Method for producing o-substituted serine derivative

Abstract

The present invention addresses the problem of providing a method for producing an O-substituted serine derivative, which makes it possible to produce an O-substituted serine derivative in fewer steps. The present inventors have made extensive and intensive studies on the reductive hydrogenation of a cyclic N,O-acetal. As a result, the present inventors have discovered a method for producing an O-substituted serine derivative in fewer steps, the method having excellent regioselectivity and chemical yield while keeping optical purity.

Description

Method for producing O-substituted serine derivatives

[0001] The present invention relates to O-substituted serine derivatives useful as pharmaceutical intermediates, cyclic N,O-acetals useful for the production of the derivatives, and methods for producing the derivatives.

[0002] Compared to small molecules, medium-molecular-weight compounds (molecular weight 500-2000) may be superior in accessing tough targets, such as inhibiting protein-protein interactions. Furthermore, medium-molecular-weight compounds may be superior to antibodies in terms of their ability to enter cells. Among physiologically active medium-molecular-weight compounds, peptide drugs are highly valuable molecular species, with over 40 types already on the market (Non-Patent Document 1). Representative examples of peptide drugs include cyclosporin A and polymyxin B. Focusing on their structures reveals that they contain several unnatural amino acids. Unnatural amino acids are amino acids that are not naturally encoded by mRNA. Naturally occurring cyclosporin A and polymyxin B contain unnatural amino acids, and it is intriguing that these unnatural structural moieties interact with in vivo sites of action to exert pharmacological activity. An example of the interaction of unnatural amino acids with in vivo sites of action is the study of the interaction between the O-substituted serine moiety of lacosamide and sodium channels (Non-Patent Document 2).

[0003] Among the methods for producing O-substituted serine derivatives, the following methods are known for producing O-alkyl-substituted serine derivatives: 1. A method of producing O-alkyl-substituted serine derivatives from serine and an alkyl halide in the presence of a base using the Williamson ether synthesis method, or an improved method thereof (Non-Patent Document 3). 2. A synthesis method applying Schmidt glycosylation, in which O-alkyl-substituted serine derivatives are produced from serine and trichloroacetimidate in the presence of an acid catalyst (Non-Patent Document 4). 3. A synthesis method of producing O-alkyl-substituted serine derivatives from serine and an allyl carbonate ester in the presence of a palladium catalyst (Non-Patent Document 5). These methods directly introduce an alkyl group into serine. 4. A synthesis method in which an aziridine compound derived from serine is reacted with an alcohol in the presence of a Lewis acid or Bronsted acid catalyst (Patent Documents 1 and 2). 5. A method in which a cyclic sulfamidate derived from serine is reacted with an alcohol (Patent Document 3). These methods are methods for producing O-alkyl-substituted serine derivatives via an intermediate derived from serine.

[0004] Japanese Patent Application Laid-Open No. 57-159747 International Publication No. 2010 / 053050 International Publication No. 2020 / 095983

[0005] Future Med. Chem. 2009, 1,1289-1310J. Med. Chem., 2010, 53(15), 5716-5726Tetrahedron Letters, 2012, 53,3225-3229Bioorganic & MedicinalChemistry Letters, 1992, 2, 579-582Journal of the American Chemical Society, 2014, 136, 12469-12478

[0006] The methods using aziridines derived from serine described in Patent Documents 1 and 2 and Non-Patent Document 2 have the problem of regioselectivity of the reaction site. The method described in Non-Patent Document 3, which uses a base, is known to result in the elimination of the hydroxyl group of serine, and is limited to the production of highly reactive benzyl ethers. In the production method from trichloroacetimidate described in Non-Patent Document 4, the substituent on the oxygen of the O-substituted serine derivative that can be produced is limited to an allyl group. In the method using an allyl ether coupling reaction described in Non-Patent Document 5, the substituent on the oxygen of the O-substituted serine derivative that can be produced is limited to an allyl group. Patent Document 3 develops a method for producing O-substituted serine derivatives via sulfamidate, which has high regioselectivity, chemical yield, and optical purity. This method includes an oxidation step using an oxidizing agent and requires four or five steps starting from a commercially available serine derivative.

[0007] An object of the present invention is to provide a method for producing an O-substituted serine derivative, which method allows for the production of an O-substituted serine derivative with a small number of steps.

[0008] The present inventors have intensively investigated the reductive hydrogenation of cyclic N,O-acetals and as a result have found a method for producing O-substituted serine derivatives in a short process, which has excellent regioselectivity and chemical yield while maintaining optical purity, and have thus completed the present invention.

[0009] That is, the present invention includes the following: [1] A method for producing a compound represented by the following general formula (1), or a salt thereof, or a solvate thereof, the method comprising the step of: (A) 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): [In the formula, R １ is an electron-withdrawing group, R ２ and R ３ (i) each independently represents hydrogen, optionally substituted C １ -C ６ alkyl, optionally substituted C ３ -C ６ cycloalkyl, optionally substituted C ２ -C ６Alkenyl, optionally substituted C ２ -C ６ or (ii) is selected from the group consisting of alkynyl, optionally substituted aralkyl, optionally substituted aryl, and optionally substituted heteroaryl, or (ii) is taken together with the intervening carbon atoms to form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring; R ４ and R ５ (i) each independently represents hydrogen, optionally substituted C １ -C ６ alkyl, optionally substituted C ３ -C ６ cycloalkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ or (ii) is selected from the group consisting of alkynyl, optionally substituted aralkyl, optionally substituted aryl, and optionally substituted heteroaryl, or (ii) is taken together with the intervening carbon atoms to form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring; R ６ is hydrogen, optionally substituted C １ -C ６ alkyl or optionally substituted aralkyl, R ７ is -OR ８ , -NR ９ R ９’ , an amino acid residue, or a peptide residue; R ８ , R ９ and R ９’ are each independently hydrogen, optionally substituted C １ -C ６ alkyl, or optionally substituted aralkyl, or R ９ and R ９’ together with the intervening nitrogen atom form a 4- to 7-membered saturated heterocyclic ring; １ is a single bond or -CH ２ - and L ２ is a single bond or -CH ２ - and L３ is a single bond or -CH ２ -, where L １ Ga-CH ２ -, then L ２ is a single bond, and L ２ Ga-CH ２ -, then L １ and L ３ is a single bond, and L ３ Ga-CH ２ -, then L ２ is a single bond.] [1-1] A method for producing a compound represented by the following general formula (1), or a salt thereof, or a solvate thereof, the method comprising the step of: (A) 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): [In the formula, R １ is an electron-withdrawing group, an amino acid residue, or a peptide residue; R ２ and R ３ (i) each independently represents hydrogen, optionally substituted C １ -C ６ alkyl, optionally substituted C ３ -C ６ cycloalkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ or (ii) is selected from the group consisting of alkynyl, optionally substituted aralkyl, optionally substituted aryl, and optionally substituted heteroaryl, or (ii) is taken together with the intervening carbon atoms to form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring; R ４ and R ５ (i) each independently represents hydrogen, optionally substituted C １ -C ６ alkyl, optionally substituted C ３ -C ６ cycloalkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C６ or (ii) is selected from the group consisting of alkynyl, optionally substituted aralkyl, optionally substituted aryl, and optionally substituted heteroaryl, or (ii) is taken together with the intervening carbon atoms to form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring; R ６ is hydrogen, optionally substituted C １ -C ６ alkyl or optionally substituted aralkyl, R ７ is -OR ８ , -NR ９ R ９’ , an amino acid residue, or a peptide residue; R ８ , R ９ and R ９’ are each independently hydrogen, optionally substituted C １ -C ６ alkyl, or optionally substituted aralkyl, or R ９ and R ９’ together with the intervening nitrogen atom form a 4- to 7-membered saturated heterocyclic ring; １ is a single bond or -CH ２ - and L ２ is a single bond or -CH ２ - and L ３ is a single bond or -CH ２ -, where L １ Ga-CH ２ -, then L ２ is a single bond, and L ２ Ga-CH ２ -, then L １ and L ３ is a single bond, and L ３ Ga-CH ２ -, then L ２is a single bond.] [2] The method according to [1], wherein step (A) is carried out in the presence of an acid. [3] The method according to [2], wherein the acid is a metal Lewis acid. [4] The method according to [3], wherein the metal Lewis acid is at least one selected from the group consisting of metal halides, metal triflates, metal alkoxides, and metal halide alkoxides. [5] The method according to [3] or [4], wherein the metal in the metal Lewis acid is at least one selected from the group consisting of titanium, tin, scandium, zirconium, zinc, and aluminum. [6] The method according to [5], wherein the metal in the metal Lewis acid is at least one selected from the group consisting of titanium, tin, and scandium. [7] The method according to [4], wherein the metal Lewis acid is at least one selected from the group consisting of titanium tetrahalide, tin tetrahalide, scandium triflate, tetraalkoxytitanium, and alkoxytrichlorotitanium. [8] The method according to [7], wherein the metal Lewis acid is at least one selected from the group consisting of titanium tetrachloride, tin tetrachloride, scandium triflate, tetraisopropyl orthotitanate, and isopropoxytrichlorotitanium. [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.

[10] The method according to [9], wherein the metal Lewis acid is a combination of titanium tetrahalide and tetraalkoxytitanium.

[11] The method according to

[10] , wherein the metal Lewis acid is a combination of titanium tetrachloride and tetraisopropyl orthotitanate.

[12] The method according to

[11] , wherein the metal Lewis acid is a combination of titanium tetrachloride and tetraisopropyl orthotitanate in a molar ratio of 2 to 4:1.

[13] The method according to

[11] , wherein the metal Lewis acid is a combination of titanium tetrachloride and tetraisopropyl orthotitanate in a molar ratio of 3:1.

[14] The method according to [4], wherein the metal Lewis acid is one selected from the group consisting of titanium tetrahalide, tin tetrahalide, scandium triflate, and alkoxytrichlorotitanium.

[15] The method according to

[14] , wherein the metal Lewis acid is one selected from the group consisting of titanium tetrachloride, tin tetrachloride, scandium triflate, and isopropoxytrichlorotitanium.

[16] The method according to

[15] , wherein the metal Lewis acid is isopropoxytrichlorotitanium.

[17] The method according to any one of [1] to

[16] , wherein the reducing agent used in step (A) is a hydride reducing agent.

[18] The method according to

[17] , wherein the hydride reducing agent is at least one selected from the group consisting of silane reducing agents and borane reducing agents.

[19] The method according to

[18] , wherein the silane reducing agent is at least one selected from the group consisting of triethylsilane, triisopropylsilane, tristrimethylsilylsilane, phenylsilane, dimethylphenylsilane, tetraphenyldisilane, poly(methylhydrosiloxane), and 1,1,3,3-tetramethyldisiloxane.

[20] The method according to

[19] , wherein the silane-based reducing agent is at least one selected from the group consisting of triethylsilane, poly(methylhydrosiloxane), and 1,1,3,3-tetramethyldisiloxane.

[21] The method according to any one of [2] to

[20] , wherein the amount of the acid used in step (A) is 0.1 to 20 equivalents relative to the compound represented by general formula (2), and the amount of the reducing agent used is 0.5 to 30 equivalents relative to the compound represented by general formula (2).

[22] The method according to any one of [2] to

[20] , wherein the amount of the acid used in step (A) is 0.1 to 20 equivalents, 0.3 to 7 equivalents, or 0.5 to 5 equivalents relative to the compound represented by general formula (2).

[23] The method according to any one of [2] to

[20] , wherein the amount of the acid used in the step (A) is 1 equivalent to 3 equivalents, both inclusive, relative to the compound represented by general formula (2).

[24] The method according to any one of [1] to

[20] , wherein the amount of the reducing agent used in the step (A) is 0.5 equivalents to 30 equivalents, 1 equivalent to 20 equivalents, or 1.5 equivalents to 10 equivalents, both inclusive, relative to the compound represented by general formula (2).

[25] The method according to any one of [1] to

[20] , wherein the amount of the reducing agent used in step (A) is 2 to 7 equivalents relative to the amount of the compound represented by formula (2).

[26] The method according to any one of [1] to

[25] , wherein 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.

[27] The method according to

[26] , wherein the halogenated solvent is at least one selected from the group consisting of dichloromethane, 1,2-dichloroethane, and chloroform, and the benzene-based solvent is at least one selected from the group consisting of toluene, chlorobenzene, fluorobenzene, and benzotrifluoride.

[28] The method according to

[26] , wherein the solvent is at least one selected from the group consisting of dichloromethane, toluene, and chlorobenzene.

[29] The method according to any one of [1] to

[28] , wherein step (A) is further carried out in the presence of a solubilizing agent.

[30] The method according to

[29] , wherein the solubilizing agent is at least one selected from the group consisting of a fluoroalcohol, an alcohol, a nitrile solvent, and an ester solvent.

[31] The method according to

[30] , wherein 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, and the ester solvent is at least one selected from the group consisting of ethyl acetate and dimethyl carbonate.

[32] The method according to

[29] , wherein the solubilizing agent is 2,2,2-trifluoroethanol or 1,1,1,3,3,3-hexafluoro-2-propanol.

[33] The method according to any one of [1] to

[32] , wherein the step (A) is carried out at a temperature of -50°C to 50°C for 5 minutes to 24 hours.

[34] The method according to any one of [1] to

[32] , wherein the step (A) is carried out at a temperature of -50°C to 50°C, -40°C to 40°C, or -30°C to 30°C.

[35] The method according to any one of [1] to

[32] , wherein the step (A) is carried out at a temperature of -20°C to 25°C.

[36] The method according to any one of [1] to

[32] , wherein the step (A) is carried out for 5 minutes to 24 hours, 10 minutes to 12 hours, or 20 minutes to 8 hours.

[37] The method according to any one of [1] to

[32] , wherein the step (A) is carried out for 30 minutes to 5 hours.

[38] The method according to any one of [1] to

[32] , wherein the step (A) is carried out at a temperature of -20°C to 25°C for 30 minutes to 5 hours.

[39] The method according to any one of [1] to

[38] , comprising a base treatment step of further adding a base after the step (A) to reduce the content of compound (4) in the reaction mixture. [In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , L １ , L ２ , and L ３has the same meaning as defined in [1].]

[40] The method of

[39] , wherein the base is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, and tetraalkylammonium hydroxide.

[41] The method of

[40] , wherein the base is sodium hydroxide or potassium hydroxide.

[42] The method of any one of [1] to

[41] , wherein the base treatment step is carried out 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.

[43] The method of any one of [1] to

[41] , wherein the base treatment step is carried out at a temperature of 10°C to 25°C.

[44] The method of any one of [1] to

[41] , wherein the base treatment step is carried out for 30 minutes to 5 hours.

[45] The method according to any one of [1] to

[40] , wherein the base treatment step is carried out using sodium hydroxide or potassium hydroxide for 30 minutes to 5 hours at a temperature of 10° C. to 25° C.

[46] The method according to any one of [1] to

[45] , further comprising, before the step (A), a step of: (B) reacting a compound represented by the following general formula (3) with an aldehyde, a ketone, an acetal, or a vinyl ether to obtain a compound represented by the following general formula (2): [In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , L １ , L ２ , and L ３is defined as defined in [1].]

[47] The method according to

[46] , wherein the step (B) is a step of reacting with an aldehyde or a ketone in the presence of an acid to obtain a compound represented by general formula (2).

[48] The method according to

[47] , wherein the acid is a Lewis acid.

[49] The method according to

[48] , wherein the Lewis acid is at least one selected from the group consisting of a complex of boron trifluoride with an ethereal solvent and a trialkylsilyl triflate.

[50] The method according to

[49] , wherein the Lewis acid is at least one selected from the group consisting of a boron trifluoride-tetrahydrofuran complex, a boron trifluoride-diethyl ether complex, and trimethylsilyl triflate.

[51] The method according to any one of

[46] to

[50] , wherein the step (B) is further carried out in the presence of a silylating agent.

[52] The method according to

[51] , wherein 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.

[53] The method according to

[52] , wherein the silylating agent is N,O-bis(trimethylsilyl)trifluoroacetamide.

[54] The method according to any one of

[46] to

[53] , wherein 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 to 6 hours.

[55] The method according to any one of

[46] to

[53] , wherein step (B) is carried out at a temperature of 20°C to 50°C.

[56] The method according to any one of

[46] to

[53] , wherein step (B) is carried out for 30 minutes to 3 hours.

[57] The method according to any one of

[46] to

[53] , wherein the step (B) is carried out at a temperature of 20°C to 50°C for 30 minutes to 3 hours. ７ is -OR ８ and R ８ is hydrogen, optionally substituted C １ -C ６

[59] The method according to any one of [1] to

[57] , wherein R is alkyl, or aralkyl which may have a substituent. ７[59-1] The method according to

[58] , wherein R is —OH. ７ Ha-OR ８ and R ８ is C １ -C ６ [59-2] The method according to

[58] , wherein R is alkyl. ７ Ha-OR ８ and R ８

[60] The method according to

[58] , wherein R is methyl. ７ is -NR ９ R ９’ and R ９ and R ９’ are each independently hydrogen, optionally substituted C １ -C ６ alkyl, or optionally substituted aralkyl, or R ９ and R ９’

[61] The method according to any one of [1] to

[57] , wherein R is taken together with the intervening nitrogen atom to form a 4- to 7-membered saturated heterocycle. ７ is an amino acid residue or a peptide residue. ７ has a C-terminus of C １ -C ６

[62] A method for producing a compound represented by the following general formula (16), or a salt thereof, or a solvate thereof, comprising a step of producing the following compound (11) by the method described in any of [1] to

[61] above: [In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , L １ , L ２ , and L ３ is the same as defined in [1], and R １０ and R １１ (i) each independently represents hydrogen, optionally substituted C １ -C ６alkyl, optionally substituted C ３ -C ６ cycloalkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ or (ii) is selected from the group consisting of alkynyl, optionally substituted aralkyl, optionally substituted aryl, and optionally substituted heteroaryl, or forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring together with an intervening carbon atom.]

[63] The method according to

[62] , further comprising, after the step of producing compound (11) below, a step of: (C) reacting a compound represented by general formula (11) below with an aldehyde, a ketone, an acetal, or a vinyl ether in the presence of a Lewis acid to obtain a compound represented by general formula (15) below, and (D) reacting a compound represented by general formula (15) below with a reducing agent in the presence of a Lewis acid to obtain a compound represented by general formula (16) below. [In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R １０ , R １１ , L １ , L ２ , and L ３are defined as defined in [1] and

[62] .]

[64] The method according to

[63] , wherein the Lewis acid in step (C) is at least one selected from the group consisting of a boron trifluoride-ether complex, trialkylsilyl triflate, titanium tetrachloride, and tetraalkoxytitanium.

[65] The method according to

[64] , wherein the Lewis acid in step (C) is a boron trifluoride-diethyl ether complex or a boron trifluoride-tetrahydrofuran complex.

[66] The method according to any one of

[63] to

[65] , wherein the Lewis acid in step (D) is at least one selected from the group consisting of a boron trifluoride-alkyl ether complex, trialkylsilyl triflate, titanium tetrachloride, and tetraalkoxytitanium.

[67] The method according to

[66] , wherein the Lewis acid in step (D) is trimethylsilyl triflate.

[68] The method according to any one of

[63] to

[67] , wherein the reducing agent in step (D) is a hydride reducing agent.

[69] The method according to

[68] , wherein the hydride reducing agent is at least one selected from the group consisting of silane reducing agents and borane reducing agents.

[70] The method according to

[69] , wherein the silane reducing agent is at least one selected from the group consisting of triethylsilane, triisopropylsilane, tristrimethylsilylsilane, phenylsilane, dimethylphenylsilane, tetraphenyldisilane, poly(methylhydrosiloxane), and 1,1,3,3-tetramethyldisiloxane.

[71] The method according to

[69] , wherein the silane reducing agent is at least one selected from the group consisting of triethylsilane, poly(methylhydrosiloxane), and 1,1,3,3-tetramethyldisiloxane.

[72] R １ But -C(=O)-R １２ , -C(=O)-OR １３ , -S(=O) ２ -R １４ , -S(=O) ２ -OR １５ , -P(=O)-R １６ R １７ , or -P(=O)-(OR １８ ) ２ where R １２, R １３ , R １４ , R １５ , R １６ , R １７ , and R １８ is an optionally substituted C １ -C ６ alkyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl; 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 forms a 3- to 8-membered alicyclic ring together with the carbon atom to which it is attached, and 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, or R ４ and R ５ forms a 3- to 8-membered alicyclic ring together with the carbon atom to which it is attached, and R ６ is hydrogen, methyl, ethyl, n-propyl, n-butyl, or benzyl; L １ , L ２ , and L ３

[73] The method according to any one of [1] to

[71] , wherein R １ But -C(=O)-R １２ , -C(=O)-OR １３ , -S(=O) ２ -R １４ , -S(=O) ２ -OR １５ , -P(=O)-R １６ R １７ , or -P(=O)-(OR １８ ) ２ where R １２ , R １３ , R １４ , R １５ , R１６ , R １７ , and R １８ is an optionally substituted C １ -C ６

[74] The method according to any one of [1] to

[72] , wherein R is alkyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl. １ But -C(=O)-R １２ , -C(=O)-OR １３ , or -S(=O) ２ -R １４ where R １２ , R １３ , and R １４ is an optionally substituted C １ -C ６

[75] The method according to

[73] , wherein R is alkyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl. １

[76] The method according to

[74] , wherein R is benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl, trifluoroacetyl, methanesulfonyl, para-toluenesulfonyl, (trifluoromethyl)sulfonyl, or 2-nitrobenzenesulfonyl (Nosyl). １ The method according to

[75] , wherein R is benzyloxycarbonyl (Cbz) or 9-fluorenylmethyloxycarbonyl (Fmoc). 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 forms a 3- to 8-membered alicyclic ring together with the carbon atom to which it is attached, and R ４ and R ５are each independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, tert-butyl, isobutyl, isopentyl, benzyl, phenyl, and pyridyl, or R ４ and R ５ forms a 3- to 8-membered alicyclic ring together with the carbon atom to which it is attached, and R ６ is hydrogen, methyl, ethyl, n-propyl, n-butyl, or benzyl; L １ , L ２ , and L ３ [76-2] The method according to any one of [1] to

[71] , wherein R １ is an amino acid residue or peptide residue whose N-terminus is protected with benzyloxycarbonyl (Cbz) or 9-fluorenylmethyloxycarbonyl (Fmoc). １ is an amino acid residue whose N-terminus is protected with benzyloxycarbonyl (Cbz) or 9-fluorenylmethyloxycarbonyl (Fmoc). 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

[78] The method according to any one of [1] to

[76] , wherein R is, together with the carbon atom to which it is attached, a 3- to 8-membered alicyclic ring. ２ is methyl, ethyl, n-propyl, n-butyl, or isobutyl, and R ３ is hydrogen or methyl, or R ２ and R ３

[79] The method according to

[77] , wherein R is taken together with the carbon atom to which it is attached to form a 4- to 6-membered alicyclic ring. ４ and R ５are each independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, tert-butyl, isobutyl, isopentyl, benzyl, phenyl, and pyridyl, or R ４ and R ５

[80] The method according to any one of [1] to

[78] , wherein R is, together with the carbon atom to which it is attached, a 3- to 8-membered alicyclic ring. ４ is hydrogen, methyl, ethyl, n-propyl, n-butyl, or isobutyl, and R ５

[81] The method according to

[79] , wherein R is hydrogen. ４ is hydrogen or methyl, and R ５

[82] The method according to

[80] , wherein R is hydrogen. ６

[83] The method according to any one of [1] to

[81] , wherein R is hydrogen, methyl, ethyl, n-propyl, n-butyl, or benzyl. ６

[84] The method according to

[82] , wherein L is hydrogen. １ , L ２ , and L ３is a single bond.

[85] A method for producing a peptide compound, comprising the method of any of [1] to

[84] .

[86] A method for producing a peptide compound, comprising: (i) producing compound (11) or (16) by the method of any of [1] to

[85] above, and (ii) condensing, in a solvent, the carboxy group of compound (11) or (16) obtained in step (i) with an amino acid having an amino group or a peptide having an amino group.

[87] 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, 4-(cyclobutoxymethyl)-5-oxo-oxazolidine-3-carboxylate benzyl, 4-{[1-methoxy-1-oxapropan-2-yl]carbamoyl}-2,2,5-trimethyloxazolidine-3-carboxylate benzyl, A compound selected from the group consisting of N-(benzyloxy)carbonyl-O-isopropyl-threonyl-alanine methyl ester and N-[(9H-fluoren-9-ylmethoxycarbonyl)-leucyl]-O-isopropyl-threonine, or a salt thereof, or a solvate thereof.

[88] (2S)-2-(benzyloxycarbonylamino)-3-(cyclobutoxy)propanoic acid, a salt thereof, or a solvate thereof.

[89] (2S)-2-(benzyloxycarbonylamino)-3-isopentyloxypropanoic acid, a salt thereof, or a solvate thereof.

[90] (2S,3R)-2-(benzyloxycarbonylamino)-3-isopropoxybutanoic acid, a salt thereof, or a solvate thereof.

[91] (2S)-2-[benzyloxycarbonyl(methyl)amino]-3-(cyclobutoxy)propanoic acid, a salt thereof, or a solvate thereof.

[92] (4S)-3-benzyloxycarbonyl-2-ethyl-oxazolidine-4-carboxylic acid or its salt or solvate thereof.

[93] (4S)-3-benzyloxycarbonyl-2-isobutyl-oxazolidine-4-carboxylic acid or its salt or solvate thereof.

[94] (4S)-4-(cyclobutoxymethyl)-5-oxo-oxazolidine-3-carboxylate benzyl or its salt or solvate thereof.

[95] (4S,5R)-4-{[(S)-1-methoxy-1-oxapropan-2-yl]carbamoyl}-2,2,5-trimethyloxazolidine-3-carboxylate benzyl or its salt or solvate thereof.

[96] N-(benzyloxy)carbonyl-O-isopropyl-L-threonyl-L-alanine methyl ester or its salt or solvate thereof.

[97] N-[(9H-Fluoren-9-ylmethoxycarbonyl)-L-leucyl]-O-isopropyl-L-threonine or a salt thereof, or a solvate thereof. In the above numbering system, the numbers referred to in the dependent claims include their subnumbers unless otherwise specified. For example, [1] referred to in the dependent claims indicates that it includes [1] as well as its subnumber [1-1]. The same applies to other numbering systems.

[0010] According to the present invention, there can be provided a method for producing an O-substituted serine derivative, which method enables the production of an O-substituted serine derivative with a small number of steps.

[0011] (Abbreviations) Examples of abbreviations used in this specification are listed below along with their meanings: MTBE: tert-butyl methyl ether HFIP: 1,1,1,3,3,3-hexafluoro-2-propanol DCHA: dicyclohexylamine MeTHF: 2-methyltetrahydrofuran CPME: cyclopentyl methyl ether PMHS: poly(methylhydrosiloxane) TMDS: 1,1,3,3-tetramethyldisiloxane

[0012] (Definition of Terms) As used herein, "room temperature" means a temperature of about 20°C to about 25°C.

[0013] In this specification, the term "electron-withdrawing group" refers to a substituent that more easily attracts electrons from the atom to which it is bonded than a hydrogen atom. Examples of electron-withdrawing groups include -C(=O)-R １２ , -C(=O)-OR １３ , -S(=O) ２ -R １４ , -S(=O) ２ -OR １５ , -P(=O)-R １６ R １７ , or -P(=O)-(OR １８ ) ２ (where R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , and R １８ is an optionally substituted C １ -C ６ alkyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl).

[0014] As used herein, the term "halogen atom" includes, for example, F, Cl, Br, or I.

[0015] As used herein, "alkyl" refers to a monovalent group derived from an aliphatic hydrocarbon by removing any one hydrogen atom, and does not contain heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds in the skeleton, but has a subset of hydrocarbyl or hydrocarbon group structures containing hydrogen and carbon atoms. Alkyl includes not only linear but also branched chain alkyls. Alkyl preferably has 1 to 20 carbon atoms (C １ -C ２０ , hereinafter referred to as “C ｐ -C ｑ " means that the number of carbon atoms is p to q), and preferably C １ -C １０ Alkyl, more preferably C １ -C ６Specific examples of the alkyl 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, 3,3-dimethylbutyl, 1-ethylbutyl, and 2-ethylbutyl.

[0016] As used herein, "alkenyl" refers to an alkyl group having at least one double bond (two adjacent SP ２ It is a monovalent group having 1 carbon atom. Depending on the configuration of the double bond and the substituents (if any), the geometry of the double bond can be in the Entgegen (E) or Zusammen (Z), cis or trans configuration. Alkenyl includes not only straight chains but also branched chains. C is preferred as alkenyl. ２ -C １０ alkenyl, more preferably C ２ -C ６ Specific examples include alkenyl, such as vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl, and hexenyl.

[0017] As used herein, "alkynyl" refers to a monovalent group having at least one triple bond (two adjacent SP carbon atoms). Alkynyl includes not only straight chain but also branched chain. C ２ -C １０ Alkynyl, more preferably C ２ -C ６Specific examples include 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, and 3-methyl-(5-phenyl)-4-pentynyl.

[0018] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, including monocyclic, bicyclic, and spirocyclic rings. ３ -C ８ Specific examples include cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, and spiro[3.3]heptyl.

[0019] As used herein, the term "aryl" refers to a monovalent aromatic hydrocarbon ring or aromatic hydrocarbon ring group. Preferred examples of aryl include C ６ -C １０ Specific examples of the aryl include phenyl and naphthyl (for example, 1-naphthyl and 2-naphthyl).

[0020] As used herein, the term "heteroaryl" refers to an aromatic cyclic monovalent group or aromatic heterocyclic group containing 1 to 5 heteroatoms in addition to carbon atoms. The ring may be a monocyclic ring or a condensed ring with another ring, and may be partially saturated. The number of atoms constituting the heteroaryl ring is preferably 5 to 10 (5- to 10-membered heteroaryl), and more preferably 5 to 7 (5- to 7-membered heteroaryl). Specific examples of heteroaryl 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, imidazopyridyl, pyrazolopyridyl, imidazopyridyl, triazolopyridyl, pyrrolopyrazinyl, and furopyridyl.

[0021] As used herein, "aralkyl (arylalkyl)" refers to a group in which at least one hydrogen atom of an "alkyl" as defined above is substituted with an "aryl" as defined above. ７ -C １４ Aralkyl is preferred, C ７ -C １０ Aralkyl is more preferred. Specific examples of aralkyl include benzyl, phenethyl, and 3-phenylpropyl.

[0022] As used herein, "alicyclic ring" refers to a non-aromatic hydrocarbon ring. The alicyclic ring may have an unsaturated bond within the ring, or may be a polycyclic ring having two or more rings. Furthermore, the carbon atoms constituting the ring may be oxidized to form a carbonyl. Preferred examples of the alicyclic ring include 3- to 8-membered alicyclic rings. Specific examples of the alicyclic ring 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.

[0023] As used herein, the term "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 within the ring. The saturated heterocycle may be a monocycle or may form a condensed 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. Specific examples of the saturated heterocycle include 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, a piperidine ring, a 4-oxopiperidine ring, a piperazine ring, a pyrazolidine ring, an imidazolidine ring, an oxazolidine ring, an isoxazolidine ring, a thiazolidine ring, an isothiazolidine ring, a thiadiazolidine ring, an oxazolidone ring, a dioxolane ring, a dioxane ring, a thietane ring, an octahydroindole ring, an indoline ring, an azepane ring, a dioxepane ring, and a 5,9-dioxaspiro[3.5]nonane ring.

[0024] The compounds described herein can be their salts or solvates.Salts of compounds include, for example, hydrochloride; hydrobromide; hydroiodide; phosphate; phosphonate; sulfate; sulfonate such as methanesulfonate and p-toluenesulfonate; carboxylate such as acetate, citrate, malate, tartrate, succinate, salicylate; alkali metal salt such as sodium salt and potassium salt; alkaline earth metal salt such as magnesium salt and calcium salt; ammonium salt such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, tetraalkylammonium salt, etc.These salts can be prepared, for example, by contacting the compound with an acid or base.In this specification, the term "solvate" refers to a compound that forms a molecular group together with a solvent. Examples of solvates include hydrates, alcoholates (ethanol solvates, methanol solvates, 1-propanol solvates, 2-propanol solvates, etc.), and solvates with a single solvent such as dimethyl sulfoxide, as well as solvates formed with multiple solvents per molecule of the compound, or solvates formed with multiple types of solvents per molecule of the compound. When the solvent is water, the solvate is called a hydrate. As the solvate of the compound of the present invention, hydrates are preferred, and specific examples of such hydrates include mono- to decahydrates, preferably mono- to pentahydrates, and more preferably mono- to trihydrates.

[0025] As used herein, "amino acid" includes natural amino acids and unnatural amino acids (sometimes referred to as amino acid derivatives). Furthermore, as used herein, "amino acid" may refer to amino acid residues. As used herein, "natural amino acids" refer to Gly, Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg, and Pro. Unnatural amino acids (amino acid derivatives) are not particularly limited, but examples include β-amino acids, D-amino acids, N-substituted amino acids, α,α-disubstituted amino acids, amino acids with side chains different from those of natural amino acids, and hydroxycarboxylic acids. As used herein, amino acids may have any stereoconfiguration. The side chain of an amino acid is not particularly limited, and may be freely selected from, in addition to a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, a heteroaralkyl group, a cycloalkyl group, and a spiro-linked cycloalkyl group. Each of these may have a substituent, and the substituents are not limited, and may be independently selected from any substituents containing, for example, a halogen atom, an O atom, a S atom, a N atom, a B atom, a Si atom, or a P atom. Examples of such substituents include optionally substituted alkyl groups, alkoxy groups, alkoxyalkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups, and cycloalkyl groups, as well as oxo, aminocarbonyl, and halogen atoms. In a non-limiting embodiment, the amino acid herein may be a compound having a carboxyl group and an amino group in the same molecule. Specific examples include 4-aminobutanoic acid, 5-aminopentanoic acid, 6-aminohexanoic acid, 4-piperidinecarboxylic acid, and 4-aminobenzoic acid.

[0026] As used herein, "peptide" and "peptide compound" are not particularly limited as long as they are peptides formed by amide bonds or ester bonds between natural amino acids and / or unnatural amino acids. Peptide compounds are preferably peptides of 5 to 30 residues, more preferably 7 to 15 residues, and even more preferably 9 to 13 residues. Peptides are preferably peptides of 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.

[0027] In this specification, the "amino acid residues" and "peptide residues" that constitute a peptide compound may be simply referred to as "amino acids" and "peptides".

[0028] As used herein, the term "optionally substituted" means that a group may be substituted with any substituent. Furthermore, each of these groups may be substituted with a substituent, and the substituents are not limited thereto. For example, one or more of the substituents may be independently selected from any substituents containing a halogen atom, an oxygen atom, a sulfur atom, a nitrogen atom, a boron atom, a silicon atom, or a phosphorus atom. Examples of the substituent include alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, oxo, aminocarbonyl, alkylsulfonyl, alkylsulfonylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, halogen, nitro, amino, monoalkylamino, dialkylamino, cyano, carboxyl, alkoxycarbonyl, and formyl.

[0029] In this specification, examples of halogen-based solvents include dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, etc. Among these, dichloromethane, chloroform, and 1,2-dichloroethane are preferred.

[0030] In this specification, examples of benzene-based solvents include benzene, toluene, xylene, fluorobenzene, chlorobenzene, 1,2-dichlorobenzene, bromobenzene, anisole, ethylbenzene, nitrobenzene, cumene, benzotrifluoride, etc. Among these, toluene, fluorobenzene, chlorobenzene, and benzotrifluoride are preferred.

[0031] In this specification, 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, and tetraglyme.

[0032] In this specification, examples of the ester solvent include methyl acetate, ethyl acetate, butyl acetate, methyl propionate, propyl acetate, isopropyl acetate, isobutyl acetate, pentyl acetate, dimethyl carbonate, diethyl carbonate, γ-valerolactone, etc. Among these, ethyl acetate and dimethyl carbonate are preferred.

[0033] In this specification, examples of nitrile solvents include acetonitrile, propionitrile, etc. Among these, acetonitrile is preferred.

[0034] In this specification, examples of fluoroalcohols include 2,2,2-trifluoroethanol and 1,1,1,3,3,3-hexafluoro-2-propanol.

[0035] In this specification, examples of alcohol include methanol, ethanol, n-propanol, 2-propanol, etc. Among these, methanol, ethanol, and 2-propanol are preferred.

[0036] As used herein, "one or more" means one or more than one. When "one or more" is used in the context of substituents on a group, the term means a number from one to the maximum number of substituents permitted by that group. Specific examples of "one or more" include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and / or more.

[0037] As used herein, the term "and / or" includes any combination of "and" and "or." Specifically, for example, "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, and (vii) A, B, and C.

[0038] (General Production Method) A general production method for the compound of the present invention will be described. In one aspect, the compound represented by formula (1) can be produced, for example, by Production Method 1 including Step A shown below.

[0039] Manufacturing method 1:

[0040] R in the formula １ is an electron-withdrawing group. １ is preferably —C(═O)—R １２ , -C(=O)-OR １３ , -S(=O) ２ -R １４ , -S(=O) ２ -OR １５ , -P(=O)-R １６ R １７ , or -P(=O)-(OR １８ ) ２ where R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , and R １８ is an optionally substituted C １ -C ６R is alkyl, aralkyl which may have a substituent, aryl which may have a substituent, or heteroaryl which may have a substituent, and specific examples thereof include methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, isopentyl, trifluoromethyl, phenyl, nitrophenyl, pyridyl, benzyl, methoxybenzyl, fluorobenzyl, and 9-fluorenylmethyl. １ More preferably, —C(═O)—R １２ , -C(=O)-OR １３ , or -S(=O) ２ -R １４ where R １２ , R １３ , and R １４ is an optionally substituted C １ -C ６ R is alkyl, aralkyl which may have a substituent, aryl which may have a substituent, or heteroaryl which may have a substituent, and specific examples thereof include methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, isopentyl, trifluoromethyl, phenyl, nitrophenyl, pyridyl, benzyl, methoxybenzyl, fluorobenzyl, and 9-fluorenylmethyl. １ More preferred as R are benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl, trifluoroacetyl, methanesulfonyl, para-toluenesulfonyl, (trifluoromethyl)sulfonyl, and 2-nitrobenzenesulfonyl (Nosyl). １ Particularly preferred as R are benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc). １ is an amino acid residue or a peptide residue. In this case, R １is preferably an amino acid residue or peptide residue whose N-terminus is protected with benzyloxycarbonyl (Cbz) or 9-fluorenylmethyloxycarbonyl (Fmoc), and more preferably an amino acid residue whose N-terminus is protected with benzyloxycarbonyl (Cbz) or 9-fluorenylmethyloxycarbonyl (Fmoc).

[0041] R in the formula ２ and R ３ are each independently hydrogen, optionally substituted C １ -C ６ alkyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl, or R ２ and R ３ together with the carbon atom to which it is attached form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring. 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 attached. ２ When R is methyl, ethyl, n-propyl, n-butyl, or isobutyl, ３ is hydrogen or methyl, or R ２ and R ３ together with the carbon atom to which it is attached form a 4- to 6-membered alicyclic ring.

[0042] R in the formula ４ and R ５ are each independently hydrogen, optionally substituted C １ -C ６ alkyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl, or R ４ and R ５together with the carbon atom to which it is attached form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring. 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 together with the carbon atom to which it is attached form a 3- to 8-membered alicyclic ring. 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.

[0043] R in the formula ６ is hydrogen, optionally substituted C １ -C ６ It is alkyl or aralkyl which may have a substituent. Preferably, R ６ is hydrogen, methyl, ethyl, n-propyl, n-butyl, or benzyl, and more preferably R ６ is hydrogen.

[0044] R in the formula ７ is -OR ８ , -NR ９ R ９’ , an amino acid residue, or a peptide residue; R ８ , R ９ and R ９’ are each independently hydrogen, optionally substituted C １ -C ６ alkyl, or optionally substituted aralkyl, or R ９ and R ９’ together with the intervening nitrogen atom form a 4- to 7-membered saturated heterocyclic ring. ７ is -OR ８ and more preferably R ７ is —OH. In some embodiments, preferably R ７ Ha-OR ８ and R８ is C １ -C ６ alkyl, more preferably R ７ Ha-OR ８ and R ８ is methyl. In some embodiments, preferably R ７ has a C-terminus of C １ -C ６ It is an amino acid residue protected with an alkyl ester.

[0045] L in the formula １ , L ２ , and L ３ is a single bond or -CH ２ -, where L １ Ga-CH ２ -, then L ２ is a single bond, and L ２ Ga-CH ２ -, then L １ and L ３ is a single bond, and L ３ Ga-CH ２ -, then L ２ is a single bond. Preferably, L １ , L ２ , and L ３ is a single bond.

[0046] Step A of Production Method 1 is a step of producing an O-substituted serine derivative (1) by a reductive hydrogenation reaction involving ring-opening of a cyclic N,O-acetal derivative (2). This step can be 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, or in the presence or absence of a solubilizing agent, at a temperature of preferably −50° C. to 50° C., more preferably −40° C. to 40° C., even more preferably −30° C. to 30° C., and particularly preferably −20° C. to 25° C., for preferably 5 minutes to 24 hours, more preferably 10 minutes to 12 hours, even more preferably 20 minutes to 8 hours, and particularly preferably 30 minutes to 5 hours.

[0047] The reducing agent may be a hydride-based reducing agent, such as silane-based reducing agents such as triethylsilane, triisopropylsilane, tristrimethylsilylsilane, phenylsilane, dimethylphenylsilane, tetraphenyldisilane, poly(methylhydrosiloxane), and 1,1,3,3-tetramethyldisiloxane, or a borane-based reducing agent. Of these, triethylsilane, poly(methylhydrosiloxane), and 1,1,3,3-tetramethyldisiloxane are preferably used, and triethylsilane is more preferably used.

[0048] The amount of the reducing agent used is not particularly limited, but can be, for example, 0.5 to 30 equivalents relative to the compound represented by formula (2), preferably 1 to 20 equivalents, more preferably 1.5 to 10 equivalents, and even more preferably 2 to 7 equivalents.

[0049] Examples of the acid that can be used include Bronsted acids such as trifluoromethanesulfonic acid (TfOH), methanesulfonic acid (MsOH), and trifluoroacetic acid (TFA), complexes of boron trifluoride with ether solvents, and non-metallic Lewis acids such as trialkylsilyl triflates, as well as metallic Lewis acids described below, with metallic Lewis acids being preferred.

[0050] Here, the metal Lewis acid refers to a Lewis acid composed of a metal and an anion group, and examples thereof include metal halides, metal triflates, metal alkoxides, and metal halide alkoxides.The metal in the metal Lewis acid may be a known polyvalent metal, and examples thereof include titanium, tin, scandium, zirconium, zinc, aluminum, calcium, bismuth, antimony, cadmium, vanadium, molybdenum, tungsten, iron, copper, cobalt, lead, nickel, silver, and rare earth metals.Among these, titanium, tin, scandium, zirconium, zinc, and aluminum are preferred, titanium, tin, and scandium are more preferred, and titanium and tin are even more preferred. The anionic group in the metal Lewis acid may be a known anionic group, such as an anionic group derived from trifluoromethanesulfonic acid (TfOH), methanesulfonic acid (MsOH), bis(trifluoromethanesulfonyl)imide (TfNH), tris(trifluoromethanesulfonyl)methane (HCTf), pentafluorophenylbis(triflyl)methane (CHCHTf), trifluoroacetic acid (TFA), 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, methanol, ethanol, n-propanol, isopropanol, n-butanol, phenol, or the like, or a combination of one or more independently selected from the group consisting of these anionic groups.

[0051] Specific examples of the metal Lewis acid include metal halides such as titanium tetrahalides (e.g., titanium tetrachloride (TiCl4)) and tin tetrahalides (e.g., tin tetrachloride (SnCl4)), metal triflates such as scandium triflate (Sc(OTf)3), metal alkoxides such as tetraalkoxytitanium (e.g., tetraisopropyl orthotitanate (Ti(OiPr)4)), and alkoxytrichlorotitanium (e.g., isopropoxytrichlorotitanium (TiCl3(OiPr))), with isopropoxytrichlorotitanium being preferred. The metal Lewis acid may also be a combination of multiple types, such as a combination of a titanium tetrahalide and a tetraalkoxytitanium, with a combination of titanium tetrachloride and tetraisopropyl orthotitanate being preferred. In this case, the molar ratio of the titanium tetrahalide to the tetraalkoxytitanium is not particularly limited, but is preferably 2 to 4:1, and more preferably 3:1.

[0052] The amount of the acid used is not particularly limited, but can be, for example, 0.1 to 20 equivalents relative to the compound represented by formula (2), preferably 0.5 to 5 equivalents, and more preferably 1 to 3 equivalents.

[0053] Examples of the solvent include halogenated solvents such as dichloromethane, 1,2-dichloroethane, and chloroform, and benzene-based solvents such as toluene, chlorobenzene, fluorobenzene, and benzotrifluoride, and among these, dichloromethane, toluene, and chlorobenzene are preferably used.

[0054] Step A of Production Method 1 can be further carried out in the presence of a solubilizing agent. Examples of the solubilizing agent include fluoroalcohols such as 2,2,2-trifluoroethanol and 1,1,1,3,3,3-hexafluoro-2-propanol, alcohols such as methanol, ethanol, and 2-propanol, nitrile solvents such as acetonitrile, and ester solvents such as ethyl acetate and dimethyl carbonate. Among these, 2,2,2-trifluoroethanol and 1,1,1,3,3,3-hexafluoro-2-propanol are preferably used.

[0055] In one aspect, by adding a base in the post-treatment step of step A of production method 1, the content of compound (4) contained as an impurity in the reaction mixture can be reduced.

[0056] Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, and tetraalkylammonium hydroxide (for example, tetramethylammonium hydroxide), and among these, sodium hydroxide and potassium hydroxide are preferably used.

[0057] This base treatment step can be carried out at a temperature of preferably -5°C to 50°C, more preferably 0°C to 40°C, even more preferably 5°C to 30°C, and particularly preferably 10°C to 25°C, for preferably 5 minutes to 24 hours, more preferably 10 minutes to 12 hours, even more preferably 20 minutes to 8 hours, and particularly preferably 30 minutes to 5 hours.

[0058] In one aspect, among the O-substituted serine derivatives (1) obtained by step A of production method 1, R ７ For the O-substituted serine derivative (11) in which is —OH, the content of impurities in the reaction mixture can be reduced by forming a salt with a secondary amine, a tertiary amine, an alkali metal, or an alkaline earth metal and then crystallizing the salt.

[0059] Examples of the salt include dicyclohexylamine, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, etc., and among these, dicyclohexylamine is preferably used.

[0060] In one aspect, the cyclic N,O-acetal derivative (2) used as the starting material in step A of production method 1 can be produced by a method including step B shown below using compound (3) as the starting material.

[0061] R in the formula １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , L １ , L ２ , and L ３ is the R of step A １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , L １ , L ２ , and L ３ are synonymous with each other.

[0062] In the formula, Ra and Rb each independently represent C １ -C ６ It is an alkyl group or, together with the intervening oxygen and carbon atoms, forms a 5- to 7-membered saturated heterocyclic ring.

[0063] R in the formula ３’ is hydrogen, optionally substituted C １ -C ６ alkyl, optionally substituted C ３ -C ６ cycloalkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６is selected from the group consisting of alkynyl, optionally substituted aralkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R ３’ is R ２ and together with the intervening carbon atoms form a 4- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.

[0064] Step B of Production Method 1 is a step of reacting compound (3) with an aldehyde, a ketone, an acetal, or a vinyl ether to produce a cyclic N,O-acetal derivative (2). This step can be carried out in the presence or absence of an acid, a solvent, or a silylating agent, at a temperature of preferably −10° C. to 80° C., more preferably 0° C. to 70° C., even more preferably 10° C. to 60° C., and particularly preferably 20° C. to 50° C., for preferably 5 minutes to 24 hours, more preferably 10 minutes to 12 hours, even more preferably 20 minutes to 6 hours, and particularly preferably 30 minutes to 3 hours.

[0065] Examples of the acid that can be used include Bronsted acids such as trifluoromethanesulfonic acid (TfOH), methanesulfonic acid (MsOH), and trifluoroacetic acid (TFA), complexes of boron trifluoride with ether solvents, non-metallic Lewis acids such as trialkylsilyl triflates, and the above-mentioned metallic Lewis acids, and Lewis acids are preferred.

[0066] Specific examples of the Lewis acid include boron trifluoride-tetrahydrofuran complex, boron trifluoride-diethyl ether complex, and trimethylsilyl triflate.

[0067] The amount of the acid used is not particularly limited, but can be, for example, 0.05 to 1 equivalent relative to the compound represented by formula (3), preferably 0.1 to 0.5 equivalents.

[0068] Examples of the solvent include halogenated solvents such as dichloromethane, 1,2-dichloroethane, and chloroform; benzene-based solvents such as toluene, chlorobenzene, fluorobenzene, and benzotrifluoride; and ether-based solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, and cyclopentyl methyl ether. Of these, dichloromethane, toluene, and 2-methyltetrahydrofuran are preferably used.

[0069] Step B of Production Method 1 can be further carried out in the presence of a silylating agent, such as N,O-bis(trimethylsilyl)trifluoroacetamide, N,O-bis(trimethylsilyl)acetamide, and 1-trimethylsilylimidazole, with N,O-bis(trimethylsilyl)trifluoroacetamide being preferred.

[0070] In one aspect, among the O-substituted serine derivatives (1) obtained by step A of production method 1, R ７ Using the O-substituted serine derivative (11) in which is —OH as a starting material, a substituent (—CHR １０ R １１ ) can be prepared.

[0071] R in the formula １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , L １ , L ２ , and L ３ is the R of step A １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , L １ , L ２ , and L ３ are synonymous with each other.

[0072] In the formula, Ra and Rb have the same meanings as Ra and Rb in step B, respectively.

[0073] R in the formula １０ and R １１ are each independently hydrogen, optionally substituted C １ -C ６ alkyl, optionally substituted C ３ -C ６ cycloalkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ It is selected from the group consisting of alkynyl, optionally substituted aralkyl, optionally substituted aryl, and optionally substituted heteroaryl, or together with the intervening carbon atoms forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.

[0074] R in the formula １１’ is hydrogen, optionally substituted C １ -C ６ alkyl, optionally substituted C ３ -C ６ cycloalkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ is selected from the group consisting of alkynyl, optionally substituted aralkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R １１’ is R １０ and together with the intervening carbon atoms form a 4- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.

[0075] In step C, the O-substituted serine derivative (11) is reacted with an aldehyde, a ketone, an acetal, or a vinyl ether to give the oxazolidinone compound (15), for example, according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81.) This step can be carried out in the presence or absence of a Lewis acid and in the presence or absence of a solvent.

[0076] As the Lewis acid, for example, a complex of boron trifluoride with an ether solvent, a non-metallic Lewis acid such as trialkylsilyl triflate, or the above-mentioned metallic Lewis acid can be used.

[0077] Specific examples of Lewis acids include boron trifluoride-tetrahydrofuran complex, boron trifluoride-diethyl ether complex, trimethylsilyl triflate, titanium tetrachloride, and tetraalkoxytitanium, and among these, boron trifluoride-tetrahydrofuran complex and boron trifluoride-diethyl ether complex are preferred.

[0078] The amount of Lewis acid used is not particularly limited, but can be, for example, 0.2 to 5 equivalents relative to the compound represented by formula (11), preferably 0.5 to 3 equivalents, and more preferably 1 to 2 equivalents.

[0079] Examples of the solvent include halogenated solvents such as dichloromethane, 1,2-dichloroethane, and chloroform, and benzene-based solvents such as toluene, chlorobenzene, fluorobenzene, and benzotrifluoride, and among these, dichloromethane, toluene, and chlorobenzene are preferably used.

[0080] In the step D, the oxazolidinone compound (15) is subjected to a reductive ring-opening reaction to form a substituent (—CHR １０ R １１ This step can be carried out in the presence or absence of an acid, a reducing agent, and a solvent.

[0081] Examples of the acid that can be used include Bronsted acids such as trifluoromethanesulfonic acid (TfOH), methanesulfonic acid (MsOH), and trifluoroacetic acid (TFA), complexes of boron trifluoride with ether solvents, non-metallic Lewis acids such as trialkylsilyl triflates, and the above-mentioned metallic Lewis acids, and Lewis acids are preferred.

[0082] Specific examples of Lewis acids include boron trifluoride-tetrahydrofuran complex, boron trifluoride-diethyl ether complex, trimethylsilyl triflate, titanium tetrachloride, and tetraalkoxytitanium, and among these, trimethylsilyl triflate is preferred.

[0083] The amount of Lewis acid used is not particularly limited, but can be, for example, 0.2 to 5 equivalents relative to the compound represented by formula (15), preferably 0.5 to 3 equivalents, and more preferably 1 to 2 equivalents.

[0084] The reducing agent may be a hydride-based reducing agent, such as silane-based reducing agents such as triethylsilane, triisopropylsilane, tristrimethylsilylsilane, phenylsilane, dimethylphenylsilane, tetraphenyldisilane, poly(methylhydrosiloxane), and 1,1,3,3-tetramethyldisiloxane, or a borane-based reducing agent. Of these, triethylsilane, poly(methylhydrosiloxane), and 1,1,3,3-tetramethyldisiloxane are preferably used, and triethylsilane is more preferably used.

[0085] The amount of the reducing agent used is not particularly limited, but can be, for example, 1 to 20 equivalents relative to the compound represented by formula (15), preferably 1.5 to 10 equivalents, and more preferably 2 to 5 equivalents.

[0086] Examples of the solvent include halogenated solvents such as dichloromethane, 1,2-dichloroethane, and chloroform, and benzene-based solvents such as toluene, chlorobenzene, fluorobenzene, and benzotrifluoride, and among these, dichloromethane, toluene, and chlorobenzene are preferably used.

[0087] In one aspect, a peptide compound can be produced by using the O-substituted serine derivative represented by formula (11) or formula (16) obtained by the above production method, for example, by the production method described in WO2021132545 (Method for synthesizing peptide compounds). Specifically, in 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), mer), Cbz-Leu-MeLeu-Val-MeGly-MeIle-Ser(tBu)-MePhe-MeVal-Asp(tBu)-piperidine (9 mer), Cbz-MePhe-Leu-MeLeu-Val-MeGly-MeIle-Ser(tBu)-MePhe-MeVal-Asp(tBu)-piperidine (10 mer), or Cbz-MeAla-MePhe-Leu-MeLeu-Val-MeGly-MeIle-Ser(tBu)-MePhe-MeVal-Asp(tBu)-piperidine (11 mer) are described in the above publications. However, a peptide compound can be produced by using an O-substituted serine derivative represented by formula (11) or (16) in place of Cbz-Ser(tBu)-OH in a similar manner. In this case, １ is a protecting group for an amino group, preferably Cbz. Although an example of an amino acid sequence is given above, the type of amino acid is not limited.

[0088] In one aspect, a peptide compound or a cyclic peptide compound can be produced using an O-substituted serine derivative represented by formula (11) or (16), for example, by the production method described in WO2013100132 (Method for Cyclizing Peptide Compounds). Specifically, a peptide compound or a cyclic peptide compound can be produced by using an O-substituted serine derivative represented by formula (11) or (16) instead of Fmoc-Ser(tBu)-OH according to the method for producing a peptide compound or a method for producing a cyclic peptide compound described in Examples 18 to 20 of WO2013100132. In this case, R １ is a protecting group for an amino group, preferably Fmoc. Although an example of an amino acid sequence is given above, the type of amino acid is not limited.

[0089] In one aspect, the present invention provides a method for the preparation of compounds of the present invention, comprising the steps of: 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, The compound or a salt thereof, or a solvate thereof, selected from the group consisting of N-(benzyloxy)carbonyl-O-isopropyl-threonyl-alanine methyl ester and N-[(9H-fluoren-9-ylmethoxycarbonyl)-leucyl]-O-isopropyl-threonine, can be produced by the production method described herein.

[0090] In one aspect, the present invention is the following compounds or a salt thereof or a solvate thereof or a salt thereof or a solvate thereof: (2S)-2-(benzyloxycarbonylamino)-3-(cyclobutoxy)propanoic acid or a salt thereof or a solvate thereof or a salt thereof or a solvate thereof, (2S)-2-(benzyloxycarbonylamino)-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 salt thereof or a solvate thereof, (4S)-3-benzyloxycarbonyl-2-isobutyl-oxazolidine-4-carboxylic acid or a salt thereof or a solvate thereof, (4S)-4-(cyclobutoxymethyl)-5-oxo-oxazolidine-3-carboxylate benzyl or a salt thereof or a solvate thereof, (4S,5R)-4-{[(S)-1-methoxy-1-oxapropan-2-yl]carbamoyl}-2,2,5-trimethyloxazolidine-3-carboxylate benzyl or a salt thereof or a solvate thereof, N-(benzyloxy)carbonyl-O-isopropyl-L-threonyl-L-alanine methyl ester or a salt thereof or a solvate thereof, and N-[(9H-fluoren-9-ylmethoxycarbonyl)-L-leucyl]-O-isopropyl-L-threonine or a salt thereof or a solvate thereof. These compounds, salts thereof, and solvates thereof can be produced by the production methods described herein.

[0091] All prior art documents cited in this specification are hereby incorporated by reference.

[0092] The present disclosure will be described in more detail below based on examples, but the present disclosure is not limited to the following examples.

[0093] In the following examples, high performance liquid chromatography (HPLC) analysis was performed using one of the analytical conditions described below. Detection of each compound was performed using a photodiode array detector or a mass spectrometer, but other techniques such as evaporative light scattering detection may also be used.

[0094] HPLC analysis conditions Method 1 Apparatus: Waters ACQUITY UPLC H-Class Column: Ascentis Express 90A C18 (Sigma-Aldrich), 2.1 mm ID × 50 mm, 2.7 μm Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B) Elution method: B) 5% (0 min) → 100% (5 min) → 5% (5.1 min) → 5% (7 min) Flow rate: 0.5 mL / min Column temperature: 35 °C Detection wavelength: 210 nm (PDA)

[0095] HPLC analysis conditions: Method 2. Apparatus: Waters ACQUITY UPLC H-Class. Column: CHIRALPAK IC-3 (Daicel) 4.6 mm ID x 150 mm, 3 μm. Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B). Elution method: B) 5% (0 min) → 60% (20 min) → 5% (20.1 min) → 5% (25 min). Flow rate: 1.0 mL / min. Column temperature: 30 °C. Detection wavelength: 210 nm (PDA).

[0096] HPLC analysis conditions: Method 3. Apparatus: Waters ACQUITY UPLC H-Class + ACQUITY QDA. Column: Ascentis Express 90A C18 (Sigma-Aldrich), 2.1 mm ID x 50 mm, 2.7 μm. Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B). Elution method: B) 5% (0 min) → 100% (6 min) → 5% (6.1 min) → 5% (8 min). Flow rate: 0.5 mL / min. Column temperature: 35 °C. Detection wavelength: 210 nm (PDA).

[0097] HPLC analysis conditions method4 Instrument: Waters ACQUITY UPLC H-Class Column: Ascentis Express C18 (Sigma-Aldrich)4.6 mm ID x 10 cm, 2.7 μm Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B) Elution method: B) 20% (0min)→100% (9min)→20%(9.1min)→20% (13min) Flow rate: 0.7 mL / min Column temperature: 35 ℃ Detection wavelength: 210nm (PDA)

[0098] HPLC analysis conditions: Method 5. Apparatus: Waters ACQUITY UPLC H-Class + ACQUITY QDA. Column: CAPCELL CORE ADME (OSAKA SODA), 2.1 mm ID x 50 mm, 2.7 μm. Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B). Elution method: B): 5% (0 min) → 100% (5 min) → 5% (5.1 min) → 5% (7 min). Flow rate: 0.5 mL / min. Column temperature: 35°C. Detection wavelength: 210 nm (PDA).

[0099] HPLC analysis conditions: Method 6. Apparatus: Waters ACQUITY UPLC H-Class. Column: CHIRALPAK IC-3 (Daicel) 4.6 mm ID x 150 mm, 3 μm. Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B). Elution method: B) 35% (0 min) → 90% (20 min) → 100% (20.1 min) → 100% (22 min) → 35% (22.1 min) → 35% (27 min). Flow rate: 1.0 mL / min. Column temperature: 30 °C. Detection wavelength: 210 nm (PDA).

[0100] 1 ​H-NMR spectra were measured using a JEOL ECX500II nuclear magnetic resonance spectrometer and referenced to the deuterium lock signal from the sample solvent. Commercially available deuterated solvents were used as the sample solvent depending on the purpose of the measurement. The chemical shift of tetramethylsilane, used as the internal standard, was set to 0 ppm, and the chemical shifts of the analyte signals were expressed in ppm. Signal abbreviations are: s = singlet, brs = broad singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, and m = multiplet. Signal splitting widths are expressed as J values ​​(Hz). Signal integration values ​​were calculated based on the ratio of the signal area intensities of each signal.

[0101] Measurement by qNMR was performed by dissolving the residue containing the target compound and an internal standard in DMSO-d6 under the following analytical conditions. The yield was calculated 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, according to the following formula: Measurement equipment: JNM-ECZ500R Internal standard substance: 3,5-bis(trifluoromethyl)benzoic acid Measurement conditions ( 1 H-NMR): DMSO-d6, pulse angle 90°C, digital resolution 0.25Hz, relaxation time 60 seconds, no spin, number of accumulations 8

[0102] Example 1: Examination of reaction conditions for the synthesis of (2S)-2-(benzyloxycarbonylamino)-3-propoxy-propanoic acid (compound 3A) and (2S)-2-(benzyloxycarbonylamino)-3-isopropoxy-propanoic acid (compound 3B) (1-1): Synthesis of (4S)-3-benzyloxycarbonyl-2-ethyl-oxazolidine-4-carboxylic acid (compound 2A) After purging the reaction vessel with nitrogen, N-benzyloxycarbonyl-L-serine (compound 1) (2.01 g, 8.40 mmol), magnesium sulfate (3.01 g, 25 mmol), and toluene (10 mL) were added to the reaction vessel at room temperature. Propionaldehyde (0.90 mL, 12.6 mmol) and boron trifluoride diethyl ether complex (0.21 mL, 1.7 mmol) were then added and stirred at 40 °C for 2.5 hours. The reaction mixture was filtered, and water (10 mL) was added to the filtrate and stirred. The aqueous layer was discarded, and the resulting organic layer was washed twice with 5% aqueous sodium carbonate (10 mL). The resulting aqueous layers were combined, 5% aqueous sodium hydrogen sulfate monohydrate (55 mL) was added, and the mixture was then washed three times with toluene (10 mL). The resulting organic layers were combined and washed with 5% brine (10 mL). The resulting organic layer was concentrated, followed by azeotropic dehydration with toluene (6 mL) three times to obtain 2.26 g of residue containing compound 2A (content 86.5%) (83.2% yield based on HPLC and qNMR analysis). UV intensity ratio (as diastereomeric mixture): 98.0% (detection wavelength 210 nm, retention times 2.735 and 2.776 min, HPLC analysis condition method 1).

[0103] (1-2): Examination of various acid conditions for the synthesis of (2S)-2-(benzyloxycarbonylamino)-3-propoxy-propanoic acid (compound 3A) The reaction products obtained under the conditions using various acids listed in Table 1 below were investigated as follows. (4S)-3-benzyloxycarbonyl-2-ethyl-oxazolidine-4-carboxylic acid (compound 2A) (63.3 mg, 0.20 mmol) obtained in (1-1) above, dichloromethane (0.28 mL), and triethylsilane (0.16 mL, 0.98 mmol) were added to a reaction vessel, and an acid (0.20 mmol) listed in Table 1 was added at an external temperature of 0°C. The mixture was stirred at an external temperature of 0°C for 1 hour. The resulting reaction mixture was subjected to HPLC analysis using HPLC analysis condition method 1. The results are shown in Table 1. Table 1 shows the peak area ratios of compound 3A, compound 4A, compound 2A, or compound 1 relative to all peaks.

[0104] Compound 3A: Retention time 2.836 min, LCMS m / z 282 [M+H] + Compound 4A: Retention time 2.418 min, LCMS m / z 282 [M+H] + (Structure of Compound 4A) Compound 2A (diastereomeric mixture): Retention time 2.744 and 2.783 min, LCMS m / z 280 [M+H] + Compound 1: Retention time 1.829 min, LCMS m / z 240 [M+H] +

[0105]

[0106] The above results confirmed the formation of the target compound 3A regardless of the acid used. However, when BF3·OEt2 was used, more impurity 4A than compound 3A was produced (run 1). In contrast, when metal Lewis acids such as TiCl4, Sc(OTf)3, SnCl4, and ZrCl4 were used, the formation of impurity 4A was reduced, and compound 3A was selectively obtained (runs 2–5).

[0107] (1-3): Study of reducing agents, solvents, and solubilizers in the synthesis of (2S)-2-(benzyloxycarbonylamino)-3-propoxypropanoic acid (Compound 3A). The effects of the acids, reducing agents, solvents, and solubilizers listed in Table 2 below were investigated as follows. (4S)-3-benzyloxycarbonyl-2-ethyl-oxazolidine-4-carboxylic acid (Compound 2A) (68.4 mg, 0.21 mmol) obtained in (1-1) above, solvent (0.30 mL), solubilizer (0.85 mmol), and reducing agent (1.06 mmol) were added to a reaction vessel, and then an acid (0.21 mmol) listed in Table 2 was added at an external temperature of 0°C. The mixture was stirred at an external temperature of 0°C for 1 hour. The resulting reaction mixture was subjected to HPLC analysis using HPLC analysis condition Method 1. The results are shown in Table 2. Table 2 shows the peak area ratios of Compound 3A, Compound 4A, Compound 2A, or Compound 1 relative to all peaks.

[0108] Compound 3A: Retention time 2.836 min, LCMS m / z 282 [M+H] + Compound 4A: Retention time 2.418 min, LCMS m / z 282 [M+H] + (Structure of Compound 4A) Compound 2A (diastereomeric mixture): Retention time 2.744 and 2.783 min, combined value, LCMS m / z 280 [M+H] + Compound 1: Retention time 1.829 min, LCMS m / z 240 [M+H] +

[0109]

[0110] The above results confirmed that this reaction can also yield the desired compound 3A in toluene (run 5). When we investigated conditions using a Brønsted acid such as trifluoromethanesulfonic acid (TfOH) instead of a metal Lewis acid, we obtained compound 3A, but almost the same amount of impurity 4A was also produced (run 6). Although insoluble matter can sometimes be generated and the reaction becomes heterogeneous when using toluene, we confirmed that the reaction proceeds even with the addition of solubilizing agents such as HFIP and MeCN (runs 2 and 3). Furthermore, we confirmed that the desired compound 3A can be selectively obtained over impurity 4A when using hydride reducing agents other than triethylsilane (PMHS, TMDS) (runs 7 and 8).

[0111] (1-4): 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 a reaction vessel. Boron trifluoride diethyl ether complex (0.19 mL, 1.5 mmol) was added at room temperature, followed by stirring at an external temperature of 40 °C for 45 minutes. Triethylamine (0.20 mL, 1.5 mmol) was then added at room temperature and stirred for 5 minutes. The resulting residue was concentrated, and toluene (18 mL) and water (21 mL) were added and stirred. After the aqueous layer was discarded, the resulting organic layer was washed with 5% brine (10.5 mL). The azeotropic dehydration with toluene (10.5 mL) was repeated three times to obtain 4.43 g of a residue containing compound 2B (12.7 mmol) (yield: 87.1% based on HPLC and qNMR analysis). UV intensity ratio: 96.7% (detection wavelength 210 nm, retention time 2.673 minutes, HPLC analysis conditions method 1)

[0112] (1-5): Examination of solvents and solubilizing agents in the synthesis of (2S)-2-(benzyloxycarbonylamino)-3-isopropoxy-propanoic acid (compound 3B) The effects of the solvent and solubilizing agent listed in Table 3 below were investigated as follows. (4S)-3-benzyloxycarbonyl-2,2-dimethyl-oxazolidine-4-carboxylic acid (Compound 2B) (69.0 mg, 0.20 mmol) obtained in (1-4) above, solvent (0.28 mL), solubilizing agent (0.79 mmol), and reducing agent (0.99 mmol) were added to a reaction vessel, and then an acid listed in Table 3 (0.20 mmol) was added at an external temperature of 0°C. The mixture was stirred at an external temperature of 0°C for 1 hour. The resulting reaction mixture was subjected to HPLC analysis using HPLC analysis condition Method 1. The results are shown in Table 3. Table 3 shows the peak area ratios of Compound 3B, Compound 4B, Compound 2B, or Compound 1 relative to all peaks.

[0113] Compound 3B: Retention time 2.776 min, LCMS m / zm / z 282 [M+H] + Compound 4B: Retention time 2.346 min, LCMS m / zm / z 282 [M+H]+ (Structure of Compound 4B) Compound 2B: Retention time 2.675 minutes, LCMS m / zm / z 280 [M+H] + Compound 1: Retention time 1.833 min, LCMS m / z 240 [M+H] +

[0114]

[0115] The above results confirmed that this reaction can also produce the desired compound 3B in toluene (run 2). Although toluene can produce insoluble matter and result in heterogeneity, the reaction also proceeds with the addition of solubilizing agents such as MeCN, ethyl acetate, and HFIP (runs 3-5). Furthermore, the addition of HFIP as a solubilizing agent tends to produce compound 3B in high yield.

[0116] (1-6): Investigation of Acids and Solvents in the Synthesis of (2S)-2-(Benzyloxycarbonylamino)-3-isopropoxy-propanoic Acid (Compound 3B) The effects of the acids and solvents listed in Table 4 below were investigated as follows. (4S)-3-Benzyloxycarbonyl-2,2-dimethyl-oxazolidine-4-carboxylic acid (Compound 2B) (0.11 g, 0.34 mmol) obtained in (1-4) above, solvent (0.47 mL), and triethylsilane (1.68 mmol) were mixed to prepare a substrate solution. In a separate reaction vessel, a 1 M toluene solution of TiCl4 (0.25 mL, 0.25 mL), Ti(OiPr)4 (0.084 mmol), and HFIP (0.21 mL, 2.0 mmol) were added to prepare a solution containing TiCl3(OiPr) (1 equivalent). After cooling the solution containing TiCl3(OiPr) to an external temperature of 0°C, the substrate solution prepared above was added. After stirring at an external temperature of 0°C for 0.5 hours, the resulting reaction mixture was analyzed by HPLC using HPLC analysis conditions, method 1 (Table 4, run 3: TiCl 4、(A solution containing Ti(OiPr)4 and TiCl3(OiPr) was prepared using chlorobenzene.) The results are shown in Table 4. Table 4 shows the peak area ratio of Compound 3B, Compound 4B, Compound 2B, or Compound 1 to all peaks.

[0117]

[0118] From the above results, it was found that this reaction proceeded with even higher selectivity when TiCl3(OiPr), which has a reduced Lewis acidity compared to TiCl4, was used (runs 1 and 2). Furthermore, it was confirmed that the target compound 3B could be obtained with high selectivity not only in aromatic hydrocarbon solvents such as toluene but also in halogenated aromatic solvents such as chlorobenzene (run 3).

[0119] Example 2: Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-propoxy-propanoic acid dicyclohexylamine salt (compound 3A DCHA salt) (2-1): Synthesis of (4S)-3-benzyloxycarbonyl-2-ethyl-oxazolidine-4-carboxylic acid (compound 2A) After purging the reaction vessel with nitrogen, N-benzyloxycarbonyl-L-serine (compound 1) (10.0 g, 41.8 mmol), magnesium sulfate (15.1 g, 125 mmol), and toluene (50 mL) were added to the reaction vessel at room temperature. Propionaldehyde (4.50 mL, 62.7 mmol) and boron trifluoride diethyl ether complex (1.06 mL, 8.36 mmol) were then added and stirred at 40 °C for 3 hours. Triethylamine (1.17 mL, 8.36 mmol) was then added and stirred. Water (50 mL) was added at an external temperature of 25 °C and the mixture was stirred for 1 hour. The aqueous layer was then discarded, and the resulting organic layer was washed with water (50 mL). 10% aqueous sodium carbonate solution (50 mL) was added to the resulting organic layer and stirred, and the organic layer was discarded. 10% aqueous sodium hydrogen sulfate monohydrate solution (140 mL) and toluene (100 mL) were added to the resulting aqueous layer and stirred. After the aqueous layer was removed, the resulting organic layer was washed with water (30 mL). The resulting organic layer was concentrated, followed by azeotropic dehydration with toluene (20 mL) three times to obtain 10.8 g of a residue containing compound 2A. UV intensity ratio (as a diastereomeric mixture): 97.7% (detection wavelength 210 nm, retention times 2.744 and 2.783 minutes, HPLC analysis condition method 1).

[0120] (2-2): Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-propoxy-propanoic acid (compound 3A) A substrate solution was prepared by adding chlorobenzene (25 mL) and triethylsilane (14.3 mL, 89.3 mmol) to the residue (10.8 g) containing compound 2A obtained in (2-1) above. After purging the reaction vessel with nitrogen, chlorobenzene (25 mL) and titanium tetrachloride (6.69 mL, 60.7 mmol) were added. Next, 2,2,2-trifluoroethanol (7.65 mL, 107 mmol) and tetraisopropyl orthotitanate (5.75 mL, 19.6 mmol) were added at an external temperature of -10 °C. The substrate solution was added at an external temperature of -10 °C and stirred for 4 hours at an external temperature, then at an external temperature of 0 °C for 1.5 hours. A 10% aqueous ammonium chloride solution (50 mL) was added with stirring, followed by stirring for 10 minutes at an external temperature of 25 °C. After discharging the aqueous layer, toluene (50 mL) and citric acid (50 mL) were added and stirred. After discharging the aqueous layer, the resulting organic layer was washed with water (50 mL). (A portion of the resulting organic layer was analyzed by HPLC under HPLC analysis conditions, method 1, and the area ratio of compound 3A (retention time 2.818 min) to compound 4A (retention time 2.399 min) was 90.6:9.4.) 2 M aqueous sodium hydroxide solution (50 mL) was added to the resulting organic layer and stirred for 1 hour. (A portion of the resulting aqueous layer was analyzed by HPLC under HPLC analysis conditions, method 1, and the area ratio of compound 3A (retention time 2.852 min) to compound 4A (retention time 2.399 min) was 99.9:0.1.) After discharging the organic layer, the resulting aqueous layer was washed with CPME (50 mL). 2 M hydrochloric acid (50 mL) and toluene (50 mL) were added to the resulting aqueous layer and stirred, after which the aqueous layer was discarded. The resulting organic layer was washed twice with water (50 mL). The resulting organic layer was concentrated, followed by azeotropic dehydration twice with toluene (25 mL) to obtain 7.99 g of a residue containing compound 3A. UV intensity ratio: 94.6% (detection wavelength: 210 nm, retention time: 2.912 min, HPLC analysis condition: method 1).

[0121] (2-3): Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-propoxy-propanoic acid dicyclohexylamine salt (compound 3A DCHA salt) To the residue (7.99 g) containing compound 3A obtained in (2-2) above, toluene (68 mL) and DCHA (5.64 mL, 28.0 mmol) were added with stirring at an external temperature of 25 °C. Heptane (38 mL) and the seed crystals (39.1 mg) obtained in (2-4) below were then added, and the mixture was stirred for 30 minutes. Heptane (150 mL) was then added over 1 hour, followed by stirring for 2 hours. The resulting solid was filtered and washed under reduced pressure (washing solvent: toluene 24 mL + heptane 41 mL) and dried under reduced pressure to obtain compound 3A DCHA salt (9.89 g, 51.1% yield for the three steps) as a white solid. Optical purity: 99.7%ee (detection wavelength 210 nm, retention time 12.896 minutes, HPLC analysis conditions method 2) UV intensity ratio: 99.9% (detection wavelength 210 nm, retention time 2.880 minutes, HPLC analysis conditions method 1) 1 H-NMR(DMSO-d6,500 MHz) δ: 8.78 (brs, 1H), 7.33-7.26 (m, 5H), 6.55 (s,1H), 4.97 (s, 2H), 3.78-3.75 (s, 1H), 3.59-3.51 (m, 2H), 3.29-3.20 (m, 3H),2.86 (brs, 2H), 1.89-1.87 (m, 4H), 1.67-1.63 (m, 4H), 1.56-1.53 ​​(m, 2H),1.43-1.36 (m, 2H), 1.23-1.13 (m, 8H), 1.07-1.02 (m, 2H), 0.77 (t, J = 7.4 Hz, 3H)

[0122] (2-4): Preparation of seed crystals of (2S)-2-(benzyloxycarbonylamino)-3-propoxypropanoic acid dicyclohexylamine salt (Compound 3A DCHA salt) MTBE (4.0 mL) and DCHA (0.32 mL) were added to the residue (0.50 g) containing Compound 3A obtained by the same method as in (2-2) above, and the mixture was stirred at room temperature for 10 minutes to obtain Compound 3A DCHA salt (0.60 g) as powdery crystals.

[0123] In Example 2, it was found that the method of the present invention can produce compound 3A-DCHA salt in 51.1% yield from the starting compound 1 in three steps. Furthermore, in step (2-2) above, the reaction product obtained by acid treatment contained more than 9% of compound 4A as an impurity. However, by treating with a base (aqueous sodium hydroxide solution), the content of compound 4A could be reduced to less than 0.1%. The method of the present invention does not require column purification and is adaptable to large-scale synthesis.

[0124] 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 a reaction vessel. Boron trifluoride diethyl ether complex (0.19 mL, 1.5 mmol) was added at room temperature, followed by stirring at an external temperature of 40 °C for 45 minutes. Triethylamine (0.20 mL, 1.5 mmol) was then added at room temperature and stirred for 5 minutes. The resulting residue was concentrated, and toluene (18 mL) and water (21 mL) were added and stirred. After the aqueous layer was discarded, the resulting organic layer was washed with 5% brine (10.5 mL). The azeotropic dehydration with toluene (10.5 mL) was repeated three times to obtain 4.43 g of a residue containing compound 2B (12.7 mmol) (yield: 87.1% based on HPLC and qNMR analysis). UV intensity ratio: 96.7% (detection wavelength 210 nm, retention time 2.673 minutes, HPLC analysis conditions method 1)

[0125] (3-2): Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-isopropoxy-propanoic acid (compound 3B) The residue containing compound 2B (1.62 g, containing 4.64 mmol of compound 2B) obtained in (3-1) above was mixed with triethylsilane (3.70 mL, 23.2 mmol) and toluene (6.5 mL) to prepare a substrate solution. After purging the reaction vessel with nitrogen, a titanium tetrachloride toluene solution (1.0 M, 5.6 mL) was added. HFIP (2.89 mL, 27.8 mmol) was added at an external temperature of -5 °C. The substrate solution was then added at an external temperature of -6 °C. After stirring for 45 minutes at an external temperature of -5 °C, 10% aqueous ammonium chloride solution (3.9 mL) was added. The mixture was then stirred at room temperature, the aqueous layer was discarded, and the resulting organic layer was washed twice with 5% aqueous sodium carbonate solution (12 mL, followed by 5 mL). The resulting aqueous layers were mixed, and 5% aqueous sodium hydrogen sulfate monohydrate solution (42 mL) was added. The resulting aqueous layer was washed three times with toluene and then three times with CPME. The resulting organic layers were combined and washed with 5% brine (6 mL). Sodium sulfate was added to the resulting organic layer to dehydrate it, then filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol) to obtain white solid A of compound 3B (0.496 g, 38.0% yield) and white solid B of compound 3B (0.481 g, 36.9% yield). Optical purity (analysis of white solid B): 99.8% ee (detection wavelength 210 nm, retention time 13.166 min, HPLC analysis condition method 2). UV intensity ratio (white solid A): 99.2% (detection wavelength 210 nm, retention time 2.770 min, HPLC analysis condition method 1). UV intensity ratio (white solid B): 99.8% (detection wavelength 210 nm, retention time 2.764 min, HPLC analysis condition method 1).

[0126] (3-3): Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-propoxypropanoic acid dicyclohexylamine salt (compound 3B DCHA salt) Compound 3B (0.407 g, 1.45 mmol) obtained in (3-2) above was dissolved in MTBE (1.6 mL). DCHA (0.289 mL, 1.45 mmol) and heptane (3.3 mL) were then added at room temperature, and the resulting precipitate was collected by filtration under reduced pressure. The resulting solid was dried under reduced pressure to obtain 0.608 g (90.8% yield) of compound 3B-DCHA salt as a white solid. UV intensity ratio: 99.2% (detection wavelength: 210 nm, retention time: 2.787 min, HPLC analysis condition: method 3). 1 H-NMR(DMSO-d6,500 MHz) δ: 8.85 (brs, 1H), 7.35-7.28 (m, 5H), 6.49 (d,J = 6.5 Hz, 1H), 5.01 (s, 2H), 3.82-3.75 (m, 1H), 3.64-3.55 (m, 2H), 3.52-3.45(m, 1H), 3.43 (brs, 1H), 2.91 (brs, 2H), 1.92 (s, 4H), 1.73-1.67 (m, 4H), 1.58(d, J = 12.5 Hz, 2H), 1.28-1.18 (m, 8H), 1.10-1.04 (m, 2H), 1.01 (d, J = 6.1 Hz, 6H)

[0127] In Example 3 above, it was found that Compound 3B·DCHA salt can be obtained in a yield of 59% or more from the starting compound 1 in three steps by the method of the present invention.

[0128] 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 a reaction vessel at room temperature. After purging the reaction vessel with nitrogen, N,O-bis(trimethylsilyl)trifluoroacetamide (3.00 mL, 11.3 mmol) was added at an external temperature of 0°C and stirred for 10 minutes. Subsequently, cyclobutanone (0.94 mL, 12.4 mmol) and trimethylsilyl trifluoromethanesulfonate (0.41 mL, 2.3 mmol) were added and stirred at an external temperature of 0°C for 2 hours. 5% aqueous potassium hydrogen phosphate (8.1 mL) was added, followed by water (8.1 mL) at room temperature and stirring. After the aqueous layer was discarded, 10% aqueous potassium carbonate (10.8 mL) was added. After discarding the organic layer, 2 M hydrochloric acid (9.5 mL) and toluene (10.8 mL) were added to the resulting aqueous layer and stirred. After the aqueous layer was removed, the resulting organic layer was washed twice with water (10.8 mL). The resulting organic layer was concentrated and azeotropically dehydrated three times with toluene (8.1 mL) to obtain 4.66 g of a residue containing compound 2C (9.35 mmol) (yield: 82.8% based on HPLC and qNMR analysis). UV intensity ratio: 98.9% (detection wavelength: 210 nm, retention time: 5.347 min, HPLC analysis condition: method 4).

[0129] (4-2): Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-(cyclobutoxy)propanoic acid (compound 3C) A substrate solution was prepared by adding triethylsilane (4.53 mL, 28.4 mmol) and chlorobenzene (5 mL) to the residue (4.66 g) containing compound 2C (9.35 mmol) obtained in (4-1) above. The reaction vessel was purged with nitrogen, and chlorobenzene (6.9 mL) was added. 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 then added at an external temperature of -16 °C and stirred. The substrate solution prepared above was then added at an external temperature of -16 °C, and the mixture was stirred for 1 hour and 15 minutes at an external temperature of -6 °C. (A portion of the reaction mixture obtained here was subjected to HPLC analysis under HPLC analysis condition method 1, and the area ratio of compound 3C (retention time 3.031 minutes) to compound 4C (retention time 2.572 minutes) was 87.7:12.3.) (Structure of compound 4C) Next, 10% aqueous ammonium chloride solution (13.8 mL) was added and stirred at room temperature. After the aqueous layer was discarded, 5% aqueous citric acid solution (13.8 mL) and MTBE (8.3 mL) were added to the resulting organic layer and stirred. After discarding the aqueous layer, the resulting organic layer was washed with water (13.8 mL). After discarding the aqueous layer, 2 M aqueous sodium hydroxide solution (13.8 mL) was added and stirred for 1.5 hours. (A portion of the resulting aqueous layer was analyzed by HPLC using HPLC analysis condition method 1, and the area ratio of compound 3C (retention time 3.004 min) to compound 4C (retention time 2.548 min) was 99.4:0.6.) After discarding the organic layer, the resulting aqueous layer was washed with MTBE (13.8 mL). To the resulting aqueous layer, 2 M hydrochloric acid (13.5 mL) and toluene (27.6 mL) were added and stirred. After discarding the aqueous layer, the resulting organic layer was washed with water (13.8 mL). Toluene (8.3 mL) was then added and azeotropic dehydration was repeated three times to obtain a residue (6.18 g) containing compound 3C. Toluene (15.2 mL) was added to the resulting residue, and seed crystals (9.7 mg) of compound 3C obtained in (4-3) below were added at room temperature and stirred for 20 minutes. Heptane (19.6 mL) was then added dropwise over 1 hour with stirring, followed by stirring for 1.5 hours. The resulting precipitate was collected by filtration under reduced pressure, and the resulting solid was dried under reduced pressure to obtain compound 3C (1.78 g, yield 64.9%) as a white solid. Optical purity: 99.9% ee (detection wavelength 210 nm, retention time 13.647 minutes, HPLC analysis condition method 2). UV intensity ratio: 99.9% (detection wavelength 210 nm, retention time 2.986 minutes, HPLC analysis condition method 1). 1 H-NMR(DMSO-d6,500 MHz) δ: 12.77 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H),7.37-7.30 (m, 5H), 5.04 (s, 2H), 4.18-4.14 (m, 1H), 3.92-3.87 (m, 1H),3.54-3.51 (m, 2H), 2.12-2.07 (m, 2H), 1.84-1.76 (m, 2H), 1.63-1.57 (m, 1H),1.47-1.40 (m, 1H)

[0130] (4-3): Preparation of seed crystals of (2S)-2-(benzyloxycarbonylamino)-3-(cyclobutoxy)propanoic acid (Compound 3C) To the residue (0.87 g) containing Compound 3C obtained by the same method as in (4-2) above, toluene (1.0 mL) and heptane (1.0 mL) were added and stirred at room temperature until a solid was formed. After further addition of heptane and stirring, the resulting precipitate was collected by filtration under reduced pressure to obtain Compound 3C (0.46 g) as a powdery crystal.

[0131] In Example 4, it was found that the method of the present invention can produce compound 3C in a yield of 53% or more in two steps from the starting compound 1. Furthermore, in step (4-2) above, the reaction product contained 12% or more of compound 4A as an impurity. However, by treating with a base (aqueous sodium hydroxide solution), the content of compound 4A could be reduced to less than 1%. The method of the present invention does not require column purification and is therefore adaptable to large-scale synthesis.

[0132] 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 a reaction vessel at an external temperature of 25 °C. After purging the reaction vessel with nitrogen, toluene (15 mL), isovaleraldehyde (2.05 mL, 19.1 mmol), and boron trifluoride tetrahydrofuran complex (0.28 mL, 2.5 mmol) were added and stirred at 25 °C for 2 h. Triethylamine (0.35 mL, 2.5 mmol) was added to the reaction vessel and stirred for 5 min. The mixture was washed with water (15 mL × 2) and 5% brine (15 mL), and then subjected to azeotropic dehydration twice with toluene (15 mL) to obtain 7.47 g of a residue containing compound 2D. UV intensity ratio (as diastereomeric mixture): 95.8% (detection wavelength 210 nm, retention time 3.224 and 3.250 minutes, HPLC analysis condition method 5)

[0133] (5-2): Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-isopentyloxy-propanoic acid (compound 3D) The residue (7.47 g) containing compound 2D obtained in (5-1) above was mixed with triethylsilane (5.07 mL, 31.8 mmol) to prepare a substrate solution. After purging the reaction vessel with nitrogen, chlorobenzene (7.5 mL) and titanium tetrachloride (2.38 mL, 21.6 mmol) were added. At an external temperature of -15 °C, 2,2,2-trifluoroethanol (2.72 mL, 38.1 mmol) and tetraisopropyl orthotitanate (2.05 mL, 7.0 mmol) were added and stirred. The substrate solution prepared above was added at an external temperature of -15 °C, and the external temperature was adjusted to 0 °C and stirred for 4 hours. After stirring at 10 °C for 1 hour, the external temperature was adjusted to -10 °C and 5% aqueous ammonium chloride solution (15 mL) was added. The external temperature was adjusted to 25 °C and stirred for 5 minutes. The aqueous layer was then discarded, and the resulting organic layer was washed with 5% aqueous citric acid solution (15 mL) and water (15 mL). After the aqueous layer was discarded, 2 M aqueous sodium hydroxide solution (9 mL) and MTBE (9 mL) were added to the resulting organic layer, and the mixture was stirred at an external temperature of 25°C for 3.5 hours. 2 M aqueous sodium hydroxide solution (6 mL) was added, and the mixture was stirred for 0.5 hours. After discarding the organic layer, the resulting aqueous layer was washed with MTBE (15 mL). 2 M hydrochloric acid (15 mL) and MeTHF (30 mL) were added to the resulting aqueous layer, and the mixture was stirred for 10 minutes. After discarding the aqueous layer, the resulting organic layer was washed with 5% brine (15 mL). Subsequently, azeotropic dehydration was performed three times with MeTHF (15 mL) to obtain a MeTHF solution (9 mL) containing compound 3D. UV intensity ratio: 88.6% (detection wavelength: 210 nm, retention time: 3.290 min, HPLC analysis condition: method 5).

[0134] (5-3): Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-isopentyloxy-propanoic acid dicyclohexylamine salt (compound 3D DCHA salt) To the MeTHF solution (9 mL) containing compound 3D obtained in (5-2) above, DCHA (2.53 mL, 12.7 mmol) and heptane (9 mL) were added with stirring at an external temperature of 25°C. The resulting solid was collected by filtration and washed under reduced pressure (washing solution: 10 mL of MeTHF + 40 mL of heptane) and dried under reduced pressure to obtain compound 3D-DCHA salt (3.94 g, 63.2% yield over three steps) as a white solid. Optical purity: 99.9% ee (detection wavelength 210 nm, retention time 15.933 min, HPLC analysis method 2). UV intensity ratio: 99.0% (detection wavelength 210 nm, retention time 3.232 min, HPLC analysis method 5). 1 H-NMR(DMSO-d6,500 MHz) δ: 8.83 (brs, 1H), 7.37-7.29 (m, 5H), 6.58 (s,1H), 5.00 (s, 2H), 3.81-3.79 (m, 1H), 3.63-3.55 (m, 2H), 3.37-3.32 (m, 3H),2.91 (brs, 2H), 1.91 (brs, 4H), 1.70 (brs, 4H), 1.63-1.57 (m, 2H), 1.35-1.30(m, 2H), 1.27-1.21 (m, 8H), 1.13-1.04 (m, 2H), 0.86 (t, J = 6.7 Hz, 1H), 0.83(dd, J = 6.7, 1.7Hz, 6H)

[0135] In Example 5, it was found that the compound 3D-DCHA salt can be obtained in 63.2% yield in three steps from the starting compound 1 by the method of the present invention. The method of the present invention does not require column purification at any time and is adaptable to large-scale synthesis.

[0136] 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 added to a reaction vessel at an external temperature of 25 °C, and the vessel was purged with nitrogen. Boron trifluoride tetrahydrofuran complex (0.087 mL, 0.79 mmol) was then added and stirred at 40 °C for 0.5 hours. Triethylamine (0.11 mL, 0.79 mmol) was then added at an external temperature of 25 °C and stirred for 5 minutes. The resulting residue was concentrated, and toluene (5 mL) was added and further concentrated. Toluene (3 mL) and water (5 mL) were added to the resulting concentrate and stirred at 25 °C for 10 minutes. After the aqueous layer was discarded, the resulting organic layer was washed with 5% brine (5 mL) and azeotropically dehydrated three times with toluene (5 mL) to obtain 3.39 g of a residue containing compound 6B. UV intensity ratio (as diastereomeric mixture): 98.3% (detection wavelength 210 nm, retention time 2.783 min, HPLC analysis condition method 3)

[0137] (6-2): Synthesis of (2S,3R)-2-(benzyloxycarbonylamino)-3-isopropoxy-butanoic acid (compound 7B) A substrate solution was prepared by adding triethylsilane (1.58 mL, 9.89 mmol) to the residue (3.39 g) containing compound 6B obtained in (6-1) above. After purging the reaction vessel with nitrogen, chlorobenzene (2.5 mL) and titanium tetrachloride (0.74 mL, 6.7 mmol) were added. At an external temperature of -15°C, 2,2,2-trifluoroethanol (0.85 mL, 11.9 mmol) and tetraisopropyl orthotitanate (0.64 mL, 2.2 mmol) were added and stirred. The substrate solution prepared above was added at an external temperature of -15°C, and the external temperature was set to 0°C and stirred for 2 hours. (A portion of the reaction solution obtained was subjected to HPLC analysis using HPLC analysis conditions, method 3, and no compound 8B was detected.) (Structure of Compound 8B) The external temperature was set to -10°C, and 5% aqueous ammonium chloride solution (5 mL) was added. The external temperature was then set to 25°C. MTBE (3 mL) was then added and stirred for 10 minutes. After the aqueous layer was discarded, the resulting organic layer was washed with 5% aqueous citric acid solution (5 mL) and water (5 mL). After the aqueous layer was discarded, 1 M aqueous sodium hydroxide solution (5 mL) was added to the resulting organic layer and stirred at an external temperature of 25°C for 2 hours. After the organic layer was discarded, 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 resulting aqueous layer and stirred for 10 minutes. After the aqueous layer was discarded, the resulting organic layer was washed with 5% brine (5 mL). Subsequently, azeotropic dehydration was performed twice with MTBE (10 mL) to obtain an MTBE solution (4 mL) containing compound 7B. UV intensity ratio: 97.7% (detection wavelength: 210 nm, retention time: 2.842 minutes, HPLC analysis condition: method 3).

[0138] (6-3): Synthesis of (2S,3R)-2-(benzyloxycarbonylamino)-3-isopropoxybutanoic acid dicyclohexylamine salt (compound 7B DCHA salt) To the MTBE solution (4 mL) containing compound 7B obtained in (6-2) above, DCHA (0.788 mL, 3.96 mmol) and heptane (4 mL) were added with stirring at room temperature. The resulting solid was collected by filtration and washed under reduced pressure (washing solution: MTBE 2.5 mL + heptane 7.5 mL) and dried under reduced pressure to obtain compound 7B-DCHA salt (1.29 g, 68.2% yield over three steps) as a white solid. Diastereomeric excess (7B and diastereomeric 7B'): 99.7% de (detection wavelength 210 nm, retention time 13.367 min, HPLC analysis condition method 2). UV intensity ratio: 99.1% (detection wavelength 210 nm, retention time 2.851 minutes, HPLC analysis conditions method 3) 1H-NMR(DMSO-d6,500 MHz) δ: 7.39-7.29 (m, 5H), 6.07 (d, J = 7.2Hz, 1H), 5.02 (s, 2H), 3.97-3.92 (m, 1H), 3.66-3.59 (m, 2H), 3.37 (brs, 2H),2.87 (brs, 2H), 1.92-1.90 (m, 4H), 1.77-1.66 (m, 4H), 1.59-1.57 (m,2H),1.27-1.15 (m, 8H), 1.11-1.05 (m, 2H), 1.02 (d, J = 6.5 Hz, 3H), 1.00 (d, J =6.1 Hz, 3H), 0.97-0.93 (d, J = 6.1 Hz, 3H)

[0139] In Example 6, it was found that the method of the present invention can produce compound 7B DCHA salt in a yield of 68.2% in three steps from the starting compound 5. The method of the present invention does not require column purification at any time and is adaptable to large-scale synthesis.

[0140] 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), and 2,2-dimethoxypropane (1.52 mL, 12.4 mmol) were added to a reaction vessel at an external temperature of 25°C, and the vessel was purged with nitrogen. Boron trifluoride tetrahydrofuran complex (0.068 mL, 0.62 mmol) was then added and stirred at 40°C for 1 hour. Triethylamine (0.087 mL, 0.62 mmol) was then added at an external temperature of 25°C and stirred for 5 minutes. The resulting residue was concentrated, and methylene chloride (5 mL) and water (5 mL) were added to the resulting concentrate and stirred at room temperature for 10 minutes. The aqueous layer was discarded, and the resulting organic layer was dehydrated by adding magnesium sulfate. The residue containing compound 10B was obtained by filtration and subsequent concentration under reduced pressure, and methylene chloride was added to obtain a methylene chloride solution (3 mL) containing compound 10B. UV intensity ratio (as a diastereomeric mixture): 84.9% (detection wavelength 210 nm, retention time 3.283 min, HPLC analysis condition method 3).

[0141] (7-2): Synthesis of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-isopropoxy-propanoic acid (Compound 11B) A substrate solution was prepared by adding triethylsilane (1.24 mL, 7.76 mmol) to a methylene chloride solution (3 mL) containing compound 10B obtained in (7-1) above. After purging the reaction vessel with nitrogen, methylene chloride (2.5 mL) and titanium tetrachloride (0.41 mL, 3.7 mmol) were added. The substrate solution was added at an external temperature of -15°C, and the mixture was stirred at 0°C for 2 hours. (A portion of the reaction solution obtained was subjected to HPLC analysis using HPLC analysis condition method 3. The area ratio of compound 11B (retention time 3.424 min) to compound 12B (retention time 3.022 min) was 98.2:1.8.) The external temperature was set to -10°C, and 5% aqueous ammonium chloride solution (5 mL) was added. The external temperature was then set to 25°C. MTBE (5 mL) was then added and the mixture was stirred for 5 minutes. After the aqueous layer was discarded, the resulting organic layer was washed with 5% aqueous citric acid solution (5 mL) and 5% brine (5 mL). After discarding the aqueous layer, azeotropic dehydration was performed using MTBE. The resulting residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol) to obtain 0.783 g of compound 11B (68.3% yield over two steps) as a white solid. Optical purity: 99.8% ee (detection wavelength 210 nm, retention time 17.398 min, HPLC analysis condition method 2). UV intensity ratio: 91.8% (detection wavelength 210 nm, retention time 3.408 min, HPLC analysis condition method 3). 1 H-NMR(DMSO-d6,500 MHz) δ: 12.74 (brs, 1H), 7.90 (d, J = 7.6 Hz, 2H),7.75 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 8.4 Hz, 1H), 7.44-7.41 (m, 2H),7.34-7.31 (m, 2H), 4.31-4.27 (m, 2H), 4.25-4.21 (m, 1H), 4.17-4.14 (m, 1H),3.64-3.53 (m, 3H), 1.07 (t, J = 5.0 Hz, 6H)

[0142] In the above Example 7, it was found that compound 11B can be obtained in 68.3% yield from the starting compound 9 in two steps by the method of the present invention.

[0143] 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. After purging the reaction vessel with nitrogen, N,O-bis(trimethylsilyl)acetamide (4.8 mL, 19.6 mmol) was added at room temperature and stirred for 15 minutes. Subsequently, cyclobutanone (1.78 mL, 23.6 mmol) and trimethylsilyl trifluoromethanesulfonate (3.49 mL, 19.3 mmol) were added and stirred at room temperature for 2.5 hours. 5% aqueous potassium hydrogen phosphate (15.5 mL) was added and stirred. CPME (10.3 mL) was added and stirred, and the aqueous layer was then discarded. The resulting organic layer was washed with 10% aqueous potassium carbonate (26 mL). The resulting aqueous layer was collected, and 2 M hydrochloric acid (21 mL) and toluene (52 mL) were added and stirred. After the aqueous layer was removed, the resulting organic layer was washed with water (15.5 mL). The resulting organic layer was concentrated and azeotropically dehydrated with toluene (15.5 mL) to obtain 7.09 g of a residue containing compound 2C. UV intensity ratio: 95.8% (detection wavelength: 210 nm, retention time: 5.381 min, HPLC analysis condition: method 4).

[0144] (8-2): Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-(cyclobutoxy)propanoic acid (compound 3C) From the 7.09 g residue containing compound 2C obtained in (8-1) above, 3.47 g was removed and triethylsilane (3.57 mL) and chlorobenzene (3.9 mL) were added to prepare a substrate solution. After purging the reaction vessel with nitrogen, chlorobenzene (5.4 mL), titanium tetrachloride (1.36 mL), tetraisopropyl orthotitanate (1.20 mL), and 2,2,2-trifluoroethanol (2.13 mL) were added and stirred. The substrate solution prepared above was then added at an external temperature of -6°C and stirred for 1.5 hours. 10% aqueous ammonium chloride (11 mL) was then added and stirred at room temperature. After the aqueous layer was discarded, 5% aqueous citric acid (11 mL) and MTBE (11 mL) were added to the resulting organic layer and stirred. After discarding the aqueous layer, the resulting organic layer was washed with water (11 mL). After discarding the aqueous layer, 2 M aqueous sodium hydroxide (11 mL) was added and stirred for 2 hours. After the organic layer was discarded, the resulting aqueous layer was washed with MTBE (11 mL). 2 M hydrochloric acid (10 mL) and toluene (17.5 mL) were added to the resulting aqueous layer and stirred. After discarding the aqueous layer, the resulting organic layer was washed with water (11 mL). Subsequently, toluene (7 mL) was added and azeotropic dehydration was performed to obtain a residue containing compound 3C (3.59 g). Toluene (10.8 mL) was added to the resulting residue, and seed crystals of compound 3C (6.4 mg) obtained in (4-3) above were added at room temperature and stirred for 20 minutes. Heptane (13.3 mL) was then added with stirring, followed by stirring for 1 hour. The resulting precipitate was collected by filtration under reduced pressure, and the resulting solid was dried under reduced pressure to obtain compound 3C (1.19 g) as a white solid. UV intensity ratio: 99.9% (detection wavelength 210 nm, retention time 3.039 minutes, HPLC analysis condition method 1).

[0145] (8-3): Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-(cyclobutoxy)propanoic acid (compound 3C) From the 7.09 g residue containing compound 2C obtained in (8-1) above, 3.31 g was removed and triethylsilane (3.41 mL) and chlorobenzene (3.7 mL) were added to prepare a substrate solution. After purging the reaction vessel with nitrogen, chlorobenzene (5.2 mL) and titanium tetrachloride (1.33 mL) were added. Next, 2,2,2-trifluoroethanol (1.53 mL) and tetraisopropyl orthotitanate (1.15 mL) were added at an external temperature of -16 °C and stirred. The substrate solution prepared above was then added at an external temperature of -16 °C. After stirring for 3 hours at an external temperature of -6 °C, 10% aqueous ammonium chloride solution (10.4 mL) was added and stirred at room temperature. After discharging the aqueous layer, 5% aqueous citric acid solution (10.4 mL) and toluene (10.4 mL) were added to the resulting organic layer and stirred. After discharging the aqueous layer, the resulting organic layer was washed with water (10.4 mL). After the aqueous layer was drained, 2 M aqueous sodium hydroxide solution (10.4 mL) was added and 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 resulting aqueous layer and stirred. After draining the aqueous layer, the resulting organic layer was washed with water (10.4 mL). Toluene (6 mL) was then added and azeotropic dehydration was performed to obtain a residue containing compound 3C (4.72 g). Toluene (10.1 mL) was added to the resulting residue, and seed crystals (6.8 mg) of compound 3C obtained in (4-3) above were added at room temperature and stirred for 30 minutes. Heptane (13.7 mL) was then added with stirring, followed by stirring for 6 hours. The resulting precipitate was collected by filtration under reduced pressure, and the resulting solid was dried under reduced pressure to obtain compound 3C (1.20 g) as a white solid. UV intensity ratio: 99.9% (detection wavelength 210 nm, retention time 3.042 minutes, HPLC analysis conditions method 1)

[0146] (8-4): Synthesis of (4S)-4-(cyclobutoxymethyl)-5-oxo-oxazolidine-3-carboxylate benzyl (compound 13C) Paraformaldehyde (1.26 g, 90% content, 37.7 mmol), compound 3C (1.85 g, 6.30 mmol) obtained in (8-2) and (8-3) above, magnesium sulfate (0.76 g, 6.3 mmol), and toluene (9.2 mL) were added to a reaction vessel. After purging the reaction vessel with nitrogen, boron trifluoride diethyl ether complex (0.80 mL, 6.3 mmol) was added at room temperature and stirred for 2 hours. The resulting mixture was filtered, and the filtrate was washed twice with 10% aqueous potassium carbonate (9.2 mL) and once with water (9.2 mL). The resulting organic layer was filtered and washed with water (9.2 mL). The resulting organic layer was concentrated and azeotropically dehydrated with toluene (5.5 mL) to obtain 3.75 g of a residue containing compound 13C. UV intensity ratio: 98.5% (detection wavelength 210 nm, retention time 3.620 minutes, HPLC analysis conditions method 1)

[0147] (8-5): Synthesis of (2S)-2-[benzyloxycarbonyl(methyl)amino]-3-(cyclobutoxy)propanoic acid (compound 14C) Of the 3.75 g of residue containing compound 13C obtained in (8-4) above, 2.92 g was removed and transferred to a reaction vessel. Triethylsilane (1.69 mL, 10.6 mmol) and chlorobenzene (3.3 mL) were added. After purging the reaction vessel with nitrogen, trimethylsilyl trifluoromethanesulfonate (0.64 mL, 3.5 mmol) was added at an external temperature of -3 °C and the mixture was stirred at room temperature for 2 hours. 5% dipotassium hydrogen phosphate (3 mL) was added at an external temperature of -3 °C and the mixture was stirred at room temperature. After the aqueous layer was discarded, 10% aqueous potassium carbonate solution (5.4 mL) was added to the resulting organic layer and stirred. After discarding the organic layer, 2 M hydrochloric acid (4.3 mL) and toluene (8.6 mL) were added to the resulting aqueous layer and stirred. After discarding the aqueous layer, the resulting organic layer was washed with water (5.4 mL). Toluene (3.2 mL) was added and azeotropic dehydration was performed to obtain a residue containing compound 14C (1.09 g). UV intensity ratio: 99.6% (detection wavelength 210 nm, retention time 3.117 minutes, HPLC analysis conditions method 1)

[0148] (8-6): Synthesis of (2S)-2-[benzyloxycarbonyl(methyl)amino]-3-(cyclobutoxy)propanoic acid dicyclohexylamine salt (compound 14C DCHA salt) MTBE (3.8 mL) was added to the residue (1.09 g) containing compound 14C obtained in (8-5) above. DCHA (0.63 mL) was then added with stirring at room temperature, followed by MTBE (3.8 mL). The resulting solid was filtered and washed under reduced pressure (washing solution: MTBE 5 mL) and dried under reduced pressure to obtain compound 14C-DCHA salt (1.46 g) as a white solid. UV intensity ratio: 99.8% (detection wavelength: 210 nm, retention time: 3.110 min, HPLC analysis condition: method 1). 1 H-NMR(DMSO-d6,500 MHz) δ: 8.70 (brs, 1H), 7.38-7.28 (m, 5H),5.09-4.98 (m, 2H), 4.51-4.43 (m, 1H), 3.92-3.84 (m, 1H), 3.67 (dd, J = 10.8,4.1 Hz, 1H), 3.52-3.44 (m, 2H), 2.91 (brs, 2H), 2.78 (d, J = 20.9 Hz, 3H),2.11-2.05 (m, 2H), 1.92 (brs, 4H), 1.81-1.69 (m, 6H), 1.61-1.57 (m, 3H),1.47-1.36 (m, 1H), 1.31-1.18 (m, 8H), 1.10-1.05 (m, 2H)

[0149] In Example 8, it was demonstrated that the compound 14C-DCHA salt can be obtained in five steps from the starting compound 1 using the method of the present invention. This method is adaptable to large-scale synthesis without requiring column purification. Furthermore, it was demonstrated that the method of the present invention can also be applied to the synthesis of O-substituted serine derivatives with N-substituents.

[0150] 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 purging the reaction vessel with nitrogen, N-benzyloxycarbonyl-L-serine (Compound 1) (4.02 g, 16.8 mmol), magnesium sulfate (2.02 g, 16.8 mmol), and toluene (20 mL) were added to the reaction vessel at room temperature. Isobutyraldehyde (2.30 mL, 25.2 mmol) and boron trifluoride tetrahydrofuran complex (0.37 mL, 3.4 mmol) were then added and stirred at 25°C for 2 hours. Triethylamine (0.47 mL, 3.4 mmol) was then added and stirred for 5 minutes. Water (20 mL) was added to the reaction mixture and stirred. The aqueous layer was discarded, and the resulting organic layer was washed with water (20 mL) and 5% brine (15 mL). The resulting organic layer was concentrated, followed by azeotropic dehydration with toluene (20 mL), filtration, and concentration to obtain a residue (8.83 g) containing compound 2E (15.2 mmol) (yield 90.7% based on HPLC and qNMR analysis). UV intensity ratio (as a diastereomeric mixture): 97.1% (detection wavelength 210 nm, retention times 2.993 and 3.048 min, HPLC analysis condition method 3).

[0151] (9-2): Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-isobutyloxypropanoic acid (compound 3E) The residue containing compound 2E (7.85 g, containing 13.5 mmol of compound 2E) obtained in (9-1) above was mixed with triethylsilane (5.4 mL, 34 mmol) and chlorobenzene (6 mL) to prepare a substrate solution. After purging the reaction vessel with nitrogen, chlorobenzene (10 mL) and titanium tetrachloride (2.76 mL, 25.1 mmol) were added. Subsequently, 2,2,2-trifluoroethanol (2.90 mL, 40.6 mmol) and tetrabutyl orthotitanate (2.53 mL, 7.45 mmol) were added at an external temperature of -15°C. The substrate solution was then added at an external temperature of -15°C, followed by stirring at an external temperature of 0°C for 3 hours. (A portion of the reaction solution was analyzed by HPLC using HPLC analysis condition method 1. The area ratio of compound 3E (retention time 3.230 min) to compound 4E (retention time 2.755 min) was 93.2:6.8.) Next, 5% aqueous ammonium chloride (20 mL) was added at an external temperature of -10°C. MTBE (12 mL) was added at room temperature, stirred, and the aqueous layer was discarded. The resulting organic layer was washed with 5% aqueous citric acid (20 mL) and water (20 mL). 1 M aqueous NaOH (20 mL) was added to the resulting organic layer and stirred for 3.5 hours. 1 M aqueous NaOH (4 mL) was added and stirred for 1.5 hours, followed by 1 M aqueous NaOH (20 mL) and stirring for an additional 1.5 hours. (A portion of the resulting aqueous layer was analyzed by HPLC using HPLC analysis condition method 1, and the area ratio of compound 3E (retention time 3.229 min) to compound 4E (retention time 2.751 min) was 99.4:0.6.) The organic layer was discarded, and the resulting aqueous layer was washed with MTBE (24 mL). 2 M hydrochloric acid (16 mL) and toluene (40 mL) were added to the resulting aqueous layer and stirred, and the aqueous layer was discarded. The resulting organic layer was washed with 5% brine (24 mL) and then concentrated under reduced pressure. The resulting residue was filtered and then concentrated under reduced pressure to obtain a residue containing compound 3E (4.44 g). Toluene (9.7 mL) and heptane (19.5 mL) were added to the resulting residue, and a seed crystal suspension of compound 3E (obtained in (9-3) below, approximately 0.3 mL) was added at an external temperature of 25 °C and stirred for 20 minutes. Heptane (19.5 mL) was then added over 1 hour with stirring at an external temperature of 10 °C, followed by stirring for 3.5 hours. The resulting precipitate was collected by filtration under reduced pressure, and the resulting solid was dried under reduced pressure to obtain 2.76 g (yield 68.1%) of compound 3E as a white solid. Optical purity: 99.6%ee (detection wavelength 210 nm, retention time 14.302 minutes, HPLC analysis conditions method 2) UV intensity ratio: 98.9% (detection wavelength 210 nm, retention time 3.209 minutes, HPLC analysis conditions method 1) 1H-NMR(DMSO-d6, 500 MHz) δ: 12.77 (brs, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.38-7.31 (m, 5H), 5.08-5.01 (m, 2H), 4.23-4.19 (m, 1H), 3.61 (d, J = 5.4 Hz, 2H), 3.19-3.11 (m, 2H), 1.91-1.71 (m, 1H), 0.84 (d, J = 6.7 Hz, 6H)

[0152] (9-3): Preparation of a seed crystal suspension of compound 3E Toluene (0.1 mL) and heptane (0.2 mL) were added to a residue (0.1 g) containing compound 3E obtained by the same method as in (9-2) above, and the mixture was allowed to stand at an external temperature of −20° C. until a solid was formed, thereby obtaining a seed crystal suspension of compound 3E.

[0153] In Example 9 above, it was found that Compound 3E can be obtained in a yield of 61% or more from the starting compound 1 in two steps by the method of the present invention.

[0154] 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 ester (compound 15) (1.22 g, 4.82 mmol), acetone (6 mL), and 2,2-dimethoxypropane (1.12 mL, 9.63 mmol) were added to a reaction vessel. Boron trifluoride tetrahydrofuran complex (0.11 mL, 0.96 mmol) was added at room temperature, followed by stirring at room temperature for 1 hour. 2,2-Dimethoxypropane (0.59 mL, 4.8 mmol) was added and the mixture was stirred for an additional hour. Triethylamine (0.13 mL, 0.96 mmol) was then added at room temperature, followed by stirring for 5 minutes. The resulting residue was concentrated, and toluene (6 mL) and water (6 mL) were added and stirred. The aqueous layer was discarded, and the resulting organic layer was washed with 5% brine (6 mL). Toluene (6 mL) was then added and azeotropic dehydration was repeated twice to obtain 1.64 g of the residue containing compound 16B (4.15 mmol) (yield 86.1% based on HPLC and qNMR analysis). UV intensity ratio: 90.47% (detection wavelength 210 nm, retention time 3.234 min, HPLC analysis condition method 3).

[0155] (10-2): Synthesis of methyl (2S)-2-(benzyloxycarbonylamino)-3-isopropoxypropanoate (Compound 17B) The residue containing compound 16B (0.28 g, containing 0.70 mmol of compound 16B) obtained in (10-1) above was mixed with triethylsilane (0.56 mL, 3.5 mmol), acetic acid (0.08 mL, 1.4 mmol), and methylene chloride (1.0 mL) to prepare a substrate solution. After purging the reaction vessel with nitrogen, methylene chloride (1.0 mL), titanium tetrachloride (0.29 mL, 2.6 mmol), and tetraisopropyl orthotitanate (0.26 mL, 0.86 mmol) were added at an external temperature of 0 °C. The substrate solution was then added at an external temperature of 0 °C, followed by stirring at room temperature for 90 minutes. (A portion of the resulting reaction solution was analyzed by HPLC using HPLC analysis condition method 3. The area ratio of compound 17B (retention time 3.293 min) to compound 18B (retention time 2.761 min) was 98.8:1.2.) Subsequently, 5% aqueous ammonium chloride solution (1.0 mL) was added at an external temperature of 0°C. After stirring at room temperature and discarding the aqueous layer, the resulting organic layer was washed with 5% aqueous citric acid solution (1.0 mL), water (1.0 mL), and 5% aqueous dipotassium hydrogen phosphate solution (1.0 mL). Magnesium sulfate was added to the resulting organic layer, which was then dehydrated, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (eluent: water / acetonitrile) to obtain compound 17B as a white solid (0.151 g, yield 72.9%). Optical purity: 99.5% ee (detection wavelength 210 nm, retention time 17.720 min, HPLC analysis condition method 2). UV intensity ratio: 99.2% (detection wavelength 210 nm, retention time 3.289 min, HPLC analysis condition method 3). 1 H-NMR(DMSO-d6, 500 MHz) δ: 7.65 (d, J = 7.9 Hz, 1H), 7.39-7.23 (m, 5H), 5.04 (s, 2H), 4.27-4.23 (m, 1H), 3.64-3.50 (m, 6H), 1.06-1.04 (m, 6H)

[0156] In Example 10 above, it was found that compound 17B can be obtained in a yield of 62% or more from the starting compound 15 in two steps by the method of the present invention.

[0157] 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 a reaction vessel. Boron trifluoride tetrahydrofuran complex (0.36 mL, 3.3 mmol) was added at room temperature, followed by stirring at room temperature for 1 hour. Triethylamine (0.46 mL, 3.3 mmol) was then added at room temperature and stirred for 5 minutes. The resulting residue was concentrated, and MTBE (20 mL) and water (20 mL) were added and stirred. After the aqueous layer was drained, MTBE (20 mL) was added to the resulting organic layer. The mixture was azeotropically evaporated (three times) and filtered to obtain 6.96 g of a residue containing compound 6B (yield 96.0% based on HPLC and qNMR analysis). UV intensity ratio: 98.82% (detection wavelength 210 nm, retention time 2.856 minutes, HPLC analysis conditions method 3)

[0158] (11-2): Synthesis of benzyl (4S,5R)-4-{[(S)-1-methoxy-1-oxapropan-2-yl]carbamoyl}-2,2,5-trimethyloxazolidine-3-carboxylate (Compound 19B) To the residue containing compound 6B (2.97 g, containing 6.73 mmol of compound 6B) obtained in (11-1) above, L-alanine methyl ester hydrochloride (0.99 g, 7.0 mmol), MeTHF (8 mL), acetonitrile (4 mL), and N,N-diisopropylethylamine (4.7 mL, 27 mmol) were added. Subsequently, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 3.1 g, 8.1 mmol) was added at room temperature and stirred for 90 minutes. Subsequently, MeTHF (8 mL), 5% aqueous potassium carbonate (4 mL), and 1-methylimidazole (0.54 mL, 6.7 mmol) were added and stirred for 10 minutes. 10% aqueous ammonia (6 mL) was added and stirred, and the aqueous layer was then discarded. The resulting organic layer was washed sequentially with 10% aqueous ammonia (10 mL), 5% sulfuric acid (10 mL, then 16 mL), and 5% aqueous potassium carbonate (10 mL). MeTHF (10 mL) was added to the resulting organic layer, and azeotropic dehydration was performed twice to obtain 3.26 g of residue containing compound 19B (5.87 mmol) (87.2% yield based on HPLC and qNMR analysis). UV intensity ratio: 96.4% (detection wavelength: 210 nm, retention time: 2.899 min, HPLC analysis condition: method 3).

[0159] (11-3): Synthesis of N-(benzyloxy)carbonyl-O-isopropyl-L-threonyl-L-alanine methyl ester (compound 20B) The residue containing compound 19B (0.633 g, containing 1.14 mmol of compound 19B) obtained in (11-2) above was mixed with triethylsilane (0.91 mL, 5.7 mmol), acetic acid (0.13 mL, 2.3 mmol), and methylene chloride (2.2 mL) to prepare a substrate solution. After purging the reaction vessel with nitrogen, methylene chloride (2.2 mL), titanium tetrachloride (0.38 mL, 3.4 mmol), and tetraisopropyl orthotitanate (0.33 mL, 1.1 mmol) were added at an external temperature of 0 °C. The substrate solution was then added at an external temperature of 0 °C, followed by stirring at room temperature for 90 minutes. (A portion of the reaction solution was subjected to HPLC analysis using HPLC analysis conditions, method 3; compound 21B was not detected.) Subsequently, 5% aqueous ammonium chloride solution (2.2 mL) was added at an external temperature of 0°C. After stirring at room temperature and discarding the aqueous layer, the resulting organic layer was washed with 5% aqueous citric acid solution (2.2 mL x 2), water (2.2 mL), and 5% aqueous sodium dihydrogen phosphate solution (2.2 mL). Magnesium sulfate was added to the resulting organic layer, which was then dehydrated, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (eluent: water / acetonitrile) to obtain compound 20B as a white solid (0.239 g, 55.0% yield). UV intensity ratio: 98.7% (detection wavelength: 210 nm, retention time: 3.245 min, HPLC analysis condition: method 3). 1 H-NMR(DMSO-d6, 500 MHz) δ: 8.30 (d, J = 6.7 Hz, 1H), 7.37-7.30 (m, 5H), 6.94 (d, J = 9.4 Hz, 1H), 5.08-5.02 (m, 2H), 4.32-4.27 (m, 1H), 4.06-4.01 (m, 1H), 3.75-3.70 (m, 1H), 3.65-3.59 (m, 4H), 1.29-1.21 (m, 3H), 1.07 (d, J = 6.1 Hz, 3H), 1.03 (d, J = 5.9 Hz, 3H), 0.99 (d, J = 6.1 Hz, 3H)

[0160] In the above Example 11, it was found that Compound 20B can be obtained in a yield of 46% or more from the starting compound 5 in three steps by the method of the present invention.

[0161] 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 (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. After purging the reaction vessel with nitrogen, methylene chloride (0.98 mL), titanium tetrachloride (0.13 mL, 1.2 mmol), and tetrabutyl orthotitanate (0.12 mL, 0.36 mmol) were added at an external temperature of 0 °C. The substrate solution was then added at an external temperature of 0 °C and stirred at room temperature for 60 minutes. (A portion of the resulting reaction solution was analyzed by HPLC using HPLC analysis condition method 1; the UV intensity ratio of target product 23B to starting material 22B was 26.1:73.9. Compound 24B was not detected by HPLC analysis using HPLC analysis condition method 3.) Subsequently, 5% aqueous ammonium chloride (1 mL) was added. After stirring at room temperature and discarding the aqueous layer, the resulting organic layer was washed with 5% aqueous ammonium chloride (1 mL) and water (1 mL). The resulting organic layer was concentrated under reduced pressure, followed by azeotropic dehydration with MTBE (5 mL) four times. The resulting residue was purified by reverse-phase column chromatography (eluent: water / acetonitrile) to obtain 29.0 mg of target product 23B (15% yield) and 14.2 mg of target product 23B containing starting material 22B (UV intensity ratio of target product 23B to starting material 22B: 93.7:6.3 in HPLC analysis using HPLC analysis condition method 1). Diastereomer (23B and diastereomer 23B') excess: 99.9%de (detection wavelength 210 nm, retention time 8.790 min, HPLC analysis condition method 6). UV intensity ratio: 99.5% (detection wavelength 210 nm, retention time 3.839 minutes, HPLC analysis conditions method 1) 1 H-NMR (DMSO-d6, 500 MHz) δ: 12.58 (s, 1H), 7.89 (d, J = 7.5 Hz, 2H), 7.71 (t, J = 8.5 Hz, 2H), 7.65 (d, J = 9.2 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.41 (dd, J = 7.5, 7.5 Hz, 2H), 7.34-7.30 (m, 2H), 4.31-4.14 (m, 5H), 4.02-3.97 (m, 1H), 3.61-3.56 (m, 1H), 1.64-1.60 (m, 1H), 1.53-1.43 (m, 2H), 1.02 (t, J = 6.5 Hz, 6H), 0.99 (d, J = 6.0 Hz, 3H), 0.89 (d, J = 6.5 Hz, 3H), 0.85 (d, J = 6.5 Hz, 3H)

[0162] The present invention provides a method for producing O-substituted serine derivatives, which can produce O-substituted serine derivatives with a small number of steps. By using the production method of the present invention, unnatural amino acids useful for the discovery of peptide pharmaceuticals and / or the supply of pharmaceutical active ingredients can be provided with high regioselectivity, chemical yield, and optical purity.

Claims

1. A method for producing a compound represented by the following general formula (1), a salt thereof, or a solvate thereof, (A) The method comprising 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). 【Chemistry 1】 [In the formula, R １ This is an electron-withdrawing group, an amino acid residue, or a peptide residue. R ２ and R ３ each independently is selected from the group consisting of hydrogen, optionally substituted C １ -C ６ alkyl, optionally substituted C ３ -C ６ cycloalkyl, optionally substituted C ２ -C ６ alkenyl, optionally substituted C ２ -C ６ alkynyl, optionally substituted aralkyl, optionally substituted aryl, and optionally substituted heteroaryl, or (ii) together with intervening carbon atoms forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, R ４ and R ５ (i) Each independently has hydrogen, and C which may have substituents. １ -C ６ C, which may have alkyl or substituents ３ -C ６ Cycloalkyl, C which may have substituents ２ -C ６ C, which may have an alkenyl substituent. ２ -C ６ (ii) A molecule selected from the group consisting of alkynyl, optionally substituted aralkyl, optionally substituted aryl, and optionally substituted heteroaryl, or (ii) a molecule that, together with an intervening carbon atom, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle. R ６ C may have hydrogen and substituents. １ -C ６ Alkyl or optionally substituted aralkyl, 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 of these independently may have hydrogen or substituents. １ -C ６ Alkyl, or optionally substituted aralkyl, or R ９ and R ９’ It forms a 4- to 7-membered saturated heterocycle together with the intervening nitrogen atom. L １ This is a single bond or -CH ２ - and L ２ This is a single bond or -CH ２ - and L ３ This is a single bond or -CH ２ - and However, L １ ga-CH ２ - If L ２ It is a single bond, L ２ ga-CH ２ - If L １ and L ３ It is a single bond, L ３ ga-CH ２ - If L ２ This is a single bond.

2. The method according to claim 1, wherein step (A) is carried out in the presence of an acid.

3. The method according to claim 2, wherein the acid is a metallic Lewis acid.

4. The method according to claim 3, wherein the metallic Lewis acid is at least one selected from the group consisting of titanium tetrachloride, tin tetrachloride, scandium triflate, tetraisopropyl orthotitanate, and isopropoxytrichlorotitanium.

5. The method according to any one of claims 1 to 4, wherein the reducing agent used in step (A) is a hydride-based reducing agent.

6. The method according to claim 2 or 3, wherein the amount of acid used in step (A) is 0.1 equivalents or more and 20 equivalents or less relative to the compound represented by general formula (2), and the amount of reducing agent used is 0.5 equivalents or more and 30 equivalents or less relative to the compound represented by general formula (2).

7. The method according to claim 1 or 2, wherein 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.

8. The method according to claim 1 or 2, wherein step (A) is further carried out in the presence of a solubilizing agent.

9. The method according to claim 1 or 2, wherein step (A) is performed at a temperature of -50°C to 50°C for 5 minutes to 24 hours.

10. The method according to claim 1 or 2, further comprising a base treatment step of adding a base after step (A) to reduce the amount of compound (4) contained in the reaction mixture. 【Chemistry 2】 [In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , L １ , L ２ , and L ３ This is synonymous with the definition in claim 1.

11. Before step (A) above, (B) The method according to claim 1 or 2, comprising the 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). 【Transformation 3】 [In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , L １ , L ２ , and L ３ This is synonymous with the definition in claim 1.

12. A method for producing a compound represented by the following general formula (16), a salt thereof, or a solvate thereof, A method comprising the step of producing the following compound (11) by the method described in claim 1 or 2. 【Chemistry 4】 [In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , L １ , L ２ , and L ３ This is synonymous with the definition in claim 1, R １０ and R １１ are each independently selected from the group consisting of (i) hydrogen, C １ -C ６ alkyl optionally having a substituent, C ３ -C ６ cycloalkyl optionally having a substituent, C ２ -C ６ alkenyl optionally having a substituent, C ２ -C ６ alkynyl, aralkyl optionally having a substituent, aryl optionally having a substituent, and heteroaryl optionally having a substituent, or (ii) together with the intervening carbon atoms form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.]

13. After the process of producing the following compound (11), (C) A step of reacting a compound represented by the following general formula (11) with aldehydes, ketones, acetals, or vinyl ethers in the presence of a Lewis acid to obtain a compound represented by the following general formula (15), and (D) A step of reacting a compound represented by the following general formula (15) in the presence of a Lewis acid and a reducing agent to obtain a compound represented by the following general formula (16), The method according to claim 12, including the method described in claim 12. 【Transformation 5】 [wherein, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R １０ , R １１ , L １ , L ２ , and L ３ are synonymous with the definitions recited in claims 1 and 12.]

14. R １ However, -C(=O)-R １２ , -C(=O)-OR １３ , -S (=O) ２ -R １４ , -S (=O) ２ -OR １５ , -P(=O)-R １６ R １７ , or -P(=O)-(OR １８ ) ２ And here R １２ , R １３ , R １４ , R １５ , R １６ , R １７ and R １８ C may have substituents. １ -C ６ The alkyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl, R ２ and R ３ However, each is 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 It forms a 3- to 8-membered alicyclic ring together with the bonded carbon atoms. R ４ and R ５ However, each is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, tert-butyl, isobutyl, isopentyl, benzyl, phenyl, and pyridyl, or R ４ and R ５ It forms a 3- to 8-membered alicyclic ring together with the bonded carbon atoms. R ６ However, it is hydrogen, methyl, ethyl, n-propyl, n-butyl, or benzyl. L １ , L ２ , and L ３ However, it is a single bond. The method according to claim 1 or 2.

15. A method for producing peptide compounds, (i) A step of producing the compound (11) or (16) by the method described in claim 1 or 2, and (ii) A step of condensing the carboxyl group of compound (11) or (16) obtained in step (i) above with an amino acid having an amino group or a peptide having an amino group in a solvent. A manufacturing method that includes this.

16. 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, 4-(cyclobutoxymethyl)-5-oxo-oxazolidine-3-carboxylate benzyl 4-{[1-Methoxy-1-oxapropan-2-yl]carbamoyl}-2,2,5-trimethyloxazolidine-3-carboxylate benzyl N-(benzyloxy)carbonyl-O-isopropyl-threonyl-alanine methyl ester, and A compound selected from the group consisting of N-[(9H-fluoren-9-ylmethoxycarbonyl)-leucyl]-O-isopropyl-threonine, or a salt thereof, or a solvate thereof.

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