METHOD OF SYNTHESIZING A SUBSTANTIALLY MONODISPERSED MIXTURE OF OLIGOMERS

• US 20110118480A1
• Filed: 08/28/2008
• Published: 05/19/2011
• Est. Priority Date: 07/14/2008
• Status: Active Grant

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Biocon Limited (Biocon Incorporated)
• Inventors: Vijayaraghavan, Reena, Aswathanarayanappa, Chandrashekar, Venkata, Srinivas Pullela
• Granted Patent: US 9,040,723 B2
• Time in Patent Office: Days
• US Class Current: 548/542
• CPC Class Codes: C07D 207/46 with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C08G 65/3322 acyclic
• CPC Class Codes: C08G 65/33337 cyclic

Abstract

The present invention relates to methods of synthesizing oligomeric compounds, and more particularly, to methods of synthesizing oligomer compounds comprising polyethylene glycol moieties. The present invention provides improved methods for synthesizing oligomers comprising polyethylene glycol moieties. Methods according to embodiments of the present invention may utilize reaction conditions that are milder, efficacious than those taught by conventional methods.

Claims

1. A method of synthesizing a substantially monodispersed mixture of oligomers comprising polyethylene glycol moieties of compounds represented by Formula IV, said method comprising steps of:

a. reacting a substantially monodispersed mixture of compounds having the structure of formula I

2. The method as claimed in claim 1, wherein the step (a) is performed at a temperature of 0°

C. to 40°

C.

3. The method as claimed in claim 2, wherein the step (a) is performed at a temperature of about 25°

C.

4. The method as claimed in claim 1, wherein the base employed in step (a) is selected from the group consisting of Sodium methoxide, Sodium ethoxide (NaOEt), Sodium metal (Na metal), Sodium hydroxide (NaOH), Potassium hydroxide (KOH), Lithium hydroxide (LiOH), Sodium hydride (NaH), Calcium hydroxide (Ca(OH)₂), Sodium carbonate (Na₂CO₃) and Barium hydroxide (Ba(OH)₂).

5. The method as claimed in claim 4, wherein the base employed in step (a) is sodium methoxide.

6. The method as claimed in claim 1, wherein the conversion of a compound of formula II to a compound of formula III in step (b) is carried out in the presence of acid selected from the group consisting of p-Toluene sulphonic acid (PTSA), Pyridinium p-toluenesulfonate (PPTS), Trifluoro acetic acid (TFA), Methane sulphonic acid (MeSO₃H), Ethane sulphonic acid (EtSO₃H), Benzene sulphonic acid (PhSO₃H) and Sulphuric acid (H₂SO₄).

7. The method as claimed in claim 1, wherein the step (b) is performed at a temperature of 0°

C. to 80°

C.

8. The method as claimed in claim 7, wherein the step (b) is performed at a temperature of about 80°

C.

9. The method as claimed in claim 1, wherein the conversion of a compound of formula III to a compound of formula IV in step (c) is carried out in the presence of a chlorinating agent selected from the group consisting of Thionyl chloride and Oxalyl chloride.

10. The method as claimed in claim 1, wherein the conversion of a compound of formula III to a compound of formula IV in step (c) is carried out in the presence of an aprotic solvent.

11. The method as claimed in claim 10, wherein the aprotic solvent employed in step (c) is selected from the group consisting of N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), dimethyl sulfoxide, hexamethylphosphoric triamide, tetrahydrofuran (THF), dioxane, diethyl ether, methyl t-butyl ether (MTBE), toluene, benzene, hexane, pentane, N-methylpyrollidinone, dichloromethane, chloroform, tetrahydronaphthalene, decahydronaphthalene, 1,2-dichlorobenzene, 1,3-dimethyl-2-imidazolidinone and a mixture thereof.

12. The method as claimed in claim 10, wherein the aprotic solvent is N,N-dimethylformamide.

13. The method as claimed in claim 1, wherein the step (c) is performed at a temperature of 0°

C. to 40°

C.

14. The method as claimed in claim 1, wherein the compound of formula III is activated in the presence of N-hydroxysuccinimide

15. The method as claimed in claim 1, wherein the activation as in step (c) is carried out in the presence of an aliphatic amine selected from the group consisting of monomethylamine, dimethylamine, trimethylamine, monoethylamine, diethylamine, triethylamine, monoisopropylamine, diisopropylamine, mono-n-butylamine, di-n-butylamine, tri-n-butylamine, monocyclohexylamine, dicyclohexylamine and mixtures thereof.

16. The method as claimed in claim 15, wherein the aliphatic amine is triethyl amine.