Method for the preparation of tetrahydrobenzothiepines

Abstract

Among its several embodiments, the present invention provides an improved process for the preparation of tetrahydrobenzothiepine-1,1-dioxide compounds; the provision of a process for preparing a diastereomeric mixture of tetrahydrobenzothiepine-1,1-dioxide compounds from a single diastereomer of such compounds; the provision of a process for the preparation of 3-bromo-2-substituted propionaldehyde compounds; and the provision of a process for the preparation of 3-thio-2-substituted propionaldehyde compounds.

1 . A method for the preparation of a benzylammonium compound having the structure of Formula 60 
       
         
           
           
               
               
           
         
         wherein the method comprises treating a benzyl alcohol ether compound having the structure of formula (61)  
         
           
             
             
                 
                 
             
           
         
         under derivatization conditions to form a derivatized benzyl ether compound having the structure of Formula (62)  
         
           
             
             
                 
                 
             
           
         
         and contacting the derivatized benzyl ether compound with an amine having the structure of Formula (42)  
         
           
             
             
                 
                 
             
           
         
         under amination conditions thereby producing the benzylammonium compound or a derivative thereof, wherein:  
         R 1  and R 2  independently are C 1  to about C 20  hydrocarbyl;  
         R 3 , R 4 , and R 5  independently are selected from the group consisting of H and C 1  to about C 20  hydrocarbyl, wherein optionally one or more carbon atom of the hydrocarbyl is replaced by O, N, or S, and wherein optionally two or more of R 3 , R 4 , and R 5  taken together with the atom to which they are attached form a cyclic structure;  
         R 9  is selected from the group consisting of H, hydrocarbyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl, polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR 3 , NR 3 R 4 , N + R 3 R 4 R 5 A − , SR 3 , S(O)R 3 , SO 2 R 3 , SO 3 R 3 , oxo, CO 2 R 3 , CN, halogen, NCO, CONR 3 R 4 , SO 2 OM, SO 2 NR 3 R 4 , PO(OR 23 )OR 24 , P + R 3 R 4 R 5 A − , S + R 3 R 4 A − , and C(O)OM;  
         R 23  and R 24  are independently selected from the substituents constituting R 3  and M;  
         n is a number from 0 to 4;  
         A −  is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation; and  
         X is a nucleophilic substitution leaving group.  
       
     
     
         2 - 336 . (canceled)  
     
     
         337 . A method for the preparation of a benylammonium compound having the structure of Formula (1)  
       
         
           
           
               
               
           
         
       
       wherein the method comprises treating a benzyl alcohol ether compound having the structure of Formula (6)  
       
         
           
           
               
               
           
         
       
       under derivatization conditions to form a derivatized benzyl ether compound having the structure of Formula (2)  
       
         
           
           
               
               
           
         
       
       and contacting the derivatized benzyl ether compound with an amine having the structure of Formula (42):  
       
         
           
           
               
               
           
         
       
       under amination conditions thereby producing the benzylammonium compound or a derivative thereof, wherein: 
 R 1  and R 2  independently are C 1  to about C 20  hydrocarbyl;  
 R 3 , R 4 , and R 5  independently are selected from the group consisting of H and C 1  to about C 20  hydrocarbyl, wherein optionally one or more carbon atoms of the hydrocarbyl is replaced by O, N or S, and wherein optionally two or more of R 3 , R 4 , and R 5  taken together with the atom to which they are attached form a cyclic structure; and  
 X is a nucleophilic substitution leaving group.  
 
     
     
         338 . The method of  claim 337  wherein R 3 , R 4 , and R 5  independently are selected from the group consisting of H and C 1  to about C 20  hydrocarbyl.  
     
     
         339 . The method of  claim 338  wherein R 3 , R 4 , and R 5  independently are selected from the group consisting of H and C 1  to about C 10  hydrocarbyl.  
     
     
         340 . The method of  claim 339  wherein R 3 , R 4 , and R 5  independently are H and C 1  to about C 10  hydrocarbyl.  
     
     
         341 . The method of  claim 340  wherein R 3 , R 4 , and R 5  independently are H and C 1  to about C 5  hydrocarbyl.  
     
     
         342 . The method of  claim 341  wherein R 3 , R 4  and R 5  independently are selected from the group consisting of methyl, ethyl, and propyl.  
     
     
         343 . The method of  claim 342  wherein R 3 , R 4 , and R 5  are each methyl.  
     
     
         344 . The method of  claim 337  wherein the amine comprises a heterocycle.  
     
     
         345 . The method of  claim 344  wherein amine comprises a bycyclic heterocycle.  
     
     
         346 . The method of  claim 345  wherein the amine is 1,4-diazabicyclo[2.2.2]octane and the benzylammonium compound has the structure of Formula (3)  
       
         
           
           
               
               
           
         
       
     
     
         347 . The method of  claim 337  wherein R 1  and R 2  independently are C 1  to about C 10  hydrocarbyl.  
     
     
         348 . The method of  claim 337  wherein R 1  and R 2  independently are C 1  to about C 5  hydrocarbyl.  
     
     
         349 . The method of  claim 348  wherein R 1  and R 2  are both butyl.  
     
     
         350 . The method of  claim 349  wherein the benzylammonium compound is an essentially racemic mixture of enantiomers.  
     
     
         351 . The method of  claim 349  wherein the benzylammonium compound produced by the method comprises a (4R,5R) enantiomer that preponderates over a (4S,5S) enantiomer.  
     
     
         352 . The method of  claim 344  wherein one R 1  and R 2  is ethyl and the other of R 1  and R 2  is butyl.  
     
     
         353 . The method of  claim 352  wherein the benzylammonium compound produced comprises a (3R) enantiomer that preponderates over a (3S) enantiomer.  
     
     
         354 . The method of  claim 352  wherein the benzylammonium compound produced comprises a (3S) enantiomer that preponderates over a (3R) enantiomer.