Synthesis and formulations of salts of isophosphoramide mustard and analogs thereof

Abstract

Disclosed herein are formulations and methods of manufacture of compounds of formula (E): wherein X and Y independently represent leaving groups; and A + is an ammonium cation.

1 .- 18 . (canceled) 
     
     
         19 . A method for the preparation of a compound of formula (B): 
       
         
           
           
               
               
           
         
         comprising treating a compound of formula (A): 
       
       
         
           
           
               
               
           
         
         with an alcohol R 1 —OH under condensation conditions, wherein, as valence and stability permit,
 X 1  independently for each occurrence, is selected from Cl, I, and Br, 
 R 1  is benzyl optionally substituted with one or more substituents selected from halogen, —R 2 , —OR 2  and —NR 2   2  wherein R 2  is selected in each occurrence from H and lower alkyl. 
 
       
     
     
         20 . The method of  claim 19 , wherein the condensation conditions comprise an amine base. 
     
     
         21 . The method of  claim 20 , wherein the amine base is triethylamine. 
     
     
         22 . The method of  claim 19 , wherein the compound of formula (A) is P(O)Cl 3 . 
     
     
         23 . The method of  claim 19 , wherein R 1  is unsubstituted benzyl. 
     
     
         24 . The method of any of  claim 19 , wherein the condensation conditions comprise an aprotic organic solvent. 
     
     
         25 . The method of  claim 24 , wherein the organic solvent comprises acetonitrile. 
     
     
         26 . The method of  claim 19 , wherein the condensation conditions comprise approximately equimolar amounts of the compound of formula (A) and substitution reagent R 1 —OH. 
     
     
         27 . The method of  claim 19 , wherein the condensation conditions comprise maintaining a temperature between −35 to −25° C. 
     
     
         28 . The method of  claim 27 , wherein the condensation conditions comprise maintaining a temperature of about −30° C. 
     
     
         29 . A method for the preparation of a compound of formula (C): 
       
         
           
           
               
               
           
         
         comprising treating a compound of formula (B): 
       
       
         
           
           
               
               
           
         
         with amines XCH 2 CH 2 NH 2  and YCH 2 CH 2 NH 2  or salts thereof under condensation conditions, wherein, as valence and stability permit,
 X and Y independently represent leaving groups which may be the same or different; and 
 R 1  is benzyl optionally substituted with one or more substituents selected from halogen, —R 2 , —OR 2  and —NR 2   2  wherein R 2  is selected in each occurrence from H and lower alkyl. 
 
       
     
     
         30 . The method of  claim 29 , wherein the condensation conditions comprise approximately equimolar amounts of amines XCH 2 CH 2 NH 2  and YCH 2 CH 2 NH 2  or salts thereof. 
     
     
         31 . The method of  claim 29 , wherein the condensation conditions comprise approximately two equivalents of amine or salts thereof per equivalent of the compound of formula (B). 
     
     
         32 . The method of  claim 29 , wherein the condensation conditions comprise sequential addition of amines XCH 2 CH 2 NH 2  and YCH 2 CH 2 NH 2  or salts thereof to a compound of formula (B). 
     
     
         33 . The method of  claim 29 , wherein X and Y are both halogen. 
     
     
         34 . The method of  claim 33 , wherein X and Y are both Cl. 
     
     
         35 . The method of  claim 29 , wherein the condensation conditions comprise an amine base. 
     
     
         36 . The method of  claim 35 , wherein the amine base is triethylamine. 
     
     
         37 . A method for the preparation of a compound of formula (C): 
       
         
           
           
               
               
           
         
         comprising
 a. treating a compound of formula (A): 
 
       
       
         
           
           
               
               
           
         
         with an alcohol R 1 —OH under condensation conditions to generate a compound of formula (B): 
       
       
         
           
           
               
               
           
         
          and
 b. treating a compound of formula (B) with amines XCH 2 CH 2 NH 2  and YCH 2 CH 2 NH 2  or a salt thereof under condensation conditions, wherein, independently for each occurrence and as valence and stability permit, 
 X and Y independently represent leaving groups; 
 X 1  independently for each occurrence, is selected from Cl, I, and Br, 
 R 1  is benzyl optionally substituted with one or more substituents selected from halogen, —R 2 , —OR 2  and —NR 2   2  wherein R 2  is selected in each occurrence from H and lower alkyl. 
 
       
     
     
         38 . The method of  claim 29 , wherein the condensation conditions comprise maintaining a temperature between −35 to −25° C. 
     
     
         39 . The method of  claim 38 , wherein the condensation conditions comprise maintaining a temperature of about −30° C. 
     
     
         40 .- 55 . (canceled)