Synthetic processes and intermediates for production of ribrutinib

Abstract

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

Description

Technical Field

[0001] The present invention provides a new synthetic route, a new chemical reaction and a new synthetic intermediate which can be used for preparing N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide. Background Art

[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:

[0003]

[0004] Ribrutinib was first disclosed in Example 6 of WO 2015 / 079417 filed on November 28, 2014. WO 2015 / 079417 is incorporated by reference in its entirety. In Example 6(2) of WO 2015 / 079417, ributinib is prepared by cross-coupling "INT 5" with "INT 8" to obtain "INT 9":

[0005]

[0006] INT 9 is then deprotected with TFA (Example 6(3)), reacted with acrylic acid, and purified to give ributinib (Example 6(4)). INT 5 is a key intermediate in this method, constituting half of the structure of the final product ributinib. The preparation of INT 5 is described in Example 1(5) of WO 2015 / 079417: INT 5 is prepared by amide coupling of INT 3 and INT 4:

[0007]

[0008] However, it has been found that INT 3 (5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline) is a compound with mutagenic potential and is therefore an undesirable intermediate in the synthesis of pharmaceutical products. The genotoxicity of INT 3 is reported for the first time in this application.

[0009] Therefore, the object of the present invention is to provide a new synthetic route for Ribrutinib that minimizes contact with genotoxic agents such as INT 3. In addition, the present invention provides improved coupling conditions for the preparation of INT 9 (herein referred to as F7) with higher yields and avoids the need to use undesirable solvents such as DCM (carcinogen), DME (impairs fertility), DMF (impairs fertility), 1,2-dichloromethane (carcinogen). Summary of the invention

[0010] In a first embodiment, the present invention provides a synthesis method comprising converting compound X6b and compound F6 into compound F7:

[0011]

[0012] wherein X and Y are each independently F, Cl, Br, or I, and wherein P is an amine protecting group.

[0013] In a second embodiment, the present invention provides a synthesis method comprising borylation of X6b to obtain X6a:

[0014]

[0015] wherein X is F, Cl, Br, or I, n is 0 or 1, and R is F, Cl, Br, or I, OH, OC1-C6 alkyl, N(C1-C6 alkyl)2, aryl, or wherein two or three R groups other than F, Cl, Br, I, or OH may together form a cyclic boronate, such as pinacol borate, or N-methyliminodiacetic acid (MIDA) borate.

[0016] In a third embodiment, the present invention provides a synthetic intermediate X6b:

[0017]

[0018] wherein X is Cl, Br, or I, preferably Br. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 An overview of a convergent and atom-efficient synthetic route for the preparation of ribuzinib is provided. X6b is a key intermediate in this synthetic route.

[0020] Figure 2 Exemplary reaction conditions for the pathway from F1 to F6 are shown.

[0021] Figure 3 Exemplary reaction conditions for the pathway from N6e to X6b are shown.

[0022] Figure 4 Exemplary reaction conditions for the pathway from X6i to X6b are shown.

[0023] Figure 5 Exemplary reaction conditions for the pathway from X6b to F11 are shown. DETAILED DESCRIPTION

[0024] The present invention can be used to prepare N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (also known as ributinib), which is a highly effective and selective oral Bruton's tyrosine kinase (BTK) inhibitor:

[0025]

[0026] In any embodiment herein, ributinib or any other compound described herein can be provided as a salt. As used herein, the term "salt (salt or salts)" refers to an acid addition salt or a base addition salt of the compounds of the present invention. "Salt" particularly includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compounds of the present invention, and is typically not biologically or otherwise undesirable. In many cases, due to the presence of an amino group and / or a carboxyl group or a group similar thereto, the compounds of the present invention are able to form acid salts and / or base salts. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlortheophyllonate, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactobionate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluenesulfonate 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 bases and organic bases. Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, these salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts, 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. Some organic amines include isopropylamine, benzathine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine and trimethamine. Pharmaceutically acceptable salts of the present invention can be synthesized from base or acid moieties by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg, or K), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid.Typically, such reactions are carried out in water or in an organic solvent or in a mixture of the two. Usually, where feasible, it is desirable to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. The list of other suitable salts can be found in, for example, "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., (1985); and Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection and Use" (Wiley-VCH, Weinheim, Germany, 2002).

[0027] Many organic solvents are suitable for the chemical reactions described herein. For example, the reactions described herein can be carried out in aprotic organic solvents. 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), derivatives of THF, such as methyl-THF; ester compounds, such as ethyl acetate and isopropyl acetate; amines, such as pyridine; polyethylene glycol (PEG); especially PEG with an average molecular weight of about 100 g / mol to about 2000 g / mol, such as PEG200, PEG600, PEG1000 and PEG2000, derivatives thereof, such as mono- or dialkyl PEG, especially mono- or dimethyl PEG, mono- or diethyl PEG and mono- or dipropyl PEG; and polypropylene glycol (PPG). Protic solvents can also be used in the reactions described herein. Protic solvents include: water; alcohols such as C 1-10Aliphatic branched or straight-chain alcohols, particularly C1-C6 alcohols; and carboxylic acids such as formic acid, acetic acid, propionic acid, etc. Preferred solvents include toluene, ethanol, ethyl acetate, isopropyl acetate, methyl-THF, heptane and isopropanol. Preferably, the reaction described herein is carried out in the absence of 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 from 0.1% to 99% (v / v), from 0.1% to 80% (v / v), from 0.1% to 75% (v / v), from 0.1% to 50% (v / v), from 1% to 40% (v / v), from 2% to 30% (v / v), from 4% to 25% (v / v) or from 5% to 20% (v / v).

[0028] Some chemical reactions described herein can be carried out under acidic conditions, for example, at a pH of less than 7, not more than 6, not more than 5, not more than 4, not more than 3, not more than 2, or not more than 1. Acids suitable for the 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; halogenated acids, such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid; organic acids, such as carboxylic acids and derivatives thereof, such as acetic acid, 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 in order to avoid the generation of fluorinated wastes.

[0029] Some chemical reactions described herein can be carried out under alkaline conditions, for example, 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 chemical reactions described herein are known to the skilled person. Commonly used bases include inorganic bases, such as hydroxides of alkali metals and alkaline earth metals, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide. Strong bases can be prepared by adding alkaline earth metals to hydrocarbons, amines, and dihydrogen. Examples include butyl lithium, lithium diisopropylamide (LDA), lithium diethylamide (LDEA), sodium amide, sodium hydride (NaH), and bis(trimethylsilyl) lithium amide. Weaker bases include ammonia and amines, such as trialkylamines, such as triethylamine and diisopropylethylamine, and anions of weak acids, such as acetate (e.g., sodium acetate, potassium acetate), and carbonate (e.g., sodium carbonate, potassium carbonate).

[0030] Reaction as herein described can be carried out to reach the time required for reaction completion or at least to reach acceptable product yield.For example, the duration of 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.Reaction times can especially depend on reaction scale.Technicians can monitor the process of reaction in many different ways, and these ways include by monitoring physical change, such as color change, or by using analytical method monitoring reaction, these analytical methods such as NMR, FT-IR, XRPD or chromatogram, for example thin layer chromatography (TLC) or liquid chromatography and mass spectrometry (LC-MS).

[0031] Upon completion of the reactions described herein, the reaction mixture is optionally purified. Purification techniques are known to the skilled person and include: chromatography (e.g., HPLC, which may be reverse phase or normal phase); liquid-liquid separation, e.g., using a variety of immiscible solvents; and / or liquid-solid separation, e.g., using filtration, decantation, (re)crystallization, grinding, evaporation, freeze drying.

[0032] Reactions as described herein can be carried out on any suitable scale. In one embodiment, the reaction mixture is industrial scale. It can, for example, have a volume of 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. It can, for example, have a volume of 10 ml or less, particularly 1 ml or less, 100 μ l or less, 10 μ l or less, or 1 μ l or less.

[0033] The reaction described herein can be part of a series of reactions including synthesis. When multiple reactions are described, these can be carried out in a sequential manner or in a one-pot manner. Sequential reactions typically include completing a first reaction, subsequently treating and purifying the reaction, and then carrying out a second reaction, continuing to react further until the desired product is obtained. In contrast, in a one-pot manner, the first reaction can be completed, and then the second reaction can be carried out using one or more products of the first reaction without separation. One-pot reactions are advantageous because they avoid unnecessary purification steps, saving time and materials. In the synthesis of Ribrutinib described herein, some or all reactions can be carried out in a one-pot manner, or alternatively some or all reactions can be carried out in a sequential manner.

[0034] In addition to its literal meaning, the expression "comprises" as used herein also includes and specifically refers to the expressions "consisting essentially of" and "consisting of...." Thus, the expression "comprising" refers to embodiments in which the subject matter "comprising" the specifically listed elements may and / or does include additional elements, as well as embodiments in which the subject matter "comprising" the specifically listed elements does not include the additional elements.

[0035] Numerical ranges described herein include numbers that define ranges. The titles provided herein are not limitations on the various aspects or embodiments of the present invention, which can be read with reference to the entire specification. According to one embodiment, the subject matter described herein as comprising certain steps in the case of a method or as comprising certain components in the case of a composition refers to the subject matter consisting of the corresponding steps or components. It is preferred to select and combine specific aspects and embodiments described herein, and the specific subject matter produced by the corresponding combination of specific embodiments also belongs to the present disclosure.

[0036] The present invention provides a new synthetic route for Ribrutinib that avoids the formation of the genotoxic intermediate INT 3. The key to avoiding INT 3 is to prepare the aryl halide X6b, which does not contain borate, and can therefore be synthesized via N6a instead of INT 3, as stated below. In addition, the claimed method minimizes the purification step, improves the overall yield and provides a more efficient method. The method can also be efficiently carried out in a green solvent.

[0037] Preparation of F7

[0038] The present invention provides a synthesis method, which comprises converting compound X6b and compound F6 into compound F7:

[0039]

[0040] wherein X and Y are each independently Cl, Br, or I, and wherein P is an amine protecting group.

[0041] 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 X and Y groups present on synthetic precursors of X6b and F6, respectively.

[0042] The protecting group P can be any suitable amine protecting group that is stable during any chemical transformation described herein (except the deprotection step). The amine protecting group can be removed by specific 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), tert-butyl carbamate (Boc), or benzyl carbamate (Cbz); acetamide protecting groups, such as acetamide, trifluoroacetamide, or benzylamide; and sulfonamide protecting groups, such as p-toluenesulfonamide.

[0043] X6b and F6 can be converted to F7 according to coupling conditions suitable for forming carbon-carbon bonds. For example, the coupling of X6b and F6 can be achieved using an organometallic cross-coupling reaction, in which the two fragments are linked together with the aid of a metal catalyst. Cross-coupling conditions that can be used in the coupling of X6b and F6 include: Kumada coupling; Negishi coupling; Stiller coupling; Suzuki-Miyaura coupling, and Hiyama coupling. In a typical cross-coupling reaction, an RM-type compound (R = first organic fragment, M = metal or main group compound) is reacted with an R'-X-type organic halide (R' = second organic fragment, X = halide) to form a new carbon-carbon bond in the product R-R'.

[0044] Thus, in some embodiments, the preparation of F7 comprises converting F6 into a precursor F6' by replacing Y with "M" (a metal-containing moiety or a main group element-containing moiety), for example, where M contains Zn (Negishi), B (Suzuki-Miyaura), Mg (Kumada), Sn (Stiller), or Si (Hiyama):

[0045]

[0046] wherein P is an amine protecting group, such as Boc.

[0047] F6' can be reacted with X6b under cross-coupling conditions to obtain F7. In some embodiments, the conversion of F6 to F6' and the cross-coupling of F6' and X6b are performed in a one-pot reaction. In some embodiments, the conversion of F6 to F6' and the cross-coupling of F6' and X6b are performed in a sequential reaction.

[0048] Alternatively, the preparation of F7 involves converting X6b to a precursor compound X6b' by replacing X with "M" (a metal-containing moiety or a main group element-containing moiety), for example, where M contains Zn (Negishi), B (Suzuki-Miyaura), Mg (Kumada), Sn (Stiller), or Si (Hiyama):

[0049]

[0050] Precursor compound X6b' can be reacted with F6 under cross-coupling conditions to obtain F7. In some embodiments, the conversion of X6b to X6b' and the cross-coupling of X6b' and F6 are performed in a one-pot reaction. In some embodiments, the conversion of X6b to X6b' and the cross-coupling of X6b' and F6 are performed in a sequential reaction.

[0051] Preparation of X6a-Borylation Reaction

[0052] The present invention provides a synthesis method, which comprises borylating X6b to obtain X6a:

[0053]

[0054] wherein X is F, Cl, Br, or I; n is 0 or 1, and R is F, Cl, Br, or I, OH, OC1-C6 alkyl, N(C1-C6 alkyl)2, aryl, or wherein two or three R groups other than F, Cl, Br, I, or OH may together form a cyclic boronate, such as pinacol borate, or N-methyliminodiacetic acid (MIDA) borate.

[0055] The borylation of X6b can be achieved using one or more catalysts, one or more ligands, one or more borylation agents, one or more bases, and / or one or more additives. In some embodiments, the borylation comprises one or more catalysts, one or more ligands, one or more borylation agents, and one or more bases. In some embodiments, the borylation further comprises one or more additives.

[0056] Borylating agent is a boron-containing compound, which is usually capable of converting an organic halide compound into a boric acid or a boric ester under metal-catalyzed cross-coupling conditions. In some embodiments, the boronylating agent is selected from the group consisting of a diboryl compound, boric acid, borane, a trihalide boron, and a boric ester. In some embodiments, the boronylating agent is selected from the group consisting of: bis(pinacol)diboron, B2(NMe2)4, B2F4, B2Cl4, B2Br4, B2l4, diboric acid, pinacol borane, HB(NMe2)2, B(OH)3, BF3, BCl3, BBr3, BI3, mono-, di- or tri-C1-C6 alkyl borate, mono-, di- or tri-methyl borate, mono-, di- or tri-ethyl borate, and mono-, di- or tri-propyl borate, preferably bis(pinacol)diboron or diboric acid. Compared with pinacol borane or bis(pinacol)diboron, the use of bisboronic acid may be attractive because it can allow lower catalyst loadings, milder reaction conditions, and avoid the formation of pinacol-related impurities. It also allows the use of green solvents (such as alcohol solvents) and milder reaction conditions (e.g., lower temperatures).

[0057] The metal catalyst used in the borylation reaction may contain palladium, nickel, or copper, or a combination thereof, preferably palladium.

[0058] In certain embodiments, the metal catalyst is provided as a precatalyst complex, such as Buchwald G1, G2, G3 or G4 precatalysts complexed with a phosphine ligand. Buchwald precatalysts are used to generate active Pd (0) in situ via rapid deprotonation and reduction elimination. Precatalysts are useful because they allow low catalytic loading and are stable to air, moisture and heat, with good solubility. These precatalysts have been optimized to further enhance the functionality and solubility from 1 generation to 4 generations (G1 to G4). These precatalysts are composed of cyclopalladium complexes (shown below) with a phenyl or 1,1-biphenyl backbone, wherein L represents a bound phosphine ligand, such as XPhos, SPhos, etc. (see below), and wherein the bound amine substituents and leaving groups (Cl, OMs) vary based on generation (Generation).

[0059] Examples of Buchwald precatalysts complexed with palladium and with exemplary XPhos ligands are shown below:

[0060]

[0061] Any of the other phosphine ligands described herein may be used in place of XPhos as L in the table above.

[0062] Other precatalysts for borylation may include Pd(TFA)2, PdBr2 or Pd(MeCN)2Cl2. Such precatalysts may be used in the presence of ligands such as Ph2P(t-Bu); Cy3P-HBF4; RuPHOS; S-PHOS, Cy-BIPHEP; SPHOS-SO3Na.

[0063] In some embodiments, the borylation of X6b includes an additional ligand in addition to the ligand L that forms part of the pre-catalyst complex. In other embodiments, no additional ligand is required. In some embodiments, the borylation of X6b uses a catalyst and a ligand without using a pre-catalyst (Pd(0) catalyst; e.g., Pd(PPh3)4).

[0064] Extensive ligands can be used for borylation reaction, and ligands can affect the reactivity of reagents.For example, ligands can increase the electron density at the metal center of metal complex, which can improve the oxidation addition step.In addition, bulky ligands help to reduce the elimination step.In certain embodiments, the ligand used in the borylation of X6b is selected from the group consisting of organophosphine, N-heterocyclic carbene, diazabutadiene, dibenzylideneacetone and combinations thereof.

[0065] In a preferred embodiment, the ligand is an organophosphine ligand, such as 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. The phosphine ligands are depicted in the following table:

[0066]

[0067]

[0068]

[0069] The borylation of X6b may include a base. In some embodiments, the base is an organic or inorganic salt such as NaOH, Ca(OH)2, Na2CO3, K2CO3, K3PO4, Cs2CO3, 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.

[0070] The borylation of X6b may include an additive, for example an alcohol such as ethylene glycol. In some embodiments, the borylation of X6b does not include an additive.

[0071] The borylation of X6b can be carried out in any suitable solvent. Examples of suitable organic solvents include polar solvents, non-polar solvents, protic solvents, aprotic solvents, polar protic solvents and polar aprotic solvents. In one embodiment, the borylation can be carried out in alcoholic solvents, and these alcoholic solvents include tert-amyl alcohol, hexanol, amyl alcohol, butanols (tert-butyl alcohol, isobutyl alcohol and n-butyl alcohol), propanol (isopropyl alcohol and n-propyl alcohol), ethanol and / or methanol. Preferably, the borylation is carried out in methanol, toluene and / or MeTHF, most preferably in MeTHF. Other solvents can also be used, for example halogenated alkane solvents, such as dichloromethane. Ether-based solvents can also be used, such as dioxane, MeTHF, THF, and dialkyl ethers, such as diethyl ether. The borylation can also be carried out in an aqueous environment including a micellar environment. In certain embodiments, a mixture of solvents is used.

[0072] The borylation of X6b can be achieved using one or more catalysts, one or more ligands, one or more borylation agents, one or more bases, and / or optionally one or more additives. The skilled person can determine the appropriate amounts of these reagents. However, in some embodiments of the borylation reaction:

[0073] i) the catalyst or precatalyst 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 mol% to 1 mol%, preferably 0.25 mol% and more preferably 0.5 mol% relative to the moles of X6b;

[0074] ii) the amount of the ligand is 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 moles of X6b;

[0075] iii) the molar number of the ligand is twice or three times the molar number of the catalyst or precatalyst; preferably twice;

[0076] iv) the borylation agent is present in an amount of 1 to 3 molar equivalents, preferably 1 to 2 molar equivalents, more preferably 1.05 or 1.5 molar equivalents, relative to X6b;

[0077] v) the amount of the base is 2 to 5 molar equivalents, preferably 2 to 3 molar equivalents, most preferably 2.5 or 3 molar equivalents relative to the moles of X6b; and / or

[0078] vi) Additives are optional and, when present, are present in an amount of 2 to 5 molar equivalents compared to X6b; preferably, no additives are present.

[0079] The borylation reaction may be characterized by any one of i) to vi) above. The borylation reaction may be characterized by any two of i) to vi) above. The borylation reaction may be characterized by any three of i) to vi) above. The borylation reaction may be characterized by any four of i) to vi) above. The borylation reaction may be characterized by any five of i) to vi) above. The borylation reaction may be characterized by all of i) to vi).

[0080] The borylation reaction may be characterized by i) and ii) above. The borylation reaction may be characterized by i) and iii) above. The borylation reaction may be characterized by i) and iv) above. The borylation reaction may be characterized by i) and v) above. The borylation reaction may be characterized by i) and vi) above. The borylation reaction may be characterized by ii) and iii) above. The borylation reaction may be characterized by ii) and iv) above. The borylation reaction may be characterized by ii) and v) above. The borylation reaction may be characterized by ii) and vi) above. The borylation reaction may be characterized by iii) and iv) above. The borylation reaction may be characterized by iii) and v) above. The borylation reaction may be characterized by iii) and vi) above. The borylation reaction may be characterized by iv) and v) above. The borylation reaction may be characterized by iv) and vi) above.

[0081] In one example, a borylation reaction with excellent yield and minimal byproducts can be:

[0082]

[0083] In one embodiment, the borylation reaction with excellent yield and minimal by-product formation is characterized by at least one of the following:

[0084] i) the catalyst is Pd(MeCN)2Cl2, in an amount of 0.1 mol% to 2 mol% relative to the moles of X6b, or 0.1 mol% to 1.5 mol%, preferably 0.25 mol% or more preferably 0.5 mol% relative to the moles of X6b;

[0085] ii) the ligand is tBuPPh2, and its amount is 0.2 mol% to 4 mol% relative to the molar number of X6b, and is 0.2 mol% to 3 mol% relative to the molar number of X6b, preferably 0.5 mol% or more preferably 1 mol%;

[0086] iii) the catalyst is Pd(MeCN)2Cl2, the ligand is tBuPPh2, and the molar number of tBuPPh2 is two or three times the molar number of Pd(MeCN)2Cl2, preferably two times the molar number of Pd(MeCN)2Cl2;

[0087] iv) the borylation agent is bis(pinacol)diboron, and its amount is 1 to 2 molar equivalents relative to X6b, preferably about 1.05 molar equivalents relative to X6b;

[0088] v) the base is KOAc in an amount of 2 to 5 molar equivalents relative to X6b, preferably 2.5 equivalents relative to X6b; and

[0089] vi) the absence of additives; and / or

[0090] vii) The reaction temperature is 30°C to 120°C, such as 40°C to 50°C, preferably 60°C or 70°C.

[0091] The borylation reaction may be characterized by any one of i) to vii) above. The borylation reaction may be characterized by any two of i) to vi) above. The borylation reaction may be characterized by any three of i) to vii) above. The borylation reaction may be characterized by any four of i) to vii) above. The borylation reaction may be characterized by any five of i) to vii) above. The borylation reaction may be characterized by any six of i) to vii) above. The borylation reaction may be characterized by all of i) to vii) above.

[0092] The borylation reaction may be characterized by i) and ii) above. The borylation reaction may be characterized by i) and iii) above. The borylation reaction may be characterized by i) and iv) above. The borylation reaction may be characterized by i) and v) above. The borylation reaction may be characterized by i) and vi) above. The borylation reaction may be characterized by i) and vii) above. The borylation reaction may be characterized by ii) and iii) above. The borylation reaction may be characterized by ii) and iv) above. The borylation reaction may be characterized by ii) and v) above. The borylation reaction may be characterized by ii) and vii) above. The borylation reaction may be characterized by iii) and iv) above. The borylation reaction may be characterized by iii) and v) above. The borylation reaction may be characterized by iii) and vi) above. The borylation reaction may be characterized by iii) and vii) above. The borylation reaction may be characterized by iv) and v) above. The borylation reaction may be characterized by iv) and vi) above. The borylation reaction may be characterized by iv) and vii) above. The borylation reaction may be characterized by v) and vi) above. The borylation reaction may be characterized by v) and vii) above. The borylation reaction may be characterized by vi) and vi) above.

[0093] In one embodiment, the borylation reaction with good yield and minimal by-product formation is characterized by at least one of the following:

[0094] i) the catalyst is a precatalyst, which is Pd-XPhos-2G, and its amount is 0.05 mol% to 0.5 mol% relative to the molar number of X6b, preferably 0.25 mol% relative to the molar number of X6b;

[0095] ii) the ligand is XPhos, and its amount is 0.1 mol% to 1 mol% relative to the molar number of X6b; preferably 0.5 mol% relative to the molar number of X6b;

[0096] iii) the catalyst is Pd-XPhos-2G, the ligand is XPhos, and the molar number of XPhos is twice the molar number of Pd-XPhos-2G;

[0097] iv) the borylation agent is bisboronic acid, and its amount is 1 to 3 molar equivalents compared to X6b, preferably 1.5 molar equivalents compared to X6b;

[0098] v) the base is potassium acetate, and its amount is 2 to 5 molar equivalents, preferably 3 molar equivalents relative to X6b;

[0099] 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

[0100] vii) The reaction temperature is 30°C to 70°C, preferably 40°C to 50°C, more preferably 50°C.

[0101] The borylation reaction may be characterized by any one of i) to vii) above. The borylation reaction may be characterized by any two of i) to vi) above. The borylation reaction may be characterized by any three of i) to vii) above. The borylation reaction may be characterized by any four of i) to vii) above. The borylation reaction may be characterized by any five of i) to vii) above. The borylation reaction may be characterized by any six of i) to vii) above. The borylation reaction may be characterized by all of i) to vii) above.

[0102] The borylation reaction may be characterized by i) and ii) above. The borylation reaction may be characterized by i) and iii) above. The borylation reaction may be characterized by i) and iv) above. The borylation reaction may be characterized by i) and v) above. The borylation reaction may be characterized by i) and vi) above. The borylation reaction may be characterized by i) and vii) above. The borylation reaction may be characterized by ii) and iii) above. The borylation reaction may be characterized by ii) and iv) above. The borylation reaction may be characterized by ii) and v) above. The borylation reaction may be characterized by ii) and vii) above. The borylation reaction may be characterized by iii) and iv) above. The borylation reaction may be characterized by iii) and v) above. The borylation reaction may be characterized by iii) and vi) above. The borylation reaction may be characterized by iii) and vii) above. The borylation reaction may be characterized by iv) and v) above. The borylation reaction may be characterized by iv) and vi) above. The borylation reaction may be characterized by iv) and vii) above. The borylation reaction may be characterized by v) and vi) above. The borylation reaction may be characterized by v) and vii) above. The borylation reaction may be characterized by vi) and vii) above.

[0103] In another example, the borylation reaction can be:

[0104]

[0105] In one embodiment, the borylation reaction with good yield and minimal by-product formation is characterized by at least one of the following:

[0106] i) the catalyst is Pd-cataCXium-3G, and its amount is 0.001 mol% to 0.5 mol% relative to the molar number of X6b, preferably 0.05 mol% relative to the molar number of X6b;

[0107] ii) the ligand is cataCXium, and its amount is 0.02 mol% to 1 mol% relative to the molar number of X6b, preferably 0.1 mol% relative to the molar number of X6b;

[0108] iii) the catalyst is Pd-cataCXium-3G, the ligand is cataCXium, and the molar number of cataCXium is twice the molar number of Pd-cataCXium-3-3G;

[0109] iv) the boronating agent is diboric acid, and its amount is 1 to 3 molar equivalents relative to X6b, preferably 1.5 molar equivalents relative to X6b;

[0110] v) the base is N,N-diisopropylethylamine in an amount of 2 to 5 molar equivalents relative to X6b, preferably an equivalent relative to X6b; and

[0111] vi) the absence of additives; and / or

[0112] vii) The reaction temperature is 30°C to 70°C, preferably 40°C to 50°C, more preferably 50°C.

[0113] The borylation reaction may be characterized by any one of i) to vii) above. The borylation reaction may be characterized by any two of i) to vi) above. The borylation reaction may be characterized by any three of i) to vii) above. The borylation reaction may be characterized by any four of i) to vii) above. The borylation reaction may be characterized by any five of i) to vii) above. The borylation reaction may be characterized by any six of i) to vii) above. The borylation reaction may be characterized by all of i) to vii) above.

[0114] The borylation reaction may be characterized by i) and ii) above. The borylation reaction may be characterized by i) and iii) above. The borylation reaction may be characterized by i) and iv) above. The borylation reaction may be characterized by i) and v) above. The borylation reaction may be characterized by i) and vi) above. The borylation reaction may be characterized by i) and vii) above. The borylation reaction may be characterized by ii) and iii) above. The borylation reaction may be characterized by ii) and iv) above. The borylation reaction may be characterized by ii) and v) above. The borylation reaction may be characterized by ii) and vii) above. The borylation reaction may be characterized by iii) and iv) above. The borylation reaction may be characterized by iii) and v) above. The borylation reaction may be characterized by iii) and vi) above. The borylation reaction may be characterized by iii) and vii) above. The borylation reaction may be characterized by iv) and v) above. The borylation reaction may be characterized by iv) and vi) above. The borylation reaction may be characterized by iv) and vii) above. The borylation reaction may be characterized by v) and vi) above. The borylation reaction may be characterized by v) and vii) above. The borylation reaction may be characterized by vi) and vii) above.

[0115] For example, the reaction could be:

[0116]

[0117] Coupling of X6a and F6

[0118] In some embodiments of the present invention, the borylation of X6b is used in the method for synthesizing compound F7 to obtain X6a. In such an embodiment, X6b is converted into X6a, and then X6a and F6 are reacted under cross-coupling conditions to produce F7. In a preferred embodiment, the conversion of X6b to X6a and the cross-coupling of X6a and F6 are carried out in a one-pot reaction. In certain embodiments, the conversion of X6b to X6a and the cross-coupling of X6a and F6 are carried out in a sequential reaction.

[0119] According to the present invention, borylated compound X6a can be made to react with aryl halide with cross coupling reaction. In one embodiment, the coupled reaction is carried out using one or more catalysts, one or more parts, one or more bases, and / or one or more additives. In one embodiment, the coupled reaction is carried out using one or more catalysts, one or more parts and one or more bases. In certain embodiments, coupling includes one or more additives in addition.

[0120] The metal catalyst used in the cross-coupling reaction may contain palladium, nickel, or copper, or a combination thereof, preferably palladium.

[0121] Extensive ligands can be used for the cross-coupling reaction of X6a and F6, and ligands can affect the reactivity of coupling reagents.For example, ligands can increase the electron density at the metal center of metal complex, which can improve the oxidation addition step.In addition, bulky ligands contribute to the reduction elimination step.In certain embodiments, the ligand used in the coupling of X6a and F6 is selected from the group consisting of organophosphine, N-heterocyclic carbene, diazabutadiene, dibenzalacetone and combinations thereof.In a preferred embodiment, the ligand is an organophosphine ligand, such as 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, most preferably tBuPPh2.

[0122] In the coupling of X6a and F6, the metal catalyst and the ligand can be provided as a pre-catalyst complex, such as a Buchwald G1, G2, G3, or G4 pre-catalyst complexed with a phosphine ligand, such as an organophosphine ligand, preferably G2, the organophosphine being 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, and most preferably tBuPPh2.

[0123] In some embodiments, a precatalyst containing a phosphine ligand is used, and no additional phosphine ligand is used. Alternatively, a precatalyst containing a phosphine ligand is used, and additional phosphine ligands are also used. Examples of precatalysts for cross-coupling reactions may include Pd(TFA)2, PdBr2, or Pd(MeCN)2Cl2. These precatalysts may be used in the presence of ligands such as Ph2P(t-Bu); Cy3P-HBF4; RuPHOS; S-PHOS, Cy-BIPHEP; SPHOS-SO3Na.

[0124] The coupling of X6a and F6 can include a base. In certain embodiments, the base is an organic or inorganic salt, such as KOH, NaOH, Ca (OH) 2, Na2CO3, K2CO3, K3PO4, Cs2CO3, 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.

[0125] The coupling of X6a and F6 may optionally include an additive, for example an alcohol such as ethylene glycol, for example when the PdXPhos-2G / XPhos complex is used.

[0126] The coupling of X6a and F6 can be carried out in any suitable solvent. The example of suitable organic solvent includes polar solvent, non-polar solvent, protic solvent, aprotic solvent, polar protic solvent and polar aprotic solvent. In a preferred embodiment, the cross-coupling reaction can be carried out in an alcohol solvent, and these alcohol solvents include tert-amyl alcohol, hexanol, amyl alcohol, butanol (tert-butyl alcohol, isobutyl alcohol and n-butyl alcohol), propanol (isopropyl alcohol and n-propyl alcohol), ethanol and / or methanol. Other solvents can also be used, for example halogenated alkane solvents, such as dichloromethane. Ether solvents can also be used, such as dioxane, MeTHF, THF, and dialkyl ethers, such as diethyl ether. Coupling can also be carried out in an aqueous environment including a micellar environment. In certain embodiments, a mixture of solvents, such as MeTHF and water, is used. When methanol is used, the reaction mixture can be precipitated, simplifying purification.

[0127] The coupling of X6a and F6 can be achieved using one or more catalysts, one or more ligands, one or more borylation agents, one or more bases, and / or one or more additives. The skilled person can use their common knowledge to determine the appropriate amounts of these reagents.

[0128] In one embodiment, the coupling reaction with excellent yield and minimal by-product formation is characterized by at least one of the following:

[0129] i) the catalyst or precatalyst 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 moles of F6 or X6a;

[0130] ii) the molar amount of the ligand, if present, is two or three times, preferably two times, the molar amount of the catalyst or precatalyst;

[0131] iii) the molar ratio of F6:X6a is from 2:1 to 1:2, or from 1.5:1 to 1:1.5, 1.2:1 to 1:1.2 or 1:1;

[0132] iv) said additive is optional and, when present, is present in an amount of 2 to 5 molar equivalents relative to F6 or X6a; and / or

[0133] v) The base is present in an amount of 2 to 5 molar equivalents, preferably 2 to 3 molar equivalents, and most preferably 3 molar equivalents, relative to the molar number of F6 or X6a.

[0134] 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). The coupling reaction may be characterized by any three of i) to v). The coupling reaction may be characterized by any four of i) to v). The coupling reaction may be characterized by all of i) to v).

[0135] 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.

[0136] In one embodiment, the coupling reaction with good yield and minimal by-product formation is characterized by at least one of the following:

[0137] i) the catalyst and ligand are provided as a pre-catalyst-ligand complex, the complex being Pd and X-Phos-2G in an amount of 0.5 mol% to 2 mol% relative to the moles of F6 or X6a;

[0138] ii) the base is triethylamine, and its amount is 2 to 5 molar equivalents, preferably 3 molar equivalents relative to F6 or X6a;

[0139] iii) the additive is ethylene glycol, and its amount is 2 to 5 molar equivalents, preferably 3 molar equivalents relative to F6 or X6a;

[0140] iv) the reaction is carried out in an alcohol solvent, preferably methanol; and

[0141] v) The reaction temperature is 30°C to 70°C, preferably 40°C to 50°C, more preferably 50°C.

[0142] 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). The coupling reaction may be characterized by any three of i) to v). The coupling reaction may be characterized by any four of i) to v). The coupling reaction may be characterized by all of i) to v).

[0143] 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.

[0144] In preferred embodiments, the coupling reaction with excellent yield and minimal by-product formation is characterized by at least one of the following:

[0145] i) the catalyst is Pd(MeCN)2Cl2, the amount of which is 0.25mol% to 2mol% relative to the molar number of X6b, and 0.25mol% to 1.5mol%, preferably 0.5mol% or more preferably 1mol% relative to the molar number of X6b; (the conversion rate of X6b to X6a is about 98%)

[0146] ii) the ligand is tBuPPh2, and its amount is 0.5 mol% to 4 mol% relative to the molar number of X6b, preferably 1 mol% or 2 mol% relative to the molar number of X6b; in particular, the catalyst is Pd(MeCN)2Cl2, the ligand is tBuPPh2, and the molar number of tBuPPh2 is twice the molar number of Pd(MeCN)2Cl2;

[0147] iii) the base is KOH, and its amount is 2 to 5 molar equivalents, preferably 3 molar equivalents relative to X6b;

[0148] iv) the reaction is carried out in a mixture of MeTHF and water; and

[0149] v) The reaction temperature is 30°C to 70°C, preferably 60°C.

[0150] 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). The coupling reaction may be characterized by any three of i) to v). The coupling reaction may be characterized by any four of i) to v). The coupling reaction may be characterized by all of i) to v).

[0151] 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.

[0152] In a preferred embodiment, the borylation of X6b to X6a and the cross-coupling of X6a with F6 are performed in a one-pot reaction.

[0153] Preparation of X6b

[0154] X6b is a key intermediate in the novel synthesis described herein. Therefore, the present invention provides a synthetic intermediate, X6b:

[0155]

[0156] wherein X is F, Cl, Br, or I. Preferably, X is Br.

[0157] X6b itself can be synthesized in any suitable manner. The present invention provides a method for preparing the synthetic intermediate X6b:

[0158]

[0159] wherein X is F, Cl, Br, or I, preferably Br.

[0160] In some embodiments, the method comprises reacting compound X6d with compound N6a

[0161]

[0162] wherein X is Cl, Br, or I, preferably Br.

[0163] 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 the carboxylic acid group to an activated group that can more readily react with an amine.

[0164] Thus, in one embodiment, the synthesis of X6b includes converting the carboxylic acid group of X6d into an activated carboxylic acid group using. For example, the method may include converting compound X6d into compound X6c:

[0165]

[0166] Where R 10 is an activated carboxylic acid group, such as an acyl anhydride, an acyl halide, or an acyl phosphate, and wherein 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 performed in a one-pot synthesis or sequentially. The formation of N6a from N6b can also be incorporated into this one-pot synthesis, whereby X6c and N6a are prepared separately but then coupled.

[0167] Alternatively, X6b is prepared directly from X6d and N6a by using a carboxylic acid activating reagent. Carboxylic acid activating reagents 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).

[0168] The coupling of X6d or X6c with 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 with N6a can be carried out in isopropyl acetate, toluene, or preferably a mixture thereof.

[0169] X6d can be prepared from X6e:

[0170]

[0171] 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.

[0172] X6e can be prepared from X6f:

[0173]

[0174] wherein X is Cl, Br, or I.

[0175] X6e was prepared by contacting X6f with X6g under cross-coupling conditions:

[0176]

[0177] wherein X is F, Cl, Br, or I, m is 2 or 3, and R is F, Cl, Br, or I, OH, OC1-C6 alkyl, N(C1-C6 alkyl)2, aryl, or wherein two or three R groups other than F, Cl, Br, I, or OH may together form a cyclic boronate, such as pinacol borate, or N-methyliminodiacetic acid (MIDA) borate.

[0178] The coupling of organoboron and aryl halide compounds is as described above for the coupling of X6b and F7, and similar conditions can be used to form X6e.

[0179] X6f can be prepared from X6h:

[0180]

[0181] wherein X is Cl, Br, or I.

[0182] X6f can be prepared by diazotization of X6h under acidic conditions, for example with nitrous acid or sodium nitrite, followed by cyanation of the diazo compound, for example using CuCN and / or NaCN.

[0183] X6h can be prepared from X6i:

[0184]

[0185] X6h can be prepared by contacting X6i with a halogenating agent, for example a chlorinating agent such as AlCl3, 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, Br2 and FeBr3, HBr, tribromoisocyanuric acid, ammonium bromide and ozone, TBBDA, and combinations thereof; or an iodinating agent such as N-iodosuccinimide. X6h can also be prepared via a Sandmeyer reaction.

[0186] Preparation of N6a

[0187] N6a is used in the preparation of X6b. N6a can be prepared from N6b:

[0188]

[0189] wherein Y is Cl, Br, or I.

[0190] 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; Urushibara 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 bisulfite; hydrogen sulfide and base; hydroiodic acid; 1,3-dimethyl-2-imidazolidinone and sodium triethylsilanethiolate; and combinations thereof. In some embodiments, this reaction is carried out under micellar conditions.

[0191] N6b can be prepared from N6c:

[0192]

[0193] N6b can be prepared by contacting X6h with a halogenating agent, such as a chlorinating agent, such as AlCl3, 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, Br2 and FeBr3, HBr, tribromoisocyanuric acid, ammonium bromide and ozone, TBBDA, and combinations thereof; or an iodinating agent, such as N-iodosuccinimide. X6h can also be prepared via a Sandmeyer reaction.

[0194] N6c can be prepared from N6d:

[0195]

[0196] N6c can be prepared by contacting N6d with a nitrating agent, such as 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; isoamyl nitrate, trifluoromethanesulfonic acid, and 1-ethyl-3-methylimidazolium trifluoromethanesulfonate; H-β zeolite catalyst and N2O5; acetyl nitrate; and combinations thereof.

[0197] N6d can be prepared from N6e:

[0198]

[0199] 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.

[0200] Preparation of F6

[0201] F6 is used in the preparation of F7, and it can itself be prepared by any suitable method. In one embodiment of the present invention, F6 is prepared from F2 and F3:

[0202]

[0203] wherein Y is independently Cl, Br, or I.

[0204] In some embodiments, the preparation of F6 comprises reacting compound F2 with compound F3 to obtain compound F4:

[0205]

[0206] The reaction of F2 and F3 can be carried out under Mitsunobu conditions, for example in the presence of a phosphine compound such as PPh3 (optionally on a resin support) and an azodicarboxylate 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 a water content of less than 0.5 wt%, for example 0.1 wt%.

[0207] The preparation of F6 may include converting F4 to F6:

[0208]

[0209] The conversion of F4 to F6 can be carried out using any suitable aminating agent such as ammonium hydroxide or water and ammonia. In one embodiment, the solvent is an alcohol solvent such as iPrOH.

[0210] The reaction of F2 with F3 to give F4 and the conversion of F4 to compound F6 can be carried out as a sequential reaction or as a one-pot reaction.

[0211] Alternatively, F2 can be converted to F2' via amination. Amination reagents include water and ammonia, or ammonium hydroxide, and this reaction can 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, for example in the presence of a phosphine compound such as PPh3 and an azodicarboxylate such as DIAD or DEAD, to give F6:

[0212]

[0213] These reactions can be performed in a sequential manner or in a one-pot manner.

[0214] Preparation of F11

[0215] Any of the reactions described herein can be used in the synthesis of compound F11:

[0216]

[0217] In one embodiment of the method of the present invention, F7 is converted to F11 in one or more synthesis steps. For example, in one embodiment, the method of the present invention may further include deprotecting F7 to obtain F8:

[0218]

[0219] In some embodiments, P is a Boc group and deprotection is achieved using an acid (eg, HCl).

[0220] The method of the present invention may further comprise the conversion of F8 to F11:

[0221]

[0222] Conversion of F8 to F11 can be achieved by contacting F8 with F9:

[0223]

[0224] Formation of F11 by F8 and F9 can be achieved in the presence of alkali (such as Na CO ) and a suitable solvent (such as ethyl acetate). Alternatively, the reaction can be carried out in a suitable solvent without alkali. Acryloyl chloride can be used to replace F9, or acrylic acid and a carboxylic acid activating agent (such as HBT, HATU, HBTU, TBTU, HOBt, PyAOP, HCTU, PyClocK, TFFH, carbodiimide (such as DCC), carbonyl diimidazole (CDI) or phosphonium salt (such as T P, SOCl BOP, PyBOP)) can be used in series. However, it is preferred to use acrylic anhydride because it avoids the need for chromatography, which is different from acrylic acid.

[0225] Products prepared according to the method of the present invention and their use

[0226] The present invention provides a synthetic route to the compound ributinib. Therefore, the protection provided by the patent generated by this application can be extended to the direct product of the method herein, i.e. ributinib.

[0227] The present invention provides compound F11 (rebtinib) prepared or preparable by the methods described herein. The synthesis of rebtinib described herein does not include INT 3 at any stage. Therefore, in one embodiment, rebtinib prepared or preparable by the methods described herein is substantially free of INT 3 (5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline). For example, the amount of INT 3 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, rebtinib prepared or preparable by the methods described herein is free of INT 3 (5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline). Alternatively or in addition, ributinib prepared or preparable by the methods described herein is substantially free of (3-amino-5-fluoro-2-methylphenyl)boric acid. For example, the amount of (3-amino-5-fluoro-2-methylphenyl)boric 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, ributinib prepared or preparable by the methods described herein is free of 3-amino-5-fluoro-2-methylphenyl)boric acid.

[0228] The present invention also provides a pharmaceutical composition comprising ribuzinib prepared or preparable by the methods described herein, and thus may be substantially free of INT 3. In one embodiment, the composition also contains at least one pharmaceutically acceptable excipient, and generally 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 purpose and scope of the present application.

[0229] As used herein, the term "pharmaceutically acceptable excipient" includes any and all solvents, carriers, diluents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents, antioxidants), isotonic agents, absorption delaying agents, salts, drug stabilizers, binders, additives, bulking agents, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, as would be known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Printing Company, 1990, pp. 1289-1329). It should be understood that unless the conventional excipient is incompatible with the active ingredient, the present application contemplates the use of any conventional excipient in any therapeutic or pharmaceutical composition.

[0230] The pharmaceutical composition can be formulated for a specific route of administration, such as oral administration, parenteral administration, and rectal administration, etc. In addition, the pharmaceutical composition of the present invention can be in solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories), or in liquid form (including but not limited to solutions, suspensions or emulsions). The pharmaceutical composition can be subjected to conventional pharmaceutical operations (such as sterilization) and / or can contain conventional inert diluents, lubricants, carriers or buffers, and adjuvants (such as solvents, preservatives, stabilizers, wetting agents, emulsifiers and swelling agents, etc.).

[0231] Typically, pharmaceutical compositions are tablets or capsules containing the active ingredient together with at least one excipient, such as:

[0232] a) diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0233] b) lubricants, for example, silicon dioxide, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; for tablets, also

[0234] c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, if desired;

[0235] d) carriers, such as aqueous vehicles containing cosolvating materials, such as captisol, PEG, glycerol, cyclodextrin, etc.;

[0236] e) disintegrants, for example, starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or

[0237] f) Adsorbents, colorants, flavorings and sweeteners.

[0238] 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 tablets or capsules, and optionally packaged in a multi-dose form suitable for storing and / or distributing unit doses of pharmaceutical products. Examples of suitable packaging include, but are not limited to, airtightly sealed foil, unit dose containers (e.g., vials), blister packs, and strip packs.

[0239] Tablets can contain active ingredients mixed with non-toxic pharmaceutically acceptable excipients suitable for making tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; adhesives such as starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, and thereby provide sustained action over a long period of time. For example, time-delay materials such as monostearate or distearate can be used. Oral formulations can be presented in the form of hard gelatin capsules, where the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or in the form of soft gelatin capsules, where the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).

[0240] The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising as an active ingredient ribuzinib prepared or preparable by the methods described herein, since water can promote the degradation of certain compounds.

[0241] The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-water content ingredients and low moisture or low humidity conditions. Anhydrous pharmaceutical compositions can be prepared and stored so as to maintain their anhydrous nature. Therefore, it is preferred to package the anhydrous compositions using materials known to prevent exposure to water so that they can be included in a suitable formulation kit. 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.

[0242] The present invention further provides pharmaceutical compositions and dosage forms comprising one or more agents that reduce the rate at which the compounds of the present invention as active ingredients decompose. Such agents (referred to herein as "stabilizers") include, but are not limited to, antioxidants (such as ascorbic acid), pH buffers, or salt buffers, etc.

[0243] For a subject of about 50-70kg, the pharmaceutical composition of the present invention or combination can be in a unit dose of about 1-1000mg one or more active ingredients, or about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg, or about 10-50mg active ingredients. Preferably, the pharmaceutical composition of the present invention or combination can be in a unit dose of about 10mg, about 25mg or about 50mg. The therapeutically effective dose or amount of compound, pharmaceutical composition or combination thereof depends on the species, body weight, age and individual condition, disorder or disease or its severity of the subject. A physician, clinician or veterinarian with ordinary skills can easily determine the effective amount of each active ingredient necessary for prevention, treatment or inhibition of disorder or disease progression.

[0244] The above dosage characteristics are demonstrated in in vitro and in vivo tests using advantageous mammals (e.g., mice, rats, dogs, monkeys) or isolated organs, tissues and preparations thereof. The compounds of the invention can be applied in vitro in the form of solutions (e.g., preferably aqueous solutions), and in vivo enterally, parenterally, advantageously intravenously, for example, as a suspension or in an aqueous solution. In vitro doses can be administered at about 10 -3 Molar concentration and 10 -9 In the range between molar concentration.Depending on the route of administration, the in vivo therapeutic effective amount can be between about 0.1-500mg / kg, or in the range between about 1-100mg / kg.Preferably, the in vivo therapeutic effective amount is about 10mg to about 200mg daily, for example, in the range of about 10mg, about 20mg, about 25mg, about 35mg, about 50mg, about 100mg or about 200mg daily.Preferably, the in vivo therapeutic effective amount is selected from about 10mg, about 35mg, about 50mg or about 100mg, once a day.Also preferably, the in vivo therapeutic effective amount is selected from about 10mg, about 25mg, about 50mg or about 100mg, twice a day.

[0245] In another aspect, the present invention also provides a method for treating a disorder mediated by BTK or ameliorated by inhibiting BTK, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of ribuzinib prepared or preparable by the methods described herein.

[0246] In another aspect, the present invention also provides the use of ribuzinib prepared or preparable by the method described herein for the preparation of a medicament for treating a disorder mediated by BTK or a disorder improved by inhibiting BTK.

[0247] In another aspect, the present invention also provides ribuzinib prepared or preparable by the methods described herein for use in treating a disorder mediated by BTK or a disorder ameliorated by inhibiting BTK.

[0248] Ribrutinib prepared or preparable by the methods described herein can be used to treat the following diseases or disorders mediated by BTK or improved by inhibiting BTK: autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection; diseases with abnormal or impaired antibody production, antigen presentation, cytokine production or lymphoid organogenesis; including rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic urticaria (chronic spontaneous urticaria, induced urticaria), chronic allergies (atopic dermatitis, contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes mellitus, type 2 diabetes mellitus, 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; myeloid metaplastic myelofibrosis; and Walden disease.

[0249] Ribrutinib prepared or preparable by the methods described herein is particularly useful for treating rheumatoid arthritis; chronic urticaria, preferably chronic spontaneous urticaria; Sjögren's syndrome, multiple sclerosis, atopic dermatitis or asthma.

[0250] Examples

[0251] The following non-limiting examples illustrate the present disclosure.

[0252] An overview of the synthetic routes described herein and exemplified below is provided in the accompanying figures. The reactions are described in more detail below.

[0253] Example 1-Preparation of F2

[0254]

[0255] To a suspension of AlCl3 in xylene was added a xylene solution of F1 at 5°C over 40 minutes. The mixture was warmed to 30°C over 60 minutes and stirred at this temperature overnight. EtOAc was added and the resulting solution was quenched with 0.5N aqueous HCl solution at 0°C over 1 hour. The mixture was warmed to 25°C and the phases were separated. The aqueous layer was discarded and the organic layer was concentrated. The resulting dilute suspension was cooled to 20°C at 0.3K / min. The solid was filtered, the filter cake was washed with a 1:1 solution of xylene and heptane, and dried to give F2 as a white solid with a yield of about 83%.

[0256] Example 2-Preparation of F6

[0257]

[0258] Preparation of F3 solution : 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 were loaded into a reaction flask. The internal temperature was adjusted to 10° C.-30° C. The reaction mixture was stirred for 25 to 35 minutes. Boc anhydride (37.8 g, 1.00 eq.) was added dropwise, and the reaction mixture was stirred for another 6-12 hours at 10° C. to 30° C. The reaction was quenched with water (13.0 g), and the resulting two-phase mixture was stirred for 25-35 minutes. The lower aqueous layer was removed, and the organic layer was washed with another portion of water (13.0 g). The organic layer was used directly in the next step.

[0259] The Mitsunobu reaction to obtain F4 : A solution of F3 (1.4 eq) in toluene was dried by Dean Stark distillation to reach a water content of NMT 0.07 wt%. Triphenylphosphine (42 g, 1.32 eq) was added to the dry solution of F3 at 20°C-30°C, and the reaction mixture was stirred at room temperature until a clear solution was observed. The reactor was inerted and cooled to about -30°C. F2 (20 g, 1.0 eq) was then added, followed by DIAD (31.8 g, 1.30 eq) over 4 to 8 hours, keeping the internal temperature between -25°C. The slightly turbid solution was warmed to 10°C within 4 hours, and stirred for an additional 15 to 20 hours between 5°C and 15°C. After the reaction was complete, toluene was distilled at 55°C to obtain a slightly viscous tan suspension. The mixture was cooled to 10°C, and n-heptane (140 g) was added. The mixture was stirred for 2 hours to obtain a light brown, well-stirred suspension. The suspension was filtered and the filter cake was washed with cooled n-heptane. The filter cake containing triphenylphosphine oxide and H2-DIAD was discarded. The combined mother liquor and washings were concentrated to about 1 / 3 of their initial volume at JT 55°C and 150 mbar to give a clear yellow solution of F4.

[0260] Amination of F6 :The solvent of F4 solution was then converted to iPrOH via distillation and addition of iPrOH. H2O (3.5w / w wrt F2) and 25wt% NH3 solution (3.5w / w F2) were added to the yellow solution of F4 in iPrOH. The resulting yellow solution was stirred at 70°C for 16 hours. Slight gas release (NH3) was observed when the temperature was raised to 70°C. After the reaction was completed, the resulting yellow solution was cooled to 45°C over 40 minutes, and F6 seeds were added as a suspension in iPrOH. The suspension was aged for about 20 minutes. The dilute suspension was then cooled to 10°C-20°C at 10°C / hour and aged for an additional 30 minutes. The suspension was filtered, and the filter cake was washed with a mixture (40g) of H2O and iPrOH (1:1). The wet product was dried at 50°C under complete vacuum (about 20 hours) to obtain F6 as a white crystalline solid with a yield of about 70%.

[0261] Example 3 - Preparation of X6b

[0262]

[0263] The synthesis of X6b is a highly convergent process that starts with preparing a solution of N6a, preparing a solution of the acid chloride X6c and combining the two solutions to form X6b.

[0264] Autoclave: Preparation of N6a solution N6b (20 g, 1.0 eq.) was charged into an autoclave under N2 and diluted with isopropyl acetate (105 g). Then, about 1 wt% wet Pt(V) / C (0.126 g dry weight) was added and the atmosphere was changed from N2 to H2. Hydrogenation was carried out at 3 bar of H2 at an internal temperature below 30°C for 12 hours. At the end of the reaction, the suspension was filtered to remove the catalyst. The reactor and filter cake were rinsed with isopropyl acetate. The N6a solution can be azeotropically distilled to remove water or used directly.

[0265] Reactor A: Preparation of X6c solution : Under N2 atmosphere, X6d (17g, 1.1 equivalents) was suspended in toluene (56g). A catalytic amount of pyridine was added, and the reaction mixture was heated to 50°C. Thionyl chloride was then added dropwise over 2 hours, and the resulting mixture was stirred at 50°C for 1 hour. The turbid solution was then distilled to half volume, the reactor was refilled to its initial volume with toluene, and the operation was repeated to remove excess thionyl chloride. The X6c mixture was then cooled to room temperature.

[0266] Reactor A: Formation of X6b: To a solution of X6c (1.1 eq.) in toluene was added a solution of N6a (1.0 eq.) prepared previously in iPrOAc over 1 hour. At the end of the addition, DIPEA (13.4 g, 1.2 eq.) was carefully added over 2 hours. After the DIPEA addition was complete, the reaction mixture was stirred for 3 hours and the reaction was quenched with iPrOH (26.4 g). The reactants were stirred at room temperature overnight and the suspension was filtered. The wet cake was rinsed with iPrOH and iPrOH / water. The cake was discharged and dried under reduced pressure. X6b was typically isolated in 87%-93% yield.

[0267] Example 4a: Optimization of Suzuki conditions for converting X6a to F7

[0268] Previously, it was reported (DOI: 10.1021 / acs.jmedchem.9b01916 ) The coupling reaction between F6 and X6a was carried out using 1 equivalent of F6, 1.15 equivalents of X6a, 5 mol% Pd(PPh3)2Cl2, 3 equivalents of Na2CO3, 12 volumes of DME, and 10 volumes of water at 75°C for 8 hours with a conversion of 74% isolated yield.

[0269] Optimize the cross-coupling reaction to replace DME solvent with a Class 3 solvent suitable for a commercial process while also reducing Pd loading and production cost

[0270]

[0271] Design and experimental details

[0272] 1) Using 1.15 equivalents of X6a, in the presence of 3.0 eq K3PO4 at 2.0 mol% Pd level, Suzuki screened 12 precatalysts and 6 solvent systems (80°C: tert-amyl alcohol, CPME and toluene; 60°C: THF, Me-THF and MeCN, each combined with water). After 16 hours, it was found that a series of precatalyst / solvent combinations could promote complete conversion of the reaction, with de-boronate being the main byproduct; it was decided to perform full ligand screening in both toluene (80°C) and Me-THF (60°C).

[0273] 2) Screening 48 ligands using 2.0 mol% Pd(OAc)2, 1.1 equivalents of deborate and 3.0 equivalents of K3PO4 at 60°C in 10.0 vol Me-THF / 3.0 vol water or at 80°C in 10.0 vol toluene / 3.0 vol water. After 16 hours, it was found that 5 ligands (RuPhos, dppf, S-Phos, Cy3P·HBF4 and Ph2P(t-Bu)) at 60°C can promote the complete conversion of the reaction in Me-THF / water to give the primary Prod / IS, and the deborate byproduct can be controlled at 3% to 8% level

[0274]

[0275] 3) Maintaining the P:Pd ratio at 2:1, six Pd precursors (Pd(OAc)2, [Pd(C3H5)Cl]2, Pd(TFA)2, Pd(MeCN)2Cl2, Pd2(dba)3 and PdBr2) were screened at 60°C in the presence of 3.0 equivalents of K3PO4 and 1.05 equivalents of X6a in 10.0 volumes of Me-THF / 3.0 volumes of water, respectively, at a Pd level of 1.0 mol%. After 16 hours, Cy3P·HBF4 and Ph2P(t-Bu) were still retained as the best ligand candidates, while Pd(TFA)2, Pd(MeCN)2Cl2 and PdBr2 were the primary Pd precursors.

[0276]

[0277] 4) Keeping P:Pd at a 2:1 ratio, using Cy3P·HBF4 and / or Ph2P(t-Bu) as ligands, combined with Pd(TFA)2, Pd(MeCN)2Cl2 and PdBr2, respectively, in the presence of 3.0 equivalents of K3PO4 and 1.05 equivalents of X6a in 10.0 volumes of Me-THF / 3.0 volumes of water at 60°C, screening Pd loadings from 0.1 mol% to 2.0 mol%. After 16 hours, it was found that Pd(MeCN)2Cl2 / Ph2P(t-Bu) was the first best pre-catalyst combination, and the Pd loading could be reduced to 0.3 mol% to 0.5 mol%, and the de-boronate / productivity (De-Boronate / Prod) could be controlled at about 1%.

[0278]

[0279] 5) Using Pd(MeCN)2Cl2 / Ph2P(t-Bu) as the best precatalyst combination and 1.05 equivalents of X6a, the loading amount from 0.1mol% to 0.5mol% was screened in the presence of K2CO3, Cs2CO3, K3PO4 and KF, respectively. K3PO4 was found to be the best base, and 0.3mol% to 0.5mol% Pd(MeCN)2Cl2 / Ph2P(t-Bu) precatalyst was recommended in the scale-up reaction.

[0280] Optimal conditions

[0281] 1) 1.0 eq F6, 1.05 eq X6a, 0.5 mol% Pd(MeCN)2Cl2, 1.0 mol% Ph2P(t-Bu), 3.0 eq K3PO4 in 10.0 vol Me-THF / 3.0 vol water at 60°C for 16 hours to achieve complete conversion, HPLC IPC purity of 90.6%, deborate / productivity of 1%

[0282] 2) 1.0 eq F6, 1.05 eq X6a, 0.3 mol% Pd(MeCN)2Cl2, 0.6 mol% Ph2P(t-Bu), 3.0 eq K3PO4 in 10.0 vol Me-THF / 3.0 vol water at 60°C for 16 hours to 99% conversion, 88.5% HPLC IPC purity, 1% deborate / productivity

[0283]

[0284] The best conditions for the next

[0285] 1) 1.0 eq F6, 1.05 eq X6a, 0.8 mol% Pd(TFA)2, 1.6 mol% Ph2P(t-Bu), 3.0 eq K3PO4 in 10.0 vol Me-THF / 3.0 vol water at 60°C for 16 hours, reaction reached complete conversion, HPLC IPC purity of 90.9%, deborate / productivity of 2%

[0286] 2) 1.0 eq F6, 1.05 eq X6a, 0.8 mol% Pd(MeCN)2Cl2, 1.6 mol% Ph2P(t-Bu), 3.0 eq K3PO4 in 10.0 vol Me-THF / 3.0 vol water at 60°C for 16 hours, reaction reached complete conversion, HPLC IPC purity of 91.2%, deborate / productivity of 2%

[0287] Example 4b - Preparation of F7, one-pot borylation-Suzuki crossover from X6b using optimized conditions from Example 4a Coupling

[0288]

[0289] Miyaura borylation : Under N2 atmosphere, X6b (1.0 equivalent), B2pin2 (1.06 equivalent) and KOAc (2.5 equivalent) were loaded into a reactor containing degassed Me-THF. The water content of the reaction mixture was measured and adjusted to between 1000ppm and 2500ppm. After the vessel was inerted, a solution of Pd(MeCN)2Cl2 (0.5mol%) in degassed MeTHF and a solution of PPh2tBu (1.0mol%) in degassed MeTHF were added successively. The reaction mixture was then heated to 70°C for 16 hours.

[0290] Suzuki coupling :Once the complete conversion of X6b is achieved (X6b<0.25%, conversion rate is about 98%), the reaction mixture is cooled to room temperature, and the reaction mixture is quenched with KOH aqueous solution (21%wt / wt). Separate and discard the water layer, and add the KOH aqueous solution (21%wt / wt) of fresh part. Add F6 (0.96 equivalent compared with X6b) as solid, then, after appropriate degassing, add the second portion of PPh2tBu (2mol%) in degassed MeTHF and the second portion of Pd(MeCN)2Cl2 (1mol%) in degassed MeTHF. Then the reaction mixture is heated to 60 ℃ for about 24 hours. After the reaction is completed, at 60 ℃, N-acetylcysteine ​​aqueous solution is added to the reaction mixture. After stirring for 2 hours, the water layer is discarded. Add another portion of N-acetylcysteine ​​aqueous solution, and pH is adjusted to ≥9.5 by adding the KOH aqueous solution. After stirring for 2 hours, the water layer is discarded. The organic layer was then washed with water for 30 minutes, and the aqueous layer was discarded. The solution was filtered through activated carbon at 60°C, and the solution was concentrated to half of its volume by reduced pressure distillation. N-heptane was slowly added, and the resulting suspension was cooled to 20°C, stirred for 2 hours, and filtered. The filter cake was washed with a mixture of 1:5 Me-THF and n-heptane. In the case of unsatisfactory purity, the wet cake can be re-slurried in Me-THF and n-heptane (1:5). The cake was discharged and dried under reduced pressure. F7 is typically isolated with a 92% yield.

[0291] Example 4c - Development of a one-pot borylation / Suzuki cross-coupling using tetrahydroxydiboron for the preparation of F7

[0292] A one-pot borylation / Suzuki cross-coupling using tetrahydroxydiboron has been developed for the synthesis of F7 from X6b using BBA as the borylation agent. This approach is characterized by utilizing a significantly low loading of Pd catalyst, avoiding pinacol hydrate precipitation in the final product, and using methanol as the green alcohol solvent in both steps. This approach solves some of the aforementioned problems associated with the use of bis(pinacolato)diboron as the borylation agent, thus becoming a more atom-efficient and cost-effective approach. Preliminary results demonstrate the feasibility of this one-pot approach at a 2.2 g scale using a FlexyALR reactor.

[0293]

[0294] Scheme 1: Reaction Overview

[0295] Results and discussion

[0296] Miyaura borylation To develop the optimal reaction conditions for Miyaura borylation using BBA, we screened key reaction parameters such as catalyst system, base, solvent and temperature. This borylation was limited to the use of Pd(II)-precatalysts that promote rapid Pd(0) formation. In fact, the use of a 2nd generation Buchwald precatalyst in combination with two equivalents of an additional ligand proved to be the best catalytic system in our reaction (Table 1, entries 1-6). Among all the precatalysts screened, only Pd-XPhos-2G provided complete conversion of the starting material while providing the highest yield and selectivity for X6a formation (entry 2). In a similar manner, the use of ethylene glycol as an additive also proved to be very beneficial, as complete conversion could not be achieved without it (entry 1 vs. entry 2). BBA can be stabilized in situ by forming the corresponding boronate derivative, allowing the amount of borylation agent and Pd to be reduced while increasing the borylation rate. Further reductions in catalyst loading were attempted (entries 8-10). Surprisingly, decreasing the catalyst loading provided lower amounts of the reduction and dimerization products IMP1 and IMP2, while still providing nearly complete conversion of X6b (entry 8). Additionally, higher conversions were observed by increasing the reaction time, thus indicating that BBA was still present in the reaction mixture (entry 9). These results may indicate that the boronic acid formed may undergo a Pd(II)-catalyzed decomposition pathway, and that higher amounts of Pd source in the presence of trace oxygen may favor this pathway. Finally, complete conversion to the final product with high selectivity and yield was observed simply by increasing the reaction temperature to 50°C (entry 10).

[0297] Table 1. Screening results from Miyaura borylation using BBA and KOAc.

[0298]

[0299]

[0300] Reaction conditions: X6b (1.0 equiv), BBA (1.5 equiv), KOAc (3.0 equiv), ethylene glycol (3.0 equiv), Pd-precatalyst (1 mol%), ligand (2 mol%), MeOH (0.1 M), T (°C), 17 hours. a HPLC area percentage of the compound

[0301] (LCAP). b Reaction time: 20 hours.

[0302] We also decided to evaluate the reaction using amine bases, DIPEA, and other Buchwald precatalysts in place of ethylene glycol to see if we could further improve the results of the Miyaura borylation and increase the amount of working catalyst (Table 2, entries 1-5). Although most catalysts performed poorly under these conditions, a hit was found using Pd-cataCXium 3G (entry 5). Although slightly higher amounts of IMP1 and IMP2 were formed compared to the previously optimized conditions, these results are promising considering the superior performance of cataCXium over XPhos when used in combination with DIPEA (entry 5 vs. entry 1). With this result in hand, we screened a number of key reaction parameters to see if this result could be further improved (entries 6-9). Given our previous results, a reduction in catalyst loading was first examined (entry 6). Importantly, we found that 0.05 mol% Pd was sufficient to drive the reaction to completion, indicating that the catalytic activity of Pd-cataCXium-3G was much higher than that of Pd-XPhos-2G under these conditions. Importantly, heating to 50 °C was found to be optimal, as lowering 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 indicating that the cyclic diboron species may be less reactive under these conditions (entry 8). Although significantly high catalytic activity was observed under these newly optimized conditions, the relative amounts of byproducts IMP1 and IMP2 could not be further reduced and the conditions based on the use of Pd-Xphos-2G, KOAc and ethylene glycol remained superior.

[0303] Table 2. Screening results from Miyaura borylation using BBA and DIPEA.

[0304]

[0305]

[0306]

[0307] Reaction conditions: X6b (1.0 equiv), BBA (1.5 equiv), DIPEA (3.0 equiv), Pd-precatalyst (0.25 mol%), ligand (0.5 mol%), MeOH (0.1 M), T (°C), 17 hours. a Liquid chromatography area percentage (LCAP) of the compound.

[0308] b Ethylene glycol (3.0 eq.) was added to the reaction mixture.

[0309] Suzuki cross coupling : Having mastered two groups of optimized conditions for the synthesis of boronic acid X6a by using BBA as a borylation agent, we studied the feasibility of the subsequent Suzuki coupling, with the ultimate goal of developing a one-pot method for the synthesis of F7. To this end, we initially attempted a Suzuki coupling of X6a and F6 at 60°C under the reaction conditions previously developed by Molanders (Gurung, SR et al., Org. Process Res. Dev. 2017, 21, 65-74) (Table 3, entry 1). However, disappointingly, after heating to 60°C for 17 hours, uneven and incomplete conversion of X6a and F6 was observed. In addition, we found that F6 was converted to F6 by S N Ar path partially reacts with EtOH to form corresponding ether. At this point, we wonder whether the use of milder organic bases (such as amines) can help reduce this side reaction. In fact, using Et3N causes the formation of minimal CO coupling products, resulting in uniform and almost complete conversion of X6a and F6 (entry 2). Finally, we unexpectedly found that MeOH is better than EtOH, providing complete conversion of X6a and F6, and a higher yield of coupling products (entry 3). In addition, F7 is precipitated directly from the reaction mixture, thus significantly simplifying the final post-processing purification. Although the formation of reduction and dimerization products IMP1 and IMP2 proves that there is trace oxygen in the reaction solvent, the scale-up of our expected method will effectively eliminate this problem (entries 1-3).

[0310] Table 3. Screening results from Suzuki coupling with F6.

[0311]

[0312]

[0313] Reaction conditions: X6a (1.1 equivalent), F6 (1.0 equivalent), base (3.0 equivalent), ethylene glycol (3.0 equivalent), Pd-XPhos 2G (1.0 mol%), solvent (0.2 M), 60 ° C,

[0314] 17 hours. a Liquid chromatography area percentage (LCAP) of the compound.

[0315] One-pot borylation and coupling : Since Pd-XPhos 2G and Pd-cataCXium 3G are the first precatalysts in Miyaura borylation 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 proved to be superior to Pd-cataCXium 3G in a one-pot procedure, giving F7 with a purity of 78% in 79% isolated yield starting from X6b. As expected, the workup and purification of F7 can be carried out by direct filtration and washing the formed precipitate with a MeOH / H2O mixture.

[0316] Table 4. Screening results from one-pot reactions.

[0317]

[0318]

[0319] Miyaura borylation : Reaction conditions: X6b (1.0 equivalent), BBA (1.5 equivalent), KOAc

[0320] (3.0 equiv), ethylene glycol (3.0 equiv), Pd-XPhos 2G (0.25 mol%), XPhos (0.5 mol%), MeOH (0.1 M), 50° C., 17 hours. Suzuki coupling : X6a (1.0 equiv), F6 (0.95 equiv), Et3N (3.0 equiv), Pd-XPhos2G (1.0 mol%), MeOH (0.1 M), 50°C, 17 hours. a Liquid chromatography area percentage (LCAP) of the compound.

[0321] Scaling up Using the conditions developed for the two steps in MeOH, a one-pot reaction was attempted at a larger scale (2.2 g X6b) using a Flexy ALR-1 300 ml reactor under mild conditions using the same precatalyst (Table 5).

[0322] X6b (2.20 g, 1.0 eq.), potassium acetate (1.76 g, 3.0 eq.), ethylene glycol (1.0 ml, 3.0 eq.) and MeOH (100 ml) were charged into a 300 ml FlexyALR reactor. The reaction mixture was degassed by continuous vacuum / N2 cycles, and a solid mixture of BBA (807 mg, 1.5 eq.), Pd XPhos 2G (12 mg, 0.25 mol%) and XPhos (14 mg, 0.50 mol%) was added under N2. After the second degassing, the reactants were heated to 50°C and stirred overnight. The boric acid-containing mixture was then cooled to 20°C, and F6 (1.73 g, 0.95 eq.), Pd XPhos 2G (24 mg, 0.5 mol%), Et3N (2.5 ml) and degassed water (30 ml) were added under N2. The reaction was degassed for the third time and stirred at 60°C overnight. Subsequently, it was cooled to 40°C and concentrated under reduced pressure (removal of about 40 ml of MeOH). The reaction mixture was then cooled to 20°C and stirred for 3 hours. The light brown suspension was filtered off, washed with a cold solution of MeOH / H2O 4 / 1 (40 ml) and dried to give F7 (1.87 g, 56%) as a brown solid.

[0323] Table 5. Scale-up of the one-pot process.

[0324]

[0325] Miyaura borylation : Reaction conditions: X6b (1.0 equivalent), BBA (1.5 equivalent), KOAc

[0326] (3.0 equivalents), ethylene glycol (3.0 equivalents), Pd-XPhos 2G (0.25 mol%),

[0327] XPhos (0.5 mol%), MeOH (0.1 M), 50° C., 17 hours. Suzuki coupling :

[0328] X6a (1.0 eq), F6 (0.95 eq), Et3N (3.0 eq), Pd-XPhos 2G (0.5 mol%), MeOH (0.1 M), 60°C, 17 hours. a Liquid chromatography area percentage (LCAP) of the compound.

[0329] We expected to find that Miyaura borylation of X6b worked well to provide the desired intermediate X6a in excellent yield and selectivity. Interestingly, as described by Molander for the use of Pd-XPhos 2G, the end of the borylation was evidenced by an abrupt color change of the reaction mixture from white to light orange. Subsequently, F6, a fresh batch of catalyst, Et3N and H2O were added to the reaction mixture for Suzuki coupling. The final product was filtered and washed to afford F7 in 56% isolated yield and 87% IPC purity in two steps. Importantly, as we expected, the formation of byproducts IMP1 and IMP2 was minimized by performing these two steps in the reactor to exclude all traces of oxygen.

[0330] Example 5-Preparation of F8:

[0331]

[0332] F7 was suspended in isopropyl acetate at 25°C, and concentrated hydrochloric acid (approximately 37% w / w, 4.1 equivalents) was added over 2 hours to remove the Boc protecting group. After the addition was complete, the suspension was stirred for about 5 hours to ensure complete conversion to F8. Water was then added at 25°C to dissolve the dihydrochloride salt of F8. The resulting two-phase mixture was stirred at 35°C for about 2 hours to ensure dissolution of the desired product. The layers were separated at JT 30°C: the lower aqueous phase (containing the product) was transferred to a tank, while the upper organic phase (containing impurities from F7) was discarded. The aqueous phase was transferred to a new reactor via an online filter. IPC of the aqueous layer was then performed to ensure the absence of F7. In the case where F7 was not completely converted, the temperature was raised to 40°C for 1 hour, and the solution was then cooled to room temperature. The resulting aqueous solution containing the product was then neutralized with sodium hydroxide (approximately 30% w / w) at 25°C until the pH reached 5.0-5.5. Ethanol was then added to the resulting suspension, and the temperature was increased to 60°C. Subsequently, 1 M aqueous sodium hydroxide solution was added until the pH reached 7.5-8.5. The product suspension was cooled to 25°C within 2 hours and stirred for another hour. The F8 crystals were separated by filtration and the filter cake was washed with ethanol. The F8 wet product was dried under reduced pressure at JT 50°C.

[0333] Example 6: Preparation of F11

[0334] Raw 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 about 30 minutes. After adding water, the reaction mixture is stirred at 65°C for about 30 minutes. The phases are separated at 60°C, and the aqueous phase is removed. 0.05M sulfuric acid is added to the organic phase and stirred at 60°C for about 15 minutes. The aqueous phase is removed at 60°C. Thereafter, the organic phase is washed with water and the aqueous phase is removed at 60°C. The final organic phase is treated by low in particles filtration at 65°C. Distillation is carried out under reduced pressure at an internal temperature of 60°C to remove about 25% of the solvent mixture, while ethyl acetate is added to keep the solvent level roughly constant. Thereby reducing the water content. A seed suspension of a crystalline form (anhydrous variant A as disclosed in WO 2020 / 234779) is added to the solution. The suspension is stirred for at least 15 minutes. A second distillation is performed under reduced pressure at an internal temperature of 60°C to remove about 12% of the solvent mixture, while adding ethyl acetate to keep the solvent level approximately constant. The suspension is cooled to 30°C within 200 minutes. A third distillation is performed under reduced pressure at an internal temperature of 30°C while adding ethyl acetate to keep the solvent level approximately constant. The suspension is cooled to 0°C within 200 minutes and kept stirring at 0°C for at least 240 minutes. The product is separated by centrifugation, and the filter cake is washed twice with ethyl acetate. At 40°C, the separated wet product is dried under vacuum on a tray in a drying oven. Product F11 is obtained.

[0335] Example 7-5-Fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Genotoxicity ("INT3" from WO2015 / 079417)

[0336] Compound INT 3 is a key intermediate for the synthesis of ributinib described in Example 6 of WO 2015 / 079417. Therefore, INT 3 was subjected to the AMES test (bacterial reverse mutation test) to determine whether there were any genotoxicity-related safety issues. Under the experimental conditions used and applying standard mutagenicity criteria, INT 3 was found to have mutagenic potential in the test strain TA97a in the presence of metabolic activation.

[0337] The purpose of the Salmonella / microsome assay is to evaluate the mutagenic potential of a test item by its effect on one or more histidine-requiring strains of Salmonella typhimurium in the absence and presence of the liver metabolic system. The Ames assay is a rapid, reliable, and economical method for screening potentially genetically active compounds at the nucleotide level. A large database has been accumulated using this assay, demonstrating its ability to detect genetically active compounds of most chemical classes with approximately 80% to 90% sensitivity and specificity.

[0338] With the exception of strain TA102, these strains require biotin as well as histidine for growth. In strain TA102, a 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 because the pKM101 plasmid encodes an error-prone DNA repair system. (1、3) .

[0339] When exposed to a mutagen, some bacteria in the treated population undergo genetic changes through chemical interactions with the compound, which causes them to revert to a non-histidine requiring state and therefore grow in the absence of exogenous histidine. Different test strains are used because each strain is mutated by a specific chemical class of compounds. A compound that is mutagenic in one strain may not be so in another. (1、3) .

[0340] method

[0341] Test Project :INT 3, also known as 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. vehicle :Dimethyl sulfoxide (DMSO) Purity / content of the drug :97.95%. Molecular structure :

[0342]

[0343] S. Typhimurium strains used (4、5、6) :TA98, TA100, TA1535, TA97a and TA102. Metabolic activation system (2) : S-9 mixture from liver of male rats pretreated with Aroclor 1254. 0.5 mL of 5% S-9 mixture was added to each plate. Comparison: Control treatments included additions at the same volume / plate (0.1 mL) as the test item solution. Negative controls included treatments with the selected vehicle. Positive control chemicals were provided and used as shown in the following table:

[0344]

[0345] *Obtained from Sigma-Aldrich.

[0346] **Stock solutions are prepared in DMSO.

[0347] result

[0348] Concentration tested (mutagenicity studies) : 50, 158, 501, 1582 and 5000 μg / plate (all strains + / - S-9 were used). Precipitation and toxicity : In the preliminary cytotoxicity as well as mutagenicity tests, none of the test items indicated any cytotoxicity in any strain in the presence and absence of metabolic activation. The test items also did not precipitate to the highest concentration in the presence and absence of metabolic activation. Mutagenicity : Data from control treatments confirmed correct strain and assay functionality and the data were accepted as valid.

[0349] After treatment with INT3 in Experiment 1, an increase in the number of revertants was observed in strain TA97a at 5000 μg / plate in the presence of metabolic activation, exceeding 2-fold (2.3-fold) the parallel vehicle control. To further evaluate these increases in the number of revertants, additional experiments were performed for strain TA97a in the presence and absence of metabolic activation.

[0350] After treatment with INT3 in experiment 2, no doubling of the number of revertants was observed in the strain TA97a at 5000 μg / plate in the presence of metabolic activation relative to the parallel vehicle control (which is formally the standard for a positive reaction). However, at the highest concentration tested, a 1.8-fold increase was obtained. An increase of 2.3-fold (exceeding the 2-fold threshold, indicating the mutagenic potential of the test item) and 1.8-fold in two independent experiments indicates that the test item INT3 is considered to have a weak mutagenic potential in the strain TA97a in the presence of metabolic activation.

[0351] No other increase in the number of revertants of at least 2-fold (1.5-fold for strain TA102) relative to the concurrent vehicle control was observed following treatment with any of the other strains.

[0352] Acceptance criteria : An assay is considered valid when all of the following criteria are met:

[0353] 1. Vehicle control counts are within normal range;

[0354] 2. The positive control chemical induced a 5 to 30 fold increase in the number of revertants for the different strains when compared to the parallel vehicle control and active S-9 preparations demonstrating differentiation between the different strains.

[0355] Evaluation Criteria : For valid data, if a concentration-related increase in the number of revertants was observed that was ≥2 times the parallel vehicle control value (in strains TA98, TA100, TA1535 or TA97a) or ≥1.5 times the parallel vehicle control value (in strain TA102), the test item was considered mutagenic in this assay. If the above criteria were met, the test item was considered positive in this assay. If the above criteria were not met, the test item was considered negative in this assay.

[0356] References (for Example 7)

[0357] 1) Bruce N.Ames, Joyce Mccann and Edith Yamasaki, 1975. Methods for detecting carcinogens and mutagens with Salmonella / Mammalian-Microsomemutagenicity test. Mut. Res., 31: 347-364.

[0358] 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.

[0359] 3) Dorothy M. Maron and Bruce N. Ames, 1983, Revised methods for the Salmonella mutagenicity test. Mut. Res., 113: 173-215.

[0360] 4)ICH Harmonised Tripartite Guideline Guidance;S2(R1),“OnGenotoxicityTesting and Data Interpretation for Pharmaceuticals Intended forHuman Use”;AtStep 4 of the Process the final draft is recommended foradoption to theregulatory bodies Current Step 4 version,dated 9 November2011.

[0361] 5)Lutz Müller et.al.,1999,ICH-Harmonised guidances ongenotoxicitytesting of pharmaceuticals:evolution,reasoning andimpact.Mut.Res.,436:195-225.

[0362] 6)OECD Guidelines for the Testing of Chemicals;No.471;“BacterialReverse Mutation Test”;Adopted 21st July 1997.

Claims

1. A synthesis method comprising converting compound X6b and compound F6 into compound F7: wherein X and Y are each independently Cl, Br, or I, and wherein P is an amine protecting group.

2. The method according to claim 1, wherein: P is a carbamate protecting group such as 9-fluorenylmethyl carbamate (Fmoc), tert-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 synthesis method comprising borylating X6b to obtain X6a: wherein X is F, Cl, Br, or I, n is 0 or 1, and R is F, Cl, Br, or I, OH, OC1-C6 alkyl, N(C1-C6 alkyl)2, aryl, or wherein two or three R groups other than F, Cl, Br, I, or OH may together form a cyclic boronate, such as pinacol borate, or N-methyliminodiacetic acid (MIDA) borate.

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

5. The method according to claim 3 or 4, wherein: The borylation is performed using one or more catalysts, one or more ligands, one or more borylating agents, and / or one or more bases, and optionally one or more additives.

6. The method according to claim 5, wherein: The borylation agent is selected from the group consisting of diboron compounds, boric acid, and organic borate esters.

7. The method according to claim 6, wherein: The boronating agent is selected from the group consisting of bis(pinacolato)diboron, bis(catechol)diborate, B2(NMe2)4, diboric acid, mono-, di- or tri-C1-C6 alkyl borate, mono-, di- or tri-methyl borate, mono-, di- or tri-ethyl borate, mono-, di- or tri-propyl borate, mono-, di- or tri-propenyl borate, preferably bis(pinacolato)diboron or diboric acid, most preferably diboric acid.

8. The method according to any one of claims 5 to 7, wherein: The metal catalyst contains palladium, nickel, or copper, or a combination thereof, preferably palladium.

9. The method according to claim 8, wherein: The metal catalyst is provided as a pre-catalyst complex, such as PdCl2(PtBuPh2)2 or a Buchwald G1, G2, G3, or G4 pre-catalyst complexed with a phosphine ligand.

10. The method according to claim 8, wherein: The metal catalyst is provided as a precatalyst, for example Pd(MeCN)2Cl2, Pd(TFA)2, PdBr2, together with a ligand, such as t-BuPPh2.

11. The method according to any one of claims 5 to 10, wherein: The ligand is selected from the group consisting of organic phosphines, N-heterocyclic carbenes, diazabutadiene, dibenzylideneacetone, and combinations thereof.

12. The method according to claim 11, wherein: The ligand is an organic phosphine ligand, for example an organic phosphine selected from the group consisting of XPhos, APhos, CPhos, RuPhos, SPhos, cataCXium, DavePhos, JohnPhos, MePhos, XantPhos, Cy3P-HBF4, SPhos-SO3Na, Cy-BIPHEP, t-BuPPh2 and PPh3 and combinations thereof, preferably XPhos, APhos, CPhos, RuPhos, SPhos, cataCXium, more preferably XPhos, cataCXium and t-BuPPh2, and most preferably t-BuPPh2.

13. The method according to claim 11 or 12, wherein: The ligand:catalyst molar ratio is from 1:1 to 3:1, preferably 2:

1.

14. The method according to any one of claims 5 to 13, wherein: The base is an inorganic salt such as KOH, NaOH, Ca(OH)2, Na2CO3, K2CO3, Cs2CO3, KOAc, or NaOAc, a tertiary amine such as diisopropylethylamine (DIPEA), or triethylamine, or a combination thereof, preferably the base is KOAc or KOH.

15. The method according to any one of claims 5 to 14, wherein: The additive is present and is an alcohol, such as ethylene glycol.

16. The method according to any one of claims 5 to 15, wherein: The borylation step is characterized by at least one of the following: i) the catalyst is a precatalyst, which is Pd-XPhos-2G, and its amount is 0.05 mol% to 0.5 mol% relative to the molar number of X6b, preferably 0.25 mol% relative to the molar number of X6b; ii) the ligand is XPhos, and its amount is 0.1 mol% to 1 mol% relative to the molar number of X6b; preferably 0.5 mol% relative to the molar number of X6b; iii) the catalyst is Pd-XPhos-2G, the ligand is XPhos, and the molar number of XPhos is twice the molar number of Pd-XPhos-2G; iv) the borylation agent is bisboronic acid, and its amount is 1 to 3 molar equivalents compared to X6b, preferably 1.5 molar equivalents compared to X6b; v) the base is potassium acetate, and its amount is 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, more preferably 50°C.

17. The method according to claim 16, wherein: The reaction is:

18. The method according to any one of claims 5 to 15, wherein: The borylation step is characterized by at least one of the following: i) the catalyst is Pd-cataCXium-3G, and its amount is 0.001 mol% to 0.5 mol% relative to the molar number of X6b, preferably 0.05 mol% relative to the molar number of X6b; ii) the ligand is cataCXium, and its amount is 0.02 mol% to 1 mol% relative to the molar number of X6b, preferably 0.1 mol% relative to the molar number of X6b; iii) the catalyst is Pd-cataCXium-3G, the ligand is cataCXium, and the molar number of cataCXium is twice the molar number of Pd-cataCXium-3-3G; iv) the boronating agent is diboric acid, and its amount is 1 to 3 molar equivalents relative to X6b, preferably 1.5 molar equivalents relative to X6b; v) the base is N,N-diisopropylethylamine, and its amount is 2 to 5 molar equivalents relative to X6b, preferably an equivalent relative to X6b; vi) the amount of the additive is 2 to 5 molar equivalents relative to X6b; and / or vii) The reaction temperature is 30°C to 70°C, preferably 40°C to 50°C, more preferably 50°C.

19. The method according to claim 18, wherein: The reaction is:

20. The method according to any one of claims 5 to 14, wherein: The borylation step is characterized by at least one of the following: i. The catalyst is Pd(MeCN)2Cl2, in an amount of 0.1 mol% to 2 mol% relative to the mole number of X6b, 0.1 mol% to 1.5 mol%, preferably 0.25 mol% or more preferably 0.5 mol% relative to the mole number of X6b; ii. the ligand is tBuPPh2, and its amount is 0.2 mol% to 4 mol% relative to the mole number of X6b, and is 0.2 mol% to 3 mol% relative to the mole number of X6b, preferably 0.5 mol% or more preferably 1 mol%; iii. The catalyst is Pd(MeCN)2Cl2, the ligand is tBuPPh2, and the molar number of tBuPPh2 is two or three times the molar number of Pd(MeCN)2Cl2, preferably twice the molar number of Pd(MeCN)2Cl2; iv. the boronizing agent is bis(pinacol)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 equivalents relative to X6b; vi. The reaction temperature is 30°C to 120°C, such as 40°C to 50°C, preferably 60°C or 70°C.

21. The method according to claim 20, wherein: The reaction is:

22. The method according to any one of claims 3 to 21, wherein: X6a and F6 are converted to F7 via Suzuki coupling, wherein the Suzuki coupling is performed using one or more catalysts, one or more ligands, and / or one or more bases, and optionally one or more additives.

23. The method according to claim 22, wherein: The metal catalyst contains palladium, nickel, or copper, or a combination thereof, preferably palladium.

24. The method according to any one of claims 22 or 23, wherein: The ligand is selected from the group consisting of organic phosphines, N-heterocyclic carbenes, diazabutadiene, dibenzylideneacetone, and combinations thereof.

25. The method according to claim 24, wherein: The ligand is an organic phosphine ligand, for example, an organic phosphine selected from the group consisting of XPhos, APhos, CPhos, RuPhos, SPhos, Sphos-SO3Na, cataCXium, DavePhos, JohnPhos, MePhos, XantPhos, t-BuPPh2, PPh3 and combinations thereof, preferably XPhos, APhos, CPhos, RuPhos, SPhos, cataCXium, more preferably XPhos, cataCXium, t-BuPPh2, and most preferably t-BuPPh2.

26. The method according to any one of claims 22 to 25, wherein: The metal catalyst and ligand are provided together as a pre-catalyst complex, for example a Buchwald G1, G2, G3, or G4 pre-catalyst complex with a phosphine ligand such as XPhos, APhos, CPhos, RuPhos, SPhos, cataCXium, or a combination thereof.

27. The method according to any one of claims 22 to 25, wherein: The metal catalyst is provided as a precatalyst (eg, Pd(MeCN)2Ph2) together with a ligand (eg, t-BuPPh2).

28. The method according to any one of claims 22 to 27, wherein: The coupling is carried out in an alcohol solvent, an ether-based solvent (eg, THF, Me-THF), an aqueous solvent or a mixture thereof.

29. The method according to any one of claims 22 to 28, wherein: The coupling is characterized by at least one of the following: i. The catalyst or pre-catalyst 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%, 0.5 mol% or preferably 1 mol% relative to the molar number of F6 or X6a; ii. the molar amount of the ligand, if present, is two or three times, preferably two times, the molar amount of the catalyst or precatalyst; iii. the molar ratio of F6:X6a is from 2:1 to 1:2, or from 1.5:1 to 1:1.5, 1.2:1 to 1:1.2 or 1:1; iv. the additive is optional and, when present, is present in an amount of 2 to 5 molar equivalents relative to F6 or X6a; and / or v. The base is in an amount of 2 to 5 molar equivalents, preferably 2 to 3 molar equivalents, and most preferably 3 molar equivalents, relative to the molar number of F6 or X6a.

30. The method according to any one of claims 22 to 29, wherein: The coupling is characterized by one or more of the following: i. The catalyst and the ligand are provided as a pre-catalyst-ligand complex, the complex being Pd and X-Phos-2G in an amount of 0.5 mol% to 2 mol%, preferably 1%, relative to the molar number 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 / or v. The reaction temperature is 30°C to 70°C, preferably 40°C to 50°C, more preferably 50°C.

31. The method according to claim 30, wherein: The reaction is:

32. The method according to any one of claims 22 to 29, wherein: The coupling is characterized by at least one of the following: i) the catalyst is Pd(MeCN)2Cl2, the amount of which is 0.25mol% to 2mol% relative to the molar number of X6b, and 0.25mol% to 1.5mol%, preferably 0.5mol% or more preferably 1mol% relative to the molar number of X6b; (the conversion rate of X6b to X6a is about 98%) ii) the ligand is tBuPPh2, and its amount is 0.5 mol% to 4 mol% relative to the molar number of X6b, preferably 1 mol% or 2 mol% relative to the molar number of X6b; in particular, the catalyst is Pd(MeCN)2Cl2, the ligand is tBuPPh2, and the molar number of tBuPPh2 is twice the molar number of Pd(MeCN)2Cl2; iii) the base is KOH, and its amount is 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 vi) The reaction temperature is 30°C to 70°C, preferably 60°C.

33. The method of claim 32, wherein: The reaction is:

34. The method according to any one of claims 3 to 21 in combination with the method according to any one of claims 22 to 33, wherein The borylation and coupling were performed in a one-pot synthesis.

35. The method according to claims 20 and 32, wherein: The borylation and coupling were performed in a one-pot synthesis.

36. The method of claim 35, wherein: The reaction is:

37. A method according to any preceding claim, 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. A method for preparing a synthetic intermediate X6b: wherein X is F, Cl, Br, or I; the method comprises reacting compound X6d with compound N6a: wherein X is Cl, Br, or I, preferably Br.

39. The method of claim 38, comprising converting compound X6d to compound X6c: Where R 10 is an activated carboxylic acid group, such as an acyl anhydride, an acyl halide, or an acyl phosphate, and wherein X is Cl, Br, or I; and Compound X6c is reacted with compound N6a to form compound X6b.

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 method according to any one of claims 38 to 40, wherein: Coupling of X6d and N6a includes activating reagents such as HBT, HATU, HBTU, TBTU, HOBt, PyAOP, SOCl2, HCTU, PyClocK, TFFH, carbodiimides (e.g., DCC), carbonyldiimidazole (CDI), or phosphonium salts (e.g., BOP, PyBOP).

42. The method according to any one of claims 38 to 41, wherein: The coupling of X6d with N6a involves a base, preferably a tertiary alkylamine base such as triethylamine or DIPEA, or an arylamine base such as pyridine.

43. A method according to any one of claims 38 to 42, wherein: The formation of X6b is carried out in a mixture of solvents such as toluene and isopropyl acetate.

44. A process according to any one of claims 38 to 43, comprising preparing X6d from X6e:

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

46. ​​The method of claim 44 or 45, comprising preparing X6e from X6f: wherein X is Cl, Br, or I.

47. The method of claim 46, wherein: X6e was prepared by contacting X6f with X6g under coupling conditions: wherein X is F, Cl, Br, or I, m is 2 or 3, and R is F, Cl, Br, or I, OH, OC1-C6 alkyl, N(C1-C6 alkyl)2, aryl, or wherein two or three R groups other than F, Cl, Br, I, or OH may together form a cyclic boronate, such as pinacol borate, or N-methyliminodiacetic acid (MIDA) borate.

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

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

50. The method of claim 48 or 49, comprising preparing X6h from X6i:

51. The method of claim 50, wherein: X6h is prepared by contacting X6i with a halogenating agent, for example a chlorinating agent such as AlCl3, or N-chlorosuccinimide; a brominating agent selected from the group consisting of N-bromosuccinate, N-bromosuccinimide, DBDMH, TBAB, phosphorus tribromide, bromine chloride, aluminum tribromide, Br2 and FeBr3, HBr, tribromoisocyanuric acid, ammonium bromide with ozone, N,N,N',N'-tetrabromobenzene-1,3-disulfonamide (TBBDA), and combinations thereof; or an iodinating agent such as N-iodosuccinimide.

52. A process according to any preceding claim, comprising preparing N6a from N6b: wherein Y is Cl, Br, or I.

53. The method of claim 52, wherein: N6a is 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; HCl and SnCl2; samarium and NH4Cl; NH4Cl and iron; FeCl3, hydrazine hydrate; sodium bisulfite; hydrogen sulfide and alkali; hydroiodic acid; 1,3-dimethyl-2-imidazolidinone and sodium triethylsilanethiolate; and combinations thereof.

54. The process of claim 52 or 53, comprising preparing N6b from N6c:

55. The method of claim 54, wherein: N6b is prepared by contacting X6h with a halogenating agent, for example a chlorinating agent such as AlCl3, 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, Br2 and FeBr3, HBr, tribromoisocyanuric acid, ammonium bromide with ozone, TBBDA, and combinations thereof; or an iodinating agent such as N-iodosuccinimide.

56. The process of claim 54 or 55, comprising preparing N6c from N6d:

57. The method of claim 56, wherein: N6c is prepared by contacting N6d with a nitrating agent, such as 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; isoamyl nitrate, trifluoromethanesulfonic acid, and 1-ethyl-3-methylimidazolium trifluoromethanesulfonate; H-beta zeolite catalyst and N2O5; acetyl nitrate; and combinations thereof.

58. The process of claim 56 or 57, comprising preparing N6d from N6e:

59. The method of claim 58, wherein: N6d is prepared by contacting X6h with a diazotizing agent such as nitrous acid or sodium nitrite, followed by a fluorinating agent such as HF, under acidic conditions.

60. A process according to any preceding claim, comprising reacting compound F2 with compound F3 to obtain compound F6:

61. The method of claim 60, wherein: The method comprises reacting compound F2 with compound F3 to obtain compound F4:

62. The method of claim 61, wherein: The reaction of F2 and F3 is carried out under Mitsunobu reaction conditions, for example in the presence of a phosphine compound such as PPh3 and an azodicarboxylate such as DIAD or DEAD, preferably DIAD.

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

64. The method of any one of claims 60 to 62, comprising converting compound F4 to compound F6:

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

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

67. The method according to any one of claims 60 to 65, wherein: The method comprises reacting compound F2 with compound F3 in a one-pot reaction to obtain compound F4 and converting compound F4 into compound F6.

68. The process according to any one of claims 60 to 66, comprising preparing F2 from F1:

69. The method of claim 68, wherein: F2 is prepared from F1 using AlCl3, optionally wherein the solvent is xylene.

70. A method according to any preceding claim, wherein: The method was used in the synthesis of compound F11:

71. A method according to any preceding claim, comprising deprotecting F7 to obtain F8:

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

73. The method of any one of claims 71 or 72, comprising converting F8 to F11:

74. The method of claim 73, wherein: F11 was prepared by reacting F8 with acrylic anhydride (F9).

75. A synthetic intermediate X6b: wherein X is Cl, Br, or I, preferably Br.

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