Crystalline salts of (z)-o-octadec-9-en-1-yl o,o-dihydrogen phosphorothioate

Abstract

Here provided are a salt of Z)—O-octadec-9-en-1-yl O,O-dihydrogen phosphorothioate with an L-lysine addition in crystalline form and methods of making and using the same.

We claim: 
     
         1 . A method for producing Rx100.L-lysine crystalline salts, comprising the steps of:
 a. mixing Rx100 free acid with L-lysine; and   b. allowing the Rx100.L-Lysine salt to form in the presence of a suitable amount of a solvent.   
     
     
         2 . The method of  claim 1 , wherein L-lysine base is used at molar equivalents of 1.0 of the free acid. 
     
     
         3 . The method of  claim 1 , wherein L-lysine base is used at molar equivalents of 1.5 of the free acid. 
     
     
         4 . The method of  claim 1 , wherein L-lysine base is used at molar equivalents of 2.0 of the free acid. 
     
     
         5 . The method of  claim 1 , wherein L-lysine base is used at molar equivalents of 3.0 of the free acid. 
     
     
         6 . The method of  claim 1 , wherein the solvent is selected from the group consisting of methanol, Isopropyl alcohol (IPA), IPA:water (95:5 vol), tert-Butyl methyl ether (tBME), Ethyl acetate, IPA:water (1:1 vol), Diethyl ether, tetrahydrofuran, or a combination thereof. 
     
     
         7 . The method of  claim 1 , wherein the amount of solvent is 3 to 20 volumes of the Rx100.FA, preferably between 5-8 volumes. 
     
     
         8 . The method of  claim 1 , wherein the solvent is a mixture of methanol and water. 
     
     
         9 . The method of  claim 1 , wherein the solvent is a mixture of methanol, water, and IPAc. 
     
     
         10 . The method of  claim 9 , the mixture of methanol, water, and IPAc is at a weight ratio of 10:2:1.5. 
     
     
         11 . The method of  claim 1 , wherein the solvent is a mixture of methanol and 10-50% IPAc, preferably 20-50% IPAc. 
     
     
         12 . The method of  claim 1 , wherein the solvent is methanol alone. 
     
     
         13 . The method of  claim 12 , wherein the methanol is about 5 to 20 molar equivalent, preferably about 12 molar equivalent of Rx100 free acid. 
     
     
         14 . The method of  claim 1 , wherein the crystalline salts form in the solvent in which the Rx100. free acid and L-lysine base are mixed. 
     
     
         15 . The method of  claim 1 , further comprising the steps of depleting the solvent in which the Rx100.FA and L-lysine base are mixed is first depleted after the mixing step (a) is carried out, and adding a fresh solvent in the dried material so that crystalline salts form in the fresh solvent. 
     
     
         16 . The method of  claim 15 , wherein the fresh solvent is the same solvent as that in which the Rx100.FA and L-lysine base are mixed. 
     
     
         17 . The method of  claim 15 , wherein the fresh solvent is a different solvent from that in which the Rx100.FA and L-lysine base are mixed. 
     
     
         18 . The method of  claim 1  further comprising the step of: filtering, washing and drying the Rx100.L-Lysine crystalline salt. 
     
     
         19 . The method of  claim 18 , wherein filtering is carried out by using a filtering membrane. 
     
     
         20 . A method for producing a (Z)—O-octadec-9-en-1-yl O,O-dihydrogen phosphorothioate free acid, comprising the steps of:
 a. mixing a thiophosphoryl chloride (PSCl 3 ) with oleyl alcohol in a reaction that also include a base and a solvent to obtain an intermediate O—(Z)-oleyl dichloridothiophosphate; and 
 b. allowing a hydrolysis reaction of the intermediate O—(Z)-oleyl dichloridothiophosphate to form (Z)—O-octadec-9-en-1-yl O,O-dihydrogen phosphorothioate free acid.