EA043098B1 - SUBSTITUTED QUINOLINYLCYCLOHEXYLPROPANAMIDE COMPOUNDS AND IMPROVED METHODS FOR THEIR PREPARATION - Google Patents

Description

The present invention relates to improved processes for the preparation of substituted quinolinylcyclohexylpropanamide compounds.

State of the art invention

Indolamine 2,3-dioxygenase (IDO; also known as IDO1) is a target gene for IFN-γ (interferon gamma) involved in immunomodulation. IDO plays an important role in immune regulation and its immunosuppressive function has several manifestations. There is a pathophysiological link between IDO and cancer. Impaired immune homeostasis is closely associated with tumor growth and progression, and IDO expression in the tumor microenvironment appears to aid tumor growth and metastasis. In addition, elevated levels of IDO activity have been associated with a number of different tumors (Brandacher, G. et al., Clin. Cancer Res., 12(4):1144-1151 (Feb. 15, 2006)). In addition to cancer, IDO has been implicated in immunosuppression, chronic infections, and autoimmune diseases or disorders (eg, rheumatoid arthritis), as well as other pathological conditions.

Substituted quinolinylcyclohexylpropanamide pharmaceutical compounds have already been described which inhibit IDO and can be used in the treatment of cancer. See, for example, WO 2016/073770. Therefore, there is a need for improved methods for the preparation of such compounds that reduce manufacturing costs and improve product safety.

The essence of the invention

The present invention relates to processes for the preparation of a compound of formula I or a stereoisomer thereof:

where R ¹ is C _1-6 alkyl, aryl selected from phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl and tetrahydronaphthyl, or C _1-6 haloalkyl, with a mixture of C _1-6 alkoxide salt and di-C _1-6 alkyl malonate in a suitable organic solvent to replace the sulfonate group and form a compound of formula III or a stereoisomer thereof:

and contacting a compound of formula III or a stereoisomer thereof with a suitable organic acid in a suitable aqueous solvent for hydrolysis and decarboxylation to obtain a compound of formula I or a stereoisomer thereof.

Also described are methods for preparing intermediates such as compounds of formula II and their stereoisomers.

Detailed description of the invention

The following is a detailed description of the invention, including a glossary of terms and examples, completing the description, which allows a more complete understanding of the present invention. It is to be appreciated that certain features of the compositions and methods of the invention, which for better understanding are described in the context of separate aspects of the invention, may also be provided together in one aspect of the invention. Conversely, various features of the compositions and methods of the invention, which, for brevity, are described in the context of one aspect of the invention, may also be provided singly or in any subcombination.

In the context of this description, the term alkyl includes saturated aliphatic hydrocarbon groups, both branched and straight chain, containing the specified number of carbon atoms. For example, C ₁ -C ₆ -alkyl or C ₁ . ₆ alkyl means alkyl containing from 1 to 6 carbon atoms. Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (for example, n-propyl and isopropyl), butyl (for example, n-butyl, isobutyl, t-butyl) and pentyl (for example, n-pentyl, isopentyl, neopentyl), but are not limited to them.

When in this description the number of carbon atoms is indicated using ranges of values, such as Ci. ₆ , all ranges are included, as well as specific values indicating the number of carbon atoms. For example, Cm includes C _1-3 , C1.2, C ₂ . ₃ , C1, C2 and C ₃ .

As used herein, the term haloalkyl includes both branched and straight chain saturated aliphatic hydrocarbon groups containing the number of carbon atoms substituted with one or more halogen atoms. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include fluoroalkyl, which, as used herein, includes both straight and branched saturated aliphatic hydrocarbon groups containing the number of carbon atoms substituted with one or more fluorine atoms.

The term cycloalkyl refers to cyclized alkyl groups. It is assumed that C ₃ . ₆ cycloalkyl includes C ₃ , C ₄ , C 5 and C ₆ cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Included in the definition of cycloalkyl are branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl.

The term cycloalkenyl refers to cyclized alkenyl groups. C _4-6 cycloalkenyl is meant to include C ₄ , C ₅ and C ₆ cycloalkenyl groups. Examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, and cyclohexenyl.

The term heterocycloalkyl refers to any 5-10 membered monocyclic or bicyclic saturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S atoms. The heterocycloalkyl group may be attached through any heteroatom or carbon atom of the ring with the formation of a stable structure. Examples of suitable heterocycloalkyl groups include, without limitation, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydro furanyl, tetrahydropyranyl, piperazinyl, etc. .P.

In the context of this description, the term alkoxy refers to an -O-alkyl group.

In the context of this description, the term aryl refers to an aromatic ring system, which includes, without limitation, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl and tetrahydronaphthyl.

As used herein, the term heteroaryl refers to aryl mono- or bicyclic rings which contain from one to five heteroatoms selected from N, O and S atoms, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized(s). ). The heteroaryl group may be attached to the rest of the molecule via a heteroatom or via a carbon atom. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indole isinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl , imidazopyridines, benzothiazolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, etc.

In the context of this description, the term halo or halogen includes fluorine, chlorine, bromine and iodine atoms.

In the context of this description, pharmaceutically acceptable salts refer to derivatives of the compounds of the invention and are salts formed with acids or bases of the original compound as a result of its modification. Examples of pharmaceutically acceptable salts include, without limitation, salts formed with inorganic or organic acids and basic groups of the compound, such as amino groups, and alkaline or organic salts of acidic groups, such as carboxyl groups. Pharmaceutically acceptable salts include standard non-toxic salts or quaternary ammonium salts of the parent compound, formed with, for example, non-toxic inorganic or organic acids. For example, such standard non-toxic salts include salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric, and salts formed with organic acids such as acetic, aspartic, propionic, succinic, glycolic, stearic, lactic, malic (e.g. L-malic), tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanyl, 2-acetoxybenzoic, fumaric, p-toluenesulfonic, methanesulfonic, ethane disulfonic (e.g. ethane-1,2-disulfonic), oxalic, isethionic, naphthalene-1,5-disulfonic, naphthalene-2-disulfonic, benzenesulfonic, gluconic, hippuric, glutaric, charcoal, isobutyric, malonic, suberic, almond, phthalic, camphorsulfonic and so on.

In addition, in the compounds according to the present invention, the relative abundance of one, two, three or more isotopes of one or more than one atom, which is part of such compounds, may deviate from the relative abundance found in nature. The non-natural abundance of an isotope can be defined as the range from an amount found in nature to an amount consisting of 100% of a specified atom. For example, compounds may include radioactive isotopes such as, for example, tritium ( ³ H), iodine-125 ( ¹²⁵ I), fluoro-18 ( ¹⁸ F) and/or carbon-14 ( ¹⁴ C), or non-radioactive isotopes such as deuterium ( ² H), carbon-13 ( ¹³ C) and/or nitrogen-15 ( ¹⁵ N). Such isotopic variants may provide additional uses along with the uses described herein. For example, isotopic variants of the compounds of the invention may find additional uses, including, without limitation, their use as diagnostic and/or imaging reagents or as cytotoxic/radiotoxic therapeutic agents. In addition, isotopic variants of the compounds of the invention may have altered pharmacokinetic and pharmacodynamic characteristics that may improve safety, tolerability, or efficacy during treatment. All isotopic variants of the compounds of the present invention, both radioactive and non-radioactive, are intended to be included within the scope of the present invention.

Also included within the scope of the present invention are co-crystals of the compounds of the invention, such as co-crystals comprising Compound 1. Typical substances suitable for co-crystal formation include amino acids, for example co-crystals with proline, glycine, alanine, histidine, arginine, lysine, and the like can be prepared. . Other exemplary materials suitable for co-crystal formation include sugars such as monosaccharides such as glucose and fructose. Other materials suitable for co-crystal formation include sugar alcohols such as, for example, mannitol and sorbitol. Other substances suitable for the formation of co-crystals are amides, including, for example, urea, nicotinamide and isonicotinamide. Amines are also suitable for co-crystal formation and include, for example, imidazole and N-meglumine.

Pharmaceutically acceptable salts and co-crystals of the present invention can be synthesized from a parent compound that contains a basic or acid moiety using standard chemical techniques. Typically, such salts and co-crystals can be obtained by reacting these compounds in the form of a free acid or base with a stoichiometric amount of a suitable base or acid or a substance suitable for forming co-crystals, in water or in an organic solvent, or in a mixture of water and an organic solvent; it is generally preferred to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. See, for example, Allen, Jr., LV, ed., Remington: The Science and Practice of Pharmacy, ^22nd Edition, Pharmaceutical Press, London, UK (2012). The contents of this guide are incorporated into this description by reference.

The following acronyms and abbreviations are used in the description of the invention:

HPLC = high performance liquid chromatography,

PEPPSI™-IPr = [1,3-bis-(2,6-duisopronulfenyl)umidazol-2-uludene](3-chloropirudyl)nα-lladium(II) dichloride,

Ms = mesyl (-S(O) ₂ -O-CH ₃ ),

MsCl = mesyl chloride (Cl-S(O) ₂ -O-CH ₃ ),

DME = dimethoxyethane, dr = diastereomeric ratio,

PivCl = pivaloyl chloride (trimethylacetyl chloride),

AcOH = acetic acid,

NaHMDS = hexamethyldisilazane sodium salt (sodium bis-(trimethylsilyl)amide),

T3P™ = propylphosphonic anhydride (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinan-2,4,6 trioxide, solution),

DMAC = dimethylacetamide,

MeCN = acetonitrile (ACN),

NMP = N-methyl-2-pyrrolidone,

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Pyr = pyridine,

TCFH = Ν,Ν,Ν',N'-tetramethylchloroformamidinium hexafluorophosphate,

N-Me-Imid = N-methylimidazole,

KF = analysis using Karl Fischer titration, a titration technique for determining the amount of water in a sample.

The present invention relates to improved processes for the preparation of compounds of formula I, as well as their stereoisomers, as well as their salts:

Compounds of formula I can be obtained as an individual stereoisomer, for example I-A or I-B. Alternatively, the compounds of formula I can be obtained as a mixture of stereoisomers I-A and I-B. In those embodiments of the present invention that use a mixture of stereoisomers, i.e. a mixture of compounds I-A and I-B, the mixture may contain 99% (by weight) of compound I-A. Alternatively, the mixture may contain about 95% (by weight), 90% (by weight), 85% (by weight),

80% (by mass), 75% (by mass), 70% (by mass), 65% (by mass), 60% (by mass), 55% (by mass),

50% (by mass), 45% (by mass), 40% (by mass), 35% (by mass), 30% (by mass), 25% (by mass),

20% (w/w), 15% (w/w), 10% (w/w) or approximately 5% (w/w) Compound I-A.

Those of ordinary skill in the art will readily appreciate that the methods described herein can also be used to prepare compounds of formula I-A, as well as their stereoisomers, as well as their salts:

where R ₁₀ and R11 independently represent a hydrogen atom, a halogen atom, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, phenyl, heteroaryl, C _1-4 alkyl, C _1-4 alkoxy, CN, -SO ₂ NH ₂ , NHSO ₂ CH ₃ , NHSO ₂ CF ₃ , OCF ₃ , SO ₂ CH ₃ , SO ₂ CF ₃ or conh ₂ .

Compounds of formula I (or stereoisomers or salts of these compounds) can be prepared according to Scheme 1.

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Scheme 1

T

According to the present invention, the compounds of formula I, or their stereoisomers, or their salts, are obtained by contacting a compound of formula II or its stereoisomer:

where R ₁ represents C ₁ . ₆ alkyl, aryl or C ₁ . ₆ haloalkyl, with a mixture of C ₁ . ₆ alkoxide salt and di-C ₁ . ₆ alkyl malonate in a suitable organic solvent for a time and temperature sufficient to replace the sulfonate moiety and form a compound of formula III or a stereoisomer thereof:

The compound of formula II may be an individual stereoisomer or a mixture of stereoisomers. For example, the compound of formula II can be obtained as an individual isomer, which is:

Alternatively, a compound of formula II may be prepared as a mixture of compounds II-A and II-B. In those embodiments of the present invention that use a mixture of stereoisomers, i.e. a mixture of compounds II-A and II-B, the mixture may contain 99% (by weight) of compound II-B. Alternatively, the mixture may contain about 95% (w/w), 90% (w/w), 85% (w/w), 80% (w/w), 75% (w/w), 70% (w/w), 65% (by mass), 60% (by mass), 55% (by mass), 50% (by mass), 45% (by mass), 40% (by mass), 35% (by mass), 30% ( by weight), 25% (by weight), 20% (by weight), 15% (by weight), 10% (by weight) or about 5% (by weight) of compound II-B.

The compound of formula III can be obtained as an individual isomer or as a mixture of stereoisomers. For example, a compound of formula III can be obtained as an individual isomer, i.e. connections

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V.

Alternatively, a compound of formula III may be prepared as a mixture of compounds III-A and III-B. In those embodiments of the present invention that use a mixture of stereoisomers, i.e. a mixture of compounds III-A and III-B, the mixture may contain 99% (by weight) of compound III-A. Alternatively, the mixture may contain about 95% (w/w), 90% (w/w), 85% (w/w), 80% (w/w), 75% (w/w), 70% (w/w), 65% (by mass), 60% (by mass), 55% (by mass), 50% (by mass), 45% (by mass), 40% (by mass), 35% (by mass), 30% ( by weight), 25% (by weight), 20% (by weight), 15% (by weight), 10% (by weight) or about 5% (by weight) of compound III-A.

According to the present invention, R1 may be C ₁ . ₆ alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl. According to preferred aspects of the present invention, R1 is methyl.

According to other aspects of the present invention, R1 is aryl. According to some embodiments of the invention, R1 is phenyl. According to other embodiments of the invention R1 is a substituted phenyl, eg phenyl substituted with a halogen atom (eg F or Cl atom), C ₁ . ₆ alkyl (eg methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl) or C ₁ . ₆ haloalkyl (eg -CF ₃ , -CHF ₂ , -CH ₂ F or -CH2CF3).

According to other aspects of the present invention, R1 is C ₁ . ₆ haloalkyl, for example -CF3, -CHF2, -CH2F or -CH2CF3.

C ₁ is used to convert compounds of formula II to compounds of formula III. ₆ alkoxide salt. Preferred C ₁ . _{The 6} alkoxide salt is sodium amylate (NaOC(CH ₃ ) ₂ CH ₂ CH ₃ ). Other suitable C ₁ . ₆ alkoxide salts include potassium amylate, NaOBut and KOBut. Others C ₁ . ₆ alkoxide salts include lithium amylate and LiOBut.

A mixture of C ₁ is used to convert compounds of formula II to compounds of formula III. ₆ alkoxide salt and di-C ₁ . ₆ alkyl malonate. According to the present invention C ₁ . _{The 6} malonate alkyl groups are independently selected. For example, according to some aspects of the present invention di-C ₁ . ₆ alkyl malonate contains the same C ₁ . ₆ alkyl groups, eg di-C ₁ . ₆ alkyl malonate is di-tert-butyl malonate, di-methyl malonate, di-ethyl malonate, di-isopropyl malonate. According to other aspects of the present invention di-C ₁ . ₆ alkyl malonate contains different C ₁ . ₆ alkyl groups, for example du-C ₁ . ₆ alkyl malonate is CH3OC(O)CH2C(O)OBut.

According to preferred embodiments of the present invention, the molar ratio of C ₁ . ₆ alkoxide salt and di-C ₁ . ₆ alkyl malonate is approximately 1:1. According to other embodiments of the present invention, the molar ratio of C ₁ . ₆ alkoxide salt and di-C ₁ . ₆ alkyl malonate is from about 0.5:1 to about 1.5:1, for example, about 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9: 1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, or approximately 1.5:1. Typical molar ratios of C ₁ . ₆ alkoxide salt and di-C ₁ . ₆ alkyl malonate is from about 0.8:1 to 1.2:1, or from about 0.8:1 to 1.1:1.

According to preferred embodiments of the present invention C ₁ . ₆ alkoxide salt and di-C ₁ . ₆ alkyl malonate is used in an amount equivalent to the amount of the compound of formula II, or in excess with respect to this compound. For example, in typical embodiments of the invention, the molar ratio of C ₁ . ₆ alkoxide salt/di-C ₁ . ₆ alkyl malonate and compounds of formula II is approximately 1.5:1. According to other embodiments of the invention, the molar ratio of C ₁ . ₆ alkoxide salt/di-C ₁ . _{6 of} the alkyl malonate and the compound of formula II is from about 1:1 to about 3:1, for example, about 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.1:1, 2.2:1, 2.3: 1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1, or approximately 3:1.

The conversion of compounds of formula II to compounds of formula III is carried out in a suitable organic solvent. Mixtures of organic solvents may also be used. Suitable organic solvents for the conversion include, for example, aromatic hydrocarbons such as toluene and anisole, it is particularly preferred to use toluene. Other suitable solvents include ethereal solvents such as, for example, tetrahydrofuran, dimethoxyethane and dioxane. This transformation can also be carried out in a polar solvent such as tert-amyl alcohol or N-methyl-2-pyrrolidone.

The conversion of compounds of formula II to compounds of formula III is carried out at a temperature

- 6 043098 for replacing the sulfonate group of a compound of formula II to obtain a compound of formula III. Those of ordinary skill in the art will have no difficulty in determining the appropriate temperature using the techniques described herein and knowledge in the art. It is preferable to use a temperature of the reaction mixture which is above ambient temperature, i.e. above 25°C, and preferably equal to about 35 or above 35°C. For example, the temperature suitable for obtaining the compound of formula III is equal to or below the reflux temperature of the reaction solvent. According to other aspects of the present invention, the temperature suitable for obtaining the compound of formula III is below the reflux temperature of the reaction solvent. According to other aspects of the present invention, it is preferable to use a temperature of approximately 80°C or higher. In the context of this description, temperature refers to the internal temperature of the reaction mixture.

Those of ordinary skill in the art, using the techniques described herein and knowledge in the art, will readily determine the amount of time required to convert compounds of formula II to compounds of formula III. For example, this conversion may be carried out until the conversion is substantially complete as determined by HPLC analysis. According to some aspects of the present invention, the amount of time required for substantial conversion to compounds of formula III is approximately 24 hours.

According to other aspects of the present invention, the amount of time required for significant conversion is less than 24 hours, for example, about 20, 18, 16, 14, 12, 10, or about 8 hours. According to other aspects of the present invention, the amount of time required for significant conversion is less than 8 hours. According to preferred embodiments of the present invention, the amount of time required for significant conversion is approximately 12 hours.

The methods described in this document, allow you to get the compound of formula III or its stereoisomer. Compounds of formula III may contain the same or different C ₁ . ₆ alkyl groups. Preferred compounds of formula III are compounds in which each C ₁ .6 alkyl is tert-butyl. According to other aspects of the present invention, one C ₁ .6alkul is tert-butyl and the other is -C(CH ₃ ) ₂ CH ₂ CH ₃ .

According to preferred embodiments of the present invention, the compounds of formula III are not isolated and are used without isolation or purification in subsequent conversion reactions. Alternatively, a compound of formula III may be isolated and optionally purified using techniques known in the art.

According to the present invention, a compound of formula III, or a stereoisomer thereof, can be converted to a compound of formula I, or a stereoisomer thereof, by contacting a compound of formula III with a suitable organic acid in a suitable aqueous organic solvent for a time and at a temperature sufficient for hydrolysis and decarboxylation, resulting in the formation of a compound of formula I or a stereoisomer thereof.

Suitable organic acids for converting a compound of formula III to a compound of formula I include, for example, sulfonic acids such as methanesulfonic acid, which is particularly preferred. Trifluoroacetic acid is also a suitable acid. It is preferred to use an acid whose pKa is less than or equal to 0. According to other embodiments of the present invention, a compound of formula III is converted to a compound of formula I by contacting a compound of formula III with an inorganic acid such as H ₂ SO ₄ .

According to preferred embodiments of the present invention, the organic acid is used in a molar excess relative to the compound of formula III. For example, the molar ratio of organic acid to compound of formula III ranges from about 2:1 to about 20:1, or from about 8:1 to about 10:1, for example, about 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17: 1, 18:1, 19:1 or approximately 20:1.

The solvent used to convert the compound of formula III to the compound of formula I is an aqueous organic solvent, i.e. a solvent containing water in an amount of at least 0.05% (by weight) based on the weight of the solvent. It is preferable to use an aqueous solvent containing approximately 1% (by weight) of water. In addition to water, this aqueous solvent includes one organic solvent or a mixture of organic solvents, preferably a mixture of organic solvents. In some aspects of the present invention, the solvent is an aromatic hydrocarbon (eg, toluene, anisole), an ethereal solvent (eg, tetrahydrofuran, dimethoxyethane, dioxane), or a polar solvent (eg, tertamyl alcohol, K-methyl-2-pyrrolidone, sulfolane), or a mixture of these solvents. According to some aspects of the present invention, the aqueous solvent is a mixture of water, sulfolane and another organic solvent, preferably toluene.

The conversion of compounds of formula III to compounds of formula I is carried out at a temperature sufficient to hydrolyze and decarboxylate the compound of formula III, leading to the formation of compounds

- 7 043098 variant of formula I. Those of ordinary skill in the art will have no difficulty in determining the appropriate temperature using the techniques described herein and knowledge in the art. Preferred temperatures are above 25°C. According to some aspects of the present invention, the same temperature can be used for both hydrolysis and decarboxylation. According to other aspects of the present invention, the hydrolysis is performed at one temperature and the decarboxylation is performed at a different temperature. In those embodiments of the present invention that use different temperatures for hydrolysis and decarboxylation, hydrolysis can be performed at a lower temperature (for example, in the range from about 30 to about 80°C, preferably in the range from about 40 to about 60°C) and decarboxylation can be performed at a higher temperature (for example, in the range from about 90 to about 115°C, preferably in the range from about 100 to about 110°C, a temperature of about 105°C is particularly preferred). In the context of this description, temperature refers to the internal temperature of the reaction mixture.

Those of ordinary skill in the art, using the techniques described herein and knowledge in the art, will readily determine the amount of time required to convert compounds of formula III to compounds of formula I. For example, this conversion can be carried out as long as the conversion will not be substantially completed according to HPLC analysis. According to some aspects of the present invention, the amount of time required for substantial conversion to a compound of Formula I is about 30 hours. According to other aspects of the present invention, the amount of time required for significant conversion is about 24 hours or less, for example, about 24, 22, 20, 18, 16, 14, 12, 10, or about 8 hours. According to other aspects of the present invention, the amount of time required for substantial conversion is less than 8 hours. In preferred embodiments, the amount of time required for significant conversion is approximately 15 hours. In those aspects of the present invention where hydrolysis is performed at one temperature and decarboxylation is performed at a different temperature, hydrolysis can be performed in about 12 hours or less. For example, hydrolysis can be performed within about 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 hours, or about 1 hour. In these embodiments, decarboxylation can be performed within about 24 hours. or less. For example, decarboxylation can be performed for about 24, 22, 20, 18, 16, 14, 12, 10, or about 8 hours.

Compounds of formula I, synthesized according to the preparation methods described, may be isolated and optionally purified using techniques known to those of ordinary skill in the art. According to other embodiments of the present invention, the compounds of formula I can be used in subsequent reactions without isolation or purification.

Alternatively, compounds of formula I, or stereoisomers thereof, can be prepared from compounds of formula II, or stereoisomers thereof, according to Scheme 2.

Scheme 2

In addition to the methods described for the preparation of compounds of formula I and their stereoisomers, the present invention also provides methods for the preparation of intermediates, for example compounds of formula II and their stereoisomers. Scheme 3 shows a process for the preparation of compounds of formula II and their stereoisomers.

Scheme 3

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Compounds of formula II are obtained by contacting a compound of formula IV

with a Lewis acid and a hydride source in a suitable alcoholic organic solvent for a time and temperature sufficient to reduce the carbonyl and form the compound of formula V or its stereoisomer:

The compound of formula V may be an individual stereoisomer or a mixture of stereoisomers. For example, the compound of formula V can be obtained as an individual isomer, which is:

Alternatively, a compound of formula V may be prepared as a mixture of compounds V-A and V-B. In those embodiments of the present invention that use a mixture of stereoisomers, i.e. a mixture of compounds V-A and V-B, this mixture may contain 99% (by mass) of compounds V-B. Alternatively, the mixture may contain about 95% (w/w), 90% (w/w), 85% (w/w), 80% (w/w), 75% (w/w), 70% (w/w), 65% (by mass), 60% (by mass), 55% (by mass), 50% (by mass), 45% (by mass), 40% (by mass), 35% (by mass), 30% ( by weight), 25% (by weight), 20% (by weight), 15% (by weight), 10% (by weight) or about 5% (by weight) of compound V-B.

In some embodiments of the present invention, the compound of formula IV is provided as a salt of the compound of formula IV. Suitable salts include any salt such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic, phosphorous, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, camphorsulfonic or methanesulfonic acid.

In those aspects of the present invention in which the compound of formula IV is provided in the form of a salt, the salt form of the compound may be treated with a suitable base (eg sodium carbonate, potassium carbonate) to provide the compound of formula IV in free base form. A molar excess of a suitable base is used to convert a compound of formula IV to the free base. The compound of formula IV in free form may be isolated and optionally purified prior to use in subsequent reactions using techniques known to those of ordinary skill in the art. Alternatively, a compound of formula IV in free form may be used in subsequent transformations without prior isolation.

Lewis acids used to convert compounds of formula IV to compounds of formula V are known and include, for example, calcium halides (eg CaCl ₂ ), lithium halides (eg LiBr, LiCl), magnesium halides (eg MgBr ₂ ), zinc halides (eg ZnCl ₂ , ZnBr ₂ ) and cerium halides (eg CeBr ₃ , CeCl ₃ ). Preferred Lewis acids are cerium halides, and CeCl ₃ is particularly preferred (eg CeCl ₃ heptahydrate).

Hydride (H ^- ) sources used to convert compounds of formula IV to compounds of formula V are known and include, for example, NaBH ₄ , LiAlH ₄ , diisobutylaluminum hydride and NaCNBH ₄ . Especially preferred is NaBH ₄ . An alternative hydride source is NaH.

According to preferred embodiments of the present invention, the molar ratio of the Lewis acid to the compound of formula IV is in the range of from about 0.05:1 to about 0.5:1, or from about 0.1:1 to about 0.3:1. For example, the molar ratio of the Lewis acid and the compound of formula IV is approximately 0.05:1, 0.1:1, 0.15:1,

0.2:1, 0.25:1, 0.3:1, 0.35:1, 0.4:1, 0.45:1, or about 0.5:1.

According to preferred embodiments of the present invention, the molar ratio of hydride to compound of formula IV is in the range of from about 0.5:1 to about 5:1, or from about 0.8:1 to about 2:1. For example, the molar ratio of hydride to compound of formula IV is approximately 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.5:1 , 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, or approximately 5:1.

According to preferred embodiments of the present invention, the molar ratio of Lewis acid to hydride is in the range of from about 0.01:1 to about 0.5:1, or from 0.05:1 to about 0.375:1. For example, the molar ratio of Lewis acid to hydride is approximately 0.01:1, 0.02:1, 0.03:1, 0.04:1, 0.05:1, 0.06:1, 0.07: 1, 0.08:1, 0.09:1, 0.1:1, 0.125:1, 0.15:1, 0.175:1, 0.2:1, 0.225:1, 0.25:1, 0.275:1, 0.3:1, 0.325:1, 0.35:1, 0.375:1, 0.4:1, 0.425:1, 0.45:1, 0.475:1 or approximately 0.5:1 .

According to preferred embodiments of the present invention, the Lewis acid and the compound of formula IV are mixed before the hydride source is added to the reaction mixture.

The solvents used to convert compounds of formula IV to compounds of formula V are alcoholic solvents or mixtures of alcoholic solvents. Suitable alcoholic solvents include, for example, methanol, ethanol, isopropanol, and mixtures thereof. Alcoholic solvents used to convert compounds of formula IV to compounds of formula V may also include non-alcoholic organic solvents, preferably in an amount that is less than 10% (by weight) of the total weight of the solvent. Suitable organic solvents that may be present in the alcohol solvent include, for example, ethyl acetate, acetone, tetrahydrofuran, methyl t-butyl ether, isopropyl acetate, acetonitrile, dimethoxyethane, and mixtures thereof. According to preferred embodiments of the present invention, the alcoholic solvent is usually an anhydrous solvent, i.e. has a KF value (Karl Fischer water content) of 2% or less, preferably 1% or less, preferably 0.05% or less.

The conversion of compounds of formula IV to compounds of formula V is carried out at a temperature sufficient to reduce the carbonyl of the compound of formula IV to give the compound of formula V. Those of ordinary skill in the art will readily determine the appropriate temperature using the techniques described herein and knowledge in the art. . Preferred temperatures are below 25°C. According to some aspects of the present invention, the temperature is below about 20°C, more preferably below about 10°C. According to some aspects of the present invention, the temperature is approximately 0°C. According to preferred aspects of the present invention, the temperature values are in the range from about -5 to about 5°C. In the context of this description, temperature refers to the internal temperature of the reaction mixture.

Those of ordinary skill in the art, using the techniques described herein and knowledge in the art, will readily determine the amount of time needed to convert compounds of formula IV to compounds of formula V. For example, this conversion can be carried out until the conversion is will be essentially completed according to HPLC analysis. For example, according to some aspects of the present invention, the required amount of time is approximately 12 hours or less. For example, the amount of time required may be about 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or about 1 hour. In preferred embodiments, the amount of time required is about 2 hours or less.

The compound of formula V or its stereoisomer can be used in subsequent transformations without isolation or purification. According to other aspects of the present invention, the compounds of formula V or their stereoisomers before use in subsequent transformations can be isolated and optionally purified using techniques known to those of ordinary skill in the art.

According to the present invention, a compound of formula V, or a stereoisomer thereof, is converted to a compound of formula II, or a stereoisomer thereof, by contacting a compound of formula V, or a stereoisomer thereof, with X-SO2R1 in the presence of an alkylamine base in a suitable anhydrous organic solvent for a time and at a temperature sufficient to displace X to form a compound of formula II or a stereoisomer thereof.

According to the present invention X in the X-SO2R1 reagent is a halogen atom, preferably Cl or Br. R1 is as defined above. Preferred X-SO2R1 reagents include, for example, methanesulfonyl chloride.

Furthermore, according to the present invention, a compound of formula V, or a stereoisomer thereof, is converted to a compound of formula II, or a stereoisomer thereof, by contacting a compound of formula V, or a stereoisomer thereof, with R1SO2-O-SO2R1 in the presence of an alkylamine base in a suitable anhydrous organic solvent for a period of time and at temperature sufficient to displace -O-SO2R1 to form a compound of formula II or a stereoisomer thereof. The preferred reagent R1SO2-O-SO2R1 is methanesulfonic anhydride.

Suitable alkylamine bases for use in the conversion of compounds of formula V to compounds of formula II include, for example, trimethylamine, N,N-diisopropylethylamine, and the like. Mixtures of alkylamine bases may also be used.

Anhydrous organic solvents suitable for use in the reaction of converting a compound of formula V to a compound of formula II typically have a KF value of less than 2%. In a preferred embodiment of the invention, the KF value of the anhydrous organic solvent is usually less than 1%, preferably less than 0.5%, more preferably less than 0.05%. The anhydrous organic solvent is an individual solvent or a mixture of solvents. Suitable anhydrous organic solvents include halogenated solvents such as dichloromethane. Other suitable anhydrous organic solvents include aromatic hydrocarbons (eg, toluene, anisole), acetonitrile, and isopropyl acetate. Dichloromethane is a particularly preferred anhydrous organic solvent.

The conversion of compounds of formula V to compounds of formula II is carried out at a temperature sufficient to replace the X moiety of X-SO2R1 (or the -O-SO2R1 moiety of R1SO2-O-SO2R1) to give a compound of formula II. Those of ordinary skill in the art will have no difficulty in determining the appropriate temperature using the techniques described herein and knowledge in the art. Preferred temperatures are below 25°C. According to some aspects of the present invention, the temperature is below about 20°C, more preferably below about 10°C. According to some aspects of the present invention, the temperature is approximately 0°C or less. According to preferred aspects of the present invention, the temperature values are in the range from about -10 to about -5°C. In the context of this description, temperature refers to the internal temperature of the reaction mixture.

Those of ordinary skill in the art, using the techniques described herein and knowledge in the art, will readily determine the amount of time required to convert compounds of formula V to compounds of formula II. For example, this conversion may be carried out until the conversion is substantially complete as determined by HPLC analysis. For example, according to some aspects of the present invention, the required amount of time is about 8 hours or less. For example, the amount of time required may be about 8, 7, 6, 5, 4, 3, 2, or about 1 hour. In preferred embodiments, the amount of time required is about 2 hours or less, more preferably about 1 hour.

Compounds of formula II can be obtained as an individual isomer, i. as a compound of formula II-A or II-B. Alternatively, a compound of formula II may be prepared as a mixture of compounds II-A and II-B. In those embodiments of the present invention in which a mixture of stereoisomers is obtained, i.e. a mixture of compounds II-A and II-B, this mixture may contain 99% (by weight) of compound II-B. Alternatively, the mixture may contain about 95% (w/w), 90% (w/w), 85% (w/w), 80% (w/w), 75% (w/w), 70% (w/w), 65% (by mass), 60% (by mass), 55% (by mass), 50% (by mass), 45% (by mass), 40% (by mass), 35% (by mass), 30% ( by weight), 25% (by weight), 20% (by weight), 15% (by weight), 10% (by weight) or about 5% (by weight) of compound II-B.

Compounds of formula II or their stereoisomers can be used in subsequent transformations without isolation. According to other aspects of the present invention, the compounds of formula II or their stereoisomers before use in subsequent transformations can be isolated and optionally purified using techniques known to those of ordinary skill in the art.

Alternatively, compounds of formula II can be prepared from compounds of formula IV according to Scheme 4.

Scheme 4

The present invention also relates to processes for the preparation of intermediates of formula IV. Methods for preparing compounds of formula IV are shown in Schemes 5 and 6.

- 11 043098

Scheme 5

According to these methods, compounds of formula IV are obtained by contacting a compound of formula VI-A or formula VI-B:

where n is 1 or 2, with a compound of formula VII

where Y is a halogen atom, in the presence of a suitable C _1-6 alkylsilylamine base in a suitable organic solvent for a time and temperature sufficient to displace Y to form a compound of formula VIII-A or VIII-B:

Those of ordinary skill in the art will readily appreciate that compounds and stereoisomers of formula IC can be prepared by replacing a compound of formula VII with a compound of formula VII-A, wherein Y, R ₁₀ and Rn are as defined above.

- 12 043098

Compounds of formula VII-A are known in the art or may be prepared using procedures known to those of ordinary skill in the art. See, for example, WO 2016/073770. According to preferred aspects of the present invention, Y is Cl.

Compounds of formula VI-A and VI-B are known and/or can be prepared using procedures known to those of ordinary skill in the art. According to the present invention, the C _1-6 alkyl moieties in compounds VI-A and VI-B are independently selected from C _1-6 alkyl, eg methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like. In those embodiments of the present invention that use compounds of formula VI-A, the preferred value of n is 1.

Compounds of formula VII are known in the art or can be prepared using procedures known to those of ordinary skill in the art. See, for example, WO 2016/073770. According to preferred aspects of the present invention, Y is Cl.

In preferred embodiments of the conversion of compounds of formula VI-A/VI-B and formula VII to compounds of formula VIII-A/VIII-B, the compounds of formula VI-A/VI-B are used in a molar excess relative to the compounds of formula VII. For example, according to the preferred methods of the invention, the molar ratio of compounds of formula VI-A/VI-B and compounds of formula VII is in the range from about 1.1:1 to about 2:1, or from about 1.5 to about 2:1, for example is approximately 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1 or approximately 2:1.

According to the methods of the invention, the preparation of compounds of formula VIII-A or formula VIII-B is carried out in the presence of a suitable C _1-6 silylamine base. Typical C _1-6 silylaminoβ bases are sodium hexamethyldisilazane (sodium bis-(trimethylsilyl)amide, NaHMDS, ((CH ₃ ) ₃ Si) ₂ NNa).

According to preferred aspects of the present invention, a C _1-6 molar excess of the silylamine base is used relative to the compound of formula VI-A/VI-B. For example, in preferred methods of the invention, the C _1-6 molar ratio of the silylamine base to the compound of formula VI-A or VI-B ranges from about 1.1:1 to about 5:1, for example, about 1:1, about 2 :1, about 3:1, about 4:1 or about 5:1, for example about 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.1:1, 2.2:1, 2.3:1, 2.4: 1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1, 3:1, 3.1:1, 3.2:1, 3, 3:1, 3.4:1, 3.5:1, 3.6:1, 3.7:1, 3.8:1, 3.9:1, 4:1, 4.2:1, 4.3:1, 4.4:1, 4.5:1, 4.6:1, 4.7:1, 4.8:1, 4.9:1, or approximately 5:1.

Suitable organic solvents used to prepare compounds of formula VIII-A or formula VIII-B may include an individual solvent or mixture of solvents. Representative organic solvents include, for example, toluene, anisole, dimethylformamide, tetrahydrofuran, and mixtures thereof. Mixtures of toluene and tetrahydrofuran are particularly preferred.

The conversion of compounds of formula VI-A/VI-B and compounds of formula VII to compounds of formula VIII-A or VIII-B is carried out at a temperature sufficient to replace the Y moiety in the compound of formula VII. Those of ordinary skill in the art will have no difficulty in determining the appropriate temperature using the techniques described herein and knowledge in the art. Preferred temperatures are below 25°C. According to some aspects of the present invention, the temperature is below about 20°C, more preferably below about 10°C. According to some aspects of the present invention, the temperature is approximately 0°C or less. According to preferred aspects of the present invention, the temperature is below about -10°C, preferably -20°C or below -20°C. In the context of this description, temperature refers to the internal temperature of the reaction mixture.

Those of ordinary skill in the art, using the techniques described herein and knowledge in the art, will readily determine the amount of time required to convert compounds of formula VI-A/VI-B and compounds of formula VII to compounds of formula VIII-A or VIII -B. For example, this conversion may be carried out until the conversion is substantially complete as determined by HPLC analysis. For example, according to some aspects of the present invention, the required amount of time is about 8 hours or less. For example, the amount of time needed may be about 8, 7, 6, 5, 4, 3, 2, or about 1 hour.

- 13 043098 time is about 4 hours or less, preferably about 3 hours.

Compounds of formula VIII-A and formula VIII-B can be used without isolation or purification in subsequent conversion reactions. Alternatively, compounds of formula VIII-A and formula VIIIB may be isolated and optionally purified before use in subsequent reactions.

According to the present invention, compounds of formula VIII-A/VIII-B can be used to prepare compounds of formula IX-A/IX-B. Compounds of formula IX-A and IX-B can be prepared by contacting a compound of formula VIII-A or VIII-B with a suitable hydroxide base in a suitable aqueous solvent for a time and temperature sufficient to hydrolyse to form a compound of formula IX-A. or formula IX-B:

Representative hydroxide bases include KOH and NaOH. Mixtures of hydroxide bases can also be used. According to typical embodiments of the present invention, the hydroxide base is present in the form of an aqueous solution, preferably in the form of approximately 5N. or about 10n. aqueous solution.

According to preferred embodiments of the present invention, the hydroxide base is used in a molar excess relative to the compound of formula VIII-A/VIII-B. For example, the molar ratio of hydroxide base to compound of formula VTII-A/VIII-B ranges from 1:1 to about 50:1, or from 5:1 to about 50:1, or from about 1:1 to about 10: 1, such as 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12: 1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 30:1, 40:1, or approximately 50:1.

Suitable aqueous solvents used to prepare compounds of formula IX-A and IX-B include mixtures of water and one or more organic solvents. Suitable organic solvents include ethanol, toluene, anisole, dimethylformamide, tetrahydrofuran, and mixtures thereof. A particularly preferred aqueous solvent is a mixture of water, tetrahydrofuran and toluene.

The conversion of compounds of formula VIII-A/VIII-B to compounds of formula IX-A or IX-B is carried out at a temperature sufficient to hydrolyze the compounds of formula VIII-A and VIII-B. Those of ordinary skill in the art will have no difficulty in determining the appropriate temperature using the techniques described herein and knowledge in the art. Preferred temperatures are above 25°C. According to some aspects of the present invention, the temperature is about 50°C or more, preferably about 60°C or more. In the context of this description, temperature refers to the internal temperature of the reaction mixture.

Those of ordinary skill in the art, using the techniques described herein and knowledge in the art, will readily determine the amount of time required to convert compounds of formula VIII-A/VIII-B to compounds of formula IX-A and IX-B. For example, this conversion may be carried out until the conversion is substantially complete as determined by HPLC analysis. For example, according to some aspects of the present invention, the required amount of time is about 24 hours or less. For example, the required amount of time may be approximately 24, 22, 20, 18, 16, 14, 13, 12, 10, 8, 7, 6, 5, 4, 3, 2, or approximately 1 hour. the amount of time is about 20 hours or less, preferably about 10 hours.

Compounds of formula IV may be prepared from compounds of formula IX-A or IX-B by contacting a compound of formula IX-A or IX-B with a suitable inorganic acid in a suitable aqueous solvent for a time and temperature sufficient to hydrolyze to form a compound of formula IV.

Suitable inorganic acids that can be used to prepare compounds of formula IV include, for example, HCl, HBr, H ₂ SO ₄ , HNO ₃ , H ₃ PO ₄ and combinations thereof. The preferred inorganic acid is HCl.

According to preferred embodiments of the present invention, the inorganic acid is used in a molar excess relative to the compound of formula IX-A/IX-B. For example, the molar ratio of inorganic acid to compound of formula IX-A/IX-B ranges from about 5:1 to about 50:1, or from about 5:1 to about 7:1, such as about 5:1.6: 1, 7:1, 8:1, 9:1, 10:1, 15:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1 or

- 14 043098 approximately 50:1.

Suitable aqueous solvents used to prepare compounds of formula IV include mixtures of water and one or more organic solvents. Suitable organic solvents include ethanol, toluene, anisole, dimethylformamide, tetrahydrofuran, and mixtures thereof. A particularly preferred aqueous solvent is a mixture of water, tetrahydrofuran and toluene.

The conversion of compounds of formula IX-A/IX-B to compounds of formula IV is carried out at a temperature sufficient to hydrolyze and decarboxylate compounds of formula IX-A and IX-B. Those of ordinary skill in the art will have no difficulty in determining the appropriate temperature using the techniques described herein and knowledge in the art. Preferred temperatures are above 25°C. According to some aspects of the present invention, the temperature is about 50°C or more, preferably about 60°C or more. The preferred temperature range is from about 55 to about 65°C. In the context of this description, temperature refers to the internal temperature of the reaction mixture.

Those of ordinary skill in the art, using the techniques described herein and knowledge in the art, will readily determine the amount of time needed to convert compounds of formula IX-A/IX-B to compounds of formula IV. For example, this conversion may be carried out until the conversion is substantially complete as determined by HPLC analysis. For example, according to some aspects of the present invention, the required amount of time is about 24 hours or less. For example, the required amount of time may be approximately 24, 22, 20, 18, 16, 14, 13, 12, 10, 8, 7, 6, 5, 4, 3, 2, or approximately 1 hour. the amount of time is about 20 hours or less, preferably about 10 hours or less, more preferably about 3 hours.

Alternatively, compounds of formula IV can be prepared according to Scheme 7.

Scheme 7

IV

Compounds of formula IV can be used without isolation or purification in subsequent reactions. Alternatively, compounds of formula IV may be isolated and optionally purified before use in subsequent reactions using techniques known to those of ordinary skill in the art.

The compounds of formula I can be used to prepare pharmaceutical compounds, for example IDO inhibitors. Compound 1 and its stereoisomers, as well as isotopic variants and pharmaceutically acceptable salts and co-crystals, are exemplary embodiments of such IDO inhibitors. Isotopic variants of compound 1 include those containing one or more ¹³ C atoms, one or more ² H atoms, one or more ¹⁸ F atoms, one or more ¹⁵ N atoms, or combinations thereof.

F

Compound 1

A preferred salt of compound 1, as well as its stereoisomers, is the salt of compound 1 formed with methanesulfonic acid.

- 15 043098

Compounds of formula I can be converted to compound 1 and its stereoisomers using procedures already known in the art, such as those described in WO 2016/073770. Alternatively, the compounds of formula I and their stereoisomers can be converted to compound 1 or its stereoisomer according to Scheme 8.

Scheme 8

According to other aspects of the present invention, the compounds of formula I and their stereoisomers can be converted to compound 1 or its stereoisomer in accordance with scheme 9.

Scheme 9

Pharmaceutically acceptable salts and co-crystals of compound 1 can also be obtained using the methods described in the present description and known in the art.

Also included within the scope of the present invention are alternative procedures for the preparation of compounds of formula X and their stereoisomers:

- 16 043098

Compounds of formula X may be prepared as individual stereoisomers using the procedures described herein and the knowledge of one of ordinary skill in the art:

Mixtures of stereoisomers can also be obtained, ie. mixtures of any two compounds selected from X-A, X-B, X-C and X-D, in any amount.

Compounds of formula X or their stereoisomers can be prepared according to Scheme 10 below.

Scheme 10

aqueous organic solvent, hydroxide base

According to the present invention, a compound of formula XI, or a stereoisomer thereof, is converted to a compound of formula XII, or a stereoisomer thereof, by contacting the compound of formula XI (or a stereoisomer thereof) with a rare earth catalyst, such as a rare earth triflate or a rare earth alkoxide, in the presence of an alkyl alcohol, as solvent, for a time and at a temperature sufficient to form a compound of formula XII (or a stereoisomer thereof).

Suitable rare earth triflates include, for example, Yb(OTf) ₃ and Y(OTf) ₃ and mixtures thereof. In preferred embodiments of the invention, a catalytic amount of rare earth triflate is used. For example, about 10 mole % of the rare earth triflate relative to the compound of formula XI may be used. Less than 10% mole may also be used, such as about 1, 2, 3, 4, 5, 6, 7, 8, or 9% mole.

Suitable rare earth alkoxides include, for example, Yb(OCH ₃ ) ₃ and Y(OCH ₃ ) ₃ and mixtures thereof. In preferred embodiments, a catalytic amount of a rare earth alkoxide is used. For example, about 10 mole % rare earth alkoxide relative to the compound of formula XI may be used. Less than 10% mole may also be used, such as about 1, 2, 3, 4, 5, 6, 7, 8, or 9% mole.

Suitable alkyl alcohols used as solvent are C _1-6 alkyl alcohols which include methanol, ethanol, isopropanol, propanol, butanol, t-butanol and mixtures thereof. Methanol is a particularly preferred alkyl alcohol used as a solvent.

The conversion of compounds of formula XI to compounds of formula XII is carried out at a temperature up to

- 17 043098 sufficient to replace the oxazolidinone group. Those of ordinary skill in the art will have no difficulty in determining the appropriate temperature using the techniques described herein and knowledge in the art. Preferred temperatures are at ambient temperature, eg about 25°C. According to other embodiments of the present invention, the temperature values are above ambient temperature, for example, the temperature value is equal to the reflux temperature of the alkyl alcohol used as a solvent. According to some aspects of the present invention, the temperature is approximately 60°C. In the context of this description, temperature refers to the internal temperature of the reaction mixture.

Those of ordinary skill in the art, using the techniques described herein and knowledge in the art, will readily determine the amount of time needed to convert compounds of formula XI to compounds of formula XII. For example, the conversion may be carried out until the conversion is substantially complete as determined by HPLC analysis. According to some aspects of the present invention, the amount of time required for substantial conversion to a compound of formula I is about 10 hours. According to other aspects of the present invention, the amount of time required for significant conversion is about 10 hours or less, for example, about 1, 2, 3, 4, 5, 6, 7, 8 or approximately 9 hours.

The compounds of formula XII, obtained in accordance with the described methods, can be isolated and/or purified using methods known to those of ordinary skill in the art. According to other embodiments of the present invention, the compounds of formula XII can be used in subsequent reactions without isolation and/or purification.

Compounds of formula XII or their stereoisomers can be converted to compounds of formula X or their stereoisomers by contacting a compound of formula XII (or its stereoisomer) with a hydroxide base in an aqueous organic solvent for a time and at a temperature sufficient to form the compound of formula X or its stereoisomer .

Representative hydroxide bases include KOH and NaOH. Mixtures of hydroxide bases can also be used. According to typical embodiments of the present invention, the hydroxide base is present in the form of an aqueous solution, preferably in the form of approximately 5N. or about 10n. aqueous solution.

According to preferred embodiments of the present invention, the hydroxide base is used in a molar excess relative to the compound of formula XI. For example, the molar ratio of the hydroxide base to the compound of formula XI ranges from about 5:1 to about 50:1, or from about 5:1 to about 10:1, such as about 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, or approximately 50:1.

Suitable aqueous solvents used to prepare compounds of formula X include mixtures of water and one or more organic solvents. Suitable organic solvents include ethanol, toluene, anisole, dimethylformamide, tetrahydrofuran, N,N-dimethylacetamide, and mixtures thereof. A particularly preferred aqueous solvent is a mixture of water and N,N-dimethylacetamide.

The conversion of compounds of formula XII to compounds of formula X is carried out at a temperature sufficient to obtain a compound of formula X. Those of ordinary skill in the art will readily determine the appropriate temperature using the techniques described herein and knowledge in the art. Preferred temperatures are above 25°C. According to some aspects of the present invention, the temperature is approximately 30°C. In the context of this description, temperature refers to the internal temperature of the reaction mixture.

Those of ordinary skill in the art, using the techniques described herein and knowledge in the art, will readily determine the amount of time needed to convert compounds of formula XII to compounds of formula X. For example, the conversion can be carried out until the conversion is essentially completed according to HPLC analysis. For example, according to some aspects of the present invention, the required amount of time is about 30 hours or less. For example, the required amount of time may be approximately 30, 28, 26, 24, 22, 20, 18, 16, 14, 13, 12, 10, 8, 7, 6, 5, 4, 3, 2, or approximately 1 hour. In preferred embodiments, the required amount of time is about 20 hours or less, preferably about 20 hours.

Compounds of formula X, obtained in accordance with the described methods, can be isolated and optionally purified using methods known to those of ordinary skill in the art. According to other embodiments of the present invention, the compounds of formula X can be used in subsequent reactions without isolation or purification.

The compounds described in this document may be obtained as a free compound

- 18 043098 or in the form of an appropriate salt form, if possible. Preferred salts include, for example, those formed with inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic or phosphorous. acid, etc., as well as salts formed with relatively non-toxic organic acids, such as acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, paratolylsulfonic, citric, tartaric, camphorsulfonic, methanesulfonic and the like. Especially preferred are camphorsulfonic and methanesulfonic acids.

In particular, Compound 1 and its stereoisomers may optionally be converted to salts formed with methanesulfonic acid and other suitable pharmaceutically acceptable salts or co-crystals using techniques known in the art.

For example, such salts of compound 1 can be formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids, and with organic acids such as acetic, aspartic, propionic, succinic, glycolic, stearic, lactic, malic ( e.g. L-malic), tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2acetoxybenzoic, fumaric, p-toluenesulfonic, ethanesulfonic, ethane disulfonic (e.g. ethane-1,2- disulfonic), oxalic, isethionic, naphthalene-1,5-disulfonic, naphthalene-2-disulfonic, benzenesulfonic, gluconic, hippuric, glutaric, carbonic, isobutyric, malonic, suberic, almond, phthalic, camphorsulfonic, etc.

Also included within the scope of the present invention are co-crystals of Compound 1 formed by Compound 1 with a suitable co-crystal forming agent. Typical materials suitable for co-crystal formation include amino acids, for example, proline, glycine, alanine, histidine, arginine, lysine, and the like can be co-crystalled. Other exemplary materials suitable for co-crystal formation include sugars such as monosaccharides such as glucose and fructose. Other materials suitable for co-crystal formation include sugar alcohols such as, for example, mannitol and sorbitol. Other substances suitable for the formation of co-crystals are amides, including, for example, urea, nicotinamide and isonicotinamide. Amines are also suitable for co-crystal formation and include, for example, imidazole and N-meglumine.

The following stereoisomer of Compound 1 is particularly preferred:

The following salt of the stereoisomer of compound 1, formed with methanesulfonic acid, is particularly preferred due to its beneficial biological, pharmacokinetic and physicochemical properties:

Also included within the scope of the present invention is the hydrochloride salt of Compound 1.

Also included within the scope of the present invention is the hydrobromide salt of Compound 1.

The nitric acid salt of Compound 1 is also included within the scope of the present invention.

Also included within the scope of the present invention is the salt of Compound 1 formed with carbonic acid.

Also included within the scope of the present invention is the salt of compound 1 formed with monohydrocarbonic acid.

The phosphoric acid salt of Compound 1 is also included within the scope of the present invention.

- 19 043098

The scope of the present invention also includes a salt of compound 1 formed with monohydrophosphoric (monohydrogenphosphoric) acid.

Also included within the scope of the present invention is the salt of Compound 1 formed with dihydrophosphoric (dihydrogenphosphoric) acid.

Also included within the scope of the present invention is the salt of compound 1 formed with sulfuric acid.

Also included within the scope of the present invention is the salt of compound 1 formed with sulfamic acid.

Also included within the scope of the present invention is the salt of compound 1 formed with monohydrosulfuric (monohydrogensulfuric) acid.

Also included within the scope of the present invention is the hydroiodic acid salt of Compound 1.

The acetic acid salt of Compound 1 is also included within the scope of the present invention.

Also included within the scope of the present invention is the salt of Compound 1 formed with aspartic acid.

Also included within the scope of the present invention is the propionic acid salt of Compound 1.

The isobutyric acid salt of Compound 1 is also included within the scope of the present invention.

Also included within the scope of the present invention is the malonic acid salt of Compound 1.

Also included within the scope of the present invention is the salt of compound 1 formed with benzoic acid.

Also included within the scope of the present invention is the succinic acid salt of Compound 1.

Also included within the scope of the present invention is the glycolic acid salt of Compound 1.

Also included within the scope of the present invention is the salt of compound 1 formed with stearic acid.

The lactic acid salt of Compound 1 is also included within the scope of the present invention.

Also included within the scope of the present invention is the salt of compound 1 formed with L-malic acid.

Also included within the scope of the present invention is the salt of compound 1 formed with L-tartaric acid.

The citric acid salt of Compound 1 is also included within the scope of the present invention.

Also included within the scope of the present invention is the salt of compound 1 formed with L-ascorbic acid.

Also included within the scope of the present invention is the pamoic acid salt of Compound 1.

Also included within the scope of the present invention is the maleic acid salt of Compound 1.

Also included within the scope of the present invention is the salt of compound 1 formed with hydroxymaleic acid.

Also included within the scope of the present invention is the salt of compound 1 formed with phenylacetic acid.

Also included within the scope of the present invention is the salt of Compound 1 formed with glutamic acid.

Also included within the scope of the present invention is the salt of compound 1 formed with salicylic acid.

Also included within the scope of the present invention is the sulfanilic acid salt of Compound 1.

Also included within the scope of the present invention is the salt of compound 1 formed with 2-acetoxybenzoic acid.

The fumaric acid salt of Compound 1 is also included within the scope of the present invention.

Also included within the scope of the present invention is the p-toluenesulfonic acid salt of Compound 1.

Also included within the scope of the present invention is the salt of compound 1 formed with ethane-1,2disulfonic acid.

- 20 043098

Also included within the scope of the present invention is the salt of compound 1 formed with oxalic acid.

The isethionic acid salt of Compound 1 is also included within the scope of the present invention.

Also included within the scope of the present invention is the salt of Compound 1 formed with suberic acid.

Also included within the scope of the present invention is the mandelic acid salt of Compound 1.

Also included within the scope of the present invention is the phthalic acid salt of Compound 1.

Also included within the scope of the present invention is the salt of Compound 1 formed with benzenesulfonic acid.

Also included within the scope of the present invention is the salt of Compound 1 formed with camphorsulfonic acid.

Also included within the scope of the present invention is the salt of compound 1 formed with naphthalene-1,5-disulfonic acid and gluconic acid.

Also included within the scope of the present invention is the hippuric acid salt of Compound 1.

Also included within the scope of the present invention is the salt of compound 1 formed with glutaric acid.

Also included within the scope of the present invention is the salt of compound 1 formed with naphthalene-2-disulfonic acid.

Also included within the scope of the present invention is a co-crystal of compound 1 with proline.

Also included within the scope of the present invention is a co-crystal of Compound 1 with glycine.

Also included within the scope of the present invention is a co-crystal of compound 1 with alanine.

Also included within the scope of the present invention is a co-crystal of compound 1 with histidine.

Also included within the scope of the present invention is a co-crystal of compound 1 with arginine.

Also included within the scope of the present invention is a co-crystal of compound 1 with lysine.

Also included within the scope of the present invention is a co-crystal of Compound 1 with glucose.

Also included within the scope of the present invention is a co-crystal of Compound 1 with fructose.

Also included within the scope of the present invention is a co-crystal of Compound 1 with mannitol.

Also included within the scope of the present invention is a co-crystal of Compound 1 with sorbitol.

Also included within the scope of the present invention is a co-crystal of Compound 1 with urea.

Also included within the scope of the present invention is a co-crystal of compound 1 with nicotinamide.

Also included within the scope of the present invention is a co-crystal of compound 1 with isonicotinamide.

Also included within the scope of the present invention is a co-crystal of Compound 1 with imidazole.

Also included within the scope of the present invention is a co-crystal of Compound 1 with N-meglumine.

Compounds of the invention containing one or more radioisotopes may be used for imaging. See, for example, WO 2018/017529. For example, compounds of the invention labeled with a radioactive isotope can be used in positron emission tomography (PET). Such techniques can be used to visualize cancer in a subject. A preferred radiolabelled compound is ¹⁸ P]-Compound 1.

Also included within the scope of the present invention are pharmaceutically acceptable salts of [ ¹⁸ F] Compound 1. A typical procedure for the preparation of [ ¹⁸ F] Compound 1 is shown in the scheme below.

- 21 043098

Also included within the scope of the present invention is the following compound, which can be used as an intermediate in the preparation of [ ¹⁸ F] Compound 1:

ABOUT

The following is a description of typical methods and compounds of the invention with specific examples and with reference to general procedures for their preparation. Those skilled in the art will appreciate that, in order to prepare various compounds as described herein, the starting materials may be chosen such that the desired substituents that the compound should end up with will be retained throughout the reaction sequence to produce the desired product. Alternatively, if necessary or desirable, instead of the desired substituent that the compound should end up with, a suitable group can be used, which can be retained during the course of the reaction scheme and finally replaced, if necessary, with the desired substituent.

The knowledge of a person skilled in the art, combined with the description of the present invention, is sufficient to prepare the compounds of the invention.

Examples

Example 1

4-(6-Fluoroquinolin-4-yl)cyclohexan-1-one yl)methanesulfonate ((1 R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1 -

A 3000 L chemical reactor (Reactor A) was equipped with a mechanical stirrer, a nitrogen outlet, and a Dean-Stark apparatus. 220 kg of ethyl 4-oxocyclohexane-1-carboxylate (1.4 eq.) were added to this reactor. Then 1463 kg of toluene and 131 kg of ethylene glycol (2.1 eq.) were added. 2.2 kg of (1R)-(-)-10-camphorsulfonic acid (0.010 eq.) was added to this mixture. The contents of the reactor were heated to reflux temperature (~60-65°C) under vacuum using a Dean-Stark trap. The mixture was kept in the reactor for ~3-4 h until the reaction was complete. Then, 402 L of 5% (by weight) aqueous NaHCO ₃ solution (2.4 L, 2.4 L/kg) was added to the mixture. After stirring for 30 minutes, the mixture

- 22 043098 kept until phase separation and the lower aqueous layer was removed. To this mixture was added 402 L of 5% (w/w) NaHCO ₃ aqueous solution (2.4 L, 2.4 L/kg). The organic layer was washed with water (403 L) and the contents of the reactor were concentrated to a volume of 850 L until the KF value became <0.02%.

168.0 kg of 4-chloro-6-fluoroquinoline was added to an 8000 L chemical reactor (reactor B) and then a solution of toluene and 790.0 kg of N,N-dimethylformamide was added to reactor A, which was used to wash reactor A. Stirred, until the mixture became homogeneous, and cooled to -20°C. 1841 kg of a 1 M NaHMDS solution in THF (tetrahydrofuran) was introduced into reactor B, keeping the temperature <-20°C, and then 92 kg of THF. This reaction mixture was kept for 3 hours at <-20°C until the reaction was completed.

10 l of a 12% (by weight) aqueous ammonium chloride solution was introduced into the reactor B, keeping the temperature below 20°C. After stirring for 30 minutes, the mixture was allowed to stand until the phases separated, and the lower aqueous phase was removed. To this mixture was added 840 L of 12% aqueous sodium chloride solution. After stirring for 30 minutes, the mixture was allowed to stand until the phases separated and the lower aqueous phase was removed. Washing with aqueous sodium chloride solution was repeated two more times and the organic layer was concentrated under vacuum at 50° C. to a volume of 840 L. This mixture was diluted with ethanol (541 kg).

To the resulting mixture was added 598 kg of 10N. potassium hydroxide solution, and this mixture was heated to 60°C for 10 h until the hydrolysis was complete. The contents of the reactor were cooled to 20°C. In a chemical reactor with a volume of 8000 l (reactor C) made 504 kg of water and then 650 kg of 37% (by weight) hydrochloric acid. This solution was kept at 60°C and then the reaction mixture was transferred from reactor B to reactor C, maintaining the temperature in the range of 55-65°C. Observed the evolution of carbon dioxide, and controlled the addition of the mixture. The contents of the reactor were kept at 60-65°C until the reaction was completed, and then cooled to 35°C.

To the resulting mixture was added 366 kg of 10N. potassium hydroxide solution for 2 hours, maintaining the temperature <45°C. To this mixture was added 2267 kg of ethyl acetate and 336 kg of water. The contents of the reactor were cooled to 25°C, the mixture was kept until phase separation and the lower aqueous layer was removed. To this mixture was added 504 kg of a 12% aqueous sodium chloride solution. After stirring for 30 minutes, the mixture was allowed to stand until the phases separated and the lower aqueous phase was removed. Washing with aqueous sodium chloride solution was repeated three more times and the organic layer was concentrated under vacuum at <60° C. to a volume of 810 L. The solvent of the mixture was changed to ethyl acetate under vacuum at <60° C. and the KF value was adjusted to <0.05% and the volume of the mixture was adjusted to 9 volumes. The solid was removed using a fine filter while transferring the mixture to chemical reactor D. Reactor C and fine filter were washed with ethyl acetate (360 L) which was transferred to reactor D. Reactor D was heated to 35°C.

215 kg of (1R)-(-)-10-camphorsulfonic acid (1.0 eq.), 2873 kg of ethyl acetate were added to chemical reactor E and the mixture was kept at 60° C. until the mixture became homogeneous. The contents of reactor D were added to reactor E along with 0.8 kg of seed crystals to induce crystallization. Reactor D was washed with ethyl acetate (151 kg), which was then transferred to reactor E, and the resulting suspension was kept for 1 hour at 60°C. The suspension was cooled to 20° C. over 1 hour and held for 8 hours. The solid was filtered off and washed twice with ethyl acetate (973 kg). The solid was dried under vacuum at <50° C. to give 340.2 kg of a yellowish solid (yield: 73.8%).

If desired, recrystallization of the obtained substance can be performed. 50.0 g of 4-(6-fluoroquinolin-4-yl)cyclohexan-1-one ((1R)-7,7- dimethyl 2-oxobicyclo[2.2.1]heptan-1yl)methanesulfonate and then 200 ml of acetonitrile. This mixture was heated to 60° C. until a homogeneous solution was obtained. The mixture was then cooled to 47° C. and 0.20 g seed crystals were added. This suspension was kept for 1 hour at 45°C and 1 liter of MTBE (methyl tert-butyl ether) was added over 2 hours while maintaining temperatures in the range of 43-47°C. The suspension was cooled to 20° C. and held for 3 hours. The solid was filtered off, washed with acetonitrile:MTBE (1:5; 150 ml) and then washed twice with MTBE (150 ml). The solid was dried under vacuum at 50° C. to give 46.4 g of product (yield: 92.8%; desired compound content: 96.0%).

1H NMR (400 MHz, DMSO-d6) δ 9.21 (d, J=5.6 Hz, 1H), 8.56 (dd, J=10.5, 2.7 Hz, 1H), 8.36 (dd, J=9.3, 5.3 Hz, 1H) , 8.09-7.98 (m, 2H), 6.68-6.58 (m, 4H), 4.17 (m, 1H), 2.96 (d, J=14.7 Hz, 1H), 2.84 (m, 2H), 2.722.55 (m , 1H), 2.50-2.46 (m, 1H), 2.42-2.33 (m, 2H), 2.29-2.05 (m, 5H), 2.02-1.79 (m, 3H), 1.38-1.25 (m, 2H), 1.05 (s, 3H), 0.75 (s, 3H);

¹³ C NMR (101 MHz, DMSO-d6) δ 216.0, 209.4, 162.5, 161.8, 161.8, 160.0, 145.1, 136.0, 128.3, 128.2, 125.9, 125.8, 123.8, 123.5, 1 19.6, 109.3, 109.1, 58.1, 47.1, 46.9, 42.2, 42.1, 40.3, 36.8, 31.8, 26.3, 24.1, 19.9, 19.5;

MS-ESR (electrospray ionization mass spectrometry): calculated for free base C15H15FNO ([M+H]+) 244.11; found 244.32.

- 23 043098

HPLC analysis: Column: Waters XBridge VEN C8 3.5 µm, inner diameter 150x4.6 mm;

Solvent A: water: MeCN (95:5 v/v) with 0.05% TFA (trifluoroacetic acid);

Solvent B: water: MeCN (5:95 v/v) with 0.05% TFA;

Gradient: %B: 0 min 0%; 22 min 50%; 27 min 100%; 30 min 100%;

Stop time: 30 min;

Flow rate: 1.2 ml/min;

Column temperature: 50°C;

Wavelength: 220 nm.

The retention time of 4-(6-fluoroquinolin-4-yl)cyclohexan-1-one ((1R)-7,7-dimethyl-2oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate was 7.4 minutes.

Example 1A.

Ethyl 4-oxocyclohexane-1-carboxylate 12 (129 kg, 1.4 eq.), toluene (1122 kg), ethylene glycol (93 kg, 2.1 eq.) and (1R)-(-)- 10-camphorsulfonic acid (CSA) (1.6 kg, 0.010 eq.). This mixture was heated to reflux (60° C.) under vacuum using a Dean-Stark apparatus. The mixture was kept for 4 h, then cooled to 25°C. The organic stream was washed with 5% aqueous NaHCO ₃ (2x325 kg). The organic layer was washed with water (309 kg) and then the organic layer was concentrated to a volume of 650 L. The resulting mixture was added to a solution of 4-chloro-6-fluoroquinoline (129 kg, 1.0 eq.) and DMF (N,N-dimethylformamide) (611 kg). Then the solution was stirred until the solution became homogeneous, and cooled to -20°C. To this solution was added a 40% solution (by weight) of NaHMDS in THF (719 kg), maintaining the temperature <-20°C, and then added THF (92 kg). This reaction mixture was kept for 3 hours at <-20°C. The mixture was then quenched by adding 12% (by weight) aqueous solution of NH ₄ Cl (1417 kg), maintaining the temperature below 20°C. This mixture was stirred, kept until phase separation and the lower aqueous layer was removed. The mixture was then washed with 12% (w/w) NaCl aqueous solution (3x662 kg). Ethanol was added several times and the mixture was distilled at <50° C. until a volume of 650 L was obtained when the THF content was <10.0% and the toluene content was <2.0%. The mixture was diluted with ethanol (424 kg) and a solution of potassium hydroxide (200 kg, 5.0 eq.) and water (258 kg) was added. This mixture was heated to 55-60°C for 10-24 hours Then the contents of the reactor were cooled to 20°C. A mixture of water (338 kg) and 37% (by weight) aqueous HCl solution (519 kg, 7.0 eq.) was heated to 60-65°C. The reaction product stream, mixed with EtOH, was directed to a hot aqueous HCl solution, which caused gas evolution. The reaction mixture was kept for 3 hours at 60-65° C., during which time further gas evolution occurred. The reaction mixture was cooled to 35°C and added 10N. potassium hydroxide (256 kg) for 2 hours, maintaining the temperature <45°C. EtOAc (1735 kg) was added to this mixture. The mixture was cooled to 25°C, kept until the phases separated and the lower aqueous layer was removed. The organic layer was washed with 12% aqueous sodium chloride solution (4x485 kg). The organic layer was concentrated under vacuum at <60°C. EtOAc was added several times and the mixture was distilled at <60°C until a volume of 520 L was obtained, when the KF value became <0.050%. The organic stream was diluted by adding EtOAc (360 kg). The solid was removed using a fine filter, and then this filter was washed with ethyl acetate (205 kg).

(1R)-(-)-10-Camphorsulfonic acid (147 kg, 1.0 eq.) and EtOAc (2057 kg) were added to a separate chemical reactor and heated to 60°C. 45% of the product stream in mixture with EtOAc was sent to a mixture of (1R)-(-)-10-camphorsulfonic acid and EtOAc. Seed crystals of the product (0.6 kg, 0.005 eq.) were added and the suspension was held for 1 hour at 60°C. The remaining 55% of the product stream mixed with EtOAc was added over 4 hours. This suspension was held for 1 hour at 60°C, cooled to 20°C for 2 hours and then held for 8 hours. washed with EtOAc (2x617 kg). The solid was then dried under vacuum at <50° C. to give 340.2 kg of product (yield: 84.8%; peak area: 98.0% of HPLC area) as a yellowish solid.

¹ H NMR (400 MHz, DMSO-d6) δ 9.21 (d, J=5.6 Hz, 1H), 8.56 (dd, J=10.5, 2.7 Hz, 1H), 8.36 (dd, J=9.3, 5.3 Hz, 1H ), 8.09-7.98 (m, 2H), 6.68-6.58 (m, 4H), 4.17 (m, 1H), 2.96 (d, J=14.7 Hz, 1H), 2.84 (m, 2H), 2.722.55 ( m, 1H), 2.50-2.46 (m, 1H), 2.42-2.33 (m, 2H), 2.29-2.05 (m, 5H), 2.02-1.79 (m, 3H), 1.38-1.25 (m, 2H), 1.05 (s, 3Н), 0.75 (s, 3Н);

¹³ C NMR (100 MHz, DMSO-d6) δ 216.0, 209.4, 162.5, 161.8, 161.8, 160.0, 145.1, 136.0, 128.3, 128.2, 125.9, 125.8, 123.8, 123.5, 1 19.6, 109.3, 109.1, 58.1, 47.1, 46.9, 42.2, 42.1, 40.3, 36.8, 31.8, 26.3, 24.1, 19.9, 19.5;

HRMS-ESI (high resolution electrospray ionization mass spectrometry): calculated for C ₁₅ H ₁₅ FNO free base ([M+H]+) 244.1132; found 244,1142.

- 24 043098

Example 2

(1R,4R)-4-(6-Fluoroquinolin-4-yl)cyclohexyl methanesulfonate

OMs

338 kg of 4-(6-fluoroquinolin-4-yl)cyclohexan-1-one ((1R)-7,7-dimethyl-2oxobicyclo[2.2 .1]heptan-1-yl)methanesulfonate (1.0 eq.) and 2275.2 kg of ethyl acetate and a solution of sodium carbonate (152.0 kg, 2.0 eq.) in water (1690 kg). This mixture was stirred for 30 minutes until the mixture became homogeneous. Stirring was stopped, the mixture was kept until the phases separated, and the lower aqueous layer was removed. 264.0 kg of sodium chloride in water (1487 kg) was added to the organic phase. This mixture was stirred, kept until phase separation and the lower aqueous layer was removed. The organic layer was concentrated under vacuum at <50° C. to a volume of 1250 L. Ethyl acetate was replaced with another solvent, ethanol, until KF was <2.0% and residual ethyl acetate was reduced to <2.0%. The volume was adjusted with ethanol to 1250 liters. The mixture was cooled to -5°C.

1071.2 kg of ethanol and 54 kg of cerium trichloride heptahydrate were introduced into chemical reactor B filled with an inert gas with a volume of 8000 l, coated on the inside with enamel. This mixture was kept for 1 h at 25°C until the mixture became homogeneous, and then cooled to 5°C. The contents of reactor B were transferred to reactor A, maintaining the temperature <5°C. The transferred mixture was washed with ethanol (68.7 kg). The mixture was then cooled to -5°C and kept for 30 minutes. To the mixture was added 0.08 kg of sodium borohydride (1.0 eq.) in 4 doses, making sure that the temperature of the mixture in the reactor did not exceed 0°C. The mixture was kept for 1 h at -5°C until the transformation reaction was completed. 213.1 kg of citric acid monohydrate in water (1879.0 kg) was added to the mixture while maintaining the temperature <20° C., and then the mixture was washed with ethanol (68.7 kg). The pH was adjusted to 4-6 by adding 142.1 kg of sodium bicarbonate in water (1626 kg) while maintaining the temperature at 20°C.

To this solution was added 2238 kg of dichloromethane. The mixture was stirred, kept until the phases separated, and the lower organic layer was transferred to reactor C. 2238 kg of dichloromethane was added to the solution. The mixture was stirred, kept until the phases separated, and the lower organic layer was transferred to reactor C.

213.0 kg of citric acid monohydrate in 1879 kg was added to reactor C. Then 1420.0 kg sodium bicarbonate in water (1626 kg) was added. This mixture was stirred, allowed to phase separate, and the lower organic layer was transferred to reactor D. 142.1 kg of sodium bicarbonate in water (1627 kg) was added to reactor D. This mixture was stirred, kept until the phases separated, and the lower organic layer was transferred to reactor E. 169.0 kg of sodium chloride in water (1530 kg) was added to reactor E. This mixture was stirred, kept until the phases separated, and the lower organic layer was transferred to reactor F. 1798.0 kg of dichloromethane were added several times to reactor F and the mixture was distilled at a temperature <50°C until a volume of 1250 l was obtained, when the KF value became <0 .05% and the content of residual ethanol was reduced to <0.50%. The resulting solution was cooled to 20° C. and 122.4 kg of triethylamine was added. This mixture was cooled to -5°C and added to 98.6 kg of methanesulfonylchloride, maintaining the temperature <0°C. The contents of the reactor were kept for 1 h at -5°C until the conversion reaction was complete. 143.0 kg of ammonium chloride in water (1047.0 kg) was added to reactor E, keeping the temperature <20°C, and the mixture was heated to 20°C. 1802 kg of dichloromethane was added to the mixture. This mixture was stirred, aged until phase separation, and the lower organic layer was transferred to reactor G. 1190.0 kg of water was added to the mixture. This mixture was stirred, kept until the phases separated, and the lower organic layer was transferred to reactor H. The mixture was subjected to vacuum distillation at a temperature <45°C to obtain a volume of 875 liters. 1800 kg of tetrahydrofuran was added to the mixture, and the mixture was subjected to distillation to obtain a volume of 875 liters. The distillation and addition of tetrahydrofuran was repeated three times until the KF value became <0.05% and the DCM content decreased to <0.50%.

The mixture was then filtered into reactor H through a fine filter, washed with THF (156.0 kg) and subjected to vacuum distillation at <45° C. to a volume of 875 L. The reactor contents were cooled to 20° C. and 0.9 kg of seed crystals were added. To the resulting suspension was added 1161.0 kg of n-heptane over 6.5 hours. The suspension was kept for 3 hours at 20° C. and filtered. The filter cake was washed with THF:n-heptane (201.1 and 307.0 kg, respectively) and then washed with n-heptane (462.0 kg). The filter cake was then dried under vacuum at <50° C. to give 156.4 kg of a yellowish solid (yield: 67.6%).

Can be performed recrystallization of the resulting substance. 20.13 g of (1R,4R)-4-(6-fluoroquinolin-4-yl)cyclohexyl methanesulfonate and 200 ml of tetrahydrofuran were added to reactor A. This mixture was heated to 45°C and filtered through a fine filter into reactor B equipped with a stirrer.

- 25 043098 with top drive, thermocouple and nitrogen outlet. The resulting solution was concentrated to a volume of 140 ml (7 volumes) at 45°C and cooled to 20°C. Then seed crystals were added to the mixture and the mixture was aged for 1 hour. 200 ml (10 volumes) of n-heptane were added over 4 hours and the suspension was aged overnight. The solid was collected by filtration and washed with 40 ml (2 volumes) of n-heptane. The solid was then dried under vacuum at <50° C. to give 17.73 g of product (yield: 89.6%; peak area: 99.38% of HPLC area).

¹ H NMR (601 MHz, DMSO-d6) δ 8.80 (d, J=4.5 Hz, 1H), 8.08 (t, J=7.7 Hz, 1H), 8.02 (d, J=10.4 Hz, 1H), 7.65 ( m, 1H), 7.40 (d, J=4.7 Hz, 1H), 4.77-4.68 (m, 1H), 3.40-3.30 (m, 1H), 2.19 (m, 2H), 1.95-1.81 (m, 4H) , 1.76-1.64 (m, 2H);

¹³ C NMR (151 MHz, DMSO-d6) δ 160.8, 159.1, 151.1, 149.8, 145.1, 132.6, 127.2, 119.1, 118.9, 118.2, 107.3, 107.1, 80.6, 37.8, 36. 0, 32.2, 30.5;

MS-ESI: calculated for free base C ₁₆ H ₁₉ FNO ₃ S ([M+H]+) 324.11; found, 324.17.

HPLC analysis: Column: Zorbax Eclipse Plus C18 1.8 µm, inner diameter 50x4.6 mm.

Solvent A: 10 mM NH ₄ OAc containing water:MeCN (90/10 v/v).

Solvent B: 10 mM NH ₄ OAc containing water:MeCN (10/90 v/v).

Gradient: %B: 0 min 0%; 17 min 55%; 20 min 100%; 24 min 100%.

Stop time: 24 min.

Flow rate: 1.3 ml/min.

Column temperature: 25°C.

Wavelength: 220 nm.

The retention time of (1R,4R)-4-(6-fluoroquinolin-4-yl)cyclohexyl methanesulfonate was 12.6 minutes.

Example 2A.

4-(6-Fluoroquinolin-4-yl)cyclohexan-1-one ((II)-7,7-dimethyl-2oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (243.6 kg, 1.0 eq.), ethyl acetate (1747 kg) and 8.3% (by weight) aqueous sodium carbonate solution (1324 kg). This mixture was stirred for 30 minutes until the mixture became homogeneous. Stirring was stopped, the mixture was kept until the phases separated, and the lower aqueous layer was removed. The organic stream was washed with 15% (w/w) NaCl aqueous solution (1336 kg). Ethanol was added several times and the mixture was distilled at <50° C. until a volume of 980 L was obtained, when the KF value became <2.0% and the amount of residual ethyl acetate decreased to <2.0%.

Cerium (III) trichloride heptahydrate (38.2 kg, 0.20 equiv.) and ethanol (771 kg) were added to a separate chemical reactor. This mixture was kept for 1 h at 25°C until the mixture became homogeneous, cooled to 5°C and then transferred into a solution of the reagent and ethanol. The reaction stream was cooled to -10°C. Added sodium borohydride (19.4 kg) in 4 doses, making sure that the temperature of the mixture in the reactor does not exceed 0°C. The mixture was kept for 1 h, increasing the temperature from -10 to 0°C. The reaction was stopped by adding 10% (by weight) aqueous citric acid solution (1508 kg), maintaining the temperature <20°C. The temperature was brought to 20° C. and the mixture was stirred for 4 hours. The pH was adjusted to 4-6 by adding 7.9% (by weight) aqueous sodium bicarbonate solution (1156 kg). Dichloromethane (1617 kg) was added. This mixture was stirred for 30 min, kept until the phases separated, and the upper aqueous layer was transferred to a separate chemical reactor. The aqueous layer was back-extracted with dichloromethane (1617 kg). The organic layers were combined and 10% (w/w) aqueous citric acid (1508 kg) was added followed by 7.9% (w/w) aqueous sodium bicarbonate (1156 kg). This mixture was stirred, kept until the phases separated, and the upper aqueous layer was removed. The organic layer was washed with 4.9% (w/w) aqueous sodium bicarbonate (1276 kg), and then washed with 10% (w/w) aqueous NaCl (1348 kg).

Dichloromethane was added several times and the mixture was distilled at <40° C. until a volume of 980 L was obtained, when the KF value became <0.05% and the amount of residual ethanol decreased to <0.50%. The reaction mixture was cooled to 20° C. and triethylamine (88.4 kg, 1.7 eq.) was added. This mixture was cooled to -5°C and added methanesulfonylchloride (70.5 kg, 1.2 eq.), maintaining the temperature <0°C. The contents of the reactor were kept for 1 h, increasing the temperature from -10 to 0°C. The reaction was stopped by adding 12% (by weight) aqueous ammonium chloride solution (887 kg), maintaining the temperature <20°C, and this mixture was heated to 20°C. Dichloromethane (1293 kg) was added. This mixture was stirred, kept until the phases separated and the upper aqueous layer was removed. The organic stream was washed with water (850 kg). THF was added several times and the mixture was distilled at <45°C until a volume of 730 L was obtained, when the KF value became <0.05% and the dichloromethane content decreased to <0.50%

The mixture was filtered through a fine filter, washed with THF (434 kg) and subjected to vacuum distillation at a temperature <45°C to obtain a volume of 850 liters. The reactor contents were cooled to 20° C. and 0.1 kg of seed crystals were added. Added over 3 hours

- 26 043098 n-heptane (835 kg). The resulting suspension was kept for 3 hours at 20°C and filtered. The filter cake was washed with a solution previously prepared by mixing THF (145 kg) and n-heptane (223 kg) and then washed with n-heptane (334 kg). The filter cake was then dried under vacuum at <50° C. to obtain 124.4 kg of product (yield: 75.1%; peak area:

99.0% of HPLC area) as a yellowish solid.

Ή NMR (600 MHz, DMSO-d6) δ 8.80 (d, J=4.5 Hz, 1H), 8.08 (t, J=7.7 Hz, 1H), 8.02 (d, J=10.4 Hz, 1H), 7.65 (m , 1H), 7.40 (d, J=4.7 Hz, 1H), 4.77-4.68 (m, 1H), 3.40-3.30 (m, 1H), 2.19 (m, 2H), 1.95-1.81 (m, 4H), 1.76-1.64 (m, 2H);

^13C NMR (150 MHz, DMSO-66) δ 160.8, 159.1, 151.1, 149.8, 145.1, 132.6, 127.2, 119.1, 118.9, 118.2, 107.3, 107.1, 80.6, 37.8, 36. 0, 32.2, 30.5;

HRMS-ESI: calculated for C ₁₆ H ₁₉ FNO ₃ S [M+H]+: 324.1064; found: 324,1077.

Example 3

2-((1S,4S)-4-(6-Fluoroquinolin-4-yl)cyclohexyl)acetic acid

848.8 kg of toluene and 68.6 kg of sodium tert-amylate were introduced into a chemical reactor A filled with an inert gas with a volume of 5000 l, coated on the inside with enamel. This mixture was heated to 35°C and added to 140.2 kg of di-tert-butyl ester of malonic acid, maintaining the temperature at 35°C. The mixture was stirred for 1 hour and 140.0 kg of (1R,4R)-4-(6-fluoroquinolin-4yl)cyclohexyl methanesulfonate and 364.1 kg of toluene were added. This mixture was heated to 90° C. and held for 12 hours until the reaction was complete. The mixture was cooled to 40° C. and 21.0 kg of water and 883.1 kg of sulfolane and then 415.9 kg of methanesulfonic acid were added. This mixture was heated to 60° C. and held for 1 hour. The mixture was then heated to 105° C. and held for 14 hours until the reaction was complete. The mixture was cooled to 60° C. and 560.2 kg of water was added. After cooling to 25° C., 330 kg of potassium hydroxide was added as an aqueous solution prepared using 407 kg of water. This mixture was held for 1 hour at 25° C. until all solid dissolved, stirring was stopped, the mixture was held until phase separation, and the lower aqueous phase was transferred to an 8000 L chemical reactor B, enameled on the inside. The pH was adjusted to 5.5 using an aqueous solution of acetic acid prepared from 144.1 kg of acetic acid and 1226.6 kg of water. This mixture was kept for 3 hours and filtered. The wet filter cake was washed twice with water (700 kg) and twice with toluene (608 kg). After drying under vacuum at <50° C., 109.2 kg of product (yield: 87.8%)) was obtained as a yellowish solid.

1H NMR (601 MHz, DMSO-d ₆ ) δ 12.07 (br. s, 1H), 8.79 (d, J=4.3 Hz, 1H), 8.07 (dd,J=9.1, 5.9 Hz, 1H), 7.92 (dd , J=10.8, 2.4 Hz, 1H), 7.63 (td, J=8.6, 2.5 Hz, 1H), 7.48 (d, J=4.5 Hz, 1H), 3.43-3.25 (m, 1H), 2.42 (d, J=7.7 Hz, 2H), 2.34-2.19 (m, 1H), 1.89-1.76 (m, 2H), 1.72-1.60 (m, 6H);

¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 174.2, 160.7, 159.1, 152.3, 149.8, 145.1, 132.7, 127.2, 118.6, 107.2, 37.5, 36.2, 29.5, 29.1, 27. 4;

ESI MS: calculated for Ci ₇ Hi ₉ FNO2 ([M+H]+) 288.14; found 288.23.

HPLC analysis: Column: Zorbax Eclipse Plus C18 1.8 µm, inner diameter 50x4.6 mm.

Solvent A: 10 mM NH ₄ OAc (adjusted pH 7.7) containing water:MeOH (80/20 v/v).

Solvent B: 10 mM NH ₄ OAc (adjusted pH 7.7) containing MeOH:water:MeCN (10/20/70 v/v).

Gradient: %B: 0 min 14%; 9 min 20%; 19 min 85%; 20 min 85%; 20.5 min 100%.

Stop time: 21 min.

Flow rate: 2.0 ml/min.

Column temperature: 45°C.

Wavelength: 220 nm.

The retention time of 2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)acetic acid was 3.30 minutes.

Example 3A.

Toluene (1035 kg) and sodium tertoxide (115.2 kg, 1.70 eq.) were added to the chemical reactor. This mixture was heated to 35°C and di-tert-butyl malonic acid ester (232.9 kg, 1.75 eq.) was added while maintaining the temperature at 35°C. This mixture was stirred for 1 h and added

- 27 043098 (1R,4R)-4-(6-fluoroquinolin-4-yl)cyclohexyl methanesulfonate (199.0 kg, 1.0 eq.) and toluene (515 kg). The mixture was heated to 85°C and held for 12 h.

The mixture was cooled to 55° C. and water (40 kg) and sulfolane (1255 kg) were added followed by methanesulfonic acid (532.2 kg, 9.0 eq.). This mixture was heated to 60°C and held for 1 hour. The mixture was then heated to 105°C and held for 14 hours. The mixture was cooled to 60°C and water (792 kg) was added. After cooling to 25° C., an aqueous potassium hydroxide solution (442 kg KOH and 535 kg water) was added. This mixture was held for 1 hour at 25° C. until all solid dissolved, stirring was stopped, the mixture was held until phase separation and the lower aqueous phase was transferred to a separate chemical reactor. The pH was adjusted to 5.5 using an aqueous solution of acetic acid prepared from 88.7 kg of acetic acid and 1287 kg of water. The mixture was kept for 2 h and filtered. The wet filter cake was washed with water (2x990 kg) and toluene (2x862 kg). Drying under vacuum at <50° C. yielded 156.9 kg of product (yield: 88.7%; peak area: 99.5% of HPLC area) as a yellowish solid.

1H NMR (600 MHz, DMSO-d ₆ ) δ 12.07 (br. s, 1H), 8.79 (d, J=4.3 Hz, 1H), 8.07 (dd, J=9.1, 5.9 Hz, 1H), 7.92 (dd , J=10.8, 2.4 Hz, 1H), 7.63 (td, J=8.6, 2.5 Hz, 1H), 7.48 (d, J=4.5 Hz, 1H), 3.43-3.25 (m, 1H), 2.42 (d, J=7.7 Hz, 2H), 2.34-2.19 (m, 1H), 1.89-1.76 (m, 2H), 1.72-1.60 (m, 6H);

¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 174.2, 160.7, 159.1, 152.3, 149.8, 145.1, 132.7, 127.2, 118.6, 107.2, 37.5, 36.2, 29.5, 29.1, 27. 4;

HRMS-ESI: calculated for C17H19FNO2 [M+H]+: 288.1394; found 288,1406.

Example 4

(R)-3-(2-((1S,4S)-4-(6-Fluoroquinolin-4-yl)cyclohexyl)acetyl)-4-phenyloxazolidin-2-one o o

THF (1121.7 kg) and 2-((18.48)-4-(6-fluoroquinolin-4-yl)cyclohexyl)acetic acid (105.1 kg). Reactor A was flushed with THF (15.8 kg). The mixture was cooled to -5-5°C. Added pivaloylchloride (64.0 kg), maintaining the temperature in the range -5-5°C. Triethylamine (101.1 kg) was added while maintaining the temperature in the range of -5-5°C. This mixture was kept at -5-5° C. under nitrogen protection for 1 hour. (R)-(-)-4-phenyl-2-oxazolidinone (68.1 kg ). Lithium chloride (20.2 kg, ~4.6 kg/batch) was added in four additions at 10-15 min intervals at -5-5°C. The wall of reactor A was washed with THF (15.8 kg). The mixture was heated to 20-25° C. and held for 8 hours until the reaction was complete.

Water (1050.6 kg) and isopropyl acetic acid (825.8 kg) were added to the mixture. The mixture was stirred for 1 hour. Stirring was stopped, the mixture was allowed to stand until the phases separated, and the lower aqueous layer was removed. In a chemical reactor B with a volume of 2000 l, coated on the inside with enamel, a solution of sodium chloride (105.0 kg) in purified water (948.2 kg) was obtained, and then the contents of the reactor B were transferred to the previously obtained organic phase at 20-30 ° WITH. This mixture was stirred for 0.5 h. Stirring was stopped, the mixture was allowed to stand until the phases separated, and the lower aqueous layer was removed. The organic phase was concentrated until 500 L remained. Isopropyl acetic acid (466.3 kg) was added to the mixture. The organic phase was concentrated until 500 L remained. Acetic acid isopropyl ester (1850.5 kg) was added to the mixture at 45–55°C and stirred for 0.5–1 h. 187.0 kg). The combined filtrate was concentrated under reduced pressure until 700 L remained.

The organic stream was heated to 70-75° C. until the solid was completely dissolved. The mixture was cooled to 43-47° C. and then seed crystals (0.2 kg) were added to the mixture. The mixture was stirred for 1 hour at 43-47°C. n-Heptane (1178.5 kg) was added to the mixture over 3 hours, then the mixture was held for 1 hour at 43-47°C. The mixture was cooled to 8-12° C. over 4 hours and then aged for 6 hours. The resulting suspension was filtered using a centrifuge. The solid was washed with a solution of isopropyl acetic acid (45.2 kg) and n-heptane (321.5 kg) through an inline filter. The solid was then washed twice with n-heptane (2x358.2 kg). The filter cake was dried under vacuum at <50° C. to obtain 139.6 kg of product (yield: 88.2%) as a white solid.

1H NMR (601 MHz, DMSO-d ₆ ) δ 8.80 (d, J=4.5 Hz, 1H), 8.08 (dd, J=9.2, 5.8 Hz, 1H), 7.92 (dd, J=10.9, 2.6 Hz, 1H ), 7.63 (td, J=8.7, 2.6 Hz, 1H), 7.43 (d, J=4.5 Hz, 1H), 7.39-7.35 (m, 2H), 7.34-7.27 (m, 3H), 5.50 (dd, J=8.7, 3.8Hz, 1H), 4.75(t, J=8.7Hz, 1H), 4.16(dd, J=8.7, 3.8Hz, 1H), 3.34-3.25(m, 1H), 3.17(dd, J =15.6,

- 28 043098

6.8 Hz, 1H), 3.02 (dd, J=15.7, 8.0 Hz, 1H), 2.35 (br. s, 1H), 1.83-1.75 (m, 2H), 1.73-1.56 (m, 6H);

¹³ C NMR (151 MHz, DMSOL) δ 171.6, 160.7, 159.1, 153.7, 152.2, 152.1, 149.8, 145.1, 140.0, 132.6, 132.6, 128.7, 127.9, 127.1, 127. 1, 125.7, 119.0, 118.8, 118.4, 107.1, 107.0, 69.9, 57.0, 37.4, 36.5, 29.6, 29.0, 28.7, 27.4;

MS-ESI: calculated for free base C ₂₆ H ₂₆ FN ₂ O ₃ ([M+H]+) 433.19; found 433.19.

HPLC analysis: Column: Kinetex C18 100A 2.6 µm, inner diameter 150x4.6 mm.

Solvent A: 10 mM NH ₄ OAc containing water:MeCN (95/5 v/v).

Solvent B: 10 mM NH4OAc containing water:MeCN (5/95 v/v).

Gradient: %B: 0 min 15%; 1 min 15%; 9 min 65%; 12 min 65%; 16 min 90%; 19.9 min 100%; 23 min 100%.

Stop time: 23 min.

Flow rate: 1.0 ml/min.

Column temperature: 25°C.

Wavelength: 220 nm.

The retention time of (R)-3-(2-(( 1 S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)acetyl)-4-phenyloxazolidin-2-one was 14.0 min.

Example 4A.

THF (1138 kg) and 2-((1S,4S)-4-(6-fluoroquinolin-4yl)cyclohexyl)acetic acid (105.1 kg, 1.0 eq.) were added to the chemical reactor. This mixture was cooled to -5-5°C. Pivaloyl chloride (64.0 kg, 1.45 eq.) was added. Triethylamine (101.1 kg, 2.70 eq.) was added maintaining the temperature in the range of -5 to 5°C and then the mixture was held for 1 hour. (R)-(-)-4-phenyl-2oxazolidinone was added (68.1 kg, 1.15 eq.) and lithium chloride (20.2 kg, 1.30 eq.), then the reactor wall was washed with THF (15.8 kg). The mixture was heated to 25°C and held for 8 h.

Water (1050.6 kg) and isopropyl acetic acid (825.8 kg) were added to the mixture. After stirring for 1 hour, the mixture was allowed to stand until the phases separated and the lower aqueous layer was removed. The organic stream was then washed with 10% (w/w) NaCl aqueous solution (1050 kg). The organic stream was concentrated until 500 L remained. Acetic acid isopropyl ester (466.3 kg) was added and the organic stream was concentrated until 500 L remained. Isopropyl acetate (1850.5 kg) was added to the mixture at 45-55°C and stirred for 1 hour. The organic stream was filtered to remove inorganics and the filter was washed with isopropyl acetate (187.0 kg). The combined organic stream was concentrated under reduced pressure until 700 L remained.

The organic stream was heated to 70-75° C. until the solid was completely dissolved. The mixture was cooled to 45° C. and then seed crystals (0.2 kg) were added to the mixture. The mixture was stirred for 1 hour. n-heptane (1178.5 kg) was added to the mixture over 3 hours, then the mixture was kept for 1 hour at 45°C. The mixture was cooled to 10° C. over 4 hours and then aged for 6 hours. The resulting suspension was filtered using a centrifuge. The solid was washed with a solution previously prepared by mixing isopropyl acetic acid (45.2 kg) and ngeptane (321.5 kg). The solid was then washed with n-heptane (2x358.2 kg). The filter cake was dried under vacuum at <50° C. to give 139.6 kg of product (yield: 88.2%; peak area: 99.95% of HPLC area) as a white solid.

1H NMR (600 MHz, DMSO-d ₆ ) δ 8.80 (d, J=4.5 Hz, 1H), 8.08 (dd, J=9.2, 5.8 Hz, 1H), 7.92 (dd, J=10.9, 2.6 Hz, 1H ), 7.63 (td, J=8.7, 2.6 Hz, 1H), 7.43 (d, J=4.5 Hz, 1H), 7.39-7.35 (m, 2H), 7.34-7.27 (m, 3H), 5.50 (dd, J=8.7, 3.8Hz, 1H), 4.75(t, J=8.7Hz, 1H), 4.16(dd, J=8.7, 3.8Hz, 1H), 3.34-3.25(m, 1H), 3.17(dd, J =15.6, 6.8 Hz, 1H), 3.02 (dd, J=15.7, 8.0 Hz, 1H), 2.35 (br. s, 1H), 1.83-1.75 (m, 2H), 1.73-1.56 (m, 6H);

¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171.6, 160.7, 159.1, 153.7, 152.2, 152.1, 149.8, 145.1, 140.0, 132.6, 132.6, 128.7, 127.9, 127.1, 127.1, 125.7, 119.0, 118.8, 118.4 , 107.1, 107.0, 69.9, 57.0, 37.4, 36.5, 29.6, 29.0, 28.7, 27.4;

HRMS-ESI: calculated for C ₂₆ H ₂₆ FN ₂ O ₃ [M+H] ⁺ : 433.1922; found: 433,1936.

Example 5

(R)-3-((R)-2-((1S,4S)-4-(6-Fluoroquinolin-4-yl)cyclohexyl)propanoyl)-4-phenyloxazolidin-2-one o o

94.96 kg of (R)-3-(2-((1S,4S)-4-(6fluoroquinoline -4-yl)cyclohexyl)acetyl)-4-phenyloxazolidin-2-one and 838.1 kg of THF. This mixture for

- 29 043098 was heated to 45°and then added to 84.6 kg of THF. In a chemical reactor with a volume of 2000 l (reactor B) made 84.7 kg of THF. The mixture from reactor A was transferred through a filter to reactor B and reactor A was washed with 41.1 kg of THF, which was then transferred to reactor B. The mixture was cooled to -20° C. and 21.1 kg of THF was added. 50.1 kg MeI was added to the mixture while maintaining the temperature at -20°C. To the mixture was added 4.8 kg of THF and then 252.3 kg of a 1 M solution of sodium bis(trimethylsilyl)amide (NaHMDS) in THF while maintaining the temperature at -20°C. 21.0 kg of THF was added to the mixture, and the mixture was kept at -20° C. until the starting material was consumed.

In reactor C, a solution of acetic acid (16.5 kg) in THF (340.6 kg) was obtained and this solution was kept at -10°C. The contents of Reactor B were transferred to Reactor C, keeping Reactor C at <-10°C. Reactor B was washed with 21.0 kg of THF, which was then transferred to reactor C. This mixture was heated to 20°C. 65.0 kg of sodium chloride and 454.3 kg of water were introduced into a 1000 L chemical reactor (reactor D). The contents of reactor C were transferred to the sodium chloride solution in reactor D. After stirring for 30 minutes, the mixture was allowed to stand until phase separation and the lower aqueous layer was removed.

The organic layer was transferred to a 3000 L chemical reactor (reactor E) and subjected to vacuum distillation keeping the temperature at 50° C. until a volume of 500 L was obtained. 741 kg of acetonitrile was added to the mixture, and the resulting mixture was subjected to distillation, reducing the volume to 500 L. 741 kg of acetonitrile was added to the mixture, and the resulting mixture was subjected to distillation, reducing the volume to 500 L. To the mixture was added 377.7 kg of acetonitrile, this solution was heated to 60°C and kept for 30 min at 60°C. 252.2 kg of water was added to the solution over 2.5 hours and the temperature was lowered to 52°C. Then, 0.95 kg of seed crystals were added to the solution, the resulting suspension was held for 2 hours, and 603.7 kg of water was added over 3 hours while maintaining the temperature at 52°C. The suspension was cooled to 20°C for 2.5 hours and kept for 4 hours Then the suspension was filtered in two steps. Each portion was washed twice with 212 kg of an aqueous solution of acetonitrile prepared from 378.3 kg of acetonitrile and 475.1 kg of water, and then washed with water (237 kg) and n-heptane (162 kg). The filter cakes were combined and dried at 55° C. to give 80.9 kg of a yellowish solid (yield: 83%).

Can be performed recrystallization of the resulting substance. To perform recrystallization, 80.9 kg of (R)-3-((R)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoyl)-4-phenyloxazolidine -2-one and then 572.3 kg of acetonitrile. This mixture was heated to 60° C. until the mixture became homogeneous. The resulting solution was kept for 30 min at 60°C. 214.4 kg of water was added to the solution over 2.5 hours and the temperature was lowered to 52°C. Then, 0.81 kg of seed crystals were added to the solution, the resulting suspension was held for 2 hours, and 513.7 kg of water was added over 3 hours while maintaining the temperature at 52°C. The slurry was cooled to 20° C. over 2.5 h and held for 4 h. The slurry was then filtered and washed twice with an aqueous solution of acetonitrile, which was prepared from 159.0 kg of acetonitrile and 202.3 kg of water, and then washed with water (404 .5 kg) and n-heptane (276.7 kg).

1H NMR (601 MHz, DMSO-d6) δ 8.85 (d, J=4.5 Hz, 1H), 8.10 (dd, J=9.2, 5.8 Hz, 1H), 7.97 (dd, J=10.9, 2.6 Hz, 1H) , 7.66 (dd, J=8.7, 2.6 Hz, 1H), 7.41-.40 (m, 3H), 7.32-7.30 (m, 3H), 5.53 (dd, J=8.7, 3.8 Hz, 1H), 4.76 ( t, J=8.7 Hz, 1H), 4.29 (m, 1H), 4.15 (dd, J=8.6, 4.2 Hz, 1H), 3.42-3.38 (m, 1H), 2.05-2.01 (dd, 1H), 1.83 -1.58 (m, 1H), 1.05 (d, J=8.7 Hz, 3H);

¹³ C NMR (151 MHz, CDCl3-d) δ 172.1, 161.7, 153.8, 152.1; 149.7, 145.5, 139.1, 132.9, 132.8, 129.2, 128.8, 125.9, 119.1, 118.8, 118.3, 106.7, 106.5, 69.9, 57.7, 38.5, 37.3, 30.3, 29.8, 29.2, 27.9, 27.8;

MS-ESI: calculated for C ₂₇ H ₂₈ FN ₂ O ₃ ([M+H]+) 447.51; found 447.40.

HPLC analysis: Column: Supelco Ascentis Express C8 2.7 µm, 150x4.6 mm PN=USZB002789.

Solvent A: 10 mM ammonium acetate in a mixture of water (80%) and MeOH (20%).

Solvent B: 10 mM ammonium acetate in a mixture of acetonitrile (75%), MeOH (20%) and water (5%). Gradient: %B: 0 min 10%; 2 min 10%; 7 min 55%; 20 min 68%; 24 min 100%; 26 min 0%.

Stop time: 30 min.

Flow rate: 1 ml/min.

Wavelength: 218 nm.

Temperature regime of the thermostat: 30°С.

The retention time of (R)-3-((R)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoyl)-4phenyloxazolidin-2-one was 16.4 minutes.

Example 5A.

(R)-3-(2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)acetyl)-4phenyloxazolidin-2-one (95.0 kg, 1.0 eq.) and THF (838.1 kg). This mixture was heated to 45° C. and then THF (85 kg) was added. The organic stream was transferred through the filter to another reactor and the filter was washed with THF (41.1 kg). The mixture was cooled to -20° C. and THF (21 kg) was added. Methyl iodide (50.1 kg, 1.60 eq.) and 1 M solution of sodium bis-(trimethylsilyl)amide (NaHMDS) in THF (252.3 kg, 1.25 eq.) were added, keeping the temperature at -20° WITH. The reactor was flushed with THF

- 30 043098 (25.8 kg), then the organic stream was kept for 3 hours at -20°C. The reaction was stopped by adding 4.6% (by weight) of an aqueous solution of acetic acid (357 kg), maintaining the temperature below -10°C. The organic stream was heated to 25° C. and 12.5% (w/w) NaCl aqueous solution (519 kg) was added. After stirring for 30 minutes, the mixture was allowed to stand until the phases separated, and the lower aqueous layer was removed. The organic layer was concentrated to a volume of 500 L. Acetonitrile (2x741 kg) was added and the resulting mixture was distilled twice, reducing the volume to 500 L. Acetonitrile (378 kg) was added and the solution was heated to 60° C. and maintained at the same temperature for 30 minutes. Water (252 kg) was added over 2.5 hours and the temperature was lowered to 52°C. Seed crystals (1.0 kg) were added, the resulting suspension was held for 2 h and water (604 kg) was added over 3 h while maintaining the temperature at 52°C. The slurry was cooled to 20° C. over 2.5 hours and held for 4 hours. The slurry was filtered, then washed twice (2x424 kg) with a solution previously prepared by mixing acetonitrile (378 kg) and water (475 kg), and then washed water (237 kg) and n-heptane (162 kg). The filter cake was dried at 55° C. to give 80.9 kg of product (yield: 83%; peak area: 99.94% of HPLC area) as a yellowish solid.

¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.85 (d, J=4.5 Hz, 1H), 8.10 (dd, J=9.2, 5.8 Hz, 1H), 7.97 (dd, J=10.9, 2.6 Hz, 1H), 7.66 (dd, J=8.7, 2.6 Hz, 1H), 7.41-7.40 (m, 3H), 7.32-7.30 (m, 3H), 5.53 (dd, J=8.7, 3.8 Hz, 1H), 4.76 (t, J=8.7 Hz, 1H), 4.29 (m, 1H), 4.15 (dd, J=8.6, 4.2 Hz, 1H), 3.42-3.38 (m, 1H), 2.05-2.01 (dd, 1H), 1.831.58 (m, 1H), 1.05 (d, J=8.7 Hz, 3H);

¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 175.9, 160.7, 159.1, 153.6, 152.3, 152.3, 149.8, 145.2, 139.9, 132.7, 132.6, 128.8, 127.9, 127.2, 127.1, 125.5, 119.0, 118.9, 118.3 , 107.2, 107.0, 68.8, 57.0, 37.1, 36.0, 34.7, 28.4, 27.9, 27.5, 26.1, 15.8;

HRMS-ESI: calculated for C ₂₇ H ₂₈ FN ₂ O ₃ [M+H]+: 447.2079; found: 447,2091.

Example 6

(R)-2-(( 1 S,4S)-4-(6-Fluoroquinolin-4-yl)cyclohexyl)propanoic acid

254.1 kg of THF and 57.0 kg of (R)-3-((R)-2-((1S,4S)- 4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoyl)-4phenyloxazolidin-2-one followed by 127.0 kg of THF. To this mixture was added 66.9 kg of a 30% solution (w/w) of hydrogen peroxide (4.6 eq.) in water and then 2.0 kg of water. This mixture was heated to 25° C. and a solution of LiOH monohydrate (8.7 kg) in water (57.3 kg) was added over 4 hours, maintaining the temperature at 25° C. and oxygen level <2.5%. Then 9.9 kg of water and 152.4 kg of THF were added to the reactor. The reaction was carried out until the conversion was complete.

The mixture was cooled to 5°C and 73.2 kg of sodium bisulfite in water (171.8 kg) was slowly added while maintaining the temperature <30°C. The mixture was held for 30 minutes with stirring, then held for 30 minutes without stirring. The phases were separated and the lower aqueous layer was removed. 161.0 kg of N,N-dimethylacetamideα (DMAC) and 48.9 kg of THF were added to the mixture, and then vacuum distillation was performed at 130 mbar until the temperature reached 70°C. 26.8 kg of DMAC were added to the mixture at 70° C. and then 154.6 kg of water were added over 30 minutes. The contents of the reactor were kept for 1.5 hours at 70° C. and 103.0 kg of water were added over 30 minutes. The contents of the reactor were kept for 1.5 h at 70°C. The mixture was then cooled over 6 hours to 20° C. and held for 60 hours. The resulting suspension was filtered and washed twice with DMA:water (1:1; 167 kg). The filter cake was washed twice with acetonitrile:water (1:3; 162 kg) and dried at 50° C. under vacuum to give 35.0 kg of a white solid (yield: 91.1%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.95 (br. s, 1H), 8.80 (d, 1H), 8.08 (dd, 1H), 7.95 (dd, 1H), 7.65 (t, 1H), 7.50 (d, 1H), 3.38 (br. 1H), 2.78–2.66 (m, 1H), 1.86–1.61 (m, 9H), 1.09 (d, 3H);

¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 177.7, 159.9 (d, 1С), 152.2 (d, 1С), 149.8 (d, 1С), 145.1, 132.6 (d, 1С), 127.2 (d, 1С ), 118.9 (d, 1С), 118.7, 107.1 (d, 1С), 39.1, 37.2, 35.7, 28.7, 27.8, 27.2, 26.2, 15.6;

LC-MS ESI (+) m/z: 302 (M+H).

HPLC analysis: Column: Ascentis Express C18 2.7 µm, inner diameter 150x4.6 mm.

Solvent A: 0.05% TFA in water:acetonitrile (95:5).

Solvent B: 0.05% TFA in water:acetonitrile (5:95).

Gradient: %B: 0 min 15%; 12 min 60%; 14 min 100%; 16 min 100%.

Stop time: 16 min.

- 31 043098

Flow rate: 1 ml/min.

Wavelength: 218 nm.

The retention time of (R)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoic acid was 7.0 minutes.

Example 6A.

THF (640 kg) and (R)-3-((R)-2-((1S,4S)-4-(6-fluoroquinolin-4yl)cyclohexyl)propanoyl)-4-phenyloxazolidin-2- he (144 kg, 1.0 eq.) and then THF (320 kg). A 35% (w/w) aqueous hydrogen peroxide solution (144 kg, 4.6 eq.) was added to the reactor followed by water (14 kg). This mixture was heated to 25° C. and the nitrogen flow rate was adjusted so as to control the content of oxygen evolved in the reactor during the addition of the LiOH solution. A solution of anhydrous LiOH (12.4 kg, 1.6 equiv.) in water (144 kg) was added over 6 h in two steps (3 h each) in water (144 kg), maintaining the temperature at 25°C and the oxygen level in the free volume of the reactor <2 ,5%. After adding the first portion of the LiOH solution, THF (128 kg) was added. After adding the second portion of the LiOH solution, water (14 kg) and THF (128 kg) were added to the reactor. The reaction was carried out for 3 h.

The mixture was then cooled to 10°C, and 30% (by weight) aqueous sodium bisulfite solution (601 kg) was slowly added while maintaining the temperature <35°C. After stirring for 30 minutes, the mixture was allowed to stand until the phases separated, and the lower aqueous layer was removed. Then N,N-dimethylacetamide (DMAc) (541 kg) was added to the mixture. The mixture was stirred for 1 hour at 25° C. and then filtered through a fine filter into a distillation vessel. The fine filter was washed with THF (128 kg), which was then transferred to a distillation vessel, the filtrate was subjected to vacuum distillation at 130 mbar until the temperature reached 70°C. DMAc (68 kg) was added to the reactor at 70° C., then water (389 kg) was added over 30 minutes. The contents of the reactor were kept for 1.5 hours at 70° C., then an additional portion of water (158 kg) was added over 2 hours. The contents of the reactor were kept for 1.5 h at 70°C. The mixture was cooled to 20° C. over 6 hours and then aged for at least 8 hours. The resulting suspension was filtered and washed with a solution previously obtained by mixing DMAc (203 kg) and water (216 kg). The solid was further washed with a solution previously prepared by mixing acetonitrile (171 kg) and water (648 kg). The solid was then dried at 50° C. under vacuum to give 86.5 kg of product (yield: 89%; peak area: 99.7% of HPLC area) as a white solid.

¹ H NMR (600 MHz, DMSO-d6) δ 12.09 (s, 1H), 8.80 (d, J=4.5 Hz, 1H), 8.06 (dd, J=9.2, 5.8 Hz, 1H), 7.91 (dd, J =10.9, 2.8 Hz, 1H), 7.61 (ddd, J=9.1, 8.2, 2.8 Hz, 1H), 7.45 (d, J=4.5 Hz, 1H), 3.41-3.27 (m, 1H), 2.72-2.63 ( m, 1H), 1.86-1.61 (m, 9H), 1.08 (d, J=6.8 Hz, 3H);

¹³ C NMR (150 MHz, DMSO-d6) δ 177.7, 159.9, 152.2, 149.8, 145.1, 132.6, 127.2, 118.9, 118.7, 107.1, 39.1, 37.2, 35.7, 28.7, 27.8, 27.2, 26.2, 15.6;

HRMS-ESI: calculated for C ₁₈ H ₂₁ FNO ₂ [M+H]+: 302.1551; found: 302,1563.

Example 7

(R)-N-(4-Chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide

13.75 kg of acetonitrile, then 2.68 kg of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) were introduced into a chemical reactor with a volume of 50 l, coated on the inside with enamel, in a nitrogen atmosphere, and the reactor was washed with acetonitrile (2. 0 kg). 2.03 kg of N-methylimidazole was added followed by 1.95 kg of acetonitrile. 2.48 kg of (R)-2-((1S,4S)-(6-fluoroquinolin-4-yl)cyclohexyl)propanoic acid was added followed by 1.05 kg of acetonitrile. This mixture was held for 0.5 h, then 1.21 kg of 4-chloroaniline and then 1.0 kg of acetonitrile were added. The temperature of the mixture was maintained at 20°C until the reaction was completed according to HPLC analysis. The resulting solution was then heated to 60° C. and 9.25 kg of water was added. Then the solution was cooled to 40°C, the mixture was kept for 1 h, seed crystals (32 g) were added and washed with a mixture of water:acetonitrile (2:1; 1.15 kg), the resulting suspension was kept for 1 h. Then the suspension was cooled to 20°C and added 25.75 kg of water. The suspension was filtered and the filter cake was washed three times with water:acetonitrile (2:1; 6.9 kg). The filter cake was dried under vacuum at 50° C. to give 3.33 kg of (R)-N-(4-chlorophenyl)-2((18.48)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide hydrate as a white solid (yield: 94.1%).

1H NMR (600 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.86 (d, J=4.5 Hz, 1H), 8.08 (dd, J=9.0, 5.6 Hz, 1H), 7.95 (dd, J= 10.9, 2.6 Hz, 1H), 7.70-7.60 (m, 3H), 7.54 (d, J=4.5 Hz, 1H), 7.33 (d, J=9.0 Hz, 2H), 3.43-3.31 (m, 3H), 2.90-2.80 (m, 1H), 1.99-1.55 (m, 9H), 1.13 (d, J=6.8 Hz, 3H);

- 32 043098 ¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 175.0, 159.9, 152.4, 149.7, 145.2, 138.1, 132.7, 128.5, 127.2, 126.7,

120.8, 119.0, 118.6, 107.2, 40.2, 37.4, 35.6, 28.5, 27.6, 27.4, 26.3, 16.1;

HRMS-ESI: calculated for C ₂₄ H ₂₄ ClFN ₂ O ([M+H]+) 411.1619; found 411,1649.

Example 7A.

N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (95 kg, 1.25 eq.) and acetonitrile (237 kg) were added to the chemical reactor. N-methylimidazole (69 kg, 3.10 eq.) was added followed by acetonitrile (32 kg). (R)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoic acid (82.0 kg, 1.0 eq.) was added followed by acetonitrile (63 kg). This mixture was held for 0.5 h, then a solution of 4-chloroaniline (40 kg, 1.15 eq.) in acetonitrile (96 kg) was added followed by acetonitrile (63 kg). The temperature of the mixture was maintained for 3 hours at 20° C., then acetonitrile (128 kg) was added. The resulting solution was then heated to 60° C. and water (303 kg) was added. The solution was cooled to 40°C, seed crystals (0.8 kg) were added and the resulting suspension was held for 1 hour. Then the suspension was cooled over 3 hours to 20°C. Water (820 kg) was added over 1.5 h and the suspension was kept for 1 h. The suspension was then filtered and the filter cake was washed three times (3x455 kg) with a solution previously obtained by mixing water (325 kg) and acetonitrile (130 kg) . The filter cake was dried at 50°C and the dried filter cake was dissolved in ethyl acetate (1055 kg). Seed crystals (1.7 kg) were added to this organic stream. A solution of methanesulfonic acid (28 kg) in ethyl acetate (453 kg) was added over 2 hours and the suspension was held for 1 hour. The suspension was then filtered and washed with ethyl acetate (3x320 kg). The filter cake was dried under vacuum at 50° C. to give 124.8 kg of product (yield: 90%; peak area: 99.94% of HPLC area) as a white solid.

1H NMR (600 MHz, DMSO-06) δ 10.19 (s, 1H), 9.24 (d, J=5.7 Hz, 1H), 8.40 (dd, J=10.3, 2.6 Hz, 1H), 8.33 (dd, J= 9.4, 5.3 Hz, 1H), 8.09 (d, J=5.7 Hz, 1H), 8.04 (t, J=8.6 Hz, 1H), 7.71-7.64 (m, 2H), 7.37-7.30 (m, 2H), 3.64 (ddt, J=10.8, 7.3, 3.8 Hz, 1H), 2.98-2.89 (m, 1H), 2.43 (s, 3H), 2.05-1.60 (m, 9H), 1.14 (d, J=6.7 Hz, 3H);

¹³ C NMR (150 MHz, DMSO-d6) δ 175.0, 162.7, 161.1, 145.4, 138.2, 136.8, 128.6, 128.1, 126.7, 126.4, 123.3, 120.8, 119.8, 109.0, 3 9.8, 39.7, 38.6, 35.5, 28.3, 27.6, 27.2, 26.1, 16.2;

HRMS-ESI: calculated for C24H25OTN2O [M+H] ⁺ 410.1634; found 410,1625.

Example 8

(R)-N-(4-Chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide salts and co-crystals.

349 g of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and 2 L of acetonitrile were added to a 10 L chemical reactor with enamel on the inside under a nitrogen atmosphere. 245 g of N-methylimidazole was added and then 0.3 l of acetonitrile. 300 g of (R)-2-((1S,4S)-4-(6fluoroquinolin-4-yl)cyclohexyl)propanoic acid was added followed by 0.3 L of acetonitrile. This mixture was held for 0.5 h, then 139 g of 4-chloroaniline and then 0.4 l of acetonitrile were added. The temperature of the mixture was maintained at 20°C until the reaction was completed according to HPLC analysis. Then the resulting solution was heated to 60°and added to 1.2 l of water. Then the solution was cooled to 40°C, seed crystals (3 g) were added and the resulting suspension was kept for 1 hour. Then the suspension was cooled to 20°C and 2.7 l of water was added. The suspension was filtered and the filter cake was washed three times with water:acetonitrile (2:1; 3 L).

The filter cake was dissolved in about 5 L of an organic solvent and this solution was subjected to vacuum distillation at a temperature of about 40° C. until a volume of about 4 L was obtained. The resulting slurry was cooled to approximately 20° C. and an appropriate amount of acid or co-crystal forming agent was added as a solution, for example in water or an organic solvent. This suspension was then filtered, washed and dried to give approximately 445 g of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide as salt or co-crystal.

Example 9

(R)-N-(4-Chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-propanamide methanesulfonate

349 g of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and 2 liters of acetonitrile were added to a 10-liter chemical reactor coated on the inside with enamel under a nitrogen atmosphere. 245 g of N-methylimidazole was added and then 0.3 l of acetonitrile. 300 g of (R)-2-((1S,4S)-4-(6fluoroquinolin-4-yl)cyclohexyl)propanoic acid was added followed by 0.3 L of acetonitrile. This mixture was held for 0.5 h, then 139 g of 4-chloroaniline and then 0.4 l of acetonitrile were added. Temperature

- 33 043098 mixture was maintained at 20°C until the reaction was completed according to HPLC analysis. Then the resulting solution was heated to 60°and added to 1.2 l of water. Then the solution was cooled to 40°C, seed crystals (3 g) were added and the resulting suspension was kept for 1 hour. Then the suspension was cooled to 20°C and 2.7 l of water was added. The suspension was filtered and the filter cake was washed three times with water:acetonitrile (2:1; 3 L). The filter cake was dissolved in 5.1 L of ethyl acetate and this solution was subjected to vacuum distillation at 41° C. until a volume of 4.2 L was obtained. The resulting suspension was cooled to 20° C., 4.14 g seed crystals were added and a solution of methanesulfonic acid (95.7 g) in ethyl acetate (2.9 L) was added. This suspension was then filtered, washed twice with ethyl acetate (1.65 L) and dried under vacuum at 50° C. to obtain 445 g of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4- (6-Fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate as a white solid (yield: 88%).

1H NMR (600 MHz, DMSOL) δ 10.19 (s, 1H), 9.24 (d, J=5.7 Hz, 1H), 8.40 (dd, J=10.3, 2.6 Hz, 1H), 8.33 (dd, J=9.4, 5.3 Hz, 1H), 8.09 (d, J=5.7 Hz, 1H), 8.04 (t, J=8.6 Hz, 1H), 7.71-7.64 (m, 2H), 7.37-7.30 (m, 2H), 3.64 ( ddt, J=10.8, 7.3, 3.8 Hz, 1H), 2.98-2.89 (m, 1H), 2.43 (s, 3H), 2.05-1.60 (m, 9H), 1.14 (d, J=6.7 Hz, 3H) ;

¹³ C NMR (126 MHz, DMSO-d ₆ ) δ 175.0, 162.7, 161.1, 145.4, 138.2, 136.8, 128.6, 128.1, 126.7, 126.4, 123.3, 120.8, 119.8, 109.0, 39.8, 39.7, 38.6, 35.5, 28.3 , 27.6, 27.2, 26.1, 16.2;

MS-ESI: calculated for C ₂₄ H ₂₄ ClFN ₂ O ([M+H]+) 410.16; found 410.15.

HPLC analysis: Column: Sigma-Aldrich Supelco Ascentis Express C18 2.7 µm, id 150x4.6 mm.

Solvent A: 0.05% TFA containing MeCN:water (5/95 v/v).

Solvent B: 0.05% TFA containing MeCN:water (95/5 v/v).

Gradient: %B: 0 min 15%; 1 min 15%; 13 min 55%; 19 min 65%; 24 min 100%; 24.1 15%; 28 min 15%.

Stop time: 24 min.

Flow rate: 1.0 ml/min.

Column temperature: 30°C.

Wavelength: 218 nm.

The retention time of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, as indicated by the HPLC peak, was 12.6 min. .

Example 10

Methyl (R)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoate

Methanol (300.0 ml) was added to a 250 ml glass chemical reactor followed by T(OTf) ₃ (0.606 g, 1.12 mmol) under nitrogen atmosphere, then the mixture was heated for 1 h to 60°C. (4R)-3-[(2R)-2-[4-(6-fluoro-4-quinolyl)cyclohexyl]propanoyl]-4-phenyl-oxazolidin-2-one (10.00 g, 22 .40 mmol) as a solid. Then this reaction mixture was kept for 3 hours, the Reaction mixture was cooled to 30°C and concentrated to dryness under vacuum.

1H NMR (400 MHz, CDCl ₃ ) δ 8.82 (d, 1H), 8.12 (dd, 1H), 7.75-7.62 (m, 1H), 7.54-7.43 (m, 1H), 7.35 (d, 1H), 3.71 (s, 3H), 3.36-3.20 (m, 1H), 2.89-2.72 (m, 1H), 2.05-1.91 (m, 2H), 1.90-1.63 (m, 7H), 1.21 (d, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 177.2, 160.5 (d, 1С), 152.0 (d, 1С), 149.6, 145.6, 132.9 (d, 1С), 127.7 (d, 1С), 119.0 (d, 1С ), 118.3, 106.7 (d, 1C), 51.5, 39.9, 38.3, 36.3, 29.4, 27.9, 27.7, 26.9, 15.7;

LC/MS-ESR (+) m/z: 316 (M+H).

HPLC analysis: Column: Ascentis Express C18 2.7 µm, inner diameter 150x4.6 mm.

Solvent A: 0.05% TFA in water:acetonitrile (95:5).

Solvent B: 0.05% TFA in water:acetonitrile (5:95).

Gradient: %B: 0 min 15%; 12 min 60%; 14 min 100%; 16 min 100%.

Stop time: 16 min.

Flow rate: 1 ml/min.

Wavelength: 218 nm.

The retention time of methyl (R)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoate was 9.2 minutes.

Example 11.

(R)-2-((1S,4S)-4-(6-Fluoroquinolin-4-yl)cyclohexyl)propanoic acid

- 34 043098

To crude methyl (R)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoate at 30°C was added DMAC (50.0 ml) and then 5.0 M NaOH was added (13.0 ml, 65.0 mmol). This reaction mixture was allowed to stir for 20 hours. A 50% (by weight) solution of citric acid (25.0 ml) was added slowly to adjust the pH. The reaction mixture was heated to 70° C., then water (20 ml) was added over 2 hours and then the mixture was aged for 1 hour. The resulting suspension was cooled to 20° C. over 6 hours, then aged overnight. The slurry was filtered, washed with DMAC/water (1:1; 30 ml), MeCN/water (1:3; 2x30 ml), then dried in a drying oven at 50° C. with a nitrogen wash. (R)-2-((1S,4S)-4-(6-Fluoroquinolin-4-yl)cyclohexyl)propanoic acid (5.52 g, 18.3 mmol, yield: 81.8%) was isolated as white solid.

1H NMR (400 MHz, DMSO-06) δ 12.95 (br. s, 1H), 8.80 (d, 1H), 8.08 (dd, 1H), 7.95 (dd, 1H), 7.65 (t, 1H), 7.50 ( d, 1H), 3.38 (br. 1H), 2.78–2.66 (m, 1H), 1.86–1.61 (m, 9H), 1.09 (d, 3H);

¹³ C NMR (151 MHz, DMSO-d6) δ 177.7, 159.9 (d, 1С), 152.2 (d, 1С), 149.8 (d, 1С), 145.1, 132.6 (d, 1С), 127.2 (d, 1С) , 118.9 (d, 1С), 118.7, 107.1 (d, 1С), 39.1, 37.2, 35.7, 28.7, 27.8, 27.2, 26.2, 15.6;

LC/MS-ESR (+) m/z: 302 (M+H).

HPLC analysis: Column: Ascentis Express C18 2.7 µm, inner diameter 150x4.6 mm.

Solvent A: 0.05% TFA in water:acetonitrile (95:5).

Solvent B: 0.05% TFA in water:acetonitrile (5:95).

Gradient: %B: 0 min 15%; 12 min 60%; 14 min 100%; 16 min 100%.

Stop time: 16 min.

Flow rate: 1 ml/min.

Wavelength: 218 nm.

The retention time of (R)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoic acid was 7.0 minutes.

Example 12.

O

N/A έ ^{Η he}

Getting ^N .

An empty 250 ml round bottom flask was charged with the compound described in Example 11 (9.5 g, 30 mmol), tetrahydroxydiboron (7.28 g, 78.8 mmol) and a magnetic stir bar. 100 ml of methanol was added followed by N,N-diisopropylethylamine (19.4 ml, 110 mmol), this solution was bubbled for 20 minutes. Nickel nitrate (0.463 g, 1.58 mmol) and tricyclohexylphosphonium tetrafluoroborate (1.29 g, 3.47 mmol) in 50 ml of methanol with a pale green solution was obtained, which was bubbled for 20 minutes. After bubbling both solutions for 20 min, a Ni/PCy ₃ solution was added by cannula to a 250 ml RBF. The combined mixtures were sparged for an additional 45 minutes at room temperature with magnetic stirring. The mixture was then heated to 55°C. After 5 hours and 15 minutes, the mixture was cooled to room temperature and 35 ml of TFA, 170 ml of water and 50 ml of methanol were added. Then 400 ml of heptane were added, the mixture was stirred and the phases were separated. The enriched aqueous layer was then applied in 75 ml aliquots directly onto the purification column.

Column: Biotage Ultra C18 400 g, 25 µm spherical particles.

Mobile phase A: water/acetonitrile/TFA (95/5/0.2).

Mobile phase B: acetonitrile.

Gradient: 0-3.7 column volume (CV, abbreviated from the English column volume) (1 CV = 760 ml): 10-25% B (linearly changing), 50 ml / min; 3.7-4.8 CV: 90% B (retention), 50 ml/min; 4.8-5.8 CV: 10% B (retention), 50 ml/min.

Fractions containing the desired product were combined, diluted with water (7.4 L) and applied in one go to the same SPE column. The loaded column was washed with water/acetonitrile (95/5) and eluted with 100% THF. Fractions containing the desired product were combined and concentrated by rotary evaporation to give 5.52 g of the desired compound as a white solid (yield: 56%).

- 35 043098

1Н NMR (600 MHz, DMSO-d ₆ ) δ 12.14 (br. s, 1H), 8.82 (d, J=4.6 Hz, 1H), 8.71 (s, 1H), 8.39 (br. s, 2H),

8.10 (d, J=8.5 Hz, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.45 (d, J=4.6 Hz, 1H), 3.63-3.44 (m, 2H), 2.76-2.67 (m , 1H),

1.87 (br. d, J=10.3 Hz, 2Н), 1.82-1.66 (m, 7Н), 1.11 (d, J=6.7 Hz, 3Н);

¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 177.8, 153.4, 150.8, 148.8, 133.8, 132.1, 130.2, 128.4, 125.7, 118.0,

39.1, 37.2, 35.7, 29.0, 28.1, 27.4, 26.5, 15.7;

HRMS-ESI: calculated for C ₁₈ H ₂₃ O ₄ NB ([M+H]+) 328.1715; found 328,1718.

Example 13

Receipt

An empty 25 ml round bottom flask was charged with the compound described in Example 12 (A, 0.500 g, 1.53 mmol), pinacol (0.190 g, 1.61 mmol) and tetrahydrofuran (5.00 ml, 61.4 mmol). This mixture was stirred on a magnetic stirrer for 90 minutes at room temperature. The mixture was then cooled to 0° C. and 1-methylimidazole (0.730 mL, 9.17 mmol) was added followed by propylphosphonic anhydride (1.67 mol/L) in ethyl acetate (4.58 mL, 7.65 mmol) and 4- chloraniline (391.0 mg, 3.065 mmol).

The reaction was completed after 2 hours and the whole mixture was poured into 25 ml of sodium bicarbonate (1.03 mol/l) and water (15 ml, 832.649 mmol), pre-cooled to 0°C. Ethyl acetate (5 ml) was added and the phases were separated using a separating funnel. The aqueous layer was back extracted with ethyl acetate (40 ml, 400 mmol). The enriched organic phases were combined and washed with saturated NaHCO ₃ (aq.):water (15 ml; 1:1). The enriched organic phases were then dried using 1 g MgSO ₄ and filtered. The crude filtrate was then purified by column chromatography.

Column: Biotage Ultra silica gel 25 g, 25 µm spherical particles.

Mobile phase A: dichloromethane.

Mobile phase B: ethyl acetate.

Gradient: 0-20 CV (1 CV=33 ml): 30-100% EtOAc in DCM (linear), 26 ml/min.

Fractions containing the desired product were combined and concentrated by rotary evaporation to give 369 mg of the desired compound as a white solid (yield: 59%).

1H NMR (600 MHz, DMSO-d ₆ ) δ10.11 (s, 1H), 8.92 (d, J=4.6 Hz, 1H), 8.50 (s, 1H), 8.01 (d, J=8.5 Hz, 1H) , 7.95 (d, J=8.4 Hz, 1H), 7.68-7.64 (m, 2H), 7.56 (d, J=4.6 Hz, 1H), 7.35-7.32 (m, 2H), 3.46 (br. t, J =10.9 Hz, 1H), 2.89-2.83 (m, 1H), 2.00-1.93 (m, 2H), 1.87 (br. d, J=12.6 Hz, 1H), 1.78-1.59 (m, 6H), 1.33 ( s, 12H), 1.13 (d, J=6.7 Hz, 3H);

^13C NMR (126 MHz, DMSO-d6) δ 175.0, 170.3, 153.2, 151.4, 149.4, 138.1, 133.3, 130.4, 129.4, 128.5, 126.7, 125.6, 120.8, 118.5, 8 4.0, 59.7, 40.3, 37.2, 35.6, 28.6, 28.0, 27.6, 26.5, 24.7, 24.7, 20.7, 16.0, 14.1;

HRMS-ESI: calculated for C ₃₀ H ₃₇ O ₃ N ₂ BCl ([M+H]+) 519.2580; found 519,2579.

Example 14

Receipt

Automated synthesis was performed using a commercially available Synthera synthesis module (IBA) synthesizer and self-selected HPLC system components. Automatic synthesis of [ ¹⁸ F](R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide was performed using a cassette-type IBA Synthera synthesis module with a set of components of an integrated liquid processor selected for a given reaction. Then, transfer was performed to an automated system of self-selected components for purification and recomposition of the resulting product using HPLC. The set of integrated fluid processor (IFP) components and self-selected components of the automated system, into which precursors suitable for synthesis were added, are shown in the table below. Purification was performed on a Varian HPLC unit with filling of the dosing loop controlled by a constant flow of nitrogen.

- 36 043098

Bottle 1 (VI) 6 mg potassium trifluoromethanesulfonate 1.5 mg potassium carbonate 0.5 ml distilled water 1.0 ml acetonitrile QMA Sep-Pak Accell Plus QMA Carbonate Plus Light Cartridge, 46 mg, particle size: 40 µm (Waters: PN 186004540) Before use, the cartridge is activated with using: 1) 10 ml ethanol 2) 900 mg of potassium trifluoromethanesulfonate in 10 ml of distilled water 3) 10 ml of distilled water Bottle 2 (V2) 2 mg (7?)-A-(4-chlorophenyl)-2-((15.45)-4-(6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)quinoline-4- yl)cyclohexyl)propanamide 7 mg copper (II) trifluoromethanesulfonate 40 µl pyridine 0.7 ml L/L'-Dimethylformamide Bottle 4 (V4) 2.5 ml distilled water 1.5 ml acetonitrile HPLC: column Phenomenex Luna, 5 µm C 18(2) 100 A, 250 x 10 mm (PN 00G4252-N0) HPLC: solvent 40% acetonitrile in 0.1% aqueous trifluoroacetic acid HPLC: flow rate 4.0 ml/min flask for dilution 30 ml distilled water Cartridge Phenomenex Strata C18-U (55 µm, 7θΑ), 100 mg/1 ml vial (PN 8B-S002-EAK.) Before use, the cartridge is activated with using: 1) 5 ml ethanol 2) 10 ml distilled water Bottle 5 (V5) 1 ml ethanol bottle for product 4 ml sodium chloride solution in water (0.9%)

An aqueous solution of [ ¹⁸ F] fluoride (2.0 ml, 59.2 GBq/1.6 Ci) was added to a Sep-Pak QMA Light (46 mg) cartridge that had been pre-activated. After completion of the transfer, aqueous [ ¹⁸ F] fluoride was released from the QMA Sep-Pak by adding the elution mixture (from V1) to the reactor. The solvent was evaporated under a gentle flow of nitrogen and then under vacuum. Then, a solution containing the precursor (V2) was added to the dried [ ¹⁸ F] fluoride, and the mixture was heated for 30 min at 110°C. The mixture was then diluted with distilled water (2.5 ml) and acetonitrile (1.5 ml) (from V4) and transferred to an intermediate vial (Pre-HPLC).

This mixture was then injected into a 5 ml sample loop dispenser and then into a semi-preparative HPLC column. The column was washed with a mixture of 40% acetonitrile in 0.1% aqueous trifluoroacetic acid at a rate of 4.0 ml/min, under a pressure of 1850 psi (12.76x106 Pa), UV 220 nm. The product was collected over a range of 22 to 24 minutes in a dilution flask which contained 30 ml of distilled water. The entire content was transferred to a C18 SPE cartridge (pre-activated), which was then washed with 1 ml ethanol (from V5) into a product vial containing 4 ml aqueous sodium chloride solution to obtain 20% ethanol in aqueous sodium chloride solution for sample injection. . The activity of [ ¹⁸ F](R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin4-yl)cyclohexyl)propanamide was 31.2 mCi (1.15 GBq).

This product was analyzed using reverse phase HPLC and chemically identified.

- 37 043098 were cited by introducing together with (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide as a non-radioactive reference sample, radiochemical purity, chemical purity and specific activity were determined. The isolated product, which was eluted with the non-radioactive reference sample at 16 minutes, had a radiochemical purity of 99%, a chemical purity of 95%, a specific activity of 0.38 GBq/nmol (10.47 mCi/nmol). The chiral purity of this product was analyzed using chiral HPLC by adding (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide (10 min) and (S)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide (11.5 min) as non-radioactive samples for comparison . The isolated product, eluted with the non-radioactive reference sample at 10 minutes, had an enantiomeric excess of >99.5%.

Claims (15)

1. A process for preparing a compound of formula I or a stereoisomer thereof: o comprising contacting a compound of formula II or a stereoisomer thereof: where R1 is C _1-6 alkyl, aryl selected from phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl and tetrahydronaphthyl, or C _1-6 haloalkyl; with a mixture of C _1-6 alkoxide salt and di-C _1-6 alkyl malonate in a suitable organic solvent to replace the sulfonate group and form a compound of formula III or a stereoisomer thereof: With ι-valalkyl x and contacting the compound of formula III or its stereoisomer with a suitable organic acid in a suitable aqueous organic solvent for hydrolysis and decarboxylation and obtain a compound of formula I or its stereoisomer, where the C _1-6 alkoxide salt is selected from sodium amylate (NaOC(CH ₃ ) ₂ CH ₂ CH ₃ ), potassium amylate, NaOC(CH ₃ ) ₃ , KOS(CH ₃ ) ₃ , lithium amylate and LiOC(CH ₃ ) ₃ ; di-C _1-6 alkyl malonate is selected from di-t-butyl malonate, di-methyl malonate, di-ethyl malonate and di-isopropyl malonate; a suitable organic solvent is selected from toluene, anisole, tetrahydrofuran, dimethoxyethane, dioxane, t-amyl alcohol and N-methyl-2-pyrrolidone; suitable organic acid is selected from methanesulfonic acid, trifluoroacetic acid and mixtures thereof. 2. The method according to claim 1, wherein the C _1-6 alkoxide salt is sodium t-amylate and the di-C _1-6 alkyl malonate is di-t-butyl malonate. 3. Process according to claim 1 or 2, characterized in that the organic acid is methanesulfonic acid. 4. The method according to any one of the preceding claims, characterized in that R1 is methyl. 5. Process according to any one of the preceding claims, characterized in that a compound of formula II or a stereoisomer thereof is obtained by contacting a compound of formula IV - 38 043098 with a Lewis acid and a source of hydride in a suitable alcoholic organic solvent to reduce the carbonyl and form a compound of formula V or a stereoisomer thereof: and contacting the compound of formula V or its stereoisomer with X-SO2-R1, X is a halogen atom, or with R1-SO ₂ -O-SO ₂ -R1 in the presence of an alkyl amine base in a suitable anhydrous organic solvent to displace X to form a compound of formula II or a stereoisomer thereof; where R1 has the meanings as defined in clause 1; the Lewis acid is selected from calcium halides, lithium halides, magnesium halides, zinc halides, cerium halides and their hydrates; the hydride source is selected from NaBH4, LiAlH4, diisobutylaluminum hydride, NaCNBH4 and NaH; a suitable alcoholic organic solvent is selected from methanol, ethanol, isopropanol and mixtures thereof; the alkylamine base is selected from trimethylamine and N,N-diisopropylethylamine; a suitable anhydrous organic solvent is selected from dichloromethane, toluene, anisole, acetonitrile and isopropyl acetate. 6. The method of claim 5, wherein the Lewis acid is CeCl ₃ or a hydrate thereof and the hydride source is NaBH 4 . 7. Method according to claim 5 or 6, characterized in that X is Cl and R1 is methyl. 8. The method according to any one of claims 5 to 7, characterized in that the alkyl amine base is trimethylamine. 9. The method according to any one of claims 5 to 8, characterized in that the compound of formula IV is obtained by contacting a compound of formula VI-A or VI-B: W η Ci-balkyl O. .O-Cmalkyl C(O)OC1-balkyl yj e C(O)OC1-balkyl ... V1-D, where n is 1 or 2, with a compound of formula VII where Y represents a halogen atom, in the presence of a suitable C ₁ . ₆ alkylsilylamine base in a suitable organic solvent to displace Y to form a compound of formula VIII-A or formula VIII-B: and contacting a compound of formula VIII-A or formula VIII-B with a suitable hydroxide base in a suitable aqueous solvent for hydrolysis to form a compound of formula IX-A or formula IX-B: - 39 043098 contacting a compound of formula IX-A or formula IX-B with a suitable inorganic acid in a suitable aqueous solvent for hydrolysis and decarboxylation to form a compound of formula IV; where is the appropriate C1. _{The 6} alkylsilylamine base is hexamethyldisilazane sodium salt (NaHMDS); a suitable organic solvent is selected from toluene, anisole, dimethylformamide, tetrahydrofuran and mixtures thereof; suitable hydroxide base is selected from KOH, NaOH and mixtures thereof; a suitable aqueous solvent is water and one or more organic solvents selected from ethanol, toluene, anisole, dimethylformamide, tetrahydrofuran, and mixtures thereof; the suitable inorganic acid is selected from HCl, HBr, H ₂ SO ₄ , HNO ₃ , H ₃ PO ₄ and combinations thereof. 10. The method according to claim 9, characterized in that η has a value of 1. 11. Method according to claim 9 or 10, characterized in that Υ is C1. 12. The method according to any one of claims 9-11, characterized in that the hydroxide base is KOH or NaOH. 13. The method according to any one of claims 9 to 12, characterized in that the inorganic acid is HCl. 14. The method according to any one of the preceding claims, characterized in that the compound of formula I is about 15. The method according to any one of the preceding claims, characterized in that the compound of formula II is where Ri has values as defined in π. 1.