Process for preparing BTK inhibitor intermediates

Abstract

Crystalline forms of intermediate compound (190) in the preparation of 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; methods of preparing such crystalline forms; compositions including such crystalline forms; and uses of such crystalline forms are provided herein.

Description

[0001] PROCESS FOR PREPARING BTK INHIBITOR INTERMEDIATES

[0002] This application claims priority from EP24189599.4 filed 18 July 2024, the contents and elements of which are herein incorporated by reference for all purposes.

[0003] BACKGROUND

[0004] The present disclosure relates generally to methods of preparing certain crystal forms of an intermediate compound in the preparation of Bruton’s Tyrosine Kinase (“BTK”) inhibitor compound 2-{3'-hydroxymethyl-l-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-l-yl)- pyridin-2-ylamino] -6-oxo- 1, 6-dihydro-[3,4']bipyridinyl-2'-yl}-7,7-diamethyl-3, 4,7,8- tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[l,2-a]pyrazin-l-one. The intermediate compound has the structure:

[0005] The BTK inhibitor compound 2-{3'-hydroxymethyl-l-methyl-5-[5-((S)-2-methyl-4-oxetan-3- yl-piperazin-l-yl)-pyridin-2-ylamino]-6-oxo-l,6-dihydro-[3,4']bipyridinyl-2'-yl}-7,7- dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[l,2-a]pyrazin-l-one of the following structure: is known from U.S. publication US 2013 / 0116235 Al as a BTK inhibitor that is useful for the treatment of diseases or disorders, such as those selected from immune disorders, cancer, cardiovascular disease, viral infection, inflammation, metabolism / endocrine function disorders, and neurological disorders. US 2013 / 0116235 is incorporated herein by reference in its entirety. Alternative names for 2-{3'-hydroxymethyl-l-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[l,2-a]pyrazin-l-one can be used, but the shown chemical structure controls. 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-l,6-dihydro-[3,4'-bipyridin]-2' yl)-7,7-dimethyl-2,3,4,6,7,8-hexahydro-lH- cyclopenta[4,5]pyrrolo[l,2 a]pyrazin-l-one. The US 2013 / 0116235 publication discloses a useful method for preparing 2-{3'-hydroxymethyl-l-methyl-5-[5-((S)-2-methyl-4-oxetan-3- yl-piperazin-l-yl)-pyridin-2-ylamino]-6-oxo-l,6-dihydro-[3,4']bipyridinyl-2'-yl}-7,7- dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[l,2-a]pyrazin-l-one, but the method requires chromatographic purification and a low yield was achieved.

[0006] A useful process for preparing 2-{3'-hydroxymethyl-l-methyl-5-[5-((S)-2-methyl-4-oxetan-3- yl-piperazin-l-yl)-pyridin-2-ylamino]-6-oxo-l,6-dihydro-[3,4']bipyridinyl-2'-yl}-7,7- dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[l,2-a]pyrazin-l-one is further known from US 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. US 2018 / 0230155 and the Zhang publication are incorporated herein by reference in its entirety.

[0007] A need exists for improved methods for preparing 2-{3'-hydroxymethyl-l-methyl-5-[5-((S)- 2-methyl-4-oxetan-3-yl-piperazin-l-yl)-pyridin-2-ylamino]-6-oxo-l,6-dihydro- [3,4']bipyridinyl-2'-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[l,2- a]pyrazin-l-one and the intermediate compound noted above. For example, there is a need for improved methods with higher yield, lower presence of byproduct, predictable crystal form generation, predictable impurity profile or combinations thereof.

[0008] BRIEF DESCRIPTION

[0009] A first aspect of the disclosure is directed to a method of preparing a crystalline Form C of compound 190, or a tautomer thereof, the method comprising: combining a solution comprising compound 190 in ethanol with a seed crystal of the crystalline Form C of compound 190, or the tautomer thereof, to form a seeded solution, wherein the structure of compound 190 is: wherein the crystalline Form C of compound 190, or the tautomer thereof, exhibits an XRPD pattern with peaks at 6.8 ± 0.2 °2Theta (Cu Kai), 15.4 ± 0.2 °2Theta (Cu Kai), and 10.7 ± 0.2 °2Theta (Cu Kai); and wherein the method precipitates > 50% of compound 190 in the seeded solution as the crystalline Form C of compound 190, or the tautomer thereof.

[0010] In some embodiments, > 75% of compound 190 in the seeded solution is precipitated as the crystalline Form C of compound 190, or the tautomer thereof, or > 90% of compound 190 in the seeded solution is precipitated as the crystalline Form C of compound 190, or the tautomer thereof.

[0011] In some embodiments, the crystalline Form C of compound 190, or the tautomer thereof, exhibits an XRPD pattern with peaks at 6.8 ± 0.2 °2Theta (Cu Kai), 15.4 ± 0.2 °2Theta (Cu K«i), 10.7 ± 0.2 °2Theta (Cu Kai), and one or more of 7.7 ± 0.2 °2Theta (Cu Kai), 11.6 ± 0.2 °2Theta (Cu K«i), and 19.3 ± 0.2 °2Theta (Cu K«i).

[0012] In some embodiments, the crystalline Form C of compound 190, or the tautomer thereof exhibits an XRPD pattern with peaks at 6.8 ± 0.2 °2Theta (Cu Kai), 15.4 ± 0.2 °2Theta (Cu K«i), 10.7 ± 0.2 °2Theta (Cu Kai), 7.7 ± 0.2 °2Theta (Cu K«i), 11.6 ± 0.2 °2Theta (Cu K«i), and 19.3 ± 0.2 °2Theta (Cu Kai).

[0013] In some embodiments, combining the solution and the seed crystal is performed at a temperature that is > 65°C and < 75°C, the method further comprising, after combining the solution and the seed crystal, cooling the seeded solution at a rate of > l°C / h and < 9°C / h. In some embodiments, the seeded solution is cooled at a first cooling rate and then a second cooling rate, wherein the first cooling rate is slower than the second cooling rate, and optionally wherein the first cooling rate is > l°C / h and < 9°C / h, and the second cooling rate is > 5°C / h and < 15°C / h.

[0014] In some embodiments, the cooling of the seeded solution is performed to a final temperature that is > 5°C and < 15°C, or a final temperature that is about 10°C.

[0015] In some embodiments, after cooling of the seeded solution there is a step of aging at a temperature that is > 5°C and < 15°C or about 10°C, for at least 5 hours.

[0016] In some embodiments, the crystalline Form C of compound 190, or the tautomer thereof, is formed as a component of a composition, wherein the composition contains the crystalline Form C of compound 190, or the tautomer thereof, in an amount > 75wt%, or wherein the composition contains the crystalline Form C of compound 190, or the tautomer thereof, in an amount > 90wt%.

[0017] In some embodiments, the ratio of ethanol volume to compound 190 by weight in the seeded solution is > 3 L / kg and < 13 L / kg, and optionally wherein the total weight of compound 190 in the seeded solution is at least 100kg.

[0018] In some embodiments, the compound 190 in the solution is prepared by a method comprising: (a) forming a reaction mixture comprising compound 170, compound 181, a palladium catalyst, and a solvent system comprising water, an aprotic solvent and a base; and (b) reacting the reaction mixture to form a reaction product mixture comprising compound 190 according to the following scheme:

[0019] (c) carrying out a solvent swap, wherein the aprotic solvent in the solvent system of the reaction product mixture is substantially swapped for ethanol. In some embodiments, the method further comprises the step of reacting the crystalline Form C of compound 190, or a tautomer thereof, to form compound 200, or a stereoisomer, geometric isomer, tautomer or salt thereof, the reaction comprising: (a) reacting the crystalline Form C of compound 190, or tautomer thereof, with a reducing agent and a base in the presence of a solvent to form compound 200, or the stereoisomer, geometric isomer, tautomer or salt thereof, according to the following scheme

[0020] In a second aspect, the present disclosure provides an isolated crystalline Form C of compound 190, or tautomer thereof, wherein the structure of compound 190 is: wherein the crystalline Form C of compound 190, or the tautomer thereof, exhibits an XRPD pattern with peaks at 6.8 ± 0.2 °2Theta (Cu Kai), 15.4 ± 0.2 °2Theta (Cu Kai), and 10.7 ± 0.2 °2Theta (Cu K«i).

[0021] In some aspects, the isolated crystalline Form C of compound 190, or the tautomer thereof, exhibits an XRPD pattern with peaks at 6.8 ± 0.2 °2Theta (Cu Kai), 15.4 ± 0.2 °2Theta (Cu

[0022] K«i), 10.7 ± 0.2 °2Theta (Cu Kai), and one or more of 7.7 ± 0.2 °2Theta (Cu Kai), 11.6 ± 0.2 °2Theta (Cu K«i), and 19.3 ± 0.2 °2Theta (Cu K«i). In some aspects, the isolated crystalline Form C of compound 190, or the tautomer thereof, exhibits an XRPD pattern with peaks at 6.8 ± 0.2 °2Theta (Cu Kai), 15.4 ± 0.2 °2Theta (Cu K«i), 10.7 ± 0.2 °2Theta (Cu Kai), 7.7 ± 0.2 °2Theta (Cu K«i), 11.6 ± 0.2 °2Theta (Cu K«i), and 19.3 ± 0.2 °2Theta (Cu Kai).

[0023] In some aspects, the isolated crystalline Form C of the second aspect is obtained or obtainable by the method of the first aspect.

[0024] In a third aspect, the present disclosure provides a composition comprising the isolated crystalline Form C of the second aspect, wherein the crystalline Form C of compound 190, or the tautomer thereof, is present in the composition in an amount > 75 wt%, or wherein the crystalline Form C of compound 190, or the tautomer thereof, is present in the composition in an amount > 90 wt%.

[0025] In some embodiments, in the isolated crystalline Form C of the second aspect, or the composition of the third aspect, the total weight of compound 190 is at least 100 kg.

[0026] In a fourth aspect, the present disclosure provides the use of the isolated crystalline Form C of the second aspect, or the composition of the third aspect, in the preparation of compound 200,

[0027] In a fifth aspect, the present invention provides a composition comprising compound 200 or a stereoisomer, geometric isomer, tautomer or salt thereof, and the isolated crystalline Form C of compound 190, or the tautomer thereof, of the second aspect, wherein the structure of compound 200 is:

[0028] 200

[0029] In a sixth aspect, the present disclosure provides a polymorphic Form B of compound 190, or tautomer thereof, wherein the structure of compound 190 is:

[0030] ; and wherein Form B of compound 190, or the tautomer thereof, exhibits an XRPD pattern with peaks at 19.0 ± 0.2 °2Theta (Cu xi), 6.5 ± 0.2 °2Theta (Cu Kai), and 17.8 ± 0.2 °2Theta (Cu xi).

[0031] In some embodiments, the polymorphic Form B of compound 190, or the tautomer thereof, exhibits an XRPD pattern with peaks at 19.0 ± 0.2 °2Theta (Cu Kai), 6.5 ± 0.2 °2Theta (Cu K«i), 17.8 ± 0.2 °2Theta (Cu Kai), and one or more of 16.4 ± 0.2 °2Theta (Cu Kai), 11.2 ± 0.2 °2Theta (Cu Kai), and 7.2 ± 0.2 °2Theta (Cu Kai).

[0032] In some embodiments, the polymorphic Form B of compound 190, or the tautomer thereof, exhibits an XRPD pattern with peaks at 19.0 ± 0.2 °2Theta (Cu Kai), 6.5 ± 0.2 °2Theta (Cu K«i), 17.8 ± 0.2 °2Theta (Cu xi), 16.4 ± 0.2 °2Theta (Cu xi), 11.2 ± 0.2 °2Theta (Cu Kxi), and 7.2 ± 0.2 °2Theta (Cu Kai).

[0033] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows a method for the preparation of compounds 141 and 180.

[0034] FIG. 2 shows a method for the preparation of compound 141, and another method for the preparation of compound 180. FIG. 3 shows a method for the preparation of compound 141 and another method for the preparation of compound 180.

[0035] FIG. 4 shows a method for the preparation of compound 182.

[0036] FIG. 5A shows a first method for the preparation of compound 190.

[0037] FIG. 5B shows a second method for the preparation of compound 190.

[0038] FIG. 6 shows a method for the preparation of compound 200.

[0039] FIG. 7 shows a method for the preparation of compounds 160 and 170.

[0040] FIG. 8 shows a method for the preparation of compounds 120, 130, and 160.

[0041] FIG. 9 shows a method for the preparation of compounds 120, 121, 130, and 160.

[0042] FIG. 10 shows a method for the preparation of compounds 122, 130, and 160.

[0043] FIG. 11 shows a method for the preparation of compound 170.

[0044] FIG. 12A shows a method for the preparation of compound 140.

[0045] FIG. 12B shows methods for the preparation of compounds 154A, 153, and 140.

[0046] FIG. 13 shows an overall process for the process for the preparation of compound 200, where “Comp” refers to compound.

[0047] FIG. 14 is an XRPD spectrum of the crystalline ethanol hemi-solvate form of fenebrutinib, obtained in Example 12.

[0048] FIG. 15 is an XRPD spectrum of the crystalline toluene solvate form of fenebrutinib, obtained in Example 12.

[0049] FIG. 16 is an XRPD spectrum of the crystalline ethanol solvate form of fenebrutinib, obtained in Example 12.

[0050] FIG. 17 shows a method for the preparation of Compound 190 Form C.

[0051] FIG. 18 is the XRPD pattern exhibited by crystalline Form C of compound 190.

[0052] FIG. 19 is a DSC curve of crystalline Form C of compound 190.

[0053] FIG. 20 is a TG-FTIR curve of crystalline Form C of compound 190.

[0054] FIG. 21 is a Raman spectrum of crystalline Form C of compound 190.

[0055] FIG. 22 is an IR spectrum of crystalline Form C of compound 190. FIG. 23 is a DVS isotherm of crystalline Form C of compound 190.

[0056] FIG. 24 is a plot showing the change in mass during a DVS experiment of crystalline Form C of compound 190.

[0057] FIG. 25 is the XRPD pattern exhibited by the crystalline Form A of compound 190.

[0058] FIG. 26 is a DSC curve of crystalline Form A of compound 190.

[0059] FIG. 27 is a TGA curve of crystalline Form A of compound 190.

[0060] FIG. 28 is a Raman spectrum of crystalline Form A of compound 190.

[0061] FIG. 29 is an IR spectrum of crystalline Form A of compound 190.

[0062] FIG. 30 is a DVS isotherm of crystalline Form A of compound 190.

[0063] FIG. 31 is a plot showing the change in mass during a DVS experiment of the crystalline Form A of compound 190.

[0064] FIG. 32 is the XRPD pattern exhibited by the crystalline Form B of compound 190.

[0065] FIG. 33 is a DSC curve of crystalline Form B of compound 190.

[0066] FIG. 34 is a TGA curve of crystalline Form B of compound 190.

[0067] FIG. 35 is a Raman spectrum of crystalline Form B of compound 190.

[0068] FIG. 36 is an IR spectrum of crystalline Form B of compound 190.

[0069] FIG. 37 is an overlay of the XRPD patterns for Form A (bottom), Form B (middle) and Form C (top).

[0070] FIG. 38 is the XRPD pattern exhibited by the product of a method of preparing compound 190 according to WO 2022 / 233801. The XRPD demonstrates that pure Form A is produced by the method according to WO 2022 / 233801.

[0071] DETAILED DESCRIPTION

[0072] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of 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 differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, 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.

[0073] Definitions

[0074] When indicating the number of substituents, the term "one or more" refers to the range from one substituent to the highest possible number of substitution, i.e., replacement of one hydrogen up to replacement of all hydrogens by substituents. The term "substituent" denotes an atom or a group of atoms replacing a hydrogen atom on the parent molecule. The term "substituted" denotes that a specified group bears one or more substituents. Where any group may carry multiple substituents and a variety of possible substituents is provided, the substituents are independently selected and need not to be the same. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents, independently chosen from the group of possible substituents. When indicating the number of substituents, the term "one or more" means from one substituent to the highest possible number of substitution, i.e., replacement of one hydrogen up to replacement of all hydrogens by substituents.

[0075] As used herein, “alkyl" refers to a monovalent linear or branched saturated hydrocarbon moiety, consisting solely of carbon and hydrogen atoms, having from one to twenty carbon atoms. "Lower alkyl" refers to an alkyl group of one to six carbon atoms, i.e., Ci-Ce 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 optionally substituted, such as with one or more halogens. As used herein, “cycloalkyl” refers to a carbocyclic moiety consisting of monocyclic or polycyclic rings. Cycloalkyl can optionally be substituted as defined herein. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl (z.e., “Cy”), cycloheptyl, and the like. Polycyclic ring structures include fused and bridged bicyclic, fused and bridged polycyclic and spirocyclic hydrocarbon ring system such as, for example, bicyclo[2.2.1]heptane, pinane, bicyclo[2.2.2]octane, adamantane, and norborene. Cycloalkyls may be saturated or partially unsaturated (e.g., cycloalkenyl).

[0076] As used herein, “aryl” refers to a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms (C6-C20). Aryl includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic ring. Typical aryl groups include, but are not limited to, radicals derived from benzene (phenyl), substituted benzenes, 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 aspects, aryl may be substituted with alkyl, cycloalkyl, halogen, or haloalkyl.

[0077] As used herein, “alkoxy" refers to a moiety of the structure -OR, wherein R is an alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

[0078] 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 a different halogen. Exemplary haloalkyls include -CH2CI, -CH2CF3, -CH2CCI3, -CF3, CHF2, and the like.

[0079] As used herein, “halogen” refers to chlorine, fluorine, bromine and iodine.

[0080] As used herein, “amino” refers to a moiety of the structure -NRR' wherein R and R' each hydrogen, “monoalkylamino” refers to such a structure where one of R and R’ is hydrogen and the other of R and R’ is alkyl, and “dialkylamino” refers to such a structure where each of R and R' is alkyl.

[0081] As used herein, "optionally substituted" as used herein refers to a moiety that may be unsubstituted or substituted with specific groups. Examples of substituents include, but are not limited to hydroxy, alkyl, alkoxy, halo, haloalkyl, oxo, amino, monoalkylamino, or dialkylamino. As used herein, "chiral" refers to molecules which have the property of non- superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner.

[0082] 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.

[0083] 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, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.

[0084] As used herein, "enantiomers" refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.

[0085] 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 invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, 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. In describing an optically active compound, the prefixes D and L, or Rand S, are used to denote the absolute configuration of the molecule about its chiral center (s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. Enantiomers may be separated from a racemic mixture by a chiral separation method, such as supercritical fluid chromatography (SFC). Assignment of configuration at chiral centers in separated enantiomers may be tentative, while stereochemical determination awaits, such as x-ray crystallographic data.

[0086] As used herein, the terms "tautomer" and "tautomeric form" refers to structural isomers of different energies which 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.

[0087] As used herein, the term “salt” refers to both acid addition salts and base addition salts. “Acid addition salt” refers to salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as fomlic 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 salicyclic acid. “Base addition salt” refers to salts formed with an organic or inorganic base.

[0088] As used herein an “inorganic base” generally includes sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. 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 hydrogen carbonate and sodium hydrogen carbonate; and alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide. The inorganic bases may be used singly, or in combination of two or more kinds thereof. As used herein, an “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.

[0089] As used herein, “non-polar solvent” refers to a solvent without significant partial charges on any atoms or a solvent where polar bonds are arranged in such a way that the effect of their partial charges cancel out. Non-limiting examples of non-polar solvents include pentane, hexane, heptane, cyclocpentane, cyclohexane, benzene, toluene, 1 ,4-dioxane, dichloromethane (“DCM”), methyl tert-butyl ether (“MTBE”), chloroform, carbon tetrachloride, and diethyl ether.

[0090] As used herein, an “aprotic solvent” refers to a solvent that does not donate hydrogen. As used herein, “polar aprotic solvent” refers to a solvent having high dielectric constants and high dipole movements and that lack an acidic hydrogen. Non-limiting examples of polar aprotic solvents include tetrahydrofuran (“THF”), methyl tetrahydrofuran (“Me-THF”), ethyl acetate (“EA”), acetone, dimethylformamide (“DMF”), acetonitrile (“ACN”), cyclopropylmethyl ether (“CPME”), petroleum ether, N-methyl-2-pyrrolidone (“NMP”), trifluorotoluene, chlorobenzene, anisole, and dimethyl sulfoxide. In some aspects, the aprotic solvent is a low molecular weight ester. Non-limiting examples of aprotic low molecular weight ester solvents include methyl acetate, ethyl acetate, / / -propyl acetate, z-propyl acetate, z-butyl acetate, propylene glycol methyl ether acetate, monoethyl ether acetate, and combinations thereof.

[0091] As used herein, “polar protic solvent” refers to a solvent having a labile hydrogen bound to an oxygen atom or a nitrogen atom. Non-limiting examples of polar protic solvents include formic acid, / / -butanol, z-propanol, / / -propanol, ethanol, methanol, acetic acid and water.

[0092] As used herein, “solvent” refers to a non-polar solvent, an aprotic solvent, a polar protic solvent, and combinations thereof. As used herein, a “palladium catalyst” refers to any palladium catalyst that affects the rate and conversion of a chemical substrate compound to a product compound at a commercially acceptable yield and conversion. 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 commercial Pd(0) complexes such as Pd(PPhs)4, Pd(PCys)2, Pd(PtBus)2 or similar Pd(0) complexes), or may be formed from a palladium source in combination either with a ligand and / or a base (e.g., KOtBu, KOH, NaOAc, K3PO4, K2CO3, Hiinig’s base, NEts, NPn). 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 aspects, the palladium source is selected from the following non-exclusive listing: [PdCl(X)]2 (X= e.g., allyl, cinnamyl, or crotyl), [PdCl(X)PR3] (R= alkyl or aryl), [Pd(X)(Y)] (Y= e.g., cyclopentadienyl or p-cymyl), Pd(dba)2, Pd2(dba)3, Pd(OAc)2, PdZ2 (Z= Cl, Br, I), Pd2Z2(PR3)2, or Pd(TFA)2. In some aspects, the catalytic palladium species is a palladium source selected from the following non-exclusive listing: [Pd(allyl)Cl]2, Pd(MeCN)2Ch, Pd(benzonitrile)2C12, Pd(dba)2, Pd(OAc)2, PdCl2, PdBr2, Pd(TFA)2, Pd(MeCN)4(BF4)2, Pd2(dba)3, Pd(PCy3)2C12, Pd(acac)2, and Pd(PPh3)4. In some such aspects, the palladium source is Pd2(dba)3 or Pd(OAc)2. In some embodiments, the palladium source is Pd(PCy3)2. In some other aspects, the catalytic palladium species can be formed in situ from a palladium source, such as 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, PPI13, XantPhos, and N-XantPhos, DPEPhos. In some aspects, the ligand is an aryl phosphate. In some aspects, the ligand is XPhos, XantPhos, or DPEPhos In particular aspects, the ligand is XPhos (2-dicyclohexylphosphino-2’, 4 ’,6 ’-triisopropylbiphenyl), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) or DPEPhos (Oxydi-2,1- phenylene)bis(diphenylphosphine) of the following structures:

[0093]

[0094] In some aspects, the catalyst comprises a palladium(II) species, a phosphine ligand, and at least one palladium-carbon bond. For example, the catalyst may be selected from: a cationic palladium species comprising an inorganic or organic counterion X; and a neutral palladium species comprising a coordinated inorganic or organic ligand X. X may be a halogen; a carboxylate, such as, but not limited to, CH3C(O)O', tBuC(O)O', or CF3C(O)O'; a sulfonate such as, but not limited to, triflate (CFTSO,-), tosylate, besylate, or nosylate; or an inorganic anion, such as, but not limited to, PFe’, BFF, B(CeF5)4', NCh', or SCh2'. In some aspects, the Pd catalyst is neutral or cationic; and may further comprises a counterion. In some aspects, 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 aspects, the catalytic source is a preformed catalyst. Non-limiting examples of preformed catalysts include Pd(dppf)C12, Pd(dppe)C12, Pd(PCy3)2C12, bis(triethylphospine)palladium(II) chloride, Pdlz-BmPhCF, Pd[P(o-tol)3]2C12, Pd(PPh3)2Cl2, Pd(OAc)2(PPh3)2, and Pd(CH3CN)2Cb. In some such aspects, the preformed catalyst is Pd(dppf)C12. In some further aspects, the catalyst source or preformed catalyst may complex with a solvent such as dichloromethane, chloroform or acetonitrile. Nonlimiting examples of such complexes include Pd(dppf)C12*DCM, Pd2(dba)3*CHC13 and Pd(PPh3)2C12*ACN.

[0095] As used herein, a “borylation reagent” refers to any borylation reagent capable of crosscoupling with an aryl halide to form an aryl boronate. Examples of borylation reagents include, without limitation, tetrahydroxyboron, catecholborane, 4,4,5,5-tetramethyl-l,3,2- dioxaborolane, 4,6,6-trimethyl-l,3,2-dioxaborinane, diisopropylamine borane, bis(neopentyl glycolato)diboron, bis(catecholato)diboron, bis(hexylene glycolato)diboron, bis(pinacolato)diboron, 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)- l-(triisopropylsilyl)-lH-pyrrolo[2,3-b]pyridine, bis(2,4-dimethylpentane-2,4- glycolato)diboron, phenyl boronic acid, diisopropoxy methyl borane, and methyl boronic acid.

[0096] As used herein “reducing agent” refers to a compound that donates an electron. Non-limiting examples of reducing agents include sodium borohydride, potassium borohydride, sodium bis(2-methoxyethoxy)aluminum hydride, sodium bisulfite, sodium hydrogensulfite, sodium hydrosulfite, sodium tetrahydroborate, potassium tetrahydroborate, sodium triacetoxyborohydride, trichlorosilane, triphenylphosphite, triethylsilane, trimethylphosphine, triphenylphosphine, diborane, diethoxymethylsilane, diisobutylaluminum hydride, diisopropylaminoborane, lithium aluminum hydride, and lithium triethylborohydride.

[0097] As used herein “protecting group” refers to group used for protection of remote functionality (e.g., primary or secondary amine) of intermediates. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups include acetyl trifluoroacetyl, 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.

[0098] Some embodiments herein refer to purity or content (e.g., of a desired compound or an undesired compound) using area% as measured by HPLC. Suitable methods of HPLC to evaluate area% are known to those of skill in the art, and include the methods, for example, that were used in Examples 6-9 of the present disclosure, and which are described in detail in the Analytical Methods section.

[0099] As used herein, “predominant” and “predominantly” refer to greater 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.

[0100] As used herein, the term "amorphous" or "amorphous form" indicates the substance, component, or product is not essentially crystalline as determined, for instance, by XRPD. In certain aspects, a sample comprising an amorphous form of a substance may be essentially free of other amorphous forms and / or crystalline forms.

[0101] As used herein, the terms "crystalline" and "crystal" refer to a crystalline solid form of a chemical compound, including, but not limited to, a single-component or multiple-component crystal form, e.g., a polymorph of a compound; or a solvate, a hydrate, a clathrate, a cocrystal, a salt of a compound, or a polymorph thereof. The term "crystal forms" and related terms herein refers to the various crystalline modifications of a given substance, including, but not limited to, polymorphs, solvates, hydrates, co-crystals and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, other molecular complexes of salts, and polymorphs thereof. Crystal forms of a substance can be obtained by a number of methods, as known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces such as, e.g., in nanopores or capillaries, recrystallization on surfaces or templates such as, e.g., on polymers, recrystallization in the presence of additives, such as, e.g., co-crystal counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding and solvent-drop grinding.

[0102] Techniques for characterizing crystal forms and amorphous forms are known in the art and include, but are not limited to, thermogravimetric analysis ("TGA"), differential scanning calorimetric ("DSC"), X-ray powder diffraction ("XRPD"), single crystal X-ray diffractometry, vibrational spectroscopy, e.g., IR 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.

[0103] IR spectra were recorded without any sample preparation using a ThermoNicolet iS5 FTIR spectrometer with ATR accessory. The spectral range is between 4000 cm'1and 650 cm'1, resolution 2 cm'1and 50 co-added scans were collected, except for Form C where resolution 4 cm'1and 32 co-added scans were collected. Happ-Genzel apodization was applied. Using ATR FTIR will cause the relative intensities of infrared bands to differ from those seen in a transmission FTIR spectrum using KBr disc or nujol mull sample preparations. Due to the nature of ATR FTIR, the bands at lower wavenumber are more intense than those at higher wavenumber. Peakpicking was performed using Thermo Scientific Omnic 9.11 software using the automated ‘Find Peaks’ function. The ‘threshold’ and ‘sensitivity’ were manually adjusted to get a representative number of peaks.

[0104] The FT-Raman spectrum was recorded without any sample preparation using a Bruker MultiRam FT-Raman spectrometer equipped with a liq N2 cooled Germanium detector and 1064 nmNdYAG laser. The spectral range is between 4000 cm'1and 50 cm'1, resolution 2 cm'1and 2048 co-added scans were collected. The laser power was set to 300 mW and Blackman- Harris 4-Term apodization was applied. Peakpicking was performed using Thermo Scientific Omnic 9.11 software using the automated ‘Find Peaks’ function. The ‘threshold’ and ‘sensitivity’ were manually adjusted to get a representative number of peaks.

[0105] The DSC-thermograms are recorded using a Mettler-Toledo differential scanning calorimeter DSC 1 / 2 or TA Instruments Discovery series. System suitability tests and calibrations are carried out according to the internal standard operating procedure. For the measurements, approximately 2 to 6 mg of sample are placed in aluminum pans, accurately weighed and hermetically closed with perforation lids. Prior to measurement, the perforation lids are pierced resulting in approx. 0.5 mm pin holes. In order to measure the sample under pressure, closed lids can also be used. The samples are then heated under a flow of nitrogen of about 100 mL / min applying a heating rate of typically 1 to 20, usually 10 K / min to a maximum temperature of typically 180 °C - 350 °C (depending on decomposition temperature).

[0106] Thermogravimetric analyses (TGA) are performed on a Mettler-Toledo thermogravimetric analyzer TGA / DSC1 or TGA / DSC3+. System suitability tests and calibrations are carried out according to the internal standard operating procedure. For the thermogravimetric analyses, approximately 5 to 15 mg of sample are placed in aluminum pans, accurately weighed and hermetically closed with perforation lids. Prior to measurement, the lids are automatically pierced resulting in approx. 0.5 mm pin holes. The samples are then heated under a flow of nitrogen of about 50 mL / min applying a heating rate of 5 K / min up to a maximum temperature of typically 350 °C.

[0107] Thermogravimetric analyses (TG-FTIR) are performed on a Netzsch TG 209 Fl Libra coupled to a Bruker Vertex 70 IR spectrometer to analyze the evolving gas stream at the TG outlet. System suitability tests and calibrations are carried out according to the internal standard operating procedure. For the thermogravimetric analyses, approximately 5 to 15 mg of sample are placed in aluminum pans, accurately weighed and hermetically closed with perforation lids. Prior to measurement, the lids are automatically pierced resulting in approx. 0.5 mm pin holes. The samples are then heated under a flow of nitrogen of about 20mL / min. TG-FTIR measurements are typically performed with increased heating rates of 10 K / min in order to increase the quality of the determination as more solvent reaches the FTIR at a time. Moisture sorption / desorption data (DVS) are collected on a D VS -Advantage, DVS Resolution or a DVS Intrinsic (SMS Surface Measurements Systems) moisture balance system. The sorption / desorption isotherms are measured stepwise in a range of 0 %-RH to 90 %-RH at 25 °C. A weight change of typically <0.001 % / min is chosen as criterion to switch to the next level of relative humidity (with a maximum equilibration time of typically 24 hours, if the weight change criterion is not met). The data are corrected for the initial moisture content of the samples by taking the weight after drying of the samples at 0 %-RH as zero point. The hygroscopicity of a given substance is characterized (by close analogy with the European Pharmacopoeia) by the increase in mass when the relative humidity is raised from 0 %-RH to 90 %-RH: Non-hygroscopic: weight increase Am < 0.2%; slightly hygroscopic: weight increase 0.2% < Am < 2.0%; hygroscopic: weight increase 2.0% < Am < 15.0%; very hygroscopic: weight increase Am > 15.0%; deliquescent: sufficient liquid is adsorbed to form a liquid.

[0108] Compound. 190 Crystalline Form A

[0109] In some aspects, a crystalline form of compound 190 (or a tautomer thereof) can be prepared in accordance with the methods disclosed in WO2022233801 Al . The crystalline form obtainabed by following the method in WO2022233801A1 is characterized herein (for example, by XRPD pattern peak positions, or the XRPD patterns per se) and is referred to as “Form A”. “Form A” as used herein is a label for the crystalline form defined herein, for example with reference to the peak positions in the XRPD spectrum that it produces. A “crystal form” defined by, for example, XRPD peaks at 10.4, 13.1, and 17.0 °2Theta (± 0.2 °2Theta) is equivalent to a “crystal Form A” defined by the same XRPD peaks.

[0110] The inventors have prepared Form A of compound 190 by following a method according to WO2022233801 Al . The XRPD of the Form A product prepared by following the method according to WO2022233801A1 is shown in Fig. 38. It can be seen that the XRPD is consistent with pure Form A.

[0111] In some embodiments, the crystalline Form A is characterized by the XRPD pattern that it exhibits. In some embodiments, Form A is characterized by an XRPD pattern comprising one or more (e.g. one, two, three, four, five, six, seven, eight, nine, ten, or greater than ten, or at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) characteristic peaks selected from Table A . Table A: XRPD peak list for Form A polymorph of compound 190. The positional error for each individual peak is ± 0.2° 2Theta. In some embodiments, Form A exhibits an XRPD pattern with peaks at one or more of (e.g. all of) 10.4, 13.1, and 17.0 °2Theta (± 0.2 °2Theta). In some embodiments, Form A exhibits an XRPD pattern with peaks at one or more of (e.g. all of) 10.4, 13.1, 17.0, 18.6 and 20.8 °2Theta (± 0.2 °2Theta). In some embodiments, Form A exhibits an XRPD pattern substantially as shown in Fig. 25. In some embodiments, Form A exhibits an XRPD pattern as shown in Fig. 25.

[0112] In some embodiments, the crystalline Form A is characterized by DSC. In some embodiments, the DSC curve exhibits an endothermic peak (an endothermic event) in the region of 200°C to 220°C, or 205°C to 215°C, or at about 211°C. In some embodiments the DSC curve comprises one significant peak. In some embodiments, the DSC curve comprises one significant peak in the temperature range of 40°C to 280°C. In some embodiments, the DSC curve comprises a peak with an onset in the temperature range 195°C to 205°C, or about 201°C. In some embodiments, Form A exhibits a DSC curve substantially as shown in Fig. 26. In some embodiments, Form A exhibits a DSC curve as shown in Fig. 26.

[0113] In some embodiments, the crystalline Form A is characterized by TGA. In some embodiments, Form A shows a weight loss of 1.0 wt% between 25°C and 125°C. In some embodiments, Form A exhibits a TGA curve substantially as shown in Fig. 27. In some embodiments, Form A exhibits a TGA curve as shown in Fig. 27.

[0114] In some embodiments, the crystalline Form A is characterized by Raman spectrscopy. In some embodiments, Form A exhibits a Raman spectrum substantially as shown in Fig. 28. In some embodiments, Form A exhibits a Raman spectrum as shown in Fig. 28. In some embodiments, the Raman spectrum of Form A exhibits peaks at one or more of (e.g. all of) 760 cm'1, 470 cm'1, and 240 cm'1± 2 cm'1. A table of peak positions exhibited by the Raman spectrum of Form A is given below in Table Al. In some embodiments, the Raman spectrum of Form A exhibits peaks at one or more (e.g. one, two, three, four, five, six, seven, eight, nine, ten, or greater than ten, or at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) characteristic peaks selected from Table Al.

[0115] Table Al: Peak positions exhibited by Raman spectrum of Form A (± 2cm'1).

[0116] In some embodiments, the crystalline Form A is characterized by IR spectroscopy. In some embodiments, Form A exhibits an IR spectrum substantially as shown in Fig. 29. In some embodiments, Form A exhibits an IR spectrum as shown in Fig. 29. In some embodiments, the IR spectrum of Form A exhibits peaks at one or more of (e.g. all of) 1655 cm'1, 1598 cm'x, and 790 cm'1± 2 cm'1. A table of peak positions exhibited by the IR spectrum of Form A is given below in Table All. In some embodiments, the IR spectrum of Form A exhibits peaks at one or more (e.g. one, two, three, four, five, six, seven, eight, nine, ten, or greater than ten, or at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) characteristic peaks selected from Table AIL

[0117] Table All: Peak positions exhibited by IR spectrum of Form A (± 2cm'1).

[0118] In some embodiments, the crystalline Form A is characterized a DVS isotherm. In some embodiments, Form A exhibits a DVS isotherm substantially as shown in Fig. 30. In some embodiments, Form A exhibits a DVS isotherm as shown in Fig. 30.

[0119] In some embodiments, crystalline Form A is characterized by a change in mass during a DVS experiment. In some embodiments, Form A exhibits a change of mass during a DVS experiment substantially as shown in Fig. 31. In some embodiments, Form A exhibits a change of mass during a DVS experiment as shown in Fig. 31. In some embodiments, Form A exhibits a DVS isotherm comprising vapour sorption in two distinct phases and no significant differences between the two cycles are observed. In some embodiments, both phases of the sorption are continuous until 90%RH (relative humidity) with about 3.4wt% of water sorption. In some embodiments, Form A can be assessed as hygroscopic.

[0120] Compound. 190 Crystalline Form C

[0121] In one aspect the present disclosure relates generally to a crystalline form of compound 190 (or a tautomer thereof), that exhibits an XRPD pattern with peaks at 6.8 ± 0.2 °2Theta (Cu K«i), 15.4 ± 0.2 °2Theta (Cu Kai), and 10.7 ± 0.2 °2Theta (Cu Kai). The disclosure also relates to effective methods of preparation of such a crystalline form, to compositions comprising the crystalline form, and to the use of the crystalline form in chemical synthesis. The crystalline form of compound 190 that exhibits an XRPD pattern with peaks at 6.8 ± 0.2 °2Theta (Cu Kai), 15.4 ± 0.2 °2Theta (Cu Kai), and 10.7 ± 0.2 °2Theta (Cu Kai) is referred to as “Form C”. “Form C” as used herein is a label for the crystalline form defined herein, for example with reference to the peak positions in the XRPD spectrum that it produces. A “crystal form” defined by, for example, XRPD peaks at 6.8 ± 0.2 °2Theta (Cu Kai), 15.4 ± 0.2 °2Theta (Cu Kai), and 10.7 ± 0.2 °2Theta (Cu Kai), is equivalent to a “crystal Form C” defined by the same XRPD peaks.

[0122] In some embodiments, crystalline Form C of compound 190 comprises ethanol and optionally also water in the crystal lattice. In such a case, Form C may be referred to as a crystalline hydrate or a crystalline solvate of Form C, as appropriate. In some embodiments, crystalline Form C comprises > 0 wt% and < 6 wt%, > 0.1 wt% and < 4 wt%, or > 0.5 wt% and < 4 wt%, or > 2 wt% and < 4 wt%, or > 2 wt% and < 3 wt%, or about 2.7 wt% water in the crystal lattice. In some embodiments, crystalline Form C comprises > 4 wt% and < 7 wt%, or >4.5 wt% and < 6.75 wt%, or >5.0 wt% and < 6.75 wt%, or > 6.25 wt% and < 6.75 wt%, or > 6.4 wt% and < 6.6 wt%, or about 6.5 wt% ethanol in the crystal lattice.

[0123] Form C of compound 190 is characterized by the XRPD pattern that it exhibits. In some embodiments, Form C is characterized by an XRPD pattern comprising one or more (e.g. one, two, three, four, five, six, seven, eight, nine, ten, or greater than ten, or at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) characteristic peaks selected from Table C. Table C: XRPD peak list for crystalline Form C of compound 190. The positional error for each individual peak is ± 0.2 °2Theta.

[0124] Form C of compound 190 typically exhibits an XRPD pattern with peaks at 6.8 ± 0.2 °2Theta (Cu Kai), 15.4 ± 0.2 °2Theta (Cu Kai), and 10.7 ± 0.2 °2Theta (Cu Kai). Optionally, Form C of compound 190 exhibits an XRPD pattern with peaks at 6.8 ± 0.2 °2Theta (Cu Kai), 15.4 ± 0.2 °2Theta (Cu Kai), and 10.7 ± 0.2 °2Theta (Cu Kai) wherein all three of those peaks are in the top 6 most relatively intense peaks in the spectrum (e.g. a spectrum of pure Form B). In some embodiments, Form C of compound 190 exhibits an XRPD pattern with peaks at one or more of (e.g. all of) 6.8, 15.4, 10.7, 7.7, 11.6, and 19.3 °2Theta (± 0.2 °2Theta). The aforementioned peak positions may be freely combined, including those in Table C. In some embodiments, Form C of compound 190 exhibits an XRPD pattern with a peak at 6.8 °2Theta (± 0.2 °2Theta). In some embodiments, Form C of compound 190 exhibits an XRPD pattern with a peak at 15.4 °2Theta (± 0.2 °2Theta). In some embodiments, Form C of compound 190 exhibits an XRPD pattern with a peak at 10.7 °2Theta (± 0.2 °2Theta). In some embodiments, Form C of compound 190 exhibits an XRPD pattern with a peak at 7.7 °2Theta (± 0.2 °2Theta). In some embodiments, Form C of compound 190 exhibits an XRPD pattern with a peak at 11.6 °2Theta (± 0.2 °2Theta). In some embodiments, Form C of compound 190 exhibits an XRPD pattern with a peak at 19.3 °2Theta (± 0.2 °2Theta). In some embodiments, Form C of compound 190 exhibits an XRPD pattern substantially as shown in Fig. 18. In some embodiments, Form C of compound 190 exhibits an XRPD pattern as shown in Fig. 18.

[0125] In some embodiments, Form C of compound 190 is characterized by DSC. In some embodiments, the DSC curve exhibits an endothermic peak (representing an endothermic event) in the region of 155°C to 160°C, 156°C to 159°C, or at about 157°C. In some embodiments, the DSC curve comprises one significant endothermic peak. In some embodiments, the DSC curve comprises one significant endothermic peak in the temperature range of 40°C to 280°C. In some embodiments, the DSC curve comprises an endothermic peak with an onset in the temperature range 145°C to 155°C, or about 151°C. In some embodiments, Form C of compound 190 exhibits a DSC curve substantially as shown in Fig. 19. In some embodiments, Form C of compound 190 exhibits a DSC curve as shown in Fig. 19.

[0126] In some embodiments, Form C of compound 190 is characterized by TG-FTIR. In some embodiments the TG-FTIR curve exhibits a mass change (weight loss) upon heating from 140°C to 190°C. In some embodiments, the TG-FTIR curve exhibits a mass change of between 4% and 6%. In some embodiments, the TG-FTIR curve exhibits a mass change of about 5%. In this case, the mass change is due to the loss of ethanol; the mass change exhibited by the TG-FTIR curve at a temperature significantly above the boiling point of ethanol demonstrates that the ethanol being lost is leaving the lattice of Form C. In some embodiments, the TG-FTIR curve comprises two mass changes (losses). In some embodiments the TG-FTIR curve exhibits a mass change (weight loss) between 25°C and 140°C which represents a loss of 1.7%w / w of water. In some embodiments, Form C of compound 190 exhibits a TG-FTIR curve substantially as shown in Fig. 20. In some embodiments, Form C of compound 190 exhibits a TG-FTIR curve as shown in Fig. 20. In some embodiments, Form C of compound 190 is characterized by Raman spectroscopy. In some embodiments Form C of compound 190 exhibits a Raman spectrum substantially as shown in Fig. 21. In some embodiments Form C of compound 190 exhibits a Raman spectrum as shown in Fig. 21. In some embodiments, the Raman spectrum of Form C exhibits peaks at one or more of (e.g. all of) 3068 cm'1, 948 cm'1, and 635 cm'1± 2 cm'1. A table of peak positions exhibited by the Raman spectrum of Form C is given below in Table CI. In some embodiments, the Raman spectrum of Form C exhibits peaks at one or more (e.g. one, two, three, four, five, six, seven, eight, nine, ten, or greater than ten, or at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) characteristic peaks selected from Table CI.

[0127] Table CI: Peak positions exhibited by Raman spectrum of Form C (± 2cm'1).

[0128] In some embodiments, Form C of compound 190 is characterized by IR spectroscopy. In some embodiments, Form C of compound 190 exhibits an IR spectrum substantially as shown in Fig. 22. In some embodiments, Form C of compound 190 exhibits an IR spectrum as shown in Fig. 22. In some embodiments, the IR spectrum of Form C exhibits peaks at one or more of (e.g. all of) 1475 cm'1, 1384 cm'1, and 698 cm'1± 2 cm'1. A table of peak positions exhibited by the IR spectrum of Form C is given below in Table CII. In some embodiments, the IR spectrum of Form C exhibits one or more (e.g. one, two, three, four, five, six, seven, eight, nine, ten, or greater than ten, or at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) characteristic peaks selected from Table CII.

[0129] Table CII: Peak positions exhibited by IR spectrum of Form C (± 2cm'1).

[0130] In some embodiments, Form C of compound 190 is characterized by a DVS isotherm. In some embodiments, Form C of compound 190 exhibits a DVS isotherm substantially as shown in Fig. 23. In some embodiments, Form C of compound 190 exhibits a DVS isotherm as shown in Fig. 23.

[0131] In some embodiments, Form C of compound 190 is characterized by a change in mass during a DVS experiment. In some embodiments, Form C of compound 190 exhibits a change of mass during a DVS experiment substantially as shown in Fig. 24. In some embodiments, Form C of compound 190 exhibits a change of mass during a DVS experiment as shown in Fig. 24.

[0132] In some embodiments, Form C exhibits a DVS isotherm comprising the vapor sorption in two distinct phases starting at 30 %-RH and no significant differences between the two cycles can be observed. In some embodiments, both phases of the sorption are continuous until 90 %- RH with about 4.0 %-w / w of water sorption. In some embodiments, Form C can be assessed as hygroscopic.

[0133] In the method of preparing the crystalline form of compound 190 (or a tautomer thereof), a solution comprising compound 190 and ethanol is combined (i.e. seeded) with a seed crystal of the crystalline form of compound 190. The solution comprising compound 190 and ethanol described here also refers to suspensions, partial suspensions or solutions near, at, or beyond their compound 190 saturation point.

[0134] The use of a seed crystal of Form C (i.e. seeding) in the present invention promotes the formation (i.e. crystallization or precipitation) of compound 190 Form C. Here, the seeding provides a nucleation point for crystallization of Form C to propagate from. The result is that a high purity crystal of compound 190 Form C is formed. That is, a composition produced by the preparation method described herein comprises a high wt% of compound 190 Form C, with few impurities. Importantly, in the method, compound 190 Form C is produced in a consistent and predictable way. Control over the crystal form of pharmaceutical intermediates, and therefore control over the impurity profile of such intermediates, is very important for the overall viability and utility of a synthetic route.

[0135] The amount of seed crystal is not particularly limited but in some embodiments the amount of seed crystal used is 0.05 to 5 wt% of the amount of compound 190 in the solution being seeded. In some embodiments, the amount of seed crystal used is 0.1 to 2.5 wt%, 0.25 to 1 wt% or about 0.5 wt% of the amount of compound 190 in the solution being seeded.

[0136] The method precipitates (i.e. converts) > 50% of compound 190 in the seeded solution as Form C of compound 190. That is, greater than or equal to 50% of the compound 190 present in the seeding solution, excluding the seed crystal(s), crystallizes to compound 190 Form C. In some embodiments, >75%, or > 90% of compound 190 in the seeded solution is precipitated as crystalline Form C.

[0137] In some embodiments, the method of preparing crystalline Form C of compound 190 comprises a step of stirring the seed crystal in the solution comprising compound 190 and ethanol. That is, the stirring step occurs after, for example immediately after, the seeded solution is formed. In some examples, this stirring step is carried out at a temperature of > 60°C and < 80°C, or at a temperature of > 65°C and < 75°C, or at about 70 °C. In some embodiments, the step of stirring is for between 0.5 and 5 hours. In some embodiments, the step of stirring is for between 1 and 3 hours. In some embodiments, the step of stirring is for about 2 hours. In some embodiments, the temperature of the stirring step is substantially constant.

[0138] In some embodiments, the seed crystals are added as a solid composition (e.g., as dry crystals, or essentially dry crystals, or crystals comprising less than 5% or less than 1% solvent, ethanol or water). In other embodiments, the solution comprising compound 190 and ethanol is combined (i.e. seeded) with a suspension of Form C compound 190 in protic solvent to promote crystallization. In some such embodiments, the suspension comprises from about 2.5% to about 10% by weight, or from about 5% to about 8% by weight, of compound 190 in protic solvent (such as an alcohol, for example ethanol). The above described characterizing features of Form C apply equally to the Form C seed crystal, where appropriate. In some embodiments, the seed crystal of Form C may be provided as part of a composition comprising further crystal forms of compound 190, however Form C is preferred thermodynamically or kinetically in ethanol in the claimed methods, and hence is the dominant and persistent crystal form in the product. In some embodiments, the seed crystal may be part of a population of seed crystals, wherein Form C only makes up a portion of the population, for example < 10 wt%, < 5 wt%, < 1 wt% or < 0.1 wt%, however in such a scenario Form C is preferred thermodynamically or kinetically in ethanol in the claimed methods, and hence is the dominant and persistent crystal form in the product.

[0139] In some embodiments, after combining (for example, immediately after combining) the seed crystal with the solution comprising ethanol and compound 190, and optionally also after stirring (for example, immediately after stirring), the method comprises a cooling step. In some embodiments the cooling step comprises cooling at a rate of > l°C / h and < 9°C / h, > 2°C / h and < 8°C / h, > 3°C / h and < 7°C / h, > 3°C / h and < 6°C / h, > 3°C / h and < 5°C / h, about 4°C / h, or 4°C / h. In some embodiments, the cooling is carried out at a single, substantially constant rate.

[0140] In some embodiments the cooling step comprises a first cooling period followed by (for example, immediately followed by) a second cooling period. In some embodiments, the first cooling period is at a slower cooling rate than the second cooling period. In some embodiments, the first cooling period is at a rate of > l°C / h and < 9°C / h, or > 2°C / h and < 8°C / h, or > 3°C / h and < 7°C / h, or > 3°C / h and < 6°C / h, or > 3°C / h and < 5°C / h, or about 4°C / h, or 4°C / h. In some embodiments, the second cooling period is at a rate of > 5°C / h and < 15°C / h, or > 7°C / h and < 13°C / h, or > 9°C / h and < 1 l°C / h, or about 10°C / h, or 10°C / h. In some embodiments, the final temperature reached during the cooling step is > 5°C and < 15°C, or about 10°C, or 10°C.

[0141] Cooling at a slower rate favors the production of compound 190 Form C. Without wishing to be bound by theory, it is thought that a slower cooling rate, for example a slower cooling rate in the first cooling period, prolongs the time spent at higher temperatures, and gives the solution more time to crystallize as Form C. For example, if any Form A is produced, there is sufficient thermal energy and time to equilibrate to Form C.

[0142] In some embodiments, the cooling step is followed (for example, immediately followed by) an aging step. In some embodiments, the aging step is at a temperature that is > 5 °C and < 15°C, or about 10°C, or 10°C. In some embodiments, the aging step last for at least an hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours or at least 10 hours. The use of the above-described cooling step, featuring the above-described cooling rates, followed by an aging step, promotes crystal growth, and further promotes the preferential growth of crystalline Form C of compound 190.

[0143] In some embodiments, Form C is formed as a component of a composition. In some embodiments, the composition comprises Form C in an amount > 75 wt%, or > 90 wt%. The remaining weight of the composition may comprise impurities, for example solvents, amorphous forms of compound 190, and other crystalline forms of compound 190 in trace amounts. In some embodiments, the composition is a substantially solid composition, or is a solid composition.

[0144] In some embodiments, the ratio of ethanol volume to compound 190 by weight in the seeded solution is > 3 L / kg and < 13 L / kg, or > 5 L / kg and < 12 L / kg, or > 7 L / kg and < 10 L / kg. At such quantities, the seeded solution may be near, at or beyond the saturation point of compound 190 in ethanol. At such quantities, crystallization of Form C is promoted. In some embodiments, the total weight of compound 190 in the seeded solution is at least 100 kg, at least 200 kg, at least 500 kg, at least 750 kg or at least 1000 kg. The use of a seed crystal of Form C is particularly beneficial when synthesis is on a large scale, for example a production scale that is greater than 100 kg.

[0145] In some embodiments, the method of preparing crystalline Form C of compound 190 is part of a larger synthetic pathway. In some embodiments, the compound 190 in the solution with ethanol is prepared by a method comprising (a) forming a reaction mixture comprising compound 170, compound 181, a palladium catalyst, and a solvent system comprising water, an aprotic solvent and a base; and (b) reacting the reaction mixture to form a reaction product mixture comprising compound 190 according to the following scheme: (c) carrying out a solvent swap, wherein the aprotic solvent in the solvent system of the reaction product mixture is substantially swapped for ethanol. All features of the preparation of compound 190 provided herein, for example under “preparation of compound 190” apply to the present invention and to this synthetic step, in so far as it relates to the preparation of compound 190.

[0146] In some embodiments, the method further comprises the step of reacting the crystalline form of compound 190, or a tautomer thereof, to form compound 200, or a stereoisomer, geometric isomer, tautomer or salt thereof, the reaction comprising: (a) reacting the crystalline form of compound 190, or tautomer thereof, with a reducing agent and a base in the presence of a solvent to form compound 200, or the stereoisomer, geometric isomer, tautomer or salt thereof, according to the following scheme

[0147] All features of the preparation of compound 200 provided herein, for example under “preparation of compound 200” apply equally to the present invention, in so far as it relates to the preparation of compound 200.

[0148] In some aspects, the present disclosure provides the use of crystalline Form C in the preparation of compound 200. Form C is a desirable synthetic intermediate, owing at least to its thermodynamic stability in ethanol. Preparing crystalline Form C of compound 190 by the methods described herein provides for high levels of control over impurities, and therefore allows for good, and predictable production of compound 200.

[0149] In some aspects, the present disclosure provides a composition comprising compound 200 (or a stereoisomer, geometric isomer, tautomer or salt thereof) and the isolated crystalline form of compound 190. In some embodiments, the crystalline form of compound 190 is present in the composition at < 10 wt%, < 5 wt%, < 1 wt%, < 0.5 wt%, < 0.1 wt% or < 0.01 wt%. That is, in some embodiments, herein provided is a composition comprising compound 200 and trace amounts of crystalline Form C of compound 190. More particularly, the composition can comprise compound 200 and between 1 ppb (parts per billion in weight) and 100 ppm (parts per million in weight) of isolated crystalline compound 190 of Form C as defined previously, in particular having between 1 ppb and 1 ppm of crystalline compound 190 of Form C as defined previously.

[0150] Compound. 190 Crystalline Form B

[0151] In some aspects, a further crystalline form of compound 190 can be prepared, that is not Form C or Form A. Herein, this polymorphic form is referred to as “Form B”. “Form B” as used herein is a label for the crystalline form defined herein, for example with reference to the peak positions in the XRPD spectrum that it produces. A “crystal form” defined by, for example, XRPD peaks at 19.0 ± 0.2 °2Theta (Cu Kai), 6.5 ± 0.2 °2Theta (Cu Kai), and 17.8 ± 0.2 °2Theta (Cu Kai) is equivalent to a “crystal Form B” defined by the same XRPD peaks.

[0152] Form B may be prepared by drying Form C at > 40°C, for example at > 50°C and < 60 °C, for a sufficient length of time, for example > 3 hours, under vacuum.

[0153] Form B may also be formed by reslurrying compound 190 in a solvent comprising 2- methyltetrahydrofuran (2-MeTHF), for example in a mixture of 2-MeTHF and ethyl acetate. To carry out such a (re)crystallization, there may be a step of mixing in which the compound 190 in the MeTHF solvent is warmed, for example to > 70°C and < 90°C, and held there for some period of time, for example an hour. The solution is then cooled. Cooling may be at a rate of, for example, 4°C / h to about 40°C and then at about 10°C / h to about 10°C. The solution / suspension may optionally be stirred after cooling. Following this, standard crystal isolation may follow. For example, the suspension can be vacuum filtered, then the reaction vessel and the crystals washed with 2-MeTHF, and then the crystals can be dried.

[0154] In some embodiments, the crystalline Form B is characterized by the XRPD pattern that it exhibits. In some embodiments, Form B is characterized by an XRPD pattern comprising one or more (e.g. one, two, three, four, five, six, seven, eight, nine, ten, or greater than ten, or at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) characteristic peaks selected from Table B. Table B: XRPD peak list for Form B polymorph of compound 190. The positional error for each individual peak is ± 0.2° 2Theta.

[0155] Typically, Form B is characterized by having an XRPD pattern that exhibits peaks at 19.0 ± 0.2 °2Theta (Cu Kai), 6.5 ± 0.2 °2Theta (Cu xi), and 17.8 ± 0.2 °2Theta (Cu Kai).

[0156] Optionally, Form B exhibits has an XRPD pattern that exhibits peaks at 19.0 ± 0.2 °2Theta (Cu Kai), 6.5 ± 0.2 °2Theta (Cu Kai), and 17.8 ± 0.2 °2Theta (Cu Kai), wherein all three of those peaks are in the top 6 most relatively intense peaks in the spectrum (e.g. a spectrum of pure Form B). In some embodiments, Form B exhibits an XRPD pattern with peaks at one or more of (e.g. all of) 19.0, 6.5, 17.8, 16.4, 11.2, and 7.2 (± 0.2 °2Theta). The aforementioned peak positions may be freely combined, including those in Table B. In some embodiments, Form B exhibits an XRPD pattern with a peak at 19.0 ± 0.2 °2Theta. In some embodiments, Form B exhibits an XRPD pattern with a peak at 6.5 ± 0.2 °2Theta. In some embodiments, Form B exhibits an XRPD pattern with a peak at 17.8 ± 0.2 °2Theta. In some embodiments, Form B exhibits an XRPD pattern with a peak at 16.4 ± 0.2 °2Theta. In some embodiments, Form B exhibits an XRPD pattern with a peak at 11.2 ± 0.2 °2Theta. In some embodiments, Form B exhibits an XRPD pattern with a peak at 7.2 ± 0.2 °2Theta. In some embodiments, Form B exhibits an XRPD pattern substantially as shown in Fig. 32. In some embodiments, Form B exhibits an XRPD pattern as shown in Fig. 32.

[0157] In some embodiments, crystalline Form B is characterized by DSC. In some embodiments, the DSC curve exhibits an endothermic peak (endothermic event) in the region of 200°C to 220°C, 205°C to 215°C, or at about 209°C. In some embodiments the DSC curve comprises one significant peak. In some embodiments, the DSC curve comprises one significant peak in the temperature range of 40°C to 280°C. In some embodiments, the DSC curve comprises a peak with an onset in the temperature range 200°C to 210°C, or about 204°C. In some embodiments, Form B exhibits a DSC curve substantially as shown in Fig. 33. In some embodiments, Form B exhibits a DSC curve as shown in Fig. 33.

[0158] In some embodiments, crystalline Form B is characterized by TGA. In some embodiments, Form B shows a weight loss of < 0.1 wt% between 25°C and 100°C. In some embodiments, Form B exhibits a TGA curve substantailly as shown in Fig. 34. In some embodiments, Form B exhibits a TGA curve as shown in Fig. 34.

[0159] In some embodiments, crystalline Form B is characterized by Raman spectroscopy. In some embodiments, Form B exhibits a Raman spectrum substantailly as shown in Fig. 35. In some embodiments, Form B exhibits a Raman spectrum as shown in Fig. 35. In some embodiments, the Raman spectrum of Form B exhibits peaks at one or more of (e.g. all of) 1639 cm'1, 1306 cm'1, and 215 cm'1± 2 cm'1. A table of peak positions exhibited by the Raman specturm of Form B is given below in Table BI. In some embodiments, the Raman spectrum of Form B exhibits one or more (e.g. one, two, three, four, five, six, seven, eight, nine, ten, or greater than ten, or at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) characteristic peaks selected from Table BI.

[0160] Table BI: Peak positions exhibitied by Raman spectrum of Form B (± 2cm'1).

[0161] In some embodiments, crystalline Form B is characterized by IR spectroscopy. In some embodiments, Form B exhibits an IR spectrum substantially as shown in Fig. 36. In some embodiments, Form B exhibits an IR spectrum as shown in Fig. 36. In some embodiments, the IR spectrum of Form B exhibits peaks at one or more of (e.g. all of) 1632 cm'1, 851 cm'1, and 686 cm'1± 2 cm'1. A table of peak positions exhibited by the IR spectrum of Form B is given below in Table BIT In some embodiments, the IR spectrum of Form B exhibits one or more (e.g. one, two, three, four, five, six, seven, eight, nine, ten, or greater than ten, or at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) characteristic peaks selected from Table BIT

[0162] Table BII: Peak positions exhibited by IR spectrum of Form B (± 2cm'1).

[0163] Preparation of Form C seed crystal

[0164] The present invention relates to a method of preparing crystalline Form C of compound 190, that makes use of a seed crystal of Form C. The skilled person is able to use known methods to obtain compound 190, and is able to obtain crystals of Form C, e.g. as part of a composition which may comprise other crystal forms of compound 190, by using routine (re)crytsllization techniques and screening technqiues that are part of their common general knowledge. In particular, the skilled person may make use of solvent drop grinding, for example solvent drop grinding of amorphous compound 190 with ethanol to generate Form C seed crystals

[0165] Under the conditions used during crystalization in the present invention (i.e. when in ethanol; ‘77? situ” Form C is thermodynamically more stable than Form A described herein, and kinetically more accessible than Form B described herein. The superior thermodynamic stability of Form C when compared to Form A in situ is demonstrated by carrying out a competition slurry experiment between Form A and Form C. The solvent used is ethanol containing 2 %-m / m (with and without 0.4 %-m / m water), 6 %-m / m (with and without 0.4 %-m / m), 8 %-m / m, and 10 %-m / m of ethyl acetate. The temperatures used were 0 °C (only for 2 %-m / m and 6 %-m / m of ethyl acetate with and without 0.4 %-m / m of water), 10 °C, 20 °C, 40 °C, 50 °C and 60 °C. The equilibration time in all cases was approximately 7 days. The equilibration was carried out under agitation by magnetic stirring. The details of the experiment are in Table C-EQ below. As can be seen from Table C-EQ, all experiments yielded Form C. Form C was more stable than Form A under all conditions detailed in Table C-EQ. The conclusion is that Form C is more stable than Form A (which is more soluble) under the process conditions described herein for the crystallisation of compound 190, and in particular more stable in ethanol.

[0166] Table C-EQ

[0167] Because of Form C’s thermodynamic and kinetic availability, even if only a small amount of Form C is crystallized in a first generation sample, for example amongst other crystal forms, this first generation sample can be used to seed a further crystallization where the content of Form C grows in the second generation sample that is produced. By optionally repeating the seeding again with the second generation sample, the third generation sample, the fourth generation sample, and so on, a high purity seed crystal of Form C is obtainable. Generally speaking, the second generation sample will be high purity Form C, usable as a seed crystal.

[0168] Alternatively, Form C is initially producible in small amounts by equilibriating Form A in ethanol at elevated temperatures (for example > 40°C and < 60°C). The results in Table C-EQ also serve to demonstrate that such equilibration of Form A is able to produce Form C.

[0169] Preparation of Compound 190

[0170] In some aspects of the present invention, compound 190, stereoisomers thereof, geometric isomers thereof, tautomers thereof, and salts thereof, may first be prepared from compounds 170 and 181 according to the following reaction scheme:

[0171] In some aspects, compound 190 (or a stereoisomer, geometric isomers, tautomer, or salt thereof) may be prepared according to the method depicted in FIG. 5A and in FIG. 5B.

[0172] In some embodiments compound 190 (or a stereoisomer, geometric isomers, 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 reacting the reaction mixture to form a reaction product mixture comprising compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof. In certain embodiments, the solvent system further comprises a polar aprotic solvent. In some embodiments, the polar aprotic solvent is an ester, such as a low molecular weight ester. In certain embodiments, the solvent system comprises a low molecule weight ester, such as a lower-alkyl ester of acetic acid. In some embodiments, the low molecular weight ester is ethyl acetate or isopropyl acetate. In certain embodiments, the solvent system comprises water and ethyl acetate. In some embodiments of the methods provided herein, using a solvent system comprising water and an ester, such as a low molecular weight ester, produces compound 190, or a stereoisomer, geometric isomer, tautomer, or salt thereof, at a higher yield, or with lower level of impurities, or both, than methods using a different solvent system. In some embodiments, in the reaction mixture, the equivalent ratio of compound 181 to compound 170 is greater than 1:1, from 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 constructed therefrom.

[0173] The palladium catalyst may be a palladium catalyst as described elsewhere herein. In some particular aspects, the palladium catalyst comprises a palladium(II) species containing a phosphine ligand and at least one palladium-carbon bond. In some aspects, the fragment giving rise to the palladium-carbon bond is an allyl derivative of the formula: wherein each of R6to R10is independently selected from the group consisting of H, optionally substituted Ci-6 alkyl, optionally substituted Ce aryl, and optionally substituted heteroaryl; and R6and R10may optionally come together to form a fused bicycle comprising an aromatic ring. In some particular aspects of the allyl derivative: each of R6to R10is H; R6is -CH3 and each of R7to R10is H; R7is -CH3 and each of R6and R8to R10is H; R8is -CH3 and each of R6, R7, R9and R10is H; R6is -phenyl and each of R7to R10is H; or R7is -phenyl and each of R6and R8to R10is H.

[0174] In some aspects, R6and R10together with the atoms to which they are attached form a fused bicycle comprising an aromatic ring. In some embodiments, R6and R10together with the atoms to which they are attached form a five-membered carbocycle fused to a phenyl ring. In some such embodiments, R7, R8, and R9are H. In other embodiments, two of R7, R8, and R9are H, and the remainder is Ci-10 alkyl.

[0175] For example, in some aspects, the fragment giving rise to the palladium-carbon bond is an indenyl of the formula wherein R11is Ci-10 alkyl. In some particular aspects, the allyl derivative of the structure:

[0176] In some aspects, the phosphine ligand is of the formula: wherein R1and R2are each independently selected from the group consisting of: optionally substituted C1-12 alkyl, optionally substituted C3-C20 cycloalkyl, and optionally substituted C5 or Ce aryl; or C1-4 alkyl, and C3-6 cycloalkyl. In some aspects, R3to R5are each independently selected from the group consisting of: H, optionally substituted C1-6 alkyl, alkoxide of the formula -O-C1-6 alkyl, and amine of the formula -N(R12)(R13) wherein R12and R13are independently selected from H and C1-6 alkyl. In some aspects, R3to R5are each independently -O-C1-4 alkyl and R12and R13are independently selected from H and C1-4 alkyl. In some aspects, the phosphine ligand is SPhos, having the following structure:

[0177] In some aspects, the Pd catalyst is selected from: a cationic palladium species comprising an inorganic or organic counterion X; and a neutral palladium species comprising a coordinated inorganic or organic ligand X. In such aspects, X may be selected from a halogen, a carboxylate, a sulfonate, and an inorganic anion. In such aspects, the carboxylate may be as defined elsewhere herein, such as CH3C(O)O', tBuC(O)O', or CF3C(O)O"’. In such aspects, the sulfonate may be as defined elsewhere herein, such as triflate (CF3SO3’), tosylate, besylate, or nosylate. In such aspects, the inorganic anion may be as defined elsewhere herein, such as PFe’, BF4', B(CeF5)4', NCh', and SC2'. In one aspect, X is CFsSC '. In some aspects, the Pd catalyst is neutral or cationic. In certain embodiments, the catalyst further comprises a counterion, such as a cationic catalyst further comprising an anionic counterion. In some aspects, 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 aspect, the catalyst is [(SPhos)Pd(allyl)]CF3SO3.

[0178] The equivalent ratio of the 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 constructed therefrom, such as from about 0.001:1 to about 0.01:1, from about 0.001:1 to less than 0.05:1, from about 0.001:1 to about 0.0045:1, or from about 0.001:1 to about 0.003:1.

[0179] In some aspects, the reaction mixture base is an inorganic base. In some particular aspects, the base is K3PO4 or K2HPO4.

[0180] 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 constructed therefrom, such as from about 1:0.05 to about 1:2, or from about 1:0.1 to about 1:1. In some particular embodiments, the aprotic solvent is an ester. In certain embodiments, the aprotic solvent is a low molecular weight ester, such as an ester of acetic acid with Ci-ealkyl, such as Ci-3alkyl. In some embodiments, the ester is isopropyl acetate, or ethyl acetate. In some particular aspects, the solvent system comprises water and ethyl acetate, predominantly comprises water and ethyl acetate, consists essentially of water and ethyl acetate, or consists of water and ethyl acetate. In some aspects, the ratio of the solvent system volume in the reaction mixture to compound 170 weight may 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 from about 5:1 to about 30:1 L / kg, from about 5:1 to about 20:1 L / kg, from about 5:1 to about 15:1 L / kg, or from about 7.5:1 to about 12.5:1 L / kg. In certain embodiments, using a solvent system comprising water and an ester (such as ethyl acetate) results in higher product yield, or a lower amount of impurities, or both, compared to using other solvent systems. In some embodiments, the ratio of ethyl acetate to water is from about 1:0.1 to about 1:1, or about 1:0.1 to about 1:0.8, or about 1:0.1 to about 1:0.5, or about 1:0.1 to about 1:0.3.

[0181] In some aspects, the catalyst is [(SPhos)Pd(allyl)]CF3SO3, the solvent system predominantly comprises ethyl acetate and water wherein the volume ratio of ethyl acetate to water is from about 1:0.1 to about 1:1 (such as about 1:0.3), and the boronate is 4,4,5,5-tetramethyl-l,3,2- dioxaborolane of the structure:

[0182] In some embodiments, the reaction temperature for forming compound 190 is greater than about 40°C, greater than about 50°C, greater than about 60°C, greater than about 70°C, or between about 40°C to about 80°C, between about 50°C to about 80°C, between about 60°C to about 80°C, between about 65°C to about 75°C , is about 60°C, is about 70°C, or is 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.

[0183] The reaction may be deemed complete when the area% concentration by HPLC of compound 170 is less than 2, less than 1, less than 0.5 or less than 0.1. In some embodiments, the reaction is deemed complete when the area% concentration by HPLC of compound 170 is less than 0.5, or not detectible. The reaction time to completion may be about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours. In some aspects, the reaction time to completion is less than 5 hours, such as less than 2 hours or less than 3 hours. In some embodiments, the reaction time is about 1 hour, or about 2 hours.

[0184] Without wishing to be bound by theory, the combination of solvent system, catalyst, and temperature described herein may lead to lower reaction times than other combinations. For example, in some embodiments, a combination of a catalyst comprising palladium(II) species containing a phosphine ligand and at least one palladium-carbon bond, solvent system comprising water and an ester (such as a low molecular weight ester, such as ethyl acetate), and a reaction temperature of between about 60°C to about 80°C (such as between about 65°C to about 75°C, such as about 70°C), may lead to the production of compound 190 or a salt thereof at higher yields in a shorter period of time (such as less than 5 hours, less than 3 hours, or less than 2 hours), or with lower impurities, or both, compared to other conditions.

[0185] In some aspects of the invention, the methods of producing compound 190 (or a stereoisomer, geometric isomers, tautomer, or salt thereof) further comprise one or more purification steps. In some embodiments, the one or more purification steps comprise one or more aqueous washes, for example two aqueous washes, or three aqueous washes. In certain embodiments, the one or more purification steps comprise an aqueous N-acetyl-cysteine wash followed by an aqueous base wash, and then a water wash. In certain embodiments, additional purification steps are included, such as filtration.

[0186] In some such aspects, the temperature of the reaction product mixture may be adjusted from about 10°C to about 65°C or from about 25°C to about 60°C or from about 45°C to about 60°C (such as about 55°C) and combined with agitation with aqueous N-acetyl-L-cysteine having a N-acetyl-L-cysteine concentration of about 3 wt.%, about 5.5 wt.%, about 6 wt.% or about 9 wt.%, and ranges thereof, such as from about 3 wt.% to about 9 wt.%. The weight ratio of N-acetyl-L-cysteine to compound 190 may be from about 1:5 to about 1:25, or from about 1:10 to about 1:20, or about 1:15. The ratio of aqueous N-acetyl-L-cysteine volume (such as about 3 wt.% to about 9 wt.% aqueous N-acetyl-L-cysteine) to compound 190 weight may be about 1 L / kg, about 2 L / kg or about 3 L / kg, and ranges thereof, such as from about 1 L / kg to about 3 L / kg. Following agitation with aqueous N-acetyl-L-cysteine, in some embodiments additional organic solvent is added with agitation. The additional organic solvent may be the same organic solvent present in the reaction, for example a low molecular weight ester such as ethyl acetate. In some embodiments, the ratio of additional organic solvent to compound 190 weight is from about 1:3 to about 1:1, or about 1:2 to about 1:1, or about 1:2.5. An aqueous layer is separated and an organic layer comprising compound 190 is collected. The organic layer may be further optionally combined with a base solution, wherein the concentration of base may be from about 3 wt.% to about 7 wt.%, or about 5 wt.%. In some embodiments, the base is sodium bicarbonate (NaHCCb). In certain embodiments, the ratio of the base solution volume to compound 190 weight 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 thereof, such as from about 0.5 L / kg to about 2.5 L / kg. In such aspects, an aqueous layer is separated and an organic layer comprising compound 190 is collected. The organic layer comprising compound 190 may, in some embodiments, undergo additional washing steps, such as a water wash. In some embodiments, the organic layer comprising compound 190 is combined with water under agitation. In certain embodiments, the ratio of water volume to compound 190 weight may about 0.5 L / kg, about 1 L / kg, about 2 L / g, about 3 L / kg, or about 4 L / kg, or ranges thereof, such as from about 0.5 L / kg to about 4 L / kg, or from about 1 L / kg to about 3 L / kg, or about 2 L / kg. In such aspects, an aqueous layer is separated and an organic layer comprising compound 190 is collected. In some aspects, any of the various organic layers comprising compound 190 may be contacted with activated charcoal, such filtration through a charcoal bed or by suspending activated charcoal in the organic phase followed by charcoal separation and removal such as by filtration or centrifugation. In certain embodiments, a stereoisomer, geometric isomer, tautomer, or salt of compound 190 is produced, and all comparisons and / or ratios made relative to the amount of compound 190 are instead relative to the amount of stereoisomer, geometric isomer, tautomer, or salt of compound 190.

[0187] Compound 190 may optionally be isolated from the reaction product mixture or from the organic layer comprising compound 190 from the work up step(s). Such isolation may include, for example, one or more solvent swap, distillation, and / or crystallization steps. Such crystallization steps are described in more detail elsewhere in the present disclosure, for example in relation to Forms A and C. In some such aspects, the collected organic layer comprising compound 190, may be processed by a solvent swap step where the aprotic solvent may be swapped for a polar protic solvent as described elsewhere herein. In some aspects, the polar protic solvent is an alcohol. In some such aspects, the polar protic solvent is ethanol. In some such aspects, the solvent swap may be done by reducing the volume of the composition comprising compound 190 by vacuum distillation, and the reduced volume comprising compound 190 may be diluted with the polar protic solvent. For example, a reduced volume comprising compound 190 may be diluted with a polar protic solvent at a ratio of 1:6, 1:5, 1:4, 1:3, or 1:2, or any ranges therein, such as from 1:6 to 1:1, or 1:5 to 1:4, or about 1 :4.5. In some embodiments, the ratio of volume of polar protic solvent to compound 190 weight is about 20 L / kg, 15 L / kg, 10 L / kg, 5 L / kg, or ranges therein, such as from about 20 L / kg to about 5 L / kg, or about 15 L / kg to about 5 L / kg, or is about 10 L / kg. In some embodiments, polar protic solvent is added to the reduced volume comprising compound 190 to a total solvent volume of from about 20 to about 5 L solvent per kg of compound 190, or from about 8 to about 12 L 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 describe herein. The volume of the solution of purified compound 190 may be reduced by distillation to a reduced volume of such as from about 3 to about 13 L, from about 3 to about 7 L, from about 6 to about 10 L, or from about 7 to about 9 L of solvent per kg of compound 190. The polar protic solvent (ethanol) dilution and distillation step may be repeated one or more times. In some embodiments, distillation of the aprotic solvent under vacuum is performed at the same time as the addition of the polar protic solvent such that the volume of the reaction product mixture is kept substantially constant (i.e. concerted distillation and addition; or a constant volume distillation / solvent swap). The constant volume of the reaction product mixture may be such that the total solvent volume compared to the amount of compound 190 is about 20 to about 5 L solvent per kg of compound 190, or from about 8 to about 12 L solvent per kg of compound 190. When such a concerted solvent swap is used, in some embodiments there may be an additional distillation step subsequently, to reduce the reaction product mixture to a desired volume. If such an additional distillation step is carried out, it may be done to the extent that the volume of solvent compared to the amount of compound 190 is about 3 to about 13 L, from about 3 to about 7 L, from about 6 to about 10 L, or from about 7 to about 9 L of solvent per kg of compound 190. In some embodiments, the polar protic solvent dilution and distillation steps is performed one or more times until the content of residual aprotic solvent is less than 15% w / w, or less than 12% w / w, or 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 comprise crystallizing compound 190, or stereoisomer, geometric isomer, tautomer, or salt thereof. The manner of crystallization, and the nature of the crystallization products obtainable are described in more detail elsewhere in the present disclosure. In particular, the preparation of Form C is achieved through seeding using a seed crystal of Form C. Such crystallization may, for example, follow the solvent swap and / or distillation steps described herein. That is, the methods described for the preparation of compound 190 Form C may, for example, follow the solvent swap and / or distillation steps described herein (e.g. immediately follow).

[0188] The yield of compound 190, or stereoisomer, geometric isomer, tautomer, or salt thereof, based on compound 170 is at least 80%, at least 85%, at least 90%, 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 stereoisomer, geometric isomer, tautomer, or salt thereof is at least 98.5% w / w, at least 99% w / w, at or at least 99.5% w / w. The content of a dimer impurity, depicted below, is less than 0.15 area%, less than 0.1 area%, less than 0.05 area%, or is undetectable as measured by an HPLC method according to the present disclosure. In some embodiments, the content of a dimer impurity, 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 a ketone and alcohol impurity, 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%, no more than 0.05 area%, or is undetectable as measured by HPLC. In certain embodiments, area% is evaluated using the HPLC method according to the present disclosure.

[0189] The catalytic system described in detail herein displays much higher activity for the coupling of compounds 170 and 181 to yield compound 190 as compared to other, previously disclosed catalytic systems employing a Pd(dppf)Ch catalyst. The higher activity results in a catalysts loading of as low as about 0.1 mol% or about 0.2 mol% (0.001 eq or about 0.002 eq) based on compound 170 as compared to previously disclosed loading of about 1 mol%. The improved catalyst system has the advantage of higher yields and lower byproduct impurities. For example, in some embodiments the present catalytic system provides for compound 190 yield, based on compound 170, of at least 90%, or at least 93%; and dimer impurity content of less than 0.15 area%, or less than 0.1 area%, or is undetectable. The increased yield and decreased impurity profile using the improved catalytic system described herein may be reflected in particular at higher batch sizes, such as when using greater than 100 g of starting material 170, such as 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 processes for producing compound 190, increasing batch size (such as from 50 g to 0.75 kg starting material 170) resulted in a decrease in yield of compound 190 obtained. Thus, in certain aspects the presently described catalytic system 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, such as 160-185 kg). Further, in some embodiments, the catalytic system described herein exhibits higher activity in a solvent system comprising water and an aprotic ester solvent, compared to previously used solvent systems. Using a solvent system comprising water and an aprotic solvent, wherein the solvent is an ester, in combination with the catalytic system described herein results in a higher yield, or lower level of impurities, or both, compared to prior systems using other solvents. In addition, the methods described herein may be carried out at higher temperatures, and / or shorter reaction times, compared to prior methods, and the change of these parameters may have additional advantages.

[0190] The presently described combination of catalyst, solvent, and base, referred to as the catalytic system, further provides for compound 190 purity on the order of about 99.8 area% (HPLC) or greater as compared to purity of up to 99.5 area% described by previous methods.

[0191] Concomitant with an improved impurity profile, the present catalytic system provides for a significant reduction in the generation of certain impurities that are difficult to remove, thereby obviating the need for certain purification steps. For instance, three impurity byproducts of the compound 170-181 coupling reaction include a dimer impurity, a secalcohol impurity, and a ketone impurity as follows:

[0192] Representative compound 190 impurity profiles for the previously disclosed and the presently described catalytic systems are shown in the table below, using the same HPLC method for quantification. The combination of catalytic system described herein, solvent system comprising an ester, and increased reaction temperature compared to other, previous methods, advantageously provides one or more (including a combination of some, or all) of: higher yields of compound 190 (particularly at larger batch sizes), lower levels of impurities (including decreasing some impurities below detectable levels), a more efficient reaction work-up, and shorter reaction times than previously required.

[0193] Further provided herein are compositions comprising compound 190 (e.g. as described herein), or 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% compound 190 (e.g. as described herein), or stereoisomer, geometric isomer, tautomer, or salt thereof. In some embodiments, the composition has a compound 190 (e.g. as described herein) purity of at least 99 area%, at least 99.5 area%, at least 99.6 area%, at least 99.7 area%, at least 99.8 area%, or at least 99.9 area% by HPLC. In some embodiments, the composition has a content of a dimer impurity of less than 0.15 area%, less than 0.10 area%, less than 0.05 area%, or is not detectible, based on compound 190 (e.g. as described herein); or has a dimer impurity content 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; wherein the dimer impurity is of the structure

[0194] In some embodiments, the composition has a combined content of an alcohol and a ketone impurity based on compound 190 (e.g. as described herein) 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%, no more than 0.05 area%, or is undetectable, wherein the alcohol and ketone impurities are of the structure:

[0195]

[0196] Alcoho1and Ketone

[0197] 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. as described herein), for example between 1-200 kg, or between 5-100 kg, or between 50-200 kg, or between 100-200 kg of compound 190 (e.g. as described herein).

[0198] In certain embodiments, a stereoisomer, geometric isomer, tautomer, or salt of compound 190 (e.g. as described herein) is produced, and all comparisons and / or ratios made relative to the amount of compound 190 (e.g. as described herein) are instead relative to the amount of stereoisomer, geometric isomer, tautomer, or salt of compound 190 (e.g. as described herein).

[0199] Preparation of Compound. 200

[0200] In some embodiments compound 200 (or a stereoisomer, geometric isomer, tautomer, or salt thereof) is prepared from a second reaction mixture comprising compound 190, for example Form C of compound 190 (or a tautomer thereof), a reducing agent, a base and a solvent. The second reaction mixture is reacted to reduce the aldehyde moiety of compound 190 and form a reaction product mixture comprising compound 200 as generally depicted below

[0201] In some aspects, compound 200 may be prepared according to the method depicted in FIG. 6.

[0202] In some aspects, the solvent is selected from Ci-4 alcohols, ethers and cyclic ethers. In some particular aspects, the solvent an aprotic solvent, such as THF, methyl tert-butyl ether, or 2- Me-THF. The ratio of solvent volume to compound 190 weight may be about 2:1 L / kg, about 3:1 L / kg, about 4:1 L / kg, about 5:1 L / kg, about 6:1 L / kg, about 7:1 L / kg, about 8:1 L / kg, about 9:1 L kg, about 10:1 L / kg, and ranges thereof, such as from about 2:1 to about 10:1 L / kg, or from about 4:1 to about 8:1 L / kg. In some aspects, the solvent predominantly comprises or consists of THF. In some aspects, the base in the reaction mixture is an inorganic base, such as an alkali hydroxide. In one such aspect, 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 from about 0.1:1 to about 0.9:1 or from about 0.3:1 to about 0.7:1. In any of the various aspects, the reducing agent is as described elsewhere herein. In some particular aspects, the reducing agent is sodium borohydride. The equivalent ratio of the 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, or about 0.9:1, and ranges thereof, such as from about 0.1:1 to about 0.9: 1 or from about 0.2: 1 to about 0.8:1. In some embodiments, the base and reducing agent are added to the reaction mixture in the form of solids, or an aqueous solution, or a combination. 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 the 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 from 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.

[0203] The reaction temperature for forming compound 200 is suitably 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.

[0204] The reaction may be deemed complete when the area% concentration by HPLC of compound 200 is less than 2, less than 1, less than 0.5 or less than 0.1. In some aspects, the reaction time to completion may be 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, or more. The yield of compound 200 or 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 salt thereof is at least 90%, and the purity is at least 99.9 area% by HPLC.

[0205] In some aspects, compound 200 may be isolated from the reaction product mixture. In some such aspects, compound 200 may be isolated by admixing the second reaction product mixture with an aqueous solution of a base, such as an inorganic base (e.g., monopotassium phosphate); or admixing with an aqueous solution of an inorganic acid, such as phosphoric acid (i.e. H3PO4). In some embodiments, the aqueous base or inorganic acid in a volume ratio to compound 200 weight of from about 0.5 L to about 2 L of about 10 percent by weight to about 25 percent by weight aqueous base or acid (e.g., monopotassium phosphate or phosphoric acid) solution per kg of compound 200. In some embodiments, such admixing is performed at a temperature of about 15 °C to about 50 °C, such as about 20 °C, or about 30 °C, or about 40 °C. An aqueous layer is separated and an organic layer comprising compound 200 in solution is collected. The organic layer comprising compound 200 may optionally be treated with activated charcoal. The organic layer comprising compound 200 may be filtered.

[0206] In some aspects where the solvent is an aprotic solvent (e.g., THF), the filtrate may be distilled to a volume of from about 2 to about 4 L / kg of compound 200. A suitable solvent, such as a C1-4 alcohol (e.g., methanol) may be added to the distilled filtrate to a total volume of from about 6 to about 8 L / kg of compound 200. In some aspects, from about 0.2 to about 0.8 percent by weight 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, for instance 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 aspects, the distillate may be aged for at least one hour, such as about 1 hour, about 2 hours, about 3 hours, or about 4 hours at a temperature of at least 40°C, for instance about 45°C, about 50°C, about 55°C, about 40°C,or about 65°C. The distilled mixture of compound 200 may be cooled, such as to less than 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 an amount of time, such as for instance about 30 minutes, about 1 hour, about 2 hours, about 3 hours, or about 4 hours. Compound 200 crystals may be optionally collected and dried. Drying may suitably be done under vacuum and an inert gas purge (e.g. , argon or nitrogen) at a temperature of, for instance, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, or about 60°C to for a time sufficient to remove the desired amount of solvent, such as for instance about 6 hours, about 12 hours, about 18 hours, about 24 hours, or about 30 hours.

[0207] In some aspects, the purified compound 200 crystals may be recrystallized in a purification step. In some such aspects, compound 200 may be combined with a Ci-4 alcohol (e.g., ethanol) at a ratio of alcohol volume to compound 200 weight of from about 1 L / kg to about 10 L / kg or from about 1 L / kg to about 5 L / kg or from about 4 L / kg to about 10 L / kg or from about 6 L / kg to about 8 L / kg, and with toluene at a ratio of toluene volume to compound 200 weight of from about 1 L / kg to about 5 L / kg or from about 1.5 L / kg to about 3.5 L / kg and with agitation. The mixture may be heated, such as to from about 65 to about 85°C, with agitation and held until a solution is obtained. The solution may then be cooled, such as to from about 60°C to about 70°C, or from about 65°C 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 with sufficient additional alcohol such that the alcohol : toluene ratio is about 90:10, or about 80:20, or about 70:30, or any ranges within, and then seed crystals are added, such as from about 0.5 wt% to about 4 wt%, or from about 0.5 wt% to about 3 wt%, or from about 0.5 wt% to about 1.5 wt% compound 200 seed crystals, to form a slurry. In some embodiments, the solution is further cooled between alcohol addition and seed crystal addition. Alternatively, the solution is first combined with seed crystals and then additional alcohol, such as from about 0.5 wt% to about 4 wt%, or from about 0.5 wt% to about 3 wt%, or from about 0.5 wt% to about 1.5 wt% compound 200 seed crystals, to form a slurry; and then combined with alcohol at a ratio of alcohol volume to compound 200 weight of from about 5 L / kg to about 25 L / kg or from about 10 L / kg to about 20 L / kg. In either aspect, the slurry may be further cooled, such as to from about -5 to about 15°C, and held for at least 15 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 4 hours, or at least 8 hours to crystallize compound 200. In some embodiments, one or more thermocycles are involved after the initial cooling step, such as raising the temperature to between about 30°C to about 50°C, or about 35°C to about 50°C, holding for at least 15 minutes, or at least 30 minutes, or at least 1 hour, then cooling again to from about -5 to about 15°C and holding to crystallize compound 200. The crystals may be collected, such as by filtration or centrifugation, and washed with alcohol. The washed crystals may be dried under vacuum with a N2 purge at from about 40 to about 60°C for at least 4 hours, at least 8 hours, at least 12 hours, or at least 20 hours to produce purified compound 200.

[0208] Preparation of Compound. 141

[0209] In some aspects of the present disclosure, compound 141 may be prepared from compound 140 according to the following reaction scheme:

[0210] 140 H2141

[0211] The method for preparing compound 141 comprises forming a reaction mixture comprising compound 140, a transition metal catalyst, hydrogen, and a suitable solvent. In some embodiments, the method comprises: forming a reaction mixture comprising compound 140 and a solvent comprising organic solvent and water; and contacting said reaction mixture with a transition metal catalyst in the presence of hydrogen to form a product mixture comprising compound 141.

[0212] Preparation of Compound 180

[0213] In some aspects of the present disclosure, compound 180 may be prepared from compounds

[0214] 90 and 141 according to the following reaction scheme where “LG” is a leaving group:

[0215] 141 Base

[0216] Solvent

[0217] In some aspects, the leaving group is a halogen or triflate. In one aspect, the leaving group is Br.

[0218] In some aspects, compound 180 may be prepared by any of the methods depicted in FIGS. 1 to 3. The method for preparing compound 180 comprises forming a reaction mixture comprising compound 141, compound 90, a palladium catalyst and an aryl phosphate catalyst ligand, a base, and an aprotic solvent. The reaction mixture is reacted to form a reaction product mixture comprising compound 180. Compound 180 is optionally isolated from the reaction product mixture.

[0219] Preparation of Compound. 181

[0220] In some aspects of the present disclosure, compound 181 may be prepared from compound 180 according to the following reaction scheme:

[0221] The method for preparing compound 181 comprises forming a reaction mixture comprising compound 180, a palladium catalyst, a catalyst ligand, a borylation reagent, and a polar aprotic solvent. The reaction mixture may also comprise an alkali metal acetate salt. The reaction mixture is reacted to form a reaction product mixture comprising compound 181. Compound 181 is optionally isolated from the reaction product mixture.

[0222] In some aspects, compound 182 may be prepared according to the method depicted in FIG. 4.

[0223] Preparation of Compound 160

[0224] In some aspects, compound 160 may be prepared according to methods disclosed in International Publication Number WO 2018 / 109050 as generally depicted in the three schemes below and as further depicted the reaction schemes of FIGS. 8-10:

[0225] MeMgCI

[0226] CuCI POCI3

[0227] Solvent Solvent Comp. 10

[0228] Comp. 110 - ► Comp. 120 - ► Comp. 130 - ► Comp. 160

[0229] Base

[0230] Solvent MeMgCI

[0231] CuCI NaHSO3NaHCO3POCI3

[0232] Solvent Water Water Solvent Comp. 10

[0233] MeMgCI

[0234] CuCI

[0235] Trimethyl silyl

[0236] Comp. 110 Comp. 122 Comp. 130 Comp. 160

[0237] Base Solvent

[0238] In some such aspects, compounds 120, 130, and 160 may be prepared according to the methods described in WO 2018 / 109050, depicted in FIG. 8.

[0239] In some aspects, compound 120 may be prepared from compound 110 according to the following reaction scheme:

[0240] Solvent

[0241] MeMgCI

[0242] The method for preparing compound 120 comprises forming a reaction mixture comprising a polar aprotic solvent, methyl magnesium chloride, copper (I) chloride and compound 110.

[0243] The reaction mixture is reacted to form a reaction product mixture comprising compound 120.

[0244] In some such aspects, compound 130 may be prepared from compound 120 according to the following reaction scheme:

[0245] The method for preparing compound 130 comprises forming a reaction mixture comprising a polar aprotic solvent, a non-polar solvent, phosphorous oxychloride and compound 120. The reaction mixture may be reacted to form a reaction product mixture comprising compound 130.

[0246] In some particular aspects, compounds 120, 130 and 160 may be prepared according to the method of WO 2018 / 109050, depicted in FIG. 9.

[0247] In some such aspects, compound 120 may be prepared according to FIG. 8. Compound 120 may be purified by a solid ketone bisulfite adduct route depicted in FIG. 9. The purification method comprises forming a first reaction mixture comprising crude compound 120, an organic solvent that is not miscible with water (e.g., heptane), and an aqueous solution of sodium bisulfite, and reacting the first reaction mixture to form a first reaction product mixture comprising the solid ketone bisulfite adduct of compound 121:

[0248] 121

[0249] Compound 121 is isolated from the first reaction product mixture. A second reaction mixture is formed comprising isolated compound 121, water, a low boiling solvent that is not miscible with water, and sodium bicarbonate. In some aspects, the solvent is DCM. The second reaction mixture is reacted to form a second reaction product mixture comprising a first phase comprising the solvent and the predominant amount of purified compound 120 is in solution in the first phase, and a second phase comprising water. The first phase comprising the purified compound 120 is separated from the aqueous phase.

[0250] In some aspects, compound 130 may be prepared from compound 120 according to the method depicted in FIG. 8.

[0251] In some particular aspects, compounds 130 and 160 may be prepared according to method described in WO 2018 / 109050, depicted in FIG. 10.

[0252] In some such aspects of the present disclosure, compound 130 in the below reaction scheme may be prepared from a trimethyl silyl intermediate of compound 120, designated as compound 122 in the below reaction scheme. The reaction scheme is as follows: MeMgCI

[0253] CuCI, LiCI

[0254] Trimethylsilyl chloride POCI3

[0255] Solvent Solvent First Reaction Second Reaction

[0256] 122 130

[0257] The method for preparing compound 130 comprises forming a first reaction mixture comprising a first polar aprotic solvent, methyl magnesium chloride, copper (I) chloride, lithium chloride, chlorotrimethylsilane (TMSC1), and compound 110. The first reaction mixture is reacted to form a first reaction product mixture comprising 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 an organic phase comprising the predominant amount of compound 122 is collected and concentrated to obtain compound 122 in solution. A second reaction mixture comprising a second polar aprotic solvent, phosphorous oxychloride, and the solution of compound 122 is formed. The second reaction mixture is reacted to form a second reaction product mixture comprising compound 130. The second reaction product mixture is quenched with a second quenching agent in aqueous solution. The phases are separated and an organic phase comprising the predominant amount of compound 130 in solution is collected.

[0258] In some aspects, compound 130 may be prepared from compound 120 according to the method depicted in FIG. 8.

[0259] Preparation of Compound. 170

[0260] In some aspects, compound 170 may be prepared according to methods disclosed in International Publication Number WO 2018 / 10905.

[0261] In some such aspects, compound 170 may be prepared according to the method of WO 2018 / 10905, depicted in FIGS. 7 and 13 and reproduced below, by forming a reaction mixture comprising compound 160, a stoichiometric excess of compound 100, a palladium catalyst and a catalyst ligand, a base and a polar aprotic solvent:

[0262] The reaction mixture is reacted to form a reaction product mixture comprising compound 170. Compound 170 may optionally be isolated from the reaction mixture.

[0263] In some particular aspects, compound 170 may be prepared according to the method disclosed in International Publication Number WO 2018 / 10905 as depicted in FIG. 11.

[0264] Preparation of Compound. 140

[0265] In general, compound 140 may be prepared from compounds 153 and 20 according to the following scheme:

[0266] 140

[0267] Wherein the secondary amine of compound 153 is alkylated with compound 20 in a reductive alkylation reaction in the presence of a reducing agent to form compound 140. In some aspects, compound 140 may be prepared as depicted in FIG. 12A, and further described herein.

[0268] In some aspects, provided herein is a method of preparing compound 140, the method comprising:

[0269] (a) forming a reaction mixture comprising compound 153, compound 20, NaBH(OAc)s, and a solvent; and

[0270] (b) reacting the reaction mixture to form a reaction product mixture comprising compound 140 according to the following scheme: In other aspects, compound 140 may be prepared according to the method of WO 2018 / 10905 as depicted in the last step of FIG. 12B.

[0271] Preparation of Compound 153

[0272] In general, In general, compound 153 may be prepared according to the following scheme:

[0273] Pd catalyst halogen halogen = Br or Cl

[0274] In such aspects, compound 154A may be prepared from a reaction mixture comprising compound 50, compound 40, dioxane, K3PO4, Pd(OAc)2 catalyst, and BINAP ligand.

[0275] In such aspects, compound 153 may be prepared from compound 154A according to the following reaction scheme:

[0276] 154A 153

[0277] The method for preparing compound 153 comprises forming a reaction mixture comprising compound 154A having a protecting group moiety, PG, hydrochloric acid, and a solvent comprising water. The reaction mixture is reacted to form a reaction product mixture comprising deprotected compound 154A. Compound 153 may optionally be isolated from the reaction product mixture.

[0278] Overall Process

[0279] Compound 200 may be prepared in an overall process as depicted in FIG. 13 where steps 1-3 and 7-10 relate to the general methods of International Publication Number WO 2018 / 109050 described elsewhere herein, and where step 11 particularly relates to the present disclosure.

[0280] Advantageously, the various crystal forms of compound 190 described herein do not significantly alter the reaction steps required to obtain compound 200 described herein. The method used to form compound 190 Form C is advantageous because it provides a more predicatable and consistent crystal form purity of compound 190 and a more predicatable and consistent impurity profde of the compound 190 product. This advantageously allows improved control over the total synthesis of compound 200 that is not provided, or provided to a lesser degree, by the other crystal forms of compound 190.

[0281] Solvates of Compound. 200

[0282] Further provided herein are solvates of compound 200, such as those that may be produced during manufacturing of compound 200. In some embodiments, said solvates are crystalline solvates. In certain embodiments, the crystalline solvate is an ethanol hemi-solvate. In some embodiments, the crystalline solvate is a toluene solvate. In some embodiments, the crystalline solvate is an ethanol solvate.

[0283] In some embodiments, the crystalline ethanol hemi-solvate is characterized by an XRPD pattern comprising one or more (e.g., one, two, three, four, five, six, seven, eight, nine, ten, or greater than ten; or at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) characteristic peaks selected from Table X. In some embodiments, the crystalline ethanol hemi-solvate is characterized by an XRPD pattern comprising at least four, at least five, or all six of the following peaks: 7.0, 14.0, 15.0, 17.5, 19.2, and 21.1 °2Theta (±0.2° 2Theta). In some embodiments, the crystalline ethanol hemi-solvate has an XRPD pattern essentially as provided in FIG. 14.

[0284] In some embodiments, the crystalline toluene solvate is characterized by an XRPD pattern comprising one or more (e.g., one, two, three, four, five, six, seven, eight, nine, ten, or greater than ten; or at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) characteristic peaks selected from Table X. In some embodiments, the crystalline toluene solvate has an XRPD pattern essentially as provided in FIG. 15. In some embodiments, the crystalline toluene solvate is characterized by an XRPD pattern comprising at least four, or all five of the following peaks: 4.2, 6.9, 14.2, 15.6, and 16.8 °2Theta (±0.2° 2Theta).

[0285] In some embodiments, the crystalline ethanol solvate is characterized by an XRPD pattern comprising one or more (e.g., one, two, three, four, five, six, seven, eight, nine, ten, or greater than ten; or at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) characteristic peaks selected from Table X. In some embodiments, the crystalline ethanol solvate has an XRPD pattern essentially as provided in FIG. 16. In some embodiments, the crystalline ethanol solvate is characterized by an XRPD pattern comprising at least four, at lesat five, at least six, or all seven of the following peaks: 5.4, 5.6, 8.5, 13.8, 14.0, 14.6, and 17.0 °2Theta (±0.2° 2Theta).

[0286] Table X: XRPD Peak list for selected compound 200 solvate polymorphs. The positional error for each individual peak is ±0.2° 2Theta. Ethanol Hemi-Solvate Toluene Solvate Ethanol Solvate

[0287] EXAMPLES

[0288] The Figures and Examples provide exemplary methods for preparing the disclosed compounds; those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds. Although 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. In addition, 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.

[0289] In the Examples, equivalents and equivalent ratios are based on the referenced starting material for each reaction. Volume per weight values, such as L / kg and mL / g, refer to a volume of a liquid component based on the weight of the referenced starting material for each reaction.

[0290] Analytical Methods

[0291] High pressure liquid chromatography (HPLC) may be performed as follows.

[0292] HPLC Method 1 - Examples 2—10; and Comparative Examples 2-4: Instruments and column. HPLC system: Agilent Series 1260, quaternary pump, and autosampler. Integration system: Waters Empower. Configuration: Jetweaver V380 mixer not used, pulse compensation, 0.12 mm capillaries (red), and 10 mm flow cell. Delay volume: 0.51 mL. Dosage: Automatic burettes (e.g., Metrohm 725 Dosimat) or volumetric pipettes, Piston-stroke pipettes for pL range. Stationary phase: Poroshell 120 Bonus-RP, L = 150 mm, ID = 4.6 mm, 2.7 pm.

[0293] Solutions. 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 if necessary with acetic acid. 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).

[0294] Pump program.

[0295] Column oven temperature: 25°C. Column back pressure: About 300 bar (initial conditions). Injection volume: 3.0 pL. Needle wash: Wash vial. Sampler thermostat temperature: 5°C. Column flushing: Water / acetonitrile 2:8. Column storage: acetonitrile. Detection: DAD: 245 nm, band width 4 nm. Reference wavelength: Off. Slit: 4 nm. Data rate: 5 Hz, by peak width > 0.05 min, response time 1 s.

[0296] Sample preparation. The blank solution was the diluent. For stock solution 1, the following reference standards were dissolved in 10.0 mL diluent: 7.0 to 8.0 Des-Brom impurity; 7.0 to 8.0 mg Cysteine adduct impurity; 7.0 to 8.0 mg Regioisomer impurity (compound 190 regioisomer); and 7.0 to 8.0 mg Chloride (compound 170). For stock solution 2, 7.0 to 8.0 Boronate (compound 182) was dissolved in 10.0 mL acetonitrile. For stock solution 3, the following reference standards were dissolved in 100.0 mL methylene chloride: 7.0 to 8.0 mg Dimer impurity; 7.0 to 8.0 mg sec Alcohol impurity; 7.0 to 8.0 mg Ketone impurity. For the system suitability test (“SST”) solution 1 (0.05%), 7.0 to 8.0 reference standard compound 200 was dissolved in 9.93 mL diluent followed by addition of 5.0 pL of stock solution 1, 5.0 pL of stock solution 2, and 50.0 pL of stock solution 3. For the SST solution 2 (for peak assignment of the THF-Impurity), 7.0 to 8.0 mg of the THF impurity was dissolved in 10.0 mL diluent. Sample reaction mixtures were prepared by dissolving a 50 pL organic phase sample in 10.0 mL diluent.

[0297] System suitability test. Blank chromatogram: The blank chromatogram was compared with the chromatogram depicted in the analytical method; System peaks or peaks resulting from the chemicals used must not interfere with the analysis. Selectivity: The chromatograms of the SST solutions were comparable to the enclosed chromatogram with respect to selectivity and retention times. Sensitivity, peak symmetry: The chromatogram of the SST solutions were checked by visual inspection. Action: In the case of failure, the sample analysis was not valid. After correcting the source of error, the blank, SST(s) and sample analysis were repeated.

[0298] The identity of a compound corresponds if the retention time of the main peak in the sample chromatogram corresponds to the retention time of the main peak in the SST solution chromatograms. Area percent is where: Xi = percentage of analyte i (% area); Ai = area of the peak obtained for the analyte i

[0299] (mAU*s) or (pA*s) or (counts*s); and A = area of the peak obtained for the analyte j = 1 to n

[0300] (mAU*s) or (pA*s) or (counts*s). The reduced area percent took into account only the selected analytes.

[0301] Integration range. Area percent: Peaks present in the blank chromatogram were disregarded for area percent analysis. Reduced area percent analysis: Integrate only Chloride impurity and aldehyde impurity; The reaction was determined to be finished if the reduced area percent of compound 170 (“Chloride”) is below the specification limit. Integration parameters. The integration parameters are adjusted in order to integrate all peaks

[0302] > half of the reporting level (“RL”). The peak of any impurity that is not completely separated from the main peak was preferably integrated by valley-to-valley extrapolation (tangential skim).

[0303] The peak table is as follows: aOnly in SST solutions

[0304] Peak table, for peak assignment / information only

[0305] The amount of dimer on a % w / w by the HPLC Method 1 described above correlates to the amount of dimer on an area% HPLC method as reported in the correlation table below.

[0306] Correlation of dimer % w / w evaluated by HPLC Method 1 with area% as determined by other HPLC methods, from the same sample.

[0307] Analytical methods for Comparative Example 1 Comparative Example 1 : Column: (1) Agilent PLRP-S 100A, 150 mm x 4.6 mm, 3pm or (2) Agilent PLRP-S 100 A, 250 mm x 4.6 mm, 5 pm. Mobile phase A: lOmM aqueous NaOH. Mobile phase B: acetonitrile. Flow Rate: 1.0 mL / min. Injection Volume: 1.0 uL. Column temperature: (1) 20°C; (2) 15°C.

[0308] Liquid chromatograph mass spectrometry (LCMS) may be performed as follows. Column: XDB-C18 4.6mm x 50mm, 1.8 pm. Mobile Phase A: Water / 0.05% TFA. Mobile Phase B: CH3CN / 0.05% TFA. Flow Rate: 1.2 mL / min. Injection Volume: 10.0 uL. Column Temperature: 40°C. Diluent: 30:70 (v / v) CH3CN / H2O. Interface Type: ES-API +. Drying Gas Temp: 250°C. Nebulizer Pressure: 35 psig. Drying Gas Flow: 13 L / min. Capillary Voltage: 3000 V. Scan Range: 150-600 m / z. Gas chromatography (GC) may be performed as follows. An Agilent 7890A series GC system with an Agilent HP-5 (30 m*0.32 mm*0.25 pm) column. Flow rate: 2.0 mL / min. Injection volume: 10.0 uL. Carrier gas: N2. Diluent: methanol.

[0309] Mass spectrometry (MS) may be performed using a (1) Sciex 15 mass spectrometer in ES+ mode, or (2) Shimadzu LCMS 2020 mass spectrometer in ESI+ mode. Mass spectra data generally only indicates the parent ions unless otherwise stated. MS or HRMS data is provided for a particular intermediate or compound where indicated.

[0310] Nuclear magnetic resonance spectroscopy (NMR) may be performed using any suitable instrument, including, but not limited to, a (1) Bruker AV III 300 NMR spectrometer, (2) Bruker AV III 400 NMR spectrometer, or (3) Bruker AV III 500 NMR spectrometer, and referenced to tetramethylsilane. NMR data is provided for a particular intermediate or compound where indicated.

[0311] Example 1

[0312] Compound 140 was prepared as according to the reaction scheme in FIG. 12A, and as depicted below:

[0313] To a warm suspension (35°C) of NaBH(OAc)s (71.5 g, 337 mmol) in THF (110 g) was added a cold (10°C) preformed mixture of (5)-2-methyl-l-(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 a period of 1-2 h. The mixture was stirred at 35°C until full conversion was achieved (typically 1 h). Then the reaction mixture was cooled to 25°C and quenched upon addition to water (135 g) at 40°C. After phase separation, NaOH (99.6 g, 28 %) was added at 40°C to achieve pH 12. After phase separation, the organic phase was polish filtered at 40°C, concentrated and followed by a continuous exchange of THF with 2-PrOH under vacuum (300 mbar), whereupon the crystallization was initiated. The crystal slurry was cooled to 5°C and stirred for at least 2 h. The crystals were filtered off, washed with cold 2-PrOH and dried under reduced pressure until constant weight was attained. The compound (S)-2-methyl-l-(6- nitropyridin-3-yl)-4-(oxetan-3-yl)piperazine (compound 140) was isolated in 89% yield (55.8 g) as yellow crystals. ’H-NMR (600 MHz, DMSO-t / 6) 8 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): calc, for C13H18N4O3: 278.1379; found: 278.1406.

[0314] Example 2

[0315] Compounds 141 and 180 were prepared according to the reaction scheme in FIG. 1, and as depicted in more detail below:

[0316] 2) water

[0317] 3) solvent swap to 1 -BuOH

[0318] A solution of (5)-2-methyl-l-(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 a 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 (A)-5-(2-methyl-4-(oxetan-3-yl)piperazin-l- yl)pyridin-2-amine (compound 141). After pressure release, the catalyst was filtered off, the autoclave was rinsed with THF, and the filter cake was washed with THF. THF was distilled off from the solution to achieve a reactor volume of ca 120 mL. Anisole was added and the remaining THF was removed by distillation under reduced pressure (120-150 mbar, Ti 90+5 °C) to achieve a reactor volume of 250 mL (5 V).

[0319] To the solution of compound 141, 3,4-dibromo-l-lmethylpyridin-2-one (compound 90) (1.05 eq.) and K2CO3 (1.5 eq.) were then added at a temperature of 90°C under an argon / nitrogen stream, followed by the dropwise addition of water (1.0 eq.). 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 full conversion to compound 180 was achieved (15-20 h). The reaction mixture was diluted with anisole (2V) followed by water addition (4V) resulting in a temperature of 90 °C. The organic and aqueous phases were separated. Anisole was partially removed from the organic phase under vacuum (120-150 mbar) to achieve a reactor volume of 150 mL (3 V). 1 -butanol (5 V) and water (4 V) were then added followed by separation of the organic and aqueous phases. The organic phase comprising anisole, 1 -butanol and compound 180 was transferred to a pre-heated (90 °C) reactor and the volume of the reaction mixture was reduced under vacuum (120-150 mbar) to achieve a reactor volume of 200 mL, whereupon the crystallization was initiated. 1 -butanol (3 V) 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 for at least 6 h at a temperature of-10°C. The crystals were collected by filtration, washed with cold (-5 ±2 °C) MeOH / FLO (1:1 v / v, 1.5V) and with cold (-5 ±2°C) 1-butanol (2.5 V), and dried at 70 °C under vacuum (2-10 mbar) until weight constancy to give compound 180 as beige-yellowish solid in 75-78% yield and >99.0 wt% assay. ’H NMR (600 MHz, DMSO-< / 6) 8 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): calc, for Ci^BrNsCh 433.1113; found: 433.1130.

[0320] Example 3

[0321] Compounds 141 and 180 were prepared as according to the reaction scheme in FIG. 2, and as depicted in more detail below:

[0322] 141

[0323] 8) filtration

[0324] 9) wash with MeOH / H2O (1 :1)

[0325] 180 and MeOH

[0326] 10) drying

[0327] 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 by anisole by continuous distillation to result in a reactor volume of about 75 mL. The mixture was cooled to 50°C, followed by the sequential addition of compound 90 (16.93 g, 63.42 mmol, Eq: 1.05), sodium methoxide anhydrous (3.92 g, 72.48 mmol, Eq: 1.2) and finally, a premixed, red suspension of palladium (II) acetate (203.4 mg, 906.1 pmol, Eq: 0.015) and DPEphos (975.9 mg, 1.812 mmol, Eq: 0.030) in anisole (6.93 g, 7 ml). The reaction mixture was then heated to 92°C, whereupon a suspension was formed. The mixture was then stirred until full conversion was achieved, then quenched upon the addition of water (120 g). The reaction mixture was then cooled to 10°C at a rate of l°C / min. Crystalline compound 180 was then isolated by filtration and washed with a sequence of MeOH (45 mL), H2O / MeOH (1:1 v / v, 20 mL), and MeOH (30 mL). The crystals were dried at 45°C under vacuum until weight constancy to yield compound 180 as beige solid in 82.5% yield (12.6 g) and in > 99 area% purity.

[0328] Example 4

[0329] Example 3 was repeated except where triphenylphosphine (4.5 mol%) was added to the reaction mixture comprising the solution of compound 141 (see Fig. 3). The reaction provided 82.4% yield at 98.3% purity.

[0330] Example 5

[0331] Compound 141 was prepared and isolated from solution according to the following scheme:

[0332] 140 THF / n-heptane 141

[0333] 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 a Pt / V / @C catalyst (6.0 g, 2 w%) at 60 °C and 4 bar of hydrogen for 16 h to produce compound 141 in solution. After cooling to ambient temperature and release of the pressure, the catalyst was collected by filtration, the autoclave was rinsed with THF, and the filter cake is washed with THF (177.8 g total THF rinse). From the combined solutions, THF was distilled off (70°C, 350 mbar) to achieve a reactor volume of about 1.5 L followed by cooling to 37°C. n-heptane (1 L) was added, whereupon compound 141 crystallization was initiated and the suspension is stirred at 27°C for 1.5h. Additional n-heptane (1.25 L) was added then, the suspension was stirred at 25°C for 15 minutes, and 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 vacuum to give compound 141 in 90.7 % yield (242.8 g) and in >99 area% purity.1H-NMR (600 MHz, CDCI3): 8ppm 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), 3.19-3.35 (M, 1 H), 2.98-3.06 (m, 2 H), 2.51-2.70 (m, 2 H), 2.27-2.46 (m, 1 H), 2.06 (dd, 1 H), 0.92 (d, 3 H). HR-MS (ESI): calc, for C13H20N4O: 248.1637; found: 248.1647. XRF: < 1 ppm Pt; < 2 ppm V.

[0334] Example 6

[0335] Catalysts for the preparation of compound 141 from compound 140 were evaluated according to the method of Example 5. The results are reported in Table 1 below.

[0336] Table 1: Summary of compound 141 syntheses

[0337] In the above table, experiments 1 and 3 used 50-56 g compound 140, 10V solvent, a 1.5 L autoclave with glass insert, and 16 hour reaction time. The catalyst for experiment 1 was Noblyst P8078, and the catalyst for experiment 3 was E101 NE / W. Experiments 2, 4 and 5 used 5 g compound 140, 10V solvent, a 185 mL autoclave, and a 16 hour reaction time. Experiments 6-10 used 200 mg compound 140, 10V solvent, a 35 mL autoclave with glass insert and shaker, and a 16 hour reaction time.

[0338] Example 7 Compound 190 was prepared from compounds 170 and 182, utilizing various catalysts at two catalyst concentrations of 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 at a volume ratio of THF to water was 4: 1, the ratio of solvent volume to compound 170 was 10:1 L / kg, the equivalent ratio of compound 182 to compound 170 was 1.1 : 1 , the base was K3PO4, (1.5 eq based on compound 170), the reaction temperature was

[0339] 50°C, and the reaction time was 18 hours. After 18 hours, 0.25 equivalents of acetyl cysteine as a 60 mg / mL solution in H2O was added to the reaction mixture; the mixture stirred for 10 minutes; and a sample removed for HPLC analysis. The results are reported below 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; “des brom” refers to the DesBr impurity depicted below; and the results are reported in HPLC area%. The results in Tables 2 and 3 are in-process values expressed in HPLC area% measured after 18 hours of reaction time at 50°C.

[0340] Table 2 reports the activity of cationic and neutral Pd(SPhos)(allyl) compounds at 1 mol % catalyst loading. This table demonstrates that, compared to previously disclosed [Pd(dppf)C12] catalyst, the amount of compound 190 produced was greater and the amount of dimer formed was much less (0.87 for Pd(dppf)Ch 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 the best at 0.1 mol % (higher amount of compound 190, and lower amount of dimer).

[0341] Table 2: Summary of results using 1 mol% loading of various cationic and neutral Pd(SPhos)(allyl) catalysts, and previously used catalyst Pd(dppf)Ch Table 3: Summary of results using 0.1 mol% loading of various cationic and neutral Pd(SPhos)(allyl) catalysts

[0342] The data demonstrate that an improved impurity profile is achieved using (SPhos)Pd(allyl)- counter anion catalysts.

[0343] Example 8

[0344] Compound 190 was prepared from compounds 170 and 182 according to the reaction scheme in FIG. 5B. Compound 170 (27.5 g, 80.0 mmol, 1.0 eq) and compound 182 (46.3 g, 88.0 mmol, 1.1 eq) were suspended with stirring in ethyl acetate (222 mL, 200 g) 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 minutes. A solution of potassium phosphate (25 g) in in water (60.0 g ) at 70°C ± 5°C was then added over a period of 55-65 minutes. The reaction product mixture was stirred at 70°C until an in-process control indicated less than 1.0 area% compound 170. The reaction time was 1-2 hours.

[0345] The reaction product mixture was cooled to 20°C Ti and then combined with a solution of N- acetyl cysteine (3.27 g) in water (60.0 g) that had been degassed with Ar by bubbling. The aqueous N-acetyl cysteine vessel and transfer line were washed forward into the reaction product mixture with ethyl acetate (22.4 g, 25.0 mL). The mixture was stirred for 15 minutes at 20°C ± 3°C. After phase separation, the lower aqueous phase was removed. The remaining organic phase was combined with stirring with 5% aqueous NaHCO, solution (100 g, 98 mL) at 20°C ± 3°C. The stirring was stopped allowing for phase separation (15 minutes). The lower aqueous phase was removed and the remaining organic phase was combined with water (100 g). The mixture was stirred for 15 minutes at 20°C ± 3°C. The stirring was stopped allowing for phase separation (15 minutes). The lower 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 formerly containing the organic phase and the filter were rinsed twice with ethyl acetate (22.4 g, 25 mL for each rinse) into the flask containing the filtrate.

[0346] The filtrate was concentrated under about 200-300 mbar vacuum at about 85°C to a residual volume of about 100 mL. Ethanol (350 g, 450 mL) was then added at 50°C to 70°C to form a suspension. The suspension was concentrated at reflux (about 85 °C) and atmospheric pressure to a residual volume of about 400 mL. At reflux, as solution was obtained which was maintained throughout the concentration step. An in process control sample was collected and tested for residual ethyl acetate, and concentration was continued until the fraction of EtOAc in the EtOAc / EtOH mixture was no more than 6.0%. If that level is not achieved then additional ethanol may be added to the solution followed by concentration to about 400 mL. After the EtOAc content was reduced to no more than 6.0%, the solution was cooled to 75°C ± 2°C and seeded with a suspension of compound 190 (273 mg compound 190 in 10.0 mL ethanol). Seeding with Form A will result in Form A being formed. Seeding with Form C will result in Form C being formed. The formed suspension was stirred for 30 minutes at 75°C ± 2°C and then cooled to 5°C ± 3°C at a rate of 10°C per hour (about 7 hours). The suspension was aged for at least 7 hours at 5°C ± 3°C. Compound 190 was isolated by filtration over a nutsche with filter paper at a vacuum of about 500 mbar. The collected solid compound 190 was washed two times with 4°C to 6°C ethanol at a total ethanol volume of 74.9 g. The compound 190 product was dried overnight at 50°C under 5 mbar vacuum to yield 48.6 g of compound 190 (99.7 area% assay and 91.4% yield).

[0347] The above method for preparing compound 190 was repeated in triplicate (experiments 1 to 3) with the exception that the solvent exchange from ethyl acetate to ethanol in experiment 3 was done 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 in process control test results; “IPC water” refers to the water content as measured in the IPC EtOAc fraction test. Table 4 : Summary of experimental characterization in process (IPC) and after completion, for three triplicate experiments preparing compound 190 using [(SPhos)Pd(allyl)]OTf and ethyl acetate.

[0348] Example 9 The reaction described herein for preparing compound 190 from compounds 182 and 170 was compared to a previously used reaction for preparing compound 190 from compounds 182 and 170. The reaction conditions are summarized in Table 5. Using the known catalytic system of Pd(dppf)Ch, a ketone impurity was observed over a wide range, and up to 0.29 area% (see Table 5). In contrast, using the herein preferred catalytic system, the amount of ketone impurity observed is maintained within a narrow range, with a much lower upper bound (up to 0.06 area%). Table 5: Summary of conditions from previously-used and presently-described methods. Yield, purity, and by-product content were evaluated in isolated compound after work-up. The “Present Disclosure” values are an average over 3 batches, 800 kg product in total. The dimer, alcohol and ketone impurities are depicted below.

[0349] The alcohol impurity that may be formed during this reaction may be oxidized to the corresponding ketone impurity before detection.

[0350] Example 10 Compound 200 was prepared from Compound 190 as provided in the following scheme:

[0351]

[0352] Compound 190 (for example, Form C compound 190) (50 g, 75.4 mmol, 1 eq) was charged to a reactor. THF (267 g) was added, followed by K2HPO4 (6.16 g, 35.4 mmol, 0.469 eq) and water (42.5 g). The mixture was heated to 40-45°C and agitated for about 20 minutes. Then, an aqueous mixture of sodium hydroxide and sodium borohydride (12 w / w NaBF , 40 w / w NaOH, 11.9 g total aqueous solution added) was added over 10-20 minutes while maintaining a temperature of 40-45°C. The reactor contents were monitored until the concentration of compound 190 remaining was less than or equal to 0.20 area% (about one hour). 85% aqueous phosphoric acid (10.5 g) then added to the reaction product mixture comprising product compound 200, the reactor heated to 60°C, and the contents agitated until the content of borane adducts fell to at or below 0.05 area% (about 2 hours).

[0353] Borane adduct 1 Borane adduct 2

[0354] The contents were agitated for another three hours, then cooled to 40-45°C, and an organic phase separated, removed, and filtered over activated charcoal. The filtrate was then solventswapped by concentrating under atmospheric pressure at 65 °C to a minimum volume of 2.6 L / kg starting material compound 190, and methanol added to a final volume of 6.6 L / kg starting material compound 190. The mixture was seeded to begin crystallization of compound 200, and the solvent swap continued at constant volume until the THF concentration fell at or below 5.0 % w / w. The resulting suspension was aged for at least 30 min, cooled to 5°C over 5 h, and held for at least 3 h at 5°C before filtering off crystals of compound 200 using a nutsche and washing twice with methanol. Crystals were dried under reduced pressure until constant weight was attained (90% yield, assay: 99.1% w / w, purity: 99.7 area%).

[0355] Example 11

[0356] Compound 200 obtained from the synthesis outlined in Example 10 was recrystallized from toluene / ethanol in a cooling crystallization process.

[0357] 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 70-75 °C. The suspension was transferred via a polish filter unit into a second reactor, followed by a rinse of the first reactor with 60 / 40 w / w toluene / ethanol. The concentration of compound 200 in the second reactor was about 20% w / w. Ethanol was added, maintaining a temperature of 70-75°C, until a 20:80 w / w ratio of toluene:ethanol was reached. This solution was cooled to 50°C, seeded with a 10% w / w suspension of compound 200 in ethanol (to about 2% w / w). The seeded suspension was aged for four hours, cooled to -10°C, aged for 10 min, heated to 45°C within 15 min, and aged for 30 minutes. This thermocycle was repeated three times (heat to 45°C, age, cool to -10°C, age), and after the fourth thermocycle, the suspension cooled to between -15°C to -10°C.

[0358] After further aging for at least six hours, the suspension is filtered, the filter cake washed with ethanol (-10°C), and the washed filter cake dried at 50°C at reduced pressure overnight.

[0359] Comparative Example 1

[0360] This comparative example presents a previously-used method of preparing compound 182.

[0361] Compound 180 prepared as in Comparative Example 2 was boronated to form compound 182 according to the following scheme:

[0362] Compound 180 (1.2 kg, 2.763 mol, 1 eq.), bis(pinacolato)diboron (1.052 kg, 4.145 mol, 1.5 eq.), and KO Ac (0.542 kg, 5.526 mol, 2 eq.) were charged to an inerted reactor. Excess THF (15 L) was charged to a holding vessel and was sparged subsurface with N2 for at least 1 hour to form degassed THF. Degassed THF (9.78 kg, 11 L) was charged to the reactor with agitation. Pd2(dba)s (6.52 g, 6.91 mmol, 0.0025 eq.), XPhos (8.15 g, 16.58 mmol, 0.006 eq.) and degassed THF (0.445 kg, 0.5 L) were combined with agitation to form a mixture in a catalyst preparation vessel. The catalyst mixture was then added to the reactor with agitation. The contents of the reactor were sparged subsurface with N2 for a minimum of 1 hour. The contents of the reactor were heated to 60 to 70°C and aged for a minimum of 12 hours. The contents of the reactor 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 to 30°C to form a crude reaction mixture comprising compound 182. Water (3.6 kg, 3 L / kg) was charged to the reactor and the reactor contents were agitated for a minimum of 10 minutes. The aqueous layer was removed from the reactor. The organic layer remaining in the reactor may be optionally washed with brine. The reactor contents were heated to 55 to 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 to 65°C and vacuum distilled to 4 L (3.3 L / kg). The THF / distillation step was repeated. The THF / distillation step may be further repeated, as necessary, to reduce the water content in the reactor contents to no more than 3%. 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 comprising compound 182. The filtrate was heated to 55 to 65°C and was vacuum distilled at a temperature of at least 40°C to a reduced volume of 2 to 3 L. MTBE (8.9 kg, 10 L / kg) was charged to the reduced volume and the resulting mixture was vacuum distilled at a temperature of at least 40°C to a reduced volume of 2 to 3 L. MTBE (8.9 kg, 10 L / kg) was charged to the reduced volume and the resulting mixture comprising compound 182 was aged at 50 to 60°C for 2 hours followed by cooling to 0 to 10°C and aging for a minimum of 2 hours. The mixture was filtered and compound 182 was collected as a filter cake. The filter cake was washed with MTBE (1.86 kg, 2 L / kg) twice. The isolated compound 182 solids were dried under reduced pressure at 50°C with N2 sweep for a minimum of 15 hours to provide 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).

[0363] The major impurities were a DesBr impurity and a Dimer impurity as follows:

[0364]

[0365] The crude reaction mixture contained from 0.5% to 1% DesBr and from 0.1% to 0.5% dimer and the isolated solids contained from 0.1% to 0.4% DesBr and from 0 to 0.1% dimer.

[0366] The above method for preparing compound 180 from compound 170 was repeated without the MTBE charge and distillation step. Compound 180 at 92.7 w / w% comprising 2.4 wt% THF, 6.7 wt% MTBE, 0.6% residue on ignition (ROI) and 90.1% yield was produced.

[0367] Comparative Example 2

[0368] This comparative example presents previously-used methods for preparing compound 190 using a Pd(dppf)C12 catalytic system with THF and H2O as solvents. Compound 182 was reacted with compound 170 to form compound 190 according to the following scheme:

[0369] 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 with THF (196 g) and water (60 g). The mixture was degassed with argon. Separately, Pd(dppf)C12 (0.639 g) was suspended in THF (8.9 g) and the mixture degassed with argon, then that mixture added to the first reactor. The reactor was heated to 50°C and stirred until less than 0.2 area% compound 170 was observed (at least 15 h).

[0370] The reaction mixture was cooled to 20°C, 6 wt% aqueous / V-acctyl cysteine (about 60 mL) added, and the resulting mixture stirred for 15 minutes. The layers were separated, the organic layers washed with saturated aqueous NaCl (about 60 mL), and then dried azeotropically at atmospheric pressure using THF until water was reduced to less than 2.0% w / w. The resulting mixture was filtered over activated charcoal at 40°C, then the filtrate underwent solvent exchange to ethanol by charging to a reactor and distilled to approximately 150 mL at 50°C under reduced pressure, then addition of ethanol (118 g). Under these conditions, compound 190 crystallizes, and suspension aged for 2 h then cooled to 20°C over 3 h, and held at 20°C to promote crystal formation. The resulting crystals were filtered off using a nutsche and washed three times with EtOH, then dried at 50°C under reduced pressure until constant weight was attained. An isolated yield of 49.7 g compound 190 was obtained as a bright yellow powder (yield: 86%; assay: 99.8% w / w; purity: 99.2 area%), evaluated using the analytical method HPLC Method 1 as described above.

[0371] This procedure was repeated three times, obtaining the following results:

[0372] Comparative Example 3

[0373] The methods for preparing compound 190 as described in Comparative Example 2 (“previous process”) and Example 8 (“present process”) were repeated at laboratory scale, and then further evaluated at pilot scale and production scale multiple times. The amount of dimer, alcohol, and ketone impurities present in isolated compound 190 (after work-up, including recrystallization) were evaluated, and is summarized below in Table 14. Lab scale batch size was approximately 30 g compound 170; pilot scale was approximately 1.2-2.4 kg compound 170; and production scale was approximately 175 kg compound 170. The amount of dimer present in process (IPC) was also monitored for different batch sizes prepared generally following the procedure of Example 8, and is summarized in Table 15, as area% via HPLC.

[0374] Table 14: Summary of impurities detected in isolated compound 190 produced according to previously-disclosed methods, compared with methods of the present disclosure, at different batch sizes.

[0375] Table 15: Amount of dimer observed in process (IPC) in different batch sizes prepared according to the present process (sample taken when amount of compound 170 remaining was < 1%).

[0376] Comparative Example 4

[0377] Compound 190 was prepared generally following the procedure of Comparative Example 2 (“previous process”) and Example 8 (“present process”), on a production scale. The compound 190 from each process was then used to prepare compound 200 and compound 200 isolated as generally described in Examples 10 and 11.

[0378] The impurity profiles observed in compound 200 production scale batches prior to the final isolation steps, and after the final isolation steps (as described in Example 11), prepared using compound 190 from the previous compared to the present methods, is summarized in Table 16 below. Preparing compound 190 according to the present methods results in lower impurities in the downstream compound 200 both before and after final isolation, compared to using previously-described methods for preparing compound 190.

[0379] Table 16: Summary of impurity profiles in compound 200 prior to and after final recrystallization from toluene and ethanol, when using different methods to prepare compound 190 (previous method vs. present method).

[0380] Example 12: Preparation of various crystalline solvates of compound 200

[0381] Ethanol hemi-solvate: 100.9 mg of amorphous compound 200 was suspended in 1.2 mL of ethanol and aged at 0 °C for 5 days. The white suspension was isolated at 0 °C by centrifugal filtration. The wet filter cake was dried upon open storage at ambient temperature. The sample was further dried at 50 °C under vacuum for 3 days, then characterized by XRPD. The XRPD spectrum is provided in FIG. 14, and the peak list is provided in Table X.

[0382] Toluene solvate: 203.2 mg of amorphous compound 200 was exposed to toluene vapors at ambient temperature for 7 days. The resulting wet powder was gently dried under toluene vapor at 100 mbar / ambient temperature for 2 days, then characterized by XRPD. The XRPD spectrum is provided in FIG. 15, and the peak list is provided in Table X.

[0383] Ethanol solvate: 98.1 mg of amorphous compound was dissolved in 10 mL of ethanol at 80 °C. The solution was cooled and polished filtered to obtain a particle-free solution. The clear solution was reheated to 80°C and then rapidly cooled under stirring. The resulting suspension was agitated for 2 days at -10°C. The crystals were isolated by filtration and characterized by XRPD. The XRPD spectrum is provided in FIG. 16, and the peak list is provided in Table X.

[0384] XRPD Characterization: X-ray diffraction patterns were recorded at ambient conditions in transmission geometry with a Stoe Stadi P diffractometer (Cu Kai radiation [1.5406 A], primary Ge-monochromator, Mythen IK silicon strip detector, angular range 3° to 42° 2Theta, stepwidth 0.02° 2Theta and 20 seconds measurement time per step). The samples were prepared and analyzed without further processing (e.g. grinding or sieving) of the substance. Measurement and evaluation of the X-ray diffraction data is done using WinXPOW software (STOE & Cie GmbH, Darmstadt, Germany). The positional error for each individual peak is ±0.2° 2Theta.

[0385] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, 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 in their entirety by reference. Example 13: Preparation of crystalline Form C of compound 190

[0386] Raw materials used in the preparation of crystalline From C of compound 190 are detailed in the table 131 below.

[0387] Table 131 The following reaction was performed under very strict exclusion of oxygen up to (and including) A-acctyl cysteine wash since the presence of oxygen in the presence of the palladium catalyst will lead to the formation of dimer impurity.

[0388] Reaction

[0389] In reactor 1 (500 mL) under N2 27.7g (1.00 eq.) 170, (27.5 g without assay correction; all g / g and mL / g values are relative to 27.5 g 170) 46.0 g (1.10 eq.) 181 and 113 mg (0.0020 eq.) [(SPhos)Pd(allyl)]OTf are charged and suspended with stirring (350 rpm) in 282 g (10.26 g / g) ethyl acetate (313 mL) at 20 °C Ti (± 3 °C). The obtained suspension is degassed by sparging argon through the suspension (with help of the glass tube with frit) for 10 minutes. The reaction mixture is heated to 69 °C Ti (± 1°C) within 90 minutes. After reaching the temperature start immediately (within 10 minutes) with the next step.

[0390] To the light greyish yellow suspension, while stirring at 500 rpm, a solution of 23.8 g (1.40 eq.) potassium phosphate in 60.0 g (2.18 g / g) water is added in 90 minutes at 69°C Ti (± 1°C) by use of a syringe-pump. The suspension is stirred at 69°C Ti (± 1°C) for 1-2 hour (suspension turns into a dark biphasic solution) and the reaction mixture is sampled for IPC 1.

[0391] IPC 1: determination of residual 170 (target value is max. 1.0 red. area% 170).

[0392] If desired conversion is not reached, the suspension is further stirred until either IPC complies with the target value or until a steady state is reached (one of the two starting materials is consumed). Subsequently, the reaction mixture is cooled to 55 °C Ti (± 2°C) in ca. 15 min.

[0393] Work-up

[0394] In reactor 2 (500 mL) under N2 3.27 g (0.25 eq.) N-acetyLcysteine is dissolved in 60.0 g (2.18 g / g) water and the solution is degassed by bubbling argon through the solution (with help of the glasstube with frit) for 15 minutes. The reaction mixture from reactor 1 is transferred to reactor 2 (stirring at 250 rpm) at 55°C Ti (± 2°C). Reactor 1 and the transfer line are rinsed with 22.4 g (0.81 g / g) ethyl acetate (25.0 mL) and the rinse solvent is added to reactor 2. The mixture is stirred (250 rpm) for 10 minutes 55°C Ti (± 2°C) and stirring is stopped. After phase separation (settle time is at least 15 minutes), the lower dark red aqueous phase is removed. To the organic phase 100 g (3.64 g / g) 5% aq. NaHCCh solution (98 mL) is added and the biphasic mixture is stirred (250 rpm) for 10 minutes at 55°C Ti (± 2°C). Stirring is stopped and the phases are settled for at least 15 minutes (the undissolved solid is 170). The lower yellowish aqueous phase is removed and 100 g (3.64 g / g) water (100 mL) is added to the organic phase. The biphasic mixture is stirred (250 rpm)for 10 minutes at 55°C Ti (± 2°C). Stirring is stopped and the phases are settled for at least 15 minutes. The lower yellowish aqueous phase is removed. The organic phase is filtered over an activated charcoal cartridge (Zetacarbon R55SP) within ca. 1 h at 55°C Ti (± 2°C). The filtrate is collected in a Schott flask. Reactor 2 and the filter are rinsed twice with 22.4 g (25 mL), i.e. 44.8 g (1.63 g / g) ethyl acetate (50.0 mL). The filtrate is transferred back to reactor 2 and the Schott flask is rinsed with 18.0 g (0.65 g / g) ethyl acetate (20.0 mL) and added to reactor 2. The content of reactor 2 is heated to 55°C Ti (± 2°C).

[0395] Distillation and. Crystallization

[0396] From the solution, solvent is distilled off under vacuum (typically 500 mbar at Tj = 85°C), while at the same time the volume is kept constant (at ca. 475 mL (17.3 mL / g)) by addition of 490 g (17.8 g / g) ethanol (621 mL). At the end of this solvent exchange the solution is concentrated to reach a final volume of 450 mL (16.4 mL / g). The vacuum is lifted and the solution is warmed to 75°C Ti (± 2°C). The reaction mixture is sampled for IPC 2.

[0397] IPC 2: determination of residual ethyl acetate and water in the reaction mixture (target value is max. 10.0% ethyl acetate (fraction ethyl acetate in ethyl acetate / ethanol mixture); water is reported).

[0398] If IPC criterion is not met, an appropriate amount of EtOH is added and the mixture is concentrated under vacuum (typically 500 mbar at Tj = 85°C) to a volume of 450 mL. Afterwards, IPC 2 is repeated at 75°C Ti (± 2°C).

[0399] The solution is cooled to 70°C Ti (± 2°C) within ca. 30 min., while stirring at 400 rpm, and seeded at this temperature with a suspension of 273 mg (0.010 g / g) Compound 190 Form C (0.52% of theory 190) in 4.0 g (0.16 g / g) ethanol (5.0 mL). The formed thin suspension is stirred for 2 h at 70°C Ti (± 2°C) and subsequently cooled to 40°C Ti (± 2°C) within 7.5 hours (4°C / h) and subsequently to 10 °C Ti (± 2°C) within 2.5 hours (10°C / h). After reaching the target temperature, the suspension is aged for a minimum of 5 hours. Isolation

[0400] The suspension is filtered over a nutsche with filter paper using light vacuum (500 mbar) and the filter cake is washed 2 times with 79.4 g ethanol, altogether 159 g (5.78 g / g) ethanol (201 mL). The wet product is dried for min. 4 hours at 30 °C (Tj) / 5 mbar and 49.7 g (assay 92.1%, 86.3% yield) of 190 are obtained as Form C.

[0401] Theoretical Yield 190 Form C: 53.0 g (80.0 mmol) (53.0 g 190 is the theory of unsolvated 190. The obtained product is corrected by assay and evaluated against this theoretical amount.)

[0402] The compound 190 Form C produced by the above method is characterized by XRPD (Fig. 18), DSC (Fig. 19), TGA (Fig. 20), Raman spectroscopy (Fig. 21), IR spectroscopy (Fig. 22),

[0403] DVS isotherm and mass change experiments (Fig. 23 and Fig. 24, respectively). The above procedure is summarized in the scheme in Fig. 17.

Claims

CLAIMSWhat is claimed is:

1. A method of preparing a crystalline Form C of compound 190, or a tautomer thereof, the method comprising: combining a solution comprising compound 190 in ethanol with a seed crystal of the crystalline Form C of compound 190, or the tautomer thereof, to form a seeded solution, wherein the structure of compound 190 is:wherein the crystalline Form C of compound 190, or the tautomer thereof, exhibits an XRPD pattern with peaks at 6.8 ± 0.2 °2Theta (Cu Kai), 15.4 ± 0.2 °2Theta (Cu Kai), and 10.7 ± 0.2 °2Theta (Cu Kai); and wherein the method precipitates > 50% of compound 190 in the seeded solution as the crystalline Form C of compound 190, or the tautomer thereof.

2. The method of claim 1, wherein > 75% of compound 190 in the seeded solution is precipitated as the crystalline Form C of compound 190, or the tautomer thereof, or wherein > 90% of compound 190 in the seeded solution is precipitated as the crystalline Form C of compound 190, or the tautomer thereof.

3. The method of claim 1 or claim 2, wherein the crystalline Form C of compound 190, or the tautomer thereof, exhibits an XRPD pattern with peaks at 6.8 ± 0.2 °2Theta (Cu Kai), 15.4 ± 0.2 °2Theta (Cu Kai), 10.7 ± 0.2 °2Theta (Cu Kai), and one or more of 7.7 ± 0.2 °2Theta (Cu Kai), 11.6 ± 0.2 °2Theta (Cu Kai), and 19.3 ± 0.2 °2Theta (Cu Kai).

4. The method of any one of claims 1 to 3, wherein the crystalline Form C of compound 190, or the tautomer thereof, exhibits an XRPD pattern with peaks at 6.8 ± 0.2 °2Theta (CuK„i), 15.4 ± 0.2 °2Theta (Cu Kai), 10.7 ± 0.2 °2Theta (Cu K«i), 7.7 ± 0.2 °2Theta (Cu K«i), 11.6 ± 0.2 °2Theta (Cu Kxi), and 19.3 ± 0.2 °2Theta (Cu Kxi).

5. The method of any one of claims 1 to 4, wherein combining the solution and the seed crystal is performed at a temperature that is > 65°C and < 75°C, the method further comprising, after combining the solution and the seed crystal, cooling the seeded solution at a rate of > l°C / h and < 9°C / h.

6. The method of claim 5, wherein the seeded solution is cooled at a first cooling rate and then a second cooling rate, wherein the first cooling rate is slower than the second cooling rate, and optionally wherein the first cooling rate is > l°C / h and < 9°C / h, and the second cooling rate is > 5°C / h and < 15°C / h.

7. The method of any one of claims 1 to 6, wherein the cooling of the seeded solution is performed to a final temperature that is > 5°C and < 15°C, or a final temperature that is about 10°C.

8. The method of any one of claims 5 to 7, wherein after cooling of the seeded solution there is a step of aging at a temperature that is > 5 °C and < 15 °C or about 10°C, for at least 5 hours.

9. The method of any one of claims 1 to 8, wherein the crystalline Form C of compound 190, or the tautomer thereof, is formed as a component of a composition, wherein the composition contains the crystalline Form C of compound 190, or the tautomer thereof, in an amount > 75wt%, or wherein the composition contains the crystalline Form C of compound 190, or the tautomer thereof, in an amount > 90wt%.

10. The method of any one of claims 1 to 9, wherein the ratio of ethanol volume to compound 190 weight in the seeded solution is > 3L / kg and < 13 L / kg, and optionally wherein the total weight of compound 190 in the seeded solution is at least 100kg.

11. The method of any one of claims 1 to 10, wherein the compound 190 in the solution is prepared by a method comprising:(a) forming a reaction mixture comprising compound 170, compound 181, a palladium catalyst, and a solvent system comprising water, an aprotic solvent and a base; and(b) reacting the reaction mixture to form a reaction product mixture comprising compound 190 according to the following scheme:(c) carrying out a solvent swap, wherein the aprotic solvent in the solvent system of the reaction product mixture is substantially swapped for ethanol.

12. The method of any one of claims 1 to 11, further comprising the step of reacting the crystalline Form C of compound 190, or a tautomer thereof, to form compound 200, or a stereoisomer, geometric isomer, tautomer or salt thereof, the reaction comprising:(a) reacting the crystalline Form C of compound 190, or tautomer thereof, with a reducing agent and a base in the presence of a solvent to form compound 200, or the stereoisomer, geometric isomer, tautomer or salt thereof, according to the following scheme13. An isolated crystalline Form C of compound 190, or tautomer thereof, wherein the structure of compound 190 is:the isolated crystalline Form C of compound 190, or the tautomer thereof, exhibits an XRPD pattern with peaks at 6.8 ± 0.2 °2Theta (Cu Kai), 15.4 ± 0.2 °2Theta (Cu Kai), and 10.7 ± 0.2 °2Theta (Cu K«i).

14. The isolated crystalline Form C of claim 13, wherein the isolated crystalline Form C of compound 190, or the tautomer thereof, exhibits an XRPD pattern with peaks at 6.8 ± 0.2 °2Theta (Cu Kai), 15.4 ± 0.2 °2Theta (Cu Kai), 10.7 ± 0.2 °2Theta (Cu Kai), and one or more of 7.7 ± 0.2 °2Theta (Cu K«i), 11.6 ± 0.2 °2Theta (Cu K«i), and 19.3 ± 0.2 °2Theta (Cu K«i).

15. The isolated crystalline Form C of claim 13 or claim 14, wherein the isolated crystalline Form C of compound 190, or the tautomer thereof, exhibits an XRPD pattern with peaks at 6.8 ± 0.2 °2Theta (Cu Kai), 15.4 ± 0.2 °2Theta (Cu Kai), 10.7 ± 0.2 °2Theta (Cu K«i), 7.7 ± 0.2 °2Theta (Cu K«i), 11.6 ± 0.2 °2Theta (Cu Kai), and 19.3 ± 0.2 °2Theta (Cu K«l).

16. The isolated crystalline Form C of any one of claims 13 to 15, obtained or obtainable by the method of any one of claims 1 to 12.

17. A composition comprising the isolated crystalline Form C of any one of claims 13 to 16, wherein the crystalline Form C of compound 190, or the tautomer thereof, is present in the composition in an amount > 75wt%, or wherein the crystalline Form C of compound 190, or the tautomer thereof, is present in the composition in an amount > 90wt%.

18. The isolated crystalline Form C of any one of claims 13 to 16, or the composition of claim 17, wherein the total weight of compound 190 is at least 100kg.

19. Use of the isolated crystalline Form C of any one of claims 13 to 16, or the composition of claim 17, in the preparation of compound 200,20. A composition comprising compound 200 or a stereoisomer, geometric isomer, tautomer or salt thereof, and the isolated crystalline Form C of compound 190, or the tautomer thereof, of any one of claims 13 to 16, wherein the structure of compound 200 is:

21. A polymorphic Form B of compound 190, or tautomer thereof, wherein the structure of compound 190 is:whereinForm B of compound 190, or the tautomer thereof, exhibits an XRPD pattern with peaks at 19.0 ± 0.2 °2Theta (Cu Kai), 6.5 ± 0.2 °2Theta (Cu Kai), and 17.8 ± 0.2 °2Theta (Cu K«l).

22. The polymorphic Form B of claim 21, wherein Form B of compound 190, or the tautomer thereof, exhibits an XRPD pattern with peaks at 19.0 ± 0.2 °2Theta (Cu Kai), 6.5 ± 0.2 °2Theta (Cu Kai), 17.8 ± 0.2 °2Theta (Cu Kai), and one or more of 16.4 ± 0.2 °2Theta (Cu Kai), 11.2 ± 0.2 °2Theta (Cu Kai), and 7.2 ± 0.2 °2Theta (Cu Kai).

23. The polymorphic Form B of claim 21 or claim 22, wherein Form B of compound 190, or the tautomer thereof, exhibits an XRPD pattern with peaks at 19.0 ± 0.2 °2Theta (Cu Kai), 6.5 ± 0.2 °2Theta (Cu Kai), 17.8 ± 0.2 °2Theta (Cu Kai), 16.4 ± 0.2 °2Theta (Cu xi), 11.2 ± 0.2 °2Theta (Cu Kai), and 7.2 ± 0.2 °2Theta (Cu Kai).

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