Process for production of O-substituted serine derivatives

Abstract

The problem addressed by the present invention is to provide a method for producing an O-substituted serine derivative, which makes it possible to produce an O-substituted serine derivative in fewer steps. The inventors have made a wide and in-depth study on the reductive hydrogenation of cyclic N, O-acetal. As a result, the present inventors have found a method for producing an O-substituted serine derivative in fewer steps, which has excellent regioselectivity and chemical yield while maintaining optical purity.

Description

Technical Field

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

[0002] Medium-sized molecules (molecular weight of 500 to 2000) may be superior to small molecules in achieving thorny goals (such as inhibiting protein-protein interactions). Medium-sized molecules may also be superior to antibodies because these molecules can migrate into cells. Among the medium-sized molecules with biological activity, peptide drugs are high-value molecular species, and 40 or more of them have been marketed (non-patent document 1). Representative examples of peptide drugs include cyclosporin A and polymyxin B. As can be seen from these structures, they are peptide compounds containing several non-natural amino acids. Non-natural amino acids are amino acids that are not naturally encoded on mRNA. It is very interesting that non-natural amino acids are contained in cyclosporin A and polymyxin B of natural origin, and these non-natural structural sites interact with the site of action in vivo to express pharmacological activity. Known examples of the interaction of non-natural amino acids with the site of action in vivo include studies on the interaction of the O-substituted serine site of lacosamide with known sodium channels (non-patent document 2).

[0003] Among the methods for producing an O-substituted serine derivative, the following method is known as a method for producing an O-alkyl-substituted serine derivative.

[0004] 1. A method for producing an O-substituted serine derivative from serine and an alkyl halide in the presence of a base using the Williamson ether synthesis method or a modified method thereof (Non-Patent Document 3).

[0005] 2. A synthetic method for producing an O-substituted serine derivative from serine and a trichloroacetimidate using the Schmidt glycosylation method in the presence of an acid catalyst (Non-Patent Document 4).

[0006] 3. A synthetic method for producing an O-substituted serine derivative from serine and allyl carbonate in the presence of a palladium catalyst (Non-Patent Document 5).

[0007] These methods are methods of directly introducing an alkyl group into serine.

[0008] 4. In the presence of Lewis acid or Bronsted acid A synthesis method comprising reacting an aziridine compound derived from serine with an alcohol in the presence of a catalyzer (Patent Documents 1 and 2).

[0009] 5. A method of reacting a cyclic sulfamidate derived from serine with an alcohol (Patent Document 3).

[0010] These methods are methods for producing O-alkyl-substituted serine derivatives via intermediates derived from serine.

[0011] Citation List

[0012] Patent Literature

[0013] Patent Document 1: Japanese Patent Application Publication No. S57-159747

[0014] Patent document 2: International Publication No. WO2010 / 053050

[0015] Patent Document 3: International Publication No. WO2020 / 095983

[0016] Non-patent literature

[0017] Non-patent document 1: Future Med. Chem., 2009, 1, 1289-1310

[0018] Non-patent document 2: J. Med. Chem., 2010, 53(15), 5716-5726

[0019] Non-patent document 3: Tetrahedron Letters, 2012, 53, 3225-3229

[0020] Non-patent document 4: Bioorganic & Medicinal Chemistry Letters, 1992, 2, 579-582

[0021] Non-patent document 5: Journal of the American Chemical Society, 2014, 136, 12469-12478 Summary of the invention

[0022] Technical issues

[0023] The methods described in Patent Documents 1, 2 and Non-Patent Document 2 using aziridine derived from serine have a problem regarding the regioselectivity of the reaction site.

[0024] In the method described in Non-Patent Document 3 which is performed in the presence of a base, it is known that the hydroxyl group in serine is eliminated, and the method is limited to producing highly reactive benzyl ether.

[0025] The method described in Non-Patent Document 4 (method for production from trichloroacetimidate) can be used only to produce an O-substituted serine derivative in which the substituent on oxygen is an allyl group.

[0026] The method described in Non-Patent Document 5 (which is a method by a coupling reaction of allyl ether) can be used only to produce an O-substituted serine derivative in which the substituent on oxygen is an allyl group.

[0027] In order to obtain high position selectivity, chemical yield and optical purity, a method for producing O-substituted serine derivatives via sulfonamides was developed in Patent Document 3. The method includes an oxidation step using an oxidant and requires 4 or 5 steps starting from a commercially available serine derivative.

[0028] An object of the present invention is to provide a method for producing an O-substituted serine derivative, wherein the O-substituted serine derivative can be obtained in a small number of steps.

[0029] Solution to the problem

[0030] The present inventors have intensively studied the reductive hydrogenation of cyclic N,O-acetals. As a result, the present inventors have found a short-step method for producing O-substituted serine derivatives with excellent position selectivity and chemical yield while maintaining optical purity, and have completed the present invention.

[0031] That is, the present invention includes the following contents.

[0032] [1] A method for producing a compound represented by the following formula (1) or a salt thereof or a solvate thereof, the method comprising the steps of:

[0033] (A) reacting a compound represented by the following formula (2) with a reducing agent to obtain a compound represented by the following formula (1):

[0034] [Formula 1]

[0035]

[0036] in

[0037] R1 is an electron-withdrawing group;

[0038] (i) R2 and R3 are each independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aralkyl, optionally substituted aryl and optionally substituted heteroaryl, or (ii) R2 and R3 together with the intervening carbon atom form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring;

[0039] (i) R4 and R5 are each independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aralkyl, optionally substituted aryl and optionally substituted heteroaryl, or (ii) R4 and R5 together with the intervening carbon atom form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring;

[0040] R6 is hydrogen, a C1-C6 alkyl group which may have a substituent, or an aralkyl group which may have a substituent;

[0041] R7 is -OR8, -NR9R 9' , amino acid residues or peptide residues;

[0042] R8, R9 and R 9' are each independently hydrogen, an optionally substituted C1-C6 alkyl group or an optionally substituted aralkyl group, or R9 and R 9' Together with the intervening nitrogen atom, it forms a 4- to 7-membered saturated heterocyclic ring;

[0043] L1 is a single bond or -CH2-;

[0044] L2 is a single bond or -CH2-;

[0045] L3 is a single bond or -CH2-;

[0046] Provided that, when L1 is -CH2-, L2 is a single bond; when L2 is -CH2-, L1 and L3 are each a single bond; and when L3 is -CH2-, L2 is a single bond.

[0047] [1-1] A method for producing a compound represented by the following formula (1) or a salt thereof or a solvate thereof, the method comprising the steps of:

[0048] (A) reacting a compound represented by the following formula (2) with a reducing agent to obtain a compound represented by the following formula (1):

[0049] [Formula 2]

[0050]

[0051] in

[0052] R1 is an electron-withdrawing group, an amino acid residue or a peptide residue;

[0053] (i) R2 and R3 are each independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aralkyl, optionally substituted aryl and optionally substituted heteroaryl, or (ii) R2 and R3 together with the intervening carbon atom form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring;

[0054] (i) R4 and R5 are each independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aralkyl, optionally substituted aryl and optionally substituted heteroaryl, or (ii) R4 and R5 together with the intervening carbon atom form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring;

[0055] R6 is hydrogen, a C1-C6 alkyl group which may have a substituent, or an aralkyl group which may have a substituent;

[0056] R7 is -OR8, -NR9R 9' , amino acid residues or peptide residues;

[0057] R8, R9 and R 9' are each independently hydrogen, an optionally substituted C1-C6 alkyl group or an optionally substituted aralkyl group, or R9 and R 9' Together with the intervening nitrogen atom, it forms a 4- to 7-membered saturated heterocyclic ring;

[0058] L1 is a single bond or -CH2-;

[0059] L2 is a single bond or -CH2-;

[0060] L3 is a single bond or -CH2-;

[0061] Provided that, when L1 is -CH2-, L2 is a single bond; when L2 is -CH2-, L1 and L3 are each a single bond; and when L3 is -CH2-, L2 is a single bond.

[0062] [2] The method according to [1], wherein step (A) is carried out in the presence of an acid.

[0063] [3] The method according to [2], wherein the acid is a metal Lewis acid.

[0064] [4] The method according to [3], wherein the metal Lewis acid is at least one selected from the group consisting of a metal halide, a metal triflate, a metal alkoxide, and a metal halide alkoxide.

[0065] [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.

[0066] [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.

[0067] [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 trifluoromethanesulfonate, tetraalkoxytitanium, and alkoxytitanium trichloride.

[0068] [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 trifluoromethanesulfonate, tetraisopropyl orthotitanate, and isopropoxytitanium trichloride.

[0069] [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.

[0070]

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

[0071]

[11] The method according to

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

[0072]

[12] The method according to

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

[0073]

[13] The method according to

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

[0074]

[14] 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 trifluoromethanesulfonate, and alkoxytitanium trichloride.

[0075]

[15] The method according to

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

[0076]

[16] The method according to

[15] , wherein the metal Lewis acid is isopropoxytitanium trichloride.

[0077]

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

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

[0078]

[18] The method according to

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

[0079]

[19] The method according to

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

[0080]

[20] The method according to

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

[0081]

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

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

[0082]

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

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

[0083]

[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 or more and 3 equivalents or less relative to the compound represented by formula (2).

[0084]

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

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

[0085]

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

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

[0086]

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

[25] , wherein step (A) is performed in the presence of a solvent, and the solvent is at least one selected from the group consisting of a halogenated solvent and a benzene solvent.

[0087]

[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 solvent is at least one selected from the group consisting of toluene, chlorobenzene, fluorobenzene and trifluorotoluene.

[0088]

[28] The method according to

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

[0089]

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

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

[0090]

[30] The method according to

[29] , wherein the solubilizing agent is at least one selected from the group consisting of fluoroalcohols, alcohols, nitrile solvents and ester solvents.

[0091]

[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 ethyl acetate and dimethyl carbonate.

[0092]

[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.

[0093]

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

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

[0094]

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

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

[0095]

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

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

[0096]

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

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

[0097]

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

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

[0098]

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

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

[0099]

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

[38] , which comprises, after step (A), a base treatment step of further adding a base to reduce the content of compound (4) contained in the reaction mixture:

[0100] [Formula 3]

[0101]

[0102] wherein R1, R2, R3, R4, R5, R6, R7, L1, L2 and L3 are as defined in [1].

[0103]

[40] The method according to

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

[0104]

[41] The method according to

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

[0105]

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

[41] , wherein the alkali 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.

[0106]

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

[41] , wherein the alkali treatment step is performed at a temperature of 10°C to 25°C.

[0107]

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

[41] , wherein the alkali treatment step is performed for 30 minutes to 5 hours.

[0108]

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

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

[0109]

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

[45] , before step (A), the method further comprises the following steps:

[0110] (B) reacting a compound represented by the following formula (3) with an aldehyde, a ketone, an acetal or a vinyl ether to obtain a compound represented by the following formula (2):

[0111] [Formula 4]

[0112]

[0113] wherein R1, R2, R3, R4, R5, R6, R7, L1, L2 and L3 are as defined in [1].

[0114]

[47] The method according to

[46] , wherein 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 formula (2).

[0115]

[48] ​​The method according to

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

[0116]

[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 and an ether solvent and trialkylsilyl trifluoromethanesulfonate.

[0117]

[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 trifluoromethanesulfonate.

[0118]

[51] The method according to any one of

[46] to

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

[0119]

[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.

[0120]

[53] The method according to

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

[0121]

[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.

[0122]

[55] The method according to any one of

[46] to

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

[0123]

[56] The method according to any one of

[46] to

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

[0124]

[57] The method according to any one of

[46] to

[53] , wherein the step (B) is performed at a temperature of 20°C to 50°C for 30 minutes to 3 hours.

[0125]

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

[57] , wherein R7 is -OR8; and R8 is hydrogen, an optionally substituted C1-C6 alkyl group, or an optionally substituted aralkyl group.

[0126]

[59] The method according to

[58] , wherein R7 is -OH.

[0127] [59-1] The method according to

[58] , wherein R7 is -OR8; and R8 is C1-C6 alkyl.

[0128] [59-2] The method according to

[58] , wherein R7 is -OR8; and R8 is methyl.

[0129]

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

[57] , wherein R7 is -NR9R 9' ; and R9 and R 9' are each independently hydrogen, an optionally substituted C1-C6 alkyl group or an optionally substituted aralkyl group, or R9 and R 9' Together with the intervening nitrogen atom, it forms a 4- to 7-membered saturated heterocyclic ring.

[0130]

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

[57] , wherein R7 is an amino acid residue or a peptide residue.

[0131] [61-1] The method according to any one of [1] to

[57] , wherein R7 is an amino acid residue whose C-terminus is protected by a C1-C6 alkyl ester.

[0132]

[62] A method for producing a compound represented by the following formula (16) or a salt thereof or a solvate thereof, the method comprising the steps of:

[0133] The following compound (11) is produced by the method described in any one of [1] to

[61] :

[0134] [Formula 5]

[0135]

[0136] wherein R1, R2, R3, R4, R5, R6, L1, L2 and L3 have the same meanings as defined in [1]; and

[0137] (i)R 10 and R 11 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl optionally having a substituent, C3-C6 cycloalkyl optionally having a substituent, C2-C6 alkenyl optionally having a substituent, C2-C6 alkynyl optionally having a substituent, aralkyl optionally having a substituent, aryl optionally having a substituent and heteroaryl optionally having a substituent, or (ii) R 10 and R 11 Together with the intervening carbon atom, it forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.

[0138]

[63] The method according to

[62] , further comprising the following step after the step of producing the following compound (11):

[0139] (C) reacting the compound represented by the following formula (11) with an aldehyde, a ketone, an acetal or a vinyl ether in the presence of a Lewis acid to obtain a compound represented by the following formula (15); and

[0140] (D) reacting the compound represented by the following formula (15) with a reducing agent in the presence of a Lewis acid to obtain a compound represented by the following formula (16):

[0141] [Formula 6]

[0142]

[0143] Among them, R1, R2, R3, R4, R5, R6, R 10 , R 11 , L1, L2 and L3 are as defined in [1] and

[62] .

[0144]

[64] The method according to

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

[0145]

[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.

[0146]

[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 boron trifluoride-alkyl ether complex, trialkylsilyl trifluoromethanesulfonate, titanium tetrachloride and tetraalkoxytitanium.

[0147]

[67] The method according to

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

[0148]

[68] The method according to any one of

[63] to

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

[0149]

[69] The method according to

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

[0150]

[70] The method according to

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

[0151]

[71] The method according to

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

[0152]

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

[71] , wherein

[0153] R1 is -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 R12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 Each is an optionally substituted C1-C6 alkyl group, an optionally substituted aralkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group;

[0154] R2 and R3 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

[0155] R2 and R3 together with the carbon atoms to which they are attached form a 3- to 8-membered alicyclic ring;

[0156] R4 and R5 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 R4 and R5 together with the carbon atoms to which they are attached form a 3- to 8-membered alicyclic ring;

[0157] R6 is hydrogen, methyl, ethyl, n-propyl, n-butyl or benzyl; and

[0158] L1, L2 and L3 are each a single bond.

[0159]

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

[72] , wherein

[0160] R1 is -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 Each is a C1-C6 alkyl group optionally having a substituent, an aralkyl group optionally having a substituent, an aryl group optionally having a substituent, or a heteroaryl group optionally having a substituent.

[0161]

[74] The method according to

[73] , wherein

[0162] R1 is -C(=O)-R12 、-C(=O)-OR 13 or -S(=O)2-R 14 , where R 12 , R 13 and R 14 Each is a C1-C6 alkyl group optionally having a substituent, an aralkyl group optionally having a substituent, an aryl group optionally having a substituent, or a heteroaryl group optionally having a substituent.

[0163]

[75] The method according to

[74] , wherein R1 is benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), acetyl, trifluoroacetyl, methanesulfonyl, p-toluenesulfonyl, (trifluoromethyl)sulfonyl or 2-nitrobenzenesulfonyl (Nosyl).

[0164]

[76] The method according to

[75] , wherein R1 is benzyloxycarbonyl (Cbz) or 9-fluorenylmethoxycarbonyl (Fmoc).

[0165] [76-1] The method according to any one of [1] to

[71] , wherein R1 is an amino acid residue or a peptide residue;

[0166] R2 and R3 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

[0167] R2 and R3 together with the carbon atoms to which they are attached form a 3- to 8-membered alicyclic ring;

[0168] R4 and R5 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 R4 and R5 together with the carbon atoms to which they are attached form a 3- to 8-membered alicyclic ring;

[0169] R6 is hydrogen, methyl, ethyl, n-propyl, n-butyl or benzyl; and

[0170] L1, L2 and L3 are each a single bond.

[0171] [76-2] The method according to [76-1], wherein R1 is an amino acid residue or a peptide residue whose N-terminus is protected by a benzyloxycarbonyl (Cbz) or 9-fluorenylmethoxycarbonyl (Fmoc) group.

[0172] [76-3] The method according to [76-1], wherein R1 is an amino acid residue whose N-terminus is protected by a benzyloxycarbonyl (Cbz) group or a 9-fluorenylmethoxycarbonyl (Fmoc) group.

[0173]

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

[76] , wherein R2 and R3 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 R2 and R3 together with the carbon atoms to which they are attached form a 3- to 8-membered alicyclic ring.

[0174]

[78] The method according to

[77] , wherein R2 is methyl, ethyl, n-propyl, n-butyl or isobutyl and R3 is hydrogen or methyl, or R2 and R3 together with the carbon atoms to which they are attached form a 4- to 6-membered alicyclic ring.

[0175]

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

[78] , wherein R4 and R5 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 R4 and R5 together with the carbon atoms to which they are attached form a 3- to 8-membered alicyclic ring.

[0176]

[80] The method according to

[79] , wherein R4 is hydrogen, methyl, ethyl, n-propyl, n-butyl or isobutyl, and R5 is hydrogen.

[0177]

[81] The method according to

[80] , wherein R4 is hydrogen or methyl, and R5 is hydrogen.

[0178]

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

[81] , wherein R6 is hydrogen, methyl, ethyl, n-propyl, n-butyl or benzyl.

[0179]

[83] The method according to

[82] , wherein R6 is hydrogen.

[0180]

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

[83] , wherein L1, L2 and L3 are each a single bond.

[0181]

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

[84] .

[0182]

[86] A method for producing a peptide compound, the method comprising the following steps:

[0183] (i) producing the above-mentioned compound (11) or (16) by the method described in any one of [1] to

[85] ; and

[0184] (ii) condensing the carboxyl group of the compound (11) or (16) obtained in the above step (i) with an amino acid having an amino group or a peptide having an amino group in a solvent.

[0185]

[87] A compound selected from the group consisting of:

[0186] 2-(Benzyloxycarbonylamino)-3-(cyclobutyloxy)propanoic acid;

[0187] 2-(Benzyloxycarbonylamino)-3-isopentyloxy-propionic acid;

[0188] 2-(Benzyloxycarbonylamino)-3-isopropoxy-butyric acid;

[0189] 2-[Benzyloxycarbonyl(methyl)amino]-3-(cyclobutyloxy)propanoic acid;

[0190] 3-Benzyloxycarbonyl-2-ethyl-oxazolidine-4-carboxylic acid;

[0191] 3-Benzyloxycarbonyl-2-isobutyl-oxazolidine-4-carboxylic acid;

[0192] 4-(Cyclobutyloxymethyl)-5-oxo-oxazolidine-3-carboxylic acid benzyl ester;

[0193] Benzyl 4-{[1-methoxy-1-oxapropan-2-yl]carbamoyl}-2,2,5-trimethyloxazolidine-3-carboxylate;

[0194] N-(Benzyloxy)carbonyl-O-isopropyl-threonyl-alanine methyl ester; and

[0195] N-[(9H-fluoren-9-ylmethoxycarbonyl)-leucyl]-O-isopropyl-threonine or a salt thereof or a solvate thereof.

[0196]

[88] (2S)-2-(Benzyloxycarbonylamino)-3-(cyclobutyloxy)propanoic acid or a salt or a solvate thereof.

[0197]

[89] (2S)-2-(Benzyloxycarbonylamino)-3-isopentyloxy-propionic acid or a salt thereof or a solvate thereof.

[0198]

[90] (2S,3R)-2-(Benzyloxycarbonylamino)-3-isopropoxy-butyric acid or a salt thereof or a solvate thereof.

[0199]

[91] (2S)-2-[Benzyloxycarbonyl(methyl)amino]-3-(cyclobutyloxy)propionic acid or a salt thereof or a solvate thereof.

[0200]

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

[0201]

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

[0202]

[94] (4S)-4-(Cyclobutyloxymethyl)-5-oxo-oxazolidine-3-carboxylic acid benzyl ester or a salt thereof or a solvate thereof.

[0203]

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

[0204]

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

[0205]

[97] N-[(9H-Fluoren-9-ylmethoxycarbonyl)-L-leucyl]-O-isopropyl-L-threonine or a salt thereof or a solvate thereof.

[0206] In the above numbering, unless otherwise specified, the number cited in the dependent item includes the branch number of the number. For example, [1] cited in the dependent item indicates that it includes not only [1] but also its branch number [1-1]. The same applies to other numbers.

[0207] Effects of the Invention

[0208] According to the present invention, there can be provided a method for producing an O-substituted serine derivative, wherein the O-substituted serine derivative can be obtained in a small number of steps. DETAILED DESCRIPTION

[0209] (abbreviation)

[0210] Listed below are examples and meanings of abbreviations as used herein.

[0211] MTBE: tert-butyl methyl ether

[0212] HFIP: 1,1,1,3,3,3-hexafluoro-2-propanol

[0213] DCHA: Dicyclohexylamine

[0214] MeTHF: 2-methyltetrahydrofuran

[0215] CPME: Cyclopentyl Methyl Ether

[0216] PMHS: Poly(methylhydrogensiloxane)

[0217] TMDS: 1,1,3,3-Tetramethyldisiloxane

[0218] (the term)

[0219] As used herein, the term "room temperature" means a temperature of about 20°C to about 25°C.

[0220] As used herein, the term "electron withdrawing group" is a substituent that easily withdraws electrons from the side of the atom to which it is attached compared to 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 represented by a group, wherein R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 Each is a C1-C6 alkyl group optionally having a substituent, an aralkyl group optionally having a substituent, an aryl group optionally having a substituent, or a heteroaryl group optionally having a substituent.

[0221] As used herein, examples of the "halogen atom" include F, Cl, Br and I.

[0222] As used herein, the term "alkyl" is a monovalent group derived by removing any one hydrogen atom from an aliphatic hydrocarbon, and has a hydrocarbon group or a subset of hydrocarbon group structures that do not contain heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds, and contain hydrogen and carbon atoms in the main chain. Alkyl groups include not only straight chain forms but also branched chain forms. Preferred examples of alkyl groups include groups having 1 to 20 carbon atoms (C1-C 20 ; later "C p -C q " means an alkyl group having p to q carbon atoms, preferably C1-C 10 Alkyl, and more preferably C1-C6 alkyl. Specific examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl (2-methylpropyl), n-pentyl, sec-pentyl (1-methylbutyl), tert-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.

[0223] As used herein, the term "alkenyl" is a group having at least one double bond (two adjacent SP 2 The double bond geometry may be entgegen (E) or zusammen (Z) and cis or trans conformation, depending on the configuration of the double bond and substituents (if any). Alkenyl includes not only straight chain forms but also branched forms. Preferred examples of alkenyl include C2-C 10 The present invention relates to an alkenyl group, and more preferably a C2-C6 alkenyl group. Specific examples thereof include vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl and hexenyl.

[0224] As used herein, the term "alkynyl" is a monovalent group having at least one triple bond (two adjacent SP carbon atoms). Alkynyl groups include not only straight chain forms but also branched chain forms. Preferred examples of alkynyl groups include C2-C 10 Alkynyl, and more preferably C2-C6 alkynyl. Specific examples thereof include 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.

[0225] As used herein, the term "cycloalkyl" means a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group and includes monocyclic, bicyclic and spirocyclic rings. Preferred examples of cycloalkyl include C3-C8 cycloalkyl. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl and spiro[3.3]heptyl.

[0226] As used herein, the term "aryl" means a monovalent aromatic hydrocarbon ring and an aromatic hydrocarbon ring group. Preferred examples of the aryl group include C6-C 10 Aryl group. Specific examples of the aryl group include phenyl and naphthyl (eg, 1-naphthyl and 2-naphthyl).

[0227] As used herein, the term "heteroaryl" means an aromatic cyclic monovalent group and an 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 other rings, 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 groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, 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 fluoropyridyl.

[0228] As used herein, the term "aralkyl (arylalkyl)" means a group in which at least one hydrogen atom in the "alkyl" as defined above is replaced by an "aryl" as defined above. 14 Arylalkyl is preferred, and C7-C 10 Aralkyl groups are more preferred. Specific examples of the aralkyl groups include benzyl, phenethyl and 3-phenylpropyl.

[0229] As used herein, the term "alicyclic ring" means a non-aromatic hydrocarbon ring. The alicyclic ring may have an unsaturated bond in the ring and may be a polycyclic ring having two or more rings. The carbon atoms constituting the ring may form a carbonyl group by oxidation. The alicyclic ring is preferably a 3- to 8-membered alicyclic ring. 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.

[0230] As used herein, the term "saturated heterocycle" means a non-aromatic heterocycle containing 1 to 5 heteroatoms in addition to carbon atoms and having no double bonds and / or triple bonds in the ring. The saturated heterocycle may be a monocyclic ring, or may form a condensed ring with another ring (e.g., 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 heterocyclic ring include an azetidine ring, an oxazetidine 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 oxazolidinone ring, a dioxolane ring, a dioxane ring, a thietane ring, an octahydroindole ring, a dihydroindole ring, an azepane ring, a dioxepane ring, and a 5,9-dioxaspiro[3.5]nonane ring.

[0231] The compounds described herein may be salts thereof or solvates thereof. Examples of salts of compounds include: hydrochlorides; hydrobromides; hydroiodides; phosphates; phosphonates; sulfates; sulfonates, such as methanesulfonates and p-toluenesulfonates; carboxylates, such as acetates, citrates, malates, tartrates, succinates and salicylates; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as magnesium and calcium salts; and ammonium salts, such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts and tetraalkylammonium salts. These salts are produced, for example, by contacting the compound with an acid or a base. As used herein, "solvate" refers to a population of molecules formed by a compound together with a solvent. Examples of solvates include hydrates, alcohol solvates (such as ethanol solvates, methanol solvates, 1-propanol solvates or 2-propanol solvates), including not only solvates formed with a single solvent such as dimethyl sulfoxide, but also solvates formed with multiple solvents per compound molecule, or solvates formed with multiple types of solvents per compound molecule. When the solvent is water, the solvate is called a hydrate. The solvate of the compound of the present invention is preferably a hydrate. Specific examples of such hydrates include monohydrates to decahydrates, preferably monohydrates to pentahydrates, and more preferably monohydrates to trihydrates.

[0232] As used herein, "amino acid" includes natural amino acids and non-natural amino acids (sometimes also referred to as amino acid derivatives). As used herein, "amino acid" may refer to amino acid residues. As used herein, the term "natural amino acid" refers to Gly, Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg or Pro. Non-natural amino acids (amino acid derivatives) are not particularly limited, and examples thereof include β-amino acids, D-type 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 amino acids used herein, amino acids with any conformation are acceptable. The selection of the side chain of amino acids is not particularly limited, and in addition to hydrogen atoms, the side chain can also be freely selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl and spiral bonded cycloalkyl. Each of the side chains may have a substituent. Substituents are also not limited, and one or two or more substituents can be independently and freely selected from any substituent including, for example, halogen atoms, O atoms, S atoms, N atoms, B atoms, Si atoms or P atoms. That is, the example of side chain includes alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl or substituted cycloalkyl, or oxo, aminocarbonyl and halogen atoms. In a non-limiting aspect, amino acid herein can be a compound with carboxyl and amino in the same molecule, and its specific examples include 4-aminobutyric acid, 5-aminopentanoic acid, 6-aminocaproic acid, 4-piperidinic acid and 4-aminobenzoic acid.

[0233] As used herein, "peptides" and "peptide compounds" are not particularly limited as long as they are peptides formed by natural amino acids and / or non-natural amino acids linked by amide bonds or ester bonds. The number of residues contained in the peptide compound is preferably 5 to 30 residues, more preferably 7 to 15 residues, and further preferably 9 to 13 residues. The number of residues contained in the peptide is preferably 2 to 29 residues, more preferably 2 to 14 residues, and further preferably 2 to 12 residues. The peptide and peptide compound may be a linear peptide or a cyclic peptide.

[0234] As used herein, the "amino acid residue" and "peptide residue" constituting a peptide compound are sometimes simply referred to as "amino acid" and "peptide residue", respectively.

[0235] As used herein, the term "optionally substituted" means that a group may be substituted by any substituent. Substituents may be further added to each of the substituents. Such substituents are not limited and may be independently selected from one or two or more of any substituents including halogen atoms, oxygen atoms, sulfur atoms, nitrogen atoms, boron atoms, silicon atoms or phosphorus atoms. Examples of substituents include alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, oxo, aminocarbonyl, alkylsulfonyl, alkylsulfonylamino, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, halogen, nitro, amino, monoalkylamino, dialkylamino, cyano, carboxyl, alkoxycarbonyl and formyl.

[0236] Examples of the halogenated solvent as used herein include dichloromethane, chloroform, 1,2-dichloroethane and carbon tetrachloride. Among them, dichloromethane, chloroform and 1,2-dichloroethane are preferred.

[0237] Examples of the benzene-based solvent used herein include benzene, toluene, xylene, fluorobenzene, chlorobenzene, 1,2-dichlorobenzene, bromobenzene, anisole, ethylbenzene, nitrobenzene, cumene, and trifluorotoluene. Among them, toluene, fluorobenzene, chlorobenzene, and trifluorotoluene are preferred.

[0238] Examples of the ether solvent as used herein include diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, 1,2-dimethoxyethane, diisopropyl ether, cyclopentyl methyl ether, tert-butyl methyl ether, 4-methyltetrahydropyran, diglyme, triglyme and tetraglyme.

[0239] Examples of the ester solvent used herein include methyl acetate, ethyl acetate, butyl acetate, methyl propionate, propyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, dimethyl carbonate, diethyl carbonate and γ-valerolactone. Among them, ethyl acetate and dimethyl carbonate are preferred.

[0240] Examples of the nitrile solvent used herein include acetonitrile and propionitrile. Among them, acetonitrile is preferred.

[0241] Examples of fluoroalcohols as used herein include 2,2,2-trifluoroethanol and 1,1,1,3,3,3-hexafluoro-2-propanol.

[0242] Examples of alcohols used herein include methanol, ethanol, n-propanol and 2-propanol. Among them, methanol, ethanol and 2-propanol are preferred.

[0243] As used herein, the term "one / kind or more / kind" means a number of 1 or 2 or more. When the term "one / kind or more / kind" is used in the context of a substituent of a group, the term means a number from 1 to the maximum number of substituents that the group can accept. Specific examples of the term "one / kind or more / kind" include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and / or larger numbers.

[0244] As used herein, the meaning of the term "and / or" includes any combination in which "and" and "or" are appropriately combined. Specifically, for example, the term "A, B and / or C" includes the following seven variations:

[0245] (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, and (vii) A, B and C.

[0246] (General production method)

[0247] A general method for producing the compound of the present invention will be described.

[0248] In one aspect, the compound represented by formula (1) can be produced, for example, by production method 1 including step A shown below.

[0249] Production method 1:

[0250] [Formula 7]

[0251]

[0252] In the formula, R1 is an electron withdrawing group; R1 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 18Each is a C1-C6 alkyl group optionally having a substituent, an aralkyl group optionally having a substituent, an aryl group optionally having a substituent, or a heteroaryl group optionally having a substituent. Specific examples include methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, isopentyl, trifluoromethyl, phenyl, nitrophenyl, pyridyl, benzyl, methoxybenzyl, fluorobenzyl, and 9-fluorenylmethyl. R1 is more preferably -C(=O)-R 12 、-C(=O)-OR 13 or -S(=O)2-R 14 , where R 12 , R 13 and R 14 R1 is preferably C1-C6 alkyl, aralkyl, aryl or heteroaryl. Specific examples include methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, isopentyl, trifluoromethyl, phenyl, nitrophenyl, pyridyl, benzyl, methoxybenzyl, fluorobenzyl and 9-fluorenylmethyl. R1 is further preferably benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), acetyl, trifluoroacetyl, mesyl, p-toluenesulfonyl, (trifluoromethyl) sulfonyl and 2-nitrobenzenesulfonyl (Nosyl). R1 ​​is particularly preferably benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc). On the one hand, R1 is an amino acid residue or a peptide residue. In this case, R1 is preferably an amino acid residue or peptide residue whose N-terminus is protected by benzyloxycarbonyl (Cbz) or 9-fluorenylmethoxycarbonyl (Fmoc), more preferably an amino acid residue whose N-terminus is protected by benzyloxycarbonyl (Cbz) or 9-fluorenylmethoxycarbonyl (Fmoc).

[0253] R2 and R3 in the formula are each independently hydrogen, a C1-C6 alkyl group optionally having a substituent, an aralkyl group optionally having a substituent, an aryl group optionally having a substituent, or a heteroaryl group optionally having a substituent, or R2 and R3 together with the carbon atoms to which they are connected form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring. Preferably, R2 and R3 are each independently hydrogen, methyl, ethyl, n-propyl, n-butyl, tert-butyl, isobutyl, isopentyl, benzyl, phenyl or pyridyl, or R2 and R3 together with the carbon atoms to which they are connected form a 3- to 8-membered alicyclic ring. More preferably, when R2 is methyl, ethyl, n-propyl, n-butyl or isobutyl, R3 is hydrogen or methyl, or R2 and R3 together with the carbon atoms to which they are connected form a 4- to 6-membered alicyclic ring.

[0254] R4 and R5 in the formula are each independently hydrogen, a C1-C6 alkyl optionally with a substituent, an aryl optionally with a substituent or a heteroaryl optionally with a substituent, or R4 and R5 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring together with the carbon atoms to which they are connected. Preferably, R4 and R5 are each independently hydrogen, methyl, ethyl, n-propyl, n-butyl, tert-butyl, isobutyl, isopentyl, benzyl, phenyl or pyridyl, or R4 and R5 form a 3- to 8-membered alicyclic ring together with the carbon atoms to which they are connected. More preferably, R4 is hydrogen, methyl, ethyl, n-propyl, n-butyl or isobutyl, and R5 is hydrogen. Further preferably, R4 is hydrogen or methyl and R5 is hydrogen.

[0255] R6 in the formula is hydrogen, a C1-C6 alkyl group optionally having a substituent, or an aralkyl group optionally having a substituent. Preferably, R6 is hydrogen, methyl, ethyl, n-propyl, n-butyl or benzyl, and more preferably, R6 is hydrogen.

[0256] In the formula, R7 is -OR8, -NR9R 9' , amino acid residues or peptide residues; and R8, R9 and R 9' are each independently hydrogen, an optionally substituted C1-C6 alkyl group or an optionally substituted aralkyl group, or R9 and R 9' Together with the intervening nitrogen atom, a 4- to 7-membered saturated heterocyclic ring is formed. Preferably, R7 is -OR8, and more preferably, R7 is -OH. In one aspect, preferably, R7 is -OR8, and R8 is a C1-C6 alkyl, more preferably, R7 is -OR8, and R8 is a methyl. In one aspect, preferably, R7 is an amino acid residue whose C-terminus is protected by a C1-C6 alkyl ester.

[0257] In the formula, L1, L2 and L3 are each a single bond or -CH2-, provided that when L1 is -CH2-, L2 is a single bond; when L2 is -CH2-, L1 and L3 are each a single bond; and when L3 is -CH2-, L2 is a single bond. Preferably, L1, L2 and L3 are each a single bond.

[0258] Step A of production method 1 is a step of producing an O-substituted serine derivative (1) by a ring-opening reduction hydrogenation reaction of a cyclic N,O-acetal derivative (2). The step may be carried out in the presence or absence of a reducing agent, in the presence or absence of an acid, in the presence or absence of a solvent, and in the presence or absence of a solubilizing agent, preferably at a temperature of -50°C to 50°C, more preferably at a temperature of -40°C to 40°C, further preferably at a temperature of -30°C to 30°C, particularly preferably at a temperature of -20°C to 25°C, preferably for 5 minutes to 24 hours, more preferably for 10 minutes to 12 hours, further preferably for 20 minutes to 8 hours, particularly preferably for 30 minutes to 5 hours.

[0259] As the reducing agent, a hydride-based reducing agent can be used, and examples thereof include silane-based reducing agents such as triethylsilane, triisopropylsilane, tris(trimethylsilyl)silane, phenylsilane, dimethylphenylsilane, tetraphenyldisilane, poly(methylhydrogensiloxane), and 1,1,3,3-tetramethyldisiloxane, and borane-based reducing agents. Among them, triethylsilane, poly(methylhydrogensiloxane), and 1,1,3,3-tetramethyldisiloxane are preferably used, and triethylsilane is more preferably used.

[0260] The amount of the reducing agent used is not particularly limited, and examples thereof include 0.5 equivalents or more and 30 equivalents or less relative to the compound represented by formula (2). The amount is preferably 1 equivalent or more and 20 equivalents or less, more preferably 1.5 equivalents or more and 10 equivalents or less, and further preferably 2 equivalents or more and 7 equivalents or less.

[0261] Examples of acids that can be used include Bronsted acids such as trifluoromethanesulfonic acid (TfOH), methanesulfonic acid (MsOH) and trifluoroacetic acid (TFA); non-metallic Lewis acids such as complexes of boron trifluoride with ether solvents and trialkylsilyl trifluoromethanesulfonate; and metal Lewis acids as described below, and metal Lewis acids are preferred.

[0262] The metal Lewis acid herein means a Lewis acid consisting of a metal and an anionic group, and examples thereof include metal halides, metal trifluoromethanesulfonates, 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 them, titanium, tin, scandium, zirconium, zinc, and aluminum are preferred, titanium, tin, and scandium are more preferred, and titanium and tin are further preferred. The anionic group in the metal Lewis acid can be a known anionic group, and examples thereof include an anionic group derived from trifluoromethanesulfonic acid (TfOH), methanesulfonic acid (MsOH), bis(trifluoromethanesulfonyl)imide (Tf2NH), tris(trifluoromethanesulfonyl)methane (HCTf3), pentafluorophenylbis(trifluoromethanesulfonyl)methane (C6H5CHTf2), trifluoroacetic acid (TFA), 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, methanol, ethanol, n-propanol, isopropanol, n-butanol and phenol. The anionic group can be independently selected from one or more combinations of the group consisting of these anionic groups.

[0263] Specific examples of metal Lewis acids include metal halides such as titanium tetrahalides (e.g., titanium tetrachloride (TiCl4)) and tin tetrahalides (e.g., tin tetrachloride (SnCl4)), metal trifluoromethanesulfonates such as scandium trifluoromethanesulfonate (Sc(OTf)3), metal alkoxides such as tetraalkoxytitanium (e.g., tetraisopropyl orthotitanate (Ti(OiPr)4)) and alkoxytitanium trichloride (e.g., isopropoxytitanium trichloride (TiCl3(OiPr))). Among them, isopropoxytitanium trichloride is preferred. The metal Lewis acid may also be a combination of multiple Lewis acids, such as a combination of titanium tetrahalides and tetraalkoxytitanium. Among them, a combination of titanium tetrachloride and tetraisopropyl orthotitanate is preferred. In this case, the molar ratio of titanium tetrahalide:tetraalkoxytitanium is not particularly limited, but is preferably 2 to 4:1, more preferably 3:1.

[0264] The amount of the acid used is not particularly limited, and examples thereof include 0.1 equivalent or more and 20 equivalents or less relative to the compound represented by formula (2). The amount is preferably 0.5 equivalent or more and 5 equivalents or less, and more preferably 1 equivalent or more and 3 equivalents or less.

[0265] 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 trifluorotoluene. Among them, dichloromethane, toluene and chlorobenzene are preferably used.

[0266] Step A of production method 1 may 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 them, 2,2,2-trifluoroethanol and 1,1,1,3,3,3-hexafluoro-2-propanol are preferably used.

[0267] In one aspect, the addition of a base in the post-treatment step of step A of production method 1 can reduce the content of compound (4) contained as an impurity in the reaction mixture.

[0268] [Formula 8]

[0269]

[0270] Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and tetraalkylammonium hydroxides such as tetramethylammonium hydroxide. Among them, sodium hydroxide and potassium hydroxide are preferably used.

[0271] The alkali treatment step can be preferably carried out at a temperature of -5°C to 50°C, more preferably at a temperature of 0°C to 40°C, further preferably at a temperature of 5°C to 30°C, particularly preferably at a temperature of 10°C to 25°C, preferably for 5 minutes to 24 hours, more preferably for 10 minutes to 12 hours, further preferably for 20 minutes to 8 hours, particularly preferably for 30 minutes to 5 hours.

[0272] On the one hand, in the O-substituted serine derivative (1) obtained by step A of production method 1, for the O-substituted serine derivative (11) wherein R7 is -OH, the content of impurities contained 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 performing crystallization.

[0273] Examples of the salt include dicyclohexylamine, lithium hydroxide, sodium hydroxide, potassium hydroxide, and calcium hydroxide, and among them, dicyclohexylamine is preferably used.

[0274] In one aspect, the cyclic N,O-acetal derivative (2) used as a starting material in step A of production method 1 can be produced by a method including step B shown below using compound (3) as a starting material.

[0275] [Formula 9]

[0276]

[0277] In the formula, R1, R2, R3, R4, R5, R6, R7, L1, L2 and L3 have the same meanings as R1, R2, R3, R4, R5, R6, R7, L1, L2 and L3 defined in step A.

[0278] In the formula, Ra and Rb are each independently a C1-C6 alkyl group, or Ra and Rb together with the intervening oxygen atom and carbon atom form a 5- to 7-membered saturated heterocyclic ring.

[0279] In the formula, R 3’ is selected from the group consisting of hydrogen, C1-C6 alkyl optionally having a substituent, C3-C6 cycloalkyl optionally having a substituent, C2-C6 alkenyl optionally having a substituent, C2-C6 alkynyl optionally having a substituent, aralkyl optionally having a substituent, aryl optionally having a substituent, and heteroaryl optionally having a substituent, or R 3’ and R2 together with the intervening carbon atom form a 4- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.

[0280] Step B of Production Method 1 is a step of reacting Compound (3) with an aldehyde, ketone, acetal or vinyl ether to produce a cyclic N,O-acetal derivative (2). The step may be performed in the presence or absence of an acid, in the presence or absence of a solvent and in the presence or absence of a silylating agent, preferably at a temperature of -10°C to 80°C, more preferably at a temperature of 0°C to 70°C, further preferably at a temperature of 10°C to 60°C, particularly preferably at a temperature of 20°C to 50°C, preferably for 5 minutes to 24 hours, more preferably for 10 minutes to 12 hours, further preferably for 20 minutes to 6 hours, particularly preferably for 30 minutes to 3 hours.

[0281] Examples of usable acids include Bronsted acids such as trifluoromethanesulfonic acid (TfOH), methanesulfonic acid (MsOH) and trifluoroacetic acid (TFA); non-metallic Lewis acids such as complexes of boron trifluoride with ether solvents and trialkylsilyl trifluoromethanesulfonate; and metal Lewis acids as described above, and Lewis acids are preferred.

[0282] Specific examples of the Lewis acid include a boron trifluoride-tetrahydrofuran complex, a boron trifluoride-diethyl ether complex, and trimethylsilyl trifluoromethanesulfonate.

[0283] The amount of the acid used is not particularly limited, and examples thereof include 0.05 equivalent or more and 1 equivalent or less relative to the compound represented by formula (3). The amount is preferably 0.1 equivalent or more and 0.5 equivalent or less.

[0284] Examples of the solvent include halogenated solvents such as dichloromethane, 1,2-dichloroethane and chloroform; benzene solvents such as toluene, chlorobenzene, fluorobenzene and trifluorotoluene; and ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran and cyclopentyl methyl ether. Among them, dichloromethane, toluene and 2-methyltetrahydrofuran are preferably used.

[0285] Step B of Production Method 1 may be further performed in the presence of a silylating agent. Examples of the silylating agent may include N,O-bis(trimethylsilyl)trifluoroacetamide, N,O-bis(trimethylsilyl)acetamide, and 1-trimethylsilylimidazole, and among them, N,O-bis(trimethylsilyl)trifluoroacetamide is preferably used.

[0286] In one aspect, in the O-substituted serine derivative (1) obtained by step A of production method 1, an O-substituted serine derivative (11) in which R7 is -OH can be produced by a method including step C and step D shown below using as a starting material a substituent (-CHR 10 R 11 )'s O-substituted serine derivatives (16).

[0287] [Formula 10]

[0288]

[0289] In the formula, R1, R2, R3, R4, R5, R6, R7, L1, L2 and L3 have the same meanings as R1, R2, R3, R4, R5, R6, R7, L1, L2 and L3 defined in step A.

[0290] Ra and Rb in the formula have the same meanings as Ra and Rb in step B, respectively.

[0291] In the formula, R 10 and R 11 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl optionally having a substituent, C3-C6 cycloalkyl optionally having a substituent, C2-C6 alkenyl optionally having a substituent, C2-C6 alkynyl optionally having a substituent, aralkyl optionally having a substituent, aryl optionally having a substituent, and heteroaryl optionally having a substituent, or R 10 and R 11 Together with the intervening carbon atom, it forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.

[0292] In the formula, R 11'is selected from the group consisting of hydrogen, C1-C6 alkyl optionally having a substituent, C3-C6 cycloalkyl optionally having a substituent, C2-C6 alkenyl optionally having a substituent, C2-C6 alkynyl optionally having a substituent, aralkyl optionally having a substituent, aryl optionally having a substituent, and heteroaryl optionally having a substituent, or R 11' and R 10 Together with the intervening carbon atom, it forms a 4- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.

[0293] The above step C is a step of obtaining oxazolidinone (15) by reacting an O-substituted serine derivative (11) with an aldehyde, ketone, acetal or vinyl ether according to the method of, for example, Freidinger et al. (J. Org. Chem., 1983, 48 (1), 77-81). The step can be carried out in the presence or absence of a Lewis acid and in the presence or absence of a solvent.

[0294] Examples of Lewis acids that can be used include non-metallic Lewis acids such as a complex of boron trifluoride with an ether solvent and trialkylsilyl trifluoromethanesulfonate; and the metal Lewis acids described above.

[0295] Specific examples of the Lewis acid include boron trifluoride-tetrahydrofuran complex, boron trifluoride-diethyl ether complex, trimethylsilyl trifluoromethanesulfonate, titanium tetrachloride and tetraalkoxytitanium, and among them, boron trifluoride-tetrahydrofuran complex and boron trifluoride-diethyl ether complex are preferred.

[0296] The amount of the Lewis acid used is not particularly limited, and examples thereof include 0.2 equivalents or more and 5 equivalents or less relative to the compound represented by formula (11). The amount is preferably 0.5 equivalents or more and 3 equivalents or less, and more preferably 1 equivalent or more and 2 equivalents or less.

[0297] 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 trifluorotoluene. Among them, dichloromethane, toluene and chlorobenzene are preferably used.

[0298] The above step D is to perform a reductive ring-opening reaction on oxazolidinone (15) to produce a compound having a substituent (-CHR 10 R 11 ) is prepared by the step of preparing an O-substituted serine derivative (16) of the present invention. The step can be carried out in the presence or absence of an acid, in the presence or absence of a reducing agent, and in the presence or absence of a solvent.

[0299] Examples of usable acids include Bronsted acids such as trifluoromethanesulfonic acid (TfOH), methanesulfonic acid (MsOH) and trifluoroacetic acid (TFA); non-metallic Lewis acids such as complexes of boron trifluoride with ether solvents and trialkylsilyl trifluoromethanesulfonate; and metal Lewis acids as described above, and Lewis acids are preferred.

[0300] Specific examples of the Lewis acid include boron trifluoride-tetrahydrofuran complex, boron trifluoride-diethyl ether complex, trimethylsilyl trifluoromethanesulfonate, titanium tetrachloride, and tetraalkoxytitanium, and among them, trimethylsilyl trifluoromethanesulfonate is preferred.

[0301] The amount of the Lewis acid used is not particularly limited, and examples thereof include 0.2 equivalents or more and 5 equivalents or less relative to the compound represented by formula (15). The amount is preferably 0.5 equivalents or more and 3 equivalents or less, and more preferably 1 equivalent or more and 2 equivalents or less.

[0302] As the reducing agent, a hydride-based reducing agent can be used, and examples thereof include silane-based reducing agents such as triethylsilane, triisopropylsilane, tris(trimethylsilyl)silane, phenylsilane, dimethylphenylsilane, tetraphenyldisilane, poly(methylhydrogensiloxane), and 1,1,3,3-tetramethyldisiloxane, and borane-based reducing agents. Among them, triethylsilane, poly(methylhydrogensiloxane), and 1,1,3,3-tetramethyldisiloxane are preferably used, and triethylsilane is more preferably used.

[0303] The amount of the reducing agent used is not particularly limited, and examples thereof include 1 equivalent or more and 20 equivalents or less relative to the compound represented by formula (15). The amount is preferably 1.5 equivalents or more and 10 equivalents or less, and more preferably 2 equivalents or more and 5 equivalents or less.

[0304] 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 trifluorotoluene. Among them, dichloromethane, toluene and chlorobenzene are preferably used.

[0305] On the one hand, the O-substituted serine derivative represented by formula (11) or formula (16) obtained by the above-mentioned production method can be used to produce a peptide compound, for example, by the production method described in WO2021132545 (synthesis method of a peptide compound). Specifically, by reacting with Cbz-Ser(tBu)-MePhe-MeVal-Asp(tBu)-piperidine (4mer), Cbz-MeIle-Ser(tBu)-MePhe-MeVal-Asp(tBu)-piperidine (5mer), Cbz-MeGly-MeIle-Ser(tBu)-MePhe-MeVal-Asp(tBu)-piperidine (6mer), Cbz-MeLeu-Val-MeGly-MeIle-Ser(tBu)-MePhe-MeVal-Asp(tBu)-piperidine (7mer), Cbz-Val-MeGly-MeIle-Ser(tBu)-MePhe-MeVal-Asp(tBu)-piperidine (8mer), and Cbz-Val-MeGly-MeIle-Ser(tBu)-MePhe-MeVal-Asp(tBu)-piperidine (9mer). In a similar manner to the production examples of Cbz-Ser(tBu)-OH, Cbz-Leu-MeLeu-Val-MeGly-MeIle-Ser(tBu)-MePhe-MeVal-Asp(tBu)-piperidine (9mer), Cbz-MePhe-Leu-MeLeu-Val-MeGly-MeIle-Ser(tBu)-MePhe-MeVal-Asp(tBu)-piperidine (10mer) or Cbz-MeAla-MePhe-Leu-MeLeu-Val-MeGly-MeIle-Ser(tBu)-MePhe-MeVal-Asp(tBu)-piperidine (11mer), a peptide compound can be produced by using an O-substituted serine derivative represented by formula (11) or formula (16) instead of Cbz-Ser(tBu)-OH. In this case, R1 in formula (11) or formula (16) is a protecting group for an amino group, preferably Cbz. The above-mentioned amino acid sequence is just an example, and the types of amino acids are not limited.

[0306] On the one hand, the O-substituted serine derivative represented by formula (11) or formula (16) can be used to produce a peptide compound or a cyclic peptide compound, for example, by the production method described in WO2013100132 (cyclization method of a peptide compound). Specifically, the peptide compound or the cyclic peptide compound can be produced according to the method for producing a peptide compound or a cyclic peptide compound in Examples 18 to 20 of WO2013100132 by using an O-substituted serine derivative represented by formula (11) or formula (16) instead of Fmoc-Ser(tBu)-OH. In this case, R1 in formula (11) or formula (16) is a protecting group for an amino group, preferably Fmoc. The above amino acid sequence is only an example, and the type of amino acid is not limited.

[0307] In one aspect, the present invention is a compound or a salt or a solvate thereof selected from the group consisting of:

[0308] A compound selected from the group consisting of:

[0309] 2-(Benzyloxycarbonylamino)-3-(cyclobutyloxy)propanoic acid;

[0310] 2-(Benzyloxycarbonylamino)-3-isopentyloxy-propionic acid;

[0311] 2-(Benzyloxycarbonylamino)-3-isopropoxy-butyric acid;

[0312] 2-[Benzyloxycarbonyl(methyl)amino]-3-(cyclobutyloxy)propanoic acid;

[0313] 3-Benzyloxycarbonyl-2-ethyl-oxazolidine-4-carboxylic acid;

[0314] 3-Benzyloxycarbonyl-2-isobutyl-oxazolidine-4-carboxylic acid;

[0315] 4-(Cyclobutyloxymethyl)-5-oxo-oxazolidine-3-carboxylic acid benzyl ester;

[0316] Benzyl 4-{[1-methoxy-1-oxapropan-2-yl]carbamoyl}-2,2,5-trimethyloxazolidine-3-carboxylate;

[0317] N-(Benzyloxy)carbonyl-O-isopropyl-threonyl-alanine methyl ester; and

[0318] N-[(9H-Fluoren-9-ylmethoxycarbonyl)-leucyl]-O-isopropyl-threonine.

[0319] These compounds or their salts or their solvates can be produced by the production methods described herein.

[0320] In one aspect, the present invention is the following compound or a salt or solvate thereof:

[0321] (2S)-2-(Benzyloxycarbonylamino)-3-(cyclobutyloxy)propanoic acid or a salt or a solvate thereof;

[0322] (2S)-2-(Benzyloxycarbonylamino)-3-isopentyloxy-propionic acid or a salt or a solvate thereof;

[0323] (2S,3R)-2-(Benzyloxycarbonylamino)-3-isopropoxy-butyric acid or a salt thereof or a solvate thereof;

[0324] (2S)-2-[Benzyloxycarbonyl(methyl)amino]-3-(cyclobutyloxy)propionic acid or a salt thereof or a solvate thereof;

[0325] (4S)-3-Benzyloxycarbonyl-2-ethyl-oxazolidine-4-carboxylic acid or a salt thereof or a solvate thereof;

[0326] (4S)-3-Benzyloxycarbonyl-2-isobutyl-oxazolidine-4-carboxylic acid or a salt thereof or a solvate thereof;

[0327] (4S)-4-(Cyclobutyloxymethyl)-5-oxo-oxazolidine-3-carboxylic acid benzyl ester or a salt thereof or a solvate thereof;

[0328] (4S,5R)-4-{[(S)-1-methoxy-1-oxapropan-2-yl]carbamoyl}-2,2,5-trimethyloxazolidine-3-carboxylic acid benzyl ester or a salt thereof or a solvate thereof;

[0329] N-(Benzyloxy)carbonyl-O-isopropyl-L-threonyl-L-alanine methyl ester or a salt thereof or a solvate thereof; and

[0330] N-[(9H-fluoren-9-ylmethoxycarbonyl)-L-leucyl]-O-isopropyl-L-threonine or a salt thereof or a solvate thereof.

[0331] These compounds or their salts or their solvates can be produced by the production methods described herein.

[0332] It should be noted that all prior art cited herein is incorporated herein by reference.

[0333] Examples

[0334] Hereinafter, the present disclosure will be described in more detail based on examples, but the present disclosure is not limited to the following examples.

[0335] In the following examples, high performance liquid chromatography (HPLC) analysis was performed using any of the following analytical conditions. 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.

[0336] HPLC analysis conditions method 1

[0337] Apparatus: Waters ACQUITY UPLC H-Class

[0338] Column: Ascentis Express 90A C18 (Sigma-Aldrich Co.LLC), 2.1mm ID×50mm, 2.7μm

[0339] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0340] Elution method: B): 5% (0min) → 100% (5min) → 5% (5.1min) → 5% (7min)

[0341] Flow rate: 0.5mL / min

[0342] Column temperature: 35°C

[0343] Detection wavelength: 210nm (PDA)

[0344] HPLC analysis conditions method 2

[0345] Apparatus: Waters ACQUITY UPLC H-Class

[0346] Column: CHIRALPAK IC-3 (Daicel Corporation) 4.6 mm ID x 150 mm, 3 μm

[0347] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0348] Elution method: B): 5% (0min) → 60% (20min) → 5% (20.1min) → 5% (25min)

[0349] Flow rate: 1.0mL / min

[0350] Column temperature: 30°C

[0351] Detection wavelength: 210nm (PDA)

[0352] HPLC analysis conditions method 3

[0353] Device: Waters ACQUITY UPLC H-Class + ACQUITY QDA

[0354] Column: Ascentis Express 90A C18 (Sigma-Aldrich Co.LLC), 2.1mm ID×50mm, 2.7μm

[0355] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0356] Elution method: B): 5% (0min) → 100% (6min) → 5% (6.1min) → 5% (8min)

[0357] Flow rate: 0.5mL / min

[0358] Column temperature: 35°C

[0359] Detection wavelength: 210nm (PDA)

[0360] HPLC analysis conditions method 4

[0361] Apparatus: Waters ACQUITY UPLC H-Class

[0362] Column: Ascentis Express C18 (Sigma-Aldrich Co.LLC), 4.6mm ID×10cm, 2.7μm

[0363] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0364] Elution method: B): 20% (0min) → 100% (9min) → 20% (9.1min) → 20% (13min)

[0365] Flow rate: 0.7mL / min

[0366] Column temperature: 35°C

[0367] Detection wavelength: 210nm (PDA)

[0368] HPLC analysis conditions method 5

[0369] Device: Waters ACQUITY UPLC H-Class + ACQUITY QDA

[0370] Column: CAPCELL CORE ADME (OSAKA SODA CO., LTD.), 2.1 mm ID × 50 mm, 2.7 μm

[0371] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0372] Elution method: B): 5% (0min) → 100% (5min) → 5% (5.1min) → 5% (7min)

[0373] Flow rate: 0.5mL / min

[0374] Column temperature: 35°C

[0375] Detection wavelength: 210nm (PDA)

[0376] HPLC analysis conditions method 6

[0377] Apparatus: Waters ACQUITY UPLC H-Class

[0378] Column: CHIRALPAK IC-3 (Daicel Corporation) 4.6 mm ID x 150 mm, 3 μm

[0379] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0380] Elution method: B) 35% (0min) → 90% (20min) → 100% (20.1min) → 100% (22min) → 35% (22.1min) → 35% (27min)

[0381] Flow rate: 1.0mL / min

[0382] Column temperature: 30°C

[0383] Detection wavelength: 210nm (PDA)

[0384] 1H-NMR spectrum is measured using nuclear magnetic resonance device ECX500II (manufactured by JEOL Ltd.) and reference to the deuterium lock signal from the sample solvent. As the sample solvent, a commercially available deuterated solvent is used according to the measurement purpose. The chemical shift of tetramethylsilane used as an internal standard is set to 0ppm, and the chemical shift of the signal of the compound to be analyzed is expressed in ppm. The abbreviations of the signals are as follows: s=singlet, brs=broad singlet, d=doublet, t=triplet, q=quartet, dd=double doublet, and m=multiplet. The split width of the signal is expressed as J value (Hz). The integral value of the signal is calculated according to the ratio of the signal area intensity of each signal.

[0385] The residue containing the target compound and the internal standard were dissolved in DMSO-d6 and subjected to the following analysis conditions to perform the measurement method of qNMR. The yield was calculated by the following expression using the value of the content of the target compound in the residue calculated by qNMR and the value of the purity of the target compound in the residue calculated by HPLC.

[0386] [Expression 1]

[0387]

[0388] Measuring equipment: JNM-ECZ500R

[0389] Internal standard: 3,5-bis(trifluoromethyl)benzoic acid

[0390] Measurement conditions ( 1 H-NMR): DMSO-d6, pulse angle 90°, digital resolution 0.25 Hz, relaxation time 60 seconds, no rotation, cumulative number 8 times

[0391] Example 1: For (2S)-2-(benzyloxycarbonylamino)-3-propoxy-propionic acid (Compound 3A) and (2S)-2-(benzyloxycarbonylamino)-3-propoxy-propionic acid (Compound 3A) Condition screening for the synthesis of (1,2-dioxycarbonylamino)-3-isopropoxy-propionic acid (compound 3B)

[0392] (1-1): Synthesis of (4S)-3-benzyloxycarbonyl-2-ethyl-oxazolidine-4-carboxylic acid (Compound 2A)

[0393] [Formula 11]

[0394]

[0395] After the atmosphere in the reaction vessel was replaced 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. Then, propionaldehyde (0.90 mL, 12.6 mmol) and boron trifluoride diethyl ether complex (0.21 mL, 1.7 mmol) were added, and the mixture was stirred at 40 ° C for 2.5 hours. The reaction mixture was filtered, and then water (10 mL) was added to the filtrate and the resulting mixture was stirred. After discarding the water layer, the resulting organic layer was washed twice with 5% sodium carbonate aqueous solution (10 mL). The resulting water layers were mixed, 5% sodium bisulfate monohydrate aqueous solution (55 mL) was added, and then the resulting mixture was washed three times with toluene (10 mL). The resulting organic layer was washed with 5% NaCl aqueous solution (10 mL). The obtained organic layer was concentrated, and then azeotropic dehydration with the addition of toluene (6 mL) was repeated three times to obtain 2.26 g of a residue containing Compound 2A (86.5% content) (yield according to HPLC and qNMR analysis: 83.2%).

[0396] UV intensity ratio (as a diastereoisomer mixture): 98.0%

[0397] (Detection wavelength 210nm, retention time 2.735 minutes and 2.776 minutes, HPLC analysis conditions method 1)

[0398] (1-2): Screening of acids for the synthesis of (2S)-2-(benzyloxycarbonylamino)-3-propoxy-propionic acid (Compound 3A)

[0399] [Formula 12]

[0400]

[0401] The reaction products obtained under the conditions using the various acids described in Table 1 below were examined as follows.

[0402] To the reaction vessel were added (4S)-3-benzyloxycarbonyl-2-ethyl-oxazolidine-4-carboxylic acid (Compound 2A) (63.3 mg, 0.20 mmol) obtained in the above (1-1), dichloromethane (0.28 mL) and triethylsilane (0.16 mL, 0.98 mmol), and the acid (0.20 mmol) described 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 obtained reaction mixture was analyzed using HPLC analysis conditions Method 1.

[0403] The results are shown in Table 1. Table 1 shows the HPLC area ratio of the peak of Compound 3A, Compound 4A, Compound 2A, or Compound 1 relative to all peaks.

[0404] Compound 3A: retention time 2.836 min, LCMS m / z 282 [M+H] +

[0405] Compound 4A: retention time 2.418 min, LCMS m / z 282 [M+H] +

[0406] (Structure of Compound 4A)

[0407] [Formula 13]

[0408]

[0409] Compound 2A (diastereoisomer mixture): total retention time 2.744 min and 2.783 min, LCMS m / z 280 [M+H] +

[0410] Compound 1: retention time 1.829 min, LCMS m / z 240 [M+H] +

[0411] [Table 1]

[0412]

[0413] From the above results, it can be seen that the target compound 3A is generated regardless of the acid used. However, when BF3·OEt2 is used, the production of impurity 4A is greater than the production of compound 3A (Run 1). On the contrary, when a metal Lewis acid such as TiCl4, Sc(OTf)3, SnCl4 or ZrCl4 is used, the production of impurity 4A is reduced, and it is found that compound 3A is selectively obtained (Runs 2 to 5).

[0414] (1-3): Screening of reducing agents, solvents and solubilizing agents for the synthesis of (2S)-2-(benzyloxycarbonylamino)-3-propoxy-propionic acid (Compound 3A)

[0415] The effects of the acid, reducing agent, solvent and solubilizing agent described in Table 2 below were examined as follows.

[0416] To the reaction vessel, (4S)-3-benzyloxycarbonyl-2-ethyl-oxazolidine-4-carboxylic acid (Compound 2A) (68.4 mg, 0.21 mmol) obtained in the above (1-1), a solvent (0.30 mL), a solubilizing agent (0.85 mmol) and a reducing agent (1.06 mmol) were added, and the acid (0.21 mmol) described 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. For the obtained reaction mixture, HPLC analysis was performed using HPLC analysis conditions method 1.

[0417] The results are shown in Table 2. Table 2 shows the HPLC area ratio of the peak of Compound 3A, Compound 4A, Compound 2A, or Compound 1 relative to all peaks.

[0418] Compound 3A: retention time 2.836 min, LCMS m / z 282 [M+H] +

[0419] Compound 4A: retention time 2.418 min, LCMS m / z 282 [M+H] +

[0420] (Structure of Compound 4A)

[0421] [Formula 14]

[0422]

[0423] Compound 2A (diastereoisomer mixture): total retention time 2.744 min and 2.783 min, LCMS m / z 280 [M+H] +

[0424] Compound 1: retention time 1.829 min, LCMS m / z 240 [M+H] +

[0425] [Table 2]

[0426]

[0427] *) The amount of solvent in runs 5 and 6 was 4 v / w.

[0428] The above results confirm that the compound of interest 3A can be obtained by the present reaction even when toluene solvent is used (Run 5). After checking the conditions using a Bronsted acid such as trifluoromethanesulfonic acid (TfOH) instead of a metal Lewis acid, compound 3A was obtained, but approximately the same amount of impurity 4A was generated (Run 6). It should be noted that reactions in toluene solvent sometimes generate insoluble materials, resulting in the formation of a heterogeneous mixture, and it has been confirmed that the reaction progresses even when a solubilizing agent such as HFIP or MeCN is added (Runs 2 and 3). In addition, it has been confirmed that the target compound 3A is selectively obtained relative to impurity 4A even when a hydride reducing agent other than triethylsilane such as PMHS or TMDS is used (Runs 7 and 8).

[0429] (1-4): Synthesis of (4S)-3-benzyloxycarbonyl-2,2-dimethyl-oxazolidine-4-carboxylic acid (Compound 2B) [Formula 15]

[0430]

[0431] N-benzyloxycarbonyl-L-serine (Compound 1) (3.49 g, 14.6 mmol), acetone (17.4 mL) and 2,2-dimethoxypropane (15.7 mL, 128 mmol) were added to the reaction vessel. Boron trifluoride diethyl ether complex (0.19 mL, 1.5 mmol) was added at room temperature, and the mixture was then stirred at an external temperature of 40 ° C for 45 minutes. Subsequently, triethylamine (0.20 mL, 1.5 mmol) was added at room temperature and the mixture was stirred for 5 minutes. The resulting residue was concentrated, and toluene (18 mL) and water (21 mL) were added, and the mixture was stirred. After discarding the water layer, the resulting organic layer was washed with a 5% NaCl aqueous solution (10.5 mL). Then the azeotropic dehydration of adding toluene (10.5 mL) was repeated three times to obtain 4.43 g of a residue containing compound 2B (12.7 mmol) (the yield according to HPLC and qNMR analysis was 87.1%).

[0432] UV intensity ratio: 96.7 percent

[0433] (Detection wavelength 210nm, retention time 2.673 minutes, HPLC analysis conditions method 1)

[0434] (1-5): Screening of solvents and solubilizers for the synthesis of (2S)-2-(benzyloxycarbonylamino)-3-isopropoxy-propionic acid (Compound 3B)

[0435] [Formula 16]

[0436]

[0437] The effects of the solvents and solubilizing agents described in Table 3 below were examined as follows.

[0438] To the reaction vessel, (4S)-3-benzyloxycarbonyl-2,2-dimethyl-oxazolidine-4-carboxylic acid (Compound 2B) (69.0 mg, 0.20 mmol) obtained in (1-4) above, a solvent (0.28 mL), a solubilizing agent (0.79 mmol) and a reducing agent (0.99 mmol) were added, and the acid (0.20 mmol) described in Table 3 was added at an external temperature of 0° C. The mixture was stirred at an external temperature of 0° C. for 1 hour. The obtained reaction mixture was analyzed using HPLC analysis conditions method 1.

[0439] The results are shown in Table 3. Table 3 shows the HPLC area ratio of the peak of Compound 3B, Compound 4B, Compound 2B, or Compound 1 relative to all peaks.

[0440] Compound 3B: retention time 2.776 min, LCMS m / z 282 [M+H] +

[0441] Compound 4B: retention time 2.346 min, LCMS m / z 282 [M+H] +

[0442] (Structure of Compound 4B)

[0443] [Formula 17]

[0444]

[0445] Compound 2B: retention time 2.675 min, LCMS m / z 280 [M+H] +

[0446] Compound 1: retention time 1.833 min, LCMS m / z 240 [M+H] +

[0447] [Table 3]

[0448]

[0449] From the above results, it was confirmed that the compound of interest 3B (Run 2) can be obtained even when the reaction is carried out using a toluene solvent. It should be noted that the reaction in a toluene solvent sometimes generates insoluble materials, resulting in the formation of a heterogeneous mixture, and it has been confirmed that the reaction progresses even when a solubilizing agent such as MeCN, ethyl acetate and HFIP is added (Runs 3 to 5). In particular, compound 3B was obtained in high yield under the condition of adding HFIP as a solubilizing agent.

[0450] (1-6): Screening of acids and solvents for the synthesis of (2S)-2-(benzyloxycarbonylamino)-3-isopropoxy-propionic acid (Compound 3B)

[0451] The effects of the acids and solvents described in Table 4 below were examined as follows.

[0452] (4S)-3-benzyloxycarbonyl-2,2-dimethyl-oxazolidine-4-carboxylic acid (Compound 2B) (0.11 g, 0.34 mmol) obtained in the above (1-4), a solvent (0.47 mL) and triethylsilane (1.68 mmol) were mixed to prepare a substrate solution.

[0453] To another reaction vessel, a 1M solution of TiCl4 in toluene (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). The solution containing TiCl3(OiPr) was cooled at an external temperature of 0°C, and then the substrate solution prepared above was added thereto. After stirring at an external temperature of 0°C for 0.5 hours, the resulting reaction mixture was analyzed by using HPLC analysis conditions method 1 (for Table 4, Run 3, a solution containing TiCl3(OiPr) was prepared using TiCl4, Ti(OiPr)4 and chlorobenzene).

[0454] The results are shown in Table 4. Table 4 shows the area ratio of the peak of Compound 3B, Compound 4B, Compound 2B, or Compound 1 relative to all peaks.

[0455] [Table 4]

[0456]

[0457] As can be seen from the above results, when TiCl3(OiPr) having a Lewis acidity lower than that of TiCl4 is used, the present reaction proceeds with higher selectivity (Runs 1 and 2). It was also confirmed that compound 3B can be obtained with high selectivity using not only aromatic hydrocarbon solvents such as toluene but also halogen aromatic solvents such as chlorobenzene (Run 3).

[0458] Example 2: (2S)-2-(Benzyloxycarbonylamino)-3-propoxy-propionic acid·dicyclohexylamine salt (Compound 3A· Synthesis of DCHA salt

[0459] (2-1): Synthesis of (4S)-3-benzyloxycarbonyl-2-ethyl-oxazolidine-4-carboxylic acid (Compound 2A)

[0460] [Formula 18]

[0461]

[0462] After the atmosphere in the reaction vessel was replaced 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. Then, propionaldehyde (4.50 mL, 62.7 mmol) and boron trifluoride diethyl ether complex (1.06 mL, 8.36 mmol) were added, and the resulting mixture was stirred at 40 ° C for 3 hours. Subsequently, triethylamine (1.17 mL, 8.36 mmol) was added and the mixture was stirred. Water (50 mL) was then added at an external temperature of 25 ° C and the mixture was stirred for 1 hour. The water layer was discarded, and the resulting organic layer was washed with water (50 mL). A 10% sodium carbonate aqueous solution (50 mL) was added to the resulting organic layer and the mixture was stirred, and then the organic layer was discarded. A 10% sodium bisulfate monohydrate aqueous solution (140 mL) and toluene (100 mL) were added to the resulting water layer. The resulting mixture was stirred. The aqueous layer was discarded, and then the obtained organic layer was washed with water (30 mL). The obtained organic layer was concentrated. Azeotropic dehydration with the addition of toluene (20 mL) was repeated three times to obtain 10.8 g of a residue containing Compound 2A.

[0463] UV intensity ratio (as a diastereoisomer mixture): 97.7 percent

[0464] (Detection wavelength 210nm, retention time 2.744min and 2.783min, HPLC analysis conditions method 1)

[0465] (2-2): Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-propoxy-propionic acid (Compound 3A)

[0466] [Formula 19]

[0467]

[0468] Chlorobenzene (25mL) and triethylsilane (14.3mL, 89.3mmol) were added to the residue (10.8g) containing compound 2A obtained in (2-1) above to prepare a substrate solution. After the atmosphere in the reaction vessel was replaced with nitrogen, chlorobenzene (25mL) and titanium tetrachloride (6.69mL, 60.7mmol) were added. Then 2,2,2-trifluoroethanol (7.65mL, 107mmol) and tetraisopropyl orthotitanate (5.75mL, 19.6mmol) were added to the reaction vessel at an external temperature of -10°C. The substrate solution was added to the reaction vessel at an external temperature of -10°C. The mixture was then stirred at an external temperature of -10°C for 4 hours, and then stirred at an external temperature of 0°C for 1.5 hours. A 10% aqueous solution of ammonium chloride (50mL) was added while stirring, and the resulting mixture was then stirred at an external temperature of 25°C for 10 minutes. After discarding the aqueous layer, toluene (50 mL) and citric acid (50 mL) were added to the obtained organic layer, and the obtained mixture was stirred.The aqueous layer was discarded, and then the obtained organic layer was washed with water (50 mL).

[0469] (HPLC analysis was performed using a portion of the organic layer obtained here using HPLC analysis conditions method 1, and the peak area ratio of the generated compound 3A (retention time 2.818 minutes): compound 4A (retention time 2.399 minutes) was 90.6:9.4.)

[0470] To the obtained organic layer was added 2M aqueous sodium hydroxide solution (50 mL), and the mixture was stirred for 1 hr.

[0471] (Using a part of the aqueous layer obtained here, HPLC analysis was performed using HPLC analysis condition method 1, and the area ratio of the produced compound 3A (retention time 2.852 minutes):compound 4A (retention time 2.399 minutes) was 99.9 or more:0.1 or less).

[0472] After discarding the organic layer, the obtained water layer was washed with CPME (50 mL). 2M hydrochloric acid (50 mL) and toluene (50 mL) were added to the obtained water layer, and the mixture was stirred. After discarding the water layer, the obtained organic layer was washed twice with water (50 mL). The obtained organic layer was concentrated, and the azeotropic dehydration of adding toluene (25 mL) was repeated twice to obtain 7.99 g of the residue containing compound 3A.

[0473] UV intensity ratio: 94.6 percent

[0474] (Detection wavelength 210nm, retention time 2.912 minutes, HPLC analysis conditions method 1)

[0475] (2-3): Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-propoxy-propionic acid·dicyclohexylamine salt (Compound 3A·DCHA salt)

[0476] [Formula 20]

[0477]

[0478] Toluene (68 mL) and DCHA (5.64 mL, 28.0 mmol) were added to the residue (7.99 g) containing compound 3A obtained in (2-2) above, while 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. Subsequently, heptane (150 mL) was added over a period of 1 hour, and the mixture was then stirred for 2 hours. The resulting solid was filtered and washed under reduced pressure (washing solvent: 24 mL toluene + 41 mL heptane), and dried under reduced pressure to obtain 9.89 g of compound 3A DCHA salt as a white solid (3-step yield was 51.1%).

[0479] Optical purity: 99.7%ee

[0480] (Detection wavelength 210nm, retention time 12.896 minutes, HPLC analysis conditions method 2)

[0481] UV intensity ratio: 99.9 percent

[0482] (Detection wavelength 210nm, retention time 2.880 minutes, HPLC analysis conditions method 1)

[0483] 1 H-NMR(DMSO-d6,500MHz)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),1.4 3-1.36(m,2H),1.23-1.13(m,8H),1.07-1.02(m,2H),0.77(t,J=7.4Hz,3H)

[0484] (2-4): Preparation of Seed Crystals of (2S)-2-(Benzyloxycarbonylamino)-3-propoxy-propionic acid·dicyclohexylamine salt (Compound 3A·DCHA salt)

[0485] To the residue containing Compound 3A (0.50 g) obtained by the same method as above (2-2) were added MTBE (4.0 mL) and DCHA (0.32 mL), and the mixture was stirred at room temperature for 10 minutes to obtain Compound 3A·DCHA salt (0.60 g) as powder crystals.

[0486] The above Example 2 shows that the compound 3A·DCHA salt is obtained in 3 steps with a yield of 51.1% using the compound 1 as the starting material by the present method. In addition, in the above step (2-2), the reaction mixture obtained by the acid treatment contains 9% or more of the compound 4A as an impurity, but the content of the compound 4A can be reduced to less than 0.1% by treating with an alkali (aqueous sodium hydroxide solution). The present method does not require purification by column chromatography and is therefore applicable to large-scale synthesis.

[0487] Example 3: (2S)-2-(Benzyloxycarbonylamino)-3-propoxy-propionic acid·dicyclohexylamine salt (Compound 3B· Synthesis of DCHA salt

[0488] (3-1): Synthesis of (4S)-3-benzyloxycarbonyl-2,2-dimethyl-oxazolidine-4-carboxylic acid (Compound 2B)

[0489] [Formula 21]

[0490]

[0491] N-Benzyloxycarbonyl-L-serine (Compound 1) (3.49 g, 14.6 mmol), acetone (17.4 mL) and 2,2-dimethoxypropane (15.7 mL, 128 mmol) were added to the reaction vessel. Boron trifluoride diethyl ether complex (0.19 mL, 1.5 mmol) was added to the reaction vessel at room temperature, and the mixture was then stirred at an external temperature of 40 ° C for 45 minutes. Subsequently, triethylamine (0.20 mL, 1.5 mmol) was added to the mixture at room temperature and the resulting mixture was stirred for 5 minutes. The resulting residue was concentrated, and toluene (18 mL) and water (21 mL) were added, and the mixture was stirred. The resulting aqueous layer was discarded, and the resulting organic layer was then washed with a 5% NaCl aqueous solution (10.5 mL). Azeotropic dehydration with the addition of toluene (10.5 mL) was then repeated three times to obtain 4.43 g of a residue containing Compound 2B (12.7 mmol) (yield according to HPLC and qNMR analysis: 87.1%).

[0492] UV intensity ratio: 96.7 percent

[0493] (Detection wavelength 210nm, retention time 2.673 minutes, HPLC analysis conditions method 1)

[0494] (3-2): Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-isopropoxy-propionic acid (Compound 3B)

[0495] [Formula 22]

[0496]

[0497] Triethylsilane (3.70 mL, 23.2 mmol) and toluene (6.5 mL) were added to the residue containing compound 2B obtained in (3-1) above (1.62 g, containing 4.64 mmol of compound 2B) to prepare a substrate solution. The reaction vessel was replaced with nitrogen, and a solution of titanium tetrachloride in toluene (1.0 M, 5.6 mL) was added. HFIP (2.89 mL, 27.8 mmol) was then added to the reaction vessel at an external temperature of -5 ° C. Subsequently, the substrate solution was added to the mixture in the reaction vessel at an external temperature of -6 ° C. The mixture was stirred at -5 ° C for 45 minutes, and then a 10% aqueous solution of ammonium chloride (3.9 mL) was added. Subsequently, the mixture was stirred at room temperature and the water layer was discarded. The obtained organic layer was washed twice with a 5% aqueous sodium carbonate solution (12 mL, followed by 5 mL). The obtained water layer was mixed, and then a 5% aqueous sodium bisulfate monohydrate solution (42 mL) was added. The obtained aqueous solution was washed three times with toluene, and then washed three times with CPME. The obtained organic layer was washed with 5% NaCl aqueous solution (6 mL). The obtained organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol) to obtain a white solid A (0.496 g, 38.0% yield) of compound 3B and a white solid B (0.481 g, 36.9% yield) of compound 3B.

[0498] Optical purity (analysis of white solid B): 99.8%ee

[0499] (Detection wavelength 210nm, retention time 13.166 minutes, HPLC analysis conditions method 2)

[0500] UV intensity ratio (white solid A): 99.2% (detection wavelength 210nm, retention time 2.770 minutes, HPLC analysis conditions method 1)

[0501] UV intensity ratio (white solid B): 99.8%

[0502] (Detection wavelength 210nm, retention time 2.764 minutes, HPLC analysis conditions method 1)

[0503] (3-3): Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-propoxy-propionic acid·dicyclohexylamine salt (Compound 3B·DCHA salt)

[0504] [Formula 23]

[0505]

[0506] The compound 3B (0.407 g, 1.45 mmol) obtained in (3-2) above was dissolved in MTBE (1.6 mL). Subsequently, DCHA (0.289 mL, 1.45 mmol) and heptane (3.3 mL) were added at room temperature, and the resulting precipitate was filtered under reduced pressure. The resulting solid was dried under reduced pressure to obtain 0.608 g of compound 3B·DCHA salt as a white solid (yield 90.8%).

[0507] UV intensity ratio: 99.2 percent

[0508] (Detection wavelength 210nm, retention time 2.787 minutes, HPLC analysis conditions method 3)

[0509] 1 H-NMR (DMSO-d6, 500MHz) δ: 8.85 (brs, 1H), 7.35-7.28 (m, 5H), 6.49 (d, J = 6. 5Hz,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=12.5Hz,2H),1.28-1.18(m,8H),1.10-1.04(m,2H),1.01(d,J=6.1Hz,6H)

[0510] The above Example 3 shows that the compound 3B·DCHA salt can be obtained in 3 steps with a yield of 59% or more using the compound 1 as the starting material by the present method.

[0511] Example 4: Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-propoxy-propionic acid (Compound 3C)

[0512] (4-1): Synthesis of (7S)-8-benzyloxycarbonyl-5-oxa-8-azaspiro[3.4]octane-7-carboxylic acid (Compound 2C)

[0513] [Equation 24]

[0514]

[0515] N-Benzyloxycarbonyl-L-serine (Compound 1) (2.70 g, 11.3 mmol) and MeTHF (10.8 mL) were placed in a reaction vessel at room temperature. After the reaction vessel was replaced with nitrogen, N, O-bis (trimethylsilyl) trifluoroacetamide (3.00 mL, 11.3 mmol) was added at an external temperature of 0 ° C, and the mixture was stirred for 10 minutes. Subsequently, cyclobutanone (0.94 mL, 12.4 mmol) and trimethylsilyl trifluoromethanesulfonate (0.41 mL, 2.3 mmol) were added, and the resulting mixture was stirred at an external temperature of 0 ° C for 2 hours. 5% potassium dihydrogen phosphate aqueous solution (8.1 mL) was added, and then water (8.1 mL) was added at room temperature and the mixture was stirred. The water layer was discarded, and then 10% potassium carbonate aqueous solution (10.8 mL) was added. After the organic layer was discharged, 2M hydrochloric acid (9.5 mL) and toluene (10.8 mL) were added to the resulting water layer, and the resulting mixture was stirred. After discarding the aqueous layer, the organic layer was washed twice with water (10.8 mL). The organic layer was concentrated and then subjected to azeotropic dehydration by adding toluene (8.1 mL) three times to obtain 4.66 g of a residue containing Compound 2C (9.35 mmol) (yield according to HPLC and qNMR analysis: 82.8%).

[0516] UV intensity ratio: 98.9 percent

[0517] (Detection wavelength 210nm, retention time 5.347 minutes, HPLC analysis conditions method 4)

[0518] (4-2): Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-(cyclobutyloxy)propanoic acid (Compound 3C)

[0519] [Formula 25]

[0520]

[0521] Triethylsilane (4.53 mL, 28.4 mmol) and chlorobenzene (5 mL) were added to the residue (4.66 g) containing compound 2C (9.35 mmol) obtained in (4-1) above to prepare a substrate solution. After the atmosphere in the reaction vessel was replaced with nitrogen, chlorobenzene (6.9 mL) was added. Subsequently, titanium tetrachloride (1.77 mL, 16.1 mmol), 2,2,2-trifluoroethanol (2.03 mL, 28.4 mmol) and tetraisopropyl orthotitanate (1.53 mL, 5.20 mmol) were added at an external temperature of -16 ° C, and the mixture was stirred. Then, the substrate solution prepared above was added at an external temperature of -16 ° C, and the mixture was stirred for 1 hour and 15 minutes, while the external temperature was set to -6 ° C.

[0522] (HPLC analysis was performed using a portion of the reaction solution obtained here using HPLC analysis conditions method 1, and the peak area ratio of the generated compound 3C (retention time 3.031 minutes): compound 4C (retention time 2.572 minutes) was 87.7:12.3.)

[0523] (Structure of Compound 4C)

[0524] [Equation 26]

[0525]

[0526] Then add 10% ammonium chloride aqueous solution (13.8mL), and the resulting mixture is stirred at room temperature. After discarding the water layer, 5% citric acid aqueous solution (13.8mL) and MTBE (8.3mL) are added to the resulting organic layer. After the mixture is stirred, the water layer is discarded, and then the resulting organic layer is washed with water (13.8mL). 2M sodium hydroxide aqueous solution (13.8mL) is added to the resulting organic layer, and the resulting mixture is stirred for 1.5 hours.

[0527] (HPLC analysis was performed using a portion of the aqueous layer obtained here using HPLC analysis conditions method 1, and the peak area ratio of the generated compound 3C (retention time 3.004 minutes): compound 4C (retention time 2.548 minutes) was 99.4:0.6.)

[0528] After discarding the organic layer, the obtained water layer was washed with MTBE (13.8mL). 2M hydrochloric acid (13.5mL) and toluene (27.6mL) were added to the obtained water layer, and the mixture was stirred. The water layer was discarded, and then the obtained organic layer was washed with water (13.8mL). Then, the azeotropic dehydration of adding toluene (8.3mL) three times was carried out to obtain a residue (6.18g) containing compound 3C. Toluene (15.2mL) was added to the obtained residue, and the seed crystal (9.7mg) of the compound 3C obtained in (4-3) below was added at room temperature, and the mixture was stirred for 20 minutes. Then heptane (19.6mL) was added dropwise over 1 hour while stirring, and then the mixture was stirred for 1.5 hours. The obtained precipitate was filtered under reduced pressure, and the obtained solid was dried under reduced pressure to obtain 1.78g of compound 3C (yield 64.9%) as a white solid.

[0529] Optical purity: 99.9%ee

[0530] (Detection wavelength 210nm, retention time 13.647 minutes, HPLC analysis conditions method 2)

[0531] UV intensity ratio: 99.9 percent

[0532] (Detection wavelength 210nm, retention time 2.986 minutes, HPLC analysis conditions method 1)

[0533] 1 H-NMR (DMSO-d6, 500MHz) δ: 12.77 (s, 1H), 7.51 (d, J = 8.0Hz, 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) (4-3): Preparation of Seed Crystals of (2S)-2-(Benzyloxycarbonylamino)-3-(cyclobutyloxy)propanoic acid (Compound 3C)

[0534] Toluene (1.0 mL) and heptane (1.0 mL) were added to the residue containing compound 3C obtained by the same method as above (4-2) (0.87 g), and the mixture was stirred at room temperature until a precipitate was formed. Heptane was further added, and the mixture was stirred again, and then the resulting precipitate was filtered under reduced pressure to obtain compound 3C (0.46 g) as powder crystals.

[0535] The above Example 4 shows that compound 3C can be obtained in 2 steps with a yield of 53% or more using compound 1 as a starting material by the present method. In addition, in the above step (4-2), the reaction mixture contains 12% or more of compound 4A as an impurity, but the content of compound 4A can be reduced to less than 1% by treating with an alkali (aqueous sodium hydroxide solution). The present method does not require purification by column chromatography and is therefore applicable to large-scale synthesis.

[0536] Example 5: (2S)-2-(Benzyloxycarbonylamino)-3-isopentyloxy-propionic acid·dicyclohexylamine salt (Compound 3D· Synthesis of DCHA salt

[0537] (5-1): Synthesis of (4S)-3-benzyloxycarbonyl-2-isobutyl-oxazolidine-4-carboxylic acid (Compound 2D)

[0538] [Formula 27]

[0539]

[0540] N-benzyloxycarbonyl-L-serine (Compound 1) (3.04 g, 12.7 mmol) and magnesium sulfate (1.51 g, 12.5 mmol) were added to the reaction vessel at an external temperature of 25°C. After the atmosphere in the reaction vessel was replaced 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 the mixture was stirred at 25°C for 2 hours. Triethylamine (0.35 mL, 2.5 mmol) was then added, and the resulting mixture was stirred for 5 minutes. The mixture was washed with water (15 mL x 2) and then washed with a 5% NaCl aqueous solution (15 mL), followed by azeotropic dehydration of the resulting organic layer of toluene (15 mL) added twice to obtain 7.47 g of a residue containing compound 2D.

[0541] UV intensity ratio (as a mixture of diastereoisomers): 95.8 percent

[0542] (Detection wavelength 210nm, retention time 3.224min and 3.250min, HPLC analysis condition method 5)

[0543] (5-2): Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-isopentyloxy-propionic acid (Compound 3D)

[0544] [Equation 28]

[0545]

[0546] Triethylsilane (5.07mL, 31.8mmol) was added to the residue (7.47g) containing compound 2D obtained in (5-1) above to prepare a substrate solution. After the atmosphere in the reaction vessel was replaced with nitrogen, chlorobenzene (7.5mL) and titanium tetrachloride (2.38mL, 21.6mmol) were added. Then 2,2,2-trifluoroethanol (2.72mL, 38.1mmol) and tetraisopropyl orthotitanate (2.05mL, 7.0mmol) were added to the reaction vessel at an external temperature of -15°C, and the mixture was stirred. The substrate solution prepared above was added to the mixture in the reaction vessel at an external temperature of -15°C, and the resulting mixture was stirred at an external temperature of 0°C for 4 hours. The resulting mixture was stirred for another 1 hour at an external temperature of 10°C, and then a 5% aqueous ammonium chloride solution (15mL) was added at an external temperature of -10°C. The resulting mixture was stirred at an external temperature of 25°C for 5 minutes. After discarding the water layer, the organic layer was washed with 5% citric acid aqueous solution (15mL), and then washed with water (15mL). The water layer was discharged, and then 2M sodium hydroxide aqueous solution (9mL) and MTBE (9mL) were added to the organic layer, and the mixture was stirred for 3.5 hours at an external temperature of 25°C. 2M sodium hydroxide aqueous solution (6mL) was added to the mixture, and then the mixture was stirred for another 0.5 hour. After discarding the organic layer, the water layer was washed with MTBE (15mL). 2M hydrochloric acid (15mL) and MeTHF (30mL) were added to the water layer, and the mixture was stirred for 10 minutes. The water layer was discarded, and then the organic layer was washed with 5% NaCl aqueous solution (15mL). Then, the azeotropic dehydration of the organic layer of MeTHF (15mL) was added three times to obtain a MeTHF solution (9mL) containing compound 3D.

[0547] UV intensity ratio: 88.6%

[0548] (Detection wavelength 210nm, retention time 3.290 minutes, HPLC analysis conditions method 5)

[0549] (5-3): Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-isopentyloxy-propionic acid·dicyclohexylamine salt (Compound 3D·DCHA salt)

[0550] [Equation 29]

[0551]

[0552] 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 while stirring at an external temperature of 25° C. The resulting solid was filtered and washed under reduced pressure (washing solution: 10 mL MeTHF + 40 mL heptane), and dried under reduced pressure to obtain 3.94 g of compound 3D·DCHA salt as a white solid (3-step yield of 63.2%).

[0553] Optical purity: 99.9%ee

[0554] (Detection wavelength 210nm, retention time 15.933 minutes, HPLC analysis conditions method 2)

[0555] UV intensity ratio: 99.0 percent

[0556] (Detection wavelength 210nm, retention time 3.232 minutes, HPLC analysis conditions method 5)

[0557] 1 H-NMR(DMSO-d6,500MHz)δ:8.83(brs,1H),7.37-7.29(m,5H),6.58(s,1H),5.0 0(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=6.7Hz,1H),0.83(dd,J=6.7,1.7Hz,6H)

[0558] The above Example 5 shows that the compound 3D·DCHA salt can be obtained in 3 steps with a yield of 63.2% using the compound 1 as the starting material by the present method. The present method does not require purification by column chromatography and is therefore suitable for large-scale synthesis.

[0559] Example 6: (2S,3R)-2-(Benzyloxycarbonylamino)-3-isopropoxy-butyric acid·dicyclohexylamine salt (Compound Synthesis of 7B·DCHA salt (6-1): Synthesis of (4S,5R)-3-benzyloxycarbonyl-2,2,5-trimethyl-oxazolidine-4-carboxylic acid (Compound 6B)

[0560] [Formula 30]

[0561]

[0562] 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 the reaction vessel at an external temperature of 25°C, and the atmosphere in the reaction vessel was replaced with nitrogen. Boron trifluoride tetrahydrofuran complex (0.087 mL, 0.79 mmol) was added, and the mixture was 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 the mixture was stirred for 5 minutes. The resulting residue was concentrated, toluene (5 mL) was added to the resulting residue and the residue was further concentrated. Toluene (3 mL) and water (5 mL) were added to the resulting residue, and the mixture was stirred at 25°C for 10 minutes. After discarding the aqueous layer, the resulting organic layer was washed with a 5% NaCl aqueous solution (5 mL). Azeotropic dehydration of the organic layer by adding toluene (5 mL) three times was performed to obtain 3.39 g of a residue containing Compound 6B.

[0563] UV intensity ratio (as a diastereoisomer mixture): 98.3 percent

[0564] (Detection wavelength 210nm, retention time 2.783 minutes, HPLC analysis conditions method 3)

[0565] (6-2): Synthesis of (2S,3R)-2-(benzyloxycarbonylamino)-3-isopropoxy-butyric acid (Compound 7B)

[0566] [Equation 31]

[0567]

[0568] Triethylsilane (1.58 mL, 9.89 mmol) was added to the residue (3.39 g) containing compound 6B obtained in (6-1) above to prepare a substrate solution. After the atmosphere in the reaction vessel was replaced with nitrogen, chlorobenzene (2.5 mL) and titanium tetrachloride (0.74 mL, 6.7 mmol) were added. Then 2,2,2-trifluoroethanol (0.85 mL, 11.9 mmol) and tetraisopropyl orthotitanate (0.64 mL, 2.2 mmol) were added to the reaction vessel at an external temperature of -15 ° C, and the mixture was stirred. The substrate solution prepared above was then added to the mixture in the reaction vessel at an external temperature of -15 ° C, and the resulting mixture was stirred at an external temperature of 0 ° C for 2 hours. (Using a portion of the reaction solution obtained here, compound 8B was not detected by HPLC analysis using HPLC analysis condition method 3).

[0569] (Structure of Compound 8B)

[0570] [Formula 32]

[0571]

[0572] 5% ammonium chloride aqueous solution (5mL) was added at an external temperature of -10°C, and the external temperature was then set to 25°C. Subsequently, MTBE (3mL) was added and the mixture was stirred for 10 minutes. After discarding the water layer, the organic layer was washed with 5% citric acid aqueous solution (5mL), and then washed with water (5mL). The water layer was discarded, and then 1M sodium hydroxide aqueous solution (5mL) was added to the organic layer, and the mixture was stirred for 2 hours at an external temperature of 25°C. After discarding the organic layer, the water layer was washed with MTBE (5mL). 2M hydrochloric acid (2.5mL) and MTBE (10mL) were added to the water layer, and the mixture was stirred for 10 minutes. After discarding the water layer, the organic layer was washed with 5% NaCl aqueous solution (5mL). The azeotropic dehydration of the organic layer added with MTBE (10mL) twice was performed to obtain an MTBE solution (4mL) containing compound 7B.

[0573] UV intensity ratio: 97.7 percent

[0574] (Detection wavelength 210nm, retention time 2.842 minutes, HPLC analysis conditions method 3)

[0575] (6-3): Synthesis of (2S,3R)-2-(benzyloxycarbonylamino)-3-isopropoxy-butyric acid·dicyclohexylamine salt (Compound 7B·DCHA salt)

[0576] [Formula 33]

[0577]

[0578] DCHA (0.788 mL, 3.96 mmol) and heptane (4 mL) were added to the MTBE solution (4 mL) containing compound 7B obtained in (6-2) above while stirring at room temperature. The resulting solid was filtered and washed under reduced pressure (washing solution: 2.5 mL MTBE + 7.5 mL heptane), and dried under reduced pressure to obtain 1.29 g of compound 7B · DCHA salt as a white solid (3-step yield of 68.2%).

[0579] Diastereomeric excess (7B and diastereomer 7B'): 99.7% de

[0580] (Detection wavelength 210nm, retention time 13.367 minutes, HPLC analysis conditions method 2)

[0581] [Equation 34]

[0582]

[0583] UV intensity ratio: 99.1 percent

[0584] (Detection wavelength 210nm, retention time 2.851 minutes, HPLC analysis conditions method 3)

[0585] 1 H-NMR(DMSO-d6,500MHz)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=6.5Hz,3H),1.00(d,J=6.1Hz,3H),0.97-0.93(d,J=6.1Hz,3H)

[0586] The above Example 6 shows that the compound 7B·DCHA salt can be obtained in 3 steps with a yield of 68.2% using the compound 5 as the starting material by the present method. The present method does not require purification by column chromatography and is therefore suitable for large-scale synthesis.

[0587] Example 7: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-isopropoxy-propionic acid (Compound 11B) synthesis

[0588] (7-1): (4S)-3-(9H-fluoren-9-ylmethoxycarbonyl)-2,2-dimethyl-oxazolidine-4-carboxylic acid (Compound 10B)

[0589] [Formula 35]

[0590]

[0591] N-[(9H-fluorene-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 the reaction vessel at an external temperature of 25°C, and the atmosphere in the reaction vessel was replaced with nitrogen. Boron trifluoride tetrahydrofuran complex (0.068 mL, 0.62 mmol) was added, and the mixture was stirred at 40°C for 1 hour. Subsequently, triethylamine (0.087 mL, 0.62 mmol) was added at an external temperature of 25°C and the mixture was stirred for 5 minutes. After concentrating the residue, dichloromethane (5 mL) and water (5 mL) were added to the resulting concentrate, and the resulting mixture was stirred at room temperature for 10 minutes. The aqueous layer was discarded, and the resulting organic layer was dried by adding magnesium sulfate. Filtration followed by concentration under reduced pressure gave a residue containing Compound 10B, and then dichloromethane was added to the residue to obtain a dichloromethane solution (3 mL) containing Compound 10B.

[0592] UV intensity ratio (as a mixture of diastereoisomers): 84.9 percent

[0593] (Detection wavelength 210nm, retention time 3.283 minutes, HPLC analysis conditions method 3)

[0594] (7-2): Synthesis of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-isopropoxy-propionic acid (Compound 11B)

[0595] [Equation 36]

[0596]

[0597] Triethylsilane (1.24 mL, 7.76 mmol) was added to the dichloromethane solution (3 mL) containing compound 10B obtained in (7-1) above to prepare a substrate solution. After the atmosphere in the reaction vessel was replaced with nitrogen, dichloromethane (2.5 mL) and titanium tetrachloride (0.41 mL, 3.7 mmol) were added. The substrate solution prepared above was added to the reaction vessel at an external temperature of -15 ° C, and the resulting mixture was stirred at an external temperature of 0 ° C for 2 hours. (Using a portion of the reaction solution obtained here, HPLC analysis was performed using HPLC analysis condition method 3, and the area ratio of the resulting compound 11B (retention time 3.424 minutes): compound 12B (retention time 3.022 minutes) was 98.2:1.8.)

[0598] [Formula 37]

[0599]

[0600] 5% aqueous ammonium chloride solution (5mL) was added at an external temperature of -10°C, and then the external temperature was 25°C. MTBE (5mL) was added and the mixture was stirred for another 5 minutes. After discarding the water layer, the organic layer was washed with 5% aqueous citric acid solution (5mL), and then washed with 5% NaCl aqueous solution (5mL). After discarding the water layer, the organic layer was azeotropically dehydrated by adding MTBE. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol) to obtain 0.783g of compound 11B (2-step yield was 68.3%) as a white solid.

[0601] Optical purity: 99.8%ee

[0602] (Detection wavelength 210nm, retention time 17.398 minutes, HPLC analysis conditions method 2)

[0603] UV intensity ratio: 91.8 percent

[0604] (Detection wavelength 210nm, retention time 3.408 minutes, HPLC analysis conditions method 3)

[0605] 1 H-NMR(DMSO-d6,500MHz)δ:12.74(brs,1H),7.90(d,J=7.6Hz,2H),7.75(d,J=7.6Hz,2H),7.56(d,J=8.4Hz,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=5.0Hz,6H)

[0606] The above Example 7 shows that compound 11B can be obtained in 68.3% yield in 2 steps using compound 9 as the starting material by this method.

[0607] Example 8: (2S)-2-[Benzyloxycarbonyl(methyl)amino]-3-(cyclobutyloxy)propionic acid·dicyclohexylamine salt (compound Synthesis of 14C·DCHA salt

[0608] (8-1): Synthesis of (7S)-8-benzyloxycarbonyl-5-oxa-8-azaspiro[3.4]octane-7-carboxylic acid (Compound 2C)

[0609] [Equation 38]

[0610]

[0611] 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 the atmosphere in the reaction vessel was replaced with nitrogen, N,O-bis(trimethylsilyl)acetamide (4.8 mL, 19.6 mmol) was added at room temperature, and the mixture was stirred for 15 minutes. Subsequently, cyclobutanone (1.78 mL, 23.6 mmol) and trimethylsilyl trifluoromethanesulfonate (3.49 mL, 19.3 mmol) were added, and the mixture was stirred at room temperature for 2.5 hours. A 5% aqueous solution of potassium dihydrogen phosphate (15.5 mL) was added and the mixture was stirred. After stirring and adding CPME (10.3 mL), the aqueous layer was discarded. The resulting organic layer was treated with a 10% aqueous solution of potassium carbonate (26 mL). The resulting aqueous layer was collected, 2M hydrochloric acid (21 mL) and toluene (52 mL) were added, and the mixture was stirred. After discarding the aqueous layer, the obtained organic layer was washed with water (15.5 mL).The obtained organic layer was concentrated and then subjected to azeotropic dehydration with the addition of toluene (15.5 mL) to obtain 7.09 g of a residue containing Compound 2C.

[0612] UV intensity ratio: 95.8 percent

[0613] (Detection wavelength 210nm, retention time 5.381 minutes, HPLC analysis conditions method 4)

[0614] (8-2): Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-(cyclobutyloxy)propanoic acid (Compound 3C)

[0615] [Equation 39]

[0616]

[0617] 3.47 g was taken out from 7.09 g of the residue containing compound 2C obtained in (8-1) above, and triethylsilane (3.57 mL) and chlorobenzene (3.9 mL) were added thereto to prepare a substrate solution. After the atmosphere in the reaction vessel was replaced 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 the mixture was stirred. Then, the substrate solution prepared above was added to the reaction vessel at an external temperature of -6 ° C, and the mixture was stirred for 1.5 hours. Then a 10% aqueous solution of ammonium chloride (11 mL) was added, and the mixture was stirred at room temperature. After discarding the water layer, a 5% aqueous solution of citric acid (11 mL) and MTBE (11 mL) were added to the resulting organic layer and the mixture was stirred. After the mixture was stirred, the water layer was discarded, and the resulting organic layer was washed with water (11 mL). Aqueous layer is discarded, and then 2M aqueous sodium hydroxide solution (11mL) is added to the organic layer, and the resulting mixture is stirred for 2 hours. After discarding the organic layer, the resulting water layer is washed with MTBE (11mL). 2M hydrochloric acid (10mL) and toluene (17.5mL) are added to the resulting water layer, and the mixture is stirred. After discarding the water layer, the resulting organic layer is washed with water (11mL). Then, the azeotropic dehydration of the organic layer of toluene (7mL) is added to obtain the residue (3.59g) containing compound 3C. Toluene (10.8mL) is added to the residue obtained, and the seed (6.4mg) of the compound 3C obtained in the above (4-3) is added at room temperature, and the mixture is stirred for 20 minutes. Then heptane (13.3mL) is added while stirring, and then the mixture is stirred for 1 hour. The resulting precipitation is filtered under reduced pressure, and the solid obtained is dried under reduced pressure, to obtain compound 3C (1.19g) as a white solid.

[0618] UV intensity ratio: 99.9 percent

[0619] (Detection wavelength 210nm, retention time 3.039 minutes, HPLC analysis conditions method 1)

[0620] (8-3): Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-(cyclobutyloxy)propanoic acid (Compound 3C)

[0621] [Formula 40]

[0622]

[0623] 3.31 g was taken out from 7.09 g of the residue containing compound 2C obtained in (8-1) above, and triethylsilane (3.41 mL) and chlorobenzene (3.7 mL) were added thereto to prepare a substrate solution. After the atmosphere in the reaction vessel was replaced with nitrogen, chlorobenzene (5.2 mL) and titanium tetrachloride (1.33 mL) were added. Then 2,2,2-trifluoroethanol (1.53 mL) and tetraisopropyl orthotitanate (1.15 mL) were added to the reaction vessel at an external temperature of -16 ° C, and the mixture was stirred. Then, the substrate solution prepared above was added to the mixture in the reaction vessel at an external temperature of -16 ° C. The resulting mixture was stirred at an external temperature of -6 ° C for 3 hours, then a 10% aqueous solution of ammonium chloride (10.4 mL) was added, and the mixture was stirred at room temperature. The water layer was discarded, and then a 5% aqueous solution of citric acid (10.4 mL) and toluene (10.4 mL) were added to the resulting organic layer and the resulting mixture was stirred. After discarding the water layer, the obtained organic layer was washed with water (10.4mL). The water layer was discharged, and then 2M sodium hydroxide aqueous solution (10.4mL) was added to the obtained organic layer, and the mixture was stirred for 1.5 hours. After discarding the organic layer, the obtained water layer was washed with MTBE (10.4mL). 2M hydrochloric acid (9.5mL) and toluene (21mL) were added to the obtained water layer, and the mixture was stirred. The water layer was discarded, and then the obtained organic layer was washed with water (10.4mL). Then, the azeotropic dehydration of the organic layer of toluene (6mL) was added to obtain the residue (4.72g) containing compound 3C. Toluene (10.1mL) was added to the obtained residue, and the seed (6.8mg) of the compound 3C obtained in the above (4-3) was added at room temperature, and the mixture was stirred for 30 minutes. Then heptane (13.7mL) was added while stirring, and then the mixture was stirred for 6 hours. The resulting precipitate was filtered under reduced pressure, and the obtained solid was dried under reduced pressure to give Compound 3C (1.20 g) as a white solid.

[0624] UV intensity ratio: 99.9 percent

[0625] (Detection wavelength 210nm, retention time 3.042 minutes, HPLC analysis conditions method 1)

[0626] (8-4): Synthesis of benzyl (4S)-4-(cyclobutyloxymethyl)-5-oxo-oxazolidine-3-carboxylic acid (Compound 13C)

[0627] [Formula 41]

[0628]

[0629] 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 the reaction vessel. After the atmosphere in the reaction vessel was replaced with nitrogen, boron trifluoride diethyl ether complex (0.80 mL, 6.3 mmol) was added to the mixture at room temperature, and the mixture was then stirred for 2 hours. The resulting mixture was filtered, and the filtrate was washed twice with 10% potassium carbonate aqueous solution (9.2 mL), and once with water (9.2 mL). The resulting organic layer was filtered and the resulting filtrate was washed with water (9.2 mL). The resulting organic layer was concentrated, and the azeotropic dehydration of toluene (5.5 mL) was subsequently performed to obtain 3.75 g of residue containing compound 13C.

[0630] UV intensity ratio: 98.5 percent

[0631] (Detection wavelength 210nm, retention time 3.620 minutes, HPLC analysis conditions method 1)

[0632] (8-5): Synthesis of (2S)-2-[Benzyloxycarbonyl(methyl)amino]-3-(cyclobutyloxy)propionic acid (Compound 14C)

[0633] [Formula 42]

[0634]

[0635] 2.92 g of the residue containing compound 13C obtained in 3.75 g of the above (8-4) was taken out and placed in a reaction vessel, and then triethylsilane (1.69 mL, 10.6 mmol) and chlorobenzene (3.3 mL) were added. After the atmosphere in the reaction vessel was replaced with nitrogen, trimethylsilyl trifluoromethanesulfonate (0.64 mL, 3.5 mmol) was added at an external temperature of -3 ° C, and the resulting mixture was stirred at room temperature for 2 hours. A 5% potassium dihydrogen phosphate aqueous solution (3 mL) was added at an external temperature of -3 ° C, and the mixture was stirred at room temperature. After discarding the water layer, a 10% potassium carbonate aqueous solution (5.4 mL) was added to the resulting organic layer and the mixture was stirred. After the organic layer was discharged, 2M hydrochloric acid (4.3 mL) and toluene (8.6 mL) were added to the resulting water layer, and the mixture was stirred. After discarding the water layer, the resulting organic layer was washed with water (5.4 mL). The organic layer to which toluene (3.2 mL) was added was subjected to azeotropic dehydration to obtain a residue containing Compound 14C (1.09 g).

[0636] UV intensity ratio: 99.6 percent

[0637] (Detection wavelength 210nm, retention time 3.117 minutes, HPLC analysis conditions method 1)

[0638] (8-6): Synthesis of (2S)-2-[benzyloxycarbonyl(methyl)amino]-3-(cyclobutyloxy)propionic acid·dicyclohexylamine salt (Compound 14C·DCHA salt)

[0639] [Formula 43]

[0640]

[0641] 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 at room temperature while stirring, and MTBE (3.8 mL) was then added in addition. The resulting solid formed was filtered, washed under reduced pressure (washing solution: 5 mL MTBE) and dried under reduced pressure to obtain compound 14C DCHA salt (1.46 g) as a white solid.

[0642] UV intensity ratio: 99.8 percent

[0643] (Detection wavelength 210 nm, retention time 3.110 minutes, HPLC analysis conditions method 1)

[0644] 1 H-NMR(DMSO-d6,500MHz)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=10.8,4.1Hz,1H),3.52-3.44(m,2H), 2.91(brs,2H),2.78(d,J=20.9Hz,3H),2.11-2.05(m,2H),1.92(brs,4H),1.81-1.6 9(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)

[0645] The above Example 8 shows that compound 14C·DCHA salt is obtained in 5 steps using compound 1 as the starting material by the present method. The present method does not require purification by column chromatography and is therefore applicable to large-scale synthesis. It is also found that the method of the present invention is applicable to the synthesis of O-substituted serine derivatives having N-substituents.

[0646] Example 9: Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-isobutoxypropionic acid (Compound 3E)

[0647] (9-1): Synthesis of (4S)-3-benzyloxycarbonyl-2-isopropyloxazolidine-4-carboxylic acid (Compound 2E)

[0648] [Formula 44]

[0649]

[0650] After the atmosphere in the reaction vessel was replaced 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 to the reaction vessel, and the mixture was stirred at 25 ° C for 2 hours. Subsequently, triethylamine (0.47 mL, 3.4 mmol) was added and the mixture was stirred for 5 minutes. Water (20 mL) was added to the reaction mixture, and the mixture was stirred. After discarding the water layer, the resulting organic layer was washed with water (20 mL), and then washed with a 5% NaCl aqueous solution (15 mL). The obtained organic layer was concentrated, and subjected to azeotropic dehydration with the addition of toluene (20 mL), filtration and concentration to obtain a residue (8.83 g) containing Compound 2E (15.2 mmol) (yield according to HPLC and qNMR analysis: 90.7%).

[0651] UV intensity ratio (as a mixture of diastereoisomers): 97.1 percent

[0652] (Detection wavelength 210nm, retention time 2.993 minutes and 3.048 minutes, HPLC analysis conditions method 3)

[0653] (9-2): Synthesis of (2S)-2-(benzyloxycarbonylamino)-3-isobutoxypropionic acid (Compound 3E)

[0654] [Formula 45]

[0655]

[0656] To the residue containing Compound 2E obtained in the above (9-1) (7.85 g, containing 13.5 mmol of Compound 2E) were added triethylsilane (5.4 mL, 34 mmol) and chlorobenzene (6 mL) to prepare a substrate solution.

[0657] After the atmosphere in the reaction vessel was replaced with nitrogen, chlorobenzene (10 mL) and titanium tetrachloride (2.76 mL, 25.1 mmol) were added. Then 2,2,2-trifluoroethanol (2.90 mL, 40.6 mmol) and tetrabutyl orthotitanate (2.53 mL, 7.45 mmol) were added to the reaction vessel at an external temperature of -15°C. Subsequently, the substrate solution was added to the mixture in the reaction vessel at an external temperature of -15°C, and the resulting mixture was then stirred at an external temperature of 0°C for 3 hours.

[0658] (HPLC analysis was performed using a portion of the reaction solution obtained here using HPLC analysis conditions method 1, and the peak area ratio of the generated compound 3E (retention time 3.230 minutes):compound 4E (retention time 2.755 minutes) was 93.2:6.8.)

[0659] [Formula 46]

[0660]

[0661] Then add 5% ammonium chloride aqueous solution (20mL) at an external temperature of -10°C. Add MTBE (12mL) at room temperature and stir the mixture. The aqueous layer is discarded, and the resulting organic layer is washed with 5% citric acid aqueous solution (20mL), and then washed with water (20mL). After adding 1MNaOH aqueous solution (20mL) to the organic layer, the mixture is stirred for 3.5 hours. Subsequently, 1MNaOH aqueous solution (4mL) is added, and the mixture is stirred for 1.5 hours, and then 1M NaOH aqueous solution (20mL) is added, and the resulting mixture is further stirred for 1.5 hours. (Using a portion of the aqueous layer obtained here, HPLC analysis was performed using HPLC analysis condition method 1, and the area ratio of the resulting compound 3E (retention time 3.229 minutes): compound 4E (retention time 2.751 minutes) was 99.4:0.6.)

[0662] After discarding the organic layer, the obtained water layer was washed with MTBE (24mL). 2M hydrochloric acid (16mL) and toluene (40mL) were added to the obtained water layer, and the mixture was stirred, and then the water layer was discharged. The obtained organic layer was washed with 5% NaCl aqueous solution (24mL) and concentrated under reduced pressure. The obtained residue was filtered and concentrated under reduced pressure to obtain a residue (4.44g) containing compound 3E. Toluene (9.7mL) and heptane (19.5mL) were added to the obtained residue, and the seed suspension (about 0.3mL) of compound 3E obtained by (9-3) was added at an external temperature of 25°C, and the mixture was stirred for 20 minutes. Then heptane (19.5mL) was added for 1 hour while stirring at an external temperature of 10°C, and then the obtained mixture was stirred for 3.5 hours. The obtained precipitate was filtered under reduced pressure, and the obtained solid was dried under reduced pressure to obtain 2.76g of compound 3E (yield 68.1 percent) as a white solid.

[0663] Optical purity: 99.6%ee

[0664] (Detection wavelength 210nm, retention time 14.302 minutes, HPLC analysis conditions method 2)

[0665] UV intensity ratio: 98.9 percent

[0666] (Detection wavelength 210nm, retention time 3.209 minutes, HPLC analysis conditions method 1)

[0667] 1 H-NMR(DMSO-d6,500MHz)δ:12.77(brs,1H),7.47(d,J=8.2Hz,1H),7.38-7.31(m,5H),5.08-5.01(m,2H ),4.23-4.19(m,1H),3.61(d,J=5.4Hz,2H),3.19-3.11(m,2H),1.91-1.71(m,1H),0.84(d,J=6.7Hz,6H)

[0668] (9-3): Preparation of seed suspension of compound 3E

[0669] To the residue (0.1 g) containing Compound 3E obtained by the same method as in the above (9-2) were added toluene (0.1 mL) and heptane (0.2 mL), and the mixture was stored at an external temperature of -20°C to give a seed suspension of Compound 3E.

[0670] The above Example 9 shows that compound 3E can be obtained in 2 steps with a yield of 61% or more using compound 1 as a starting material by the present method.

[0671] Example 10: Synthesis of methyl (2S)-2-(benzyloxycarbonylamino)-3-isopropoxypropanoate (Compound 17B)

[0672] (10-1): Synthesis of (4S)-3-benzyloxycarbonyl-2,2-dimethyl-oxazolidine-4-carboxylic acid methyl ester (Compound 16B)

[0673] [Formula 47]

[0674]

[0675] N-benzyloxycarbonyl-L-serine methyl ester (Compound 15) (1.22g, 4.82mmol), acetone (6mL) and 2,2-dimethoxypropane (1.12mL, 9.63mmol) are added to the reaction vessel. Boron trifluoride tetrahydrofuran complex (0.11mL, 0.96mmol) is added to the reaction vessel at room temperature, and the resulting mixture is stirred at room temperature for 1 hour. 2,2-dimethoxypropane (0.59mL, 4.8mmol) is added, and the mixture is further stirred for 1 hour. Subsequently, triethylamine (0.13mL, 0.96mmol) is added at room temperature and the mixture is stirred for 5 minutes. The resulting residue is concentrated, and toluene (6mL) and water (6mL) are added, and the mixture is stirred. The water layer is discharged, and then the resulting organic layer is washed with 5% NaCl aqueous solution (6mL). Then, azeotropic dehydration of the organic layer with the addition of toluene (6 mL) was repeated twice to obtain 1.64 g of a residue containing Compound 16B (4.15 mmol) (yield according to HPLC and qNMR analysis: 86.1%).

[0676] UV intensity ratio: 90.47 percent

[0677] (Detection wavelength 210nm, retention time 3.234 minutes, HPLC analysis conditions method 3)

[0678] (10-2): Synthesis of methyl (2S)-2-(benzyloxycarbonylamino)-3-isopropoxypropanoate (Compound 17B)

[0679] [Formula 48]

[0680]

[0681] To the residue containing Compound 16B obtained in the above (10-1) (0.28 g, containing 0.70 mmol of Compound 16B) were added triethylsilane (0.56 mL, 3.5 mmol), acetic acid (0.08 mL, 1.4 mmol) and dichloromethane (1.0 mL) to prepare a substrate solution.

[0682] After the atmosphere in the reaction vessel was replaced with nitrogen, dichloromethane (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. Then, the substrate solution prepared above was added to the mixture in the reaction vessel at an external temperature of 0°C, and the resulting mixture was stirred at room temperature for 90 minutes. (Using a portion of the reaction solution obtained here, HPLC analysis was performed using HPLC analysis condition method 3, and the peak area ratio of the generated compound 17B (retention time 3.293 minutes): compound 18B (retention time 2.761 minutes) was 98.8:1.2.)

[0683] [Formula 49]

[0684]

[0685] Then 5% aqueous ammonium chloride solution (1.0 mL) was added at an external temperature of 0 ° C. The resulting mixture was stirred at room temperature. After discarding the water layer, the resulting organic layer was washed with 5% aqueous citric acid solution (1.0 mL), washed with water (1.0 mL), and then washed with 5% dipotassium hydrogen phosphate aqueous solution (1.0 mL). The resulting organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by reverse phase column chromatography (eluent: water / acetonitrile) to obtain compound 17B (0.151 g, yield 72.9%) as a white solid.

[0686] Optical purity: 99.5%ee

[0687] (Detection wavelength 210nm, retention time 17.720 minutes, HPLC analysis conditions method 2)

[0688] UV intensity ratio: 99.2 percent

[0689] (Detection wavelength 210nm, retention time 3.289 minutes, HPLC analysis conditions method 3)

[0690] 1 H-NMR(DMSO-d6,500MHz)δ:7.65(d,J=7.9Hz,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)

[0691] The above Example 10 shows that Compound 17B can be obtained in 2 steps with a yield of 62% or more using Compound 15 as a starting material by the present method.

[0692] Example 11: Synthesis of N-(benzyloxy)carbonyl-O-isopropyl-L-threonyl-L-alanine methyl ester (Compound 20B) become

[0693] (11-1): Synthesis of (4S,5R)-3-benzyloxycarbonyl-2,2,5-trimethyl-oxazolidine-4-carboxylic acid (Compound 6B)

[0694] [Formula 50]

[0695]

[0696] N-Benzyloxycarbonyl-L-threonine (Compound 5) (4.15 g, 16.4 mmol), acetone (20.8 mL) and 2,2-dimethoxypropane (8.03 mL, 65.5 mmol) were added to the reaction vessel. Boron trifluoride tetrahydrofuran complex (0.36 mL, 3.3 mmol) was added at room temperature, and the resulting mixture was then stirred at room temperature for 1 hour. Subsequently, triethylamine (0.46 mL, 3.3 mmol) was added at room temperature and the mixture was stirred for 5 minutes. The resulting residue was concentrated, and MTBE (20 mL) and water (20 mL) were added, and the mixture was stirred. After discarding the water layer, azeotropic dehydration (three times) was performed by adding MTBE (20 mL), filtering and concentrating the organic layer to obtain 6.96 g of a residue containing compound 6B (96.0% yield according to HPLC and qNMR analysis).

[0697] UV intensity ratio: 98.82 percent

[0698] (Detection wavelength 210nm, retention time 2.856 minutes, HPLC analysis conditions method 3)

[0699] (11-2): Synthesis of (4S,5R)-4-{[(S)-1-methoxy-1-oxapropane-2-yl]carbamoyl}-2,2,5-trimethyloxazolidine-3-carboxylic acid benzyl ester (Compound 19B)

[0700] [Formula 51]

[0701]

[0702] To the residue containing compound 6B obtained in (11-1) above (2.97 g, containing 6.73 mmol of compound 6B) were added 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). 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, and the resulting mixture was stirred at room temperature for 90 minutes. Then, MeTHF (8 mL), 5% potassium carbonate aqueous solution (4 mL) and 1-methylimidazole (0.54 mL, 6.7 mmol) were added, and the resulting mixture was stirred for 10 minutes. After stirring and adding 10% ammonia water (6 mL), the aqueous layer was discarded. The obtained organic layer was washed with 10% aqueous ammonia (10 mL), 5% sulfuric acid (10 mL, then 16 mL), and then 5% aqueous potassium carbonate (10 mL) in sequence. Azeotropic dehydration by adding MeTHF (10 mL) was performed twice to obtain 3.26 g of a residue containing compound 19B (5.87 mmol) (yield according to HPLC and qNMR analysis was 87.2%).

[0703] UV intensity ratio: 96.4 percent

[0704] (Detection wavelength 210nm, retention time 2.899 minutes, HPLC analysis conditions method 3)

[0705] (11-3): Synthesis of N-(benzyloxy)carbonyl-O-isopropyl-L-threonyl-L-alanine methyl ester (Compound 20B)

[0706] [Formula 52]

[0707]

[0708] To the residue containing Compound 19B obtained in the above (11-2) (0.633 g, containing 1.14 mmol of Compound 19B) were added triethylsilane (0.91 mL, 5.7 mmol), acetic acid (0.13 mL, 2.3 mmol) and dichloromethane (2.2 mL) to prepare a substrate solution.

[0709] After the atmosphere in the reaction vessel was replaced with nitrogen, dichloromethane (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. Then, the substrate solution prepared above was added to the reaction vessel at an external temperature of 0°C, and the resulting mixture was stirred at room temperature for 90 minutes. (Using a portion of the reaction solution obtained here, no compound 21B was detected by HPLC analysis using HPLC analysis condition method 3).

[0710] [Formula 53]

[0711]

[0712] Then 5% aqueous ammonium chloride solution (2.2 mL) was added at an external temperature of 0 ° C. The mixture was stirred at room temperature. After discarding the water layer, the organic layer was washed with 5% aqueous citric acid solution (2.2 mL × 2), washed with water (2.2 mL) and washed with 5% aqueous sodium dihydrogen phosphate solution (2.2 mL) in sequence. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by reverse phase column chromatography (eluent: water / acetonitrile) to obtain compound 20B (0.239 g, yield 55.0%) as a white solid.

[0713] UV intensity ratio: 98.7 percent

[0714] (Detection wavelength 210nm, retention time 3.245 minutes, HPLC analysis conditions method 3)

[0715] 1 H-NMR(DMSO-d6,500MHz)δ:8.30(d,J=6.7Hz,1H),7.37-7.30(m,5H),6.94(d,J=9.4Hz,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=6.1Hz,3H),1.03(d,J=5.9Hz,3H),0.99(d,J=6.1Hz,3H)

[0716] The above Example 11 shows that the compound 20B can be obtained in 3 steps with a yield of 46% or more using the compound 5 as the starting material by the present method.

[0717] Example 12: N-[(9H-fluoren-9-ylmethoxycarbonyl)-L-leucyl]-O-isopropyl-L-threonine (Compound Synthesis of 23B)

[0718] (12-1): Synthesis of N-[(9H-fluoren-9-ylmethoxycarbonyl)-L-leucyl]-O-isopropyl-L-threonine (Compound 23B)

[0719] [Formula 54]

[0720]

[0721] Compound 22B (manufactured by Merck KGaA, 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.

[0722] After the atmosphere in the reaction vessel was replaced with nitrogen, dichloromethane (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. Then, the substrate solution prepared above was added to the reaction vessel at an external temperature of 0°C, and the resulting mixture was stirred at room temperature for 60 minutes. (Using a portion of the reaction solution obtained here, HPLC analysis was performed using HPLC analysis condition method 1, and the UV intensity ratio of the target 23B and the starting material 22B produced was 26.1:73.9. In addition, as a result of HPLC analysis using HPLC analysis condition method 3, compound 24B was not detected).

[0723] [Formula 55]

[0724]

[0725] Then add 5% ammonium chloride aqueous solution (1mL). The mixture is stirred at room temperature. After discarding the water layer, the obtained organic layer is washed with 5% ammonium chloride aqueous solution (1mL), and then washed with water (1mL). The obtained organic layer is concentrated under reduced pressure, and repeated four times by adding azeotropic dehydration of MTBE (5mL). The obtained residue is purified by reverse phase column chromatography (eluent: water / acetonitrile) to obtain 29.0mg compound 23B (15% yield) and 14.2mg target 23B containing starting material 22B (the UV intensity ratio of target 23B and starting material 22B in HPLC analysis using HPLC analysis condition method 1 is 93.7:6.3) respectively.

[0726] Diastereomeric excess (23B and diastereomer 23B'): 99.9%

[0727] (Detection wavelength 210nm, retention time 8.790 minutes, HPLC analysis conditions method 6)

[0728] [Formula 56]

[0729]

[0730] UV intensity ratio: 99.5 percent

[0731] (Detection wavelength 210nm, retention time 3.839 minutes, HPLC analysis conditions method 1)

[0732] 1 H-NMR (DMSO-d6, 500MHz) δ: 12.58 (s, 1H), 7.89 (d, J = 7.5Hz, 2H), 7.71 (t, J = 8.5Hz, 2H), 7.6 5(d,J=9.2Hz,1H),7.58(d,J=9.2Hz,1H),7.41(dd,J=7.5,7.5Hz,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=6.5Hz,6H),0.99(d,J=6.0Hz,3H),0.89(d,J=6.5Hz,3H),0.85(d,J=6.5Hz,3H)

[0733] Industrial Applicability

[0734] The present invention provides a method for producing an O-substituted serine derivative, wherein the O-substituted serine derivative can be obtained in a small number of steps. The production method of the present invention can be used to provide an unnatural amino acid that can be used to explore the supply of raw materials for peptide drugs and / or drugs with high position selectivity, chemical yield and optical purity.

Claims

1. A method for producing a compound represented by the following formula (1) or a salt thereof or a solvate thereof, the method comprising the steps of: (A) reacting a compound represented by the following formula (2) with a reducing agent to obtain a compound represented by the following formula (1): [Formula 1] in R1 is an electron-withdrawing group, an amino acid residue or a peptide residue; (i) R2 and R3 are each independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aralkyl, optionally substituted aryl and optionally substituted heteroaryl, or (ii) R2 and R3 together with the intervening carbon atom form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring; (i) R4 and R5 are each independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aralkyl, optionally substituted aryl and optionally substituted heteroaryl, or (ii) R4 and R5 together with the intervening carbon atom form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring; R6 is hydrogen, a C1-C6 alkyl group which may have a substituent, or an aralkyl group which may have a substituent; R7 is -OR8, -NR9R 9' , amino acid residues or peptide residues; R8, R9 and R 9' are each independently hydrogen, an optionally substituted C1-C6 alkyl group or an optionally substituted aralkyl group, or R9 and R 9' Together with the intervening nitrogen atom, it forms a 4- to 7-membered saturated heterocyclic ring; L1 is a single bond or -CH2-; L2 is a single bond or -CH2-; L3 is a single bond or -CH2-; Provided that, when L1 is -CH2-, L2 is a single bond; when L2 is -CH2-, L1 and L3 are single bonds; and when L3 is -CH2-, L2 is a single bond.

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

3. The method of claim 2, wherein the acid is a metal Lewis acid. 4 . The method according to claim 3 , wherein the metal Lewis acid is at least one selected from the group consisting of titanium tetrachloride, tin tetrachloride, scandium trifluoromethanesulfonate, tetraisopropyl orthotitanate, and isopropoxytitanium trichloride.

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

6. The method according to any one of claims 2 to 5, wherein the amount of the acid used in the step (A) is 0.1 equivalent or more and 20 equivalents or less relative to the compound represented by formula (2), and the amount of the reducing agent used is 0.5 equivalent or more and 30 equivalents or less relative to the compound represented by formula (2).

7. The method according to any one of claims 1 to 6, wherein the step (A) is performed in the presence of a solvent, and the solvent is at least one selected from the group consisting of a halogenated solvent and a benzene-based solvent.

8. The method according to any one of claims 1 to 7, wherein the step (A) is further performed in the presence of a solubilizing agent.

9. The method according to any one of claims 1 to 8, wherein the step (A) is performed at a temperature of -50°C to 50°C for 5 minutes to 24 hours.

10. The method according to any one of claims 1 to 9, which comprises, after step (A), a base treatment step of further adding a base to reduce the content of compound (4) contained in the reaction mixture: [Formula 2] wherein R1, R2, R3, R4, R5, R6, R7, L1, L2 and L3 are as defined in claim 1.

11. The method according to any one of claims 1 to 10, further comprising the following steps before step (A): (B) reacting a compound represented by the following formula (3) with an aldehyde, a ketone, an acetal or a vinyl ether to obtain a compound represented by the following formula (2): [Formula 3] wherein R1, R2, R3, R4, R5, R6, R7, L1, L2 and L3 are as defined in claim 1.

12. A method for producing a compound represented by the following formula (16) or a salt thereof or a solvate thereof, the method comprising the steps of: The following compound (11) is produced by the method according to any one of claims 1 to 11: [Formula 4] wherein R1, R2, R3, R4, R5, R6, L1, L2 and L3 have the same meanings as defined in claim 1; as well as (i)R 10 and R 11 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl optionally having a substituent, C3-C6 cycloalkyl optionally having a substituent, C2-C6 alkenyl optionally having a substituent, C2-C6 alkynyl optionally having a substituent, aralkyl optionally having a substituent, aryl optionally having a substituent and heteroaryl optionally having a substituent, or (ii) R 10 and R 11 Together with the intervening carbon atom, it forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.

13. The method according to claim 12, further comprising the following step after the step of producing the following compound (11): (C) reacting a compound represented by the following formula (11) with an aldehyde, a ketone, an acetal or a vinyl ether in the presence of a Lewis acid to obtain a compound represented by the following formula (15); and (D) reacting a compound represented by the following formula (15) in the presence of a Lewis acid and a reducing agent to obtain a compound represented by the following formula (16), [Formula 5] Among them, R1, R2, R3, R4, R5, R6, R 10 , R 11 , L1, L2 and L3 are as defined in claims 1 and 12.

14. The method according to any one of claims 1 to 13, wherein R1 is -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 Each is an optionally substituted C1-C6 alkyl group, an optionally substituted aralkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group; R2 and R3 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 R2 and R3 together with the carbon atoms to which they are attached form a 3- to 8-membered alicyclic ring; R4 and R5 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 R4 and R5 together with the carbon atoms to which they are attached form a 3- to 8-membered alicyclic ring; R6 is hydrogen, methyl, ethyl, n-propyl, n-butyl or benzyl; and L1, L2 and L3 are single bonds.

15. A method for producing a peptide compound, the method comprising the steps of: Step (i) producing the above compound (11) or (16) by the method according to any one of claims 1 to 14; and Step (ii) The carboxyl group of the compound (11) or (16) obtained in the above step (i) is condensed with an amino acid having an amino group or a peptide having an amino group in a solvent.

16. A compound or a salt or a solvate thereof, wherein the compound is selected from the group consisting of: 2-(Benzyloxycarbonylamino)-3-(cyclobutyloxy)propanoic acid; 2-(Benzyloxycarbonylamino)-3-isopentyloxy-propionic acid; 2-(Benzyloxycarbonylamino)-3-isopropoxy-butyric acid; 2-[Benzyloxycarbonyl(methyl)amino]-3-(cyclobutyloxy)propanoic acid; 3-Benzyloxycarbonyl-2-ethyl-oxazolidine-4-carboxylic acid; 3-Benzyloxycarbonyl-2-isobutyl-oxazolidine-4-carboxylic acid; 4-(Cyclobutyloxymethyl)-5-oxo-oxazolidine-3-carboxylic acid benzyl ester; Benzyl 4-{[1-methoxy-1-oxapropan-2-yl]carbamoyl}-2,2,5-trimethyloxazolidine-3-carboxylate; N-(Benzyloxy)carbonyl-O-isopropyl-threonyl-alanine methyl ester; and N-[(9H-Fluoren-9-ylmethoxycarbonyl)-leucyl]-O-isopropyl-threonine.

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