Methods for the preparation of intermediates in the synthesis of HIV-protease inhibitors

Abstract

Methods for the preparation of chemical intermediates in the synthesis of HIV-protease inhibitors related to and including nelfinavir mesylate are disclosed. The method of this invention comprises converting tetrohydran derivatives into oxazolines to provide key reaction intermediates for the preparation of nelfinavir. Also disclosed is a method for the preparation of a chiral amino alcohol from an epoxy-tetrahydrofuran.

We claim:  
     
         1 . A method for the preparation of an oxazoline,  
       
         
           
           
               
               
           
         
         comprising treating the tetrahydrofuran, wherein R a  is —COR(1) and R b  is hydrogen, —COR(3), —SO 2 R(2) or a suitable hydroxyl protecting group with an oxophilic electrophilic reagent in a manner that is effective to provide the oxazoline, wherein R b  is hydrogen, —COR(3), —SO 2 R(2) or a suitable hydroxyl protecting group and R c  is hydrogen, —COR(3) or —SO 2 R(2); wherein R(1), R(2) and R(3) independently represent a substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl group.  
       
     
     
         2 . The method according to  claim 1 , comprising treating the tetrahydrofuran with about 1 to about 20 molar equivalents of the oxophilic electrophilic reagent.  
     
     
         3 . The method according to  claim 1 , wherein said oxophilic electrophilic reagent comprises a combination of about 1 to about 20 molar equivalents of a suitable acid and about 1 to about 20 molar equivalents of a suitable acid anhydride, wherein the anhydride and the acid are used in a relative molar ratio of from about 1:5 to about 5:1, respectively.  
     
     
         4 . The method according to  claim 1 , wherein said oxophilic electrophilic reagent comprises a combination of about 2 to about 20 molar equivalents of a suitable acid and about 2 to about 20 molar equivalents of a suitable acid anhydride, wherein the anhydride and the acid are used in a relative molar ratio of from about 1:1 to about 5:1, respectively.  
     
     
         5 . The method according to  claim 1 , wherein said oxophilic electrophilic reagent comprises about 7.5 molar equivalents of a suitable acid and 15 molar equivalents of a suitable acid anhydride.  
     
     
         6 . The method according to  claim 1  wherein said tetrahydrofuran is treated with an anhydride under acidic conditions to form said oxazoline.  
     
     
         7 . A method for the preparation of an oxazoline having the formula:  
       
         
           
           
               
               
           
         
       
       wherein R(1), R(2) and R(3) independently represent substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl, said method comprising the steps of: 
 (1) treating an amino-tetrahydrofuran, or a salt thereof, having the formula:  
                     
  in a manner that is effective to convert said amino-tetrahydrofuran, or a salt thereof, to a tetrahydrofuran-amide, having the formula:  
                     
 (2) treating the tetrahydrofuran-amide with a substituted or unsubstituted alkyl or aryl sulfonylating reagent to convert said tetrahydrofuran-amide to an tetrahydrofuran amide-sulfonate having the formula:  
                     
  comprising the step-wise treatment of the tetrahydrofuran-amide with at least one molar equivalent amount of the sulfonylating reagent, followed by treatment with a base, wherein the molar equivalent amount of base used in the treatment is less than the molar equivalent amount of the sulfonylating reagent, and  
 (3) treating the tetrahydrofuran amide-sulfonate with an oxophilic electrophilic reagent in a manner that is effective to convert said tetrahydrofuran amide-sulfonate to said oxazoline.  
 
     
     
         8 . A method for the preparation of an oxazoline diol having the formula:  
       
         
           
           
               
               
           
         
       
       said method comprising the steps of: 
 (1) treating an amino-tetrahydrofuran, or a salt thereof, having the formula:  
                     
  in a manner that is effective to convert the amino-tetrahydrofuran, or a salt thereof, to a tetrahydrofuran-amide having the formula:  
                     
 (2) treating the tetrahydrofuran-amide with an oxophilic electrophilic reagent in a manner that is effective to convert said tetrahydrofuran-amide to an oxazoline diester having the formula:  
                     
 (3) hydrolyzing the oxazoline diester to said oxazoline diol;  
 wherein R(1) and R(3) independently represent substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl.  
 
     
     
         9 . A method for the preparation of an oxazoline diol having the formula:  
       
         
           
           
               
               
           
         
       
       comprising the steps of: 
 (1) treating an amino-tetrahydrofuran or a salt thereof, having the formula:  
                     
  in a manner that is effective to convert the amino-tetrahydrofuran or a salt thereof, to a tetrahydrofuran-amide having the formula:  
                     
 (2) treating the tetrahydrofuran-amide with a substituted or unsubstituted alkyl or aryl sulfonylating reagent, in a manner effective to convert said tetrahydrofuran-amide to a fused tetrahydrofuranyloxazoline having the formula:  
                     
 (3) hydrolyzing the fused tetrahydrofuranyloxazoline to a tetrahydrofuran-amide having the formula:  
                     
 (4) treating the tetrahydrofuran-amide with an oxophilic electrophilic reagent in a manner that is effective to convert said tetrahydrofuran-amide to an oxazoline diester having the formula:  
                     
 (5) hydrolyzing the oxazoline diester to said oxazoline diol;  
 wherein R(1) and R(3) independently represent substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl.  
 
     
     
         10 . A method for the preparation of an oxazoline having the formula:  
       
         
           
           
               
               
           
         
       
       wherein R(1) is substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl, R(10) is a suitable hydroxyl protecting group and R(11) is H or substituted alkyl sulfonyl, comprising the steps of 
 (1) treating an amino-tetrahydrofuran or a salt thereof, having the formula:  
                     
  in a manner that is effective to convert the amino-tetrahydrofuran or a salt thereof, to a tetrahydrofuran-hydroxy-amide having the formula:  
                     
 (2) treating the tetrahydrofuran-hydroxy-amide in a manner effective to protect the hydroxyl moiety of the hydroxy-amide to form a protected tetrahydrofuran-amide, having the formula:  
                     
 (3) treating the protected tetrahydrofuran-amide with an oxophilic electrophilic reagent in a manner that is effective to convert said tetrahydrofuran-amide to said protected oxazoline;  
 wherein said oxophilic electrophilic reagent is selected from an oxophilic Lewis acid, an oxophilic protic acid, or triflic anhydride.  
 
     
     
         11 . A method for the preparation of nelfinavir comprising the steps of: 
 (1) treating an amino-tetrahydrofuran, or a salt thereof, having the formula:                           in a manner that is effective to convert the amino-tetrahydrofuran, or a salt thereof, to a tetrahydrofuran-amide having the formula:                          (2) treating the tetrahydrofuran-amide to convert said tetrahydrofuran-amide to a tetrahydrofuran amide-sulfonate having the formula:                           comprising the step-wise treatment of the tetrahydrofuran-amide with at least one molar equivalent amount of the sulfonylating reagent, followed by treatment with a base, wherein the molar equivalent amount of base used in the treatment is less than the molar equivalent amount of the sulfonylating reagent, and    (3) treating the tetrahydrofuran-amide sulfonate with an oxophilic electrophilic reagent in a manner that is effective to convert said tetrahydrofuran amide-sulfonate to an oxazoline having the formula:                          (4) treating the oxazoline in a manner that is effective to convert said oxazoline to a compound having the formula:                          (5) converting said compound to nelfinavir;    wherein R(2) and R(3) are independently selected from substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl, and R(5) is a substituted or unsubstituted NH-alkyl, NH-aryl, O-alkyl, or O-aryl group, wherein each alkyl or aryl moiety may be substituted or unsubstituted.    
     
     
         12 . A method for the preparation of nelfinavir comprising the steps of: 
 (1) treating an amino-tetrahydrofuran or a salt thereof, having the formula:                           in a manner that is effective to convert the amino-tetrahydrofuran or a salt thereof, to a tetrahydrofuran-amide having the formula:                          (2) treating the tetrahydrofuran-amide with an oxophilic electrophilic reagent in a manner that is effective to convert said tetrahydrofuran-amide to an oxazoline triester having the formula:                          (3) hydrolyzing the oxazoline triester to an oxazoline triol having the formula:                          (4) protecting the oxazoline triol with a suitable hydroxyl protecting group, in a manner that is effective to convert said oxazoline triol to a di-protected oxazoline having the formula:                          (5) treating the di-protected oxazoline with a substituted or unsubstituted alkyl or aryl sulfonylating reagent, in a manner effective to convert said oxazoline to a sulfonylated-di-protected oxazoline having the formula:                          (6) treating the sulfonylated-di-protected oxazoline with 3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline in a manner that is effective to convert said oxazoline to a compound having the formula:                          (7) converting said compound to nelfinavir;    wherein R(2) and R(3) are independently selected from substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl, R(5) is a substituted or unsubstituted HN-alkyl, NH-aryl, O-alkyl, or O-aryl group, wherein each alkyl or aryl moiety may be substituted or unsubstituted , and R(7) is any suitable hydroxyl protecting group.    
     
     
         13 . A method for the preparation of nelfinavir comprising the steps of: 
 (1) treating an amino-tetrahydrofuran, or a salt thereof, having the formula:                           in a manner that is effective to convert the amino-tetrahydrofuran or a salt thereof, to a tetrahydrofuran-amide having the formula:                          (2) treating the tetrahydrofuran-amide with a substituted or unsubstituted alkyl or aryl sulfonylating reagent, in a manner effective to convert said tetrahydrofuran-amide to a fused tetrahydrofuranyloxazoline having the formula:                          (3) hydrolyzing the fused tetrahydrofuranyloxazoline to a tetrahydrofuran-amide having the formula:                          (4) treating the tetrahydrofuran-amide with an oxophilic electrophilic reagent in a manner that is effective to convert said tetrahydrofuran-amide to an oxazoline triester having the formula:                          (5) hydrolyzing the oxazoline triester to an oxazoline triol having the formula:                          (6) treating the oxazoline triol with a substituted or unsubstituted alkyl or aryl sulfonylating reagent, in a manner effective to convert said oxazoline to a protected oxazoline having the formula:                          (7) treating the protected oxazoline with 3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline in a manner that is effective to convert said oxazoline to a compound having the formula:                          (8) converting said compound to nelfinavir;    wherein R(3) is selected from substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl, R(5) is a substituted or unsubstituted HN-alkyl, NH-aryl, O-alkyl, or O-aryl group, wherein each alkyl or aryl moiety may be substituted or unsubstituted, R(8) is a substituted or unsubstituted alkyl or aryl sulfonyl and R(9) is hydrogen or R(8).    
     
     
         14 . A method for the preparation of nelfinavir comprising the steps of: 
 (1) treating an amino-tetrahydrofuran, or a salt thereof, having the formula:                           in a manner that is effective to convert the amino-tetrahydrofuran or a salt thereof, to a tetrahydrofuran-amide having the formula:                          (2) treating the tetrahydrofuran-amide in a manner that is effective to convert the tetrahydrofuran-amide to a protected tetrahydrofuran-amide, having the formula:                          (3) treating the protected tetrahydrofuran-amide with an oxophilic electrophilic reagent selected from an oxophilic Lewis acid, an oxophilic protic acid, or triflic anhydride in a manner that is effective to convert the tetrahydrofuran-amide to a protected oxazoline having the formula:                          (4) treating the protected oxazoline with 3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline in a manner that is effective to convert said oxazoline to a compound having the formula:                          (5) converting said compound to nelfinavir;    wherein R(1) is substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl, R(5) is a substituted or unsubstituted NH-alkyl, NH-aryl, O-alkyl, or O-aryl group, wherein each alkyl or aryl moiety may be substituted or unsubstituted, R(10) is a suitable hydroxyl protecting group and R(11) is H or substituted alkyl sulfonyl.    
     
     
         15 . The method according to any one of  claims 1  to  10  wherein R(1) is CF 3 , a substituted or unsubstituted phenyl, or a C 1 -C 6  alkyl.  
     
     
         16 . The method according to any one of  claims 1  to  10  wherein R(1) is  
       
         
           
           
               
               
           
         
       
     
     
         17 . The method according to any one of  claims 7  to  9  or  11  to  13 , comprising treating the tetrahydrofuran with about 1 to about 20 molar equivalents of the oxophilic electrophilic reagent.  
     
     
         18 . The method according to any one of  claims 7  to  9  or  11  to  13 , wherein said oxophilic electrophilic reagent comprises a combination of about 1 to about 20 molar equivalents of a suitable acid and about 1 to about 20 molar equivalents of a suitable acid anhydride, wherein the anhydride and the acid are used in a relative molar ratio of from about 1:5 to about 5:1, respectively.  
     
     
         19 . The method according to any one of  claims 7  to  9  or  11  to  13 , wherein said oxophilic electrophilic reagent comprises a combination of about 2 to about 20 molar equivalents of a suitable acid and about 2 to about 20 molar equivalents of a suitable acid anhydride, wherein the anhydride and the acid are used in a relative molar ratio of from about 1:1 to about 5:1, respectively.  
     
     
         20 . The method according to any one of  claims 7  to  9  or  11  to  13 , wherein said oxophilic electrophilic reagent comprises about 7.5 molar equivalents of a suitable acid and 15 molar equivalents of a suitable acid anhydride.  
     
     
         21 . The method according to any one of  claims 7  to  9  or  11  to  13 , wherein R(3) is methyl or phenyl.  
     
     
         22 . The method according to any one of  claims 7  to  9  or  11  to  13 , wherein said tetrahydrofuran-amide is treated with acetic anhydride and sulfuric acidic to form said oxazoline.  
     
     
         23 . The method according to  claim 15  wherein R(3) is methyl.  
     
     
         24 . The method according to any one of  claims 7  to  10 , wherein the amino-tetrahydrofuran is treated with an compound having the formula R(1)COX, wherein X is chloro or bromo, to form the tetrahydrofuran-amide and R(1) is  
       
         
           
           
               
               
           
         
       
     
     
         25 . The method according to  claims 11  to  14  wherein R(5) is HN-t-Bu.  
     
     
         26 . The method according to  claim 12 , wherein R(7) is trialkylsilyl, dialkyl-monoarylsilyl, diaryl-monoalkylsilyl, substituted or unsubstituted aroyl or alkanoyl.  
     
     
         27 . The method according to  claim 12 , wherein R(7) is trimethylsilyl, tert-butyl-di-methylsilyl, benzoyl, or para-nitrobenzoyl.  
     
     
         28 . The method according to  claim 12 , wherein R(7) is a para-nitrobenzoyl.  
     
     
         29 . The method according to  claim 13 , wherein R(8) is a substituted or unsubstituted alkyl or aryl sulfonyl.  
     
     
         30 . The method according to  claim 13 , wherein R(8) is p-toluenesulfonyl.  
     
     
         31 . A method of the preparation of a chiral amino-tetrahydrofuran, 1, or a salt thereof:  
       
         
           
           
               
               
           
         
       
       said method comprising the steps of: 
 (1) treating an epoxy-tetrahydrofuran having the formula:  
                     
  with an aminating reagent to form a stereoisomeric mixture of amino-tetrahydrofurans having the formulae:  
                     
 (2) treating the amino-tetrahydrofuran mixture in a manner effective to separate the amino-tetrahydrofuran stereoisomers, and  
 (3) isolating the amino-tetrahydrofuran, 1, or a salt thereof;  
 wherein R(6) is hydrogen or a suitable nitrogen protecting group.  
 
     
     
         32 . The method according to  claim 31 , wherein the amino-tetrahydrofuran, 1, is substantially enantiomerically pure.  
     
     
         33 . The method according to  claim 31 , wherein R(6) is a substituted or unsubstituted alkanoyl, aroyl, arylalkylcarbonyl, arylalkyl, heteroarylalkyl, wherein the alkyl, aryl or heteroaryl is substituted or unsubstituted.  
     
     
         34 . The method according to  claim 31 , wherein the aminating reagent is a chiral aminating reagent.  
     
     
         35 . The method according to  claim 34 , wherein R(6) is  
       
         
           
           
               
               
           
         
       
     
     
         36 . The method according to  claim 34 , comprising separating the amino-tetrahydrofuran stereoisomers by crystallization or chromatography.  
     
     
         37 . The method according to  claim 36 , further comprising removing the R(6) substituent from the separated amino-tetrahydrofuran stereoisomers.  
     
     
         38 . The method according to  claim 31 , wherein the aminating reagent is an achiral aminating reagent.  
     
     
         39 . The method according to  claim 38  further comprising treating the amino-tetrahydrofuran mixture with a chiral auxiliary reagent to produce diastereomeric amino-tetrahydrofurans.  
     
     
         40 . The method according to  claim 39 , comprising separating the amino-tetrahydrofuran diastereomers by crystallization or chromatography.  
     
     
         41 . The method according to  claim 40 , further comprising removing the chiral auxiliary reagent from the separated amino-tetrahydrofuran stereoisomers.