Antifungal Compound Process

Abstract

The present invention relates to a process for preparing compound 1 that is useful as an antifungal agent. In particular, the invention seeks to provide new methodology for preparing compound 1 and substituted derivatives thereof.

1 - 12 . (canceled) 
     
     
         13 . A process to prepare compound 1 or 1a, or a mixture thereof: 
       
         
           
           
               
               
           
         
         comprising reacting morpholine amide 2b: 
       
       
         
           
           
               
               
           
         
         with 
       
       
         
           
           
               
               
           
         
         to provide ketone 3, 
       
       
         
           
           
               
               
           
         
         wherein M is Mg or MgX, Li, AlX 2 ; and X is halogen, alkyl, or aryl; and 
         R 1  is halo or 
       
       
         
           
           
               
               
           
         
       
     
     
         14 . (canceled) 
     
     
         15 . The process of  claim 14 , wherein M is Mg or MgX, and X is halogen. 
     
     
         16 . The process of  claim 13 , further comprising amidation of ester 2: 
       
         
           
           
               
               
           
         
         with morpholine to provide morpholine amide 2b: 
       
       
         
           
           
               
               
           
         
         wherein each R 1  is independently halo or 
       
       
         
           
           
               
               
           
         
       
     
     
         17 . (canceled) 
     
     
         18 . The process of  claim 13 , further comprising:
 (i) arylating ketone 3,   
       
         
           
           
               
               
           
         
       
       to provide aryl-pyridine 1-4, 
       
         
           
           
               
               
           
         
         (ii) forming the epoxide of aryl-pyridine 1-4, 
       
       
         
           
           
               
               
           
         
       
       to provide epoxide 5, 
       
         
           
           
               
               
           
         
         (iii) ring-opening epoxide 5, 
       
       
         
           
           
               
               
           
         
       
       to provide amino-alcohol ±1-6, 
       
         
           
           
               
               
           
         
         (iv) enriching the enantiomeric purity of amino-alcohol ±1-6, 
       
       
         
           
           
               
               
           
         
       
       to provide enantio-enriched amino-alcohol 1-6* or 1-7*, 
       
         
           
           
               
               
           
         
       
       or a mixture thereof; and
 (v) forming the tetrazole of enantio-enriched amino-alcohol 1-6* or 1-7*, 
 
       
         
           
           
               
               
           
         
       
       or a mixture thereof, to provide compound 1 or 1a, 
       
         
           
           
               
               
           
         
       
       or a mixture thereof;
 wherein each R 1  is independently halo or 
 
       
         
           
           
               
               
           
         
       
     
     
         19 - 22 . (canceled) 
     
     
         23 . The process of  claim 13 , further comprising:
 (i) forming the epoxide of ketone 3,   
       
         
           
           
               
               
           
         
       
       to provide epoxide 4, 
       
         
           
           
               
               
           
         
         (iii) ring-opening epoxide 4, 
       
       
         
           
           
               
               
           
         
       
       to provide amino-alcohol ±4b, 
       
         
           
           
               
               
           
         
         (iii) enriching the enantiomeric purity of amino-alcohol ±4b, 
       
       
         
           
           
               
               
           
         
       
       to provide enantio-enriched amino-alcohol 4b or 4c: 
       
         
           
           
               
               
           
         
       
       or a mixture thereof;
 (iv) arylating enantio-enriched amino-alcohol 4b or 4c, 
 
       
         
           
           
               
               
           
         
       
       or a mixture thereof, to provide enantio-enriched aryl-pyridine 1-6* or 1-7*, 
       
         
           
           
               
               
           
         
       
       or a mixture thereof; and
 (v) forming the tetrazole of enantio-enriched aryl-pyridine 1-6* or 1-7*, 
 
       
         
           
           
               
               
           
         
       
       or a mixture thereof, to provide compound 1 or 1a, 
       
         
           
           
               
               
           
         
       
       or a mixture thereof;
 wherein each R 1  is independently halo or 
 
       
         
           
           
               
               
           
         
       
     
     
         24 - 29 . (canceled) 
     
     
         30 . The process of  claim 13 , further comprising:
 (i) forming the epoxide of ketone 3,   
       
         
           
           
               
               
           
         
       
       to provide epoxide 4, 
       
         
           
           
               
               
           
         
         (ii) ring-opening epoxide 4, 
       
       
         
           
           
               
               
           
         
       
       to provide amino-alcohol ±4b, 
       
         
           
           
               
               
           
         
         (iii) enriching the enantiomeric purity of amino-alcohol ±4b, 
       
       
         
           
           
               
               
           
         
       
       to provide enantio-enriched amino-alcohol 4b or 4c: 
       
         
           
           
               
               
           
         
       
       or a mixture thereof;
 (iv) forming the tetrazole of enantio-enriched amino-alcohol 4b or 4c: 
 
       
         
           
           
               
               
           
         
       
       or a mixture thereof, to provide tetrazole 21 or 21a, 
       
         
           
           
               
               
           
         
       
       or a mixture thereof; and
 (v) arylating tetrazole 21 or 21a, 
 
       
         
           
           
               
               
           
         
       
       or a mixture thereof, to provide compound 1 or 1a, 
       
         
           
           
               
               
           
         
       
       or a mixture thereof;
 wherein each R 1  is independently halo of 
 
       
         
           
           
               
               
           
         
       
     
     
         31 - 89 . (canceled) 
     
     
         90 . A process to prepare compound 1 or 1a, or a mixture thereof: 
       
         
           
           
               
               
           
         
         comprising 
         (i) displacing the morpholino portion of morpholine amide 2b, 
       
       
         
           
           
               
               
           
         
       
       to provide ketone 3, 
       
         
           
           
               
               
           
         
         (ii) forming the epoxide of ketone 3, 
       
       
         
           
           
               
               
           
         
       
       to provide epoxide 4, 
       
         
           
           
               
               
           
         
         (iii) ring-opening epoxide 4, 
       
       
         
           
           
               
               
           
         
       
       to provide amino-alcohol ±4b, 
       
         
           
           
               
               
           
         
         (iv) enriching the enantiomeric purity of amino-alcohol ±4b, 
       
       
         
           
           
               
               
           
         
       
       to provide enantio-enriched amino-alcohol 4b or 4c: 
       
         
           
           
               
               
           
         
       
       or a mixture thereof;
 (v) forming the tetrazole of enantio-enriched amino-alcohol 4b or 4c: 
 
       
         
           
           
               
               
           
         
       
       or a mixture thereof, to provide tetrazole 21 or 21a, 
       
         
           
           
               
               
           
         
       
       or a mixture thereof; and
 (vi) arylating tetrazole 21 or 21a, 
 
       
         
           
           
               
               
           
         
       
       or a mixture thereof, to provide compound 1 or 1a, 
       
         
           
           
               
               
           
         
       
       or a mixture thereof;
 wherein each R 1  is independently halo or 
 
       
         
           
           
               
               
           
         
       
     
     
         91 . A process to prepare compound 1 or 1a, or a mixture thereof: 
       
         
           
           
               
               
           
         
         comprising 
         (i) displacing the morpholino portion of morpholine amide 2b, 
       
       
         
           
           
               
               
           
         
       
       to provide ketone 3, 
       
         
           
           
               
               
           
         
         (ii) forming the epoxide of ketone 3, 
       
       
         
           
           
               
               
           
         
       
       to provide epoxide 4, 
       
         
           
           
               
               
           
         
         (iii) ring-opening epoxide 4, 
       
       
         
           
           
               
               
           
         
       
       to provide amino-alcohol ±4b, 
       
         
           
           
               
               
           
         
         (iv) enriching the enantiomeric purity of amino-alcohol ±4b, 
       
       
         
           
           
               
               
           
         
       
       to provide enantio-enriched amino-alcohol 4b or 4c: 
       
         
           
           
               
               
           
         
       
       or a mixture thereof;
 (v) arylating enantio-enriched amino-alcohol 4b or 4c, 
 
       
         
           
           
               
               
           
         
       
       or a mixture thereof, to provide enantio-enriched aryl-pyridine 1-6* or 1-7*, 
       
         
           
           
               
               
           
         
       
       or a mixture thereof; and
 (vi) forming the tetrazole of enantio-enriched aryl-pyridine 1-6* or 1-7*, 
 
       
         
           
           
               
               
           
         
       
       or a mixture 
       thereof, to provide compound 1 or 1a, 
       
         
           
           
               
               
           
         
       
       or a mixture thereof;
 wherein each R 1  is independently halo or