Reacting polyalkylene oxide with base, tertiary alkyl haloacetate, then acid to prepare polyalkylene oxide carboxylic acid
View Patent ↗A new method of preparing a tertiary alkyl ester of a polyalkylene oxide is provided. The new method employs milder conditions that avoid the back reaction to the starting polyalkylene oxide. The tertiary alkyl ester of a polyalkylene oxide is then reacted with a suitable acid to produce a polyalkylene oxide acid.
1. A method of preparing a polyalkylene oxide carboxylic acid, consisting essentially of:
(a) reacting a polyalkylene oxide with a base, in a first solvent system, for a time period ranging from about 10 minutes to about 60 minutes;
(b) reacting the product of step (a) in a second solvent system, with a tertiary alkyl haloacetate for a time period up to about 1 hour to form a tertiary alkyl ester of a polyalkylene oxide; and
(c) reacting the tertiary alkyl ester of a polyalkylene oxide obtained from step (b) with an acid to form a polyalkylene oxide carboxylic acid,
wherein the reaction of steps (a) and (b) are conducted at a temperature that ranges from about 10° C. to about 35° C.
2. The method of claim 1 , wherein the polyalkylene oxide is polyethylene glycol.
3. The method of claim 1 , further comprising separating the resulting tertiary alkyl ester of a polyalkylene oxide from the second solvent system.
4. The method of claim 2 , wherein the polyethylene glycol is omega methoxypolyethylene glycol.
5. The method of claim 1 , wherein the tertiary alkyl haloacetate comprises the formula:
wherein
X is chlorine, bromine or iodine; and
R 1-3 are independently selected from the group consisting of C 1-8 alkyls, C 1-8 substituted alkyls, C 1-8 branched alkyls and aryls.
6. The method of claim 5 , wherein the tertiary alkyl haloacetate is tertiary butyl haloacetate.
7. The method of claim 6 , wherein the t-butyl haloacetate is t-butyl bromoacetate or t-butyl chloroacetate.
8. The method of claim 1 , wherein the molar ratio of the polyalkylene oxide to the base ranges from 1:1 to about 1:2.
9. The method of claim 1 , wherein the base is selected from the group consisting of potassium t-butoxide, butyl lithium, sodium amide, sodium hydride, and combinations thereof.
10. The method of claim 9 , wherein the base is potassium t-butoxide.
11. The method of claim 1 , wherein the acid is selected from the group consisting of trifluoroacetic acid, sulfuric acid, phosphoric acid, and hydrochloric acid.
12. The method of claim 1 , wherein the acid is trifluoroacetic acid.
13. The method of claim 1 , wherein the reaction of step (a) is conducted for a time period ranging from about 20 minutes to 40 minutes.
14. The method of claim 1 , wherein the solvent system comprises toluene and the reactions of steps (a) and (b) are carried out at a temperature ranging from about 25 to about 31° C.
15. The method of claim 12 , wherein step (c) comprises methylene chloride, and the reactions of steps (a) and (b) are carried out at a temperature ranging from about 20 to about 31° C.
16. The method of claim 1 wherein the reaction of step (c) is conducted at a temperature ranging from about 18 to about 30° C.
17. The method of claim 1 , wherein the ratio of polyalkylene oxide to solvent system is 1 g polyalkylene oxide to from about 15 to about 25 ml of solvent system.
18. The method of claim 1 , wherein the polyalkylene oxide has a molecular weight of from about 200 to about 100,000.
19. The method of claim 18 , wherein the polyalkylene oxide has a molecular weight of from about 2,000 to about 80,000.
20. The method of claim 18 , wherein the polyalkylene oxide has a molecular weight of from about 4,000 to about 50,000.
21. The method of claim 1 , wherein the purity of the produced polyalkylene oxide carboxylic acid is greater than 99% as determined by 13 C NMR.
22. The method of claim 1 wherein the polyalkylene oxide is either a straight chain or a branched chain.
23. The method of claim 1 , wherein the polyalkylene oxide has the formula
wherein j is an integer from about 10 to about 340.
24. A method of preparing a polyalkylene oxide-biologically active nucleophile conjugate, comprising reacting the polyalkylene oxide carboxylic acid of claim 1 with a biologically active agent containing a nucleophile to form a polyalkylene oxide-biologically active nucleophile conjugate.
25. The method of claim 1 , wherein the reaction of step (b) is conducted for a time period ranging from about 1 minute to about 30 minutes.
26. The method of claim 1 , wherein the reaction of step (b) is conducted for a time period of from about 1 minute to about 15 minutes.
27. The method of claim 12 , wherein the polyalkylene oxide is a straight, star-shaped or multi-armed polyethylene glycol.