Synthesis of omecamutibumecarbir

Abstract

Provided herein are synthetic methods for preparing intermediates utilized in the synthesis of omecamtiv mecarbil dihydrochloride.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 159,227, filed Mar. 10, 2021, the disclosure of which is hereby incorporated by reference in its entirety for all purposes.

Background Art

[0002] Cardiac myocytes are the basic units of the heart's muscle contraction. Cardiac myocytes are highly ordered cytoskeletal structures composed of cardiac myosin, actin, and a series of regulatory proteins. The discovery and development of small - molecule cardiac myosin activators could lead to promising treatments for acute and chronic heart failure and dilated cardiomyopathy (DCM), as well as conditions related to left and / or right ventricular systolic dysfunction or contractile reserve. Cardiac myosin is the cytoskeletal motor protein of cardiac muscle cells. It is directly involved in the conversion of chemical energy into mechanical force, which causes cardiac muscle contraction.

[0003] Current positive inotropes, such as beta - adrenergic receptor agonists or inhibitors of phosphodiesterase activity, increase the concentration of intracellular calcium, thereby increasing the contractility of cardiac myocytes. However, the increase in calcium levels increases the rate of cardiac muscle contraction and shortens the systolic ejection time, which is associated with potentially life - threatening side effects. In contrast, cardiac myosin activators function by a mechanism that directly stimulates the activity of the cardiac myosin motor protein without increasing intracellular calcium concentration. They accelerate the rate - limiting step of the myosin enzyme cycle and change it to select the force - generating state. Instead of increasing the rate of cardiac contraction, this mechanism lengthens the systolic ejection time, thereby increasing cardiac muscle contractility and cardiac output in a potentially oxygen - efficient way.

[0004] U.S. Patent No. 7,507,735 (incorporated herein by reference) discloses a genus of compounds comprising omecamtiv mecarbil (AMG423, CK-1827452) (hereinafter referred to as "omecamtiv mecarbil: OM") having the following structure: [ka]

[0005] OM is the first direct activator in the class of cardiac myosin, a motor protein that causes cardiac contraction. It is being evaluated as a potential treatment for heart failure in both intravenous and oral formulations, with the aim of establishing a new set of patient care in both hospital and outpatient settings. OM dihydrochloride hydrate is used orally as a treatment for heart failure. Specific conditions include, but are not limited to, acute (or decompensated) congestive heart failure and chronic congestive heart failure, particularly diseases associated with systolic cardiac dysfunction. Methods for manufacturing OM are disclosed in WO2014 / 152270 ("270 WO International Publication") and WO2019 / 006231 ("231 WO International Publication"). [ka]

[0006] The method for preparing OM disclosed in WO2014 / 152270 is summarized in Scheme 1. The method disclosed in '270 International Publication involves the preparation of the adjustable API starting materials piperazine nitro (PIPN)HCl and phenyl carbamate (PCAR)HCl from commercially available raw materials, 2-fluoro-3-nitrotoluene (FNT) and 5-amino-2-methylpyridine (APYR). Subsequently, PIPN is used together with other advanced intermediate compounds to produce OM. The method in '270 WO International Publication involves the use of the intermediate PMEC free base. PMEC free base is commercially available as an oil, but it contains varying amounts of piperazine, leading to the formation of undesirable BISN impurities in the PIPN product, as shown in Scheme 2. [ka]

[0007] The methods disclosed in the 231 WO International Public Publication describe commercially available methods for preparing OM, including methods utilizing stable crystalline salts of PMEC (i.e., PMEC phosphate hydrate) having low and constant levels of piperazine (Scheme 3). [ka]

[0008] The method for preparing OM disclosed in the 270 WO International Publication and the 231 WO International Publication uses FNT as a starting material. FNT is a raw material currently produced from 2-fluorotoluene using a short synthetic sequence. The drawback of this method is the necessary fractional distillation step of the isomer mixture produced to obtain the desired positional isomer, 2-fluoro-3-nitro-toluene, in acceptable purity, where the other isomers are less than 0.5% as measured by gas chromatography. Furthermore, the yield of the desired positional isomer of FNT obtained by this method is less than 10%. Considering the above, there is a need for the reproducible and efficient preparation of FNT and other compounds useful for the production of OM. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] U.S. Patent No. 7,507,735 [Patent Document 2] International Publication No. 2014 / 152270 [Patent Document 3] International Publication No. 2019 / 006231 [Overview of the project] [Means for solving the problem]

[0010] This disclosure relates to 2-fluoro-3-nitrotoluene. [ka] A method for synthesizing (FNT) is provided, comprising: (a) mixing 2-fluorotoluene with one or more bases and a boronating reagent to form a boronic acid; and (b) mixing the obtained boronic acid with iron nitrate or its hydrate to form FNT.

[0011] The disclosure also provides a method for synthesizing FNT, comprising (a) mixing 2-fluorotoluene with one or more bases and a boronating reagent to form a boronic acid, and (b) mixing the resulting boronic acid with nitric acid to form FNT.

[0012] This disclosure relates to 1-(bromomethyl)-2-fluoro-3-nitrobenzene [ka] A method for synthesizing (FNB), (a) Mix 2-fluoro-3-nitrotoluene (FNT) with a brominating agent in the presence of blue LED light to form a mixture with FNB and 1-(dibromomethyl)-2-fluoro-3-nitrobenzene [Chemical formula] (FNBr2), and (b) Mix the FNB / FNBr2 mixture with a dialkyl phosphite to form FNB, and (c) Optionally, (i) purify the FNB formed in step (b) by washing it with a dialkyl phosphite and a trialkylamine, or (ii) extract the FNB with an organic solvent and wash it with an aqueous base, and Further provide a method comprising.

Brief Description of the Drawings

[0013] [Figure 1] Shows a diagram of the setup for the flow chemistry preparation of LDA in Example 2-1. [Figure 2] Shows a diagram of the setup for the flow chemistry boronation reaction of 2-fluorotoluene in Example 2-1. [Figure 3] As described in Example 3, provide a diagram of the setup for the flow chemistry preparation of PIPN HBr from FNT. [Figure 4] As described in Example 3, shows a graph summarizing the concentration data of the fractions collected for the crude PIPN stream from the flow chemistry preparation of PIPN HBr from FNT.

Modes for Carrying Out the Invention

[0014] This specification provides methods for preparing FNT, as well as other compounds useful in the manufacture of OM and its salts and hydrates (e.g., OM dihydrochloride monohydrate). In some embodiments, the present disclosure provides methods for manufacturing starting materials and intermediate compounds used in commercial methods for preparing OM dihydrochloride monohydrate.

[0015] In some embodiments, the disclosed method is carried out in batch mode (i.e., “batch chemistry”). In other embodiments, the disclosed method is carried out using a continuous manufacturing method (i.e., “flow chemistry” or “continuous chemistry”). As used herein, continuous manufacturing refers to an integrated system of unit operations having a constant flow (steady or periodic). Disclosed methods utilizing continuous chemistry can provide the production of active pharmaceutical ingredient (API) in quantities from grams to metric tons. In yet another example, the disclosed method includes a combination of steps carried out using batch chemistry and steps carried out using continuous chemistry.

[0016] FNT synthesis method This disclosure provides a method for preparing FNT. In some embodiments, the method for synthesizing FNT comprises (a) mixing 2-fluorotoluene with one or more bases and a boronating reagent to form a boronic acid, and (b) mixing the resulting boronic acid with iron nitrate or its hydrate to form FNT. Alternatively, in some embodiments, this disclosure provides a method for preparing FNT in which step (a) is as described above, and step (b) is mixing the resulting boronic acid with nitric acid to form FNT. Exemplary embodiments of this method are shown in Scheme 4A and Scheme 4B, where the method shown in Scheme 4A represents a batch method, and the method shown in Scheme 4B includes a continuous production method (e.g., a flow chemistry method). [ka]

[0017] The disclosed method offers several advantages over previous preparations of FNT from 2-fluorotoluene, which is a readily available and relatively inexpensive starting material. For example, the borylation reaction of 2-fluorotoluene facilitates the improved regioselectivity of the method. The disclosed method advantageously provides a more regiospecific method for producing FNT with minimal byproducts compared to previous methods by providing the selective nitration of 2-fluorotoluene, thereby avoiding fractional distillation steps to obtain the desired regioisomers. In some embodiments, the FNT is further purified, for example, by simple distillation or crystallization (e.g., aqueous methanol). Further purification of FNT prepared by the disclosed method is simplified because byproducts (e.g., undesirable regioisomers) are minimal.

[0018] In addition, the disclosed method provides an improved FNT yield compared to previous methods using 2-fluorotoluene as a starting material, which provide FNT in a yield of only about 10%. In some embodiments, the disclosed method provides FNT in a total yield of more than 10%, for example, 15%, 20%, 25%, 30%, 35%, or 40% or more of 2-fluorotoluene.

[0019] base The disclosed method involves using one or more bases in a borylation reaction (i.e., step (a)). Any suitable base, such as an organic base, can be used in step (a). In some embodiments, one or more bases include lithium diisopropylamide (LDA), which can be formed, for example, by deprotonation of diisopropylamine (DIPA) with n-butyllithium.

[0020] In some embodiments, the disclosed method, in conjunction with other embodiments described above or below, further comprises treating the product from step (b) with a second base. In these embodiments, the second base may include any suitable base capable of neutralizing any excess acid. Suitable second bases include, for example, alkaline hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, barium hydroxide, tetramethylammonium hydroxide, and combinations thereof). In some embodiments, the second base includes sodium hydroxide (NaOH) (e.g., an aqueous solution of NaOH).

[0021] Boronation reaction A disclosed method for preparing FNT comprises a boration reaction in which a boronic acid is formed using a borating reagent. The borating reagent can be any suitable borating reagent. Suitable borating reagents include, for example, trialkyl borate. In some embodiments, the borating reagent comprises trimethyl (MeO)3B borate. In some embodiments, the borating reagent comprises triethyl (EtO)3B borate.

[0022] In some embodiments, in conjunction with other embodiments described herein, the LDA borylation reaction step is carried out as a flow chemistry step.

[0023] solvent In some embodiments, the methods disclosed herein are carried out in one or more suitable solvents. Exemplary suitable solvents include, for example, polar aprotic solvents, polar protic solvents, and nonpolar solvents. Suitable polar aprotic solvents include, for example, tetrahydrofuran, 1,2-dichloroethane (DCE), acetonitrile (MeCN), and mixtures thereof. Suitable nonpolar solvents include, for example, cyclohexane, pentane, hexane, benzene, toluene, diethyl ether, and combinations thereof. Suitable polar protic solvents include, for example, alcohols (e.g., methanol).

[0024] In some embodiments, in conjunction with other embodiments described above or below, step (a) is carried out in a solvent containing a polar aprotic solvent (e.g., tetrahydrofuran).

[0025] In conjunction with other embodiments described above or below, in some embodiments, step (b) is carried out in a solvent containing a nonpolar solvent (e.g., cyclohexane).

[0026] In some embodiments, in conjunction with other embodiments described above or below, step (b) is carried out in a solvent containing a polar aprotic solvent (e.g., DCE). In some embodiments in which step (b) is carried out in DCE, the DCE is present in an amount of 10 volumes relative to the boronic acid reagent.

[0027] In some embodiments, in conjunction with other embodiments described above and below, the disclosed method includes a solvent switch in which one or more additional solvents are introduced into the reaction vessel. In some embodiments, the one or more additional solvents substantially replace the solvent present before the introduction of the one or more solvents. For example, in some embodiments of the nitration reaction disclosed herein, the nitration reaction is carried out in a solvent containing 1,2-dichloroethane, and during the workup of the reaction, a solvent switch is performed so that methanol is introduced into the organic phase.

[0028] Nitration reaction A disclosed method for preparing FNT comprises nitrating a boronic acid to form FNT. In some embodiments, the disclosed method comprises mixing the boronic acid with iron nitrate or its hydrate to form FNT. In some embodiments, the iron nitrate is hydrated. In some embodiments, the iron nitrate has the formula Fe(NO3)3·XH2O, where X is an integer from 1 to 9. In some embodiments, the iron nitrate has the formula Fe(NO3)3·9H2O.

[0029] In some embodiments, in conjunction with other embodiments described above or below, the disclosed method includes mixing a boronic acid with nitric acid to form FNT. In embodiments involving nitration with nitric acid, the concentration of nitric acid may be any preferred concentration. In some embodiments, the concentration of nitric acid is 70% or more aqueous (e.g., 80% or more or 90% aqueous). In some embodiments, the disclosed method includes mixing the boronic acid with nitric acid while heating the reaction mixture. For example, the reaction mixture is heated to 50°C or above (e.g., 55°C, 60°C, 65°C, 70°C, 75°C, or 80°C or above).

[0030] Furthermore, in some embodiments, the reactants are heated for at least 8 hours, in conjunction with other embodiments described above or below. In some embodiments, the reactants are heated to 50°C or higher for at least 8 hours. In some embodiments, the reactants are heated to 60°C or higher for at least 8 hours. In some embodiments, the reactants are heated to 70°C or higher for at least 8 hours. In some embodiments, the reactants are heated to 80°C or higher for at least 8 hours. In various cases, the reactants are heated for 8 to 24 hours (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours). In some embodiments, the reactants are heated for 8 to 12 hours.

[0031] In some embodiments, in conjunction with other embodiments described above or below, the method further includes adding water to the reactants. For example, in some embodiments, 10 volumes of water are added to the boronic acid reagent. Furthermore, in some embodiments, the organic phase is washed with an aqueous solution of a base (e.g., sodium bicarbonate). In addition, in some embodiments, one or more additional organic solvents are added to facilitate the isolation of the product (e.g., solvent switch).

[0032] In some embodiments, the solvent is removed by distillation (e.g., vacuum distillation under reduced pressure). For example, in some embodiments, the solvent containing 1,2-dichloroethane is removed by vacuum distillation under reduced pressure (e.g., 35 Torr).

[0033] Crude FNT is purified using any preferred technique. In some embodiments, in conjunction with other embodiments described above or below, FNT is crystallized from methanol / water. In some embodiments, in conjunction with other embodiments described above or below, FNT is purified by fractional distillation at 110-120°C.

[0034] In some embodiments, in conjunction with other embodiments described herein, the nitration reaction is carried out in batch mode after the borylation reaction, which is carried out using a continuous production method.

[0035] Compounds useful for the preparation of OM In various embodiments, the disclosure provides methods for preparing intermediate compounds useful for preparing OM (e.g., FNT, FNB, PIPN or salts thereof, PMEC, PCAR, and / or PIPA), wherein the synthesis of the intermediate compounds includes the use of FNT. In some embodiments, FNT is prepared according to the methods described herein.

[0036] FNB In some embodiments, this disclosure relates to 1-(bromomethyl)-2-fluoro-3-nitrobenzene: [ka] This provides a method for synthesizing (FNB). In various embodiments, in conjunction with other embodiments described above or below, the disclosed method for synthesizing FNB involves mixing FNT with a brominating agent in the presence of blue LED light to produce FNB and the dibrominated compound 1-(dibromomethyl)-2-fluoro-3-nitrobenzene [ka] This involves forming a mixture with (FNBr2), where the FNB / FNBr2 mixture is mixed with dialkyl phosphite to form FNB.

[0037] As used herein, “blue LED light” refers to light emitted at a wavelength of 400 nm to 460 nm (e.g., 435 to 445 nm). An example of blue LED light is commercially available from MilliporeSigma (St. Louis, MO) with an LED light ring (IP68) having a wavelength of 435 to 445 nm.

[0038] In some embodiments, the disclosed method further includes further purification of the FNB by, for example, further washing and / or extraction methods. For example, in some embodiments, the FNB is further purified by washing it with dialkyl and trialkylamine phosphite bases, or by extracting the FNB with an organic solvent and washing it with an aqueous base. In some embodiments, the organic solvent for the FNB is toluene. In some embodiments, the aqueous base is an aqueous solution of sodium hydroxide.

[0039] In various embodiments, the FNT used to prepare the FNB is prepared according to the methods disclosed herein.

[0040] The brominater can be any suitable brominater. In some embodiments, the brominater is N-bromosuccinimide (NBS).

[0041] The dialkyl phosphite can be any suitable dialkyl phosphite. In some embodiments, the dialkyl phosphite is selected from the group consisting of dimethyl phosphite, diethyl phosphite, and combinations thereof. In some embodiments, the dialkyl phosphite is diethyl phosphite.

[0042] In various embodiments, the disclosed method for preparing FNB further comprises converting FNB, omecamutib mecarbil, to another compound suitable for preparation.

[0043] PIPN or its salt In some embodiments, the present disclosure relates to 4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate methyl [ka] The present invention provides a method for preparing (PIPN) or a salt thereof. Exemplary salts of PIPN include hydrobromide, hydrochloride, and mixtures thereof. In some embodiments, PIPN is prepared and / or isolated as hydrobromide.

[0044] PIPN-Photochemical Bromination In some embodiments, the Disclosure provides a method for preparing PIPN or a salt thereof, including a photochemical bromination reaction. For example, the Disclosure provides a method for synthesizing PIPN or a salt thereof from FNB prepared according to the photochemical method described herein. In various embodiments, the method involves FNB, a trialkylamine base, and piperazine methylcarboxylate. [ka] (PMEC) The process involves mixing phosphate hydrates to form PIPN or a salt thereof.

[0045] As used herein, a trialkylamine base may be any suitable trialkylamine base. Exemplary suitable trialkylamine bases include, for example, diisopropylethylamine (i.e., Hünig base), trimethylamine, and mixtures thereof.

[0046] PIPN-Free Radical Bromination In some embodiments, the Disclosure provides methods for preparing PIPN or a salt thereof from FNT obtained as described herein, wherein the bromination reaction is free radical bromination. For example, in some embodiments, the disclosed methods include mixing FNT, benzoyl peroxide, NBS, and acetic acid at a temperature of 70–95°C to form FNB; optionally extracting the FNB with toluene, washing the FNB with an aqueous basic solution, or both; and mixing the FNB, a trialkylamine base, and PMEC phosphate hydrate to form PIPN or a salt thereof.

[0047] In some embodiments, in conjunction with other embodiments described above or below, the method further comprises purifying the FNB formed before further transformation. For example, in some embodiments, the method further comprises extracting the FNB formed with toluene and washing it with an aqueous sodium hydroxide solution before mixing it with the trialkylamine base and PMEC phosphate hydrate. Furthermore, in some embodiments, the method further comprises washing the FNB formed with an aqueous sodium thiosulfate solution and an aqueous sodium chloride solution before mixing it with the trialkylamine base and PMEC phosphate hydrate.

[0048] Regardless of whether the bromination reaction is catalyzed by a photochemical or free radical method, it is desirable to minimize the amount of FNBr2 formed. In some embodiments, in conjunction with other embodiments described above or below, the method further includes adding dialkyl phosphite (e.g., diethyl phosphite) and a trialkylamine base before mixing FNB, a trialkylamine base, and a trialkylamine base, and mixing the resulting mixture at a temperature of 30-65°C.

[0049] In some embodiments, in conjunction with other embodiments described above or below, the present disclosure provides a continuous manufacturing method for producing PIPN·HBr using PMEC phosphate, as shown in Scheme 5. [ka]

[0050] As shown in Scheme 5, PIPN is isolated as hydrobromide. This is in contrast to the previous synthesis, which isolated PIPN as hydrochloride, inevitably resulting in a mixture of PIPN hydrobromide and PIPN hydrochloride. Thus, producing the corresponding PIPN salt using HBr instead of HCl provides only the PIPN HBr salt, which can be equally easily and effectively utilized in downstream synthetic routes. The flow method for preparing PIPN HBr (in contrast to the batch method used to prepare PIPN HCl) also provides the synthesis of the same required intermediate while reducing the number of unit operations.

[0051] In some embodiments, step (a) is performed in the presence of a polar aprotic solvent (e.g., acetonitrile), as described herein. In certain embodiments, step (a) is performed in the presence of an acid. Exemplary suitable acids include, for example, acetic acid, trifluoroacetic acid (TFA), and mixtures thereof.

[0052] In some embodiments, in conjunction with other embodiments described above or below, step (a) is heated (for example, to at least 80°C, or 80°C to 120°C, or 80°C to 100°C). In some embodiments, step (a) is heated for a period of time, for example, 5 to 20 minutes (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 minutes). In some embodiments, step (a) is heated to 80°C for 15 minutes.

[0053] In some embodiments, steps (b) and / or (c) are mixed in the presence of a polar protic solvent (e.g., MeOH) as described herein. In some embodiments, step (b) is mixed in the presence of a base (e.g., a trialkylamine base). In some embodiments, the trialkylamine is diisopropylethylamine (Hünig base).

[0054] In certain embodiments, step (b) is heated (for example, to 50°C, or 50°C to 80°C, or 50°C to 60°C). In some embodiments, step (b) is heated to 50°C for 10 minutes.

[0055] In some embodiments, step (c) is heated (for example, to 60°C, or 60°C to 90°C, or 60°C to 70°C). In some embodiments, step (c) is heated to 60°C for 10 minutes.

[0056] In some embodiments, before mixing the FNB, base, and PMEC phosphate hydrate in step (c), the method further includes adding diethyl phosphite and a trialkylamine base, and mixing the resulting mixture at a temperature of 30-65°C.

[0057] PMEC A disclosed method for preparing PIPN or a salt thereof involves using PMEC phosphate hydrate. In various embodiments, PMEC phosphate hydrate is prepared by a method comprising: (a) mixing piperazine and methyl chloroformate to form PMEC; (b) mixing PMEC with 0.5 molar equivalents of phosphoric acid to form PMEC phosphate hydrate; and (c) optionally filtering the PMEC phosphate hydrate from the mixture in step (b).

[0058] In some embodiments, step (a) is carried out in an aqueous solution and / or step (a) is carried out at a temperature of 20 to 55°C for a certain period of time (e.g., 1 to 12 hours).

[0059] In some embodiments, in conjunction with other embodiments described above or below, the disclosed method for preparing PIPN or a salt thereof further comprises isolating the PMEC formed from step (a) as a solution in a solvent selected from methylene chloride, dichloroethane, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, the PMEC is isolated by (i) washing the PMEC obtained from step (a) with an organic solvent, (ii) modifying the pH from 8 to 14 by adding a base to form a basic aqueous solution, and (iii) extracting the PMEC from the basic aqueous solution of step (ii) using methylene chloride, dichloroethane, 2-methyltetrahydrofuran, or a mixture thereof.

[0060] PIPA In some embodiments, this disclosure relates to 4-(3-amino-2-fluorobenzyl)piperazine-1-carboxylate methyl (PIPA): [ka] This provides a method for preparing (PIPA).

[0061] In various embodiments, the Disclosure provides a method for preparing PIPA from PIPN or a salt thereof obtained according to the Disclosed Method. In some embodiments, the Disclosure provides a method for synthesizing PIPA, comprising: (a) mixing PIPN or a salt thereof, an aqueous solution of an inorganic base, and toluene to form a free base solution of PIPN; (b) hydrogenating the free base solution of PIPN in a solvent containing a mixture of toluene and an alcohol solvent in the presence of a palladium catalyst to form crude PIPA (wherein the alcohol includes ethanol or isopropanol); and (c) crystallizing PIPA from the crude PIPA in heptane and toluene.

[0062] In some embodiments, the inorganic base includes sodium hydroxide.

[0063] PCAR, APYR, and NPYR In some embodiments, the present disclosure relates to phenyl(6-methylpyridine-3-yl)carbamate [ka] The disclosed method provides for (PCAR) or a salt thereof (e.g., PCAR hydrochloride). [ka] The process involves mixing (APYR) and phenyl chloroformate in acetonitrile to form PCAR or a salt thereof, wherein the mixing is carried out in the absence of N-methyl-2-pyrrolizinone (NMP). In some embodiments, PCAR is formed as a hydrochloride salt.

[0064] In some embodiments, the mixing is carried out at a temperature of 15–30°C for 1–15 hours.

[0065] In conjunction with other embodiments described above or below, in some embodiments, a disclosed method for synthesizing PCAR or a salt thereof further comprises purifying APYR by (i) washing a crude APYR isopropyl acetate solution containing up to 10% by weight of APYR hydrochloride with an aqueous sodium hydroxide solution, and mixing the washed APYR with charcoal to form an APYR solution after filtration, before mixing APYR with phenyl chloroformate, and (ii) crystallizing APYR derived from the APYR solution of step (i) from isopropyl acetate and heptane.

[0066] In some embodiments, in conjunction with other embodiments described above or below, APYR is (i) 2-methyl-5-nitropyridine (NPYR) in the presence of a palladium catalyst. [ka] It is prepared by a method comprising (ii) hydrogenating to form crude APYR, and (ii) crystallizing the crude APYR from isopropyl acetate and heptane.

[0067] In some embodiments, NPYR is washed with an aqueous sodium hydroxide solution of isopropyl acetate before step (i), and then the washed NPYR in isopropyl acetate is mixed with charcoal.

[0068] In some embodiments, the disclosed method further includes crystallizing the PCAR, in conjunction with other embodiments described above or below.

[0069] OM This disclosure provides a method for preparing OM (e.g., omecamutib mecarbil dihydrochloride monohydrate; "OM 2HCl H2O") from one or more intermediate compounds (e.g., FNT, FNB, PIPN or its salts, PIPA, PCAR, APYR, and / or NPYR) obtained from the methods disclosed herein.

[0070] In some embodiments, a disclosed method for preparing OM dihydrochloride monohydrate comprises (a) mixing PIPA, PCAR, and a trialkylamine base in acetonitrile and tetrahydrofuran to form a crude OM solution; (b) isolating the OM free base from the crude OM solution; and (c) mixing the isolated OM free base with isopropanol and 2-3 molar equivalents of hydrochloric acid in water to form OM dihydrochloride monohydrate. [ka]

[0071] The trialkylamine base is any preferred trialkylamine base as described herein.

[0072] In some embodiments, the isolation of step (b) includes crystallizing the free omecamutib mecarbil base by adding water to a solution of crude omecamutib mecarbil from step (a), and filtering the crystallized free omecamutib mecarbil base.

[0073] In some embodiments, the disclosed method further comprises crystallizing omecamutib mecarbil dihydrochloride monohydrate from isopropanol and water.

[0074] In some embodiments, in conjunction with other embodiments described above or below, the PCAR is prepared according to the methods disclosed herein.

[0075] In some embodiments, the present disclosure provides a process for preparing omecamutib mecarbil dihydrochloride monohydrate, comprising: (a) mixing PIPA, triphosgene, and a trialkylamine in acetonitrile and tetrahydrofuran to form PIPA isocyanate; (b) mixing PIPA isocyanate and APYR to form OM free base; and (c) mixing the OM free base with isopropanol and 2-3 molar equivalents of hydrochloric acid in water to form OM dihydrochloride monohydrate.

[0076] In some embodiments, step (a) is carried out via a continuous process, which includes mixing a first solution containing PIPA and a trialkylamine in acetonitrile with a second solution containing triphosgene in tetrahydrofuran using a micromixer tip and a reaction loop to form PIPA isocyanate.

[0077] In some embodiments, in conjunction with other embodiments described above or below, step (b) is carried out via a continuous process, which includes mixing a solution containing PIPA isocyanate with a solution containing AYPR using a Y mixer and a reaction loop.

[0078] Some of the methods disclosed herein include steps described as optional. In some cases, optional steps are not performed. In other cases, optional steps are performed.

[0079] Embodiment A method for synthesizing 1,2-fluoro-3-nitrotoluene ("FNT"), (a) Mixing 2-fluorotoluene with one or more bases and a boronating reagent to form a boronic acid, (b) Mixing the obtained boronic acid with iron nitrate or its hydrate to form the FNT, The method, including the method described above.

[0080] 2. The method according to Embodiment 1, wherein the one or more bases include lithium diisopropylamide (LDA).

[0081] 3. The method according to Embodiment 2, wherein the LDA is added in the presence of diisopropylamine (DIPA).

[0082] 4. The method according to any one of Embodiments 1 to 3, wherein step (a) is carried out in a polar aprotic solvent.

[0083] 5. The method according to Embodiment 4, wherein the polar aprotic solvent includes tetrahydrofuran (THF).

[0084] 6. The method according to any one of Embodiments 1 to 5, wherein step (b) is carried out in a nonpolar solvent.

[0085] 7. The method according to Embodiment 6, wherein the nonpolar solvent includes cyclohexane.

[0086] 8. The method according to any one of Embodiments 1 to 7, wherein the iron nitrate is hydrated.

[0087] 9. The iron nitrate is of the formula Fe(NO3)3 * The method according to Embodiment 8, comprising 9H2O.

[0088] 10. The method according to any one of Embodiments 1 to 9, further comprising treating the product from step (b) with a second base.

[0089] 11. A method for synthesizing 2-fluoro-3-nitrotoluene ("FNT"), (a) Mixing 2-fluorotoluene with one or more bases and a boronating reagent to form a boronic acid, (b) The obtained boronic acid is mixed with nitric acid to form the FNT, The method, including the method described above.

[0090] 12. The method according to Embodiment 11, wherein one or more bases include lithium diisopropylamide (LDA).

[0091] 13. The method according to Embodiment 12, wherein the LDA is added in the presence of diisopropylamine (DIPA).

[0092] 14. The method according to any one of Embodiments 11 to 13, wherein step (a) is carried out in a polar aprotic solvent.

[0093] 15. The method according to Embodiment 14, wherein the polar aprotic solvent includes tetrahydrofuran (THF).

[0094] 16. The method according to any one of Embodiments 11 to 15, wherein step (b) is carried out in a polar aprotic solvent.

[0095] 17. The method according to Embodiment 16, wherein the polar aprotic solvent comprises 1,2-dichloroethane (DCE).

[0096] 18. The method according to Embodiment 17, wherein the DCE is present in an amount of 10 volumes relative to the boronating reagent.

[0097] 19. The method according to any one of Embodiments 11 to 18, wherein the nitric acid is 90% aqueous.

[0098] 20. The method according to any one of embodiments 11 to 19, further comprising heating the mixture formed in step (b).

[0099] 21. The method according to Embodiment 20, wherein the mixture is heated for 8 hours or more.

[0100] 22. The method according to Embodiment 20 or 21, wherein the mixture is heated to 70°C for 8 hours or more.

[0101] 23. The method according to any one of embodiments 11 to 22, further comprising adding water to the mixture formed in step (b).

[0102] 24. The method according to Embodiment 23, wherein 10 volumes of water are added to the boronating reagent.

[0103] 25.1-(bromomethyl)-2-fluoro-3-nitrobenzene [ka] A method for synthesizing (FNB), (a) Mix 2-fluoro-3-nitrotoluene (FNT) with a brominating agent in the presence of blue LED light to produce FNB and 1-(dibromomethyl)-2-fluoro-3-nitrobenzene [ka] To form a mixture with (FNBr2), (b) The FNB / FNBr2 mixture is mixed with dialkyl phosphite to form FNB, (c)Optionally, purify the FNB formed in step (b) by (i) washing the FNB with dialkyl phosphite and trialkylamine, or (ii) extracting the FNB with an organic solvent and washing it with an aqueous base. The method, including the method described above.

[0104] 26. The method according to Embodiment 25, wherein the FNT is prepared by the method according to any one of Embodiments 1 to 24.

[0105] 27. The method according to Embodiment 25 or 26, wherein the organic solvent is toluene.

[0106] 28. The method according to any one of Embodiments 25 to 27, wherein the base is sodium hydroxide.

[0107] 29. The method according to any one of embodiments 25 to 28, wherein the brominating agent is selected from N-bromosuccinimide.

[0108] 30. The method according to any one of Embodiments 25 to 29, wherein the dialkyl phosphite is selected from the group consisting of dimethyl phosphite, diethyl phosphite, and combinations thereof.

[0109] 31. (d) The FNB, trialkylamine base, and piperazine methylcarboxylate [ka] (PMEC) phosphate hydrate is mixed with 4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate methyl [ka] The method according to any one of embodiments 25 to 30, further comprising forming (PIPN) or a salt thereof.

[0110] 32. (c) Mix the FNT, benzoyl peroxide, N-bromosuccinimide, and acetic acid at a temperature of 70-95°C to form 1-(bromomethyl)-2-fluoro-3-nitrobenzene [ka] Forming (FNB) and (d) Optionally, extract FNB with toluene, wash FNB with a basic aqueous solution, or both. (e) FNB, trialkylamine base, and piperazine methylcarboxylate [ka] (PMEC) phosphate hydrate is mixed with 4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate methyl [ka] (PIPN) or the formation of a salt thereof, The method according to any one of embodiments 1 to 24, further comprising:

[0111] 33. The method according to Embodiment 32, wherein FNB is extracted with toluene and washed with an aqueous sodium hydroxide solution before step (e).

[0112] 34. The method according to any one of embodiments 31 to 33, wherein the PIPN is formed as a hydrobromide salt.

[0113] 35. The PMEC phosphate hydrate is (a) Mixing piperazine and methyl chloroformate to form PMEC, (b) Mix PMEC with 0.5 molar equivalents of phosphoric acid to form PMEC phosphate hydrate, (c) Optionally, filter the PMEC phosphate hydrate from the mixture of step (b), The method according to any one of embodiments 31 to 34, prepared by a method including the following:

[0114] 36. The method according to embodiment 35, further comprising isolating the PMEC formed from step (a) as a solution in a solvent selected from methylene chloride, dichloroethane, 2-methyltetrahydrofuran, and mixtures thereof.

[0115] 37. The above isolation is (i) Wash the PMEC obtained from step (a) with an organic solvent, (ii) Modifying the pH from 8 to 14 by adding a base to form a basic aqueous solution, (iii) Extracting the PMEC from the basic aqueous solution of step (ii) using methylene chloride, dichloroethane, 2-methyltetrahydrofuran, or a mixture thereof, The method according to embodiment 36, as implemented by [the present invention].

[0116] 38. The method according to any one of embodiments 35 to 37, wherein step (a) is carried out in an aqueous solution.

[0117] 39. The method according to any one of embodiments 35 to 38, wherein step (a) is carried out at a temperature of 20 to 55°C for 1 to 12 hours.

[0118] 40. The method according to any one of Embodiments 31 to 39, wherein the trialkylamine base comprises diisopropylethylamine or triethylamine.

[0119] 41. The method according to any one of Embodiments 31 to 40, further comprising adding diethyl phosphite and the trialkylamine base before mixing the FNB, the trialkylamine base and the PMEC phosphate hydrate, and mixing the resulting mixture at a temperature of 30 to 65°C.

[0120] 42. (f) Mixing the PIPN or its salt, an aqueous solution of an inorganic base, and toluene to form a free PIPN base solution, (g) In the presence of a palladium catalyst in a solvent containing toluene and alcohol, the PIPN free base solution is hydrogenated to obtain crude 4-(3-amino-2-fluorobenzyl)piperazine-1-carboxylate methyl (PIPA): [ka] This involves forming (PIPA), The alcohol includes ethanol or isopropanol, and the formation is (h) Crystallizing the crude PIPA in heptane and toluene, The method according to any one of embodiments 31 to 41, further comprising:

[0121] 43. The method according to Embodiment 42, wherein the inorganic base contains sodium hydroxide.

[0122] 44. (i) The PIPA, phenyl(6-methylpyridine-3-yl)carbamate [ka] (PCAR) and a trialkylamine base are mixed in acetonitrile and tetrahydrofuran to form a crude omecamutib mecarbil solution, (j) Isolating the free omecamutib mecarbil base from the crude omecamutib mecarbil solution, (k) The isolated omecamutib mecarbil free base is mixed with isopropanol and 2-3 molar equivalents of hydrochloric acid in water to obtain omecamutib mecarbil dihydrochloride hydrate. [ka] To form, The method according to embodiment 42 or 43, further comprising the above.

[0123] 45. The method according to Embodiment 44, wherein the trialkylamine base comprises diisopropylethylamine or triethylamine.

[0124] 46. ​​The method according to Embodiment 44 or 45, wherein the isolation in step (h) comprises crystallizing the free omecamutib mecarbil base by adding water to the solution of crude omecamutib mecarbil from step (g), and filtering the crystallized free omecamutib mecarbil base.

[0125] 47. The method according to any one of Embodiments 44 to 46, further comprising crystallizing omecamutib mecarbil dihydrochloride hydrate from isopropanol and water.

[0126] 48. The PCAR or a salt thereof 5-amino-2-methylpyridine [ka] The method according to any one of Embodiments 44 to 47, wherein the preparation is carried out by a method comprising mixing (APYR) and phenyl chloroformate in acetonitrile to form PCAR or a salt thereof, the mixing being carried out in the absence of N-methyl 2-pyrrolidinone (NMP).

[0127] 49. The method according to Embodiment 48, wherein the mixing is carried out at a temperature of 15 to 30°C for 1 to 15 hours.

[0128] 50. The method according to Embodiment 48 or 49, wherein the PCAR is formed as a hydrochloride salt.

[0129] 51. The aforementioned APYR (i) 2-methyl-5-nitropyridine in the presence of a palladium catalyst [ka] The process involves hydrogenating (NPYR) to form crude APYR, (ii) Crystallizing the crude product from isopropyl acetate and heptane, The method according to any one of embodiments 48 to 50, prepared by a method comprising:

[0130] 52. The method according to Embodiment 51, further comprising washing the NPYR in isopropyl acetate with an aqueous sodium hydroxide solution before step (i), and then mixing the washed NPYR in isopropyl acetate with charcoal.

[0131] 53. Before mixing APYR and phenyl chloroformate, (i) Washing a crude APYR solution containing up to 10% by weight of APYR hydrochloride with an isopropyl acetate solution using an aqueous sodium hydroxide solution, and then mixing the washed APYR with charcoal, and after filtration, forming an APYR solution, (ii) Crystallizing the APYR derived from the APYR solution of step (i) from isopropyl acetate and heptane, The method according to any one of embodiments 48 to 52, further comprising purifying APYR by a method including the above.

[0132] 54. The method according to any one of embodiments 48 to 53, further comprising crystallizing PCAR.

[0133] 55. (i) Mixing the PIPA, triphosgene, and trialkylamine in acetonitrile and tetrahydrofuran to form PIPA isocyanate, (j) The PIPA isocyanate and 5-amino-2-methylpyridine [ka] (APYR) is mixed to form omecamutib mecarbil free base, (k) Mixing the free omecamutib mecarbil base with isopropanol and 2-3 molar equivalents of hydrochloric acid in water to form omecamutib mecarbil dihydrochloride hydrate, The method according to embodiment 42 or 43, further comprising the above.

[0134] 56. The method according to Embodiment 55, which is carried out via a continuous manufacturing process, wherein step (g) includes mixing a first solution containing PIPA and the trialkylamine in acetonitrile with a second solution containing triphosgene in tetrahydrofuran using a micromixer tip and a reaction loop to form the PIPA isocyanate.

[0135] 57. The method according to Embodiment 55 or 56, wherein step (h) is carried out via a continuous manufacturing process, comprising mixing the solution containing the PIPA isocyanate with the solution containing the AYPR using a Y mixer and a reaction loop.

[0136] 58. A method for preparing omecamutibumecarbil or a salt thereof, a hydrate thereof, or a salt hydrate thereof, comprising the method described in any one of Embodiments 1 to 43.

[0137] 59. The method according to Embodiment 58, wherein the omecamutibumecarbil, its salt, its hydrate, or its salt hydrate is omecamutibumecarbil dihydrochloride hydrate. [Examples]

[0138] The following embodiments further illustrate the methods of disclosure, but should not be interpreted as limiting their scope in any way.

[0139] The following abbreviations are used in the examples: PFR refers to a plug flow reactor; CSTR refers to a continuous stirred tank reactor; MTBE refers to methyl tert-butyl ether; NaOH refers to sodium hydroxide; LiCl refers to lithium chloride; EtOH refers to ethanol; and LCAP refers to liquid chromatography area percentage.

[0140] Example 1-1: Preparation of 2-fluoro-3-methylbenzeneboronic acid (2). This example demonstrates a method for preparing 2-fluoro-3-methylbenzeneboronic acid (i.e., boronic acid) according to embodiments of the present disclosure. [ka]

[0141] 320 mL of THF and 154.3 g of diisopropylamine were added to a 2 L four-necked round-bottom flask. The resulting mixture was cooled to -15°C and stirred. Then, while maintaining the temperature below -10°C, 582 mL of n-BuLi (2.5 M in n-hexane) was added dropwise under a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at -15°C for 30 minutes and then cooled to -35°C. Subsequently, while maintaining the temperature below -30°C, 80 g of 2-fluorotoluene(1) in 160 mL of THF solution was added dropwise. The resulting mixture was then stirred at -35°C for 1 hour. Then, while maintaining the temperature below -30°C, 158.5 g of trimethyl borate was added to the reaction mixture (an exothermic reaction was observed). The reaction mixture was stirred at -35°C for 2 hours and then warmed to room temperature.

[0142] Next, the reaction was quenched by adding 658 g of water and 343 g of 30% HCl solution while maintaining the temperature below 30°C. The resulting mixture was extracted with MTBE (3 × 160 mL). The organic layers were combined and a 1 M NaOH / H2O solution was added until the pH exceeded 10. The aqueous layer was then washed once with 160 mL of MTBE. 240 mL of MTBE and a 1 M HCl solution were added to the aqueous layer until the pH became 1. The aqueous layer was then further extracted with MTBE (2 × 240 mL). The resulting organic layers were combined, washed once with 160 mL of water, and then concentrated to obtain compound 2 as a white powder. This was used directly in the next reaction.

[0143] Examples 1-2: Preparation of 2-fluoro-3-nitrotoluene (FNT)(3). This example demonstrates a method for preparing FNT according to one embodiment of the present disclosure. [ka]

[0144] In a 1 L four-necked round-bottom flask, product 2 obtained from Example 1-1 was added to a mixture of 4 volumes of cyclohexane and 100 g (0.5 equivalents) of iron nitrate (Fe(NO3)3·9H2O). The resulting reaction mixture was stirred at 65–75°C for 12 hours. The reaction was monitored by HPLC until less than 5% of compound 2 was present. At this point, the reaction mixture was cooled to room temperature and filtered. The filtrate was washed with cyclohexane. The combined filtrate was then washed with 2 × 150 mL of 5% NaOH (aqueous solution), and then with 1 × 150 mL of water. The filtrate was concentrated and then distilled (e.g., at 40–60 mmHg and 110–115°C) to obtain 38–42 g of FNT(3).

[0145] Example 2-1: Flow preparation of 2-fluoro-3-methylbenzeneboronic acid (2). This example demonstrates a method for preparing 2-fluoro-3-methylbenzeneboronic acid (i.e., boronic acid) according to embodiments of the present disclosure.

[0146] The flow chemistry setup was as shown in Figure 1. Feeds A (THF) and B (DIPA) were connected via a T mixer at the relative flow rates described below. Subsequently, the T mixer connected the resulting flow to feed C, and lithiation was carried out in a PFR with a residence time of 5 minutes and a bath temperature of -40 to -10°C. The resulting mixtures were then passed through two continuous stirred tank reactors (CSTRs) with residence times of 12 to 14 minutes, maintaining an internal temperature of -5 to 30°C for each. The resulting solutions were collected under a nitrogen atmosphere and corresponded to a solution of approximately 1.5 M LDA in THF / hexane (Table 1). [Table 1]

[0147] The flow chemistry settings for the boration reaction procedure were as shown in Figure 2 under the conditions shown in Table 2. Feeds A and B were supplied to the continuous stirred tank reactor 1 (CSTR1) (internal temperature = -10 to 35°C) at a relative flow rate of 1:1.255 g / min (A:B) and a target residence time of approximately 40 minutes. The overflow from CSTR1 was supplied to CSTR2 (internal temperature 0 to 30°C, residence time approximately 40 minutes), and finally to CSTR3 (internal temperature 0 to 30°C, residence time = approximately 30 minutes). Feed C was supplied to CSTR3 at a relative flow rate of 1.40 g / min. [Table 2]

[0148] Batch isolation: The reaction mixture was quenched to 15-20 vol. of 4 M HCl aqueous solution below 30°C, the mixture was separated, and the aqueous phase was extracted with MTBE (3 × 5 vol.). The organic phase was added, and the pH was adjusted with 10% NaOH / H2O until the pH exceeded 10. The aqueous phase was washed with MTBE (1 × 3 vol.). Then, MTBE (5 vol.) was added to the aqueous phase, and the pH was adjusted with 1 M HCl until it reached 1-3. The resulting aqueous phase was extracted with MTBE (2 × 5 vol.). The organic phase was added, and washed once with water (3 vol.). Then, the organic phase was concentrated to 1-1.5 vol., water (5 vol.) was added for crystallization, and the reaction mixture was cooled to 0-10°C. After stirring for 2 hours, the mixture was filtered and rinsed with water (2 vol.). The crude solid was slurryed with heptane (3 vol.) for 1-3 hours, then the mixture was filtered and rinsed with heptane (1 vol.). The solid was dried with nitrogen at a temperature below 35°C to obtain 2-fluorotolueneboronic acid as a grayish-white or pale yellow powder.

[0149] Example 2-2: Preparation of 2-fluoro-3-nitrotoluene (FNT)(3) via nitric acid [ka] 2-fluoro-3-methylbenzeneboronic acid (2) was added to reactor 1. A NaOH scrubber was then attached to reactor 1 to quench the release of NO2 gas. Next, 1,2-dichloroethane (10 volumes) was added to reactor 1 at room temperature, and stirring was started, heating the reaction contents to 70°C. When reactor 1 reached 70°C ± 5°C, HNO3 (fuming, 90%, 1.3 equivalents) was added to the reactor. The reaction mixture was then stirred at 70°C ± 5°C for 8 hours.

[0150] Next, the reaction contents were cooled to 20°C. Then, water (10 vol) was added to reactor 1 and stirred for 30 minutes. Next, the contents of reactor 1 were polish-filtered and the aqueous phase was discarded. Next, sodium bicarbonate aqueous solution (10 vol) was added and stirred for 30 minutes, and the aqueous phase was discarded. Next, another sodium bicarbonate aqueous solution (10 vol) was added and stirred for 30 minutes, and the aqueous phase was discarded. Next, the solvent switch in the organic phase was performed from 1,2-dichloroethane to MeOH (8 vol). Norix-SX1 charcoal (2.5 wt%) was added and stirred for 2 hours. The contents of the reactor were filtered to remove the charcoal and the filter was washed with MeOH (2 vol). The contents of reactor 1 were cooled to 10°C, and while maintaining the temperature at 10°C, water (5 vol) was added over 3 hours. The contents of reactor 1 were held at 10°C for a further 30 minutes, and then cooled to 1-3°C. Next, the solid contents of reactor 1 were isolated by filtration and washed with 1:1 MeOH / water pre-cooled to 3°C. The resulting solid was dried under vacuum at 3°C ​​for 16 hours, and 3 was isolated as a pale yellow solid.

[0151] Alternative distillation purification: Next, 1,2-dichloroethane was removed by concentration under reduced pressure. The resulting brown oily substance was purified by distillation at 35 Torr. The product was distilled at 110-120°C, and a suitable fraction was collected to obtain a pale green liquid, which was then solidified to obtain the product as a white solid at room temperature.

[0152] Example 3: Flow preparation of PIPN HBr from FNT This embodiment demonstrates a flow chemistry method according to one embodiment of the present disclosure. [ka]

[0153] A stock solution of FNT(3) was prepared by dissolving 100 g (647 mmol) of FNT in 1087 mL of acetonitrile and 12 mL (161 mmol, 0.25 equivalents) of trifluoroacetic acid. Then, NBS (143 g, 806 mmol, 1.25 equivalents) was added while stirring the solution in the presence of blue LED light until it was homogeneous.

[0154] A diethyl phosphite stock solution was prepared by dissolving 33 mL (258 mmol, 0.40 equivalents) of diethyl phosphite in 100 mL of MeOH and 73 mL (418 mmol, 2.5 equivalents) of N,N-diisopropylethylamine.

[0155] A PMEC phosphate stock solution was prepared by dissolving 144 g (648 mmol, 1.0 equivalent) of PMEC phosphate in 300 mL of MeOH and 281 mL (1611 mmol, 2.5 equivalents) of N,N-diisopropylethylamine. The dilute slurry was then filtered, and the filter was rinsed with 100 mL of MeOH.

[0156] Next, the stock solutions were pumped at flow rates set as shown in Figure 3: 2.85 mL / min for the FNT solution, 0.46 mL / min for the diethyl phosphite solution, and 1.62 mL / min for the PMEC phosphate solution. The entire reaction loop was heated in a thermostat-controlled water bath.

[0157] The above setup was maintained for approximately 4 hours, with fractions collected periodically during the process. A summary of the crude PIPN flow concentration data is shown in Figure 4. Fractions 11 to 14 (approximately 600 mL) were collected for crystallization.

[0158] For crystallization, a seedbed was prepared by adding 80 mL of acetonitrile and 1.39 g of PIPN HBr to a 2 L ChemGlass reactor and heating to 60°C. Then, the crude PIPN solution was added at an addition rate of 300 mL / hour, along with the concentrated HBr solution at a rate of 26 mL / hour. After the addition was complete, the slurry was held at 60°C for 2 hours, then cooled to 25°C over 30 minutes, and held at this temperature for another 60 minutes.

[0159] The slurry was then filtered, and the solid was washed with 3 × 4 volumes of acetonitrile at 55°C. The material was then dried under nitrogen sweep. 53.55 g of PIPN HBr (76% yield) was recovered, which had a purity of 99.9 LCAP and 97.3 wt%.

[0160] The examples described herein are merely illustrative of embodiments of the methods disclosed herein and are not intended to limit the methods disclosed. Modifications and changes that are obvious to those skilled in the art are intended to fall within the scope and nature of this disclosure as defined in the appended claims.

[0161] All references, including publications, patent applications, and patents, cited herein are incorporated by reference to the same extent as if they were included in their entirety, provided that each reference is specifically indicated to be incorporated by reference.

[0162] In the context describing embodiments of this disclosure (particularly with respect to the claims), the use of the terms “a,” “an,” “the,” and “at least one,” as well as similar demonstrative pronouns, should be interpreted as encompassing both singular and plural forms, unless otherwise indicated herein or unless clearly inconsistent with the context. The use of the term “at least one” preceding the enumeration of one or more items (e.g., “at least one of A and B”) should be interpreted as meaning one item (A or B) selected from the enumerated items, or any combination of two or more enumerated items (A and B), unless otherwise indicated herein or unless clearly inconsistent with the context. The terms “comprising,” “having,” “including,” and “containing” should be interpreted as non-restrictive (i.e., “including” does not limit itself to these) unless specifically noted. The descriptions of value ranges herein are intended solely as a concise way of referring individually to each individual value contained within that range, unless otherwise indicated herein, and each individual value is incorporated herein as if it were individually described herein. All methods described herein may be carried out in any preferred order unless otherwise indicated herein, or unless otherwise clearly contradictory by context. Any and all examples provided herein, or the use of exemplary language (e.g., "etc.") are intended merely to illustrate embodiments of the disclosure well and, unless otherwise claimed, do not limit the scope of the disclosure. Nothing herein should be construed as indicating any unclaimed element essential for the implementation of the disclosure. The present invention provides, for example, the following items: (Item 1) A method for synthesizing 2-fluoro-3-nitrotoluene ("FNT"), (a) Mixing 2-fluorotoluene with one or more bases and a boronating reagent to form a boronic acid, (b) Mixing the obtained boronic acid with iron nitrate or its hydrate to form the FNT, The method, including the method described above. (Item 2) The method according to item 1, wherein the one or more bases include lithium diisopropylamide (LDA). (Item 3) The method according to item 2, wherein the LDA is added in the presence of diisopropylamine (DIPA). (Item 4) The method according to any one of items 1 to 3, wherein step (a) is carried out in a polar aprotic solvent. (Item 5) The method according to item 4, wherein the polar aprotic solvent comprises tetrahydrofuran (THF). (Item 6) The method according to any one of items 1 to 5, wherein step (b) is carried out in a nonpolar solvent. (Item 7) The method according to item 6, wherein the nonpolar solvent includes cyclohexane. (Item 8) The method according to any one of items 1 to 7, wherein the iron nitrate is a hydrate. (Item 9) The aforementioned iron nitrate is, formula Fe(NO 3 ) 3 * 9H 2 The method described in item 8, having O. (Item 10) The method according to any one of items 1 to 9, further comprising treating the product from step (b) with a second base. (Item 11) A method for synthesizing 2-fluoro-3-nitrotoluene ("FNT"), (a) Mixing 2-fluorotoluene with one or more bases and a boronating reagent to form a boronic acid, (b) The obtained boronic acid is mixed with nitric acid to form the FNT, The method, including the method described above. (Item 12) The method according to item 11, wherein the one or more bases include lithium diisopropylamide (LDA). (Item 13) The method according to item 12, wherein the LDA is added in the presence of diisopropylamine (DIPA). (Item 14) The method according to any one of items 11 to 13, wherein step (a) is carried out in a polar aprotic solvent. (Item 15) The method according to item 14, wherein the polar aprotic solvent comprises tetrahydrofuran (THF). (Item 16) The method according to any one of items 11 to 15, wherein step (b) is carried out in a polar aprotic solvent. (Item 17) The method according to item 16, wherein the polar aprotic solvent comprises 1,2-dichloroethane (DCE). (Item 18) The method according to item 17, wherein the DCE is present in an amount of 10 volumes relative to the boronating reagent. (Item 19) The method according to any one of items 11 to 18, wherein the nitric acid is 90% aqueous. (Item 20) The method according to any one of items 11 to 19, further comprising heating the mixture formed in step (b). (Item 21) The method according to item 20, wherein the mixture is heated for 8 hours or more. (Item 22) The method according to item 20 or 21, wherein the mixture is heated to 70°C for 8 hours or more. (Item 23) The method according to any one of items 11 to 22, further comprising adding water to the mixture formed in step (b). (Item 24) The method according to item 23, wherein 10 volumes of water are added to the boronating reagent. (Item 25) 1-(bromomethyl)-2-fluoro-3-nitrobenzene

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Claims

1. A method for synthesizing 2-fluoro-3-nitrotoluene ("FNT"), (a) Mixing 2-fluorotoluene with one or more bases and a boronating agent to form a boronic acid, (b) Mixing the obtained boronic acid with iron nitrate or its hydrate to form the FNT, The method, including the method described above.

2. The method according to claim 1, wherein the one or more bases include lithium diisopropylamide (LDA).

3. The method according to claim 2, wherein the LDA is added in the presence of diisopropylamine (DIPA).

4. The method according to any one of claims 1 to 3, wherein step (a) is carried out in a polar aprotic solvent.

5. The method according to claim 4, wherein the polar aprotic solvent comprises tetrahydrofuran (THF).

6. The method according to any one of claims 1 to 5, wherein step (b) is carried out in a nonpolar solvent.

7. The method according to claim 6, wherein the nonpolar solvent includes cyclohexane.

8. The method according to any one of claims 1 to 7, wherein the iron nitrate is a hydrate.

9. The method according to claim 8, wherein the iron nitrate has the formula Fe(NO₃)₃*9H₂O.

10. The method according to any one of claims 1 to 9, further comprising treating the product from step (b) with a second base.

11. A method for synthesizing 2-fluoro-3-nitrotoluene ("FNT"), (a) Mixing 2-fluorotoluene with one or more bases and a boronating agent to form a boronic acid, (b) Mixing the obtained boronic acid with nitric acid to form the FNT, The method, including the method described above.

12. The method according to claim 11, wherein the one or more bases include lithium diisopropylamide (LDA).

13. The method according to claim 12, wherein the LDA is added in the presence of diisopropylamine (DIPA).

14. The method according to any one of claims 11 to 13, wherein step (a) is carried out in a polar aprotic solvent.

15. The method according to claim 14, wherein the polar aprotic solvent comprises tetrahydrofuran (THF).

16. The method according to any one of claims 11 to 15, wherein step (b) is carried out in a polar aprotic solvent.

17. The method according to claim 16, wherein the polar aprotic solvent comprises 1,2-dichloroethane (DCE).

18. The method according to claim 17, wherein the DCE is present in an amount of 10 volumes relative to the boronating reagent.

19. The method according to any one of claims 11 to 18, wherein the nitric acid is 90% aqueous.

20. The method according to any one of claims 11 to 19, further comprising heating the mixture formed in step (b).

21. The method according to claim 20, wherein the mixture is heated for 8 hours or more.

22. The method according to claim 20 or 21, wherein the mixture is heated to 70°C for 8 hours or more.

23. The method according to any one of claims 11 to 22, further comprising adding water to the mixture formed in step (b).

24. The method according to claim 23, wherein 10 volumes of water are added to the boronation reagent.

25. 1-(bromomethyl)-2-fluoro-3-nitrobenzene 【Transformation 36】 A method for synthesizing (FNB), (a) Mix 2-fluoro-3-nitrotoluene (FNT) with a brominating agent in the presence of blue LED light to obtain FNB and 1-(dibromomethyl)-2-fluoro-3-nitrobenzene 【Chemistry 37】 (FNBr ２ ) forming a mixture with, (b) The FNB / FNBr ２ The mixture is mixed with dialkyl phosphite to form FNB, The method comprising, wherein the FNT is prepared by the method described in any one of claims 1 to 24.

26. The method of claim 25, further comprising (i) purifying the FNB formed in step (b) by washing the FNB with dialkyl phosphite and trialkylamine, or (ii) extracting the FNB with an organic solvent and washing with an aqueous base.

27. ​​The method according to claim 26, wherein the organic solvent is toluene.

28. The method according to claim 26 or claim 27, wherein the base is sodium hydroxide.

29. The method according to any one of claims 25 to 28, wherein the brominating agent is selected from N-bromosuccinimide.

30. The method according to any one of claims 26 to 29, wherein the dialkyl phosphite is selected from the group consisting of dimethyl phosphite, diethyl phosphite, and combinations thereof.

31. (d) The FNB, trialkylamine base, and piperazine methylcarboxylate 【Transformation 38】 (PMEC) phosphate hydrate is mixed to form 4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate methyl 【Chemistry 39】 The method according to any one of claims 25 to 30, further comprising forming (PIPN) or a salt thereof.

32. (c) Mix the FNT, benzoyl peroxide, N-bromosuccinimide, and acetic acid at a temperature of 70 to 95°C to form 1-(bromomethyl)-2-fluoro-3-nitrobenzene 【Chemistry 40】 Forming (FNB) and (e) FNB, trialkylamine base, and piperazine methylcarboxylate 【Chemistry 41】 (PMEC) phosphate hydrate is mixed to form 4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate methyl 【Chemistry 42】 Forming (PIPN) or a salt thereof, The method according to any one of claims 1 to 24, further comprising:

33. (d) Extracting FNB with toluene, washing FNB with an aqueous basic solution, or both. The method according to claim 32, further comprising:

34. The method according to claim 32 or 33, wherein, prior to step (e), FNB is extracted with toluene and washed with an aqueous sodium hydroxide solution.

35. The method according to any one of claims 31 to 34, wherein the PIPN is formed as a hydrobromide salt.

36. The PMEC phosphate hydrate is (a) Mixing piperazine and methyl chloroformate to form PMEC, (b) Mix PMEC with 0.5 molar equivalents of phosphoric acid to form PMEC phosphate hydrate, The method according to any one of claims 31 to 35, prepared by a method comprising:

37. The method according to claim 36, further comprising filtering the PMEC phosphate hydrate from the mixture of step (b).

38. The method according to claim 37, further comprising isolating the PMEC formed from step (a) as a solution in a solvent selected from methylene chloride, dichloroethane, 2-methyltetrahydrofuran, and mixtures thereof.

39. The isolation is (i) Washing the PMEC obtained from step (a) with an organic solvent, (ii) Forming a basic aqueous solution by adding a base to change the pH from 8 to 14, (iii) Extracting the PMEC from the basic aqueous solution of step (ii) using methylene chloride, dichloroethane, 2-methyltetrahydrofuran, or a mixture thereof, The method according to claim 38, as implemented by [the specified method].

40. The method according to any one of claims 36 to 39, wherein step (a) is carried out in an aqueous solution.

41. The method according to any one of claims 36 to 40, wherein step (a) is carried out at a temperature of 20 to 55°C for 1 to 12 hours.

42. The method according to any one of claims 31 to 41, wherein the trialkylamine base comprises diisopropylethylamine or triethylamine.

43. The method according to any one of claims 31 to 42, further comprising adding diethyl phosphite and the trialkylamine base before mixing the FNB, the trialkylamine base and the PMEC phosphate hydrate, and mixing the resulting mixture at a temperature of 30 to 65°C.

44. (f) Mixing the PIPN or its salt, an aqueous solution of an inorganic base, and toluene to form a PIPN free base solution, (g) In the presence of a palladium catalyst in a solvent containing toluene and alcohol, the PIPN free base solution is hydrogenated to obtain crude 4-(3-amino-2-fluorobenzyl)piperazine-1-carboxylate methyl (PIPA): 【Chemistry 43】 This involves forming (PIPA), The alcohol includes ethanol or isopropanol, and the formation is (h) Crystallizing the crude PIPA in heptane and toluene, The method according to any one of claims 31 to 43, further comprising:

45. The method according to claim 44, wherein the inorganic base comprises sodium hydroxide.

46. (i) The PIPA, phenyl(6-methylpyridine-3-yl)carbamate 【Chemistry 44】 (PCAR) and a trialkylamine base are mixed in acetonitrile and tetrahydrofuran to form a crude omecamutib mecarbil solution, (j) Isolating the free omecamutib mecarbil base from the aforementioned solution of crude omecamutib mecarbil, (k) The isolated omecamutib mecarbil free base is mixed with isopropanol and 2 to 3 molar equivalents of hydrochloric acid in water to obtain omecamutib mecarbil dihydrochloride hydrate. 【Chemistry 45】 To form, This also includes, The method according to claim 44 or claim 45.

47. The method according to claim 46, wherein the trialkylamine base comprises diisopropylethylamine or triethylamine.

48. The method according to claim 46 or 47, wherein the isolation in step (j) comprises adding water to the solution of crude omecamutibumecarbil from step (i) to crystallize the omecamutibumecarbil free base, and filtering the crystallized omecamutibumecarbil free base.

49. The method according to any one of claims 46 to 48, further comprising crystallizing the omecamutib mecarbil dihydrochloride hydrate from isopropanol and water.

50. The aforementioned PCAR or a salt thereof 5-amino-2-methylpyridine 【Chemistry 46】 It is prepared by a method comprising mixing (APYR) and phenyl chloroformate in acetonitrile to form PCAR or a salt thereof, wherein the mixing is carried out in the absence of N-methyl 2-pyrrolizinone (NMP). The method according to any one of claims 46 to 49.

51. The method according to claim 50, wherein the mixing is carried out at a temperature of 15 to 30°C for 1 to 15 hours.

52. The method according to claim 50 or 51, wherein the PCAR is formed as a hydrochloride salt.

53. The APYR is (i) 2-methyl-5-nitropyridine in the presence of a palladium catalyst 【Chemistry 47】 The process involves hydrogenating (NPYR) to form crude APYR, (ii) Crystallizing the crude product from isopropyl acetate and heptane, The method according to any one of claims 50 to 52, prepared by a method comprising:

54. The method according to claim 53, further comprising washing NPYR in isopropyl acetate with an aqueous sodium hydroxide solution before step (i), and then mixing the washed NPYR in isopropyl acetate with charcoal.

55. Before mixing APYR and phenyl chloroformate, (i) Washing a crude APYR solution containing up to 10% by weight of APYR hydrochloride with an isopropyl acetate solution with an aqueous sodium hydroxide solution, and then mixing the washed APYR with charcoal, and after filtration, forming an APYR solution, (ii) Crystallizing the APYR derived from the APYR solution of step (i) from isopropyl acetate and heptane, The method according to any one of claims 50 to 54, further comprising purifying APYR by a method including the above.

56. The method according to any one of claims 50 to 55, further comprising crystallizing PCAR.

57. (i) Mixing the PIPA, triphosgene, and trialkylamine in acetonitrile and tetrahydrofuran to form a PIPA isocyanate, (j) The PIPA isocyanate and 5-amino-2-methylpyridine 【Chemistry 48】 Mixing (APYR) to form omecamutib mecarbil free base, (k) Mixing the free omecamutib mecarbil base with isopropanol and 2 to 3 molar equivalents of hydrochloric acid in water to form omecamutib mecarbil dihydrochloride hydrate, This also includes, The method according to claim 44 or claim 45.

58. The method of claim 57, wherein step (i) is carried out via a continuous manufacturing process, comprising mixing a first solution containing PIPA and the trialkylamine in acetonitrile and a second solution containing triphosgene in tetrahydrofuran using a micromixer tip and a reaction loop to form the PIPA isocyanate.

59. The method according to claim 57 or 58, wherein step (j) is carried out via a continuous manufacturing process, comprising mixing the solution containing the PIPA isocyanate with the solution containing the AYPR using a Y mixer and a reaction loop.

60. A method for preparing omecamutibumecarbil or a salt thereof, a hydrate thereof, or a salt hydrate thereof, comprising the method according to any one of claims 1 to 45.

61. The method according to claim 60, wherein the omecamutibumecarbil, its salt, its hydrate, or its salt hydrate is omecamutibumecarbil dihydrochloride hydrate.

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