Process for synthesizing aspartic and glutamic acid derivatives especially useful as intermediates in the manufacture of a caspase inhibitor

Abstract

The invention relates to novel diazoketone derivatives. The invention also relates to processes for homologation of these diazoketone derivatives. The processes are useful for preparing compounds that are caspase inhibitors.

1 - 5 . (canceled) 
     
     
         6 . A process for producing a compound of the formula 2: 
       
         
           
           
               
               
           
         
       
       from a compound of the formula 1: 
       
         
           
           
               
               
           
         
       
       said process comprising the steps of providing a mixture of compound 1 and an organic solvent and subjecting the mixture to conditions that effect the rearrangement of compound 1 to compound 2; 
       wherein:
 R 1  is hydrogen; an amine protecting group; or a P2-P4 moiety of a caspase inhibitor, or portion thereof, 
 R x  is H; 
 R y  is OR 2 ; 
 or R x  and R y  are taken together to form —O(CH 2 ) y O— or ═O; y is 2-3; provided that when R x  and R y  are taken together to form ═O, R 1  is other than H; 
 each R 2  is independently hydrogen or an alcohol protecting group; 
 R 4  is OR, OR 2 , N(R) 2 , N(R 6 ) 2 , N(R 6 )(R 7 ), or N(R 7 ) 2 ; 
 R 5  is an electronegative leaving group, halo, OR, or SR; 
 each R is independently hydrogen; C1-C6 aliphatic; or Ar; wherein said aliphatic is optionally substituted with one or more substituents halo, C1-C6 alkoxy, cyano, nitro, oxo, OR 2 , OR 7 , N(R 6 ) 2 , N(R 7 ) 2 , N(R 6 )(R 7 ), Ar, Ar 1 , O—Ar, or O—Ar 1 ; 
 Ar is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring structure, wherein each ring contains 5 to 7 ring atoms and each ring optionally contains from 1 to 4 heteroatoms selected from O, N and S; 
 wherein Ar is optionally substituted at one or more ring atoms with one or more substituents independently selected from halo; C1-C6 alkoxy; cyano; nitro; oxo; OR 2 ; OR 7 ; SR 7 ; N(R 6 ) 2 ; N(R 7 ) 2 ; N(R 6 )(R 7 ); C(O)R 7 ; C(O)OR 7 ; C(O)N(R 7 ) 2 ; NR 7 C(O)R 7 ; NR 7 C(O)N(R 7 ) 2 ; NR 7 SO 2 R 7 ; SO 2 N(R 7 ) 2 ; NR 7 SO 2 N(R 7 ) 2 ; Ar 1 ; O—Ar 1 ; C1-C6 aliphatic optionally substituted with halo, C1-C6 alkoxy, cyano, nitro, oxo, OR 2 , OR 7 , SR 7 , N(R 6 ) 2 , N(R 7 ) 2 , or N(R 6 )(R 7 ); or O—C1-C6 aliphatic optionally substituted with halo, C1-C6 alkoxy, cyano, nitro, oxo, OR 2 , OR 7 , SR 7 , N(R 6 ) 2 , N(R 7 ) 2 , or N(R 6 )(R 7 ); 
 Ar 1  is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring structure, wherein each ring contains 5 to 7 ring atoms and each ring optionally contains from 1 to 4 heteroatoms selected from O, N, and S; 
 each R 6  is independently hydrogen or an amine protecting group; 
 each R 7  is independently hydrogen; C1-C6 aliphatic optionally substituted with halo, C1-C6 alkoxy, cyano, nitro, amino, oxo or hydroxy; or a saturated, partially saturated or unsaturated monocyclic or bicyclic ring structure, wherein each ring contains 5 to 7 ring atoms and each ring optionally contains from 1 to 4 heteroatoms selected from O, N, and S, and wherein each ring atom is optionally substituted with 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, nitro, amino, and hydroxy; 
 n is 0-6; and 
 p is 0-6. 
 
     
     
         7 . The process according to  claim 6 , further comprising the steps of:
 a) providing a mixture of compound 1 and an organic solvent;   b) adding to the mixture produced in step a):   i) a base; and   
       ii) a silver salt selected from Ag 2 O and
 AgO 2 CPh; 
 c) adjusting the resulting solution to a temperature in the range of −50° C. and about 150° C. for a period of between about 1 minute and about 48 hours to provide compound 2. 
 
     
     
         8 . The process according to  claim 7  wherein a compound R 4 H is added to the step a) mixture before step b). 
     
     
         9 . The process according to  claim 7 , comprising the further step of purifying compound 2. 
     
     
         10 . The process according to  claim 6  wherein said compound of formula 2 is produced in greater than about 50% diastereomeric excess and greater than about 50% enantiomeric excess. 
     
     
         11 . The process according to  claim 6  wherein said compound of formula 2 is produced in greater than about 95% enantiomeric excess. 
     
     
         12 . The process according to  claim 6  wherein said compound of formula 2 is produced in greater than about 98% enantiomeric excess. 
     
     
         13 . The process according to  claim 6  wherein said compound of formula 1 is in greater than about 50% diastereomeric excess and greater than about 50% enantiomeric excess. 
     
     
         14 . The process according to  claim 6  wherein said compound of formula 1 is in greater than about 95% enantiomeric excess. 
     
     
         15 . The process according to  claim 6  wherein said compound of formula 1 is in greater than about 98% enantiomeric excess. 
     
     
         16 . The process according to  claim 6  for producing a compound of formula 2a or 2b: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The process according to  claim 6 , wherein R x  is H and R y  is OR 2 ; R 4  is OR; R is CH 3 , Bn, or t-butyl; R 5  is F; n is 0 or 1; and p is 0. 
     
     
         18 . The process according to  claim 6 , wherein the silver salt is AgO 2 CPh. 
     
     
         19 . A process for producing a compound of the formula 2: 
       
         
           
           
               
               
           
         
       
       from a compound of the formula 1: 
       
         
           
           
               
               
           
         
       
       said process comprising the steps of:
 a) providing a mixture of compound 1 and an organic solvent; 
 b) heating the mixture formed in step a) to provide compound 2; and the process optionally comprising the further step of: 
 c) purifying compound 2; 
 
       wherein:
 R 1  is hydrogen; an amine protecting group; or a P2-P4 moiety of a caspase inhibitor, or portion thereof; 
 R x  is H; 
 R y  is OR 2 ; 
 or R x  and R y  are taken together to form —O(CH 2 ) y O— or ═O; y is 2-3; provided that when R x  and R y  are taken together to form ═O, R 1  is other than H; 
 each R 2  is independently hydrogen or an alcohol protecting group; 
 R 4  is OR, OR 2 , N(R) 2 , N(R 6 ) 2 , N(R 6 )(R 7 ), or N(R 7 ) 2 ; 
 R 5  is an electronegative leaving group, halo, OR, or SR; 
 each R is independently hydrogen; C1-C6 aliphatic; or Ar; wherein said aliphatic is optionally substituted with one or more substituents halo, C1-C6 alkoxy, cyano, nitro, oxo, OR 2 , OR 7 , SR 7 , N(R 6 ) 2 , N(R 7 ) 2 , N(R 6 )(R 7 ), Ar, Ar 1 , O—Ar, or O—Ar 1 ; 
 Ar is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring structure, wherein each ring contains 5 to 7 ring atoms and each ring optionally contains from 1 to 4 heteroatoms selected from O, N and S; 
 wherein Ar is optionally substituted at one or more ring atoms with one or more substituents independently selected from halo; C1-C6 alkoxy; cyano; nitro; oxo; OR 2 ; OR 7 ; SR 7 ; N(R 6 ) 2 ; N(R 7 ) 2 ; N(R 6 )(R 7 ); C(O)R 7 ; C(O)OR 7 ; C(O)N(R 7 ) 2 ; NR 7 C(O)R 7 ; NR 7 C(O)N(R 7 ) 2 ; NR 7 SO 2 R 7 ; SO 2 N(R 7 ) 2 ; NR 7 SO 2 N(R 7 ) 2 ; Ar 1 ; O—Ar 1 ; C1-C6 aliphatic optionally substituted with halo, C1-C6 alkoxy, cyano, nitro, oxo, OR 2 , OR 7 , SR 7 , N(R 6 ) 2 , N(R 7 ) 2 , or N(R 6 )(R 7 ); or O—C1-C6 aliphatic optionally substituted with halo, C1-C6 alkoxy, cyano, nitro, oxo, OR 2 , OR 7 , SR 7 , N(R 6 ) 2 , N(R 7 ) 2 , or N(R 6 )(R 7 ); 
 Ar 1  is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring structure, wherein each ring contains 5 to 7 ring atoms and each ring optionally contains from 1 to 4 heteroatoms selected from O, N, and S; 
 each R 6  is independently hydrogen or an amine protecting group; 
 each R 7  is independently hydrogen; C1-C6 aliphatic optionally substituted with halo, C1-C6 alkoxy, cyano, nitro, amino, oxo or hydroxy; or a saturated, partially saturated or unsaturated monocyclic or bicyclic ring structure, wherein each ring contains 5 to 7 ring atoms and each ring optionally contains from 1 to 4 heteroatoms selected from O, N, and S, and wherein each ring atom is optionally substituted with 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, nitro, amino, and hydroxy; 
 n is 0-6; and 
 p is 0-6. 
 
     
     
         20 . A process for producing a compound of the formula 2: 
       
         
           
           
               
               
           
         
       
       from a compound of the formula 1: 
       
         
           
           
               
               
           
         
       
       said process comprising the steps of:
 a) providing a mixture of compound 1 and an organic solvent; and 
 b) exposing the mixture formed in step a) to UV light to provide 2; 
 
       wherein:
 R 1  is hydrogen; an amine protecting group; or a P2-P4 moiety of a caspase inhibitor, or portion thereof; 
 R x  is H; 
 R y  is OR 2 ; 
 or R x  and R y  are taken together to form —O(CH 2 ) y O— or ═O; y is 2-3; provided that when R x  and R y  are taken together to form ═O, R 1  is other than H; 
 each R 2  is independently hydrogen or an alcohol protecting group; 
 R 4  is OR, OR 2 , N(R) 2 , N(R 6 ) 2 , N(R 6 )(R 7 ), or N(R 7 ) 2 ; 
 R 5  is an electronegative leaving group, halo, OR, or SR; 
 each R is independently hydrogen; C1-C6 aliphatic; or Ar; wherein said aliphatic is optionally substituted with one or more substituents halo, C1-C6 alkoxy, cyano, nitro, oxo, OR 2 , OR 7 , SR 7 , N(R 6 ) 2 , N(R 7 ) 2 , N(R 6 )(R 7 ), Ar, Ar 1 , O—Ar, or O—Ar 1 ; 
 Ar is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring structure, wherein each ring contains 5 to 7 ring atoms and each ring optionally contains from 1 to 4 heteroatoms selected from O, N and S; 
 wherein Ar is optionally substituted at one or more ring atoms with one or more substituents independently selected from halo; C1-C6 alkoxy; cyano; nitro; oxo; OR 2 ; OR 7 ; SR 7 ; N(R 6 ) 2 ; N(R 7 ) 2 ; N(R 6 )(R 7 ); C(O)R 7 ; C(O)OR 7 ; C(O)N(R 7 ) 2 ; NR 7 C(O)R 7 ; NR 7 C(O)N(R 7 ) 2 ; NR 7 SO 2 R 7 ; SO 2 N(R 7 ) 2 ; NR 7 SO 2 N(R 7 ) 2 ; Ar 1 ; O—Ar 1 ; C1-C6 aliphatic optionally substituted with halo, C1-C6 alkoxy, cyano, nitro, oxo, OR 2 , OR 7 , SR 7 , N(R 6 ) 2 , N(R 7 ) 2 , or N(R 6 )(R 7 ); or O—C1-C6 aliphatic optionally substituted with halo, C1-C6 alkoxy, cyano, nitro, oxo, OR 2 , OR 7 , SR 7 , N(R 6 ) 2 , N(R 7 ) 2 , or N(R 6 )(R 7 ); 
 Ar 1  is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring structure, wherein each ring contains 5 to 7 ring atoms and each ring optionally contains from 1 to 4 heteroatoms selected from O, N, and S; 
 each R 6  is independently hydrogen or an amine protecting group; 
 each R 7  is independently hydrogen; C1-C6 aliphatic optionally substituted with halo, C1-C6 alkoxy, cyano, nitro, amino, oxo or hydroxy; or a saturated, partially saturated or unsaturated monocyclic or bicyclic ring structure, wherein each ring contains 5 to 7 ring atoms and each ring optionally contains from 1 to 4 heteroatoms selected from O, N, and S, and wherein each ring atom is optionally substituted with 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, nitro, amino, and hydroxy; 
 n is 0-6; and 
 p is 0-6. 
 
     
     
         21 - 52 . (canceled)