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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
  • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D263/18—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D263/18—Oxygen atoms
  • C07D263/20—Oxygen atoms attached in position 2
  • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
  • C07K1/026—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution by fragment condensation in solution
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
  • C07K5/06043—Leu-amino acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/02—Ortho- or ortho- and peri-condensed systems
  • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
  • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
  • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
  • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
  • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

• the present invention relates to O-substituted serine derivatives useful as pharmaceutical intermediates, cyclic N,O-acetals useful for their production, and methods for producing them.
• medium-molecular compounds molecular weight 500-2000
• low-molecular-weight compounds in terms of access to tough targets, typified by inhibition of protein-protein interactions.
• middle-molecular compounds may be superior in that they can be transferred into cells.
• peptide drugs are highly valuable molecular species, with more than 40 types already on the market (Non-Patent Document 1).
• Representative examples of peptide drugs include cyclosporin A and polymyxin B. Looking at these structures, we find that they are peptide compounds containing several unnatural amino acids.
• Unnatural amino acids are amino acids that are not naturally encoded on mRNA.In addition to naturally occurring cyclosporin A and polymyxin B, which contain unnatural amino acids, these unnatural structural sites are It is very interesting that the drug interacts with the action site of the drug and exhibits pharmacological activity. As an example of the interaction of unnatural amino acids with in vivo action sites, research on the interaction between the O-substituted serine site of lacosamide and sodium channels (Non-Patent Document 2) is known.
• Non-Patent Document 3 A method for producing from serine and alkyl halide in the presence of a base using the Williamson ether synthesis method, or an improved method thereof.
• Non-Patent Document 4 A synthetic method applying Schmidt Glycosylation, which is produced from serine and trichloroacetimidate in the presence of an acid catalyst.
• Non-Patent Document 5 A synthetic method for producing from serine and allyl carbonate in the presence of a palladium catalyst.
• Patent Documents 1 and 2 A synthetic method in which an aziridine compound derived from serine is reacted with an alcohol in the presence of a Lewis acid or Br ⁇ nsted acid catalyst. 5. A method of reacting a cyclic sulfamidate derived from serine with alcohol (Patent Document 3). These are methods for producing O-alkyl-substituted serine derivatives via intermediates derived from serine.
• Patent Document 5 In the method using the coupling reaction of allyl ether described in Non-Patent Document 5, the substituents on oxygen of the O-substituted serine derivative that can be produced are limited to allyl groups.
• Patent Document 3 a method for producing O-substituted serine derivatives via sulfamidate is developed with high regioselectivity, chemical yield, and optical purity. The method has an oxidation step using an oxidizing agent and requires 4 or 5 steps from commercially available serine derivatives.
• An object of the present invention is to provide a method for producing an O-substituted serine derivative, which allows the O-substituted serine derivative to be obtained in a small number of steps.
• a method for producing a compound represented by the following general formula (1), a salt thereof, or a solvate thereof comprising: (A) The method described above, including the step of reacting a compound represented by the following general formula (2) with a reducing agent to obtain a compound represented by the following general formula (1).
• R 1 is an electron-withdrawing group
• R 2 and R 3 are (i) each independently hydrogen, C 1 -C 6 alkyl which may have a substituent, C 3 -C 6 cycloalkyl which may have a substituent, C2 - C6 alkenyl which may have a substituent, C2 - C6 alkynyl which may have a substituent, aralkyl which may have a substituent, (ii) taken together with intervening carbon atoms to form a 3- to 8-membered alicyclic ring or a 4- to 7-membered alicyclic ring; It forms a member-saturated heterocycle
• R 4 and R 5 are (i) each independently hydrogen, C 1 -C 6 alkyl which may have a substituent, C 3 -C 6 cycloalkyl which may have a substituent; C2 - C6 alkenyl which may have a substituent, C2 - C6 alkynyl which
• a method for producing a compound represented by the following general formula (1) or a salt thereof or a solvate thereof comprising: (A) The method described above, including the step of reacting a compound represented by the following general formula (2) with a reducing agent to obtain a compound represented by the following general formula (1).
• R 1 is an electron-withdrawing group, an amino acid residue, or a peptide residue
• R 2 and R 3 are (i) each independently hydrogen, C 1 -C 6 alkyl which may have a substituent, C 3 -C 6 cycloalkyl which may have a substituent, C2 - C6 alkenyl which may have a substituent, C2 - C6 alkynyl which may have a substituent, aralkyl which may have a substituent, (ii) taken together with intervening carbon atoms to form a 3- to 8-membered alicyclic ring or a 4- to 7-membered alicyclic ring; It forms a member-saturated heterocycle
• R 4 and R 5 are (i) each independently hydrogen, C 1 -C 6 alkyl which may have a substituent, C 3 -C 6 cycloalkyl which may have a substituent; C2 - C6 alkenyl which may have a substituent
• [2] The method according to [1], wherein the step (A) is performed in the presence of an acid.
• the acid is a metal Lewis acid.
• the metal Lewis acid is at least one selected from the group consisting of metal halides, metal triflates, metal alkoxides, and metal halide alkoxides.
• the metal in the metal Lewis acid is at least one selected from the group consisting of titanium, tin, scandium, zirconium, zinc, and aluminum.
• metal in the metal Lewis acid is at least one selected from the group consisting of titanium, tin, and scandium.
• the metal Lewis acid is at least one selected from the group consisting of titanium tetrahalide, tin tetrahalide, scandium triflate, tetraalkoxytitanium, and alkoxytrichlorotitanium. .
• the metal Lewis acid according to [7] is at least one selected from the group consisting of titanium tetrachloride, tin tetrachloride, scandium triflate, tetraisopropyl orthotitanate, and isopropoxytrichlorotitanium.
• Method. [9] The method according to [4], wherein the metal Lewis acid is a combination of at least one selected from metal halides and at least one selected from metal alkoxides.
• the method according to [9], wherein the metal Lewis acid is a combination of titanium tetrahalide and tetraalkoxytitanium.
• metal Lewis acid is one selected from the group consisting of titanium tetrahalide, tin tetrahalide, scandium triflate, and alkoxytrichlorotitanium.
• metal Lewis acid is one selected from the group consisting of titanium tetrachloride, tin tetrachloride, scandium triflate, and isopropoxytrichlorotitanium.
• metal Lewis acid is isopropoxytrichlorotitanium.
• the silane reducing agent is triethylsilane, triisopropylsilane, tristrimethylsilylsilane, phenylsilane, dimethylphenylsilane, tetraphenyldisilane, poly(methylhydrosiloxane), and 1,1,3,3-tetramethyl
• the silane-based reducing agent is at least one selected from the group consisting of triethylsilane, poly(methylhydrosiloxane), and 1,1,3,3-tetramethyldisiloxane. Method described.
• the amount of the acid used in the step (A) is 0.1 equivalent or more and 20 equivalents or less with respect to the compound represented by the general formula (2), and the amount of the reducing agent used is the amount of the reducing agent represented by the general formula (2).
• the amount of acid to be used in the step (A) is 0.1 equivalent or more and 20 equivalents or less, 0.3 equivalent or more and 7 equivalents or less, or 0.
• the amount of acid used in the step (A) is 1 equivalent or more and 3 equivalents or less relative to the compound represented by general formula (2), according to any one of [2] to [20]. the method of. [24]
• the amount of the reducing agent used in the step (A) is 0.5 equivalent or more and 30 equivalents or less, 1 equivalent or more and 20 equivalents or less, or 1.5 equivalents or more, relative to the compound represented by general formula (2).
• the amount of the reducing agent used in the step (A) is 2 equivalents or more and 7 equivalents or less with respect to the compound represented by the general formula (2), in any one of [1] to [20].
• the step (A) is carried out in the presence of a solvent, and the solvent is at least one selected from the group consisting of halogenated solvents and benzene-based solvents, [1] to [25] The method described in any of the above.
• the halogenated solvent is at least one selected from the group consisting of dichloromethane, 1,2-dichloroethane, and chloroform
• the benzene solvent is toluene, chlorobenzene, fluorobenzene, and benzotrifluoride.
• the fluoroalcohol is at least one selected from the group consisting of 2,2,2-trifluoroethanol and 1,1,1,3,3,3-hexafluoro-2-propanol
• the alcohol is at least one selected from the group consisting of methanol, ethanol, and 2-propanol
• the nitrile solvent is acetonitrile
• the ester solvent is the group consisting of ethyl acetate and dimethyl carbonate.
• step (A) is carried out at a temperature of -50° C. to 50° C. for 5 minutes to 24 hours. ) is carried out at a temperature of -50°C to 50°C, -40°C to 40°C, or -30°C to 30°C.
• step (A) is carried out at a temperature of -20°C to 25°C.
• step (A) is performed for 5 minutes to 24 hours, 10 minutes to 12 hours, or 20 minutes to 8 hours.
• the base is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, and tetraalkylammonium hydroxide.
• the base is sodium hydroxide or potassium hydroxide.
• the base treatment step is performed at a temperature of -5°C to 50°C, 0°C to 40°C, or 5°C to 30°C for 5 minutes to 24 hours, 10 minutes to 12 hours, or 20 minutes to 8 hours.
• step (B) A step of reacting a compound represented by the following general formula (3) with aldehydes, ketones, acetals, or vinyl ethers to obtain a compound represented by the following general formula (2), The method according to any one of [1] to [45]. [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 1 , L 2 and L 3 have the same meanings as defined in [1]. ] [47] The method according to [46], wherein the step (B) is a step of obtaining a compound represented by general formula (2) by reacting with aldehydes or ketones in the presence of an acid.
• the silylating agent is at least one selected from the group consisting of N,O-bis(trimethylsilyl)trifluoroacetamide, N,O-bis(trimethylsilyl)acetamide, and 1-trimethylsilylimidazole, [ 51].
• the step (B) is carried out at a temperature of -10°C to 80°C, 0°C to 70°C, or 10°C to 60°C, for 5 minutes to 24 hours, 10 minutes to 12 hours, or 20 minutes.
• R 7 is -OR 8
• R 8 is hydrogen, C 1 -C 6 alkyl which may have a substituent, or aralkyl which may have a substituent, The method according to any one of [1] to [57].
• [59] The method according to [58], wherein R 7 is -OH.
• [59-1] The method according to [58], wherein R 7 is -OR 8 and R 8 is C 1 -C 6 alkyl.
• R59-2] The method according to [58], wherein R 7 is -OR 8 and R 8 is methyl.
• R 7 is -NR 9 R 9' , and R 9 and R 9' are each independently hydrogen, C 1 -C 6 alkyl which may have a substituent, or substituted [1 ] to [ 57 ] method described in any of the above.
• R 9 The method according to any one of [1] to [57], wherein R 7 is an amino acid residue or a peptide residue.
• R 7 is an amino acid residue whose C-terminus is protected with a C 1 -C 6 alkyl ester.
• a method for producing a compound represented by the following general formula (16) or a salt thereof or a solvate thereof comprising: A method comprising the step of producing the following compound (11) by the method described in any one of [1] to [61] above.
• R 10 and R 11 are (i) each independently hydrogen, C 1 -C 6 alkyl which may have a substituent, C 3 -C 6 cycloalkyl which may have a substituent; C2 - C6 alkenyl which may have a substituent, C2 - C6 alkynyl which may have a substituent, aralkyl which may have a substituent, (ii) taken together with intervening carbon atoms to form a 3- to 8-membered alicyclic ring or a 4- to 7-membered alicyclic ring; It forms a member-saturated heterocycle.
• step (D) a step of reacting a compound represented by the following general formula (15) with a reducing agent in the presence of a Lewis acid to obtain a compound represented by the following general formula (16);
• the Lewis acid in step (C) is at least one selected from the group consisting of a complex of boron trifluoride with an ether solvent, trialkylsilyl triflate, titanium tetrachloride, and tetraalkoxytitanium.
• step (C) is a boron trifluoride/diethyl ether complex or a boron trifluoride/tetrahydrofuran complex.
• the Lewis acid in step (D) is at least one selected from the group consisting of boron trifluoride/alkyl ether complex, trialkylsilyl triflate, titanium tetrachloride, and tetraalkoxytitanium, [63 ] to [65].
• step (D) is trimethylsilyl triflate.
• step (D) is a hydride reducing agent.
• the hydride reducing agent is at least one selected from the group consisting of a silane reducing agent and a borane reducing agent.
• the silane reducing agent is triethylsilane, triisopropylsilane, tristrimethylsilylsilane, phenylsilane, dimethylphenylsilane, tetraphenyldisilane, poly(methylhydrosiloxane), and 1,1,3,3-tetramethyl
• the method according to [69] which is at least one selected from the group consisting of disiloxanes.
• the silane-based reducing agent is at least one selected from the group consisting of triethylsilane, poly(methylhydrosiloxane), and 1,1,3,3-tetramethyldisiloxane. Method described.
• R 2 and R 3 are each independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, isopentyl, benzyl, phenyl, and pyridyl; , or R 2 and R 3 together with the carbon atoms to which they are bonded form a 3- to 8-membered alicyclic ring, and R 4 and R 5 each independently represent hydrogen, methyl, ethyl, selected from the group consisting of n-propyl, n-butyl, tert-butyl, isobutyl, isopentyl, benzyl, phenyl, and pyridyl, or R 4 and R 5 taken together with the carbon atoms to which they are attached are 3 ⁇ It forms an 8-membered alicyclic ring, R 6 is hydrogen, methyl, methyl,
• the heteroaryl is a good heteroaryl.
• R 1 is benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl, trifluoroacetyl, methanesulfonyl, para-toluenesulfonyl, (trifluoromethyl)sulfonyl, or 2- The method according to [74], which is nitrobenzenesulfonyl (Nosyl). [76] The method according to [75], wherein R 1 is benzyloxycarbonyl (Cbz) or 9-fluorenylmethyloxycarbonyl (Fmoc).
• R 1 is an amino acid residue or a peptide residue
• R 2 and R 3 are each independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, isopentyl, benzyl, phenyl, and pyridyl; , or R 2 and R 3 together with the carbon atoms to which they are bonded form a 3- to 8-membered alicyclic ring
• R 4 and R 5 each independently represent hydrogen, methyl, ethyl, selected from the group consisting of n-propyl, n-butyl, tert-butyl, isobutyl, isopentyl, benzyl, phenyl, and pyridyl, or R 4 and R 5 taken together with the carbon atoms to which they are attached are 3 ⁇ It forms an 8-membered alicycl
• R 1 is an amino acid residue or peptide residue whose N-terminus is protected with benzyloxycarbonyl (Cbz) or 9-fluorenylmethyloxycarbonyl (Fmoc), [76-1 ].
• R 2 and R 3 are each independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, isopentyl, benzyl, phenyl, and pyridyl or R 2 and R 3 together with the bonded carbon atoms form a 3- to 8-membered alicyclic ring, the method according to any one of [1] to [76]. .
• R 2 is methyl, ethyl, n-propyl, n-butyl, or isobutyl
• R 3 is hydrogen or methyl, or R 2 and R 3 taken together with the carbon atom to which they are bonded are The method according to [77], wherein a 4- to 6-membered alicyclic ring is formed.
• R 4 and R 5 are each independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, tert-butyl, isobutyl, isopentyl, benzyl, phenyl, and pyridyl.
• a method for producing a peptide compound comprising: (i) the step of producing the above compound (11) or (16) by the method described in any one of [1] to [85] above, and (ii) the step of producing the above compound (11) or (16) in a solvent, a step of condensing the carboxy group of compound (11) or (16) with an amino acid having an amino group or a peptide having an amino group; manufacturing method, including.
• room temperature means a temperature of about 20°C to about 25°C.
• the term "electron-withdrawing group” refers to a substituent that is more likely to attract electrons from the bonded atom side than a hydrogen atom.
• halogen atom examples include F, Cl, Br, or I.
• alkyl is a monovalent group derived from an aliphatic hydrocarbon by removing one arbitrary hydrogen atom, and has a heteroatom (atom other than carbon and hydrogen atoms) in the skeleton. ) or have a subset of hydrocarbyl or hydrocarbon group structures that do not contain unsaturated carbon-carbon bonds and contain hydrogen and carbon atoms.
• Alkyl includes not only linear ones but also branched ones.
• the alkyl is preferably an alkyl having 1 to 20 carbon atoms (C 1 -C 20 , hereinafter "C p -C q " means p to q carbon atoms), and preferably C 1 -C 10 alkyl, more preferably C 1 -C 6 alkyl.
• alkyl examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, isobutyl (2-methylpropyl), n-pentyl, s-pentyl (1- methylbutyl), t-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2 -Methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1,2,2-tetramethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl , 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,
• alkenyl is a monovalent group having at least one double bond (two adjacent SP 2 carbon atoms). Depending on the configuration of the double bond and substituents (if present), the geometry of the double bond can be Entadel (E) or Entumble (Z), cis or trans configuration.
• Alkenyl includes not only straight chain but also branched alkenyl.
• Preferred alkenyls include C 2 -C 10 alkenyl, more preferably C 2 -C 6 alkenyl. Specific examples include vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl, hexenyl and the like.
• alkynyl is a monovalent group having at least one triple bond (two adjacent SP carbon atoms). Alkynyl includes not only straight chain but also branched chain. Preferred alkynyl is C 2 -C 10 alkynyl, more preferably C 2 -C 6 alkynyl.
• ethynyl 1-propynyl, propargyl, 3-butynyl, pentynyl, hexynyl, 3-phenyl-2-propynyl, 3-(2'-fluorophenyl)-2-propynyl, 2-hydroxy-2 -propynyl, 3-(3-fluorophenyl)-2-propynyl, 3-methyl-(5-phenyl)-4-pentynyl, and the like.
• cycloalkyl means a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, and includes a monocyclic ring, a bicyclo ring, and a spiro ring.
• Preferred examples of cycloalkyl include C 3 -C 8 cycloalkyl. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, spiro[3.3]heptyl, and the like.
• aryl means a monovalent aromatic hydrocarbon ring and an aromatic hydrocarbon ring group.
• Preferred aryl is C 6 -C 10 aryl.
• Specific examples of aryl include phenyl, naphthyl (eg, 1-naphthyl, 2-naphthyl), and the like.
• heteroaryl means an aromatic cyclic monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms, and an aromatic heterocyclic group.
• the ring may be a monocyclic ring, a fused ring with another ring, or a partially saturated ring.
• the number of atoms constituting the ring of heteroaryl is preferably 5 to 10 (5 to 10 membered heteroaryl), more preferably 5 to 7 (5 to 7 membered heteroaryl).
• heteroaryl examples include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl.
• benzothiadiazolyl benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, Examples include imidazopyridyl, pyrazolopyridyl, imidazopyridyl, triazolopyridyl, pyrrolopyrazinyl, furopyridyl, and the like.
• aralkyl (arylalkyl) means a group in which at least one hydrogen atom of "alkyl” defined above is substituted with “aryl” defined above.
• aralkyl C 7 -C 14 aralkyl is preferred, and C 7 -C 10 aralkyl is more preferred.
• Specific examples of aralkyl include benzyl, phenethyl, and 3-phenylpropyl.
• Alicyclic ring as used herein means a non-aromatic hydrocarbon ring.
• the alicyclic ring may have an unsaturated bond in the ring, or may be a polycyclic ring having two or more rings. Further, carbon atoms constituting the ring may be oxidized to form carbonyl.
• Preferred examples of the alicyclic ring include 3- to 8-membered alicyclic rings.
• alicyclic ring examples include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, and a bicyclo[2.2.1]heptane ring.
• saturated heterocycle refers to a non-aromatic heterocycle containing 1 to 5 heteroatoms in addition to carbon atoms and containing no double and/or triple bonds in the ring. do.
• the saturated heterocycle may be a monocyclic ring, or may form a fused ring with another ring, for example, an aromatic ring such as a benzene ring.
• Preferred examples of the saturated heterocycle include 4- to 10-membered saturated heterocycles.
• the saturated heterocycle includes, for example, an azetidine ring, an oxoazetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine ring, a pyrrolidine ring, a 2-oxopyrrolidine ring, a 4-oxopyrrolidine ring, and a piperidine ring.
• Ring 4-oxopiperidine ring, piperazine ring, pyrazolidine ring, imidazolidine ring, oxazolidine ring, isoxazolidine ring, thiazolidine ring, isothiazolidine ring, thiadiazolidine ring, oxazolidone ring, dioxolane ring, dioxane ring, thietane ring, octa Examples include hydroindole ring, indoline ring, azepane ring, dioxepane ring, and 5,9-dioxaspiro[3.5]nonane ring.
• the compounds described herein can be salts thereof or solvates thereof.
• Salts of compounds include, for example, hydrochlorides; hydrobromides; hydroiodides; phosphates; phosphonates; sulfates; sulfonates such as methanesulfonates and p-toluenesulfonates.
• solvate refers to a compound in which a compound forms one molecular group together with a solvent.
• Examples include hydrates, alcoholates (ethanolates, methanolates, 1-propanolates, 2-propanolates, etc.), and solvates with a single solvent such as dimethyl sulfoxide. , one in which a solvate is formed with a plurality of solvents for one molecule of the compound, or one in which a solvate is formed with a plurality of types of solvents in one molecule of the compound. If the solvent is water, it is called a hydrate.
• hydrates are preferable, and specific examples of such hydrates include 1 to 10 hydrates, preferably 1 to 5 hydrates, and more preferably 1 to 3 hydrates. Examples include hydrates.
• amino acid as used herein includes natural amino acids and unnatural amino acids (sometimes referred to as amino acid derivatives). Moreover, in this specification, “amino acid” may mean an amino acid residue. "Natural amino acids” as used herein include Gly, Ala, Ser, Thr, Val, Leu, He, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg, Pro.
• Unnatural amino acids are not particularly limited, but examples include ⁇ -amino acids, D-type amino acids, N-substituted amino acids, ⁇ , ⁇ -disubstituted amino acids, amino acids whose side chains differ from those of natural amino acids, hydroxycarboxylic acids, etc. . Any steric configuration is acceptable for the amino acids herein.
• side chains of amino acids include alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups, heteroaralkyl groups, cycloalkyl groups, and spiro bonds.
• cycloalkyl groups Each may be provided with a substituent, and these substituents are not limited, for example, any substituent containing a halogen atom, an O atom, an S atom, a N atom, a B atom, a Si atom, or a P atom.
• substituents are not limited, for example, any substituent containing a halogen atom, an O atom, an S atom, a N atom, a B atom, a Si atom, or a P atom.
• One or more may be independently selected from the following. That is, optionally substituted alkyl groups, alkoxy groups, alkoxyalkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups, cycloalkyl groups, or oxo, aminocarbonyl, halogen atoms, etc. Illustrated.
• the amino acid herein may be a compound having a carboxyl group and an amino group in the same molecule, and specifically, 4-aminobutanoic acid, 5-aminopentanoic acid, 6-aminopentanoic acid, etc. Examples include hexanoic acid, 4-piperidinecarboxylic acid, and 4-aminobenzoic acid.
• Peptide and peptide compound in this specification are not particularly limited as long as they are peptides formed by amide bonding or ester bonding of natural amino acids and/or unnatural amino acids.
• the peptide compound is preferably a peptide with 5 to 30 residues, more preferably 7 to 15 residues, and still more preferably 9 to 13 residues.
• the peptide preferably has 2 to 29 residues, more preferably 2 to 14 residues, and even more preferably 2 to 12 residues.
• Peptides and peptide compounds may be linear or cyclic peptides.
• amino acid residues and “peptide residues” constituting a peptide compound are sometimes simply referred to as “amino acids” and “peptides.”
• a substituent may be substituted means that a certain group may be substituted with any substituent.
• a substituent may be added to each of these, and these substituents are not limited, for example, any substituent containing a halogen atom, an oxygen atom, a sulfur atom, a nitrogen atom, a boron atom, a silicon atom, or a phosphorus atom.
• One or more may be independently selected from among the groups.
• substituents examples include alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, oxo, aminocarbonyl, alkylsulfonyl, alkylsulfonylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, halogen, nitro , amino, monoalkylamino, dialkylamino, cyano, carboxyl, alkoxycarbonyl, formyl and the like.
• examples of the halogen-based solvent include dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, and the like. Among these, dichloromethane, chloroform, and 1,2-dichloroethane are preferred.
• examples of the benzene solvent include benzene, toluene, xylene, fluorobenzene, chlorobenzene, 1,2-dichlorobenzene, bromobenzene, anisole, ethylbenzene, nitrobenzene, cumene, benzotrifluoride, and the like.
• toluene, fluorobenzene, chlorobenzene, and benzotrifluoride are preferred.
• examples of ether solvents include diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, 1,2-dimethoxyethane, diisopropyl ether, cyclopentyl methyl ether, t -butyl methyl ether, 4-methyltetrahydropyran, diglyme, triglyme, tetraglyme and the like.
• ester solvents include methyl acetate, ethyl acetate, butyl acetate, methyl propionate, propyl acetate, isopropyl acetate, isobutyl acetate, pentyl acetate, dimethyl carbonate, diethyl carbonate, ⁇ -valerolactone, and the like. Can be mentioned. Among these, ethyl acetate and dimethyl carbonate are preferred.
• nitrile solvents examples include acetonitrile, propionitrile, and the like. Among these, acetonitrile is preferred.
• fluoroalcohols examples include 2,2,2-trifluoroethanol and 1,1,1,3,3,3-hexafluoro-2-propanol.
• examples of alcohol include methanol, ethanol, n-propanol, 2-propanol, and the like. Among these, methanol, ethanol, and 2-propanol are preferred.
• one or more means a number of one or more.
• substituents of a group the term means one up to the maximum number of substituents allowed by the group.
• One or more specifically includes, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and/or a larger number.
• A, B, and/or C includes the following seven variations; (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, (vii) A, B, and C.
• R 1 in the formula is an electron-withdrawing group.
• Aryl specifically methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, isopentyl, trifluoromethyl, phenyl, nitrophenyl, pyridyl
• Examples include methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, isopentyl, trifluoromethyl, phenyl, nitrophenyl, pyridyl, benzyl, methoxybenzyl, fluorobenzyl. , and 9-fluorenylmethyl.
• R 1 is benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl, trifluoroacetyl, methanesulfonyl, para-toluenesulfonyl, (trifluoromethyl)sulfonyl, and 2- It is nitrobenzenesulfonyl (Nosyl).
• Particularly preferred as R 1 are benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc).
• R 1 is an amino acid residue or a peptide residue.
• R 1 is preferably an amino acid residue or a peptide residue whose N-terminus is protected with benzyloxycarbonyl (Cbz) or 9-fluorenylmethyloxycarbonyl (Fmoc), and more preferably an N-terminus is an amino acid residue protected with benzyloxycarbonyl (Cbz) or 9-fluorenylmethyloxycarbonyl (Fmoc).
• R 2 and R 3 are each independently hydrogen, C 1 -C 6 alkyl which may have a substituent, aralkyl which may have a substituent, and R 3 which does not have a substituent.
• aryl which may optionally have a substituent, or heteroaryl which may have a substituent, or the carbon atom to which R 2 and R 3 are bonded together to form a 3- to 8-membered alicyclic ring or a 4- to It forms a 7-membered saturated heterocycle.
• R 2 and R 3 are preferably each independently hydrogen, methyl, ethyl, n-propyl, n-butyl, tert-butyl, isobutyl, isopentyl, benzyl, phenyl, pyridyl, or R 2 and R 3 forms a 3- to 8-membered alicyclic ring together with the carbon atom to which it is bonded. More preferably, when R 2 is methyl, ethyl, n-propyl, n-butyl, or isobutyl, R 3 is hydrogen or methyl, or R 2 and R 3 together with the carbon atoms to which they are attached to form a 4- to 6-membered alicyclic ring.
• R 4 and R 5 each independently represent hydrogen, C 1 -C 6 alkyl which may have a substituent, aralkyl which may have a substituent, and R 5 which does not have a substituent.
• aryl which may optionally have a substituent, or heteroaryl which may have a substituent, or the carbon atom to which R 4 and R 5 are bonded together to form a 3- to 8-membered alicyclic ring or a 4- to 4-membered alicyclic ring. It forms a 7-membered saturated heterocycle.
• R 4 and R 5 are preferably each independently hydrogen, methyl, ethyl, n-propyl, n-butyl, tert-butyl, isobutyl, isopentyl, benzyl, phenyl, pyridyl, or R 4 and R 5 forms a 3- to 8-membered alicyclic ring together with the carbon atom to which it is bonded. More preferably, R 4 is hydrogen, methyl, ethyl, n-propyl, n-butyl, or isobutyl and R 5 is hydrogen. More preferably, R 4 is hydrogen or methyl and R 5 is hydrogen.
• R 6 in the formula is hydrogen, C 1 -C 6 alkyl which may have a substituent, or aralkyl which may have a substituent.
• R 6 is hydrogen, methyl, ethyl, n-propyl, n-butyl, or benzyl, more preferably R 6 is hydrogen.
• R 7 is -OR 8 , -NR 9 R 9' , an amino acid residue, or a peptide residue
• R 8 , R 9 and R 9' each independently represent hydrogen or a substituent.
• C 1 -C 6 alkyl which may have a substituent, or aralkyl which may have a substituent, or R 9 and R 9' together with the intervening nitrogen atom are 4- to 7-membered. Forms a saturated heterocycle.
• R 7 is -OR 8 , more preferably R 7 is -OH.
• R 7 is -OR 8 and R 8 is C 1 -C 6 alkyl, more preferably R 7 is -OR 8 and R 8 is methyl.
• R 7 is an amino acid residue protected at the C-terminus with a C 1 -C 6 alkyl ester.
• L 1 , L 2 , and L 3 are a single bond or -CH 2 -, provided that when L 1 is -CH 2 -, L 2 is a single bond, and L 2 is -CH 2 - . -, L 1 and L 3 are single bonds, and when L 3 is -CH 2 -, L 2 is a single bond.
• L 1 , L 2 and L 3 are single bonds.
• Step A of Production Method 1 is a step of producing an O-substituted serine derivative (1) by subjecting the cyclic N,O-acetal derivative (2) to a reductive hydrogenation reaction accompanied by ring opening.
• This step is carried out in the presence of a reducing agent, in the presence or absence of an acid, in the presence or absence of a solvent, in the presence or absence of a solubilizing agent, preferably at a temperature of -50°C to 50°C, more preferably is a temperature of -40°C to 40°C, more preferably a temperature of -30°C to 30°C, particularly preferably a temperature of -20°C to 25°C, preferably for 5 minutes to 24 hours, more preferably for 10 minutes to 12
• the reaction time can be more preferably 20 minutes to 8 hours, particularly preferably 30 minutes to 5 hours.
• a hydride reducing agent can be used, such as triethylsilane, triisopropylsilane, tristrimethylsilylsilane, phenylsilane, dimethylphenylsilane, tetraphenyldisilane, poly(methylhydrosiloxane), and 1,1 , silane-based reducing agents such as 3,3-tetramethyldisiloxane, and borane-based reducing agents.
• triethylsilane, poly(methylhydrosiloxane), and 1,1,3,3-tetramethyldisiloxane are preferably used, and triethylsilane is more preferably used.
• the amount of the reducing agent used is not particularly limited, but may be, for example, 0.5 equivalent or more and 30 equivalents or less relative to the compound represented by formula (2). Preferably it is 1 equivalent or more and 20 equivalents or less, more preferably 1.5 equivalents or more and 10 equivalents or less, and still more preferably 2 equivalents or more and 7 equivalents or less.
• acids include Br ⁇ nsted acids such as trifluoromethanesulfonic acid (TfOH), methanesulfonic acid (MsOH), and trifluoroacetic acid (TFA), complexes of boron trifluoride with ether solvents, and trialkylsilyl triflates. or the metal Lewis acids described below, with metal Lewis acids being preferred.
• the metal Lewis acid herein means a Lewis acid composed of a metal and an anion group, and includes, for example, metal halides, metal triflates, metal alkoxides, and metal halide alkoxides.
• the metal in the metal Lewis acid may be a known polyvalent metal, such as titanium, tin, scandium, zirconium, zinc, aluminum, calcium, bismuth, antimony, cadmium, vanadium, molybdenum, tungsten, iron, copper, cobalt. , lead, nickel, silver, and rare earth metals.
• titanium, tin, scandium, zirconium, zinc, and aluminum are preferred, titanium, tin, and scandium are more preferred, and titanium and tin are still more preferred.
• the anion group in the metal Lewis acid may be a known anion group, such as trifluoromethanesulfonic acid (TfOH), methanesulfonic acid (MsOH), bis(trifluoromethanesulfonyl)imide (Tf 2 NH), Tris(trifluoromethanesulfonyl)methane (HCTf 3 ), pentafluorophenylbis(triflyl)methane (C 6 H 5 CHTf 2 ), trifluoroacetic acid (TFA), 2,2,2-trifluoroethanol, 1,1, Examples include anion groups derived from 1,3,3,3-hexafluoro-2-propanol, methanol, ethanol, n-propanol, isopropanol, n-butanol, phenol, etc.; It may be one or more combinations selected.
• TfOH trifluoromethanesulfonic acid
• MsOH methanesulfonic acid
• metal Lewis acids include metal halides such as titanium tetrahalide (e.g., titanium tetrachloride (TiCl 4 )), tin tetrahalide (e.g., tin tetrachloride (SnCl 4 )), scandium triflate ( Metal triflates such as Sc(OTf) 3 ), metal alkoxides such as tetraalkoxytitaniums (e.g. tetraisopropyl orthotitanate (Ti(OiPr) 4 )), and alkoxytrichlorotitaniums (e.g. isopropoxytrichlorotitanium (TiCl 3 )).
• metal halides such as titanium tetrahalide (e.g., titanium tetrachloride (TiCl 4 )), tin tetrahalide (e.g., tin tetrachloride (SnCl
• the metal Lewis acid may be a combination of multiple types, such as a combination of titanium tetrahalide and tetraalkoxytitanium, and a combination of titanium tetrachloride and tetraisopropyl orthotitanate is particularly preferred.
• the molar ratio of titanium tetrahalide to titanium tetraalkoxy is not particularly limited, but is preferably 2 to 4:1, more preferably 3:1.
• the amount of acid used is not particularly limited, but can be, for example, 0.1 equivalent or more and 20 equivalents or less relative to the compound represented by formula (2). Preferably, it is 0.5 equivalent or more and 5 equivalents or less, and more preferably 1 equivalent or more and 3 equivalents or less.
• the solvent examples include halogenated solvents such as dichloromethane, 1,2-dichloroethane, and chloroform; benzene solvents such as toluene, chlorobenzene, fluorobenzene, and benzotrifluoride; among these, dichloromethane, toluene, Chlorobenzene is preferably used.
• halogenated solvents such as dichloromethane, 1,2-dichloroethane, and chloroform
• benzene solvents such as toluene, chlorobenzene, fluorobenzene, and benzotrifluoride
• dichloromethane, toluene, Chlorobenzene is preferably used.
• Step A of Production Method 1 can be further carried out in the presence of a solubilizing agent.
• solubilizing agents include fluoroalcohols such as 2,2,2-trifluoroethanol and 1,1,1,3,3,3-hexafluoro-2-propanol, methanol, ethanol, and 2-propanol.
• examples include alcohol, nitrile solvents such as acetonitrile, and ester solvents such as ethyl acetate and dimethyl carbonate.
• 2,2,2-trifluoroethanol, 1,1,1,3,3,3 -hexafluoro-2-propanol is preferably used.
• Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, tetraalkylammonium hydroxide (e.g., tetramethylammonium hydroxide), and among these, sodium hydroxide and hydroxide Potassium is preferably used.
• This base treatment step is preferably carried out at a temperature of -5°C to 50°C, more preferably at a temperature of 0°C to 40°C, even more preferably at a temperature of 5°C to 30°C, particularly preferably at a temperature of 10°C to 25°C. , preferably from 5 minutes to 24 hours, more preferably from 10 minutes to 12 hours, even more preferably from 20 minutes to 8 hours, particularly preferably from 30 minutes to 5 hours.
• the O-substituted serine derivative (11) in which R 7 is -OH is a secondary amine, a tertiary amine,
• the content of impurities contained in the reaction mixture can be reduced.
• Examples of the salt include dicyclohexylamine, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, etc. Among these, dicyclohexylamine is preferably used.
• the cyclic N,O-acetal derivative (2) used as a starting material in Step A of Production Method 1 can be produced by a method including Step B shown below using Compound (3) as a starting material. Can be done.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 1 , L 2 , and L 3 in the formula are R 1 , R 2 , R 3 , R 4 in Step A, Each has the same meaning as R 5 , R 6 , R 7 , L 1 , L 2 and L 3 .
• Ra and Rb in the formula are each independently a C 1 -C 6 alkyl group, or together with the intervening oxygen and carbon atoms form a 5- to 7-membered saturated heterocycle.
• R 3' in the formula is hydrogen, C 1 -C 6 alkyl which may have a substituent, C 3 -C 6 cycloalkyl which may have a substituent, and C2 - C6 alkenyl which may have a substituent, C2 - C6 alkynyl which may have a substituent, aralkyl which may have a substituent, aryl which may have a substituent, and a substituent. or R 3' taken together with R 2 and any intervening carbon atoms constitutes a 4- to 8-membered alicyclic ring or a 4- to 7-membered saturated heteroaryl ring. forming a ring.
• Step B of Production Method 1 is a step of producing a cyclic N,O-acetal derivative (2) by reacting the compound (3) with aldehydes, ketones, acetals, or vinyl ethers.
• This step is carried out in the presence or absence of an acid, in the presence or absence of a solvent, in the presence or absence of a silylating agent, preferably at a temperature of -10°C to 80°C, more preferably 0°C to 70°C. temperature, more preferably at a temperature of 10°C to 60°C, particularly preferably at a temperature of 20°C to 50°C, preferably for 5 minutes to 24 hours, more preferably for 10 minutes to 12 hours, even more preferably for 20 minutes to 6 hours. , particularly preferably for 30 minutes to 3 hours.
• acids include Br ⁇ nsted acids such as trifluoromethanesulfonic acid (TfOH), methanesulfonic acid (MsOH), and trifluoroacetic acid (TFA), complexes of boron trifluoride with ether solvents, and trialkylsilyl triflates. or the metal Lewis acids mentioned above, with Lewis acids being preferred.
• TfOH trifluoromethanesulfonic acid
• MsOH methanesulfonic acid
• TFA trifluoroacetic acid
• complexes of boron trifluoride with ether solvents and trialkylsilyl triflates.
• Lewis acids being preferred.
• Lewis acids include boron trifluoride/tetrahydrofuran complex, boron trifluoride/diethyl ether complex, and trimethylsilyl triflate.
• the amount of acid used is not particularly limited, but can be, for example, 0.05 equivalent or more and 1 equivalent or less with respect to the compound represented by formula (3). Preferably, it is 0.1 equivalent or more and 0.5 equivalent or less.
• solvent examples include halogenated solvents such as dichloromethane, 1,2-dichloroethane, and chloroform, benzene solvents such as toluene, chlorobenzene, fluorobenzene, and benzotrifluoride, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, and cyclopentyl methyl ether.
• halogenated solvents such as dichloromethane, 1,2-dichloroethane, and chloroform
• benzene solvents such as toluene, chlorobenzene, fluorobenzene, and benzotrifluoride
• ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, and cyclopentyl methyl ether.
• solvents examples include dichloromethane, toluene, and 2-methyltetrahydrofuran.
• Step B of Manufacturing Method 1 can be further performed in the presence of a silylating agent.
• a silylating agent examples include N,O-bis(trimethylsilyl)trifluoroacetamide, N,O-bis(trimethylsilyl)acetamide, and 1-trimethylsilylimidazole; (Trimethylsilyl)trifluoroacetamide is preferably used.
• the O-substituted serine derivative (11) in which R 7 is -OH is used as a starting material, and the following steps are carried out.
• An O-substituted serine derivative (16) having a substituent (-CHR 10 R 11 ) on the nitrogen atom can be produced by the method including Step C and Step D.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 1 , L 2 , and L 3 in the formula are R 1 , R 2 , R 3 , R 4 in Step A, Each has the same meaning as R 5 , R 6 , R 7 , L 1 , L 2 and L 3 .
• Ra and Rb in the formula have the same meanings as Ra and Rb in Step B, respectively.
• R 10 and R 11 are each independently hydrogen, C 1 -C 6 alkyl which may have a substituent, C 3 -C 6 cycloalkyl which may have a substituent, C2 - C6 alkenyl which may have a substituent, C2 - C6 alkynyl which may have a substituent, aralkyl which may have a substituent, a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heteroaryl; forming a ring.
• R 11' in the formula is hydrogen, C 1 -C 6 alkyl which may have a substituent, C 3 -C 6 cycloalkyl which may have a substituent, or C 2 -C 6 alkenyl which may have a substituent, C 2 -C 6 alkynyl which may have a substituent, aralkyl which may have a substituent, aryl which may have a substituent, and a substituent or R 11' taken together with R 10 and any intervening carbon atoms constitutes a 4- to 8-membered alicyclic ring or a 4- to 7-membered saturated heteroaryl ring. forming a ring.
• step C for example, according to the method of Freidinger et al.
• This is a step of obtaining an oxazolidinone compound (15) by reacting with a compound or a vinyl ether.
• This step can be carried out in the presence or absence of a Lewis acid, in the presence or absence of a solvent.
• Lewis acid for example, a complex of boron trifluoride with an ether solvent, a nonmetal Lewis acid such as trialkylsilyl triflate, or the above-mentioned metal Lewis acid can be used.
• Lewis acids include boron trifluoride/tetrahydrofuran complex, boron trifluoride/diethyl ether complex, trimethylsilyl triflate, titanium tetrachloride, and tetraalkoxytitanium. Preferred are tetrahydrofuran complex and boron trifluoride/diethyl ether complex.
• the amount of Lewis acid used is not particularly limited, but can be, for example, 0.2 equivalent or more and 5 equivalents or less with respect to the compound represented by formula (11). Preferably, it is 0.5 equivalent or more and 3 equivalents or less, more preferably 1 equivalent or more and 2 equivalents or less.
• the solvent examples include halogenated solvents such as dichloromethane, 1,2-dichloroethane, and chloroform; benzene solvents such as toluene, chlorobenzene, fluorobenzene, and benzotrifluoride; among these, dichloromethane, toluene, Chlorobenzene is preferably used.
• halogenated solvents such as dichloromethane, 1,2-dichloroethane, and chloroform
• benzene solvents such as toluene, chlorobenzene, fluorobenzene, and benzotrifluoride
• dichloromethane, toluene, Chlorobenzene is preferably used.
• step D an O-substituted serine derivative (16) having a substituent (-CHR 10 R 11 ) on the nitrogen atom is produced by performing a reductive ring-opening reaction on the oxazolidinone (15). It is a process.
• This step can be carried out in the presence or absence of an acid, in the presence of a reducing agent, and in the presence or absence of a solvent.
• acids include Br ⁇ nsted acids such as trifluoromethanesulfonic acid (TfOH), methanesulfonic acid (MsOH), and trifluoroacetic acid (TFA), complexes of boron trifluoride with ether solvents, and trialkylsilyl triflates. or the metal Lewis acids mentioned above, with Lewis acids being preferred.
• TfOH trifluoromethanesulfonic acid
• MsOH methanesulfonic acid
• TFA trifluoroacetic acid
• complexes of boron trifluoride with ether solvents and trialkylsilyl triflates.
• Lewis acids being preferred.
• Lewis acid examples include boron trifluoride/tetrahydrofuran complex, boron trifluoride/diethyl ether complex, trimethylsilyl triflate, titanium tetrachloride, and tetraalkoxytitanium, and among these, trimethylsilyl triflate is preferred.
• the amount of Lewis acid used is not particularly limited, but can be, for example, 0.2 equivalent or more and 5 equivalents or less relative to the compound represented by formula (15). Preferably, it is 0.5 equivalent or more and 3 equivalents or less, more preferably 1 equivalent or more and 2 equivalents or less.
• a hydride reducing agent can be used, such as triethylsilane, triisopropylsilane, tristrimethylsilylsilane, phenylsilane, dimethylphenylsilane, tetraphenyldisilane, poly(methylhydrosiloxane), and 1,1 , silane-based reducing agents such as 3,3-tetramethyldisiloxane, and borane-based reducing agents.
• triethylsilane, poly(methylhydrosiloxane), and 1,1,3,3-tetramethyldisiloxane are preferably used, and triethylsilane is more preferably used.
• the amount of the reducing agent used is not particularly limited, but may be, for example, 1 equivalent or more and 20 equivalents or less relative to the compound represented by formula (15). Preferably it is 1.5 equivalents or more and 10 equivalents or less, more preferably 2 equivalents or more and 5 equivalents or less.
• the solvent examples include halogenated solvents such as dichloromethane, 1,2-dichloroethane, and chloroform; benzene solvents such as toluene, chlorobenzene, fluorobenzene, and benzotrifluoride; among these, dichloromethane, toluene, Chlorobenzene is preferably used.
• halogenated solvents such as dichloromethane, 1,2-dichloroethane, and chloroform
• benzene solvents such as toluene, chlorobenzene, fluorobenzene, and benzotrifluoride
• dichloromethane, toluene, Chlorobenzene is preferably used.
• the O-substituted serine derivative represented by formula (11) or formula (16) obtained by the above production method is used to produce a peptide, for example, by the production method described in WO2021132545 (method for synthesizing peptide compounds). Compounds can be manufactured.
• Example 14 of WO2021132545 Cbz-Ser(tBu)-MePhe-MeVal-Asp(tBu)-piperidine (4 mer), Cbz-MeIle-Ser(tBu)-MePhe-MeVal-Asp(tBu )-piperidine(5 mer), Cbz-MeGly-MeIle-Ser(tBu)-MePhe-MeVal-Asp(tBu)-piperidine(6 mer), Cbz-MeLeu-Val-MeGly-MeIle-Ser(tBu)-MePhe -MeVal-Asp(tBu)-piperidine(7 mer), Cbz-Val-MeGly-MeIle-Ser(tBu)-MePhe-MeVal-Asp(tBu)-piperidine(8 mer), Cbz-Leu-MeLeu-Val- MeG
• a peptide compound can be produced by using a similar method using an O-substituted serine derivative represented by formula (11) or formula (16) instead of Cbz-Ser(tBu)-OH.
• R 1 in formula (11) or formula (16) is an amino group protecting group, preferably Cbz.
• a peptide compound or a cyclic peptide compound is produced using an O-substituted serine derivative represented by formula (11) or formula (16), for example, by the production method described in WO2013100132 (method for cyclizing a peptide compound).
• formula (11) or formula (16) instead of Fmoc-Ser(tBu)-OH, formula (11) or formula (16) is used.
• Peptide compounds or cyclic peptide compounds can be produced by using the O-substituted serine derivatives shown.
• R 1 in formula (11) or formula (16) is an amino group protecting group, preferably Fmoc.
• the invention provides: 2-(benzyloxycarbonylamino)-3-(cyclobutoxy)propanoic acid, 2-(benzyloxycarbonylamino)-3-isopentyloxy-propanoic acid, 2-(benzyloxycarbonylamino)-3-isopropoxy-butanoic acid, 2-[benzyloxycarbonyl(methyl)amino]-3-(cyclobutoxy)propanoic acid, 3-benzyloxycarbonyl-2-ethyl-oxazolidine-4-carboxylic acid, 3-benzyloxycarbonyl-2-isobutyl-oxazolidine-4-carboxylic acid, benzyl 4-(cyclobutoxymethyl)-5-oxo-oxazolidine-3-carboxylate, Benzyl 4- ⁇ [1-methoxy-1-oxapropan-2-yl]carbamoyl ⁇ -2,2,5-trimethyloxazolidine-3-carboxylate, N-
• the invention is the following compounds or salts thereof or solvates thereof or salts thereof or solvates thereof: (2S)-2-(benzyloxycarbonylamino)-3-(cyclobutoxy)propanoic acid or its salts or their solvates or their salts or their solvates, (2S)-2-(benzyloxycarbonyl amino)-3-isopentyloxy-propanoic acid or a salt thereof or a solvate thereof or a salt thereof or a solvate thereof, (2S,3R)-2-(benzyloxycarbonylamino)-3-isopropoxy-butanoic acid or a salt thereof or a solvate thereof, (2S)-2-[benzyloxycarbonyl(methyl)amino]-3-(cyclobutoxy)propanoic acid or a salt thereof or a solvate thereof, (4S)-3-benzyloxycarbonyl-2-ethyl-oxazolidine-4-carboxylic acid or a
• HPLC high performance liquid chromatography
• HPLC analysis conditions Method2 Equipment: Waters ACQUITY UPLC H-Class Column: CHIRALPAK IC-3 (Daicel) 4.6 mm ID x 150 mm, 3 ⁇ m Mobile phase: 0.05% TFA/water (A), 0.05% TFA/MeCN (B) Elution method: B) 5% (0min) ⁇ 60% (20min) ⁇ 5%(20.1min) ⁇ 5% (25min) Flow rate: 1.0 mL/min Column temperature: 30°C Detection wavelength: 210nm (PDA)
• 1 H-NMR spectra were measured using a nuclear magnetic resonance apparatus ECX500II (manufactured by JEOL), and referenced to the deuterium lock signal from the sample solvent.
• Commercially available deuterated solvents were used as sample solvents depending on the purpose of the measurement.
• the chemical shift of tetramethylsilane used as an internal standard substance was set to 0 ppm, and the chemical shift of the signal of the target compound was expressed in ppm.
• the signal integral value was calculated based on the ratio of signal area intensity of each signal.
• the measurement method by qNMR was performed by dissolving the residue containing the target compound and the internal standard substance in DMSO-d 6 under the following analysis conditions.
• the yield was calculated using the following formula using the content of the target substance in the residue calculated by qNMR and the purity of the target substance in the residue calculated by HPLC analysis.
• Measuring device JNM-ECZ500R
• Internal standard substance 3,5-bis(trifluoromethyl)benzoic acid
• Example 1 (2S)-2-(benzyloxycarbonylamino)-3-propoxy-propanoic acid (compound 3A) and (2S)-2-(benzyloxycarbonylamino)-3-isopropoxy-propanoic acid (compound Examination of reaction conditions in the synthesis of 3B) (1-1): Synthesis of (4S)-3-benzyloxycarbonyl-2-ethyl-oxazolidine-4-carboxylic acid (compound 2A) After purging the reaction vessel with nitrogen, add N-benzyloxycarbonyl-L-serine (compound 1) (2.01 g, 8.40 mmol), magnesium sulfate (3.01 g, 25 mmol), and toluene (10 mL) to the reaction vessel at room temperature.
• Example 2 it was found that by the method of the present invention, Compound 3A/DCHA salt could be obtained from Compound 1 as a raw material in three steps with a yield of 51.1%.
• the reaction product obtained by acid treatment contained 9% or more of compound 4A as an impurity, but by treatment with a base (aqueous sodium hydroxide solution), compound 4A was successfully reduced to less than 0.1%.
• the method of the present invention does not require any column purification and is applicable to large-scale synthesis.
• Example 3 Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-propoxy-propanoic acid/dicyclohexylamine salt (compound 3B/DCHA salt) (3-1): Synthesis of (4S)-3-benzyloxycarbonyl-2,2-dimethyl-oxazolidine-4-carboxylic acid (compound 2B) N-benzyloxycarbonyl-L-serine (compound 1) (3.49 g, 14.6 mmol), acetone (17.4 mL), and 2,2-dimethoxypropane (15.7 mL, 128 mmol) were added to the reaction vessel.
• the substrate solution was added at an external temperature of -6°C. After stirring for 45 minutes at an external temperature of -5°C, 10% ammonium chloride aqueous solution (3.9 mL) was added. Subsequently, after stirring at room temperature and discharging the aqueous layer, the obtained organic layer was washed twice (12 mL, then 5 mL) with a 5% aqueous sodium carbonate solution. The resulting aqueous layers were mixed, and a 5% aqueous solution of sodium hydrogen sulfate monohydrate (42 mL) was added. The resulting aqueous layer was washed three times with toluene and then three times with CPME.
• the obtained organic layers were mixed and washed with 5% brine (6 mL).
• the obtained organic layer was dehydrated by adding sodium sulfate, filtered, and then concentrated under reduced pressure.
• the obtained residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol) to obtain white solid A of compound 3B (0.496 g, yield 38.0%) and white solid B of compound 3B (0.481 g, yield 36.9%).
• Example 3 it was found that by the method of the present invention, Compound 3B DCHA salt could be obtained from Compound 1 as a raw material in three steps with a yield of 59% or more.
• Example 4 Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-propoxy-propanoic acid (compound 3C) (4-1): Synthesis of (7S)-8-benzyloxycarbonyl-5-oxa-8-azaspiro[3.4]octane-7-carboxylic acid (compound 2C) N-benzyloxycarbonyl-L-serine (compound 1) (2.70 g, 11.3 mmol) and MeTHF (10.8 mL) were added to the reaction vessel at room temperature.
• N,O-bis(trimethylsilyl)trifluoroacetamide (3.00 mL, 11.3 mmol) was added at an external temperature of 0°C, and the mixture was stirred for 10 minutes.
• a 5% aqueous dipotassium hydrogen phosphate solution (8.1 mL) was added, and then water (8.1 mL) was added and stirred at room temperature.
• titanium tetrachloride (1.77 mL, 16.1 mmol), 2,2,2-trifluoroethanol (2.03 mL, 28.4 mmol), and tetraisopropyl orthotitanate (1.53 mL, 5.20 mmol) were added at an external temperature of -16°C. It was added and stirred. Next, the substrate solution prepared above was added at an external temperature of -16°C, the external temperature was set at -6°C, and the mixture was stirred for 1 hour and 15 minutes.
• Example 4 it was found that by the method of the present invention, Compound 3C could be obtained from Compound 1 as a raw material in two steps with a yield of 53% or more.
• the reaction product obtained contained 12% or more of compound 4A as an impurity, but by treating with a base (aqueous sodium hydroxide solution), compound 4A was reduced to 1%. was able to be reduced to less than The method of the present invention does not require any column purification and is applicable to large-scale synthesis.
• Example 5 Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-isopentyloxy-propanoic acid/dicyclohexylamine salt (compound 3D/DCHA salt) (5-1): Synthesis of (4S)-3-benzyloxycarbonyl-2-isobutyl-oxazolidine-4-carboxylic acid (compound 2D) N-benzyloxycarbonyl-L-serine (compound 1) (3.04 g, 12.7 mmol) and magnesium sulfate (1.51 g, 12.5 mmol) were added to the reaction vessel at an external temperature of 25°C.
• 2,2,2-trifluoroethanol (2.72 mL, 38.1 mmol) and tetraisopropyl orthotitanate (2.05 mL, 7.0 mmol) were added and stirred at an external temperature of -15°C.
• the substrate solution prepared above was added at an external temperature of -15°C, the external temperature was set to 0°C, and the mixture was stirred for 4 hours. After stirring for 1 hour at an external temperature of 10°C, the external temperature was set at -10°C and a 5% aqueous ammonium chloride solution (15 mL) was added. After setting the external temperature to 25°C, the mixture was stirred for 5 minutes.
• the obtained organic layer was washed with a 5% aqueous citric acid solution (15 mL) and water (15 mL).
• a 5% aqueous citric acid solution 15 mL
• water 15 mL
• 2 M aqueous sodium hydroxide solution 9 mL
• MTBE MTBE
• Example 5 it was found that by the method of the present invention, Compound 3D DCHA salt could be obtained from Compound 1 as a raw material in three steps with a yield of 63.2%.
• the method of the present invention is applicable to large-scale synthesis without requiring any column purification.
• Example 6 Synthesis of (2S,3R)-2-(benzyloxycarbonylamino)-3-isopropoxy-butanoic acid/dicyclohexylamine salt (Compound 7B/DCHA salt) (6-1): Synthesis of (4S,5R)-3-benzyloxycarbonyl-2,2,5-trimethyl-oxazolidine-4-carboxylic acid (compound 6B) N-benzyloxycarbonyl-L-threonine (compound 5) (1.00 g, 3.96 mmol), acetone (5 mL), and 2,2-dimethoxypropane (1.94 mL, 15.8 mmol) were placed in a reaction vessel at an external temperature of 25°C.
• reaction vessel was purged with nitrogen. Subsequently, boron trifluoride tetrahydrofuran complex (0.087 mL, 0.79 mmol) was added, and the mixture was stirred at 40°C for 0.5 hour. Subsequently, triethylamine (0.11 mL, 0.79 mmol) was added at an external temperature of 25°C, and the mixture was stirred for 5 minutes. The obtained residue was concentrated, toluene (5 mL) was added, and the mixture was further concentrated. Toluene (3 mL) and water (5 mL) were added to the obtained concentrate, and the mixture was stirred at 25°C for 10 minutes.
• MTBE (3 mL) was added and stirred for 10 minutes.
• the obtained organic layer was washed with a 5% aqueous citric acid solution (5 mL) and water (5 mL).
• a 1 M aqueous sodium hydroxide solution (5 mL) was added to the obtained organic layer, and the mixture was stirred at an external temperature of 25°C for 2 hours.
• the resulting aqueous layer was washed with MTBE (5 mL). 2 M hydrochloric acid (2.5 mL) and MTBE (10 mL) were added to the obtained aqueous layer and stirred for 10 minutes.
• Diastereomeric (7B and diastereomeric 7B') excess 99.7% de (Detection wavelength 210 nm, retention time 13.367 minutes, HPLC analysis conditions method 2) UV intensity ratio: 99.1% (Detection wavelength 210 nm, retention time 2.851 minutes, HPLC analysis conditions method 3)
• Example 6 it was found that by the method of the present invention, Compound 7B DCHA salt could be obtained from Compound 5 as a raw material in three steps with a yield of 68.2%.
• the method of the present invention is applicable to large-scale synthesis without requiring any column purification.
• Example 7 Synthesis of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-isopropoxy-propanoic acid (Compound 11B) (7-1): Synthesis of (4S)-3-(9H-fluoren-9-ylmethoxycarbonyl)-2,2-dimethyl-oxazolidine-4-carboxylic acid (compound 10B) N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-serine (compound 9) (1.02 g, 3.10 mmol), acetone (5.1 mL), 2,2-dimethoxypropane (1.52 mL, 12.4 mmol).
• Example 7 it was found that by the method of the present invention, Compound 11B could be obtained from Compound 9 as a raw material in two steps with a yield of 68.3%.
• Example 8 Synthesis of (2S)-2-[benzyloxycarbonyl(methyl)amino]-3-(cyclobutoxy)propanoic acid/dicyclohexylamine salt (compound 14C/DCHA salt) (8-1): Synthesis of (7S)-8-benzyloxycarbonyl-5-oxa-8-azaspiro[3.4]octane-7-carboxylic acid (compound 2C) N-benzyloxycarbonyl-L-serine (compound 1) (5.13 g, 21.4 mmol), toluene (10.3 mL), and acetonitrile (10.3 mL) were added to a reaction vessel at room temperature.
• N,O-bis(trimethylsilyl)acetamide (4.8 mL, 19.6 mmol) was added at room temperature, and the mixture was stirred for 15 minutes.
• cyclobutanone (1.78 mL, 23.6 mmol) and trimethylsilyl trifluoromethanesulfonate (3.49 mL, 19.3 mmol) were added, and the mixture was stirred at room temperature for 2.5 hours.
• a 5% aqueous dipotassium hydrogen phosphate solution (15.5 mL) was added and stirred. After adding CPME (10.3 mL) and stirring, the aqueous layer was discharged.
• the substrate solution prepared above was added at an external temperature of -6°C and stirred for 1.5 hours. Then, 10% ammonium chloride aqueous solution (11 mL) was added, and the mixture was stirred at room temperature. After discharging the aqueous layer, 5% citric acid aqueous solution (11 mL) and MTBE (11 mL) were added to the obtained organic layer and stirred. After draining the aqueous layer, the resulting organic layer was washed with water (11 mL). After discharging the aqueous layer, a 2 M aqueous sodium hydroxide solution (11 mL) was added, and the mixture was stirred for 2 hours.
• the resulting organic layer was washed with water (10.4 mL). After discharging the aqueous layer, a 2 M aqueous sodium hydroxide solution (10.4 mL) was added, and the mixture was stirred for 1.5 hours. After draining the organic layer, the resulting aqueous layer was washed with MTBE (10.4 mL). 2 M hydrochloric acid (9.5 mL) and toluene (21 mL) were added to the obtained aqueous layer and stirred. After discharging the aqueous layer, the obtained organic layer was washed with water (10.4 mL).
• Example 8 it was found that Compound 14C DCHA salt could be obtained from Compound 1 as a raw material in 5 steps by the method of the present invention. It does not require any column purification and can be applied to large-scale synthesis. Furthermore, the method of the present invention was shown to be applicable to the synthesis of O-substituted serine derivatives having N-substituents.
• Example 9 Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-isobutyloxypropanoic acid (compound 3E) (9-1): Synthesis of (4S)-3-benzyloxycarbonyl-2-isopropyloxazolidine-4-carboxylic acid (compound 2E) After replacing the reaction vessel with nitrogen, add N-benzyloxycarbonyl-L-serine (compound 1) (4.02 g, 16.8 mmol), magnesium sulfate (2.02 g, 16.8 mmol), and toluene (20 mL) to the reaction vessel at room temperature. Added in.
• Example 9 it was found that by the method of the present invention, Compound 3E could be obtained from the starting material Compound 1 in two steps with a yield of 61% or more.
• Example 10 Synthesis of methyl (2S)-2-(benzyloxycarbonylamino)-3-isopropoxypropanoate (compound 17B) (10-1): Synthesis of methyl (4S)-3-benzyloxycarbonyl-2,2-dimethyl-oxazolidine-4-carboxylate (compound 16B) N-benzyloxycarbonyl-L-serine methyl (compound 15) (1.22 g, 4.82 mmol), acetone (6 mL), and 2,2-dimethoxypropane (1.12 mL, 9.63 mmol) were added to the reaction vessel.
• the substrate solution was added at an external temperature of 0°C, and then stirred at room temperature for 90 minutes.
• the area ratio of compound 17B (retention time 3.293 minutes): compound 18B (retention time 2.761 minutes) was 98.8:1.2.
• 5% ammonium chloride aqueous solution (1.0 mL) was added at an external temperature of 0°C.
• the obtained organic layer was washed with 5% citric acid aqueous solution (1.0 mL), water (1.0 mL), and 5% dipotassium hydrogen phosphate aqueous solution (1.0 mL).
• the obtained organic layer was dehydrated by adding magnesium sulfate, filtered, and then concentrated under reduced pressure.
• the obtained residue was purified by reverse phase column chromatography (eluent: water/acetonitrile) to obtain a white solid of compound 17B (0.151 g, yield 72.9%).
• Example 10 it was found that by the method of the present invention, Compound 17B could be obtained from the starting material Compound 15 in two steps with a yield of 62% or more.
• Example 11 Synthesis of N-(benzyloxy)carbonyl-O-isopropyl-L-threonyl-L-alanine methyl ester (compound 20B) (11-1): Synthesis of (4S,5R)-3-benzyloxycarbonyl-2,2,5-trimethyl-oxazolidine-4-carboxylic acid (compound 6B) N-benzyloxycarbonyl-L-threonine (compound 5) (4.15 g, 16.4 mmol), acetone (20.8 mL), and 2,2-dimethoxypropane (8.03 mL, 65.5 mmol) were added to the reaction vessel.
• the substrate solution was added at an external temperature of 0°C, and then stirred at room temperature for 90 minutes.
• 5% ammonium chloride aqueous solution (2.2 mL) was added at an external temperature of 0°C.
• the obtained organic layer was washed with 5% citric acid aqueous solution (2.2 mL x 2), water (2.2 mL), and 5% sodium dihydrogen phosphate aqueous solution (2.2 mL). did.
• the obtained organic layer was dehydrated by adding magnesium sulfate, filtered, and then concentrated under reduced pressure.
• the obtained residue was purified by reverse phase column chromatography (eluent: water/acetonitrile) to obtain a white solid of compound 20B (0.239 g, yield 55.0%).
• Example 11 it was found that by the method of the present invention, Compound 20B could be obtained from the starting material Compound 5 in three steps with a yield of 46% or more.
• Example 12 Synthesis of N-[(9H-fluoren-9-ylmethoxycarbonyl)-L-leucyl]-O-isopropyl-L-threonine (Compound 23B) (12-1): Synthesis of N-[(9H-fluoren-9-ylmethoxycarbonyl)-L-leucyl]-O-isopropyl-L-threonine (compound 23B) Compound 22B (manufactured by MERCK, catalog number: 8.52184.0001, 197 mg, 0.398 mmol) was dissolved in dichloromethane (0.98 mL), and triethylsilane (0.32 mL, 2.0 mmol) was added to prepare a substrate solution.
• the obtained residue was purified by reverse phase column chromatography (eluent: water/acetonitrile) to obtain 29.0 mg of target product 23B (yield 15%) and 14.2 mg of target product 23B containing raw material 22B (HPLC analysis conditions method
• the UV intensity ratio of target product 23B and raw material 22B (93.7:6.3) in HPLC analysis using 1 was obtained as a white solid, respectively.
• the present invention provides a method for producing O-substituted serine derivatives, which allows O-substituted serine derivatives to be obtained with a small number of steps.
• unnatural amino acids useful for searching for peptide drugs and/or supplying pharmaceutical drug substances can be provided with high regioselectivity, chemical yield, and optical purity. .

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