Methods of synthesizing a prostacyclin analog

Abstract

or a pharmaceutically acceptable salt thereof, wherein R10 is a linear or branched C1-6 alkyl. The processes of the present invention comprise steps that generate improved yields and fewer byproducts than traditional methods. The processes of the present invention employ reagents (e.g., the oxidizing reagent) that are less toxic that those used in the traditional methods (e.g., oxalyl chloride). Many of the processes of the present invention generate intermediates with improved e.e. and chemical purity; thereby eliminating the need of additional chromatography steps. And, the processes of the present invention are scalable to generate commercial quantities of the final compound.

What is claimed is: 
     
         1 . A compound of Formula 13 
       
         
           
           
               
               
           
         
         wherein R 1  is C 1-6  alkyl and each R 2  is independently selected from C 1-6  alkyl or phenyl. 
       
     
     
         2 . A method of generating a compound of Formula 13 
       
         
           
           
               
               
           
         
       
       wherein R 1  is C 1-6  alkyl and each R 2  is independently selected from C 1-6  alkyl or phenyl, comprising
 x) reacting a compound of Formula 12 with (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole in the presence of an organic solvent comprising THF and toluene to generate a compound of Formula 13 
 
       
         
           
           
               
               
           
         
       
       wherein the compound of Formula 13 has a chemical purity of about 97% or greater and a d.e. of about 97% or greater. 
     
     
         3 . A method of generating a compound of Formula I 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, comprising the steps of:
 xv) reacting a compound of Formula 21a with n-butyllithium in the presence of an organic solvent and a transition metal catalyst to generate a compound of Formula 22a 
 
       
         
           
           
               
               
           
         
       
       wherein R 1  is C 1-6  alkyl; and
 xvi) converting the compound of Formula 22a to the compound of Formula I. 
 
     
     
         4 . The method of  claim 3 , wherein the transition metal catalyst comprises a compound or complex either of which comprises copper having a +1 oxidation state. 
     
     
         5 . The method of  claim 4 , wherein the transition metal catalyst comprises CuI. 
     
     
         6 . The method of  claim 3 , further comprising the steps of:
 xvii) reacting a compound of Formula 19a with triisopropylbenzenesulfonyl chloride under basic conditions to generate a compound of Formula 20a; and   
       
         
           
           
               
               
           
         
         xviii) reacting the compound of Formula 20a with methanol under basic conditions to generate the compound of Formula 21a. 
       
     
     
         7 . The method of  claim 6 , further comprising the steps of
 xix) reacting a compound of Formula 16a with a reducing agent to generate a compound of Formula 17a;   
       
         
           
           
               
               
           
         
         xx) reacting the compound of Formula 17a with TBDPSCl under basic conditions to generate a compound of Formula 18a; and 
       
       
         
           
           
               
               
           
         
         xxi) selectively deprotecting the compound of Formula 18a to generate the compound of Formula 19a. 
       
     
     
         8 . The method of  claim 7 , further comprising the steps of:
 xii) hydrogenating a compound of Formula 15a   
       
         
           
           
               
               
           
         
       
       in the presence of an alcohol, optionally substituted THF, or any combination thereof to generate the compound of Formula 16a. 
     
     
         9 . The method of  claim 8 , further comprising the steps of:
 x) reacting a compound of Formula 12a with a reducing agent to generate a compound of Formula 13a; and   
       
         
           
           
               
               
           
         
         xiv) converting the compound of Formula 13a to the compound of Formula 15a. 
       
     
     
         10 . The method of  claim 9 , further comprising the step of:
 v) reacting a compound of Formula 11a   
       
         
           
           
               
               
           
         
       
       with an oxidizing agent to generate the compound of Formula 12a, wherein the oxidizing agent comprises MnO 2 . 
     
     
         11 . The method of  claim 9 , further comprising the steps of:
 i) reacting a compound of Formula 9 with an oxidizing agent to generate a compound of Formula 10; and   
       
         
           
           
               
               
           
         
         ii) reacting the compound of Formula 10 with a compound of Formula 5a in the presence of a base and an organic solvent to generate a compound of Formula 11a 
       
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 11 , further comprising the steps of:
 iv) refluxing the compound of Formula 1a in the presence of methanol to generate a compound of Formula 1 having an e.e. of greater than about 98%;   
       
         
           
           
               
               
           
         
         v) reacting the compound of Formula 1 with TBSCl under basic conditions to generate the compound of Formula 2a; 
       
       
         
           
           
               
               
           
         
         vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to generate the compound of Formula 3a; and 
       
       
         
           
           
               
               
           
         
         vii) converting the compound of Formula 3a to the compound of Formula 5a. 
       
     
     
         13 . The method of  claim 12 , further comprising the steps of:
 xxii) reacting a compound of Formula 7a with a 3-haloprop-1-ene in the presence of a base and an organic solvent to generate a compound of Formula 8a; and   
       
         
           
           
               
               
           
         
         xxiii) deprotecting the compound of Formula 8a to generate the compound of Formula 9. 
       
     
     
         14 . A method of generating a compound of Formula I 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, comprising the steps of:
 i) reacting a compound of Formula 9 with an oxidizing agent to generate a compound of Formula 10; 
 
       
         
           
           
               
               
           
         
         ii) reacting the compound of Formula 10 with a compound of Formula 5a in the presence of a base and an organic solvent to generate a compound of Formula 11a; 
       
       
         
           
           
               
               
           
         
         iv) refluxing the compound of Formula 1a in the presence of methanol to generate a compound of Formula 1 having an e.e. of greater than about 98%; 
       
       
         
           
           
               
               
           
         
         v) reacting the compound of Formula 1 with TBSCl under basic conditions to generate the compound of Formula 2a; 
       
       
         
           
           
               
               
           
         
         vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to generate the compound of Formula 3a; 
       
       
         
           
           
               
               
           
         
         vii) converting the compound of Formula 3a to the compound of Formula 5a; 
         viii) reacting a compound of Formula 11a with an oxidizing agent to generate the compound of Formula 12a, wherein the oxidizing agent comprises MnO 2 ; 
       
       
         
           
           
               
               
           
         
         x) reacting a compound of Formula 12a with a reducing agent to generate a compound of Formula 13a; 
       
       
         
           
           
               
               
           
         
         xiv) converting the compound of Formula 13a to the compound of Formula 15a; 
       
       
         
           
           
               
               
           
         
         xii) hydrogenating a compound of Formula 15a in the presence of methanol, ethanol, THF, 2-methyl-THF, or any combination thereof to generate the compound of Formula 16a; 
       
       
         
           
           
               
               
           
         
         xix) reacting a compound of Formula 16a with a reducing agent to generate a compound of Formula 17a; 
         xx) reacting the compound of Formula 17a with TDPSCl under basic conditions to generate a compound of Formula 18a; 
       
       
         
           
           
               
               
           
         
         xxi) selectively deprotecting the compound of Formula 18a to generate the compound of Formula 19a; 
       
       
         
           
           
               
               
           
         
         xvii) reacting a compound of Formula 19a with triisopropylbenzenesulfonyl chloride under basic conditions to generate a compound of Formula 20a; 
       
       
         
           
           
               
               
           
         
         xviii) reacting the compound of Formula 20a with methanol under basic conditions to generate the compound of Formula 21a; 
       
       
         
           
           
               
               
           
         
         xv) reacting a compound of Formula 21a with n-butyllithium in the presence of an organic solvent and a transition metal catalyst to generate a compound of Formula 22a; and 
       
       
         
           
           
               
               
           
         
         xvi) converting the compound of Formula 22a to the compound of Formula I. 
       
     
     
         15 . The method of  claim 14 , further comprising the step of:
 xxiv) reacting the compound of Formula I with diethanolamine in the presence of an organic solvent to generate the diethanolamine salt of the compound of Formula I.   
     
     
         16 . A compound of Formula 1a 
       
         
           
           
               
               
           
         
       
     
     
         17 . A method of purifying a compound of Formula 1 comprising: 
       
         
           
           
               
               
           
         
         xxx) reacting a compound of Formula 1 with a derivatizing reagent to generate a precipitate that is substantially insoluble in dichloromethane or mixtures thereof; 
         xxxi) collecting the precipitate and refluxing the precipitate in a solvent comprising an alcohol to generate the compound of Formula 1 having a chemical purity of about 98% or greater and an e.e. of about 98% or greater; 
         wherein the method excludes the use of any column chromatography. 
       
     
     
         18 . The method of  claim 17 , wherein the derivatizing reagent comprises 3,5-dinitrobenzoyl chloride and the alcohol comprises methanol. 
     
     
         19 . A method of purifying a compound of Formula 9 comprising: 
       
         
           
           
               
               
           
         
         xl) reacting a compound of Formula 9, wherein R 1  is C 1-6  alkyl, with 3,5-dinitrobenzoyl chloride to generate a precipitate comprising a compound of Formula 9A; and 
       
       
         
           
           
               
               
           
         
         xli) collecting the precipitate and treating the precipitate with a base in the presence of an alcohol to generate the compound of Formula 9 having a chemical purity of about 95% or greater; 
         wherein the method excludes the use of any column chromatography. 
       
     
     
         20 . The method of  claim 19 , further comprising the step:
 xlii) recrystallizing the precipitate of step xli).   
     
     
         21 . A compound of Formula 9a 
       
         
           
           
               
               
           
         
       
       wherein R 1  is C 1-6  alkyl.