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 composition, comprising a mixture of a polymer derivative having the structure R-O-POLY-R′ and a polymer derivative having the structure R-O-POLY-O-R, wherein POLY is a water-soluble and non-peptidic polymer, R is alkyl and R′ is a functional group,
wherein POLY is a poly(alkylene glycol), and
wherein R′ is selected from the group consisting of hydroxyl, mesylate, tosylate, tresylate, —O—CO 2 R 3 wherein R 3 is H, alkyl or N-succinimidyl, —O—(CH 2 ) n —CO 2 R 3 wherein n is 1-6 and R 3 is H, alkyl or N-succinimidyl, —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 1-6, and Z is O or S, R 5 is H or alkyl, Ar—CH═CH—CH═CH—CO 2 —, wherein Ar represents a moiety selected from the group consisting of phenyl, substituted phenyl, biphenyl, substituted biphenyl, polycyclic aryls, substituted polycyclic aryls, and heterocyclic aryls, —O—(CH 2 ) n —CHO where n n is 1-6, —O 2 CCH 2 CH 2 CO 2 R 6 , wherein R 6 is H or N-succinimidyl. CH 2 ═CH—CO 2 —, and —O—CH 2 —CO 2 CH(CH 3 )CH 2 CO 2 —NHS. wherein NHS is N-succinimidyl.
2. The polymer composition of claim 1 , wherein POLY is poly(ethylene glycol).
3. The polymer composition of claim 2 , wherein POLY has the formula —CH 2 CH 2 —O—(CH 2 CH 2 O) n —CH 2 CH 2 —, where n is from about 8 to about 4000.
4. The polymer composition of claim 1 , wherein R is methyl.
5. The polymer composition of claim 1 , wherein R′ is hyroxyl.
6. The polymer composition of claim 1 , wherein R′ is —O—CO 2 R 3 or —O—(CH 2 ) n —CO 2 R 3 wherein R 3 is H, alkyl or N-succinimidyl.
7. The polymer composition of claim 1 , wherein R 3 is N-succinimidyl.
8. The polymer composition of claim 1 , wherein R′ is —O—(CH 2 ) n —CHO wherein n is 1-6.
9. The polymer composition of claim 1 , wherein R′ is —O—(CH 2 ) n —CH(ZR 5 ) 2 wherein n is 1-6, and Z is O or S, R 5 is H or alkyl.
10. The polymer composition of claim 1 , wherein POLY is poly(ethylene glycol), R is methyl, and R′ is —O—(CH 2 ) n CHO wherein n is 2.
11. The polymer composition of claim 10 , wherein POLY has the formula —CH 2 CH 2 —O—(CH 2 CH 2 O) n —CH 2 CH 2 —, where n is from about 8 to about 4000.
12. The polymer composition of claim 1 , wherein POLY is poly(ethylene glycol), R is methyl, and R′ is hydroxyl.
13. The polymer composition of claim 12 , wherein POLY ha the formula —CH 2 CH 2 —O—(CH 2 CH 2 O) n —CH 2 CH 2 —, where n is from about 8 to about 4000.
14. A polymer composition, comprising a polymer derivative having the structure R-O-POLY-R′ and a polymer derivative having the structure R-O-POLY-O-R, wherein POLY is a water-soluble and non-peptidic polymer, R is alkyl and R′ is —O—(CH 2 ) n —CHO or —O—(CH 2 ) n —CH(ZR 5 ) 2 wherein n is 1-6, and Z is O or S, R 5 is H or alkyl, in the absence of HO-POLY-OH, and wherein POLY is a poly(alkylene glycol).
15. The polymer composition of claim 14 , wherein POLY is poly(ethylene glycol).
16. The polymer composition of claim 15 , wherein POLY has the formula —CH 2 CH 2 —O—(CH 2 CH 2 O) n —CH 2 CH 2 —, where n is from about 8 to about 4000.
17. The polymer composition of claim 16 , wherein R methyl.
18. The polymer composition of claim 14 , wherein POLY is poly(ethylene glycol), R is methyl, and R′ is —O—(CH 2 ) n —CHO wherein n is 2.
19. The polymer composition of claim 18 , wherein POLY ha the formula —CH 2 CH 2 —O—(CH 2 CH 2 O) n —CH 2 CH 2 —, where n is from about 8 to about 4000.
20. The polymer composition of claim 14 , wherein POLY is poly(ethylene glycol) and R is methyl.
21. The polymer composition of claim 20 , wherein POLY has the formula —CH 2 CH 2 —O—(CH 2 CH 2 O) n —CH 2 CH 2 —, where n is from about 8 to about 4000.