Process for preparing bicyclic amine derivatives

Abstract

The present invention provides a process for preparing a bicyclic amine derivative of the formula (Ia) or (Ib), comprising the rhodium-catalyzed asymmetric hydrogenation of an enamine of the formula (II), in the presence of a chiral ligand, wherein the chiral ligand is a chiral phosphine ligand.

1 . A process for preparing a bicyclic amine derivative of the formula (Ia) or (Ib), 
       
         
           
           
               
               
           
         
         wherein 
         A is a 5- or 6-membered ring; 
         R is hydrogen, halogen, —CN, hydroxyl which optionally carries a protecting group, a group Y′-A 2 -X 1 —, or a group R 1 —W-A 1 -Q-Y-A 2 -X 1 —; 
         R 1  is hydrogen, C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl, halogenated C 1 -C 6 -alkyl, tri-(C 1 -C 4 -alkyl)-silyl-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylcarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkyloxycarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylaminocarbonylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylaminocarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylsulfonylamino-C 1 -C 4 -alkyl, (optionally substituted C 6 -C 12 -aryl-C 1 -C 6 -alkyl)amino-C 1 -C 4 -alkyl, optionally substituted C 6 -C 12 -aryl-C 1 -C 4 -alkyl, optionally substituted C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, halogenated C 1 -C 6 -alkoxycarbonyl, C 6 -C 12 -aryloxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, (halogenated C 1 -C 4 -alkyl)aminocarbonyl, C 6 -C 12 -arylaminocarbonyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C 1 -C 6 -alkoxy, halogenated C 1 -C 6 -alkoxy, C 1 -C 6 -hydroxyalkoxy, C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy, amino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino-C 1 -C 4 -alkoxy, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylcarbonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 -arylcarbonylamino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkoxycarbonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 -aryl-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylsulfonylamino-C 1 -C 4 -alkoxy, (halogenated C 1 -C 6 -alkyl)sulfonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 -arylsulfonylamino-C 1 -C 4 -alkoxy, (C 6 -C 12 -aryl-C 1 -C 6 -alkyl)sulfonylamino-C 1 -C 4 -alkoxy, C 3 -C 12 -heterocyclylsulfonylamino-C 1 -C 4 -alkoxy, C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy, C 6 -C 12 -aryloxy, C 3 -C 12 -heterocyclyloxy, C 1 -C 6 -alkylthio, halogenated C 1 -C 6 -alkylthio, C 1 -C 6 -alkylamino, (halogenated C 1 -C 6 -alkyl)amino, di-C 1 -C 6 -alkylamino, di-(halogenated C 1 -C 6 -alkyl)amino, C 1 -C 6 -alkylcarbonylamino, (halogenated C 1 -C 6 -alkyl)carbonylamino, C 6 -C 12 -arylcarbonylamino, C 1 -C 6 -alkylsulfonylamino, (halogenated C 1 -C 6 -alkyl)sulfonylamino, C 6 -C 12 -arylsulfonylamino or optionally substituted C 3 -C 12 -heterocyclyl; 
         W is —NR 8 — or a bond; 
         A 1  is optionally substituted C 1 -C 4 -alkylene or a bond; 
         Q is —S(O) 2 — or —C(O)—; 
         Y is —NR 9 — or a bond; 
         Y′ is Y which optionally carries a protecting group; 
         A 2  is optionally substituted C 1 -C 4 -alkylene, C 1 -C 4 -alkylene-CO—, —CO—C 1 -C 4 -alkylene, C 1 -C 4 -alkylene-O—C 1 -C 4 -alkylene, C 1 -C 4 -alkylene-NR 10 —C 1 -C 4 -alkylene, optionally substituted C 2 -C 4 -alkenylene, optionally substituted C 2 -C 4 -alkynylene, optionally substituted C 6 -C 12 -arylene, optionally substituted C 6 -C 12 -heteroarylene or a bond; 
         X 1  is —O—, —NR 11 —, —S—, optionally substituted C 1 -C 4 -alkylene, optionally substituted C 2 -C 4 -alkenylene, optionally substituted C 2 -C 4 -alkynylene; 
         R 2  is hydrogen, halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, —CN, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C 1 -C 6 -alkoxy, halogenated C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxycarbonyl, C 2 -C 6 -alkenyloxy, C 6 -C 12 -aryl-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylcarbonyloxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, aminosulfonyl, amino, C 1 -C 6 -alkylamino, C 2 -C 6 -alkenylamino, nitro or optionally substituted C 3 -C 12 -heterocyclyl, or two radicals R 2  together with the ring atoms of A to which they are bound form a 5- or 6-membered ring; 
         A 3  is —O—, —S—, —NR 16 —, a bond or C 1 -C 2 -alkylene; 
         R 3  is hydrogen, halogen, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy, or two radicals R 3  together with the carbon atom to which they are attached form a carbonyl group; 
         R 4a  is C 1 -C 4 -alkylcarbonyl, (halogenated C 1 -C 4 -alkyl)carbonyl or C 6 -C 12 -arylcarbonyl; 
         R 4b  is hydrogen or C 1 -C 6 -alkyl; or 
         R 4a , R 4b  
 together are C 2 -C 10 -alkylenecarbonyl; 
 
         X 2  is —O—, —NR 6 —, >CR 12a R 12b  or a bond; 
         X 3  is —O—, —NR 7 —, —S—, >CR 13a R 13b  or a bond; 
         R 5  is optionally substituted C 6 -C 12 -aryl, optionally substituted C 3 -C 12 -cycloalkyl or optionally substituted C 3 -C 12 -heterocyclyl; 
         R 6  is hydrogen or C 1 -C 6 -alkyl; 
         R 7  is hydrogen or C 1 -C 6 -alkyl; 
         R 8  is hydrogen or C 1 -C 6 -alkyl; 
         R 9  is hydrogen, C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl, amino-C 1 -C 6 -alkyl, optionally substituted C 6 -C 12 -aryl-C 1 -C 4 -alkyl or C 3 -C 12 -heterocyclyl; or 
         R 9 , R 1  
 together are C 1 -C 4 -alkylene; or 
 
         R 9  is C 1 -C 4 -alkylene that is bound to a carbon atom in A 2  and A 2  is C 1 -C 4 -alkylene or to a carbon atom in X 1  and X 1  is C 1 -C 4 -alkylene; 
         R 10  is hydrogen, C 1 -C 6 -alkyl or C 1 -C 6 -alkylsulfonyl; 
         R 11  is hydrogen or C 1 -C 6 -alkyl, or 
         R 9 , R 11  
 together are C 1 -C 4 -alkylene, 
 
         R 12a  is hydrogen, optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, C 3 -C 12 -heterocyclyl-C 1 -C 6 -alkyl, optionally substituted C 6 -C 12 -aryl or hydroxy; 
         R 12b  is hydrogen or C 1 -C 6 -alkyl, or 
         R 12a , R 12b  
 together are carbonyl or optionally substituted C 1 -C 4 -alkylene, wherein one —CH 2 — of C 1 -C 4 -alkylene may be replaced by an oxygen atom or —NR 14 —; 
 
         R 13a  is hydrogen, optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, C 3 -C 12 -heterocyclyl-C 1 -C 6 -alkyl, optionally substituted C 6 -C 12 -aryl or hydroxy; 
         R 13b  is hydrogen or C 1 -C 6 -alkyl, or 
         R 13a , R 13b  
 together are carbonyl or optionally substituted C 1 -C 4 -alkylene, wherein one —CH 2 — of C 1 -C 4 -alkylene may be replaced by an oxygen atom or —NR 15 —; 
 
         R 14  is hydrogen or C 1 -C 6 -alkyl; 
         R 15  is hydrogen or C 1 -C 6 -alkyl; and 
         R 16  is hydrogen, C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, CH 2 CN, C 6 -C 12 -aryl-C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl, —CHO, C 1 -C 4 -alkylcarbonyl, (halogenated C 1 -C 4 -alkyl)carbonyl, C 6 -C 12 -arylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 6 -C 12 -aryloxycarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 2 -C 6 -alkenyl, —C(═NH)NH 2 , —C(═NH)NHCN, C 1 -C 6 -alkylsulfonyl, C 8 -C 12 -arylsulfonyl, amino, —NO or C 3 -C 12 -heterocyclyl, 
         or a salt thereof; 
         comprising the rhodium-catalyzed asymmetric hydrogenation of an enamine of the formula (II), 
       
       
         
           
           
               
               
           
         
         wherein A, A 3 , R, R 2 , R 3 , R 4a , R 4b , R 5 , X 2  and X 3  are as defined above, 
         or of a salt thereof; 
         in the presence of a chiral ligand, wherein the chiral ligand is a chiral phosphine ligand. 
       
     
     
         2 . The process as claims in  claim 1 , wherein the rhodium catalyst is a rhodium(I) compound. 
     
     
         3 . The process as claimed in  claim 2 , wherein the rhodium(I) compound is of formula (IIIa), (IIIb) or (IIIc),
   [RhLi 1 An] 2   (IIIa)
     [RhLi 2   2 An] n   (IIIb)
     [RhLi 1   2 An]  (IIIc)
   wherein   Li 1  is C 5 -C 12 -alkadiene, C 5 -C 12 -cycloalkadiene or C 5 -C 12 -bicycloalkadiene;   Li 2  is C 2 -C 12 -alkene or C 5 -C 8 -cycloalkene;   n is 1 or 2; and   An is halide, tetrafluoroborate, trifluoromethanesulfonate or acetylacetonate.   
     
     
         4 . The process as claimed in  claim 3 , wherein the rhodium(I) compound is of formula (IIIa) with Li 1  being C 6 -C 10 -cycloalkadiene or C 5 -C 12 -bicycloalkadiene, in particular 1,5-cyclooctadiene or norbornadiene, and An being chloride. 
     
     
         5 . The process as claimed in  claim 1 , wherein the chiral phosphine ligand is a chiral diphosphine ligand. 
     
     
         6 . The process as claimed in  claim 5 , wherein the diphosphine ligand comprises a ferrocene moiety. 
     
     
         7 . The process as claimed in  claim 6 , wherein the diphosphine ligand is of the formula (IVa), (IVb), (IVc) or (IVd), 
       
         
           
           
               
               
           
         
         wherein 
         R 18 , R 19 , R 21 , and R 21 , independently of each other, are selected from the group consisting of C 1 -C 12 -alkyl, C 5 -C 7 -cycloalkyl, C 3 -C 6 -hetaryl and C 6 -C 12 -aryl, wherein C 3 -C 6 -hetaryl and C 6 -C 12 -aryl are unsubstituted or carry 1, 2, 3, 4 or 5 substituents selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and di-C 1 -C 4 -alkylamine. 
       
     
     
         8 . The process as claimed in  claim 7 , wherein the diphosphine ligand is of the formula (IVa) or (IVb) with R 18  and R 19  having the same meaning and R 20  and R 21  having the same meaning. 
     
     
         9 . The process as claimed in  claim 8 , wherein R 18  and R 19  are both C 1 -C 12 -alkyl and R 20  and R 21  are both optionally substituted C 3 -C 5 -hetaryl or optionally substituted C 6 -C 10 -aryl. 
     
     
         10 . The process as claimed in  claim 9 , wherein R 18  and R 19  are both tert-butyl and R 20  and R 21  are both 1-naphthyl or 2-furyl. 
     
     
         11 . The process as claimed in  claim 1 , which further comprises:
 (a) providing a ketone of the formula (V),   
       
         
           
           
               
               
           
         
         
           wherein A, A 3 , R, R 2 , R 3 , R 5 , X 2  and X 3  are as defined in  claim 1 ; 
         
         and 
         (b) converting the ketone of the formula (V) into the enamine of the formula (II), wherein A, A 3 , R, R 2 , R 3 , R 4a , R 4b , R 5 , X 1 , and X 2  are as defined in  claim 1 . 
       
     
     
         12 . The process as claimed in  claim 1 , wherein the bicyclic amine derivative is a compound of the formula (Ia) and the chiral phosphine ligand is the diphosphine of formula (IVa), as defined in  claim 1 . 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . The process as claimed in  claim 1 , wherein, in formulae (Ia), (Ib) and (II), R 4a  is C 1 -C 4 -alkylcarbonyl or (halogenated C 1 -C 4 -alkyl)carbonyl and R 4b  is hydrogen or C 1 -C 6 -alkyl;
 or R 4a , R 4b  together are C 2 -C 6 -alkylenecarbonyl.   
     
     
         16 . The process as claimed in  claim 1 , further comprising crystallizing from heptane, methanol or a mixture of heptane and methanol the compound of formula (Ia) or (Ib), wherein A is a benzene ring, R is —OCH 3 , R 2  is hydrogen, A 3  is R 3  is hydrogen, R 4a  is ethoxycarbonyl, R 4b  is hydrogen, X 2  is X 3  is a bond, and R 5  is phenyl. 
     
     
         17 . A bicyclic amine derivative of the formula (Ia) or the formula (Ib), 
       
         
           
           
               
               
           
         
         wherein 
         A, A 3 , R, R 2 , R 3 , R 4a , R 4b , R 5 , X 2  and X 3  are as defined in  claim 1 . 
       
     
     
         18 . An enamine of the formula (II), 
       
         
           
           
               
               
           
         
         wherein A, A 3 , R, R 2 , R 3 , R 4a , R 4b , R 5 , X 2  and X 3  are as defined in  claim 1 . 
       
     
     
         19 . A ketone of the formula (V′), 
       
         
           
           
               
               
           
         
         wherein A, A 3 , R 2 , R 3 , R 5 , X 2  and X 3  are as defined in  claim 1 , and R is halogen, methoxymethoxy, methoxyethoxymethoxy, tert-butyloxy, allyloxy, 2-tetrapyranyloxy, benzyloxy, acetyloxy, pivaloyloxy, benzoyloxy, tert-butyldimethylsilyloxy or tert-butyldiphenylsilyloxy, preferably halogen and in particular bromine. 
       
     
     
         20 . The ketone of  claim 19  having the formula (V′-1), 
       
         
           
           
               
               
           
         
       
     
     
         21 . The bicyclic amine derivative of  claim 17  having the formula (Ia′) or the formula (Ib′), 
       
         
           
           
               
               
           
         
         wherein 
         R a  is halogen, in particular bromine, or C 1 -C 4 -alkoxy, in particular methoxy; 
         R 4a  is C 1 -C 4 -alkylcarbonyl, in particular ethylcarbonyl; 
         R 4b  is hydrogen; or 
         R 4a , R 4b  together are C 2 -C 6 -alkylenecarbonyl. 
       
     
     
         22 . The enamine of  claim 18  having the formula (II′),