Method for producing hetero-type monodisperse polyethylene glycol derivative

Patent metadata

Field	Value
Publication number	US-12030833-B2
Application number	US-202017599172-A
Country	US
Kind code	B2
Filing date	Mar 25, 2020
Priority date	Mar 29, 2019
Publication date	Jul 9, 2024
Grant date	Jul 9, 2024

Abstract

A method for producing a hetero-type monodisperse polyethylene glycol, which includes (A) carrying out a nucleophilic substitution reaction between a compound of formula (2) and a compound of formula (3) so as to satisfy expression (F1) to obtain a compound of formula (4), (B) of carrying out a Michaels addition reaction of a compound of formula (5) to the compound of formula (4) at a temperature condition of 10° C. or lower to obtain a compound of formula (6), (C) detritylating or debenzylating the compound of the formula (6) to obtain a reaction product containing a compound of formula (7), (D) purifying the compound of formula (7) from the reaction product, (E) reacting the compound of formula (7) with phthalimide and performing dephthalimidation to obtain a compound of formula (8), and (F) subjecting the compound of formula (8) to an acid hydrolysis treatment to obtain a compound represented by formula (1).

First claim

The invention claimed is:

1. A method for producing a hetero-type monodisperse polyethylene glycol represented by the formula (1), which comprises the following steps (A), (B), (C), (D), (E) and (F):

wherein, in the formula (1), a represents an integer of 6 to 12,
Step (A): a step of carrying out a nucleophilic substitution reaction between a compound of the formula (2) and a compound of the formula (3) so as to satisfy the requirement of the expression (F1) to obtain a compound of the formula (4):

wherein, in the formula (2), b represents an integer of 3 to 9,

wherein, in the formula (3), L represents a mesyl group or a tosyl group, R 1 represents a trityl group or a benzyl group, and c represents an integer of 3 to 9,

wherein, in the formula (4), R 1 represents a trityl group or a benzyl group and a represents an integer of 6 to 12;
Step (B): a step of carrying out Michael addition reaction of a compound of the formula (5) to the compound of the formula (4) obtained in the step (A) under a temperature condition of 10° C. or lower to obtain a compound of the formula (6),

wherein, in the formula (5), R 2 represents a hydrocarbon group having 1 to 6 carbon atoms,

wherein, in the formula (6), R 1 represents a trityl group or a benzyl group, R 2 represents a hydrocarbon group having 1 to 6 carbon atoms, and a represents an integer of 6 to 12;
Step (C): a step of detritylating or debenzylating the compound of the formula (6) obtained in the step (B) to obtain a reaction product containing a compound of the formula (7),

wherein, in the formula (7), R 2 represents a hydrocarbon group having 1 to 6 carbon atoms and a represents an integer of 6 to 12;
Step (D): a step of purifying the compound of the formula (7) from the reaction product obtained in the step (C);
Step (E): a step of reacting the compound of the formula (7) obtained in the step (D) with phthalimide and performing dephthalimidation to obtain a compound of the formula (8),

wherein, in the formula (8), R 2 represents a hydrocarbon group having 1 to 6 carbon atoms and a represents an integer of 6 to 12; and
Step (F): a step of subjecting the compound of the formula (8) obtained in the step (E) to an acid hydrolysis treatment to obtain the compound represented by the formula (1).

2. The method according to claim 1 , wherein the compound of the formula (7) is purified using dichloromethane or chloroform in the step (D).

3. The method according to claim 1 , wherein the compound of the formula (7) is purified using water or an aqueous solution having a concentration of an inorganic salt of 10% by weight or less in the step (D).

4. The method according to claim 1 , wherein the step (D) comprises a washing step at a temperature of 1 to 25° C.

5. A method for producing a hetero-type monodisperse polyethylene glycol represented by the formula (1), which comprises the following steps (A), (B), (C), (E), (F) and (G):

wherein, in the formula (1), a represents an integer of 13 to 40,
Step (A): a step of carrying out a nucleophilic substitution reaction between a compound of the formula (2) and a compound of the formula (3) so as to satisfy the requirement of the expression (F1) to obtain a compound of the formula (4):

wherein, in the formula (2), b represents an integer of 3 to 37,

wherein, in the formula (3), L represents a mesyl group or a tosyl group, R 1 represents a trityl group or a benzyl group, and c represents an integer of 3 to 37,

wherein, in the formula (4), R 1 represents a trityl group or a benzyl group and a represents an integer of 13 to 40;
Step (B): a step of carrying out Michael addition reaction of a compound of the formula (5) to the compound of the formula (4) obtained in the step (A) under a temperature condition of 10° C. or lower to obtain a compound of the formula (6),

wherein, in the formula (5), R 2 represents a hydrocarbon group having 1 to 6 carbon atoms,

wherein, in the formula (6), R 1 represents a trityl group or a benzyl group, R 2 represents a hydrocarbon group having 1 to 6 carbon atoms, and a represents an integer of 13 to 40;
Step (C): a step of detritylating or debenzylating the compound obtained in the step (B) to obtain a compound of the formula (7),

wherein, in the formula (7), R 2 represents a hydrocarbon group having 1 to 6 carbon atoms and a represents an integer of 13 to 40;
Step (E): a step of reacting the compound of the formula (7) obtained in the step (C) with phthalimide and performing dephthalimidation to obtain a compound of the formula (8),

wherein, in the formula (8), R 2 represents a hydrocarbon group having 1 to 6 carbon atoms and a represents an integer of 13 to 40;
Step (F): a step of subjecting the compound of the formula (8) obtained in the step (E) to an acid hydrolysis treatment to obtain a reaction product containing the compound of the formula (1); and
Step (G): a step of purifying the compound of the formula (1) from the reaction product obtained in the step (F).

6. The method according to claim 5 , wherein an organic solvent to be used for the purifying is dichloromethane or chloroform in the step (G).

7. The method according to claim 5 , wherein an aqueous solution to be used for the purifying is a basic aqueous solution of pH 8 or higher in the step (G).

8. The method according to claim 1 , wherein R 2 of the compound of the formula (5) is an isopropyl group or a tert-butyl group in the step (B).

9. The method according to claim 1 , wherein flaky potassium hydroxide or powdery potassium hydroxide is used as a base in the step (B).

10. The method according to claim 2 , wherein the compound of the formula (7) is purified using water or an aqueous solution having a concentration of an inorganic salt of 10% by weight or less in the step (D).

11. The method according to claim 2 , wherein the step (D) comprises a washing step at a temperature of 1 to 25° C.

Assignees

• Nof Corp

Inventors

• ONOZAWA Akihide
• Ichikawa Takashi

Classifications

• C08G65/33341

  aromatic · CPC title

• C08G65/3322

  acyclic · CPC title

• C08G65/30 Primary

  Post-polymerisation treatment, e.g. recovery, purification, drying · CPC title

• C08G65/08

  Saturated oxiranes · CPC title

• C07C213/10

  Separation; Purification; Stabilisation; Use of additives · CPC title