Processes for preparing 3-benzazepines

Abstract

The present invention provides processes and intermediates for the preparation of 3-benzazepines and salts thereof which can be useful as serotonin (5-HT) receptor agonists for the treatment of, for example, central nervous system disorders such as obesity.

1 - 651 . (canceled) 
     
     
         652 . A method of resolving a mixture of compounds of Formula Va and Vb: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H or C 1 -C 8  alkyl; 
 R 2  is C 1 -C 8  alkyl, —CH 2 —O—(C 1 -C 8  alkyl), C(O)O—(C 1 -C 8  alkyl), —C(O)NH—(C 1 -C 8  alkyl), OH, C 1 -C 4  haloalkyl, or CH 2 OH; 
 R 3 , R 4 , R 5 , and R 6  are each, independently, H, halo, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 7  cycloalkyl, C 1 -C 8  haloalkyl, hydroxy, OR 9 , alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl, NR 10 R 11 , CN, NO 2 , heterocycloalkyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from C 1 -C 8  alkyl, halo, C 1 -C 8  haloalkyl, and alkoxy; or R 4  and R 5  together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; 
 R 8a  and R 8b  are each, independently, H, halo, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 7  cycloalkyl, C 1 -C 8  haloalkyl, alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, or R 8a  and R 8b  together with the carbon atom to which they are attached form a C 3 -C 7  cycloalkyl group; 
 R 9  is H, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 7  cycloalkyl, C 1 -C 8  haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl; and 
 R 10  and R 11  are each, independently, H, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 7  cycloalkyl, C 1 -C 8  haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R 10  and R 11  together with the N atom to which they are attached form a heterocyclic ring; 
 comprising: 
 contacting said mixture of compounds with a chiral resolving acid to form chiral resolving acid salts of said compounds, wherein said chiral resolving acid comprises substantially one stereoisomer; and 
 precipitating said chiral resolving acid salts of said compounds, wherein the resulting precipitate is enriched in the chiral resolving acid salt of one of said compounds of Formula Va or Vb. 
 
     
     
         653 . The method of  claim 652 , wherein said chiral resolving acid is tartaric acid. 
     
     
         654 . The method of  claim 652 , wherein said chiral resolving acid is L-(+)-tartaric acid. 
     
     
         655 . The method of  claim 652 , wherein said precipitate is enriched in the chiral resolving acid salt of said compound of Formula Vb. 
     
     
         656 . The method of  claim 652 , wherein R 1  is H, R 2  is Me, R 3  is H, R 4  is Cl, R 5  is H, R 6  is H, R 8a  is H, and R 8b  is H. 
     
     
         657 . A chiral resolving acid salt of a compound of Formula Va or Vb: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H or C 1 -C 8  alkyl; 
         R 2  is C 1 -C 8  alkyl, —CH 2 —O—(C 1 -C 8  alkyl), C(O)O—(C 1 -C 8  alkyl), —C(O)NH—(C 1 -C 8  alkyl), OH, C 1 -C 4  haloalkyl, or CH 2 OH; 
         R 3 , R 4 , R 5 , and R 6  are each, independently, H, halo, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 7  cycloalkyl, C haloalkyl, hydroxy, OR 9 , alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl, NR 10 R 11 , CN, NO 2 , heterocycloalkyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from C 1 -C 8  alkyl, halo, C 1 -C 8  haloalkyl, and alkoxy; or R 4  and R 5  together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; 
         R 8a  and R 8b  are each, independently, H, halo, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 7  cycloalkyl, C 1 -C 8  haloalkyl, alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, or R 8a  and R 8b  together with the carbon atom to which they are attached form a C 3 -C 7  cycloalkyl group; 
         R 9  is H, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 7  cycloalkyl, C 1 -C 8  haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl; and 
         R 10  and R 11  are each, independently, H, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 7  cycloalkyl, C 1 -C 8  haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R 10  and R 11  together with the N atom to which they are attached form a heterocyclic ring. 
       
     
     
         658 . The salt of  claim 657 , wherein said salt is a tartaric acid salt. 
     
     
         659 . The salt of  claim 657 , wherein said tartaric acid is L-(+)-tartaric acid. 
     
     
         660 . The salt of  claim 657 , having Formula Vb. 
     
     
         661 . The salt of  claim 660 , wherein R 1  is H, R 2  is Me, R 3  is H, R 4  is Cl, R 5  is H, R 6  is H, R 8a  is H, and R 8b  is H. 
     
     
         662 . A composition comprising at least one chiral resolving acid salt of  claim 657 . 
     
     
         663 . The composition of  claim 662 , wherein said composition comprises said tartaric acid salt form of a compound of Formula Va and said tartaric acid salt form of a compound of Formula Vb, wherein said composition is enriched in one of either of said tartaric acid salt form of a compound of Formula Va or said tartaric acid salt form of a compound of Formula Vb. 
     
     
         664 . A compound of Formula IX or X: 
       
         
           
           
               
               
           
         
         or salt form thereof, 
         wherein: 
         R 1  is H or C 1 -C 8  alkyl; 
         R 2  is C 1 -C 8  alkyl, —CH 2 —O—(C 1 -C 8  alkyl), C(O)O—(C 1 -C 8  alkyl), —C(O)NH—(C 1 -C 8  alkyl), or C 1 -C 4  haloalkyl; 
         R 3 , R 4 , R 5 , and R 6  are each, independently, H, halo, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 7  cycloalkyl, C 1 -C 8  haloalkyl, hydroxy, OR 9 , alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl, NR 10 R 11 , CN, NO 2 , heterocycloalkyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from C 1 -C 8  alkyl, halo, C 1 -C 8  haloalkyl, and alkoxy; or R 4  and R 5  together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; 
         R 8a  and R 8b  are each, independently, H, halo, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 7  cycloalkyl, C 1 -C 8  haloalkyl, alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH— alkyl, or hydroxyalkyl, or R 8a  and R 8b  together with the carbon atom to which they are attached form a C 3 -C 7  cycloalkyl group; 
         R 9  is H, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 7  cycloalkyl, C 1 -C 8  haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl; 
         R 10  and R 11  are each, independently, H, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 7  cycloalkyl, C 1 -C 8  haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R 10  and R 11  together with the N atom to which they are attached form a heterocyclic ring; 
         X 2  is halo or SO 2 R″; and 
         R″ is C 1 -C 8  alkyl, aryl, or heteroaryl each optionally substituted by one or more halo, cyano, nitro, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  alkoxy, or C 1 -C 4  haloalkoxy. 
       
     
     
         665 . The compound of  claim 665 , wherein X 2  is Cl. 
     
     
         666 . The compound of  claim 665 , wherein R 1  is H, R 2  is Me, R 3  is H, R 4  is Cl, R 5  is H, R 6  is H, R 8a  is H, and R 8b  is H. 
     
     
         667 . The compound of  claim 665 , wherein X 2  is Cl, R 1  is H, R 2  is Me, R 3  is H, R 4  is Cl, R 5  is H, R 6  is H, R 8a  is H, and R 8b  is H.