Processes for the preparation of 5-ht2c receptor agonists

Abstract

The present invention relates to processes and intermediates useful in the preparation of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (lorcaserin), a serotonin (5-HT) receptor modulator that is useful in the treatment of, for example, central nervous system disorders, such as obesity.

1 . A process for preparing a compound selected from: 2-chloro-N-(4-chlorophenethyl)propan-1-amine (Compound VI), which has the following structure: 
       
         
           
           
               
               
           
         
         and salts thereof; comprising the following steps: 
         (a) reacting 2-(4-chlorophenyl)ethanol (Compound II): 
       
       
         
           
           
               
               
           
         
         
           or a salt thereof, with a first chlorinating agent to form 1-chloro-4-(2-chloroethyl)benzene (Compound III): 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein
 said reacting 2-(4-chlorophenyl)ethanol or a salt thereof, with said first chlorinating agent, is performed in the presence of a first catalyst, wherein said first catalyst comprises N,N-dimethylacetamide; 
 
           
         
         (b) reacting said 1-chloro-4-(2-chloroethyl)benzene (Compound III) with 1-aminopropan-2-ol (Compound IV): 
       
       
         
           
           
               
               
           
         
         
           or a salt thereof, to form 1-(4-chlorophenethylamino)propan-2-ol (Compound V): 
         
       
       
         
           
           
               
               
           
         
         
           or a salt thereof; and 
         
         (c) reacting said 1-(4-chlorophenethylamino)propan-2-ol (Compound V) or a salt thereof, with a second chlorinating agent to form said compound selected from: 2-chloro-N-(4-chlorophenethyl)propan-1-amine (Compound VI) and salts thereof,
 wherein said reacting said 1-(4-chlorophenethylamino)propan-2-ol (Compound V or a salt thereof, with said second chlorinating agent, comprises formation of a reaction mixture by addition of said 1-(4-chlorophenethylamino)propan-2-ol to said second chlorinating agent. 
 
       
     
     
         2 . The process according to  claim 1  wherein said first chlorinating agent comprises thionyl chloride. 
     
     
         3 . The process according to  claim 1 , wherein said reacting 2-(4-chlorophenyl)ethanol or a salt thereof, with said first chlorinating agent, is performed in the substantial absence of solvent. 
     
     
         4 . The process according to  claim 1 , wherein said reacting 2-(4-chlorophenyl)ethanol or a salt thereof, with said first chlorinating agent, is performed at a temperature of about 50° C. to about 75° C. 
     
     
         5 . The process according to  claim 1 , wherein the molar ratio of said first chlorinating agent and said 2-(4-chlorophenyl)ethanol or a salt thereof is about 1.2:1 to about 1:1. 
     
     
         6 . (canceled) 
     
     
         7 . The process according to  claim 1 , wherein the molar ratio of said 2-(4-chlorophenyl)ethanol or a salt thereof and said first catalyst is about 25:1 to about 5:1. 
     
     
         8 . The process according to  claim 1 , wherein the molar ratio of said 2-(4-chlorophenyl)ethanol or a salt thereof and said first catalyst is about 20:1. 
     
     
         9 . The process according to  claim 1 , wherein said reacting 1-chloro-4-(2-chloroethyl)benzene with 1-aminopropan-2-ol or a salt thereof, is performed in the substantial absence of solvent. 
     
     
         10 . The process according to  claim 1 , wherein said reacting 1-chloro-4-(2-chloroethyl)benzene with 1-aminopropan-2-ol or a salt thereof, is performed in the presence of toluene. 
     
     
         11 . The process according to  claim 9 , wherein said reacting 1-chloro-4-(2-chloroethyl)benzene with 1-aminopropan-2-ol or a salt thereof, is performed at a temperature of about 75° C. to about 100° C. 
     
     
         12 . The process according to  claim 1 , wherein the molar ratio of said 1-aminopropan-2-ol or a salt thereof and said 1-chloro-4-(2-chloroethyl)benzene is about 5:1. 
     
     
         13 . The process according to  claim 1 , wherein said second chlorinating agent comprises thionyl chloride. 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . The process according to  claim 1 , wherein said reacting 1-(4-chlorophenethylamino)propan-2-ol or a salt thereof, with said second chlorinating agent, is performed in the substantial absence of solvent. 
     
     
         19 . The process according to  claim 1 , wherein said reacting 1-(4-chlorophenethylamino)propan-2-ol or a salt thereof, with said second chlorinating agent, is performed in the presence of a first halogenated solvent, wherein said first halogenated solvent comprises chlorobenzene. 
     
     
         20 . The process according to  claim 1 , wherein said reacting 1-(4-chlorophenethylamino)propan-2-ol or a salt thereof, with said second chlorinating agent, is performed in the presence of a second aprotic solvent, wherein said second aprotic solvent comprises toluene. 
     
     
         21 . The process according to  claim 1 , wherein said reacting 1-(4-chlorophenethylamino)propan-2-ol or a salt thereof, with said second chlorinating agent, is performed at a temperature of about 50° C. to about 75° C. 
     
     
         22 . The process according to  claim 1 , wherein the molar ratio of said second chlorinating agent and said 1-(4-chlorophenethylamino)propan-2-ol or a salt thereof is about 2:1 to about 1:1. 
     
     
         23 . The process according to  claim 1 , wherein said reacting 1-(4-chlorophenethylamino)propan-2-ol or a salt thereof, with a second chlorinating agent, is performed in the substantial absence of an amide catalyst. 
     
     
         24 . A process for preparing a compound selected from: 2-chloro-N-(4-chlorophenethyl)propan-1-amine (Compound VI): 
       
         
           
           
               
               
           
         
         and salts thereof, comprising reacting 1-(4-chlorophenethylamino)propan-2-ol (Compound V): 
       
       
         
           
           
               
               
           
         
         or a salt thereof, with a second chlorinating agent to form said compound selected from: 2-chloro-N-(4-chlorophenethyl)propan-1-amine (Compound VI) and salts thereof; wherein said reacting 1-(4-chlorophenethylamino)propan-2-ol (Compound V) or a salt thereof, with a second chlorinating agent, is carried out in the presence of a first halogenated solvent, wherein said first halogenated solvent comprises chlorobenzene, and wherein said reacting comprises formation of a reaction mixture by addition of said 1-(4-chlorophenethylamino)propan-2-ol (Compound V) or a salt thereof, to said second chlorinating agent. 
       
     
     
         25 . A process for preparing a compound selected from: 2-chloro-N-(4-chlorophenethyl)propan-1-amine (Compound VI): 
       
         
           
           
               
               
           
         
         and salts thereof, comprising reacting 1-(4-chlorophenethylamino)propan-2-ol (Compound V): 
       
       
         
           
           
               
               
           
         
         or a salt thereof, with a second chlorinating agent to form said compound selected from: 2-chloro-N-(4-chlorophenethyl)propan-1-amine (Compound VI) and salts thereof; wherein said reacting comprises formation of a reaction mixture by addition of said 1-(4-chlorophenethylamino)propan-2-ol to said second chlorinating agent. 
       
     
     
         26 . (canceled) 
     
     
         27 . The process according to  claim 25 , wherein said reacting 1-(4-chlorophenethylamino)propan-2-ol or a salt thereof, with said second chlorinating agent, is performed in the substantial absence of solvent. 
     
     
         28 . The process according to  claim 25 , wherein said reacting 1-(4-chlorophenethylamino)propan-2-ol or a salt thereof, with said second chlorinating agent, is performed in the presence of a first halogenated solvent, wherein said first halogenated solvent comprises chlorobenzene. 
     
     
         29 . The process according to  claim 25 , wherein said reacting 1-(4-chlorophenethylamino)propan-2-ol or a salt thereof, with said second chlorinating agent, is performed in the presence of a second aprotic solvent, wherein said second aprotic solvent comprises toluene. 
     
     
         30 . The process according to  claim 24 , wherein said second chlorinating agent comprises thionyl chloride. 
     
     
         31 . The process according to  claim 24 , wherein said reacting 1-(4-chlorophenethylamino)propan-2-ol or a salt thereof, with said second chlorinating agent, is performed at a temperature of about 50° C. to about 75° C. 
     
     
         32 . The process according to  claim 24 , wherein the molar ratio of said second chlorinating agent and said 1-(4-chlorophenethylamino)propan-2-ol or a salt thereof is about 2:1 to about 1:1. 
     
     
         33 . The process according to  claim 24 , wherein said reacting 1-(4-chlorophenethylamino)propan-2-ol or a salt thereof, with a second chlorinating agent, is performed in the substantial absence of an amide catalyst. 
     
     
         34 . (canceled) 
     
     
         35 . (canceled) 
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
         38 . (canceled) 
     
     
         39 . (canceled) 
     
     
         40 . (canceled) 
     
     
         41 . (canceled) 
     
     
         42 . (canceled) 
     
     
         43 . (canceled) 
     
     
         44 . (canceled) 
     
     
         45 . (canceled) 
     
     
         46 . (canceled) 
     
     
         47 . A compound selected from: 2-chloro-N-(4-chlorophenethyl)propan-1-amine (Compound VI), and salts thereof, wherein a solution of said compound in methanol with a concentration of 40 mg/mL, has a maximum UV absorbance of about 0.100 AU or less between about 300 nm and about 350 nm, wherein said compound is singly-crystallized. 
     
     
         48 . A compound selected from: 2-chloro-N-(4-chlorophenethyl)propan-1-amine (Compound VI), and salts thereof, prepared by a process according to  claim 1 , wherein a solution of said compound in methanol with a concentration of 40 mg/mL, has a maximum UV absorbance of about 0.100 AU or less between about 300 nm and about 350 nm, and wherein said process does not comprise recrystallization of said compound selected from: 2-chloro-N-(4-chlorophenethyl)propan-1-amine (Compound VI), and salts thereof. 
     
     
         49 . (canceled) 
     
     
         50 . The method according to  claim 1 , wherein said reacting 2-(4-chlorophenyl)ethanol or a salt thereof, with said first chlorinating agent, is performed in the presence of a first aprotic solvent, wherein said first aprotic solvent comprises toluene.