Chemical Intermediate

Abstract

An acid addition salt of a compound of Formula I, wherein R 2 represents C 1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl) or aryl, wherein each aryl and aryloxy group, unless otherwise specified, is optionally substituted.

1 . An acid addition salt of a compound of Formula I 
     
       
         
         
             
             
         
       
     
     wherein R 2  represents C 1-6  alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl) or aryl, wherein each aryl and aryloxy group, unless otherwise specified, is optionally substituted. 
   
   
       2 . A salt according to  claim 1  in which the acid component of the acid addition salt is represented by formula A 
     
       
         
         
             
             
         
       
     
     wherein R 16  represents unsubstituted C 1-4  alkyl, C 1-4  perfluoroalkyl or phenyl, which latter group is optionally substituted by one or more substituents selected from C 1-6  alkyl, halo, nitro and C 1-6  alkoxy, and R 2  is as defined above. 
   
   
       3 . A salt according to  claim 2  wherein the salt is a toluenesulfonate, benzenesulfonate, nosylate, brosylate, besylate or mesitylate salt. 
   
   
       4 . A salt according to any previous claim in which the salt is in solid form. 
   
   
       5 . A salt according to any previous claim which is [2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-ethyl]-carbamic acid tert-butyl ester 2,4,6-trimethylbenzenesulfonic acid. 
   
   
       6 . A process for the preparation of a compound of Formula II 
     
       
         
         
             
             
         
       
     
     wherein R 1  represents a structural fragment of formula Ia 
     
       
         
         
             
             
         
       
     
     in which A represents CH 2  and R 3  represents —OH or —N(H)R 7 ;
 R 4  represents H, C 1-6  alkyl or, together with R 3 , represents ═O; 
 R 5  represents phenyl or pyridyl, both of which groups are optionally substituted by one or more substituents selected from —OH, cyano, halo, nitro, C 1-6  alkyl (optionally terminated by —N(H)C(O)OR 13a ), C 1-6  alkoxy, 
 —N(R 14a )R 14b , —C(O)R 14c , —C(O)OR 14d , —C(O)N(R 14e )R 14f , —N(R 14g )C(O)R 14h , 
 —N(R 14i )C(O)N(R 14j )R 14k , —N(R 14m )S(O) 2 R 13b , —S(O) 2 R 13c  and/or 
 —OS(O) 2 R 13d ; 
 R 7  represents H, C 1-6  alkyl, -E-aryl, -E-Het 1 , —C(O)R 9a , —C(O)OR 9b , 
 —S(O) 2 R 9c , —[C(O)] p N(R 10a )R 10b  or —C(NH)NH 2 ; 
 R 9a  to R 9d  independently represent, at each occurrence when used herein, C 1-6  alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het 2 ), aryl, Het 3 , or R 9a  and R 9d  independently represent H; 
 R 10a  and R 10b  independently represent, at each occurrence when used herein, H or C 1-6  alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het 4 ), aryl, Het 5 , or together represent C 3-6  alkylene, optionally interrupted by an O atom; 
 E represents, at each occurrence when used herein, a direct bond or C 1-4  alkylene; 
 B represents -Z-, -Z-N(R 12 )—, —N(R 12 )-Z-, -Z-S(O) n — or -Z-O— (in which latter two groups, Z is attached to the carbon atom bearing R 3  and R 4 ); 
 Z represents a direct bond or C 1-4  alkylene; 
 R 11  and R 12  independently represent H or C 1-6  alkyl; 
 R 13a  to R 13d  independently represent C 1-6  alkyl; 
 R 14a  and R 14b  independently represent H, C 1-6  alkyl or together represent C 3-6  alkylene, resulting in a four- to seven-membered nitrogen-containing ring; 
 R 14c  to R 14m  independently represent H or C 1-6  alkyl; and 
 n represents 0, 1 or 2; 
 p represents 1 or 2; 
 Het 1  to Het 5  independently represent, at each occurrence when used herein, five- to twelve-membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which heterocyclic groups are optionally substituted by one or more substituents selected from ═O, —OH, cyano, halo, nitro, C 1-6  alkyl, C 1-6  alkoxy, aryl, aryloxy, —N(R 15a )R 15b , —C(O)R 15c , —C(O)OR 15d , —C(O)N(R 15e )R 15f , —N(R 15g )C(O)R 15h  and —N(R 15i )S(O) 2 R 15j ; 
 R 15a  R 15i  independently represent C 1-6  alkyl aryl or R 15a  to R 15i  independently represent H; 
 and R 2  represents C 1-6  alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl) or aryl, wherein each aryl and aryloxy group, unless otherwise specified, is optionally substituted. 
 wherein a salt of a compound of Formula I 
 
     
       
         
         
             
             
         
       
     
     in which R 2  is as previously defined is reacted with a compound of Formula III 
     
       
         
         
             
             
         
       
     
     wherein Y represents O or N(R 7 ) and R 4 , R 5 , R 7  and B are as hereinbefore defined, at a temperature in the range of 0° C. to 100° C. for example at elevated temperature (e.g. 60° C. to reflux) in the presence of a water and in the presence of a base. 
   
   
       7 . A process according to  claim 6  in which the salt has been previously isolated in solid form. 
   
   
       8 . A process according to either  claim 6  or  claim 7  for the preparation of tert-butyl 2-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]-non-3-yl}ethylcarbamate which comprises reacting a salt of [2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-ethyl]-carbamic acid tert-butyl ester with 4-[(2S)-oxiranylmethoxy]benzonitrile at a temperature in the range of 0° C. to 100° C. in the presence of water and in the presence of a base. 
   
   
       9 . A process according to any one of  claims 6 ,  7  or  8  in which an isolated salt of [2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-ethyl]-carbamic acid tert-butyl ester is used. 
   
   
       10 . A process according to either  claim 9  wherein the salt is the 2,4,6-trimethylbenzenesulfonic acid salt.