Selective and specific preparation of discrete PEG compounds

• US 7,888,536 B2
• Filed: 08/15/2005
• Issued: 02/15/2011
• Est. Priority Date: 02/13/2004
• Status: Active Grant

• Current Assignee: Quanta Biodesign LLC
• Original Assignee: Quanta BioDesign, Ltd.
• Inventors: Davis, Paul D., Crapps, Edward C.
• Primary Examiner(s): Sullivan; Daniel M
• Assistant Examiner(s): VALENROD, YEVGENY
• Application Number:
  US11/203,950
• Publication Number:
  US 20060020134A1
• Time in Patent Office: 2,010 Days
• Field of Search: None
• US Class Current: 568/622
• CPC Class Codes: C07C 247/04 being saturated
• CPC Class Codes: C07C 319/12 by reactions not involving the formation of mercapto groups
• CPC Class Codes: C07C 323/12 the carbon skeleton being acyclic and saturated
• CPC Class Codes: C07C 41/16 by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
• CPC Class Codes: C07C 43/11 Polyethers containing —O—(C—C—O—)n units with ≤ 2 n≤ 10
• CPC Class Codes: C07C 43/164 containing six-membered aromatic rings
• CPC Class Codes: C07C 43/1785 having more than one ether bound
• CPC Class Codes: C08G 65/331 containing oxygen cyclic ether compounds C08G65/26
• CPC Class Codes: C08L 71/02 Polyalkylene oxides
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Aspects of the present invention are directed to novel methods for making discrete polyethylene compounds selectively and specifically to a predetermined number of ethylene oxide units. Methods which can be used to build up larger dPEG compounds (a) containing a wider range of utility to make useful homo- and heterofunctional and branched species, and (b) under reaction configurations and conditions that are milder, more efficient, more diverse in terms of incorporating useful functionality, more controllable, and more versatile then any conventional method reported in the art to date. In addition, the embodiments of the invention allow for processes that allow for significantly improving the ability to purify the intermediates or final product mixtures, making these methods useful for commerial manufacturing dPEGs. Protecting groups and functional groups can be designed to make purification at large scale a practical reality. The novel dPEG products form the compositional and material basis for making other novel compounds of valuable application in the fields of diagnostics and therapeutics, amongst others.

Claims

1. A method for selectively making specific discrete (polyethylene glycol) (dPEG) compounds containing a discrete and predetermined number of ethylene oxide moieties, which comprises the steps of:

(a) forming a reaction mixture comprising one or more of

(i) a first dPEG reactant having the general structural formula I

R¹-dPEG_x-OH 

 

I

and a second dPEG reactant having the general structural formula II

R²-dPEG_y-OR² 

 

II

or

(ii) a first dPEG reactant having the general structural formula I′

R¹-dPEG_x-OR² 

 

I′

and a second dPEG reactant having the general structural formula II′

HO-dPEG_y-OH 

 

II′

(b) adding a non-sodium hydride ionizing agent, which is potassium t-butoxide, to said reaction mixture in the presence of a catalyst and under reaction conditions to produce a dPEG compound having the general structural formula III

R¹-dPEG_2x+y-R¹ 

 

III

wherein said ionizing compound is added to a reaction mixture of compounds I and II, or I′ and

II′

, at a rate that is about equal to the rate at which compound XXII or compound XXII′

, respectively, reacts with compound II or II′

, respectively, forming XXII or XXII′

, respectively, in situ, wherein

R¹-dPEG_x-O⁻

M⁺ 

 

XXII

HO-dPEG_y-O⁻

M⁺ 

 

XXII′

wherein dPEG represents a (OCH₂CH₂) moiety, each R¹ independently is one or more of a removable hydroxyl protecting group (PG), where PG is removable under mild acid conditions and is stable to base, a protected functional group, or a functional group (FG);

x ranges from about 1 to 300;

R² is a leaving group, and y ranges from about 1 to 300.

2. The method of claim 1, wherein said steps are carried out at a temperature ranging from about 20°

to about 40°

C.

3. The method of claim 1, wherein said reactants are dispersed in a solvent.

4. The method of claim 3, wherein said solvent is one or more of tetrahydrofuran (THF), toluene, dioxane, trichloroethylene, or tetrachloroethylene.

5. The method of claim 1, where R¹ is a PG group, and further comprising R¹ of compound III is removed produce a compound of formula IV:

HO-dPEG_2x+y-OH 

 

IV.

6. The method of claim 5, wherein compound IV is converted to a compound of formula V:

R²-dPEG_2x+y-OR² 

 

V.

7. The method of claim 6, further comprising:

forming a reaction mixture comprising said dPEG compound V or XVIII′ and

a dPEG compound having the structure of formula XVIII or IV, respectively'"'"';

R¹-dPEG_z-OH 

 

XVIII

R¹-dPEG_z-OR² 

 

XVIII′

and;

adding an ionizing agent to said reaction mixture in the presence of a catalyst and under reaction conditions to produce a dPEG compound having the general structural formula VI

R¹-dPEG_2x+y+2z-R¹ 

 

VI

wherein z is 1 to 300 and R² is a leaving group.

8. The method of claim 7, wherein said ionizing agent is added to compound XVIII in the presence of a catalyst before said reaction mixture is formed.

9. The method of claim 5, further comprising:

forming a reaction mixture comprising said dPEG compound IV and a dPEG compound having the structure of formula XVIII′

R¹-dPEG_z-OR² 

 

XVIII′

and;

adding an ionizing agent to said reaction mixture in the presence of a catalyst and under reaction conditions to produce a dPEG compound having the general structural formula VI

R¹-dPEG_2x+y+2z-R¹ 

 

VI

wherein z is 1 to 300 and R² is a leaving group.

10. The method of claim 9, wherein said ionizing agent is added to compound XVIII′

in the presence of a catalyst before said reaction mixture is formed.

11. The method of claim 1, wherein the molar ratio of compound I to compound II is between about 2:

1 and about 2.1;

1.

12. The method of claim 7, wherein the molar ratio of compound XVIII to compound V is between about 2:

1 and about 2.1;

1.

13. The method of claim 9, wherein the molar ratio of compound XVIII′

to compound IV is between about 2;

1 and about 2.1;

1.

14. The method of claim 1, wherein the purity of compound III produced is greater than about 98%.

15. The method of claim 7, where R¹ is a PG group, and further comprising R¹ of compound VI is removed produce a compound of formula VII:

HO-dPEG_2x+y+2z-OH 

 

VII.

16. The method of claim 9, where R¹ is a PG group, and further comprising R¹ of compound VI is removed produce a compound of formula VI:

HO-dPEG_2x+y+2z-OH 

 

VII.

17. The method of claim 1, wherein said reaction mixture in step (b) containing compound III is worked up by the steps comprising:

(c) excess ionizing agent is quenched;

(d) solvent is removed;

(e) water is added to said reaction mixture;

(f) extract said reaction mixture with an organic cosolvent;

(g) compound III remaining in water, optionally containing salting agents, in step (f) is extracted again with methylene chloride;

(h) purifying extracted compound III; and

(i) converting compound III to compound IV.

18. The method of claim 1, wherein said reaction mixture in step (b) containing compound III is worked up by the steps comprising:

(c) excess ionizing agent is quenched;

(d) solvent is removed;

(e) water is added to said reaction mixture;

(f) the aqueous reaction mixture is extracted with an organic solvent to form an aqueous layer and an organic solvent layer;

(g) the organic solvent layer is washed with water to remove water soluble materials;

(h) the organic solvent layer from the washed organic solvent layer is removed;

(i) compound III is removed from under conditions for converting compound III into compound IV;

(j) compound IV is dissolved in water optionally containing salting agents to form an aqueous layer;

(k) the aqueous layer in step (j) is extracted with an organic solvent to remove by-products and reagents are removed and to form an organic layer;

(l) water is removed from said organic layer of step (k); and

(m) purifying compound IV.

19. The method of claim 18, wherein said solvent in step (f) comprises methylene chloride.

20. The method of claim 1, which includes said catalyst to promote the complexation of M⁺.

21. The method of claim 7, which includes said catalyst to promote the complexation of M⁺.

22. The method of claim 21, wherein said catalyst is one or more of 18-crown-6 or a derivative of 18-crown-6.

23. The method of claim 1, wherein R¹ is a functional group.

24. The method of claim 7, wherein R¹ is a functional group.

25. The method of claim 23, wherein R¹ functional group is one or more of a protected amine, an alkoxy group, an aryloxy group, a protected carboxy group, a nitrile, a protected aldehyde, or a protected thiol.

26. The method of claim 24, wherein R¹ is a protected amine.

27. The method of claim 25, wherein said protected amine is one or more of an azido group, benzyl group, a substituted benzyl group, a phthalimido group, a trityl, or a substituted trityl.

28. The method of claim 26, wherein said protected amine is one or more of an azido group, benzyl group, a substituted benzyl group, a phthalimido, a trityl, or a substituted trityl.

29. The method of claim 27, wherein said protected amine is an azido group, which is subsequently reduced to an amine group with triphenyl phosphine.

30. The method of claim 27, wherein said protected amine is an azido group, which is subsequently reduced to an amine group with triphenyl phosphine.

31. The method of claim 23, wherein said thiol group is protected with one or more of an aralkyl group, a trityl group, or a substituted trityl group.

32. The method of claim 24, wherein said thiol group is protected with one or more of an aralkyl group, or a trityl group, a substituted.

33. The method of claim 7, wherein R¹ in compound VI is converted into one or more of an OH group, an ester group, a carboxyl group, an amine group, or a thiol group.

34. The method of claim 1, wherein R¹ in structure III is a protective group that is subsequently removed under acidic conditions.

35. The method of claim 34, wherein said acidic conditions include the use of one or more of tetrahyropyran-2-yl (THP), TMB (2,4,6-trimethylbenzyl), 4-alkoxybenzyl-, 3,4-dialkoxybenzyl, 4-aralkylxoxybenzyl-, 3,4-d iaralkyloxybenzyl-, trityl, or substituted trityl.

36. The method of claim 34, wherein R¹ is one or more of THP, a trityl, a substituted trityl or TMB protecting group.

37. The method of claim 1, wherein R¹ in structure III is a protective group that is subsequently removed under reducing conditions.

38. The method of claim 37, wherein said reducing conditions comprise one or more of a metal catalyst and hydrogen or a Raney/Ni reducing system.

39. The method of claim 37, wherein R¹ is one or more of benzyl, TMB, PMB and p-alkoxybenzyl, DMB, 4-aralkylxoxybenzyl-, 3,4-diaralkyloxybenzyl-, or 3,4-dialkoxybenzyl.

40. The method of claim 38, wherein said reducing conditions comprise a Raney/Ni reducing system and R¹ is one or more of benzyl, TMB, PMB and p-alkoxybenzyl, DMB, 4-aralkylxoxybenzyl-, 3,4-diaralkyloxybenzyl- or 3,4-dialkoxybenzyl.

41. The method of claim 1, wherein R¹ is one or more of p-alkoxybenzyl, 3,4-dialkoxybenzyl, 4-aralkylxoxybenzyl, or 3,4-diaralkyloxybenzyl protecting groups, where the alkyl of the alkoxy ranges from C₁-C₂₂.

44. The method of claim 34, wherein said acidic conditions include the use of a pyridinium p-toluene sulfonate.

45. The method of claim 35, wherein said acidic conditions include the use of a pyridinium p-toluene sulfonate.

42. A method for selectively making specific discrete (polyethylene glycol) (dPEG) compounds containing a discrete and predetermined number of ethylene oxide moieties, which comprises the steps of:

(a) forming a reaction mixture comprising a first dPEG reactant having the general structural formula I

R¹-dPEG_x-OR² 

 

I′

and an excess of at least about 5 equivalents of a second dPEG reactant having the general structural formula II″

HO-dPEG_y-OH 

 

II″

(b) adding a non-sodium hydride ionizing agent, which is potassium t-butoxide, to said reaction mixture in the presence of a catalyst and under reaction conditions to produce a dPEG compound having the general structural formula III″

R¹-dPEG_x+y-OH 

 

III″

wherein said ionizing compound is added to a reaction mixture of compounds I and II, or I′ and

II′

, at a rate that is about equal to the rate at which compound XXII or compound XXII′

, respectively, reacts with compound II or II′

, respectively, forming XXII or XXII′

, respectively, in situ, wherein

R¹-dPEG_x-O⁻

M⁺ 

 

XXII

HO-dPEG_y-O⁻

M⁺ 

 

XXII′

wherein dPEG represents a (OCH₂CH₂) moiety, each R¹ independently is one or more of a removable hydroxyl protecting group (PG) or a functional group (FG);

x ranges from about 1 to 300; and

y ranges from about 1 to 6.

43. The method of claim 42, wherein compound III″

is converted to the following compound L;

R¹-dPEG_x+y-OR² 

 

L

where R² is a leaving group;

and where compound L is used one or more times in forming the reaction mixture in step (a) for form compound L having a desired number of dPEG groups.