Method for preparing antimicrobial compounds and intermediates thereof

Abstract

This disclosure provides a method for preparing the antimicrobial compound of formula I, (S)-6-(5-(((2-(7-fluoro-1-methyl-2-oxo-1,2-dihydroquinoline-8-yl)ethyl)amino)methyl)-2-oxoxazolidine-3-yl)-2H-pyrazino[2,3-b][1,4]oxazine-3(4H)-ongnate. This disclosure also provides intermediates for the compound of formula I and their preparation. This disclosure further provides a method for preparing the compound of formula I in improved yield and high purity. JPEG2026520028000054.jpg60170

Description

[Technical Field]

[0001] This disclosure relates in general to methods for preparing antimicrobial compounds, and more particularly to compounds of formula I, which are clinical development drug candidates exhibiting potent antimicrobial activity against various Gram-negative and Gram-positive bacteria, including multidrug-resistant bacterial pathogens.

[0002] More specifically, this disclosure relates to the large-scale or industrial-scale production of the compound of formula I, namely (S)-6-(5-(((2-(7-fluoro-1-methyl-2-oxo-1,2-dihydroquinoline-8-yl)ethyl)amino)methyl)-2-oxoxazolidine-3-yl)-2H-pyrazino[2,3-b][1,4]oxazine-3(4H)-ongate, in improved yield and high purity.

[0003] [ka] [Background technology]

[0004] Antimicrobial resistance (AMR) has been identified as a major public health concern that could reverse the progress made in modern medicine, and therefore a global approach to combat it is needed. The World Health Organization (WHO) is calling for swift action to address this challenge and prevent a future where common infections become unmanageable. Therefore, there is an urgent need for research and development of new antibiotics to strengthen the readiness and responsiveness of health management systems to combat any such threat. Thus, the development of new antibiotics is essential to halt the growing threat of antimicrobial resistance and prevent the transmission of deadly infections. (https: / / www.who.int / news-room / fact-sheets / detail / antimicrobial-resistance)

[0005] International Publication No. 2018 / 225097 provides a synthetic oxazolidinone-based, broad-spectrum antimicrobial agent, one such antibiotic compound of formula I, which is chemically called (S)-6-(5-(((2-(7-fluoro-1-methyl-2-oxo-1,2-dihydroquinoline-8-yl)ethyl)amino)methyl)-2-oxoxazolidine-3-yl)-2H-pyrazino[2,3-b][1,4]oxazine-3(4H)-onformate. This compound exhibits potent activity against a wide range of bacteria, including those resistant to current antibiotics. Furthermore, this compound has been demonstrated to be free from cross-resistance with current antibiotics and is a promising candidate for the treatment of infections caused by multidrug-resistant bacteria.

[0006] In this respect, the compound of formula I has shown promising results in preclinical studies and has the potential to develop into a new class of antibiotic. Further research and clinical trials are needed to fully evaluate its safety and efficacy. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] International Publication No. 2018 / 225097 [Non-patent literature]

[0008] [Non-Patent Document 1] https: / / www.who.int / news-room / fact-sheets / detail / antimicrobial-resistance [Non-Patent Document 2] Advanced Organic Chemistry, 5th edition, Jerry March and Michael Smith, published by John Wiley & Sons, 2001. [Non-Patent Document 3] T.W. Greene, Protective Groups in Organic Synthesis, published by John Wiley and Sons, 1991

Summary of the Invention

Problems to be Solved by the Invention

[0009] However, the existing synthetic processes described in the preparation of the compounds of formula I that have been reported are small-scale processes used during the optimization phase of pharmaceutical chemistry and are not suitable for the large-scale synthesis of the active pharmaceutical ingredients required for clinical trial development and commercial supply. Therefore, further process development and optimization are required to ensure the scalability and cost-effectiveness of the synthetic routes for the compounds of formula I for clinical trial supply and commercial manufacturing. Accordingly, there is a need for a simple, concise, and economical synthetic route for the large-scale manufacture of the compounds of formula I that still provides improved yields and high purity.

Means for Solving the Problems

[0010] In one aspect of the present disclosure, a method for preparing a compound of formula I, comprising: a) reacting a compound of formula 5A with an amine to obtain a compound of formula 11;

[0011]

Chemical Formula

[0012] b) reacting the compound of formula 11 with a compound of formula 12 to obtain a compound of formula I

[0013]

Chemical Formula

[0014] is provided.

[0015] In another aspect of the present disclosure, a method for preparing a compound of formula I, comprising a) A step of reacting the compound of formula 5A with an amine to obtain the compound of formula 11,

[0016] [ka]

[0017] b) Equation 10 (wherein R is non-substituted or substituted C) 1~6 A step of treating a compound (which is alkyl) with acid to obtain the compound of formula 12,

[0018] [ka]

[0019] c) A step of reacting the compound of formula 11 with the compound of formula 12 to obtain the compound of formula I.

[0020] [ka]

[0021] A method is provided that includes this.

[0022] Another aspect of the present disclosure provides a method for obtaining a high-purity compound of formula I, comprising: (i) adding a polar protic solvent and formic acid to a compound of formula I to obtain a first mixture; (ii) adding a species of compound of formula I and a polar protic solvent to the first mixture while stirring at a temperature in the range of 5 to 20°C, followed by filtration to obtain a solid product; and (iii) drying the solid product under reduced pressure at a temperature in the range of 50 to 70°C to obtain a high-purity compound of formula I.

[0023] Further embodiments of this disclosure provide compounds of formula 5, stereoisomers thereof, racemic compounds, hydrates, solvates, intermediates, or pharmaceutically acceptable salts thereof.

[0024] [ka]

[0025] In other aspects of this disclosure, compounds of formula 5A, hydrates, solvates, intermediates thereof, or pharmaceutically acceptable salts thereof are provided.

[0026] [ka]

[0027] In further aspects of this disclosure, Formula 10 (wherein R is non-substituted or substituted C) is used. 1~6 Compounds of alkyl groups, their hydrates, solvates, intermediates, or pharmaceutically acceptable salts thereof are provided.

[0028] [ka]

[0029] A further aspect of the present disclosure provides a method for preparing a compound of formula 5A, comprising the step of reacting a compound of formula 21 with a compound of formula 1 in the presence of a second reagent, a first base, and a second solvent.

[0030] [ka]

[0031] Further aspects of the present disclosure provide a method for preparing a compound of formula 10, comprising the step of reacting a compound of formula 9 with a borate ester in the presence of a first catalyst, a second base, and a third solvent.

[0032] [ka]

[0033] Further aspects of the present disclosure provide a method for preparing a compound of formula 5A, comprising the step of reacting a compound of formula 4 with a phthalimide or a salt thereof in an organic solvent, optionally in the presence of a basic agent.

[0034] [ka]

[0035] These and other features, aspects, and advantages of the subject matter will be better understood by referring to the following description and the appended claims. This summary is provided to introduce the selection of concepts in a simple form. This summary is not intended to identify any material or essential features of the disclosure, nor is it intended to be used to limit the scope of the claimed subject matter. [Modes for carrying out the invention]

[0036] Those skilled in the art will recognize that this disclosure is subject to changes and modifications other than those specifically described herein. It should be understood that this disclosure encompasses all such changes and modifications. This disclosure also encompasses all such processes, features, compositions and compounds mentioned or indicated herein individually or collectively, as well as any and all combinations of any or more of such processes or features.

[0037] definition For convenience, before further description of this disclosure, certain terms used herein and in the examples are summarized below. These definitions should be read and understood by those skilled in the art in light of the remainder of this disclosure. The terms used herein have meanings that are recognized and known to those skilled in the art, but for convenience and completeness, certain terms and their meanings are given below.

[0038] The articles "a," "an," and "the" are used to refer to one or more (i.e., at least one) grammatical objects of the article.

[0039] The terms “comprise” and “comprising” are used in a comprehensive, open sense, meaning that further elements may be included. Throughout this specification, unless the context requires otherwise, the word “comprise,” and variations such as “comprises” and “comprising,” are understood to imply the inclusion of the elements or processes, or groups of elements or processes, described, but not the exclusion of any other elements or processes, or groups of elements or processes.

[0040] The term "including" is used to mean "including, but not limited to." "Including" and "including, but not limited to" are interchangeable.

[0041] In the structural formulas shown in this specification and throughout this disclosure, unless otherwise specifically stated, the following terms have the meanings given.

[0042] As used herein, the term “substitution” is intended to include all permissible substituents of an organic compound. In broad embodiments, permissible substituents include any group such as halogens, cyano, amino, hydroxyl, thio, sulfo, sulfide, oxo, acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of the organic compound. Exemplary substituents include, for example, those described herein. Permissible substituents may be one or more, and may be the same or different for a given organic compound. Heteroatoms may have any permissible substituent of the organic compound described herein that satisfies the hydrogen substituent and / or the valence of the heteroatom. It should be understood that substituents may be further substituted.

[0043] In the structural formulas shown in this specification and throughout this disclosure, unless otherwise specifically stated, the following terms have the meanings given.

[0044] The term "alkyl" refers to a linear or branched aliphatic hydrocarbon group having a specific number of carbon atoms, which are bonded to the rest of the molecule by a single atom and may be substituted by one or more substituents. 1~6 The term alkyl refers, in particular, to alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. Preferred alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like. The alkyl groups of this disclosure may optionally be substituted.

[0045] The compounds described herein may contain one or more chiral centers and / or double bonds, and therefore may exist as stereoisomers, e.g., double bond isomers (i.e., geometric isomers), positional isomers, enantiomers, or diastereomers. Accordingly, the chemical structures shown herein encompass all possible enantiomers and stereoisomers of the exemplary or specified compounds, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or pure as a diastereomer), as well as enantiomers and stereoisomer mixtures. Enantiomers and stereoisomer mixtures can be broken down into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to those skilled in the art. The compounds may also exist in several tautomeric forms, including enol forms, keto forms, and mixtures thereof. Accordingly, the chemical structures shown herein encompass all possible tautomeric forms of the exemplary or specified compounds.

[0046] The term "racemic compound" refers to a mixture containing pairs of optical isomers. A racemic compound is an equimolar mixture of pairs of enantiomers. Racemic compounds do not exhibit optical activity.

[0047] The term "pharmaceutically acceptable" means a compound, material, composition, and / or dosage form that is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio, within the bounds of sound medical judgment.

[0048] "Pharmacologically acceptable salts" include salts with pharmaceutically acceptable acids or bases. Pharmaceutically acceptable acids include both inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphate, hydrobromic acid, hydroiodic acid, and nitric acid, and organic acids, such as formic acid, citric acid, fumaric acid, maleic acid, malic acid, mandelic acid, ascorbic acid, oxalic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal (e.g., sodium or potassium) and alkaline earth metal (e.g., calcium or magnesium) hydroxides, and organic bases, such as alkylamines, arylalkylamines, and heterocyclic amines.

[0049] For example, salts and solvates or related solvents having pharmaceutically unacceptable counterions for use as intermediates in the preparation of other compounds, as well as pharmaceutically acceptable salts thereof, are within the scope of this disclosure. Accordingly, one embodiment of this disclosure encompasses the compounds and salts thereof disclosed herein. Compounds containing basic functional groups can be treated with a suitable acid to form pharmaceutically acceptable acid addition salts. Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids. Typical pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, hydroxyacetate, phenyl acetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, glycolate, lactate, heptane, phthalate, oxalate, succinate, benzoate, acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, and hydroxybenzoate. It contains nathoate, methoxybenzoate, naphthoate, hydroxynaphthoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate, estrulate, methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate, benzenesulfonate (vesylate), aminobenzenesulfonate, p-toluenesulfonate (tosylate), and naphthalene-2-sulfonate.

[0050] As used herein, the term "solvate" refers to a crystalline form of a substance containing a solvent.

[0051] As used herein, the term "hydrate" refers to a solvate in which the solvent is water.

[0052] The term "intermediate" refers to a compound that has the same core structure as the compound of this disclosure at various specific possible positions (e.g., alkyl chains).

[0053] The term intermediate also refers to the final product of metabolism, including metabolites that retain the function of the compound of formula I. A metabolite is a compound obtained under physiological conditions that can result in the compound of formula I.

[0054] Compounds prepared by the methods described herein may also exhibit polymorphism. The present invention further includes different polymorphisms of the compounds of the present invention. The term "polymorphism" refers to a specific crystalline state of a substance having specific physical properties such as X-ray diffraction, IR spectrum, and melting point. Polymorphs have the same chemical composition but differ in packing, geometric arrangement, and other properties of the crystalline solid state. Thus, polymorphs may have different physical properties such as shape, density, hardness, deformability, stability, and solubility. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which can be used for identification. For example, it should be recognized that different polymorphs can be produced by changing or adjusting the reaction conditions or reagents used to prepare the compound. For example, changes in temperature, pressure, or solvent can result in polymorphism. In addition, one polymorph may spontaneously transform into another under certain conditions.

[0055] As used herein, the term "inorganic acid" refers to any acid derived from an inorganic group capable of donating hydrogen ions and forming a conjugate base. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or combinations thereof.

[0056] Once a term is used, the same meaning applies throughout this disclosure.

[0057] As discussed in the background, existing methods for obtaining compounds of formula I are not suitable for large-scale production. Therefore, there is a need to develop synthetic methods to ensure scalability and cost-effectiveness in the preparation of compounds of formula I, essentially for clinical trial supply and commercial production. An effective synthetic route should yield higher yields and purity while following a minimum number of iterations. Furthermore, the method should utilize low-hazard reagents and chemicals and therefore be environmentally friendly. Accordingly, this disclosure provides a method for preparing compounds of formula I, comprising a novel intermediate with a small number of process steps. This disclosure also relates to a method for producing a novel intermediate compound with improved yield and higher purity. The method of this disclosure includes the use of reagents, catalysts, and reaction conditions that have been found to significantly enhance efficiency and improve yield. This disclosure also provides a method for obtaining high-purity compounds of formula I.

[0058] One embodiment of the present disclosure provides a method for preparing a compound of formula I, comprising the steps of: a) reacting a compound of formula 5A with an amine to obtain a compound of formula 11;

[0059] [ka]

[0060] b) A step of reacting the compound of formula 11 with the compound of formula 12 to obtain the compound of formula I.

[0061] [ka]

[0062] A method is provided that includes this.

[0063] In one embodiment of the present disclosure, a method for preparing a compound of formula I as disclosed herein, wherein the compound of formula 12 is a compound of formula 10 (wherein R is unsubstituted or substituted C). 1~6A method is provided for obtaining a compound (which is alkyl) by treating it with an acid. In another embodiment of this disclosure, R is C2 alkyl.

[0064] [ka]

[0065] Embodiments of this disclosure provide a method for preparing a compound of formula I as disclosed herein, wherein the amine is hydrazine, C 1~6 Alkylhydrazine, C 1~6 A method is provided which is selected from alkylamines or combinations thereof. In another embodiment of the present disclosure, the amine is hydrazine or hydrazine hydrate. In another embodiment of the present disclosure, the amine is methylamine, ethylamine, n-propylamine, isopropylamine, or n-butylamine.

[0066] One embodiment of the present disclosure provides a method for preparing a compound of formula I, a) Equation 10 (wherein R is either non-substituted or substituted C) 1~6 A step of treating a compound (which is alkyl) with acid to obtain the compound of formula 12,

[0067] [ka]

[0068] b) A step of reacting the compound of formula 11 with the compound of formula 12 to obtain the compound of formula I. A method is provided that includes this.

[0069] One embodiment of the present disclosure provides a method for preparing a compound of formula I, a) A step of reacting the compound of formula 5A with an amine to obtain the compound of formula 11,

[0070] [ka]

[0071] b) Equation 10 (wherein R is non-substituted or substituted C) 1~6 A step of treating a compound (which is alkyl) with acid to obtain the compound of formula 12,

[0072] [ka]

[0073] c) A step of reacting the compound of formula 11 with the compound of formula 12 to obtain the compound of formula I.

[0074] [ka]

[0075] A method is provided that includes this.

[0076] In one embodiment of the present disclosure, a method is provided for preparing a compound of formula I as disclosed herein, wherein the step of reacting a compound of formula 11 with a compound of formula 12 is carried out in the presence of a first reagent and a first solvent at a temperature in the range of 5 to 50°C. In another embodiment of the present disclosure, the step of reacting a compound of formula 11 with a compound of formula 12 is carried out in the presence of a first reagent and a first solvent at a temperature in the range of 5 to 50°C for at least 5 hours. In yet another embodiment of the present disclosure, the step of reacting a compound of formula 11 with a compound of formula 12 is carried out at a temperature in the range of 10 to 40°C for a time in the range of 10 to 30 hours.

[0077] In one embodiment of the present disclosure, a method is provided for preparing a compound of formula I as disclosed herein, wherein the first reagent is selected from picoline borane complex, formic acid, acetic acid, trifluoroacetic acid, or a combination thereof; and the first solvent is selected from dichloromethane, methanol, or a combination thereof. In another embodiment of the present disclosure, the first reagent is a combination of picoline borane complex and formic acid; and the first solvent is dichloromethane, methanol, or a combination thereof.

[0078] In one embodiment of the present disclosure, a method is provided for preparing a compound of formula I as disclosed herein, wherein the step of reacting a compound of formula 5A with an amine is carried out at a temperature in the range of 5 to 50°C. In another embodiment of the present disclosure, the step of reacting a compound of formula 5A with an amino is carried out at a temperature in the range of 5 to 50°C for at least 1 hour. In yet another embodiment of the present disclosure, the step of reacting a compound of formula 5A with an amine is carried out at a temperature in the range of 15 to 50°C for 1 to 24 hours. In yet another embodiment of the present disclosure, the step of reacting a compound of formula 5A with a hydrazine is carried out at a temperature in the range of 5 to 50°C for 10 to 24 hours.

[0079] In one embodiment of the present disclosure, a method is provided for preparing a compound of formula I as disclosed herein, wherein the step of treating the compound of formula 10 is carried out at a temperature in the range of 20 to 60°C; and the acid is an inorganic acid, preferably hydrochloric acid. In another embodiment of the present disclosure, the inorganic acid, preferably hydrochloric acid, is used at a concentration in the range of a 0.1 N to 14.0 N solution.

[0080] One embodiment of the present disclosure provides a method for preparing a compound of formula I as disclosed herein, wherein the compound of formula I has a yield of at least 70% and a purity of at least 90%. Another embodiment of the present disclosure provides a compound of formula I having a yield in the range of 70–95% and a purity in the range of 90–100%.

[0081] One embodiment of the present disclosure provides a method for preparing a compound of formula I as disclosed herein, wherein the compound of formula 5A is obtained by reacting a compound of formula 21 with a compound of formula 1 in the presence of a second reagent, a first base, and a second solvent.

[0082] [ka]

[0083] In one embodiment of the present disclosure, a method is provided for preparing a compound of formula I as disclosed herein, wherein a second reagent is selected from tris(dibenzylideneacetone)dipalladium(0)-chloroform (Pd2(dba)3CHCl3), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-Bu XPhos), or a combination thereof; a second solvent is selected from toluene, dimethylformamide, 1,4-dioxane, dimethylacetamide, N-methylpyrrolidine, n-butanol, or a combination thereof; and a first base is selected from potassium carbonate, potassium phosphate, triethylamine, sodium t-butoxide, potassium t-butoxide, 1,8-diazabicyclo(5.4.0)undeca-7-ene (DBU), 1,4-diazabicyclo(2.2.2)octane (DABCO), or a combination thereof. In another embodiment of the present disclosure, the second reagent is tris(dibenzylideneacetone)dipalladium(0)-chloroform (Pd2(dba)3CHCl3), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-Bu XPhos), or a combination thereof; the second solvent is selected from toluene, dimethylformamide, or a combination thereof; and the first base is potassium carbonate. In yet another embodiment of the present disclosure, the second solvent is a mixture of 1,4-dioxane and dimethylformamide in a volume ratio of 1:1 to 1:10. In yet another embodiment of the present disclosure, the second solvent is a mixture of toluene and dimethylformamide in a volume ratio of 1:1 to 1:10.

[0084] In one embodiment of the present disclosure, a method is provided for preparing a compound of formula I as disclosed herein, wherein the compound of formula 5A is obtained by reacting a compound of formula 21 with a compound of formula 1 at a temperature in the range of 90 to 110°C. In another embodiment of the present disclosure, the compound of formula 5A is obtained by reacting a compound of formula 21 with a compound of formula 1 for at least 1 hour at a temperature in the range of 90 to 110°C. In yet another embodiment of the present disclosure, the compound of formula 5A is obtained by reacting a compound of formula 21 with a compound of formula 1 for 1 to 24 hours at a temperature in the range of 90 to 110°C.

[0085] In one embodiment of the present disclosure, a method is provided for preparing a compound of formula I as disclosed herein, wherein the compound of formula 5A has a yield of at least 70% and a purity of at least 90%. In another embodiment of the present disclosure, the compound of formula 5A has a yield in the range of 70 to 95% and a purity in the range of 90 to 99.9%.

[0086] In one embodiment of the present disclosure, a method is provided for preparing a compound of formula I as disclosed herein, wherein the compound of formula 21 is obtained by reacting a compound of formula 2 with phthalimide. In another embodiment of the present disclosure, the compound of formula 21 is obtained by reacting a compound of formula 2 with phthalimide for at least 30 minutes at a temperature in the range of -10 to 30°C. In yet another embodiment of the present disclosure, the compound of formula 21 is obtained by reacting a compound of formula 2 with phthalimide for at a temperature in the range of 1 to 20 hours at a temperature in the range of 0 to 20°C.

[0087] In one embodiment of the present disclosure, there is provided a method for preparing a compound of formula I as disclosed herein, wherein the compound of formula 2 is obtained by treating 3-amino-1,2-propanediol with triphosgene or di-t-butyl dicarbonate (Boc anhydride), followed by treatment with potassium t-butoxide. In another embodiment of the present disclosure, the compound of formula 2 is obtained by treating 3-amino-1,2-propanediol with triphosgene at a temperature in the range of 5 to 50 °C for at least 2 hours. In yet another embodiment of the present disclosure, the compound of formula 2 is obtained by treating 3-amino-1,2-propanediol with triphosgene at a temperature in the range of 5 to 40 °C for a time in the range of 2 to 22 hours.

[0088]

Chemical formula

[0089] In one embodiment of the present disclosure, there is provided a method for preparing a compound of formula I as disclosed herein, wherein the compound of formula 10 is obtained by reacting a compound of formula 9 with a boronic acid ester having R selected from unsubstituted or substituted C 1~6 alkyl in the presence of a first catalyst, a second base, and a third solvent. In another embodiment of the present disclosure, the compound of formula 10 is obtained by reacting a compound of formula 9 with a boronic acid ester at a temperature in the range of 20 to 80 °C in the presence of a first catalyst, a second base, and a third solvent. In one embodiment of the present disclosure, the compound of formula 10 is obtained by reacting a compound of formula 9 with a boronic acid ester at a temperature in the range of 25 to 70 °C in the presence of a first catalyst, a second base, and a third solvent.

[0090]

Chemical formula

[0091] In one embodiment of the present disclosure, a method is provided for preparing a compound of formula I as disclosed herein, wherein the first catalyst is selected from [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl2), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane (Pd(dppf)Cl2.CH2Cl2), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Pd(amphos)Cl2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), or a combination thereof; the second base is selected from potassium carbonate, sodium carbonate, sodium acetate, potassium acetate, or a combination thereof; and the third solvent is selected from dichloromethane, water, 2-methyltetrahydrofuran, dimethoxyethane, or a combination thereof. In another embodiment of the present disclosure, the first catalyst is [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl2); the second base is potassium carbonate; and the third solvent is dichloromethane, water, or a combination thereof.

[0092] In one embodiment of the present disclosure, a method is provided for preparing a compound of formula I as disclosed herein, wherein the compound of formula 10 has a yield of at least 70% and a purity of at least 90%. In another embodiment of the present disclosure, the compound of formula 10 has a yield in the range of 70 to 95% and a purity in the range of 90 to 99.9%.

[0093] One embodiment of the present disclosure provides a method for preparing a compound of formula I as disclosed herein, wherein the compound of formula I is further subjected to a purification process to obtain a high-purity compound of formula I.

[0094] One embodiment of the present disclosure provides a method for preparing a compound of formula I, a. A step of treating 3-amino-1,2-propanediol with triphosgene to obtain the compound of formula 2, b. A step of obtaining the compound of formula 21 by reacting the compound of formula 2 with phthalimide, c. A step of reacting the compound of formula 21 with the compound of formula 1 in the presence of a second reagent, a first base, and a second solvent to produce the compound of formula 5A, d. A step of reacting the compound of formula 9 with a boric acid ester in the presence of a first catalyst, a second base, and a third solvent to obtain the compound of formula 10, e. A step of reacting the compound of formula 5A with an amine to obtain the compound of formula 11, f. Equation 10 (wherein R is non-substituted or substituted C) 1~6 A step of treating a compound (which is alkyl) with acid to obtain the compound of formula 12, g. A step of reacting the compound of formula 11 with the compound of formula 12 to obtain the compound of formula I. A method is provided that includes this.

[0095] One embodiment of the present disclosure provides a method for preparing a compound of formula I as disclosed herein, comprising the step of treating 3-amino-1,2-propanediol with di-t-butyl dicarbonate (Boc anhydride) and subsequently with potassium t-butoxide to obtain a compound of formula 2.

[0096] One embodiment of the present disclosure provides a method for preparing a compound of formula I, a. A step of treating 3-amino-1,2-propanediol with triphosgene to obtain the compound of formula 2, b. A step of obtaining the compound of formula 21 by reacting the compound of formula 2 with phthalimide, c. A step of reacting the compound of formula 21 with the compound of formula 1 in the presence of a second reagent, a first base, and a second solvent to produce the compound of formula 5A, d. A step of reacting the compound of formula 9 with a boric acid ester in the presence of a first catalyst, a second base, and a third solvent to obtain the compound of formula 10, e. A step of reacting the compound of formula 5A with an amine to obtain the compound of formula 11, f. Equation 10 (wherein R is non-substituted or substituted C)1~6 A step of treating a compound (which is alkyl) with acid to obtain the compound of formula 12, g. A step of reacting the compound of formula 11 with the compound of formula 12 to obtain the compound of formula I, h. A step of subjecting the compound of formula I to a purification process to obtain a high-purity compound of formula I. A method is provided that includes this.

[0097] One embodiment of the present disclosure provides a method for obtaining a high-purity compound of formula I, comprising: (i) adding a polar protic solvent and formic acid to a compound of formula I to obtain a first mixture; (ii) adding a species of compound of formula I and a polar protic solvent to the first mixture while stirring at a temperature in the range of 5 to 20°C, followed by filtration to obtain a solid product; and (iii) drying the solid product under reduced pressure at a temperature in the range of 50 to 70°C to obtain a high-purity compound of formula I.

[0098] In one embodiment of the present disclosure, a method is provided for obtaining a compound of formula I of high purity as disclosed herein, wherein the polar protic solvent is selected from methanol, ethanol, propanol, butanol, pentanol, or a combination thereof. In another embodiment of the present disclosure, the polar protic solvent is methanol.

[0099] In one embodiment of the present disclosure, a method is provided for obtaining a compound of formula I of high purity as disclosed herein, wherein the compound of formula I and the polar protic solvent are in a mass ratio in the range of 1:5 to 1:15. In another embodiment of the present disclosure, the compound of formula I and the polar protic solvent are in a mass ratio in the range of 1:7 to 1:11. In yet another embodiment of the present disclosure, the compound of formula I and the polar protic solvent are in a mass ratio of 1:10.

[0100] In one embodiment of the present disclosure, a method is provided for obtaining a compound of formula I of high purity as disclosed herein, wherein the compound of formula I and formic acid are in a mass ratio in the range of 1:1 to 1:7. In another embodiment of the present disclosure, the compound of formula I and formic acid are in a mass ratio in the range of 1:2 to 1:5. In yet another embodiment of the present disclosure, the compound of formula I and formic acid are in a mass ratio of 1:3.

[0101] One embodiment of the present disclosure provides a method for obtaining a compound of formula I in high purity as disclosed herein, wherein the compound of formula I has a yield of at least 70% and a purity of at least 95%. Another embodiment of the present disclosure provides a compound of formula I in high purity having a yield in the range of 70-95% and a purity in the range of 95-100%.

[0102] One embodiment of the present disclosure provides a compound of formula 5, its stereoisomers, racemic compounds, hydrates, solvates, intermediates, or pharmaceutically acceptable salts thereof.

[0103] [ka]

[0104] One embodiment of the present disclosure provides a compound of formula 5A, a hydrate, a solvate, an intermediate thereof, or a pharmaceutically acceptable salt thereof.

[0105] [ka]

[0106] One embodiment of the present disclosure provides a compound of formula 5B, a hydrate, a solvate, an intermediate thereof, or a pharmaceutically acceptable salt thereof.

[0107] [ka]

[0108] In one embodiment of the present disclosure, formula 10 (wherein R is non-substituted or substituted C) is used. 1~6 Compounds of alkyl groups, their hydrates, solvates, intermediates, or pharmaceutically acceptable salts thereof are provided.

[0109] [ka]

[0110] In one embodiment of the present disclosure, a compound of formula 10 as disclosed herein is provided, wherein the compound is formula 10A having a C2 alkyl group as R.

[0111] [ka]

[0112] One embodiment of the present disclosure provides a method for preparing a compound of formula 5A, comprising the step of reacting a compound of formula 21 with a compound of formula 1 in the presence of a second reagent, a first base, and a second solvent.

[0113] [ka]

[0114] In one embodiment of the present disclosure, a method is provided for preparing the compound of formula 5A as disclosed herein, wherein the second reagent is selected from tris(dibenzylideneacetone)dipalladium(0)-chloroform (Pd2(dba)3CHCl3), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-Bu XPhos), or a combination thereof; the second solvent is selected from toluene, dimethylformamide, 1,4-dioxane, dimethylacetamide, N-methylpyrrolidine, n-butanol, or a combination thereof; and the first base is selected from potassium carbonate, potassium phosphate, triethylamine, sodium t-butoxide, potassium t-butoxide 1,8-diazabicyclo(5.4.0)undeca-7-ene (DBU), 1,4-diazabicyclo(2.2.2)octane (DABCO), or a combination thereof. In another embodiment of the present disclosure, the second reagent is a combination of tris(dibenzylideneacetone)dipalladium(0)-chloroform (Pd2(dba)3CHCl3) and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-Bu XPhos), the second solvent is a combination of toluene and dimethylformamide (DMF); and the first base is selected from potassium carbonate.

[0115] In one embodiment of the present disclosure, a method is provided for preparing a compound of formula 5A, comprising the step of reacting a compound of formula 4 with phthalimide or a salt thereof in an organic solvent, optionally in the presence of a basic agent. In another embodiment of the present disclosure, the basic agent is selected from potassium carbonate, sodium carbonate, ammonium carbonate, or a combination thereof; the organic solvent is selected from dimethylformamide, dimethyl sulfoxide, or a combination thereof. In yet another embodiment of the present disclosure, the compound of formula 5A is obtained by reacting a compound of formula 4 with potassium phthalimide in the presence of an organic solvent.

[0116] [ka]

[0117] One embodiment of the present disclosure provides a method for preparing a compound of formula 10A, comprising the step of reacting a compound of formula 9 with a borate ester in the presence of a first catalyst, a second base, and a third solvent.

[0118] [ka]

[0119] In one embodiment of the present disclosure, a method is provided for preparing a compound of formula 10A as disclosed herein, wherein the first catalyst is selected from [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl2), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane (Pd(dppf)Cl2.CH2Cl2), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Pd(amphos)Cl2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), or a combination thereof; the second base is potassium carbonate, sodium carbonate, sodium acetate, potassium acetate; and the third solvent is selected from dichloromethane, water, 2-methyltetrahydrofuran, dimethoxyethane, or a combination thereof. In another embodiment of the present disclosure, the first catalyst is [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl2); the second base is potassium carbonate; and the third solvent is selected from dichloromethane.

[0120] The subject is described in considerable detail with reference to specific embodiments and their implementations, but other implementations are possible. [Examples]

[0121] The Disclosure is illustrated below by examples intended to illustrate the implementation of the Disclosure and not to be understood as any limitation that implies any limitation on the scope of the Disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the Disclosure belongs. Similar or equivalent methods and materials may be used in the implementation of the processes, compounds, and methods of the Disclosure, but illustrative descriptions are provided herein. It should be understood that the Disclosure is not limited to such methods and experimental conditions to which the specific methods and conditions described herein may be applied.

[0122] Where used herein, the symbols and conventions, schemes, and examples used in these processes are consistent with those used in the modern scientific literature. Unless otherwise stated, all starting materials were obtained from commercially available sources and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout this specification.

[0123] abbreviation

[0124] [Table 1]

[0125] The following abbreviations are used elsewhere in the examples and this specification.

[0126] The following examples provide details of the synthesis of the compound and intermediate of Formula I of this disclosure. It should be understood that these are representative examples and the present invention is not limited to the details shown in these examples.

[0127] If not commercially available, the starting materials required for the procedures described herein may be prepared by a procedure selected from standard organic chemistry techniques, techniques similar to those used for the synthesis of known structurally similar compounds, or techniques similar to those described in the procedures or examples.

[0128] It should be noted that many of the starting materials for the synthesis methods described herein are commercially available and / or widely reported in the scientific literature, or can be prepared from commercially available compounds using adaptations of processes reported in the scientific literature. Readers should further consult Advanced Organic Chemistry, 5th edition, Jerry March and Michael Smith, published by John Wiley & Sons, 2001, for general guidance on reaction conditions and reagents.

[0129] Furthermore, it should be noted that in some of the reactions described herein, it may be necessary or desirable to protect any of the sensitive groups of the compound. Examples of necessary or desirable protection, and suitable methods for such protection, are known to those skilled in the art. Conventional protecting groups may be used as described above herein, in accordance with standard practice (see TW Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991, for an explanation).

[0130] Experimental procedure: Synthesis of 6-chloro-2H-pyrazino[2,3-b][1,4]oxazine-3(4H)-one (Formula 1)

[0131] [ka]

[0132] A stirred solution of 3-bromo-6-chloropyrazine-2-amine (CAS: 212779-21-0, 3.5 kg, 16.79 mol) and t-AmONa (sodium tert-pentoxide, CAS: 14593-46-5, 6.0 kg, 54.48 mol) in THF (35 L) was heated to 55°C, ethyl 2-hydroxyacetate (CAS: 623-50-7, 5.3 kg, 50.96 mol) was added, and the mixture was stirred at 55-65°C for 3 hours. After the reaction was complete, the reaction mixture was cooled to 5°C, neutralized to pH 5-7 with 1.5 N HCl solution, and concentrated to 5-6 volumes under reduced pressure (by removing THF (solvent) from approximately 10 volumes to 5-6 volumes). The residue was diluted with water (17.5 L), concentrated to 8-9 volumes under reduced pressure, filtered, and dried in vacuum to obtain the compound of formula 1 as a yellow solid (2.8 kg, 90%). 1 H NMR (300 MHz, DMSO-d6): 11.85 (s, 1H), 7.85 (s, 1H), 4.90 (s, 2H).

[0133] Synthesis of (S)-2-((2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazolidine-6-yl)oxazolidine-5-yl)methyl)isoindoline-1,3-dione (formula 5A)

[0134] [ka]

[0135] Step 1: (R)-5-(hydroxymethyl)oxazolidine-2-one (Formula 2) To a stirred solution of (R)-3-aminopropane-1,2-diol (CAS: 66211-46-9, 4.0 kg, 43.91 mol) and Na2CO3 (14.0 kg, 132.08 mol) in water (60 L), triphosgene (9.8 kg, 32.93 mol) was added and the mixture was stirred at 35°C to 40°C for 21 hours. After the reaction was complete, the reaction mixture was cooled to 5°C, stirred for 1.5 hours, filtered, and rinsed with cold water (8 L). The filtrate was concentrated to 2-3 volumes under reduced pressure, EtOH (40 L) was added, and the mixture was concentrated to 3-4 volumes under reduced pressure. The residue was diluted with EtOH (40 L) and sampled for KF. The above process was repeated until the KF NMT was 3.0%, and EtOH (40 L) was added to the residue. This was then heated to 35°C, stirred for 1 hour, and filtered. The obtained filtrate, i.e., cake, was washed with EtOH (8 L). The filtrate was concentrated to 2-3 volumes under reduced pressure and diluted with n-BuOH (20 L). The mixture was concentrated to 2-3 volumes, and the filtrate was sampled in area % of GC:EtOH NMT 1.0%. The residue was then cooled to 20-30°C and stirred for 1 hour. The obtained slurry was then filtered and washed with n-BuOH (4 L). The filtered cake was dried under reduced pressure at 50°C to obtain a white solid of formula 2 (3.6 kg, 70.1%). 1 H NMR (300 MHz, DMSO-d6): 7.37 (brs, 1H), 5.07 (brs, 1H), 3.56-3.42 (m, 3H), 3.23 (dd, J=9.0, 6.0 Hz, 1H).

[0136] Step 2: (R)-2-((2-oxoxazolidine-5-yl)methyl)isoindoline-1,3-dione (Formula 21) To a stirred solution of PPh3 (triphenylphosphine, 6.7 kg, 25.54 mol) in DCM (52 L) cooled to 0°C, phthalimide (3.3 kg, 22.43 mol) was added and the mixture was stirred for 0.5 hours. To the resulting solution, the compound of formula 2 (2.6 kg, 22.20 mol) was added and the mixture was stirred at 0°C for 0.5 hours. Then, DEAD (diethyl azodicarboxylate, 4.5 kg, 25.54 mol) was added dropwise and the mixture was stirred for 16 hours. After the reaction was complete, the reaction mixture was quenched with water (26 L), warmed to 20°C, stirred for 0.5 hours, and the organic phase was collected. The organic phase was then concentrated to 7 volumes under reduced pressure. MeOH (13 L) was added to the residue and concentrated to 7 volumes. This procedure was repeated twice. The filtrate was then sampled for GC:DCM NMT 1%. Next, the residue was cooled to 20°C and stirred for 1 hour. The slurry mass was filtered and rinsed with MeOH (5.2 L). The resulting filtered cake was refluxed in MeOH (13 L) for 1 hour. Next, the slurry was cooled to 20°C and stirred for 1 hour. Next, the slurry mass was filtered and the cake was rinsed with MeOH (5.2 L). The resulting solid was dried under vacuum to obtain a white solid of formula 21 (3.05 kg, 55.2%). 1 H NMR (300 MHz, DMSO-d6): 7.90-7.83 (m, 4H), 7.57 (s, 1H), 4.80 (ddt, J=8.6, 7.0, 5.3 Hz, 1H), 3.87 (dd, J=14.4, 7.0 Hz, 1H), 3.78 (dd, J=14.4, 5.1 Hz, 1H), 3.61 (t, J=8.9 Hz, 1H), 3.31 (d, J=9.2, 5.5 Hz, 1H).

[0137] Step 3: (S)-2-((2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazolidine-6-yl)oxazolidine-5-yl)methyl)isoindoline-1,3-dione (Formula 5A) Compound 1 (2.26 kg, 12.18 mol), compound 21 (3.00 kg, 12.18 mol), and K2CO3 (first base, 3.37 kg, 24.36 mol) were added to toluene (33.9 L) as the solvent (second solvent). The mixture was refluxed for 2 hours using a Dean-Stark apparatus, then cooled to 25°C and degassed with nitrogen gas for 2 hours. To the resulting mixture, Pd2(dba)3CHCl3 (second reagent, 378 g, 0.37 mol), t-BuXPhos (second reagent, 310 g, 0.74 mol), and DMF (second solvent, 11.3 L) were added. The resulting mixture was degassed with a nitrogen gas stream for 1 hour. The mixture was then heated to 100°C and stirred for 16 hours. After the reaction was complete, the reaction mixture was cooled to 20°C and stirred for 1 hour. The solid was filtered and rinsed with toluene (4.5 L). The filtered cake was slurryed with 1.5 N HCl solution (33.9 L) at 30°C for 1 hour, then the slurry mass was filtered, and the filtered cake was rinsed with water (4.5 L). The resulting solid was dried under vacuum to obtain an off-white solid of formula 5A (4.90 kg crude, QNMR assay: 85.4%, corrected yield: 85.1%). 1 H NMR (300 MHz, DMSO-d6): 11.68 (s, 1H), 8.34 (s, 1H), 7.93-7.85 (m, 4H), 4.98 (dq, J=8.4, 6.0 Hz, 1H), 4.85 (s, 2H), 4.22 (dd, J=10.2, 8.6 Hz, 1H), 4.01 (d, J=5.6 Hz, 1H), 3.93 (dd, J=10.2, 6.4 Hz, 1H).

[0138] The process showed the best conversion rate and higher purity when using 1,4-dioxane as the solvent and K2CO3 as the base at 95-105°C, or when using toluene / DMF as the solvent and K2CO3 as the base at 95-105°C.

[0139] The importance of the first base: The above reaction, which yielded the compound of formula 5A from the compounds of formulas 1 and 21, was carried out with various bases (first base) selected from potassium phosphate, triethylamine, sodium t-butoxide, potassium t-butoxide, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), and 1,4-diazabicyclo(2.2.2)octane (DABCO), and these resulted in higher yields of formula 5A. However, it was observed that the compound of formula 5A was not formed with the use of other bases such as Cs2CO3.

[0140] The importance of temperature range: In another example, the compound of formula 5A was prepared by treating the compounds of formulas 1 and 21 in 1,4-dioxane (second solvent) as the solvent. The mixture was refluxed for 2 hours using a Dean-Stark apparatus, then cooled to 25°C and degassed with nitrogen gas for 2 hours. Pd2(dba)3CHCl3 (second reagent), t-BuXPhos (second reagent), and DMF (second solvent) were added to the resulting mixture. The resulting mixture was degassed with a nitrogen gas stream for 1 hour. The mixture was then heated to a temperature of 55-65°C and stirred for 16 hours. After the reaction was complete, the reaction mixture was cooled to 20°C and stirred for 1 hour. The solid was filtered and rinsed with 1,4-dioxane. The filtered cake was slurryed with 1.5N HCl solution at 30°C for 1 hour, then the slurry mass was filtered and the filtered cake was rinsed with water. The obtained solid was dried under vacuum to obtain an off-white solid of formula 5A. The yield was found to be in the range of 50–55%. Furthermore, when the compound of formula 5A was prepared by the process described herein, with the temperature of the mixture being heated varying in the range of 75–85°C, the yield of formula 5A was found to be in the range of 50–55%.

[0141] Therefore, it was found that the optimal temperature range for yielding at least 70% higher yields of the compound of formula 5A was in the range of 90–110°C, above which the yield decreased and the conversion to formula 5A took a long time.

[0142] It should be noted that while the method for preparing the compound of formula I via formula 5A did not involve the use of strong chemicals, existing processes for preparing the compound of formula I use hazardous chemicals such as sodium azide and mesityl chloride.

[0143] Alternative process for preparing the compound of formula 5A Alternatively, the compound of formula 5A was prepared by reacting the compound of formula 4 (International Publication No. 2018 / 225097) with potassium phthalimide in dimethyl sulfoxide (DMSO) as a solvent, yielding formula 5A in 23% yield.

[0144] [ka]

[0145] Purification of formula 5A Crude formula 5A (4.90 kg) was combined with crude materials from the other four batches. Crude formula 5A (23.3 kg, QNMR = 86.3%) was mixed with DMSO (627.7 kg). The mixture was heated to 50-55°C and stirred for 2 hours. The slurry was then cooled to 30-35°C, stirred for 1 hour, filtered, and the filtered cake was washed with DMSO (13.1 kg). 3-mercaptopropyl ethyl sulfide silica (4.66 kg) was added to the filtrate, and the mixture was stirred at 30-35°C for 16 hours. The mixture was then filtered, and the cake was washed with DMSO (13.5 kg). 0.1N HCl (300.1 kg) was added to the remaining filtrate, stirred at 25°C for 1 hour, and filtered. The filtered cake was slurryed using 0.1N HCl (224 kg) at 25°C for 1 hour. The slurry was filtered, and the cake was rinsed with water (47.2 kg). The filtered cake was dried under vacuum to obtain formula 5A (19.2 kg, QNMR = 95.3% (purity), 91.5% (yield)). 1H NMR (300 MHz, DMSO-d6): 11.68 (s, 1H), 8.34 (s, 1H), 7.93-7.85 (m, 4H), 4.98 (dq, J=8.4, 6.0 Hz, 1H), 4.85 (s, 2H), 4.22 (dd, J=10.2, 8.6 Hz, 1H), 4.01 (d, J=5.6 Hz, 1H), 3.93 (dd, J=10.2, 6.4 Hz, 1H).

[0146] Synthesis of (E)-8-(2-ethoxyvinyl)-7-fluoro-1-methylquinoline-2(1H)-one (Formula 10A)

[0147] [ka]

[0148] Step 5: (E)-3-ethoxyacryloyl chloride (Formula 6) To a stirred solution of (E)-3-ethoxyacrylic acid (CAS: 6192-01-4, 5.0 kg, 43.07 mol) in toluene (30 L), SOCl2 (thionyl chloride, 6.7 kg, 56.32 mol) was added at 65°C over 6 hours. The resulting mixture was heated and stirred at 95°C for 9 hours. After the reaction was complete, the reaction mixture was concentrated to 2 volumes under reduced pressure. The acid chloride material (Formula 6) was taken for the next step without purification.

[0149] Step 6: (E)-N-(2-bromo-3-fluorophenyl)-3-ethoxyacrylamide (Formula 7) To a stirred solution of 2-bromo-3-fluoroaniline (3.0 kg, 15.79 mol) in THF (24 L), the compound of formula 6 (4.8 kg crude product, QNMR = 44.2%, 15.61 mol) was added at 5°C. Then, pyridine (1.9 kg, 24.02 mol) was added in a THF (6.0 L) solution at 5°C. The resulting mixture was warmed and stirred at 20°C for 16 hours. After the reaction was complete, water (30 L) and ethyl acetate (18 L) were added to the reaction mixture. The organic phase was further washed sequentially with 2N HCl solution (30 L), saturated NaHCO3 solution (30 L), and brine (9 L). The organic phase was concentrated to approximately 2 volumes under reduced pressure. Then, the residue was warmed to 50°C, and n-heptane (12 L) was added at 50°C. The obtained concentrated slurry was cooled to 5°C and stirred for 1 hour. The resulting slurry mass was filtered, rinsed with n-heptane (6 L), and dried in vacuum to obtain a white solid according to formula 7 (3.35 kg, 73.6%). 1 H NMR (400 MHz, DMSO-d6): 9.27 (s, 1H), 7.61 (dt, J=8.3, 1.4 Hz, 1H), 7.53 (d, J=12.3 Hz, 1H), 7.38 (td, J=8.3, 6.4 Hz, 1H), 7.15 (tt, J=8.4, 1.1 Hz, 1H), 5.79 (dd, J=12.4, 1.3 Hz, 1H), 3.97 (q, J=7.0 Hz, 2H), 1.28 (t, J=7.0 Hz, 3H).

[0150] Step 7: (E)-N-(2-bromo-3-fluorophenyl)-3-ethoxy-N-methylacrylamide (Formula 8) To a stirred solution of the compound of formula 7 (4.3 kg, 14.92 mol) in DMF (25.8 L), t-BuOK (potassium butoxide, 2.0 kg, 17.83 mol) was added at -5°C and the mixture was stirred for 1 hour. Then, MeI (methyl iodide, 3.2 kg, 22.55 mol) was added and the mixture was stirred at -5°C for 30 minutes. After the reaction was complete, the reaction mixture was quenched with water (43 L), and the material was extracted three times with MTBE (methyl tert-butyl ether, 21.5 L, 12.9 L, and 12.9 L). The combined organic phase was washed twice with 10% LiCl solution (21.5 L). The organic phase was then concentrated to 5 volumes under reduced pressure and cooled to 20°C. To the residue, n-heptane (21 L) was added and the mixture was then concentrated to 5 volumes. The obtained slurry was cooled to 0-5°C over 1 hour, the resulting solid was filtered, rinsed with n-heptane (4.3 L), and dried in vacuum to obtain a white solid (3.75 kg, 83.1%) according to Equation 8. ¹H NMR (300 MHz, DMSO-d6): 7.55-7.40 (m, 3H), 7.31 (d, J=7.8 Hz, 1H), 4.77 (d, J=12.0 Hz, 1H), 3.73 (q, J=7.0 Hz, 2H), 3.09 (s, 3H), 1.11 (t, J=7.0 Hz, 3H).

[0151] Step 8: 8-Bromo-7-fluoro-1-methylquinoline-2(1H)-one (Formula 9) A solution of the compound of formula 8 (7.6 kg, 25.16 mol) in concentrated H2SO4 (38 L) was stirred at 25°C for 20 hours. After the reaction was complete, the reaction mixture was added to water (152 L) at 5°C and stirred for 1 hour. The resulting slurry was filtered. The resulting cake was slurryed using H2O (38 L), the resulting solid was filtered, rinsed with water (15.2 L), and dried in vacuum to obtain the yellow solid of formula 9 (5.9 kg, 91.6%). 1 H NMR (300 MHz, DMSO-d6): 7.91 (d, J=9.5 Hz, 1H), 7.79 (dd, J=8.6, 6.48 Hz, 1H), 7.30 (t, J=8.5 Hz, 1H), 6.62 (d, J=9.7 Hz, 1H), 3.84 (s, 3H).

[0152] Step 9: (E)-8-(2-ethoxyvinyl)-7-fluoro-1-methylquinoline-2(1H)-one (Formula 10A) To a degassed solvent mixture of DCM (third solvent, 22 L) and water (third solvent, 8.8 L), the compound of formula 9 (2.2 kg, 8.59 mol), Pd-118 (Pd(dtbpf)Cl2, first catalyst, 56.0 g, 0.086 mol), and K2CO3 (second base, 4.75 kg, 34.37 mol) were added. The resulting mixture was degassed with a nitrogen gas stream for 30 minutes, and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (boric acid ester, 2.04 kg, 10.30 mol) was added. The mixture was then degassed with a nitrogen gas stream for 30 minutes and stirred at 35-40°C for 24 hours. After the reaction was complete, the organic phase was separated, washed with water (11.0 L), and concentrated to 2.0–2.5 volumes under reduced pressure. Toluene (11.0 L) was added to the residue. The resulting mass was concentrated to 2.0–2.5 volumes, and then toluene (33 L) was added. NAC (N-acetylcysteine, 0.44 kg, 2.70 mol) and DIEA (0.33 kg, 2.55 mol) were added to this mixture, and the mixture was heated to 63–67°C and stirred for 16 hours. Subsequently, the mass was cooled to 25°C and water (11 L) was added. The organic phase was separated and washed with a 2% NaCl solution in water (11 L). Silica gel (0.46 kg, 0.2 w / w) was added to the organic phase, and the mixture was heated to 63–67°C and stirred for 16 hours. The obtained mass was cooled to 25°C, filtered, and rinsed with toluene (4.6 L). Charcoal (0.46 kg, 0.2 w / w) was added to the filtrate, and the mixture was heated to 63-67°C and stirred for 16 hours. The mixture was then cooled to 25°C, filtered, and rinsed with toluene (4.6 L). The filtrate was concentrated to 2 volumes. n-heptane (11.5 L) was added to the residue at 25°C and stirred for 2 hours. The slurry mass was filtered, rinsed with n-heptane (4.6 L), and dried under vacuum to obtain a deep yellow solid of formula 10 (1.82 kg, 82.0%). 1H NMR (300 MHz, DMSO-d6): 7.73 (d, J=9.4 Hz, 1H), 7.50 (t, J=7.5 Hz, 1H), 7.01 (t, J=9.0 Hz, 1H), 6.50 (d, J=13.1 Hz, 1H), 6.42 (d, J=9.4 Hz, 1H), 5.74 (d, J=13.1 Hz, 1H), 3.82 (q, J=7.0 Hz, 2H), 3.53 (s, 3H), 1.15 (t, J=7.0 Hz, 3H), 0.95 (s, 6H).

[0153] The above reaction showed that when DCM and water were used as solvents, less of the dibrominated compound of Equation 9 was formed. Furthermore, it was found that the amount of Pd present in the formed product was less than 30 ppm.

[0154] Synthesis of (S)-6-(5-(aminomethyl)-2-oxoxazolidine-3-yl)-2H-pyrazino[2,3-b][1,4]oxazine-3(4H)-one (Formula 11)

[0155] [ka]

[0156] Step 10: (S)-6-(5-(aminomethyl)-2-oxoxazolidine-3-yl)-2H-pyrazino[2,3-b][1,4]oxazine-3(4H)-one (Formula 11) To a solution of compound 5A (9.22 kg, 23.32 mol) in DCM (285.00 kg) or MeOH (36.8 kg), 80% hydrazine hydrate (amine, 8.36 kg, 139.92 mol) was added and the mixture was stirred at 25°C for 16 hours. Compound 5A (9.22 kg, 23.32 mol) and DCM (24.45 kg) were added to the stirred solution mass and the mixture was stirred for 16 hours. After the reaction was complete, formic acid (20.65 kg, 448.91 mol) and water (124.50 kg) were added to the reaction mass, which was then filtered and rinsed with water (36.20 kg). The aqueous phase of the filtrate was collected. The filtered cake contained a slurry of formic acid (4.10 kg) and water (53.90 kg) along with the solvent (DCM). Next, the reaction mass was stirred for 1 hour, filtered, and rinsed with water (36.50 kg). The combined filtrate was diluted with DCM (85.65 kg), stirred for 5 minutes, and separated into layers. 3-mercaptopropyl ethyl sulfide silica (3.70 kg, 0.20 w / w) was added to the collected aqueous phase, stirred for 16 hours, filtered, and the cake was rinsed with water (35.70 kg). The filtrate was cooled to 10°C, basicized to pH 9.0 with a 20% NaOH solution, stirred for 16 hours, filtered the resulting slurry mass, rinsed with water (36.10 kg), and dried in vacuum to obtain a crude bright yellow solid of formula 11 (9.7 kg, 36.58 mol).

[0157] Crude formula 11 (9.7 kg, 36.58 mol) was added to a mixture of water (97.8 kg) and formic acid (3.5 kg, 76.09 mol) at 20°C and stirred to obtain a clear solution. The solution was filtered twice through a carbon cartridge. To the filtrate, the seed of formula 11 was added at 10°C and stirred for 30 minutes, and the solution was basicized to pH 9.0 with a 20% NaOH solution. The resulting slurry was stirred for 16 hours, filtered, and rinsed with water (19.95 kg). The resulting wet material was dried in vacuum to obtain a bright yellow solid of formula 11 (7.74 kg, purity 99.6%, 64.9%). 1H NMR (400 MHz, DMSO-d6): 8.39 (s, 1H), 4.85 (s, 2H), 4.67 (p, J=5.3 Hz, 1H), 4.08 (t, J=9.3 Hz, 1H), 3.85 (dd, J=9.8, 6.5 Hz, 1H), 2.88 (dd, J=13.7, 4.7 Hz, 1H), 2.82 (dd, J=13.6, 5.0 Hz, 1H).

[0158] For the effective conversion of the compound of formula 5A to the compound of formula 11, the addition and stirring time after adding hydrazine hydrate to the reaction mixture are essential. When the above reaction was carried out with a shorter addition and stirring time of hydrazine hydrate (less than 6 hours), wall cake formation was observed. Therefore, a longer addition time (at least 16 hours) eliminated wall cracking and resulted in an improved yield of formula 11.

[0159] Synthesis of 2-(7-fluoro-1-methyl-2-oxo-1,2-dihydroquinoline-8-yl)acetaldehyde (formula 12)

[0160] [ka]

[0161] Step 11: 2-(7-fluoro-1-methyl-2-oxo-1,2-dihydroquinoline-8-yl)acetaldehyde (Formula 12) Formula 10 (3.87 kg, 15.65 mol) was added to a stirred mixture of HCl (inorganic acid, 5.74 kg), water (14.54 kg), and acetone (15.25 kg), and the mixture was heated to 40°C and stirred for 16 hours. After the reaction was complete, the reaction mixture was concentrated to 4.5-5.5 volumes under reduced pressure, extracted twice with DCM (30.84 kg), and washed with 10% Na2CO3 solution (25.57 kg) and water (23.18 kg). The organic phase was concentrated to 2-3 volumes under atmospheric pressure. DCM (7.86 kg) was added to the residue at 20°C, concentrated to 2-3 volumes under atmospheric pressure, and cooled to 10°C. Then, n-heptane (21.4 kg) was added to the residue at 10°C. The slurry was stirred for 16 hours, the resulting solid was filtered, rinsed with n-heptane (10.68 kg), and dried in vacuum to obtain a white solid of formula 12 (3.23 kg, 93.1%). 1 H NMR (300 MHz, CDCl3): 9.82 (s, 1H), 7.50 (d, J=9.4 Hz, 1H), 7.38 (dd, J=8.6, 6.4 Hz, 1H), 6.92 (t, J=3.2 Hz, 2H), 3.54 (s, 3H).

[0162] The previously described method for obtaining the compound of formula 12, reported in International Publication No. 2018 / 225097, involved the use of hazardous reagents such as allyltributyltin and K2OsO4, which were eliminated in the method of this disclosure. Furthermore, the yield of the compound of formula 12 obtained by the method of this disclosure was significantly higher compared to the previously reported procedure (International Publication No. 2018 / 225097).

[0163] Synthesis of (S)-6-(5-(((2-(7-fluoro-1-methyl-2-oxo-1,2-dihydroquinoline-8-yl)ethyl)amino)methyl)-2-oxoxazolidine-3-yl)-2H-pyrazino[2,3-b][1,4]oxazine-3(4H)-onformate (Formula I)

[0164] [ka]

[0165] Step 12: (S)-6-(5-(((2-(7-fluoro-1-methyl-2-oxo-1,2-dihydroquinoline-8-yl)ethyl)amino)methyl)-2-oxoxazolidine-3-yl)-2H-pyrazino[2,3-b][1,4]oxazine-3(4H)-onformate (Formula I) To a solvent mixture of DCM (first solvent, 148.60 kg) and MeOH (first solvent, 88.25 kg), the compound of formula 11 (7.57 kg, 28.54 mol) and the compound of formula 12 (6.20 kg, 28.54 mol) were added, and the mixture was stirred at 25°C for 2 hours. To the resulting mixture, the 2-picolinborane complex (first reagent, 2.96 kg, 27.69 mol) was added, and the mixture was stirred at 25°C for 2 hours. Then, formic acid (first reagent, 6.45 kg, 140.22 mol) was added, and the mixture was stirred at 25°C for 16 hours. After the reaction was complete, the slurry was filtered, rinsed with DCM (first solvent, 40.40 kg), and dried in vacuum to obtain the crude material of formula I (12.91 kg) with a purity of 95%.

[0166] The compound of formula I obtained by the method of this disclosure contained no dimeric impurities, whereas the existing method for obtaining formula I contained more than 10% by mass of dimeric impurities in the final product, as shown below.

[0167] [ka]

[0168] While existing methods yielded compounds of formula I in the range of 30-60%, the method of this disclosure yielded a yield of at least 70-90%. Therefore, it is clearly demonstrated that the method of this disclosure, comprising compounds of formula 5A and formula 10A, thereby forming compounds of formula 11 and 12, respectively, yielded high-purity compounds of formula I in improved yields. Thus, the method of this disclosure was found to be an efficient preparation method.

[0169] Synthesis of high-purity compounds of formula I To a stirred solution of formic acid (39.40 kg) and MeOH (10.25 kg), the crude material of formula I obtained above (12.85 kg, 24.98 mol) was added at 10°C and stirred to obtain a clear solution. The solution was filtered and rinsed with MeOH (20.15 kg). To the filtrate, MeOH (20.40 kg) and the seed of formula I (0.0643 kg, 0.12 mol) were added and stirred at 10°C for 30 minutes. MeOH (81.35 kg) was added to the slurry mass and stirred for 2 hours. The resulting solid was filtered, rinsed with MeOH (21 kg), and dried in vacuum to obtain the off-white solid of formula I with a purity of >99% (11.66 kg, yield: 79.7%). Methanol and formula I were taken in a mass ratio of 9:1 to 10:1, particularly 9.5:1; and formic acid and formula I were taken in a mass ratio of 2.5:1 to 3.5:1, particularly 3:1, to obtain a high-purity compound of formula I. 1 H NMR (400 MHz, DMSO-d6): 8.38 (s, 1H), 8.16 (s, 1H), 7.84 (d, J=9.4 Hz, 1H), 7.63 (dd, J=8.6, 6.6 Hz, 1H), 7.14 (dd, J=9.9, 8.6 Hz, 1H), 6.54 (d, J=9.4 Hz, 1H), 4.86 (s, 2H), 4.81-4.75 (m, 1H), 4.09 (t, J=9.4 Hz, 1H), 3.82 (dd, J=9.8, 6.5 Hz, 1H), 3.72 (s, 3H), 3.16-3.13 (m, 2H), 2.97-2.88 (m, 2H), 2.87-2.83 (m, 2H).

[0170] When the above purification process was carried out using acetonitrile as the solvent, the resulting compound of formula I was found to be unstable, and it was observed that acylated impurities were further formed. Therefore, it was found that polar protic solvents are favorable for obtaining high-purity compound of formula I with a purity of at least 90%.

[0171] Benefits of this disclosure This disclosure provides a simple method for preparing a clinical development drug candidate of formula I. Compounds of formula I exhibit potent antimicrobial activity against various Gram-negative and Gram-positive bacteria, including multidrug-resistant bacterial pathogens. The method of this disclosure provides a novel method for producing compounds of formula I in improved yield and higher purity. Compared to existing methods, the method of this disclosure is carried out with fewer steps and avoids the use of hazardous reagents. The method of this disclosure proposes a more sustainable and cost-effective route for producing compounds of formula I in high purity and yield. The method of this disclosure provides an efficient synthetic method for the large-scale industrial production of compounds of formula I.

Claims

1. A method for preparing the compound of formula I, a) A step of reacting the compound of formula 5A with an amine to obtain the compound of formula 11, 【Chemistry 1】 b) A step of reacting the compound of formula 11 with the compound of formula 12 to obtain the compound of formula I. 【Chemistry 2】 Methods that include...

2. The compound of formula 12 is the compound of formula 10 (wherein R is unsubstituted or substituted C). 1～6 The method according to claim 1, obtained by treating a compound (which is alkyl) with an acid. 【Transformation 3】

3. The amine is hydrazine, C 1～6 Alkylhydrazine, C 1～6 The method according to claim 1, selected from alkylamines or combinations thereof.

4. The method according to claim 1, wherein the step of reacting the compound of formula 11 with the compound of formula 12 is carried out in the presence of a first reagent and a first solvent at a temperature in the range of 5 to 50°C.

5. The method according to claim 4, wherein the first reagent is selected from a picoline borane complex, formic acid, or a combination thereof, and the first solvent is selected from dichloromethane, methanol, or a combination thereof.

6. The method according to claim 1, wherein the step of reacting the compound of formula 5A with an amino acid is carried out at a temperature in the range of 5 to 50°C.

7. The method according to claim 2, wherein the step of treating the compound of formula 10 is carried out at a temperature in the range of 20 to 60°C, and the acid is an inorganic acid, preferably hydrochloric acid.

8. The method according to claim 1, wherein the compound of formula I has a yield of at least 70% and a purity of at least 90%.

9. The method according to claim 1, wherein the compound of formula 5A is obtained by reacting the compound of formula 21 with the compound of formula 1 in the presence of a second reagent, a first base, and a second solvent. 【Chemistry 4】

10. The second reagent is tris(dibenzylideneacetone)dipalladium(0)-chloroform(Pd 2 (dba) 3 CHCl 3 The method according to claim 9, wherein the first base is selected from ), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-Bu XPhos), or a combination thereof; the second solvent is selected from toluene, dimethylformamide, 1,4-dioxane, dimethylacetamide, N-methylpyrrolidine, n-butanol, or a combination thereof; and the first base is selected from potassium carbonate, potassium phosphate, triethylamine, sodium t-butoxide, potassium t-butoxide, 1,8-diazabicyclo(5.4.0)undeca-7-ene (DBU), 1,4-diazabicyclo(2.2.2)octane (DABCO), or a combination thereof.

11. The method according to claim 9, which is carried out at a temperature in the range of 90 to 110°C.

12. The method according to claim 9, wherein the compound of formula 5A has a yield of at least 70% and a purity of at least 90%.

13. The method according to claim 9, wherein the compound of formula 21 is obtained by reacting the compound of formula 2 with phthalimide. 【Transformation 5】

14. The method according to claim 13, wherein the compound of formula 2 is obtained by treating 3-amino-1,2-propanediol with triphosgene, or by treating 3-amino-1,2-propanediol with di-t-butyl dicarbonate (Boc anhydride) followed by treatment with potassium t-butoxide. 【Transformation 6】

15. Formula 10 (wherein R is either unsubstituted or substituted C) 1～6 The method according to claim 2, wherein a compound (which is alkyl) is obtained by reacting a compound of formula 9 with a borate ester in the presence of a first catalyst, a second base, and a third solvent. 【Transformation 7】

16. The first catalyst is selected from [1,1'-bis(di-tert-butylphosphino)ferrocene] dichloropalladium(II) (Pd(dtbpf)Cl 2 ), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) dichloromethane (Pd(dppf)Cl 2 .CH 2 Cl 2 ), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(II) (Pd(amphos)Cl 2 ), tetrakis(triphenylphosphine) palladium (Pd(PPh 3 )) 4 ), or a combination thereof; the second base is selected from potassium carbonate, sodium carbonate, sodium acetate, potassium acetate, or a combination thereof; the third solvent is selected from dichloromethane, water, 2-methyltetrahydrofuran, dimethoxyethane, or a combination thereof, the method according to claim 15.

17. The method according to claim 15, which is carried out at a temperature in the range of 20 to 80°C.

18. The method according to claim 15, wherein the compound of formula 10 has a yield of at least 70% and a purity of at least 90%.

19. The method according to claim 1, wherein the compound of formula I is further subjected to a purification process to obtain a high-purity compound of formula I.

20. A method for obtaining a high-purity compound of formula I as defined in claim 19, i. A step of adding a polar protic solvent and formic acid to the compound of formula I to obtain a first mixture, ii. A step of adding a compound species of formula I and a polar protic solvent to the first mixture while stirring at a temperature in the range of 5 to 20°C, followed by filtration to obtain a solid product. iii. A step of drying the solid product under reduced pressure at a temperature in the range of 50 to 70°C to obtain a high-purity compound of formula I. Methods that include...

21. The method according to claim 20, wherein the polar protic solvent is selected from methanol, ethanol, propanol, butanol, pentanol, or a combination thereof.

22. The method according to claim 20, wherein the compound of formula I of high purity has a yield of at least 70% and a purity of at least 95%.

23. The method according to claim 20, wherein the compound of formula I and the polar protic solvent are in a mass ratio in the range of 1:5 to 1:

15.

24. The method according to claim 20, wherein the compound of formula I and formic acid are in a mass ratio in the range of 1:1 to 1:

7.

25. Compounds of formula 5, their stereoisomers, racemic compounds, hydrates, solvates, intermediates, or pharmaceutically acceptable salts thereof. 【Transformation 8】

26. Compounds of formula 5A, their hydrates, solvates, intermediates, or pharmaceutically acceptable salts thereof. 【Chemistry 9】

27. Formula 10 (wherein R is either unsubstituted or substituted C) 1～6 Compounds of alkyl groups, their stereoisomers, hydrates, solvates, intermediates, or pharmaceutically acceptable salts thereof. 【Chemistry 10】

28. R as C 2 The compound of formula 10 according to claim 27, which is a compound of formula 10A having an alkyl group. 【Chemistry 11】

29. A method for preparing the compound of formula 5A, comprising the step of reacting the compound of formula 4 with phthalimide or a salt thereof in an organic solvent, optionally in the presence of a basic agent. 【Chemistry 12】

30. A method for preparing the compound of formula 5A according to claim 29, wherein the basic agent is selected from potassium carbonate, sodium carbonate, ammonium carbonate, or a combination thereof, and the organic solvent is selected from dimethylformamide, dimethyl sulfoxide, or a combination thereof.

31. A method for preparing the compound of formula 10A, comprising the step of reacting the compound of formula 9 with a borate ester in the presence of a first catalyst, a second base, and a third solvent. 【Chemistry 13】

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