Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
  • C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
  • C07K1/062—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups for alpha- or omega-carboxy functions
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
  • C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
  • C07K1/065—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups for hydroxy functions, not being part of carboxy functions
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C43/00—Ethers; Compounds having groups, groups or groups
  • C07C43/02—Ethers
  • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
  • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
  • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
  • C07D219/08—Nitrogen atoms
  • C07D219/10—Nitrogen atoms attached in position 9
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/78—Ring systems having three or more relevant rings
  • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
  • C07D311/82—Xanthenes
  • C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/78—Ring systems having three or more relevant rings
  • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
  • C07D311/82—Xanthenes
  • C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
  • C07D311/86—Oxygen atoms, e.g. xanthones
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/78—Ring systems having three or more relevant rings
  • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
  • C07D311/82—Xanthenes
  • C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
  • C07D311/88—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
  • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D335/10—Dibenzothiopyrans; Hydrogenated dibenzothiopyrans
  • C07D335/12—Thioxanthenes
  • C07D335/14—Thioxanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
  • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D335/10—Dibenzothiopyrans; Hydrogenated dibenzothiopyrans
  • C07D335/12—Thioxanthenes
  • C07D335/14—Thioxanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
  • C07D335/16—Oxygen atoms, e.g. thioxanthones
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
  • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D335/10—Dibenzothiopyrans; Hydrogenated dibenzothiopyrans
  • C07D335/12—Thioxanthenes
  • C07D335/14—Thioxanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
  • C07D335/18—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
• • 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
  • C07K5/08—Tripeptides
  • C07K5/0815—Tripeptides with the first amino acid being basic
  • C07K5/0817—Tripeptides with the first amino acid being basic the first amino acid being Arg
• • 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
  • C07K5/10—Tetrapeptides
  • C07K5/1002—Tetrapeptides with the first amino acid being neutral
  • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
  • C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/64—Cyclic peptides containing only normal peptide links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/02—Ortho- or ortho- and peri-condensed systems
  • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
  • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
  • C07C2603/24—Anthracenes; Hydrogenated anthracenes
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/02—Ortho- or ortho- and peri-condensed systems
  • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
  • C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present disclosure relates to a method for producing a peptide compound, a reagent for forming a protecting group, and a condensed polycyclic compound.
• Examples of the peptide production method include a solid phase method and a liquid phase method.
• the solid-phase method is advantageous in that the isolation and purification after the reaction can be performed only by washing the resin, but the reaction is essentially a heterogeneous phase, and an excess amount of reaction reagent is used to compensate for the low reactivity. It is necessary or problematic in terms of tracking the reaction and analyzing the reaction product while supported on a carrier.
• the liquid phase method has good reactivity, and the intermediate peptide can be purified by extraction washing, isolation and the like after the condensation reaction. However, the liquid phase method still has problems in each step of coupling reaction and deprotection.
• Patent Document 1 International Publication No. 2018/021233
• Patent Document 2 International Publication No. 2010/1133939
• Patent Document 1 only describes a xanthene compound that is difficult to precipitate in an organic solvent and is easy to separate and purify by a liquid-liquid phase separation operation, and a xanthene compound suitable for solid-liquid phase separation is used. There is no description or suggestion regarding the protective group that was present.
• An object to be solved by one embodiment of the present disclosure is to provide a method for producing a peptide compound having excellent deprotection rate and stability over time.
• Another problem to be solved by another embodiment of the present disclosure is to provide a reagent for forming a protecting group, which is excellent in deprotection rate and stability over time.
• a problem to be solved by yet another embodiment of the present disclosure is to provide a novel condensed polycyclic compound.
• a method for producing a peptide compound which comprises a step of using a compound represented by the following formula (1).
• Y 1 represents -OR 17 , -NHR 18 , -SH, or a halogen atom
• R 17 represents a hydrogen atom, an active ester-type carbonyl group, or an active ester-type sulfonyl group
• R 18 represents a hydrogen atom, an alkyl group, an arylalkyl group or a heteroarylalkyl group, or a 9-fluorenylmethoxycarbonyl group.
• R 110 represents RA or an alkyl group
• R 100 to R 107 independently represent a hydrogen atom or an alkyl group.
• R 1 to R 8 independently represent RA , a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group, and at least one of R 1 to R 8 and Y 2 has RA
• the above RA represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and when only one RA is present, the number of carbon atoms of the above aliphatic hydrocarbon group of RA is 12 or more.
• R a there are a plurality number of carbon atoms of at least one of said aliphatic hydrocarbon group R a may be 12 or more, However, RA does not have a silyl group and a hydrocarbon group having a silyloxy structure.
• the step of using the compound represented by the above formula (1) is a C-terminal protection step of protecting the carboxy group or amide group of the amino acid compound or peptide compound by the compound represented by the above formula (1).
• 1> The method for producing a peptide compound.
• ⁇ 3> The method for producing a peptide compound according to ⁇ 2>, wherein the amino acid compound or peptide compound in the C-terminal protection step is an N-terminal protected amino acid compound or an N-terminal protected peptide compound.
• N-terminal deprotection step of deprotecting the N-terminal of the N-terminal protected C-terminal protected amino acid compound or the N-terminal protected C-terminal protected peptide compound obtained in the above C-terminal protection step, and the N-terminal deprotection step.
• a peptide chain extension step of condensing the N-terminal protected amino acid compound or the N-terminal protected peptide compound with the N-terminal of the C-terminal protected amino acid compound or the C-terminal protected peptide compound obtained in the above N-terminal deprotection step is further included.
• 3> The method for producing a peptide compound.
• ⁇ 5> The method for producing a peptide compound according to ⁇ 4>, further comprising a precipitation step of precipitating the N-terminal protected C-terminal protected peptide compound obtained in the peptide chain extension step.
• Step6> After the precipitation step, Step of deprotecting the N-terminal of the obtained N-terminal protected C-terminal protected peptide compound, A step of condensing an N-terminal protected amino acid compound or an N-terminal protected peptide compound with the N-terminal of the obtained C-terminal protected peptide compound, and
• the method for producing a peptide compound according to ⁇ 5> which further comprises the step of precipitating the obtained N-terminal protected C-terminal protected peptide compound at least once in this order.
• ⁇ 7> The method for producing a peptide compound according to any one of ⁇ 1> to ⁇ 6>, further comprising a C-terminal deprotection step of deprotecting a C-terminal protecting group.
• ⁇ 8> The total number of carbon atoms in all the aliphatic hydrocarbon group in which all of R A has found 18 at least, ⁇ 1> to any one method for producing a peptide according to the ⁇ 7>.
• ⁇ 9> The method for producing a peptide compound according to any one of ⁇ 1> to ⁇ 8>, wherein the total carbon number of all aliphatic hydrocarbon groups possessed by all RA is 36 to 80.
• ⁇ 10> The method for producing a peptide according to any one of ⁇ 1> to ⁇ 9>, wherein at least one of R 3 and R 6 in the above formula (1) is RA .
• the R A is independently, a manufacturing method of a group represented by the following formula (f1) or formula (a1) ⁇ 1> ⁇ peptide compound according to any one of ⁇ 10>.
• the wavy line portion represents the coupling position with other configurations, and m9 represents an integer of 1 to 3.
• X 9 independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-.
• Each R 9 independently represents a divalent aliphatic hydrocarbon group.
• Ar 1 represents a (m10 + 1) -valent aromatic group or a (m10 + 1) -valent complex aromatic group.
• m10 represents an integer of 1 to 3 and represents X 10 independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-.
• Each of R 10 independently represents a monovalent aliphatic hydrocarbon group, and at least one of R 10 is a monovalent aliphatic hydrocarbon group having 5 or more carbon atoms.
• the wavy line portion represents the coupling position with other configurations.
• m20 represents an integer from 1 to 10.
• X 20 independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-.
• At least one of R 20 is a divalent aliphatic hydrocarbon group having 5 or more carbon atoms.
• the wavy line portion represents the coupling position with other configurations
• m10 represents an integer of 1 to 3
• m11 represents an integer of 1 to 3.
• X 10 independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-.
• Each of R 10 independently represents a monovalent aliphatic hydrocarbon group having 5 or more carbon atoms.
• Y 1 represents -OR 17 , -NHR 18 , -SH, or a halogen atom
• R 17 represents a hydrogen atom, an active ester-type carbonyl group, or an active ester-type sulfonyl group
• R 18 represents a hydrogen atom, an alkyl group, an arylalkyl group, a heteroarylalkyl group, or a 9-fluorenylmethoxycarbonyl group.
• R 110 represents RA or an alkyl group
• R 100 to R 107 independently represent a hydrogen atom or an alkyl group.
• R 1 to R 8 independently represent RA , a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group, and at least one of R 1 to R 8 and Y 2 has RA
• the above RA Represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and at least one of the above aliphatic hydrocarbon groups in RA has 12 or more carbon atoms.
• RA does not have a silyl group and a hydrocarbon group having a silyloxy structure.
• reagent for forming a protecting group according to ⁇ 14> wherein the reagent for forming a protecting group is a reagent for forming a protecting group of a carboxy group or an amide group.
• reagent for forming a protecting group is a reagent for forming a protecting group of a carboxy group or an amide group.
• Ya 1 represents -ORa 17 , -NHRa 18 , -SH, or a halogen atom
• Ra 17 represents a hydrogen atom, an active ester-type carbonyl group, or an active ester-type sulfonyl group
• Ra 18 represents a linear or branched alkyl group having a hydrogen atom or 10 or less carbon atoms, an arylalkyl group or a heteroarylalkyl group, or a 9-fluorenylmethoxycarbonyl group.
• Ra 1 to Ra 8 independently represent RA , a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms.
• At least one of Ra 2 to Ra 7 has RA , RA represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and RA represents at least one of the above aliphatic groups.
• the hydrocarbon group has 12 or more carbon atoms, However, RA does not have a silyl group and a hydrocarbon group having a silyloxy structure.
• the wavy line portion represents the coupling position with other configurations
• m9 represents an integer of 1 to 3
• X 9 independently represents a single coupling, -O-, -S-, and -COO-.
• R 9 independently represents a divalent aliphatic hydrocarbon group
• Ar 1 has a (m10 + 1) valence.
• m10 represents an integer of 1 to 3
• X 10 independently represents a single bond, -O-, -S-, -COO.
• each R 10 is independently, represents a monovalent aliphatic hydrocarbon group, at least one of R 10 Is a monovalent aliphatic hydrocarbon group having 5 or more carbon atoms.
• the wavy line portion represents the coupling position with other configurations
• m20 represents an integer of 1 to 10
• X 20 independently represents a single bond, -O-, -S-, and -COO.
• the wavy line portion represents the connection position with other configurations
• m10 represents an integer of 1 to 3
• m11 represents an integer of 1 to 3
• X 10 is an independent single bond.
• R 10 is an independent one with 5 or more carbon atoms.
• X 20 which binds with another configuration in the formula (a1) is condensed polycyclic compound according to an -O- ⁇ 19>.
• a method for producing a peptide compound having excellent deprotection rate and stability over time it is possible to provide a reagent for forming a protecting group having excellent deprotection rate and stability over time.
• a novel condensed polycyclic compound can be provided.
• each term has the following meaning.
• the numerical range represented by using "-" means a range including the numerical values before and after "-" as the lower limit value and the upper limit value.
• the upper limit value or the lower limit value described in one numerical range may be replaced with the upper limit value or the lower limit value of another numerical range described stepwise. Good.
• the upper limit value or the lower limit value of the numerical range may be replaced with the value shown in the examples.
• process is included in this term as long as the intended purpose of the process is achieved, not only in an independent process but also in cases where it cannot be clearly distinguished from other processes.
• substitution or non-substitution includes those having no substituent as well as those having a substituent.
• alkyl group includes not only an alkyl group having no substituent (unsubstituted alkyl group) but also an alkyl group having a substituent (substituted alkyl group).
• the chemical structural formula may be described by a simplified structural formula in which a hydrogen atom is omitted.
• the alkyl group may be chain-like or branched, and may be substituted with a halogen atom or the like.
• Examples of the alkyl group having 1 to 6 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like.
• Examples of the alkenyl group having 2 to 6 carbon atoms include 1-propenyl.
• the aryl group is preferably an aryl group having 6 to 14 carbon atoms, and examples thereof include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a biphenylyl group and a 2-anthryl group. Of these, an aryl group having 6 to 10 carbon atoms is more preferable, and a phenyl group is particularly preferable.
• Examples of the silyl group include trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl and the like.
• Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
• Examples of the alkoxy group having 1 to 6 carbon atoms include methoxy, ethoxy, propoxy and the like.
• Benzyl is mentioned as an aralkyl group having 7 to 10 carbon atoms.
• Examples of the acyl group having 1 to 6 carbon atoms include acetyl and propionyl.
• Examples of the aralkyl-carbonyl group having 7 to 10 carbon atoms include benzylcarbonyl.
• Examples of the alkoxycarbonyl group having 1 to 6 carbon atoms include methoxycarbonyl, ethoxycarbonyl, and Boc group.
• the Boc group means a tert-butoxycarbonyl group.
• Examples of the aralkyloxycarbonyl group having 7 to 14 carbon atoms include benzyloxycarbonyl and Fmoc group.
• the Fmoc group means a 9-fluorenylmethoxycarbonyl group.
• the method for producing a peptide compound according to the present disclosure includes a step of using a compound represented by the following formula (1).
• Y 1 represents -OR 17 , -NHR 18 , -SH, or a halogen atom
• R 17 represents a hydrogen atom, an active ester-type carbonyl group, or an active ester-type sulfonyl group.
• the R 18 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms in a straight chain or a branched chain, an arylalkyl group, a heteroarylalkyl group, or a 9-fluorenylmethoxycarbonyl group (hereinafter, Fmoc).
• R 110 represents RA or an alkyl group
• R 100 to R 107 independently represent a hydrogen atom or an alkyl group.
• R 1 to R 8 independently represent RA , a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, and among R 1 to R 8 and Y 2 .
• At least one has RA
• the RA represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and when only one RA is present, the above RA of RA .
• the aliphatic hydrocarbon group has 12 or more carbon atoms and a plurality of RAs are present, at least one of the above aliphatic hydrocarbon groups in RA has 12 or more carbon atoms.
• RA does not have a silyl group and a hydrocarbon group having a silyloxy structure.
• the present disclosure it is possible to provide a method for producing a peptide compound having an excellent yield.
• a method for producing a peptide compound having excellent deprotection rate and stability over time The detailed mechanism by which the above effect is obtained is unknown, but it is presumed as follows.
• the excellent stability over time means that the condensed polycyclic compound represented by the formula (1) according to the present disclosure does not decompose during storage, or the condensed polycyclic compound represented by the formula (1) according to the present disclosure. It means that the compound protected by the ring compound does not deprotect and decompose except under the deprotection conditions.
• the protected compound Since the compound represented by the formula (1) according to the present disclosure has at least one aliphatic hydrocarbon group having 12 or more carbon atoms, the protected compound is excellent in hydrophobic solvent solubility. Further, with respect to the hydrophilic solvent, the aliphatic hydrocarbon groups in RA aggregate and have a condensed polycyclic structure, so that the peptide compound obtained has a stacking interaction between the condensed polycyclic structures. As a result, it is excellent in crystallization, purification and separability. In other words, when the compound protected by the formula (1) is subjected to the reaction, the reaction proceeds rapidly because it is excellent in solvent solubility in the hydrophobic solvent which is the reaction solvent, and the polarity is poor at the time of purification. Since the target product is efficiently crystallized and purified by adding a solvent, it is suitable for solid-liquid phase separation, and it is estimated that the yield of the obtained compound (peptide compound, etc.) is excellent.
• the compound protected by the compound represented by the formula (1) according to the present disclosure has a high deprotection rate, so that side reactions are suppressed, and the yield of the obtained peptide compound or the like is excellent.
• the reason why the deprotection rate is excellent is that the compound represented by the formula (1) has a condensed polycyclic structure as compared with the diphenylmethane type compound described in Patent Document 2, and the electron donating property of Y 2 is excellent. the substituents, electron density of the carbon atom to which Y 1 is connected is estimated to be because the excellent deprotection rate to increase.
• the compound represented by the formula (1) and the compound protected by the compound represented by the formula (1) according to the present disclosure are aliphatic hydrocarbon groups having no silyloxy structure described in Patent Document 1. Therefore, it is presumed that the product is solid at room temperature and is inferior in reactivity between molecules, so that it is excellent in storage stability and the production of by-products is suppressed, so that the yield is excellent.
• Patent Document 1 which describes a protecting group suitable for liquid-liquid phase separation
• a hydrocarbon group having a silyloxy structure of a protecting group suitable for liquid-liquid phase separation is referred to as an aliphatic hydrocarbon group having 12 or more carbon atoms. There is no description or suggestion to change to.
• the storage stability of pharmaceutical raw materials is important for quality control (GMP) in pharmaceutical manufacturing.
• the compound represented by the formula (1) and the compound protected by the compound represented by the formula (1) according to the present disclosure are excellent in storage stability and can be used particularly preferably for the production of pharmaceutical products. From the above, the compound protected by the compound represented by the formula (1) according to the present disclosure can achieve both the deprotection rate and the stability over time. In this specification, it is said that a high deprotection speed is excellent in deprotection speed.
• the C-terminal protecting group can be deprotected even under weak acid conditions, the side reaction of the obtained peptide can be suppressed, and an acid-sensitive peptide, for example, an N-alkylamide structure can be produced. It is suitable for peptide synthesis.
• the compound represented by the formula (1) not only forms a protecting group, but also modifies the peptide compound, adjusts the solubility in water or an organic solvent, and crystallizes. It can be used for improvement, multimerization, etc.
• the compound represented by the formula (1) is preferably used for forming a protecting group, and more preferably used for forming a C-terminal protecting group in an amino acid compound or a peptide compound.
• Y 1 in the formula (1) represents -OR 17 , -NHR 18 , -SH, or a halogen atom
• R 17 represents a hydrogen atom, an active ester-type carbonyl group, or an active ester-type sulfonyl group
• R 18 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms in a straight chain or a branched chain, an arylalkyl group, or a heteroarylalkyl group.
• halogen atom a bromine atom and a chlorine atom are preferable from the viewpoint of reaction yield and storage stability.
• Examples of the active ester-type carbonyl group in R 17 include an imide carbonyloxysuccinate, an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group, and the like, and carbonyloxysuccinic acid from the viewpoint of deprotection rate and stability over time. Imide and the like are preferably mentioned.
• Examples of the active ester-type sulfonyl group in R 17 include an alkylsulfonyl group and an arylsulfonyl group.
• R 17 is preferably a hydrogen atom or an active ester-type protecting group, and more preferably a hydrogen atom.
• Examples of the alkyl group in R 18 include an alkyl group having 1 to 30 carbon atoms, preferably an alkyl group having 1 to 10 carbon atoms, and more preferably an alkyl group having 1 to 6 carbon atoms. Of these, a methyl group and an ethyl group are more preferable.
• Examples of the arylalkyl group in R 18 include an arylalkyl group having 7 to 30 carbon atoms, preferably an arylalkyl group having 7 to 20 carbon atoms, and an aralkyl group having 7 to 16 carbon atoms (for example, an aralkyl group having 7 to 16 carbon atoms).
• a group in which an alkylene group having 1 to 6 carbon atoms is bonded to an aryl group of 6 to 10) is more preferable.
• Preferable specific examples include a benzyl group, a 1-phenylethyl group, a 2-phenylethyl group, a 1-phenylpropyl group, a naphthylmethyl group, a 1-naphthylethyl group, a 1-naphthylpropyl group and the like, and a benzyl group. Is more preferably mentioned.
• the heteroaryl group in R 18, include heteroaryl groups having 5 to 30 carbon atoms, preferably a heteroaryl group having 5 to 20 carbon atoms, heteroarylalkyl groups having 5 to 16 carbon atoms (For example, a group in which an alkylene group having 1 to 6 carbon atoms is bonded to a heteroaryl group having 4 to 10 carbon atoms) is more preferable. Suitable specific examples include an indolylmethyl group, a furfuryl group, a benzofuranylmethyl group, a thiophenylmethyl group, a benzothiophenylmethyl group and the like.
• R 18 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, preferably an aryl alkyl group or Fmoc group having 7 to 16 carbon atoms, a hydrogen atom, It is more preferably a methyl group, an ethyl group, a benzyl group or an Fmoc group, and further preferably a hydrogen atom or an Fmoc group.
• R 18 is Fmoc group, by deprotecting the Fmoc group with a base DBU to be described later, since the Y A is -NH 2, if R 18 is Fmoc group, and, R 18 is It can be considered to be equivalent to the case of a hydrogen atom.
• Y 1 -OR 17 (R 17 is a hydrogen atom or an active ester-type protecting group)
• - NHR 18 R 18 is a hydrogen atom or a linear or branched It is preferably an alkyl group having 1 to 6 carbon atoms, an aralkyl group, or an Fmoc group), or a halogen atom
• ⁇ OR 17 R 17 is a hydrogen atom or an active ester-type protecting group
• -NHR 18 (R 18 is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, or Fmoc is a group) are more preferably, -NHR 18 (R 18 is a hydrogen atom or It is more preferably an alkyl group having 1 to 6 carbon atoms in a straight chain or a branched chain).
• R 110 is preferably RA .
• RA has the same meaning as RA described later, and the preferred embodiment is also the same.
• the alkyl group in R 100 to R 107 is preferably an alkyl group having 1 to 5 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, and an alkyl having 1 or 2 carbon atoms. It is more preferably a group.
• R 102 ⁇ R 105 in may be different from each is preferably a R 102 and R 104 and R 103 and R 105 are identical groups respectively .
• the R 102 and R 104 are more preferably an alkyl group or a hydrogen atom having 1 to 5 carbon atoms, further preferably an alkyl group or a hydrogen atom having 1 to 3 carbon atoms, and 1 carbon atom. Alternatively, it is particularly preferably an alkyl group of 2 or a hydrogen atom, and most preferably both are hydrogen atoms.
• the R 103 and R 105 are more preferably an alkyl group or a hydrogen atom having 1 to 5 carbon atoms, further preferably an alkyl group or a hydrogen atom having 1 to 3 carbon atoms, and 1 carbon atom. Alternatively, it is particularly preferably an alkyl group of 2 or a hydrogen atom, and most preferably both are hydrogen atoms. Specific examples include -CH 2- CH 2- and the like.
• the R 106 R 107 in ⁇ CR 106 R 107 ⁇ is preferably the same group, more preferably an alkyl group having 1 to 5 carbon atoms, and an alkyl group having 1 to 3 carbon atoms. Is more preferable, and an alkyl group having 1 or 2 carbon atoms is particularly preferable. Specific examples include -CH 2- , -C (CH 3 ) 2- , -C (C 2 H 5 ) 2-, and the like.
• R 1 to R 8 independently represent RA , a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, and among R 1 to R 8 and Y 2 respectively .
• At least one has RA and the above RA represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group.
• the aliphatic hydrocarbon group has 12 or more carbon atoms, and when a plurality of RAs are present in the compound, at least one of the aliphatic hydrocarbons is present.
• the group has 12 or more carbon atoms.
• RA does not have a silyl group and a hydrocarbon group having a silyloxy structure.
• R 1 ⁇ R 8 is R A, more preferably only R 3 or R 6 is R A, R 1 ⁇ R 5 and R 7 ⁇ R 8 are each independently , Hydrogen atom, halogen atom, alkyl group or alkoxy group, and R 3 or R 6 is more preferably RA .
• R 1 to R 8 RA a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or an alkoxy group is preferable, and RA , a hydrogen atom, a fluorine atom or a chlorine atom is more preferable.
• the "organic group having an aliphatic hydrocarbon group” in RA means a monovalent organic having an aliphatic hydrocarbon group in its molecular structure (one bonder bonded to ring A). It is a group.
• the "aliphatic hydrocarbon group” in the “organic group having an aliphatic hydrocarbon group” is a linear, branched, or cyclic saturated or unsaturated aliphatic hydrocarbon group, and is a fat having 5 or more carbon atoms.
• Group hydrocarbon groups are preferable, aliphatic hydrocarbon groups having 5 to 60 carbon atoms are more preferable, aliphatic hydrocarbon groups having 5 to 30 carbon atoms are more preferable, and aliphatic hydrocarbon groups having 10 to 30 carbon atoms are particularly preferable. preferable.
• the site of the "aliphatic hydrocarbon group" in the "organic group having an aliphatic hydrocarbon group” is not particularly limited, and may be present at the terminal (monovalent group) or at any other site. (For example, a divalent group).
• Examples of the "aliphatic hydrocarbon group” include an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group and the like.
• a pentyl group such as an icosyl group, a tetracosyl group, a lauryl group, a tridecyl group, a myristyl group, an oleyl group, and an isostearyl group, and a divalent group derived from them (1 hydrogen atom from the above monovalent group).
• alkyl group for example, an alkyl group having 5 to 30 carbon atoms is preferable, and for example, a pentyl group, a hexyl group, an octyl group, a decyl group, a hexadecyl group, an octadecyl group, an icosyl group, a tetracosyl group, a lauryl group, etc.
• Examples thereof include a tridecyl group, a myristyl group and an isostearyl group, with an octadecyl group, an icosyl group, a docosyl group or a tetracosyl group being preferable, and an icosyl group, a docosyl group or a tetracosyl group being more preferable.
• a cycloalkyl group for example, a cycloalkyl group having 5 to 30 carbon atoms is preferable, and examples thereof include a cyclopentyl group, a cyclohexyl group, an isobornyl group, a tricyclodecanyl group and the like.
• alkenyl group for example, an alkenyl group having 5 to 30 carbon atoms is preferable, and examples thereof include a vinyl group, a 1-propenyl group, an allyl group, an isopropenyl group, a butenyl group, an isobutenyl group and the like.
• alkynyl group for example, an alkynyl group having 5 to 30 carbon atoms is preferable, and examples thereof include a 4-pentynyl group and a 5-hexenyl group.
• steroid group for example, cholesterol, estradiol and the like are preferable.
• the site other than the "aliphatic hydrocarbon group" in the "organic group having an aliphatic hydrocarbon group” can be arbitrarily set. For example, it has sites such as -O-, -S-, -COO-, -OCONH-, -CONH-, and hydrocarbon groups (monovalent or divalent groups) other than "aliphatic hydrocarbon groups”. May be.
• hydrocarbon groups monovalent or divalent groups
• Examples of the "hydrocarbon group” other than the "aliphatic hydrocarbon group” include aromatic hydrocarbon groups, and specifically, for example, monovalent groups such as aryl groups and derived from them. The divalent group to be used is used.
• hydrocarbon group other than the above-mentioned aliphatic hydrocarbon group and the above-mentioned aliphatic hydrocarbon group may be substituted with a substituent selected from a halogen atom, an oxo group and the like.
• the bonds (substitutions) of R 1 to R 8 of the "organic group having an aliphatic hydrocarbon group” are mediated by the "aliphatic hydrocarbon group” or the "hydrocarbon group” existing in the above RA , that is, direct carbon - even those that are bound by a carbon bond, -O present in the R a -, - S -, - COO -, - OCONH -, - CONH- sites such as those through the There may be.
• the binding (substitution) of R 1 to R 8 is preferably via -O-, -S-, -COO- or -CONH-. It is particularly preferable that it is mediated by —O—.
• the bond (substitution) of the "organic group having an aliphatic hydrocarbon group" to N in Y 2 is via the "hydrocarbon group" present in the above RA from the viewpoint of ease of compound synthesis. That is, those directly bonded by a carbon-nitrogen bond are preferable.
• R A is present only one, when the total number of carbon atoms of all the aliphatic hydrocarbon groups of the R A is, R A there are multiple is the total number of carbon atoms in all the aliphatic hydrocarbon group having all of R a, in view of the deprotection rate and stability over time, is preferably 18 or more, more preferably 24 to 200, It is more preferably 32 to 100, particularly preferably 34 to 80, and most preferably 36 to 80.
• the compound represented by formula (1) according to the present disclosure is a compound having at least one of 12 or more aliphatic hydrocarbon group having a carbon in at least one of R A, at least one of R A, carbon A compound having at least one aliphatic hydrocarbon group having 12 to 100 carbon atoms is preferable, and a compound having at least one aliphatic hydrocarbon group having 18 to 40 carbon atoms is more preferable, and the compound has 20 to 20 carbon atoms. More preferably, the compound has at least one of 36 aliphatic hydrocarbon groups.
• the aliphatic hydrocarbon group is preferably an alkyl group, more preferably a linear alkyl group, from the viewpoint of stability over time.
• the carbon number of one RA is preferably 12 to 200, more preferably 18 to 150, further preferably 18 to 100, and preferably 20 to 80, respectively. Especially preferable.
• R 1 ⁇ R 8 is preferably R A, at least one of R 2 ⁇ R 7 , RA , and at least one selected from the group consisting of R 2 , R 3 , R 6 , and R 7 is even more preferably RA , any of R 3 and R 6 .
• R 3 or R 6 is most preferably RA .
• At least one RA is represented by any of the following formulas (f1), formulas (a1), formulas (b1) or formulas (e1) from the viewpoint of deprotection rate and stability over time. It is preferable that the group is represented by the following formula (f1) or (a1), and it is particularly preferable that the group is represented by the following formula (f1).
• the wavy line portion represents the coupling position with other configurations
• m9 represents an integer of 1 to 3
• X 9 independently represents a single coupling, -O-, -S-, -COO-. , -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-
• R 9 independently represents a divalent aliphatic hydrocarbon group
• Ar 1 is (m10 + 1). It represents a valent aromatic group or a (m10 + 1) valent heteroaromatic group
• m10 represents an integer of 1 to 3
• X 10 are independently single-bonded, -O-, -S-,-, respectively.
• R 10 independently represents a monovalent aliphatic hydrocarbon group, at least 1 of R 10 .
• One is a monovalent aliphatic hydrocarbon group having 5 or more carbon atoms.
• the wavy line portion represents the coupling position with other configurations
• m20 represents an integer of 1 to 10
• X 20 independently represents a single bond, -O-, -S-, and -COO.
• the wavy line portion represents the coupling position with other configurations
• mb represents 1 or 2
• b1 to b4 each independently represent an integer of 0 to 2
• X b1 to X b4 represent an integer of 0 to 2.
• Each independently represents a single bond, -O-, -S-, -COO-, -OCONH-, or -CONH-
• R b2 and R b4 independently represent a hydrogen atom, a methyl group, or a carbon. It represents an aliphatic hydrocarbon group having 5 or more carbon atoms
• R b3 represents an aliphatic hydrocarbon group having 5 or more carbon atoms.
• the wavy line portion represents a bond position with another configuration
• X e1 represents a single bond, -O-, -S-, -NHCO-, or -CONH-
• me is 0 to 0 to.
• e1 represents an integer of 0 to 11
• e2 represents an integer of 0 to 5
• X e2 independently represent a single bond, -O-, -S-, -COO-, -OCONH.
• R e2 each independently represents a hydrogen atom, a methyl group, an organic group having an aliphatic hydrocarbon group having 5 or more carbon atoms.
• the m9 in the formula (f1) is preferably 1 or 2, and more preferably 1.
• X 9 and X 10 in the formula (f1) are preferably -O-, -S-, -COO-, -OCONH-, or -CONH-, and more preferably -O-. preferable.
• Each of R 9 in the formula (f1) is preferably an alkylene group having 1 to 10 carbon atoms independently, more preferably an alkylene group having 1 to 4 carbon atoms, and particularly preferably a methylene group.
• R 10 in the formula (f1) is preferably a monovalent aliphatic hydrocarbon group having 5 to 60 carbon atoms, and more preferably a monovalent aliphatic hydrocarbon group having 12 to 50 carbon atoms.
• a monovalent aliphatic hydrocarbon group having 18 to 40 carbon atoms is more preferable, and a monovalent aliphatic hydrocarbon group having 20 to 32 carbon atoms is particularly preferable.
• each of R 10 is preferably a linear alkyl group or a branched alkyl group independently, and more preferably a linear alkyl group.
• the m10 in the formula (f1) is preferably 2 or 3, and more preferably 2.
• Ar 1 in the formula (f1) is preferably an aromatic group having a (m10 + 1) valence, and is a group obtained by removing (m10 + 1) hydrogen atoms from benzene, or removing (m10 + 1) hydrogen atoms from naphthalene. It is more preferably a naphthalene group, and particularly preferably a group obtained by removing (m10 + 1) hydrogen atoms from benzene.
• the group represented by the above formula (f1) is preferably a group represented by the following formula (f2) from the viewpoint of deprotection rate and stability over time.
• the wavy line portion represents the connection position with other configurations
• m10 represents an integer of 1 to 3
• m11 represents an integer of 1 to 3
• X 10 is an independent single bond.
• R 10 is an independent one with 5 or more carbon atoms.
• m10 in formula (f2), X 10 and R 10 has the same meaning as m10, X 10 and R 10 in the formula (f1), preferable embodiments thereof are also the same.
• M11 in the formula (f2) is preferably 1 or 2, and more preferably 1.
• the m20 in the formula (a1) is preferably 1 or 2, and more preferably 1.
• To X 20 are each independently of formula (a1), -O -, - S -, - COO -, - OCONH-, or preferably from -CONH-, more preferably -O-.
• R 20 in the formula (a1) is preferably 5 or more divalent aliphatic hydrocarbon group having a carbon, more preferably a divalent aliphatic hydrocarbon group having 5 to 60 carbon atoms, carbon It is more preferably a divalent aliphatic hydrocarbon group having a number of 8 to 40, and particularly preferably a divalent aliphatic hydrocarbon group having 12 to 32 carbon atoms.
• R 20 is preferably a linear alkylene group.
• the mb in the formula (b1) is preferably 1.
• B1 to b4 in the formula (b1) are preferably 1 or 2, respectively, and more preferably 1.
• X b1 to X b4 in the formula (b1) are preferably -O-, -S-, -COO-, -OCONH-, or -CONH-, and more preferably -O-.
• R b2 and R b4 in the formula (b1) are preferably hydrogen atoms, methyl groups, or aliphatic hydrocarbon groups having 5 to 60 carbon atoms, respectively, and have hydrogen atoms, methyl groups, or carbon atoms.
• R b3 in the formula (b1) is preferably a monovalent aliphatic hydrocarbon group having 5 to 60 carbon atoms, and more preferably a monovalent aliphatic hydrocarbon group having 5 to 60 carbon atoms.
• a monovalent aliphatic hydrocarbon group having 8 to 40 carbon atoms is more preferable, and a monovalent aliphatic hydrocarbon group having 12 to 32 carbon atoms is particularly preferable.
• R b3 is preferably a linear alkyl group.
• the compound represented by the above formula (1) is preferably a compound represented by the following formula (10) from the viewpoint of deprotection rate and stability over time.
• Y 1 represents -OR 17 , -NHR 18 , -SH, or a halogen atom
• R 17 represents a hydrogen atom, an active ester-type carbonyl group, or an active ester-type sulfonyl group.
• the above R 18 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms in a linear or branched chain, an arylalkyl group, a heteroarylalkyl group, or an Fmoc group.
• the aliphatic hydrocarbon group has 12 or more carbon atoms, except that RA does not have a silyl group and a hydrocarbon group having a silyloxy structure, and n10 and n11 are independently integers of 0 to 4, respectively. , And neither n10 nor n11 becomes 0.
• Y 1 and RA are synonymous with Y 1 and RA in formula (1), respectively, and the preferred embodiments are also the same. It is preferable that n10 and n11 in the formula (10) are independently integers of 0 to 2, and it is more preferable that one of n10 and n11 is 0 and the other is 1. From the viewpoint of deprotection rate and stability over time, RA is preferably bonded to any of the 2-position, 3-position, 4-position, 5-position, 6-position and 7-position of the condensed polycycle, and the condensed polycycle It is more preferable to bind to any of the 2-position, 3-position, 6-position and 7-position, and further preferably to any of the 3-position and 6-position of the condensed polycycle.
• the compound represented by the formula (10) is preferably a compound represented by the formula (100) or the formula (200) from the viewpoint of the deprotection rate and the stability over time, and is represented by the formula (100). More preferably, it is a compound.
• Y 1 represents -OH or -NHR 18
• R 18 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms in a linear or branched chain.
• R 18 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms in a linear or branched chain.
• R 18 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms in a linear or branched chain.
• R 18 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms in a linear or branched chain.
• RA represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and at least one fat of RA.
• the number of carbon atoms of the group hydrocarbon group is 12 or more, provided that, R a is a silyl group, and does not have a hydrocarbon group having a silyloxy structure, respectively the n100 and n200 independently an integer of 1-4 Represent
• RA in the formulas (100) and (200) is synonymous with RA in the formula (1), and the preferred embodiment is also the same.
• R 18 in Y 1 in the formula (100) and (200) is synonymous with R 18 in Y 1 in the formula (1), and the preferred embodiment is also the same.
• RA is preferably bonded to any of the 2-position, 3-position, and 4-position of the condensed polycycle, and the 2-position and 3-position of the condensed polycycle. It is more preferable to bind to any of the above, and it is further preferable to bind to the 3-position of the condensed polycycle.
• n100 and n200 are preferably integers of 1 to 3, preferably 1 or 2, and more preferably 1.
• RA in the formulas (10), (100) and (200) is the above formula (f1), formula (a1), formula (b1) or formula (e1) from the viewpoint of deprotection speed and stability over time. It is preferable that the group is represented by any of the above formulas (f1), more preferably the group is represented by either the above formula (f1) or the above formula (a1), and the group represented by the above formula (f1). It is more preferable that the group is represented by the above formula (f2).
• Equation (10) as the R 18 in Y 1 in the formula (100) and (200), from the viewpoint of the deprotection rate and stability over time, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, having a carbon number of 7 to It is preferably an arylalkyl group or Fmoc group of 16, more preferably a hydrogen atom, a methyl group, an ethyl group, a benzyl group or an Fmoc group, and even more preferably a hydrogen atom or an Fmoc group.
• RA is bound to the 3-position of the fused polycycle from the viewpoint of deprotection rate and stability over time
• Y 1 is -NHR 18 (preferably a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an arylalkyl group or an Fmoc group having 7 to 16 carbon atoms, and more preferably a hydrogen atom, a methyl group, an ethyl group, a benzyl group or an Fmoc group. It represents a group, more preferably a hydrogen atom or an Fmoc group), and RA preferably has the above formula (f1) (preferably a group represented by (f2)).
• the molecular weight of the compound represented by the formula (1) is not particularly limited, but is preferably 340 to 3,000 from the viewpoint of deprotection rate, crystallization property, solvent solubility, and yield. It is more preferably 400 to 2,000, further preferably 500 to 1,500, and particularly preferably 800 to 1,300. Further, when the molecular weight is 3,000 or less, the ratio of the formula (1) to the target product is appropriate, and the ratio of the compound obtained by deprotecting the formula (1) does not decrease, so that the productivity is excellent. ..
• the method for producing the compound represented by the formula (1) according to the present disclosure is not particularly limited, but can be produced by referring to a known method.
• the starting compound used for producing the compound represented by the formula (1) may be a commercially available compound, or may be produced according to a method known per se or a method similar thereto. it can.
• the produced compound represented by the formula (1) may be purified by a known purification method. For example, a method of isolating and purifying by recrystallization, column chromatography, or the like, a method of purifying by reprecipitation by means for changing the solution temperature, a means for changing the solution composition, or the like can be performed.
• the method for synthesizing the compound represented by the formula (1) according to the present disclosure is not particularly limited, but for example, it can be synthesized according to the following scheme using 3-hydroxyxanthone or the like as a starting material. In addition, it is also possible to synthesize by referring to the synthesis method described in International Publication No. 2018/021233.
• R 1r to R 8r independently represent RA , a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, and at least one of R 1r to R 8r and Y2.
• One represents RA .
• X 100 represents Cl, Br, I.
• R 180 represents a hydrogen atom, an alkyl group, or an Fmoc group.
• the step of using the compound represented by the above formula (1) protects the carboxy group or the amide group of the amino acid compound or the peptide compound by the compound represented by the above formula (1). It is preferable that the C-terminal protection step is performed.
• the method for producing a peptide compound according to the present disclosure is a carboxy group or an amide group of an amino acid compound or a peptide compound depending on the compound represented by the above formula (1) from the viewpoint of ease of synthesis of the peptide compound and yield.
• the N-terminal deprotection step that deprotects the N-terminal of the N-terminal protected C-terminal protected amino acid compound or the N-terminal protected C-terminal protected peptide compound obtained in the above C-terminal protection step, and Further includes a peptide chain extension step of condensing the N-terminal protected amino acid compound or the N-terminal protected peptide compound with the N-terminal of the C-terminal protected amino acid compound or the C-terminal protected peptide compound obtained in the above N-terminal deprotection step.
• the method for producing a peptide compound according to the present disclosure preferably further includes a C-terminal deprotection step of deprotecting a C-terminal protecting group. Further, the method for producing a peptide compound according to the present disclosure preferably further includes a dissolution step of dissolving the compound represented by the above formula (1) in a solvent before the C-terminal protection step.
• the method for producing a peptide compound according to the present disclosure preferably includes a dissolution step of dissolving the compound represented by the above formula (1) in a solvent before the C-terminal protection step.
• a solvent a general organic solvent can be used for the reaction, but the higher the solubility in the solvent, the better the reactivity can be expected. Therefore, the condensed polycyclic aromatic hydrocarbon represented by the formula (1) can be expected. It is preferable to select a solvent having a high solubility of the compound.
• halogenated hydrocarbons such as chloroform and dichloromethane
• non-polar organic solvents such as 1,4-dioxane, tetrahydrofuran and cyclopentyl methyl ether. Two or more of these solvents may be mixed and used in an appropriate ratio.
• the above-mentioned carbon halides and non-polar organic solvents aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile and propionitrile; ketones such as acetone and 2-butanone; N, N -Amids such as dimethylformamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide may be mixed and used in an appropriate ratio as long as the compound represented by the formula (1) can be dissolved.
• the solvent described in Organic Process Research & Development, 2017, 21, 3, 365-369 may be used.
• the method for producing a peptide compound according to the present disclosure preferably includes a C-terminal protection step of protecting the carboxy group or amide group of the amino acid compound or peptide compound with the compound represented by the above formula (1).
• the amino acid compound or peptide compound used in the C-terminal protection step is not particularly limited, and known ones can be used, but the N-terminal protected amino acid compound or the N-terminal protected peptide compound may be used. It is more preferably an Fmoc-protected amino acid compound or an Fmoc-protected peptide compound.
• the amino acid compound used in the C-terminal protection step or the hydroxy group, amino group, carbonyl group, amide group, imidazole group, indol group, guanidyl group, mercapto group and the like other than the C-terminal portion of the peptide compound will be described later. It is preferably protected by a known protective group such as a protective group.
• the amount of the amino acid compound or peptide compound used as the reaction substrate is preferably 1 molar equivalent to 10 molar equivalents, preferably 1 molar equivalent to 5 molar equivalents, relative to 1 molar equivalent of the compound represented by the above formula (1). It is more preferably 1 molar equivalent to 2 molar equivalents, and particularly preferably 1 to 1.5.
• the condensing agent is used in a solvent that does not affect the reaction in the presence of a condensation additive (condensation activator). Is preferably added or reacted in an acid catalyst.
• a condensation additive condensation activator
• the condensing agent is added in the presence of the condensation additive (condensation activator), or the condensing agent is used. It is preferable to react with a base.
• the amount of the condensation additive used is preferably 0.05 molar equivalent to 1.5 molar equivalent with respect to 1 molar equivalent of the condensed polycyclic aromatic hydrocarbon compound represented by the above formula (1).
• a condensing agent generally used in peptide synthesis can be used without limitation in the present disclosure, and is not limited to this, for example, 4- (4,6-dimethoxy-1,3,5).
• -Triazine-2-yl) -4-methylmorphonium chloride DMT-MM
• O- (benzotriazole-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) O- (7-azabenzotriazole-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU)
• O- (6-chlorobenzotriazole-1-yl) -1, 1,3,3-Tetramethyluronium hexafluorophosphate HBTU (6-Cl)
• O- (benzotriazole-1-yl) -1,1,3,3-tetramethyluronium tetrafluorobolate TBTU
• the amount of the condensing agent used is preferably 1 molar equivalent to 10 molar equivalents, more preferably 1 molar equivalent to 5 molar equivalents, relative to 1 molar equivalent of the compound represented by the above formula (1). ..
• an acid catalyst generally used in peptide synthesis can be used without limitation, and examples thereof include methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid. Of these, methanesulfonic acid and p-toluenesulfonic acid are preferable.
• the amount of the acid catalyst used is preferably 4.0 molar equivalents, which exceeds 0 molar equivalents, and is 0.05 molar equivalents to 1.5 molar equivalents, relative to 1 molar equivalent of the compound represented by the above formula (1).
• the equivalent is more preferably 0.1 molar equivalent to 0.3 molar equivalent.
• an activator in the above C-terminal protection step, in order to promote the reaction and suppress side reactions such as racemization, It is preferable to add an activator.
• the activator in the present disclosure is a reagent that, when coexisting with a condensing agent, leads an amino acid to a corresponding active ester, symmetric acid anhydride, or the like to facilitate the formation of a peptide bond (amide bond).
• an activator generally used in peptide synthesis can be used without limitation, for example, 4-dimethylaminopyridine, N-methylimidazole, boronic acid derivative, 1-hydroxybenzotriazole (HOBt).
• Ethyl 1-hydroxytriazole-4-carboxylate (HOCt), 1-hydroxy-7-azabenzotriazole (HOAt), 3-hydroxy-1,2,3-benzotriazodin-4 (3H) -one ( HOOBt), N-Hydroxysuccinimide (HOSu), N-Hydroxyphthalimide (HOPht), N-Hydroxy-5-norbornene-2,3-dicarboxyimide (HONb), pentafluorophenol, ethyl (hydroxyimino) cyanoacetate (Oxyma) ) Etc.
• HOCt 1-hydroxytriazole-4-carboxylate
• HOAt 1-hydroxy-7-azabenzotriazole
• HONb 3-hydroxy-1,2,3-benzotriazodin-4 (3H) -one
• HOBt N-Hydroxysuccinimide
• HPht N-Hydroxyphthalimide
• HONb N-H
• the amount of the activator to be used is preferably more than 0 molar equivalent and 4.0 molar equivalent, more preferably 0.1 molar equivalent to 1.5 molar equivalent, relative to the amino acid compound or peptide compound. ..
• a base generally used in peptide synthesis can be used without limitation, and examples thereof include a tertiary amine such as diisopropylethylamine.
• the solvent the above-mentioned solvent can be preferably used in the above-mentioned dissolution step.
• the reaction temperature is not particularly limited, but is preferably ⁇ 10 ° C. to 80 ° C., and more preferably 0 ° C. to 40 ° C.
• the reaction time is not particularly limited, but is preferably 1 hour to 30 hours.
• a method similar to that of a general liquid phase organic synthesis reaction can be applied. That is, the reaction can be traced using thin layer silica gel chromatography, high performance liquid chromatography, NMR or the like.
• the N-terminal protected C-terminal protected amino acid compound or the N-terminal protected C-terminal protected peptide compound obtained by the above C-terminal protection step may be purified.
• the obtained N-terminal protected C-terminal protected amino acid compound or N-terminal protected C-terminal protected peptide compound is dissolved in a solvent (reaction solvent), and the product obtained after carrying out the desired organic synthesis reaction is isolated.
• a method of changing the solvent in which the N-terminal protected C-terminal protected amino acid compound or the N-terminal protected C-terminal protected peptide compound is dissolved eg, changing the solvent composition, changing the type of solvent
• reprecipitating is preferable.
• the reaction is carried out under conditions in which the N-terminal protected C-terminal protected amino acid compound or the N-terminal protected C-terminal protected peptide compound is dissolved.
• the solvent is distilled off and then the solvent is replaced, or by adding a polar solvent to the reaction system without distilling off the solvent, the agglomerates are precipitated and impurities are eliminated.
• polar organic solvents such as methanol, acetonitrile and water are used alone or in combination.
• the reaction is carried out under conditions in which the N-terminal protected C-terminal protected amino acid compound or the N-terminal protected C-terminal protected peptide compound is dissolved, and after the reaction, the solvent substitution is, for example, a halogenated solvent, THF or the like for dissolution.
• a polar organic solvent such as methanol, acetonitrile or water for precipitation.
• the method for producing a peptide compound according to the present disclosure includes an N-terminal deprotection step of deprotecting the N-terminal of the N-terminal protected C-terminal protected amino acid compound or the N-terminal protected C-terminal protected peptide compound obtained in the above C-terminal protection step. It is preferable to include it.
• the N-terminal protecting group a protecting group for an amino group described later, which is generally used in technical fields such as peptide chemistry, can be used, but in the present disclosure, a Boc group and a benzyloxycarbonyl group (hereinafter, Cbz) can be used.
• a group or Z group) or Fmoc group is preferably used.
• the deprotection conditions are appropriately selected depending on the type of the temporary protecting group, but a group that can be deprotected under conditions different from the removal of the protecting group derived from the compound represented by the above formula (1) is preferable.
• a group that can be deprotected under conditions different from the removal of the protecting group derived from the compound represented by the above formula (1) is preferable.
• an Fmoc group it is carried out by treating with a base
• a Boc group it is carried out by treating with an acid.
• the reaction is carried out in a solvent that does not affect the reaction.
• the above-mentioned solvent can be preferably used in the above-mentioned dissolution step.
• the method for producing a peptide compound according to the present disclosure is a method for producing an N-terminal protected amino acid compound or an N-terminal protected peptide compound at the N-terminal of the C-terminal protected amino acid compound or C-terminal protected peptide compound obtained in the above N-terminal deprotection step. It is preferable to include a peptide chain extension step of condensing.
• the peptide chain extension step is preferably carried out under peptide synthesis conditions generally used in the field of peptide chemistry, using the above-mentioned condensing agent, condensation additive and the like.
• the N-terminal protected amino acid compound or N-terminal protected peptide compound is not particularly limited and any desired compound can be used, but an Fmoc-protected amino acid compound or Fmoc-protected peptide compound can be preferably used.
• the hydroxy group, amino group, carbonyl group, amide group, imidazole group, indol group, guanidyl group, mercapto group and the like other than the C-terminal portion of the N-terminal protected amino acid compound or the N-terminal protected peptide compound are protective groups described later. It is preferable that it is protected by a known protective group such as.
• the method for producing a peptide compound according to the present disclosure preferably further includes a precipitation step of precipitating the N-terminal protected C-terminal protected peptide compound obtained in the peptide chain extension step.
• the precipitation step can be carried out in the same manner as the purification (reprecipitation) of the C-terminal protection step.
• the polar solvent is added to the reaction system without distilling off the reaction solvent after the reaction in the previous stage.
• THF is used as the non-polar organic solvent as the reaction solvent
• acetonitrile is used as the polar solvent.
• the ratio (volume basis) of the non-polar organic solvent to the polar solvent is preferably 1: 1 to 1: 100, more preferably 1: 3 to 1:50, and even more preferably 1: 5 to 1:20.
• the N-terminal protected C-terminal protected amino acid compound or the N-terminal protected C-terminal protected peptide compound can be efficiently precipitated, and the desired product can be efficiently purified.
• the method for producing a peptide compound according to the present disclosure is a step of deprotecting the N-terminal of the obtained N-terminal protected C-terminal protected peptide compound after the precipitation step, and the N-terminal of the obtained C-terminal protected peptide compound. It is preferable that the step of condensing the N-terminal protected amino acid compound or the N-terminal protected peptide compound and the step of precipitating the obtained N-terminal protected C-terminal protected peptide compound are further included once or more in this order. By repeating the above three steps, the chain extension of the obtained peptide compound can be easily performed. Each step in the above three steps can be performed in the same manner as each corresponding step described above.
• the method for producing a peptide compound according to the present disclosure preferably further includes a C-terminal deprotection step of deprotecting a C-terminal protecting group.
• the final target product is obtained by removing the C-terminal protecting group formed by the compound represented by the above formula (1) in the C-terminal protected peptide compound having a desired number of amino acid residues.
• a certain peptide compound can be obtained.
• a method for removing the C-terminal protecting group a deprotection method using an acidic compound is preferably mentioned. For example, a method of adding an acid catalyst and a method of hydrogenating using a metal catalyst can be mentioned.
• the acid catalyst examples include trifluoroacetic acid (TFA), hydrochloric acid, trifluoroethanol (TFE), hexafluoroisopropanol (HFIP), acetic acid, etc.
• TFA trifluoroacetic acid
• TFE trifluoroethanol
• HFIP hexafluoroisopropanol
• acetic acid etc.
• TFA trifluoroacetic acid
• TFE trifluoroethanol
• HFIP hexafluoroisopropanol
• acetic acid etc.
• concentration of the acid can be appropriately selected depending on the side chain protecting group of the extending amino acid and the deprotection conditions, and may be 0.01% by mass to 100% by mass with respect to the total mass of the solvent used.
• the concentration of TFA is preferably 70% by mass or less, more preferably 50% by mass or less, further preferably 30% by mass or less, and particularly preferably 10% by mass or less.
• the concentration of TFA is preferably 10% by volume or less, more preferably 5% by volume or less, further preferably 5% by volume or less, and particularly preferably 1% by volume or less, based on the total volume of the solvent used.
• the lower limit is preferably 0.01% by volume, more preferably 0.1% by volume, and even more preferably 0.5% by volume.
• the deprotection time is preferably 5 hours or less, more preferably 3 hours or less, and even more preferably 1 hour or less.
• Peptides that are suitable for deprotecting the C-terminal protecting group under weak acid conditions include, for example, peptides having an N-alkylamide structure.
• the method for producing the peptide compound according to the present disclosure is preferably a method for producing a peptide compound that is sensitive to an acid, and a peptide compound having an N-alkylamide structure. The manufacturing method of is more preferable.
• the peptide compound which is the final target product obtained by the method for producing a peptide compound according to the present disclosure, can be isolated and purified according to a method commonly used in peptide chemistry.
• the final target peptide compound can be isolated and purified by extracting and washing the reaction mixture, crystallization, chromatography and the like.
• the type of peptide produced by the method for producing a peptide compound according to the present disclosure is not particularly limited, but the number of amino acid residues of the peptide compound is preferably, for example, about several tens or less.
• the peptides obtained by the method for producing a peptide compound according to the present disclosure are similar to existing or unknown synthetic peptides and natural peptides, and are used in various fields such as, but not limited to, pharmaceuticals, foods, cosmetics, electronic materials, and biosensors. It can be used in fields such as sensors.
• the precipitation step can be appropriately omitted as long as it does not affect the reaction in the next step.
• amino acid compound used in the method for producing a peptide compound according to the present disclosure and the peptide compound have a hydroxy group, an amino group, a carboxy group, a carbonyl group, a guadinyl group, a mercapto group, etc., these groups are subjected to peptide chemistry or the like.
• a commonly used protective group may be introduced, and the target compound can be obtained by removing the protective group if necessary after the reaction.
• Examples of the hydroxy group protective group include an alkyl group having 1 to 6 carbon atoms, an aryl group, a trityl group, an aralkyl group having 7 to 10 carbon atoms, a formyl group, an acyl group having 1 to 6 carbon atoms, a benzoyl group, and carbon.
• Examples thereof include an aralkyl-carbonyl group having a number of 7 to 10, a 2-tetrahydropyranyl group, a 2-tetrahydrofuranyl group, a silyl group, and an alkenyl group having 2 to 6 carbon atoms.
• These groups may be substituted with 1 to 3 substituents selected from the group consisting of halogen atoms, alkyl groups having 1 to 6 carbon atoms, and nitro groups.
• amino group protecting group examples include a formyl group, an acyl group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms, a benzoyl group, an aralkyl-carbonyl group having 7 to 10 carbon atoms, and 7 to 7 carbon atoms.
• aralkyloxycarbonyl group trityl group, monomethoxytrityl group, 1- (4,4-Dimethyl-2,6-dioxocyclohex-1-ylidene) -3-methylbutyl group, phthaloyl group, N, N-dimethylaminomethylene
• examples thereof include a group, a silyl group, and an alkenyl group having 2 to 6 carbon atoms. These groups may be substituted with 1 to 3 substituents selected from the group consisting of halogen atoms, alkoxy groups having 1 to 6 carbon atoms, and nitro groups.
• carboxy group protecting group examples include the above hydroxy group protecting group and trityl group.
• Examples of the carbonyl group protecting group include cyclic acetals (eg, 1,3-dioxane), acyclic acetals (eg, di (alkyls having 1 to 6 carbon atoms) acetals) and the like.
• Examples of the protecting group of the guanidyl group include 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl group, 2,3,4,5,6-pentamethylbenzenesulfonyl group, tosyl group and nitro. Examples include groups.
• Examples of the protective group of the mercapto group include a trityl group, a 4-methylbenzyl group, an acetylaminomethyl group, a t-butyl group, a t-butylthio group and the like.
• the method for removing these protecting groups may be carried out according to a known method, for example, the method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980).
• a method using an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide and the like, a reduction method and the like are used.
• the reagent for forming a protecting group according to the present disclosure contains a compound represented by the above formula (1). According to another embodiment of the present invention, a reagent for forming a protecting group having excellent yield can be provided. In particular, it is possible to provide a reagent for forming a protecting group, which is excellent in deprotection rate and stability over time.
• the protecting group forming reagent according to the present disclosure is preferably a carboxy group or amide group protecting group forming reagent, and more preferably a C-terminal protecting group forming reagent of an amino acid compound or a peptide compound.
• the preferred embodiment of the compound represented by the formula (1) in the reagent for forming a protecting group according to the present disclosure is the same as the preferred embodiment of the compound represented by the formula (1) according to the present disclosure described above.
• the content of the condensed polycyclic aromatic hydrocarbon compound represented by the formula (1) in the protecting group forming reagent according to the present disclosure is not particularly limited, but is 0. It is preferably from 1% by mass to 100% by mass, more preferably from 1% by mass to 100% by mass, and even more preferably from 3% by mass to 100% by mass.
• the reagent for forming a protecting group according to the present disclosure may contain components other than the compound represented by the formula (1).
• Ya 1 represents -ORa 17 , -NHRa 18 , -SH, or a halogen atom
• Ra 17 represents a hydrogen atom, an active ester-type carbonyl group, or an active ester-type sulfonyl group
• Ra 18 represents a hydrogen atom or a linear or branched alkyl group having 10 or less carbon atoms, an arylalkyl group or a heteroarylalkyl group, or an Fmoc group.
• Ra 1 to Ra 8 independently represent RA , a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms.
• At least one of Ra 2 to Ra 7 has RA , RA represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and RA represents at least one aliphatic hydrocarbon.
• the hydrogen group has 12 or more carbon atoms, However, RA does not have a silyl group and a hydrocarbon group having a silyloxy structure.
• the condensed polycyclic compound represented by the formula (1a), which is the compound according to the present disclosure, is a novel compound and can be suitably used for the production of a peptide compound.
• it can be suitably used as a reagent for forming a protecting group, more preferably used as a reagent for forming a protecting group of a carboxy group or an amide group, and particularly as a reagent for forming a C-terminal protecting group of an amino acid compound or a peptide compound. It can be preferably used.
• Ra 17 and Ra 18 have the same meaning as R 17 and R 18 in formula (1), and so do preferred embodiments.
• Ya 2 in the formula (1a) has the same meaning as Y 2 in the formula (1), and the preferred embodiment is also the same.
• R A in formula (1a) are the same as R A in the formula (1), a preferable embodiment thereof is also the same.
• the condensed polycyclic compound represented by the formula (1a) in the compound according to the present disclosure is the above-mentioned method for producing a peptide compound according to the present disclosure, except that at least one of Ra 2 to Ra 7 has RA . It is the same as the compound represented by the above-mentioned formula (1), and the same applies to preferred embodiments other than the preferred embodiments described later.
• the fused polycyclic compound represented by the above formula (1a) is a compound in which at least one of Ra 2 to Ra 7 has RA , and from the viewpoint of deprotection rate and stability over time, Ra 3 and Ra 6 preferably, at least one is a compound having a R a, one of Ra 3 and Ra 6 is more preferably a compound having a R a.
• the condensed polycyclic compound represented by the above formula (1a) is preferably a compound represented by either the following formula (100a) or the formula (200a) from the viewpoint of deprotection rate and stability over time. It is more preferable that the compound is represented by the following formula (100a).
• Y 1 represents -OH or -NH 2
• RA represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group.
• RA has at least one aliphatic hydrocarbon group having 12 or more carbon atoms, except that RA does not have a silyl group and a hydrocarbon group having a silyloxy structure.
• the RA in the compound represented by the above formula (100a) and the formula (200a) is synonymous with the RA in the compound represented by the above formula (1a), and the preferred embodiment is also the same.
• the condensed polycyclic compound represented by the above formula (1a) can be synthesized in the same manner as the compound represented by the above formula (1).
• purification by column chromatography is performed by an automatic purification device ISOLERA (manufactured by Biotage) or a medium pressure liquid chromatograph YFLC-Wprep2XY. N (manufactured by Yamazen Corporation) was used.
• ISOLERA manufactured by Biotage
• YFLC-Wprep2XY. N manufactured by Yamazen Corporation
• SNAPKP-SilCartridge manufactured by Biotage
• high flash columns W001, W002, W003, W004 or W005 were used as carriers in silica gel column chromatography.
• the mixing ratio in the eluent used for column chromatography is the volume ratio.
• the MS spectrum was measured using ACQUITY SQD LC / MS System (manufactured by Waters, ionization method: ESI (ElectroSpray Ionization, electrospray ionization) method).
• the NMR spectrum was measured using Bruker AV300 (Made by Bruker, 300 MHz) or Bruker AV400 (manufactured by Bruker, 400 MHz) using tetramethylsilane as an internal reference, and the total ⁇ value was expressed in ppm.
• the HPLC purity was measured using ACQUITY UPLC (manufactured by Waters, column: CSH C18 1.7 ⁇ m).
• Intermediate (1-1) was synthesized by the method described in European Patent Application Publication No. 2518041.
• Intermediate (1-1) (4.00 g, 5.16 mmol), 3-hydroxyxanthene-9-one (1.31 g, 6.24 mmol), potassium carbonate (1.43 g, 10.3 mmol), N-methyl Pyrrolidone (NMP, 40 mL) was mixed and stirred at 110 ° C. for 3 hours under a nitrogen atmosphere.
• the reaction solution was cooled to 55 ° C. and extracted with toluene and water.
• the solid precipitated by adding methanol to the obtained organic layer was filtered and dried under reduced pressure to obtain an intermediate (1-2) (4.66 g, yield 95%).
• Diazabicycloundecene (DBU, 391 ⁇ L, 2.57 mmol) was added to the mixture of compound (1-NF-1) (1.51 g, 1.29 mmol) and tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 2 hours. did. After completion of the reaction, acetonitrile (80 mL) was added, the mixture was stirred, and the precipitate was filtered and dried under reduced pressure to give compound (1-N-1) (1.15 g, yield 94%).
• DBU Diazabicycloundecene
• Example 2 and 3 and Comparative Examples 1 and 2 Compound (1-NF-2), compound (1-NF-3), comparative compound (1-NF-1), comparative, similar to the method for obtaining N-protected C-protected amino acids (1-N-1).
• the corresponding N-protected C-protected amino acid was synthesized by condensing compound (2-NF-1) with N-[(9H-fluoren-9-ylmethoxy) carbonyl] -L-leucine.
• N-methylmorpholine (2.05 molar equivalents) and methanesulfonic acid (2.0 molar equivalents) were added in that order, followed by Fmoc-Gly-OH (1.25 molar equivalents), (1- Cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholinocarbenium hexafluorophosphate (COMU, 1.25 molar equivalents) was added and stirred.
• N-methylmorpholine (2.05 molar equivalents) and methanesulfonic acid (2.0 molar equivalents) were added in that order, followed by Fmoc-Cys (Trt-OH (1.25 molar equivalents), ( 1-Cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholinocarbenium hexafluorophosphate (COMU, 1.25 molar equivalents) was added and stirred.
• N-methylmorpholine (2.05 molar equivalents) and methanesulfonic acid (2.0 molar equivalents) were added in that order, followed by Fmoc-Arg (Pbf) -OH (1.25 molar equivalents).
• Fmoc-Arg (Pbf) -OH (1.25 molar equivalents).
• 1-Cyano-2-ethoxy-2-oxoethylideneaminooxy Dimethylaminomorpholinocarbenium hexafluorophosphate (COMU, 1.25 molar equivalents) was added and stirred.
• N-methylmorpholine (2.05 molar equivalents) and methanesulfonic acid (2.0 molar equivalents) were added in that order, followed by Fmoc-MeNle-OH (1.25 molar equivalents), (1- Cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholinocarbenium hexafluorophosphate (COMU, 1.25 molar equivalents) was added and stirred.
• Example 8 Synthesis of Fmoc-MeNle-MeNle-Arg (Pbf) -Cys (Trt) -Gly-NH-XantTAG (1)
• Fmoc-MeNle-Arg (Pbf) -Cys (Trt) -Gly-NH-XantTAG (1) (2.00 g, 1.70 mmol) was dissolved in tetrahydrofuran (17 mL) and diazabicycloundecene (DBU, 2). (0.0 molar equivalent) was added and stirred.
• DBU diazabicycloundecene
• N, N-diisopropylethylamine (6.05 eq) and methanesulfonic acid (2.0 eq) were added in sequence, followed by Fmoc-MeNle-OH (2.0 eq), (. 7-azabenzotriazole-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyAOP, 2.0 molar equivalents) was added and stirred.
• the method for producing a peptide compound including the step of using the compound represented by the formula (1) according to the present disclosure has a high yield of the peptide compound obtained in any of the examples, and is total. It can be seen that the yield is also excellent.
• Trp Boc-protected tryptophan residue Boc: tert-butylcarbonyl group Ser (Trt): Trt-protected serine residue Leu: Leucine residue His (Boc): Boc-protected histidine residue Asn (Trt): Trt-protected asparagine Residue MeAla: N-methylalanine residue Ph: Phenylalanine residue ClAc: Chloroacetyl group
• Example 9 Synthesis of cyclic peptide A
• ClAc-Phe-MeAla-Asn-Pro-His-Leu-Ser-Trp-Ser-Trp-MeNle-MeNle-Arg-Cys-Gly-NH 2 (0.167 g) at room temperature, acetonitrile and 0.1 mol / A 1/1 mixed solution (138 mL) of L triethylammonium dicarbonate buffer and a 0.5 mol / L tris (2-carboxyethyl) phosphine aqueous solution (138 ⁇ L) were added, and the mixture was stirred for 2 hours.
• Example 10 Synthesis of cyclic peptide B) ClAc-Phe-MeAla-Asn (Mmt) -Pro-His-Leu-Ser-Trp-Ser-Trp-MeNle-MeNle-Arg (Pbf) -Cys-Gly-NH 2 (39.4 mg) at room temperature.
• a 1/1 mixture (11 mL) of acetonitrile and 0.1 mol / L triethylammonium dicarbonate buffer and a 0.5 mol / L tris (2-carboxyethyl) phosphine aqueous solution (23 ⁇ L) were added, and the mixture was stirred for 2 hours.
• Examples 9 and 10 according to the method for producing a peptide compound according to the present disclosure, it can also be applied to the production of a cyclic peptide compound having an N-alkylamide structure.
• the C-terminal protecting group could be deprotected even under weak acid conditions, the side reaction of the obtained peptide could be suppressed, the purity was high, and the yield was high.

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