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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
  • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
  • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
  • C07C211/30—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by two rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
  • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
  • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
  • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• • 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
  • C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
• • 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
  • 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
• • 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 aromatic hydrocarbon 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.
• 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.
• the liquid phase method still has problems in each step of coupling reaction and deprotection.
• Patent Document 1 As conventional reagents for forming a protecting group, a compound having a fluorene structure described in Patent Document 1 and a compound having a diphenylmethane structure described in Patent Document 2 are known.
• Patent Document 1 International Publication No. 2010/104169
• Patent Document 2 International Publication No. 2010/1133939
• a method for producing a peptide compound which comprises a step of using a condensed polycyclic aromatic hydrocarbon compound represented by the following formula (1).
• Ring A represents a condensed polycyclic aromatic hydrocarbon ring.
• Y A represents -OH, -NHR, SH, or an -X 0,
• R represents a hydrogen atom, an alkyl group, an aromatic group substituted alkyl group, a heteroaromatic group substituted alkyl group or a 9-fluorenylmethoxycarbonyl group.
• X 0 represents Cl, Br or I
• R A is independently an aliphatic hydrocarbon group, or represents an organic group having an aliphatic hydrocarbon group
• R B independently, a monovalent aliphatic hydrocarbon group
• RC independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group.
• n 1 or 2
• a represents an integer of 0 to 5
• c represents an integer of 0 to 5
• the R B be a monovalent aliphatic hydrocarbon group
• R A, of R B and R C the number of carbon atoms of at least one of said aliphatic hydrocarbon group is 12 or more.
• the step of using the condensed polycyclic aromatic hydrocarbon compound represented by the above formula (1) is the carboxy of the amino acid compound or the peptide compound by the condensed polycyclic aromatic hydrocarbon compound represented by the above formula (1).
• the method for producing a peptide compound according to ⁇ 1> which is a C-terminal protection step for protecting a group or an amide group.
• N-terminal deprotection step for deprotecting the N-terminal of the N-terminal protected C-terminal protected amino acid compound or N-terminal protected C-terminal protected peptide compound obtained in the above C-terminal protection step, and an 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.
• ⁇ 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>, which further comprises a C-terminal deprotection step of deprotecting a C-terminal protecting group.
• ⁇ 8> The method for producing a peptide compound according to any one of ⁇ 1> to ⁇ 7>, wherein the ring A is a naphthalene ring.
• All R A, the total number of carbon atoms in all the aliphatic hydrocarbon groups of the R B and R C is a 36 to 80 ⁇ 1> to peptide compound according to any one of ⁇ 8> Manufacturing method.
• the condensed polycyclic aromatic hydrocarbon compound represented by the above formula (1) is a compound represented by either the following formula (10) or the formula (20) of ⁇ 1> to ⁇ 9>.
• Y B represents -OH, -NHR, -SH, or -X 0
• R represents a hydrogen atom, an alkyl group, an aromatic group substituted alkyl group, a heteroaromatic group substituted alkyl group or a 9-fluorenylmethoxycarbonyl group (Fmoc group).
• X 0 represents Cl, Br or I
• R r100 represents a hydrogen atom, an aryl group or a heteroaryl group.
• R s independently represent a substituent or RA , respectively.
• n10 represents an integer from 0 to 5 and represents Adjacent R s may be bonded to each other to form a ring through a substituent
• R r10 and R r11 independently represent a hydrogen atom, a substituent, a group represented by the above formula (10-A), or RA .
• Either R r10 or R r11 is a group represented by the above formula (10-A). * Represents the connection position with R r10 or R r11 .
• R r12 to R r17 independently represent a hydrogen atom, a substituent, or RA , respectively.
• At least one of R s and R r10 to R r17 is RA .
• R A is independently an aliphatic hydrocarbon group, or represents an organic group having an aliphatic hydrocarbon group, and (with at least one R A) the number of carbon atoms of at least one of said aliphatic hydrocarbon group , 12 or more.
• Y B represents -OH, -NHR, -SH, or -X 0
• R represents a hydrogen atom, an alkyl group, an aromatic group substituted alkyl group, a heteroaromatic group substituted alkyl group or a 9-fluorenylmethoxycarbonyl group (Fmoc group).
• X 0 represents Cl, Br or I
• R r200 represents a hydrogen atom, an alkyl group, an aryl group or a heteroaryl group.
• R r201 represents an alkyl group R r20 and R r21 independently represent a hydrogen atom, a substituent, a group represented by the above formula (20-A), or RA .
• R r20 or R r21 is a group represented by the above formula (20-A). * Represents the connection position with R r20 or R r21 .
• R r22 ⁇ R r27 are each independently a hydrogen atom, a substituent or represents R A, R r201 has 12 or more carbon atoms, or at least one of R r20 to R r27 is RA .
• R A is independently an aliphatic hydrocarbon group, or represents an organic group having an aliphatic hydrocarbon group, and (with at least one R A) the number of carbon atoms of at least one of said aliphatic hydrocarbon group , 12 or more.
• the wavy line portion represents the coupling position with other structures
• 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 bonding position with other structures
• m20 represents an integer of 1 to 10
• X 20 is independently single-bonded, -O-, -S-, and -COO.
• R 20 each independently represents a divalent aliphatic hydrocarbon group, at least one of R 20 Is a divalent aliphatic hydrocarbon group having 5 or more carbon atoms.
• the wavy line portion represents the connection position with other structures
• 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.
• Ring A represents a condensed polycyclic aromatic hydrocarbon ring.
• Y A represents -OH, -NHR, SH, or an -X 0,
• R represents a hydrogen atom, an alkyl group, an aromatic group substituted alkyl group, a heteroaromatic group substituted alkyl group or a 9-fluorenylmethoxycarbonyl group (Fmoc group).
• X 0 represents Cl, Br or I
• RA independently represent an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group.
• R B each independently represent a monovalent aliphatic hydrocarbon group, a (1 + c) valent aromatic group, or (1 + c) valent heteroaromatic group, Each RC independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group.
• m represents 1 or 2
• a represents an integer from 0 to 5 and represents c represents an integer from 0 to 5 and represents If a and c are both a 0,
• R B is a monovalent aliphatic hydrocarbon group, (R A, of R B and R C) the number of carbon atoms of at least one of said aliphatic hydrocarbon group is 12 or more.
• 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.
• Ring A represents a condensed polycyclic aromatic hydrocarbon ring.
• Y A represents -OH, -NHR, -SH, or, the -X 0, R represents a hydrogen atom, an alkyl group having 10 or less carbon atoms, an aromatic group-substituted alkyl group, a heteroaromatic group-substituted alkyl group or a 9-fluorenylmethoxycarbonyl group (Fmoc group).
• X 0 represents Cl, Br or I
• RA independently represent an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group.
• R B each independently represent a monovalent aliphatic hydrocarbon group, a (1 + c) valent aromatic group, or (1 + c) valent heteroaromatic group,
• Each RC independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group.
• m represents 1 or 2
• a represents an integer from 0 to 5 and represents c represents an integer from 0 to 5 and represents If a and c are both a 0,
• R B is a monovalent aliphatic hydrocarbon group, (R A, R B and R C) the number of carbon atoms of at least one aliphatic hydrocarbon group is at least 18, If R B is a monovalent aliphatic hydrocarbon group, including saturated aliphatic hydrocarbon group of linear with the number 18 or more carbon atoms.
• the condensed polycyclic aromatic hydrocarbon compound represented by the above formula (1a) is a compound represented by either the following formula (10a) or the formula (20a) in ⁇ 17> or ⁇ 18>.
• Y B represents -OH, -NHR, -SH, or -X 0
• R represents a hydrogen atom, an alkyl group having 10 or less carbon atoms, an aromatic group-substituted alkyl group, a heteroaromatic group-substituted alkyl group or a 9-fluorenylmethoxycarbonyl group (Fmoc group).
• X 0 represents Cl, Br or I
• R r100 represents a hydrogen atom, an aryl group or a heteroaryl group.
• R s may independently represent a substituent or RA
• n10 may represent an integer of 0 to 5
• adjacent R s may be linked to each other via a substituent to form a ring.
• R r10 and R r11 independently represent a hydrogen atom, a substituent, a group represented by the above formula (10a-A), or RA .
• Either R r10 or R r11 is a group represented by the above formula (10a-A).
• * represents the connection position with R r10 or R r11 .
• R r12 to R r17 independently represent a hydrogen atom, a substituent, or RA , respectively.
• At least one of R s and R r10 to R r17 is RA .
• R A is independently an aliphatic hydrocarbon group, or has an aliphatic hydrocarbon group, and the carbon number of (at least one of R A has the) at least one of said aliphatic hydrocarbon group is, 18 or more Is
• Y B represents -OH, -NHR, -SH, or -X 0
• R represents a hydrogen atom, an alkyl group having 10 or less carbon atoms, an aromatic group-substituted alkyl group, a heteroaromatic group-substituted alkyl group or a 9-fluorenylmethoxycarbonyl group (Fmoc group).
• X 0 represents Cl, Br or I
• R r200 represents a hydrogen atom, an alkyl group, an aryl group or a heteroaryl group.
• R r201 represents an aliphatic hydrocarbon group and represents R r20 and R r21 independently represent a hydrogen atom, a substituent, a group represented by the above formula (20a-A), or RA .
• Either R r20 or R r21 is a group represented by the above formula (20a-A). * Represents the connection position with R r20 or R r21 .
• R r22 ⁇ R r27 are each independently a hydrogen atom, a substituent or represents R A, If R B is an aliphatic hydrocarbon group, or contains a saturated aliphatic hydrocarbon group having a straight chain having 18 or more carbon atoms, or at least one of R r20 ⁇ R r27 is R A, R A are each Independently, the aliphatic hydrocarbon group or the at least one said aliphatic hydrocarbon group having an aliphatic hydrocarbon group and having at least one RA has 18 or more carbon atoms.
• the wavy line portion represents the coupling position with other structures
• 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 bonding position with other structures
• m20 represents an integer of 1 to 10
• X 20 is independently single-bonded, -O-, -S-, and -COO.
• R 20 each independently represents a divalent aliphatic hydrocarbon group, at least one of R 20 Is a divalent aliphatic hydrocarbon group having 5 or more carbon atoms.
• the wavy line portion represents the connection position with other structures
• 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 in the formula (a1) is condensed polycyclic aromatic hydrocarbon compound according to an -O- ⁇ 20>.
• a method for producing a peptide compound having an excellent yield it is possible to provide a reagent for forming a protecting group having an excellent yield.
• a novel condensed polycyclic aromatic hydrocarbon 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 and 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 condensed polycyclic aromatic hydrocarbon compound represented by the following formula (1).
• Ring A represents a condensed polycyclic aromatic hydrocarbon ring.
• Y A represents -OH, -NHR, SH, or an -X 0,
• R represents a hydrogen atom, an alkyl group, an aromatic group-substituted alkyl group, a heteroaromatic group-substituted alkyl group or an Fmoc group.
• X 0 represents Cl, Br or I
• R A is independently an aliphatic hydrocarbon group, or represents an organic group having an aliphatic hydrocarbon group
• R B independently, a monovalent aliphatic hydrocarbon group
• RC independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group.
• n 1 or 2
• a represents an integer of 0 to 5
• c represents an integer of 0 to 5
• the R B be a monovalent aliphatic hydrocarbon group
• R a, R B and R C the number of carbon atoms of at least one of said aliphatic hydrocarbon group is 12 or more.
• 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. Furthermore, with respect to the hydrophilic solvent, each R A, and that between aliphatic hydrocarbon group in R B and R C are aggregated, by having a condensed polycyclic aromatic hydrocarbon ring as the ring A, In the obtained peptide compound, ⁇ - ⁇ interaction ( ⁇ - ⁇ stacking) between condensed polycyclic aromatic hydrocarbon rings occurs, so that the crystallization property is excellent, and the purification and separability are also excellent.
• the reaction proceeds rapidly because the solvent solubility in the hydrophobic solvent which is the reaction solvent is excellent, and a polar solvent which is a poor solvent is added at the time of purification. It is presumed that the yield of the obtained compound (peptide compound, etc.) is excellent because the target product is efficiently crystallized and purified. Further, by having a Y A that binds to the condensed polycyclic aromatic hydrocarbon ring via a mono- or di-substituted methylene group, is excellent in the deprotection rate. This is because the condensed polycyclic aromatic hydrocarbon ring contributes to electron donation or cation stabilization.
• the compound represented by the formula (1) according to the present disclosure can suppress side reactions and synthesize peptides with high purity due to the above structure, and is stable and deprotected (removed) during the peptide synthesis reaction. ) Is easy. Furthermore, even poorly synthesized peptides such as unnatural peptides containing unnatural amino acids that easily cause side reactions can be synthesized with high purity by suppressing side reactions.
• 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 condensed polycyclic aromatic hydrocarbon compound represented by the formula (1) not only forms a protective group, but also modifies the peptide compound and has a solubility in water or an organic solvent. It can be used for adjustment of, improvement of crystallinity, multimerization and the like.
• the condensed polycyclic aromatic hydrocarbon 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.
• Ring A represents a condensed polycyclic aromatic hydrocarbon ring.
• Y A represents -OH, -NHR, SH, or an -X 0,
• R represents a hydrogen atom, an alkyl group, an aromatic group-substituted alkyl group, a heteroaromatic group-substituted alkyl group or an Fmoc group.
• X 0 represents Cl, Br or I
• R A is independently an aliphatic hydrocarbon group, or represents an organic group having an aliphatic hydrocarbon group
• R B independently, a monovalent aliphatic hydrocarbon group
• RC independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group.
• m represents 1 or 2
• a represents an integer of 0 to 5
• c represents an integer of 0 to 5
• the R B be a monovalent aliphatic hydrocarbon group
• the number of carbon atoms of at least one of said aliphatic hydrocarbon group is 12 or more.
• At least one aliphatic hydrocarbon group having 12 or more carbon atoms may be used in the compound.
• at least one of them may have an aliphatic hydrocarbon group having 12 or more carbon atoms.
• Ring A in the formula (1) two or more aromatic hydrocarbon ring represents a fused condensed polycyclic aromatic hydrocarbon ring, also Ring A is a methylene group Y A and R B are linked, and , RA may have additional substituents.
• ring A is preferably a fused polycyclic aromatic hydrocarbon ring having 2 to 4 rings, and a condensed polycyclic aromatic ring having 2 or 3 rings. It is more preferably a group hydrocarbon ring, and particularly preferably a two-ring condensed polycyclic aromatic hydrocarbon ring.
• the ring A is preferably a naphthalene ring, an anthracene ring, phenanthrene ring, tetracene ring, triphenylene ring, pyrene ring, or chrysen ring from the viewpoint of deprotection rate, crystallization property, and yield. It is more preferably a naphthalene ring, an anthracene ring, or a phenanthrene ring, and particularly preferably a naphthalene ring. Further, the ring A is preferably a ring having at least a naphthalene ring structure from the viewpoint of yield.
• the ring A may have a substituent, and as described later, two or more substituents may be bonded to form a ring structure, and the ring A may have an aliphatic hydrocarbon ring or a fat. It may have a structure in which a group heterocycle, a heteroaromatic ring and the like are further condensed.
• the alkyl group in R include alkyl groups having 1 to 30 carbon atoms (also referred to as “carbon atoms”), preferably alkyl groups having 1 to 10 carbon atoms, and alkyl groups having 1 to 6 carbon atoms. More preferably it is a group. Of these, a methyl group and an ethyl group are more preferable.
• Examples of the aromatic group-substituted alkyl group in R include an aromatic group-substituted alkyl group having 7 to 30 carbon atoms, preferably an aromatic group-substituted alkyl group having 7 to 20 carbon atoms, and 7 to 16 carbon atoms. (For example, a group in which an aromatic group (aryl group) having 6 to 10 carbon atoms is bonded to an alkylene group having 1 to 6 carbon atoms) 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.
• the heteroaromatic group-substituted alkyl group in R include a heteroaromatic group-substituted alkyl group having 5 to 30 carbon atoms, and a heteroaromatic group-substituted alkyl group having 5 to 20 carbon atoms is preferable.
• a heteroaromatic group-substituted alkyl group of 5 to 16 (for example, a group in which an alkylene group having 1 to 6 carbon atoms is bonded to a heteroaromatic group having 4 to 10 carbon atoms (heteroaryl group)) 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 is preferably a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aromatic group-substituted alkyl group having 7 to 16 carbon atoms or an Fmoc group, and is a hydrogen atom, a methyl group, an ethyl group, a benzyl group or a hydrogen atom. It is more preferably an Fmoc group, and even more preferably a hydrogen atom or an Fmoc group.
• R is Fmoc group, described below 1,8-diazabicyclo [5.4.0] -7-base with Fmoc group undecene (DBU) by deprotecting the Y A is -NH 2 Therefore, when R is an Fmoc group and when R is a hydrogen atom, it can be regarded as equivalent.
• the compound represented by formula (1), the substituents having on the ring A, as a substituent, or R A having on R B, group having a ring A having a methylene group Y A and R B are linked , or it may have a group having a ring a and Y a having a methylene group Y a and R B are linked.
• the compound represented by the formula (1) may be a multimer such as a dimer.
• the multimer is preferably a dimer to a hexamer, more preferably a dimer to a tetramer, and particularly preferably a dimer from the viewpoint of ease of synthesis.
• R A is a number of substituents R A on ring A in the formula (1) is deprotected speed, solvent solubility, and, in view of the yield, preferably an integer of 1 to 4, from 1 to 3 It is more preferably an integer, and particularly preferably 1 or 2.
• the expression c is a substitution number of R C on R B in (1), the deprotection rate, solvent solubility, and, in view of the yield, preferably 0 to 4 integer, 0 ⁇ It is more preferably an integer of 2, further preferably 0 or 1, and particularly preferably 0.
• a + c in the formula (1) is 0 or more, and is preferably an integer of 1 to 6 from the viewpoint of deprotection rate, solvent solubility, and yield, and is an integer of 1 to 4. It is more preferably present, more preferably 1 to 3, and particularly preferably 1.
• Each of RA independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group.
• each RC independently represents an aliphatic hydrocarbon group or an organic group having the above-mentioned aliphatic hydrocarbon group.
• the "organic group having an aliphatic hydrocarbon group” is a monovalent (one bond) organic group having an aliphatic hydrocarbon group in its molecular structure.
• the "aliphatic hydrocarbon group” is a linear, branched, or cyclic saturated or unsaturated aliphatic hydrocarbon group having 5 or more carbon atoms, and has solvent solubility, crystallization, and yield.
• an aliphatic hydrocarbon group having 5 to 60 carbon atoms is preferable, an aliphatic hydrocarbon group having 5 to 30 carbon atoms is more preferable, and an aliphatic hydrocarbon group having 10 to 30 carbon atoms is particularly preferable.
• the "aliphatic hydrocarbon group” preferably has 12 or more carbon atoms, more preferably 14 or more carbon atoms, and more preferably 14 or more carbon atoms, from the viewpoint of solvent solubility, crystallization, and yield. It is more preferably 16 or more, and particularly preferably 18 or more carbon atoms.
• 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 another site (for example, divalent). Group).
• Examples of the "aliphatic hydrocarbon group” include an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group and the like. Specific examples thereof include a pentyl group, a hexyl group, an octyl group, a decyl group, a hexadecyl group and an octadecyl group.
• a monovalent group such as an icosyl group, a docosyl 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 (hydrogen from the above monovalent group).
• alkyl group is preferably, for example, an alkyl group having 5 to 30 carbon atoms, and for example, a pentyl group, a hexyl group, an octyl group, a 2-ethylhexyl group, a decyl group, a hexadecyl group, an octadecyl group, and an icosyl group.
• 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 pentenyl group, a hexenyl group, an oleyl 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, a group having a cholesterol structure, a group having an estradiol structure, or the like is preferable.
• the organic group may be further substituted with a silyl group, a hydrocarbon group having a silyloxy structure, or an organic group having a perfluoroalkyl structure.
• silyl group a trialkylsilyl group is preferable, and a silyl group having three alkyl groups having 1 to 3 carbon atoms is more preferable.
• the silyloxy structure of the hydrocarbon group having a silyloxy structure is preferably a trialkylsilyloxy structure, and more preferably a silyloxy structure having three alkyl groups having 1 to 3 carbon atoms.
• the hydrocarbon group having a silyloxy structure preferably has 1 to 3 silyloxy structures.
• the number of carbon atoms of the hydrocarbon group having a silyloxy structure is preferably 10 or more, more preferably 10 to 100, and particularly preferably 16 to 50.
• hydrocarbon group having the silyloxy structure a group represented by the following formula (Si) is preferably mentioned.
• R si1 is a single bond, or represents an alkylene group having 1 to 3 carbon atoms
• R si2 represents an alkylene group having 1 to 3 carbon atoms
• R si3 and R si4 are each independently , Hydrogen atom, alkyl group having 1 to 6 carbon atoms, or -OSiR si5 R si6 R si7
• R si5 to R si7 independently represent an alkyl group having 1 to 6 carbon atoms or an aryl group. ..
• Each of R si5 to R si7 in the formula (Si) is preferably an alkyl group having 1 to 6 carbon atoms or a phenyl group independently, and more preferably an alkyl group having 1 to 6 carbon atoms. It is particularly preferably 1 to 4 linear or branched alkyl groups.
• the perfluoroalkyl structure in the organic group having a perfluoroalkyl structure is preferably a perfluoroalkyl structure having 1 to 20 carbon atoms, more preferably a perfluoroalkyl structure having 5 to 20 carbon atoms, and carbon. It is particularly preferable that the perfluoroalkyl structure has a number of 7 to 16. Further, the perfluoroalkyl structure may be linear, may have a branch, or may have a ring structure.
• the organic group having a perfluoroalkyl structure is preferably a perfluoroalkyl group, an alkyl group having a perfluoroalkyl structure, or an alkyl group having a perfluoroalkyl structure and an amide bond in the alkyl chain.
• the number of carbon atoms of the organic group having a perfluoroalkyl structure is preferably 5 or more, more preferably 10 or more, further preferably 10 to 100, and particularly preferably 16 to 50. ..
• the organic group having the perfluoroalkyl structure for example, the groups shown below are preferably mentioned.
• 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.
• the hydrocarbon group other than the aliphatic hydrocarbon group include an aliphatic hydrocarbon group having 1 to 4 carbon atoms, an aromatic hydrocarbon group and the like, and specifically, for example, having 1 to 4 carbon atoms.
• a monovalent group such as an alkyl group and an aryl group, and a divalent group derived from them are used.
• the "aryl group” is preferably, for example, 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, a 2-anthryl group and the like. Of these, an aryl group having 6 to 10 carbon atoms is more preferable, and a phenyl group is particularly preferable. Further, the 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.
• binding to the ring A of the organic group having an aliphatic hydrocarbon group (substituted) may be via an aliphatic hydrocarbon group or the hydrocarbon group present in the R A, i.e., direct carbon - even those that are bound by a carbon bond, -O present in the R a -, - S -, - COO -, - OCONH -, - CONH- , etc. be via a site Good. From the viewpoint of ease of synthesizing the compound, it is preferably mediated by -O-, -S-, -COO- or -CONH-, and particularly preferably mediated by -O-. ..
• all of R A, the total number of carbon atoms in all the aliphatic hydrocarbon groups of the R B and R C is, solvent solubility, crystal segregation and, From the viewpoint of yield, it is preferably 24 or more, more preferably 24 to 200, further preferably 32 to 100, particularly preferably 34 to 80, and 36 to 80. Is the most preferable.
• the total number of carbon atoms in all the aliphatic hydrocarbon group having all of R A, solvent solubility, crystal segregation, and the yield viewpoint is preferably 24 or more, more preferably 24 to 200, further 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 R A, compound the carbon number of at least one aliphatic hydrocarbon group having R B and R C is 12 or more carbon atoms, solubility in solvents From the viewpoint of sex, crystallization, and yield, the compound preferably has at least one aliphatic hydrocarbon group having 12 or more carbon atoms in at least one RA or RC , and at least one RA.
• the compound having at least one aliphatic hydrocarbon group having 12 to 100 carbon atoms is more preferable, and the compound having at least one aliphatic hydrocarbon group having 18 to 40 carbon atoms is more preferable. It is particularly preferable that the compound has at least one aliphatic hydrocarbon group having 20 to 36 carbon atoms.
• R A the number of carbon atoms of at least one aliphatic hydrocarbon group having R B and R C is preferably 14 or more, more preferably 16 or more, more preferably Is 18 or more, particularly preferably 20 or more, and a more excellent effect is exhibited.
• the reason is that as the number of carbon atoms increases, the contribution of hydrophobicity to the entire molecule increases, making it easier to dissolve in hydrophobic solvents, and for hydrophilic solvents, the increase in carbon number causes cohesion. This is thought to be because the force increases and crystallization becomes easier.
• the aliphatic hydrocarbon group is preferably an alkyl group, more preferably a straight chain alkyl group, from the viewpoint of crystallization and yield.
• one of R A, R B, or the carbon number of R C is independently solvent solubility, crystal segregation, and, in terms of yield, it is preferably 12 to 200, with 18 to 150 It is more preferably 18 to 100, and particularly preferably 20 to 80.
• aliphatic hydrocarbon group having 12 or more carbon atoms the compounds have the formula (1) according to the present disclosure, R A, is included in at least one of R B and R C, solvent solubility sex, crystallization segregation, and, in terms of yield, it is preferable to contain at least one R a and R C, and more preferably contained in at least one of R a.
• m in the formula (1) is preferably 1. Further, m in the formula (1) is preferably 2 from the viewpoint of detachability.
• a (1 + c) -valent aromatic group having 6 to 20 carbon atoms it is more preferably a (1 + c) -valent aromatic group having 6 to 20 carbon atoms, a monovalent alkyl group having 1 to 22 carbon atoms, or a (1 + c) -valent aromatic group having 6 to 10 carbon atoms. It is particularly preferable that it is a group.
• Monovalent alkyl groups in R B, (1 + c) valent aromatic group and (1 + c) -valent heterocyclic aromatic group may have a substituent.
• the substituent is not particularly limited, but is an alkoxy group, an aryloxy group, a halogen atom, an alkyl group, an aryl group, an acyl group, an acyloxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, an alkylthio group, an arylthio group, and R.
• Examples thereof include st- CO-NR st- , -CON (R st ) 2 , a dialkylamino group, an alkylarylamino group, a diarylamino group, and a group in which two or more of these are combined.
• R st represents a hydrogen atom, an alkyl group or an aryl group.
• the (1 + c) valent aromatic group in R B for example, a phenyl group, fluorophenyl group, difluorophenyl group, chlorophenyl group, dichlorophenyl group, trichlorophenyl group, methylphenyl group (tolyl group), a dimethylphenyl group (xylyl Group), methoxyphenyl group, dimethoxyphenyl group, trimethoxyphenyl group, phenylene group, benzenetriyl group, 1-naphthyl group, 2-naphthyl group, naphthylene group, naphthalenetriyl group and the like.
• phenyl group, methylphenyl group, dimethylphenyl group, methoxyphenyl group, dimethoxyphenyl group, or a tri-methoxyphenyl group are preferred, phenyl A group, a methylphenyl group or a methoxyphenyl group is more preferable.
• a phenyl group, methylphenyl group, dimethylphenyl group, methoxyphenyl group, dimethoxyphenyl group, or a tri-methoxyphenyl group are preferred, methylphenyl A group, a dimethylphenyl group, a methoxyphenyl group, a dimethoxyphenyl group, or a trimethoxyphenyl group is more preferable.
• a phenyl group, fluorophenyl group, difluorophenyl group, chlorophenyl group, dichlorophenyl group, or a tri-chlorophenyl group preferably fluoro A phenyl group, a difluorophenyl group, a chlorophenyl group, a dichlorophenyl group, or a trichlorophenyl group is more preferable.
• the (1 + c) valent heteroaromatic group in R B (1 + c) -valent, nitrogen-containing heterocyclic aromatic group mono-, oxygen-containing heteroaromatic group of a single ring, monocyclic sulfur heteroaromatic group , Monocyclic nitrogen-containing oxygen-containing heteroaromatic group, monocyclic nitrogen-containing sulfur-containing heteroaromatic group, bicyclic nitrogen-containing heteroaromatic group, bicyclic oxygen-containing heteroaromatic group, bicyclic Examples thereof include sulfur-containing heteroaromatic groups, bicyclic nitrogen-containing oxygen-containing heteroaromatic groups, and bicyclic nitrogen-containing heteroaromatic groups.
• pyridyl group furanyl group, thienyl group, pyrrolyl group, oxazolyl group, imidazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, pyridinediyl group, pyridinetriyl group, frangyl group, thiophendiyl group.
• Pyrroldiyl group benzofurandiyl group, benzothiopheneyl group, indoldiyl group and the like.
• At least one RA or RC is the following formula (f1), formula (a1), formula (b1) or formula (b1) from the viewpoint of solvent solubility, crystallization and yield. It is preferably a group represented by any one of e1), more preferably a group represented by the following formula (f1) or formula (a1), and a group represented by the following formula (f1). Is particularly preferred.
• the wavy line portion represents the coupling position with other structures
• 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 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 bonding position with other structures
• m20 represents an integer of 1 to 10
• X 20 is independently single-bonded, -O-, -S-, and -COO.
• R 20 each independently represents a divalent aliphatic hydrocarbon group, at least one of R 20 Is a divalent aliphatic hydrocarbon group having 5 or more carbon atoms.
• the wavy line portion represents the bonding position with another structure
• 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 structure
• 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 solvent solubility, crystallization and yield.
• the wavy line portion represents the connection position with other structures
• 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.
• 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 formula (1) according to the present disclosure preferably includes a branched aliphatic hydrocarbon group as the above-mentioned aliphatic hydrocarbon group, and the groups shown below are preferable. Is more preferably mentioned.
• the wavy line portion represents a bonding position with another structure, nt2 represents an integer of 3 or more, and nt3 represents an integer set so that the total carbon number of the following groups is 14 to 300.
• the compound substituent which may have on the ring A and R B of the formula (1) is not particularly limited, an alkyl group having 1 to 4 carbon atoms, an alkoxy group, an aryloxy group, Halogen atom, alkyl group, alkyl halide group, aryl group, acyl group, acyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, alkylthio group, arylthio group, R st- CO-NR st- , -CON (R st ) 2. Examples thereof include a dialkylamino group, an alkylarylamino group, a diarylamino group, and a group in which two or more of these are combined.
• R st represents a hydrogen atom, an alkyl group or an aryl group.
• the condensed polycyclic aromatic hydrocarbon compound represented by the above formula (1) is represented by the following formula (10) or formula (20) from the viewpoints of deprotection rate, crystallization property, solvent solubility, and yield. It is preferably a compound represented by the following formula, and more preferably a compound represented by the following formula (10).
• Y B represents -OH, -NHR, -SH, or -X 0
• R represents a hydrogen atom, an alkyl group, an aromatic group-substituted alkyl group, a heteroaromatic group-substituted alkyl group or an Fmoc group.
• X 0 represents Cl, Br or I
• R r100 represents a hydrogen atom, an aryl group or a heteroaryl group.
• R s represents a substituent or R A
• n10 represents an integer of 0 to 5, and adjacent R s may be linked to each other via a substituent to form a ring.
• R r10 and R r11 independently represent a hydrogen atom, a substituent, a group represented by the above formula (10-A), or RA .
• Either R r10 or R r11 is a group represented by the above formula (10-A), and * represents a connection position with R r10 or R r11 .
• R r12 to R r17 independently represent a hydrogen atom, a substituent, or RA , respectively.
• At least one of R s and R r10 to R r17 is RA .
• R A is independently an aliphatic hydrocarbon group, or represents an organic group having an aliphatic hydrocarbon group, and at least one of said aliphatic hydrocarbon group having at least one R A is the number of carbon atoms, 12 That is all.
• Y B represents -OH, -NHR, -SH, or -X 0
• R represents a hydrogen atom, an alkyl group, an aromatic group substituted alkyl group, a heteroaromatic group substituted alkyl group or a 9-fluorenylmethoxycarbonyl group (Fmoc group).
• X 0 represents Cl, Br or I
• R r200 represents a hydrogen atom, an alkyl group, an aryl group or a heteroaryl group.
• R r201 represents an alkyl group R r20 and R r21 independently represent a hydrogen atom, a substituent, a group represented by the above formula (20-A), or RA .
• R r20 or R r21 is a group represented by the above formula (20-A). * Represents the connection position with R r20 or R r21 .
• R r22 ⁇ R r27 are each independently a hydrogen atom, a substituent or represents R A, R r201 has 12 or more carbon atoms, or at least one of R r20 to R r27 is RA .
• Each RA independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and at least one RA has at least one aliphatic hydrocarbon group having 12 or more carbon atoms. Is.
• R A, R and X 0 has the same meaning as Y A, R A, R and X 0 in formula (1), a preferable embodiment thereof is also the same.
• R r100 in the formula (10) is preferably a hydrogen atom or an aryl group, and further, compound stability of the peptide condensate. From the viewpoint of the above, a hydrogen atom is particularly preferable.
• the substituent in R s of the formula (10) is not particularly limited, but an alkoxy group, an aryloxy group, a halogen atom, an alkyl group, an alkyl halide group, an aryl group, an acyl group, an acyloxy group, an alkoxycarbonyl group, Aryloxycarbonyl group, alkylthio group, arylthio group, R st- CO-NR st- , -CON (R st ) 2 , dialkylamino group, alkylarylamino group, diarylamino group, cyano group, and 2 or more of these. Examples include combined groups.
• R st represents a hydrogen atom, an alkyl group or an aryl group.
• the substituent in R s is preferably a group having 0 to 4 carbon atoms. Among them, examples of the substituent in R s, alkoxy group, aryloxy group, a halogen atom, an alkyl group, a halogenated alkyl group, or, more preferably an aryl group, an alkoxy group, or an alkyl group Is more preferable, and an alkoxy group is particularly preferable.
• R s in the formula (10) is preferably a substituent, preferably an alkyl group, an alkoxy group, an aryloxy group, a halogen atom, an alkyl halide group, or a cyano group. More preferred.
• R r100 is a hydrogen atom, it is more preferably an alkyl group or an alkoxy group from the viewpoint of desorption rate, and particularly preferably a methoxy group.
• R s is preferably a halogen atom, more preferably a fluorine atom or a chlorine atom from the viewpoint of compound stability of the peptide condensate.
• N10 in the formula (10) is preferably an integer of 0 to 3, and more preferably an integer of 0 to 2.
• R r10 and R r11 in the formula (10) are each independently preferably a hydrogen atom, a group represented by the above formula (10-A), or RA , and are a hydrogen atom or the above formula (10). It is more preferable that the group is represented by —A). Further, it is preferable that R r11 in the formula (10) is at least a group represented by the above formula (10-A), R r10 is a hydrogen atom, and R r11 is represented by the above formula (10-A). It is more preferable that it is a hydrogen atom.
• the substituents in R r10 to R r17 of the formula (10) are synonymous with the substituents in R s , and the preferred embodiment is also the same.
• R r12 to R r17 in the formula (10) are preferably a hydrogen atom, an alkoxy group, an aryloxy group, a halogen atom, an alkyl group, an alkyl halide group, a cyano group, or RA , preferably a hydrogen atom or an alkoxy. It is more preferably a group, a halogen atom, an alkyl group, or RA , and particularly preferably a hydrogen atom or RA .
• the carbon number of at least one aliphatic hydrocarbon group possessed by at least one RA is 12 or more, preferably 14 or more, and more preferably 16 or more. , 18 or more, and particularly preferably 20 or more and 40 or less.
• At least one of R r14 ⁇ R r17 is preferably R A, and more preferably R r15 is R A.
• the number of R A in the R r10 ⁇ R r17 is preferably 1 or 2, and more preferably 1.
• R r200 in the formula (20) is preferably a hydrogen atom or an alkyl group, and more preferably a hydrogen atom. ..
• R r201 in the formula (20) is preferably an alkyl group having 1 to 30 carbon atoms, and an alkyl having 8 to 30 carbon atoms. It is more preferably a group, and particularly preferably an alkyl group having 12 to 24 carbon atoms.
• R r20 and R r21 in the formula (20) are each independently preferably a hydrogen atom, a group represented by the above formula (20-A), or RA , and are a hydrogen atom or the above formula (20). It is more preferable that the group is represented by —A). Further, it is preferably a group R r21 in the formula (20) is represented by at least the formula (20-A), R r20 is a hydrogen atom, and is represented by R r21 the formula (20-A) It is more preferable that it is a hydrogen atom.
• the substituents in R r20 to R r27 of the formula (20) are synonymous with the substituents in R s , and the preferred embodiment is also the same.
• R r22 to R r27 in the formula (20) are preferably a hydrogen atom, an alkoxy group, an aryloxy group, a halogen atom, an alkyl group, an alkyl halide group, a cyano group, or RA , preferably a hydrogen atom and an alkoxy. It is more preferably a group, a halogen atom, an alkyl group, or RA , and particularly preferably a hydrogen atom or RA . Further, in the formula (20), if R r201 has 12 or more carbon atoms, or at least one of R r20 to R r27 is RA , and if it has RA , at least one RA has it.
• the carbon number of at least one aliphatic hydrocarbon group is 12 or more, at least one of R r20 to R r27 is RA , and the carbon of at least one aliphatic hydrocarbon group possessed by at least one RA.
• the number is preferably 12 or more.
• the number of carbon atoms of the aliphatic hydrocarbon group is preferably 14 or more, more preferably 16 or more, further preferably 18 or more, and particularly preferably 20 or more and 40 or less.
• at least one of R r24 ⁇ R r27 is preferably R A, and more preferably R r25 is R A.
• the number of R A in the R r20 ⁇ R r27 is preferably 1 or 2, and more preferably 1.
• the RA in the formula (10) or the formula (20) is the above formula (f1), the formula (a1), the formula (b1) or the formula (e1) from the viewpoint of solvent solubility, crystallization and yield. 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).
• the condensed polycyclic aromatic hydrocarbon compound represented by the above formula (1) has the following formula (30) or formula (40) from the viewpoints of deprotection rate, crystallization property, solvent solubility, and yield. ) Is more preferable, and the compound represented by the following formula (40) is particularly preferable.
• Y B represents -OH, -NHR, -SH, or -X 0
• R represents a hydrogen atom, an alkyl group, an aromatic group-substituted alkyl group, a heteroaromatic group-substituted alkyl group or an Fmoc group.
• X 0 represents Cl, Br or I
• RD represents an alkyl group, an aryl group or a heteroaryl group.
• RE represents a hydrogen atom, an alkyl group, an aryl group or a heteroaryl group.
• RA represents an aliphatic hydrocarbon group having 12 or more carbon atoms or an organic group having an aliphatic hydrocarbon group having 12 or more carbon atoms.
• RA40 independently represent an alkyl group having 12 or more carbon atoms or an alkoxy group having 12 or more carbon atoms.
• m40 represents an integer of 1 to 3.
• R A, R and X 0 has the same meaning as Y A, R A, R and X 0 in formula (1), a preferable embodiment thereof is also the same.
• the RD in the formula (30) or the formula (40) is preferably an alkyl group or an aryl group from the viewpoint of deprotection rate, crystallization property, solvent solubility, and yield, and is preferably an aryl group. More preferably.
• R E is a hydrogen atom and Y B of -OH, phenyl group, alkylphenyl group, or, if preferred alkoxyphenyl group, R E is a hydrogen atom and Y B of -NHR, alkylphenyl group, alkoxyphenyl A group, a dialkylphenyl group, or a dialkoxyphenyl group is preferable, and a dialkylphenyl group or a dialkoxyphenyl group is more preferable.
• the carbon number of RD is preferably 1 to 30, more preferably 5 to 30, and particularly preferably 6 to 24.
• each of the RA40s in the formula (40) is an alkoxy group having 12 or more carbon atoms independently.
• the carbon number of RA40 is preferably 14 or more, more preferably 16 or more, further preferably 18 or more, and particularly preferably 20 or more and 40 or less.
• substitution position of RA40 on the benzene ring is not particularly limited, but is preferably any of the 3rd to 5th positions when the bonding position of the two OCH groups on the benzene ring is the 1st position.
• the m40 in the formula (40) is preferably 1 or 2, and more preferably 2.
• 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 condensed polycyclic aromatic hydrocarbon compound represented by the formula (1) is not particularly limited, but it can be produced by referring to a known method. Unless otherwise specified, as the raw material compound used for producing the condensed polycyclic aromatic hydrocarbon compound represented by the formula (1), a commercially available compound may be used, or a method known per se, or these. It can also be manufactured according to a similar method. Further, if necessary, the produced condensed polycyclic aromatic hydrocarbon compound represented by the formula (1) may be purified by a known purification method.
• 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 condensed polycyclic aromatic hydrocarbon compound represented by the formula (1) is not particularly limited, but for example, it can be synthesized according to the following scheme. In addition, it is also possible to synthesize by referring to the synthesis method described in International Publication No. 2010/1133939.
• R al represents an alkyl group
• R X represents an alkyl group, an aryl group or a heteroaryl group
• R 100 represents a hydrogen atom or OR 101
• R 101 represents an alkyl group
• X 100 is Cl, Br or I
• R 102 represents a hydrogen atom, an alkyl group or an Fmoc group.
• the step of using the condensed polycyclic condensed aromatic hydrocarbon compound represented by the above formula (1) is the condensed polycyclic aromatic hydrocarbon represented by the above formula (1). It is preferably a C-terminal protection step in which the carboxy group or amide group of the amino acid compound or peptide compound is protected by the hydrogen compound.
• the method for producing a peptide compound according to the present disclosure is an amino acid compound or peptide using a condensed polycyclic aromatic hydrocarbon compound represented by the above formula (1) from the viewpoint of ease of synthesis of the peptide compound and yield.
• the N-terminal of the N-terminal protected C-terminal protected amino acid compound or N-terminal protected C-terminal protected peptide compound obtained in the above C-terminal protection step is deprotected.
• the N-terminal protected amino acid compound or N-terminal protected peptide compound is condensed with the N-terminal of the C-terminal protected amino acid compound or C-terminal protected peptide compound obtained in the N-terminal deprotection step and the N-terminal deprotection step.
• a peptide chain extension step further preferably to further include a precipitation step of precipitating the N-terminal protected C-terminal protected peptide compound obtained in the peptide chain extension step, which is obtained after the precipitation step.
• a step of deprotecting the N-terminal of the N-terminal protected C-terminal protected peptide compound, a step of condensing the N-terminal protected amino acid compound or the N-terminal protected peptide compound with the N-terminal of the obtained C-terminal protected peptide compound and It is particularly preferable to further include the step of precipitating the obtained N-terminal protected C-terminal protected peptide compound at least once in this order.
• 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 further includes a dissolution step of dissolving a condensed polycyclic aromatic hydrocarbon compound represented by the above formula (1) in a solvent before the C-terminal protection step. Is preferable.
• a dissolution step of dissolving a condensed polycyclic aromatic hydrocarbon 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 a condensed polycyclic aromatic hydrocarbon 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.
• aromatic hydrocarbons such as benzene, toluene and xylene are added to the above carbon halides and non-polar organic solvents; nitriles such as acetonitrile and propionitrile; ketones such as acetone and 2-butanone; N, N.
• sulfoxides such as dimethyl sulfoxide are mixed at an appropriate ratio as long as the condensed polycyclic aromatic hydrocarbon compound represented by the formula (1) can be dissolved. You may use it.
• 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 includes a C-terminal protection step of protecting the carboxy group or amide group of the amino acid compound or peptide compound with the condensed polycyclic aromatic hydrocarbon 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 with respect to 1 molar equivalent of the condensed polycyclic aromatic hydrocarbon compound represented by the above formula (1). It is more preferably 1 molar equivalent to 5 molar equivalents, even more preferably 1 molar equivalent to 2 molar equivalents, and particularly preferably 1 to 1.5 molar equivalents.
• a condensation additive In the presence of the condensation activator, it is preferable to add a condensing agent or react in an acid catalyst.
• a condensation additive condensation activator
• 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, preferably 1 molar equivalent to 5 molar equivalents, relative to 1 molar equivalent of the condensed polycyclic aromatic hydrocarbon compound represented by the above formula (1). More preferably, it is equivalent.
• 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 more than 0 molar equivalents and 4.0 molar equivalents with respect to 1 molar equivalent of the condensed polycyclic aromatic hydrocarbon compound represented by the above formula (1), preferably 0.05. It is more preferably molar equivalent to 1.5 molar equivalent, and even more preferably 0.1 molar equivalent to 0.3 molar equivalent.
• condensation 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).
• a condensation activator generally used in peptide synthesis can be used without limitation, and for example, 4-dimethylaminopyridine, N-methylimidazole, boronic acid derivative, 1-hydroxybenzotriazole (1-hydroxybenzotriazole).
• HOBt ethyl 1-hydroxytriazole-4-carboxylate
• HACt 1-hydroxy-7-azabenzotriazole
• HONb 3-hydroxy-1,2,3-benzotriazodin-4 (3H)- On
• HOOBt N-Hydroxysuccinimide
• HPht N-Hydroxyphthalimide
• HONb N-Hydroxy-5-norbornene-2,3-dicarboxyimide
• pentafluorophenol ethyl (hydroxyimino) cyanoacetate (Oxyma) and the like can be mentioned.
• 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 N-terminal is used in order to isolate the product obtained after dissolving the obtained N-terminal protected C-terminal protected amino acid compound or N-terminal protected C-terminal protected peptide compound in a solvent and carrying out the desired organic synthesis reaction.
• a method of changing the solvent in which the 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 preferably mentioned.
• 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 is distilled off and then the solvent is replaced. After the reaction, the agglomerates are precipitated and impurities are eliminated by adding a polar solvent to the reaction system without distilling off the solvent.
• 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, also referred to as a Z group) or an Fmoc group is preferably used.
• the deprotection condition is appropriately selected depending on the type of the temporary protecting group, but is a group that can be deprotected under conditions different from the removal of the protecting group derived from the condensed polycyclic aromatic hydrocarbon compound represented by the above formula (1). Is preferable. For example, in the case of an Fmoc group, it is carried out by treating with a base, and in the case of 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 precipitation method in purification which may be carried out after the C-terminal protection step described above.
• 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 C-terminal protective group formed by the condensed polycyclic aromatic hydrocarbon compound represented by the above formula (1) in the C-terminal protected peptide compound having a desired number of amino acid residues is removed.
• the peptide compound which is the final target can be obtained.
• a method for removing the C-terminal protecting group a deprotection method using an acidic compound is preferably mentioned.
• a method of adding an acid catalyst and a method of hydrogenating using a metal catalyst can be mentioned.
• the acid catalyst include trifluoroacetic acid (TFA), hydrochloric acid, trifluoroethanol (TFE), hexafluoroisopropanol (HFIP), acetic acid, etc.
• TFA trifluoroacetic acid
• TFE trifluoroethanol
• HFIP hexafluoroisopropanol
• acetic acid etc.
• TFA trifluoroethanol
• HFIP hexafluoroisopropanol
• the 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 examples thereof include 1% 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. In the present disclosure, it is possible to deprotect the C-terminal protecting group even under weak acid conditions, and it is possible to suppress the side reaction of the obtained peptide.
• 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.
• 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, trityl group, and the like.
• 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 condensed polycyclic aromatic hydrocarbon compound represented by the following formula (1).
• Ring A represents a condensed polycyclic aromatic hydrocarbon ring.
• Y A represents -OH, -NHR, SH, or an -X 0,
• R represents a hydrogen atom, an alkyl group, an aromatic group substituted alkyl group or a heteroaromatic group substituted alkyl group or a 9-fluorenylmethoxycarbonyl group (Fmoc group).
• X 0 represents Cl, Br or I
• R A is independently an aliphatic hydrocarbon group, or represents an organic group having an aliphatic hydrocarbon group
• R B independently, a monovalent aliphatic hydrocarbon group
• RC independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group.
• n 1 or 2
• a represents an integer of 0 to 5
• c represents an integer of 0 to 5
• the R B be a monovalent aliphatic hydrocarbon group
• R a the number of carbon atoms of at least one of said aliphatic hydrocarbon group R B and R C is 12 or more.
• 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.
• a preferred embodiment of the condensed polycyclic aromatic hydrocarbon compound represented by the formula (1) in the reagent for forming a protecting group according to the present disclosure is the condensed polycyclic aromatic represented by the formula (1) according to the present disclosure described above. This is similar to the preferred embodiment of the hydrocarbon compound.
• the reagent for forming a protecting group according to the present disclosure may be a solid reagent or a liquid reagent.
• 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 condensed polycyclic aromatic hydrocarbon compound represented by the formula (1).
• Other components may include known components. For example, water, an organic solvent, an antioxidant, a pH adjuster and the like can be mentioned.
• the compound according to the present disclosure is a condensed polycyclic aromatic hydrocarbon compound represented by the following formula (1a).
• Ring A represents a condensed polycyclic aromatic hydrocarbon ring.
• Y A represents -OH, -NHR, -SH, or, the -X 0, R represents a hydrogen atom, an alkyl group having 10 or less carbon atoms, an aromatic group-substituted alkyl group or a hetero-aromatic group-substituted alkyl group or a 9-fluorenylmethoxycarbonyl group (Fmoc group).
• X 0 represents Cl, Br or I
• RA independently represent an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group.
• R B each independently represent a monovalent aliphatic hydrocarbon group, a (1 + c) valent aromatic group, or (1 + c) valent heteroaromatic group,
• Each RC independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group.
• m represents 1 or 2
• a represents an integer from 0 to 5 and represents c represents an integer from 0 to 5 and represents If a and c are both a 0,
• R B is a monovalent aliphatic hydrocarbon group
• R A the number of carbon atoms of at least one of said aliphatic hydrocarbon group R B and R C is, is at least 18, If R B is a monovalent aliphatic hydrocarbon group, including saturated aliphatic hydrocarbon group of linear with the number 18 or more carbon atoms.
• the condensed polycyclic aromatic hydrocarbon 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 producing 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.
• Condensed polycyclic aromatic hydrocarbon compound represented by formula (1a) in the compounds of the present disclosure at least one of R A, when R C, or R B is an alkyl group, at least one having at least one R A It is the same as the condensed polycyclic aromatic hydrocarbon compound represented by the above formula (1) in the method for producing a peptide compound according to the present disclosure, except that one aliphatic hydrocarbon group has 18 or more carbon atoms. The same applies to preferred embodiments other than the preferred embodiments described later.
• the condensed polycyclic aromatic hydrocarbon compound represented by the above formula (1a) is represented by the following formula (10a) or formula (20a) from the viewpoints of deprotection rate, crystallization property, solvent solubility, and yield. It is preferably a compound represented by the following formula, and more preferably a compound represented by the following formula (10a).
• Y B represents -OH, -NHR, -SH, or -X 0
• R represents a hydrogen atom, an alkyl group having 10 or less carbon atoms, an aromatic group-substituted alkyl group or a hetero-aromatic group-substituted alkyl group or a 9-fluorenylmethoxycarbonyl group (Fmoc group).
• X 0 represents Cl, Br or I
• R r100 represents a hydrogen atom, an aryl group or a heteroaryl group.
• R s may independently represent a substituent or RA
• n10 may represent an integer of 0 to 5
• adjacent R s may be linked to each other via a substituent to form a ring.
• R r10 and R r11 independently represent a hydrogen atom, a substituent, a group represented by the above formula (10a-A), or RA .
• Either R r10 or R r11 is a group represented by the above formula (10a-A).
• * represents the connection position with R r10 or R r11 .
• R r12 to R r17 independently represent a hydrogen atom, a substituent, or RA , respectively.
• At least one of R s and R r10 to R r17 is RA .
• R A is independently an aliphatic hydrocarbon group, or has an aliphatic hydrocarbon group, and the number of carbon atoms of at least one of the aliphatic hydrocarbon group having at least one R A is, is 18 or more
• Y B represents -OH, -NHR, -SH, or -X 0
• R represents a hydrogen atom, an alkyl group having 10 or less carbon atoms, an aromatic group-substituted alkyl group or a hetero-aromatic group-substituted alkyl group or a 9-fluorenylmethoxycarbonyl group (Fmoc group).
• X 0 represents Cl, Br or I
• R r200 represents a hydrogen atom, an alkyl group, an aryl group or a heteroaryl group.
• R r201 represents an aliphatic hydrocarbon group and represents R r20 and R r21 independently represent a hydrogen atom, a substituent, a group represented by the above formula (20a-A), or RA .
• Either R r20 or R r21 is a group represented by the above formula (20a-A). * Represents the connection position with R r20 or R r21 .
• R r22 ⁇ R r27 are each independently a hydrogen atom, a substituent or represents R A, If R B is an aliphatic hydrocarbon group, or contains a saturated aliphatic hydrocarbon group having a straight chain having 18 or more carbon atoms, or at least one of R r20 ⁇ R r27 is R A, R A are each Independently, the aliphatic hydrocarbon group or the at least one said aliphatic hydrocarbon group having an aliphatic hydrocarbon group and having at least one RA has 18 or more carbon atoms.
• the compound represented by the above formula (10a) is the above-mentioned method for producing a peptide compound according to the present disclosure, except that at least one RA has at least one aliphatic hydrocarbon group having 18 or more carbon atoms.
• the compound represented by the above formula (20a) is the above-described method for producing a peptide compound according to the present disclosure, except that at least one RA has at least one aliphatic hydrocarbon group having 18 or more carbon atoms.
• the RA in the compound represented by either the above formula (10a) or the above formula (20a) is synonymous with the RA in the condensed polycyclic aromatic hydrocarbon compound represented by the above formula (1a), and is a preferred embodiment. Is the same. Further, the condensed polycyclic aromatic hydrocarbon compound represented by the above formula (1a) can be synthesized in the same manner as the condensed polycyclic aromatic hydrocarbon 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 (Waters, ionization method: ESI (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 shown in ppm.
• Intermediate (1-1) was synthesized by the method described in European Patent Application Publication No. 2518041.
• Intermediate (1-1) (3.00 g, 3.87 mmol), 6-hydroxy-2-naphthaldehyde (1.33 g, 7.72 mmol), potassium carbonate (2.14 g, 15.5 mmol), N-methyl Pyrrolidone (NMP, 40 mL) was mixed and stirred at 100 ° C. for 6 hours under a nitrogen atmosphere.
• the reaction solution was cooled to room temperature (25 ° C., the same applies hereinafter) and extracted with cyclopentyl methyl ether and water.
• the comparative compound (1-1) was synthesized by the method described in International Publication No. 2010/1133939.
• the comparative compound (1-N-1) was also synthesized by the method described in International Publication No. 2010/1133939.
• Comparative compound (2-1) was synthesized by the method described in International Publication No. 2010/104169.
• Example 2 and Comparative Example 1 Similar to the method for obtaining N-protected C-protected amino acid (1-1), compound (1-1) and comparative compound (1-1) are N-[(9H-fluorene-9-ylmethoxy) carbonyl] -L. The corresponding N-protected C-protected amino acids were synthesized by condensation with leucine.
• A The survival rate is 99% or more.
• B The survival rate is 97% or more and less than 99%.
• C The residual rate is 95% or more and less than 97%.
• D The survival rate is less than 95%.
• the condensed polycyclic aromatic hydrocarbon compound represented by the formula (1) used in Example 1 or Example 2 is superior in solution stability to the compound shown in Comparative Example 1, and thus is a peptide compound. Excellent yield.
• the condensed polycyclic aromatic hydrocarbon compound represented by the formula (1) used in Example 4 can load amino acids in a high yield, so that the yield of the peptide compound is excellent.
• N-methylmorpholine (2.05 molar equivalents) and methanesulfonic acid (2.0 molar equivalents) were added in that order, and then 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 sequence, 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.
• Example 8 Synthesis of Fmoc-MeNle-Arg (Pbf) -Cys (Trt) -Gly-NH-O-2NaphTAG (1)
• Fmoc-Arg (Pbf) -Cys (Trt) -Gly-O-2NaphTAG (1) (1.60 g, 0.78 mmol) was dissolved in tetrahydrofuran (3.9 mL) and diazabicycloundecene (DBU, 2). (0.0 molar equivalent) was added and stirred.
• DBU diazabicycloundecene
• N-methylmorpholine (2.05 molar equivalents) and methanesulfonic acid (2.0 molar equivalents) were added in sequence, 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.
• 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 condensed polycyclic aromatic hydrocarbon compound represented by the formula (1) has an excellent yield of the obtained peptide compound. Further, as shown in Examples 5 to 9, the condensed polycyclic aromatic hydrocarbon compound represented by the formula (1) has a high yield in any of the examples, and the total yield is also excellent. Understand. 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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