Processes for the preparation of substituted tetrahydro beta-carbolines

Abstract

Provided herein are improved processes for the synthesis of substituted tetrahydro beta-carboline derivatives. In particular, provided herein are improved processes useful for the preparation of (S)-4-chlorophenyl 6-chloro-1-(4-methoxyphenyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate. Formula (I):

1 . A process for preparing a compound of Formula (II): 
       
         
           
           
               
               
           
         
         comprising the steps of:
 i) reacting about one equivalent of a compound of Formula (IV) with about 0.5 equivalents of a chiral acid in a first solvent mixture of water and absolute ethanol, wherein said absolute ethanol has about 0% water, and about 2% to about 5% by volume of water is added to said absolute ethanol: 
 
       
       
         
           
           
               
               
           
         
         
            and 
           ii) recrystallizing the reaction product in a second solvent to provide the compound of Formula (II), wherein 
           X is halogen; and 
           R is substituted or unsubstituted C 1  to C 8  alkyl. 
         
       
     
     
         2 . The process of  claim 1 , wherein X is chloro. 
     
     
         3 . The process of  claim 1 , wherein R is C 1  to C 8  alkyl substituted with one or more substituents selected from halogen, hydroxyl or C 1  to C 8  alkoxy. 
     
     
         4 . The process of  claim 1 , wherein R is methyl. 
     
     
         5 . The process of  claim 1 , wherein X is chloro and R is methyl. 
     
     
         6 - 12 . (canceled) 
     
     
         13 . The process of  claim 1 , wherein the second solvent is absolute ethanol having about 0% water. 
     
     
         14 - 16 . (canceled) 
     
     
         17 . A process for preparing a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof: 
       
         
           
           
               
               
           
         
         comprising the steps of:
 i) reacting about one equivalent of a compound of Formula (IV), with about 0.5 equivalents of a chiral acid in a first solvent mixture of water and absolute ethanol, wherein said absolute ethanol has about 0% water, and about 2% to about 5% by volume of water is added to said absolute ethanol: 
 
       
       
         
           
           
               
               
           
         
         
           to provide a compound of Formula (II), wherein 
           X is halogen; and 
           R is substituted or unsubstituted C 1  to C 8  alkyl; and 
           ii) reacting the compound of Formula (II) with a compound of Formula (III) in the presence of a base and a second solvent mixture comprising water and a solvent: 
         
       
       
         
           
           
               
               
           
         
         
           to provide a compound of Formula (I), wherein 
           X is at each occurrence independently halogen; and 
           R is substituted or unsubstituted C 1  to C 8  alkyl. 
         
       
     
     
         18 - 22 . (canceled) 
     
     
         23 . The process of  claim 17 , wherein the solvent in the second solvent mixture is iPrOAc, EtOAc, MTBE, MEK, DCM, DCE, toluene, DMA or a mixture thereof. 
     
     
         24 . The process of  claim 23 , wherein the solvent in the second solvent mixture is EtOAc or MEK or a mixture thereof. 
     
     
         25 . The process of  claim 24 , wherein the solvent in the second solvent mixture is MEK. 
     
     
         26 . The process of  claim 1 , wherein a compound of Formula (I) is a compound of Formula (X): 
       
         
           
           
               
               
           
         
       
     
     
         27 . The process of any one of  claims 1  and  17 , wherein the compound of Formula (II) is 
       
         
           
           
               
               
           
         
       
     
     
         28 . The process of any of  claims 1  and  17 , wherein the chiral acid is N-acetyl-L-phenylalanine, (S)-2-(methoxycarbonylamino)-3-phenylpropanoic acid, (S)-2-(isopropoxycarbonylamino)-3-phenylpropanoic acid, (S)-2-benzamido-3-phenylpropanoic acid, (S)-2-(4-chlorobenzamido)-3-phenylpropanoic acid, (S)-2-(4-methoxybenzamido)-3-phenylpropanoic acid, (S)-3-phenyl-2-(4-(trifluoromethyl)benzamido)propanoic acid, (S)-2-isobutyramido-3-phenylpropanoic acid, (S)-3-phenyl-2-(phenylsulfonamido)propanoic acid, (S)-3-phenyl-2-(4-(trifluoromethyl)phenylsulfonamido)propanoic acid, (S)-2-(4-methoxyphenylsulfonamido)-3-phenylpropanoic acid or (S)-2-(4-methylphenylsulfonamido)-3-phenylpropanoic acid. 
     
     
         29 . The process of any of  claims 1  and  17 , wherein the chiral acid is N-acetyl-L-phenylalanine. 
     
     
         30 . The process of  claim 1 , further comprising the step of preparing a compound of Formula (IV) by reacting a compound of Formula (V): 
       
         
           
           
               
               
           
         
         with a solvated base, wherein
 X is halogen, 
 R is substituted or unsubstituted C 1  to C 8  alkyl, and 
 HB is an acid suitable to form a salt with a compound of Formula (V), 
 
         wherein HB is selected from hydrochloric acid or acetic acid; and 
         wherein the solvated base is aqueous ammonium hydroxide in a mixture with a solvent selected from ethyl acetate or isopropyl acetate. 
       
     
     
         31 . (canceled) 
     
     
         32 . The process of  claim 30 , further comprising the step of preparing a compound of Formula (V) by reacting a compound of Formula (VII): 
       
         
           
           
               
               
           
         
         with a compound of Formula (VI): 
       
       
         
           
           
               
               
           
         
         in the presence of a suitable acid in a suitable solvent, wherein
 X is halogen, 
 R is substituted or unsubstituted C 1  to C 8  alkyl, and 
 HB′ is an acid suitable to form a salt with the amino group of a compound of Formula (VII); and 
 
         wherein the suitable acid is hydrochloric acid, the suitable solvent is selected from water or EtOAc and HB′ is selected from hydrochloric acid or acetic acid. 
       
     
     
         33 . (canceled)