Substantially Stereomerically Pure Fused Bicyclic Proline Compounds and Processes for Preparing Boceprevir

Abstract

The present disclosure provides substantially enantiomerically pure heterobicyclic compounds of the following structural formulas, wherein A, M, M′, and R 5 are as described herein, and to biocatalytic processes for their preparation, and to the enzymes used in those processes.

1 - 48 . (canceled) 
     
     
         49 . A substantially stereomerically pure compound according to structural formulas II(a), II(b), III(a), or IV(a): 
       
         
           
           
               
               
           
         
       
       including salts and hydrate thereof, wherein:
 A is CR 1 R 2 , wherein R 1  and R 2  are each independently selected from —H, —COOH, —X, —NH 2 , —CH 2 NHC(NH)NH 2 , —CX 3 , —CH 3 , —CH 2 CH 3 , and wherein X is selected from F, Cl, and Br; 
 M and M′ are both absent. 
 
     
     
         50 . The compound according to  claim 49  in which A is selected from the group consisting of —CH 2 —, —CH(CH 3 )—, —CH(C 2 H 5 )—, —C(CH 3 ) 2 —, —C(C 2 H 5 ) 2 —, —CF 2 —, —CCl 2 —, —CBr 2 —, —C(CF 3 ) 2 —, —CH(COOH)—, —C(COOH) 2 —, —CH(NH 2 )—, and —CH(CH 2 NHC(NH)NH 2 )—. 
     
     
         51 . The compound according to  claim 49  in which A is —CH 2 —. 
     
     
         52 . The compound according to  claim 49  in which A is —C(CH 3 ) 2 —. 
     
     
         53 . The compound according to  claim 49  in which A is —C(CF 3 ) 2 —. 
     
     
         54 . 6. The compound according to  claim 49 , wherein the substantially stereomerically pure compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         55 . The compound according to  claim 49 , wherein the substantially stereomerically pure compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         56 . The compound according to  claim 49 , wherein the substantially stereomerically pure compound is: 
       
         
           
           
               
               
           
         
       
     
     
         57 . A mixture comprising a pair of substantially stereomerically pure compounds of  claim 49 , wherein the pair of compounds selected from: (i) compounds of structural formulas II(a) and II(b); (ii) compounds of structural formulas III(a) and III(b); and (iii) compounds of structural formulas IV(a) and IV(b). 
     
     
         58 . The mixture of  claim 57 , wherein the pair of compounds is of structural formulas III(a) and III(b) and the amount of the compound of structural formula III(a) in the mixture is greater than the amount of the compound of structural formula III(b) in the mixture. 
     
     
         59 . The mixture of  claim 58 , wherein the ratio of the amount of the compound of structural formula III(a) to the amount of the compound of structural formula III(b) is at least 5:1. 
     
     
         60 . The mixture of  claim 59 , wherein the pair of compounds is of structural formulas IV(a) and IV(b) and the amount of the compound of structural formula IV(a) in the mixture is greater than the amount of the compound of structural formula IV(b) in the mixture. 
     
     
         61 . The mixture of  claim 60 , wherein the ratio of the amount of the compound of structural formula IV(a) to the amount of the compound of structural formula IV(b) is at least 10:1. 
     
     
         62 . A method of preparing a substantially stereomerically pure amino acid compound according to structural formula VI: 
       
         
           
           
               
               
           
         
       
       including salts thereof, wherein:
 A is CR 1 R 2 , wherein R 1  and R 2  are each independently selected from —H, —COOH, —X, —NH 2 , —CH 2 NHC(NH)NH 2 , —CX 3 , —CH 3 , —CH 2 CH 3 , and wherein X is selected from F, Cl, and Br; 
 M and M′ are both absent; 
 the method comprising contacting a substantially enantiomerically pure aminonitrile compound according to structural formula IV(a): 
 
       
         
           
           
               
               
           
         
       
       wherein A, M and M′ are as defined for the amino compound of structural formula VI, with an acid and water under conditions in which the aminonitrile compound is converted to the substantially stereomerically pure amino acid compound according to structural formula VI. 
     
     
         63 . A method of preparing a substantially stereomerically pure amino acid compound according to structural formula VI: 
       
         
           
           
               
               
           
         
       
       including salts thereof, wherein:
 A is CR 1 R 2 , wherein R 1  and R 2  are each independently selected from —H, —COOH, —X, —NH 2 , —CH 2 NHC(NH)NH 2 , —CX 3 , —CH 3 , —CH 2 CH 3 , and wherein X is selected from F, Cl, and Br; 
 M and M′ are both absent; 
 the method comprising contacting a stereomerically pure bisulfite amine adduct compound according to structural formula III(a), substantially stereomerically pure bisulfite amine adduct compound according to structural formula III(b) or a mixture thereof 
 
       
         
           
           
               
               
           
         
         with cyanide under conditions which yield the substantially stereomerically pure aminonitrile compound according to structural formula IV(a) 
       
       
         
           
           
               
               
           
         
       
       wherein A, M and M′ are as defined for the amino compound of structural formula VI; and
 contacting the aminonitrile compound of structural formula IV(a) with an acid and water under conditions in which the aminonitrile compound is converted to the substantially stereomerically pure amino acid compound according to structural formula VI. 
 
     
     
         64 . A method of preparing a substantially enantiomerically pure compound according to structural formula V: 
       
         
           
           
               
               
           
         
       
       including salts thereof, wherein:
 R 5  is (C 1 -C 6 )alkyl; 
 A is CR 1 R 2 , wherein R 1  and R 2  are each independently selected from —H, —COOH, —X, —NH 2 , —CH 2 NHC(NH)NH 2 , —CX 3 , —CH 3 , —CH 2 CH 3 , and wherein X is selected from F, Cl, and Br; 
 M and M′ are both absent; 
 the method comprising contacting a substantially stereomerically pure amino acid compound according to structural formula VI 
 
       
         
           
           
               
               
           
         
         wherein A, M and M′ are as defined for the amino acid compound of structural formula V with an acid and a compound selected from the group consisting of R 5 —OH and R 5 OC(O)CH 3  under conditions in which the amino acid compound according to structural formula VI is converted to the substantially enantiomerically pure aminoester compound according to structural formula V. 
       
     
     
         65 . A method of preparing a substantially stereomerically pure amino ester compound according to structural formula V: 
       
         
           
           
               
               
           
         
       
       including salts thereof, wherein:
 R 5  is (C 1 -C 6 )alkyl, A is CR 1 R 2 , wherein R 1  and R 2  are each independently selected from —H, —COOH, —X, —NH 2 , —CH 2 NHC(NH)NH 2 , —CX 3 , —CH 3 , —CH 2 CH 3 , and wherein X is selected from F, Cl, and Br; 
 M and M′ are both absent; 
 the method comprising contacting a stereomerically pure bisulfite amine adduct compound according to structural formula III(a), substantially stereomerically pure bisulfite amine adduct compound according to structural formula III(b) or a mixture thereof 
 
       
         
           
           
               
               
           
         
         with cyanide under conditions which yield the substantially stereomerically pure aminonitrile compound according to structural formula IV(a) 
       
       
         
           
           
               
               
           
         
       
       wherein A, M and M′ are as defined for the amino compound of structural formula VI; and
 contacting the aminonitrile compound of structural formula IV(a) with an acid and an alcohol under conditions in which the aminonitrile compound is converted to the substantially stereomerically pure amino ester compound according to structural formula V. 
 
     
     
         66 . A method of preparing a substantially stereomerically pure amino amide compound according to structural formula VII: 
       
         
           
           
               
               
           
         
       
       including salts thereof, wherein:
 A is CR 1 R 2 , wherein R 1  and R 2  are each independently selected from —H, —COOH, —X, —NH 2 , —CH 2 NHC(NH)NH 2 , —CX 3 , —CH 3 , —CH 2 CH 3 , and wherein X is selected from F, Cl, and Br; 
 M and M′ are both absent; 
 the method comprising contacting a stereomerically pure bisulfite amine adduct compound according to structural formula III(a), substantially stereomerically pure bisulfite amine adduct compound according to structural formula III(b) or a mixture thereof 
 
       
         
           
           
               
               
           
         
         with cyanide under conditions which yield the substantially stereomerically pure aminonitrile compound according to structural formula IV(a) 
       
       
         
           
           
               
               
           
         
       
       wherein A, M and M′ are as defined for the amino compound of structural formula VI; and
 contacting the aminonitrile compound of structural formula IV(a) with an acid under conditions in which the aminonitrile compound is converted to the substantially stereomerically pure amino amide compound according to structural formula VII.