Substituted heterocycle fused gamma-carbolines synthesis

Abstract

The present invention provides improved methods for the preparation of substituted heterocycle fused gamma-carbolines, intermediates useful in producing them and methods for producing such intermediates and such heterocycle fused gamma-carbolines.

What is claimed is: 
     
         1 . A method for preparing (A) a compound of Formula 1I: 
       
         
           
           
               
               
           
         
         wherein:
 R is H or C 1-4  alkyl (e.g., methyl); 
 
         in free or salt form, comprising the steps of
 (a) reacting a compound of Formula 1E: 
 
       
       
         
           
           
               
               
           
         
         
           
             in free or salt form, wherein (i) A is selected from Br, Cl and I; (ii) R is selected from H and C 1-4  alkyl (e.g. methyl); and (iii) B is a protecting group; 
             with (i) a transition metal catalyst selected from the group consisting of Groups 8-11 of the periodic table, (ii) optionally a base, (iii) optionally an alkali metal iodide (e.g. potassium iodide), and (iv) optionally a monodentate or bidentate ligand, to form an intermediate of Formula 1F: 
           
         
       
       
         
           
           
               
               
           
         
         
           
             in free or salt form, wherein (i) R is selected from H and C 1-4  alkyl (e.g. methyl); and (ii) B is a protecting group; 
           
           (b) reducing the amide carbonyl of the compound of Formula 1F to yield an intermediate of Formula 1H, 
         
       
       
         
           
           
               
               
           
         
         
           
             in free or salt form, wherein (i) R is selected from H and C 1-4  alkyl (e.g. methyl); and (ii) B is a protecting group; and 
           
           (c) deprotecting the piperidine nitrogen of the compound of Formula 1H to yield the compound of Formula 1I, 
         
       
       
         
           
           
               
               
           
         
         
           in free or salt form, wherein (i) R is selected from H and C 1-4  alkyl (e.g. methyl); or (B) a compound of Formula 1J: 
         
       
       
         
           
           
               
               
           
         
         wherein:
 R is H or C 1-4  alkyl (e.g., methyl); and 
 Q is selected from 4-(4-fluorophenyl)-4-oxobutyl and 3-(4-fluorophenoxy)propyl, 
 
         in free or salt form, comprising the steps of
 (a) reacting a compound of Formula 1E: 
 
       
       
         
           
           
               
               
           
         
         
           
             in free or salt form, wherein (i) A is selected from Br, Cl and I; (ii) R is selected from H and C 1-4  alkyl (e.g. methyl); and (iii) B is a protecting group; 
             with (i) a transition metal catalyst selected from the group consisting of Groups 8-11 of the periodic table, (ii) optionally a base, (iii) optionally an alkali metal iodide (e.g. potassium iodide), and (iv) optionally a monodentate or bidentate ligand, to form an intermediate of Formula 1F: 
           
         
       
       
         
           
           
               
               
           
         
         
           
             in free or salt form, wherein (i) R is selected from H and C 1-4  alkyl (e.g. methyl); and (ii) B is a protecting group; 
           
           (b) reducing the amide carbonyl of the compound of Formula 1F to yield an intermediate of Formula 1H, 
         
       
       
         
           
           
               
               
           
         
         
           
             in free or salt form, wherein (i) R is selected from H and C 1-4  alkyl (e.g. methyl); and (ii) B is a protecting group; and 
           
           (c) deprotecting the piperidine nitrogen of the compound of Formula 1H to yield the compound of Formula 1I, 
         
       
       
         
           
           
               
               
           
         
         
           
             in free or salt form, wherein (i) R is selected from H and C 1-4  alkyl (e.g. methyl); 
           
           (d) alkylating the piperidine nitrogen of the compound of Formula 1I with a suitable alkylating agent to yield the compound of Formula 1J, in free or salt form; and optionally 
           (e) converting the compound of Formula 1J in free form to a compound of Formula 1J in salt form, e.g., pharmaceutically acceptable salt form, such as acid addition salt form (e.g., tosylate salt form). 
         
       
     
     
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         25 . A method for preparing a compound of Formula 1J: 
       
         
           
           
               
               
           
         
         wherein:
 R is H or C 1-4  alkyl (e.g., methyl); and 
 Q is selected from 4-(4-fluorophenyl)-4-oxobutyl and 3-(4-fluorophenoxy)propyl, 
 
         in pharmaceutically acceptable salt form, wherein the method comprises the step of
 (a) converting a compound of Formula 1J, wherein R and Q are as defined above, in free form or in salt form, into the compound of Formula 1J in pharmaceutically acceptable salt form, such as acid addition salt form (e.g., tosylate salt form). 
 
       
     
     
         26 . The method according to  claim 25 , wherein the method begins with a compound of Formula 1J or 2J in free base form, and wherein the method comprises the step (a) of converting said compound of Formula 1J or 2J in free base form into the compound of Formula 1J or 2J in pharmaceutically acceptable salt form, e.g., acid addition salt form (e.g., a tosylate salt form, e.g., mono-tosylate and/or di-tosylate salt form). 
     
     
         27 . The method according to  claim 25 , wherein the method begins with a compound of Formula 1J or 2J in salt form, e.g., acid addition salt form, and wherein the method comprises the step (a) of converting said compound of Formula 1J or 2J in salt form into the compound of Formula 1J or 2J in pharmaceutically acceptable salt form which is a different salt form, e.g., a different acid addition salt form (e.g., a tosylate salt form, e.g., mono-tosylate and/or di-tosylate salt form). 
     
     
         28 . An active pharmaceutical composition (active pharmaceutical ingredient) comprising the compound of Formula 1J: 
       
         
           
           
               
               
           
         
         wherein:
 R is H or C 1-4  alkyl (e.g., methyl); and 
 Q is selected from 4-(4-fluorophenyl)-4-oxobutyl and 3-(4-fluorophenoxy)propyl, 
 
         in pharmaceutically acceptable salt form, wherein the composition comprises at least 97% by weight of said compound (measured as the salt form). 
       
     
     
         29 . A pharmaceutical composition comprising the compound of Formula 1J: 
       
         
           
           
               
               
           
         
         wherein:
 R is H or C 1-4  alkyl (e.g., methyl); and 
 Q is selected from 4-(4-fluorophenyl)-4-oxobutyl and 3-(4-fluorophenoxy)propyl, 
 
         in free or salt form, 
         in admixture with toluenesulfonic acid and at least one excipient, diluent, or solvent. 
       
     
     
         30 . A compound selected from the group consisting of:
 Formula 1I:   
       
         
           
           
               
               
           
         
         
           wherein:
 R is H or C 1-4  alkyl (e.g., methyl); 
 in free or salt form, e.g., in acid addition salt form, 
 wherein the compound is in solid form; 
 
         
         or