Method of preparing polymers having terminal amine groups
View Patent ↗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 polyalkylene oxide;
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 said polyalkylene oxide is selected from the group consisting of polyethylene glycol and polypropylene glycol.
6. The method of claim 5 , 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.
7. 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-trimethoxyphenyl)phosphine, tris(2,6-dimethoxyphenyl)phosphine, tris(2-methoxyphenyl)-phosphine, tris(3-chlorophenyl)phosphine, tris(3-methoxyphenyl)phosphine, tris(4-fluorophenyl)phosphine, tris(4-methoxyphenyl)phosphine, tris(p-chlorophenyl)-phosphine, and tris(pentafluorophenyl)phosphine.
8. The method of claim 7 , wherein the phosphine-based reducing agent is triphenylphosphine.
9. 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.
10. The method of claim 9 , wherein the alkali metal borohydride reducing agent is sodium borohydride.
11. The method of claim 1 , wherein the polyalkylene oxide has a weight average molecular weight from about 200 to about 100,000 Daltons.
12. The method of claim 11 , wherein the polyalkylene oxide has a weight average molecular weight from about 2,000 to about 48,000 Daltons.
13. The method of claim 1 , wherein the solvent is a polar solvent or a C 1-10 alcohol.
14. The method of claim 13 , wherein the polar solvent is selected from the group consisting of methanol, ethanol, butanol, isopropanol, THF, DMF, and dioxane.
15. The method of claim 14 , wherein the polar solvent is methanol.
16. 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).
17. The method of claim 1 , wherein the compound of formula (I) is:
N 3 —O—(CH 2 CH 2 O) x —N 3 (Ia).
18. The method of claim 16 , 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).
19. The method of claim 1 , wherein the purity of the polymer containing said terminal amine formed by said process is greater than about 95%.
20. The method of claim 19 , wherein the purity of the polymer containing said terminal amine formed by said process is greater than 98%.
21. The method of claim 20 , wherein the purity of the polymer containing said terminal amine formed by said process is greater than 99%.
22. 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.