Process for synthesizing bicyclic compounds from piperazic acid or an ester thereof especially useful as an intermediate in the manufacture of a caspase inhibitor

Abstract

The invention relates to a process for simultaneously N(2)-acylating piperazic acid or an ester thereof and forming a bicyclic ring structure. The invention also relates to the use of that process step in a method of synthesizing a bicyclic compound useful as an intermediate for the production of an inhibitor of a caspase, particularly an inhibitor of interleukin-1β converting enzyme (“ICE”).

We claim:  
     
         1 . A process for converting compound G to compound H:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is a C 2-4  straight chain alkyl substituted at the carbon alpha to the COOH moiety with N(R 4 )(R 4 ), NO 2  or N 3  and optionally substituted at any other carbon with one or more substituents independently selected from C 1-6  straight or branched alkyl, C 2-4  straight or branched alkenyl or alkynyl, O—[C 1-6  straight or branched alkyl], O—[C 2-6  straight or branched alkenyl or alkynyl], oxo, or halo; wherein  
 each R 4  is independently selected from H or an amino protecting group, with the proviso that both R 4  are not simultaneously hydrogen;  
 R 2  is selected from hydrogen, C 1-6  straight or branched alkyl, C 2-6  straight or branched alkenyl or alkynyl, or Ar, wherein said alkyl, alkenyl or alkynyl is optionally substituted with Ar; wherein  
 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 3 heteroatoms selected from O, N and S; and  
 Ar is optionally substituted at one or more ring atoms with one or more substituents independently selected from C 1-6  straight or branched alkyl, C 2-6  straight or branched alkenyl or alkynyl, O—[C 1-6  straight or branched alkyl], O—[C 2-6  straight or branched alkenyl or alkynyl], oxo, halo, NO 2 , N(R 4 )(R 4 ), or CN;  
 n is 0 or 1;  
 any substitutable ring carbon is optionally substituted by Q 1 ; wherein  
 each Q 1  is independently selected from —Ar 1 , -T 1 -R 9 , or (CH 2 ) 1-3 -T 1 -R 9 ; provided that when —Ar 1  is substituted with a Q 1  which comprises one or more additional —Ar 1  groups, said additional —Ar 1  groups are not substituted with Q 1 ; wherein  
 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 3 heteroatoms selected from O, N and S; and  
 wherein each Ar 1  is optionally singly or multiply substituted at any ring atom by —N(R 9 )(R 9 ), halo, —NO 2 , —CN, ═O, —OH, -perfluoro C 1-3  alkyl,  
                     
 or -Q 1 ;  
 wherein each R 9  is a C 1-6  straight or branched alkyl group optionally substituted with one or more substituents independently selected from —F, ═O or Ar 1 , wherein any R 9  may be substituted with a maximum of two Ar 1 ;  
 T 1  is selected from a valence bond, —CH═CH—, —O—, —S—, —SO—, —SO 2 —, —NR 10 —, —NR 10 —C(O)—, —C(O)—, —O—C(O)—, —C(O)—O—, —C(O)—NR 10 —, O—C(O)—NR 10 —, —NR 10 —C(O)—O—, —NR 10 —C(O)—NR 10 —, —S(O) 2 —NR 10 —, —NR 10 —S(O) 2 —, or —NR 10 —S(O) 2 —NR 10 —; and  
 each R 10  is independently selected from —H or C 1-6  straight or branched alkyl; said process comprising the steps of:  
 a) combining compound G with an organic solvent selected from dichloroethane, dichloromethane, toluene, chlorobenzene, chloroform, monoglyme, diglyme, THF, or CCl 4 ;  
 b) adding less than about 0.2 equivalents of DMF;  
 c) adjusting the temperature of the resulting mixture to between 20° C. and 100° C.;  
 d) adding about 2 or more equivalents of SOCl 2  to said mixture over a period of between 2 and 24 hours.  
 
     
     
         2 . A process for producing a compound of the formula H:  
       
         
           
           
               
               
           
         
       
       from a compound of the formula A:  
       
         
           
           
               
               
           
         
       
       comprising the steps of: 
 a) halogenating compound A to produce compound B:  
                     
 b) esterifying the carboxylic acid moiety on compound B to produce compound C:  
                     
 c) reacting compound C with compound D:  
                     
 to produce compound E:  
                     
 d) reacting compound E with compound F:  
                     
 to produce compound G:  
                     
 e) combining compound G with an organic solvent selected from dichloroethane, dichloromethane, toluene, chlorobenzene, chloroform, monoglyme, diglyme, THF, or CCl 4 ;  
 f) adding less than about 0.2 equivalents of DMF;  
 g) adjusting the temperature of the resulting mixture to between 20° C. and 100° C.;  
 h) adding about 2 or more equivalents of SOCl 2  to said mixture over a period of between 2 and 24 hours;  
 wherein:  
 R 1  is a C 2-4  straight chain alkyl substituted at the carbon alpha to the COOH moiety with N(R 4 )(R 4 ), NO 2  or N 3  and optionally substituted at any other carbon with one or more substituents independently selected from C 1-6  straight or branched alkyl, C 2-4  straight or branched alkenyl or alkynyl, O—[C 1-6  straight or branched alkyl], O—[C 2-6  straight or branched alkenyl or alkynyl], oxo, or halo; wherein  
 each R 4  is independently selected from H or an amino protecting group, with the proviso that both R 4  are not simultaneously hydrogen;  
 R 2  is selected from hydrogen, C 1-6  straight or branched alkyl, C 2-6  straight or branched alkenyl or alkynyl, or Ar, wherein said alkyl, alkenyl or alkynyl is optionally substituted with Ar; wherein  
 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 3 heteroatoms selected from O, N and S; and  
 Ar is optionally substituted at one or more ring atoms with one or more substituents independently selected from C 1-6  straight or branched alkyl, C 2-6  straight or branched alkenyl or alkynyl, O—[C 1-6  straight or branched alkyl], O—[C 2-6  straight or branched alkenyl or alkynyl], oxo, halo, NO 2 , N(R 4 )(R 4 ), or CN;  
 n is 0 or 1;  
 any substitutable ring carbon is optionally substituted by Q 1 ; wherein  
 each Q 1  is independently selected from —Ar 1 , -T 1 -R 9 , or (CH 2 ) 1-3 -T 1 -R 9 ; provided that when —Ar 1  is substituted with a Q 1  which comprises one or more additional —Ar 1  groups, said additional —Ar 1  groups are not substituted with Q 1 ; wherein  
 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 3 heteroatoms selected from O, N and S; and  
 wherein each Ar 1  is optionally singly or multiply substituted at any ring atom by —N(R 9 )(R 9 ), halo, —NO 2 , H 2 —CN, ═O, —OH, -perfluoro C 1-3  alkyl,  
                     
 or -Q 1 ;  
 wherein each R 9  is a C 1-6  straight or branched alkyl group optionally substituted with one or more substituents independently selected from —F, ═O or Ar 1 , wherein any R 9  may be substituted with a maximum of two Ar 1 ;  
 T 1  is selected from a valence bond, —CH═CH—, —O—, —S—, —SO—, —SO 2 —, —NR 10 —, —NR 10 —C(O)—, —C(O)—, —O—C(O)—, —C(O)—O—, —C(O)—NR 10 —, O—C(O)—NR 10 —, —NR 10 —C(O)—O—, —NR 10 —C(O)—NR 10 —, —S(O) 2 —NR 10 —, —NR 10 —S(O) 2 —, or —NR 10 —S(O) 2 —NR 10 —; and  
 each R 10  is independently selected from —H or C 1-6  straight or branched alkyl;  
 each R′ is a carboxy protecting, either the same or different; and  
 each “Hal” is a halogen, either the same or different.  
 
     
     
         3 . The process according to  claim 1  or  2 , wherein R 1  is:  
       
         
           
           
               
               
           
         
       
     
     
         4 . The process according to  claim 3 , wherein n is 1.  
     
     
         5 . The process according to  claim 4 , wherein R 2  is t-butyl.  
     
     
         6 . The process according to  claim 5 , wherein compound G has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         7 . The process according to  claim 1  or  2 , wherein in step (a) of  claim 1  or in step (e) of  claim 2  the organic solvent is dichloroethane.  
     
     
         8 . The process according to  claim 7 , wherein in step (b) of  claim 1  or step (f) of  claim 2  about 0.1 equivalent of DMF is used.  
     
     
         9 . The process according to  claim 8  wherein step (c) of  claim 1  or step (g) of  claim 2  is carried out at about 60° C.  
     
     
         10 . The process according to  claim 9 , wherein in step (d) of  claim 1  or step (h) of  claim 2 , about 2 equivalents of SOCl 2  is used; and wherein said SOCl 2  is added over a period of about 2 hours.  
     
     
         11 . The process according to  claim 1  or  2 , wherein at step (b) in  claim 1  or at step (f) of  claim 2 , excess equivalents of a base selected from pyridine, collidine, lutidine, NaHCO 3 , imidazole, triethylamine, N-methylmorpholine, diisopropylethylamine or K 2 CO 3  are added to the solution containing compound G.  
     
     
         12 . The process according to  claim 11 , wherein said base is 2,6-lutidine of which about 5 equivalents are added.  
     
     
         13 . A process for producing a compound of formula (I) from compound G:  
       
         
           
           
               
               
           
         
       
       wherein: 
 any ring is optionally substituted at any carbon by Q 1 , at any nitrogen by R 5 , and at any atom by ═O, —OH, —COOH, or halogen;  
 X 1  is CH or N;  
 g is 0 or 1;  
 m is 0, 1 or 2;  
 n is 0 or 1;  
 each J is independently selected from —H, —OH, or —F, provided that when a first and a second J are bound to a C, and said first J is —OH, then said second J is —H;  
 T is —Ar 3 , —OH, —CF 3 , —C(O)—C(O)—OH, —C(O)—OH or any biosteric replacement for —C(O)—OH;  
 R 3  is —CN, —CH═CH—R 9 , CH═N—O—R 9 , —(CH 2 ) 1-3 -T 1 -R 9 , —CJ 2 -R 9 , —C(O)—R 13 , or —C(O)—C(O)—N(R 5 )(R 10 );  
 T 1  is —CH═CH—, —O—, —S—, —SO—, —SO 2 —, —NR 10 —, —NR 10 —C(O)—, —C(O)—, —O—C(O)—, —C(O)—O—, —C(O)—NR 10 —, O—C(O)—NR 10 —, —NR 10 —C(O)—O—, —NR 10 —C(O)—NR 10 —, —S(O) 2 —NR 10 —, —NR 10 —S(O) 2 — or —NR 10 —S(O) 2 —NR 10 —;  
 each R 5  is independently selected from —H, —Ar 1 , —C(O)—Ar 1 , —S(O) 2 —Ar 1 , —R 9 , —C(O)—NH 2 , —S(O) 2 —NH 2 , —C(O)—R 9 , —C(O)—O—R 9 , —S(O) 2 —R 9 , —C(O)—N(R 10 )(Ar 1 ), —S(O) 2 —N(R 10 )(Ar 1 ), —C(O)—N(R 10 )(R 9 ), or —S(O) 2 —N(R 10 )(R 9 );  
 each R 9  is a C 1-6  straight or branched alkyl group optionally singly or multiply substituted with —OH, —F, ═O or Ar 1 , wherein any R 9  may be substituted with a maximum of two Ar 1 ;  
 each R 10  is independently selected from —H or C 1-6  straight or branched alkyl;  
 R 13  is —H, —Ar 1 , —R 9 , -T 1 -R 9  or —(CH 2 ) 1-3 -T 1 -R 9 ;  
 each Ar 1  is a cyclic group independently selected from a monocyclic, bicyclic or tricyclic aryl group containing 6, 10, 12 or 14 carbon atoms; a monocyclic, bicyclic or tricyclic cycloalkyl group containing between 3 and 15 carbon atoms, said cycloalkyl group being optionally benzofused; or a monocyclic, bicyclic or tricyclic heterocycle group containing between 5 and 15 ring atoms and at least one heteroatom group selected from —O—, —S—, —SO—, —SO 2 —, ═N—, or —NH—, wherein said heterocycle group optionally contains one or more double bonds and optionally comprises one or more aromatic rings;  
 Ar 3  is a cyclic group selected from phenyl, a 5-membered heteroaromatic ring or a 6-membered heteroaromatic ring, wherein said heteroaromatic rings comprise from 1-3 heteroatom groups selected from —O—, —S—, —SO—, —SO 2 —, ═N—, or —NH—;  
 wherein each Ar 1  or Ar 3  is optionally singly or multiply substituted at any ring atom by —NH 2 , —C(O)—OH, —Cl, —F, —Br, —I, —NO 2 , —CN, ═O, —OH, -perfluoro C 1-3 alkyl,  
                     
 or -Q 1 ; and  
 each Q 1  is independently selected from —Ar 1 , —R 9 , -T 1 -R 9 , or (CH 2 ) 1-3 -T 1 -R 9 ; provided that when —Ar 1  is substituted with a Q 1  which comprises one or more additional —Ar 1  groups, said additional —Ar 1  groups are not substituted with Q 1 ; said process comprising the steps of:  
 a) combining compound G with an organic solvent selected from dichloroethane, dichloromethane, toluene, chlorobenzene, chloroform, monoglyme, diglyme, THF, or CCl 4 ;  
 b) adding less than about 0.2 equivalents of DMF;  
 c) adjusting the temperature of the resulting mixture to between 20° C. and 100° C.;  
 d) adding about 2 or more equivalents of SOCl 2  to said mixture over a period of between 2 and 24 hours;  
 e) removing the amine protecting group from compound H to form amine J;  
 f) coupling of R 5  to amine J to form ester K;  
 g) deprotecting ester K to form acid L; and  
 h) coupling acid L to  
                     
 to form a compound of formula I.  
 
     
     
         14 . The process according to  claim 13 , wherein m is 2 and n is 1.  
     
     
         15 . The process according to  claim 14 , wherein the terminal R 5  is selected from —C(O)—Ar 1 , —C(O)—NH 2 , —C(O)—R 9 , —C(O)—O—R 9 , —C(O)—N(R 10 )(Ar 1 ), or —C(O)—N(R 10 )(R 9 ).  
     
     
         16 . The process according to  claim 15 , wherein: 
 X 1  is CH;    each J is H;    m′ is 1;    T is —COOH or a biosteric replacement for —COOH;    g is 0; and    R 3  is —C(O)—R 13 .    
     
     
         17 . The process according to  claim 16 , wherein compound I has the structure:  
       
         
           
           
               
               
           
         
       
     
     
         18 . A process for producing a compound of formula (II) from compound G:  
       
         
           
           
               
               
           
         
       
       wherein: 
 Z is selected from  
                     
 p is 1 or 2;  
 each R 5′  is independently selected from —C(O)—R 10′ , —C(O)O—R 9′ , —C(O)—N(R 10′ )(R 10′ ), —S(O) 2 —R 9′ , —S(O) 2 —NH—R 10′ , —C(O)—CH 2 —O—R 9′ , —C(O)C(O)—R 10′ , —R 9′ , —H, —C(O)C(O)—OR 10′ , or —C(O)C(O)—N(R 9′ )(R 10′ );  
 each R 9′  is independently selected from —Ar 1  or a —C 1-6  straight or branched alkyl group optionally substituted with Ar 1 , wherein the —C 1-6  alkyl group is optionally unsaturated;  
 each R 10′  is independently selected from —H, —Ar 1 , a —C 3-6  cycloalkyl group, or a —C 1-6  straight or branched alkyl group optionally substituted with Ar 3′ , wherein the —C 1-6  alkyl group is optionally unsaturated;  
 R 13′  is selected from H, Ar 1 , or a C 1-6  straight or branched alkyl group optionally substituted with Ar 1 , —CONH 2 , —OR 5′ , —OH, —OR 9′ , or —CO 2 H;  
 each R 51  is independently selected from R 9′ , —C(O)—R 9′ , —C(O)—N(H)—R 9′ , or two R 51  taken together form a saturated 4-8 member carbocyclic ring or heterocyclic ring containing —O—, —S—, or —NH—;  
 each R 21  is independently selected from —H or a —C 1-6  straight or branched alkyl group;  
 Y 2  is —H 2  or ═O  
 each Ar 1  is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings and an aromatic heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, and —NH—, said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by -Q 1 ; and  
 each Q 1  is independently selected from the group consisting of —NH 2 , —CO 2 H, —Cl, —F, —Br, —I, —NO 2 , —CN, ═O, —OH, -perfluoro C 1-3  alkyl, R 5′ , —OR 5′ , —NHR 5′ —, OR 9′ , —N(R 9′ )(R 10′ ), R 9′ , —C(O)—R 10′ , and  
                     
 provided that when —Ar 1  is substituted with a Q 1  group which comprises one or more additional —Ar 1  groups, said additional —Ar 1  groups are not substituted with another —Ar 1 , said process comprising the steps of:  
 a) combining compound G with an organic solvent selected from dichloroethane, dichloromethane, toluene, chlorobenzene, chloroform, monoglyme, diglyme, THF, or CCl 4 ;  
 b) adding less than about 0.2 equivalents of DMF;  
 c) adjusting the temperature of the resulting mixture to between 20° C. and 100° C.;  
 d) adding about 2 or more equivalents of SOCl 2  to said mixture over a period of between 2 and 24 hours;  
 e) removing the amine protecting group from compound H to form amine J;  
 f) coupling of R 5  to amine J to form ester K;  
 g) deprotecting ester K to form acid L; and  
 h) coupling acid L to —NH-Z to form a compound of formula II.  
 
     
     
         19 . The process according to  claim 18 , wherein in compound II, Y 2  is O and R 21  is H.  
     
     
         20 . The process according to  claim 19 , wherein in compound II, R 5′ , is selected from —C(O)—R 10 ′, —C(O)O—R 9′ , —C(O)—N(R 10′ )(R 10′ ), —C(O)—CH 2 —O—R 9′ , —C(O)C(O)—R 10′ , —C(O)C(O)—OR 10′ , or —C(O)C(O)—N(R 9′ )(R 10′ ).  
     
     
         21 . The process according to  claim 20 , wherein in compound II, 
 z is                          p is 1; and    R 51  is selected from —Ar 1 , —C 1-6  straight or branched alkyl or —C 1-6  straight or branched alkyl substituted with Ar 1 .    
     
     
         22 . The process according to  claim 21 , wherein compound II has the structure:  
       
         
           
           
               
               
           
         
       
       .