WO2023210692A1 - ポリペプチド化合物の製造方法 - Google Patents

ポリペプチド化合物の製造方法 Download PDF

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WO2023210692A1
WO2023210692A1 PCT/JP2023/016457 JP2023016457W WO2023210692A1 WO 2023210692 A1 WO2023210692 A1 WO 2023210692A1 JP 2023016457 W JP2023016457 W JP 2023016457W WO 2023210692 A1 WO2023210692 A1 WO 2023210692A1
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group
formula
compound
groups
peptide
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French (fr)
Japanese (ja)
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尚 山本
倫弘 服部
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Chubu University
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Chubu University
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Priority to EP23796432.5A priority Critical patent/EP4516799A4/en
Priority to US18/859,216 priority patent/US20250296954A1/en
Priority to JP2023574848A priority patent/JP7674770B2/ja
Publication of WO2023210692A1 publication Critical patent/WO2023210692A1/ja
Priority to JP2024177370A priority patent/JP2025004189A/ja
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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
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
    • C07K1/063—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups for alpha-amino functions
    • 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
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/08—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using activating agents
    • C07K1/088—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using activating agents containing other elements, e.g. B, Si, As
    • 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 novel method for producing polypeptide compounds.
  • Non-patent Documents 1 to 3 Non-patent Documents 1 to 3
  • amidation which is the most important step in peptide synthesis
  • the cost of disposal and purification of by-products accounts for most of the costs of peptide synthesis and is one of the biggest barriers to the development of this field.
  • Peptide synthesis using amino acids or their derivatives as raw materials requires highly stereoselective amidation.
  • Highly stereoselective amidation includes in vivo enzymatic reactions.
  • peptides are synthesized with extremely high stereoselectivity by skillfully utilizing enzymes and hydrogen bonds.
  • enzymatic reactions are not suitable for mass production, and when applied to synthetic chemistry, require enormous financial and time costs.
  • amidation using catalysts is also being considered, but in conventional methods, amide bonds are formed mainly by activating carboxylic acids, resulting in rapid racemization and high yields. It is difficult to stereoselectively and efficiently synthesize amide compounds.
  • ligation Chemical Ligation
  • Amidation methods for ligation of such peptides include a method in which an amino acid having a sulfur atom is used and ligation is performed by utilizing the high reactivity of the sulfur atom (Non-Patent Document 4), and a method in which a hydroxyamine of an amino acid is synthesized.
  • Non-patent Document 5 a method of ligation using the high reactivity of hydroxyamine is known (Non-patent Document 5), but the former is difficult to synthesize amino acids with sulfur atoms, and the latter requires several steps of hydroxyamine synthesis. Since these methods are required separately, they are both time-consuming and costly, and have difficulty in terms of efficiency.
  • Patent Document 1 A method of amidating a carboxylic acid/ester compound having a hydroxy group at the ⁇ -position in the presence of a specific metal catalyst (Patent Document 1), using a hydroxyamino/imino compound as an amino acid precursor, and A method in which a carboxylic acid/ester compound is amidated in the presence of a specific metal catalyst and then reduced in the presence of a specific metal catalyst (Patent Document 2), A method in which a carboxylic acid/ester compound is amidated in the presence of a specific metal catalyst (Patent Document 2) A technique for synthesizing amide compounds with high chemoselectivity has been developed, such as in Patent Document 3).
  • the carboxyl group of the N-terminally protected amino acid/peptide and the amino group of the C-terminally protected amino acid/peptide are subjected to an amide reaction in the presence of a specific silylating agent (and a Lewis acid catalyst optionally used in combination).
  • a specific silylating agent and a Lewis acid catalyst optionally used in combination.
  • Patent Document 4 technology for highly efficient and highly selective synthesis of peptides consisting of various amino acid residues by deprotection (Patent Document 4); Synthesize peptides composed of various amino acid residues with high efficiency and high selectivity by subjecting the amino groups of protected or unprotected amino acids and peptides to an amide reaction in the presence of a specific silylating agent, followed by deprotection.
  • Patent Documents 5 and 6 technology to carry out an amidation reaction using Br ⁇ nsted acid as a catalyst
  • Patent Document 7 a novel silane-containing condensed ring dipeptide compound, and a novel method for synthesizing peptides using the same.
  • Patent Document 8 a novel peptide synthesis method using regioselective C—N bond cleavage of lactams
  • the peptide bond-forming reaction has lower reactivity than a normal amidation reaction, and it is difficult to complete the reaction within the channel.
  • the use of a condensing agent which is essential in conventional peptide synthesis reactions, causes clogging in the flow path.
  • undesired side reactions may occur, such as unreacted amino acids mixed in the first stage unintentionally reacting with the amino acids to be subjected to the amidation reaction in the second stage. For this reason, it has conventionally been extremely difficult to perform a peptide synthesis reaction continuously by flow reaction.
  • an N-terminally protected amino acid or peptide ester (R1 ) is used as an electrophilic compound, and this is mixed with a nucleophilic compound such as an amino acid or peptide or its ester (R2) to cause a peptide bond reaction, and then the N-terminally protected amino acid or peptide (S1) obtained by the reaction is ) by deprotecting the N-terminus of the amino acid or peptide (P1), and then subjecting the deprotected amino acid or peptide (P1) as a nucleophilic compound (R2) to a peptide bonding reaction with an electrophilic compound (R1) again.
  • the inventors have discovered that elongation of a peptide chain by a binding reaction can be carried out continuously, making it possible to efficiently synthesize a desired peptide chain, and have thus arrived at the present invention.
  • a method for producing a polypeptide compound comprising: (i) The substituted carboxyl group on the right side of the N-terminal protected amino acid ester or peptide ester compound represented by the following formula (R1) and the amino acid or peptide or amino acid ester or peptide ester compound represented by the following formula (R2) By forming an amide bond between the left amino group and the amino group in the formula, an N-terminally protected peptide compound represented by the following formula (S1) is obtained, (ii) By deprotecting the N-terminus of the compound of formula (S1) obtained in step (i), a peptide compound represented by the following formula (P1) is obtained, (iii) Using the compound of formula (P1) obtained in step (ii) as the compound of formula (R2) in step (i), by repeating steps (i) and (ii), amidation A manufacturing method comprising elongating a peptide chain by In formula
  • R 13 represents a hydrogen atom, a carboxyl group, a hydroxyl group, a monovalent aliphatic hydrocarbon group that may have one or more substituents, an aromatic hydrocarbon group, or a heterocyclic group; , where, in the case of a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group, it may be bonded to the nitrogen atom via a linking group, Alternatively, R 11 and R 13 are bonded to each other to form a heterocycle which may have one or more substituents together with the carbon atom to which R 11 is bonded and the nitrogen atom to which R 13 is bonded.
  • a 11 and A 12 each independently represent a divalent aliphatic hydrocarbon group having 1 to 3 carbon atoms which may have one or more substituents, p11 and p12 each independently represent 0 or 1, n 1 is an integer of 1 or more and represents the number of structural units represented by the structure in [ ]. However, when n 1 is 2 or more, the plurality of structural units represented by the structures in [ ] may be the same or different.
  • T b represents a hydrogen atom or a monovalent substituent
  • R 21 and R 22 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, or a thiol group, or an amino group which may have one or more substituents.
  • R23 represents a hydrogen atom, a carboxyl group, a hydroxyl group, a monovalent aliphatic hydrocarbon group that may have one or more substituents, an aromatic hydrocarbon group, or a heterocyclic group; , where, in the case of a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group, it may be bonded to the nitrogen atom via a linking group, Alternatively, R 21 and R 23 are bonded to each other to form a heterocycle which may have one or more substituents together with the carbon atom to which R 21 is bonded and the nitrogen atom to which R 23 is bonded.
  • a 21 and A 22 each independently represent a divalent aliphatic hydrocarbon group having 1 to 3 carbon atoms which may have one or more substituents, p21 and p22 each independently represent 0 or 1, n 2 is an integer of 1 or more and represents the number of structural units represented by the structure in [ ]. However, when n 2 is 2 or more, the plurality of structural units represented by the structures in [ ] may be the same or different.
  • R 11 , R 12 , R 13 , A 11 , A 12 , p11, p12, and n 1 represent the same groups as defined in the formula (R1), R21 , R22 , R23 , A21 , A22, p21 , p22, n2 , and Tb represent the same groups as defined in formula (R2) above.
  • step (i) The production method according to Item 1 or 2, wherein in the reaction of step (i), the compound of formula (R1) and the compound of formula (R2) are used in a substantially equimolar ratio.
  • the group Ta of formula (R1) is one or Item 4.
  • the protecting group PG a of formula (R1) may have one or more substituents, a monovalent hydrocarbon group, an acyl group, a hydrocarbon oxycarbonyl group, a hydrocarbon sulfonyl group , and an amide group, the production method according to any one of Items 1 to 4.
  • Deprotection of the N-terminal protecting group of formula (S1) in step (ii) is carried out by passing the compound of formula (S1) through a column packed with a basic ion exchange resin. 5.
  • the basic ion exchange resin is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-based resin, 1,5-diazabicyclo[4.3.0]nona-5- Select from ene (DBN)-based resin, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD)-based resin, piperazine-based resin, dimethylaminopyridine-based resin, and ammonium-based resin.
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • DBN 1,8-diazabicyclo[4.3.0]nona-5- Select from ene
  • TBD 1,5,7-triazabicyclo[4.4.0]dec-5-ene
  • piperazine-based resin dimethylaminopyridine-based resin
  • ammonium-based resin ammonium-based resin.
  • FIG. 1 shows the production of the amino acid H 2 N-AA n -AA n-1 -((7)-AA 2 -AA 1 -O-tBu using a preferred embodiment of the production method of the present invention by flow reaction.
  • FIG. 2 is a diagram schematically showing a manufacturing procedure for synthesizing a polypeptide consisting of the sequence (AA 1 , AA 2 , . . . AA n-1 , AA n each represents an amino acid residue).
  • a pentafluorophenyl (Pfp) group is used as the T a group in formula (R1)
  • an Fmoc group is used as the PG a group
  • a t-butyl (tBu) group is used as the T b group in formula (R2).
  • amino acid means a compound having a carboxyl group and an amino group.
  • the type of amino acid is not particularly limited.
  • it may be a D form, an L form, or a racemic form.
  • it may be any of ⁇ -amino acids, ⁇ -amino acids, ⁇ -amino acids, ⁇ -amino acids, ⁇ -amino acids, etc.
  • amino acids include, but are not limited to, natural amino acids that constitute proteins, and specific examples include valine, leucine, isoleucine, alanine, arginine, glutamine, lysine, aspartic acid, and glutamic acid. , proline, cysteine, threonine, methionine, histidine, phenylalanine, tyrosine, tryptophan, asparagine, glycine, serine and the like.
  • peptide refers to a compound in which multiple amino acids are linked via peptide bonds.
  • the plurality of amino acid units constituting the peptide may be of the same type, or may be two or more different types of amino acid units.
  • the number of amino acids constituting the peptide is not particularly limited as long as it is 2 or more. Examples include 2 (also referred to as a "dipeptide"), 3 (also referred to as a "tripeptide"), 4 (also referred to as a "tetrapeptide”), 5 (also referred to as a "pentapeptide"), 6, 7, 8, 9 , 10, 15, 20, 30, 40, 50, 100, or more.
  • a peptide larger than a tripeptide is sometimes referred to as a "polypeptide.”
  • an "amino group” refers to a group obtained by removing hydrogen from ammonia, a primary amine, or a secondary amine, each having the formula -NH 2 , -NRH, or -NRR' (where R and R' each means a substituent.) means a functional group represented by.
  • hydrocarbon groups may be aliphatic or aromatic.
  • the aliphatic hydrocarbon group may be chain or cyclic.
  • the chain hydrocarbon group may be linear or branched.
  • the cyclic hydrocarbon group may be monocyclic, bridged cyclic, or spirocyclic.
  • the hydrocarbon group may be saturated or unsaturated, in other words may contain one or more carbon-carbon double bonds and/or triple bonds.
  • hydrocarbon group is a concept that includes an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, an aryl group, an arylalkyl group, an alkylaryl group, and the like.
  • one or more hydrogen atoms in the hydrocarbon group may be substituted with any substituent, and one or more carbon atoms in the hydrocarbon group may be substituted with any substituent depending on the valence. It may be replaced with any heteroatom.
  • hydrocarbon oxy group means a group in which the above-defined hydrocarbon group is connected to one bond of an oxy group (-O-). That is, the term “hydrocarbonoxy group” includes alkyloxy groups, alkenyloxy groups, alkynyloxy groups, cycloalkyloxy groups, cycloalkenyloxy groups, cycloalkynyloxy groups, aryloxy groups, and the like.
  • a "heterocyclic group” may be saturated or unsaturated, in other words, it may contain one or more carbon-carbon double bonds and/or triple bonds. Further, the heterocyclic group may be monocyclic, bridged cyclic, or spirocyclic. Furthermore, the heteroatoms contained in the heterocyclic atoms of the heterocyclic group are not limited, but examples include nitrogen, oxygen, sulfur, phosphorus, silicon, and the like.
  • heterocyclic oxy group means a group in which the above-defined heterocyclic group is connected to one bond of an oxy group (-O-).
  • a "metaloxy group” (which may have one or more substituents) means a group represented by the formula (R) n -M-O-.
  • M means any metal element
  • R means any substituent
  • n means an integer of 0 or more and 8 or less that can be taken depending on the coordination number of the metal element M. do.
  • substituted refers to any substituent, which is not particularly limited as long as the amidation step in the production method of the present invention proceeds, unless otherwise specified.
  • substituent examples include, but are not limited to, halogen atoms, hydroxyl groups, carboxyl groups, nitro groups, cyano groups, thiol groups, sulfonic acid groups, amino groups, amide groups, imino groups, imido groups, hydrocarbon groups , heterocyclic group, hydrocarbonoxy group, hydrocarbon carbonyl group (acyl group), hydrocarbon oxycarbonyl group, hydrocarbon carbonyloxy group, hydrocarbon-substituted amino group, hydrocarbon-substituted aminocarbonyl group, hydrocarbon carbonyl-substituted amino group, hydrocarbon-substituted thiol group, hydrocarbon sulfonyl group, hydrocarbon oxysulfonyl group, hydrocarbon sulfonyloxy group, heterocyclic oxy group, heterocyclic oxy group, heterocyclic
  • amino acids and their residues may be represented by three-letter abbreviations that are well known to those skilled in the art.
  • the three letter abbreviations of the main amino acids used in this disclosure are shown in the table below.
  • ⁇ -homoamino acids and their residues may be represented by adding “Ho” in front of the three-letter abbreviation of the corresponding ⁇ -amino acid.
  • One aspect of the present invention is a method for producing a polypeptide compound, which includes at least the following steps (i) to (iii) (hereinafter referred to as the "method for producing a peptide compound of the present invention” or simply “method for producing a peptide compound of the present invention” as appropriate). (referred to as “the manufacturing method of the present invention”).
  • an N-terminally protected amino acid or peptide ester (R1) whose C-terminus has been esterified with an aromatic hydrocarbon group or a heterocyclic group Ta having an electron-withdrawing substituent is electrophilic.
  • step (i) This is mixed with a nucleophilic compound such as an amino acid or peptide or its ester (R2) to form a peptide bond (condensation reaction) (step (i)), and the N-terminally protected amino acid obtained by the reaction is Alternatively, the N-terminus of the peptide (S1) is deprotected (step (ii)), and then the deprotected amino acid or peptide (P1) is used as a nucleophilic compound (R2) again to form an electrophilic compound (R1). (step (iii)).
  • the peptide chain can be continuously extended by the peptide bonding reaction, and a desired peptide chain can be efficiently synthesized.
  • electrophilic By using it as a seed, the reactivity of the electrophilic amino acid can be dramatically improved, and the reaction can proceed quantitatively even when the molar ratio of electrophilic amino acid to nucleophilic amino acid is close to 1:1. becomes possible. This can prevent the generation of surplus amino acids that do not participate in the reaction, and can avoid side reactions caused by unreacted substances.
  • N-terminal protecting group PG a of the electrophilic amino acid or peptide ester (R1)
  • a specific protecting groups can be used as the N-terminal protecting group PG a of the electrophilic amino acid or peptide ester (R1).
  • This allows a peptide bonding reaction (step (i)) by mixing the electrophilic N-terminal amino acid or peptide ester (R1) with the nucleophilic amino acid or peptide (R2), and the N-terminal Deprotection of the protected amino acid or peptide (S1) using a basic ion exchange resin (step (ii)) can be carried out continuously as a series of reactions.
  • the deprotected amino acid or peptide (P1) is used as a nucleophilic compound (R2) to undergo a peptide bonding reaction with the electrophilic compound (R1) again (step (iii)), and by repeating the above, Elongation of a peptide chain by a peptide bonding reaction can be carried out continuously by a flow reaction, making it possible to efficiently synthesize a desired peptide chain.
  • Non-patent document 7 J. Med. Chem., 2001, 44, 3896-3903
  • Non-patent document 8 Chem. Eur. J., 2019, 25, 15759-15764
  • Non-patent document 9 Org. Biomol. Chem., 2003, 1, 965-972
  • Non-Patent Document 10 J. Org. Chem., 1995, 60, 6, 1733-1740
  • R 11 , R 12 , R 21 , and R 22 each independently have a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, or a thiol group, or one or more substituents.
  • the type is as described above. Specific examples of the number of substituents are, for example, 5, 4, 3, 2, 1, or 0.
  • R 11 , R 12 , R 21 , and/or R 22 is a monovalent hydrocarbon group or a heterocyclic group that may have one or more substituents
  • a linking group may be present between the hydrocarbon group or heterocyclic group and the carbon atom to which it is bonded.
  • Such linking groups are not limited to, but are each independently selected from, for example, the structures shown below (in the following chemical formula, each A independently has one or more substituents). represents a monovalent hydrocarbon group or a heterocyclic group, which may be a monovalent hydrocarbon group or a heterocyclic group. If two A's are present in the same group, they may be the same or different.)
  • the number of carbon atoms in the hydrocarbon group is not particularly limited, but the upper limit is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less.
  • the lower limit varies depending on the type of hydrocarbon group, but is 1 or more for alkyl groups, 2 or more for alkenyl or alkynyl groups, and 3 or more for cycloalkyl groups, such as 4 or more, or 5 or more.
  • Specific examples of the number of atoms include, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. It is.
  • the total number of carbon atoms and heteroatoms of the heterocyclic group is not particularly limited, but the upper limit is, for example, 20 or less, 15 or less, 10 or less, 8 or less, Or 6 or less.
  • the lower limit varies depending on the type of heterocyclic structure, but is usually 3 or more, for example 4 or more, or 5 or more. Specific examples of the number of atoms are, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • R 11 , R 12 , R 21 , and R 22 are each independently a hydrogen atom, a hydroxyl group, a thiol group, a carboxyl group, a nitro group, a cyano group, or a halogen atom, or one or more substituted It is preferably an amino group, an alkyl group, an alkenyl group, a cycloalkyl group, an alkoxy group, an aryl group, an aryloxy group, an acyl group, a heterocyclic group, a heterocyclic oxy group, etc., which may have a group. .
  • R 11 , R 12 , R 21 , and R 22 include, but are not limited to, the following.
  • ⁇ Hydrogen atom hydroxyl group, thiol group, carboxyl group, nitro group, cyano group
  • ⁇ Halogen atoms such as fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms
  • the group having a carboxyl group may or may not have a protecting group. Although it differs depending on the reactivity of compound (R1) and compound (R2) used in the reaction, when a group having a carboxyl group among the above groups has a protecting group, usually the right side in the formula of compound (R2) is The reaction selectivity with the carboxylic acid ester group is improved compared to the reaction selectivity with the carboxyl group present in other substituents.
  • R 13 and R 23 each independently represent a hydrogen atom, a carboxyl group, a hydroxyl group, or a monovalent hydrocarbon group or a heterocyclic group which may have one or more substituents. .
  • substituents when a substituent is present, the type thereof is as described above. Specific examples of the number of substituents are, for example, 5, 4, 3, 2, 1, or 0.
  • R 13 and/or R 23 is a monovalent hydrocarbon group or a heterocyclic group which may have one or more substituents
  • a linking group may be present between the formula group and the nitrogen atom to which it is bonded.
  • Such linking groups are not limited to, but are each independently selected from, for example, the structures shown below (in the following chemical formula, each A independently has one or more substituents).
  • the upper limit of the number of carbon atoms in the hydrocarbon group is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less.
  • the lower limit varies depending on the type of hydrocarbon group, but is 1 or more for alkyl groups, 2 or more for alkenyl or alkynyl groups, and 3 or more for cycloalkyl groups, such as 4 or more, or 5 or more.
  • Specific examples of the number of atoms include, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. It is.
  • the upper limit of the total number of carbon atoms and heteroatoms of the heterocyclic group is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less.
  • the lower limit varies depending on the type of heterocyclic structure, but is usually 3 or more, for example 4 or more, or 5 or more. Specific examples of the number of atoms are, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • R 13 and R 23 are each independently a hydrogen atom, a hydroxyl group, or a carboxyl group, or an alkyl group, an alkenyl group, a cycloalkyl group, which may have one or more substituents, Preferably, it is an alkoxy group, an aryl group, an aryloxy group, an acyl group, a heterocyclic group, a heterocyclic oxy group, or the like.
  • R 13 and R 23 include, but are not limited to, the following.
  • ⁇ Hydrogen atom hydroxyl group, carboxyl group
  • R 11 and R 13 are bonded to each other to form a heterocycle which may have one or more substituents together with the carbon atom to which R 11 is bonded and the nitrogen atom to which R 13 is bonded.
  • a heterocyclic ring in which R 21 and R 23 are bonded to each other, and the carbon atom to which R 21 is bonded and the nitrogen atom to which R 23 is bonded may have one or more substituents. may be formed.
  • the type thereof is as described above. Specific examples of the number of substituents are, for example, 5, 4, 3, 2, 1, or 0.
  • the upper limit of the total number of carbon atoms and heteroatoms of the heterocyclic group is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less.
  • the lower limit varies depending on the type of heterocyclic structure, but is usually 3 or more, for example 4 or more, or 5 or more. Specific examples of the number of atoms are, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • heterocycles include, but are not limited to, pyrrolinyl, pyrrolyl, 2,3-dihydro-1H-pyrrolyl, piperidinyl, piperazinyl, homopiperazinyl, and morpholino groups.
  • thiomorpholino group 1,2,4,6-tetrahydropyridyl group, hexahydropyrimidyl group, hexahydropyridazyl group, 1,2,4,6-tetrahydropyridyl group, 1,2,4,6 -tetrahydropyridazyl group, 3,4-dihydropyridyl group, imidazolyl group, 4,5-dihydro-1H-imidazolyl group, 2,3-dihydro-1H-imidazolyl group, pyrazolyl group, 4,5-dihydro-1H -pyrazolyl group, 2,3-dihydro-1H-pyrazolyl group, oxazolyl group, 4,5-dihydro-1,3-oxazolyl group, 2,3-dihydro-1,3-oxazolyl group, 2,5-dihydro- 1,3-oxazolyl group, thiazolyl group,
  • a 11 , A 12 , A 21 and A 22 each independently represent a divalent aliphatic hydrocarbon group having 1 to 3 carbon atoms which may have one or more substituents.
  • substituents include, but are not limited to, methylene groups, ethylene groups, propylene groups, isopropylene groups, and groups in which these groups are substituted with one or more of the above substituents. Can be mentioned.
  • Specific examples of the number of substituents are, for example, 3, 2, 1, or 0.
  • p11, p12, p21, and p22 each independently represent 0 or 1.
  • n 1 is an integer of 1 or more representing the number of amino acid units in [ ] in general formula (R1).
  • n 1 is 1, the compound (R1) is an amino acid, and when n 1 is 2 or more, the compound (R1) is a peptide.
  • the upper limit of n1 is not particularly limited as long as the amination step proceeds, but is, for example, 100 or less, 80 or less, 60 or less, 50 or less, 40 or less, 30 or less, 20 or less, 15 or less, 12 or less, or 10 or less. etc.
  • Specific examples of n 1 are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30 , 35, 40, 45, 50, 60, 70, 80, 90, 100, etc.
  • n 2 is an integer of 1 or more representing the number of amino acid units in [ ] in general formula (R2).
  • n 2 is 1, the compound (R2) is an amino acid, and when n 2 is 2 or more, the compound (R2) is a peptide.
  • the upper limit of n2 is not particularly limited as long as the amination step proceeds, and examples thereof include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and the like.
  • R 11 , R 12 , R 13 , A 11 , A 12 , p11, and p12 defining the structure in [ ] are Amino acid units may be the same or different.
  • R 21 , R 22 , R 23 , A 21 , A 22 , p21, and p22 defining the structure in [ ] are the same among multiple amino acid units. may be different. That is, when compound (R1) and/or compound (R2) is a peptide, the plurality of amino acid units constituting the peptide may be the same or different.
  • T a represents a monovalent aromatic hydrocarbon group or a heterocyclic group having one or more electron-withdrawing substituents. Details of T a will be described later.
  • T b represents a hydrogen atom or a monovalent substituent.
  • the type thereof is not particularly limited, but in addition to the groups mentioned above as R 13 and R 23 , protective groups for carboxyl groups (hereinafter referred to as PG b as appropriate) may be mentioned. It will be done.
  • the carboxyl group protecting group PG b is not particularly limited as long as it can protect the carboxyl group from reacting in the amidation reaction and can be deprotected and converted into a carboxyl group after the reaction. . Details of the carboxyl group protecting group PG b will be described later.
  • the amino group on the left side of the formula may form a salt with another acid.
  • other acids include, but are not limited to, aliphatic carboxylic acids having 1 to 5 carbon atoms such as acetic acid and propionic acid; trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and nitric acid. , phosphoric acid, boric acid, sulfonic acid and the like.
  • each of the above-mentioned substrate compounds (R1) and (R2) may be used singly, or two or more compounds may be used in combination in any combination and ratio.
  • part or all of the above-mentioned substrate compound (R1) or (R2) may be linked and immobilized to a carrier such as a substrate or a resin at any substituent.
  • a carrier such as a substrate or a resin
  • the type of carrier such as the substrate or resin is not limited. It is possible to use any conventionally known carrier such as a substrate or resin without substantially inhibiting the amide bond reaction in the production method of the present invention and without departing from the spirit of the present invention. There are no limitations on the manner of connection and immobilization between the substrate compound and a carrier such as a substrate or resin, but any substituent that the substrate compound has and a substituent that exists on the carrier such as a substrate or resin. It is preferable to form a covalent bond between them.
  • each substituent or the method for forming a covalent bond there are no limitations on the type of each substituent or the method for forming a covalent bond. Any type of substituent and method for forming a covalent bond known in the art may be used without substantially inhibiting the amide bond reaction in the production method of the present invention and without departing from the spirit of the present invention. It is possible.
  • the substrate compound can be linked/fixed to a carrier such as a substrate or resin by a covalent bond using a carboxyl group or an amino group (other than the carboxylic acid ester group or amino group that is the target of formation of an amide bond reaction) that the substrate compound has.
  • Such an embodiment can be regarded as the same as an embodiment in which a carboxyl group or an amino group (other than the carboxylic acid ester group or amino group to be formed in the amide bond reaction) of the substrate compound is protected by introducing a protecting group. It is possible.
  • ⁇ C-terminal substituent T a of electrophilic substrate compound (R1) In compound (R1), Ta represents a monovalent aromatic hydrocarbon group or a heterocyclic group having one or more electron-withdrawing substituents.
  • Examples of the monovalent aromatic hydrocarbon group include, but are not limited to, a phenyl group, a benzyl group, a tolyl group, a naphthyl group, an anthracenyl group, and the like.
  • the number of carbon atoms is not limited, but is usually 6 or more and usually 14 or less, or 10 or less.
  • Examples of the monovalent heterocyclic group include, but are not limited to, a furanyl group, a thiophenyl group, a pyranyl group, a pyrrolinyl group, a pyrrolyl group, a 2,3-dihydro-1H-pyrrolyl group, a piperidinyl group, Piperazinyl group, homopiperazinyl group, morpholino group, thiomorpholino group, 1,2,4,6-tetrahydropyridyl group, hexahydropyrimidyl group, hexahydropyridazyl group, 1,2,4,6-tetrahydropyridyl group , 1,2,4,6-tetrahydropyridazyl group, 3,4-dihydropyridyl group, imidazolyl group, 4,5-dihydro-1H-imidazolyl group, 2,3-dihydro-1H-imidazolyl group, pyr
  • Examples of the electron-withdrawing substituent that the monovalent aromatic hydrocarbon group or heterocyclic group has are not limited, but include, for example, the following.
  • ⁇ Halogen atoms e.g. fluorine, chlorine, bromine, iodine, etc., preferably fluorine or chlorine, etc.
  • ⁇ Halogen-substituted alkyl group a group in which the aforementioned various alkyl groups are substituted with one or more of the aforementioned halogen atoms
  • ⁇ Halogen-substituted alkoxy group a group in which the aforementioned various halogen-substituted alkyl groups are connected to an oxy group (-O-)
  • the number of electron-withdrawing substituents in the aromatic hydrocarbon group or heterocyclic group of Ta is 1 or 2 or more.
  • the upper limit is not particularly limited, and may be less than or equal to the upper limit determined depending on the type of monovalent aromatic hydrocarbon group or heterocyclic group, and may be, for example, 5 or less.
  • ⁇ Protecting group for amino group A wide variety of known protecting groups PGa for amino groups are known. Examples include monovalent hydrocarbon groups that may have one or more substituents, monovalent heterocyclic groups that may have one or more substituents, etc. Can be mentioned. Among these, monovalent hydrocarbon groups which may have one or more substituents are preferred.
  • a linking group may be present between the hydrocarbon group or heterocyclic group and the nitrogen atom of the amino group it protects. Such linking groups are not limited to, but are each independently selected from, for example, the linking groups shown below (in the following chemical formula, each A independently has one or more substituents). It represents a monovalent hydrocarbon group or a heterocyclic group which may be a monovalent hydrocarbon group or a heterocyclic group. If two A's are present in the same group, they may be the same or different.)
  • the number of carbon atoms in the protective group is usually 1 or more, or 3 or more, and usually 20 or less, or 15 or less.
  • protecting groups for amino groups include monovalent hydrocarbon groups, acyl groups, hydrocarbon oxycarbonyl groups, hydrocarbon sulfonyl groups, and amide groups, which may have one or more substituents.
  • it is one or more groups selected from the group consisting of:
  • protecting groups for amino groups are listed below.
  • names for the protecting group of an amino group in addition to the name of the functional group bonded to the nitrogen atom of the amino group, there are also names that include the nitrogen atom, and the following names also include both. It is.
  • unsubstituted or substituted hydrocarbon groups include alkyl groups such as methyl, ethyl, and propyl; alkenyl groups such as ethenyl, propenyl, and allyl; alkynyl groups such as propargyl; cyclopropyl; cycloalkyl groups such as cyclobutyl, cyclopentyl, and cyclohexyl groups; aryl groups such as phenyl, benzyl, paramethoxybenzyl, tolyl, and triphenylmethyl (troc groups); substituted hydrocarbons such as cyanomethyl Examples include groups. The number of carbon atoms is usually 1 or more, or 3 or more, and usually 20 or less, or 15 or less.
  • unsubstituted or substituted acyl groups include benzoyl group (Bz), orthomethoxybenzoyl group, 2,6-dimethoxybenzoyl group, paramethoxybenzoyl group (PMPCO), cinnamoyl group, phthaloyl group (Phth), etc. Can be mentioned.
  • unsubstituted or substituted hydrocarbon oxycarbonyl groups include tert-butoxycarbonyl group (Boc), benzyloxycarbonyl group (Cbz or Z), methoxycarbonyl group, ethoxycarbonyl group, 2-trimethylsilylethoxycarbonyl group, 2-phenylethoxycarbonyl group, 1-(1-adamantyl)-1-methylethoxycarbonyl group, 1-(3,5-di-t-butylphenyl)-1-methylethoxycarbonyl group, vinyloxycarbonyl group, allyl Oxycarbonyl group (Alloc), N-hydroxypiperidinyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, 2-(1,3-dithianyl)methoxycarbonyl, m-nitrophenoxycarbonyl group, 3,5-dimethoxybenzyloxycarbonyl group, o-nitrobenzy
  • unsubstituted or substituted hydrocarbon sulfonyl group examples include a methanesulfonyl group (Ms), a toluenesulfonyl group (Ts), a 2- or 4-nitrobenzenesulfonyl group (Ns), and the like.
  • Ms methanesulfonyl group
  • Ts toluenesulfonyl group
  • Ns 2- or 4-nitrobenzenesulfonyl group
  • unsubstituted or substituted amide groups include acetamide, o-(benzoyloxymethyl)benzamide, 2-[(t-butyldiphenylsiloxy)methyl]benzamide, 2-toluenesulfonamide, 4-toluenesulfonamide. , 2-nitrobenzenesulfonamide, 4-nitrobenzenesulfonamide, tert-butylsulfinylamide, 4-toluenesulfonamide, 2-(trimethylsilyl)ethanesulfonamide, benzylsulfonamide, and the like.
  • Protecting groups that can be deprotected by one type of method are also mentioned as examples of protecting groups for amino groups.
  • the protecting group PGa for the terminal amino group of the electrophilic amino acid or peptide ester (R1) a protecting group that can be deprotected by passing through a basic ion exchange resin is used. It is preferable.
  • Preferred specific examples of protecting groups for amino groups include mesyl group (Ms), tert-butoxycarbonyl group (Boc), benzyl group (Bn or Bzl), benzyloxycarbonyl group (Cbz), benzoyl group (Bz), para Methoxybenzyl group (PMB), 2,2,2-trichloroethoxycarbonyl group (Troc), allyloxycarbonyl group (Alloc), 2,4-dinitrophenyl group (2,4-DNP), phthaloyl group (Phth), Examples include para-methoxybenzoyl group (PMPCO), cinnamoyl group, toluenesulfonyl group (Ts), 2- or 4-nitrobenzenesulfonyl group (Ns), cyanomethyl group, and 9-fluorenylmethyloxycarbonyl group (Fmoc). This is because, as described above, these protecting groups can easily protect an amino group and can be removed under relatively mild conditions.
  • More preferable examples of the protecting group for the amino group include mesyl group (Ms), tert-butoxycarbonyl group (Boc), benzyloxycarbonyl group (Cbz), benzyl group (Bn), paramethoxybenzyl group (PMB), 2,2,2-trichloroethoxycarbonyl group (Troc), allyloxycarbonyl group (Alloc), paramethoxybenzoyl group (PMPCO), benzoyl group (Bz), cyanomethyl group, cinnamoyl group, 2 or 4-nitrobenzenesulfonyl group ( Ns), toluenesulfonyl group (Ts), phthaloyl group (Phth), 2,4-dinitrophenyl group (2,4-DNP), and 9-fluorenylmethyloxycarbonyl group (Fmoc).
  • Ms mesyl group
  • Boc tert-butoxycarbonyl group
  • Cbz benz
  • the protecting group PG a for the terminal amino group of the electrophilic amino acid or peptide ester (R1) a protecting group that can be deprotected by passing through a basic ion exchange resin is preferable, as described above.
  • Specific examples include 9-fluorenylmethyloxycarbonyl group (Fmoc group), benzyloxycarbonyl group (Cbz group), tert-butoxycarbonyl group (Boc group), allyloxycarbonyl group (Alloc group), p- Examples include methoxybenzyl group (PMB group). Among these, Fmoc group and the like are particularly preferred.
  • Carboxyl group protecting group Various types of carboxyl group-protecting groups PGb are known. Examples include monovalent hydrocarbon groups or heterocyclic groups that may have one or more substituents. In addition, when a substituent is present, the type thereof is as described above. Specific examples of the number of substituents are, for example, 5, 4, 3, 2, 1, or 0.
  • the upper limit of the number of carbon atoms in the hydrocarbon group is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less.
  • the lower limit varies depending on the type of hydrocarbon group, but is 1 or more for alkyl groups, 2 or more for alkenyl or alkynyl groups, and 3 or more for cycloalkyl groups, such as 4 or more, or 5 or more.
  • Specific examples of the number of atoms include, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. It is.
  • the upper limit of the total number of carbon atoms and heteroatoms of the heterocyclic group is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less.
  • the lower limit varies depending on the type of heterocyclic structure, but is usually 3 or more, for example 4 or more, or 5 or more. Specific examples of the number of atoms are, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • carboxyl group protecting groups include, but are not limited to, the following.
  • a silane compound may be present in the reaction system.
  • various advantages such as improved reaction yield and stereoselectivity may be obtained.
  • silane compounds include HSi(OCH ( CF3 ) 2 ) 3 , HSi( OCH2CF3 ) 3 , HSi( OCH2CF2CF2H ) 3 , HSi(OCH2CF2CF2CF2CF) .
  • trimethylsilyl trifluoromethanesulfonate TMS-OTf
  • TMSIM 1-(trimethylsilyl)imidazole
  • DMESI dimethylethylsilylimidazole
  • DMIPSI dimethylisopropylsilylimidazole
  • TBSIM 1-(tert-butyldimethylsilyl)imidazole
  • TBSIM 1-(tert-butyldimethylsilyl)triazole
  • dimethylsilylimidazole dimethylsilyl (2 -Methyl)imidazole
  • TMBS trimethylbromosilane
  • TMCS trimethylchlorosilane
  • MSTFA N,O-bis(trimethylsilyl) trifluoro
  • a Lewis acid catalyst may be present in the reaction system.
  • various advantages such as improved reaction yield and stereoselectivity may be obtained.
  • a Lewis acid catalyst it may be necessary to separate and remove the Lewis acid catalyst from the reaction product. Therefore, it is preferable to appropriately decide whether or not to use a Lewis acid catalyst, taking into consideration the purpose of using the production method of the present invention.
  • a Lewis acid catalyst When a Lewis acid catalyst is used in the production method of the present invention, its type is not limited, but it is preferably a metal compound that functions as a Lewis acid.
  • the metal elements constituting the metal compound include various metals belonging to Groups 2 to 15 of the Periodic Table of Elements. Specific examples of the metal elements include boron, magnesium, gallium, indium, silicon, calcium, lead, bismuth, mercury, transition metals, lanthanoid elements, and the like.
  • transition metals include scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, tin, silver, cadmium, Examples include hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, and thallium.
  • lanthanoid elements include lanthanum, cerium, neodymium, samarium, europium, gadolinium, holmium, erbium, thulium, ytterbium, and the like.
  • titanium, zirconium, hafnium, tantalum, niobium, boron, vanadium, tungsten, neodymium, iron, lead, and cobalt are preferred from the viewpoint of producing amide compounds with high stereoselectivity and exhibiting an excellent reaction promotion effect.
  • metal elements contained in the metal compound may be one or two or more. When the metal compound contains two or more metal elements, these may be of the same type, or may be two or more different metal elements.
  • the ligand constituting the metal compound is appropriately selected depending on the type of metal.
  • Specific examples of the ligand include substituted or unsubstituted linear or branched chains having 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, trifluoroethoxy, and trichloroethoxy groups.
  • alkoxy groups halogen atoms such as fluorine, chlorine, bromine, and iodine; allyloxy groups having 1 to 10 carbon atoms; acetylacetonate groups (acac), acetoxy groups (AcO), trifluoromethanesulfonate groups ( TfO); substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms; phenyl group, oxygen atom, sulfur atom, group -SR (where R is a substituent, Examples include substituted or unsubstituted hydrocarbon groups having about 1 to 20 carbon atoms.), group -NRR' (where R and R' are each independently a hydrogen atom or a substituent). Examples of substituents include substituted or unsubstituted hydrocarbon groups having about 1 to 20 carbon atoms), cyclopentadienyl (Cp) groups, and the like.
  • substituents include substituted or unsubstituted hydrocarbon groups having
  • a titanium compound a zirconium compound, a hafnium compound, a tantalum compound, or a niobium compound is preferable. Specific examples of each are listed below. Incidentally, any one of these may be used alone, but two or more may be used in combination in any combination and ratio.
  • a specific example of a titanium compound is TiX 1 4 (However, each of the four X 1s is independently a ligand as exemplified above. The four X 1s may be the same ligand or may be different from each other. ) may be mentioned.
  • X 1 is an alkoxy group, preferably a straight chain or branched alkoxy group having 1 to 10 carbon atoms, especially a straight chain or branched alkoxy group having 1 to 5 carbon atoms, and more preferably a straight chain or branched alkoxy group having 1 to 5 carbon atoms. -4 linear or branched alkoxy groups, etc.
  • X 1 is an allyloxy group, preferably an allyloxy group having 1 to 20 carbon atoms, particularly an allyloxy group having 1 to 15 carbon atoms, and more preferably an allyloxy group having 1 to 10 carbon atoms.
  • These ligands may further have a substituent.
  • X 1 is a halogen atom, preferred examples include a chlorine atom and a bromine atom.
  • zirconium compound is ZrX 2 4 (however, each of the four X 2s is independently a ligand as exemplified above. The four X 2s may be the same ligand or may be different from each other).
  • X 2 is an allyloxy group, preferably an allyloxy group having 1 to 20 carbon atoms, particularly an allyloxy group having 1 to 15 carbon atoms, and more preferably an allyloxy group having 1 to 10 carbon atoms.
  • These ligands may further have a substituent.
  • X 2 is a halogen atom, preferred examples include a chlorine atom and a bromine atom.
  • hafnium compound is HfX 3 4 (however, each of the four X 3s is independently a ligand as exemplified above. The four X 3s may be the same ligand or may be different from each other. Examples include hafnium compounds represented by: When X 3 is an alkoxy group, it is preferably a straight chain or branched alkoxy group having 1 to 10 carbon atoms, especially a straight chain or branched alkoxy group having 1 to 5 carbon atoms, and more preferably a straight chain or branched alkoxy group having 1 to 5 carbon atoms. -4 linear or branched alkoxy groups, etc.
  • X 3 is an allyloxy group, preferably an allyloxy group having 1 to 20 carbon atoms, particularly an allyloxy group having 1 to 15 carbon atoms, and more preferably an allyloxy group having 1 to 10 carbon atoms.
  • These ligands may further have a substituent.
  • X 3 is a halogen atom, preferred examples include a chlorine atom and a bromine atom. Among these, for example, HfCp 2 Cl 2 , HfCpCl 3 , HfCl 4 and the like are preferred.
  • a specific example of a tantalum compound is TaX 4 5 (However, each of the five X 4s is independently a ligand as exemplified above. The five X 4s may be the same ligand or may be different from each other. ) is exemplified.
  • X 4 is an alkoxy group, it is preferably a straight or branched alkoxy group having 1 to 10 carbon atoms, especially a straight or branched alkoxy group having 1 to 5 carbon atoms, and more preferably a straight or branched alkoxy group having 1 to 5 carbon atoms. -3 linear or branched alkoxy groups, etc.
  • X 4 is an allyloxy group, preferably an allyloxy group having 1 to 20 carbon atoms, particularly an allyloxy group having 1 to 15 carbon atoms, and more preferably an allyloxy group having 1 to 10 carbon atoms. These ligands may further have a substituent.
  • X 4 is a halogen atom, preferred examples include a chlorine atom and a bromine atom.
  • tantalum alkoxide compounds for example, compounds in which X 4 is an alkoxy group
  • tantalum alkoxide compounds such as Ta(OMe) 5 , Ta(OEt) 5 , Ta(OBu) 5 , Ta(NMe 2 ) 5 , Ta(acac)(OEt) 4 , TaCl 5 , TaCl 4 (THF), TaBr 5 and the like are preferred.
  • Compounds in which X 4 is oxygen, ie Ta 2 O 5 can also be used.
  • niobium compound is NbX 5 5 (however, each of the five X 5s is independently a ligand as exemplified above. The five X 5s may be the same ligand or may be different from each other).
  • examples include niobium compounds represented by: When X 5 is an alkoxy group, preferably a straight chain or branched alkoxy group having 1 to 10 carbon atoms, especially a straight chain or branched alkoxy group having 1 to 5 carbon atoms, and more preferably a straight chain or branched alkoxy group having 1 to 5 carbon atoms. -3 linear or branched alkoxy groups, etc.
  • X 5 is an allyloxy group, preferably an allyloxy group having 1 to 20 carbon atoms, particularly an allyloxy group having 1 to 15 carbon atoms, and more preferably an allyloxy group having 1 to 10 carbon atoms.
  • These ligands may further have a substituent.
  • X 5 is a halogen atom, preferred examples include a chlorine atom and a bromine atom.
  • niobium alkoxide compounds for example, compounds in which X 5 is an alkoxy group
  • NbCl 4 (THF) NbCl 5 , Nb(OMe) 5 , Nb(OEt) 5 and the like are preferable.
  • Compounds in which X 5 is oxygen, ie Nb 2 O 5 can also be used.
  • the Lewis acid catalyst may be supported on a carrier.
  • the carrier supporting the Lewis acid catalyst is not particularly limited, and any known carrier can be used. Furthermore, known methods can be employed as a method for supporting the Lewis acid catalyst on a carrier.
  • ⁇ Other ingredients In the production method of the present invention, other components may be present in the reaction system. Examples of such other components include, but are not limited to, conventional catalysts (other than Lewis acid catalysts) that can be used in amidation reactions, bases, phosphorus compounds, solvents, and the like. Any one of these may be used alone, or two or more may be used in combination in any combination and ratio.
  • conventional catalysts other than Lewis acid catalysts
  • catalysts other than Lewis acid catalysts
  • examples of catalysts include methylaluminum bis(4-bromo-2,6-di-tert-butyl phenoxide) (MABR), trimethylsilyl trifluoromethanesulfonate (TMS-OTf), methylaluminum bis(4-bromo-2,6-di-tert-butyl phenoxide) (MABR), (2,6-di-tert-butyl phenoxide) (MAD) and the like. Any one of these may be used alone, or two or more may be used in combination in any combination and ratio.
  • the type of base is not limited, and any known base known to improve reaction efficiency can be used.
  • bases include those having 1 to 1 carbon atoms, such as tetrabutylammonium fluoride (TBAF), triethylamine (Et 3 N), diisopropylamine (i-Pr 2 NH), diisopropylethylamine (i-Pr 2 EtN), etc.
  • TBAF tetrabutylammonium fluoride
  • Et 3 N triethylamine
  • i-Pr 2 NH diisopropylethylamine
  • i-Pr 2 EtN diisopropylethylamine
  • examples include amines having 1 to 4 linear or branched alkyl groups of 10, and inorganic bases such as cesium fluoride. Can be mentioned. Any one of these may be used alone, or two or more may be used in combination in any combination and ratio.
  • phosphorus compounds include phosphine compounds (e.g., trimethylphosphine, triethylphosphine, tripropylphosphine, trimethyloxyphosphine, triethyloxyphosphine, triproxyphosphine, triphenylphosphine, trinaphthylphosphine, triphenyloxyphosphine, Tris(4-methylphenyl)phosphine, tris(4-methoxyphenyl)phosphine, tris(4-fluorophenyl)phosphine, tris(4-methylphenyloxy)phosphine, tris(4-methoxyphenyloxy)phosphine, tris(4-fluorophenyl)phosphine -fluorophenyloxy)phosphine etc.), phosphate compounds (e.g., trimethylphosphine, triethylphosphine, tripropylphosphine,
  • ⁇ Reaction solvent From the viewpoint of increasing reaction efficiency, a solvent may be used during the reaction. In particular, when implementing the production method of the present invention by flow reaction, a solvent will be used.
  • solvents include, but are not particularly limited to, aqueous solvents and organic solvents.
  • Organic solvents include, but are not limited to, aromatic hydrocarbons such as toluene and xylene, pentane, petroleum ether, tetrahydrofuran (THF), 1-methyltetrahydrofuran (1-MeTHF), diisopropyl ether (i-Pr 2 O), ethers such as diethyl ether (Et 2 O) and cyclopentyl methyl ether (CPME), nitrogen-based organic solvents such as acetonitrile (MeCN), chlorine-based organic solvents such as dichloromethane (DCM), and ethyl acetate (AcOEt). and organic acids such as acetic acid. These solvents may be used alone or in combination of two or more.
  • the solvent used in the amide bond forming reaction (step (i)) and the solvent used in the deprotection (step (ii)) may be the same or different.
  • a different solvent it is necessary to exchange the solvent of the product after carrying out the amide bond forming reaction (step (i)) and then subject it to deprotection (step (ii). Therefore, the present invention
  • the solvent used in the amide bond formation reaction (step (i)) and the solvent used in the deprotection (step (ii)) are the same. It is preferable to use it as a solvent.
  • solvents that can be suitably used for both the amide bond formation reaction (step (i)) and deprotection (step (ii)) include THF, dichloromethane, chloroform, acetonitrile, CPME, etc. Among them, THF is preferred.
  • ⁇ Amide bond formation reaction In the production method of the present invention, an amide bond is formed between the N-terminally protected amino acid or peptide ester (R1) which is the electrophilic substrate and the amino acid or peptide or its ester (R2) which is the nucleophilic substrate. , to obtain an N-terminally protected peptide (S1) (step (i)).
  • R1 N-terminally protected amino acid or peptide ester
  • R2 amino acid or peptide or its ester
  • S1 N-terminally protected peptide (S1) (step (i)).
  • the procedure and conditions for such reaction are not limited, but are preferably as follows.
  • the ratio of the electrophilic substrate compound (R1) to the nucleophilic substrate compound (R2) is not particularly limited, but the ratio of the nucleophilic substrate compound (R2) to 1 mole of the electrophilic substrate compound (R1) is not particularly limited.
  • 0.1 mol or more, or 0.2 mol or more, or 0.3 mol or more, or 0.4 mol or more, or 0.5 mol or more and also, for example, 20 mol or less, or 10 mol or less, or 5 It can be used in a range of mol or less, 4 mol or less, or 3 mol or less. Note that, as a matter of course, it is necessary to use 1 mol or more of each of the substrate compounds (R1) and (R2) with respect to the target production amount of the compound to be produced (S1).
  • the substrate compounds (R1) and (R2) when the production method of the present invention is carried out by flow reaction, it is preferable to use the substrate compounds (R1) and (R2) in a ratio as close to an equivalent ratio as possible.
  • the amount of the other substrate compound is, for example, 1.5 mol or less per 1 mol of one of the substrate compounds, It is preferable to use the amount within a range of 1.4 mol or less, 1.3 mol or less, 1.2 mol or less, 1.1 mol or less, and further 1.05 mol or less.
  • the amount of the other substrate compound is, for example, 3 mol or less, or 2.5 mol or less, or 2.0 mol or less, or 1.5 mol or less. You can use it as you see fit.
  • the amount used is not particularly limited, but when the amount of the compound of formula (R1) used is 100 mol%, for example, 0.1 mol% or more, or 0.2 mol% or more, or 0.3 mol% or more, and, for example, 50 mol% or less, or 30 mol% or less, or 20 mol% or less, or 15 mol% or less of the silane compound can be used.
  • the amount used is not particularly limited, but when the amount of the compound of formula (R1) used is 100 mol%, for example, 0.1 mol% or more, or 0.2 mol%. % or more, or 0.3 mol % or more, and for example, 50 mol % or less, or 30 mol % or less, or 20 mol % or less, or 15 mol % or less of Lewis acid catalyst can be used.
  • the amount used may be adjusted as appropriate, for example, with reference to conventional knowledge such as past patent documents (Patent Documents 1 to 8) of the present inventors.
  • all of the above components may be added to the system all at once, may be added to the system in multiple doses, or may be added to the system continuously in small amounts.
  • a solution containing each of the substrate compounds (R1) and (R2) in a reaction solvent is continuously supplied using a liquid pump or the like and brought into contact with each other while flowing through the reaction path. Just let it happen.
  • the reaction temperature is not limited as long as the reaction proceeds, but can be, for example, 0°C or higher, or 10°C or higher, or 20°C or higher, or, for example, 100°C or lower, or 80°C or lower, or 60°C or lower. .
  • the reaction pressure is also not limited as long as the reaction proceeds, and the reaction may be carried out under reduced pressure, normal pressure, or increased pressure, but usually it can be carried out at normal pressure.
  • the reaction atmosphere is not limited as long as the reaction proceeds, but the reaction can usually be carried out in an atmosphere of an inert gas such as argon or nitrogen.
  • the flow rate of each solution of the substrate compounds (R1) and (R2) is not limited as long as the reaction proceeds, but from the viewpoint of allowing the reaction to proceed sufficiently and efficiently, the flow rate is, for example, 0.01 mL/min. or more, or 0.05 mL/min or more, or 0.1 mL/min or more, and, for example, 100 mL/min or less, or 50 mL/min or less, or 20 mL/min or less.
  • the reaction time is also not limited as long as the reaction proceeds, but from the perspective of allowing the reaction to proceed sufficiently, it can be, for example, 5 minutes or more, or 10 minutes or more, or 20 minutes or more, or 30 minutes or more.
  • the upper limit is not particularly limited, but from the viewpoint of efficiency, it can be set to, for example, 50 hours or less, 20 hours or less, 5 hours or less, or 1 hour or less.
  • the time during which each solution of the substrate compounds (R1) and (R2) is brought into contact within the reaction path may be adjusted within the above range so that the reaction proceeds sufficiently and efficiently.
  • a peptide compound represented by the following formula (P1) is obtained by deprotecting the N-terminus of the N-terminally protected peptide (S1) obtained by the reaction (step (ii) )).
  • the deprotection method is not particularly limited, and an appropriate method may be selected depending on the type of protecting group PG a .
  • the deprotection method is as described above.
  • this deprotection is preferably carried out by passing the compound of formula (S1) through a column packed with a basic ion exchange resin.
  • the deprotection (step (ii)) subsequent to the above-mentioned amide bond formation reaction (step (i)) can also be carried out in a flow reaction, which in turn facilitates the production of the present invention. It becomes possible to implement the entire method according to the flow.
  • the type of the basic ion exchange resin is not particularly limited, and the type of the protecting group PG a It may be selected as appropriate depending on the manufacturing conditions and the like. Examples include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-based resin, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)-based resin, Examples include 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) resin, piperazine resin, dimethylaminopyridine resin, and ammonium resin.
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • DBN 1,5-diazabicyclo[4.3.0]non-5-ene
  • TBD 1,5,7-triazabicyclo[4.4.0]dec-5-ene
  • the deprotection procedure is not particularly limited either, and the compound of formula (S1) obtained in the above amide bond forming reaction (step (i)) may be passed through a column packed with a basic ion exchange resin.
  • the reaction solution containing the compound of formula (S1) obtained in the above-mentioned amide bond-forming reaction (step (i)) is continuously fed as it is with a liquid feeding pump or the like. , it may be passed through a column packed with a basic ion exchange resin.
  • the temperature of the column during deprotection is not limited as long as the deprotection proceeds, but is, for example, 0°C or higher, or 10°C or higher, or 20°C or higher, or, for example, 100°C or lower, or 80°C or lower, or 60°C. It can be as follows.
  • the pressure during deprotection is also not limited as long as the deprotection proceeds, and may be carried out under reduced pressure, normal pressure, or increased pressure, but usually it can be carried out at normal pressure.
  • the flow rate of the reaction solution containing the compound of formula (S1) is not limited as long as the deprotection proceeds, but from the viewpoint of sufficiently and efficiently proceeding the deprotection, the flow rate is, for example, 0.01 mL/min. or more, or 0.05 mL/min or more, or 0.1 mL/min or more, and, for example, 100 mL/min or less, or 50 mL/min or less, or 20 mL/min or less.
  • the time for deprotection is also not limited as long as deprotection proceeds, but from the viewpoint of sufficiently and efficiently proceeding deprotection, for example, 10 minutes or more, or 20 minutes or more, or 30 minutes or more, or, for example, 80 minutes or more. It can be within hours, or within 60 hours, or within 50 hours.
  • the deprotection time can be adjusted within the above range by adjusting the flow rate of the reaction solution containing the compound of formula (S1) and the length of the column packed with the basic ion exchange resin.
  • the compound of formula (P1) obtained in the deprotection (step (ii)) is Using it as a substrate compound, the above-mentioned amide bond forming reaction (step (i)) and deprotection (step (ii)) are repeatedly carried out (step (iii)).
  • the desired peptide compound (P1) can be produced by sequentially connecting desired amino acids with amide bonds to elongate the peptide chain.
  • substrate compounds (R1) and (R2) it is in principle possible to synthesize polypeptides with any number of amino acid residues and any amino acid sequence. becomes.
  • a compound consisting of the sequence H 2 N-AA n -AA n-1 -(...)-AA 2 -AA 1 -O-tBu
  • the method may be carried out according to the following steps. (See schematic diagram in Figure 1).
  • an N-terminally protected amino acid ester for example, Fmoc-AA 2 -Ot-OPfp
  • R1 electrophilic substrate compound
  • AA 1 is used as a nucleophilic substrate compound (R2).
  • an amino acid ester (H 2 N-AA 1 -O-tBu) corresponding to the amide bond formation reaction of step (i) the N-terminally protected dipeptide of formula (S1) (Fmoc-AA 2 -AA 1 -O-tBu).
  • step (ii) the compound of formula (S1) is passed through an ion exchange resin and the N-terminus is deprotected in step (ii), thereby producing a dipeptide of formula (P1) (H 2 N-AA) which is not substituted at the N-terminus. 2 -AA 1 -O-tBu).
  • this dipeptide of formula (P1) is newly used as a nucleophilic substrate compound (R2), and the N-terminally protected amino acid ester of formula (R1) corresponding to the next amino acid residue AA 3 is used to carry out step (i).
  • the amide bond formation reaction in ) and the deprotection in step (ii) are carried out.
  • the desired polypeptide H 2 N-AA n -AA n-1 -((7)- AA 2 -AA 1 -O-tBu can be synthesized.
  • the peptide compound (P1) obtained by the production method of the present invention may be further subjected to various post-treatments.
  • the produced peptide compound (P1) can be isolated and purified according to conventional methods such as column chromatography and recrystallization.
  • deprotection can be performed according to the method described below.
  • the production method of the present invention may be carried out by a sequential method (batch method) or a continuous method (flow method). Details of specific sequential (batch) and continuous (flow) method implementation procedures are known in the art. However, as detailed above, the production method of the present invention can be carried out by a continuous method (flow method), which is preferable since various advantages can be obtained.
  • the peptide compound (P1) obtained by the production method of the present invention may be further subjected to various post-treatments.
  • the peptide compound (P1) obtained by the above production method can be isolated and purified by conventional methods such as column chromatography and recrystallization.
  • the amino group protected by a protecting group can also be deprotected.
  • the method for deprotecting the protected amino group is not particularly limited, and various methods can be used depending on the type of protecting group. Examples include deprotection by hydrogenation, deprotection by weak acids, deprotection by fluorine ions, deprotection by one-electron oxidizing agents, deprotection by hydrazine, deprotection by oxygen, and the like.
  • deprotection by hydrogenation (a) deprotection by reduction in the presence of hydrogen gas using a metal catalyst such as palladium, palladium-carbon, palladium hydroxide, palladium hydroxide-carbon, etc.
  • a reduction catalyst such as palladium, palladium-carbon, palladium hydroxide, palladium hydroxide-carbon, etc., sodium borohydride, lithium aluminum hydride, lithium borohydride, diborane, etc. Examples include a method of reducing and deprotecting using a hydrogenation reducing agent.
  • the carboxyl group protected by a protecting group can also be deprotected.
  • the method for deprotecting the protected carboxyl group is not particularly limited, and various methods can be used depending on the type of protecting group. Examples include deprotection by hydrogenation, deprotection by base, deprotection by weak acid, and the like.
  • examples include a method of deprotecting using a strong base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. as the base.
  • Patent Document 4 mentioned above
  • Patent Document 5 International Publication No. 2021/085635
  • Patent Document 6 International Publication No. 2021/085636
  • Patent Document 7 International Publication No. 2021/149814
  • Patent Document 8 International Publication No. 2022/190486 (Patent Document 8 mentioned above)
  • Chem. Sci., (2022), Vol.13, pp.6309-6315 non-patent document 6 mentioned above
  • a reaction system with the configuration shown in Figure 1 was constructed, and the tripeptide H 2 N-AA 3 -AA 2 -AA 1 -OtBu was synthesized according to the above synthesis procedure (AA 1 , AA 2 , AA 3 are each represents an amino acid residue).
  • a pentafluorophenyl (Pfp) group was used as the Ta group in formula (R1)
  • an Fmoc group was used as the PG a group
  • t- the T b group in formula (R2).
  • tBu butyl
  • reaction time refers to the time from the time it enters the flow machine to just before entering the deprotection cartridge for the amide bond forming reaction in step (i), and refers to the time from the time it enters the flow machine until just before entering the deprotection cartridge.
  • reaction time refers to the time from inflow to outflow from the deprotection cartridge.
  • THF tetrahydrofuran
  • a THF solution (concentration 0.1 M) of (H-AA 1 -OtBu) was pumped into each solution (flow rate 1.0 mL/min) and joined inside the channel to carry out the amide bond formation reaction in step (i).
  • reaction temperature room temperature, reaction time ⁇ 5 minutes
  • N-terminally protected dipeptide ester Fmoc-AA 2 -AA 1 -OtBu
  • the obtained N-terminally protected dipeptide ester was pumped (flow rate 2.0 mL/min) to flow through a cartridge (length 10 cm) filled with DBU polymer.
  • the deprotection reaction in step (ii) was carried out (reaction temperature 50°C, reaction time ⁇ 5 minutes) to obtain a dipeptide ester (H 2 N-AA 2 -AA 1 -OtBu) with the N-terminus deprotected. .
  • a THF solution (concentration 0.05 M) of the obtained dipeptide ester (H 2 N-AA 2 -AA 1 -OtBu) and a pentafluorophenyl ester of another amino acid whose N-terminus was protected with Fmoc (Fmoc-AA 3 -OPfp) THF solutions (concentration 0.05M) were pumped (flow rate 1.0mL/min) to join each other inside the channels, and the amide bond formation reaction of step (i) was carried out, and the N-terminal A protected tripeptide ester (Fmoc-AA 3 -AA 2 -AA 1 -OtBu) was obtained.
  • the N-terminally protected tripeptide Fmoc-H 2 N-AA 3 -AA 2 -AA 1 -OtBu was synthesized according to the above synthesis procedure while variously changing the types of amino acids AA 1 , AA 2 and AA 3 .
  • the results are shown in the table below.
  • “quant.” in the table means a real equivalent (about 100%).
  • N-terminally protected tripeptides Fmoc-AA 3 -AA 2 -AA 1 -OtBu were passed through a cartridge filled with DBU polymer using a pump (flow rate 1.0 mL) using the same procedure as above. /min) through a cartridge (length 30 cm) filled with DBU polymer to carry out the deprotection reaction in step (ii).
  • the corresponding tripeptide ester (H 2 N-AA 3 -AA 2 -AA 1 -OtBu) with the N-terminus deprotected can be obtained.
  • a tetrapeptide in which alanine was linked as another amino acid residue AA 4 to the tripeptide ester H 2 N-AA 3 -AA 2 -AA 1 -OtBu synthesized in the above procedure was synthesized in the following procedure. did. That is, a THF solution (concentration 0.05 M) of the tripeptide ester H 2 N-AA 3 -AA 2 -AA 1 -OtBu synthesized in the above procedure and a pentafluorocarbon solution of another amino acid whose N-terminus was protected with Fmoc were added.

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