Stereoselective synthesis of intermediates for the preparation of heterocyclic compounds

Abstract

A stereoselective synthesis of an intermediate for preparing heterocyclic derivatives as cap-dependent endonuclease inhibitors is provided. This method has the advantages of simple operation, high yield, and relatively controlled stereoselectivity, making it suitable for large-scale production.

Description

[Technical Field]

[0001] The present disclosure relates to stereoselective methods for preparing substituted heterocyclic compounds. Additionally, the present disclosure also relates to intermediates for preparing substituted heterocyclic compounds. [Background technology]

[0002] Cap-dependent endonucleases are enzymes involved in the inhibition of influenza virus mRNA synthesis. Cap-dependent endonuclease inhibitors have been shown to be effective against influenza viruses A and B. Some compounds have demonstrated potent antiviral activity against influenza viruses by inhibiting cap-dependent endonucleases. PCT published application WO2019 / 144089 first disclosed novel heterocyclic compounds as potent cap-dependent endonuclease inhibitors. WO2019 / 144089 also describes a method for preparing heterocyclic compounds, including the use of racemic polycyclic compounds containing sulfur atoms as intermediates. However, synthetic control over the chirality of heterocyclic compounds is lacking in this prior art. Summary of the Invention

[0003] The present disclosure provides intermediates and synthetic routes for producing heterocyclic compounds with simple chemical unit operations, higher yields, controllable chirality, and are suitable for industrial production. In some embodiments, the present disclosure also provides manufacturing methods for producing heterocyclic compounds using stereoselective intermediates.

[0004] In at least one embodiment of the present disclosure, there is provided an intermediate represented by the following formula (I) or a salt thereof: [ka] where R1 is halogen; R1' is halogen; and "*" represents the R-enantiomer or the S-enantiomer.

[0005] In at least one embodiment of the present disclosure, there is also provided an intermediate represented by the following formula (II) or a salt thereof: [ka] where R1 is halogen, R1' is halogen, R2 is hydrogen, deuterium, halogen, or a C1-C6 alkyl group, R3 is hydrogen, NO, or NH2, m is 0, 1, 2, or 3, P is a protecting group, and "*" represents the R-enantiomer, S-enantiomer, or racemate.

[0006] In at least one embodiment of the present disclosure, a manufacturing process is provided for producing an intermediate of formula (I).

[0007] In at least one embodiment of the present disclosure, a manufacturing method is provided for producing an intermediate of formula (II). DETAILED DESCRIPTION OF THE INVENTION

[0008] To facilitate understanding of the disclosure set forth herein, several terms are defined below.

[0009] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0010] The term "about" will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. As used herein, when referring to a measurable value such as an amount, aging period, etc., the term "about" is meant to encompass a variation of ±20% or ±10% (including ±5%, ±1%, and ±0.1%) from the specified value, where such variation is appropriate for carrying out the disclosed manufacturing methods.

[0011] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0012] As used herein, "C 1-6 The term "alkyl group" refers to a straight or branched chain saturated hydrocarbon substituent containing 1 to 6 (e.g., 1 to 3, 1 to 4, and 1 to 5) carbon atoms. 1-6 Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, and an n-pentyl group.

[0013] As used herein, the term "one or more" refers to either one or a number greater than one (e.g., 2, 3, 4, 5, 6, 7 or more).

[0014] As used herein, the term "protecting group" refers to a moiety formed to render a functional moiety unreactive. The protecting group can be removed to return the functional moiety to its original state. Various protecting groups and protecting reagents (including hydroxy-protecting groups) are well known to those skilled in the art and include compounds disclosed in Protective Groups in Organic Synthesis, 4th edition, T.W. Greene and P.G.M. Butts, John Wiley & Sons, New York, 2006.

[0015] The term "salt" as used herein refers to an acid or base addition salt of a compound of the present disclosure. "Salt" includes, for example, "pharmaceutically acceptable salts." As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Examples of salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, potassium, sodium, zinc, etc. Examples of salts derived from pharmaceutically acceptable non-toxic organic bases include salts of primary, secondary, and tertiary amines, naturally occurring substituted amines, cyclic amines, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compounds used in the present disclosure are basic, salts can be prepared from pharmaceutically acceptable inorganic and organic acids. Examples of such inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, etc. Examples of such organic acids include, but are not limited to, formic acid, acetic acid, phenylacetic acid, propionic acid, stearic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, picric acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, malic acid, mandelic acid, citric acid, tartaric acid, pyranosidyl acids (e.g., glucuronic acid and galacturonic acid), amino acids (e.g., aspartic acid, glutaric acid, and glutamic acid), aromatic acids (e.g., benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, and cinnamic acid), and the like.It will be understood that, as used herein, references to the compounds of the present disclosure are meant to also include the pharmaceutically acceptable salts.

[0016] First, what is disclosed in detail in this specification is an intermediate represented by the following formula (I), or a salt thereof. [ka] wherein R1 is halogen; R1' is halogen; and "*" represents the R-enantiomer or the S-enantiomer. In at least one embodiment, R1 is fluorine and R1' is fluorine.

[0017] In at least one embodiment, the intermediate of formula (I) can be represented by formula (Ia) or formula (Ib): [ka]

[0018] In some embodiments, the intermediate of formula (I) is [ka] is.

[0019] The present disclosure also provides an intermediate represented by formula (II): [ka] wherein R1 is halogen; R1' is halogen; R2 is hydrogen, deuterium, halogen, or a C1-C6 alkyl group; R3 is hydrogen, NO, or NH2; m is 0, 1, 2, or 3; P is a protecting group; and "*" represents the R-enantiomer, S-enantiomer, or racemate. In at least one embodiment, R1 is fluorine and R1' is fluorine. In some embodiments, R2 is hydrogen, deuterium, or a methyl group. In some embodiments, R2 is hydrogen. In some embodiments, R3 is hydrogen or NO. In some embodiments, m is 0. In some embodiments, examples of protecting groups include, but are not limited to, benzyl (Bn), tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), trityl, and the like.

[0020] In at least one embodiment, the intermediate of formula (II) is of formula (IIa) or (IIb): [ka] where R1, R1', R2, R3, m, and P are defined as above.

[0021] In some embodiments, the intermediate of formula (IIa) may be represented by formula (IIa-1) or formula (IIa-2): [ka] where R1, R1', R2, m, and P are defined as above.

[0022] In at least one embodiment, the intermediate of formula (IIb) may be represented by formula (IIb-1) or formula (IIb-2): [ka] where R1, R1', R2, m, and P are defined as above.

[0023] In some embodiments, the intermediate of formula (II) is [ka] is.

[0024] In one aspect of the present disclosure, there is provided a method for preparing a compound of formula (II) from a compound of formula (I).

[0025] In at least one embodiment, the present disclosure provides a method for producing a compound of formula (IIa-1), the method comprising the step of reacting a compound of formula (I-2) below with a compound of formula (Ia) below in the presence of an inert solvent, a suitable acid, and a reducing agent at a temperature of about −20° C. to about 30° C. (e.g., −15° C. to 25° C., −10° C. to 20° C., −5° C. to 15° C., 0° C. to 10° C., 0° C. to 5° C., and 5° C. to 10° C.) to form a compound of formula (IIa-1) below or a salt thereof, as follows: [ka] where R1, R1', R2, m, and P are defined as above.

[0026] In at least one embodiment, examples of inert solvents include, but are not limited to, toluene, tetrahydrofuran (THF), methyl tert-butyl ether (MTBE), dichloromethane (DCM), diethyl ether, acetonitrile, dimethyl carbonate, ethyl acetate, isopropyl acetate, tert-butyl acetate, HO, methanol, isopropanol, ethylene glycol, ethanol, propanol, hexane, heptane, etc., or mixtures thereof. In at least one embodiment, the inert solvent is toluene, THF, mTBE, DCM, diethyl ether, acetonitrile, ethyl acetate, isopropyl acetate, tert-butyl acetate, HO, hexane, heptane, etc., or mixtures thereof.

[0027] In at least one embodiment, examples of suitable acids include, but are not limited to, acetic acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, benzoic acid, etc., or mixtures thereof. In at least one embodiment, examples of suitable acids are acetic acid, citric acid, fumaric acid, maleic acid, malic acid, tartaric acid, benzoic acid, oxalic acid, succinic acid, etc., or mixtures thereof.

[0028] In at least one embodiment, examples of reducing agents include, but are not limited to, sodium borohydride (NaBH), sodium triacetoxyborohydride (NaBH(OAc)), sodium cyanoborohydride (NaBHCN), lithium borohydride (LiBH), potassium borohydride (KBH), and the like, or mixtures thereof.

[0029] In at least one embodiment, the method for producing a compound of Formula (IIa-1) further comprises the step of subjecting the compound of Formula (IIa-1) to a nitrosation reaction in the presence of an inert solvent, a suitable acid, and a nitrite at a temperature of about −20° C. to about 30° C. (e.g., −15° C. to 25° C., −10° C. to 20° C., −5° C. to 15° C., 0° C. to 10° C., 0° C. to 5° C., and 5° C. to 10° C.) to form a compound of Formula (IIa-2) below or a salt thereof: [ka] where R1, R1', R2, m, and P are defined as above.

[0030] In at least one embodiment, examples of inert solvents include, but are not limited to, toluene, THF, MTBE, DCM, diethyl ether, acetonitrile, acetone, dimethyl carbonate, ethyl acetate, isopropyl acetate, tert-butyl acetate, HO, methanol, isopropanol, ethylene glycol, ethanol, propanol, hexane, heptane, etc., or mixtures thereof. In at least one embodiment, the inert solvent is toluene, THF, MTBE, DCM, diethyl ether, acetonitrile, ethyl acetate, isopropyl acetate, tert-butyl acetate, HO, methanol, isopropanol, ethylene glycol, hexane, heptane, etc., or mixtures thereof.

[0031] In at least one embodiment, examples of suitable acids include, but are not limited to, acetic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, benzoic acid, and the like, or mixtures thereof.

[0032] In at least one embodiment, examples of nitrites include, but are not limited to, sodium nitrite, potassium nitrite, calcium nitrite, amyl nitrite, isoamyl nitrite, butyl nitrite, and isobutyl nitrite.

[0033] In some embodiments, the method for producing a compound of Formula (IIa-2) further comprises the step of conducting a cyclization reaction of the compound of Formula (IIa-2) in the presence of an inert solvent, a suitable acid, and a catalyst at a temperature of about 30°C to about 80°C (e.g., 35°C to 75°C, 40°C to 70°C, 45°C to 65°C, 50°C to 60°C, 55°C to 60°C, and 50°C to 55°C) to form a compound of Formula (III) or a salt thereof: [ka] where R1, R1', R2, m, and P are defined as above.

[0034] In some embodiments, examples of inert solvents include, but are not limited to, toluene, THF, MTBE, diethyl ether, acetonitrile, acetone, dimethyl carbonate, ethyl acetate, isopropyl acetate, tert-butyl acetate, HO, methanol, isopropanol, ethylene glycol, ethanol, propanol, hexane, heptane, and the like, or mixtures thereof.

[0035] In at least one embodiment, examples of suitable acids include, but are not limited to, acetic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, trifluoroacetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, benzoic acid, and the like, or mixtures thereof.

[0036] In at least one embodiment, examples of catalysts include, but are not limited to, zinc, iron, manganese, copper, nickel, cobalt, and the like, or mixtures thereof.

[0037] In some embodiments, the method for producing a compound of formula (III) above further comprises the step of oxidizing and deprotecting the compound of formula (III) to form a compound of formula (IV) below or a salt thereof: [ka] where R1, R1', R2, and m are as defined above, and the oxidation reaction is carried out in the presence of a first solvent and an oxidizing agent at a temperature of about 20°C to about 60°C (e.g., 25°C to 55°C, 30°C to 50°C, 35°C to 45°C, 40°C to 45°C, 40°C to 50°C, and 45°C to 50°C). The deprotection reaction is carried out in the presence of a second solvent, a catalyst, and a suitable acid at a temperature of about 60°C to about 100°C (e.g., 65°C to 95°C, 70°C to 90°C, 75°C to 85°C, 75°C to 80°C, and 80°C to 85°C).

[0038] In at least one embodiment, examples of the first solvent include, but are not limited to, toluene, THF, MTBE, DCM, diethyl ether, acetonitrile, acetone, dimethyl carbonate, ethyl acetate, isopropyl acetate, tert-butyl acetate, HO, hexane, heptane, and the like, or mixtures thereof.

[0039] In at least one embodiment, examples of oxidizing agents include, but are not limited to, Dess-Martin periodinane, manganese dioxide, 2-iodoxybenzoic acid, tetrapropylammonium perruthenate / N-methylmorpholine N-oxide (TPAP / NMO), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), sodium periodate, dimethyl sulfoxide, sodium hypochlorite, Swern oxidation reagents, and the like.

[0040] In at least one embodiment, examples of the second solvent include, but are not limited to, toluene, THF, MTBE, DCM, diethyl ether, acetonitrile, acetone, dimethyl carbonate, dimethylacetamide, ethyl acetate, isopropyl acetate, tert-butyl acetate, HO, hexane, heptane, and the like, or mixtures thereof.

[0041] In at least one embodiment, examples of suitable acids include, but are not limited to, acetic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, trifluoroacetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, benzoic acid, and the like, or mixtures thereof.

[0042] In at least one embodiment, examples of catalysts include, but are not limited to, lithium chloride, lithium bromide, lithium iodide, magnesium bromide, magnesium chloride, magnesium iodide, zinc chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium chloride, and the like, or mixtures thereof.

[0043] In some embodiments, the method for preparing a compound of Formula (III) comprises: (1) oxidizing a compound of formula (III) in the presence of a first solvent and an oxidizing agent at a temperature of about 20°C to about 60°C (e.g., 25°C to 55°C, 30°C to 50°C, 35°C to 45°C, 40°C to 50°C, 40°C to 45°C, and 45°C to 50°C, etc.) to form a compound of formula (III-a) or a salt thereof; [ka] (2) deprotecting the compound of formula (III-a) in the presence of a second solvent, a catalyst, and a suitable acid at a temperature of about 60°C to about 100°C (e.g., 65°C to 95°C, 70°C to 90°C, 75°C to 85°C, 80°C to 85°C, and 75°C to 80°C) to form a compound of formula (IV) or a salt thereof: [ka] where R1, R1', R2, and m are defined as above.

[0044] In at least one embodiment, examples of the first solvent include, but are not limited to, toluene, THF, MTBE, DCM, diethyl ether, acetonitrile, acetone, dimethyl carbonate, ethyl acetate, isopropyl acetate, tert-butyl acetate, HO, hexane, heptane, and the like, or mixtures thereof.

[0045] In at least one embodiment, examples of oxidizing agents include, but are not limited to, Dess-Martin periodinane, manganese dioxide, 2-iodoxybenzoic acid, tetrapropylammonium perruthenate / N-methylmorpholine N-oxide (TPAP / NMO), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), sodium periodate, dimethyl sulfoxide, sodium hypochlorite, Swern oxidation reagents, and the like.

[0046] In at least one embodiment, examples of the second solvent include, but are not limited to, toluene, THF, MTBE, DCM, diethyl ether, acetonitrile, acetone, dimethyl carbonate, dimethylacetamide, ethyl acetate, isopropyl acetate, tert-butyl acetate, HO, hexane, heptane, and the like, or mixtures thereof.

[0047] In at least one embodiment, examples of suitable acids include, but are not limited to, acetic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, trifluoroacetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, benzoic acid, and the like, or mixtures thereof.

[0048] In at least one embodiment, examples of catalysts include, but are not limited to, lithium chloride, lithium bromide, lithium iodide, magnesium bromide, magnesium chloride, magnesium iodide, zinc chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium chloride, and the like, or mixtures thereof.

[0049] In some embodiments, the compounds of the present disclosure may be converted into prodrugs by any known method. For example, the method for producing the compound of formula (IV) above further comprises converting the compound of formula (IV) into a prodrug thereof having formula (V) or a pharmaceutically acceptable salt thereof in the presence of an inert solvent, a suitable base, and a catalyst at a temperature of about 30°C to about 80°C (e.g., 35°C to 75°C, 40°C to 70°C, 45°C to 65°C, 50°C to 60°C, 50°C to 55°C, and 55°C to 60°C): [ka] wherein R1, R1', R2, and m are as defined above, and G is any suitable prodrug group.

[0050] In at least one embodiment, examples of prodrug groups include, but are not limited to: [ka]

[0051] In at least one embodiment, examples of inert solvents include, but are not limited to, toluene, THF, MTBE, DMA, diethyl ether, acetonitrile, acetone, dimethyl carbonate, ethyl acetate, isopropyl acetate, tert-butyl acetate, HO, methanol, isopropanol, ethylene glycol, ethanol, propanol, hexane, heptane, and the like, or mixtures thereof.

[0052] In at least one embodiment, examples of suitable bases include, but are not limited to, alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide), alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, CsCO), alkali metal bicarbonates (e.g., sodium bicarbonate, potassium bicarbonate), alkali metal alkoxides (e.g., sodium methoxide, potassium methoxide), or organic bases, or the like, or mixtures thereof.

[0053] In at least one embodiment, examples of catalysts include, but are not limited to, lithium iodide, sodium iodide, potassium iodide, lithium bromide, sodium bromide, potassium bromide, tetrabutylammonium bromide (TBAB), and the like, or mixtures thereof.

[0054] In another aspect of the disclosure, there is provided a process for preparing the R-enantiomer or S-enantiomer of a compound of formula (I) or a salt thereof. [ka]

[0055] The production method comprises: 1-6 Alkyl sulfinamide or unsubstituted or halogen or C 1-3The process includes the steps of condensing the compound of formula (I-1) by contacting it with an (R)- or (S)-chiral resolving agent such as methylbenzylamine substituted with one or more groups including an alkyl group, reducing it with a suitable reducing agent such as a borane reagent in the presence of an inert solvent, and removing protecting moieties such as a sulfinyl group moiety and an ethylbenzene moiety by treating it with a mineral acid. [ka]

[0056] In at least one embodiment, a method for producing a compound of the following formula (Ia) or a salt thereof comprises reacting an (S)-C 1-6 Alkyl sulfinamide, or unsubstituted or halogen or C 1-3 The method includes the steps of: carrying out a condensation reaction of a compound of formula (I-1) by contacting the compound with (S)-(-)-methylbenzylamine substituted with one or more groups, including an alkyl group; reducing the compound with a suitable reducing agent, such as a borane reagent, in the presence of an inert solvent at a temperature of about -30°C to about 30°C (e.g., -25°C to 25°C, -20°C to 20°C, -15°C to 15°C, -10°C to 10°C, -10°C to 5°C, -5°C to 5°C, -5°C to 0°C, and 0°C to 5°C, etc.); and removing the sulfinyl group moiety or the ethylbenzene moiety by treating the compound with a mineral acid. [ka] [ka] where R1 is a halogen and R1' is a halogen.

[0057] In at least one embodiment, examples of transition metal catalysts include, but are not limited to, titanium ethoxide, titanium methoxide, titanium isopropoxide, titanium tert-butoxide, and the like.

[0058] In at least one embodiment, examples of borane reagents include, but are not limited to, BH3DMS, BH3-THF, BMS, BH3-Et2NPH, and the like.

[0059] In at least one embodiment, examples of inert solvents include, but are not limited to, toluene, THF, MTBE, DCM, diethyl ether, acetonitrile, ethyl acetate, isopropyl acetate, tert-butyl acetate, HO, methanol, isopropanol, ethylene glycol, ethanol, propanol, hexane, heptane, and the like, or mixtures thereof.

[0060] In at least one embodiment, examples of mineral acids include, but are not limited to, hydrochloric acid, orthophosphoric acid, trifluoroacetic acid, acetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, nitric acid, sulfuric acid, and the like, or mixtures thereof.

[0061] In some embodiments, the method for preparing a compound of formula (Ia) or a salt thereof comprises: [ka] (1) A compound of formula (I-1) is reacted with a compound of formula (I-2) to form an (S)-C 1-6 Alkyl sulfinamide, or unsubstituted or halogen or C 1-3 a step of contacting the compound with a resolving agent such as (S)-(-)-methylbenzylamine substituted with one or more groups, including an alkyl group, to carry out a condensation reaction to form a compound represented by the following formula (I-1a) or (I-1b) or a salt thereof; [ka] [ka] where R1 is halogen; R1' is halogen; and R4 is C 1-6 and R5 is a halogen or C 1-3wherein the transition metal catalyst can be titanium ethoxide, titanium methoxide, titanium isopropoxide, titanium tert-butoxide, etc.; and wherein the first solvent can be toluene, THF, MTBE, DCM, diethyl ether, acetonitrile, ethyl acetate, isopropyl acetate, tert-butyl acetate, HO, methanol, isopropanol, ethylene glycol, ethanol, propanol, hexane, heptane, etc., or a mixture thereof.

[0062] (2) reducing the compound of formula (I-1a) or (I-1b) with a suitable reducing reagent, such as a borane reagent, in the presence of a second solvent at a temperature of about −30° C. to about 30° C. (e.g., −25° C. to 25° C., −20° C. to 20° C., −15° C. to 15° C., −10° C. to 10° C., −10° C. to 5° C., −5° C. to 5° C., −5° C. to 0° C., and 0° C. to 5° C.) to form a compound of formula (I-1a-1) or (I-1b-1) below, or a salt thereof; [ka] wherein the reducing reagent can be BH3DMS, BH3-THF, BMS, BH3-Et2NPH, etc., and wherein the second solvent can be toluene, THF, MTBE, DCM, diethyl ether, acetonitrile, ethyl acetate, isopropyl acetate, tert-butyl acetate, HO, methanol, isopropanol, ethylene glycol, ethanol, propanol, hexane, heptane, etc., or a mixture thereof; and

[0063] (3) removing the sulfinyl group moiety of the compound of formula (I-1a-1) by treatment with a mineral acid, where the mineral acid can be hydrochloric acid, orthophosphoric acid, trifluoroacetic acid, acetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, nitric acid, sulfuric acid, etc., or a mixture thereof; or removing the ethylbenzene moiety of the compound of formula (I-1b-1) by treatment with a suitable reagent such as a hydrogenation reagent.

[0064] In at least one embodiment, the method for preparing a compound of formula (IIa-1) comprises reacting a compound of formula (I-1) with an (S)-C 1-6 The method includes the steps of preparing a compound of formula (Ia) by contacting the compound with an alkylsulfinamide (e.g., (S)-(-)-2-propanesulfinamide); reducing the compound with a suitable reducing agent in the presence of an inert solvent; and removing the sulfinyl moiety by treatment with a mineral acid.

[0065] Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present disclosure to its fullest extent. Accordingly, the following examples are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way. Publications cited herein are incorporated by reference in their entirety. [Example]

[0066] Example 1: Preparation of 2-methyl-propane-2-sulfinic acid (1,2-difluoro-11H-10-thia-dibenzo[a,d]cyclohepten-5-ylidene)-amide [ka] Toluene: Toluene

[0067] To a toluene solution of 1,2-difluoro-11H-10-thia-dibenzo[a,d]cyclohepten-5-one (21 g, 80 mmole) and (S)-(-)-2-propanesulfinamide (11.6 g) was added Ti(OEt)4 (titanium ethoxide, 65 g). The reaction mixture was stirred and heated to 55 °C under negative pressure for 5 h. The reaction mixture was cooled to room temperature, and ethyl acetate (EA, 80 mL) was added, followed by 1 N HCl. (aq)Hydrochloric acid (250 mL) was added and stirred for 10 minutes, and EA (200 mL) was added and stirred for 3 minutes. The phases were separated, and the separated aqueous phase was removed to obtain the organic phase. MgSO4 (magnesium sulfate, 15 g) was added and stirred for 5 minutes, followed by filtration and concentration. Next, EA (20 mL) was added and stirred. Heptane (200 mL) was then slowly added to precipitate a solid. The mixture was stirred at room temperature for 4 hours, washed with heptane (50 mL), and dried to obtain a yellow solid product (25.5 g, 87.3% yield, purity >99%).

[0068] Example 2: Preparation of 2-methyl-propane-2-sulfinic acid (1,2-difluoro-5,11-dihydro-10-thia-dibenzo[a,d]cyclohepten-5-yl)-amide [ka]

[0069] A solution of 2-methyl-propane-2-sulfinic acid (1,2-difluoro-11H-10-thia-dibenzo[a,d]cyclohepten-5-ylidene)-amide (3.65 g, 10 mmole) was added to anhydrous THF (tetrahydrofuran, 70 mL) and stirred. The reaction mixture was cooled to -10 °C. BH3DMS (2 M) was added dropwise to the above THF solution and stirred at -5 °C to 0 °C for 2 h. The completion of the reaction was confirmed by HPLC. Methanol was slowly added and stirred for 30 min. After that, ice-saturated brine (250 mL, 0 °C to 5 °C) and EA (30 mL) were added. After stirring for 10 min, the organic phase was separated and extracted. EA (20 mL) was further added to the aqueous phase and stirred for 5 min. The organic phase was again separated and extracted. The extracted organic phases were combined. MgSO4 (15 g) was added to remove water, followed by filtration and concentration to form the salt. EA (50 mL) was added with stirring. The solution was filtered through a plate filter containing Celite (15 g) and concentrated. IPA (isopropyl alcohol, 7 mL) was added and heated until the solid was completely dissolved. The solution was then cooled to room temperature, and a solid precipitated. Hexane (50 mL) was slowly added, stirred at room temperature for 2 hours, filtered, washed with hexane (30 mL), and dried to give a white solid product (2.3 g, 63% yield, purity >99%, ee value (S:R) >96%).

[0070] Example 3: Preparation of 1,2-difluoro-5,11-dihydro-10-thia-dibenzo[a,d]cyclohepten-5-ylamine [ka]

[0071] To a solution of 2-methyl-propane-2-sulfinic acid (1,2-difluoro-5,11-dihydro-10-thia-dibenzo[a,d]cyclohepten-5-yl)-amide (1.08 g, 2.94 mmole) in THF (5 mL) was slowly added 4N HCl in dioxane (3.5 mL). After complete addition of the reagent, the ice bath was removed. The reaction mixture was stirred at room temperature for 2 h. The completion of the reaction was confirmed by HPLC. The reaction mixture was cooled to 0-5 °C, and 4N sodium hydroxide (NaOH) was slowly added until the pH reached 11-12. EA (20 mL) was added, stirred for 5 min, and the organic phase was separated and extracted. Additional EA (10 mL) was added to the aqueous phase and stirred for 5 min. The organic phase was again separated and extracted. The extracted organic phases were combined. MgSO (3 g) was added, stirred to remove water, then filtered, washed with EA (10 mL), concentrated, and dried. After adding EA (3 mL), heptane (30 mL) was slowly added, stirred for 1 h, filtered, and dried to give a white solid product (0.658 g, 85% yield, >99% purity, ee value (S:R) >97%).

[0072] Example 4: Preparation of compound (IIa-1-1) [ka]

[0073] 1-((3-benzyloxy-4-oxo-4H-pyran-2-yl)-hydroxymethyl)-cyclopropanecarbaldehyde (360 g, 1.2 mole), 1,2-difluoro-5,11-dihydro-10-thia-dibenzo[a,d]cyclohepten-5-ylamine (263 g, 1 mole), THF (5 L), and acetic acid (90 mL) were added to a 10-L three-necked bottle. The reaction mixture was cooled to 5±5°C and stirred for 10 min. NaBH(OAc)3 (sodium triacetoxyborohydride, 165 g / 30 min, 3 times) was added and stirred at 5±5°C for 2 h. After the reaction was complete, MeOH (methanol, 500 mL) was added and stirred for 10 min. Then, saturated brine (5 L) and EA (2 L) were added and stirred for 10 min. The EA layer was collected. To the aqueous phase, EA (1 L) was added and stirred for 5 minutes, after which the aqueous phase was separated and removed. The collected phases were combined. MgSO (150 g) was added and stirred for 10 minutes to remove water, followed by filtration and concentration to give compound (IIa-1-1), which was used in the next step without further purification.

[0074] Example 5: Preparation of compound (IIa-2-1) [ka]

[0075] The crude residue from the above step was stirred in acetic acid (3.6 L) and HO (1 L) at 5 ± 5 °C for 10 min, followed by the addition of NaNO (sodium nitrite, 69 g / 30 min, 3 times) and stirring at 5–10 °C for 2 h. Ice-cold HO was added, stirred for 30 min, filtered, and then washed with HO (1.5 L). EA (3 L) was added to dissolve the solid, followed by the addition of saturated brine (1.5 L) and stirring for 10 min. The aqueous phase was separated and removed. MgSO (150 g) was added, stirred for 10 min to remove water, filtered, and concentrated. IPA (500 mL) was added, heated to 50 °C, and stirred for 10 min. The reaction mixture was then cooled to 40 °C, and hexane (3 L) was slowly added. After complete addition of the reagents, the reaction mixture was stirred at room temperature for 2 hours, then filtered and dried to obtain compound (IIa-2-1) (540 g, yield 93.7%, purity 99.28%).

[0076] Example 6: Preparation of Compound (III-1) [ka]

[0077] Zn (80 g) was stirred in a solution of THF (1.2 L), HO (800 mL), and AcOH (acetic acid, 100 mL) and heated to 60 °C. Compound (IIa-2-1) (115 g) was dissolved in THF (300 mL) and slowly added dropwise to the above solution, followed by stirring at 60 °C for 2 h. The reaction mixture was cooled to room temperature, filtered, and the pH was adjusted to approximately 7-8 with 2 N NaOH. The organic phase was then separated and collected. EA (500 mL) was further added to the aqueous phase, and the mixture was stirred for 5 min. The organic phase was then separated and collected again. The collected organic phases were combined. MgSO (40 g) was added, stirred at room temperature for 10 min, filtered, washed with EA (100 mL), and then concentrated. EA (200 mL) was added, stirred, and heated to 50 °C, and a solid precipitated. After stirring for 10 min, the reaction mixture was cooled to room temperature, and MTBE (methyl tert-butyl ether, 200 mL) was added. After stirring for 30 min, heptane (300 mL) was slowly added. After complete addition of the reagents, the reaction mixture was stirred at room temperature for 2 h, filtered, washed with MTBE / heptane (1:1, 100 mL, 0-5 °C), and dried under vacuum (45-50 °C) to obtain compound (III-1) (52 g, 48% yield, 94% purity).

[0078] Example 7: Preparation of compound (IV-1) [ka]

[0079] To a solution of compound (III-1) (172 g, 320 mmole) in DCM (dichloromethane, 3.6 L) was added 2,2-dimethoxypropane (DMP, 58 g). The reaction mixture was stirred and heated at approximately 40°C for 1 hour, then cooled to 25-30°C. DMP (58 g) was added, the temperature was raised to approximately 40°C, and the mixture was stirred for 1 hour, then cooled again to 25-30°C. DMP (30 g) was added, the mixture was heated to approximately 40°C, and stirred for 2 hours. The reaction mixture was cooled to room temperature, filtered, washed with DCM (400 mL), and then added to HO (4 L) with stirring. NaHCO (sodium bicarbonate, 174 g) was slowly added, followed by NaSO.5HO (sodium thiosulfate, 296 g) and stirred for 3 hours. The aqueous phase was removed, MgSO4 was added, stirred for 10 minutes to remove water, then filtered and concentrated to give compound (III-1-a), which was used in the next step without purification.

[0080] Compound (III-1-a) (133 g), LiCl (lithium chloride, 66.3 g), and DMA (dimethylacetamide, 520 mL) were added to a 3 L three-neck bottle and stirred at 80 °C for 1 h. The mixture was then cooled to 0-10 °C. THF (700 mL) and 0.5 N HCl (1.4 L) were added and stirred for 1 h. DCM (1.4 L) was added and stirred for 5 min. The mixture was extracted and washed twice with HO (1.4 L). MgSO (80 g) and activated carbon (80 g) were added and stirred for 30 min. The mixture was then filtered and concentrated to remove the DCM and THF, resulting in the precipitation of a solid. THF (200 mL) was added and stirred for 10 minutes, then MTBE (1.4 L) was added and stirred at room temperature for 2 hours. The mixture was then filtered, washed with MTBE (230 mL), and vacuum dried (40°C to 45°C) to obtain compound (IV-1) (115.8 g, yield 80%, purity 99%).

[0081] Other embodiments All features disclosed in this disclosure can be combined in any combination. Each feature disclosed in this disclosure may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each disclosed feature is only an example of a series of equivalent or similar features.

[0082] From the above description, those skilled in the art can easily ascertain the features of the present disclosure, and can make various changes and modifications to the present disclosure to adapt it to various uses and conditions without departing from the scope of the present disclosure. Accordingly, other embodiments are also within the scope of the following claims.

Claims

1. A compound represented by the following formula (I) or a salt thereof: 【Chemical 1】 Here, R １ is a halogen; R １ ' is halogen; '*' represents the R-enantiomer or the S-enantiomer.

2. The compound according to claim 1 , wherein the compound is represented by the following formula (Ia) or formula (Ib) or a salt thereof: 【Chemistry 2】

3. The following formula: 【Chemistry 3】 That is, The compound according to claim 2 or a salt thereof.

4. A compound represented by the following formula (II) or a salt thereof: 【Chemistry 4】 Here, R １ is a halogen; R １ ' is halogen; R ２ is hydrogen, deuterium, a halogen, or C １ -C ６ is an alkyl group; R ３ is hydrogen, NO, or NH ２ m is 0, 1, 2, or 3; P is a protecting group; and "*" represents the R-enantiomer, S-enantiomer, or racemate.

5. The compound according to claim 4 or a salt thereof, wherein the compound is represented by the following formula (IIa) or formula (IIb): 【Chemistry 5】

6. The compound according to claim 5, wherein the compound is represented by the following formula (IIa-1), formula (IIa-2), formula (IIb-1), or formula (IIb-2), or a salt thereof: 【Chemistry 6】

7. The following formula: 【Chemistry 7】 The compound according to claim 6, or a salt thereof, represented by:

8. A compound of the following formula (I-1) and (S)-C １－６ Alkyl sulfinamide, or unsubstituted or halogen or C １－３ A method for producing a compound of formula (Ia) or a salt thereof, comprising the step of carrying out a condensation reaction by contacting (S)-(-)-methylbenzylamine substituted with one or more groups, including an alkyl group, with the compound of formula (Ia) or a salt thereof: 【Chemistry 8】 【Chemistry 9】 Here, R １ is a halogen, and R １ ' is a halogen.

9. The method of claim 8 further comprising a reduction step.

10. A method for producing a compound of formula (IIa-1) or a salt thereof, comprising the step of reacting a compound of formula (I-2) with a compound of formula (Ia) to form a compound of formula (IIa-1) or a salt thereof: 【Chemistry 10】 Here, R １ is a halogen; R １ ' is halogen; R ２ is hydrogen, deuterium, halogen, or C １ -C ６ is an alkyl group; m is an integer of 0, 1, 2, or 3; and P is a protecting group.

11. A compound of the following formula (I-1) and (S)-C １－６ Alkyl sulfinamide, or unsubstituted or halogen or C １－３ The method according to claim 10, further comprising the step of conducting a condensation reaction by contacting (S)-(-)-methylbenzylamine substituted with one or more groups, including an alkyl group, to form a compound of formula (Ia) or a salt thereof. 【Chemistry 11】

12. The method according to claim 10, further comprising the step of subjecting the compound of formula (IIa-1) to a nitrosation reaction to form a compound of formula (IIa-2) or a salt thereof: 【Chemistry 12】

13. The method according to claim 12, further comprising a step of cyclizing the compound of formula (IIa-2) to form a compound of formula (III) or a salt thereof: 【Chemistry 13】

14. The method of claim 13, further comprising the step of oxidizing and deprotecting the compound of formula (III) to form a compound of formula (IV) or a salt thereof: 【Chemistry 14】

15. The method according to claim 14, further comprising a step of converting the compound of formula (IV) into a prodrug represented by the following formula (V) or a pharmaceutically acceptable salt thereof: 【Chemistry 15】 where G is a prodrug group; The prodrug group is 【Chemistry 16】 It is selected from the group consisting of:

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