O-substituted serine derivative production method

Abstract

To provide methods for producing O-substituted serine derivatives useful as pharmaceutical intermediates and sulfamidates useful for producing them with excellent regioselectivity, chemical yield, and optical purity.SOLUTION: It was discovered that a cyclic sulfamidate can be produced by reacting an amino acid derivative with a cyclization reagent. In addition, it was discovered that an O-substituted serine derivative can be produced by reacting a cyclic sulfamidate with an alcohol.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an O-substituted serine derivative useful as a pharmaceutical intermediate, a cyclic sulfamidate useful for its production, and methods for producing them.

Background Art

[0002] Access to tough targets, typified by inhibition of protein-protein interactions, may be superior for medium-sized compounds (molecular weight 500-2000) compared to low-molecular-weight compounds. Also, compared to antibodies, medium-sized compounds may be superior in that they can translocate into cells. Among medium-sized compounds with biological activity, peptide pharmaceuticals are valuable molecular species for which more than 40 types have already been marketed (Non-Patent Document 1). Representative examples of peptide pharmaceuticals include cyclosporin A and polymyxin B. Looking at these structures, it can be seen that they are peptide compounds containing several non-natural amino acids. Non-natural amino acids are amino acids that are not naturally encoded on mRNA. In addition to the fact that natural-derived cyclosporin A and polymyxin B contain non-natural amino acids, it is very interesting that these non-natural structural sites interact with the action sites in the living body to exhibit pharmacological activity. As an example of the interaction between a non-natural amino acid and an action site in the living body, a study on the interaction between the O-substituted serine site of lacosamide and a sodium channel (Non-Patent Document 2) is known.

[0003] Among the methods for producing O-substituted serine derivatives, the following methods are known as methods for producing O-alkyl-substituted serine derivatives. 1. A method of producing from serine and an alkyl halide in the presence of a base using the Williamson ether synthesis method, or an improved method thereof (Non-Patent Document 3). 2. A synthesis method applying Schmidt Glycosylation, which is produced from serine and trichloroacetimidate in the presence of an acid catalyst (Non-Patent Document 4). 3. A synthesis method of producing from serine and allyl carbonate in the presence of a palladium catalyst (Non-Patent Document 5). These are methods for directly introducing an alkyl group into serine. 4. A synthetic method in which an aziridine compound derived from serine is reacted with an alcohol in the presence of a Lewis acid or a Bronsted acid catalyst (Patent Documents 1 and 2). 5. A method in which a cyclic sulfamidate derived from serine is reacted with an alcohol in the presence of a base (Non-Patent Document 6). These are methods for producing O-alkyl-substituted serine derivatives via intermediates derived from serine.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0005]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Summary of the Invention

Problems to be Solved by the Invention

[0006] In the method using aziridine derived from serine described in Patent Documents 1 and 2, there is a problem of regioselectivity of the reaction site. In the method using aziridine derived from serine described in Non-Patent Document 2, there is a problem of regioselectivity of the reaction site. In the method in the presence of a base described in Non-Patent Document 3, it is known that the hydroxyl group of serine is eliminated, and it is limited to the production of highly reactive benzyl ethers. In the method of producing from trichloroacetimidate described in Non-Patent Document 4, the substituent on oxygen of the O-substituted serine derivative that can be produced is limited to an allyl group. In the method by the coupling reaction of allyl ether described in Non-Patent Document 5, the substituent on oxygen of the O-substituted serine derivative that can be produced is limited to an allyl group. In the method using sulfamidate derived from serine described in Non-Patent Document 6, the O-substituted serine derivatives that can be produced in high yield are limited to O-substituted serines substituted with aromatic rings such as phenol, and only one example has been reported in which the synthesis of O-alkyl-substituted serine derivatives obtained by reacting with alkyl alcohols is obtained in a yield of only 16%. That is, it can be said that the examples of synthesizing O-alkyl-substituted serine derivatives that achieve satisfactory regioselectivity, yield, and optical purity by reacting cyclic sulfamidate with alcohol are extremely limited.

[0007] An object of the present invention is to provide a method for producing an O-substituted serine derivative useful as a pharmaceutical intermediate and a sulfamidate useful for its production, with satisfactory regioselectivity, chemical yield, and optical purity.

Means for Solving the Problems

[0008] As a result of intensive studies on the reaction of a cyclic sulfamidate derived from an amino acid derivative with an alcohol, the present inventors have found a method for producing an O-substituted serine derivative (I) having excellent regioselectivity and chemical yield while maintaining optical purity, using the following Scheme 1 or Scheme 2, and have completed the present invention. [Chemical formula]

[0009] The present invention includes the following in one non-limiting specific aspect. [1] A method for producing a compound represented by the general formula (I): [Chemical formula] [wherein, R1 is C1-C6 alkyl which may have a substituent, C3-C8 cycloalkyl which may have a substituent, aralkyl which may have a substituent, or heteroaralkyl which may have a substituent, R2 is C1-C6 alkyl or a protecting group for an amino group, R4 is a protecting group for a carboxyl group, L1 is a single bond or -CH2-, L2 is a single bond or -CH2-, n is 1 or 2, provided that when L1 is -CH2-, L2 is a single bond, and when L2 is -CH2-, L1 is a single bond.] its chemically acceptable salt, or a solvate thereof: Step A: Reacting a cyclization reagent with a compound represented by the general formula (V): [Chemical formula] [wherein, R2, R4, L1, L 2、 and n are as defined above.] to obtain a compound represented by the general formula (IV): [Chemical formula] [wherein, R2, R4, L1, L 2、 and n are as defined above.] A step of obtaining a compound represented by the formula, a chemically acceptable salt thereof, or a solvate thereof, Step B: Reacting a compound represented by the general formula (IV), a chemically acceptable salt thereof, or a solvate thereof with an oxidizing agent to obtain a compound represented by the general formula (II): [Chemical formula] [wherein, R2, R4, L1, L 2、 and n are as defined above.] A step of obtaining a compound represented by the formula, a chemically acceptable salt thereof, or a solvate thereof, and Step C: Reacting a compound represented by the general formula (II), a chemically acceptable salt thereof, or a solvate thereof with R1OH (wherein, R1 is as defined above) to obtain a compound represented by the general formula (I), a chemically acceptable salt thereof, or a solvate thereof. [2] The following steps are included for the general formula (I): [Chemical formula] [wherein, R1 is C1-C6 alkyl which may have a substituent, C3-C8 cycloalkyl which may have a substituent, aralkyl which may have a substituent, or heteroaralkyl which may have a substituent, R2 is hydrogen, R4 is a protecting group for a carboxyl group, L1 is a single bond or -CH2-, L2 is a single bond or -CH2-, n is 1 or 2, provided that when L1 is -CH2-, L2 is a single bond, and when L2 is -CH2-, L1 is a single bond.] A method for producing a compound represented by formula (I), a chemically acceptable salt thereof, or a solvate thereof: Step A: A cyclizing reagent is reacted with a compound represented by the general formula (V’):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Advantages of the Invention

[0010] According to the present invention, unnatural amino acids useful for the search for peptide pharmaceuticals and / or the supply of drug raw materials can be provided with high regioselectivity, chemical yield, and optical purity.

Modes for Carrying Out the Invention

[0011] The abbreviations used in this specification are described below. AcOEt: Ethyl acetate Alloc group: Allyloxycarbonyl group t-Bu group: tert-Butyl group Boc group: tert-Butoxycarbonyl group Cbz group: Benzyloxycarbonyl group DIPEA: N,N-Diisopropylethylamine DMA: N,N-Dimethylacetamide DME: 1,2-Dimethoxyethane DMF: N,N-Dimethylformamide DMSO: Dimethyl sulfoxide EtOH: Ethanol Fmoc group: 9-Fluorenylmethyloxycarbonyl group MeCN: Acetonitrile NMP: N-Methylpyrrolidone TEA: Triethylamine TFE: 2,2,2-Trifluoroethanol THF: Tetrahydrofuran

[0012] As used herein, "alkyl" refers to a monovalent group derived by removing any one hydrogen atom from an aliphatic hydrocarbon, which does not contain a heteroatom (an atom other than a carbon and hydrogen atom) or an unsaturated carbon-carbon bond in its skeleton, and has a subset of a hydrocarbyl or hydrocarbon group structure containing hydrogen and carbon atoms. The alkyl group includes linear or branched-chain ones. Examples of the alkyl group include those having 1 to 20 carbon atoms (C1-C 20 , hereinafter "C p -C q " means having p to q carbon atoms.), preferably a C1-C6 alkyl group. Specific examples of the alkyl include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, tert-butyl group, sec-butyl group, etc.

[0013] As used herein, "cycloalkyl" refers to a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, including monocyclic, bicyclic, and spiro rings. Preferably, C3-C8 cycloalkyl is mentioned. The cycloalkyl group may be partially unsaturated. Specific examples of the cycloalkyl include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0014] As used herein, "aryl" refers to a monovalent aromatic hydrocarbon ring, preferably C6-C 10 aryl. Specific examples of the aryl include, for example, phenyl, naphthyl (e.g., 1-naphthyl, 2-naphthyl), etc.

[0015] As used herein, "heteroaryl" means a monovalent group of an aromatic ring that preferably contains 1 to 4 heteroatoms among the atoms constituting the ring (also referred to as "within the ring" herein), and may be partially saturated. The ring may be a monocyclic ring or two fused rings (for example, a bicyclic heteroaryl fused with benzene or a monocyclic heteroaryl). The number of atoms constituting the ring is preferably 5 to 10 (5-membered - 10-membered heteroaryl). Specific examples of heteroaryl include, for example, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, benzofuranyl, benzothienyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, and the like.

[0016] As used herein, "arylalkyl (aralkyl)" means a group containing both aryl and alkyl, for example, a group in which at least one hydrogen atom of the alkyl is substituted by aryl, and preferably, "C6-C 10 aryl C1-C6 alkyl" can be mentioned. Specific examples of arylalkyl include, for example, benzyl, phenethyl, and the like.

[0017] As used herein, "heteroarylalkyl (heteroaralkyl)" means a group containing both heteroaryl and alkyl, for example, a group in which at least one hydrogen atom of the alkyl is substituted by heteroaryl, and preferably, "5-membered - 10-membered heteroaryl C1-C6 alkyl" can be mentioned. Specific examples of heteroarylalkyl include, for example, pyridylmethyl, thienylmethyl, furylmethyl, and the like.

[0018] As used herein, "alkylene" means a divalent group derived by further removing one arbitrary hydrogen atom from the above-mentioned "alkyl", and preferred examples of alkylene include C1-C6 alkylene. Specific examples of such alkylene include, for example, methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene, tetramethylene, pentamethylene, hexamethylene, and the like.

[0019] As used herein, "phosphate" means a salt in which the anion is a phosphate ion (PO4 3- ), or a hydrogen phosphate ion (H2PO4 - , or HPO4 2- ), and the cation is a metal ion. Here, the metal ion is selected from alkali metal ions or alkaline earth metal ions, preferably an alkali metal ion, preferably a sodium ion, a potassium ion, or a cesium ion. Phosphates preferably include disodium hydrogen phosphate anhydride, dipotassium hydrogen phosphate anhydride, or dicesium hydrogen phosphate anhydride, and hydrates thereof.

[0020] As used herein, "acidic salt" means a salt that generates hydrogen ions when dissolved in a solvent, and includes sodium dihydrogen phosphate anhydride (NaH2PO4), potassium dihydrogen phosphate anhydride (KH2PO4), cesium dihydrogen phosphate anhydride (CsH2PO4), disodium hydrogen phosphate anhydride, dipotassium hydrogen phosphate anhydride, dicesium hydrogen phosphate anhydride, sodium hydrogen sulfate anhydride, potassium hydrogen sulfate anhydride, cesium hydrogen sulfate anhydride, and hydrates thereof.

[0021] In the production method described below, when the defined group undergoes an unwanted chemical conversion under the conditions of the implementation method, for example, by using means such as protection and deprotection of functional groups, the production of the compounds of the present invention can be carried out. Here, the selection of the protecting group and the desorption operation can include, for example, the methods described in "Greene’s, “Protective Groups in Organic Synthesis” (5th Edition, John Wiley & Sons 2014)", and these can be appropriately used according to the reaction conditions. Also, if necessary, the order of reaction steps such as substituent introduction can be changed. For example, protecting groups for amino groups include Fmoc, Boc, Cbz, or Alloc groups, etc. These carbamate groups can be introduced by reacting the amino group with a carbamating agent in the presence of a base catalyst. Examples of carbamating agents include Boc2O, BocOPh, FmocOSu, FmocCl, CbzCl, AllocCl, etc. Examples of base catalysts include lithium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium phosphate, potassium phosphate, N-methylmorpholine, triethylamine, diisopropylethylamine, N,N-dimethylaminopyridine, etc. The carbamate group, which is a protecting group for the amino group, can be removed under basic conditions, acidic conditions, or conditions of a hydrogenolysis reaction, etc.

[0022] Examples of protecting groups for carboxyl groups include alkyl groups and benzyl groups. Protecting groups such as alkyl groups and benzyl groups can be removed by hydrolysis reactions under basic or acidic conditions, hydrogenolysis reactions in the presence of transition metal catalysts, etc.

[0023] The compounds represented by the formulas of the present invention may be their chemically acceptable salts or their chemically acceptable solvates. Chemically acceptable salts of the compounds represented by the formulas include, for example, hydrochloride; hydrobromide; hydroiodide; phosphate; phosphonate; sulfate; sulfonates such as methanesulfonate, p-toluenesulfonate; carboxylates such as acetate, citrate, malate, tartrate, succinate, salicylate; or alkali metal salts such as sodium salt, potassium salt; alkaline earth metal salts such as magnesium salt, calcium salt; ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, tetraalkylammonium salt, etc. These salts are produced by contacting the compound with an acid or a base that can be used in the production of pharmaceuticals. The chemically acceptable solvate of the compound represented by the formulas of the present invention refers to the phenomenon in which solute molecules strongly attract solvent molecules in a solution to form a single molecular aggregate, and is called a hydrate if the solvent is water. In addition, the solvates of the compounds of the present invention include not only solvates with a single solvent such as water, alcohol (e.g., methanol, ethanol, 1-propanol, 2-propanol, etc.), dimethylformamide, but also solvates with a plurality of solvents.

[0024] As used herein, "amino acid" includes natural amino acids and unnatural amino acids (amino acid derivatives). The compounds of the present invention may be amino acids, preferably amino acid derivatives. As used herein, "natural amino acid" refers to Gly, Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg, Pro. Unnatural amino acids are not particularly limited, and examples include N-alkyl amino acids, β-amino acids, γ-amino acids, D-amino acids, N-substituted serines, α,α-disubstituted serines, amino acids with side chains different from natural amino acids, O-substituted serines, etc. The selection of the substituent (referred to as the side chain of the amino acid) bonded to the main chain of the amino acid is not particularly limited, and in addition to a hydrogen atom, it can be freely selected from, for example, an alkyl group, an aryl group, a heteroaryl group, an aralkyl group, a heteroaralkyl group, or a cycloalkyl group, etc. One or two methylene groups not directly bonded to the main chain of the amino acid in these groups may be substituted with an atom or group selected from the group consisting of an oxygen atom, a nitrogen atom, a carbonyl group (-CO-), or a sulfonyl group (-SO2-), and each may be substituted with an arbitrary substituent, and these substituents are also not limited. For example, examples include an optionally substituted alkyl group, aryl group, heteroaryl group, aralkyl group, heteroaralkyl group, cycloalkyl group, or alkoxyalkyl group (e.g., methoxymethyl group, etc.). Also, the amino acid as used herein may be a compound having a carboxy group and an amino group in the same molecule. As the amino acid as used herein, any configuration is acceptable.

[0025] The amino group of the main chain of the amino acid may be unsubstituted (NH2 group) or may be substituted. The carboxyl group of the main chain of the amino acid may be unsubstituted (CO2H group) or may be substituted. The "amino acids" in this specification include all corresponding isotopes. The isotope of an "amino acid" is one in which at least one atom is replaced by an atom having the same atomic number (number of protons) but a different mass number (sum of the number of protons and neutrons). Examples of the isotopes included in the "amino acids" in this specification include hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorus atom, sulfur atom, fluorine atom, chlorine atom, etc., respectively, 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 35 S, 18 F, 36 Cl, etc. are included.

[0026] In this specification, the "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.

[0027] In this specification, when a halogen atom serves as a substituent such as an aromatic carbon ring or an aromatic heterocycle, preferred halogen atoms include a fluorine atom or a chlorine atom. Specifically, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 5-fluoro-2-pyridyl group, or 5-fluoro-3-pyridyl group, etc. can be mentioned.

[0028] In the present specification, when a halogen atom is a substituent of an alkyl group or an alkoxy group, a preferred halogen atom is a fluorine atom. Specifically, a trifluoromethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 2,2,3,3-tetrafluoropropyl group, heptafluoropropyl group, trifluoromethoxy group, 2,2,2-trifluoroethoxy group, pentafluoroethoxy group, 2,2,3,3-tetrafluoropropoxy group, heptafluoropropoxy group, etc. may be mentioned.

[0029] In the present specification, "having a heteroatom in the ring" means containing a heteroatom among the atoms constituting the ring, and examples of such groups include heteroaryl groups such as a pyridyl group or a thienyl group, a piperidyl group, a morpholino group, etc. Further, when the heteroatom is an oxygen atom, it is expressed as "having an oxygen atom in the ring", etc.

[0030] In the present specification, the "oxidizing agent" is used in the reaction to obtain a cyclic sulfamidate by oxidizing the sulfur atom in the ring of the cyclic sulfamidite from sulfoxide to sulfone, and examples thereof include hydrogen peroxide, organic peracids, persulfates, halogen oxide salts, or a combination of a halogen oxide salt and a transition metal catalyst. Preferably, examples include 3-chloroperbenzoic acid, Oxone, and a combination of a periodate and a ruthenium catalyst. The periodate is exemplified by sodium periodate or potassium periodate. The ruthenium catalyst includes ruthenium trichloride anhydride or ruthenium trichloride hydrate.

[0031] One aspect of the present invention is to provide a non-natural amino acid useful for the search for peptide pharmaceuticals. Another aspect of the present invention is to provide a method for producing a high-quality non-natural amino acid for the supply of a pharmaceutical drug substance.

[0032] (General production method) Next, the general production method of the compound of the present invention will be described. In a certain situation, the compound represented by formula (I) can be produced, for example, by production method 1 including the following step C (addition ring-opening reaction). Manufacturing Method 1

Chemical formula

[0033] R1 in the formula is C1-C6 alkyl which may have a substituent, C3-C8 cycloalkyl which may have a substituent, aralkyl which may have a substituent, or heteroaralkyl which may have a substituent. Preferably, R1 is C1-C6 alkyl, C3-C8 cycloalkyl, aralkyl, or heteroaralkyl which may have one or more substituents independently selected from halogen, aryl (the aryl may be substituted by halogen, etc.), or hydroxyl group. Specifically, examples of R1 include methyl, ethyl, i-propyl, n-propyl, n-butyl, i-pentyl, 3,3,3-trifluoro-2-hydroxypropyl, 2,2,3,3-tetrafluoropropyl, 2-hydroxypropyl, 2-hydroxy-2-methyl-propyl, 3-hydroxy-3-methyl-butyl, cyclopropyl, benzyl, fluorobenzyl, thienylmethyl, furanylmethyl, and the like.

[0034] R2 in the formula is a protecting group for a C1-C6 alkyl or amino group. Such R2 includes, for example, methyl, ethyl, benzyl, Fmoc, Boc, Cbz, or Alloc group, etc.

[0035] R4 in the formula is a protecting group for a carboxyl group. Such R4 includes, for example, alkyl such as t-butyl, and trityl, cumyl, allyl, benzyl, etc.

[0036] In the formula, L1 is a single bond or -CH2-, and L2 is a single bond or -CH2-. Here, when L1 is -CH2-, L2 is a single bond, and when L2 is -CH2-, L1 is a single bond. That is, as combinations of L1 and L2, specifically, (i) L1 = single bond, L2 = single bond, (ii) L1 = -CH2-, L2 = single bond, and (iii) L1 = single bond, L2 = -CH2- are included.

[0037] In the formula, n represents the number of methylene groups, and n is 1 or 2.

[0038] Step C (addition ring-opening reaction) of Production Method 1 is a step of producing the O-substituted serine derivative (I) by subjecting the cyclic sulfamidate derivative (II) to a nucleophilic substitution reaction with the alcohol derivative (III) to introduce R1. This step can be carried out by stirring the reaction mixture for 1 hour to 48 hours at a temperature of -20°C to near the boiling point of the solvent, preferably 0°C to 180°C, in the presence or absence of a dissolution auxiliary solvent and in the presence or absence of an acidic salt.

[0039] As the alcohol derivative (III) represented by R1-OH, any alcohol derivative having R1 defined above can be used. Non-limiting examples of such alcohol derivatives include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 3-methylbutanol, 3,3,3-trifluoropropane-1,2-diol, 2,2,3,3-tetrafluoropropyl alcohol, 2-hydroxypropyl alcohol, 2-methylpropane-1,2-diol, 3-hydroxy-3-methyl-butyl alcohol, cyclopropyl alcohol, benzyl alcohol, 3-fluorobenzyl alcohol, 2-thiophenemethanol, 2-furfuryl alcohol, and the like.

[0040] Examples of the solubilizing co-solvent include halogenated solvents such as 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, dichloromethane, and chloroform; ether solvents such as diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, cyclopentyl methyl ether, and dimethoxyethane; benzene solvents such as toluene and benzotrifluoride; ester solvents such as ethyl acetate, isopropyl acetate, and butyl acetate; and ketone solvents such as acetone and methyl ethyl ketone. Among these, 2,2,2-trifluoroethanol or 1,1,1,3,3,3-hexafluoro-2-propanol and 2-methyltetrahydrofuran are preferably used.

[0041] Examples of the acidic salt include sodium dihydrogen phosphate anhydride (NaH2PO4), potassium dihydrogen phosphate anhydride (KH2PO4), cesium dihydrogen phosphate anhydride (CsH2PO4), disodium hydrogen phosphate anhydride, dipotassium hydrogen phosphate anhydride, dicesium hydrogen phosphate anhydride, sodium hydrogen sulfate anhydride, potassium hydrogen sulfate anhydride, cesium hydrogen sulfate anhydride, and their hydrates. Among these, NaH2PO4, KH2PO4, or CsH2PO4 is preferred. Moreover, it is preferable to use 2 to 5 equivalents of these acidic salts with respect to the starting material. By using the acidic salt, the target compound can be obtained efficiently.

[0042] Step C may further include a step of extracting the reaction mixture with an organic solvent, and the extract can be used in the next step without concentration to dryness.

[0043] In one aspect, the compound of the present invention represented by the formula (I) can be produced, for example, by Production Method 2 including Step C (addition ring-opening reaction) shown below. Manufacturing Method 2

Chemical formula

[0044] In the formula, R1 is C1-C6 alkyl which may have a substituent, C3-C8 cycloalkyl which may have a substituent, aralkyl which may have a substituent, or heteroaralkyl which may have a substituent. Preferably, R1 is C1-C6 alkyl, C3-C8 cycloalkyl, aralkyl, or heteroaralkyl which may have one or more substituents independently selected from halogen, aryl (the aryl may be substituted by halogen etc.), or hydroxyl group. Specifically, examples of R1 include methyl, ethyl, i-propyl, n-propyl, n-butyl, i-pentyl, 3,3,3-trifluoro-2-hydroxypropyl, 2,2,3,3-tetrafluoropropyl, 2-hydroxypropyl, 2-hydroxy-2-methyl-propyl, 3-hydroxy-3-methyl-butyl, cyclopropyl, benzyl, fluorobenzyl, thienylmethyl, furanylmethyl, and the like.

[0045] In the formula, R2 is hydrogen.

[0046] In the formula, R 2’ is a protecting group for the amino group. Such R 2’ includes, for example, Fmoc, Boc, Cbz, or Alloc group, etc.

[0047] In the formula, R4 is a protecting group for the carboxyl group. Such R4 includes, for example, alkyl such as t-butyl, and trityl, cumyl, allyl, benzyl, etc.

[0048] In the formula, L1 is a single bond or -CH2-, and L2 is a single bond or -CH2-. Here, when L1 is -CH2-, L2 is a single bond, and when L2 is -CH2-, L1 is a single bond. That is, specifically, there are three combinations of L1 and L2: (i) L1 = single bond, L2 = single bond; (ii) L1 = -CH2-, L2 = single bond; (iii) L1 = single bond, L2 = -CH2-.

[0049] In the formula, n represents the number of methylene groups, and n is 1 or 2.

[0050] In Step C (addition ring-opening reaction) of Production Method 2, an alcohol derivative (III) is subjected to a nucleophilic substitution reaction with a cyclic sulfamidate derivative (II’), whereby R1 is introduced and R 2’ is removed to produce an O-substituted serine derivative (I) having a free amino group. This reaction can be carried out by stirring the reaction mixture at a temperature of -20°C to near the boiling point of the solvent, preferably 0°C to 180°C, for 1 hour to 48 hours, in the presence or absence of a dissolution auxiliary solvent and in the presence or absence of an acidic salt.

[0051] As the alcohol derivative (III) represented by R1-OH, any alcohol derivative having R1 defined above can be used. Non-limiting examples of such alcohol derivatives include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 3-methylbutanol, 3,3,3-trifluoropropane-1,2-diol, 2,2,3,3-tetrafluoropropyl alcohol, 2-hydroxypropyl alcohol, 2-methylpropane-1,2-diol, 3-hydroxy-3-methyl-butyl alcohol, cyclopropyl alcohol, benzyl alcohol, 3-fluorobenzyl alcohol, 2-thiophenemethanol, 2-furfuryl alcohol, and the like.

[0052] As the dissolution auxiliary solvent, the same one as that used in the dissolution auxiliary solvent in Step C of Production Method 1 can be used.

[0053] As the acidic salt, the same one as that used in the acidic salt in Step C of Production Method 1 can be used.

[0054] Step C may further include a step of extracting the reaction mixture with an organic solvent, and the extract can be used in the next step without concentration to dryness.

[0055] The compound of formula (I) obtained via Process C can be further subjected to the following Process D (deprotection reaction), which is also included in Production Method 1 or Production Method 2.

Chemical formula

[0056] R1, R2, R4, L1, L in the formula 2、 and n are synonymous with R1, R2, R4, L1, L 2、 and n in Production Method 1 and Production Method 2, respectively.

[0057] This process is a process for producing an O-substituted serine derivative (I') by deprotecting the protecting group (R4) of the carboxyl group of the O-substituted serine derivative of formula (I). This reaction can be carried out by stirring the reaction mixture at a temperature of 0 °C to near the boiling point of the solvent for 1 hour to 24 hours in the presence or absence of a metal catalyst, preferably a Pd catalyst, or an acid catalyst, and in the presence or absence of a hydrogen source.

[0058] Examples of the metal catalyst include those in which a metal catalyst is supported on a solid represented by activated carbon, such as palladium carbon and palladium hydroxide carbon, palladium oxide, platinum oxide, Raney nickel, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium, palladium acetate, and the like.

[0059] Examples of the acid catalyst include hydrochloric acid, hydrobromic acid, trifluoromethanesulfonic acid, sulfuric acid, and the like.

[0060] Examples of the hydrogen source include hydrogen gas, formic acid, or ammonium formate.

[0061] The reaction can be carried out in a solvent such as ethyl acetate, isopropyl acetate, butyl acetate, methanol, ethanol, or the like.

[0062] The compound of formula (I') obtained via Process D can be further subjected to the following Process E (reaction for introducing R3), which process is also included in Production Method 1 or Production Method 2. [Chemical formula]

[0063] R1, R2, L1, L in the formula 2、 and n are synonymous with R1, R2, L1, L 2、 and n in Production Method 1 and Production Method 2, respectively.

[0064] R3 in the formula is a protecting group for an amino group or C1-C4 alkyl. Preferred examples of the protecting group for an amino group include a Boc group, an Fmoc group, a Cbz group, an Alloc group, etc., and preferred examples of C1-C4 alkyl include methyl, ethyl, or propyl.

[0065] Introduction of the protecting group (R3) to the amino group can be carried out by reacting the α-amino group site of the O-substituted serine derivative (I') with a carbamate-forming agent. This reaction can be carried out by stirring the reaction mixture for 1 hour to 24 hours at a temperature of -10°C to near the boiling point of the solvent in the presence or absence of a base catalyst.

[0066] Examples of the carbamate-forming agent include Boc2O, BocOPh, FmocOSu, FmocCl, CbzCl, AllocCl, etc.

[0067] Examples of the base catalyst include lithium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, cesium hydrogen carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium phosphate, potassium phosphate, N-methylmorpholine, triethylamine, diisopropylethylamine, N,N-dimethylaminopyridine, etc.

[0068] As the solvent, acetonitrile, DMF, NMP or the like can be preferably used.

[0069] In addition, the introduction of the alkyl group (R3) to the amino group can be carried out by the method of Freidinger et al. (U.S. Patent No. 4,535,167), in which the α-amino group site of the O-substituted serine derivative (I') is reacted with an alkyl aldehyde in a solvent in the presence of an acid catalyst to form an oxazolidinone ring, and then ring-opening reduction is carried out using a trialkylsilane in the presence of an acid. These reactions can be carried out by stirring the reaction mixture at a reaction temperature from 0 °C to near the boiling point of the solvent for 1 to 24 hours.

[0070] Regarding the step of forming the oxazolidinone ring, examples of the alkyl aldehyde include formaldehyde, acetaldehyde, propanal, butanal, 2-methylpropanal, etc.; examples of the trialkylsilane include triethylsilane, etc.; examples of the acid catalyst include p-toluenesulfonic acid, camphorsulfonic acid, etc.; examples of the solvent include toluene, THF, etc. Regarding the ring-opening reduction step, examples of the acid include trifluoroacetic acid, etc.

[0071] The introduction of the alkyl group (R3) to the amino group can also be carried out by the method of Shimokawa et al. (Bioorg. Med. Chem. Lett., 2009, 19(1), 92-95) or Prashad et al. (Org. Lett., 2003, 5(2), 125-128), in which an alkylating agent is allowed to act on an amino acid with a protected N-terminus in an organic solvent in the presence of a base to obtain an N-alkyl amino acid. This reaction can be carried out by stirring the reaction mixture at a reaction temperature from 0 °C to near the boiling point of the solvent for 1 to 24 hours.

[0072] In this case, examples of the alkylating agent include alkyl halides such as methyl iodide, ethyl iodide, propyl iodide, butyl iodide, etc., or dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dipropyl sulfate, dibutyl sulfate, etc. Examples of the organic solvent include THF, DMF, DMA, or NMP, etc. Examples of the base include sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate, etc.

[0073] In one aspect, the compound of the present invention can be produced by Production Method 3 shown below. This production method is an embodiment of Production Method 1. It is a method of using a compound of formula (IIb) in which R2 of the compound of formula (II) is Fmoc as a starting material, and obtaining a compound of formula (I’b) through Step C and Step D. Manufacturing Method 3 [Chemical formula]

[0074] R1, R4, L1, L in the formula 2、 and n are respectively synonymous with R1, R4, L1, L 2、 and n in Production Method 1.

[0075] Step C (addition ring-opening reaction) is a step of introducing R1 by subjecting a cyclic sulfamidate derivative (IIb) protected by an Fmoc group to a nucleophilic substitution reaction with an alcohol derivative (III) to produce an O-substituted serine derivative (Ib) protected by an Fmoc group. This reaction can be carried out by stirring the reaction mixture at a temperature of -20°C to near the boiling point of the solvent, preferably 0°C to 180°C, for 1 hour to 48 hours in the presence or absence of a dissolution-assisting solvent and in the presence or absence of an acidic salt.

[0076] As the auxiliary solvent for dissolution and the acidic salt, those same as the auxiliary solvent for dissolution and the acidic salt in Step C of Production Method 1 can be used respectively. In this production method, as the auxiliary solvent for dissolution, trifluoroethanol, hexafluoroisopropyl alcohol, dioxane, tetrahydrofuran, NMP are preferably used, and as the acidic salt, NaH2PO4, KH2PO4, or CsH2PO4 is preferably used.

[0077] Step D (deprotection reaction) is a step of producing an O-substituted serine derivative (I’b) in which the carboxyl group is deprotected while the amino group is protected by the Fmoc group by deprotecting the protecting group (R4) of the carboxyl group of the O-substituted serine derivative (Ib) protected by the Fmoc group. This reaction can be carried out by stirring the reaction mixture at a temperature of 0 °C to near the boiling point of the solvent for 1 hour to 24 hours in the presence or absence of a metal catalyst, preferably a Pd catalyst, or an acid catalyst, and in the presence or absence of a hydrogen source.

[0078] As the metal catalyst, acid catalyst, hydrogen source, and solvent, those same as the metal catalyst, acid catalyst, hydrogen source, and solvent in Step D of Production Method 1 can be used respectively. In this production method, as the metal catalyst, for example, those in which a metal catalyst such as palladium on carbon or palladium hydroxide on carbon is supported on a solid represented by activated carbon, palladium oxide, platinum oxide, Raney nickel, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium, palladium acetate, etc. are used, as the acid catalyst, for example, hydrochloric acid, hydrobromic acid, trifluoromethanesulfonic acid, sulfuric acid, etc. are used, as the hydrogen source, hydrogen gas, formic acid, or ammonium formate, etc. are used, and as the solvent, short-chain alkyl alcohols such as methanol and ethanol, and acetate ester derivatives such as ethyl acetate and isopropyl acetate are preferably used.

[0079] In a certain aspect, the compound of the present invention can be produced by Production Method 4-1 shown below. This production method is an embodiment of Production Method 1. Using the compound of formula (IIc) in which R2 of the compound of formula (II) is alkyl as a starting material, through Step C and Step D, a compound of formula (I'c) which is an N-alkyl amino acid is obtained, and further through Step E, a compound of formula (I''c) is obtained. Manufacturing Method 4-1

Chemical formula

[0080] R1, R3, R4, L1, L in the formula 2、 and n are respectively synonymous with R1, R3, R4, L1, L 2、 and n in Production Method 1, and Alk is C1-C4 alkyl.

[0081] Step C (addition ring-opening reaction) is a step of producing an O-substituted serine derivative (Ic) substituted with an alkyl group by subjecting a cyclic sulfamidate derivative (IIc) substituted with an alkyl group to a nucleophilic substitution reaction with an alcohol derivative (III) to introduce R1. This reaction can be carried out by stirring the reaction mixture for 1 hour to 48 hours at a temperature of -20°C to near the boiling point of the solvent, preferably 0°C to 180°C, in the presence or absence of a dissolution auxiliary solvent and in the presence or absence of an acidic salt.

[0082] As the dissolution auxiliary solvent and the acidic salt, the same ones as those of the dissolution auxiliary solvent and the acidic salt in Step C of Production Method 1 can be used. In this production method, it is preferable to use trifluoroethanol, hexafluoroisopropyl alcohol, dioxane, tetrahydrofuran, NMP as the dissolution auxiliary solvent, and NaH2PO4, KH2PO4, or CsH2PO4 as the acidic salt.

[0083] Step D (deprotection reaction) is a step of producing an O-substituted serine derivative (I'c) in which the carboxyl group is deprotected while the amino group remains substituted with an alkyl group by deprotecting the protecting group (R4) of the carboxyl group of the O-substituted serine derivative (Ic) substituted with an alkyl group. This reaction can be carried out by stirring the reaction mixture at a temperature of 0 °C to near the boiling point of the solvent for 1 hour to 24 hours in the presence or absence of a metal catalyst, preferably a Pd catalyst, or an acid catalyst, and in the presence or absence of a hydrogen source.

[0084] As the metal catalyst, acid catalyst, hydrogen source, and solvent in Step D of Production Method 1, the same ones can be used respectively. In this production method, as the metal catalyst, for example, those in which a metal catalyst such as palladium carbon or palladium hydroxide carbon is supported on a solid such as activated carbon, palladium oxide, platinum oxide, Raney nickel, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium, palladium acetate, etc., as the acid catalyst, for example, hydrochloric acid, hydrobromic acid, trifluoromethanesulfonic acid, sulfuric acid, etc., as the hydrogen source, hydrogen gas, formic acid, or ammonium formate, etc., and as the solvent, short-chain alkyl alcohols such as methanol and ethanol, and acetate ester derivatives such as ethyl acetate and isopropyl acetate are preferably used.

[0085] Step E (protection group introduction reaction) is a step of producing an O-disubstituted serine derivative (I''c) by reacting the amino group of the O-substituted serine derivative (I'c) in which the amino group is substituted with an alkyl group and the carboxyl group is deprotected with a carbamate agent to introduce a protecting group (R3) to the amino group. This reaction can be carried out by stirring the reaction mixture at a temperature of -10 °C to near the boiling point of the solvent for 1 hour to 24 hours in the presence or absence of a base catalyst.

[0086] The carbamoylating agent, base catalyst, and solvent can be the same as those of the carbamoylating agent, base catalyst, and solvent in Step E of Production Method 1, respectively. In this production method, for example, Boc2O, BocOPh, FmocOSu, FmocCl, CbzCl, AllocCl, etc. can be used as the carbamoylating agent, and for example, lithium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, cesium hydrogen carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium phosphate, potassium phosphate, N-methylmorpholine, triethylamine, diisopropylethylamine, N,N-dimethylaminopyridine, etc. can be used as the base catalyst. As the solvent, it is preferable to use acetonitrile, dichloromethane, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, NMP, etc.

[0087] In one aspect, the compound of the present invention can be produced by Production Method 4-2 shown below. This production method is an embodiment of Production Method 2, and is a method in which a compound of formula (I') having a free amino group, synthesized through Step C and Step D, is subjected to Step E to obtain a compound of formula (I''c) which is an N-alkylamino acid. Manufacturing Method 4-2 [Chemical formula]

[0088] R1, R2, L1, L in the formula 2、 and n are synonymous with R1, R2, and L1, L 2、 n in Production Method 2, respectively, and Alk is C1-C4 alkyl.

[0089] Process E (the reaction for introducing an alkyl group) can be carried out, as described above, by using the method of Freidinger et al. (U.S. Patent No. 4,535,167), or the methods of Shimokawa et al. (Bioorg. Med. Chem. Lett., 2009, 19(1), 92 - 95) or Prashad et al. (Org. Lett., 2003, 5(2), 125 - 128).

[0090] In a certain aspect, the compound of the present invention can be produced by Production Method 5 - 1 shown below. This production method is an embodiment of Production Method 1, which is a method of using the compound of formula (IId) in which R4 of the compound of formula (II) is -C(R5)3 as a starting material, and obtaining the compound of formula (I’d) through Step C. Manufacturing Method 5-1

Chemical formula

[0091] R1, R2, L1, L in the formula 2、 and n are respectively synonymous with R1, R2, L1, L 2、 and n in Production Method 1.

[0092] R5 in the formula is an optionally substituted C1 - C6 alkyl group or an aromatic ring. Such R5 includes, for example, methyl, ethyl, phenyl, etc.

[0093] This Step C (the addition - ring - opening reaction) is a step of producing an N,O - disubstituted serine derivative (I’d) by subjecting the cyclic sulfamidate derivative (IId) to a nucleophilic substitution reaction with an alcohol derivative (III). This reaction can be carried out by stirring the reaction mixture at a temperature of -20°C to near the boiling point of the solvent, preferably 0°C to 180°C, for 1 hour to 48 hours, in the presence or absence of a dissolution - assisting solvent and in the presence or absence of an acidic salt.

[0094] The solubilizing co-solvent and the acidic salt can be the same as those of the solubilizing co-solvent and the acidic salt in Step C of Production Method 1. In this production method, as the solubilizing co-solvent, trifluoroethanol, hexafluoroisopropyl alcohol, dioxane, tetrahydrofuran, NMP are preferably used, and as the acidic salt, NaH2PO4, KH2PO4, or CsH2PO4 is preferably used.

[0095] In one aspect, the compound of the present invention can be produced by Production Method 5-2 shown below. This production method is an aspect of Production Method 2, and is a method of using a compound of formula (II’d) in which R4 of the compound of formula (II) is -C(R5)3 as a starting material, and obtaining a compound of formula (I’d) through Step C. Manufacturing Method 5-2

Chemical formula

[0096] R1, R2, R in the formula 2’ , L1, L 2、 and n are synonymous with R1, R2, R 2’ , L1, L 2、 and n in Production Method 2, respectively.

[0097] R5 in the formula is a C1-C6 alkyl group or an aromatic ring which may have a substituent. Such R5 includes, for example, methyl, ethyl, phenyl, etc.

[0098] This Step C (addition ring-opening reaction) is a step of producing an O-substituted serine derivative (Id) by subjecting a cyclic sulfamidate derivative (II’d) to a nucleophilic substitution reaction with an alcohol derivative (III). This reaction can be carried out by stirring the reaction mixture for 1 hour to 48 hours at a temperature of -20°C to near the boiling point of the solvent, preferably 0°C to 180°C, in the presence or absence of a solubilizing co-solvent and in the presence or absence of an acidic salt.

[0099] The solubilizing co-solvent and the acidic salt can be the same as those of the solubilizing co-solvent and the acidic salt in Step C of Production Method 2, respectively. In this production method, as the solubilizing co-solvent, trifluoroethanol, hexafluoroisopropyl alcohol, dioxane, tetrahydrofuran, NMP, and as the acidic salt, NaH2PO4, KH2PO4, or CsH2PO4 are preferably used.

[0100] In one aspect, the compound of the present invention can be produced, for example, by Production Method 6 shown below. This production method is an embodiment of Production Method 2, and R of the compound of formula (II’) 2’ is a Boc group, and R4 is C(R5)3. Using the compound of formula (II’e) as a starting material, through Steps C to E, a method for producing the compound of formula (I’’e) is provided. Manufacturing Method 6

Chemical formula

[0101] R1, R2, R3, L1, L in the formula 2、 and n are synonymous with R1, R2, R3, L1, L 2、 and n in Production Method 2, respectively.

[0102] R5 in the formula is a C1-C6 alkyl or aromatic ring which may have a substituent. Such R5 includes, for example, methyl, ethyl, phenyl, etc.

[0103] Step C (addition ring-opening reaction) is a step of producing an O-substituted serine derivative (Ie) having a free amino group by subjecting an N-Boc cyclic sulfamidate derivative (II’e) to a nucleophilic substitution reaction with an alcohol derivative (III). This reaction can be carried out by stirring the reaction mixture for 1 hour to 48 hours at a temperature of -20°C to near the boiling point of the solvent, preferably 0°C to 180°C, in the presence or absence of a solubilizing co-solvent and in the presence or absence of an acidic salt.

[0104] As the auxiliary solvent for dissolution and the acidic salt, those same as the auxiliary solvent for dissolution and the acidic salt in Step C of Production Method 2 can be used respectively. In this production method, as the auxiliary solvent for dissolution, trifluoroethanol, hexafluoroisopropyl alcohol, dioxane, tetrahydrofuran, NMP are preferably used, and as the acidic salt, NaH2PO4, KH2PO4, or CsH2PO4 is preferably used.

[0105] Step D (deprotection reaction) is a step of producing an O-substituted serine derivative (I’e) having a free amino group and a free carboxyl group by deprotecting the protecting group (C(R5)3) of the carboxyl group of the O-substituted serine derivative (Ie). This reaction can be carried out by stirring the reaction mixture at a temperature of 0°C to near the boiling point of the solvent for 1 hour to 24 hours in the presence or absence of a metal catalyst, preferably a Pd catalyst, or an acid catalyst, and in the presence or absence of a hydrogen source.

[0106] As the metal catalyst, acid catalyst, hydrogen source, and solvent, those same as the metal catalyst, acid catalyst, hydrogen source, and solvent in Step D of Production Method 1 can be used respectively. In this production method, as the metal catalyst, for example, palladium carbon, palladium hydroxide on carbon (supported on a solid represented by activated carbon), palladium oxide, platinum oxide, Raney nickel, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium, palladium acetate, etc. are used. As the acid catalyst, for example, hydrochloric acid, hydrobromic acid, trifluoromethanesulfonic acid, sulfuric acid, etc. are used. As the hydrogen source, hydrogen gas, formic acid, or ammonium formate, etc. are used. As the solvent, short-chain alkyl alcohols such as methanol and ethanol, and acetate ester derivatives such as ethyl acetate and isopropyl acetate are preferably used.

[0107] Step E (reaction for introducing a protecting group) is a step of producing an O-substituted serine derivative (I’’e) having a free carboxyl group by introducing R3 (i.e., a protecting group for the amino group or an alkyl group) to the amino group of the O-substituted serine derivative (I’e).

[0108] When introducing a protecting group for the amino group, a carbamating agent is reacted with the α-amino group site of the O-substituted serine derivative (I’e). This reaction can be carried out by stirring the reaction mixture for 1 hour to 24 hours at a temperature of -10°C to near the boiling point of the solvent in the presence or absence of a base catalyst.

[0109] As the carbamating agent, base catalyst, and solvent, the same ones as those in the carbamating agent, base catalyst, and solvent in Step E of Production Method 2 can be used respectively. In this production method, as the carbamating agent, for example, Boc2O, BocOPh, FmocOSu, FmocCl, CbzCl, AllocCl, etc. are used, and as the base catalyst, for example, lithium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, cesium hydrogen carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium phosphate, potassium phosphate, N-methylmorpholine, triethylamine, diisopropylethylamine, N,N-dimethylaminopyridine, etc. are used, and as the solvent, acetonitrile, dichloromethane, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, NMP, etc. are preferably used.

[0110] When introducing an alkyl group, as described above, the method of Freidinger et al. (U.S. Patent No. 4535167), or the methods of Shimokawa et al. (Bioorg. Med. Chem. Lett., 2009, 19(1), 92-95) or Prashad et al. (Org. Lett., 2003, 5(2), 125-128) can be used.

[0111] In one aspect, the cyclic sulfamidate derivative (II) of the present invention used as the starting material in Step C of Production Method 1 can be produced by a method including the following Steps A and B using a known compound as the starting material.

Chemical formula

[0112] In the formula, R2 is a protecting group for a C1-C6 alkyl group or an amino group. Such R2 includes, for example, methyl, ethyl, benzyl, Fmoc, Boc, Cbz, or Alloc group, etc.

[0113] In the formula, R4 is a protecting group for a carboxyl group. Such R4 includes, for example, alkyls such as t-butyl, and trityl, cumyl, allyl, benzyl, etc.

[0114] In the formula, L1 is a single bond or -CH2-, and L2 is a single bond or -CH2-. Here, when L1 is -CH2-, L2 is a single bond, and when L2 is -CH2-, L1 is a single bond. That is, as combinations of L1 and L2, there are three cases: (i) L1 = single bond, L2 = single bond, (ii) L1 = -CH2-, L2 = single bond, (iii) L1 = single bond, L2 = -CH2-.

[0115] In the formula, n represents the number of methylene groups, and n is 1 or 2.

[0116] Step A is a step of cyclizing an α-amino acid (V) having a hydroxyl group using a cyclizing reagent to produce a cyclic sulfamidite derivative (IV). This reaction can be carried out by stirring the reaction mixture for 1 hour to 24 hours at a temperature of -40°C to 25°C, preferably -40°C to 0°C, in the presence or absence of a solvent and in the presence or absence of a base.

[0117] Specific examples of the cyclizing reagent include thionyl chloride, sulfuryl chloride, etc., and thionyl chloride is preferably used. Also, 1.5 to 5 equivalents of the cyclizing reagent can preferably be used with respect to the starting material.

[0118] Examples of the solvent include ethyl acetate, isopropyl acetate, butyl acetate, dichloromethane, acetonitrile, etc.

[0119] Examples of the base include pyridine, TEA, DIPEA, etc., and pyridine can be preferably used.

[0120] Step B is a step of oxidizing the sulfur atom in the ring of the cyclic sulfamidite derivative (IV) to sulfone using an oxidizing agent to produce the cyclic sulfamidate derivative (II). This reaction can be carried out by stirring the reaction mixture at a temperature of -20°C to 25°C for 1 hour to 24 hours in the presence or absence of a solvent.

[0121] Specific examples of the oxidizing agent include hydrogen peroxide, organic peracids, persulfates, halogen oxide salts, or a combination of a halogen oxide salt and a transition metal catalyst. Among these, a combination of 3-chloroperbenzoic acid, Oxone, and a combination of a periodate salt and a ruthenium catalyst is preferably used. As the periodate salt, more specifically, sodium periodate or potassium periodate can be preferably used. As the ruthenium catalyst, more specifically, ruthenium(III) chloride anhydride or ruthenium(III) chloride hydrate is preferably used. When a combination of a periodate salt and a ruthenium catalyst is used as the oxidizing agent, 1.5 to 5 equivalents of the periodate salt and 0.01 to 0.2 equivalents of the ruthenium catalyst are preferably used relative to the starting material.

[0122] As the solvent, preferably, acetonitrile, water, ethyl acetate, isopropyl acetate, and combinations thereof are used, and a mixed solvent of acetonitrile and water is more preferably used.

[0123] In one aspect, the cyclic sulfamidate derivative (II') of the present invention used as the starting material in Step C of Production Method 2 can be produced by a method including the following Steps A and B using a known compound as the starting material.

Chemical formula

[0124] R in the formula 2’is a protecting group for an amino group. Such R 2’ includes, for example, Fmoc, Boc, Cbz, or Alloc group, etc.

[0125] R4 in the formula is a protecting group for a carboxyl group. Such R4 includes, for example, alkyls such as t-butyl, and trityl, cumyl, allyl, benzyl, etc.

[0126] L1 in the formula is a single bond or -CH2-, and L2 is a single bond or -CH2-. Here, when L1 is -CH2-, L2 is a single bond, and when L2 is -CH2-, L1 is a single bond. That is, as combinations of L1 and L2, there are three cases: (i) L1 = single bond, L2 = single bond, (ii) L1 = -CH2-, L2 = single bond, (iii) L1 = single bond, L2 = -CH2-.

[0127] n in the formula represents the number of methylene groups, and n is 1 or 2.

[0128] Step A is a step of cyclizing an α-amino acid (V') having a hydroxyl group using a cyclizing reagent to produce a cyclic sulfamidite derivative (IV'). This reaction can be carried out by stirring the reaction mixture at a temperature of -40°C to 25°C, preferably -40°C to 0°C, for 1 hour to 24 hours in the presence or absence of a solvent and in the presence or absence of a base.

[0129] Specific examples of the cyclizing reagent include thionyl chloride, sulfuryl chloride, etc., and thionyl chloride is preferably used. Also, 1.5 to 5 equivalents of the cyclizing reagent can be preferably used with respect to the starting material.

[0130] Examples of the solvent include ethyl acetate, isopropyl acetate, butyl acetate, dichloromethane, acetonitrile, etc.

[0131] Examples of the base include pyridine, TEA, DIPEA, etc., and pyridine can be preferably used.

[0132] Step B is a step of oxidizing a sulfur atom in the ring of the cyclic sulfamidite derivative (IV’) to a sulfone using an oxidizing agent to produce the cyclic sulfamidate derivative (II’). This reaction can be carried out by stirring the reaction mixture at a temperature of -20°C to 25°C for 1 hour to 24 hours in the presence or absence of a solvent.

[0133] Specific examples of the oxidizing agent include hydrogen peroxide, organic peracids, persulfates, halogenate salts, or a combination of a halogenate salt and a transition metal catalyst. Among these, a combination of 3-chloroperbenzoic acid, Oxone, a combination of a periodate salt and a ruthenium catalyst is preferably used. As the periodate salt, more specifically, sodium periodate or potassium periodate can be preferably used. As the ruthenium catalyst, more specifically, ruthenium(III) chloride anhydrous or ruthenium(III) chloride hydrate is preferably used. Further, when a combination of a periodate salt and a ruthenium catalyst is used as the oxidizing agent, 1.5 to 5 equivalents of the periodate salt and 0.01 to 0.2 equivalents of the ruthenium catalyst are preferably used relative to the starting material.

[0134] As the solvent, preferably, acetonitrile, water, ethyl acetate, isopropyl acetate, and combinations thereof are used, and a mixed solvent of acetonitrile and water is more preferably used.

[0135] In one aspect, the cyclic sulfamidate derivative (IId or IIe) used as the starting material in Step C can be produced by a method including the following Step A and Step B using a known compound as the starting material.

Chemical formula

[0136] R5 in the formula is a C1-C6 alkyl or aromatic ring which may have a substituent, and is preferably, for example, methyl, ethyl, phenyl, etc.

[0137] In the formula, L1 is a single bond or -CH2-, and L2 is a single bond or -CH2-. Here, when L1 is -CH2-, L2 is a single bond, and when L2 is -CH2-, L1 is a single bond. That is, as combinations of L1 and L2, there are three cases: (i) L1 = single bond, L2 = single bond; (ii) L1 = -CH2-, L2 = single bond; (iii) L1 = single bond, L2 = -CH2-.

[0138] In the formula, n represents the number of methylene groups, and n is 1 or 2.

[0139] Step A is a step of cyclizing an α-amino acid (Vd) or (Ve) having a hydroxyl group using a cyclizing reagent to produce a cyclic sulfamidite derivative (IVd) or (IVe). This reaction can be carried out by stirring the reaction mixture for 1 hour to 24 hours at a temperature of -40°C to 25°C, preferably -40°C to 0°C, in the presence or absence of a solvent and in the presence or absence of a base.

[0140] Step B is a step of oxidizing the sulfur atom in the ring of the cyclic sulfamidite derivative (IVd) or (IVe) to a sulfone using an oxidizing agent to produce a cyclic sulfamidate derivative (IId) or (IIe). This reaction can be carried out by stirring the reaction mixture for 1 hour to 24 hours at a temperature of -20°C to 25°C in the presence or absence of a solvent.

[0141] In steps A and B, the reactions can be carried out using the cyclizing reagent, oxidizing agent, solvent, and base as described above respectively. Also, the obtained cyclic sulfamidate derivative (IId) or (IIe) can be used as a starting material not only in production method 1 but also in production method 2. In this case, R2 in the formula is read as R 2’ and replaced.

[0142] Isolation and purification of the target compound obtained through the above-mentioned respective reaction steps can be carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatographies.

[0143] In addition, the compounds of the present invention and their chemically acceptable salts include all stereoisomers of the target compounds obtained through each of the above reaction steps (for example, enantiomers, diastereomers (including cis and trans geometric isomers)), racemates of the above isomers, and other mixtures. For example, the compounds of the present invention may have one or more asymmetric points in the above formulas (I), (I'), (I''), and the above formula (II), and the present invention includes racemic mixtures, diastereomer mixtures, and enantiomers of such compounds.

[0144] When the compound according to the present invention is obtained as a free form, the compound can be converted into the state of a salt, hydrate, or solvate that the compound may form according to a conventional method.

[0145] Also, when the compound according to the present invention is obtained as a salt, hydrate, or solvate of the compound, the compound can be converted into its free form according to a conventional method.

[0146] All prior art documents cited in this specification are incorporated herein by reference.

Examples

[0147] Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0148] High Performance Liquid Chromatography Conditions 1 Apparatus: UPLC ACQUITY manufactured by Waters; Column: BEH (1.7 μm, 2.1 mm I.D. x 50 mm, manufactured by Waters); Mobile phase: water (A) containing 0.05% trifluoroacetic acid and acetonitrile (B) containing 0.05% trifluoroacetic acid; Elution method: Stepwise solvent gradient elution from 5% B to 100% B (4.0 minutes), held at 100% B (0.5 minutes); Flow rate: 0.5 mL / min. Column temperature: 35 °C.

[0149] High Performance Liquid Chromatography Conditions 2 Apparatus: UPLC ACQUITY manufactured by Waters; Column: BEH (1.7 μm, 2.1 mm I.D. x 50 mm, manufactured by Waters); Mobile phase: Water containing 0.1% formic acid (A) and acetonitrile containing 0.1% formic acid (B); Elution method: Stepwise solvent gradient elution from 5% B to 100% B (4.0 minutes), held at 100% B (0.5 minutes); Flow rate: 0.5 mL / min. Column temperature: 25 °C.

[0150] High Performance Liquid Chromatography Conditions 3 Apparatus: UPLC ACQUITY manufactured by Waters; Column: CHIRALCELL OD-3R (3.0 μm, 4.6 mm I.D. x 50 mm, manufactured by Daicel); Mobile phase: Water containing 0.1% formic acid (A) and acetonitrile containing 0.1% formic acid (B); Elution method: Stepwise solvent gradient elution from 5% B to 100% B (4.0 minutes), held at 100% B (0.5 minutes); Flow rate: 1.5 mL / min. Column temperature: 25 °C.

[0151] High Performance Liquid Chromatography Conditions 4 Apparatus: UPLC ACQUITY manufactured by Waters; Column: CHIRALPAK IA-3 (3.0 μm, 4.6 mm I.D. x 50 mm, manufactured by Daicel); Mobile phase: Water containing 10 mM ammonium acetate (A) and methanol containing 10 mM ammonium acetate (B); Elution method: Stepwise solvent gradient elution from 5% B to 60% B (0.5 minutes), 60% B to 80% B (3.0 minutes), 80% B to 100% B (0.5 minutes), held at 100% B (0.5 minutes); Flow rate: 1.2 mL / min. Column temperature: 25 °C.

[0152] High Performance Liquid Chromatography Conditions 5 Apparatus: UPLC ACQUITY manufactured by Waters; Column: CHIRALPAK IG-3 (3.0 μm, 4.6 mm I.D. x 50 mm, manufactured by Daicel); Mobile phase: water (A) containing 10 mM ammonium acetate and methanol (B) containing 10 mM ammonium acetate; Elution method: Stepwise solvent gradient elution of 5% B to 60% B (0.1 minute), 60% B to 100% B (3.4 minutes), and held at 100% B (1.0 minute); Flow rate: 1.2 mL / min. Column temperature: 25 °C.

[0153] 1 The 1H-NMR spectrum was measured using an AVANCE III HD 400 BBFO-SMART probe (manufactured by Bruker). The chemical shift of Me4Si used as the internal standard substance was set to 0 ppm, and the deuterium lock signal from the sample solvent was referenced. The chemical shifts of the signals of the compound to be analyzed were expressed in ppm. The abbreviations for signal splitting were expressed as s = singlet, brs = broad singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, m = multiplet, and the splitting width of the signal was expressed as the J value (Hz). The integral value of the signal was calculated based on the ratio of the signal area intensities of each signal.

[0154] Production example using Boc-Ser-OBzl as the starting material Example 1: Benzyl (4S)-5-tert-butoxycarbonyl-1,2,5-sulfamidate-4-carboxylate

Chemical formula

[0155] 2) A solution consisting of 23.9 g of the crude product of (4S)-5-t-butoxycarbonyl-1,2,5-sulfamiditecarboxylic acid benzyl and 100 mL of acetonitrile was cooled to 0°C, and a solution consisting of 21.7 g (101 mmol) of sodium periodate, 0.14 g (0.68 mmol) of ruthenium chloride hydrate, and 300 mL of water was added dropwise over 8 minutes. After stirring at the same temperature for 22 minutes, the mixture was stirred at room temperature for 1 hour. After adding 60 mL of 10% aqueous sodium carbonate, 100 mL of water, and 220 mL of ethyl acetate to the reaction mixture, it was separated into an organic layer and an aqueous layer. After adding 100 mL of ethyl acetate to the obtained aqueous layer again, it was separated into an organic layer and an aqueous layer. The obtained organic layers were combined and washed with 200 mL of 10% saline, and then concentrated under reduced pressure to obtain 22.3 g of (4S)-5-t-butoxycarbonyl-1,2,5-sulfamidatecarboxylic acid benzyl as a crude product.

[0156] 3) A mixture consisting of 22.3 g of the crude purified product of (4S)-5-t-butoxycarbonyl-1,2,5-sulfamidatocarboxylic acid benzyl and 70 mL of ethyl acetate was heated to 50 °C. After adding 280 mL of hexane to the solution and the precipitate appeared, it was stirred at room temperature for 2 hours, and the precipitate was collected by filtration under reduced pressure. The obtained crystals were dried under reduced pressure to obtain 19.8 g of (4S)-5-t-butoxycarbonyl-1,2,5-sulfamidatocarboxylic acid benzyl (yield: 81.6% in two steps) as white crystals.

[0157] (4S)-5-tert-butoxycarbonyl-1,2,5-sulfamidate-4-carboxylic acid benzyl

Chemical formula

[0158] Example 2: Fmoc-Ser(n-Pr)-OH

Chemical formula

[0159] H-Ser(n-Pr)-OBzl

Chem.

[0160] 2) A mixture of 0.6 g of 10% palladium on carbon and 30 mL of methanol was added to an ethyl acetate solution of H-Ser(n-Pr)-OBzl, and then stirred at room temperature for 2 hours under a hydrogen gas atmosphere. The palladium catalyst was filtered off under reduced pressure using celite, and the resulting mixture was concentrated under reduced pressure to obtain 7.82 g of H-Ser(n-Pr)-OH as a crude product.

[0161] 3) A solution consisting of 7.82 g of H-Ser(n-Pr)-OH, 96 mL of water, and 4.80 g (45.2 mmol) of sodium carbonate was cooled to 0 °C, and a solution consisting of 4.00 g (11.8 mmol) of FmocOSu and 96 mL of acetonitrile was added dropwise over 5 minutes. After stirring at room temperature for 24 hours, 48 mL of 2N-hydrochloric acid and 48 mL of water were added to the reaction mixture over 10 minutes. After the precipitate appeared, the mixture was stirred at room temperature for 2 hours. 24 mL of water was added to the reaction mixture, and the mixture was stirred for 1 hour. After adding another 24 mL of water and stirring for 2 hours, the precipitate was collected by filtration under reduced pressure. The obtained crystals were dried under reduced pressure to obtain 3.60 g of Fmoc-Ser(n-Pr)-OH (yield: 58.4% over 3 steps) as white crystals.

[0162] Fmoc-Ser(n-Pr)-OH

Chem.

[0163] Example 3: Fmoc-Ser(i-Pr)-OH

Chem.

[0164] H-Ser(i-Pr)-OBzl

Chem.

[0165] 2) A mixture of 0.15 g of 10% palladium on carbon and 5 mL of methanol was added to an ethyl acetate solution of H-Ser(i-Pr)-OBzl, and the mixture was stirred at room temperature for 2 hours under a hydrogen gas atmosphere. The palladium catalyst was filtered off under reduced pressure using celite, and the resulting mixture was concentrated under reduced pressure to obtain 842 mg of H-Ser(i-Pr)-OH as a crude product.

[0166] 3) A solution consisting of 842 mg of H-Ser(i-Pr)-OH, 6 mL of water, and 0.31 g (2.9 mmol) of sodium carbonate was cooled to 0 °C, and a solution consisting of 0.66 g (2.0 mmol) of FmocOSu and 6 mL of acetonitrile was added dropwise over 2 minutes. After stirring at room temperature for 3 hours, 10 mL of 1N hydrochloric acid was added dropwise to the reaction mixture over 5 minutes until a precipitate appeared, and then the mixture was stirred at room temperature for 3 hours. After stirring the reaction mixture for 3 hours, the precipitate was collected by filtration under reduced pressure. The obtained crystals were dried under reduced pressure to obtain 667 mg of Fmoc-Ser(i-Pr)-OH (yield: 63.5% over 3 steps) as white crystals.

[0167] Fmoc-Ser(i-Pr)-OH

Chemical formula

[0168] Example 4: H-Ser(2-hydroxy-2-methylpropyl)-OBzl

Chemical formula

[0169] H-Ser(2-hydroxy-2-methylpropyl)-OBzl

Chemical Structure

[0170] Example 5: H-Ser(n-Bu)-OBzl

Chemical Structure

[0171] H-Ser(n-Bu)-OBzl

Chemical Structure

[0172] Example 6: H-Ser(3-methylbutyl)-OBzl [Chemistry] A mixture consisting of 25 mg (0.07 mmol) of benzyl (4S)-5-t-butoxycarbonyl-1,2,5-sulfamidatocarboxylate and 0.50 mL of 3-methylbutanol was stirred for 24 hours while heating to 80 °C, and the reaction mixture was analyzed using HPLC.

[0173] H-Ser(3-methylbutyl)-OBzl [Chemistry] UV intensity ratio: 73.9% (detection wavelength 205 nm, retention time 2.00 minutes, HPLC condition 1) ESI (LC / MS positive mode) m / z: 266.52 (M+H + )

[0174] Example 7: Benzyl (4S)-1,2,5-sulfamidate-4-carboxylate [Chemistry] A mixture consisting of 1.00 g (2.8 mmol) of (4S)-5-t-butoxycarbonyl-1,2,5-sulfamidatocarboxylic acid benzyl ester and 10 mL of 2,2,2-trifluoroethanol was stirred for 4 hours while heating to 70 °C. After adding 20 mL of ethyl acetate and 40 mL of 5% brine to the reaction mixture, it was separated into an organic layer and an aqueous layer. The organic layer was concentrated under reduced pressure to obtain 734 mg of benzyl (4S)-1,2,5-sulfamidatocarboxylate as a crude product. The obtained crude product was purified by silica gel column chromatography (elution solvent: ethyl acetate - hexane) to obtain 649 mg (yield: 90.2%) of benzyl (4S)-1,2,5-sulfamidatocarboxylate as a pale yellow solid.

[0175] (4S)-1,2,5-sulfamidate carboxylic acid benzyl [Chemistry] UV intensity ratio: 99.6% (detection wavelength 205 nm, retention time 1.94 minutes, HPLC condition 1) 1 H-NMR (CDCl3, 400 MHz) δ: 4.44 - 4.52 (1H, m), 4.56 (1H, dd, J = 8.8, 5.6), 4.74 (1H, dd, J = 8.8, 7.6), 5.09 - 5.18 (1H, m), 5.27 (1H, d, J = 11.6), 5.30 (1H, d, J = 11.6), 7.32 - 7.44 (5H, m)

[0176] Production example using D-Boc-Ser-OBzl as the starting material Example 8: Benzyl (4R)-5-tert-butoxycarbonyl-1,2,5-sulfamidate-4-carboxylate

Chemical formula

[0177] 2) A solution consisting of 10.76 g of the crude purified product of (4R)-5-t-butoxycarbonyl-1,2,5-sulfamiditecarboxylic acid benzyl and 160 mL of acetonitrile was cooled to 0 °C, and a solution consisting of 10.7 g (50 mmol) of sodium periodate, 62 mg (0.30 mmol) of ruthenium chloride hydrate, and 160 mL of water was added dropwise over 15 minutes. The mixture was stirred at the same temperature for 2 hours. 160 mL of 5% aqueous sodium hydrogen carbonate and 160 mL of ethyl acetate were added to the reaction mixture, and then the organic layer and the aqueous layer were separated. After adding 160 mL of ethyl acetate again to the obtained aqueous layer, the organic layer and the aqueous layer were separated. The combined obtained organic layers were washed with 160 mL of 10% brine and then concentrated under reduced pressure to obtain 10.44 g of (4R)-5-t-butoxycarbonyl-1,2,5-sulfamidatecarboxylic acid benzyl as a crude purified product.

[0178] 3) A mixture consisting of 10.44 g of the crude purified product of (4R)-5-t-butoxycarbonyl-1,2,5-sulfamidatecarboxylic acid benzyl and 30 mL of ethyl acetate was heated to 40 °C. After adding 120 mL of hexane to the solution and the precipitate appeared, the mixture was stirred at room temperature for 2 hours, and the precipitate was collected by filtration under reduced pressure. The obtained crystals were dried under reduced pressure to obtain 9.00 g (yield: 74.5% in two steps) of (4R)-5-t-butoxycarbonyl-1,2,5-sulfamidatecarboxylic acid benzyl as white crystals.

[0179] (4R)-5-tert-butoxycarbonyl-1,2,5-sulfamidate carboxylic acid benzyl [Chemical formula] Optical purity: 99.9% ee (detection wavelength 205 nm, retention time 2.93 minutes, HPLC condition 3) UV intensity ratio: 97.7% (detection wavelength 205 nm, retention time 2.77 minutes, HPLC condition 2) 11H-NMR (CDCl3, 400 MHz) δ: 1.49 (9H, s), 4.67 (1H, dd, J = 9.6, 2.2), 4.76 (1H, dd, J = 9.6, 6.4), 4.80 - 4.86 (1H, m), 5.23 (1H, d, J = 12.0), 5.32 (1H, d, J = 12.0), 7.30 - 7.42 (5H, m)

[0180] Example 9: Racemization of D-H-Ser(n-Pr)-OBzl [Chemical formula] 1) Reaction mixture: A mixture consisting of 1.00 g (2.8 mmol) of benzyl (4R)-5-t-butoxycarbonyl-1,2,5-sulfamidatocarboxylate and 20 mL of 1-propanol was stirred for 15 hours while heating to 90 °C, and the reaction mixture was analyzed using HPLC.

[0181] D-H-Ser(n-Pr)-OBzl [Chemical formula] Optical purity: 99.9% ee (detection wavelength 205 nm, retention time 2.54 minutes, HPLC condition 4) UV intensity ratio: 82.1% (detection wavelength 205 nm, retention time 1.40 minutes, HPLC condition 2)

[0182] 2) Ethyl acetate solution 1: 40 mL of ethyl acetate and 40 mL of 5% aqueous sodium hydrogen carbonate were added to the reaction mixture, and then the organic layer and the aqueous layer were separated. The obtained organic layer was analyzed using HPLC. Optical purity: 99.9% ee (detection wavelength 205 nm, retention time 2.55 minutes, HPLC condition 4) UV intensity ratio: 84.7% (detection wavelength 205 nm, retention time 1.42 minutes, HPLC condition 2)

[0183] 3) Ethyl acetate solution 2: The obtained ethyl acetate solution 1 was divided into two parts, and one of them was washed twice with 20 mL of 10% saline, and the obtained organic layer was analyzed using HPLC. Optical purity: 99.8% ee (detection wavelength 205 nm, retention time 2.55 minutes, high performance liquid chromatography condition 4) UV intensity ratio: 85.1% (detection wavelength 205 nm, retention time 1.42 minutes, high performance liquid chromatography condition 2)

[0184] 4) Crude purification product 1: The obtained ethyl acetate solution 2 was divided into two parts. One of them was concentrated under reduced pressure with a water bath set at 25 °C, and the obtained crude purification product of D-H-Ser(n-Pr)-OBzl was analyzed using HPLC. Optical purity: 82.8% ee (detection wavelength 205 nm, retention time 2.54 minutes, high performance liquid chromatography condition 4) UV intensity ratio: 79.7% (detection wavelength 205 nm, retention time 1.39 minutes, high performance liquid chromatography condition 2)

[0185] 5) Crude purification product 2: The other organic layer divided into two parts was concentrated under reduced pressure with a water bath set at 50 °C, and the obtained crude purification product of D-H-Ser(n-Pr)-OBzl was analyzed using HPLC. Optical purity: 72.6% ee (detection wavelength 205 nm, retention time 2.53 minutes, high performance liquid chromatography condition 4) UV intensity ratio: 79.1% (detection wavelength 205 nm, retention time 1.39 minutes, high performance liquid chromatography condition 2)

[0186] Example 10: Optical Purity Stability of D-H-Ser(n-Pr)-OBzl 1) The two types of ethyl acetate solutions produced in Example 9 were allowed to stand at room temperature for 3 days and analyzed using HPLC. Ethyl acetate solution 1: Optical purity: 91.5% ee (detection wavelength 205 nm, retention time 2.54 minutes, high performance liquid chromatography condition 4) Ethyl acetate solution 2: Optical purity: 94.7% ee (detection wavelength 205 nm, retention time 2.54 minutes, high performance liquid chromatography condition 4)

[0187] 2) The two ethyl acetate solutions prepared in Example 9 were allowed to stand at room temperature for 5 days and analyzed using HPLC. Ethyl acetate solution 1: Optical purity: 85.6% ee (detection wavelength 205 nm, retention time 2.56 minutes, HPLC condition 4) Ethyl acetate solution 2: Optical purity: 88.9% ee (detection wavelength 205 nm, retention time 2.55 minutes, HPLC condition 4)

[0188] 3) The two ethyl acetate solutions prepared in Example 9 were allowed to stand at room temperature for 10 days and analyzed using HPLC. Ethyl acetate solution 1: Optical purity: 76.8% ee (detection wavelength 205 nm, retention time 2.55 minutes, HPLC condition 4) Ethyl acetate solution 2: Optical purity: 82.9% ee (detection wavelength 205 nm, retention time 2.54 minutes, HPLC condition 4)

[0189] Example 11: D-Fmoc-Ser(n-Pr)-OH

Chemical formula

[0190] 2) A solution consisting of 845 mg of D-H-Ser(n-Pr)-OH, 8 mL of water, and 0.40 g (3.77 mmol) of sodium carbonate was cooled to 0 °C, and a solution consisting of 337 mg (1.00 mmol) of FmocOSu and 8 mL of acetonitrile was added dropwise over 5 minutes. After stirring at room temperature for 3 hours, 8 mL of 1N-hydrochloric acid was added to the reaction mixture. After a precipitate appeared, the mixture was stirred at room temperature for 1 hour and 20 minutes. 2 mL of 0.1N-hydrochloric acid was added to the reaction mixture, and after stirring for an additional 1 hour and 20 minutes, the precipitate was collected by filtration under reduced pressure. The obtained crystals were dried under reduced pressure to obtain 3.60 g of D-Fmoc-Ser(n-Pr)-OH (yield: 58.4% over 3 steps) as white crystals.

[0191] D-Fmoc-Ser(n-Pr)-OH

Chemical formula

[0192] Example 12: D-Fmoc-Ser(i-Pr)-OH

Chemical formula

[0193] D-H-Ser(i-Pr)-OBzl

Chemical formula

[0194] 2) A mixture of 15 mg of 10% palladium on carbon and 1 mL of methanol was added to the ethyl acetate solution of D-H-Ser(i-Pr)-OBzl, and then it was stirred at room temperature for 1 hour under a hydrogen gas atmosphere. The palladium catalyst was filtered off under reduced pressure using celite, and the resulting mixture was concentrated under reduced pressure to obtain 27 mg of D-H-Ser(i-Pr)-OH as a crude product.

[0195] 3) A solution consisting of 27 mg of D-H-Ser(i-Pr)-OH, 0.5 mL of water, and 25 mg (0.235 mmol) of sodium carbonate was cooled to 0 °C, and a solution consisting of 33 mg (0.098 mmol) of FmocOSu and 0.5 mL of acetonitrile was added dropwise over 2 minutes. After stirring at room temperature for 5 hours, 10 mL of 1N hydrochloric acid was added dropwise over 5 minutes to the reaction mixture until a precipitate appeared, then it was stirred at room temperature for 2 hours, and the reaction mixture was analyzed using HPLC.

[0196] D-Fmoc-Ser(i-Pr)-OH

Chemical formula

[0197] Example 13: D-H-Ser(2-hydroxy-2-methylpropyl)-OBzl

Chem.

[0198] D-H-Ser(2-hydroxy-2-methylpropyl)-OBzl

Chem.

[0199] Production example using Fmoc-Ser-OBzl as the starting material Example 14: Benzyl (4S)-5-(9-fluorenyl)methoxycarbonyl-1,2,5-sulfamidate-4-carboxylate

Chem.

[0200] 2) A solution consisting of 28.0 g of the crude product of benzyl (4S)-5-(9-fluorenyl)methoxycarbonyl-1,2,5-sulfamiditecarboxylate and 200 mL of acetonitrile was cooled to -10°C, and a solution consisting of 19.3 g (90 mmol) of sodium periodate, 0.12 g (0.6 mmol) of ruthenium chloride hydrate, and 300 mL of water was added dropwise over 15 minutes. After stirring at the same temperature for 15 minutes, the mixture was stirred at room temperature for 23 hours. After adding 100 mL of water and 300 mL of ethyl acetate to the reaction mixture, it was separated into an organic layer and an aqueous layer. The obtained organic layer was washed with 200 mL of 10% brine, and then concentrated under reduced pressure to obtain 28.7 g of a crude product of benzyl (4S)-5-(9-fluorenyl)methoxycarbonyl-1,2,5-sulfamidatecarboxylate.

[0201] 3) The obtained crude product was purified by silica gel column chromatography (elution solvent: ethyl acetate - hexane) to obtain 15.2 g (yield: 53.0% over two steps) of benzyl (4S)-5-(9-fluorenyl)methoxycarbonyl-1,2,5-sulfamidatecarboxylate as a white powder.

[0202] (4S)-5-(9-Fluorenyl)methoxycarbonyl-1,2,5-sulfamidatocarboxylic acid benzyl

Chemical formula

[0203] Example 15: Fmoc-Ser(i-Pr)-OBzl (with sodium dihydrogen phosphate added)

Chem.

[0204] Fmoc-Ser(i-Pr)-OBzl

Chem.

[0205] Fmoc-Ser(i-Pr)-O(i-Pr)

Chem.

[0206] Fmoc-Ser-OBzl

Chemical formula

[0207] 2) After adding a mixture of 0.10 g of 10% palladium on carbon and 4 mL of methanol to an ethyl acetate solution of Fmoc-Ser(i-Pr)-OBzl, the mixture was stirred at room temperature for 1 hour and 30 minutes under a hydrogen gas atmosphere. The palladium catalyst was filtered off under reduced pressure using celite, and the resulting mixture was concentrated under reduced pressure to obtain 0.80 g of Fmoc-Ser(i-Pr)-OH as a crude product.

[0208] Fmoc-Ser(i-Pr)-OH

Chemical formula

[0209] (3) A solution consisting of 0.80 g of Fmoc-Ser(i-Pr)-OH, 6 mL of water, 0.30 g (2.8 mmol) of sodium carbonate, and 2 mL of acetonitrile was stirred at room temperature for 3 hours. Then, 5 mL of ethyl acetate was added to the reaction mixture, and it was separated into an organic layer and an aqueous layer. The aqueous layer was obtained as an aqueous solution of Fmoc-Ser(i-Pr)-OH. After adding 6 mL of 1N-hydrochloric acid to the obtained aqueous solution of Fmoc-Ser(i-Pr)-OH and the precipitate appeared, it was stirred at room temperature for 4 hours. The precipitate was collected by filtration under reduced pressure, and the obtained wet powder was analyzed using HPLC.

[0210] Fmoc-Ser(i-Pr)-OH

Chemical formula

[0211] Example 16: Fmoc-Ser(i-Pr)-OBzl (without sodium dihydrogen phosphate added)

Chemical formula

[0212] Fmoc-Ser(i-Pr)-OBzl

Chemical formula

[0213] Fmoc-Ser(i-Pr)-O(i-Pr) [Chemical] UV intensity ratio: 1.93% (detection wavelength 205 nm, retention time 3.42 minutes, high-performance liquid chromatography condition 2)

[0214] Fmoc-Ser-OBzl [Chemical] UV intensity ratio: 21.6% (detection wavelength 205 nm, retention time 2.87 minutes, high-performance liquid chromatography condition 2)

[0215] Example 17: Fmoc-Ser(n-Pr)-OBzl (with sodium dihydrogen phosphate added) [Chemical] A mixture consisting of 50 mg (0.10 mmol) of benzyl (4S)-5-(9-fluorenyl)methoxycarbonyl-1,2,5-sulfamidatocarboxylate, 24 mg of sodium dihydrogen phosphate, 0.20 mL of 1-propanol, and 0.10 mL of 2,2,2-trifluoroethanol was stirred for 2 hours while heating to 70 °C, and the reaction mixture was analyzed using HPLC.

[0216] Fmoc-Ser(n-Pr)-OBzl [Chemical] UV intensity ratio: 81.3% (detection wavelength 205 nm, retention time 3.56 minutes, high-performance liquid chromatography condition 2)

[0217] Fmoc-Ser(n-Pr)-O(n-Pr) [Chemical] UV intensity ratio: 1.4% (detection wavelength 205 nm, retention time 3.46 minutes, high-performance liquid chromatography condition 2)

[0218] Fmoc-Ser-OBzl

Chem.

[0219] Example 18: Fmoc-Ser(n-Pr)-OBzl (without sodium dihydrogen phosphate added)

Chem.

[0220] Fmoc-Ser(n-Pr)-OBzl

Chem.

[0221] Fmoc-Ser(n-Pr)-O(n-Pr)

Chem.

[0222] Fmoc-Ser-OBzl

Chem.

[0223] Example 19: Fmoc-Ser(2-hydroxy-2-methylpropyl)-OBzl (without sodium dihydrogen phosphate added)

Chem.

[0224] Fmoc-Ser(2-hydroxy-2-methylpropyl)-OBzl

Chem.

[0225] Fmoc-Ser(2-hydroxy-2-methylpropyl)-OH

Chem.

[0226] Fmoc-Ser-OBzl

Chem.

[0227] Fmoc-Ser-OH

Chem.

[0228] Example 20: Fmoc-Ala(Cl)-OBzl

Chem.

[0229] Fmoc-Ala(Cl)-OBzl

Chem.

[0230] Production example using Fmoc-Ser-Ot-Bu as the starting material Example 21: (4S)-5-(9-Fluorenyl)methoxycarbonyl-1,2,5-sulfamidato-4-carboxylic acid tert-butyl

Chem.

[0231] 2) A solution consisting of 2.22 g of the crude product of tert-butyl (4S)-5-(9-fluorenyl)methoxycarbonyl-1,2,5-sulfamiditecarboxylate and 30 mL of acetonitrile was cooled to 0 °C, and a solution consisting of 1.67 g (7.8 mmol) of sodium periodate, 11 mg (0.05 mmol) of ruthenium chloride hydrate, and 30 mL of water was added dropwise over 5 minutes. After stirring at the same temperature for 1 hour 30 minutes, the mixture was stirred at room temperature for 20 minutes. After adding 60 mL of 5% NaHCO3, 60 mL of water, and 40 mL of ethyl acetate to the reaction mixture, it was separated into an organic layer and an aqueous layer. 40 mL of ethyl acetate was added to the obtained aqueous layer, and it was separated into an organic layer and an aqueous layer again. The combined obtained organic layers were washed with 30 mL of 10% brine, and then concentrated under reduced pressure to obtain 2.25 g of a crude product of tert-butyl (4S)-5-(9-fluorenyl)methoxycarbonyl-1,2,5-sulfamidatecarboxylate.

[0232] 3) The obtained crude product was purified by silica gel column chromatography (elution solvent: ethyl acetate - hexane) to obtain 1.87 g of tert - butyl (4S)-5-(9 - fluorenyl)methoxycarbonyl - 1,2,5 - sulfamidatocarboxylate (yield: 83.9% in two steps) as a white powder.

[0233] (4S)-5-(9-Fluorenyl)methoxycarbonyl-1,2,5-sulfamidatocarboxylic acid tert-butyl

Chem.

[0234] Production example using H - MeSer - OBzl as the starting material Example 22: (4S)-5-Methyl-1,2,5-sulfamidato-4-carboxylic acid benzyl

Chem.

[0235] 2) A solution consisting of 2.06 g of the crude product of benzyl (4S)-5-methyl-1,2,5-sulfamiditecarboxylate and 20 mL of acetonitrile was cooled to -5 °C, and a solution consisting of 3.21 g (15 mmol) of sodium periodate, 62 mg (0.3 mmol) of ruthenium chloride hydrate, and 30 mL of water was added dropwise over 5 minutes. After stirring at the same temperature for 5 minutes, the mixture was stirred at room temperature for 30 minutes. After adding 20 mL of water and 40 mL of ethyl acetate to the reaction mixture, it was separated into an organic layer and an aqueous layer. The obtained organic layer was washed with 20 mL of 10% brine, and then concentrated under reduced pressure to obtain 1.87 g of a crude product of benzyl 5-methyl-1,2,5-sulfamidatecarboxylate.

[0236] 3) A mixture consisting of the obtained crude product and 4 mL of ethyl acetate was heated to 40 °C, 12 mL of hexane was added to the solution, and after the precipitate appeared, the mixture was stirred at room temperature for 50 minutes, and the precipitate was collected by filtration under reduced pressure. The obtained crystals were dried under reduced pressure to obtain 1.14 g (yield: 42.0% in two steps) of benzyl (4S)-5-methyl-1,2,5-sulfamidatecarboxylate as pale yellow crystals. Optical purity: 99.9% ee (detection wavelength 205 nm, retention time 2.58 minutes, HPLC condition 3)

[0237] (4S)-5-Methyl-1,2,5-sulfamidatocarboxylic acid benzyl

Chemical formula

[0238] Example 23: H-MeSer(n-Pr)-OBzl

Chem.

[0239] Example 24: Fmoc-Ser(CH 2 CH(OH)CF 3 )-OH (with sodium dihydrogen phosphate added)

Chem.

[0240] Fmoc-Ser(CH 2 CH(OH)CF 3 )-OBzl [Chemical formula] UV intensity ratio: 50.9% (detection wavelength 205 nm, retention time 3.24 minutes, high performance liquid chromatography condition 2) ESI (LC / MS positive mode) m / z: 530.59 (M+H + )

[0241] 2) 20 mg of 10% palladium on carbon was added to the ethyl acetate solution of Fmoc-Ser(CH2CH(OH)CF3)-OBzl, and then stirred at room temperature for 3 hours under a hydrogen gas atmosphere to obtain an ethyl acetate solution of Fmoc-Ser(CH2CH(OH)CF3)-OH.

[0242] Fmoc-Ser(CH 2 CH(OH)CF 3 )-OH [Chemical formula] UV intensity ratio: 52.3% (detection wavelength 205 nm, retention time 2.52 minutes, high performance liquid chromatography condition 2) ESI (LC / MS negative mode) m / z: 438.39 (M−H +)

[0243] Example 25: Fmoc-Ser(Bzl)-OH (with sodium dihydrogen phosphate added)

Chem.

[0244] Fmoc-Ser(Bzl)-OH

Chem.

[0245] Fmoc-Ser(Bzl)-Ot-Bu

Chem.

[0246] Fmoc-Ser(Bzl)-OBzl

Chem.

[0247] Example 26: Fmoc-Ser(CH 2 -3F-C 6 H 4 )-OH (with sodium dihydrogen phosphate added)

Chem.

[0248] Fmoc-Ser(CH 2 -3F-C 6 H 4 )-OH

Chem.

[0249] Fmoc-Ser(CH 2 -3F-C 6 H 4 )-Ot-Bu

Chem.

[0250] Fmoc-Ser(CH2 -3F-C 6 H 4 )-OCH 2 -3F-C 6 H 4

Chem.

[0251] Example 27: Fmoc-Ser(CH 2 -2-thienyl)-OH (with sodium dihydrogen phosphate added)

Chem.

Chem.

[0252] Fmoc-Ser(CH 2 -2-thienyl)-Ot-Bu

Chem.

[0253] Example 28: Fmoc-Ser(CH 2 -2-furyl)-Ot-Bu (with sodium dihydrogen phosphate added)

Chem.

Chem.

[0254] Production example using Boc-homoSer-OBzl as the starting material Example 29: Benzyl (4S)-3-tert-butoxycarbonyl-2,2-dioxo-1,2,3-oxathiazinan-4-carboxylate

Chem.

[0255] 2) A solution consisting of 10.90 g of the crude purified product of benzyl (4S)-3-tert-butoxycarbonyl-2-oxo-1,2,3-oxathiadinane-4-carboxylate and 90 mL of acetonitrile was cooled to -10°C, and a solution consisting of 10.05 g (47.0 mmol) of sodium periodate, 195 mg (0.94 mmol) of ruthenium chloride hydrate, and 150 mL of water was added dropwise over 10 minutes. After stirring at -10°C for 15 minutes, the mixture was stirred at room temperature for 1 hour and 40 minutes. After adding 50 mL of water and 150 mL of ethyl acetate to the reaction mixture, it was separated into an organic layer and an aqueous layer. 40 mL of ethyl acetate was added to the obtained aqueous layer, and it was separated into an organic layer and an aqueous layer again. The obtained organic layer was washed with a mixture consisting of 20 mL of 2N HCl aqueous solution and 200 mL of 10% brine and then concentrated under reduced pressure to obtain 6.72 g of benzyl (4S)-3-tert-butoxycarbonyl-2,2-dioxo-1,2,3-oxathiadinane-4-carboxylate as a crude purified product.

[0256] 3) The obtained crude product was purified by silica gel column chromatography (elution solvent: ethyl acetate - hexane) to obtain 1.75 g of benzyl (4S)-3-t-butoxycarbonyl-2,2-dioxo-1,2,3-oxathiazinan-4-carboxylate (yield: 15.1% in two steps) as a white powder and 2.50 g of (S)-Boc-Gly(2-chloroethyl)-OBzl (yield: 22.5% in two steps) as a pale yellow powder.

[0257] (4S)-3-tert-butoxycarbonyl-2,2-dioxo-1,2,3-oxathiazinan-4-carboxylate benzyl

Chemical formula

[0258] (S)-Boc-Gly(2-chloroethyl)-OBzl

Chemical formula

[0259] Example 30: H-homoSer(n-Pr)-OH

Chem.

[0260] H-homoSer(n-Pr)-OBzl

Chem.

[0261] Example 31: H-homoSer(i-Pr)-OH

Chem.

[0262] H-homoSer(i-Pr)-OBzl [Chemical formula] UV intensity ratio: 84.2% (detection wavelength 205 nm, retention time 1.47 minutes, high-performance liquid chromatography condition 2) ESI (LC / MS positive mode) m / z: 252.60 (M+H + )

[0263] Example 32: H-homoSer(3-methylbutyl)-OBzl [Chemical formula] A mixture consisting of 50 mg (0.134 mmol) of benzyl (4S)-3-t-butoxycarbonyl-2,2-dioxo-1,2,3-oxathiazinan-4-carboxylate and 1 mL of 3-methylbutanol was stirred for 40 hours while heating to 80 °C, and then the reaction mixture was analyzed using HPLC.

[0264] H-homoSer(3-methylbutyl)-OBzl [Chemical formula] UV intensity ratio: 84.8% (detection wavelength 205 nm, retention time 1.84 minutes, high-performance liquid chromatography condition 2) ESI (LC / MS positive mode) m / z: 280.62 (M+H + )

[0265] Example 33: H-homoSer(2-hydroxy-2-methylpropyl)-OBzl [Chemical formula] (4S)-3-tert-Butoxycarbonyl-2,2-dioxo-1,2,3-oxathiazinan-4-carboxylic acid benzyl 50 mg (0.134 mmol) and 2-methylpropane-1,2-diol 1 mL were stirred for 40 hours while heating to 80 °C, and then the reaction mixture was analyzed using HPLC.

[0266] H-homoSer(2-hydroxy-2-methylpropyl)-OBzl

Chemical formula

[0267] Production example using Fmoc-Asp(Ot-Bu)-OL as the starting material Example 34: tert-Butyl (4S)-5-(9-fluorenyl)methoxycarbonyl-1,2,5-sulfamidate-4-acetate

Chemical formula

[0268] 2) A solution consisting of 4.65 g of the crude product of tert-butyl (4R)-5-(9-fluorenyl)methoxycarbonyl-1,2,5-sulfamidite-4-acetate and 20 mL of acetonitrile was cooled to -10°C, and a solution consisting of 3.21 g (15.0 mmol) of sodium periodate, 21 mg (0.1 mmol) of ruthenium chloride hydrate, and 60 mL of water was added dropwise over 10 minutes. After stirring at -20°C for 5 minutes, it was stirred at room temperature for 3 hours. 1.20 g (11.3 mmol) of sodium carbonate, 60 mL of water, and 90 mL of ethyl acetate were added to the reaction mixture, and then it was separated into an organic layer and an aqueous layer. The obtained organic layer was washed with a mixture consisting of 6.00 g (102 mmol) of NaCl and 54 mL of water, and then concentrated under reduced pressure to obtain 4.31 g of tert-butyl (4S)-5-(9-fluorenyl)methoxycarbonyl-1,2,5-sulfamidate-4-acetate as a crude product.

[0269] (4S)-5-(9-fluorenyl)methoxycarbonyl-1,2,5-sulfamidate-4-acetate tert-butyl

Chemical formula

[0270] Example 35: (3S)-3-(9-fluorenyl)methoxycarbonylamino-4-n-propoxybutyric acid (with sodium dihydrogen phosphate added)

Chemical formula

[0271] (3S)-3-(9-fluorenyl)methoxycarbonylamino-4-n-propoxybutyric acid

Chemical formula

[0272] (3S)-3-(9-fluorenyl)methoxycarbonylamino-4-n-propoxybutyric acid tert-butyl

Chemical formula

[0273] Example 36: (3S)-3-(9-fluorenyl)methoxycarbonylamino-4-i-propoxybutyric acid (with sodium dihydrogen phosphate added)

Chemical formula

[0274] (3S)-3-(9-Fluorenyl)methoxycarbonylamino-4-i-propoxybutyric acid

Chemical formula

[0275] (3S)-3-(9-Fluorenyl)methoxycarbonylamino-4-i-propoxybutyric acid tert-butyl

Chemical formula

[0276] Production example using (2S)-3-(9-fluorenyl)methoxycarbonylamino-2-hydroxymethylpropionic acid benzyl as the starting material Example 37: Benzyl (5S)-3-(9-fluorenyl)methoxycarbonyl-2,2-dioxo-1,2,3-oxathiazinane-5-carboxylate

Chemical formula

[0277] 2) A solution consisting of the above crude purification product of benzyl (5S)-3-((9H-fluoren-9-yl)methoxycarbonyl)-2,2-dioxo-1,2,3-oxathiazinane-5-carboxylate and 20 mL of acetonitrile is cooled to -10 °C, and a solution consisting of 3.21 g (15.0 mmol) of sodium periodate, 21 mg (0.1 mmol) of ruthenium(III) chloride hydrate, and 60 mL of water is added dropwise over 10 minutes. After stirring at -20 °C for 5 minutes, the mixture is stirred at room temperature for 3 hours. The reaction mixture is separated into an organic layer and an aqueous layer by adding 1.20 g (11.3 mmol) of sodium carbonate, 60 mL of water, and 90 mL of ethyl acetate. The obtained organic layer is washed with a mixture consisting of 6.00 g (102 mmol) of NaCl and 54 mL of water and then concentrated under reduced pressure to obtain benzyl (5S)-3-((9H-fluoren-9-yl)methoxycarbonyl)-2,2-dioxo-1,2,3-oxathiazinane-5-carboxylate as a crude purification product.

[0278] Example 38: Benzyl (2S)-2-(9-fluorenyl)methoxycarbonylaminomethyl-3-n-propoxypropionate (with sodium dihydrogen phosphate added)

Chemical Structure

[0279] Example 39: Benzyl (2S)-2-(9-fluorenyl)methoxycarbonylaminomethyl-3-i-propoxypropionate (with sodium dihydrogen phosphate added)

Chemical formula

[0280] Production example using (2R)-3-(9-fluorenyl)methoxycarbonylamino-2-hydroxymethylpropionic acid benzyl as the starting material Example 40: Benzyl (5R)-3-(9-fluorenyl)methoxycarbonyl-2,2-dioxo-1,2,3-oxathiazinane-5-carboxylate

Chemical formula

[0281] 2) A solution consisting of the above crude purified product of benzyl (5R)-3-((9H-fluoren-9-yl)methoxycarbonyl)-2,2-dioxo-1,2,3-oxathiazinane-5-carboxylate and 20 mL of acetonitrile is cooled to -10 °C, and a solution consisting of 3.21 g (15.0 mmol) of sodium periodate, 21 mg (0.1 mmol) of ruthenium(III) chloride hydrate, and 60 mL of water is added dropwise over 10 minutes. After stirring at -20 °C for 5 minutes, the mixture is stirred at room temperature for 3 hours. The reaction mixture is separated into an organic layer and an aqueous layer by adding 1.20 g (11.3 mmol) of sodium carbonate, 60 mL of water, and 90 mL of ethyl acetate. The resulting organic layer is washed with a mixture consisting of 6.00 g (102 mmol) of NaCl and 54 mL of water and then concentrated under reduced pressure to obtain benzyl (5R)-3-((9H-fluoren-9-yl)methoxycarbonyl)-2,2-dioxo-1,2,3-oxathiazinane-5-carboxylate as a crude purified product.

[0282] Example 41: Benzyl (2R)-2-(9-fluorenyl)methoxycarbonylaminomethyl-3-n-propoxypropionate (with sodium dihydrogen phosphate added)

Chemical formula

[0283] Example 42: Benzyl (2R)-2-(9-fluorenyl)methoxycarbonylaminomethyl-3-i-propoxypropionate (with sodium dihydrogen phosphate added)

Chemical formula

Industrial applicability

[0284] The present invention provides a novel method for producing O-substituted serine derivatives. By using the production method of the present invention, non-natural amino acids useful for the search for peptide pharmaceuticals and / or the supply of drug active ingredients can be provided with high regioselectivity, chemical yield, and optical purity.

Claims

1. A compound represented by the following structural formula (1) or (2), a chemically acceptable salt thereof, or a solvate thereof: 【Chemical 1】 (In formula (1) or (2), R １ is n-propyl or i-propyl, R ２ is a protecting group for hydrogen, C １ -C ６ alkyl or an amino group, R ４ (wherein R is hydrogen or a protecting group for a carboxyl group).

2. R ２ is hydrogen, a Boc group, a Fmoc group, a Cbz group or an Alloc group, and R ４ is hydrogen, benzyl or tert-Bu, the compound according to claim 1, its chemically acceptable salt, or a solvate thereof.

3. The compound according to claim 1 or 2, a chemically acceptable salt thereof, or a solvate thereof, selected from the following. [Chemical Formula 2]

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