Process for the preparation of phenyltetrahydrofuran compounds

Abstract

Phenyltetrahydrofuran compounds useful as intermediates in the preparation of pharmaceutical compounds are provided, and further methods for the preparation of phenyltetrahydrofuran compounds are provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 268,652, filed February 28, 2022, the entire contents of which are incorporated herein by reference. [Technical field]

[0002] Field of the Disclosure The field of the disclosure relates generally to phenyltetrahydrofuran compounds that are useful as intermediates in the preparation of pharmaceutical compounds and methods for the preparation of phenyltetrahydrofuran compounds. [Background technology]

[0003] Short Description Methods useful for the preparation of certain substituted 2-phenyltetrahydrofuran intermediate compounds are known from U.S. Pat. No. 10,710,994. Examples of such intermediates include the following compounds: An example is TIFF2025508888000001.tif35170.

[0004] However, multiple work-up steps and chromatographic purification of certain intermediates of the above compounds are disclosed, and the overall yields are relatively low.

[0005] Thus, there is a need for improved methods for preparing substituted phenyltetrahydrofuran compounds for use in the preparation of TRPA1 inhibitors, as described in U.S. Pat. No. 10,710,994. Summary of the Invention

[0006] Short Description In some embodiments, the present disclosure provides a compound (3): TIFF2025508888000002.tif42170, comprising: step 2: forming a reaction mixture comprising CO, H, a rhodium catalyst, a ligand, a solvent, and compound (2); and reacting the reaction mixture to form a reaction product mixture comprising compound (3), wherein compound (2) has the structure: TIFF2025508888000003.tif33170, where each * independently represents a chiral center; 1 ~R 5 is independently selected from hydrogen, halo, cyano, unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, and substituted C1-C6 alkoxy; 1 ~R 5 is halo, and the at least one halo is selected from Cl and F.

[0007] In some other aspects, the present disclosure provides a compound (4): TIFF2025508888000004.tif49170, comprising: step 3: forming a reaction mixture comprising a hydroxylamine solution, a solvent, and compound (3); and reacting the reaction mixture to form a reaction product mixture comprising compound (4), compound (3) having the structure: TIFF2025508888000005.tif42170, where each * independently represents a chiral center; E / Z represents an E / Z isomer; R 1 ~R 5 is independently selected from hydrogen, halo, cyano, unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, and substituted C1-C6 alkoxy; 1 ~R 5 is halo, and the at least one halo is selected from Cl and F.

[0008] In some other aspects, the disclosure provides a compound of the structure: TIFF2025508888000006.tif40170, or a salt thereof, wherein each * independently represents a chiral center; R 1 ~R 5 is independently selected from hydrogen, halo, cyano, unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, and substituted C1-C6 alkoxy; 1 ~R 5 is halo, and at least one halo is selected from Cl and F, or a salt thereof.

[0009] In some other aspects, the disclosure provides a compound of the structure: TIFF2025508888000007.tif47170, or a salt thereof, wherein each * independently represents a chiral center; E / Z represents an E / Z isomer; R 1 ~R 5 is independently selected from hydrogen, halo, cyano, unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, and substituted C1-C6 alkoxy; 1 ~R 5 is halo, and at least one halo is selected from Cl and F, or a salt thereof.

[0010] In some other aspects, the disclosure provides a compound of the structure: TIFF2025508888000008.tif47170, or a salt thereof, wherein each * independently represents a chiral center; R 1 ~R 5 is independently selected from hydrogen, halo, cyano, unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, and substituted C1-C6 alkoxy; 1 ~R 5 is halo, and at least one halo is selected from Cl and F, or a salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Detailed Description Reference will now be made in detail to certain embodiments of the present disclosure, examples of which are illustrated in the accompanying structures and formulas. It will be understood that although the present disclosure will be described in conjunction with the enumerated embodiments, they are not intended to limit the present disclosure to these embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications and equivalents that may be included within the scope of the present disclosure as defined by the claims. Those skilled in the art will recognize numerous methods, processes and materials similar or equivalent to those described herein that can be used to implement the present disclosure. The present disclosure is in no way limited to the methods, processes and materials described. In the event that one or more of the incorporated literature, patents and similar materials differs from or contradicts this application, including but not limited to defined terms, usage of terms, techniques described, etc., this application shall prevail. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Although methods, processes and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods, processes and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0012] In some aspects, the present disclosure provides improved methods for preparing the compounds disclosed herein. Among other advantages, compared to known methods, the present disclosure allows for the elimination of a chromatographic purification step, preserving compound purity and allowing for improved yields.

[0013] definition

[0014] As used herein, the term "alkyl," alone or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon group. The number of carbons may be 1-20, 1-12, 1-8, 1-6, or 1-4, as appropriate. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. The term "alkenyl" refers to an unsaturated alkyl group having one or more double bonds. Similarly, the term "alkynyl" refers to an unsaturated alkyl group having one or more triple bonds. Non-limiting examples of such unsaturated alkyl groups include straight chain and branched groups including vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, and 3-butynyl, as well as the higher homologs and isomers.

[0015] The terms "alkoxy," "alkylamino," and "alkylthio" are used in their conventional sense to refer to an alkyl group that is appended to the remainder of the molecule through an oxygen atom ("oxy"), an amino group ("amino"), or a thio group, and further include mono- and poly-halogenated variants thereof. Additionally, for dialkylamino groups, the alkyl portions may be the same or different.

[0016] The terms “cycloalkyl” and “cycloalkylene” refer to monocyclic or bicyclic (including bridged bicyclic) rings and saturated or partially unsaturated carbocyclic moieties having 3 to 10 carbon atoms in the ring (i.e., (C 10(C-C)cycloalkyl). The cycloalkyl moiety may be optionally substituted with one or more substituents. In certain embodiments, the cycloalkyl contains 3 to 8 carbon atoms (i.e., (C-C)cycloalkyl). In other certain embodiments, the cycloalkyl contains 3 to 6 carbon atoms (i.e., (C-C)cycloalkyl). Non-limiting examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, as well as their partially unsaturated (cycloalkenyl) derivatives (e.g., cyclopentenyl, cyclohexenyl, and cycloheptenyl).

[0017] The terms "heterocyclyl" and "heterocycloalkylene" refer to 4-, 5-, 6-, and 7-membered monocyclic heterocyclic moieties, or 7-, 8-, 9-, and 10-membered bicyclic or polycyclic (including bridged bicyclic) heterocyclic moieties that are saturated or partially unsaturated and have one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from phosphorus, oxygen, nitrogen, and sulfur in the ring, and the remaining ring atoms are carbon. In some embodiments, a "heterocyclyl" or "heterocycloalkylene" group has 4 to 10 ring atoms, including 1, 2, 3, or 4 heteroatoms selected from P, N, O, and S, and the remaining ring atoms are carbon.

[0018] The term "aryl" refers to a cyclic aromatic hydrocarbon moiety having a monocyclic, bicyclic, or tricyclic aromatic ring of 5 to 16 carbon ring atoms. Bicyclic aryl ring systems include fused bicycles having two fused 5-membered aryl rings (designated 5-5), fused bicycles having a 5-membered aryl ring and a fused 6-membered aryl ring (designated 5-6), and bicycles having two fused 6-membered aryl rings (designated 6-6). The aryl group may be optionally substituted as defined herein. Non-limiting examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, indenyl, pentalenyl, and azulenyl. In some embodiments, the aryl group has 6 to 10 carbon ring atoms. In some embodiments, the aryl group has 6 to 12 carbon ring atoms.

[0019] The term "heteroaryl" may refer to an aromatic heterocyclic monocyclic or bicyclic ring system of 5 to 12 ring atoms containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon. Bicyclic heteroaryl ring systems include fused bicycles having two fused 5-membered heteroaryl rings (designated 5-5), fused bicycles having a 5-membered heteroaryl ring and a fused 6-membered heteroaryl ring (designated 5-6), and fused bicycles having two fused 6-membered heteroaryl rings (designated 6-6). Heteroaryl groups may be optionally substituted as defined herein. Non-limiting examples of heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, and benzothiazolyl. , benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, purinyl, pyridopyrimidinyl, pyrrolopyrimidinyl, imidazotriazinyl, pyrazolopyrimidinyl, pyrimidopyridazinyl, pyrimidopyrimidinyl, thiazolopyrimidinyl, pyrazolopyridinyl, imidazopyridazinyl, pyridopyrazinyl, triazolopyrimidinyl, isoxazolopyrimidinyl and quinoxalinyl.

[0020] Substituted and unsubstituted alkyl, alkenyl, alkoxy, alkylamino and alkylthio moieties may optionally contain one or more heteroatoms. As used herein, the term heteroatom is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

[0021] Substituents for the alkyl, alkenyl, alkoxy, alkylamino, alkylthio, cycloalkyl, cycloalkylene, heterocyclyl, heterocycloalkylene, aryl and heteroaryl groups are selected from the group consisting of -halogen, =O, -OR', -NR'R'', -SR', -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -CONR'R'', -OC(O)NR'R'', -NR''C(O )R', -NR'''C(O)NR'R'', -NR''C(O)2R', -NHC(NH2)=NH, -NRC(NH2)=NH, -NHC(NH2)=NR', -NR'''C(NR'R'')=N-CN, -NR'''C( NR'R'')=NOR', -NHC(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NR'S(O)2R'', -NR'''S(O)2NR'R'', -CN, -NO2, -(CH2) 1~4 -OR', -(CH2) 1~4 -NR'R'', -(CH2) 1~4 -SR', -(CH2) 1~4 -SiR'R''R''', -(CH2) 1~4 -OC(O)R', -(CH2) 1~4 -C(O)R', -(CH2) 1~4 -CO2R' and -(CH2) 1~4 CONR' can be a variety of groups including, but not limited to, R'R'', where m' is the total number of carbon atoms in such group. R', R'', and R''' can each be independently selected from, for example, hydrogen, unsubstituted C, C, C' ... 1~6 Alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C 1~6 Alkyl, C 1~6 Alkoxy or C 1~6 Thioalkoxy group or unsubstituted aryl-C 1~4It refers to groups including alkyl groups, unsubstituted heteroaryl and substituted heteroaryl. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6- or 7-membered ring. For example, -NR'R'' is meant to include 1-pyrrolidinyl and 4-morpholinyl. Other substituents for alkyl groups, including heteroalkyl, alkylene, include, for example, =O, =NR', =N-OR', =N-CN and =NH, where R' includes the above substituents. Substituents for alkyl groups (including groups often referred to as alkylene, alkenyl, alkynyl, heteroalkyl and cycloalkyl) can be alkylene, alkenylene or alkynylene linkers (e.g., for alkylene, -(CH2) 1~4 When the linker contains -NR'R'', the alkylene linker also includes halo variants. For example, the linker "-(CH2) 1~4 "-" is meant to include difluoromethylene, 1,2-difluoroethylene, and the like.

[0022] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, "C 1~4 The term "haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, and the like. As used herein, the term "(halo)alkyl" includes optionally halogenated alkyl. Thus, the term "(halo)alkyl" includes both alkyl and haloalkyl (e.g., monohaloalkyl and polyhaloalkyl). In some embodiments, a haloalkyl is a C1-C6 haloalkyl. In some embodiments, a haloalkyl is a C1-C4 haloalkyl.

[0023] Examples of oxidizing agents within the scope of the present disclosure include N-bromosuccinimide; N-chlorosuccinimide; N-iodosuccinimide; N-chlorosuccinimide; NaOCl; chloramine-T hydrate; 1,3-dichloro-5,5-dimethylhydrantoin; 2-chlorobenzo[d]isothiazol-3(2H)one 1,1-dioxide; CCl4; CCl3Br; CB4; tetraiodomethane; CHI3; C2Cl6; hexachloroacetonitrile. The oxidizing agent includes, but is not limited to, N-chlorosuccinimide, NaOCl, chloramine-T hydrate, 1,3-dichloro-5,5-dimethylhydantoin, and 2-chlorobenzo[d]isothiazol-3(2H)one 1,1-dioxide.

[0024] As used herein, the term "solvent" refers to both polar aprotic solvents, polar protic solvents and nonpolar solvents.

[0025] As used herein, the term "non-polar solvent" refers to a solvent characterized by having a low dielectric constant. Examples include, but are not limited to, pentane (e.g., n-pentane), hexane (e.g., n-hexane), heptane (e.g., n-heptane), cyclopentane, methyl tert-butyl ether (MTBE), diethyl ether, toluene, benzene, 1,4-dioxane, carbon tetrachloride, chloroform, and dichloromethane (DCM). In some embodiments, non-polar solvents have a dielectric constant of less than 2, examples of which include, but are not limited to, n-pentane, n-hexane, and n-heptane. Compared to other non-polar solvents, DCM exhibits some polarity at the bond level (i.e., between carbon and chlorine), but only a little polarity at the molecular level due to the offset based on polar symmetry.

[0026] As used herein, the term "polar aprotic solvent" refers to any polar solvent that does not have proton-donating ability. Examples include, but are not limited to, 2-methyltetrahydrofuran, tetrahydrofuran, ethyl acetate, propyl acetate (e.g., isopropyl acetate, iPrOAc), acetone, dimethylsulfoxide, N,N-dimethylformamide, acetonitrile (CH3CN), N,N-dimethylacetamide, N-methylpyrrolidone (NMP), hexamethylphosphoramide, and propylene carbonate.

[0027] As used herein, the term "polar protic solvent" refers to any polar solvent that has proton-donating capability. Examples include, but are not limited to, water; C 2 -based solvents such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and 1-pentanol; 1~5 alcohol; formic acid; nitromethane; and acetic acid.

[0028] As used herein, the term "polar organic solvent" refers to both polar aprotic solvents and polar protic solvents excluding water.

[0029] As used herein, the term "anti-solvent" refers to a solvent in which the referenced compound is poorly soluble and which induces precipitation or crystallization of said compound from solution.

[0030] As used herein, the term "organic base" refers to an organic compound that contains one or more nitrogen atoms and acts as a base. Examples of organic bases include, but are not limited to, tertiary amine bases. Examples of organic bases include, but are not limited to, N-methyl-morpholine (NMM), triethylamine (TEA), N,N'-diisopropylethylamine (DIPEA) and 1,4-diazabicyclo[2.2.2]octane. In some embodiments, the organic base is DIPEA.

[0031] As used herein, the term "salt" is meant to include salts of active compounds (e.g., pharmaceutically acceptable salts) prepared using relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganous, manganous, potassium, sodium, zinc, etc. Salts derived from pharma- ceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, neat or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and the like, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like.Also included are salts of amino acids, such as arginates, and salts of organic acids, such as glucuronic or galactunoric acids (see, for example, Berge, SM et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0032] The neutral forms of the compounds of the present disclosure may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to the parent form of the compound for purposes of this disclosure.

[0033] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, positional isomers and individual isomers (e.g., separate enantiomers) are all intended to be embraced within the scope of the present disclosure.

[0034] As used herein, the term "chiral" refers to a molecule that has the property of not being superimposable on its mirror image partner, while the term "achiral" refers to a molecule that is superimposable on its mirror image partner.

[0035] As used herein, the term "chiral purity" refers to the mole percent of one chiral compound based on the total moles of chiral compounds.

[0036] As used herein, the term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0037] As used herein, the term E / Z refers to the IUPAC isomerism rules in which the substituents at each end of a double bond are assigned a priority based on their atomic number: if the higher priority substituents are on the same side of the bond, Z is assigned, and if the higher priority substituents are on opposite sides of the bond, E is assigned.

[0038] In the structures shown herein where the stereochemistry of any particular chiral atom is not specified, all stereoisomers are contemplated and included as compounds of the present disclosure. When stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, that stereoisomer is so specified and defined. Unless otherwise stated, when a solid wedge or dashed line is used, relative stereochemistry is intended.

[0039] In the description herein, if there is a discrepancy between a depicted structure and a name given to that structure, the depicted structure controls.

[0040] As used herein, the term "reaction mixture" refers to a mixture of reactants. As used herein, the term "reaction product mixture" refers to a mixture of reaction products formed from the reaction mixture.

[0041] As used herein, "leaving group" refers to an atom or group of atoms that are removed as a stable species in a chemical reaction. Suitable leaving groups are well known in the art, see, for example, March's Advanced Organic Chemistry, 5th Ed., Ed. Smith, MB and March, J., John Wiley & Sons, New York: 2001 and TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991, the entire contents of each of which are incorporated herein by reference. Such leaving groups include, but are not limited to, halogen, alkoxy, sulfonyloxy, optionally substituted alkylsulfonyl, optionally substituted alkenylsulfonyl, optionally substituted arylsulfonyl and diazonium moieties. Some examples of leaving groups include chloro, iodo, bromo, fluoro, methanesulfonyl (mesyl), tosyl, trifluoromethanesulfonate (i.e., triflate), nitro-phenylsulfonyl (nosyl) and bromo-phenylsulfonyl (brosyl).

[0042] As used herein, the terms "predominantly" and "substantially" refer to greater than 50%, at least 75%, at least 90%, at least 95%, or at least 99% on a population %, w / w%, w / v%, v / v%, or molar % basis.

[0043] As used herein, unless otherwise indicated, the term "percent yield" refers to the yield on a molar basis for the indicated reaction calculated from the actual yield to the theoretical yield based on a non-stoichiometric excess of reactants. For example, when 1.0 mole of compound A is reacted with 1.1 molar equivalents of compound B to form 0.9 moles of compound C, the percent yield (based on compound A) is (0.9) / (1.0)×100=90%.

[0044] As used herein, the term "purity" refers to the amount of a compound in a sample compared to the total amount of the compound in the sample, unless otherwise specified. In some embodiments, purity can be measured by high pressure liquid chromatography (HPLC) analysis, where the area percentage of the product represents the purity.

[0045] As used herein, the term "area percent" or "area %" with respect to purity refers to the area percent of a compound's peak in a chromatogram (such as an HPLC chromatogram) as a percentage of the total area of ​​all peaks.

[0046] It should be readily understood that where the applicant has defined an embodiment or portions thereof using non-limiting terms such as "comprising," the statement (unless otherwise expressly stated) should be construed to also describe such embodiments using the terms "consisting essentially of" or "consisting of."

[0047] The transitional phrase "consisting essentially of" is used to define a composition, method, or process that includes materials, steps, features, components, or elements in addition to those literally disclosed, but these additional materials, steps, features, components, or elements do not materially affect the basic and novel characteristics of the claim.

[0048] As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains," "containing," "characterized by," or any other variations thereof, are intended to include a non-exclusive inclusion, subject to any limitations expressly stated. For example, a composition, mixture, process, or method that includes a list of elements is not necessarily limited to only those elements and may include other elements not expressly listed or inherent to such composition, mixture, process, or method.

[0049] When referring to the number of substituents, the terms "at least one" and "one or more" refer to a range from one substituent to the maximum number of substitutions possible, i.e., from the replacement of one hydrogen to the replacement of all hydrogens with a substituent. The term "substituent" refers to an atom or group of atoms that replaces a hydrogen atom of the parent molecule. The term "substituted" refers to the specified group carrying one or more substituents. When any group may have multiple substituents and a variety of possible substituents are provided, the substituents are independently selected and need not be the same. The term "unsubstituted" means that the specified group does not carry any substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents independently selected from a group of possible substituents. When referring to the number of substituents, the terms "at least one" and "one or more" refer to a range from one substituent to the maximum number of substitutions possible, i.e., from the replacement of one hydrogen to the replacement of all hydrogens with a substituent.

[0050] As used herein, the indefinite articles "a" and "an" preceding an element or component of the disclosure are intended to be non-limiting with respect to the number of instances (i.e., occurrences) of the element or component. Thus, "a" or "an" should be read to include one or at least one, and the singular form of an element or component also includes the plural, unless the number is clearly meant to be singular.

[0051] Preparation of compound (3)

[0052] One embodiment of the present disclosure relates to a method for preparing compound (3) by a hydroformylation reaction, the method comprising: Step 2: forming a reaction mixture comprising CO, H, a rhodium catalyst, a ligand, a solvent, and compound (2) and reacting the resulting mixture with the following reaction scheme: and reacting the reaction mixture according to TIFF2025508888000009.tif43170 to form a reaction product mixture comprising compound (3), wherein each * independently represents a chiral center, R 1 ~R 5 each is independently selected from hydrogen; halo; cyano; unsubstituted and substituted alkyl; unsubstituted and substituted alkenyl; unsubstituted and substituted alkoxy; unsubstituted and substituted alkylamino; and unsubstituted and substituted alkylthio; 1 ~R 5 at least one of is halo, and the at least one halo is selected from Cl and F. In some embodiments, each of the unsubstituted and substituted alkyl, unsubstituted and substituted alkenyl, unsubstituted and substituted alkoxy, unsubstituted and substituted alkylamino, and unsubstituted and substituted alkylthio, independently, contains 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In some embodiments, R 1 ~R 5is independently selected from hydrogen, halo, cyano, unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, and substituted C1-C6 alkoxy; 1 ~R 5 at least one of is halo, and the at least one halo is selected from Cl and F.

[0053] R 1 ~R 5 In some embodiments where at least one of R is halo, at least one of R is Cl. 1 ~R 5 In some embodiments, at least one of R is halo, at least one of R is F. 1 , R 2 , R 3 and R 4 is hydrogen, and R 5 is Cl or F. In some embodiments, R 1 , R 2 , R 3 , and R 4 is hydrogen, and R 5 is Cl. In some embodiments, R 1 , R 2 , R 3 and R 4 is hydrogen, and R 5 is F.

[0054] Rhodium catalysts within the scope of the present disclosure are provided in the form of a compound such as a hydride, a halide, an organic acid salt, a ketonate, an inorganic acid salt, an oxide, a carbonyl compound or an amine compound, or a combination of two or more thereof. In some embodiments, the catalyst is a rhodium carbonyl catalyst. In some embodiments, the catalyst is a Rh(I) complex. Non-limiting examples of Rh(I) complexes include Rh(acac)(CO), Rh(acac)(PPh)(CO), Rh(acac)((R)-Ph-BPE, Rh(acac)(C2H)2, Rh(acac)(C8H) 14)2 (acetylacetonate(cyclooctene)rhodium(I)), Rh(acac)(COD), bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate, bis(norbornadiene)rhodium(I) tetrafluoroborate, chlorobis(cyclooctene)rhodium(I) dimer, Rh2Cl2(C2H4)4, Rh2Cl2(CO)4, chloronorbornadienerhodium(I) dimer, bis(triphenylphosphine)rhodium carbonyl chloride, RhCl(PPh3)3 and methoxy(cyclooctadiene)rhodium(I) dimer, or a combination of two or more thereof. As used herein, "acac" is an acetylacetonate group; "OAc" is an acetyl group; "COD" is 1,5-cyclooctadiene; and "Ph" is a phenyl group.

[0055] In some embodiments of the present disclosure, the catalyst is a rhodium carbonyl catalyst. In one embodiment, the rhodium catalyst is dicarbonyl(acetylacetonato)rhodium. In another embodiment, the rhodium catalyst is Rh(acac)(PPh3)(CO).

[0056] In some embodiments, the mol% ratio of rhodium catalyst to compound (2) is suitably about 0.1 mol%, about 0.25 mol%, about 0.5 mol%, about 0.75 mol%, about 1 mol%, about 1.25 mol%, about 1.5 mol%, about 1.75 mol%, or about 2 mol%, and any ranges building therein, such as about 0.1 mol% to about 2 mol%, about 0.5 mol% to about 2 mol%, about 0.5 mol% to about 1.5 mol%, or about 0.75 mol% to about 1.25 mol%.

[0057] In some embodiments of the present disclosure, rhodium catalyst ligands within the scope of the present disclosure include, for example, but are not limited to, mono- and bis-phosphines, mono- and bis-phosphonites, mono- and bis-phosphites, mono- and bis-phosphinites, mono- and bis-phosphoramidites, and mixed phosphoramidite-phosphine ligands. In some embodiments, the ligands are selected from mono- and bis-phosphines, mono- and bis-phosphonites, and mono- and bis-phosphites.

[0058] One example of a class of ligands suitable for practicing the present disclosure is the BPE family of ligands. Some such ligands have the structure: TIFF2025508888000010.tif24170, where each R is selected from methyl, ethyl, i-propyl, and phenyl. Non-limiting examples of BPE ligands include (R,R)-Me-BPE, (S,S)-Me-BPE, (R,R)-Et-BPE, (S,S)-Et-BPE, (R,R)-Ph-BPE, (S,S)-Ph-BPE, (R,R)-i-Pr-BPE, and (S,S)-i-Pr-BPE. In one embodiment, the BPE ligand is (R,R)-Ph-BPE.

[0059] Another example of a class of ligands suitable for practicing the present disclosure is the DuPhos family of ligands. Some such ligands have the structure: TIFF2025508888000011.tif24170, where each R is selected from methyl, ethyl, and i-propyl. Non-limiting examples of DuPhos ligands include (R,R)-Me-DuPhos, (S,S)-Me-DuPhos, (R,R)-Et-DuPhos, (S,S)-Et-DuPhos, (R,R)-i-Pr-DuPhos, and (S,S)-i-Pr-DuPhos.

[0060] Another example of a class of ligands suitable for practicing the present disclosure is the bisdiazaphos family of ligands. Some such ligands have the structure: TIFF2025508888000012.tif38170, wherein each R is H or the structure: TIFF2025508888000013.tif24170 bis[(S,S,S)-diazaphos-SPE]

[0061] Another example of a class of ligands suitable for the practice of the present disclosure is the IndolPhos family of ligands. One non-limiting example of such a ligand is: TIFF2025508888000014.tif32170, where each R is C1-C6 alkyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylene, 4-10 membered heterocyclyl having 1, 2, 3 or 4 heteroatoms selected from P, N, O and S, 4-10 membered heterocycloalkylene having 1, 2, 3 or 4 heteroatoms selected from P, N, O and S, C6-C 10 aryl, and 5-10 membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, S and N, each of which may be independently substituted or unsubstituted. In some embodiments, each R is independently selected from methyl, ethyl, i-propyl and phenyl. In one embodiment, each R is methyl. In some embodiments, each R' is independently selected from methyl, ethyl, i-propyl and phenyl. In one embodiment, each R' is i-propyl. In one embodiment, each R is methyl and each R' is i-propyl.

[0062] Another example of a class of ligands suitable for the practice of the present disclosure is the ferrocene family of ligands. One non-limiting example of such a ligand is: TIFF2025508888000015.tif32170, where each R is selected from methyl, ethyl, i-propyl, and phenyl; or two R groups, taken together with the P to which they are attached, form a 3-, 4-, 5-, or 6-membered ring substituted with two R', where each R' is independently selected from methyl and ethyl. In some embodiments, each R' is methyl. In some embodiments, each R' is ethyl. In one aspect, each R is i-Pr and the ligand is dppf. In some embodiments, two R groups, taken together with the P to which they are attached, form a 4-membered ring substituted with two ethyl groups. In some embodiments, where two R groups, taken together with the P to which they are attached, form a 4-membered ring substituted with two ethyl groups, the ligand is (R,R)-Et-FerroTANE. In some embodiments where two R groups, taken together with the P to which they are attached, form a four-membered ring substituted with two ethyl groups, the ligand is (S,S)-Et-FerroTANE. In some embodiments where two R groups, taken together with the P to which they are attached, form a five-membered ring substituted with two methyl groups. In some embodiments where two R groups, taken together with the P to which they are attached, form a five-membered ring substituted with two methyl groups, the ligand is (R,R)-Me-Ferrocerane. In some embodiments where two R groups, taken together with the P to which they are attached, form a five-membered ring substituted with two methyl groups, the ligand is (S,S)-Me-Ferrocerane. In some embodiments where two R groups, taken together with the P to which they are attached, form a five-membered ring substituted with two ethyl groups. In some embodiments where two R groups, together with the P to which they are attached, form a five-membered ring substituted with two ethyl groups, the ligand is (R,R)-Et-ferrocerane. In some embodiments where two R groups, together with the P to which they are attached, form a five-membered ring substituted with two ethyl groups, the ligand is (S,S)-Et-ferrocerane.

[0063] Another example of a class of ligands suitable for the practice of the present disclosure is the xanthene family of ligands. One non-limiting example of such a ligand is: TIFF2025508888000016.tif22170, where each R is C1-C6 alkyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylene, 4-10 membered heterocyclyl having 1, 2, 3 or 4 heteroatoms selected from P, N, O and S, 4-10 membered heterocycloalkylene having 1, 2, 3 or 4 heteroatoms selected from P, N, O and S, C6-C 10 aryl, and 5-10 membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, S and N, each of which may be independently substituted or unsubstituted; R' and R'' are independently selected from methyl, ethyl, i-propyl, t-butyl, phenyl, Me2P-, Et2P-, i-Pr2P-, t-Bu2P-, Ph2P-, Structure (I): TIFF2025508888000017.tif68170, wherein each R''' is independently selected from hydrogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylene, 4-10 membered heterocyclyl having 1, 2, 3 or 4 heteroatoms selected from P, N, O and S, 4-10 membered heterocycloalkylene having 1, 2, 3 or 4 heteroatoms selected from P, N, O and S, C6-C 10 aryl, and 5-10 membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, S and N, each of which may be independently substituted or unsubstituted. In some aspects, each R is independently selected from methyl, ethyl, i-propyl, t-butyl and phenyl. In one aspect, each R is t-butyl. In one aspect, each R"' is independently selected from hydrogen, methyl, ethyl, i-propyl and phenyl. In some embodiments, each R"' is independently selected from hydrogen, methyl and phenyl.

[0064] In one embodiment, each R is t-butyl. In one embodiment, R' is phenyl. In one embodiment, R' is -P(Ph)2. In one embodiment, R" is of structure (I) above and each R'" is phenyl. In one embodiment, each R is t-butyl, R' is phenyl, R" is of structure (I) above and each R'" is phenyl. In one embodiment, each R is t-butyl, R' is -P(Ph)2, R" is of structure (I) above and each R'" is phenyl.

[0065] In some embodiments, the equivalent ratio of ligand to rhodium catalyst is suitably about 1.1:1, about 1.5:1, about 1.75:1, about 2:1, about 2.25:1, about 2.5:1, about 2.75:1 or about 3:1, and any ranges built therein, such as from about 1.1:1 to about 3:1, from about 1.5:1 to about 2.5:1 or from about 1.75:1 to about 2.25:1.

[0066] In some embodiments, the solvent comprises primarily at least one non-polar solvent, hi some embodiments, the solvent comprises primarily toluene.

[0067] In some embodiments, the reaction pressure is about 1 bar, about 2 bar, about 3 bar, about 4 bar, about 5 bar, about 6 bar, about 7 bar, about 10 bar, about 15 bar, or about 20 bar, and any range constructed therein, such as about 1 bar to about 20 bar, about 4 bar to about 15 bar, or about 5 bar to about 10 bar.

[0068] In some embodiments, the reaction temperature is suitably about 20° C. to reflux. For example, without limitation, in some embodiments, when the solvent comprises primarily toluene, the reaction temperature is about 20° C. to reflux, about 50° C. to reflux, about 50° C. to about 100° C., or about 70° C. to about 90° C.

[0069] In some embodiments, the reaction product mixture comprises compound (3) in solution. In such embodiments, the solution of compound (3) can be used directly in a subsequent reaction.

[0070] In some aspects, the solution of compound (3) may be worked up by, for example, but not limited to, one or more of: filtration; treatment with a metal scavenger; washing with an aqueous phase (e.g., a brine solution); neutralization with an aqueous solution of an acid or base; solvent exchange; phase separation; treatment with an oxidizing agent; crystallization or precipitation by addition of an anti-solvent and optionally seeding and cooling; evaporation; distillation; and drying. In some aspects, compound (3) may be optionally isolated from the reaction product mixture by precipitation and / or crystallization, for example, by one or more of the following: addition of an anti-solvent; cooling; pH adjustment; and seeding, to form a slurry. In some embodiments, solid compound (3) may be suitably isolated from the slurry by, for example, filtration or centrifugation, and optionally washed and optionally dried.

[0071] In any of the various embodiments of the present disclosure, the conversion of compound (2) to compound (3) is at least 80%, at least 85%, at least 90%, or at least 95%.

[0072] In any of the various embodiments of the present disclosure, the purity of compound (3) is at least 90 area % or at least 95 area % as measured by high performance liquid chromatography.

[0073] In any of the various embodiments of the present disclosure, the chiral purity of compound (3) is at least 90 area % or at least 95 area %.

[0074] In some embodiments of the present disclosure, compound (2) has the structure (2a): The file is TIFF2025508888000018.tif27170.

[0075] In some embodiments of the present disclosure, compound (3) has the structure (3a): The file is TIFF2025508888000019.tif37170.

[0076] Preparation of compound (2)

[0077] An embodiment of the present disclosure further includes a method for preparing compound (2) by a Heck arylation reaction, comprising the steps of: Step 1: reacting the compound according to the following reaction scheme: forming a reaction mixture comprising compound (1), 2,3-dihydrofuran, a transition metal catalyst, a ligand, a solvent, and a base according to TIFF2025508888000020.tif35170; and reacting the reaction mixture to form a reaction product mixture comprising compound (2), wherein R 1 ~R 5 and the asterisk is as defined elsewhere herein, and LG is a leaving group. In some embodiments, LG is trifluoromethanesulfonate (triflate).

[0078] Transition metal catalysts within the scope of the present disclosure include catalysts such as palladium, platinum, gold, ruthenium, rhodium and iridium catalysts.

[0079] In some embodiments, the transition metal catalyst is a palladium catalyst. In some embodiments, the palladium catalyst is selected from the group consisting of [PdCl(X)]2, where X is allyl, cinnamyl, or crotyl; [Pd(X)PR'], where R' is alkyl or aryl; [Pd(X)(Y)], where X is allyl, cinnamyl, or crotyl and Y is cyclopentadienyl or p-cymyl; Pd(dba)2; Pd2(dba)3; Pd(OAc)2; PdZ2, where Z is Cl, Br, or I; Pd2 Z2(PR')2 (wherein Z is Cl, Br or I, and R' is alkyl or aryl); Pd(TFA)2; Pd(dppf)Cl2; Pd(dppe)Cl2; Pd2(dba)3; Pd(PCy3)2Cl2; Pd(PPh3)2Cl2; Pd(OAc)2(PPh3)2; Pd(PPh3)4; Pd(PPh3)4Cl2, Pd(PCy3)2; Pd(PCy3)2Cl2; and Pd(t-Bu3P)2. In some embodiments, the transition metal catalyst is selected from Pd(OAc)2, Pd(PPh3)2Cl2 and Pd2(dba)3. In some such embodiments, the transition metal catalyst is Pd(OAc)2. In some such embodiments, the transition metal catalyst is Pd(TFA)2.

[0080] In some embodiments of the present disclosure, the mol% ratio of transition metal catalyst to compound (1) is suitably about 0.5 mol%, about 0.75 mol%, about 1 mol%, about 1.25 mol%, about 1.5 mol%, about 1.75 mol%, about 2 mol%, about 2.5 mol%, or about 3 mol% and any ranges building therein, such as about 0.25 mol% to about 3 mol%, about 0.75 mol% to about 2.5 mol%, or about 1 mol% to about 2 mol%.

[0081] In some embodiments, transition metal catalyst ligands within the scope of the present disclosure include the ligand classes BINAP, WALPHOS, JOSIPHOS, TANIAPHOS, MANDYPHOS, CHENPHOS, MeO-BIPHEP, PPHOS, DUPHOS, TUNEPHOS, SYNPHOS, and SEGPHOS. Non-limiting examples of transition metal catalyst ligands include (R)-Segphos, (R)-DM-Segphos, (R)-DTBM-Segphos, P(o-tolyl)3, P(m-tolyl)3, (p-tolyl)3, (R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, (S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, (R)-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl, (S)-2,2'-bis (Di-p-tolylphosphino)-1,1'-binaphthyl, (R)-2,2'-bis[di(3,5-xylyl)phosphino]-1,1'-binaphthyl, (S)-2,2'-bis[di(3,5-xylyl)phosphino]-1,1'-binaphthyl, (R)-5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole, (S)-5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole, (R)-5,5'-bis(di[3 ,5-xylyl]phosphino)-4,4'-bi-1,3-benzodioxole, (S)-5,5'-bis(di[3,5-xylyl]phosphino)-4,4'-bi-1,3-benzodioxole, (R)-5,5'-bis(di[3,5-di-t-butyl-4-methoxyphenyl]phosphino)-4,4'-bi-1,3-benzodioxole, (S)-5,5'-bis(di[3,5-di-t-butyl-4-methoxyphenyl]phosphino)-4,4'-bi-1,3-benzodioxole Sol, (R)-1,13-bis(diphenylphosphino)-7,8-dihydro-6H-dibenzo[f,h][1,5]dioxine, (S)-1,13-bis(diphenylphosphino)-7,8-dihydro-6H-dibenzo[f,h][1,5]dioxine, (R)-2,2',6,6'-tetramethoxy-4,4'-bis(diphenylphosphino)-3,3'-bipyridine, (S)-2,2',6,6'-tetramethoxy-4,4'-bis(diphenylphosphino)-3,3'-Bipyridine, (R)-2,2',6,6'-tetramethoxy-4,4'-bis(di[3,5-xylyl]phosphino)-3,3'-bipyridine, (S)-2,2',6,6'-tetramethoxy-4,4'-bis(di[3,5-xylyl]phosphino)-3,3'-bipyridine, (R)-2,2'-bis(diphenylphosphino)-6,6'-dimethoxy-1,1'-biphenyl, (S)-2,2'-bis(diphenylphosphino)-6,6'-dimethoxy-1,1'-biphenyl, (R)-bis(diphenylphosphino)-4,4',6,6'-tetramethoxy tetramethoxy-1,1'-biphenyl, (S)-bis(diphenylphosphino)-4,4',6,6'-tetramethoxy-1,1'-biphenyl, (R)-6,6'-bis(diphenylphosphino)-2,2',3,3'-tetrahydro-5,5'-bi-1,4-benzodioxin, (S)-6,6'-bis(diphenylphosphino)-2,2',3,3'-tetrahydro-5,5'-bi-1,4-benzodioxin, (R)-(+)-2,2'-bis(diphenylphosphino)-5,5',6,6',7,7',8,8'-octahydro-1,1'-bina phthalocyanine, (S)-(-)-2,2'-bis(diphenylphosphino)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl, (R)-5,5'-bis(diphenylphosphino)-2,2,2',2'-tetrafluoro-4,4'-bi-1,3-benzodioxole, (S)-5,5'-bis(diphenylphosphino)-2,2,2',2'-tetrafluoro-4,4'-bi-1,3-benzodioxole, (R)-1-[(R)-1-[di(3,5-xylyl)phosphino]ethyl]-2-[2-[di(3,5-xylyl)phosphino]ethyl] sphino]phenyl]ferrocene, (S)-1-[(S)-1-[di(3,5-xylyl)phosphino]ethyl]-2-[2-[di(3,5-xylyl)phosphino]phenyl]ferrocene, (R)-1-[(R)-1-[bis[3,5-bis(trifluoromethyl)phenyl]phosphino]ethyl]-2-[2-(diphenylphosphino)phenyl]ferrocene and (S)-1-[(S)-1-[bis[3,5-bis(trifluoromethyl)phenyl]phosphino]ethyl]-2-[2-(diphenylphosphino)phenyl]ferrocene.

[0082] In some embodiments, the ligand is selected from a Segphos ligand, a P(o-tolyl)3 ligand, a P(m-tolyl)3 ligand, and a P(p-tolyl)3 ligand. In some embodiments, the ligand is a Segphos ligand selected from (R)-Segphos, (R)-DM-Segphos, and (R)-DTBM-Segphos.

[0083] In some embodiments, the ligand is selected from MeO-BIPHEP ligands. In some embodiments, the MeO-BIPHEP ligand is selected from (R)-hexaMeOBIPHEP and (R)-o-An-MeOBIPHEP: TIFF2025508888000021.tif47170. In some embodiments, the MeO-BIPHEP ligand is a GARPHOS ligand.

[0084] In some embodiments of the present disclosure, the equivalent ratio of ligand to transition metal catalyst is suitably 1:1, about 1.1:1, about 1.25:1 or about 1.5:1.

[0085] In some embodiments, the solvent comprises primarily at least one non-polar solvent or at least one polar aprotic solvent or any combination of the foregoing. In some such embodiments, the solvent comprises primarily toluene, tetrahydrofuran or 2-methyltetrahydrofuran (2-MeTHF) or any combination of the foregoing. In some embodiments, the solvent system comprises primarily toluene and tetrahydrofuran or toluene and 2-methyltetrahydrofuran. In such embodiments, the volume ratio of toluene to THF or 2-MeTHF is suitably about 90:10, about 75:25, about 60:40, about 50:50, about 40:60, about 25:75 or about 10:90, and any range built therefrom, such as about 90:10 to about 10:90, about 75:25 to about 25:75 or about 60:40 to about 40:60.

[0086] In some aspects, the base is an organic base. In some such aspects, the organic base is selected from triethylamine, N,N'-diisopropylethylamine and 1,4-diazabicyclo[2.2.2]octane. In one aspect, the base is N,N'-diisopropylethylamine. In some embodiments, the base is in stoichiometric excess compared to compound (1), for example, about 1.1:1, about 1.25:1, about 1.5:1, about 1.75:1, about 2:1 or about 2.5:1 equivalent ratio.

[0087] In some embodiments, the equivalent ratio of 2,3-dihydrofuran to compound (1) is suitably about 1.1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, or about 10:1, and any ranges built therein, such as about 1.1:1 to about 10:1, about 3:1 to about 8:1, about 4:1 to about 6:1.

[0088] In some embodiments, the reaction temperature is about 30° C., about 35° C., about 40° C., about 50° C., about 60° C., about 70° C., about 80° C., or about 90° C., or reflux, and any range constructed therefrom, such as about 30° C. to about 90° C., about 35° C. to about 80° C., about 40° C. to about 70° C., etc. For example, but not limited to, in some embodiments, when the solvent comprises primarily toluene and 2-methyltetrahydrofuran, the reaction temperature is suitably about 30° C. to about 70° C., about 35° C. to about 60° C., or about 40° C. to about 50° C.

[0089] In some embodiments of the present disclosure, the reaction product mixture containing compound (2) may be worked up and optionally isolated, such as, but not limited to, one or more of: filtration; treatment with a metal scavenger; washing with an aqueous phase (e.g., a brine solution); neutralization with an aqueous solution of an acid or base; solvent exchange; phase separation; treatment with an oxidizing agent; crystallization or precipitation by addition of an anti-solvent and optionally seeding and cooling; evaporation; distillation; and drying.

[0090] In some embodiments, the reaction product mixture can be filtered; the filtrate can be treated with a transition metal scavenger (e.g., an aqueous solution of APDTC (ammonium pyrrolidine dithiocarbamate) to scavenge palladium); the treated filtrate can be evaporated to form a compound (2) residue; the residue can be treated with an oxidizing agent (such as an aqueous solution of TEMPO); the resulting solution of compound (2) can be distilled to form an oil comprising compound (2).

[0091] In any of the various embodiments of the present disclosure, the conversion of compound (1) to compound (2) is at least 70%, at least 75%, at least 80%, or at least 85%.

[0092] In any of the various embodiments of the present disclosure, the purity of compound (2) is at least 90 area % or at least 95 area % as measured by high performance liquid chromatography.

[0093] In any of the various embodiments of the present disclosure, the chiral purity of compound (2) is at least 90 area % or at least 95 area %.

[0094] In some embodiments of the present disclosure, compound (1) has the structure (1a): TIFF2025508888000022.tif22170, where OTf represents trifluoromethanesulfonate.

[0095] Preparation of compound (4)

[0096] An embodiment of the present disclosure further includes a method for preparing compound (4), which includes step 3: forming a reaction mixture comprising a hydroxylamine solution, a solvent, and compound (3) and reacting the reaction mixture according to the following reaction scheme: and reacting the reaction mixture according to TIFF2025508888000023.tif51170 to form a reaction product mixture comprising compound (4), wherein R 1 ~R 5and the asterisk is as defined elsewhere herein, and E / Z represents the E / Z isomer.

[0097] In some embodiments, NH2OH is suitably present in its aqueous solution, such as, but not limited to, a 50% by weight aqueous solution. In some embodiments, the equivalent ratio of NH2OH to compound (3) is suitably about 1.05:1, about 1:1, about 1.15:1, about 1.2:1, about 1.25:1, about 1.3:1, about 1.5:1, about 2:1 or about 2.5:1, and any ranges built therein, such as about 1.05:1 to about 2.5:1, about 1.1:1 to about 2:1 or about 1.1:1 to about 1.5:1.

[0098] In some embodiments, the solvent comprises primarily at least one non-polar solvent. In some embodiments, the solvent comprises primarily toluene. In some embodiments, a solution of compound (3), as described elsewhere herein, such as in a non-polar solvent, such as toluene, is used to form the reaction mixture.

[0099] In some embodiments, the reaction temperature is suitably about 5°C, about 10°C, about 20°C, about 30°C, about 40°C, about 50°C, about 60°C, or about 70°C, or any range derived therefrom, such as about 5°C to about 70°C, about 10°C to about 50°C, or about 20°C to about 40°C.

[0100] In some embodiments, the reaction product mixture containing compound (4) may be optionally worked up. In some work-up aspects, the reaction product mixture may be quenched with a brine solution, and then an organic phase containing compound (4) may be isolated, such as by phase separation. The isolated organic phase may optionally be washed with water, and then the washed organic phase may be isolated.

[0101] In some work-up embodiments, the organic phase may be concentrated, such as under vacuum, to form a residue. The residue may be optionally filtered and then dissolved in a non-polar solvent system, such as toluene or a combination of toluene and MTBE. Compound (4) may then be isolated from the solution by the addition of an anti-solvent, such as n-heptane, and optionally seed crystals of compound (4) to form a slurry containing compound (4). Compound (4) may then be isolated by filtration or centrifugation. The isolated solid may then be optionally washed, such as with toluene / n-heptane, and dried.

[0102] In any of the various embodiments of the present disclosure, the conversion of compound (3) to compound (4) is at least 70%, at least 75%, at least 80%, or at least 85%.

[0103] In any of the various embodiments of the present disclosure, the purity of compound (4) is at least 90 area%, at least 95 area%, or at least 98 area% as measured by high performance liquid chromatography.

[0104] In any of the various embodiments of the present disclosure, the chiral purity of compound (4) is at least 90 area % or at least 95 area %.

[0105] In some embodiments of the present disclosure, compound (4) has the structure (4a): TIFF2025508888000024.tif40170, where E / Z represents the E / Z isomer.

[0106] First Preparation Route of Compound (6)

[0107] An embodiment of the present disclosure further includes a method for preparing compound (5) from compound (4) and for preparing compound (6) from compound (5).

[0108] The method for preparing compound (5) includes, step 4a: forming a reaction mixture containing compound (4), a reagent and a solvent, and reacting the reaction mixture according to the following reaction scheme: and reacting the reaction mixture according to TIFF2025508888000025.tif50170 to form a reaction product mixture comprising compound (5), wherein R 1 ~R 5 , asterisk and E / Z are as defined elsewhere herein.

[0109] In some embodiments, the reagent is a dehydration reagent. Non-limiting examples of the reagent include carbonyldiimidazole, acetic anhydride, trifluoroacetic anhydride, T3P (1-propanephosphonic anhydride), EDCI (N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride), DIC (N,N'-diisopropylcarbodiimide), PyCloP (chlorotripyrrolidinophosphonium hexafluorophosphate), Ac2O, POCl3, SOCl2, Na2CO3, Burgess's reagent, CH3S02O, DBU, DCM, CH3SOC12, Et3N and CuOAc2. In some embodiments, the reagent is carbonyldiimidazole.

[0110] In some embodiments, the equivalent ratio of reagent to compound (4) is suitably about 1.05:1, about 1.1:1, about 1.2:1, about 1.25:1, about 1.3:1, about 1.4:1, about 1.5:1, or about 2:1, and any ranges built therein, such as from about 1.05:1 to about 2:1, from about 1.1:1 to about 1.5:1, or from about 1.2:1 to about 1.3:1.

[0111] In some embodiments, the solvent comprises primarily at least one non-polar solvent or at least one polar solvent or a combination of any of the foregoing. 1~6 Alcohol, C. 1~6The solvent is selected from esters and ethers, or any combination of the foregoing. In some embodiments, the solvent comprises primarily MTBE, ethyl acetate, ethanol, methanol, i-propanol, THF, or 2-MeTHF, or a combination of two or more thereof. In some embodiments, the solvent comprises primarily MTBE. The reaction mixture comprises compound (4) dissolved in the solvent.

[0112] In some embodiments, the reaction product mixture containing compound (5) in solution can be used directly without isolation for conversion to compound (6).

[0113] In some embodiments, the reaction product mixture containing compound (5) in solution can be worked up, such as, but not limited to, one or more of filtration, washing with an aqueous phase, neutralization by contact with an aqueous acid or base, solvent exchange, phase separation, crystallization or precipitation by addition of an anti-solvent and optional seeding and cooling, evaporation, distillation, and drying.

[0114] In some work-up embodiments, the reaction product mixture may be water washed by combining the reaction product mixture with water followed by phase separation to isolate the organic phase containing compound (5). The reaction product mixture or the isolated washed organic phase may be washed with an aqueous acid solution followed by phase separation and isolation of the organic phase. In some embodiments, the acid is a weak acid such as, for example, but not limited to, citric acid. The acid wash may be optionally followed by a water wash followed by phase separation and isolation of the organic phase. The water wash and aqueous neutralization step may be followed by drying using, for example, but not limited to, a drying agent (e.g., Na2SO4 or MgSO4). The reaction product mixture or any organic phase may be optionally filtered. In some embodiments, the reaction product mixture or the final processed organic phase containing compound (5) may be concentrated to an oil containing compound (5) in solution and used directly to form compound (6). Concentration may be performed by methods known in the art such as distillation or evaporation. In some embodiments, compound (6) can be isolated by, for example, but not limited to, anti-solvent addition, optional seeding, cooling and filtration.

[0115] In some embodiments, compound (5) has the structure (5a): The file is TIFF2025508888000026.tif29170.

[0116] The method for preparing compound (6) includes, step 5a: forming a reaction mixture comprising compound (5), hydroxylamine and a polar solvent, and reacting the reaction mixture according to the following reaction scheme: and reacting the reaction mixture according to TIFF2025508888000027.tif47170 to form a reaction product mixture comprising compound (6), wherein R 1 ~R 5 and the asterisk is as defined elsewhere herein.

[0117] In some embodiments, the equivalent ratio of hydroxylamine to compound (5) is suitably about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 2.5:1 or about 3:1, and any ranges built therein, such as from about 1.1:1 to about 3:1, from about 1.2:1 to about 2:1 or from about 1.3:1 to about 1.7:1.

[0118] In some embodiments, the solvent comprises predominantly at least one polar protic solvent. In some embodiments, the solvent comprises predominantly C 1~5 In some embodiments, the solvent comprises primarily t-amyl alcohol, i-propyl alcohol, methanol, or ethanol. In some embodiments, the solvent comprises primarily i-propyl alcohol. In some embodiments, the solvent comprises primarily t-amyl alcohol.

[0119] The reaction product mixture containing compound (6) in solution can be worked up, for example, but not limited to, by one or more of the following: filtration; washing with an aqueous phase; neutralization by contact with an aqueous acid or base; solvent exchange; phase separation; crystallization or precipitation by addition of an anti-solvent and optional seeding and cooling; evaporation; distillation; and drying.

[0120] In some embodiments, the reaction product mixture can be combined with water and compound (6) seeds and cooled to form a slurry of compound (6). Compound (6) can be isolated from the slurry by filtration or centrifugation. The isolated compound (6) can be optionally washed with a poor solvent, such as n-heptane, and then dried.

[0121] In any of the various embodiments of the present disclosure, the yield of compound (6) based on compound (4) is at least 75%, at least 80%, or at least 85%.

[0122] In some embodiments, compound (6) has the structure (6a): The file is TIFF2025508888000028.tif40170.

[0123] Second Preparation Route of Compound (6)

[0124] An embodiment of the present disclosure further includes a method for preparing compound (7) from compound (4), and for preparing compound (6) from compound (7).

[0125] The method for preparing compound (5) includes, step 4b: forming a reaction mixture comprising compound (4), an oxidizing agent, an acid, and a solvent, and reacting the reaction mixture according to the following reaction scheme: and reacting the reaction mixture according to TIFF2025508888000029.tif53170 to form a reaction product mixture comprising compound (7), wherein R 1 ~R 5 , asterisk and E / Z are as defined elsewhere herein.

[0126] In some embodiments, the oxidizing agent is as disclosed elsewhere herein. In some embodiments, the oxidizing agent is selected from N-chlorosuccinimide, t-BuOCl, chloramine-T, NaOCl, 1,3 dichloro-5,5-dimethylhydantoin, N-chlorophthalimide, and 2-chlorobenzo[d]isothiazol-3(2H)one 1,1 dioxide. In one embodiment, the oxidizing agent is N-chlorosuccinimide. In some embodiments, the equivalent ratio of oxidizing agent to compound (4) is suitably about 1.01:1, about 1.05:1, about 1.1:1, about 1.15:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, or about 2:1, and any range therein, such as from about 1.01:1 to about 2:1, from about 1.01:1 to about 1.5:1, or from about 1.05:1 to about 1.2:1.

[0127] In some aspects, the acid is an inorganic acid, such as, but not limited to, HCl, H2SO4, HNO3 or H3PO4. In some aspects, the acid is a concentrated acid, such as a concentrated aqueous acid. In one aspect, the acid is concentrated aqueous HCl. In some embodiments, the equivalent ratio of the acid to compound (4) is suitably about 0.01:1, about 0.05:1, about 0.1:1, about 0.15:1, about 0.2:1, about 0.3:1, about 0.4:1 or about 0.5:1, and any ranges built therein, such as about 0.01:1 to about 0.5:1, about 0.05:1 to about 0.3:1 or about 0.05:1 to about 0.2:1.

[0128] In some embodiments, the solvent comprises primarily at least one non-polar solvent or at least one polar solvent or a combination of any of the foregoing. In some embodiments, the solvent comprises primarily MTBE, EtOAc, DMF, DCM, MeOH, ACN, toluene, IPAc, or DMF, or a combination of any of the foregoing. In some embodiments, the solvent comprises primarily MTBE. In some embodiments, the solvent comprises primarily EtOAc. The reaction mixture comprises compound (4) dissolved in the solvent.

[0129] In some aspects, the reaction product mixture containing compound (7) in solution can be used directly without isolation for conversion to compound (6). In some embodiments, compound (7) is dissolved in the organic phase.

[0130] In some embodiments, the reaction product mixture containing compound (7) in solution can be worked up and optionally isolated. Compound (7) can be worked up by, for example, but not limited to, one or more of the following: filtration; washing with an aqueous phase; neutralization by contact with an aqueous acid or base; solvent exchange; phase separation; crystallization or precipitation by addition of an anti-solvent and optional seeding and cooling; evaporation; distillation; and drying.

[0131] In some embodiments, compound (7) is compound (7a) of the following structure: The file is TIFF2025508888000030.tif43170.

[0132] The method for preparing compound (6) includes, step 5b: forming a reaction mixture comprising compound (7), ammonia and a polar solvent, and reacting the reaction mixture according to the following reaction scheme: and reacting the reaction mixture according to TIFF2025508888000031.tif49170 to form a reaction product mixture comprising compound (6), wherein R 1 ~R 5 and the asterisk is as defined elsewhere herein.

[0133] In some embodiments, the solvent comprises primarily at least one non-polar solvent or at least one polar solvent or a combination of any of the foregoing. In some embodiments, the solvent comprises primarily ethyl acetate or MTBE. In some embodiments, the solvent comprises primarily ethyl acetate. In some embodiments, the solvent comprises primarily MTBE. The reaction mixture comprises compound (7) dissolved in the solvent.

[0134] In some embodiments, the ammonia is 1~4 In some such embodiments, the ammonia is dissolved in methanol.

[0135] In some embodiments, the reaction product mixture containing compound (6) in solution can be worked up and optionally isolated. Compound (6) can be worked up by, for example, but not limited to, one or more of the following: filtration; washing with an aqueous phase; neutralization by contact with an aqueous acid or base; solvent exchange; phase separation; crystallization or precipitation by addition of an anti-solvent and optional seeding and cooling; evaporation; distillation; and drying.

[0136] In some work-up embodiments, the reaction product mixture may be water washed by combining the reaction product mixture with water, followed by phase separation to isolate the organic phase containing compound (6). The washed organic phase may be dried, such as, but not limited to, a drying agent (e.g., Na2SO4 or MgSO4). In some embodiments, the dried organic phase is treated with charcoal and then filtered. The organic phase may optionally be concentrated by evaporation or distillation. The optionally concentrated organic phase may then be combined with a poor solvent (e.g., n-heptane) and optional seed crystals. In some embodiments, the resulting mixture may be concentrated by evaporation or distillation and cooled to form a slurry of compound (6). Compound (6) may be isolated from the slurry by filtration or centrifugation, and the collected solids may then be optionally dried.

[0137] In any of the various embodiments of the present disclosure, the yield of compound (6) based on compound (4) is at least 75%, at least 80%, or at least 85%.

[0138] Compounds (3), (4) and (7)

[0139] Some embodiments of the present disclosure include a compound (3) of the following structure: TIFF2025508888000032.tif40170 or a salt thereof, 1 ~R 5 and the asterisk are as defined elsewhere herein.

[0140] Some embodiments of the present disclosure include compounds of the following species of compound (3): TIFF2025508888000033.tif34170 or a salt thereof.

[0141] Some embodiments of the present disclosure include a compound (4) having the following structure: TIFF2025508888000034.tif48170 or a salt thereof, 1 ~R 5, asterisk and E / Z are as defined elsewhere herein.

[0142] Some embodiments of the present disclosure include compound (4a), which is of the compound (4) species: TIFF2025508888000035.tif40170, or a salt thereof, wherein E / Z are as defined elsewhere herein.

[0143] Some embodiments of the present disclosure include a compound (7) having the following structure: TIFF2025508888000036.tif47170 or a salt thereof, 1 ~R 5 and the asterisk are as defined elsewhere herein.

[0144] Some embodiments of the present disclosure include compounds of the following species of compound (7): TIFF2025508888000037.tif43170 or a salt thereof.

[0145] Integrated process scheme

[0146] Some embodiments of the present disclosure include the steps of steps 1 to 3 as follows: The present invention relates to a general method for preparing compound (4) according to TIFF2025508888000038.tif90170.

[0147] In the scheme of steps 1 to 3, R 1 ~R 5;LG;asterisk;E / Z;The transition metal catalyst, ligand, solvent, base, and reaction conditions for step 1; the Rh catalyst, ligand, solvent, and reaction conditions for step 2, and the solvent and reaction conditions for step 3 are as described elsewhere herein. In some embodiments, compound (3) is not isolated prior to step 3. In some embodiments, compound (1) is a species of compound (1a), compound (2) is a species of compound (2a), compound (3) is a species of compound (3a), and compound (4) is a species of compound (4a), each as described elsewhere herein.

[0148] Some embodiments of the present disclosure are directed to a general method for preparing compound (6) according to steps 1-3 above, comprising steps 4a and 5a as follows: The present invention relates to a general method further comprising: TIFF2025508888000039.tif37170.

[0149] In the schemes of steps 4a and 5a, R 1 ~R 5 ;asterisk;E / Z;reagents and solvents for step 4a; and polar solvent for step 5a are as described elsewhere herein. In some embodiments, compound (5) is not isolated prior to step 5a. In some embodiments, compound (4) is a species of compound (4a), compound (5) is a species of compound (5a), and compound (6) is a species of compound (6a), each as described elsewhere herein.

[0150] Some embodiments of the present disclosure are directed to a general method for preparing compound (6) according to steps 1-3 above, comprising steps 4b and 5b as follows: The present invention relates to a general method further comprising: TIFF2025508888000040.tif42170.

[0151] In the schemes of steps 4b and 5b, R 1 ~R 5;asterisk;E / Z; the oxidizing agent, acid, and solvent of step 4b are as described elsewhere herein. In some embodiments, compound (7) is not isolated prior to step 5b. In some embodiments, compound (4) is a species of compound (4a), compound (7) is a species of compound (7a), and compound (6) is a species of compound (6a), each as described elsewhere herein. EXAMPLES

[0152] Example 1. Preparation of compound (2a) by hexarylation

[0153] Compound (2a) ((R)-2-(4-chlorophenyl)-2,3-dihydrofuran) was prepared from compound (1a) (4-chlorophenyl trifluoromethanesulfonate) according to the following reaction step 1′. TIFF2025508888000041.tif40170

[0154] To a solution of compound (1a) (336 g, 1.29 mol, 1 equiv.) in a mixture of 2-MeTHF (840 mL) and toluene (840 mL) was charged DIPEA (336 mL, 1.93 mol, 1.5 equiv.). The solution was sparged with N2 at room temperature for 30 min, followed by sequential charging of Pd(OAc)2 (6.38 g, 19.4 mmol, 0.015 equiv.), (R)-SEGPHOS (11.72 g, 19.4 mmol, 0.015 equiv.) and 2,3-dihydrofuran (6.45 mol, 5.0 equiv.). The suspension was then sparged with N2 at room temperature (rt) for 30 min, after which the reactor was warmed to 45° C. and stirred at this temperature for 20 h. The reactor was then cooled to room temperature and filtered through a pad of Celite. Aqueous APDTC (0.02 wt % in 336 mL water) was added to the resulting filtrate and the suspension was stirred at 25° C. for 5 h. The layers were then separated and the organic phase was concentrated to dryness. TEMPO (2 wt %) was added to the resulting residue and the resulting solution was distilled under vacuum (oil bath, 110° C., 5 Torr) to give a colorless oil (194 g, 82%, 95.4% HPLC purity, 96.5% chiral purity). 1H NMR(400MHz,DMSO-d6)δ7.48-7.28(m,5H), 6.57(q,J=2.5Hz,1H), 5.51(dd,J=10.7,8.1Hz,1H), 4.98(q,J=2.5 Hz,1H), 3.39(dd,J=3.2,1.7Hz,1H), 3.05(ddt,J=15.4,10.7,2.4Hz,1H), 2.42(ddt,J=15.3,8.1,2.4Hz,1H). 13 C NMR (101MHz, DMSO-d6) δ145.76, 142.50, 132.52, 128.84, 127.74, 99.39, 81.05, 37.84. HRMS:C 10 H 10 ClO[M+H] + Calculated value: 181.0420, measured value: 180.0419.

[0155] Example 2. Preparation of compound (3a) ((3S,5R)-5-(4-chlorophenyl)tetrahydrofuran-3-carbaldehyde) by hydroformylation

[0156] Compound (3a) was prepared from compound (2a) according to the following reaction step 2'. TIFF2025508888000042.tif36170

[0157] Preparation of catalyst solution. In a glovebox (<1 ppm O2), a 250 mL flask was charged with Rh(CO)2(acac) (1.71 g, 0.007 mol, 0.010 equiv.) and dissolved in 40 mL toluene. (R,R)-Ph-BPE (6.73 g, 0.013 mol, 0.020 equiv.) was added slowly (strong gas evolution) and the weighing bottle and flask neck were rinsed with 20 mL toluene. After stirring for 15 min, a yellow solution was obtained. The solution was transferred to an addition vessel and the flask was rinsed twice with 10 mL toluene. The addition vessel was closed and removed from the glovebox.

[0158] Preparation of the reaction mixture. In air, a 2000 mL autoclave was charged with compound (2a) (120 g, 98.36 mL, 0.664 mol, 1 eq.) and dissolved in toluene (degassed, 69.2 g, 80 mL, 1.13 eq.). The autoclave was sealed. The addition vessel containing the catalyst was connected to the autoclave. The lines to the autoclave and the addition vessel were purged three times with 7 bar argon. The catalyst solution was then added to the autoclave under argon pressure. The addition vessel was rinsed into the autoclave with toluene (degassed, 17.3 g, 20 mL, 0.283 eq.). After placing everything in the autoclave, the autoclave was purged three times with 10 bar H2 / CO and the relative working pressure was set to a working pressure of 5 bar. The autoclave contents were heated to 70° C. and stirred at 1200 rpm. After 22 hours, the autoclave was cooled to room temperature and the pressure was released to obtain a crude solution of compound (3a). The test showed 89.1% conversion of compound (2a) (compound (3a) contained 3.4% of the regioisomer). Without workup, the solution of crude compound (3a) was telescoped to the next step. 1 H NMR(400MHz,CDCl3)δ9.78(d,J=1.8Hz,1H), 7.29-7.24(m,4H), 4.95-4.89(m,1H), 4.27 -4.19(m,2H), 3.29-3.16(m,2H), 2.69(ddd,J=12.9,6.8,4.2Hz,1H), 2.05-1.96(m,1H). 13 C NMR (101MHz, DMSO-d6) δ202.78, 141.84, 132.26, 128.70, 127.99, 79.30, 67.28, 51.47, 34.98. HRMS C 11 H 12 Calculated ClO2: 211.0526, Found: 211.0523.

[0159] Example 3. Preparation of oxime compound (4a) ((E)-5-(4-chlorophenyl)tetrahydrofuran-3-carbaldehyde oxime) by addition of hydroxylamine

[0160] Compound (4a) was prepared from compound (3a) according to the following reaction step 3'. TIFF2025508888000043.tif37170

[0161] A 2500 mL four-necked sulfonation flask was charged with a solution of crude compound (3a) (139.88 g, 0.664 mol, 1 eq.) dissolved in toluene (1.03 kg, 1.2 L, 16.9 eq.). To the stirred solution was added hydroxylamine solution (50% in water, 51.91 g, 48.15 mL, 0.797 mol, 1.2 eq.) over 30 min. After stirring for an additional 80 min, the reaction was quenched with half-saturated brine (200 mL) and stirred for 20 min. The layers were separated and the organic phase was washed with water (200 g, 200 mL, 16.72 eq.). The orange organic phase was concentrated in vacuo (40 °C, 100-70 mbar) to give a residue (445.95 g). The orange residue was filtered through a silica pad (240 g silica) and washed with MTBE (884.7 g, 1.2 L, 15.11 equiv). The yellow filtrate was concentrated in vacuo (40° C., 220-10 mbar) to give crude compound (4a) (155.80 g), which was then dissolved in toluene (519 g, 600 mL, 8.48 equiv) at room temperature. To the solution was added n-heptane (256.5 g, 375 mL, 3.86 equiv) over 10 min. To the yellow solution was added compound (4a) seeds (1.00 g, 0.004 mol, 0.007 equiv) and the mixture was stirred at room temperature for 60 min. To the resulting suspension was added n-heptane (769.5 g, 1.13 L, 11.57 equiv) over 2 h. The suspension was stirred for 17 h and then filtered. The flask and wet cake were washed twice with a 1:1 v / v mixture of toluene (86.5 g, 100 mL, 1.41 equiv.) and n-heptane (68.4 g, 100 mL, 1.03 equiv.). The solid was dried at 40° C. and 10 mbar for 4 h to give compound (4a) as pale yellow crystals (110.8 g, 72.8% yield, 98.4% purity). 1H NMR (400MHz, CDCl3) δ 8.69 (s, 0.1H minor isomer), 8.24 (s, 1H OH, major isomer), 7.46(d,J=6.7Hz,1H,major isomer), 7.34-7.19(m,4H), 6.81(d,J=6.2Hz,0.1H,minor isomer), 5.02(t,J=7.0Hz,1H), 4.26(dd,J=8. 8,7.3Hz,1H), 3.86(dd,J=8.8,6.8Hz,1H), 3.21-3.15(m,1H), 2.37(ddd,J=12.8,7.3,6.1Hz,1H), 2.06(ddd,J=12.7,8.4,6.7Hz,1H). 13 C NMR (101 MHz, CDCl3) δ 151.51, 140.97, 133.13, 128.58, 126.88, 79.63, 79.63, 71.05, 39.39, 38.64. HRMS: calculated for C11H13ClNO2: 226.0635, found: 226.0629.

[0162] Example 4.

[0163] Compound (5a) ((3R,5R)-5-(4-chlorophenyl)tetrahydrofuran-3-carbonitrile) was prepared from compound (4a) according to the following reaction step 4a', and compound (6a) ((3R,5R,Z)-5-(4-chlorophenyl)-N'-hydroxytetrahydrofuran-3-carboximidamide) was prepared from compound (5a) according to the following reaction step 5a'. TIFF2025508888000044.tif32170

[0164] In step 4a', a glass reactor under nitrogen gas was charged with compound (4a) (30.0 g, 123 mmol, 1.0 equiv., E / Z 2:1 ratio) and MTBE (240 mL, 8 V) to obtain a solution. The internal temperature was adjusted to 25° C., solid 1,1-carbonylimidazole (24.9 g, 154 mmol, 1.25 equiv.) was added in portions (exotherm observed, significant off-gassing), and the reaction was left stirring at 25° C. overnight. The reaction was sampled for IPC (target (HPLC): compound (4a)≦1.0% area, result: 0% area, conforms). Water (150 mL, 5 V) was added and the phases were separated. The organic phase containing compound (5a) was washed with citric acid (150 mL, 5 V, 5 wt.% in water) followed by water (150 mL, 5 V). The organic phase was dried over NaSO4 and filtered. In step 5a', the organic phase containing compound (5a) was concentrated to an oil, then isopropyl alcohol (105 mL, 4 V) was added. The temperature was adjusted to 40° C. and hydroxylamine (11.6 mL, 190 mmol, 1.5 eq, 50 wt % aqueous solution) was charged over 1 h. The reaction was stirred for 12 h. The reaction was sampled for IPC ((target (HPLC): compound (5a)≦1.0% area, result: 0% area, conforms). Water (26 mL, 1 V) was charged and stirred for 30 min. The reaction mixture was cooled to 25° C., seed crystals were added (2 wt %) and the reaction mixture was maintained for 1 h. Water (184 mL, 7 V) was then added over 1 h and the temperature was then adjusted to 0° C. over 6 h.) The temperature was then adjusted to 40° C., maintained for 3 h and cooled to 0° C. over 6 h. The slurry was filtered and the cake was washed three times with heptane (30 mL, 1V). The solid was dried at room temperature to give 27.5 g of white solid compound (6a) (80%).

[0165] Example 5.

[0166] Example 4 was repeated using different ligands.

[0167] BPE Catalyst Reactions using TIFF2025508888000045.tif24170 resulted in 90%-95% conversion of compound (2a) to compound (3a).

[0168] Bisdiazaphos Ligand Reaction with TIFF2025508888000046.tif39170 resulted in greater than 99% conversion of compound (2a) to compound (3a).

[0169] Indolephos Ligand Reaction with TIFF2025508888000047.tif32170 resulted in greater than 99% conversion of compound (2a) to compound (3a).

[0170] Ferrocene Ligand Reaction with TIFF2025508888000048.tif32170, where R was phenyl, resulted in greater than 99% conversion of compound (2a) to compound (3a). Reaction with the ferrocene ligand, where R was i-Pr, resulted in greater than 99% conversion of compound (2a) to compound (3a).

[0171] Xanthene Ligands Reaction with TIFF2025508888000049.tif52170 resulted in greater than 99% conversion of compound (2a) to compound (3a).

[0172] Example 6.

[0173] Compound (5a) was prepared from compound (4a) according to the following reaction process 4a'', and compound (6a) was prepared from compound (5a) according to the following reaction process 5a''. TIFF2025508888000050.tif31170

[0174] In step 4a, a glass reactor (R1) under nitrogen gas was charged with compound 4a (100.0 g, 425 mmol, 1.0 equiv., E / Z 2:1 ratio) and MTBE (400 mL, 4V) to obtain a solution. The internal temperature was adjusted to 25° C. A second glass reactor (R2) was charged with solid 1,1-carbonylimidazole (88.0 g, 532 mmol, 1.25 equiv.) and MTBE (400 mL, 4V) to produce a slurry. The contents of R2 were vacuum transferred in portions to R1 to keep the Ti below 35° C. (exotherm observed, significant off-gassing) and the reaction was left stirring at 25° C. overnight. The reaction was sampled for IPC (target (HPLC): compound 4a ≦1.0% area, result: 0% area, conforms). Water (500 mL, 5 V) was added and the phases were separated. The organic phase containing compound 5a was washed with citric acid (500 mL, 5 V, 5 wt % in water) followed by water (500 mL, 5 V). The organic phase was filtered (solids were discarded). The batch was split into two equal parts by mass (2×44 g based on maximum theoretical yield). Using distillation, the organic phase containing compound 5a was concentrated to 4 V. Continuous distillation was then used to achieve MTBE<1 wt %. A solvent exchange was performed from MTBE (176 mL, 4 V) to t-AmOH (176 mL, 4 V) until 40° C. In step 5a″, the temperature was adjusted to 40° C. and hydroxylamine (17.6 mL, 288 mmol, 1.4 equiv., 50 wt % in water) was charged over 6 h. The reaction was stirred for 16 h. The reaction was sampled for IPC (target (HPLC): compound 5a≦1.0% area, result: 0% area, conforms). The reaction mixture was cooled to 25° C. and seeds of compound 6a were added (0.2 g, 0.5 wt %) and the reaction mixture was maintained for 0.5 h to form a seed bed. The mixture was grown on a 1000 ml bed. Heptane (440 mL, 10 V) was charged over 3 h and stirred for 30 min. The temperature was adjusted to 0° C. over 3 h and stirred overnight. The slurry was filtered and the cake was washed three times with heptane (44 mL, 1 V). The solid was dried at 23° C. to give 43.9 g of white solid compound 6a (85% corrected yield calculated for half of the initial batch).

[0175] Example 7.

[0176] Compound (7a) ((3S,5R,Z)-5-(4-chlorophenyl)-N-hydroxytetrahydrofuran-3-carbimidoyl chloride) was prepared from compound (4e) according to the following reaction step 4b', and compound (6a) was prepared from compound (7a) according to the following reaction step 5b'. TIFF2025508888000051.tif37170

[0177] In step 4b', a glass reactor under nitrogen gas was charged with compound (4a) (5.0 g, 22.2 mmol, 1.0 equiv, E / Z 2:1 ratio) and EtOAc (50 mL, 10V) to give a suspension. The reaction was stirred at room temperature until complete dissolution was achieved. The internal temperature was adjusted to 0°C and solid N-chlorosuccinimide (3.2 g, 24.4 mmol, 1.1 equiv) was added portionwise (a small exotherm was observed, the color of the reaction mixture did not change) to give a white suspension. Concentrated aqueous HCl (0.2 g, 2.2 mmol, 0.1 equiv) was added dropwise (the color of the reaction mixture changed to blue) and the reaction was left stirring at 0°C for 16 h. The reaction was sampled for IPC ((target (HPLC): compound (4a) ≦1.0% area, result: 0% area). In step 5b', T iA solution of NH3 in MeOH (9.5 mL, 66.5 mmol, 2 M solution, 3.0 equiv.) was added slowly to keep the pH below 5° C. The reaction was stirred for 30 min. The reaction was sampled for IPC (target (HPLC): compound (7a)≦1.0% area, result: 0% area). The reaction mixture was warmed to 10° C. Water (15 mL, 3 V) was charged and stirred for 30 min. The temperature was allowed to increase to 20° C. The organic phase was washed two more times with water (15 mL, 3 V) before being dried over MgSO4. The cake was washed with additional EtOAc (10 mL, 2 V). The combined organic phase containing compound 6(a) was then subjected to charcoal treatment (20 wt%) and then filtered. The cake was washed with EtOAc (10 mL, 2 V). A solution of compound (6a) in EtOAc (70 mL, 14 V) was concentrated to 4 V. After adjusting the temperature to 40° C., heptane (20 mL, 4 V) was added slowly. Compound (6a) seeds (0.2 wt %) were added and the slurry was aged for 30 min. Distillation was then carried out until about 3 V of solvent was removed. The slurry was cooled to 25° C. over 1 h and then filtered. The collected cake was washed with EtOAc:heptane mixture (1:3) and then dried at room temperature to give 3.47 g of a white solid (65%). 1 H NMR(400MHz,DMSO)δ8.98(s,1H), 7.41-7.31(m,4H), 5.44(s,2H), 4.96(t,J=7.0Hz,1H), 4.15(t,J=7.9Hz, 1H), 3.84(dd,J=8.3,7.4Hz,1H), 2.99-2.90(m,1H), 2.49-2.45(m,1H), 1.87(ddd,J=12.4,8.7,6.6Hz,1H). 13 C NMR (101MHz, DMSO) δ152.7, 142.8, 131.9, 128.6, 127.9, 79.3, 71.1, 40.7, 38.1. HRMS C 11 H 14 ClN2O2[M+H] + Calculated value: 241.0738, actual value: 241.0737.

[0178] This specification uses illustrative examples to describe the disclosure, including the best mode, and to enable those skilled in the art to practice the disclosure, including making and using any devices or systems, and performing any incorporated methods and processes. The patentable scope of the disclosure is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements that have insubstantial differences from the literal language of the claims.

Claims

1. Compound (3) A method for preparing CO, H ２ forming a reaction mixture comprising a rhodium catalyst, a ligand, a solvent, and compound (2); and reacting the reaction mixture to form a reaction product mixture comprising compound (3); (i) Compound (2) has the structure is; (ii) each * independently represents a chiral center; (iii) R １ ~R ５ Each of is independently hydrogen, halo, cyano, unsubstituted C １ ~C ６ Alkyl, substituted C １ ~C ６ Alkyl, unsubstituted C １ ~C ６ Alkoxy and substituted C １ ~C ６ alkoxy; R １ ~R ５ at least one of is halo, wherein at least one halo is selected from Cl and F; method.

2. The method of claim 1 , wherein the rhodium catalyst is a rhodium(I) complex.

3. The rhodium catalyst is Rh(acac)(CO) ２ ;Rh(acac)(PPh ３ )(CO);Rh(acac)((R)-Ph-BPE;Rh(acac)(C ２ H ４ ) ２ ; Rho (acac) (C) ８ h １４ ) ２ ; Rh(acac)(COD);Bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate;Bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate;Bis(norbornadiene)rhodium(I) tetrafluoroborate;Chlorobis(cyclooctene)rhodium(I) dimer;Rh ２ C ２ (C ２ H ４ ) ４ , Rh ２ C ２ (CO) ４ ;Chloronorbornadiene rhodium(I) dimer;Bis(triphenylphosphine)rhodium carbonyl chloride;RhCl(PPh ３ ) ３ and methoxy(cyclooctadiene)rhodium(I) dimer.

4. 4. The method according to any one of claims 1 to 3, wherein the ligands are selected from mono-phosphine ligands, bis-phosphine ligands, mono-phosphonite ligands, bis-phosphonite ligands, mono-phosphite ligands, bis-phosphite ligands, mono-phosphoramidite ligands, bis-phosphoramidite ligands and mixed phosphoramidite-phosphine ligands.

5. The method according to any one of claims 1 to 4, wherein the ligand is selected from BPE, bisdiazaphos, xanthene, indolphos and DPPF ligands.

6. The method of any one of claims 1 to 5, wherein the ligand is (R,R)-Ph-BPE.

7. The method of any one of claims 1 to 6, wherein the solvent comprises predominantly at least one non-polar solvent.

8. The method of any one of claims 1 to 7, wherein the solvent comprises primarily toluene or Me-THF.

9. The method of any one of claims 1 to 7, wherein the solvent comprises primarily toluene.

10. The process of any one of claims 1 to 9, wherein the reaction pressure is from about 1 bar to about 20 bar, from about 4 bar to about 15 bar, or from about 5 bar to about 10 bar.

11. The process of any one of claims 1 to 10, wherein the solvent comprises primarily toluene and the reaction temperature is from about 50°C to reflux, from about 50°C to about 100°C, or from about 70°C to about 90°C.

12. The method of any one of claims 1 to 11, wherein at least one halo is Cl.

13. R １ , R ２ , R ３ and R ４ is hydrogen; ５ The method according to any one of claims 1 to 11, wherein is Cl or F.

14. The process according to any one of claims 1 to 13, wherein the conversion of compound (2) to compound (3) is at least 85%, at least 90% or at least 95%.

15. The method according to any one of claims 1 to 14, wherein the purity of compound (3) is at least 90 area % or at least 95 area % as measured by high performance liquid chromatography.

16. The method according to any one of claims 1 to 15, wherein the chiral purity of compound (3) is at least 90 area % or at least 95 area %.

17. preparing compound (2), the method comprising forming a reaction mixture comprising compound (1), 2,3-dihydrofuran, a transition metal catalyst, a ligand, a solvent, a base, and reacting the reaction mixture to form a reaction product mixture comprising compound (2); (i) Compound (1) has the structure is; (ii) LG is a leaving group; (iii) R １ ~R ５ Each of is independently hydrogen, halo, cyano, unsubstituted C １ ~C ６ Alkyl, substituted C １ ~C ６ Alkyl, unsubstituted C １ ~C ６ Alkoxy and substituted C １ ~C ６ alkoxy; R １ ~R ５ The method of any one of claims 1 to 16, wherein at least one of is halo, and the at least one halo is selected from Cl and F.

18. 18. The method of claim 17, wherein the transition metal catalyst is a palladium catalyst.

19. The palladium catalyst is Pd(OAc) ２ , Pd(TFA) ２ Pd(PPh ３ ) ２ C ２ and Pd ２ (dba) ３ 20. The method of claim 18, wherein the

20. The palladium catalyst is Pd(OAc) ２ or Pd(TFA) ２ 20. The method of claim 18, wherein:

21. 21. The method of any one of claims 17 to 20, wherein the ligand is selected from SEGPHOS, BINAP, WALPHOS, JOSIPHOS, TANIAPHOS, MANDYPHOS, CHENPHOS, MeO-BIPHOS, PPHOS, DUPHOS, TUNEPHOS and SYNPHOS ligands.

22. 21. The method of any one of claims 17 to 20, wherein the ligand is a SEGPHOS ligand selected from (R)-Segphos, (R)-DM-Segphos and (R)-DTBM-Segphos.

23. The method of any one of claims 17 to 22, wherein the leaving group is trifluoromethanesulfonate.

24. 24. The method of any one of claims 17 to 23, wherein the solvent comprises predominantly at least one non-polar solvent, at least one polar aprotic solvent, or a combination thereof.

25. 25. The method of any one of claims 17 to 24, wherein the solvent comprises primarily toluene, tetrahydrofuran, 2-methyltetrahydrofuran, or a combination thereof.

26. The method according to any one of claims 17 to 25, wherein the base is an organic base.

27. 27. The method of claim 26, wherein the organic base is selected from triethylamine, N,N'-diisopropylethylamine and 1,4-diazabicyclo[2.2.2]octane.

28. 27. The method of claim 26, wherein the organic base is N,N'-diisopropylethylamine.

29. The method of any one of claims 17 to 28, wherein the equivalent ratio of 2,3-dihydrofuran to compound (1) is from about 1.1:1 to about 10:1, from about 3:1 to about 8:1, from about 4:1 to about 6:

1.

30. 30. The method of any one of claims 17 to 29, wherein the solvent comprises primarily toluene and 2-methyltetrahydrofuran and the reaction temperature is from about 30°C to about 70°C, from about 35°C to about 60°C, or from about 40°C to about 50°C.

31. The process according to any one of claims 17 to 30, wherein the conversion of compound (1) to compound (2) is at least 70%, at least 75% or at least 80%.

32. The method according to any one of claims 17 to 31, wherein the purity of compound (2) as measured by high performance liquid chromatography is at least 90 area % or at least 95 area %.

33. The method according to any one of claims 17 to 32, wherein the chiral purity of compound (2) is at least 90 area % or at least 95 area %.

34. The method of any one of claims 17 to 33, wherein halo is Cl.

35. R １ , R ２ , R ３ and R ４ is hydrogen; ５ The method of any one of claims 17 to 34, wherein is Cl or F.

36. Compound (2) has the structure (2a) and Compound (3) has the structure (3a) The method according to any one of claims 1 to 35,

37. Compound 1 has the structure (1a) The Wherein OTf is trifluoromethanesulfonate. The method according to any one of claims 17 to 36.

38. Compound (4) A method for preparing forming a reaction mixture comprising a hydroxylamine solution, a solvent and compound (3); and reacting the reaction mixture to form a reaction product mixture comprising compound (4); (i) Compound (3) has the structure is; (ii) each * independently represents a chiral center; (iii) E / Z represents the E / Z isomer; (iv) R １ ~R ５ Each of is independently hydrogen, halo, cyano, unsubstituted C １ ~C ６ Alkyl, substituted C １ ~C ６ Alkyl, unsubstituted C １ ~C ６ Alkoxy and substituted C １ ~C ６ alkoxy; R １ ~R ５ at least one of is halo, wherein at least one halo is selected from Cl and F; method.

39. 40. The method of claim 38, wherein the solvent comprises primarily at least one non-polar solvent.

40. 40. The method of claim 38 or claim 39, wherein the solvent comprises primarily toluene.

41. 41. The method of any one of claims 38 to 40, wherein compound (3) used to form the reaction mixture comprises compound (3) dissolved in a non-polar solvent.

42. 42. The method of claim 41, wherein compound (3) is dissolved in a non-polar solvent comprising primarily toluene.

43. The method of any one of claims 38 to 42, wherein halo is Cl.

44. R １ , R ２ , R ３ and R ４ is hydrogen; ５ The method of any one of claims 38 to 43, wherein is Cl or F.

45. The process of any one of claims 38 to 44, wherein the conversion of compound (3) to compound (4) is at least 70%, at least 75% or at least 80%.

46. The method according to any one of claims 38 to 45, wherein the purity of compound (4) is at least 95 area % or at least 98 area % as measured by high performance liquid chromatography.

47. The method according to any one of claims 38 to 46, wherein the chiral purity of compound (4) is at least 90 area % or at least 95 area %.

48. Compound (3) has the structure (3a) and Compound (4) has the structure (4a) The wherein E / Z represents the E / Z isomer.

48. The method according to any one of claims 38 to 47.

49. preparing compound (5), the method comprising forming a reaction mixture comprising compound (4), a reagent and a solvent, and reacting the reaction mixture to form a reaction product mixture comprising compound (5); (i) Compound (5) has the structure is; (ii) the reagent is a dehydrating reagent; (iii) each * independently represents a chiral center; (iv) R １ ~R ５ is independently selected from hydrogen, halogen, cyano, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; １ ~R ５ at least one of is a halo; (v) R １ ~R ５ The method according to any one of claims 38 to 48, wherein at least one of is selected from Cl and F.

50. 50. The method of claim 49, wherein the solvent comprises primarily at least one non-polar solvent.

51. 51. The method of claim 50, wherein the solvent comprises primarily methyl tert butyl ether.

52. 52. The method of claim 50 or claim 51, wherein the dehydrating reagent is carbonyldiimidazole.

53. The method according to any one of claims 49 to 52, wherein compound (5) is dissolved in an organic phase.

54. 53. The method of any one of claims 49 to 52, wherein compound (5) is isolated from the reaction product mixture.

55. The method of any one of claims 49 to 54, wherein halo is Cl.

56. R １ , R ２ , R ３ and R ４ is hydrogen; ５ The method of any one of claims 49 to 55, wherein is Cl or F.

57. Compound (5) has the structure (5a) The method according to any one of claims 49 to 56,

58. preparing compound (6), the method comprising forming a reaction mixture comprising compound (5), hydroxylamine and a polar solvent, and reacting the reaction mixture to form a reaction product mixture comprising compound (6); (i) Compound (6) has the structure is; (ii) each * independently represents a chiral center; (iii) R １ ~R ５ is independently selected from hydrogen, halogen, cyano, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; １ ~R ５ at least one of is a halo; (iv) R １ ~R ５ The method of any one of claims 49 to 57, wherein at least one of is selected from Cl and F.

59. 60. The method of claim 58, wherein the solvent comprises predominantly at least one polar protic solvent.

60. The solvent is mainly C １～４ 60. The method of claim 59, comprising alcohol; comprising predominantly isopropyl alcohol; or comprising predominantly t-amyl alcohol.

61. 61. The method of any one of claims 58 to 60, wherein the yield of compound (6) based on compound (4) is at least 75%, at least 80% or at least 85%.

62. The method of any one of claims 58 to 61, wherein halo is Cl.

63. R １ , R ２ , R ３ and R ４ is hydrogen; ５ The method of any one of claims 58 to 62, wherein is Cl or F.

64. Compound (6) has the structure (6a) The method according to any one of claims 58 to 63,

65. preparing compound (7), the method comprising forming a reaction mixture comprising compound (4), an oxidizing agent, an acid, and a solvent, and reacting the reaction mixture to form a reaction product mixture comprising compound (7); (i) Compound (7) has the structure is; (ii) each * independently represents a chiral center; (iii) R １ ~R ５ is independently selected from hydrogen, halogen, cyano, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; １ ~R ５ at least one of is a halo; (iv) R １ ~R ５ The method according to any one of claims 38 to 48, wherein at least one of is selected from Cl and F.

66. 66. The method of claim 65, wherein the oxidizing agent is selected from N-chlorosuccinimide, NaOCl, chloramine-T hydrate, 1,3-dichloro-5,5-dimethylhydrantoin, and 2-chlorobenzo[d]isothiazol-3(2H)one 1,1-dioxide.

67. 67. The method of claim 65 or claim 66, wherein the solvent comprises predominantly at least one non-polar solvent.

68. 68. The method of claim 67, wherein the solvent comprises primarily methyl tert butyl ether.

69. The method according to any one of claims 65 to 68, wherein compound (7) is dissolved in an organic phase.

70. 70. The method of any one of claims 65 to 69, wherein compound (7) is isolated from the reaction product mixture.

71. The method of any one of claims 65 to 70, wherein halo is Cl.

72. R １ , R ２ , R ３ and R ４ is hydrogen; ５ The method of any one of claims 65 to 71, wherein is Cl or F.

73. Compound (7) has the structure compound (7a): The method according to any one of claims 65 to 72,

74. preparing compound (6), the method comprising forming a reaction mixture comprising compound (7), ammonia and a polar solvent, and reacting the reaction mixture to form a reaction product mixture comprising compound (6); (i) Compound (6) has the structure is; (ii) each * independently represents a chiral center; (iii) R １ , R ２ , R ３ and R ４ is independently selected from hydrogen, halogen, cyano, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; １ ~R ５ at least one of is a halo; (iv) R １ ~R ５ The method of any one of claims 65 to 73, wherein at least one of is selected from Cl and F.

75. 75. The method of claim 74, wherein the solvent comprises primarily at least one non-polar solvent.

76. 76. The method of claim 75, wherein the solvent comprises primarily methyl tert butyl ether.

77. Ammonia is C １～４ 77. The method according to any one of claims 74 to 76, wherein the compound is dissolved in alcohol or dissolved in methyl alcohol.

78. 78. The method of any one of claims 74 to 77, wherein compound (6) is isolated from the reaction product mixture.

79. 79. The method of claim 78, wherein compound (6) is isolated from the reaction product mixture by crystallization.

80. 80. The method of any one of claims 74 to 79, wherein the yield of compound (6) based on compound (4) is at least 75%, at least 80% or at least 85%.

81. The method of any one of claims 74 to 80, wherein halo is Cl.

82. R １ , R ２ , R ３ and R ４ is hydrogen; ５ The method of any one of claims 74 to 81, wherein is Cl or F.

83. The method according to any one of claims 38 to 82, wherein compound (3) is prepared by the method according to any one of claims 1 to 37.

84. The structure: or a salt thereof, During the ceremony: (i) each * independently represents a chiral center; (ii) R １ ~R ５ is independently selected from hydrogen, halogen, cyano, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; １ ~R ５ at least one of is a halo; (iii) R １ ~R ５ At least one of is selected from Cl and F; A compound or a salt thereof.

85. The structure:

85. The compound according to claim 84, or a salt thereof.

86. The structure: or a salt thereof, During the ceremony: (i) each * independently represents a chiral center; (ii) E / Z represents the E / Z isomer; (iii) R １ ~R ５ is independently selected from hydrogen, halogen, cyano, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; １ ~R ５ at least one of is a halo; (iv) R １ ~R ５ At least one of is selected from Cl and F; A compound or a salt thereof.

87. The structure:

87. The compound according to claim 86, or a salt thereof, In the formula, E / Z represents the E / Z isomer. A compound or a salt thereof.

88. The structure: or a salt thereof, During the ceremony: (i) each * independently represents a chiral center; (ii) R １ ~R ５ is independently selected from hydrogen, halogen, cyano, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; １ ~R ５ at least one of is a halo; (iii) R １ ~R ５ At least one of is selected from Cl and F; A compound or a salt thereof.

89. The structure:

89. The compound according to claim 88, or a salt thereof.

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