Method for synthesizing naphthyridine derivatives and intermediates thereof

Abstract

The present disclosure provides a method for a cross-coupling reaction, the method comprising: (a) exposing a mixture comprising a nickel(II) pre-catalyst, a phosphine, and an electrolyte in a solvent to an electric current to generate a nickel(0) catalyst; and (b) catalyzing the cross-coupling reaction with the nickel(0) catalyst. The present disclosure also provides methods for preparing Compound (A), or a salt thereof, Compound (F), and Compound (I), as described herein. TIFF2026508266000036.tif27170

Description

[Background technology]

[0001] Naphthyridine derivatives and intermediates have been shown to be important in many biological applications. To investigate their effectiveness, large amounts of material are required. Therefore, there is a need for an efficient, cost-effective process for preparing naphthyridine derivatives that is suitable for large scale. Summary of the Invention [Means for solving the problem]

[0002] The present disclosure provides a method for a cross-coupling reaction, the method comprising: (a) exposing a mixture comprising a nickel(II) pre-catalyst, a phosphine, and an electrolyte in a solvent to an electric current to generate a nickel(0) catalyst; and (b) catalyzing a cross-coupling reaction with the nickel(0) catalyst.

[0003] The present disclosure also provides Compound A or a salt thereof: [ka] (a) preparing a nickel(0) catalyst by exposing a mixture of a nickel(II) precatalyst, a phosphine, and an electrolyte in a solvent to an electric current to produce the nickel(0) catalyst; (b) preparing the nickel(0) catalyst by reacting the nickel(0) catalyst with compound B in the mixed solvent. [ka] and Compound C [ka] to form Compound A or a salt thereof, wherein Z is an amine protecting group and LG is a leaving group.

[0004] The present disclosure further provides compound F [ka] 1. A method for preparing a compound H comprising: (a) dissolving a compound H in a first solvent; [ka] with an organolithium reagent to form a lithiated intermediate; (b) reacting the lithiated intermediate with compound G in a second solvent; [ka] wherein X is a halogen and PG is a protecting group to form compound F.

[0005] The present disclosure also provides a method for preparing compound (I) using the processes disclosed herein. [ka] A method for preparing DETAILED DESCRIPTION OF THE INVENTION

[0006] Provided herein are methods for preparing various compounds useful as active pharmaceutical ingredients (APIs) and / or synthetic intermediates thereof (e.g., Compound A or a salt thereof, Compound F, and Compound I, as described herein).

[0007] Thus, the disclosed methods provide reduced environmental impact (eg, improved process "greenness"), as measured, for example, by a reduction in halogenated solvents.

[0008] The disclosed methods offer several advantages over conventional methods. For example, in various embodiments, the disclosed methods provide electrochemical processes that replace more expensive conventional processes that use harsh conditions (e.g., toxic metal reagents) or require more difficult reaction conditions (e.g., air-sensitive reagents). The disclosed methods also offer reduced environmental impact (e.g., improved process "greenness"), as measured, for example, by reduced waste streams. These advantages are particularly important when preparing APIs, which require strict control of conditions to minimize toxic impurities and waste by-products, especially when produced on an industrial scale.

[0009] In some embodiments, the disclosed methods provide electrochemical processes that replace the use of harsh metal bases (e.g., n-butyllithium and hexylmagnesium chloride, manganese and zinc metal reducing agents). In some embodiments, the disclosed methods use nickel(II)-containing compounds, which are air-stable and less expensive than other conventional reactants.

[0010] In some embodiments, the disclosed methods are carried out using a continuous manufacturing process (i.e., "flow chemistry" or "continuous chemistry"). As used herein, continuous manufacturing refers to an integrated system of units of operation with a constant flow rate (steady or cyclical). The disclosed methods utilizing continuous chemistry can provide for the production of gram to metric ton quantities of active pharmaceutical ingredients (APIs). In some embodiments, the disclosed methods include a combination of steps carried out using batch chemistry and steps carried out using continuous chemistry (i.e., "semi-batch mode").

[0011] The continuous processes disclosed herein advantageously provide reduced reaction times and reduced reaction by-products (e.g., as measured by solid formation). In some embodiments, the disclosed flow processes for preparing compound F include residence times (e.g., reaction times) as short as 30 seconds, compared to approximately 3 hours in conventional processes. Furthermore, the continuous processes disclosed herein improve overall efficiency and synthetic operations. For example, in some embodiments, the continuous process for preparing compound F described herein has a single crystallization step, replacing the three crystallization and carbon treatment steps in conventional processes—thereby reducing the number of operations and improving overall yield and efficiency.

[0012] In some embodiments involving a continuous process, the process is carried out in a continuous process apparatus. An illustrative continuous process apparatus is a plug flow reactor.

[0013] In some embodiments, the disclosed processes are carried out in batch mode (i.e., "batch chemistry" or "fed-batch mode").

[0014] In some embodiments, the present disclosure provides a method for a cross-coupling reaction, the method comprising: (a) exposing a mixture comprising a nickel(II) pre-catalyst, a phosphine, and an electrolyte in a solvent to an electric current to generate a nickel(0) catalyst; and (b) catalyzing a cross-coupling reaction with the nickel(0) catalyst.

[0015] Cross-coupling reaction In some embodiments, the disclosed methods provide methods for cross-coupling reactions. As understood, a cross-coupling reaction occurs when two fragments (e.g., a metal-containing fragment and an electrophile fragment) are joined together, typically using a metal catalyst. A cross-coupling reaction can be used to form a carbon-carbon bond or a carbon-heteroatom bond. In some cases, the metal-containing fragment and the electrophile fragment are present in the same compound (i.e., an intramolecular cross-coupling reaction). In some cases, the metal-containing fragment and the electrophile fragment are present in separate compounds (i.e., an intermolecular cross-coupling reaction).

[0016] In some embodiments, the cross-coupling reaction disclosed herein for carbon-carbon bonds (i.e., carbon-carbon cross-coupling reactions) is a Kumada reaction, a Heck reaction, a Sonogashira reaction, a Negishi reaction, a Stille reaction, a Suzuki reaction, or a Fukuyama reaction. In some embodiments, the carbon-carbon coupling reaction is a Suzuki reaction (e.g., Suzuki-Miyaura). As will be appreciated, a Suzuki reaction typically involves a cross-coupling reaction between a metal-containing compound (e.g., a boron-containing compound) and an electrophile, catalyzed by a palladium metal catalyst.

[0017] In some embodiments, the cross-coupling reaction is a reaction of a) a boron-, zinc-, or magnesium-containing compound with b) an electrophile, examples of which are described below.

[0018] Boron-containing compounds In some embodiments, the cross-coupling reaction is a reaction between a boron-containing compound and an electrophile. In some embodiments, the boron-containing compound is an aryl boronic acid, a heteroaryl boronic acid, an aryl boronic acid ester, or a heteroaryl boronic acid ester. In some embodiments, the boron-containing compound is a heteroaryl boronic acid.

[0019] The term "aryl" refers to an aromatic hydrocarbon group having 6 to 20 carbon atoms in the ring portion. Typically, aryl is a monocyclic, bicyclic, or tricyclic aryl having 6 to 20 carbon atoms. Furthermore, as used herein, the term "aryl" refers to an aromatic substituent, which may be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl, each of which may be optionally substituted with 1 to 4 substituents, such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(O)-O-, aryl-O-, heteroaryl-O-, amino, thiol, alkyl-S-, aryl-S-, nitro, cyano, carboxy, alkyl-OC(O)--, carbamoyl, alkyl-S(O)-, sulfonyl, sulfonamido, phenyl, and heterocyclyl.

[0020] The term "heteroaryl" refers to rings having 5 to 10 members, of which 1 to 4 (or 1 to 3) ring atoms are heteroatoms selected from N, O, and S, including monocyclic heteroaromatic rings and polycyclic aromatic rings (wherein a monocyclic aromatic ring is fused to one or more other aromatic rings).

[0021] Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, or thiadiazolyl (e.g., 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5 ... isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thia Zolyl, 2-triazolyl, 5-triazolyl, tetrazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzothienyl, benzofuranyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, benzisoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).

[0022] Compound B In some embodiments, the heteroaryl boronic acid is compound B [ka] wherein Z is an amine protecting group. The amine protecting group, Z, can be any suitable amine protecting group. In some embodiments, Z is a carbamate, such as tert-butoxycarbonyl (Boc), such that compound B has the formula: [ka] It has.

[0023] electrophiles The electrophile can be any suitable electrophile capable of reacting with a metal-containing compound in a cross-coupling reaction. In some embodiments, the electrophile is an alkenyl electrophile, an alkynyl electrophile, or an aryl electrophile. In some embodiments, the electrophile comprises a halide (e.g., F, Cl, Br, or I), a sulfonate ester, or a sulfamate.

[0024] Compound C In some embodiments, in conjunction with other embodiments disclosed herein, the electrophile is compound C [ka] where LG is a leaving group. The leaving group LG can be any suitable leaving group. In some embodiments, LG is a sulfonate ester, sulfamate, or halide. In some embodiments, the sulfonate ester is tosyl, mesyl, nosyl, or triflyl. In some embodiments, the sulfonate ester is tosyl, such that compound C has the formula [ka] It has.

[0025] Nickel(II) precatalyst As described herein, the disclosed cross-coupling reactions involve generating a nickel(0) catalyst using a nickel(II) precatalyst. The nickel(II) precatalyst can be any suitable precatalyst capable of generating a nickel(0) catalyst under the conditions described herein. In some embodiments, the nickel(II) precatalyst comprises a nickel(II) salt (e.g., a nickel(II) halide). In some embodiments, the nickel(II) halide is NiCldppp, NiClDME, NiCldppe, NiBrDME, NiCl6H0, NiBr3H0, NiI, NiCl, NiBr, NiCl(PPh3)2, NiCl2(PCy3)2, or NiCl2(dppf). In some embodiments, the nickel(II) precatalyst is NiClDME.

[0026] The nickel(II) pre-catalyst is present in any suitable concentration. In some embodiments, the nickel(II) pre-catalyst is present at 0.01 to 20 mole % based on Compound B (e.g., 0.01, 0.05, 0.10, 0.50, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, or 20.0 mole % based on Compound B). Alternatively, or in addition, in some embodiments, the nickel(II) pre-catalyst can be present at 0.1 to 10 mol % (e.g., 0.2 to 9.0, 0.3 to 8.0, 0.4 to 7.0, 0.5 to 6.0, 1.0 to 6.0, 2.0 to 6.0, or 3.0 to 6.0 mol % based on compound B) based on compound B. In some embodiments, the nickel(II) pre-catalyst is present at 5.0 mol % based on compound B.

[0027] electrolyte As described herein, the disclosed cross-coupling reactions are carried out in an electrolyte in a solvent. The electrolyte can be any suitable electrolyte capable of conducting an electric current. Illustrative electrolytes include, for example, alkylammonium salts and / or imide salts or alkali metal salts. In some embodiments, the electrolyte is an alkylammonium salt, for example, an alkali metal salt of NBu4PF6, NBu4BF4, NBu4ClO4, NBu4Cl, NBu4Br, or a combination thereof. In some embodiments, the electrolyte comprises an alkali metal salt of NBu4PF6.

[0028] In some embodiments, the alkali metal salt is LiCl, NaCl, KCl, KPF6, LiClO4, LiC2F6NO4S2, or a combination thereof.

[0029] In some embodiments, the electrolyte comprises LiC2F6NO4S2 (ie, lithium bis(trifluoromethanesulfonyl)imide).

[0030] The electrolyte is present in any suitable concentration. In some embodiments, the electrolyte is present in a concentration of 0.001 to 1.0 molar (e.g., 0.01, 0.05, 0.10, 0.10, 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, or 1.0 molar). Alternatively, or in addition, in some embodiments, the electrolyte can be present in a concentration of 0.01 to 0.5 molar (e.g., 0.01 to 0.4, 0.01 to 0.3, or 0.1 to 0.3 molar). In some embodiments, the electrolyte is present in a concentration of 0.1 molar. In some embodiments, the electrolyte is present in a concentration of 0.2 molar.

[0031] solvent Any suitable solvent can be used in the methods disclosed herein. In some embodiments, the solvent comprises acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, dimethylacetamide, dimethylformamide, acetone, water, methanol, ethanol, isopropanol, toluene, dichloromethane (DCM), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), or a combination thereof. In some embodiments, the solvent comprises acetonitrile and 2-methyltetrahydrofuran.

[0032] The solvent is present in any suitable amount. Typically, the solvent is present in an amount of 0 to 50 L / kg (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 L / kg). Alternatively, or in addition, in some embodiments, the solvent can be present in an amount of 1 to 25 L / kg (e.g., 1 to 20, 1 to 15, 2 to 10, or 2 to 5 L / kg). In some embodiments, the solvent is present in an amount of 4 L / kg.

[0033] phosphine The disclosed cross-coupling reaction involves generating a nickel(0) catalyst by exposing a mixture comprising a nickel(II) precatalyst, a phosphine, and an electrolyte to an electric current. Typically, the phosphine comprises a suitable ligand. In some embodiments, the phosphine comprises a monodentate phosphine ligand or a bidentate phosphine ligand.

[0034] In some embodiments, the monodentate phosphine ligand is P(nBu) 3 , P(tBu) 3 , or PCy 3 .

[0035] In some embodiments, the bidentate phosphine ligand is xantphos, dppe, dppp, or HP(nBu)3-BF4.

[0036] The phosphine is present in any suitable amount. In some embodiments, the phosphine is present in an amount of 0.03 to 50 mole % based on compound B (e.g., 0.03, 0.05, 0.10, 0.50, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22. 0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0, 30.5, 31.0, 31.5, 32.0, 32.5, 33.0, 33.5, 34.0, 34.5, 35.0, 35.5 , 36.0, 36.5, 37.0, 37.5, 38.0, 38.5, 39.0, 39.5, 40.0, 41.5, 42.0, 42.5, 43.0, 43.5, 44.0, 44.5, 45.0, 45.5, 46.0, 46.5, 47.0, 47.5, 48.0, 49.5, or 50.0 mol % based on Compound B. Alternatively, or in addition, in some embodiments, the phosphine can be present at 1.0 to 30 mol % (e.g., 5.0 to 25.0, 5.0 to 20.0, or 10.0 to 20.0 mol % based on Compound B). In some embodiments, the phosphine is present at 15 mol % based on Compound B.

[0037] current The disclosed cross-coupling reaction involves generating a nickel(0) catalyst by exposing a mixture containing a nickel(II) precatalyst, phosphine, and an electrolyte to an electric current. Typically, the electric current is applied to an anode and a cathode. Illustrative anodes include, for example, anodes comprising graphite, SS, Ni, Zn, Al, Fe, Mg, vitreous carbon, reticulated vitreous carbon, boron-doped diamond, platinum, copper, gold, or combinations thereof. In some embodiments, the anode comprises Zn, Mg, Al, Fe, Ni, or combinations thereof.

[0038] Illustrative cathodes include, for example, cathodes comprising graphite, SS, Ni, vitreous carbon, Zn, Al, Fe, reticulated vitreous carbon, boron-doped diamond, platinum, copper, gold, or combinations thereof.

[0039] In some embodiments, in conjunction with other embodiments disclosed herein, the current is 0 mA / cm at the cathode. 2 ~-100mA / cm 2 and 0 mA / cm at the anode 2 ~+100mA / cm 2 In some embodiments, in conjunction with other embodiments disclosed herein, the current is -20 mA / cm at the cathode. 2 and +20mA / cm at the anode 2 It has a density of

[0040] In some embodiments, in conjunction with other embodiments disclosed herein, the charge (i.e., the total charge passed) is about 2-10 F / mol (e.g., 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10 F / mol). In some embodiments, the total charge passed is 2-10 F / mol (e.g., 3-9 F / mol, 4-8 F / mol, or 5-7 F / mol). In some embodiments, the total charge passed is 5 F / mol.

[0041] base In some embodiments, the mixture comprising the nickel(II) pre-catalyst and the electrolyte further comprises a base. Illustrative suitable bases include, for example, alkylamine bases. In some embodiments, the alkylamine base is triethylamine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, or a combination thereof. In some embodiments, the alkylamine base comprises trimethylamine.

[0042] The base is present in a suitable amount. In some embodiments, the base is present in an amount of 0.1 to 5.0 equivalents relative to Compound B (e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0 equivalents relative to Compound B). Alternatively, or in addition, in some embodiments, the base can be present in 0.1 to 2.0 equivalents based on Compound B (e.g., 0.1 to 1.5, 0.1 to 1.0, 0.1 to 0.9, 0.1 to 0.8, 0.1 to 0.7, 0.1 to 0.6, or 0.2 to 0.5 equivalents based on Compound B). In some embodiments, the base is present in 0.3 equivalents based on Compound B.

[0043] In some embodiments, the mixture comprising the nickel(II) pre-catalyst and the electrolyte does not comprise a base. In these embodiments, the anode may be referred to as a "sacrificial anode" and comprises Zn, Mg, Al, Fe, Ni, or a combination thereof.

[0044] Cross-coupling reaction temperature The disclosed cross-coupling reactions are carried out at a suitable temperature. Typically, the cross-coupling reactions are carried out at a temperature between 20 and 80°C (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128 The cross-coupling reaction is carried out at a temperature of 6, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80° C. Alternatively, or in addition, in some embodiments, the reaction can be carried out at a temperature of, for example, 25-75° C., 30-70° C., 35-65° C., or 40-60° C. In some embodiments, the cross-coupling reaction is carried out at a temperature of 70° C.

[0045] Process for Compound A In some embodiments, the present disclosure provides a method for preparing Compound A or a salt thereof, the method comprising using the cross-coupling process disclosed herein. In conjunction with other embodiments disclosed herein, in some embodiments, the present disclosure provides a method for preparing Compound A or a salt thereof, the method comprising: (a) preparing a nickel(0) catalyst by exposing a mixture comprising a nickel(II) pre-catalyst, a phosphine, and an electrolyte in a solvent to an electric current to produce the nickel(0) catalyst; and (b) contacting the nickel(0) catalyst with Compound B and Compound C in the mixed solvent to form Compound A or a salt thereof, as described herein.

[0046] In some embodiments, the disclosure provides a method for preparing compound A or a salt thereof, comprising: (a) preparing a nickel(0) catalyst by exposing a mixture comprising a nickel(II) precatalyst (e.g., NiClDME), a phosphine (e.g., HP(n-Bu)BF), and an electrolyte (NBuPF or LiCFNOS) in a solvent (e.g., acetonitrile or 2-MeTHF) to an electric current to generate the nickel(0) catalyst; and (b) reacting the nickel(0) catalyst with compound B of the formula: [ka] and compound C of the formula [ka] to form Compound A or a salt thereof.

[0047] Mixed solvents In some embodiments, the mixed solvent comprises acetonitrile, 2-methyltetrahydrofuran, dimethylacetamide, dimethylformamide, acetone, water, methanol, ethanol, isopropanol, toluene, DCM, DMSO, NMP, water, or a combination thereof. In some embodiments, the mixed solvent is a mixture of an organic solvent and water. In some embodiments, the mixed solvent comprises 2-methyltetrahydrofuran and water.

[0048] The solvent mixture is present in a suitable amount. Typically, the solvent mixture is present in an amount of 1.0 to 50 L / kg (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 L / kg). Alternatively, or in addition, in some embodiments, the solvent can be present in an amount of 1 to 25 L / kg (e.g., 1 to 20, 1 to 15, 2 to 10, or 2 to 5 L / kg). In some embodiments, the mixed solvent is present at 22 L / kg, for example, 4 L / kg water and 18 L / kg 2-methyltetrahydrofuran.

[0049] In some embodiments, the mixed solvent further comprises an inorganic salt, hi some embodiments, the inorganic salt comprises potassium phosphate (K3PO4).

[0050] The inorganic salt is present in a suitable amount. Typically, the inorganic salt is present in 1 to 5 equivalents (e.g., 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0 equivalents). In some embodiments, the inorganic salt is present in 2 to 3 equivalents (e.g., 2.5 equivalents).

[0051] Process for Compound F In some embodiments, the present disclosure provides compound F [ka] wherein PG is a protecting group. The PG protecting group can be any suitable protecting group. In some embodiments, PG is a carbamate, trialkylsilyl, benzyl, trityl, or sulfonyl protecting group. Exemplary carbamates include Boc, FMOC, and CZB (benzyloxycarbonyl). Exemplary trialkylsilyls include TBS, TMD, TBDPS, and TES. In some embodiments, PG is Boc, FMOC, or BnO. In some embodiments, PG is Boc.

[0052] As described herein, the disclosed methods for preparing compound F offer several advantages over conventional processes (e.g., Grignard processes), including shorter reaction times and milder conditions.

[0053] The present disclosure provides a method for preparing compound F, comprising: (a) dissolving compound H in a first solvent; [ka] with an organolithium reagent to form a lithiated intermediate; (b) reacting the lithiated intermediate with compound G in a second solvent; [ka] wherein X is a halogen (e.g., F, Cl, Br, or I) to form compound F. In some embodiments, X is Br.

[0054] Organolithium Reagents In some embodiments, the organolithium reagent is an alkyllithium reagent. In some embodiments, the organolithium reagent is nBuLi.

[0055] The organolithium reagent is present in a suitable amount. In some embodiments, the organolithium reagent is present in 1.1 to 3 molar equivalents relative to Compound H. Thus, the organolithium reagent can be present in 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 molar equivalents relative to Compound H. In some embodiments, the organolithium reagent is present in 1.0 to 3.0, 1.5 to 3.0, 1.5 to 2.5, or 2.0 to 3.0 molar equivalents relative to Compound H. In some embodiments, the organolithium reagent is present in 2.5 molar equivalents relative to Compound H. In some embodiments, the organolithium reagent is present in 1.1 molar equivalents relative to Compound H.

[0056] First and second solvents The process for preparing compound F is carried out in a first solvent and a second solvent. In some embodiments, the first solvent comprises 2-methyltetrahydrofuran, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, heptane, hexane, cyclohexane, or a combination thereof. In some embodiments, the first solvent comprises 2-methyltetrahydrofuran.

[0057] In some embodiments, the second solvent comprises 2-methyltetrahydrofuran, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, or a combination thereof, hi some embodiments, the second solvent comprises 2-methyltetrahydrofuran.

[0058] In some embodiments, the first solvent and the second solvent are the same solvent.

[0059] temperature The processes disclosed herein for preparing compound F are carried out at a suitable temperature. In some embodiments, the processes are carried out at a temperature of -70°C to -50°C (e.g., -65 to -55°C and -60°C). In some embodiments, the reaction is carried out at a temperature of -60°C.

[0060] acidic solution In some embodiments, the disclosed process further includes (c) combining compound F with an acidic solution to form a quenched reaction mixture.

[0061] When present, the acidic solution can comprise any suitable acid. For example, in some embodiments, the acidic solution comprises hydrochloric acid. In some embodiments, the acidic solution further comprises an organic solvent. For example, in some embodiments, the acidic solution comprises hydrochloric acid and isopropanol.

[0062] In embodiments that include an acidic solution, the acidic solution has a suitable acid concentration. For example, in some embodiments, the acidic solution has an acid concentration of 0.5 to 4 molar (e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 molar). In some embodiments, the acidic solution has a concentration of 0.5 to 3.5 molar, 0.5 to 3.0 molar, 0.5 to 2.5 molar, 0.5 to 2.0 molar, 0.5 to 1.5 molar, or 1.0 to 1.5 molar, hi some embodiments, the acidic solution has a concentration of 1.3 molar.

[0063] In some embodiments, the acidic solution is present in an amount of 2.5 to 8 volume equivalents based on compound G. For example, the acidic solution can be present in 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0 volume equivalents based on compound G. In some embodiments, the acidic solution can be present in an amount of 2.5 to 8, 3.0 to 7.5, 3.5 to 7.0, 4.0 to 6.5, or 4.5 to 6.0 volume equivalents based on compound G.

[0064] Pre-crystallization mixture In some embodiments, the disclosed process further comprises combining the quenched reaction mixture with aqueous citric acid, brine, or both to form a pre-crystallization mixture. In some embodiments, the disclosed process further comprises crystallizing Compound F from the pre-crystallization mixture to provide crystalline Compound F.

[0065] In embodiments involving crystallizing Compound F, the crystallization is carried out using toluene and n-heptane as crystallization solvents.

[0066] Continuous Process In some embodiments, the process for preparing compound F, as described herein, is carried out in continuous process equipment or in semi-batch mode. When carried out as a continuous process, the continuous process (or process steps) are carried out in suitable equipment (e.g., a plug flow reactor).

[0067] Additionally, the continuous processes disclosed herein are carried out at a flow rate appropriate to provide a suitable residence time. Typically, the process is carried out at a total flow rate of 2 to 5,000 mL / min (e.g., 5, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1,000, 1,250, 1,500, 1,750, 2,000, 2,250, 2,500, 2,750, 3,000, 3,250, 3,500, 3,750, 4,000, 4,250, 4,500, 4,750, or 5,000 mL / min). For example, in some embodiments, the disclosed processes are performed at an overall flow rate of 60 mL / min. Alternatively, or in addition, the flow rate of each step of the process is performed at a suitable flow rate. In some embodiments, each step of the process is performed at a flow rate corresponding to the overall flow rates described herein. In some embodiments, each step of the process is performed at a flow rate of 15-100 mL / min (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mL / min). In some embodiments, in conjunction with other embodiments disclosed herein, the process is carried out to have a total residence time of 10 seconds to 5 minutes (e.g., 10 seconds, 15 seconds, 30 seconds, 45 seconds, 60 seconds, 1 minute, 1.5 minutes, 2 minutes, 2.5 minutes, 3.0 minutes, 3.5 minutes, 4.0 minutes, 4.5 minutes, or 5 minutes). In some embodiments, the residence time is 5 seconds to 1 minute (e.g., 15 seconds to 1 minute).

[0068] Process for Compound I In various embodiments, in conjunction with other embodiments disclosed herein, the present disclosure provides compounds of formula I [ka] A process for preparing

[0069] For example, compound F prepared according to the processes disclosed herein can be used in a subsequent process to provide compound I. For example, compound F prepared according to the processes disclosed herein can be converted to a compound of the formula: [ka] can be converted to [ka]

[0070] A compound of the formula [ka] can be reacted with Compound A or a salt thereof to produce Compound (I), which can be prepared according to the processes herein. This is illustrated in the retrosynthetic analysis of Compound (I) shown below. [ka]

[0071] Embodiment 1. A method for a cross-coupling reaction, comprising: (a) exposing a mixture comprising a nickel(II) pre-catalyst, a phosphine, and an electrolyte in a solvent to an electric current to produce a nickel(0) catalyst; and (b) catalyzing the cross-coupling reaction with the nickel(0) catalyst. 2. The method of embodiment 1, wherein the cross-coupling reaction is a carbon-carbon cross-coupling reaction. 3. The method of embodiment 1 or 2, wherein the carbon-carbon coupling reaction is a Kumada reaction, a Heck reaction, a Sonogashira reaction, a Negishi reaction, a Stille reaction, a Suzuki reaction, or a Fukuyama reaction. 4. The method of embodiment 3, wherein the carbon-carbon coupling reaction is a Suzuki-Miyaura reaction. 5. The method of any one of embodiments 1 to 4, wherein the cross-coupling reaction is a reaction between a) a boron-, zinc-, or magnesium-containing compound and b) an electrophile. 6. The method of embodiment 5, wherein the boron-containing compound is an aryl boronic acid, heteroaryl boronic acid, aryl boronic acid ester, or heteroaryl boronic acid ester. 7. The method of embodiment 6, wherein the boron-containing compound is a heteroarylboronic acid. 8. The method of any one of embodiments 5 to 7, wherein the electrophile is an alkenyl electrophile, an alkynyl electrophile, or an aryl electrophile. 9. The method of any one of embodiments 5-8, wherein the electrophile comprises a halide, sulfonate ester, or sulfamate. 10. The method of any one of embodiments 1-9, wherein the nickel(II) pre-catalyst comprises a nickel(II) salt. 11. The method of embodiment 10, wherein the nickel(II) salt comprises a nickel(II) halide. 12. The method of embodiment 11, wherein the nickel(II) halide is NiCl2dppp, NiCl2DME, NiCl2dppe, NiBr2DME, NiCl26H2O, NiBr23H2O, NiI2, NiCl2, NiBr2, NiCl2(PPh3)2, NiCl2(PCy3)2, or NiCl2(dppf). 13. The method of any one of embodiments 10-12, wherein the nickel(II) pre-catalyst is NiCl2DME. 14. The method of any one of embodiments 1-13, wherein the electrolyte comprises an alkylammonium salt, an imide salt, or a combination thereof. 15. The method of embodiment 14, wherein the alkylammonium salt is an alkali metal salt of NBu4PF6, NBu4BF4, NBu4ClO4, NBu4Cl, NBu4Br, or a combination thereof. 16. The method of embodiment 15, wherein the alkali metal salt is LiCl, NaCl, KCl, KPF6, LiClO4, or a combination thereof. 17. The method of any one of embodiments 1-16, wherein the electrolyte comprises an alkali metal salt of NBu4PF6. 18. The method of any one of embodiments 1-17, wherein the electrolyte comprises LiC2F6NO4S2. 19. The method of any one of embodiments 1-18, wherein the solvent comprises acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, dimethylacetamide, dimethylformamide, acetone, water, methanol, ethanol, isopropanol, toluene, dichloromethane, dimethyl sulfoxide, N-methyl-2-pyrrolidone, or a combination thereof. 20. The method of embodiment 19, wherein the solvent comprises acetonitrile and 2-methyltetrahydrofuran. 21. The method of any one of embodiments 1 to 20, wherein the phosphine comprises a monodentate phosphine ligand or a bidentate phosphine ligand. 22. The method of embodiment 21, wherein the monodentate phosphine ligand is P(nBu)3, P(tBu)3, or PCy3. 23. The method of embodiment 21, wherein the bidentate phosphine ligand is xantphos, dppe, dppp, or HP(nBu)3-BF4. 24. The method of embodiment 23, wherein the phosphine comprises HP(nBu)3-BF4. 25. The method of any one of embodiments 1 to 24, wherein an electric current is applied to the anode and the cathode. 26. The method of embodiment 25, wherein the anode comprises graphite, SS, Ni, Zn, Al, Fe, Mg, vitreous carbon, reticulated vitreous carbon, boron-doped diamond, platinum, copper, gold, or a combination thereof. 27. The method of embodiment 26, wherein the anode comprises Zn, Mg, Al, Fe, Ni, or a combination thereof. 28. The method of any one of embodiments 25-27, wherein the cathode comprises graphite, SS, Ni, vitreous carbon, Zn, Al, Fe, reticulated vitreous carbon, boron-doped diamond, platinum, copper, gold, or a combination thereof. 29. The current is 0 mA / cm at the cathode. 2~-100mA / cm 2 and 0 mA / cm at the anode 2 ~+100mA / cm 2 29. The method of any one of embodiments 1 to 28, wherein the density is 30. The current is -20mA / cm at the cathode. 2 and +20mA / cm at the anode 2 30. The method of embodiment 29, wherein the density is 31. The method of any one of embodiments 1 to 26 and 28 to 30, wherein the mixture further comprises a base. 32. The method of embodiment 31, wherein the base comprises an alkylamine base. 33. The method of embodiment 32, wherein the alkylamine base is triethylamine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, or a combination thereof. 34. The method of embodiment 33, wherein the alkylamine base comprises triethylamine. 35. Compound A or a salt thereof: [ka] 1. A method for preparing (a) preparing a nickel(0) catalyst by exposing a mixture comprising a nickel(II) precatalyst, a phosphine, and an electrolyte in a solvent to an electric current to produce the nickel(0) catalyst; (b) contacting a nickel(0) catalyst with compound B and compound C in a mixed solvent to form compound A or a salt thereof; [ka] where Z is an amine protecting group and LG is a leaving group. 36. The method of embodiment 35, wherein the nickel(II) pre-catalyst is a nickel(II) salt. 37. The method of embodiment 36, wherein the nickel(II) salt is a nickel(II) halide. 38. The method of embodiment 37, wherein the nickel(II) halide is NiCl2dppp, NiCl2DME, NiCl2dppe, NiBr2DME, NiCl26H2O, NiBr23H2O, NiI2, NiCl2, NiBr2, NiCl2(PPh3)2, NiCl2(PCy3)2, or NiCl2(dppf). 39. The method of any one of embodiments 35-38, wherein the nickel(II) pre-catalyst is NiCl2DME. 40. The method of any one of embodiments 35-39, wherein the electrolyte comprises an alkylammonium salt, an imide salt, or a combination thereof. 41. The method of embodiment 40, wherein the alkylammonium salt is an alkali metal salt of NBu4PF6, NBu4BF4, NBu4ClO4, NBu4Cl, NBu4Br, or a combination thereof. 42. The method of embodiment 41, wherein the alkali metal salt is LiCl, NaCl, KCl, KPF6, LiClO4, or a combination thereof. 43. The method of any one of embodiments 35-42, wherein the electrolyte comprises NBu4PF6, LiC2F6NO4S2, or a combination thereof. 44. The method of embodiment 43, wherein the electrolyte comprises an alkali metal salt of NBu4PF6. 45. The method of embodiment 44, wherein the electrolyte comprises LiC2F6NO4S2. 46. ​​The method of any one of embodiments 35-45, wherein the solvent comprises acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, dimethylacetamide, dimethylformamide, acetone, water, methanol, ethanol, isopropanol, toluene, dichloromethane, dimethyl sulfoxide, N-methyl-2-pyrrolidone, or a combination thereof. 47. The method of embodiment 46, wherein the solvent comprises acetonitrile and 2-methyltetrahydrofuran. 48. The method of any one of embodiments 35-47, wherein the phosphine comprises a monodentate phosphine ligand or a bidentate phosphine ligand. 49. The method of embodiment 48, wherein the monodentate phosphine ligand is P(nBu)3, P(tBu)3, or PCy3. 50. The method of embodiment 48, wherein the bidentate phosphine ligand is xantphos, dppe, dppp, or HP(nBu)3-BF4. 51. The method of embodiment 50, wherein the phosphine comprises HP(nBu)3-BF4. 52. The method of any one of embodiments 35 to 51, wherein an electric current is applied to an anode and a cathode. 53. The method of embodiment 52, wherein the anode comprises graphite, SS, Ni, Zn, Al, Fe, Mg, vitreous carbon, reticulated vitreous carbon, boron-doped diamond, platinum, copper, gold, or a combination thereof. 54. The method of embodiment 53, wherein the anode comprises Zn, Mg, Al, Fe, Ni, or a combination thereof. 55. The method of any one of embodiments 52-54, wherein the cathode comprises graphite, SS, Ni, graphite, SS, Ni, Zn, Al, Fe, Mg, vitreous carbon, reticulated vitreous carbon, boron-doped diamond, platinum, copper, gold, or a combination thereof. 56. The current is 0 mA / cm at the cathode. 2 ~-100mA / cm 2 and 0 mA / cm at the anode 2 ~+100mA / cm 2 56. The method of any one of embodiments 35 to 55, wherein the density is 57. The current is -20mA / cm at the cathode. 2 and +20mA / cm at the anode 2 57. The method of embodiment 56, wherein the densities of the densities are 5 F / mol. 58. The method of any one of embodiments 35-53 and 55-57, wherein the mixture further comprises a base. 59. The method of embodiment 58, wherein the base comprises an alkylamine base. 60. The method of embodiment 59, wherein the alkylamine base comprises triethylamine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, or a combination thereof. 61. The method of embodiment 59 or 60, wherein the base comprises triethylamine. 62. The method of any one of embodiments 35-61, wherein Z is a carbamate. 63. The method of embodiment 63, wherein the carbamate is tert-butoxycarbonyl (Boc). 64. The method of any one of embodiments 35-63, wherein LG is a sulfonate ester, sulfamate, or halide. 65. The method of embodiment 64, wherein the sulfonate ester is tosyl, mesyl, nosyl, or triflyl. 66. The method of embodiment 66, wherein the sulfonate ester is tosyl. 67. The method of any one of embodiments 35-66, wherein the mixed solvent comprises acetonitrile, 2-methyltetrahydrofuran, dimethylacetamide, dimethylformamide, acetone, water, methanol, ethanol, isopropanol, toluene, DCM, DMSO, NMP, water, or a combination thereof. 68. The method of embodiment 67, wherein the mixed solvent comprises 2-methyltetrahydrofuran and water. 69. The method of any one of embodiments 35 to 68, wherein the mixed solvent further comprises an inorganic salt. 70. The method of embodiment 69, wherein the inorganic salt comprises potassium phosphate (K3PO4). 71. The method of any one of embodiments 35 to 70, wherein the mixing is carried out in a continuous mode. 72. Compound F [ka] 1. A method for preparing (a) Compound H in a first solvent [ka] with an organolithium reagent to form a lithiated intermediate; (b) reacting the lithiated intermediate with compound G in a second solvent; [ka] wherein X is a halogen and PG is a protecting group to form compound F. 73. The method of embodiment 72, wherein the organolithium reagent is an alkyllithium reagent. 74. The method of embodiment 73, wherein the organolithium reagent is nBuLi. 75. The method of any one of embodiments 72-74, wherein the organolithium reagent is present in 1.1 to 3 molar equivalents relative to compound H. 76. The method of embodiment 75, wherein the organolithium reagent is present in 1.1 molar equivalents based on compound H. 77. The method of any one of embodiments 72-76, wherein the first solvent comprises 2-methyltetrahydrofuran, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, heptane, hexane, cyclohexane, or a combination thereof. 78. The method of embodiment 77, wherein the first solvent comprises 2-methyltetrahydrofuran. 79. The method of any one of embodiments 72-78, wherein the second solvent comprises 2-methyltetrahydrofuran, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, or a combination thereof. 80. The method of embodiment 79, wherein the second solvent comprises 2-methyltetrahydrofuran. 81. The method of any one of embodiments 72-80, wherein the first solvent and the second solvent are the same solvent. 82. The method of any one of embodiments 72-81, wherein X is F, Cl, Br, or I. 83. The method of embodiment 82, wherein X is Br. 84. The method of any one of embodiments 72-83, wherein PG is a carbamate, trialkylsilyl, benzyl, trityl, or sulfonyl protecting group. 85. The method of embodiment 84, wherein PG is Boc, FMOC, or BnO. 86. The method of embodiment 85, wherein PG is Boc. 87. The method of any one of embodiments 72 to 86, carried out at a temperature of -70°C to -50°C. 88. The method of any one of embodiments 71-87, further comprising: (c) combining compound F with an acidic solution to form a quenched reaction mixture. 89. The method of embodiment 88, wherein the acidic solution comprises hydrochloric acid. 90. The method of embodiment 88 or 89, wherein the acidic solution comprises hydrochloric acid and isopropanol. 91. The method of any one of embodiments 88 to 90, wherein the acidic solution has an acid concentration of 0.5 to 4 molar. 92. The method of embodiment 91, wherein the acidic solution has a concentration of 1.3 molar. 93. The method of any one of embodiments 88-92, wherein the acidic solution is present in 2.5 to 8 volume equivalents based on compound G. 94. The method of any one of embodiments 99-93, further comprising combining the quenched reaction mixture with aqueous citric acid, brine, or both to form a pre-crystallization mixture. 95. The method of embodiment 94, further comprising crystallizing Compound F from the pre-crystallization mixture to provide crystalline Compound F. 96. The method of embodiment 95, wherein the crystallization is carried out using toluene and n-heptane as crystallization solvents. 97. The method of any one of embodiments 72 to 96, carried out in a continuous process equipment or in semi-batch mode. 98. The method of embodiment 97, wherein the continuous process equipment is a plug flow reactor. 99. The method of embodiment 97 or 98, wherein steps a, b, and optionally c have a total residence time of 10 seconds to 5 minutes. 100. The method of embodiment 99, wherein the residence time is from 5 seconds to 1 minute. 101. The method of any one of embodiments 98 to 100, wherein steps a, b, and optionally c have a flow rate of 15 to 100 mL / min. 102. The method of embodiment 101, having an overall flow rate of 60 mL / min. 103. Using compound F, compound I [ka] 103. The method of any one of embodiments 72-102, further comprising preparing [Example]

[0072] The following examples further illustrate the disclosed methods but, of course, should not be construed as in any way limiting their scope.

[0073] Example 1 All charges are with respect to the arylboronic acid (ie, compound B).

[0074] Nickel(0) catalyst preparation A first reaction vessel was charged with NiCl2DME (5 mol%) as the nickel(II) precatalyst, tetrabutylammonium tetrafluoroborate (15 mol%) as the phosphine, NBu4PF6 (0.1 M) as the supporting electrolyte, and acetonitrile (4 L / kg) as the solvent. The reactor was equipped with a graphite cathode and a graphite anode and sealed. The reaction vessel was sparged with nitrogen, and triethylamine (0.3 equiv.) was added as a base. While under nitrogen, the reaction was stirred, and the current density at the cathode was maintained at −20 mA / cm until the required charge (5 F / mol) had passed. 2 maintained at

[0075] Cross Coupling A reaction vessel was charged with compound B, Z=Boc (1 equivalent), and 2-MeTHF (9 L / kg). The reaction vessel was sparged with nitrogen. A second reaction vessel was charged with compound C, LG=OTs (1.5 equivalents), and 2-MeTHF (9 L / kg) as a solvent. The second reaction vessel was sparged with nitrogen, charged with water, and sparged with nitrogen. A third reaction vessel was charged with potassium phosphate (2.5 equivalents). Water (4 L / kg) from the second reaction vessel was charged to the third reaction vessel and stirred until all the potassium phosphate was dissolved. The contents of the third reaction vessel were charged to the second reaction vessel. The second reaction vessel was stirred and heated to 70°C. The prepared nickel catalyst solution from the first reaction vessel was charged to the second reaction vessel. The contents of the first reactor 1 were charged to reactor 2 over 2.5 hours and stirred for 4 hours at 70° C. The second reactor was then cooled to 20° C. and held for 12 hours.

[0076] Post-treatment and crystallization A second reaction vessel was charged with HCl (2M, 6 L / kg) to provide a crystalline solid, which was then filtered. The resulting cake was washed with water (10 L / kg) and IPA (10 L / kg) to afford compound A (75% yield).

[0077] Example 2 Compound (A) - Electrochemical Catalyst Preparation Procedure: All charges are with respect to DABOchlor.

[0078] DABOchlor deprotection In reactor 1, the following [ka] DABOchlor (1 equivalent), 2-MeTHF (9 L / kg), water (8.8 L / kg), and acetic acid (0.23 L / kg) were charged. The contents of Reactor 1 were then stirred at 20° C. for 1 hour. A phase separation was performed and the aqueous layer was removed. A 10 wt % NaCl solution in water (9 L / kg) was prepared in Vessel 1. The contents of Vessel 1 were then charged to Reactor 1. Reactor 1 was stirred for 1 hour. A phase separation was performed and the aqueous layer was removed. The organic layer was saved for use in a later step.

[0079] Catalyst preparation Reactor 2 was charged with NiCl2DME (5 mol%), tributylphosphonium tetrafluoroborate (15 mol%), supporting electrolyte (0.2 M LiC2F6NO4S2 or 0.1 M NBu4PF6), and solvent (4 L / kg, MeCN or 2-MeTHF). Reactor 2 was equipped with a cathode (graphite, Ni, SS) and an anode (graphite, Zn, Ni) and sealed. Reactor 2 was sparged with nitrogen. Triethylamine (0.3 equiv.) was charged to Reactor 2. While under nitrogen, the reactants were stirred and the current density at the cathode was maintained at −20 mA / cm until the required charge (5 F / mol) had passed. 2 maintained at

[0080] Suzuki Cross Coupling Reactor 3 was charged with compound C (1.5 equivalents) and 2-MeTHF (9 L / kg). Reactor 3 was sparged with nitrogen. Vessel 2 was charged with water and sparged with nitrogen. Vessel 3 was charged with K3PO4 (2.5 equivalents). Water (4 V) from vessel 2 was charged to vessel 3 and stirred until all the K3PO4 was dissolved. The contents of vessel 3 were charged to reactor 3. Reactor 3 was stirred and heated to 70°C. The prepared nickel catalyst solution from reactor 2 was charged to reactor 3. The contents of reactor 1 were charged to reactor 3 over 2.5 hours. Reactor 3 was stirred at 70°C for 4 hours. Reactor 3 was then cooled to 20°C and held for 12 hours.

[0081] Post-treatment and crystallization Reactor 3 was charged with HCl (2 M, 6 L / kg). The contents of reactor 3 were then filtered. The resulting cake was washed with water (10 L / kg) and IPA (10 L / kg) to provide the hydrochloride salt of compound A.

[0082] Example 3 Lithiation Flow Procedure: Compound H, X-Br (1.05 equivalents, 1 M solution in 2-MeTHF) was lithiated with n-hexyllithium (2.3 M in hexane, 1.12 equivalents) in a pre-cooled -60°C plug flow reactor (11 seconds residence time). This stream was added to (compound G, PG = Boc) (1.0 equivalent, 1 M in 2-MeTHF) and reacted in a second pre-cooled -60°C plug flow reactor (7 seconds residence time). This additional stream was quenched with HCl (1.05 equivalents, 1.25 M in IPA) in a third pre-cooled -60°C plug flow reactor (5 seconds residence time). The product stream was quenched with 8.7 L / kg 2.5 wt% aqueous citric acid solution. After the flow process was completed, the product stream was charged to the reactor and the solution was mixed for 10 minutes. The lower aqueous phase was removed, and the organic phase was washed with 10.4 L / kg of 0.1 M potassium phosphate buffer (pH 7.4), followed by 8.7 L / kg of deionized water. The crude organic phase was heated to 50°C (jacket temperature) and distilled until approximately 4.3 L / kg remained. The solvent was then exchanged with toluene through two addition and removal distillations. In the final distillation, the solution was concentrated until approximately 5.2 L / kg remained. The solution was then heated to 45°C, and 8.7 L / kg of heptane was added over 30 minutes. The solution was seeded with 0.5 wt% pure compound F, PG=Boc, and then cooled to 0°C over 2 hours. After a 2-hour hold at 0°C, the crystallized material was filtered, and the reactor and cake were washed with 5.2 L / kg of 2:1 heptane:toluene (pre-cooled to 0°C), followed by 5.2 L / kg of heptane. The cake was dried under a stream of nitrogen for 12 hours to give compound F, PG=Boc (yield 74.8%).

[0083] Lithiation can also be carried out using n-butyllithium (2.5 M in hexane or 1.6 M in hexane) without significant change in purity. During development, the batch reaction may also be quenched with 3 M HCl in cyclopentyl methyl ether (CPME) without significant change in LC purity.

[0084] All references, including publications, patent applications, and patents, cited in this specification are herein incorporated by reference to the same extent as if each individual reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein.

[0085] Recitation of ranges of values ​​herein, unless otherwise indicated herein, is merely intended to serve as a shorthand method of referring individually to each separate value and each endpoint within the range, and each separate value and endpoint is incorporated herein as if each separate value and endpoint were individually recited herein.

[0086] The terms "a," "an," "the," and "the," and similar references, as used in the context of describing the present invention (particularly in the context of the claims below), should be construed to encompass both the singular and the plural, unless specifically stated otherwise herein or clearly contradicted by context. The use of the term "at least one" (e.g., "at least one of A and B") followed by a list of one or more items should be construed to mean one item (A or B) selected from the listed items or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" should be construed as open-ended terms (i.e., meaning "including but not limited to"), unless otherwise noted. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each alternative value falling within the range, unless otherwise indicated herein, and each alternative value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is merely intended to further clarify the disclosure and does not pose a limitation on the scope of the invention unless otherwise asserted. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

Claims

1. 1. A method for a cross-coupling reaction, comprising: (a) exposing a mixture comprising a nickel(II) pre-catalyst, a phosphine, and an electrolyte in a solvent to an electric current to form a nickel(0) catalyst; and (b) catalyzing the cross-coupling reaction with the nickel(0) catalyst.

2. 2. The method of claim 1, wherein the cross-coupling reaction is a reaction between a) a boron-, zinc-, or magnesium-containing compound and b) an electrophile.

3. 3. The method of claim 2, wherein the boron-containing compound is an aryl boronic acid, a heteroaryl boronic acid, an aryl boronic acid ester, or a heteroaryl boronic acid ester.

4. 4. The method of claim 2 or 3, wherein the electrophile comprises a halide, a sulfonate ester, or a sulfamate.

5. The method of any one of claims 1 to 4, wherein the nickel(II) pre-catalyst comprises a nickel(II) salt.

6. The nickel(II) pre-catalyst is NiCl ２ The method of claim 5, wherein the solvent is DME.

7. The method of any one of claims 1 to 6, wherein the electrolyte comprises an alkylammonium salt, an imide salt, or a combination thereof.

8. The electrolyte is NBu ４ PF ６ 8. The method of claim 7, comprising an alkali metal salt of

9. The electrolyte is LiC ２ F ６ NO ４ S ２ 9. The method of claim 7 or 8, comprising:

10. 10. The method of any one of claims 1 to 9, wherein the phosphine comprises a monodentate phosphine ligand or a bidentate phosphine ligand.

11. The monodentate phosphine ligand is P(nBu) ３ , P(tBu) ３ , or PCy ３ The method of claim 10, wherein

12. The bidentate phosphine ligand is xantphos, dppe, dppp, or HP(nBu). ３ -BF ４ The method of claim 10, wherein

13. The phosphine is HP(nBu) ３ -BF ４ 13. The method of claim 12, comprising:

14. The method according to any one of claims 1 to 13, wherein the electric current is applied to an anode and a cathode.

15. 15. The method of claim 14, wherein the anode comprises graphite, SS, Ni, Zn, Al, Fe, Mg, vitreous carbon, reticulated vitreous carbon, boron-doped diamond, platinum, copper, gold, or a combination thereof.

16. 16. The method of claim 15, wherein the anode comprises Zn, Mg, Al, Fe, Ni, or a combination thereof.

17. 17. The method of any one of claims 14 to 16, wherein the cathode comprises graphite, SS, Ni, vitreous carbon, Zn, Al, Fe, reticulated vitreous carbon, boron-doped diamond, platinum, copper, gold, or a combination thereof.

18. The current is 0 mA / cm at the cathode. ２ ~-100mA / cm ２ And 0 mA / cm at the anode ２ ~+100mA / cm ２ The method according to any one of claims 1 to 17, wherein the granules have a density of

19. The current is −20 mA / cm at the cathode ２ And +20mA / cm at the anode ２ 20. The method of claim 18, wherein the granular material has a density of

20. The method of any one of claims 1 to 15 and 17 to 19, wherein the mixture further comprises a base.

21. Compound A or a salt thereof: 【Chemistry 1】 1. A method for preparing (a) preparing a nickel(0) catalyst by exposing a mixture comprising a nickel(II) pre-catalyst, a phosphine, and an electrolyte in a solvent to an electric current to produce the nickel(0) catalyst; (b) reacting the nickel(0) catalyst with Compound B and Compound C in a mixed solvent: 【Chemistry 2】 wherein Z is an amine protecting group and LG is a leaving group to form Compound A or a salt thereof.

22. The nickel(II) pre-catalyst is NiCl ２ 22. The method of claim 21, wherein the compound is DME.

23. 23. The method of claim 21 or 22, wherein the electrolyte comprises an alkylammonium salt, an imide salt, or a combination thereof.

24. The electrolyte is NBu ４ PF ６ The method of any one of claims 21 to 23, comprising an alkali metal salt of

25. The electrolyte is LiC ２ F ６ NO ４ S ２ 25. The method of claim 24, comprising:

26. 26. The method of any one of claims 21 to 25, wherein the solvent comprises acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, dimethylacetamide, dimethylformamide, acetone, water, methanol, ethanol, isopropanol, toluene, dichloromethane, dimethylsulfoxide, N-methyl-2-pyrrolidone, or a combination thereof.

27. 27. The method of any one of claims 21 to 26, wherein the phosphine comprises a monodentate phosphine ligand or a bidentate phosphine ligand.

28. The phosphine is HP(nBu) ３ -BF ４ 28. The method of claim 27, comprising:

29. The method of any one of claims 21 to 28, wherein the electric current is applied to an anode and a cathode.

30. The method of any one of claims 21 to 29, wherein the mixture further comprises a base.

31. 31. The method of any one of claims 21 to 30, wherein the carbamate is tert-butoxycarbonyl (Boc).

32. 32. The method of any one of claims 21 to 31, wherein LG is a sulfonate ester, sulfamate, or halide.

33. 33. The method of any one of claims 21 to 32, wherein the mixed solvent comprises acetonitrile, 2-methyltetrahydrofuran, dimethylacetamide, dimethylformamide, acetone, water, methanol, ethanol, isopropanol, toluene, DCM, DMSO, NMP, water, or a combination thereof.

34. The method according to any one of claims 21 to 33, wherein the mixed solvent further comprises an inorganic salt.

35. The method of any one of claims 21 to 34, wherein the mixing is carried out in a continuous mode.

36. Compound F 【Transformation 3】 1. A method for preparing (a) Compound H in a first solvent 【Chemistry 4】 with an organolithium reagent to form a lithiated intermediate; (b) reacting the lithiated intermediate with compound G in a second solvent; 【Transformation 5】 wherein X is a halogen and PG is a protecting group to form compound F.

37. 37. The method of claim 36, wherein the organolithium reagent is an alkyllithium reagent.

38. 38. The method of claim 36 or 37, wherein the first solvent comprises 2-methyltetrahydrofuran, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, heptane, hexane, cyclohexane, or a combination thereof.

39. 39. The method of any one of claims 36 to 38, wherein the second solvent comprises 2-methyltetrahydrofuran, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, or a combination thereof.

40. 40. The method of any one of claims 36 to 39, wherein the first solvent and the second solvent are the same solvent.

41. 41. The method of any one of claims 36 to 40, wherein X is F, Cl, Br, or I.

42. 42. The method of any one of claims 36 to 41, wherein PG is a carbamate, trialkylsilyl, benzyl, trityl, or sulfonyl protecting group.

43. 43. The method of any one of claims 36 to 42, carried out in a continuous process equipment or in semi-batch mode.

44. Compound F was used to produce Compound I 【Transformation 6】 44. The method of any one of claims 36 to 43, further comprising preparing

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