+

WO2023033016A1 - Dérivé d'arginine - Google Patents

Dérivé d'arginine Download PDF

Info

Publication number
WO2023033016A1
WO2023033016A1 PCT/JP2022/032699 JP2022032699W WO2023033016A1 WO 2023033016 A1 WO2023033016 A1 WO 2023033016A1 JP 2022032699 W JP2022032699 W JP 2022032699W WO 2023033016 A1 WO2023033016 A1 WO 2023033016A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
ring
boc
hydrogen atom
groups
Prior art date
Application number
PCT/JP2022/032699
Other languages
English (en)
Japanese (ja)
Inventor
真也 矢野
卓 松本
Original Assignee
積水メディカル株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 積水メディカル株式会社 filed Critical 積水メディカル株式会社
Publication of WO2023033016A1 publication Critical patent/WO2023033016A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/24—Y being a hetero atom
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • 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 arginine derivatives or salts thereof.
  • amino acid amide means a structure in which the C-terminal carboxy group (--COOH) of an amino acid is replaced by an amide group (--CONH 2 ).
  • peptide amide means a structure in which the C-terminal carboxyl group of a peptide is an amide group.
  • the above-mentioned step that is, dissolving the amino acid etc. bound to the carrier in the organic layer, unnecessary components such as surplus raw material amino acids used in the peptide elongation reaction, It is a step of dissolving in the water layer the decomposition product, the compound by-produced when the protecting group of the starting amino acid is deprotected, and the like.
  • liquid-phase peptide synthesis carried out in an organic solvent using a carrier for liquid-phase peptide synthesis when a compound obtained by protonating the guanidyl group of an arginine is subjected to a peptide elongation reaction, the organic layer and the aqueous layer are separated by emulsification. In some cases, liquid-liquid separation of arginines bound to the obtained carrier for liquid-phase peptide synthesis could not be performed. It was also found that when liquid-liquid separation is carried out under acidic conditions in order to eliminate emulsification, a problem arises in that protective groups for amino acids and carboxyl groups are removed.
  • an object of the present invention is to provide guanidyl group-protected arginines that enable good liquid-liquid separation after binding to a carrier for liquid-phase peptide synthesis when a compound having a guanidyl group is used in a liquid-phase peptide synthesis reaction, and to provide a peptide synthesis method using the same.
  • the present inventors conducted various studies on means for protecting the guanidyl group of arginines used in liquid-phase peptide synthesis.
  • the inventors have found that the liquid-liquid separation after binding with is good and that the Boc protecting group can be removed under mild conditions, and completed the present invention.
  • R 1 and R 2 are the same or different and represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, A represents a hydrogen atom or a protective group for an amino group;
  • R 3 and R 4 represent a hydrogen atom or a Boc group, either one or both of which is a Boc group,
  • R 5 and R 6 represent a hydrogen atom or a Boc group, one or both of which is a Boc group,
  • R 7 and R 8 represent a hydrogen atom or a Boc group, one or both of which is a Boc group
  • n is an integer of 1 to 6 (except when n is 3, R 1 and R 2 are hydrogen atoms or methyl groups, and R 3 to R 8 are Boc groups)
  • liquid-phase peptide synthesis is performed using the arginine derivative of the present invention or a salt thereof, liquid-liquid separation between the compound obtained by binding the arginine derivative of the present invention and the carrier for liquid-phase peptide synthesis and other unnecessary components is excellent. and deprotection of the guanidyl group portion of the arginine derivative can be carried out under mild conditions. Therefore, peptides having arginine residues can be efficiently produced by the liquid phase method.
  • the arginine derivative or salt thereof of the present invention is characterized in that one or both of the amino group and imino group in the guanidino group are protected with a Boc group. Specifically, it is an arginine derivative represented by the following formula (1), (2) or (3) or a salt thereof.
  • R 1 and R 2 are the same or different and represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, A represents a hydrogen atom or a protective group for an amino group;
  • R 3 and R 4 represent a hydrogen atom or a Boc group, either one or both of which is a Boc group,
  • R 5 and R 6 represent a hydrogen atom or a Boc group, one or both of which is a Boc group,
  • R 7 and R 8 represent a hydrogen atom or a Boc group, one or both of which is a Boc group,
  • n is an integer of 1 to 6 (except when n is 3, R 1 and R 2 are hydrogen atoms or methyl groups, and R 3 to R 8 are Boc groups);
  • arginines refer to compounds such as arginine and homoarginine, which have a guanidinoalkylglycine structure and have an alkyl group or protective group on the guanidino group, ⁇ -amino group or carboxyl group.
  • the structures represented by the above formulas (1), (2) and (3) are E/Z isomers or imino/amino isomers, and the arginine derivative of the present invention is a mixture of these isomers. There may be.
  • R 1 and R 2 are the same or different and represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
  • alkyl groups having 1 to 4 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group and tert-butyl group.
  • a methyl group, an ethyl group, an n-propyl group and an n-butyl group are preferred, a methyl group and an ethyl group are more preferred, and an ethyl group is even more preferred.
  • Both R 1 and R 2 are more preferably ethyl groups.
  • A represents a hydrogen atom or a protective group for an amino group.
  • the amino-protecting group includes Boc (tert-butoxycarbonyl) group, Fmoc (9-fluorenylmethyloxycarbonyl) group, Cbz (benzyloxycarbonyl) group, Trt (trityl) group, Mmt (mono methoxytrityl) group, ivDde (4,4-dimethyl-2,6-dioxocyclohex-1-ylidene-3-methylbutyl) group, Ns (2-nitrobenzenesulfonyl) group, DNs (2,4-dinitrobenzenesulfonyl ) group, Nos (4-nitrobenzenesulfonyl) group, Alloc (allyloxycarbonyl) group, Teoc (2-(trimethylsilyl)ethoxycarbonyl) group, Troc (2,2,2-trichloroethoxycarbonyl) group, Phth (phthaloyl
  • A is preferably an amino group-protecting group that can be deprotected under conditions different from the Boc group, more preferably a hydrogen atom, an Fmoc group or a Cbz group, and still more preferably an Fmoc group.
  • R 3 and R 4 represent a hydrogen atom or a Boc group, one or both of which are a Boc group
  • R 5 and R 6 represent a hydrogen atom or a Boc group, one or both of which are a Boc group
  • R 7 and R 8 represent a hydrogen atom or a Boc group, either one or both of which is a Boc group. From the viewpoint of protecting the guanidino group and improving liquid-liquid separation in peptide synthesis, all of R 3 to R 8 are preferably Boc groups.
  • n an integer of 1 to 6. Of these, 3 to 6 are preferred, 3 to 5 are more preferred, and 4 is even more preferred.
  • R 1 and R 2 are preferably a methyl group or an ethyl group, more preferably an ethyl group;
  • A is preferably a hydrogen atom, an Fmoc group or a Cbz group, more preferably an Fmoc group;
  • all of 3 to R 8 are Boc groups;
  • n is preferably 3 to 6, more preferably 3 to 5, and even more preferably 4.
  • Salts of arginine derivatives represented by the above formula include acid addition salts such as hydrochloride, sulfate, nitrate, acetate, phosphate, formate, and oxalate; sodium salt, potassium salt, calcium salt; metal salts such as
  • the arginine derivative represented by the formula (1), (2) or (3) or a salt thereof is, for example, an arginine compound represented by the following formula (4), (5) or (6) or a salt thereof , di-tert-butyl dicarbonate, N-tert-butoxycarbonylimidazole, or other Boc agent.
  • the amount of the Boc agent to be added may be 1 equivalent or more, more preferably 1 to 15 equivalents, still more preferably 1 to 10 equivalents, relative to the arginine derivative.
  • R 1 and R 2 are the same or different and represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, A represents a hydrogen atom or a protective group for an amino group; n represents an integer of 1 to 6 (except when n is 3, R 1 and R 2 are hydrogen atoms or methyl groups, and R 3 to R 8 are hydrogen atoms))
  • the Boc-forming reaction is preferably carried out in a solvent in the presence of a base.
  • the base may be an organic base such as pyridine, triethylamine, DMAP (4-dimethylaminopyridine), N-methylimidazole, or a mixed organic base thereof, and an inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide.
  • a base may be used.
  • the amount of the base to be added may be 0.1 equivalent or more, more preferably 0.1 to 30 equivalents, still more preferably 1 to 20 equivalents, relative to the arginine derivative.
  • reaction solvent water, THF, 2-MeTHF, 1,4-dioxane, toluene, DMF, acetonitrile, dichloromethane, chloroform, methanol, ethanol, or a mixed solvent thereof is used.
  • the reaction is preferably carried out at 0° C. to 40° C. for 1 to 24 hours.
  • the arginine derivative of the present invention is useful as a raw material for arginines in solid-phase peptide synthesis or liquid-phase peptide synthesis. Moreover, when used for liquid-phase peptide synthesis, the liquid-liquid separation is excellent, and the elimination reaction of the Boc group is possible under mild conditions.
  • the liquid-phase peptide synthesis reaction is preferably carried out using a recently developed carrier for liquid-phase peptide synthesis.
  • step b and step c do not matter, and step b may be followed by step c, that is, the organic solvent layer containing the condensate may be obtained after removing the protective group for the amino group, or step c may be followed by step c.
  • the protective group for the amino group may be removed in the order of step b, that is, after obtaining the organic solvent layer containing the condensate.
  • reaction of condensing the arginine derivative of the present invention with a carrier for liquid-phase peptide synthesis or 2. a step of condensing the arginine derivative of the present invention with an amino acid, peptide, amino acid amide or peptide amide bound to a carrier for liquid phase peptide synthesis; b. removing the amino-protecting group (e.g., Fmoc group) of the arginine derivative in the reaction solution; c. After adding an aqueous solution to the reaction solution, liquid separation is performed, 1. a condensate of the arginine derivative from which the amino-protecting group has been removed and a carrier for liquid-phase peptide synthesis; or 2.
  • amino-protecting group e.g., Fmoc group
  • a step of adding a quenching agent for the amino acid active ester produced in step a to the reaction solution after the condensation reaction in step a may be included.
  • the amino acid active ester quenching agent is a compound having an amino group in the molecule, and compounds described in Patent Documents 23 to 25, Non-Patent Document 5, etc. can be used.
  • quenching agents include hydroxylamine, amidosulfuric acid, hydroxylamine-O-sulfonic acid, hydroxylamine-O-phosphonic acid, alkylamines having primary or secondary amines, fragrances having primary or secondary amines.
  • Group amines can be used, and tertiary amines can also be used.
  • excess quenching agent can be removed to the aqueous layer by liquid-liquid separation, it is preferably water-soluble, and amines having hydrophilic substituents such as hydroxyl group, sulfo group, sulfate group and phosphoric acid group are preferred. Further, the number of amino groups in the compound may be one (monovalent), or may be bivalent or more.
  • NMI N-methylimidazole
  • DMAP dimethylaminopyridine
  • trimethylamine can be mentioned.
  • the carrier for liquid-phase peptide synthesis used in step a is a carrier that protects amino acids, peptides, amino acid amides or peptide amides (amino acids, etc.) and solubilizes the protected amino acids, etc. in organic solvents.
  • Examples of such carriers for liquid-phase peptide synthesis include compounds represented by the following formula (I).
  • Ring A represents a C4-20 aromatic ring which may contain heteroatoms and may be polycyclic;
  • R 11 is a hydrogen atom, or when ring A is a benzene ring and Rb is a group represented by the following formula (b), together with R 13 represents a single bond, and ring A and may form a fluorene ring together with ring B, or may form a xanthene ring together with ring A and ring B via an oxygen atom;
  • p R 12 are each independently an aliphatic hydrocarbon group, an aliphatic hydrocarbon group substituted with an aliphatic hydrocarbon group via an oxygen atom, or an
  • R 16 represents a linear or branched alkylene group having 6 to 16 carbon atoms
  • R 17 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
  • A represents either a silyl group or an alkyl group to which a silyloxy group is attached; p represents an integer of 1 to 4; Ring A is, in addition to p X 1 R 12 , a halogen atom, a C1-6 alkyl group optionally substituted with a halogen atom, and a C1-6 alkoxy group optionally substituted with a halogen atom It may have a substituent selected from the group consisting of; Ra represents a hydrogen atom or an aromatic ring optionally substituted with a halogen atom; Rb represents a hydrogen atom, an aromatic ring optionally substituted with a halogen atom, or a group represented by formula (b);
  • R 16 represents a linear or branched alkylene group having 6 to 16 carbon atoms
  • R 17 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms
  • A represents either a silyl group or an alkyl group to which a silyloxy group is attached
  • R 13 represents a hydrogen atom, represents a single bond together with R 11 to form a fluorene ring together with ring A and ring B, or forms a xanthene ring together with ring A and ring B through an oxygen atom.
  • Ring B in addition to q X 2 R 14 , further comprises a halogen atom, a C1-6 alkyl group optionally substituted with a halogen atom, and a C1-6 alkoxy group optionally substituted with a halogen atom may have a substituent selected from the group consisting of ) Y represents a hydroxy group, a thiol group, NHR 20 (R 20 represents a hydrogen atom, an alkyl group or an aralkyl group) or a halogen atom. ]
  • Ring A in formula (I) represents a C4-20 aromatic ring which may contain a heteroatom and may be monocyclic or polycyclic.
  • the aromatic ring includes a C6-20 aromatic hydrocarbon ring and a C4-10 aromatic heterocyclic ring.
  • Specific C6-20 aromatic hydrocarbon rings include benzene ring, naphthalene ring, anthracene ring, phenanthrene ring, triphenylene ring, tetracene ring, indane ring, indene ring, fluorene ring, biphenyl ring, 1,1′- A binaphthalene ring and the like can be mentioned.
  • the C4-10 aromatic heterocycle is preferably a 5- to 10-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms, specifically , pyrrole ring, furan ring, thiophene ring, indole ring, benzofuran ring, benzothiophene ring, carbazole ring, pyrazole ring, indazole ring, imidazole ring, pyridine ring, quinoline ring, isoquinoline ring and the like.
  • a 5- to 8-membered aromatic heterocyclic ring containing 1 to 3 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a heteroatom is preferable, a pyrrole ring, a furan ring, a thiophene ring, an indole ring, A benzofuran ring, a benzothiophene ring, a carbazole ring, a pyrazole ring, and an indazole ring are more preferred.
  • R 11 represents a hydrogen atom, or represents a single bond together with R 13 when ring A is a benzene ring and Rb is a group represented by the formula (b); and ring B together to form a fluorene ring, or may form a xanthene ring together with ring A and ring B via an oxygen atom.
  • the ring which may be formed by R 11 and R 13 together is preferably a fluorene ring or a xanthene ring.
  • R 15 represents a hydrogen atom, an alkyl group or an aralkyl group
  • R 15 is preferably a hydrogen atom, a C1-10 alkyl group or a C7-20 aralkyl group.
  • alkyl group include straight-chain or branched-chain C1 to Ten alkyl groups are mentioned.
  • Aralkyl groups include C7-16 aralkyl groups such as benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, naphthylmethyl and 1-naphthylethyl groups.
  • p R 12 are each independently an aliphatic hydrocarbon group, an aliphatic hydrocarbon group substituted with an aliphatic hydrocarbon group via an oxygen atom, or an organic group represented by formula (a) indicates
  • R 16 represents a linear or branched alkylene group having 6 to 16 carbon atoms
  • R 17 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms
  • A represents either a silyl group or an alkyl group to which a silyloxy group is bonded.
  • p represents an integer of 1-4.
  • an organic group having an aliphatic hydrocarbon group is a monovalent organic group having an aliphatic hydrocarbon group in its molecular structure.
  • the site of the aliphatic hydrocarbon group in the organic group having the aliphatic hydrocarbon group is not particularly limited, and may be present at the terminal or at any other site.
  • the aliphatic hydrocarbon group present in the organic group is a linear, branched or cyclic saturated or unsaturated aliphatic hydrocarbon group.
  • a hydrogen group is preferred, a C5-50 aliphatic hydrocarbon group is more preferred, and a C8-30 aliphatic hydrocarbon group is even more preferred.
  • the aliphatic hydrocarbon group examples include an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group and the like, with alkyl groups, cycloalkyl groups and alkenyl groups being particularly preferred, and alkyl groups being more preferred.
  • a C5-30 linear or branched alkyl group, a C3-8 cycloalkyl group, a C5-30 linear or branched alkenyl group are preferred, and a C5-30 linear or branched alkyl group.
  • a C3-8 cycloalkyl group is more preferred, a C5-30 linear or branched alkyl group is more preferred, and a C8-30 linear or branched alkyl group is even more preferred.
  • alkyl group examples include alkyl groups having 1 to 30 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group and pentyl group.
  • branched alkyl group includes 2,3-dihydrophytyl group and 3,7,11-trimethyldodecyl group.
  • X 1 R 12 includes 2,2,4,8,10,10-hexamethyl-5-dodecanoic acid amide.
  • the alkenyl group includes monovalent groups such as vinyl group, 1-propenyl group, allyl group, isopropenyl group, butenyl group, isobutenyl group and oleyl group, and divalent groups derived therefrom.
  • the alkynyl group includes an ethynyl group, a propargyl group, a 1-propynyl group and the like.
  • the above aliphatic hydrocarbon group may be substituted with an aliphatic hydrocarbon group via an oxygen atom.
  • the aliphatic hydrocarbon group capable of substituting an oxygen atom on the aliphatic hydrocarbon group include straight-chain or branched-chain alkoxy groups having 1 to 20 carbon atoms, alkenyloxy groups having 2 to 20 carbon atoms, and 3 carbon atoms. monovalent groups such as cycloalkyloxy groups of up to 6, divalent groups derived therefrom, and the like. Further, it may have a repeating structure in which an aliphatic hydrocarbon group substituted with an aliphatic hydrocarbon group through an oxygen atom is further substituted with an aliphatic hydrocarbon group through an oxygen atom.
  • R 12 12-docosyloxy-1-dodecyl group, 3,4,5-tris(octadecyloxy)benzyl group, 2,2,2-tris(octadecyloxymethyl)ethyl group, 3,4 , 5-tris(octadecyloxy)cyclohexylmethyl group and the like.
  • the above aliphatic hydrocarbon group may be substituted with an organic group represented by formula (a).
  • R 16 represents a linear or branched alkylene group having 6 to 16 carbon atoms
  • X 3 is an oxygen atom or —C( ⁇ O)NR 17 —(R 17 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms
  • A represents a silyl group or an alkyl group to which a silyloxy group is bonded
  • the silyl group is preferably a silyl group substituted by three groups selected from linear or branched alkyl groups having 1 to 6 carbon atoms and aryl groups which may have a substituent.
  • examples of the aryl group which may have a substituent include a phenyl group and a naphthyl group.
  • a preferred silyl group is a silyl group substituted with three linear or branched alkyl groups having 1 to 6 carbon atoms, more preferably three linear or branched alkyl groups having 1 to 4 carbon atoms. It is a substituted silyl group.
  • the three alkyl groups or aryl groups substituting on the silyl group may be the same or different.
  • one silyloxy group substituted by three selected from linear or branched alkyl groups having 1 to 6 carbon atoms and aryl groups which may have substituents is used as the alkyl group to which the silyloxy group is bonded.
  • a linear or branched alkyl group having 1 to 13 carbon atoms with ⁇ 3 bonds is preferred.
  • a preferred silyloxy group is a silyloxy group substituted with three linear or branched alkyl groups having 1 to 6 carbon atoms, more preferably three linear or branched alkyl groups having 1 to 4 carbon atoms. It is a substituted silyloxy group.
  • the three alkyl groups or aryl groups substituted on the silyloxy group may be the same or different.
  • the linear or branched alkyl group having 1 to 13 carbon atoms is preferably branched, and more preferably has a quaternary carbon atom.
  • p represents an integer of 1 to 4.
  • p is preferably 1-3, more preferably 1-2.
  • Ring A is, in addition to p X 1 R 12 , a halogen atom, a C1-6 alkyl group optionally substituted with a halogen atom, and a C1-6 alkoxy group optionally substituted with a halogen atom may have a substituent selected from the group consisting of Halogen atoms include chlorine, fluorine, bromine and iodine atoms.
  • the C1-6 alkyl group optionally substituted with a halogen atom includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group and a hexyl group. , a dichloromethyl group, a trichloromethyl group, a trifluoromethyl group, and the like.
  • the C1-6 alkoxy group optionally substituted with a halogen atom includes a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a butyloxy group, an isobutyloxy group, a sec-butyloxy group, a tert-butyloxy group, and a trichloromethoxy group. groups, trifluoromethoxy groups, and the like.
  • Ra represents a hydrogen atom or an aromatic ring optionally substituted with a halogen atom.
  • the aromatic ring includes a C6-18 aromatic hydrocarbon ring and a C4-10 aromatic heterocyclic ring.
  • Specific C6-18 aromatic hydrocarbon rings include benzene ring, naphthalene ring, anthracene ring, phenanthrene ring, triphenylene ring, tetracene ring, indane ring, indene ring, fluorene ring and biphenyl ring.
  • a benzene ring, a naphthalene ring, a phenanthrene ring, and a fluorene ring are more preferable.
  • the C4-10 aromatic heterocyclic ring is preferably a 5- to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and specifically, pyrrole. ring, furan ring, thiophene ring, indole ring, benzofuran ring, benzothiophene ring, carbazole ring, pyrazole ring, indazole ring, imidazole ring, pyridine ring, quinoline ring, isoquinoline ring and the like.
  • a 5- to 8-membered heterocyclic ring containing 1 to 3 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a heteroatom is preferable, and a pyrrole ring, a furan ring, a thiophene ring, an indole ring, and a benzofuran ring.
  • benzothiophene ring, carbazole ring, pyrazole ring and indazole ring are more preferred.
  • the aromatic ring of Ra may be substituted with 1 to 3 halogen atoms.
  • Rb represents a hydrogen atom, an aromatic ring optionally substituted with a halogen atom, or a group represented by the above formula (a).
  • q in formula (a) represents an integer of 0-4. q is preferably 0 to 3, more preferably 1 to 3, even more preferably 1 to 2.
  • R 18 represents a hydrogen atom, an alkyl group or an aralkyl group
  • R 18 is preferably a hydrogen atom, a C1-10 alkyl group or a C7-20 aralkyl group.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl groups.
  • Aralkyl groups include C7-16 aralkyl groups such as benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, naphthylmethyl and 1-naphthylethyl groups.
  • q R 14 are independently an aliphatic hydrocarbon group, an aliphatic hydrocarbon group substituted with an aliphatic hydrocarbon group via an oxygen atom, or an organic group represented by formula (a) show.
  • R 16 represents a linear or branched alkylene group having 6 to 16 carbon atoms
  • R 17 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms
  • A represents either a silyl group or an alkyl group to which a silyloxy group is attached.
  • Examples of the organic group represented by R 14 include the same groups as those for R 12 above, and preferably the same groups as those for R 12 above.
  • R 13 represents a hydrogen atom, represents a single bond together with R 11 to form a fluorene ring together with ring A and ring B, or forms a xanthene ring together with ring A and ring B through an oxygen atom. may be formed.
  • Ring B in addition to q X 2 R 14 , further comprises a halogen atom, a C1-6 alkyl group optionally substituted with a halogen atom, and a C1-6 alkoxy group optionally substituted with a halogen atom may have a substituent selected from the group consisting of Halogen atoms include chlorine, fluorine, bromine and iodine atoms.
  • the C1-6 alkyl group optionally substituted with a halogen atom includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group and a hexyl group. , a dichloromethyl group, a trichloromethyl group, a trifluoromethyl group, and the like.
  • the C1-6 alkoxy group optionally substituted with a halogen atom includes a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a butyloxy group, an isobutyloxy group, a sec-butyloxy group, a tert-butyloxy group, and a trichloromethoxy group. groups, trifluoromethoxy groups, and the like.
  • Y represents a hydroxy group, a thiol group, NHR 20 (R 20 represents a hydrogen atom, an alkyl group or an aralkyl group) or a halogen atom.
  • R 20 is preferably a hydrogen atom, a C1-10 alkyl group or a C7-20 aralkyl group.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl groups.
  • Aralkyl groups include C7-16 aralkyl groups such as benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, naphthylmethyl and 1-naphthylethyl groups.
  • Yb is --CH 2 OR 34 (wherein R 34 represents a hydrogen atom, a halogenocarbonyl group, an active ester carbonyl group or an active ester sulfonyl group), --CH 2 NHR 35 (wherein R 35 represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, or an aralkyl group), a halogenomethyl group, a formyl group, or an oxime, and R 21 , R 22 , R 23 , R 24 and at least one of R 25 represents a group represented by formula (8), the remainder represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms;
  • R 26 represents a linear or branched alkylene group having 6 to 16 carbon atoms
  • X 3 represents O or CONR 36 (wherein R 36 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms);
  • A is represented by formula (9), (10), (11), (12), (13), (14), (15), (16), (17), (18) or (19) indicates a group.
  • R 27 , R 28 and R 29 are the same or different and represent a linear or branched alkyl group having 1 to 6 carbon atoms or an aryl group which may have a substituent; 30 represents a single bond or a linear or branched alkylene group having 1 to 3 carbon atoms, and R 31 , R 32 and R 33 each represent a linear or branched alkylene group having 1 to 3 carbon atoms)
  • the compound represented by formula (20) can be used as a carrier for liquid-phase peptide synthesis (Patent Documents 15, 16, 19).
  • R 51 represents a hydrogen atom, an active ester carbonyl group or an active ester sulfonyl group
  • R 51 represents a hydrogen atom, an active ester carbonyl group or an active ester sulfonyl group
  • —NHR 35 azide, halogen, isocyanate
  • X 5 is a hydrogen atom or a linear or branched alkyl or alkenyl group having 1 to 4 carbon atoms , or represents a cycloalkyl group
  • X 4 isocyanate
  • X 5 represents a linear or branched alkyl group or alkenyl group having 1 to 4 carbon atoms, or a cycloalkyl group
  • At least one of R 41 to R 50 represents a group represented by formula (2), and the remainder represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an
  • the compound represented by formula (21) can be used as a carrier for liquid-phase peptide synthesis (Patent Documents 17 and 18).
  • X 6 represents a hydroxy group or a halogen atom
  • at least one of R 61 to R 75 represents a group represented by formula (2), and the remainder are hydrogen atoms, halogen atoms, and 1 carbon atom.
  • 4 alkyl group or alkoxy group having 1 to 4 carbon atoms; may form
  • Patent Documents 7 to 25, etc. can be referred to, and can be carried out by methods well known to those skilled in the art.
  • step c as a method for separating the peptide bound to the carrier for liquid-phase peptide synthesis, the difference in solubility in a solvent between the peptide bound to the carrier for liquid-phase peptide synthesis and unnecessary components is used to purify by solidification. It is also possible to
  • Cbz-Lys-OH, EtNH-C(SO 3 H) NEt
  • Cbz-hArg(Et) 2 -OH, Cbz-hArg(Et) 2 (Boc) 2 -OH, H-hArg(Et) 2 (Boc) 2 -OH, Fmoc-OSu and Fmoc-hArg(Et) 2 (Boc) 2 -OH represent the structures in the above reaction formula, where Cbz-hArg(Et) 2 (Boc) 2 -OH , H-hArg(Et) 2 (Boc) 2 -OH, and Fmoc-hArg(Et) 2 (Boc) 2 -OH each represent a mixture of three isomers in the reaction formula.
  • Example (1-a) Cbz-Lys-OH 2.00 g (7.13 mmol) was dissolved in a mixed solution of water 7.13 mL, acetonitrile 7.13 mL, 20% sodium hydroxide aqueous solution (20% NaOHaq.) 1.28 mL, EtNH-C ( SO 3 H) NEt 2.25 g (12.5 mmol) was added and stirred at room temperature. Then 20% NaOHaq. 301 ⁇ L was added in small portions and stirred at room temperature for 22 hours and 30 minutes while maintaining the pH of the reaction solution at 8.0 to 12.8. Acetonitrile 7.13 mL, ethyl acetate 18.8 mL, 6N HClaq.
  • Example (1-b) 6.57 g (30.1 mmol) of di-tert-butyl dicarbonate was dissolved in 30.1 mL of 1,4-dioxane. To this solution was added 7.53 mL of 1,4-dioxane and 5N NaOHaq. Cbz-hArg(Et) 2 -OH 1.71 g (4.52 mmol) dissolved in 15.1 mL was added dropwise and stirred at room temperature for 17 hours. 126 mL of dichloromethane, 93.0 mL of water, and 3.70 mL of acetic acid were added and separated. The obtained organic layer was washed with 93.0 mL of saturated saline.
  • Example (1-c) 2.09 g (3.61 mmol) of Cbz-hArg(Et) 2 (Boc) 2 -OH was dissolved in 20.9 mL of methanol, and 0.139 g of 5% Pd/C (wet with ca. 55% water) was added. under a hydrogen atmosphere at room temperature for 2 hours. The reaction solution was filtered through celite, and the filtrate was washed with 20 mL of methanol. The obtained filtrate was concentrated under reduced pressure and then dried under reduced pressure to obtain 1.28 g of H-hArg(Et) 2 (Boc) 2 -OH. ESIMS (m/z) 445.4 (M+H) + (mixture of 3 isomers)
  • Example (1-d) 0.427 g (5.08 mmol) of sodium bicarbonate and 1.13 g (2.54 mmol) of H-hArg(Et) 2 (Boc) 2 -OH were added to 9.99 mL of water, dissolved, and cooled to 5°C. 0.900 g (2.67 mmol) of Fmoc-OSu dissolved in 9.99 mL of 1,4-dioxane was added dropwise to this solution, and the mixture was stirred at 5° C. for 1 hour and 5 minutes. The temperature was raised to room temperature, and the mixture was stirred for 3 hours and 25 minutes.
  • Cbz-D-Lys-OH, Cbz-D-hArg(Et) 2 -OH, Cbz-D-hArg(Et) 2 (Boc) 2 -OH, HD-hArg(Et) 2 (Boc ) 2 -OH, Fmoc-D-hArg(Et) 2 (Boc) 2 -OH represent structures in the reaction formula, where Cbz-D-hArg(Et) 2 (Boc) 2 -OH, HD -hArg(Et) 2 (Boc) 2 -OH and Fmoc-D-hArg(Et) 2 (Boc) 2 -OH each represent a mixture of three isomers in the reaction formula.
  • Example (2-a) 4.57 g of Cbz-D-hArg(Et) 2 -OH was obtained from 4.80 g of Cbz-D-Lys-OH in the same manner as in Example (1-a).
  • CPME cyclopentyl methyl ether
  • DMF N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • AEE 2-(2-Aminoethoxy)ethanol
  • Example (3-c) To the resulting mixture, CPME 2.20 mL, DMF 8.30 mL, Fmoc-Pro-OH.H 2 O 0.782 g (2.20 mmol), DIPEA 1.28 mL (7.33 mmol), COMU 0.942 g ( 2.20 mmol) was added and stirred at room temperature for 50 minutes. 44.0 ⁇ L (0.444 mmol) of AEE was added, and the mixture was stirred at room temperature for 15 minutes.
  • Comparative examples (1-a), (1-b), (1-c) H-Pro-D-Ala-NH(D2-STag) was prepared from 2.00 g (1.83 mmol) of Fmoc-NH(D2-STag) in the same manner as in Examples 3-a, 3-b, and 3-c.
  • Example 3-d shows the interface between the organic layer and the aqueous layer, and the liquid-liquid separation was good.
  • the comparative example (1-d) shown in FIG. 2 shows the entire inside of the separating funnel, and the emulsion did not disappear even after standing at room temperature for 25 minutes, and the organic layer and the aqueous layer could be separated. I didn't.
  • Table 1 shows the results of Example 3 and Comparative Example 1.
  • Example 3 using Boc-protected Fmoc-hArg(Et) 2 (Boc) 2 -OH of the present invention, liquid separation was good and the purity of the target product was as high as 76.2%. We were able to synthesize a peptide with On the other hand, in Comparative Example 1 using Fmoc-hArg(Et) 2 -OH.HCl, which was only proton-protected instead of the Boc group, liquid separation was not possible, and the purity of the target product in the emulsion was 10. It was remarkably low at 4%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne les éléments suivants : un composé d'arginine protégé par guanidyle qui, lorsqu'il est utilisé dans une réaction de synthèse peptidique en phase liquide, rend possible une séparation liquide-liquide satisfaisante ; et un procédé de synthèse peptidique au cours duquel le composé d'arginine protégé par guanidyle est utilisé.　La présente invention concerne un dérivé d'arginine de formule (1), (2), ou (3) ou un de ses sel. (Dans les formules, R1 et R2 sont identiques ou différents et représentent chacun un atome d'hydrogène ou un groupe alkyle en C1 à C4, A représente un atome d'hydrogène ou un groupe amino-protecteur, R3 et R4 représentent chacun un atome d'hydrogène ou un groupe Boc, à condition qu'au moins l'un d'entre eux soit un groupe Boc, R5 et R6 représentent chacun un atome d'hydrogène ou un groupe Boc, à condition qu'au moins l'un d'eux soit un groupe Boc, R7 et R8 représentent chacun un atome d'hydrogène ou un groupe Boc, à condition qu'au moins l'un d'eux soit un groupe Boc, et n représente un nombre entier de 1 à 6 (à condition que soit exclu le cas où n est 3, R1 et R2 sont chacun un atome d'hydrogène ou un groupe méthyle, et R3 à R8 sont des groupes Boc).
PCT/JP2022/032699 2021-09-01 2022-08-31 Dérivé d'arginine WO2023033016A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2021142161A JP2025001049A (ja) 2021-09-01 2021-09-01 アルギニン誘導体
JP2021-142161 2021-09-01

Publications (1)

Publication Number Publication Date
WO2023033016A1 true WO2023033016A1 (fr) 2023-03-09

Family

ID=85411318

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2022/032699 WO2023033016A1 (fr) 2021-09-01 2022-08-31 Dérivé d'arginine

Country Status (3)

Country Link
JP (1) JP2025001049A (fr)
TW (1) TW202328059A (fr)
WO (1) WO2023033016A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024071178A1 (fr) * 2022-09-28 2024-04-04 積水メディカル株式会社 Procédé de production d'un composé benzylamine à substitution alkylsilyloxy

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5962556A (ja) * 1982-06-10 1984-04-10 シンテツクス（ユ−・エス・エ−）インコ−ポレイテイド 非天然アミノ酸
JP2002516342A (ja) * 1998-05-22 2002-06-04 アボット・ラボラトリーズ 抗血管新生作用を有するペプチド医薬
JP2017526620A (ja) * 2014-06-10 2017-09-14 アムジェン インコーポレイテッド アペリンポリペプチド
WO2019118878A1 (fr) * 2017-12-15 2019-06-20 Stealth Biotherapeutics Corp. Peptides ciblant les mitochondries

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5962556A (ja) * 1982-06-10 1984-04-10 シンテツクス（ユ−・エス・エ−）インコ−ポレイテイド 非天然アミノ酸
JP2002516342A (ja) * 1998-05-22 2002-06-04 アボット・ラボラトリーズ 抗血管新生作用を有するペプチド医薬
JP2017526620A (ja) * 2014-06-10 2017-09-14 アムジェン インコーポレイテッド アペリンポリペプチド
WO2019118878A1 (fr) * 2017-12-15 2019-06-20 Stealth Biotherapeutics Corp. Peptides ciblant les mitochondries

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL SOCIETY OF JAPAN: "NEW LECTURES ON EXPERIMENTAL CHEMISTRY", 1 January 2005, MARUZEN, TOKYO, , JP , ISBN: 4-621-07315-X, article CHEMICAL SOCIETY OF JAPAN: "Passage; Lecture on Experimental Chemistry 5th Edition Synthesis of 16 Organic Chemicals IV—Carboxylic Acids, Amino Acids, Peptides", pages: 243 - 246, XP009544042 *
DAISUKE TAKAHASHI; TATSUJI INOMATA; TATSUYA FUKUI: "AJIPHASE®: A Highly Efficient Synthetic Method for One‐Pot Peptide Elongation in the Solution Phase by an Fmoc Strategy", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, VERLAG CHEMIE, HOBOKEN, USA, vol. 56, no. 27, 7 June 2017 (2017-06-07), Hoboken, USA, pages 7803 - 7807, XP072088667, ISSN: 1433-7851, DOI: 10.1002/anie.201702931 *
GAZDIK MICHELLE; JARMAN KATE E.; O’NEILL MATTHEW T.; HODDER ANTHONY N.; LOWES KYM N.; JOUSSET SABROUX HELENE; COWMAN ALAN F.: "Exploration of the P3region of PEXEL peptidomimetics leads to a potent inhibitor of thePlasmodiumprotease, plasmepsin V", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 24, no. 9, 16 March 2016 (2016-03-16), AMSTERDAM, NL, pages 1993 - 2010, XP029500706, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2016.03.027 *
SARA TOMMASI, CHIARA ZANATO, REY CARABEO, ARDUINO MANGONI, SERGIO DALL’ANGELO, MATTEO ZANDA: "An Efficient Route to N-Monosubstituted Guanidino-Lactams", SYNTHESIS, GEORG THIEME VERLAG, STUTTGART, DE., vol. 47, no. 19, 17 September 2015 (2015-09-17), STUTTGART, DE. , pages 3067 - 3078, XP055483066, ISSN: 0039-7881, DOI: 10.1055/s-0034-1378845 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024071178A1 (fr) * 2022-09-28 2024-04-04 積水メディカル株式会社 Procédé de production d'un composé benzylamine à substitution alkylsilyloxy

Also Published As

Publication number Publication date
TW202328059A (zh) 2023-07-16
JP2025001049A (ja) 2025-01-08

Similar Documents

Publication Publication Date Title
JP6092513B2 (ja) フルオレン化合物
JP7139511B2 (ja) ペプチド化合物の製造方法、保護基形成用試薬、及び、縮合多環芳香族炭化水素化合物
CN107810189B (zh) 用于制备氮芥衍生物的方法
WO2015198505A1 (fr) Procédé de production d'un pentapeptide synthétique
JP2023007949A (ja) Ｆｍоｃ基を除去する方法
WO2023033016A1 (fr) Dérivé d'arginine
WO2019049824A1 (fr) Dérivé de l-carnosine protégé, l-carnosine et procédé de production d'un complexe l-carnosine-zinc cristallin
TWI816708B (zh) 用於合成環狀縮肽的方法
WO2023033015A1 (fr) Procédé de production d'un composé contenant un groupe amino protégé par fmoc
WO2023033017A1 (fr) Procédé pour la production de ganirélix ou d'un sel de celui-ci
CN105936626B (zh) 一种氨基保护基的制备方法
JP5807140B1 (ja) 合成ペンタペプチドの製造法
EP2231670A2 (fr) Procédé de préparation de dérivés d'acide 2-((amino primaire/secondaire)hydrocarbyl) carbamoyl-7-oxo-2,6-diazabicycloý3.2.0.¨heptane-6-sulfonique
SK16332002A3 (sk) Spôsob prípravy bifenylových zlúčenín
EP4081503A1 (fr) Procédé de synthèse de melphalan
JP2020529472A (ja) ペプチド化合物の環化放出関連する出願の相互参照
CA2694320C (fr) Procede de fabrication d'un derive de n-(halopropyl)amino acide optiquement actif
JP5420549B2 (ja) エピポドフィロトキシンの（ポリ）アミノアルキルアミノアセトアミドの抗腫瘍性誘導体の合成方法
JP5982720B2 (ja) 高分子固体状支持体を用いたヒスチジル−プロリンアミド誘導体の製造方法
CN119859139A (zh) 双盐酸安罗替尼的固体形式及其制备方法
TWI430996B (zh) 製備富含鏡像異構物之ｎ－羧酸酐之方法
JP2017516790A (ja) Ａｚｄ５３６３の製造方法およびそれに用いられる新規中間体
WO2013140331A1 (fr) Nouveaux dérivés de 1,2,4-oxadiazole, leur procédé de préparation et utilisation de ceux-ci comme intermédiaires dans la préparation d'alcaloïdes indoliques
WO2022196797A1 (fr) Procédé de production d'un acide aminé ou d'un peptide, réactif pour former un groupe protecteur, et composé
JP2019131532A (ja) 酸無水物、および該酸無水物を用いたｌ−カルノシンの製造方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22864598

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22864598

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载