Synthetic methods and intermediates

Abstract

The present invention relates to a novel process for the synthesis of N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide and intermediates used in such process.

Description

[Technical Field]

[0001] The present invention provides new synthetic routes, new chemical reactions and new synthetic intermediates useful in the preparation of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide. [Background technology]

[0002] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, also known as remibrutinib, is a highly potent and selective oral Bruton's tyrosine kinase (BTK) inhibitor: [ka]

[0003] Remibrutinib was first disclosed in WO 2015 / 079417, Example 6, filed November 28, 2014. WO 2015 / 079417 is incorporated by reference in its entirety. In WO 2015 / 079417, Example 6(2), remibrutinib is prepared by cross-coupling of "INT5" with "INT8" to give "INT9": [ka]

[0004] INT9 is then deprotected with TFA (Example 6(3)), reacted with acrylic acid, and purified to give remibrutinib (Example 6(4)). INT5 is a key intermediate in this process and constitutes half of the structure of the final product, remibrutinib. The preparation of INT5 is described in Example 1(5) of WO 2015 / 079417: INT5 is prepared by amide coupling of INT3 and INT4: [ka]

[0005] However, INT3 (5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline) was discovered to be a potentially mutagenic compound and therefore a harmful intermediate in the synthesis of pharmaceuticals. The genotoxicity of INT3 is reported for the first time in this application.

[0006] Therefore, it is an object of the present invention to provide a new synthetic route to remibrutinib that minimizes exposure to genotoxic agents such as INT3. Additionally, the present invention provides improved coupling conditions for the preparation of INT9 (referred to herein as F7) with higher yields and that avoid the need to use harmful solvents such as DCM (carcinogenic), DME (fertility damaging), DMF (fertility damaging), and 1,2-dichloromethane (carcinogen). Summary of the Invention

[0007] In a first embodiment, the present invention provides a synthetic method comprising converting a compound X6b and a compound F6 into a compound F7: [ka] The synthetic method is provided wherein X and Y are each independently F, Cl, Br, or I, and P is an amine protecting group.

[0008] In a second embodiment, the present invention provides a synthetic method comprising boronation of X6b to give X6a, comprising: [ka] The present invention provides a synthetic method in which X is F, Cl, Br, or I, n is 0 or 1, and R is F, Cl, Br, or I, OH, OCl-C6 alkyl, N(C1-C6 alkyl)2, aryl, or two or three R groups other than F, Cl, Br, I, or OH can together form a cyclic boronic ester, such as pinacolboronic acid or N-methyliminodiacetic acid (MIDA) boronate.

[0009] In a third embodiment, the present invention provides a synthetic intermediate X6b comprising: [ka] X is Cl, Br or I, preferably Br, to provide synthetic intermediate X6b. [Brief explanation of the drawings]

[0010] [Figure 1] Figure 1 provides an overview of a convergent and atom-efficient synthetic route for preparing remibrutinib. X6b is a key intermediate in this synthetic route. [Figure 2] FIG. 2 shows exemplary reaction conditions for routes F1 to F6. [Figure 3] FIG. 3 shows exemplary reaction conditions for the route from N6e to X6b. [Figure 4] FIG. 4 shows exemplary reaction conditions for the route from X6i to X6b. [Figure 5] FIG. 5 shows exemplary reaction conditions for the route from X6b to F11. DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention is useful in the preparation of the highly potent and selective oral Bruton's tyrosine kinase (BTK) inhibitor N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, also known as remibrutinib: [ka]

[0012] In any embodiment herein, remibrutinib or any other compound described herein may be provided as a salt. As used herein, the term "salt(s)" refers to acid addition salts or base addition salts of the compounds of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and that are typically not biologically undesirable. In many cases, the compounds of the present invention are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, such as acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, and the like. Salts include, for example, monosodium salts, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I through XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly suitable salts including ammonium, potassium, sodium, calcium, and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and trimethamine. The pharmaceutically acceptable salts of the present invention can be synthesized from basic or acidic components by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (such as hydroxide, carbonate, bicarbonate, Na, Ca, Mg, or K, or the like) or by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. Generally, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable where feasible. Lists of additional suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences," 20th ed., Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0013] Many organic solvents are suitable for the chemical reactions described herein. For example, the reactions described herein may be carried out in an aprotic organic solvent. Suitable examples include acetonitrile; dimethyl sulfoxide (DMSO); dimethylformamide (DMF); halogenated alkanes such as dichloromethane (DCM); aromatic compounds such as benzene, toluene, xylene, mesitylene, and naphthalene; alkanes such as hexane, heptane, and octane; ketones such as acetone; ether compounds such as diethyl ether, tetrahydrofuran (THF), and THF derivatives such as methyl THF; ester compounds such as ethyl acetate and isopropyl acetate; amines such as pyridine; polyethylene glycol (PEG); particularly PEG having an average molecular weight of about 100 g / mol to about 2000 g / mol, such as PEG200, PEG600, PEG1000, and PEG2000; mono- or di-alkyl PEG, particularly derivatives thereof such as mono- or di-dimethyl PEG, mono- or di-ethyl PEG, and mono- or di-propyl PEG; and polypropylene glycol (PPG). Protic solvents may also be used in the reactions described herein. Protic solvents include: water; 1~10 Alcohols, such as aliphatic branched or straight-chain alcohols, particularly C1-C6 alcohols; and carboxylic acids, such as methanoic acid, acetic acid, and propanoic acid. Preferred solvents include toluene, ethanol, ethyl acetate, isopropyl acetate, methyl THF, heptane, and isopropanol. Preferably, the reactions described herein are carried out avoiding undesirable solvents, such as DCM, DME, DMF, dioxane, and 1,2-dichloroethane or other carcinogenic or teratogenic solvents. In certain embodiments, the amount of solvent in the reaction mixture is in the range of 0.1% to 99% (v / v), 0.1% to 80% (v / v), 0.1% to 75% (v / v), 0.1% to 50% (v / v), 1% to 40% (v / v), 2% to 30% (v / v), 4% to 25% (v / v), or 5% to 20% (v / v).

[0014] Some chemical reactions described herein can be carried out under acidic conditions, for example, at a pH of less than 7, 6 or less, 5 or less, 4 or less, 3 or less, 2 or less, or 1 or less. Suitable acids for the described chemical reactions are known to those skilled in the art. Commonly used acids include inorganic acids, such as sulfuric acid, phosphoric acid, and nitric acid; boric acid; haloacids, such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid; organic acids, such as carboxylic acids and their derivatives, such as acetic acid and benzoic acid; and halogenated acetic acids, such as trifluoroacetic acid and dichloroacetic acid. Preferably, the acid is HF, HCl, or H2SO4. Preferably, fluorinated acids, such as TFA, are avoided to avoid the generation of fluorinated waste products.

[0015] Some chemical reactions described herein can be carried out under basic conditions, e.g., at a pH greater than 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, or at least 14. Basic compounds suitable for the chemical reactions described herein are known to those skilled in the art. Commonly used bases include inorganic bases, e.g., alkali metal and alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide. Stronger bases can be made from the addition of alkaline earth metals to hydrocarbons, amines, and dihydrogen. Examples include butyllithium, lithium diisopropylamide (LDA), lithium diethylamide (LDEA), sodium amide, sodium hydride (NaH), and lithium bis(trimethylsilyl)amide. Weaker bases include ammonia and amines, e.g., trialkylamines such as triethylamine and diisopropylethylamine, as well as anions of weak acids, such as acetates (e.g., sodium acetate), potassium acetate, and carbonates (e.g., sodium carbonate, potassium carbonate).

[0016] The reactions described herein can be continued for as long as necessary to achieve completion of the reaction or at least an acceptable yield of product. For example, the duration of the reaction can be less than 1 minute, less than 5 minutes, less than 10 minutes, less than 30 minutes, less than 1 hour, less than 2 hours, less than 3 hours, less than 5 hours, less than 10 hours, less than 20 hours, less than 30 hours, less than 40 hours, less than 50 hours, or less than 60 hours. The reaction time can depend, among other things, on the scale of the reaction. One skilled in the art can monitor the progress of the reaction in many different ways, including by monitoring a physical change, such as a color change, or by monitoring the reaction using analytical methods such as NMR, FT-IR, XRPD, or chromatography, e.g., thin-layer chromatography (TLC) or liquid chromatography coupled to mass spectrometry (LC-MS).

[0017] Upon completion of the reactions described herein, the reaction mixture is optionally purified. Purification techniques are known to those skilled in the art and include chromatography (e.g., HPLC, which may be reverse-phase or normal-phase); liquid-liquid separation, for example, using multiple immiscible solvents; and / or liquid-solid separation, for example, using filtration, decantation, (re)crystallization, trituration, evaporation, lyophilization.

[0018] The reactions described herein may be carried out at any suitable scale. In one embodiment, the reaction mixture is industrial-scale. The reaction mixture may have a volume of, for example, at least 1 L, particularly at least 10 L, at least 100 L, or at least 1000 L. In another embodiment, the reaction mixture is microscale. The reaction mixture may have a volume of, for example, 10 ml or less, particularly 1 ml or less, 100 μl or less, 10 μl or less, or 1 μl or less.

[0019] The reactions described herein may be part of a series of reactions, including synthesis. When multiple reactions are described, they can be carried out sequentially or in one pot. Sequential reactions typically involve completing a first reaction, followed by workup and purification of that reaction before carrying out a second reaction, and continuing further reactions until the desired product is produced. In contrast, in one pot, the first reaction may be completed, and then a second reaction may be carried out using one or more products from the first reaction without isolation. One-pot reactions are advantageous because they avoid unnecessary purification steps, saving time and materials. In the synthesis of remibrutinib described herein, some or all of the reactions may be carried out in one pot, or alternatively, some or all of the reactions may be carried out sequentially.

[0020] As used herein, the phrase "comprising" also includes and specifically refers to the phrases "consisting essentially of" and "consisting of," in addition to its literal meaning. Thus, the phrase "comprising" refers to embodiments in which the subject matter "comprising" the specifically recited elements may and / or does include additional elements, as well as embodiments in which the subject matter "comprising" the specifically recited elements does not include the additional elements.

[0021] Numerical ranges described herein are inclusive of the numbers defining the range. The headings provided herein are not limitations of the various aspects or embodiments of the present invention, which can be read by reference to the entire specification. According to one embodiment, subject matter described herein as comprising a particular step in the case of a method or a particular component in the case of a composition refers to the subject matter consisting of each step or component. Selecting and combining specific aspects and embodiments described herein is preferred, and specific subject matter resulting from each combination of specific embodiments also exists as part of this disclosure.

[0022] The present invention provides a new synthetic route to remibrutinib that avoids the formation of the genotoxic intermediate INT3. The key to avoiding INT3 is the preparation of aryl halide X6b, which does not contain a boronate ester and can therefore be synthesized via N6a instead of INT3, as described below. Furthermore, the claimed process minimizes purification steps, improves overall yield, and provides a more efficient process. The process can also be efficiently carried out in green solvents.

[0023] Preparation of F7 The present invention provides a synthetic method comprising converting compound X6b and compound F6 to compound F7: [ka] The synthetic method is provided wherein X and Y are each independently Cl, Br, or I, and P is an amine protecting group.

[0024] In some embodiments, X is Cl or Br. In some embodiments, Y is Cl or Br. In some embodiments, X and Y are each Cl or Br. In some embodiments, X is Br. In some embodiments, Y is Cl. In some embodiments, X is Br and Y is Cl. These embodiments apply to any and all instances of X and Y described herein, including the X and Y groups present in the synthetic precursors of X6b and F6, respectively.

[0025] The protecting group P can be any suitable amine protecting group that is stable during any of the chemical transformations described herein (except for the deprotection step). The amine protecting group may be removed by certain conditions, such as acid, base, hydrogenation, light, heat, etc. Examples of suitable amine protecting groups include carbamate protecting groups such as 9-fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (Boc), or benzyl carbamate (Cbz); acetamide protecting groups such as acetamide, trifluoroacetamide, or benzylamide; and sulfonamide protecting groups such as p-toluenesulfonamide.

[0026] X6b and F6 can be converted to F7 using suitable coupling conditions to form a carbon-carbon bond. For example, the coupling of X6b and F6 can be achieved using an organometallic cross-coupling reaction, whereby the two fragments are linked together with the aid of a metal catalyst. Cross-coupling conditions that may be used in the coupling of X6b and F6 include the Kumada coupling, Negishi coupling, Stille coupling, Suzuki-Miyaura coupling, and Hiyama coupling. In a typical cross-coupling reaction, a compound of type RM (R = first organic fragment, M = metal or typical compound) reacts with an organic halide of type R'-X (R' = second organic fragment, X = halide) to form a new carbon-carbon bond in the product R-R'.

[0027] Thus, in some embodiments, the preparation of F7 involves the conversion of F6 to the precursor F6' by replacement of Y with "M", a metal-containing or main group element-containing component, e.g., M containing Zn (Negishi), B (Suzuki-Miyaura), Mg (Kumada), Sn (Still), or Si (Hiyama): [ka] P is an amine protecting group, such as Boc.

[0028] F6' can be reacted with X6b under cross-coupling conditions to give F7. In some embodiments, the conversion of F6 to F6' and the cross-coupling of F6' with X6b are carried out in a one-pot reaction. In some embodiments, the conversion of F6 to F6' and the cross-coupling of F6' with X6b are carried out in sequential reactions.

[0029] Alternatively, the preparation of F7 involves the conversion of X6b to the precursor compound X6b' by replacement of X with "M", a metal- or main group element-containing component, e.g., M containing Zn (Negishi), B (Suzuki-Miyaura), Mg (Kumada), Sn (Still), or Si (Hiyama): [ka]

[0030] The precursor compound X6b' can be reacted with F6 under cross-coupling conditions to give F7. In some embodiments, the conversion of X6b to X6b' and the cross-coupling of X6b' with F6 are carried out in a one-pot reaction. In some embodiments, the conversion of X6b to X6b' and the cross-coupling of X6b' with F6 are carried out in sequential reactions.

[0031] Preparation of X6a - boronation reaction The present invention provides a synthetic method comprising boronation of X6b to give X6a: [ka] X is F, Cl, Br, or I, n is 0 or 1, and R is F, Cl, Br, or I, OH, OCl-C6 alkyl, N(C1-C6 alkyl)2, aryl, or two or three R groups other than F, Cl, Br, I, or OH can together form a cyclic boronic ester, such as pinacol boronic acid or N-methyliminodiacetic acid (MIDA) boronate.

[0032] The boronation of X6b can be achieved using one or more catalysts, one or more ligands, one or more boronating agents, one or more bases, and / or one or more additives. In some embodiments, the boronation comprises one or more catalysts, one or more ligands, one or more boronating agents, and one or more bases. In some embodiments, the boronation additionally comprises one or more additives.

[0033] A boronating agent is a boron-containing compound capable of converting an organohalogen compound to a boronic acid or boronate ester, typically under metal-catalyzed cross-coupling conditions. In some embodiments, the boronating agent is selected from the group consisting of diboron compounds, boronic acids, boranes, boron trihalides, and borates. In some embodiments, the boronating agent is selected from the group consisting of bis(pinacolato)diboron, B2(NMe2)4, B2F4, B2Cl4, B2Br4, B2I4, bisboronic acid, pinacolborane, HB(NMe2)2, B(OH)3, BF3, BCl3, BBr3, BI3, C1-C6 mono-, di-, or tri-alkyl borates, mono-, di-, or trimethyl borates, mono-, di-, or triethyl borates, and mono-, di-, or tritripropyl borates, preferably bis(pinacolato)diboron or bisboronic acid. The use of bisboronic acids may be attractive because they can allow for lower catalyst usage, milder reaction conditions, and avoid the formation of pinacol-related impurities compared to pinacolborane or bis(pinacolato)diboron. Bisboronic acids also allow for the use of green solvents, such as alcohol solvents, and milder reaction conditions (e.g., lower temperatures).

[0034] The metal catalyst used in the boration reaction may contain palladium, nickel or copper or a combination thereof, preferably palladium.

[0035] In some embodiments, the metal catalyst is provided as a catalyst precursor complex, e.g., a Buchwald G1, G2, G3, or G4 catalyst precursor complexed with a phosphine ligand. The Buchwald catalyst precursor is used to generate active Pd(0) in situ via rapid deprotonation and reductive elimination. The catalyst precursors are useful because they allow low catalyst loading, are stable to air, moisture, and heat, and have good solubility. These catalyst precursors have been optimized from generations 1 through 4 (G1 through G4) to further improve functionality and solubility. The catalyst precursors are composed of palladacycles (shown below) with a phenyl or 1,1-biphenyl backbone, where L represents the attached phosphine ligand, e.g., XPhos, SPhos, etc. (see below), and the attached amine substituent and leaving group (Cl, OMs) vary depending on the generation.

[0036] Examples of Buchwald catalyst precursors complexed with palladium and with exemplary XPhos ligands are shown below.

[0037] [Table 1]

[0038] Any other phosphine ligand described herein may be used as L in place of XPhos in the table above.

[0039] Other catalyst precursors for boronation may include Pd(TFA), PdBr, or Pd(MeCN)Cl, which can be used in the presence of ligands such as PhP(t-Bu); CyP-HBF; RuPHOS; S-PHOS, Cy-BIPHEP; SPHOS-SONa, etc.

[0040] In some embodiments, the boronation of X6b involves an additional ligand in addition to the ligand L that forms part of the catalyst precursor complex. In other embodiments, no additional ligand is required. In some embodiments, the boronation of X6b uses a catalyst and ligand without a catalyst precursor (Pd(0) catalyst; e.g., Pd(PPh3)4).

[0041] A wide range of ligands can be used in the boronation reaction, and the ligand can affect the reactivity of the reagent. For example, the ligand can increase the electron density at the metal center of the metal complex, which can improve the oxidative addition step. In addition, bulky ligands are useful in the reductive elimination step. In some embodiments, the ligand used in the boronation of X6b is selected from the group consisting of organophosphines, N-heterocyclic carbenes, diazabutadienes, dibenzylideneacetones, and combinations thereof.

[0042] In a preferred embodiment, the ligand is an organic phosphine ligand, such as an organic phosphine selected from the group consisting of XPhos, APhos, CPhos, RuPhos, SPhos, cataCXium, DavePhos, JohnPhos, MePhos, XantPhos, CyP-HBF, Cy-BIPHEP, SPhos-SONa, PPh, tBuPPh, and combinations thereof, preferably XPhos, APhos, CPhos, RuPhos, SPhos, cataCXium, more preferably XPhos, cataCXium, and tBuPPh, most preferably tBuPPh. The phosphine ligands are represented in the table below.

[0043] [Table 2]

[0044] [Table 3]

[0045] The boronation of X6b can involve a base. In some embodiments, the base is an organic or inorganic salt such as NaOH, Ca(OH), NaCO, KCO, KPO, CsCO, KOAc, KOPh, or NaOAc, a tertiary amine such as diisopropylethylamine (DIPEA), triethylamine, or a combination thereof. Preferably, the base is DIPEA, KOAc, or KOH, most preferably KOAc.

[0046] The boronation of X6b can include an additive, for example, an alcohol such as ethylene glycol. In some embodiments, the boronation of X6b does not include an additive.

[0047] The boronation of X6b can be carried out in any suitable solvent. Examples of suitable organic solvents include polar solvents, nonpolar solvents, protic solvents, aprotic solvents, polar protic solvents, and polar aprotic solvents. In one embodiment, the boronation can be carried out in an alcoholic solvent, including t-amyl alcohol, hexanol, pentanol, butanol (tert-butanol, isobutanol, and n-butanol), propanol (isopropanol and n-propanol), ethanol, and / or methanol. Preferably, the boronation is carried out in methanol, toluene, and / or MeTHF, most preferably MeTHF. Other solvents, such as halogenated alkane solvents such as dichloromethane, can also be used. Ether solvents, such as dioxane, MeTHF, THF, and dialkyl ethers such as diethyl ether, can also be used. The boronation can also be carried out in an aqueous environment, including a micellar environment. In some embodiments, a mixture of solvents is used.

[0048] The boronation of X6b can be achieved using one or more catalysts, one or more ligands, one or more boronating agents, one or more bases, and / or optionally one or more additives. Those skilled in the art can determine the appropriate amounts of these reagents. Nevertheless, in some embodiments of the boronation reaction: i) the catalyst or catalyst precursor is present in an amount of 0.01 mol% to 3 mol%, 0.05 mol% to 2 mol%, 0.1 mol% to 2 mol%, 0.1 to 1 mol%, preferably 0.25 mol%, more preferably 0.5 mol% relative to the number of moles of X6b; ii) the ligand is present in an amount of 0.02 mol% to 6 mol%, 0.1 mol% to 2 mol%, 0.2 mol% to 1 mol%, 0.5 mol%, or 1 mol% relative to the number of moles of X6b; iii) the number of moles of ligand is two or three times the number of moles of catalyst or catalyst precursor; preferably two times; iv) the boronating agent is present in an amount of 1 to 3 molar equivalents relative to X6b, preferably 1 to 2 molar equivalents relative to X6b, more preferably 1.05 or 1.5 molar equivalents; v) the base is present in an amount of 2 to 5 molar equivalents, preferably 2 to 3 molar equivalents, and most preferably 2.5 or 3 molar equivalents relative to the number of moles of X6b; and / or vi) Additives are optional and, if present, are in an amount of 2 to 5 molar equivalents compared to X6b; preferably, no additives are present.

[0049] The boronation reaction may be characterized by any one of i) to vi) above. The boronation reaction may be characterized by any two of i) to vi) above. The boronation reaction may be characterized by any three of i) to vi) above. The boronation reaction may be characterized by any four of i) to vi) above. The boronation reaction may be characterized by any five of i) to vi) above. The boronation reaction may be characterized by all of i) to vi) above.

[0050] The boronation reaction may be characterized by i) and ii) above. The boronation reaction may be characterized by i) and iii) above. The boronation reaction may be characterized by i) and iv) above. The boronation reaction may be characterized by i) and v) above. The boronation reaction may be characterized by i) and vi) above. The boronation reaction may be characterized by ii) and iii) above. The boronation reaction may be characterized by ii) and iv) above. The boronation reaction may be characterized by ii) and v) above. The boronation reaction may be characterized by ii) and vi) above. The boronation reaction may be characterized by iii) and iv) above. The boronation reaction may be characterized by iii) and v) above. The boronation reaction may be characterized by iii) and vi) above. The boronation reaction may be characterized by iv) and v) above. The boronation reaction may be characterized by iv) and vi) above. The boronation reaction may be characterized by v) and vi) above.

[0051] In one example, a boronation reaction with excellent yield and minimal by-products may be as follows: [ka]

[0052] In one embodiment, the boronation reaction having excellent yield and minimal by-product formation is characterized by at least one of the following: i) the catalyst is Pd(MeCN)Cl in an amount of 0.1 mol% to 2 mol% relative to the number of moles of X6b or 0.1 mol% to 1.5 mol% relative to the number of moles of X6b, preferably 0.25 mol% or more preferably 0.5 mol%; ii) the ligand is tBuPPh2 in an amount of 0.2 mol% to 4% relative to the number of moles of X6b, 0.2 mol% to 3 mol% relative to the number of moles of X6b, preferably 0.5 mol% or more preferably 1 mol%; iii) the catalyst is Pd(MeCN)2Cl2, the ligand is tBuPPh2, and the number of moles of tBuPPh2 is two or three times the number of moles of Pd(MeCN)2Cl2, preferably two times the number of moles of Pd(MeCN)2Cl2; iv) the boronating agent is bis(pinacolato)diboron in an amount of 1 to 2 molar equivalents relative to X6b, preferably about 1.05 molar equivalents relative to X6b; v) the base is KOAc in an amount of 2 to 5 molar equivalents relative to X6b, preferably 2.5 molar equivalents relative to X6b; and vi) no additives are present; and / or vii) The reaction temperature is 30°C to 120°C, for example, 40°C to 50°C, and preferably 60°C or 70°C.

[0053] The boronation reaction may be characterized by any one of i) to vii) above. The boronation reaction may be characterized by any two of i) to vi) above. The boronation reaction may be characterized by any three of i) to vii) above. The boronation reaction may be characterized by any four of i) to vii) above. The boronation reaction may be characterized by any five of i) to vii) above. The boronation reaction may be characterized by any six of i) to vii) above. The boronation reaction may be characterized by all of i) to vii) above.

[0054] The boronation reaction may be characterized by i) and ii) above. The boronation reaction may be characterized by i) and iii) above. The boronation reaction may be characterized by i) and iv) above. The boronation reaction may be characterized by i) and v) above. The boronation reaction may be characterized by i) and vi) above. The boronation reaction may be characterized by i) and vii) above. The boronation reaction may be characterized by ii) and iii) above. The boronation reaction may be characterized by ii) and iv) above. The boronation reaction may be characterized by ii) and v) above. The boronation reaction may be characterized by ii) and vi) above. The boronation reaction may be characterized by ii) and vii) above. The boronation reaction may be characterized by iii) and iv) above. The boronation reaction may be characterized by iii) and v) above. The boronation reaction may be characterized by iii) and vi) above. The boronation reaction may be characterized by iii) and vii) above. The boronation reaction may be characterized by iv) and v) above. The boronation reaction may be characterized by iv) and vi) above. The boronation reaction may be characterized by iv) and vii) above. The boronation reaction may be characterized by v) and vi) above. The boronation reaction may be characterized by v) and vii) above. The boronation reaction may be characterized by vi) and vi) above.

[0055] In one embodiment, the boronation reaction having good yield and minimal by-product formation is characterized by at least one of the following: i) the catalyst is a catalyst precursor, which is Pd-XPhos-2G in an amount of 0.05 mol% to 0.5 mol% relative to the moles of X6b, preferably 0.25 mol% relative to the moles of X6b; ii) the ligand is XPhos in an amount of 0.1 mol% to 1 mol% relative to the number of moles of X6b; preferably 0.5 mol% relative to the number of moles of X6b; iii) the catalyst is Pd-XPhos-2G, the ligand is XPhos, and the number of moles of XPhos is twice the number of moles of Pd-XPhos-2G; iv) the boronating agent is a bisboronic acid in an amount of 1 to 3 molar equivalents relative to X6b, preferably 1.5 molar equivalents relative to X6b; v) the base is potassium acetate in an amount of 2 to 5 molar equivalents, preferably 3 molar equivalents, relative to X6b; vi) the additive is ethylene glycol in an amount of 2 to 5 molar equivalents relative to X6b, preferably 3 molar equivalents relative to X6b; and vii) The reaction temperature is 30°C to 70°C, preferably 40°C to 50°C, and more preferably 50°C.

[0056] The boronation reaction may be characterized by any one of i) to vii) above. The boronation reaction may be characterized by any two of i) to vi) above. The boronation reaction may be characterized by any three of i) to vii) above. The boronation reaction may be characterized by any four of i) to vii) above. The boronation reaction may be characterized by any five of i) to vii) above. The boronation reaction may be characterized by any six of i) to vii) above. The boronation reaction may be characterized by all of i) to vii) above.

[0057] The boronation reaction may be characterized by i) and ii) above. The boronation reaction may be characterized by i) and iii) above. The boronation reaction may be characterized by i) and iv) above. The boronation reaction may be characterized by i) and v) above. The boronation reaction may be characterized by i) and vi) above. The boronation reaction may be characterized by i) and vii) above. The boronation reaction may be characterized by ii) and iii) above. The boronation reaction may be characterized by ii) and iv) above. The boronation reaction may be characterized by ii) and v) above. The boronation reaction may be characterized by ii) and vi) above. The boronation reaction may be characterized by ii) and vii) above. The boronation reaction may be characterized by iii) and iv) above. The boronation reaction may be characterized by iii) and v) above. The boronation reaction may be characterized by iii) and vi) above. The boronation reaction may be characterized by iii) and vii) above. The boronation reaction may be characterized by iv) and v) above. The boronation reaction may be characterized by iv) and vi) above. The boronation reaction may be characterized by iv) and vii) above. The boronation reaction may be characterized by v) and vi) above. The boronation reaction may be characterized by v) and vii) above. The boronation reaction may be characterized by vi) and vii) above.

[0058] In another example, the boronation reaction may be as follows: [ka]

[0059] In one embodiment, the boronation reaction having good yield and minimal by-product formation is characterized by at least one of the following: i) the catalyst is Pd-cataCXium-3G in an amount of 0.001 mol% to 0.5 mol% relative to the number of moles of X6b, preferably 0.05 mol% relative to the number of moles of X6b; ii) the ligand is cataCXium in an amount of 0.02 mol % to 1% relative to the number of moles of X6b, preferably 0.1 mol % relative to the number of moles of X6b; iii) the catalyst is Pd-cataCXium-3G, the ligand is cataCXium, and the number of moles of cataCXium is twice the number of moles of Pd-cataCXium-3-3G; iv) the boronating agent is a bisboronic acid in an amount of 1 to 3 molar equivalents relative to X6b, preferably 1.5 molar equivalents relative to X6b; v) the base is N,N-diisopropylethylamine in an amount of 2 to 5 molar equivalents relative to X6b, preferably an equivalent amount relative to X6b; and vi) no additives are present; and / or vii) The reaction temperature is 30°C to 70°C, preferably 40°C to 50°C, and more preferably 50°C.

[0060] The boronation reaction may be characterized by any one of i) to vii) above. The boronation reaction may be characterized by any two of i) to vi) above. The boronation reaction may be characterized by any three of i) to vii) above. The boronation reaction may be characterized by any four of i) to vii) above. The boronation reaction may be characterized by any five of i) to vii) above. The boronation reaction may be characterized by any six of i) to vii) above. The boronation reaction may be characterized by all of i) to vii) above.

[0061] The boronation reaction may be characterized by i) and ii) above. The boronation reaction may be characterized by i) and iii) above. The boronation reaction may be characterized by i) and iv) above. The boronation reaction may be characterized by i) and v) above. The boronation reaction may be characterized by i) and vi) above. The boronation reaction may be characterized by i) and vii) above. The boronation reaction may be characterized by ii) and iii) above. The boronation reaction may be characterized by ii) and iv) above. The boronation reaction may be characterized by ii) and v) above. The boronation reaction may be characterized by ii) and vi) above. The boronation reaction may be characterized by ii) and vii) above. The boronation reaction may be characterized by iii) and iv) above. The boronation reaction may be characterized by iii) and v) above. The boronation reaction may be characterized by iii) and vi) above. The boronation reaction may be characterized by iii) and vii) above. The boronation reaction may be characterized by iv) and v) above. The boronation reaction may be characterized by iv) and vi) above. The boronation reaction may be characterized by iv) and vii) above. The boronation reaction may be characterized by v) and vi) above. The boronation reaction may be characterized by v) and vii) above. The boronation reaction may be characterized by vi) and vii) above.

[0062] For example, the reaction may be as follows: [ka]

[0063] Coupling of X6a and F6 In some embodiments of the present invention, boronation of X6b to give X6a is used in a method for synthesizing compound F7. In such embodiments, X6b is converted to X6a, which is then reacted with F6 under cross-coupling conditions to produce F7. In a preferred embodiment, the conversion of X6b to X6a and the cross-coupling of X6a with F6 are carried out in a one-pot reaction. In some embodiments, the conversion of X6b to X6a and the cross-coupling of X6a with F6 are carried out in sequential reactions.

[0064] According to the present invention, the boronated compound X6a can be reacted with an aryl halide in a cross-coupling reaction. In one embodiment, the coupling reaction is carried out using one or more catalysts, one or more ligands, one or more bases, and / or one or more additives. In one embodiment, the coupling reaction is carried out using one or more catalysts, one or more ligands, and one or more bases. In some embodiments, the coupling reaction additionally comprises one or more additives.

[0065] The metal catalyst used in the cross-coupling reaction may contain palladium, nickel or copper or a combination thereof, preferably palladium.

[0066] A wide range of ligands can be used in the cross-coupling of X6a and F6, and the ligand can affect the reactivity of the coupling reagent. For example, the ligand can increase the electron density at the metal center of the metal complex, which can improve the oxidative addition step. In addition, bulky ligands are useful in the reductive elimination step. In some embodiments, the ligand used in the coupling of X6a and F6 is selected from the group consisting of organophosphines, N-heterocyclic carbenes, diazabutadienes, dibenzylideneacetones, and combinations thereof. In a preferred embodiment, the ligand is an organophosphine ligand, for example, an organophosphine selected from the group consisting of XPhos, APhos, CPhos, RuPhos, SPhos, cataCXium, DavePhos, JohnPhos, MePhos, XantPhos, PPh3, tBuPPh2, and combinations thereof, preferably XPhos, APhos, CPhos, RuPhos, SPhos, cataCXium, more preferably XPhos, cataCXium, and tBuPPh2, and most preferably tBuPPh2.

[0067] In the coupling of X6a and F6, the metal catalyst and ligand may be provided as a catalyst precursor complex, for example, a Buchwald G1, G2, G3 or G4 catalyst precursor, preferably G2, complexed with a phosphine ligand, for example, an organophosphine selected from the group consisting of XPhos, APhos, CPhos, RuPhos, SPhos, cataCXium, DavePhos, JohnPhos, MePhos, XantPhos, Cy3P-HBF4, Cy-BIPHEP, SPHOS-SO3Na, PPh3, tBuPPh2, and combinations thereof, preferably XPhos, APhos, CPhos, RuPhos, SPhos, cataCXium, more preferably XPhos, cataCXium and tBuPPh2, most preferably tBuPPh2.

[0068] In some embodiments, a catalyst precursor containing a phosphine ligand is used, and no additional phosphine ligand is used. Alternatively, a catalyst precursor containing a phosphine ligand is used, and an additional phosphine ligand is also used. Examples of catalyst precursors for cross-coupling reactions may include Pd(TFA)2, PdBr2, or Pd(MeCN)2Cl2. These catalyst precursors can be used in the presence of ligands such as Ph2P(t-Bu); Cy3P-HBF4; RuPHOS; S-PHOS, Cy-BIPHEP; SPHOS-SO3Na, etc.

[0069] The coupling of X6a and F6 can involve a base. In some embodiments, the base is an organic or inorganic salt such as KOH, NaOH, Ca(OH), NaCO, KCO, KPO, CsCO, KOAc, KOPh, or NaOAc, a tertiary amine such as diisopropylethylamine (DIPEA), triethylamine, or a combination thereof. Preferably, the base is triethylamine or KOH, most preferably KOH.

[0070] The coupling of X6a and F6 can optionally involve an additive, for example an alcohol such as ethylene glycol when, for example, a PdXPhos-2G / XPhos complex is used.

[0071] The coupling of X6a and F6 can be carried out in any suitable solvent. Examples of suitable organic solvents include polar solvents, nonpolar solvents, protic solvents, aprotic solvents, polar protic solvents, and polar aprotic solvents. In a preferred embodiment, the cross-coupling reaction is carried out in an alcoholic solvent, including t-amyl alcohol, hexanol, pentanol, butanol (tert-butanol, isobutanol, and n-butanol), propanol (isopropanol and n-propanol), ethanol, and / or methanol. Other solvents, such as halogenated alkane solvents such as dichloromethane, can also be used. Ether solvents, such as dioxane, MeTHF, THF, and dialkyl ethers such as diethyl ether, can also be used. The coupling can also be carried out in an aqueous environment, including a micellar environment. In some embodiments, a mixture of solvents, such as MeTHF and water, is used. When methanol is used, the reaction mixture may be precipitated to simplify purification.

[0072] The coupling of X6a and F6 can be achieved using one or more catalysts, one or more ligands, one or more boronating agents, one or more bases, and / or one or more additives. Those skilled in the art can use their general knowledge to determine the appropriate amounts of these reagents.

[0073] In one embodiment, the coupling reaction having excellent yield and minimal by-product formation is characterized by at least one of the following: i) the catalyst or catalyst precursor is present in an amount of 0.1 mol % to 5 mol %, 0.25 mol % to 3 mol %, 0.5 mol % to 1.5 mol %, preferably 0.5 mol % or more preferably 1 mol % relative to the number of moles of F6 or X6a; ii) the number of moles of ligand, when present, is two or three times, preferably two times, the number of moles of catalyst or catalyst precursor; iii) the molar ratio of F6:X6a is 2:1 to 1:2, i.e., 1.5:1 to 1:1.5, 1.2:1 to 1:1.2, or 1:1; iv) additives are optional and, if present, are in an amount of 2 to 5 molar equivalents relative to F6 or X6a; and / or v) The amount of the base is 2 to 5 molar equivalents, preferably 2 to 3 molar equivalents, and most preferably 3 molar equivalents, relative to the number of moles of F6 or X6a.

[0074] The coupling reaction may be characterized by any one of i) to v) above. The coupling reaction may be characterized by any two of i) to v) above. The coupling reaction may be characterized by any three of i) to v) above. The coupling reaction may be characterized by any four of i) to v) above. The coupling reaction may be characterized by all of i) to v) above.

[0075] The coupling reaction may be characterized by i) and ii) above. The coupling reaction may be characterized by i) and iii) above. The coupling reaction may be characterized by i) and iv) above. The coupling reaction may be characterized by i) and v) above. The coupling reaction may be characterized by ii) and iii) above. The coupling reaction may be characterized by ii) and iv) above. The coupling reaction may be characterized by ii) and v) above. The coupling reaction may be characterized by iii) and iv) above. The coupling reaction may be characterized by iii) and v) above. The coupling reaction may be characterized by iv) and v) above.

[0076] In one embodiment, a coupling reaction having good yield and minimal by-product formation is characterized by at least one of the following: i) the catalyst and ligand are provided as a catalyst precursor-ligand complex, which is Pd and X-Phos-2G in an amount of 0.5 mol% to 2 mol% relative to the number of moles of F6 or X6a; ii) the base is triethylamine in an amount of 2 to 5 molar equivalents, preferably 3 molar equivalents, relative to F6 or X6a; iii) the additive is ethylene glycol in an amount of 2 to 5 molar equivalents, preferably 3 molar equivalents, relative to F6 or X6a; iv) the reaction is carried out in an alcohol solvent, preferably methanol; and v) The reaction temperature is 30°C to 70°C, preferably 40°C to 50°C, and more preferably 50°C.

[0077] The coupling reaction may be characterized by any one of i) to v) above. The coupling reaction may be characterized by any two of i) to v) above. The coupling reaction may be characterized by any three of i) to v) above. The coupling reaction may be characterized by any four of i) to v) above. The coupling reaction may be characterized by all of i) to v) above.

[0078] The coupling reaction may be characterized by i) and ii) above. The coupling reaction may be characterized by i) and iii) above. The coupling reaction may be characterized by i) and iv) above. The coupling reaction may be characterized by i) and v) above. The coupling reaction may be characterized by ii) and iii) above. The coupling reaction may be characterized by ii) and iv) above. The coupling reaction may be characterized by ii) and v) above. The coupling reaction may be characterized by iii) and iv) above. The coupling reaction may be characterized by iii) and v) above. The coupling reaction may be characterized by iv) and v) above.

[0079] In a preferred embodiment, the coupling reaction having excellent yield and minimal by-product formation is characterized by at least one of the following: i) the catalyst is Pd(MeCN)Cl in an amount of 0.25 mol% to 2 mol% relative to the number of moles of X6b, 0.25 mol% to 1.5 mol% relative to the number of moles of X6b, preferably 0.5 mol% or more preferably 1 mol%; (the conversion of X6b to X6a is about 98%) ii) the ligand is tBuPPh2 in an amount of 0.5 mol% to 4 mol% relative to the number of moles of X6b, preferably 1 mol% or 2 mol% relative to the number of moles of X6b; in particular, the catalyst is Pd(MeCN)2Cl2, the ligand is tBuPPh2, and the number of moles of tBuPPh2 is twice the number of moles of Pd(MeCN)2Cl2; iii) the base is KOH in an amount of 2 to 5 molar equivalents, preferably 3 molar equivalents, relative to X6b; iv) the reaction is carried out in a mixture of MeTHF and water; and v) The reaction temperature is 30°C to 70°C, preferably 60°C.

[0080] The coupling reaction may be characterized by any one of i) to v) above. The coupling reaction may be characterized by any two of i) to v) above. The coupling reaction may be characterized by any three of i) to v) above. The coupling reaction may be characterized by any four of i) to v) above. The coupling reaction may be characterized by all of i) to v) above.

[0081] The coupling reaction may be characterized by i) and ii) above. The coupling reaction may be characterized by i) and iii) above. The coupling reaction may be characterized by i) and iv) above. The coupling reaction may be characterized by i) and v) above. The coupling reaction may be characterized by ii) and iii) above. The coupling reaction may be characterized by ii) and iv) above. The coupling reaction may be characterized by ii) and v) above. The coupling reaction may be characterized by iii) and iv) above. The coupling reaction may be characterized by iii) and v) above. The coupling reaction may be characterized by iv) and v) above.

[0082] In a preferred embodiment, the boronation of X6b to X6a and the cross-coupling of X6a and F6 are carried out in a one-pot reaction.

[0083] Preparation of X6b X6b is a key intermediate in the novel synthesis described herein. Accordingly, the present invention provides a synthetic intermediate, X6b: [ka] X is F, Cl, Br or I. Preferably, X is Br.

[0084] X6b can itself be synthesized by any suitable means. The present invention provides a method for preparing the synthetic intermediate X6b: [ka] X is F, Cl, Br or I, preferably Br.

[0085] In some embodiments, the method includes reacting compound X6d with compound N6a; [ka] X is Cl, Br or I, preferably Br.

[0086] Carboxylic acid coupling reactions, including amidation reactions, are well known to those skilled in the art and typically involve reacting an amine with a carboxylic acid under coupling conditions or converting a carboxylic acid group into an activated group that can more readily react with an amine.

[0087] Thus, in one embodiment, the synthesis of X6b involves converting the carboxylic acid group of X6d to an activated carboxylic acid group using For example, the method can include converting compound X6d to compound X6c: [ka] R 10 is an activated carboxylic acid group, such as an acyl anhydride, acyl halide, or acyl phosphate, and X is Cl, Br, or I. For example, conversion of X6d to the corresponding acyl chloride can be achieved using thionyl chloride. The solvent can be an aromatic solvent such as toluene. The base can be pyridine. X6c can then be reacted with N6a to form compound X6b. These reactions can be carried out as a one-pot synthesis or sequentially. The formation of N6a from N6b can also be linked to this one-pot synthesis, where X6c and N6a are prepared separately but then coupled.

[0088] Alternatively, X6b can be prepared directly from X6d and N6a by using a carboxylic acid activating reagent, which are well known and include HBT, HATU, HBTU, TBTU, HOBt, PyAOP, HCTU, PyClocK, TFFH, carbodiimides (e.g., DCC), carbonyldiimidazole (CDI), and phosphonium salts (e.g., BOP, PyBOP).

[0089] The coupling of X6d or X6c and N6a can be carried out in the presence of a base, preferably a tertiary alkylamine base such as triethylamine or DIPEA, or an arylamine base such as pyridine. The coupling of X6d or X6c and N6a can be carried out in isopropyl acetate, toluene, or preferably a mixture thereof.

[0090] X6d can be prepared from X6e: [ka]

[0091] In one embodiment, X6d is prepared by contacting X6e with a base, such as sodium hydroxide, which converts the cyano group to a carboxylic acid group.

[0092] X6e can be prepared from X6f: [ka] X is Cl, Br or I.

[0093] X6e is prepared by contacting X6f with X6g under cross-coupling conditions: [ka] X is F, Cl, Br, or I, m is 2 or 3, and R is F, Cl, Br, or I, OH, OCl-C6 alkyl, N(C1-C6 alkyl)2, aryl, or two or three R groups other than F, Cl, Br, I, or OH can together form a cyclic boronic ester, such as pinacol boronic acid or N-methyliminodiacetic acid (MIDA) boronate. The coupling of organoboron and aryl halide compounds is described above in connection with the coupling of X6b and F7, and similar conditions can be used for the formation of X6e.

[0094] X6f can be prepared from X6h: [ka] X is Cl, Br or I.

[0095] X6f can be prepared by diazotization of X6h with, for example, nitrous acid or sodium nitrite under acidic conditions, followed by cyanation of the diazonium compound using, for example, CuCN and / or NaCN.

[0096] X6h can be prepared from X6i: [ka]

[0097] X6h can be prepared by contacting X6i with a halogenating agent, for example, a chlorinating agent such as AlCl or N-chlorosuccinimide, a brominating agent selected from the group consisting of N-bromosuccinate, 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), N-bromosuccinimide, TBAB, phosphorus tribromide, bromine chloride, aluminum tribromide, Br and FeBr, HBr, tribromoisocyanuric acid, ozone and ammonium bromide, TBBDA, and combinations thereof, or an iodinating reagent such as N-iodosuccinimide. X6h can also be prepared via the Sandmeyer reaction.

[0098] Preparation of N6a N6a is used in the preparation of X6b. N6a can be prepared from N6b: [ka] Y is Cl, Br or I.

[0099] N6a can be prepared by contacting N6b with a reducing agent, such as a reducing agent selected from the group consisting of H2 and Pt(V) / C; Raney nickel catalyst and H2; Urushihara nickel catalyst and H2; Adams catalyst (PtO2) and H2; TiCl3 and H2; HCl and iron; NH4Cl and iron; HCl and SnCl2; samarium and NH4Cl; FeCl3, hydrazine hydrate; sodium hydrosulfite; hydrogen sulfide and base; hydroiodic acid; 1,3-dimethyl-2-imidazolidinone and sodium triethylsilanethiolate; and combinations thereof. In some embodiments, the reaction is carried out under micellar conditions.

[0100] N6b can be prepared from N6c: [ka]

[0101] N6b can be prepared by contacting X6h with a halogenating agent, e.g., a chlorinating agent such as AlCl or N-chlorosuccinimide, a brominating agent selected from the group consisting of N-bromosuccinate, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), TBAB, phosphorus tribromide, bromine chloride, aluminum tribromide, Br and FeBr, HBr, tribromoisocyanuric acid, ozone and ammonium bromide, TBBDA, and combinations thereof, or an iodinating reagent such as N-iodosuccinimide. X6h can also be prepared via the Sandmeyer reaction.

[0102] N6c can be prepared from N6d: [ka]

[0103] N6c can be prepared by contacting N6d with a nitrating agent, for example, a nitrating agent selected from the group consisting of: nitric acid and sulfuric acid; nitric acid and acetic anhydride; tetrachloromethane, nitric acid and phosphorus pentoxide; isopentyl nitrate, trifluoromethanesulfonic acid and 1-ethyl-3-methylimidazolium triflate; H-beta zeolite catalyst and N2O5; acetyl nitrate; and combinations thereof.

[0104] N6d can be prepared from N6e: [ka]

[0105] N6d can be prepared by contacting N6e with a diazotizing agent such as nitrous acid or sodium nitrite under acidic conditions, followed by a fluorinating agent such as HF.

[0106] Preparation of F6 F6 is used in the preparation of F7, which itself can be prepared by any suitable method. In one embodiment of the present invention, F6 is prepared from F2 and F3: [ka] Y is independently Cl, Br, or I.

[0107] In some embodiments, the preparation of F6 comprises reacting compound F2 with compound F3 to obtain compound F4: [ka]

[0108] The reaction of F2 and F3 can be carried out under Mitsunobu conditions in the presence of a phosphine compound, such as PPh3 (optionally on a resin support) and an azodicarbocylate, such as DIAD or DEAD. In one embodiment, the reaction is carried out in an aromatic solvent, such as toluene. In one embodiment, the solvent is dried to have a water content of less than 0.5 wt %, e.g., 0.1 wt %.

[0109] The preparation of F6 may involve the conversion of F4 to F6: [ka]

[0110] Conversion of F4 to F6 may be carried out using any suitable aminating reagent, such as ammonium hydroxide or water and ammonia. In one embodiment, the solvent is an alcohol solvent, such as iPrOH.

[0111] The reaction of F2 with F3 to give F4 and the conversion of F4 to compound F6 may be carried out in sequential reactions or in a one-pot reaction.

[0112] Alternatively, F2 can be converted to F2' via amination. Aminating reagents include water and ammonia or ammonium hydroxide, and the reaction may be carried out in a polar solvent, such as an alcohol solvent, such as iPrOH. F2 can then be reacted with F3, optionally under Mitsunobu conditions, in the presence of a phosphine compound, such as PPh3, and an azodicarboxylate, such as DIAD or DEAD, to give F6: [ka]

[0113] These reactions can be carried out sequentially or in one pot.

[0114] Preparation of F11 Any of the reactions described herein can be used in the synthesis of compound F11: [ka]

[0115] In one embodiment of the method of the invention, F7 is converted to F11 in one or more synthetic steps. For example, in one embodiment, the method of the invention may further comprise deprotection of F7 to give F8: [ka]

[0116] In some embodiments, P is a Boc group and deprotection is achieved using an acid, for example, HCl.

[0117] The process of the present invention may further comprise the conversion of F8 to F11: [ka]

[0118] Conversion of F8 to F11 can be achieved by contacting F8 with F9: [ka]

[0119] The formation of F11 from F8 and F9 can be achieved in the presence of a base such as Na2CO3 and a suitable solvent such as ethyl acetate. Alternatively, the reaction can be carried out without a base in a suitable solvent. In place of F9, acryloyl chloride can be used, or acrylic acid can be used, along with a carboxylic acid activating reagent such as HBT, HATU, HBTU, TBTU, HOBt, PyAOP, HCTU, PyClocK, TFFH, carbodiimides (e.g., DCC), carbonyldiimidazole (CDI), or phosphonium salts (e.g., T3P, SOCl2BOP, PyBOP). However, the use of acrylic anhydride is preferred because, unlike acrylic acid, it avoids the need for chromatography.

[0120] Products prepared according to the process of the present invention and uses thereof The present invention provides a synthetic route to the compound Remibrutinib. Therefore, the protection conferred by any patent arising from this application may be extended to the direct product of the process herein, which is Remibrutinib.

[0121] The present invention provides compound F11 (remibrutinib) prepared or preparable by the processes described herein. The synthesis of remibrutinib described herein does not include INT3 at any stage. Thus, in one embodiment, remibrutinib prepared or preparable by the processes described herein is substantially free of INT3 (5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline). For example, the amount of INT3 may be less than 100 ppm (parts per million), less than 10 ppm, less than 1 ppm, less than 100 ppb (parts per billion), less than 10 ppb, or less than 1 ppb. In one embodiment, remibrutinib prepared or preparable by the processes described herein does not contain INT3 (5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline). Alternatively or additionally, remibrutinib prepared or preparable by the processes described herein is substantially free of (3-amino-5-fluoro-2-methylphenyl)boronic acid. For example, the amount of (3-amino-5-fluoro-2-methylphenyl)boronic acid may be less than 100 ppm (parts per million), less than 10 ppm, less than 1 ppm, less than 100 ppb (parts per billion), less than 10 ppb, or less than 1 ppb. In one embodiment, remibrutinib prepared or preparable by the processes described herein does not contain 3-amino-5-fluoro-2-methylphenyl)boronic acid.

[0122] The present invention also provides pharmaceutical compositions containing remibrutinib prepared or preparable by the processes described herein, and thus may be substantially free of INT3. In one embodiment, the composition also contains at least one pharmaceutically acceptable excipient, and often contains at least two or more pharmaceutically acceptable excipients. Some suitable excipients are disclosed herein. Other excipients known in the art may be used without departing from the spirit and scope of this application.

[0123] As used herein, the term "pharmaceutically acceptable excipient" includes any and all solvents, carriers, diluents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal, antioxidants), isotonicity agents, absorption delaying agents, salts, drug stabilizers, binders, additives, fillers, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, that would be known to those of skill in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). It should be understood that the use of any conventional excipient in any therapeutic or pharmaceutical composition is contemplated by the present application, unless such excipient is incompatible with the active ingredient.

[0124] Pharmaceutical compositions can be formulated for a particular route of administration, such as oral administration, parenteral administration, and rectal administration. In addition, pharmaceutical compositions of the present invention can be made up in solid form (including, without limitation, capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including, without limitation, solutions, suspensions, or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and / or can contain conventional inert diluents, lubricants, carriers, or buffers, as well as adjuvants such as solvents, preservatives, stabilizers, wetting agents, emulsifiers, fillers, and the like.

[0125] Typically, the pharmaceutical composition is a tablet or capsule containing the active ingredient together with at least one excipient such as: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; for tablets, further c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired; d) a carrier such as an aqueous vehicle containing a co-solvating material such as Captisol, PEG, glycerin, cyclodextrin or the like; e) disintegrants, such as starch, agar, alginic acid or its sodium salts or effervescent mixtures; and / or f) Absorbents, colorants, flavorings and sweeteners.

[0126] Tablets may be film-coated or enteric-coated according to methods known in the art. Preferably, the compound or composition is prepared for oral administration, such as, for example, a tablet or capsule, optionally packaged in a multi-dose form suitable for storing and / or dispensing unit doses of the pharmaceutical product. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, unit-dose containers (e.g., vials), blister packs, and strip packs.

[0127] Tablets may contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0128] Because water may facilitate the disintegration of certain compounds, the present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising remibrutinib as an active ingredient, prepared or preparable by the methods described herein.

[0129] The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-moisture ingredients and low-moisture or low-humidity conditions. Anhydrous pharmaceutical compositions can be prepared and stored so that their anhydrous nature is maintained. Therefore, to enable the anhydrous compositions to be included in suitable prescribed kits, anhydrous compositions are preferably packaged using materials known to prevent exposure to water. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit-dose containers (e.g., vials), blister packs, and strip packs.

[0130] The present invention further provides pharmaceutical compositions and dosage forms that comprise one or more agents that reduce the decomposition rate of a compound of the invention as an active ingredient. Such agents, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0131] The pharmaceutical compositions or combinations of the present invention can be formulated as unit dosages of about 1 to 1,000 mg of active ingredient(s), or about 1 to 500 mg, about 1 to 250 mg, about 1 to 150 mg, about 0.5 to 100 mg, or about 10 to 50 mg of active ingredient for a subject weighing about 50 to 70 kg. Preferably, the pharmaceutical compositions or combinations of the present invention can be formulated as unit dosages of about 10 mg, about 25 mg, or about 50 mg. The therapeutically effective dosage or amount of the compound, pharmaceutical composition, or combination thereof depends on the species, weight, age, and individual condition of the subject, and the disorder or disease being treated or its severity. A physician, clinician, or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients required to prevent, treat, or inhibit the progression of the disorder or disease.

[0132] The efficacy of the dosages mentioned above can be demonstrated in vitro and in vivo tests, advantageously using mammals, such as mice, rats, dogs, monkeys, or their isolated organs, tissues, and preparations. The compounds of the present invention can be applied in vitro in the form of liquids, for example, preferably aqueous solutions, and in vivo, for example, as suspensions or in aqueous solutions, enterally, parenterally, advantageously intravenously. The dosage in vitro is about 10 -3 Molar concentration ~10 -9The therapeutically effective amount in vivo may range between about 0.1 and 500 mg / kg or between about 1 and 100 mg / kg, depending on the route of administration. Preferably, the therapeutically effective amount in vivo ranges between about 10 mg and about 200 mg daily, for example, about 10 mg, about 20 mg, about 25 mg, about 35 mg, about 50 mg, about 100 mg, or about 200 mg daily. Preferably, the therapeutically effective amount in vivo is selected from about 10 mg, about 35 mg, about 50 mg, or about 100 mg once daily. More preferably, the therapeutically effective amount in vivo is selected from about 10 mg, about 25 mg, about 50 mg, or about 100 mg twice daily.

[0133] In another aspect, the present invention also provides a method for the treatment of a disorder mediated by or ameliorated by the inhibition of BTK, comprising administering to a patient in need of such treatment a therapeutically effective amount of remibrutinib prepared or preparable by the methods described herein.

[0134] In another aspect, the present invention also provides the use of remibrutinib prepared or preparable by the methods described herein for the preparation of a medicament for the treatment of a disorder mediated by or ameliorated by inhibition of BTK.

[0135] In another aspect, the present invention also provides remibrutinib prepared or preparable by the methods described herein for use in the treatment of disorders mediated by or ameliorated by inhibition of BTK.

[0136] Remibrutinib prepared or preparable by the methods described herein is useful in the treatment of the following diseases or disorders that are mediated by BTK or are ameliorated by BTK inhibition: autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection; diseases in which antibody production, antigen presentation, cytokine production, or lymphoid organogenesis is abnormal or deleterious; rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren's syndrome, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic urticaria (chronic urticaria), and the like. Spontaneous urticaria, induced urticaria), chronic allergies (atopic dermatitis, contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, pancreatitis, glomerulonephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-mediated transplant rejection (AMR), graft-versus-host disease, B-cell mediated hyperacute, acute, and chronic transplant rejection; thromboembolic disorders, myocardial infarction, angina pectoris, stroke, ischemic disorders, pulmonary embolism; cancers of hematopoietic origin, including, but not limited to, multiple myeloma; leukemia; acute myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin's lymphoma; lymphoma; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Waldenstrom's disease.

[0137] Remibrutinib prepared or preparable by the methods described herein is particularly useful in the treatment of rheumatoid arthritis; chronic urticaria, preferably chronic idiopathic urticaria; Sjogren's syndrome, multiple sclerosis, atopic dermatitis or asthma. [Example]

[0138] The following non-limiting examples are illustrative of the present disclosure.

[0139] An overview of the synthetic routes described herein and exemplified below is provided in the Figures. The reactions are described in more detail below.

[0140] Preparation of Example 1-F2 [ka] To a suspension of AlCl3 in xylene at 5°C, the xylene solution of F1 is added over 40 min. The mixture is warmed to 30°C over 60 min and stirred at this temperature overnight. EtOAc is added and the resulting solution is quenched with a 0.5N aqueous solution of HCl at 0°C for 1 h. The mixture is warmed to 25°C and the phases are separated. The aqueous layer is discarded and the organic layer is concentrated. The resulting thin suspension is cooled to 20°C at 0.3 K / min. The solid is filtered, and the filter cake is washed with a 1:1 solution of xylene and heptane and dried to give F2 as a white solid in approximately 83% yield.

[0141] Example 2 - Preparation of F6 [ka] Preparation of F3 solution: Charge 13.0 g of water, 2.4 g of 30% sodium hydroxide solution, 68.0 g of toluene, and 13.0 g of 2-methylaminoethanol to a reaction flask. Adjust the internal temperature to 10-30°C. Stir the reaction mixture for 25-35 minutes. Add Boc anhydride (37.8 g, 1.00 equiv.) dropwise and stir the reaction mixture for an additional 6-12 hours at 10-30°C. Quench the reaction with water (13.0 g) and stir the resulting biphasic mixture for 25-35 minutes. Remove the lower aqueous layer and wash the organic layer with additional water (13.0 g). Use the organic layer directly in the next step.

[0142] Mitsunobu reaction to F4: A solution of F3 (1.4 eq) in toluene is dried by Dean-Stark distillation to a water content of 0.07 wt% NMT. ​​Triphenylphosphine (42 g, 1.32 eq) is added to the dried solution of F3 at 20–30 °C, and the reaction mixture is stirred at room temperature until a clear solution is observed. The reactor is inertized and cooled to approximately -30 °C. F2 (20 g, 1.0 eq) is then added, followed by DIAD (31.8 g, 1.30 eq) over 4–8 h while maintaining the internal temperature between -25 °C. The slightly cloudy solution is warmed to 10 °C within 4 h and stirred for an additional 15–20 h between 5–15 °C. After completion of the reaction, toluene is distilled at 55 °C to produce a slightly viscous, yellow-brown suspension. The mixture is cooled to 10 °C, and n-heptane (140 g) is added. The mixture is stirred for 2 hours to give a light brown, well-stirred suspension. The suspension is filtered and the filter cake is washed with chilled n-heptane. The filter cake containing triphenylphosphine oxide and H2-DIAD is discarded. The combined mother liquor and washes are concentrated to approximately 1 / 3 of the original volume at 55°C and 150 mbar to produce a clear, yellow solution of F4.

[0143] Amination to F6: The solution of F4 is then solvent switched to iPrOH via distillation and addition of iPrOH. To a yellow solution of F4 in iPrOH, HO (3.5 w / w wrt F2) and 25 wt% NH3 solution (3.5 w / w F2) are added. The resulting yellow solution is stirred at 70 °C for 16 h. Upon warming to 70 °C, slight gas evolution (NH3) is observed. After completion of the reaction, the resulting yellow solution is cooled to 45 °C over 40 min, and F6 seeds are added as a suspension in iPrOH. The suspension is aged for approximately 20 min. The thin suspension is then cooled to 10-20 °C at 10 °C / h and aged for an additional 30 min. The suspension is filtered, and the filter cake is washed with a mixture of HO and iPrOH (1:1) (40 g). The wet product is dried at 50° C. under full vacuum (approximately 20 hours) to give F6 as a white crystalline solid in approximately 70% yield.

[0144] Example 3 - Preparation of X6b [ka] The synthesis of X6b is a highly convergent process starting from the preparation of a solution of N6a, the preparation of a solution of the acyl chloride X6c, and the combination of the two solutions to form X6b.

[0145] Autoclave: Preparation of N6a solution: N6b (20 g, 1.0 equivalent) is charged into an autoclave under N2 and diluted with isopropyl acetate (105 g). Approximately 1 wt% of wet Pt(V) / C (0.126 g dry weight) is then added and the atmosphere is changed from N2 to H2. Hydrogenation is carried out under 3 bar H2 for 12 hours with an internal temperature below 30 °C. At the end of the reaction, the suspension is filtered to remove the catalyst. The reactor and filter cake are rinsed with isopropyl acetate. The N6a solution can be azeotropically distilled to remove water or used as is.

[0146] Reactor A: Preparation of X6c solution: Under a N2 atmosphere, X6d (17 g, 1.1 eq) is suspended in toluene (56 g). A catalytic amount of pyridine is added and the reaction mixture is heated to 50°C. Thionyl chloride is then added dropwise over 2 hours, and the resulting mixture is stirred at 50°C for 1 hour. The cloudy solution is then distilled to half its volume, the reactor is refilled with toluene to its original volume, and the process is repeated to remove excess thionyl chloride. The X6c mixture is then cooled to RT.

[0147] Reactor A: Formation of X6b: To a solution of X6c (1.1 equiv.) in toluene is added the previously prepared solution of N6a (1.0 equiv.) in iPrOAc over 1 h. At the end of the addition, DIPEA (13.4 g, 1.2 equiv.) is carefully added over 2 h. The reaction mixture is stirred for 3 h after the end of the DIPEA addition, and the reaction is quenched with iPrOH (26.4 g). The reaction is stirred overnight at RT, and the suspension is filtered. The wet cake is rinsed with iPrOH and iPrOH / water. The cake is drained and dried under reduced pressure. X6b is typically isolated in 87-93% yield.

[0148] Example 4a: Optimization of Suzuki conditions for the conversion of X6a to F7 Previously, it was reported that the coupling reaction between F6 and X6a was carried out using 1 eq of F6, 1.15 eq of X6a, 5 mol% Pd(PPh3)2Cl2, 3 eq of Na2CO3, 12 vol DME, and 10 vol water at 75 °C for 8 h, with an isolated yield of 74% for the conversion (DOI:10.1021 / acs.jmedchem.9b01916).

[0149] The cross-coupling reaction was optimized to replace DME solvent with a Class 3 solvent suitable for commercial processes, while also reducing Pd usage and production costs. [ka]

[0150] Design and Experimental Details 1) Screening of 12 Suzuki catalyst precursors and six solvent systems (80°C: tert-amyl alcohol, CPME, and toluene; 60°C: THF, Me-THF, and MeCN, each combined with water) using 1.15 eq. X6a in the presence of 3.0 eq. K3PO4 at a 2.0 mol% Pd level found a series of catalyst precursor / solvent combinations that were able to drive the reaction after 16 h, with full conversion and deboronate being the main by-product; it was decided to perform screening of all ligands in both toluene (80°C) and Me-THF (60°C). 2) 48 ligands were screened using 2.0 mol% Pd(OAc)2, 1.1 eq. boronate, and 3.0 eq. K3PO4 in 10.0 vol. Me-THF / 3.0 vol. water at 60 °C or in 10.0 vol. toluene / 3.0 vol. water at 80 °C. After 16 h, five ligands (RuPhos, dppf, S-Phos, Cy3P·HBF4, and Ph2P(t-Bu)) were found to be capable of promoting the reaction, leading to complete conversion of Prod / IS in Me-THF / water at 60 °C, while controlling the deboronate byproduct at levels between 3% and 8%.

[0151] [Table 4]

[0152] 3) Keeping the P:Pd ratio at 2:1, six Pd precursors (Pd(OAc)2, [Pd(C3H5)Cl]2, Pd(TFA)2, Pd(MeCN)2Cl2, Pd2(dab)3, and PdBr2) were screened in combination with RuPhos, dppf, S-Phos, Cy3P·HBF4, and Ph2P(t-Bu), respectively, at a 1.0 mol% Pd level in the presence of 3.0 eq. K3PO4 and 1.05 eq. X6a in 10.0 vol. Me-THF / 3.0 vol. water at 60 °C. After 16 h, Cy3P·HBF4 and Ph2P(t-Bu) were found to be the best ligand candidates, while Pd(TFA)2, Pd(MeCN)2Cl2, and PdBr2 remained excellent Pd precursors.

[0153] [Table 5]

[0154] 4) By maintaining a P:Pd ratio of 2:1, Cy3P·HBF4 and / or Ph2P(t-Bu) were used as the ligands in combination with Pd(TFA)2, Pd(MeCN)2Cl2, and PdBr2, respectively. Pd loadings of 0.1-2.0 mol% were screened in 10.0 vol. Me-THF / 3.0 vol. water at 60°C in the presence of 3.0 eq. K3PO4 and 1.05 eq. X6a. After 16 h, Pd(MeCN)2Cl2 / Ph2P(t-Bu) was found to be the optimal catalyst precursor combination, and the Pd loading could be reduced to 0.3-0.5 mol% and the deboronate / Prod ratio could be controlled to around 1%.

[0155] [Table 6]

[0156] 5) The optimal catalyst precursor combination was Pd(MeCN)2Cl2 / Ph2P(t-Bu) and 1.05 eq. X6a. Pd loadings of 0.1-0.5 mol% were screened in the presence of K2CO3, Cs2CO3, K3PO4, and KF, respectively. K3PO4 was found to be the optimal base, and 0.3-0.5 mol% Pd(MeCN)2Cl2 / Ph2P(t-Bu) catalyst precursor was recommended for scale-up reactions.

[0157] Best conditions 1) The reaction of 1.0 eq. F6, 1.05 eq. X6a, 0.5 mol% Pd(MeCN)2Cl2, 1.0 mol% Ph2P(t-Bu), and 3.0 eq. K3PO4 in 10.0 vol. Me-THF / 3.0 vol. water at 60 °C for 16 h achieved complete conversion, with an IPC purity of 90.6% by HPLC and a deboronate / Prod of 1%. 2) The reaction of 1.0 eq. F6, 1.05 eq. X6a, 0.3 mol% Pd(MeCN)2Cl2, 0.6 mol% Ph2P(t-Bu), and 3.0 eq. K3PO4 in 10.0 vol. Me-THF / 3.0 vol. water at 60 °C for 16 h achieved 99% conversion, an IPC purity of 88.5% by HPLC, and a deboronate / Prod of 1%. [ka]

[0158] Next best conditions 1) The reaction of 1.0 eq. F6, 1.05 eq. X6a, 0.8 mol% Pd(TFA)2, 1.6 mol% Ph2P(t-Bu), and 3.0 eq. K3PO4 in 10.0 vol. Me-THF / 3.0 vol. water at 60 °C for 16 h achieved complete conversion, with an IPC purity of 90.9% by HPLC and a deboronate / Prod of 2%. 2) The reaction of 1.0 eq. F6, 1.05 eq. X6a, 0.8 mol% Pd(MeCN)2Cl2, 1.6 mol% Ph2P(t-Bu), and 3.0 eq. K3PO4 in 10.0 vol. Me-THF / 3.0 vol. water at 60 °C for 16 h achieved complete conversion, with an IPC purity of 91.2% by HPLC and a deboronate / Prod of 2%.

[0159] Example 4b - Preparation of F7 via one-pot borylation-Suzuki cross-coupling from X6b using optimized conditions of Example 4a [ka] Miyaura boronation: X6b (1.0 equiv.), B2pin2 (1.06 equiv.), and KOAc (2.5 equiv.) are charged to a reactor under a N2 atmosphere containing degassed MeTHF. The water content of the reaction mixture is measured and adjusted to between 1000 and 2500 ppm. After inertization of the vessel, a solution of Pd(MeCN)2Cl2 (0.5 mol%) in degassed MeTHF and a solution of PPh2tBu (1.0 mol%) in degassed MeTHF are added sequentially. The reaction mixture is then heated to 70 °C for 16 h.

[0160] Suzuki Coupling: Once complete conversion of X6b is achieved (X6b<0.25%, approximately 98% conversion), the reaction mixture is cooled to RT and quenched with an aqueous solution of KOH (21% wt / wt). The aqueous layer is separated and discarded, and a fresh aqueous solution of KOH (21% wt / wt) is added. F6 (0.96 equivalents relative to X6b) is added as a solid, followed by the addition of another 2 mol% PPh2tBu in degassed MeTHF and another 1 mol% Pd(MeCN)2Cl2 in degassed MeTHF after appropriate degassing. The reaction mixture is then heated to 60 °C for approximately 24 h. After completion of the reaction, an aqueous solution of N-acetylcysteine ​​is added to the reaction mixture at 60 °C. After stirring for 2 h, the aqueous layer is discarded. Another aqueous solution of N-acetylcysteine ​​is added, and the pH is adjusted to ≥ 9.5 by the addition of an aqueous solution of KOH. After stirring for 2 h, the aqueous layer is discarded. The organic layer is then washed with water for 30 minutes, and the aqueous layer is discarded. The solution is filtered through activated carbon at 60°C, and the solution is concentrated to half its volume by vacuum distillation. n-Heptane is added slowly, and the resulting suspension is cooled to 20°C, stirred for 2 hours, and filtered. The filter cake is washed with a 1:5 mixture of Me-THF and n-heptane. If the purity is not satisfactory, the wet cake can be reslurried in Me-THF and n-heptane (1:5). The cake is drained and dried under reduced pressure. F7 is typically isolated in 92% yield.

[0161] Example 4c - Development of a one-pot borylation / Suzuki cross-coupling using tetrahydroxydiboron for use in the preparation of F7 A one-pot borylation / Suzuki cross-coupling using tetrahydroxydiboron was developed for the synthesis of F7 from X6b using BBA as the borylation reagent. This process is characterized by the utilization of significantly lower Pd-catalyst loadings, the avoidance of pinacol hydrate precipitation in the final product, and the use of methanol as a green alcohol solvent throughout both steps. This process addresses some of the previous issues associated with the use of bis(pinacolato)diboron as the borylation reagent, thus resulting in a more atom-efficient and cost-effective approach. Preliminary results demonstrated the feasibility of this one-pot process at a 2.2 g scale using a FlexyALR reactor. [ka]

[0162] Results and Discussion Miyaura boronation: To develop optimal reaction conditions for the Miyaura boronation using BBA, we screened crucial reaction parameters, including catalyst system, base, solvent, and temperature. This boronation was limited to the use of a Pd(II)-catalyst precursor, which promotes rapid Pd(0) formation. Indeed, the use of a second-generation Buchwald catalyst precursor in combination with two equivalents of an additional ligand proved to be the best catalyst system for our reaction (Table 1, entries 1–6). Of all the catalyst precursors screened, only Pd-XPhos-2G afforded complete conversion of the starting material while providing the highest yield and selectivity toward the formation of X6a (entry 2). Similarly, the use of ethylene glycol as an additive also proved highly beneficial, as complete conversion could not be achieved without ethylene glycol (entries 1 vs. 2). BBA can be stabilized in situ through the formation of the corresponding boronic ester derivative, increasing the rate of boronation while reducing the amount of boronation reagent and Pd. Further reduction in catalyst loading was attempted (entries 8–10). Surprisingly, lowering the catalyst loading yielded smaller amounts of the reduction and dimerization products IMP1 and IMP2 while still obtaining nearly complete conversion of X6b (entry 8). Furthermore, higher conversions were observed by increasing the reaction time, thus suggesting that BBA was still present in the reaction mixture (entry 9). These results indicated that the formed boronic acid might undergo a Pd(II)-catalyzed decomposition pathway and that a larger amount of Pd source in the presence of trace amounts of oxygen might facilitate this pathway. Finally, by simply increasing the reaction temperature to 50 °C, complete conversion to the final product was observed with high selectivity and yield (entry 10).

[0163] [Table 7]

[0164] We also decided to evaluate the reaction by replacing ethylene glycol with an amine base, DIPEA, and other Buchwald catalyst precursors to see if we could further improve the Miyaura boronation results and increase the amount of catalyst used (Table 2, entries 1–5). While most catalysts did not work well under these conditions, we found success with Pd-cataCXium 3G (entry 5). Although slightly higher amounts of IMP1 and IMP2 were formed compared to the already optimized conditions, these results were promising given that cataCXium outperforms XPhos when used in combination with DIPEA (entry 5 vs. 1). While considering these results, we screened several critical reaction parameters to see if we could further improve these results (entries 6–9). Given our previous results, we first investigated lowering the catalyst usage (entry 6). Importantly, we found that 0.05 mol% Pd was sufficient to drive the reaction to completion, suggesting that the catalytic activity of Pd-cataCxium-3G under these conditions was much higher than that of Pd-XPhos-2G. Importantly, heating to 50 °C was found to be optimal, as reducing the temperature resulted in an incomplete reaction (entry 7). Surprisingly, we found that the addition of ethylene glycol was detrimental to the conversion of the reaction, thus suggesting that the cyclic diboron species may not be as reactive under these conditions (entry 8). Although significantly higher catalytic activity was observed under these newly optimized conditions, the relative amounts of the byproducts IMP1 and IMP2 could not be further reduced, and conditions based on the utilization of Pd-Xphos-2G, KOAc, and ethylene glycol remained superior.

[0165] [Table 8]

[0166] Suzuki Cross-Coupling: Having explored two sets of optimized conditions for the synthesis of boronic acid X6a by using BBA as a boronation reagent, we investigated the feasibility of subsequent Suzuki couplings with the ultimate goal of developing a one-pot process for the synthesis of F7. To this end, we first attempted the Suzuki coupling of X6a and F6 at 60 °C under the reaction conditions previously developed by Molander (Gurung, SR, et al., Org. Process Res. Dev. 2017, 21, 65-74) (Table 3, entry 1). However, contrary to expectations, heterogeneous and incomplete conversion of X6a and F6 was observed after heating to 60 °C for 17 h. Furthermore, we found that F6 was easily converted to F7 by the addition of EtOH and S N We found that the reaction partially proceeded via the Ar pathway to form the corresponding ether. At this point, we wondered whether the use of a milder organic base, such as an amine, could help reduce this side reaction. Indeed, the use of EtN resulted in minimal formation of the CO coupling product, leading to uniform and nearly complete conversion of X6a and F6 (entry 2). Finally, we were surprised to find that MeOH outperformed EtOH, providing complete conversion of X6a and F6 and higher yields of the coupling product (entry 3). Furthermore, F7 precipitated directly from the reaction mixture, thus significantly simplifying the final workup purification. Although the formation of the reduction and dimerization products IMP1 and IMP2 evidenced the presence of trace amounts of oxygen in the reaction solvent, we anticipated that scale-up of the process should effectively eliminate this issue (entries 1–3).

[0167] [Table 9]

[0168] One-pot boronation and coupling: Since Pd-XPhos 2G and Pd-cataCXium 3G were excellent catalyst precursors for the Miyaura boronation using BBA, we decided to compare the efficiency of these two catalysts using our optimized conditions in a one-pot process (Table 4). As shown in entry 1, Pd-XPhos 2G outperformed Pd-cataCXium 3G in the one-pot procedure, demonstrating a 79% isolated yield of F7 with 78% purity starting from X6b. As expected, workup and purification of F7 could be carried out via direct filtration and washing of the formed precipitate with a MeOH / HO mixture.

[0169] [Table 10]

[0170] Scale-up: Having developed conditions for both steps in MeOH using the same catalyst precursor under mild conditions, the one-pot reaction was attempted on a larger scale (2.2 g of X6b) using a Flexy ALR-1 300 ml reactor (Table 5).

[0171] X6b (2.20 g, 1.0 equiv.), potassium acetate (1.76 g, 3.0 equiv.), ethylene glycol (1.0 mL, 3.0 equiv.), and MeOH (100 mL) were charged to a 300 mL FlexyALR reactor. The reaction mixture was degassed through successive vacuum / N cycles, and a solid mixture of BBA (807 mg, 1.5 equiv.), Pd XPhos 2G (12 mg, 0.25 mol%), and XPhos (14 mg, 0.50 mol%) was added under N. After a second degassing, the reaction was heated to 50 °C and stirred overnight. The mixture containing the boronic acid was then cooled to 20 °C, and F6 (1.73 g, 0.95 equiv.), Pd XPhos 2G (24 mg, 0.5 mol%), EtN (2.5 mL), and degassed water (30 mL) were added under N. The reaction was degassed a third time and stirred overnight at 60° C. Afterwards, the reaction was cooled to 40° C. and concentrated under reduced pressure (approximately 40 ml of MeOH was removed). The reaction mixture was then cooled to 20° C. and stirred for 3 h. The light brown suspension was filtered, washed with a cold solution of MeOH / HO 4 / 1 (40 ml), and dried to give F7 (1.87 g, 56%) as a brown solid.

[0172] [Table 11]

[0173] We found that the Miyaura borylation of X6b was successful, affording the desired intermediate X6a in excellent yield and selectivity. Interestingly, completion of the borylation was evidenced by a sudden color change of the reaction mixture from white to pale orange-yellow, as described by Molander using Pd-XPhos 2G. The Suzuki coupling was then carried out by adding F6, another batch of catalyst, Et3N, and HO to the reaction mixture. Filtration and washing of the final product afforded F7 in 56% isolated yield over both steps, with an IPC purity of 87%. Importantly, as we predicted, performing both steps in the same reactor minimized the formation of the byproducts IMP1 and IMP2 by eliminating all traces of oxygen.

[0174] Preparation of Example 5-F8: [ka] F7 is suspended in isopropyl acetate at 25°C, concentrated, and hydrochloric acid (approximately 37% w / w, 4.1 equivalents) is added over 2 hours to remove the Boc protecting group. Once the addition is complete, the suspension is stirred for approximately 5 hours to ensure complete conversion to F8. Water is then added at 25°C to dissolve the bis-hydrochloride salt of F8. The resulting biphasic mixture is stirred at 35°C for approximately 2 hours to ensure dissolution of the desired product. The layers are separated at 30°C: the lower aqueous phase (containing the product) is transferred to a tank, and the upper organic phase (containing impurities from F7) is discarded. The aqueous phase is transferred to a new reactor via an in-line filter. An IPC of the aqueous layer is then taken to ensure the absence of F7. If F7 is not completely converted, the temperature is increased to 40°C for 1 hour before cooling the solution to RT. The resulting product-containing aqueous solution is then neutralized with sodium hydroxide (approximately 30% w / w) at 25°C until a pH value of 5.0-5.5 is reached. Ethanol is then added to the resulting suspension, and the temperature is increased to 60°C. 1 M aqueous sodium hydroxide solution is then added until a pH value of 7.5-8.5 is reached. The product suspension is cooled to 25°C over 2 hours and stirred for approximately another hour. The F8 crystals are isolated by filtration, and the filter cake is washed with ethanol. The F8 wet product is dried under reduced pressure at 50°C.

[0175] Example 6: Preparation of F11 The starting material F8 is suspended in ethyl acetate. Sodium carbonate (1.2 equivalents) is added to the suspension. The suspension is heated to 50°C. A solution of acrylic anhydride (F9, 1.05 equivalents) in ethyl acetate is added to the suspension over at least 1 hour. The reaction mixture is stirred at 50°C for approximately 30 minutes. After the addition of water, the reaction mixture is stirred at 65°C for approximately 30 minutes. The phases are separated at 60°C, and the aqueous phase is removed. 0.05 M sulfuric acid is added to the organic phase and stirred at 60°C for approximately 15 minutes. The aqueous phase is removed at 60°C. The organic phase is then washed with water, and the aqueous phase is removed at 60°C. The final organic phase is subjected to low-in-particle filtration at 65°C. At an internal temperature of 60°C, distillation is carried out under reduced pressure to remove approximately 25% of the solvent mixture, while simultaneously adding ethyl acetate to keep the solvent level approximately constant, thereby reducing the water content. A seed suspension of the crystalline form (anhydrous variant A disclosed in WO 2020 / 234779) in ethyl acetate is added to the solution. The suspension is stirred for at least 15 minutes. A second distillation with an internal temperature of 60°C is carried out under reduced pressure to remove approximately 12% of the solvent mixture, and ethyl acetate is simultaneously added to keep the solvent level approximately constant. The suspension is cooled to 30°C for 200 minutes. At an internal temperature of 30°C, a third distillation is carried out under reduced pressure, and ethyl acetate is simultaneously added to keep the solvent level approximately constant. The suspension is cooled to 0°C within 200 minutes and left stirring at 0°C for at least 240 minutes. The product is isolated by centrifugation, and the filter cake is washed twice with ethyl acetate. The isolated wet product is dried on a tray in a dryer under vacuum at 40°C. Product F11 is obtained.

[0176] Example 7 - Genotoxicity of 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline ("INT3" in WO 2015 / 079417) The compound INT3 is a key intermediate in the synthesis of remibrutinib, which is described in Example 6 of WO 2015 / 079417. INT3 was therefore subjected to the AMES test (bacterial reverse mutation assay) to determine whether it poses any genotoxicity-related safety concerns. Under the test conditions used and applying standard mutagenicity criteria, INT3 was found to have mutagenic potential in the test strain TA97a in the presence of metabolic activation.

[0177] The purpose of the Salmonella / microsome assay is to evaluate the mutagenic potential of a test substance by its effect on one or more histidine-requiring strains of Salmonella typhimurium in the absence and presence of the hepatic metabolic system. The Ames assay is a rapid, reliable, and economical method for screening compounds for potential genetic activity at the nucleotide level. A large database has been compiled using this assay, confirming its ability to detect genetically active compounds of most chemical classes with a sensitivity and specificity of around 80-90%.

[0178] With the exception of strain TA102, these strains require biotin and histidine for growth. In strain TA102, the critical mutation in the histidine gene is located on the multicopy plasmid pAQ1. This strain is particularly sensitive to the activity of oxidative and cross-linking mutagens. Plasmid derivatives (TA98, TA100, TA97a, and TA102) have increased sensitivity to certain mutagens, and the pKM101 plasmid encodes an error-prone DNA repair system ( 1,3 ).

[0179] Upon exposure to a mutagen, some bacteria in the treated population undergo genetic changes through chemical interaction with the compound, thereby reverting to a non-histidine auxotrophic state and allowing growth in the absence of exogenous histidine. A variety of test strains are used, each mutated by compounds of a particular chemical class. Compounds that are mutagenic in one strain need not be mutagenic in another. (1,3) .

[0180] method Test substance: INT3, also known as 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. Vehicle: Dimethyl sulfoxide (DMSO). Drug purity / content: 97.95%. Molecular structure: [ka]

[0181] Salmonella typhimurium strain used (4,5,6) : TA98, TA100, TA1535, TA97a and TA102. Metabolic activation system (2) : Liver S-9 mix from male rats, pre-treated with Aroclor 1254. 0.5 mL of 5% S-9 mix was added per plate. Control: Control treatments contained the same volume (0.1 mL) of additive per plate as the test substance solution. Negative controls included treatment with the selected vehicle. Positive control chemicals were sourced and used as shown in the table below:

[0182] [Table 12]

[0183] result Concentrations tested (mutagenicity studies): 50, 158, 501, 1582, and 5000 μg / plate (all strains + / - S-9 used). Precipitation and Toxicity: In preliminary cytotoxicity and mutagenicity studies, the test article did not exhibit any cytotoxicity in any of the strains, both in the presence and absence of metabolic activation. Furthermore, the test article did not precipitate up to the highest concentration, both in the presence and absence of metabolic activation. Mutagenicity: Data from control treatments confirmed accurate strain and assay functioning, and the data were considered valid.

[0184] After treatment with INT3 in experiment 1, a more than two-fold increase in the number of revertants (2.3-fold) over the parallel vehicle control was observed in strain TA97a at 5000 μg / plate in the presence of metabolic activation. To further characterize these increases in revertant numbers, additional experiments were performed in strain TA97a in the presence and absence of metabolic activation.

[0185] Following treatment in experiment 2 with INT3, no doubling of the number of revertants above the parallel vehicle control (officially the measure of a positive response) was observed in strain TA97a at 5000 μg / plate in the presence of metabolic activation. However, at the highest test concentration, a 1.8-fold increase was obtained. The 2.3-fold (above the 2-fold threshold indicating mutagenic potential of the test substance) and 1.8-fold increases in two independent experiments indicated that the test substance, INT3, was considered to have weak mutagenic potential in strain TA97a in the presence of metabolic activation.

[0186] No other increase in revertant numbers of at least 2-fold (1.5-fold for strain TA102) over parallel vehicle controls was observed after treatment with any other strain.

[0187] Acceptance criteria: An assay was considered valid when all of the following criteria were met: 1. Vehicle control counts fell within the normal range; 2. Positive control chemicals induced a 5- to 30-fold increase in revertant numbers for the various strains when compared to parallel vehicle controls, confirming differences between the various strains and the active S-9 preparation.

[0188] Evaluation criteria: For valid data, a test substance was considered mutagenic in this assay if a concentration-related increase in the number of revertants of ≥ 2-fold (in strains TA98, TA100, TA1535, or TA97a) or ≥ 1.5-fold (in strain TA102) above the parallel vehicle control value was observed. If the above criteria were met, the test substance was considered positive in this assay. If the above criteria were not met, the test substance was considered negative in this assay.

[0189] References (for Example 7) 1) Bruce N. Ames, Joyce Mccann and Edith Yamasaki, 1975. Methods for detecting carcinogens and mutagens with Salmonella / Mammalian-Microsome mutagenicity test. Mut. Res.,31:347-364. 2) Bruce N. Ames, William E. Durston, Edith Yamasaki and Frank D. Lee, 1973, Carcinogens are mutagens: A simple test system combining liver homogenates for activation and bacteria for detection. Proc. Nat. Acad. Sci. USA., 70 No. 8: 2281-2285. 3) Dorothy M. Maron and Bruce N. Ames, 1983, Revised methods for the Salmonella mutagenicity test. Mut. Res., 113:173 - 215. 4) ICH Harmonised Tripartite Guideline Guidance; S2 (R1), “On Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use”; At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies Current Step 4 version, dated 9 November 2011. 5) Lutz Mueller et. al., 1999, ICH - Harmonised guidances on genotoxicity testing of pharmaceuticals: evolution, reasoning and impact. Mut. Res., 436:195 - 225. 6) OECD Guidelines for the Testing of Chemicals; No.471; “Bacterial Reverse Mutation Test”; Adopted 21st July 1997. The present invention includes the following aspects. <1> A synthetic method comprising converting compound X6b and compound F6 to compound F7: [Chemical] The synthetic method wherein X and Y are each independently Cl, Br, or I, and P is an amine protecting group. <2> P is a carbamate protecting group such as 9-fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (Boc) or benzyl carbamate (Cbz), or an acetamide protecting group such as acetamide, trifluoroacetamide or benzylamide, or a sulfonamide protecting group such as p-toluenesulfonamide; <1> The method described below. <3> A synthetic method comprising boronation of X6b to give X6a:

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Claims

1. 1. A synthetic method comprising converting compound X6b and compound F6 to compound F7: 【Chemistry 1】 The synthetic method wherein X and Y are each independently Cl, Br, or I, and P is an amine protecting group.

2. 2. The method of claim 1, wherein P is a carbamate protecting group such as 9-fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (Boc) or benzyl carbamate (Cbz), or an acetamide protecting group such as acetamide, trifluoroacetamide or benzylamide, or a sulfonamide protecting group such as p-toluenesulfonamide.

3. A synthetic method comprising boronation of X6b to give X6a: 【Chemistry 2】 X is F, Cl, Br or I, n is 0 or 1, and R is F, Cl, Br or I, OH, OC １ ~C ６ Alkyl, N(C １ ~C ６ alkyl) ２ , aryl, or other than F, Cl, Br, I, or OH, two or three R groups can together form a cyclic boronic ester, such as pinacolboronic acid or N-methyliminodiacetic acid (MIDA) boronate.

4. The method according to claim 3, which is used in the method according to claim 1 or 2.

5. 4. The method of claim 3, wherein the boration is carried out using one or more catalysts, one or more ligands, one or more boronating agents and / or one or more bases and optionally one or more additives.

6. 6. The method of claim 5, wherein the boronating agent is selected from the group consisting of diboron compounds, boronic acids, and organoborates.

7. The boronating agent is bis(pinacolato)diboron, bis(catecholate)diborane, B ２ (NMe ２ ) ４ , bisboronic acid, C １ ~C ６ 7. The method of claim 6, wherein the alkyl group is selected from the group consisting of mono-, di-, or trialkyl borates, mono-, di-, or trimethyl borates, mono-, di-, or triethyl borates, mono-, di-, or tritripropyl borates, and mono-, di-, or tripropenylate acid.

8. 6. The method of claim 5, wherein the catalyst is a metal catalyst containing palladium, nickel, or copper, or a combination thereof.

9. The metal catalyst is PdCl ２ (PtBuPh ２ ) ２ or as a complex of a catalyst precursor which is a Buchwald catalyst precursor selected from: 【Transformation 3】 The method of claim 8 wherein the catalyst precursor is complexed with a phosphine ligand.

10. The metal catalyst is Pd(MeCN) ２ Cl ２ , Pd(TFA) ２ , and PdBr ２ As a catalyst precursor selected from the ligand t-BuPPh ２ The method of claim 8 , provided together with

11. 6. The method of claim 5, wherein the ligand is selected from the group consisting of organophosphines, N-heterocyclic carbenes, diazabutadienes, dibenzylidene acetone, and combinations thereof.

12. The ligand may be an organic phosphine ligand, such as XPhos, APhos, CPhos, RuPhos, SPhos, cataCXium, DavePhos, JohnPhos, MePhos, XantPhos, Cy ３ P-HBF ４ , SPhos-SO ３ Na, Cy-BIPHEP, t-BuPPh ２ and PPh ３ and combinations thereof.

13. 12. The method of claim 11, wherein the ligand:catalyst molar ratio is from 1:1 to 3:

1.

14. The base is KOH, NaOH, Ca(OH) ２ , Na ２ CO ３ , K. ２ CO ３ , Cs ２ CO ３ 6. The method of claim 5, wherein the base is an inorganic salt such as KOAc or NaOAc, a tertiary amine such as diisopropylethylamine (DIPEA) or triethylamine, or a combination thereof.

15. 6. The method of claim 5, wherein the additive is present and is an alcohol such as ethylene glycol.

16. 11. The method of claim 5, 9 or 10, wherein the boronization step is characterized by at least one of the following: i) the catalyst is a catalyst precursor, which is Pd-XPhos-2G in an amount of 0.05 mol% to 0.5 mol% relative to the mole number of X6b; ii) the ligand is XPhos in an amount of 0.1 mol% to 1 mol% compared to the number of moles of X6b; iii) the catalyst is Pd-XPhos-2G, the ligand is XPhos, and the number of moles of XPhos is twice the number of moles of Pd-XPhos-2G; iv) the boronating agent is a bisboronic acid in an amount of 1 to 3 molar equivalents relative to X6b; v) the base is potassium acetate in an amount of 2 to 5 molar equivalents relative to X6b; vi) the additive is ethylene glycol in an amount of 2 to 5 molar equivalents relative to X6b; and vii) The temperature of the reaction is between 30°C and 70°C.

17. 17. The method of claim 16, wherein the reaction is as follows: 【Chemistry 4】

18. The boronation step comprises the steps of: i) the catalyst is Pd-cataCXium-3G in an amount of 0.001 mol% to 0.5 mol% relative to the mole number of X6b; ii) the ligand is cataCXium in an amount of 0.02 mol% to 1% relative to the number of moles of X6b; iii) the catalyst is Pd-cataCXium-3G, the ligand is cataCXium, and the number of moles of cataCXium is twice the number of moles of Pd-cataCXium-3-3G; iv) the boronating agent is a bisboronic acid in an amount of 1 to 3 molar equivalents relative to X6b; v) the base is N,N-diisopropylethylamine in an amount of 2 to 5 molar equivalents relative to X6b; vi) the additive is in an amount of 2 to 5 molar equivalents relative to X6b; and / or vii) The reaction temperature is between 30°C and 70°C The method of claim 5, characterized by at least one of the following:

19. 19. The method of claim 18, wherein the reaction is as follows: 【Transformation 5】

20. The boronation step comprises the steps of: i. The catalyst is Pd(MeCN) in an amount of 0.1 mol% to 2 mol% relative to the moles of X6b. ２ Cl ２ is; ii. The ligand is tBuPPh in an amount of 0.2 mol% to 4% relative to the mole number of X6b. ２ is; iii. The catalyst is Pd(MeCN) ２ Cl ２ and the ligand is tBuPPh ２ and tBuPPh ２ The number of moles of Pd(MeCN) ２ Cl ２ is two or three times the number of moles of iv. the boronating agent is bis(pinacolato)diboron in an amount of 1 to 2 molar equivalents relative to X6b; v. The base is KOAc in an amount of 2 to 5 molar equivalents relative to X6b; vi. The reaction temperature is 30°C to 120°C The method of claim 5 characterized by at least one of the following:

21. 21. The method of claim 20, wherein the reaction is as follows: 【Transformation 6】

22. 5. The method of claim 4, wherein X6a and F6 are converted to F7 via a Suzuki coupling, wherein the Suzuki coupling is carried out using one or more catalysts, one or more ligands and / or one or more bases and optionally one or more additives.

23. 23. The method of claim 22, wherein the catalyst is a metal catalyst containing palladium, nickel, or copper, or a combination thereof.

24. 23. The method of claim 22, wherein the ligand is selected from the group consisting of organophosphines, N-heterocyclic carbenes, diazabutadienes, dibenzylidene acetone, and combinations thereof.

25. The ligands are XPhos, APhos, CPhos, RuPhos, SPhos, Sphos-SO3Na, cataCXium, DavePhos, JohnPhos, MePhos, XantPhos, t-BuPPh ２ , PPh ３ and combinations thereof.

26. the metal catalyst and ligand are complexed with a phosphine ligand selected from XPhos, APhos, CPhos, RuPhos, SPhos, cataCXium, or a combination thereof; 【Transformation 7】 24. The method of claim 23, wherein the catalyst precursors are provided together as a complex of catalyst precursors that are Buchwald catalyst precursors selected from:

27. The metal catalyst is a catalyst precursor Pd(MeCN) ２ Ph ２ The ligand t-BuPPh ２ 24. The method of claim 23, provided together with

28. 23. The method of claim 22, wherein the coupling is carried out in an alcoholic solvent, an ethereal solvent, an aqueous solvent, or a mixture thereof.

29. The coupling may be: i. the catalyst or catalyst precursor is present in an amount of 0.1 mol % to 5 mol % relative to the number of moles of F6 or X6a; ii. The number of moles of ligand, when present, is two or three times the number of moles of catalyst or catalyst precursor; iii. The molar ratio of F6:X6a is from 2:1 to 1:2, i.e., from 1.5:1 to 1:1.5, from 1.2:1 to 1:1.2, or 1:1; iv. the additive is optional and, if present, is in an amount of 2 to 5 molar equivalents relative to F6 or X6a; and / or v. The base is present in an amount of 2 to 5 molar equivalents relative to the number of moles of F6 or X6a.

23. The method of claim 22, characterized by at least one of the following:

30. The coupling may be: i. The catalyst and ligand are provided as a catalyst precursor-ligand complex, which is Pd and X-Phos-2G in an amount of 0.5 mol% to 2 mol% relative to the number of moles of F6 or X6a; ii. The base is triethylamine in an amount of 2 to 5 molar equivalents relative to F6 or X6a; iii. The additive is ethylene glycol in an amount of 2 to 5 molar equivalents relative to F6 or X6a; iv. the reaction is carried out in an alcohol solvent; and / or v. The reaction temperature is 30°C to 70°C.

23. The method of claim 22, characterized by one or more of:

31. 31. The method of claim 30, wherein the reaction is: 【Transformation 8】

32. The coupling may be: i) the catalyst is Pd(MeCN) in an amount of 0.25 mol% to 2 mol% relative to the number of moles of X6b ２ Cl ２ is; ii) the ligand is tBuPPh in an amount of 0.5 mol % to 4% relative to the number of moles of X6b; ２ is; iii) the base is KOH in an amount of 2 to 5 molar equivalents relative to X6b; iv) the reaction is carried out in a mixture of MeTHF and water; and v) The reaction temperature is between 30°C and 70°C.

23. The method of claim 22, characterized by at least one of the following:

33. 33. The method of claim 32, wherein the reaction is: 【Chemistry 9】

34. 23. The method of claim 3 in combination with the method of claim 22, wherein the boronation and coupling are carried out in a one-pot synthesis.

35. 33. The method of claim 32, wherein the boronation to form X6a and coupling to form F7 are carried out in a one-pot synthesis.

36. 36. The method of claim 35, wherein the reaction is: 【Chemistry 10】

37. 2. The method of claim 1, wherein the reaction is carried out in a polar organic solvent, for example an ether solvent such as methyl THF or an alcohol solvent such as propanol, ethanol or methanol.

38. Synthetic intermediate X6b: 【Chemistry 11】 wherein X is Cl, Br or I; reacting compound X6d with compound N6a: 【Chemistry 12】 wherein X is Cl, Br or I.

39. Conversion of compound X6d to compound X6c: 【Chemistry 13】 R １０ is an activated carboxylic acid group, such as an acyl anhydride, acyl halide, or acyl phosphate; and 39. The method of claim 38, comprising reacting compound X6c with compound N6a to form compound X6b.

40. 40. The method of claim 39, wherein the conversion of X6d to X6c is carried out in an aromatic solvent such as toluene.

41. The coupling of X6d and N6a can be carried out using activating reagents such as HBT, HATU, HBTU, TBTU, HOBt, PyAOP, SOCl ２ , HCTU, PyClocK, TFFH, a carbodiimide, carbonyldiimidazole (CDI), or a phosphonium salt.

42. 39. The method of claim 38, wherein the reaction of X6d and N6a comprises a base.

43. 39. The method of claim 38, wherein the formation of X6b is carried out in a mixture of solvents such as toluene and isopropyl acetate.

44. 39. The method of claim 38, comprising preparing X6d from X6e. 【Chemistry 14】

45. 45. The method of claim 44, wherein X6d is prepared by contacting X6e with a base, such as sodium hydroxide.

46. preparing X6e from X6f: 【Chemistry 15】 45. The method of claim 44, wherein X is Cl, Br, or I.

47. X6e under coupling conditions: 【Chemistry 16】 (X is Cl, Br or I, m is 2 or 3 and R is F, Cl, Br or I, OH, OC １ ~C ６ Alkyl, N(C １ ~C ６ alkyl) ２ 47. The method of claim 46, wherein two or three R groups are aryl or other than F, Cl, Br, I, or OH, and together can form a cyclic boronic ester, e.g., pinacol boronic acid or N-methyliminodiacetic acid (MIDA) boronate, by contacting X6f with X6g.

48. preparing X6f from X6h: 【Chemistry 17】 47. The method of claim 46, wherein X is Cl, Br, or I.

49. 49. The method of claim 48, wherein X6f is prepared by diazotization of X6h with nitrous acid or sodium nitrite under acidic conditions, followed by cyanation of the diazonium compound using CuCN and / or NaCN.

50. 49. The method of claim 48, comprising preparing X6h from X6i. [Chemistry 18]

51. X6h is a halogenating agent for X6i, such as AlCl ３ or a chlorinating agent such as N-chlorosuccinimide, N-bromosuccinate, N-bromosuccinimide, DBDMH, TBAB, phosphorus tribromide, bromine chloride, aluminum tribromide, Br ２ and FeBr ３ , HBr, tribromoisocyanuric acid, ozone with a brominating agent selected from the group consisting of ammonium bromide, N,N,N',N'-tetrabromobenzene-1,3-disulfonamide (TBBDA), and combinations thereof, or an iodinating reagent such as N-iodosuccinimide.

52. Preparing N6a from N6b: 【Chemistry 19】 39. The method of claim 38, wherein X is Cl, Br, or I.

53. N6a is a reducing agent, for example: ２ and Pt(V) / C; Raney nickel catalyst and H ２ Urushihara nickel catalyst and H ２ Adams catalyst (PtO ２ ) and H ２ ; TiCl ３ and H ２ HCl and iron; HCl and SnCl ２ ; samarium and NH ４ Cl; NH ４ Cl and iron; FeCl ３ hydrazine hydrate; sodium hydrosulfite; hydrogen sulfide and a base; hydroiodic acid; 1,3-dimethyl-2-imidazolidinone and sodium triethylsilanethiolate; and combinations thereof.

54. 53. The method of claim 52, comprising preparing N6b prepared from N6c. 【Chemistry 20】

55. N6b is a halogenating agent such as AlCl ３ or a chlorinating agent such as N-chlorosuccinimide, N-bromosuccinate, 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), N-bromosuccinimide, TBAB, phosphorus tribromide, bromine chloride, aluminum tribromide, Br ２ and FeBr ３ 55. The method of claim 54, wherein the compound is prepared by contacting the compound with a brominating agent selected from the group consisting of ozone and ammonium bromide, HBr, tribromoisocyanuric acid, ozone and ammonium bromide, TBBDA, and combinations thereof, or an iodinating reagent such as N-iodosuccinimide.

56. 56. The method of claim 54 or 55, comprising preparing N6c from N6d. 【Chemistry 21】

57. N6c is a nitrating agent, such as: nitric acid and sulfuric acid; nitric acid and acetic anhydride; tetrachloromethane, nitric acid and phosphorus pentoxide; isopentyl nitrate, trifluoromethanesulfonic acid and 1-ethyl-3-methylimidazolium triflate; H-beta zeolite catalyst and N ２ O ５ acetyl nitrate; and combinations thereof.

58. 57. The method of claim 56, comprising preparing N6d from N6e. 【Chemistry 22】

59. 59. The method of claim 58, wherein N6d is prepared by contacting N6e with a diazotizing agent such as nitrous acid or sodium nitrite under acidic conditions, followed by a fluorinating agent such as HF.

60. 10. The method of claim 1, comprising reacting compound F2 with compound F3 to obtain compound F6. 【Chemistry 23】

61. 61. The method of claim 60, wherein the method comprises reacting compound F2 with compound F3 to obtain compound F4, and converting compound F4 to compound F6. 【Chemistry 24】 【Chemistry 25】

62. The reaction of F2 and F3 can be carried out under Mitsunobu reaction conditions, e.g., with PPh ３ 62. The method of claim 61, wherein the method is carried out in the presence of a phosphine compound such as and an azodicarboxylate such as DIAD or DEAD.

63. 63. The method of claim 62, wherein the reaction is carried out in an aromatic solvent such as toluene.

64. 64. The method of claim 63, wherein the reaction is carried out using water and ammonia.

65. 64. The method of claim 63, wherein the reaction is carried out in an alcohol solvent such as iPrOH.

66. 61. The method of claim 60, wherein the method comprises reacting compound F2 with compound F3 to obtain compound F4 and converting compound F4 to compound F6 in a one-pot reaction.

67. 61. The method of claim 60, comprising preparing F2 from F1. 【Chemistry 26】

68. F2 is AlCl ３ 68. The method of claim 67, wherein the solvent is prepared from F1 using a solvent selected from the group consisting of HCl, ...

69. The method of claim 1 , wherein the method is used in the synthesis of compound F11. 【Chemistry 27】

70. 10. The method of claim 1, comprising deprotection of F7 to give F8. 【Chemistry 28】

71. 71. The method of claim 70, wherein P is a Boc group and the deprotection is achieved using an acid, such as HCl.

72. 71. The method of claim 70, comprising converting F8 to F11. 【Chemistry 29】

73. 73. The method of claim 72, wherein F11 is prepared by reacting F8 with acrylic anhydride (F9).

74. Synthetic intermediate X6b: 【Transformation 30】 X is Cl, Br or I.

75. Synthetic intermediate X6b: 【Chemistry 31】 X is Br.

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