Method for preparing polyethylene glycol dialdehyde derivative
The present invention relates to an improved method for preparing a high purity polyethylene glycol dialdehyde derivative. The preparation method can provide the polyethylene glycol dialdehyde derivative suitable as a raw material for pharmaceuticals because of high purity and terminal activity, by using PEG-diacetal, which is prepared by reacting polyethyleneglycol methanesulfonate with dialkoxy-1-propanol, as an intermediate.
1. A method for preparing a polyethylene glycol dialdehyde derivative represented by the following formula 4, comprising
(1) subjecting a compound of the following formula 2 to an activation treatment with a metal base and then subjecting it to a pegylation with a compound of the following formula 1 to prepare a compound of the following formula 3; and
(2) subjecting the compound of formula 3 to an acid treatment:
wherein Ms is methanesulfonyl, R 1 and R 2 are the same or different from each other and each independently represents a (C1-C9) alkyl group, and n is an integer of 3 to 2000.
2. The method according to claim 1 , characterized in that the metal base is at least one selected from the group consisting of a metal alkoxide and a metal hydride.
3. The method according to claim 2 , characterized in that the metal alkoxide is at least one selected from the group consisting of sodium methoxide, sodium ethoxide, sodium t-butoxide, sodium t-pentoxide, potassium t-butoxide and potassium t-pentoxide.
4. The method according to claim 2 , characterized in that the metal hydride is sodium hydride.
5. The method according to claim 1 , characterized in that the activation treatment is carried out at from 20° C. to 90° C.
6. The method according to claim 1 , characterized in that the pegylation is carried out at a temperature of 0° C. to 90° C.
7. The method according to claim 1 , characterized in that step (1) is carried out under an inert gas atmosphere or under an inert atmosphere in which an inert gas is continuously introduced.
8. The method according to claim 7 , characterized in that the inert atmosphere is formed by introducing at least one inert gas selected from the group consisting of nitrogen, argon and helium.
9. The method according to claim 1 , characterized in that step (1) is carried out in at least one solvent selected from the group consisting of toluene, dichloromethane, chloroform, tetrahydrofuran, acetonitrile and 1,4-dioxane.
10. The method according to claim 1 , characterized in that the compound of formula 3 prepared in step (1) is applied, as it is, in situ to step (2).
11. The method according to claim 1 , characterized in that the acid treatment in step (2) is carried out using at least one acid selected from the group consisting of hydrochloric acid, acetic acid, formic acid, trifluoroacetic acid and phosphoric acid.
12. The method according to claim 1 , characterized in that the acid treatment of step (2) is carried out at a temperature between 0° C. and 50° C.
13. The method according to claim 1 , characterized in that step (2) is carried out in at least one solvent selected from the group consisting of water, methanol, ethanol, propanol and t-butanol.
14. The method according to claim 1 , characterized in that the compound of formula 1 is prepared by reacting polyethylene glycol (PEG) and methanesulfonyl halide (halide=Cl, Br, or F) in the presence of base.
15. The method according to claim 14 , characterized in that the base is at least one selected from the group consisting of triethylamine and tributylamine.