Heterobifunctional poly(ethylene glycol) derivatives and methods for their preparation
View Patent ↗This invention provides a method for preparing, in high purity and high yield, heterobifunctional derivatives of poly(ethylene glycol) or related polymers. A chromatographic purification step is not necessary in the method. In accordance with the method of the invention, an intermediate polymer having a formula of W-Poly-OH is provided bearing a removable group W at one terminus. The intermediate polymer W-Poly-OH is first altered by modifying the OH group to a first functional group X, followed by the removal of W to generate a second hydroxyl group. The latter hydroxyl group may then be further converted to a second functional group Y, thus providing the desired heterobifunctional derivative.
1. A polymer derivative comprising the formula:
wherein:
X is selected from the group consisting of: hydroxyl; mesylate; tosylate; tresylate; —O—(CH 2 ) n —CO 2 H wherein (n) is a number of 1-6; —O—(CH 2 ) n —CO 2 R 3 wherein (n) is a number of 1-6 and R 3 is an alkyl group; —NHR 4 wherein R 4 is H or alkyl or an amine protecting group; —O—(CH 2 ) n —CH(ZR 5 ) 2 wherein (n) is a number of 1-6, Z is O or S, and R 5 is H or an alkyl group; Ar—CH═CH—CH═CH—CO 2 —, where Ar represents a moiety selected from the group consisting of phenyl, biphenyl, polycyclic aryls, and heterocyclic aryls; —O—(CH 2 ) n —CHO wherein (n) is a number of 1-6; and —O 2 CCH 2 CH 2 CO 2 R 6 , wherein R 6 is H or N-succinimidyl;
POLY is a poly(ethylene glycol) having the formula —CH 2 CH 2 —O—(CH 2 CH 2 O) n′ —CH 2 CH 2 — and (n′) is from about 45 to about 4000;
(p) is zero or a number of 1-6;
(q) is zero of a number of 1-6;
(r) is either zero or one, wherein if (r) is one, the polymer derivative has a positive charge;
each R 10 , when present, is independently H or and alkyl group;
each R 11 , when present, is independently H or and alkyl group;
each R 12 , when present, is independently H or and alkyl group;
each R 13 , when present, is independently H or and alkyl group;
R 14 is H or methyl or ethyl;
R 15 , when present, is H, methyl or ethyl; and
Ar′ is a moiety selected from the group consisting of phenyl, biphenyl, polycyclic aryls, and heterocyclic aryls; —O—(CH 2 ) n —CHO wherein (n) is a number of 1-6; and —O 2 CCH 2 CH 2 CO 2 R 6 , wherein R 6 is H or N-succinimidyl, and salt forms thereof.
2. The polymer derivative of claim 1 , wherein:
each R 10 , when present, is H;
each R 11 , when present, is H;
each R 12 , when present, is H; and
each R 13 , when present, is H.
3. The polymer derivative of claim 1 , wherein (p) is zero.
4. The polymer derivative of claim 1 , wherein (q) is 1.
5. The polymer derivative of claim 3 , wherein Ar′ is phenyl.
6. The polymer derivative of claim 3 , wherein R 14 is methyl or ethyl.
7. The polymer derivative of claim 6 , wherein R 14 is methyl.
8. The polymer derivative of claim 1 , wherein (r) is one.
9. The polymer derivative of claim 8 , wherein R 15 is methyl or ethyl.
10. The polymer derivative of claim 8 , wherein R 15 is methyl.
11. The polymer derivative of claim 10 , wherein the polymer derivative is in the form of a salt.
12. The polymer derivative of claim 11 , wherein anion of the salt is selected from the group consisting of chloride, bromide and iodide.
13. The polymer derivative of claim 1 , wherein X is hydroxyl.
14. A composition comprising the polymer derivative of claim 1 and a macromolecule.
15. A polymer derivative having the following structure:
wherein (n) is from about 45 to about 4000.