WO2023136301A1 - ペプチド化合物の製造方法 - Google Patents

ペプチド化合物の製造方法 Download PDF

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WO2023136301A1
WO2023136301A1 PCT/JP2023/000653 JP2023000653W WO2023136301A1 WO 2023136301 A1 WO2023136301 A1 WO 2023136301A1 JP 2023000653 W JP2023000653 W JP 2023000653W WO 2023136301 A1 WO2023136301 A1 WO 2023136301A1
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formula
substituents
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French (fr)
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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 JP2023574074A priority Critical patent/JP7651094B2/ja
Priority to EP23740309.2A priority patent/EP4446332A4/en
Priority to US18/729,323 priority patent/US20250092088A1/en
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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
    • C07K1/06—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B51/00—Introduction of protecting groups or activating groups, not provided for in the preceding 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
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • 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
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala

Definitions

  • the present invention relates to a novel method for producing peptide compounds.
  • Non-Patent Documents 1-3 Non-Patent Documents 1-3.
  • carboxylic acid activators for amidation which is most important for peptide synthesis. Therefore, it is necessary to use a reaction mode that produces a large amount of by-products, and moreover, peptide synthesis that repeats multi-step reactions is extremely inefficient synthesis from the viewpoint of atom economy (atomic yield). is a huge amount, and there are few effective purification means.
  • the cost of disposal and purification of by-products accounts for most of the costs involved in peptide synthesis and constitutes one of the greatest barriers to the development of this field.
  • a peptide formed by linking a plurality of amino acids or derivatives thereof is further ligated with an amino acid or a derivative thereof via an amide bond (Chemical Ligation), or two or more peptides are ligated via an amide bond.
  • Examples of amidation methods for ligation to such peptides include a method of using an amino acid having a sulfur atom and performing ligation by utilizing the high reactivity of the sulfur atom (Non-Patent Document 4), and a method of synthesizing hydroxyamine of an amino acid.
  • Non-Patent Document 5 a method of ligation using the high reactivity of hydroxylamine is known (Non-Patent Document 5), but the former is difficult to synthesize amino acids having a sulfur atom, and the latter requires several steps to synthesize hydroxylamine. is required separately.
  • the present inventors have proposed 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. is amidated in the presence of a specific metal catalyst and then reduced in the presence of a specific metal catalyst (Patent Document 2), and a method of amidating a carboxylic acid/ester compound in the presence of a specific metal catalyst (A technique for synthesizing an amide compound with high chemoselectivity has been developed, for example, in Patent Document 3).
  • Non-Patent Document 7 a technique of linking a peptide chain with a silyl ester group as a protective group has also been reported (Non-Patent Document 7).
  • a highly reactive silyl ester group is used as a protective group, reaction conditions applicable to peptide binding reactions are limited.
  • deprotection of the ester may occur during the reaction process, and in fact deprotection is frequently confirmed and reported in this literature.
  • the present inventors subjected an amino acid or peptide whose terminal carboxyl group and/or terminal amino group were protected by a silicon-containing hydrophobic substituent having a specific structure to elongation of the peptide chain by a peptide bonding reaction.
  • a silicon-containing hydrophobic substituent having a specific structure to elongation of the peptide chain by a peptide bonding reaction.
  • the gist of the present invention resides in the following.
  • [Item 1] A method for producing a polypeptide compound, wherein the carboxyl group on the right side of the amino acid or peptide compound represented by the following formula (R1) and the amino acid ester or peptide represented by the following formula (R2) A production method comprising obtaining a peptide compound represented by the following formula (P1) by subjecting an ester compound to an amide formation reaction with the amino group on the left side of the formula.
  • Ta represents a hydrogen atom or a monovalent substituent
  • R 11 and R 12 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 optionally having one or more substituents.
  • R 13 represents a hydrogen atom, a carboxyl group, a hydroxyl group, or a monovalent aliphatic hydrocarbon group optionally having 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 together to form a heterocyclic ring optionally having 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 represents 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 optionally having one or more substituents.
  • R 23 represents a hydrogen atom, a carboxyl group, a hydroxyl group, or a monovalent aliphatic hydrocarbon group optionally having 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 heterocyclic ring optionally having 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.
  • R x represents a divalent, trivalent, or tetravalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group, which may have one or more substituents;
  • L represents a single bond or a divalent linking group, m x represents an integer of 0 or 1, provided that when m x is 0, L represents a single bond;
  • Z independently represents a carbon atom (C) or a silicon atom (Si),
  • R z1 , R z2 and R z3 are each independently a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group or silicon-containing hydrocarbon group optionally having one or more substituents , or represents a heterocyclic group, provided that the three substituents -Z (R z1 ) (R z2 ) (R z3 ) enclosed in parentheses in formula (T1) may be the same or different,
  • n x is an integer of 1 to 3 and represents the number of substituents represented by the structure in ⁇
  • T a , R 11 , R 12 , R 13 , A 11 , A 12 , p11, p12, and n 1 represent the same groups as defined in formula (R1); R 21 , R 22 , R 23 , A 21 , A 22 , p21, p22, n 2 and T b represent the same groups as defined in formula (R2) above.
  • TAG(Si) group is a group having a structure represented by the following formula (T1), (T2), or (T3).
  • R x1 represents a divalent aliphatic hydrocarbon group, an aromatic hydrocarbon group, or a heterocyclic group, which may have one or more substituents
  • L, R z1 , R z2 and R z3 each independently have the same definition as formula (T).
  • R x2 represents a trivalent or tetravalent aliphatic hydrocarbon group, an aromatic hydrocarbon group, or a heterocyclic group, which may have one or more substituents
  • L, R z1 , R z2 and R z3 each independently have the same definition as formula (T)
  • ny is an integer of 2 or 3 and represents the number of substituents represented by the structure in ⁇ ⁇ .
  • R x3 represents a trivalent or tetravalent aliphatic hydrocarbon group, an aromatic hydrocarbon group, or a heterocyclic group, which may have one or more substituents;
  • R z1 , R z2 , and R z3 each independently have the same definition as formula (T);
  • ny is an integer of 2 or 3 and represents the number of substituents represented by the structure in ⁇ ⁇ .
  • two or three substituents enclosed by ⁇ ⁇ in formula (T3) may be the same or different.
  • [Item 4] The production method according to any one of items 1 to 3, wherein the reaction is carried out in the presence of a Lewis acid catalyst.
  • the Lewis acid catalyst is a metal compound containing one or more metals selected from the group consisting of aluminum, titanium, zirconium, hafnium, tantalum, and niobium.
  • the reaction is carried out in the presence of a phosphorus compound.
  • the phosphorus compound is a phosphine compound or a phosphate compound.
  • the production method according to any one of Items 1 to 8, further comprising a step of removing the -C( O)-TAG(Si) group to deprotect the terminal amino group of the peptide compound.
  • the T b group of the formula (R2) is a —TAG(Si) group, and after the peptide compound of the formula (P1) is synthesized, the —TAG(Si) group of the peptide compound is removed. 10.
  • each definition of R 11 , R 12 , R 13 , A 11 , A 12 , p11, p12, n 1 , and TAG(Si) is the definition of the group with the same sign as described in Item 1. is identical to [Item 13]
  • each definition of R 21 , R 22 , R 23 , A 21 , A 22 , p21, p22, n 2 , and TAG(Si) is the definition of the group with the same sign as described in Item 1. is identical to [Item 14]
  • the definition of TAG(Si) is the same as the definition of the group with the same sign described in Item 1.
  • a compound represented by the following formula (C1) the definition of TAG(Si) is the same as the definition of the group with the same sign described in item 1, R C1 is any monovalent group.
  • R C21 and R C22 are each independently any monovalent group.
  • an amino acid or peptide whose terminal carboxyl group and/or terminal amino group is protected by a silicon-containing hydrophobic substituent having a specific structure is subjected to peptide chain elongation by a peptide bonding reaction.
  • amino acid means a compound having a carboxyl group and an amino group.
  • the type of amino acid is not particularly limited. For example, from the viewpoint of optical isomerism, it may be D-, L-, or racemic. From the viewpoint of the relative positions of the carboxyl group and the amino group, any of ⁇ -amino acid, ⁇ -amino acid, ⁇ -amino acid, ⁇ -amino acid, ⁇ -amino acid and the like may be used.
  • 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 means a compound in which multiple amino acids are linked via peptide bonds. Unless otherwise specified, a plurality of amino acid units constituting a peptide may be the same type of amino acid unit, or may be two or more different types of amino acid units. The number of amino acids that constitute the peptide is not particularly limited as long as it is two or more. Examples include 2 (also referred to as “dipeptide”), 3 (also referred to as “tripeptide”), 4 (also referred to as “tetrapeptide”), 5 (also referred to as "pentapeptide"), 6, 7, 8, 9 , 10, 15, 20, 30, 40, 50, 100, or more. In some cases, the term “polypeptide” refers to a peptide that is more than a tripeptide.
  • amino group refers to the formulas -NH 2 , -NRH, or -NRR' (wherein R and R' each means a substituent.).
  • the hydrocarbon group may be aliphatic or aromatic.
  • the aliphatic hydrocarbon group may be chain or cyclic.
  • a chain hydrocarbon group may be linear or branched.
  • Cyclic hydrocarbon groups may be monocyclic, bridged, or spirocyclic.
  • Hydrocarbon groups may be saturated or unsaturated, in other words may contain one or more carbon-carbon double and/or triple bonds.
  • the hydrocarbon group is a concept including 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 Any heteroatom may be substituted.
  • the "hydrocarbon oxy group” means a group in which the hydrocarbon group defined above is linked to one bond of the oxy group (-O-). That is, the hydrocarbonoxy group is a concept including an alkyloxy group, an alkenyloxy group, an alkynyloxy group, a cycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxy group, an aryloxy group and the like.
  • heterocyclic group may be saturated or unsaturated, in other words, it may contain one or more carbon-carbon double bonds and/or triple bonds.
  • heterocyclic groups may be monocyclic, bridged, or spirocyclic.
  • the heteroatoms included in the heterocyclic ring-constituting atoms of the heterocyclic group are not limited, but examples thereof include nitrogen, oxygen, sulfur, phosphorus, silicon and the like.
  • heterocyclic oxy group means a group in which the heterocyclic group defined above is linked to one bond of the oxy group (-O-).
  • the “metaloxy group” (which may have one or more substituents) means a group represented by the formula (R) n —MO—.
  • 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 according to the coordination number of the metal element M. do.
  • substituteduents means any substituent independently, unless otherwise specified, and is not particularly limited as long as the amidation step in the production method of the present invention proceeds. Examples include, but are not limited to, halogen atoms, hydroxyl groups, carboxyl groups, nitro groups, cyano groups, thiol groups, sulfonic acid groups, amino groups, amido groups, imino groups, imido groups, hydrocarbon groups.
  • heterocyclic group hydrocarbonoxy group, hydrocarboncarbonyl group (acyl group), hydrocarbonoxycarbonyl group, hydrocarboncarbonyloxy group, hydrocarbon-substituted amino group, hydrocarbon-substituted aminocarbonyl group, hydrocarboncarbonyl-substituted amino group, hydrocarbon-substituted thiol group, hydrocarbon sulfonyl group, hydrocarbon oxysulfonyl group, hydrocarbon sulfonyloxy group, heterocyclic oxy group, heterocyclic carbonyl group, heterocyclic oxycarbonyl group, heterocyclic carbonyloxy group, heterocyclic amino group, heterocyclic aminocarbonyl group, heterocyclic carbonyl-substituted amino group, heterocyclic-substituted thiol group, heterocyclic sulfonyl group, heterocyclic oxysulfonyl group, heterocyclic thiol group, heterocyclic sulfonyl group, heterocyclic oxy
  • amino acids and their residues may be referred to by their three letter abbreviations well known to those of skill in the art.
  • Three-letter abbreviations for the primary amino acids used in this disclosure are shown in the table below.
  • ⁇ -homoamino acids and residues thereof may be denoted by adding "Ho" before the three-letter abbreviation of the corresponding ⁇ -amino acid.
  • One aspect of the present invention is a method for producing a polypeptide compound, comprising: A production method comprising obtaining the peptide compound of formula (P1) by an amide formation reaction with the amino group on the left side of the formula (hereinafter referred to as the “peptide compound production method of the present invention” or simply “the production method of the present invention”). ).
  • R 11 , R 12 , 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 have one or more substituents; represents a monovalent hydrocarbon group or heterocyclic group which may be In addition, when these groups have substituents, the types thereof are 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 heterocyclic group optionally having one or more substituents
  • a linking group may be interposed between the hydrocarbon group or heterocyclic group and the carbon atom to which it is attached.
  • Such linking groups are not limited, but are each independently selected, for example, from the structures shown below (where each A independently has one or more substituents in the chemical formulas below. represents a monovalent hydrocarbon group or heterocyclic group which may be optionally substituted.When two A 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, it is 1 or more for alkyl groups, 2 or more for alkenyl groups and alkynyl groups, and 3 or more, for example, 4 or more, or 5 or more for cycloalkyl groups.
  • Specific examples of the number of atoms are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, etc. is.
  • the total number of carbon atoms and heteroatoms (including the substituents, if any) 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. Although the lower limit varies depending on the type of heterocyclic structure, it 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 each independently represent a hydrogen atom, a hydroxyl group, a thiol group, a carboxyl group, a nitro group, a cyano group, a halogen atom, or one or more substituents. 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, or a heterocyclic oxy group, which may have a group. .
  • R 11 , R 12 , R 21 and R 22 include, but are not limited to, the following.
  • the group having a carboxyl group may or may not have a protecting group.
  • the right side of the formula of the compound (R2) is usually is improved over the reaction selectivity with carboxyl groups 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 or heterocyclic group optionally having one or more substituents .
  • substituents when it has a substituent, it is as having described the kind previously. 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 heterocyclic group optionally having one or more substituents
  • such hydrocarbon group or heterocyclic ring A linking group may be interposed between the formula group and the nitrogen atom to which it is attached.
  • Such linking groups are not limited, but are each independently selected, for example, from the structures shown below (where each A independently has one or more substituents in the chemical formulas below. represents a monovalent hydrocarbon group or heterocyclic group which may be optionally substituted.When two A are present in the same group, they may be the same or different.).
  • the upper limit of the number of carbon atoms of 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, it is 1 or more for alkyl groups, 2 or more for alkenyl groups and alkynyl groups, and 3 or more, for example, 4 or more, or 5 or more for cycloalkyl groups.
  • Specific examples of the number of atoms are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, etc. is.
  • the upper limit of the total number of carbon atoms and heteroatoms (including the substituents if any) 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, it 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 each independently represent a hydrogen atom, a hydroxyl group, a carboxyl group, or an alkyl group, alkenyl group, cycloalkyl group, which may have one or more substituents,
  • An alkoxy group, an aryl group, an aryloxy group, an acyl group, a heterocyclic group, a heterocyclic oxy group, or the like is preferable.
  • R 13 and R 23 include, but are not limited to, the following.
  • R 11 and R 13 are bonded together to form a heterocyclic ring optionally having 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 optionally 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 may form
  • when it has a substituent it is as having described the kind previously. 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 (including the substituents if any) 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, it 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.
  • heterocyclic rings 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 -tetrahydropyridyl 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, 4,5
  • a 11 , A 12 , A 21 and A 22 each independently represents a divalent aliphatic hydrocarbon group having 1 to 3 carbon atoms which may have one or more substituents. Specific examples include, but are not limited to, methylene group, ethylene group, propylene group, isopropylene group, and the like, and groups in which these groups are substituted with one or more of the above substituents. 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 [ ] of the general formula (R1).
  • compound (R1) is an amino acid
  • compound (R1) is a peptide.
  • the upper limit of n 1 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 [ ] of general formula (R2).
  • compound (R2) is an amino acid
  • 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.
  • n 2 is preferably 1, ie compound (R2) is preferably an amino acid.
  • n2 is 1, i.e., when compound (R2) is an amino acid, it reacts with the aluminum compound of formula (A) above to form an aluminum atom It is speculated that a cyclization intermediate containing is formed, which contributes to the improvement of the reaction efficiency.
  • R 11 , R 12 , R 13 , A 11 , A 12 , p11 and p12 defining the structure in [ ] may be a plurality of The 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.
  • Ta represents a hydrogen atom or a monovalent substituent.
  • the type thereof is not particularly limited, but in addition to the groups described above as R 13 and R 23 , an amino group-protecting group (hereinafter referred to as PG a as appropriate), and silicon-containing hydrophobic substituents TAG(Si).
  • the amino group-protecting group PG a is not particularly limited as long as it can protect the amino group so that it does not react in the amidation reaction and can be deprotected after the reaction to be converted into an amino group. . Details of the amino group-protecting group PG a and the silicon-containing hydrophobic substituent TAG(Si) will be described later.
  • T b represents a hydrogen atom or a monovalent substituent.
  • a monovalent substituent the type thereof is not particularly limited, but in addition to the groups described above as R 13 and R 23 , a carboxyl group-protecting group (hereinafter referred to as PG b as appropriate), and silicon-containing hydrophobic substituents TAG(Si).
  • the carboxyl-protecting group PG b is not particularly limited as long as it can protect the carboxyl group so that it does not react in the amidation reaction, and can be deprotected after the reaction to convert to the carboxyl group. . Details of the carboxyl group-protecting group PG b and the silicon-containing hydrophobic substituent TAG(Si) will be described later.
  • the left amino group in 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, nitric acid. , phosphoric acid, boric acid, sulfonic acid and the like.
  • one compound may be used alone, or two or more compounds may be used in any combination and ratio.
  • part or all of the above substrate compound (R1) or (R2) may be linked/immobilized to a carrier such as a substrate or resin at any substituent.
  • the type of carrier such as substrate or resin is not limited. Any conventionally known carrier such as substrates and resins can be used without substantially inhibiting the amide bond reaction in the production method of the present invention and within the scope of the present invention.
  • the mode of connection and immobilization between the substrate compound and a carrier such as a substrate or resin is not limited at all. It is preferable to form a covalent bond between The type of each substituent and the method of forming a covalent bond are not limited at all.
  • any type of conventionally known method for forming a substituent and a covalent bond can be used without substantially inhibiting the amide bond reaction in the production method of the present invention and within the scope of the present invention. It is possible.
  • the substrate compound is linked and fixed to a carrier such as a substrate or a resin by a covalent bond using a carboxyl group or amino group (other than the carboxylic acid ester group or amino group to be formed in the amide bond reaction) of the substrate compound. may be changed.
  • a carrier such as a substrate or a resin
  • Such an aspect can be regarded in the same way as an aspect in which the carboxyl group or 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.
  • a wide variety of known amino group-protecting groups PG a are known. Examples include a monovalent hydrocarbon group optionally having one or more substituents, or a monovalent heterocyclic group optionally having one or more substituents. mentioned. Among them, a monovalent hydrocarbon group optionally having one or more substituents is preferred.
  • a linking group may be interposed between such a hydrocarbon group or heterocyclic group and the nitrogen atom of the amino group it protects.
  • Such linking groups are not limited, but are each independently selected, for example, from the linking groups shown below (where each A is independently one or more substituents in the chemical formulas below). represents a monovalent hydrocarbon group or heterocyclic group which may be substituted.When two A are present in the same group, they may be the same or different.).
  • the number of carbon atoms in the protecting group is usually 1 or more, or 3 or more, and usually 20 or less, or 15 or less.
  • the amino group-protecting group is a monovalent hydrocarbon group, an acyl group, a hydrocarbon oxycarbonyl group, a hydrocarbon sulfonyl group, and an amide group, which may have one or more substituents. It is preferably one or more groups selected from the group consisting of:
  • amino-protecting groups are listed below.
  • the functional group that binds to the nitrogen atom of the amino group there are also names that include the nitrogen atom as the name of the protective group for the amino group, and the following names also include both.
  • 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; cycloalkyl groups such as group, cyclobutyl group, cyclopentyl group and cyclohexyl group; aryl groups such as phenyl group, benzyl group, paramethoxybenzyl group, tolyl group and triphenylmethyl group (troc group); substituted hydrocarbons such as cyanomethyl group and the like.
  • 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) and the like. 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 hydrocarbonsulfonyl groups include a methanesulfonyl group (Ms), a toluenesulfonyl group (Ts), a 2- or 4-nitrobenzenesulfonyl group (Ns) group, 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 and 4-toluenesulfonamide. , 2-nitrobenzenesulfonamide, 4-nitrobenzenesulfonamide, tert-butylsulfinylamide, 4-toluenesulfonamide, 2-(trimethylsilyl)ethanesulfonamide, benzylsulfonamide and the like.
  • Protecting groups that can be deprotected by a single method are also examples of protecting groups for amino groups.
  • amino-protecting 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), paramethoxybenzoyl group (PMPCO), cinnamoyl group, toluenesulfonyl group (Ts), 2- or 4-nitrobenzenesulfonyl group (Ns), cyanomethyl group, 9-fluorenylmethyloxycarbonyl group (Fmoc) and the like. This is because these protective groups can easily protect the amino group and can be removed under relatively mild conditions, as described above.
  • amino-protecting groups include a mesyl group (Ms), a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), a benzyl group (Bn), a 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), 9-fluorenylmethyloxycarbonyl group (Fmoc) and the like.
  • Ms mesyl group
  • Boc tert-butoxycarbonyl group
  • Various carboxyl-protecting groups PG b are known. Examples include monovalent hydrocarbon groups or heterocyclic groups, which may have one or more substituents. In addition, when it has a substituent, it is as having described the kind previously. 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 of 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, it is 1 or more for alkyl groups, 2 or more for alkenyl groups and alkynyl groups, and 3 or more, for example, 4 or more, or 5 or more for cycloalkyl groups.
  • Specific examples of the number of atoms are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, etc. is.
  • the upper limit of the total number of carbon atoms and heteroatoms (including the substituents if any) 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, it 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-protecting groups include, but are not limited to, the following.
  • TAG (Si) One of the main characteristics of the method of the present invention is to satisfy the following (i) and/or (ii).
  • T a in formula (R1) is a group represented by —OC( ⁇ O)—TAG(Si).
  • T b in formula (R2) is a group represented by —TAG(Si).
  • —TAG(Si) is a silicon-containing hydrophobic substituent having a structure represented by formula (T) below.
  • the amino group on the left side of the amino acid or peptide compound of formula (R1) and/or the carboxyl group on the right side of the amino acid ester or peptide ester compound of formula (R2) is One of its main characteristics is that it is protected by the silicon-containing hydrophobic substituent TAG(Si) of the above formula (T) (or a group containing it).
  • R x is a divalent, trivalent, or tetravalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic ring which may have one or more substituents. represents a formula group.
  • the divalent, trivalent, or tetravalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group the above monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic ring Any divalent, trivalent, or tetravalent radical derived from the formula radicals by removing any one, two, or three hydrogen atoms, respectively, is included.
  • it has a substituent it is as having described the kind previously. Specific examples of the number of substituents are, for example, 5, 4, 3, 2, 1, or 0.
  • the number of carbon atoms in a divalent, trivalent, or tetravalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group (including the substituent if it has a substituent) of R x is an upper limit. is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. Although the lower limit varies depending on the type of hydrocarbon group, it is 1 or more for an alkyl group, 2 or more for an alkenyl group or an alkynyl group, and 3 or more, for example, 4 or more, or 5 or more for a cycloalkyl group. . Specific examples of the number of atoms are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, etc. is.
  • L represents a single bond or a divalent linking group.
  • the divalent linking group is not limited, but is each independently selected, for example, from the structures shown below (the right and left direction in the following chemical formula is arbitrary, and the right-hand side in the following formula The bond may be positioned on the right side in formula (T), the left bond in the following formula may be positioned on the left in formula (T), and the right bond in the following formula may be in the formula (T ), and the bond on the left side in the following formula may be positioned on the right side in formula (T).).
  • m x represents an integer of 0 or 1; However, when m x is 0, L represents a single bond.
  • Z independently represents a carbon atom (C) or a silicon atom (Si).
  • R z1 , R z2 and R z3 are each independently a monovalent aliphatic hydrocarbon group or aromatic hydrocarbon group optionally having one or more substituents. , a silicon-containing hydrocarbon group, or a heterocyclic group.
  • monovalent aliphatic and/or aromatic hydrocarbon group alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, cycloalkynyl group, aryl group, arylalkyl group, alkylaryl group, etc.
  • the formula groups are as described separately. Specific examples include, but are not limited to, the following.
  • Examples of monovalent silicon-containing hydrocarbon groups include groups obtained by replacing any one or two or more carbon atoms of a monovalent aliphatic hydrocarbon group or aromatic hydrocarbon group with silicon atoms.
  • R z1 , R z2 , and/or R z3 are monovalent aliphatic hydrocarbon groups or aromatic hydrocarbon groups
  • the number of carbon atoms is Independently, the upper limit is, for example, 40 or less, 35 or less, 30 or less, or 25 or less.
  • the lower limit varies depending on the type of hydrocarbon group, it is 1 or more for an alkyl group, 2 or more for an alkenyl group or an alkynyl group, and 3 or more, for example, 4 or more, or 5 or more for a cycloalkyl group. .
  • R z1 , R z2 and/or R z3 are monovalent heterocyclic groups
  • the total number of carbon atoms and heteroatoms (including substituents if any) is is, for example, 40 or less, 35 or less, 30 or less, or 25 or less.
  • the lower limit varies depending on the type of heterocyclic structure, it is usually 3 or more, for example 4 or more, or 5 or more.
  • Specific examples of the number of atoms are, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40.
  • R z1 , R z2 and R z3 linked to Z in formula (T1) may be the same or different.
  • at least one, two, or all three of R z1 , R z2 , and R z3 are preferably groups with low polarity, specifically, monovalent It is preferably an aliphatic hydrocarbon group, an aromatic hydrocarbon group or a heterocyclic group.
  • the three substituents —Z(R z1 ) (R z2 ) (R z3 ) linked to Si in formula (T1) may be the same or different.
  • n x is an integer of 1 to 3 and represents the number of substituents represented by the structure in ⁇ ⁇ . However, when m x is 2 or 3, the 2 or 3 substituents enclosed by ⁇ ⁇ in formula (T) may be the same or different.
  • the silicon-containing hydrophobic substituent TAG(Si) of the formula (T) protects the protecting group of the terminal amino group on the left side of the amino acid or peptide compound of the formula (R1)
  • the terminal amino group of the amino acid or peptide compound of formula (R1) and/or the terminal amino group of formula (R2) By protecting the terminal carboxyl group of an amino acid or a peptide compound and subjecting it to elongation of the peptide chain by a peptide binding reaction using these compounds, it is possible to prevent the solubility of the peptide chain in an organic solvent from decreasing. can improve the reactivity of the peptide chain and the operability in the purification process.
  • the silicon-containing hydrophobic substituent TAG(Si) can also be used to protect the N-terminal amino group of the amino acid or peptide compound of formula (R1).
  • Peptide bond forming reactions are generally carried out by N-terminal extension.
  • N-terminal protective groups such as Fmoc, Boc, Cbz, Trt, and Ac are overwhelmingly lacking in diversity compared to C-terminal protective groups.
  • these protecting groups are focused on short peptide synthesis and have little effect on depolarizing longer peptides. From these points of view, the synthesis of N-terminal protective groups with a view to long-chain peptide synthesis is important, and the silicon-containing hydrophobic substituent TAG(Si) according to the present invention is very useful in this respect. .
  • TAG(Si) group is not limited, it is preferably selected from groups having structures represented by the following formulas (T1), (T2), or (T3).
  • R x1 represents a divalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group optionally having one or more substituents. Examples are as described above.
  • L, R z1 , R z2 and R z3 each independently have the same definition as in formula (T).
  • R x2 represents a trivalent or tetravalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group optionally having one or more substituents . Examples are as described above.
  • L, R z1 , R z2 and R z3 each independently have the same definition as in formula (T).
  • ny is an integer of 2 or 3 and represents the number of substituents represented by the structure in ⁇ ⁇ . However, two or three substituents enclosed by ⁇ ⁇ in formula (T2) may be the same or different.
  • R x3 represents a trivalent or tetravalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group optionally having one or more substituents . Examples are as described above. Among them, R x3 is obtained by removing any two or three hydrogen atoms from the above-mentioned monovalent aromatic hydrocarbon group (aryl group, alkylaryl group, arylalkyl group) or heterocyclic group. Any trivalent or tetravalent group is preferred. Specific examples thereof are as described above.
  • R z1 , R z2 and R z3 each independently have the same definition as in formula (T).
  • ny is an integer of 2 or 3 and represents the number of substituents represented by the structure in ⁇ ⁇ . However, two or three substituents enclosed by ⁇ ⁇ in formula (T3) may be the same or different.
  • silicon-containing hydrophobic substituents represented by formula (T1), formula (T2), and formula (T3) are not limited to these, but are shown in Examples 1 to 3 below, respectively.
  • the method of protecting the terminal amino group of the amino acid or peptide compound of formula (R1) or the terminal carboxyl group of the amino acid or peptide compound of formula (R2) with a silicon-containing hydrophobic substituent TAG (Si) is not particularly limited. However, it can be implemented using various known techniques. For example, an alcohol compound having a structure of the following formula (T0) in which a silicon-containing hydrophobic substituent TAG(Si) is bonded to a hydroxyl group (OH) (this is appropriately referred to as "TAG(Si)-OH”) is produced, It can be realized by binding such an alcohol compound TAG(Si)-OH to the terminal amino group or terminal carboxyl group of an amino acid or peptide compound.
  • the alcohol compound TAG1(Si)-OH having TAG1(Si) as the silicon-containing hydrophobic substituent TAG(Si) moiety can be prepared by reacting an appropriate monosubstituted trichlorosilane compound with a trisubstituted chlorosilane compound to form a supersilyl structure Si Synthesis can be accomplished by forming a backbone with (Si) 3 and then attaching a suitable linker via carboxylic acid-silicon bond formation.
  • the alcohol compound TAG2(Si)-OH having TAG2(Si) as the silicon-containing hydrophobic substituent TAG(Si) moiety can be synthesized by reacting an alcohol with a trisubstituted chlorosilane compound to form its basic skeleton. can be done.
  • the alcohol compound TAG3(Si)-OH having TAG3(Si) as the silicon-containing hydrophobic substituent TAG(Si) moiety forms its basic skeleton through the reaction of aromatically substituted bromine with a trisubstituted chlorosilane compound. and can be synthesized.
  • Coupling of the alcohol compound TAG(Si)-OH of formula (T0) with the terminal amino group of a substrate compound is carried out under basic conditions using a known carbamate reagent such as triphosgene. It can be formed by reacting both compounds.
  • the bonding between the alcohol compound TAG(Si)-OH of the formula (T0) and the terminal carboxyl group of the substrate compound can be achieved by DCC (N,N'-dicyclohexylcarbodiimide) or DMAP (4-dimethyl It can be formed by reacting both compounds in the presence of a known condensing agent such as aminopyridine.
  • amino acid or peptide compounds of formulas (R1) and (R2) and the peptide compound of formula (P1) having a silicon-containing hydrophobic substituent TAG (Si) on the terminal amino group and/or terminal carboxyl group are each novel. and are subject of the present invention.
  • ⁇ Silane compounds In the production method (1) of the present invention, a silane compound may coexist in the reaction system. By carrying out the reaction in the presence of a silane compound in the reaction system, various advantages such as an improvement in reaction yield and an improvement in stereoselectivity may be obtained.
  • silane compounds include HSi(OCH( CF3 ) 2 ) 3 , HSi ( OCH2CF3 ) 3 , HSi( OCH2CF2CF2H ) 3 , HSi( OCH2CF2CF2CF 2 H) 3 and other tris ⁇ halo (preferably fluorine) substituted alkyl ⁇ silanes, as well as trimethylsilyl trifluoromethanesulfonate (TMS-OTf), 1-(trimethylsilyl)imidazole (TMSIM), dimethylethylsilylimidazole (DMESI ), dimethylisopropylsilylimidazole (DMIPSI), 1-(tert-butyldimethylsilyl)imidazole (TBSIM), 1-(trimethylsilyl)triazole, 1-(tert-butyldimethylsilyl)triazole, dimethylsilylimidazole, dimethylsilyl (2 -methyl)imid
  • a Lewis acid catalyst may coexist in the reaction system.
  • various advantages such as improvement in reaction yield and improvement in 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, whether or not to use a Lewis acid catalyst is preferably determined appropriately in consideration of the purpose of using the production method of the present invention.
  • the type is not limited, but it is preferably a metal compound that functions as a Lewis acid.
  • Metal elements constituting the metal compound include various metals belonging to groups 2 to 15 of the periodic table. Specific examples of metal elements include boron, magnesium, gallium, indium, silicon, calcium, lead, bismuth, mercury, transition metals, and lanthanoid elements.
  • transition metals include scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, tin, silver, cadmium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, thallium and the like.
  • lanthanoid elements include lanthanum, cerium, neodymium, samarium, europium, gadolinium, holmium, erbium, thulium, and ytterbium.
  • titanium, zirconium, hafnium, tantalum, niobium, boron, vanadium, tungsten, neodymium, iron, lead, and cobalt are preferred from the viewpoint of producing an amide compound with high stereoselectivity by exhibiting an excellent reaction promoting effect.
  • metal compounds copper, silver, palladium, tin, thallium and the like are preferred, and one or more selected from titanium, zirconium, hafnium, tantalum, niobium and the like are preferred.
  • the number of metal elements contained in the metal compound may be one or two or more. When the metal compound contains two or more metal elements, each of these may be the same kind of element, or two or more different kinds of metal elements.
  • the ligand that constitutes the metal compound is appropriately selected according to the type of metal.
  • Specific examples of ligands 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 group halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom; aryloxy group having 1 to 10 carbon atoms; TfO); substituted or unsubstituted straight-chain or branched-chain alkyl group having 1 to 10 carbon atoms; phenyl group, oxygen atom, sulfur atom, group —SR (where R is a substituent, a substituent Examples include substituted or unsubstituted hydrocarbon groups having about 1 to 20 carbon atoms.), the group -NRR' (wherein R and R' are each independently a hydrogen atom or a substituent and examples of substituents include substituted or unsubstituted hydrocarbon groups having about 1 to 20 carbon atoms.), cyclopentadienyl (Cp) group, and the like.
  • halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom
  • titanium compounds, zirconium compounds, hafnium compounds, tantalum compounds, or niobium compounds are preferable as metal compounds. Specific examples of each are given below. Any one of these may be used alone, or two or more of them may be used in any combination and ratio.
  • TiX 14 A specific example of the titanium compound is TiX 14 (wherein the four X 1 are independently the ligands exemplified above. The four X 1 may be the same ligand or different from each other ) . may be used.).
  • X 1 is an alkoxy group, it is preferably a straight or branched alkoxy group having 1 to 10 carbon atoms, more preferably a straight or branched alkoxy group having 1 to 5 carbon atoms, more preferably 1 carbon atom to 4 linear or branched alkoxy groups, and the like.
  • X 1 is an aryloxy group, it preferably includes an aryloxy group having 1 to 20 carbon atoms, particularly an aryloxy group having 1 to 15 carbon atoms, and further an aryloxy group having 1 to 10 carbon atoms. These ligands may further have substituents.
  • X 1 is a halogen atom, it is preferably a chlorine atom, a bromine atom, or the like.
  • zirconium compound is ZrX 2 4 (wherein the four X 2 are each independently the ligands exemplified above.
  • the four X 2 may be the same ligand or different from each other). may be used.
  • X 2 is an alkoxy group, it is preferably a straight or branched alkoxy group having 1 to 10 carbon atoms, more preferably a straight or branched alkoxy group having 1 to 5 carbon atoms, more preferably 1 carbon atom. to 4 linear or branched alkoxy groups, and the like.
  • X 2 is an aryloxy group, it preferably includes an aryloxy group having 1 to 20 carbon atoms, particularly an aryloxy group having 1 to 15 carbon atoms, and more preferably an aryloxy group having 1 to 10 carbon atoms. These ligands may further have substituents.
  • X 2 is a halogen atom, it is preferably a chlorine atom, a bromine atom, or the like.
  • hafnium compound is HfX 3 4 (wherein the four X 3 are each independently the ligands exemplified above. The four X 3 may be the same ligand or different from each other). and hafnium compounds represented by When X 3 is an alkoxy group, it is preferably a straight or branched alkoxy group having 1 to 10 carbon atoms, more preferably a straight or branched alkoxy group having 1 to 5 carbon atoms, more preferably 1 carbon atom to 4 linear or branched alkoxy groups, and the like.
  • X 3 is an aryloxy group, it is preferably an aryloxy group having 1 to 20 carbon atoms, particularly an aryloxy group having 1 to 15 carbon atoms, more preferably an aryloxy group having 1 to 10 carbon atoms. These ligands may further have substituents.
  • X 3 is a halogen atom, it is preferably a chlorine atom, a bromine atom, or the like. Among these, HfCp 2 Cl 2 , HfCpCl 3 , HfCl 4 and the like are preferable.
  • tantalum compound is TaX 4 5 (wherein the five X 4 are each independently the ligands exemplified above.
  • the five X 4 may be the same ligand or different from each other).
  • X 4 is an alkoxy group, it is preferably a straight or branched alkoxy group having 1 to 10 carbon atoms, more preferably a straight or branched alkoxy group having 1 to 5 carbon atoms, more preferably 1 carbon atom. to 3 linear or branched alkoxy groups, and the like.
  • X 4 is an aryloxy group, it is preferably an aryloxy group having 1 to 20 carbon atoms, particularly an aryloxy group having 1 to 15 carbon atoms, and more preferably an aryloxy group having 1 to 10 carbon atoms. These ligands may further have substituents.
  • X 4 is a halogen atom, it is preferably a chlorine atom, a bromine atom, or the like.
  • 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 be used.
  • NbX 55 A specific example of the niobium compound is NbX 55 (wherein the five X 5 are each independently the ligands exemplified above. The five X 5 may be the same ligand or different from each other). ) can be mentioned.
  • X 5 is an alkoxy group, it is preferably a straight or branched alkoxy group having 1 to 10 carbon atoms, more preferably a straight or branched alkoxy group having 1 to 5 carbon atoms, more preferably 1 carbon atom. to 3 linear or branched alkoxy groups, and the like.
  • X 5 is an aryloxy group
  • it is preferably an aryloxy group having 1 to 20 carbon atoms, particularly an aryloxy group having 1 to 15 carbon atoms, more preferably an aryloxy group having 1 to 10 carbon atoms.
  • These ligands may further have substituents.
  • X 5 is a halogen atom, it is preferably a chlorine atom, a bromine atom, or the like.
  • niobium alkoxide compounds eg, compounds in which X 5 is an alkoxy group
  • Compounds in which X 5 is oxygen can also be used, ie Nb 2 O 5 .
  • the Lewis acid catalyst may be supported on a carrier.
  • the carrier for supporting the Lewis acid catalyst is not particularly limited, and known ones can be used. A known method can also be employed as a method for supporting the Lewis acid catalyst on the carrier.
  • catalysts other than Lewis acid catalysts
  • MABR methylaluminum bis(4-bromo-2,6-di-tert-butylphenoxide)
  • TMS-OTf trimethylsilyl trifluoromethanesulfonate
  • MAD methylaluminum bis (2,6-di-tert-butylphenoxide) and the like. Any one of these may be used alone, or two or more thereof may be used in any combination and ratio.
  • the type of base is not limited, and known bases known to improve reaction efficiency can be used.
  • bases include tetrabutylammonium fluoride (TBAF), triethylamine (Et 3 N), diisopropylamine (i-Pr 2 NH), diisopropylethylamine (i-Pr 2 EtN), and the like.
  • examples include amines having 1 to 4 linear or branched alkyl groups of 10 and inorganic bases such as cesium fluoride. mentioned. Any one of these may be used alone, or two or more thereof may be used in any combination and ratio.
  • Examples of phosphorus compounds include phosphine compounds such as trimethylphosphine, triethylphosphine, tripropylphosphine, trimethyloxyphosphine, triethyloxyphosphine, tripropyloxyphosphine, 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) -fluorophenyloxy)phosphine), phosphate compounds (e.g.
  • a solvent may be used during the reaction.
  • the solvent include, but are not 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), diethyl ether (Et 2 O), ethers such as cyclopentyl methyl ether (CPME), nitrogen-based organic solvents such as acetonitrile (MeCN), chlorine-based organic solvents such as dichloromethane (DCM), ethyl acetate (AcOEt) and organic acids such as acetic acid. These solvents may be used singly or in combination of two or more.
  • the amino acid or peptide compound of the formula (R1) as a substrate compound and the amino acid ester or peptide ester compound of the formula (R2) are combined with the amidation reagent of the formula ( It may be mixed with the aluminum compound of A) and reacted.
  • the amidation reagent of the formula It may be mixed with the aluminum compound of A
  • silane compounds, Lewis acid catalysts, and/or other components they can be combined with the above substrate compounds and amides. It may be mixed with a chemical reactant. If a solvent is optionally used, each of the above components may be added to the solvent and mixed in the solvent.
  • any of the above components may be added to the system in its entirety at once, divided into multiple times, or continuously added in small amounts to the system.
  • the amount of each component to be used is not limited, but is preferably as follows.
  • the amount ratio of the amino acid or peptide compound of formula (R1) and the amino acid ester or peptide ester compound of formula (R2) is not particularly limited, but the compound of formula (R2) is added to 1 mol of the compound of formula (R1). for example 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, or for example 20 mol or less, or 10 mol or less, or 5 It can be used in the range of mol or less, or 4 mol or less, or 3 mol or less. In addition, it is preferable to use the compound of the formula (R2) more than the compound of the formula (R1) in terms of increasing the efficiency of the reaction.
  • the compound of formula (R2) can be used in an amount of about 2 mol per 1 mol of the compound of formula (R1).
  • the amount of the aluminum compound of formula (A) to be used varies from the amino acid or peptide compound of formula (R1) and the amino acid ester or peptide ester compound of formula (R2) to the peptide compound of formula (P1) through the practice of the production method of the present invention.
  • the aluminum compound of formula (A) is not particularly limited as long as it is an amount that can induce the formation reaction of For example, 0.1 mol or more, or 0.2 mol or more, or 0.3 mol or more, or 0.4 mol or more of the aluminum compound of formula (A) is added to 1 mol of the compound of formula (R1), or 0.5 mol or more, or, for example, 20 mol or less, or 10 mol or less, or 5 mol or less, or 4 mol or less, or 3 mol or less.
  • the total amount of the two or more types of aluminum compounds of formula (A) should satisfy the above range.
  • a silane compound When a silane compound is used, its usage amount is not particularly limited, but when the usage amount of the compound of formula (R1) 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 usage amount of the compound of formula (R1) 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. % 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 Lewis acid catalyst can be used.
  • the amount used may be appropriately adjusted by referring to conventional knowledge such as past patent documents (Patent Documents 1 to 6) of the present inventors.
  • reaction conditions in the production method (1) of the present invention are not limited as long as the reaction proceeds, but are exemplified below.
  • 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 it 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 also not limited as long as the reaction proceeds, but it can usually be carried out in an atmosphere of an inert gas such as argon or nitrogen.
  • the reaction time is not limited as long as the reaction proceeds. It can be within 60 hours or within 50 hours.
  • the production method (1) 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) processes are well known in the art.
  • the peptide compound (P1) obtained by the production method (1) of the present invention may be further subjected to various post-treatments.
  • the produced peptide compound (P1) can be isolated and purified by conventional methods such as column chromatography and recrystallization.
  • the produced peptide compound (P1) has an amino group and/or a carboxyl group protected with a protecting group or the like, deprotection can be carried out according to the method described later.
  • the produced peptide compound (P1) may be subjected directly, or after isolation/purification, to the latter step of the production method (2) of the present invention to be described later to produce a polypeptide with further extended amino acid residues. good.
  • polypeptide compound of formula (P1) or formula (P2) obtained by the production method described above may be further subjected to various post-treatments.
  • polypeptide compound of formula (P1) or formula (P2) obtained by the above-described production method can be isolated and purified by conventional methods such as column chromatography and recrystallization.
  • the amino group protected by the protecting group can be deprotected.
  • a method for deprotecting a 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 acid, deprotection by fluorine ion, deprotection by one-electron oxidants, deprotection by hydrazine, deprotection by oxygen, and the like.
  • (a) reduction is performed using a metal catalyst such as palladium, palladium-carbon, palladium hydroxide, palladium hydroxide-carbon, etc. as a reduction catalyst in the presence of hydrogen gas.
  • a metal catalyst such as palladium, palladium-carbon, palladium hydroxide, palladium hydroxide-carbon, etc.
  • sodium borohydride, lithium aluminum hydride, lithium borohydride, diborane, etc. in the presence of a metal catalyst such as palladium, palladium-carbon, palladium hydroxide, palladium hydroxide-carbon, etc.
  • a method of deprotection by reduction using a hydrogenating reducing agent and the like can be mentioned.
  • the carboxyl group protected by the protecting group can be deprotected.
  • a method for deprotecting a 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. In the case of deprotection with a base, a method of deprotection using a strong base such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be mentioned.
  • polypeptide compound of formula (P1) or formula (P2) obtained by the above-described production method further may be used as the peptide compound of the formula (R1) and subjected again to the production method (1) or (2) of the present invention.
  • the polypeptide compound of formula (P1) or formula (P2) obtained by the above-described production method (after undergoing treatment such as deprotection and/or conversion of substituents, if necessary) is prepared as a conventionally known may be subjected to other amidation methods or peptide production methods.
  • a polypeptide compound of formula (P1) or formula (P2) can be linked to other amino acids or peptides via an amide bond and amino acid residues can be extended to synthesize larger polypeptides.
  • 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
  • the silicon-containing hydrophobic substituent TAG (Si) used in the present invention is not limited to protection of amino acids and peptides, and can also be used to protect various other organic molecules.
  • organic molecules include, but are not limited to, sugars (various monosaccharides, disaccharides, polysaccharides, etc.), lipids (fatty acids, triacylglycerols, etc.), complex proteins (glycoproteins, lipoproteins, etc.). ), complex lipids (glycolipids, sphingolipids, phospholipids, etc.), and the like.
  • the carboxyl group and/or amino group of these organic molecules can be protected by binding the silicon-containing hydrophobic substituent TAG(Si) by the above-described technique or a technique similar thereto.
  • various organic molecules with low solubility in organic solvents such as saccharides, glycoproteins, lipoproteins, etc., have carboxyl groups and/or amino groups using the silicon-containing hydrophobic substituent TAG (Si) of the present invention.
  • the silicon-containing hydrophobic substituent TAG(Si) of the present invention can be used to protect both the carboxyl group and the amino group, it is possible to protect the group that does not interfere with the reaction depending on the type of desired reaction. There is also an advantage that the degree of freedom is extremely high. Such application of the silicon-containing hydrophobic substituent TAG(Si) of the present invention to organic molecules other than amino acids or peptides is also subject of the present invention.
  • the alcohol compound described above in which the silicon-containing hydrophobic substituent TAG (Si) is bonded to the hydroxyl group (OH), that is, the alcohol compound having the structure of the following formula (T0) is also a subject of the present invention.
  • R C1 in formula (C1) and R C21 and R C22 in formula (C2) each independently represent an arbitrary monovalent group.
  • R C1 , R C21 , and R C22 include the aforementioned monovalent substituents such as halogen atoms, hydroxyl groups, carboxyl groups, nitro groups, cyano groups, thiol groups, sulfonic acid groups, amino groups, and amide groups.
  • R C1 , R C21 and R C22 include the aforementioned organic molecules such as sugars (various monosaccharides, disaccharides, polysaccharides, etc.), lipids (fatty acids, triacylglycerols, etc.), Monovalent groups derived from complex proteins (glycoproteins, lipoproteins, etc.), complex lipids (glycolipids, sphingolipids, phospholipids, etc.) and the like are also included.
  • R C1 in formula (C1) is preferably a monovalent group obtained by removing a carboxyl group from any organic molecule having a carboxyl group.
  • the compound of formula (C1) corresponds to a compound in which the carboxyl group of the organic molecule is protected with the silicon-containing hydrophobic substituent TAG(Si).
  • Such a compound of formula (C1) can be obtained by reacting the organic molecule with an alcohol compound having a structure of formula (T0) below by the known method described above.
  • At least one of R C21 and R C22 in formula (C2) is preferably a monovalent group obtained by removing an amino group from any organic molecule having an amino group.
  • the compound of formula (C2) corresponds to a compound in which the amino group of the organic molecule is protected with the silicon-containing hydrophobic substituent TAG(Si).
  • Such a compound of formula (C2) can be obtained by reacting the organic molecule with an alcohol compound having a structure of formula (T0) below by the known method described above.
  • a supersilyl-containing compound TAG1 (Si) (1.16 mmol, 1.0 equivalent) of formula S2 was added dropwise to a methanol/tetrahydrofuran mixed solution at room temperature under a nitrogen atmosphere. After cooling to 0° C., sodium borohydride (2.3 mmol, 2.0 eq) was added dropwise. After reaching room temperature, the mixture was stirred for 20 hours. Saturated sodium hydrogen chloride was added, and the mixture was separated and extracted with ethyl acetate.
  • the alcohol compound TAG1(Si)-OH (0.15 mmol, 1.0 equivalent) was added dropwise to dichloromethane (1.5 mL) at room temperature. After adding Fmoc-Ala-OH (0.45 mmol, 3.0 equivalents) into the reaction solution, DMAP (0.18 mmol, 1.2 equivalents) and DCC (0.45 mmol, 3.0 equivalents) were added. . After stirring overnight at room temperature, filtration was performed with a filter, and the solvent was distilled off with an evaporator.
  • decapeptide 13 H -Thr(t-Bu)-Lys(Boc)-Pro-Val-Lys(Boc)-Pro-Lys(Boc)-Lys(Boc)-Val-Ala-O-TAG2
  • a compound of formula S8 was added to tetrahydrofuran (24 mL) at -78°C under a nitrogen atmosphere.
  • Pentapeptide 15 (Fmoc-Ala-Ala-Ala-Ala-Ala-O-TAG3) was obtained with a yield of 85% by repeating the above operations (1) and (2). Furthermore, the above operations (1) and (2) were repeated twice each to obtain heptapeptide 16 (Fmoc-Ala-Ala-Ala-Ala-Ala-O-TAG3) with a yield of 64%.
  • TAG3-Phe-OMe was obtained in 76% yield (160 mg).
  • the resulting characterization data for TAG3-Phe-OMe are shown below.
  • TAG3-Phe-OMe (0.1 mmol) and lithium hydroxide monohydrate (1 equivalent) in THF/MeOH/H 2 O (0.1 mL/0.3 mL/0.1 mL) were added at room temperature to 1 Stirred for .5 hours and then at 50° C. for 2 hours.
  • the resulting solution was diluted with chloroform (2 mL), hydrochloric acid (2N, 1 equivalent) was added, and the mixture was separated and extracted with water/chloroform. After drying the oil phase with sodium sulfate, the solvent was distilled off with an evaporator.

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