Method for preparing BTK inhibitors

Abstract

This invention provides a method for preparing an intermediate for preparing an NTK inhibitor. [Solution] a) Form a reaction mixture comprising the following compound 170, the following compound 181, a palladium catalyst, and a solvent system containing a base, wherein the equivalent ratio of the palladium catalyst to compound 170 is less than approximately 0.001:1 to 0.005:1, (b) The following scheme: TIFF2026086461000160.tif47170 A method is provided which involves reacting a reaction mixture according to the method to form a reaction product mixture containing compound 190.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to European Application No. 21181156.7 filed on 23 June 2021 and European Application No. 21172180.8 filed on 5 May 2021, the contents of which are incorporated by reference in their entirety.

[0002] This disclosure generally relates to a method for preparing the Bruton's tyrosine kinase ("BTK") inhibitor compound 2-{3'-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-ylpiperazine-1-yl)-pyridine-2-ylamino]-6-oxo-1,6-dihydro-[3,4']bipyridinyl-2'-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1-one. This disclosure further generally relates to a method for preparing intermediates in the synthesis of the aforementioned BTK inhibitor compounds, such as tricyclic lactam compounds. [Background technology]

[0003] The following structure: The BTK inhibitor compound 2-{3'-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-ylpiperazine-1-yl)-pyridine-2-ylamino]-6-oxo-1,6-dihydro-[3,4']bipyridinyl-2'-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1-one It is known from U.S. published literature, U.S. Patent No. 2013 / 0116235A1, as a BTK inhibitor useful in the treatment of diseases or disorders selected from immunodeficiencies, cancer, cardiovascular diseases, viral infections, inflammation, metabolic / endocrine dysfunction, and neurological disorders. U.S. Patent No. 2013 / 0116235 is incorporated herein by reference in its entirety. An alternative name may be used for 2-{3'-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazine-1-yl)-pyridine-2-ylamino]-6-oxo-1,6-dihydro-[3,4']bipyridinyl-2'-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1-one, but is the chemical structure control shown. One such alternative name is (S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazine-1-yl)pyridine-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridine]-2'yl)-7,7-dimethyl-2,3,4,6,7,8-hexahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1-one. U.S. Patent No. 2013 / 0116235 discloses a useful method for preparing 2-{3'-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-ylpiperazine-1-yl)-pyridine-2-ylamino]-6-oxo-1,6-dihydro-[3,4']bipyridinyl-2'-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1-one, but this method requires chromatographic purification and achieves low yields.

[0004] Useful methods for preparing 2-{3'-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-ylpiperazine-1-yl)-pyridine-2-ylamino]-6-oxo-1,6-dihydro-[3,4']bipyridinyl-2'-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1-one are known from U.S. Patent No. 2018 / 0230155 and further from Zhang, H. et al., "Development of an Efficient Manufacturing Process for Reversible Bruton's Tyrosine Kinase Inhibitor GDC-0853", Org. Process Res. Dev. 2018, 22, 8, 978-990. U.S. Patent No. 2018 / 0230155 and Zhang's publications are incorporated herein by reference in their entirety.

[0005] There is a need for improved methods for preparing 2-{3'-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-ylpiperazine-1-yl)-pyridine-2-ylamino]-6-oxo-1,6-dihydro-[3,4']bipyridinyl-2'-yl}7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1-one and its intermediate compounds. For example, there is a need for improved methods having higher yields, fewer by-products, or a combination of these. [Overview of the project]

[0006] One aspect of the present disclosure relates to a method for preparing compound 190, or its stereoisomers, geometric isomers, tautomers, or salts. The method comprises forming a reaction mixture comprising compound 170, compound 181, a palladium catalyst, a solvent system including water, and a base, wherein the equivalent ratio of the palladium catalyst to compound 170 is less than about 0.001:1 to less than 0.005:1. The reaction mixture is as follows: The reaction is carried out according to TIFF2026086461000002.tif52170 to form a reaction product mixture containing compound 190 (or its stereoisomers, geometric isomers, tautomers, or salts).

[0007] In some embodiments, the Pd catalyst comprises a palladium(II) species containing a phosphine ligand and at least one palladium-carbon bond. In some embodiments, the fragment that gives rise to the palladium-carbon bond is of formula: TIFF2026086461000003.tif19170 (in the formula, R 6 ~R 10 Each of these is independently H, and C may be substituted. 1~6 Selected from the group consisting of alkyl, optionally substituted C6 aryl, and optionally substituted heteroaryl, R 6 and R 10 (These may optionally combine to form a fused dicyclic ring containing an aromatic ring.) It is an allyl derivative of [compound name]. In some embodiments, the yield of compound 190 (or its stereoisomers, geometric isomers, tautomers, or salts) is at least 50% based on compound 170.

[0008] One aspect of this disclosure relates to a method for reducing byproduct formation in a Suzuki coupling reaction. The method involves forming a reaction mixture comprising compound 170, compound 181, a palladium catalyst, a solvent system including water, and a base, wherein the equivalent ratio of the palladium catalyst to compound 170 is less than about 0.001:1 to 0.005:1, and the following scheme: The method includes reacting a reaction mixture according to TIFF2026086461000004.tif46170 to form a reaction product mixture containing compound 190 (or its stereoisomers, geometric isomers, tautomers, or salts).

[0009] In some embodiments, the Pd catalyst contains a palladium(II) species containing a phosphine ligand and at least one palladium-carbon bond. In some embodiments, the fragment that forms the palladium-carbon bond has the formula: TIFF2026086461000005.tif19170(where R 6 ~R 10 each independently is selected from the group consisting of H, optionally substituted C 1~6 alkyl, optionally substituted C6 aryl, and optionally substituted heteroaryl, and R 6 and R 10 may optionally combine together to form a fused bicyclic ring containing an aromatic ring) is an allyl derivative of. In some embodiments, the content of dimer impurities in the resulting reaction product mixture is less than 0.3 area% based on compound 190 (or its stereoisomer, geometric isomer, tautomer or salt), where the dimer impurity has the structure: TIFF2026086461000006.tif66170.

[0010] In some embodiments, the combined content of ketone impurities and alcohol impurities in the resulting reaction product mixture is less than 0.25 area% based on compound 190 (or its stereoisomer, geometric isomer, tautomer or salt), where the ketone impurity and the alcohol impurity have the structure: TIFF2026086461000007.tif80170.

[0011] One aspect of the present disclosure is directed to a method for improving the yield in a Suzuki coupling reaction. The method comprises a reaction mixture comprising compound 170, compound 181, a palladium catalyst, a solvent system containing water, and a base, wherein the equivalent ratio of the palladium catalyst to compound 170 is less than about 0.001:1 to 0.005:1, forming a reaction mixture, and the following scheme: The process includes forming a reaction product mixture containing compound 190 (or its stereoisomers, geometric isomers, tautomers, or salts) in accordance with TIFF2026086461000008.tif47170.

[0012] In some embodiments, the Pd catalyst comprises a palladium(II) species containing a phosphine ligand and at least one palladium-carbon bond. In some embodiments, the fragment that gives rise to the palladium-carbon bond is of formula: TIFF2026086461000009.tif19170 (in the formula, R 6 ~R 10 Each of these is independently H, and C may be substituted. 1~6 Selected from the group consisting of alkyl, optionally substituted C6 aryl, and optionally substituted heteroaryl, R 6 and R 10 (These may optionally combine to form a fused dicyclic ring containing an aromatic ring.) It is an allyl derivative of compound 170. In some embodiments, the yield of compound 190 (or its stereoisomers, geometric isomers, tautomers, or salts) based on compound 170 is at least 80%, or at least 85%.

[0013] One aspect of this disclosure relates to a method for preparing compound 180, its stereoisomers, its geometric isomers, its tautomers, or salts thereof. The method is as follows: The method comprises forming a first reaction mixture comprising compound 140, a platinum / vanadium carbon catalyst, a solvent, and hydrogen, in accordance with TIFF2026086461000010.tif36170, and reacting the first reaction mixture to form a first reaction product mixture comprising compound 141.

[0014] The above method involves forming a second reaction mixture containing compound 141, compound 90, a palladium catalyst, a catalytic ligand, a base, and a solvent, and the following scheme: The method further comprises reacting a second reaction mixture to form a second reaction product mixture containing compound 180, in accordance with TIFF2026086461000011.tif47170.

[0015] In some embodiments, the yield of compound 141 based on compound 140 is at least 90%, or at least 95%, the yield of compound 180 based on compound 141 is at least 60%, at least 70%, or at least 80%, and the purity of compound 180 is at least 95%, at least 98%, or at least 99%.

[0016] Another aspect of the present disclosure is a composition comprising at least 98.5 w / w% of compound 190, or its stereoisomers, geometric isomers, tautomers, or salts, TIFF2026086461000012.tif55170 Here, (a) The content of dimer impurities is less than 0.15 area percent based on compound 190 (or its stereoisomers, geometric isomers, tautomers, or salts), where the dimer impurity is structural This is from TIFF2026086461000013.tif76170. (b) The combined content of alcohol impurities and ketone impurities is less than 0.35 area percent based on compound 190 (or its stereoisomers, geometric isomers, tautomers, or salts), where the alcohol impurities and ketone impurities are structurally This applies to compositions that are included in TIFF2026086461000014.tif89170. [Brief explanation of the drawing]

[0017] [Figure 1] The methods for preparing compounds 141 and 180 are shown. [Figure 2] The method for preparing compound 141 and another method for preparing compound 180 are shown. [Figure 3] The method for preparing compound 141 and another method for preparing compound 180 are shown. [Figure 4] The method for preparing compound 182 is shown. [Figure 5A] The first method for preparing compound 190 is shown. [Figure 5B] A second method for preparing compound 190 is shown. [Figure 6] The method for preparing compound 200 is shown below. [Figure 7] The methods for preparing compounds 160 and 170 are shown. [Figure 8] The methods for preparing compounds 120, 130, and 160 are shown. [Figure 9] The methods for preparing compounds 120, 121, 130, and 160 are shown. [Figure 10] The methods for preparing compounds 122, 130, and 160 are shown. [Figure 11] The method for preparing compound 170 is shown. [Figure 12A] The method for preparing compound 140 is shown. [Figure 12B] The methods for preparing compounds 154A, 153, and 140 are shown. [Figure 13] The overall method for preparing compound 200 is shown, where "Comp" refers to the compound. [Figure 14A] This graph shows the area % of compound 141, evaluated by ultra-high performance liquid chromatography (UHPLC) measurements from the fractionated reactor output, monitoring the continuous processing method for producing compound 141 from compound 140 as described in Example 12. [Figure 14B] This graph shows the area percentage of compound 140, including azo + azoxy impurities and dimer impurities, as evaluated by ultra-high performance liquid chromatography (UHPLC) measurements from the fractionated reactor output, monitoring the continuous processing method for producing compound 141 from compound 140 as described in Example 12. [Figure 15] This graph shows the theoretically predicted throughput compared to the actual experimental output achieved, as observed in the continuous processing method described in Example 12. [Figure 16]This is a schematic diagram of the continuous processing setup described in Example 12, including real-time analysis by inline FT-IR and online UHPLC. P indicates a pressure sensor and T indicates a temperature sensor. [Figure 17] This is the XRPD spectrum of the crystalline ethanol semisolvate form of fenebrutinib obtained in Example 14. [Figure 18] This is the XRPD spectrum of the crystalline ethanol semisolvate form of fenebrutinib obtained in Example 14. [Figure 19] This is the XRPD spectrum of the crystalline ethanol semisolvate form of fenebrutinib obtained in Example 14. [Figure 20] Table 21 is a graph summarizing the performance of different catalysts in 141 flow hydrogenation processes under the reaction conditions reported in Entry 3. [Figure 21] Table 21 is a graph summarizing the performance over time of two different 5% Pt / C catalysts in reducing compound 140 under the reaction conditions reported in Entry 3. [Figure 22] This graph shows the purity of the aminopyridine 141 solution obtained by sampling at regular intervals in the scaled-up continuous flow described in Example 13. [Figure 23] This is a schematic diagram of the continuous processing setup described in Example 13, using a fixed-bed catalyst in metallic form, deposited on a solid support and housed in a tubular reactor. [Modes for carrying out the invention]

[0018] References to certain embodiments of the present invention will now be made in detail, examples of which are illustrated in the accompanying structures and formulas. While the present invention will be described in relation to the listed embodiments, it will be understood that they are not intended to limit the invention to these embodiments. In contrast, the present invention is intended to encompass all substitutes, modifications, and equivalents that may fall within the scope of the invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar to or equivalent to those described herein that may be used in the practice of the present invention. The present invention is by no means limited to the methods and materials described. If one or more incorporated documents, patents, and similar materials, including but not limited to defined terms, usage of terms, and described techniques, differ from or conflict with this application, this application shall prevail. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to the extent of the present invention. While similar or equivalent methods and materials may be used in the practice or testing of the invention, preferred methods and materials are described below. All published documents, patent applications, patents, and other references mentioned herein are incorporated in their entirety by reference.

[0019] definition When indicating the number of substituents, the term "one or more" refers to the maximum number of substitutions possible from a single substituent, i.e., from the substitution of one hydrogen to the substitution of all hydrogens. The term "substituent" refers to an atom or group of atoms that substitutes for a hydrogen atom in the parent molecule. The term "substituted" indicates that the specified group has one or more substituents. Any group can have multiple substituents, and if a variety of possible substituents are provided, the substituents are selected independently and do not need to be the same. The term "unsubstituted" means that the specified group does not have substituents. The term "may be substituted" means that the specified group is either unsubstituted or substituted with one or more substituents independently selected from the group of possible substituents. When indicating the number of substituents, the term "one or more" refers to the maximum number of substitutions possible from a single substituent, i.e., from the substitution of one hydrogen to the substitution of all hydrogens.

[0020] As used herein, “alkyl” refers to a monovalent, linear or branched saturated hydrocarbon moiety consisting only of carbon and hydrogen atoms, having 1 to 20 carbon atoms. “Lower alkyl” refers to alkyl groups with 1 to 6 carbon atoms, i.e., C1 to C6 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, and dodecyl. Alkyl groups may be substituted, for example, with one or more halogens.

[0021] As used herein, “cycloalkyl” refers to a carbocyclic moiety consisting of a monocyclic or polycyclic ring. Cycloalkyls may be substituted as defined herein. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl (i.e., “Cy”), and cycloheptyl. Polycyclic ring structures include condensed bicyclic and bridging bicyclic, condensed polycyclic and bridging polycyclic, and spirocyclic hydrocarbon ring systems, such as bicyclo[2.2.1]heptane, pinan, bicyclo[2.2.2]octane, adamantane, and norbornene. Cycloalkyls may be saturated or partially unsaturated (e.g., cycloalkenyl).

[0022] As used herein, "aryl" refers to a group of 6 to 20 carbon atoms (C6-C6). 20 This refers to a monovalent aromatic hydrocarbon group. Aryls include saturated, partially unsaturated rings, or bicyclic groups containing aromatic rings condensed to aromatic carbocyclic rings. Typical aryl groups include, but are not limited to, groups derived from benzene (phenyl), substituted benzenes, naphthalene, anthracene, biphenyl, indenyl, indanyl, 1,2-dihydronaphthalene, and 1,2,3,4-tetrahydronaphthyl. The aryl group may be independently substituted with one or more substituents described herein. In some embodiments, the aryl may be substituted with alkyl, cycloalkyl, halogen, or haloalkyl groups.

[0023] As used herein, “alkoxy” refers to the structural-OR (wherein R is the alkyl moiety as defined herein) portion. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, and isopropoxy.

[0024] As used herein, “haloalkyl” refers to an alkyl group as defined herein, in which one or more hydrogen atoms are replaced by the same or different halogens. Exemplary haloalkyl groups include -CH2Cl, -CH2CF3, -CH2CCl3, -CF3, CHF2, and the like.

[0025] As used herein, "halogen" refers to chlorine, fluorine, bromine, and iodine.

[0026] As used herein, “amino” refers to the structural -NRR' (wherein R and R' are each hydrogen), “monoalkylamino” refers to a structure in which one of R and R' is hydrogen and the other of R and R' is alkyl, and “dialkylamino” refers to a structure in which each of R and R' is alkyl.

[0027] As used herein, “may be substituted” refers to a moiety that may be unsubstituted or that may be substituted with a particular group. Examples of substituents include, but are not limited to, hydroxy, alkyl, alkoxy, halo, haloalkyl, oxo, amino, monoalkylamino, or dialkylamino.

[0028] As used herein, the term "chiral" refers to a molecule that cannot be superimposed on its mirror image partner, while the term "achiral" refers to a molecule that can be superimposed on its mirror image partner.

[0029] As used herein, “stereoisomer” refers to a compound that has the same chemical structure but differs in the arrangement of atoms or groups in space.

[0030] As used herein, "diastereomer" refers to a stereoisomer having two or more chirality centers, the molecules of which are not mirror images of each other. Diastereomers have different physical properties (e.g., melting point, boiling point, spectroscopic properties) and reactivity. Mixtures of diastereomers can be separated under high-resolution analytical procedures such as electrophoresis and chromatography.

[0031] As used herein, "enantiomer" refers to two stereoisomers of a compound that are mirror images of each other and cannot be superimposed.

[0032] The stereochemical definitions and conventions used herein generally follow SP. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof, such as racemic mixtures, are intended to form parts of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l, or (+) and (-), are used to indicate the rotational characteristics of plane polarization by a compound, with (-) or l meaning the compound is levorotatory. Compounds with (+) or d as prefixes are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Certain stereoisomers are also sometimes called enantiomers, and mixtures of such isomers are often called enantiomer mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemic compound, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemic compound” refer to an equimolar mixture of two enantiomer species that lack optical activity. Enantiomers may be separated from racemic mixtures by chiral separation methods, such as supercritical fluid chromatography (SFC).The assignment of stereochemistry at the chiral center in the separated enantiomer may be temporary, while the determination of stereochemistry is about to occur, for example, through X-ray crystallographic data.

[0033] As used herein, the term “tautomer” or “tautomer form” refers to structural isomers of different energies that are interconvertible across a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversions via rearrangement of some bonding electrons.

[0034] As used herein, the term “salt” refers to both acid addition salts and base addition salts. “Acid addition salt” refers to salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, and phosphoric acid, as well as with organic acids of the aliphatic, alicyclic, aromatic, aromaticaliphatic, heterocyclic, carboxylic acid, and sulfonic acid types, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid mesylate, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. “Base addition salt” refers to salts formed with organic or inorganic bases.

[0035] As used herein, "inorganic bases" generally include salts of sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Non-limiting examples include phosphates, e.g., dipotassium monohydrogen phosphate, potassium dihydrogen phosphate, tripotassium phosphate, disodium monohydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, diammonium monohydrogen phosphate, ammonium dihydrogen phosphate, and triammonium phosphate; acetates, e.g., potassium acetate, sodium acetate, and ammonium acetate; formates, e.g., potassium formate and sodium formate; carbonates, e.g., potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate; and alkali metal hydroxides, e.g., lithium hydroxide, sodium hydroxide, and potassium hydroxide. Inorganic bases may be used individually or in combination of two or more.

[0036] As used herein, “organic base” generally includes primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as pyridine, isopropylamine, trimethylamine, diethylamine, triethylamine, triethanolamine, diisopropylamine, ethanolamine, 2-diethylaminoethanol, trimethylamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

[0037] As used herein, “nonpolar solvent” refers to a solvent in which no significant partial loads are present on any atom or solvent, and in which polar bonds are arranged such that the action of those partial loads is canceled out. Non-limiting examples of nonpolar solvents include pentane, hexane, heptane, cyclopentane, cyclohexane, benzene, toluene, 1,4-dioxane, dichloromethane ("DCM"), methyl tert-butyl ether ("MTBE"), chloroform, carbon tetrachloride, and diethyl ether.

[0038] As used herein, “aprotic solvent” refers to a solvent that does not donate hydrogen. As used herein, “polar aprotic solvent” refers to a solvent that lacks acidic hydrogen and has a high dielectric constant and a high dipole moment. Non-limiting examples of polar aprotic solvents include tetrahydrofuran ("THF"), methyltetrahydrofuran ("Me-THF"), ethyl acetate ("EA"), acetone, dimethylformamide ("DMF"), acetonitrile ("ACN"), cyclopropyl methyl ether ("CPME"), petroleum ether, N-methyl-2-pyrrolidone ("NMP"), trifluorotoluene, chlorobenzene, anisole, and dimethyl sulfoxide. In some embodiments, the aprotic solvent is a low molecular weight ester. Non-limiting examples of aprotic low molecular weight ester solvents include methyl acetate, ethyl acetate, n-propyl acetate, i-propyl acetate, i-butyl acetate, propylene brichol methyl ether acetate, monoethyl ether acetate, and combinations thereof.

[0039] As used herein, “polar protic solvent” refers to a solvent having an unstable hydrogen atom bonded to an oxygen or nitrogen atom. Non-limiting examples of polar protic solvents include formic acid, n-butanol, i-propanol, n-propanol, ethanol, methanol, acetic acid, and water.

[0040] As used herein, “solvent” refers to nonpolar solvents, aprotic solvents, polar protic solvents, and combinations thereof.

[0041] As used herein, “palladium catalyst” refers to any palladium catalyst that affects the rate and conversion rate of a chemical compound to a product compound in a commercially acceptable yield and conversion rate. In some embodiments, the palladium-catalyzed reactions described herein require a zero-valent palladium species (Pd(0)). Exemplary catalytically active (Pd(0)) species may be applied directly (e.g., as commercially available Pd(0) complexes, e.g., Pd(PPh3)4, Pd(PCy3)2, Pd(PtBu3)2, or as similar Pd(0) complexes) or formed from a palladium source in combination with either a ligand and / or a base (e.g., KOtBu, KOH, NaOAc, K3PO4, K2CO3, Hünig base, NEt3, NPr3). In some embodiments, the palladium catalyst comprises a palladium(II) species. In some embodiments, the catalyst further comprises a ligand. In some embodiments, the ligand is a phosphine ligand. In some embodiments, the palladium source is selected from a non-exclusive enumeration: [PdCl(X)]2 (X = e.g., allyl, cinnamyl, or clotyl), [PdCl(X)PR3] (R = alkyl or aryl), [Pd(X)(Y)] (Y = e.g., cyclopentadienyl or p-simyl), Pd(dba)2, Pd2(dba)3, Pd(OAc)2, PdZ2 (Z = Cl, Br, I), Pd2Z2(PR3)2, or Pd(TFA)2. In some embodiments, the catalytic palladium species is selected from the non-exclusive enumeration: [Pd(allyl)Cl]2, Pd(MeCN)2Cl2, Pd(benzonitrile)2Cl2, Pd(dba)2, Pd(OAc)2, PdCl2, PdBr2, Pd(TFA)2, Pd(MeCN)4(BF4)2, Pd2(dba)3, Pd(PCy3)2Cl2, Pd(acac)2, and Pd(PPh3)4. In some such embodiments, the palladium source is Pd2(dba)3 or Pd(OAc)2. In some embodiments, the palladium source is Pd(PCy3)2. In some other embodiments, the catalytic palladium species can be formed in situ from a palladium source such as those listed above, and one or more ligands.Non-limiting examples of ligands include DPPF, DTPBF, BINAP, DPPE, DPPP, DCPE, RuPhos, SPhos, APhos(amphos), CPhos, XPhos, t-BuXPhos, Me4t-BuXPhos, neopentyl(t-Bu)2P, (t-Bu)2PMe, (t-Bu)2PPh, PCy3, PPh3, xanthophos and N-xanthophos, and DPEPhos. In some embodiments, the ligand is an aryl phosphate. In some embodiments, the ligand is XPhos, xanthophos, or DPEPhos. In certain embodiments, the ligand is XPhos(2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl), xanthophos(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene), or the following structures: TIFF2026086461000015.tif46170 is DPEPhos(oxydi-2,1-phenylene)bis(diphenylphosphine). In some embodiments, the catalyst comprises a palladium(II) species, a phosphine ligand, and at least one palladium-carbon bond. For example, the catalyst may be selected from a cationic palladium species containing an inorganic or organic counterion X; and a neutral palladium species containing a coordinated inorganic or organic ligand X, where X is a halogen; a carboxylate, for example, CH3C(O)O, but not limited to... - ,tBuC(O)O - Or CF3C(O)O - ;Sulfonates, for example, triflates (CF3SO3) - ), tosylates, vesylates or nosilates; or inorganic anions, for example, but not limited to PF6 - BF4 - , B(C6F5)4 - NO3 - or SO4 2-It may also be neutral or cationic and may further contain counterions. In some embodiments, the catalyst is [(SPhos)Pd(allyl)]CF3SO3, [(SPhos)Pd(allyl)]CH3CO2, [(SPhos)Pd(allyl)]NO3, [(SPhos)Pd(allyl)Cl], [(SPhos)Pd(clotyl)Cl], [(SPhos)Pd(allyl)]PF6, or [(SPhos)Pd(allyl)]CF3CO2. In some other embodiments, the catalyst source is a preformed catalyst. Non-limiting examples of preformed catalysts include Pd(dppf)Cl2, Pd(dppe)Cl2, Pd(PCy3)2Cl2, bis(triethylphosphine)palladium(II) chloride, Pd(t-Bu3P)2Cl2, Pd[P(o-tol)3]2Cl2, Pd(PPh3)2Cl2, Pd(OAc)2(PPh3)2, and Pd(CH3CN)2Cl2. In some such embodiments, the preformed catalyst is Pd(dppf)Cl2. In some further embodiments, the catalyst source or the preformed catalyst may be compounded with a solvent, such as dichloromethane, chloroform, or acetonitrile. Non-limiting examples of such complexes include Pd(dppf)Cl2·DCM, Pd2(dba)3·CHCl3, and Pd(PPh3)2Cl2·ACN.

[0042] As used herein, “boronating reagent” refers to any boronating reagent capable of cross-linking with an aryl halide to form an aryl boronate. Examples of boronating reagents include, but are not limited to, tetrahydroxyborone, catecholborane, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 4,6,6-trimethyl-1,3,2-dioxaborinane, diisopropylamineborane, bis(neopentylglycolato)diborone, bis(catecholato)diborone, bis(hexyleneglycolato)diborone, bis(pinacolate)diborone, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-5-(trifluoromethyl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine, bis(2,4-dimethylpentane-2,4-glycolato)diborone, phenylboronic acid, diisopropylmethylborane, and methylboronic acid.

[0043] As used herein, “reducing agent” refers to a compound that donates electrons. Non-limiting examples of reducing agents include sodium borohydride, potassium borohydride, sodium bis(2-methoxyethoxy)aluminum hydroxide, sodium bisulfite, sodium bisulfite, sodium hydrosulfite, sodium tetrahydroborate, potassium tetrahydroborate, sodium triacetoxyborohydride, trichlorosilane, triphenyl phosphite, triethylsilane, trimethylphosphine, triphenylphosphine, diborane, diethoxymethylsilane, diisobutylaluminum hydrate, diisopropylaminoborane, lithium aluminum hydroxide, and lithium triethylborohydride.

[0044] As used herein, “protecting group” refers to a group used to protect the remote functionality (e.g., primary or secondary amine) of an intermediate. The need for such protection varies depending on the nature of the remote functionality and the conditions of the preparation method. Suitable amino protecting groups include acetyltrifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). For a general description of protecting groups and their uses, see TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0045] Some embodiments herein refer to the purity or content (for example, of a desired or undesirable compound) using area percentages measured by HPLC. Preferred HPLC methods for evaluating area percentages are known to those skilled in the art and include, for example, the methods used in Examples 6-9 of this disclosure and the methods described in detail in the chapter on analytical methods.

[0046] As used herein, “dominant” and “dominantly” mean more than 50%, at least 75%, at least 90%, at least 95%, at least 99%, or at least 99.9% based on weight, volume, moles, equivalents, v / w%, w / w%, w / v%, or v / v%.

[0047] As used herein, the terms “amorphous” or “amorphous form” indicate that a substance, component, or product is not essentially crystalline, as determined, for example, by XRPD. In certain embodiments, a sample containing an amorphous form of a substance may not essentially contain other amorphous and / or crystalline forms.

[0048] As used herein, the terms “crystalline” and “crystal” refer to single-component or multi-component crystalline forms, such as polymorphs of a compound; or crystalline solid forms of a chemical compound, including but not limited to solvates, hydrates, inclusion compounds, cocrystals, salts of a compound, or polymorphs thereof. The terms “crystalline form” and related terms herein refer to various crystalline modifications of a given substance, including but not limited to polymorphs, solvates, hydrates, cocrystals, and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, other molecular complexes of salts, and polymorphs thereof. Crystalline forms of substances can be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces such as nanopores or capillaries, recrystallization on surfaces or templates such as polymers, recrystallization in the presence of additives such as cocrystallizing countermolecules, desolvation, dehydration, rapid distillation, rapid cooling, slow cooling, vapor diffusion, sublimation, polishing, and solvent droplet polishing.

[0049] Techniques for characterizing crystalline and amorphous forms are known in the art and include, but are not limited to, thermogravimetric analysis ("TGA"), differential scanning calorimetry ("DSC"), X-ray powder diffraction ("XRPD"), single-crystal X-ray analysis, vibrational spectroscopy, such as IR spectroscopy and Raman spectroscopy, solid-state nuclear magnetic resonance ("NMR"), optical microscopy, hot-stage optical microscopy, scanning electron microscopy ("SEM"), electron crystallography and quantitative analysis, particle size analysis ("PSA"), surface area analysis, solubility studies and dissolution studies.

[0050] Preparation of compound 190 In some aspects of the present invention, compound 190, its stereoisomers, its geometric isomers, its tautomers, and its salts are reacted in the following scheme: It can be prepared from compounds 170 and 181 according to TIFF2026086461000016.tif48170.

[0051] In some embodiments, compound 190 (or its stereoisomers, geometric isomers, tautomers, or salts) can be prepared according to the methods depicted in Figure 5A and Figure 5B.

[0052] Compound 190 (or its stereoisomers, geometric isomers, tautomers, or salts) is prepared from a reaction mixture containing compound 170, compound 181, a palladium catalyst, a solvent system containing water, and a base. The reaction mixture is reacted to form a reaction product mixture containing compound 190, or its stereoisomers, geometric isomers, tautomers, or salts. In some embodiments, the solvent system further comprises a polar aprotic solvent. In some embodiments, the polar aprotic solvent is an ester, such as a low molecular weight ester. In certain embodiments, the solvent system comprises a low molecular weight ester, such as a lower alkyl ester of acetic acid. In some embodiments, the low molecular weight ester is ethyl acetate or isopropyl acetate. In certain embodiments, the solvent system comprises water and ethyl acetate. In some embodiments of the methods provided herein, the use of a solvent system comprising water and esters, such as low molecular weight esters, yields compound 190, or its stereoisomers, geometric isomers, tautomers, or salts, in higher yields, with lower levels of impurities, or both, than methods using different solvent systems.

[0053] In some embodiments, the equivalent ratio of compound 181 to compound 170 in the reaction mixture is greater than 1:1, greater than 1:1 to about 1.5:1, about 1.01:1, about 1.05:1, about 1.1:1, about 1.15:1, about 1.2:1, about 1.25:1, about 1.3:1, about 1.35:1, about 1.4:1, about 1.45:1, or about 1.5:1, and any range produced therefrom.

[0054] The palladium catalyst may be any palladium catalyst described elsewhere in this specification. In some specific embodiments, the Pd catalyst comprises a palladium(II) species containing a phosphine ligand and at least one palladium-carbon bond. In some embodiments, the fragment giving rise to the palladium-carbon bond is of formula: TIFF2026086461000017.tif23170 (in the formula, R 6 ~R 10 Each of these is independently H, and C may be substituted. 1~6 Selected from the group consisting of alkyl, optionally substituted C6 aryl, and optionally substituted heteroaryl, R 6 and R 10 (These may optionally combine to form a fused dicyclic ring containing an aromatic ring.) It is an allyl derivative of [the compound]. In some specific embodiments of the allyl derivative, R 6 ~R 10 Each of them is H; R 6 is -CH3, R 7 ~R 10 Each of them is H; R 7 is -CH3, R 6 and R 8 ~R 10 Each of them is H; R 8 is -CH3, R 6 , R 7 , R 9 and R 10 Each of them is H; R 6 is phenyl, and R 7 ~R 10 Each of them is H; or R 7 is phenyl, and R 6 and R 8 ~R 10 Each of them is H.

[0055] In some embodiments, R 6 and R 10 These, together with the atoms to which they are bonded, form a fused dicyclic ring containing an aromatic ring. In some embodiments, R 6 and R10 These, together with the atoms to which they are bonded, form a five-membered carbon ring to the phenyl ring. In some embodiments, R 7 , R 8 and R 9 In other embodiments, R 7 , R 8 and R 9 Two of them are H, and the rest are C 1~10 It is alkyl.

[0056] For example, in some embodiments, the fragment that gives rise to the palladium-carbon bond is given by formula: TIFF2026086461000018.tif23170 (in the formula, R 11 C 1~10 (It is alkyl.) It is the indenyl. In some specific aspects, the structure: It is an allyl derivative of TIFF2026086461000019.tif24170.

[0057] In some embodiments, the phosphine ligand is expressed by the formula: TIFF2026086461000020.tif34170 (in the formula, R 1 and R 2 Each of these can be independently substituted. 1~12 Alkyl, possibly substituted C3-C 20 Cycloalkyls, and optionally substituted C5 or C6 aryls; or C 1~4 Alkyl, and C 3~6 (Selected from the group consisting of cycloalkyl groups) It is of the nature of R. In some embodiments, 3 ~R 5 These are H and C, which may be substituted, independently of each other. 1~6 Alkyl, formula -OC 1~6 Alkyl alkoxides, and formula -N(R 12 )(R 13 )(wherein, R 12 and R 13 H and C are independent of each other. 1~6(selected from amines selected from alkyl) selected from the group consisting of. In some embodiments, R 3 ~R 5 are each independently -O-C 1~4 alkyl, and R 12 and R 13 are independently selected from H and C 1~4 alkyl. In some embodiments, the phosphine ligand has the following structure: It is SPhos having TIFF2026086461000021.tif36170.

[0058] In some embodiments, the Pd catalyst is selected from cationic palladium species containing an inorganic or organic counterion X; and neutral palladium species containing a coordinated inorganic or organic ligand X. In such embodiments, X can be selected from halogens, carboxylates, sulfonates, and inorganic anions. In such embodiments, the carboxylate can be as defined elsewhere in this specification, for example CH3C(O)O - , tBuC(O)O - , or CF3C(O)O - . In such embodiments, the sulfonate can be as defined elsewhere in this specification, for example triflate (CF3SO3 - ), tosylate, besylate, or nosylate. In such embodiments, the inorganic anion can be as defined elsewhere in this specification, for example PF6 - , BF4 - , B(C6F5)4 - , NO3 - and SO4 2- . In one embodiment, X is CF3SO3 - .

[0059] In some embodiments, the Pd catalyst is neutral or cationic. In certain embodiments, the catalyst further comprises a cationic catalyst further containing a counterion, such as an anionic counterion. In some embodiments, the catalyst is selected from the group consisting of [(SPhos)Pd(allyl)]CF3SO3, [(SPhos)Pd(allyl)]CH3CO2, [(SPhos)Pd(allyl)]NO3, [(SPhos)Pd(allyl)Cl], [(SPhos)Pd(clotyl)Cl], [(SPhos)Pd(allyl)]PF6, and [(SPhos)Pd(allyl)]CF3CO2. In one embodiment, the catalyst is [(SPhos)Pd(allyl)]CF3SO3.

[0060] The equivalent ratios of the palladium catalyst to compound 170 are approximately 0.001:1, 0.0015:1, 0.002:1, 0.0025:1, 0.003:1, 0.004:1, 0.0045:1, 0.005:1, 0.006:1, 0.007:1, 0.008:1, 0.009:1, or 0.01:1, and any range derived therefrom, e.g., 0.001:1 to 0.01:1, 0.001:1 to less than 0.05:1, 0.001:1 to 0.0045:1, or 0.001:1 to 0.003:1.

[0061] In some embodiments, the reaction mixture base is an inorganic base. In some specific embodiments, the base is K3PO4 or K2HPO4.

[0062] In some embodiments, the reaction mixture solvent system comprises, predominantly comprises, consists essentially of, or consists of water and at least one aprotic solvent as defined elsewhere in this specification. The volume ratio of the aprotic solvent to water is about 1:0.05, about 1:0.1, about 1:0.5, about 1:1, about 1:1.5, or about 1:2, and any range generated therefrom, such as about 1:0.05 to about 1:2, or about 1:0.1 to about 1:1. In some particular embodiments, the aprotic solvent is an ester. In certain embodiments, the aprotic solvent is a low molecular weight ester, such as an ester of acetic acid, and is a C 1~6 alkyl, such as a C 1~3 alkyl. In some embodiments, the ester is isopropyl acetate or ethyl acetate. In some particular embodiments, the solvent system comprises, predominantly comprises, consists essentially of, or consists of water and ethyl acetate. In some embodiments, the ratio of the volume of the solvent system in the reaction mixture to compound 170 is less than 20:1 L / kg, about 5:1 L / kg, about 7.5:1 L / kg, about 10:1 L / kg, about 12.5:1 L / kg, about 15:1 L / kg, about 20:1 L / kg, about 25:1 L / kg, or about 30:1 L / kg, and ranges thereof, such as about 5:1 to about 30:1 L / kg, about 5:1 to about 20:1 L / kg, about 5:1 to about 15:1 L / kg, or about 7.5:1 to about 12.5:1 L / kg. In certain embodiments, the use of a solvent system comprising water and an ester (such as ethyl acetate) results in a higher product yield, or a lower amount of impurities, or both, compared to the use of other solvent systems. In some embodiments, the ratio of ethyl acetate to water is about 1:0.1 to about 1:1, or about 1:0.1 to about 1:0.8, or about 1:0.1 to about 1:0.5, or about 1:0.1 to about 1:0.3.

[0063] In some embodiments, the catalyst is [(SPhos)Pd(allyl)]CF3SO3, the solvent system predominantly consists of ethyl acetate and water, where the volume ratio of ethyl acetate to water is about 1:0.1 to about 1:1 (e.g., about 1:0.3), and the boronate has the structure: This is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane from TIFF2026086461000022.tif20170.

[0064] In some embodiments, the reaction temperature for forming compound 190 is greater than about 40°C, greater than about 50°C, greater than about 60°C, greater than about 70°C, or between about 40°C and about 80°C, between about 50°C and about 80°C, between about 60°C and about 80°C, between about 65°C and about 75°C, about 60°C, about 70°C, or about 80°C. In some embodiments, the reaction temperature is about 70°C. In some embodiments, the solvent system comprises ethyl acetate and water, and a temperature of about 70°C is used.

[0065] The reaction is considered complete when the area % concentration of compound 170 by HPLC is less than 2, less than 1, less than 0.5, or less than 0.1. In some embodiments, the reaction is considered complete when the area % concentration of compound 170 by HPLC is less than 0.5 or undetectable. The reaction time to completion may be about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours. In some embodiments, the reaction time to completion is less than 5 hours, for example, less than 2 hours, or less than 3 hours. In some embodiments, the reaction time is about 1 hour, or about 2 hours.

[0066] While we do not wish to be bound by theory, the combinations of solvent systems, catalysts, and temperatures described herein can lead to shorter reaction times than other combinations. For example, in some embodiments, a combination of a catalyst containing a palladium(II) species containing a phosphine ligand and at least one palladium-carbon bond, a solvent system containing water and an ester (e.g., a low molecular weight ester, e.g., ethyl acetate), and a reaction temperature between about 60°C and about 80°C (e.g., between about 65°C and about 75°C, e.g., about 70°C) can lead to the production of compound 190, or a salt thereof, in a shorter time period (e.g., less than 5 hours, less than 3 hours, or less than 2 hours) in higher yield, with fewer impurities, or both, compared to other conditions.

[0067] In some embodiments of the present invention, a method for producing compound 190 (or its stereoisomers, geometric isomers, tautomers, or salts) further comprises one or more purification steps. In some embodiments, one or more purification steps comprise one or more aqueous washes, e.g., two or three aqueous washes. In certain embodiments, one or more purification steps comprise an aqueous base wash followed by an aqueous N-acetylcysteine ​​wash, and then an aqueous wash. In certain embodiments, an additional purification step, e.g., filtration, is included.

[0068] In some such embodiments, the temperature of the reaction product mixture may be adjusted to about 10°C to about 35°C, or about 15°C to about 30°C, or about 15°C to about 25°C (e.g., about 20°C), and may be combined with aqueous N-acetyl-L-cysteine ​​having an N-acetyl-L-cysteine ​​concentration of about 3 wt.%, about 5.5 wt.%, about 6 wt.%, or about 9 wt.%, and in the ranges therein, e.g., about 3 wt.% to about 9 wt.%, with vigorous stirring. The weight ratio of N-acetyl-L-cysteine ​​to compound 190 may be about 1:5 to about 1:25, or about 1:10 to about 1:20, or about 1:15. The ratio of aqueous N-acetyl-L-cysteine ​​volume (e.g., about 3 wt.% to about 9 wt.% aqueous N-acetyl-L-cysteine) to the weight of compound 190 may be about 1 L / kg, about 2 L / kg, or about 3 L / kg, and in that range, for example, about 1 L / kg to about 3 L / kg. Following vigorous stirring with aqueous N-acetyl-L-cysteine, in some embodiments, an additional organic solvent is added with vigorous stirring. The additional organic solvent may be the same organic solvent present in the reactant, for example, a low molecular weight ester, for example, ethyl acetate. In some embodiments, the ratio of the additional organic solvent to the weight of compound 190 is about 1:3 to about 1:1, or about 1:2 to about 1:1, or about 1:2.5. The aqueous layer is separated and the organic layer containing compound 190 is recovered. The organic layer may optionally be further combined with a base solution, where the concentration of the base may be about 3 wt.% to about 7 wt.% or about 5 wt.%. In some embodiments, the base is sodium bicarbonate (NaHCO3). In certain embodiments, the ratio of the volume of the base solution to the weight of compound 190 may be about 0.5 L / kg, about 1 L / kg, about 1.5 L / kg, about 2 L / kg, or about 2.5 L / kg, and in that range, for example, about 0.5 L / kg to about 2.5 L / kg. In such embodiments, the aqueous layer is separated and the organic layer containing compound 190 is recovered. In some embodiments, the organic layer containing compound 190 may undergo an additional washing step, for example, washing with water. In some embodiments, the organic layer containing compound 190 is combined with water under vigorous stirring.In certain embodiments, the ratio of the volume of water to the weight of compound 190 may be about 0.5 L / kg, about 1 L / kg, about 2 L / g, about 3 L / kg, or about 4 L / kg, or a range thereof, for example, about 0.5 L / kg to about 4 L / kg, or about 1 L / kg to about 3 L / kg, or about 2 L / kg. In such embodiments, the aqueous layer is separated and the organic layer containing compound 190 is recovered. In some embodiments, any of the various organic layers containing compound 190 may be brought into contact with activated carbon, and such filtration may be by passing through a carbon bed or by suspending activated carbon in the organic phase followed by carbon separation, and by removal by filtration or centrifugation. In certain embodiments, stereoisomers, geometric isomers, tautomers, or salts of compound 190 are produced, and all comparisons and / or ratios made with respect to the amount of compound 190 are instead made with respect to the amount of stereoisomers, geometric isomers, tautomers, or salts of compound 190.

[0069] Compound 190 may be optionally isolated from the work-up step, from the reaction product mixture, or from the organic layer containing compound 190. Such isolation may include, for example, one or more solvent swap, distillation, and / or crystallization steps. In some such embodiments, the recovered organic layer containing compound 190 may be processed by a solvent swap step, where the aprotic solvent may be swapped for a polar protic solvent as described elsewhere in this specification. In some such embodiments, the polar protic solvent is an alcohol. In some such embodiments, the polar protic solvent is ethanol. In some such embodiments, the solvent swap may be performed by reducing the volume of the composition containing compound 190 by vacuum distillation, and the reduced volume containing compound 190 may be diluted with the polar protic solvent. For example, the reduced volume containing compound 190 may be diluted with a polar protic solvent in a ratio of 1:6, 1:5, 1:4, 1:3, or 1:2, or any range therein, for example, 1:6 to 1:1, or 1:5 to 1:4, or about 1:4.5. In some embodiments, the ratio of the volume of polar protic solvent to the weight of compound 190 is about 20 L / kg, 15 L / kg, 10 L / kg, 5 L / kg, or a range therein, for example, about 20 L / kg to about 5 L / kg, or about 15 L / kg to about 5 L / kg, or about 10 L / kg. In some embodiments, the polar protic solvent is added to the reduced volume containing compound 190 to the total solvent volume of about 20 to about 5 L of solvent per kg of compound 190, or about 8 to about 12 L of solvent per kg of compound 190, to produce a diluted solution of compound 190. The diluted mixture may optionally be treated with activated carbon as described herein. The volume of the solution of purified compound 190 may be reduced by distillation to a reduced volume, for example, about 3 to about 13 L, about 3 to about 7 L, about 6 to about 10 L, or about 7 to about 9 L of solvent per kg of compound 190. The dilution and distillation steps of the polar protic solvent (ethanol) may be repeated one or more times.In some embodiments, the dilution and distillation steps of the polar protic solvent are carried out one or more times until the content of the remaining aprotic solvent is less than 10% w / w, or less than 8% w / w, or less than 6% w / w, or less than 4% w / w. In some embodiments, the method herein further comprises crystallizing compound 190, or its stereoisomers, geometric isomers, tautomers, or salts. Such crystallization follows, for example, the solvent swap and / or distillation steps described herein. The solution of compound 190 may be cooled to, for example, less than 25°C to crystallize the purified compound 190. In some embodiments, the solution is cooled to about 70°C to about 80°C, for example about 75°C, and then to about 0°C to about 10°C, for example about 5°C. The purified compound 190 crystals are recovered, for example by filtration or centrifugation, and dried to obtain purified dried compound 190 crystals, or its stereoisomers, geometric isomers, tautomers, or salts. In some embodiments, a solution of compound 190 is seeded with crystals of compound 190 to promote crystallization. In some embodiments, the seed crystals are added as a solid composition (e.g., as dry crystals, or as essentially dry crystals, or as crystals containing less than 5% or less than 1% solvent). In other embodiments, a solution of compound 190 is seeded with a suspension of compound 190 in a protic solvent to promote crystallization. In some such embodiments, the suspension contains about 2.5% to about 10% by weight, or 5% to about 8% by weight, of the compound in a protic solvent (e.g., alcohol, e.g., ethanol). In certain embodiments, the solution is seeded at a temperature of about 70°C to about 80°C, for example, about 75°C, and then the seeded solution is cooled to about 0°C to about 10°C, for example, about 5°C to produce crystals. In some embodiments, the cooled solution is stirred for at least 5 hours, at least 7 hours, at least 9 hours, at least 11 hours, or for example, 5 to 15 hours, and then the crystals are isolated. The compound 190 crystals were recovered by filtration or centrifugation and cooled to cold C. 1~4The crystals may be washed with alcohol and / or water. In some such embodiments, the crystals may be washed with alcohol, water / alcohol (e.g., in a 1:1 v / v ratio), and then with alcohol. In some such embodiments, the alcohol is methanol. The washed compound 190 crystals may be dried under reduced pressure, for example, at a temperature of about 30°C to about 70°C (e.g., about 35°C to about 65°C, or about 45°C to about 55°C) and under a vacuum of about 2 to 10 millibars.

[0070] The yield of compound 190 based on compound 170, or its stereoisomers, geometric isomers, tautomers, or salts, is at least 80%, at least 85%, or at least 95%. In some embodiments, the yield is at least 91%. In some embodiments, the yield is at least 93%. In certain embodiments, the yield is at least 96%. In some embodiments, the purity of compound 190, as determined by HPLC, is at least 99 area%, at least 99.5 area%, at least 99.6 area%, at least 99.7 area%, at least 99.8 area%, or at least 99.9 area%. In some embodiments, the content of compound 190, or its stereoisomers, geometric isomers, tautomers, or salts, is at least 98.5% w / w, at least 99% w / w, or at least 99.5% w / w. The content of the dimer impurities described below is less than 0.15 area%, less than 0.1 area%, less than 0.05 area%, or undetectable when measured by HPLC according to this disclosure. In some embodiments, the content of the dimer impurities described below is less than 0.29% w / w, less than 0.25% w / w, less than 0.2% w / w, less than 0.15% w / w, or 0.1% w / w. In some embodiments, the combined content of the ketone impurities and alcohol impurities described below is less than 0.3 area%, less than 0.25 area%, less than 0.2 area%, less than 0.15 area%, less than 0.1 area%, less than 0.05 area%, 0.05 area%, or undetectable when measured by HPLC. In certain embodiments, the area percentage is evaluated using the HPLC method according to this disclosure.

[0071] The catalyst system of this disclosure yields compound 190 by exhibiting significantly higher activity for the coupling of compound 170 and compound 181 compared to previously disclosed catalyst systems utilizing Pd(dppf)Cl2 catalysts. The higher activity results in a catalyst packing amount that is about 0.1 mol% or about 0.2 mol% (0.001 equivalent or about 0.002 equivalent) based on compound 170, compared to a previously disclosed packing amount of about 1 mol%. The improved catalyst system has the advantages of higher yield and lower by-product impurities, as described herein and illustrated in the examples. For example, in some embodiments, the catalyst system yields a compound 190 yield of at least 90% or at least 93% based on compound 170, and a dimer impurity content of less than 0.15 area%, or less than 0.1 area%, or undetectable. The increased yield and reduced impurity profiles achieved using the improved catalyst systems described herein can be particularly reflected in higher batch sizes, for example, when using more than 100 g of starting material 170, e.g., at least 100 g, at least 250 g, at least 500 g, at least 750 g, at least 1 kg, or at least 2 kg of compound 170. In the previously described methods for producing compound 190, increasing batch sizes (e.g., 50 g to 0.75 kg of starting material 170) result in a decrease in the yield of the resulting compound. Therefore, in certain embodiments, the catalyst systems described herein are advantageous when preparing larger batch sizes of compound 190 (e.g., at least 1 kg, or at least 5 kg, or at least 50 kg, or at least 100 kg, or at least 150 kg, or about 175 kg, e.g., 160 to 185 kg), resulting in higher yields of compound 190 with lower levels of impurities, e.g., dimers, alcohols, and ketones. Furthermore, in some embodiments, the catalyst systems described herein exhibit higher activity in solvent systems containing water and aprotic ester solvents compared to previously used solvent systems.The use of solvent systems containing esters, including water and aprotic solvents in combination with the catalyst systems described herein, results in higher yields, lower levels of impurities, or both, compared to the aforementioned systems using other solvents. In addition, the methods described herein can be carried out at higher temperatures and / or in fewer reaction cycles compared to the aforementioned methods, and modifications to these parameters may yield additional advantages.

[0072] This combination of catalyst, solvent, and base, referred to as the catalyst system, provides compound 190 purity in the order of approximately 99.8 area% (HPLC) or higher, compared to the maximum purity of 99.5 area% described by the previously described method. Along with the improved impurity profile, this catalyst system brings about a significant reduction in the production of certain impurities that are difficult to remove, thereby preventing the need for certain purification steps. For example, the three impurity by-products of the compound 170-181 coupling reaction include: Examples include dimer impurities such as TIFF2026086461000023.tif95170, sec-alcohol impurities, and ketone impurities.

[0073] The impurity profiles of 190 representative compounds for this catalyst system, which were disclosed previously, are shown in the table below, using the same HPLC method for quantification. TIFF2026086461000024.tif31170

[0074] The combination of the catalyst system, the ester-containing solvent system, and the increased reaction temperature described herein offers, compared to previous methods, one or more of the following advantages: a higher yield of compound 190 (especially in larger batch sizes), lower levels of impurities (including reducing some impurities to below undetectable levels), a more efficient reaction workup, and shorter reaction times than previously required (including some combinations or all of these).

[0075] Further provided herein are compositions comprising compound 190, or its stereoisomers, geometric isomers, tautomers, or salts, with low levels of impurities. Such compositions may, for example, contain at least 98.5 w / w%, at least 99.0 w / w%, at least 99.3 w / w%, at least 99.5 w / w%, or at least 99.7 w / w% of compound 190, or its stereoisomers, geometric isomers, tautomers, or salts. In some embodiments, the compositions have a compound 190 purity of at least 99 area%, at least 99.5 area%, at least 99.6 area%, at least 99.7 area%, at least 99.8 area%, or at least 99.9 area%, as determined by HPLC. In some embodiments, the composition has a dimer impurity content of less than 0.15 area%, less than 0.10 area%, less than 0.05 area%, or undetectable, or less than 0.29% w / w, less than 0.25% w / w, less than 0.2% w / w, less than 0.15% w / w, or less than 0.1% w / w based on compound 190, where the dimer impurity is structure: This is from TIFF2026086461000025.tif66170.

[0076] In some embodiments, the composition has a combined content of alcohol impurities and ketone impurities based on compound 190 that is less than 0.35 area%, less than 0.30 area%, less than 0.25 area%, less than 0.20 area%, less than 0.15 area%, less than 0.1 area%, less than 0.05 area%, 0.05 area%, or undetectable, where alcohol impurities and ketone impurities are defined as having the following structure: This is from TIFF2026086461000026.tif85170.

[0077] In some embodiments, the composition comprises at least 1 kg, at least 2 kg, at least 5 kg, at least 25 kg, at least 50 kg, at least 75 kg, at least 100 kg, at least 125 kg, at least 150 kg, or at least 175 kg of compound 190, for example, between 1 kg and 200 kg, or between 5 kg and 100 kg, or between 50 kg and 200 kg, or between 100 kg and 200 kg.

[0078] In certain embodiments, stereoisomers, geometric isomers, tautomers, or salts of compound 190 are produced, and all comparisons and / or ratios made relative to the amount of compound 190 are instead made relative to the amount of the stereoisomers, geometric isomers, tautomers, or salts of compound 190.

[0079] Preparation of compound 200 Compound 200 (or its stereoisomers, geometric isomers, tautomers, or salts) is prepared from a second reaction mixture containing compound 190 (or its stereoisomers, geometric isomers, tautomers, or salts), a reducing agent, a base, and a solvent. Generally, As depicted in TIFF2026086461000027.tif48170, the second reaction mixture is reacted to reduce the aldehyde moiety of compound 190 and form a reaction product mixture containing compound 200.

[0080] In some embodiments, compound 200 may be prepared according to the method described in Figure 6.

[0081] In some embodiments, the solvent is C 1~4The solvent is selected from alcohols, ethers, and cyclic ethers. In some specific embodiments, the solvent is an aprotic solvent, such as THF, methyl tert-butyl ether, or 2-Me-THF. The ratio of the solvent system volume to 190 weight of the compound may be about 2:1 L / kg, about 3:1 L / kg, about 4:1 L / kg, about 5:1 L / kg, about 6:1 L / kg, about 7:1 L / kg, about 8:1 L / kg, about 9:1 L / kg, about 10:1 L / kg, and in the ranges therefrom, for example, about 2:1 to about 10:1 L / kg, or about 4:1 to about 8:1 L / kg. In some embodiments, the solvent is predominantly THF or consists of THF. In some embodiments, the base in the reaction mixture is an inorganic base, such as an alkali hydroxide. In one such embodiment, the base is sodium hydroxide. The equivalent ratios of the base to compound 190 are about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, or about 0.9:1, and their ranges, for example, about 0.1:1 to about 0.9:1, or about 0.3:1 to about 0.7:1. In any of the various embodiments, the reducing agent is one described elsewhere in this specification. In some specific embodiments, the reducing agent is sodium boro hydroxide. The equivalent ratios of the reducing agent to compound 190 are approximately 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, and ranges therefrom, for example, approximately 0.1:1 to 0.9:1, or approximately 0.2:1 to 0.8:1. In some embodiments, the base and reducing agent are added to the reaction mixture in the form of solids, aqueous solutions, or combinations thereof. In some embodiments, the base and reducing agent are added separately, while in other embodiments, they are added together. In some embodiments, the base and reducing agent are added together to the reaction mixture, for example, as an aqueous mixture. In certain embodiments, the molar ratio of base to reducing agent is approximately 0.5:1 to 0.5:2, for example, approximately 0.5:1.25 to 0.5:1.75, for example, approximately 0.5:1.57.

[0082] The reaction temperature for forming compound 200 is preferably about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, or about 60°C. The reaction may be considered complete when the area % concentration of compound 200 by HPLC is less than 2, less than 1, less than 0.5, or less than 0.1. In some embodiments, the reaction time to completion is 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, or longer. The yield of compound 200 or a salt thereof is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, or at least 95%, and the purity of compound 200 by HPLC is at least 99 area%, at least 99.5 area%, at least 99.9 area%, or 100 area%. In some embodiments, the yield of compound 200 or its salt is at least 90%, and the purity is at least 99.9% by HPLC.

[0083] In some embodiments, compound 200 can be isolated from the reaction product mixture. In some such embodiments, compound 200 can be isolated by adding and mixing the second reaction product mixture with an aqueous solvent of a base, such as an inorganic base (e.g., monopotassium phosphate), or with an aqueous solution of an inorganic acid such as phosphoric acid (i.e., H3PO4). In some embodiments, the aqueous base or inorganic acid in volume ratio to the weight of compound 200 is about 0.5 L to about 2 L of aqueous base or acid (e.g., monopotassium phosphate or phosphoric acid) solution at about 10 wt percent to about 25 wt percent per kg of compound 200. In some embodiments, such addition and mixing is carried out at a temperature of about 15°C to about 50°C, for example, about 20°C, or about 30°C, or about 40°C. The aqueous layer is separated, and the organic layer containing compound 200 is recovered in solution. The organic layer containing compound 200 may optionally be treated with activated carbon. The organic layer containing compound 200 may be filtered.

[0084] In some embodiments where the solvent is an aprotic solvent (e.g., THF), the filtrate may be distilled to a volume of compound 200 at about 2 to about 4 L / kg. Suitable solvents include, for example, C 1~4 An alcohol (e.g., methanol) may be added to the distilled filtrate in an amount of about 6 to about 8 L / kg of compound 200 total volume. In some embodiments, about 0.2 to about 0.8 wt% of compound 200 crystals may be added to form a mixture. The mixture may be distilled to reduce the volume of compound 200 to at least 1 L / kg, for example, about 2 L / kg, about 3 L / kg, about 4 L / kg, about 5 L / kg, about 6 L / kg, about 7 L / kg, or about 8 L / kg. In some embodiments, the distillate may be aged for at least 1 hour, for example, about 1 hour, about 2 hours, about 3 hours, or about 4 hours at a temperature of at least 40°C, for example, about 45°C, about 50°C, about 55°C, about 40°C, or about 65°C. The distilled mixture of compound 200 may be cooled to, for example, below 20°C to form a slurry of compound 200 crystallized from the cooled mixture. In some embodiments, crystals may begin to form before distillation. The slurry may be aged for a certain amount of time, for example, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, or about 4 hours. The compound 200 crystals may optionally be recovered and dried. Drying may be carried out preferably under reduced pressure and under an inert gas purge (e.g., argon or nitrogen) at temperatures, for example, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, or about 60°C, for a time sufficient to remove the desired amount of solvent, for example, about 6 hours, about 12 hours, about 18 hours, about 24 hours, or about 30 hours.

[0085] In some embodiments, the purified compound 200 crystals may be recrystallized in the purification process. In some embodiments, compound 200 is C 1~4The mixture may be combined with an alcohol (e.g., ethanol) in a ratio of alcohol volume to 200 units of compound weight of about 1 L / kg to about 10 L / kg, or about 1 L / kg to about 5 L / kg, or about 4 L / kg to about 10 L / kg, or about 6 L / kg to about 8 L / kg, and may also be combined with toluene in a ratio of toluene volume to 200 units of compound weight of about 1 L / kg to about 5 L / kg, or about 1.5 L / kg to about 3.5 L / kg, while vigorously stirring. The mixture may be heated, for example, to about 65 to about 85°C with stirring and held until a solution is obtained. The solution may then be cooled, for example, to about 60 to about 70°C, or about 65 to about 75°C, and combined with additional alcohol and seed crystals. In some embodiments, the cooled solution is first combined with additional alcohol, for example, a sufficient amount of additional alcohol such that the alcohol:toluene ratio is about 90:10, or about 80:20, or about 70:30, or any range therein; then seed crystals are added, for example, 200 compound crystals in amounts of about 0.5 wt% to about 4 wt%, or about 0.5 wt% to about 3 wt%, or about 0.5 wt% to about 1.5 wt%, to form a slurry. In some embodiments, the solution is further cooled between the alcohol addition and the seed crystal addition. Alternatively, the solution is first combined with a seed crystal, then with additional alcohol, for example, about 0.5 wt% to about 4 wt%, or about 0.5 wt% to about 3 wt%, or about 0.5 wt% to about 1.5 wt%, to form a slurry, which is then combined with alcohol, at a ratio of alcohol volume to the weight of compound 200, about 5 L / kg to about 25 L / kg, or about 10 L / kg to about 20 L / kg. In either embodiment, the slurry may be further cooled, for example, to about -5 to about 15°C, and held for at least 15 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 4 hours, or at least 8 hours to crystallize compound 200.In some embodiments, one or more thermocycles are involved after the initial cooling step, for example, raising the temperature between 30°C and about 50°C, or between about 35°C and about 50°C, and holding for at least 15 minutes, at least 30 minutes, or at least 1 hour, and then cooling again to about -5 to about 15°C and holding to crystallize compound 200. The crystals may be recovered by, for example, filtration or centrifugation and washed with alcohol. The washed crystals may be dried under reduced pressure and N2 purging at about 40 to about 60°C for at least 4 hours, at least 8 hours, at least 12 hours, or at least 20 hours to produce purified compound 200.

[0086] Preparation of compound 141 In some aspects of this disclosure, compound 141 is reacted in the following scheme: It can be prepared from compound 140 according to TIFF2026086461000028.tif36170.

[0087] A method for preparing compound 141 includes forming a reaction mixture comprising compound 140, a transition metal catalyst, hydrogen, and a suitable solvent. In some embodiments, the method includes forming a reaction mixture comprising compound 140 and a solvent comprising an organic solvent and water, and contacting the reaction mixture with a transition metal catalyst in the presence of hydrogen to form a product mixture comprising compound 141.

[0088] Compound 141 can be produced via batch processing or continuous flow processing.

[0089] In some embodiments, the transition metal catalyst comprises one or more transition metals and may optionally include one or more additional components, such as one or more non-transition metals, nonmetals, metal oxides, solid supports, or any combination thereof. In some embodiments, the one or more transition metals are selected from the group consisting of Pd, Pt, Co, Ra, and Ni. The transition metal catalyst is preferably selected from Pd / C, Sponge-Ni (including Ra-Ni), Ra-Co, Pt / V@C, and Beller-type catalysts, such as Co@Chitin, Ni-phen@SiO2, or Ni-phen@TiO2. In some embodiments, the catalyst is preferably selected from Ra-Ni, Ra-Co, Pt / V@C, and Beller-type catalysts, such as Co@Chitin, Ni-phen@SiO2, or Ni-phen@TiO2. In some embodiments, the catalyst is preferably selected from Pd / C, Sponge-Ni (this may include Ra-Ni), Pt / V@C, Co@Chitin, and Ni-phen@TiO2. In one embodiment, the catalyst is Pt / V@C. Pt / V@C (i.e., platinum and vanadium supported on carbon) may also be known as Pt-V / C or Pt / V / C. In some embodiments, such catalysts are used in batch processing methods. In some embodiments, the catalyst comprises Pd, Pt, Al or C, or any combination thereof, for example, Pd or Pt and Al or C. In some embodiments, the catalyst is Pd / Al2O3, Pt / Al2O3, Pd / C, or Pt / C. In some embodiments, the catalyst comprises Pd and Al, for example, Pd / Al2O3. As is known to those skilled in the art, alternative formats exist for describing catalysts, and in some formats, for example, the support is sometimes referred to with the symbol "@" or alternatively with " / ". For example, Pt / V@C may also be referred to as Pt / V / C or Pt-V / C, Pd / C may be referred to as Pd@C, Co@Chitin may be referred to as Co / Chitin, Ni-phen@SiO2 as Ni-phen / SiO2, Ni-phen@TiO2 as Ni-phen / TiO2, and so on.

[0090] In some embodiments, such catalysts are used in continuous flow processing. Catalysts used in continuous flow processing may be, for example, in the form of packed bed catalysts or immobilized catalysts. Immobilized catalysts may be formed by electroplating, spray coating, or slurry coating of the catalyst on a solid support. Suitable solid supports may be, for example, polymer-based, carbon-based, or metal-based supports, or any combination thereof (e.g., polymer-based carbon supports). In some embodiments, the immobilized catalyst includes a catalyst static mixer (CSM) support. One or more of these supports may be used. Such CSMs may be prepared, for example, by methods including selective laser melting or 3D printing techniques.

[0091] Beller-type catalysts are known in the art. For example, see: Formenti, D. et al., "A State-of-the-Art Heterogeneous Catalyst for Efficient and General Nitrile Hydrogenation," Chem.Eur.J.2020, 26, 15589; Sahoo, B. et al., "Biomass-Derived Catalysts for Selective Hydrogenation of Nitroarenes," ChemSusChem 2017, 10, 3035; and Bachmann, S. et al., "Nitrogen containing biopolymer-based Catalysts, a Process for their Preparation and Uses thereof," WO2018 / 114777. These references are incorporated herein by reference in their entirety. The catalyst may preferably contain transition metal content of about 1 wt.%, about 2 wt.%, about 3 wt.%, about 4 wt.%, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, about 11 wt.%, about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 20 wt.%, or about 25 wt.%, and any range derived therefrom, for example, about 1 wt.% to about 25 wt.%, about 1 wt.% to about 15 wt.%, or about 2 wt.% to about 10 wt.%. In some embodiments, the Ni and Co catalysts may preferably contain transition metal content of about 0.5 mol%, 1 mol%, 1.5 mol%, 2 mol%, 2.5 mol%, 3 mol%, 3.5 mol%, 4 mol%, 4.5 mol%, 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol%, or 10 mol%, and any range derived therefrom, for example, about 0.5 mol% to about 10 mol%, about 1 mol% to about 7 mol%, or about 2 mol% to about 5 mol%.Preferably, the catalytic amount of the transition metal is about 0.1 wt.%, about 0.5 wt.%, about 1 wt.%, about 2 wt.%, about 3 wt.%, about 4 wt.%, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, or about 10 wt.%, and any range generated therefrom, for example, about 0.1 wt.% to about 10 wt.%, about 0.1 wt.% to about 5 wt.%, about 1 wt.% to about 5 wt.%, or about 2 wt.% to about 4 wt.%. For Ni and Co catalysts, catalyst amounts are approximately 0.5 mol%, approximately 1 mol%, approximately 1.5 mol%, approximately 2 mol%, approximately 2.5 mol%, approximately 3 mol%, approximately 3.5 mol%, approximately 4 mol%, approximately 5 mol%, approximately 6 mol%, or approximately 7 mol%, and any range derived therefrom, e.g., approximately 0.5 mol% to approximately 7 mol%, approximately 1 mol% to approximately 5 mol%, or approximately 2 mol% to approximately 4 mol%. In reference to catalyst amount, wt% may refer to the weight of a wet catalyst, e.g., a catalyst containing some water and not completely dried. For example, catalysts, e.g., Pt-V@C and Pd / C, if not completely dried, may contain approximately 50 wt% water, or between approximately 50 wt% and approximately 70 wt%, e.g., approximately 60 wt% to approximately 65 wt% water. Thus, in some embodiments, for example, a wet catalyst with approximately 2% w / w catalyst packing may correspond to approximately 0.76% w / w dry catalyst. In some embodiments, the catalyst packing is approximately 0.5% w / w to approximately 1% w / w of dry catalyst. In other embodiments, wt% may refer to the weight of the dry catalyst, which is typically dry, for example, Beller-type catalysts. References to mol% refer to the molar amount of catalyst species, independent of water content.

[0092] In some embodiments, the solvent is selected from nonpolar solvents, polar aprotic solvents, and polar protic solvents. In some embodiments, the solvent is selected from alcohols, ethers, esters, toluene, dichloromethane, water, and combinations thereof. In some embodiments, the solvent is selected from ethers (including cyclic ethers), alcohols, and combinations thereof. In some embodiments, the solvent is selected from methanol, ethanol, isopropanol, dioxane, toluene, THF and Me-THF, water, and combinations thereof. In some embodiments, the solvent predominantly comprises water and a cosolvent. In some embodiments, the solvent predominantly comprises THF, predominantly comprises toluene and methanol, or predominantly comprises THF and water. In embodiments where the solvent predominantly contains water and a cosolvent, the volume ratio of the cosolvent to water is about 50:1, about 40:1, about 30:1, about 20:1, about 10:1, or about 1:1, and any range resulting from them, e.g., about 1:1 to about 50:1, about 10:1 to about 40:1, or about 10:1 to about 30:1. When the solvent system predominantly contains a combination of two organic solvents (e.g., toluene and methanol), the volume ratio between the solvents is preferably about 10:1, about 5:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:5, or about 1:10. In some embodiments, the solvent predominantly contains THF, and, for example, no cosolvent is used at all or essentially not at all (e.g., intentionally not included at all or not added at all). In some embodiments, water may be present. For example, when using a certain catalyst that has not been dried before use, a small amount of water may be present even if no further water is added separately. In certain embodiments, additional water is intentionally omitted or not added beyond what is present with the catalyst. The presence of residual water with the catalyst may occur, for example, in batch processing. In some embodiments, water is generated during the reaction even if it is not added to the initial reaction mixture, for example in batch processing. In other embodiments, for example in certain continuous flow processing, additional water may be present in the reaction mixture.The ratio of solvent volume to compound 140 by weight is less than about 3:1 L / kg, about 5:1 L / kg, about 10:1 L / kg, about 15:1 L / kg, or about 20:1 L / kg, and ranges therefrom, for example, about 3:1 to about 20:1 L / kg, about 3:1 to about 10:1 L / kg, or about 4:1 to about 6:1 L / kg. On a wt.% basis, the concentration of compound 140 in the reaction mixture is preferably about 5 wt.%, about 10 wt.%, about 15 wt.%, about 20 wt.%, about 25 wt.%, about 30 wt.%, or about 35 wt.%, and any range derived from them, for example, about 5 wt.% to about 35 wt.%, or about 10 wt.% to about 25 wt.%.

[0093] The reaction to form compound 141 may be carried out with N2 purging before introducing H2. The reaction is typically carried out at temperatures of about 20°C, about 30°C, about 40°C, about 50°C, about 60°C, about 70°C, about 80°C, about 90°C, about 100°C, about 125°C, about 150°C, about 175°C, or about 200°C, and any range from there to produce the compound, for example, about 20°C to about 200°C or about 40°C to about 80°C. The hydrogen pressure in the reaction is preferably about 0.1 bar, about 0.5 bar, about 1 bar, about 2 bar, about 3 bar, about 4 bar, about 5 bar, about 6 bar, about 7 bar, about 8 bar, about 9 bar, about 10 bar, about 20 bar, about 30 bar, about 40 bar, about 45 bar, about 50 bar, about 60 bar, about 70 bar, about 80 bar, about 90 bar, about 100 bar, about 125 bar, about 150 bar, about 175 bar, or about 200 bar, and any range derived from them, for example, about 0.1 bar to about 200 bar, about 0.5 bar to about 100 bar, or about 1 bar to about 45 bar. For the Pt / V@C catalyst, the preferred hydrogen pressure range is about 1 bar to about 10 bar, about 2 bar to about 8 bar, or about 4 bar. For the Ni-phen and Co@chitin catalysts, the preferred hydrogen pressure range is about 10 bar to about 100 bar, about 20 bar to about 70 bar, or about 40 bar. In some embodiments, the reaction time to completion may be about 4 hours, about 6 hours, about 12 hours, about 18 hours, about 24 hours, or longer. The reaction may be considered complete when the area % concentration of compound 140 by HPLC is less than 2, less than 1, less than 0.5, or less than 0.1. The reaction product mixture contains compound 141 in solution. The reaction product mixture may optionally be filtered.

[0094] In some embodiments, a method for producing compound 141 includes forming a reaction mixture comprising compound 140, a platinum-containing catalyst, a solvent, and hydrogen, and reacting the reaction mixture to form a product mixture comprising compound 141. In some embodiments, the platinum-containing catalyst is a Pt / V carbon catalyst. In certain embodiments, the catalyst packing is 1–4%, or about 1–3%, or about 2%, as weight percent. In some embodiments, the catalyst packing refers to a wet catalyst, i.e., a wet catalyst that is not completely dry and may contain some water. In some such embodiments, the amount of water present is about 50%–70%, or about 60%–65%. For example, in some embodiments, the catalyst packing is about 1–4%, or about 1–3%, or about 2%, as weight percent of a wet catalyst; or a dry catalyst of about 0.35–1.6% w / w, or about 0.5–1.0% w / w, or about 0.7–0.8% w / w. In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the polar aprotic solvent is THF. In even further embodiments, the reaction mixture is reacted at a temperature between 20°C and 200°C, for example, 40 to 80°C, for example, about 60°C. In yet further embodiments, the hydrogen pressure is 0.1 to 200 bar, for example, 1 to 45 bar, for example, 1 to 8 bar, or about 4 bar. In certain embodiments, a combination of a platinum catalyst (e.g., Pt / V carbon), a catalyst packing amount of 1–4 wt% (e.g., 1–3 wt%, or about 2 wt%), a polar aprotic solvent (e.g., THF), a temperature between 40°C and 80°C (e.g., between 50°C and 70°C, or about 60°C), and a hydrogen pressure of 1–45 bar (e.g., 1–8 bar, or about 4 bar) yields the conversion of compound 140 to compound 141 in higher yield, or with higher selectivity, or both, compared to previously used methods. Such yields may be, for example, greater than 99%, greater than 99.5%, greater than 99.8%, or greater than 99.9%. In some embodiments, the selectivity is greater than 99%, for example, at least 99.1%, at least 99.2%, at least 99.3%, or at least 99.4%.In certain embodiments, such a method is carried out using batch processing.

[0095] In some embodiments, the reaction mixture comprises about 10 wt.% of compound 141 in THF and about 2 wt.% of the Pt / V@C catalyst, and the reaction is carried out at about 60°C under about 4 bar of hydrogen for a reaction time of about 16 hours. In some such embodiments, the catalyst is a "wet" catalyst containing about 50 wt% to about 70 wt% or about 60 wt% to about 65 wt% of water.

[0096] In other embodiments, the method for producing compound 141 includes a continuous flow method. In some such embodiments, the method comprises producing a reaction mixture comprising compound 140 and a solvent, and contacting the reaction mixture with a transition metal catalyst in the presence of hydrogen to form a product mixture comprising compound 141, wherein the method is a continuous flow reaction. In some embodiments, the solvent is an organic solvent, such as a polar aprotic solvent. In some embodiments, the solvent optionally includes water. In some embodiments, the solvent includes water. In yet other embodiments, the solvent does not contain water, is essentially water-free, or contains less than 1% v / v water, or less than 0.5% v / v water, or less than 0.1% v / v water. In some embodiments, compound 140 is present in the reaction mixture at a concentration between 0.1 M and 0.8 M, between 0.2 M and 0.6 M, between 0.3 M and 0.5 M, between 0.35 M and 0.45 M, or about 0.4 M. In some embodiments, the continuous flow reaction is carried out at a temperature between 80°C and 140°C, or between 100°C and 140°C, or between 110°C and 130°C, or about 100°C, or about 120°C. In certain embodiments, the transition metal catalyst comprises palladium or platinum, e.g., Pd / Al2O3 or Pt / Al2O3. In some embodiments, the catalyst is Pd / Al2O3. In some embodiments, the transition metal catalyst is in the form of a packed bed catalyst. In some embodiments, the transition metal catalyst is an immobilized catalyst, formed, for example, by electroplating, spray coating, or slurry coating of a solid support with the catalyst. Such a solid support may be any suitable support, which may include one or more catalyst static mixers (CSMs). In some embodiments, the catalyst comprises a solid support. For example, the solid support is in the form of spheres or granules. In some embodiments, the support is metal or carbon. In certain embodiments, the support comprises aluminum or carbon. In certain embodiments, the catalyst contains Pt or Pd in ​​a packing amount between about 3% and 5% on a solid support containing aluminum or carbon.In some embodiments, the catalyst is 3% Pd Al2O3 spheres, or 3% Pt Al2O3 spheres, or 3% Pt activated C granules, or 3% Pd activated C granules, or 5% Pd Al2O3 spheres, or 5% Pt Al2O3 spheres, or 5% Pt activated C granules, or 5% Pd activated C granules, where the metal filling amount is wt%. In some embodiments, the filling amount is dry wt%. In further embodiments, the solvent, which includes an organic solvent and water, comprises a polar aprotic solvent and about 1 to 10 equivalents of water, or about 2 to 8 equivalents of water, or about 4, about 6, or about 8 equivalents of water, compared to the amount of compound 140. In some embodiments, the solvent is essentially composed of an organic solvent and water, for example, essentially composed of a polar aprotic solvent and water. In some embodiments, the polar aprotic solvent is THF. In some embodiments, hydrogen is present in excess compared to the amount of compound 140. For example, in some embodiments, hydrogen is present in amounts of more than 3 equivalents, between 3 and 5 equivalents, between 3 and 4 equivalents, or about 3.3 equivalents, or about 3.75 equivalents, relative to the amount of compound 140. In some embodiments, the flow of hydrogen to the continuous flow reactor is adjusted to supply an excess amount of hydrogen. In some embodiments, the continuous flow reaction is carried out at pressures between 1 bar and 50 bar, between 1 bar and 40 bar, between 10 bar and 30 bar, between 15 bar and 25 bar, or about 20 bar. In some embodiments, the reactor flow rate is 2–40 mL / min, 2–35 mL / min, 10–40 mL / min, 20–40 mL / min, 15–30 mL / min, 2–20 mL / min, 2–12 mL / min, 4–10 mL / min, 2–8 mL / min, 6–8 mL / min, approximately 2 mL / min, approximately 4 mL / min, approximately 6 mL / min, approximately 8 mL / min, approximately 16 mL / min, approximately 20 mL / min, approximately 24 mL / min, approximately 27 mL / min, or approximately 30 mL / min.In some embodiments, a method for producing compound 141 comprises forming a reaction mixture comprising compound 140 and a solvent containing THF and about 2 to 8 equivalents of water, and contacting the reaction mixture with a transition metal catalyst containing Pd (e.g., Pd / Al2O3) in the presence of excess hydrogen to form a product mixture containing compound 141, where water and hydrogen are compared with compound 140, where the reaction is a continuous flow reaction, carried out at a pressure between 10 bar and 30 bar, with a flow rate of about 2 to 8 mL / min, and a temperature between 110°C and 130°C. In some embodiments, a method for producing compound 141 comprises forming a reaction mixture comprising compound 140 and a solvent containing THF, and contacting the reaction mixture with a transition metal catalyst containing Pd or Pt (e.g., Pd / Al2O3 or Pt / Al2O3) in the presence of an excess amount of hydrogen to form a product mixture containing compound 141, where hydrogen is compared with compound 140, where the reaction is a continuous flow reaction, carried out at a pressure between 10 bar and 30 bar, with a flow rate of about 2 to 8 mL / min, and a temperature between 110°C and 130°C. In some embodiments, water is also included in the solvent system. In some embodiments, water is included in the solvent system where the catalyst is included as one or more catalyst static mixers. In other embodiments, where the catalyst is included in a form other than one or more catalyst static mixers, for example, when the catalyst is contained on a solid support, for example, in the form of spheres or granules, the solvent system is water-free, basically water-free, or contains less than 1% v / v or less than 0.5% v / v of water. In some embodiments, when the catalyst is contained on a solid support, water is present, or when the system contains the catalyst on a solid support (e.g., 3-5% Pd Al2O3 spheres or activated C granules, or 3-5% Pt Al2O3 spheres or activated C granules), the water has little effect on the yield and impurities. In some embodiments, the catalyst packing amount is dry wt%.

[0097] In certain embodiments, a combination of a solid-supported transition metal catalyst (e.g., one containing Pd, e.g., Pd / Al2O3), water in the solvent system (e.g., about 2–8 equivalents of water, or about 4, about 6, or about 8 equivalents of water), a temperature between 100°C and 140°C (e.g., 110–130°C, or about 120°C), and a flow rate of 2–40 mL / min (e.g., 20–40 mL / min, about 30 mL / min, 2–10 mL / min, 4–8 mL / min, or about 4 mL / min, 6 mL / min, or 8 mL / min) results in a high conversion rate of compound 140 to compound 141 while maintaining low levels of undesirable impurities. In some embodiments, the flow rate is 4 mL / min and contains about 2–8 equivalents of water. In some embodiments, the flow rate is 6 mL / min and contains about 8 equivalents of water. In some embodiments, the flow rate is 8 mL / min and contains about 8 equivalents of water. In some embodiments, the flow rate is 4–8 mL / min, and it contains approximately 8 equivalents of water.

[0098] In certain embodiments, a combination of a solid-supported transition metal catalyst (e.g., one containing Pt, e.g., Pt / C, e.g., 5% Pt / active C granules), a solution of compound 140 at a concentration of 0.1–1 M in a solvent system that is essentially water-free or contains less than 1% v / v or less than 0.5% v / v of water, a temperature between 80°C and 140°C (e.g., 90–110°C, or about 10°C), a hydrogen:solution flow rate ratio of about 50–5 mL / min, or about 40–10 mL / min, or about 35–25 mL / min, or about 30 mL / min, a system pressure of about 10–30 bar, about 15–25 bar, or about 20 bar, and a ratio of hydrogen to compound 140 in the range of about 5–1, about 4–2, about 3.5–2.5, or about 3 results in a high conversion rate of compound 140 to compound 141 while maintaining low levels of undesirable impurities. In some embodiments, the solvent system is polar aprotic, e.g., THF. In some embodiments, the reduction of compound 140 occurs at a rate of about 40 g / hour to 80 g / hour, or about 50 g / hour to 70 g / hour, or about 60 g / hour. In some embodiments, compound 141 is achieved with a purity of over 98%, or over 98.5%, or over 99%, or over 99.1%, as measured by HPLC. In some embodiments, compound 141 is achieved in a yield of over 70%, or over 75%, or over 80%, or over 85%, relative to compound 140. In some embodiments, combined azo and azoxy impurities are less than 0.05%, dimer impurities are less than 0.2%, e.g., less than 0.015%, and other impurities are less than 1%, less than 0.75%, less than 0.6%, or less than 0.5%.

[0099] Some conditions used in the continuous process methods provided herein may not be achievable in certain types of batch processing, such as batch processing methods that cannot reach similarly high temperatures or achieve the short residence times possible in continuous flow. Such situations may become apparent to those skilled in the art. The combination of including water in the solvent system, high temperature, and increasing flow rate used in the continuous processing methods described herein can achieve unexpectedly correlated effects that are not observed by adjusting only one of these parameters, and furthermore, can achieve a higher total output of the desired product over time while maintaining an acceptablely low level of undesirable impurities compared to other methods, including certain types of batch processing methods. In some embodiments, the continuous processing methods described herein achieve a conversion rate of compound 140 to compound 141 in yields of over 98.5 area%, over 99 area%, over 99.5 area%, over 99.8 area%, or over 99.9 area%. In certain embodiments, the yield conversion may be similar to or lower than that of other methods, but the higher throughput using continuous processing under the conditions described herein is advantageous because it can achieve a greater total output of product per hour while maintaining low impurity levels. In certain embodiments, the combined level of azo and azoxy impurities (shown below) is maintained at less than 0.1 area%, less than 0.09 area%, less than 0.08 area%, less than 0.07 area%, less than 0.06 area%, less than 0.05 area%, less than 0.04 area%, or less than 0.03 area%. In certain embodiments, the level of dimer impurities (shown below) is maintained at less than 0.1 area%, less than 0.09 area%, less than 0.08 area%, less than 0.07 area%, less than 0.06 area%, less than 0.05 area%, less than 0.04 area%, or less than 0.03 area%.In some embodiments, the levels of dimer impurities and the combined levels of azo and azoxy impurities are less than 0.04 area%, less than 0.09 area%, less than 0.05 area%, less than 0.09 area%, or less than 0.04 area%, less than 0.08 area%, respectively. In some embodiments, the combined total content of azo, azoxy, and dimer impurities (shown below) is maintained at less than 0.20 area%, or 0.15 area%, or less than 0.13 area%, or less than 0.1 area%. TIFF2026086461000029.tif46170

[0100] In some embodiments, a reaction product mixture containing compound 141 in solution may be subjected to a solvent exchange step to swap the solvent in the reaction product mixture with a solvent system for the reaction coupling compound 141 and compound 90 to form compound 180. Solvent exchange may be carried out by methods known in the art, for example and without limitation, by distillation or evaporation to dry, removing the solvent and subsequently dissolving it in a replacement solvent, or by solvent exchange distillation. For example and without limitation, alcohols, ethers, esters, toluene, dichloromethane, water, and combinations thereof present in the reaction product mixture containing compound 141 may be exchanged for an aprotic solvent by methods described elsewhere herein for the reaction mixture containing compounds 141 and 90. In some embodiments, the aprotic solvent is selected from THF, toluene, Me-THF, 1,4-dioxane, anisole, and combinations thereof. In some specific embodiments, the solvent is 1,4-dioxane, anisole, or a combination thereof. In a particular embodiment, the reaction product mixture containing compound 141 is predominantly THF, which is exchanged for anisole. The concentration of compound 141 after solvent exchange is preferably about 5:1 L / kg, about 10:1 L / kg, or about 15:1 L / kg, or about 20:1 L / kg, and a range therefrom, for example, about 5:1 to about 20:1 L / kg, or about 5:1 to about 15:1 L / kg. In some such embodiments, the final concentration of compound 141 is about 5 to about 15 weight percent.

[0101] In some embodiments, compound 141 can optionally be isolated from the reaction product mixture as a residue by concentration of the filtrate to near-dryness. In some embodiments, compound 141 can optionally be crystallized from the reaction product mixture by concentration to remove the solvent, followed by the addition of an antisolvent such as n-heptane, and cooling thereof. In some embodiments, concentration may be carried out in vacuum at a temperature below 60°C. In some embodiments, the yield of compound 141 is at least 90%, or at least 95%.

[0102] Preparation of compound 180 In some aspects of this disclosure, compound 180 is reacted in the following reaction scheme: Compounds 90 and 141 can be prepared according to TIFF2026086461000030.tif43170, where "LG" is a leaving group. In some embodiments, the leaving group is a halogen or a triflate. In one embodiment, the leaving group is Br.

[0103] In some embodiments, compound 180 may be prepared by any of the methods described in Figures 1-3.

[0104] A method for preparing compound 180 involves forming a reaction mixture comprising compound 141, compound 90, a palladium catalyst and an aryl phosphate catalyst ligand, a base, and an aprotic solvent. The reaction mixture is allowed to react to form a reaction product mixture containing compound 180. Compound 180 is optionally isolated from the reaction product mixture.

[0105] In some embodiments of the preparation of compound 180, compound 141 is used directly and not isolated. In such embodiments, the solvent in the reaction product mixture containing compound 141 may be replaced with a solvent for forming a reaction mixture containing compound 141, compound 90, a Pd catalyst and ligand, and a base. Solvent exchange may be carried out by methods known to those skilled in the art, as described elsewhere in this specification. In one such embodiment, a portion of the solvent contained in the compound 141 reaction product mixture (e.g., THF) may be removed by distillation under reduced pressure. For example, about 40%, about 50%, about 60%, about 70%, or about 80% of the solvent may be removed. In one embodiment, the solvent content may be reduced from about 10 volumes (V) to about 2-3V. Then, a solvent for the compound 141 / 90 reaction mixture (e.g., anisole) may be added and subsequently distilled to remove most of the remaining solvent from the compound 141 reaction product mixture, for example, to achieve a total volume of about 3V, 4V, 5V, 6V, or 7V.

[0106] The reaction mixture contains approximately equimolar amounts of compounds 90 and 141, in a slightly stoichiometric excess of compound 90, for example, in an equivalent ratio of 1.05:1 or 1.1:1. The solvent for the reaction mixture may preferably be an aprotic solvent as described elsewhere herein, or a polar aprotic solvent as described herein. Non-limiting examples of suitable solvents include THF, 2-Me-THF, tert-butyl methyl ether, cyclopropyl methyl ether, toluene, anisole, trifluorotoluene, chlorobenzene, and mixtures thereof. In some embodiments, the solvent is anisole.

[0107] The concentration of compound 141 in the solution is preferably about 10 wt.%, about 15 wt.%, about 20 wt.%, about 25 wt.%, or about 30 wt.% and any range derived therefrom, for example, about 5 wt.% to about 30 wt.%, about 10 wt.% to about 25 wt.%, about 10 wt.% to about 20 wt.%, or about 15 wt.% to about 25 wt.%.

[0108] The palladium catalyst is preferably a Pd complex and a ligand. In some embodiments, the Pd complex is preformed. In some embodiments, the Pd complex is formed in situ. In any embodiment, the Pd complex is formed from a Pd precursor Pd(II) complex, for example, but not limited to, Pd(OAc)2, [PdCl(allyl)]2, or [PdCl(cinnamyl)]2, or from a Pd(0) complex, e.g., [Pd(PPh3)4], [Pd(P(oTol)3)2], Pd2(dba)3, or Pd(dba)2. In some embodiments, the ligand is a phosphine ligand. Unrealistic examples of phosphine ligands include xanthophos, PEPhos, dppf, and dppp. In some embodiments, the catalyst is Pd(OAc)2 and the ligand is xanthophos. In some embodiments, the catalyst is Pd(OAc)2 and the ligand is DPEPhos. In some embodiments, the palladium catalyst is Pd2(dba)3 and the catalytic ligand is xanthophos. The equivalent ratio of the palladium catalyst to compound 141 is about 0.005:1 to about 0.05:1, about 0.01:1 to about 0.03:1, or about 0.01:1 to about 0.02:1. The molar ratio of the catalytic ligand to the catalyst is about 1.2:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, about 2.5:1, or about 3:1, and any range derived from them, e.g., about 1.2:1 to about 3:1, about 1.5:1 to about 2.5:1, or about 1.8:1 to about 2.2:1.

[0109] In some embodiments, the base is an inorganic base as described elsewhere in this specification. In some embodiments, the base is an alkali metal carbonate of the formula M2CO3 (wherein M is Na or K). In some embodiments, the base is an organic base as described elsewhere in this specification, for example, of the formula MOR' (wherein M is Na or K and R' is C 1~6The alkyl group is, for example, methyl, ethyl, n-propyl, i-propyl, or t-amyl. In some such embodiments, the organic base is NaOMe. The equivalent ratio of the base to compound 141 is preferably about 1.2:1 to about 3:1, for example about 1.5:1 or about 2:1.

[0110] The reaction mixture may optionally contain additives. An example of an additive is triphenylphosphine ("PPh3"). Preferred additive concentrations are about 1 mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 4.5 mol%, about 5 mol%, or about 6 mol%, and any range derived from them, e.g., about 1 mol% to about 6 mol%, about 3 mol% to about 5 mol%, or about 4 mol% to about 5 mol%.

[0111] The reaction to form compound 180 may be carried out under an inert atmosphere, for example, by Ar or N2 purging and / or Ar or N2 blanketing. The reaction may be carried out at temperatures of about 20°C, about 30°C, about 40°C, about 50°C, about 60°C, about 70°C, about 80°C, about 90°C, about 100°C, about 110°C, about 115°C, about 120°C, about 130°C, about 140°C, or about 150°C, and any range derived from them, for example, about 20°C to about 150°C, about 70°C to about 120°C, or about 20°C to about 115°C. The reaction may be considered complete when the area % concentration of compound 180 by HPLC is less than 2, less than 1, less than 0.5, or less than 0.1. In some embodiments, the reaction time to completion may be approximately 4 hours, approximately 6 hours, approximately 12 hours, approximately 16 hours, approximately 18 hours, approximately 24 hours, or longer.

[0112] In some specific embodiments, the catalyst is Pd(OAc)2, the ligand is DPEPhos, and the base is an organic base. In some embodiments, the organic base is sodium or potassium methoxide. In some such embodiments, the reaction solvent mixture predominantly contains anisole, and the reaction temperature is about 80°C to about 100°C, for example, about 90°C. The reaction time to complete conversion is about 2 hours, 4 hours, about 8 hours, about 12 hours, or about 16 hours. In some optional embodiments, the reaction mixture may further contain an additive, for example, PPh3.

[0113] In some specific embodiments, the catalyst is Pd(OAc)2, the ligand is xanthophos, and the base is an inorganic base. In some embodiments, the inorganic base is sodium carbonate or potassium carbonate. In some such embodiments, the reaction mixture solvent predominantly contains anisole and water, and the reaction temperature is about 100°C to about 125°C, for example, about 110°C to about 115°C. The reaction time to complete conversion is about 8 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, or about 24 hours.

[0114] In some specific embodiments, the catalyst is Pd(OAc)2, the ligand is DPEPhos, and the base is NaOMe. In some embodiments, the additive PPh3 is included. In some specific embodiments, about 0.5–2.5 mol% Pd(OAc)2, about 2–4 mol% DPEPhos, and about 1–1.5 equivalents of NaOMe are used, along with optionally about 3–6 mol% PPh3. In certain embodiments, the reaction temperature is about 90°C. In some specific embodiments, the catalyst is Pd(OAc)2 (about 1.5 mol%), the ligand is DPEPhos (about 3 mol%), the additive is PPh3 (about 4.5 mol%), the base is NaOMe (about 1.2 equivalents), and the reaction temperature is about 90°C.

[0115] In some embodiments, producing compound 180 using Pd(OAc)2, DPEPhos, PPh3, and NaOMe can be done with shorter reaction times, lower reaction temperatures, and less complex workup than previously used methods for preparing compound 180. For example, in some embodiments, the method for purifying compound 180 using Pd(OAc)2, xanthophos, and K2CO3 may require longer reaction times, higher reaction temperatures, and more complex workup methods to isolate compound 180.

[0116] In some embodiments, compound 180 can be isolated from the reaction product mixture.

[0117] In embodiments where the catalyst is Pd(OAc)2 and the ligand is XamtPhos, the reaction product mixture may be washed with water. In such embodiments, an additional solvent may optionally be added to the reaction product mixture with stirring, followed by the addition of water in a volume ratio of about 5:1, about 3:1, about 2:1, about 1:1, or about 1:2 of the reaction product mixture or diluted reaction product mixture to water. The temperature is preferably about 40°C to about 100°C, for example, about 50°C, about 60°C, about 70°C, about 80°C, about 85°C, about 90°C, or about 95°C. The water may be removed by phase separation, and the organic phase of the washed and recovered reaction product mixture may be distilled to reduce its volume. The concentration of compound 180 after volume reduction is preferably about 0.2 g / mL, about 0.25 g / mL, about 0.3 g / mL, about 0.35 g / mL, about 0.4 g / mL, about 0.45 g / mL, about 0.5 g / mL, about 0.55 g / mL, or about 0.6 g / mL, and any range derived from them, for example, about 0.2 g / mL to about 0.6 g / mL, about 0.3 g / mL to about 0.5 g / mL, or about 0.35 g / mL to about 0.45 g / mL.

[0118] The compound 180 concentrate may be washed with water. In some such embodiments, the compound 180 concentrate is washed with an organoprotic antisolvent (e.g., C 1~6Alcohol and water may be mixed and combined. In such embodiments, the volume ratio of the organoprotic antisolvent to water may be about 3:1, about 2.5:1, about 2:1, about 1.5:1, about 1:1, about 1:1.5, about 1:2, about 1:2.5, or about 1:3, and any range resulting from them, for example, about 3:1 to about 1:3, about 2:1 to about 1:1.5, or about 1.5:1 to about 1:1. In such embodiments, the volume ratio of the organoprotic solvent to compound 180 concentrate may be about 3:1, about 2.5:1, about 2:1, about 1.5:1, about 1:1, about 1:1.5, or about 1:2, and any range resulting from them, for example, about 3:1 to about 1:2, about 2.5:1 to about 1:1, or about 2:1 to about 1.5:1. Water may be removed by phase separation, and the organic phase of the washed and recovered compound 180 concentrate, which contains aprotic and protic solvents, may be distilled to reduce its volume. The concentration of compound 180 after volume reduction is preferably about 0.15 g / mL, about 0.2 g / mL, about 0.25 g / mL, about 0.3 g / mL, about 0.35 g / mL, about 0.4 g / mL, about 0.45 g / mL, about 0.5 g / mL, about 0.55 g / mL, or about 0.6 g / mL, and any range derived therefrom, for example, about 0.15 g / mL to about 0.6 g / mL, about 0.2 g / mL to about 0.4 g / mL, or about 0.25 g / mL to about 0.35 g / mL. Additional protic antisolvents may be added in volume ratios of compound 180 concentrate to the added antisolvent, about 3:1, about 2.5:1, about 2:1, about 1.5:1, about 1:1, or about 1:1.5, and any range resulting from them, for example, about 3:1 to about 1:1.5, about 2:1 to about 1:1, or about 1.5:1 to about 1:1. In some embodiments, the protic antisolvent is methanol, ethanol, or 1-butanol. In one embodiment, the protic antisolvent is 1-butanol.

[0119] The mixture of compound 180 and the antisolvent may be cooled to below 0°C, for example, about -5°C or -10°C, while mixing, at a preferred rate, for example, about 5°C / hour, 10°C / hour, or 15°C / hour, to crystallize compound 180. The crystal slurry may be aged at the final temperature for at least 2 hours, at least 4 hours, or at least 6 hours to complete crystallization. The compound 180 crystals may be recovered by filtration or centrifugation and washed with a cold protic antisolvent and water. In some embodiments, when the antisolvent is 1-butanol, the recovered crystals may be washed with cooled (e.g., -5°C ± 5°C) methanol or ethanol and water (e.g., in a volume ratio of alcohol to water, about 3:1 to about 1:3, for example, about 1:1), and then washed with cooled 1-butanol. The washed compound 180 crystals may be dried under reduced pressure, for example, at a temperature of about 30°C to about 80°C (e.g., about 60°C to about 75°C) and in a vacuum of about 2 to 10 millibars.

[0120] In embodiments where the catalyst is Pd(OAc)2 and the ligand is DPEPhos, the reaction product mixture may be quenched with water, and the reaction product mixture comprises a suspension of compound 180. The volume ratio of water to the reaction product mixture is preferably about 3:1, about 2:1, about 1.5:1, about 1:1, about 1:1, about 1:1.5, about 1:2, or about 1:3, and any range derived therefrom, for example, about 3:1 to about 1:3, or about 1.5:1, or about 1:1.5. The quenched reaction product mixture may then be cooled to about 0°C, about 5°C, about 10°C, about 15°C, or about 20°C, and any range derived therefrom, for example, about 0°C to about 20°C, or about 5°C to about 15°C. The cooling rate may preferably be about 0.5°C / min, about 1°C / min, about 1.5°C / min, about 2°C / min, about 2.5°C / min, or about 3°C / min, and any range derived therefrom, for example, about 0.5°C / min to about 3°C / min, or about 0.5°C / min to about 1.5°C / min. The compound 180 crystals are recovered by filtration or centrifugation and cooled to cold C 1~4The crystals may be washed with alcohol and / or water. In some such embodiments, the crystals may be washed with alcohol, water / alcohol (e.g., in a 1:1 v / v ratio), and then with alcohol. In some such embodiments, the alcohol is methanol. The washed compound 180 crystals may be dried under vacuum, for example, at about 30°C to about 70°C (e.g., about 35°C to about 55°C) and under a vacuum of about 2 to 10 millibars.

[0121] In some embodiments, the yield of compound 180 is about 70%, about 75%, or about 80%. The purity of compound 180 is at least 98.5 area%, at least 99 area%, at least 99.5 area%, 99 area%, 99.1 area%, 99.2 area%, 99.3 area%, 99.4 area%, 99.5 area%, 99.6 area%, 99.7 area%, or 99.8 area%.

[0122] Preparation of compound 181 In some aspects of this disclosure, compound 181 is reacted in the following reaction scheme: It can be prepared from compound 180 according to TIFF2026086461000031.tif47170.

[0123] A method for preparing compound 181 involves forming a reaction mixture comprising compound 180, a palladium catalyst, a catalytic ligand, a boronating reagent, and a polar aprotic solvent. The reaction mixture may also contain an alkali metal acetate. The reaction mixture is allowed to react to form a reaction product mixture containing compound 181. Compound 181 is optionally isolated from the reaction product mixture.

[0124] Palladium catalysts and catalytic ligands are generally described elsewhere in this specification. In some embodiments, the palladium catalyst is Pd2(dba)3 and the catalytic ligand is an aryl phosphate ligand. In some such embodiments, the aryl phosphate ligand is XPhos. The equivalent ratio of the palladium catalyst to compound 180 is about 0.001:1, about 0.002:1, about 0.003:1, about 0.004:1, or about 0.005:1, and their ranges, e.g., 0.001:1 to about 0.005:1. The equivalent ratio of the catalytic ligand to the catalyst is about 1.3:1, about 1.5:1, about 1.7:1, about 1.9:1, about 2.5:1, or about 3:1, and their ranges, e.g., about 1.3:1 to about 3, or about 1.5:1 to about 2.5:1. The boronating reagent is described elsewhere in this specification. The solvent is a polar aprotic solvent as described elsewhere in this specification. In some embodiments, the polar aprotic solvent is THF. The ratio of solvent volume to compound 180 by weight is about 3:1 L / kg, about 5:1 L / kg, about 10:1 L / kg, about 20:1 L / kg, or about 25:1 L / kg, and ranges therefrom, e.g., about 3:1 to about 25:1 L / kg, about 5:1 to about 20:1 L / kg, or about 5:1 to about 15:1 L / kg. In some embodiments, the reaction mixture contains compound 180 concentrations of about 0.1 moles / L, about 0.2 moles / L, about 0.3 moles / L, about 0.4 moles / L, or about 0.5 moles / L, and ranges therefrom, e.g., about 0.1 to about 0.5 moles / L. The equivalent ratio of alkali metal acetate to compound 180 is greater than 1:1. In some embodiments, the alkali metal acetate is potassium acetate. In some embodiments, the boronating agent is bis(pinacolate)diborone and the boronate is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The equivalent ratio of the boronating agent to compound 180 is greater than 1:1, about 1.2:1, about 1.5:1, or about 2:1, and in the range between them, for example, between 1:1 and 2:1. In some embodiments, the boronating agent is bis(pinacolate)diborone and the boronate is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane.In this embodiment, boronate compound 181 is compound 182: This is the seed for TIFF2026086461000032.tif52170.

[0125] In some embodiments, compound 182 may be prepared according to the method described in Figure 4.

[0126] The reaction to form compound 181 or 182 may be carried out under an inert atmosphere, for example, by N2 purging and / or N2 blanketing. The reaction may typically be carried out at a reflux temperature between about 60°C and about 80°C. The reaction may be considered complete when the area % concentration of compound 160 by HPLC is less than 1, less than 0.5, or less than 0.1. In some embodiments, the reaction time to completion may be about 6 hours, about 12 hours, about 18 hours, about 24 hours, or longer.

[0127] In some embodiments, compound 181 or 182 may be isolated from the reaction product mixture. In some embodiments, the reaction product mixture may be combined with water in a ratio of water volume to the weight of compound 181 or 182 of about 2 L / kg, about 3 L / kg, about 4 L / kg, or about 5 L / kg, and in a range thereof, for example, about 1 to about 5 L / kg, or about 2 to about 4 L / kg. The aqueous layer may be separated to recover an organic layer containing compound 181 or 182 in solution. The organic layer may be distilled to a reduced volume in a ratio of volume to the weight of compound 181 or 182 of about 2 L / kg, about 3 L / kg, about 4 L / kg, or about 5 L / kg, and in a range thereof, for example, about 2 to about 5 L / kg. Distillation is preferably vacuum distillation, for example, at a temperature of at least 40°C. Alternatively, distillation may be carried out at atmospheric pressure. The reduced volume containing compound 181 or 182 may be diluted with a polar aprotic solvent, such as THF, in a ratio of solvent volume to the weight of compound 181 or 182 of about 5 L / kg to about 8 L / kg, and the diluted mixture may optionally be filtered and distilled to a reduced volume of about 2 to about 4 L per kg of compound 181 or 182. The dilution and distillation steps with the polar aprotic solvent may be repeated one or more times. The reduced volume may be combined with a nonpolar solvent, such as MTBE, in a ratio of nonpolar solvent volume to the weight of compound 181 or 182 of about 5 L / kg, about 10 L / kg, about 15 L / kg, or about 20 L / kg, and in those ranges, for example, about 5 to about 20 L / kg, or about 5 to about 15 L / kg. The mixture may be cooled to about 0°C to about 15°C to form compound 181 or 182 as a solid dispersion. The solid compound 181 or 182 may be recovered, for example by filtration or centrifugation, and dried to form solid compound 181 or 182.

[0128] Alternatively, after the reaction to form compound 181 or 182 is complete, the inorganic salt may be filtered off at 60–65°C. The filtrate is cooled, for example, to 40–45°C and filtered through carbon. The volume of the filtrate may then be reduced under atmospheric pressure. The reduced volume may be combined with a nonpolar solvent, such as MTBE, in a ratio of the volume of the nonpolar solvent to the weight of compound 181 or 182, approximately 5 L / kg, approximately 10 L / kg, approximately 15 L / kg, or approximately 20 L / kg, and in a range therefrom, for example, approximately 5–20 L / kg, or approximately 5–15 L / kg.

[0129] The yield of compound 181 or 182 based on compound 180 is at least 80%, at least 85%, or at least 90%. The purity of compound 181 or 182, as determined by HPLC, is at least 95 area%, at least 98 area%, or at least 99 area%.

[0130] Preparation of compound 160 In some embodiments, compound 160 may be prepared according to the method disclosed in International Publication No. 2018 / 109050, which generally follows three schemes: This is described in TIFF2026086461000033.tif96170 and further depicted in the reaction schemes in Figures 8-10.

[0131] In some such embodiments, compounds 120, 130, and 160 may be prepared according to the method described in WO2018 / 109050, as depicted in Figure 8.

[0132] In some embodiments, compound 120 is reacted in the following scheme: It can be prepared from compound 110 according to TIFF2026086461000034.tif32170.

[0133] A method for preparing compound 120 involves forming a reaction mixture containing a polar aprotic solvent, methylmagnesium chloride, copper(I) chloride, and compound 110. The reaction mixture is allowed to react to form a reaction product mixture containing compound 120.

[0134] Polar aprotic solvents are described elsewhere in this specification. In some embodiments, the polar aprotic solvent is THF.

[0135] The reaction mixture may be formed under an N2 blanket and / or under an N2 purge. In some embodiments, a polar aprotic solvent may be packed into the reactor and added and mixed with CuCl and MeMgCl. The ratio of the volume of polar aprotic solvent to the weight of compound 110 starting material is about 3 to about 12 L / kg, or about 5 to about 9 L / kg. The equivalent ratio of CuCl to compound 110 starting material is about 0.1:1 to about 0.5:1, or about 0.1:1 to about 0.3:1. The equivalent ratio of MeMgCl to compound 110 starting material is about 0.05:1 to about 0.3:1, or about 0.05:1 to about 0.15:1. The mixture is stirred at a temperature of about -30 to about -10°C, and then compound 110 is added to the reactor while maintaining the temperature. Additional MeMgCl is added to the reactor at a temperature of approximately -30 to approximately -10°C, where the equivalent ratio of the additional MeMgCl to compound 110 is approximately 0.9:1 to approximately 1.5:1, or approximately 1:1 to approximately 1.2:1. A reaction product mixture containing compound 120 is formed in solution. In some embodiments, the reaction time to completion may be at least 1 hour or longer. The reaction may be considered complete when the area % concentration of compound 110 by HPLC is less than 5, less than 2, less than 1, less than 0.5, or less than 0.1.

[0136] Compound 120 may be isolated from the reaction product mixture. In some such embodiments, the pH of the reaction product mixture can be adjusted to about 3 to about 4 with an aqueous mineral acid solution, for example, 3 to 10 w / w% HCl. The resulting aqueous phase containing compound 10 in solution and the organic phase (e.g., THF) may be separated. The aqueous phase may be extracted with a nonpolar solvent (e.g., MTBE) at a volume ratio of solvent to the starting material weight of compound 110, in the range of about 2 L / kg to about 10 L / kg, or about 3 L / kg to about 7 L / kg. The organic phase is combined with an aqueous inorganic base (e.g., NaHCO3) and washed, followed by brine washing. The washed organic phase may then be dried with a desiccant, for example, MgSO4. The desiccant may be removed, for example, by filtration or centrifugation. The organic phase may be concentrated to a volume ratio of about 3 to about 15 L / kg, for example, about 5 L / kg, or about 10 L / kg, to the starting material weight of compound 110. Concentration can preferably be carried out at atmospheric pressure and a temperature of approximately 50 to 70°C.

[0137] In some embodiments, compound 120 may be purified by fractional distillation as follows: The combined or concentrated organic phase is first distilled at a temperature below 60°C to remove a first (previous) fraction predominantly containing the solvent. Distillation may be continued to produce a compound 120 product fraction recovered at a temperature between 60°C and 90°C (P ≤ -0.09 MPa). In such embodiments, the yield of compound 120 is at least 40% or 50%, and the HPLC purity of compound 120 is at least 95 area%, at least 98 area%, or at least 99 area%, as determined by HPLC. Distillation may be optionally continued to remove one or more additional fractions.

[0138] In some specific embodiments, the solvent is THF, the molar ratio of magnesium methyl chloride to compound 110 in the reaction mixture is between 1:1 and 2:1, or 1.1:1 to about 1.4:1, and the molar ratio of copper(I) chloride to compound 110 in the reaction mixture is about 0.1:1 to about 0.5:1, or about 0.15:1 to about 0.25:1.

[0139] In some such embodiments, compound 130 reacts according to the following scheme: It can be prepared from compound 120 according to TIFF2026086461000035.tif37170.

[0140] A method for preparing compound 130 involves forming a reaction mixture containing a polar aprotic solvent, a nonpolar solvent, phosphorus oxychloride, and compound 120. The reaction mixture may be reacted to form a reaction product mixture containing compound 130.

[0141] Polar aprotic solvents are described elsewhere in this specification. In some embodiments, the polar aprotic solvent is DMF. Nonpolar solvents are described elsewhere in this specification. In some embodiments, the nonpolar solvent is DCM.

[0142] The reaction mixture may be formed as follows, and the reaction may be carried out under an N2 blanket and / or under an N2 purge. The reactor may be filled with a nonpolar solvent (e.g., DCM) in a ratio of the volume of the nonpolar solvent to the weight of compound 120 starting material of about 3 to about 15 L / kg, or about 5 to about 11 L / kg, or filled with a polar aprotic solvent (e.g., DMF) in an equivalent ratio of the polar aprotic solvent to compound 120 starting material of about 1.5:1 to about 5:1, or about 2:1 to about 3:1. The temperature for combining the solvents is adjusted to about 5 to about 25°C, and POCl3 is added to the reactor, where the equivalent ratio of POCl3 to compound 120 is about 1.5:1 to about 3:1, or about 2:1 to about 2.25:1. The mixture may optionally be stirred at the temperature for at least 0.5 hours. Next, compound 120 is added to the reactor at a temperature such as about 5°C to about 25°C to form a reaction mixture. The reaction mixture may then be heated, for example, to about 35°C to about 55°C to form a reaction product mixture containing compound 130. In some embodiments, the reaction time to completion may be at least 6 hours or longer. The reaction may be considered complete when the area % concentration of compound 120 by HPLC is less than 5, less than 2, less than 1, less than 0.5, or less than 0.1.

[0143] Compound 130 may be purified at an optional rate. In some such embodiments, the reaction product mixture may be combined with water, where the ratio of the volume of water to the weight of the starting material compound 120 is about 3 to about 20 L / kg, or about 5 to about 15 L / kg. The temperature may preferably be about 30 to about 50°C, and the mixture may be vigorously stirred for at least 0.25 hours, at least 0.5 hours, or at least 1 hour. The mixture may be cooled to, for example, about 15 to about 35°C and filtered through a filter medium, such as diatomaceous earth. The filtrate may be separated into an aqueous phase and an organic phase, the organic phase of which may be recovered and optionally washed with water and brine. The organic phase may then be concentrated to, for example, a ratio of the volume to the weight of the starting material compound 120 of about 2 to about 5 L / kg, or about 2 to about 4 L / kg. An organic solvent (e.g., toluene or NMP) may be added to the concentrated organic phase in a ratio of the organic solvent to the starting material weight of compound 120 of about 1 to about 2 L / kg. The volume may be reduced, for example, under reduced pressure and at a temperature below 40°C to produce a solution of compound 130. In some embodiments, the organic solvent is DCM, and compound 130 is in solution in DCM.

[0144] Compound 160 can be prepared by forming a reaction mixture containing an organic solvent, an organic base, and compounds 130 and 10, and by reacting the reaction mixture to form a reaction product mixture containing the tricyclic lactam of compound 160.

[0145] The organic bases are those described elsewhere in this specification. In some embodiments, the organic base is a tri-C1-6 alkylamine. In some specific embodiments, the organic base is selected from 4-methylmorpholine and N-ethyldiisopropylamine.

[0146] In some embodiments, the organic solvent is a polar aprotic solvent as described elsewhere herein. In some specific embodiments, the solvent is selected from NMP and DMF.

[0147] In some embodiments, the concentration of compound 130 in the reaction mixture is about 0.25 to about 2 moles / L, about 0.5 to about 1.5 moles / L, or about 0.5 to about 1 moles / L. In some embodiments, the ratio of solvent volume to the weight of compound 130 is about 1.5:1 to about 10:1 L / kg, about 2:1 to about 6:1 L / kg, or about 2:1 to about 4:1 L / kg. The equivalent ratio of the organic base to compound 130 is about 1:1 to about 2:1, about 1.05:1 to about 1.9:1, or about 1.1:1 to about 1.5:1. In some embodiments, compound 130 is present in a chemological excess amount exceeding compound 10. In some embodiments, the equivalent ratio of compound 10 to compound 130 is between 0.7:1 and 1:1, for example, about 0.75:1 to about 0.95:1.

[0148] The reaction to form a reaction product mixture containing compound 160 may be carried out by N2 purging and / or N2 blanket. In some embodiments, an organic solvent, an organic base, and compound 10 are combined in a reactor with vigorous stirring at a temperature of about 95 to about 125°C, or about 100 to about 120°C. Compound 130 is then added to the reactor with vigorous stirring while maintaining this temperature. In some embodiments, compound 130 is in solution in an organic solvent (e.g., toluene or NMP) as described elsewhere herein. In some embodiments, the reaction time to completion may be about 0.25 hours, about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, or longer. The reaction may be considered complete when the area % concentration of compound 130 by HPLC is less than 5, less than 2, less than 1, less than 0.5, or less than 0.1.

[0149] Compound 160 may be isolated from the reaction product mixture. In some isolation embodiments, the reaction product mixture may be cooled to, for example, about 80 to about 95°C. Water may then be combined with the reaction product mixture to form a mixture, where the ratio of water volume to the starting material weight of compound 130 is about 3:1 to about 15:1 L / kg, or about 5:1 to about 10:1 L / kg. The mixture is cooled to about 5 to about 30°C and stirred at the temperature for at least 0.5 hours to form a slurry containing solid compound 160. The solid compound 160 can be recovered, for example, by filtration or centrifugation. The solid may optionally be subjected to a second water slurry and recovery step. Next, acetone may be combined with the solid compound 160 to form a slurry, for example, at a temperature of about 10°C to about 30°C, where the ratio of the volume of acetone to the weight of the starting material compound 130 is about 1.5:1 to about 6:1 L / kg, or about 2:1 to about 4:1 L / kg. The slurry may be vigorously stirred for at least 1 hour. The solid compound 160 may be isolated, for example, by filtration or centrifugation. The recovered solid may be optionally washed with acetone. The solid compound 160 may be dried. In some drying methods, drying may be carried out under reduced pressure at a temperature of about 25°C to about 50°C. The yield of compound 160 is at least 50%, at least 60%, or at least 70%. The purity of compound 160 by HPLC is at least 98 area%, at least 99 area%, or at least 99.5 area%.

[0150] In some specific embodiments, compounds 120, 130, and 160 may be prepared according to the method of WO2018 / 109050, as depicted in Figure 9.

[0151] In some such embodiments, compound 120 may be prepared according to Figure 8. Compound 120 may be purified by the solid ketone bisulfite adduct route depicted in Figure 9. The purification method comprises forming a first reaction mixture comprising crude compound 120, an organic solvent immiscible with water (e.g., heptane), and an aqueous solution of sodium bisulfite, and reacting the first reaction mixture to form a first reaction product mixture comprising a solid ketone bisulfite adduct of compound 121. TIFF2026086461000036.tif24170

[0152] Compound 121 is isolated from the first reaction product mixture. The second reaction mixture is formed comprising the isolated compound 121, water, a low-boiling point solvent that is miscible with water, and sodium bicarbonate. In some embodiments, the solvent is DCM. The second reaction mixture is reacted to form a second reaction product mixture comprising a first phase containing the solvent, with a dominant amount of purified compound 120 present in the first phase and the second phase containing water. The first phase containing purified compound 120 is separated from the aqueous phase.

[0153] In this embodiment, the pH of the reaction product mixture containing crude compound 120 can be adjusted to less than 5 with an aqueous mineral acid solution, for example aqueous HCl, yielding about 1.2 to about 1.4 equivalents of HCl per equivalent of compound 120.

[0154] In the first reaction mixture, the pH-adjusted reaction product mixture may be combined with a solvent that is immiscible with water (e.g., hexane), where the crude compound 120 is soluble in the solvent. In some embodiments, the ratio of solvent volume to the weight of compound 120 is about 5 L / kg to about 25 L / kg, about 10 L / kg to about 20 L / kg, or about 10 L / kg to about 15 L / kg. The ratio of water volume in the first reaction mixture to the weight of crude compound 120 is about 1:1 L / kg to about 10:1 L / kg, about 1.5:1 L / kg to about 4:1 L / kg, or about 2:1 L / kg to about 3:1 L / kg. The equivalent ratio of sodium bisulfite to compound 120 in the first reaction mixture is about 2:1 to about 5:1, or 3:1 to about 5:1.

[0155] The first reaction mixture is formed by combining a pH-adjusted reaction product mixture with water and an immiscible solvent at a temperature of about 10 to about 30°C with vigorous stirring. The resulting mixture is combined with a filter aid (e.g., diatomaceous earth), and the solids are removed, for example, by centrifugation or filtration. The filtrate is separated to form an organic phase containing compound 120 and an aqueous phase. The organic phase is concentrated at a temperature below about 75°C by reducing its volume to a ratio of compound 120 weight to the total volume, about 1.5 L / kg to about 4 L / kg, or about 1.5 L / kg to about 2.5 L / kg. The reduced volume of the organic phase is cooled, for example, to about 10 to about 30°C, optionally filtered, and combined with an aqueous NaHSO3 solution to form a slurry containing solid compound 121, yielding about 2 to about 5 equivalents of NaHSO3 per equivalent of compound 120, or about 3 to about 4.5 equivalents of NaHSO3 per equivalent of compound 120. The solid compound 121 is isolated, for example, by filtration or centrifugation, and the recovered solid is slurryed in a solvent immiscible with water (e.g., hexane). The ratio of solvent volume to the weight of compound 121 is preferably about 3 L / kg to about 13 L / kg, or about 5 L / kg to about 9 L / kg. The solid compound 121 is isolated, for example, by filtration or centrifugation. The isolated compound 121 solid is optionally washed with a low-boiling point solvent immiscible with water (e.g., DCM).

[0156] The second reaction mixture contains a ratio of water volume to the weight of 121 of isolated solids, approximately 5:1 L / kg to approximately 15:1 L / kg, or approximately 7.5:1 L / kg to approximately 10.5:1 L / kg. The ratio of water volume in the second reaction mixture to the immiscible low-boiling solvent (e.g., DCM) is approximately 1:1 to approximately 3:1, or approximately 1.5:1 to approximately 2.5:1. The ratio of the volume of the immiscible solvent to the weight of 121 of compound is approximately 2 L / kg to approximately 9 L / kg, approximately 3 L / kg to approximately 7 L / kg, or approximately 4 L / kg to approximately 6 L / kg. The equivalent ratio of sodium bicarbonate to compound 121 in the second reaction mixture is between 1:1 and 2:1, or approximately 1.25:1 to approximately 1.75:1. In some embodiments, sodium bicarbonate is an aqueous solution of sodium bicarbonate.

[0157] A second reaction mixture is formed by combining the solids of compound 121 with water while vigorously stirring. A low-boiling solvent that is miscible with water is added, followed by a solution of sodium bicarbonate to form a second reaction product mixture containing compound 120. The resulting mixture may be combined with a filter aid (e.g., diatomaceous earth), and the solids are removed from the mixture by filtration or centrifugation. The filtrate or centrifugated liquid is separated into an organic phase and an aqueous phase, and these phases are separated and recovered. The aqueous phase may optionally be extracted with a low-boiling solvent that is miscible with water, and the organic phase is combined. The combined organic phase may be washed with brine. The combined and washed organic phase may be concentrated at a temperature below about 70°C to a total volume of about 1.5 L / kg to about 4 L / kg, or about 1.5 L / kg to about 2.5 L / kg, by weight of compound 120, and the solution contains compound 120. The assay concentration of the solution is preferably about 30% to about 50%, about 35% to about 45%, or about 40%. The yield of compound 120 is at least 50%, at least 60%, or at least 70%.

[0158] In some embodiments, compound 130 can be prepared from compound 120 according to the method depicted in Figure 8.

[0159] Compound 160 may be isolated from the reaction product mixture. In some isolation embodiments, the reaction product mixture may be cooled to, for example, about 80°C to about 95°C. Water may then be added to the reaction product mixture to form a mixture, where the ratio of water volume to the starting material weight of compound 130 is about 3:1 to about 15:1 L / kg, or about 5:1 to about 10:1 L / kg. The mixture is cooled to about 5°C to about 30°C and stirred at the temperature for at least 0.5 hours to form a slurry containing solid compound 160. The solid compound 160 may be recovered, for example, by filtration or centrifugation. The solid may optionally be subjected to a second water slurry and recovery step. Next, acetone may be added to the solid compound 160, for example, at a temperature of about 10°C to about 30°C, to form a slurry, where the ratio of the volume of acetone to the weight of the starting material compound 130 is about 1.5:1 to about 6:1 L / kg, or about 2:1 to about 4:1 L / kg. The slurry may be vigorously stirred for at least 1 hour. The solid compound 160 may be isolated, for example, by filtration or centrifugation. The recovered solid may be optionally washed with acetone. The solid compound 160 may be dried. In some drying methods, drying may be carried out under reduced pressure at a temperature of about 25°C to about 50°C. The yield of compound 160 is at least 50%, at least 60%, or at least 70%. The purity of compound 160 by HPLC is at least 98 area%, at least 99 area%, or at least 99.5 area%.

[0160] In some such embodiments, compounds 130 and 160 may be prepared according to the method described in WO2018 / 109050, as depicted in Figure 10.

[0161] In some such aspects of this disclosure, compound 130 in the following reaction scheme may be prepared from a trimethylsilyl intermediate of compound 120, which is designated as compound 122 in the following reaction scheme. The reaction scheme is as follows: TIFF2026086461000037.tif37170

[0162] A method for preparing compound 130 involves forming a first reaction mixture comprising a first polar aprotic solvent, magnesium methyl chloride, copper(I) chloride, lithium chloride, chlorotrimethylsilane (TMSCl), and compound 110. The first reaction product mixture is reacted to form a first reaction product mixture comprising compound 122. The first reaction product mixture is quenched in aqueous solution with a first quenching agent, and a nonpolar, water-immiscible solvent is added to the quenched reaction product mixture. The phases are separated, and an organic phase containing a dominant amount of compound 122 is recovered and concentrated to obtain compound 122 in solution. A second reaction product mixture is formed comprising a solution containing a second polar aprotic solvent, phosphorus oxychloride, and a solution of compound 122. The second reaction mixture is reacted to form a second reaction product mixture comprising compound 130. The second reaction product mixture is quenched in aqueous solution with a second quenching agent. The phases are separated, and an organic phase containing a dominant amount of compound 130 in solution is recovered.

[0163] The first and second polar aprotic solvents are described elsewhere in this specification. In some embodiments, the first polar aprotic solvent is THF. In some embodiments, the second polar aprotic solvent is DMF. In some embodiments, the first quenching agent is ammonium chloride. In some embodiments, the second quenching agent is potassium phosphate.

[0164] In some embodiments, the first reaction mixture comprises from about 0.25 to about 2 moles per liter of compound 110, or from about 0.5 to about 1.1 moles per liter of compound 110. In some other embodiments, the ratio of the first polar aprotic volume to the weight of compound 110 is from about 3 to about 11 L / kg, or from about 5 to about 9 L / kg. MeMgCl is present in a stoichiometric excess compared to compound 110. In some other embodiments, MeMgCl is in solution in THF, for example a 3M solution. In some embodiments, the molar ratio of MeMgCl to compound 110 is between 1:1 and 1.5:1, or from about 1.1:1 to about 1.3:1. TMSCl is present in a stoichiometric excess compared to compound 110. In some embodiments, the molar ratio of TMSCl to compound 110 is between 1:1 and 1.2:1, or from about 1.01:1 to about 1.1:1. The molar ratio of CuCl to compound 110 is from about 0.05:1 to about 0.2:1, or from about 0.05:1 to about 0.15:1. The molar ratio of LiCl to compound 110 is from about 0.05:1 to about 0.2:1, or from about 0.07:1 to about 0.15:1.

[0165] In some embodiments, the second reaction product mixture comprises from about 0.5 to about 2 moles per liter of compound 122, or from about 0.7 to about 1.3 moles per liter of compound 122. The molar ratio of phosphorus oxychloride to compound 122 is from about 1.5:1 to about 3.1:1, or from about 2.1:1 to about 2.6:1.

[0166] In the first reaction, in some embodiments, CuCl, LiCl, and the first polar aprotic solvent may be combined in a reactor at a temperature of about 10 to about 35°C in an N2 atmosphere and cooled to about -10 to about 10°C. Compound 110 and TMSCl are added to the reactor at about -10 to about 10°C. A first reaction product mixture containing compound 122 is formed. In some embodiments, the reaction time to completion may be at least 0.5 hours, at least 1 hour, or longer. The reaction may be considered complete when the area % concentration of compound 110 by HPLC is less than 5, less than 2, less than 1, less than 0.5, or less than 0.1. The reaction is quenched, for example, with an aqueous solution of ammonium chloride, where the equivalent ratio of ammonium chloride to compound 110 is greater than 1:1, about 1.1:1, about 1.2:1, or about 1.3:1. The ratio of the volume of ammonium chloride solution to compound 110 is approximately 2:1 to 10:1 L / kg, or approximately 3:1 to 7:1 L / kg. The organic phase and the aqueous phase are separated and recovered. The organic layer contains compound 122 in solution and may optionally be washed with brine. The optionally washed organic layer may be concentrated until the ratio of the recovered distillate volume to the weight of compound 110 is approximately 8 L / kg to 10 L / kg. The concentrated first reaction product mixture may be diluted with a nonpolar solvent (e.g., toluene), where the ratio of the volume of added nonpolar solvent to the weight of compound 110 is approximately 1 L / kg to 3 L / kg. In such embodiments, the diluted mixture may be concentrated to remove an approximate volume of added nonpolar solvent to produce a solution of compound 122. The compound 122 assay in solution is approximately 40 w / w% to approximately 60 w / w%, or approximately 45 w / w% to approximately 55 w / w%. The yield of compound 122 based on compound 110 is at least 60%, at least 70%, at least 80%, or at least 80%, and the HPLC purity of compound 122 is at least 85 area%, or at least 90 area%, as determined by HPLC.

[0167] In the second reaction, the solution from the first reaction is diluted with a nonpolar solvent to achieve a compound 122 assay of about 25 to about 45 w / w%, or about 30 to about 40 w / w%, or about 35 w / w%. In some embodiments, the nonpolar solvent is toluene. The first POCl3 addition may be carried out where the equivalent ratio of POCl3 to the weight of compound 110 is about 0.2:1 to about 0.4:1, or about 0.3:1, and the temperature is about 5 to about 35 °C. DMF is added after the equivalent ratio of POCl3 to compound 110 reaches about 1.5:1 to about 3:1, or about 1.5:1 to about 2.5:1. A second POCl3 addition is carried out, where the equivalent ratio of POCl3 to the weight of compound 110 is about 1.5:1 to about 2.5:1, or about 2:1, and the mixture is heated to about 50 °C to about 70 °C to form a second reaction product mixture containing compound 130. In some embodiments, the reaction time to completion may be at least 2 hours, or more. The reaction can be considered complete when the area% concentration of compound 110 by HPLC is less than 5, less than 2, less than 1, less than 0.5, or less than 0.1. The reaction product mixture is combined with an aqueous potassium phosphate solution to result in an equivalent ratio of potassium phosphate to compound 110 of about 1.2:1 to about 2:1, or about 1.4:1 to about 1.8:1. The ratio of the volume of the potassium phosphate solution to the weight of compound 110 is about 3 to about 12 L / kg, or about 6 to about 9 L / kg. It is separated and recovered to form an organic phase and an aqueous phase. The organic layer is washed with a potassium phosphate solution and water to obtain a washed organic phase (e.g., toluene) containing compound 130 in the solution and having a pH of more than 7. The organic phase is filtered to produce compound 130 in a solution (e.g., toluene). The yield of compound 130 based on compound 110 is at least 70%, or at least 75%, and the purity of compound 130 is at least 85%, or at least 88% by HPLC.

[0168] In some embodiments, compound 130 can be prepared from compound 120 according to the method depicted in FIG. 8.

[0169] Preparation of Compound 170 In some embodiments, compound 170 may be prepared according to the method disclosed in International Publication No. 2018 / 10905.

[0170] In some such embodiments, compound 170 may be prepared according to the method of WO2018 / 10905, as depicted in Figures 7 and 13, and is reproduced below by forming a reaction mixture comprising compound 160, a chemotherapeutic excess of compound 100, a palladium catalyst and catalytic ligand, a base, and a polar aprotic solvent: The reaction mixture is reacted to form a reaction product mixture containing compound 170. Compound 170 may be optionally isolated from the reaction mixture.

[0171] The equivalent ratio of compound 100 to compound 160 in the reaction mixture is greater than 1:1, for example, between about 1:1 and about 1.7:1, or about 1.05:1 to about 1.5:1, or about 1.05 to about 1.2:1. The palladium catalyst may be any palladium catalyst that affects the rate and conversion of the chemical compound to the product compound as a rate to a commercially acceptable yield and conversion rate. In some embodiments, the catalyst palladium species is a palladium source selected from the non-exclusive enumeration [Pd(allyl)Cl]2, Pd(MeCN)2Cl2, Pd(benzonitrile)2Cl2, Pd(dba)2, Pd(OAc)2, PdCl2, PdBr2, Pd(TFA)2, Pd(MeCN)4(BF4)2, Pd2(dba)3, PdCy3Cl2, Pd(acac)2, and Pd(PPh3)4. In some such embodiments, the palladium catalyst is Pd2(dba)3 or Pd(OAc)2, or Pd(OAc)2. Non-limiting examples of ligands include DPPF, DTPBF, BINAP, DPPE, DPPP, DCPE, RuPhos, SPhos, APhos(amphos), CPhos, XPhos, t-BuXPhos, Me4t-BuXPhos, neopentyl(t-Bu)2P, (t-Bu)2PMe, (t-Bu)2PPh, PCy3, PPh3, xanthophos, and N-xanthophos. In some embodiments, the ligand is DPPF. Polar aprotic solvents are those described elsewhere in this specification. In some embodiments, the solvent is THF. The ratio of solvent volume to compound 160 weight in the reaction mixture may be about 2:1 to about 30:1 L / kg, about 5:1 to about 20:1 L / kg, or about 5:1 to about 15:1 L / kg. The concentration of compound 160 in the reaction mixture may be about 0.1 mol / L to about 1 mol / L, or about 0.2 to about 0.5 mol / L. The equivalent ratio of catalyst to compound 160 may be about 0.01:1 to about 0.05:1, or about 0.01:1 to about 0.03:1. The equivalent ratio of ligand to catalyst may be about 1.2:1 to about 3:1, or about 1.5:1 to about 2.5:1.In some embodiments, the base is an inorganic base, such as, for example, an alkali metal hydroxide, alkali metal carbonate, or alkali metal bicarbonate, without limitation. One such inorganic base is potassium carbonate. The equivalent ratio of the base to compound 160 is preferably between 1:1 and 2:1, or about 1.2:1 to about 1.8:1. The reaction may typically be carried out at a reflux temperature between about 60°C and about 80°C. The reaction may be considered complete when the area % concentration of compound 160 by HPLC is less than 3, less than 2, less than 1, or less than 0.5. In some embodiments, the reaction time to completion may be 2 hours, 6 hours, 10 hours, 14 hours, 18 hours, 22 hours, or longer.

[0172] Compound 170 may be isolated from the reaction product mixture. In some embodiments, water may be added to the reaction product mixture in a ratio of water volume to the weight of compound 160 of about 2:1 to about 20:1, or about 2:1 to about 10:1. The temperature may be lowered to, for example, about 5°C to about 30°C, or about 15°C to about 25°C, and held at that temperature for at least 1 hour to induce crystallization of compound 170 and form a suspension of solid compound 170. The solid compound 170 may be isolated from the reaction mixture, for example, by filtration or centrifugation. The isolated compound 170 may be optionally dried. In some embodiments of drying, drying is carried out under partial reduced pressure and N2 purging at a temperature of about 15°C to about 60°C, or about 30°C to about 60°C, or about 15°C to about 50°C, or about 15°C to about 40°C, or about 15°C to about 30°C for at least 2 hours. The yield of compound 170 based on compound 160 is at least 80%, at least 85%, or at least 90%. The purity of compound 170, as determined by HPLC, is at least 95 area%, at least 98 area%, or at least 99 area%.

[0173] In some specific embodiments, compound 170 may be prepared according to the method disclosed in International Publication No. 2018 / 10905, as depicted in Figure 11.

[0174] Preparation of compound 140 Generally, compound 140 follows the scheme: It can be prepared from compounds 153 and 20 according to TIFF2026086461000039.tif38170.

[0175] Here, the secondary amine of compound 153 is alkylated with compound 20 in the presence of a reducing agent in a reductive alkylation reaction to form compound 140. In some embodiments, compound 140 can be prepared as depicted in Figure 12A and as further described herein.

[0176] In some embodiments, what is provided herein is a method for preparing compound 140, (a) Form a reaction mixture containing compound 153, compound 20, NaBH(OAc)3 and a solvent, (b) The following scheme: According to TIFF2026086461000040.tif32170, the reaction mixture is reacted to form a reaction product mixture containing compound 140. This method includes [something].

[0177] In some embodiments, acetic acid is not added separately, but some may be formed from the presence of remaining water. In some embodiments, the reaction product mixture formed in step (a) contains less than 10% by weight, less than 5% by weight, less than 1% by weight, or is essentially acetic acid-free. In some embodiments, NaBH - The combined OAc -The ratio of to the total HOAc is less than 1:3.1, or less than 1:3.05, or less than 1:3.01. The solvent may be, for example, an organic solvent, such as an aprotic organic solvent. In some embodiments, the solvent is THF or Me-THF. In some embodiments, the solvent is THF. In some embodiments, the source of compound 153 and compound 20 is a solvent solution of compound 153 and compound 20, for example, about 20 wt% to about 50 wt% of compound 153, or about 30 wt% to about 40 wt% of compound 153, and about 5 wt% to about 20 wt% of compound 20, or about 10 wt% to about 20 wt% of compound 20. In some embodiments, this solution is prepared by adding compound 153 to a solvent solution of compound 20 at a temperature between about 5°C and about 15°C, or about 10°C. In some embodiments, a solvent solution of compound 153 of compound 20 is combined with a solvent suspension of NaBH(OAc)3 to form a reaction mixture. In any of the various embodiments, the concentration of compound 153 in the reaction mixture may be about 10 wt% to about 30 wt%, or about 15 wt% to about 25 wt%, or about 20 wt%. In any of the various embodiments, the concentration of compound 20 in the reaction mixture may be about 5 wt% to about 15 wt%, or about 6 wt% to about 10 wt%, or about 8 wt%. The equivalent ratio of compound 20 to compound 153 in the reaction mixture may be about 1.1:1 to about 1.9:1, or about 1.2:1 to about 1.4:1, or about 1.3:1. The equivalent ratio of NaBH(OAc)3 to compound 153 may be about 2:1 to about 1:1, or about 1.7:1 to about 1.3:1, or about 1.5:1. The reaction to form compound 140 may be carried out by N2 purging and / or in an N2 blanket. The reaction is typically carried out at a temperature of about 25°C to about 45°C, or about 30°C to about 40°C, or about 35°C. In some embodiments, the reaction time to completion may be about 0.5 hours, about 1 hour, about 2 hours, about 4 hours, or longer. The reaction may be considered complete when the area % concentration of compound 153 by HPLC is less than 2, less than 1, less than 0.5, or less than 0.1.

[0178] In some embodiments, the reaction product mixture is subsequently combined with water and a base, where water and the base may be added separately. The reaction product mixture may be combined with water in a ratio of water volume to 140 weight of compound, of about 1:1 to about 5:1 L / kg, or about 2:1 to about 3:1 L / kg. In certain embodiments, the weight ratio of water added to the solvent in the mixture is about 0.4:1 to about 0.8:1, or about 0.6:1. The phases are then separated to form an aqueous phase and an organic phase, to which a base may be added. In some embodiments, the base is an inorganic base. In certain embodiments, the base is NaOH. The base may be added, for example, as an aqueous solution, for example, as an aqueous solution of NaOH, at a concentration of about 20 wt% to about 40 wt%, or about 30 wt%. The amount of base may be added so that the pH of the aqueous phase reaches about 12. The base may be added, for example, in a ratio of the base to compound 140 of about 3:1 to about 1:1, or about 2:1.

[0179] Compound 140 may then be isolated, which may include, for example, one or more solvent swaps, distillation, and / or crystallization. For example, in some embodiments, following the addition of a base, the organic layer containing compound 140 is isolated and optionally filtered, and the solvent in the organic phase containing compound 140 is replaced with another solvent. Solvent exchange may be carried out by methods known to those skilled in the art, as described elsewhere herein. In one such embodiment, a portion of the solvent (e.g., THF) in the organic phase containing compound 140 may be removed by distillation under reduced pressure. For example, about 40%, about 50%, about 60%, about 70%, or about 80% of the solvent may be stripped, for example, under a low atmosphere, for example, at about 250 to 350 millibars, or about 300 millibars. The stripped solvent may be replaced with another solvent, for example, an organoprotic solvent. The organoprotic solvent may be an alcohol. In some embodiments, the organopolar protic solvent is isopropanol. In some embodiments, the methods herein further include crystallizing compound 140. Such crystallization may follow, for example, a solvent swap step as described herein. The solution of compound 140 may be cooled, for example, to below 40°C, below 20°C, or below about 5°C, with stirring while crystals of compound 140 are formed. The crystals may then be isolated, for example, by filtration, optionally washed with an additional solvent, and dried under reduced pressure to obtain dry compound 140 crystals. In some embodiments, the solution of compound 140 is seeded with crystals of compound 140 to promote crystallization. The yield of compound 140 may be at least 85%, or at least 90%. The purity of compound 140 may be at least 95%, at least 98%, or at least 98.5%, as determined by HPLC.

[0180] In other embodiments, compound 140 may be prepared according to the method of WO2018 / 10905, as depicted in the final step of Figure 12B.

[0181] Preparation of compound 153 Generally, compound 153 follows the scheme: TIFF2026086461000041.tif can be prepared according to 32170.

[0182] In such an embodiment, compound 154A can be prepared from a reaction mixture comprising compound 50, compound 40, dioxane, K3PO4, Pd(OAc)2 catalyst and BINAP ligand. In the reaction mixture, the concentration of compound 50 in dioxane is about 10 w / w%, the equivalent ratio of K3PO4 to compound 50 is about 2, the equivalent ratio of Pd(OAc)2 catalyst to compound 50 is about 0.012:1, and the equivalent ratio of Pd(OAc)2 catalyst to BINAP ligand is about 1:1. The reaction mixture is reacted at about 95 °C to about 105 °C for about 15 hours to form a reaction product mixture comprising BOC-protected compound 154 in a yield of about 79%. A reaction mixture comprising compound 154A, methanol, 10% palladium on carbon catalyst and hydrogen is formed. In the reaction mixture, the ratio of the volume of methanol to the weight of compound 154A is about 5:1, and the weight ratio of the palladium on carbon catalyst to compound 154A is about 0.05:1. In some embodiments where PG is BOC, compound 154A is designated as compound 154.

[0183] In such an embodiment, compound 153 can be prepared from compound 154A according to the following reaction scheme: TIFF2026086461000042.tif can be prepared from compound 154A according to 33170.

[0184] The method for preparing compound 153 involves forming a reaction mixture comprising compound 154A having a solvent containing a protecting group moiety, PG, hydrochloric acid, and water. The reaction mixture is reacted to form a reaction product mixture comprising deprotected compound 154A. Compound 153 may optionally be isolated from the reaction product mixture.

[0185] The reaction to form compound 153 may be carried out by N2 purging and / or in an N2 blanket. The reaction is typically carried out at a temperature of about 40–70°C or about 50–60°C. In some embodiments, the reaction time to completion may be at least 1 hour or longer. The reaction may be considered complete when the area % concentration of compound 154A by HPLC is less than 2, less than 1, less than 0.5, or less than 0.1.

[0186] In some embodiments, compound 153 may be isolated from the reaction product mixture. In such embodiments, the reaction product mixture may be cooled to, for example, about 10 to about 30°C, and the reaction mixture may be extracted with a nonpolar solvent (e.g., DCM) as described elsewhere herein, at a ratio of solvent volume to the weight of compound 153 of about 3:1 L / kg to about 11:1 L / kg, or about 5:1 L / kg to about 9 L / kg. The aqueous phase may be recovered and its pH adjusted to greater than 11 with a strong aqueous inorganic base, for example, about 30% NaOH. The pH-adjusted aqueous phase may be extracted with a nonpolar solvent (e.g., DCM) at a ratio of solvent volume to the weight of compound 153 of about 5:1 L / kg to about 20:1 L / kg, or about 8:1 L / kg to about 15:1 L / kg. A second aqueous phase extraction with a nonpolar solvent may be performed. The organic phases are combined and may be washed at least once with water in a volume generally corresponding to the volume of each nonpolar solvent extract. The combined and washed organic phases may then be dried with a drying agent (e.g., MgSO4) and filtered. The filtrate contains compound 153 in a solution at a concentration of about 2–about 8 w / w%, or about 2–about 6 w / w%. In some embodiments, the solid compound 153 may be obtained by solvent evaporation under reduced pressure. In some embodiments, the solvent used is an ester. In certain embodiments, the solid compound 153 is obtained by solvent evaporation from isopropyl acetate. In some other embodiments, a solution of compound 153 may be used directly for the preparation of compound 140. The yield of compound 153 is at least 80%, or at least 90%.

[0187] Overall method Compound 200 may be prepared by the general method described in Figure 13, where steps 1-3 and 7-10 relate to the general method of International Publication No. 2018 / 109050 as otherwise described herein, and where steps 4-6 and 10-12 relate to the reaction of this disclosure.

[0188] Solvate of compound 200 Further provided herein are solvates of compound 200, for example, those that may be produced during the manufacture of compound 200. In some embodiments, the solvate is a crystalline solvate. In certain embodiments, the crystalline solvate is ethanol hemisolvate. In some embodiments, the crystalline solvate is toluene solvate. In some embodiments, the crystalline solvate is ethanol solvate.

[0189] In some embodiments, the crystalline ethanol hemisolvate is characterized by an XRPD pattern containing one or more characteristic peaks selected from Table X (e.g., one, two, three, four, five, six, seven, eight, nine, ten, or more than ten, or at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten). In some embodiments, the crystalline ethanol hemisolvate is characterized by an XRPD pattern containing at least four, at least five, or all six peaks from the peaks 7.04, 14.05, 15.03, 17.48, 19.23, and 21.11 (±0.2° 2-theta). In some embodiments, the crystalline ethanol hemisolvate has essentially the XRPD pattern shown in Figure 17.

[0190] In some embodiments, the crystalline toluene solvate is characterized by an XRPD pattern containing one or more characteristic peaks selected from Table X (e.g., one, two, three, four, five, six, seven, eight, nine, ten, or more than ten, or at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten). In some embodiments, the crystalline toluene solvate has essentially the XRPD pattern shown in Figure 18. In some embodiments, the crystalline toluene solvate is characterized by an XRPD pattern containing at least four, or all five, of the peaks: 4.18, 6.91, 14.20, 15.59, and 16.83 (±0.2°² theta).

[0191] In some embodiments, the crystalline ethanol solvate is characterized by an XRPD pattern containing one or more characteristic peaks selected from Table X (e.g., one, two, three, four, five, six, seven, eight, nine, ten, or more than ten; or at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten). In some embodiments, the crystalline ethanol solvate has essentially the XRPD pattern shown in Figure 19. In some embodiments, the crystalline ethanol solvate is characterized by an XRPD pattern containing at least four, at least five, at least six, or all seven peaks from among 5.41, 5.64, 8.46, 13.83, 14.02, 14.56, and 16.96 (±0.2°² theta). Table X: XRPD peak list for 200 solvent polymorphs of selected compounds. The error in the position of each individual peak is ±0.2°² theta. TIFF2026086461000043.tif215170

[0192] Exemplary Embodiments E1. A method for preparing compound 190, or its stereoisomers, geometric isomers, tautomers, or salts, (a) To form a reaction mixture comprising compound 170, compound 181, a palladium catalyst, and a solvent system containing a base, wherein the equivalent ratio of the palladium catalyst to compound 170 is less than approximately 0.001:1 to 0.005:1, (b) The following scheme: According to TIFF2026086461000044.tif47170, the reaction mixture is reacted to form a reaction product mixture containing compound 190. Includes, Here, the Pd catalyst comprises a phosphine ligand and a palladium(II) species containing at least one palladium-carbon bond. Here, (i) A fragment that forms a palladium-carbon bond is given by formula: TIFF2026086461000045.tif23170 (in the formula, R 6 ~R 10 Each of these is independently H, and C may be substituted. 1~6 Selected from the group consisting of alkyl, optionally substituted C6 aryl, and optionally substituted heteroaryl, R 6 and R 10 (These may optionally combine to form a fused dicyclic ring containing an aromatic ring.) It is an allyl derivative of, A method wherein the yield of compound 190, or its stereoisomer, geometric isomer, tautomer, or salt, is at least 50% based on compound 170. E2. The fragment that forms the palladium-carbon bond is given by formula: TIFF2026086461000046.tif23170 (in the formula, R 11 C 1~10 (It is alkyl.) The indenyl of the E1 method. E3. Allyl derivatives, (a)R 6 ~R 10 A derivative in which each of the following is H, (b)R 6 ga-CH 3 And R 7 ~R 10 A derivative in which each of the following is H, (c)R 7 is -CH3, R 6 and R 8 ~R 10 A derivative in which each of the following is H, (d)R 8 is -CH3, R 6 , R 7 , R 9 and R 10 A derivative in which each of the following is H, (e)R 6 is -phenyl, and R 7 ~R 10 A derivative in which each of the following is H, (f)R 7 is -phenyl, and R 6 and R 8 ~R 10 A derivative in which each of the following is H, (g) Structure: Method E1 or E2, selected from TIFF2026086461000047.tif24170. E4. Phosphine ligand, formula: TIFF2026086461000048.tif34170 Here, R 1 and R 2 Each of these can be independently substituted. 1~12 Alkyl, possibly substituted C3-C 20 Selected from cycloalkyls and optionally substituted C5 or C6 aryls, R 3 ~R 5 These are H and C, which may be substituted, independently of each other. 1~6 Alkyl, formula -OC 1~6 Alkyl alkoxides, and formula -N(R 12 )(R 13 )(wherein, R 12 and R 13 H and C are independent of each other.1~6 (Selected from alkyl groups) (Selected from amine groups) One of the methods E1 through E3. E5. The phosphine ligand has the following structure: One of the methods E1 through E4 for SPhos of TIFF2026086461000049.tif36170. E6.Pd catalyst, (a) Cationic palladium species containing inorganic or organic counterions X, and (b) Neutral palladium species containing coordinated inorganic or organic ligand X One of the following methods, selected from E1 to E5. Method E6, wherein E7.X is selected from halogens, carboxylates, sulfonates, and inorganic anions. E8. (a) The carboxylate is CH3C(O)O - and tBuC(O)O - Selected from, (b) Sulfonate is CF3SO3 - Selected from tosylate, vesylate and nosylate, (c) Inorganic anions are PF6 - BF4 - , B(C6F5)4 - NO3 - and SO4 2- The E7 method is selected from the options. E9.X is CF3SO3 - The method is E7 or E8. E10. Palladium catalyst, CF3SO3 - It contains an organic counterion, where the phosphine ligand is SPhos, and where R 6 ~R 10 Each of these is H in one of the ways E1 through E9. E11. Any one of the methods from E1 to E10, wherein the solvent system predominantly consists of an aprotic low molecular weight ester solvent and water, the volume ratio of the aprotic low molecular weight ester solvent to water is about 1:0.1 to about 1:1, and the reaction mixture is heated to about 60°C to about 80°C. E12. Any one of the methods E1 to E11, wherein the equivalent ratio of compound 181 to compound 170 is greater than 1:1, and the equivalent ratio of the palladium catalyst to compound 170 is about 0.001:1 to about 0.003:1, or about 0.002:1. E13. (a) The catalyst is [(SPhos)Pd(allyl)]CF3SO3, (b) The solvent system predominantly consists of ethyl acetate and water, where the volume ratio of ethyl acetate to water is approximately 1:0.1 to approximately 1:1. (c) Boronate, structure: TIFF2026086461000050.tif23170 is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, one of the methods E1 to E12. E14. One of the methods E1 to E13, wherein the yield of compound 190, or its stereoisomer, geometric isomer, tautomer, or salt, is at least 60%, at least 70%, at least 80%, or at least 90%, and the purity of compound 190, or its stereoisomer, geometric isomer, tautomer, or salt, is at least 99 area%, or at least 99.5 area%. E15. (a) The content of dimer impurities is less than 0.1 area percent based on compound 190, or its stereoisomers, geometric isomers, tautomers, or salts, where the dimer impurity has the following structure: This is from TIFF2026086461000051.tif61170. (b) The combined content of alcohol impurities and ketone impurities is less than 0.25 area percent based on compound 190, or its stereoisomers, geometric isomers, tautomers, or salts, where the alcohol impurities and ketone impurities have the following structure: One of the methods E1 through E14 for TIFF2026086461000052.tif79170. E16. Further comprising reacting compound 190, or its stereoisomers, geometric isomers, tautomers, or salts thereof, to form compound 200, or its stereoisomers, geometric isomers, tautomers, or salts thereof, wherein the reaction is (a) The following scheme In accordance with TIFF2026086461000053.tif53170, compound 190, or its stereoisomers, geometric isomers, tautomers, or salts, is brought into contact with a reducing agent and a base in the presence of a solvent to form compound 200, or its stereoisomers, geometric isomers, tautomers, or salts. (b) Isolating compound 200, or its stereoisomers, geometric isomers, tautomers, or salts. Includes, Herein, one of the methods E1 to E15 wherein the yield of compound 200 based on compound 170, or its stereoisomer, geometric isomer, tautomer, or salt, is at least 60%, at least 70%, at least 80%, or at least 85%, and the purity of compound 200, or its stereoisomer, geometric isomer, tautomer, or salt, is at least 99 area%, or at least 99.5 area%, is at least 99 area%, or at least 99.5 area%,. E17. Any one of the methods from E1 to E16, further comprising isolating compound 190, or its stereoisomers, geometric isomers, tautomers, or salts, from a reaction product mixture. E18. Compound 181 is (a) Forming a first reaction mixture comprising compound 140, a palladium / vanadium carbon catalyst, a solvent, and hydrogen, (b) React the first reaction mixture to the following scheme In accordance with TIFF2026086461000054.tif37170, a first reaction product mixture containing compound 140 is formed, (c) Forming a second reaction mixture comprising compound 141, compound 90, palladium catalyst, catalyst ligand, base and solvent, (d) The following schemes in which LG is a leaving group In accordance with TIFF2026086461000055.tif49170, the second reaction mixture is reacted to form a second reaction product mixture containing compound 180, (e) Compound 180, in the following scheme According to TIFF2026086461000056.tif49170, compound 181 is formed by reacting it with a boronating agent in the presence of a solvent. Includes, Here, the yield of compound 141 based on compound 140 is at least 90%, or at least 95%. Herein, one of the methods E1 to E17, wherein the yield of compound 180 based on compound 141 is at least 60%, at least 70%, at least 80%, and the purity of compound 180 is at least 95%, at least 98%, or at least 99%. E19. Compound 181 is (a) A process comprising forming a first reaction mixture comprising compound 140 and a solvent comprising an organic solvent and water, and contacting the reaction mixture with a transition metal catalyst in the presence of hydrogen to form a first product mixture comprising compound 141, wherein the process is a continuous flow process, TIFF2026086461000057.tif30170(b) A process for forming a second reaction mixture comprising compound 141, compound 90, a palladium catalyst, a catalytic ligand, a base, and a solvent, (c) The following schemes in which LG is a leaving group A process to react a second reaction mixture to form a second reaction product mixture containing compound 180, according to TIFF2026086461000058.tif49170, (d) Compound 180, in the following scheme According to TIFF2026086461000059.tif49170, the process involves reacting a boronating agent with a solvent in the presence of a solvent to form compound 181. Prepared by, Here, the yield of compound 141 based on compound 140 is at least 90%, or at least 95%. Herein, one of the methods E1 to E17, wherein the yield of compound 180 based on compound 141 is at least 60%, at least 70%, at least 80%, and the purity of compound 180 is at least 95%, at least 98%, or at least 99%. E20. The method of E18 or E19, wherein the palladium catalyst is Pd(OAc)2, the ligand is xanthophos, the base is K2CO3, and the solvent predominantly contains anisole. E21. The method of E20, wherein the palladium catalyst is Pd(OAc)2, the ligand is DPEPhos, the base is NaOMe, and the solution predominantly contains anisole. E22. One of the methods from E18 to E21, wherein the leaving group is a halogen or a triflate, or Br. E23. One of the methods E18 to E22, wherein compound 141 is isolated from the first reaction product mixture before the formation of the second reaction product mixture. E24. Compound 140 is (a) Form a reaction mixture containing compound 153, compound 20, NaBH(OAc)3, and a solvent, (b) The following scheme: According to TIFF2026086461000060.tif32170, the reaction mixture is reacted to form a reaction product mixture containing compound 140. One of the methods E18 to E23, prepared by: E25. The method of E24, wherein the solvent in step (a) is an organic solvent, optionally an aprotic organic solvent, and optionally THF or Me-THF. E26.NaBH - The combined OAc - The E24 or E25 method wherein the ratio of to HOAc to the total is less than 1:3.1, and the solvent in step (a) is THF. E27. A method for reducing by-product formation in the Suzuki coupling reaction, (a) To form a reaction mixture comprising compound 170, compound 181, a palladium catalyst, a solvent system, and a base, wherein the equivalent ratio of the palladium catalyst to compound 170 is less than approximately 0.001:1 to 0.005:1, (b) The following scheme: In accordance with TIFF2026086461000061.tif43170, the reaction mixture is reacted to form a reaction product mixture containing compound 190, or its stereoisomers, geometric isomers, tautomers, or salts. Includes, Here, the Pd catalyst comprises a palladium(II) species containing a phosphine ligand, and at least one palladium-carbon bond. Here, (i) A fragment that forms a palladium-carbon bond is given by formula: TIFF2026086461000062.tif18170 (in the formula, R 6 ~R 10 Each of these is independently H, and C may be substituted. 1~6 Selected from the group consisting of alkyl, optionally substituted C6 aryl, and optionally substituted heteroaryl, R 6 and R 10 (These may optionally combine to form a fused dicyclic ring containing an aromatic ring.) It is an allyl derivative of, Here, (a) The content of dimer impurities is less than 0.1 area percent based on compound 190, or its stereoisomers, geometric isomers, tautomers, or salts, where the dimer impurity is structural This is from TIFF2026086461000063.tif57170. (b) The combined content of alcohol impurities and ketone impurities is less than 0.25 area percent based on compound 190, or its stereoisomers, geometric isomers, tautomers, or salts, where the alcohol impurities and ketone impurities are structural The method described is for TIFF2026086461000064.tif59170. E28. The fragment that forms the palladium-carbon bond is given by formula: TIFF2026086461000065.tif20170 (in the formula, R 11 C 1~10 (It is alkyl.) The indenyl of the E1 method. E29. Allyl derivatives, (a)R 6 ~R 10 A derivative in which each of the following is H, (b)R 6 ga-CH 3 And R 7 ~R 10 A derivative in which each of the following is H, (c)R 7 is -CH3, R 6 and R 8 ~R 10 A derivative in which each of the following is H, (d)R 8 is -CH3, R 6 , R 7 , R 9 and R 10 A derivative in which each of the following is H, (e)R 6 is -phenyl, and R 7 ~R 10 A derivative in which each of the following is H, (f)R 7 is -phenyl, and R 6 and R 8 ~R 10 A derivative in which each of the following is H, (g) Structure: Derivative of TIFF2026086461000066.tif27170 The E27 or E28 method, selected from the options provided. E30. Phosphine ligand, formula: TIFF2026086461000067.tif30170 Here, R 1 and R 2 Each of these can be independently substituted. 1~12 Alkyl, possibly substituted C3-C 20Selected from cycloalkyls and optionally substituted C5 or C6 aryls, R 3 ~R 5 These are H and C, which may be substituted, independently of each other. 1~6 Alkyl, formula -OC 1~6 Alkyl alkoxides, and formula -N(R 12 )(R 13 )(wherein, R 12 and R 13 H and C are independent of each other. 1~6 (Selected from alkyl groups) (Selected from amine groups) One of the methods from E27 to E29. E31. The phosphine ligand has the following structure One of the SPhos formats E27 through E30 for TIFF2026086461000068.tif30170. E32.Pd catalyst, (a) Cationic palladium species containing inorganic or organic counterions X, and (b) Neutral palladium species containing coordinated inorganic or organic ligand X One of the methods from E27 to E31, selected from the options provided. Method of E32, wherein E33.X is selected from halogens, carboxylates, sulfonates, and inorganic anions. E34. (a) The carboxylate is CH3C(O)O - and tBuC(O)O - Selected from, (b) Sulfonate is CF3SO3 - Selected from tosylate, vesylate and nosylate, (c) Inorganic anions are PF6 - BF4 - , B(C6F5)4 - NO3 - and SO4 2- The E7 method is selected from the options. E35.X is CF3SO3 - This is the E33 or E34 method. E36. Palladium catalyst, CF3SO3 - It contains an organic counterion, where the phosphine ligand is SPhos, and where R 6 ~R 10 Each of these is H, in one of the methods from E27 to E35. E37. Any one of the methods from E27 to E36, wherein the solvent system predominantly consists of an aprotic low molecular weight ester solvent and water, the volume ratio of the aprotic low molecular weight ester solvent to water is about 1:0.1 to about 1:1, and the reaction mixture is heated to about 60°C to about 80°C. E38. Any one of the methods from E27 to E37, wherein the equivalent ratio of compound 181 to compound 170 is greater than 1:1, and the equivalent ratio of the palladium catalyst to compound 170 is about 0.001:1 to about 0.003:1, or about 0.002:1. E39. (a) The catalyst is [(SPhos)Pd(allyl)]CF3SO3, (b) The solvent system predominantly consists of ethyl acetate and water, where the volume ratio of ethyl acetate to water is approximately 1:0.1 to approximately 1:1. (c) Boronate, structure: TIFF2026086461000069.tif19170 is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, one of the methods from E27 to E38. E40. Any one of the methods from E27 to E39, wherein the yield of compound 190 based on compound 170 is at least 60%, at least 70%, at least 80%, or at least 90%, and the purity of compound 190 is at least 99 area%, or at least 99.5 area%. E41. A method for improving the yield in the Suzuki coupling reaction, (a) To form a reaction mixture comprising compound 170, compound 181, a palladium catalyst, a solvent system, and a base, wherein the equivalent ratio of the palladium catalyst to compound 170 is less than approximately 0.001:1 to 0.005:1, (b) The following scheme: In accordance with TIFF2026086461000070.tif47170, the reaction mixture is reacted to form a reaction product mixture containing compound 190, or its stereoisomers, geometric isomers, tautomers, or salts. Includes, Here, the Pd catalyst comprises a palladium(II) species containing a phosphine ligand and at least one palladium-carbon bond. Here, (i) A fragment that forms a palladium-carbon bond is given by formula: TIFF2026086461000071.tif18170 (in the formula, R 6 ~R 10 Each of these is independently H, and C may be substituted. 1~6 Selected from the group consisting of alkyl, optionally substituted C6 aryl, and optionally substituted heteroaryl, R 6 and R 10 (These may optionally combine to form a fused dicyclic ring containing an aromatic ring.) It is an allyl derivative of, A method wherein the yield of compound 190 based on compound 170, or its stereoisomers, geometric isomers, tautomers, or salts, is at least 80%, or at least 85%. E42. The fragment that gives rise to the palladium-carbon bond is given by formula: TIFF2026086461000072.tif23170 (in the formula, R 11 C 1~10 (It is alkyl.) The indenyl of the E1 method. E43. Allyl derivatives, (a)R 6 ~R 10 A derivative in which each of the following is H, (b)R 6 ga-CH 3 And R 7 ~R 10 A derivative in which each of the following is H, (c)R 7 is -CH3, R 6 and R 8 ~R10 A derivative in which each of the following is H, (d)R 8 is -CH3, R 6 , R 7 , R 9 and R 10 A derivative in which each of the following is H, (e)R 6 is -phenyl, and R 7 ~R 10 A derivative in which each of the following is H, (f)R 7 is -phenyl, and R 6 and R 8 ~R 10 A derivative in which each of the following is H, (g) Structure: Derivative of TIFF2026086461000073.tif26170 The E41 or E42 method, selected from the options provided. E44. Phosphine ligand, formula: TIFF2026086461000074.tif34170 (in the formula, R 1 and R 2 Each of them is independent of C 1~6 Selected from alkyl and C5 or C6 aryl groups, R 3 ~R 5 These are H and C, respectively, independently. 1~6 (Selected from alkyl, ether, and amine) One of the methods E41 to E43. E45. Phosphine ligand has the following structure One of the SPhos methods from E41 to E44 for TIFF2026086461000075.tif30170. E46.Pd catalyst, (a) Cationic palladium species containing inorganic or organic counterions X, and (b) Neutral palladium species containing coordinated inorganic or organic ligand X One of the methods E41 through E45 is selected from the options provided. Method of E46, wherein E47.X is selected from halogens, carboxylates, sulfonates, and inorganic anions. E48. (a) The carboxylate is CH3C(O)O - and tBuC(O)O - Selected from, (b) Sulfonate is CF3SO3 - Selected from tosylate, vesylate and nosylate, (c) Inorganic anions are PF6 - BF4 - , B(C6F5)4 - NO3 - and SO4 2- The E47 method is selected from the options. E49.X is CF3SO3 - The method is E47 or E48. E50. Palladium catalyst, CF3SO3 - It contains an organic counterion, where the phosphine ligand is SPhos, and where R 6 ~R 10 Each of these is H, in one of the methods from E41 to E49. E51. Any one of the methods from E41 to E50, wherein the solvent system predominantly consists of an aprotic low molecular weight ester solvent and water, the volume ratio of the aprotic low molecular weight ester solvent to water is about 1:0.1 to about 1:1, and the reaction mixture is heated to about 60°C to about 80°C. E52. Any one of the methods from E41 to E51, wherein the equivalent ratio of compound 181 to compound 170 is greater than 1:1, and the equivalent ratio of the palladium catalyst to compound 170 is about 0.001:1 to about 0.003:1, or about 0.002:1. E53. (a) The catalyst is [(SPhos)Pd(allyl)]CF3SO3, (b) The solvent system predominantly consists of ethyl acetate and water, where the volume ratio of ethyl acetate to water is approximately 1:0.1 to approximately 1:1. (c) Boronate, structure: TIFF2026086461000076.tif23170 is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, one of the methods from E41 to E52. E54. (a) The content of dimer impurities is less than 0.1 area% based on compound 190, where the dimer impurities are structured as follows: This is from TIFF2026086461000077.tif62170. (b) The combined content of alcohol impurities and ketone impurities is less than 0.25 area% based on compound 190, where the alcohol and ketone impurities are structurally This is from TIFF2026086461000078.tif74170. (c) Any one of the methods E41 to E53, wherein the purity of compound 190 is at least 95 area% and at least 99.5 area%. E55. A method for preparing compound 180, its stereoisomers, its geometric isomers, its tautomers, and salts thereof, (a) Forming a first reaction mixture comprising compound 140, a palladium / vanadium carbon catalyst, a solvent, and hydrogen, (b) The following scheme In accordance with TIFF2026086461000079.tif36170, the first reaction mixture is reacted to form a first reaction product mixture containing compound 141, (c) Forming a second reaction mixture comprising compound 141, compound 90, palladium catalyst, catalyst ligand, base and solvent, (d) The following scheme In accordance with TIFF2026086461000080.tif47170, the second reaction mixture is reacted to form a second reaction product mixture containing compound 180. Includes, Here, the first reaction mixture catalyst is selected from the group consisting of Ra-Ni, Ra-Co, Pt / V@C, Co@Chitin, Ni-phen@SiO2, and Ni-phen@TiO2. Here, the yield of compound 141 based on compound 140 is at least 90%, or at least 95%. A method wherein the yield of compound 180 based on compound 141 is at least 60%, at least 70%, at least 80%, and the purity of compound 180 is at least 95%, at least 98%, or at least 99%. E56. Compound 180, its stereoisomers, its geometric isomers, its tautomers, and methods for preparing salts thereof, (a) A process comprising forming a first reaction mixture comprising compound 140 and a solvent comprising an organic solvent and water, and contacting the reaction mixture with a transition metal catalyst in the presence of hydrogen to form a first product mixture comprising compound 141, wherein the process is a continuous flow process, TIFF2026086461000081.tif29170(b) A process for forming a second reaction mixture comprising compound 141, compound 90, a palladium catalyst, a catalytic ligand, a base, and a solvent, (c) The following schemes in which LG is a leaving group A process to react a second reaction mixture to form a second reaction product mixture containing compound 180, according to TIFF2026086461000082.tif43170, (d) Compound 180, in the following scheme According to TIFF2026086461000083.tif47170, the process involves reacting a boronating agent with a solvent in the presence of a solvent to form compound 181. Includes, Here, the yield of compound 141 based on compound 140 is at least 90%, or at least 95%. A method wherein the yield of compound 180 based on compound 141 is at least 60%, at least 70%, at least 80%, and the purity of compound 180 is at least 95%, at least 98%, or at least 99%. E57. The method of E55 or E56, wherein compound 141 is not isolated from the first reaction product mixture before the formation of the second reaction product mixture. E58. Any one of the methods from E55 to E57, wherein the first reaction mixture solvent and the second reaction mixture solvent each predominantly consist of polar aprotic solvents. E59. The method of E58, wherein the first reaction mixture solvent predominantly contains tetrahydrofuran. E60. Any one of the methods from E51 to E59, further comprising a solvent exchange step in which the solvent of the first reaction product mixture is predominantly replaced with a polar aprotic solvent before the formation of the second reaction reaction. E61. The method according to E60, wherein the solvent of the first reaction product mixture is predominantly replaced with anisole, and the solvent of the second reaction mixture predominantly contains anisole. E62. One of the methods from E55 to E61, wherein the palladium catalyst is Pd(OAc)2 and the catalytic ligand is xanthophos or DPEPhos. E63. Any one of the methods from E55 to E62, wherein the palladium catalyst is Pd(OAc)2, the catalytic ligand is xanthophos, and the base is K2CO3, or the palladium catalyst is Pd(OAc)2, the catalytic ligand is DPEPhos, and the base is NaOMe. E64. One of the methods from E55 to E62, wherein the first reaction mixture catalyst is Pt / V@C. E65. One of the methods from E56 to E62, wherein the first reaction mixture catalyst is Pd / Al2O3, Pt / Al2O3, Pd / C, or Pt / C. E66. One of the methods from E56 to E65, (e) A step of bringing the second reactant into contact with an aqueous wash, (f) A step of isolating and concentrating an organic phase, wherein the organic phase predominantly contains all of the compounds 180 contained in the second reaction product mixture, (g) A step of combining the concentrated organic phase with alcohol and water, (h) A step of isolating the organic phase which predominantly contains the second reaction product mixture solvent, alcohol, and compound 180, (i) A step of concentrating the isolated organic phase, (j) A step of combining the concentrated organic phase with an alcohol and cooling it to form a crystalline compound 180, (k) A step to isolate crystalline compound 180 and The following steps further include isolating compound 180: method. E67. The method of E65, wherein the alcohol is 1-butanol. E68. A composition comprising at least 98.5 w / w% of compound 190, or its stereoisomers, geometric isomers, tautomers, or salts, TIFF2026086461000084.tif49170 Here, (a) The content of dimer impurities is less than 0.15 area% based on compound 190, where the dimer impurities are structured as follows: This is from TIFF2026086461000085.tif67170. (b) The combined content of alcohol impurities and ketone impurities is less than 0.35 area% based on compound 190, where the alcohol impurities and ketone impurities are structurally A composition belonging to TIFF2026086461000086.tif63170. E68-1. A method for preparing compound 180, its stereoisomers, its geometric isomers, its tautomers, and salts thereof, (a) A process comprising forming a first reaction mixture comprising compound 140 and a solvent comprising an organic solvent, and contacting the reaction mixture with a transition metal catalyst in the presence of hydrogen to form a first product mixture comprising compound 141, wherein the process is a continuous flow process, TIFF2026086461000087.tif28170(b) A process for forming a second reaction mixture comprising compound 141, compound 90, a palladium catalyst, a catalytic ligand, a base, and a solvent, (c) The following schemes in which LG is a leaving group A process to react a second reaction mixture to form a second reaction product mixture containing compound 180, according to TIFF2026086461000088.tif47170, (d) Compound 180, in the following scheme According to TIFF2026086461000089.tif48170, the process involves reacting a boronating agent with a solvent in the presence of a solvent to form compound 181. Includes, Here, the yield of compound 141 based on compound 140 is at least 90%, or at least 95%. A method wherein the yield of compound 180 based on compound 141 is at least 60%, at least 70%, at least 80%, and the purity of compound 180 is at least 95%, at least 98%, or at least 99%. E69. A composition of E68 or E68-1 in which the content of dimer impurities is less than 0.10 area% based on compound 190. E70. A composition of E69 in which the dimer impurity content is less than 0.05 area% based on compound 190. E71. Any one of the compositions from E68 to E70, wherein the combined content of alcohol impurities and ketone impurities is less than 0.30 area% based on compound 190. E72. A composition of E71 in which the combined content of alcohol impurities and ketone impurities is less than 0.25 area% based on compound 190. E73. A composition of E72 in which the combined content of alcohol impurities and ketone impurities is less than 0.20 area% based on compound 190. E74. One composition from E68 to E73 comprising at least 98.0 w / w% of compound 190, or its stereoisomers, geometric isomers, tautomers, or salts. E75. A composition of E74 comprising at least 98.5 w / w% of compound 190, or its stereoisomers, geometric isomers, tautomers, or salts. [Examples]

[0193] The figures and examples provide exemplary methods for preparing the disclosed compounds, and those skilled in the art will understand that other synthetic routes may be used to synthesize the compounds. Although specific starting materials and reagents are depicted and examined in the figures and examples, other starting materials and reagents may be substituted to provide a variety of derivatives and / or reaction conditions. In addition, many of the described and exemplary methods may be further modified in light of this disclosure using conventional chemical properties well known to those skilled in the art.

[0194] In the examples, equivalents and equivalence ratios are based on the starting materials mentioned for each reaction. Volume values ​​per unit weight, e.g., L / kg and mL / g, refer to the volume of the liquid component based on the weight of the starting materials mentioned for each reaction.

[0195] Analysis method High-pressure liquid chromatography (HPLC) can be performed as follows.

[0196] HPLC Method 1 - Examples 2-10, and Comparative Examples 4-6: Apparatus and Column. HPLC System: Agilent Series 1260, quaternary pump, and autosampler. Integration System: Waters Empower. Configuration: Jetweaver V380 mixer not used, pulse compensation, 0.12 mm capillary (red), and 10 mm flow cell. Delay Volume: 0.51 mL. Dosage: Automatic bullet (e.g., Metrohm 725 Dosimat) or volumetric pipette, Piston-stroke pipette for μL range. Stationary Phase: Poroshell 120 Bonus-RP, L=150 mm, ID=4.6 mm, 2.7 μm.

[0197] Solution. Buffer solution: 20 mM ammonium acetate in water, 1.52-1.56 g of ammonium acetate, 1000 mL of water, pH 5.8 ± 0.1, adjust pH with acetic acid if necessary. Mobile phase A: 950 mL of buffer solution, 50 mL of acetonitrile. Mobile phase B: 950 mL of acetonitrile, 50 mL of buffer solution. Diluent: Water / acetonitrile 1:9 v / v (e.g., 100 mL of water and 900 mL of acetonitrile).

[0198] Pump program. TIFF2026086461000090.tif48170

[0199] Column oven temperature: 25°C. Column back pressure: approx. 300 bar (initial conditions). Injection volume: 3.0 μL. Needle wash: Wash vial. Sampler thermostat temperature: 5°C. Column flushing: Water / acetonitrile 2:8. Column storage: Acetonitrile. Detection: DAD: 245 nm, bandwidth 4 nm. Reference wavelength: Off. Slit: 4 nm. Data rate: 5 Hz, peak width > 0.05 min, reaction time 1 second.

[0200] Sample preparation. The blank solution was used as a diluent. For stock solution 1, the following standard references were dissolved in 10.0 mL of diluent: 7.0-8.0 mg Des-Brom impurity; 7.0-8.0 mg cysteine ​​adduct impurity; 7.0-8.0 mg positional isomer impurity (positional isomer of compound 190); and 7.0-8.0 mg chloride (compound 170). For stock solution 2, 7.0-8.0 mg boronate (compound 182) was dissolved in 10.0 mL of acetonitrile. For stock solution 3, the following standard references were dissolved in 100.0 mL of methylene chloride: 7.0-8.0 mg dimer impurity; 7.0-8.0 mg sec alcohol impurity; and 7.0-8.0 mg ketone impurity. For System Suitability Test ("SST") Solution 1 (0.05%), 7.0–8.0 standard reference compound 200 was dissolved in 9.93 mL of diluent, followed by the addition of 5.0 μL of stock solution 1, 5.0 μL of stock solution 2, and 50.0 μL of stock solution 3. For SST solution 2 (for peak assignment of THF impurities), 7.0–8.0 mg of THF impurities were dissolved in 10.0 mL of diluent. The sample reaction mixture was prepared by dissolving 50 μL of organic phase sample in 10.0 mL of diluent.

[0201] System suitability testing. Blank chromatogram: The blank chromatogram was compared to the chromatogram depicted in the analytical method, and system peaks or peaks resulting from the chemicals used should not interfere with this analysis. Selectivity: The chromatogram of the SST solution was comparable to that of a closed-type chromatogram in terms of selectivity and residence time. Sensitivity and peak symmetry: The chromatogram of the SST solution was examined visually. Action: In cases of malfunction, the sample analysis was not considered valid. After correcting the source of the error, the blank, SST, and sample analyses were repeated.

[0202] If the residence time of the major peak in the sample chromatogram matches the residence time of the major peak in the SST solution chromatogram, then the compound is identified. Area percentage is: TIFF2026086461000091.tif20170(where xi=percentage of analyte i(%area);Ai=percentage of analyte i(mAU * s) or (pA * s) or (counts * Area of ​​the peak obtained for s); and Aj = analyte j = 1 ~ n (mAU) * s) or (pA * s) or (counts * The area of ​​the peak obtained for s). The percentage reduction in area takes into account only the selected analyte.

[0203] Integration range. Area percentage: Peaks present in the blank chromatogram were ignored for area percentage analysis. Analysis of reduced area percentage: Only chloride and aldehyde impurities were integrated; the reaction was determined to be complete when the reduced area percentage of compound 170 ("chloride") fell below the specification limit.

[0204] Integration parameters. The integration parameters were adjusted to integrate all peaks to half of the reported level ("RL"). Any impurity peaks that were not completely separated from the main peak were integrated, preferably by trough-to-tough extrapolation (tangential skim).

[0205] The peak table is as follows: TIFF2026086461000092.tif89170 a Only in SST solution The peak table is for peak allocation / information purposes only. TIFF2026086461000093.tif45170

[0206] The amount of dimer in %w / w obtained by HPLC method 1 described above correlates with the amount of dimer obtained by the area %HPLC method, as reported in the correlation table below. Correlation between dimer %w / w evaluated by HPLC method 1 and area % from the same sample determined by other HPLC methods. TIFF2026086461000094.tif27170

[0207] Analysis methods for Comparative Examples 1-3 Comparative Example 1: Column: Waters Atlantis T3 (4.6 * Column (150 mm, 3 μm). Mobile phase A: 10 mM ammonium formate, pH 3.7. Mobile phase B: CH3CN. Flow rate: 1.0 mL / min. Injection volume: 2.0 μL. Column temperature: 45°C. UV detection wavelength: 315 nm. Diluent: ACN.

[0208] Comparative Example 3: Column: (1) Agilent PLRP-S 100A, 150 mm × 4.6 mm, 3 μm, or (2) Agilent PLRP-S 100A, 250 mm × 4.6 mm, 5 μm. Mobile phase A: 10 mM aqueous NaOH. Mobile phase B: Acetonitrile. Flow rate: 1.0 mL / min. Injection volume: 10.0 μL. Column temperature: (1) 20°C, (2) 15°C.

[0209] Liquid chromatography-mass spectrometry (LCMS) can be performed as follows: Column: XDB-C18 4.6mm x 50mm, 1.8μm. Mobile phase A: Water / 0.05% TFA. Mobile phase B: CH3CN / 0.05% TFA. Flow rate: 1.2mL / min. Injection volume: 10.0uL. Column temperature: 40℃. Diluent: 30:70(v / v)CH3CN / H2O. Interface type: ES-API+. Dry gas temperature: 250℃. Nebulizer pressure: 35psig. Dry gas flow rate: 13L / min. Capillary voltage: 3000V. Scan range: 150~600m / z.

[0210] Gas chromatography (GC) can be performed as follows: Agilent HP-5 (30m * 0.32mm * Agilent 7890A series GC system with a 0.25 μm column. Flow rate: 2.0 mL / min. Injection volume: 10.0 μL. Carrier gas: N2. Diluent: Methanol.

[0211] Mass spectrometry (MS) can be performed (1) using a Sciex 15 mass spectrometer in ES+ mode, or (2) using a Shimadzu LCMS 2020 mass spectrometer in ESI+ mode. Mass spectrometry data generally show only the parent ion unless otherwise specified. MS or HRMS data are provided for the specific intermediate or compound indicated.

[0212] Nuclear magnetic resonance (NMR) analysis may be performed using any suitable instrument, including but not limited to (1) a Bruker AV III 300 NMR spectrometer, (2) a Bruker AV III 400 NMR spectrometer, or (3) a Bruker AV III 500 NMR spectrometer, with reference to tetramethylsilane. NMR data are provided for the specific intermediate or compound shown.

[0213] Example 1 Compound 140 was prepared according to the reaction scheme in Figure 12A and as described below. TIFF2026086461000095.tif38170

[0214] To a warm (35°C) suspension of NaBH(OAc)3 (71.5 g, 337 mmol) in THF (110 g), (S)-2-methyl-1-(6-nitropyridine-3-yl)piperazine (50 g, 225 mmol, compound 153) and oxetane-3-one (21.2 g, 292 mmol, compound 20) in a cold (10°C) preformed mixture in THF (136.4 g) was added over 1-2 hours. The mixture was stirred at 35°C until complete conversion was achieved (typically 1 hour). The reaction mixture was then cooled to 25°C and quenched at 40°C upon addition to water (135 g). After phase separation, NaOH (99.6 g, 28%) was added at 40°C to achieve pH 12. After phase separation, the organic phase was polished and filtered at 40°C, concentrated, and then subjected to continuous exchange of THF with 2-PrOH under reduced pressure (300 mg / L) to initiate crystallization. The crystal slurry was cooled to 5°C and stirred for at least 2 hours. The crystals were filtered off, washed with cold 2-PrOH, and dried under reduced pressure until a constant weight was obtained. Compound (S)-2-methyl-1-(6-nitropyridine-3-yl)-4-(oxetan-3-yl)piperidine (compound 140) was isolated as yellow crystals in 89% yield (55.8 g). 1 H-NMR (600 MHz, DMSO-d6) δ ppm 8.22 (d, 1 H), 8.11 - 8.18 (m, 1 H), 7.44 (dd, 1 H), 4.40 - 4.62 (m, 3 H), 4.30 - 4.40 (m, 1 H), 3.83 (br d, 1 H), 3.42 (q, 1 H), 3.08 - 3.18 (m, 1 H), 2.79 - 2.90 (m, 1 H), 2.66 (br d, 1 H), 2.08 - 2.20 (m, 1 H), 1.92 - 2.03 (m, 1 H), 1.21 (d, 3) H). HR-MS (ESI): C 13 H 18 Calculated value of N4O3: 278.1379; Measured value: 278.1406.

[0215] Example 2 Compounds 141 and 180 were prepared according to the reaction scheme in Figure 1, and as described in more detail below: TIFF2026086461000096.tif85170

[0216] A solution of (S)-2-methyl-1-(6-nitropyridine-3-yl)-4-(oxetan-3-yl)piperazine (56 g, 201.3 mmol) (compound 140) in THF (495.8 g) was transferred to a steel autoclave and hydrogenated at 60°C and 4 bar of hydrogen for 16 hours in the presence of a Pt / V@C catalyst (1.12 g, 2 w%) to produce a solution of (S)-5-(2-methyl-4-(oxetan-3-yl)piperazine-1-yl)pyridine-2-amine (compound 141). After pressure release, the catalyst was filtered off, the autoclave was rinsed with THF, and the filter cake was washed with THF. THF was distilled from the solution to a reactor volume of approximately 120 mL. Anisole was added, and the remaining THF was removed by distillation under reduced pressure (120-150 millibars, Ti90±5℃) to a reactor volume of 250 mL (5V).

[0217] Next, 3,4-dibromo-1-1-methylpyridine-2-one (compound 90) (1.05 equivalents) and K2CO3 (1.5 equivalents) were added to a solution of compound 141 at a temperature of 90°C under an argon / nitrogen flow, followed by the dropwise addition of water (1.0 equivalent). Finally, xanthophos (3 mol%) and Pd(OAc)2 (1.5 mol%) were added to form a mixture. The mixture was heated to a temperature of 112–114°C and stirred until complete conversion to compound 180 was achieved (15–20 hours). The reaction mixture was diluted with anisole (2V), followed by the addition of water (4V) to bring the temperature to 90°C. The organic phase and aqueous phase were separated. Anisole was partially removed from the organic phase under reduced pressure (120–150 mgbar) to a reactor volume of 150 mL (3V). Next, 1-butanol (5V) and water (4V) were added, followed by separation into an organic phase and an aqueous phase. The organic phase, containing anisole, 1-butanol, and compound 180, was transferred to a preheated (90°C) reactor, and the volume of the reaction mixture was reduced under reduced pressure (120-150 mg / mV) to a reactor volume of 200 mL, at which point crystallization was initiated. 1-butanol (3V) was added to achieve a crystallization volume of 350 mL. The suspension was cooled to -10°C at a rate of 10°C / hour and stirred at -10°C for at least 6 hours. The crystals were recovered by filtration, washed with cold (-5±2°C) MeOH / H2O (1:1 v / v, 1.5V) and cold (-5±2°C) 1-butanol (2.5V), and dried under reduced pressure (2-10 mgbar) at 70°C until gravimetrically stable, yielding compound 180 as a beige-yellow solid in 75-78% yield and >99.0% assay. 1H NMR (600 MHz, DMSO-d6) δ ppm 8.47 - 8.62 (m, 2 H), 7.92 (d, 1 H), 7.33 - 7.51 (m, 2 H), 7.26 (d, 1 H), 4.39 - 4.69 (m, 4 H), 3.73 (br d, 1 H), 3.51 (s, 3 H), 3.38 - 3.45 (m, 1 H), 3.08 - 3.17 (m, 1 H), 2.90 - 3.04 (m, 1 H), 2.58 (br d, 1 H), 2.27 - 2.40 (m, 2 H), 2.18 (br t, 1 H), 0.96 (d, 3 H). HR-MS (ESI): C 19 H 24 Calculated value of BrN5O2: 433.1113; Measured value: 433.1130.

[0218] Example 3 Compounds 141 and 180 were prepared according to the reaction scheme in Figure 2 and as described below. TIFF2026086461000097.tif106170

[0219] Compound 141 was prepared by the method of Example 2. A solution of Compound 141 (152.04 g, containing 15 g of Compound 141) in THF was heated to 85°C, and the THF was replaced with anisole by continuous distillation to obtain a reactor volume of approximately 75 mL. The mixture was cooled to 50°C, and then Compound 90 (16.93 g, 63.42 mmol, equivalent: 1.05) and anhydrous sodium methoxide (3.92 g, 72.48 mmol, equivalent: 1.2) were added in succession, and finally, a premixed red suspension of palladium(II) acetate (203.4 mg, 906.1 μmol, equivalent: 0.015) and DPEphos (975.9 mg, 1.812 mmol, equivalent: 0.030) in anisole (6.93 g, 7 ml) was added. Next, the reaction mixture was heated to 92°C to form a suspension. The mixture was then stirred until complete conversion was achieved, and then quenched upon addition of water (120 g). The reaction mixture was then cooled to 10°C at a rate of 1°C / min. Crystalline compound 180 was then isolated by filtration and washed sequentially with MeOH (45 mL), H2O / MeOH (1:1 v / v, 20 mL), and MeOH (30 mL). The crystals were dried under reduced pressure at 45°C to a gravimetrically stable state to obtain compound 180 as a beige solid in 82.5% yield (12.6 g) and with a purity of >99 area%.

[0220] Example 4 Example 3 was repeated, except that triphenylphosphine (4.5 mol%) was added to the reaction mixture containing a solution of compound 141. This reaction yielded 82.4% yield with 98.3% purity.

[0221] Example 5 Compound 141 is used in the following scheme: Prepared according to TIFF2026086461000098.tif37170 and isolated from solution.

[0222] A solution of compound 140 (300 g, 1.078 mol) in THF (1.06 kg) was placed in an autoclave and hydrogenated with hydrogen at 60°C and 4 bar for 16 hours in the presence of a Pt / V / @C catalyst (6.0 g, 2 w%) to produce compound 141 in solution. After cooling to room temperature and releasing the pressure, the catalyst was recovered by filtration, the autoclave was rinsed with THF, and the filtration cake was washed with THF (total THF rinsing volume 177.8 g). From the combined solution, THF was removed by distillation (70°C, 350 mg bar) to a reactor volume of approximately 1.5 L, and then cooled to 37°C. n-heptane (1 L) was added, and at this point, crystallization of compound 141 was started, and the suspension was stirred at 27°C for 1.5 hours. Next, an additional 1.25 L of n-heptane was added, and the suspension was stirred at 25°C for 15 minutes, then cooled to 3–5°C and stirred for 30 minutes. The crystals were then collected by filtration, washed with 1 L of n-heptane, and dried under reduced pressure to obtain compound 141 in 90.7% yield (242.8 g) and >99 area% purity. 1 H-NMR (600 MHz, CDCl3): δppm 7.86 (dd, 1 H), 7.26 (dd, 1 H), 6.49 (dd, 1 H), 4.53-477 (m, 4 H), 4.27 (br s, 2 H), 3.45-3.62 (m, 1 H), HR-MS (ESI): C 13 H 20 Calculated N4O value: 248.1637; Measured value: 248.1647. XRF: < 1 ppm Pt; < 2 ppm V.

[0223] Example 6 The catalyst for preparing compound 141 from compound 140 was evaluated according to the method of Example 5. The results are reported in Table 1 below. Table 1: Overview of Compound 141 Synthesis TIFF2026086461000099.tif104170

[0224] In the table above, experiments 1 and 3 used 50-56 g of compound 140, 10V solvent, a 1.5 L autoclave with a glass insert, and a reaction time of 16 hours. The catalyst for experiment 1 was Noblyst P8078, and the catalyst for experiment 3 was E101 NE / W. Experiments 2, 4, and 5 used 5 g of compound 140, 10V solvent, a 185 mL autoclave, and a reaction time of 16 hours. Experiments 6-10 used 200 mg of compound 140, 10V solvent, a 35 mL autoclave with a glass insert and vibrator, and a reaction time of 16 hours.

[0225] Example 7 Compound 190 was prepared from compounds 170 and 182 using various catalysts at at least two different catalyst concentrations: 0.001 equivalents per equivalent of compound 170 (0.1 mol%), or 0.01 equivalents per equivalent of compound 170 (1 mol%). In each experiment, the solvents were THF and water, with a volume ratio of THF to water of 4:1, a ratio of solvent volume to compound 170 of 10:1 L / kg, an equivalent ratio of compound 182 to compound 170 of 1.1:1, a base of K3PO4 (1.5 equivalents based on compound 170), a reaction temperature of 50°C, and a reaction time of 18 hours. After 18 hours, 0.25 equivalents of acetylcysteine ​​as a 60 mg / mL solution in H2O were added to the reaction mixture, the mixture was stirred for 10 minutes, and the sample was taken out for HPLC analysis. The results are reported in Tables 2 and 3, where "Comp.190" refers to compound 190, "Comp.170" refers to compound 170, "Ketone" refers to ketone impurities, "sec alcohol" refers to sec alcohol impurities, "Dimer" refers to dimer impurities, "Comp.182" refers to compound 182, and "des brom" refers to DesBr impurities as described below. The results are reported in HPLC area %. TIFF2026086461000101.tif44170

[0226] The results in Tables 2 and 3 are in-process values ​​expressed as HPLC area % measured after a reaction time of 18 hours at 50°C.

[0227] Table 2 reports the activity of cationic and neutral Pd(SPhos)(allyl) compounds at a 1 mol% catalyst packing density. This table clearly shows that, compared to the previously disclosed [Pd(dppf)Cl2] catalyst, a larger amount of compound 190 was produced and a much smaller amount of dimer was formed (0.87 for Pd(dppf)Cl2 versus 0.02-0.08 for Pd(SPhos(allyl) catalyst). Table 3 clearly shows that among the catalysts that performed better at 1 mol%, [(SPhos)Pd(allyl)]OTf performed best at 0.1 mol% (a larger amount of compound 190 and a smaller amount of dimer). Table 2: Summary of results using various cationic and neutral Pd(SPhos)(allyl) catalysts in 1 mol% packing amounts, as well as the previously used catalyst Pd(dppf)Cl2. Table 3 of TIFF2026086461000102.tif58170: Summary of results using various cationic and neutral Pd(SPhos)(allyl) catalysts at 0.1 mol% packing levels. TIFF2026086461000103.tif58170

[0228] The data clearly demonstrates that using the (SPhos)Pd(allyl) counter anion described in this disclosure achieved an improved impurity profile compared to previously used catalysts.

[0229] Example 8 Compound 190 was prepared from compounds 170 and 182 according to the reaction scheme in Figure 5B. Compound 170 (27.5 g, 80.0 mmol, 1.0 equivalent) and compound 182 (46.3 g, 88.0 mmol, 1.1 equivalent) were suspended in ethyl acetate (222 mL, 200 g) with stirring at 70°C, and then completely degassed for 10 minutes. A single dose of [(SPhos)Pd(allyl)]OTf catalyst (113 mg) was added, and the suspension was heated to 70°C ± 3°C for 25-35 minutes. Next, a solution of potassium phosphate (25 g) in water (60.0 g) was added at 70°C ± 5°C over a period of 55-65 minutes. The reaction product mixture was stirred at 70°C until the in-process control showed less than 1.0 area % of compound 170. The reaction time was 1-2 hours.

[0230] The reaction product mixture was cooled to 20°C Ti and then combined with a solution of N-acetylcysteine ​​(3.27 g) degassed with Ar by bubbling in water (60.0 g). The aqueous N-acetylcysteine ​​container and transfer line were washed with ethyl acetate (22.4 g, 25.0 mL) and extruded into the reaction product mixture. The mixture was stirred at 20°C ± 3°C for 15 minutes. After phase separation, the smaller aqueous phase was removed. The remaining organic phase was combined with 5% aqueous NaHCO3 solution (100 g, 98 mL) at 20°C ± 3°C with stirring. Stirring was stopped to allow phase separation (15 minutes). The smaller aqueous phase was removed and the remaining organic phase was combined with water (100 g). The mixture was stirred at 20°C ± 3°C for 15 minutes. Stirring was stopped to allow phase separation (15 minutes). The remaining aqueous phase was removed, and the organic phase was heated to 40°C ± 3°C and then filtered over activated carbon R55SP. The filtrate was collected in a Schott flask, and the container that had previously contained the organic phase and filter was rinsed twice with ethyl acetate into the flask containing the filtrate (22.4 g, 25 mL for each rinse).

[0231] The filtrate was concentrated to a remaining volume of approximately 100 mL under reduced pressure of approximately 200–300 millibars at approximately 85°C. Then, ethanol (350 g, 450 mL) was added at 50°C–70°C to form a suspension. The suspension was concentrated to a remaining volume of approximately 400 mL under reflux (approximately 85°C) and atmospheric pressure. The solution was obtained under reflux and maintained throughout the concentration process. An in-process control sample was collected and tested for the remaining ethyl acetate, and the concentration was continued until the fraction of ethyl acetate in the ethyl acetate / EtOH mixture was 6.0% or less. If this level was not achieved, additional ethanol may be added to the solution to a concentration of approximately 400 mL. After the ethyl acetate content was reduced to 6.0% or less, the solution was cooled to 75°C ± 2°C and seeded with a suspension of compound 190 (273 mg of compound 190 in 10.0 mL of ethanol). The prepared suspension was stirred at 75°C ± 2°C for 30 minutes, and then cooled to 5°C ± 3°C at a rate of 10°C per hour (approximately 7 hours). The suspension was aged at 5°C ± 3°C for at least 7 hours. Compound 190 was isolated by filtration across Nutsche using filter paper under a vacuum of approximately 500 millibars. The recovered solid compound 190 was washed twice with ethanol at 4°C to 6°C, with a total ethanol volume of 74.9 g. The compound 190 product was dried overnight at 50°C under reduced pressure of 5 millibars to obtain 48.6 g of compound 190 (99.7 area % assay and 91.4% yield).

[0232] The above method for preparing compound 190 was repeated three times, except that the solvent exchange from ethyl acetate to ethanol in Experiment 3 was carried out as follows (Experiments 1-3): The organic phase was concentrated to 80 mL, and ethanol (268 g, 340 mL) was added. The results are shown in Table 4 below, where "IPC" refers to the in-process control test results, and "IPC water" refers to the water content measured in the IPC Ã fraction test. Table 4: Summary of experimental characterization, both in-process (IPC) and after completion, for three triple experiments preparing compound 190 using [(SPhos)Pd(allyl)]OTf and ethyl acetate. TIFF2026086461000104.tif142170

[0233] Example 9 The reaction described herein for preparing compound 190 from compounds 182 and 170 was compared with the previously used reaction for preparing compound 190 from compounds 182 and 170. The reaction conditions are summarized in Table 5. Using the older catalyst system of Pd(dppf)Cl2, ketone impurities were observed over a wide area, up to a maximum of 0.29 area% (see Table 5). In contrast, using the new catalyst system, the amount of observed ketone impurities was kept within a narrow range with a much lower upper limit (up to 0.06 area%). Table 5: Summary of the previously used method and the conditions from the method described above. Yield, purity, and by-product content of the isolated compound after workup were evaluated. The "Disclosure" values ​​are averages across three batches, totaling 800 kg of product. TIFF2026086461000105.tif94170

[0234] The dimer, alcohol, and ketone impurities are described below: TIFF2026086461000106.tif59170

[0235] Alcohol impurities that may form during this reaction may be oxidized to the corresponding ketone impurities before detection.

[0236] Example 10 Compound 200 is used in the following scheme: It was prepared from compound 190 as shown in TIFF2026086461000107.tif48170.

[0237] Compound 190 (50 g, 75.4 mmol, 1 equivalent) was loaded into the reactor. THF (267 g) was added, followed by K2HPO4 (6.16 g, 35.4 mmol, 0.469 equivalents) and water (42.5 g). The mixture was heated to 40-45°C and vigorously stirred for about 20 minutes. Then, while maintaining the temperature at 40-45°C, an aqueous mixture of sodium hydroxide and sodium borohydride (12 w / w NaBH4, 40 w / w NaOH, and 11.9 total aqueous solution was added) was added over 10-23 minutes. The contents of the reactor were monitored until the concentration of remaining compound 190 was 0.20 area% or less (about 1 hour). Next, 85% aqueous phosphoric acid (10.5 g) was added to the reaction product mixture containing product compound 200, the reactor was heated to 60°C, and the contents were vigorously stirred until the borane adduct content fell to 0.05 area% or less (approximately 2 hours). TIFF2026086461000108.tif52170

[0238] The contents were vigorously stirred for a further 3 hours, then cooled to 40-45°C to separate and remove the organic phase, which was then filtered through activated carbon. The filtrate was then concentrated at 65°C under atmospheric pressure by solution swapping to obtain a minimum volume of 2.6 L / kg of starting compound 190, to which methanol was added to the final volume of 6.6 L / kg of starting compound 190. The mixture was seeded to initiate the crystallization of compound 200, and solvent swapping was continued at a constant volume until the THF concentration fell to below 5.0% w / w. The resulting suspension was aged for at least 30 minutes, cooled to 5°C for 5 hours, and kept at 5°C for at least 3 hours. After that, the crystals of compound 200 were filtered off using a Nutsche filter and washed twice with methanol. The crystals were dried under reduced pressure until a certain weight (90% yield; assay: 99.1% w / w, purity: 99.7% area) was achieved.

[0239] Example 11 Compound 200, obtained from the synthesis summarized in Example 10, was recrystallized from toluene / ethanol using a cooling crystallization method.

[0240] Crude compound 200 was suspended in a 60:40 w / w toluene:ethanol mixture in a first reactor at room temperature, and then heated between 70°C and 75°C. The suspension was transferred to a second reactor via a polish filter unit, and the first reactor was then rinsed with 60 / 40 w / w toluene / ethanol. The concentration of compound 200 in the second reactor was approximately 20% w / w. Ethanol was added, and the temperature was maintained at 70-75°C until a toluene:ethanol ratio of 20:80 w / w was reached. This solution was cooled to 50°C and seeded with a suspension of compound 200 in 10% w / w ethanol (to approximately 2% w / w). The seeded suspension was aged for 4 hours, cooled to -10°C, aged for 10 minutes, heated to 45°C within 15 minutes, and aged for 30 minutes. This thermocycle (heating to 45°C, aging, cooling to -10°C, aging) was repeated three times. After the fourth thermocycle, the suspension was cooled between -15°C and -10°C. After further aging for at least 6 hours, the suspension was filtered, the filter cake was washed with ethanol (-10°C), and the washed filter cake was dried overnight under reduced pressure at 50°C.

[0241] Comparative Example 1 This comparative example presents a previously used method for synthesizing compound 141. Compound 141, It was prepared from compound 140, as shown in TIFF2026086461000109.tif36170.

[0242] Methanol (675 mL) was packed into the reaction flask. Compound 140 (135 g, 98.9 A%, 537.7 mmol, 1 equivalent), followed by 10% palladium-carbon catalyst (27 g, 20 w / w%, 59% wet), was packed into the reaction flask with vigorous stirring. The reaction flask was emptied, refilled three times with N2, then emptied and refilled three times with H2. The mixture was heated at 45–55°C for 15 hours. The mixture was cooled to 20–25°C and then filtered. The filtrate was concentrated under vacuum at a temperature below 60°C until almost dry to form a residue. The residue was combined with dioxane (675 mL), and the resulting mixture was concentrated under vacuum at a temperature below 60°C until almost dry to form a residue. The residue was diluted with dioxane (1200 mL) to form a solution of compound 141 in dioxane (1295.5 g). The yield of compound 141 was 90.3%, the assay yield was 8.3%, and the methanol residue was 0.13% as measured by GC.

[0243] Various solvents were evaluated for the preparation of compound 141 from compound 140 according to the method described above. The results are summarized in Table 6 of Comparative Example 1, where "Exp." refers to the experiment, "C140" refers to compound 140, "C141" refers to compound 141, "Pd / C" refers to the palladium-carbon catalyst, where 10% Pd / C catalyst is 59% wet, and "Crude" refers to the assay in area % HPLC purity of the mentioned compound in the reaction product mixture before work-up (filtration). Comparative Example 1 Table 6 TIFF2026086461000110.tif33170

[0244] The amount of palladium-carbon catalyst packed was evaluated for the preparation of compound 141 from compound 140 according to the method described above. The results are summarized in Table 7 of Comparative Example 1, where "Exp." refers to the experiment, "C140" refers to compound 140, where the purity of compound 140 is 98.4%, "C141" refers to compound 141, and "crude" refers to the assay by HPLC of the area % of the mentioned compound in the reaction product mixture before work-up (filtration). Comparative Example 1 Table 7 TIFF2026086461000111.tif33170

[0245] The recovery and reuse of the palladium-carbon catalyst was evaluated for the preparation of compound 141 from compound 140 according to the method described above, where the starting amount of compound 140 in each of the following experiments 1 to 4 was 35.9 mmol. The results are summarized in Table 8 of Comparative Example 1 below, where "Exp." refers to the experiment, "C140" refers to compound 140, where the purity of compound 140 was 98.4%, "Pd / C" refers to the palladium-carbon catalyst, "crude" refers to the compound 140 assay in the reaction product mixture and in area % of the mentioned compound before work-up (filtration) by HPLC, and "RT" refers to the reaction time in minutes. Comparative Example 1 Table 8 TIFF2026086461000112.tif48170

[0246] Comparative Example 2 This comparative example presents the previously used method for preparing compound 180. Compound 141, prepared in Comparative Example 1, is used in the following scheme: Compound 180 was formed by reacting it with compound 90 according to TIFF2026086461000113.tif62170.

[0247] A solution of compound 141 in dioxane (1295.5 g, 8.3% assay, 433 mmol, 1 equivalent) was packed into the reaction flask. Compound 90 (119.5 g, 96.7% assay, 433 mmol, 1 equivalent) and K2CO3 (121 g, 99% assay, 17.3 mmol, 2 equivalents) were packed into the reaction flask with vigorous stirring. The reaction flask was removed three times and refilled with N2. Pd2(dba)3 catalyst (9.05 g, 99% assay, 8.66 mmol, 0.02 equivalents) and xanthophosligand (10.2 g, 98% assay, 17.3 mmol, 0.04 equivalents) were packed into the reaction flask with vigorous stirring. The reaction flask was removed three times and refilled with N2. The reaction mixture was heated to 105-115°C and the mixture was stirred under N2 for 24 hours. The mixture was cooled to 65-75°C and filtered. The recovered solid was rinsed with hot dioxane. The filtrate and the dioxane washing solution were combined and concentrated under vacuum at 55-65°C until almost dry to form the residue.

[0248] Methanol (550 mL) was added to the residue, and the mixture was stirred at 0°C for 2 hours. The mixture was filtered to recover crude compound 180 as a solid, and the recovered crude compound 180 was washed with cold methanol. Crude compound 180 was dried under vacuum at 55-65°C for 1 hour. The crude product was weighed and assayed by HPLC to obtain 151 g of compound 180 with a purity of 97.6 area%. The crude product was combined with dioxane (211 g), and the mixture was heated under reflux and stirred under reflux for 15 minutes. i-propanol (500 mL) was added dropwise to the mixture while maintaining reflux. The mixture was cooled to 15-25°C and stirred at that temperature for 1 hour. The mixture was filtered, and the recovered compound 180 solid was rinsed with i-propanol and dried under vacuum at 60-70°C for 5 hours. Compound 180 (188 g) was recovered by HPLC with a purity of 99.1 area%, an assay yield of 97.6%, and an assay yield of 74.1%.

[0249] K3PO4 was evaluated for the preparation of compound 180 from compounds 141 and 90 according to the method described above. The results are presented in Table 10 of Comparative Example 2, where "Exp." refers to the experiment, "C141" refers to compound 141, "C180" refers to compound 180, "C90" refers to compound 90, "Catalyst" refers to the Pd2(dba)3 catalyst, and "Crude" refers to the assay in area % of the mentioned compound in the reaction product mixture after 14.3 minutes of reaction time and before work-up. Comparative Example 2 Table 10 TIFF2026086461000114.tif22170

[0250] The solvents dioxane and toluene were evaluated as solvents for the palladium-catalyzed coupling reaction for the preparation of compound 180 from compounds 141 and 90 according to the method described above, with a reaction time of 15 hours. The results are shown in Table 11 of Comparative Example 2 below, where the amounts of compound 90 and compound 141 were 24.2 mmol for each experiment, and the equivalent amounts of catalyst and ligand are based on the equivalent amounts of compound 141 and compound 90. In this table, "Exp" refers to the experiment number. Comparative Example 2 Table 11 TIFF2026086461000115.tif22170

[0251] The effect of methanol was evaluated in a palladium-catalyzed coupling reaction of compound 180 prepared from compound 141 and compound 90 according to the method described above. The results are shown in Table 12 of Comparative Example 2 below, where the amounts of compound 90 and compound 141 were 34.6 mmol for experiments 1-3 and 2 mmol for experiment 4. In this table, "Exp" refers to the experiment number and "RT" refers to the reaction time. Comparative Example 2 Table 12 TIFF2026086461000116.tif38170

[0252] Compound 180 (5g, 94.3A%) crystallized from a variety of solvent systems in numerous experiments. The results are summarized in Table 13 of Comparative Example 2. Comparative Example 2 Table 13 TIFF2026086461000117.tif33170

[0253] Comparative Example 3 This comparative example presents the previously used method for preparing compound 182. Compound 180 prepared in Comparative Example 2 is prepared using the following scheme: According to TIFF2026086461000118.tif44170, compound 182 was borated.

[0254] Compound 180 (1.2 kg, 2.763 mol, 1 equivalent), bis(pinacolate)diboron (1.052 kg, 4.145 mol, 1.5 equivalents), and KOAc (0.542 kg, 5.526 mol, 2 equivalents) were packed into the inert reactor. An excess amount of THF (15 L) was packed into a holding container, and the surface was sparged with N2 for at least 1 hour to form degassed THF. Degassed THF (9.78 kg, 11 L) was packed into the reactor with vigorous stirring. Pd2(dba)3 (6.52 g, 6.91 mmol, 0.0025 equivalents), XPhos (8.15 g, 16.58 mmol, 0.006 equivalents), and degassed THF (0.445 kg, 0.5 L) were combined with vigorous stirring to form a mixture in the catalyst preparation container. Next, the catalyst mixture was added to the reactor while vigorously stirring. The contents of the reactor were sparged with N2 on the subsurface for a minimum of 1 hour. The contents of the reactor were heated to 60-70°C and aged for a minimum of 12 hours. The contents of the reactor were sampled and evaluated by HPLC for compound 170, and the reaction was continued until the compound 170 content was 0.9 area% by HPLC. The contents of the reactor were cooled to 20-30°C to form a crude reaction mixture containing compound 182. Water (3.6 kg, 3 L / kg) was added to the reactor, and the contents of the reactor were vigorously stirred for a minimum of 10 minutes. The aqueous layer was removed from the reactor. The organic layer remaining in the reactor may optionally be washed with brine. The contents of the reactor were heated to 55-65°C and vacuum distilled to 4 L (3.3 L / kg). THF (7.11 kg, 8 L, 6.7 L / kg) was packed into the reactor, the reactor contents were heated to 55-65°C, and vacuum distilled to 4 L (3.3 L / kg). The THF / distillation process was repeated. The THF / distillation process may be repeated further as needed to reduce the water content in the reactor contents to 3% or less. The reactor contents were filtered through Celite (0.2 kg), followed by rinsing with THF (1.1 kg, 1.2 L, 1 L / kg) to produce a filtrate containing compound 182. The filtrate was heated to 55-65°C and vacuum distilled to a reduced volume of 2-3 L at a temperature of at least 40°C. MTBE (8.9 kg, 10 L / kg) was packed into the reduced volume, and the resulting mixture was vacuum evaporated to a reduced volume of 2-3 L at a temperature of at least 40°C.MTBE (8.9 kg, 10 L / kg) was packed into a reduced volume, and the resulting mixture containing compound 182 was aged at 50°C to 60°C for 2 hours, followed by cooling to 0 to 10°C for a minimum of 2 hours. The mixture was filtered, and compound 182 was recovered as a filter cake. The filter cake was washed twice with MTBE (1.86 kg, 2 L / kg). The isolated compound 182 solid was dried under reduced pressure at 50°C by N2 sweeping for a minimum of 15 hours to yield compound 182 (1.334 kg, 90.3 w / w%, 6.2 wt% THF, 2 wt% MTBE, 1.2% residue on ignition (ROI), 90.6% yield).

[0255] The main impurities are, The impurities were DesBr and dimer impurities, such as TIFF2026086461000119.tif64170.

[0256] The crude reaction mixture contained 0.5%–1% DesBr and 0.1%–0.5% dimer, while the isolated solid contained 0.1%–0.4% DesBr and 0–0.1% dimer.

[0257] The above method for preparing compound 180 from compound 170 was repeated without the MTBE packing and distillation steps. Compound 180 was produced in 92.7 w / w% with 2.4 wt% THF, 6.7 wt% MTBE, 0.6% residue on ignition (ROI), and a yield of 90.1%.

[0258] Comparative Example 4 This comparative example presents a previously used method for preparing compound 190 using a Pd(dppf)Cl2 catalyst system with THF and H2O as solvents.

[0259] Compound 182 is used in the following scheme: Compound 190 was formed by reacting compound 170 with compound 170 according to TIFF2026086461000120.tif47170.

[0260] Compound 170 (30.0 g, 1 equivalent), Compound 182 (50.1 g, 1.1 equivalents), and potassium phosphate (27.8 g, 1.5 equivalents) were loaded into the reactor with THF (196 g) and water (60 g). The mixture was degassed with argon. Separately, Pd(dppf)Cl2 (0.639 g) was suspended in THF (8.9 g), the mixture was degassed with argon, and then this mixture was added to the first reactor. The reactor was heated to 50°C and stirred until less than 0.2 area% of Compound 170 was observed (at least 15 hours).

[0261] The reaction mixture was cooled to 20°C, and approximately 60 mL of 6 wt% aqueous N-acetylcysteine ​​was added. The resulting mixture was stirred for 15 minutes. The layers were separated, and the organic layer was washed with approximately 60 mL of saturated aqueous NaCl. The mixture was then azeotropically dried at atmospheric pressure using THF until the water content was reduced to less than 20% w / w. The resulting mixture was filtered across activated carbon at 40°C, and the filtrate was then transferred to a reactor for solvent exchange to ethanol. The filtrate was distilled to approximately 150 mL at 50°C under low pressure, and ethanol (118 g) was added. Under these conditions, compound 190 crystallized. The suspension was aged for 2 hours, then cooled to 20°C over 3 hours and maintained at 20°C to promote crystal formation. The resulting crystals were filtered using a Nutsche filter, washed three times with EtOH, and then dried under reduced pressure at 50°C until a constant weight was achieved. The isolated yield of 49.7 g of compound 190 was obtained as a bright yellow powder (yield: 86%; assay: 99.8% w / w; purity: 99.2 area%) and evaluated using the HPSC method 1 described above.

[0262] This procedure was repeated three times, and the following results were obtained: TIFF2026086461000121.tif27170

[0263] Comparative Example 5 The methods for preparing compound 190 described in Comparative Example 4 (previous method) and Example 8 (present method) were repeated on a laboratory scale, and then further evaluated multiple times on a pilot scale and production scale. The amounts of dimer, alcohol, and ketone impurities present in the isolated compound 190 were evaluated (after work-up including recrystallization) and are summarized below in Table 14. The laboratory scale batch size was approximately 30 g of compound 170, the pilot scale was approximately 1.2–2.4 kg of compound 170, and the production scale was approximately 175 kg of compound 170. The amount of dimer present in the method (IPC) was also monitored for different batch sizes prepared generally according to the procedure of Example 8 and is summarized in Table 15 as area % via HPLC. Table 14: Summary of impurities detected in isolated compound 190 prepared according to the previously disclosed method, compared to the method disclosed herein, at different batch sizes. TIFF2026086461000122.tif42170 Table 15: Dimer amounts observed in process (IPC) in different batch sizes prepared according to this process (samples taken when the amount of remaining compound 170 was <1%) TIFF2026086461000123.tif22170

[0264] Comparative Example 6 Compound 190 was prepared on a production scale, generally following the procedures of Comparative Example 4 ("Previous Method") and Example 8 ("The Present Method"). Compound 200 was prepared using Compound 190 from each method, and Compound 200 was isolated as generally described in Examples 10 and 11.

[0265] The impurity profiles observed in production-scale batches of compound 200 prepared using compound 190 from the previously described method compared to this method, both before the final isolation step and after the final isolation step (as described in Example 11), are summarized in Table 16 below. The preparation of compound 190 according to this method results in fewer impurities in downstream compound 200 both before and after the final isolation compared to the previously described method for preparing compound 190. Table 16: Summary of impurity profiles in compound 200 before and after final recrystallization from toluene and ethanol when different methods were used to prepare compound 190 (previous method vs. present method). TIFF2026086461000124.tif32170

[0266] Example 12 Continuous processing method for the hydrogenation of compound 140 TIFF2026086461000125.tif36170

[0267] The hydrogenation of compound 140 to produce compound 141 was carried out in an Ehrfeld Miprowa Lab reactor (0224-2-2004-F, Hastelloy C-276) as part of the Ehrfeld Modular MicroReaction System (MMRS). This reactor contains reaction channels with a rectangular cross-section (1.5 mm × 12 mm × 300 mm). Four reactors (4CSM or 8CSM setup) or eight reactors (16CSM setup) were sequentially connected using designated flanges to reduce the number of channels used. A schematic diagram of the setup is shown in Figure 16. The catalytic static mixer (CSM) was manufactured from 316L stainless steel powder by selective laser melting according to the design by CSIRO (Avril, A. et al., Continuous Flow Hydrogenations Using Novel Catalytic Static Mixers inside a Tubular Reactor. React. Chem. Eng. 2017, 2, 180~188; Hornung, CH et al., Use of Catalytic Static Mixers for Continuous Flow Gas-Liquid and Transfer Hydrogenations in Organic Synthesis. Org. Process Res. Dev. 2017, 21, 1311~1319; Hornung, CH et al., Additive Layer Manufacturing of Catalytic Static Mixers for Continuous Flow Reactors. Johnson Matthey Technol. Rev. 2018, 62, 350~360; Lebl, R. et al., Scalable Continuous Flow Hydrogenations Using Pd / Al2O3-Coated Rectangular Cross-Section 3D-Printed Static). Mixers.Catal.Today 2020).

[0268] Pd CSM was produced via electroplating. To produce Pd / Al2O3 CSM, a 3D-printed static mixer was coated with Pd / Al2O3 using slurry coating technology by CSIRO and Precision Plating Australia. The reactor was filled with CSM as detailed below. The reactor volume was calculated as 2.7 mL per CSM when considering the total channel volume, or estimated as 1.7 mL per CSM when considering only the void volume (channel volume minus the volume occupied by the CSM itself).

[0269] 4CSM Setup: The number of channels was limited to four using flanges. The first two channels were filled with standard herringbone-shaped flow baffles (3 layers, 45° angle, strut width 1.0 mm, void 2.0 mm, length 300 mm) from Hastelloy C-276 (6114-1-3244). The last two channels were filled with four 150 mm long catalytic static mixers (CSMs), each (two per channel).

[0270] 8CSM setup: The number of channels was limited to four using flanges. All four channels were filled with eight 150mm long catalytic static mixers (CSMs), each consisting of two CSMs per channel.

[0271] 16CSM Setup: The number of channels was expanded to a total of eight by opening the flanges. All four channels were filled with 16 catalytic static mixers (CSMs), each 150 mm long (two per channel).

[0272] The reaction progress and products were monitored using both online and offline UHPLC analysis.

[0273] Offline UHPLC: The following tests were performed on a Shimadzu Nexera X2 with a Waters XSelect CSH C18 XP column (150 × 3 mm, 2.5 μm particle size) immobilized.

[0274] Mobile phase A: Aqueous ammonium formate (10 mM) adjusted to pH 9.0 with ammonium hydroxide.

[0275] Mobile phase B: Acetonitrile Total flow rate: 1 mL / min with the following gradient program. The TIFF2026086461000126.tif33170 sample was analyzed at a wavelength of 238 nm. The reporting limit (rl) was set to 0.025 area%.

[0276] Online UHPLC analysis was performed using a Shimadzu Nexera X2 system with a fixed Kinetex biphenyl column (100 × 2.1 mm size, 1.7 μm particle size) under the following conditions.

[0277] An isocratic method was used with a fixed concentration of 40% solvent B and a total flow rate of 0.4 mL / min. The samples were analyzed at a wavelength of 238 nm using a relative absorption ratio of 2.27 between compound 141 and compound 140.

[0278] Solvent A: Aqueous H3PO4 / KH2PO4 buffer (10 mM) with 0.33 mM sodium n-octyl sulfonate added.

[0279] Solvent B: H3PO4 / KH2PO4 buffer (10 mM) with 67% MeOH, 33% water, and 0.33 mM sodium n-octylsulfonate added.

[0280] Typical continuous flow procedure: An input solution of compound 140 was prepared in a volumetric measuring flask with the required amount of water (if indicated), and then filled with THF to the mark. This solution was degassed with nitrogen while stirring or by ultrasonic treatment. The following startup procedure was then followed: 1. Flush the reactor with methanol at the desired reaction flow rate. 2. Set the back pressure control factor to the desired reaction pressure. 3. Start flushing the reactor with THF at the desired reaction flow rate. 4. Set the thermostat to the desired reaction temperature and allow it to reach it. 5. Allow the system to balance for at least 30 minutes. 6. Set the H2 flow rate and allow it to build up to the required pressure level. 7. Once the H2 reaches the reaction pressure, temporarily suspend the H2 flow. 8. Briefly switch off the liquid pump to allow the input to switch to the substrate solution (using a valve). 9. Start the pump and H2 flow, as well as UHPLC injection and FT-IR measurement.

[0281] The references to azo, azoxy, and dimer impurities in compound 140 in terms of hydrogenation are shown in the following structure: This refers to TIFF2026086461000127.tif46170.

[0282] Initial evaluation of continuous processing parameters The initial parameters were as follows: 0.2 M compound 140 in THF, no water added, a pressure of 20 bar, a jacket temperature of 80°C, and the use of four catalytic static mixers (CSMs). The Pd-electroplating CSM exhibited only minimal reaction (approximately 6% conversion rate), while the Pd / Al2O3 slurry coating CSM was substantially more effective under the same conditions (achieving 98.632 area % for compound 141). While we do not wish to be bound by theory, this may contribute to the significantly higher effective surface area of ​​the Pd / Al2O3 variant.

[0283] Increasing the flow rate by 1–2 mL / min resulted in incomplete conversion of compound 140, and this conversion appeared to decrease over 30 minutes where these conditions were applied. This effect became increasingly apparent at higher flow rates (3, 4, and 5 mL / min), which appeared to indicate a decrease in conversion rate at a constant gradient. When the flow rate was returned to 1 mL / min, complete substrate conversion was no longer observed (approximately 95% conversion rate). The results are summarized in Table 17. Table 17: Offline UHPLC results from the first flow screen TIFF2026086461000128.tif35170

[0284] This type of performance degradation can be observed before using CSM and may contribute to time-dependent catalytic inhibition by the reactant species (Lebl, R. et al., Scalable Continuous Flow Hydrogenations Using Pd / Al2O3-Coated Rectangular Cross-Section 3D-Printed Static Mixers. Catal. Today 2020). One approach to address this issue is to include a polar solvent and a higher reaction temperature.

[0285] In the second set of experiments, the jacket temperature was increased in 20°C increments from 60°C to 140°C, which appeared to have a significant positive effect on the reaction in terms of conversion and the reduction of its erosion over time. The gradient of conversion loss was substantially shallower at 80°C compared to 60°C and not observed at all at 120°C. To determine whether any changes occurred over this period, the final set of conditions was a replica of the initial conditions. A substantial difference was observed between the two examples (78% conversion rate before vs. 56% conversion rate after), suggesting that some performance loss also occurred at higher temperatures, and that this would have had an effect in longer processing times.

[0286] The approach of adding a protic solvent was also investigated by adding methanol as a cosolvent. The reactivity and impurity profiles were extremely affected by the inclusion of methanol, as shown in Table 17. Table 17 Offline UHPLC results from reactions using methanol as a cosolvent TIFF2026086461000129.tif27170

[0287] It was thought that water (2 equivalents) would be produced as a byproduct of the hydrogenation reaction, and therefore its presence might not be detrimental to the reaction performance. However, CSM uses Al2O3 as a catalyst support material, which raises concerns regarding CSM stability and catalytic degradation under aqueous conditions.

[0288] To test catalytic decomposition, a single CSM was exposed to increasing amounts of water (4–512 equivalents) in a control experiment (512 equivalents, corresponding to a THF:water volume ratio of approximately 2:1.9). Surprisingly, no loss of activity or visible degradation was observed. Inductively coupled plasma mass spectrometry (ICP-MS) of the reactor effluent showed no elevated levels of palladium, indicating that the CSM remained stable even in the presence of such high levels of water. In terms of remarkable stability in the presence of water, the development of reaction conditions continued without concern regarding the effect of water on the stability of the CSM.

[0289] Using a second HPLC pump, 1–4 equivalents of water were introduced along with the reaction flow. The presence of water appeared to significantly improve the reaction rate and also inhibited catalytic deactivation over time. The maximum value investigated, 4 equivalents, resulted in a conversion rate almost twice as high as under conditions without water (38% vs. 73%).

[0290] The reaction concentration was also investigated using a 0.5 M solution of compound 140 diluted with THF, using a second pump. A downward trend was observed over time at the highest concentration (0.5 M), due to catalyst deactivation at higher concentrations. Reaction conditions: pressure = 20 bar, jacket temperature = 80°C, H2 = 4.5 equivalents, total liquid flow rate = 2.0 mL / min. The results are summarized in Table 18 below. For the remainder of the experiment, 0.4 M compound 140 was used. Table 18: Offline UHPLC results from compound 140 concentration screens TIFF2026086461000130.tif35170

[0291] Using this reactor setup, a range of reaction parameters rapidly shielded across multiple experimental runs. Temperature, water content, and pressure were all varied. From these experiments (25 in total, including two repeats), it was determined that temperature, followed by H2O packing, was by far the most important parameter. Conversely, reaction temperature had a relatively small effect. Counter-plots representing predictions of conversion rates under different conditions were plotted from this data. A clear trend was observed where higher temperatures and higher H2O packing rates improved the conversion rate.

[0292] Separately, experiments determined that, as long as sufficient H2 was supplied, the H2 flow rate had no effect on the reaction performance. Residence time was not affected by excess gas, which may be due to the layered fluid regime within the reactor.

[0293] Further evaluation at 8CSM Further experiments were conducted in 8CSM to evaluate the potential throughput that should have been achieved in this reaction system. The key to this evaluation was the amount of impurities (total azo + azoxy, and dimers) observed with increasing flow rates. Previous experiments in four CSMs determined that higher flow rates resulted in increased levels of these impurities, but that the addition of water to the input solution (due to shorter residence times) could also reduce them. A range of conditions were investigated, with varying flow rates and water content (Table 19). The jacket temperature was set to 120°C, the pressure to 20 bar, and the H2 equivalent to 3.3 equivalents (10% excess). Table 19: Offline UHPLC analysis of 8CSM processes with varying flow rates and water content TIFF2026086461000131.tif51170r.l = Reporting limit, 0.025 area%

[0294] All results (with the exception of entry 7) showed levels of the desired product >98.5 area % and starting compound 141 <0.1 area % and demonstrated a clear trend observed in the amount of impurities measured. At low flow rates (entries 1-3), all results showed impurity levels <0.1 area %, while at increased flow rates of 6 mL / min and 8 mL / min (entries 7-9) (entries 4-6), impurity levels were <0.1 area % only when 8 equivalents of H2O were present in the feed solution. These experiments demonstrated that a flow rate of 8 mL / min (corresponding to a throughput of 192 mmol / hour) may be possible with an acceptable purity profile.

[0295] Next, the longer-term stability of the reactor system was investigated by conducting a continuous flow reaction over two working days, for 10 hours followed by 6 hours, with the solvent washed between the two periods. The reactor was then stored overnight in MeOH under ambient conditions between the two runs. This allowed for evaluation of the reactor's behavior, the impurity profile over time, and the detection of any potential catalyst leaching or deactivation. The experimental conditions chosen for this demonstration were: pressure = 20 bar, jacket temperature = 120°C, H2 = 3.3 equivalents, liquid flow rate = 8 mL / min, 6 equivalents of H2O, and compound 140 concentration = 0.4 M. During the course of this experiment, 16 fractions were collected for detailed offline analysis (one per hour). Offline analysis of the fractionated reactor output showed that the amount of compound 141 was 99.2 area % in the first fraction measured, and that there was no decrease over time; in fact, a gradual increase was observed (Figure 14A). The starting compound 140 and the (combined) azo + azoxy and dimer impurities were present in small amounts in the first fraction and decreased over time (Figure 14B). None of the recovered fractions yielded >0.1 area % of combined azo + azoxy or dimer impurities. Over this period, 850 g (3.07 mol) of the starting material was processed, and there was no loss of catalytic activity over time. Based on a total Pd packing of 96 mg (0.9 mmol, 12 mg per CSM), this represents an effective catalyst packing of just 0.011 wt%, which is expected to decrease with longer processing times. Catalyst leaching is a concern when considering the long-term stability of such a process. Therefore, ICP-MS measurements were performed on six of the recovered fractions and compared with the measurements of the input reaction mixture blank and the solvent blank.No detectable levels of A1 were observed in any of the samples, suggesting that there was no degradation of the alumina support over time, which is consistent with previous work using this type of CMA (Lebl, R. et al., Scalable Continuous Flow Hydrogenations Using Pd / Al2O3-Coated Rectangular Cross-Section 3D-Printed Static Mixers. Catal. Today 2020).

[0296] Evaluated maximum throughput processing (16CSM) The increase in possible throughput from 4CSM to 8CSM was higher than the expected linear scale-up (48 mmol / hour to 192 mmol / hour, a fourfold increase). While we do not wish to be bound by theory, this may be due to improved mixing achieved at higher flow rates, but could also be influenced by the slight temperature increase due to the exothermic nature of the reaction. To assess the maximum achievable productivity in the reactor setup used, additional experiments were conducted using the full capacity of the 16CSM with smaller modifications, including a pre-reactor heat exchanger and four additional internal temperature sensors inside the reactor itself.

[0297] Initial screening experiments investigated reaction performance at 16 mL / min (due to linear scalability from eight CSM setups), as well as at 20, 24, 27, and 30 mL / min. Surprisingly, even at 30 mL / min, a good impurity profile was observed, with (combined) azo+azoxy at a level of 0.082 area % and exceptionally low levels (0.039 area %) of dimer impurities. These conditions were run for 1 hour to ensure stability, and large volumes of material were processed. Throughput achieved a significant improvement compared to the expected value (Figure 15). This coincides with the increasing space-time yield with scale-up, likely due to improved mixing with higher flow rates. The maximum space-time yield achieved here was 26.2 mol / L / hour (27.2 mL void volume) for the small reactor channel used.

[0298] Comparative Example 7 Preparation of compound 141 via two batch methods compared to a continuous flow processing method. Both the continuous flow processing method and the batch process described in Example 12, which used a THF / water solvent system (approximately 5% vol of water), were compared with the previously published batch method using a toluene / methanol solvent system (Zhang, H. et al., Development of an Efficient Manufacturing Process for Reversible Bruton's Tyrosine Kinase Inhibitor GDC-0853. Org. Process Res. Dev. 2018, 22, 978-990).

[0299] Batch procedure for PhMe / MeOH: Compound 140 (4.8 g, 17.2 mmol) was dissolved in a mixture of PhMe and MeOH (1:1 v / v, 27 mL) in a glass autoclave vessel. Then, Pd / C 5% (wet, 56.8% H2O, 222 mg), as well as acetic acid (492 μL) and water (60 μL) were added. The reactor was closed and sealed, purged three times with H2 (at 1 bar), and then pressurized to 20 bar. The reactor was then heated to 50°C with slow stirring. The temperature was then adjusted by changing the stirring speed and maintained below 55°C. The reaction mixture was stirred for 3 hours and raised to 60°C for the last 1.5 hours. The reaction mixture was then cooled to 35°C, then reduced in pressure, and sampled for UHPLC analysis using the UHPLC procedure described in Example 7 above.

[0300] Batch procedure in THF / H2O: A glass autoclave vessel was filled with 5% Pd / C (wet, 56.8% H2O, 154 mg) and 30 mL of 0.4 M compound 140 solution in THF (total 12 mmol), and 2.4 M added water. The reactor was closed and sealed, purged three times with H2 (at 1 bar), and then pressurized to 20 bar. The reactor was then heated to 50°C with slow stirring. Exothermic reaction was observed at the start of the reaction, and the reaction temperature reached 61°C. The temperature was then controlled by reducing the stirring rate and maintained below 60°C. The reaction mixture was stirred for 3 hours, and the temperature was raised to 60°C for the last 1.5 hours. The reaction mixture was then cooled to 35°C, then reduced in pressure, and sampled for UHPLC analysis using the UHPLC procedure described in Example 7 above.

[0301] Continuous flow procedure: The results of the 8CSM, 16-hour (10 hours + 6 hours) run described in Example 12 above were used. The jacket temperature was set to 120°C, the pressure to 20 bar, the H2 equivalent to 3.3 equivalents (10% excess), 0.4 M compound 140 was used, the flow rate was 8 mL / min, and 6 equivalents of H2O were used. Table 20: Offline UHPLC results from batch comparisons compared with CSM flow procedures TIFF2026086461000132.tif27170r.l. = Reporting limit, 0.025 area%

[0302] Example 13 Additional continuous processing methods Additional continuous processing experiments were conducted to investigate the effect of using a metal catalyst on a spherical support in the preparation of aminopyridine 141. A schematic diagram of the experimental setup used is shown in Figure 23. A fixed-bed catalyst was placed in a tubular reactor and continuously supplied with hydrogen gas (at a rate controlled by a mass flow controller) and a solution of nitropyridine 140 (at a rate controlled by an HPLC pump). After passing through the fixed-bed catalyst, the solution resulting from the hydrogenation reaction (containing the product aminopyridine 141) was sampled via a manual sampling unit, passed through a pressure control vessel and back pressure regulator, and then recovered during gas / liquid separation.

[0303] The initial reaction conditions investigated used a 3% Pd / Al2O3 catalyst (Al2O3 spheres supplied by Johnson Matthey, code 110002). Using a small reactor (0.6 cm inner diameter, 15 cm length), the reactor temperature was first determined by supplying a 0.36 M solution of nitropyridine 140 in THF at a flow rate of 1 mL / min. The H2 supply was maintained at 30 mL / min, and the system pressure was maintained at 20 bar. The conversion rate of nitropyridine 140 to aminopyridine 141 improved when the temperature was increased above 60°C. Simultaneously, the amounts of known undesirable impurities (azo, azoxy, and dimer) were reduced to less than 0.20 area%, each determined by HPLC. The sum of undefined impurities also decreased with increasing temperature, as summarized in Table 21. mantel The optimal conditions were reached at 100℃ (Entry 3). mantel Further increases in temperature to 120°C did not yield any benefits, because it generated a larger amount of unknown impurities (Entry 4). Table 21: HPLC results of nitro reduction of compound 140 obtained with a 3% Pd / Al2O3 catalyst at different reactor temperatures. TIFF2026086461000133.tif31170

[0304] After setting the reactor temperature to 100°C, the system pressure was briefly measured, but no significant difference was observed in the range of 10–30 bar, so it was decided to maintain this value at 20 bar for further investigation. Regarding H2 supply, it was observed that a slight excess of H2 (i.e., 3 equivalents relative to nitropyridine 140) was necessary for both chemical aspects of the reaction, but a large excess provided no advantage whatsoever. In contrast to what was observed in the case of the catalytic static mixer (see Example 12), the use of water as an additive provided no particular advantage (Table 22), and it was decided to continue the experiment in the absence of this additive. Table 22: Table 21, Entry 2 (T mantel Results obtained under reported conditions (=80°C) with and without water as an additive. TIFF2026086461000134.tif21170

[0305] After establishing reaction conditions for the reduction of nitropyridine 140 (see Table 21, Entry 3), different catalyst types (metal support = alumina spheres and carbon granules) were tested. Alumina-supported Pd and Pt particles with a 3% metal content performed very similarly in terms of product purity, reaching 98.90 area% and 98.70 area% of compound 141, respectively. Next, activated carbon granules with a 5% metal packing were tested under the same conditions, yielding a product with purity >99.0 area%. These carbon-based catalysts further demonstrated that platinum performed better than palladium. The best result, with a product purity of 99.61 area% at complete conversion, was obtained with the 5% Pt / C catalyst NOBLYST® P8109 supplied by Evonik (Figure 20). The catalyst packing amounts shown in this Example 13 are dry wt%.

[0306] Two 5% Pt / C catalysts (one being type 110001 by Johnson Mattehy and the other being type Noblyst® P8109 by Evonik) were identified as the most promising, and these catalysts were then evaluated over time in the formation of compound 141. Figure 21 summarizes the observed results, which show the superior performance of NOBLYST® P8109 over a long period, while JM110001 appeared to exhibit decreased performance after approximately 2 hours under the selected reaction conditions for the reaction under investigation.

[0307] Finally, incorporating the above assessment, the reduction of nitropyridine 140 scaled up the hydrogenation process, increasing reactor volume and throughput, as described below.

[0308] Liquid feed: A 0.36 M solution of nitropyridine 140 in degassed THF was prepared as the liquid feed for the continuous hydrogenation system.

[0309] A catalyst bed tubular reactor (1.2 cm inner diameter, 15 cm length) was packed with 5% Pt / C Evonik NOBLYST® P8109 catalyst (4.9 g).

[0310] Before starting the reaction, the reactor was flushed with THF at a rate of 5 mL / min for 20 minutes. During this time, the reactor was brought to the desired temperature (T mantel The system was heated to 100°C, and hydrogen was supplied to the reactor at a rate of 150 mL / min using a mass flow controller, with the system pressure set to 20 bar. Once the system was preconditioned, the liquid feed was switched from THF to the nitropyridine 140 solution prepared above. The liquid feed rate was maintained at 10 mL / min, and the H2 feed rate was increased to 300 mL / min, and the reaction conditions were set to T mantelThe system was maintained at 100°C and 20 bar, during which the output reaction mixture was sampled at regular intervals (every 20 minutes) and collected over time. Hydrogenation was continued for a total of 6 hours. After this time, the system was cleansed by switching the liquid feed back to THF, then cooled, and deinerted again by switching the gas feed back to argon. The following day, the entire procedure for initiating the reaction was repeated, and the hydrogenation of nitripyridine 140 was restarted under the same conditions as described above and maintained for 1 hour. The goal was to demonstrate that the catalyst bed could be reused with comparable results. In total, continuous hydrogenation was carried out using the same catalyst bed for a total of 7 hours, reducing nitripyridine 140 at a rate of 60 g / hour.

[0311] The reaction results and process stability over time were monitored by HPLC analysis of sampled reaction solutions, paying close attention to the purity of the desired product and the formation of undesirable impurities. Figure 22 summarizes the HPLC purity of aminopyridine 141 sampled from the solution generated over time from the fixed bed.

[0312] Two portions of the solution obtained from the hydrogenation process were collected separately to evaluate the overall purity and yield of the material recovered at two different stages of the overall process. Portion A consists of 50 g of solution collected during the first 195 minutes of the flow process. Portion B consists of 100 g of solution collected between 195 and 380 minutes of the reaction time. The products present in each portion were isolated by evaporating the solvent under reduced pressure until a constant weight was achieved, yielding aminopyridine 141 in yields of 85.6% and 89.6%, respectively. The purity of the two isolated materials is reported in Table 23. Table 23: Purity of isolated substances from 140 fluid hydrogenation operations using a fixed catalyst bed. TIFF2026086461000135.tif21170

[0313] XRF analysis of materials isolated from parts A and B detected no traces (rl=1 ppm) of Pt or any other metal, indicating that no metal leaching into the product occurred during this process.

[0314] Example 14 Preparation of various crystalline solvates of compound 200 Ethanol semisolvate: 100.9 mg of amorphous compound 200 was suspended in 1.2 mL of ethanol and aged at 0°C for 5 days. The white suspension was isolated at 0°C by centrifugation filtration. The wet filter cake was dried at room temperature in open storage. The sample was further dried at 50°C under reduced pressure for 3 days and then characterized by XRPD. The XRPD spectrum is shown in Figure 17, and the peak list is shown in Table X.

[0315] Toluene solvate: 203.2 mg of amorphous compound 200 was exposed to toluene vapor at room temperature for 7 days. The resulting wet powder was gently dried under toluene vapor at 100 mg / room temperature for 2 days and then characterized by XRPD. The XRPD spectrum is shown in Figure 18, and the peak list is shown in Table X.

[0316] Ethanol solvate: 98.1 mg of amorphous compound was dissolved in 10 mL of ethanol at 80°C. The solution was cooled and filtered by polishing to obtain a particle-free solution. The clarified solution was reheated to 80°C and then rapidly cooled with stirring. The resulting suspension was vigorously stirred at -10°C for 2 days. The crystals were isolated by filtration and characterized by XRPD. The XRPD spectrum is shown in Figure 19, and the peak list is shown in Table X.

[0317] XRPD Characterization: X-ray diffraction patterns are analyzed using a Stoe Stadi P diffractometer (Cu K α1The data was recorded under ambient conditions in transmission geometry using an irradiation [1.5406 Å], a primary Ge monochromator, a Mythen 1K silicon strap detector, an angular range of 3° to 42°² theta, a step width of 0.02°² theta, and a measurement time of 20 seconds per step. Samples were prepared and analyzed without further processing of the material (e.g., polishing or sieving). X-ray diffraction data were measured and evaluated using WinXPOW software (STOE & Cie GmbH, Darmstadt, Germany). The positional error for each individual peak is ±0.2°² theta.

[0318] The aforementioned invention is described in some detail using examples and embodiments for the purpose of clarity of understanding, but the description and embodiments should not be construed as limiting the scope of the invention. Therefore, all suitable modifications and equivalents can be considered to fall within the scope of the invention as defined by the subsequent claims. All patent and scientific literature disclosures cited herein are expressly incorporated by reference in their entirety.

Claims

1. A method for preparing compound 190, or its stereoisomers, geometric isomers, tautomers, or salts, a) To form a reaction mixture comprising compound 170, compound 181, a palladium catalyst, and a solvent system containing a base, wherein the equivalent ratio of the palladium catalyst to compound 170 is approximately 0.001:1 to less than 0.005:1, (b) The following scheme: The reaction mixture is reacted accordingly to form a reaction product mixture containing compound 190. Includes, Here, the Pd catalyst comprises a palladium(II) species containing a phosphine ligand and at least one palladium-carbon bond. Here, (i) A fragment that forms a palladium-carbon bond is given by formula: (In the formula, R ６ ~R １０ Each of these is independently H, and C may be substituted. １～６ Alkyl, optionally substituted C ６ Selected from the group consisting of aryls and optionally substituted heteroaryls, R ６ and R １０ (These may optionally combine to form a fused dicyclic ring containing an aromatic ring.) It is an allyl derivative of, A method wherein the yield of compound 190, or its stereoisomer, geometric isomer, tautomer, or salt, is at least 50% based on compound 170.

2. (a) The content of dimer impurities is less than 0.1 area percent based on compound 190, or its stereoisomers, geometric isomers, tautomers, or salts, where the dimer impurity is structural It is, (b) The combined content of alcohol impurities and ketone impurities is less than 0.25 area percent based on compound 190, or its stereoisomers, geometric isomers, tautomers, or salts, where the alcohol impurities and ketone impurities are structural The method according to claim 1.

3. The reaction further comprises reacting compound 190, or its stereoisomers, geometric isomers, tautomers, or salts, to form compound 200, or its stereoisomers, geometric isomers, tautomers, or salts, wherein the reaction is (a) The following scheme Accordingly, compound 190, or its stereoisomers, geometric isomers, tautomers, or salts, is brought into contact with a reducing agent and a base in the presence of a solvent to form compound 200, or its stereoisomers, geometric isomers, tautomers, or salts. (b) Isolating compound 200, or its stereoisomers, geometric isomers, tautomers, or salts. Includes, The method according to claim 1 or 2, wherein the yield of compound 200 based on compound 170, or its stereoisomer, geometric isomer, tautomer, or salt, is at least 60%, at least 70%, at least 80%, or at least 85%, and the purity of compound 200, or its stereoisomer, geometric isomer, tautomer, or salt, is at least 99 area%, or at least 99.5 area%,

4. A method for reducing by-product formation in the Suzuki coupling reaction, (a) To form a reaction mixture comprising compound 170, compound 181, a palladium catalyst, a solvent system, and a base, wherein the equivalent ratio of the palladium catalyst to compound 170 is less than about 0.001:1 to 0.005:

1. (b) The following scheme: Accordingly, the reaction mixture is reacted to form a reaction product mixture containing compound 190, or its stereoisomers, geometric isomers, tautomers, or salts. Includes, Here, the Pd catalyst comprises a palladium(II) species containing a phosphine ligand and at least one palladium-carbon bond. Here, (i) A fragment that forms a palladium-carbon bond is given by formula: (wherein each of R ６ to R １０ is independently selected from the group consisting of H, optionally substituted C １～６ alkyl, optionally substituted C ６ aryl, and optionally substituted heteroaryl, and R ６ and R １０ may optionally combine together to form a fused bicyclic ring containing an aromatic ring) It is an allyl derivative of, Here, (a) The content of dimer impurities is less than 0.1 area percent based on compound 190, or its stereoisomers, geometric isomers, tautomers, or salts, where the dimer impurity is structural It is, (b) The combined content of alcohol impurities and ketone impurities is less than 0.25 area percent based on compound 190, or its stereoisomers, geometric isomers, tautomers, or salts, where the alcohol impurities and ketone impurities are structural A method that is of the sort.

5. A method for improving the yield in the Suzuki coupling reaction, (a) To form a reaction mixture comprising compound 170, compound 181, a palladium catalyst, a solvent system, and a base, wherein the equivalent ratio of the palladium catalyst to compound 170 is less than about 0.001:1 to 0.005:

1. (b) The following scheme: Accordingly, the reaction mixture is reacted to form a reaction product mixture containing compound 190, or its stereoisomers, geometric isomers, tautomers, or salts. Includes, Here, the Pd catalyst comprises a palladium(II) species containing a phosphine ligand and at least one palladium-carbon bond. Here, (i) A fragment that forms a palladium-carbon bond is given by formula: (In the formula, R ６ ~R １０ Each of these is independently H, and C may be substituted. １～６ Alkyl, optionally substituted C ６ Selected from the group consisting of aryls and optionally substituted heteroaryls, R ６ and R １０ (These may optionally combine to form a fused dicyclic ring containing an aromatic ring.) It is an allyl derivative of, A method wherein the yield of compound 190 based on compound 170, or its stereoisomer, geometric isomer, tautomer, or salt, is at least 80%, or at least 85%.

6. The fragment that forms the palladium-carbon bond is given by formula: (In the formula, R １１ C １～１０ (It is alkyl.) The method according to any one of claims 1 to 5, wherein the indenyl is...

7. Allyl derivatives (a) R ６ ~R １０ Derivatives in which each of the following is H, (b) R ６ ga-CH ３ And R ７ ~R １０ Derivatives in which each of the following is H, (c) R ７ ga-CH ３ And R ６ and R ８ ~R １０ Derivatives in which each of the following is H, (d) R ８ ga-CH ３ And R ６ , R ７ , R ９ and R １０ Derivatives in which each of the following is H, (e) R ６ is -phenyl, R ７ ~R １０ Derivatives in which each of the following is H, (f) R ７ is -phenyl, R ６ and R ８ ~R １０ Derivatives in which each of the following is H, (g) Structure: derivatives The method according to any one of claims 1 to 6, selected from the following.

8. The phosphine ligand has the formula: (In the formula, R １ and R ２ Each of these can be independently substituted. １～１２ Alkyl, optionally substituted C ３ ~C ２０ Cycloalkyl and optionally substituted C ５ or C ６ Selected from the alphabet, R ３ ~R ５ These are H and C, which may be substituted, independently of each other. １～６ Alkyl, formula -O-C １～６ Alkyl alkoxides, and formula -N(R １２ ) (Caution １３ ) (wherein, R １２ and R １３ H and C are independent of each other. １～６ (Selected from alkyl groups) (Selected from amine groups) The method described in any one of items 1 to 7.

9. The phosphine ligand has the following structure The method according to any one of claims 1 to 8, wherein the SPhos is...

10. Pd catalyst, (a) Cationic palladium species containing inorganic or organic counterions X, and (b) Neutral palladium species containing coordinated inorganic or organic ligand X The method according to any one of claims 1 to 9, selected from the following.

11. The method according to claim 10, wherein X is selected from halogens, carboxylates, sulfonates, and inorganic anions.

12. (a) Carboxylate is CH ３ C(O)O － and tBuC(O)O － Selected from, (b) Sulfonate, CF ３ SO ３ － Selected from tosylate, vesylate and nosylate, (c) Inorganic anions, PF ６ － BF ４ － , B (C ６ F ５ ) ４ － NO ３ － and SO ４ ２－ The method according to claim 11, selected from the following.

13. X is CF ３ SO ３ － The method according to claim 11 or 12.

14. Palladium catalyst, CF ３ SO ３ － It contains an organic counterion, where the phosphine ligand is SPhos, and where R ６ ~R １０ The method according to any one of claims 1 to 13, wherein each of is H.

15. The method according to any one of claims 1 to 14, wherein the solvent system predominantly comprises an aprotic low molecular weight ester solvent and water, the volume ratio of the aprotic low molecular weight ester solvent to water is about 1:0.1 to about 1:1, and the reaction mixture is heated to about 60°C to about 80°C.

16. The method according to any one of claims 1 to 15, wherein the equivalent ratio of compound 181 to compound 170 is greater than 1:1, and the equivalent ratio of the palladium catalyst to compound 170 is about 0.001:1 to about 0.003:1, or about 0.002:

1.

17. (a) The catalyst is [(SPhos)Pd(allyl)]CF ３ SO ３ And, (b) The solvent system predominantly consists of ethyl acetate and water, where the volume ratio of ethyl acetate to water is approximately 1:0.1 to approximately 1:

1. (c) Boronate, structure: It is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The method according to any one of claims 1 to 16.

18. A method for preparing compound 180, its stereoisomers, its geometric isomers, its tautomers, and salts thereof, (a) Forming a first reaction mixture comprising compound 140, a catalyst, a solvent, and hydrogen, (b) The following scheme In accordance with this, the first reaction mixture is reacted to form a first reaction product mixture containing compound 141, (c) Forming a second reaction mixture comprising compound 141, compound 90, palladium catalyst, catalyst ligand, base and solvent, (d) The following scheme Accordingly, the second reaction mixture is reacted to form a second reaction product mixture containing compound 180. Includes, Here, the first reaction mixture catalyst is selected from the group consisting of Ra-Ni, Ra-Co, Pt / V@C, Co@Chitin, Ni-phen@SiO ２ and Ni-phen@TiO ２ and is selected from the group consisting of Here, the yield of compound 141 based on compound 140 is at least 90%, or at least 95%. A method wherein the yield of compound 180 based on compound 141 is at least 60%, at least 70%, at least 80%, and the purity of compound 180 is at least 95%, at least 98%, or at least 99%.

19. A method for preparing compound 180, its stereoisomers, its geometric isomers, its tautomers, and salts thereof, (a) A process comprising forming a first reaction mixture comprising compound 140 and a solvent comprising an organic solvent, and contacting the reaction mixture with a transition metal catalyst in the presence of hydrogen to form a first product mixture comprising compound 141, wherein the process is a continuous flow process, (b) A process for forming a second reaction mixture comprising compound 141, compound 90, a palladium catalyst, a catalytic ligand, a base, and a solvent, (c) The following schemes in which LG is a leaving group A process to react the second reaction mixture according to the method to form a second reaction product mixture containing compound 180, (d) Compound 180, in the following scheme The process involves reacting a boronating agent with a solvent in the presence of a solvent to form compound 181. Includes, Here, the yield of compound 141 based on compound 140 is at least 90%, or at least 95%. A method wherein the yield of compound 180 based on compound 141 is at least 60%, at least 70%, at least 80%, and the purity of compound 180 is at least 95%, at least 98%, or at least 99%.

20. The method according to claim 18 or 19, wherein compound 141 is not isolated from the first reaction product mixture before the formation of the second reaction product mixture.

21. The method according to any one of claims 18 to 20, wherein the first reaction mixture solvent and the second reaction mixture solvent each predominantly comprise a polar aprotic solvent.

22. The method according to claim 21, wherein the first reaction mixture solvent predominantly comprises tetrahydrofuran.

23. Palladium catalyst, Pd(OAc) ２ The method according to any one of claims 18 to 23, wherein the catalytic ligand is xanthophos or DPEPhos.

24. Palladium catalyst, Pd(OAc) ２ The catalytic ligand is xanthophos, and the base is K ２ CO ３ It is; or, the palladium catalyst is Pd(OAc) ２ The method according to any one of claims 18 to 23, wherein the catalytic ligand is DPEPhos and the base is NaOMe.

25. The method according to any one of claims 18 to 23, wherein the first reaction mixture catalyst is Pt / V@C.

26. The first reaction mixture catalyst is Pd / Al ２ O ３ , Pt / Al ２ O ３ , Pd / C or Pt / C, the method according to any one of claims 19 to 23.

27. At least 98.5 w / w% of compound 190 or a composition comprising its stereoisomers, geometric isomers, tautomers, or salts, Here, (a) The content of dimer impurities is less than 0.15 area% based on compound 190, where the dimer impurities are structural It is, (b) The combined content of alcohol impurities and ketone impurities is less than 0.35 area percent based on compound 190, where the alcohol impurities and ketone impurities are structural A composition that is of the same nature.

28. The composition according to claim 27, wherein the content of dimer impurities is less than 0.10 area percent based on compound 190.

29. The composition according to claim 28, wherein the content of dimer impurities is less than 0.05 area percent based on compound 190.

30. The composition according to any one of claims 27 to 29, wherein the combined content of alcohol impurities and ketone impurities is less than 0.30 area percent based on compound 190.

31. The composition according to claim 30, wherein the combined content of alcohol impurities and ketone impurities is less than 0.25 area percent based on compound 190.

32. The composition according to claim 31, wherein the combined content of alcohol impurities and ketone impurities is less than 0.20 area percent based on compound 190.

33. The composition according to any one of claims 27 to 32, comprising at least 99.0 w / w% of compound 190, or its stereoisomers, geometric isomers, tautomers, or salts.

34. The composition according to claim 33, comprising at least 99.5 w / w% of compound 190, or its stereoisomers, geometric isomers, tautomers, or salts.

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