Preparation of trifarotene and intermediates and polymorphs thereof

Abstract

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.

What is claimed is: 
     
         1 . 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 C 1 -C 8  alkanoyl group, a substituted or unsubstituted linear or branched C 1 -C 8  alkenoyl group, a substituted or unsubstituted linear or branched C 1 -C 8  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 C 1 -C 8  alkanoyl group comprising a heteroatom; and 
           wherein Y is a nitrile (CN) or amide (CONH 2 ); 
         
         to obtain the compound of formula (I). 
       
     
     
         2 . The process according to  claim 1 , wherein R 4  is an acetyl group. 
     
     
         3 . The process according to  claim 1 , wherein R 4  is hydrogen. 
     
     
         4 . The process according to  claim 3 , further comprising 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 C 1 -C 8  alkyl group, a substituted or unsubstituted linear or branched C 1 -C 8  alkenyl group, a substituted or unsubstituted linear or branched C 1 -C 8  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 C 1 -C 8  alkyl group comprising a heteroatom; and 
 wherein Y is a nitrile (CN) or amide (CONH 2 ); 
 
         to obtain the compound of formula (V). 
       
     
     
         5 . The process according to  claim 4 , wherein R 3  is methyl. 
     
     
         6 . The process according to any one of  claims 1  to  5 , wherein the hydrolysis is performed in the presence of a solvent comprising water, methanol (MeOH), ethanol (EtOH), propanol (PrOH), isopropanol (IPA), or any mixture thereof. 
     
     
         7 . The process according to  claim 6 , wherein the solvent comprises water and ethanol. 
     
     
         8 . The process according to any one of  claims 4  to  7 , wherein the base comprises sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), barium hydroxide (Ba(OH) 2 ), or any mixture thereof. 
     
     
         9 . The process according to any one of  claims 4  to  8 , wherein 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). 
     
     
         10 . The process according to any one of  claims 4  to  9 , wherein 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). 
     
     
         11 . The process according to  claim 10 , wherein 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). 
     
     
         12 . The process according to any one of  claims 4  to  11 , further comprising preparing the compound of formula (IV) by reacting a compound of formula (TI) 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently hydrogen or a linear or branched C 1 -C 3  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) 
       
         
           
           
               
               
           
         
       
       in the presence of a catalyst,
 wherein R 3  is hydrogen, a hydroxyl group, a halogen, a substituted or unsubstituted linear or branched C 1 -C 8  alkyl, a substituted or unsubstituted linear or branched C 1 -C 8  alkenyl group, a substituted or unsubstituted linear or branched C 1 -C 8  alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted C 1 -C 8  alkyl group comprising a heteroatom; 
 wherein X is a halogen or triflate; and 
 wherein Y is a nitrile or amide, 
 
       to obtain the compound of formula (IV). 
     
     
         13 . The process according to  claim 12 , wherein the R 3  is methyl and X is iodine. 
     
     
         14 . The process according to  claim 12  or  13 , wherein 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 (IPA), dimethyl ether (DME), diethyl ether, or any mixture thereof. 
     
     
         15 . The process according to any one of  claims 12  to  14 , wherein the reaction is performed in the presence of a base comprising K 2 CO 3 , CH 3 CO 2 K, K 3 PO 4 , KOtBu, Na 2 CO 3 , NaHCO 3 , NaOMe, Cs 2 CO 3 , Ag 3 PO 4 , Ag 2 O, Tl 2 CO 3 , TlOEt, TlOH, t-BuNH 2 , KOH, NaOH, LiOH, Ba(OH) 2 , or combination thereof. 
     
     
         16 . The process according to any one of  claims 12  to  15 , wherein the catalyst comprises a metal selected from Pd, Cu, or Ni. 
     
     
         17 . The process according to  claim 16 , wherein the catalyst comprises at least two atoms of the metal. 
     
     
         18 . The process according to  claim 16 , wherein the catalyst is a Pd catalyst selected from:
 Pd(PPh 3 ) 2 Cl 2  [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-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) Methanesulfonate];   SPhos-Pd-G2 [Chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)];   CATACXIUM® A Pd-G3 [Mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II), [(Di(1-adamantyl)-butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II) Methanesulfonate];   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(Cy 3 ) Pd-G3 [(Tricyclohexylphosphine)-2-(2′-aminobiphenyl)]palladium(II) Methanesulfonate];   Allylpalladium(II) chloride dimer Bis(allyl)dichlorodipalladium; or   Pd(dppf)Cl 2  [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)].   
     
     
         19 . The process according to any one of  claims 12  to  18 , wherein 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. 
     
     
         20 . The process according to any one of  claims 12  to  19 , wherein 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). 
     
     
         21 . The process according to any one of  claims 12  to  20 , wherein 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). 
     
     
         22 . The process according to any one of  claims 15  to  21 , wherein 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). 
     
     
         23 . A process for the preparation of a compound of formula (I) [Trifarotene], or a salt thereof 
       
         
           
           
               
               
           
         
         comprising 
         a) reacting a compound of formula (HI) 
       
       
         
           
           
               
               
           
         
         
           wherein R 1  and R 2  are independently hydrogen or a linear or branched C 1 -C 3  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 C 1 -C 8  alkyl, a substituted or unsubstituted linear or branched C 1 -C 8  alkenyl group, a substituted or unsubstituted linear or branched C 1 -C 8  alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted C 1 -C 8  alkyl group comprising a heteroatom; 
           wherein X is a halogen or triflate; and 
           wherein Y is a nitrile (CN) or amide (CONH 2 ), 
         
         in the presence of a catalyst, to obtain a compound of formula (IV) 
       
       
         
           
           
               
               
           
         
         
           wherein R 3  is as defined above; and 
         
         b) hydrolyzing the compound of formula (IV) in the presence of a base, to obtain Trifarotene. 
       
     
     
         24 . The process according to  claim 23 , wherein R 3  is methyl, X is iodine, and Y is nitrile. 
     
     
         25 . A compound of formula (III) 
       
         
           
           
               
               
           
         
         wherein R 3  is a substituted or unsubstituted linear or branched C 1 -C 8  alkyl group, substituted or unsubstituted linear or branched C 1 -C 8  alkenyl group, substituted or unsubstituted linear or branched C 1 -C 8  alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted C 1 -C 8  alkyl group comprising a heteroatom; 
         wherein X is a halogen or triflate; and 
         wherein Y is a nitrile or amide. 
       
     
     
         26 . The compound according to  claim 25 , wherein R 3  is methyl and X is iodine. 
     
     
         27 . A compound of formula (V) 
       
         
           
           
               
               
           
         
         wherein R 1  is hydrogen, a substituted or unsubstituted linear or branched C 1 -C 8  alkanoyl group, a substituted or unsubstituted linear or branched C 1 -C 8  alkenoyl group, a substituted or unsubstituted linear or branched C 1 -C 8  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 C 1 -C 8  alkanoyl group comprising a heteroatom; and 
         wherein Y is a nitrile (CN) or amide (CONH 2 ). 
       
     
     
         28 . The compound of  claim 27 , wherein R 4  is hydrogen. 
     
     
         29 . The compound according to  claim 27 , wherein R 4  is acetyl. 
     
     
         30 . A Form A polymorph of the compound of formula (I) [Trifarotene-HCl], wherein the Form A polymorph shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2θ of 7.6, 11.5, 15.4, 21.1, and 23.2 degrees. 
     
     
         31 . The Form A polymorph of  claim 30 , further showing peaks at 8.6, 9.0, 17.7, 18.3, 19.5, and 22.5 degrees. 
     
     
         32 . A Form B polymorph of the compound of formula (I) [Trifarotene-HCl], wherein the Form B polymorph shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2θ of 12.6, 19.5, 19.8, 24.6, and 29.5 degrees. 
     
     
         33 . The Form B polymorph of  claim 32 , further showing peaks at 8.4, 12.0, 17.4, 21.1, 23.2, 31.0, and 32.1 degrees. 
     
     
         34 . 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 2θ of 7.9, 15.6, 20.0, 23.6, and 27.8 degrees. 
     
     
         35 . The Form C polymorph of  claim 34 , further showing peaks at 12.1, 16.4, 17.4, and 28.8 degrees. 
     
     
         36 . 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 2θ of 8.5, 16.2, 18.6, and 23.1 degrees. 
     
     
         37 . The Form D polymorph of  claim 36 , further showing peaks at 12.2, 12.8, and 14.1 degrees. 
     
     
         38 . 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 2θ of 8.6, 12.8, 14.2, 17.9, and 24.0 degrees. 
     
     
         39 . The Form E polymorph of  claim 38 , further showing peaks at 10.6, 15.3, 16.3, 19.3, and 22.0 degrees. 
     
     
         40 . 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 2θ of 5.2, 6.3, 14.9, 18.0, and 19.1 degrees. 
     
     
         41 . The Form F polymorph of  claim 40 , further showing peaks at 8.5, 15.6, 16.3, 18.5, and 22.9 degrees. 
     
     
         42 . 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 2θ of 10.6, 11.5, 17.4, and 19.7 degrees. 
     
     
         43 . The Form G polymorph of  claim 42 , further showing peaks at 8.9, 10.0, 14.7, and 16.2 degrees. 
     
     
         44 . A process for preparing a Form A polymorph of Trifarotene-HCl, comprising:
 a) providing trifarotene according to the process of any one of  claims 1  to  24 ;   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.   
     
     
         45 . A process for preparing a Form B polymorph of Trifarotene-HCl, comprising:
 a) providing trifarotene according to the process of any one of  claims 1  to  24 ;   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.   
     
     
         46 . A process for preparing a Form C polymorph of Trifarotene-HCl, comprising:
 a) providing trifarotene according to the process of any one of  claims 1  to  24 ;   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.   
     
     
         47 . The process of any of  claims 44  to  46 , wherein the pH is adjusted using hydrochloric acid (HCl). 
     
     
         48 . A process for preparing a Form D polymorph of trifarotene, comprising:
 a) providing trifarotene according to the process of any one of  claims 1  to  24 ; and   b) adjusting pH of the trifarotene to a pH of about 5 to about 6, to obtain a Form D polymorph of trifarotene.   
     
     
         49 . The process of  claim 48 , wherein the pH is adjusted using an acid comprising HCl, acetic acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, trifluoroacetic acid, p-toluene sulfonic acid, methane-sulfonic acid, or any mixture thereof. 
     
     
         50 . A process for preparing a Form E polymorph of trifarotene, comprising:
 a) providing trifarotene according to the process of any one of  claims 1  to  24 ;   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.   
     
     
         51 . A process for preparing a Form F polymorph of trifarotene, comprising:
 a) providing trifarotene according to the process of any one of  claims 1  to  24 ;   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.   
     
     
         52 . A process for preparing a Form G polymorph of Trifarotene Na salt, comprising:
 a) providing trifarotene according to the process of any one of  claims 1  to  24 ; 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.   
     
     
         53 . The process of  claim 52 , wherein the pH is adjusted using sodium hydroxide.