WO2012108408A1 - Procédé de production d'un peptide et d'un tripeptide - Google Patents

Procédé de production d'un peptide et d'un tripeptide Download PDF

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Publication number
WO2012108408A1
WO2012108408A1 PCT/JP2012/052684 JP2012052684W WO2012108408A1 WO 2012108408 A1 WO2012108408 A1 WO 2012108408A1 JP 2012052684 W JP2012052684 W JP 2012052684W WO 2012108408 A1 WO2012108408 A1 WO 2012108408A1
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WIPO (PCT)
Prior art keywords
protected
amino acid
dipeptide
glutamylvalylglycine
tripeptide
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Ceased
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PCT/JP2012/052684
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English (en)
Japanese (ja)
Inventor
正和 中沢
廣瀬　直子
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Ajinomoto Co Inc
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Ajinomoto Co Inc
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Priority to JP2012556889A priority Critical patent/JPWO2012108408A1/ja
Publication of WO2012108408A1 publication Critical patent/WO2012108408A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms

Definitions

  • the present invention relates to a method for efficiently producing a dipeptide such as Val-Gly and a tripeptide such as ⁇ -Glu-X-Gly (X is an amino acid or amino acid derivative) obtained therefrom.
  • Patent Document 1 discloses a synthesis method based on a complete protection method. Improvement of the synthesis method is demanded because it is difficult to improve.
  • N-phthaloylglutamic anhydride when N-phthaloylglutamic anhydride is reacted with an amino acid, a ⁇ -peptide is selectively obtained.
  • hydrazine having mutagenicity is essential for deprotection and is unsuitable for commercial production.
  • a method for producing an N-protected glutamic acid ⁇ -derivative a method is known in which an N-protected glutamic anhydride is reacted with an amino acid or a derivative thereof in the presence of N-hydroxysuccinimide (Patent Document 2).
  • this method can also be suitably applied to the production of ⁇ -Glu-X-Gly, that is, can be suitably applied to the reaction of N-protected glutamic anhydride and X-Gly type peptide. It is not clear whether or not. Therefore, a method for producing ⁇ -Glu-X-Gly efficiently and economically is required.
  • the present inventors reacted N-protected neutral amino acid with N-hydroxysuccinimide to form N-hydroxysuccinimide ester of N-protected amino acid which is an active ester, and further reacted with neutral amino acid.
  • N-protected neutral amino acid with N-hydroxysuccinimide
  • N-hydroxysuccinimide ester of N-protected amino acid which is an active ester
  • neutral amino acid is an active ester
  • a dipeptide in which one of the terminal amino groups is protected can be efficiently produced, particularly when the reaction is carried out under conditions of pH 8.5 to 11.5.
  • this dipeptide is used as a raw material, the terminal amino group is deprotected (N deprotection) and then reacted with N-protected glutamic anhydride in the presence of N-hydroxysuccinimide for efficient and high efficiency.
  • the present invention provides a method for producing a dipeptide having a terminal amino group protected, which comprises reacting a neutral amino acid with an N-hydroxysuccinimide ester of an N-protected neutral amino acid.
  • the present invention also provides a method for producing a dipeptide which performs N deprotection of the dipeptide obtained by the above method.
  • the present invention also provides an N-protected glutamic acid ⁇ , wherein the dipeptide obtained by N deprotection by the above method is reacted with an N-protected glutamic anhydride in the presence of N-hydroxysuccinimide.
  • the present invention also provides Z- ⁇ -glutamylvalylglycine, or a salt thereof. Furthermore, crystals of Z- ⁇ -glutamyl valylglycine are provided.
  • the present invention also provides a method for producing glutamic acid ⁇ -tripeptide, which performs N deprotection of the tripeptide obtained by the above method.
  • the present invention also provides a method for producing Z- ⁇ -glutamylvalylglycine, characterized by reacting valylglycine with Z-glutamic anhydride in the presence of N-hydroxysuccinimide,
  • the present invention also provides a method for producing ⁇ -glutamylvalylglycine, which N-deprotects the obtained Z- ⁇ -glutamylvalylglycine.
  • a dipeptide with a short reaction time and few by-products can be produced.
  • N-protected glutamic acid ⁇ -tripeptide can be produced efficiently and highly selectively, although the raw materials used are inexpensive and the reaction operation is simple.
  • 3 shows a powder X-ray crystal diffraction pattern of Z- ⁇ -glutamylvalylglycine A crystal.
  • 3 shows a powder X-ray crystal diffraction pattern of Z- ⁇ -glutamylvalylglycine B crystal.
  • 2 shows a powder X-ray crystal diffraction pattern of Z- ⁇ -glutamylvalylglycine C crystal.
  • 3 shows a powder X-ray crystal diffraction pattern of Z- ⁇ -glutamylvalylglycine D crystal.
  • 3 shows a powder X-ray crystal diffraction pattern of Z- ⁇ -glutamylvalylglycine E crystal.
  • 3 shows a powder X-ray crystal diffraction pattern of Z- ⁇ -glutamylvalylglycine F crystal.
  • 2 shows a powder X-ray crystal diffraction pattern of ⁇ -glutamylvalylglycine crystal.
  • the neutral amino acid targeted in the present invention refers to an amino acid having no amino group or carboxyl group in the side chain, and includes glycine (Gly), alanine (Ala), ⁇ -alanine, valine (Val), and leucine (Leu). , Isoleucine (Ile), norvaline (Nva), 2-aminobutanoic acid (Abu), proline (Pro), methionine (Met), serine (Ser), threonine (Thr), phenylalanine (Phe), tyrosine (Tyr) and the like. can give.
  • glycine, alanine, ⁇ -alanine, valine, leucine, isoleucine, norvaline and 2-aminobutanoic acid are preferred.
  • the amino group of the neutral amino acid is protected with a protecting group such as benzyloxycarbonyl group (Z), t-butyloxycarbonyl group (Boc), formyl group, etc. Can be given.
  • a protecting group such as benzyloxycarbonyl group (Z), t-butyloxycarbonyl group (Boc), formyl group, etc.
  • Z benzyloxycarbonyl group
  • Boc t-butyloxycarbonyl group
  • formyl group etc.
  • the same or different amino acid as the N-protected one can be used as the neutral amino acid.
  • N-hydroxysuccinimide ester of N-protected neutral amino acid is 0.5 to 2 moles, preferably 1.0 to 1 mole of N-protected neutral amino acid in an organic solvent such as ethyl acetate, acetonitrile or tetrahydrofuran.
  • the reaction of N-hydroxysuccinimide ester of N-protected neutral amino acid with neutral amino acid is, for example, 0.5 to 2 moles compared to N-hydroxysuccinimide ester of N-protected neutral amino acid, Preferably, 0.8 to 1.2 moles of neutral amino acid is carried out in a solvent at ⁇ 20 to 80 ° C., preferably 0 to 50 ° C., for 30 minutes to 24 hours. At this time, the reaction is preferably carried out under conditions of pH 8.5 to 10.5, more preferably 8.5 to less than 9.5. Further, when the reaction is carried out at a low temperature, it is also preferably carried out at a pH of 9.5 to 10.5.
  • solvent used in the reaction examples include organic solvents such as ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, chloroform and N, N-dimethylformamide. These solvents may be used as a mixture, or a mixed solvent with water may be used.
  • N deprotection of the dipeptide obtained by the above method is then performed by a conventional method.
  • the dipeptide reaction solution obtained by the above method is preferably substituted with argon, palladium carbon is added, and hydrogen is substituted to deprotect N.
  • the dipeptide obtained by N-deprotection by the above method is then reacted with N-protected glutamic anhydride in the presence of N-hydroxysuccinimide to give N-protected glutamic acid ⁇ -tri A peptide is produced.
  • the N-protected glutamic acid ⁇ -tripeptide means a tripeptide in which the ⁇ -position of N-protected glutamic acid is bound to a dipeptide.
  • Z- ⁇ -glutamylvalylglycine is a novel compound and is extremely useful as an intermediate for production of ⁇ -glutamylvalylglycine.
  • crystals of Z- ⁇ -glutamyl valyl glycine may be obtained. In this case, purification becomes extremely easy, and high purity ⁇ -glutamyl valyl glycine can be produced. .
  • crystals of Z- ⁇ -glutamylvalylglycine have diffraction angles (2 ⁇ ) of 10.9, 16.3, 19.2, 19.7, 20.3 in the powder X-ray diffraction pattern. It is characterized by showing a peak.
  • N-protected glutamic anhydride can be produced by a conventional method such as treating N-protected glutamic acid with a dehydrating agent such as dicyclohexylcarbodiimide (DDC) or acetic anhydride.
  • a dehydrating agent such as dicyclohexylcarbodiimide (DDC) or acetic anhydride.
  • the reaction of the above dipeptide with N-protected glutamic anhydride is, for example, 0.5 to 2-fold mol, preferably 0.8 to 1.2-fold mol of dipeptide with respect to N-protected glutamic anhydride.
  • N-hydroxysuccinimide (HOSu) in a solvent at ⁇ 20 to 80 ° C., preferably 0 to 50 ° C. for 30 minutes.
  • the reaction is preferably carried out in the presence of an alkali metal carbonate.
  • Alkali metal carbonates include normal salts (sodium carbonate, potassium carbonate, etc.) or bicarbonates (sodium bicarbonate, potassium bicarbonate, etc.). Preferred are sodium hydrogen carbonate and potassium hydrogen carbonate.
  • the alkali metal carbonate is preferably used in an amount of 1.0 to 1.2 times the amount of N-protected glutamic acid.
  • the solvent used in the reaction include organic solvents such as ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, chloroform and N, N-dimethylformamide. These solvents may be used as a mixture, or a mixed solvent with water may be used.
  • N deprotection of the tripeptide obtained by the above method is performed by a conventional method.
  • the tripeptide reaction solution obtained by the above method is replaced with argon, palladium carbon is added, and hydrogen is replaced with N. It should be deprotected.
  • the by-product ⁇ -form may be separated from the ⁇ -form by a conventional method such as crystallization or chromatography before or after removal of the protecting group.
  • a conventional method such as crystallization or chromatography before or after removal of the protecting group.
  • the salt of Z- ⁇ -glutamylvalylglycine produced by the method of the present invention include sodium salt and potassium salt.
  • Run 6 was performed as follows. To 1.57 g (1.05 eq) of glycine was dissolved by adding 25 ml of water, and 5.1 g (3.0 eq) of sodium bicarbonate was added and stirred. To this solution, an ethyl acetate solution (19.9 mmol) of hydroxysuccinimide ester of Z-valine was added and stirred at 40 ° C. for 18 hours. 6M hydrochloric acid was added and stirred to adjust the pH to 8. The reaction solution was purged with argon, 0.05 g of 50% wet 10% palladium on carbon was added, purged with hydrogen, and stirred overnight at room temperature. After replacing the reaction solution with argon, palladium carbon was removed by separation. The reaction solution was separated to obtain an aqueous solution of valylglycine. Yield 87.4%
  • the precipitated dicyclohexylurea was separated by filtration and washed with 37 ml of ethyl acetate. An ethyl acetate solution of Z-glutamic anhydride was obtained. 7.36 g (1.0 eq vs. Z-Glu) of sodium hydrogen carbonate was added to and dissolved in the valylglycine aqueous solution (including HOSu) produced in Run 3 of Example 1, and an ethyl acetate solution of Z-glutamic anhydride was added thereto. It was dripped at room temperature over 1.5 hours. After completion of the dropping, the mixture was stirred for 1 hour to obtain a layer separation and an aqueous solution of Z- ⁇ -glutamylvalylglycine.
  • Z- ⁇ -glutamylvalylglycine has the following crystal polymorphs of A crystal to F crystal. Of these, the crystal E is preferred as the crystal.
  • the main peak [diffraction angle (2 ⁇ )] and production examples are shown below.
  • the powder X-ray crystal diffraction patterns of these A crystals to F crystals are shown in FIGS.
  • Crystal A Crystals crystallized acidic (10.9, 16.3, 19.2, 19.7, 20.3)
  • Crystal B Crystal obtained by slurry washing with methanol (6.0, 7.3, 8.3, 15.0, 20.0) 1.5 ml of methanol was added to the crystal A (0.3 g) of the crude Z- ⁇ -glutamylvalylglycine obtained in (3) and stirred at 20 ° C.
  • Crystals Crystal obtained by recrystallizing Crystal A from ethanol (6.1, 15.1, 17.7, 24.6, 26.9) Ethanol (10 ml) was added to the crude Z- ⁇ -glutamylvalylglycine crystal A (1.0 g) obtained in (3), and the mixture was stirred at 30 ° C. for 3 hours and further at 50 ° C. for 1 hour. Thereafter, the mixture was cooled to 20 ° C. over 6 hours and stirred at 20 ° C. overnight. The crystals were separated and dried under reduced pressure overnight at 40 ° C. to obtain 0.85 g of Z- ⁇ -glutamylvalylglycine crystals (C crystals).
  • Crystal D Crystal obtained by recrystallizing Crystal B from ethanol (6.6, 6.7, 19.0, 19.5, 31.9) 108 B of ethanol was added to B crystal (6.0 g) of crude Z- ⁇ -glutamylvalylglycine, and the mixture was stirred at 65 ° C. for 1 hour. Thereafter, the mixture was cooled to 10 ° C. over 10 hours and stirred at 10 ° C. overnight. The crystals were separated and dried under reduced pressure at 40 ° C. overnight to obtain 3.8 g of Z- ⁇ -glutamylvalylglycine crystals (crystal D).
  • Crystal E Crystal obtained by recrystallizing Crystal A from methanol (8.5, 14.1, 18.0, 21.6, 22.9) 73.3 ml of methanol was added to the crude Z- ⁇ -glutamylvalylglycine obtained in (3) above and stirred at 40 ° C. for 3 hours. Thereafter, the mixture was cooled to 10 ° C. over 3 hours and stirred at 10 ° C. overnight. The crystals were separated, washed with 12 ml of methanol, and dried under reduced pressure at 40 ° C. overnight to obtain 8.0 g of Z- ⁇ -glutamylvalylglycine crystals.
  • the precipitated dicyclohexylurea was removed by filtration and washed with 40 ml of ethyl acetate to obtain a solution of Z-glutamic anhydride in ethyl acetate.
  • 7.36 g (1.0 eq vs. Z-Glu) of sodium bicarbonate was added to an aqueous valylglycine solution (including HOSu) and stirred, and the ethyl acetate solution of Z-glutamic anhydride prepared above was added dropwise over 1.5 hours. did. After the dropwise addition, the mixture was stirred at room temperature for 1 hour, 70 ml of THF was added, and the mixture was heated to 40 ° C.
  • Concentrated hydrochloric acid (22 ml) was added to adjust to pH 3.0 and extraction was performed. The layers were separated, and the ethyl acetate layer was washed with 100 ml of water. To the ethyl acetate layer, 120 ml of water and 0.75 g of 50% wet 10% palladium carbon were added to replace with hydrogen, followed by deprotection with stirring at 40 ° C. After completion of the reaction, palladium carbon was filtered and separated. The aqueous layer was concentrated to 100 ml under reduced pressure, insoluble material was removed by Millipore filtration (0.45 ⁇ m), and the mixture was again concentrated to 50 g under reduced pressure.
  • FIG. 7 shows a powder X-ray crystal diffraction pattern of the crystals of ⁇ -glutamylvalylglycine.
  • Example 3 Synthesis of norvalylglycine and ⁇ -glutamylnorvalylglycine (1) Synthesis of hydroxysuccinimide ester of Z (benzyloxycarbonyl) -norvaline Z-norvaline 10 g (39.8 mmol) was dissolved in 60 ml of ethyl acetate, and 4.59 g (1 eq) of N-hydroxysuccinimide (HOSu) was dissolved. ) And cooled to 5 ° C. 8.21 g (1 eq) of N, N-dicyclohexylcarbodiimide was dissolved in 25 ml of ethyl acetate and slowly added at 10 ° C. or lower.
  • the precipitated dicyclohexylurea was removed by filtration and washed with 20 ml of ethyl acetate to obtain a solution of Z-glutamic anhydride in ethyl acetate.
  • 3.68 g (1.0 eq vs. Z-Glu) of sodium hydrogen carbonate was added to an aqueous solution of norvalylglycine (including HOSu) and stirred, and the ethyl acetate solution of Z-glutamic anhydride prepared above was added over 1.5 hours. It was dripped. After dropping, the mixture was stirred at room temperature for 1 hour and heated to 40 ° C. Concentrated hydrochloric acid (11 ml) was added to adjust to pH 3.0 and extraction was performed.
  • the layers were separated, and the ethyl acetate layer was washed with 50 ml of water.
  • the ethyl acetate layer was purged with hydrogen by adding 50 ml of water, 25 ml of methanol, and 0.37 g of 50% wet 10% palladium on carbon, and deprotected by stirring at 20 to 25 ° C.
  • palladium carbon was removed by Millipore filtration (0.45 ⁇ m), and the mixture was concentrated under reduced pressure to 40 g.
  • the mixture was heated to 50 ° C. and 50 ml of methanol was added dropwise.

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Abstract

Un γ-tripeptide d'acide glutamique peut être obtenu de façon efficace par un procédé de production d'un γ-tripeptide d'acide glutamique N-protégé, ledit procédé comprenant un procédé dans lequel un acide aminé neutre N-protégé est converti en ester de N-hydroxysuccinimide puis réagit avec un acide aminé neutre de sorte à synthétiser un peptide comportant un groupement amino terminal protégé, puis, après la mise en œuvre d'une N-déprotection, ledit peptide ainsi obtenu réagit avec un anhydride d'acide glutamique N-protégé en présence de N-hydroxysuccinimide.
PCT/JP2012/052684 2011-02-08 2012-02-07 Procédé de production d'un peptide et d'un tripeptide Ceased WO2012108408A1 (fr)

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JP2012556889A JPWO2012108408A1 (ja) 2011-02-08 2012-02-07 ジペプチド及びトリペプチドの製造方法

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2883960A4 (fr) * 2012-08-10 2016-05-18 Ajinomoto Kk Procédé de production d'un cristal de -glutamyl-valyl-glycine
CN113969297A (zh) * 2021-10-30 2022-01-25 福州三合元生物科技有限公司 一种寡聚γ-氨基丁酸及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08119916A (ja) * 1994-10-20 1996-05-14 Ajinomoto Co Inc Ｎ−保護グルタミン酸γ−誘導体の選択的製造法
JP2009514791A (ja) * 2005-11-09 2009-04-09 味の素株式会社 コク味付与剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08119916A (ja) * 1994-10-20 1996-05-14 Ajinomoto Co Inc Ｎ−保護グルタミン酸γ−誘導体の選択的製造法
JP2009514791A (ja) * 2005-11-09 2009-04-09 味の素株式会社 コク味付与剤

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ANDERSON GW. ET AL.: "The Use of Esters of N-Hydroxysuccinimide in Peptide Synthesis", J. AM. CHEM. SOC., vol. 86, no. 9, 1964, pages 1839 - 1842 *
GUARNACCIA R. ET AL.: "Co-oligopeptides of aromatic amino acids and glycine with a variable distance between the aromatic residues. III. Co-oligopeptides of L-phenylalanine, L-tryptophan, and Glycine: synthesis and ultraviolet absorption properties", BIOPOLYMERS, vol. 15, no. 6, 1976, pages 1103 - 1117 *
TAKEDA K. ET AL.: "An Improved Method for the Synthesis of Active Esters of N-Protected Amino Acids and Subsequent Synthesis of Dipeptides", SYNTHESIS, vol. 1991, no. 9, 1991, pages 689 - 691 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2883960A4 (fr) * 2012-08-10 2016-05-18 Ajinomoto Kk Procédé de production d'un cristal de -glutamyl-valyl-glycine
US9512177B2 (en) 2012-08-10 2016-12-06 Ajinomoto Co., Inc. Method for producing γ-glutamyl-valyl-glycine crystal
CN113969297A (zh) * 2021-10-30 2022-01-25 福州三合元生物科技有限公司 一种寡聚γ-氨基丁酸及其制备方法
CN113969297B (zh) * 2021-10-30 2024-03-26 福州三合元生物科技有限公司 一种寡聚γ-氨基丁酸及其制备方法

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