Synthesis

Abstract

The present invention provides an improved process for the production of [(±)-endo]-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1 ]non-4-yl)benzamide hydrochloride, compositions thereof, and intermediates thereto.

1 - 6 . (canceled)  
   
   
       7 . A process for the preparation of compound (14) from compound (7)  
     
       
         
         
             
             
         
       
     
     comprising decomplexation of the amine of compound (7) by reflux in toluene followed by azeotropic drying of the produced compound (14).  
   
   
       8 . A process for the preparation of compound (7) from compound (6)  
     
       
         
         
             
             
         
       
     
     comprising reacting compound (6) with sodium followed by reaction with carbon dioxide characterised in that the reaction of compound (6) with sodium is carried out in butanol.  
   
   
       9 . A compound of formula (7)  
     
       
         
         
             
             
         
       
     
   
   
       10 . A process for the formation of compound (6) from compound (5)  
     
       
         
         
             
             
         
       
     
     comprising formation of oxime (6) from compound (5) by the reverse addition of compound (5) in butanol to a slurry of hydroxylamine hydrochloride.  
   
   
       11 . A process for the preparation of compound (5) from ethyl nipecotate comprising: 
 1) production of compound (3) from ethyl nipecotate                          by reaction of ethyl nipecotate with ethyl acrylate    2) production of compound (4) from compound (3)                          by reflux of compound (3) with base;    and 3) formation of compound (5) from compound (4)                          by reaction of compound (4) with aqueous HCl followed by sodium hydroxide.    
   
   
       12 . A process as claimed in  claim 11  wherein the reaction of ethyl nipecotate and ethyl acrylate is carried out in toluene and compound (3) is reacted with tBuOK.  
   
   
       13 . A process for the preparation of acid (11) from compound (10)  
     
       
         
         
             
             
         
       
     
     by the addition of aqueous sodium hydroxide to a slurry of compound (10) in water, followed by precipitation of acid ( 11) by the addition of hydrochloric acid.  
   
   
       14 . A process for the preparation of acid (16): 
 from compound (10):                          by reaction with aqueous potassium hydroxide and ethanol followed by the addition of hydrochloric acid.    
   
   
       15 . A process for the preparation of amine (14) from ethyl nipecotate comprising a) formation of compound (5) as claimed in  claim 11  and b) conversion of compound (5) to amine (14) comprising: 
 1)                          formation of oxime (6) from compound (5) by the reverse addition of compound (5) in butanol to a slurry of hydroxylamine hydrochloride;    2)                          reacting compound (6) with sodium followed by reaction with carbon dioxide characterised in that the reaction of compound (6) with sodium is carried out in butanol; and    3)                          decomplexation of the amine of compound (7) by reflux in toluene followed by azeotropic drying of the produced compound (14).    
   
   
       16 - 20 . (canceled)  
   
   
       21 . A compound of formula (8)  
     
       
         
         
             
             
         
       
     
     produced by the process comprising 
 1) preparing acid chloride (13) from acid (11)  
                     
 by reacting acid ( 11) with oxalyl chloride or thionyl chloride in dichloromethane, toluene, dimethylformamide (DMF) or tetrahydrofuran (THF)  
 2) reacting the acid chloride (13) in toluene with amine (14)  
                     
 and isolating the product (8) therefrom.  
 
   
   
       22 . A compound of formula (9)  
     
       
         
         
             
             
         
       
     
     produced from acid 16 and amine (14)  
     
       
         
         
             
             
         
       
     
     by a process comprising reacting the acid (16) with DMF, triethylamine and ethyl chloroformate then reacting the in situ acid chloride with amine (14) in toluene.  
   
   
       23 . A compound of formula (14) as produced by the process of  claim 7   
     
       
         
         
             
             
         
       
     
   
   
       24 . A compound of formula (5) as produced by the process of  claim 11   
     
       
         
         
             
             
         
       
     
   
   
       25 . A compound of formula (11) as produced by the process of  claim 13   
     
       
         
         
             
             
         
       
     
   
   
       26 . A compound of formula (16) as produced by the process of  claim 14   
     
       
         
         
             
             
         
       
     
   
   
       27 . A pharmaceutical composition comprising a compound of formula (9), according to  claim 22 , or the hydrochloride salt thereof and a pharmaceutically acceptable excipient  
   
   
       28 . A method of treating a disorder relating to impaired gastro-intestinal motility comprising administering to a subject in need thereof a compound of formula (9), according to  claim 22 ,  
   
   
       29 . A method as claimed in  claim 28  wherein the disorder is one or more of irritable bowel syndrome, retarded or delayed gastric emptying, dyspepsia, oesophageal reflux, peptic ulcer, flatulence, impaired evacuation, constipation, diabetic neuropathy, functional abdominal bloating or abdominal pain.  
   
   
       30 . A compound as claimed in  claim 21  wherein the preparation of the acid chloride (13) is carried out by reacting acid (11) with DMF and thionyl chloride in the presence of THF, wherein the DMF is added to the acid prior to the thionyl chloride and carrying out a solvent exchange with toluene prior to the reaction of the acid chloride with amine (14).  
   
   
       31 . A process as claimed in  claim 22 , wherein acid (16) is produced by the process as claimed in  claim 14