Process for the preparation of activated polyethylene glycols

1. A process for preparing a bis-activated polyethylene glycol having the formula:

Y-Q-O—(CH 2 —CH 2 —O) n -Q-Y

wherein

n is an integer between 4 and 800;

Y is selected from the group consisting of a halide group, a mesyl group, a tosyl group, an imidazolyl group, an N-hydroxy-succinimidyl group, a phenoxyl group, and a substituted phenoxyl group; and

Q is selected from the group consisting of SO 2 , CO(CHR 1 ) t SO 2 , CO—O—(CHR 1 ) t —O—SO 2 , C(O), SO 2 (CHR 1 ) t SO 2 , SO 2 —O—(CHR 1 ) t —O—SO 2 , CO—O—(CHR 1 ) t —CR 2 ═CR 3 —(CHR 4 ) t —O—CO, and SO 2 —O—(CHR 1 ) t —CR 2 ═CR 3 —(CHR 4 ) t —O—SO 2 ,

wherein

t is 1, 2, or 3; and

R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, a lower alkyl group, a lower branched alkyl group, an aryl group, and an aralkyl group;

the process consisting essentially of reacting under stoichiometric conditions a polyethylene glycol having the formula:

H—(O—CH 2 —CH 2 —) n —OH

wherein

n is an integer between 4 and 800;

with an activator having the formula of Y-Q-X;

wherein

X and Y independently are selected from the group consisting of a halide group, a mesyl group, a tosyl group, an imidazolyl group, an N-hydroxy-succinimidyl group, a phenoxyl group, and a substituted phenoxy group; and

Q is selected from the group consisting of SO 2 , CO(CHR 1 ) t SO 2 , CO—O—(CHR 1 ) t —O—SO 2 , C(O), SO 2 (CHR 1 ) t SO 2 , SO 2 —O—(CHR 1 ) t —O—SO 2 , CO—O—(CHR 1 ) t —CR 2 ═CR 3 —(CHR 4 ) t —O—CO, and SO 2 —O—(CHR 1 ) t —CR 2 ═CR 3 —(CHR 4 ) t —O—SO 2 ,

wherein

t is 1, 2, or 3; and

R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of H, a lower alkyl group, a lower branched alkyl group, an aryl group, and an aralkyl group;

in the presence of a solvent and an aromatic nitrogen-containing heterocyclic base having the formula:

wherein

(NR 5 R 6 ) c is located either in the ortho or para position;

R 5 and R 6 are independently selected from the group consisting of a lower straight alkyl group, a lower branched alkyl group, an aryl group, and an aralkyl group; and

c is 1 or 2;

to produce said bis-activated polyethylene glycol.

2. The process of claim 1 , wherein the activator is selected from the group consisting of Cl—CO—O-Ph-NO 2 , Cl—SO 2 —O—CH 2 —CH 2 —O—SO 2 —Cl, Cl—SO 2 —O—CH 2 —CH 2 —O—CO—Cl, and Cl—CO—O—CH 2 —CH═CH—CH 2 —O—CO—Cl.

3. The process of claim 1 , wherein said process is carried out at temperatures ranging from about 20° C. to about 30° C.

4. The process of claim 1 , wherein the aromatic nitrogen-containing heterocyclic base is 4-dimethylaminopyridine.

5. The process of claim 4 , wherein reacting the polyethylene glycol with the activator is in the presence of six molar equivalents or less of 4-dimethylaminopyridine.

6. A process for preparing a bis-activated polyethylene glycol having the formula:

Y-Q-O—(CH 2 —CH 2 —O) n -Q-Y

wherein

n is an integer between 4 and 800;

Y is selected from the group consisting of a halide group, a mesyl group, a tosyl group, an imidazolyl group, an N-hydroxy-succinimidyl group, a phenoxyl group, and a substituted phenoxyl group; and

Q is selected from the group consisting of SO 2 , CO(CHR 1 ) t SO 2 , CO—O—(CHR 1 ) t —O—SO 2 , C(O), SO 2 (CHR 1 ) t SO 2 , SO 2 —O—(CHR 1 ) t —O—SO 2 , CO—O—(CHR 1 ) t —CR 2 ═CR 3 —(CHR 4 ) t —O—CO, and SO 2 —O—(CHR 1 ) t —CR 2 ═CR 3 —(CHR 4 ) t —O—SO 2 ,

wherein

t is 1, 2, or 3; and

R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, a lower alkyl group, a lower branched alkyl group, an aryl group, and an aralkyl group;

the process consisting essentially of reacting a polyethylene glycol having the formula:

H—(O—CH 2 —CH 2 —) n —OH

wherein

n is an integer between 4 and 800;

with an activator having the formula of Y-Q-X;

wherein

X and Y are different and independently selected from the group consisting of a halide group, a mesyl group, a tosyl group, an imidazolyl group, an N-hydroxy-succinimidyl group, a phenoxyl group, and a substituted phenoxyl group; and

Q is selected from the group consisting of SO 2 , CO(CHR 1 ) t SO 2 , CO—O—(CHR 1 ) t —O—SO 2 , C(O), SO 2 (CHR 1 ) t SO 2 , SO 2 —O—(CHR 1 ) t —O—SO 2 , CO—O—(CHR 1 ) t —CR 2 ═CR 3 —(CHR 4 ) t —O—CO, and SO 2 —O—(CHR 1 ) t —CR 2 ═CR 3 —(CHR 4 ) t —O—SO 2 ,

wherein

t is 1, 2, or 3; and

R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of H, a lower alkyl group, a lower branched alkyl group, an aryl group, and an aralkyl group;

in the presence of a solvent and an aromatic nitrogen-containing heterocyclic base having the formula:

wherein

(NR 5 R 6 ) c is located either in the ortho or para position;

R 5 and R 6 are independently selected from the group consisting of a lower straight alkyl group, a lower branched alkyl group, an aryl group, and an aralkyl group; and

c is 1 or 2;

to produce said bis-activated polyethylene glycol.

7. The process of claim 6 , wherein the activator is 4-nitrophenyl chloroformate.

8. The process of claim 6 , wherein the aromatic nitrogen-containing heterocyclic base is 4-dimethylaminopyridine.

9. The process of claim 6 , wherein reacting the polyethylene glycol with the activator is under stoichiometric conditions.

10. The process of claim 6 , wherein at least one of X and Y is a halide group.

11. The process of claim 9 , wherein at least one of X and Y is a halide group.

12. A process for preparing a bis-activated polyethylene glycol having the formula:

Y-Q-O—(CH 2 —CH 2 —O) n -Q-Y

wherein

n is an integer between 4 and 800;

Y is selected from the group consisting of a halide group, a mesyl group, a tosyl group, an imidazolyl group, an N-hydroxy-succinimidyl group, a phenoxyl group, and a substituted phenoxyl group; and

Q is selected from the group consisting of SO 2 , CO(CHR 1 ) t SO 2 , CO—O—(CHR 1 ) t —O—SO 2 , C(O), SO 2 (CHR 1 ) t SO 2 , SO 2 —O—(CHR 1 ) t —O—SO 2 , CO—O—(CHR 1 ) t —CR 2 ═CR 3 —(CHR 4 ) t —O—CO, and SO 2 —O—(CHR 1 ) t —CR 2 ═CR 3 —(CHR 4 ) t —O—SO 2 ,

wherein

t is 1, 2, or 3; and

R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, a lower alkyl group, a lower branched alkyl group, an aryl group, and an aralkyl group;

the process consisting essentially of reacting a polyethylene glycol having the formula:

H—(O—CH 2 —CH 2 —) n —OH

wherein

n is an integer between 4 and 800;

with an activator having the formula of Y-Q-X;

wherein

X and Y independently are selected from the group consisting of a halide group, a mesyl group, a tosyl group, an imidazolyl group, an N-hydroxy-succinimidyl group, a phenoxyl group, and a substituted phenoxyl group, provided that at least one of X and Y is a halide group; and

Q is selected from the group consisting of SO 2 , CO(CHR 1 ) t SO 2 , CO—O—(CHR 1 ) t —O—SO 2 , C(O), SO 2 (CHR 1 ) t SO 2 , SO 2 —O—(CHR 1 ) t —O—SO 2 , CO—O—(CHR 1 ) t —CR 2 ═CR 3 —(CHR 4 ) t —O—CO, and SO 2 —O—(CHR 1 ) t —CR 2 ═CR 3 —(CHR 4 ) t —O—SO 2 ,

wherein

t is 1, 2, or 3; and

R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of H, a lower alkyl group, a lower branched alkyl group, an aryl group, and an aralkyl group;

in the presence of a solvent and an aromatic nitrogen-containing heterocyclic base having the formula:

wherein

(NR 5 R 6 ) c is located either in the ortho or para position;

R 5 and R 6 are independently selected from the group consisting of a lower straight alkyl group, a lower branched alkyl group, an aryl group, and an aralkyl group; and

c is 1 or 2;

to produce said bis-activated polyethylene glycol.

13. The process of claim 12 , wherein the activator is selected from the group consisting of Cl—CO—O-Ph-NO 2 , Cl—SO 2 —O—CH 2 —CH 2 —O—SO 2 —Cl, Cl—SO 2 —O—CH 2 —CH 2 —O—CO—Cl, and Cl—CO—O—CH 2 —CH═CH—CH 2 —O—CO—Cl.

14. The process of claim 12 , wherein the aromatic nitrogen-containing heterocyclic base is 4-dimethylaminopyridine.

15. The process of claim 12 , wherein reacting the polyethylene glycol with the activator is under stoichiometric conditions.

16. The process of claim 12 , wherein reacting the polyethylene glycol with the activator is at room temperature.

17. The process of claim 16 , wherein X and Y are different.

18. A process for preparing a bis-activated polyethylene glycol having the formula:

Y-Q-O—(CH 2 —CH 2 —O) n -Q-Y

wherein

n is an integer between 4 and 800;

Y is selected from the group consisting of a halide group, a mesyl group, a tosyl group, an imidazolyl group, an N-hydroxy-succinimidyl group, a phenoxyl group, and a substituted phenoxyl group; and

Q is selected from the group consisting of SO 2 , CO(CHR 1 ) t SO 2 , CO—O—(CHR 1 ) t —O—SO 2 , C(O), SO 2 (CHR 1 ) t SO 2 , SO 2 —O—(CHR 1 ) t —O—SO 2 , CO—O—(CHR 1 ) t —CR 2 ═CR 3 —(CHR 4 ) t —O—CO, and SO 2 —O—(CHR 1 ) t —CR 2 ═CR 3 —(CHR 4 ) t —O—SO 2 ,

wherein

t is 1, 2, or 3; and

R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, a lower alkyl group, a lower branched alkyl group, an aryl group, and an aralkyl group;

the process consisting essentially of reacting a polyethylene glycol having the formula:

H—(O—CH 2 —CH 2 —) n —OH

wherein

n is an integer between 4 and 800;

with an activator having the formula of Y-Q-X;

wherein

X and Y independently are selected from the group consisting of a halide group, a mesyl group, a tosyl group, an imidazolyl group, an N-hydroxy-succinimidyl group, a phenoxyl group, and a substituted phenoxyl group; and

Q is selected from the group consisting of SO 2 , CO(CHR 1 ) t SO 2 , CO—O—(CHR 1 ) t —O—SO 2 , C(O), SO 2 (CHR 1 ) t SO 2 , SO 2 —O—(CHR 1 ) t —O—SO 2 , CO—O—(CHR 1 ) t —CR 2 ═CR 3 —(CHR 4 ) t —O—CO, and SO 2 —O—(CHR 1 ) t —CR 2 ═CR 3 —(CHR 4 ) t —O—SO 2 ,

wherein

t is 1, 2, or 3; and

R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of H, a lower alkyl group, a lower branched alkyl group, an aryl group, and an aralkyl group;

at a temperature range between about 20° C. and about 30° C., and in the presence of a solvent and an aromatic nitrogen-containing heterocyclic base having the formula:

wherein

(NR 5 R 6 ) c is located either in the ortho or para position;

R 5 and R 6 are independently selected from the group consisting of a lower straight alkyl group, a lower branched alkyl group, an aryl group, and an aralkyl group; and

c is 1 or 2;

to produce said bis-activated polyethylene glycol.

19. The process of claim 18 , wherein the activator is selected from the group consisting of Cl—CO—O-Ph-NO 2 , Cl—SO 2 —O—CH 2 —CH 2 —O—SO 2 —Cl, Cl—SO 2 —O—CH 2 —CH 2 —O—CO—Cl, and Cl—CO—O—CH 2 —CH═CH—CH 2 —O—CO—Cl.

20. The process of claim 18 , wherein the aromatic nitrogen-containing heterocylic base is 4-dimethylaminopyridine.

21. The process of claim 18 , wherein X and Y are different.

22. The process of claim 21 , wherein reacting the polyethylene glycol with the activator is under stoichiometric conditions.

23. The process of claim 22 , wherein at least one of X and Y is a halide group.