Enzymatic resolution of selective estrogen receptor modulators

Abstract

The present invention relates to a process for preparing 5-substitued-6-cyclic-5,6,7,8-tetrahydronaphthalen-2-ol compounds useful as an estrogen agonist.

1 .- 23 . (canceled)  
   
   
       24 . A process for preparing a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 A is selected from CH 2  and NR;  
 B, D and E are independently selected from CH and N;  
 Y is 
 (a) phenyl, optionally substituted with 1-3 substituents independently selected from R 4 ;  
 (b) naphthyl, optionally substituted with 1-3 substituents independently selected from R 4 ;  
 (c) C 3 -C 8  cycloalkyl, optionally substituted with 1-2 substituents independently selected from R 4 ;  
 (d) C 3 -C 8  cycloalkynyl, optionally substituted with 1-2 substituents independently selected from R 4 ;  
 (e) a five membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR 2 — and —S(O) n —, optionally substituted with 1-3 substituents independently selected from R 4 ;  
 (f) a six membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR 2 —and —S(O) n — optionally substituted with 1-3 substituents independently selected from R 4 ; or  
 (g) a bicyclic ring system consisting of a five or six membered heterocyclic ring fused to a phenyl ring, said heterocyclic ring containing up to two heteroatoms selected from the group consisting of —O—, —NR 2 —, NR 2 — and —S(O) n —, optionally substituted with 1-3 substituents independently selected from R 4 ;  
 
 Z 1  is 
 (a) —(CH 2 ) p W(CH 2 ) q —;  
 (b) —O(CH 2 ) p CR 5 R 6 —;  
 (c) —O(CH 2 ) p W(CH 2 ) q ;  
 (d) —OCHR 2 CHR 3 —; or  
 (e) —SCHR 2 CHR 3 —;  
 
 G is 
 (a) —NR 7 R 8 ;  
 (b)  
                     wherein n is 0, 1 or 2; m is 1, 2 or 3; Z 2  is —NH—, —O—, —S—, or —CH 2 —; optionally fused on adjacent carbon atoms with one or two phenyl rings and, optionally independently substituted on carbon with one to three substituents and, optionally, independently on nitrogen with a chemically suitable substituent selected from R 4 ; or    
 (c) a bicyclic amine containing five to twelve carbon atoms, either bridged or fused and optionally substituted with 1-3 substituents independently selected from R 4 ;  
 
 Z 1  and G in combination may be  
                     
 W is 
 (a) —CH 2 —;  
 (b) —CH═CH—;  
 (c) —O—;  
 (d) —NR 2 —;  
 (e) —S(O) n —;  
 (f)  
                     
 (g) —CR 2 (OH)—;  
 (h) —CONR 2 —;  
 (i) —NR 2 CO—;  
 (j)  
                     
 (k) —C≡C—;  
 
 R is hydrogen or C 1 -C 6  alkyl;  
 R 2  and R 3  are independently 
 (a) hydrogen; or  
 (b) C 1 -C 4  alkyl;  
 
 R 4  is 
 (a) hydrogen;  
 (b) halogen;  
 (c) C 1 -C 6  alkyl;  
 (d) C 1 -C 4  alkoxy;  
 (e) C 1 -C 4  acyloxy;  
 (f) C 1 -C 4  alkylthio;  
 (g) C 1 -C 4  alkylsulfinyl;  
 (h) C 1 -C 4  alkylsulfonyl;  
 (i) hydroxy (C 1 -C 4 )alkyl;  
 (j) aryl (C 1 -C 4 )alkyl;  
 (k) —CO 2 H;  
 (l) —CN;  
 (m) —CONHOR;  
 (n) —SO 2 NHR;  
 (o) —NH 2 ;  
 (p) C 1 -C 4  alkylamino;  
 (q) C 1 -C 4  dialkylamino;  
 (r) —NHSO 2 R;  
 (s) —NO 2 ;  
 (t) -aryl; or  
 (u) —OH.  
 
 R 5  and R 6  are independently C 1 -C 8  alkyl or together form a C 3 -C 10  carbocyclic ring;  
 R 7  and R 8  are independently 
 (a) phenyl;  
 (b) a C 3 -C 10  carbocyclic ring, saturated or unsaturated;  
 (c) a C 3 -C 10  heterocyclic ring containing up to two heteroatoms, selected from —O—, —N— and —S—;  
 (d) H;  
 (e) C 1 -C 6  alkyl; or  
 (f) form a 3 to 8 membered nitrogen containing ring with R 5  or R 6 ;  
 
 R 7  and R 8  in either linear or ring form may optionally be substituted with up to three substituents independently selected from C 1 -C 6  alkyl, halogen, alkoxy, hydroxy and carboxy;  
 a ring formed by R 7  and R 8  may be optionally fused to a phenyl ring;  
 e is 0, 1 or 2;  
 m is 1, 2 or 3;  
 n is 0, 1 or 2;  
 p is 0, 1, 2 or 3;  
 q is 0, 1,2 or 3;  
 and optical and geometric isomers thereof;  
 comprising enzymatically resolving of a compound of the formula  
                     
  in the presence of a lipase and an acetylating agent, and (b) reacting the compound of formula IV so formed  
                     
  wherein R 1  is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl wherein the alkyl, alkenyl or alkynyl groups are optionally substituted by one to three halo, with a base in the presence of a polar protic solvent.  
 
   
   
       25 . A process according to  claim 24 , wherein the hydrolytic enzyme is a lipase.  
   
   
       26 . A process according to  claim 24 , wherein the lipase is GC-4, PS30, AY30, PGE, AK, N, L-10, AP-12, FAP-15, R-10, G, MAP10, SAM II, lipase from  Pseudomonas fluorescens , lipase from  Candida cylindracea , Lip-300, lipase from  Chromobacterium viscosum , lipase from  Mucor miehei , lipase from Pancreatic, lipase from  Pseudomonas fluorescens , lipase from  Rhizopus niveus , PPL, type II, lipase from Wheat germ, lipase from  Rhizopus arrhizus , lipase from  Mucor javanicus , lipase from  Pseudomonas cepacia , lipase from  Cadia lipolytica , lipase from  Penicillium roqueforti , lipoprotein lipase ca#70-6571 -01, lipase from Porcine pancreas, and lipoprotein lipase ca# 70-1481-01.  
   
   
       27 . A process according to  claim 24 , wherein the acetylating agent is ethyl acetate, vinyl acetate, chloroacetate or trifluoroacetate.  
   
   
       28 . A process according to  claim 24 , wherein the base is sodium methoxy, sodium hydroxide, lithium hydroxide or potassium hydroxide.  
   
   
       29 . A process according to  claim 24 , wherein the polar protic solvent is methanol, ethanol or water.  
   
   
       30 . A process according to  claim 24 , wherein the lipase is immobilized on a solid support.  
   
   
       31 . A process according to  claim 24 , wherein the lipase is a cross-linked enzyme.  
   
   
       32 . A process according to  claim 24 , wherein the lipase is in pure crystalline form.  
   
   
       33 . A process according to  claim 24 , for preparing a compound of the formula  
     
       
         
         
             
             
         
       
     
     comprising enzymatically resolving of a compound of the formula  
     
       
         
         
             
             
         
       
     
     in the presence of a lipase and acetylating agent, and (b) reacting the compound of Formula X so formed  
     
       
         
         
             
             
         
       
     
     wherein R 1  is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl wherein the alkyl, alkenyl or alkynyl groups are optionally substituted by one to three halo, with a base in the presence of a polar protic solvent.  
   
   
       34 . A process for preparing a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 A is selected from CH 2  and NR;  
 B, D and E are independently selected from CH and N;  
 Y is 
 (a) phenyl, optionally substituted with 1-3 substituents independently selected from R 4 ;  
 (b) naphthyl, optionally substituted with 1-3 substituents independently selected from R 4 ;  
 (c) C 3 -C 8  cycloalkyl, optionally substituted with 1-2 substituents independently selected from R 4 ;  
 (d) C 3 -C 8  cycloalkynyl, optionally substituted with 1-2 substituents independently selected from R 4 ;  
 (e) a five membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR 2 — and —S(O) n —, optionally substituted with 1-3 substituents independently selected from R 4 ;  
 (f) a six membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR 2 — and —S(O) n — optionally substituted with 1-3 substituents independently selected from R 4 ; or  
 (g) a bicyclic ring system consisting of a five or six membered heterocyclic ring fused to a phenyl ring, said heterocyclic ring containing up to two heteroatoms selected from the group consisting of —O—, —NR 2 —, NR 2 — and —S(O) n —, optionally substituted with 1-3 substituents independently selected from R 4 ;  
 
 Z 1  is 
 (a) —(CH 2 ) p W(CH 2 ) q —;  
 (b) —O(CH 2 ) p CR 5 R 6 —;  
 (c) —O(CH 2 ) p W(CH 2 ) q ;  
 (d) —OCHR 2 CHR 3 —; or  
 (e) —SCHR 2 CHR 3 —;  
 
 G is 
 (a) —NR 7 R 8 ;  
 (b)  
                     wherein n is 0, 1 or 2; m is 1, 2 or 3; Z 2  is —NH—, —O—, —S—, or —CH 2 —; optionally fused on adjacent carbon atoms with one or two phenyl rings and, optionally independently substituted on carbon with one to three substituents and, optionally, independently on nitrogen with a chemically suitable substituent selected from R 4 ; or    
 (c) a bicyclic amine containing five to twelve carbon atoms, either bridged or fused and optionally substituted with 1-3 substituents independently selected from R 4 ;  
 
 Z 1  and G in combination may be  
                     
 W is 
 (a) —CH 2 —;  
 (b) —CH═CH—;  
 (c) —O—;  
 (d) —NR 2 —;  
 (e) —S(O) n —;  
 (f)  
                     
 (g) —CR 2 (OH)—;  
 (h) —CONR 2 —;  
 (i) —NR 2 CO—;  
 (j)  
                     
 (k) —C≡C—;  
 
 R is hydrogen or C 1 -C 6  alkyl;  
 R 2  and R 3  are independently 
 (a) hydrogen; or  
 (b) C 1 -C 4  alkyl;  
 
 R 4  is 
 (a) hydrogen;  
 (b) halogen;  
 (c) C 1 -C 6  alkyl;  
 (d) C 1 -C 4  alkoxy;  
 (e) C 1 -C 4  acyloxy;  
 (f) C 1 -C 4  alkylthio;  
 (g) C 1 -C 4  alkylsulfinyl;  
 (h) C 1 -C 4  alkylsulfonyl;  
 (i) hydroxy (C 1 -C 4 )alkyl;  
 (j) aryl (C 1 -C 4 )alkyl;  
 (k) —CO 2 H;  
 (l) —CN;  
 (m) —CONHOR;  
 (n) —SO 2 NHR;  
 (o) —NH 2 ;  
 (p) C 1 -C 4  alkylamino;  
 (q) C 1 -C 4  dialkylamino;  
 (r) —NHSO 2 R;  
 (s) —NO 2 ;  
 (t) -aryl; or  
 (u) —OH.  
 
 R 5  and R 6  are independently C 1 -C 8  alkyl or together form a C 3 -C 10  carbocyclic ring;  
 R 7  and R 8  are independently 
 (a) phenyl;  
 
 (b) a C 3 -C 10  carbocyclic ring, saturated or unsaturated; 
 (c) a C 3 -C 10  heterocyclic ring containing up to two heteroatoms, selected from —O—, —N— and —S—;  
 (d) H;  
 (e) C 1 -C 6  alkyl; or  
 (f) form a 3 to 8 membered nitrogen containing ring with R 5  or R 6 ;  
 
 R 7  and R 8  in either linear or ring form may optionally be substituted with up to three substituents independently selected from C 1 -C 6  alkyl, halogen, alkoxy, hydroxy and carboxy;  
 a ring formed by R 7  and R 8  may be optionally fused to a phenyl ring;  
 e is 0, 1 or 2;  
 m is 1, 2 or 3;  
 n is 0, 1 or 2;  
 p is 0, 1, 2 or 3;  
 q is 0, 1, 2 or 3;  
 and optical and geometric isomers thereof;  
 comprising enzymatically resolving of a compound of the formula  
                     
  wherein R 1  is (C 1 -C 6 )alkyl, in the presence of lipase.  
 
   
   
       35 . A process according to  claim 34 , wherein the lipase is  Mucor miehei.    
   
   
       36 . A process according to  claim 34 , wherein the lipase is immobilized on a solid support.  
   
   
       37 . A process according to  claim 34 , wherein the lipase is a cross-linked enzyme.  
   
   
       38 . A process according to  claim 34 , wherein the lipase is in pure crystalline form.  
   
   
       39 . A process according to  claim 34 , wherein the hydrolytic enzyme is lipase from Porcine pancreas, cholesterol esterase from  Pseudomonas Fluorscens  and cholesterol esterase from Porcine pancreas.  
   
   
       40 . A process according to  claim 34 , for preparing a compound of the formula  
     
       
         
         
             
             
         
       
     
     comprising enzymatically resolving of a compound of the formula  
     
       
         
         
             
             
         
       
     
     in the presence of lipase.