Process of making 3-(4'-aminophenyl)-2-methoxypropionic acid, and analogs and intermediates thereof

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, ligand-activated transcription factors that regulate gene expression. Certain PPARs play a role in regulating cellular differentiation, development, and metabolism in higher organisms.

[0002] Three types of PPARs have been identified: α, expressed in the liver, kidney, heart and other tissues and organs; β / δ, expressed, for example, in the brain; and γ, expressed in three forms: γ1, γ2 and γ3. PPARγ receptors have been linked to many disease states, including fibrotic diseases, dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, atherogenesis, 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.

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

[0004] Therefore, effective methods for generating compounds capable of modulating the activity of PPAR receptors are needed to address the treatment of such diseases. Summary of the Invention [Means for solving the problem]

[0005] overview The disclosure provides, for example, methods for preparing compounds that can be modulators of PPAR receptors.

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

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

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

[0009] In one embodiment, at least some of the compounds identified as intermediates, e.g., as part of the synthetic schemes disclosed herein, may be a compound of the present disclosure, e.g., a compound represented by formula (I): [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Detailed Description The features and other details of the present disclosure will now be described in more detail.Before further description of the present disclosure, certain terms used in this specification, examples and appended claims are summarized here.These definitions should be read in light of the remaining parts 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, such as, as used herein, C2 to C6, respectively. 12 Alkenyl, C2-C 10Alkenyl and C2-C6 alkenyl refer to straight or branched groups of 2 to 12, 2 to 10, or 2 to 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, 4-(2-methyl-3-butene)-pentenyl, and the like.

[0012] The term "alkoxy" as used herein refers to an alkyl group linked to oxygen (-O-alkyl). Exemplary alkoxy groups include those described herein as C1 to C6, respectively. 12 These include, but are not limited to, groups having alkyl, alkenyl or alkynyl groups of 1 to 12, 1 to 8, or 1 to 6 carbon atoms, referred to as alkoxy, C1-C8 alkoxy, and C1-C6 alkoxy. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, and the like. Similarly, exemplary "alkenoxy" groups include, but are not limited to, vinyloxy, allyloxy, butenoxy, and the like.

[0013] As used herein, the term "alkyl" refers to any alkyl group having a C1 to C6 carbon atom, each of which is an alkyl group. 12 Alkyl, C1-C 10 Alkyl, C1-C6 alkyl, C 1~4 Alkyl and C 1~3 The term alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group 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 Examples of alkyl include, but are not limited to, -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, and the like. In certain embodiments, alkyl refers to C1-C6 alkyl. In certain embodiments, cycloalkyl refers to C3-C6 cycloalkyl.

[0014] The alkyl, alkenyl, and alkynyl groups, in some embodiments, can be optionally substituted or optionally interrupted with at least one group selected from alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, 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.

[0015] The term "alkynyl" as used herein refers to an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon triple bond, such as, as used herein, C2 to C6, respectively. 12 Alkynyl refers to straight or branched groups of 2 to 12, 2 to 8, or 2 to 6 carbon atoms, referred to as alkynyl, C2-C8 alkynyl, and C2-C6 alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, 4-butyl-2-hexynyl, and the like.

[0016] As used herein, the term "amide" or "amido" refers to a -R a C(O)N(Rb )-, -R a C(O)N(R b )R c - or -C(O)NR b R c R a , R b and R c are each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocyclyl, and hydrogen. Amides are formed from carbon, nitrogen, R b , R c or R a The amide can also be cyclic, e.g., R b and R c , R a and R b or R a and R c can be linked to form a 3- to 12-membered ring, for example a 3- to 10-membered ring or a 5- or 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 independently be selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, and heterocyclyl.

[0018] As used herein, the term "amine" or "amino" refers to -NR d R e , -N(R d )R e -or-R e N(R d )R f -, where R d , R e and R f is independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. Amino is selected from nitrogen, R d , R e or Rf The amino can also be cyclic, e.g., R d , R e or R f Any two of may be joined together or with N to form a 3-12 membered ring, e.g., morpholino or piperidinyl. The term amino refers to the corresponding quaternary ammonium salt of any amino group, e.g., -[N(R d )(R e )(R f )] + Exemplary amino groups include R d , R e or R f At least one of the groups is an alkyl group.

[0019] The term "aryl" as used herein refers to mono-, bi- or other polycarbocyclic aromatic ring systems. In certain embodiments, aryl refers to monocyclic and / or bicyclic 6- to 10-membered rings. The aromatic ring may be substituted at one or more ring positions with a substituent selected from alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, 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. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings (these rings are "fused rings"), where at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, and / or aryl. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.

[0020] The term "arylalkyl" as used herein refers to an aryl group having at least one alkyl substituent, such as -aryl-alkyl. Exemplary arylalkyl groups include, but are not limited to, arylalkyls having a monocyclic aromatic ring system, the ring containing 6 carbon atoms. For example, "phenylalkyl" includes phenylC4 alkyl, benzyl, 1-phenylethyl, 2-phenylethyl, and the like.

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

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

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

[0024] The term "cycloalkyl" as used herein refers to a monovalent saturated or unsaturated cyclic, bicyclic or bridged bicyclic hydrocarbon radical of 3 to 12, 3 to 8, 4 to 8, or 4 to 6 carbons derived from a cycloalkane, and is used herein, for example, as "C 4~8Cycloalkyl groups are referred to as "cycloalkyl". 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, amido, 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. Cycloalkyl groups can be fused to other cycloalkyl, aryl, or heterocyclyl groups. In certain embodiments, cycloalkyl refers to a C3-C6 alkyl.

[0025] The term “halo” or “halogen” as used herein refers 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 --NO.

[0028] The term "phenyl" as used herein refers to a 6-membered carbocyclic aromatic ring. Phenyl groups can also be fused to cyclohexane or cyclopentane rings. Phenyl can be substituted with one or more substituents, including alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, 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.

[0029] As used herein, the term "phosphate" refers to the group -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, and each R aa may be selected from, for example, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, hydrogen, haloalkyl, heteroaryl, and heterocyclyl.

[0030] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein refers to any solvent, dispersion medium, coating, isotonicity agent, absorption retardant, etc., that are compatible with pharmaceutical administration. The use of such media and agents 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 functions.

[0031] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharma- ceutically acceptable carriers.

[0032] As used herein, the term "pharmaceutically acceptable salts" refers to salts of acidic or basic groups that may be present in the compounds used in the compositions. Compounds included in the compositions that are basic in nature can form a wide variety of salts with various inorganic and organic acids. Acids which may be used to prepare pharma- ceutically acceptable acid addition salts of such basic compounds are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds contained in the present composition that contain amino moieties can form pharmaceutically acceptable salts with various amino acids in addition to the above acids. Compounds contained in the present composition that are acidic in nature can form base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium and iron salts.

[0033] The compounds of the present disclosure may contain one or more stereocenters and / or double bonds and therefore may exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. As used herein, the term "stereoisomer" consists of all geometric isomers, enantiomers or diastereomers. These compounds may be represented by the symbols "R" or "S", depending on the arrangement of the substituents around the asymmetric carbon atom. The present disclosure encompasses the various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be represented in the nomenclature as "(±)", although one of skill in the art will recognize that the structure may implicitly display chiral centers.

[0034] Individual stereoisomers of the compounds of the present disclosure can be prepared synthetically from commercially available starting materials containing an asymmetric or stereogenic center, or by preparation of racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) coupling of the mixture of enantiomers to a chiral auxiliary, recrystallization or chromatographic separation of the resulting mixture of diastereomers, and liberation of the optically pure product from the auxiliary, (2) salt formation with an optically active resolving agent, or (3) direct separation of the mixture of optical enantiomers on a chiral chromatographic column. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods such as chiral phase gas chromatography, chiral phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

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

[0036] Alternatively, substituents around a carbon-carbon double bond can be designated as "cis" or "trans", with "cis" designating substituents on the same side of the double bond and "trans" designating substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring is designated as "cis" or "trans". The term "cis" designates substituents on the same side of the plane of the ring and the term "trans" designates substituents on opposite sides of the plane of the ring. A mixture of compounds in which substituents are disposed on both the same and opposite sides of the plane of the ring is designated 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 (e.g., a compound described herein), mean that at least 95% of the compound, e.g., at least 96%, at least 97%, or at least 98%, has a desired stereocenter in a given configuration. It will be understood that the percentage is expressed as a percentage of both enantiomers of the compound. For example, a compound of formula VII is substantially optically pure if it is at least 95% (S)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid (levorotatory enantiomer), based on the sum of both levorotatory and dextrorotatory enantiomers.

[0038] The compounds disclosed herein can exist in solvated and unsolvated forms with pharma- ceutically acceptable solvents such as water, ethanol, and the like, and the present disclosure provides both solvated and unsolvated forms. In some embodiments, the compound is in an amorphous form. In some embodiments, the compound is in a crystalline form. In some embodiments, the compound is a polymorph.

[0039] The present disclosure also encompasses isotopically labeled compounds of the present disclosure that are identical to those listed herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that may be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as isotopes of each of the following: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 Examples include Cl.

[0040] Certain isotopically labeled disclosed compounds (e.g., 3 H and 14 C-labeled compounds) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium (i.e., 2 Substitution with heavier isotopes, such as H, may confer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent, for example, by following procedures similar to those disclosed in the Examples herein.

[0041] The term "prodrug" refers to a compound that is transformed in vivo to yield the disclosed compound or a pharma- ceutically acceptable salt, hydrate, or solvate of the compound. The transformation can occur by various mechanisms, such as hydrolysis in blood. For example, if a compound of the present disclosure or a pharma- ceutically acceptable salt, hydrate, or solvate of the compound contains a carboxylic acid functional group, the prodrug can be a compound in which the hydrogen atom of the acid group is replaced by a (C1-C8) alkyl, (C2-C 12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, can include esters formed by replacing the aryl groups 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, when a compound of the present disclosure contains an alcohol functional group, it may be selected from the group consisting of (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 (wherein each α-aminoacyl group is independently selected from naturally occurring L-amino acids), P(O)(OH), -P(O)(O( C1 Prodrugs can be formed by replacing the hydrogen atom of the alcohol group with a group such as .about.C.sub.-6)alkyl)2 or glycosyl (the group resulting from removal of the hydroxyl group of the hemiacetal form of a carbohydrate).

[0043] When the compounds of the present disclosure incorporate an amine functionality, they can be R-carbonyl, RO-carbonyl, NRR′-carbonyl, where R and R′ are each independently (C1-C 10 ) alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is 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, and Y 3 is (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, and Y 5Prodrugs can be formed by replacing the hydrogen atom in the amine group with a group such as: (I) is mono-N- or di-N,N-(C1-C6) alkylamino, morpholino, piperidin-1-yl, or pyrrolidin-1-yl.

[0044] The present disclosure provides compounds represented, at least in part, by Formula (I), Formula (IV), Formula (V), Formula (VI) and Formula (VII), as depicted below. Pharmaceutical compositions comprising compounds represented by Formula (I), Formula (IV), Formula (V), Formula (VI) and Formula (VII), and, for example, a pharma- ceutically acceptable excipient and / or carrier, are also contemplated herein.

[0045] compound One is a substantially optically pure compound of formula (VII): [ka] A method for preparing Compounds of formula (I): [ka] with an activating agent, optionally in the presence of a base, to give an intermediate of formula (IA): [ka] (wherein LG is a leaving group); and forming The intermediate of formula (IA) is treated with a base solution in the presence of an alcohol solvent to form the deprotected aryl group. Removal of the leaving group, thereby forming an intermediate of formula (IB): [ka] and forming The intermediate of formula (IB) is hydrolyzed to give a compound of formula (IV): [ka] and forming The compound of formula (IV) is hydrogenated to give a compound of formula (V): [ka] and forming Optionally, the compound of formula (V) may be resolved to obtain a substantially optically pure compound of formula (VI): [ka] and forming acylation of said compound of formula (VI) to form a compound of formula (VII); Provided herein is a method comprising:

[0046] Reacting the compound of formula (I) with an activating agent may include 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 can be toluene. The base can be, for example, an amine base selected from the group consisting of triethylamine, N,N-diisopropylethylamine and pyridine. For example, the amine base can be triethylamine.

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

[0048] Contemplated activating agents include sulfonylating agents or halogenating agents. For example, the activating agent may be selected from the group consisting of methanesulfonyl chloride, p-toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, phenyltriflimide, trifluoromethanesulfonic anhydride and nonafluorobutanesulfonic anhydride. In some embodiments, the activating agent is methanesulfonyl chloride.

[0049] In some embodiments, the leaving group is -OSO2-aryl, -OSO2-C 1~4 is selected from the group consisting of alkyl, chloro, bromo and iodo, 1~4 The alkyl and aryl, at each occurrence, may be optionally substituted with one or more substituents each independently selected from the group consisting of fluoro, bromo, and -CH. For example, a leaving group is -OSO-phenyl or -OSO-C. 1~4 It may be alkyl.

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

[0051] Contemplated alcohol solvents 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 includes at least one of sodium hydroxide, lithium hydroxide, and potassium hydroxide. For example, the base solution can include sodium hydroxide, such as 30% sodium hydroxide.

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

[0054] In some embodiments, 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, e.g., a catalyst selected from the group consisting of PtO2, Pd(OH)2 / C, Pt / C, 10% Pd / C and 5% Pd / C, e.g., a 5% Pd / C catalyst. The hydrogenation is carried out at a temperature of about 60-80° C. The hydrogenation may be carried out at a reaction temperature maintained between about 3-5 atm, about 3.5-4.5 atm, or about 4.0-4.5 atm. For example, the 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 30% aqueous ammonia.

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

[0056] Resolving the compound of formula (V) to form a substantially optically pure compound of formula (VI) may include: a) resolving a compound of formula (V) in the presence of a chiral acid, thereby forming a chiral salt of a compound of formula (VI); and b) neutralizing the chiral salt of a compound of formula (VI), thereby forming a 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-phenyltanesulfonic acid, dibenzoyl-L-tartaric acid, glutamic acid, (1R,3S)-camphoric acid, (1S)-camphanic acid and (R)-(-)-mandelic acid, and all other chiral acids that can bring about the resolution of a racemic mixture or its enantiomers, such as (S)-(+)-camphor-10-sulfonic acid.

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

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

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

[0061] For example, the initiator may be [ka] It can be represented by:

[0062] At the end of the split, if specifications are not met, reprocessing can be performed by maintaining the solution at the split temperature with stirring for a longer period of time.

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

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

[0065] In some embodiments, after optionally resolving the compound of formula (V) to form a substantially optically pure compound of formula (VI), the mother liquor derived from the resolution step may still contain the desired enantiomer (as a salt of the resolving agent) along with the undesired enantiomer. In these embodiments, the resolution may be a) recovering the mixture of enantiomers (as a chiral salt of a resolving agent) from the mother liquor, neutralizing the chiral salt to form a compound of formula (V), and 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) distilling a portion of the mother liquor and precipitating the desired enantiomer from the mother liquor as the salt of the chiral resolving agent, thereby increasing the overall process yield; may optionally further comprise.

[0066] Also contemplated herein is a method of racemizing the undesired enantiomer, or its chiral salt, in the presence of a base, and resolving the resulting mixture of (R) and (S) enantiomers to form the desired enantiomer using the resolution methods contemplated herein.

[0067] Contemplated bases include those selected from the group consisting of hydroxides, alkoxides (e.g., methoxide), amides (e.g., lithium diisopropylamide), hydrides (e.g., NaH), organolithium, and Grignard reagents. For bases that require a counterion, exemplary counterions contemplated herein may include alkali 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, e.g., 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) is produced.

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

[0070] In another embodiment, the disclosed preparation of a substantially optically pure compound of formula (VII) includes acylation of racemic compound (V) to obtain a racemic mixture of 3-(4-acetamidophenyl)-2-methoxypropionic acid, and resolving 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) includes: a) resolving a racemic mixture of 3-(4-acetamidophenyl)-2-methoxypropionic acid in the presence of a chiral base, thereby forming a chiral salt of the compound; and b) neutralising the chiral salt of said compound, thereby forming a 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, dehydroabietylamine, N,α-dimethylbenzylamine, N,N-dimethyl-1-phenylethylamine, ephedrine, α-methylbenzylamine, 1-(2-naphthyl)ethylamine, quinidine, quinine, strychnine, valine, and any other chiral base that can effect resolution of a racemic mixture. For example, a chiral salt of a compound is [ka] It can be expressed as:

[0072] In certain embodiments, the present disclosure provides a compound of formula (I): [ka] A method for preparing Compounds of formula (II): [ka] and a compound of formula (III): [ka] preparing a mixture of contacting the mixture with a base (e.g., in a solvent such as tetrahydrofuran), thereby forming a compound of formula (I).

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

[0074] In some embodiments, [ka] or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, are provided herein.

[0075] In some embodiments, compounds of formula (I) may exist as a mixture of stereoisomers. Contemplated stereoisomers of formula (I) include, for example, compounds of formula (a), formula (b), formula (c), or formula (d). [ka]

[0076] One is a substantially optically pure compound of formula (VI): [ka] A method for preparing Compounds of formula (I): [ka] with an activating agent, optionally in the presence of a base, to give an intermediate of formula (IA): [ka] (wherein LG is a leaving group); and forming The intermediate of formula (IA) is treated with a base solution in the presence of an alcohol solvent to remove the leaving group, thereby producing an intermediate of formula (IB): [ka] and forming The intermediate of formula (IB) is hydrolyzed to give a compound of formula (IV): [ka] and forming The compound of formula (IV) is hydrogenated to give a compound of formula (V): [ka] and forming and resolving said compound of formula (V) to form a substantially optically pure compound of formula (VI), wherein the methods and variables are as defined herein.

[0077] Procedures for making 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, amino or carboxyl groups) to avoid their undesired participation 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 carried out by removing the protected The removal of the group may be the final step in the synthesis to give the compound of formula I disclosed herein. The starting materials used in the following schemes can be purchased or can be prepared by methods described in the chemical literature or by modifications thereof using methods known to those skilled in the art. The order in which the steps are carried out may vary depending on the groups 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 a number of ways based on the teachings contained herein and the synthetic procedures known in the art.In the description of the synthetic methods described below, it should be understood that all proposed reaction conditions, including the selection of solvents, reaction atmospheres, reaction temperatures, experimental durations and post-treatment procedures, can be selected to be standard conditions for the reaction, unless otherwise indicated.Those skilled in the art of organic synthesis will understand that the functional groups present on various parts of the molecule should be compatible with the proposed reagents and reactions.Substituents that are not compatible with the reaction conditions will be obvious to those skilled in the art, and therefore alternative methods are shown.The starting materials of the examples are commercially available or easily prepared by standard methods from known materials.

[0079] At least some of the compounds identified as intermediates, for example as part of the synthetic schemes disclosed herein, are contemplated as compounds of the present disclosure.

[0080] Abbreviation: 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] Common experiments: Using a Varian Gemini 200 NMR spectrometer operating at 200 MHz or 600 MHz, 1 H NMR spectra were recorded. Proton chemical shifts were reported as parts per million on the δ scale using the solvent residual peak (DMSO-d6: 2.50 ppm) as the internal standard. The data are expressed as follows: chemical shift (δ), polymorphism (δ), Severity (s=singlet, d=doublet, t=triplet, q=quartet, qn=quintet, sx=sexlet, sp=septet, m=multiplet, br=broad, dd=doublet of doublets, dt=doublet of triplets, qd=quartet of doublets, dquin=doublet of quintets), coupling constants (J, Hz) and integrals (#H).

[0082] 13 C NMR was recorded dissolving samples in DMSO-d6 operating at 600 MHz. Fully decoupled spectra were acquired.

[0083] Mass spectra were recorded on a Thermo-Finnigan LCQ-Advantage mass spectrometer or on a Thermo LCQ-fleet MS. LC / MS data were analyzed using positive / negative mode switching or by isobaric ion (M–H) analysis of the sample. - The signal corresponding to 236 m / z was acquired using negative mode polarity with acquisition parameters optimized in negative polarity.

[0084] Elemental analysis (CHN) was performed with a Carlo Erba EA 1108 instrument under the following conditions: sample weight: 0.5–2 mg; furnace temperature: 1010 °C; column temperature: 80 °C; gas: He; flow rate: 100 mL / min. Elemental analysis (oxygen) was performed with a Carlo Erba EA 1108 instrument under the following conditions: sample weight: 0.5–2 mg; furnace temperature: 1010 °C; column temperature: 80 °C; gas: He; flow rate: 100 mL / min. The analysis was carried out with an Erba EA 1108 apparatus: sample weight: 0.5-2 mg; furnace temperature: 1010 °C; column temperature: 60 °C; gas: He; flow rate: 100 mL / min.

[0085] FT-IR spectroscopy FT-IR / ATR was performed using a Perkin The samples were analyzed using an Elmer spectrophotometer model Spectrum Two instrument. -1 Spectra were collected over a frequency range of

[0086] The UV-visible spectrum was measured using a Shimadzu UV spectrophotometer operating under the following conditions: Recorded using a 2600: cuvette: quartz 1 cm; range: 200-600 nm; scan speed: medium; scan step: 1 nm; slit width: 1.0 nm; reference solution: methanol; sample solution: 1 mg of sample was dissolved in 100 mL 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 sample was accurately weighed in a 50 mL volumetric flask, dissolved in methanol and made to volume (concentration: 10 mg / mL, corresponding to 1% w / v). The rotation angle of the resulting solution was determined using a polarimeter tube with an optical path length corresponding to 1 dm. The specific rotation was referenced to the dried material using the following formula: [ka] Calculate: (α×50×100) / (W×(100−m)), where α=read rotation angle; W=sample weight (g); m=sample moisture content (%). Chiral purity (HPLC) was determined as follows.

[0089] [Table 1A]

[0090] Preparation of solutions

[0091] - Sample solution: Accurately weigh 10 mg of sample into a 10 mL measuring flask, then dissolve in the mobile phase and adjust to the constant 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 and volume to volume with the mobile phase.

[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 and vol. 10 with the mobile phase (final concentration of dextrorotatory enantiomer: 10 μg / mL, corresponding to 1% in the sample solution and a chiral purity of (S)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid of 99%).

[0094] System Suitability Tests and Procedures

[0095] 20 μl of the sample solution and the SST solution are injected into the chromatograph and the chromatograms are recorded.

[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] A chromatographic system can be used for the test if it has an h / v ratio of 1.5 or greater, where h is the distance between the apex of the peak due to the dextrorotatory enantiomer and the baseline, and v is the distance between the bottom of the valley defined between the dextrorotatory and levorotatory enantiomer peaks and the baseline.

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

[0099] The above methods can be used to determine the optical or enantiomeric purity of the compounds referred to herein.

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

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

[0102] A stainless steel reactor was charged with 4-nitrobenzaldehyde (50 kg), methyl methoxyacetate (55 kg) and tetrahydrofuran (100 kg) and cooled to -5 to +5°C with stirring.

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

[0104] A stainless steel reactor was flushed with nitrogen (twice) and charged with sodium methoxide (30.0 kg) and tetrahydrofuran (75 kg) while flushing with nitrogen. The reactor was then flushed with nitrogen for 1 minute and the sodium methoxide solution was cooled to -10 to -5°C while stirring. The cooled solution was then treated with a previously prepared suspension of methyl methoxyacetate and 4-nitrobenzaldehyde in tetrahydrofuran while maintaining the temperature of the reaction mass below 10°C. After the addition was complete, the empty reactor was rinsed with tetrahydrofuran (25.0 kg) and poured into the reaction. The reaction was stirred at -10 to +10°C for not more than 5 minutes. While maintaining the temperature at -10 to +10°C, cold toluene (100 kg, -10 to 0°C) was slowly added followed by glacial acetic acid (50 kg) and the reaction was stirred at -10 to +10°C for 10 minutes. Deionized water (150 kg) was added and the reaction mass was stirred for at least 10 minutes at 0-10 °C and then at least 10 minutes at 20-30 °C to allow complete dissolution, after which the stirring was stopped and the phases were allowed to separate. The aqueous phase was removed and the separated organic phase was treated with aqueous sodium chloride solution (previously 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. The stirring was stopped and the phases were allowed to separate. The aqueous phase was removed and the organic phase was treated with sodium chloride (previously prepared by adding 10 kg of sodium chloride to 100 kg of deionized water). The mass was extracted once more using the same protocol. The separated organic phase was then distilled under vacuum without exceeding 80 °C to remove THF. The reactor with the hot residue was flushed with nitrogen and then treated with toluene (50 kg) and the toluene was distilled under vacuum without exceeding 80 °C. The resulting hot residue was flushed with nitrogen and then treated with toluene (75 kg) and the mass was stirred for at least 30 min at 30-45 °C to ensure good product precipitation. The mixture was then cooled to -10-0 °C and stirred at that temperature for at least 1 h. The resulting suspension was divided, centrifuged, and washed with cold toluene (25 kg) to give moist methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate (I) (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 m / z for NO6: 255, observed: 254 (MH); 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 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] A nitrogen flushed (twice) stainless steel reactor was charged with moist methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate (I) (84 kg) and toluene (283 kg) and then cooled to 0-10°C with nitrogen flush. While maintaining the temperature at 0-10°C, triethylamine (42.3 kg) and methanesulfonyl chloride (36.3 kg) were added and the reaction was stirred at 0-10°C for 30 minutes. Deionized water (145 kg) was added slowly and the resulting mass was stirred at 50-60°C for 10 minutes after which the stirring was stopped and the phases were allowed to separate. The aqueous phase was removed and the organic phase was filtered and washed with toluene (7.3 kg). The toluene was removed by distillation under vacuum without exceeding 60°C to give an oily residue. The resulting residue was then treated with methanol (218 kg), transferred to another reactor, flushed with nitrogen, cooled to 20-30°C and slowly treated with 30% sodium hydroxide (94 kg). The reaction 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 pH ≤ 3.0. The resulting precipitated product 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] Methyl 2-methoxy-3-((methylsulfonyl)oxy)-3-(4-nitrophenyl)propanoate (I-A1): LCMS (+) ESI: C 12 H 15 Calculated m / z for NO8S: 333; Found 356 (M+Na); 1H 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] Methyl 2-methoxy-3-(4-nitrophenyl)acrylate (IB): LCMS (-) APCI: C 11 H 11 Calculated m / z for NO5: 237, observed: 236 (M−H); 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 for H9NO5: m / z: 223, Found: 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] A suitable stainless steel reactor was charged with N,N-dimethylformamide (17.2 kg), 5% palladium on carbon (7.7 kg) and N,N-dimethylformamide (2×2.65 kg) and the suspension was stirred thoroughly.

[0114] A nitrogen flushed (2 times) stainless steel reactor was charged with methanol (252 kg), cooled to 0-10 °C, and dry 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV) (50.4 kg) was added. The resulting solution was flushed with nitrogen (2 times), treated with a previously prepared solution of 5% palladium on carbon in N,N-dimethylformamide, and the empty vessel was washed with N,N-dimethylformamide (2.65 kg). The reaction was flushed with nitrogen (2 times) and heated to 60-80 °C, then charged with hydrogen until a pressure of 3.5 and 4.5 atm was obtained. The reaction was allowed to proceed, maintaining a pressure of 3.5-4.5 atm, until hydrogen consumption ceased and the reaction was determined to be complete. The reactor was returned to atmospheric pressure, the reaction cooled to 20-30°C, flushed with nitrogen (twice), treated successively with 30% ammonia (20.2 kg) and deionized water (12.6 kg), and stirred at 20-30°C until complete dissolution. The solution was filtered through a sparkler filter washed with deionized water (25.2 kg). The reactor was flushed with nitrogen 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), flushed with nitrogen, and stirred at 60-70°C for at least 10 minutes. Stirred for 15 minutes. The reaction mass 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) (about 37.5 kg).

[0115] 3-(4-aminophenyl)-2-methoxyacrylic acid (IC): LCMS (+) ESI: C 10 H 11 Calculated m / z for NO3: 193, found: 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 No.3 Calculated m / z for: 195, found: 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 Calculated analysis 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] A stainless steel reactor was charged with 3-(4-aminophenyl)-2-methoxypropanoic acid (V) (37.5 kg) and acetone (113 kg) while flushing with nitrogen. Deionized water (15.0 kg) and (S)-(+)-camphor-10-sulfonic acid (46.2 kg) were added and the reactor was flushed with nitrogen. The reaction 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 was stirred at 30-35 °C for at least 3 h until good precipitation occurred. 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] A stainless steel reactor was charged with deionized water (98 kg) and wet ((S)-(-)-3- (4-Aminophenyl)-2-methoxypropionic acid S-(+)-camphor-10-sulfonate (VI)·(S)-CSA (41.7 kg) was charged, flushed with nitrogen, and heated at 20-30 °C for at least 10 min until complete dissolution occurred. The solution was filtered and washed with deionized water (7.0 kg) and then ethyl acetate (35.0 kg). The resulting solution was flushed with nitrogen, 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 min, then 80% acetic acid (4.38 kg) was added through the filter, the reaction was flushed with nitrogen, stirred at 50-60 °C for at least 30 min, then cooled to 10-20 °C and stirred for at least 1 h. The reaction mixture 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 give (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 for NO3: 195, measured 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 Analysis calculated 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] Under nitrogen flush, a stainless steel reactor was charged with dry (S)-3-(4-aminophenyl)-2-methoxypropanoic acid (VI) (9.6 kg) and ethyl acetate (14.4 kg) at 0-10°C. The reaction mass was heated to 60-70°C and acetic anhydride (5.6 kg) was added through a cartridge filter over a period of about 30 minutes. The reaction mass was stirred at 60-70°C for 1 hour and 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 and stirred for at least 30 minutes and then centrifuged and the resulting solid was washed with ethyl acetate (4.80 kg) and deionized water (14.4 kg). The resulting product was dried at 60-70° C. for 13-16 hours and ground to give (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 m / z for NO4: 237; Found 238 (M+H); 1 H 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 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate (I): Scheme 8. [ka] [Table 8]

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

[0128] A stainless steel reactor was charged with 4-nitrobenzaldehyde (47.5 kg), methyl methoxyacetate (52 kg) and tetrahydrofuran (47.5 kg) and cooled to -10 to -5°C with stirring.

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

[0130] The stainless steel reactor was flushed with nitrogen (twice) and charged with sodium methoxide (28.5 kg) and tetrahydrofuran (119 kg) while flushing with nitrogen. The reactor was then flushed with nitrogen for 1 minute and the sodium methoxide solution was cooled to -10 to -7 °C while stirring. The cooled solution was then treated with a previously prepared suspension of methyl methoxyacetate and 4-nitrobenzaldehyde in tetrahydrofuran while maintaining the temperature of the reaction mass below 0 °C. After the addition was complete, the empty reactor was rinsed with tetrahydrofuran (23.8 kg) and poured into the reaction. The reaction was stirred at -5 to 0 °C for not more than 5 minutes. Cold toluene (95 kg, -10 to 0 °C) was quickly added while maintaining the temperature at -10 to 0 °C, followed by , glacial acetic acid (36 kg) was added quickly and the reaction mass was stirred at -10 to +10 °C for 10 minutes. Deionized water (143 kg) was added and the reaction mass was stirred at 0 to 10 °C for at least 10 minutes and then at 25 to 30 °C for at least 10 minutes to dissolve completely, after which the stirring was stopped and the phases were allowed to separate. The aqueous phase was removed and the separated organic phase was treated with aqueous sodium chloride solution (previously prepared by adding 4.75 kg of sodium chloride to 48 kg of deionized water). The mass was then heated to 25 to 30 °C with stirring for at least 15 minutes. The stirring was stopped and the phases were allowed to separate. 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 an oily residue. The reactor containing the hot residue was flushed with nitrogen and then treated with toluene (47.5 kg) and the toluene was distilled under vacuum to a temperature of 70 to 80 °C to obtain an oily residue. The resulting hot residue was flushed with nitrogen and then treated with toluene (221 kg) and the mass was stirred for at least 10 minutes at 40-50° C. This solution was used as is in the next step.

[0131] [Example 4] Method for the preparation of (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] With nitrogen flushing, methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate (I) in toluene solution in a stainless steel reactor was cooled to 0-10 °C and, while maintaining the temperature at 0-10 °C, triethylamine (42.8 kg) and methanesulfonyl chloride (38 kg) were added and the reaction was stirred at 0-10 °C for 60 min. Deionized water (143 kg) was added slowly and the resulting mass was stirred at 55-60 °C for 10 min, after which the stirring was stopped and the phases were allowed to separate. The aqueous phase was removed (199 kg) and the organic phase was filtered, washing the filter with toluene (7.1 kg). The filtered solution was heated to 55-60 °C for 10 min. The stirring was stopped and the phases were allowed to separate. The possible aqueous phase was sent to waste (3.5 kg). Under vacuum and stirring, an aliquot of toluene was distilled taking into account the following proportions: for 50 kg of nitrobenzaldehyde used in scheme 8, about 5 kg of toluene was distilled and an aliquot 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 residue obtained was then treated with methanol (147 kg), flushed with nitrogen, cooled to 20-30 °C and slowly treated with 30% sodium hydroxide (88 kg). The reaction 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 a pH ≦ 3.0. The resulting precipitated product was stirred at 60-65 °C for at least 30 min, then cooled to 35-40 °C and stirred for at least 30 min. The mixture was centrifuged and washed with deionized water (190 kg) and then 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. [ka] [Table 10]

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

[0136] A suitable stainless steel reactor was charged with deionized water (9.5 kg), 5% palladium on carbon (4.75 kg), and then the bag was washed twice with deionized water (2×2.4 kg).

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

[0138] A stainless steel reactor flushed with nitrogen (twice) was charged with wet 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV) (82 kg), methanol (143 kg) and 30% ammonia (14.3 kg). After returning to atmospheric pressure, the mixture was stirred at 20-30 °C until complete dissolution. The resulting solution was flushed with nitrogen (twice) and dissolved in 5% perchlorate in deionized water. The reaction was treated with a previously prepared solution of radium carbon and the empty vessel was washed with deionized water (2.4 kg). The reaction was flushed with nitrogen (2 times) and heated to 60-80 °C, then hydrogen was charged until a pressure of 4.0-4.5 atm was obtained. The reaction was allowed to proceed, maintaining a pressure of 4.0-4.5 atm, until hydrogen consumption ceased and the reaction was confirmed to be complete. The reactor was returned to atmospheric pressure, the reaction was cooled to 20-30 °C, filtered through a sparkler filter, flushed with nitrogen (2 times), and treated with deionized water (19 kg), which was combined with the solution containing the product. The solvent was distilled under stirring and under vacuum until an oily residue was obtained, without exceeding 50 °C. 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 the mixture was treated with ethyl acetate (71 kg), flushed with nitrogen and stirred at 65-70°C for at least 15 minutes. The reaction mass 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 give 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] A stainless steel reactor was charged with 3-(4-aminophenyl)-2-methoxypropanoic acid (V) (40.5 kg) and (S)-(+)-camphor-10-sulfonic acid (49.9 kg). It was flushed with nitrogen and acetone (81 kg) was added. Deionized water (6.5 kg) was added. The reaction was heated to about 58 °C for 2 hours (reflux, no dissolution occurred). Acetone (81 kg) was added (temperature about 58 °C) and the reaction mass was maintained at reflux (about 58 °C) for 1 hour. The reaction mass was then cooled to 37-42 °C, centrifuged in portions, and washed with acetone (61 kg). The centrifuged product (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid S-(+)-camphor-10-sulfonate (VI)·(S)-C The SA (43.1 kg wet weight, 36.1 kg dry) was used directly in the next step.

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

[0142] A stainless steel reactor was charged with deionized water (72 kg) and wet ((S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid S-(+)-camphor-10-sulfonate (VI)·(S)-CSA (43.1 kg wet weight, 36.1 kg dry), flushed with nitrogen and heated at 20-40 °C for at least 10 min until complete dissolution occurred. The solution was filtered and washed with deionized water (7.2 kg) followed by ethyl acetate (36.1 kg). The resulting solution was flushed with nitrogen, heated to 55-60 °C and 30% ammonia (4.54 kg) was added to dissolve the product. The resulting mixture was stirred at 55-60°C for at least 15 minutes, then 80% acetic acid (1.81 kg) was added through a filter, the reaction was flushed with nitrogen and 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, centrifuged, washed with deionized water (25.3 kg), ethyl acetate (25.3 kg) to give wet (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) (wet weight 11.8 kg, dry weight 10.8 kg), which was used directly in the next step (wet).

[0143] Preparation of (S)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid (VII): Scheme 14. [ka] [Table 13]

[0144] A stainless steel reactor was charged with wet (S)-3-(4-aminophenyl)-2-methoxypropanoic acid (VI) (11.8 kg wet, 10.8 kg dry) and ethyl acetate (16.2 kg) under nitrogen. The mixture was heated to 65-70°C and acetic anhydride (7.0 kg) was added through a cartridge filter over about 15 minutes. The reaction was stirred at 65-70°C for 60 minutes and stirred continuously until completion of the reaction was detected and a precipitate formed. The mixture was cooled to 10-20°C and 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 ground to give (S)-3-(4-acetamidophenyl)-2-methoxypropanoic acid (VII) (12.3 kg).

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

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

[0147] A stainless steel reactor was charged with 4-nitrobenzaldehyde (380 kg), methyl methoxyacetate (418 kg) and tetrahydrofuran (380 kg) and cooled to -10 to -5°C with stirring.

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

[0149] A stainless steel reactor was flushed with nitrogen (twice) and charged with sodium methoxide (228 kg) and tetrahydrofuran (1100 kg) while flushing with nitrogen. The reactor was then flushed with nitrogen for 1 minute and the sodium methoxide solution was cooled to -15 to -10 °C while stirring. The cooled solution was then treated with a previously prepared suspension of methyl methoxyacetate and 4-nitrobenzaldehyde in tetrahydrofuran while maintaining the temperature of the reaction mass below 0 °C. After the addition was complete, the empty reactor was rinsed with tetrahydrofuran (40 kg) and poured into the reaction. The reaction was stirred at -5 to 0 °C for not more than 5 minutes. While maintaining the temperature at -10 to 0 °C, cold toluene (760 kg, -10 to 0 °C) and simultaneously glacial acetic acid (285 kg) were quickly added and the reaction was stirred at -10 to +10 °C for 10 minutes. Deionized water (1140 kg) was added and the reaction mass was stirred for at least 10 minutes at 0-10°C and then at 25-30°C for at least 10 minutes to allow complete dissolution, after which the stirring was stopped and the phases were allowed to separate. The aqueous phase was removed and the separated organic phase was treated with an aqueous sodium chloride solution (previously 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. The stirring was stopped and the phases were allowed to separate. The aqueous phase was removed. The separated organic phase was then dried under vacuum to a temperature of 70-80°C to give an oily residue. The hot residue was flushed with nitrogen and then treated with toluene (380 kg) and the toluene was distilled under vacuum to a temperature of 70-80°C to obtain an oily residue. The resulting hot residue was flushed with nitrogen and then treated with toluene (1767 kg) and the mass was stirred at 40-50°C for at least 10 minutes. This solution was used as is in the next step.

[0150] [Example 6] (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) and method for preparing (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] With nitrogen flushing, methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate (I) in toluene solution in a stainless steel reactor was cooled to 0-10 °C and, while maintaining the temperature at 0-10 °C, triethylamine (342 kg) and methanesulfonyl chloride (304 kg) were added and the reaction was stirred at 0-10 °C for 60 min. Deionized water (1140 kg) was added slowly and the resulting mass was stirred at 55-60 °C for 10 min, after which the stirring was stopped and the phases were allowed to separate. The aqueous phase was removed and 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 min. The stirring was stopped and the phases were allowed to separate. Possible aqueous phase was sent to waste. Under vacuum and stirring, an aliquot of toluene was distilled taking into account the following proportions: for 380 kg of nitrobenzaldehyde used in scheme 15, about 38 kg of toluene was distilled and an aliquot 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 residue obtained was then treated with methanol (1178 kg), flushed with nitrogen, cooled to 20-30 °C and slowly treated with 30% sodium hydroxide (707 kg). The reaction 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 a pH ≦ 3.0. The resulting precipitated product was stirred at 60-65 °C for at least 30 min, then cooled to 35-40 °C and stirred for at least 30 min. The mixture was centrifuged and washed with deionized water (1520 kg) and then with toluene (912 kg). The wet product (about 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 on carbon in water:

[0155] A suitable stainless steel reactor was charged with deionized water (76 kg), 5% palladium on carbon (38 kg), and then the bag was washed with deionized water (19 kg).

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

[0157] A stainless steel reactor flushed with nitrogen (twice) was charged with wet 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV) (786 kg), methanol (1140 kg) and 30% ammonia (114 kg). After returning to atmospheric pressure, the mixture was stirred at 20-30 °C until complete dissolution. The resulting solution was flushed with nitrogen (twice), treated with a previously prepared solution of 5% palladium on carbon in deionized water, and the empty vessel was washed with deionized water (19 kg). The reaction was flushed with nitrogen (twice) and heated to 60-80 °C, then hydrogen was charged until a pressure of 4.0-4.5 atm was obtained. The reaction was allowed to proceed, maintaining a pressure of 4.0-4.5 atm, until hydrogen consumption ceased and the reaction was confirmed to be complete. The reactor was returned to atmospheric pressure, the reaction mass was cooled to 20-30°C, filtered through a sparkler filter, flushed with nitrogen (twice), and treated with deionized water (152 kg), which was then separated into the product-containing 100 ml of water. The mixture was combined with the solution of ethyl acetate (570 kg), flushed with nitrogen and stirred at 65-70 °C for at least 15 minutes. The reaction mass 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 wet product was granulated and dried at 60-70° C. to give 3-(4-aminophenyl)-2-methoxypropanoic acid (V) (about 295 kg).

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

[0159] The starting material 3-(4-aminophenyl)-2-methoxypropanoic acid derived from the two batches was combined (one whole batch and an aliquot from the other batch) to give a total of 400 kg of 3-(4-aminophenyl)-2-methoxypropanoic acid, equivalent to the amount that would have been obtained starting from 500 kg of 4-nitrobenzaldehyde. [Table 17]

[0160] A stainless steel reactor was charged with 3-(4-aminophenyl)-2-methoxypropanoic acid (V) (400 kg) and (S)-(+)-camphor-10-sulfonic acid (493 kg). It was flushed with nitrogen and acetone (800 kg) was added. Deionized water (64 kg) was added. The reaction was heated to about 58°C for 1 hour (reflux, no dissolution occurs). Acetone (800 kg) was added (temperature about 58°C) and the reaction mass was maintained at reflux (about 58°C) for 1 hour. The reaction mass was then cooled to 37-42°C, centrifuged in portions and washed with acetone (600 kg) (during all centrifugation steps, an aliquot of the suspension not involved in the centrifugation was first heated to brown by keeping it at 45-50°C and then the suspension was again heated to 37-42°C before the next centrifugation). 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] A stainless steel reactor was charged with 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), flushed with nitrogen and heated at 20-40 °C for at least 10 min until complete dissolution occurred. The solution was filtered and washed with deionized water (82 kg) followed by ethyl acetate (410 kg). The resulting solution was flushed with nitrogen and heated to 55-60 °C and 30% ammonia (51 kg) was added to precipitate the product. The resulting mixture was stirred at 55-60°C for at least 15 minutes, then 80% acetic acid (20.5 kg) was added through a filter, the reaction was flushed with nitrogen and 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, centrifuged, washed with deionized water (287 kg), 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] A stainless steel reactor was charged with wet (S)-3-(4-aminophenyl)-2-methoxypropanoic acid (VI) (162 kg wet, 138.8 kg dry) and ethyl acetate (208 kg) under nitrogen. The mixture was heated to 65-70°C and acetic anhydride (90 kg) was added through a cartridge filter over approximately 15 minutes. The reaction was stirred at 65-70°C for 90 minutes and stirred continuously until completion of the reaction was detected and a precipitate formed. The mixture was cooled to 10-20°C and 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 ground to give (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 m / z for NO4: 237; Found 236 (MH) - ; 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 C 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°C (onset 159°C). 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 the structure determination were obtained by vapor diffusion of an ethanolic solution of the compound of formula (VII) and L-proline (2:1) using heptane as the antisolvent. 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 is composed of two compounds of formula (VII) and two L-proline molecules.

[0168] Analysis of the single crystal diffraction data indicates that the absolute configuration of the α carbon to the carboxylic acid group is (S). Based on these results, the absolute stereochemistry of the compound of formula (VII) is shown in the structure below. [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 resolving a racemic mixture always uses the same reagents, the characterization that the obtained product has the (S) configuration is confirmed by the specific optical rotation.

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

[0171] The single crystal X-ray diffraction crystallographic data and structure refinement of the compound of formula (VII): L-proline derivative are shown below. Empirical formula C 17 H 24 N2O6 Formula weight 352.38 Temperature 296(2)K Diffractometer 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 Z8 Density (calculated value) 1.287 Mg / m 3 Absorption coefficient 0.098 mm -1 F(000) 1504 Crystal size: 0.49 x 0.25 x 0.08 mm 3 Theta range for data collection: 0.83–28.75°. Exponent range -10<=h<=8,-12<=k<=12,-54<=l<=63 Collected Reflections 19513 Independent reflection 8598 [R(int)=0.0437] Perfection to Theta = 25.00° 99.7% Absorption correction: equivalent to semi-empirical Maximum and minimum transmission 0.992 and 0.777 Refinement method F 2 Total matrix least squares for 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 structural parameter -0.8(13) Maximum diffraction peak and hole 0.382 and -0307 e.Å -3 Calculation program (Bruker) Smart 5.6 / Saint 5.0 / Shelxtl-NT 6.1

[0172] Incorporation by Reference All publications and patents mentioned in this specification, including those listed below, are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0173] Equivalent Although specific embodiments of the present disclosure have been described, the above specification is illustrative and not restrictive. Various modifications of the present disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the present disclosure should be determined by reference to the claims, together with their full scope of equivalents, and the specification, together with such modifications.

[0174] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties to be obtained by the present invention. For example, the present invention provides the following: (Item 1) A substantially optically pure compound of formula (VII): [ka] A method for preparing Compounds of formula (I): [ka] with an activating agent, optionally in the presence of a base, to give an intermediate of formula (IA): [ka] (wherein LG is a leaving group). and forming The intermediate of formula (IA) is treated with a base solution in the presence of an alcohol solvent to remove the leaving group, thereby producing an intermediate of formula (IB): [ka] and forming The intermediate of formula (IB) is hydrolyzed to give a compound of formula (IV): [ka] and forming The compound of formula (IV) is hydrogenated to give a compound of formula (V): [ka] and forming The compound of formula (V) is resolved to obtain a substantially optically pure compound of formula (VI): [ka] and forming acylation of said compound of formula (VI) to form a compound of formula (VII); A method comprising: (Item 2) 2. The method according to claim 1, wherein reacting the compound of formula (I) with an activating agent comprises reacting in the presence of a base and a solvent. (Item 3) 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. (Item 4) 4. The method according to claim 2 or 3, wherein the solvent is toluene. (Item 5) 5. The method according to any one of items 1 to 4, wherein the base is an amine base. (Item 6) 6. The method of claim 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. 8. The method according to any one of items 1 to 7, wherein the activating agent is a sulfonylating agent or a halogenating agent. (Item 9) The method according to any one of items 1 to 8, wherein the activating agent is selected from the group consisting of methanesulfonyl chloride, p-toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, phenyltriflimide, trifluoromethanesulfonic anhydride and nonafluorobutanesulfonic anhydride. (Item 10) 10. The method according to any one of items 1 to 9, wherein the activating agent is methanesulfonyl chloride. (Item 11) The leaving group is -OSO2-aryl, -OSO2-C 1~4 is selected from the group consisting of alkyl, chloro, bromo and iodo, 1~4 The method of any one of items 1 to 7, wherein the alkyl and aryl, at each occurrence, can be optionally substituted with one or more substituents each independently selected from the group consisting of fluoro, bromo and -CH3. (Item 12) The leaving group is -OSO2-phenyl or -OSO2-C 1~4 12. The method according to any one of claims 11, wherein the aryl group is alkyl. (Item 13) The leaving group is -OSOMe, [ka] , -OSO2CF3 [ka] 13. The method of any one of items 11 or 12, wherein said compound is independently selected from the group consisting of -OSO2CF2CF2CF2CF3 and -OSO2CF2CF2CF2CF3. (Item 14) 14. The method according to any one of items 1 to 13, wherein the leaving group is -OSO2Me. (Item 15) 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) 16. The method of claim 15, wherein the alcohol solvent comprises methanol. (Item 17) 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) 18. The method of claim 17, wherein the base solution comprises sodium hydroxide. (Item 19) 19. The method according to any one of items 1 to 18, wherein the base solution comprises about 30% sodium hydroxide. (Item 20) hydrolyzing the intermediate of formula (IB) to form a compound of formula (IV), (i) contacting the intermediate of formula (IB) with an alkali hydroxide and water; (ii) neutralizing to form a compound of formula (IV) 20. The method according to any one of items 1 to 19, comprising: (Item 21) 21. The method of claim 20, wherein the alkali hydroxide is sodium hydroxide. (Item 22) 22. The method of claim 20 or 21, wherein neutralizing comprises acidifying to a pH less than or equal to 3 by adding an acid. (Item 23) 24. The method according to claim 22, wherein the acid is phosphoric acid or hydrochloric acid or a mixture thereof. 24. The method of any one of items 1 to 23, wherein hydrogenating the compound of formula (IV) to form a compound of formula (V) comprises contacting the compound of formula (IV) with hydrogen and a catalyst. (Item 25) 25. The method of claim 24, wherein the catalyst is about 5% Pd / C. (Item 26) 26. The process according to any one of items 1 to 25, wherein the hydrogenation is carried out at a reaction temperature maintained between about 60-80° C. and at a pressure of about 3-5 atm. (Item 27) resolving said compound of formula (V) to form a substantially optically pure compound of formula (VI), (a) resolving a compound of formula (V) in the presence of a chiral acid, thereby forming a chiral salt of a compound of formula (VI); (b) neutralizing the chiral salt of the compound of formula (VI), thereby forming the compound of formula (VI); 27. The method according to any one of items 1 to 26, comprising: (Item 28) 28. The method of 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. (Item 29) 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) [ka] 30. The method according to any one of Items 27 to 29, (Item 31) 31. The method according to any one of items 1 to 30, wherein the dividing step further comprises maintaining a temperature of 55-60° C. with stirring. (Item 32) 32. The method according to any one of items 27 to 31, wherein neutralizing comprises (i) contacting the chiral salt of the compound of formula (VI) with an aqueous base solution, and then (ii) acidifying the solution by adding an acid. (Item 33) 33. The method of claim 32, wherein the aqueous base comprises an aqueous ammonium hydroxide solution. (Item 34) Acylation may be achieved by reacting the compound of formula (VI) with ethyl acetate, tetrahydrofuran, 34. The process according to any one of items 1 to 33, comprising contacting with an acylating agent in the presence of an organic solvent selected from the group consisting of diethyl ether, dichloromethane and toluene. (Item 35) 35. The method of claim 34, wherein the acylating agent is acetic anhydride. (Item 36) 36. The method according to claim 34 or 35, wherein the organic solvent is ethyl acetate. (Item 37) The method according to any one of items 1 to 36, wherein the acylation occurs at a temperature of 60 to 70° C. (Item 38) 38. The process according to any one of items 1 to 37, wherein the compound of formula (VII) is produced on a multi-kilogram scale. (Item 39) 39. The process according to item 38, wherein at least about 130 kg of the compound of formula (VII) is obtained. (Item 40) The substantially optically pure compound of formula (VII) is composed of at least 98% of the enantiomer: [ka] (expressed as a percentage of both enantiomers). (Item 41) 41. The purified compound of formula (VII) according to item 40, having a content of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid of not more than 0.15% by HPLC. (Item 42) Compounds of formula (I): [ka] A method for preparing Compounds of formula (II): [ka] and a compound of formula (III): [ka] and contacting the mixture with a base, thereby forming a compound of formula (I). (Item 43) Item 43. The method of item 42, wherein the contacting is carried out in a solvent. (Item 44) 44. The method of claim 42 or 43, wherein the solvent is tetrahydrofuran. (Item 45) 45. The method according to any one of items 42 to 44, wherein the contacting is carried out at a temperature less than or equal to 0°C. (Item 46) 46. ​​The method according to any one of items 42 to 45, wherein the contacting comprises stirring for about 5 minutes and / or is carried out at a reaction temperature maintained at −5 to 0° C. (Item 47) 47. The method according to any one of items 42 to 46, wherein the base is an alkali metal alkoxide. (Item 48) Item 48. The method of item 47, wherein the alkali metal alkoxide is selected from the group consisting of sodium methoxide, lithium methoxide and potassium methoxide. (Item 49) 49. The method according to claim 47 or 48, wherein the alkali metal alkoxide is sodium methoxide. (Item 50) [ka] or a pharma- ceutically acceptable salt thereof. (Item 51) A purified compound of formula (VII) obtainable by the method according to any one of items 1 to 40: [ka] 1. The purified compound of formula (VII), having a content of (S)-(−)-3-(4-aminophenyl)-2-methoxypropionic acid of 0.15% or less by HPLC.

Claims

1. A substantially optically pure compound of formula (VII): 【Chemistry 51】 A method for preparing Compounds of formula (I): 【Chemistry 52】 with an activating agent to produce an intermediate of formula (IA): 【Chemistry 53】 (wherein LG is a leaving group). and forming The intermediate of formula (IA) is treated with a base solution in the presence of an alcohol solvent to remove the leaving group, thereby producing an intermediate of formula (IB): 【Chemical 54】 and forming The intermediate of formula (IB) is hydrolyzed to give a compound of formula (IV): 【Chemistry 55】 and forming The compound of formula (IV) is hydrogenated to give a compound of formula (V): 【Chemistry 56】 and forming The compound of formula (V) is resolved to obtain a substantially optically pure compound of formula (VI): 【Chemistry 57】 and forming acylation of said compound of formula (VI) to form a compound of formula (VII); Including, The substantially optically pure compound of formula (VI) can be represented by the enantiomers: 【Chemistry 67】 At least 95% of method.

2. 2. The method of claim 1, wherein reacting the compound of formula (I) with an activating agent comprises reacting in the presence of a base and a solvent.

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

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

5. Compounds of formula (I): 【Chemistry 52】 to produce an intermediate of formula (IA): 【Chemistry 53】 The method of any one of claims 1 to 4, wherein forming is in the presence of an amine base.

6. 6. The method of 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 activating agent is a sulfonylating agent or a halogenating agent.

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

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

11. The leaving group is -OSO ２ -aryl, -OSO ２ -C １～４ is selected from the group consisting of alkyl, chloro, bromo and iodo, １～４ Alkyl and aryl, at each occurrence, are fluoro, bromo and -CH ３ The method of any one of claims 1 to 7, optionally substituted with one or more substituents each independently selected from the group consisting of:

12. The leaving group is -OSO ２ -phenyl or -OSO ２ -C １～４ 12. The method of claim 11, wherein the alkyl group is an alkyl group.

13. 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 13. The method of claim 11 or 12, wherein the compound is independently selected from the group consisting of:

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

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

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

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

18. 20. The method of claim 17, wherein the base solution comprises sodium hydroxide.

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

20. hydrolyzing the intermediate of formula (IB) to form a compound of formula (IV), (i) contacting the intermediate of formula (IB) with an alkali hydroxide and water; (ii) neutralizing to form a compound of formula (IV) The method according to any one of claims 1 to 19, comprising:

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

22. 22. The method of claim 20 or 21, wherein neutralizing comprises acidifying to a pH less than or equal to 3 by adding an acid.

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

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

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

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

27. resolving said compound of formula (V) to form a substantially optically pure compound of formula (VI), (a) resolving a compound of formula (V) in the presence of a chiral acid, thereby forming a chiral salt of a compound of formula (VI); (b) neutralizing the chiral salt of the compound of formula (VI), thereby forming the compound of formula (VI); The method according to any one of claims 1 to 26, comprising:

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

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

31. 31. The method of any one of claims 1 to 30, wherein the dividing step further comprises maintaining a temperature of 55-60°C with stirring.

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

33. 33. The method of claim 32, wherein the aqueous base solution comprises aqueous ammonium hydroxide.

34. 34. The method of any one of claims 1 to 33, wherein acylating 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. 35. The method of claim 34, wherein the acylating agent is acetic anhydride.

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

37. A process according to any one of claims 1 to 36, wherein the acylation takes place at a temperature of 60 to 70°C.

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

39. 39. The method of claim 38, wherein at least about 130 kg of the compound of formula (VII) is obtained.

40. Use of a compound obtained from a method as defined in claims 1 to 39 for the manufacture of a medicament for treating a disease, characterized in that said compound is capable of modulating the activity of a PPAR receptor.

41. The use of claim 40, wherein the disease is selected from the group consisting of fibrotic diseases, dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, atherogenesis, 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.

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

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