Classifications

• • 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
  • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
• • 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

Definitions

• the present invention relates to a novel method for producing peptide compounds using a novel silyl tag.
• Non-Patent Documents 1-3 Non-Patent Documents 1-3.
• amidation which is the most important step in peptide synthesis
• reaction methods that produce large amounts of by-products, and peptide synthesis, which involves repeated reactions in multiple stages, is extremely inefficient from the perspective of atom economy (atomic yield), and the by-products are produced in huge quantities, and there are few effective purification methods.
• the cost of disposing of and purifying the by-products accounts for most of the necessary expenses in peptide synthesis, and is one of the biggest obstacles to the development of this field.
• highly stereoselective amidation is required.
• An example of highly stereoselective amidation is an enzyme reaction that occurs in vivo.
• peptides are synthesized in vivo with extremely high stereoselectivity by making clever use of enzymes and hydrogen bonds.
• enzyme reactions are not suitable for mass production, and applying them to synthetic chemistry requires huge financial and time costs.
• the present inventors have developed technologies for synthesizing amide compounds with high chemical selectivity, such as 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), a method of using a hydroxyamino/imino compound as an amino acid precursor, amidating this in the presence of a specific metal catalyst, and then reducing it 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 (Patent Document 3).
• 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 2 a method of using a hydroxyamino/imino compound as an amino acid precursor, amidating this in the presence of a specific metal catalyst, and then reducing it in the presence of a specific metal catalyst
• Patent Document 4 a technique for synthesizing peptides consisting of various amino acid residues with high efficiency and high selectivity by amidating the carboxyl group of an N-terminal protected amino acid/peptide with the amino group of a C-terminal protected amino acid/peptide in the presence of a specific silylating agent (and a Lewis acid catalyst optionally used in combination), followed by deprotection
• Patent Document 4 a technique for synthesizing peptides consisting of various amino acid residues with high efficiency and high selectivity by amidating the carboxyl group of an N-terminal protected or unprotected amino acid/peptide with the amino group of a C-terminal protected or unprotected amino acid/peptide in the presence of a specific silylating agent, followed by deprotection
• Patent Documents 5 and 6 a technique for performing an amidation reaction using a Brönsted acid as a catalyst
• Patent Document 7 a novel silane-containing condensed ring dipeptide compound and
• peptide drugs currently on the market are oligopeptides with five or more amino acid residues.
• the polarity of the peptide increases significantly, and the solubility in the organic solvent used as the reaction solvent decreases significantly. This not only significantly reduces the reactivity of the peptide chain, but also poses a major disadvantage in terms of operability during the purification process. Therefore, in the synthesis of oligopeptides, a strategy that can ensure solubility in organic solvents during the peptide chain extension reaction is essential.
• Non-Patent Document 6 As a technique for ensuring the solubility and reactivity of a peptide chain in an organic solvent, a technique has been reported in which an alkoxybenzyl ester (TAGa) group, in which a long-chain alkyl is linked to an aromatic ring, is linked to the peptide chain as a protecting group (Non-Patent Document 6).
• TAGa alkoxybenzyl ester
• this technique has a limited effect of improving the solubility of the peptide chain in an organic solvent.
• insoluble solids were observed during the reaction process in this technique, suggesting the possibility that deprotection of the ester may occur during the reaction process.
• Non-Patent Document 7 Another technique has been reported in which a silyl ester group is used as a protecting group to link to a peptide chain.
• this technique uses a highly reactive silyl ester group as a protecting group, which limits the reaction conditions that can be applied to peptide bond reactions.
• this technique may also result in deprotection of the ester during the reaction, and in fact deprotection has been frequently confirmed and reported in this document.
• the inventors have found, through extensive research, that by subjecting an amino acid or peptide in which the terminal carboxyl group and/or terminal amino group is protected by a silicon-containing hydrophobic substituent having a specific structure to peptide chain elongation by a peptide bond reaction, it is possible to prevent a decrease in the solubility of the peptide chain in organic solvents, and to maintain and improve the reactivity of the peptide chain and the operability during the purification process.
• a method for producing a polypeptide compound comprising: subjecting a carboxyl group on the right side of an amino acid or peptide compound represented by the following formula (R1) to an amide-forming reaction with an amino group on the left side of an amino acid ester or peptide ester compound represented by the following formula (R2), thereby obtaining a peptide compound represented by the following formula (P1):
• T a represents a hydrogen atom or a monovalent substituent
• R 11 and R 12 each independently represent 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, a monovalent aliphatic hydrocarbon group, a monovalent aromatic hydrocarbon group, or a monovalent heterocyclic group, each of which may have one or more substituents
• R 13 represents a hydrogen atom or a monovalent substituent
• T b represents a hydrogen atom or a monovalent substituent
• R 21 and R 22 each independently represent 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, a monovalent aliphatic hydrocarbon group, a monovalent aromatic hydrocarbon group, or a monovalent heterocyclic group, which may have one or more substituents
• R 23 represents a hydrogen atom, a carboxyl group, a hydroxyl group, or a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group which may have one or more substituents, and in the case of a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group, it may be bonded to a nitrogen atom via a
• T b is a group represented by -TAG(Si).
• -TAG(Si) is a group having the following formula structure.
• R x represents a divalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group, which may have one or more substituents
• R z1 to R z9 each independently represent a monovalent aliphatic hydrocarbon group, an aromatic hydrocarbon group, a silicon-containing hydrocarbon group, or a heterocyclic group, which may have one or more substituents, provided that at least one of R z1 to R z9 is an aliphatic hydrocarbon group having 7 or more carbon atoms which may have one or more substituents.
• T a , R 11 , R 12 , R 13 , A 11 , A 12 , p11 , p12 and n 1 each represent the same group as defined in formula (R1); R21 , R22 , R23 , A21 , A22 , p21, p22, n2 , and Tb each represent the same group as defined in formula (R2).
• R21 , R22 , R23 , A21 , A22 , p21, p22, n2 , and Tb each represent the same group as defined in formula (R2).
• Tb each represent the same group as defined in formula (R2).
• R x is a divalent aliphatic hydrocarbon having 2 or more carbon atoms.
• R x is a divalent aliphatic hydrocarbon having 2 or more carbon atoms.
• R x is a divalent aliphatic hydrocarbon having 2 or more carbon atoms.
• R x is a divalent aliphatic hydrocarbon having 2 or more carbon atoms.
• R x is a divalent aliphatic hydrocarbon having 2 or more carbon atoms.
• the reaction is carried out in an organic solvent.
• 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.
• TAG(Si) is the same as the definition of the group having the same symbol described in section 1.
• [Item 16] A compound represented by the following formula (C0). In formula (C0), the definition of TAG(Si) is the same as the definition of the group having the same symbol described in item 1.
• [Item 17] A compound represented by the following formula (C1). In formula (C1), the definition of TAG(Si) is the same as the definition of the group having the same symbol 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 bond reaction, thereby preventing a decrease in the solubility of the peptide chain in organic solvents, and thus improving the reactivity of the peptide chain and the operability during the purification process.
• silicon-containing hydrophobic substituents are stable and do not decompose under the conditions for deprotecting the amino group protecting group, and can be efficiently removed by hydrolysis after completion of peptide elongation, making it possible to obtain the desired peptide with high efficiency.
• amino acid refers to a compound having a carboxyl group and an amino group.
• the type of amino acid is not particularly limited.
• it may be D-form, L-form, or racemic.
• it may be any of ⁇ -amino acid, ⁇ -amino acid, ⁇ -amino acid, ⁇ -amino acid, ⁇ -amino acid, 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, glutamic acid, proline, cysteine, threonine, methionine, histidine, phenylalanine, tyrosine, tryptophan, asparagine, glycine, serine, etc.
• peptide refers to a compound in which multiple amino acids are linked via peptide bonds.
• the multiple 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 constituting a peptide is not particularly limited as long as it is two or more. Examples include 2 (also called “dipeptides”), 3 (also called “tripeptides”), 4 (also called “tetrapeptides”), 5 (also called “pentapeptides”), 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 100, or more.
• polypeptide may refer to a peptide that is tripeptide or more.
• amino group refers to a functional group represented by the formula -NH2 , -NRH, or -NRR' (wherein R and R' each represent a substituent) obtained by removing hydrogen from ammonia, a primary amine, or a secondary amine, respectively.
• the hydrocarbon group may be aliphatic or aromatic.
• the aliphatic hydrocarbon group may be linear or cyclic.
• the linear hydrocarbon group may be linear or branched.
• the cyclic hydrocarbon group may be monocyclic, bridged, 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. That is, the concept of the hydrocarbon group includes alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, aryl groups, arylalkyl groups, alkylaryl groups, and the like.
• one or more hydrogen atoms of the hydrocarbon group may be replaced with any substituent, and one or more carbon atoms of the hydrocarbon group may be replaced with any heteroatom depending on the valence.
• hydrocarbon oxy group refers to a group in which a hydrocarbon group as defined above is linked to one of the bonds of an oxy group (-O-).
• the concept of a hydrocarbon oxy group includes alkyloxy groups, alkenyloxy groups, alkynyloxy groups, cycloalkyloxy groups, cycloalkenyloxy groups, cycloalkynyloxy groups, aryloxy groups, etc.
• the concept of a hydrocarbon carbonyl group includes alkylcarbonyl groups, alkenylcarbonyl groups, alkynylcarbonyl groups, cycloalkylcarbonyl groups, cycloalkenylcarbonyl groups, cycloalkynylcarbonyl groups, arylcarbonyl groups, etc.
• hydrocarbonsulfonyl group encompasses alkylsulfonyl groups, alkenylsulfonyl groups, alkynylsulfonyl groups, cycloalkylsulfonyl groups, cycloalkenylsulfonyl groups, cycloalkynylsulfonyl groups, arylsulfonyl groups, etc.
• 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.
• a heterocyclic group may be monocyclic, bridged, or spirocyclic.
• the heteroatoms contained in the heterocyclic ring atoms of a heterocyclic group are not limited, but examples include nitrogen, oxygen, sulfur, phosphorus, silicon, etc.
• heterocyclic oxy group refers to a group in which a heterocyclic group as defined above is linked to one bond of an oxy group (-O-).
• a "metalloxy group” (which may have one or more substituents) refers to a group represented by the formula (R) n -M-O-, where M refers to any metal element, R refers to any substituent, and n refers to an integer of 0 to 8 that can take a value depending on the coordination number of the metal element M.
• substituteduents refer to any substituent, each independently and unless otherwise specified, without any particular limitation as long as the amidation step in the production method of the present invention proceeds.
• alkyl group include, but are not limited to, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, a thiol group, a sulfonic acid group, an amino group, an amido group, an imino group, an imido group, a hydrocarbon group, a heterocyclic group, a hydrocarbonoxy group, a hydrocarboncarbonyl group (acyl group), a hydrocarbonoxycarbonyl group, a hydrocarboncarbonyloxy group, a hydrocarbon-substituted amino group, a hydrocarbon-substituted aminocarbonyl group, a hydrocarboncarbonyl-substituted amino group, a hydrocarbon-substituted thiol group, a hydrocarbons
• amino acids and their residues may be represented by three-letter abbreviations 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 following table.
• ⁇ -homo amino acids and their residues may be represented by adding "Ho" before the three-letter abbreviation of the corresponding ⁇ -amino acid.
• protecting group refers to a functional group that can be introduced onto the nitrogen atom of an amino or amide group under specific reaction conditions and can be removed under specific reaction conditions. Representative protecting groups are described in detail in several textbooks, such as Peter G. M. Wuts, Green's Protective Groups in Organic Synthesis, 5th Edition, Wiley, 2014.
• alkyl-type protecting group refers to a hydrocarbon group that can be easily attached to and detached from the nitrogen atom of an amino group or an amide group. Examples include an unsubstituted or substituted benzyl group, an unsubstituted or substituted allyl group, etc.
• the term "electron-withdrawing protecting group” refers to a protecting group that acts as a protecting group for an amino group or an amide group, and that attracts electrons on the nitrogen atom toward the protecting group.
• Examples include acyl groups, alkyloxycarbonyl groups, alkylsulfonyl groups, and arylsulfonyl groups.
• One aspect of the present invention relates to a method for producing a polypeptide compound, which comprises subjecting a carboxyl group on the right side of an amino acid or peptide compound of formula (R1) to an amide-forming reaction with an amino group on the left side of an amino acid ester or peptide ester compound of formula (R2) to obtain a peptide compound of formula (P1) (hereinafter referred to as the "method for producing the peptide compound of the present invention” or simply the "production method of the present invention” as appropriate).
• R11 , R12 , R21 , and R22 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, or a thiol group, or a monovalent hydrocarbon group or heterocyclic group which may have one or more substituents.
• substituents When these groups have a substituent, the type of the substituent is as described above.Specific examples of the number of the substituents are, for example, 5, 4, 3, 2, 1, or 0.
• R 11 , R 12 , R 21 , and/or R 22 are monovalent hydrocarbon groups or heterocyclic groups which 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, but may be independently selected from, for example, the structures shown below (in the chemical formulas below, each A independently represents a monovalent hydrocarbon group or heterocyclic group which may have one or more substituents. When there are two A's 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 groups and alkynyl groups, and 3 or more for cycloalkyl groups, 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, or 20.
• the total number of carbon atoms and heteroatoms (including substituents, if any) in a 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 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 one or more substituents.
• 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. Although it depends on the reactivity of the compound (R1) and compound (R2) used in the reaction, when the group having a carboxyl group among the above groups has a protecting group, the reaction selectivity with the carboxylic acid ester group on the right side of the formula of compound (R2) is usually improved compared to the reaction selectivity with the carboxyl groups present in other substituents.
• R13 and R23 each independently represent a hydrogen atom, a carboxyl group, or a hydroxyl group, or a monovalent hydrocarbon group or heterocyclic group which may have one or more substituents. If the group has a substituent, the type of the substituent is as described above. Specific examples of the number of the substituents are, for example, 5, 4, 3, 2, 1, or 0.
• R 13 and/or R 23 are monovalent hydrocarbon groups or heterocyclic groups which may have one or more substituents
• a linking group may be present between the hydrocarbon group or heterocyclic group and the nitrogen atom to which it is bonded.
• Such linking groups are not limited, but are each independently selected from the structures shown below (note that in the chemical formulas below, each A independently represents a monovalent hydrocarbon group or heterocyclic group which may have one or more substituents. When there are two A's in the same group, they may be the same or different).
• 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 groups and alkynyl groups, and 3 or more for cycloalkyl groups, 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, or 20.
• the upper limit of the total number of carbon atoms and heteroatoms (including substituents, if any) in a 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.
• R13 and R23 are each independently a hydrogen atom, a hydroxyl group, or a carboxyl group, or 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 one or more substituents.
• R 13 and R 23 include, but are not limited to, the following:
• Hydrogen atom, hydroxyl group, carboxyl group - alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, decyl, and nonyl groups; alkenyl groups such as ethenyl, propenyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, and octenyl; - alkynyl groups such as propargyl groups; - cycloalkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a bi
• R 11 and R 13 may be bonded to each other to form a heterocycle that 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
• R 21 and R 23 may be bonded to each other to form a heterocycle that 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.
• the type 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 (including substituents, if any) in a 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, morpholino, thiomorpholino, 1,2,4,6-tetrahydropyridyl, hexahydropyrimidyl, hexahydropyridazyl, 1,2,4,6-tetrahydropyridyl, 1,2,4,6-tetrahydropyridazyl, 3,4-dihydropyridyl, imidazolyl, 4,5-dihydropyridyl, 5,6-dihydropyridyl, 6,7-dihydropyridyl, 7,8-dihydropyridyl, 8,9-dihydropyridyl, 9,10-dihydropyridyl, 11,11-dihydropyrid
• 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, a methylene group, an ethylene group, a propylene group, an isopropylene group, and the like, as well as groups in which these groups are substituted with one or more of the above-mentioned substituents.
• 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.
• n1 is an integer of 1 or more, which represents the number of amino acid units in [ ] of general formula (R1).
• compound (R1) becomes an amino acid
• compound (R1) becomes a peptide.
• the upper limit of n1 is not particularly limited as long as the amination process proceeds, and 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.
• Specific examples of n1 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.
• n2 is an integer of 1 or more, which represents the number of amino acid units in [ ] of general formula (R2).
• n2 is 1, compound (R2) becomes an amino acid, and when n2 is 2 or more, compound (R2) becomes a peptide.
• the upper limit of n2 is not particularly limited as long as the amination process proceeds, and examples thereof include 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.
• n2 is preferably 1, that is, compound (R2) is preferably an amino acid.
• n2 is 1, that is, when compound (R2) is an amino acid, it reacts with the aluminum compound of formula (A) to form a cyclized intermediate containing an aluminum atom, which is one of the factors that improve the reaction efficiency.
• R11 , R12 , R13, A11, A12, p11, and p12 that define the structure in [ ] may be the same or different among the multiple amino acid units.
• R21, R22, R23 , A21 , A22 , p21 , and p22 that define the structure in [ ] may be the same or different among the multiple amino acid units. That is, when compound (R1) and/or compound (R2) are peptides, the multiple amino acid units that constitute the peptide may be the same or different.
• T a represents a hydrogen atom or a monovalent substituent.
• the type is not particularly limited, but in addition to the groups described above as R 13 and R 23 , examples include a protecting group for an amino group (hereinafter referred to as PG a appropriately) and a silicon-containing hydrophobic substituent TAG (Si) described below.
• the protecting group PG a for an amino group 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 convert it to an amino group. The details of the protecting group PG a for an amino group and the silicon-containing hydrophobic substituent TAG (Si) will be described later.
• T b represents a hydrogen atom or a monovalent substituent.
• the type is not particularly limited, and examples thereof include the groups described above as R 13 and R 23 , as well as a protective group for a carboxyl group (hereinafter referred to as PG b as appropriate) and a silicon-containing hydrophobic substituent TAG (Si) described below.
• the protective group for a carboxyl 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 it to a carboxyl group.
• the details of the protective group for a carboxyl group PG b and the silicon-containing hydrophobic substituent TAG (Si) will be described later.
• the amino group on the left side of the formula may form a salt with another acid.
• the other acid may include, but is 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, etc.
• substrate compounds (R1) and (R2) may each be used as a single compound, or as a mixture of two or more compounds in any combination and ratio.
• a part or all of the above-mentioned substrate compound (R1) or (R2) may be linked and fixed to a support such as a substrate or resin at any of the substituents.
• the type of the support such as the substrate or resin is not limited. Any conventionally known support such as a substrate or resin 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 linking and fixing the substrate compound to the support such as the substrate or resin is not limited in any way, but it is preferable to form a covalent bond between any of the substituents possessed by the substrate compound and the substituents present on the support such as the substrate or resin.
• each substituent or the method of forming the covalent bond there is also no limitation in the type of each substituent or the method of forming the covalent bond. Any conventionally known type of substituent and method of forming the 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.
• the substrate compound may be linked and fixed to a support such as a substrate or resin by a covalent bond using a carboxyl group or amino group (other than the carboxylate group or amino group that is the target of the amide bond reaction) possessed by the substrate compound.
• This embodiment can be considered similar to an embodiment in which a carboxyl group or amino group (other than the carboxylic acid ester group or amino group that is the target of the amide bond reaction) in the substrate compound is protected by introducing a protecting group.
• amino group protecting groups PG a are known. Examples include monovalent hydrocarbon groups which may have one or more substituents, or monovalent heterocyclic groups which may have one or more substituents. Among them, monovalent hydrocarbon groups which may have one or more substituents are preferred. However, 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 from the linking groups shown below (note that in the following chemical formula, A each independently represents a monovalent hydrocarbon group or heterocyclic group which may have one or more substituents. When there are two A 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 protecting group for the amino group is one or more groups selected from the group consisting of monovalent hydrocarbon groups, acyl groups, hydrocarbonoxycarbonyl groups, and hydrocarbonsulfonyl groups, which may have one or more substituents, and amide groups.
• protecting groups for amino groups include not only the names of the functional groups bonded to the nitrogen atom of the amino group, but also names that include the nitrogen atom, and the names below 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 cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; aryl groups such as phenyl, benzyl, paramethoxybenzyl, tolyl, and triphenylmethyl (toroc) groups; and substituted hydrocarbon groups such as cyanomethyl.
• 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 (Bz), ortho-methoxybenzoyl, 2,6-dimethoxybenzoyl, para-methoxybenzoyl (PMPCO), cinnamoyl, and phthaloyl (Phth) groups.
• 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, allyloxycarbonyl group, Examples include a carboxyl group (Alloc), an N-hydroxypiperidinyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a 2-(1,3-dithianyl)methoxycarbonyl group, a m-nitrophenoxycarbonyl group, a 3,5
• unsubstituted or substituted hydrocarbon sulfonyl groups include methanesulfonyl groups (Ms), toluenesulfonyl groups (Ts), and 2- or 4-nitrobenzenesulfonyl groups (Ns).
• Ms methanesulfonyl groups
• Ts toluenesulfonyl groups
• Ns 2- or 4-nitrobenzenesulfonyl groups
• 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, and benzylsulfonamide.
• examples of protecting groups for amino groups include protecting groups that can be deprotected by at least one of the following techniques: deprotection by hydrogenation, deprotection by a weak acid, deprotection by fluoride ions, deprotection by a one-electron oxidant, deprotection by hydrazine, and deprotection by oxygen.
• Preferred specific examples of the protecting group for the amino group include mesyl group (Ms), tert-butoxycarbonyl group (Boc), benzyl group (Bn or Bzl), benzyloxycarbonyl group (Cbz), benzoyl group (Bz), paramethoxybenzyl 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), etc.
• these protecting groups can easily protect the amino group and can be removed under relatively mild conditions.
• amino protecting groups include mesyl (Ms), tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), paramethoxybenzyl (PMB), 2,2,2-trichloroethoxycarbonyl (Troc), allyloxycarbonyl (Alloc), paramethoxybenzoyl (PMPCO), benzoyl (Bz), cyanomethyl, cinnamoyl, 2- or 4-nitrobenzenesulfonyl (Ns), toluenesulfonyl (Ts), phthaloyl (Phth), 2,4-dinitrophenyl (2,4-DNP), and 9-fluorenylmethyloxycarbonyl (Fmoc).
• Ms mesyl
• Boc tert-butoxycarbonyl
• Cbz benzyloxycarbonyl
• PMB paramethoxybenzyl
• Troc 2,2,2-trichlor
• Carboxyl protecting group Various types of carboxyl group protecting group PGb are known. Examples include monovalent hydrocarbon groups or heterocyclic groups which may have one or more substituents. If the group has a substituent, the type of the substituent is as described above. Specific examples of the number of the 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 groups and alkynyl groups, and 3 or more for cycloalkyl groups, 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, or 20.
• the upper limit of the total number of carbon atoms and heteroatoms (including substituents, if any) in a 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.
• protecting groups for carboxyl groups include, but are not limited to, the following:
• alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, decyl, and nonyl groups; alkenyl groups such as ethenyl, propenyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, and octenyl; - alkynyl groups such as propargyl groups; - cycloalkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a bicyclooctyl group, and a spiro
• Silicon-containing hydrophobic substituent TAG(Si) One of the main features of the method of the present invention is that it satisfies the following (i) and/or (ii): (i) T a in formula (R1) is a group represented by —O—C( ⁇ O)-TAG(Si). (ii) 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 the following formula (T).
• one of the main features of the method of the present invention is that the amino group on the left side of the formula of the amino acid or peptide compound of formula (R1) and/or the carboxyl group on the right side of the formula of the amino acid ester or peptide ester compound of formula (R2) are protected by the silicon-containing hydrophobic substituent TAG(Si) (or a group containing it) of the above formula (T).
• Rx represents a divalent, trivalent, or tetravalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group, which may have one or more substituents.
• the divalent, trivalent, or tetravalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group may be any divalent, trivalent, or tetravalent group obtained by removing any one, two, or three hydrogen atoms from the monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group. If the group has a substituent, the type of the substituent is as described above. Specific examples of the number of the substituents are, for example, 5, 4, 3, 2, 1, or 0.
• the upper limit of the number of carbon atoms in the divalent, trivalent, or tetravalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group (including the substituent if any) of Rx 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 an alkyl group, 2 or more for an alkenyl group or alkynyl group, and 3 or more for a cycloalkyl group, 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, or 20.
• R x is preferably a divalent aliphatic hydrocarbon having 2 or more carbon atoms.
• R x may be a divalent aliphatic hydrocarbon having 2 or more carbon atoms containing one or more unsaturated bonds (double bonds or triple bonds).
• R x is preferably -C ⁇ C-.
• R z1 to R z9 each independently represent a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, silicon-containing hydrocarbon group, or heterocyclic group, which may have one or more substituents.
• the 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.
• heterocyclic group is as explained separately. Specific examples include, but are not limited to, the following:
• alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, decyl, and nonyl groups; alkenyl groups such as ethenyl, propenyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, and octenyl; - alkynyl groups such as propargyl groups; - cycloalkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a bicyclooctyl group, and a spiro
• Examples of monovalent silicon-containing hydrocarbon groups include groups obtained by replacing any one or more carbon atoms of a monovalent aliphatic or aromatic hydrocarbon group with a silicon atom.
• R z1 to R z9 are monovalent aliphatic hydrocarbon groups or aromatic hydrocarbon groups
• the upper limit of the number of carbon atoms 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, but is 1 or more for alkyl groups, 2 or more for alkenyl groups or alkynyl groups, and 3 or more for cycloalkyl groups, for example, 4 or more, or 5 or more.
• R z1 , R z2 , and/or R z3 are monovalent heterocyclic groups
• the upper limit of the total number of carbon atoms and heteroatoms 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, but is usually 3 or more, for example, 4 or more, or 5 or more.
• Specific examples of the number of atoms include 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, etc.
• At least one, preferably at least two, more preferably at least three of R z1 to R z9 are aliphatic hydrocarbon groups having 7 or more carbon atoms which may have one or more substituents.
• the aliphatic hydrocarbon groups may be saturated or unsaturated, and may be linear, branched, or cyclic.
• unsubstituted or substituted aliphatic hydrocarbon groups having 7 or more carbon atoms include alkyl groups (linear or branched) such as tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, and heptyl groups, alkenyl or alkynyl groups obtained by unsaturating one or more of these carbon-carbon bonds, and groups obtained by substituting these groups with one or more substituents.
• alkyl groups linear or branched
• pentadecyl pentadecyl
• hexadecyl hexadecyl
• heptadecyl octadecyl
• nonadecyl icosyl
• heptyl groups alkenyl or alkynyl groups obtained by unsaturating one or more of these carbon-carbon bonds
• R z1 to R z9 are aliphatic hydrocarbon groups having 7 or more carbon atoms. It is also preferred that one or more of R z1 to R z3 (particularly two or more, particularly all three), one or more of R z4 to R z6 (particularly two or more, particularly all three), and one or more of R z7 to R z9 (particularly two or more, particularly all three) are aliphatic hydrocarbon groups having 7 or more carbon atoms which may have one or more substituents.
• the silicon-containing hydrophobic substituent TAG(Si) of the above formula (T) protects the protecting group of the terminal amino group on the left side of the formula of the amino acid or peptide compound of the formula (R1)
• the terminal amino radical -N(R 13 )- of the compound of the formula (R1) usually bonds to the group -TAG(Si) via the carbonyloxy group -C( ⁇ O)-O- to form a structure represented by -N(R 13 )-C( ⁇ O)-O-TAG(Si).
• the silicon-containing hydrophobic substituent TAG(Si) of the above formula (T) protects the carboxyl group on the right side of the formula of the terminal amino acid ester or peptide ester compound of the formula (R2)
• the terminal carboxyl radical -C( ⁇ O)-O- of the compound of the formula (R2) usually bonds directly to the group -TAG(Si) to form a structure represented by -C( ⁇ O)-O-TAG(Si).
• the terminal amino group of the amino acid or peptide compound of formula (R1) and/or the terminal carboxyl group of the amino acid or peptide compound of formula (R2) are protected using a silicon-containing hydrophobic substituent TAG(Si) having such a specific structure, and the peptide chain is subjected to elongation by a peptide bond reaction using these compounds, thereby preventing a decrease in the solubility of the peptide chain in an organic solvent, and thus improving the reactivity of the peptide chain and the operability in the purification process.
• the silicon atom is not directly bonded to the terminal carboxyl group of the amino acid or peptide compound, but is bonded via the R x group and the L group, so there is little risk of deprotection of the ester depending on the reaction conditions, and it is possible to handle a variety of reaction conditions.
• silicon-containing hydrophobic substituents are stable and do not undergo decomposition under the conditions for deprotecting the amino group-protecting group, and can be efficiently removed by hydrolysis after completion of peptide elongation. Therefore, by carrying out a peptide elongation reaction using this silicon-containing hydrophobic substituent, it is possible to obtain the desired peptide with high efficiency.
• the method of the present invention has a great advantage in that 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 formation reactions are carried out by N-terminal extension.
• N-terminal protecting groups are overwhelmingly lacking in diversity compared to C-terminal protecting groups such as Fmoc, Boc, Cbz, Trt, and Ac.
• these protecting groups focus on short-chain peptide synthesis and are almost ineffective in reducing polarity to long-chain peptides. From these perspectives, the synthesis of N-terminal protecting groups with a view to long-chain peptide synthesis is important, and the silicon-containing hydrophobic substituent TAG(Si) of the present invention is very useful in this respect.
• Silane compounds In the production method (1) of the present invention, a silane compound may be present in the reaction system. By carrying out the reaction in the presence of a silane compound in the reaction system, various advantages such as improved reaction yield and improved stereoselectivity may be obtained.
• silane compounds include HSi(OCH( CF3 ) 2 ) 3 , HSi ( OCH2CF3 ) 3 , HSi ( OCH2CF2CF2H ) 3 , and HSi( OCH2CF2CF2CF2CF2H ) .
• trimethylsilyl trifluoromethanesulfonate such as 3
• TMS-OTf trimethylsilyl trifluoromethanesulfonate
• TMSIM 1-(trimethylsilyl)imidazole
• DMESI dimethylethylsilylimidazole
• DMIPSI dimethylisopropylsilylimidazole
• TBSIM 1-(tert-butyldimethylsilyl)imidazole
• TMSIM 1-(trimethylsilyl)triazole, 1-(tert-butyldimethylsilyl)triazole, dimethylsilylimidazole, dimethylsilyl ( 2-methyl)imidazole
• TMBS trimethylbromosilane
• TMCS trimethylchlorosilane
• MSTFA N,O-bis(trimethylsilyl)trifluoroacetamide
• a Lewis acid catalyst may be present in the reaction system.
• various advantages such as improved reaction yield and improved 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 determine whether or not to use a Lewis acid catalyst, taking into consideration the purpose of using the production method of the present invention, etc.
• the type is not limited, but it is preferable that the catalyst is 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, lanthanoid elements, etc.
• 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, etc.
• lanthanoid elements include lanthanum, cerium, neodymium, samarium, europium, gadolinium, holmium, erbium, thulium, ytterbium, etc.
• lanthanoid elements include lanthanum, cerium, neodymium, samarium, europium, gadolinium, holmium, erbium, thulium, ytterbium, etc.
• the metal compound may contain one or more metal elements. When the metal compound contains two or more metal elements, these may be the same type of element, or two or more different metal elements.
• the ligands constituting the metal compound are appropriately selected according to the type of metal.
• Specific examples of ligands include substituted or unsubstituted linear or branched alkoxy groups having 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, trifluoroethoxy, and trichloroethoxy groups; halogen atoms such as fluorine, chlorine, bromine, and iodine atoms; aryloxy groups having 1 to 10 carbon atoms; acetylacetonate (acac), acetoxy (AcO), and trifluoromethanesulfonate (TfO); and substituted or unsubstituted carbon Examples include linear or branched alkyl groups with a prime number of 1 to 10; phenyl groups, oxygen atoms, sulfur atoms, -SR groups (where R is a substituent, and examples of the substituent include substituted or unsubstituted hydrocarbon groups with
• the metal compounds are preferably titanium compounds, zirconium compounds, hafnium compounds, tantalum compounds, or niobium compounds. Specific examples of each are given below. These may be used alone or in any combination and ratio of two or more.
• titanium compounds include titanium compounds represented by TiX 1 4 (wherein each of the four X 1 is independently a ligand exemplified above. The four X 1 may be the same ligand or may be different from each other).
• X 1 is an alkoxy group, it is preferably a linear or branched alkoxy group having 1 to 10 carbon atoms, particularly a linear or branched alkoxy group having 1 to 5 carbon atoms, and further a linear or branched alkoxy group having 1 to 4 carbon atoms.
• X 1 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 further an aryloxy group having 1 to 10 carbon atoms. These ligands may further have a substituent.
• X 1 is a halogen atom, it is preferably a chlorine atom, a bromine atom, and the like.
• zirconium compound examples include zirconium compounds represented by ZrX 2 4 (wherein each of the four X 2 is independently a ligand exemplified above. The four X 2 may be the same ligand or may be different from each other).
• X 2 is an alkoxy group, it is preferably a linear or branched alkoxy group having 1 to 10 carbon atoms, particularly a linear or branched alkoxy group having 1 to 5 carbon atoms, and further a linear or branched alkoxy group having 1 to 4 carbon atoms.
• X 2 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 further an aryloxy group having 1 to 10 carbon atoms. These ligands may further have a substituent.
• X 2 is a halogen atom, it is preferably a chlorine atom, a bromine atom, and the like.
• hafnium compounds include hafnium compounds represented by HfX 3 4 (wherein each of the four X 3 is independently a ligand exemplified above. The four X 3 may be the same ligand or may be different from each other).
• X 3 is an alkoxy group, it is preferably a linear or branched alkoxy group having 1 to 10 carbon atoms, particularly a linear or branched alkoxy group having 1 to 5 carbon atoms, and further a linear or branched alkoxy group having 1 to 4 carbon atoms.
• X 3 is an allyloxy group, it is preferably an allyloxy group having 1 to 20 carbon atoms, particularly an allyloxy group having 1 to 15 carbon atoms, and further an allyloxy group having 1 to 10 carbon atoms. These ligands may further have a substituent.
• X 3 is a halogen atom, it is preferably a chlorine atom, a bromine atom, and the like. Among these, for example, HfCp 2 Cl 2 , HfCpCl 3 , HfCl 4 , and the like are preferable.
• tantalum compounds include tantalum compounds represented by TaX 4 5 (wherein each of the five X 4 is independently a ligand exemplified above. The five X 4 may be the same ligand or may be different from each other).
• X 4 is an alkoxy group, it is preferably a linear or branched alkoxy group having 1 to 10 carbon atoms, particularly a linear or branched alkoxy group having 1 to 5 carbon atoms, and further a linear or branched alkoxy group having 1 to 3 carbon atoms.
• 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 further an aryloxy group having 1 to 10 carbon atoms. These ligands may further have a substituent.
• X 4 is a halogen atom, it is preferably a chlorine atom, a bromine atom, and the like.
• tantalum alkoxide compounds e.g., compounds in which X4 is an alkoxy group
• tantalum alkoxide compounds e.g., compounds in which X4 is an alkoxy group
• Ta(OMe) 5 Ta(OEt) 5
• Ta(OBu) 5 Ta( NMe2 ) 5
• Ta(acac)(OEt) 4 TaCl5 , TaCl4 (THF), TaBr5 , etc.
• a compound in which X4 is oxygen i.e. , Ta2O5 .
• niobium compounds include niobium compounds represented by NbX 5 5 (wherein each of the five X 5 is independently a ligand exemplified above. The five X 5 may be the same ligand or may be different from each other).
• X 5 is an alkoxy group, it is preferably a linear or branched alkoxy group having 1 to 10 carbon atoms, particularly a linear or branched alkoxy group having 1 to 5 carbon atoms, and further a linear or branched alkoxy group having 1 to 3 carbon atoms.
• 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, and further an aryloxy group having 1 to 10 carbon atoms.
• These ligands may further have a substituent.
• X 5 is a halogen atom, it is preferably a chlorine atom, a bromine atom, and the like.
• niobium alkoxide compounds e.g., compounds in which X5 is an alkoxy group
• NbCl4 THF
• NbCl5 Nb(OMe) 5
• Nb(OEt) 5 Compounds in which X5 is oxygen, i.e., Nb2O5 , can also be used.
• the Lewis acid catalyst may be supported on a carrier.
• a carrier that supports the Lewis acid catalyst
• any known carrier can be used.
• any known method can be used to support the Lewis acid catalyst on a carrier.
• ⁇ Other ingredients In the production method (1) of the present invention, in addition to the substrate compounds, the amino acid or peptide compound of the formula (R1) and the amino acid ester or peptide ester compound of the formula (R2), the aluminum compound of the formula (A) as the amidation reactant, and further the silane compound and/or Lewis acid catalyst that are optionally used, other components may be present. 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, etc. Any one of these may be used alone, or two or more may be used in any combination and ratio.
• 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)
• the type of base is not limited, and any known base that is known to improve the reaction efficiency can be used.
• bases include amines having 1 to 4 linear or branched alkyl groups having 1 to 10 carbon atoms, such as tetrabutylammonium fluoride (TBAF), triethylamine (Et 3 N), diisopropylamine (i-Pr 2 NH), and diisopropylethylamine (i-Pr 2 EtN), and inorganic bases such as cesium fluoride. These may be used alone or in any combination and ratio of two or more.
• TBAF tetrabutylammonium fluoride
• Et 3 N triethylamine
• i-Pr 2 NH diisopropylamine
• i-Pr 2 EtN diisopropylethylamine
• phosphorus compounds include phosphine compounds (e.g., 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, etc.), phosphate compounds (e.g., trimethylphosphate, triethylphosphate, tripropylphosphate, trimethyloxyphosphine, phosphate, triethy
• a solvent may be used during the reaction.
• the solvent is not particularly limited, but examples thereof include aqueous solvents and organic solvents.
• the organic solvent is not limited, but examples thereof include aromatic hydrocarbons such as toluene and xylene, ethers such as pentane, petroleum ether, tetrahydrofuran (THF), 1-methyltetrahydrofuran (1-MeTHF), diisopropyl ether (i-Pr 2 O), 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), esters such as ethyl acetate (AcOEt), and organic acids such as acetic acid. These solvents may be used alone or in combination of two or more.
• the amino acid or peptide compound of the formula (R1) and the amino acid ester or peptide ester compound of the formula (R2), which are substrate compounds may be mixed with the aluminum compound of the formula (A), which is an amidation reactant, and reacted.
• a silane compound, a Lewis acid catalyst, and/or other components such as a catalyst other than a Lewis acid catalyst, a base, and/or a phosphorus compound
• they may be mixed with the substrate compound and the amidation reactant.
• a solvent is used optionally, the above components may be added to a solvent and mixed in the solvent.
• the entire amount may be added to the system at once, or may be added to the system in multiple batches, or may be added to the system in small amounts continuously.
• ⁇ Ratio of each ingredient used In the production method (1) of the present invention, the amounts of each component used are not limited, but are preferably as follows.
• the ratio of the amount of the amino acid or peptide compound of formula (R1) to the amino acid ester or peptide ester compound of formula (R2) is not particularly limited, but the compound of formula (R2) can be used in a range of, for example, 0.1 moles or more, 0.2 moles or more, 0.3 moles or more, 0.4 moles or more, or 0.5 moles or more, and for example, 20 moles or less, 10 moles or less, 5 moles or less, 4 moles or less, or 3 moles or less, per mole of the compound of formula (R1). It is preferable to use more of the compound of formula (R2) than the compound of formula (R1) in terms of increasing the reaction efficiency.
• the compound of formula (R2) can be used in an amount of about 2 moles per mole of the compound of formula (R1). It is necessary to use at least 1 mole of each of the compound of formula (R1) and the compound of formula (R2) as substrates for the target production amount of the compound of formula (P1) to be produced.
• the amount of the aluminum compound of formula (A) used is not particularly limited, so long as it is an amount that can induce the formation reaction of the peptide compound of formula (P1) from the amino acid or peptide compound of formula (R1) and the amino acid ester or peptide ester compound of formula (R2) through the implementation of the production method of the present invention.
• the aluminum compound of formula (A) can be used in a range of, for example, 0.1 moles or more, or 0.2 moles or more, or 0.3 moles or more, or 0.4 moles or more, or 0.5 moles or more, and, for example, 20 moles or less, or 10 moles or less, or 5 moles or less, or 4 moles or less, or 3 moles or less, per mole of the compound of formula (R1).
• the total amount of the two or more aluminum compounds of formula (A) should be within the above range.
• the amount used is not particularly limited, but when the amount of the compound of formula (R1) used is taken as 100 mol%, the silane compound can be used in an amount of, for example, 0.1 mol% or more, or 0.2 mol% or more, or 0.3 mol% or more, or, for example, 50 mol% or less, or 30 mol% or less, or 20 mol% or less, or 15 mol% or less.
• the amount used is not particularly limited, but when the amount of the compound of formula (R1) used is taken as 100 mol%, the amount of the Lewis acid catalyst that can be used is, 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.
• Patent Documents 1 to 6 When other optional ingredients are used, the amount of each ingredient may be adjusted as appropriate, for example, by referring to the prior art and findings of the inventors in their previous patent documents (Patent Documents 1 to 6).
• reaction conditions in the production method (1) of the present invention are not limited as long as the reaction proceeds, and examples thereof are as follows.
• the reaction temperature is not limited as long as the reaction proceeds, but can be, for example, 0°C or higher, 10°C or higher, or 20°C or higher, and can be, for example, 100°C or lower, 80°C or lower, or 60°C or lower.
• the reaction pressure is not limited as long as the reaction proceeds, and the reaction may be carried out under reduced pressure, normal pressure, or increased pressure, but is usually carried out at normal pressure.
• the reaction atmosphere is not limited as long as the reaction proceeds, but it is usually 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, but from the viewpoint of allowing the reaction to proceed sufficiently and efficiently, it can be, for example, 10 minutes or more, 20 minutes or more, or 30 minutes or more, and can be, for example, 80 hours or less, 60 hours or less, or 50 hours or less.
• the manufacturing method (1) of the present invention may be carried out as a sequential method (batch method) or a continuous method (flow method).
• a sequential method batch method
• a continuous method flow method
• the specific details of the implementation procedures of the sequential method (batch method) and the continuous method (flow method) are known in the art.
• the peptide compound (P1) obtained by the production method (1) of the present invention may be subjected to various post-treatments.
• the produced peptide compound (P1) may be isolated and purified by a conventional method such as column chromatography or recrystallization.
• the produced peptide compound (P1) has an amino group and/or a carboxyl group protected by a protecting group or the like, it may be deprotected by the method described below.
• the produced peptide compound (P1) may be directly or after isolation and purification subjected to the latter step of the production method (2) of the present invention described below to produce a polypeptide having further extended amino acid residues.
• polypeptide compound of formula (P1) or formula (P2) obtained by the above-mentioned production method may be further subjected to various post-treatments.
• polypeptide compound of formula (P1) or formula (P2) obtained by the above-mentioned 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 the protecting group. Examples include deprotection by hydrogenation, deprotection by weak acid, deprotection by fluoride ion, deprotection by one-electron oxidizing agent, deprotection by hydrazine, and deprotection by oxygen.
• examples include (a) a method of deprotection by reduction 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, and (b) a method of deprotection by reduction using a hydrogenation reducing agent such as sodium borohydride, lithium aluminum hydride, lithium borohydride, and diborane in the presence of a metal catalyst such as palladium, palladium-carbon, palladium hydroxide, palladium hydroxide-carbon, etc.
• a metal catalyst such as palladium, palladium-carbon, palladium hydroxide, palladium hydroxide-carbon, etc.
• the carboxyl group protected by a protecting group can also be deprotected.
• the method for deprotecting the protected carboxyl group there are no particular limitations on the method for deprotecting the protected carboxyl group, and various methods can be used depending on the type of protecting group. Examples include deprotection by hydrogenation, deprotection by a base, and deprotection by a weak acid.
• examples include a method of deprotection using a strong base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide as the base.
• polypeptide compound of formula (P1) or formula (P2) obtained by the above-mentioned production method may be used as the peptide compound of formula (R1) and may be 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-mentioned production method may be subjected to other conventionally known amidation methods or peptide production methods.
• Patent Document 4 2019/208731
• 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
• the silicon-containing hydrophobic substituent TAG(Si) used in the present invention is not limited to the protection of amino acids and peptides, but 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.).
• the carboxyl and/or amino groups of these organic molecules can be protected by binding the silicon-containing hydrophobic substituent TAG(Si) to them using the above-mentioned method or a method similar thereto.
• various organic molecules that have low solubility in organic solvents such as sugars, glycoproteins, lipoproteins, etc., can be made more soluble in organic solvents by protecting the carboxyl and/or amino groups using the silicon-containing hydrophobic substituent TAG(Si) of the present invention. This makes it easier to use these organic molecules in various reactions (especially flow reactions).
• the silicon-containing hydrophobic substituent TAG(Si) of the present invention can be used to protect both carboxyl groups and amino groups, and therefore can protect whichever group does not interfere with the reaction depending on the type of desired reaction, which has the advantage of providing extremely high flexibility.
• the application of the silicon-containing hydrophobic substituent TAG(Si) of the present invention to organic molecules other than amino acids or peptides is also within the scope of the present invention.
• the present invention also covers the above-mentioned alcohol compounds in which the silicon-containing hydrophobic substituent TAG(Si) is bonded to a hydroxyl group (OH), that is, alcohol compounds having the structure of the following formula (C0).
• the present invention also covers compounds in which the carboxyl and/or amino groups of various organic molecules produced in such a protection reaction are protected with the silicon-containing hydrophobic substituent TAG(Si), i.e., compounds represented by, for example, the following formula (C1) or (C2).
• R C1 in formula (C1), and R C21 and R C22 in formula (C2) each independently represent any monovalent group.
• R, R , and R include the monovalent substituents described above, such as a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, a thiol group, a sulfonic acid group, an amino group, an amido group, an imino group, an imido group, a hydrocarbon group, a heterocyclic group, a hydrocarbonoxy group, a hydrocarboncarbonyl group (acyl group), a hydrocarbonoxycarbonyl group, a hydrocarboncarbonyloxy group, a hydrocarbon-substituted amino group, a hydrocarbon-substituted aminocarbonyl group, a hydrocarboncarbonyl-substituted amino group, a hydrocarbon-substituted thiol group, a hydrocarbonsulfonyl group, a hydro
• R , R , and R include monovalent groups derived from the aforementioned organic molecules, such as sugars (various monosaccharides, disaccharides, polysaccharides, etc.), lipids (fatty acids, triacylglycerols, etc.), complex proteins (glycoproteins, lipoproteins, etc.), complex lipids (glycolipids, sphingolipids, phospholipids, etc.), etc.
• R 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 by the silicon-containing hydrophobic substituent TAG(Si).
• the compound of formula (C1) can be obtained by reacting the organic molecule with an alcohol compound having the structure of formula (C0) by the above-mentioned known method.
• At least one of R and R 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 by 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 the structure of formula (C0) by the above-mentioned known method.
• Tetrahydrofuran (8 mL) was added to a flame-dried flask containing a magnetic stir bar (Sm-CO) and compound 23 (210.3 mg, 1.5 mmol, 1.5 equiv) at ⁇ 78° C.
• n-Butyllithium (1.55 M in hexanes, 0.97 mL, 1.5 mmol, 1.5 equiv) was added dropwise. The resulting mixture was stirred at ⁇ 78° C. for 1.5 hours, after which tris(trimethylsilyl)silyl chloride (283.1 mg, 1.0 mmol, 1.0 equiv) was added.
• reaction mixture was quenched with saturated ammonium chloride (NH 4 Cl) solution (10 mL) and the layers were separated. The aqueous layer was extracted with hexane (3 ⁇ 10 mL). The combined organic layers were dried over anhydrous sodium sulfate (Na 2 SO 4 ), filtered, and concentrated. The resulting residue was used in the next step without purification.
• NH 4 Cl saturated ammonium chloride
• Tetrahydrofuran (20 mL) was added to a flame-dried flask containing lithium (granular, 222.1 mg, 32.0 mmol, 8.0 equiv) under nitrogen atmosphere at room temperature.
• Trichloro(phenyl)silane (0.641 mL, 4.0 mmol, 1.0 equiv) and butylchlorodimethylsilane (2.15 mL, 12.4 mmol, 3.1 equiv) were added together.
• the reaction was stirred at room temperature for 18 hours.
• the reaction mixture was then poured into a separatory funnel containing 50 mL of hexane and 50 mL of water.
• Tetrahydrofuran 60 mL was added to a flame-dried flask containing a magnetic stir bar (Sm-Co) and dichloromethylsilane (1.23 mL, 12 mmol, 1.0 equiv) at 0° C. under nitrogen atmosphere.
• n-BuMgCl 2.0 M in THF, 15 mL, 30 mmol, 2.5 equiv was added dropwise.
• the resulting mixture was allowed to warm slowly to room temperature and stirred for 21 h.
• the reaction mixture was quenched with saturated ammonium chloride (NH 4 Cl) solution (60 mL) and the layers were separated.
• the aqueous layer was extracted with hexanes (3 ⁇ 60 mL).
• the combined organic layers were dried over anhydrous sodium sulfate (Na 2 SO 4 ), filtered, and concentrated to give dibutyl(methyl)silane as a colorless oil (83% yield, 1.58 g).
• Tetrahydrofuran (15 mL) was added to a flame-dried flask containing lithium (granular, 170.0 mg, 24.5 mmol, 8.0 equiv) under nitrogen atmosphere at room temperature.
• Trichloro(phenyl)silane (0.491 mL, 3.1 mmol, 1.0 equiv) and dibutylchloro(methyl)silane (1.83 g, 9.5 mmol, 3.1 equiv) were added together.
• the reaction was stirred at room temperature for 6 days.
• the reaction mixture was then poured into a separatory funnel charged with 30 mL of hexane and 30 mL of water.
• Tetrahydrofuran (20 mL) was added to a flame-dried flask containing lithium (granular, 222.1 mg, 32.0 mmol, 8.0 equiv) under nitrogen atmosphere at room temperature.
• Trichloro(phenyl)silane (0.641 mL, 4.0 mmol, 1.0 equiv) and decyldimethylchlorosilane (3.35 mL, 12.4 mmol, 3.1 equiv) were added together.
• the reaction was stirred at room temperature for 16 hours.
• the reaction mixture was poured into a separatory funnel containing 50 mL of hexane and 50 mL of water.
• Tetrahydrofuran (20 mL) was added to a flask containing lithium (granular, 222.1 mg, 32.0 mmol, 8.0 equiv) under nitrogen atmosphere at 0° C.
• Trichloro(phenyl)silane (0.641 mL, 4.0 mmol, 1.0 equiv) and chloro(dimethyl)octadecylsilane (4.30 g, 12.4 mmol, 3.1 equiv) were added together.
• the reaction was stirred at 0° C. for 4 hours and then at room temperature for 66 hours.
• the reaction mixture was then poured into a separatory funnel containing 50 mL of hexane and 50 mL of water.
• Tetrahydrofuran (3 mL) was added to a flask containing a magnetic stir bar (Sm-Co) and tris(trimethylsilyl)silyl chloride (141.6 mg, 0.5 mmol, 1.0 equiv) at 0° C. under nitrogen atmosphere.
• Ethynylmagnesium chloride (0.5 M in THF, 1.5 mL, 0.75 mmol, 1.5 equiv) was added dropwise. The resulting mixture was stirred at room temperature for 20 hours. Upon completion, the reaction mixture was quenched with saturated ammonium chloride (NH 4 Cl) solution (10 mL) and the layers were separated. The aqueous layer was extracted with hexane (3 ⁇ 10 mL).
• Tetrahydrofuran (10 mL) was added to another flame-dried flask containing a magnetic stir bar (Sm-Co) and compound 23 (252.3 mg, 1.8 mmol, 1.8 equiv) under nitrogen atmosphere at 78° C.
• n-Butylithium (1.55 M in hexanes, 1.16 mL, 1.8 mmol, 1.8 equiv) was added dropwise. The resulting mixture was stirred at ⁇ 78° C. for 1.5 hours. Then, the above 24e-OTF solution was slowly transferred to the reaction mixture. The reaction mixture was slowly warmed to room temperature and stirred for 4 hours.
• reaction mixture was quenched with saturated aqueous ammonium chloride (NH 4 Cl) solution (10 mL) and the layers were separated. The aqueous layer was extracted with hexane (3 ⁇ 10 mL). The combined organic layers were dried over anhydrous sodium sulfate (Na 2 SO 4 ), filtered and concentrated. The residue was used in the next step without further purification.
• NH 4 Cl saturated aqueous ammonium chloride
• Esterification Test 1 Synthesis of Boc-Ala-OTAG10 (3-(1,3-didecyl-2-(decyldimethylsilyl)-1,1,3,3-tetramethyltrisilan-2-yl)prop-2-yn-1-yl(tert-butoxycarbonyl)-L-alaninate)
• Tolerance Test 1 Synthesis of H-Ala-OTAG10 (3-(1,3-didecyl-2-(decyldimethylsilyl)-1,1,3,3-tetramethyltrisilan-2-yl)prop-2-yn-1-yl L-alaninate)
• Tolerance Test 2 Synthesis of H-Ala-OTAG10 (3-(1,3-didecyl-2-(decyldimethylsilyl)-1,1,3,3-tetramethyltrisilan-2-yl)prop-2-yn-1-yl L-alaninate)

Landscapes

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

Priority Applications (1)

Applications Claiming Priority (2)

Publications (1)

Family

ID=92590666

Family Applications (1)

Country Status (2)

Citations (2)

• 2024
  • 2024-03-01 JP JP2024540986A patent/JP7625769B1/ja active Active
  • 2024-03-01 WO PCT/JP2024/007779 patent/WO2024181560A1/ja not_active Ceased

Patent Citations (2)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events