Method for producing 3-(4'-aminophenyl)-2-methoxypropionic acid, as well as its analogs and intermediates.

Abstract

To provide a process for the preparation of 3-(4'-aminophenyl)-2-methoxypropionic acid, and analogs and intermediates thereof.SOLUTION: The disclosure provides a process for the preparation of 3-(4'-aminophenyl)-2-methoxypropionic acid, and analogs and intermediates thereof, which are considered capable of modulating the activity of receptors, e.g., PPAR receptors. In one embodiment, at least some of the compounds identified as intermediates, e.g., as part of a synthetic scheme disclosed herein are contemplated as compounds of the disclosure, e.g., a compound represented by Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof.SELECTED DRAWING: None

Description

[Background technology]

[0001] background Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily, which are ligand-activated transcription factors that regulate gene expression. Specific PPARs play a role in regulating cell differentiation, development, and metabolism in higher organisms.

[0002] Three types of PPARs have been identified: α is expressed in the liver, kidneys, heart, and other tissues and organs; β / δ is expressed in the brain, for example; and γ is expressed in three forms: γ1, γ2, and γ3. PPARγ receptors are associated with many disease conditions, including fibrous diseases, dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, eye disorders, IBD (irritable bowel disease), ulcerative colitis, and Crohn's disease.

[0003] Furthermore, treatment of tumor cells with PPARγ receptor ligands can induce decreased cell proliferation, cell differentiation, and apoptosis, and therefore may be useful in preventing carcinogenesis. The anti-inflammatory activity of the intestine may depend on the binding and subsequent activation of PPARγ receptors.

[0004] Therefore, effective methods for producing compounds that can modulate the activity of PPAR receptors are needed to address the treatment of such diseases. [Overview of the Initiative] [Means for solving the problem]

[0005] overview This disclosure provides, for example, a method for preparing compounds that may be modulators of PPAR receptors.

[0006] This disclosure relates, in part, to a compound of formula (VII): [ka] A method for preparing [the product] is provided.

[0007] One embodiment is a compound of formula (VI): [ka] This provides a method for preparing [the substance].

[0008] Methods for preparing these analogs and intermediates are also intended herein.

[0009] In one embodiment, as an intermediate, at least some of the compounds identified as part of the synthesis scheme disclosed herein are compounds of the disclosure, for example, compounds represented by formula (I): [ka] Alternatively, it is intended as a pharmaceutically acceptable salt or stereoisomer thereof. [Modes for carrying out the invention]

[0010] Detailed explanation Herein, we will describe in more detail the features and other details of this disclosure. Before further description of this disclosure, the specific terms used herein, in the examples and in the appended claims are summarized here. These definitions should be read in light of the remainder of this disclosure and should be understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0011] definition As used herein, the term "alkenyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon double bond, for example, C2-C2 in this specification. 12 Alkenyl, C2~C 10Alkenyls and C2-C6 alkenyls refer to linear or branched groups of 2-12, 2-10, or 2-6 carbon atoms. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and 4-(2-methyl-3-butene)-pentenyl.

[0012] As used herein, the term "alkoxy" refers to an alkyl group (-O-alkyl) bonded to oxygen. Exemplary alkoxy groups are C1-C113 12 This includes, but is not limited to, groups having alkyl, alkenyl, or alkynyl groups with 1 to 12, 1 to 8, or 1 to 6 carbon atoms, known as alkoxy, C1-C8 alkoxy, and C1-C6 alkoxy. Exemplary alkoxy groups include, but are not limited to, methoxy and ethoxy. Similarly, exemplary alkenoxy groups include, but are not limited to, vinyloxy, allyloxy, and butenoxy.

[0013] As used herein, the term "alkyl" refers to C1 to C1, respectively. 12 Alkyl, C1-C 10 Alkyl, C1-C6 alkyl, C 1~4 Alkyl and C 1~3 Alkyl groups refer to saturated linear or branched hydrocarbons, such as linear or branched groups of 1 to 12, 1 to 10, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3 -Methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc. are included, but not limited thereto. In certain embodiments, alkyl refers to C1-C6 alkyl. In certain embodiments, cycloalkyl refers to C3-C6 cycloalkyl.

[0014] Alkyl, alkenyl, and alkynyl groups, in some embodiments, may be optionally substituted with at least one group selected from alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amide, amidino, amino, aryl, arylalkyl, azide, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamide, sulfonyl, and thiocarbonyl, or may be optionally interrupted.

[0015] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon triple bond, e.g., herein, each C2-C 12 Refers to straight-chain or branched groups of 2-12, 2-8, or 2-6 carbon atoms called alkynyl, C2-C8 alkynyl, and C2-C6 alkynyl. Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl, etc., but are not limited thereto.

[0016] As used herein, the term "amide" or "amido" refers to -R a C(O)N(Rb )-,-R a C(O)N(R b )R c -or -C(O)NR b R c It refers to the base of the form, R a , R b and R c Each is independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocyclyl, and hydrogen. The amide is carbon, nitrogen, R b , R c or R a It can be bonded to another group via . Amides can also be cyclic, for example, R b and R c , R a and R b or R a and R c These can combine to form a 3- to 12-membered ring, for example, a 3- to 10-membered ring or a 5- to 6-membered ring.

[0017] As used herein, the term "amidino" refers to a group of the form -C(=NR)NR'R'', where R, R', and R'' can each be independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, and heterocyclyl.

[0018] As used herein, the terms "amine" or "amino" are -NR d R e , -N(R d )R e -or -R e N(R d )R f - refers to the base of the form, in the formula, R d , R e and R f The amino is independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. The amino is nitrogen, R d , R e or Rf It can be bonded to the parent molecule via R. Amino can also be cyclic, for example, R d , R e or R f Any two of these groups together or bonded to N can form a 3- to 12-membered ring, such as morpholino or piperidinyl. The term amino refers to the corresponding quaternary ammonium salt of any amino group, such as -[N(R d )(R e )(R f )] + It also includes R. An example of an amino group is R d , R e or R f It contains aminoalkyl groups in which at least one of the elements is an alkyl group.

[0019] As used herein, the term “aryl” refers to monocyclic, dicyclic, or other polycyclic aromatic ring systems. In certain embodiments, aryl refers to monocyclic and / or bicyclic 6- to 10-membered rings. Aromatic rings may be substituted at one or more ring positions with substituents selected from alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amide, amidino, amino, aryl, arylalkyl, azide, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamide, sulfonyl, and thiocarbonyl substituents. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbon atoms are common to two adjacent rings (these rings are "condensed rings"), and at least one of the rings is aromatic, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, and / or aryl. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azlenyl, and naphthyl, as well as benzo-condensed carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.

[0020] As used herein, the term “arylalkyl” refers to an aryl group having at least one alkyl substituent, e.g., arylalkyl. Exemplary arylalkyls include, but are not limited to, arylalkyls having a monocyclic aromatic ring system, the ring containing six carbon atoms. For example, “phenylalkyl” includes phenyl C4 alkyl, benzyl, 1-phenylethyl, 2-phenylethyl, and the like.

[0021] As used herein, the term "carbonyl" refers to the group -C(O)-.

[0022] As used herein, the term "carboxy" refers to the group -COOH or its corresponding salt, such as -COONa.

[0023] As used herein, the term "cyano" refers to the group -CN.

[0024] As used herein, the term "cycloalkyl" refers to a monovalent saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group derived from cycloalkanes, comprising 3 to 12, 3 to 8, 4 to 8, or 4 to 6 carbon atoms, and is used herein for example, "C 4~8These are called "cycloalkyl groups." Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclohexene, cyclopentane, cyclopentene, cyclobutane, and cyclopropane. Cycloalkyl groups can be substituted with alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amide, amidino, amino, aryl, arylalkyl, azide, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamide, sulfonyl, and thiocarbonyl groups. Cycloalkyl groups can be condensed with other cycloalkyl, aryl, or heterocyclyl groups. In certain embodiments, cycloalkyl refers to C3-C6 alkyl groups.

[0025] As used herein, the terms "halo" or "halogen" refer to F, Cl, Br, or I.

[0026] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms.

[0027] As used herein, the term "nitro" refers to the group -NO2.

[0028] As used herein, the term "phenyl" refers to a six-membered carbocyclic aromatic ring. The phenyl group may also be condensed to a cyclohexane or cyclopentane ring. Phenyl can be substituted with one or more substituents, including alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amide, amidino, amino, aryl, arylalkyl, azide, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamide, sulfonyl, and thiocarbonyl substituents.

[0029] As used herein, the term "phosphate" refers to the base-OP(O)(OR aa )2 or its anion. The term "phosphonate" refers to the group -P(O)(OR aa )2 or its anion. The term "phosphinate" refers to the group-PR aa (O)(OR aa ) or its anion, each R aa These can be selected from, for example, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, hydrogen, haloalkyl, heteroaryl, and heterocyclyl.

[0030] As used herein, the terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” refer to any solvent, dispersion medium, coating, isotonic agent, and absorption retarder, etc., that is suitable for pharmaceutically active administration. The use of such media and factors for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide supplementary, additional, or enhanced therapeutic function.

[0031] As used herein, the term “pharmaceutical composition” means a composition comprising at least one compound disclosed herein, formulated with one or more pharmaceutically acceptable carriers.

[0032] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of an acidic or basic group that may be present in the compounds used in this composition. Compounds in this composition that are basic in nature can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds include, but are not limited to, acids that form pharmaceutically acceptable anion-containing salts, including, non-toxic acid addition salts such as malates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, bisulfates, phosphates, acidic phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbicates, succinates, maleates, gentisinates, fumarates, glucons, glucurons, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds contained in this composition, including the amino portion, can form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Compounds contained in this composition that are acidic can form base salts with various pharmaceutically acceptable cations. Examples of such salts include salts of alkali metals or alkaline earth metals, particularly salts of calcium, magnesium, sodium, lithium, zinc, potassium, and iron.

[0033] The compounds of this disclosure may contain one or more stereocenters and / or double bonds, and therefore stereoisomers such as geometric isomers, enantiomers or diastereomers. They may exist as such. As used herein, the term “stereoisomer” encompasses all geometric isomers, enantiomers, or diastereomers. These compounds may be denoted by the symbols “R” or “S” depending on the arrangement of substituents around the chiral carbon atom. This disclosure encompasses various stereoisomers and mixtures thereof of these compounds. Stereoiomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be nominally denoted as “(±)”, but those skilled in the art will recognize that the structure may implicitly represent a chiral center.

[0034] The individual stereoisomers of the compounds disclosed herein can be prepared synthetically from commercially available starting materials containing asymmetric or stereocenters, or by the preparation of racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods include (1) binding of the enantiomer mixture to a chiral auxiliary, separation of the resulting diastereomer mixture by recrystallization or chromatography, and liberation of the optically pure product from the auxiliary, (2) salt formation using an optically active resolving agent, or (3) direct separation of the optical enantiomer mixture by chiral chromatography column. The stereoisomer mixture can also be separated into its component stereoisomers by well known methods such as chiral phase gas chromatography, chiral phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Stereoisomers can also be obtained from stereoisomerically pure intermediates, reagents, and catalysts by well known asymmetric synthesis methods.

[0035] Geometric isomers may also exist in the compounds of this disclosure. [ka] This refers to a bond that may be a single, double, or triple bond as described herein. This disclosure encompasses a variety of geometric isomers and mixtures thereof arising from the arrangement of substituents around a carbon-carbon double bond or a carbocyclic ring. Substituents around a carbon-carbon double bond are designated as being in a "Z" or "E" configuration, and the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures exhibiting a double bond encompass both "E" and "Z" isomers.

[0036] Alternatively, substituents around a carbon-carbon double bond can be described as "cis" or "trans," where "cis" refers to substituents on the same side of the double bond and "trans" refers to substituents on the opposite side. The arrangement of substituents around a carbocyclic ring is described as "cis" or "trans." The term "cis" refers to substituents on the same side of the ring's plane, and the term "trans" refers to substituents on the opposite side of the ring's plane. A mixture of compounds in which substituents are located on both the same and opposite sides of the ring's plane is described as "cis / trans."

[0037] The terms “substantially optically pure,” “substantially enantiomerically pure,” “optically pure,” or “enantiomerically pure,” as used herein when referring to a compound (for example, a compound described herein), mean that at least 95%, e.g., at least 96%, at least 97%, or at least 98% of the compound has the desired stereocenter in a given configuration. It will be understood that the percentage is expressed as the percentage of both enantiomers of the compound. For example, the compound of formula VII is substantially optically pure if, based on the sum of both the levorotatory and dextrorotatory enantiomers, at least 95% is (S)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid (the levorotatory enantiomer).

[0038] The compounds disclosed herein can exist in solvated and non-solvated forms with pharmaceutically acceptable solvents such as water and ethanol, and this disclosure applies to both solvated and non-solvated forms. It is intended to encompass both the compound and its combined form. In some embodiments, the compound is amorphous. In some embodiments, the compound is crystalline. In some embodiments, the compound is polymorphic.

[0039] This disclosure also includes isotope-labeled compounds of this disclosure that are identical to those enumerated herein, except that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that may be incorporated into the compounds of this disclosure are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, respectively. 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl is one example.

[0040] Specific isotope-labeled disclosed compounds (e.g., 3 H and 14 Compounds labeled with 1C are useful in compound and / or substrate tissue distribution assays. Tritiation (i.e., 3 H) and carbon-14 (i.e., 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, deuterium (i.e., 2 Substitution with heavier isotopes, such as H), may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced required dose), and may therefore be preferable in some situations. The isotope-labeled compounds of this disclosure can generally be prepared by replacing a non-isotopically labeled reagent with an isotope-labeled reagent, for example, by following a procedure similar to the one disclosed in the examples herein.

[0041] The term "prodrug" refers to a compound that is converted in vivo to produce the disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of said compound. Conversion can occur by various mechanisms, such as hydrolysis in the blood. For example, if the compound disclosed or a pharmaceutically acceptable salt, hydrate, or solvate of said compound contains a carboxylic acid functional group, the prodrug is a compound in which the hydrogen atoms of the acid group are (C1-C8) alkyl, (C2-C 12 ) Alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having 4-9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having 5-10 carbon atoms, alkoxycarbonyloxymethyl having 3-6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4-7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5-8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3-9 carbon atoms, having 4-10 carbon atoms This may include esters formed by substitution with groups such as 1-(N-(alkoxycarbonyl)amino)ethyl, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolactone-4-yl, di-N,N-(C1~C2)alkylamino(C2~C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1~C2)alkyl, N,N-di(C1~C2)alkylcarbamoyl-(C1~C2)alkyl, and piperidino-, pyrrolidino-, or morpholino(C2~C3)alkyl.

[0042] Similarly, if the compounds of this disclosure contain an alcohol functional group, then (C1~C6)alkanoyloxymethyl, 1-((C1~C6)alkanoyloxy)ethyl, 1-methyl-1-((C1~C6)alkanoyloxy)ethyl(C1~C6)alkoxycarbonyloxymethyl, N-(C1~C6)alkoxycarbonylaminomethyl, succinoyl, (C1~C6)alkanoyl, α-amino(C1~C4)alkanoyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl (where each α-aminoacyl group is independently selected from naturally occurring L-amino acids), P(O)(OH)2, -P(O)(O( C1 Prodrugs can be formed by substituting a hydrogen atom of an alcohol group with a group such as C6 alkyl 2 or glycosyl (a group resulting from the removal of a hydroxyl group from the hemiacetal form of a carbohydrate).

[0043] When the compounds disclosed herein incorporate amine functional groups, they are R-carbonyl, RO-carbonyl, NRR'-carbonyl (wherein R and R' are independently (C1~C 10 )alkyl, (C3~C7)cycloalkyl, benzyl, or R-carbonyl (natural α-aminoacyl or natural α-aminoacyl-natural aminoacyl), -C(OH)C(O)OY 1 (Y 1 (is H, (C1~C6) alkyl or benzyl), -C(OY 2 )Y 3 (Y 2 is (C1~C4) alkyl, Y 3 (C1~C6)alkyl, carboxy(C1~C6)alkyl, amino(C1~C4)alkyl or mono-N- or di-N,N-(C1~C6)alkylaminoalkyl), -C(Y 4 )Y 5 (Y 4 is H or methyl, Y 5Prodrugs can be formed by substituting a hydrogen atom in the amine group with a group such as mono-N- or di-N,N-(C1~C6)alkylamino, morpholino, piperidine-1-yl, or pyrrolidine-1-yl.

[0044] This disclosure provides compounds represented, at least in part, by formulas (I), (IV), (V), (VI), and (VII) shown below. Pharmaceutical compositions comprising the compounds represented by formulas (I), (IV), (V), (VI), and (VII), as well as, for example, pharmaceutically acceptable excipients and / or carriers, are also intended herein.

[0045] compound One example is a compound of formula (VII) that is substantially optically pure: [ka] A method for preparing, Compound of formula (I): [ka] This is reacted with an activator, if necessary, in the presence of a base, to obtain the intermediate of formula (IA): [ka] (In the formula, LG is a leaving group); To form, The intermediate of formula (IA) is treated with a base solution in the presence of an alcohol solvent to remove the Remove the desorbent group, thereby obtaining the intermediate of formula (IB): [ka] To form, The intermediate of formula (IB) is hydrolyzed to obtain the compound of formula (IV): [ka] To form, The compound of formula (IV) is hydrogenated to obtain the compound of formula (V): [ka] To form, If necessary, the compound of formula (V) is divided to obtain a substantially optically pure compound of formula (VI): [ka] To form, The compound of formula (VI) is acylated to form the compound of formula (VII), Methods including the above are provided herein.

[0046] Reacting the compound of formula (I) with an activator may involve reacting in the presence of a base and a solvent. In some embodiments, the solvent is selected from the group consisting of toluene, dichloromethane, tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, and acetonitrile, for example, the solvent may be toluene. The base may be an amine base selected from the group consisting of triethylamine, N,N-diisopropylethylamine, and pyridine, for example, the amine base may be triethylamine.

[0047] The compound of formula (I) may be a solid isolated prior to this step, or it may be dissolved in a suitable solvent, such as the solvent used for the preparation or post-processing of the compound of formula (I). For example, the compound of formula (I) may not be isolated and may be dissolved in an organic solvent, such as toluene, prior to this step. It is possible.

[0048] The intended activators include sulfonylated agents or halogenated agents. For example, the activator may be selected from the group consisting of methanesulfonyl chloride, p-toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, phenyltrifluimide, trifluoromethanesulfonic anhydride, and nonafluorobutanesulfonic anhydride. In some embodiments, the activator is methanesulfonyl chloride.

[0049] In some embodiments, the leaving group is -OSO2-aryl, -OSO2-C 1~4 Selected from the group consisting of alkyl, chloro, bromo, and iodine, in the formula, C 1~4 Alkyl and aryl groups may, as needed, be substituted with one or more substituents independently selected from the group consisting of fluoro, bromo, and -CH3, each time they appear. For example, the leaving group may be -OSO2-phenyl or -OSO2-C 1~4 It can be alkyl.

[0050] In some embodiments, the leaving group is selected from the following group: -OSO2Me, [ka] -OSO2CF3, [ka] and -OSO2CF2CF2CF2CF3, for example, The leaving group can be -OSO2Me.

[0051] The assumed alcohol solvent may include at least one of methanol, ethanol, isopropanol, and butanol. For example, the alcohol solvent may include methanol.

[0052] In some embodiments, the base solution comprises at least one of sodium hydroxide, lithium hydroxide, and potassium hydroxide. For example, the base solution may contain sodium hydroxide, for example, 30% sodium hydroxide.

[0053] In some embodiments, hydrolysis of the intermediate of formula (IB) to form the compound of formula (IV) includes contacting the intermediate of formula (IB) with an alkali hydroxide (e.g., sodium hydroxide) and water, and neutralizing it to form the compound of formula (IV). Neutralization may include acidifying the solution to a pH of less than 3 or equal to 3 by adding an acid, such as phosphoric acid or hydrochloric acid, or a mixture thereof.

[0054] In some embodiments, hydrogenating a compound of formula (IV) to form a compound of formula (V) involves contacting the compound of formula (IV) with hydrogen and a catalyst, for example, a catalyst selected from the group consisting of PtO2, Pd(OH)2 / C, Pt / C, 10% Pd / C, and 5% Pd / C, for example, a 5% Pd / C catalyst. The hydrogenation is carried out at approximately 60-80°C. The reaction temperature may be maintained during the process and the pressure may be between approximately 3–5 atm, approximately 3.5–4.5 atm, or approximately 4.0–4.5 atm. For example, hydrogenation may be carried out in the presence of one or more hydrogenation solvents selected from the group consisting of aqueous ammonia, methanol, ethanol, isopropanol, N,N-dimethylformamide, tetrahydrofuran, and ethyl acetate, such as aqueous ammonia, methanol, or N,N-dimethylformamide. In some embodiments, the hydrogenation solvent is methanol or a mixture of methanol and ammonia, such as a 30% aqueous ammonia solution.

[0055] After hydrogenation, the compound of formula (V) can be isolated, if necessary, by contacting the solution with an acid, such as acetic acid or hydrochloric acid, or a mixture thereof.

[0056] The act of dividing a compound of formula (V) to form a substantially optically pure compound of formula (VI) may include the following: a) To cleave the compound of formula (V) in the presence of a chiral acid, thereby forming a chiral salt of the compound of formula (VI), and b) Neutralizing the chiral salt of the compound of formula (VI) to form the compound of formula (VI).

[0057] In some embodiments, the chiral acid is selected from the group consisting of (S)-(+)-camphor-10-sulfonic acid, (2R,3R)-(+)-tartaric acid, (S)-(-)-malic acid, (1S)-(+)-3-bromocamphor-10-sulfonic acid, (S)-1-phenyltansulfonic acid, dibenzoyl-L-tartaric acid, glutamic acid, (1R,3S)-camphoric acid, (1S)-camfanic acid and (R)-(-)-mandelic acid, as well as all other chiral acids that can result in the separation of a racemic mixture or its enantiomer, such as (S)-(+)-camphor-10-sulfonic acid.

[0058] In some embodiments, the chiral salt of the compound of formula (VI) is [ka] That is the case.

[0059] In various embodiments, the division may further include adding a primer and maintaining a temperature of 30–35°C while stirring, and / or being carried out in the presence of acetone and water. In some embodiments, the division may further include maintaining a temperature of 55–60°C (e.g., 58°C) while stirring, and / or being carried out in the presence of acetone and water.

[0060] The initiator may be a substantially optically pure chiral salt of the compound of formula (VI). In some embodiments, the chiral acid is (S)-(+)-camphor-10-sulfonic acid.

[0061] For example, an initiator is [ka] It can be represented by:

[0062] If the specifications are not met at the end of the splitting process, a reprocessing step may be performed, in which the solution is maintained at the splitting temperature while being stirred for a longer period of time.

[0063] Neutralization may involve (i) contacting the chiral salt of the compound of formula (VI) with an aqueous solution of a base (e.g., ammonium hydroxide), and then (ii) acidifying the solution by adding an acid (e.g., acetic acid). Neutralization may occur in the presence of one or more solvents, for example, water and ethyl acetate.

[0064] Acylation may involve contacting the compound of formula (VI) with an acylating agent (e.g., acetic anhydride) in the presence of an organic solvent selected from the group consisting of ethyl acetate, tetrahydrofuran, diethyl ether, dichloromethane, and toluene, for example, ethyl acetate. Such acylation may occur at a temperature between 60 and 70°C, for example, between 65 and 70°C. The acylation may further involve dissolving the compound isolated from the previous step in one or more solvents, for example, water and / or ethyl acetate, to prepare a solution, and then contacting this solution with an acylating agent, for example, acetic acid. Such a step may be carried out at a temperature between 60 and 70°C, for example, between 65 and 70°C.

[0065] In some embodiments, after the compound of formula (V) is divided as needed to form a substantially optically pure compound of formula (VI), the mother liquor derived from the division step may still contain the desired enantiomer (as a salt of the dividing agent) along with the undesired enantiomer. In these embodiments, the division is a) Recover the enantiomer mixture (as a chiral salt of the resolving agent) from the mother liquor, neutralize the chiral salt to form the compound of formula (V), resolving the compound of formula (V) to provide a further substantially optically pure compound of formula (VI), thereby increasing the overall process yield, or b) Distill a portion of the mother liquor to precipitate the desired enantiomer from the mother liquor as a salt of the chiral resolving agent, thereby increasing the overall yield. This may further include as needed.

[0066] A method is also described herein for racemizing an undesirable enantiomer or its chiral salt in the presence of a base, and then dividing the resulting mixture of (R) and (S) enantiomers using the division method described herein to form the desired enantiomer.

[0067] The bases intended include those selected from the group consisting of hydroxides, alkoxides (e.g., methoxides), amides (e.g., lithium diisopropylamide), hydrides (e.g., NaH), organolithium, and Grignard reagents. For bases requiring counterions, the exemplary counterions intended herein may include alkali metals or alkaline earth metals, such as lithium, sodium, potassium, or calcium, or organic counterions, such as tetraalkylammonium.

[0068] In some embodiments, the compound of formula (VII) can be produced on a multi-kilogram scale, for example, yielding at least about 8-11 kg, about 13-15 kg, or about 130-150 kg. In some embodiments, at least about 130 kg of the compound of formula (VII) can be obtained.

[0069] In some embodiments, a substantially optically pure compound of formula (VII) is at least 98% of the desired enantiomer: [ka] (Expressed as a percentage of both enantiomers). In some embodiments, the content of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid may be 0.15% or less, for example, according to HPLC.

[0070] In another embodiment, a disclosed preparation of a substantially optically pure compound of formula (VII) includes acylating a racemic compound (V) to obtain a racemic mixture of 3-(4-acetamidophenyl)-2-methoxypropionic acid, and splitting the racemic 3-(4-acetamidophenyl)-2-methoxypropionic acid to provide a substantially enantiomerically pure compound of formula (VII). For example, forming a substantially optically pure compound of formula (VII) is a) Dividing a racemic mixture of 3-(4-acetamidophenyl)-2-methoxypropionic acid in the presence of a chiral base to form a chiral salt of the compound, and b) This may include neutralizing the chiral salt of the compound to form the compound of formula (VII).

[0071] In some embodiments, the chiral base is selected from the group consisting of, for example, enantiomerically pure 1-amino-2-propanol, brucine, dehydroabiethylamine, N,α-dimethylbenzylamine, N,N-dimethyl-1-phenylethylamine, ephedrine, α-methylbenzylamine, 1-(2-naphthyl)ethylamine, quinidine, quinine, strychnine, valine, and all other chiral bases that can result in the separation of racemic mixtures. For example, the chiral salt of a compound is, [ka] It can be represented by [this].

[0072] In certain embodiments, this disclosure relates to a compound of formula (I): [ka] A method for preparing, Compound of formula (II): [ka] and the compound of formula (III): [ka] To prepare the mixture, The present invention provides a method comprising contacting the aforementioned mixture with a base (for example, in a solvent such as tetrahydrofuran) to form a compound of formula (I).

[0073] Contact may be carried out at a temperature below or equal to 10°C, for example, involving stirring for about 5 minutes, and / or at a reaction temperature maintained between -10 and 10°C, for example between -5 and 0°C. The base may be an alkali metal alkoxide selected from the group consisting of sodium methoxide, lithium methoxide, and potassium methoxide, for example, sodium methoxide.

[0074] In some embodiments, [ka] Compounds represented by or pharmaceutically acceptable salts thereof, or stereoisomers thereof, are provided herein.

[0075] In some embodiments, the compound of formula (I) may exist as a mixture of stereoisomers. Examples of intended stereoisomers of formula (I) include the compounds of formula (a), formula (b), formula (c), or formula (d). [ka]

[0076] One example is a compound of formula (VI) that is substantially optically pure: [ka] A method for preparing, Compound of formula (I): [ka] This is reacted with an activator, if necessary, in the presence of a base, to obtain the intermediate of formula (IA): [ka] (In the formula, LG is a leaving group); To form, The intermediate of formula (IA) is treated with a base solution in the presence of an alcohol solvent to remove the leaving group, thereby obtaining the intermediate of formula (IB): [ka] To form, The intermediate of formula (IB) is hydrolyzed to obtain the compound of formula (IV): [ka] To form, The compound of formula (IV) is hydrogenated to obtain the compound of formula (V): [ka] To form, A method is also provided herein, comprising dividing the compound of formula (V) to form a substantially optically pure compound of formula (VI), wherein the method and variables are as defined herein.

[0077] Procedures for preparing the compounds described herein are provided below with reference to Schemes 1-21. In the reactions described below, it may be necessary to protect reactive functional groups (such as hydroxyl groups, amino groups, or carboxyl groups) to avoid their undesirable involvement in the reaction. The incorporation of such groups, as well as the methods required to introduce and remove such groups, are known to those skilled in the art (see, for example, Greene, Wuts, Protective Groups in Organic Synthesis 4th Ed. (2007)). The deprotection step is a protection step. The removal of the group may be the final step in the synthesis, giving the compound of formula I disclosed herein. The starting materials used in the following scheme are available for purchase or can be prepared by methods known to those skilled in the art, by methods described in the chemical literature, or by modifications thereof. The order in which the steps are carried out may vary depending on the group introduced and the reagents used, but will be obvious to those skilled in the art. [Examples]

[0078] The procedures disclosed herein can be carried out in numerous ways based on the teachings contained herein and synthetic procedures known in the art. In the descriptions of the synthetic methods described below, it should be understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected to be standard conditions for the reaction unless otherwise specified. Those skilled in the art of organic synthesis will understand that functional groups present in various parts of a molecule should be compatible with the proposed reagents and reactions. Substituents that are incompatible with the reaction conditions are obvious to those skilled in the art, and alternative methods are therefore shown. The starting materials for the examples are commercially available or readily prepared by standard methods from known materials.

[0079] As intermediates, for example, at least some of the compounds identified as part of the synthetic scheme disclosed herein are assumed to be compounds of this disclosure.

[0080] Abbreviations: General: APCI Atmospheric Pressure Chemical Ionization DSC Differential Scanning Calorimetry EA Elemental Analysis ESI Electrospray Ionization GC Gas Chromatography HPLC High Performance Liquid Chromatography ICP-AES Inductively Coupled Plasma Atomic Emission Spectroscopy LC Liquid Chromatography MHz Megahertz MS Mass Spectrometry NMR Nuclear Magnetic Resonance TLC Thin Layer Chromatography Me Methyl Ph Phenyl Et Ethyl Solvents and Reagents CSA Camphorsulfonic Acid DMF N,N-Dimethylformamide EtOAc Ethyl Acetate Mesyl Methanesulfonyl NaOMe Sodium Methoxide THF Tetrahydrofuran

[0081] General Experiments: 1H NMR spectra were recorded using a Varian Gemini 200 NMR spectrometer operating at 200 MHz or 600 MHz. Proton chemical shifts were reported in parts per million on the δ scale using the solvent residual peak (DMSO-d6: 2.50 ppm) as an internal standard. The data are presented as follows: chemical shift (δ), multiplicity 1 (s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, sx = sextet, sp = septet, m = multiplet, br = broad, dd = doublet of doublets, dt = doublet of triplets, qd = doublet of quartets, dquin = doublet of quintets), coupling constant (J, Hz) and integration (#H). (s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, sx = sextet, sp = septet, m = multiplet, br = broad, dd = doublet of doublets, dt = doublet of triplets, qd = doublet of quartets, dquin = doublet of quintets), coupling constant (J, Hz) and integration (#H).

[0082] 13 3C NMR was recorded by dissolving the sample in DMSO-d6 operating at 600 MHz. Fully decoupled spectra were obtained.

[0083] Mass spectra were recorded using a Thermo-Finnigan LCQ-Advantage mass spectrometer or MS Thermo LCQ-fleet. LC / MS data were obtained using positive / negative mode switching, or by analyzing the sample's quasi-molecular ions [MH]. - This was obtained using negative mode polarity with optimized acquisition parameters on the corresponding signal at 236 m / z.

[0084] Elemental analysis (CHN) was performed using a Carlo Erba EA 1108 instrument under the following conditions: Sample weight: 0.5-2 mg; Furnace temperature: 10-10°C; Column temperature: 80°C; Gas: He; Flow rate: 100 mL / min. Elemental analysis (oxygen) was performed using a Carlo Erba instrument under the following conditions. The procedure was performed using an Erba EA 1108 instrument: Sample weight: 0.5-2 mg; Furnace temperature: 10-10°C; Column temperature: 60°C; Gas: He; Flow rate: 100 mL / min.

[0085] FT-IR spectroscopy (FT-IR / ATR) is a Perkin spectroscopy method equipped with a diamond probe. The procedure was performed directly on the sample using the Elmer Spectrum Two spectrophotometer model. (450–4000 cm⁻¹) -1 Spectra were collected in the frequency range.

[0086] The UV-Vis spectrum is measured using a Shimadzu UV spectrophotometer operating under the following conditions. Recorded using 2600: Cuvette: Quartz 1cm; Range: 200~600nm; Scan speed: Medium; Scan step: 1nm; Slit width: 1.0nm; Reference solution: Methanol; Sample solution: 1mg of sample dissolved in 100mL of methanol.

[0087] DSC was performed using a Mettler-Toledo TGA-DSC1 instrument operating under the following conditions: pan: aluminum (open); heating rate: 10°C / min; gas: nitrogen; flow rate: 30 mL / min.

[0088] The specific rotation was determined as follows: 0.5 g of the sample was accurately weighed into a 50 mL volumetric flask, dissolved in methanol, and brought to a constant volume (concentration: 10 mg / mL, equivalent to 1% w / v). The rotation angle of the resulting solution was determined using a polarimeter tube with a path length equivalent to 1 dm. The specific rotation referenced to the dried substance was calculated using the following formula. [ka] The formula is calculated as follows: (α × 50 × 100) / (W × (100 - m)) (where α = reading rotation angle; W = sample weight (g); m = sample moisture content (%)). The chiral purity (HPLC) was determined as follows:

[0089] [Table 1A]

[0090] Solution preparation

[0091] - Sample solution: Accurately weigh 10 mg of the sample into a 10 mL volumetric flask, then dissolve it in the mobile phase and bring to a final volume (concentration: 1000 μg / mL).

[0092] - Reference solution: Accurately weigh 10 mg of (R,S)-3-(4-acetamidophenyl)-2-methoxypropionic acid standard into a 100 mL volumetric flask, then dissolve it in the mobile phase and bring to the final volume.

[0093] - System Suitability Test (SST) Solution: Accurately weigh 10 mg of (S)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid standard into a 10 mL volumetric flask, add 2 mL of the reference solution, then dissolve with the mobile phase and make up to the mark (final concentration of the dextrorotatory enantiomer: 10 μg / mL, corresponding to 1% relative to the sample solution and equivalent to the chiral purity of 99% of (S)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid).

[0094] System Suitability Test and Procedure

[0095] Inject 20 μL of the sample solution and the SST solution into the chromatograph and record the chromatogram.

[0096] The elution order of the main peaks is as follows. (R)-(+)-3-(4-acetamidophenyl)-2-methoxypropionic acid (dextrorotatory enantiomer): RRT = 0.9; and (S)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid (levorotatory enantiomer): RRT = 1.0

[0097] The chromatographic system can be used for the test when the h / v ratio is 1.5 or more, where h is the distance between the peak apex of the dextrorotatory enantiomer and the baseline, and v is the distance between the lowest point of the valley defined between the dextrorotatory enantiomer peak and the levorotatory enantiomer peak and the baseline.

[0098] The chiral purity % is calculated from the following formula: (A l × 100) / (A l + A d )(where A l = the peak area of (S)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid (levorotatory enantiomer) in the sample solution and A d = the peak area of (R)-(+)-3-(4-acetamidophenyl)-2-methoxypropionic acid (dextrorotatory enantiomer) in the sample solution).

[0099] The above method may be used to determine the optical purity or enantiomer purity of the compounds referred to herein.

[0100] [Example 1] Preparation of methyl(I) 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate Scheme 1 [ka] [Table 1]

[0101] Preparation of 4-nitrobenzaldehyde in methyl methoxyacetate and tetrahydrofuran suspension:

[0102] 4-nitrobenzaldehyde (50 kg), methyl methoxyacetate (55 kg), and tetrahydrofuran (100 kg) were added to a stainless steel reactor and cooled to -5 to +5°C while stirring.

[0103] Methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate (I Preparation of:

[0104] Nitrogen was flowed into a stainless steel reactor (twice), and sodium methoxide (30.0 kg) and tetrahydrofuran (75 kg) were added while flowing nitrogen. Next, nitrogen was flowed into the reactor for 1 minute, and the sodium methoxide solution was cooled to -10 to -5°C while stirring. Then, while maintaining the temperature of the reaction mixture below 10°C, the cooled solution was treated with a pre-prepared suspension of methyl methoxyacetate and 4-nitrobenzaldehyde in tetrahydrofuran. After the addition was complete, the empty reactor was rinsed with tetrahydrofuran (25.0 kg) and poured into the reaction mixture. The reaction mixture was stirred at -10 to +10°C for no more than 5 minutes. While maintaining the temperature at -10 to +10°C, cold toluene (100 kg, -10 to 0°C), followed by glacial acetic acid (50 kg), was slowly added, and the reaction mixture was stirred at -10 to +10°C for 10 minutes. Deionized water (150 kg) was added, and the reaction mass was stirred at 0-10°C for at least 10 minutes, then at 20-30°C for at least 10 minutes, until completely dissolved. After stirring was stopped, the phases were separated. The aqueous phase was removed, and the separated organic phase was treated with an aqueous sodium chloride solution (prepared by adding 10 kg of sodium chloride to 100 kg of deionized water). The mass was then heated to 50-60°C with stirring for at least 10 minutes. Stirring was stopped, and the phases were separated. The aqueous phase was removed, and the organic phase was treated with sodium chloride (prepared by adding 10 kg of sodium chloride to 100 kg of deionized water). The mass was extracted again using the same protocol. The separated organic phase was then distilled under vacuum without exceeding 80°C to remove THF. Nitrogen was passed through the reactor containing the hot residue, and then it was treated with toluene (50 kg), and the toluene was distilled under vacuum without exceeding 80°C. The resulting high-temperature residue was passed through with nitrogen, then treated with toluene (75 kg), and the mass was stirred at 30-45°C for at least 30 minutes to ensure good product precipitation. The mixture was then cooled to -10-0°C and stirred at that temperature for at least 1 hour. The resulting suspension was divided, centrifuged, and washed with cold toluene (25 kg) to obtain wet methyl(I) 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate (84 kg), which was used directly.

[0105] Methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate (I): IR: 3468, 1737, 1514, 1350, 1201, 1101 cm -1 LCMS(-)APCI:C 11 H 13 Calculated value for NO6 in m / z: 255, measured value: 254 (MHz); 1 H NMR (200 MHz, DMSO-d6): δ 8.16 (AA'BB' system, J = 8.8 Hz, 2 H), 7.62 (AA'BB' system, J = 8.8 Hz, 2 H), 5.97 (d, J = 6.0 Hz, 1 H), 5.05 (dd, J = 6.0, 4.0 Hz, 1 H), 4.10 (d, J = 4.0 Hz, 1 H), 3.60 (s, 3 H), 3.20 (s, 3 H); 13 C NMR (150 MHz, DMSO-d6): δ 170.2, 149.4, 146.7, 127.8, 122.9, 84.1, 72.7, 58.2, 51.6; UV-Vis (MeOH): λmax 202, 270;(C 11 H 13 Analytical calculation value for NO6): C 51.97; H 5.16; N 5.42; O 37.52.

[0106] [Example 2] Preparation of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) and (S)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid (VII) Scheme 2. [ka]

[0107] Preparation of 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV): Scheme 3. [ka] [Table 2]

[0108] In a stainless steel reactor circulated with nitrogen (twice), wet methyl(I) 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate (84 kg) and toluene (283 kg) were added, and the mixture was cooled to 0-10°C while circulating nitrogen. While maintaining the temperature at 0-10°C, triethylamine (42.3 kg) and methanesulfonyl chloride (36.3 kg) were added, and the reaction mixture was stirred at 0-10°C for 30 minutes. Deionized water (145 kg) was slowly added, and the resulting mass was stirred at 50-60°C for 10 minutes, after which stirring was stopped and the phases were separated. The aqueous phase was removed, the organic phase was filtered, and washed with toluene (7.3 kg). Toluene was removed by distillation under vacuum at temperatures not exceeding 60°C to obtain an oily residue. Next, the resulting residue was treated with methanol (218 kg), transferred to another reactor, and cooled to 20-30°C under a flow of nitrogen, and slowly treated with 30% sodium hydroxide (94 kg). The reaction mixture was stirred at 20-30°C for 2 hours. Deionized water (290 kg) was added, and the solution was heated to 55-65°C. At this temperature, 85% phosphoric acid (94 kg) was slowly added until the pH was ≤3.0. The resulting precipitate was stirred at 55-65°C for at least 30 minutes, then cooled to 25-30°C and stirred for at least 30 minutes. The mixture was centrifuged and washed with deionized water (36.3 kg), toluene (73 kg), and deionized water (145 kg). The product was granulated and dried at 70-80°C to obtain 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV) (50.4 kg).

[0109] 2-Methoxy-3-((methylsulfonyl)oxy)-3-(4-nitrophenyl)propanoate methyl(I-A1):LCMS(+)ESI:C 12 H 15 Calculated m / z value for NO8S: 333; Measured value: 356 (M+Na); 11H NMR (200 MHz, DMSO-d6): δ 8.25 (AA'BB' system, J = 8.5 Hz, 2 H), 7.72 (AA'BB' system, J = 8.5 Hz, 2 H), 6.00 (d, J = 4.0 Hz, 1 H), 4.41 (d, J = 4.0 Hz, 1 H), 3.65 (s, 3 H), 3.21 (s, 3 H), 3.11 (s, 3 H).

[0110] 2-Methoxy-3-(4-nitrophenyl)methyl acrylate (IB):LCMS(-)APCI:C 11 H 11 Calculated value for NO5 in m / z: 237, measured value: 236 (MH); 1 H NMR (200 MHz, DMSO-d6): δ 8.20 (AA'BB' system, J = 8.8 Hz, 2 H), 7.99 (AA'BB' system, J = 8.8 Hz, 2 H), 6.98 (s, 1 H), 3.80 (s, 3 H), 3.78 (s, 3 H).

[0111] 2-Methoxy-3-(4-nitrophenyl)acrylic acid (IV):LCMS(-)APCI:C 10 Calculated m / z value for H9NO5: m / z: 223, measured value: 222 (MH); 1 H NMR (200 MHz, DMSO-d6): δ 13.37 (s, 1 H), 8.21 (AA'BB' system, J = 9.1 Hz, 2 H), 7.98 (AA'BB' system, J = 9.1 Hz, 2 H), 6.93 (s, 1 H), 3.79 (s, 3 H).

[0112] Preparation of 3-(4-aminophenyl)-2-methoxypropanoic acid (V): Scheme 4. [ka] [Table 3]

[0113] N,N-dimethylformamide (17.2 kg), 5% palladium carbon (7.7 kg), and N,N-dimethylformamide (2 × 2.65 kg) were added to a suitable stainless steel reactor, and the suspension was thoroughly stirred.

[0114] Methanol (252 kg) was added to a stainless steel reactor that had been circulated with nitrogen (twice), cooled to 0-10°C, and dried 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV) (50.4 kg) was added. The resulting solution was circulated with nitrogen (twice) and treated with a pre-prepared solution of 5% palladium carbon in N,N-dimethylformamide, and the empty vessel was washed with N,N-dimethylformamide (2.65 kg). The reactants were circulated with nitrogen (twice) and heated to 60-80°C, then hydrogen was added until pressures of 3.5 and 4.5 atm were achieved. The reaction was allowed to proceed while maintaining a pressure of 3.5-4.5 atm until hydrogen consumption stopped and it was confirmed that the reaction was complete. The reactor was returned to atmospheric pressure, the reactants were cooled to 20-30°C, nitrogen was passed through (twice), and the mixture was sequentially treated with 30% ammonia (20.2 kg) and deionized water (12.6 kg), stirring at 20-30°C until completely dissolved. The solution was filtered through a sparkler filter washed with deionized water (25.2 kg). Nitrogen was passed through the reactor, and the solvent was removed by vacuum distillation at a temperature not exceeding 70°C. The residue was treated with deionized water (151 kg), heated to 60-70°C, and the product was precipitated by adding 80% acetic acid (25.2 kg). The mixture was stirred at 60-70°C for at least 10 minutes, then treated with ethyl acetate (50 kg), nitrogen was passed through, and the mixture was heated at 60-70°C for at least The mixture was stirred for 15 minutes. The reaction mixture was cooled to 10-20°C and stirred for at least 30 minutes. The suspension was divided, centrifuged, and washed with deionized water (101 kg) and ethyl acetate (25.2 kg). The wet product was granulated and dried at 60-70°C to obtain 3-(4-aminophenyl)-2-methoxypropanoic acid (V) (approximately 37.5 kg).

[0115] 3-(4-aminophenyl)-2-methoxyacrylate (IC):LCMS(+)ESI:C 10 H 11 Calculated value for NO3 in m / z: 193, measured value: 194 (M+H); 1 H NMR (200 MHz, DMSO-d6): δ 12.00 (br s, 1 H), 7.43 (AA'BB' system, J = 8.4 Hz, 2 H), 6.76 (s, 1 H), 6.53 (AA'BB' system, J = 8.4 Hz, 2 H), 5.80 (br s, 2 H), 3.61 (s, 3 H).

[0116] 3-(4-aminophenyl)-2-methoxypropanoic acid (V): IR: 3044, 2950-2830, 2623-2064, 1618-1516, 1106 cm -1 ;LCMS(+)ESI:C 10 H 13 NO3 Calculated value for m / z: 195, measured value: 196 (M+H); 1 H NMR (200 MHz, DMSO-d6): δ 8.40-6.40 (br s, 3 H), 6.83 (AA'BB' system, J = 8.1 Hz, 2 H), 6.41 (AA'BB' system, J = 8.1 Hz, 2 H), 3.77 (ABX system, J = 7.5, 5.3 Hz, (C 10 H 13 Analytical calculation values ​​for NO3): C 61.40; H 6.81; N 7.11; O 24.91

[0117] Preparation of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid S-(+)-camphor-10-sulfonate: Scheme 5. [ka] [Table 4]

[0118] While flowing nitrogen, 3-(4-aminophenyl)-2-methoxypropanoic acid (V) (37.5 kg) and acetone (113 kg) were added to a stainless steel reactor. Deionized water (15.0 kg) and (S)-(+)-camphor-10-sulfonic acid (46.2 kg) were added, and nitrogen was flowed into the reactor. The reaction mixture was heated to 45-55°C until dissolution was complete. Acetone (75 kg) was added, the solution was cooled to 30-35°C, and treated with the initiator (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid S-(+)-camphor-10-sulfonate (VI)·(S)-CSA (0.38 kg). The reaction mixture was stirred at 30-35°C for at least 3 hours until a good precipitate formed. The suspension was divided, centrifuged, and washed with acetone (75 kg). The centrifuged product (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid S-(+)-camphor-10-sulfonate (VI)·(S)-CSA (41.7 kg) was used directly in the next step.

[0119] Preparation of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI): Scheme 6. [ka] [Table 5]

[0120] Preparation of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI):

[0121] Deionized water (98 kg) and moistened ((S)-(-)-3- (4-aminophenyl)-2-methoxypropionic acid S-(+)-camphor-10-sulfonate (VI)·(S)-CSA (41.7 kg) was added, nitrogen was flowed through, and the mixture was heated at 20-30°C for at least 10 minutes until complete dissolution occurred. The solution was filtered and washed with deionized water (7.0 kg) and then ethyl acetate (35.0 kg). Nitrogen was flowed through the resulting solution and the mixture was heated to 50-60°C, and 30% ammonia (6.3 kg) was added to precipitate the product. The resulting mixture was stirred at 50-60°C for at least 5 minutes, then 80% acetic acid (4.38 kg) was added through a filter, nitrogen was flowed through the reactants, and the mixture was stirred at 50-60°C for at least 30 minutes, then cooled to 10-20°C and stirred for at least 1 hour. The reaction product was divided, centrifuged, washed with deionized water (17.5 kg), ethyl acetate (17.5 kg), and deionized water (17.5 kg), and dried at 50-60°C to obtain (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) (9.6 kg, 27%), which was used directly in the next step.

[0122] (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI):[α] D 20 -30~-26(1% w / v H2O / CH3OH(1:1 v / v));IR: 2931, 2891, 2826, 2625, 2136, 1587, 1548, 1512, 1106, 1092 cm -1 ;LCMS(+)ESI:C 10 H 13 Calculated m / z value for NO3: 195, measured value 196(M+H); 1 H NMR (200 MHz, DMSO-d6): δ 9.0-6.0 (br s, 3 H), 6.83 (AA'BB' system, J = 8.1 Hz, 2 H), 6.43 (AA'BB' system, J = 8.1 Hz, 2 H), 3.76 (ABX system, J = 7.5, 5.3 Hz, 1 H), 3.19 (s, 3 H), 2.75 (ABX system, J = 13.9, 5.3 Hz, 1 H), 2.65 (ABX system, J = 13.9, 7.5 Hz, 1 H). (C 10 H 13 Analytical calculation values ​​for NO3): C 61.45; H 6.79; N 7.12; O 24.65.

[0123] Preparation of (S)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid (VII): Scheme 7. [ka] [Table 6]

[0124] While circulating nitrogen, (S)-3-(4-aminophenyl)-2-methoxypropanoic acid (VI) (9.6 kg) and ethyl acetate (14.4 kg), dried at 0-10°C, were added to a stainless steel reactor. The reaction mixture was heated to 60-70°C, and acetic anhydride (5.6 kg) was added over approximately 30 minutes through a cartridge filter. The reaction mixture was stirred at 60-70°C for 1 hour, then treated with deionized water (0.5 kg), and stirred at 60-70°C for at least 15 minutes, during which time a precipitate formed. The mixture was cooled to 10-20°C, stirred for at least 30 minutes, then centrifuged, and the resulting solid was washed with ethyl acetate (4.80 kg) and deionized water (14.4 kg). The obtained product was dried at 60-70°C for 13-16 hours and then ground to obtain (S)-3-(4-acetamidophenyl)-2-methoxypropanoic acid (VII) (10.3 kg).

[0125] (S)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid:(VII):[α]] D 20-26~-19 (1% w / v H2O / CH3OH (1:1 v / v));IR: 3322, 3089, 2930, 2827, 2714, 2490, 1722, 1637, 1601, 1551, 1516, 1231, 1207, 1120, 1110cm -1 ;LCMS(+)ESI:C 12 H 15 Calculated value of m / z for NO4: 237; Measured value: 238 (M+H); 1 1H NMR (200 MHz, DMSO-d6): δ 12.96 (s, 1 H), 9.84 (s, 1 H), 7.43 (AA'BB' system, J = 8.5 Hz, 2 H), 7.10 (AA'BB' system, J = 8.5 Hz, 2 H), 3.86 (ABX system, J = 7.6, 5.2 Hz, 1 H), 3.00 (s, 3 H), 2.95-2.70 (ABX system, J = 13.9, 7.6, 5.2 Hz, 2 H), 2.00 (s, 3 H). [Table 7]

[0126] [Example 3] Preparation of methyl(I) 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate: Scheme 8. [ka] [Table 8]

[0127] Preparation of 4-nitrobenzaldehyde in methyl methoxyacetate and tetrahydrofuran suspension:

[0128] 4-nitrobenzaldehyde (47.5 kg), methyl methoxyacetate (52 kg), and tetrahydrofuran (47.5 kg) were added to a stainless steel reactor and cooled to -10 to -5°C while stirring.

[0129] Preparation of methyl(I) 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate:

[0130] Nitrogen was flowed into the stainless steel reactor (twice), and sodium methoxide (28.5 kg) and tetrahydrofuran (119 kg) were added while flowing nitrogen. Then, nitrogen was flowed into the reactor for 1 minute, and the sodium methoxide solution was cooled to -10 to -7°C while stirring. Next, while maintaining the temperature of the reaction mixture below 0°C, the cooled solution was treated with a pre-prepared suspension of methyl methoxyacetate and 4-nitrobenzaldehyde in tetrahydrofuran. After the addition was complete, the empty reactor was rinsed with tetrahydrofuran (23.8 kg) and poured into the reaction mixture. The reaction mixture was stirred at -5 to 0°C for no more than 5 minutes. While maintaining the temperature at -10 to 0°C, cold toluene (95 kg, -10 to 0°C) was rapidly added, and then... Glacial acetic acid (36 kg) was quickly added, and the reaction mixture was stirred at -10 to +10°C for 10 minutes. Deionized water (143 kg) was added, and the reaction mixture was stirred at 0 to 10°C for at least 10 minutes, then at 25 to 30°C for at least 10 minutes, until completely dissolved. After stirring was stopped, the phases were separated. The aqueous phase was removed, and the separated organic phase was treated with an aqueous sodium chloride solution (prepared by adding 4.75 kg of sodium chloride to 48 kg of deionized water). The mixture was then heated to 25 to 30°C with stirring for at least 15 minutes. Stirring was stopped, and the phases were separated. The aqueous phase was removed (64 kg). The separated organic phase was then distilled under vacuum to a temperature of 70 to 80°C to obtain an oily residue. Nitrogen was flowed through the reactor containing the high-temperature residue, and then treated with toluene (47.5 kg). The toluene was then distilled under vacuum to a temperature of 70 to 80°C to obtain an oily residue. The resulting high-temperature residue was passed through with nitrogen, then treated with toluene (221 kg), and the mass was stirred at 40-50°C for at least 10 minutes. This solution was then used directly in the next step.

[0131] [Example 4] Method for preparing (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) and (S)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid (VII) Scheme 9. [ka]

[0132] Preparation of 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV): Scheme 10. [ka] [Table 9]

[0133] While flowing nitrogen, methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate (I) in a toluene solution in a stainless steel reactor was cooled to 0 - 10°C. While maintaining the temperature at 0 - 10°C, triethylamine (42.8 kg) and methanesulfonyl chloride (38 kg) were added, and the reaction mixture was stirred at 0 - 10°C for 60 minutes. Deionized water (143 kg) was slowly added, and the resulting mass was stirred at 55 - 60°C for 10 minutes. Then, stirring was stopped and the phases were separated. The aqueous phase was removed (199 kg), the organic phase was filtered, and the filter was washed with toluene (7.1 kg). The filtered solution was heated to 55 - 60°C for 10 minutes. Stirring was stopped and the phases were separated. The possible aqueous phase was sent to waste (3.5 kg). Under vacuum and with stirring, a certain amount of toluene was distilled considering the following ratio: for 50 kg of nitrobenzaldehyde used in Scheme 8, about 5 kg of toluene was distilled, and a certain amount of this distilled toluene was sent to waste. Toluene was removed by distillation without exceeding 60°C under vacuum to obtain an oily residue. Then, the obtained residue was treated with methanol (147 kg), nitrogen was flowed, it was cooled to 20 - 30°C, and slowly treated with 30% sodium hydroxide (88 kg). The reaction mixture was stirred at 20 - 30°C for 3 hours. Deionized water (184 kg) was added, and the solution was heated to 60 - 65°C. At this temperature, 37% hydrochloric acid (35.2 kg) and 85% phosphoric acid (7.6 kg) were slowly added to precipitate the product. If necessary, 85% phosphoric acid was added to obtain pH ≤ 3.0. The obtained precipitated product was stirred at 60 - 65°C for at least 30 minutes, then cooled to 35 - 40°C and stirred for at least 30 minutes. The mixture was centrifuged, washed with deionized water (190 kg), and then washed with toluene (114 kg) (mother liquor: 749 kg). The wet product (about 82 kg) was used in the next step.

[0134] Preparation of 3-(4-aminophenyl)-2-methoxypropanoic acid (V): Scheme 11.

Chemical formula

Table 10

[0135] Preparation of an aqueous suspension of 5% palladium carbon in water:

[0136] Deionized water (9.5 kg) and 5% palladium carbon (4.75 kg) were added to a suitable stainless steel reactor, and then the bags were washed twice with deionized water (2 × 2.4 kg).

[0137] Preparation of 3-(4-aminophenyl)-2-methoxypropanoic acid (V):

[0138] In a stainless steel reactor that had been supplied with nitrogen (twice), wet 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV) (82 kg), methanol (143 kg), and 30% ammonia (14.3 kg) were added. After returning to atmospheric pressure, the mixture was stirred at 20-30°C until completely dissolved. The resulting solution was supplied with nitrogen (twice), and 5% phosphate in deionized water was added. The reaction mixture was treated with a pre-prepared solution of radium-carbon, and the empty container was washed with deionized water (2.4 kg). Nitrogen was passed through the reaction mixture (twice), and the mixture was heated to 60-80°C, then hydrogen was added until a pressure of 4.0-4.5 atm was achieved. The reaction was allowed to proceed while maintaining a pressure of 4.0-4.5 atm until hydrogen consumption stopped and it was confirmed that the reaction was complete. The reactor was returned to atmospheric pressure, the reaction mixture was cooled to 20-30°C, filtered through a sparkler filter, treated with nitrogen (twice), and deionized water (19 kg), and this was combined with the solution containing the product. The solvent was distilled under stirring and vacuum without exceeding 50°C until an oily residue remained. The residue was treated with deionized water (95 kg), heated to 65-70°C, and the product was precipitated by adding 37% hydrochloric acid (15.2 kg) and 80% acetic acid (10.5 kg). The mixture was stirred at 65-70°C for at least 10 minutes, then treated with ethyl acetate (71 kg), nitrogen was flowed over it, and the mixture was stirred at 65-70°C for at least 15 minutes. The reaction mixture was cooled to 15-20°C and stirred for at least 30 minutes. The suspension was divided, centrifuged, and washed with deionized water (47.5 kg) and ethyl acetate (47.5 kg). The wet product was dried at 60-70°C to obtain 3-(4-aminophenyl)-2-methoxypropanoic acid (V) (40.5 kg).

[0139] Preparation of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid S-(+)-camphor-10-sulfonate: Scheme 12. [ka] [Table 11]

[0140] 3-(4-aminophenyl)-2-methoxypropanoic acid (V) (40.5 kg) and (S)-(+)-camphor-10-sulfonic acid (49.9 kg) were placed in a stainless steel reactor. Nitrogen was introduced, and acetone (81 kg) was added. Deionized water (6.5 kg) was added. The reaction mixture was heated to approximately 58°C for 2 hours (reflux, no dissolution occurred). Acetone (81 kg) was added (temperature approximately 58°C), and the reaction mixture was maintained under reflux (approximately 58°C) for 1 hour. The reaction mixture was then cooled to 37-42°C, divided, centrifuged, and washed with acetone (61 kg). The centrifuged product was (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid S-(+)-camphor-10-sulfonate (VI)·(S)-C SA (wet weight 43.1 kg, dry weight 36.1 kg) was used directly in the following process.

[0141] Preparation of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI): Scheme 13. [ka] [Table 12]

[0142] Deionized water (72 kg) and wet ((S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid S-(+)-camphor-10-sulfonate (VI)·(S)-CSA (wet weight 43.1 kg, 36.1 kg when dry) were charged into a stainless steel reactor, nitrogen was passed through, and it was heated at 20 - 40 °C for at least 10 minutes until complete dissolution occurred. The solution was filtered and washed with deionized water (7.2 kg) and then ethyl acetate (36.1 kg). Nitrogen was passed through the obtained solution, heated to 55 - 60 °C, and 30% ammonia (4.54 kg) was added to precipitate the product. The obtained mixture was stirred at 55 - 60 °C for at least 15 minutes, then 80% acetic acid (1.81 kg) was added through a filter, nitrogen was passed through the reactant, stirred at 55 - 60 °C for at least 30 minutes, then cooled to 2 - 7 °C and stirred for at least 1 hour. The reaction mass was divided and centrifuged, washed with deionized water (25.3 kg) and ethyl acetate (25.3 kg) to obtain wet (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) (wet weight 11.8 kg, 10.8 kg when dry), which was used directly in the next step (wet).

[0143] Preparation of (S)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid (VII): Scheme 14.

Chemical formula

Table 13

[0144] Wet (S)-3-(4-aminophenyl)-2-methoxypropanoic acid (VI) (wet weight 11.8 kg, dry weight 10.8 kg) and ethyl acetate (16.2 kg) were added to a stainless steel reactor under nitrogen. The mixture was heated to 65-70°C, and acetic anhydride (7.0 kg) was added over approximately 15 minutes through a cartridge filter. The reaction mixture was stirred at 65-70°C for 60 minutes, and after the end of the reaction was detected, it was stirred continuously until a precipitate formed. The mixture was cooled to 10-20°C, stirred at 10-20°C for 30 minutes, then centrifuged, and the resulting solid was washed with ethyl acetate (5.4 kg) and deionized water (16.2 kg). The resulting product was dried at 60-70°C for 13-16 hours and pulverized to obtain (S)-3-(4-acetamidophenyl)-2-methoxypropanoic acid (VII) (12.3 kg).

[0145] [Example 5] Preparation of methyl(I) 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate: Scheme 15. [ka] [Table 14]

[0146] Preparation of 4-nitrobenzaldehyde in methyl methoxyacetate and tetrahydrofuran suspension:

[0147] 4-nitrobenzaldehyde (380 kg), methyl methoxyacetate (418 kg), and tetrahydrofuran (380 kg) were added to a stainless steel reactor and cooled to -10 to -5°C while stirring.

[0148] Preparation of methyl(I) 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate:

[0149] Nitrogen was flowed into a stainless steel reactor (twice), and sodium methoxide (228 kg) and tetrahydrofuran (1100 kg) were added while flowing nitrogen. Next, nitrogen was flowed into the reactor for 1 minute, and the sodium methoxide solution was cooled to -15 to -10°C while stirring. Then, while maintaining the temperature of the reaction mixture below 0°C, the cooled solution was treated with a pre-prepared suspension of methyl methoxyacetate and 4-nitrobenzaldehyde in tetrahydrofuran. After the addition was complete, the empty reactor was rinsed with tetrahydrofuran (40 kg) and poured into the reaction mixture. The reaction mixture was stirred at -5 to 0°C for no more than 5 minutes. While maintaining the temperature at -10 to 0°C, cold toluene (760 kg, -10 to 0°C) and glacial acetic acid (285 kg) were rapidly added, and the reaction mixture was stirred at -10 to +10°C for 10 minutes. Deionized water (1140 kg) was added, and the reaction mass was stirred at 0-10°C for at least 10 minutes, then at 25-30°C for at least 10 minutes to completely dissolve it. After stirring was stopped, the phases were separated. The aqueous phase was removed, and the separated organic phase was treated with an aqueous sodium chloride solution (prepared by adding 38 kg of sodium chloride to 380 kg of deionized water). The mass was then heated to 25-30°C with stirring for at least 10 minutes. Stirring was stopped, and the phases were separated. The aqueous phase was removed. The separated organic phase was then subjected to a vacuum to a temperature of 70-80°C to remove the oily residue. The mixture was distilled to a certain temperature. Nitrogen was passed through the reactor containing the high-temperature residue, followed by treatment with toluene (380 kg). The toluene was then distilled under vacuum to a temperature of 70-80°C to obtain an oily residue. Nitrogen was passed through the obtained high-temperature residue, followed by treatment with toluene (1767 kg), and the mixture was stirred at 40-50°C for at least 10 minutes. This solution was then used directly in the next step.

[0150] [Example 6] (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid Method for preparing (VI) and (S)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid (VII) Scheme 16. [ka]

[0151] Preparation of 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV): Scheme 17. [ka] [Table 15]

[0152] While flowing nitrogen, methyl(I) 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate in a toluene solution in a stainless steel reactor was cooled to 0-10°C. While maintaining the temperature at 0-10°C, triethylamine (342 kg) and methanesulfonyl chloride (304 kg) were added, and the reaction mixture was stirred at 0-10°C for 60 minutes. Deionized water (1140 kg) was slowly added, and the resulting mass was stirred at 55-60°C for 10 minutes, after which stirring was stopped and the phases were separated. The aqueous phase was removed, the organic phase was filtered, and the filter was washed with toluene (57 kg). The filtered solution was heated to 55-60°C for 10 minutes. Stirring was stopped and the phases were separated. Any available aqueous phase was sent to the waste. Under vacuum and with stirring, a fixed amount of toluene was distilled considering the following proportions: from 380 kg of nitrobenzaldehyde used in Scheme 15, approximately 38 kg of toluene was distilled, and a fixed amount of this distilled toluene was sent to waste. Toluene was removed by distillation under vacuum without exceeding 60°C to obtain an oily residue. The obtained residue was then treated with methanol (1178 kg), cooled to 20-30°C with nitrogen flow, and slowly treated with 30% sodium hydroxide (707 kg). The reaction mixture was stirred at 20-30°C for 3 hours. Deionized water (1474 kg) was added, and the solution was heated to 60-65°C. At this temperature, 37% hydrochloric acid (281 kg) and 85% phosphoric acid (61 kg) were slowly added to precipitate the product. If necessary, 85% phosphoric acid was added to obtain pH ≤ 3.0. The resulting precipitate was stirred at 60–65°C for at least 30 minutes, then cooled to 35–40°C and stirred for at least 30 minutes. The mixture was centrifuged, washed with deionized water (1520 kg), and then washed with toluene (912 kg). The wet product (approximately 786 kg) was used in the next step.

[0153] Preparation of 3-(4-aminophenyl)-2-methoxypropanoic acid (V): Scheme 18. [ka] [Table 16]

[0154] Preparation of an aqueous suspension of 5% palladium carbon in water:

[0155] Deionized water (76 kg) and 5% palladium carbon (38 kg) were added to a suitable stainless steel reactor, and then the bags were washed with deionized water (19 kg).

[0156] Preparation of 3-(4-aminophenyl)-2-methoxypropanoic acid (V):

[0157] In a stainless steel reactor that had been supplied with nitrogen (twice), wet 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV) (786 kg), methanol (1140 kg), and 30% ammonia (114 kg) were added. After returning to atmospheric pressure, the mixture was stirred at 20-30°C until completely dissolved. The resulting solution was supplied with nitrogen (twice), treated with a pre-prepared solution of 5% palladium carbon in deionized water, and the empty vessel was washed with deionized water (19 kg). The reactants were supplied with nitrogen (twice), heated to 60-80°C, and then hydrogen was added until a pressure of 4.0-4.5 atm was achieved. The reaction was allowed to proceed while maintaining a pressure of 4.0-4.5 atm until hydrogen consumption stopped and it was confirmed that the reaction was complete. The reactor is returned to atmospheric pressure, the reactants are cooled to 20-30°C, filtered through a sparkler filter, nitrogen is passed through (twice), and treated with deionized water (152 kg) to obtain the product. The solution was combined with the other components. The solvent was distilled under stirring and vacuum, without exceeding 50°C, until an oily residue remained. The residue was treated with deionized water (760 kg), heated to 65-70°C, and the product was precipitated by adding 37% hydrochloric acid (122 kg) and 80% acetic acid (84 kg). The mixture was stirred at 65-70°C for at least 10 minutes. At this stage, it was confirmed that the pH was between 3.8 and 4.2 (below 4.2), and the mixture was then treated with ethyl acetate (570 kg), nitrogen was flowed over it, and the mixture was stirred at 65-70°C for at least 15 minutes. The reaction mixture was cooled to 15-20°C and stirred for at least 30 minutes. The suspension was divided, centrifuged, and washed with deionized water (380 kg) and ethyl acetate (380 kg). The moist product was granulated and dried at 60-70°C to obtain 3-(4-aminophenyl)-2-methoxypropanoic acid (V) (approximately 295 kg).

[0158] Preparation of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid S-(+)-camphor-10-sulfonate: Scheme 19. [ka]

[0159] The starting materials 3-(4-aminophenyl)-2-methoxypropanoic acid derived from two batches were combined (one from the entire batch and a fixed amount from the other) to obtain a total of 400 kg of 3-(4-aminophenyl)-2-methoxypropanoic acid. This amount is equal to the amount that would have been obtained starting from 500 kg of 4-nitrobenzaldehyde. [Table 17]

[0160] 3-(4-aminophenyl)-2-methoxypropanoic acid (V) (400 kg) and (S)-(+)-camphor-10-sulfonic acid (493 kg) were added to a stainless steel reactor. Nitrogen was introduced and acetone (800 kg) was added. Deionized water (64 kg) was added. The reaction mixture was heated to approximately 58°C for 1 hour (reflux, no dissolution occurred). Acetone (800 kg) was added (temperature approximately 58°C), and the reaction mixture was maintained under reflux (approximately 58°C) for 1 hour. The reaction mixture was then cooled to 37-42°C, divided, centrifuged, and washed with acetone (600 kg). (Between all centrifugation steps, a certain amount of the suspension that did not participate in centrifugation was first heated to 45-50°C until brown, and then, before the next centrifugation, the suspension was again heated to 37- The mixture was cooled to 42°C. The centrifuged product, (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid S-(+)-camphor-10-sulfonate (VI)·(S)-CSA (wet weight 470 kg, dry weight 409.7 kg), was used directly in the next step.

[0161] Preparation of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI): Scheme 20. [ka] [Table 18]

[0162] Deionized water (819 kg) and wet ((S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid S-(+)-camphor-10-sulfonate (VI)·(S)-CSA (wet weight 470 kg, dry weight 409.7 kg) were placed in a stainless steel reactor, nitrogen was flowed through, and the reactor was heated at 20-40°C for at least 10 minutes until complete dissolution occurred. The solution was filtered and washed with deionized water (82 kg), then ethyl acetate (410 kg). Nitrogen was flowed through the resulting solution and heated to 55-60°C, and 30% ammonia (51 kg) was added to precipitate the product. The mixture was then stirred at 55-60°C for at least 15 minutes, then 80% acetic acid (20.5 kg) was added through a filter, nitrogen was passed over the reactants, and the mixture was stirred at 55-60°C for at least 30 minutes, then cooled to 2-7°C and stirred for at least 1 hour. The reaction mass was divided and centrifuged, washed with deionized water (287 kg) and ethyl acetate (287 kg) to obtain wet (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) (wet weight 162 kg, dry weight 138.8 kg), which was used directly in the next step (wet).

[0163] Preparation of (S)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid (VII): Scheme 21. [ka] [Table 19]

[0164] Wet (S)-3-(4-aminophenyl)-2-methoxypropanoic acid (VI) (wet weight 162 kg, dry weight 138.8 kg) and ethyl acetate (208 kg) were added to a stainless steel reactor under nitrogen. The mixture was heated to 65-70°C, and acetic anhydride (90 kg) was added over approximately 15 minutes through a cartridge filter. The reaction mixture was stirred at 65-70°C for 90 minutes, and after the end of the reaction was detected, it was stirred continuously until a precipitate formed. The mixture was cooled to 10-20°C, stirred at 10-20°C for 30 minutes, then centrifuged, and the resulting solid was washed with ethyl acetate (69 kg) and deionized water (208 kg). The resulting product was dried at 60-70°C for 19 hours and pulverized to obtain (S)-3-(4-acetamidophenyl)-2-methoxypropanoic acid (VII) (154.5 kg).

[0165] (S)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid (VII):IR: 3319, 2888, 2825, 1718, 1633, 1599, 1548, 1107 cm -1 ;LCMS(+)ESI:C 12 H 15 Calculated value for NO4 in m / z: 237; measured value: 236 (MHz) - ; 1 H NMR (600 MHz, DMSO-d6): δ 12.70 (s, 1 H), 9.85 (s, 1 H), 7.45 (d, 2 H), 7.12 (d, 2 H), 3.90 (dd, 1 H), 3.20 (s, 3 H), 2.80 (ABd, 2 H), 2.00 (s, 3 H). 13 ¹¹C NMR (600 MHz, DMSO-d6): δ 24.09 ( C H3-CO-NH-), 37.94 (-C- C H2-C-), 57.47 ( C H3-O-), 80.98 (-C- CH(O)-C-), 119.25 (2C, aromatic), 129.65 (2C, aromatic), 132.24 (1C, aromatic), 137.87 (1C, aromatic), 168.47 (CH3- C O-NH-), 173.21 (-COOH). EA: C 60.82% (theor. 60.75%), H 6.44% (theor. 6.37%), N 5.91% (theor. 5.90%), O 26.97% (theor. 26.97%). DSC: Melting 154~167℃ (starting at 159℃). Specific rotation: -22.7. (S)-3-(4-aminophenyl)-2-methoxypropanoic acid (HPLC): 0.06% (HPLC). Chiral purity (HPLC): 99.7% (HPLC). Residual solvent (ethyl acetate): 277 ppm (GC).

[0166] [Example 7] X-ray crystal structure determination of the compound of formula (VII)

[0167] The crystals used for structural determination were obtained by vapor diffusion of an ethanol solution of the compound of formula (VII) and L-proline (2:1) using heptane as the reverse solvent. Single-crystal X-ray diffraction analysis was performed. The results of this analysis are shown in Figure 1. Refinement of the P212121 space group results in an R index of 0.062. The asymmetric unit consists of two compounds of formula (VII) and two L-proline molecules.

[0168] Analysis of single-crystal diffraction data shows that the absolute configuration of the α-carbon relative to the carboxylic acid group is (S). Based on these results, the absolute stereochemistry of the compound of formula (VII) is shown in the following structure. [ka]

[0169] The optical rotation of the same compound, i.e., the compound of formula (VII), is negative, meaning that the compound of formula (VII) directs plane-polarized light to the left. The specific optical rotation specification for the pure compound is -26.0° to -19.0°. Therefore, since the procedure for dividing the racemic mixture always uses the same reagents, the characterization of the obtained product having a (S) configuration is confirmed by its specific optical rotation.

[0170] Furthermore, the chiral purity (HPLC) of the compound of formula (VII) can be determined, for example, using the methods described herein.

[0171] The single-crystal X-ray diffraction data and structural refinement of the compound of formula (VII): L-proline derivative are shown below. Experimental formula C 17 H 24 N2O6 Formula weight 352.38 Temperature 296(2)K Diffraction meter Bruker Smart-Apex (area detector) Wavelength 0.71073Å Crystal system Orthorhombic system Space group P212121 Unit cell dimensions a = 7.7813 (5) Å α = 90° b = 9.5414 (6) Å β = 90° c = 49.006 (3) Å γ = 90° Volume 3638.4(4)Å 3 Z 8 Density (calculated value): 1.287 Mg / m³ 3 Absorption coefficient 0.098 mm -1 F(000) 1504 Crystal size: 0.49 × 0.25 × 0.08 mm 3 Theta range for data acquisition is 0.83 to 28.75°. Exponential range: -10<=h<=8, -12<=k<=12, -54<=l<=63 Collected reflections 19513 Independent reflection 8598 [R(int)=0.0437] Completeness to theta = 25.00° 99.7% Absorption correction: Semi-empirical from equivalents Maximum and minimum transmission: 0.992 and 0.777 Refinement method F 2 Least squares of all matrices for the given matrix Data / Suppression / Parameters 8598 / 0 / 474 F 2 Goodness of fit for 0.984 Final R-index [I>2 sigma(I)]: R1=0.0623, wR2=0.1517 R-index (all data): R1 = 0.1217, wR2 = 0.1843 Absolute structure parameter -0.8(13) Maximum diffraction peaks and Halls: 0.382 and -0307 e. Å -3 Calculation program (Bruker): Smart 5.6 / Saint 5.0 / Shelxtl-NT 6.1

[0172] Built-in by reference All publications and patents referenced herein, including those listed below, are incorporated herein by reference in their entirety for all purposes, as if each individual publication or patent were incorporated specifically and individually by reference. In the event of any conflict, the present application, including any definitions herein, shall prevail.

[0173] Equal parts While specific embodiments of this disclosure have been described, the above specification is illustrative and not limiting. By examining this specification, various modifications of this disclosure will become obvious to those skilled in the art. The full scope of this disclosure should be determined by referring to the claims together with the full scope of its equivalents and this specification together with such modifications.

[0174] Unless otherwise stated, all figures representing quantities of components, reaction conditions, etc., used herein and in the claims should be understood in all cases to be modified by the term "approximately." Therefore, unless otherwise stated, the numerical parameters described herein and in the appended claims are approximations that may vary depending on the desired properties to be obtained by the present invention. For example, the present invention provides the following items: (Item 1) Compounds of formula (VII) that are substantially optically pure: [ka] A method for preparing, Compound of formula (I): [ka] This is reacted with an activator, if necessary, in the presence of a base, to obtain the intermediate of formula (IA): [ka] (In the formula, LG is a leaving group.) To form, The intermediate of formula (IA) is treated with a base solution in the presence of an alcohol solvent to remove the leaving group, thereby obtaining the intermediate of formula (IB): [ka] To form, The intermediate of formula (IB) is hydrolyzed to obtain the compound of formula (IV): [ka] To form, The compound of formula (IV) is hydrogenated to obtain the compound of formula (V): [ka] To form, The compound of formula (V) is divided to obtain a substantially optically pure compound of formula (VI): [ka] To form, The compound of formula (VI) is acylated to form the compound of formula (VII), Methods that include... (Item 2) The method according to item 1, wherein the reaction of the compound of formula (I) with an activator is carried out in the presence of a base and a solvent. (Item 3) The method according to item 2, wherein the solvent is selected from the group consisting of toluene, dichloromethane, tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, and acetonitrile. (Item 4) The method according to item 2 or 3, wherein the solvent is toluene. (Item 5) The method according to any one of items 1 to 4, wherein the base is an amine base. (Item 6) The method according to item 5, wherein the amine base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, and pyridine. (Item 7) The method according to any one of items 5 to 6, wherein the amine base is triethylamine. (Item 8) The method according to any one of items 1 to 7, wherein the activator is a sulfonylated agent or a halogenated agent. (Item 9) The method according to any one of items 1 to 8, wherein the activator is selected from the group consisting of methanesulfonyl chloride, p-toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, phenyltrifluimide, trifluoromethanesulfonic anhydride, and nonafluorobutanesulfonic anhydride. (Item 10) The method according to any one of items 1 to 9, wherein the activator is methanesulfonyl chloride. (Item 11) The leaving group is -OSO2-aryl, -OSO2-C 1~4 Selected from the group consisting of alkyl, chloro, bromo, and iodine, in the formula, C 1~4 The method according to any one of items 1 to 7, wherein each alkyl and aryl can be optionally substituted with one or more substituents independently selected from the group consisting of fluoro, bromo, and -CH3, respectively, for each occurrence. (Item 12) The leaving group is -OSO2-phenyl or -OSO2-C 1~4 The method according to any one of item 11, wherein the alkyl group is alkyl. (Item 13) The leaving group is -OSO2Me, [ka] -OSO2CF3 [ka] The method according to either item 11 or 12, independently selected from the group consisting of -OSO2CF2CF2CF2CF3. (Item 14) The method according to any one of items 1 to 13, wherein the leaving group is -OSO2Me. (Item 15) The method according to any one of items 1 to 14, wherein the alcohol solvent comprises at least one of methanol, ethanol, isopropanol, and butanol. (Item 16) The method according to item 15, wherein the alcohol solvent comprises methanol. (Item 17) The method according to any one of items 1 to 16, wherein the base solution comprises at least one of sodium hydroxide, lithium hydroxide, and potassium hydroxide. (Item 18) The method according to item 17, wherein the base solution contains sodium hydroxide. (Item 19) The method according to any one of items 1 to 18, wherein the base solution contains about 30% sodium hydroxide. (Item 20) The intermediate of formula (IB) can be hydrolyzed to form the compound of formula (IV), (i) Contacting the intermediate of formula (IB) with alkali hydroxide and water, (ii) Neutralizing to form the compound of formula (IV), The method described in any one of items 1 through 19, including the method described in item 1. (Item 21) The method according to item 20, wherein the alkali hydroxide is sodium hydroxide. (Item 22) The method according to item 20 or 21, wherein neutralization includes acidifying to a pH of less than 3 or equal to 3 by adding an acid. (Item 23) The method according to item 22, wherein the acid is phosphoric acid, hydrochloric acid, or a mixture thereof. (Item 24) The method according to any one of items 1 to 23, wherein hydrogenating the compound of formula (IV) to form the compound of formula (V) comprises contacting the compound of formula (IV) with hydrogen and a catalyst. (Item 25) The method according to item 24, wherein the catalyst has a concentration of approximately 5% Pd / C. (Item 26) The method according to any one of items 1 to 25, wherein the hydrogenation is carried out at a reaction temperature maintained between approximately 60 and 80°C and at a pressure of approximately 3 to 5 atm. (Item 27) The compound of formula (V) can be divided to form a substantially optically pure compound of formula (VI), (a) To cleave the compound of formula (V) in the presence of a chiral acid and thereby form a chiral salt of the compound of formula (VI), (b) Neutralizing the chiral salt of the compound of formula (VI) to form the compound of formula (VI), The method described in any one of items 1 through 26, including the method described in item 1 through 26. (Item 28) The method according to item 27, wherein the chiral acid is selected from the group consisting of (S)-(+)-camphor-10-sulfonic acid, (2R,3R)-(+)-tartaric acid, (S)-(-)-malic acid and (R)-(-)-mandelic acid or enantiomers thereof. (Item 29) The method according to item 27 or 28, wherein the chiral acid is (S)-(+)-camphor-10-sulfonic acid. (Item 30) The chiral salt of the compound of formula (VI) is [ka] The method described in any one of items 27-29. (Item 31) The method according to any one of items 1 to 30, further comprising dividing while maintaining a temperature of 55-60°C with stirring. (Item 32) The method according to any one of items 27 to 31, wherein neutralization comprises (i) contacting the chiral salt of the compound of formula (VI) with an aqueous solution of a base, and then (ii) acidifying the solution by adding an acid. (Item 33) The method according to item 32, wherein the aforementioned aqueous base solution contains an aqueous solution of ammonium hydroxide. (Item 34) Acylation is performed on the compound of formula (VI) with ethyl acetate, tetrahydrofuran, The method according to any one of items 1 to 33, comprising contacting an acylating agent in the presence of an organic solvent selected from the group consisting of diethyl ether, dichloromethane, and toluene. (Item 35) The method according to item 34, wherein the acylating agent is acetic anhydride. (Item 36) The method according to item 34 or 35, wherein the organic solvent is ethyl acetate. (Item 37) The method described in any one of items 1 to 36, wherein acylation occurs at a temperature of 60 to 70°C. (Item 38) The method according to any one of items 1 to 37, wherein the compound of formula (VII) is produced on a multi-kilogram scale. (Item 39) The method according to item 38 yields at least about 130 kg of the compound of formula (VII). (Item 40) The substantially optically pure compound of formula (VII) is at least 98% enantiomer: [ka] The method described in any one of items 1 to 39, which is expressed as a percentage of both enantiomers. (Item 41) A purified compound of formula (VII) as described in item 40, having a (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid content of 0.15% or less as determined by HPLC. (Item 42) Compound of formula (I): [ka] A method for preparing, Compound of formula (II): [ka] and the compound of formula (III): [ka] A method comprising preparing a mixture of and contacting the mixture with a base to form a compound of formula (I). (Item 43) The method according to item 42, wherein the contact is carried out in a solvent. (Item 44) The method according to item 42 or 43, wherein the solvent is tetrahydrofuran. (Item 45) The method according to any one of items 42 to 44, wherein contact is made at a temperature below or equal to 0°C. (Item 46) The method according to any one of items 42 to 45, wherein the contact is carried out at a reaction temperature maintained at -5 to 0°C, comprising stirring for about 5 minutes. (Item 47) The method according to any one of items 42 to 46, wherein the base is an alkali metal alkoxide. (Item 48) The method according to item 47, wherein the alkali metal alkoxide is selected from the group consisting of sodium methoxide, lithium methoxide, and potassium methoxide. (Item 49) The method according to item 47 or 48, wherein the alkali metal alkoxide is sodium methoxide. (Item 50) [ka] A compound represented by or a pharmaceutically acceptable salt thereof. (Item 51) A purified compound of formula (VII) obtainable by the method described in any one of items 1 to 40: [ka] A purified compound of formula (VII) having a content of 0.15% or less of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid according to HPLC.

Claims

1. Compounds of formula (VII) that are substantially optically pure: 【Chemistry 51】 A method for preparing, Compound of formula (I): 【Chemistry 52】 This is reacted with an activator to form the intermediate of formula (I-A): 【Chemistry 53】 (In the formula, LG is a leaving group.) To form, In the presence of an alcohol solvent, the intermediate of formula (I-A) is treated with a base solution to remove the leaving group, thereby obtaining the intermediate of formula (I-B): 【Chemistry 54】 To form, The intermediate of formula (I-B) is hydrolyzed to obtain the compound of formula (IV): 【Transformation 55】 To form, The compound of formula (IV) is hydrogenated to obtain the compound of formula (V): 【Transformation 56】 To form, The compound of formula (V) is divided to obtain a substantially optically pure compound of formula (VI): 【Chemistry 57】 To form, The compound of formula (VI) is acylated to form the compound of formula (VII), Includes, The substantially optically pure compound of formula (VI) is expressed as a percentage of both enantiomers: 【Transformation 67】 It is at least 95% of method.

2. The method according to claim 1, wherein the reaction of the compound of formula (I) with an activator is carried out in the presence of a base and a solvent.

3. The method according to claim 2, wherein the solvent is selected from the group consisting of toluene, dichloromethane, tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, and acetonitrile.

4. The method according to claim 2 or 3, wherein the solvent is toluene.

5. Compound of formula (I): 【Chemistry 52】 By reacting them, we obtain the intermediate of formula (I-A): 【Chemistry 53】 The method according to any one of claims 1 to 4, wherein the formation is performed in the presence of an amine base.

6. The method according to claim 5, wherein the amine base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, and pyridine.

7. The method according to any one of claims 5 to 6, wherein the amine base is triethylamine.

8. The method according to any one of claims 1 to 7, wherein the activator is a sulfonylated agent or a halogenated agent.

9. The method according to any one of claims 1 to 8, wherein the activator is selected from the group consisting of methanesulfonyl chloride, p-toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, phenyltrifluimide, trifluoromethanesulfonic anhydride, and nonafluorobutanesulfonic anhydride.

10. The method according to any one of claims 1 to 9, wherein the activator is methanesulfonyl chloride.

11. The aforementioned leaving group is -OSO ２ -Aryl, -OSO ２ -C １～４ Selected from the group consisting of alkyl, chloro, bromo, and iodine, in the formula, C １～４ Alkyl and aryl are, with each occurrence, fluoro, bromo, and -CH ３ The method according to any one of claims 1 to 7, wherein substitution may be made as necessary with one or more substituents independently selected from the group consisting of the following.

12. The leaving group is -OSO ２ -phenyl or -OSO ２ -C １～４ The method according to any one of claims 11, wherein the alkyl group is alkyl.

13. where the leaving group is -OSO ２ Me, 【Chemistry 58】 、-OSO ２ CF ３ 【Chemistry 59】 and -OSO ２ CF ２ CF ２ CF ２ CF ３ A method according to any one of claims 11 or 12, independently selected from the group consisting of the following.

14. The leaving group is -OSO ２ The method according to any one of claims 1 to 13, wherein Me.

15. The method according to any one of claims 1 to 14, wherein the alcohol solvent comprises at least one of methanol, ethanol, isopropanol, and butanol.

16. The method according to claim 15, wherein the alcohol solvent comprises methanol.

17. The method according to any one of claims 1 to 16, wherein the base solution comprises at least one of sodium hydroxide, lithium hydroxide, and potassium hydroxide.

18. The method according to claim 17, wherein the base solution contains sodium hydroxide.

19. The method according to any one of claims 1 to 18, wherein the base solution contains 30% sodium hydroxide.

20. The intermediate of formula (I-B) is hydrolyzed to form the compound of formula (IV), (i) Contacting the intermediate of formula (I-B) with alkali hydroxide and water, (ii) Neutralizing to form the compound of formula (IV), The method according to any one of claims 1 to 19, including the method described in any one of claims 1 to 19.

21. The method according to claim 20, wherein the alkali hydroxide is sodium hydroxide.

22. The method according to claim 20 or 21, wherein neutralization includes acidifying the pH to less than 3 or equal to 3 by adding an acid.

23. The method according to claim 22, wherein the acid is phosphoric acid, hydrochloric acid, or a mixture thereof.

24. The method according to any one of claims 1 to 23, wherein hydrogenating the compound of formula (IV) to form the compound of formula (V) includes contacting the compound of formula (IV) with hydrogen and a catalyst.

25. The method according to claim 24, wherein the catalyst is 5% Pd / C.

26. The method according to any one of claims 1 to 25, wherein the hydrogenation is carried out at a reaction temperature maintained between 60 and 80°C and at a pressure of 3 to 5 atm.

27. The compound of formula (V) can be divided to form a substantially optically pure compound of formula (VI), (a) To cleave the compound of formula (V) in the presence of a chiral acid and thereby form a chiral salt of the compound of formula (VI), (b) Neutralizing the chiral salt of the compound of formula (VI) to form the compound of formula (VI), The method according to any one of claims 1 to 26, including the method described in any one of claims 1 to 26.

28. The method according to claim 27, wherein the chiral acid is selected from the group consisting of (S)-(+)-camphor-10-sulfonic acid, (2R,3R)-(+)-tartaric acid, (S)-(-)-malic acid and (R)-(-)-mandelic acid or enantiomers thereof.

29. The method according to claim 27 or 28, wherein the chiral acid is (S)-(+)-camphor-10-sulfonic acid.

30. The chiral salt of the compound of formula (VI) is 【Transformation 60】 The method according to any one of claims 27 to 29.

31. The method according to any one of claims 1 to 30, further comprising maintaining a temperature of 55 to 60°C while stirring during the division.

32. The method according to any one of claims 27 to 31, wherein neutralization comprises (i) contacting the chiral salt of the compound of formula (VI) with an aqueous solution of a base, and then (ii) acidifying the solution by adding an acid.

33. The method according to claim 32, wherein the base aqueous solution contains an aqueous solution of ammonium hydroxide.

34. The method according to any one of claims 1 to 33, wherein acylation comprises contacting the compound of formula (VI) with an acylating agent in the presence of an organic solvent selected from the group consisting of ethyl acetate, tetrahydrofuran, diethyl ether, dichloromethane, and toluene.

35. The method according to claim 34, wherein the acylating agent is acetic anhydride.

36. The method according to claim 34 or 35, wherein the organic solvent is ethyl acetate.

37. The method according to any one of claims 1 to 36, wherein acylation occurs at a temperature of 60 to 70°C.

38. The method according to any one of claims 1 to 37, wherein the compound of formula (VII) is produced on a multi-kilogram scale.

39. The method according to claim 38, wherein at least 130 kg of the compound of formula (VII) can be obtained.

40. Use of a compound obtained by a method according to claims 1 to 39, wherein the use is for the manufacture of a pharmacopoeia for treating a disease, and the compound is capable of regulating the activity of a PPAR receptor.

41. The use according to claim 40, wherein the disease is selected from the group consisting of fibrous diseases, dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular disease, cardiovascular disease, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, eye disorders, IBD (irritable bowel disease), ulcerative colitis, and Crohn's disease.

42. The use according to any one of claims 40 or 41, wherein the disease is a skin disorder.

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