Process for the preparation of opiod modulators

Abstract

The present invention is directed to novel processes for the preparation of opioid modulators (agonists and antagonists) and intermediates in their synthesis. The opioid modulators are useful for the treatment and prevention of as pain and gastrointestinal disorders.

1 . A process for the preparation of a compound of formula (I) 
     
       
         
         
             
             
         
       
       wherein 
     
     
       
         
         
             
             
         
       
     
     is C 6-10 aryl or a heteroaryl selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl, benzimidazol, benzthiazolyl, benzoxazolyl, quinolizinyl, quinolinyl, isoquinolinyl and quinazolinyl;
 each R 41P  is independently selected from C 1-6 alkyl, C 1-6 alkoxy or fluoro; 
 R J  and R K  are each independently selected from hydrogen or C 1-4 alkyl; alternatively, R J  and R K  are taken together with the nitrogen atom to which they are bound to form a five to seven membered heterocyclyl; 
 Pg 1  is a nitrogen protecting group; 
 comprising 
 
     
       
         
         
             
             
         
       
       reacting a compound of formula (X), wherein X P  is selected from OH, CN, —CO 2 H, —C(O)—Cl or —C(O)—OC 1-4 alkyl and wherein Y P  is selected from Br, Cl or I, to yield the corresponding compound of formula (XII); 
     
     
       
         
         
             
             
         
       
       reacting the compound of formula (XII) with a suitably substituted compound of formula (XVIII); in the presence of palladium catalyst; in the presence of an organic or inorganic base; in an organic solvent; at a temperature greater than about room temperature; to yield the corresponding compound of formula (XIX); 
     
     
       
         
         
             
             
         
       
       reacting the compound of formula (XIX) with hydrogen or a source of hydrogen; in the presence of a catalyst; in a solvent; at a temperature greater than about room temperature; to yield the corresponding compound of formula (XX); 
     
     
       
         
         
             
             
         
       
       reacting the compound of formula (XX) with an aqueous base; in an organic solvent; to yield the corresponding compound of formula (I). 
     
   
   
       2 . The process as in  claim 1 , wherein 
     
       
         
         
             
             
         
       
     
     is phenyl;
 the phenyl is substituted with a R 41P  group at the 2-position and a second R 41P  group at the 4-position; 
 each R 41P  is independently selected from C 1-2 alkyl, C 1-2 alkoxy or fluoro; 
 R J  and R K  are each independently selected from hydrogen or C 1-4 alkyl; 
 alternatively, R J  and R K  are taken together with the nitrogen atom to which they are bound to form a five to seven membered heterocyclyl; and 
 Pg 1  is a nitrogen protecting group. 
 
   
   
       3 . The process as in  claim 1 , wherein 
     
       
         
         
             
             
         
       
     
     is phenyl; the phenyl is substituted with a R 41P  group at the 2-position and a second R 41P  group at the 4-position; each R 41P  is methyl; R J  and R K  are each hydrogen; and Pg 1  is a t-butoxycarbonyl. 
   
   
       4 . A process for the preparation of a compound of formula (I) 
     
       
         
         
             
             
         
       
       wherein 
     
     
       
         
         
             
             
         
       
     
     is C 6-10 aryl or a heteroaryl selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolizinyl, quinolinyl, isoquinolinyl and quinazolinyl;
 each R 41P  is independently selected from C 1-6 alkyl, C 1-6 alkoxy or fluoro; 
 R J  and R K  are each independently selected from hydrogen or C 1-4 alkyl; alternatively, R J  and R K  are taken together with the nitrogen atom to which they are bound to form a five to seven membered heterocyclyl; 
 Pg 1  is a nitrogen protecting group; 
 comprising 
 
     
       
         
         
             
             
         
       
       reacting the compound of formula (XIX) with hydrogen or a source of hydrogen; in the presence of a catalyst; in a solvent; at a temperature greater than about room temperature; to yield the corresponding compound of formula (XX); 
     
     
       
         
         
             
             
         
       
       reacting the compound of formula (XX) with an aqueous base; in an organic solvent; to yield the corresponding compound of formula (I). 
     
   
   
       5 . A process for the preparation of a compound of formula (Ia) 
     
       
         
         
             
             
         
       
       comprising 
     
     
       
         
         
             
             
         
       
       reacting a compound of formula (Xa), wherein X P  is selected from OH, CN, —CO 2 H, —C(O)—Cl or —C(O)—OC 1-4 alkyl and wherein Y P  is selected from Br, Cl or I, to yield the corresponding compound of formula (XIIa); 
     
     
       
         
         
             
             
         
       
       reacting the compound of formula (XIIa) with a suitably substituted compound of formula (XVIIIa); in the presence of palladium catalyst; in the presence of an organic or inorganic base; in an organic solvent; at a temperature greater than about room temperature; to yield the corresponding compound of formula (XIXa); 
     
     
       
         
         
             
             
         
       
       reacting compound of formula (XIXa) with hydrogen gas, at a pressure sufficient to hydrogenate; in the presence of a suitable chiral catalyst; at a temperature greater than about room temperature; in an organic solvent; to yield the corresponding compound of formula (XXa); 
     
     
       
         
         
             
             
         
       
       reacting the compound of formula (XXa) with an aqueous base; in an organic solvent; to yield the corresponding compound of formula (Ia). 
     
   
   
       6 . The process as in  claim 5 , wherein X P  is —OH and wherein Y P  is Br. 
   
   
       7 . The process as in  claim 6 , further comprising 
     
       
         
         
             
             
         
       
       reacting the compound of formula (Xa), with a triflating reagent; in the presence of an organic or inorganic base; to yield the corresponding compound of formula (XIa); 
     
     
       
         
         
             
             
         
       
       reacting the compound of formula (XIa) with carbon monoxide and a suitable source of ammonia; in the presence of a palladium catalyst in combination with a suitable ligand; or in the presence of a palladium:ligand complex; at a temperature in the range of from about 50° C. to about 160° C.; in an organic solvent; to yield the corresponding compound of formula (XII). 
     
   
   
       8 . The process as in  claim 5 , wherein the compound of formula (XIIa) is reacted with the compound of formula (XVIIIa) in the presence of Pd 2 (dba) 3  and P(o-toluene) 3 . 
   
   
       9 . The process as in  claim 5 , wherein the chiral catalyst is [Rh(cod)(R,R-DIPAMP)] + BF 4   − . 
   
   
       10 . A process for the preparation of the compound of formula (Ia) 
     
       
         
         
             
             
         
       
       comprising 
     
     
       
         
         
             
             
         
       
       reacting compound of formula (XIXa) with hydrogen gas, at a pressure sufficient to hydrogenate; in the presence of a suitable chiral catalyst; at a temperature greater than about room temperature; in an organic solvent; to yield the corresponding compound of formula (XXa); 
     
     
       
         
         
             
             
         
       
       reacting the compound of formula (XXa) with an aqueous base; in an organic solvent; to yield the corresponding compound of formula (Ia). 
     
   
   
       11 . A product prepared according to the process of  claim 1 . 
   
   
       12 . A product prepared according to the process of  claim 4 . 
   
   
       13 . A product prepared according to the process of  claim 5 . 
   
   
       14 . A product prepared according to the process of  claim 10 . 
   
   
       15 . A process for the preparation of compounds of formula (II) 
     
       
         
         
             
             
         
       
       wherein 
     
     
       
         
         
             
             
         
       
     
     is C 6-10 aryl or a heteroaryl selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolizinyl, quinolinyl, isoquinolinyl and quinazolinyl;
 each R 41P  is independently selected from C 1-6 alkyl, C 1-6 alkoxy or fluoro; 
 R J  and R K  are each independently selected from hydrogen or C 1-4 alkyl; alternatively, R J  and R K  are taken together with the nitrogen atom to which they are bound to form a five to seven membered heterocyclyl; 
 R 1  is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclyl, aryl(C 1-6 )alkyl, and heteroaryl(C 1-6 )alkyl;
 wherein when R 1  is phenyl(C 1-6 )alkyl, phenyl is optionally fused to a heterocyclyl or cycloalkyl; 
 wherein when R 1  is C 1-2 alkyl, said C 1-2 alkyl is optionally substituted with one to two substituents independently selected from the group consisting of C 1-6 alkoxy, aryl, cycloalkyl, heterocyclyl, hydroxy, cyano, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, trifluoromethyl, and carboxy; 
 and further, wherein when R 1  is C 3-6 alkyl, said C 3-6 alkyl is optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkoxy, aryl, cycloalkyl, heterocyclyl, hydroxy, cyano, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, trifluoromethyl, and carboxy; 
 wherein the cycloalkyl and heterocyclyl of C 1-2 alkyl and C 3-6 alkyl are optionally substituted with one to two substituents independently selected from the group consisting of C 1-6 alkyl, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, hydroxy, cyano, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, trifluoromethyl, carboxy, aryl(C 1-6 )alkoxycarbonyl, C 1-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, and aminosulfonyl; 
 furthermore, wherein the cycloalkyl and heterocyclyl of R 1  are optionally substituted with one to two substituents independently selected from the group consisting of C 1-6 alkyl, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, hydroxy, cyano, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, trifluoromethyl, carboxy, aryl(C 1-6 )alkoxycarbonyl, C 1-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, and aminosulfonyl; 
 furthermore, wherein the aryl and heteroaryl portion of the R 1  substituents aryl(C 1-6 )alkyl and heteroaryl(C 1-6 )alkyl, are optionally substituted with one to three R 11  substituents independently selected from the group consisting of C 1-6 alkyl; hydroxy(C 1-6 )alkyl; C 1-6 alkoxy; C 6-10 aryl(C 1-6 )alkyl; C 6-10 aryl(C 1-6 )alkoxy; C 6-10 aryl; heteroaryl optionally substituted with one to two substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, and carboxy; cycloalkyl; heterocyclyl; C 6-10 aryloxy; heteroaryloxy; cycloalkyloxy; heterocyclyloxy; amino; C 1-6 alkylamino; (C 1-6 alkyl) 2 amino; C 3-6 cycloalkylaminocarbonyl; hydroxy(C 1-6 )alkylaminocarbonyl; C 6-10 arylaminocarbonyl wherein C 6-10 aryl is optionally substituted with carboxy or C 1-4 alkoxycarbonyl; heterocyclylcarbonyl; carboxy; C 1-6 alkylcarbonyloxy; C 1-6 alkoxycarbonyl; C 1-6 alkylcarbonyl; C 1-6 alkylcarbonylamino; aminocarbonyl; C 1-6 alkylaminocarbonyl; (C 1-6 alkyl) 2 aminocarbonyl; cyano; halogen; trifluoromethyl; trifluoromethoxy; and hydroxy; 
 provided that no more than one R 11  substituent is selected from the group consisting of C 6-10 aryl(C 1-6 )alkyl; C 6-10 aryl(C 1-6 )alkoxy; C 6-10 aryl; heteroaryl optionally substituted with one to two substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, and carboxy; cycloalkyl; heterocyclyl; C 6-10 aryloxy; heteroaryloxy; cycloalkyloxy; C 6-10 arylaminocarbonyl, heterocyclylcarbonyl; and heterocyclyloxy; 
 
 R 2  is hydrogen, C 1-8 alkyl, hydroxy(C 1-8 )alkyl, C 6-10 aryl(C 1-6 )alkoxy(C 1-6 )alkyl, or C 6-10 aryl(C 1-8 )alkyl;
 wherein the C 6-10 aryl group in the C 6-10 aryl-containing substituents of R 2  is optionally substituted with one to two substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, hydroxy, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, cyano, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; and, wherein the C 1-6 alkyl and C 1-6 alkoxy substituents of aryl are optionally substituted with hydroxy, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, or aryl; 
 
 A is selected from the group consisting of aryl, ring system a-1, a-2, a-3, and a-4, optionally substituted with R 3  and R 5 ; 
 
     
       
         
         
             
             
         
       
       
         wherein A-B is selected from the group consisting of N—C, C—N, N—N and C—C; wherein D-E is selected from the group consisting of O—C, S—C, and O—N; and wherein F-G is selected from the group consisting of N—O and C—O; 
       
       R 3  is one to two substituents independently selected from the group consisting of C 1-6 alkyl, aryl, aryl(C 1-6 )alkyl, aryl(C 2-6 )alkenyl, aryl(C 2-6 )alkynyl, heteroaryl, heteroaryl(C 1-6 )alkyl, heteroaryl(C 2-6 )alkenyl, heteroaryl(C 2-6 )alkynyl, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, arylamino, heteroarylamino, aryloxy, heteroaryloxy, trifluoromethyl, and halogen;
 wherein the aryl and heteroaryl, as well as the aryl and heteroaryl of aryl(C 1-6 )alkyl, aryl(C 2-6 )alkenyl, aryl(C 2-6 )alkynyl, heteroaryl(C 1-6 )alkyl, heteroaryl(C 2-6 )alkenyl, heteroaryl(C 2-6 )alkynyl, arylamino, heteroarylamino, aryloxy, and heteroaryloxy, are optionally substituted with one to five fluoro substituents or one to three substituents independently selected from the group consisting of C 1-6 alkyl, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, C 6-10 aryl(C 1-6 )alkyl, C 6-10 aryl(C 1-6 )alkoxy, C 6-10 aryl, C 6-10 aryloxy, heteroaryl(C 1-6 )alkyl, heteroaryl(C 1-6 )alkoxy, heteroaryl, heteroaryloxy, C 6-10 arylamino, heteroarylamino, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, carboxy(C 1-6 )alkylamino, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, carboxy(C 1-6 )alkylaminocarbonyl, cyano, halogen, trifluoromethyl, trifluoromethoxy, hydroxy, C 1-6 alkylsulfonyl, and C 1-6 alkylsulfonylamino; provided that not more than one R 3  is selected from the group consisting of aryl, heteroaryl, aryl(C 1-6 )alkyl, aryl(C 2-6 )alkenyl, aryl(C 2-6 )alkynyl, heteroaryl, heteroaryl(C 1-6 )alkyl, heteroaryl(C 2-6 )alkenyl, heteroaryl(C 2-6 )alkynyl, arylamino, heteroarylamino, aryloxy, and heteroaryloxy; and wherein C 1-6 alkyl, and C 1-6 alkyl of aryl(C 1-6 )alkyl and heteroaryl(C 1-6 )alkyl, are optionally substituted with a substituent selected from the group consisting of hydroxy, carboxy, C 1-4 alkoxycarbonyl, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, aminocarbonyl, (C 1-4 )alkylaminocarbonyl, di(C 1-4 )alkylaminocarbonyl, aryl, heteroaryl, arylamino, heteroarylamino, aryloxy, heteroaryloxy, aryl(C 1-4 )alkoxy, and heteroaryl(C 1-4 )alkoxy; 
 
       R 5  is a substituent on a nitrogen atom of ring A selected from the group consisting of hydrogen and C 1-4 alkyl; 
       R a  and R b  are independently selected from the group consisting of hydrogen, C 1-6 alkyl, and C 1-6 alkoxycarbonyl; alternatively, when R a  and R b  are each other than hydrogen, R a  and R b  are optionally taken together with the nitrogen atom to which they are both attached to form a five to eight membered monocyclic ring; 
       and pharmaceutically acceptable enantiomers, diastereomers, racemates, and salts thereof; 
       comprising 
     
     
       
         
         
             
             
         
       
       reacting a compound of formula (X), wherein X P  is selected from OH, CN, —CO 2 H, —C(O)—Cl or —C(O)—OC 1-4 alkyl and wherein Y P  is selected from Br, Cl or I, to yield the corresponding compound of formula (XII); 
     
     
       
         
         
             
             
         
       
       reacting the compound of formula (XII) with a suitably substituted compound of formula (XVIII), wherein Pg 1  is a nitrogen protecting group; in the presence of palladium catalyst; in the presence of an organic or inorganic base; in an organic solvent; at a temperature greater than about room temperature; to yield the corresponding compound of formula (XIX); 
     
     
       
         
         
             
             
         
       
       reacting the compound of formula (XIX) with hydrogen or a source of hydrogen; in the presence of a catalyst; in a solvent; at a temperature greater than about room temperature; to yield the corresponding compound of formula (XX); 
     
     
       
         
         
             
             
         
       
       reacting the compound of formula (XX) with an aqueous base; in an organic solvent; to yield the corresponding compound of formula (I); 
     
     
       
         
         
             
             
         
       
       reacting the compound of formula (I), to yield the corresponding compound of formula (II). 
     
   
   
       16 . The process as in  claim 15 , wherein 
     
       
         
         
             
             
         
       
     
     is phenyl;
 the phenyl is substituted with a R 41P  group at the 2-position and a second R 41P  group at the 4-position; 
 each R 41P  is independently selected from C 1-2 alkyl, C 1-2 alkoxy or fluoro; 
 R J  and R K  are each independently selected from hydrogen or C 1-4 alkyl; alternatively, R J  and R K  are taken together with the nitrogen atom to which they are bound to form a five to seven membered heterocyclyl; and 
 Pg 1  is a nitrogen protecting group. 
 
   
   
       17 . The process as in  claim 15 , wherein 
     
       
         
         
             
             
         
       
     
     is phenyl; the phenyl is substituted with a R 41P  group at the 2-position and a second R 41P  group at the 4-position; each R 41P  is methyl; R J  and R K  are each hydrogen; and Pg 1  is a t-butoxycarbonyl. 
   
   
       18 . A product prepared according to the process of  claim 15 .