Phosphonate Ester Derivatives and Methods of Synthesis Thereof

Abstract

The disclosure describes methods of synthesis of phosphonate ester derivatives. Preferred methods according to the disclosure allow for large-scale preparation of phosphonate ester compounds having high purity. In some embodiments, preferred methods according to the disclosure also allow for the preparation of phosphonate ester derivatives without the use of chromatographic purification methods and in better yield than previously used methods for preparing such compounds. Also disclosed are morphic forms of phosphonate ester derivatives.

What is claimed is: 
     
         1 . A method for synthesizing phosphonic acid, P-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-, mono[3-(hexadecyloxy)propyl]ester, sodium salt, in high yield comprising:
 (a) contacting (dichlorophosphoryl)methyl 4-methylbenzenesulfonate with 3-(hexadecyloxy)propan-1-ol in the presence of a base in a first suitable solvent to form a resultant mixture;   (b) quenching the resultant mixture with water; and   (c) dissolving the resultant mixture in a second suitable solvent, for producing high yield of the phosphonic acid, P-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-, mono[3-(hexadecyloxy)propyl]ester, sodium salt.   
     
     
         2 . The method of  claim 1 , wherein the phosphonic acid, P-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-, mono[3-hexadecyloxy)propyl]ester, sodium salt is synthesized in high yield having a purity of greater than or equal to 80%, 82.5%, 85%, 87.5%, 90.0%, 92.5%, 95%, 97.5%, or 99%. 
     
     
         3 . The method of  claim 1 , further comprising (d) treating the second suitable solvent in step (c) with sodium hydroxide. 
     
     
         4 . The method of  claim 1 , wherein the phosphonic acid, P-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-, mono[3-hexadecyloxy)propyl]ester, sodium salt is synthesized with a purity of greater than or equal to 98%. 
     
     
         5 . The method of  claim 1 , wherein the phosphonic acid, P-[[[(4-methylphenyesulfonyl]oxy]methyl]-, mono[3-(hexadecyloxy)propyl]ester, sodium salt contains less than or equal to 1%, 0.5%, 0.25%, 0.1%, or 0.01% of: 
       
         
           
           
               
               
           
         
       
       as impurity. 
     
     
         6 . The method of  claim 1 , further comprising synthesizing the (dichlorophosphoryl)methyl 4-methylbenzenesulfonate by:
 (a) contacting diethyl (tosyloxy)methylphosphonate and acetonitrile with bromotrimethylsilane and heating to form a resultant mixture; and   (b) adding a suitable solvent and oxalyl chloride to the resultant mixture to form the (dichlorophosphoryl)methyl 4-methylbenzenesulfonate.   
     
     
         7 . The method of  claim 1 , further comprising synthesizing the 3-(hexadecyloxy)propan-1-ol by:
 (a) contacting 1,3-propanediol in (N,N-dimethylformamide) with sodium hydride to form a resultant mixture; and   (b) adding a solution of hexadecyl methanesulfonate dissolved in (N,N-dimethylformamide) to the resultant mixture to form the 3-(hexadecyloxy)propan-1-ol.   
     
     
         8 . The method of  claim 7 , further comprising synthesizing the hexadecyl methanesulfonate by:
 (a) contacting 1-hexadecanol, dichloromethane and diisopropylethylamine to form a resultant mixture; and   (b) adding methanesulfonyl chloride to the resultant mixture to form the hexadecyl methanesulfonate.   
     
     
         9 . A method for synthesizing phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl]ester, comprising:
 contacting (S)—N 1 -[(2-hydroxy-3-(PG-O)-propyl]cytosine with phosphonic acid, P-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-, mono[3-(hexadecyloxy)propyl]ester, sodium salt in the presence of magnesium di-tert-butoxide and a suitable organic solvent A to form [3-(hexadecyloxy)propyl]hydrogen [[[(S)-1-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(PG-O)-propan-2-yl]oxy]methyl]phosphonate; and   contacting [3-(hexadecyloxy)propyl]hydrogen [[[(S)-1-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(PG-O)-propan-2-yl]oxy]methyl]phosphonate with a protecting-group removal agent in the presence of a suitable organic solvent B to form phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl]ester;   
       wherein PG is a hydroxyl protecting group. 
     
     
         10 . The method of  claim 9 , further comprising recrystallizing the phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl]ester in a suitable recrystallizing organic solvent to produce a morphic form of said phosphonic acid (Form A) characterized by an X-ray diffraction pattern including peaks at about 5.5, 19.3, 20.8, and 21.3 degrees 2θ. 
     
     
         11 . The method of  claim 9 , further comprising synthesizing the (S)—N 1 -[(2-hydroxy-3-(PG-O)-propyl]cytosine by:
 contacting cytosine with (S)-2-(PG-O-methyl)oxirane in the presence of a metal carbonate and a suitable organic solvent C to form (S)—N 1 -[(2-hydroxy-3-(PG-O)-propyl]cytosine. 
 
     
     
         12 . The method of  claim 9 , wherein PG is triphenylmethyl. 
     
     
         13 . The method of  claim 9 , wherein the solvent A is N,N-dimethylformamide. 
     
     
         14 . The method of  claim 9 , wherein the solvent B is an alcohol. 
     
     
         15 . The method of  claim 14 , wherein the solvent B is methanol. 
     
     
         16 . The method  claim 11 , wherein the solvent C is N,N-dimethylformamide. 
     
     
         17 . The method of  claim 9 , further comprising recrystallizing the phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl]ester from methanol. 
     
     
         18 . The method of  claim 17 , wherein the recrystallized phosphonic acid, [[(S)-2-(4-amino-2-oxo-1 (2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl]ester is isolated from methanol at a temperature no lower than 20° C. 
     
     
         19 . A morphic form of phosphonic acid [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl]ester. 
     
     
         20 . The morphic form according to  claim 19 , wherein the morphic form is greater than or equal to 91% wt/wt pure. 
     
     
         21 . The morphic form according to  claim 19 , wherein the morphic form is not a hydrate. 
     
     
         22 . A crystalline form of phosphonic acid [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl]ester. 
     
     
         23 . The crystalline form according to  claim 22 , wherein the crystalline form is greater than or equal to 91% wt/wt pure. 
     
     
         24 . The crystalline form according to  claim 22  isolated from methanol at a temperature no lower than 20° C.