Methods of preparing a monodisperse oligo(ethylene glycol) reagent composition
Methods of preparing monodisperse oligomer reagent compositions such as oligo(ethylene glycol) reagent compositions are described herein. The methods involve reacting a halo-terminated oligomer such as an oligo(ethylene oxide) having (m) monomers with a hydroxyl-terminated oligomer such as a hydroxyl-terminated oligo(ethylene oxide) having (n) monomers.
1. A method of preparing a monodisperse oligo(ethylene glycol) reagent composition, comprising:
(i) reacting a halo-terminated oligo(ethylene glycol) having (m) monomer subunits and a C1-C2 alkoxy (methoxy or ethoxy) end-capping group with a first hydroxyl-terminated oligo(ethylene glycol), HO—(CH 2 CH 2 O) n —H, having (n) monomer subunits, under conditions effective to displace the halo group from the halo-terminated oligo(ethylene glycol) to thereby form an oligo(ethylene glycol) having (m)+(n) monomer subunits (OEG m+n ), wherein reacting the halo-terminated oligo(ethylene glycol) with the first hydroxyl-terminated oligo (ethylene glycol) comprises adding a 1:1 molar ratio of the halo-terminated oligo(ethylene glycol) to the first hydroxyl-terminated oligo (ethylene glycol) in a solution, where halo is selected from chloro, bromo, and iodo;
(ii) converting the terminal hydroxyl group of OEG m+n into a halo group, —X, to form OEG m+n− X; and
(iii) reacting OEG m+n− X with a second hydroxyl-terminated oligo(ethylene glycol) having (n) monomer subunits under conditions effective to displace the halo group of OEG m+n− X to thereby form an oligo(ethylene glycol) having (m)+2(n) monomer subunits (OEG m+2n ), wherein reacting the OEG m+n− X with the second hydroxyl-terminated oligo (ethylene glycol) comprises adding a 1:1 molar ratio of OEG m+n− X to the second hydroxyl-terminated oligo (ethylene glycol) in a solution;
where (m) and (n) each independently range from 1-6 in each occurrence, and (OEG m+2n ) corresponds to a structure CH 3 (CH 2 ) 0,1 O(CH 2 CH 2 O) m+2n H, and is present as part of a monodisperse composition of CH 3 (CH 2 ) 0,1 O(CH 2 CH 2 O) m+2n H.
2. The method of claim 1 , where (m) is 1, 2, or 3 and (n) in each occurrence ranges from 2-6.
3. The method of claim 1 , wherein reacting steps (i) and (iii) are carried out in the presence of a strong base.
4. The method of claim 3 , wherein the strong base is selected from sodium, potassium, sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, sodium tert-butoxide, and potassium tert-butoxide.
5. The method of claim 1 , wherein the C1-C2 alkoxy end-capping group of the halo-terminated oligo(ethylene glycol) having (m) monomer subunits is methoxy.
6. The method of claim 1 , wherein reacting steps (i) and (iii) are carried out in an organic solvent at a temperature ranging from about 0° C. to about 80° C.
7. The method of claim 1 , wherein halo is bromo.
8. The method of claim 1 , further comprising purifying the monodisperse composition of CH 3 (CH 2 ) 0,1 O(CH 2 CH 2 O) m+2n H formed in step (iii) to form a purified composition.
9. The method of claim 8 , wherein the purifying comprises chromatography.
10. The method of claim 8 , further comprising converting the hydroxyl terminus of CH 3 (CH 2 ) 0,1 O(CH 2 CH 2 O) m+2n H to an active group suitable for coupling to a small molecule.
11. The method of claim 10 , wherein the active group is selected from an aldehyde and an activated carboxylic ester.