EA046346B1 - METHOD FOR PRODUCING 3-(4'-AMINOPHENYL)-2-METHOXYPROPIONIC ACID AND ITS ANALOGUES AND INTERMEDIATES - Google Patents

Description

State of the art

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily, which are ligand-activated transcription factors that regulate gene expression. Specific PPARs play roles in regulating differentiation, development, and metabolism in higher cells.

Three types of PPAR have been identified: alpha, expressed in the liver, kidney, heart and other tissues and organs, beta/delta, expressed in the brain for example, and gamma, expressed in three forms: gamma1, gamma2 and gamma3. PPARy receptors are associated with a number of disease states including fibrotic diseases, dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, atherogenesis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, Alzheimer's disease, skin diseases, respiratory diseases, ophthalmological disorders, IBD (irritable bowel syndrome), ulcerative colitis and Crohn's disease.

In addition, treatment with PPARy receptor ligands on tumor cells can reduce cell proliferation, cell differentiation, and apoptosis and may therefore be used to prevent carcinogenesis. Intestinal anti-inflammatory activity may depend on binding and subsequent activation of PPARy receptors.

Therefore, in order to treat such diseases, it is necessary to have effective methods for obtaining compounds capable of modulating the activity of PPAR receptors.

The essence of the invention

The invention provides, for example, a method for producing compounds that can be modulators of PPAR receptors.

Furthermore, the present invention provides a method for preparing a compound of formula (VII):

In one embodiment, a method for preparing a compound of formula (VI) is provided:

In addition, the invention proposes a method for obtaining its analogues and intermediate compounds.

In one embodiment, at least some of the compounds identified as intermediates, for example within the synthetic scheme disclosed in the invention, are intended to be compounds of the invention, for example a compound represented by formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof:

Detailed description of the invention

The features and other details of the invention will now be described more specifically. Before the present invention is further described, the invention defines specific terms used in the description of the invention, in the examples and in the appended claims. Those skilled in the art should understand these definitions as consistent with the remainder of the invention. Unless otherwise defined, all technical and scientific terms used in the invention have the same meaning as commonly understood by those of ordinary skill in the art.

Definitions

As used herein, the term alkenyl refers to an unsaturated linear or branched hydrocarbon having at least one carbon-carbon double bond, such as a linear or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as _C2 - _C12 alkenyl, _C2 - _C10 alkenyl, and _C2 - _C6 alkenyl, respectively. Examples of 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 so on.

As used herein, the term alkoxy refers to an alkyl group attached to oxygen (-O-alkyl). Examples of alkoxy groups include, but are not limited to, groups with al

- 1,046,346 alkyl, alkenyl or alkynyl group of 1-12, 1-8 or 1-6 carbon atoms, referred to in the invention as C1- _C12 alkoxy, C1- _C8 alkoxy and C1- _C6 alkoxy, respectively. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, etc. Similarly, examples of alkoxy groups include, but are not limited to, vinyloxy, allyloxy, butenoxy, etc.

As used herein, the term alkyl refers to a saturated linear or branched hydrocarbon, such as a linear or branched group of 1-12, 1-10, 1-6, 1-4, or 1-3 carbon atoms, referred to as C1- _C12 alkyl, C1- _C10 alkyl, C1- _C6 alkyl, _C1-4 alkyl, and _C1-3 alkyl, respectively. Examples of 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, 3methyl-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, etc. In certain embodiments, alkyl refers to C1- _C6 alkyl. In certain embodiments, cycloalkyl refers to _C3 - _C6 cycloalkyl.

Alkyl, alkenyl, and alkynyl groups may, in some embodiments, be optionally substituted or disconnected by at least one group selected from alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl, and thiocarbonyl.

As used herein, the term alkynyl refers to an unsaturated linear or branched hydrocarbon having at least one carbon-carbon triple bond, such as a linear or branched group of 2-12, 2-8, or 2-6 carbon atoms, referred to herein as _C2 - _C12 alkynyl, _C2 - _C8 alkynyl, and _C2 - _C6 alkynyl, respectively. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentenyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentenyl, and 4-butyl-2-hexynyl, etc.

As used in the invention, the term amide or amido refers to a radical of the formula -R _a C(O)N(R _b )-, -R _a C(O)N(R _b )Rc- or -C(O)NR _b Rc, where R _a , R _b and R _c are each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocyclyl and hydrogen. An amide may be attached to another group through carbon, nitrogen, R _b , R _c or R _a . An amide may also be cyclic, for example, R _b and Rc, R _a and R _b , or R _a and Rc may be combined to form a 3-12 membered ring, such as a 3-10 membered ring or a 5-6 membered ring.

As used herein, the term amidino refers to a radical of the formula -C(=NR)NR'R, wherein R, R' and R may each be independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl and heterocyclyl.

As used herein, the term "amine" or "amino" refers to a radical of the formula -NR _d R _e , -N(Rd)R _e - or -R _e N(R _d ) R f , wherein R _d , R _e and R f are independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl and hydrogen. The amino may be attached to the parent molecular group via nitrogen, R _d , Re or R f . The amino may also be cyclic, for example, any two of R _d , R _e or R f may be combined together or with N to form a 312 membered ring, for example, morpholino or piperidinyl. The term "amino" also includes the corresponding quaternary ammonium salt of any amino group, for example, -[N(R _d )(R _e )(R f )] + . Examples of amino groups include aminoalkyl groups wherein at least one of Rd, Re or Rf is an alkyl group.

As used herein, the term aryl refers to a mono-, bi-, or other polycarbocyclic aromatic ring system. In particular embodiments, aryl refers to a monocyclic and/or bicyclic 6-10 membered ring. The aromatic ring may be substituted at one or more positions on the ring with substituents selected from alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl, and thiocarbonyl. The term aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings (these rings are fused rings), wherein at least one of the rings is aromatic, for example, the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls and/or aryls. Examples of 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.

As used herein, the term "arylalkyl" refers to an aryl group having at least one alkyl substituent, such as -aryl-alkyl. Examples of arylalkyl groups include, but are not limited to, arylalkyls having a monocyclic aromatic ring

- 2 046346 system, where the ring includes 6 carbon atoms. For example, phenylalkyl includes phenylC ₄ alkyl, benzyl, 1-phenylethyl, 2-phenylethyl, and so on.

As used herein, the term carbonyl refers to the radical -C(O)-.

As used herein, the term carboxy refers to the radical -COOH or its corresponding salts, such as -COONa, etc.

As used herein, the term cyano refers to the radical -CN.

As used herein, the term cycloalkyl refers to a monovalent saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein as, for example, C _4-8 cycloalkyl derived from a cycloalkane. Examples of cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, cyclopentenes, cyclobutanes, and cyclopropanes. Cycloalkyl groups may be substituted with alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl, and thiocarbonyl. Cycloalkyl groups may be fused to other cycloalkyl, aryl, or heterocyclyl groups. In certain embodiments, cycloalkyl refers to _C3C6 cycloalkyl.

As used herein, the term halogen refers to F, Cl, Br or I.

As used herein, the term haloalkyl refers to an alkyl group substituted by one or more halogen atoms.

As used in this invention, the term nitro refers to the radical -NO2.

The term phenyl as used in the invention refers to a 6-membered carbocyclic aromatic ring. The phenyl group may also be fused to a cyclohexane or cyclopentane ring. Phenyl may be substituted with one or more substituents including alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.

As used in the invention, the term phosphate refers to the radical -OP(O)(OR _aa ) ₂ or its anions. The term phosphonate refers to the radical -P(O)(OR _aa ) ₂ or its anions. The term phosphinate refers to the radical -PR _aa (O)(OR _aa ) or its anions, where each R _aa can be selected, for example, from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, hydrogen, haloalkyl, heteroaryl and heterocyclyl.

As used in the invention, the term pharmaceutically acceptable carrier or pharmaceutically acceptable excipient refers to any solvents, dispersants, coatings, isotonic and absorption delaying agents, and other similar substances that are appropriate for the route of administration of the drug. The use of such media and substances for pharmaceutically active substances is well known. The compositions may also contain other active compounds that provide auxiliary, additional or enhanced therapeutic functions.

As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed in the invention together with one or more pharmaceutically acceptable carriers.

As used herein, the term pharmaceutically acceptable salt(s) refers to salts formed by groups with acidic or basic properties that may be present in the compounds used in the compositions of the present invention. The compounds introduced in the compositions of the present invention that have basic properties 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 such compounds with basic properties are those acids 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, hydrogen phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e. 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds incorporated into the compositions of the present invention that include an amino moiety can form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above. Compounds incorporated into the compositions of the present invention that have acidic properties are capable of forming base addition salts with various

- 3 046346 pharmacologically acceptable cations. Examples of such salts include alkali or alkaline earth metal salts and, in particular, calcium, magnesium, sodium, lithium, zinc, potassium and iron salts.

The compounds of the invention may contain one or more stereogenic centers and/or one or more double bonds and therefore exist in the form of stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term stereoisomers as used herein includes all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols R or S depending on the configuration of the substituents around the stereogenic carbon atom. The present invention includes various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated (±) in the nomenclature, but it is obvious to those skilled in the art that the structure may implicitly indicate the presence of a chiral center.

Individual stereoisomers of the compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. Examples of these resolution methods are:

(1) adding a mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography and isolating the optically pure product from the auxiliary, (2) forming a salt using an optically active resolving reagent, or (3) directly separating a mixture of optical enantiomers on chiral chromatographic columns.

Stereoisomeric mixtures may also be separated into their component stereoisomers by well-known methods such as chiral phase gas chromatography, chiral phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Stereoisomers may also be prepared by known methods of asymmetric synthesis from stereomerically pure intermediates, reagents, and catalysts.

The compounds of the present invention may also exist in the form of geometric isomers. The symbol —— represents a bond, which may be a single, double or triple bond as described herein. The present invention includes various geometric isomers and mixtures thereof, arising depending on the arrangement of substituents around a carbon-carbon double bond or the arrangement of substituents around a carbocyclic ring. Substituents around a carbon-carbon double bond are designated as being in the Z or E configuration, where the terms Z and E are used in accordance with IUPAC nomenclature. Unless otherwise indicated, structures depicting double bonds include both E and Z isomers.

Alternatively, the substituents around a carbon-carbon double bond may be designated by a cis or trans configuration, where cis refers to the configuration of the substituents on the same side of the double bond and trans refers to the configuration of the substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring is designated by a cis or trans configuration. The term cis refers to the configuration of the substituents on the same side of the plane of the ring, and the term trans refers to the configuration of the substituents on opposite sides of the plane of the ring. Mixtures of compounds in which the substituents are located on both the same and opposite sides of the plane of the ring are designated cis/trans.

As used herein, the term substantially optically pure, substantially enantiomerically pure, optically pure, or enantiomerically pure with respect to a compound (e.g., a compound described herein) means that at least 95%, such as at least 96%, at least 97%, or at least 98%, of the compound has the desired stereogenic center in a given configuration. It should be understood that the percentage is expressed as a percentage of both enantiomers of the compound. For example, a compound of formula VII is substantially optically pure if, based on the sum of both the levorotatory and dextrorotatory enantiomers, at least 95% is (S)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid (levorotatory enantiomer).

The compounds disclosed in the invention may exist in both solvated and unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol and other similar solvents, and the invention is intended to encompass both solvated and unsolvated forms. In some embodiments, the compound is amorphous. In some embodiments, the compound is in crystalline form. In some embodiments, the compound is a polymorph.

The invention also encompasses isotopically labeled compounds of the present invention which are identical to the compounds of the invention except that one or more atoms therein are replaced by an atom having an atomic mass or mass number different from the atomic mass.

- 4 046 346 sy or mass number commonly found in nature. Examples of isotopes that can be introduced into the compounds of the invention 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, respectively.

Certain isotopically labeled compounds described (e.g., labeled with ³ H and ¹⁴ C) are useful in studying the distribution of a compound and/or substrate in tissues. Particularly preferred are the isotopes of tritium (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) due to their ease of preparation and detection. In addition, substitution with heavier isotopes, such as deuterium (i.e., ² H), allows for certain therapeutic advantages associated with greater metabolic stability (e.g., increased half-life in vivo or decreased dose requirements), and may therefore be preferred in some circumstances. Isotopically labeled compounds of the present invention can generally be prepared by the following methods, analogous to the methods described in the examples provided herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

The term prodrug refers to compounds that undergo conversion in vivo to form a compound disclosed herein or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The conversion may occur by various mechanisms, such as through hydrolysis in the blood. For example, if a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functionality, the prodrug may include an ester formed by replacing a hydrogen atom in the acidic group with a group such as (C ₁ -C ₈ )alkyl, (C ₂ -C ₁₂ )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl containing from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(αlkoxycarbonyl)aminomethyl containing from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-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 )αalkylcarbamoyl-(C ₁ -C ₂ )αalkyl and piperidino-, pyrrolidino- or morpholino(C ₂ -C ₃ )alkyl.

Similarly, if a compound of the invention contains an alcohol functional group, the prodrug can be formed by replacing a hydrogen atom of the alcohol group with a group such as C1- _C6 )alkanoyloxymethyl, 1-((C1- _C6 )alkanoyloxy)ethyl, 1-methyl-1-(( _C1 - _C6 )alkanoyloxy)ethyl, (C1- _C6 )alkoxycarbonyloxymethyl, N-( _C1 - _C6 )alkoxycarbonylaminomethyl, succinoyl, (C1- _C6 )alkanoyl, α-amino(C1- _C4 )alkanoyl, arylacyl and α-aminoacyl or α-aminoacyl-α-aminoacyl, wherein each α-aminoacyl group is independently selected from natural L-amino acids, P(O)(OH) ₂ , -P(O)(O(C1- _C6 )alkyl) ₂ or glycosyl (a radical formed by removing the hydroxyl group of the hemiacetal form of a carbohydrate).

If the compound of the present invention includes an amine functional group, the prodrug can be formed by replacing a hydrogen atom in the amino group with a group such as Rcarbonyl, RO-carbonyl, NRR'-carbonyl, wherein R and R' are each independently (C1- _C10 )alkyl, ( _C3 - _C7 )cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or a natural α-aminoacyl-natural α-aminoacyl, -C(OH)C(O) ^OY1 , where ^Y1 is H, (C1-C6)alkyl or benzyl, -C( ^OY2 ) ^Y3 , where ^Y2 is (C1-C4)alkyl, and ^Y3 is (C1-C6)alkyl, carboxy(C1-C6)alkyl, amino(C1-C4)alkyl or mono-N- or di-N,N-(C1-C6)alkylaminoalkyl, -C(Y ⁴ )Y ⁵ , where Y ⁴ is H or methyl, and Y ⁵ is mono-N- or di-N,N(C1-C6)alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl.

The invention provides at least some compounds represented by the following formula (I), formula (IV), formula (V), formula (VI), and formula (VII). In addition, the invention provides pharmaceutical compositions that include compounds represented by formula (I), formula (IV), formula (V), formula (VI), and formula (VII), and, for example, a pharmaceutically acceptable excipient and/or carrier.

Connections.

The invention provides, among other things, a method for producing a substantially optically pure compound of formula (VII):

- 5 046346 where the method comprises reacting a compound of formula (I):

with an activating reagent in the optional presence of a base to form an intermediate compound of formula (I-A):

where LG represents the leaving group;

treating the intermediate compound of formula (I-A) with a solution of a base in the presence of an alcoholic solvent to remove the leaving group and thereby form an intermediate compound of formula (I-B):

hydrolysis of the intermediate compound of formula (I-B) to form a compound of formula (IV):

hydrogenation of a compound of formula (IV) to form a compound of formula (V):

optionally optically resolving the compound of formula (V) to obtain a substantially optically pure compound of formula (VI):

acylating a compound of formula (VI) to obtain a compound of formula (VII). Reacting a compound of formula (I) with an activating reagent may comprise reacting in the presence of a base and a solvent. In some embodiments, the solvent is selected from the group consisting of toluene, dichloromethane, tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran and acetonitrile, for example, the solvent may be toluene. The base may be an amine, for example, selected from the group consisting of triethylamine, N,N-diisopropylethylamine and pyridine. For example, the amine may be triethylamine.

The compound of formula (I) may be isolated in the solid state prior to this step or may be dissolved in an appropriate solvent, for example a solvent used in the preparation or processing of the compound of formula (I). For example, the compound of formula (I) may not be isolated and may be dissolved in an organic solvent, for example toluene, prior to this step.

The provided activating reagent includes a sulfonylating reagent or a halogenating reagent. For example, the activating reagent can be selected from the group consisting of methanesulfonyl chloride, p-toluenesulfonyl chloride, p-bromobenzene sulfonyl chloride, phenyl triflimide, trifluoromethanesulfonic anhydride, and nonafluorobutanesulfonic anhydride. In some embodiments, the activating reagent is methanesulfonyl chloride.

In some embodiments, the leaving group is selected from the group consisting of OSO ₂ -arylα, -OSO ₂ -C _1-4 alkyl, chloro, bromo, and iodino; wherein the C _1-4 alkyl and aryl may be optionally substituted with one or more substituents, each independently selected, in each

- 6 046346 when present, from the group consisting of fluorine, bromine and -CH ₃ . For example, the leaving group may be -OSO ₂ -phenyl or -OSO ₂ -C _1-4 alkyl.

In some embodiments, the leaving group is independently selected from the group consisting of:

for example, the leaving group might be -OSO ₂ Me.

The provided alcohol solvents may include at least one alcohol solvent from methanol, ethanol, isopropanol and butanol. For example, the alcohol solvent may include methanol.

In some embodiments, the base solution comprises at least one of sodium hydroxide, lithium hydroxide, and potassium hydroxide. For example, the base solution may comprise sodium hydroxide, such as 30% sodium hydroxide.

In some embodiments, hydrolysis of an intermediate of formula (I-B) to form a compound of formula (IV) comprises: contacting the intermediate of formula (I-B) with an alkali metal hydroxide (e.g., sodium hydroxide) and water and neutralizing to form a compound of formula (IV). Neutralization may comprise acidifying to a pH of less than or equal to 3 by adding an acid, e.g., phosphoric acid or hydrochloric acid, or a mixture thereof.

In some embodiments, hydrogenating a compound of formula (IV) to form a compound of formula (V) comprises contacting a compound of formula (IV) with hydrogen and a catalyst, such as a catalyst selected from the group consisting of PtO ₂ , Pd(OH) ₂ /C, Pt/C, 10% Pd/C, and 5% Pd/C, such as a 5% Pd/C catalyst. The hydrogenation can be carried out at a temperature maintained in the range of 60-80 °C and at a pressure of about 0.3 to 0.5 MPa, about 0.35 to 0.45 MPa, or about 0.4 to 0.45 MPa. For example, the hydrogenation can be carried out in the presence of one or more hydrogenation solvents selected from the group consisting of aqueous ammonia, methanol, ethanol, isopropanol, N,N-dimethylformamide, tetrahydrofuran, and ethyl acetate, such as aqueous ammonia, methanol, or N,N-dimethylformamide. In some embodiments, the hydrogenation solvent is methanol or a mixture of methanol and ammonia, such as 30% aqueous ammonia.

After hydrogenation, the compound of formula (V) can optionally be isolated by contacting the solution with an acid, for example, acetic acid, hydrochloric acid, or a mixture thereof.

The optical resolution of a compound of formula (V) to form a substantially optically pure compound of formula (VI) may comprise:

a) separating the compound of formula (V) in the presence of a chiral acid to thereby form a chiral salt of the compound of formula (VI); and

b) neutralizing a chiral salt of a compound of formula (VI) to form a compound of formula (VI).

In some embodiments, the chiral acid is selected from the group consisting of (S)(+)-camphor-10-sulfonic acid, (2R,3R)-(+)-tartaric acid, (S)-(-)-malic acid, (1S)-(+)-3bromocamphor-10-sulfonic acid, (S)-1-phenylethanesulfonic acid, dibenzoyl-L-tartaric acid, glutamic acid, (1R,3S)-kαmphoric acid, (1S)-camphoric acid, and (R)-(-)-mandelic acid, and all other chiral acids that can result in the resolution of a racemic mixture or an enantiomer thereof, such as (S)-(+)-camphor-10-sulfonic acid.

In some embodiments, the chiral salt of the compound of formula (VI) is:

_H2N

OH •(51-(+)- ^ka mphor-10-sulfonic acid

In various embodiments, the separation may further comprise adding a primer and maintaining the temperature in the range of 30-35°C while stirring, and/or may occur in the presence of acetone and water. In some embodiments, the separation may further comprise maintaining the temperature in the range of 55-60°C (e.g., 58°C) while stirring, and/or may occur in the presence of acetone and water.

The primer may be a substantially optically pure salt of a chiral acid and

- 7 046346 compounds of formula (VI). In some embodiments, the chiral acid is (S)-(+)-camphor-10-sulfonic acid.

For example, a primer can be represented by the structural formula: O

ABOUT.

Η ₂ Ν •('5 _? )-(+)-camphor-10-sulfonic acid

At the end of the separation, if the purity specifications are not met, re-treatment can be carried out where the solution is kept at the separation temperature with stirring for a longer time.

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

The acylation may comprise contacting a compound of formula (VI) with an acylating reagent (e.g. acetic anhydride) in the presence of an organic solvent selected from the group consisting of ethyl acetate, tetrahydrofuran, diethyl ether, dichloromethane and toluene, e.g. ethyl acetate. Such acylation may be carried out at a temperature in the range of from 60 to 70°C, e.g. from 65 to 70°C. The acylation may further comprise dissolving the compound isolated in the preceding step in one or more solvents, e.g. water and/or ethyl acetate, to form a solution, and contacting the solution with an acylating reagent, e.g. acetic acid. Such a step may be carried out at a temperature in the range of from 60 to 70°C, e.g. at a temperature in the range of from 65 to 70°C.

In some embodiments, after optionally resolving the compound of formula (V) to obtain a substantially optically pure compound of formula (VI), the mother liquor resulting from the resolving step may still contain the desired enantiomer (in the form of a salt with the resolving reagent) along with the undesired enantiomer. In these embodiments, the resolving may optionally further comprise:

a) recovering the mixture of enantiomers (in the form of chiral salts with a resolving reagent) from the mother liquor, neutralizing the chiral salts to form a compound of formula (V), and separating the compound of formula (V) to obtain an additional amount of substantially optically pure compound of formula (VI), thereby increasing the overall yield in this process; or

b) distilling off a portion of the mother liquor and precipitating the desired enantiomer in the form of a salt with a chiral separation reagent from the mother liquor, thereby increasing the overall yield in this process.

Furthermore, the invention provides a method for racemizing an unwanted enantiomer or a chiral salt thereof in the presence of a base and separating the resulting mixture of (R) and (S) enantiomers using the separation method provided in the invention to obtain the desired enantiomer.

Provided bases include bases selected from the group consisting of hydroxides, alkoxides (e.g. methoxide), amides (e.g. lithium diisopropylamide), hydrides (e.g. NaH), organolithium compounds and Grignard reagents. In the case of bases that require a counterion, examples of counterions provided in the invention may include alkali metals or alkaline earth metals, e.g. lithium, sodium, potassium or calcium, or organic counterions, e.g. tetraalkylammonium ions.

In some embodiments, the compound of formula (VII) can be produced on a multi-kilogram scale, such as in an amount of at least about 8 to 11 kg, about 13 to 15 kg, or about 130 to 150 kg. In some embodiments, at least about 130 kg of the compound of formula (VII) is produced.

In some embodiments, the substantially optically pure compound of formula (VII) contains at least 98% of the desired enantiomer:

ABOUT

(based on the total amount of both enantiomers). In some embodiments, the content of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid can be, for example, no more than 0.15% when analyzed by high performance liquid chromatography (HPLC).

In an alternative embodiment, the invention discloses obtaining essentially opti

- 8 046 346 of a theoretically pure compound of formula (VII) comprises acylating a racemic compound (V) to obtain a racemic mixture of 3-(4-acetamidophenyl)-2-methoxypropionic acid, and resolving the racemic 3-(4-acetamidophenyl)-2-methoxypropionic acid to obtain a substantially enantiomerically pure compound of formula (VII). For example, obtaining a substantially optically pure compound of formula (VII) may comprise:

a) resolving a racemic mixture of 3-(4-acetamidophenyl)-2-methoxypropionic acid in the presence of a chiral base to thereby obtain a chiral salt of the compound; and

b) neutralizing the chiral salt of the compound to obtain a compound of formula (VII).

In some embodiments, the chiral base is selected from the group consisting of, for example, enantiomerically pure 1-amino-2-propanol, brucine, dehydroabietylamine, N,α-dimethylbenzylamine, N,N-dimethyl-1-phenylethylamine, ephedrine, α-methylbenzylamine, 1-(2-naphthyl)ethylamine, quinidine, quinine, strychnine, valine, and all other chiral bases that allow resolution of a racemic mixture. For example, a chiral salt of the compound can be represented as follows:

In specific embodiments, the present invention provides a method for preparing a compound of formula (I):

where the method comprises obtaining a mixture of a compound of formula (II):

and compounds of formula (III):

and contacting the mixture with a base (for example, in a solvent such as tetrahydrofuran) to thereby obtain a compound of formula (I).

The contacting may be carried out at a temperature below or equal to 10°C, for example, it may involve stirring for about 5 minutes and/or it may be carried out at a temperature maintained in the range from -10 to 10°C, for example from -5 to 0°C. The base may be an alkali metal alkoxide, for example selected from the group consisting of sodium methoxide, lithium methoxide and potassium methoxide, for example sodium methoxide.

In some embodiments, the invention provides compounds represented by the formula:

or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, a compound of formula (I) may exist in the form of a mixture of stereoisomers. Contemplated stereoisomers of formula (I) include, for example, compounds of formula (a), formula (b), formula (c), or formula (d):

- 9 046346

total

In addition, the invention proposes, in addition to the theoretically pure compound of formula (VI):

other, the method of obtaining essentially the op-

where the method comprises reacting a compound of formula (I):

with an activating reagent, optionally in the presence of a base, to obtain an intermediate compound of formula (I-A):

where LG represents the leaving group;

treating the intermediate compound of formula (I-A) with a solution of a base in the presence of an alcoholic solvent to remove the leaving group and thereby obtain an intermediate compound of formula (I-B):

hydrolysis of the intermediate compound of formula (I-B) to obtain a compound of formula (IV):

hydrogenation of the compound of formula (IV) to obtain the compound of formula (V):

optical resolution of a compound of formula (V) to obtain a substantially optically pure compound of formula (VI), wherein the method and variables are as defined in the invention.

Methods for obtaining the compounds described in the invention are presented below with reference to schemes 1-21. When carrying out the reactions described below, it may be necessary to protect the reaction

- 10 046 346 capable functional groups (such as a hydroxyl group, an amino group or a carboxyl group), in order to prevent their unwanted participation in reactions. The introduction of protective groups and the methods required for their introduction and removal are known to those skilled in the art (see, for example, the monograph Greene, Wuts, Protective Groups in Organic Synthesis. 4th Ed. (2007)). The deprotection step may be the last step in the synthesis, so that the removal of the protecting groups leads to the compound of formula (I) disclosed in the invention. The starting materials used in the schemes below can be purchased or prepared by methods described in the chemical literature or by adapting methods known to those skilled in the art. It is obvious to those skilled in the art that the order of the steps may be varied depending on the groups introduced and the reagents used.

Examples

The methods disclosed in the invention can be carried out in many ways based on the teachings contained in the invention and synthetic methods known in the art. It should be understood that in describing the synthetic methods given below, all suggested reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration, and work-up procedures, can be selected as standard conditions for carrying out the reaction, unless otherwise indicated. It is obvious to one of ordinary skill in the art of organic synthesis that the functional groups present in the various parts of the molecule must be compatible with the proposed reagents and reactions. Those substituents that are incompatible with the reaction conditions are obvious to one of ordinary skill in the art, and, therefore, alternative methods are suggested in this case. The starting materials used in the examples are either commercially available or are readily prepared by standard methods from known materials.

At least some of the compounds referred to as intermediates, for example in the synthesis scheme described in the invention, are considered to be compounds of the invention.

Conventional abbreviations

General: APCI chemical ionization at atmospheric pressure DSC differential scanning calorimetry EA elemental analysis ESI electrospray ionization GC gas chromatography HPLC high performance liquid chromatography ICP-AES Inductively coupled atomic emission spectrometry plasma

LC liquid chromatography MHz megahertz MS mass spectrometry NMR nuclear magnetic resonance TLC thin layer chromatography Me methyl Ph phenyl Et ethyl

Solvents and reagents:

CSA camphorsulfonic acid DMF N,N-dimethylformamide YU Ace ethyl acetate Mesyl methanesulfonyl NaOMe sodium methoxide THF tetrahydrofuran

- 11 046346

General methodology for conducting the experiment.

1H NMR spectra were recorded on a Varian Gemini 200 NMR spectrometer at 200 MHz or 600 MHz. Proton chemical shifts were measured in parts per million (ppm) on a 5-point scale using the residual solvent peak (DMSO-d6: 2.50 ppm) as an internal standard. Data are presented as follows: chemical shift (8), multiplicity (s=singlet, d=doublet, t=triplet, qv=quartet, qvn=quintet, sext=sextet, cpt=septet, m=multiplet, br=broad, dd=double doublet, dt=double triplet, qd=quartet of doublets, dqvn=doublet of quintets), coupling constant (J, Hz), and summation (# H).

^13C NMR spectra were recorded at 600 MHz by dissolving the sample in DMSO-d6. A fully resolved spectrum was obtained.

Mass spectra were recorded on a Thermo-Finnigan LCQ-Advantage mass spectrometer or a Thermo LCQ-fleet ion trap MS mass spectrometer. Liquid chromatography/mass spectrometry (LC/MS) data were acquired using positive/negative ionization switching or using negative polarity mode with acquisition parameters optimized for negative polarity at the 236 m/z signal corresponding to the [M-H]- quasi-molecular ion of the sample.

Elemental analysis (carbon, hydrogen, nitrogen) was carried out 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 carried out 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.

Attenuated total reflectance Fourier transform infrared (FT-IR/ATR) spectroscopy was performed on the sample as is using a PerkinElmer Spectrum Two spectrometer equipped with a diamond-coated probe. The spectrum was recorded in the frequency range 450-4000 cm ^-1 .

The UV-visible spectrum was recorded on a Shimadzu UV 2600 spectrophotometer operating under the following conditions: cuvette: 1 cm quartz; range: 200-600 nm; scan speed: medium; scan step: 1 nm; slit width: 1.0 nm; reference solution: methanol; sample solution: 1 mg of sample was dissolved in 100 mL of methanol.

Differential scanning calorimetry (DSC) was performed on a Mettler-Toledo TGA-DSC1 instrument operating under the following conditions: crucible: aluminum (open); heating rate: 10°C/min; gas: nitrogen; flow rate: 30 ml/min.

The specific optical rotation was determined using the following procedure. In a 50 ml volumetric flask, 0.5 g of the sample was accurately weighed, dissolved in methanol and brought to a volume of 50 ml with methanol (concentration: 10 mg/ml, which corresponds to 1% w/v). The angle of rotation of the resulting solution was determined using a polarimeter tube with an optical length corresponding to 1 _dm . The specific optical ^rotation was calculated based on the dry substance using the following formula:

(a x 50x100) / (W x (100 - w)), where is the measured rotation angle; W=sample mass (g) and m=water content of the sample (%). Chiral purity (HPLC) was determined as follows.

Conventional abbreviations

General: APCI chemical ionization at atmospheric pressure DSC differential scanning calorimetry EA elemental analysis ESI electrospray ionization GC gas chromatography HPLC high performance liquid chromatography ICP-AES Inductively coupled atomic emission spectrometry plasma

- 12 046346

LC liquid chromatography MHz megahertz MS mass spectrometry NMR nuclear magnetic resonance TLC thin layer chromatography Me methyl

Ph phenyl Et ethyl

Solvents and reagents:

CSA camphorsulfonic acid DMF N,N-dimethylformamide YU Ace ethyl acetate Mesyl methanesulfon they l NaOMe sodium methoxide THF Device and operating mode: tetrahydrofuran Chromatograph HPLC Waters equipped with pump, dispenser, UV-Vis spectrophotometer and Empower (or equivalent) data acquisition and processing system Column DaicelChiralpak WH, 10 µm 250 mm x 4.6 mm ID (Daicel Chemical Industries DAIC25625) Mobile phase A Mobile phase Dissolve 62.5 mg CUSO4 5H2O in 1000 ml water Prepare a 90:10 (by volume) mixture of mobile phase A/acetonitrile Expense 1 ml/min Column temperature 45°С Volume of sample to be injected 20 microns Wavelength 258 nm

Preparation of solutions.

Sample solution: 10 mg of sample is carefully weighed in a 10 ml volumetric flask, then diluted and made up to 10 ml with mobile phase solution (concentration: 1000 μg/ml).

Reference solution: 10 mg of the (R,S)-3-(4-α-acetamidophenyl)-2-methoxypropionic acid standard are carefully weighed in a 100 ml volumetric flask, then diluted and brought to a volume of 100 ml using the mobile phase solution.

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

Testing the suitability of the chromatographic system and the methodology for its implementation.

Inject 20 µl of the sample solution and SST solution into the chromatograph and record the chromatogram.

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

- 13 046346

The chromatographic system can be used for the analysis if 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, v is the distance between the lowest point of the trough, determined between the peak of the dextrorotatory enantiomer and the peak of the levorotatory enantiomer and the baseline.

Chiral purity % is calculated by the following formula: (A ₁ x100)/(A ₁ +Ad), where A ₁ = peak area of (S)-(-)- 3-(4-acetamidophenyl)-2-methoxypropionic acid in the sample solution (levorotatory enantiomer) and Ad = peak area of (R)-(+)-3-(4-acetamidophenyl)-2-methoxypropionic acid in the sample solution (dextrorotatory enantiomer).

The above method can be used to determine the optical purity or enantiomeric purity of a compound as follows.

Example 1. Preparation of methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate (I).

Scheme 1

(ABOUT

Table 1

Consumables for obtaining a batch of the product on an industrial scale (synthesis of compound (I))_______________

Material Expense ratio* Quantity (kg) sodium methoxide 0,6 30,0 THF 1,5 75 4-nitrobenzaldehyde 1,0 50 methyl methoxy acetate 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 z,o 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

* Consumption coefficient relative to the amount of 4-nitrobenzaldehyde used.

Preparation of 4-nitrobenzaldehyde in a suspension of methyl methoxyacetate and tetrahydrofuran.

4-nitrobenzaldehyde (50 kg), methyl methoxyacetate (55 kg) and tetrahydrofuran (100 kg) were loaded into a stainless steel reactor and cooled to a temperature in the range of -5 to +5°C with stirring.

Obtaining methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate (I).

A stainless steel reactor was purged with nitrogen (2x) and charged with sodium methoxide (30.0 kg) and tetrahydrofuran (75 kg) under nitrogen purge. The reactor was then purged with nitrogen for 1 min and the sodium methoxide solution was cooled to a temperature in the range of -10 to -5°C with stirring. The cooled solution was then treated with the previously prepared suspension of 4-nitrobenzaldehyde in methyl methoxyacetate and tetrahydrofuran, maintaining the reaction temperature at

- 14 046346 mass below 10°C. After completion of the addition, the empty reactor was rinsed with tetrahydrofuran (25.0 kg) and filled with the reaction mass. The reaction mixture was stirred at a temperature in the range from -10 to +10°C for no more than 5 min. Maintaining the temperature from -10 to +10°C, cold toluene (100 kg, temperature from -10 to 0°C), then glacial acetic acid (50 kg) were slowly added, and the reaction mixture was stirred for 10 min at a temperature in the range from -10 to +10°C. Deionized water (150 kg) was added and the reaction mass was stirred at a temperature in the range from 0 to 10 °C for at least 10 min, then at a temperature in the range from 20 to 30 °C for at least 10 min to achieve complete dissolution, after which stirring was stopped and the phases were separated. The aqueous phase was discarded and the separated organic phase was treated with an aqueous solution of sodium chloride (prepared in advance by adding 10 kg of sodium chloride to 100 kg of deionized water). The mass was then heated to a temperature in the range from 50 to 60 °C with stirring for at least 10 min. Stirring was stopped and the phases were separated. The aqueous phase was discarded and the organic phase was treated with an aqueous solution of 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 procedure. The separated organic phase was then stripped under vacuum without exceeding 80°C to remove THF. The reactor containing the hot residue was purged with nitrogen, then treated with toluene (50 kg), and the toluene was stripped under vacuum without exceeding 80°C. The resulting hot residue was purged with nitrogen, then treated with toluene (75 kg), and the mass was stirred for at least 30 min at a temperature in the range of 30 to 45°C to ensure good precipitation of the product. The mixture was then cooled to a temperature in the range of -10 to 0°C and stirred at this temperature for at least 1 h. Portions of the resulting suspension were centrifuged, washing with cold toluene (25 kg), to yield wet methyl 3-hydroxy-2-methoxy-3(4-nitrophenyl)propanoate (I) (84 kg), which was then used without further purification.

Methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate (I): IR: 3468, 1737, 1514, 1350, 1201, 1101 cm-1; LCMS (-)APCI: m/z calculated for CnH ₁₃ NO ₆ : 255, found: 254 (M-H); ¹ H NMR (200 MHz, DMSO-d6): 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); 13C NMR (150 MHz, DMSO-d6): δ 170.2, 149.4, 146.7, 127.8, 122.9, 84.1, 72.7, 58.2, 51.6; UV-visible region (MeOH): λ max 202.270; elemental analysis data calculated for C11H13NO6: C 51.97; H 5.16; N 5.42; O 37.52.

Example 2. Preparation of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) and (S)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid (VII).

Scheme 2

(VI).(S)-CSA

Obtaining 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV).

Scheme 3

- 15 046346

Table 2

Consumables for obtaining a batch of the product on an industrial scale (synthesis of compound (IV))

Material Expense ratio* Quantity (kg) methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate, wet 1,0 84 (72.6 kg dry matter basis) toluene 3.9 283 triethylamine 0,5833 42.3 methanesulfonylchloride 0,5 36.3 deionized water 2.0 145 toluene 0,1 7.3 methanol z,o 218 sodium hydroxide 30% 1,3 94 deionized water 4.0 290 phosphoric acid 85% 1,3 94 phosphoric acid 85% - up to pH<3.0 deionized water 0,5 36.3 toluene 1,0 73 deionized water 2.0 145

* Consumption coefficient relative to the amount of methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate used (calculated on dry matter).

A stainless steel reactor was purged with nitrogen (2x) and charged with wet methyl 3hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate (I) (84 kg) and toluene (283 kg), then cooled to 0 to 10 °C under nitrogen purging. Triethylamine (42.3 kg) and methanesulfonyl chloride (36.3 kg) were added while maintaining the temperature at 0 to 10 °C and the reaction mixture was stirred at 0 to 10 °C for 30 min. Deionized water (145 kg) was added slowly and the resulting mass was stirred at 50 to 60 °C for 10 min, after which stirring was stopped and the phases were separated. The aqueous phase was discarded and the organic phase was filtered, washing with toluene (7.3 kg). Toluene was removed by vacuum distillation without exceeding a temperature above 60°C to give an oily residue. The resulting residue was then treated with methanol (218 kg), transferred to another reactor, purged with nitrogen, cooled to a temperature in the range of 20 to 30°C and slowly treated with 30% sodium hydroxide solution (94 kg). The reaction mixture was stirred at a temperature in the range of 20 to 30°C for 2 h. Deionized water (290 kg) was added and the solution was heated to a temperature in the range of 55 to 65°C. At this temperature, 85% phosphoric acid (94 kg) was slowly added until a pH of < 3.0 was achieved. The resulting precipitated product was stirred at a temperature in the range of 55 to 65 °C for at least 30 min, then cooled to a temperature in the range of 25 to 30 °C and stirred for at least 30 min. The mixture was centrifuged, washing with deionized water (36.3 kg), toluene (73 kg) and deionized water (145 kg). The product was granulated and dried at a temperature in the range of 70 to 80 °C to obtain 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV) (50.4 kg).

Methyl 2-methoxy-3-((methylsulfonyl)oxy)-3-(4-nitrophenyl)propanoate (Ι-Ai): LCMS (+)ESI: m/z calculated for C ₁₂ H ₁₅ NO ₈ S: 333; found: 356 (M+Na); ¹ H NMR (200 MHz, DMSO-d6): 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).

Methyl 2-methoxy-3-(4-nitrophenyl)acrylate (I-B): LCMS (-)APCI: m/z calculated for C11H11NO5:

- 16 046346

237; detected: 236 M-H); 1H 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).

2-Methoxy-3-(4-nitrophenyl)acrylic acid (IV): LCMS (-)APCI: m/z calculated for C ₁₀ H ₉ NO5: 223, found: 222 (M-H); 1H NMR (200 MHz, DMSO-d6): 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).

Obtaining 3-(4-aminophenyl)-2-methoxypropanoic acid (V).

Scheme 4

Table 3

Consumables for obtaining a batch of the product on an industrial scale (synthesis of compound (V))

Material Expense ratio* Quantity (kg) 2-methoxy-3-(4-nitrophenyl)acrylic acid, dry 1,0 50.4 methanol 5.0 252 N,N-dimethylformamide 0.3421 17.2 palladium on carbon 5% (containing 50% water) 0,1 7,7 N,N-dimethylformamide 0,0526 2.65 N,N-dimethylformamide 0,0526 2.65 N,N-dimethylformamide 0,0526 2.65 ammonia (30%) 0,4 20.2 deionized water 0.25 12.6 deionized water 0,5 25.2 deionized water z,o 151 acetic acid 80% 0,5 25.2 ethyl acetate 1,0 50 deionized water 2.0 101 ethyl acetate 0,5 25.2

* Consumption coefficient relative to the amount of dry 2-methoxy-3-(4-nitrophenyl)acrylic acid used.

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 thoroughly mixed. The stainless steel reactor was purged with nitrogen (2x), charged with methanol (252 kg), cooled to a temperature in the range 0 to 10 °C and dry 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV) (50.4 kg) was added. The resulting solution was purged with nitrogen (2x) and treated with a previously prepared solution of 5% palladium on carbon in N,N-dimethylformamide and the empty reactor was washed with N,N-dimethylformamide (2.65 kg). The reaction mixture was purged with nitrogen (2x), then heated to a temperature in the range of 60 to 80 °C, charged with hydrogen until the pressure reached a value of 0.35 to 0.45 MPa. The reaction was carried out, maintaining the pressure of 0.35 to 0.45 MPa, until the consumption of hydrogen ceased and the completion of the reaction was confirmed. The reactor was restored to atmospheric pressure and the reaction mixture was cooled to a temperature in the range of 20 to 30 °C, purged with nitrogen (2x) and treated successively with 30% ammonia (20.2 kg) and deionized water (12.6 kg), stirring at a temperature of 20 to 30 °C until complete dissolution was achieved. The solution was filtered through a filter press, washing with deionized

- 17 046346 water (25.2 kg). The reactor was purged with nitrogen and the solvents were removed by vacuum distillation at a temperature not exceeding 70 °C. The residue was treated with deionized water (151 kg), heated to a temperature in the range of 60 to 70 °C, and the product was precipitated by adding 80% acetic acid (25.2 kg). The mixture was stirred at a temperature in the range of 60 to 70 °C for at least 10 min, then treated with ethyl acetate (50 kg), purged with nitrogen and stirred at a temperature in the range of 60 to 70 °C for at least 15 min. The reaction mass was cooled to a temperature in the range of 0 to 20 °C and stirred for at least 30 min. Portions of the suspension were centrifuged, washing with deionized water (101 kg) and ethyl acetate (25.2 kg). The wet product was granulated and dried at a temperature in the range of 60 to 70 °C to obtain 3-(4-aminophenyl)-2-methoxypropanoic acid (V) (~37.5 kg).

3-(4-Aminophenyl)-2-methoxyacrylic acid (IC): LCMS (+)ESI: m/z calculated for C ₁₀ HnNO ₃ : 193, found: 194 (M+H); 1H NMR (200 MHz, DMSO-d6): 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).

3-(4-Aminophenyl)-2-methoxypropanoic acid (V): IR: 3044, 2950-2830, 2623-2064, 1618-1516, 1106 cm-1; LCMS (+)ESI: m/z calculated for C ₁₀ H ₁₃ NO ₃ : 195, found: 196 (M+H); 1H NMR (200 MHz, DMSO-d6): 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 (AVH system, J=13.9, 5.3 Hz, 1H), 2.65 (AVH system, J=13.9, 7.5 Hz, 1H). Elemental analysis data calculated for (C ₁₀ H ₁₃ NO ₃ ): C 61.40; H 6.81; N 7.11; O 24.91.

Preparation of (8)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid salt of S-(+)-camphor-10sulfonic acid.

Scheme 5

O (5)-(+)-camphor-10-O

II sulfonic acid H camphor-10A O acetone/H ₂ O D' J o sulfonic acid (CSА)

H2N~ _H2N (V)(VI).(S)-CSA

Table 4

Consumables for obtaining a batch of the product on an industrial scale (synthesis of compound (VI)-(S)-CSA)

Material Expense ratio* Quantity (kg) 3-(4-aminophenyl)-2-methoxy-propanoic acid 1,0 37,5 acetone 3.0 FROM deionized water 0,4 15,0 (S)-(+)-10-camphor sulfonic acid 1,2321 46.2 acetone 2.0 75 (S)-(-)-3-(4-aminophenyl)-2- methoxypropionic acid salt of S-(+)camphor-10-sulfonic acid, dried (primer) 0,01 0.38 acetone 2.0 75

* Consumption coefficient relative to the amount of 3-(4-aminophenyl)-2-methoxypropanoic acid (dried) used.

A stainless steel reactor was charged with 3-(4-aminophenyl)-2-methoxypropanoic acid (V) (37.5 kg) and acetone (113 kg) under nitrogen purge. Deionized water (15.0 kg) and (S)-(+)camphor-10-sulfonic acid (46.2 kg) were added and the reactor was purged with nitrogen. The reaction mixture was heated to a temperature in the range of 45 to 55 °C until complete dissolution was achieved. Acetone (75 kg) was added and the solution was cooled to a temperature in the range of 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 mixture was stirred at a temperature in the range from 30 to 35 °C for at least 3 h until precipitation occurred. Portions of the suspension were centrifuged, washing with acetone (75 kg). The centrifuged product (S)-(-)-3-(4

- 18 046346 aminophenyl)-2-methoxypropionic acid salt S-(+)-camphor-10-sulfonic acid (VI)-(S)-CSA (41.7 kg) was used directly in the next step.

Obtaining (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI).

Scheme 6

(5)-(+)-camphor-10- H ₂ O/E1OAc sulfonic acid (CSA) (VI).(S)-CSA

Table 5

Consumables for obtaining a batch of the product on an industrial scale (synthesis of compound (VI))

Material Expense ratio* Quantity (kg) (S)-(-)-3 -(4-aminophenyl)-2methoxypropionic acid salt of S-(+)camphor-10-sulfonic acid, wet 1,0 41.7 (35.0 kg dry matter basis) deionized water 2.8 98 deionized water 0,2 7.0 ethyl acetate 1,0 35,0 ammonia 30% 0,1792 6.3 acetic acid 80% 0,125 4.38 deionized water 0,5 17,5 ethyl acetate 0,5 17,5 deionized water 0,5 17,5

* Consumption coefficient relative to the amount of (S)-(-)-3-(4-aminophenyl)-2methoxypropionic acid, salt of S-(+)-camphor-10-sulfonic acid used (calculated on dry matter).

Obtaining (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI).

A stainless steel reactor was charged with deionized water (98 kg) and wet ((S)-(-)-3(4-aminophenyl)-2-methoxypropionic acid salt of S-(+)-camphor-10-sulfonic acid (VI)-(S)CSA (41.7 kg), purged with nitrogen, and heated for at least 10 min at 20 to 30 °C until complete dissolution was achieved. The solution was filtered, washing with deionized water (7.0 kg) then ethyl acetate (35.0 kg). The resulting solution was purged with nitrogen, heated to 50 to 60 °C, and 30% ammonia (6.3 kg) was added to precipitate the product. The resulting mixture was stirred for at least 5 min at 50 to 60 °C, then 80% acetic acid was added through the filter. acid (4.38 kg), and the reaction mixture was purged with nitrogen and stirred at a temperature in the range of 50 to 60 °C for at least 30 min, then cooled to 10-20 °C and stirred for at least 1 h. The reaction mixture was centrifuged in portions 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 give (S)-(-)-3-(4-aminophenyl)-2methoxypropionic acid (VI) (9.6 kg, 27%), which was used directly in the next step.

(S)-(-)-3-(4-Aminophenyl)-2-methoxypropionic acid (VI): [a]D ²⁰ -30 to -26 (1% w/v H2O/CH3OH (1:1 v/v)); PC: 2931, 2891, 2826, 2625, 2136, 1587, 1548, 1512, 1106, 1092 cm-1; LCMS (+) ESI: m/z calculated for C10H13N03: 195, found: 196 (M+H); ¹ H NMR (200 MHz, DMSO-d6): 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). Elemental analysis data calculated for (C10H ₁₃ NO ₃ ): C, 61.45; H, 6.79; N7.12; O, 24.65.

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Preparation of (S)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid (VII). Scheme 7

< ^VI > (VII)

Table 6

Consumables for obtaining a batch of the product on an industrial scale (synthesis of compound (VII))

Material Expense ratio* Quantity (kg) (S)-(-)-3-(4-aminophenyl)-2- methoxypropionic acid 1,0 9.6 ethyl acetate 1,5 14.4 acetic anhydride 0,5833 5,6 deionized water 0,05 0,5 ethyl acetate 0,5 4.80 deionized water 1,5 14.4

* Consumption coefficient relative to the amount of (S)-(-)-3-(4-aminophenyl)-2methoxypropionic acid used.

A stainless steel reactor was charged with dry (8)-3-(4-aminophenyl)-2-methoxypropanoic acid (VI) (9.6 kg) and ethyl acetate (14.4 kg) at a temperature in the range of 0 to 10 °C under a nitrogen purge. The reaction mass was heated to a temperature in the range of 60 to 70 °C and acetic anhydride (5.6 kg) was added to a filter with an insert filter element over a period of approximately 30 min. The reaction mixture was stirred at a temperature in the range of 60 to 70 °C for 1 h, then treated with deionized water (0.5 kg) and stirred at a temperature in the range of 60 to 70 °C for at least 15 min, during which time a precipitate was formed. The mixture was cooled to a temperature in the range of 0 to 20 °C and stirred for at least 30 min, 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 a temperature in the range of 60 to 70 °C for 13-16 h and ground to give (S)-3-(4-acetamidophenyl)-2-methoxypropanoic acid (VII) (10.3 kg).

(S)-(-)-3-(4-Acetamidophenyl)-2-methoxypropionic acid: (VII): [a]D ²⁰ -26 to -19 (1% w/v H2O/CH3OH (1:1 v/v)); IR: 3322, 3089, 2930, 2827, 2714, 2490, 1722, 1637, 1601, 1551, 1516, 1231, 1207, 1120, 1110 cm-1; LCMS (+)ESI: m/z calculated for C ₁₂ H ₁₅ NO ₄ : 237, found: 238 (M+H); Ή NMR (200 MHz, DMSO-d6): δ 12.96 (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).

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Table 7

Technical characteristics of (S)-3-(4-acetamidophenyl)-2-methoxypropanoic acid (VII) obtained according to scheme 7

(8)-(+)-camphor-10-sulfonic acid No more than 0.1% (by HPLC method) (S)-3-(4-aminophenyl)-2- methoxypropanoic acid No more than 0.15% (by HPLC method) Other impurities No more than 0.1% (by HPLC method) Palladium No more than 10 ppm (ICP-AES method) Chiral purity Not less than 98% (by HPLC method) Acetic acid No more than 5000 ppm (GC method) Residual solvents (ethyl acetate) No more than 5000 ppm (GC method)

Example 3. Preparation of methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate (I).

Scheme 8 o

(I)

Table 8

Consumables for obtaining a batch of the product on an industrial scale (synthesis of compound (I))________________

Material Expense ratio* Quantity (kg) sodium methoxide 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 z,o 143 deionized water 1,0 48 sodium chloride 0,1 4.75 toluene 1,0 47,5 toluene 4.65 221

* Consumption coefficient relative to the amount of 4-nitrobenzaldehyde used.

- 21 046346

Preparation of a suspension of 4-nitrobenzaldehyde in methyl methoxyacetate and tetrahydrofuran.

4-Nitrobenzaldehyde (47.5 kg), methyl methoxyacetate (52 kg), and tetrahydrofuran (47.5 kg) were loaded into a stainless steel reactor and cooled to a temperature in the range of -10 to -5°C with stirring.

Obtaining methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate (I).

A stainless steel reactor was purged with nitrogen (2x) and charged with sodium methoxide (28.5 kg) and tetrahydrofuran (119 kg) under nitrogen purge. The reactor was then purged with nitrogen for 1 min and the sodium methoxide solution was cooled to a temperature in the range of -10 to -7 °C with stirring. The cooled solution was then treated with the previously prepared suspension of 4-nitrobenzaldehyde in methyl methoxyacetate and tetrahydrofuran while maintaining the temperature of the reaction mass below 0 °C. After complete addition, the empty reactor was rinsed with tetrahydrofuran (23.8 kg) and the reaction mixture was poured into it. The reaction mixture was stirred at a temperature in the range of -5 to 0 °C for no more than 5 min. Maintaining the temperature between -10 and 0°C, cold toluene (95 kg, temperature between -10 and 0°C) was quickly added, followed by rapid addition of glacial acetic acid (36 kg), and the reaction mixture was stirred for 10 min at a temperature in the range of 10 to +10°C. Deionized water (143 kg) was added and the reaction mass was stirred at a temperature in the range of 0 to 10°C for at least 10 min, then at a temperature in the range of 25 to 30°C for at least 10 min to achieve complete dissolution, after which stirring was stopped and the phases were separated. The aqueous phase was discarded and the separated organic phase was treated with an aqueous solution of sodium chloride (previously prepared by adding 4.75 kg of sodium chloride to 48 kg of deionized water). The mass was then heated to a temperature in the range of 25 to 30 °C with stirring for at least 15 min. Stirring was stopped and the phases were separated. The aqueous phase was discarded (64 kg). The separated organic phase was then subjected to vacuum distillation to an oily residue at a temperature in the range of 70 to 80 °C. The reactor containing the hot residue was purged with nitrogen then treated with toluene (47.5 kg), and the toluene was distilled under vacuum at a temperature in the range of 70 to 80 °C, obtaining an oily residue. The resulting hot residue was purged with nitrogen then treated with toluene (221 kg), and the mass was stirred for at least 10 min at a temperature in the range of 40 to 50 °C. The solution was used without purification in the next step.

Example 4. Method for obtaining (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) and (S)-(-)3-(4-acetamidophenyl)-2-methoxypropionic acid (VII).

Scheme 9

he (57-(+)-camphor-10sulfonic acid acetone/N ₂ O ^H 2 ^N •(S7-(+)- camphor-102.

sulfonic acid (CSA) (VIJ-fS)-CSA acetic acid _H2O /EIOAc

_1.NH4OH

H2O/EUAC

HE (VI) o

Acetic anhydride

EtOAc, 65-70 °C

he (VII)

Obtaining 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV).

Scheme 10

1. _H2O

2. H ₃ PO ₄ , CH ₃ OH/H ₂ O

(IV)

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Table 9

Consumables for obtaining a batch of the product on an industrial scale (synthesis of compound (IV))

Material Expendable Quantity (kg) methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate, solution in toluene 1,0 The entire solution obtained according to scheme 8 triethylamine 0.9 42.8 methanesulfonylchloride 0.8 38 deionized water z,o 143 toluene 0,15 7.1 methanol 3.1 147 sodium hydroxide 30% 1.86 88 deionized water 3.88 184 hydrochloric acid 37% 0.74 35.2 phosphoric acid 85% 0.16 7.6 phosphoric acid 85% - to pH<3.0 deionized water 4.0 190 toluene 2,4 114

* Consumption coefficient relative to the amount of 4-nitrobenzaldehyde used.

A solution of methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate (I) in toluene in a stainless steel reactor was cooled to 0 to 10 °C under nitrogen purge and triethylamine (42.8 kg) and methanesulfonyl chloride (38 kg) were added while maintaining the temperature at 0 to 10 °C and the reaction mixture was stirred at 0 to 10 °C for 60 min. Deionized water (143 kg) was slowly added and the resulting mass was stirred at 55 to 60 °C for 10 min, after which stirring was stopped and the phases were separated. The aqueous phase was discarded (199 kg) and the organic phase was filtered, washing the filter with toluene (7.1 kg). The filtered solution was heated to a temperature in the range of 55 to 60 °C for 10 min. Stirring was stopped and the phases were separated; the resulting aqueous phase was discarded (3.5 kg). An aliquot of toluene was distilled under vacuum and with stirring taking into account the following proportion: for 50 kg of nitrobenzaldehyde used in Scheme 8, approximately 5 kg of toluene was distilled and this aliquot of the distilled toluene was discarded. Toluene was removed by distillation under vacuum, not exceeding a temperature of 60 °C, to obtain an oily residue. The resulting residue was then treated with methanol (147 kg), purged with nitrogen, cooled to a temperature in the range of 20 to 30 °C and slowly treated with 30% sodium hydroxide (88 kg). The reaction mixture was stirred at a temperature in the range of 20 to 30 °C for 3 h. Deionized water (184 kg) was added and the solution was heated to a temperature in the range of 60 to 65 °C. At this temperature, 37% hydrochloric acid (35.2 kg) and 85% phosphoric acid (7.6 kg) were slowly added to precipitate the product. If necessary, 85% phosphoric acid was added to adjust the pH < 3.0. The resulting precipitated product was stirred at a temperature in the range of 60 to 65 °C for at least 30 min, then cooled to a temperature in the range of 35 to 40 °C and stirred for at least 30 min. The mixture was centrifuged, washing with deionized water (190 kg), and then washed with toluene (114 kg), (mother liquor: 749 kg). The wet product (approximately 82 kg) was used in the next step.

Obtaining 3-(4-aminophenyl)-2-methoxypropanoic acid (V).

Scheme 11

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Table 10

Consumables for obtaining a batch of the product on an industrial scale (synthesis of compound (V))

Material Expense ratio* Quantity (kg) 2-methoxy-3-(4-nitrophenyl)-acrylic acid, wet 1,0 82 methanol z,o 143 ammonia 30% o,z 14.3 deionized water 0,2 9.5 palladium on carbon 5% (containing 50% water) or palladium on carbon 5% (recycled) 0,1 4.75 deionized water 0,05 2,4 deionized water 0,05 2,4 deionized water 0,05 2,4 deionized water 0,4 19 deionized water 2.0 95 hydrochloric acid 37% 0.32 15.2 acetic acid 80% 0.22 10,5 ethyl acetate 1,5 71 deionized water 1,0 47,5 ethyl acetate 1,0 47,5

* Consumption coefficient relative to the amount of 4-nitrobenzaldehyde used.

Preparation of an aqueous suspension of 5% palladium on carbon in water.

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

Obtaining 3-(4-aminophenyl)-2-methoxypropanoic acid (V).

A stainless steel reactor was purged with nitrogen (2x) and charged with wet 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV) (82 kg), methanol (143 kg) and 30% ammonia (14.3 kg). After the reactor was returned to atmospheric pressure, the mixture was stirred at a temperature in the range of 20 to 30 °C until complete dissolution was achieved. The resulting solution was purged with nitrogen (2x) and treated with a previously prepared solution of 5% palladium on carbon in deionized water, and the empty reactor was rinsed with deionized water (2.4 kg). The reaction mixture was purged with nitrogen (2x), heated to a temperature in the range of 60 to 80 °C, then charged with hydrogen until the reactor pressure reached 0.40 to 0.45 MPa. The reaction was carried out maintaining the pressure in the range of 0.40 to 0.45 MPa until all hydrogen was consumed and the reaction was confirmed to be complete. The reactor was restored to atmospheric pressure and the reaction mixture was cooled to a temperature in the range of 20 to 30 °C, filtered through a filter press, purged with nitrogen (2x) and treated with deionized water (19 kg), which was combined with the solution containing the product. At a temperature not exceeding 50 °C, the solvent was distilled off with stirring and under vacuum to an oily residue. The residue was treated with deionized water (95 kg), heated to a temperature in the range of 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 a temperature in the range of 65 to 70 °C for at least 10 min, and then the mixture was treated with ethyl acetate (71 kg), purged with nitrogen and stirred at a temperature in the range of 65 to 70 °C for at least 15 min. The reaction mass was cooled to a temperature in the range of 15 to 20 °C and stirred for at least 30 min. The suspension was centrifuged in portions, washing with deionized

- 24 046346 bath water (47.5 kg) and ethyl acetate (47.5 kg). The wet product was dried at a temperature in the range from 60 to 70 °C to obtain 3-(4-aminophenyl)-2-methoxypropanoic acid (V) (40.5 kg).

Obtaining (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid salt of S-(+)-camphor-10sulfonic acid.

Scheme 12 o

(S)-(+)-camphor-10sulfonic acid D| I acetone /H ₂ O ^Η 2 ^Ν • camphor-10-sulfonic acid (CSA) (VI)*(S)-CSA

Table 11

Consumables for obtaining a batch of the product on an industrial scale (synthesis of the compound (VIV(S)-CSA)

Material Expense ratio* Quantity (kg) 3-(4-aminophenyl)-2-methoxy-propanoic 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

* Consumption coefficient relative to the amount of 3-(4-aminophenyl)-2methoxypropanoic acid (dried) used.

A stainless steel reactor was charged with 3-(4-aminophenyl)-2-methoxypropanoic acid (V) (40.5 kg) and (S)-(+)-camphor-10-sulfonic acid (49.9 kg), purged with nitrogen, and added acetone (81 kg). Deionized water (6.5 kg) was added. The reaction mixture was heated to approximately 58 °C for 2 h (under reflux, no dissolution occurred). Acetone (81 kg) was added (temperature approximately 58 °C), and the reaction mass was refluxed (at approximately 58 °C) for 1 h. The reaction mass was then cooled to a temperature in the range of 37 to 42 °C and centrifuged in portions, washing with acetone (61 kg). The centrifuged product (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid salt of S-(+)-camphor-10-sulfonic acid (VI)-(S)-CSA (wet weight: 43.1 kg, 36.1 kg dry weight) was directly used in the next step.

Obtaining (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI).

Scheme 13 o o

1. ACETIC ACID * H ₂ N ./3)-(+)-camphor-10- _acid * H2O/EuAc VI sulfonic acid (CSA) (VI).(S)-CSA

Table 12

Consumables for obtaining a batch of the product on an industrial scale (synthesis of compound (VI))

Material Expense ratio* Quantity (kg) deionized water 2.0 72

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(8)-(-)-3 -(4-aminophenyl)-2methoxypropionic acid salt of S-(+)camphor-10-sulfonic acid, wet 1,0 43.1 (36.1 kg dry matter basis) deionized water 0,2 7.2 ethyl acetate 1,0 36.1 ammonia 30% 0,1257 4.54 acetic acid 80% 0,05 1.81 deionized water 0,7 25.3 ethyl acetate 0,7 25.3

* Consumption coefficient relative to the amount of (S)-(-)-3-(4-αaminophenyl)-2methoxypropionic acid salt of S-(+)-camphor-10-sulfonic acid used (calculated on dry matter).

A stainless steel reactor was charged with deionized water (72 kg) and wet ((S)-(-)-3(4-aminophenyl)-2-methoxypropionic acid salt of S-(+)-camphor-10-sulfonic acid (VI)-(S)CSA (wet weight: 43.1 kg, 36.1 kg dry basis), purged with nitrogen, and heated for at least 10 min at a temperature in the range of 20 to 40 °C until completely dissolved. The solution was filtered and washed with deionized water (7.2 kg) then ethyl acetate (36.1 kg). The resulting solution was purged with nitrogen, heated to a temperature in the range of 55 to 60 °C, and 30% ammonia (4.54 kg) was added to precipitate the product. The resulting mixture was stirred for at least 15 min at a temperature in the range of 55 to 60 °C, then 80% acetic acid (1.81 kg) was added through a filter, and the reaction mixture was purged with nitrogen and stirred at a temperature in the range of 55 to 60 °C for at least 30 min, then cooled to 2-7 °C and stirred for at least 1 h. The reaction mass was centrifuged in portions and washed with deionized water (25.3 kg), ethyl acetate (25.3 kg) to obtain wet (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) (wet weight 11.8 kg, 10.8 kg based on dry matter), which was used directly (wet) in the next step.

Preparation of (S)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid (VII).

Scheme 14

(VI) (VII)

Table 13

Consumables for obtaining a batch of the product on an industrial scale (synthesis of compound (VII))

Material Expense ratio* Quantity (kg) wet (S)-(-)-3-(4-aminophenyl)-2- methoxypropionic acid 1,0 11.8 (10.8 kg dry matter basis) ethyl acetate 1,5 16.2 acetic anhydride 0.65 7.0 ethyl acetate 0,5 5.4 deionized water 1,5 16.2

* Consumption coefficient relative to the amount of (S)-(-)-3-(4-aminophenyl)-2methoxypropionic acid used (calculated on dry matter).

A stainless steel reactor was charged with wet (S)-3-(4-aminophenyl)-2-methoxypropanoic acid (VI) (wet weight 11.8 kg, dry weight 10.8 kg) and ethyl acetate (16.2 kg) under nitrogen. The mixture was heated to a temperature in the range of 65 to 70 °C and acetic anhydride (7.0 kg) was added through a filter with an insert filter element over a period of approximately

- 26 046346 min. The reaction mixture was stirred at a temperature in the range of 65 to 70 °C for 60 min, and after the completion of the reaction was detected, it was continuously stirred until a precipitate was formed. The mixture was cooled to a temperature in the range of 0 to 20 °C and stirred at a temperature in the range of 10 to 20 °C for 30 min, 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 a temperature in the range of 60 to 70 °C for 13-16 h and ground to obtain (S)-3-(4-acetamidophenyl)-2-methoxypropanoic acid (VII) (12.3 kg).

Example 5. Preparation of methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate (I).

Scheme 15 o

O _0N Q

JI, NaOMe JI

Γί ⁿ -------------- ί ' ⁰

Λ THF, -5-0 °C

_{O2NO2N (} I)

Table 14 Consumables for obtaining a batch of the product on an industrial scale (synthesis of compound (I))

Material Expense ratio* Quantity (kg) sodium methoxide 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 z,o 1140 deionized water 1,0 380 sodium chloride 0,1 38 toluene 1,0 380 toluene 4.65 1767

* Consumption coefficient relative to the amount of 4-nitrobenzaldehyde used.

Preparation of a suspension of 4-nitrobenzaldehyde in methyl methoxy acetate and tetrahydrofuran.

4-nitrobenzaldehyde (380 kg), methyl methoxyacetate (418 kg), and tetrahydrofuran (380 kg) were loaded into a stainless steel reactor and cooled to a temperature in the range of -10 to -5°C with stirring.

Obtaining methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate (I).

A stainless steel reactor was purged with nitrogen (2x) and charged with sodium methoxide (228 kg) and tetrahydrofuran (1100 kg) under nitrogen purging. The reactor was then purged with nitrogen for 1 min and the sodium methoxide solution was cooled to a temperature in the range of -15 to -10 °C with stirring. The cooled solution was then treated with the previously prepared suspension of 4-nitrobenzaldehyde in methyl methoxyacetate and tetrahydrofuran, maintaining the temperature of the reaction mass below 0 °C. After complete addition, the empty reactor was rinsed with tetrahydrofuran (40 kg) and the reaction mixture was poured into it. The reaction mixture was stirred at a temperature in the range of -5 to 0 °C for no more than 5 min. Maintaining the temperature between -10 and 0°C, cold toluene (760 kg, temperature between -10 and 0°C) and simultaneously glacial acetic acid (285 kg) were added rapidly and the reaction mixture was stirred for 10 min at a temperature in the range of -10 to +10°C. Deionized water (1140 kg) was added and the reaction mass was stirred at a temperature in the range of 0 to 10°C for at least 10 min, then at a temperature in the range of 25 to

- 27 046346

30°C for at least 10 min to achieve complete dissolution, after which stirring was stopped and the phases were separated. The aqueous phase was discarded and the separated organic phase was treated with an aqueous solution of sodium chloride (previously prepared by adding 38 kg of sodium chloride to 380 kg of deionized water). The mass was then heated to a temperature in the range of 25 to 30°C with stirring for at least 10 min. Stirring was stopped and the phases were separated. The aqueous phase was discarded. The separated organic phase was then distilled under vacuum at a temperature in the range of 70 to 80°C to obtain an oily residue. The reactor containing the hot residue was purged with nitrogen, then treated with toluene (380 kg), and the toluene was distilled under vacuum at a temperature in the range of 70 to 80°C to obtain an oily residue. The resulting hot residue was purged with nitrogen, then treated with toluene (1767 kg), and the mass was stirred for at least 10 min at a temperature in the range of 40 to 50°C. The solution was used directly in the next step.

Example 6. Method for obtaining (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) and (S)-()-3-(4-acetamidophenyl)-2-methoxypropionic acid (VII).

Scheme 16

1. _H2O

2. H ₃ PO ₄ , HCI

he (IV)

_H2 , Pd/C 0.40-0.45 MPa

60-80°C

MeOH, _NH4OH

it is acetone/ _H2O (5)-(+)- camphor-10sulfonic acid

He

H _? N • (S)-(+)- camphor-10sulfonic acid (CSA) (VI).(S)-CSA acetic

2- acid

H ₂ O/EuAs

1. IN ₄ HE

H ₂ O/EuAs

HE (VI)

Acetic anhydride

EUS, 65-70 "C

he (VII)

Obtaining 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV).

Scheme 17

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Table 15

Consumables for obtaining a batch of the product on an industrial scale (synthesis of compound (IV)

Material Expense ratio* Quantity (kg) methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate, solution in toluene 1,0 The entire solution obtained in scheme 15 triethylamine 0.9 342 methanesulfonylchloride 0,8 304 deionized water 3.0 1140 toluene 0,15 57 methanol 3.1 1178 sodium hydroxide 30% 1.86 707 deionized water 3.88 1474 hydrochloric acid 37% 0.74 281 phosphoric acid 85% 0.16 61 phosphoric acid 85% - up to pH<3.0 deionized water 4.0 1520 toluene 2,4 912

* Consumption coefficient relative to the amount of 4-nitrobenzaldehyde used.

A solution of methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate (I) in toluene in a stainless steel reactor was cooled to a temperature in the range of 0 to 10 °C under nitrogen purging and, while maintaining the temperature at 0 to 10 °C, triethylamine (342 kg) and methanesulfonyl chloride (304 kg) were added and the reaction mixture was stirred at a temperature in the range of 0 to 10 °C for 60 min. Deionized water (1140 kg) was slowly added and the resulting mass was stirred at a temperature in the range of 55 to 60 °C for 10 min, after which stirring was stopped and the phases were separated. The aqueous phase was discarded and the organic phase was filtered, washing the filter with toluene (57 kg). The filtered solution was heated to a temperature in the range of 55 to 60 °C for 10 min. The stirring was stopped and the phases were separated, the aqueous phase was discarded. An aliquot of toluene was distilled under vacuum and with stirring taking into account the following proportion: for 380 kg of nitrobenzaldehyde used in Scheme 15, approximately 38 kg of toluene was distilled and this aliquot of the distilled toluene was discarded. Toluene was removed by distillation under vacuum at a temperature not exceeding 60 °C to obtain an oily residue. The resulting residue was then treated with methanol (1178 kg), purged with nitrogen, cooled to a temperature in the range of 20 to 30 °C and slowly treated with 30% sodium hydroxide (707 kg). The reaction mixture was stirred at a temperature in the range of 20 to 30 °C for 3 h. Deionized water (1474 kg) was added and the solution was heated to a temperature in the range of 60 to 65 °C. At this temperature, 37% hydrochloric acid (281 kg) and 85% phosphoric acid (61 kg) were slowly added to precipitate the product. If necessary, 85% phosphoric acid was added to adjust the pH to < 3.0. The resulting precipitated product was stirred at a temperature in the range of 60 to 65 °C for at least 30 min, then cooled to a temperature in the range of 35 to 40 °C and stirred for at least 30 min. The mixture was centrifuged, washing with deionized water (1520 kg), and then washed with toluene (912 kg). The wet product (approximately 786 kg) was used in the next step.

Obtaining 3-(4-aminophenyl)-2-methoxypropanoic acid (V).

Scheme 18

- 29 046346

Consumables for obtaining a batch of the product on an industrial scale (synthesis of compound (V))

Table 16

Material Expense ratio* Quantity (kg) 2-methoxy-3-(4-nitrophenyl)-acrylic acid, wet 1,0 786 methanol z,o 1140 ammonia 30% o,z 114 deionized water 0,2 76 palladium on carbon 5% (containing 50% water) or palladium on carbon 5% (recycled) 0,1 38 deionized water 0,05 19 deionized water 0,05 19 deionized water 0,4 152 deionized water 2.0 760 hydrochloric acid 37% 0.32 122 acetic acid 80% 0.22 84 ethyl acetate 1,5 570 deionized water 1,0 380 ethyl acetate 1,0 380

* Consumption coefficient relative to the amount of 4-nitrobenzaldehyde used.

Preparation of an aqueous suspension of 5% palladium on carbon in water.

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

Obtaining 3-(4-aminophenyl)-2-methoxypropanoic acid (V).

A stainless steel reactor was purged with nitrogen (2x) and charged with wet 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV) (786 kg), methanol (1140 kg), and 30% ammonia (114 kg). After the reactor was returned to atmospheric pressure, the mixture was stirred at 20 to 30 °C until completely dissolved. The resulting solution was purged with nitrogen (2x) and treated with a previously prepared solution of 5% palladium on carbon in deionized water, and the empty reactor was rinsed with deionized water (19 kg). The reaction mixture was purged with nitrogen (2x), heated to 60 to 80 °C, then charged with hydrogen until the reactor pressure reached 0.40 to 0.45 MPa. The reaction was carried out maintaining the pressure in the range of 0.40 to 0.45 MPa until the hydrogen was consumed and the end of the reaction was confirmed. The reactor was restored to atmospheric pressure and the reaction mixture was cooled to a temperature in the range of 20 to 30 °C, filtered through a filter press, purged with nitrogen (2x) and treated with deionized water (152 kg), which was combined with the solution containing the product. At a temperature not exceeding 50 °C, the solvent was distilled off with stirring and under vacuum to an oily residue. The residue was treated with deionized water (760 kg), heated to a temperature in the range of 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 a temperature in the range of 65 to 70 °C for at least 10 min; at this stage, it was confirmed that the pH was from 3.8 to 4.2 (not more than 4.2), and then the mixture was treated with ethyl acetate (570 kg), purged with nitrogen and stirred at a temperature in the range of 65 to 70 °C for at least 15 min. The reaction mass was cooled

- 30 046346 was allowed to reach a temperature in the range of 15 to 20 °C and stirred for at least 30 min. The suspension was centrifuged in portions, washing with deionized water (380 kg) and ethyl acetate (380 kg). The wet product was granulated and dried at a temperature in the range of 60 to 70 °C to obtain 3-(4-aminophenyl)-2-methoxypropanoic acid (V) (~295 kg).

Preparation of (s)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid salt of s-(+)-camphor-10sulfonic acid

Scheme 19 o

(5)-(+)-camphor-10sulfonic acid I acetone /H ₂ O ^Η;Ν ♦(5.H+Namphor-10sulfonic acid (CSA) (VI).(S)-CSA

The starting material 3-(4-aminophenyl)-2-methoxypropanoic acid, obtained in two batches, was combined (one full batch and an aliquot from the second batch) to yield a total of 400 kg of 3-(4-aminophenyl)-2-methoxypropanoic acid. This amount is equivalent to the amount that could be obtained from 500 kg of 4-nitrobenzaldehyde.

Table 17

Consumables for obtaining a batch of the product on an industrial scale (synthesis of compound (VI)-(S)-CSA)

Material Expense ratio* Quantity (kg) 3-(4-aminophenyl)-2-methoxy- propanoic 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

Consumption coefficient relative to the amount of 3-(4-aminophenyl)-2methoxypropanoic acid (dried) used.

A stainless steel reactor was charged with 3-(4-aminophenyl)-2-methoxypropanoic acid (V) (400 kg) and (S)-(+)-camphor-10-sulfonic acid (493 kg), purged with nitrogen, and acetone (800 kg) was added. Deionized water (64 kg) was added. The reaction mixture was heated to approximately 58 °C for 1 h (under reflux, no dissolution occurred). Acetone (800 kg) was added (temperature approximately 58°C) and the reaction mixture was refluxed (approximately 58°C) for 1 h, then the reaction mixture was cooled to a temperature in the range of 37 to 42°C and centrifuged in portions, washing with acetone (600 kg) (between each centrifugation step, an aliquot of the suspension that was not centrifuged was first heated at a temperature in the range of 45 to 50°C and then, before the next centrifugation, the suspension was cooled again to a temperature in the range of 37 to 42°C). The centrifuged product (S)-(-)-3-(4aminophenyl)-2-methoxypropionic acid salt of S-(+)-camphor-10-sulfonic acid (VI)-(S)-CSA (wet weight: 470 kg, 409.7 on a dry matter basis) was directly used in the next step.

Preparation of (s)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI).

Scheme 20 o

1. yn ₄ he Ya n ₂ o/eyuas

-----------► Ao-.

acetic H ₂ N + acid. H ₂ O/EtOAc (VI) sulfonic acid (CSA) (VI).fS)-CSA

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Table 18

Consumables for obtaining a batch of the product on an industrial scale (synthesis of compound (VI))

Material Expense ratio* Quantity (kg) deionized water 2.0 819 (S)-(-)-3 -(4-aminophenyl)-2methoxypropionic acid salt of S-(+)camphor-10-sulfonic acid, wet 1,0 470 (409.7 kg dry matter basis) deionized water 0,2 82 ethyl acetate 1,0 410 ammonia 30% 0,1257 51 acetic acid 80% 0,05 20,5 deionized water 0,7 287 ethyl acetate 0,7 287

* Consumption coefficient relative to the amount of (S)-(-)-3-(4-aminophenyl)-2methoxypropionic acid, salt of S-(+)-camphor-10-sulfonic acid used (calculated on dry matter).

A stainless steel reactor was charged with deionized water (819 kg) and wet ((S)-(-)-3(4-aminophenyl)-2-methoxypropionic acid salt of S-(+)-camphor-10-sulfonic acid (VI)-(S)CSA (wet weight: 470 kg, 409.7 dry basis), purged with nitrogen and heated for at least 10 min at a temperature in the range of 20 to 40 °C until completely dissolved. The solution was filtered, washing with deionized water (82 kg) then ethyl acetate (410 kg). The resulting solution was purged with nitrogen, heated to a temperature in the range of 55 to 60 °C and 30% ammonia (51 kg) was added to precipitate the product. The resulting mixture was stirred for at least 15 min at a temperature in the range of 55 to 60°C, then 80% acetic acid (20.5 kg) was added through a filter and the reaction mixture was purged with nitrogen and stirred at a temperature in the range of 55 to 60°C for at least 30 min, then cooled to 2-7°C and stirred for at least 1 h. The reaction mass was centrifuged in portions and washed with deionized water (287 kg), ethyl acetate (287 kg) to obtain wet (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) (wet weight 162 kg, 138.8 kg dry basis), which was used directly (in wet form) in the next step.

Preparation of (s)-(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid (VII).

Scheme 21

(VI) (VII)

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Table 19

Consumables for obtaining a batch of the product on an industrial scale (synthesis of compound (VII)) Material Expense ratio* Quantity (kg) wet (S)-(-)-3-(4-amino-phenyl)-2- methoxypropionic acid 1,0 162 (138.8 kg dry matter basis) ethyl acetate 1,5 208 acetic anhydride 0.65 90 ethyl acetate 0,5 4.80 deionized water 1,5 208

* Consumption coefficient relative to the amount of (B)-(-)-3-(4-aminophenyl)-2methoxypropionic acid used (calculated on dry matter).

A stainless steel reactor was charged with wet (S)-3-(4-aminophenyl)-2-methoxypropanoic acid (VI) (wet weight 162 kg, dry weight 138.8 kg) and ethyl acetate (208 kg) under nitrogen atmosphere. The mixture was heated to a temperature in the range of 65 to 70 °C and acetic anhydride (90 kg) was added through a filter with an insert filter element over approximately 15 min. The reaction mixture was stirred at a temperature in the range of 65 to 70 °C for 90 min and, after the end of the reaction was detected, it was continuously stirred until a precipitate formed. The mixture was cooled to a temperature in the range of 10 to 20 °C and stirred at a temperature in the range of 10 to 20 °C for 30 min, then centrifuged and the resulting solid was washed with ethyl acetate (69 kg) and deionized water (208 kg). The resulting product was dried at a temperature in the range of 60 to 70 °C for 19 h and ground to give (S)-3-(4-acetamidophenyl)-2-methoxypropanoic acid (VII) (154.5 kg).

(S)-(-)-3-(4-Acetamidophenyl)-2-methoxypropionic acid (VII): IR: 3319, 2888, 2825, 1718, 1633, 1599, 1548, 1107 cm ^-1 ; LCMS (+) ESI: m / z calculated for C12H15NO4: 237, found: 236 (M-H) ^- ; 1H NMR (600 MHz, DMSO-d6): δ 12.70 (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-d6): δ 24.09 (CH3-CO-NH-), 37.94 (-C-CH2-C), 57.47 (CH3-O-), 80.98 (-C-CH(O)-C-), 119.25 (2C, aromatic), 129.65 (2C, aromatic), 132.24 (1C, aromatic), 137.87 (1C, aromatic), 168.47 (CH3-CO-NH-), 173.21 (-COOH). Elemental analysis: C 60.82% (theoretical 60.75%), H 6.44% (theoretical 6.37%), N 5.91% (theoretical 5.90%), O 26.97% (theoretical 26.97%). DSC: melting point 154-167°C (onset 159°C). Specific optical rotation: -22.7. (S)-3-(4-aminophenyl)-2-methoxypropanoic acid (HPLC method): 0.06% (HPLC method). Chiral purity (HPLC method): 99.7% (HPLC method). Residual solvents (ethyl acetate): 277 ppm (GC method).

Example 7. Determination of the crystal structure of the compound of formula (VII) by X-ray structural analysis.

The crystal used for the structure determination was obtained by vapor diffusion of a solution of the compound of formula (VII) and L-proline (2:1) in ethanol using heptane as an antisolvent. X-ray structural analysis of the single crystal was performed. The results of this analysis are presented below. Refinement of the symmetry group of the crystal lattice P212121 resulted in an R index value of 0.062. The symmetrically independent part of the cell consists of two compounds of formula (VII) and two molecules of L-proline

Analysis of single crystal X-ray diffraction data shows that the absolute configuration of the alpha carbon with respect to the carboxylic acid group is (S). Based on these results, the absolute stereochemistry of the compound of formula (VII) is shown in the structure below.

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The optical rotation for this compound, i.e. the compound of formula (VII), is negative, meaning that plane-polarized light is rotated to the left. The specific rotation specification for the pure compound is -26.0° to -19.0°. Accordingly, since the same reagents are always used in the procedure for resolving a racemic mixture, the conclusion that the product obtained has the (S) configuration is supported by the specific optical rotation data.

Furthermore, the chiral purity of the compound of formula (VII) (by HPLC) can be determined, for example, using the method described in the invention.

The X-ray diffraction data on the crystal structure and the refinement of the crystal structure for a single crystal of the compound of formula (VII): L-proline derivative are presented below.

Empirical formula Molecular weight by compound formula Temperature Diffractometer Wavelength Crystallographic system Crystal lattice symmetry group Lattice constants Volume Z Density (calculated) Absorption coefficient F(000) Crystal size Theta angle range for data collection Index ranges Collected reflections Independent reflections Completeness for theta=25.00° Absorption correction C17H24N2O6 352.38 296(2) K Bruker Smart-Apex (two-coordinate detector) 0.71073 A Rhombic rg^A a=7.7813(5) Aa=90° b=9.5414(6) A β= 90° c=49.006(3) A γ=90° 3638.4(4) A ³ 8 1.287 mg/mm ³ 0.098 mm' ¹ 1504 0.49x0.25x0.08 mm ³ From 0.83 to 28.75° -10<=h<=8, -12<= k<=12, -54<=1<=63 19513 8598 [R(int) = 0.0437] 99.7% Semi-empirical from equivalents Maximum and minimum transmission 0.992 and 0.777 Refinement method Least squares search for the complete matrix on F ² Data/constraints/parameters 8598/0/474 Agreement on alignment on F ² 0.984 End indices R |T>2sigma(1)] Rl=0.0623, wR2=0.1517 R indices (all data) Rl=0.1217, wR2=0.1843 Absolute structural parameter -0.8(13) The biggest difference is for peaks and holes 0.382 and -0307 e.A' ³ Computer programs (Bruker) Smart 5.6/Saint 5.0/Shelxtl-NT 6.1

Incorporation of the contents of cited literature into the invention by reference.

The entire contents of all publications and patents mentioned in this invention, including those publications listed below, are in all cases incorporated by reference into this invention as if each individual publication or patent was specifically and individually indicated to be incorporated by reference into this invention. In the event of a conflict, the present invention, including any definitions contained in the invention, will control.

Equivalents.

Although specific embodiments of the present invention have been disclosed, the above description of the invention is illustrative and does not limit the invention in any way. After reading the description of the invention, it will be obvious to those skilled in the art that many other embodiments of the invention may exist. The full scope of the invention should be determined only by the claims, but also by the full scope of equivalents and by the description together with such embodiments.

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Unless otherwise indicated, all numerical values expressing quantities of ingredients, reaction conditions, etc., used in the description and claims are to be understood as subject to change, which in all cases is defined by the term approximately. Accordingly, unless otherwise indicated, the numerical parameters given in this description and the appended claims are approximate, which may vary depending on the desired properties to be achieved as a result of the implementation of the present invention.

Claims (50)

1. Method for obtaining a compound of formula (VII) wherein the method comprises reacting a compound of formula (I) with an activating reagent to form an intermediate compound of formula (I-A) where LG represents the leaving group; treating the intermediate compound of formula (I-A) with a solution of a base in the presence of an alcoholic solvent to remove the leaving group and thereby obtain an intermediate compound of formula (I-B) hydrolysis of the intermediate compound of formula (I-B) to obtain a compound of formula (IV) hydrogenation of a compound of formula (IV) to obtain a compound of formula (V) optical resolution of a compound of formula (V) to obtain a substantially optically pure compound of formula (VI) - 35 046346 acylation of a compound of formula (VI) to obtain a compound of formula (VII); wherein the compound of formula (VII) consists of at least 95% of the enantiomer ABOUT (expressed as a percentage of both enantiomers). 2. The method according to claim 1, wherein the reaction of the compound of formula (I) with the activating reagent is carried out in the presence of a base and a solvent. 3. The method according to claim 2, wherein the solvent is selected from the group consisting of toluene, dichloromethane, tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran and acetonitrile. 4. The method according to claim 2 or 3, wherein the solvent is toluene. 5. The method according to any one of claims 2 to 4, wherein the base is an amine. 6. The method according to claim 5, wherein the amine is selected from the group consisting of triethylamine, N,N-diisopropylethylamine and pyridine. 7. The method according to any one of paragraphs 5, 6, wherein the amine is triethylamine. 8. The method according to any one of claims 1 to 7, wherein the activating reagent is a sulfonylating reagent or a halogenating reagent. 9. The method according to any one of claims 1 to 8, wherein the activating reagent is selected from the group consisting of methanesulfonyl chloride, p-toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, phenyltriflimide, trifluoromethanesulfonic anhydride and nonafluorobutanesulfonic anhydride. 10. The method according to any one of claims 1 to 9, wherein the activating reagent is methanesulfonyl chloride. 11. The method according to any one of claims 1 to ₇ , wherein the leaving group is selected from the group consisting of OSO ₂ -aryl, -OSO ₂ -C _1-4 alkyl, chlorine, bromine and iodine; wherein the C _1-4 alkyl and aryl may be optionally substituted by one or more substituents each independently selected, at each occurrence, from the group consisting of fluorine, bromine and -CH ₃ . 12. The method according to claim 11, wherein the leaving group is -OSO ₂ -phenyl or -OSO _{2 -C 1-4 αalkyl} . 13. The method according to claim 11, wherein the leaving group is independently selected from the group consisting of °v°y fΎ o ΓΎ ъ -OSO ₂ Me, -OSO ₂ CF ₃ , ^Br and -OSO ₂ CF ₂ CF ₂ CF ₂ CF ₃ . 14. The method according to any one of claims 1 to 13, wherein the leaving group is -OSO ₂ Me. 15. The method according to any one of claims 1 to 14, wherein the alcohol solvent comprises at least one alcohol solvent from methanol, ethanol, isopropanol and butanol. 16. The method according to claim 15, wherein the alcohol solvent comprises methanol. 17. The method according to any one of claims 1 to 16, wherein the base solution comprises at least one base from sodium hydroxide, lithium hydroxide and potassium hydroxide. 18. The method according to claim 17, wherein the base solution comprises sodium hydroxide. 19. The method according to any one of claims 1 to 18, wherein the base solution comprises approximately 30% sodium hydroxide solution. 20. The method according to any one of claims 1 to 19, wherein the hydrolysis of the intermediate compound of formula (I-B) to form the compound of formula (IV) comprises: (i) contacting the intermediate of formula (I-B) with an alkali metal hydroxide and water and (ii) neutralizing the reaction mixture from step (i) with an acid to form a compound of formula (IV). 21. The method according to claim 20, wherein the alkali metal hydroxide is sodium hydroxide. 22. The method according to claim 20 or 21, wherein the neutralization comprises acidifying to a pH value less than or equal to 3 by adding an acid. 23. The method according to claim 22, wherein the acid is phosphoric acid or hydrochloric acid, or a mixture thereof. 24. The method according to any one of claims 1 to 23, wherein hydrogenating the compound of formula (IV) to form the compound of formula (V) comprises contacting the compound of formula (IV) with hydrogen and a catalyst. 25. The method according to claim 24, wherein the catalyst is 5% Pd/C. 26. The method according to any one of claims 1 to 25, wherein the hydrogenation is carried out at a temperature maintained in the range of 60-80°C and at a pressure of 0.3 to 0.5 MPa. - 36 046346 27. The method according to any one of claims 1 to 26, wherein the optical resolution of a compound of formula (V) to form a substantially optically pure compound of formula (VI) comprises: (a) separating the compound of formula (V) in the presence of a chiral acid to thereby form a chiral salt of the compound of formula (VI); and (b) neutralizing the chiral salt of the compound of formula (VI) to thereby form a compound of formula (VI). 28. The method according to claim 27, wherein the chiral acid is selected from the group consisting of (S)-(+)-camphor-10sulfonic acid, (2R,3R)-(+)-tartaric acid, (S)-(-)-malic acid and (R)-(-)-mandelic acid or its enantiomer. 29. The method according to claim 27 or 28, wherein the chiral acid is (S)-(+)-camphor-10sulfonic acid. 30. The method according to any one of claims 27 to 29, wherein the chiral salt of the compound of formula (VI) is ABOUT ABOUT... h ₂ n - camphor-10-sulfonic acid 31. The method according to any one of claims 1 to 30, wherein the separation further comprises maintaining the temperature in the range of 55-60°C while stirring. 32. The method according to any one of claims 27 to 31, wherein the neutralizing comprises: (i) contacting a chiral salt of a compound of formula (VI) with an aqueous base; and then (ii) acidifying the solution by adding an acid. 33. The method according to claim 32, wherein the aqueous base comprises aqueous ammonium hydroxide. 34. The method according to any one of claims 1 to 33, wherein the acylation comprises contacting a compound of formula (VI) with an acylating reagent in the presence of an organic solvent selected from the group consisting of ethyl acetate, tetrahydrofuran, diethyl ether, dichloromethane and toluene. 35. The method according to claim 34, wherein the acylating reagent is acetic anhydride. 36. The method according to claim 34 or 35, wherein the organic solvent is ethyl acetate. 37. The method according to any one of claims 1 to 36, wherein the acylation is carried out at a temperature in the range of 60-70°C. 38. The method according to any one of claims 1 to 37, wherein the compound of formula (VII) is obtained on a multi-kilogram scale. 39. The method according to claim 38, wherein at least about 130 kg of the compound of formula (VII) is obtained. 40. The method according to any one of claims 1 to 39, wherein the substantially optically pure compound of formula (VII) contains at least 98% of the desired enantiomer ABOUT (based on the total amount of both enantiomers). 41. The method according to any one of claims 1 to 40, wherein the compound of formula (VII) contains no more than 0.15% (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid, as determined by high performance liquid chromatography (HPLC). 42. A method for producing a compound of formula (I) where the method comprises obtaining a mixture of a compound of formula (II) - 37 046346 and compounds of formula (III) o ⁰ (ΠΙ) and bringing the mixture into contact with a base; resulting in a compound of formula (I). 43. The method according to claim 42, wherein the contacting is carried out in a solvent. 44. The method according to claim 42 or 43, wherein the solvent is tetrahydrofuran. 45. The method according to any one of claims 42 to 44, wherein the contacting is carried out at a temperature below or equal to 0°C. 46. The method according to any one of claims 42 to 45, wherein the contacting comprises stirring for about 5 minutes and/or is carried out at a reaction temperature which is maintained in the range from -5 to 0°C. 47. The method according to any one of claims 42 to 46, wherein the base is an alkali metal alkoxide. 48. The method according to claim 47, wherein the alkali metal alkoxide is selected from the group consisting of sodium methoxide, lithium methoxide and potassium methoxide. 49. The method according to claim 47 or 48, wherein the alkali metal alkoxide is sodium methoxide. 50. The compound represented by the formula _O2N IT or a pharmaceutically acceptable salt thereof.