US 12,030,833 B2Granted

Method for producing hetero-type monodisperse polyethylene glycol derivative

AssigneeNof Corporation

InventorsAkihide Onozawa, Takashi Ichikawa

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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).

Claims20

Dependent claims

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, R1 represents a trityl group or a benzyl group, and c represents an integer of 3 to 9,
wherein, in the formula (4), R1 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), R2 represents a hydrocarbon group having 1 to 6 carbon atoms,
wherein, in the formula (6), R1 represents a trityl group or a benzyl group, R2 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), R2 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), R2 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).

18 more elements

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, R1 represents a trityl group or a benzyl group, and c represents an integer of 3 to 37,
wherein, in the formula (4), R1 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), R2 represents a hydrocarbon group having 1 to 6 carbon atoms,
wherein, in the formula (6), R1 represents a trityl group or a benzyl group, R2 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), R2 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), R2 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).

18 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/599,172Filed 25 Mar 2020
Priority: JP 2019-06552829 Mar 2019
Published: US 2022/0153683 A119 May 2022
Granted: 9 Jul 2024
Term ends: Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07C 213/06
Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same…:…
C07C 41/16
Preparation of ethers: by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
C07C 67/31
By modifying the acid moiety of the ester, such modification not being an introduction of an ester group: by introduction of functional groups…
C07C 213/02
Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same…: by…