Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
  • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
  • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
• • 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
• • 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
  • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
• • 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 method for producing an alkylsilyloxy-substituted benzyl compound.
• liquid-phase peptide synthesis carrier a liquid-phase peptide synthesis carrier (Tag) has been reported. Since the carrier for liquid-phase peptide synthesis (Tag) is a highly hydrophobic compound, by binding highly hydrophilic amino acids, peptides or amino acid amides (hereinafter sometimes referred to as amino acids, etc.) to this carrier, organic solvent The solubility in can be greatly improved.
• the amino acid or the like bound to the carrier is dissolved in the organic layer, and unnecessary components such as surplus raw material amino acids used in the peptide elongation reaction and its By dissolving in the aqueous layer the decomposition products and compounds produced as by-products when the protective groups of the starting amino acids are deprotected, there is an advantage that the amino acids bound to the carrier can be simply purified by liquid-liquid separation.
• an object of the present invention is to provide an industrial process for producing an alkylsilyloxy-substituted benzyl compound in which the reaction steps are easy to control.
• the present inventors introduced a hydroxyalkyloxy group to a compound having a benzoyl skeleton, a diphenylketone skeleton (benzophenone skeleton) or a xanthone skeleton, and then introduced an alkylsilyl group to the hydroxyl group.
• Br--(CH 2 ) 11 --O--TIPS which is a raw material which has caused problems of poor stability and difficulty in separating from the intermediate compound in the conventional method.
• the reaction process can be easily controlled, and the raw materials or decomposition products of the raw materials can be easily removed.
• the present inventors have found that an alkylsilyloxy-substituted benzyl compound can be industrially advantageously obtained, and have completed the present invention.
• the term “solid” refers to both those having a crystalline structure and amorphous-like solids.
• 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 alkyl group having 1 to 4 carbon atoms. showing 4 alkoxy groups;
• R B is a hydrogen atom, a hydroxy group, an alkoxy group having 1 to 6 carbon atoms or the following formula
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder are hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or An alkoxy group or when R B has the structure of this formula, R 5b may combine with R 5b in formula (3) to form an ether bond (--O--). indicates the binding site with RB .
• R 5b may combine with R 5b in formula (3) to form an ether bond (--O--). indicates the binding site with RB .
• FIG.) shows the group represented by General formula (5) characterized by reacting an alkyl silylating agent with a benzoyl compound represented by
• 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 are hydrogen atoms, halogen atoms, 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 hydroxy group, an alkoxy group having 1 to 6 carbon atoms or 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 are hydrogen atoms, halogen atoms, or 4 alkyl group or alkoxy group having 1 to 4 carbon atoms, or when R C has the structure of this formula, R 5c is an ether bond (—O -), where * indicates a binding site with R C ). shows the group represented by A method for producing an alkylsilyloxy-substituted benzoyl compound represented by [2] 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 alkyl group having 1 to 4 carbon atoms. showing 4 alkoxy groups;
• R B is a hydrogen atom, a hydroxy group, an alkoxy group having 1 to 6 carbon atoms or the following formula
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder are hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or represents an alkoxy group, or when R B represents the structure of this formula, R 5b may form an ether bond (—O—) together with R 5b in formula (3)) represents a group represented by Note that * indicates a binding site with RB .
• An alkyl silylating agent is reacted with a benzoyl compound represented by the general formula (5)
• 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 are hydrogen atoms, halogen atoms, 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 hydroxy group, an alkoxy group having 1 to 6 carbon atoms or 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 are hydrogen atoms, halogen atoms, or 4 alkyl group or C 1-4 alkoxy group), or when R C shows the structure of this formula, R 5c is the same as R 5c in formula (5) may form an ether bond (-O-). Note that * indicates a binding site with R C . ) (6), characterized by obtaining an alkylsilyloxy-substituted benzoyl compound represented by and then reducing the alkylsilyloxy-substituted benzoyl compound
• RD is a hydrogen atom or 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 are hydrogen atoms, halogen atoms, or 4 alkyl group or C 1-4 alkoxy group, or when R D shows the structure of this formula, R 5c together with R 5c in formula (6) is an ether bond (-O -), where * indicates the binding site with R D ). shows the group represented by A method for producing an alkylsilyloxy-substituted benzyl compound represented by [3]
• the alkylsilyloxy-substituted benzoyl compound represented by the general formula (3) is represented by the general formula (1)
• 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 hydroxy group, an alkoxy group having 1 to 6 carbon atoms or 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 has the structure of this formula, R 5a may combine with R 5a in formula (1) to form an ether bond (--O--). Note that * indicates a binding site with RA .
• 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 alkyl group having 1 to 4 carbon atoms. showing 4 alkoxy groups;
• R B is a hydrogen atom, a hydroxy group, an alkoxy group having 1 to 6 carbon atoms or the following formula
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder are hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or An alkoxy group or when R B has the structure of this formula, R 5b may combine with R 5b in formula (3) to form an ether bond (--O--). indicates the binding site with RB .) shows the group represented by Benzoyl compound represented by.
• the method of the present invention there is no need to use raw materials that have caused problems of poor stability and difficulty in separating from intermediate compounds in conventional methods.
• the intermediate compound is solid, the reaction process can be easily controlled, and the raw materials or decomposition products of the raw materials can be easily removed, and the alkylsilyloxy-substituted benzyl compound can be obtained industrially advantageously.
• 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 hydroxy group, an alkoxy group having 1 to 6 carbon atoms or 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 R A represents the structure of this formula
• R 5a may form an ether bond (--O--) together with R 5a in formula (1), and * indicates the bonding site with R A show.) showing a group represented by; 1 to 5 of R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder are hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms or alkoxy groups having 1 to 4 carbon atoms. indicating a group; R B is a hydrogen atom, a hydroxy group, an alkoxy group having 1 to 6 carbon atoms or the following formula
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder are hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or An alkoxy group or when R B has the structure of this formula, R 5b may combine with R 5b in formula (3) to form an ether bond (--O--). indicates the binding site with RB .) showing a group represented by; 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 are hydrogen atoms, halogen atoms, or 1 to 1 carbon atoms. 4 alkyl group or an alkoxy group having 1 to 4 carbon atoms; R C is a hydrogen atom, a hydroxy group, an alkoxy group having 1 to 6 carbon atoms or 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 are hydrogen atoms, halogen atoms, or 4 alkyl group or alkoxy group having 1 to 4 carbon atoms, or when R C has the structure of this formula, R 5c is an ether bond (—O -), where * indicates a binding site with R C ). showing a group represented by; RD is a hydrogen atom or 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 are hydrogen atoms, halogen atoms, or 4 alkyl group or C 1-4 alkoxy group, or when R D shows the structure of this formula, R 5c together with R 5c in formula (6) is an ether bond (-O -), where * indicates the binding site with R D ). shows the group represented by
• the present invention provides an alkylsilyloxy-alkyloxybenzoyl compound represented by the general formula (5), characterized by reacting the hydroxyalkyloxybenzoyl compound represented by the general formula (3) with an alkylsilylating agent. manufacturing method. This structure is indicated when the term "alkylsilyloxy-substituted benzoyl compound" is used in the specification.
• the hydroxyalkyloxybenzoyl compound represented by the general formula (3) is reacted with an alkylsilylating agent to obtain an alkylsilyloxy-alkyloxybenzoyl compound represented by the general formula (5), and then A method for producing an alkylsilyloxy-alkyloxybenzyl compound represented by the general formula (6), characterized by reducing the alkylsilyloxy-alkyloxybenzoyl compound.
• This structure is indicated when the term "alkylsilyloxy-substituted benzyl compound" is used in the specification.
• the hydroxyalkyloxybenzoyl compound represented by the general formula (3) is preferably obtained by reacting the hydroxybenzoyl compound represented by the general formula (1) with a halogenated alcohol. Moreover, since the hydroxyalkyloxybenzoyl compound represented by the general formula (3) is a novel compound, the present invention provides the hydroxyalkyloxybenzoyl compound.
• 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.
• the number of hydroxy groups is preferably 1 to 4, more preferably 2 to 4, still more preferably 2 to 3, and even more preferably 2.
• the remaining group includes a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, and a hydrogen atom, a halogen atom, or an alkyl group having 1 to 4 carbon atoms is preferable. , more preferably a hydrogen atom.
• the alkyl group having 1 to 4 carbon atoms includes methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group and the like.
• alkoxy groups having 1 to 4 carbon atoms include methoxy, ethoxy, n-propyloxy, isopropyloxy and n-butyloxy groups.
• Halogen atoms include chlorine, bromine, fluorine and iodine atoms.
• R A is a hydrogen atom, a hydroxy group, an alkoxy group having 1 to 6 carbon atoms or 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 R A represents the structure of this formula
• R 5a may form an ether bond (--O--) together with R 5a in formula (1), and * indicates the bonding site with R A show.
• Alkoxy groups having 1 to 6 carbon atoms include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, n-pentyl and n-hexyl groups.
• an alkoxy group having 1 to 5 carbon atoms is preferable, and an alkoxy group having 1 to 4 carbon atoms is more preferable.
• the groups represented by R 1a to R 5a the same groups as described above are preferred.
• a benzoyl compound of general formula (3) is obtained by reacting a compound of general formula (1) with a halogenated alcohol (2) (described as Hal-alcohol in the formula).
• Halogenated alcohols include halogenated alcohols having 1 to 16 carbon atoms, preferably halogenated alcohols having 2 to 16 carbon atoms, more preferably halogenated alcohols having 4 to 16 carbon atoms, and still more preferably. is a halogenated alcohol having 6 to 16 carbon atoms, more preferably a halogenated alcohol having 8 to 16 carbon atoms.
• Halogen atoms include bromine, chlorine, iodine and fluorine atoms, with bromine, chlorine and iodine atoms being preferred.
• Alcohols include straight or branched chain alcohols.
• reaction of the compound of general formula (1) and halogenated alcohol (2) is preferably carried out in the presence of a base in a solvent.
• Reaction solvents used include dimethylformamide (hereinafter referred to as DMF), diethylformamide, 1-methyl-2-pyrrolidone (hereinafter referred to as NMP), amide solvents such as dimethylacetamide, and 1,3-dimethyl-2-imidazolidinium.
• Urea solvents such as non (hereinafter referred to 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, methanol, ethanol, isopropanol, n alcoholic solvents such as -propanol and n-butanol; polar solvents such as acetonitrile; and mixed solvents of these.
• amide-based solvents and urea-based solvents are preferred, and DMF and DMI are more preferred.
• inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, potassium hydride, and their hydrates, lithium Metal alkoxides such as methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, 1,8-diazabicyclo[5.4.0]-7-undecene, diisopropylethylamine, triethylamine, dimethylaniline , and imidazole.
• 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, 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 (3) obtained by this reaction can be isolated as a solid, so it is easy to purify and easy to handle. Isolation and purification can be easily carried out by means such as washing, recrystallization, and the like, which are usually industrially applicable.
• R 1b to R 5b in general formula (3) represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder are hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or It represents an alkoxy group having 1 to 4 carbon atoms.
• the number of hydroxyalkyloxy 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 includes a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, and a hydrogen atom, a halogen atom, or an alkyl group having 1 to 4 carbon atoms is preferable. , more preferably a hydrogen atom.
• R B is a hydrogen atom, a hydroxy group, an alkoxy group having 1 to 6 carbon atoms or the following formula
• R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder are hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or An alkoxy group or when R B has the structure of this formula, R 5b may combine with R 5b in formula (3) to form an ether bond (--O--). indicates the binding site with RB .) represents a group represented by Here, the groups such as hydroxyalkyloxy groups having 1 to 16 carbon atoms are preferably the same as the above R 1b to R 5b .
• 1 to 5 of R 1b to R 5b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder are hydrogen atoms, halogen atoms, and carbon atoms. an alkyl group of 1 to 4 or an alkoxy group of 1 to 4 carbon atoms; R B is a hydrogen atom, a hydroxy group, an alkoxy group having 1 to 6 carbon atoms or the following formula
• R 1b to R 4b represent a hydroxyalkyloxy group having 1 to 16 carbon atoms, and the remainder are hydrogen atoms, halogen atoms, alkyl groups having 1 to 4 carbon atoms, or
• R B represents the structure of this formula
• R 5b forms an ether bond (--O--) together with R 5b in formula (3), where * represents R B and indicates the binding site of It may be a compound showing a group represented by.
• the alkyl silylating agent (4) used in this reaction is a silylating agent having 1 to 3 alkylsilyl groups, and is a silyl having an alkylsilyl group represented by the following formulas (7) to (17). agents are preferred.
• * in the figure indicates the bonding point of the hydroxy group with the oxygen atom.
• R 7 , R 8 and R 9 are the same or different and represent 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
• the linear or branched alkyl group having 1 to 6 carbon atoms includes methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group and tert-butyl group. , n-pentyl group, n-hexyl group and the like. Among them, an alkyl group having 1 to 4 carbon atoms is more preferable, and a methyl group, a tert-butyl group and an isopropyl group are more preferable.
• the aryl group which may have a substituent includes an aryl group having 6 to 10 carbon atoms, specifically a phenyl group and a naphthyl group optionally substituted by an alkyl group having 1 to 3 carbon atoms. etc. Among these, a phenyl group is more preferable.
• Alkyl silylating agents include alkylsilyl halides, alkylsilylimidazoles, alkylsilylbenztriazoles, alkylsilyltrifluoromethanesulfonyl and the like.
• the halogen atom includes a bromine atom, a chlorine atom and an iodine atom.
• reaction between the benzoyl compound of general formula (3) and the alkyl silylating agent (4) is preferably carried out in a solvent in the presence of a base.
• reaction solvents 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, and acetone. , methyl ethyl ketone, methyl isobutyl ketone, polar solvents such as acetonitrile, and various mixed solvents thereof.
• Bases 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 their hydrates, lithium Metal alkoxides such as methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, 1,8-diazabicyclo[5.4.0]-7-undecene, diisopropylethylamine, triethylamine, dimethyl Organic bases such as aniline and imidazole are included.
• 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 their hydrates
• lithium Metal alkoxides such as methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide,
• Preferred bases include imidazole.
• the reaction may be carried out at a temperature of 0°C to 150°C, preferably 20°C to 100°C, more preferably 50°C to 80°C. Also, the reaction is preferably carried out for 15 minutes to 48 hours. In this reaction, a slight amount of silyl-based compound derived from the alkyl silylating agent may be by-produced in the reaction mixture. In that case, it is preferable to remove the silyl compound by liquid-liquid separation.
• the target alkylsilyloxy-substituted benzoyl compound (5) dissolves in an alkane solvent such as heptane.
• liquid-liquid separation is preferably carried out using a polar solvent such as acetonitrile, methanol, DMF or dimethylsulfoxide. It is preferable to use a mixed solvent of two or more polar solvents, and a combination of acetonitrile and methanol is particularly preferable.
• a polar solvent such as acetonitrile, methanol, DMF or dimethylsulfoxide. It is preferable to use a mixed solvent of two or more polar solvents, and a combination of acetonitrile and methanol is particularly preferable.
• R 1c to R 5c in general formula (5) represent an alkyloxy group having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups, the remainder being hydrogen atoms; It represents 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 the alkyloxy group having 1 to 29 carbon atoms substituted with this alkylsilyloxy group is represented by the following formula.
• R E represents a linear or branched alkyl group having 1 to 16 carbon atoms
• A represents formulas (7) to (17).
• * is a benzoyl skeleton or diphenyl ketone skeleton, which is a mother nucleus. , indicates the bonding site with the carbon atom on the xanthone skeleton.
• the alkyloxy group having 1 to 29 carbon atoms is the number of carbon atoms in the hydroxyalkyloxy chain having 1 to 16 carbon atoms derived from the halogenated alcohol (2) and the silylating agent represented by formulas (7) to (17). Of these, it is the total number of carbon atoms contained in R 10 , R 11 , R 12 and R 13 .
• the alkyloxy group having 1 to 29 carbon atoms substituted with the 1 to 3 alkylsilyloxy groups is preferably 1 to 4, more preferably 2 to 4, even more preferably 2 to 3, and 2 is even more preferable.
• the remaining group includes a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, and a hydrogen atom, a halogen atom, or an alkyl group having 1 to 4 carbon atoms is preferable. , more preferably a hydrogen atom.
• R C is a hydrogen atom, a hydroxy group, an alkoxy group having 1 to 6 carbon atoms or 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 are hydrogen atoms, halogen atoms, or 4 alkyl group or alkoxy group having 1 to 4 carbon atoms, or when R C has the structure of this formula, R 5c is an ether bond (—O -), where * indicates a binding site with R C ).
• R 5c is an ether bond (—O -), where * indicates a binding site with R C ).
• R 5c is an ether bond (—O -), where * indicates a binding site with R C ).
• R 1c represents a group represented by
• examples of the alkyloxy group having 1 to 29 carbon atoms substituted with 1 to 3 alkylsilyloxy groups are the same as the above alkylsilyl groups.
• other substituents of R 1c to R 5c are preferably the same as those of R 1b to R 5b .
• the alkylsilyloxy-alkyloxybenzyl compound of general formula (6) is obtained.
• the reduction reaction is not particularly limited as long as it can reduce a carbonyl group, but a method using a reducing agent is preferred.
• reducing agents include iron (II) ions, lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium bis(2-ethoxyethoxy)aluminum hydride (hereinafter referred to as SBAH), borane, diisobutylaluminum hydride, and the like. is mentioned.
• the reduction reaction can be carried out using aromatic hydrocarbon solvents such as benzene and toluene, ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran and cyclopentyl methyl ether, and alcohol solvents such as methanol, ethanol, isopropanol, n-propanol and n-butanol. , or a mixed solvent thereof at a temperature of 0° C. to 100° C. for 15 minutes to 48 hours.
• aromatic hydrocarbon solvents such as benzene and toluene
• ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran and cyclopentyl methyl ether
• alcohol solvents such as methanol, ethanol, isopropanol, n-propanol and n-butanol.
• a mixed solvent thereof at a temperature of 0° C. to 100° C. for 15 minutes to 48 hours.
• Alkylsilyloxy-alkyloxybenzyl compounds of general formula (6) are useful as carriers for liquid-phase peptide synthesis, as described in Patent Documents 1-3. Also, the hydroxy group in formula (6) can be converted to a halogenocarbonyloxy group, an active ester-type carbonyloxy group, an active ester-type sulfonyloxy group, or the like.
• the above heptane and DMF separation washes were carried out one more time.
• 71 mL of heptane was added to the obtained heptane layer, and the layer was separated and washed once with 71 mL of 1M aqueous hydrochloric acid solution, once with 71 mL of 5% aqueous sodium hydrogen carbonate solution, and once with 71 mL of distilled water.
• 71 mL of heptane was added to the obtained heptane layer, and the layer was separated and washed once with 71 mL of DMF and once with 71 mL of acetonitrile.
• TIPS2-Dpm-OH TIPS2-Dpm-C O 0.81 g (0.93 mmol) was dissolved in a mixed solution of THF (anhydrous) 7.1 mL and methanol 0.36 mL, sodium borohydride 42 mg (1.12 mmol) was added, Stirred for .5 hours. 0.89 mL of 1M aqueous hydrochloric acid solution was added to the reaction solution to stop the reaction, 20.3 mL of cyclopentyl methyl ether was added, and 6.1 mL of 1 M aqueous hydrochloric acid solution was added once, 6.1 mL of 5% aqueous sodium hydrogen carbonate solution was added once, and distilled water was added.
• 94 mL of SBAH (70% toluene solution) was added dropwise over 30 minutes, and the mixture was further stirred under ice cooling for 2 hours.
• 584 mL of a 30% sodium potassium tartrate aqueous solution was added dropwise, and the mixture was further stirred for 1 hour.
• the mixture was warmed to room temperature, transferred to a separatory funnel with 150 mL of toluene, and the upper layer was recovered. Concentration under reduced pressure gave TIPS2-Dpm-OH 145 g (yield 99%).
• the amount of HO-(CH 2 ) 11 -OTIPS contained as an impurity in TIPS2-Dpm-OH was analyzed by the same method as in Comparative Example 1. HO-(CH 2 ) 11 -OTIPS contained in TIPS2-Dpm-OH was 1.6% by weight.
• SBAH 50% toluene solution
• 4.0 mL of a 30% sodium potassium tartrate aqueous solution was added dropwise, and the mixture was further stirred for 1 hour. After raising the temperature to room temperature, the mixture was transferred to a separatory funnel and the upper layer was collected. The resulting upper layer was dried over anhydrous magnesium sulfate and then filtered. The resulting solution was concentrated under reduced pressure to obtain 1.0 g (quant.) of TIPS2-Dpm-OH.
• the amount of HO-(CH 2 ) 11 -OTIPS contained as an impurity in TIPS2-Dpm-OH was analyzed by the same method as in Comparative Example 1. HO-(CH 2 ) 11 -OTIPS contained in TIPS2-Dpm-OH was below the detection limit.
• an organic solvent such as methanol that has a high dissolving power for 11-bromo-1-undecanol.
• the purity of the crude TIPS2-Dpm-OH, which is the final target product could be improved.
• HO-(CH 2 ) 11 -OTIPS contained in the target TIPS2-Dpm-OH was 1.6% by weight, which was lower than in Comparative Example 1.
• the amount of HO--( CH.sub.2 ) .sub.11 --OTIPS which is an impurity that is difficult to separate, can be significantly reduced in the production method of the present invention compared to the conventional method. Since it is difficult to liquid-liquid separate HO-(CH 2 ) 11 -OTIPS by conventional methods, it is necessary to further refine the resulting HO-(CH 2 ) 11 -OTIPS by column chromatography or the like. there were. Thus, it has been difficult to mass-produce alkylsilyloxy-alkyloxybenzyl compounds on an industrial scale by conventional methods.
• the production method of the present application can greatly reduce the amount of HO--(CH 2 ) 11 --OTIPS mixed in, making it possible to industrially obtain an alkylsilyloxy-substituted benzyl compound.
• 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 avoids using unstable raw materials. There is also the advantage of
• TIPS2-B-CHO and TIPS2-B-OH refer to structures in the figure.
• the above heptane and DMF separation washes were carried out one more time. 8.2 mL of heptane was added to the obtained heptane layer, and the layer was separated and washed once with 8.2 mL of 1M hydrochloric acid aqueous solution, once with 8.2 mL of 5% aqueous sodium hydrogen carbonate solution, and once with 8.2 mL of distilled water. 8.2 mL of heptane was added to the obtained heptane layer, and the layer was separated and washed with 8.2 mL of DMF.
• residue A was subjected to silica gel column chromatography, and Br-(CH 2 ) 11 -O-TIPS and its HO--(CH 2 ) 11 --O--TIPS, which is a decomposed product, was removed.
• TIPS2-B-OH TIPS2-B-CHO 0.49 g (0.62 mmol) was dissolved in a mixed solution of THF (anhydrous) 4.7 mL, methanol 0.24 mL, cooled to 5 ° C., sodium borohydride 28 mg (0.75 mmol) Add and stir for 1 hour. 0.59 mL of 1M hydrochloric acid aqueous solution was added to the reaction solution to terminate the reaction, 12.3 mL of cyclopentyl methyl ether was added, 3.7 mL of 1M aqueous hydrochloric acid solution was added three times, 3.7 mL of 5% aqueous sodium hydrogen carbonate solution was added once, and distilled water was added.
• HO2-B-CO 2 Me and TIPS2-B-CO 2 Me indicate the structures in the formulas.
• the filtered solid was suspended in 4.5 L of acetonitrile and stirred at room temperature for 2 hours. The solid was filtered and washed with acetonitrile. The resulting solid was dried under reduced pressure to obtain 814 g of HO2-B-CO 2 Me (yield 90%).
• TIPS2-B- CO2Me 813 g (1.60 mol) of HO2-B-CO 2 Me and 489 g (7.18 mol) of imidazole were dissolved in 4872 mL of DMF, and after adding 975 mL (4.60 mol) of TIPS-Cl, the mixture was stirred at room temperature for 1.5 hours. 570 mL of methanol was added and stirred for 1.5 hours. Further, 5690 mL of distilled water and 4880 mL of heptane were added, stirred at room temperature for 15 minutes, allowed to stand, and the lower layer was discarded.
• TIPS2-B-OH 844 g (1.03 mol) of TIPS2-B-CO 2 Me was dissolved in 3282 mL of toluene and cooled with ice under a nitrogen stream. 445 mL of SBAH (70% toluene solution) was added dropwise over 30 minutes, and the mixture was further stirred for 30 minutes under ice cooling. 3282 mL of a 30% sodium potassium tartrate aqueous solution was added dropwise, and the mixture was further stirred for 1 hour. After raising the temperature to room temperature and separating the layers, anhydrous magnesium sulfate was added to the upper layer, and after stirring for 1 hour, filtration and washing with toluene were performed. After concentration under reduced pressure, 758 g of TIPS2-B-OH concentration residue was obtained.
• Example 2 the intermediate HO2-B-CO 2 Me, side chain extended with 11-bromo-1-undecanol, was a solid. Therefore, 11-bromo-1-undecanol can be easily removed by washing HO2-B-CO 2 Me with an organic solvent such as acetonitrile, which has a high dissolving power for 11-bromo-1-undecanol. , the purity of the final target TIPS2-B-OH concentrated residue could be improved.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)

Priority Applications (1)

Applications Claiming Priority (2)

Publications (1)

Family

ID=85156028

Family Applications (1)

Country Status (3)

Citations (13)

• 2022
  • 2022-08-05 TW TW111129490A patent/TW202311275A/zh unknown
  • 2022-08-05 WO PCT/JP2022/030045 patent/WO2023013757A1/ja not_active Ceased
  • 2022-08-05 JP JP2023540423A patent/JPWO2023013757A1/ja active Pending

Patent Citations (13)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events