Method for preparing 3-(4'-aminophenyl)-2-methoxypropionic acid and its analogs and intermediates

Abstract

The present disclosure provides methods for preparing 3-(4'-aminophenyl)-2-methoxypropionic acid and its analogs and intermediates, which are expected to modulate the activity of receptors such as PPARs receptors.

Description

Background Art

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

[0002] Three types of PPARs have been identified: the alpha type, which is expressed in the liver, kidney, heart and other tissues and organs, the beta / delta type, which is expressed, for example, in the brain, and the gamma type, which is expressed in three forms: gamma 1, gamma 2 and gamma 3. 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, IBDs (irritable bowel disease), ulcerative colitis and Crohn's disease.

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

[0004] Accordingly, there is a need for effective methods to prepare compounds capable of modulating the activity of PPARs receptors in order to address the treatment of such diseases. SUMMARY OF THE INVENTION

[0005] The present disclosure provides, for example, methods of preparing compounds that can act as PPARs receptor modulators.

[0006] Part of the present disclosure provides a method for preparing a compound of formula (VII):

[0007]

[0008] One embodiment provides a method for preparing a compound of formula (VI):

[0009]

[0010] Also contemplated herein are methods of making analogs and intermediates thereof.

[0011] In one embodiment, at least some of the compounds identified as intermediates, for example as part of the synthetic schemes disclosed herein, are contemplated to be compounds of the present disclosure, such as compounds represented by formula (I) or pharmaceutically acceptable salts or stereoisomers thereof:

[0012] DETAILED DESCRIPTION OF THE INVENTION

[0014] The features and other details of the present disclosure will be described in more detail. Before the present disclosure is further described, some terms used in the specification, examples and appended claims are collected here. These definitions should be read with reference to other parts of the present disclosure and understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as generally understood by those skilled in the art.

[0015] definition

[0016] The term "alkenyl" as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-12, 2-10 or 2-6 carbon atoms, referred to herein as C 2- C 12 Alkenyl, C 2- C 10 Alkenyl and C 2- C 6 Alkenyl. 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.

[0017] The term "alkoxy" as used herein refers to an alkyl group attached to an oxygen (-O-alkyl). Exemplary alkoxy groups include, but are not limited to, groups of alkyl, alkenyl, or alkynyl groups having 1-12, 1-8, or 1-6 carbon atoms, referred to herein as C 1 -C 12 Alkoxy, C 1 -C 8 Alkoxy, and C 1 -C 6 Alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, and the like. Similarly, exemplary "alkenyloxy" groups include, but are not limited to, vinyloxy, allyloxy, butenyloxy, and the like.

[0018] The term "alkyl" as used herein refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, 1-6, 1-4 or 1-3 carbon atoms, respectively referred to herein as C 1 -C 12 Alkyl, C 1 -C 10 Alkyl, C 1 -C 6 Alkyl, C 1-4 Alkyl and C 1-3Alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, and the like. In certain embodiments, alkyl refers to C 1 -C 6 In certain embodiments, cycloalkyl refers to C 3 -C 6 Cycloalkyl.

[0019] The alkyl, alkenyl and alkynyl groups can, in certain embodiments, be optionally substituted or interrupted with at least one group selected from alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amide, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphate, phosphino, sulfate, thioether, sulfonamido, sulfonyl and thiocarbonyl.

[0020] The term "alkynyl" as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-12, 2-8 or 2-6 carbon atoms, referred to herein as C 2 -C 12 Alkynyl, C 2- C 8 Alkynyl and C 2- C 6 Alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl, and the like.

[0021] The term "amide" or "amide group" as used herein refers to an amido group of the formula -R a C(O)N(R b )-、-R a C(O)N(R b )R c -or-C(O)NR b R c The residues, R a , R b and R cEach independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocyclyl and hydrogen. Amide can be through the carbon, the nitrogen, R b , R c or R a to another group. Amides can also be cyclic, for example R b and R c , R a and R b , or R a and R c They may be joined together to form a 3- to 12-membered ring, such as a 3- to 10-membered ring or a 5- to 6-membered ring.

[0022] The term "amidino" as used herein refers to a residue of the formula -C(=NR)NR'R" wherein R, R' and R" can each be independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl and heterocyclyl.

[0023] The term "amine" or "amino" as used herein refers to an amino group of the formula -NR d R e 、-N(R d )R e -or-R e N(R d )R f - residues, where R d , R e and R f is independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl and hydrogen. d , R e or R f Attached to the parent molecular group. The amino group can also be cyclic, such as R d , R e or R f Any two of the amino groups may be linked together or to N to form a 3- to 12-membered ring, such as morpholino or piperidinyl. The term amino group also includes the corresponding quaternary ammonium salts of any amino group, such as -[N(R d )(R e )(R f )] + Exemplary amino groups include aminoalkyl groups, wherein R d , R e or R f At least one of them is an alkyl group.

[0024] The term "aryl" as used herein refers to one, two or other polycarbocyclic aromatic ring systems. In certain embodiments, aryl refers to a monocyclic and / or bicyclic 6 to 10 membered ring. The aromatic ring can be substituted at one or more ring positions by substituents selected from the following: alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amide, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclic, hydroxyl, imino, ketone, nitro, phosphate, phosphate, phosphino, sulfate, thioether, sulfonamido, sulfonyl and thiocarbonyl. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings, wherein two adjacent rings share two or more carbons (the rings are "fused rings"), wherein at least one ring is aromatic, e.g., the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, and / or aryl. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.

[0025] The term "arylalkyl" as used herein refers to an aryl group having at least one alkyl substituent, for example -aryl-alkyl. Exemplary arylalkyl groups include, but are not limited to, arylalkyl groups having a monocyclic aromatic ring system, wherein the ring contains 6 carbon atoms. For example, "phenylalkyl" includes phenylC 4 Alkyl, benzyl, 1-phenylethyl, 2-phenylethyl, etc.

[0026] The term "carbonyl" as used herein refers to the residue -C(O)-.

[0027] The term "carboxy" as used herein refers to the residue -COOH or its corresponding salt, such as -COONa and the like.

[0028] The term "cyano" as used herein refers to the residue -CN.

[0029] The term "cycloalkyl" as used herein refers to a monovalent saturated or unsaturated cyclic, bicyclic or bridged bicyclic hydrocarbon group of 3-12, 3-8, 4-8 or 4-6 carbon atoms, referred to herein as "C" derived from cycloalkane, for example. 4-8"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, amide, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphate, phosphino, sulfate, thioether, sulfonamido, sulfonyl, and thiocarbonyl. Cycloalkyl groups can be fused to other cycloalkyl, aryl, or heterocyclyl groups. In certain embodiments, cycloalkyl refers to C 3 -C 6 alkyl.

[0030] The term "halo" or "halogen" as used herein refers to F, Cl, Br or I.

[0031] The term "haloalkyl" as used herein refers to an alkyl group substituted with one or more halogen atoms.

[0032] The term "nitro" as used herein refers to the residue -NO 2 .

[0033] The term "phenyl" as used herein refers to a 6-membered carbocyclic aromatic ring. Phenyl can also be fused to a cyclohexane or cyclopentane ring. Phenyl can be substituted with one or more substituents including alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amide, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclic, hydroxyl, imino, ketone, nitro, phosphate, phosphate, phosphino, sulfate, thioether, sulfonamido, sulfonyl and thiocarbonyl.

[0034] The term "phosphate" as used herein refers to the residue -OP(O)(OR aa ) 2 or its anion. The term "phosphonate" refers to the residue -P(O)(OR aa ) 2 or its anion. The term "phosphite" refers to the residue -PR aa (O)(OR aa ) or anions thereof, wherein each R aa It can be selected from, for example, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, hydrogen, haloalkyl, heteroaryl and heterocyclyl.

[0035] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein refers to any of various solvents, dispersion media, coatings, isotonic agents and absorption delaying agents, etc. that are compatible with drug 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.

[0036] The term "pharmaceutical composition" as used herein refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0037] The term "pharmaceutically acceptable salt" as used herein refers to salts of acidic or basic groups that may be present in the compounds used in the compositions of the present invention. The basic compounds included in the compositions of the present invention are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of the basic compounds are those that 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, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Compounds that include an amino moiety included in the compositions of the present invention can form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above. The acidic compounds included in the compositions of the present invention are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, and in particular calcium, magnesium, sodium, lithium, zinc, potassium and iron salts.

[0038] Compounds of the present disclosure may contain one or more stereocenters and / or double bonds, and therefore exist as stereoisomers such as geometric isomers, enantiomers or diastereomers. The term "stereoisomer" as used herein includes all geometric isomers, enantiomers or diastereomers. These compounds can be specified by the symbols "R" or "S", depending on the configuration of the substituents around the carbon atom that produces stereoisomerism. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. A mixture of enantiomers or diastereomers can be specified by the "(±)" nomenclature, but the skilled person will recognize that the structure can implicitly represent a chiral center.

[0039] Individual stereoisomers of the disclosed compounds can be synthetically prepared from commercially available raw materials containing asymmetric or stereogenic centers, or by preparing a racemic mixture followed by resolution methods well known to those of ordinary skill in the art. These resolution methods are such as (1) attaching the enantiomeric mixture to a chiral adjuvant, separating the resulting diastereomeric mixture by recrystallization or chromatography, and releasing the optically pure product from the adjuvant, (2) salifying with an optically active resolving agent, or (3) directly separating a mixture of optically active enantiomers on a chiral chromatographic column. Mixtures of stereoisomers 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 stereoisomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthesis methods.

[0040] Book The disclosed compounds may also exist as geometric isomers. - The representation bond can be a single bond, double bond or triple bond as described herein. The disclosure encompasses various geometric isomers and mixtures thereof resulting from the arrangement of substituents around carbon-carbon double bonds or around carbocyclic rings. Substituents around carbon-carbon double bonds are designated as "Z" or "E" configurations, wherein the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise specified, the structure describing the double bond encompasses both "E" and "Z" isomers.

[0041] Substituents around a carbon-carbon double bond can alternatively be referred to as "cis" or "trans," where "cis" represents substituents on the same side of the double bond and "trans" represents substituents on opposite sides of the double bond. Arrangements of substituents around a carbocyclic ring are designated as "cis" or "trans." The term "cis" represents substituents on the same side of the ring plane and the term "trans" represents substituents on opposite sides of the ring plane. Mixtures of compounds in which substituents are located on the same and opposite sides of the ring plane are designated as "cis / trans."

[0042] The terms "substantially optically pure", "substantially enantiomerically pure", "optically pure" or "enantiomerically pure" as used herein in the context of describing a compound (e.g., a compound described herein) means that at least 95%, e.g., at least 96%, at least 97%, or at least 98% of the compound has a stereocenter of a desired given configuration. It should be recognized that the percentages are expressed as percentages of both enantiomers of the compound. For example, a compound of Formula VII is substantially optically pure if at least 95% is (S)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid (the levorotatory enantiomer) based on the sum of the levorotatory and dextrorotatory enantiomers.

[0043] The compounds disclosed herein can exist in solvated and unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc., and it is expected that the disclosure encompasses both solvated and unsolvated forms. In certain embodiments, the compound is amorphous. In certain embodiments, the compound is in crystalline form. In certain embodiments, the compound is a polymorph.

[0044] The present disclosure also encompasses isotopically-labeled compounds of the present disclosure which are equivalent to those described herein but for the fact 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 usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl.

[0045] Certain isotopically labeled disclosed compounds (e.g., 3 H and 14 C-labeled) for use in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (also known as 14 C) isotopes are particularly preferred because of their ease of preparation and detection. In addition, heavier isotopes such as deuterium (i.e. 2 H) Substitution may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and thus may be preferred in certain circumstances. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Examples herein, substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0046] The term "prodrug" refers to a compound that is transformed in vivo to produce a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms, such as hydrolysis in the blood. For example, if a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, then the prodrug can comprise an ester formed by replacing the hydrogen atom of the acid group with a group such as (C 1 -C 8 ) alkyl, (C 2 -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, 1-(N-(alkoxycarbonyl)amino)ethyl having 4 to 10 carbon atoms, 3-hydroxymethylbenzoyl, 4-crotonyl, γ-butyrolactone-4-yl, di-N,N-(C 1 -C 2 ) alkylamino (C 2 -C 3 ) alkyl (such as β-dimethylaminoethyl), carbamoyl-(C 1 -C 2 ) alkyl, N,N-di(C 1 -C 2 )alkylcarbamoyl-(C 1 -C 2 )alkyl and piperidino-, pyrrolidino- or morpholino (C 2 -C 3 )alkyl.

[0047] Similarly, if the disclosed compound contains an alcohol functional group, a prodrug can be formed by replacing the hydrogen atom of the alcohol group with a group such as (C 1 -C 6 )alkanoyloxymethyl, 1-((C 1 -C 6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1 -C 6 )alkanoyloxy)ethyl(C 1 -C 6 ) alkoxycarbonyloxymethyl, N-(C 1 -C 6 ) alkoxycarbonylaminomethyl, succinyl, (C 1 -C 6 ) alkanoyl, α-amino (C 1 -C 4 )alkanoyl, aryl acyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, wherein each α-aminoacyl is independently selected from natural L-amino acids, P(O)(OH) 2 , -P(O)(O(C 1 -C 6 )alkyl) 2 or a glycosyl group (a residue formed by removing a hydroxyl group from the hemiacetal form of a carbohydrate).

[0048] If the disclosed compounds include an amine functional group, a prodrug can be formed by replacing the hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR′-carbonyl wherein R and R′ are each independently (C 1 -C 10 ) alkyl, (C 3 -C 7 )cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or a natural α-aminoacyl-natural α-aminoacyl, -C(OH)C(O)OY 1 where Y 1 is H, (C 1 -C 6 )alkyl or benzyl, -C(OY 2 )Y 3 where Y 2 Yes (C 1 -C 4 ) alkyl and Y 3 Yes (C 1 -C 6 ) alkyl, carboxyl (C 1 -C 6 ) alkyl, amino (C 1 -C 4 )alkyl or mono-N- or di-N,N-(C 1 -C 6 )alkylaminoalkyl, -C(Y 4 )Y 5 where Y 4 is H or methyl and Y 5 Is one-N- or two-N,N-(C 1 -C 6 ) alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl.

[0049] At least a portion of the present disclosure provides compounds represented by formula (I), formula (IV), formula (V), formula (VI) and formula (VII), as described below. Pharmaceutical compositions are also contemplated herein, which include compounds represented by formula (I), formula (IV), formula (V), formula (VI) and formula (VII) and, for example, pharmaceutically acceptable excipients and / or carriers.

[0050] Compound

[0051] In one aspect, a method for preparing a substantially optically pure compound of formula (VII) is provided:

[0052]

[0053] The method comprises:

[0054] The compound of formula (I):

[0055] Reaction with an activating agent in the optional presence of a base to form an intermediate of formula (IA):

[0056] Where LG is the leaving group;

[0057] The intermediate of formula (IA) is treated with a base solution in the presence of an alcoholic solvent to eliminate the leaving group and thereby form the intermediate of formula (IB):

[0058]

[0059] The intermediate of formula (IB) is hydrolyzed to form a compound of formula (IV):

[0060]

[0061] Hydrogenating a compound of formula (IV) to form a compound of formula (V):

[0062]

[0063] Optionally resolving the compound of formula (V) to form a substantially optically pure compound of formula (VI):

[0064] and

[0065] Acylation of the compound of formula (VI) to form the compound of formula (VII).

[0066] Reacting the compound of formula (I) with an activator may include reacting in the presence of a base and a solvent. In certain embodiments, the solvent is selected from toluene, dichloromethane, tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran and acetonitrile, for example, the solvent may be toluene. The base may be an amine base, for example, selected from triethylamine, N,N-diisopropylethylamine and pyridine. For example, the amine base may be triethylamine.

[0067] The compound of formula (I) can be an isolated solid prior to this step or can be dissolved in a suitable solvent such as the solvent used to prepare or process the compound of formula (I). For example, the compound of formula (I) can be unisolated and dissolved in an organic solvent such as toluene prior to this step.

[0068] The expected activator includes a sulfonylating agent or a halogenating agent. For example, the activator can be selected from methanesulfonyl chloride, p-toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, phenylbis(trifluoromethanesulfonyl)imide, trifluoromethanesulfonic anhydride, and nonafluorobutanesulfonic anhydride. In certain embodiments, the activator is methanesulfonyl chloride.

[0069] In certain embodiments, the leaving group is selected from -OSO 2 -Aryl, -OSO2 -C 1-4 Alkyl, chlorine, bromine and iodine; among which C 1-4 Alkyl and aryl groups may be optionally substituted with one or more substituents, each specific value of which is independently selected from fluorine, bromine and -CH 3 For example, the leaving group can be -OSO 2 -phenyl or -OSO 2 -C 1-4 alkyl.

[0070] In certain embodiments, the leaving group is selected from:

[0071] -OSO 2 Me, -OSO 2 CF 3 , and-OSO 2 CF 2 CF 2 CF 2 CF 3 , for example, the leaving group can be -OSO 2 Me.

[0072] The contemplated alcohol solvent may include at least one of methanol, ethanol, isopropanol and butanol. For example, the alcohol solvent may include methanol.

[0073] In certain embodiments, the alkaline solution comprises at least one of: sodium hydroxide, lithium hydroxide, and potassium hydroxide. For example, the alkaline solution may include sodium hydroxide, such as 30% sodium hydroxide.

[0074] In certain embodiments, hydrolyzing the intermediate of formula (IB) to form the compound of formula (IV) comprises: contacting the intermediate of formula (IB) with an alkali metal hydroxide (e.g., sodium hydroxide) and water; and neutralizing to form the compound of formula (IV). Neutralization can include acidifying to a pH of less than or equal to 3 by adding an acid such as phosphoric acid or hydrochloric acid or a mixture thereof.

[0075] In certain 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, for example, the catalyst is selected from PtO 2 、Pd(OH) 2 / C, Pt / C, 10% Pd / C and 5% Pd / C, such as 5% Pd / C catalyst. Hydrogenation can be carried out at a reaction temperature maintained at about 60-80°C and a pressure of about 3 to 5atm, about 3.5 to 4.5atm or about 4.0 to 4.5atm. For example, hydrogenation can be carried out in the presence of one or more hydrogenation solvents, the solvent being selected from an aqueous solution of ammonia, methanol, ethanol, isopropanol, N,N-dimethylformamide, tetrahydrofuran and ethyl acetate, such as an aqueous solution of ammonia, methanol or N,N-dimethylformamide. In certain embodiments, the hydrogenation solvent is a mixture of methanol or methanol and ammonia, such as a 30% aqueous ammonia solution.

[0076] 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.

[0077] Resolving the compound of formula (V) to form a substantially optically pure compound of formula (VI) may comprise:

[0078] a) resolving the compound of formula (V) in the presence of a chiral acid thereby forming a chiral salt of the compound of formula (VI); and

[0079] b) neutralizing the chiral salt of the compound of formula (VI) thereby forming the compound of formula (VI).

[0080] In certain embodiments, the chiral acid is selected from (S)-(+)-camphor-10-sulfonic acid, (2R,3R)-(+)-tartaric acid, (S)-(-)-malic acid, (1S)-(+)-3-bromocamphor-10-sulfonic acid, (S)-1-phenylethanesulfonic 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 result in resolution of a racemic mixture or its enantiomers, such as (S)-(+)-camphor-10-sulfonic acid.

[0081] In certain embodiments, the chiral salt of the compound of formula (VI) is:

[0082]

[0083] ·S)-(+)-Camphor-10-sulfonic acid.

[0084] In various embodiments, the splitting may further include adding primers and maintaining the temperature at 30-35° C. under stirring, and / or may occur in the presence of acetone and water. In certain embodiments, the splitting may further include maintaining the temperature at 55-60° C. (e.g., 58° C.) under stirring, and / or may occur in the presence of acetone and water.

[0085] The primer may be a substantially optically pure chiral acid salt of the compound of formula (VI). In certain embodiments, the chiral acid is (S)-(+)-camphor-10-sulfonic acid.

[0086] For example, a primer can be represented by the formula:

[0087]

[0088] ·S)-(+)-Camphor-10-sulfonic acid.

[0089] At the resolution endpoint, if the requirements are not met, a reprocessing can be performed in which the solution is kept at the resolution temperature for a longer time under stirring.

[0090] Neutralization may comprise (i) contacting a chiral salt of a compound of formula (VI) with an aqueous base solution (e.g., ammonium hydroxide); and then (ii) acidifying the solution by adding an acid (e.g., acetic acid). Neutralization may occur in the presence of one or more solvents, such as water and ethyl acetate.

[0091] Acylation may comprise contacting a compound of formula (VI) with an acylating agent (e.g. acetic anhydride) in the presence of an organic solvent selected from ethyl acetate, tetrahydrofuran, diethyl ether, dichloromethane and toluene, such as ethyl acetate. The acylation may occur at a temperature of 60 to 70° C., such as 65 to 70° C. The acylation may further comprise dissolving the compound isolated from the previous step in one or more solvents such as water and / or ethyl acetate to prepare a solution and contacting the solution with an acylating agent such as acetic acid. The step may occur at a temperature of 60 to 70° C., such as 65 to 70° C.

[0092] In certain embodiments, after optionally splitting the compound of formula (V) to form a substantially optically pure compound of formula (VI), the mother liquor from the splitting step may still contain the desired enantiomer (as the salt of the splitting agent) and the undesired enantiomer. In these embodiments, the splitting may optionally further comprise:

[0093] a) recovering the mixture of enantiomers (chiral salt of the 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 additional substantially optically pure compound of formula (VI), thereby increasing the overall process yield; or

[0094] b) Distilling a portion of the mother liquor and precipitating the desired enantiomer from the mother liquor (salt as chiral resolving agent), thereby increasing the overall process yield.

[0095] Also contemplated herein is a process of racemizing the undesired enantiomer or a chiral salt thereof 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.

[0096] Contemplated bases include those selected from hydroxides, alkoxides (e.g., methoxides), amides (e.g., lithium diisopropylamide), hydrides (e.g., NaH), organic lithiums, and Grignard reagents. For bases requiring counterions, exemplary counterions contemplated herein may include alkali metals or alkaline earth metals such as lithium, sodium, potassium, or calcium; or organic counterions such as tetraalkylammonium.

[0097] In certain embodiments, the compound of formula (VII) can be prepared on a multi-kilogram scale, for example, at least about 8 to 11 kg, about 13 to 15 kg, or about 130 to 150 kg are obtained. In certain embodiments, at least about 130 kg of the compound of formula (VII) is obtained.

[0098] In certain embodiments, the substantially optically pure compound of formula (VII) is at least 98% of the desired enantiomer:

[0099]

[0100] (Expressed as percentages of the two enantiomers.) In certain embodiments, the content of (S)-(-)-3-(4-aminophenyl)-2-methoxypropanoic acid is no more than 0.15%, as determined, for example, by HPLC.

[0101] In an alternative embodiment, the preparation of the substantially optically pure compound of formula (VII) disclosed comprises acylation of racemic compound (V) to produce a racemic mixture of 3-(4-acetylaminophenyl)-2-methoxypropionic acid, and resolution of racemic 3-(4-acetylaminophenyl)-2-methoxypropionic acid to provide a substantially enantiomerically pure compound of formula (VII). For example, the formation of a substantially optically pure compound of formula (VII) may comprise:

[0102] a) resolving a racemic mixture of 3-(4-acetylaminophenyl)-2-methoxypropionic acid in the presence of a chiral base thereby forming a chiral salt of said compound; and

[0103] b) neutralizing said chiral salt of said compound thereby forming a compound of formula (VII).

[0104] In certain embodiments, the chiral base is selected from, for example, enantiomerically pure 1-amino-2-propanol, strychnine, dehydroabietinamine, N,α-dimethylbenzylamine, N,N-dimethyl-1-phenylethylamine, ephedrine, α-methylbenzylamine, 1-(2-naphthyl)ethylamine, quinidine, quinine, strychnine, valine, and all other chiral bases that can result in resolution of a racemic mixture. For example, a chiral salt of a compound can be represented by the following formula:

[0105]

[0106] Chiral bases.

[0107] In certain embodiments, the present disclosure provides methods for preparing compounds of formula (I):

[0108]

[0109] The method comprises providing a compound of formula (II):

[0110]

[0111] And a compound of formula (III):

[0112]

[0113] and contacting the mixture with a base (eg in a solvent such as tetrahydrofuran); thereby forming a compound of formula (I).

[0114] The contacting can be carried out at a temperature of less than or equal to 10° C., for example, can include stirring for about 5 minutes and / or at a reaction temperature maintained at -10 to 10° C., for example -5 to 0° C. The base can be an alkali metal alkoxide, for example selected from sodium methoxide, lithium methoxide and potassium methoxide, for example sodium methoxide.

[0115] In certain embodiments, provided herein are compounds represented by the following formula:

[0116]

[0117] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0118] In certain embodiments, the compound of formula (I) may exist as a mixture of stereoisomers. Expected stereoisomers of formula (I) include, for example, compounds of formula (a), formula (b), formula (c) or formula (d):

[0119]

[0120] Also provided in part herein is a method for preparing a substantially optically pure compound of formula (VI):

[0121]

[0122] The method comprises: treating a compound of formula (I):

[0123]

[0124] Reaction with an activating agent in the optional presence of a base to form an intermediate of formula (IA):

[0125]

[0126] (IA), wherein LG is a leaving group;

[0127] The intermediate of formula (IA) is treated with a base solution in the presence of an alcoholic solvent to eliminate the leaving group and thereby form the intermediate of formula (IB):

[0128]

[0129] The intermediate of formula (IB) is hydrolyzed to form a compound of formula (IV):

[0130]

[0131] Hydrogenating a compound of formula (IV) to form a compound of formula (V):

[0132]

[0133] Resolving a compound of formula (V) to form a substantially optically pure compound of formula (VI), wherein the methods and variables are as defined herein.

[0134] Procedures for preparing the compounds described herein are provided below with reference to Schemes 1-21. In the reactions described below, it may be necessary to protect reactive functional groups (such as hydroxyl, amino or carboxyl) to prevent them from undesirably participating in the reaction. The introduction of the groups and the methods required for their introduction and removal are known to those skilled in the art (e.g., see Greene, Wuts, Protective Groups in Organic Synthesis. 4th Ed. (2007)). The deprotection step may be the final step in the synthesis, thereby removing the protecting groups to provide the compounds of Formula I disclosed herein. The raw materials used in the following schemes can be purchased or prepared by methods described in the chemical literature or variations thereof, using methods known to those skilled in the art. The order in which the steps are performed can vary depending on the groups introduced and the reagents used, but will be apparent to those skilled in the art. Example

[0135] The procedures disclosed herein can be carried out in many ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods below, it should be understood that all proposed reaction conditions, including solvent selection, reaction atmosphere, reaction temperature, experimental duration and post-processing procedures, can be selected to become the standard conditions of the reaction unless otherwise specified. Those skilled in the art of organic synthesis will understand that the functional groups present on each part of the molecule should be compatible with the described reagents and reactions. Substituents incompatible with the reaction conditions are obvious to those skilled in the art, and therefore alternative methods are pointed out. The raw materials of the embodiments are commercially available or easily prepared from known substances by standard methods.

[0136] At least some of the compounds identified as intermediates (eg, as part of the synthetic schemes disclosed herein) are expected to be compounds of the disclosure.

[0137] abbreviation:

[0138] generally:

[0139] APCI Atmospheric Pressure Chemical Ionization

[0140] DSC Differential Scanning Calorimetry

[0141] EA Element Analysis

[0142] ESI Electrospray ionization

[0143] GC Gas Chromatography

[0144] HPLC High Performance Liquid Chromatography

[0145] ICP-AES Inductively Coupled Plasma Atomic Emission Spectroscopy

[0146] LC Liquid Chromatography

[0147] MHz Megahertz

[0148] MS

[0149] NMR Nuclear Magnetic Resonance

[0150] TLC Thin layer chromatography

[0151] Me Methyl

[0152] Ph Phenyl

[0153] Et Ethyl

[0154] Solvents and reagents

[0155] CSA Camphorsulfonic Acid

[0156] DMF N,N-Dimethylformamide

[0157] EtOAc Ethyl acetate

[0158] Mesyl

[0159] NaOMe Sodium Methanol

[0160] THF Tetrahydrofuran

[0161] General experiments:

[0162] 1H NMR spectra were recorded on a Varian Gemini 200 NMR spectrometer operating at 200 MHz or 600 MHz. Proton chemical shifts are reported as delta scale in ppm, with the solvent residual peak (DMSO-d 6 : 2.50 ppm) as internal standard. Data are expressed as follows: chemical shift (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, sx = sextet, sp = septet, m = multiplet, br = broad, dd = doublet of doublets, dt = doublet of triplets, qd = quadruple doublet, dquin = double quintet), coupling constant (J, Hz) and integration (#H).

[0163] The sample was dissolved in DMSO-d 6 Record 13 C NMR, operating at 600 MHz. Completely decoupled spectra were obtained.

[0164] Mass spectra were recorded on a Thermo-Finnigan LCQ-Advantage mass spectrometer or MS thermal LCQ-fleet. LC / MS data were acquired using positive / negative mode switching or using negative mode polarity, with acquisition parameters optimized in negative polarity for the signal 236 m / z, corresponding to the quasi-molecular ion [MH] of the sample. - .

[0165] Elemental analysis (CHN) was performed on a Carlo Erba EA1108 instrument under the following conditions: sample weight: 0.5-2 mg; oven temperature: 1010°C; column temperature: 80°C; gas: He; flow rate: 100 mL / min. Elemental analysis (oxygen) was performed on a Carlo Erba EA1108 instrument under the following conditions: sample weight: 0.5-2 mg; oven temperature: 1010°C; column temperature: 60°C; gas: He; flow rate: 100 mL / min.

[0166] FT-IR Spectroscopy FT-IR / ATR was performed on the samples as received using a Perkin Elmer spectrometer model Spectrum Two equipped with a diamond probe. The spectra were taken in the frequency range 450–4000 cm -1 collect.

[0167] UV-visible spectra were recorded with a spectrophotometer Shimadzu UV 2600 operating under the following conditions: cell: 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 sample dissolved in 100 mL methanol.

[0168] DSC was carried out with a Mettler-Toledo TGA-DSC1 apparatus, operating under the following conditions (tray: aluminum (open); heating rate: 10°C / min; gas: nitrogen; flow rate: 30 mL / min). The specific rotation was determined as follows. 0.5 g of the sample was accurately weighed in a 50 mL volumetric flask, dissolved and diluted to volume with methanol (concentration: 10 mg / mL, corresponding to 1% w / v). The optical rotation angle of the resulting solution was determined using a polarimeter tube with an optical rotation length equivalent to 1 dm. The specific rotation was calculated with reference to the dry matter using the following formula (α x 50 x 100) / (W x (100-m)), where α = the optical rotation angle read; W = sample weight (g); and m = sample water content (%).

[0169] Chiral purity (HPLC) was determined as follows.

[0170] Equipment and operating conditions

[0171]

[0172] Prepare solutions

[0173] -Sample solution: Accurately weigh 10 mg of sample in a 10 mL volumetric flask, then dissolve and dilute to volume with the mobile phase (concentration: 1000 μg / mL).

[0174] - Reference solution: Accurately weigh 10 mg of (R,S)-3-(4-acetylaminophenyl)-2-methoxypropionic acid standard in a 100 mL volumetric flask, then dissolve and dilute to volume with the mobile phase.

[0175] -System suitability test (SST) solution: Accurately weigh 10 mg of (S)-(-)-3-(4-acetylaminophenyl)-2-methoxypropionic acid standard in a 10 mL volumetric flask, add 2 mL of reference solution, then dissolve and dilute to volume with mobile phase (final concentration of right-hand enantiomer: 10 μg / mL, corresponding to 1% of the sample solution, corresponding to 99% chiral purity of (S)-(-)-3-(4-acetylaminophenyl)-2-methoxypropionic acid).

[0176] System suitability tests and procedures

[0177] 20 μl of sample solution and SST solution were injected in the chromatograph and the chromatograms were recorded.

[0178] The elution order of the major peaks is as follows: (R)-(+)-3-(4-acetylaminophenyl)-2-methoxypropanoic acid (dextrorotatory enantiomer): RRT=0.9; and (S)-(-)-3-(4-acetylaminophenyl)-2-methoxypropanoic acid (levorotatory enantiomer): RRT=1.0.

[0179] The chromatographic system can be used for the test under the condition that the h / v ratio is not less than 1.5, where h is the distance between the top of the dextrorotatory enantiomer peak and the baseline, and v is the distance between the lowest point of the concave region defined by the dextrorotatory enantiomer peak and the laevorotatory enantiomer peak and the baseline.

[0180] The chiral purity % is calculated from the following formula: (A l x 100) / (A l +A d ), where A l = the peak area of ​​(S)-(-)-3-(4-acetylaminophenyl)-2-methoxypropionic acid (levorotatory enantiomer) and A d = Peak area of ​​(R)-(+)-3-(4-acetylaminophenyl)-2-methoxypropionic acid (dextral enantiomer) in the sample solution.

[0181] The above methods can be used to determine the optical purity or enantiomeric purity of the compounds described herein.

[0182] Example 1: Preparation of methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate (I)

[0183] Solution 1.

[0184]

[0185] Table 1. Production scale batch formulation (synthesis of compound (I))

[0186] substance factor* Quantity(kg) Sodium Methanol 0.6 30.0 THF 1.5 75 4-Nitrobenzaldehyde 1.0 50 Methyl methoxyacetate 1.1 55 THF 2.0 100 THF 0.5 25.0 Cold Toluene 2.0 100 Glacial acetic acid 1.0 50 Deionized water 3.0 150 Deionized water 2.0 100 Sodium chloride 0.2 10 Deionized water 2.0 100 Sodium chloride 0.2 10 Toluene 1.0 50 Toluene 1.5 75 Cold Toluene 0.5 25

[0187] *The factor refers to the amount of 4-nitrobenzaldehyde used

[0188] Preparation of 4-nitrobenzaldehyde in a suspension of methyl methoxyacetate and tetrahydrofuran:

[0189] 4-Nitrobenzaldehyde (50 kg), methyl methoxyacetate (55 kg) and tetrahydrofuran (100 kg) were added to a stainless steel reactor under stirring and cooled to -5 to +5°C. Preparation of methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate (I):

[0190] The stainless steel reactor was flushed with nitrogen (2x) and sodium methoxide (30.0 kg) and tetrahydrofuran (75 kg) were added 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 tetrahydrofuran of 4-nitrobenzaldehyde, maintaining the reaction mass temperature below 10°C. After the addition was complete, the empty reactor was flushed with tetrahydrofuran (25.0 kg) and poured into the reaction. The reaction was stirred at -10 to +10°C for no more than 5 minutes. 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 at 0 to 10°C for at least 10 minutes, and then at 20 to 30°C for at least 10 minutes to ensure complete dissolution, after which time stirring was stopped and the phases were allowed to separate. The aqueous phase was eliminated, and the separated organic phase was treated with an aqueous sodium chloride solution (prepared in advance by adding 10 kg of sodium chloride to 100 kg of deionized water). The mass was then heated to 50 to 60°C while stirring for at least 10 minutes. Stirring was stopped and the phases were allowed to separate. The aqueous phase was eliminated, and the organic phase was treated with sodium chloride (prepared in advance by adding 10 kg of sodium chloride to 100 kg of deionized water). The mass was extracted again using the same protocol. The separated organic phase was then distilled under reduced pressure at no more than 80°C to remove THF. The reactor containing the hot residue was flushed with nitrogen and then treated with toluene (50 kg), and the toluene was distilled under reduced pressure at no more than 80°C. The resulting hot residue was flushed with nitrogen and then treated with toluene (75 kg), and the mass was stirred at 30 to 45°C for at least 30 minutes to ensure good product precipitation. The mixture was then cooled to -10 to 0°C and stirred at this temperature for at least 1 hour. The resulting suspension was centrifuged batchwise and washed with cold toluene (25 kg) to obtain wet methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate (I) (84 kg), which was used directly.

[0191] 3-Hydroxy-2-methoxy-3-(4-nitrophenyl)propionic acid methyl ester (I): IR: 3468, 1737, 1514, 1350, 1201, 1101 cm -1 ; LCMS(-)APCI:C 11 H 13 NO 6 m / z calculated: 255, found: 254 (MH); 1 H NMR (200 MHz, DMSO-d 6): δ 8.16 (AA'BB' system, J = 8.8 Hz, 2H), 7.62 (AA'BB' system, J = 8.8 Hz, 2H), 5.97 (d, J = 6.0 Hz, 1H), 5.05 (dd, J = 6.0, 4.0 Hz, 1H), 4.10 (d, J = 4.0 Hz, 1H), 3.60 (s, 3H), 3.20 (s, 3H); 13 C NMR (150 MHz, DMSO-d 6 ): δ170.2, 149.4, 146.7, 127.8, 122.9, 84.1, 72.7, 58.2, 51.6; UV-Vis (MeOH): λ max 202,270; Analysis and calculation: (C 11 H 13 NO 6 ): C 51.97; H 5.16; N 5.42; O37.52.

[0192] Example 2: Preparation of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) and (S)-(-)-3-(4-acetylaminophenyl)-2-methoxypropionic acid (VII)

[0193] Solution 2.

[0194]

[0195] Preparation of 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV):

[0196] Solution 3.

[0197]

[0198] Table 2. Production scale batch formulation (synthesis of compound (IV))

[0199]

[0200] *Factor refers to the amount of methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl) propionate (dry)

[0201] A stainless steel reactor flushed with nitrogen (2x) was loaded with wet methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate (I) (84 kg) and toluene (283 kg), then cooled to 0 to 10°C under nitrogen flushing. Maintaining the temperature at 0 to 10°C, triethylamine (42.3 kg) and methanesulfonyl chloride (36.3 kg) were added, and the reaction was stirred at 0 to 10°C for 30 minutes. Deionized water (145 kg) was slowly added, and the resulting mass was stirred at 50 to 60°C for 10 minutes, after which time stirring was stopped and the phases were allowed to separate. The aqueous phase was eliminated, and the filtered organic phase was washed with toluene (7.3 kg). Toluene was removed by distillation under reduced pressure and not exceeding 60°C to obtain an oily residue. The resulting residue was then treated with methanol (218 kg), transferred to another reactor, flushed with nitrogen, cooled to 20 to 30°C, and slowly treated with 30% sodium hydroxide (94 kg). The reaction was stirred at 20 to 30° C. for 2 hours. Deionized water (290 kg) was added and the solution was heated to 55 to 65° C. At this temperature, 85% phosphoric acid (94 Kg) was slowly added until a pH of ≤ 3.0 was obtained. The resulting precipitated product was stirred at 55 to 65° C. for at least 30 minutes, then cooled to 25 to 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 to 80° C. to obtain 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV) (50.4 kg).

[0202] 2-methoxy-3-((methylsulfonyl)oxy)-3-(4-nitrophenyl)propanoic acid methyl ester (I-A1): LCMS (+) ESI: C 12 H 15 NO 8 m / z calculated for S: 333; found: 356 (M+Na); 1 H NMR (200 MHz, DMSO-d 6 ): δ 8.25 (AA'BB' system, J = 8.5 Hz, 2H), 7.72 (AA'BB' system, J = 8.5 Hz, 2H), 6.00 (d, J = 4.0 Hz, 1H), 4.41 (d, J = 4.0 Hz, 1H), 3.65 (s, 3H), 3.21 (s, 3H), 3.11 (s, 3H).

[0203] 2-Methoxy-3-(4-nitrophenyl)acrylate methyl ester (IB): LCMS(-)APCI: C 11 H 11 NO 5 m / z calculated: 237; found: 236M-H); 1 H NMR (200 MHz, DMSO-d6 ): δ 8.20 (AA'BB' system, J = 8.8 Hz, 2H), 7.99 (AA'BB' system, J = 8.8 Hz, 2H), 6.98 (s, 1H), 3.80 (s, 3H), 3.78 (s, 3H).

[0204] 2-Methoxy-3-(4-nitrophenyl)acrylic acid (IV): LCMS(-)APCI: C 10 H 9 NO 5 m / z calculated: 223, found: 222 (MH); 1 H NMR (200 MHz, DMSO-d 6 ): δ 13.37 (s, 1H), 8.21 (AA'BB' system, J = 9.1 Hz, 2H), 7.98 (AA'BB' system, J = 9.1 Hz, 2H), 6.93 (s, 1H), 3.79 (s, 3H).

[0205] Preparation of 3-(4-aminophenyl)-2-methoxypropanoic acid (V):

[0206] Solution 4.

[0207]

[0208] Table 3. Production scale batch formulation (synthesis of compound (V))

[0209]

[0210] * Factor refers to the amount of dry 2-methoxy-3-(4-nitrophenyl)acrylic acid

[0211] 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 x 2.65 kg) and the suspension was stirred thoroughly.

[0212] A stainless steel reactor charged with methanol (252 kg) flushed with nitrogen (2x) was cooled to 0 to 10°C and anhydrous 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV) (50.4 kg) was added. The resulting solution was flushed with nitrogen (2x) and treated with a previously prepared 5% palladium / carbon solution in N,N-dimethylformamide, and the empty container was washed with N,N-dimethylformamide (2.65 kg). The reaction was flushed with nitrogen (2x), heated to 60 to 80°C and then hydrogen was added until pressures of 3.5 and 4.5 atm were obtained. The reaction was allowed to proceed, maintaining a pressure of 3.5 to 4.5 atm until hydrogen consumption ceased and the reaction was deemed complete. The reactor was returned to atmospheric pressure, the reaction was cooled to 20 to 30°C, flushed with nitrogen (2x) and treated with 30% ammonia (20.2 kg) and deionized water (12.6 kg) in sequence, and stirred at 20 to 30°C until complete dissolution occurred. The solution was filtered through a sparkler filter and washed with deionized water (25.2 kg). The reactor was flushed with nitrogen and the solvent was removed by distillation under reduced pressure at a temperature not exceeding 70°C. The residue was treated with deionized water (151 kg), heated to 60 to 70°C, and the product was precipitated by adding 80% acetic acid (25.2 kg). The mixture was stirred at 60 to 70°C for at least 10 minutes and then treated with ethyl acetate (50 kg), flushed with nitrogen and stirred at 60 to 70°C for at least 15 minutes. The reaction mass was cooled to 10 to 20°C and stirred for at least 30 minutes. The suspension was centrifuged in batches, washed with deionized water (101 kg) and ethyl acetate (25.2 kg). The wet product was granulated and dried at 60 to 70°C to obtain 3-(4-aminophenyl)-2-methoxypropionic acid (V) (~37.5 kg).

[0213] 3-(4-Aminophenyl)-2-methoxyacrylic acid(IC):LCMS(+)ESI:C 10 H 11 NO 3 m / z calculated: 193, found: 194 (M+H); 1 H NMR (200 MHz, DMSO-d 6 ): δ 12.00 (br s, 1H), 7.43 (AA'BB' system, J=8.4 Hz, 2H), 6.76 (s, 1H), 6.53 (AA'BB' system, J=8.4 Hz, 2H), 5.80 (br s, 2H), 3.61 (s, 3H).

[0214] 3-(4-Aminophenyl)-2-methoxypropionic acid (V): IR: 3044, 2950-2830, 2623-2064, 1618-1516, 1106cm -1 ; LCMS (+) ESI: C 10 H 13NO 3 m / z calculated: 195, found: 196 (M+H); 1 H NMR (200 MHz, DMSO-d 6 ): δ 8.40-6.40 (br s, 3H), 6.83 (AA'BB' system, J = 8.1 Hz, 2H), 6.41 (AA'BB' system, J = 8.1 Hz, 2H), 3.77 (ABX system, J = 7.5, 5.3 Hz, 1H), 3.19 (s, 3H), 2.74 (ABX system, J = 13.9, 5.3 Hz, 1H), 2.65 (ABX system, J = 13.9, 7.5 Hz, 1H). Analytical calculation: (C 10 H 13 NO 3 ): C 61.40; H 6.81; N7.11; O 24.91.

[0215] Preparation of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid S-(+)-camphor-10-sulfonate:

[0216] Solution 5.

[0217]

[0218] Table 4. Production scale batch formulation (synthesis of compound (VI)·(S)-CSA)

[0219]

[0220] *Factor refers to the amount of 3-(4-aminophenyl)-2-methoxypropionic acid (dry)

[0221] A stainless steel reactor was loaded with 3-(4-aminophenyl)-2-methoxypropionic acid (V) (37.5 kg) and acetone (113 kg) under nitrogen flushing. 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 to 55° C. until dissolution was complete. Acetone (75 kg) was added, the solution was cooled to 30 to 35° C. and treated with the primer (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid S-(+)-camphor-10-sulfonic acid salt (VI)·(S)-CSA (0.38 kg). The reaction was stirred at 30 to 35° C. for at least 3 hours until good precipitation occurred. The suspension was centrifuged in batches 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 directly used in the next step.

[0222] Preparation of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI):

[0223] Solution 6.

[0224]

[0225] Table 5. Production scale batch formulation (synthesis of compound (VI))

[0226]

[0227] *The factor refers to the amount of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid S-(+)-camphor-10-sulfonate (dry).

[0228] Preparation of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI):

[0229] 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), flushed with nitrogen and heated at 20 to 30° C. for at least 10 minutes until complete dissolution occurred. The solution was filtered and washed with deionized water (7.0 kg) and then ethyl acetate (35.0 kg). The resulting solution was flushed with nitrogen, heated to 50 to 60° C. and 30% ammonia (6.3 kg) was added to precipitate the product. The resulting mixture After stirring at 50-60° C. for at least 5 minutes, 80% acetic acid (4.38 kg) was added through the filter, the reaction was flushed with nitrogen and stirred at 50 to 60° C. for at least 30 minutes, then cooled to 10-20° C. and stirred for at least 1 hour. The reaction was centrifuged and washed with deionized water (17.5 kg), ethyl acetate (17.5 kg) and deionized water (17.5 kg), and dried at 50-60° C. to obtain (S)-(-)-3-(4-aminophenyl)-2-methoxypropanoic acid (VI) (9.6 kg, 27%), which was used directly in the subsequent step.

[0230] (S)-(-)-3-(4-Aminophenyl)-2-methoxypropionic acid (VI): [α] D 20 -30 to -26 (1% w / v H 2 O / CH 3 OH(1:1v / v)); IR: 2931, 2891, 2826, 2625, 2136, 1587, 1548, 1512, 1106, 1092cm -1 ; LCMS (+) ESI: C 10 H 13NO 3 m / z calculated: 195, found: 196 (M+H); 1 H NMR (200 MHz, DMSO-d 6 ): δ 9.0-6.0 (br s, 3H), 6.83 (AA'BB' system, J = 8.1 Hz, 2H), 6.43 (AA'BB' system, J = 8.1 Hz, 2H), 3.76 (ABX system, J = 7.5, 5.3 Hz, 1H), 3.19 (s, 3H), 2.75 (ABX system, J = 13.9, 5.3 Hz, 1H), 2.65 (ABX system, J = 13.9, 7.5 Hz, 1H). Analytical calculation: (C 10 H 13 NO 3 ): C, 61.45; H, 6.79; N 7.12; O 24.65.

[0231] Preparation of (S)-(-)-3-(4-acetylaminophenyl)-2-methoxypropionic acid (VII):

[0232] Solution 7.

[0233]

[0234] Table 6. Production scale batch formulation (synthesis of compound (VII))

[0235]

[0236] * Factor refers to the amount of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid

[0237] Anhydrous (S)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) (9.6 kg) and ethyl acetate (14.4 kg) were added to a stainless steel reactor at 0 to 10°C under nitrogen flushing. The reaction mass was heated to 60 to 70°C and acetic anhydride (5.6 kg) was added through a filter column over about 30 minutes. The reaction was stirred at 60 to 70°C for 1 hour, then treated with deionized water (0.5 kg) and stirred at 60 to 70°C for at least 15 minutes, during which time a precipitate formed. The mixture was cooled to 10 to 20°C and stirred for at least 30 minutes, then centrifuged and the resulting solid was washed with ethyl acetate (4.80 kg) and deionized water (14.4 kg). The resulting product was dried at 60 to 70°C for 13-16 hours and ground to obtain (S)-3-(4-acetylaminophenyl)-2-methoxypropionic acid (VII) (10.3 kg).

[0238] (S)-(-)-3-(4-Acetylaminophenyl)-2-methoxypropionic acid: (VII): [α]D 20 -26 to -19 (1% w / vH 2 O / CH 3 OH(1:1v / v)); IR: 3322, 3089, 2930, 2827, 2714, 2490, 1722, 1637, 1601, 1551, 1516, 1231, 1207, 1120, 1110cm -1 ; LCMS (+) ESI: C 12 H 15 NO 4 m / z calculated: 237, found: 238 (M+H); 1 HNMR (200 MHz, DMSO-d 6 ): δ12.96 (s, 1H), 9.84 (s, 1H), 7.43 (AA'BB' system, J=8.5 Hz, 2H), 7.10 (AA'BB' system, J=8.5 Hz, 2H), 3.86 (ABX system, J=7.6, 5.2 Hz, 1H), 3.00 (s, 3H), 2.95-2.70 (ABX system, J=13.9, 7.6, 5.2 Hz, 2H), 2.00 (s, 3H).

[0239] Table 7. Specifications of (S)-3-(4-acetylaminophenyl)-2-methoxypropanoic acid (VII) prepared by Scheme 7

[0240] (S)-(+)-Camphor-10-sulfonic acid Not more than 0.1% (HPLC) (S)-3-(4-Aminophenyl)-2-methoxypropionic acid Not more than 0.15% (HPLC) Other impurities Not more than 0.1% (HPLC) palladium No more than 10ppm (ICP-AES) Chiral purity Not less than 98% (HPLC) Acetic acid Not more than 5000ppm (GC) Residual solvent (ethyl acetate) Not more than 5000ppm (GC)

[0241] Example 3: Preparation of methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate (I):

[0242] Solution 8.

[0243]

[0244] Table 8. Production scale batch formulation (synthesis of compound (I))

[0245] substance factor* Quantity(kg) Sodium Methanol 0.6 28.5 THF 2.5 119 4-Nitrobenzaldehyde 1.0 47.5 Methyl methoxyacetate 1.1 52 THF 1.0 47.5 THF 0.5 23.8 Cold Toluene 2.0 95 Glacial acetic acid 0.75 36 Deionized water 3.0 143 Deionized water 1.0 48 Sodium chloride 0.1 4.75 Toluene 1.0 47.5 Toluene 4.65 221

[0246] *Factor refers to the dosage of 4-nitrobenzaldehyde

[0247] Preparation of 4-nitrobenzaldehyde in a suspension of methyl methoxyacetate and tetrahydrofuran:

[0248] 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.

[0249] Preparation of methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate (I):

[0250] The stainless steel reactor was flushed with nitrogen (2x), and sodium methoxide (28.5 kg) and tetrahydrofuran (119 kg) were added 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 with stirring. The cooled solution was then treated with a previously prepared suspension of 4-nitrobenzaldehyde in methyl methoxyacetate and tetrahydrofuran while maintaining the reaction mass temperature below 0°C. After the addition was complete, the empty reactor was flushed with tetrahydrofuran (23.8 kg) and poured into the reaction. The reaction was stirred at -5 to 0°C for no more than 5 minutes. Maintaining the temperature at -10 to 0°C, cold toluene (95 kg, -10 to 0°C) was added rapidly, followed by glacial acetic acid (36 kg) and the reaction 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, then at 25 to 30 ° C for at least 10 minutes to ensure complete dissolution, after which time stirring was stopped and the phases were allowed to separate. The aqueous phase was eliminated and the separated organic phase was treated with an aqueous sodium chloride solution (prepared in advance by adding 4.75 kg of sodium chloride to 48 kg of deionized water). The mass was then heated to 25 to 30 ° C while stirring for at least 15 minutes. Stirring was stopped and the phases were allowed to separate. The aqueous phase (64 kg) was eliminated. The separated organic phase was then distilled under reduced pressure at a temperature of up to 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 toluene was distilled under reduced pressure at a temperature of up to 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 at 40 to 50 ° C for at least 10 minutes. The solution was used as is in the subsequent steps.

[0251] Example 4: Method for preparing (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) and (S)-(-)-3-(4-acetylaminophenyl)-2-methoxypropionic acid (VII)

[0252] Solution 9.

[0253]

[0254] Preparation of 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV):

[0255] Solution 10.

[0256]

[0257] Table 9. Production scale batch formulation (synthesis of compound (IV))

[0258]

[0259] *Factor refers to the dosage of 4-nitrobenzaldehyde

[0260] A toluene solution of methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate (I) in a stainless steel reactor was cooled to 0 to 10°C under nitrogen flushing, while maintaining the temperature at 0 to 10°C, triethylamine (42.8 kg) and methanesulfonyl chloride (38 kg) were added, and the reaction was stirred at 0 to 10°C for 60 minutes. Deionized water (143 kg) was slowly added, and the resulting mass was stirred at 55 to 60°C for 10 minutes, after which time stirring was stopped and the phases were allowed to separate. The aqueous phase (199 kg) was eliminated, the organic phase was filtered, and the filter was washed with toluene (7.1 kg). The filtered solution was heated to 55 to 60°C for 10 minutes. Stirring was stopped and the phases were allowed to separate; the possible aqueous phase was sent to waste (3.5 kg). An aliquot of toluene is distilled under vacuum and under stirring, taking into account the following ratios: for 50 kg of nitrobenzaldehyde used in Scheme 8, approximately 5 kg of toluene is distilled, and this aliquot of the distilled toluene is sent to waste. The toluene is distilled off under reduced pressure and at a temperature not exceeding 60° C., obtaining an oily residue. The resulting residue is then treated with methanol (147 kg), flushed with nitrogen, cooled to 20 to 30° C., and slowly treated with 30% sodium hydroxide (88 kg). The reaction is stirred at 20 to 30° C. for 3 hours. Deionized water (184 kg) is added, and the solution is heated to 60 to 65° C. At this temperature, 37% hydrochloric acid (35.2 kg) and 85% phosphoric acid (7.6 kg) are slowly added to precipitate the product. If necessary, 85% phosphoric acid is added to obtain a pH ≤ 3.0. The resulting precipitated product is stirred at 60 to 65° C. for at least 30 minutes and then cooled to 35 to 40° C., and stirred for at least 30 minutes. The mixture was centrifuged, 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 subsequent step.

[0261] Preparation of 3-(4-aminophenyl)-2-methoxypropanoic acid (V):

[0262] Solution 11.

[0263]

[0264] Table 10. Production scale batch formulation (synthesis of compound (V))

[0265]

[0266]

[0267] *Factor refers to the dosage of 4-nitrobenzaldehyde

[0268] Prepare a 5% palladium / carbon suspension in water:

[0269] A suitable stainless steel reactor was charged with deionized water (9.5 kg), 5% palladium on carbon (4.75 kg) and the bag was then washed twice with deionized water (2 x 2.4 kg).

[0270] Preparation of 3-(4-aminophenyl)-2-methoxypropanoic acid (V):

[0271] A stainless steel reactor flushed with nitrogen (2x) was loaded with wet 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV) (82 kg), methanol (143 kg) and 30% ammonia (14.3 kg). After restoring atmospheric pressure, the mixture was stirred at 20 to 30°C until complete dissolution. The resulting solution was flushed with nitrogen (2x) and treated with a pre-prepared 5% palladium / carbon solution in deionized water, and the empty container was washed with deionized water (2.4 kg). The reaction was flushed with nitrogen (2x), heated to 60 to 80°C and then hydrogen was added until a pressure of 4.0 to 4.5 atm was obtained. The reaction was allowed to proceed, maintaining a pressure of 4.0 to 4.5 atm until hydrogen consumption ceased and the reaction was confirmed to be complete. The reactor was restored to atmospheric pressure and the reaction was cooled to 20 to 30°C, filtered through a sparkler filter, flushed with nitrogen (2x) and treated with deionized water (19 kg), which was combined with the solution containing the product. The solvent was distilled under reduced pressure to an oily residue under stirring at no more than 50°C. The residue was treated with deionized water (95 kg), heated to 65 to 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 to 70° C. for at least 10 minutes, then the mixture was treated with ethyl acetate (71 kg), flushed with nitrogen and stirred at 65 to 70° C. for at least 15 minutes. The reaction mass was cooled to 15 to 20° C. and stirred for at least 30 minutes. The suspension was centrifuged in batches and washed with deionized water (47.5 kg) and ethyl acetate (47.5 kg). The wet product was dried at 60 to 70° C. to obtain 3-(4-aminophenyl)-2-methoxypropionic acid (V) (40.5 kg).

[0272] Preparation of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid S-(+)-camphor-10-sulfonate:

[0273] Solution 12.

[0274]

[0275] Table 11. Production scale batch formulation (synthesis of compound (VI)·(S)-CSA)

[0276] substance factor* Quantity(kg) 3-(4-Aminophenyl)-2-methoxypropionic acid 1.0 40.5 (S)-(+)-10-Camphor-sulfonic acid 1.2321 49.9 acetone 2.0 81 Deionized water 0.16 6.5 acetone 2.0 81 acetone 1.5 61

[0277] *Factor refers to the amount of 3-(4-aminophenyl)-2-methoxypropionic acid (dry)

[0278] A stainless steel reactor was loaded with 3-(4-aminophenyl)-2-methoxypropionic acid (V) (40.5 kg) and (S)-(+)-camphor-10-sulfonic acid (49.9 kg); 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 to 42° C., centrifuged in batches, and washed with acetone (61 kg). The centrifuged product (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid S-(+)-camphor-10-sulfonic acid salt (VI)·(S)-CSA (wet weight: 43.1 kg, dry weight: 36.1 kg) was used directly in the subsequent step.

[0279] Preparation of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI):

[0280] Solution 13.

[0281]

[0282] Table 12. Production scale batch formulation (synthesis of compound (VI))

[0283]

[0284]

[0285] *The factor refers to the amount of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid S-(+)-camphor-10-sulfonate (dry).

[0286] 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 (wet weight: 43.1 kg, 36.1 kg, dry), flushed with nitrogen and heated at 20 to 40° C. for at least 10 minutes until complete dissolution occurred. The solution was filtered and washed with deionized water (7.2 kg) and then ethyl acetate (36.1 kg). The resulting solution was flushed with nitrogen, heated to 55 to 60° C. and 30% ammonia (4.54 kg) was added. The product was precipitated. The resulting mixture was stirred at 55 to 60° C. for at least 15 minutes, then 80% acetic acid (1.81 kg) was added through the filter, the reaction was flushed with nitrogen and stirred at 55 to 60° C. for at least 30 minutes, then cooled to 2-7° C. and stirred for at least 1 hour. The reaction mass was centrifuged and washed with deionized water (25.3 kg), ethyl acetate (25.3 kg) in batches to obtain wet (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) (wet weight 11.8 kg, dry weight 10.8 kg), which (wet) was used directly in the subsequent step.

[0287] Preparation of (S)-(-)-3-(4-acetylaminophenyl)-2-methoxypropionic acid (VII):

[0288] Solution 14.

[0289]

[0290] Table 13. Production scale batch formulation (synthesis of compound (VII))

[0291]

[0292]

[0293] *Factor refers to the amount of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (dry)

[0294] A stainless steel reactor was charged with wet (S)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) (11.8 kg wet weight, 10.8 kg dry) and ethyl acetate (16.2 kg) under nitrogen. The mixture was heated to 65 to 70°C and acetic anhydride (7.0 kg) was added through a filter column over about 15 minutes. The reaction was stirred at 65 to 70°C for 60 minutes, and once the reaction endpoint was detected, stirring was continued until a precipitate formed. The mixture was cooled to 10 to 20°C and stirred at 10 to 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 to 70°C for 13-16 hours and ground to obtain (S)-3-(4-acetylaminophenyl)-2-methoxypropionic acid (VII) (12.3 kg).

[0295] Example 5: Preparation of methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate (I):

[0296] Solution 15.

[0297]

[0298] Table 14. Production scale batch formulation (synthesis of compound (I))

[0299] substance factor* Quantity(kg) Sodium Methanol 0.6 228 THF 2.895 1100 4-Nitrobenzaldehyde 1.0 380 Methyl methoxyacetate 1.1 418 THF 1.0 380 THF 0.105 40 Cold Toluene 2.0 760 Glacial acetic acid 0.75 285 Deionized water 3.0 1140 Deionized water 1.0 380 Sodium chloride 0.1 38 Toluene 1.0 380 Toluene 4.65 1767

[0300] *Factor refers to the dosage of 4-nitrobenzaldehyde

[0301] Preparation of 4-nitrobenzaldehyde in a suspension of methyl methoxyacetate and tetrahydrofuran:

[0302] 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.

[0303] Preparation of methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate (I):

[0304] The stainless steel reactor was flushed with nitrogen (2x), and sodium methoxide (228 kg) and tetrahydrofuran (1100 kg) were added 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 with stirring. The cooled solution was then treated with a previously prepared suspension of methyl methoxyacetate and tetrahydrofuran of 4-nitrobenzaldehyde while maintaining the reaction mass temperature below 0°C. After the addition was complete, the empty reactor was flushed with tetrahydrofuran (40 kg) and poured into the reaction. The reaction was stirred at -5 to 0°C for no more than 5 minutes. Maintaining the temperature at -10 to 0°C, cold toluene (760 kg, -10 to 0°C) and simultaneously glacial acetic acid (285 kg) were added rapidly 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 at 0 to 10 ° C for at least 10 minutes, and then at 25 to 30 ° C for at least 10 minutes to ensure complete dissolution, after which time stirring was stopped and the phases were allowed to separate. The aqueous phase was eliminated, and the separated organic phase was treated with an aqueous sodium chloride solution (prepared in advance by adding 38 kg of sodium chloride to 380 kg of deionized water). The mass was then heated to 25 to 30 ° C while stirring for at least 10 minutes. Stirring was stopped and the phases were allowed to separate. The aqueous phase was eliminated. The separated organic phase was then distilled under reduced pressure at a temperature of up to 70 to 80 ° C to an oily residue. The reactor containing the hot residue was flushed with nitrogen and then treated with toluene (380 kg), and toluene was distilled under reduced pressure at a temperature of up to 70 to 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 to 50 ° C for at least 10 minutes. The solution was used as it was in the subsequent steps.

[0305] Example 6: Method for preparing (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) and (S)-(-)-3-(4-acetylaminophenyl)-2-methoxypropionic acid (VII)

[0306] Solution 16.

[0307]

[0308] Preparation of 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV):

[0309] Solution 17.

[0310]

[0311] Table 15. Production scale batch formulation (synthesis of compound (IV))

[0312]

[0313] *Factor refers to the dosage of 4-nitrobenzaldehyde

[0314] A toluene solution of methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate (I) in a stainless steel reactor was cooled to 0 to 10° C. under nitrogen flushing, while maintaining the temperature at 0 to 10° C., triethylamine (342 kg) and methanesulfonyl chloride (304 kg) were added, and the reaction was stirred at 0 to 10° C. for 60 minutes. Deionized water (1140 kg) was slowly added, and the resulting mass was stirred at 55 to 60° C. for 10 minutes, after which stirring was stopped and the phases were allowed to separate. The aqueous phase was eliminated and the organic phase was filtered, and the filter was washed with toluene (57 kg). The filtered solution was heated to 55 to 60° C. for 10 minutes. Stirring was stopped and the phases were allowed to separate; the possible aqueous phase was sent to waste. An aliquot of toluene was distilled under vacuum and under stirring, taking into account the following ratio: for 380 kg of nitrobenzaldehyde used in Scheme 15, approximately 38 kg of toluene was distilled and this aliquot of the distilled toluene was sent to waste. Toluene is removed by distillation under reduced pressure and not more than 60°C to obtain an oily residue. The resulting residue is then treated with methanol (1178kg), flushed with nitrogen, cooled to 20 to 30°C, and slowly treated with 30% sodium hydroxide (707kg). The reaction is stirred at 20 to 30°C for 3 hours. Deionized water (1474kg) is added and the solution is heated to 60 to 65°C. At this temperature, 37% hydrochloric acid (281kg) and 85% phosphoric acid (61kg) are slowly added to precipitate the product. If necessary, 85% phosphoric acid is added to obtain a pH of ≤3.0. The resulting precipitated product is stirred at 60 to 65°C for at least 30 minutes and then cooled to 35 to 40°C, and stirred for at least 30 minutes. The mixture is centrifuged, washed with deionized water (1520kg) and then washed with toluene (912kg). The wet product (about 786kg) is used for subsequent steps.

[0315] Preparation of 3-(4-aminophenyl)-2-methoxypropanoic acid (V):

[0316] Solution 18.

[0317]

[0318] Table 16. Production scale batch formulation (synthesis of compound (V))

[0319]

[0320]

[0321] *Factor refers to the dosage of 4-nitrobenzaldehyde

[0322] Prepare a 5% palladium / carbon suspension in water:

[0323] A suitable stainless steel reactor was charged with deionized water (76 kg), 5% palladium on carbon (38 kg), and the bag was then rinsed with deionized water (19 kg).

[0324] Preparation of 3-(4-aminophenyl)-2-methoxypropanoic acid (V):

[0325] A stainless steel reactor flushed with nitrogen (2x) was loaded 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 to 30°C until complete dissolution. The resulting solution was flushed with nitrogen (2x) and treated with a previously prepared 5% palladium / carbon solution in deionized water, and the empty container was washed with deionized water (19 kg). The reaction was flushed with nitrogen (2x), heated to 60 to 80°C and then hydrogen was added until a pressure of 4.0 to 4.5 atm was obtained. The reaction was allowed to proceed, maintaining a pressure of 4.0 to 4.5 atm until hydrogen consumption ceased and the reaction was deemed complete. The reactor was returned to atmospheric pressure, the reaction was cooled to 20 to 30°C, filtered through a sparkler filter, flushed with nitrogen (2x) and treated with deionized water (152 kg), which was combined with the solution containing the product. The solvent was distilled under stirring and under vacuum to an oily residue at no more than 50°C. The residue was treated with deionized water (760 kg), heated to 65 to 70°C, and the product was precipitated by adding 37% hydrochloric acid (122 kg) and 80% acetic acid (84 kg). The mixture was stirred at 65 to 70°C for at least 10 minutes; at this stage it was confirmed that the pH was 3.8 to 4.2 (no more than 4.2), and then the mixture was treated with ethyl acetate (570 kg), flushed with nitrogen and stirred at 65 to 70°C for at least 15 minutes. The reaction mass was cooled to 15 to 20°C and stirred for at least 30 minutes. The suspension was centrifuged in batches and washed with deionized water (380 kg) and ethyl acetate (380 kg). The wet product was granulated and dried at 60 to 70°C to obtain 3-(4-aminophenyl)-2-methoxypropionic acid (V) (~295 kg).

[0326] Preparation of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid S-(+)-camphor-10-sulfonate:

[0327] Solution 19.

[0328]

[0329] The starting 3-(4-aminophenyl)-2-methoxypropionic acid derived from two batches (one complete batch and an aliquot from the second batch) was combined to obtain a total of 400 kg of 3-(4-aminophenyl)-2-methoxypropionic acid. This amount is equivalent to the amount that would be obtained starting from 500 kg of 4-nitrobenzaldehyde.

[0330] Table 17. Production scale batch formulation (synthesis of compound (VI)·(S)-CSA)

[0331] substance factor* Quantity(kg) 3-(4-Aminophenyl)-2-methoxypropionic acid 1.0 400 (S)-(+)-10-Camphor-sulfonic acid 1.2321 493 acetone 2.0 800 Deionized water 0.16 64 acetone 2.0 800 acetone 1.5 600

[0332] *Factor refers to the amount of 3-(4-aminophenyl)-2-methoxypropionic acid (dry)

[0333] A stainless steel reactor was loaded with 3-(4-aminophenyl)-2-methoxypropionic acid (V) (400 kg) and (S)-(+)-camphor-10-sulfonic acid (493 kg); flushed with nitrogen and acetone (800 kg) was added. Deionized water (64 kg) was added. The reaction was heated to approximately 58° C. for 1 hour (reflux, no dissolution occurred). Acetone (800 kg) was added (temperature approximately 58° C.) and the reaction mass was maintained at reflux (approximately 58° C.) for 1 hour; the reaction mass was then cooled to 37 to 42° C. and centrifuged in batches, washed with acetone (600 kg) (between each centrifugation step, the aliquot of the suspension not used for centrifugation was first heated and then maintained at 45 to 50° C., and the suspension was then cooled to 37 to 42° C. again before the subsequent 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) was directly used in the subsequent step.

[0334] Preparation of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI):

[0335] Plan 20.

[0336]

[0337] Table 18. Production scale batch formulation (synthesis of compound (VI))

[0338]

[0339] *The factor refers to the amount of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid S-(+)-camphor-10-sulfonate (dry).

[0340] 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 to 40° C. for at least 10 minutes until complete dissolution occurred. The solution was filtered and washed with deionized water (82 kg) and then ethyl acetate (410 kg). The resulting solution was flushed with nitrogen, heated to 55 to 60° C. and 30% ammonia (51 kg) was added to precipitate. The resulting mixture was stirred at 55 to 60° C. for at least 15 minutes, then 80% acetic acid (20.5 kg) was added through the filter, the reaction was flushed with nitrogen and stirred at 55 to 60° C. for at least 30 minutes, then cooled to 2-7° C. and stirred for at least 1 hour. The reaction mass was centrifuged and washed with deionized water (287 kg), ethyl acetate (287 kg) in batches to obtain wet (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) (wet weight 162 kg, dry weight: 138.8 kg), which (wet) was used directly in the subsequent step.

[0341] Preparation of (S)-(-)-3-(4-acetylaminophenyl)-2-methoxypropionic acid (VII):

[0342] Solution 21.

[0343]

[0344] Table 19. Production scale batch formulation (synthesis of compound (VII))

[0345]

[0346] *Factor refers to the amount of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (dry)

[0347] Wet (S)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) (wet weight 162 kg, dry weight 138.8 kg) and ethyl acetate (208 kg) were added to a stainless steel reactor under nitrogen. The mixture was heated to 65 to 70°C and acetic anhydride (90 kg) was added through a filter column over about 15 minutes. The reaction was stirred at 65 to 70°C for 90 minutes, and once the reaction endpoint was detected, stirring was continued until a precipitate formed. The mixture was cooled to 10 to 20°C and stirred at 10 to 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 to 70°C for 19 hours and ground to obtain (S)-3-(4-acetylaminophenyl)-2-methoxypropionic acid (VII) (154.5 kg).

[0348] (S)-(-)-3-(4-Acetylaminophenyl)-2-methoxypropionic acid (VII): IR: 3319, 2888, 2825, 1718, 1633, 1599, 1548, 1107 cm -1 ; LCMS (+) ESI: C 12 H 15 NO 4 m / z calculated: 237, found: 236 (MH) - ; 1 HNMR (600 MHz, DMSO-d 6 ): δ12.70 (s, 1H), 9.85 (s, 1H), 7.45 (d, 2H), 7.12 (d, 2H), 3.90 (dd, 1H), 3.20 (s, 3H), 2.80 (ABd, 2H), 2.00 (s, 3H). 13 C NMR (600 MHz, DMSO-d 6 ): δ24.09(CH 3 -CO-NH-), 37.94(-C-CH 2 -C-), 57.47(CH 3 -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 (CH 3 -CO-NH-), 173.21 (-COOH). EA: C 60.82% (theoretical value 60.75%), H 6.44% (theoretical value 6.37%), N 5.91% (theoretical value 5.90%), O2 6.97% (theoretical value 26.97%). DSC: melting 154-167 ° C (onset temperature 159 ° C). Specific rotation: -22.7. (S)-3-(4-aminophenyl)-2-methoxypropionic acid (HPLC): 0.06% (HPLC). Chiral purity (HPLC): 99.7% (HPLC). Residual solvent (ethyl acetate): 277 ppm (GC).

[0349] Example 7: X-ray crystal structure determination of the compound of formula (VII)

[0350] The crystals used in the structural determination were obtained by vapor diffusion of an ethanol solution of the compound of formula (VII) and L-proline (2:1) using heptane as an antisolvent. Single crystal X-ray diffraction analysis was performed. The results of this analysis are shown below. 1 2 1 2 1Refinement of the space group gave an R index of 0.062. The asymmetric unit consists of two compounds of formula (VII) and two L-proline molecules.

[0351] Analysis of the single crystal diffraction data showed that the absolute configuration of carbon alpha to the carboxylic acid group was (S). Based on these results, the absolute stereochemistry of the compound of formula (VII) is shown in the following structure.

[0352]

[0353] The optical rotation of the same compound, i.e. the compound of formula (VII), is negative, which means that plane polarized light is rotated to the left. The specific rotation specification of the pure compound is -26.0° to -19.0°. Accordingly, since the procedure for resolving the racemic mixture always uses the same reagent, the characterization of the obtained product with (S) configuration is confirmed by the specific rotation.

[0354] Furthermore, the chiral purity (HPLC) of compounds of formula (VII) can be determined, for example, using the methods described herein.

[0355] The crystal data and structure refinement of the single crystal X-ray diffraction of the compound of formula (VII): F-proline derivative are shown below.

[0356]

[0357]

[0358] Join by reference

[0359] All publications and patents mentioned herein, including those listed below, are fully incorporated herein by reference for all intents and purposes to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In the event of a conflict, the present application, including any definitions herein, will control.

[0360] Equivalent

[0361] Although specific embodiments of the present disclosure have been discussed, the above description is exemplary and non-restrictive. After reference to this description, many changes of the present disclosure will be apparent to those skilled in the art. The full scope of the present disclosure should be determined with reference to the full scope of the claims and their equivalents and the description and the changes described therein.

[0362] Unless otherwise specified, all numerical values ​​expressing ingredients, reaction conditions, and the like used in the specification and claims are understood to be modified in all cases by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters described in this specification and the appended claims are approximate values ​​that may vary depending upon the desired properties desired to be obtained by the present disclosure.

Claims

1. A method for preparing a substantially optically pure compound of formula (VII): The method comprises: The compound of formula (I): Reaction with an activating agent to form an intermediate of formula (IA): Where LG is the leaving group; The intermediate of formula (IA) is treated with a base solution in the presence of an alcoholic solvent to eliminate the leaving group and thereby form the intermediate of formula (IB): The intermediate of formula (IB) is hydrolyzed to form a compound of formula (IV): Hydrogenating a compound of formula (IV) to form a compound of formula (V): Resolving the compound of formula (V) to form a substantially optically pure compound of formula (VI): wherein the substantially optically pure compound of formula (VI) is at least 95% of the following enantiomer: and Acylation of the compound of formula (VI) to form a compound of formula (VII), wherein the substantially optically pure compound of formula (VII) is at least 95% of the following enantiomer:

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

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

5. The method according to any one of claims 1 to 3, wherein the compound of formula (I): The intermediate of formula (IA) is formed: The reaction is carried out in the presence of an amine base.

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

7. The process of claim 6 wherein the amine base is triethylamine.

8. The process of any one of claims 1 to 3, wherein the activating agent is a sulfonylating agent or a halogenating agent.

9. The process of any one of claims 1 to 3, wherein the activating agent is selected from the group consisting of methanesulfonyl chloride, p-toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, phenylbis(trifluoromethanesulfonyl)imide, trifluoromethanesulfonic anhydride and nonafluorobutanesulfonic anhydride.

10. The process of any one of claims 1 to 3, wherein the activating agent is methanesulfonyl chloride.

11. The method of any one of claims 1 to 3, wherein the leaving group is selected from -OSO2-aryl, -OSO2-C 1-4 Alkyl, chlorine, bromine and iodine; among which C 1-4 Alkyl and aryl groups may be optionally substituted with one or more substituents, each specific value of which is independently selected from fluorine, bromine and -CH3.

12. The method of claim 11, wherein the leaving group is -OSO2-phenyl or -OSO2-C 1-4 alkyl.

13. The method of claim 11, wherein the leaving group is independently selected from: -OSO2Me, -OSO2CF3, and -OSO2CF2CF2CF2CF3.

14. The method of any one of claims 1 to 3, wherein the leaving group is -OSO2Me.

15. The method of any one of claims 1 to 3, wherein the alcohol solvent comprises at least one of methanol, ethanol, isopropanol and butanol.

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

17. The method of any one of claims 1-3, wherein the alkaline solution comprises at least one of the following: sodium hydroxide, lithium hydroxide and potassium hydroxide.

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

19. The method of any one of claims 1 to 3, wherein the alkaline solution comprises 30% sodium hydroxide.

20. The method of any one of claims 1-3, wherein hydrolyzing the intermediate of formula (IB) to form the compound of formula (IV) comprises: (i) contacting an intermediate of formula (IB) with an alkali metal hydroxide and water; and (ii) neutralization to form a compound of formula (IV).

21. The process of claim 20 wherein the alkali metal hydroxide is sodium hydroxide.

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

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

24. The method of any one of claims 1-3, wherein hydrogenating the compound of formula (IV) to form the compound of formula (V) comprises contacting the compound of formula (IV) with hydrogen and a catalyst.

25. The process of claim 24 wherein the catalyst is 5% Pd / C.

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

27. The method of any one of claims 1-3, wherein resolving the compound of formula (V) to form a substantially optically pure compound of formula (VI) comprises: (a) resolving a compound of formula (V) in the presence of a chiral acid to thereby form a chiral salt of a compound of formula (VI); and (b) neutralizing the chiral salt of the compound of formula (VI) thereby forming the compound of formula (VI).

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

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

30. The method of claim 27, wherein the chiral salt of the compound of formula (VI) is: (S)-(+)-Camphor-10-sulfonic acid.

31. The method of any one of claims 1-3, wherein resolving further comprises maintaining the temperature at 55-60°C under stirring.

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

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

34. The process of any one of claims 1 to 3, wherein the acylation comprises contacting the compound of formula (VI) with an acylating agent in the presence of an organic solvent selected from the group consisting of ethyl acetate, tetrahydrofuran, diethyl ether, dichloromethane and toluene.

35. The process of claim 34, wherein the acylating agent is acetic anhydride.

36. The process of claim 34, wherein the organic solvent is ethyl acetate.

37. The process of any one of claims 1 to 3, wherein the acylation occurs at a temperature of 60-70°C.

38. The process of any one of claims 1-3, wherein the compound of formula (VII) is produced on a multi-kilogram scale.

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

40. The method of any one of claims 1 to 3, wherein the substantially optically pure compound of formula (VII) is at least 98% of the following enantiomer:

41. A method for preparing a compound of formula (I): The method comprises providing a compound of formula (II): And a compound of formula (III): and contacting the mixture with a base, wherein the base is an alkali metal alkoxide; thereby forming a compound of formula (I).

42. The method of claim 41, wherein the contacting occurs in a solvent.

43. The process of claim 41 or 42, wherein the solvent is tetrahydrofuran.

44. The method of claim 41 or 42, wherein the contacting is performed at a temperature less than or equal to 0°C.

45. The method of claim 41 or 42, wherein the contacting comprises stirring for 5 minutes and / or is carried out at a reaction temperature maintained at -5 to 0°C.

46. ​​The process of claim 41 wherein the alkali metal alkoxide is selected from the group consisting of sodium methoxide, lithium methoxide and potassium methoxide.

47. The process of claim 46 wherein the alkali metal alkoxide is sodium methoxide.

Images