Methods of synthesizing substantially monodispersed mixtures of polymers having polyethylene glycol moieties

• US 20030004304A1
• Filed: 06/04/2001
• Published: 01/02/2003
• Est. Priority Date: 06/04/2001
• Status: Active Grant

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Nobex Corporation (Biocon Incorporated)
• Inventors: Odenbaugh, Amy L., Ekwuribe, Nnochiri N., Price, Christopher H., Ansari, Aslam M.
• Granted Patent: US 6,835,802 B2
• Time in Patent Office: Days
• US Class Current: 528/425
• CPC Class Codes: C08G 65/334 containing sulfur
• CPC Class Codes: C08L 71/00 Compositions of polyethers obtained by reactions forming an ether link in the main chain of polyacetals C08L59/00; of epoxy resins C08L63/00; of polythioether-ethers C08L81/02; of polyether-sulfones C08L81/06; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 71/02 Polyalkylene oxides

Abstract

Methods of synthesizing a substantially monodispersed mixture of polymers comprising polyethylene glycol moieties include:

reacting a substantially monodispersed mixture of compounds having the structure of Formula I:

R¹(OC₂H₄)_n—O⁻X⁺  (I)

wherein R¹ is H or a lipophilic moiety; n is from 1 to 25; and X⁺ is a positive ion, with a substantially monodispersed mixture of compounds having the structure of Formula II:

R²(OC₂H₄)_m—OMs  (II)

wherein R² is H or a lipophilic moiety; and m is from 1 to 25, under conditions sufficient to provide a substantially monodispersed mixture of polymers comprising polyethylene glycol moieties and having the structure of Formula III:

R²(OC₂H₄)_m+n—OR¹  (III).

Claims

1. A method of synthesizing a substantially monodispersed mixture of polymers comprising polyethylene glycol moieties, said method comprising:

reacting a substantially monodispersed mixture of compounds having the structure of Formula I;

R¹(OC₂H₄)_m—

O⁻

X⁺ 

 

(I)

wherein R¹ is H or a lipophilic moiety;

m is from 1 to 25; and

X⁺ is a positive ion, with a substantially monodispersed mixture of compounds having the structure of Formula II;

R²(OC₂H₄)_n—

OMs 

 

(II)

wherein R² is H or a lipophilic moiety; and

n is from 1 to 25, under conditions sufficient to provide a substantially monodispersed mixture of polymers comprising polyethylene glycol moieties and having the structure of Formula III;

R²(OC₂H₄)_m+n+—

OR¹ 

 

(III).

2. The method according to claim 1, wherein the molar ratio of the compounds of Formula I to the compounds of Formula II is greater than about 1:

1.

3. The method according to claim 1, wherein the molar ratio of the compounds of Formula I to the compounds of Formula II is at least about 2:

1.

4. The method according to claim 1, wherein R² is a lipophilic moiety selected such that the polymers of Formula III are substantially insoluble in water.

5. The method according to claim 1, wherein R² is a lipophilic moiety selected such that the polymers of Formula III have a Log K_ow greater than about 0.

6. The method according to claim 1, wherein R² is a fatty acid moiety or an ester of a fatty acid moiety.

7. The method according to claim 6, wherein the fatty acid moiety or the ester of a fatty acid moiety comprises an alkyl moiety at least n carbon atoms in length.

8. The method according to claim 7, wherein the molar ratio of the compounds of Formula I to the compounds of Formula II are greater than 1:

1 such that the reaction of the compounds of Formula I with the compounds of Formula II provide a mixture comprising the polymers of Formula III and an excess of compounds of Formula I, said method further comprising;

separating the excess compounds of Formula I from the polymers of Formula III.

9. The method according to claim 8, wherein the separating step comprises:

contacting the mixture of the excess compounds of Formula I and the polymers of Formula III with an aqueous medium; and

collecting the polymers of Formula III.

10. The method according to claim 8, wherein the separating step comprises:

contacting the mixture of the excess compounds of Formula I and the polymers of Formula III with an organic medium;

removing the excess of compounds of Formula I from the organic medium; and

recovering the polymers of Formula III from the organic medium.

11. The method according to claim 1, further comprising:

reacting a substantially monodispersed mixture of compounds having the structure of Formula V;

R²(OC₂H₄)_n—

OH 

 

(V)

with a methanesulfonyl halide under conditions sufficient to provide a substantially monodispersed mixture of compounds having the structure of Formula II;

R²(OC₂H₄)_n—

OMs 

 

(II).

12. The method according to claim 11, wherein the methanesulfonyl halide is methane sulfonyl chloride.

13. The method according to claim 11, wherein the molar ratio of the methanesulfonyl halide to the compounds of Formula V is greater than about 1:

1.

14. The method according to claim 11, wherein the molar ratio of the methanesulfonyl halide to the compounds of Formula V is at least about 2:

1.

15. The method according to claim 11, wherein the reacting of a substantially monodispersed mixture of compounds having a structure of Formula V with a methanesulfonyl halide to provide a substantially monodispersed mixture of compounds of Formula II is performed at a temperature between about 0°

C. and about 40°

C.

16. The method according to claim 11, wherein the reacting of a substantially monodispersed mixture of compounds of Formula V with a methanesulfonyl halide to provide a substantially monodispersed mixture of compounds of Formula II is performed at a temperature between about 15°

C. and about 35°

C.

17. The method according to claim 11, wherein the reacting of a substantially monodispersed mixture of compounds of Formula V with methane sulfonyl halide to provide a substantially monodispersed mixture compounds of Formula II is performed for a period of time between about 0.25 hours and about 2 hours.

18. The method according to claim 11, further comprising:

reacting a substantially monodispersed mixture of compounds having the structure of Formula VI;

R²—

OMs 

 

(VI)

wherein R² is a lipophilic moiety;

with a substantially monodispersed mixture of compounds having the structure of Formula VII;

R³(OC₂H₄)_m—

O⁻

X₂⁺ 

 

(VII)

wherein R³ is benzyl, trityl, or trimethylsilyl; and

X₂⁺ is a positive ion;

under conditions sufficient to provide a substantially monodispersed mixture of compounds having the structure of Formula VIII;

R³(OC₂H₄)_m—

OR² 

 

(VIII); and

reacting the substantially monodispersed mixture of compounds having the structure of Formula VIII under conditions sufficient to provide a substantially monodispersed mixture of compounds having the structure of Formula V;

R²(OC₂H₄)_m—

OH 

 

(V).

19. The method according to claim 18, wherein R³ is benzyl.

20. The method according to claim 1, further comprising:

reacting a substantially monodispersed mixture of compounds having the structure of Formula IV;

R¹(OC₂H₄)_n—

OH 

 

(IV)

under conditions sufficient to provide a substantially monodispersed mixture of compounds having the structure of Formula I;

R¹(OC₂H₄)_n—

O⁻

X⁺ 

 

(I).

21. The method according to claim 20, wherein the reacting of a substantially monodispersed mixture of compounds having a structure of Formula IV under conditions sufficient to provide a substantially monodispersed mixture of compounds of Formula I comprises:

reacting a substantially monodispersed mixture of compounds having the structure of Formula IV with a compound capable of ionizing the hydroxyl moiety of the compound of Formula IV under conditions sufficient to provide the substantially monodispersed mixture of compounds having the structure of Formula I.

22. The method according to claim 21, wherein the molar ratio of the compound capable of ionizing the hydroxyl moiety to the compound of Formula I is greater than about 1:

1.

23. The method according to claim 21, wherein the molar ratio of the compound capable of ionizing the hydroxyl moiety to the compound of Formula I is at least about 2:

1.

24. The method according to claim 21, wherein the compound capable of ionizing the hydroxyl moiety is a strong base.

25. The method according to claim 24, wherein the strong base is selected from the group consisting of sodium hydride, potassium hydride, sodium t-butoxide, potassium t-butoxide, and sodium amide.

26. The method according to claim 24, wherein the strong base is sodium hydride.

27. The method according to claim 20, wherein the reacting of a substantially monodispersed mixture of compounds of Formula IV under conditions sufficient to provide a substantially monodispersed mixture of compounds of Formula I is performed at a temperature between about 0°

C. and about 40°

C.

28. The method according to claim 20, wherein the reacting of a substantially monodispersed mixture of compounds of Formula IV under conditions sufficient to provide a substantially monodispersed mixture of compounds of Formula I is performed at a temperature between about 15°

C. and about 35°

C.

29. The method according to claim 20, wherein the reacting of a substantially monodispersed mixture of compounds of Formula IV under conditions sufficient to provide a substantially monodispersed mixture of compounds of Formula I is performed for a period of time between about 0.25 and about 4 hours.

30. The method according to claim 1, wherein at least about 96, 97, 98 or 99 percent of the compounds in the mixture of polymers of Formula III have the same molecular weight.

31. The method according to claim 1, wherein the mixture of polymers of Formula III is a monodispersed mixture.

32. A monodispersed mixture of polymers comprising polyethylene glycol moieties, said polymers synthesized by the method of claim 1.

33. A method of synthesizing a substantially monodispersed mixture of polymers comprising polyethylene glycol moieties, said method comprising:

reacting a substantially monodispersed mixture of compounds having the structure of Formula I;

R¹(OC₂H₄)_m—

O⁻

X₁⁺ 

 

(I)

wherein R¹ is H or lower alkyl;

m is from 1 to 25; and

X₁⁺ is a positive ion, with a substantially monodispersed mixture of compounds having the structure of Formula II;

R²(OC₂H₄)_n—

OMs 

 

(II)

wherein R² is H or lower alkyl; and

n is from 1 to 25, under conditions sufficient to provide a substantially monodispersed mixture of polymers comprising polyethylene glycol moieties and having the structure of Formula III;

R²(OC₂H₄)_m+n—

OR¹ 

 

(III).

34. The method according to claim 33, wherein m+n is at least 7.

35. The method according to claim 33, wherein R¹ is H and R² is methyl.

36. The method according to claim 33, further comprising:

reacting the substantially monodispersed mixture of polymers comprising polyethylene glycol moieties and having the structure of Formula III;

R²(OC₂H₄)_m+n—

OR¹ 

 

(III)

wherein R¹ is H and R² is lower alkyl, with a methane sulfonyl halide under conditions sufficient to provide a substantially monodispersed mixture of polymers having the structure of Formula IX;

R²(OC₂H₄)_m+n—

OMs 

 

(IX); and

reacting the substantially monodispersed mixture of polymers having the structure of Formula IX with a substantially monodispersed mixture of compounds having the structure of Formula X;

H(OC₂H₄)_p—

O⁻

X₂⁺ 

 

(X)

wherein X₂⁺ is a positive ion; and

p is from 1 to 25, under conditions sufficient to provide a substantially monodispersed mixture of polymers having the structure of Formula XI;

R²(OC₂H₄)_m+n+p—

OH 

 

(XI).

38. The method according to claim 37, further comprising:

reacting the substantially monodispersed mixture of polymers having the structure of Formula III under conditions sufficient to hydrolyze the ester moiety to provide a carboxylic acid moiety.

39. The method according to claim 37, further comprising:

reacting a substantially monodispersed mixture of compounds having the structure of Formula VI;

R²—

OMs 

 

(VI)

wherein R² is an ester of a fatty acid, with a substantially monodispersed mixture of compounds having the structure of Formula VII;

R³(OC₂H₄)_n—

O⁻

X₂⁺ 

 

(VII)

wherein R³ is benzyl, trityl, or THP;

n is from 1 to 25; and

X₂⁺ is a positive ion;

under conditions sufficient to provide a substantially monodispersed mixture of compounds having the structure of Formula VIII;

R³(OC₂H₄)_n—

OR² 

 

(VIII);

reacting the substantially monodispersed mixture of compounds having the structure of Formula VIII under conditions sufficient to provide a substantially monodispersed mixture of compounds having the structure of Formula V;

H(OC₂H₄)_n—

OR² 

 

(V); and

reacting the substantially monodispersed mixture of compounds having the structure of Formula V under conditions sufficient to provide a substantially monodispersed mixture of compounds having the structure of Formula II.

40. The method according to claim 39, wherein R² is an ester of a fatty acid having the formula:

R⁴O(O)C(CH₂)_q—

wherein R⁴ is lower alkyl, and q is from 1 to 24.

41. The method according to claim 40, wherein R⁴ is ethyl.

37. A method of synthesizing a substantially monodispersed mixture of polymers comprising polyethylene glycol moieties, said method comprising:

reacting a substantially monodispersed mixture of compounds having the structure of Formula I;

R¹(OC₂H₄)_m—

O⁻

X₁⁺ 

 

(I)

wherein R¹ is lower alkyl;

m is from 1 to 25; and

X₁⁺ is a positive ion, with a substantially monodispersed mixture of compounds having the structure of Formula II;

R²(OC₂H₄)_n—

OMs 

 

(II)

wherein n is from 1 to 25; and

R² is an ester of a fatty acid, under conditions sufficient to provide a substantially monodispersed mixture of polymers comprising polyethylene glycol moieties and having the structure of Formula III;

R²(OC₂H₄)_m+n—

OR¹ 

 

(III).