Method of preparing polyalkyene oxide carboxylic acids

• US 5,756,593 A
• Filed: 06/27/1997
• Issued: 05/26/1998
• Est. Priority Date: 05/15/1995
• Status: Expired due to Term

• Current Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Original Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Inventors: Greenwald, Richard B., Martinez, Anthony J.
• Primary Examiner(s): GULAKOWSKI, RANDY P
• Application Number:
  US08/883,150
• Time in Patent Office: 333 Days
• Field of Search: 525/408, 525/409, 525/403, 528/300, 528/302, 528/310, 528/322, 528/332, 528/361
• US Class Current: 525/403
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: C08G 65/3322 acyclic
• CPC Class Codes: C08G 65/33396 having oxygen in addition to nitrogen

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 trifloroacetic acid. The resultant polymer carboxylic acids are of sufficient plurty so that expensive and time consuming purification steps required for pharmaceutical grade polymers are avoided.

Claims

1. A method of preparing an amine-terminated polyalkylene oxide 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) converting said polyalkylene oxide containing said terminal carboxylic acid to an amine-terminated polyalkylene oxide.

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

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

5. The method of claim 1, wherein said tertiary alkyl haloacetate comprises the formula:

##STR3## wherein X is chlorine, bromine or iodine;

R_1-3 are independently selected from the group consisting of C_1-8 alkyls, or C_1-8 branched alkyls and aryls.

6. The method of claim 5, wherein R_1-3 are independently selected C_1-3 alkyls.

7. The method of claim 5, wherein R_1-3 are methyl.

8. The method of claim 5, wherein said tertiary alkyl haloacetate is a tertiary butyl haloacetate.

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

10. The method of claim 8, wherein said t-butyl haloacetate is t-butyl chloroacetate.

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

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

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

1.

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

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

16. The method of claim 1, wherein said reacting step ii) is carried out at a temperature of from about 0°

to about 50°

C.

17. The method of claim 16, wherein said reacting step ii) is carried out at a temperature of from about 20°

to about 30°

C.

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

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

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

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

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

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

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

2. A method of preparing a succinimidyl ester-terminated polyalkylene oxide 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) converting said polyalkylene oxide containing said terminal carboxylic acid to an succinimidyl ester-terminated polyalkylene oxide.