WO2019009317A1 - Composé benzyle - Google Patents

Composé benzyle Download PDF

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Publication number
WO2019009317A1
WO2019009317A1 PCT/JP2018/025303 JP2018025303W WO2019009317A1 WO 2019009317 A1 WO2019009317 A1 WO 2019009317A1 JP 2018025303 W JP2018025303 W JP 2018025303W WO 2019009317 A1 WO2019009317 A1 WO 2019009317A1
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Prior art keywords
group
peptide
amino acid
substituent
hydrocarbon group
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PCT/JP2018/025303
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English (en)
Japanese (ja)
Inventor
昭裕 長屋
まりこ 石田
直彦 安田
道玄 半田
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日産化学株式会社
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Priority to JP2019527739A priority Critical patent/JP7163916B2/ja
Publication of WO2019009317A1 publication Critical patent/WO2019009317A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/68—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07K1/13—Labelling of peptides
    • 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
    • C07K1/14—Extraction; Separation; Purification
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel benzyl compound and a method of synthesizing a peptide using the compound.
  • organic tag examples include 3,5-bis (docosyloxy) benzyl alcohol compound. Using this organic tag, isolation and purification of the peptide can be performed only by filtration and washing by changing the solvent composition after the reaction (Patent Document 2, Non-patent Document 1).
  • Non-patent Document 1 a protecting group which can be deprotected under acidic conditions such as Boc group as a temporary protecting group at the N-terminus. At that time, it is desirable that the organic tag have high acid stability, but the acid stability of the conventional organic tag was not sufficient.
  • the present invention includes providing the following.
  • [4] The compound according to [1] or [2], wherein the total number of carbon atoms in -NR a R b is 40 to 80.
  • [5] The compound according to any one of [1] to [4], wherein n is 1 or 2, and at least one —NR a R b is substituted at the meta position of —CH 2 Y on the benzene ring .
  • [6] The compound according to any one of [1] to [5], wherein n is 1.
  • [7] The compound according to any one of [1] to [6], wherein Y is a hydroxy group.
  • R a and R b are —C (O) R c (wherein R c is a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, a substituent) And N represents a substituted or unsubstituted aromatic hydrocarbon group or an optionally substituted aromatic heterocyclic group), and the total number of carbon atoms in -NR a R b is 22 to 80, 1]
  • R c is a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, a substituent
  • N represents a substituted or unsubstituted aromatic hydrocarbon group or an optionally substituted aromatic heterocyclic group
  • R a is an aliphatic hydrocarbon group which may have a substituent
  • R b is —C (O) R c (wherein R c has a hydrogen atom or a substituent) also represents an aliphatic hydrocarbon group, an aromatic optionally substituted hydrocarbon group or optionally substituted aromatic heterocyclic group.) represent, in -NR a R b
  • [15] The compound according to any one of [1], [13] and [14], wherein n is 1 and -NR a R b is substituted at the meta position of -CH 2 Y on a benzene ring.
  • [16] The compound according to any one of [1] and [13] to [15], wherein Y is a hydroxy group.
  • [17] The compound according to [16], which is N- (2 ′, 3′-dihydrophytyl) -N- (3-hydroxymethylphenyl) acetamide or N-triacontyl-N- (3-hydroxymethylphenyl) acetamide.
  • a reagent for protecting a carboxy group in an amino acid or peptide comprising the compound according to any one of [1] to [17].
  • a reagent for protecting a C-terminus in an amino acid or a peptide comprising the compound according to any one of [1] to [17].
  • a method for producing an organic tag protected amino acid or peptide comprising the following steps (1) and (2): (1) Formula (I): [In the formula, Y represents a hydroxy group or -NHR (wherein R represents a hydrogen atom or a C 1-6 alkyl group), R a and R b each independently represent an aliphatic hydrocarbon group which may have a substituent, —C (O) R c or —S (O) 2 R c wherein R c is And a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent And the total number of carbon atoms in -NR a R b is 22 or more, n represents an integer of 1 to 5; ] Bonding the compound represented by and an amino acid or a peptide.
  • a step of precipitating or separating the combined product of a compound and an amino acid or peptide obtained in step (1) comprising the following steps (1) to (4):
  • Y represents a hydroxy group or -NHR (wherein R represents a hydrogen atom or a C 1-6 alkyl group)
  • R a and R b each independently represent an aliphatic hydrocarbon group which may have a substituent, —C (O) R c or —S (O) 2 R c wherein R c is And a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent
  • the total number of carbon atoms in -NR a R b is 22 or more
  • n represents an integer of 1 to 5;
  • step (1) Removing the N-terminal protecting group of the amino acid or peptide obtained in step (1).
  • step (2) Removing the N-terminal protecting group of the amino acid or peptide obtained in step (1).
  • step (3) A step of condensing an N-protected amino acid or an N-protected peptide at the N-terminus of the amino acid or peptide obtained in step (2).
  • step (3) Step of precipitating or separating the peptide obtained in step (3).
  • step (3) A step of condensing an N-protected amino acid or an N-protected peptide at the N-terminus of the amino acid or peptide obtained in step (2).
  • the method according to [22] or [23] which comprises the step of removing the C-terminal protecting group of the C-protected peptide after step (4).
  • the method according to [22] or [23] comprising one or more repetitions of the following steps (5) to (7). (5) Removing the N-terminal protecting group of the peptide obtained in step (4).
  • R a and R b each independently represent an aliphatic hydrocarbon group which may have a substituent, —C (O) R c or —S (O) 2 R c wherein R c is And a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent And the total number of carbon atoms in -NR a R b is 22 or more, n represents an integer of 1 to 5; Z is -OX or -NR-X (wherein, X represents an amino acid or a peptide, and R represents a hydrogen atom or a C 1-6 alkyl group).
  • An organic tag protected amino acid or peptide represented by [28] The organic tag protected amino acid or peptide as described in [27] whose R a and R b are an aliphatic hydrocarbon group which may respectively independently have a substituent. [29] The organic tag protected amino acid or peptide as described in [27] or [28] which -O or -NR in Z couple
  • the present invention provides a compound which can be used as an organic tag having high stability under acidic conditions in peptide synthesis and the like.
  • the present invention also provides a highly efficient method for producing a peptide using the compound as an organic tag.
  • n- is normal, “i-” is iso, “s-” and “sec-” are secondary, “t-” and “tert-” are tertiary, and “Boc” is Tertiary butoxycarbonyl, “Cbz” means benzyloxycarbonyl, “Fmoc” means 9-fluorenylmethoxycarbonyl, “Me” means methyl, “Bu” means butyl.
  • halogen atom means, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples thereof include methyl group, ethyl group, n-propyl group, isopropyl And n-butyl group, isobutyl group, t-butyl group, n-pentyl group, n-hexyl group and the like.
  • the “C 1-6 alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, and specific examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, and an iso group. Examples thereof include propoxy group, n-butoxy group, isobutoxy group, t-butoxy group, n-pentyloxy group and n-hexyloxy group.
  • the “C 1-6 alkoxycarbonyl group” means a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms, and specific examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, n- Propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, t-butoxycarbonyl group, n-pentyloxycarbonyl group, n-hexyloxycarbonyl group and the like.
  • the "mono C 1-6 alkylamino group” means a group in which one of the “C 1-6 alkyl groups” is bonded to an amino group, and as a specific example, a monomethylamino group, a monoethylamino group, Mono-n-propylamino group, monoisopropylamino group, mono-n-butylamino group, monoisobutylamino group, mono-t-butylamino group, mono-n-pentylamino group, mono-n-hexylamino group, etc. Can be mentioned.
  • the “di C 1-6 alkylamino group” means a group in which the same or different two “C 1-6 alkyl groups” are bonded to an amino group, and as a specific example, a dimethylamino group, a diethylamino group , Di-n-propylamino group, diisopropylamino group, di-n-butylamino group, diisobutylamino group, di-t-butylamino group, di-n-pentylamino group, di-n-hexylamino group, N -Ethyl-N-methylamino group, N-methyl-Nn-propylamino group, N-isopropyl-N-methylamino group, Nn-butyl-N-methylamino group, N-isobutyl-N-methylamino group Amino group, N-tert-butyl-N-methylamino group, N-methyl-N-pentyl
  • the "mono C 1-6 alkylamino carbonyl group” means a group in which one of the “C 1-6 alkyl groups” is bonded to an amino carbonyl group, and as a specific example, a monomethyl amino carbonyl group, monoethyl group Aminocarbonyl group, mono-n-propylaminocarbonyl group, monoisopropylaminocarbonyl group, mono-n-butylaminocarbonyl group, monoisobutylaminocarbonyl group, mono-t-butylaminocarbonyl group, mono-n-pentylaminocarbonyl group And mono-n-hexylaminocarbonyl group.
  • the “C 1-6 alkylcarbonylamino group” means a group in which one of the “C 1-6 alkyl groups” is bonded to a carbonylamino group, and as a specific example, a methylcarbonylamino group, ethylcarbonylamino Group, n-propylcarbonylamino group, isopropylcarbonylamino group, n-butylcarbonylamino group, isobutylcarbonylamino group, t-butylcarbonylamino group, n-pentylcarbonylamino group, n-hexylcarbonylamino group and the like. .
  • C 3-6 cycloalkyl group means a cycloalkyl group having 3 to 6 carbon atoms, and specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like.
  • the " C3-6 cycloalkoxy group” means a cycloalkoxy group having 3 to 6 carbon atoms, and specific examples thereof include a cyclopropoxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group and the like. .
  • the “C 2-6 alkenyl group” means a linear or branched alkenyl group having 2 to 6 carbon atoms, and specific examples thereof include a vinyl group, 1-propenyl group, allyl group and iso.
  • the propenyl group, butenyl group, isobutenyl group and the like can be mentioned.
  • C 2-6 alkynyl group means a linear or branched alkynyl group having 2 to 6 carbon atoms, and specific examples include an ethynyl group, a 1-propynyl group and the like.
  • C 7-10 aralkyl group means an aralkyl group having 7 to 10 carbon atoms, and specific examples thereof include benzyl group, 1-phenylethyl group, 2-phenylethyl group, 1-phenylpropyl Groups, naphthylmethyl group, 1-naphthylethyl group, 1-naphthylpropyl group and the like.
  • the “C 6-14 aryl group” means an aromatic hydrocarbon group having 6 to 14 carbon atoms, and specific examples thereof include phenyl group, 1-naphthyl group, 2-naphthyl group, 1- Examples include anthracenyl group, 2-anthracenyl group, 9-anthracenyl group, biphenyl group and the like.
  • the “C 6-14 aryloxy group” means an aryloxy group having 6 to 14 carbon atoms, and specific examples thereof include phenoxy group, 1-naphthyloxy group, 2-naphthyloxy group, 1- Anthracenyloxy group, 2-anthracenyloxy group, 9-anthracenyloxy group, biphenyloxy group and the like can be mentioned.
  • tri C 1-6 alkylsilyloxy group means a group in which the same or different three “C 1-6 alkyl groups” are bonded to a silyloxy group, and as a specific example, a trimethylsilyloxy group, triethyl group A silyloxy group, triisopropylsilyloxy group, t-butyldimethylsilyloxy group, di-t-butylisobutylsilyloxy group and the like can be mentioned.
  • the "5- to 10-membered heterocyclic group” means that the number of atoms constituting the ring is 5 to 10, and among the atoms constituting the ring, it is independently selected from the group consisting of nitrogen atom, oxygen atom or sulfur atom Or a heterocyclic group of a single ring system or a fused ring system containing 1 to 4 hetero atoms selected differently.
  • the heterocyclic group may be saturated, partially unsaturated or unsaturated, and specific examples thereof include pyrrolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group, piperidyl group, tetrahydropyranyl group and tetrahydrothiopyranyl group.
  • the “aliphatic hydrocarbon group” is a linear, branched or cyclic, saturated or unsaturated aliphatic hydrocarbon group, and examples thereof include an alkyl group, a cycloalkyl group, an alkenyl group, and an alkynyl group.
  • aromatic hydrocarbon group is a hydrocarbon group composed of a single ring or a plurality of rings, and means a group in which at least one ring exhibits aromaticity, and specific examples thereof include a phenyl group and a naphthyl group. Groups, anthracenyl group, indenyl group, phenacenyl group, indanyl group and the like.
  • aromatic heterocyclic group means a heterocyclic group composed of a single ring or a plurality of rings exhibiting aromaticity, and specific examples thereof include a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group and a furanyl group.
  • the type of “arbitrary substituent” is not particularly limited as long as the substituent does not adversely affect the reaction targeted by the present invention.
  • the “substituent” in the “aliphatic hydrocarbon group which may have a substituent (s)” is, for example, a C 6-14 aryl group, a C 6-14 aryloxy group, a 5-10 member heterocyclic group, a hydroxy group, C 1-6 alkoxy, C 3-6 cycloalkoxy group, an acetoxy group, a benzoyloxy group, an amino group, a mono C 1-6 alkylamino group, N- acetylamino group, di C 1-6 alkylamino group , Halogen atom, C 1-6 alkoxycarbonyl group, phenoxycarbonyl group, N-methylcarbamoyl group, N-phenylcarbamoyl group, cyano group, nitro group, carboxy group, mono C 1-6 alkylamino carbonyl group, C 1- 6 alkylcarbonylamino group, tri C 1-6 alkylsilyloxy group, t-butyldipheny
  • C 6-14 aryl group a C 1-6 alkoxy group, a C 3-6 cycloalkoxy group or a diC 1-6 alkylamino group, and more preferably a C 1-6 alkoxy group.
  • Examples of the “substituent” in the “optionally substituted aromatic hydrocarbon group” and the “optionally substituted aromatic heterocyclic group” include a C 1-6 alkyl group, C 3-6 cycloalkyl group, C 6-14 aryl group, C 6-14 aryloxy group, 5-10 membered heterocyclic group, hydroxy group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group, acetoxy Group, benzoyloxy group, amino group, mono C 1-6 alkylamino group, N-acetylamino group, di C 1-6 alkylamino group, halogen atom, C 1-6 alkoxycarbonyl group, phenoxycarbonyl group, N- methylcarbamoyl group, N- phenylcarbamoyl group, a cyano group, a nitro group, a carboxyl group and the like, preferably, C 1-6 alkoxy group, or a di-C 1-6 alkylamine An amino
  • the present invention provides a compound having a specific structure containing a benzyl group (hereinafter also referred to as "the compound of the present invention").
  • the compound of the present invention is a compound represented by the following formula (I):
  • Formula (I): [In the formula, Y represents a hydroxy group or -NHR (wherein R represents a hydrogen atom or a C 1-6 alkyl group), R a and R b each independently represent an aliphatic hydrocarbon group which may have a substituent, —C (O) R c or —S (O) 2 R c wherein R c is And a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent And the total number of carbon atoms in -NR a R b is 22 or more, n represents an integer of 1 to 5; ]
  • R a and R b are the total number of carbon atoms each having at least one of R a and R b have the substituent In the case, the number of carbon atoms in the substituent is also included.
  • R a and R b are preferably each independently an aliphatic hydrocarbon group or —C (O) R c (wherein R c represents a hydrogen atom or an aliphatic hydrocarbon group).
  • R a and R b is —C (O) R c (wherein R c is a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, a substituent) (Wherein the total number of carbon atoms in -NR a R b is 22 or more), and preferred is an aromatic hydrocarbon group which may be substituted or an aromatic heterocyclic group which may be substituted. 22 to 200, more preferably 40 to 80.
  • N is an integer of 1 to 5, preferably 1 or 2, and more preferably 1.
  • the substitution position of -NR a R b is not limited, in terms of acid stability, it is preferable that at least one -NR a R b is bonded to the meta position on the benzene ring.
  • the meta position means the meta position relative to the —CH 2 Y group of the compound represented by the formula (I). Accordingly, since there are two meta positions to the —CH 2 Y group of the compound represented by the formula (I), for example, when n is 2, —NR a R b is one of the two meta positions It is preferred to bind to at least one or both or both, and when n is 1, it is preferred that -NR a R b is bound to any one of the two meta positions.
  • Y is preferably a hydroxy group, or —NH 2 (ie, R is a hydrogen atom), more preferably a hydroxy group.
  • the aliphatic hydrocarbon group is a linear, branched or cyclic, saturated or unsaturated aliphatic hydrocarbon group, preferably a linear or branched, saturated or unsaturated aliphatic hydrocarbon It is a group, more preferably a linear saturated aliphatic hydrocarbon group or a branched unsaturated aliphatic hydrocarbon group.
  • the compound of the present invention is a compound represented by the following formula (I):
  • Formula (I): [In the formula, Y represents a hydroxy group or -NHR (wherein R represents a hydrogen atom or a C 1-6 alkyl group), R a and R b each independently represent an aliphatic hydrocarbon group which may have a substituent, and the total number of carbon atoms in -NR a R b is 22 or more, n represents an integer of 1 to 5; ]
  • R represents a hydroxy group or -NHR (wherein R represents a hydrogen atom or a C 1-6 alkyl group), R a and R b each independently represent an aliphatic hydrocarbon group which may have a substituent, and the total number of carbon atoms in -NR a R b is 22 or more, n represents an integer of 1 to 5;
  • R a and R b are the total number of carbon atoms each having at least one of R a and R b have the substituent In the case, the number of carbon atoms in the substituent is also included.
  • R a and R b are preferably each independently an aliphatic hydrocarbon group.
  • the total number of carbon atoms in —NR a R b is 22 or more, preferably 22 to 200, more preferably 40 to 80.
  • N is an integer of 1 to 5, preferably 1 or 2, and more preferably 1.
  • the substitution position of -NR a R b is not limited, in terms of acid stability, it is preferable that at least one -NR a R b is bonded to the meta position on the benzene ring.
  • the meta position means the meta position relative to the —CH 2 Y group of the compound represented by the formula (I). Accordingly, since there are two meta positions to the —CH 2 Y group of the compound represented by the formula (I), for example, when n is 2, —NR a R b is one of the two meta positions It is preferred to bind to at least one or both or both, and when n is 1, it is preferred that -NR a R b is bound to any one of the two meta positions.
  • Y is preferably a hydroxy group, or —NH 2 (ie, R is a hydrogen atom), more preferably a hydroxy group.
  • the aliphatic hydrocarbon group is a linear, branched or cyclic, saturated or unsaturated aliphatic hydrocarbon group, preferably a linear or branched, saturated or unsaturated aliphatic hydrocarbon It is a group, more preferably a linear saturated aliphatic hydrocarbon group or a branched unsaturated aliphatic hydrocarbon group.
  • the compound of the present invention may be introduced as a protecting group (organic tag) such as a carboxy group, ie, an amino acid or the C-terminus of a peptide, in an organic synthesis reaction, preferably in peptide synthesis and the like.
  • a protecting group organic tag
  • the compound of the present invention can be contained in an agent for protecting a carboxy group in an amino acid or peptide, or in an agent for protecting the C-terminus in an amino acid or peptide.
  • the reagent for protecting the carboxy group in the amino acid or peptide, or the reagent for protecting the C-terminus in the amino acid or peptide consists of the compound of the present invention.
  • the compounds of the invention can be linked to the compounds intended for protection via the Y group. That is, the compounds of the present invention in which Y is a hydroxy group or -NHR can be bonded to the C-terminus of an amino acid or peptide to protect it.
  • the compounds into which the compound of the present invention has been introduced preferably have high stability even under acidic conditions.
  • High stability under acidic conditions means, for example, stability under conditions in which strong acids coexist.
  • the compound into which the compound of the present invention is introduced has high stability even in a solution of trifluoroacetic acid or hydrogen chloride in an organic solvent.
  • the compound into which the compound of the present invention has been introduced is stable under the condition where 10 mass times amount of 4 M hydrogen chloride / 1,4-dioxane is present relative to the compound into which the compound of the present invention is introduced.
  • the compounds represented by the formula (I) can be synthesized by the method shown below.
  • the following manufacturing method shows an example of a general manufacturing method, and the manufacturing method of a compound is not limited to this.
  • the starting compounds can be readily obtained as commercial products unless otherwise stated, or can be produced according to known methods or methods analogous thereto.
  • the compound represented by the formula (I) can be obtained, as necessary, by column chromatography, thin layer chromatography, high performance liquid chromatography (HPLC), recrystallization, washing with a solvent, etc. to obtain high purity compounds. be able to.
  • a protective group generally used in organic synthesis etc. may be introduced into these groups, In that case, the target compound can be obtained by removing the protecting group after the reaction, if necessary.
  • the compound represented by formula (I) can be produced, for example, by the following steps.
  • R 1 represents a hydrogen atom or an OR 2 group (wherein R 2 represents a hydrogen atom or a C 1-6 alkyl group, etc.), and the other symbols are as defined above].
  • the step is a step of producing compound (IV) by alkylating, acylating or sulfonylating compound (III).
  • compound (III) is reacted with a halide (chloride, bromide, or iodide) having a group corresponding to Ra or Rb in the presence of a base in a solvent that does not adversely influence the reaction. It is done from the thing.
  • a halide chloride, bromide, or iodide
  • Examples of the base in the case of alkylating the compound (III) include potassium carbonate, sodium hydroxide, potassium hydroxide, sodium nitrite and the like, among which potassium carbonate is preferable.
  • examples of solvents which do not adversely affect the reaction include alcohols (methanol, ethanol, ethylene glycol etc.), ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane etc.), Aromatic hydrocarbons (toluene, xylene etc.), nitriles (acetonitrile, propionitrile etc.), amides (N, N-dimethylformamide, N-methylpyrrolidinone, N, N-dimethylacetamide etc.), sulfoxides (ex. Dimethyl sulfoxide etc.).
  • they are amides, more preferably N-methyl pyrrolidinone.
  • the reaction temperature is usually any temperature in the range of 0 ° C. to the boiling point of the solvent used, preferably in the range of 60 ° C. to the boiling point of the solvent, and the reaction time is It is usually 1 to 120 hours, preferably 1 to 72 hours.
  • Examples of the base in the case of acylating or sulfonylating compound (III) include aliphatic amines (eg, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine), aromatic amines (eg, pyridine), etc. It can be mentioned. Preferably, it is an aliphatic amine, more preferably N, N-diisopropylethylamine.
  • examples of solvents which do not adversely affect the reaction include halogenated hydrocarbons (chloroform, dichloromethane and the like), aromatic hydrocarbons (toluene, xylene and the like), ether And mixtures thereof (diethyl ether, tetrahydrofuran, 1,4-dioxane etc.), nitriles (acetonitrile etc.), or mixtures thereof.
  • halogenated hydrocarbons chloroform, dichloromethane and the like
  • aromatic hydrocarbons toluene, xylene and the like
  • ether And mixtures thereof diethyl ether, tetrahydrofuran, 1,4-dioxane etc.
  • nitriles acetonitrile etc.
  • they are halogenated hydrocarbons, more preferably dichloromethane.
  • reaction temperature is usually any temperature within the range of 0 ° C. to the boiling point of the solvent used, preferably 10 ° C. to the boiling point of the solvent,
  • reaction time is usually 1 to 24 hours, preferably 1 to 5 hours.
  • Step (b) The step is a step of producing a compound (V) by reducing the compound (IV).
  • the reaction is a reduction reaction and can be performed by a method using a reducing agent.
  • Examples of the reducing agent used for the reduction reaction include metal hydrides (sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, dibutylaluminum hydride, aluminum hydride, hydrogenation Aluminum lithium etc. etc. are mentioned. Among these, lithium aluminum hydride is preferable.
  • the reaction is carried out in a solvent that does not adversely affect the reaction.
  • solvent for example, alcohols (methanol, ethanol etc.), ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane etc.), aromatic hydrocarbons (toluene, xylene etc.), or mixtures thereof Can be mentioned.
  • tetrahydrofuran is preferred.
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 10 ° C. to 40 ° C., and the reaction time is usually 1 to 24 hours, preferably 1 to 5 hours.
  • Step (c) The step is a step of producing compound (VI) by amination of compound (V).
  • the step can be carried out, for example, by an amination reaction using phthalimide, phthalimide potassium salt, and then, if necessary, a reaction using, for example, hydrazine monohydrate.
  • the step can also be carried out, for example, by a bromination reaction using, for example, acetyl bromide, phosphorus tribromide, triphenylphosphine / bromine and the like, followed by reaction with RNH 2 .
  • the reaction is carried out in a solvent that does not adversely affect the reaction.
  • solvent for example, alcohols (methanol, ethanol, ethylene glycol etc.), ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane etc.), aromatic hydrocarbons (toluene, xylene etc.), nitrile (Acetonitrile, propionitrile etc.), amides (N, N-dimethylformamide, N-methylpyrrolidinone, N, N-dimethylacetamide etc.), sulfoxides (dimethyl sulfoxide etc.), halogenated hydrocarbons (chloroform, Dichloromethane and the like).
  • aromatic hydrocarbons, ethers, and halogenated hydrocarbons are preferable, and toluene, tetrahydrofuran and chloroform are more preferable.
  • the reaction temperature is usually from 0 ° C. to the boiling point of the solvent used, preferably from 10 ° C. to the boiling point of the solvent, and the reaction time is usually from 1 to 24 hours, Preferably, it is 1 to 5 hours.
  • the introduction and removal reaction of the organic tag using the compound represented by the formula (I) and the production of the peptide including the step of introducing the organic tag can be carried out by the following method.
  • the compound represented by the formula (I) is a C-terminal functional group (such as a carboxy group, a carboxamide group, a thiol group) and a side chain functional group (hereinafter referred to as , C-terminal etc.), and is preferably introduced as a protecting group of carboxy group.
  • C-terminal functional group such as a carboxy group, a carboxamide group, a thiol group
  • C-terminal etc. side chain functional group
  • the compound represented by formula (I) can be used as a reagent (organic tag compound) for protecting various organic compounds.
  • a compound (organic tag conjugate) to which an organic tag is bound can be produced by a method comprising the following steps (i) to (iv).
  • the solvent a general organic solvent can be used for the reaction, but as the solubility of the compound in the solvent is higher, excellent reactivity can be expected. Therefore, the solvent having a high solubility of the compound represented by formula (I) It is preferable to select As such a solvent, for example, halogenated hydrocarbons (chloroform, dichloromethane and the like), nonpolar organic solvents (1, 4-dioxane, tetrahydrofuran and the like) can be mentioned. These solvents may be used as a mixture of two or more at an appropriate ratio.
  • aromatic hydrocarbons benzene, toluene, xylene, etc.
  • nitriles acetonitrile, pro It is also possible to use a mixture of pironitrile etc., ketones (acetone, 2-butanone etc.), amides (N, N-dimethylformamide etc.), sulfoxides (dimethyl sulfoxide etc.) in an appropriate ratio.
  • the reaction substrate is, for example, a substance having -COOH such as an amino acid to be protected, and the amount of the reaction substrate used can be 1 to 10 moles, preferably 1 to 1 mole of the compound of the present invention. It is ⁇ 5 moles.
  • the reaction is carried out in a solvent that does not adversely affect the reaction.
  • a condensing agent By adding a condensing agent, an ester bond is formed when Y is a hydroxy group, and an amide bond is formed when Y is -NHR.
  • the amount of the condensing agent to be used can be 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of the compound represented by the formula (I).
  • the reaction temperature is generally ⁇ 10 ° C. to 30 ° C., preferably 0 ° C. to 20 ° C., and the reaction time is generally 1 to 30 hours.
  • additives and a base can be appropriately used as long as they do not interfere with the reaction.
  • Suitable additives include 4-dimethylaminopyridine (DMAP), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-1H-1,2,3-triazole-5-carboxylic acid ethyl ester (HOCt), 1 And -hydroxy-7-dibenzotriazole (HOAt), ethyl (hydroxyimino) cyanoacetate (OxymaPure) and the like.
  • DMAP 4-dimethylaminopyridine
  • HOBt 1-hydroxybenzotriazole
  • HOCt 1-hydroxy-1H-1,2,3-triazole-5-carboxylic acid ethyl ester
  • HOAt 1 And -hydroxy-7-dibenzotriazole
  • OxymaPure ethyl (hydroxyimino) cyanoacetate
  • the amount of the additive used is preferably 0.01 to 5 moles, and preferably 0.1 to 2 moles, per mole of the compound of the present invention.
  • the suitable base is not particularly limited, and examples thereof include aliphatic amines (eg, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine), aromatic amines (eg, pyridine) and the like.
  • aliphatic amines eg, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine
  • aromatic amines eg, pyridine
  • it is an aliphatic amine, more preferably N, N-diisopropylethylamine.
  • the amount of the base used is preferably 0.1 to 50 mol, and preferably 1 to 5 mol, per 1 mol of the compound represented by formula (I).
  • the confirmation of the progress of the reaction can be carried out using the same method as general liquid phase organic synthesis reaction. That is, the reaction can be traced using thin layer chromatography, high performance liquid chromatography, high performance liquid chromatography / mass spectrometry (LC / MS) and the like.
  • the bound product obtained in the above step (ii) or the product obtained after dissolving the bound product in a soluble solvent and carrying out the desired organic synthesis reaction is In order to separate, it is a step of changing the solvent in which the conjugate or the product is dissolved (for example, changing the solvent composition, changing the type of solvent), and performing precipitation or liquid separation operation. That is, the reaction is carried out under conditions such that the bound substance is dissolved, and after the reaction, the solvent is distilled off, and the bound substance is precipitated by solvent substitution, and impurities are removed by liquid separation operation.
  • the substitution solvent for example, a halogenated solvent or cyclopentyl methyl ether is used for dissolution, and a polar organic solvent such as methanol or acetonitrile is used for precipitation.
  • the deprotection is carried out by a hydrogenation reaction.
  • the reagent to be used include palladium carbon etc. Specific examples are 10% carbon powder PE type, 5% carbon powder STD type, 5% carbon powder NX type, 5% carbon powder AER type, 5% carbon powder PE type, ASCA-2, 5% alumina powder, CGS-10DR, SGS-1-DR, BNA-5D can be mentioned. Among them, 5% carbon powder PE type is preferable.
  • the amount of palladium carbon to be used is not particularly limited as long as it does not interfere with the reaction, but is preferably 0.01 times by mass to 2 times by mass the mass of the reaction substrate, more preferably 0.1 times by mass The amount is 1 times by mass.
  • the reaction temperature is usually 0 ° C.-80 ° C., preferably 0 ° C.-30 ° C., and the reaction time is usually 1-48 hours.
  • the peptide can be produced by carrying out the method including the following steps (1) to (4) including the organic tag introducing step.
  • the compound represented by the formula (I) is condensed with the N-protected amino acid or C-terminus of the N-protected peptide, C-protected amino acid or C-protected peptide, That is, it is a process of obtaining a benzyl compound adduct.
  • it can implement according to the organic tag introduction process mentioned above.
  • N-protected amino acid and “N-protected peptide” mean amino acids and peptides wherein the amino group is protected and the carboxy group is unprotected, these are “P-AA-OH”. (Here, P is a protective group for an amino group, and sometimes referred to as a “temporary protective group”).
  • the number of residues of the amino acid or peptide protected by the compound represented by the formula (I) is not particularly limited, but is preferably 20 residues or less, more preferably 10 residues or less, still more preferably 4 Less than residue.
  • amino acids which can be protected according to the present invention are organic compounds having both amino and carboxy functional groups, preferably ⁇ -amino acids, ⁇ -amino acids, ⁇ -amino acids or ⁇ -amino acids, more preferably ⁇ -Amino acid or ⁇ -amino acid, more preferably ⁇ -amino acid.
  • amino acids which constitute the peptides which can be protected according to the invention are, for example, the above-mentioned amino acids.
  • the three-dimensional structure of the ⁇ -amino acid is not particularly limited, but is preferably L-form.
  • the condensation reaction between the compound represented by the formula (I) and the N-protected amino acid or N-protected peptide at the C-terminus is a process for producing the organic tag conjugate described above (ii): It can be carried out in the presence of / or additives.
  • Examples of the solvent used in this step include halogenated hydrocarbons (chloroform, dichloromethane and the like) and nonpolar organic solvents (1,4-dioxane, tetrahydrofuran and the like). These solvents may be used as a mixture of two or more at an appropriate ratio. Among them, dichloromethane is preferred.
  • the amount of the solvent used is not limited as long as it does not interfere with the reaction, but it is preferably 1 to 100 times by mass, more preferably 2 to 50 times by mass, relative to the mass of the reaction substrate.
  • the reaction temperature is usually ⁇ 10 to 40 ° C., preferably 0 to 30 ° C., and the reaction time is usually 1 to 72 hours.
  • Step (2) N-Terminal Deprotection Step The step is a step of removing the protective group at the N-terminus of the amino acid or peptide obtained in the above-mentioned step (1).
  • N-terminal protecting group the amino group protecting groups described later generally used in the technical field such as peptide chemistry can be used.
  • a t-butoxycarbonyl group hereinafter also referred to as Boc group
  • a benzyloxycarbonyl group and / or a 9-fluorenylmethoxycarbonyl group (hereinafter also referred to as Fmoc group) are suitably used.
  • Deprotection conditions are suitably selected according to the kind of protective group, However, Conditions different from the removal of an organic tag are preferable.
  • deprotection is carried out by treatment with a base
  • deprotection is carried out by treatment with an acid.
  • the reaction is carried out in a solvent that does not adversely affect the reaction.
  • dimethylamine, diethylamine, piperidine and the like can be mentioned.
  • acid to be used hydrochloric acid, sulfuric acid, trifluoroacetic acid, trifluoromethanesulfonic acid and the like can be mentioned.
  • halogenated hydrocarbons chloroform, dichloromethane etc.
  • aromatic hydrocarbons toluene, xylene etc.
  • ethers diethyl ether, tetrahydrofuran, 1,4-dioxane etc.
  • nitrile And mixtures thereof acetonitrile, etc.
  • Step (3) Peptide Chain Extension Step This step is a step of condensing the N-protected amino acid or N-protected peptide at the N-terminus of the N-terminal deprotected amino acid or peptide obtained in step (2) It is.
  • the said process can use the condensing agent, additive, etc. which are used at the above-mentioned organic tag introduce
  • Step (4) Purification Step The step can be carried out in the same manner as step (iii) in the above-mentioned reaction for introducing an organic tag.
  • the peptide chain is elongated by repeating the following steps (5) to (7) the desired number of times with respect to the N-protected amino acid or N-protected peptide obtained in step (4) it can. (5) removing the N-terminal protecting group of the peptide obtained in the purification step, (6) a step of condensing an N-protected amino acid or an N-protected peptide at the N-terminus of the peptide obtained in the step (5), and (7) precipitating the peptide obtained in the step (7) or Separation step. All can be carried out by the same operation as the steps (2) to (4).
  • a step of deprotecting the C terminus of the C-terminal-protected peptide with a benzyl compound can be further included.
  • the said process can be performed, for example according to the above-mentioned manufacturing process (iv) of the organic tag conjugate: deprotection step.
  • the organic synthesis reaction or the peptide synthesis reaction includes multiple steps, it is possible to omit the purification step appropriately, as long as the reaction in the next step is not affected.
  • reaction substrate has a hydroxy group, an amino group, a carboxy group, or a carbonyl group (especially when the amino acid or peptide has a functional group in the side chain), these groups are generally used in peptide chemistry etc.
  • a protecting group as used may be introduced, in which case the target compound can be obtained by removing the protecting group as required after the reaction.
  • a hydroxy-protecting group in the reaction substrate for example, a C 1-6 alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, butyl, t-butyl), a phenyl group, a trityl group, C 7-10 Aralkyl group (eg, benzyl), formyl group, C 1-6 alkyl-carbonyl group (eg, acetyl, propionyl), benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzyl carbonyl), 2-tetrahydropyranyl Group, 2-tetrahydrofuranyl group, silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, t-butyldimethylsilyl, t-butyldiethylsilyl), C 2-6 alkenyl group (eg, 1-allyl
  • These groups are a halogen atom (eg, fluorine, chlorine, bromine, iodine), a C 1-6 alkyl group (eg, methyl, ethyl, propyl), a C 1-6 alkoxy group (eg, methoxy, ethoxy, propoxy) And may be substituted by 1 to 3 substituents selected from nitro group and the like.
  • halogen atom eg, fluorine, chlorine, bromine, iodine
  • C 1-6 alkyl group eg, methyl, ethyl, propyl
  • C 1-6 alkoxy group eg, methoxy, ethoxy, propoxy
  • Examples of the protecting group for amino group in the reaction substrate include formyl group, C 1-6 alkyl-carbonyl group (eg, acetyl, propionyl), C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, Boc group), benzoyl group, C 1-6 aralkyl-carbonyl group (eg, benzyl carbonyl), C 7-14 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, Fmoc group), trityl group, phthaloyl group, N, N-dimethylaminomethylene group, silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, t-butyldimethylsilyl, t-butyldiethylsilyl), C 1-6 alkenyl group (eg, 1-allyl), etc.
  • Be These groups are substituted by 1 to 3 substituents selected from halogen atoms (eg, fluorine, chlorine, bromine, iodine), C 1-6 alkoxy groups (eg, methoxy, ethoxy, propoxy), nitro groups and the like. It may be done.
  • halogen atoms eg, fluorine, chlorine, bromine, iodine
  • C 1-6 alkoxy groups eg, methoxy, ethoxy, propoxy
  • a C 1-6 alkyl group eg, methyl, ethyl, propyl, isopropyl, butyl, t-butyl
  • a C 1-6 aralkyl group eg, benzyl
  • Phenyl group, trityl group silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, t-butyldimethylsilyl, t-butyldiethylsilyl, t-butyldiphenylsilyl), C 1-6 alkenyl group (eg, 1- Allyl) and the like.
  • halogen atoms eg, fluorine, chlorine, bromine, iodine
  • C 1-6 alkoxy groups eg, methoxy, ethoxy, propoxy
  • Examples of the protective group for the carbonyl group in the reaction substrate include cyclic acetal (eg, 1,3-dioxane), non-cyclic acetal (eg, di-C 1-6 alkyl acetal) and the like.
  • protection and deprotection reactions for example, Protective Groups in Organic Synthesis, Fourth edition
  • protecting groups for example, Protective Groups in Organic Synthesis, Fourth edition
  • (v / v) means (volume / volume). Further, in the case where amino acids and the like are indicated by abbreviations in the present specification, each indication is based on the abbreviation by IUPAC-IUB Commission on Biochemical Nomenclature or the abbreviation commonly used in the art.
  • proton nuclear magnetic resonance JNM-ECP300; manufactured by JEOL Ltd. (JEOL) or JNM-ECX300; manufactured by JEOL Ltd .; tetramethylsilane It was measured at 300 MHz as an internal standard.
  • the measurement result represents chemical shift ⁇ (unit: ppm) (split pattern, integral value) of a signal using tetramethylsilane as an internal standard (0.0 ppm).
  • MALDI-TOF-MS mass spectrometry
  • MALDI-TOF-MS mass spectrometry
  • Bruker ⁇ -cyano-4-hydroxycinnamic acid (CHCA) or 2,5-dihydroxybenzoic acid (DHB) was used unless otherwise stated.
  • CHCA ⁇ -cyano-4-hydroxycinnamic acid
  • DVB 2,5-dihydroxybenzoic acid
  • silica gel column chromatography used Hi-Flash column manufactured by Yamazen, silica gel 60 manufactured by Merck, or PSQ 60B manufactured by Fuji Silysia Chemical.
  • Boc-Val-Pro -OBzl (3-N (C 22 H 45) 2) (200.0mg, 0.19mmol) was dissolved in dichloromethane (164.0 g), 4M hydrogen chloride / 1,4 Dioxane (2.0 g) was added dropwise with ice cooling and the mixture was stirred for 3 hours. The reaction solution was concentrated under reduced pressure to obtain HCl ⁇ H-Val-Pro-OBzl (3-N (C 22 H 45 ) 2 ).
  • 3-Diphytylamino-benzyl alcohol (0.25 g, 0.37 mmol) and Fmoc-MePhe-OH (0.22 g, 0.56 mmol) are dissolved in dichloromethane (5 mL), 1-ethyl-3- (3) -Dimethylaminopropyl) carbodiimide hydrochloride (0.11 g, 0.58 mmol) and 4-dimethylaminopyridine (5.1 mg, 0.04 mmol) were added and the mixture was stirred at room temperature for 3 hours. The reaction solution was washed successively with 1 M hydrochloric acid (5 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL).
  • reaction solution was washed successively with 8% by mass hydrochloric acid (6 mL), saturated aqueous sodium hydrogen carbonate solution (6 mL), and aqueous sodium chloride solution (6 mL).
  • the organic layer was concentrated and then purified by silica gel column chromatography to obtain a condensate (0.84 g, yield 81.2%) as a colorless liquid.
  • MASS (TOF-MS) m / z; 851.63 (M + Na) +
  • lithium borohydride (0.069 g, 3.15 mmol) was added and the mixture was stirred for 17 hours.
  • Lithium borohydride (0.071 g, 3.26 mmol) and methanol (0.2 mL) were added to this solution and stirred for 4 hours.
  • To the reaction solution was added 4% by mass hydrochloric acid (18 mL) and chloroform (100 mL), and the phases were separated. The organic layer was concentrated and then purified by silica gel column chromatography to obtain N-triacontyl-N- (3-hydroxymethylphenyl) acetamide (0.16 g, yield 50.4%) as a white solid.
  • N- (3- (didocosylamino) benzyl) phthalimide (1.91 g, yield 101.1%) as a yellow solid.
  • N- (3- (didocosylamino) benzyl) phthalimide (1.91 g, 2.20 mmol) and hydrazine monohydrate (2.20 g, 43.9 mmol) are dissolved in tetrahydrofuran (28.7 g), and the mixture is mixed The reaction mixture was stirred for 4 hours while heating under reflux. The reaction solution was allowed to cool to room temperature and then concentrated, and methanol (50 g) was added.
  • Test Example 1 Comparison of the stability to acid of the condensate of Synthesis Examples 2 to 7 and the condensate of Reference Synthesis Examples 1 to 6
  • Test compounds Compounds obtained by introducing the compound of the present invention or the organic tag described in Patent Document 1 into amino acids synthesized in Synthesis Examples 2 to 7 and Reference Synthesis Examples 1 to 6 (hereinafter referred to as Synthesis Example Compounds 2 to 7 and Reference Synthesis respectively Examples compounds 1 to 6 were used as test compounds.
  • test Method To each test compound, 10 mass volumes of 4 M hydrogen chloride / 1,4-dioxane was added, and the mixture was stirred at 25 ° C. and 40 ° C. The peak area of HPLC after each lapse of time was measured, the ratio (area%) of each test compound in the total area was determined, and the results for the synthetic example compounds were compared with the results for the reference synthetic example compounds (Table 1) ⁇ 6). In addition, the area% in each time was described by the ratio which made the area% of 0 hour 100.
  • HPLC measurement condition device Shimadzu LC-20A
  • Column Poroshell 120 EC-C18 (2.7 ⁇ m, 3.0 ⁇ 100 mm)
  • Eluent A: 0.01% aqueous ammonium acetate solution
  • B tetrahydrofuran
  • a / B 25/75 (0-5 min)
  • 25 / 75-5 / 95 5-15 min
  • V / v Eluent velocity 0.5 mL / min
  • Detection wavelength 230 nm
  • Test Results The synthesis example compounds 2 to 9 suppressed the decrease in area% as compared to the reference synthesis example compounds 1 to 8. Moreover, at 40 ° C., the difference in area% between the case of the synthesis example compound and the case of the reference synthesis example compound was more remarkable.
  • Test Example 2 Comparison of the stability to acid of the condensate of Synthesis Examples 12, 14, 16 and 18 and the condensate of Reference Synthesis Example 1
  • Test compounds Compounds obtained by introducing the organic tag of the present invention or the organic tag described in Patent Document 1 into Fmoc-MePhe-OH synthesized in Synthesis Examples 12, 14, 16 and 18 and Reference Synthesis Example 1 (hereinafter referred to respectively as Each of Synthesis Example Compounds 12, 14, 16, and 18 and Reference Synthesis Synthesis Example Compound 1 are used as test compounds.
  • Test Method To each test compound, 10 mass volumes of 4 M hydrogen chloride / 1,4-dioxane was added, and the mixture was stirred at 25 ° C. and 40 ° C. The peak area of HPLC after each lapse of time was measured, the ratio (area%) of each test compound in the total area was determined, and the result for the compound of synthesis example was compared with the result for the compound of reference synthesis example (Table 7) ⁇ 10). In addition, the area% in each time was described by the ratio which made the area% of 0 hour 100. The results obtained in Test Example 1 were used for Reference Synthesis Example Compound 1.
  • the compounds into which the compound of the present invention has been introduced have high stability under acidic conditions. Therefore, the compound of the present invention can be used as a versatile organic tag or a protecting reagent.
  • a benzyl compound that can be used as an organic tag having high stability under acidic conditions, such as in peptide synthesis, can be provided.
  • the highly efficient manufacturing method of a peptide can also be provided by using the said benzyl compound as an organic tag.

Abstract

L'invention concerne : un nouveau composé qui peut être utilisé en tant qu'étiquette organique présentant une stabilité élevée dans des conditions acides en synthèse peptidique, etc. ; ainsi qu'un procédé de production hautement efficace d'un peptide, le composé étant utilisé en tant qu'étiquette organique.
PCT/JP2018/025303 2017-07-05 2018-07-04 Composé benzyle WO2019009317A1 (fr)

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JPH0995472A (ja) * 1995-09-29 1997-04-08 Oji Paper Co Ltd 新規アリールアミン誘導体およびその製造方法
JPH09241553A (ja) * 1996-03-08 1997-09-16 Konica Corp インクジェット記録液
JP2004035521A (ja) * 2002-07-08 2004-02-05 Nokodai Tlo Kk 液相ペプチド合成装置
JP2004059509A (ja) * 2002-07-30 2004-02-26 Nokodai Tlo Kk 液相ペプチド合成用アミノ酸試薬
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BR0112580A (pt) 2000-07-19 2003-06-17 Hoffmann La Roche Compostos, composições farmacêuticas que contêm os mesmos, utilização desses compostos, processo para tratamento terapêutico e/ou profilático e processo para a preparação desses compostos
JP4656787B2 (ja) 2001-09-28 2011-03-23 大鵬薬品工業株式会社 Ｃｄｃ２５脱リン酸化酵素阻害活性を有する新規カルボン酸誘導体及び医薬

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JPS584749A (ja) * 1981-06-05 1983-01-11 サンド・アクチエンゲゼルシヤフト アミノベンジルアミン誘導体、その製法および薬剤としての用途
JPH0995472A (ja) * 1995-09-29 1997-04-08 Oji Paper Co Ltd 新規アリールアミン誘導体およびその製造方法
JPH09241553A (ja) * 1996-03-08 1997-09-16 Konica Corp インクジェット記録液
EP1426101A1 (fr) * 2001-08-24 2004-06-09 Japan Science and Technology Agency Systeme de solvant multiphase compatible
JP2004035521A (ja) * 2002-07-08 2004-02-05 Nokodai Tlo Kk 液相ペプチド合成装置
JP2004059509A (ja) * 2002-07-30 2004-02-26 Nokodai Tlo Kk 液相ペプチド合成用アミノ酸試薬

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