Methods for Preparing BTK Inhibitors

Abstract

Methods are provided for preparing the Bruton's tyrosine kinase ("BTK") inhibitor compound 2-{3'-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-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]pyrazin-1-one.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to European Application No. 21181156.7, filed June 23, 2021, and European Application No. 21172180.8, filed May 5, 2021, the contents of which are incorporated by reference in their entirety.

[0002] The present disclosure generally relates to methods for preparing the Bruton's tyrosine kinase ("BTK") inhibitor compound 2-{3'-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-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]pyrazin-1-one. The disclosure further generally relates to methods for preparing intermediates in the synthesis of the aforementioned BTK inhibitor compounds, such as tricyclic lactam compounds. [Background technology]

[0003] The following structure: TIFF0007809139000001.tif47170 BTK inhibitor compound 2-{3'-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-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]pyrazin-1-one is known from U.S. publication U.S. Patent No. 2013 / 0116235A1 as a BTK inhibitor useful for treating diseases or disorders such as those selected from immune disorders, cancer, cardiovascular disease, viral infection, inflammation, metabolic / endocrine dysfunction, and neurological disorders. U.S. Patent No. 2013 / 0116235A1 is incorporated herein by reference in its entirety. 2-{3'-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-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]pyrazin-1-one is a BTK inhibitor useful for treating diseases or disorders such as those selected from immune disorders, cancer, cardiovascular disease, viral infection, inflammation, metabolic / endocrine dysfunction, and neurological disorders. Alternative names for 2-{3'-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-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]pyrazin-1-one may be used, but the chemical structure shown is control. One such alternative name is (S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridin]-2'yl)-7,7-dimethyl-2,3,4,6,7,8-hexahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one. Publication 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-yl-piperazin-1-yl)-pyridin-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]pyrazin-1-one, however, the method required chromatographic purification and achieved low yields.

[0004] Useful methods for preparing 2-{3'-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-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]pyrazin-1-one are further known from U.S. Patent No. 2018 / 0230155 and 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 the Zhang publication are incorporated herein by reference in their entireties.

[0005] There is a need for improved methods of preparing 2-{3'-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-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]pyrazin-1-one and its intermediate compounds. For example, there is a need for improved methods having higher yields, less by-products, or a combination thereof. Summary of the Invention

[0006] One aspect of the present disclosure is directed to a method for preparing compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof. The method includes forming a reaction mixture comprising compound 170, compound 181, a palladium catalyst, a solvent system comprising water, and a base, wherein the equivalent ratio of the palladium catalyst to compound 170 is about 0.001:1 to less than 0.005:1. The reaction mixture is reacted according to the following scheme: TIFF0007809139000002.tif52170 to form a reaction product mixture containing compound 190 (or a stereoisomer, geometric isomer, tautomer, or salt thereof).

[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 has the formula: TIFF0007809139000003.tif19170 (in the formula, R 6 ~R 10 each independently represents H, optionally substituted C 1~6 is selected from the group consisting of alkyl, optionally substituted C aryl, and optionally substituted heteroaryl; R 6 and R 10 may optionally be joined together to form a fused bicyclic ring containing an aromatic ring. In some embodiments, the yield of compound 190 (or a stereoisomer, geometric isomer, tautomer, or salt thereof) is at least 50% based on compound 170.

[0008] One aspect of the present disclosure is directed to a method for reducing by-product formation in a Suzuki coupling reaction, the method comprising forming a reaction mixture comprising Compound 170, Compound 181, a palladium catalyst, a solvent system comprising water, and a base, wherein the equivalent ratio of the palladium catalyst to Compound 170 is about 0.001:1 to less than 0.005:1; and reacting the reaction mixture with the following scheme: and reacting the reaction mixture according to TIFF0007809139000004.tif46170 to form a reaction product mixture comprising compound 190 (or a stereoisomer, geometric isomer, tautomer, or salt thereof).

[0009] 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 has the formula: TIFF0007809139000005.tif19170 (in the formula, R 6 ~R 10 each independently represents H, optionally substituted C 1~6 is selected from the group consisting of alkyl, optionally substituted C aryl, and optionally substituted heteroaryl; R 6 and R 10 may optionally be joined together to form a fused bicyclic ring containing an aromatic ring. In some embodiments, the content of a dimeric impurity in the resulting reaction product mixture is less than 0.3 area % based on compound 190 (or a stereoisomer, geometric isomer, tautomer, or salt thereof), wherein the dimeric impurity is an allyl derivative of the structure: It is TIFF0007809139000006.tif66170.

[0010] In some embodiments, the resulting reaction product mixture contains less than 0.25 area % of ketone and alcohol impurities based on Compound 190 (or a stereoisomer, geometric isomer, tautomer, or salt thereof), where the ketone and alcohol impurities have the structure: It is TIFF0007809139000007.tif80170.

[0011] One aspect of the present disclosure is directed to a method for improving yield in a Suzuki coupling reaction, comprising forming a reaction mixture comprising Compound 170, Compound 181, a palladium catalyst, a solvent system comprising water, and a base, wherein the equivalent ratio of the palladium catalyst to Compound 170 is about 0.001:1 to less than 0.005:1; and reacting the resulting mixture with the following scheme: forming a reaction product mixture comprising compound 190 (or a stereoisomer, geometric isomer, tautomer, or salt thereof) according to TIFF0007809139000008.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 has the formula: TIFF0007809139000009.tif19170 (in the formula, R 6 ~R 10 each independently represents H, optionally substituted C 1~6 is selected from the group consisting of alkyl, optionally substituted C aryl, and optionally substituted heteroaryl; R 6 and R 10 may optionally be joined together to form a fused bicyclic ring containing an aromatic ring. In some embodiments, the yield of compound 190 (or a stereoisomer, geometric isomer, tautomer, or salt thereof) based on compound 170 is at least 80%, or at least 85%.

[0013] One aspect of the present disclosure is directed to a method for preparing compound 180, its stereoisomers, its geometric isomers, its tautomers, or salts thereof, which method may be carried out according to the following scheme: forming a first reaction mixture comprising compound 140, a platinum / vanadium carbon catalyst, a solvent, and hydrogen according to TIFF0007809139000010.tif36170; and reacting the first reaction mixture to form a first reaction product mixture comprising compound 141.

[0014] The method includes forming a second reaction mixture containing compound 141, compound 90, a palladium catalyst, a catalytic ligand, a base, and a solvent, and reacting the compound 141 with the compound 90 according to the following scheme: and reacting the second reaction mixture according to TIFF0007809139000011.tif47170 to form a second reaction product mixture comprising compound 180.

[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% Compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, TIFF0007809139000012.tif55170 where, (a) containing less than 0.15 area % of a dimeric impurity based on Compound 190 (or a stereoisomer, geometric isomer, tautomer, or salt thereof), wherein the dimeric impurity has the structure It is from TIFF0007809139000013.tif76170, (b) having a combined alcohol impurity and a ketone impurity of less than 0.35 area % based on Compound 190 (or a stereoisomer, geometric isomer, tautomer, or salt thereof), wherein the alcohol impurity and the ketone impurity have the structure The present invention relates to a composition of matter, which is that of TIFF0007809139000014.tif89170. [Brief explanation of the drawings]

[0017] [Figure 1] Methods for the preparation of compounds 141 and 180 are shown. [Figure 2] A method for the preparation of compound 141 and an alternative method for the preparation of compound 180 are shown. [Figure 3] A method for the preparation of compound 141 and an alternative method for the preparation of compound 180 are shown. [Figure 4] A method for the preparation of compound 182 is shown. [Figure 5A] A first method for the preparation of compound 190 is shown. [Figure 5B] A second method for the preparation of compound 190 is shown. [Figure 6] A method for the preparation of compound 200 is shown. [Figure 7] Methods for the preparation of compounds 160 and 170 are shown. [Figure 8] Methods for the preparation of compounds 120, 130 and 160 are shown. [Figure 9] Methods for the preparation of compounds 120, 121, 130 and 160 are shown. [Figure 10] Methods for the preparation of compounds 122, 130 and 160 are shown. [Figure 11] A method for the preparation of compound 170 is shown. [Figure 12A] A method for the preparation of compound 140 is shown. [Figure 12B] Methods for the preparation of compounds 154A, 153 and 140 are shown. [Figure 13] A general method for the preparation of compound 200 is shown, where "Comp" refers to the compound. [Figure 14A] FIG. 1 is a graph of Compound 141 area % as assessed by ultra-high performance liquid chromatography (UHPLC) measurements from fractionated reactor output monitoring a continuous processing method for producing Compound 141 from Compound 140, as described in Example 12. [Figure 14B] FIG. 1 is a graph of the area % of Compound 140, combined with azo + azoxy and dimer impurities, as assessed by ultra-high performance liquid chromatography (UHPLC) measurements from fractionated reactor output monitoring the continuous processing method for producing Compound 141 from Compound 140, as described in Example 12. [Figure 15] 1 is a graph of theoretical predicted throughput compared to actual achieved experimental output observed in the continuous processing method described in Example 12. [Figure 16]FIG. 1 is a schematic diagram of the continuous processing setup described in Example 12, including real-time analysis by in-line FT-IR and online UHPLC. P denotes the pressure sensor and T denotes the temperature sensor. [Figure 17] FIG. 1 is an XRPD spectrum of the crystalline ethanol hemisolvate form of fenebrutinib obtained in Example 14. [Figure 18] FIG. 1 is an XRPD spectrum of the crystalline ethanol hemisolvate form of fenebrutinib obtained in Example 14. [Figure 19] FIG. 1 is an XRPD spectrum of the crystalline ethanol hemisolvate form of fenebrutinib obtained in Example 14. [Figure 20] 2 is a graph summarizing the performance of different catalysts in the flow hydrogenation of 141 under the reaction conditions reported in Table 21, entry 3. [Figure 21] 2 is a graph summarizing the performance of two different 5% Pt / C catalysts over time in reducing compound 140 under the reaction conditions reported in Table 21, entry 3. [Figure 22] 1 is a graph of the purity of aminopyridine 141 solution obtained by sampling at regular intervals in a scaled-up continuous flow as described in Example 13. [Figure 23] FIG. 1 is a schematic diagram of the continuous processing set-up described in Example 13, using a fixed-bed catalyst in the form of a metal deposited on a solid support and contained in a tubular reactor. DETAILED DESCRIPTION OF THE INVENTION

[0018] Reference will now be made in detail to certain embodiments of the present invention, examples of which are illustrated in the accompanying structures and formulas. While the present invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to these embodiments. On the contrary, the present invention is intended to encompass all alternatives, modifications, and equivalents that may be included within the scope of the present invention, as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that could be used in practicing the present invention. The present invention is in no way limited to the methods and materials described. In the event that one or more of the incorporated literature, patents, and similar materials, including but not limited to defined terms, term usage, described techniques, etc., differs from or contradicts this application, this application controls. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0019] definition When indicating the number of substituents, the term "one or more" refers to the maximum possible substitution from one substituent, i.e., from replacing one hydrogen with a substituent to replacing all hydrogens. The term "substituent" refers to an atom or group of atoms that replaces a hydrogen atom in a parent molecule. The term "substituted" indicates that the specified group carries one or more substituents. Any group can have multiple substituents, and when a variety of possible substituents are provided, the substituents are independently selected and need not be the same. The term "unsubstituted" means that the specified group carries no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents independently selected from a group of possible substituents. When indicating the number of substituents, the term "one or more" refers to the maximum possible substitution from one substituent, i.e., from replacing one hydrogen with a substituent to replacing all hydrogens.

[0020] As used herein, "alkyl" refers to a monovalent, straight-chain or branched, saturated hydrocarbon moiety, consisting solely of carbon and hydrogen atoms, having from 1 to 20 carbon atoms. "Lower alkyl" refers to an alkyl group of 1 to 6 carbon atoms, i.e., C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like. 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 ring or polycyclic rings. Cycloalkyls may be substituted as defined herein. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl (i.e., "Cy"), cycloheptyl, and the like. Polycyclic ring structures include fused and bridged bicyclic, fused and bridged polycyclic, and spirocyclic hydrocarbon ring systems, such as bicyclo[2.2.1]heptane, pinane, 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 an alkyl group having 6 to 20 carbon atoms (C6-C 20 (Aryl) refers to a monovalent aromatic hydrocarbon group. Aryl includes bicyclic groups containing an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic ring. Typical aryl groups include, but are not limited to, groups derived from benzene (phenyl), substituted benzene, naphthalene, anthracene, biphenyl, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like. Aryl groups are optionally substituted independently with one or more substituents described herein. In some embodiments, aryl is optionally substituted with alkyl, cycloalkyl, halogen, or haloalkyl.

[0023] As used herein, "alkoxy" refers to a moiety of the structure -OR, where R is an alkyl moiety, as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

[0024] As used herein, "haloalkyl" refers to an alkyl, as defined herein, in which one or more hydrogen atoms have been replaced with the same or different halogen. Exemplary haloalkyls 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 a moiety of the structure -NRR' where R and R' are each hydrogen, "monoalkylamino" refers to a structure where one of R and R' is hydrogen and the other of R and R' is alkyl, and "dialkylamino" refers to a structure where each of R and R' is alkyl.

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

[0028] As used herein, "chiral" refers to a molecule that has the property of not being superimposable on its mirror image partner, while the term "achiral" refers to a molecule that is superimposable on its mirror image partner.

[0029] As used herein, "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0030] As used herein, "diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties (e.g., melting points, boiling points, spectroscopic properties) and reactivities. Mixtures of diastereomers can separate under high-resolution analytical procedures such as electrophoresis and chromatography.

[0031] As used herein, "enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0032] Stereochemical definitions and conventions used herein generally follow S.P. 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 part 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 an optically active compound, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l, or (+) and (-), are used to indicate the rotation of plane-polarized light by a compound; (-) or l means the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, lacking optical activity. Enantiomers may be separated from a racemic mixture by chiral separation methods, such as supercritical fluid chromatography (SFC).The assignment of configuration at chiral centers in separated enantiomers may be tentative, while the determination of stereochemistry is likely to occur, for example, from x-ray crystallographic data.

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

[0034] As used herein, the term "salt" refers to both acid addition salts and base addition salts. "Acid addition salts" refers to salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, and phosphoric acid, and organic acids of the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acid classes, 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 salts" refers to salts formed with organic or inorganic bases.

[0035] As used herein, "inorganic base" generally includes salts of sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Non-limiting examples include phosphates such as 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 such as potassium acetate, sodium acetate, and ammonium acetate; formates such as potassium formate and sodium formate; carbonates such as potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate; and alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide. The inorganic bases may be used alone or in combination of two or more thereof.

[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, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

[0037] As used herein, "nonpolar solvent" refers to a solvent that does not have significant partial loads on any atom or solvent, and in which the polar bonds are arranged in such a way that the effects of those partial loads are cancelled 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 has a high dielectric constant and a high dipole moment and lacks acidic hydrogen. 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 glycol methyl ether acetate, monoethyl ether acetate, and combinations thereof.

[0039] As used herein, "polar protic solvent" refers to a solvent having a labile hydrogen attached 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 non-polar 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 of chemical compounds to product compounds in commercially acceptable yields and conversions. In some aspects, 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, such as Pd(PPh3)4, Pd(PCy3)2, Pd(PtBu3)2, or similar Pd(0) complexes) or may be formed from a palladium source in combination with either a ligand and / or a base (e.g., K0tBu, KOH, NaOAc, K3PO4, K2CO3, Hunig's base, NEt3, NPr3). In some aspects, 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 the non-exclusive list: [PdCl(X)] (X = e.g., allyl, cinnamyl, or crotyl), [PdCl(X)PR] (R = alkyl or aryl), [Pd(X)(Y)] (Y = e.g., cyclopentadienyl or p-cymyl), Pd(dba), Pd(dba), Pd(OAc), PdZ (Z = Cl, Br, I), PdZ(PR), or Pd(TFA). In some aspects, the catalytic palladium species is selected from the non-exclusive list: [Pd(allyl)Cl], Pd(MeCN)Cl, Pd(benzonitrile)Cl, Pd(dba), Pd(OAc), PdCl, PdBr, Pd(TFA), Pd(MeCN)(BF), Pd(dba), Pd(PCy)Cl, Pd(acac), and Pd(PPh). In some such aspects, the palladium source is Pd(dba) or Pd(OAc). In some embodiments, the palladium source is Pd(PCy). In some other aspects, the catalytic palladium species can be formed in situ from a palladium source, such as those described 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, xantphos, and N-xantphos, DPEPhos. In some embodiments, the ligand is an aryl phosphate. In some embodiments, the ligand is XPhos, xantphos, or DPEPhos. In certain embodiments, the ligand is XPhos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl), xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene), or the following structure: TIFF0007809139000015.tif46170, and 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 can be selected from cationic palladium species comprising an inorganic or organic counterion X; and neutral palladium species comprising a coordinated inorganic or organic ligand X. X can be a halogen; a carboxylate, such as, but not limited to, CH3C(O)O; - , tBuC(O)O - or CF3C(O)O - sulfonates, such as, but not limited to, triflates (CF3SO3 - ), tosylate, besylate, or nosylate; or inorganic anions, such as, but not limited to, PF6 - , BF4 - , B(C6F5)4 - , NO3 - or SO4 2-In some embodiments, the Pd catalyst may be neutral or cationic and may further comprise a counterion. In some embodiments, the catalyst is [(SPhos)Pd(allyl)]CF3SO3, [(SPhos)Pd(allyl)]CH3CO2, [(SPhos)Pd(allyl)]NO3, [(SPhos)Pd(allyl)Cl], [(SPhos)Pd(crotyl)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)Cl, Pd(dppe)Cl, Pd(PCy)Cl, bis(triethylphosphine)palladium(II) chloride, Pd(t-BuP)Cl, Pd[P(o-tol)]Cl, Pd(PPh)Cl, Pd(OAc)(PPh), and Pd(CHCN)Cl. In some such embodiments, the preformed catalyst is Pd(dppf)Cl. In some further embodiments, the catalyst source or preformed catalyst can be complexed with a solvent, such as dichloromethane, chloroform, or acetonitrile. Non-limiting examples of such complexes include Pd(dppf)Cl·DCM, Pd(dba)·CHCl, and Pd(PPh)Cl·ACN.

[0042] As used herein, "boronating reagent" refers to any boronating reagent capable of cross-coupling with an aryl halide to form an aryl boronate. Examples of boronating reagents include, but are not limited to, tetrahydroxyboron, catecholborane, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 4,6,6-trimethyl-1,3,2-dioxaborinane, diisopropylamineborane, bis(neopentylglycolato)diboron, bis(catecholato)diboron, bis(hexyleneglycolato)diboron, bis(pinacolato)diboron, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine, bis(2,4-dimethylpentane-2,4-glycolato)diboron, 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 hydrogensulfite, sodium hydrosulfite, sodium tetrahydroborate, potassium tetrahydroborate, sodium triacetoxyborohydride, trichlorosilane, triphenylphosphite, triethylsilane, trimethylphosphine, triphenylphosphine, diborane, diethoxymethylsilane, diisobutylaluminum hydrate, diisopropylaminoborane, aluminum lithium hydroxide, and lithium triethylborohydride.

[0044] As used herein, "protecting group" refers to a group used to protect a remote functionality (e.g., a 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 use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0045] Some embodiments herein refer to purity or content (e.g., of a desired or undesired compound) using area % as determined by HPLC. Suitable HPLC methods for assessing area % are known to those of skill in the art, including, for example, those used in Examples 6-9 of this disclosure and those described in detail in the Analytical Methods section.

[0046] As used herein, "predominant" and "predominantly" refer to more than 50%, at least 75%, at least 90%, at least 95%, at least 99%, or at least 99.9% on any of a weight, volume, molar, equivalent, v / w%, w / w%, w / v%, or v / v% basis.

[0047] As used herein, the terms "amorphous" or "amorphous form" indicate that a substance, component, or product is essentially non-crystalline, e.g., as determined by XRPD. In certain embodiments, a sample containing an amorphous form of a substance may be essentially free of 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, clathrates, cocrystals, salts of a compound, or polymorphs thereof. The term "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 a substance 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 a surface or template, such as on a polymer, recrystallization in the presence of additives such as co-crystallized countermolecules, desolvation, dehydration, rapid distillation, rapid cooling, slow cooling, vapor diffusion, sublimation, polishing, and solvent drop 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 diffraction, 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 embodiments of the present invention, compound 190, its stereoisomers, its geometric isomers, its tautomers and salts thereof can be prepared by the reaction of the following reaction scheme: It can be prepared from compounds 170 and 181 according to TIFF0007809139000016.tif48170.

[0051] In some embodiments, compound 190 (or a stereoisomer, geometric isomer, tautomer, or salt thereof) can be prepared according to the methods depicted in Figure 5A and in Figure 5B.

[0052] Compound 190 (or a stereoisomer, geometric isomer, tautomer, or salt thereof) is prepared from a reaction mixture comprising compound 170, compound 181, a palladium catalyst, a solvent system comprising water, and a base, and the reaction mixture is reacted to form a reaction product mixture comprising compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof. In some embodiments, the solvent system further comprises a polar aprotic solvent. In some embodiments, the polar aprotic solvent is an ester, e.g., a low molecular weight ester. In certain embodiments, the solvent system comprises a low molecular weight ester, e.g., 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 an ester, e.g., a low molecular weight ester, produces compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, in higher yield, or with lower levels of impurities, or both, than methods using a different solvent system.

[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 derived therefrom.

[0054] The palladium catalyst may be any palladium catalyst described elsewhere herein. In some particular 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 has the formula: TIFF0007809139000017.tif23170 (in the formula, R 6 ~R 10 each independently represents H, optionally substituted C 1~6 is selected from the group consisting of alkyl, optionally substituted C aryl, and optionally substituted heteroaryl; R 6 and R 10 may optionally be joined together to form a fused bicyclic ring containing an aromatic ring. In some particular embodiments of the allyl derivatives, R 6 ~R 10 Each of is H; R 6 is -CH3 and R 7 ~R 10 Each of is H; R 7 is -CH3 and R 6 and R 8 ~R 10 Each of is H; R 8 is -CH3 and R 6 , R 7 , R 9 and R 10 Each of is H; R 6 is -phenyl and R 7 ~R 10 each of which is H; or R 7 is -phenyl and R 6 and R 8 ~R 10 Each one is H.

[0055] In some embodiments, R 6 and R 10 may be taken together with the atoms to which they are attached to form a fused bicyclic ring that includes an aromatic ring. 6 and R10 are taken together with the atoms to which they are attached to form a 5-membered carbocyclic ring to a phenyl ring. 7 , R 8 and R 9 is H. 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 creates the palladium-carbon bond has the formula: TIFF0007809139000018.tif23170 (in the formula, R 11 is C 1~10 alkyl) is an indenyl. In some particular embodiments, the structure: It is an allyl derivative of TIFF0007809139000019.tif24170.

[0057] In some embodiments, the phosphine ligand has the formula: TIFF0007809139000020.tif34170 (in the formula, R 1 and R 2 each independently represents an optionally substituted C 1~12 Alkyl, optionally substituted C3-C 20 cycloalkyl, and optionally substituted C5 or C6 aryl; or C 1~4 Alkyl, and C 3~6 cycloalkyl) In some embodiments, R 3 ~R 5 are each independently H, optionally substituted C, 1~6 Alkyl, formula -OC 1~6 Alkoxides of alkyl, and compounds of the formula -N(R 12 )(R 13 )(wherein, R 12 and R 13 are independently H and C 1~6alkyl) In some embodiments, R 3 ~R 5 are each independently -OC 1~4 alkyl, and R 12 and R 13 are independently H and C 1~4 In some embodiments, the phosphine ligand is selected from the group consisting of alkyl, aryl ... SPhos with TIFF0007809139000021.tif36170.

[0058] In some embodiments, the Pd catalyst is selected from cationic palladium species comprising an inorganic or organic counterion, X; and neutral palladium species comprising a coordinated inorganic or organic ligand, X. In such embodiments, X may be selected from halogen, carboxylate, sulfonate, and inorganic anion. In such embodiments, carboxylate may be as defined elsewhere herein, e.g., CHC(O)O. - , tBuC(O)O - , or CF3C(O)O - In such embodiments, the sulfonate may be as defined elsewhere herein, such as triflate (CF3SO3 - ), tosylate, besylate, or nosylate. In such embodiments, the inorganic anion may be as defined elsewhere herein, for example, PF6 - , BF4 - , B(C6F5)4 - , NO3 - and SO4 2- In one embodiment, X is CF3SO3 - is.

[0059] In some embodiments, the Pd catalyst is neutral or cationic. In certain embodiments, the catalyst further comprises a cationic catalyst further comprising a counterion, e.g., 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(crotyl)Cl], [(SPhos)Pd(allyl)]PF6, and [(SPhos)Pd(allyl)]CF3CO2. In one embodiment, the catalyst is [(SPhos)Pd(allyl)]CF3SO3.

[0060] The equivalent ratio of palladium catalyst to compound 170 is about 0.001:1, about 0.0015:1, about 0.002:1, about 0.0025:1, about 0.003:1, about 0.004:1, about 0.0045:1, about 0.005:1, about 0.006:1, about 0.007:1, about 0.008:1, about 0.009:1, or about 0.01:1, and any range derivable therein, such as about 0.001:1 to about 0.01:1, about 0.001:1 to less than 0.05:1, about 0.001:1 to about 0.0045:1, or about 0.001:1 to about 0.003:1.

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

[0062] In some aspects, the reaction mixture solvent system comprises, predominantly comprises, consists essentially of, or consists of water and at least one aprotic solvent, as defined elsewhere herein. The volume ratio of 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 therebetween, e.g., 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, e.g., an ester of acetic acid, and C 1~6 Alkyl, e.g., C 1~3 In some embodiments, the ester is isopropyl acetate or ethyl acetate. In some particular aspects, the solvent system comprises water and ethyl acetate, comprises predominantly water and ethyl acetate, consists essentially of water and ethyl acetate, or consists of water and ethyl acetate. In some aspects, the ratio of solvent system volume to compound 170 in the reaction mixture can be 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 (e.g., ethyl acetate) results in higher product yields, lower amounts of impurities, or both, compared to the use of other solvent systems. In some embodiments, the ratio of ethyl acetate to water is from about 1:0.1 to about 1:1, or from about 1:0.1 to about 1:0.8, or from about 1:0.1 to about 1:0.5, or from about 1:0.1 to about 1:0.3.

[0063] In some embodiments, the catalyst is [(SPhos)Pd(allyl)]CF3SO3, the solvent system comprises predominantly ethyl acetate and water, where the volume ratio of ethyl acetate to water is from about 1:0.1 to about 1:1 (e.g., about 1:0.3), and the boronate has the structure: TIFF0007809139000022.tif20170 is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0064] In some embodiments, the reaction temperature to form 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 percent 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 percent concentration of compound 170 by HPLC is less than 0.5 or undetectable. The reaction time to completion can 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 aspects, the reaction time to completion is less than 5 hours, e.g., 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 not wishing to be bound by theory, the combination of solvent system, catalyst, and temperature described herein may lead to shorter reaction times than other combinations. For example, in some embodiments, the combination of a catalyst comprising a palladium(II) species containing a phosphine ligand and at least one palladium carbon-bond, a solvent system comprising water and an ester (e.g., a low molecular weight ester, such as ethyl acetate), and a reaction temperature of between about 60°C and about 80°C (e.g., between about 65°C and about 75°C, e.g., about 70°C) may lead to the production of compound 190, or a salt thereof, in higher yield, with fewer impurities, or both, in a shorter time period (e.g., less than 5 hours, less than 3 hours, or less than 2 hours) compared to other conditions.

[0067] In some aspects of the invention, the method of producing compound 190 (or a stereoisomer, geometric isomer, tautomer, or salt thereof) further comprises one or more purification steps. In some embodiments, the one or more purification steps comprise one or more aqueous washes, e.g., two aqueous washes, or three aqueous washes. In certain embodiments, the one or more purification steps comprise an aqueous base wash followed by an aqueous N-acetyl-cysteine ​​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 ranges therein, e.g., about 3 wt.% to about 9 wt.%, under 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 compound 190 weight can be about 1 L / kg, about 2 L / kg, or about 3 L / kg, and ranges therebetween, e.g., about 1 L / kg to about 3 L / kg. Following vigorous stirring with aqueous N-acetyl-L-cysteine, in some embodiments, additional organic solvent is added with vigorous stirring. The additional organic solvent can be the same organic solvent present in the reaction, e.g., a low molecular weight ester, e.g., ethyl acetate. In some embodiments, the ratio of additional organic solvent to compound 190 weight 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, wherein 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 (NaHCO). 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 ranges therein, e.g., 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, e.g., a water wash. In some embodiments, the organic layer containing Compound 190 is combined with water under vigorous stirring.In certain embodiments, the ratio of water volume to weight of compound 190 may be about 0.5 L / kg, about 1 L / kg, about 2 L / kg, about 3 L / kg, or about 4 L / kg, or a range thereof, e.g., 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 contacted with activated carbon, such as through a charcoal bed or by suspending activated carbon in the organic phase followed by charcoal separation and 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 to the amount of compound 190 are instead to the amount of a stereoisomer, geometric isomer, tautomer, or salt of compound 190.

[0069] Compound 190 may optionally be isolated from the reaction product mixture or from the organic layer containing compound 190 from a workup step. 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, in which an aprotic solvent may be swapped for a polar protic solvent described elsewhere herein. 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 a composition containing compound 190 by vacuum distillation, and the reduced volume containing compound 190 may be diluted with a polar protic solvent. For example, a 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, e.g., 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, e.g., 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 a 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 purified compound 190 solution 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 steps of dilution with polar protic solvent (ethanol) and distillation may be repeated one or more times.In some embodiments, the steps of diluting and distilling the polar protic solvent are performed one or more times until the remaining aprotic solvent content 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 methods herein further include crystallizing compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof. Such crystallization may follow, for example, the solvent swap and / or distillation steps described herein. The solution of compound 190 may be cooled, for example, to below 25°C to crystallize 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 cooled 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 a stereoisomer, geometric isomer, tautomer, or salt thereof. 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 comprises about 2.5% to about 10% by weight, or 5% to about 8% by weight of the compound in a protic solvent (e.g., an alcohol, e.g., ethanol). In certain embodiments, the solution is seeded at a temperature of about 70°C to about 80°C, e.g., about 75°C, and the seeded solution is then cooled to about 0°C to about 10°C, e.g., 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 the crystals are then isolated. Compound 190 crystals are collected by filtration or centrifugation and cooled to room temperature. 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 a vacuum of about 2 to 10 mbar.

[0070] The yield of compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, based on compound 170 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 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% by HPLC. In some embodiments, the content of compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, 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 depicted below is less than 0.15 area%, less than 0.1 area%, less than 0.05 area%, or undetectable as measured by HPLC according to the present disclosure. In some embodiments, the content of the dimer impurities depicted below is less than 0.29% w / w, or less than 0.25% w / w, or less than 0.2% w / w, or less than 0.15% w / w, or less than 0.1% w / w. In some embodiments, the combined content of the ketone impurities and alcohol impurities depicted 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%, or equal to or less than 0.05 area%, or undetectable as measured by HPLC. In certain embodiments, the area % is assessed using an HPLC method according to the present disclosure.

[0071] The catalyst system of the present disclosure exhibits much higher activity for the coupling of compound 170 and compound 181 to yield compound 190 compared to previously disclosed catalyst systems utilizing a Pd(dppf)Cl catalyst. The higher activity results in catalyst loadings as low as about 0.1 mol % or about 0.2 mol % (0.001 equivalents or about 0.002 equivalents) based on compound 170, compared to previously disclosed loadings of about 1 mol %. The improved catalyst system has the advantages of higher yields and lower by-product impurities, as described herein and illustrated in the Examples. For example, in some embodiments, the present catalyst system provides a compound 190 yield based on compound 170 of at least 90%, or at least 93%, and a dimer impurity content of less than 0.15 area %, or 0.15 area %, or less than 0.1 area %, or undetectable. The increased yield and reduced impurity profile using the improved catalyst system described herein can be particularly reflected in higher batch sizes, e.g., 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 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. Thus, in certain embodiments, the catalyst system described herein advantageously results in higher yields of compound 190 with lower levels of impurities, such as dimer, alcohol, and ketone impurities, 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). Additionally, in some embodiments, the catalyst systems described herein exhibit higher activity in solvent systems comprising water and aprotic ester solvents compared to previously used solvent systems.The use of a solvent system comprising water and an aprotic solvent in combination with the catalyst system described herein, wherein the solvent is an ester, results in higher yields, or lower levels of impurities, or both, compared to previous systems using other solvents. Additionally, the methods described herein can be carried out at higher temperatures and / or shorter reaction times compared to previous methods, and changing these parameters can have additional advantages.

[0072] This combination of catalyst, solvent, and base, referred to as the catalytic system, further provides compound 190 purity on the order of about 99.8 area % (HPLC) or greater, compared to the maximum 99.5 area % purity described by previous methods. Concomitant with the improved impurity profile, this catalytic system results in a significant reduction in the production of certain impurities that are difficult to remove, thereby obviating the need for certain purification steps. As an example, three impurity by-products of the compound 170-181 coupling reaction include: These include dimer impurities such as TIFF0007809139000023.tif95170, sec-alcohol impurities, and ketone impurities.

[0073] A representative Compound 190 impurity profile for the present catalyst system, previously disclosed, is shown in the table below, using the same HPLC method for quantitation. TIFF0007809139000024.tif31170

[0074] The combination of the catalyst system described herein, the solvent system comprising an ester, and the elevated reaction temperature, compared to previous methods, advantageously provides one or more (including some combination, or all) of higher yields of compound 190 (especially with larger batch sizes), lower levels of impurities (including reducing some impurities to below undetectable levels), more efficient reaction workup, and shorter reaction times than previously required.

[0075] Also provided herein are compositions comprising Compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, with low levels of impurities. Such compositions may comprise, for example, 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 a stereoisomer, geometric isomer, tautomer, or salt thereof. In some embodiments, the compositions have a Compound 190 purity by HPLC 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%. In some embodiments, the composition has a dimeric 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, wherein the dimeric impurity has the structure: It is TIFF0007809139000025.tif66170.

[0076] In some embodiments, the composition has a combined alcohol and ketone impurity content 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 less, or undetectable, wherein the alcohol and ketone impurity has the structure: It is TIFF0007809139000026.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, e.g., between 1 kg and 200 kg, or between 5 kg and 100, or between 50 kg and 200 kg, or between 100 kg and 200 kg of compound 190.

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

[0079] Preparation of Compound 200 Compound 200 (or a stereoisomer, geometric isomer, tautomer, or salt thereof) is prepared from a second reaction mixture containing compound 190 (or a stereoisomer, geometric isomer, tautomer, or salt thereof), a reducing agent, a base, and a solvent. The second reaction mixture reduces the aldehyde moiety of compound 190 and reacts to form a reaction product mixture that includes compound 200, as depicted in TIFF0007809139000027.tif48170.

[0080] In some embodiments, compound 200 can be prepared according to the method depicted in FIG.

[0081] In some embodiments, the solvent is C 1~4The solvent is selected from alcohols, ethers, and cyclic ethers. In some particular embodiments, the solvent is an aprotic solvent, such as THF, methyl tert-butyl ether, or 2-Me-THF. The ratio of solvent system volume to Compound 190 weight can 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 ranges therein, such as about 2:1 to about 10:1 L / kg, or about 4:1 to about 8:1 L / kg. In some embodiments, the solvent predominantly comprises 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 ratio of base to compound 190 is 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 ranges thereof, such as about 0.1:1 to about 0.9:1, or about 0.3:1 to about 0.7:1. In any of various embodiments, the reducing agent is as described elsewhere herein. In some particular embodiments, the reducing agent is sodium borohydride. The equivalent ratio of reducing agent to compound 190 is 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, about 0.9:1, and ranges thereof, such as about 0.1:1 to about 0.9:1, or about 0.2:1 to about 0.8:1. In some embodiments, the base and reducing agent are added to the reaction mixture in solid form, in aqueous solution form, or a combination 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 to the reaction mixture together, for example, as an aqueous mixture. In certain embodiments, the molar ratio of base:reducing agent is about 0.5:1 to 0.5:2, such as about 0.5:1.25 to 0.5:1.75, for example, about 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 can be considered complete when the area percent 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 more. 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 is at least 99 area%, at least 99.5 area%, at least 99.9 area%, or 100 area% by HPLC. In some embodiments, the yield of compound 200 or a salt thereof is at least 90% and the purity is at least 99.9 area % 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 admixing the second reaction product mixture with a base, such as an aqueous solution of an inorganic base (e.g., monopotassium phosphate) or an aqueous solution of an inorganic acid such as phosphoric acid (i.e., H3PO4). In some embodiments, the volume ratio of aqueous base or inorganic acid to compound 200 weight ratio is about 0.5 L to about 2 L of an aqueous base or acid (e.g., monopotassium phosphate or phosphoric acid) solution at about 10 weight percent to about 25 weight percent per kg of compound 200. In some embodiments, such admixing is performed at a temperature of about 15°C to about 50°C, e.g., about 20°C, or about 30°C, or about 40°C. The aqueous layer is separated, and an organic layer containing compound 200 in solution is recovered. 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 about 2 to about 4 L / kg of compound 200. Suitable solvents, such as C 1~4 An alcohol (e.g., methanol) may be added to the distilled filtrate to a total volume of about 6 to about 8 L / kg of compound 200. In some embodiments, about 0.2 to about 0.8 wt. % of compound 200 seed crystals may be added to form a mixture. The mixture may be distilled to reduce the volume by at least 1 L / kg of compound 200, e.g., 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 at a temperature of at least 40°C, e.g., about 45°C, about 50°C, about 55°C, about 40°C, or about 65°C, for at least 1 hour, e.g., about 1 hour, about 2 hours, about 3 hours, or about 4 hours. The distilled mixture of compound 200 may be cooled, e.g., to below 20°C, to form a slurry of crystallized compound 200 from the cooled mixture. In some embodiments, crystals may begin to form prior to distillation. The slurry may be aged for a period of time, such as, for example, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, or about 4 hours. Compound 200 crystals may optionally be recovered and dried. Drying may be carried out, preferably under reduced pressure and an inert gas purge (e.g., argon or nitrogen), at a temperature of, 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 period of time sufficient to remove the desired amount of solvent, such as, for example, about 6 hours, about 12 hours, about 18 hours, about 24 hours, or about 30 hours.

[0085] In some embodiments, purified compound 200 crystals may be recrystallized during the purification process. 1~4The mixture may be combined with alcohol (e.g., ethanol) at a ratio of alcohol volume to Compound 200 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 be combined with toluene at a ratio of toluene volume to Compound 200 weight of about 1 L / kg to about 5 L / kg, or about 1.5 L / kg to about 3.5 L / kg, with vigorous stirring. The mixture may be heated, for example, to about 65 to about 85°C with stirring, and maintained 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, enough additional alcohol to provide an alcohol:toluene ratio of about 90:10, or about 80:20, or about 70:30, or any range therein, and then seeded, 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.% Compound 200 seeds, to form a slurry. In some embodiments, the solution is further cooled between the alcohol and seed additions. Alternatively, the solution may be first combined with seed crystals, then combined with additional alcohol, e.g., 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.% Compound 200 seed crystals, to form a slurry, which is then combined with alcohol, e.g., in an alcohol volume to Compound 200 weight ratio of 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, e.g., 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, the initial cooling step is followed by one or more thermocycles, e.g., raising the temperature to between 30°C and about 50°C, or between about 35°C and about 50°C, holding for at least 15 minutes, at least 30 minutes, or at least 1 hour, and then cooling again to about -5°C to about 15°C and holding to crystallize compound 200. The crystals may be collected, e.g., by filtration or centrifugation, and washed with alcohol. The washed crystals may be dried under reduced pressure with a N purge at about 40°C 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 embodiments of the present disclosure, compound 141 can be prepared according to the following reaction scheme: It can be prepared from compound 140 according to TIFF0007809139000028.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 or continuous flow processing methods.

[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 (which may include Ra-Ni), Ra-Co, Pt / V@C, and Beller-type catalysts such as Co@Chitin, Ni-phen@SiO2, or Ni-phen@TiO2. In some aspects, 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 suitably selected from Pd / C, Sponge-Ni (which may include Ra-Ni), Pt / V@C, Co@Chitin, and Ni-phen@TiO. In one aspect, 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, such as Pd or Pt and Al or C. In some embodiments, the catalyst is Pd / AlO, Pt / AlO, Pd / C, or Pt / C. In some embodiments, the catalyst comprises Pd and Al, such as Pd / AlO. As known to those skilled in the art, alternative formats exist for describing catalysts; for example, in some formats, 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 alternatively be referred to as Co / Chitin, Ni-phen@SiO2 may be referred to as Ni-phen / SiO2, Ni-phen@TiO2 may be referred to as Ni-phen / TiO2, etc.

[0090] In some embodiments, such catalysts are used in continuous flow processing methods. The catalysts used in continuous flow processing may be, for example, in the form of a packed bed catalyst or an immobilized catalyst. Immobilized catalysts may include those formed by electroplating, spray coating, or slurry coating of the catalyst on a solid support. Suitable solid supports may include, 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 comprises a catalytic static mixer (CSM) support. One or more of such supports may be used. Such CSMs may be prepared, for example, via methods including selective laser melting or 3D printing.

[0091] Beller-type catalysts are known in the art. See, for example, 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 in their entirety. The catalyst may suitably comprise a 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 derivable therein, for example, from about 1 wt.% to about 25 wt.%, from about 1 wt.% to about 15 wt.%, or from about 2 wt.% to about 10 wt.%. In some embodiments, the Ni and Co catalysts may suitably comprise a 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 derivable therein, e.g., from about 0.5 mol% to about 10 mol%, from about 1 mol% to about 7 mol%, or from about 2 mol% to about 5 mol%.The catalytic amount of transition metal is preferably 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 derivable therein, 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, the catalyst loading may be about 0.5 mol%, about 1 mol%, about 1.5 mol%, about 2 mol%, about 2.5 mol%, about 3 mol%, about 3.5 mol%, about 4 mol%, about 5 mol%, about 6 mol%, or about 7 mol%, and any range derived therefrom, e.g., about 0.5 mol% to about 7 mol%, about 1 mol% to about 5 mol%, or about 2 mol% to about 4 mol%. In references to catalyst loadings, wt% may refer to the weight of a wet catalyst, e.g., a catalyst that contains some water and is not completely dried. For example, catalysts such as Pt-V@C and Pd / C, when not completely dried, may contain about 50 wt% water, or between about 50 wt% and about 70 wt% water, e.g., about 60 wt% to about 65 wt% water. Thus, in some embodiments, for example, a wet catalyst loading of about 2% wt / w may correspond to about 0.76% wt / w of dry catalyst. In some embodiments, the catalyst loading is about 0.5% w / w to about 1% w / w of dry catalyst. In other embodiments, wt% may refer to the weight of the dry catalyst; for example, Beller-type catalysts are typically dry. References to mol% refer to the molar amount of the catalyst species, regardless of water content.

[0092] In some embodiments, the solvent is selected from non-polar 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 co-solvent. In some embodiments, the solvent predominantly comprises THF, predominantly comprises toluene and methanol, or predominantly comprises THF and water. In embodiments in which the solvent predominantly comprises water and a cosolvent, the volume ratio of 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 derived therefrom, 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 comprises 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 comprises THF, e.g., no or essentially no cosolvent is used (e.g., no intentionally included or no added). In some embodiments, water may be present. For example, when using a catalyst that has not been dried before use, a small amount of water may be present even when no additional water is added separately. In certain embodiments, additional water is not intentionally included or added beyond that accompanying the catalyst. The presence of residual water with the catalyst may occur, for example, in batch processing methods. 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 methods. In other embodiments, additional water may be included in the reaction mixture, for example, in certain continuous flow processing methods.The ratio of solvent system volume to Compound 140 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 thereof, such as 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 derivable therein, such as 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 an N purging before introducing H. The reaction is typically carried out at a temperature 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 therein, e.g., from about 20°C to about 200°C, or from 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 therefrom, 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 Pt / V@C catalysts, preferred hydrogen pressure ranges are about 1 bar to about 10 bar, about 2 bar to about 8 bar, or about 4 bar. For Ni-phen and Co@chitin catalysts, preferred hydrogen pressure ranges are 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 more. The reaction may be considered complete when the area percent 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 loading is 1-4%, or about 1-3%, or about 2% by weight. In some embodiments, the catalyst loading refers to a wet catalyst, i.e., a wet catalyst that is not completely dried and may contain some water. In some such embodiments, the amount of water present is about 50% to about 70%, or about 60% to about 65%. Thus, for example, in some embodiments, the catalyst loading is about 1-4%, or about 1-3%, or about 2% by weight of the wet catalyst; or about 0.35-1.6% w / w, or about 0.5-1.0% w / w, or about 0.7-0.8% w / w of the dry catalyst. In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the polar aprotic solvent is THF. In still further embodiments, the reaction mixture is reacted at a temperature between 20° C. and 200° C., e.g., 40-80° C., e.g., about 60° C. In yet further embodiments, the hydrogen pressure is 0.1-200 bar, e.g., 1-45 bar, e.g., 1-8 bar, or about 4 bar. In certain embodiments, the combination of a platinum catalyst (e.g., Pt / V carbon), a catalyst loading 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) results in 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%, or greater than 99.5%, or greater than 99.8%, or greater than 99.9%. In some embodiments, the selectivity is greater than 99%, e.g., at least 99.1%, at least 99.2%, at least 99.3%, or at least 99.4%.In certain embodiments, such methods are carried out using batch processing.

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

[0096] In other embodiments, the method for producing compound 141 comprises a continuous flow process. In some such embodiments, the method comprises forming 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, e.g., a polar aprotic solvent. In some embodiments, the solvent optionally comprises water. In some embodiments, the solvent comprises water. In still other embodiments, the solvent is free of water, essentially free of water, or comprises 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 of 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 a solid support with the catalyst. Such a solid support can 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 comprises a loading of between about 3% and 5% Pt or Pd on a solid support comprising 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 loading is in wt%. In some embodiments, the loading is in dry wt%. In still further embodiments, the solvent comprising an organic solvent and water comprises a polar aprotic solvent and about 1-10 equivalents of water, or about 2-8 equivalents of water, or about 4, about 6, or about 8 equivalents of water relative to the amount of compound 140. In some embodiments, the solvent consists essentially of an organic solvent and water, e.g., consists essentially of a polar aprotic solvent and water. In some embodiments, the polar aprotic solvent is THF. In some embodiments, hydrogen is present in excess relative to the amount of compound 140. For example, in some embodiments, hydrogen is present in greater 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 provide an excess amount of hydrogen. In some embodiments, the continuous flow reaction is carried out at a pressure of 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 flow rate of the reactor is 2 to 40 mL / min, 2 to 35 mL / min, 10 to 40 mL / min, 20 to 40 mL / min, 15 to 30 mL / min, 2 to 20 mL / min, 2 to 12 mL / min, 4 to 10 mL / min, 2 to 8 mL / min, 6 to 8 mL / min, about 2 mL / min, about 4 mL / min, about 6 mL / min, about 8 mL / min, about 16 mL / min, about 20 mL / min, about 24 mL / min, about 27 mL / min, or about 30 mL / min.In some embodiments, a method for producing compound 141 includes forming a reaction mixture comprising compound 140 and a solvent comprising THF and about 2-8 equivalents of water, and contacting the reaction mixture with a transition metal catalyst comprising Pd (e.g., Pd / Al2O3) in the presence of excess hydrogen to form a product mixture comprising compound 141, wherein the water and hydrogen are condensed relative to compound 140, and wherein the reaction is a continuous flow reaction, the reaction is carried out at a pressure between 10 bar and 30 bar, the flow rate is about 2-8 mL / min, and the temperature is between 110°C and 130°C. In some embodiments, a method for producing compound 141 includes forming a reaction mixture comprising compound 140 and a solvent comprising THF, and contacting the reaction mixture with a transition metal catalyst comprising Pd or Pt (e.g., Pd / Al2O3 or Pt / Al2O3) in the presence of an excess of hydrogen to form a product mixture comprising compound 141, wherein the hydrogen is condensed with compound 140, and wherein the reaction is a continuous flow reaction, the reaction is carried out at a pressure between 10 bar and 30 bar, the flow rate is about 2-8 mL / min, and the temperature is 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 a 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 included on a solid support, such as spheres or granules, the solvent system is free of water, or essentially free of water, or contains less than 1% v / v or less than 0.5% v / v water. In some embodiments, water is included when the catalyst is included on a solid support, or when the system includes catalyst on a solid support (e.g., 3-5% PdAlOspheres or activated C granules, or 3-5% PtAlOspheres or activated C granules), water has little effect on yield and impurities. In some embodiments, this catalyst loading is a dry wt%.

[0097] In certain embodiments, the combination of a solid-supported transition metal catalyst (e.g., one comprising Pd, e.g., Pd / AlO), including 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 high conversion of compound 140 to compound 141 while maintaining low levels of undesired impurities. In some embodiments, the flow rate is 4 mL / min and about 2-8 equivalents of water are included. In some embodiments, the flow rate is 6 mL / min and about 8 equivalents of water are included. In some embodiments, the flow rate is 8 mL / min and about 8 equivalents of water are included. In some embodiments, the flow rate is 4-8 mL / min and about 8 equivalents of water are included.

[0098] In certain embodiments, the combination of a solid-supported transition metal catalyst (e.g., comprising Pt, e.g., Pt / C, e.g., 5% Pt / activated C granules), a 0.1-1 M solution of compound 140 in a solvent system that is essentially water-free or contains less than 1% v / v, or less than 0.5% v / v water, a temperature between 80°C and 140°C (e.g., 90-110°C, or about 10°C), a hydrogen:solution flow rate 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 hydrogen to compound 140 ratio in the range of about 5-1, about 4-2, about 3.5-2.5, or about 3, results in high conversion of compound 140 to compound 141 while maintaining low levels of undesired impurities. In some embodiments, the solvent system is polar aprotic, such as THF. In some embodiments, reduction of compound 140 occurs at a rate of about 40 g / hr to 80 g / hr, or about 50 g / hr to about 70 g / hr, or about 60 g / hr. In some embodiments, compound 141 is achieved in greater than 98%, or greater than 98.5%, or greater than 99%, or greater than 99.1% purity as measured by HPLC. In some embodiments, compound 141 is achieved in greater than 70% yield, or greater than 75% yield, or greater than 80% yield, or greater than 85% yield relative to compound 140. In some embodiments, the combined azo and azoxy impurities are less than 0.05%, the dimer impurity is 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 processing 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 short residence times that are possible with continuous flow. Such situations may be apparent to those skilled in the art. The combination of including water in the solvent system, high temperatures, and increased flow rates used in the continuous processing methods described herein can achieve unexpectedly correlated effects not observed by adjusting only one of these parameters, and may achieve higher overall output of the desired product over time while maintaining acceptably low levels of undesirable impurities compared to other methods, including certain types of batch processing methods. In some embodiments, the continuous processing methods described herein achieve conversion of compound 140 to compound 141 in yields of greater than 98.5 area%, greater than 99 area%, greater than 99.5 area%, or greater than 99.8 area%, or greater than 99.9 area%. In certain embodiments, yield conversion may be similar to or lower than other methods, but the higher throughput using continuous processing under the conditions described herein allows for a greater total product output per hour while maintaining low impurity levels, and is therefore advantageous compared to other methods. In certain embodiments, the combined levels of azo and azoxy impurities (shown below) are 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 level of dimer impurity and the combined levels of azo and azoxy impurities are less than 0.04 area% and less than 0.09 area%, less than 0.05 area% and less than 0.09 area%, or less than 0.04 area% and less than 0.08 area%, respectively. In some embodiments, the combined total content of azo, azoxy, and dimer impurities (listed below) is maintained at less than 0.20 area%, or less than 0.15 area%, or less than 0.13 area%, or less than 0.1 area%. TIFF0007809139000029.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 for the solvent system for the coupling reaction between compound 141 and compound 90 to form compound 180. Solvent exchange may be performed by methods known in the art, for example, and without limitation, by distillation or evaporation to dryness to remove the solvent, followed by dissolution 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 reaction mixtures 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 particular embodiments, the solvent is 1,4-dioxane, anisole, or combinations thereof. In one particular embodiment, the reaction product mixture containing compound 141 contains predominantly THF, and the THF is exchanged with anisole. The concentration of compound 141 after solvent exchange can suitably be about 5:1 L / kg, about 10:1 L / kg, or about 15:1 L / kg, or about 20:1 L / kg, and ranges therein, such as 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 be isolated from the reaction product mixture as a residue by optionally concentrating the filtrate to near dryness. In some embodiments, compound 141 can be crystallized from the reaction product mixture by concentration to remove the solvent, followed by addition of an antisolvent such as n-heptane, and cooling them. In some embodiments, concentration can be performed in vacuo 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 embodiments of the present disclosure, compound 180 can be prepared according to the following reaction scheme: 141 according to TIFF0007809139000030.tif43170, where "LG" is a leaving group. In some embodiments, the leaving group is a halogen or triflate. In one embodiment, the leaving group is Br.

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

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

[0105] In some embodiments for 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 can be exchanged with a solvent for forming a reaction mixture containing compound 141, compound 90, a Pd catalyst and ligand, and a base. The solvent exchange can be performed by methods known to those skilled in the art and described elsewhere herein. In one such embodiment, a portion of the solvent contained in the compound 141 reaction product mixture (e.g., THF) can be removed by distillation under reduced pressure. For example, about 40%, about 50%, about 60%, about 70%, or about 80% of the solvent can be stripped. In one embodiment, the solvent content can be reduced from about 10 volumes (V) to about 2-3V. A solvent for the compound 141 / 90 reaction mixture (e.g., anisole) can then be added, followed by distillation 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, with a slight stoichiometric excess of compound 90, e.g., an equivalent ratio of 1.05:1 or 1.1:1. The reaction mixture solvent may suitably be an aprotic solvent described elsewhere herein or a polar aprotic solvent 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 either embodiment, the Pd complex is formed from a Pd precursor Pd(II) complex, for example, and without limitation, Pd(OAc)2, [PdCl(allyl)]2, or [PdCl(cinnamyl)]2, or from a Pd(0) complex, such as [Pd(PPh3)4], [Pd(P(oTol)3)2], Pd2(dba)3, or Pd(dba)2. In some embodiments, the ligand is a phosphine ligand. Non-realistic examples of phosphine ligands include xantphos, PEPhos, dppf, and dppp. In some embodiments, the catalyst is Pd(OAc)2 and the ligand is xantphos. 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 Xantphos. The equivalent ratio of 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 catalytic ligand to 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 therefrom, such as 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 herein. In some embodiments, the base is an alkali metal carbonate of formula M2CO3, where M is Na or K. In some embodiments, the base is an organic base as described elsewhere herein, such as an organic base of formula MOR', where M is Na or K and R' is C 1~6In some such embodiments, the organic base is NaOMe. The equivalent ratio of base to compound 141 is preferably about 1.2:1 to about 3:1, e.g., about 1.5:1, or about 2:1.

[0110] The reaction mixture may optionally contain an additive. One example of an additive is triphenylphosphine ("PPh3"). Suitable 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 therein, such as 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 can be carried out under an inert atmosphere, such as with an Ar or N purging and / or an Ar or N blanket. The reaction can 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 therefrom, such as about 20°C to about 150°C, about 70°C to about 120°C, or about 20°C to about 115°C. The reaction can be considered complete when the area percent 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 about 4 hours, about 6 hours, about 12 hours, about 16 hours, about 18 hours, about 24 hours, or more.

[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 mixture solvent comprises predominantly anisole, and the reaction temperature is about 80°C to about 100°C, e.g., 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 comprise an additive, e.g., PPh3.

[0113] In some particular embodiments, the catalyst is Pd(OAc)2, the ligand is Xantphos, 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 comprises predominantly anisole and water, and the reaction temperature is about 100°C to about 125°C, e.g., 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 aspects, the catalyst is Pd(OAc)2, the ligand is DPEPhos, and the base is NaOMe. In some embodiments, an additive PPh3 is included. In some specific aspects, about 0.5-2.5 mol% Pd(OAc)2, about 2-4 mol% DPEPhos, and about 1-1.5 equivalents of NaOMe are used, optionally with about 3-6 mol% PPh3. In certain embodiments, the reaction temperature is about 90°C. In some specific aspects, 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 may require shorter reaction times, lower reaction temperatures, and less complex workup than previously used methods for preparing compound 180. For example, in some embodiments, methods for purifying compound 180 using Pd(OAc)2, Xantphos, 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, additional solvent may be added to the reaction product mixture, optionally with stirring, followed by 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 may suitably be about 40°C to about 100°C, such as, 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, recovered reaction product mixture may be distilled to reduce its volume. The concentration of compound 180 after volume reduction may suitably be 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 0.2 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 organic protic antisolvent (e.g., C 1~6The organic protic antisolvent (alcohol) and water may be combined by mixing. In such embodiments, the volume ratio of the organic protic 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 derivable therein, e.g., 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 organic protic solvent to the 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 derivable therein, e.g., 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, recovered compound 180 concentrate, including the aprotic and protic solvents, may be distilled to reduce the volume. The concentration of compound 180 after volume reduction may be 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 therein, such as 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. The additional protic antisolvent may be added in a volume ratio of compound 180 concentrate to added antisolvent of 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 therein, e.g., 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 antisolvent may be cooled to below 0°C, e.g., about −5°C or −10°C, with mixing at a suitable rate, e.g., 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 the crystallization. Compound 180 crystals may be recovered by filtration or centrifugation and washed with cold protic antisolvent and water. In some embodiments, when the antisolvent is 1-butanol, the recovered crystals may be washed with chilled (e.g., −5°C±5°C) methanol or ethanol and water (e.g., in a volume ratio of alcohol to water of about 3:1 to about 1:3, e.g., about 1:1), followed by chilled 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 a vacuum of about 2 to 10 mbar.

[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 may suitably be 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 derivable therein, such as 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 derivable therein, such as about 0°C to about 20°C, or about 5°C to about 15°C. The cooling rate may suitably 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 therein, such as about 0.5°C / min to about 3°C / min, or about 0.5°C / min to about 1.5°C / min. Compound 180 crystals are recovered by filtration or centrifugation and cooled to 50°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 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 a vacuum of about 2 to 10 mbar.

[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 embodiments of the present disclosure, compound 181 can be prepared according to the following reaction scheme: It can be prepared from compound 180 according to TIFF0007809139000031.tif47170.

[0123] A method for preparing compound 181 includes forming a reaction mixture containing 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 reacted to form a reaction product mixture containing compound 181. Compound 181 is optionally isolated from the reaction product mixture.

[0124] The palladium catalyst and catalyst ligand are generally as described elsewhere herein. In some embodiments, the palladium catalyst is Pd2(dba)3 and the catalyst ligand is an aryl phosphate ligand. In some such embodiments, the aryl phosphate ligand is XPhos. The equivalent ratio of 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 ranges therein, e.g., 0.001:1 to about 0.005:1. The equivalent ratio of catalyst ligand to 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 ranges therein, e.g., about 1.3:1 to about 3, or about 1.5:1 to about 2.5:1. The boronation reagent is as described elsewhere herein. The solvent is a polar aprotic solvent as described elsewhere herein. In some embodiments, the polar aprotic solvent is THF. The ratio of solvent volume to compound 180 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 thereof, such as 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 a compound 180 concentration 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 thereof, such as 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 reagent is bis(pinacolato)diboron and the boronate is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The equivalent ratio of the boronating reagent to compound 180 is greater than 1:1, about 1.2:1, about 1.5:1, or about 2:1, and ranges therebetween, for example, between 1:1 and 2:1. In some embodiments, the boronating reagent is bis(pinacolato)diboron and the boronate is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane.In such an embodiment, boronate compound 181 may be converted to compound 182: This is the seed TIFF0007809139000032.tif52170.

[0125] In some embodiments, compound 182 can be prepared according to the method depicted in FIG.

[0126] The reaction to form compound 181 or 182 can be carried out under an inert atmosphere, for example, with an N purging and / or blanket. The reaction can be carried out at reflux temperature, typically between about 60° C. and about 80° C. The reaction can be considered complete when the area percent 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 can be about 6 hours, about 12 hours, about 18 hours, about 24 hours, or more.

[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 at a water volume to compound 181 or 182 weight ratio of about 2 L / kg, about 3 L / kg, about 4 L / kg, or about 5 L / kg, and ranges thereof, such as about 1 to about 5 L / kg, or about 2 to about 4 L / kg. The aqueous layer may be separated, and an organic layer containing compound 181 or 182 in solution may be recovered. The organic layer may be distilled to a reduced volume at a volume to compound 181 or 182 weight ratio of about 2 L / kg, about 3 L / kg, about 4 L / kg, or about 5 L / kg, and ranges thereof, such as about 2 to about 5 L / kg. The distillation is preferably vacuum distillation, for example, at a temperature of at least 40° C. Alternatively, the 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 compound 181 or 182 weight of about 5 L / kg to about 8 L / kg, and the diluted mixture may be optionally filtered and distilled to a reduced volume of about 2 to about 4 L per kg of compound 181 or 182. The steps of diluting the polar aprotic solvent and distilling 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 compound 181 or 182 weight of about 5 L / kg, about 10 L / kg, about 15 L / kg, or about 20 L / kg, and ranges therebetween, such as 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. Solid compound 181 or 182 may be collected, for example, by filtration or centrifugation, and dried to form solid compound 181 or 182.

[0128] Alternatively, after completion of the reaction to form compound 181 or 182, the inorganic salts can be filtered off at 60-65°C. The filtrate can be cooled, for example, to 40-45°C, and filtered over charcoal. The volume of the filtrate can then be reduced at atmospheric pressure. The reduced volume can be combined with a nonpolar solvent, such as MTBE, at a ratio of nonpolar solvent volume to compound 181 or 182 weight of about 5 L / kg, about 10 L / kg, about 15 L / kg, or about 20 L / kg, and ranges therebetween, for example, about 5 to about 20 L / kg, or about 5 to about 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 is at least 95 area%, at least 98 area%, or at least 99 area% by HPLC.

[0130] Preparation of Compound 160 In some embodiments, compound 160 can be prepared according to the methods disclosed in WO 2018 / 109050, which generally involve the following three schemes: TIFF0007809139000033.tif96170 and further depicted in the reaction schemes of Figures 8-10.

[0131] In some such embodiments, compounds 120, 130, and 160 can be prepared according to the methods described in WO2018 / 109050, which are depicted in FIG. 8.

[0132] In some embodiments, compound 120 can be prepared according to the following reaction scheme: It can be prepared from compound 110 according to TIFF0007809139000034.tif32170.

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

[0134] The polar aprotic solvent is as described elsewhere herein. In some embodiments, the polar aprotic solvent is THF.

[0135] The reaction mixture may be formed under an N blanket and / or with an N purge. In some embodiments, a polar aprotic solvent may be charged to a reactor and mixed with CuCl and MeMgCl. The ratio of polar aprotic volume 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, followed by addition of compound 110 to the reactor while maintaining the temperature. Additional MeMgCl is added to the reactor at a temperature of about −30 to about −10° C., wherein the equivalent ratio of additional MeMgCl to compound 110 is about 0.9:1 to about 1.5:1, or about 1:1 to about 1.2:1. A reaction product mixture is formed containing compound 120 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 percent concentration by HPLC of compound 110 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 may be adjusted to about 3 to about 4 with an aqueous mineral acid, e.g., 3-10% w / w HCl. The resulting aqueous and organic phases (e.g., THF) containing Compound 10 in solution may be separated. The aqueous phase may be extracted with a nonpolar solvent (e.g., MTBE) at a volume ratio of about 2 L / kg to about 10 L / kg, or about 3 L / kg to about 7 L / kg, of the solvent relative to the weight of the Compound 110 starting material. The organic phase is combined and washed with an aqueous inorganic base (e.g., NaHCO3), followed by a brine wash. The washed organic phase may then be dried with a desiccant, e.g., MgSO4. The desiccant may be removed, e.g., by filtration or centrifugation. The organic phase may be concentrated to a volume ratio of about 3 to about 15 L / kg, e.g., about 5 L / kg, or about 10 L / kg, of the Compound 110 starting material. Concentration can be preferably carried out at atmospheric pressure and at about 50 to about 70°C.

[0137] In some embodiments, compound 120 can 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 (early) fraction containing predominantly solvent. Distillation may be continued to produce compound 120 product fractions collected at temperatures 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% by HPLC. Distillation may optionally be continued to remove one or more additional fractions.

[0138] In some particular 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 is synthesized according to the following reaction scheme: It can be prepared from compound 120 according to TIFF0007809139000035.tif37170.

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

[0141] The polar aprotic solvent is as described elsewhere herein. In some embodiments, the polar aprotic solvent is DMF. The non-polar solvent is as described elsewhere herein. In some embodiments, the non-polar solvent is DCM.

[0142] The reaction mixture may be formed as follows, and the reaction may be carried out under an N blanket and / or with an N purge. The reactor is charged with a nonpolar solvent (e.g., DCM) at a ratio of nonpolar solvent volume to compound 120 starting material weight of about 3 to about 15 L / kg, or about 5 to about 11 L / kg, and a polar aprotic solvent (e.g., DMF) at an equivalent ratio of 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 of the combined solvents is adjusted to about 5 to about 25°C, and POCl is added to the reactor, where the equivalent ratio of POCl 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 temperature for at least 0.5 hours. Compound 120 is then 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 more. The reaction may be considered complete when the area percent 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 optionally be purified. In some such embodiments, the reaction product mixture may be combined with water, wherein the ratio of water volume to compound 120 starting material weight is about 3 to about 20 L / kg, or about 5 to about 15 L / kg. The temperature may suitably 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, for example, to about 15 to about 35°C, and filtered through a filtration medium, for example, diatomaceous earth. The filtrate may be separated into an aqueous phase and an organic phase, and the organic phase may be recovered and optionally washed with water and brine. The organic phase may then be concentrated, for example, to a volume to compound 120 starting material weight ratio of about 2 to about 5 L / kg, or about 2 to about 4 L / kg. An organic solvent (e.g., toluene or NMP) can be combined with the concentrated organic phase in a ratio of about 1 to about 2 L / kg of organic solvent to the weight of compound 120 starting material. The volume can 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 reacting the reaction mixture to form a reaction product mixture containing the tricyclic lactam of compound 160.

[0145] The organic base is as described elsewhere herein. In some embodiments, the organic base is a tri-C alkylamine. In some particular embodiments, the organic base is selected from 4-methylmorpholine and N-ethyldiisopropylamine.

[0146] In some embodiments, the organic solvent is a polar aprotic solvent described elsewhere herein, hi some particular 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 compound 130 weight 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 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 stoichiometric excess over compound 10. In some embodiments, the equivalent ratio of compound 10 to compound 130 is between 0.7:1 and 1:1, e.g., about 0.75:1 to about 0.95:1.

[0148] The reaction to form a reaction product mixture containing compound 160 can be carried out with an N purging and / or an N blanket. In some embodiments, the organic solvent, 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 can be about 0.25 hours, about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, or more. The reaction can be considered complete when the area percent 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, for example, to about 80 to about 95°C. Water may then be combined with the reaction product mixture to form a mixture, wherein the ratio of water volume to compound 130 starting material weight 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 that temperature for at least 0.5 hours to form a slurry containing solid compound 160. 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. Acetone may then be combined with solid Compound 160, e.g., at a temperature of about 10°C to about 30°C, to form a slurry, where the ratio of acetone volume to weight of Compound 130 starting material 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. Solid Compound 160 may be isolated, e.g., by filtration or centrifugation. The recovered solid may optionally be washed with acetone. Solid Compound 160 may be dried. In some drying embodiments, drying may be performed 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% by HPLC.

[0150] In some particular embodiments, compounds 120, 130, and 160 can be prepared according to the method of WO2018 / 109050, which is depicted in FIG. 9.

[0151] In some such embodiments, compound 120 can be prepared according to Figure 8. Compound 120 can be purified by the solid ketone bisulfite adduct route depicted in Figure 9. The purification method includes forming a first reaction mixture including crude compound 120, a water-immiscible organic solvent (e.g., heptane), and an aqueous solution of sodium bisulfite, and reacting the first reaction mixture to form a first reaction product mixture including the solid ketone bisulfite adduct of compound 121. TIFF0007809139000036.tif24170

[0152] Compound 121 is isolated from the first reaction product mixture. A second reaction mixture is formed containing isolated compound 121, water, a low-boiling solvent that is not 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 containing a first phase containing the solvent, and a predominant amount of purified compound 120 is in the first phase and a second phase containing water. The first phase containing purified compound 120 is separated from the aqueous phase.

[0153] In such embodiments, the pH of the reaction product mixture containing crude compound 120 can be adjusted to less than 5 with an aqueous mineral acid, such as aqueous HCl, to provide about 1.2 to about 1.4 equivalents of HCl per equivalent of compound 120.

[0154] In a first reaction mixture, the pH-adjusted reaction product mixture may be combined with a water-immiscible solvent (e.g., hexane), where crude compound 120 is soluble in the solvent. In some embodiments, the ratio of solvent volume to compound 120 weight 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 to crude compound 120 weight in the first reaction mixture 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] A first reaction mixture is formed by combining the pH-adjusted reaction product mixture with a water-immiscible solvent under vigorous stirring at a temperature of about 10 to about 30°C. The resulting mixture is combined with a filter aid (e.g., diatomaceous earth), and 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 the total volume to a total volume to Compound 120 weight ratio of 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 organic phase is cooled, for example, to about 10 to about 30°C, optionally filtered, and combined with aqueous NaHSO to provide about 2 to about 5 equivalents of NaHSO per equivalent of Compound 120, or about 3 to about 4.5 equivalents of NaHSO per equivalent of Compound 120, to form a slurry containing solid Compound 121. The solid Compound 121 is isolated, for example, by filtration or centrifugation, and the recovered solid is slurried in a water-immiscible solvent (e.g., hexane). The solvent volume to Compound 121 weight ratio 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 water-immiscible low-boiling solvent (e.g., DCM).

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

[0157] A second reaction mixture is formed by combining Compound 121 solids with water under vigorous stirring. A water-immiscible low-boiling solvent 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 centrate is separated into an organic phase and an aqueous phase, which are separated and recovered. The aqueous phase may optionally be extracted with a water-immiscible low-boiling solvent, and the organic phases are combined. The combined organic phase may be washed with brine. The combined 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 of Compound 120 weight, and contains Compound 120 in solution. The assay of the solution is preferably about 30% to about 50%, about 35% to about 45%, or about 40%, and 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 FIG.

[0159] Compound 160 may be isolated from the reaction product mixture. In some isolation embodiments, the reaction product mixture may be cooled, for example, to about 80°C to about 95°C. Water may then be added to the reaction product mixture to form a mixture, wherein the ratio of water volume to compound 130 starting material weight 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 that temperature for at least 0.5 hours to form a slurry containing solid compound 160. 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. Acetone may then be combined with solid Compound 160, e.g., at a temperature of about 10°C to about 30°C, to form a slurry, where the ratio of acetone volume to weight of Compound 130 starting material 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. Solid Compound 160 may be isolated, e.g., by filtration or centrifugation. The recovered solid may optionally be washed with acetone. Solid Compound 160 may be dried. In some drying embodiments, drying may be performed 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% by HPLC.

[0160] In some such embodiments, compounds 130 and 160 can be prepared according to the methods described in WO2018 / 109050, which are depicted in FIG. 10.

[0161] In some such embodiments of the present disclosure, compound 130 in the following reaction scheme can be prepared from the trimethylsilyl intermediate of compound 120, which is designated compound 122 in the following reaction scheme. The reaction scheme is as follows: TIFF0007809139000037.tif37170

[0162] A method for preparing compound 130 includes forming a first reaction mixture containing 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 containing compound 122. The first reaction product mixture is quenched with a first quenching agent in aqueous solution, and a non-polar, water-immiscible solvent is added to the quenched reaction product mixture. The phases are separated, and the organic phase containing a predominant 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 containing compound 130. The second reaction product mixture is quenched with a second quenching agent in aqueous solution. The phases are separated and the organic phase is recovered, containing a predominant amount of compound 130 in solution.

[0163] The first and second polar aprotic solvents are as described elsewhere herein. 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 about 0.25 to about 2 moles per liter of compound 110, or 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 about 3 to about 11 L / kg, or about 5 to about 9 L / kg. MeMgCl is present in a stoichiometric excess relative to compound 110. In some other embodiments, MeMgCl is in solution in THF, e.g., a 3 M solution. In some embodiments, the molar ratio of MeMgCl to compound 110 is between 1:1 and 1.5:1, or about 1.1:1 to about 1.3:1. TMSCl is present in a stoichiometric excess relative to compound 110. In some embodiments, the molar ratio of TMSC1 to compound 110 is between 1:1 and 1.2:1, or about 1.01:1 to about 1.1:1. The molar ratio of CuCl to compound 110 is about 0.05:1 to about 0.2:1, or about 0.05:1 to about 0.15:1. The molar ratio of LiCl to compound 110 is about 0.05:1 to about 0.2:1, or about 0.07:1 to about 0.15:1.

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

[0166] In the first reaction, in some embodiments, CuCl, LiCl, and a first polar aprotic solvent may be combined in a reactor at a temperature of about 10 to about 35°C under a 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 percent 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 may be quenched, for example, with aqueous 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 ammonium chloride solution volume to compound 110 is about 2:1 to about 10:1 L / kg, or about 3:1 to about 7:1 L / kg. The organic and aqueous phases are separated and collected. 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 collected distillate volume to compound 110 weight is about 8 L / kg to about 10 L / kg. The concentrated first reaction product mixture may be diluted with a nonpolar solvent (e.g., toluene), where the ratio of added nonpolar solvent volume to compound 110 weight is about 1 L / kg to about 3 L / kg. In such an embodiment, the diluted mixture may be concentrated to remove an approximate volume of added nonpolar solvent to produce a solution of compound 122. The assay of compound 122 in solution is about 40% to about 60% w / w, or about 45% to about 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 by HPLC, or at least 90% area by HPLC.

[0167] In the second reaction, the solution from the first reaction is diluted with a nonpolar solvent to achieve about 25 to about 45 wt. %, or about 30 to about 40 wt. %, or about 35 wt. % Compound 122. In some embodiments, the nonpolar solvent is toluene. The first POCl3 addition may be carried out at an equivalent ratio of POCl3 to Compound 110 by weight of about 0.2:1 to about 0.4:1, or about 0.3:1, and at a temperature of about 5 to about 35°C. DMF is added after POCl3 to Compound 110 is at an equivalent ratio of about 1.5:1 to about 3:1, or about 1.5:1 to about 2.5:1. A second POCl3 addition is made, where the equivalent ratio of POCl3 to compound 110 by weight 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 may be considered complete when the area percent 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 provide 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 potassium phosphate solution volume to compound 110 by weight is about 3 to about 12 L / kg, or about 6 to about 9 L / kg. Organic and aqueous phases are formed, separated, and collected. The organic layer is washed with potassium phosphate solution and water to obtain a washed organic phase (e.g., toluene) containing compound 130 in solution and having a pH of 7. The organic phase is filtered to produce compound 130 in 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.

[0169] Preparation of Compound 170 In some embodiments, compound 170 can be prepared according to the methods disclosed in WO 2018 / 10905.

[0170] In some such embodiments, compound 170 can be prepared according to the methods of WO2018 / 10905, depicted in FIG. 7 and FIG. 13, and reproduced as follows by forming a reaction mixture comprising compound 160, a stoichiometric excess of compound 100, a palladium catalyst and catalytic ligand, a base, and a polar aprotic solvent: The TIFF0007809139000038.tif31170 reaction mixture is reacted to form a reaction product mixture that includes compound 170. Compound 170 may optionally be isolated from the reaction mixture.

[0171] The equivalent ratio of compound 100 to compound 160 in the reaction mixture is greater than 1:1, e.g., 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 can be any palladium catalyst that affects the rate and conversion of the chemical compound to the product compound in commercially acceptable yields and conversions. In some embodiments, the catalytic palladium species is a palladium source selected from the non-exclusive list: [Pd(allyl)Cl], Pd(MeCN)Cl, Pd(benzonitrile)Cl, Pd(dba), Pd(OAc), PdCl, PdBr, Pd(TFA), Pd(MeCN)(BF), Pd(dba), PdCyCl, Pd(acac), and Pd(PPh). In some such embodiments, the palladium catalyst is Pd(dba) or Pd(OAc) or is Pd(OAc). 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)P, (t-Bu)PMe, (t-Bu)PPh, PCy3, PPh3, xantphos, and N-xantphos. In some embodiments, the ligand is DPPF. Polar aprotic solvents are those described elsewhere herein. In some embodiments, the solvent is THF. The ratio of solvent volume to weight of compound 160 in the reaction mixture can 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 can 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 can 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 can 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, without limitation, an alkali metal hydroxide, alkali metal carbonate, or alkali metal bicarbonate. One such inorganic base is potassium carbonate. The equivalent ratio of base to compound 160 is preferably between 1:1 and 2:1, or about 1.2:1 to about 1.8:1. The reaction can typically be carried out at a reflux temperature between about 60°C and about 80°C. The reaction can be considered complete when the area percent 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 can be 2 hours, 6 hours, 10 hours, 14 hours, 18 hours, 22 hours, or more.

[0172] Compound 170 may be isolated from the reaction product mixture. In some embodiments, water may be combined with the reaction product mixture in a ratio of water volume to compound 160 weight 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. Solid compound 170 may be isolated from the reaction mixture by, for example, filtration or centrifugation. Isolated compound 170 may optionally be dried. In some drying embodiments, drying is performed under partial vacuum with a N2 purge 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 is at least 95 area%, at least 98 area%, or at least 99 area% by HPLC.

[0173] In some particular embodiments, compound 170 can be prepared according to the methods disclosed in WO 2018 / 10905, as depicted in FIG. 11.

[0174] Preparation of Compound 140 Generally, compound 140 can be prepared according to the following scheme: It can be prepared from compounds 153 and 20 according to TIFF0007809139000039.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, provided herein is a method for preparing compound 140, comprising: (a) forming a reaction mixture comprising Compound 153, Compound 20, NaBH(OAc) and a solvent; (b) the following scheme: reacting the reaction mixture to form a reaction product mixture comprising compound 140 according to TIFF0007809139000040.tif32170. The method includes:

[0177] In some aspects, acetic acid is not separately added, but some may form from the presence of remaining water. In some aspects, the reaction product mixture formed in step (a) comprises less than 10% by weight, less than 5% by weight, less than 1% by weight, or is essentially free of acetic acid. In some embodiments, NaBH - of, combined OAc -The ratio of HOAc to the total is less than 1:3.1, or less than 1:3.05, or less than 1:3.01. The solvent can 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 solution of compound 153 and compound 20 in a solvent, e.g., 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, the solution is prepared by adding compound 153 to a solution of compound 20 in a solvent at a temperature between about 5°C and about 15°C, or about 10°C. In some embodiments, a solution of compound 153 and compound 20 in a solvent is combined with a suspension of NaBH(OAc) in a solvent to form a reaction mixture. In any of various embodiments, the concentration of compound 153 in the reaction mixture can be about 10 wt% to about 30 wt%, or about 15 wt% to about 25 wt%, or about 20 wt%. In any of various embodiments, the concentration of compound 20 in the reaction mixture can 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 can 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) to compound 153 can 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 can be carried out with an N purging and / or an N 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 can be about 0.5 hours, about 1 hour, about 2 hours, about 4 hours, or more. The reaction can be considered complete when the area percent 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 the water and base may be added separately. The reaction product mixture may be combined with water at a ratio of water volume to Compound 140 weight 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 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, and 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, e.g., 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 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 swap, distillation, and / or crystallization steps. For example, in some embodiments, following the addition of base, the organic layer containing compound 140 is isolated and optionally filtered, and the solvent in the organic phase containing compound 140 is exchanged for another solvent. Solvent exchange may be performed by methods known to those skilled in the art and 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 reduced pressure, e.g., at about 250 mbar to 350 mbar, or about 300 mbar. The stripped solvent may be replaced with another solvent, e.g., an organic protic solvent. The organic protic solvent may be an alcohol. In some embodiments, the organic polar protic solvent is isopropanol. In some embodiments, the methods herein further include crystallizing compound 140. Such crystallization may, for example, follow a solvent swap process 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, during which crystals of compound 140 form. The crystals may then be isolated, for example, by filtration, optionally washed with additional solvent, and dried under reduced pressure to provide dried 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% by HPLC.

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

[0181] Preparation of Compound 153 Generally, compound 153 can be prepared according to the following scheme: It can be prepared according to TIFF0007809139000041.tif32170.

[0182] In this embodiment, compound 154A can be prepared from a reaction mixture containing compound 50, compound 40, dioxane, KPO, Pd(OAc) catalyst, and BINAP ligand. In the reaction mixture, the concentration of compound 50 in dioxane is about 10 w / w%, the equivalent ratio of KPO to compound 50 is about 2, the equivalent ratio of Pd(OAc) catalyst to compound 50 is about 0.012:1, and the equivalent ratio of Pd(OAc) 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 containing BOC-protected compound 154 in about 79% yield. A reaction mixture containing compound 154A, methanol, 10% palladium-on-carbon catalyst, and hydrogen is formed. In the reaction mixture, the ratio of methanol volume to compound 154A weight is about 5:1, and the ratio of palladium on carbon catalyst to compound 154A weight is about 0.05:1. In some embodiments where PG is BOC, compound 154A is designated compound 154.

[0183] In such embodiments, compound 153 may be prepared according to the following reaction scheme: It can be prepared from compound 154A according to TIFF0007809139000042.tif33170.

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

[0185] The reaction to form compound 153 can be carried out with an N purging and / or an N blanket. The reaction is typically carried out at a temperature of about 40 to about 70°C, or about 50 to about 60°C. In some embodiments, the reaction time to completion can be at least 1 hour, or longer. The reaction can be considered complete when the area percent concentration by HPLC of compound 154A 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, for example, to about 10 to about 30°C, and the reaction mixture may be extracted with a nonpolar solvent (e.g., DCM) described elsewhere herein at a solvent volume to compound 153 weight ratio 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 solvent volume to compound 153 weight ratio 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 may be combined and washed at least once with water in a volume generally equal to the volume of each non-polar 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 to about 8 wt% or about 2 to about 6 wt%. In some embodiments, solid compound 153 may be obtained by solvent evaporation under reduced pressure. In some embodiments, the solvent used is an ester. In certain embodiments, solid compound 153 may be obtained by solvent evaporation from isopropyl acetate. In some other embodiments, the solution of compound 153 may be used directly to prepare compound 140. The yield of compound 153 is at least 80%, or at least 90%.

[0187] Holistic approach Compound 200 can be prepared in the general method depicted in FIG. 13, where steps 1-3 and 7-10 refer to the general method of WO 2018 / 109050 described elsewhere herein, and where steps 4-6 and 10-12 refer to the reactions of the present disclosure.

[0188] Solvate of Compound 200 Further provided herein are solvates of Compound 200, such as 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 an ethanol hemisolvate. In some embodiments, the crystalline solvate is a toluene solvate. In some embodiments, the crystalline solvate is an ethanol solvate.

[0189] In some embodiments, the crystalline ethanol hemisolvate is characterized by an XRPD pattern including one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10, or at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10) characteristic peaks selected from Table X. In some embodiments, the crystalline ethanol hemisolvate is characterized by an XRPD pattern including at least four, at least five, or all six of the following 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 an XRPD pattern essentially as shown in Figure 17.

[0190] In some embodiments, the crystalline toluene solvate is characterized by an XRPD pattern including one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10, or at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10) characteristic peaks selected from Table X. In some embodiments, the crystalline toluene solvate has an XRPD pattern essentially as shown in Figure 18. In some embodiments, the crystalline toluene solvate is characterized by an XRPD pattern including at least four, or all five, of the following peaks: 4.18, 6.91, 14.20, 15.59, and 16.83 (±0.2 degrees two-theta).

[0191] In some embodiments, the crystalline ethanol solvate is characterized by an XRPD pattern including one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10; or at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10) characteristic peaks selected from Table X. In some embodiments, the crystalline ethanol solvate has an XRPD pattern essentially as shown in Figure 19. In some embodiments, the crystalline ethanol solvate is characterized by an XRPD pattern including at least four, at least five, at least six, or all seven of the following peaks: 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 selected Compound 200 solvent polymorphs. The error in the position of each individual peak is ±0.2° 2-theta. TIFF0007809139000043.tif215170

[0192] Illustrative Embodiments E1. A method for preparing compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, comprising: (a) forming a reaction mixture comprising Compound 170, Compound 181, a palladium catalyst, and a solvent system comprising a base, wherein the equivalent ratio of the palladium catalyst to Compound 170 is from about 0.001:1 to less than 0.005:1; (b) the following scheme: reacting the reaction mixture to form a reaction product mixture comprising compound 190 according to TIFF0007809139000044.tif47170. Including, wherein the Pd catalyst comprises a palladium(II) species containing a phosphine ligand and at least one palladium-carbon bond; where: (i) The fragment that gives rise to the palladium-carbon bond has the formula: TIFF0007809139000045.tif23170 (in the formula, R 6 ~R 10 each independently represents H, optionally substituted C 1~6 is selected from the group consisting of alkyl, optionally substituted C aryl, and optionally substituted heteroaryl; R 6 and R 10 may optionally be joined together to form a fused bicyclic ring containing an aromatic ring. is an allyl derivative of wherein the yield of compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, is at least 50% based on compound 170. E2. The fragment that creates the palladium-carbon bond has the formula: TIFF0007809139000046.tif23170 (in the formula, R 11 is C 1~10 alkyl) The indenyl of E1. E3. Allyl derivatives are (a)R 6 ~R 10 a derivative in which each of (b)R 6 Ga-CH 3 and R 7 ~R 10 a derivative in which each of (c)R 7 is -CH3 and R 6 and R 8 ~R 10 a derivative in which each of (d)R 8 is -CH3 and R 6 , R 7 , R 9 and R 10 a derivative in which each of (e)R 6 is -phenyl and R 7 ~R 10 a derivative in which each of (f)R 7 is -phenyl and R 6 and R 8 ~R 10 a derivative in which each of (g) Structure: Method E1 or E2, selected from TIFF0007809139000047.tif24170. E4. The phosphine ligand has the formula: TIFF0007809139000048.tif34170 where, R 1 and R 2 each independently represents an optionally substituted C 1~12 Alkyl, optionally substituted C3-C 20 cycloalkyl, and optionally substituted C5 or C6 aryl; R 3 ~R 5 are each independently H, optionally substituted C, 1~6 Alkyl, formula -OC 1~6 Alkoxides of alkyl, and compounds of the formula -N(R 12 )(R 13 )(wherein, R 12 and R 13 are independently H and C1~6 alkyl) Any one of methods E1 to E3. E5. The phosphine ligand has the following structure: Any one of methods E1 to E4, which is SPhos of TIFF0007809139000049.tif36170. E6.Pd catalyst is (a) a cationic palladium species containing an inorganic or organic counterion X, and (b) a neutral palladium species containing a coordinated inorganic or organic ligand, X; Any one of methods E1 to E5 selected from: E7. The method of E6, wherein X is selected from halogen, carboxylate, sulfonate, and an inorganic anion. E8. (a) The carboxylate is CH3C(O)O - and tBuC(O)O - is selected from (b) The sulfonate is CF3SO3 - , tosylate, besylate and nosylate; (c) The inorganic anion is PF6 - , BF4 - , B(C6F5)4 - , NO3 - and SO4 2- The method of E7, wherein the method is selected from the group consisting of: E9.X is CF3SO3 - This is method E7 or E8. E10. Palladium catalyst is CF3SO3 - and an organic counterion, wherein the phosphine ligand is SPhos, and wherein R 6 ~R 10 The method of any one of E1 to E9, wherein each of is H. E11. The process of any one of E1 to E10, wherein the solvent system predominantly comprises an aprotic low molecular weight ester solvent and water, wherein the volume ratio of aprotic low molecular weight ester solvent to water is from about 1:0.1 to about 1:1, and the reaction mixture is heated to from about 60°C to about 80°C. E12. The method of any one of E1 to E11, wherein the equivalent ratio of compound 181 to compound 170 is greater than 1:1 and the equivalent ratio of palladium catalyst to compound 170 is from 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 comprises predominantly ethyl acetate and water, wherein the volume ratio of ethyl acetate to water is from about 1:0.1 to about 1:1; (c) The boronate has the structure: Any one of methods E1 to E12, which is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane of TIFF0007809139000050.tif23170. E14. The process of any one of E1 to E13, wherein the yield of compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, is at least 60%, at least 70%, at least 80%, or at least 90%, and the purity of compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, is at least 99 area%, or at least 99.5 area%. E15. (a) containing less than 0.1 area % of a dimeric impurity based on Compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, wherein the dimeric impurity has the structure: It is from TIFF0007809139000051.tif61170, (b) having a combined alcohol impurity and a ketone impurity of less than 0.25 area % based on Compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, wherein the alcohol impurity and the ketone impurity have the structure: Any one of methods E1 to E14 from TIFF0007809139000052.tif79170. E16. Further comprising reacting compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, to form compound 200, or a stereoisomer, geometric isomer, tautomer, or salt thereof, wherein the reaction (a) The following scheme contacting compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, with a reducing agent and a base in the presence of a solvent to form compound 200, or a stereoisomer, geometric isomer, tautomer, or salt thereof, according to TIFF0007809139000053.tif53170; (b) isolating compound 200, or a stereoisomer, geometric isomer, tautomer, or salt thereof; Including, wherein the yield of compound 200, or a stereoisomer, geometric isomer, tautomer, or salt thereof, based on compound 170 is at least 60%, at least 70%, at least 80%, or at least 85%, and the purity of compound 200, or a stereoisomer, geometric isomer, tautomer, or salt thereof, is at least 99 area%, or at least 99.5 area%. E17. The process of any one of E1 to E16, further comprising isolating compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, from the reaction product mixture. E18. Compound 181 is (a) forming a first reaction mixture comprising compound 140, a palladium / vanadium on carbon catalyst, a solvent, and hydrogen; (b) reacting the first reaction mixture according to the following scheme: forming a first reaction product mixture comprising compound 140 according to TIFF0007809139000054.tif37170; (c) forming a second reaction mixture comprising Compound 141, Compound 90, a palladium catalyst, a catalytic ligand, a base, and a solvent; (d) The following scheme where LG is a leaving group: reacting the second reaction mixture according to TIFF0007809139000055.tif49170 to form a second reaction product mixture comprising compound 180; (e) Compound 180 was synthesized using the following scheme: with a boronating agent in the presence of a solvent to form compound 181 according to TIFF0007809139000056.tif49170. Including, wherein the yield of compound 141 based on compound 140 is at least 90%, or at least 95%, The method of any one of E1 to E17, wherein 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%. E19. Compound 181 is (a) 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; TIFF0007809139000057.tif30170(b) forming a second reaction mixture comprising Compound 141, Compound 90, a palladium catalyst, a catalytic ligand, a base, and a solvent; (c) The following scheme where LG is a leaving group: reacting the second reaction mixture according to TIFF0007809139000058.tif49170 to form a second reaction product mixture comprising compound 180; (d) Compound 180 was synthesized using the following scheme: with a boronating agent in the presence of a solvent to form compound 181 according to TIFF0007809139000059.tif49170. Prepared by wherein the yield of compound 141 based on compound 140 is at least 90%, or at least 95%, The method of any one of E1 to E17, wherein 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%. E20. The process of E18 or E19, wherein the palladium catalyst is Pd(OAc)2, the ligand is Xantphos, the base is K2CO3, and the solvent comprises predominantly 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 comprises predominantly anisole. E22. The method of any one of E18 to E21, wherein the leaving group is a halogen or triflate, or is Br. E23. The method of any one of E18 to E22, wherein compound 141 is isolated from the first reaction product mixture prior to forming the second reaction product mixture. E24. Compound 140 is (a) forming a reaction mixture comprising Compound 153, Compound 20, NaBH(OAc) 3 , and a solvent; (b) the following scheme: reacting the reaction mixture to form a reaction product mixture comprising compound 140 according to TIFF0007809139000060.tif32170. Prepared by any one of methods E18 to E23. E25. The process of E24, wherein the solvent in step (a) is an organic solvent, optionally an aprotic organic solvent, optionally THF or Me-THF. E26.NaBH - of combined OAc - The process of E24 or E25, wherein the ratio of to the total of HOAc is less than 1:3.1 and the solvent in step (a) is THF. E27. A method for reducing by-product formation in a Suzuki coupling reaction, comprising: (a) forming 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 from about 0.001:1 to less than 0.005:1; (b) the following scheme: reacting the reaction mixture to form a reaction product mixture comprising compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, according to TIFF0007809139000061.tif43170. Including, wherein the Pd catalyst comprises a palladium(II) species containing a phosphine ligand and at least one palladium-carbon bond; where: (i) The fragment that gives rise to the palladium-carbon bond has the formula: TIFF0007809139000062.tif18170 (in the formula, R 6 ~R 10 each independently represents H, optionally substituted C 1~6 is selected from the group consisting of alkyl, optionally substituted C aryl, and optionally substituted heteroaryl; R 6 and R 10 may optionally be joined together to form a fused bicyclic ring containing an aromatic ring. is an allyl derivative of where: (a) containing less than 0.1 area % of a dimeric impurity based on Compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, wherein the dimeric impurity has the structure It is from TIFF0007809139000063.tif57170, (b) having a combined alcohol impurity and a ketone impurity of less than 0.25 area % based on Compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, wherein the alcohol impurity and the ketone impurity have the structure TIFF0007809139000064.tif59170, Method. E28. The fragment that forms the palladium-carbon bond has the formula: TIFF0007809139000065.tif20170 (in the formula, R 11 is C 1~10 alkyl) The indenyl of E1. E29. Allyl derivatives are (a)R 6 ~R 10 a derivative in which each of (b)R 6 Ga-CH 3 and R 7 ~R 10 a derivative in which each of (c)R 7 is -CH3 and R 6 and R 8 ~R 10 a derivative in which each of (d)R 8 is -CH3 and R 6 , R 7 , R 9 and R 10 a derivative in which each of (e)R 6 is -phenyl and R 7 ~R 10 a derivative in which each of (f)R 7 is -phenyl and R 6 and R 8 ~R 10 a derivative in which each of (g) Structure: Derivative of TIFF0007809139000066.tif27170 E27 or E28 method selected from. E30. The phosphine ligand has the formula: TIFF0007809139000067.tif30170 where, R 1 and R 2 each independently represents an optionally substituted C 1~12 Alkyl, optionally substituted C3-C 20cycloalkyl, and optionally substituted C5 or C6 aryl; R 3 ~R 5 are each independently H, optionally substituted C, 1~6 Alkyl, formula -OC 1~6 Alkoxides of alkyl, and compounds of the formula -N(R 12 )(R 13 )(wherein, R 12 and R 13 are independently H and C 1~6 alkyl) Any one of E27 to E29. E31. The phosphine ligand has the following structure: Any one of E27 to E30, SPhos of TIFF0007809139000068.tif30170. E32.Pd catalyst is (a) a cationic palladium species containing an inorganic or organic counterion X, and (b) a neutral palladium species containing a coordinated inorganic or organic ligand, X; Any one of methods E27 to E31 selected from the above. E33. The method of E32, wherein X is selected from halogen, carboxylate, sulfonate, and inorganic anion. E34. (a) The carboxylate is CH3C(O)O - and tBuC(O)O - is selected from (b) The sulfonate is CF3SO3 - , tosylate, besylate and nosylate; (c) The inorganic anion is PF6 - , BF4 - , B(C6F5)4 - , NO3 - and SO4 2- The method of E7, wherein the method is selected from the group consisting of: E35.X is CF3SO3 - This is the E33 or E34 method. E36. Palladium catalyst is CF3SO3 - and an organic counterion, wherein the phosphine ligand is SPhos, and wherein R 6 ~R 10 Any of E27 to E35, each of which is H. E37. The process of any one of E27 to E36, wherein the solvent system comprises predominantly an aprotic low molecular weight ester solvent and water, wherein the volume ratio of aprotic low molecular weight ester solvent to water is from about 1:0.1 to about 1:1, and the reaction mixture is heated to from about 60°C to about 80°C. E38. The process of any one of E27 to E37, wherein the equivalent ratio of compound 181 to compound 170 is greater than 1:1 and the equivalent ratio of palladium catalyst to compound 170 is from 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 comprises predominantly ethyl acetate and water, wherein the volume ratio of ethyl acetate to water is from about 1:0.1 to about 1:1; (c) The boronate has the structure: Any one of methods E27 to E38, which is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane of TIFF0007809139000069.tif19170. E40. The process of any one of 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 a Suzuki coupling reaction, comprising: (a) forming 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 from about 0.001:1 to less than 0.005:1; (b) the following scheme: reacting the reaction mixture to form a reaction product mixture comprising compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, according to TIFF0007809139000070.tif47170. Including, wherein the Pd catalyst comprises a palladium(II) species containing a phosphine ligand and at least one palladium-carbon bond; where: (i) The fragment that gives rise to the palladium-carbon bond has the formula: TIFF0007809139000071.tif18170 (in the formula, R 6 ~R 10 each independently represents H, optionally substituted C 1~6 is selected from the group consisting of alkyl, optionally substituted C aryl, and optionally substituted heteroaryl; R 6 and R 10 may optionally be joined together to form a fused bicyclic ring containing an aromatic ring. is an allyl derivative of wherein the yield of compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, based on compound 170 is at least 80%, or at least 85%. E42. The fragment that forms the palladium-carbon bond has the formula: TIFF0007809139000072.tif23170 (in the formula, R 11 is C 1~10 alkyl) The indenyl of E1. E43. Allyl derivatives are (a)R 6 ~R 10 a derivative in which each of (b)R 6 Ga-CH 3 and R 7 ~R 10 a derivative in which each of (c)R 7 is -CH3 and R 6 and R 8 ~R10 a derivative in which each of (d)R 8 is -CH3 and R 6 , R 7 , R 9 and R 10 a derivative in which each of (e)R 6 is -phenyl and R 7 ~R 10 a derivative in which each of (f)R 7 is -phenyl and R 6 and R 8 ~R 10 a derivative in which each of (g) Structure: Derivative of TIFF0007809139000073.tif26170 The method of E41 or E42, wherein the method is selected from the group consisting of: E44. The phosphine ligand has the formula: TIFF0007809139000074.tif34170 (in the formula, R 1 and R 2 are each independently 1~6 alkyl, and C5 or C6 aryl; R 3 ~R 5 are independently H, C 1~6 alkyl, ether, and amine) Any one of methods E41 to E43. E45. The phosphine ligand has the following structure: Any one of methods E41 to E44, which is SPhos of TIFF0007809139000075.tif30170. E46.Pd catalyst is (a) a cationic palladium species containing an inorganic or organic counterion X, and (b) a neutral palladium species containing a coordinated inorganic or organic ligand, X; Any one of methods E41 to E45 selected from: E47. The method of E46, wherein X is selected from halogen, carboxylate, sulfonate and inorganic anion. E48. (a) The carboxylate is CH3C(O)O - and tBuC(O)O - is selected from (b) The sulfonate is CF3SO3 - , tosylate, besylate and nosylate; (c) The inorganic anion is PF6 - , BF4 - , B(C6F5)4 - , NO3 - and SO4 2- The method of E47, selected from E49.X is CF3SO3 - This is the E47 or E48 method. E50. Palladium catalyst is CF3SO3 - and an organic counterion, wherein the phosphine ligand is SPhos, and wherein R 6 ~R 10 Any of the methods E41 to E49, wherein each of is H. E51. The process of any one of E41 to E50, wherein the solvent system comprises predominantly an aprotic low molecular weight ester solvent and water, wherein the volume ratio of aprotic low molecular weight ester solvent to water is from about 1:0.1 to about 1:1, and the reaction mixture is heated to from about 60°C to about 80°C. E52. The method of any one of E41 to E51, wherein the equivalent ratio of compound 181 to compound 170 is greater than 1:1 and the equivalent ratio of palladium catalyst to compound 170 is from 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 comprises predominantly ethyl acetate and water, wherein the volume ratio of ethyl acetate to water is from about 1:0.1 to about 1:1; (c) The boronate has the structure: Any one of methods E41 to E52, which is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane of TIFF0007809139000076.tif23170. E54. (a) the content of a dimer impurity is less than 0.1 area % based on Compound 190, wherein the dimer impurity has the structure: It is TIFF0007809139000077.tif62170, (b) having a combined alcohol and ketone impurity content of less than 0.25 area % based on Compound 190, wherein the alcohol and ketone impurities have the structure It is from TIFF0007809139000078.tif74170, (c) The method of any one of E41 to E53, wherein the purity of compound 190 is at least 95 area %, at least 99.5 area %. E55. A method for preparing compound 180, its stereoisomers, its geometric isomers, its tautomers and salts thereof, comprising: (a) forming a first reaction mixture comprising compound 140, a palladium / vanadium on carbon catalyst, a solvent, and hydrogen; (b) The following scheme reacting the first reaction mixture according to TIFF0007809139000079.tif36170 to form a first reaction product mixture comprising compound 141; (c) forming a second reaction mixture comprising Compound 141, Compound 90, a palladium catalyst, a catalytic ligand, a base, and a solvent; (d) The following scheme reacting the second reaction mixture to form a second reaction product mixture comprising compound 180 according to TIFF0007809139000080.tif47170; Including, wherein 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; wherein the yield of compound 141 based on compound 140 is at least 90%, or at least 95%, wherein 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%. E56. A method for preparing compound 180, its stereoisomers, its geometric isomers, its tautomers, and its salts, comprising: (a) 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; TIFF0007809139000081.tif29170(b) forming a second reaction mixture comprising Compound 141, Compound 90, a palladium catalyst, a catalytic ligand, a base, and a solvent; (c) The following scheme where LG is a leaving group: reacting the second reaction mixture according to TIFF0007809139000082.tif43170 to form a second reaction product mixture comprising compound 180; (d) Compound 180 was synthesized using the following scheme: with a boronating agent in the presence of a solvent to form compound 181 according to TIFF0007809139000083.tif47170. Including, wherein the yield of compound 141 based on compound 140 is at least 90%, or at least 95%, wherein 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%. E57. The method of E55 or E56, wherein compound 141 is not isolated from the first reaction product mixture prior to formation of the second reaction product mixture. E58. The process of any one of E55 to E57, wherein the first reaction mixture solvent and the second reaction mixture solvent each comprise predominantly a polar aprotic solvent. E59. The process of E58, wherein the first reaction mixture solvent comprises predominantly tetrahydrofuran. E60. The process of any one of E51 to E59, further comprising a solvent exchange step in which the first reaction product mixture solvent is predominantly replaced with a polar aprotic solvent prior to forming the second reaction mixture. E61. The method of E60, wherein the first reaction product mixture solvent is predominantly replaced with anisole and the second reaction mixture solvent predominantly comprises anisole. E62. The process of any one of E55 to E61, wherein the palladium catalyst is Pd(OAc)2 and the catalytic ligand is Xantphos or DPEPhos. E63. The process of any one of E55 to E62, wherein the palladium catalyst is Pd(OAc)2, the catalytic ligand is Xantphos, and the base is K2CO3, or the palladium catalyst is Pd(OAc)2, the catalytic ligand is DPEPhos, and the base is NaOMe. E64. The process of any one of E55 to E62, wherein the first reaction mixture catalyst is Pt / V@C. E65. The process of any one of E56 to E62, wherein the first reaction mixture catalyst is Pd / Al2O3, Pt / Al2O3, Pd / C, or Pt / C. E66. The method of any one of E56 to E65, (e) contacting the second reactant with an aqueous wash; (f) isolating and concentrating the organic phase, wherein the organic phase comprises predominantly all of compound 180 contained in the second reaction product mixture; (g) combining the concentrated organic phase with alcohol and water; (h) isolating the organic phase containing predominantly all of the second reaction product mixture solvent, alcohol, and compound 180; (i) concentrating the isolated organic phase; (j) combining the concentrated organic phase with an alcohol and cooling it to form crystalline compound 180; (k) isolating the crystalline compound 180; further comprising isolating compound 180 by the sequence 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 a stereoisomer, geometric isomer, tautomer, or salt thereof, TIFF0007809139000084.tif49170 where, (a) the content of a dimer impurity is less than 0.15 area % based on Compound 190, wherein the dimer impurity has the structure: It is TIFF0007809139000085.tif67170, (b) having a combined alcohol impurity and ketone impurity content of less than 0.35 area % based on Compound 190, wherein the alcohol impurity and the ketone impurity have the structure Composition of TIFF0007809139000086.tif63170. E68-1. A method for preparing compound 180, its stereoisomers, its geometric isomers, its tautomers, and its salts, comprising: (a) 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; TIFF0007809139000087.tif28170(b) forming a second reaction mixture comprising Compound 141, Compound 90, a palladium catalyst, a catalytic ligand, a base, and a solvent; (c) The following scheme where LG is a leaving group: reacting the second reaction mixture according to TIFF0007809139000088.tif47170 to form a second reaction product mixture comprising compound 180; (d) Compound 180 was synthesized using the following scheme: with a boronating agent in the presence of a solvent to form compound 181 according to TIFF0007809139000089.tif48170. Including, wherein the yield of compound 141 based on compound 140 is at least 90%, or at least 95%, wherein 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%. E69. The composition of E68 or E68-1, wherein the dimeric impurity content is less than 0.10 area % based on compound 190. E70. The composition of E69, wherein the dimeric impurity content is less than 0.05 area % based on Compound 190. E71. Any one of compositions E68-E70, having a combined alcohol and ketone impurity content of less than 0.30 area % based on Compound 190. E72. The composition of E71, wherein the combined alcohol and ketone impurities content is less than 0.25 area % based on Compound 190. E73. The composition of E72, wherein the combined alcohol and ketone impurities content is less than 0.20 area % based on Compound 190. E74. Composition of any one of E68 to E73 comprising at least 98.0 w / w% of Compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof. E75. The composition of E74, comprising at least 98.5 w / w% Compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof. [Example]

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

[0194] In the examples, equivalents and equivalent ratios are based on the starting materials stated for each reaction. Volume values ​​per weight, such as L / kg and mL / g, refer to the volume of a liquid component based on the weight of the starting materials stated 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 Columns. HPLC System: Agilent Series 1260, quaternary pump, and autosampler. Integration System: Waters Empower. Configuration: Jetweaver V380 mixer without 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 ammonium acetate, 1000 mL water, pH 5.8 ± 0.1, adjust pH with acetic acid if necessary. Mobile phase A: 950 mL buffer solution, 50 mL acetonitrile. Mobile phase B: 950 mL acetonitrile, 50 mL buffer solution. Diluent: water / acetonitrile 1:9 v / v (e.g., 100 mL water and 900 mL acetonitrile).

[0198] Pump program. TIFF0007809139000090.tif48170

[0199] Column oven temperature: 25°C. Column back pressure: approx. 300 bar (initial conditions). Injection volume: 3.0 μL. Needle wash: Wash the 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, with peak width > 0.05 min, reaction time 1 s.

[0200] Sample preparation. Blank solutions were used as dilutions. For stock solution 1, the following reference standards were dissolved in 10.0 mL of dilution: 7.0–8.0 mg Des-Brom impurity; 7.0–8.0 mg cysteine ​​adduct impurity; 7.0–8.0 mg regioisomeric impurity (compound 190 regioisomer); 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 reference standards 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 mg of 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 THF impurity peak assignment), 7.0-8.0 mg of THF impurity was 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 test. Blank chromatogram: The blank chromatogram was compared with the chromatogram drawn in the analytical method; system peaks or peaks resulting from the chemicals used should not interfere with the analysis. Selectivity: The chromatogram of the SST solution was comparable to the closed-form chromatogram in terms of selectivity and retention time. Sensitivity, peak symmetry: The chromatogram of the SST solution was checked by visual inspection. Action: In case of failure, the sample analysis was not valid. After correcting the source of error, the blank, SST and sample analysis were repeated.

[0202] Compound identity is confirmed when the retention time of the major peak in the sample chromatogram matches the retention time of the major peak in the SST solution chromatogram. TIFF0007809139000091.tif20170 (where xi = percentage of analyte i (% area); Ai = percentage of analyte i (mAU) * s) or (pA * s) or (counts * s); and Aj = area of ​​the peak obtained for analyte j = 1 to n (mAU * s) or (pA * s) or (counts * s). The percent area reduction took into account only the selected analyte.

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

[0204] Integration parameters. The integration parameters are adjusted to integrate all peaks ≥ half the reporting level ("RL"). Any impurity peaks that are not completely separated from the main peak are preferably integrated by valley-to-valley extrapolation (tangential skim).

[0205] The peak table is as follows: TIFF0007809139000092.tif89170 a Only in SST solution The peak table is for peak assignment / information only. TIFF0007809139000093.tif45170

[0206] The amount of dimer in % w / w by HPLC Method 1 described above correlates with the amount of dimer in Area % HPLC Method as reported in the correlation table below. Correlation of dimer % w / w assessed by HPLC Method 1 with area % from the same sample determined by other HPLC methods. TIFF0007809139000094.tif27170

[0207] Analytical methods for Comparative Examples 1 to 3 Comparative Example 1: Column: Waters Atlantis T3 (4.6 * 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 4.6 mm x 50 mm, 1.8 μm. Mobile phase A: water / 0.05% TFA. Mobile phase B: CH3CN / 0.05% TFA. Flow rate: 1.2 mL / min. Injection volume: 10.0 μL. Column temperature: 40°C. Diluent: 30:70 (v / v) CH3CN / H2O. Interface type: ES-API+. Drying gas temperature: 250°C. Nebulizer pressure: 35 psig. Drying gas flow: 13 L / min. Capillary voltage: 3000 V. Scan range: 150-600 m / z.

[0210] Gas chromatography (GC) can be performed as follows: Agilent HP-5 (30 ml) * 0.32mm * Agilent 7890A Series GC system equipped 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 using (1) a Sciex 15 mass spectrometer in ES+ mode or (2) a Shimadzu LCMS 2020 mass spectrometer in ESI+ mode. Mass spectrometry data generally only show parent ions unless otherwise noted. MS or HRMS data are provided for specific intermediates or compounds where indicated.

[0212] Nuclear magnetic resonance analysis (NMR) 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, and referenced to tetramethylsilane. NMR data is provided for specific intermediates or compounds where indicated.

[0213] Example 1 Compound 140 was prepared according to the reaction scheme in Figure 12A and as depicted below. TIFF0007809139000095.tif38170

[0214] To a warm (35 °C) suspension of NaBH(OAc)3 (71.5 g, 337 mmol) in THF (110 g) was added a cold (10 °C) preformed mixture of (S)-2-methyl-1-(6-nitropyridin-3-yl)piperazine (50 g, 225 mmol, Compound 153) and oxetan-3-one (21.2 g, 292 mmol, Compound 20) in THF (136.4 g) over 1–2 h. The mixture was stirred at 35 °C until complete conversion was achieved (typically 1 h). 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 a pH of 12. After phase separation, the organic phase was polish filtered and concentrated at 40°C, followed by successive exchanges of THF with 2-PrOH under reduced pressure (300 mbar), at which point crystallization began. 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-nitropyridin-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 N4O3: 278.1379; Found: 278.1406.

[0215] Example 2 Compounds 141 and 180 were prepared according to the reaction scheme in Figure 1 and as depicted in more detail below: TIFF0007809139000096.tif85170

[0216] A solution of (S)-2-methyl-1-(6-nitropyridin-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 in the presence of Pt / V@C catalyst (1.12 g, 2 wt%) at 60 °C and 4 bar of hydrogen for 16 h to produce a solution of (S)-5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-amine (compound 141). After releasing the pressure, 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 remaining THF was removed by distillation under reduced pressure (120-150 mbar, Ti90±5° C.) to a reactor volume of 250 mL (5V).

[0217] Next, 3,4-dibromo-1-methylpyridin-2-one (compound 90) (1.05 equiv.) and K2CO3 (1.5 equiv.) were added to the solution of compound 141 under an argon / nitrogen flow at 90 °C, followed by the dropwise addition of water (1.0 equiv.). Finally, Xantphos (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 h). The reaction mixture was diluted with anisole (2 V), followed by the addition of water (4 V), bringing the temperature to 90 °C. The organic and aqueous phases were separated. Anisole was partially removed from the organic phase under reduced pressure (120-150 mbar) to a reactor volume of 150 mL (3 V). 1-Butanol (5V) and water (4V) were then added, followed by separation into organic and aqueous phases. 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 mbar) 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 a temperature of -10°C at a rate of 10°C / h and stirred at -10°C for at least 6 hours. The crystals were collected by filtration, washed with cold (-5±2°C) MeOH / HO (1:1 v / v, 1.5V) and cold (-5±2°C) 1-butanol (2.5V), and dried at 70°C under reduced pressure (2-10 mbar) until a constant weight was reached, affording compound 180 as a beige-yellowish 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 for BrN5O2: 433.1113; Found: 433.1130.

[0218] Example 3 Compounds 141 and 180 were prepared according to the reaction scheme in Figure 2 and as depicted below. TIFF0007809139000097.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 weight: 1.05), anhydrous sodium methoxide (3.92 g, 72.48 mmol, equivalent weight: 1.2), and finally a premixed red suspension of palladium(II) acetate (203.4 mg, 906.1 μmol, equivalent weight: 0.015) and DPEphos (975.9 mg, 1.812 mmol, equivalent weight: 0.030) in anisole (6.93 g, 7 mL) were added. The reaction mixture was then heated to 92°C, at which point a suspension formed. The mixture was then stirred until complete conversion was achieved and then quenched upon the 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 successively with MeOH (45 mL), HO / MeOH (1:1 v / v, 20 mL), and MeOH (30 mL). The crystals were dried under reduced pressure at 45°C to a constant weight to give compound 180 as a beige solid in 82.5% yield (12.6 g) and >99 area% purity.

[0220] Example 4 Example 3 was repeated except that triphenylphosphine (4.5 mol%) was added to the reaction mixture containing the solution of compound 141. The reaction gave an 82.4% yield at 98.3% purity.

[0221] Example 5 Compound 141 can be synthesized according to the following scheme: Prepared according to TIFF0007809139000098.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 in the presence of Pt / V / @C catalyst (6.0 g, 2 wt%) at 60 °C and 4 bar of hydrogen for 16 hours to produce compound 141 in solution. After cooling to ambient temperature and releasing the pressure, the catalyst was recovered by filtration, the autoclave was rinsed with THF, and the filter cake was washed with THF (total THF rinse of 177.8 g). THF was distilled off from the combined solution (70 °C, 350 mbar) to a reactor volume of approximately 1.5 L, followed by cooling to 37 °C. n-Heptane (1 L) was added, at which point compound 141 crystallization began, and the suspension was stirred at 27 °C for 1.5 hours. Additional n-heptane (1.25 L) was then added and the suspension was stirred at 25° C. for 15 min, then cooled to 3-5° C. and stirred for 30 min. The crystals were then collected by filtration, washed with n-heptane (1 L), and dried under reduced pressure to give 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: 248.1637; Found: 248.1647. XRF: < 1 ppm Pt; < 2 ppm V.

[0223] Example 6 The catalyst for the preparation of 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 TIFF0007809139000099.tif104170

[0224] In the table above, runs 1 and 3 used 50-56 g of Compound 140, 10 V solvent, a 1.5 L autoclave equipped with a glass insert, and a 16-hour reaction time. The catalyst for run 1 was Noblyst P8078, and for run 3 the catalyst was E101 NE / W. Runs 2, 4, and 5 used 5 g of Compound 140, 10 V solvent, a 185 mL autoclave, and a 16-hour reaction time. Runs 6-10 used 200 mg of Compound 140, 10 V solvent, a 35 mL autoclave equipped with a glass insert and agitator, and a 16-hour reaction time.

[0225] Example 7 Compound 190 was prepared from compounds 170 and 182 using various catalysts at at least two catalyst concentrations: 0.001 equivalent per equivalent of compound 170 (0.1 mol%) or 0.01 equivalent per equivalent of compound 170 (1 mol%). In each experiment, the solvent was THF and water, with a volume ratio of THF to water of 4:1, the solvent volume to compound 170 ratio was 10:1 L / kg, the equivalent ratio of compound 182 to compound 170 was 1.1:1, the base was KPO (1.5 equivalents based on compound 170), the reaction temperature was 50°C, and the reaction time was 18 hours. After 18 hours, 0.25 equivalents of acetylcysteine ​​as a 60 mg / mL solution in HO was added to the reaction mixture, the mixture was stirred for 10 minutes, and a sample was removed 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 the ketone impurity, "sec alcohol" refers to the sec alcohol impurity, "dimer" refers to the dimer impurity, "Comp. 182" refers to compound 182, and "des brom" refers to the DesBr impurity depicted below, and the results are reported in HPLC area %. TIFF0007809139000101.tif44170

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

[0227] Table 2 reports the activity of cationic and neutral Pd(SPhos)(allyl) compounds at 1 mol% catalyst loading. This table demonstrates that, compared to the previously disclosed [Pd(dppf)Cl2] catalyst, higher amounts of compound 190 were produced and much lower amounts of dimer were formed (0.87 for Pd(dppf)Cl2 vs. 0.02-0.08 for Pd(SPhos(allyl) catalysts). Table 3 demonstrates that, among the catalysts that performed better at 1 mol%, [(SPhos)Pd(allyl)]OTf performed best at 0.1 mol% (higher amount of compound 190 and lower amount of dimer). Table 2: Summary of results using various cationic and neutral Pd(SPhos)(allyl) catalysts at 1 mol% loading, as well as the previously used catalyst Pd(dppf)Cl2. TIFF0007809139000102.tif58170Table 3: Summary of results using a variety of cationic and neutral Pd(SPhos)(allyl) catalysts at 0.1 mol% loading. TIFF0007809139000103.tif58170

[0228] The data clearly demonstrate that improved impurity profiles were achieved using the (SPhos)Pd(allyl) counter anion described in this disclosure 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 equiv.) and compound 182 (46.3 g, 88.0 mmol, 1.1 equiv.) were suspended in ethyl acetate (222 mL, 200 g) with stirring at 70 °C, followed by thorough degassing for 10 min. [(SPhos)Pd(allyl)]OTf catalyst (113 mg) was added in one portion, and the suspension was heated to 70 °C ± 3 °C in 25–35 min. Then, a solution of potassium phosphate (25 g) in water (60.0 g) was added over a period of 55–65 min at 70 °C ± 5 °C. The reaction product mixture was stirred at 70 °C until in-process control indicated less than 1.0 area % of compound 170. The reaction time was 1–2 h.

[0230] The reaction product mixture was cooled to 20°C and then combined with a solution of N-acetylcysteine ​​(3.27 g) in water (60.0 g) that had been degassed with Ar by bubbling. The aqueous N-acetylcysteine ​​container and transfer line were washed with ethyl acetate (22.4 g, 25.0 mL) and pushed 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 (100 g, 98 mL) at 20°C ± 3°C with stirring. The stirring was stopped and the phases were allowed to separate (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. The stirring was stopped and the phases were allowed to separate (15 minutes). The smaller aqueous phase was removed and the remaining organic phase was heated to 40°C ± 3°C and then filtered over activated charcoal R55SP. The filtrate was collected in a Schott flask and the vessel previously containing 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 at approximately 85°C under reduced pressure of approximately 200-300 mbar to a remaining volume of approximately 100 mL. Ethanol (350 g, 450 mL) was then added at 50-70°C to form a suspension. The suspension was concentrated at reflux (approximately 85°C) and atmospheric pressure to a remaining volume of approximately 400 mL. A solution was obtained at reflux, which was maintained throughout the concentration process. An in-process control sample was collected and tested for remaining ethyl acetate, and concentration was continued until the fraction of EtOAc in the EtOAc / EtOH mixture was 6.0% or less. If that level was not achieved, additional ethanol could be added to the solution to bring it to a concentration of approximately 400 mL. After the EtOAc content had decreased 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 resulting 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 over a Nutsche tube using filter paper at a vacuum of approximately 500 mbar. The recovered solid Compound 190 was washed twice with ethanol at 4°C to 6°C, bringing the total ethanol volume to 74.9 g. The Compound 190 product was dried overnight at 50°C under reduced pressure at 5 mbar to give 48.6 g of Compound 190 (99.7 area % assay and 91.4% yield).

[0232] The above method for preparing compound 190 was repeated in triplicate (Runs 1-3), except that the solvent exchange from ethyl acetate to ethanol in Run 3 was performed as follows: The organic phase was concentrated to 80 mL and ethanol (268 g, 340 mL) was added. The results are presented 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 EtOAc fraction test. Table 4: Summary of in-process (IPC) and post-completion experimental characterization for three triplicate experiments to prepare compound 190 using [(SPhos)Pd(allyl)]OTf and ethyl acetate. TIFF0007809139000104.tif142170

[0233] Example 9 The disclosed reaction to prepare compound 190 from compounds 182 and 170 was compared to a previously used reaction to prepare compound 190 from compounds 182 and 170. The reaction conditions are summarized in Table 5. Using the old catalyst system of Pd(dppf)Cl, the ketone impurity was observed over a wide range, up to 0.29 area % (see Table 5). In contrast, using the new catalyst system, the amount of ketone impurity observed is kept within a narrow range with a much lower upper limit (up to 0.06 area %). Table 5: Summary of the methods used and conditions from the methods described above. Yield, purity, and by-product content in the isolated compounds after workup were assessed. "Present" values ​​are averages over three batches totaling 800 kg of product. TIFF0007809139000105.tif94170

[0234] The dimer, alcohol and ketone impurities are depicted below: TIFF0007809139000106.tif59170

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

[0236] Example 10 Compound 200 can be synthesized according to the following scheme: Prepared from compound 190 as shown in TIFF0007809139000107.tif48170.

[0237] Compound 190 (50 g, 75.4 mmol, 1 equiv.) was charged to a reactor. THF (267 g) was added, followed by KHPO (6.16 g, 35.4 mmol, 0.469 equiv.) and water (42.5 g). The mixture was heated to 40-45 °C and vigorously stirred for approximately 20 min. Then, while maintaining the temperature at 40-45 °C, an aqueous mixture of sodium hydroxide and sodium borohydride (12 wt.% NaBH, 40 wt.% NaOH, 11.9 g total aqueous solution) was added over 10-23 min. The contents of the reactor were monitored until the concentration of compound 190 remaining was 0.20 area % or less (approximately 1 h). 85% aqueous phosphoric acid (10.5 g) was then added to the reaction 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). TIFF0007809139000108.tif52170

[0238] The contents were stirred vigorously for an additional 3 hours, then cooled to 40-45°C. The organic phase was separated, removed, and filtered through activated carbon. The filtrate was then concentrated at 65°C under atmospheric pressure to a minimum volume of 2.6 L / kg starting material Compound 190, and methanol was added to a final volume of 6.6 L / kg starting material Compound 190. The mixture was seeded to initiate crystallization of Compound 200, and the solvent swap was continued at constant volume until the THF concentration fell below 5.0% w / w. The resulting suspension was aged for at least 30 minutes, cooled to 5°C over 5 hours, and held at 5°C for at least 3 hours. After that, the crystals of Compound 200 were filtered off using a funnel and washed twice with methanol. The crystals were dried under reduced pressure until a constant 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 in a cooling crystallization method.

[0240] Crude compound 200 was suspended in a 60:40 w / w toluene:ethanol mixture in a first reactor at ambient temperature and then heated to between 70 and 75°C. The suspension was transferred to a second reactor through a polish filter unit, followed by rinsing the first reactor 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 20:80 w / w toluene:ethanol ratio was reached. The solution was cooled to 50°C and seeded with a 10% w / w suspension of compound 200 in 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 (heat to 45° C., aging, cool to −10° C., aging) was repeated three times, and after the fourth thermocycle, the suspension was cooled to 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 under reduced pressure at 50° C. overnight.

[0241] Comparative Example 1 This comparative example presents a previously used method for synthesizing compound 141. Compound 141 was prepared by: Prepared from compound 140 as in TIFF0007809139000109.tif36170.

[0242] Methanol (675 mL) was charged to a reaction flask. Compound 140 (135 g, 98.9 A%, 537.7 mmol, 1 equiv.) was charged to the reaction flask, followed by 10% palladium on carbon catalyst (27 g, 20 w / w%, 59% wet) with vigorous stirring. The reaction flask was evacuated and filled with N2 three times, then evacuated and filled with H2 three times. The mixture was heated to 45-55 °C for 15 hours. The mixture was cooled to 20-25 °C and then filtered. The filtrate was concentrated to near dryness in vacuo at a temperature below 60 °C to form a residue. The residue was combined with dioxane (675 mL), and the resulting mixture was concentrated to near dryness in vacuo at a temperature below 60 °C 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%, assay was 8.3%, and methanol residue was 0.13% as determined by GC.

[0243] A variety of 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 palladium on carbon catalyst, 10% Pd / C catalyst was 59% wet, and "Crude" refers to the assay in area % HPLC purity of the referenced compound in the reaction product mixture and before workup (filtration). Comparative Example 1 Table 6 TIFF0007809139000110.tif33170

[0244] Palladium carbon catalyst loading 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 experimental, "C140" refers to compound 140, where compound 140 purity was 98.4%, "C141" refers to compound 141, and "Crude" refers to the HPLC area % assay of the referenced compound in the reaction product mixture and before workup (filtration). Comparative Example 1 Table 7 TIFF0007809139000111.tif33170

[0245] The recovery and reuse of the palladium-on-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 Experiments 1-4 below 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 compound 140 purity was 98.4%, "Pd / C" refers to the palladium-on-carbon catalyst, "Crude" refers to compound 140 assay in HPLC area % of the referenced compound in the reaction product mixture and before workup (filtration), and "RT" refers to the reaction time in minutes. Comparative Example 1 Table 8 TIFF0007809139000112.tif48170

[0246] Comparative Example 2 This comparative example presents a previously used method for preparing compound 180. Compound 141, prepared in Comparative Example 1, can be synthesized according to the following scheme: Compound 180 was formed by reacting with compound 90 according to TIFF0007809139000113.tif62170.

[0247] A solution of compound 141 in dioxane (1295.5 g, 8.3% assay, 433 mmol, 1 equiv.) was charged to a reaction flask. Compound 90 (119.5 g, 96.7% assay, 433 mmol, 1 equiv.) and K2CO3 (121 g, 99% assay, 17.3 mmol, 2 equiv.) were charged to the reaction flask with vigorous stirring. The reaction flask was evacuated and refilled with N2 three times. Pd2(dba)3 catalyst (9.05 g, 99% assay, 8.66 mmol, 0.02 equiv.) and Xantphos ligand (10.2 g, 98% assay, 17.3 mmol, 0.04 equiv.) were charged to the reaction flask with vigorous stirring. The reaction flask was evacuated and refilled with N2 three times, and the reaction mixture was heated to 105-115 °C. The mixture was stirred under N2 for 24 h. The mixture was cooled to 65-75°C and filtered. The collected solid was rinsed with hot dioxane. The filtrate and dioxane washes were combined and concentrated to near dryness in vacuo at 55-65°C to form a residue.

[0248] Methanol (550 mL) was combined with 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. The recovered crude compound 180 was washed with cold methanol. The crude compound 180 was dried in vacuo at 55-65°C for 1 hour. The crude product was weighed and assayed by HPLC to give 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 to reflux and stirred at 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 in vacuo at 60-70°C for 5 hours. Compound 180 (188 g) was recovered with a purity of 99.1 area % by HPLC, an assay 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 experimental, "C141" refers to compound 141, "C180" refers to compound 180, "C90" refers to compound 90, "Cat" refers to Pd2(dba)3 catalyst, and "Crude" refers to the assay in area % of the referenced compound in the reaction product mixture after 14.3 minutes of reaction time and before workup. Comparative Example 2 Table 10 TIFF0007809139000114.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, where the reaction time was 15 hours. The results are presented in Table 11 of Comparative Example 2 below, where the amounts of compound 90 and compound 141 were 24.2 mmol for each experiment, where the equivalents of catalyst and ligand are based on the equivalents of compound 141 and compound 90. In this table, "Exp" refers to the experiment number. Comparative Example 2 Table 11 TIFF0007809139000115.tif22170

[0251] The effect of methanol was evaluated in the palladium-catalyzed coupling reaction for the preparation of compound 180 from compound 141 and compound 90 according to the method described above. The results are presented in Table 12 of Comparative Example 2 below, where the amounts of compound 90 and compound 141 were 34.6 mmol for runs 1-3 and 2 mmol for run 4. In this table, "Exp" refers to the run number, and "RT" refers to the reaction time. Comparative Example 2 Table 12 TIFF0007809139000116.tif38170

[0252] Compound 180 (5 g, 94.3 A%) was crystallized from a variety of solvent systems in multiple experiments. The results are summarized in Table 13 of Comparative Example 2. Comparative Example 2 Table 13 TIFF0007809139000117.tif33170

[0253] Comparative Example 3 This comparative example presents a previously used method for preparing compound 182. Compound 180, prepared in Comparative Example 2, can be synthesized according to the following scheme: Boronation was performed from compound 182 according to TIFF0007809139000118.tif44170.

[0254] Compound 180 (1.2 kg, 2.763 mol, 1 equiv.), bis(pinacolato)diboron (1.052 kg, 4.145 mol, 1.5 equiv.), and KOAc (0.542 kg, 5.526 mol, 2 equiv.) were charged to an inert reactor. An excess amount of THF (15 L) was charged to a holding vessel, and the surface was sparged with N2 for at least 1 hour to form degassed THF. Degassed THF (9.78 kg, 11 L) was charged to the reactor with vigorous stirring. Pd2(dba)3 (6.52 g, 6.91 mmol, 0.0025 equiv.), XPhos (8.15 g, 16.58 mmol, 0.006 equiv.), and degassed THF (0.445 kg, 0.5 L) were combined with vigorous stirring to form a mixture in a catalyst preparation vessel. The catalyst mixture was then added to the reactor with vigorous stirring. The reactor contents were subsurface sparged with N2 for a minimum of 1 hour. The reactor contents were heated to 60-70°C and aged for a minimum of 12 hours. The reactor contents were sampled and evaluated for Compound 170 content by HPLC, and the reaction was continued until the Compound 170 content was 0.9 area% by HPLC. The reactor contents were cooled to 20-30°C to form a crude reaction mixture containing Compound 182. Water (3.6 kg, 3 L / kg) was charged to the reactor, and the reactor contents 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 reactor contents 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 charged to the reactor, and the reactor contents were heated to 55-65°C and vacuum distilled to 4 L (3.3 L / kg). The THF / distillation step was repeated. The THF / distillation step may be repeated further, as necessary, 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 a THF rinse (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 charged to 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 charged to a reduced volume, and the resulting mixture containing compound 182 was aged at 50-60 °C for 2 hours, followed by cooling to 0-10 °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 with a N sweep 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 DesBr impurities and dimer impurities were as shown in TIFF0007809139000119.tif64170.

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

[0257] The above method for preparing compound 180 from compound 170 was repeated without the MTBE charging and distillation steps to produce compound 180 at 92.7 wt% with 2.4 wt% THF, 6.7 wt% MTBE, 0.6% residue on ignition (ROI), and 90.1% yield.

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

[0259] Compound 182 was synthesized according to the following scheme: It was reacted with compound 170 to form compound 190 according to TIFF0007809139000120.tif47170.

[0260] Compound 170 (30.0 g, 1 equiv.), compound 182 (50.1 g, 1.1 equiv.), and potassium phosphate (27.8 g, 1.5 equiv.) were charged to a reactor along with THF (196 g) and water (60 g). The mixture was degassed with argon. Separately, Pd(dppf)Cl (0.639 g) was suspended in THF (8.9 g), and the mixture was degassed with argon. This mixture was then 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 h).

[0261] The reaction mixture was cooled to 20°C, and 6 wt% aqueous N-acetylcysteine ​​(approximately 60 mL) was added. The resulting mixture was stirred for 15 minutes. The layers were separated, and the organic layer was washed with saturated aqueous NaCl (approximately 60 mL) and 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 over activated carbon at 40°C, and then solvent-exchanged to ethanol by loading the filtrate into a reactor, distilling it to approximately 150 mL at 50°C under low pressure, and then adding ethanol (118 g). Under these conditions, compound 190 crystallized, and the suspension was aged for 2 hours, then cooled to 20°C over 3 hours and held at 20°C to promote crystal formation. The resulting crystals were filtered off using a funnel, washed three times with EtOH, and then dried at 50°C under reduced pressure until a constant weight was achieved. An isolated yield of 49.7 g of compound 190 was obtained as a light yellow powder (yield: 86%; assay: 99.8% w / w; purity: 99.2 area%) and was evaluated using analytical method HPSC Method 1 described above.

[0262] This procedure was repeated three times with the following results: TIFF0007809139000121.tif27170

[0263] Comparative Example 5 The methods for preparing compound 190 described in Comparative Example 4 (previous method) and Example 8 (this method) were repeated at laboratory scale and then further evaluated multiple times at pilot and production scales. The amounts of dimer, alcohol, and ketone impurities present in isolated compound 190 were evaluated (after workup, including recrystallization) and are summarized below in Table 14. The laboratory 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 process (IPC) was also monitored for different batch sizes generally prepared 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 disclosed method at different batch sizes. TIFF0007809139000122.tif42170 Table 15: Amount of dimer observed in process (IPC) for different batch sizes prepared according to this process (samples taken when the amount of compound 170 remaining was <1%) TIFF0007809139000123.tif22170

[0264] Comparative Example 6 Compound 190 was prepared on a production scale generally according to the procedures of Comparative Example 4 ("Earlier Method") and Example 8 ("Present Method"). Compound 190 from each method was used to prepare compound 200, which was isolated generally as described in Examples 10 and 11.

[0265] The impurity profiles observed in production scale batches of compound 200 prepared using compound 190 from a previous method compared to the present method, both before the final isolation step and after the final isolation step (as described in Example 11), are summarized below in Table 16. Preparation of compound 190 according to the present method results in fewer impurities in downstream compound 200 both before and after final isolation, compared to the previously described method for preparing compound 190. Table 16: Summary of impurity profile in compound 200 before and after final recrystallization from toluene and ethanol when different methods were used to prepare compound 190 (old method vs. this method) TIFF0007809139000124.tif32170

[0266] Example 12 A continuous processing method for the hydrogenation of compound 140 TIFF0007809139000125.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 an Ehrfeld Modular MicroReaction System (MMRS). The reactor contains a reaction channel with a rectangular cross section (1.5 mm × 12 mm × 300 mm). Either four reactors (4 CSM or 8 CSM setups) or eight reactors (16 CSM setups) were connected in series using designated flanges to reduce the number of channels used. A schematic diagram of the setup is shown in Figure 16. Catalytic static mixers (CSMs) were fabricated from 316L stainless steel powder by selective laser melting according to a 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, C.H. 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, C.H. 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). Mixers.Catal.Today 2020).

[0268] Pd CSM was produced via electroplating. To produce the Pd / Al2O3 CSM, a 3D-printed static mixer was coated with Pd / Al2O3 via a slurry coating technique by CSIRO and Precision Plating Australia. The reactor was packed with the CSM as detailed below. The reactor volume was calculated to be 2.7 mL per CSM when considering the total channel volume, or estimated to be 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, 1.0 mm strut width, 2.0 mm air gap, 300 mm length) manufactured by Hastelloy C-276 (6114-1-3244). The last two channels were filled with four catalytic static mixers (CSMs), each 150 mm long (two per channel).

[0270] 8 CSM setup: The number of channels was limited to 4 using flanges. All four channels were packed with eight catalytic static mixers (CSMs) of 150 mm length each (two per channel).

[0271] 16 CSM setup: The number of channels was expanded to a total of 8 by opening the flanges. All four channels were packed with 16 catalytic static mixers (CSMs), each 150 mm long (2 per channel).

[0272] Both online and offline UHPLC analysis was used to monitor the reaction progress and products.

[0273] Offline UHPLC: Shimadzu Nexera X2 equipped with a Waters XSelect CSH C18 XP column (150 x 3 mm, 2.5 μm particle size) was used under the following conditions.

[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: TIFF0007809139000126.tif33170 Analysis was performed at a wavelength of 238 nm. The reporting limit (rl) was set at 0.025 area %.

[0276] Online UHPLC analysis: was carried out using a Shimadzu Nexera X2 system fitted with a Kinetex biphenyl column (size 100 x 2.1 mm, particle size 1.7 μm) under the following conditions:

[0277] Isocratic method with a fixed concentration of 40% solvent B and a total flow rate of 0.4 mL / min. Samples were analyzed at a wavelength of 238 nm with a relative absorbance ratio of compound 141:compound 140 of 2.27.

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

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

[0280] Representative continuous flow procedure: An input solution of compound 140 was made in a volumetric flask with the required amount of water (where indicated) and then filled to the mark with THF. The solution was degassed with nitrogen while stirring or using sonication. The following start-up procedure was followed: 1. Flush the reactor with methanol at the desired reaction flow rate. 2. Set the backpressure control factor to the desired reaction pressure. 3. Begin flushing the reactor with THF at the desired reaction flow rate. 4. Set the thermostat to the desired reaction temperature and allow it to be reached. 5. Allow the system to equilibrate for at least 30 minutes. 6.Set the H2 flow rate and allow the pressure to build to the required level. 7. Once the H2 reaches the reaction pressure, pause the H2 flow. 8. Briefly turn off the liquid pump to allow the input to switch to substrate solution (using the valve). 9. Start the pump and H2 flow, as well as the UHPLC injection and FT-IR measurement.

[0281] Reference to the azo, azoxy, and dimer impurities in the hydrogenation of Compound 140 is made to the following structures: Points to TIFF0007809139000127.tif46170.

[0282] Initial evaluation of continuous processing parameters The initial parameters were: 0.2 M compound 140 in THF, no added water, 20 bar pressure, 80 °C jacket temperature, and the use of four catalytic static mixers (CSMs). The Pd-electroplated CSMs exhibited only a minimal degree of reaction (approximately 6% conversion), while the Pd / Al2O3 slurry-coated CSMs were substantially more effective under identical conditions (achieving 98.632 area % of compound 141). Without wishing to be bound by theory, this may be due to the significantly higher effective surface area of ​​the Pd / Al2O3 variant.

[0283] Increasing the flow rate from 1 to 2 mL / min resulted in incomplete conversion of compound 140, and this conversion appeared to decline over the 30 minutes these conditions were applied. This effect was increasingly evident at higher flow rates (3, 4, and 5 mL / min), which appeared to indicate a decline in conversion rate over a constant gradient. The flow rate was returned to 1 mL / min, where complete substrate conversion was no longer observed (approximately 95% conversion). The results are summarized in Table 17. Table 17: Offline UHPLC results from the first flow rate screen TIFF0007809139000128.tif35170

[0284] This type of performance degradation was observed prior to the use of CSMs and may be attributed to catalyst inhibition over time by reactive 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 addressing this issue is the inclusion of polar solvents and higher reaction temperatures.

[0285] In a second set of experiments, the jacket temperature was increased from 60°C to 140°C in 20°C steps, which appeared to have a significant positive impact on the reaction, both in conversion and in reducing its erosion over time. The slope of the conversion loss was substantially shallower at 80°C compared to 60°C, and none was observed at 120°C. To determine whether any changes occurred over this period, the final set of conditions was a duplicate of the initial conditions. A substantial difference was observed between the two examples (78% conversion before vs. 56% conversion after), suggesting that even at the higher temperature, some performance loss also occurred and would have had an effect on longer-term processing.

[0286] The protic solvent addition approach was also investigated by first adding methanol as a co-solvent. The reactivity and impurity profile was dramatically affected by the inclusion of methanol and is shown in Table 17. Table 17: Offline UHPLC results from reactions using methanol as co-solvent. TIFF0007809139000129.tif27170

[0287] It was thought that water (2 equivalents) is produced as a by-product of the hydrogenation reaction, and therefore its presence may not be detrimental to reaction performance. However, CSM uses Al2O3 as the catalyst support material, which leads to concerns over CSM stability and catalyst decomposition under aqueous conditions.

[0288] To test catalytic decomposition, one single CSM was exposed to increasing amounts of water, from 4 to 512 equivalents, in control experiments (512 equivalents corresponds 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 was stable even in the presence of such high levels of water. In view of the surprising stability in the presence of water, the evolution of reaction conditions continued without concern for the effect of water on CSM stability.

[0289] Using a second HPLC pump, 1 to 4 equivalents of water were introduced with the reaction stream. The presence of water appeared to significantly improve the rate of the reaction and also prevented catalyst deactivation over time. The highest value examined, 4 equivalents, resulted in almost double the level of conversion relative to conditions in the absence of water (38% vs. 73%).

[0290] The reaction concentration was also investigated using a 0.5 M solution of compound 140 diluted in 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 of compound 140 was used. Table 18: Offline UHPLC results from Compound 140 concentration screen TIFF0007809139000130.tif35170

[0291] Using this reactor setup, a range of reaction parameters were rapidly screened over multiple experimental runs. Temperature, water content, and pressure were all varied. From these experiments (25 in total, including two replicates), it was determined that temperature was by far the most important parameter, followed by HO loading. Conversely, reaction temperature had relatively minimal effect. Counterplots representing predicted conversion rates at different conditions were plotted from this data. A clear trend was observed, with higher temperatures and higher HO loading rates improving conversion rates.

[0292] Separately, it was determined experimentally that the flow rate of H2 had no effect on the reaction performance as long as sufficient H2 was supplied. The residence time was not affected by an excess amount of gas, which may be attributed to the stratified flow regime within the reactor.

[0293] Further evaluation at 8CSM Further experiments were performed with 8 CSMs to evaluate the potential throughput that could be reached in this reaction system. Key to this evaluation was the amount of impurities (total azo + azoxy, and dimer) observed with increasing flow rates. Previous experiments with 4 CSMs determined that higher flow rates resulted in elevated levels of these impurities, but that adding water to the input solution could also reduce them (due to shorter residence time). A series of conditions were investigated in which the flow rate and water content were varied (Table 19). The jacket temperature was set at 120°C, the pressure at 20 bar, and the H2 equivalents at 3.3 equivalents (10% excess). Table 19: Offline UHPLC analysis of 8CSM processes with varying flow rates and water content TIFF0007809139000131.tif51170r.l = Reporting limit, 0.025 area%

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

[0295] The longer-term stability of the reactor system was then investigated by conducting continuous flow reactions over two working days, for 10 hours and then 6 hours. The solvent was washed between the two periods, and the reactor was stored in MeOH overnight at ambient conditions between the two runs. This allowed for evaluation of reactor behavior, impurity profiles over time, and detection of any potential catalyst leaching or deactivation. The experimental conditions selected for this demonstration were: pressure = 20 bar, jacket temperature = 120 °C, H2 = 3.3 equivalents, liquid flow rate 8 mL / min, 6 equivalents of HO, and compound 140 concentration 0.4 M. During the course of this experiment, 16 fractions were collected (one per hour) for detailed offline analysis. Offline analysis of the fractionated reactor output showed that the amount of compound 141 was 99.2 area % in the first fraction measured and did not decrease over time; in fact, a gradual increase was observed (Figure 14A). Starting material Compound 140 and the (combined) azo + azoxy and dimer impurities were low in the first fraction and decreased over time (Figure 14B). None of the collected fractions yielded >0.1 area % of the combined azo + azoxy or dimer impurities. Over this period, 850 g (3.07 mol) of starting material was processed, with no loss in catalytic activity over time. Based on a total Pd loading of 96 mg (0.9 mmol, 12 mg per CSM), this represents an effective catalyst loading 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 collected fractions and compared to measurements of the input reaction mixture blank and solvent blank.No detectable levels of Al were observed in any of the samples, suggesting that there was no degradation of the alumina support over time, 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] Maximum evaluated throughput processing (16CSM) The increase in possible throughput from 4 to 8 CSM was higher than expected for linear scale-up (48 mmol / h to 192 mmol / h, a 4-fold increase). Without wishing to be bound by theory, this may be caused by improved mixing achieved at higher flow rates, but may also be influenced by a slight temperature increase due to the exotherm of the reaction. To assess the maximum achievable productivity in the reactor setup used, additional experiments were carried out using the full capacity of 16 CSM. Smaller modifications were made, including a heat exchanger before the reactor, and using four additional internal temperature sensors inside the reactor itself.

[0297] Initial screening experiments examined reaction performance at 16 mL / min (with linear scalability from an eight-CSM setup) as well as at 20, 24, 27, and 30 mL / min. Surprisingly, even at 30 mL / min, an excellent impurity profile was observed, with a combined azo + azoxy level of 0.082 area % and exceptionally low levels of the dimer impurity (0.039 area %). These conditions were run for 1 h to ensure stability and process large amounts of material. A significant improvement in throughput was achieved compared to the expected value (Figure 15). This is consistent 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 is 26.2 mol / L / h (27.2 mL void volume) due to the small reactor channels used.

[0298] Comparative Example 7 Preparation of Compound 141 via Two Batch Methods Compared to a Continuous Flow Processing Method The continuous flow processing method described in Example 12 and a batch process, both of which used a THF / water solvent system (approximately 5% vol water), were compared to a previously published batch method (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) that used a toluene / methanol solvent system.

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

[0300] Batch procedure in THF / HO: A glass autoclave vessel was charged with Pd / C 5% (wet, 56.8% HO, 154 mg) and 30 mL of a 0.4 M solution of Compound 140 in THF (total 12 mmol), 2.4 M added water. The reactor was closed and sealed, purged with H three times (at 1 bar), and then pressurized to 20 bar. The reactor was then heated to 50°C with slow stirring. At the start of the reaction, an exotherm was observed, and the reaction temperature reached 61°C. The temperature was then controlled by reducing the stirring speed to maintain the temperature below 60°C. The reaction was stirred for 3 hours, with the temperature increasing to 60°C for the final 1.5 hours. The reaction was then cooled to 35°C, depressurized, and sampled for UHPLC analysis using the UHPLC procedure described in Example 7 above.

[0301] Continuous flow procedure: Using the results of an 8 CSM, 16 hour (10 hour + 6 hour) run described above in Example 12. Jacket temperature was set at 120°C, pressure at 20 bar, H equivalents at 3.3 equivalents (10% excess), 0.4 M Compound 140 was used, a flow rate of 8 mL / min, and 6 equivalents of HO. Table 20: Offline UHPLC results from batch comparison compared to CSM flow procedure TIFF0007809139000132.tif27170r.l. = reporting limit, 0.025 area%

[0302] Example 13 Additional Continuous Processing Methods Additional continuous processing experiments were performed 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. The fixed-bed catalyst was housed in a tubular reactor, to which hydrogen gas (feed rate controlled by a mass flow controller) and a solution of nitropyridine 140 (feed rate controlled by an HPLC pump) were continuously fed. 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-controlled vessel and backpressure regulator, and then collected during gas / liquid separation.

[0303] The initial reaction conditions investigated used a 3% Pd / Al2O3 catalyst (Al2O3 spheres, code 110002, supplied by Johnson Matthey). Using a small reactor (0.6 cm internal diameter, 15 cm length), the reactor temperature was investigated by first feeding the reactor with a solution of nitropyridine 140 in THF (0.36 M concentration) with a flow of 1 mL / min. The H2 feed was maintained at 30 mL / min, and the system pressure was maintained at 20 bar. The conversion of nitropyridine 140 to aminopyridine 141 improved when the temperature was increased from 60 °C to higher values. At the same time, the amounts of known undesired impurities (azo, azoxy, and dimer) were reduced to less than 0.20 area % each, as determined by HPLC. The sum of undefined impurities also decreased with higher temperatures, as summarized in Table 21, and T mantel The optimum condition was reached at T = 100°C (entry 3). mantel Further increase in temperature to 120°C did not provide any benefit because it produced a higher amount of an unknown impurity (entry 4). Table 21: HPLC results of nitro reduction of compound 140 obtained with 3% Pd / Al2O3 catalyst at different reactor temperatures TIFF0007809139000133.tif31170

[0304] After setting the reactor temperature to 100°C, the system pressure was briefly checked, but no major differences were observed in the range of 10 to 30 bar, so it was decided to keep this value at 20 bar for further investigations. Regarding the H2 feed, it was observed that a slight excess of H2 (i.e., 3 equivalents with respect to nitropyridine 140) was necessary due to the stoichiometry of the reaction, but a larger excess did not provide any advantage. In contrast to what was observed in the case of the catalytic static mixer (see Example 12), the use of water as an additive did not provide any 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 in the presence and absence of water as an additive under conditions reported (=80°C). TIFF0007809139000134.tif21170

[0305] After establishing the 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 loading were tested under the same conditions, yielding a product with a purity >99.0 area%. These carbon-based catalysts further demonstrated that platinum outperformed palladium. The best result of 99.61 area% product purity at complete conversion was obtained with the 5% Pt / C catalyst NOBLYST® P8109 supplied by Evonik (Figure 20). The catalyst loadings shown in this Example 13 are dry wt%.

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

[0307] Finally, incorporating the above evaluation, reduction of nitropyridine 140 allowed for scale-up of the hydrogenation process with 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 (internal diameter 1.2 cm, length 15 cm) was packed with the catalyst 5% Pt / C Evonik NOBLYST® P8109 (4.9 g).

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

[0311] The outcome of the reaction and the stability of the process over time were monitored by HPLC analysis of sampled reaction solutions to note the purity of the desired product and the formation of undesired impurities. Figure 22 summarizes the HPLC purity of aminopyridine 141 sampled from the solution resulting from the fixed bed over time.

[0312] Two portions of the solution resulting from the hydrogenation process were collected separately to assess the overall purity and yield of the materials recovered at two different stages of the overall process. Portion A consisted of 50 g of solution collected during the first 195 minutes of the flow process. Portion B consisted of 100 g of solution collected between 195 and 380 minutes of reaction time. The products present in each portion were isolated by evaporating the solvent under reduced pressure until a constant weight was achieved, affording aminopyridine 141 in 85.6% and 89.6% yield, respectively. The purities of the two isolated materials are reported in Table 23. Table 23: Purity of isolated material from fluidized hydrogenation of 140 using a fixed catalyst bed TIFF0007809139000135.tif21170

[0313] XRF analysis of material isolated from Parts A and B did not detect any traces (rl = 1 ppm) of Pt or of other metals, indicating that no leaching of metals into the product occurred during this process.

[0314] Example 14 Preparation of Multiple Crystalline Solvates of Compound 200 Ethanol hemisolvate: 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 by centrifugal filtration at 0° C. The wet filter cake was dried at ambient temperature in open storage. The sample was further dried under reduced pressure at 50° C. for 3 days and then characterized by XRPD. The XRPD spectrum is shown in FIG. 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 ambient temperature for 7 days. The resulting wet powder was gently dried under toluene vapor at 100 mbar / ambient 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 polish filtered to obtain a particle-free solution. The clear 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 FIG. 19 and the peak list is shown in Table X.

[0317] XRPD characterization: X-ray diffraction patterns were recorded using a Stoe Stadi P diffractometer (Cu K α1The X-ray diffraction data were recorded at ambient conditions in transmission geometry using an illumination of [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). Measurement and evaluation of the X-ray diffraction data were performed using WinXPOW software (STOE & Cie GmbH, Darmstadt, Germany). The position error for each individual peak is ±0.2° 2-theta.

[0318] The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity of understanding; however, the descriptions and examples should not be construed as limiting the scope of the invention. Accordingly, all suitable modifications and equivalents may be considered to fall within the scope of the invention as defined by the claims that follow. The disclosures of all patent and scientific literature cited herein are expressly incorporated by reference in their entirety.

Claims

1. 1. A process for preparing compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, comprising: a) forming a reaction mixture comprising compound 170, compound 181, a palladium catalyst, and a solvent system comprising a base, wherein the equivalent ratio of palladium catalyst to compound 170 is from 0.001:1 to 0.005:1; (b) the following scheme: reacting the reaction mixture to form a reaction product mixture comprising compound 190 according to Including, wherein the Pd catalyst comprises a palladium(II) species containing a phosphine ligand and at least one palladium-carbon bond; where: (i) The fragment that gives rise to the palladium-carbon bond has the formula: (In the formula, R ６ ~R １０ Each of the groups independently represents H and optionally substituted C １～６ alkyl) is an allyl derivative of The phosphine ligand has the formula: (In the formula, R 1 and R 2 are each independently selected from optionally substituted C 1-12 alkyl, and optionally substituted C 3 -C 20 cycloalkyl; R 3 to R 5 are each independently selected from H and alkoxides of the formula —O—C 1-6 alkyl. It is of wherein the yield of compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, is at least 50% based on compound 170.

2. (a) containing less than 0.1 area % of a dimeric impurity based on Compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, wherein the dimeric impurity has the structure It is of (b) the combined content of alcohol impurities and ketone impurities is less than 0.25 area % based on Compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, wherein the alcohol impurities and ketone impurities have the structure The method of claim 1, wherein

3. and further comprising reacting compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, to form compound 200, or a stereoisomer, geometric isomer, tautomer, or salt thereof, wherein the reaction is (a) The following scheme contacting compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, with a reducing agent and a base in the presence of a solvent to form compound 200, or a stereoisomer, geometric isomer, tautomer, or salt thereof, according to (b) isolating compound 200, or a stereoisomer, geometric isomer, tautomer, or salt thereof; Including, 2. The method of claim 1, wherein the yield of compound 200, or a stereoisomer, geometric isomer, tautomer, or salt thereof, based on compound 170 is at least 60% and the purity of compound 200, or a stereoisomer, geometric isomer, tautomer, or salt thereof, is at least 99 area %.

4. 1. A method for reducing by-product formation in a Suzuki coupling reaction, comprising: (a) forming a reaction mixture comprising Compound 170, Compound 181, a palladium catalyst, a solvent system, and a base, wherein the equivalent ratio of palladium catalyst to Compound 170 is from 0.001:1 to 0.005:1; (b) the following scheme: to form a reaction product mixture comprising compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof; Including, wherein the Pd catalyst comprises a palladium(II) species containing a phosphine ligand and at least one palladium-carbon bond; where: (i) The fragment that gives rise to the palladium-carbon bond has the formula: (In the formula, R ６ ~R １０ Each of the groups independently represents H and optionally substituted C １～６ alkyl) is an allyl derivative of The phosphine ligand has the formula: (In the formula, R 1 and R 2 are each independently selected from optionally substituted C 1-12 alkyl, and optionally substituted C 3 -C 20 cycloalkyl; R 3 to R 5 are each independently selected from H and alkoxides of the formula —O—C 1-6 alkyl. It is of where: (a) containing less than 0.1 area % of a dimeric impurity based on Compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, wherein the dimeric impurity has the structure It is of (b) the combined content of alcohol impurities and ketone impurities is less than 0.25 area % based on Compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, wherein the alcohol impurities and ketone impurities have the structure The method is as follows.

5. 1. A method for improving yield in a Suzuki coupling reaction, comprising: (a) forming a reaction mixture comprising Compound 170, Compound 181, a palladium catalyst, a solvent system, and a base, wherein the equivalent ratio of palladium catalyst to Compound 170 is from 0.001:1 to 0.005:1; (b) the following scheme: to form a reaction product mixture comprising compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, according to Including, wherein the Pd catalyst comprises a palladium(II) species containing a phosphine ligand and at least one palladium-carbon bond; where: (i) The fragment that gives rise to the palladium-carbon bond has the formula: (In the formula, R ６ ~R １０ Each of the groups independently represents H and optionally substituted C １～６ alkyl) is an allyl derivative of The phosphine ligand has the formula: (In the formula, R 1 and R 2 are each independently selected from optionally substituted C 1-12 alkyl, and optionally substituted C 3 -C 20 cycloalkyl; R 3 to R 5 are each independently selected from H and alkoxides of the formula —O—C 1-6 alkyl. It is of wherein the yield of compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, based on compound 170 is at least 80%.

6. The allyl derivative is (a) R ６ ~R １０ each of which is H, (b) R ６ Ga-CH ３ and R ７ ~R １０ each of which is H, (c) R ７ Ga-CH ３ and R ６ and R ８ ~R １０ is H, and (d) R ８ Ga-CH ３ and R ６ , R ７ , R ９ and R １０ each of which is H, The method according to any one of claims 1 to 5, wherein the compound is selected from the group consisting of:

7. The phosphine ligand has the following structure: The method according to any one of claims 1 to 5, wherein the SPhos is

8. The Pd catalyst is (a) a cationic palladium species containing an inorganic or organic counterion X, and (b) a neutral palladium species containing a coordinated inorganic or organic ligand X The method according to any one of claims 1 to 5, wherein the compound is selected from the group consisting of:

9. 9. The method of claim 8, wherein X is selected from halogen, carboxylate, sulfonate, and inorganic anion.

10. (a) The carboxylate is CH ３ C(O)O － and tBuC(O)O － is selected from (b) the sulfonate is CF ３ SO ３ － , tosylate, besylate and nosylate; (c) The inorganic anion is PF ６ － , B.F. ４ － , B(C ６ F ５ ) ４ － , NO ３ － and S.O. ４ ２－ The method of claim 9, wherein the compound is selected from the group consisting of:

11. X is CF ３ SO ３ － The method of claim 9, wherein

12. The palladium catalyst is CF ３ SO ３ － and an organic counterion, wherein the phosphine ligand is SPhos, and wherein R ６ ~R １０ The method of claim 1 , wherein each of

13. 6. The process of any one of claims 1 to 5, 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 from 1:0.1 to 1:1, and the reaction mixture is heated to from 60°C to 80°C.

14. 6. The method of any one of claims 1 to 5, wherein the equivalent ratio of compound 181 to compound 170 is greater than 1:1 and the equivalent ratio of palladium catalyst to compound 170 is from 0.001:1 to 0.003:1, or 0.002:

1.

15. (a) The catalyst is [(SPhos)Pd(allyl)]CF ３ SO ３ and (b) the solvent system comprises predominantly ethyl acetate and water, wherein the volume ratio of ethyl acetate to water is from 1:0.1 to 1:1; (c) the boronate has the structure: 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 6. The method according to any one of claims 1 to 5.

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