Process for the preparation of activated polyethylene glycols
A process for preparing activated polyethylene glycols is disclosed. In some embodiments, the process includes reacting a molten polyethylene glycol with an activator. In other embodiments, the process includes reacting a polyethylene glycol with an activator in the absence of a solvent. The process may be carried out in an inert gas atmosphere, at a temperature at least 10° C. above the melting point of polyethylene glycol, and/or with the activator provided in molar excess of the polyethylene glycol. The invention further provides activated polyethylene glycols produced by this process and their use in a variety of pharmaceutical, medical, cosmetic and chemical applications.
1. A method for preparing an activated polyethylene glycol having the formula:
Y-Q-(OCH 2 CH 2 ) n —O-Q-Y
wherein:
Q is C(O);
Y is a leaving group; and
n is an integer greater than 2;
the method comprising:
providing a polyethylene glycol having the formula:
M-(OCH 2 CH 2 ) n —O-M
wherein:
M is selected from H, Li, Na, K, Rb, and Cs; and
n is as defined above; and
reacting in the absence of a solvent the polyethylene glycol with an activator having the formula:
Y-Q-X
wherein:
X is a leaving group; and
Q and Y are as defined above;
wherein the reaction is carried out in the absence of a base.
2. The method of claim 1 wherein Y is selected from a halide group, a mesyl group, a tosyl group, a phenoxyl group, and a substituted phenoxyl group.
3. The method of claim 2 wherein X is selected from a halide group, a mesyl group, a tosyl group, a phenoxyl group, and a substituted phenoxyl group.
4. The method of claim 1 wherein M is H.
5. The method of claim 1 wherein the activator is O 2 NPhOC(O)Cl.
6. The method of claim 1 wherein M is H, n is an integer between 150 and 250, and the reacting step is carried out at a temperature in the range of about 60-90° C.
7. The method of claim 1 wherein the molar amount of the activator is in excess of the molar amount of the polyethylene glycol.
8. The method of claim 1 wherein the molar excess is between about 50-100%.
9. The method of claim 1 , wherein the polyethylene glycol is reacted with the activator for less than or about two hours.
10. The method of claim 1 , wherein the activated polyethylene glycol has an activation degree of greater than or about 90%.
11. The method of claim 1 , comprising contacting the activated polyethylene glycol with ion exchange resins.
12. A method for preparing an activated polyethylene glycol having the formula:
Y-Q-(OCH 2 CH 2 ) n —O-Q-Y
wherein:
Q is —C(O)—;
Y is a leaving group; and
n is an integer greater than 2;
the method comprising:
providing a polyethylene glycol having the formula:
M-(OCH 2 CH 2 ) n —O-M
wherein:
M is selected from H, Li, Na, K, Rb, and Cs; and
n is as defined above; and
reacting in the absence of a solvent the polyethylene glycol with an activator having the formula:
Y-Q-X
wherein
X is a leaving group; and
Q and Y are as defined above;
wherein the polyethylene glycol is reacted with the activator for less than or about two hours.
13. The method of claim 12 , wherein M is H and n is an integer between 150 and 250.
14. The method of claim 12 , wherein the activator is O 2 NPhOC(O)Cl.
15. The method of claim 12 , wherein the molar amount of the activator is in excess of the molar amount of the polyethylene glycol.
16. The method of claim 12 , wherein the activated polyethylene glycol has an activation degree of greater than or about 90%.
17. The method of claim 12 , comprising contacting the activated polyethylene glycol with ion exchange resins.
18. A method for preparing an activated polyethylene glycol having the formula:
Y-Q-(OCH 2 CH 2 ) n —O-Q-Y
wherein:
Q is —C(O)—;
Y is a leaving group; and
n is an integer greater than 2;
the method comprising:
providing a polyethylene glycol having the formula:
M-(OCH 2 CH 2 ) n —O-M
wherein:
M is selected from H, Li, Na, K, Rb, and Cs; and
n is as defined above;
reacting in the absence of a solvent the polyethylene glycol with an activator having the formula:
Y-Q-X
wherein
X is a leaving group; and
Q and Y are as defined above; and
contacting the activated polyethylene glycol with ion exchange resins.
19. The method of claim 18 , wherein M is H and n is an integer between 150 and 250.
20. The method of claim 18 , wherein the activator is O 2 NPhOC(O)Cl.