Method for producing (6R,10S)-10-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1(6H)-pyrimidinyl}-1-(difluoromethyl)-6-methyl-1,4,7,8,9,10-hexahydro-11,15-(methano)pyrazolo[4,3-B][1,7]diazacyclotetradecine-5(6H)-one

Abstract

The present application generally relates to several methods for preparing (6R,10S)-10-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1(6H)-pyrimidinyl}-1-(difluoromethyl)-6-methyl-1,4,7,8,9,10-hexahydro-11,15-(methano)pyrazolo[4,3-b][1,7]diazacyclotetradecin-5(6H)-one (Compound 1). TIFF2023545129000148.tif129170

Description

[Technical Field]

[0001] This disclosure relates to several methods for producing (6R,10S)-10-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazole-1-yl)phenyl]-6-oxo-1(6H)-pyrimidinyl}-1-(difluoromethyl)-6-methyl-1,4,7,8,9,10-hexahydro-11,15-(methano)pyrazolo[4,3-b][1,7]diazacyclotetradecine-5(6H)-one, which is a factor XIa inhibitor useful for the treatment of thromboembolic disorders (e.g., venous thrombosis and deep vein thrombosis). [Background technology]

[0002] Factor XIa is a plasma serine protease involved in regulating blood coagulation. In vivo, tissue factor (TF) initiates binding to factor VII (FVII), producing factor VIIa (FVIIa). The resulting TF:FVIIa complex contributes to the activation of factor IX (FIX) and factor X (FX), leading to the production of factor Xa (FXa). The produced FXa acts as a catalyst, converting prothrombin to a small amount of thrombin, after which this pathway is inhibited by tissue factor pathway inhibitors (TFPIs). The catalytic amount of thrombin then triggers feedback activity to factors V, VIII, and XI, further propagating the coagulation process (Gailani, D. et al., Arterioscler. Thromb.Vasc. Biol., 27:2507-2513 (2007)). Increased thrombin levels lead to the polymerization of fibrinogen into fibrin, forming the framework of a thrombus and activating platelets, which are essential cellular coagulation components (Hoffman, M., Blood Reviews, 17:S1-S5 (2003)). Therefore, factor XIa plays a crucial role in the propagation of this amplification loop and is an attractive target in antithrombotic therapy.

[0003] U.S. Patent No. 9,453,018 discloses macrocyclic compounds as factor XIa inhibitors useful for the treatment of thromboembolic disorders. One of these compounds has the following structure. [ka]

[0004] However, applying the multi-step synthesis disclosed in U.S. Patent No. 9,453,018 to larger-scale synthesis (e.g., pilot plant or production-scale synthesis) presents various challenges. One is that the high cost of Grubbs(II) reagent makes it difficult to apply to industrial-scale synthesis. Furthermore, there is a need to continuously seek methods that yield higher results in order to reduce manufacturing costs and / or unreacted material. Preferably, inexpensive starting materials are selected in the new process.

[0005] This application relates to a method suitable for producing larger quantities of compound (I) than those typically produced by laboratory-scale methods. Furthermore, this application relates to a method for obtaining compound (I) in higher yields than previously disclosed production-scale methods.

[0006] Specifically, we adopted a different novel compound that reduces the number of synthesis steps, is inexpensive, and yields compound (I) in an extremely high yield. [Overview of the project]

[0007] This specification describes several methods for producing (6R,10S)-10-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazole-1-yl)phenyl]-6-oxo-1(6H)-pyrimidinyl}-1-(difluoromethyl)-6-methyl-1,4,7,8,9,10-hexahydro-11,15-(methano)pyrazolo[4,3-b][1,7]diazacyclotetradecine-5(6H)-one.

[0008] Accordingly, in the first embodiment, the present invention relates to the following compounds: [ka] A method for producing crystals of the solvate of; (a) The following structure: [ka] Compound A having [a certain property] is reacted with N,N-dimethylformamide dimethylacetal in a suitable solvent to obtain a mixture containing methanol as a byproduct; (b) Add the following structure to the mixture in step (a): [ka] Add compound C containing the following, and obtain the solvate of compound (I): [ka] The present invention provides a method characterized by the step of obtaining crystals.

[0009] In an embodiment of the method for producing the acetone solvate of compound (I), methanol is removed before step (b).

[0010] In an embodiment of the method for producing the acetone solvate of compound (I), after removing methanol from the mixture in step (a), acetic acid is added.

[0011] In another embodiment of the method for producing the acetone solvate of compound (I), trimethylamine is added after the addition of compound C in step (b).

[0012] In one embodiment of the method for producing the acetone solvate of compound (I), compound (I) is crystallized in a mixed solvent of methanol and water, and then washed with an aqueous acetone solution to obtain crystals of the acetone solvate of compound (I).

[0013] In a second embodiment, the present invention provides the following: [ka] Crystals of the solvate are obtained.

[0014] In this embodiment, the powder X-ray diffraction pattern of the solvate of compound (I) is characterized by including one, two, three, or four peaks selected from peaks with angle 2θ values ​​of 20.0±0.2, 21.3±0.2, 21.6±0.2, and 23.9±0.2.

[0015] An embodiment of the crystalline form of the acetone solvate of compound (I), the crystalline body is at a wavenumber (cm -1 The Fourier transform infrared absorption spectrum shows characteristic peaks represented by values ​​of approximately 1709, 1676, 1532, 1485, 1457, 1441, 1432, 1370, 1291, 1219, 1189, 1135, 1119, 1068, 1039, 994, 942, 883, 827, 801, and 696. [Brief explanation of the drawing]

[0016] The following "Modes for Carrying Out the Invention" are provided as examples, but the invention is not intended to be limited to the specific embodiments described, and can be best understood in conjunction with the accompanying drawings.

[0017] [Figure 1] Figure 1 shows the XRPD spectrum of the acetone solvate crystal of compound (I).

[0018] [Figure 2] Figure 2 shows the IR spectrum of the acetone solvate crystal of compound (I). [Modes for carrying out the invention]

[0019] This disclosure may be more readily understood by the following detailed description in conjunction with the accompanying drawings and examples that constitute part of this disclosure. The present invention is not limited to any specific device, method, application, condition or parameter described and / or shown herein, and the terms used herein are for illustrative purposes only and should be understood not to limit the claimed invention. Furthermore, the singular forms “a,” “an,” and “the” used herein and in the claims include the plural form unless otherwise explicitly stated, and references to specific numbers include at least that specific value.

[0020] The terms “contains,” “has,” “includes,” and their synonyms as used herein are intended to be unrestricted, variable phrases, terms, or words that require the presence of the specified component / step, while the presence of other components / steps is also permissible. However, these descriptions should also be interpreted as describing a composition or method as “consisting of” and “consisting essentially of” the listed compounds, in which case only the presence of the specified compound is permissible along with any pharmaceutical carrier, while other compounds are excluded.

[0021] (definition) As used herein, “pharmaceutically acceptable salt” refers to a derivative of the compound disclosed herein that has been modified by preparing the parent compound into an acid salt or base salt. Both the free and salt forms of these final compounds are included within the scope of the present invention.

[0022] Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemates are included in the scope of this invention. Various geometric isomers, such as C=C double bonds, C=N double bonds, and rings, may also exist in the compounds, and all such stable isomers are included in this invention. Cis and trans (or E and Z) geometric isomers of the compounds of this invention are described, and they may be isolated as mixtures of isomers or as separated isomers. The compounds of this invention may be isolated as optically active or racemates. Optically active compounds may be produced by re-separation of racemates or by synthesis from optically active starting materials. Optically active compounds may be produced by re-separation of racemates or by synthesis from optically active starting materials.

[0023] The term "stereoisomer" refers to an isomer of the same composition but with different spatial arrangements of atoms. Enantiomers and diastereomers are examples of stereoisomers. The term "enantiomer" refers to a type of pair of molecules that are mirror images of each other and cannot be superimposed. The term "diastereomer" refers to a stereoisomer that is not a mirror image of each other. The term "racemate" or "racemic mixture" refers to a composition in which two enantiomers are present in equimolar amounts and do not exhibit optical activity.

[0024] The symbols "R" and "S" indicate the arrangement of substituents around a chiral carbon atom. The isomer symbols "R" and "S" are used as described herein to indicate the relative arrangement of atoms to the core molecule and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68: 2193-2222 (1996)).

[0025] The term "chiral" refers to a structural characteristic of a molecule that cannot be superimposed on its own enantiomer. The term "homochiraral" refers to the state of a pure enantiomer. The term "optical activity" refers to the degree to which a chiral molecule (that is not a homochiral molecule or a racemic mixture) rotates the plane of polarization.

[0026] The compounds of the present invention, their free forms, and salts may exist in multiple tautomers, in which hydrogen atoms are replaced by those of other parts of the molecule, and the chemical bonds between atoms in the molecule are consequently transferred. Insofar as any tautomer exists, it should be understood that tautomers are included in the present invention.

[0027] IR spectroscopy, particularly FT-IR, is a technique sometimes used in conjunction with or separately from powder X-ray diffraction to evaluate the shape of solids. In IR spectroscopy, the absorbed light is plotted on the X-axis of the graph with the wavenumber (cm²). -1 The IR peak position is plotted as intensity on the Y-axis. Variations in the position of the IR peak exist and vary depending on the sample conditions as well as data acquisition and data processing. Variations in the IR spectrum described herein are generally ±2.0 cm. -1 It is reported within this range. Therefore, the use of "approximately" when referring to IR peaks means that this variation is included, and all IR peaks in this disclosure are intended to be reported including that variation.

[0028] The term "reducing agent" refers to any reagent that reduces the oxidation state of carbon atoms in a starting material by adding hydrogen atoms or electrons. These reagents are well known to those in the field. Examples of "reducing agents" include, but are not limited to, borane-dimethyl sulfide complexes, 9-borabicyclo[3.3.1]nonane (9-BBN), catecholborane, lithium borohydride, sodium borohydride, sodium borohydride-methanol complex, potassium borohydride, sodium hydroxyborohydride, lithium triethylborohydride, lithium n-butylborohydride, sodium cyanoborohydride, calcium(II) borohydride, lithium aluminum hydride, diisobutylaluminum hydride, n-butyl-diisobutylaluminum hydride, sodium bis-methoxyethoxyaluminum hydride, triethoxysilane, diethoxymethylsilane, lithium hydride, lithium, sodium, hydrogen Ni / B, etc. Certain acidic reagents and Lewis acid reagents enhance the activity of reducing agents. Examples of the above-mentioned acidic reagents include acetic acid, methanesulfonic acid, and hydrochloric acid. Examples of the above-mentioned Lewis acid reagents include trimethoxyborane, triethoxyborane, aluminum chloride, lithium chloride, vanadium(III) chloride, bis(cyclopentadienyl)titanium dichloride, cesium fluoride, potassium fluoride, zinc(II) chloride, zinc(II) bromide, and zinc(II) iodide.

[0029] The term "oxidizing agent" refers to a chemical species that accepts one or more electrons and causes a chemical reaction to proceed. Furthermore, an oxidizing agent is any substance that increases the number of bonds with oxygen or decreases the number of bonds with hydrogen. Examples of oxidizing agents include, but are not limited to, oxygen (O2), ozone (O3), hydrogen peroxide (H2O2) and other inorganic peroxides, Fenton's reagent, fluorine (F2), chlorine (Cl2), and other halogens, nitric acid (HNO3) and nitrate compounds, sulfuric acid (H2SO4), peroxodisulfuric acid (H2S2O8), persulfuric acid (H2SO5), hypochlorites, chlorites, chlorates, perchlorates, and other halogen compound analogs (e.g., household bleach (NaClO)), and hexavalent chromium compounds (e.g., chromic acid and nickel). Examples include chromic acid and chromium trioxide, pyridinium chlorochromate (PCC), and chromate / dichromate compounds, permanganate compounds (e.g., potassium permanganate (KMnO4)), sodium perborate (NaBO3), nitrous oxide (N2O), nitrogen dioxide / dinitrogen tetroxide (NO2 / N2O4), potassium nitrate (KNO3), black powder oxidizing agent sodium bismuthate (NaBiO3), cerium(IV) compounds (e.g., cerium ammonium nitrate and cerium sulfate), and lead dioxide (PbO2).

[0030] The term "dehydrating reagent" refers to any substance that dries or removes water from another substance. In a chemical reaction that causes dehydration, the reacting molecules lose water molecules. Alternatively, "dehydrating reagent" may refer to any substance that causes a dehydration reaction. Examples of organic bases include, but are not limited to, phosphoryl chloride (POCl3), (COCl)2, PCl5, SOCl2, PCl3, (chloromethylene)dimethyliminium chloride (ClCH=N(CH3)2Cl), N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N,N'-diisopropylcarbodiimide (DIC), 1-cyclohexyl-(2-morpholinoethyl)carbodiimide meth-p-toluenesulfonate (CMCT), methanesulfonyl chloride (MsCl) or 4-toluenesulfonyl chloride (TsCl) with organic bases, TiCl4 with organic bases, PPh3 with CCl4 or CBr4, SO3·Py, pivaloyl chloride with organic bases, and cyanuryl chloride with organic bases.

[0031] The term "removable protecting group" or "protecting group" refers to any group that binds to a functional site (e.g., the oxygen atom of a hydroxyl or carboxyl group, or the nitrogen atom of an amino group), preventing a reaction from occurring at these functional sites, and which can be removed by conventional chemical or enzymatic steps to reconstruct the original functional site. The type of removable protecting group used is not important.

[0032] As used herein, the term "ligand" refers to a palladium-binding phosphine derivative, such as an arylphosphine or alkylphosphine that can form a complex with a palladium atom and coordinate one or two atoms. This term is well known to those skilled in the art.

[0033] The term "chlorominating agent" or "chloromination" refers to any substance that adds a chlorine atom to a substrate. Chlorinating reagents are a specific type of oxidizing agent. Examples, but not limited to, include 1,3-dichloro-5,5-dimethylhydantoin, NCS, NaClO, trichloroisocyanuric acid, thionyl chloride (SOCl2), and oxalyl chloride ((COCl)2).

[0034] The abbreviations used in this specification are defined below. [Table 1] [Table 2]

[0035] Further abbreviations used herein are defined as follows: "℃" is Celsius temperature, "eq" is equivalent, "aq" is aqueous solution, "g" is a gram, "mg" is a milligram, "L" is a liter, "mL" is a milliliter, "μL" is a microliter, "N" is normal, "M" is molar, "mmol" is a millimole, "min" is a minute, "h" is an hour, "rt" is room temperature, "RT" is retention time, "RBF" is a round-bottom flask, "atm" is atmospheric pressure, "psi" is pounds per square inch, "conc." is concentrated, "RCM" is ring-closing metathesis, "sat" or "sat'd" is saturated, "MW" is molecular weight, "mp" is melting point, "ee" is enantiomer excess, "MS" or "Mass Spec" is mass spectrometry, "ESI" is electrospray ionization mass spectrometry, "HR" is high resolution, "HRMS" is high resolution mass spectrometer, "LCMS" is liquid chromatography mass spectrometry, "HPLC" is high-performance liquid chromatography, "RP" HPLC stands for reversed-phase HPLC, TLC stands for thin-layer chromatography, NMR stands for nuclear magnetic resonance spectroscopy, nOe stands for nuclear Overhauser effect spectroscopy. 1 "H" is a proton, "δ" is a delta, "s" is a singlet, "d" is a doublet, "t" is a triplet, "q" is a quartet, "m" is a multiplet, "br" is a broad, "Hz" is Hertz, and "α", "β", "R", "S", "E", and "Z" are stereochemical symbols well known to those skilled in the art.

[0036] (Embodiment) This application relates to a plurality of synthetic intermediates and methods for producing these intermediates and compound (I).

[0037] General embodiments of these exemplary methods are described in the schemes and examples. Each product obtained in the following procedure may be separated, isolated and / or purified as appropriate before being used in the following procedure.

[0038] Generally, the specific reaction conditions for the reaction to be carried out (e.g., temperature, reaction time, solvent, work-up procedure, etc.) are well known to those skilled in the art. Generally, the temperature is between -100°C and 200°C, the solvent is aprotic or protic, and the reaction time is between 10 seconds and 10 days. Generally, the work-up procedure consists of quenching any unreacted reagents, followed by partitioning (extracting) them into a water / organic layer, and separating the layer containing the product.

[0039] Oxidation and reduction reactions generally occur at room temperature (around 20°C), but reductions using metal hydrides are often carried out at temperatures between 0°C and -100°C. The solvent is generally aprotic in reduction reactions, while either protic or aprotic solvents can be used in oxidation reactions. The reaction time is adjusted to ensure the desired transformation is completed.

[0040] In one embodiment, the present invention provides a method for producing compound (I). In one embodiment, compound (I)·acetone: [ka] The manufacturing of, (a) The following structure: [ka] Compound A having the compound is reacted with N,N-dimethylformamide dimethylacetal in a suitable solvent to obtain a mixture containing methanol as a byproduct; (b) Add the following structure to the mixture in step (a): [ka] Add compound C containing the following, and obtain the solvate of compound (I): [ka] The process is characterized by the step of obtaining crystals.

[0041] In an embodiment of the method for producing the acetone solvate of compound (I), methanol is removed before step (b).

[0042] In an embodiment of the method for producing the acetone solvate of compound (I), acetic acid is added after methanol is removed from the mixture in step (a).

[0043] In another embodiment of the method for producing the acetone solvate of compound (I), triethylamine is added after compound C is added in step (b).

[0044] In one embodiment of the method for producing the acetone solvate of compound (I), compound (I) is crystallized in a mixed solvent of acetone and water, and then washed with an aqueous acetone solution to obtain crystals of the acetone solvate of compound (I).

[0045] In an embodiment of the method for producing the acetone solvate of compound (I), a suitable solvent for the reaction between compound A and N,N-dimethylformamide dimethyl acetal is selected from the group consisting of acetonitrile (ACN), dichloromethane (DCM), toluene, tetrahydrofuran (THF), tert-butyl methyl ether (MTBE), and ethyl acetate.

[0046] In the relevant embodiments, the present invention has the following structure: [ka] A method for producing compound A having the following characteristics: (a) The following structure: [ka] Compound 1 having the following structure is reacted with ammonia (NH3) in a suitable solvent to obtain the following structure: [ka] Obtain compound 2 having the following characteristics; (b) Compound 2 is reacted with a dehydrating agent to obtain the following structure: [ka] Obtain compound 3 having the following characteristics: (c) Compound 3 is reacted with ethyl potassium malonate, a base, and a Lewis acid to obtain compound A: [ka] This provides a method characterized by the step of obtaining [something].

[0047] In one embodiment of the method for producing compound A, calcium chloride is added as a catalyst in step (a).

[0048] In another embodiment of the method for producing compound A, the dehydrating agent in step (b) is selected from the group consisting of phosphoryl chloride (POCl3), (COCl)2, PCl5, SOCl2, PCl3, (chloromethylene)dimethyliminium chloride (ClCH=N(CH3)2Cl), N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N,N'-diisopropylcarbodiimide (DIC), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide meth-p-toluenesulfonate (CMCT), methanesulfonyl chloride (MsCl) or 4-toluenesulfonyl chloride (TsCl) with an organic base, TiCl4 with an organic base, PPh3 with CCl4 or CBr4, SO3·Py, pivaloyl chloride with an organic base, and cyanuryl chloride with an organic base. In a further embodiment, the dehydrating agent in step (b) is selected from the group consisting of phosphoryl chloride (POCl3), (COCl)2, PCl5, SOCl2, PCl3, and (chloromethylene)dimethyliminium chloride (ClCH=N(CH3)2Cl).

[0049] In an embodiment of the method for producing compound A, the Lewis acid in step (c) is selected from the group consisting of zinc chloride (ZnCl2), aluminum chloride (AlCl3), and boron trifluoride (BF3).

[0050] In another embodiment of the method for producing compound A, the base in step (c) is selected from the group consisting of triethylamine, N,N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), 1,5-diazabicyclo[4.3.0]nona-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), tetramethylethylenediamine (TMEDA), and N,N,N',N'',N''-pentamethyldiethylenetriamine (PMDTA).

[0051] In an embodiment of the method for producing compound A, a suitable solvent for dissolving ammonia is selected from the group consisting of methanol, dioxane, ethanol, isopropanol, tetrahydrofuran (THF), and water.

[0052] In the relevant embodiments, the present invention has the following structure: [ka] A method for producing compound C having the following characteristics: (a) The following structure: [ka] The hydrochloride salt of compound 15 having the above properties is dissolved in a suitable solvent. (b) Next, add the aminotransferase ATA-486 and the enzyme catalyst to compound C: [ka] This provides a method characterized by the step of obtaining [something].

[0053] In one embodiment of the method for producing compound C, the enzyme catalyst is pyridoxal 5'-phosphate hydrate (5-PLP).

[0054] In a method for producing compound C, this application relates to the following structure: [ka] A method for producing the hydrochloride salt of compound 15 having the following characteristics: (a) The following structure: [ka] Compound 8 having the following structure is obtained by reacting it with 2-methylcyclopentanone and a strong base: [ka] Obtain compound 9 having the following characteristics; (b) Compound 9 is reacted with an acidic aqueous solution to form the following structure: [ka] Obtain compound 10 having the following characteristics: (c) Compound 10 is reacted with (1R,2S)-erythro-2-amino-1,2-diphenylethanol to obtain the diastereomer salt of compound 10A: [ka] Obtaining; (d) Dissolve the diastereomer salt of compound 10A in an acidic aqueous solution and a suitable organic solvent, and compound 10A: [ka] Obtaining; (e) Compound 10A is reacted with chlorotrimethylsilane, then trimethyl orthoformate, and then a strong base to form compound 11: [ka] Obtaining; (f) Mix compound 11 with dicyclohexylamine (DCHA) to form a salt of compound 11: [ka] Obtaining; (g) dicyclohexylamine salt of compound 11 as a coupling agent and [ka] Reacting with the hydrochloride salt produces the following structure: [ka] Forming compound 14 having; (h) Compound 14 is reacted with hydrochloric acid in the presence of a metal catalyst to obtain the hydrochloride salt of compound 15: [ka] This provides a method characterized by the step of obtaining [something].

[0055] In an embodiment of the method for producing compound 15, the coupling agent in step (g) is selected from the group consisting of 1,1'-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), and 1,1'-thiocarbonyldiimidazole (TCDI).

[0056] In an embodiment of the method for producing compound 15, the acidic aqueous solution used in the production step of compound 10 is selected from the group consisting of aqueous methanesulfonic acid, dilute sulfuric acid, and hydrochloric acid.

[0057] In an embodiment of the method for producing compound 15, the appropriate organic solvent for the production step of compound 10A is selected from the group consisting of methanol, ethanol, and 2-butanone.

[0058] In an embodiment of the method for producing compound 15, the strong base used in the production step of compound 11 is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, and barium hydroxide.

[0059] In one embodiment, the present invention provides a method for obtaining a (R)-enantiomer of compound 10, characterized by fractional crystallization of the (R)-enantiomer as a diastereomer salt obtained by adding non-racemic 2-amino-1,2-diarylethanol to a solution or suspension of an enantiomer mixture of compound 10 in a solvent, where non-racemic 2-amino-1,2-diarylethanol is preferably non-racemic erythro-2-amino-1,2-diarylethanol, and particularly (1R,2S)-2-amino-1,2-diarylethanol. The adduct of the fractional crystals of (R)-compound 10 obtained as a diastereomer salt herein is non-racemic 2-amino-1,2-diphenylethanol, preferably non-racemic erythro-2-amino-1,2-diphenylethanol, and particularly preferably (1R,2S)-2-amino-1,2-diphenylethanol.

[0060] Similarly, the present invention provides a method for obtaining a (S)-enantiomer of compound 10, characterized by fractionally crystallizing the (S)-enantiomer from a solution or suspension of an enantiomer mixture of compound 10 in a solvent as a diastereomer salt to which non-racemic 2-amino-1,2-diarylethanol is added, where non-racemic 2-amino-1,2-diarylethanol is preferably non-racemic erythro-2-amino-1,2-diarylethanol, and more particularly (1S,2R)-2-amino-1,2-diphenylethanol.

[0061] In an embodiment of the fractional crystallization method for obtaining the (R)-enantiomer of compound 10, the solvent used in the fractional crystallization method is selected from the group consisting of methanol, ethanol, and 2-butanone, which may or may not contain water.

[0062] The present invention further relates to a method for racemizing an enantiomer mixture of non-racemic compound 10. The non-racemic mixture is contained in the mother liquor of the enantiomer-rich compound 10, for example, by fractional crystallization of one of the enantiomers of the above-mentioned non-racemic 2-amino-1,2-diarylethanol.

[0063] In the first step of the racemization method of the present invention, the carboxylic acid group of compound 10 is converted to an ester group for protection. In the next step, the protected derivative (compound 41) racemized at the chiral center is treated with a strong base (e.g., potassium tert-butoxide, potassium tert-pentoxide, TBD (triazabicyclodecene), and MTBD (7-methyl-1,5,7-triazabicyclo(4.4.0)deca-5-ene) to obtain compound 11. Suitable solvents for the racemization reaction are toluene, acetonitrile, MTBE, and methyl acetate. In the final step, compound 11 is deprotected to obtain a racemic mixture of enantiomers of compound 10.

[0064] In an embodiment of the method for producing compound 15, the metal catalyst in step (h) is selected from the group consisting of palladium and ruthenium. In an embodiment of the method for producing compound 15, the metal catalyst in step (h) includes a palladium catalyst selected from the group consisting of Pd(OAc)2 / Cy3P-HBF4, [Pd(allyl)Cl]2 / Ad2nBuP, and Pd(OAc)2 / BippyPhos. In an embodiment of the method for producing compound 15, the metal catalyst in step (h) includes Ru3(CO) 12 The catalysts include ruthenium catalysts selected from the group consisting of RuH2(CO)(PPh3)3 and [RuCl2(C6H6)]2.

[0065] In one embodiment, the present invention is as follows: [ka] This provides crystals of the solvate.

[0066] In this embodiment of the powder X-ray diffraction pattern of the solvate of compound (I), the powder X-ray diffraction pattern includes one, two, three, or four peaks selected from peaks represented by angle 2θ values ​​of 20.0±0.2, 21.3±0.2, 21.6±0.2, and 23.9±0.2.

[0067] In this embodiment, the crystals of the acetone solvate of compound (I) have wavenumbers (cm) of approximately 1709, 1676, 1532, 1485, 1457, 1441, 1432, 1370, 1291, 1219, 1189, 1135, 1119, 1068, 1039, 994, 942, 883, 827, 801, and 696. -1 The Fourier transform infrared absorption spectrum is shown, which has a characteristic peak represented by ).

[0068] In one embodiment of the present invention, the present application provides an alternative method for producing compound C by Claisen rearrangement.

[0069] In one embodiment, the following structure: [ka] A method for producing compound C having the following characteristics: (a) The following structure: [ka] Compound 17 having the following structure: [ka] Reacting with compound 18 having (b) Next, a non-nucleophilic base is added, followed by chlorotrimethylsilane, to form the following structure: [ka] Obtain the dihydrochloride salt of compound 20 having the following characteristics: (c) Compound 20 is reacted with a carbamate protecting group (PG) reagent, followed by propionic anhydride, and then a non-nucleophilic base to obtain the following structure: [ka] Obtain compound 21 having the following characteristics; (d) Compound 21 is reacted with a non-nucleophilic base to form the following structure: [ka] A compound 22 having the following properties was obtained; (e) Compound 22 is reacted in the presence of a metal hydride catalyst to obtain the following structure: [ka] Obtain compound 23 having the following characteristics; (f) Compound 23 is reacted with 1-(difluoromethyl)-4-nitro-1H-pyrazole (compound 12) using a metal catalyst to obtain the following structure: [ka] Obtain compound 24 having the following characteristics; (g) Compound 24 is reacted in the presence of a metal hydride catalyst to form the following structure: [ka] Obtain compound 25 having the following characteristics; (h) Compound 25 is reacted with a coupling agent to form the following structure: [ka] Obtain compound 26 having the following characteristics; (i) Compound 26 is reacted with an acid to form compound C: [ka] The process is characterized by the step of obtaining [something].

[0070] In an embodiment of the method for producing compound C, the non-nucleophilic base is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), lithium bis(trimethylsilyl)amide (LiHMDS), potassium bis(trimethylsilyl)amide (KHMDS), 1,5-diazabicyclo[4.3.0]nona-5-ene (DBN), and N,N-diisopropylethylamine (Hünig base).

[0071] In an embodiment of the method for producing compound C, the carbamate protecting group (PG) reagent in step (c) is selected from the group consisting of di-tert-butyl dicarbonate (Boc2), benzyl chloroformate (Cbz-Cl), and methyl chloroformate (CH3CO2Cl).

[0072] In an embodiment of the method for producing compound C, the metal hydride catalyst is carbon-supported ruthenium, and the Crabtree catalyst ([C8H 12 IrP(C6H 11 Selected from the group consisting of )3C5H5N]PF6) and carbon-supported palladium.

[0073] In an embodiment of the method for producing compound C, the metal catalyst used in the reaction with compound 12 in step (f) is selected from the group consisting of Pd(allyl)Cl]2 / X-Phos, XPHosPd G3, and SPhosPd G3.

[0074] In an embodiment of the method for producing compound C, the coupling agent for the reaction of compound 25 in step (h) is selected from the group consisting of 1,1'-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), and 1,1'-thiocarbonyldiimidazole (TCDI), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH).

[0075] In one embodiment of the present invention, the present application provides a method for producing compound 11 using a lactic acid derivative as a starting material.

[0076] In one embodiment, the following structure: [ka] A method for producing compound 11 having the following characteristics: (a) The following structure: [ka] Compound 27 having the following structure is reacted with (3-(1,3-dioxolan-2-yl)propyl)magnesium chloride to obtain the following structure: [ka] Obtain compound 28 having the following characteristics; (b) Compound 28 is reacted with an oxidizing agent to form the following structure: [ka] Obtain compound 29 having the following characteristics; (c) Compound 29 is reacted with N,O-dimethylhydroxylamine and a coupling agent to form the following structure: [ka] Obtain compound 30 having the following characteristics: (d) Compound 30 is reacted with 4-chloropyridine-2-ylmagnesium bromide to form the following structure: [ka] Obtain compound 31 having the following characteristics: (e) Next, add the strong acid / alcohol solution, compound 11: [ka] The process is characterized by the step of obtaining [something].

[0077] In an embodiment of the method for producing compound 11, the oxidizing agent in step (b) is selected from the group consisting of KMnO4, oxone, and NaClO2.

[0078] In an embodiment of the method for producing compound 11, the strong acid in the strong acid / alcoholic solution in step (e) is selected from the group consisting of TMSCl, MeOH, MeOH / H2SO4, and AcCl / MeOH.

[0079] In an embodiment of the method for producing compound 11, the alcohol solvent of the strong acid / alcoholic solution in step (e) is selected from the group consisting of methanol, ethanol, 2-isopropanol, n-propanol, n-butanol, and combinations thereof.

[0080] In one embodiment of the present invention, the present application provides a method for producing compound 40 using a pseudoephedrine derivative as a starting material.

[0081] In one embodiment, the following structure: [ka] A method for producing a compound 40 having the following characteristics: (a) The following structure: [ka] Compound 34 having the following structure is reacted with 2-(3-bromopropyl)-1,3-dioxolane to obtain the following structure: [ka] Obtain compound 35 having the following characteristics: (b) Compound 35 is reacted with a strong base in a suitable solvent to form the following structure: [ka] Obtain compound 36 having the following characteristics: (c) Compound 36 is reacted with benzyl alcohol and a coupling agent to form the following structure: [ka] Obtain compound 37 having the following characteristics: (d) A strong acid is reacted with compound 37, followed by the addition of an asymmetric additive along with a metal catalyst to form the following structure: [ka] Obtain compound 38 having the following characteristics; (e) Compound 38 is reacted with (4-chloropyridine-2-yl)magnesium bromide to form the following structure: [ka] Obtain compound 39 having the following characteristics; (f) Hydrolyze the ester, then add a protecting group to form compound 40: [ka] The process is characterized by the step of obtaining [something].

[0082] In an embodiment of the method for producing compound 40, the coupling agent in step (c) is selected from the group consisting of 1,1'-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), and 1,1'-thiocarbonyldiimidazole (TCDI).

[0083] In an embodiment of the method for producing compound 40, the suitable solvent for step (b) is selected from the group consisting of ethanol, methanol, tert-butanol, and combinations thereof.

[0084] In an embodiment of the method for producing compound 40, the metal catalyst in step (d) is selected from the group consisting of Ti(OEt)4, CuSO4, and Ti(OiPr)4.

[0085] In an embodiment of the method for producing compound 40, step (e) is further characterized by comprising a Lewis acid selected from ZrCl4 and BF3·OEt2.

[0086] In one embodiment of the present invention, the present application provides a synthesis method for producing compound 1 by a batch method.

[0087] In one embodiment, the following structure: [ka] A method for producing compound 1 having the following characteristics: (a) The following structure: [ka] Compound 4 having (i) React sodium nitrite and an acid in a suitable solvent to form the first mixture; (ii) Next, add the first mixture to a solution containing sodium azide and a weak base to form the second mixture; (iii) The second mixture is reacted with trimethylsilylacetylene, copper(I) iodide (CuI), and a ligand to form the following structure: [ka] Obtain compound 7 having the following characteristics; (b) Compound 7 is reacted with a chloroforming agent to obtain Compound 1: [ka] The process is characterized by the step of obtaining [something].

[0088] In an embodiment of the method for producing compound 1, the acid in step (a)(i) is selected from the group consisting of methanesulfonic acid, HBF4, TsOH, H2SO4, and HCl.

[0089] In an embodiment of the method for producing compound 1, the weak base in step (a) and (ii) is selected from the group consisting of sodium bicarbonate (NaHCO3), potassium carbonate, pyridine, 2,6-lutidine, methylamine, triethylamine, and DMF.

[0090] In an embodiment of the method for producing compound 1, the ligand in step (a)(iii) is selected from the group consisting of tetramethylethylenediamine (TMEDA), NEt2, DIPEA, TMEDTA, triethylamine, N,N-diisopropylethylamine, and N,N,N',N'',N''-pentamethyldiethylenetriamine.

[0091] In an embodiment of the method for producing compound 1, the suitable solvent for step (a)(i) is selected from the group consisting of water, ionized water, DMF, ACN, and combinations thereof.

[0092] In an embodiment of the method for producing compound 1, the aqueous solvent in step (a) and (ii) is selected from the group consisting of water, ionized water, DMF, ACN, and combinations thereof.

[0093] In an embodiment of the method for producing compound 1, the chlorinating agent in step (b) is selected from the group consisting of 1,3-dichloro-5,5-dimethylhydantoin, NCS, NaClO, and trichloroisocyanuric acid.

[0094] In one embodiment of the present invention, the present application provides a synthesis method for producing compound 1 by a flow method.

[0095] In one embodiment, the following structure: [ka] A method for producing compound 1 having the following characteristics: (a) The following structure: [ka] Compound 4 having (i) by reacting with an acid and sodium nitrite in a suitable solvent; (ii) Reacting with a water-soluble mixture of sodium azide and a weakly basic aqueous solution produces the following structure: [ka] Forms compound 6 having; (b) Next, compound 6 is coupled with chloroacetylene and a metal catalyst, and compound 1: [ka] The process is characterized by the step of obtaining [something].

[0096] In an embodiment of the method for producing compound 1, the weak base in step (a) and (ii) is selected from the group consisting of sodium bicarbonate (NaHCO3), potassium carbonate, pyridine, 2,6-lutidine, methylamine, triethylamine, and DMF.

[0097] In an embodiment of the method for producing compound 1, the metal catalyst is selected from the group consisting of copper(I) iodide, CuBr, CuCl, Cu2O, CuSO4, CuSO4(5H2O), Cu(OAc)2, Cu(acac)2, and CuCl2.

[0098] In an embodiment of the method for producing compound 1, the ligand is selected from the group consisting of tetramethylethylenediamine (TMEDA), NEt2, DIPEA, TMEDTA, triethylamine, N,N-diisopropylethylamine, and N,N,N',N'',N''-pentamethyldiethylenetriamine.

[0099] In an embodiment of the method for producing compound 1, the acid in step (a)(i) is selected from the group consisting of methanesulfonic acid, HBF4, TsOH, H2SO4, and HCl.

[0100] In one embodiment of the present invention, the present application provides a method for producing compound 33.

[0101] In one embodiment, the following structure: [ka] A method for producing a compound having the following structure: [ka] React compound 32 having it with ethyl formate to obtain compound 33:

Chemical formula

[0102] In certain embodiments, the present invention provides the following:

Chemical formula

[0103] (Examples) The following examples are for illustrative purposes only and are not intended to limit the scope of the claims appended hereto. All cited references in the examples and throughout this specification are incorporated herein for all legal purposes as if fully set forth by reference.

[0104] General aspects of these exemplary methods are described in the schemes and examples. Each product of the following methods may be separated, isolated, and / or purified as appropriate before being used in the subsequent procedures.

[0105] Also, it is recognized that another important consideration in any synthetic route plan in this field is the selection of appropriate protecting groups to be used for the protection of reactive functional groups present in the desired compounds described in the present invention. For the skilled experimenter, an authoritative literature describing many alternatives of protecting groups is Protective Groups In Organic Synthesis (Fourth Edition Wiley-Interscience (2006)) by Greene et al.

[0106] Unless otherwise specified, all reactions were carried out under nitrogen. The solvents used for extraction and reaction were of ACS grade and were used without purification. 1 H NMR and 13¹³C NMR spectra were detected using a Bruker Advance DRX 400 spectrometer, a Bruker Advance III 400 spectrometer, a Bruker Advance 500 MHz spectrometer, and a Bruker Advance III 400 spectrometer. Chemical shifts are expressed in ppm(δ), and coupling is indicated by s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or br (broad). The coupling constant J is expressed in Hz. Solvent removal was performed under vacuum (~25-40 mmHg) using a rotary evaporator.

[0107] [ka]

[0108] Step (a): Coupling reaction In a reaction vessel (1 L), ethyl (Z)-3-amino-3-(5-chloro-2-(4-chloro-1H-1,2,3-triazole-1-yl)phenyl)acrylate (compound A) (1.07 equivalents, 104.4 g), acetonitrile (6.8 L / kg, 680 mL), and N,N-dimethylformamide dimethyl acetal (1.26 equivalents, 50.1 mL) were added. The resulting solution was heated at 75°C for 30 minutes, followed by atmospheric distillation of the methanol byproduct. After cooling the reaction system to 30°C, acetic acid (10 equivalents, 170.9 mL) was added, and the mixture was stirred at 40°C for 5 hours. At 30°C, (5R,9S)-9-amino-2 1 -(difluoromethyl)-5-methyl-2 1 H-3-aza-1(4,2)-pyridina-2(5,4)-pyrazolacyclonononaphan-4-one (compound C) (1.0 equivalent, 100 mL) and acetonitrile (2.5 L / kg, 250 mL) were added, and the mixture was then heated at 65°C for 2 hours. The reaction system was cooled to 40°C, and then 254 mL (6.1 equivalents) of triethylamine was added.

[0109] Step (b): Workup Under vacuum (200 mbar), acetonitrile was replaced with trimethylamine by azeotropic distillation. 355 mL (3.55 L / kg) was distilled, and then 145 mL (3.5 equivalents) of triethylamine was added. 240 mL (2.4 L / kg) was distilled at 200 mbar, and then 145 mL (3.5 equivalents) of triethylamine was added. Finally, 225 mL (2.25 L / kg) was distilled at 200 mbar, and then 112 mL (2.7 equivalents) of triethylamine was added.

[0110] Step (c): Filtration At 45°C, water (0.32 L / kg, 32 mL) and acetone (4.4 L / kg, 440 mL) were added. The reaction system was then cooled to 25°C, filtered through charcoal, and washed with 65 mL (0.65 L / kg) of acetone.

[0111] Step (d): Crystallization At 45°C, methanol (0.68 L / kg, 68 mL) and water (0.59 L / kg, 59 mL) were added, followed by the addition of 1.0 wt% (1 g) of seed crystals, and the mixture was stirred for 2 hours. Water (140 mL (1.24 L / kg)) was added over 4 hours, followed by the addition of 275 mL (2.75 L / kg) of water over 3 hours. The mixture was then cooled to 10°C over 4 hours, maintained overnight, and filtered. The wet cake was washed with a mixed solvent of acetone / water (47 / 53) (570 mL) and vacuum-dried at 50°C for 16 hours. Compound (I) was obtained as acetone solvate in yield 89–95% (purity >99.5%).

[0112] [ka]

[0113] Step (a): Preparation of diazo intermediate (compound 5) Water (18 L, 3.6 L / kg) and methyl 2-amino-5-chlorobenzoate (compound 4) (5.00 kg, 1 equivalent) were added to a reaction vessel (50 L), and the resulting slurry was cooled to 0°C to 5°C. While maintaining the temperature at 0°C to 5°C, 70% aqueous methanesulfonic acid (8.14 kg, 2.2 equivalents) was added over 1 hour. To this reaction mixture, while maintaining the temperature at 0°C to 5°C, a solution containing sodium nitrite (2.05 kg, 1.1 equivalents) and water (5.25 kg, 1.05 V) was added over 4 hours. The resulting slurry was stirred at 0°C to 5°C for 8 hours.

[0114] Step (b): Preparation of azide intermediate (compound 6) Water (20 L, 4 L / kg), sodium bicarbonate (0.91 kg, 0.4 equivalent), sodium azide (1.8 kg, 1.0 equivalent), and 2-methyltetrahydrofuran (21.5 kg, 5.0 V) were added to a reaction vessel (100 L), and the resulting mixture was stirred at 20°C for 30 minutes. The diazo solution from step (a) was added to this solution over 4 hours while maintaining the temperature at 20°C to 25°C, and the mixture was aged at the same temperature for 2 hours. The two layers were allowed to stand and separated. The organic layer was washed twice with 18.6 w% sodium chloride aqueous solution (12.3 kg, 2 kg / kg), and magnesium sulfate (1.43 kg, 0.285 kg / kg) was added to the azide solution / MeTHF, and the mixture was stirred for 1 hour.

[0115] Step (c): Preparation of compound 7 N,N,N',N'-tetramethylethylenediamine (0.16 kg, 0.05 equivalents), copper iodide (0.26 kg, 0.05 equivalents), and trimethylsilylacetylene (2.91 kg, 1.1 equivalents) were added to a reaction vessel at 20-25°C. The reaction mixture was heated at 45°C for 1 hour and stirred at the same temperature for 10 hours. After the reaction was complete, the mixture was filtered, and the filtered cake was washed twice with 2-methyltetrahydrofuran (2 x 2.6 kg, 2 x 0.6 V). In a separate reaction vessel, a solution was prepared containing sodium chloride (2.9 kg), water (10.0 kg), and 20% by weight aqueous ammonia (9.2 kg). 11.0 kg of the solution was added to the filtrate (2.0 V) described above, and the resulting mixture was stirred at 20-25°C for 30 minutes. The mixture was filtered through Celite (1.25 kg, 0.25 kg / kg), and the filtrate cake was washed twice with 2-methyltetrahydrofuran (2 x 2.6 kg, 2 x 0.6 V). The two layers were then allowed to stand and separated. The organic layer was washed again with sodium chloride aqueous solution / ammonia aqueous solution (11.0 kg, 2.0 V) and then washed once more with saturated sodium chloride aqueous solution (8.5 kg, 1.5 V). The 2-methyltetrahydrofuran solution containing crude 5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazole-1-yl)methyl benzoate (compound 7) was then concentrated under vacuum to 2.5 V (12.5 L). The mixture was heated at 60°C to 65°C for 30 minutes, to which 2-propanol (11.8 kg, 3.0 V) was added. Once all the compounds were dissolved, the solution was cooled to 0°C to 5°C over 4 hours. Water (32.5 kg, 6.5 V) was added at 0°C to 5°C over 3 hours, and the mixture was aged at the same temperature for 2 hours. After filtration, the wet cake was washed with a mixed solvent of 2-propanol / water (14.75 kg, v / v ratio 50 / 50) and vacuum-dried at 40°C for 12 hours. Methyl 5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)benzoate (compound 7) was obtained (yield 85-88%, purity >99.5%). 1 H NMR (CDCl3, 300MHz): δ=7.87(d, J=2.4Hz, 1H), 7.77(s, 1H), 7.55(dd, J=8.5, 2.4Hz, 1H), 7.38(d, J=8.4Hz, 1H), 3.61(s, 3H), 0.32(s, 9H); 13 C NMR (CDCl3, 75MHz): δ=164.4, 146.3, 135.3, 134.4, 132.3, 130.8, 130.5, 128.6, 127.7, 52.5, -1.3ppm

[0116] Step (d): Preparation of compound 1 Add DMF (33.3 kg, 5 L / kg), compound 7 (1 equivalent, 7.1 kg), and water (0.41 kg, 1.0 equivalent) to a reaction vessel (50 L), and cool this solution to 0 - 5 °C. While maintaining the temperature below 10 °C, add 1,3-dichloro-5,5-dimethylhydantoin (3.4 kg, 0.75 equivalent) in several portions over 6 hours, and stir the reaction system at 0 - 5 °C for an additional 15 hours. After complete conversion, heat the reaction mixture to 30 °C within 2 hours and age at the same temperature for 2 hours. Add water (35.3 kg, 5 L / kg) to another reaction vessel and heat to 30 °C. While maintaining the temperature at 30 - 35 °C, add the above reaction mixture to this vessel over 5 hours. After aging for 20 minutes, cool the slurry to 15 - 20 °C over 2 hours and age at the same temperature for 2 hours. After filtration, wash the wet cake with methanol / water (methanol 1 L / kg, water 1.2 L / kg) and dry in vacuo at 40 °C for 16 hours. Methyl 5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzoate (Compound 1) was obtained (yield 89 - 93%, purity > 99.5%).

[0117]

Chemical formula

[0118] Step (a): Preparation of the diazo intermediate In a flow reaction vessel, mix a solution of methyl 2-amino-5-chlorobenzoate (Compound 4) (741.0 g, 1 equivalent), methanesulfonic acid (844 g, 2.2 equivalents), water (2223 g), and acetonitrile (1747 g) at ~0 °C with a solution of sodium nitrite (331 g, 1.2 equivalents) / water (2964 g).

[0119] Step (b): Production of azide intermediate React the diazonium solution from step (a) with a mixture of water (2964 g), sodium bicarbonate (134 g, 0.4 equivalent), sodium azide (272 g, 1.05 equivalents), and 2-methyltetrahydrofuran (2549 g) at room temperature, and remove the aqueous layer. The organic layer was used directly in the next step (in situ yield 99%).

[0120] Step (c): Production of chloroacetylene A mixture of 1,1-dichloroethene (871 g, 2.25 equivalents) / THF (1635 g) was mixed with an LDA solution (2.0 M, 2431 g, 3.0 equivalents) at -20 °C and diluted with THF (3257 g). The reaction was quenched with water (5988 g), and the aqueous layer was removed. The organic layer was used directly in the next step.

[0121] Step (d): Preparation of compound 1 The aryl azide solution of step (b) was first mixed with a solution of N,N,N',N'-tetramethylethylenediamine (101 g, 0.22 equivalent), copper(I) iodide (38 g, 0.05 equivalent), and THF (1159 g), and then the azide-copper solution was mixed with the chloroacetylene solution of step (c) at 60 °C. The reaction mixture was quenched with an ammonium chloride / ammonium hydroxide solution. The layers were separated, and the aqueous layer was back-extracted with THF. The organic layers were combined, washed with brine, the aqueous layer was back-extracted, and the organic layers were combined. THF was removed by distillation and replaced with MeOH. This was heated to 60 °C, cooled to 15 °C, and the product was crystallized by adding water to obtain Compound 1 (overall yield 92.6%, purity >99%).

[0122] TIFF0007844457000074.tif121164

[0123] Step 1: Flow synthesis procedure for compound 6 Flow parameter settings [Table 3]

[0124] The flow reaction vessel was pre-cooled to 0°C using a circulating cooling system. The flow rates of aniline (compound 4) and NaNO2 were set to 6 g / min and 1.78 g / min, respectively, and equilibration of the flow reaction vessel was started while circulating the effluent. After about 1 minute, the effluent from the reaction vessel changed from deep red to pale yellow, indicating that the reaction vessel had been fully equilibrated. While circulating the effluent, 2-MeTHF and NaN3 were flowed at flow rates of 3.2 g / min and 2.84 g / min, respectively. When each flow path reached a constant value, all valves were switched to the flow path of the loop that quenched the reaction. Rapid generation of N2 (gas) was immediately observed. The effluent after quenching was discarded until about 1 minute had elapsed. The effluent after quenching was then collected in a container. The recovery pump was started at a rate that maintained a constant volume in the container when the organic layer in the container reached the immersion tube of the pump that recovers the organic layer. The organic effluent was recovered for a total of 50 minutes. The organic layer (total 266g) was collected, and the organic layer 1 1H-NMR analysis revealed that the solution contained 17.02 wt% of compound 6 (yield: 45.3 g, yield 99%). HPLC analysis confirmed that the solution contained >99% compound 6.

[0125] Step 2: Synthesis procedure for compound 1 (flow method) Under nitrogen, THF (300 mL) was added to CuI (5.71 g, 30 mmol), followed by PMDTA (5.20 g, 30 mmol). This mixture was sonicated and completely dissolved (CuI solution). Flow parameter settings [Table 4]

[0126] Chloroacetylene solution (3.87 g / min), compound 6 solution (1.91 g / min), and CuI solution (0.763 mL / min) were added sequentially to the flow reaction vessel. After the material flowed through the system for two vessel volumes (10 minutes), recovery was initiated. Recovery was stopped once before deciding which waste to discard from the plugged flow reactor (PFR). The system was restarted in the same manner as above, and after the system was re-equilibrated for two vessel volumes (10 minutes), the material was recovered into a vessel for quenching the reaction. The material was recovered for a total of 131 minutes, consuming 193.4 mmol of compound 6. The material in the quenching vessel was transferred to a separatory funnel, and the organic layer was separated. The aqueous layer was further extracted with THF (155 mL, 3.8 volumes), and then the organic layer was washed together with 50% saline solution (155 mL, 3.8 volumes), and the resulting aqueous layer was further extracted with THF (78 mL, 1.9 volumes). Next, the organic layers are combined and 1,3,5-trimethoxybenzene is used as the internal standard. 1 Analysis using 1H NMR spectrometry confirmed the presence of compound 1. The organic layer (total 871.6g) was collected, a small sample (approximately 20mL) was taken and further analyzed, and the remaining material was concentrated under reduced pressure to obtain a light brown solid (54.7g). Quantitative analysis of this solid by NMR revealed that 95% was compound 1 and 5% was residual ethylbenzene.

[0127] Isolation The solvent was removed by distillation to 5 L / kg, and the mixture was cooled to 35°C. After adding the seed crystal, heptane (11 L / kg) was added, and the reaction mixture was cooled to 10°C. After filtration, compound 1 was obtained as a white solid (90% yield).

[0128] Example 4: Synthesis of (Z)-3-amino-3-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl) ethyl acrylate (compound A) In a reaction vessel (50 L), ammonia / methanol (7 mol / L, 30.2 kg, 7 L / kg), anhydrous calcium chloride (1.13 kg, 0.5 equivalents), and methyl 5-chloro-2-(4-chloro-1H-1,2,3-triazole-1-yl)benzoate (compound 1) (5.7 kg, 1.0 equivalent) were added, and the resulting slurry was stirred at 25°C for 20 hours. After the reaction was complete, the mixture was concentrated to a total volume of 3 L / kg, and then heated under reflux until all of the slurry was dissolved. Water (27.7 kg, 5 L / kg) was added over 3 hours at 60°C, and the mixture was cooled to 0°C to 5°C over 4 hours. After filtration, the wet cake was washed with methanol / water (0.75 L / kg methanol, 1.25 L / kg water), vacuum-dried at 40°C for 20 hours, and 5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzamide (compound 2) was obtained (yield 92-95%, purity >99.5%). 1 H NMR (DMSO-d6, 300MHz): δ=8.71(s, 1H), 8.12-8.05(br s, 1H), 7.80-7.73(m, 2H), 7.72-7.66(m, 1H), 7.66-7.59(br s, 1H)ppm

[0129] Acetonitrile (8.5 kg, 3 L / kg) and compound 2 (3.7 kg, 1.0 equivalent) were added to a reaction vessel (50 L), and then phosphoryl chloride (1.6 kg, 0.75 equivalents) was added over 20 minutes. The resulting slurry was heated at 75°C to 80°C for 90 minutes and aged at the same temperature for 5 hours. After the reaction was complete, the mixture was cooled to 60°C to 65°C, and water (17.0 kg, 4.7 L / kg) was added over 1 hour. After further cooling to 50°C to 54°C, 15% sodium hydroxide aqueous solution (6.4 kg, 1.8 kg / kg) was added over 1 hour, and the resulting slurry was cooled to 20°C to 25°C over 2 hours. After filtration, the wet cake was washed twice with water (2 x 1 L / kg) and vacuum-dried at 50°C for 19 hours to obtain 5-chloro-2-(4-chloro-1H-1,2,3-triazole-1-yl)benzonitrile (compound 3) (yield 95-98%, purity >99.5%). 1H NMR (DMSO-d6, 300MHz): δ=9.06(s, 1H), 8.38(d, J=2.4Hz, 1H), 8.08(dd, J=8.5, 2.4Hz, 1H), 7.94(d, J=8.4Hz, 1H)ppm; 13 C NMR (DMSO-d6, 75MHz): δ=136.2, 135.2, 134.8, 134.5, 134.2, 127.5, 123.8, 114.4, 108.9ppm

[0130] In a reaction vessel (30 L), ethyl acetate (6.1 kg, 5 L / kg), compound 3 (1.6 kg, 1.0 equivalent), potassium ethyl malonate (2.25 kg, 2.0 equivalents), triethylamine (1.67 kg, 2.5 equivalents), and zinc chloride (1.13 kg, 1.25 equivalents) were added. The resulting mixture was heated at 75-78°C for 2 hours and aged at the same temperature for 20 hours. After the reaction was complete, the mixture was cooled to 20-25°C, and 15% aqueous ammonia (7.5 kg, 5.2 L / kg) was added over 1 hour. Celite (0.32 kg, 0.2 kg / kg) was added, and the mixture was filtered. The wet cake was washed twice with ethyl acetate (2 x 2.85 kg, 2 L / kg). After separating into two layers, the organic layer was concentrated to a total volume of 3.1 L / kg, ethanol (7.5 kg, 6 L / kg) was added, and the mixture was concentrated to a total volume of 4.1 L / kg. The resulting slurry was then heated at 60°C until completely dissolved, water (4.75 kg, 3 L / kg) was added over 4 hours at 60°C, the mixture was cooled to 0-5°C over 4 hours, and aged at the same temperature for 4 hours. After filtration, the wet cake was washed with ethanol / water (MeOH: 0.8 L / kg, water: 1.2 L / kg), vacuum-dried at 40°C for 20 hours to obtain (Z)-3-amino-3-(5-chloro-2-(4-chloro-1H-1,2,3-triazole-1-yl)phenyl)acrylate ethyl (compound A) (yield 92-95%, purity >99.5%). 11H NMR (DMSO-d6, 300 MHz): δ = 8.63 (s, 1H), 7.86 - 7.50 (m, 3H), 7.50 - 7.02 (br s, 1H), 4.24 (s, 1H), 3.99 (q, J = 7.1 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H) ppm; 13 13C NMR (DMSO-d6, 75 MHz): δ = 168.5, 156.4, 135.5, 134.9, 133.6, 132.8, 130.3, 129.7, 128.3, 124.3, 84.4, 58.2, 14.4 ppm

[0131]

Chem.

[0132] To a slurry of 2-methylcyclopentanone (93.30 g, 931.7 mmol, 98 wt%) and methyl 4-chloropicolinate (compound 8) (158.02 g, 902.55 mmol) / THF (1500 mL, 18400 mmol), potassium tert-butoxide (1 mol / L) / THF (1200 g, 1330 mmol, 1 mol / L) was added at -30°C, and the resulting yellow slurry was stirred at -24°C to 30°C for 1 hour. In a separate reaction vessel (4 L), sulfuric acid (13.14 mol / L) / water (92 g, 660.2 mmol, 13.14 mol / L) and water (800 g, 44407.9 mmol) were added and pre-cooled to 0°C. A yellow slurry containing potassium(Z)-(4-chloropyridine-2-yl)(3-methyl-2-oxocyclopentylidene)methanolate (anion of compound 9) was poured into a cooled acidic solution to obtain a slurry. THF was distilled at 15°C under vacuum (115 mbar) with a jacket set to 45°C. Water (500 mL) was added to the slurry (~1 L). The precipitated solid was collected, the aqueous solution was removed, and the collected solid was returned to the reaction vessel with MSA (320 mL) and water (1 L). The slurry was heated to 65°C, and after 60 minutes, all solids had dissolved. This dark solution was held at 65°C for 3 hours, then cooled to room temperature, and then cooled to 0°C. A slurry was formed, which was then filtered, and the resulting residue was collected and dried at room temperature to obtain a total of 139.8 g of beige 6-(4-chloropyridine-2-yl)-2-methyl-6-oxohexanoic acid (rac-compound 10). The filtrate was returned to the reaction vessel and the pH was adjusted to 5.1 with 28 wt% NH4OH. The solid formed during pH adjustment was filtered at room temperature. A further 41 g of grayish-white 6-(4-chloropyridine-2-yl)-2-methyl-6-oxohexanoic acid (rac-compound 10) was obtained. 11H NMR (400 MHz, DMSO-d6): δ 12.07 (1H, s), 8.70 (d, J = 5.31 Hz, 1H), 7.94 (dd, J = 7.94, 1.77 Hz, 1H), 7.82 (dd, J = 5.18, 2.15 Hz, 1H), 3.15 (m, 2H), 2.35 (m, 1H), 1.60 (m, 3H), 1.42 (m, 1H), 1.05 (d, J = 6.82 Hz, 3H); LRMS: [C 12 H 14 ClNO 3+ H] + : 258.24, 256.25

[0133] Example 6: Chiral Resolution of rac-6-(4-Chloropyridin-2-yl)-2-methyl-6-oxohexanoic Acid (rac-Compound 10) by Fractional Crystallization of the (R)-Enantiomer Added with (1R,2S)-Erythro-2-amino-1,2-diphenylethanol 487 g (1.905 mol) of rac-6-(4-chloropyridin-2-yl)-2-methyl-6-oxohexanoic acid (rac-Compound 10) and 223 g (1.048 mol) of (1R,2S)-erythro-2-amino-1,2-diphenylethanol were dissolved in 4.8 kg of ethanol (96% by volume) at 70 °C. The solution was slowly cooled to room temperature and then to 0 °C. The precipitate formed was filtered, washed with cold ethanol (96% by volume), and dried to obtain (R)-6-(4-chloropyridin-2-yl)-2-methyl-6-oxohexanoic acid·(1R,2S)-erythro-2-amino-1,2-diphenylethanol·H2O, i.e., the (R)-6-(4-chloropyridin-2-yl)-2-methyl-6-oxohexanoic acid (Compound 10A) of the diastereomeric salt and (1R,2S)-erythro-2-amino-1,2-diphenylethanol monohydrate as a white needle-like solid (Yield based on the amount of the original (R)-6-(4-chloropyridin-2-yl)-2-methyl-6-oxohexanoic acid: 407 g, 91%, S / R ratio: 19.1 / 80.9).

[0134] [Chemical Structure]

[0135] Example 7: Racemization of 6-(4-chloropyridine-2-yl)-2-methyl-6-oxohexanoic acid contained in the mother liquor obtained by fractional crystallization in Example 6.

[0136] Step 1: Protection of 6-(4-chloropyridine-2-yl)-2-methyl-6-oxohexanoic acid The mother liquor from the fractional crystallization of Example 6 was concentrated and dried. The resulting residue was treated with a mixed solvent of TBME (tert-butyl methyl ether) and 0.33 M hydrochloric acid, and the organic layer was separated, dried and concentrated in the same manner as in Example 9, and the remaining 2-amino-1,2-diphenylethanol was removed. The resulting 639 g (2.50 mol) of 6-(4-chloropyridine-2-yl)-2-methyl-6-oxohexanoic acid (compound 10) was dissolved in 1.95 kg of dry methanol, and 271 g (2.50 mol) of chlorotrimethylsilane was added to this solution, and the mixture was stirred at room temperature for 12 hours. Then 1.95 kg of TBME was added, and the pH of the mixture was neutralized with saturated sodium bicarbonate aqueous solution (NaHCO3). The organic layer was separated, washed with brine, dried over sodium sulfate, concentrated under reduced pressure, and dried to obtain a product containing methyl 6-(4-chloropyridine-2-yl)-2-methyl-6,6-dimethoxyhexanoate (compound 41) as the main product and methyl 6-(4-chloropyridine-2-yl)-2-methyl-6-oxohexanoate (compound 42) as a by-product (yield: 587 g, approximately 87%).

[0137] Step 2: Racemization The product obtained in Step 1 with an S / R ratio of approximately 75:25 (587 g, approximately 1.86 mol) was dissolved in 3.34 kg of dry toluene. This solution was cooled to 0°C, 104 g (0.93 mol) of potassium tert-butoxide was added, and the mixture was stirred at room temperature for 12 hours. The mixture was then cooled to 0°C, and 1 kg of saturated NaH2PO4 aqueous solution was added. The organic layer was separated, washed with 1 kg of brine, and concentrated under reduced pressure to obtain a racemized product (compound 11). This compound may contain up to 10% by weight of tert-butyl 6-(4-chloropyridine-2-yl)-2-methyl-6,6-dimethoxyhexanoic acid. 1 The result was determined by 1H-NMR (yield: 500g, approximately 85%).

[0138] Step 3: Production of racemic 6-(4-chloropyridine-2-yl)-2-methyl-6-oxohexanoic acid by deprotection of the racemic mixture obtained in Step 2. The racemic product from Step 2 (500 g, approximately 1.58 mol) was dissolved in 2.5 kg of THF, and an aqueous sodium hydroxide solution (3.96 mol) prepared by dissolving 158 g in 1.58 kg of water was added. The mixture was stirred at room temperature for 12 hours. Then, concentrated hydrochloric acid (6.33 mol, 524 mL) was slowly added. After the conversion was completely finished (approximately 12 hours), 300 g of NaH2PO4 dissolved in 600 g of water was added, followed by the addition of a 2 M sodium hydroxide solution to adjust the pH to approximately 4-5. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain rac-6-(4-chloropyridine-2-yl)-2-methyl-6-oxohexanoic acid (rac-compound 10) (yield: 331 g, 82%).

[0139] Example 8: Recrystallization of (R)-6-(4-chloropyridine-2-yl)-2-methyl-6-oxohexanoic acid·(1R,2S)-erythro-2-amino-1,2-diphenylethanol·H2O obtained in the previous step. (R)-6-(4-chloropyridine-2-yl)-2-methyl-6-oxohexanoic acid·(1R,2S)-erythro-2-amino-1,2-diphenylethanol·H2O (diastereomer salt of compound 10A, 407 g) obtained in the previous step (Example 6) was recrystallized from 4.0 kg of ethanol (96 vol%). The salt was dissolved at 70°C, and the solution was then slowly cooled to 10°C. The precipitate of the resulting crystals was filtered, washed with cold ethanol (96 vol%), dried, and purified to obtain (R)-6-(4-chloropyridine-2-yl)-2-methyl-6-oxohexanoic acid·(1R,2S)-erythro-2-amino-1,2-diphenylethanol·H2O (yield: 326 g, 80%, S / R ratio: 7.7 / 92.3).

[0140] Example 9: Conversion of (R)-6-(4-chloropyridine-2-yl)-2-methyl-6-oxohexanoic acid·(1R,2S)-erythro-2-amino-1,2-diphenylethanol·H2O to (R)-6-(4-chloropyridine-2-yl)-2-methyl-6-oxohexanoic acid 182 g of (R)-6-(4-chloropyridine-2-yl)-2-methyl-6-oxohexanoic acid·(1R,2S)-erythro-2-amino-1,2-diphenylethanol·H2O was dissolved in 2.7 kg of TBME and 3.5 kg of 0.33 M hydrochloric acid until two homogeneous layers were obtained. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to obtain the free acid (R)-6-(4-chloropyridine-2-yl)-2-methyl-6-oxohexanoic acid (compound 10A, yield: 93.2 g, 98%).

[0141] Example 10: Conversion of (R)-6-(4-chloropyridine-2-yl)-6,6-dimethoxy-2-methylhexanoic acid to (R)-6-(4-chloropyridine-2-yl)-6,6-dimethoxy-2-methylhexanoic acid·DCHA salt

[0142] Step (a) (R)6-(4-chloropyridine-2-yl)-2-methyl-6-oxohexanoic acid (compound 10A) (5.0 g) was dissolved in dry methanol (20 g) and cooled to 0°C. Chlorotrimethylsilane (3.1 mL) was slowly added, followed by trimethyl orthoformate (6.4 mL), and the mixture was stirred at room temperature for 12 hours, then stirred at 40°C for 12 hours until the conversion was complete. After the reaction was complete, the mixture was cooled to 0°C, and barium hydroxide (9.5 g; octahydrate may be used) suspended in water (50 g) was added, and the mixture was stirred overnight at room temperature. After the conversion was complete, saturated sodium dihydrogen phosphate solution was added until the pH was 4-5. The mixture was then extracted with TBME (2 x 20 g), the organic layer was washed with brine (2 x 20 g), dried over sodium sulfate, and volatile substances were removed under reduced pressure to obtain the product as a pale yellow oil (yield: 5.78 g, 98%).

[0143] Step (b) (R)-6-(4-chloropyridine-2-yl)-6,6-dimethoxy-2-methylhexanoic acid (compound 11) (368 g) was dissolved in TBME (2400 g) and heated to 40°C. Dicyclohexylamine (175 g) was slowly added, and after precipitate formation, stirring was continued for 15 minutes until stirring became easier. The remaining dicyclohexylamine (174 g) was then slowly added, and the mixture was slowly cooled to room temperature. The solid was filtered and washed with TBME to obtain the product as a white needle-shaped solid (yield: 671.0 g (containing approximately 1.25 equivalents of DCHA and 14.5% TBME), product 570 g (88.5%)).

[0144] Example 11: Reduction of nitropyrazole

[0145] Step (a) 1-(difluoromethyl)-4-nitropyrazole (compound 12) (50 g), Pt / V / C (2.5 g), and THF (100 mL) were added to the hydrogenation reaction vessel. After creating an inert atmosphere, the reaction vessel was pressurized under a hydrogen atmosphere (0.27-0.34 MPa) and stirred under an H2 gas stream at 30°C-35°C until the conversion was complete. After the conversion was completely finished, the organic layer was filtered to remove the catalyst, concentrated to dryness, and 1-(difluoromethyl)-4-aminopyrazole (compound 13) was obtained in a quantitative yield.

[0146] Step (b) 10 g of 1-(difluoromethyl)-4-amino-pyrazole was dissolved in 22 mL of HCl-containing 2-propanol at 0°C to 5°C in 80 mL of 2-propanol. The mixture was slowly heated to 25°C over 30 minutes, and 100 mL of heptane was added. After stirring for 10 minutes, the reaction mixture was filtered and washed with heptane. The isolated substance was dried under reduced pressure at 40°C to isolate 1-(difluoromethyl)-4-amino-pyrazole·HCl salt (HCl salt of compound 13) (7.9 g, yield 60%).

[0147] Example 12: Amide Coupling In RBF (500 mL), the DCHA salt of (R)-6-(4-chloropyridine-2-yl)-6,6-dimethoxy-2-methylhexanoic acid (compound 11·DHCA) (50 g) was suspended in n-butyronitrile (300 mL) and washed with acidic aqueous solution (300 mL + 85 wt% H3PO4 (5.21 g)) until the pH became 5. After layer separation, the organic layer was concentrated to 200 mL. In a separate reaction, 1,1'-carbonyldiimidazole (1.2 equivalents, 17.6 g) was suspended in n-butyronitrile (100 mL) and heated to 40 °C. A 200 mL solution containing (R)-6-(4-chloropyridine-2-yl)-6,6-dimethoxy-2-methylhexanoic acid was added dropwise to the CDI suspension over 2 hours. After the conversion was complete, 1-(difluoromethyl)-1H-pyrazole-4-amine·HCl salt (1.2 equivalents, 18.4 g) was added all at once, and the mixture was stirred at 40°C for 6 hours. After stirring was complete and the mixture cooled to 25°C, the organic layer was first washed with aqueous sodium hydroxide solution until the pH was 12, then with aqueous phosphoric acid solution (300 mL, 5.21 g phosphoric acid), then with aqueous phosphoric acid solution (300 mL, 0.521 g phosphoric acid), and finally with aqueous sodium hydroxide solution (300 mL, 1.45 g NaOH). The organic layer was concentrated to 200 mL containing (R)-6-(4-chloropyridine-2-yl)-N-(1-(difluoromethyl)-1H-pyrazole-4-yl)-6,6-dimethoxy-2-methylhexaneamide (compound 14) (34 g, 90% yield).

[0148] Example 13: (R)-2 1 -(difluoromethyl)-9,9-dimethoxy-5-methyl-2 1 Synthesis of H-3-aza-1(4,2)-pyridina-2(5,4)-pyrazolacyclononaphan-4-one·HCl

[0149] Step (a) In an RBF (Range-Based Food) with an overhead stirrer, K2CO3 (1.2 equivalents, 12.05 g), n-butyronitrile (300 mL), Pd(allyl)(Catacxium A)Cl (0.01 equivalents, 0.393 g), and pivalic acid (0.1 equivalents, 0.822 mL) were added. After creating an inert atmosphere with nitrogen, the mixture was heated to 115°C, and (R)-6-(4-chloropyridine-2-yl)-N-(1-(difluoromethyl)-1H-pyrazole-4-yl)-6,6-dimethoxy-2-methylhexanamide (compound 14) (135.7 g) was added dropwise over 5 hours. The reaction mixture was maintained at 115°C until the conversion was complete. After cooling to room temperature, the reaction mixture was filtered with Dicalite (0.1 g / g, 100 wt%), and the cake was washed with butyronitrile. 1 -(difluoromethyl)-9,9-dimethoxy-5-methyl-2 1 We obtained H-3-aza-1(4,2)-pyridina-2(5,4)-pyrazolacyclononaphan-4-one (compound 15) (yield 90%).

[0150] Step (b) In a reaction vessel (100 mL) equipped with an overhead stirrer, add (R)-2 1 -(difluoromethyl)-9,9-dimethoxy-5-methyl-2 1 A butyronitrile solution containing H-3-aza-1(4,2)-pyridina-2(5,4)-pyrazolacyclonononaphan-4-one (compound 15) (7 g, 4.089 wt%) was stirred at 15°C, and a solution of HCl / 2-propanol (2.06 mL, 1.0 equivalent of HCl) was added dropwise over 30 minutes, and the mixture was stirred at 15°C for a further 2 hours. The reaction mixture was filtered, washed with n-butyronitrile, and the isolated substance was dried under reduced pressure at 45°C overnight to obtain (R)-2. 1 -(difluoromethyl)-9,9-dimethoxy-5-methyl-2 1 H-3-aza-1(4,2)-pyridina-2(5,4)-pyrazolacyclononaphan-4-one·HCl (HCl salt of compound 15) (3g) was isolated (yield 96%).

[0151] Example 14: (R)-21 -(difluoromethyl)-9,9-dimethoxy-5-methyl-2 1 H-3-aza-1(4,2)-pyridina-2(5,4)-pyrazolacyclononaphan-4-one·HCl-(5R,9S)-amino-2 1 -(difluoromethyl)-5-methyl-2 1 Conversion to H-3-aza-1(4,2)pyridine-2(5,4)-pyrazolocyclononaphone-4-one (R)-2 1 -(difluoromethyl)-9,9-dimethoxy-5-methyl-2 1 H-3-aza-1(4,2)-pyridina-2(5,4)-pyrazolacyclononaphan-4-one·HCl (10 g) was dissolved in water (75 mL) and heated for 18 hours. 25% of the solvent was removed by vacuum distillation and replaced with water. The reaction mixture was cooled to 5°C, 2.35 equivalents of HCl (pH=0.98) were added, followed by 4.05 equivalents of isopropylamine while slowly warming to 20°C. Finally, 1 wt% pyridoxal 5'-phosphate hydrate (5-PLP) and 1.1 wt% aminotransferase CDX-050 (also known as aminotransferase ATA-486) ​​were added, and the mixture was heated at 50°C and stirred for 24 hours. After the conversion was complete, concentrated HCl was added until the pH reached 7. Diatomaceous earth (4 wt%) was added, and the reaction mixture was heated at 80°C for 2 hours. The suspension was cooled to 20°C and filtered. NaOH (1M) was added dropwise to the obtained filtrate until the pH reached 10. After stirring for 2 hours, the reaction mixture was filtered, and the cake was washed twice with water to obtain the desired product (compound C) (yield 83%, 6.7g).

[0152] [ka]

[0153] Example 15: Synthesis of (1R,2S)-1-amino-1-(4-chloropyridine-2-yl)buta-3-en-2-ol dihydrochloride

[0154] (E)-3-bromopropa-1-en-1-yl benzoic acid (compound 17) (198 g, 821 mmol) was added to the reaction vessel, followed by the addition of THF (1 L) and indium (94.18 g, 821 mmol) at 20°C, and the mixture was stirred at 20°C for at least 12 hours. The solution was cooled to below 5°C, and to maintain the temperature below 10°C, a solution of (S,E)-N-((4-chloropyridine-2-yl)methylene)-2-methylpropane-2-sulfinamide (compound 18) (100 g, 408.5 mmol) / THF (300 mL) was added. After the addition, the solution was stirred at 10°C for at least 1 hour. The solution was filtered and diluted with MTBE (500 mL), and the organic layer was then washed with aqueous citric acid solution (200 g / 1 L water). This process was repeated once more, and the organic layer was washed twice with water (500 mL) and then with saturated NaHCO3 aqueous solution (500 mL). The organic layer was concentrated to 1-2 V, then diluted with MeOH (10 V), and this process was repeated until the MTBE in the MeOH was 2% or less. When the MTBE was 2% or less, the organic layer was adjusted to a total of 3 V of MeOH, to which DBU (81.7 mmol, 0.20 equivalents) was added. This solution was heated to 50°C and held at 50°C for at least 2 hours. After confirming completion by HPLC, TMSCl (2043 mmol, 5.0 equivalents) was added at 50°C and held at 50°C for a maximum of 30 minutes. After confirming completion by HPLC, the solution was concentrated to a total of 5 V, and iPrOAc (3 V) was added over 1 hour at 50°C. This was then cooled to below 15°C and held at below 15°C for at least 2 hours. The slurry was filtered to obtain (1R,2S)-1-amino-1-(4-chloropyridine-2-yl)buta-3-en-2-ol dihydrochloride (compound 20) (100 g, 90% yield) as a white solid. 1 H NMR (DMSO-d6, 600MHz): δ 8.81(broad s, 1H), 8.57(d, J=5.4Hz, 1H), 7.77(d, J=1.92Hz, 1H), 7.58(dd, J=1.92, 5.4Hz, 1H), 5.85(m, 1H), 5.17(dt, J =1.42, 17.3Hz, 1H), 5.11(dt, J =1.42, 10.5Hz, 1H), 4.60(m, 1H), 4.49(m, 1H); 13¹³C NMR (DMSO-d6, 151 MHz): δ 155.4, 149.4, 143.6, 136.3, 124.0, 123.9, 117.3, 71.5, 58.0; HRMS: ESI-positive HRMS [M+H] + : C9H 12 N2OCl theoretical value: 199.0633, observed value: 199.0633

[0155] Example 16: Synthesis of (2R,6S,E)-6-((tert-butoxycarbonyl)amino)-6-(4-chloropyridine-2-yl)-2-methylhexa-4-enoic acid (compound 22)

[0156] Step 1 In a round-bottom flask containing a stirring bar, (1R,2S)-1-amino-1-(4-chloropyridine-2-yl)buta-3-en-2-ol dihydrochloride (5.5 g), toluene (55 mL), saturated NaHCO3 aqueous solution (55 mL), and Boc2O (4.6 g) were added and the mixture was stirred at 20°C for 4 hours. The reaction mixture was diluted with saline solution (30 mL), and the layers were separated.

[0157] Step 2 3.5 g of propionic anhydride was added to the organic layer, followed by 250 mg of DMAP, and the mixture was stirred at room temperature for 2 hours. 3 mL of MeOH was added to quench the excess anhydride. After 30 minutes, the sample was washed with saline solution to remove DMAP, followed by washing with NaHCO3:saline solution (1:1), and then with saline solution. Toluene was distilled using a rotary evaporator (10 torr, 40°C), and then 50 mL or more of toluene was added. Distillation was repeated, and t-BuOH and water were removed by azeotropy to obtain a clear residue.

[0158] Step 3 The resulting residue was dissolved in THF (100 mL) and DMPU (68 mL), and 1 M TBSCl / THF (35 mL, 2.1 equivalents) was added. Inert nitrogen (N2) gas was added to the reaction system, and the system was then cooled to -78°C. 1.5 M LiHMDS / THF (23 mL) was added dropwise. The reaction was aged at -78°C for 30 minutes, and then slowly heated to -10°C over approximately 1 hour as the system temperature rose. The reaction was quenched by adding solid NH4F (2.4 g), followed by water (20 mL). Water was then continuously added until all of the solid NH4F was dissolved, resulting in a homogeneous single solution (total water 50 mL). Toluene (100 mL), followed by further water (100 mL) and saturated brine (20 mL), the aqueous layer was collected, and the organic layer was washed with saturated NaHCO3 aqueous solution (50 mL). The aqueous layers were combined and the pH was adjusted to 5 with phosphoric acid. The product was extracted in toluene:MTBE (1:1, 300 mL) and then washed with water:saline solution (2:1, 200 mL). Volatile substances were removed under reduced pressure to obtain a crude solid. The obtained crude solid was dissolved in toluene (40 mL) at 70°C, and then hexane (40 mL) was added. The reaction system was cooled to 55°C, a seed crystal of the product (50 mg) was added, and the mixture was stirred at 50°C for 4 hours. The sample was cooled to room temperature over 1 hour and stirred at room temperature for another 1 hour. The crystals were filtered and washed with hexane / toluene (1:1, 20 mL), and then washed with hexane (20 mL). 1 H NMR (DMSO-d6, 600MHz): δ 8.46(d, J =5.4Hz, 1H), 7.48(broad s, partial overlap, 1H), 7.47(d, J =1.92Hz, 1H), 7.39(dd, J =1.92, 5.4Hz, 1H), 5.61(m, 1H), 5.56(m, 1H), 5.17(m, 1H), 2.35(m, 1H), 2.27(m, 1H), 2.04(m, 1H), 1.37(s, 9H), 1.00(d, J=6.9Hz, 3H); 13C NMR (DMSO-d6, 151MHz): δ 176.7, 163.5, 154.8, 150.3, 143.3, 130.9, 129.0, 122.2, 120.8, 78.2, 57.4, 38.4, 35.5, 28.1, 16.3; HRMS(C 17 H 24 O4N2Cl): Theoretical value 355.1419, Delta (ppm) -0.43, RDP equivalent 6.5, Observed value: m / z 355.1418

[0159] Example 17: tert-butyl((5R,9S)-2 1 -(difluoromethyl)-5-methyl-4-oxo-2 1 Synthesis of H-3-aza-1(4,2)-pyridina-2(5,4)-pyrazolacyclononafane-9-yl)carbamate (compound 26) In a 40 mL vial containing (2R,6S,E)-6-((tert-butoxycarbonyl)amino)-6-(4-chloropyridine-2-yl)-2-methylhexa-4-enoic acid (compound 22) (226.1 mg), Crabtree catalyst (12.7 mg) and DCM (4.5 mL) were added. Approximately 2.25 mL of the above solution was purged with nitrogen about 10 times while stirring, followed by purging with H2 10 times. Under a hydrogen atmosphere, the mixture was shaken at 500 rpm for 2 days under a pressure of 40 psi. The resulting slurry was filtered, and the wet cake of (2R,6S)-6-((tert-butoxycarbonyl)amino)-6-(4-chloropyridine-2-yl)-2-methylhexanoic acid (compound 23) was further washed with n-heptane. In a 4 mL vial, allyl palladium(II) chloride (dimer) (3.5 mg), X-Phos (10.2 mg), and 2-MeTHF (2.8 mL) were added, and after 30 minutes, a solution was obtained. In an 8 mL vial, (2R,6S)-6-((tert-butoxycarbonyl)amino)-6-(4-chloropyridine-2-yl)-2-methylhexanoic acid (compound 23) (67.2 mg), 1-(difluoromethyl)-4-nitro-1H-pyrazole (compound 12) (41.4 mg), and potassium pivalate (114.8 mg) were added. In this vial, Pd / Xphos solution (1.34 mL) was added, and the mixture was heated and stirred at 80°C. At this point, the reaction material was a white slurry, and after 17 hours, the orange-brown slurry was cooled to 20°C. Potassium pivalate (54.9 mg) was added, and the reaction mixture was heated again at 80°C for 23 hours. After cooling to 20°C, 0.1 mL of allyl palladium(II) chloride (dimer) (3.5 mg) solution, X-Phos (10.2 mg), and 2-MeTHF (0.2 mL) were added. After heating again at 80°C for 18 hours, the reaction was considered complete, and the brown slurry was cooled to 20°C. The organic layer was washed with 20 wt% K3PO4, and the layers were separated. The organic layer was extracted again with 20 wt% K3PO4, and the layers were separated. The aqueous layers were combined, and 2-MeTHF and activated carbon (DARCO) were added, and 20 wt% citric acid aqueous solution was added until the pH was 4. The two layers of the reaction mixture were filtered, and the layers were separated. The upper organic layer was washed with NaCl aqueous solution, then dried over MgSO4, filtered, and concentrated. The oily residue was purified by column chromatography (SiO2; gradient: 20-100%, acetone / hexane) to isolate (2R,6S)-6-((tert-butoxycarbonyl)amino)-6-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazole-5-yl)pyridine-2-yl)-2-methylhexanoic acid (compound 24). LC / MS revealed a mass of M+1 (484.15). (2R,6S)-6-((tert-butoxycarbonyl)amino)-6-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazole-5-yl)pyridine-2-yl)-2-methylhexanoic acid (compound 24) (43.7 mg) was then dissolved in 2-MeTHF (0.43 mL), and after adding 2-MeTHF (0.43 mL), Pd / C (5.1 mg) was added. The reaction mixture was hydrogenated under an H2 pressure of 25 psi and shaken for 18 hours. The reaction mixture was then filtered, the solid was washed with DCM, and the filtrate was then concentrated to dryness. The obtained (2R,6S)-6-(4-(4-amino-1-(difluoromethyl)-1H-pyrazole-5-yl)pyridine-2-yl)-6-((tert-butoxycarbonyl)amino)-2-methylhexanoic acid (compound 25) was then macrolactamized according to the following procedure. (2R,6S)-6-(4-(4-amino-1-(difluoromethyl)-1H-pyrazole-5-yl)pyridine-2-yl)-6-((tert-butoxycarbonyl)amino)-2-methylhexanoic acid (100 mg) / THF (2.0 mL) was added by syringe over 2 hours to a solution of TCFH (0.158 g) and DIPEA (0.135 mL) / THF (15 mL). After 0.5 hours, the reaction mixture was concentrated to dryness, redissolved in toluene (15 mL), and washed with 15% NH4Cl aqueous solution. After layer separation, the organic layer was dried over MgSO4, filtered, and concentrated. The resulting residue was purified with ISCO (30-90% toluene / heptane), the solvent of the fraction was evaporated, and then 85 mg of tert-butyl((5R,9S)-2 1 -(difluoromethyl)-5-methyl-4-oxo-2 1 We obtained H-3-aza-1(4,2)-pyridina-2(5,4)-pyrazolacyclononafane-9-yl)carbamate (compound 26). 1H NMR (400MHz, DMSO-d6) 9.32(s, IH), 8.71(d, J=5.0Hz, IH), 7.96(t, J=58Hz, IH), 7.43(s, IH), 7.32(d, J=4.8Hz, IH), 7.22(d, J=7.3Hz, IH), 4.66(d, J=8.3Hz, IH), 2.62(br.s., IH), 1.88(d, J=12.8Hz, IH), 1.77-1.59(m, 2H), 1.42-1.28(m, 9H), 1.15(d, J=18.2Hz, 2H), 0.83(d, J=7.0Hz, 3H); MS(ESI)m / z: 436.3 [M+H] +

[0160] Example 18: (5R,9S)-9-amino-2 1 -(difluoromethyl)-5-methyl-2 1 Synthesis of H-3-aza-1(4,2)-pyridina-2(5,4)-pyrazolacyclononaphan-4-one (compound C) In a clean reaction vessel, add MeOH (24.2 kg) and tert-butyl((5R,9S)-2 1 -(difluoromethyl)-5-methyl-4-oxo-2 1 H-3-aza-1(4,2)-pyridina-2(5,4)-pyrazolacyclonononaphan-9-yl)carbamate (compound 26) (3 kg) and IPA / HCl (6N, 6.2 L) were added and heated at 45-55°C for at least 2 hours, or until the reaction was considered complete. The reactants were then concentrated at 55°C at a pressure below 450 mmHg to 9 L, then MeOH (48.2 kg) was added, the reactants were concentrated to 9 L, and this was repeated once more. Dowex monoshere Monosphere 550A(OH) was washed three times (48 kg each) with dry methanol until the KF was <3.0 wt%. (5R,9S)-9-amino-2 1 -(difluoromethyl)-5-methyl-2 1To a methanol solution of H-3-aza-1(4,2)-pyridina-2(5,4)-pyrazolacyclononaphan-4-one, methanol (4 L) and dry Dowex resin were added and the mixture was stirred until the pH > 8.5. The reaction mixture was filtered through Celite, and the reaction vessel and Celite were washed with methanol (6 L and 50.70 kg), respectively. The above solution was concentrated to 15 L. ACN (47.3 kg) was then added, and the reactant was concentrated to 30 L. This process was repeated at least three times. When the KF of the reaction solution showed <0.5 wt%, the temperature had dropped to 20°C. After aging for 1 hour, the resulting slurry was filtered, and the wet cake was washed with ACN (9 L). The wet cake was dried at 80°C for at least 6 hours until the compound was considered dry. (5R,9S)-9-amino-2 1 -(difluoromethyl)-5-methyl-2 1 H-3-aza-1(4,2)-pyridina-2(5,4)-pyrazolacyclononaphan-4-one (compound C) was obtained (yield 76.3%, 1.57 kg).

[0161] [ka]

[0162] Example 19: Synthesis of (R)-5-(1,3-dioxolan-2-yl)-2-methylpentanoate benzyl (compound 28) THF (3.75 mL) and ZnCl2 (0.5 M, THF solution, 1 mL) were added to a flask, and the solution was cooled to 0°C. [3-(1,3-dioxolan-2-yl)propyl]magnesium chloride (4.80 mmol, 8.0 mL) and (2R)-2-(trifluoromethylsulfonyloxy)benzyl propanoate (3.20 mmol, 1.00 g) were added over 5 minutes, and the solution was then stirred at 0°C for at least 12 hours. This was then diluted with saturated NH4Cl aqueous solution (5 V), extracted with MTBE (10 V), and the organic layer was concentrated until a residue remained. It was purified with ISCO (1%~40% Âxane) to obtain (2R)-5-(1,3-dioxolan-2-yl)-2-methylpentanoate benzyl (compound 28) (39% yield, 0.351 g, 0.351 g) as an oil. 1 1H NMR: 1 H NMR (500MHz, chloroform-d) δ 7.42-7.32(m, 5H), 5.14(s, 2H), 4.87-4.80(m, 1H), 4.00-3.82(m, 4H), 2.57-2.48(m, 1H), 1.81-1.70(m, 1H), 1.70-1.62(m, 2H), 1.55-1.40(m, 3H), 1.20(d, J=7.0Hz, 3H); 13 C NMR: 13 ¹³C NMR (126 MHz, CDCl3) δ 176.5, 136.2, 128.5, 128.1, 128.0, 104.3, 66.0, 64.8, 39.5, 33.7, 33.6, 21.7, 17.0; HRMS: ESI-positive HRMS [M+H] + C 16 H 23 O4; Theoretical value: 279.1591[M+H]; Observed value: 279.1588[M+H]

[0163] Example 20: Synthesis of (R)-6-(benzyloxy)-5-methyl-6-oxohexanoic acid (compound 29) In a round-bottom flask, (R)-5-(1,3-dioxolan-2-yl)-2-methylpentanoate benzyl (compound 28) (10 g, 36 mmol) was dissolved in THF (100 mL), and water (100 mL) and oxone (22.3 g) were added. This mixture was stirred at room temperature for 48 hours, and heptane (50 mL) was added. The aqueous layer was separated, and the organic layer was washed with water (50 mL) and then with saline solution (50 mL). The organic layer was concentrated using a rotary evaporator until a residue remained. The obtained residue was subjected to chromatography (silica; 100% DCM ~ 20% acetone / DCM) to obtain (R)-6-(benzyloxy)-5-methyl-6-oxohexanoic acid (compound 29) as an oil (8.8 g, 97% yield). 1 H NMR (DMSO-d6, 600MHz): δ 7.31-7.39(m, 5H), 5.10(s, 2H), 2.49(m, 1H), 2.19(t, J=7.1Hz, 2H), 1.60(m, 1H), 1.48(m, 2H), 1.41(m, 1H), 1.09(d, J=7.1Hz, 3H); 13 ¹¹C NMR (DMSO-d6, 151 MHz): δ 175.5, 174.3, 136.4, 128.5, 128.0, 127.8, 65.4, 38.6, 33.5, 32.7, 22.2, 16.8; HRMS data: ¹¹C 14 H 19 O4[M+H] + Theoretical value: 251.1278, Observed value: 251.1286 [Table 5]

[0164] Example 21: Synthesis of (R)-6-(methoxy(methyl)amino)-2-methyl-6-oxohexanoate benzyl (compound 30) (R)-6-(benzyloxy)-5-methyl-6-oxohexanoic acid (1 g), N,O-dimethylhydroxylamine hydrochloride (470 mg), triethylamine (1.7 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (930 mg), and dichloromethane (10 mL) were added to a round-bottom flask equipped with a stirring bar and stirred at room temperature for 16 hours. The organic layer was transferred to a separatory funnel and washed with water, then 1N hydrochloric acid, then aqueous NaHCO3 solution. The organic layer was then dried over MgSO4, filtered, and concentrated using a rotary evaporator until a residue remained. The resulting residue was subjected to chromatography (100% DCM ~ 10% MTBE / DCM) to obtain (R)-6-(methoxy(methyl)amino)-2-methyl-6-oxohexanoate benzyl (compound 30) (57% yield, 665 mg). 1 H NMR (DMSO-d6, 600MHz): δ 7.28-7.35(m, 5H), 5.05(s, 2H), 3.57(s, 3H), 3.03(s, 3H), 2.45(m, 1H), 2.30 (bs, 2H), 1.55(m, 1H), 1.44(m, 2H), 1.37(m, 1H), 1.05 (d, J=7.1Hz, 3H); 13 ¹³C NMR (DMSO-d6, 151 MHz): δ 176.3, 173.8, 136.7, 129.0, 128.5, 128.2, 65.9, 61.4, 39.1, 33.2, 32.1, 31.3, 22.2, 17.2; HRMS data: ¹³C 16 H 24 O4N [M+H] + Theoretical value: 294.1700, Observed value: 294.1708 [Table 6]

[0165] Example 22: Synthesis of (R)-6-(4-chloropyridine-2-yl)-2-methyl-6-oxohexanoate benzyl (compound 31) Under an inert nitrogen atmosphere, 240 mg of 2-bromo-4-chloropyridine and 3 mL of THF were added to a round-bottom flask equipped with a stirring bar. 1.3 M of Turbogrignard / THF (870 μL) was added to the flask at room temperature, and the mixture was stirred at room temperature for 1 hour. The mixture was then cooled to -78°C, and 300 mg of benzyl (R)-6-(methoxy(methyl)amino)-2-methyl-6-oxohexanoate, dissolved in 1 mL of THF, was added by syringe. After 10 minutes, the flask was removed from the cold bath, warmed to room temperature, quenched with aqueous NaHCO3 solution, and diluted with ethylethanol. The organic layer was transferred to a separatory funnel, and the layers were separated. The organic layer was then dried over MgSO4, filtered, and concentrated using a rotary evaporator until a residue remained. The resulting residue was subjected to chromatography (SiO:heptane (1:9)) to obtain (R)-6-(4-chloropyridine-2-yl)-2-methyl-6-oxohexanoate benzyl (compound 31) as a colorless oil (170 mg, 48% yield). 1 H NMR (DMSO-d6, 600MHz): δ 8.68(broad d, J=5.4Hz, 1H), 7.92(m, 1H), 7.79(m, 1H), 7.29-7.36(m, 5H), 5.09(s, 2H), 3.13(t, J=7.4Hz, 2H), 2.52(m, 1H), 1.62(m, 3H), 1.46(m, 1H), 1.10 (d, J=7.1Hz, 3H); 13 C NMR (DMSO-d6, 151MHz): δ 199.8, 175.4, 154.1, 150.7, 144.3, 136.3, 128.4, 127.9, 127.7, 127.4, 121.2, 65.3, 38.6, 36.9, 32.7, 20.9, 16.7 [Table 7]

[0166] Example 23: Synthesis of (R)-6-(4-chloropyridine-2-yl)-6,6-dimethoxy-2-methylhexanoic acid (compound 11) Benzyl (R)-6-(4-chloropyridine-2-yl)-2-methyl-6-oxohexanoate (30 mg) was dissolved in MeOH (300 μL), TMSCl (20 μL) and TMOF (100 μL) were added, and the mixture was held at room temperature for 12 hours. The reaction mixture was concentrated using a rotary evaporator until a residue was obtained, and aqueous NaOH (1 N, 1 mL) and MeOH (1 mL) were added to the resulting residue, and the mixture was held at room temperature for 1 hour. The reaction mixture was transferred to a separatory funnel, and the aqueous layer was washed with hexane. The aqueous layer was then acidified with 1 N hydrochloric acid to pH 3, and then extracted with ELISA. The organic layer was dried over MgSO4, filtered, concentrated using a rotary evaporator until a residue was obtained, and the product was isolated (yield 77%, 22 mg). NMR was consistent with the confirmed product, and ee was shown to be 94% by chiral HPLC.

[0167] [ka]

[0168] Example 24: Synthesis of (2R)-5-(1,3-dioxolan-2-yl)-2-methylpentanoic acid (compound 36) Lithium chloride (2.1 g, 51 mmol) was added to a flask, placed under vacuum (~25 mmHg), and heated with a heat gun (above 100°C for more than 30 minutes) to remove any small amount of water present. The flask was cooled to 20°C, and THF (22 mL), followed by diisopropylamine (5.9 g, 58 mmol) was added. This solution was cooled to -20°C, and n-BuLi [2.5 M, hexane solution] (23 mL) was added over more than 1 hour. To maintain the temperature below -10°C, a solution of N-[(1S,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl]-N-methyl-propanamide (compound 34) (25 mmol, 5.6 g) / THF (11 mL) was added dropwise, then cooled to -20°C and held for more than 1 hour. This was then heated to 0°C and held for more than 3 hours. The solution was then heated to 20°C and held for at least 45 minutes. The solution was then cooled again to 0°C, and 2-(3-bromopropyl)-1,3-dioxolane (50.61 mmol, 10.39 g) was added dropwise. The solution was then heated to 20°C over at least 10 hours, and the reaction was quenched by adding saturated NH4Cl aqueous solution (5V), followed by water (5V). MTBE (10V) was added, and the aqueous layer was separated and removed. The organic layer was washed with saline solution (5V) and then concentrated until a residue remained. The obtained residue was dissolved in t-BuOH (78 mL), Bu4NOH (40 wt% aqueous solution, 82 mL, 125 mmol), and water (233 mmol), and the two-layer mixture was heated under reflux for at least 24 hours. This solution was cooled to 20°C, MTBE (5V) was added, the aqueous layer was separated, and the organic layer was removed. The aqueous layer was acidified to pH 5.0 using H3PO4, and once the pH reached 5.0, the aqueous layer was extracted with MTBE (5V, 3 times). The organic layers were combined and dried with (Na2SO4), filtered, and concentrated to obtain crude (2R)-5-(1,3-dioxolan-2-yl)-2-methylpentanoic acid (compound 36) (96% yield, 4.52 g) as an oil. 1 H NMR(500MHz, CHCl3-d)δ 4.87(t, J=4.7Hz, 1H), 4.03-3.80(m, 4H), 2.58-2.41(m, 1H), 1.81-1.64(m, 4H), 1.56-1.40(m, 4H), 1.19-1.19(m, 1H), 1.20(d, J=7.0Hz, 3H);13 ¹³C NMR (126 MHz, CDCl3) δ 182.3, 104.3, 64.8, 39.3, 33.7, 33.3, 21.6, 16.8; HRMS: ESI-positive HRMS [M-18+H] + C9H 15 O3[M-18+H] Theoretical value: 171.1016; Observed value: 171.1014

[0169] Example 25: Synthesis of (2R)-5-(1,3-dioxolan-2-yl)-2-methylpentanoate benzyl (compound 37) (2R)-5-(1,3-dioxolan-2-yl)-2-methylpentanoic acid (106.3 mmol, 20.00 g), dichloromethane (6631 mmol, 563.2 g, 425.0 mL), benzyl alcohol (127.5 mmol, 13.79 g, 13.20 mL), and 4-dimethylaminopyridine (10.63 mmol, 1.298 g) were added to a flask. This solution was cooled to 0°C, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (117.9 mmol, 22.61 g) was added, and the mixture was stirred at 0°C for 2 hours. The mixture was then heated to 20°C and kept at that temperature overnight. This solution was washed with saturated NaHCO3 aqueous solution (5V), water (5V), and saline solution (5V). The organic layer was concentrated and purified with ISCO [0%~40% siRNA] to obtain (2R)-5-(1,3-dioxolan-2-yl)-2-methylpentanoate benzyl (compound 37) (90.0% yield, 4.10 g, 4.10 g) as a clear oil. 1 H NMR (500MHz, chloroform-d)δ 7.42-7.32(m, 5H), 5.14(s, 2H), 4.87-4.80(m, 1H), 4.00-3.82(m, 4H), 2.57-2.48(m, 1H), 1.81-1.70(m, 1H), 1.70-1.62(m, 2H), 1.55-1.40(m, 3H), 1.20(d, J=7.0Hz, 3H); 1313C NMR (126 MHz, CDCl3) δ 176.5, 136.2, 128.5, 128.1, 128.0, 104.3, 66.0, 64.8, 39.5, 33.7, 33.6, 21.7, 17.0; HRMS: ESI positive HRMS [M+H] + C 16 H 23 O4 Theoretical value: 279.1591 [M+H], 279.1588 [M+H]

[0170] Example 26: Synthesis of Benzyl (R,E)-6-(((R)-tert-butylsulfinyl)imino)-2-methylhexanoate (Compound 38) 1 1H NMR (500 MHz, CDCl3) δ 8.12 - 7.97 (m, 1H), 7.41 - 7.31 (m, 6H), 5.16 - 5.10 (m, 2H), 2.57 - 2.47 (m, 3H), 1.84 - 1.71 (m, 1H), 1.71 - 1.60 (m, 2H), 1.58 - 1.46 (m, 1H), 1.19 (s, 12H); 13 13C NMR (126 MHz, CDCl3) δ 176.1, 169.0, 136.1, 128.6, 1., 66.1, 56.50, 39.3, 35.9, 33.2, 23.0, 22.3, 17.0; HRMS: ESI positive HRMS [M+H] + C 18 H 28 O3NS Theoretical value: 338.1784 [M+H], Observed value: 338.1784 [M+H]

[0171] Example 27: Synthesis of Benzyl (2R,6S)-6-(((R)-tert-butylsulfinyl)amino)-6-(4-chloropyridin-2-yl)-2-methylhexanoate (Compound 39) Under a nitrogen inert atmosphere, 2-bromo-4-chloropyridine (350 mg) and THF (2.5 mL) were added to a round-bottom flask containing a stir bar, and 1.3 M turbo Grignard / THF (1.4 mL) was added at room temperature. The reaction system was stirred at room temperature for 30 minutes, then cooled to -78 °C, and benzyl (R,E)-6-(((R)-tert-butylsulfinyl)imino)-2-methylhexanoate (500 mg) dissolved in THF (2 mL) was added via syringe. The reaction system was warmed to room temperature over 1 hour, quenched with an aqueous NaHCO3 solution, and diluted with EtOAc. The organic layer was transferred to a separatory funnel and the layers were separated. The organic layer was then dried over MgSO4, filtered, and the volatile substances were removed under reduced pressure to obtain a concentrated residue. Chromatography (EtOAc / hexane (1 / 1) to 100% EtOAc) was performed on the obtained residue to give benzyl (2R,6S)-6-(((R)-tert-butylsulfinyl)amino)-6-(4-chloropyridin-2-yl)-2-methylhexanoate (Compound 39) as a colorless oil (530 mg, 79% yield). 1 1H NMR (DMSO-d6, 600 MHz): δ 8.46 (d, J = 5.4 Hz, 1H), 7.56 (d, J = 1.8 Hz, 1H), 7.40 (dd, J = 1.8, 5.4 Hz, 1H), 7.31 - 7.38 (m, 5H), 5.54 (d, J = 6.8 Hz, 1H), 5.06 (s, 2H), 4.28 (m, 2H), 2.45 (m, 1H), 1.82 (m, 2H), 1.58 (m, 1H), 1.38 (m, 2H), 1.07 (s, 9H), 1.05 (d, J = 7.1 Hz, 3H); 13 13C NMR (DMSO-d6, 151 MHz): δ 175.5, 164.9, 150.1, 143.2, 136.3, 128.4, 127.9, 127.7, 122.3, 121.4, 65.3, 61.2, 55.3, 38.5, 36.1, 32.8, 23.0, 22.5, 16.7

Table 8

[0172] Example 28: Synthesis of (2R,6S)-6-((tert-butoxycarbonyl)amino)-6-(4-chloropyridine-2-yl)-2-methylhexanoic acid (compound 40)

[0173] Step 1 In a round-bottom flask, (2R,6S)-6-(((R)-tert-butylsulfinyl)amino)-6-(4-chloropyridine-2-yl)-2-methylhexanoate benzyl (300 mg) was dissolved in MeOH (4 mL), and 2N NaOH aqueous solution (1 mL) was added. The reaction system was stirred at room temperature until the starting material was consumed, diluted with water, washed with hexane, and the benzyl alcohol was removed. The mixture was acidified with citric acid to pH 3, and the product was extracted to MTBE. The organic layer was concentrated using a rotary evaporator until a residue remained.

[0174] Step 2 In a round-bottom flask, the obtained residue was dissolved in MeOH (2.5 mL), and TMSCl (250 μL, 3 equivalents) was added. After the starting material was consumed, volatile substances were removed by vacuum.

[0175] Step 3 The resulting residue was dissolved in THF (2.5 mL), and Boc2O (220 mg, 1.5 equivalents) and triethylamine (280 μL, 3 equivalents) were added. After the intermediate was consumed, the reaction system was diluted with NaOH (1N, 10 mL) and hexane (10 mL). The organic layer was separated from the aqueous layer, and the aqueous layer was acidified to pH 3 with saturated citric acid aqueous solution, causing a white solid to precipitate. The white solid was filtered, washed with water (10 mL), and then dried overnight under a stream of air. (2R,6S)-6-((tert-butoxycarbonyl)amino)-6-(4-chloropyridine-2-yl)-2-methylhexanoic acid was obtained (yield 86%, 203 mg). (The properties were consistent with those of (2R,6S)-6-((tert-butoxycarbonyl)amino)-6-(4-chloropyridine-2-yl)-2-methylhexanoic acid measured previously.)

[0176] [ka] Example 29: Synthesis of 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazole-1-yl)phenyl)pyrimidine-4-ol (Compound 33) The weight of (Z)-3-amino-3-[5-chloro-2-(4-chlorotriazole-1-yl)phenyl]prop-2-enamide (compound 32) (50 mg, 0.15262 mmol, 91% by weight, 1.0 equivalent) was measured in a 4 mL vial fitted with a red pressure-release cap. Ethyl formate (0.25 mL, 3.1 mmol, 100% by weight, 20 equivalents) was added to this vial, followed by sodium ethoxide (21% by weight) / ethanol (0.15 mL, 0.40 mmol, 21% by weight, 2.6 equivalents), and the mixture was heated at 55°C for 2 hours. Subsequently, a two-layer solution of HCl (1 mol / L) / deionized water (0.23 mL, 0.23 mmol, 1 mol / L, 1.5) and 2-methyltetrahydrofuran (0.5 mL, 5 mmol, 100% by weight, 30) was added, and the layers were separated by shaking. The organic layer was washed with saline solution (0.5 mL), the layer was separated, and then the organic layer was dried further with Na2SO4, concentrated to approximately 5V, heptane (10V) was added, filtered, and dried (80% yield). 1 H NMR (400MHz, DMSO-d6)δ 12.64(br s, 1H), 8.75(s, 1H), 8.06(d, J=1.0Hz, 1H), 7.88(d, J=2.3Hz, 1H), 7.85-7.71(m, 2H), 6.34(d, J=1.0Hz, 1H)

[0177] Example 30: XRPD data of the acetone solvate crystal of compound (I) [Table 9]

[0178] Procedure: Powder X-ray diffraction (XRPD) was performed using an X'PertPRO MRD (PANalytical (Philips)) diffractometer. This instrument is equipped with a high-power fine-focus (LFF) X-ray tube, and the compound was packed into a sample holder (16 mm). [Table 10]

[0179] Example 31: Infrared data of the acetone solvate crystal of compound (I) [Table 11]

[0180] Procedure: Samples were analyzed using micro-ATR (micro-total internal reflection) with appropriate microATR accessories and the following measurement conditions. [Table 12]

[0181] The examples and embodiments described herein are for illustrative purposes only, and in some embodiments, various modifications or changes are included within the scope of this disclosure and the appended claims.

Claims

1. The acetone solvate of compound (I) shown below: 【Chemistry 1】 A method for manufacturing, (a) Compound A: 【Chemistry 2】 This is reacted with N,N-dimethylformamide dimethyl acetal in a first solvent selected from the group consisting of acetonitrile (ACN), dichloromethane (DCM), toluene, tetrahydrofuran (THF), tert-butyl methyl ether (MTBE), and ethyl acetate to obtain a mixture containing methanol as a byproduct; (b) Add compound C to the mixture from step (a): 【Transformation 3】 Add the following compounds: 【Chemistry 4】 Obtaining; (c) The compound obtained in step (b) is treated with an aqueous acetone solution to obtain the acetone solvate of compound (I): 【Transformation 5】 To obtain A method characterized by steps.

2. The method according to claim 1, wherein methanol is removed before step (b).

3. The method according to claim 2, wherein methanol is removed from the mixture of step (a) and acetic acid is added.

4. The method according to claim 1, wherein triethylamine is added after the addition of compound C.

5. The method according to claim 1, wherein the compound obtained in step (b) is crystallized in a mixed solvent of methanol and water, and then in step (c) is washed with an aqueous acetone solution to obtain the acetone solvate of compound (I).

6. Furthermore, compound A: 【Transformation 6】 Follow these steps: (d) Compound 1: 【Transformation 7】 ammonia (NH4) in a second solvent selected from the group consisting of methanol, dioxane, ethanol, isopropanol, tetrahydrofuran (THF), and water. 3 ) reacts with compound 2: 【Transformation 8】 Obtaining; (e) Compound 2 is reacted with a dehydrating agent to obtain Compound 3: 【Chemistry 9】 Obtaining; (f) Compound 3 is reacted with ethyl potassium malonate, a base, and a Lewis acid to obtain compound A: 【Chemistry 10】 To obtain The method according to claim 1, characterized by being manufactured by [method].

7. The method according to claim 6, wherein calcium chloride is added as a catalyst in step (d).

8. The dehydrating agent in step (e) is phosphoryl chloride (POCl 3 ), (COCl) 2 , PCl 5 SOCl 2 , PCl 3 , and (chloromethylene)dimethyliminium chloride (ClCH=N(CH) 3 ) 2 The method according to claim 6, selected from the group consisting of Cl).

9. The Lewis acid in step (f) is selected from the group consisting of zinc chloride (ZnCl 2 ), aluminum chloride (AlCl 3 ), and boron trifluoride (BF 3 ), the method according to claim 6.

10. The method according to claim 6, wherein the base of step (f) is selected from the group consisting of triethylamine, N,N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), 1,5-diazabicyclo[4.3.0]nona-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), tetramethylethylenediamine (TMEDA), and N,N,N',N'',N''-pentamethyldiethylenetriamine (PMDTA).

11. Furthermore, compound C: 【Chemistry 11】 Follow these steps: (g) Hydrochloride salt of compound 15: 【Chemistry 12】 Dissolve it in water, (h) Next, aminotransferase ATA-486 and pyridoxal 5'-phosphate hydrate (5-PLP) are added to compound C: 【Chemistry 13】 To obtain The method according to claim 1, characterized by being manufactured by [method].

12. Hydrochloride salt of compound 15: 【Chemistry 14】 but, (i) Compound 8: 【Chemistry 15】 This is reacted with 2-methylcyclopentanone and a strong base to form compound 9: 【Chemistry 16】 Obtaining; (j) Compound 9 is reacted with an acidic aqueous solution to obtain compound 10: 【Chemistry 17】 Obtaining; (k) Compound 10 is reacted with (1R,2S)-erythro-2-amino-1,2-diphenylethanol to obtain the diastereomer salt of compound 10A: [Chemistry 18] Obtaining; (l) Dissolve the diastereomer salt of compound 10A in an acidic aqueous solution and an organic solvent selected from the group consisting of methanol, ethanol, and 2-butanone, and compound 10A: 【Chemistry 19】 Obtaining; (m) Compound 10A is reacted with chlorotrimethylsilane, then trimethyl orthoformate, and then a strong base to obtain compound 11: 【Chemistry 20】 Obtaining; (n) Mix compound 11 with dicyclohexylamine (DCHA) to form a salt of compound 11: 【Chemistry 21】 Obtaining; (o) The dicyclohexylamine salt of compound 11 as a coupling agent and the following compounds: 【Chemistry 22】 Reacted with the hydrochloride salt, compound 14: 【Chemistry 23】 form; (p) Compound 14 is reacted with hydrochloric acid in the presence of a metal catalyst to obtain the hydrochloride salt of compound 15: 【Chemistry 24】 To obtain The method according to claim 11, characterized by being manufactured using a step.

13. The method according to claim 12, wherein the coupling agent in step (o) is selected from the group consisting of 1,1'-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), and 1,1'-thiocarbonyldiimidazole (TCDI).

14. The method according to claim 12, wherein the metal catalyst of step (p) is selected from the group consisting of palladium catalysts and ruthenium catalysts.

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