Processes and intermediates

Abstract

The invention relates to processes and compounds useful for producing modified aspartic acid derivatives, such as aspartic acid aldehyde moieties. Aspartic acid derivatives are useful for preparing caspase inhibitors and/or prodrugs thereof.

1 . A process of preparing a beta-amido carbonyl compound of formula XXX: 
       
         
           
           
               
               
           
         
         comprising the steps of:
 a) reacting a compound of formula XII: 
 
       
       
         
           
           
               
               
           
         
         with a compound of formula XIII: 
       
       
         
           
           
               
               
           
         
         in the presence of a palladium catalyst, a palladium ligand, a base, and a solvent optionally including a phase transfer catalyst and optionally including water, 
         to produce a compound of the formula XXXI 
       
       
         
           
           
               
               
           
         
         wherein:
 X is a leaving group; 
 Each R a  is H, an optionally substituted alkyl, an optionally substituted aryl, —CN, —C(O)—Oalkyl or halogen; 
 Each R 2  is independently an optionally substituted aliphatic group, an optionally substituted heterocyclic group, and an optionally substituted aryl group; 
 Each R 4  is independently an optionally substituted aliphatic, an optionally substituted heterocycle, an optionally substituted aryl, or R 2  and R 1  together with the groups to which they are bound, form an optionally substituted 5- to 8-membered heterocyclic ring; and 
 Each R 3  is an organic moiety. 
 
       
     
     
         2 . The process of  claim 1 , wherein the palladium catalyst is Pd(OAc) 2  or Pd 2  dba 3 . 
     
     
         3 . The process of  claim 1 , wherein the palladium ligand is phosphine, bisphosphine, XantPhos, DPEPhos, or bis(diphenylphosphino)ferrocene. 
     
     
         4 . The process of  claim 3 , wherein the palladium ligand is XantPhos. 
     
     
         5 . The process of  claim 1 , wherein the solvent is toluene, dioxane, THF, or a mixture thereof. 
     
     
         6 . The process of  claim 1 , wherein the base is K 2 CO 3  or Cs 2 CO 3 . 
     
     
         7 . The process of  claim 1 , wherein the reaction mixture includes a phase transfer catalyst and optionally water. 
     
     
         8 . The process of  claim 1 , wherein the palladium catalyst is Pd(OAc) 2  or Pd 2  dba 3 ; the palladium ligand is phosphine, bisphosphine, XantPhos, DPEPhos, or bis(diphenylphosphino) ferrocene; the solvent is toluene, dioxane, THF, or a mixture thereof; and the base is K 2 CO 3  or Cs 2 CO 3 . 
     
     
         9 . The process of  claim 1 , wherein R 3  is an optionally substituted aliphatic, an optionally substituted aryl, an optionally substituted heteroalkyl, an optionally substituted heteroaryl, a protecting group, P 2 -, P 3 -P 2 -, or P 4 -P 3 -P 2 -;
 P 2 - is   
       
         
           
           
               
               
           
         
         P 3 -P 2  is 
       
       
         
           
           
               
               
           
         
         P 4 -P 3 -P 2  is 
       
       
         
           
           
               
               
           
         
         T is —C(O)—, —O—C(O)—, —NHC(O)—, —C(O)C(O)— or —SO 2 —; 
         Each R is independently an optionally substituted aliphatic, or an optionally substituted aryl; 
         Each R 5  is independently H, an optionally substituted aliphatic, an optionally substituted heteroalkyl, an optionally substituted heteroaryl, or an optionally substituted phenyl; 
         Each R 6  is independently an optionally substituted aliphatic, an optionally substituted heteroalkyl, an optionally substituted heteroaryl, an optionally substituted phenyl, or R 5  and R 6  taken together with the atoms to which they are attached form a 5 to 7 membered, optionally substituted monocyclic heterocycle, or a 6 to 12 membered, optionally substituted bicyclic heterocycle, in which each heterocycle ring optionally contains an additional heteroatom selected from —O—, —S— or —NR 50 —; and 
         Each R 7  is independently H, an optionally substituted aliphatic, an optionally substituted heteroalkyl, an optionally substituted heteroaryl, or an optionally substituted phenyl, or
 R 7  and R 6  together with the atoms to which they are attached form a 5 to 7 membered, optionally substituted monocyclic heterocycle, a 5 to 7 membered, optionally substituted monocyclic aryl, a 6 to 12 membered, optionally substituted bicyclic heterocycle, or a 6 to 12 membered, optionally substituted bicyclic aryl, in which each heterocycle or aryl ring optionally contains an additional heteroatom selected from —O—, —S— or —NR 50 —, or 
 when R 5  and R 6  together to with the atoms to which they are attached form a ring, R 7  and the ring system formed by R 5  and R 6  form a 8- to 14-membered optionally substituted bicyclic fused ring system, wherein the bicyclic fused ring system is optionally further fused with an optionally substituted phenyl to form an optionally substituted 10- to 16-membered tricyclic fused ring system; 
 
         Each R 8  is independently H or a protecting group; and 
         Each R 50  is independently H, an optionally substituted aliphatic, an optionally substituted heteroalkyl, an optionally substituted heteroaryl, or an optionally substituted phenyl; and 
         m is 0 to 2. 
       
     
     
         10 . The process of  claim 9 , wherein R is aliphatic, aryl, or heteroaryl, each optionally substituted with 1 to 3 alkyl, halo, alkoxy, —CN, —NO 2 , —N(R 50 ) 2 , —SO m N(R 50 ) 2 , —NC(O)R 50 , —SO m R 50  or heterocycloalkyl. 
     
     
         11 . The process of  claim 1  further comprising reducing the compound of formula XXXI to produce a compound of Formula XXX. 
     
     
         12 . The process of  claim 11 , wherein R 4  and R 2  taken together with the atoms to which they are attached form a substituted beta-amidolactone of the formula 
       
         
           
           
               
               
           
         
         wherein R 9  is C 1 -C 5  alkyl. 
       
     
     
         13 . The process of  claim 1 , wherein R 3  has the structure 
       
         
           
           
               
               
           
         
         in which each R 5  is independently H, an optionally substituted aliphatic, an optionally substituted heteroalkyl, an optionally substituted heteroaryl, or an optionally substituted phenyl;
 each R 6  is independently an optionally substituted aliphatic, an optionally substituted heteroalkyl, an optionally substituted heteroaryl, an optionally substituted phenyl, or R 5  and R 6  taken together with the atoms to which they are attached form a 5 to 7 membered, optionally substituted monocyclic heterocycle, or a 6 to 12 membered, optionally substituted bicyclic heterocycle, in which each heterocycle ring optionally contains an additional heteroatom selected from —O—, —S— or —NR 50 —; 
 Each R 8  is independently H or a protecting group; 
 Each R 50  is independently H, an optionally substituted aliphatic, an optionally substituted heteroalkyl, an optionally substituted heteroaryl, or an optionally substituted phenyl 
 m is 0 to 2. 
 
       
     
     
         14 . The process of  claim 13 , wherein R 3  has the structure 
       
         
           
           
               
               
           
         
         in which Ring A is a 5 to 7 membered, optionally substituted monocyclic heterocycle, or a 6 to 12 membered, optionally substituted bicyclic heterocycle, in which each heterocycle ring optionally contains an additional heteroatom selected from —O—, —S— or —NR 50 —. 
       
     
     
         15 . The process of  claim 14 , wherein Ring A has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The process of  claim 15 , wherein R 3  has the structure 
       
         
           
           
               
               
           
         
       
     
     
         17 . The process of  claim 14 , wherein R 3  has the structure 
       
         
           
           
               
               
           
         
       
     
     
         18 . The process of  claim 17 , wherein R 3  has the structure 
       
         
           
           
               
               
           
         
       
     
     
         19 . The process of  claim 17 , wherein the compound of formula XII has the structure 
       
         
           
           
               
               
           
         
       
       in which R 9  is C 1 -C 5  alkyl, and the compound of formula XXXI has the structure 
       
         
           
           
               
               
           
         
       
     
     
         20 . The process of  claim 19 , wherein R 9  is —CH 2 CH 3 . 
     
     
         21 . The process of  claim 20 , wherein R 8  is a protecting group. 
     
     
         22 . The process of  claim 20 , wherein the protecting group is CBZ. 
     
     
         23 . A process of producing a compound of 
       
         
           
           
               
               
           
         
         comprising purifying a mixture of 
       
       
         
           
           
               
               
           
         
         wherein R 8  is a protecting group, and purifying includes chromatographing, selectively crystallizing, or dynamically crystallizing the mixture. 
       
     
     
         24 . The process of  claim 23 , wherein the step of purifying the mixture comprises separating the isomers by chromatography. 
     
     
         25 . The process of  claim 23 , wherein the step of purifying the mixture comprises selectively crystallizing the mixture with an organic solvent. 
     
     
         26 . The process of  claim 23 , wherein the step of purifying comprises dynamic crystallization which comprises contacting the mixture with a lewis acid and a solvent optionally including a protic acid. 
     
     
         27 . The process of  claim 26 , wherein the step of purifying comprises contacting the mixture with Al(Oalkyl) 3  in a solvent under acidic conditions. 
     
     
         28 . The process of  claim 27 , wherein the mixture is epimerized with Al(OEt) 3  in toluene in the presence of HCl. 
     
     
         29 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
     
     
         30 . A compound of formula I-A/C: 
       
         
           
           
               
               
           
         
       
     
     
         31 . A compound of formula: 
       
         
           
           
               
               
           
         
       
     
     
         32 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
     
     
         33 . A process for preparing a compound of formula IA: 
       
         
           
           
               
               
           
         
         comprising purifying a compound of formula: 
       
       
         
           
           
               
               
           
         
       
       wherein the step of purifying includes chromatographing, selectively crystallizing, or dynamically crystallizing the mixture. 
     
     
         34 . The process of  claim 33 , wherein the step of purifying the mixture comprises separating the isomers by chromatography. 
     
     
         35 . The process of  claim 33 , wherein the step of purifying the mixture comprises selectively crystallizing the mixture with an organic solvent. 
     
     
         36 . The process of  claim 35 , wherein the solvent is toluene. 
     
     
         37 . The process of  claim 33 , wherein the step of purifying comprises dynamic crystallization which comprises contacting the mixture with a lewis acid and a solvent optionally including a protic acid. 
     
     
         38 . The process of  claim 37 , wherein the step of purifying comprises contacting the mixture with Al(Oalkyl) 3  in a solvent under acidic conditions. 
     
     
         39 . The process of  claim 38 , wherein the mixture is epimerized with Al(OEt) 3  in toluene in the presence of HCl. 
     
     
         40 . A process for preparing a compound of formula I: 
       
         
           
           
               
               
           
         
         comprising:
 a) reacting a compound of formula II: 
 
       
       
         
           
           
               
               
           
         
         and a compound of formula III: 
       
       
         
           
           
               
               
           
         
         in the presence of a palladium catalyst, a palladium ligand, and a base in a solvent optionally including a phase transfer catalyst to provide the compound of formula I. 
       
     
     
         41 . The process according to  claim 40 , wherein the palladium catalyst is Pd(OAc) 2  or Pd 2  dba 3 . 
     
     
         42 . The process according to  claim 41 , wherein the palladium ligand is phosphine, bisphosphine, XantPhos, DPEPhos, or bis(diphenylphosphino)ferrocene. 
     
     
         43 . The process of  claim 42 , wherein the palladium ligand is XantPhos. 
     
     
         44 . The process of  claim 40 , wherein the solvent is toluene, dioxane, or THF, either alone or in combination. 
     
     
         45 . The process of  claim 40 , wherein the base is K 2 CO 3  or Cs 2 CO 3 . 
     
     
         46 . The process of  claim 40 , wherein the solvent includes a phase transfer catalyst. 
     
     
         47 . A process for preparing a compound of formula IV: 
       
         
           
           
               
               
           
         
         comprising reducing and deprotecting a compound of formula I: 
       
       
         
           
           
               
               
           
         
         to provide a compound of formula V: 
       
       
         
           
           
               
               
           
         
          and 
         reacting the compound of formula V with cbz-tert-leucine, under coupling conditions, to provide a compound of formula VI: 
       
       
         
           
           
               
               
           
         
         reacting the compound of formula VI under deprotection conditions to provide an amine and reacting the amine and 4-amino-3-chlorobenzoic to provide the compound of formula IV. 
       
     
     
         48 . The process of  claim 47 , wherein the compound of formula IV is represented by the structure: 
       
         
           
           
               
               
           
         
         the compound of formula I is represented by the structure: 
       
       
         
           
           
               
               
           
         
         the compound of formula V is represented by the structure: 
       
       
         
           
           
               
               
           
         
          and/or 
         the compound of formula VI is represented by the structure: 
       
       
         
           
           
               
               
           
         
       
     
     
         49 . A process for preparing a compound of formula IV: 
       
         
           
           
               
               
           
         
         comprising reacting a compound of formula I: 
       
       
         
           
           
               
               
           
         
         under deprotection conditions to provide a compound of formula VII: 
       
       
         
           
           
               
               
           
         
         reacting the compound of formula VII with cbz-tert-leucine, under coupling conditions, to provide a compound of formula VIII: 
       
       
         
           
           
               
               
           
         
         reducing and deprotecting the compound of formula VIII to provide a compound of formula IX: 
       
       
         
           
           
               
               
           
         
          and 
         reacting a compound of formula IX and 4-amino-3-chlorobenzoic acid, or a derivative thereof suitable for coupling to an amine under coupling conditions, to provide the compound of formula IV. 
       
     
     
         50 . The process of  claim 49 , wherein the compound of formula IV is represented by structure: 
       
         
           
           
               
               
           
         
       
       the compound of formula I is represented by structure: 
       
         
           
           
               
               
           
         
       
       the compound of formula VII is represented by structure: 
       
         
           
           
               
               
           
         
       
       the compound of formula VIII is represented by structure: 
       
         
           
           
               
               
           
         
       
       and/or the compound of formula IX is represented by structure: 
       
         
           
           
               
               
           
         
       
     
     
         51 . The process of  claim 50 , wherein the compound: 
       
         
           
           
               
               
           
         
       
       is obtained by purifying a compound of formula: 
       
         
           
           
               
               
           
         
       
       wherein the step of purifying includes chromatographing, selectively crystallizing, or dynamically crystallizing the mixture. 
     
     
         52 . The process of  claim 49  further comprising:
 reacting a compound of formula II: 
 
       
         
           
           
               
               
           
         
         and a compound of formula III: 
       
       
         
           
           
               
               
           
         
         in the presence of a palladium catalyst, a palladium ligand, a base, optionally a phase transfer catalyst, optionally water, and a solvent.