Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B61/00—Other general methods
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
  • C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
  • C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
  • C07C251/04—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C251/10—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
  • C07C251/16—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
• • 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
  • C07C269/04—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 from amines with 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
  • C07C271/12—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 hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
  • C07F7/02—Silicon compounds
  • C07F7/08—Compounds having one or more C—Si linkages
  • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages

Definitions

• the present invention relates to a method for producing an alkylsilyloxy-substituted benzylamine compound.
• a carrier for liquid-phase peptide synthesis (Tag) has been reported.
• the carrier for liquid-phase peptide synthesis (Tag) is a highly hydrophobic compound, so by binding highly hydrophilic amino acids, peptides, or amino acid amides (hereinafter sometimes referred to as amino acids, etc.) to this carrier, the solubility in organic solvents can be greatly improved. Therefore, when a peptide elongation reaction is carried out with amino acids, etc. bound to this carrier, the amino acids, etc.
• the liquid-phase peptide synthesis supports (Tags) shown in Patent Documents 1 to 7 and Non-Patent Document 1 have a structure in which one or more alkyloxy side chains having 1 to 16 carbon atoms and having an alkylsilyloxy group bonded thereto are bonded to a mother nucleus such as a benzyl skeleton, a diphenylmethane skeleton, or a xanthene skeleton.
• Patent No. 6116782 Japanese Patent No. 6201076 Patent No. 6283774 Patent No. 6283775 Patent No. 6322350 Patent No. 6393857 Patent No. 6531235
• an object of the present invention is to provide a method for industrially producing an alkylsilyloxy-substituted benzylamine compound, which can easily remove impurities and does not involve the intermediate alkylsilyloxy-substituted benzyl compound, which is unstable to acid.
• the present inventors have found an industrial method for producing an alkylsilyloxy-substituted benzylamine compound by introducing a hydroxyalkyloxy group into a compound having a benzoyl skeleton, a diphenyl ketone skeleton (benzophenone skeleton) or a xanthone skeleton, reacting the hydroxyalkyloxy-substituted compound with a disilazane compound, and then reacting the compound with an acid or base to remove the tri-substituted silyl group on the hydroxyl group, thereby obtaining an intermediate compound in which the carbonyl group bonded to each skeleton of the hydroxyalkyloxy-substituted compound is converted into an imino group, and then converting the imino group into a 9-fluorenylmethyloxycarbonyl-protected amino group, and then introducing an alkylsilyl group into the hydroxyl group.
• the method of the present invention it is not necessary to use Br-(CH 2 ) 11 -O-TIPS, which is a raw material that has been problematic in the conventional method due to its poor stability and difficulty in separating it from the intermediate compound.
• the intermediate compound is a solid, the raw material or decomposition products of the raw material and other impurities generated or carried over in the system can be easily removed by filtration, crystallization, or the like.
• the target compound can be obtained in high purity and high yield without passing through an alkylsilyloxy-substituted benzyl compound, which is an intermediate compound unstable to acid.
• the present inventors have found that an alkylsilyloxy-substituted benzylamine compound can be industrially advantageously obtained, and have completed the present invention.
• the term "solid" refers to both a substance having a crystalline structure and an amorphous solid.
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;
• R B is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R B represents the structure of this formula, R 5b may form an ether bond (-O-) together with R 5b in formula (2).
• * represents the bonding site with R B.
• the reaction is carried out by reacting a silazane compound with a benzoyl compound represented by the general formula (3), and then reacting the silazane compound with an acid or a base.
• R 1 to 5 of R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;
• R B is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula:
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R B represents a structure of this formula, R 5b may form an ether bond (-O-) together with R 5b in formula (3). Note that * represents the bonding site with R B.
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;
• R B is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R B represents the structure of this formula, R 5b may form an ether bond (-O-) together with R 5b in formula (2).
• * represents the bonding site with R B.
• a silazane compound is reacted with a benzoyl compound represented by the general formula (3), and then an acid or a base is reacted therewith to obtain a compound represented by the general formula (3)
• R 1 to 5 of R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;
• R B is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula:
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R B represents a structure of this formula, R 5b may form an ether bond (-O-) together with R 5b in formula (3).
• * represents the bonding site with R B.
• reacting the resulting ketimine compound with a reducing agent and an Fmoc reagent
• R 1 to 5 of R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;
• R B is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula:
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R B represents a structure of this formula, R 5b may form an ether bond (-O-) together with R 5b in formula (4). Note that * represents the bonding site with R B.
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;
• R B is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R B represents the structure of this formula, R 5b may form an ether bond (-O-) together with R 5b in formula (2).
• * represents the bonding site with R B.
• a silazane compound is reacted with a benzoyl compound represented by the general formula (3), and then an acid or a base is reacted therewith to obtain a compound represented by the general formula (3)
• R 1 to 5 of R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;
• R B is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula:
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R B represents a structure of this formula, R 5b may form an ether bond (-O-) together with R 5b in formula (3). Note that * represents the bonding site with R B.
• the ketimine compound represented by the general formula (4) is reacted with a reducing agent and an Fmoc reagent to obtain a ketimine compound represented by the general formula (4):
• R 1 to 5 of R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;
• R B is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula:
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R B represents a structure of this formula, R 5b may form an ether bond (-O-) together with R 5b in formula (4). Note that * represents the bonding site with R B. ) and then reacting the benzylamine compound with an alkylsilylating agent,
• R 1c to R 5c represent an alkyloxy group having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups, and the remainder represent a hydrogen atom, a halogen atom, an alkyloxy group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;
• R C is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula:
• R 1c to R 5c represent an alkyloxy group having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R C represents the structure of this formula, R 5c may form an ether bond (-O-) together with R 5c in formula (5). Note that * represents the bonding site with R C.
• R 1 to 5 of R 1a to R 5a represent a hydroxy group, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;
• R A is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula:
• R 1a to R 5a represent a hydroxy group, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms).
• R 5a may combine with R 5a in formula (1) to form an ether bond (-O-).
• * indicates the bonding site with R A.
• R 1 to 5 of R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;
• R B is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula:
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R B represents the structure of this formula, R 5b may form an ether bond (-O-) together with R 5b in formula (6).
• * represents the bonding site with R B.
• a compound represented by the formula: [6] General formula (4)
• R 1 to 5 of R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;
• R B is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula:
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R B represents a structure of this formula, R 5b may form an ether bond (-O-) together with R 5b in formula (4). Note that * represents the bonding site with R B.
• the benzylamine compound represented by the general formula (5) is reacted with an alkylsilylating agent.
• R 1c to R 5c represent an alkyloxy group having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups, and the remainder represent a hydrogen atom, a halogen atom, an alkyloxy group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;
• R C is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula:
• R 1c to R 5c represent an alkyloxy group having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R C represents the structure of this formula, R 5c may form an ether bond (-O-) together with R 5c in formula (5).
• * represents the bonding site with R C.
• R 1 to 5 of R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;
• R B is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula:
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R B represents a structure of this formula, R 5b may form an ether bond (-O-) together with R 5b in formula (3). Note that * represents the bonding site with R B.
• a ketimine compound represented by the general formula (4) is reacted to obtain a compound represented by the general formula (4):
• R 1 to 5 of R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;
• R B is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula:
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R B represents a structure of this formula, R 5b may form an ether bond (-O-) together with R 5b in formula (4). Note that * represents the bonding site with R B. ) and then reacting the benzylamine compound with an alkylsilylating agent,
• R 1c to R 5c represent an alkyloxy group having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups, and the remainder represent a hydrogen atom, a halogen atom, an alkyloxy group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;
• R C is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula:
• R 1c to R 5c represent an alkyloxy group having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R C represents the structure of this formula, R 5c may form an ether bond (-O-) together with R 5c in formula (5).
• * represents the bonding site with R C.
• the method of the present invention does not require the use of raw materials, which in conventional methods have problems with poor stability and difficulty in separating them from intermediate compounds.
• the intermediate compounds are solid, it is easy to remove the raw materials or decomposition products of the raw materials, as well as other impurities generated or carried over within the system, by filtration, crystallization, etc.
• R 1 to 5 of R 1a to R 5a represent a hydroxy group, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;
• R A is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula:
• R 1a to R 5a represent a hydroxy group, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R A represents the structure of this formula, R 5a may form an ether bond (-O-) together with R 5a in formula (1). Note that * indicates the bonding site with R A.
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;
• R B is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula:
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R B represents the structure of this formula, R 5b may form an ether bond (-O-) together with R 5b in formulas (2) to (4). Note that * represents the bonding site with R B.
• R 1c to R 5c represent an alkyloxy group having 1 to 29 carbon atoms substituted by 1 to 3 alkylsilyloxy groups, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;
• R C is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula:
• R 1c to R 5c represent an alkyloxy group having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R C represents the structure of this formula, R 5c may form an ether bond (-O-) together with R 5c in formula (5).
• * represents the bonding site with R C.
• One aspect of the present invention is a method for producing a ketimine compound represented by general formula (3), which comprises reacting a benzoyl compound represented by general formula (2) with a silazane compound and then reacting the benzoyl compound with an acid or a base.
• Another aspect of the present invention is a method for producing a benzylamine compound represented by general formula (4), which comprises reacting a benzoyl compound represented by general formula (2) with a silazane compound, then reacting the benzoyl compound with an acid or a base to obtain a ketimine compound represented by general formula (3), and reacting the ketimine compound with a reducing agent and an Fmoc reagent.
• Another aspect of the present invention is a method for producing an alkylsilyloxy-alkyloxybenzylamine compound represented by general formula (5), which comprises reacting a silazane compound with a benzoyl compound represented by general formula (2) and then reacting with an acid or a base to obtain a ketimine compound represented by general formula (3), reacting the ketimine compound with a reducing agent and an Fmoc reagent to obtain a benzylamine compound represented by general formula (4), and reacting the benzylamine compound thus obtained with an alkylsilylating agent.
• alkylsilyloxy-substituted benzylamine compound is used in the specification, this structure is intended to be indicated.
• the benzoyl compound represented by the general formula (2) is preferably obtained by reacting the hydroxybenzoyl compound represented by the general formula (1) with a halogenated alcohol.
• Another aspect of the present invention is a method for producing an alkylsilyloxy-alkyloxybenzylamine compound represented by general formula (5), which comprises reacting a benzylamine compound represented by general formula (4) with an alkylsilylation agent.
• Another aspect of the present invention is a method for producing an alkylsilyloxy-alkyloxybenzylamine compound represented by general formula (5), comprising reacting a ketimine compound represented by general formula (3) with a reducing agent and an Fmoc agent to obtain a benzylamine compound represented by general formula (4), and reacting the obtained benzylamine compound with an alkylsilylating agent.
• the ketimine compound represented by the general formula (3) and the benzylamine compound represented by the general formula (4) are novel compounds. Therefore, another aspect of the present invention is a compound represented by the following general formula (6):
• R 1 to 5 of R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;
• R B is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula:
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R B represents the structure of this formula, R 5b may form an ether bond (-O-) together with R 5b in formula (6).
• * represents the bonding site with R B.
• the present invention provides a compound represented by the formula:
• R 1a to R 5a 1 to 5 represent a hydroxy group, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms.
• the number of the hydroxy groups is preferably 1 to 4, more preferably 2 to 4, even more preferably 2 to 3, and even more preferably 2.
• the remaining group may be a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, with a hydrogen atom, a halogen atom, or an alkyl group having 1 to 4 carbon atoms being preferred, and a hydrogen atom being more preferred.
• examples of the alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, etc.
• alkoxy group having 1 to 4 carbon atoms examples include a methoxy group, an ethoxy group, an n-propyloxy group, an isopropyloxy group, an n-butyloxy group, etc.
• halogen atom examples include a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom.
• R A is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula:
• R 1a to R 5a represent a hydroxy group, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R A represents the structure of this formula, R 5a may form an ether bond (-O-) together with R 5a in formula (1). Note that * indicates the bonding site with R A.
• the formula (I) represents a group represented by the formula (I).
• alkoxy group having 1 to 6 carbon atoms examples include a methoxy group, an ethoxy group, an n-propyloxy group, an isopropyloxy group, an n-butyloxy group, a tert-butyloxy group, an isobutyloxy group, an n-pentyl group, an n-hexyl group, etc.
• an alkoxy group having 1 to 5 carbon atoms is preferred, and an alkoxy group having 1 to 4 carbon atoms is more preferred.
• R 1a to R 5a the same groups as those mentioned above are preferred.
• R A is preferably a group represented by the following formula:
• R 1a to R 5a represent a hydroxy group, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms.
• * represents the bonding site with R A.
• the formula (I) represents a group represented by the formula (I).
• the compound of formula (1) is reacted with a halogenated alcohol (represented as Hal-alcohol in the formula) to obtain a benzoyl compound of formula (2).
• the halogenated alcohol may be a halogenated alcohol having 1 to 16 carbon atoms, preferably a halogenated alcohol having 2 to 16 carbon atoms, more preferably a halogenated alcohol having 4 to 16 carbon atoms, even more preferably a halogenated alcohol having 6 to 16 carbon atoms, and even more preferably a halogenated alcohol having 8 to 16 carbon atoms.
• the halogen atom may be a bromine atom, a chlorine atom, an iodine atom, or a fluorine atom, with a bromine atom, a chlorine atom, or an iodine atom being preferred.
• the alcohol may be a linear or branched chain alcohol.
• the reaction of the compound of formula (1) with a halogenated alcohol is preferably carried out in a solvent in the presence of a base.
• the reaction solvent to be used include amide solvents such as dimethylformamide (hereinafter, DMF), diethylformamide, 1-methyl-2-pyrrolidone (hereinafter, NMP), and dimethylacetamide, urea solvents such as 1,3-dimethyl-2-imidazolidinone (hereinafter, DMI), halogenated solvents such as methylene chloride, ethers such as tetrahydrofuran and 2-methyltetrahydrofuran, ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, alcohol solvents such as methanol, ethanol, isopropanol, n-propanol, and n-butanol, polar solvents such as acetonitrile, and various mixed solvents of these.
• amide solvents such as
• amide solvents and urea solvents are preferred, and DMF and DMI are more preferred.
• the base include inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, and potassium hydride, as well as hydrates thereof, metal alkoxides such as lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide, and organic bases such as 1,8-diazabicyclo[5.4.0]-7-undecene, diisopropylethylamine, triethylamine, dimethylaniline, and imidazole.
• inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, and potassium hydride, as well as hydrates thereof, metal alkoxide
• Preferred bases include potassium carbonate and lithium hydroxide.
• the reaction may be carried out at a temperature of 0° C. to 200° C., preferably 50° C. to 150° C., and more preferably 70° C. to 120° C.
• the reaction is preferably carried out for 15 minutes to 48 hours.
• the benzoyl compound of general formula (2) obtained by this reaction can be isolated as a solid, making it easy to purify and easy to handle. Isolation and purification can be easily carried out by means commonly employed in industry, such as washing and recrystallization.
• 1 to 5 of R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms.
• the number of the hydroxyalkyloxy groups is preferably 1 to 4, more preferably 2 to 4, even more preferably 2 to 3, and still more preferably 2.
• the remaining group may be a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, with a hydrogen atom, a halogen atom, or an alkyl group having 1 to 4 carbon atoms being preferred, and a hydrogen atom being more preferred.
• R B is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula:
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R B represents the structure of this formula, R 5b may form an ether bond (-O-) together with R 5b in formula (2).
• * represents the bonding site with R B.
• the formula (I) represents a group represented by the formula (I).
• the group such as a hydroxyalkyloxy group having 1 to 16 carbon atoms is preferably the same as R 1b to R 5b described above.
• R B is represented by the following formula:
• R 1b to R 4b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms.
• * represents the bonding site with R B.
• the compound is a compound having a group represented by the following formula:
• the benzoyl compound of the general formula (2) is reacted with a silazane compound, and then with an acid or base to obtain a ketimine compound of the general formula (3).
• the compound of the general formula (2) is reacted with a silazane compound in the presence of a catalyst to obtain a compound in which a tri-substituted silyl group is bonded to the hydroxyl group of the hydroxyalkyloxy group.
• the resulting compound is then reacted with an acid or base to eliminate the tri-substituted silyl group, thereby obtaining a ketimine compound of the general formula (3).
• the silazane compound is a compound having a Si-NH-Si bond.
• Examples of the chain silazane compound include di-substituted disilazanes (1,3-di-substituted disilazanes), tetra-substituted disilazanes (1,1,3,3-tetra-substituted disilazanes), and hexa-substituted disilazanes (1,1,1,3,3,3-hexa-substituted disilazanes).
• the substituents in the silazane compound may be linear, branched, or cyclic aliphatic groups, and may be saturated or unsaturated.
• saturated or unsaturated linear aliphatic groups having 1 to 4 carbon atoms are preferred, with tetramethyldisilazane (1,1,3,3-tetramethyldisilazane), hexamethyldisilazane (1,1,1,3,3,3-hexamethyldisilazane), 1,3-divinyl-1,1,3,3-tetramethyldisilazane and 1,3-diphenyltetramethyldisilazane being preferred, and hexamethyldisilazane (1,1,1,3,3,3-hexamethyldisilazane) being most preferred.
• cyclic silazane compounds include 2,2,4,4,6,6-hexa-substituted cyclotrisilazane.
• the substituent may be any of linear, branched, and cyclic aliphatic groups, and may be either saturated or unsaturated. Among these, saturated or unsaturated linear aliphatic groups having 1 to 4 carbon atoms are preferred, and examples thereof include 2,2,4,4,6,6-hexamethylcyclotrisilazane and 2,4,6-trimethyl-2,4,6-trivinylcyclotrisilazane.
• the catalyst include catalysts containing metal salts having Lewis acidity.
• Metal salts include triflate salts, nonaflate salts, and trifluoromethanesulfonylimide salts, and more specifically, Sc(OTf) 3 , Y(OTf) 3 , Sm(OTf) 3 , Eu(OTf) 3 , Gd(OTf) 3 , Er(OTf) 3 , Yb(OTf) 3 , Fe(OTf) 3 , In(OTf) 3 , Sn(OTf) 3 , Bi(OTf) 3 , Sc(ONf) 3 , and Sc(ONf) 3.
• Sc(NO 3 ) 3 and BiBr 3 are also included, as well as tetrabutylammonium fluoride and tetrabutylammonium dihydrogen fluoride.
• the metal is preferably at least one selected from the group consisting of Sc, Y, Eu, Er, Yb, Fe, Sn and Bi, and the metal salt is preferably Sc(OTf) 3 .
• This reaction can be carried out in a solvent or without a solvent at 0 to 150°C for 15 minutes to 48 hours.
• solvents include aromatic hydrocarbon solvents such as chlorobenzene, toluene, and fluorobenzene, ether solvents such as tetrahydrofuran and 1,4-dioxane, and halogen solvents such as 1,2-dichloroethane. Chlorobenzene and toluene are particularly preferred, and toluene is the most preferred. Water, alcohol, silanol, etc. may also be added as a reaction promoter.
• the terminal tri-substituted silyl group on the hydroxyalkyloxy group of the side chain is deprotected by reacting with an acid or a base, and converted to a terminal alcohol.
• the acid include inorganic acids such as hydrochloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, 10-camphorsulfonic acid, and hydrogen fluoride-pyridine.
• the base examples include inorganic bases such as tetraalkylammonium fluoride, cesium fluoride, and potassium fluoride in the presence of an alcohol solvent, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, and potassium hydride, as well as hydrates thereof, and metal alkoxides such as lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide.
• an alcohol solvent such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, and potassium hydride, as well as hydrates thereof, and metal alkoxides such as lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide.
• a base to perform deprotection, and it is particularly preferable to act on the base with an alkali metal carbonate or an alkali metal hydrogen carbonate in the presence of a C1-4 alcohol such as methanol or ethanol.
• a deprotection agent for the tri-substituted silyl group is added, and the reaction is carried out at 0 to 100° C. for 15 minutes to 24 hours.
• the ketimine compound of formula (3) obtained by this reaction can be isolated as a solid, and therefore is easy to purify and has good handleability. The isolation and purification can be easily carried out by a means usually adopted in industry, such as washing and recrystallization.
• the ketimine compound of the general formula (3) is reacted with a reducing agent and an Fmoc reagent to obtain a benzylamine compound of the general formula (4).
• reducing agents include metal hydrides such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium borohydride, lithium triethylborohydride, lithium tri(sec-butyl)borohydride, sodium bis(2-ethoxyethoxy)aluminum hydride (hereinafter, SBAH), borane complexes, diisobutylaluminum hydride, and nickel borohydride.
• metal hydrides such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium borohydride, lithium triethylborohydride, lithium tri(sec-butyl)borohydride, sodium bis(2-ethoxyethoxy)aluminum hydride (hereinafter, SBAH), borane complexes, diisobutylaluminum hydride, and nickel borohydride.
• SBAH sodium bis(2-ethoxyethoxy
• the reduction reaction is preferably carried out in an aromatic hydrocarbon solvent such as benzene or toluene, an ether solvent such as tetrahydrofuran, 2-methyltetrahydrofuran, or cyclopentyl methyl ether, or an alcohol solvent such as methanol, ethanol, isopropanol, n-propanol, or n-butanol, or a mixed solvent thereof, at a temperature of 0° C. to 100° C. for 15 minutes to 48 hours.
• aromatic hydrocarbon solvent such as benzene or toluene
• an ether solvent such as tetrahydrofuran, 2-methyltetrahydrofuran, or cyclopentyl methyl ether
• an alcohol solvent such as methanol, ethanol, isopropanol, n-propanol, or n-butanol, or a mixed solvent thereof
• the Fmoc reagent may be any compound capable of introducing a 9-fluorenylmethyloxycarbonyl (Fmoc) group, and may include fluorenylmethyl halogenoformate, Fmoc-OSu, 9-fluorenylmethyl carbamate, 9-fluorenylmethyl carbazate, 1-(Fmoc-oxy)benzotriazole, 9-fluorenylmethylpentafluorophenyl carbonate, or Fmoc-Amox described in Org. Process Res. Dev. 2017, 21(10), 1533-41.
• the Fmoc reaction can be carried out immediately after the reduction reaction, and there is no need to change the reaction solvent, etc.
• An Fmoc reagent is added and the reaction is carried out at 0 to 100° C. for 10 minutes to 3 hours.
• the benzylamine compound of formula (4) obtained by this reaction can be isolated as a solid, and therefore can be easily purified and handled. The isolation and purification can be easily carried out by a means usually adopted in industry, such as washing and recrystallization.
• An alkylsilyloxy-alkyloxybenzylamine compound of general formula (5) can be obtained by reacting the benzylamine compound of general formula (4) with an alkylsilylating agent.
• the alkylsilylating agent used in this reaction is a silylating agent having 1 to 3 alkylsilyl groups, and is preferably a silylating agent having an alkylsilyl group represented by the following formulas (7) to (17), in which * indicates the bond point with the oxygen atom of the hydroxyl group.
• R 7 , R 8 and R 9 are the same or different and each represents a linear or branched alkyl group having 1 to 6 carbon atoms, or an aryl group which may have a substituent;
• R 10 represents a single bond or a linear or branched alkylene group having 1 to 3 carbon atoms, and R 11 , R 12 and R 13 each represent a linear or branched alkylene group having 1 to 3 carbon atoms).
• Examples of the linear or branched alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group, etc.
• an alkyl group having 1 to 4 carbon atoms is more preferred, and a methyl group, a tert-butyl group, and an isopropyl group are even more preferred.
• aryl group which may have a substituent examples include an aryl group having 6 to 10 carbon atoms, and specific examples thereof include a phenyl group and a naphthyl group which may be substituted with an alkyl group having 1 to 3 carbon atoms. Of these, a phenyl group is more preferred.
• alkylsilylating agents include alkylsilyl halides, alkylsilylimidazoles, alkylsilylbenztriazoles, and alkylsilyltrifluoromethanesulfonyl.
• halogen atoms include bromine atoms, chlorine atoms, and iodine atoms.
• the reaction of the benzylamine compound of the general formula (4) with an alkylsilylating agent is preferably carried out in a solvent in the presence of a base.
• the reaction solvent to be used include amide solvents such as DMF, diethylformamide, NMP, and dimethylacetamide, urea solvents such as DMI, halogenated solvents such as methylene chloride, ethers such as tetrahydrofuran and 2-methyltetrahydrofuran, ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, polar solvents such as acetonitrile, and various mixed solvents of these.
• amide solvents and urea solvents are preferred, and DMF, NMP, and DMI are more preferred.
• the base include inorganic salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, potassium hydride, and hydrates thereof, metal alkoxides such as lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide, and organic bases such as 1,8-diazabicyclo[5.4.0]-7-undecene, diisopropylethylamine, triethylamine, dimethylaniline, and imidazole.
• inorganic salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, potassium hydride, and hydrates thereof
• a preferred base is imidazole.
• the reaction may be carried out at a temperature of 0° C. to 150° C., preferably 20° C. to 100° C., and more preferably 30° C. to 50° C. The reaction is preferably carried out for 15 minutes to 48 hours.
• a small amount of a silyl-based compound derived from the alkylsilylation agent may be by-produced in the reaction mixture. In that case, it is preferable to remove the silyl-based compound by liquid-liquid separation.
• the target alkylsilyloxy-substituted benzylamine compound (5) dissolves in an alkane solvent such as heptane.
• liquid-liquid separation it is preferable to carry out liquid-liquid separation using a polar solvent such as acetonitrile, methanol, DMF, or dimethyl sulfoxide. It is preferable to use a mixed solvent of the polar solvent with water, and a combination of acetonitrile and water is particularly preferable.
• a polar solvent such as acetonitrile, methanol, DMF, or dimethyl sulfoxide
• 1 to 5 of R 1c to R 5c represent an alkyloxy group having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms.
• the structure of this alkyloxy group having 1 to 29 carbon atoms substituted with an alkylsilyloxy group is represented by the following formula.
• R E represents a straight or branched alkyl group having 1 to 16 carbon atoms
• A represents one of the formulas (7) to (17).
• * represents the bonding site with a carbon atom on the parent nucleus of the benzoyl skeleton, diphenyl ketone skeleton, or xanthone skeleton.
• the number of carbon atoms of the alkyloxy group is 1 to 29, which is the total value of the number of carbon atoms in the hydroxyalkyloxy chain having 1 to 16 carbon atoms derived from the halogenated alcohol and the number of carbon atoms contained in R 10 , R 11 , R 12 and R 13 in the silylating agents represented by formulas (7) to (17).
• the alkyloxy group having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups preferably has 1 to 4 carbon atoms, more preferably 2 to 4 carbon atoms, even more preferably 2 to 3 carbon atoms, and even more preferably 2 carbon atoms.
• the remaining group may be a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, with a hydrogen atom, a halogen atom, or an alkyl group having 1 to 4 carbon atoms being preferred, and a hydrogen atom being more preferred.
• R C is a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a group represented by the following formula:
• R 1b to R 5b represent an alkyloxy group having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups, and the remainder represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or when R C represents the structure of this formula, R 5c may form an ether bond (—O—) together with R 5c in formula (5). Note that * represents the bonding site with R C.
• the formula (I) represents a group represented by the formula (I).
• alkyloxy group having 1 to 29 carbon atoms and substituted with 1 to 3 alkylsilyloxy groups includes the same as the alkylsilyl group described above.
• other substituents of R 1c to R 5c are preferably the same as those of R 1b to R 5b .
• the alkylsilyloxylation reaction gives an alkylsilyloxy-alkyloxybenzylamine compound of the general formula (5).
• the alkylsilyloxy-alkyloxybenzylamine compound of the general formula (5) obtained by this reaction can be isolated as a solid, and therefore is easy to purify and has good handleability. The isolation and purification can be easily carried out by a means usually adopted in industry, such as washing and recrystallization.
• the alkylsilyloxy-alkyloxybenzylamine compound of the general formula (5) is useful as a support for liquid phase peptide synthesis, as described in Patent Documents 1 to 3.
• the benzoyl compound represented by general formula (2), the ketimine compound represented by general formula (3), the benzylamine compound represented by general formula (4), and the alkylsilyloxy-alkyloxybenzylamine compound represented by general formula (5) can all be obtained in solid form.
• solid refers to both a substance having a crystalline structure and an amorphous-like solid, but when each compound has the following structure, it is more likely to be obtained as a solid with a structure closer to a crystalline structure, and it is more likely to function usefully as a support (Tag) for liquid-phase peptide synthesis.
• R 1a to R 5a are hydroxyl groups and the remainder are hydrogen atoms. It is particularly preferred that R 3a is a hydroxyl group and the remainder are hydrogen atoms.
• R A is a group represented by the following formula:
• R 1a to R 5a are hydroxy groups and the remainder are hydrogen atoms. It is particularly preferred that R 3a is a hydroxy group and the remainder are hydrogen atoms (note that * indicates the bonding site with R A ).) It is preferable that the group is represented by the following formula:
• R 1b to R 5b are hydroxyalkyloxy groups having 1 to 16 carbon atoms, with the remainder being hydrogen atoms.
• R 3a is a hydroxyalkyloxy group having 1 to 16 carbon atoms, with the remainder being hydrogen atoms.
• the number of carbon atoms in the hydroxyalkyloxy group is more preferably 4 to 16, even more preferably 8 to 16, even more preferably 10 to 16, and most preferably 11 to 16.
• R B is a group represented by the following formula:
• R 1b to R 5b are hydroxyalkyloxy groups having 1 to 16 carbon atoms, and the remainder are hydrogen atoms. It is particularly preferable that R 3b is a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder are hydrogen atoms.
• the number of carbon atoms in the hydroxyalkyloxy group is more preferably 4 to 16, further preferably 8 to 16, further preferably 10 to 16, and most preferably 11 to 16. Note that * indicates the bonding site with R B.
• the group is represented by the following formula:
• R 1c to R 5c are alkyloxy groups having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups, and the remainder is a hydrogen atom.
• R 3b is an alkylsilyloxy group having 1 to 29 carbon atoms substituted with one alkylsilyloxy group, and the remainder is a hydrogen atom.
• the alkylsilyloxy group is synthesized with an alkylsilylating agent represented by the formula (7).
• R 7 , R 8 , and R 9 are linear or branched alkyl groups having 1 to 6 carbon atoms, or a phenyl group;
• R C is expressed by the following formula:
• R 1c to R 5c represent an alkyloxy group having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups, and the remainder is a hydrogen atom.
• R 3b represents an alkylsilyloxy group having 1 to 29 carbon atoms substituted with one alkylsilyloxy group, and the remainder is a hydrogen atom.
• the alkylsilyloxy group is synthesized with an alkylsilylating agent represented by formula (7).
• R 7 , R 8 , and R 9 are preferably a linear or branched alkyl group having 1 to 6 carbon atoms, or a phenyl group. Note that * indicates a bonding site with R C. ) It is preferable that the group is represented by the following formula:
• the reaction solution was filtered, and the residue was washed with 150 mL of heptane.
• the filtrate was separated, and 71 mL of heptane was added to the obtained heptane layer, and the mixture was washed with 71 mL of DMF.
• TIPS2-Dpm-OH was in the form of a viscous oil.
• Fmoc-D2-STag 1.00g (1.15mmol) of TIPS2-Dpm-OH and 0.29g (1.25mmol) of Fmoc-NH2 were dissolved in 6.5mL of toluene. 0.04g (0.32mmol) of oxalic acid dihydrate was added, and the mixture was heated to 85°C and stirred for 4 hours. 10mL of heptane and 10mL of 90% aqueous methanol were added and washed by separation. 5mL of 5% aqueous sodium bicarbonate was added to the upper layer obtained and washed by separation. 10mL of 90% aqueous methanol was added to the upper layer obtained and washed by separation three times.
• the upper layer obtained was concentrated under reduced pressure.
• the residue obtained was dissolved in 2mL of tetrahydrofuran, and the tetrahydrofuran solution was added dropwise to 20mL of methanol under stirring, and the mixture was stirred for 30 minutes after the addition.
• the process liquid in which the target product had crystallized was filtered, and the residue was washed with methanol. After drying under reduced pressure, 0.94 g (yield 74.9%) of Fmoc-D2-STag was obtained.
• the obtained Fmoc-D2-STag was a solid.
• TIPS2-Dpm-OH was a compound that was difficult to store for a long time. Furthermore, in step (1-d), a side reaction in which the TIPS group was eliminated by an acid catalyst also occurred, and in the comparative example, 0.2% of the dealkylsilyl was generated. Both side reactions caused a decrease in the yield of Fmoc-D2-STag.
• HO-Dpm-C O
• HO-Dpm-C NH
• HO-Dpm-C-NHFmoc HO-Dpm-C-NHFmoc
• Fmoc-D2-STag refer to the structures in the formula.
• the slurry was filtered, and the filter cake was washed once with 0.56L of water and once again with 0.56L of water. After washing, the filter cake was collected, 1.78L of methanol was added, and stirred at 60°C for 1 hour. After cooling to 30° C., the slurry was filtered, and the residue was washed once with 0.56 L of methanol and once again with 0.56 L of methanol. It was then dried under reduced pressure at 40° C. to obtain 474 g of HO-Dpm-C ⁇ O (yield: 97.6%). The obtained HO-Dpm-C ⁇ O was a solid.
• the reaction solution was cooled to 30°C, 0.83L of methanol and 345g (2.49mol) of potassium carbonate were added, and the mixture was stirred at 30°C for 3 hours. 1.84L of water was added, and the mixture was stirred at 50°C for 1 hour.
• the slurry was filtered, and the residue was washed once with 0.92L of water and once again with 0.92L of water. After washing, the residue was collected, and 1.84L of 50% aqueous methanol was added, and the mixture was stirred at 50°C for 1 hour. After cooling to 30°C, the slurry was filtered, and the residue was washed once with 0.92L of 50% aqueous methanol, and once again with 0.92L of 50% aqueous methanol. After washing, the residue was collected, 1.84L of acetonitrile was added, and the mixture was stirred at 50°C for 1 hour.
• the slurry was filtered and the residue was washed once with 2.9L of 50% aqueous methanol. After washing, the residue was collected, 4.97L of 50% aqueous methanol was added, and the mixture was stirred at 40°C for 1 hour. After cooling to 30°C, the slurry was filtered, and the residue was washed once with 2.90L of 50% aqueous methanol, and once again with 2.90L of 50% aqueous methanol. After washing, the residue was collected, 4.97L of acetonitrile was added, and the mixture was stirred at 40°C for 1 hour.
• the mixture was dried under reduced pressure at 40° C., and 4.0 L of acetonitrile was added to the resulting residue, and the mixture was stirred at 25° C. for 1 hour.
• the slurry was filtered, and the residue was washed with 2.0 L of acetonitrile.
• the mixture was then dried under reduced pressure at 40° C., and 521 g of Fmoc-D2-STag (yield 70.9%) was obtained.
• the resulting Fmoc-D2-STag was a solid.
• the content of the compound derived from 11-bromo-1-undecanol contained in Fmoc-D2-STag was 0.03 wt%. Furthermore, unlike the comparative example, all intermediates could be obtained in solid form, which made it possible to roughly purify the intermediates by solid-liquid separation, and the purity of the final target Fmoc-D2-STag could be improved.
• the production method of the present invention was able to significantly reduce the amount of HO-(CH 2 ) 11 -OTIPS, an impurity that is difficult to separate, compared to the conventional method.
• crude purification by solid-liquid separation became possible.
• the production method of the present application was able to significantly reduce the amount of HO-(CH 2 ) 11 -OTIPS, making it possible to obtain alkylsilyloxy-substituted benzylamine compounds in an industrially advantageous manner. Furthermore, the production method of the present application also solved the problem of intermediates being decomposed by an acid catalyst, which was a problem in the conventional method.
• Br--(CH 2 ) 11 --O-TIPS used in the conventional method is an unstable compound that gradually decomposes at room temperature, and the method of the present invention has the advantage of avoiding the use of an unstable raw material.

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