Expedient synthesis of oseltamivir and related compounds via direct olefin diazidation-diamidation reaction

Abstract

Disclosed herein are improved methods for the preparation of oseltamivir, and intermediates useful thereto.

What is claimed is: 
     
       1. A method of stereoselectively diazidating a cyclohexene compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein R 1  comprises R 1a , C(O)R 1a , C(O)OR 1a , C(O)N(R 1a ) 2 , or Si(R 1a ) 3 , wherein R 1a  is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl; 
         wherein R h  is hydrogen and R 2  comprises F, Cl, Br, I, NO 2 , CN, OTs, or OMs; 
         R 3  is selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl, 
         comprising contacting the compound of Formula (I) with: 
         a) an iron compound; 
         b) an azide source; 
         c) an activator, wherein the activator is selected from an iodine (III) compound or a peroxy compound; 
         d) a polydentate ligand; 
         to give a diazido compound of Formula (II): 
       
       
         
           
           
               
               
           
         
         wherein R 1′  is selected from R 1a′ , C(O)R 1a′ , C(O)OR 1a′ , C(O)N(R 1a′ ) 2 , Si(R 1a′ ) 3 , wherein R 1a′  is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl; 
         wherein R h  is hydrogen and R 2  comprises F, Cl, Br, I, NO 2 , CN, OTs, or OMs, or R h  and R 2  together form a double bond. 
       
     
     
       2. The method according to  claim 1 , wherein the polydentate ligand has the formula: 
       
         
           
           
               
               
           
         
         wherein m is selected from the group consisting of 0, 1, 2, and 3, and in each case R LA , R LB , R LC , and R LD  are independently selected from the group consisting of R, OR, N(R) 2 , PR 3 , SiR 3 , SR, SO 2 R, SO 2 N(R) 2 , C(O)R; C(O)OR, OCOR; C(O)N(R) 2 , OC(O)N(R) 2 , N(R)C(O)N(R) 2 , F, Cl, Br, I, cyano, and nitro, wherein R is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, and C 1-8 heterocyclyl; wherein any two or more of R LA , R LB , R LC , R LD , and R may together form a ring. 
       
     
     
       3. The method according to  claim 2 , wherein the polydentate ligand has the formula: 
       
         
           
           
               
               
           
         
         wherein each of R 7a , R 7b , R 8a , and R 8b  are independently selected from the group consisting of R, OR, N(R) 2 , PR 3 , SiR 3 , SR, SO 2 R, SO 2 N(R) 2 , C(O)R; C(O)OR, OCOR; C(O)N(R) 2 , OC(O)N(R) 2 , N(R)C(O)N(R) 2 , F, Cl, Br, I, cyano, and nitro, wherein R is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 -alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, and C 1-8 heterocyclyl; wherein any two or more of R 7a , R 7b , R 8a , R 8b , R LD , and R may together form a ring. 
       
     
     
       4. The method according to  claim 2 , wherein the polydentate ligand has the formula: 
       
         
           
           
               
               
           
         
       
     
     
       5. The method of  claim 1 , further comprising converting the compound of Formula (II) to oseltamivir or a pharmaceutically acceptable salt thereof. 
     
     
       6. The method of  claim 1 , further comprising converting the compound of Formula (II) to a compound of Formula (III): 
       
         
           
           
               
               
           
         
         wherein R 1″  is selected from R 1a″ , C(O)R 1a″ , C(O)OR 1a″ , C(O)N(R 1a″ ) 2 , Si(R 1a″ ) 3 , wherein R 1a″  is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, and heteroaryl, C 3-8 cycloalkyl. 
       
     
     
       7. The method of  claim 6 , further comprising converting the compound of Formula (III) into oseltamivir or a pharmaceutically acceptable salt thereof. 
     
     
       8. The method of  claim 6 , further comprising converting the compound of Formula (III) to a compound of Formula (IV): 
       
         
           
           
               
               
           
         
         wherein R 4 , R 4′ , R 5 , and R 5′  are independently selected from R z , C(O)R z , C(O)OR z , C(O)N(R z ) 2 , Si(R z ) 3 , wherein R z  is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl; 
         R 1′″  is selected from R 1a′″ , C(O)R 1a′″ , C(O)OR 1a′″ , C(O)N(R 1a′″ ) 2 , Si(R 1a′″ ) 3 , wherein R 1a′″  is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl. 
       
     
     
       9. The method of  claim 8 , further comprising converting the compound of Formula (IV) into oseltamivir, or a pharmaceutically acceptable salt thereof. 
     
     
       10. The method of  claim 1 , further comprising reducing the compound of Formula (II) into the compound of Formula (V): 
       
         
           
           
               
               
           
         
         wherein R 4 , R 4′ , R 5 , and R 5′  are independently selected from R z , C(O)R z , C(O)OR z , C(O)N(R z ) 2 , Si(R z ) 3 , wherein R z  is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl. 
       
     
     
       11. The method of  claim 10 , comprising further converting the compound of Formula (V) into oseltamivir, or a pharmaceutically acceptable salt thereof. 
     
     
       12. The method of  claim 1 , comprising preparing the compound of Formula (I) by cycloaddition between a compound of Formula (VI): 
       
         
           
           
               
               
           
         
         and a compound of Formula (VII): 
       
       
         
           
           
               
               
           
         
         to give the compound of Formula (I). 
       
     
     
       13. The method of  claim 10 , wherein the compound of Formula (VII) is prepared from a compound of Formula (VIII): 
       
         
           
           
               
               
           
         
         wherein R LG  represents a leaving group. 
       
     
     
       14. A method comprising
 a) conducting a cycloaddition reaction to give a cycloaddition product: 
 
       
         
           
           
               
               
           
         
         wherein R 1  comprises R 1a , C(O)R 1a , C(O)OR 1a , C(O)N(R 1a ) 2 , or Si(R 1a ) 3 , wherein R 1a  is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl; 
         wherein R h  is hydrogen and R 2  comprises F, Cl, Br, I, NO 2 , CN, OTs, or OMs; 
         R 3  is selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl; and 
         b) diazidating the cycloaddition product to give a compound of Formula (II): 
       
       
         
           
           
               
               
           
         
         wherein R 1′  is selected from R 1a′ , C(O)R 1a′ , C(O)OR 1a′ , C(O)N(R 1a′ ) 2 , Si(R 1a′ ) 3 , wherein R 1a′  is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, C 3-8 cycloalkyl, and C 1-8 heteroaryl; 
         wherein R h  is hydrogen and R 2  comprises F, Cl, Br, I, NO 2 , CN, OTs, or OMs, or R h  and R 2  together form a double bond. 
       
     
     
       15. The method according to  claim 14 , comprising further converting the compound of Formula (II) to oseltamivir, or a pharmaceutically acceptable salt thereof. 
     
     
       16. A method for preparing a compound of Formula (VIII): 
       
         
           
           
               
               
           
         
         comprising generating in situ the compound of Formula (VII): 
       
       
         
           
           
               
               
           
         
         from a compound having the formula: 
       
       
         
           
           
               
               
           
         
         in the presence of a compound of Formula (VI): 
       
       
         
           
           
               
               
           
         
         wherein R LG  is a leaving group; 
         wherein R 1  comprises R 1a , C(O)R 1a , C(O)OR 1a , C(O)N(R 1a ) 2 , or Si(R 1a ) 3 , wherein R 1a  is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 -alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl; 
         wherein R h  is hydrogen and R 2  comprises F, Cl, Br, I, NO 2 , CN, OTs, or OMs; and 
         R 3  is selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, C 3-8 cycloalkyl, and C 1-8 heteroaryl. 
       
     
     
       17. The method according to  claim 16 , further comprising converting the compound of Formula (VIII) into oseltamivir, or a pharmaceutically acceptable salt thereof. 
     
     
       18. The method according to  claim 17 , wherein the compound of Formula (VIII) is racemic and further comprising enzymatically resolving the compound of Formula (VIII) to obtain an enantioenriched compound of Formula (VIII-a) and an enantioenriched compound of Formula (IX): 
       
         
           
           
               
               
           
         
       
     
     
       19. The method according to  claim 18 , comprising further converting the compound of Formula (VIII-a) into oseltamivir, or a pharmaceutically acceptable salt thereof. 
     
     
       20. A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein R 1′  is selected from R 1a′ , C(O)R 1a′ , C(O)OR 1a′ , C(O)N(R 1a′ ) 2 , or Si(R 1a′ ) 3 , wherein R 1a′  is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, C 3-8 cycloalkyl, and C 1-8 heteroaryl; 
         wherein R h  is hydrogen and R 2  comprises F, Cl, Br, I, NO 2 , CN, OTs, or OMs, or R h  and R 2  together form a double bond; and 
         R 3  is selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl. 
       
     
     
       21. A method, comprising enantioselectively deacylating a racemic compound of Formula (VIII): 
       
         
           
           
               
               
           
         
         in the presence of a lipase enzyme and aqueous solvent, to obtain an enantioenriched compound of Formula (VIII-a) and an enantioenriched compound of Formula (IX): 
       
       
         
           
           
               
               
           
         
         wherein R 1  comprises C(O)R 1a  wherein R 1a  is selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl; 
         wherein R h  is hydrogen and R 2  comprises F, Cl, Br, I, NO 2 , CN, OTs, or OMs; and 
         R 3  is selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, C 3-8 cycloalkyl, and C 1-8 heteroaryl. 
       
     
     
       22. The method according to  claim 21 , comprising further converting the compound of Formula (VIII-a) into oseltamivir, or a pharmaceutically acceptable salt thereof.