Synthesis and purification of valacyclovir

Abstract

The present invention relates to protected valacyclovir, N-tert-butoxycarbonyl-L-valine 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy] ethyl ester, and a method of making it. The present invention further relates to a method of making valacyclovir including the steps of coupling an amine protected valine selected from N-t-butoxycarbonyl valine and N-formyl valine with acyclovir using a coupling agent to form a protected valacyclovir, and deprotecting the protected valacyclovir to form valacyclovir or a pharmaceutically acceptable salt thereof. The present invention further relates to valacyclovir in pure form, a method of making pure valacyclovir, and to compositions containing pure valacyclovir.

1 - 21 . (canceled)  
     
     
         22 . A method of making valacyclovir hydrochloride in pure form comprising the steps of: 
 forming a slurry of valacyclovir hydrochloride in a lower alkyl alcohol,    refluxing the slurry, and isolating pure valacyclovir hydrochloride from the slurry.    
     
     
         23 . The method of  claim 22  wherein the lower alkyl alcohol is ethanol.  
     
     
         24 . A method of making valacyclovir hydrochloride in pure form comprising the steps of: 
 forming a solution of valacyclovir hydrochloride in water,    mixing the solution with isopropanol to form a slurry, and    isolating valacyclovir hydrochloride in pure form from the slurry.    
     
     
         25 . A method of making valacyclovir hydrochloride in pure form comprising the steps of: 
 coupling an amine protected valine selected from N-t-butoxycarbonyl valine and N-formyl valine with acyclovir to form a protected valacyclovir, wherein the coupling is effected with a coupling agent selected from N-(3-dimethylaminopropyl)-N-ethyl carbodiimide and dicyclohexylcarbodiimide,    deprotecting the protected valacyclovir with hydrochloric acid to form valacyclovir hydrochloride,    forming a slurry of valacyclovir hydrochloride in a lower alkyl alcohol,    refluxing the slurry, and    isolating pure valacyclovir hydrochloride from the slurry.    
     
     
         26 . The method of  claim 25  wherein the amine is N-t-butoxycarbonyl valine.  
     
     
         27 . The method of  claim 25  wherein the deprotecting is effected at a temperature of from about 20° C. to about 25° C.  
     
     
         28 . The method of  claim 25  wherein the deprotecting is effected in a solvent selected from the group consisting of acetone, acetic acid, formic acid, and mixtures thereof.  
     
     
         29 . The method of  claim 25  wherein the lower alkyl alcohol is ethanol.  
     
     
         30 . A method of making valacyclovir hydrochloride in pure form comprising the steps of: 
 coupling an amine protected valine selected from N-t-butoxycarbonyl valine and N-formyl valine with acyclovir to form a protected valacyclovir, wherein the coupling is effected with a coupling agent selected from N-(3-dimethylaminopropyl)-N-ethyl carbodiimide and dicyclohexylcarbodiimide,    deprotecting the protected valacyclovir with hydrochloric acid,    forming a solution of valacyclovir hydrochloride in water,    mixing the solution with isopropanol to form a slurry, and    isolating the pure valacyclovir hydrochloride from the slurry.    
     
     
         31 . The method of  claim 30  wherein the amine protected valine is N-t-butoxycarbonyl valine.  
     
     
         32 . The process of  claim 30  wherein prior to the step of mixing the solution with isopropanol, the solution is filtered.  
     
     
         33 . The method of  claim 30  wherein the deprotecting is effected at a temperature of from about −10° C. to about 25° C.  
     
     
         34 . The method of  claim 30  wherein the deprotecting is effected in a solvent selected from the group consisting of acetone, acetic acid, formic acid, and mixtures thereof.  
     
     
         35 . Valacyclovir hydrochloride in pure form.  
     
     
         36 . The pure valacyclovir hydrochloride of  claim 35  comprising not more than about 0.7% acyclovir as determined by HPLC.  
     
     
         37 . The pure valacyclovir hydrochloride of  claim 36  comprising not more than about 0.3% acyclovir as determined by HPLC.  
     
     
         38 . The pure valacyclovir hydrochloride of  claim 37  comprising not more than about 0.1% acyclovir as determined by HPLC.  
     
     
         39 . The pure valacyclovir hydrochloride of  claim 35  comprising not more that about 0.2% of any impurity.  
     
     
         40 . The pure valacyclovir hydrochloride of  claim 39  comprising not more that about 0.1% of any impurity.  
     
     
         41 . A pharmaceutical composition comprising the pure valacyclovir hydrochloride of  claim 35  and at least one pharmaceutically acceptable excipient.  
     
     
         42 . A pharmaceutical dosage form comprising the pharmaceutical composition of  claim 41 .  
     
     
         43 . The pharmaceutical dosage form of  claim 42  wherein the dosage form is an oral dosage form.  
     
     
         44 . The pharmaceutical dosage form of  claim 43  wherein the oral dosage form is a capsule or tablet.  
     
     
         45 . A method of treating a valacyclovir hydrochloride responsive herpes virus selected from HSV-1, HSV-2, VZV, EBV, and CMV in a patient suffering from such a valacyclovir hydrochloride responsive herpes virus by administering to the patient a composition of  claim 41 .  
     
     
         46 .- 48 . (canceled)