Process for preparing an enantiomerically enriched, deuterated secondary alcohol from a corresponding ketone without reducing deuterium incorporation

Abstract

The present invention provides a process for the preparation of enantiomerically enriched, deuterated secondary alcohols of Formula 1-A by employing ketoreductases or carbonyl reductases without reducing deuterium incorporation.

1 .- 23 . (canceled) 
     
     
         24 . A process for the preparation of a compound of Formula I-A 
       
         
           
           
               
               
           
         
       
       comprising the step of reacting a compound of Formula II-A: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, with a hydride source or a deuteride source in the presence of a ketoreductase or carbonyl reductase to form a compound of Formula I-A with an enantiomeric excess of at least 80%, wherein:
 for each position designated as deuterium in the compound of Formula I-A and Formula II-A, that position has at least 90% incorporation of deuterium; 
 the ketoreductase or carbonyl reductase is selected from CRED A131, CRED A801, CRED A901, CRED A251, CRED A271, KRED-119, KRED-137, KRED-148, KRED-169, KRED-174, KRED-NAD 101, KRED-NAD 102, KRED-NAD112, KRED-NAD 126, ES-KRED-121, ES-KRED-128, ES-KRED-130, ES-KRED-142, ES-KRED-175, ES-KRED-169, and ES-KRED-171; 
 each of R 4 , R 6  and R 7  is independently selected from —CH 3  and —CD 3 ; 
 each R 5  is hydrogen or deuterium or a combination thereof; 
 each Z 2  is the same and is hydrogen or deuterium; 
 each Z 3  is the same and is hydrogen or deuterium; 
 each Z 4  is the same and is hydrogen or deuterium; 
 each Z 5  is the same and is hydrogen or deuterium; and 
 Y is H when a compound of Formula II-A is reacted with a hydride source; or 
 Y is D when a compound of Formula II-A is reacted with a deuteride source, 
 
       wherein either R 7  is —CD 3  or at least one of Z 2 , Z 3 , Z 4  and Z 5  is deuterium, and wherein the amount of deuterium incorporation at each deuterium in R 7 , Z 2 , Z 3 , Z 4  and Z 5  in the compound of Formula I-A is substantially equal to the amount of deuterium incorporation at corresponding deuterium atoms in R 7 , Z 2 , Z 3 , Z 4  and Z 5  in the compound of Formula II-A. 
     
     
         25 . The process of  claim 24 , wherein each R 7  is —CD 3 . 
     
     
         26 . The process of  claim 24 , wherein each Z 2  is deuterium. 
     
     
         27 . The process of  claim 24 , wherein each Z 2  is hydrogen. 
     
     
         28 . The process of  claim 24 , wherein each R 5  is deuterium. 
     
     
         29 . The process of  claim 24 , wherein each R 5  is hydrogen. 
     
     
         30 . The process of  claim 24 , wherein each Z 3 , Z 4  and Z 5  is hydrogen. 
     
     
         31 . The process of  claim 30 , wherein R 6  is —CH 3  and R 7  is —CD 3 . 
     
     
         32 . The process of  claim 31 , wherein R 4  is —CH 3 . 
     
     
         33 . The process of  claim 30 , wherein R 6  is —CD 3  and R 7  is —CD 3 . 
     
     
         34 . The process of  claim 24 , wherein each Z 3 , Z 4  and Z 5  is deuterium. 
     
     
         35 . The process of  claim 24 , wherein:
 a. the compound of Formula II-A is selected from any one of the following:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and
 b. the compound of Formula I-A is selected from any one of the following: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         36 . The process of  claim 24 , wherein:
 the compound of Formula II-A is   
       
         
           
           
               
               
           
         
       
       and the compound of Formula I-A 
       
         
           
           
               
               
           
         
       
     
     
         37 . The process of  claim 36 , further comprising the step of converting Compound 421(S) to Compound 121(S): 
       
         
           
           
               
               
           
         
       
     
     
         38 . The process of  claim 24 , wherein the hydride source or deuteride source is (i) a cofactor selected from NAD, NADH, NADP and NADPH, (ii) a reducing sugar and (iii) a dehydrogenase that dehydrogenates the reducing sugar. 
     
     
         39 . The process of  claim 38 , wherein Y is H; and the hydride source is (i) a cofactor selected from NAD, NADH, NADP and NADPH, (ii) glucose and (iii) glucose dehydrogenase. 
     
     
         40 . The process of  claim 24 , wherein the step of reacting a compound of Formula II-A or a salt thereof with a hydride source or a deuteride source is performed at a pH between 6.0 and 7.5. 
     
     
         41 . The process of  claim 40 , wherein the pH is between 6.90 and 7.05. 
     
     
         42 . The process of  claim 24 , wherein the ketoreductase or carbonyl reductase is selected from CRED A131, CRED A251, and KRED-NAD 101. 
     
     
         43 . The compound of  claim 24 , wherein for each position designated as deuterium, that position has at least 95% deuterium incorporation.