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WO2007114482A1 - Procédé permettant de produire un composé à chaîne glucidique - Google Patents

Procédé permettant de produire un composé à chaîne glucidique Download PDF

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Publication number
WO2007114482A1
WO2007114482A1 PCT/JP2007/057614 JP2007057614W WO2007114482A1 WO 2007114482 A1 WO2007114482 A1 WO 2007114482A1 JP 2007057614 W JP2007057614 W JP 2007057614W WO 2007114482 A1 WO2007114482 A1 WO 2007114482A1
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WO
WIPO (PCT)
Prior art keywords
sugar chain
group
formula
compound represented
residue
Prior art date
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Ceased
Application number
PCT/JP2007/057614
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English (en)
Japanese (ja)
Inventor
Yasuhiro Kajihara
Yuri Nambu
Kazuhiro Fukae
Hiroaki Asai
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Otsuka Chemical Co Ltd
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Otsuka Chemical Co Ltd
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Filing date
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Publication of WO2007114482A1 publication Critical patent/WO2007114482A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a method for producing a sugar chain compound having a free hydroxyl group at the reducing end by cleaving the reducing end C-covalent bond of the sugar chain asparagine compound.
  • glycoproteins A molecule in which a sugar chain is covalently bonded to a protein is called a glycoprotein.
  • Sugar chains in glycoproteins play a role in maintaining the three-dimensional structure of proteins, controlling solubility, and adding protease resistance. Recently, it has been revealed that sugar chains in glycoproteins are involved in vital phenomena such as fertilization, differentiation, signal transduction, canceration, intracellular transport of proteins and regulation of physiological activities. Thus, sugar chains bound to proteins play an important role in various physiological functions. However, since the structures of these sugar chains are diverse and the types are enormous, it is extremely difficult to identify which structure of the sugar chain is involved in life phenomena. In order to elucidate these functions, it is essential to synthesize glycoproteins and glycopeptides with a single-structure sugar chain.
  • Glycoproteins can be divided into two groups based on the differences in the manner of binding between sugar and protein.
  • One is an asparagine-linked sugar chain (N-linked) in which the side chain amino group of asparagine (A sn) is linked to a sugar chain.
  • the other is a mucin-linked sugar chain (O-bonded type) in which a sugar chain is bound to the hydroxyl group of serine (Se r) or threonine (T h r).
  • Patent Document 1 The inventors of the present invention established a method (Patent Document 1) for preparing a large amount of biantennary complex type glycans from chicken eggs by combining an enzyme method and a chemical method. It was shown that an aminated complex-type sugar chain derivative was produced from a complex-type sugar chain possessed, and that the obtained derivative could be selectively introduced into a thiol group of a peptide (Patent Document 2).
  • Preparation of an N-linked sugar chain having a free hydroxyl group at the reducing end of the sugar chain includes a method of cleaving the sugar chain from a sugar chain asparagine and its derivatives and glycoproteins by an enzyme and a method of chemically cleaving it.
  • a hydrazine decomposition method is used as a method of chemically cleaving.
  • Patent Document 1 W 0 0 3/0 0 8 4 3 1
  • Patent Document 2 W 0 2 0 0 4/0 1 1 0 3 6
  • anhydrous hydrazine requires careful handling due to its toxicity and ignitability, and is unsuitable for large-scale processing. Therefore, a safe and effective method for cleaving N-linked sugar chains is required. Yes.
  • An object of the present invention is to provide a method for producing an N-linked sugar chain compound having a free hydroxyl group at the reducing end, using hydrazine hydrate that is safer than anhydrous hydrazine. Disclosure of the invention
  • the present invention relates to the following inventions.
  • R 1 R 2 and R 3 are the same or different and each represents a hydrogen atom or a sugar residue.
  • R 4 represents a hydrogen atom or a fucose residue.
  • Ac represents a acetyl group.
  • R 5 is hydrogen atom, fat Represents a soluble protecting group, an amino acid residue, or a peptide residue, and R 6 represents a force lpoxyl group or a group C OR 7 .
  • R 7 represents an amino acid residue or a peptide residue.
  • the present inventors used hydrazine hydrate that could not be used because of / 3 elimination until now, hydrazine decomposition, followed by substitution with benzylamine compound, purification, and hydrolysis to the reducing end. It has been found that an N-linked sugar chain compound having a free hydroxyl group can be produced.
  • the sugar chain asparagine compound represented by the formula (1) of the present invention includes glycoproteins, glycopeptides, sugar chain asparagine and their derivatives, etc., in which the sugar chain binds to asparagine.
  • the sugar chain compound represented by the formula (2) of the present invention is an N 1-linked sugar chain compound having a free hydroxyl group at the reducing end.
  • RR 2 and R 3 are the same or different and each represents a hydrogen atom or a sugar residue.
  • R 4 represents a hydrogen atom or a fucose residue.
  • Ac represents a acetyl group.
  • R 5 represents a hydrogen atom, a lipophilic protecting group, an amino acid residue, or a peptide residue, and
  • R 6 represents a force lpoxyl group or a group —COR 7 .
  • R 7 represents an amino acid residue or a peptide residue.
  • the sugar residue may be a monosaccharide such as mannose, N-acetyl darcosamine, galactose, or fucose, which may have a hydroxyl group protected, may be substituted with a halogen atom such as fluorine, Two or more of these monosaccharides may be bonded with daricoside to form a sugar chain. Further, it may be a sugar chain containing a sialic acid which may be substituted with a halogen such as fluorine, and whose strong lpoxyl group may be protected.
  • the sugar chain asparagine compound represented by the formula (1) may be a conventionally known or unknown sugar chain asparagine, a high mannose type sugar chain asparagine compound, a complex type sugar chain asparagine compound, a hybrid sugar chain asparagine compound, It may be.
  • the sugar chain compound represented by the formula (2) may be a conventionally known or unknown sugar chain compound, and may be a high mannose type sugar chain compound, a complex type sugar chain compound, or a hybrid sugar chain compound.
  • the lipophilic protecting group is not particularly limited.
  • the introduction of the protecting group may be performed according to a known method such as Protecting groups in Organic chemistry (John Wiley & Sons INC., New York 1991, ISBN 0-471-62301-6).
  • the amino acid residue or peptide residue in R 5 is an amino acid or peptide in which an amino group of asparagine and a force loxyl group are amide-bonded, and is not particularly limited.
  • the amino acid residue or peptide residue in R 7 is an amino acid or peptide in which the carboxy group and amino group of asparagine are amide-bonded, and is not particularly limited.
  • the hydrazine hydrate used in this step can be used as long as it is conventionally known, and hydrazine monohydrate can be used as it is or diluted with water.
  • the concentration of hydrazine monohydrate is as follows. It may be about 20 to 100% by weight, particularly preferably about 40 to 100% by weight.
  • the amount of hydrazine hydrate used is not particularly limited and is 0.8 equivalents or more, preferably 1.0 equivalents or more, based on 1 equivalent of the sugar chain asparagine compound represented by the formula (1). A large excess is preferably used because it is used as a solvent.
  • the reaction in this step is carried out under heating and at the reflux temperature.
  • the sugar chain asparagine compound represented by the formula (1) reacts with hydrazine to form a hydrazino compound represented by the formula (3).
  • the / 3 elimination reaction is represented by the formula (3) in which most or all of the sugar chain asparagine compound represented by the formula (1) is represented by the formula (3). It was found to occur after conversion to a hydrazino sugar chain compound. In other words, S elimination reaction does not occur until most or all of the sugar chain asparagine compound represented by the formula (1) is converted to the hydrazino sugar chain compound represented by the formula (3). Become.
  • this reaction may be carried out until all of the sugar chain asparagine compound represented by the formula (1) is consumed, but it is preferable to terminate the reaction before consumption.
  • the reaction is preferably terminated before formation of the hydrazino sugar chain compound represented by the formula (4) generated by the j6 elimination reaction occurs.
  • the reaction is preferably carried out by thin-layer chromatography (TLC) or mass spectrometry. The reaction can be completed by stopping heating under reflux.
  • the sugar chain asparagine compound represented by the formula (1) has an amide bond-type protecting group such as an acetyl group, the protecting group is eliminated by excess hydrazine to form an amino group. Become. Therefore, N-acetylation must be performed by the action of an acetylating agent.
  • acetylating agent a conventionally known acetylating agent that can be used in the N-acetylating reaction can be used.
  • acetylated halides such as acetyl chloride and acetyl bromide can be exemplified by acetic anhydride.
  • Acetic anhydride can be preferably used.
  • the amount of the acetylating agent used may be about 1 to 20 equivalents, preferably about 1.5 to 10 equivalents, relative to 1 equivalent of the amino group.
  • acetylation reaction using an acetylating agent a conventionally known method can be applied. For example, after the excess hydrazine is distilled off from the reaction solution under reduced pressure, the acetylating agent is allowed to act in the presence of a base. It is made with.
  • the base conventionally known ones can be used. Examples thereof include alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and organic bases such as tritylamine, pyridine, etc. Is particularly preferred.
  • the amount of the base used is not particularly limited and can be used in an equal amount or more than the acetylating agent, but it is preferably used in a large excess, for example, an alkali metal carbonate such as sodium hydrogen carbonate. In this case, the saturated aqueous solution may be used in an amount of 1 to;
  • This reaction is carried out in a solvent, and examples of the solvent include water, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), tetrahydrofuran (THF) and the like. You can mix Water is preferably used. The amount of solvent used is not particularly limited.
  • the amount is usually about 10 to 2000 parts by weight, preferably about 100 to 1000 parts by weight per 1 part by weight of the sugar chain compound represented by (3).
  • the reaction is carried out at -10 to 100, preferably 0 to 50 and is usually completed in about 0.1 to 24 hours, but it is preferable to confirm the progress of the reaction by TLC or mass spectrum. .
  • the compound after the acetylation reaction is represented by the following formula (5).
  • the product containing the hydrazino sugar chain compound represented by the formula (5) obtained as described above is treated with gel filtration column chromatography to obtain fragments such as asparagine residues and j6 desorbed sugar residues. Can be removed.
  • Examples of the acid used include mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid, carboxylic acids such as formic acid, acetic acid and trifluoroacetic acid, and sulfonic acids such as methanesulfonic acid and ethanesulfonic acid. It is preferable from the viewpoint of safety and ease of use.
  • the amount of the acid used is not particularly limited as long as it is 1 equivalent or more per 1 equivalent of the hydrazino sugar chain compound represented by the formula (5), and 1 to 5 equivalents are preferable. Usually an expression
  • the reaction may be carried out at about 0 to 50 ° C, preferably about 10 to 40 ° C. Usually, the reaction is completed within about 1 to 15 hours, preferably about 2 to 10 hours, but the reaction can be carried out with TLC or mass spectrum. It is preferable to track and confirm the end.
  • a product containing the sugar chain compound represented by the formula (2) can be produced.
  • the sugar chain asparagine compound represented by the formula (1) as a raw material remains, and if the reaction proceeds slightly, the
  • the hydrazino sugar chain represented by (3) is unstable and causes ⁇ elimination over time. Therefore, the sugar chain compound represented by the formula (2) obtained at this stage includes the compound (1),
  • the amine compound is allowed to act in a solvent on the mixture of the sugar chain compound represented by the formula (2) and the other compound obtained above.
  • Examples of the amine compound include monoalkylamines having 1 to 4 carbon atoms such as methylamine, ethylamine, isopropylamine, cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, cyclooctylamine. Examples thereof include cycloalkylamines having 3 to 8 carbon atoms such as amine and benzylamines which may have a substituent.
  • Examples of the substituent of benzylamine that may have a substituent include halogen atoms such as fluorine, chlorine and bromine, alkyl groups having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group and a tert-butyl group. , A methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an alkoxy group such as a tert-butoxy group, a nitro group, etc., and these substituents can be used alone or at any position on the phenyl ring. Includes those in which ⁇ 5 are the same or differently substituted.
  • benzylamine, P-methoxybenzylamine, and 2,4,5-trimethoxybenzyl can be preferably exemplified, and p-methoxybenzylamine is particularly preferred.
  • the amount of the amine compound used is usually 1 to 20 equivalents, preferably 2 to 10 equivalents, per 1 equivalent of the sugar chain compound represented by the formula (2).
  • This reaction is preferably carried out in the presence of an acid such as camphorsulfonic acid.
  • the amount of the acid used may be 0.01 to 5 equivalents, preferably 0.05 to 1 equivalents, with respect to 1 equivalent of the sugar chain compound represented by the formula (1).
  • solvent used in this reaction examples include water, dimethyl sulfoxide (DMS O), N, N-dimethylformamide (DMF), tetrahydrofuran (TH F) and the like. These may be used alone or in combination of two or more. May be used.
  • the amount of the solvent used is not particularly limited, but is usually about 10 to 2000 parts by weight, preferably about 100 to 1000 parts by weight with respect to 1 part by weight of the sugar chain compound represented by the formula (2).
  • This reaction is usually performed at 0 to 100 ° C, preferably about 10 to 50 ° C, and is usually completed in about 1 to 24 hours. However, the reaction is followed by TLC or mass spectrum, and the raw material disappears. The reaction may be terminated at the time of performing.
  • an amino sugar chain compound represented by the formula (7) in which an amino compound is substituted at the reducing end of the sugar chain can be obtained.
  • This compound is stable to a base; It does not occur and the sugar chain structure can be maintained.
  • the hydrazino sugar chain compound represented by the formula (6) mixed in the raw material of this reaction reacts in the same manner to give the corresponding amino-substituted compound.
  • R 1 , R 2 , R 3 , R 4 and Ac are the same as above.
  • R 8 represents an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or a benzyl group that may have a substituent.
  • examples of the alkyl group having 1 to 4 carbon atoms of R 8 include a methyl group, an ethyl group, and an isopropyl group.
  • examples of the cycloalkyl group having 3 to 8 carbon atoms include a cyclopropyl group and a cyclobutyl group.
  • substituent of the benzyl group which may have a substituent include halogen atoms such as fluorine, chlorine and bromine, carbon numbers such as methyl group, ethyl group, propyl group, isopropyl group and tert-butyl group.
  • substituents can be used alone or at any position on the phenyl ring. And those in which 2 to 5 are the same or differently substituted.
  • benzyl groups a benzyl group, a p-methoxybenzyl group, and a 2,4,5-trimethoxy group can be preferably exemplified, and a p-methoxybenzyl group is particularly preferable.
  • the amino sugar chain compound represented by the formula (7) can be isolated and purified by treating the amino sugar chain compound represented by the formula (7) and other compounds by column chromatography. it can.
  • Separation by chromatography can be appropriately performed by using known chromatography alone or in combination. For example, after purification by gel filtration chromatography, reverse phase column chromatography is used. It can be purified.
  • Examples of the reverse phase column include ODS, Phenyl system, nitrile system, anion exchange system power ram, etc.
  • the amino acid of the amino sugar chain compound represented by the formula (7) The base produces a strong interaction with the octyldecyl group of the ODS column, and has excellent resolution.
  • the separation conditions and the like may be appropriately adjusted with reference to known conditions.
  • the resulting amino sugar chain compound represented by the formula (7) is a novel compound.
  • the target sugar chain compound represented by the formula (2) can be obtained by allowing an acid to act on the amino sugar chain compound represented by the formula (7) isolated by the above chromatography.
  • Examples of the acid used include mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and carboxylic acids such as formic acid, acetic acid and trifluoroacetic acid. Carboxylic acids are preferred, and among them, acetic acid is safe and simple to use. Is preferable.
  • the amount of the acid used is not particularly limited as long as it is 1 equivalent or more with respect to 1 equivalent of the amino sugar chain compound represented by the formula (7), and 1 to 5 equivalents are preferable. Usually, it is preferable to add the acid to such an extent that the aqueous solution of the compound of the formula (7) is sufficiently acidic.
  • the reaction may be carried out at about 0 to 50 ° C, preferably about 10 to 40 ° C. Usually, the reaction is completed within about 1 to 15 hours, preferably about 2 to 10 hours, but the reaction can be carried out using TLC or mass spectrum. It is preferable to track and confirm the end.
  • the obtained sugar chain compound represented by the formula (2) can be purified by chromatography or the like.
  • reaction solution was concentrated to dryness under reduced pressure, and the resulting residue was dissolved in 1 ml of water.
  • sodium hydrogen carbonate powder until saturation, followed by acetic anhydride (0.1 mL).
  • reaction solution is concentrated to dryness under reduced pressure, and the resulting residue is dissolved in 1 ml of water and subjected to gel filtration chromatography (column support: Sepha ex G-25, column size: 16 mmX 345 mm, flow rate: The fraction containing the compound (5-1) was fractionated at 0.8 ml / min, developing solvent: water, and concentrated under reduced pressure.
  • the obtained powder is purified by gel filtration column chromatography (same as above), fractions containing the target compound (2-1) are collected, concentrated under reduced pressure, and the compound (2-1) is collected. ) However, contamination of unreacted raw material derived compounds (1 1 2) and / 3 desorbed compound (8) was observed.
  • ODS column (column support: Co smo si 1 75 C 18 — OPN (manufactured by Nacalai Tesque)), in which 2 Omg of the obtained powder was dissolved in 1 OmM ammonium hydrogen carbonate aqueous solution and completely replaced with 10 mM ammonium hydrogen carbonate aqueous solution, Column size: 0.75X 0.75X 10 cm). After that, 1 OmM ammonium bicarbonate aqueous solution was flowed 5 times the amount of the carrier, and the compound (1_2) was discharged.
  • an N-linked sugar chain compound having a free hydroxyl group at the reducing end can be produced using hydrazine hydrate that is safe for hydrazine decomposition reaction.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)

Abstract

Cette invention concerne un procédé permettant de produire un composé à chaîne glucidique représenté par la formule (2). Le procédé susmentionné consiste à faire réagir un composé asparagine à chaîne glucidique représenté par la formule (1) avec de l'hydrate d'hydrazine. (1) dans cette formule, R1, R2 et R3 représentent indépendamment les uns des autres un atome d'hydrogène ou un résidu glucidique; R4 représente un atome d'hydrogène ou un résidu de fucose; Ac représente un groupe acétyle; R5 représente un atome d'hydrogène, un groupe protecteur liposoluble, un résidu d'acide aminé ou un résidu peptidique; et R6 représente un groupe carboxyle ou un groupe -COR7, R7 représentant un résidu d'acide aminé ou un résidu peptidique. (2) dans cette formule, R1, R2, R3, R4 et Ac sont tels que définis ci-dessus.
PCT/JP2007/057614 2006-03-30 2007-03-29 Procédé permettant de produire un composé à chaîne glucidique Ceased WO2007114482A1 (fr)

Applications Claiming Priority (2)

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JP2006-092702 2006-03-30
JP2006092702A JP2009155353A (ja) 2006-03-30 2006-03-30 糖鎖化合物の製造方法

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WO2007114482A1 true WO2007114482A1 (fr) 2007-10-11

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010163485A (ja) * 2009-01-13 2010-07-29 Teijin Ltd カルボキシ多糖類の溶液

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20240279364A1 (en) * 2021-03-12 2024-08-22 Daiichi Sankyo Company, Limited Glycan, and method for producing medicine containing glycan
KR20250064682A (ko) * 2022-09-09 2025-05-09 다이이찌 산쿄 가부시키가이샤 신규 올리고당, 그 올리고당의 제조 중간체, 및 그것들의 제조 방법

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Publication number Priority date Publication date Assignee Title
WO2003008431A1 (fr) * 2001-06-19 2003-01-30 Otsuka Chemical Co.,Ltd. Methode de production d'un derive d'asparagine de chaines des sucres
JP2004131424A (ja) * 2002-10-10 2004-04-30 Nippon Soda Co Ltd ４−メルカプトフェノール類の製造方法
WO2004058984A1 (fr) * 2002-12-24 2004-07-15 Otsuka Chemical Co., Ltd. Derives d'asparagine de chaine sucre, asparagine de chaine sucre, chaine sucre, et leurs procedes de production
WO2004060915A2 (fr) * 2002-12-03 2004-07-22 Sloan-Kettering Institute For Cancer Research Antigenes specifiques de la prostate, conjugues de ces antigenes, procedes correspondants d'elaboration et d'utilisation

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Publication number Priority date Publication date Assignee Title
WO2003008431A1 (fr) * 2001-06-19 2003-01-30 Otsuka Chemical Co.,Ltd. Methode de production d'un derive d'asparagine de chaines des sucres
JP2004131424A (ja) * 2002-10-10 2004-04-30 Nippon Soda Co Ltd ４−メルカプトフェノール類の製造方法
WO2004060915A2 (fr) * 2002-12-03 2004-07-22 Sloan-Kettering Institute For Cancer Research Antigenes specifiques de la prostate, conjugues de ces antigenes, procedes correspondants d'elaboration et d'utilisation
WO2004058984A1 (fr) * 2002-12-24 2004-07-15 Otsuka Chemical Co., Ltd. Derives d'asparagine de chaine sucre, asparagine de chaine sucre, chaine sucre, et leurs procedes de production

Non-Patent Citations (1)

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Title
HSING LING CHENG ET AL.: "Determination of Linkages of Linear and Branched Oligosaccharides Using Closed-Ring Chromophore Labeling and Negative Ion Trap Mass Spectrometry", AMERICAN SOCIETY FOR MASS SPECTROMETRY, vol. 13, no. 11, 2002, pages 1322 - 1330, XP004391529 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010163485A (ja) * 2009-01-13 2010-07-29 Teijin Ltd カルボキシ多糖類の溶液

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TW200804429A (en) 2008-01-16

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