Synthesis of omecamtiv mecarbil

Abstract

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

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 159,227, filed March 10, 2021, the disclosure of which is incorporated herein by reference in its entirety for all purposes. Background Technology

[0003] Cardiac sarcomeres are the basic units of muscle contraction in the heart. They are highly ordered cytoskeletal structures composed of cardiac myosin, actin, and a group of regulatory proteins. The discovery and development of small-molecule cardiac myosin activators will bring 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 systolic reserve. Cardiac myosin is a cytoskeletal motor protein in cardiomyocytes. It is directly responsible for converting chemical energy into mechanical force, thereby causing myocardial contraction.

[0004] Current positive inotropic agents, such as beta-adrenergic receptor agonists or phosphodiesterase activity inhibitors, increase intracellular calcium concentration, thereby increasing cardiac sarcomere contractility. However, increased calcium levels increase myocardial contractile velocity and shorten systolic ejection time, which has been associated with potentially life-threatening side effects. In contrast, myosin activators act through a mechanism that directly stimulates the activity of myosin motor proteins and do not increase intracellular calcium concentration. They accelerate the rate-determining step of the myosin cycle and make it favorable for force-generating state shifts. This mechanism does not increase the rate of cardiac contraction, but rather prolongs systolic ejection time, which increases myocardial contractility and cardiac output in a potentially more oxygen-efficient manner.

[0005] U.S. Patent No. 7,507,735 (incorporated herein by reference) discloses a compound comprising omecamtiv mecarbil (AMG 423, CK-1827452) (hereinafter referred to as "OM"), having the following structure:

[0006]

[0007] OM is a first-in-class direct activator of cardiac myosin, the motor protein that causes the heart to contract. It is being evaluated as a potential heart failure treatment in both intravenous and oral formulations, with the goal of establishing a new standard of care for patients in both inpatient and outpatient settings. OM dihydrochloride hydrate is used in oral formulations to treat heart failure. Specific conditions include, but are not limited to, acute (or decompensated) congestive heart failure and chronic congestive heart failure; in particular, diseases associated with systolic heart failure. Methods of making OM are disclosed in WO 2014 / 152270 (“Pub. No. ‘270 WO”) and WO 2019 / 006231 (“Pub. No. ‘231 WO”).

[0008] Scheme 1. Method of OM of WO 2014 / 152270

[0009]

[0010] The method of making OM disclosed in WO 2014 / 152270 is outlined in Scheme 1. The method disclosed in Pub. No. ‘270 WO includes making the modulating API starting materials piperazine nitro (PIPN) HC1 and phenyl carbamate (PCAR) HC1 from commercially available starting materials 2-fluoro-3-nitrotoluene (FNT) and 5-amino-2-methylpyridine (APYR). PIPN is then used with other advanced intermediate compounds to generate OM. As shown in Scheme 2, the method of Pub. No. ‘270 WO includes using the intermediate PMEC free base. Although PMEC free base is commercially available as an oil, it contains varying amounts of piperazine, resulting in the generation of an unwanted BISN impurity in the PIPN product.

[0011] Scheme 2.

[0012]

[0013] The method disclosed in Pub. No. ‘231 WO describes a commercial method of making OM, including a method that uses a stable PMEC crystalline salt (i.e., PMEC phosphate hydrate) with low and constant levels of piperazine (Scheme 3).

[0014] Scheme 3. Method of OM of WO 2019006231

[0015]

[0016] The process for the preparation of OM disclosed in publication '270WO and publication '231WO uses FNT as a starting material. FNT is a raw material manufactured today from 2-fluorotoluene using a short synthetic sequence. The disadvantage of this process is the necessary fractionation step of the isomer mixture produced in order to provide the desired positional isomer 2-fluoro-3-nitrotoluene with an acceptable purity, wherein the content of any other isomer does not exceed 0.5%, as measured by gas chromatography. Furthermore, the yield of the desired FNT positional isomer obtained by said process is less than 10%.

[0017] In view of the above, there is a need for reproducible, efficient preparation of FNT and other compounds for the manufacture of OM. SUMMARY

[0018] The present disclosure provides a process for the synthesis of 2-fluoro-3-nitrotoluene (FNT) comprising (a) mixing 2-fluorotoluene with one or more bases and a borylating reagent to form a boronic acid, and (b) mixing the resulting boronic acid with iron nitrate or a hydrate thereof to form FNT.

[0019] The present disclosure also provides a process for the synthesis of FNT comprising (a) mixing 2-fluorotoluene with one or more bases and a borylating reagent to form a boronic acid, and (b) mixing the resulting boronic acid with nitric acid to form FNT.

[0020] The present disclosure further provides a process for the synthesis of 1-(bromomethyl)-2-fluoro-3-nitrobenzene

[0021]

[0022] comprising

[0023] (a) mixing 2-fluoro-3-nitrotoluene (FNT) with a brominating agent in the presence of a blue LED light to form a mixture of FNB and 1-(dibromomethyl)-2-fluoro-3-nitrobenzene (FNBr2);

[0024] (b) mixing the FNB / FNBr2 mixture with a dialkyl phosphite to form FNB; and

[0025] (c) optionally purifying the FNB formed in step (b) by (i) washing the FNB with a dialkyl phosphite and a trialkyl amine, or (ii) extracting the FNB with an organic solvent and washing with an aqueous base. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 Schematic diagram of the setup for the flow chemistry preparation of LDA in Example 2-1.

[0027] Figure 2A schematic of the setup for the flow chemistry borylation of 2-fluorotoluene in Example 2-1 is provided.

[0028] Figure 3 A schematic of the setup for the flow chemistry preparation of PIPN HBr from FNT as described in Example 3 is provided.

[0029] Figure 4 The chart shown depicts a summary of concentration data for fractions of the crude PIPN stream collected from the flow chemistry preparation of PIPN HBr from FNT as described in Example 3. DETAILED DESCRIPTION

[0030] Provided herein are methods of preparing FNT and other compounds useful for the manufacture of OM and salts and hydrates thereof (e.g., OM dihydrochloride monohydrate). In some embodiments, the present disclosure provides methods of manufacturing starting materials and intermediate compounds for commercial processes for preparing OM dihydrochloride monohydrate.

[0031] In some embodiments, the disclosed methods are performed in batch mode (i.e., “batch chemistry”). In other embodiments, the disclosed methods are performed in a continuous manufacturing process (i.e., “flow chemistry” or “continuous chemistry”). As used herein, continuous manufacturing means an integrated system of unit operations with constant flow (steady or periodic). The disclosed methods utilizing continuous chemistry can provide production of active pharmaceutical ingredients (APIs) in kilogram to metric ton quantities. In yet other cases, the disclosed methods include a combination of steps performed using batch chemistry and steps performed using continuous chemistry.

[0032] Methods for synthesizing FNT

[0033] The present disclosure provides methods for preparing FNT. In some embodiments, the method for synthesizing FNT comprises: (a) mixing 2-fluorotoluene with one or more bases and a borylation reagent to form a boronic acid, and (b) mixing the resulting boronic acid with iron nitrate or a hydrate thereof to form FNT. Alternatively, in some embodiments, the present disclosure provides methods for preparing FNT, wherein step (a) is as described above, and step (b) is mixing the resulting boronic acid with nitric acid to form FNT. Exemplary embodiments of the method are shown in Schemes 4A and 4B, wherein the method depicted in Scheme 4A illustrates a batch process, and the method depicted in Scheme 4B includes a continuous manufacturing process (e.g., a flow chemistry process).

[0034] Schemes 4A-B:

[0035]

[0036] The disclosed methods provide a number of advantages over previous methods of preparing FNT from 2-fluorotoluene, which is an easily obtained and relatively inexpensive starting material. For example, the borylation reaction of 2-fluorotoluene helps to improve the regioselectivity of the method. In comparison to previous methods, the disclosed methods advantageously provide for the selective nitration of 2-fluorotoluene, which provides a more highly position-specific way to generate FNT with minimal byproducts, thereby avoiding the need for a fractional distillation step to obtain the desired position isomer. In some embodiments, the FNT is further purified, e.g., by simple distillation or crystallization (e.g., in methanol water). The further purification of the FNT prepared by the disclosed methods is simplified because of the minimal byproducts (e.g., unwanted position isomers).

[0037] In addition, the disclosed methods provide for improved FNT yields in comparison to previous methods that used 2-fluorotoluene as a starting material, which provided FNT yields of only about 10%. In some embodiments, the disclosed methods provide for FNT total yields of greater than 10%, e.g., 15%, 20%, 25%, 30%, 35%, or 40% or more, relative to 2-fluorotoluene.

[0038] Base

[0039] The disclosed methods include the use of one or more bases in the borylation reaction (i.e., step (a)). Any suitable base can be used in step (a), e.g., an organic base. In some embodiments, the one or more bases include lithium diisopropylamide (LDA), which can be formed by, e.g., deprotonation of n-butyllithium with diisopropylamine (DIPA).

[0040] In some embodiments, in combination with other above or below embodiments, the disclosed methods further include treating the product from step (b) with a second base. In those embodiments, the second base can include any suitable base that can neutralize any excess acid. Suitable second bases include, e.g., basic 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 NaOH solution).

[0041] Borylation reaction

[0042] The disclosed methods for preparing FNT include a borylation reaction that uses a borylating reagent to form a boronic acid. The borylating reagent can be any suitable borylating reagent. Suitable borylating reagents include, e.g., trialkyl borate. In some embodiments, the borylating reagent includes trimethyl borate (MeO)3B. In some embodiments, the borylating reagent includes triethyl borate (EtO)3B.

[0043] In some embodiments, in conjunction with other embodiments described herein, the LDA-boronation step is carried out as a flow chemistry step.

[0044] Solvent

[0045] 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).

[0046] In some embodiments, in conjunction with other above or below embodiments, step (a) is carried out in a solvent comprising a polar aprotic solvent (e.g., tetrahydrofuran).

[0047] In some embodiments, in conjunction with other above or below embodiments, step (b) is carried out in a solvent comprising a nonpolar solvent (e.g., cyclohexane).

[0048] In some embodiments, in conjunction with other above or below embodiments, step (b) is carried out in a solvent comprising 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.

[0049] In some embodiments, in conjunction with other above and below embodiments, the disclosed methods include 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 prior to introduction of the one or more solvents. For example, in some embodiments of the nitration reactions disclosed herein, the nitration reaction is carried out in a solvent comprising 1,2-dichloroethane, and during workup of the reaction, a solvent switch is performed so as to introduce methanol into the organic phase.

[0050] Nitration reaction

[0051] The disclosed methods for preparing FNTs include nitration of boronic acids to form FNTs. In some embodiments, the disclosed methods include mixing a boronic acid with ferric nitrate or a hydrate thereof to form an FNT. In some embodiments, the ferric nitrate is hydrated. In some embodiments, the ferric nitrate has the formula Fe(N03)3XH20, where X is an integer from 1 to 9. In some embodiments, the ferric nitrate has the formula Fe(N03)3 9H20.

[0052] In some embodiments, in combination with other above or below embodiments, the disclosed methods include mixing boric acid with nitric acid to form FNT. In embodiments that include nitration using nitric acid, the concentration of the nitric acid can be any suitable concentration. In some embodiments, the concentration of the nitric acid is a 70% or greater aqueous solution (e.g., 80% or greater or 90% aqueous solution). In some embodiments, the disclosed methods include mixing boric acid with nitric acid while heating the reaction mixture. For example, the reaction is heated to 50°C or greater (e.g., 55°C, 60°C, 65°C, 70°C, 75°C, or 80°C or greater).

[0053] Further, in some embodiments, in combination with other above or below embodiments, the reaction is heated for at least 8 hours. In some embodiments, the reaction is heated to 50°C or greater for at least 8 hours. In some embodiments, the reaction is heated to 60°C or greater for at least 8 hours. In some embodiments, the reaction is heated to 70°C or greater for at least 8 hours. In some embodiments, the reaction is heated to 80°C for at least 8 hours. In various cases, the reaction is heated for 8 hours 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 reaction is heated for 8 hours to 12 hours.

[0054] In some embodiments, in combination with other above or below embodiments, the method further includes adding water to the reaction. For example, in some embodiments, 10 volumes of water relative to the boric acid reagent is added. Further, in some embodiments, the organic phase is washed with an aqueous base (e.g., sodium bicarbonate). Further, in some embodiments, one or more additional organic solvents are added (e.g., solvent switching) to facilitate isolation of the product.

[0055] In some embodiments, distillation (e.g., vacuum distillation under reduced pressure) is used to remove the solvent. For example, in some embodiments, the solvent comprising 1,2-dichloroethane is removed by vacuum distillation under reduced pressure (e.g., 35 torr).

[0056] The crude FNT is purified using any suitable technique. In some embodiments, in combination with other above or below embodiments, the FNT is crystallized from methanol / water. In some embodiments, in combination with other above or below embodiments, the FNT is purified by fractional distillation at 110 to 120°C.

[0057] In some embodiments, in combination with other embodiments described herein, the nitration reaction is performed in a batch mode after the boronation reaction is performed using a continuous manufacturing method.

[0058] Compounds useful for making OM

[0059] In various embodiments, the present disclosure provides methods of making intermediate compounds (e.g., FNT, FNB, PIPN or salts thereof, PMEC, PCAR, and / or PIPA) useful for making OM, wherein the synthesis of the intermediate compounds comprises the use of FNT. In some embodiments, the FNT is made according to the methods described herein.

[0060] FNB

[0061] In some embodiments, the present disclosure provides a method for synthesizing 1- (bromomethyl)-2-fluoro-3-nitrobenzene:

[0062]

[0063] In various embodiments, in combination with other above or below embodiments, the disclosed methods for synthesizing FNB comprise mixing FNT with a brominating agent in the presence of a blue LED light to form a mixture of FNB and a dibrominated compound 1- (dibromomethyl)-2-fluoro-3-nitrobenzene (FNBr2), wherein the FNB / FNBr2 mixture is mixed with a dialkyl phosphite to form FNB.

[0064] As used herein, “blue LED light” refers to light emitted at a wavelength of 400 nm to 460 nm (e.g., 435-445 nm). An exemplary blue LED light is commercially available from MilliporeSigma (St. Louis, MO) with LED light ring (IP68) having a wavelength of 435-445 nm.

[0065] In some embodiments, the disclosed methods further comprise further purifying the FNB, for example, by a further washing and / or extraction process. For example, in some embodiments, the FNB is further purified by washing the FNB with a dialkyl phosphite and a trialkyl amine base or by extracting the FNB with an organic solvent and washing with an aqueous base. In some embodiments, the organic solvent in which the FNB is extracted is toluene. In some embodiments, the aqueous base is an aqueous sodium hydroxide solution.

[0066] In various embodiments, the FNT used to make FNB is made according to the methods disclosed herein.

[0067] The brominating agent can be any suitable brominating agent. In some embodiments, the brominating agent is N-bromosuccinimide (NBS).

[0068] 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.

[0069] In various embodiments, the disclosed methods for preparing FNB further comprise converting the FNB to other compounds suitable for use in preparing omecamtiv mecarbil.

[0070] PIPN or a salt thereof

[0071] In some embodiments, the present disclosure provides a method for preparing 4-(2- fluoro-3-nitrobenzyl)piperazine-1-carboxylic acid methyl ester (“PIPN”) or a salt thereof. Exemplary salts of PIPN include hydrobromide, hydrochloride, and mixtures thereof. In some embodiments, PIPN is prepared and / or isolated in the form of a hydrobromide salt.

[0072] PIPN - photochemical bromination

[0073] In some embodiments, the present disclosure provides a method for preparing PIPN or a salt thereof, comprising a photochemical bromination reaction. For example, the present disclosure provides a method of synthesizing PIPN or a salt thereof from FNB prepared according to the photochemical methods described herein. In various embodiments, the method comprises mixing FNB, a trialkyl amine base, and methyl piperazinecarboxylate (“PMEC”) phosphate hydrate to form PIPN or a salt thereof.

[0074] As used herein, the trialkyl amine base can be any suitable trialkyl amine base. Exemplary suitable trialkyl amine bases include, for example, diisopropylethylamine (i.e., Hunig’s base), trimethylamine, and mixtures thereof.

[0075] PIPN - radical bromination

[0076] In some embodiments, the present disclosure provides a method of preparing PIPN or a salt thereof from FNT obtained herein, wherein the bromination reaction is a radical bromination. For example, in some embodiments, the disclosed method comprises mixing FNT, benzoyl peroxide, NBS, and acetic acid at a temperature of 70 to 95 °C to form FNB; optionally extracting FNB with toluene, washing FNB with a basic aqueous solution, or both; and mixing FNB, a trialkyl amine base, and PMEC phosphate hydrate to form PIPN or a salt thereof.

[0077] In some embodiments, in combination with other above or below embodiments, the method further comprises purifying the formed FNB prior to performing further transformations. For example, in some embodiments, the method further comprises extracting the formed FNB with toluene and washing with aqueous sodium hydroxide prior to mixing with the trialkylamine base and PMEC phosphate hydrate. Further, in some embodiments, the method further comprises washing the formed FNB with aqueous sodium thiosulfate and aqueous sodium chloride prior to mixing with the trialkylamine base and PMEC phosphate hydrate.

[0078] Regardless of whether the bromination reaction is catalyzed by a photochemical method or a free radical method, it is desirable to minimize the amount of FNBr2formed. In some embodiments, in combination with other above or below embodiments, the method further comprises adding a dialkyl phosphite (e.g., diethyl phosphite) and a trialkylamine base prior to mixing the FNB, trialkylamine base, and PMEC phosphate hydrate, and mixing the resulting mixture at a temperature of 30 to 65 °C.

[0079] In some embodiments, in combination with other above or below embodiments, the present disclosure provides a continuous manufacturing process for producing PIPN HBr utilizing PMEC phosphate, as shown in Scheme 5.

[0080] Scheme 5

[0081]

[0082] As shown in Scheme 5, PIPN is isolated as the hydrobromide salt. This is in contrast to previous synthetic approaches in which PIPN is isolated as the hydrochloride salt, inevitably producing a mixture of PIPN hydrobromide and PIPN hydrochloride. Thus, generating the corresponding PIPN salt with HBr rather than HC1 provides only the PIPN HBr salt, which can be readily and efficiently used in downstream synthetic pathways. A flow process for making PIPN HBr (as opposed to a batch process for making PIPN HC1) provides the same synthesis of the desired intermediate while also reducing the number of unit operations.

[0083] As described herein, in some embodiments, step (a) is mixed in the presence of a polar aprotic solvent (e.g., acetonitrile). In particular embodiments, step (a) is mixed in the presence of an acid. Exemplary suitable acids include, for example, acetic acid, trifluoroacetic acid (TFA), and mixtures thereof.

[0084] In some embodiments, in combination with other above or below embodiments, step (a) is heated (e.g., heated to at least 80 °C, or heated to 80 °C to 120 °C, or heated to 80 °C to 100 °C). In some embodiments, step (a) is heated for a period of time, e.g., 5 to 20 minutes (e.g., 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.

[0085] As described herein, in some embodiments, step (b) and / or step (c) is mixed in the presence of a polar protic solvent (e.g., MeOH). 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 (Hunig’s base).

[0086] In particular embodiments, step (b) is heated (e.g., heated to 50 °C, or heated to 50 °C to 80 °C, or heated to 50 °C to 60 °C). In some embodiments, step (b) is heated to 50 °C for 10 minutes.

[0087] In some embodiments, step (c) is heated (e.g., heated to 60 °C, or heated to 60 °C to 90 °C, or heated to 60 °C to 70 °C). In some embodiments, step (c) is heated to 60 °C for 10 minutes.

[0088] In some embodiments, prior to mixing the FNB, base, and PMEC phosphate hydrate of step (c), the method further comprises adding diethyl phosphite with a trialkylamine base and mixing the resulting mixture at a temperature of 30 to 65 °C.

[0089] PMEC

[0090] The disclosed methods for making PIPN or a salt thereof include the use of a PMEC phosphate hydrate. In various embodiments, the PMEC phosphate hydrate is made by a method comprising: (a) mixing a piperazine with methyl chloroformate to form a PMEC; (b) mixing the PMEC with 0.5 molar equivalents of phosphoric acid to form a PMEC phosphate hydrate; and (c) optionally filtering the PMEC phosphate hydrate from the mixture of step (b).

[0091] In some embodiments, step (a) is performed in an aqueous solution and / or step (a) is performed at a temperature of 20 to 55 °C for a period of time (e.g., 1 to 12 hours).

[0092] In some embodiments, in conjunction with other embodiments above or below, the disclosed method for preparing PIPN or a salt thereof further includes separating the PMEC formed in step (a) into a solution in a solvent selected from dichloromethane, dichloroethane, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, the PMEC is separated by the following steps: (i) washing the PMEC obtained in step (a) with an organic solvent; (ii) adjusting the pH from 8 to 14 by adding a base to form an alkaline aqueous solution; and (iii) extracting the PMEC from the alkaline aqueous solution of step (ii) with dichloromethane, dichloroethane, 2-methyltetrahydrofuran, or mixtures thereof.

[0093] PIPA

[0094] In some embodiments, this disclosure provides a method for preparing methyl 4-(3-amino-2-fluorobenzyl)piperazine-1-carboxylate (PIPA):

[0095]

[0096] In various embodiments, this disclosure provides a method for preparing PIPA from PIPN or a salt thereof obtained by the disclosed method. In some embodiments, this 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 PIPN base solution; (b) hydrogenating the free PIPN base solution in a solvent containing a solvent mixture of toluene and an alcohol in the presence of a palladium catalyst to form crude PIPA, wherein the alcohol comprises ethanol or isopropanol; and (c) crystallizing the crude PIPA from heptane and toluene.

[0097] In some embodiments, the inorganic base includes sodium hydroxide.

[0098] PCAR, APYR, and NPYR

[0099] In some embodiments, this disclosure provides for use with (6-methylpyridin-3-yl)carbamate. A method for using 5-amino-2-methylpyridine (PCAR) or its salts (e.g., PCAR hydrochloride). The disclosed method includes reacting 5-amino-2-methylpyridine in acetonitrile. (APYR) is mixed with phenyl chloroformate to form PCAR or a salt thereof, wherein the mixing is carried out in the presence of N-methyl-2-pyrrolidone (NMP). In some embodiments, PCAR is formed in the form of a hydrochloride salt.

[0100] In some embodiments, the mixing is carried out at a temperature of 15 to 30°C for 1 to 15 hours.

[0101] In some embodiments, in conjunction with other above or below embodiments, the disclosed method for synthesizing PCAR or a salt thereof further comprises purifying APYR prior to mixing APYR with phenyl chloroformate by a method comprising: (i) washing a solution of crude APYR in isopropyl acetate with an aqueous sodium hydroxide solution, wherein the crude APYR comprises up to 10% by weight of APYR hydrochloride salt, and mixing the washed APYR with charcoal so as to form, upon filtration, a solution of APYR; and (ii) crystallizing APYR from the solution of APYR of step (i) in isopropyl acetate and heptane.

[0102] In some embodiments, in conjunction with other above or below embodiments, APYR is prepared by a method comprising: (i) hydrogenating 2-methyl-5-nitropyridine (NPYR) in the presence of a palladium catalyst to form crude APYR; and (ii) crystallizing the crude APYR from isopropyl acetate and heptane.

[0103] In some embodiments, prior to step (i), NPYR in isopropyl acetate is washed with an aqueous sodium hydroxide solution, followed by mixing the washed NPYR in isopropyl acetate with charcoal.

[0104] In some embodiments, in conjunction with other above or below embodiments, the disclosed method further comprises crystallizing PCAR.

[0105] OM

[0106] The present disclosure provides methods for preparing OM (e.g., omecamtiv mecarbil dihydrochloride monohydrate; “OM 2HC1 H20”) from one or more intermediate compounds obtained from the disclosed methods herein (e.g., FNT, FNB, PIPN or a salt thereof, PIPA, PCAR, APYR, and / or NPYR).

[0107] In some embodiments, the disclosed method for preparing OM dihydrochloride monohydrate comprises: (a) mixing PIPA, PCAR, and a trialkylamine base in acetonitrile and tetrahydrofuran to form a solution of crude OM; (b) isolating OM free base from the solution of crude OM; and (c) mixing the isolated OM free base with 2 to 3 molar equivalents of hydrochloric acid in isopropanol and water to form OM dihydrochloride monohydrate.

[0108]

[0109] As described herein, the trialkylamine base is any suitable trialkylamine base.

[0110] In some embodiments, the isolating of step (b) comprises crystallizing the omacetaxinel free base by adding water to the crude omacetaxinel mekaplasi solution from step (a) and filtering the crystallized omacetaxinel mekaplasi free base.

[0111] In some embodiments, the disclosed methods further comprise crystallizing omacetaxinel dihydrochloride monohydrate from isopropanol and water.

[0112] In some embodiments, in combination with other above or below embodiments, a PCAR is prepared according to the methods disclosed herein.

[0113] In some embodiments, the present disclosure provides a method for preparing omacetaxinel dihydrochloride monohydrate, comprising: (a) mixing PIPA, triphosgene, and a trialkylamine in acetonitrile and tetrahydrofuran to form PIPA isocyanate; (b) mixing the PIPA isocyanate with APYR to form OM free base; (c) mixing the OM free base with 2 to 3 molar equivalents of hydrochloric acid in isopropanol and water to form OM dihydrochloride monohydrate.

[0114] In some embodiments, step (a) is performed via continuous manufacturing comprising mixing a first solution comprising PIPA and a trialkylamine in acetonitrile and a second solution comprising triphosgene in tetrahydrofuran to form PIPA isocyanate using a micromixer chip and a reaction loop.

[0115] In some embodiments, in combination with other above or below specific embodiments, step (b) is performed via continuous manufacturing comprising mixing a solution comprising PIPA isocyanate and a solution comprising AYPR using a Y-type mixer and a reaction loop.

[0116] Many of the methods disclosed herein include steps that are labeled as optional. In some cases, the optional steps are not performed. In other cases, the optional steps are performed.

[0117] Embodiments

[0118] 1. A method for synthesizing 2-fluoro-3-nitrotoluene (“FNT”), comprising:

[0119] (a) mixing 2-fluorotoluene with one or more bases and a borylating reagent to form a boronic acid; and

[0120] (b) mixing the resulting boronic acid with iron nitrate or a hydrate thereof to form the FNT.

[0121] 2. The method of embodiment 1, wherein the one or more bases comprises lithium diisopropylamide (LDA).

[0122] 3. The method of embodiment 2, wherein the LDA is added in the presence of diisopropylamine (DIPA).

[0123] 4. The method of any one of embodiments 1 to 3, wherein step (a) is performed in a polar aprotic solvent.

[0124] 5. The method of embodiment 4, wherein the polar aprotic solvent comprises tetrahydrofuran (THF).

[0125] 6. The method of any one of embodiments 1 to 5, wherein step (b) is performed in a non-polar solvent.

[0126] 7. The method of embodiment 6, wherein the non-polar solvent comprises cyclohexane.

[0127] 8. The method of any one of embodiments 1 to 7, wherein the ferric nitrate is hydrated.

[0128] 9. The method of embodiment 8, wherein the ferric nitrate is of the formula Fe(N03)3*9H20.

[0129] 10. The method of any one of embodiments 1 to 9, further comprising treating the product from step (b) with a second base.

[0130] 11. A method for synthesizing 2-fluoro-3-nitrotoluene (“FNT”), comprising:

[0131] (a) mixing 2-fluorotoluene with one or more bases and a boronating reagent to form a boronic acid; and

[0132] (b) mixing the resulting boronic acid with nitric acid to form the FNT.

[0133] 12. The method of embodiment 11, wherein the one or more bases comprises lithium diisopropylamide (LDA).

[0134] 13. The method of embodiment 12, wherein the LDA is added in the presence of diisopropylamine (DIPA).

[0135] 14. The method of any one of embodiments 11 to 13, wherein step (a) is performed in a polar aprotic solvent.

[0136] 15. The method of embodiment 14, wherein the polar aprotic solvent comprises tetrahydrofuran (THF).

[0137] 16. The method of any one of embodiments 11 to 15, wherein step (b) is performed in a polar aprotic solvent.

[0138] 17. The method of embodiment 16, wherein the polar aprotic solvent comprises 1,2- dichloroethane (DCE).

[0139] 18. The method of embodiment 17, wherein the DCE is present at 10 volumes relative to the boronating reagent.

[0140] 19. The method of any one of embodiments 11-18, wherein the nitric acid is a 90% aqueous solution.

[0141] 20. The method of any one of embodiments 11-19, wherein the method further comprises heating the mixture formed in step (b).

[0142] 21. The method of embodiment 20, wherein the mixture is heated for no less than 8 hours.

[0143] 22. The method of embodiment 20 or 21, wherein the mixture is heated to 70 °C for no less than 8 hours.

[0144] 23. The method of any one of embodiments 11-22, further comprising adding water to the mixture formed in step (b).

[0145] 24. The method of embodiment 23, wherein 10 volumes of water relative to the boronating reagent is added.

[0146] 25. A method for synthesizing 1-(bromomethyl)-2-fluoro-3-nitrobenzene

[0147]

[0148] comprising

[0149] (a) mixing 2-fluoro-3-nitrotoluene (FNT) with a brominating agent in the presence of a blue LED light to form a mixture of FNB and 1-(dibromomethyl)-2-fluoro-3- nitrobenzene (FNBr2);

[0150] (b) mixing the FNB / FNBr2 mixture with a dialkyl phosphite to form FNB; and

[0151] (c) optionally purifying the FNB formed in step (b) by (i) washing the FNB with a dialkyl phosphite and a trialkyl amine, or (ii) extracting the FNB with an organic solvent and washing with an aqueous base.

[0152] 26. The method of embodiment 25, wherein the FNT is prepared by the method of any one of embodiments 1-24.

[0153] 27. The method of either embodiment 25 or 26, wherein the organic solvent is toluene.

[0154] 28. The method of any one of embodiments 25 to 27, wherein the base is sodium hydroxide.

[0155] 29. The method of any one of embodiments 25 to 28, wherein the brominating agent is selected from N-bromosuccinimide.

[0156] 30. The method of 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.

[0157] 31. The method of any one of embodiments 25 to 30, further comprising:

[0158] (d) mixing FNB, a trialkylamine base, and methyl piperazinecarboxylate (“PMEC”) phosphate hydrate to form methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-l- carboxylate (PIPN) or a salt thereof.

[0159] 32. The method of any one of embodiments 1 to 24, further comprising:

[0160] (c) mixing 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 (FNB);

[0161] (d) optionally extracting FNB with toluene, washing FNB with an aqueous base, or both;

[0162] (e) mixing FNB, a trialkylamine base, and methyl piperazinecarboxylate (“PMEC”) phosphate hydrate to form methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-l- carboxylate (PIPN) or a salt thereof.

[0163] 33. The method of embodiment 32, wherein FNB is extracted with toluene and washed with aqueous sodium hydroxide prior to step (e).

[0164] 34. The method of any one of embodiments 31 to 33, wherein the PIPN is formed as a hydrobromide salt.

[0165] 35. The method of any one of embodiments 31 to 34, wherein the PMEC phosphate hydrate is prepared by a method comprising:

[0166] (a) mixing piperazine with methyl chloroformate to form PMEC;

[0167] (b) mixing the PMEC with 0.5 molar equivalents of phosphoric acid to form a PMEC phosphate hydrate; and

[0168] (c) optionally filtering the PMEC phosphate hydrate from the mixture of step (b).

[0169] 36. The method of embodiment 35, further comprising isolating the PMEC formed in step (a) as a solution in a solvent selected from the group consisting of dichloromethane, dichloroethane, 2-methyltetrahydrofuran, and mixtures thereof.

[0170] 37. The method of embodiment 36, wherein the isolating is performed as follows:

[0171] (i) washing the resulting PMEC of step (a) with an organic solvent;

[0172] (ii) adjusting the pH value from 8 to 14 by adding a base to form an aqueous basic solution; and

[0173] (iii) extracting the PMEC from the aqueous basic solution of step (ii) with dichloromethane, dichloroethane, 2-methyltetrahydrofuran, or a mixture thereof.

[0174] 38. The method of any one of embodiments 35 to 37, wherein step (a) is performed in an aqueous solution.

[0175] 39. The method of any one of embodiments 35 to 38, wherein step (a) is performed at a temperature of 20 to 55 °C for 1 to 12 hours.

[0176] 40. The method of any one of embodiments 31 to 39, wherein the trialkylamine base comprises diisopropylethylamine or triethylamine.

[0177] 41. The method of any one of embodiments 31 to 40, wherein prior to mixing the FNB, the trialkylamine base, and the PMEC phosphate hydrate, the method further comprises adding diethyl phosphite and a trialkylamine base and mixing the resulting mixture at a temperature of 30 to 65 °C.

[0178] 42. The method of any one of embodiments 31 to 41, further comprising:

[0179] (f) mixing the PIPN or a salt thereof, an aqueous solution of an inorganic base, and toluene to form a PIPN free base solution;

[0180] (g) hydrogenating the PIPN free base solution in the presence of a palladium catalyst in a solvent comprising toluene and an alcohol to form crude 4-(3-amino-2- fluorobenzyl)piperazine- 1 -carboxylate methyl ester (PIPA):

[0181]

[0182] wherein the alcohol comprises ethanol or isopropanol; and

[0183] (h) crystallizing PIPA from the crude PIPA in heptane and toluene.

[0184] 43. The method of embodiment 42, wherein the inorganic base comprises sodium hydroxide.

[0185] 44. The method of embodiment 42 or 43, further comprising:

[0186] (i) mixing the PIPA, phenyl(6-methylpyridin-3-yl)carbamate (PCAR), and a trialkylamine base in acetonitrile and tetrahydrofuran to form a crude omecamtiv mecarbil solution;

[0187] (j) isolating omecamtiv mecarbil free base from the crude omecamtiv mecarbil solution; and

[0188] (k) mixing the isolated omecamtiv mecarbil free base with 2 to 3 molar equivalents of hydrochloric acid in isopropanol and water to form omecamtiv mecarbil dihydrochloride hydrate

[0189]

[0190] 45. The method of embodiment 44, wherein the trialkylamine base comprises diisopropylethylamine or triethylamine.

[0191] 46. The method of embodiment 44 or 45, wherein the isolating of step (h) comprises crystallizing omecamtiv mecarbil free base by adding water to the crude omecamtiv mecarbil solution from step (g) and filtering the crystallized omecamtiv mecarbil free base.

[0192] 47. The method of any one of embodiments 44 to 46, further comprising crystallizing the omecamtiv mecarbil dihydrochloride hydrate from isopropanol and water.

[0193] 48. The method of any one of embodiments 44 to 47, wherein the PCAR or salt thereof is prepared by a method comprising:

[0194] 5-amino-2-methylpyridine (APYR) with phenyl chloroformate to form PCAR or a salt thereof, wherein the mixing is conducted in the absence of N-methyl 2-pyrrolidone (NMP).

[0195] 49. The method of embodiment 48, wherein the mixing is conducted at a temperature of 15 to 30 °C for 1 to 15 hours.

[0196] 50. The method of embodiment 48 or 49, wherein the PCAR is formed as a hydrochloride salt.

[0197] 51. The method of any one of embodiments 48 to 50, wherein the APYR is prepared by a method comprising:

[0198] (i) hydrogenating 2-methyl-5-nitropyridine (NPYR) in the presence of a palladium catalyst to form crude APYR; and

[0199] (ii) crystallizing the crude product from isopropyl acetate and heptane.

[0200] 52. The method of embodiment 51, further comprising, prior to step (i), washing NPYR in isopropyl acetate with aqueous sodium hydroxide, followed by mixing the washed NPYR in isopropyl acetate with charcoal.

[0201] 53. The method of any one of embodiments 48 to 52, further comprising purifying APYR prior to mixing it with phenyl chloroformate by a method comprising:

[0202] (i) washing a crude APYR solution in isopropyl acetate with aqueous sodium hydroxide, wherein the crude APYR comprises up to 10% by weight of APYR hydrochloride salt, and mixing the washed APYR with charcoal to form an APYR solution after filtration; and

[0203] (ii) crystallizing APYR from the APYR solution of step (i) in isopropyl acetate and heptane.

[0204] 54. The method of any one of embodiments 48 to 53, further comprising crystallizing PCAR.

[0205] 55. The method of embodiment 42 or 43, further comprising:

[0206] (i) mixing the PIPA, triphosgene, and trialkylamine in acetonitrile and tetrahydrofuran to form PIPA isocyanate;

[0207] (j) mixing the PIPA isocyanate with 5-amino-2-methylpyridine (APYR) to form omepegilast moxiflumast free base; and

[0208] (k) mixing the omepegilast moxiflumast free base with 2 to 3 molar equivalents of hydrochloric acid in isopropanol and water to form omepegilast moxiflumast dihydrochloride hydrate.

[0209] 56. The method of embodiment 55, wherein step (g) is performed via continuous manufacturing comprising mixing a first solution comprising PIPA and trialkylamine in acetonitrile and a second solution comprising triphosgene in tetrahydrofuran using a micromixer chip and a reaction loop to form the PIPA isocyanate.

[0210] 57. The method of embodiment 55 or 56, wherein step (h) is performed via continuous manufacturing comprising mixing a solution comprising the PIPA isocyanate and a solution comprising the AYPR using a Y-type mixer and a reaction loop.

[0211] 58. A method for preparing omepegilast moxiflumast or a salt thereof, a hydrate thereof, or a salt hydrate thereof, the method comprising the method of any one of embodiments 1 to 43.

[0212] 59. The method of embodiment 58, wherein the omepegilast moxiflumast, a salt thereof, a hydrate thereof, or a salt hydrate thereof, is omepegilast moxiflumast dihydrochloride hydrate.

[0213] Example

[0214] The following examples further illustrate the disclosed process, but of course, should not be construed as in any way limiting its scope.

[0215] The following abbreviations are used in the examples: PFR refers to plug flow reactor; CSTR refers to 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 percent.

[0216] Example 1-1: Preparation of 2-fluoro-3-methylphenylboronic acid (2). This example demonstrates a method for preparing 2-fluoro-3-methylphenylboronic acid (i.e., boronic acid) according to embodiments of the disclosure.

[0217]

[0218] A 2 L four-necked round bottom flask was charged with 320 mL of THF and 154.3 g of diisopropylamine. The resulting mixture was cooled to -15 °C and stirred. Subsequently, 582 mL of n-butyllithium (2.5 M in n-hexane) was added dropwise under a nitrogen atmosphere while maintaining the temperature below -10 °C. After the addition was complete, the reaction was stirred at -15 °C for 30 minutes and then cooled to -35 °C. Subsequently, a solution of 80 g of 2-fluorotoluene (1) in 160 mL of THF was added dropwise while maintaining the temperature below -30 °C. The resulting mixture was then stirred at -35 °C for 1 hour. Subsequently, 158.5 g of trimethyl borate was added to the reaction mixture while maintaining the temperature below -30 °C (an exothermic reaction was observed). The reaction was stirred at -35 °C for 2 hours and then warmed to room temperature.

[0219] The reaction was then quenched by pouring into a solution of 658 g of water and 343 g of 30% HC1, while maintaining the temperature below 30 °C. The resulting mixture was extracted with MTBE (3 x 160 mL). The organic layers were combined and a 1 M NaOH / H2O solution was added until the pH was greater than 10. The aqueous layer was then washed once with 160 mL of MTBE. 240 mL of MTBE and a 1 M HC1 solution were added to the aqueous layer until the pH of the aqueous layer was 1. The aqueous layer was then further extracted with MTBE (2 x 240 mL). The resulting organic layers were combined and washed once with 160 mL of water and then concentrated to obtain 2 as a white powder, which was used directly in the next reaction.

[0220] Example 1-2: Preparation of 2-fluoro-3-nitrotoluene (FNT) (3). This example demonstrates a method for preparing FNT according to embodiments of the present disclosure.

[0221]

[0222] In a 1 L four-necked round bottom flask, the 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(N03)3-9H20). The resulting reaction mixture was stirred at 65 to 75 °C for 12 hours. The reaction was monitored by HPLC until less than 5% of compound 2 was present, at which point the reaction was cooled to room temperature and filtered. The filter cake was washed with cyclohexane. Subsequently, the combined filtrate was washed with 2 x 150 mL of 5% NaOH (aqueous solution) followed by water 1 x 150 mL. The filtrate was concentrated and then distilled (e.g., 110 to 115 °C at 40 to 60 mmHg) to obtain 38 to 42 g of FNT (3).

[0223] Example 2-1: Flow preparation of 2-fluoro-3-methylphenylboronic acid (2). This example demonstrates a method for preparing 2-fluoro-3-methylphenylboronic acid (i.e., boronic acid) according to embodiments of the present disclosure.

[0224] Flow chemistry apparatus such as Figure 1 Feed A (THF) was connected to Feed B (DIPA) via a T-mixer with relative flow rates as described below. The resulting stream was then connected to Feed C via a subsequent T-mixer and lithiation occurred in a PFR with a residence time of 5 minutes and a bath temperature of -40 to -10 °C. Subsequently, the resulting mixture was fed into two sequential continuous stirred tank reactors (CSTRs) with a residence time of 12 to 14 minutes each and an internal temperature maintained at -5 to 30 °C. The resulting solution was collected under a nitrogen atmosphere as a solution of approximately 1.5 M LDA in THF / hexanes (Table 1).

[0225] Table 1. LDA preparation

[0226]

[0227] Under the conditions shown in Table 2, the flow chemistry apparatus for the boronation procedure was as shown Figure 2 Feed A was fed to Continuous Stirred Tank Reactor 1 (CSTR 1) with Feed B (internal temperature -10 to 35 °C) with a relative flow rate of 1 : 1.255 g / min (A:B) and a target residence time of approximately 40 minutes. The overflow from CSTR 1 was fed to CSTR 2 (internal temperature 0 to 30 °C, residence time approximately 40 minutes) and finally to CSTR 3 (internal temperature 0 to 30 °C, residence time approximately 30 minutes). Feed C was fed to CSTR 3 at a relative flow rate of 1.40 g / min.

[0228] Table 2 - Boronation procedure

[0229]

[0230] Batch separation: The reaction mixture was quenched in 4 M aqueous HC1 (15 to 20 volumes) at below 30 °C, the mixture was separated and the aqueous phase was extracted with MTBE (3 x 5 volumes). The organic phases were combined and the pH was adjusted with 10% NaOH / H20 until the pH was greater than 10. The aqueous phase was washed with MTBE (1 x 3 volumes). Subsequently, MTBE (5 volumes) was added to the aqueous phase and adjusted with 1 M HC1 until the pH was 1 to 3. The resulting aqueous phase was extracted with MTBE (2 x 5 volumes). The organic phases were combined and washed once with water (3 volumes). Subsequently, the organic phase was concentrated to 1 to 1.5 volumes and water (5 volumes) was added for crystallization and the reaction mixture was cooled to 0 to 10 °C. After stirring for 2 hours, the mixture was filtered and rinsed with water (2 volumes). The crude solid was slurried with heptane (3 volumes) for 1 to 3 hours, then the mixture was filtered and rinsed with heptane (1 volume). The solid was dried with nitrogen at below 35 °C to yield 2-fluorotolueneboronic acid as an off-white or light yellow powder.

[0231] Example 2-2: Preparation of 2-fluoro-3-nitrotoluene (FNT) via nitric acid (3)

[0232]

[0233] 2-Fluoro-3-methylphenylboronic acid (2) was charged to reactor 1. A NaOH scrubber was installed on reactor 1 to quench the release of NO2gas simultaneously. Subsequently, 1,2-dichloroethane (10 volumes) was added to reactor 1 at room temperature and stirring was started, and the reaction contents were heated to 70 °C. Once reactor 1 reached 70 °C ± 5 °C, HNO3 (fuming, 90%, 1.3 equivalents) was charged to the reactor. The reaction was then stirred at 70 °C ± 5 °C for 8 hours.

[0234] Subsequently, the reaction contents were cooled to 20 °C. Subsequently, water (10 volumes) was charged to reactor 1 and stirred for 30 minutes. Subsequently, the contents of reactor 1 were polished filtered and the aqueous phase was removed. Subsequently, an aqueous sodium bicarbonate solution (10 volumes) was added and stirred for 30 minutes and the aqueous phase was removed. Subsequently, another aqueous sodium bicarbonate solution (10 volumes) was added and stirred for 30 minutes and the aqueous phase was removed. Subsequently, a solvent switch of the organic phase was performed from 1,2-dichloroethane to MeOH (8 volumes). Norit-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 volumes). The contents of reactor 1 were cooled to 10 °C and water (5 volumes) was added over 3 hours while maintaining the temperature at 10 °C. The contents of reactor 1 were further maintained at 10 °C for 30 minutes and then cooled to 1 to 3 °C. Subsequently, 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 vacuum dried at 3 °C for 16 hours and 3 was isolated as a light yellow solid.

[0235] Alternative distillation purification: Subsequently, the 1,2-dichloroethane was removed by concentration under reduced pressure. The resulting brown oil was purified by distillation at 35 torr. The product was distilled at 110 to 120 °C and the appropriate fractions were collected to give a light green liquid which was allowed to solidify at room temperature to give a white solid product.

[0236] Example 3: Preparation of PIPN HBr from FNT flow

[0237] This example demonstrates a flow chemistry process according to embodiments of the present disclosure.

[0238]

[0239] 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 equiv) of trifluoroacetic acid. Subsequently, NBS (143 g, 806 mmol, 1.25 equiv) was added while stirring in the presence of a blue LED light until the solution was uniform.

[0240] A stock solution of diethyl phosphite was prepared by dissolving 33 mL (258 mmol, 0.40 equiv) of diethyl phosphite in 100 mL of MeOH and 73 mL (418 mmol, 2.5 equiv) of N,N-diisopropylethylamine.

[0241] A PMEC phosphate stock solution was prepared by dissolving 144 g (648 mmol, 1.0 equiv) of PMEC phosphate in 300 mL MeOH and 281 mL (1611 mmol, 2.5 equiv) of N,N-diisopropylethylamine. Subsequently, the dilute slurry was filtered and the filter was rinsed with 100 mL MeOH.

[0242] Subsequently, the stock solution was pumped through a flow apparatus as shown in Figure 3 where the flow rate of the FNT solution was 2.85 mL / min, the flow rate of the diethyl phosphite solution was 0.46 mL / min and the flow rate of the PMEC phosphate solution was 1.62 mL / min. All reaction loops were heated in a thermostatically controlled water bath.

[0243] The above apparatus was run for approximately 4 hours during which time fractions were collected periodically. Concentration data for the crude PIPN stream is summarized in Figure 4 Table 1. Fractions 11-14 (approximately 600 mL) were collected for crystallization.

[0244] For crystallization, a seed bed was prepared by adding 80 mL acetonitrile and 1.39 g PIPN HBr to a 2-L ChemGlass reactor and heating to 60 °C. Subsequently, the crude PIPN solution was added at an addition rate of 300 mL / h and the concentrated HBr solution was added at an addition rate of 26 mL / h. After the addition was complete, the slurry was maintained at 60 °C for 2 hours, then cooled to 25 °C over 30 minutes and maintained at this temperature for an additional 60 minutes.

[0245] Subsequently, the slurry was filtered and the solid was washed with 3 x 4 volumes of acetonitrile at 55 °C. Subsequently, the material was dried under a nitrogen purge. 53.55 g of PIPN HBr was recovered (76% yield) which was 99.9 LCAP and 97.3 wt% purity.

[0246] The foregoing examples are merely illustrative of exemplary embodiments of the disclosed methods described herein and are not intended to limit the disclosed methods. Variations and modifications to the disclosed methods will occur to those of ordinary skill in the art, which variations and modifications will fall within the scope and nature of the disclosure and are intended to be included within the appended claims.

[0247] All references cited herein, including publications, patent applications, and patents, are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were in its entirety generally set forth herein.

[0248] The use of the terms "a" and "an" and "the" and "at least one" and similar referents in the context of describing the embodiments of the disclosure (especially in the context of the following claims) are to be construed to cover both the singular as well as the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term "at least one" followed by a list of one or more items (for example, "at least one of A and B") is to be construed to mean one or inherently include, any and all embodiments of the present disclosure. Therefore, the use of "including," "containing," "comprising," "having," and "encompassing," and variations thereof herein, is meant to be broad in scope and inclusive, unless otherwise expressly specified herein. Any embodiment of the present disclosure can be used in any combination of one or more of the embodiments of the present disclosure.

Claims

1. A method for synthesizing 2-fluoro-3-nitrotoluene ("FNT"), comprising: (a) Mixing 2-fluorotoluene with one or more bases and a borizing agent to form boric acid; as well as (b) The resulting boric acid is mixed with ferric nitrate or its hydrate to form the FNT.

2. The method of claim 1, wherein the one or more bases are lithium diisopropylamine (LDA).

3. The method of claim 2, wherein the LDA is formed by deprotonation of diisopropylamine (DIPA) with n-butyllithium.

4. The method of claim 1, wherein step (a) is carried out in a polar aprotic solvent.

5. The method of claim 4, wherein the polar aprotic solvent is tetrahydrofuran (THF).

6. The method of claim 1, wherein step (b) is carried out in a nonpolar solvent.

7. The method of claim 6, wherein the nonpolar solvent is cyclohexane.

8. The method of claim 1, wherein the ferric nitrate is hydrated.

9. The method of claim 8, wherein the ferric nitrate has the formula Fe(NO3)3*9H2O.

10. The method of claim 1, further comprising treating the product obtained from step (b) with a second base.

11. A method for synthesizing 2-fluoro-3-nitrotoluene ("FNT"), comprising: (a) Mixing 2-fluorotoluene with one or more bases and a borizing agent to form boric acid; as well as (b) The resulting boric acid is mixed with nitric acid to form the FNT.

12. The method of claim 11, wherein the one or more bases are lithium diisopropylamine (LDA).

13. The method of claim 12, wherein the LDA is formed by deprotonation of diisopropylamine (DIPA) with n-butyllithium.

14. The method of claim 11, wherein step (a) is carried out in a polar aprotic solvent.

15. The method of claim 14, wherein the polar aprotic solvent is tetrahydrofuran (THF).

16. The method of claim 11, wherein step (b) is carried out in a polar aprotic solvent.

17. The method of claim 16, wherein the polar aprotic solvent is 1,2-dichloroethane (DCE).

18. The method of claim 17, wherein the DCE is present in a volume of 10 relative to the boriding agent.

19. The method of claim 11, wherein the nitric acid is a 90% aqueous solution.

20. The method of claim 11, wherein the method further comprises heating the mixture formed in step (b).

21. The method of claim 20, wherein the mixture is heated for at least 8 hours.

22. The method of claim 20, wherein the mixture is heated to 70°C for at least 8 hours.

23. The method of claim 11, further comprising adding water to the mixture formed in step (b).

24. The method of claim 23, wherein water is added in a volume of 10 relative to the boriding agent.

25. A method for synthesizing 1-(bromomethyl)-2-fluoro-3-nitrobenzene (FNB) It includes (a) Mixing 2-fluoro-3-nitrotoluene (FNT) with a brominating agent in the presence of a blue LED light to form FNB and 1-(dibromomethyl)-2-fluoro-3-nitrobenzene A mixture of (FNBr2); (b) mixing the FNB / FNBr2 mixture with a dialkyl phosphite to form an FNB; and (c) The FNB formed in step (b) may be purified by (i) washing the FNB with dialkyl phosphite and trialkylamine, or (ii) extracting the FNB with an organic solvent and washing with an alkaline aqueous solution.

26. The method of claim 25, wherein the FNT is prepared by the method of claim 1 or 11.

27. The method of claim 25, wherein the organic solvent is toluene.

28. The method of claim 25, wherein the base is sodium hydroxide.

29. The method of claim 25, wherein the brominating agent is selected from N-bromosuccinimide.

30. The method of claim 25, wherein the dialkyl phosphite is selected from the group consisting of dimethyl phosphite, diethyl phosphite, and combinations thereof.

31. The method of claim 25, further comprising: (d) The FNB, trialkylamine base and methyl piperazine carboxylate are added to the solution. (PMEC) phosphate salts are mixed to form methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate. (PIPN) or its salts.

32. The method of claim 1 or 11, further comprising: (c) The FNT, benzoyl peroxide, N-bromosuccinimide, and acetic acid are mixed at a temperature of 70 to 95°C to form 1-(bromomethyl)-2-fluoro-3-nitrobenzene. (FNB); (d) Optionally extract the FNB with toluene, or optionally wash the FNB with an alkaline aqueous solution, or optionally both extract the FNB with toluene and wash the FNB with an alkaline aqueous solution. (e) FNB, trialkylamine base and methyl piperazine carboxylate (PMEC) phosphate salts are mixed to form methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate. (PIPN) or its salts.

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

34. The method of claim 32, wherein the PIPN is formed in the form of hydrobromide.

35. The method of claim 32, wherein the PMEC phosphate hydrate is prepared by a method comprising: (a) Piperazine is mixed with methyl chloroformate to form PMEC; (b) Mixing the PMEC with 0.5 molar equivalents of phosphoric acid to form a PMEC phosphate hydrate; and (c) Optionally, the PMEC phosphate hydrate is filtered out from the mixture of step (b).

36. The method of claim 35, further comprising separating the PMEC formed in step (a) into a solution in a solvent selected from dichloromethane, dichloroethane, 2-methyltetrahydrofuran, and mixtures thereof.

37. The method of claim 36, wherein the separation is performed as follows: (i) Wash the PMEC obtained in step (a) with an organic solvent; (ii) Adjusting the pH to 8 to 14 by adding alkali to form an alkaline aqueous solution; and (iii) Extract the PMEC from the alkaline aqueous solution of step (ii) using dichloromethane, dichloroethane, 2-methyltetrahydrofuran or a mixture thereof.

38. The method of claim 35, wherein step (a) is carried out in an aqueous solution.

39. The method of claim 35, wherein step (a) is performed at a temperature of 20 to 55°C for 1 to 12 hours.

40. The method of claim 32, wherein the trialkylamine base is diisopropylethylamine or triethylamine.

41. The method of claim 32, wherein before mixing the FNB, the trialkylamine base and the PMEC phosphate hydrate, the method further comprises adding diethyl phosphite and the trialkylamine base, and mixing the resulting mixture at a temperature of 30 to 65°C.

42. The method of claim 32, further comprising: (f) Mix the PIPN or its salt, an aqueous solution of an inorganic base, and toluene to form a free PIPN base solution; (g) Hydrogenation of the PIPN free alkaline solution in a solvent containing toluene and an alcohol in the presence of a palladium catalyst to form crude methyl 4-(3-amino-2-fluorobenzyl)piperazine-1-carboxylate (PIPA): (PIPE), The alcohol is ethanol or isopropanol; and (h) Crystallize PIPA from crude PIPA in heptane and toluene.

43. The method of claim 42, wherein the inorganic base is sodium hydroxide.

44. The method of claim 42, further comprising: (i) The PIPA, phenyl(6-methylpyridin-3-yl)carbamate, is reacted in acetonitrile and tetrahydrofuran. (PCAR) and trialkylamine bases are mixed to form a crude omeprazole solution; (j) Separating the free omeprazole base from the crude omeprazole solution; and (k) The separated omeccatemocarbyl free base is mixed with 2 to 3 molar equivalents of hydrochloric acid in isopropanol and water to form omeccatemocarbyl dihydrochloride hydrate. .

45. The method of claim 44, wherein the trialkylamine base is diisopropylethylamine or triethylamine.

46. ​​The method of claim 44, wherein the separation in step (j) comprises crystallizing the free omeprazole base by adding water to the crude omeprazole solution obtained from step (i), and filtering the crystallized free omeprazole base.

47. The method of claim 44, further comprising crystallizing the omeccatemocarbyl dihydrochloride hydrate from isopropanol and water.

48. The method of claim 44, wherein the PCAR or a salt thereof is prepared by a method comprising: 5-Amino-2-methylpyridine in acetonitrile (APYR) is mixed with phenyl chloroformate to form PCAR or a salt thereof, wherein the mixing is carried out in the absence of N-methyl-2-pyrrolidone (NMP).

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

50. The method of claim 48, wherein the PCAR is formed in the form of a hydrochloride salt.

51. The method of claim 48, wherein the APYR is prepared by a method comprising: (i) 2-methyl-5-nitropyridine in the presence of a palladium catalyst (NPYR) hydrogenated to form crude APYR; and (ii) Crystallize the crude product from isopropyl acetate and heptane.

52. The method of claim 51, further comprising, prior to step (i), washing the NPYR in isopropyl acetate with an aqueous sodium hydroxide solution, and then mixing the washed NPYR in isopropyl acetate with charcoal.

53. The method of claim 48, further comprising purifying APYR by the following method prior to mixing APYR with phenyl chloroformate, said method comprising: (i) Washing a crude APYR isopropyl acetate solution with an aqueous sodium hydroxide solution, wherein the crude APYR contains up to 10% by weight of APYR hydrochloride, and mixing the washed APYR with charcoal to form an APYR solution after filtration; and (ii) Crystallize APYR from the APYR solution of step (i) in isopropyl acetate and heptane.

54. The method of claim 48, further comprising crystallizing PCAR.

55. The method of claim 42, further comprising: (i) The PIPA, triphosgene and trialkylamine are mixed in acetonitrile and tetrahydrofuran to form PIPA isocyanate; (j) The PIPA isocyanate is reacted with 5-amino-2-methylpyridine (APYR) is mixed to form the omeprazole-temocarbyl free base; and (k) The free base of omeccatimocabile is mixed with 2 to 3 molar equivalents of hydrochloric acid in isopropanol and water to form omeccatimocabile dihydrochloride hydrate.

56. The method of claim 55, wherein step (i) is carried out via continuous manufacturing, the continuous manufacturing comprising mixing a first solution containing PIPA and trialkylamine in acetonitrile and a second solution containing triphosgene in tetrahydrofuran to form the PIPA isocyanate using a micromixer chip and a reaction loop.

57. The method of claim 55, wherein step (j) is carried out via continuous manufacturing, the continuous manufacturing comprising mixing a solution containing the PIPA isocyanate and a solution containing the AYPR using a Y-type mixer and a reaction loop.

58. A method for preparing omeprazole or its salt, its hydrate or its hydrate, said method comprising the method of any one of claims 1, 11 or 25.

59. The method of claim 58, wherein the omeprazole, its salt, its hydrate or its salt hydrate is omeprazole dihydrochloride hydrate.

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