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Generated: September 26, 2017

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Title: Method of preparing polyalkylene oxide carboxylic acids
Abstract:The present invention is directed to methods of preparing high purity polyalkylene oxide carboxylic acids. The methods include reacting a polyalkylene oxide such as polyethylene glycol with a t-butyl haloacetate in the presence of a base followed by treatment with an acid such as trifluoroacetic acid. The resultant polymer carboxylic acids are of sufficient purity so that expensive and time containing purification steps required for pharmaceutical grade polymers are avoided.
Inventor(s): Martinez; Anthony J. (Hamilton Square, NJ), Greenwald; Richard B. (Somerset, NJ)
Assignee: Enzon, Inc. (Piscataway, NJ)
Filing Date:Aug 13, 1996
Application Number:08/696,198
Claims:1. A method of preparing a biologically active conjugate, comprising:

i) reacting a polyalkylene oxide with a tertiary alkyl haloacetate in the presence of a base to form a tertiary alkyl ester of polyalkylene oxide;

ii) reacting said tertiary alkyl ester with an acid to form a polyalkylene oxide containing a terminal carboxylic acid; and

iii) reacting said polyalkylene oxide containing said terminal carboxylic acid with a biologically active nucleophile under conditions sufficient to form a biologically active conjugate whereby said polyalkylene oxide is linked to said biologically active nucleophile by an ester linkage.

2. The method of claim 1, wherein said polyalkylene oxide is polyethylene glycol.

3. The method of claim 1, wherein said polyalkylene oxide is omega methoxypolyethylene glycol.

4. The method of claim 1, wherein said tertiary alkyl haloacetate comprises the formula: ##STR3## wherein X is chlorine, bromine or iodine;

R.sub.1-3 are independently selected from the group consisting of C.sub.1-8 alkyls, or C.sub.1-8 branched alkyls and aryls.

5. The method of claim 4, wherein R.sub.1-3 are independently selected C.sub.1-3 alkyls.

6. The method of claim 4, wherein R.sub.1-3 are methyl.

7. The method of claim 4, wherein said tertiary alkyl haloacetate is a tertiary butyl haloacetate.

8. The method of claim 7, wherein said t-butyl haloacetate is t-butyl bromoacetate.

9. The method of claim 7, wherein said t-butyl haloacetate is t-butyl chloroacetate.

10. The method of claim 1, wherein said base is potassium t-butoxide.

11. The method of claim 1, wherein said base is selected from the group consisting of butyl lithium, sodium amide and sodium hydride.

12. The method of claim 1, wherein the molar ratio of said tertiary alkyl haloacetate to said polyalkylene oxide is greater than 1:1.

13. The method of claim 1, wherein said acid is trifluoroacetic acid.

14. The method of claim 1, wherein said acid is selected from the group consisting of sulfuric, phosphoric and hydrochloric acids.

15. The method of claim 1, wherein said reacting step ii) is carried out at a temperature of from about 0.degree. to about 50.degree. C.

16. The method of claim 15, wherein said reacting step ii) is carried out at a temperature of from about 20.degree. to about 30.degree. C.

17. The method of claim 1, wherein said reacting step ii) is carried out in the presence of water.

18. The method of claim 1, wherein said polyalkylene oxide has a number average molecular weight of from about 200 to about 100,000.

19. The method of claim 18, wherein said polyalkylene oxide has a number average molecular weight of from about 2,000 to about 80,000.

20. The method of claim 19, wherein said polyalkylene oxide has a number average molecular weight of from about 4,000 to about 50,000.

21. The method of claim 1, wherein the purity of said polyalkylene oxide carboxylic acid is greater than 92%.

22. The method of claim 21, wherein the purity of said polyalkylene oxide carboxylic acid is greater than 97%.

23. The method of claim 22, wherein the purity of said polyalkylene oxide carboxylic acid is greater than 99%.

24. The method of claim 1, wherein said biologically active nucleophile is taxol.

25. The method of claim 1, wherein said biologically active nucleophile is camptothecin.

26. The method of claim 1, wherein said biologically active nucleophile is podophyllotoxin.
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