US 10,435,509 B2Granted

Hetero type monodispersed polyethylene glycol, intermediate for production of hetero type monodispersed polyethylene glycol, methods for producing same, and hetero type monodispersed polyethylene glycol conjugate

AssigneesTohoku Techno Arch Co., Ltd., Nof Corporation

InventorsKazushi Kinbara, Takahiro Muraoka, Adam Marcin Wawro, Tomoyuki Ohtake, Eui-chul Kang, Tomoki Uruga, Ryutaro Imamura

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Abstract

A hetero type monodispersed polyethylene glycol containing a compound represented by the following formula (1): NH2—(CH2CH2O)a—CH2CH2COOH (1) (in the formula (1), a represents an integer from 6 to 40); wherein any of (A) a chromatogram detected by a differential refractometer when the hetero type monodispersed polyethylene glycol is separated using reverse phase chromatography, (B) a chromatogram detected by a differential refractometer when the hetero type monodispersed polyethylene glycol is separated using cation exchange chromatography, and (C) a chromatogram detected by a differential refractometer when the hetero type monodispersed polyethylene glycol containing a compound represented by the formula (1) shown above is derivatized and separated using anion exchange chromatography satisfy specific relational expressions, respectively.

Claims6

Dependent claims

A method for producing a hetero monodispersed polyethylene glycol comprising a compound represented by the following formula (1):

NH2—(CH2CH2O)a—CH2CH2COOH (1)
wherein, in the formula (1), a represents an integer from 6 to 40,
the method comprising:
step A of obtaining a compound represented by the following formula (5) by Michael addition reaction of a compound represented by the following formula (3) with a compound represented by the following formula (4) under temperature condition of 5° C. or less:
TsO—(CH2CH2O)a—H (3)
wherein, in the formula (3), Ts represents a tosyl group, and a represents an integer from 6 to 40,
wherein, in the formula (4), R1 represents a hydrocarbon group having from 1 to 6 carbon atoms,
TsO—(CH2CH2O)a—CH2CH2—COOR1 (5)
wherein, in the formula (5), Ts represents a tosyl group, R1 represents a hydrocarbon group having from 1 to 6 carbon atoms, and a represents an integer from 6 to 40;
step B of obtaining a compound represented by the following formula (6) by a reaction of the compound represented by the formula (5) with potassium phthalimide:
PI—(CH2CH2O)a—CH2CH2—COOR1 (6)
wherein, in the formula (6), PI represents a phthalimido group, R1 represents a hydrocarbon group having from 1 to 6 carbon atoms, and a represents an integer from 6 to 40;
step C of obtaining a compound represented by the following formula (7) by dephthalimidation of the compound represented by the formula (6):
H2N—(CH2CH2O)a—CH2CH2—COOR1 (7)
wherein, in the formula (7), R1 represents a hydrocarbon group having from 1 to 6 carbon atoms, and a represents an integer from 6 to 40;
and step D of obtaining the hetero monodispersed polyethylene glycol comprising the compound represented by the formula (1) by subjecting a reaction product comprising the compound represented by the formula (7) obtained in the step C to separatory extraction treatment and acid hydrolysis treatment.

13 more elements

A method for producing an intermediate for production of a hetero monodispersed polyethylene glycol, the intermediate comprising a compound represented by the following formula (3):

TsO—(CH2CH2O)a—H (3)
wherein, in the formula (3), Ts represents a tosyl group, and a represents an integer from 6 to 40,
the method comprising:
step a of obtaining a compound represented by the following formula (10) by subjecting a compound represented by the following formula (8) and a compound represented by the following formula (9) to a nucleophilic substitution reaction so as to satisfy a condition represented by the following formula (F5):
HO—(CH2CH2O)b—H (8)
wherein, in the formula (8), b represents an integer from 3 to 37,
LO—(CH2CH2O)c—R2 (9)
wherein, in the formula (9), L represents a tosyl group or a mesyl group, R2 represents a trityl group or a benzyl group, and c represents an integer from 3 to 37,
6≤b+c≤40 (F5)
wherein, in the formula (F5), b represents b in the formula (8), and c represents c in the formula (9)
HO—(CH2CH2O)a—R2 (10)
wherein, in the formula (10), R2 represents a trityl group or a benzyl group, and a represents an integer from 6 to 40;
step b of obtaining a compound represented by the following formula (11) by tosylation of the compound represented by the formula (10):
TsO—(CH2CH2O)a—R2 (11)
wherein, in the formula (11), Ts represents a tosyl group, R2 represents a trityl group or a benzyl group, and a represents an integer from 6 to 40;
step c of obtaining the compound represented by the formula (3) by detritylation or debenzylation of the compound represented by the formula (11);
and
step d of obtaining the intermediate for production of the hetero monodispersed polyethylene glycol by performing purification of the reaction product comprising the compound represented by the formula (3) obtained in the step c.

15 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/740,252Filed 29 Jun 2016
Priority: JP 2015-13174430 Jun 2015
Published: US 2018/0186931 A15 Jul 2018
Granted: 8 Oct 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification12 codes

B01D 15/362
Ion-exchange: cation-exchange
C08G 65/46
From hydroxy compounds or their metallic derivatives: post-polymerisation treatment, e.g. recovery, purification, drying
B01D 11/0492
Of solutions which are liquid: applications, solvents used
B01D 15/363
Ion-exchange: anion-exchange