Methods of preparing polymers having terminal amine groups

Abstract

The present invention is directed to methods of preparing linear polymers such as polyalkylene oxides containing a terminal amine in high purity. One preferred method includes reacting a polyalkylene oxide such as polyethylene glycol containing a terminal azide with a phosphine-based reducing agent such as triphenylphosphine or an alkali metal borohydride reducing agent such as sodium borohydride in a solvent to reflux. The resultant polymer-amines are of sufficient purity so that expensive and time consuming purification steps required for pharmaceutical grade polymers are avoided.

1 . A method of preparing a polymer having a terminal amine, comprising, reacting a substantially non-antigenic polymer of the formula (I)  
       R 1 —R 2 —N 3   (I)  wherein 
 R 1  is a capping group or N 3 ; and  
 R 2  is a substantially non-antigenic polymer;  
   with a phosphine-based reducing agent or an alkali metal borohydride reducing agent.    
   
   
       2 . The method of  claim 1 , wherein the reacting step is carried out in a solvent and the reactants are allowed to react for a time sufficient to cause formation of the terminal amine on said polymer.  
   
   
       3 . The method of  claim 1 , wherein the R 1  capping group is CH 3 .  
   
   
       4 . The method of  claim 1 , wherein R 1  is N 3 .  
   
   
       5 . The method of  claim 1 , wherein R 2  is a polyalkylene oxide.  
   
   
       6 . The method of  claim 5 , wherein said polyalkylene oxide is selected from the group consisting of polyethylene glycol and polypropylene glycol.  
   
   
       7 . The method of  claim 6 , wherein said polyalkylene oxide is a polyethylene glycol of the formula: —O—(CH 2 CH 2 O) x —, wherein x is an integer from about 10 to about 2,300.  
   
   
       8 . The method of  claim 1 , wherein the phosphine-based reducing agent is selected from the group consisting of triphenylphosphine, tri(tolyl)-phosphine, tributylphosphine, tert-butyldiphenylphosphine, diphenyl-(p-tolyl)-phosphine, tris(2,4,6-trimethoxy-phenyl)phosphine, tris(2,6-di-methoxyphenyl)phosphine, tris(2-methoxyphenyl)-phosphine, tris(3-chloro-phenyl)phosphine, tris(3-methoxyphenyl)phosphine, tris(4-fluorophenyl)-phosphine, tris(4-methoxyphenyl)phosphine, tris(p-chlorophenyl)-phosphine and tris(pentafluorophenyl)phosphine.  
   
   
       9 . The method of  claim 8 , wherein the phosphine-based reducing agent is triphenylphosphine.  
   
   
       10 . The method of  claim 1 , wherein the alkali metal borohydride reducing agent is selected from the group consisting of sodium borohydride, lithium borohydride and potassium borohydride.  
   
   
       11 . The method of  claim 10 , wherein the alkali metal borohydride reducing agent is sodium borohydride.  
   
   
       12 . The method of  claim 1 , wherein the substantially non-antigenic polymer has a weight average molecular weight from about 200 to about 100,000 Daltons.  
   
   
       13 . The method of  claim 12 , wherein the substantially non-antigenic polymer has a weight average molecular weight from about 2,000 to about 48,000 Daltons.  
   
   
       14 . The method of  claim 1 , wherein the solvent is a polar solvent or a C 1-10  alcohol.  
   
   
       15 . The method of  claim 14 , wherein the polar solvent is selected from the group consisting of methanol, ethanol, butanol, isopropanol, tetrahydrofuran (THF), dimethylformamide and dioxane.  
   
   
       16 . The method of  claim 15 , wherein the polar solvent is methanol.  
   
   
       17 . The method of  claim 1 , wherein the phosphine-based reducing agent is present in an amount ranging from about equimolar to molar excess with respect to the compound of formula (I).  
   
   
       18 . The method of  claim 1 , wherein the compound of formula (I) is:  
       N 3 —O—(CH 2 CH 2 O) x —N 3   (Ia)  or  CH 3 —O—(CH 2 CH 2 O) x —N 3 .  (Ib)  
   
   
       19 . The method of  claim 17 , wherein the phosphine-based reducing agent is present in an amount of at least about a two-fold to molar excess with respect to the compound of formula (I).  
   
   
       20 . The method of  claim 1 , wherein the purity of the polymer containing said terminal amine formed by said process is greater than about 95%.  
   
   
       21 . The method of  claim 20 , wherein the purity of the polymer containing said terminal amine formed by said process is greater than 98%.  
   
   
       22 . The method of  claim 21 , wherein the purity of the polymer containing said terminal amine formed by said process is greater than 99%.  
   
   
       23 . The method of  claim 1 , wherein the compound of formula (Ia) is prepared by reacting a compound of formula (II)  
       R 3 —O—(CH 2 CH 2 O) x —R 3   (II)  wherein R 3  is selected from the group consisting of Br, Cl, tosylate or mesylate, brosylate, tresylate and nosylate; and    x is the degree of polymerization;    with NaN 3  in the presence of a solvent.