Process for Preparation of Cyclic Prodrugs of PMEA and PMPA

Abstract

The method of preparing compounds of Formula I is described: wherein: M and V are cis to one another and MPO 3 H 2 is a phosphonic acid selected from the group consisting of 9-(2-phosphonylmethoxyethyl)adenine, and (R)-9-(2-phosphonylmethoxypropyl)adenine; wherein V is phenyl, optionally substituted with 1-2 substituents selected from a group consisting of fluoro, chloro, and bromo; comprising: coupling a chiral 1-phenylpropane-1,3-diol, wherein the phenyl may be optionally substituted, with MPOCl 2 or an N-6 substituted analogue thereof. Additionally, methods and salt forms are described that enable isolation and purification of the desired isomer.

1 . A method for the preparation of compounds of Formula I:  
     
       
         
         
             
             
         
       
       wherein:  
       M and V are cis to one another and MPO 3 H 2  is a phosphonic acid selected from the group consisting of 9-(2-phosphonylmethoxyethyl)adenine and (R)-9-(2-phosphonylmethoxypropyl)adenine; wherein V is phenyl, optionally substituted with 1-2 substituents selected from a group consisting of fluoro, chloro, and bromo; comprising: 
 (a) coupling a chiral 1-arylpropane-1,3-diol, wherein the aryl is a phenyl optionally substituted with 1-2 substituents selected from the group consisting of fluoro, chloro, and bromo, with MPOCl 2  or an N-6 substituted analogue thereof.  
 
     
   
   
       2 . The method of  claim 1  wherein the cis isomer has a diastereomeric excess of at least 50%.  
   
   
       3 . The method of  claim 2  further comprising adding acid to form an acid addition salt of compounds of Formula I.  
   
   
       4 . The method of  claim 3  wherein said acid is selected from the group consisting of HCl, HBr, acetic acid, citric acid, maleic acid, methanesulfonic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, and tartaric acid.  
   
   
       5 . The method of  claim 3  wherein said acid is selected from a group consisting of methanesulfonic acid, succinic acid, citric acid, and oxalic acid.  
   
   
       6 . The method of  claim 5  wherein said acid is methanesulfonic acid.  
   
   
       7 . The method of  claim 3  further comprising crystallizing said acid addition salt.  
   
   
       8 . The method of  claim 7  wherein the solvent for crystallizing said acid addition salt is selected from a group consisting of methanol, ethanol, isopropanol, acetone, toluene, and mixtures thereof.  
   
   
       9 . The method of  claim 3  further comprising: 
 (a) reacting a first acid addition salt compound of Formula I with a second acid that has a higher acid dissociation constant than the first acid, and    (b) crystallizing the desired second acid addition salt compound of Formula I.    
   
   
       10 . The method of  claim 3  further comprising: 
 (a) neutralizing a first acid addition salt compound of Formula I,    (b) obtaining the free base of the compound of Formula I,    (c) adding a pharmaceutically acceptable acid, and    (d) crystallizing the desired second acid addition salt compound of Formula I.    
   
   
       11 . The method of  claim 3  further comprising: 
 (a) utilizing an anionic resin to obtain free base of a first acid addition salt compound of Formula I,    (b) adding a pharmaceutically acceptable acid, and    (c) crystallizing the desired second acid addition salt compound of Formula I.    
   
   
       12 . The method of  claim 1  wherein the reaction solution for the coupling step is at or below −50° C.  
   
   
       13 . The method in  claim 12  wherein said reaction solution is at or below −70° C.  
   
   
       14 . The method as recited in  claim 1  wherein said MPOCl 2  is added to said chiral 1-phenylpropane-1,3-diol.  
   
   
       15 . The method of  claim 1  wherein said MPOCl 2  is added to said chiral 1-phenylpropane-1,3-diol at a reaction solution temperature at or below −50° C.  
   
   
       16 . The method of  claim 1  further comprising addition of a base to the reaction solution.  
   
   
       17 . The method of  claim 1  wherein the MPOCl 2  has an N-6 substituent to form a dialkylaminomethyleneimine.  
   
   
       18 . The method of  claim 17  wherein said N-6 substituent is produced as part of the reaction to form the dichloridate.  
   
   
       19 . The method of  claim 17  wherein said dialkylaminomethyleneimine is selected from the group consisting of dimethylaminomethyleneimine, diethylaminomethylene, dipropylaminomethyleneimine, dibutylaminomethyleneimine, N-piperidinomethyleneimine, and N-morpholinomethyleneimine.  
   
   
       20 . The method of  claim 1  wherein the compounds of Formula I have the stereochemistry of Formula II:  
     
       
         
         
             
             
         
       
     
   
   
       21 . The method of  claim 20  wherein the temperature for the coupling step is at or below −50° C.  
   
   
       22 . A method for the preparation of compounds of Formula I:  
     
       
         
         
             
             
         
       
       wherein:  
       M and V are cis to one another and MPO 3 H 2  is a phosphonic acid selected from the group consisting of 9-(2-phosphonylmethoxyethyl)adenine and (R)-9-(2-phosphonylmethoxypropyl)adenine;  
       wherein V is 3-chlorophenyl; comprising: 
 (a) coupling a chiral 1-(3-chlorophenyl)propane-1,3-diol with MPOCl 2  or an N-6 substituted analogue thereof.  
 
     
   
   
       23 . The method of  claim 22  wherein the cis isomer has a diastereomeric excess of at least 50%.  
   
   
       24 . The method of  claim 23  further comprising adding acid to form an acid addition salt of Formula I.  
   
   
       25 . The method of  claim 24  wherein said acid is selected from the group consisting of methanesulfonic acid, succinic acid, citric acid, and oxalic acid.  
   
   
       26 . The method of  claim 25  wherein said acid is methanesulfonic acid.  
   
   
       27 . The method of  claim 22  wherein the reaction solution for the coupling step is at or below −50° C.  
   
   
       28 . The method of  claim 27  wherein said reaction solution is at or below −70° C.  
   
   
       29 . The method of  claim 22  wherein said MPOCl 2  is added to said chiral 1-(3-chlorophenyl)propane-1,3-diol.  
   
   
       30 . The method of  claim 22  wherein the compounds of Formula I have the stereochemistry of Formula II:  
     
       
         
         
             
             
         
       
     
   
   
       31 . The method of  claim 30  wherein the temperature for the coupling step is at or below −50° C.  
   
   
       32 . The method of  claim 30  further comprising adding acid to form an acid addition salt of Formula II.  
   
   
       33 . The method of  claim 32  wherein said acid is selected from the group consisting of methanesulfonic acid, succinic acid, citric acid, and oxalic acid.  
   
   
       34 . The method of  claim 33  wherein said acid is methanesulfonic acid.  
   
   
       35 . The method of  claim 24  further comprising crystallizing said acid addition salt from a solvent selected from the group consisting of methanol, ethanol, isopropanol, toluene, acetone, and mixtures thereof.  
   
   
       36 . The method as recited in  claim 22  wherein the MPOCl 2  has an N-6 substituent to form a dialkylaminomethyleneimine.  
   
   
       37 . The method as recited in  claim 36  wherein the N-6 substituent is produced as part of the reaction to form the dichloridate.  
   
   
       38 . The method as recited in  claim 36  wherein the dialkylaminomethyleneimine is selected from a group consisting of dimethylaminomethyleneimine, diethylaminomethylene, dipropylaminomethyleneimine, dibutylaminomethyleneimine, N-piperidinomethyleneimine, and N-morpholinomethyleneimine.  
   
   
       39 . A method for the preparation of compounds of Formula I:  
     
       
         
         
             
             
         
       
       wherein:  
       M and V are cis to one another and MPO 3 H 2  is phosphonic acid selected from the group consisting of 9-(2-phosphonylmethoxyethyl)adenine, and (R)-9-(2-phosphonylmethoxypropyl)adenine;  
       wherein V is 2-bromophenyl; comprising: 
 (a) coupling a chiral 1-(2-bromophenyl)propane-1,3-diol with MPOCl 2  or an N-6 substituted analogue thereof.  
 
     
   
   
       40 . The method of  claim 39  wherein the cis isomer has a diastereomeric excess of at least 50%.  
   
   
       41 . The method of  claim 40  further comprising adding acid to form an acid addition salt of Formula I.  
   
   
       42 . The method of  claim 41  wherein said acid is selected from the group consisting of methanesulfonic acid, succinic acid, citric acid, and oxalic acid.  
   
   
       43 . The method of  claim 42  wherein said acid is methanesulfonic acid.  
   
   
       44 . The method of  claim 39  wherein the reaction solution for the coupling step is at or below −50° C.  
   
   
       45 . The method of  claim 44  wherein said reaction solution is at or below −70° C.  
   
   
       46 . The method of  claim 39  wherein said MPOCl 2  is added to said chiral 1-(2-bromophenyl)propane-1,3-diol.  
   
   
       47 . The method of  claim 39  wherein the compounds of Formula I have the stereochemistry of Formula II:  
     
       
         
         
             
             
         
       
     
   
   
       48 . The method of  claim 40  wherein the temperature for the coupling step is at or below −50° C.  
   
   
       49 . The method of  claim 47  further comprising adding acid to form an acid addition salt of Formula II.  
   
   
       50 . The method of  claim 49  wherein said acid is selected from the group consisting of methanesulfonic acid, succinic acid, citric acid, and oxalic acid.  
   
   
       51 . The method of  claim 50  wherein said acid is methanesulfonic acid.  
   
   
       52 . The method of  claim 41  further comprising crystallization of said acid addition salt from a solvent selected from the group consisting of methanol, ethanol, isopropanol, acetone, toluene, and mixtures thereof.  
   
   
       53 . The method of  claim 39  wherein the MPOCl 2  has an N-6 substituent to form a dialkylaminomethyleneimine.  
   
   
       54 . The method of  claim 53  wherein the N-6 substituent is produced as part of the reaction to form the dichloridate.  
   
   
       55 . The method of  claim 53  wherein the dialkylaminomethyleneimine is selected from the group consisting of dimethylaminomethyleneimine, diethylaminomethylene, dipropylaminomethyleneimine, dibutylaminomethyleneimine, N-piperidinomethyleneimine, and N-morpholinomethyleneimine.  
   
   
       56 . A method for the conversion of acid addition salt compounds of Formula I:  
     
       
         
         
             
             
         
       
       wherein:  
       M and V are cis to one another and MPO 3 H 2  is a phosphonic acid selected from the group consisting of 9-(2-phosphonylmethoxyethyl)adenine, and (R)-9-(2-phosphonylmethoxypropyl)adenine; wherein V is phenyl, optionally substituted with 1-2 substituents selected from a group consisting of fluoro, chloro, and bromo; comprising: 
 (a) reacting said first acid addition salt compound of Formula I with a second acid that has a higher acid dissociation constant than the first acid, and  
 (b) crystallizing desired second acid salt compound.  
 
     
   
   
       57 . The method of  claim 56  wherein said second acid is selected from the group consisting of HCl, HBr, acetic acid, citric acid, maleic acid, methanesulfonic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, and tartaric acid.  
   
   
       58 . The method of  claim 57  wherein said second acid is selected from the group consisting of methanesulfonic acid, succinic acid, citric acid, and oxalic acid.  
   
   
       59 . The method of  claim 58  wherein said second acid is methanesulfonic acid.  
   
   
       60 . A method for the conversion of first acid addition salt compounds of Formula I:  
     
       
         
         
             
             
         
       
       wherein:  
       M and V are cis to one another and MPO 3 H 2  is a phosphonic acid selected from the group consisting of 9-(2-phosphonylmethoxyethyl)adenine, and (R)-9-(2-phosphonylmethoxypropyl)adenine; wherein V is phenyl, optionally substituted with 1-2 substituents selected from a group consisting of fluoro, chloro, and bromo; comprising: 
 (a) neutralizing said first acid addition salt compound of Formula I,  
 (b) obtaining the free base of the compound of Formula I,  
 (c) adding pharmaceutically acceptable acid, and  
 (d) crystallizing desired second acid salt compound.  
 
     
   
   
       61 . The method of  claim 60  wherein the acid is selected from the group consisting of said pharmaceutically acceptable HCl, HBr, acetic acid, citric acid, maleic acid, methane sulfonic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, and tartaric acid.  
   
   
       62 . A method for the conversion of a first acid addition salt compounds of Formula I:  
     
       
         
         
             
             
         
       
       wherein:  
       M and V are cis to one another and MPO 3 H 2  is a phosphonic acid selected from the group consisting of 9-(2-phosphonylmethoxyethyl)adenine, and (R)-9-(2-phosphonylmethoxypropyl)adenine; wherein V is phenyl, optionally substituted with 1-2 substituents selected from a group consisting of fluoro, chloro, and bromo; comprising: 
 (a) utilizing an anionic resin to obtain the free base of the compound of Formula I,  
 (b) adding a pharmaceutically acceptable acid, and  
 (c) crystallizing the desired second acid addition salt compound of Formula I.  
 
     
   
   
       63 . The method of  claim 62  wherein said pharmaceutically acceptable acid is selected from the consisting of HCl, HBr, acetic acid, citric acid, maleic acid, methanesulfonic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, and tartaric acid.