9, and 24.0 degrees. In some embodiments, the Form E polymorph further shows peaks at 10.6, 15.3, 16.3, 19.3, and 22.0 degrees.
• the disclosure provides a Form F polymorph of the compound of Formula (I) [Trifarotene], wherein the Form F polymorph shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 20 of 5.2, 6.3, 14.9, 18.0, and 19.1 degrees. In some embodiments, the Form F polymorph further shows peaks at 8.5, 15.6, 16.3, 18.5, and 22.9 degrees.
• the disclosure provides a Form G polymorph of the compound of Formula (I) [Trifarotene Na salt], wherein the Form G polymorph shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Q of 10.6, 11.5, 17.4, and 19.7 degrees. In some embodiments, the Form G polymorph further shows peaks at 8.9, 10.0, 14.7, and 16.2 degrees.
• the disclosure provides a process for preparing a Form A polymorph of Trifarotene-HCl, comprising: (a) providing trifarotene according to a process described herein; (b) adjusting 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 a Form A polymorph of trifarotene.
• the pH is adjusted using HC1.
• the disclosure provides a process for preparing a Form B polymorph of Trifarotene-HCl, comprising: (a) providing trifarotene according to a process described herein; (b) adjusting 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 a solvent comprising acetonitrile, ethyl acetate, tetrahydrofuran, 1-butanol; or dissolving the trifarotene salt in methanol, to obtain a Form B polymorph of trifarotene.
• the pH is adjusted using HC1.
• the disclosure further provides a process for preparing a Form C polymorph of Trifarotene-HCl, comprising: providing trifarotene according to a process described herein; (b) adjusting 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 obtain a Form C polymorph of trifarotene.
• the pH is adjusted using HC1.
• the disclosure further provides a process for preparing a Form D polymorph of Trifarotene, comprising: (a) providing trifarotene according to a process described herein; and (b) adjusting pH of the trifarotene to a pH of about 5 to about 6, to obtain a Form D polymorph of trifarotene.
• the pH is adjusted using HC1, acetic acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, trifluoroacetic acid, p-toluene sulfonic acid, methane-sulfonic acid, or any mixture thereof.
• the disclosure further provides a process for preparing a Form E polymorph of Trifarotene, comprising: (a) providing trifarotene according to a process described herein; (b) adjusting pH of the trifarotene to a pH of about 5 to about 6, to obtain trifarotene; and (c) suspending the trifarotene in methanol, to obtain a Form E polymorph of trifarotene.
• the disclosure further provides a process for preparing a Form F polymorph of Trifarotene, comprising: (a) providing trifarotene according to a process described herein; (b) adjusting pH of the trifarotene to a pH of about 5 to about 6, to obtain trifarotene; and (c) dissolving the trifarotene in isopropanol, to obtain a Form F polymorph of trifarotene.
• the disclosure further provides a process for preparing a Form G polymorph of Trifarotene Na salt, comprising: (a) providing trifarotene according to a process of described herein; and (b) adjusting pH of the trifarotene to a pH of about 9 to about 12, to obtain a Form G polymorph of trifarotene.
• the pH is adjusted using sodium hydroxide.
• FIG. 1 shows an X-ray powder diffraction (XRPD) spectra of Trifarotene HC1 salt as described in embodiments herein.
• FIG. 2 shows an XRPD spectra of Trifarotene-HCl, Form A polymorph, as described in embodiments herein.
• FIG. 3 shows an XRPD spectra of Trifarotene-HCl, Form B polymorph, as described in embodiments herein.
• FIG. 4 shows an XRPD spectra of Trifarotene-HCl, Form C polymorph, as described in embodiments herein.
• FIG. 5 shows an XRPD spectra of Trifarotene, Form D polymorph, as described in embodiments herein.
• FIG. 6 shows an XRPD spectra of Trifarotene, Form E polymorph, as described in embodiments herein.
• FIG. 7 shows an XRPD spectra of Trifarotene, Form F polymorph, as described in embodiments herein.
• FIG. 8 shows an XRPD spectra of Trifarotene Na salt, Form G polymorph, as described in embodiments herein.
• FIG. 9 is an exemplary process for the preparation of Trifarotene [Formula (I)] as described in embodiments herein.
• the present disclosure relates to methods for the preparation of Trifarotene.
• the methods provided herein advantageously simplify the preparation process by reducing or eliminating reaction steps that require harsh conditions (e.g., performed in extreme heat (e.g., > 50°C) or cold (e g ⁇ , ⁇ -10°C)).
• a” or “an” may mean one or more.
• the words “a” or “an” when used in conjunction with the word “comprising,” the words “a” or “an” may mean one or more than one.
• “another” or “a further” may mean at least a second or more.
• the term “about” is used to indicate that a value includes the inherent variation of error for the method/device being employed to determine the value, or the variation that exists among the study subjects. Typically, the term “about” is meant to encompass approximately or less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% or higher variability, depending on the situation. In some embodiments, one of skill in the art will understand the level of variability indicated by the term “about,” due to the context in which it is used herein. It should also be understood that use of the term “about” also includes the specifically recited value.
• compositions e.g., formulations
• compositions e.g., formulations
• between is a range inclusive of the ends of the range.
• a number between x and y explicitly includes the numbers x and y, and any numbers that fall within x and y.
• alkyl when used alone or in combination with other groups or atoms, refers to a saturated linear or branched chain including 1 to about 10 hydrogen-substituted carbon atoms.
• Alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, isobutyl, t-butyl, 2,2-dimethylbutyl, n-pentyl, 2-methylpentyl, 3- methylpentyl, 4-methylpentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
• alkenyl refers to a partially unsaturated linear or branched chain including about 2 to about 10 hydrogen-substituted carbon atoms that contain at least one double bond.
• Alkenyl groups include, e.g., vinyl, allyl, 2-methylprop-l-enyl, but-l-enyl, but-2-enyl, but-3-enyl, buta-l,3-dienyl, penta-l,3-dienyl, penta-2,4-dienyl, 2-methylbut-l-enyl, 2- methylpent-l-enyl, 4-methylpent-l-enyl, 4-methylpent-2-enyl, 2-methylpent-2-enyl, 4- methylpenta-l,3-dienyl, hexen-l-yl, hepten-l-yl, octen-l-yl, nonen-l-yl, decen
• alkynyl refers to a partially unsaturated linear or branched chain including about 2 to about 10 hydrogen-substituted carbon atoms that contains at least one triple bond.
• Alkynyl groups include, e.g., ethynyl, 1-propynyl, 2-propynyl, 2-methylprop- 1-ynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1,3-butadiynyl, 3-methylbut-l-ynyl, 4-methylbut-ynyl, 4- methylbut-2-ynyl, 2-methylbut-l-ynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1,3- pentadiynyl, 1,4-pentadiynyl, 3-methylpent-l-ynyl, 4-methylpent-2-
• cycloalkyl refers to a saturated or unsaturated ring including about 3 to about 10 carbon atoms, that may optionally be substituted with one or more identical or different substituents, e.g., one to three, one to six, one to eight, or one to ten substituents.
• Cycloalkyl groups include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononyl, cyclodecyl, and the like.
• aryl refers to an aromatic mono- or bicyclic group containing from about 5 to about 14 carbon atoms that may be optionally fused with a fully or partially saturated or unsaturated carbocyclic ring.
• Aryl groups include, e.g., phenyl, naphthyl, indanyl, and the like.
• cycloalkyl refers to an alkane containing one or more rings of carbon atoms.
• a “heterocycle” refers to a monocyclic non-aromatic hydrocarbon ring containing about 3 to about 10 carbon atoms, or a bicyclic non-aromatic hydrocarbon ring system containing about 7 to about 14 carbon atoms, wherein one or more of the carbon atoms of the in the hydrocarbon ring or ring system is replaced by a one heteroatom.
• heterocycles include but are not limited to azepan-l-yl, piperidinyl, e.g., piperidin-1- yl and piperidin-4-yl, piperazinyl, e.g., N-piperazinyl and l-alkylpiperazine-4-yl, morpholine-4- yl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiophen, sulfolanyl, sulfolenyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxazolidinon-yl.
• heteroaryl refers to an aromatic compound containing at least one heteroatom.
• heteroaryl groups include but are not limited to pyrrolyl, dihydropyrrolyl, pyrrolidinyl, indolyl, isoindolyl, indolizinyl, imidazolyl, pyrazolyl, benzimidazolyl, imidazo(l,2-a)pyridinyl, indazolyl, purinyl, pyrrolo(2,3-c)pyridinyl, pyrrolo(3,2- c)pyridinyl, pyrrolo(2,3-b)pyridinyl, pyrazolo(l,5-a)pyridinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, 1,3,4-oxadiazolyl, 1,2,5-o
• any of the carbon chain substituents described herein e.g., alkyl, alkanoyl, alkenoyl, alkynoyl, alkanoyl, etc.
• the substituents described herein can be “substituted or unsubstituted.”
• substituted refers to the substitution of a hydrogen on the substituent with a different group, e.g., a hydroxyl, halide, alkyl (e.g., Ci-6 alkyl), alcohol, ketone, and the like.
• unsubstituted refers where the substituent has not had a hydrogen substituted with a different group.
• a “linear” molecule contains a single backbone.
• a “linear Ci-Cn” molecule includes one to n number of carbon atoms, wherein each carbon atom is bound to its two neighbors and to two hydrogen atoms (with the exception of the terminal carbons, which are bound to only one carbon atom and three hydrogen atoms).
• a “branched” molecule contains a nonlinear backbone, wherein branches can sprout from one or more atoms of the main backbone.
• a “branched Ci-Cn” molecule is derived from a linear Ci-C n molecule, except that at least one of the hydrogen atoms bound to at least one of the carbons is replaced with a substituent, e.g., an alkyl group.
• any of the cyclic groups described herein can be substituted or unsubstituted.
• a substituted cycloalkane can have substituents at any of the atoms forming the ring.
• Substituents can include any of the groups described herein, e.g., alkyl, alkenyl, alkynyl, etc.
• the present disclosure provides a process for the preparation of a compound of Formula (I) [Trifarotene], or a salt thereof comprising hydrolyzing a compound of Formula (V) wherein R 4 is hydrogen, a substituted or unsubstituted linear or branched Ci-Cx alkanoyl group, a substituted or unsubstituted linear or branched Ci-Cx alkenoyl group, a substituted or unsubstituted linear or branched Ci-Cx alkynoyl group, a substituted or unsubstituted cycloalkanoyl group, a substituted or unsubstituted aryl carbonyl group, a substituted or unsubstituted heterocyle carbonyl group, a substituted or unsubstituted heteroaryl carbonyl group, or a Ci-Cx alkanoyl group comprising a heteroatom; and wherein Y is a nitrile (CN)
• the compound of Formula (I) is Trifarotene. In some embodiments, the compound of Formula (I) is Trifarotene-HCl. In some embodiments, the compound of Formula (I) is a Trifarotene Na salt.
• 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 is an acetyl group (-COCH3). In some embodiments, the compound of Formula (V) is selected from the following: [0059] In some embodiments, Y is a nitrile. In some embodiments, Y is an amide. In some embodiments, R 4 is hydrogen, and Y is a nitrile or amide. In some embodiments, R 4 is an alkanoyl, and Y is a nitrile or amide. In some embodiments, R 4 is formyl, and Y is a nitrile or amide. In some embodiments, R 4 is acetyl, and Y is a nitrile or amide.
• R 4 is an alkenoyl, and Y is a nitrile or amide. In some embodiments, R 4 is an alkynoyl, and Y is a 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 an unsubstituted cycloalkanoyl, and Y is a nitrile or amide. In some embodiments, R 4 is a substituted aryl carbonyl group, and Y is a nitrile or amide.
• R 4 is an unsubstituted aryl carbonyl group, and Y is a nitrile or amide. In some embodiments, R 4 is a substituted heterocyle carbonyl group, and Y is a nitrile or amide. In some embodiments, R 4 is an unsubstituted heterocyle carbonyl group, and Y is a nitrile or amide. In some embodiments, R 4 is a substituted heteroaryl carbonyl group, and Y is a nitrile or amide. In some embodiments, R 4 is an unsubstituted heteroaryl carbonyl group, and Y is a nitrile or amide. In some embodiments, R 4 is a Ci-Cs alkanoyl group comprising a heteroatom, and Y is a nitrile or amide.
• the compound of Formula (V) is selected from the following: [0062]
• the term “hydrolysis” or variants thereof such as “hydrolyze” or “hydrolyzing,” refers to a reaction in which water is a reactant and becomes part of the reaction product, typically as a hydroxyl (-OH) group. Hydrolysis of nitriles or amides can form a carboxylic acid (-COOH). In some embodiments, hydrolysis is performed in the presence of water and a co-solvent.
• co-solvents that can be used with water for hydrolysis reactions include but are not limited to alcohols, e.g., methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, sec-butanol, and isobutyl alcohol; methylene chloride; acetonitrile; ethyl acetate; and tetrahydrofuran (THF).
• the hydrolysis is performed in the presence of water and an alcohol.
• the alcohol is methanol (MeOH), ethanol (EtOH), propanol (PrOH), isopropanol (IP A), or any mixture thereof.
• the hydrolysis is performed in the presence of water and ethanol.
• hydrolysis is performed further in the presence of an acid or a base.
• the acid comprises hydrochloric acid (HC1), sulfuric acid (H2SO4), nitric acid (HNO3), hydrobromic acid (HBr), hydroiodic acid (HI), perchloric acid (HClCri), chloric acid (HClCh), sulfurous acid (H2SO3), methanoic acid (HCO2H), phosphoric acid (H3PO4), nitrous acid (HNO2), hydrofluoric acid (HF), or any mixture thereof.
• the base comprises sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), barium hydroxide (Ba(OH)2), or any mixture thereof.
• R 4 is hydrogen, and Y is hydrolyzed. In some embodiments, Y is hydrolyzed to form a carboxylic acid. In some embodiments, R 4 comprises a carbonyl as described herein, and the carbonyl together with the oxygen attached thereto are hydrolyzed to generate a hydroxyl group. In some embodiments, R 4 and Y are capable of being hydrolyzed under the same reaction conditions. In some embodiments, R 4 and Y are hydrolyzed simultaneously.
• 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 performed in an acidic condition.
• the hydrolysis is performed at a pH of about 4 to about 6.5, about 4.2 to about 6.2 about 4.5 to about 6, about 4.7 to about 5.7, or about 5 to about 5.5. In some embodiments, the hydrolysis reaction is performed at pH about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6, about 6.1, about 6.2, about 6.3, about 6.4, or about 6.5.
• the disclosure provides a process for preparing the compound of Formula (V) wherein R 4 is hydrogen.
• the compound of Formula (V) is prepared by hydrolyzing a compound of Formula (IV) in the presence of a base, wherein R 3 is hydrogen, a hydroxyl group, a substituted or unsubstituted linear or branched Ci-Cx alkyl group, a substituted or unsubstituted linear or branched C i-Cx alkenyl group, a substituted or unsubstituted linear or branched Ci-Cx alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heteroaryl, or a Ci-Cx alkyl group comprising a heteroatom; and wherein Y is a nitrile (
• the ester (-COOR 3 ) of the compound of Formula (IV) is hydrolyzed to form a hydroxyl group (-OH).
• R 4 of the compound of Formula (V) is hydrogen.
• Y in the compound of Formula (IV) is as defined herein for the compound of Formula (V).
• R 3 is hydrogen, and Y is a nitrile or amide.
• R 3 is methyl, and Y is a nitrile or amide.
• R 3 is hydroxyl, and Y is a nitrile or amide.
• R 3 is methyl, and Y is a nitrile.
• the hydrolysis of the compound of Formula (IV) is performed in the presence of water and a co-solvent.
• exemplary co-solvents are provided herein.
• the hydrolysis of the compound of Formula (IV) is performed in a solvent comprising water, methanol (MeOH), ethanol (EtOH), propanol (PrOH), isopropanol (IP A), or any mixture thereof.
• the solvent comprises water and ethanol.
• the hydrolysis of the compound of Formula (IV) is performed in the presence of a base.
• a base for hydrolysis reactions are provided herein.
• the base for the hydrolysis of the compound of Formula (IV) comprises sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), barium hydroxide (Ba(OH)2), or any mixture thereof.
• 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).
• 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).
• the disclosure further provides a process for preparing the compound of Formula (IV), comprising reacting a compound of Formula (II) (Formula II), wherein R 1 and R 2 are independently hydrogen, a linear or branched C1-C3 alkyl, or a pinacolate, and wherein R 1 and R 2 can be the same or different, or R 1 and R 2 together form a pinacolate, with a compound of Formula (III) (Formula III), in the presence of a catalyst, wherein R 3 is hydrogen, a hydroxyl group, a linear or branched Ci- C8 alkyl, a linear or branched Ci-Cx alkenyl group, a linear or branched C i-Cx alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsub
• 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 a linear or branched C1-C3 alkyl group. In some embodiments, R 1 and R 2 of the compound of Formula (II) together form a pinacolate.
• the compound of Formula (II) is selected from the following: [0074] R 3 and Y of the compound of Formula (III) are defined as above for the compound of Formula (IV).
• X of the compound of Formula (III) is a leaving group for a Suzuki coupling reaction. Examples of leaving groups for Suzuki reactions are further provided in, e.g., Liu et ah, OrgLett 7(6): 1149-1151 (2005); El-Berjawi et ah, Dyes Pigments 159:551-556 (2016); Chemler et ah, Angew Chem Int Ed 40 :4544 (2001).
• X is a halogen, e.g., fluorine, chlorine, bromine, or iodine.
• X is a triflate (-OSO2CF3; also abbreviated as -OTf) group.
• R 3 is hydrogen, Y is a nitrile or amide, and X is a halogen or triflate.
• R 3 is methyl, Y is a nitrile or amide, and X is a halogen or triflate.
• R 3 is a hydroxyl, Y is a nitrile or amide, and X is a halogen or triflate.
• R 3 is methyl, Y is a nitrile, and X is iodine.
• the compound of Formula (III) is selected from the following: [0076]
• the reaction between the compounds of Formula (II) and Formula (III) is performed in the presence of a solvent comprising toluene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dioxane, n-butanol (n-BuOH), isopropanol (IP A), ethanol (EtOH), methanol (MeOH), dimethyl ether (DME), diethyl ether, or any mixture thereof.
• the reaction between the compounds of Formula (II) and Formula (III) is performed using water as solvent.
• the reaction between the compounds of Formula (II) and Formula (III) is performed in a solvent-free manner, e.g., the reaction is microwave-assisted (see, e.g., Nun et ah, Synlett 11:1761-1764 (2009)).
• the reaction between the compounds of Formula (II) and Formula (III) is performed in the presence of a base comprising potassium carbonate (K2CO3), potassium acetate (CH3CO2K), potassium phosphate (K 3 PO4), potassium tert-butoxide (KOtBu), sodium carbonate (Na2CCh), sodium bicarbonate (NaHCCh), sodium methoxide (NaOMe), sodium tert- butoxide (NaOtBu) cesium carbonate (CS2CO 3 ), silver phosphate (Ag 3 PC>4), silver oxide (Ag20), thallium carbonate (TI2CO 3 ), thallium ethoxide (TIOEt), tert-butylamine (t-BuNFh), potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), barium hydroxide (Ba(OH)2), thallium hydroxide (TIOH), or combination thereof.
• a base comprising potassium carbonate (K
• 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).
• the catalyst comprises a metal selected from Pd, Cu, or Ni.
• the catalyst comprises 1 to 6 atoms of the metal.
• the catalyst comprises 2 to 5 atoms of the metal.
• the catalyst comprises 2 to 4 atoms of the metal.
• the catalyst comprises 1, 2, 3, 4, 5, or 6 atoms of the metal. Palladium-catalyzed coupling reactions are further described, e.g., in US 2006/0264629 and US 2010/0184739.
• the catalyst is a palladium catalyst.
• the palladium catalyst is Pd(PPh 3 )2Cl2 [bis(triphenylphosphine)palladium(II) dichloride]; Pd(PPh 3 )4 [tetrakis(triphenylphosphine)palladium(0)]; Pd(OAc)2 [palladium(II) diacetate]; XPhos Pd-G3 [(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'-amino-l,l'- biphenyl)]palladium(II) methanesulfonate]; SPhos-Pd-G2 [chloro(2-dicyclohexylphosphino-2',6'- dimethoxy-l,l'-biphenyl)[2-(
• the catalyst is a copper catalyst.
• the copper catalyst is copper(I) chloride, [( -(di-/c77-butylphosphi no)-A f , A-di methyl aniline)copper iodide]2, [( -(di-/c77-butylphosphino)-A f ,A-dimethylaniline)copper fluoride]2.
• the catalyst is a nickel catalyst.
• the nickel catalyst is NiCh, NiBr2, Nib, G3DenP-Ni, (dppf)Ni(cinnamyl)Cl, (PCy3)2NiCl2, or Ni(cod)2.
• Further exemplary catalysts are provided in, e.g., Tasker et ah, Nature 509(7500):299-309 (2014); Yang et ah, Angew Chem Int Ed Engl 50(17):3904-3907 (2011); Barder et ah, J Am Chem Soc 127(13):4685-4696 (2005); Bedford et ah, Chem Commun (Camb) 42:6430-6432 (2009); and Catalysts vol. 9, ISSN 2073- 4344 (2019).
• the reaction between the compounds of Formula (II) and Formula (III) is performed further in the presence of a ligand.
• the ligand is a phosphine ligand, a carbon ligand, or a nitrogen ligand.
• the ligand is PPh3, PCy3, P(o-tolyl)3, P(i-Pr)3, P(0-Pr-i)3, n-BuP(l-Ad)2, P(t-Bu)2(p-NMe2-Ph), a dialkylbiaryl ligand (e.g., as described in Martin et ak, Acc Chem Res 41:1461 (2008)), a bidentate phosphine ligand such as DPPF, DPPE or DPPP, a carbene-type ligand (e.g., as described in Kuwano et ak, OrgLett 7:945 (2005)), an olefin-type ligand (e.g., as described in Tao et ak, J Org Chem 69:4330 (2004)), an amine, or imine (e.g., as described in Tao et ak, J Org Chem 69:4330 (2004)).
• the ligand and catalyst are provided in the reaction as a preformed complex.
• Pd(PPh3)4 includes both a palladium catalyst and phosphine ligand.
• the process for preparing a compound of Formula (IV) comprises preparing a catalyst comprising a metal and a ligand.
• the reaction does not include a catalyst. In some embodiments, the reaction does not include a ligand.
• Further exemplary reaction conditions are discussed in, e.g., Suzuki, J Or ganometallic Chem 576:147-168 (1999); Miyaura et ak, Chem Rev 95:2457-2483 (1995); Chemler et al., Angew Chem Int Ed Engl 40:4544-4568 (2001); Franzen, Can J Chem 78:957-962 (2000); Suzuki, Proc Jpn Acad, Ser B. 80(8):359 (2004); and Paul et al., RSC Adv 5:42193 (2015).
• the compounds of Formula (II) and Formula (III) are added to the reaction at 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.
• the compounds of Formula (II) and (III) are added 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).
• the catalyst is added to the reaction at 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 compounds of Formula (II) or Formula (III).
• the catalyst is added to the reaction at 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 equivalents relative to the compounds of Formula (II) or Formula (III).
• the base is added to the reaction at a 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 compounds of Formula (II) or Formula (III). In some embodiments, the base is added to the reaction at 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 compounds of Formula (II) or Formula (III).
• the disclosure provides a process for the preparation of a compound of formula (I) [Trifarotene], or a salt thereof comprising reacting a compound of formula (II) wherein R 1 and R 2 are independently hydrogen or a linear or branched C1-C3 alkyl, wherein R 1 and R 2 can be the same or different; or R 1 and R 2 together form a pinacolate, with a compound of formula (III) wherein R 3 is a substituted or unsubstituted linear or branched Ci-Cs alkyl, a substituted or unsubstituted linear or branched Ci-Cs alkenyl group, a substituted or unsubstituted linear or branched Ci-Cs alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsub
• R 1 , R 2 , R 3 , R 4 , X, and Y and the various reactions and conditions are further described herein.
• R 3 is methyl
• X is iodine
• Y is nitrile.
• the disclosure provides a process for preparing a compound of Formula (II) wherein R 1 and R 2 are independently hydrogen or a linear or branched C1-C3 alkyl, wherein R 1 and R 2 can be the same or different; or R 1 and R 2 together form a pinacolate, comprising reacting with a compound comprising -R'OBOR 2 - in the presence of a salt and a catalyst, wherein R 1 and R 2 are defined as above for the compound of Formula (II).
• the catalyst is a palladium catalyst.
• the catalyst comprises P(tBu)3.
• the catalyst is Pd-162 ([P(tBu)3] Pd(crotyl)Cl), Pd-168 ([P(tBu)3] Palladacycle), or Pd-216 ( ⁇ Pd(p- I) [P(t-Bu)3] ⁇ 2).
• the reaction is performed 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.
• the process for preparing the compound of Formula (II) provided herein is performed at room temperature. When compared with previously described methods, e.g., as described in WO 2006/066978, which perform the reaction under harsh conditions (e.g., at -78°C), the present process greatly reduces the complexity and shortens preparation time.
• the present disclosure provides novel compounds.
• the novel compounds described herein are used in the preparation of Trifarotene.
• the novel compounds provided herein can advantageously simplify the Trifarotene preparation process.
• the disclosure provides a compound of Formula (III) wherein R 3 is a substituted or unsubstituted linear or branched C i-Cx alkyl group, substituted or unsubstituted linear or branched Ci-Cs alkenyl group, substituted or unsubstituted linear or branched Ci-Cs alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heteroaryl, or a Ci-Cs alkyl group comprising a heteroatom; wherein X is a halogen or triflate; and wherein Y is a nitrile or amide. R 3 , X, and Y are further described herein.
• the compound of Formula (III) is selected from the following:
• the compound of Formula (III) is prepared by reacting with R 3 C02CH2Br, wherein X, Y, and R 3 are defined as above for the compound of Formula (III), in the presence of a strong base.
• the strong base is sodium hydride.
• the disclosure provides a compound of Formula (V) wherein R 4 is hydrogen, a substituted or unsubstituted linear or branched Ci-Cs alkanoyl group, a substituted or unsubstituted linear or branched Ci-Cs alkenoyl group, a substituted or unsubstituted linear or branched Ci-Cs alkynoyl group, a substituted or unsubstituted cycloalkanoyl group, a substituted or unsubstituted aryl carbonyl group, a substitute or unsubstituted heterocyle carbonyl group, a substituted or unsubstituted heteroaryl carbonyl group, or a Ci-Cs alkanoyl group comprising a heteroatom; and wherein Y is a nitrile (CN) or amide (CONH2).
• R 4 and Y are further described herein.
• R 4 is hydrogen.
• R 4 is a substituted or unsubstituted linear or branched Ci-Cs alkanoyl group, a substituted or unsubstituted linear or branched Ci-Cs alkenoyl group, a substituted or unsubstituted linear or branched Ci-Cs alkynoyl group, a substituted or unsubstituted cycloalkanoyl group, a substituted or unsubstituted aryl carbonyl group, a substitute or unsubstituted heterocyle carbonyl group, a substituted or unsubstituted heteroaryl carbonyl group, or a Ci-Cs alkanoyl group comprising a heteroatom.
• R 4 is a unsubstituted linear or branched Ci-Cs alkanoyl group, a unsubstituted linear or branched Ci-Cs alkenoyl group, a unsubstituted linear or branched C i-Cx alkynoyl group, a unsubstituted cycloalkanoyl group, a unsubstituted aryl carbonyl group, a unsubstituted heterocyle carbonyl group, a unsubstituted heteroaryl carbonyl group, or a Ci-Cs alkanoyl group comprising a heteroatom.
• R 4 is a unsubstituted linear or branched C1-C4 alkanoyl group, a unsubstituted linear or branched C1-C4 alkenoyl group, a unsubstituted linear or branched C1-C4 alkynoyl group, or a C1-C4 alkanoyl group comprising a heteroatom.
• R 4 is acetyl
• the compound of Formula (V) is selected from the following: [0099]
• the disclosure provides novel polymorphs of the compound of Formula (I), Trifarotene.
• the novel polymorphs described herein can be used to better characterize Trifarotene and its pharmaceutical properties.
• the disclosure provides a Form A polymorph of the compound of Formula (I) [Trifarotene-HCl], wherein the Form A polymorph shows an X-ray powder diffraction (XRPD) pattern having characteristic peaks at reflection angle 2Q of 7.6, 11.5, 15.4, 21.1, and 23.2 degrees.
• the Form A polymorph further shows peaks at peaks at 8.6, 9.0, 17.7, 18.3, 19.5, and 22.5 degrees.
• An exemplary XRPD spectra for the Form A polymorph is shown in FIG. 2.
• the disclosure further provides a process for preparing a Form A polymorph of Trifarotene-HCl, comprising: (a) providing trifarotene according to a process described herein; (b) adjusting 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 a Form A polymorph of trifarotene.
• the pH is adjusted using an acid described herein.
• the pH is adjusted using HC1.
• the disclosure provides a Form B polymorph of the compound of Formula (I) [Trifarotene - HC1], wherein the Form B polymorph shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Q of 12.6, 19.5, 19.8, 24.6, and 29.5 degrees.
• the Form B polymorph further shows peaks at 8.4, 12.0, 17.4, 21.1, 23.2, 31.0, and 32.1 degrees.
• An exemplary XRPD spectra for the Form B polymorph is shown in FIG. 3.
• the disclosure further provides a process for preparing a Form B polymorph of Trifarotene-HCl, comprising: (a) providing trifarotene according to a process described herein; (b) adjusting 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 a solvent comprising acetonitrile, ethyl acetate, tetrahydrofuran, 1-butanol; or dissolving the trifarotene salt in methanol, to obtain a Form B polymorph of trifarotene.
• the pH is adjusted using an acid described herein.
• the pH is adjusted using HC1.
• the disclosure provides a Form C polymorph of the compound of Formula (I) [Trifarotene-HCl], wherein the Form C polymorph shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Q of 7.9, 15.6, 20.0, 23.6, and 27.8 degrees. In some embodiments, the Form C polymorph further shows peaks at 12.1, 16.4, 17.4, and 28.8 degrees.
• An exemplary XRPD spectra for the Form C polymorph is shown in FIG. 4.
• the disclosure further provides a process for preparing a Form C polymorph of Trifarotene-HCl, comprising: providing trifarotene according to a process described herein; (b) adjusting 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 obtain a Form C polymorph of trifarotene.
• the pH is adjusted using an acid described herein.
• the pH is adjusted using HC1.
• the disclosure provides a Form D polymorph of the compound of Formula (I) [Trifarotene], wherein the Form D polymorph shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Q of 8.5, 16.2, 18.6, and 23.1 degrees. In some embodiments, the Form D polymorph further shows peaks at 12.2, 12.8, and 14.1 degrees.
• An exemplary XRPD spectra for the Form D polymorph is shown in FIG. 5.
• the disclosure further provides a process for preparing a Form D polymorph of Trifarotene, comprising: (a) providing trifarotene according to a process described herein; and (b) adjusting pH of the trifarotene to a pH of about 5 to about 6, to obtain a Form D polymorph of trifarotene.
• the pH is adjusted using an acid described herein.
• the pH is adjusted using HC1, acetic acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, trifluoroacetic acid, p-toluene sulfonic acid, methane-sulfonic acid, or any mixture thereof.
• the disclosure provides a Form E polymorph of the compound of Formula (I) [Trifarotene], wherein the Form E polymorph shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Q of 8.6, 12.8, 14.2, 17.9, and 24.0 degrees. In some embodiments, the Form E polymorph further shows peaks at 10.6, 15.3, 16.3, 19.3, and 22.0 degrees.
• An exemplary XRPD spectra for the Form E polymorph is shown in FIG. 6.
• the disclosure further provides a process for preparing a Form E polymorph of Trifarotene, comprising: (a) providing trifarotene according to a process described herein; (b) adjusting pH of the trifarotene to a pH of about 5 to about 6, to obtain trifarotene; and (c) suspending the trifarotene in methanol, to obtain a Form E polymorph of trifarotene.
• the disclosure provides a Form F polymorph of the compound of Formula (I) [Trifarotene], wherein the Form F polymorph shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Q of 5.2, 6.3, 14.9, 18.0, and 19.1 degrees. In some embodiments, the Form F polymorph further shows peaks at 8.5, 15.6, 16.3, 18.5, and 22.9 degrees.
• An exemplary XRPD spectra for the Form F polymorph is shown in FIG. 7.
• the disclosure further provides a process for preparing a Form F polymorph of Trifarotene, comprising: (a) providing trifarotene according to a process described herein; (b) adjusting pH of the trifarotene to a pH of about 5 to about 6, to obtain trifarotene; and (c) dissolving the trifarotene in isopropanol, to obtain a Form F polymorph of trifarotene.
• the disclosure provides a Form G polymorph of the compound of Formula (I) [Trifarotene Na salt], wherein the Form G polymorph shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Q of 10.6, 11.5, 17.4, and 19.7 degrees. In some embodiments, the Form G polymorph further shows peaks at 8.9, 10.0, 14.7, and 16.2 degrees.
• An exemplary XRPD spectra for the Form G polymorph is shown in FIG. 8.
• the disclosure further provides a process for preparing a Form G polymorph of Trifarotene Na salt, comprising: (a) providing trifarotene according to a process of described herein; and (b) adjusting pH of the trifarotene to a pH of about 9 to about 12, to obtain a Form G polymorph of trifarotene salt.
• the pH is adjusted using a base described herein.
• the pH is adjusted using sodium hydroxide.
• 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 the addition of water (625 mL). Phases were separated. The organic phase was filtered off. Toluene was distilled off in vacuum to afford oily residue.
• Trifarotene [Formula I] as a white powder with purity 99.5%; m/z 460.24.
• Trifarotene HC1 salt obtained in Example 6 was dissolved under reflux in MeOH (33 mL). The turbid solution was filtered off through glass filter paper. The solution was left for evaporation at room temperature for 3 days.
• Trifarotene HC1 salt obtained in Example 6 was suspended in methyl ethyl ketone (5 mL) and shaken at 300 rpm for 3 days at room temperature. The product was filtered off and dried under ambient conditions. The resulting crystal form is the Form A polymorph as determined by XRPD. The XRPD of a Form A polymorph is shown in FIG. 2.
• Example 10 Preparation of Trifarotene HC1 - Form C Polymorph
• 150 mg Trifarotene HC1 salt obtained in Example 6 was suspended in ethylene glycol (5 mL) and shaken at 300 rpm for 3 days at room temperature. The product was filtered off and dried under ambient conditions. The resulting crystal form is the Form C polymorph as determined by XRPD. The XRPD of a Form C polymorph is shown in FIG. 4.
• Trifarotene was dried under vacuum at 40-45°C for 12- 48 hours (18 hours) to afford 4.6 g of Trifarotene.
• the resulting crystal form is the Form D polymorph as determined by XRPD.
• the XRPD of the Form D polymorph is shown in FIG. 5.
• Trifarotene obtained in Example 11 was suspended in MeOH (5 mL) and shaken at 300 rpm for 2 days at room temperature. The product was filtered off and dried under ambient conditions for 2-6 days (3 days). The resulting crystal form is the Form E polymorph as determined by XRPD. The XRPD of the Form E polymorph is shown in FIG. 6.
• Trifarotene obtained in Example 11 was dissolved under reflux in IPA (24 mL). The turbid solution was filtered off through nylon filter paper. The solution was left for evaporation at room temperature for 3 days. The product was filtered off and washed with cold IPA (1.5 mL). The product was dried under ambient conditions for 2-6 days (3 days). The resulting crystal form is the Form F polymorph as determined by XRPD. The XRPD of the Form F polymorph is shown in FIG. 7.
• Example 14 Preparation of Trifarotene - Form G Polymorph
• Trifarotene Form A obtained according to Example 9 was suspended in MeOFfFhO 1 : 1 (400 mL). 0.1 N NaOH was added dropwise with pH control, up to pH 11.5. The mixture was stirred at room temperature for 30 minutes, and the precipitate was filtered off. The cake was washed with water (20 mL). Trifarotene sodium salt was dried under vacuum at 40-45°C for 12-48 hours (18 hours) to afford 4.3 g of Trifarotene sodium salt. The resulting crystal form is the Form G polymorph as determined by XRPD. The XRPD of the Form G polymorph is shown in FIG. 8.

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