A process of preparation of an antibacterial compound and its intermediates thereof

Abstract

The present disclosure provides a process of preparation of an antibacterial compound of Formula I, (S)-6-(5-(((2-(7-fluoro-l- methyl-2-oxo-l,2-dihydroquinolin-8-yl) ethyl) amino) methyl)-2- oxooxazolidin-3-yl)-2H-pyrazino[2,3-b] [1,4] oxazin-3(4H)-one formate salt. The present disclosure also provides intermediates of the compound of Formula I and their preparation. The present disclosure further provides a process of preparation of compound of Formula I with improved yield and high purity.

Description

A PROCESS OF PREPARATION OF AN ANTIBACTERIAL COMPOUND AND ITS INTERMEDIATES THEREOF FIELD OF INVENTION

[0001] The present disclosure, in general, relates to a process of preparing an antibacterial compound, specifically to a compound of Formula I, which is a clinical developmental drug candidate that exhibits potent antibacterial activity against a variety of Gram-negative bacteria and Gram-positive bacteria, including multidrug resistance bacterial pathogens.

[0002] More particularly, the present disclosure relates to a large-scale or an industrial scale production of a compound of Formula I, namely, (S)-6-(5-(((2-(7- fluoro-1-methyl-2-oxo-1,2-dihydroquinolin-8-yl) ethyl) amino) methyl)-2- oxooxazolidin-3-yl)-2H-pyrazino[2,3-b] [1,4] oxazin-3(4H)-one formate salt with improved yield and high purity.BACKGROUND OF THE INVENTION

[0003] Antimicrobial resistance (AMR) has been identified as a major public health concern that could reverse the progress made in modern medicine, hence there is a need for a global approach to tackle it. The World Health Organization (WHO) has called for urgent action to address this issue and prevent a future where common infections become untreatable. Therefore, there is an urgent need in research and development of new antibiotics, to strengthen the preparedness and response capabilities of healthcare systems to tackle any such threats. Hence developing new antibiotics is crucial to combating the growing threat of antimicrobial resistanceand preventing the spread of deadly infections. (https: / / www.who.int / news- room / fact-sheets / detail / antimicrobial-resistance).

[0004] WO2018225097 provides one such antibiotic compound of Formula I which is a synthetic oxazolidinone based, broad spectrum antibacterial and it is chemically called as (S)-6-(5-(((2-(7-fluoro-1-methyl-2-oxo-1,2-dihydroquinolin- 8-yl) ethyl) amino) methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b] [1,4] oxazin-3(4H)-one formate. This compound has shown potent activity against a broad range of bacteria, including those that are resistant to current antibiotics. Additionally, it had been demonstrated to have no cross-resistance with current antibiotics, making it a promising candidate for the treatment of infections caused by multi-drug resistant bacteria.

[0005] In this view, the compound of Formula I has shown promising results in pre- clinical studies and has the potential to be developed into a new class of antibiotics. Further research and clinical trials are needed to fully evaluate its safety and efficacy.

[0006] However, the existing synthetic process described in making the compound of Formula I reported is a small-scale process used during the medicinal chemistry optimization phase and is not suitable for large scale synthesis of a drug substance required for clinical trial development and commercial supply. Therefore, further process development and optimization are necessary to ensure the scalability and cost-effectiveness of the synthetic route for the compound of Formula I for clinical trial supply and commercial production. Thus, there is a need for a simple facile and economical synthetic route for large scale manufacturing of compound of Formula I yet provides improved yield and high purity. SUMMARY OF THE INVENTION

[0007] In an aspect of the present disclosure, there is provided a process for preparing a compound of Formula I, the process comprising: a) reacting a compound of Formula 5A with an amine to obtain a compound of Formula 11; andb) reacting the compound of Formula 11 with a compound of Formula 12 to obtain the compound of Formula I.

[0008] In another aspect of the present disclosure, there is provided a process for preparing a compound of Formula I, the process comprising: a) reacting a compound of Formula 5A with an amine to obtain a compound of Formula 11;b) treating a compound of Formula 10 with an acid to obtain a compound of Formula 12, wherein R is unsubstituted or substituted C1-6 alkyl; andc) reacting the compound of Formula 11 with the compound of Formula 12 to obtain the compound of Formula I..

[0009] In one another aspect of the present disclosure, there is provided a process of obtaining a highly pure compound of Formula I, the process comprising: (i) charging the compound of Formula I with a polar protic solvent and formic acid to obtain a first mixture; (ii) adding a seed of compound of Formula I and the polar protic solvent to the first mixture under stirring at a temperature in a range of 5 to 20℃, followed by filtering to obtain a solid product; and (iii) drying the solid product under reduced pressure at a temperature in a range of 50 to 70℃, to obtain the high pure compound of Formula I.

[0010] In yet another aspect of the present disclosure, there is provided a compound of Formula 5, its stereoisomers, racemates, hydrates, solvates, intermediates, or pharmaceutically acceptable salts thereof.Formula 5

[0011] In still another aspect of the present disclosure, there is provided a compound of Formula 5A, its hydrates, solvates, intermediates, or pharmaceutically acceptable salts thereof.Formula 5A

[0012] In more aspects of the present disclosure, there is provided a compound of Formula 10, its hydrates, solvates, intermediates, or pharmaceutically acceptable salts thereof, wherein R is unsubstituted or substituted C1-6alkyl.

[0013] In a further aspect of the present disclosure, there is provided a process for preparing a compound of Formula 5A, the process comprising 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.

[0014] In more aspect of the present disclosure, there is provided a process for preparing a compound of Formula 10, the process comprising reacting a compound of Formula 9 with a boric acid ester in the presence of a first catalyst, a second base and a third solvent.

[0015] In further aspect of the present disclosure, there is provided a process for preparing a compound of Formula 5A, the process comprising reacting a compound of Formula 4 with phthalimide or its salt, in an organic solvent optionally in the presence of a basic agent.

[0016] These and other features, aspects, and advantages of the present subject matter will become better understood with reference to the following description and appended claims. This summary is provided to introduce a selection of concepts in a simplified form. This summary is not intended to identify key features or essential features of the disclosure, nor is it intended to be used to limit the scope of the claimed subject matter. DETAILED DESCRIPTION OF THE INVENTION

[0017] Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such steps, features, compositionsand compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any or more of such steps or features. Definitions

[0018] For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have the meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.

[0019] The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.

[0020] The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. Throughout this specification, unless the context requires otherwise the word “comprise”, and variations, such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of elements or steps but not the exclusion of any other element or step or group of elements or steps.

[0021] The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably.

[0022] In the structural formulae given herein and throughout the present disclosure, the following terms have been indicated meaning, unless specifically stated otherwise.

[0023] As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include halogens, cyano, amino, hydroxyl, thio, sulpho, sulphido, oxo, any groups as acyclic and cyclic, branched, and unbranched, carbocyclic, and heterocyclic, aromatic, and nonaromatic substituents of organic compounds. Illustrative substituents, for example, include those described herein above. The permissible substituents can be one or more and the same or different for appropriate organic compounds. The heteroatoms may have hydrogen substituents,and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. It is understood that the substituent may be further substituted.

[0024] In the structural formulae given herein and throughout the present disclosure, the following terms have been indicated meaning, unless specifically stated otherwise.

[0025] The term “alkyl” refers to straight or branched aliphatic hydrocarbon groups having the specified number of carbon atoms, which are attached to the rest of the molecule by a single atom, and may be optionally substituted by one or more substituents. The term C1-6 alkyl, in particular, refers to an alkyl group having 1, 2, 3, 4, 5 or 6 carbons. Preferred alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like. The alkyl group of the present disclosure may be optionally substituted.

[0026] The compounds described herein may contain one or more chiral centers and / or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), regioisomers, enantiomers, or diastereomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated or identified compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the person skilled in the art. The compounds may also exist in several tautomeric forms including the enol form, the keto form, and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated or identified compounds.

[0027] The term “racemates” refers to a mixture comprising a pair of optical isomers. Racemate refers to equimolar mixture of a pair of enantiomers. Racemate does not exhibit optical activity.

[0028] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0029] “Pharmaceutically acceptable salt” embraces salts with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid and organic acids, for example formic, citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases, for example alkyl amines, arylalkyl amines and heterocyclic amines.

[0030] Salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present disclosure, for example, for use as intermediates in the preparation of other compounds, and their pharmaceutically acceptable salts. Thus, one embodiment of the disclosure embraces compounds as disclosed herein, and salts thereof. Compounds containing a basic functional group are capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids. Representative pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, hydroxyacetate, phenyl acetate, propionate, butyrate, iso-butyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, glycollate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, naphthoate, hydroxynaphthoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate, estolate, methanesulfonate (mesylate), ethanesulfonate (esylate), 2- hydroxyethanesulfonate, benzenesulfonate (besylate),aminobenzenesulfonate, p-toluenesulfonate (tosylate), and naphthalene-2- sulfonate.

[0031] The term “solvates”, as used herein, refers to a crystal form of a substance which contains solvent.

[0032] The term “hydrates”, as used herein, refers to a solvate, wherein the solvent is water.

[0033] The term “intermediates” refers to the compounds with the same core structure of the compounds of the present disclosure varying at specific allowed positions (for example alkyl chains).

[0034] The term intermediates also includes metabolites which refer to the end product of metabolism and which possess the functions of the compounds of Formula I. Metabolites are compounds obtained under physiological conditions that would result in the compounds of Formula I.

[0035] The compounds prepared by the process described herein may also exhibit polymorphism. This invention further includes different polymorphs of the compounds of the present invention. The term “polymorph” refers to a particular crystalline state of a substance, having particular physical properties such as X-ray diffraction, IR spectra, melting point, and the like. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. It will be appreciated that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

[0036] The term “inorganic acid” as used herein, refers to any acid derived from inorganic groups capable of rendering hydrogen ions and form the conjugate base. Examples of inorganic acid include but not limited to hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or combinations thereof.

[0037] A term once described, the same meaning applies to it, throughout the disclosure.

[0038] As discussed in the background, the existing processes for obtaining the compound of Formula I are not suitable for large scale production. Hence there is a need for developing synthetic processes to ensure scalability and cost-effectiveness in preparing the compound of Formula I essentially for clinical trial supply and commercial production. An effective synthetic route should follow minimum iterations yet provide higher yield and purity. It is also necessary that the process utilizes less hazardous reagents and chemicals and thus should be an environmentally benign process. Accordingly, the present disclosure provides a process for preparing the compound of Formula I, which involves novel intermediates with a reduced number of process steps. The present disclosure also relates to processes of making novel intermediate compounds with improved yield and higher purity. The processes of the present disclosure involve the use of reagents, catalysts and reaction conditions, which have been found to significantly enhance efficiency and improve yield. The present disclosure also provides a process for obtaining a highly pure compound of Formula I.

[0039] In an embodiment of the present disclosure, there is provided a process for preparing a compound of Formula I, the process comprising: a) reacting a compound of Formula 5A with an amine to obtain a compound of Formula 11; andb) reacting the compound of Formula 11 with a compound of Formula 12 to obtain the compound of Formula I.

[0040] In an embodiment of the present disclosure, there is provided a process for preparing a compound of Formula I as disclosed herein, wherein the compound of Formula 12 is obtained by treating a compound of Formula 10 with an acid, wherein R is unsubstituted or substituted C1-6alkyl. In another embodiment of the present disclosure, R is C2alkyl.

[0041] In an embodiment of the present disclosure, there is provided a process for preparing a compound of Formula I as disclosed herein, wherein the amine is selected from hydrazine, C1-6 alkyl hydrazine, C1-6 alkyl amine or combinations thereof. In another embodiment of the present disclosure, the amine is hydrazine or hydrazine hydrate. In one another embodiment of the present disclosure, the amine is methyl amine, ethyl amine, n-propyl amine, iso-propyl amine, or n-butyl amine.

[0042] In an embodiment of the present disclosure, there is provided a process for preparing a compound of Formula I, the process comprising: a) treating a compound of Formula 10 with an acid to obtain a compound of Formula 12, wherein R is unsubstituted or substituted C1-6alkyl; andb) reacting the compound of Formula 11 with the compound of Formula 12 to obtain the compound of Formula I.

[0043] In an embodiment of the present disclosure, there is provided a process for preparing a compound of Formula I, the process comprising: a) reacting a compound of Formula 5A with an amine to obtain a compound of Formula 11;b) treating a compound of Formula 10 with an acid to obtain a compound of Formula 12, wherein R is unsubstituted or substituted C1-6 alkyl; andc) reacting the compound of Formula 11 with the compound of Formula 12 to obtain the compound of Formula I..

[0044] In an embodiment of the present disclosure, there is provided a process for preparing a compound of Formula I as disclosed herein, wherein 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 a range of 5 to 50℃. In another embodiment of the present disclosure, 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 a range of 5 to 50℃ for a time period of at least 5 hours. In one another embodiment of the present disclosure, reacting the compound of Formula 11 with the compound of Formula 12 is carried out at a temperature in a range of 10 to 40℃ for a time period in a range of 10 to 30 hours.

[0045] In an embodiment of the present disclosure, there is provided a process 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 combinations thereof; and the first solvent is selected from dichloromethane, methanol, or combinations 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 combinations thereof.

[0046] In an embodiment of the present disclosure, there is provided a process for preparing a compound of Formula I as disclosed herein, wherein reacting the compound of Formula 5A with an amine is carried out at a temperature in a range of 5 to 50℃. In another embodiment of the present disclosure, wherein reacting the compound of Formula 5A with an amine is carried out at a temperature in a range of 5 to 50℃ for a time period of at least 1 hour. In one anotherembodiment of the present disclosure, wherein reacting the compound of Formula 5A with an amine is carried out at a temperature in a range of 15 to 50℃ for a time period in a range of 1 to 24 hours. In yet another embodiment of the present disclosure, wherein reacting the compound of Formula 5A with hydrazine is carried out at a temperature in a range of 5 to 50℃ for a time period of 10 to 24 hours.

[0047] In an embodiment of the present disclosure, there is provided a process for preparing a compound of Formula I as disclosed herein, wherein treating a compound of Formula 10 is carried out at a temperature in a range of 20 to 60℃; and the acid is an inorganic acid, preferably hydrochloric acid. In another embodiment of the present disclosure, wherein the inorganic acid, preferably hydrochloric acid is taken in a concentration range of 0.1N to 14.0N solution.

[0048] In an embodiment of the present disclosure, there is provided a process 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%. In another embodiment of the present disclosure, wherein the compound of Formula I has a yield in a range of 70 to 95%; and a purity in a range of 90 to 100%.

[0049] In an embodiment of the present disclosure, there is provided a process 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.

[0050] In an embodiment of the present disclosure, there is provided a process for preparing a compound of Formula I 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 combinations thereof; the second solvent isselected from toluene, dimethyl formamide, 1,4-dioxane, dimethyl acetamide, N- methyl pyrrolidine, n-butanol, or combinations thereof; and the first base is selected from potassium carbonate, potassium phosphate, triethyl amine, sodium t-butoxide, potassium t-butoxide, 1,8-diazabicyclo(5.4.0) undec-7-ene (DBU), 1,4- diazabicyclo(2.2.2) octane (DABCO), or combinations 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 combinations thereof; the second solvent is selected from toluene, dimethyl formamide, or combinations thereof; and the first base is potassium carbonate. In one another embodiment of the present disclosure, the second solvent is a mixture of 1,4-dioxane and dimethyl formamide 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.

[0051] In an embodiment of the present disclosure, there is provided a process 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 is carried out at a temperature in a range of 90 to 110℃. In another embodiment of the present disclosure, wherein the compound of Formula 5A is obtained by reacting a compound of Formula 21 with a compound of Formula 1 is carried out at a temperature in a range of 90 to 110℃ for a time period of at least 1 hour. In one another embodiment of the present disclosure, wherein the compound of Formula 5A is obtained by reacting a compound of Formula 21 with a compound of Formula 1 is carried out at a temperature in a range of 90 to 110℃ for a time period in a range of 1 to 24 hours.

[0052] In an embodiment of the present disclosure, there is provided a process for preparing a compound of Formula I as disclosed herein, wherein the compound of Formula 5A has a yield of at least 70%; and purity of at least 90 %. In another embodiment of the present disclosure, wherein the compound of Formula 5A has yield in a range of 70 to 95%; and purity in a range of 90 to 99.9%.

[0053] In an embodiment of the present disclosure, there is provided a process 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, wherein the compound of Formula 21 is obtained by reacting a compound of Formula 2 with phthalimide at a temperature in a range of -10 to 30℃ for a time period of at least 30 minutes. In one another embodiment of the present disclosure, wherein the compound of Formula 21 is obtained by reacting a compound of Formula 2 with phthalimide at a temperature in a range of 0 to 20℃ for a time period in a range of 1 hour to 20 hours.

[0054] In an embodiment of the present disclosure, there is provided a process 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 decarbonate (Boc anhydride) followed by treating with potassium t-butoxide. In another embodiment of the present disclosure, wherein the compound of Formula 2 is obtained by treating 3-amino-1,2-propanediol with triphosgene is carried out at a temperature in a range of 5 to 50℃ for a time period of at least 2 hours. In yet another embodiment of the present disclosure, wherein the compound of Formula 2 is obtained by treating 3-amino-1,2-propanediol with triphosgene is carried out at a temperature in a range of 5 to 40℃ for a time period in a range of 2 to 22 hours.

[0055] In an embodiment of the present disclosure, there is provided a process 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 boric acid ester having R selected from unsubstituted or substituted C1-6 alkyl, in presence of a first catalyst, a second base and a third solvent. In another embodimentof the present disclosure, wherein the compound of Formula 10 is obtained by reacting a compound of Formula 9 with a boric acid ester in presence of a first catalyst, a second base and a third solvent is carried out at a temperature in a range of 20 to 80℃. In one embodiment of the present disclosure, wherein the compound of Formula 10 is obtained by reacting a compound of Formula 9 with a boric acid ester in presence of a first catalyst, a second base and a third solvent is carried out at a temperature in a range of 25 to 70℃.

[0056] In an embodiment of the present disclosure, there is provided a process 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 combinations thereof; the second base is selected from potassium carbonate, sodium carbonate, sodium acetate, potassium acetate or combinations thereof; and the third solvent is selected from dichloromethane, water, 2-methyl tetrahydrofuran, dimethoxy ethane or combinations 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 combinations thereof.

[0057] In an embodiment of the present disclosure, there is provided a process for preparing a compound of Formula I as disclosed herein, wherein thecompound of Formula 10 has yield of at least 70%; and purity of at least 90 %. In another embodiment of the present disclosure, wherein the compound of Formula 10 has yield in a range of 70 to 95%; and purity in a range of 90 to 99.9%.

[0058] In an embodiment of the present disclosure, there is provided a process 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 pure compound of Formula I.

[0059] In an embodiment of the present disclosure, there is provided a process for preparing a compound of Formula I, the process comprising: a. treating 3-amino-1,2-propanediol with triphosgene to obtain a compound of Formula 2; b. obtaining a compound of Formula 21 by reacting the compound of Formula 2 with phthalimide; c. reacting the compound of Formula 21 with a compound of Formula 1 in presence of a second reagent, a first base and a second solvent to a compound of Formula 5A; d. reacting a compound of Formula 9 with a boric acid ester in presence of a first catalyst, a second base and a third solvent to obtain a compound of Formula 10; e. reacting the compound of Formula 5A with an amine to obtain a compound of Formula 11; f. treating the compound of Formula 10 with an acid, wherein R is unsubstituted or substituted C1-6 alkyl to obtain a compound of Formula 12; and g. reacting the compound of Formula 11 with the compound of Formula 12 to obtain the compound of Formula I.

[0060] In an embodiment of the present disclosure, there is provided a process for preparing a compound of Formula I as disclosed herein, the process comprising treating 3-amino-1,2-propanediol with di-t-butyl dicarbonate (Boc anhydride) followed by treating with potassium t-butoxide to obtain a compound of Formula 2.

[0061] In an embodiment of the present disclosure, there is provided a process for preparing a compound of Formula I, the process comprising: a. treating 3-amino-1,2-propanediol with triphosgene to obtain a compound of Formula 2; b. obtaining a compound of Formula 21 by reacting the compound of Formula 2 with phthalimide; c. reacting the compound of Formula 21 with a compound of Formula 1 in presence of a second reagent, a first base and a second solvent to a compound of Formula 5A; d. reacting a compound of Formula 9 with a boric acid ester in presence of a first catalyst, a second base and a third solvent to obtain a compound of Formula 10; e. reacting the compound of Formula 5A with an amine to obtain a compound of Formula 11; f. treating a compound of Formula 10 with an acid, wherein R is unsubstituted or substituted C1-6alkyl to obtain a compound of Formula 12; g. reacting the compound of Formula 11 with the compound of Formula 12 to obtain the compound of Formula I; and h. subjecting the compound of Formula I to a purification process to obtain a high pure compound of Formula I.

[0062] In an embodiment of the present disclosure, there is provided a process of obtaining a high pure compound of Formula I, the process comprising: (i) charging the compound of Formula I with a polar protic solvent and formic acid to obtain a first mixture; (ii) adding a seed of compound of Formula I and the polar protic solvent to the first mixture under stirring at a temperature in a range of 5 to 20℃, followed by filtering to obtain a solid product; and (iii) drying the solid product under reduced pressure at a temperature in a range of 50 to 70℃, to obtain the high pure compound of Formula I.

[0063] In an embodiment of the present disclosure, there is provided a process of obtaining a high pure compound of Formula I as disclosed herein,wherein the polar protic solvent is selected from methanol, ethanol, propanol, butanol, pentanol or combinations thereof. In another embodiment of the present disclosure, the polar protic solvent is methanol.

[0064] In an embodiment of the present disclosure, there is provided a process of obtaining a high pure compound of Formula I as disclosed herein, wherein the compound of Formula I and the polar protic solvent are in a weight ratio range of 1:5 to 1:15. In another embodiment of the present disclosure, wherein the compound of Formula I and the polar protic solvent are in a weight ratio range of 1:7 to 1:11. In one another embodiment of the present disclosure, wherein the compound of Formula I and the polar protic solvent are in a weight ratio of 1:10.

[0065] In an embodiment of the present disclosure, there is provided a process of obtaining a high pure compound of Formula I as disclosed herein, wherein the compound of Formula I and formic acid are in a weight ratio range of 1:1 to 1:7. In another embodiment of the present disclosure, wherein the compound of Formula I and formic acid are in a weight ratio range of 1:2 to 1:5. In one another embodiment of the present disclosure, wherein the compound of Formula I and formic acid are in a weight ratio of 1:3.

[0066] In an embodiment of the present disclosure, there is provided a process of obtaining a high pure compound of Formula I as disclosed herein, wherein the high pure compound of Formula I has yield of at least 70 %; and purity of at least 95%. In another embodiment of the present disclosure, wherein the high pure compound of Formula I has yield in a range of 70 to 95%; and purity in a range of 95 to 100%.

[0067] In an embodiment of the present disclosure, there is provided a compound of Formula 5, its stereoisomers, racemates, hydrates, solvates, intermediates, or pharmaceutically acceptable salts thereof.Formula 5

[0068] In an embodiment of the present disclosure, there is provided a compound of Formula 5A its hydrates, solvates, intermediates, or pharmaceutically acceptable salts thereof.Formula 5A

[0069] In an embodiment of the present disclosure, there is provided a compound of Formula 5B its hydrates, solvates, intermediates, or pharmaceutically acceptable salts thereof.Formula 5B

[0070] In an embodiment of the present disclosure, there is provided a compound of Formula 10, its hydrates, solvates, intermediates, or pharmaceutically acceptable salts thereof, wherein R is unsubstituted or substituted C1-6alkyl.Formula 10

[0071] In an embodiment of the present disclosure, there is provided a compound of Formula 10 as disclosed herein, wherein the compound is Formula 10A having C2 alkyl as R.Formula 10A

[0072] In an embodiment of the present disclosure, there is provided a process for preparing a compound of Formula 5A, the process comprising 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.

[0073] In an embodiment of the present disclosure, there is provided a process for preparing a 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 combinations thereof; the second solvent is selected from toluene, dimethyl formamide, 1,4-dioxane, dimethyl acetamide, N- methyl pyrrolidine, n-butanol, or combinations thereof; and the first base is selected from potassium carbonate, potassium phosphate, triethyl amine, sodium t-butoxide, potassium t-butoxide, 1,8-diazabicyclo(5.4.0) undec-7-ene (DBU), 1,4- diazabicyclo(2.2.2) octane (DABCO), or combinations thereof. In another embodiment of the present disclosure, the second reagent is a combination of tris(dibenzylideneacetone)dipalladium (0)-chloroform (Pd2(dba)3CHCl3), 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl(t-Bu XPhos), the second solvent is a combination of toluene, dimethyl formamide (DMF); and the first base is selected from potassium carbonate.

[0074] In an embodiment of the present disclosure, there is provided a process for preparing a compound of Formula 5A, the process comprising: reacting a compound of Formula 4 with phthalimide or its salt, in an organic solvent optionally in the presence of a basic agent. In another embodiment of the present disclosure, wherein the basic agent is selected from potassium carbonate, sodium carbonate, ammonium carbonate or combinations thereof; and the organic solvent is selected from dimethyl formamide, dimethyl sulfoxide, or combinations thereof. In one another embodiment of the present disclosure, the compound of Formula 5A is obtained by reacting the compound of Formula 4 with potassium phthalimide in the presence of the organic solvent.

[0075] In an embodiment of the present disclosure, there is provided a process for preparing a compound of Formula 10A, the process comprising reacting a compound of Formula 9 with a boric acid ester in the presence of a first catalyst, a second base and a third solvent.

[0076] In an embodiment of the present disclosure, there is provided a process 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 combinations thereof; the second base is potassium carbonate, sodium carbonate, sodium acetate, potassium acetate; and the third solvent is selected from dichloromethane, water, 2-methyl tetrahydrofuran, dimethoxy ethane or combinations 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.

[0077] Although the subject matter has been described in considerable detail with reference to certain examples and implementations thereof, other implementations are possible. EXAMPLES

[0078] The disclosure will now be illustrated with working examples, which is intended to illustrate the working of disclosure and not intended to take restrictively to imply any limitations on the scope of the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of the disclosed processes, compounds, and methods, the exemplary illustrations are described herein. It is to be understood that this disclosure is not limited to particular methods, and experimental conditions described, as such methods and conditions may apply.

[0079] As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientificliterature. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification: Abbreviations DCM Dichloromethane DEAD diethyl azodicarboxylate DIEA N,N-Diisopropylethylamine DMF dimethyl formamide DMSO Dimethyl Sulphoxide EtOH Ethanol GC Gas Chromatography H2SO4 Sulphuric acid HCl Hydrochloric acid KF Potassium fluoride LiCl Lithium chloride MeI Methyl iodide MeOH Methanol MTBE Methyl tert-butyl ether Na2CO3 Sodium carbonate n-BuOH n-butanol NMR Nuclear Magnetic Resonance spectroscopy NMT not more than PPh3 Triphenyl phosphine QNMR Quantitative Nuclear Magnetic resonance spectroscopy t-AmONa Sodium tert-pentoxide t-BuOK ter-potassium butoxide THF Tetrahydrofuran The following abbreviations are employed in the examples and elsewhere herein:

[0080] The following examples provide the details about the synthesis of the compound of Formula I and intermediates of the present disclosure. It should beunderstood the following is representative only, and that the invention is not limited by the details set forth in these examples.

[0081] If not commercially available, the necessary starting materials for the procedures such as those described herein may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the described procedure or the procedures described in the Examples.

[0082] It is noted that many of the starting materials for synthetic methods as described herein are commercially available and / or widely reported in the scientific literature, or could be made from commercially available compounds using adaptations of processes reported in the scientific literature. The reader is further referred to Advanced Organic Chemistry, 5th Edition, by Jerry March and Michael Smith, published by John Wiley & Sons 2001, for general guidance on reaction conditions and reagents.

[0083] It will also be appreciated that in some of the reactions mentioned herein, it may be necessary / desirable to protect any sensitive group in compounds. The instances where protection is necessary or desirable, and suitable methods for such protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Greene, Protective Groups in Organic Synthesis, published by John Wiley and Sons, 1991) and as described hereinabove. Experimental Procedure: Synthesis of 6-chloro-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one (Formula 1)Formula 1

[0084] A stirred solution of 3-bromo-6-chloropyrazin-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 warmed to 55oC, and ethyl 2- hydroxyacetate (CAS: 623-50-7, 5.3 kg, 50.96 mol) was added and stirred at 55–65oC for 3 h. After completion of the reaction, the reaction mixture was cooled to 5oC, neutralized to pH 5-7 with 1.5 N HCl solution, and was concentrated under reduced pressure to 5–6 volume (by removal of THF (solvent) from approximately 10 volume to 5–6 volume). The residue was diluted with water (17.5 L), concentrated under reduced pressure to 8–9 volume, filtered, and dried in vacuum to obtain the compound Formula 1 as a yellow solid (2.8 kg, 90%).1H NMR (300 MHz, DMSO-d6): 11.85 (s, 1H), 7.85 (s, 1H), 4.90 (s, 2H). Synthesis of (S)-2-((2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrazino[2,3- b][1,4]oxazin-6-yl)oxazolidin-5-yl)methyl)isoindoline-1,3-dione (Formula 5A)Step-1: (R)-5-(hydroxymethyl) oxazolidin-2-one (Formula 2)

[0085] 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 stirred at 35oC–40oC for 21 h. After completion of the reaction, the reaction mixture was cooled to 5oC, stirred for 1.5 h, filtered, and rinsed with cold water (8 L). Filtrate was concentrated under reduced pressure to 2-3 volume, added with EtOH (40 L), and concentrated to 3–4 volume under reduced pressure. The residue was diluted with EtOH (40 L) and sampled for KF. The above process was repeated until KF NMT 3.0% was charged with EtOH (40 L) on the residue. Then it was warmed to 35℃, stirred for 1 hour, and filtered. The obtained filtrate i.e., the cake was washed with EtOH (8 L). Filtrate wasconcentrated to 2-3 volume under reduced pressure and diluted with n-BuOH (20 L). The mixture was concentrated to 2–3 volume and the filtrate was sampled for GC: area% of EtOH NMT 1.0%. The residue was then cooled to 20–30℃ and was stirred for 1 h. The obtained slurry was then filtered and washed with n-BuOH (4 L). The filtered cake was dried under vacuum at 50℃ to obtain a white solid of Formula 2 (3.6 kg, 70.1%).1H 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). Step-2: (R)-2-((2-oxooxazolidin-5-yl) methyl) isoindoline-1,3-dione (Formula 21)

[0086] To a stirred solution of PPh3 (triphenyl phosphine, 6.7 kg, 25.54 mol) in DCM (52 L), cooled to 0oC, phthalimide (3.3 kg, 22.43 mol) was added and stirred for 0.5 h. To the resulting solution, compound Formula 2 (2.6 kg, 22.20 mol) was added and stirred at 0oC for 0.5 h. Then DEAD (diethyl azodicarboxylate, 4.5 kg, 25.54 mol) was added dropwise and stirred for 16 h. After completion of the reaction, the reaction mixture was quenched with water (26 L), warmed to 20oC, stirred for 0.5 h, and the organic phase was collected. Then the organic phase was concentrated to 7 volume under reduced pressure. To the residue, MeOH (13 L) was added and concentrated to 7 volume. The operation was repeated twice. Then the filtrate was sampled for GC: DCM NMT 1%. Then the residue was cooled to 20oC, stirred for 1 h, the slurry mass filtered, and rinsed with MeOH (5.2 L). The obtained filter cake was refluxed in MeOH (13L) for 1 h. Then the slurry was cooled to 20oC and stirred for 1 hour. The slurry mass was then filtered and the cake was rinsed with MeOH (5.2 L). The obtained solid was dried under vacuum to afford a white solid of Formula 21 (3.05 kg, 55.2%).1H 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). Step-3:(S)-2-((2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrazino[2,3-b] [1,4] oxazin-6- yl) oxazolidine-5-yl) methyl) isoindoline-1,3-dione (Formula 5A)

[0087] The compounds of Formula 1 (2.26 kg, 12.18 mol), Formula 21 (3.00 kg, 12.18 mol), and K2CO3(first base, 3.37 kg, 24.36 mol) were added in toluene (33.9 L) as solvent (second solvent). The mixture was refluxed for 2 h using the Dean-Stark apparatus, then cooled to 25oC and degassed for 2 h with nitrogen gas. 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 stream of nitrogen gas for 1 h. Then the mixture was warmed to 100oC and stirred for 16 hours. After completion of the reaction, the reaction mixture was cooled to 20oC and stirred for 1 h. The solid was filtered and rinsed with toluene (4.5 L). The filter cake was slurred with 1.5 N HCl solution (33.9 L) at 30oC for 1 h, then the slurry mass was filtered, and the filtered cake was rinsed with water (4.5 L). The obtained 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%).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).

[0088] The process exhibited the best conversion and higher purity with 1,4-dioxane as solvent and K2CO3as base at 95-105℃, or with toluene / DMF as solvent and K2CO3 as at 95-105℃. Significance of first base:

[0089] The above reaction of obtaining the compound of Formula 5A from the compounds of Formula 1 and 21 was carried out by varying the base (first base) selected from potassium phosphate, triethyl amine, 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), which resulted in higher yield of Formula 5A. However, it was observed that the use of other bases such as Cs2CO3 did not result in the formation of compound of Formula 5A. Significance of temperature range:

[0090] In another example, the compound of Formula 5A was prepared by treating the compounds of Formula 1, Formula 21 and in 1,4-dioxane as solvent(second solvent). The mixture was refluxed for 2 h using the Dean-Stark apparatus, then cooled to 25oC and degassed for 2 h with nitrogen gas. To the resulting mixture, Pd2(dba)3CHCl3 (second reagent), t-BuXPhos (second reagent) and DMF (second solvent) were added. The resulting mixture was degassed with a stream of nitrogen gas for 1 h. Then the mixture was warmed to a temperature of 55-65oC and stirred for 16 hours. After completion of the reaction, the reaction mixture was cooled to 20oC and stirred for 1 h. The solid was filtered and rinsed with 1,4- dioxane. The filter cake was slurred with 1.5 N HCl solution at 30oC for 1 h, 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 a range of 50-55%. Also, the compound of Formula 5A was prepared by the process explained herein and by varying the temperature at which the mixture was warmed in a range of 75 to 85oC, and the yield of Formula 5A was found to be in a range of 50-55%.

[0091] Thus, the optimal temperature which provided higher yield of at least 70% of compound of Formula 5A was found to be in a range of 90 to 110℃, beyond which the yield was reduced and consumed longer duration for conversion to Formula 5A.

[0092] It is to be noted that the process of preparing the compound of Formula I via Formula 5A did not involve use of harsh chemicals whereas the existing process of preparing the compound of Formula I uses hazardous chemicals such as sodium azide and mesityl chloride. Alternate process for preparing the compound of Formula 5A

[0093] Alternatively, the compound of Formula 5A was prepared by reacting the compound of Formula 4 (WO2018225097) with potassium phthalimide, in dimethyl sulfoxide (DMSO) as solvent resulted in Formula 5A with 23% yield.Purification for Formula 5A

[0094] The crude Formula 5A (4.90 kg) was combined with the other four batch crude materials. The crude Formula 5A (23.3 kg, QNMR = 86.3%) was mixed with DMSO (627.7 kg). The mixture was warmed to 50–55oC and stirred for 2 hours. Then the slurry mass was cooled to 30–35oC, stirred for 1 h, and filtered with washed cake DMSO (13.1 kg).3-Mercaptopropyl ethyl sulfide silica (4.66 kg) was charged to the filtrate, and the mixture was stirred for 16 hours at 30-35oC. Then the mixture was filtered and washed the cake with DMSO (13.5 kg). To the remaining filtrate, 0.1 N HCl (300.1 kg) was charged, stirred for 1 h at 25oC, and filtered. The filter cake was slurred with 0.1 N HCl (224 kg) for 1 h at 25oC. The slurry was filtered, and the cake was rinsed with water (47.2 kg). The filter 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). Synthesis of (E)-8-(2-ethoxyvinyl)-7-fluoro-1-methylquinolin-2(1H)-one (Formula 10A)Step-5: (E)-3-ethoxyacryloyl chloride (Formula 6)

[0095] 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 65oC over 6 h. The resulting mixture was warmed and stirred at 95oC for 9 hours. After completion of the reaction, the reaction mixture was concentrated to 2 volume under reduced pressure. The acid-chloride material (Formula 6) was taken for the next step without any purification. Step-6: (E)-N-(2-bromo-3-fluorophenyl)-3-ethoxyacrylamide (Formula 7)

[0096] To a stirred solution of 2-bromo-3-fluoroaniline (3.0 kg, 15.79 mol) in THF (24 L), compound Formula 6 (4.8 kg crude, QNMR=44.2%, 15.61 mol) was added at 5oC. Then pyridine (1.9 kg, 24.02 mol) in a THF (6.0 L) solution was added at 5oC. The resulting mixture was warmed and stirred at 20oC for 16 hours. After completion of the reaction, water (30 L) and ethyl acetate (18 L) were added to the reaction mixture. The organic phase was further washed sequentially with 2 N HCl solution (30 L), saturated NaHCO3 solution (30 L), and brine (9 L). The organic phases were concentrated under reduced pressure of approx. 2 volume. Then the residue was warmed to 50oC, and n-heptane (12 L) was charged at 50oC. The obtained thick slurry was cooled to 5oC and stirred for 1 h. The resulting slurry mass was filtered, rinsed with n-Heptane (6 L), and dried in vacuum to obtain a white solid of Formula 7 (3.35 kg, 73.6%).1H 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). Step-7: (E)-N-(2-bromo-3-fluorophenyl)-3-ethoxy-N-methylacrylamide (Formula 8)

[0097] To a stirred solution of compound 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 -5oC and stirred for 1 h. Then MeI (methyl iodide, 3.2 kg, 22.55 mol) was added and stirred at -5oC for 30 min. After completion of the reaction, the reaction mixture was quenched with water (43 L) and extracted material thrice with MTBE (methyl tert-butyl ether, 21.5 L, 12.9 L, and 12.9 L). The combined organic phases werewashed twice with a 10% LiCl solution (21.5 L). The organic phase was then concentrated under reduced pressure to 5 volume and was cooled to 20oC. To the residue, n-heptane (21 L) was added, then concentrated to 5 volume. The resulting slurry mass was cooled to 0–5oC over 1 h, and the obtained solid was filtered, rinsed with n-heptane (4.3 L), and dried in vacuum to obtain a white solid of Formula 8 (3.75 kg, 83.1%). 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). Step-8: 8-bromo-7-fluoro-1-methylquinolin-2(1H)-one (Formula 9)

[0098] The solution of compound Formula 8 (7.6 kg, 25.16 mol) in conc. H2SO4 (38 L) was stirred at 25oC for 20 h. After completion of the reaction, the reaction mixture was added to water (152 L) at 5oC, stirred for 1 h, and the resulting slurry mass was filtered. The resulting cake was slurred with H2O (38 L), obtained solid filtered, rinsed with water (15.2 L), and dried in vacuum to obtain a yellow solid of Formula 9 (5.9 kg, 91.6%).1H 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). Step-9: (E)-8-(2-ethoxyvinyl)-7-fluoro-1-methylquinolin-2(1H)-one (Formula 10A)

[0099] To a degassed solvent mixture of DCM (third solvent, 22 L) and water (third solvent, 8.8 L), compound 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 stream of nitrogen gas for 30 min and added (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (boric acid ester, 2.04 kg, 10.30 mol). Then the mixture was degassed with a stream of nitrogen gas for 30 minutes and stirred at 35–40oC for 24 hours. After completion of the reaction, the organic phase was separated, washed with water (11.0 L), and concentrated under reduced pressure to 2.0–2.5 volume. To the residue, toluene (11.0 L) was added. The resulting mass was concentrated to 2.0–2.5 volume and was then charged with toluene (33 L). To this mixture, NAC (N-acetyl cysteine, 0.44 kg, 2.70 mol) and DIEA (0.33 kg, 2.55 mol) were added,warmed to 63–67oC, and stirred for 16 h. Following that, the mass was cooled to 25oC and added water (11 L). The organic phase was separated and washed with 2% NaCl solution in water (11 L). The organic phase was charged with silica gel (0.46 kg, 0.2 w / w), warmed to 63–67oC, and stirred for 16 h. The resulting mass was cooled to 25oC, filtered, and rinsed with toluene (4.6 L). To the filtrate, charcoal (0.46 kg, 0.2 w / w) was added, warmed to 63–67℃, and stirred for 16 h. Then the mixture was cooled to 25oC, filtered, and rinsed with toluene (4.6 L). The filtrate was concentrated to 2 volume. To the residue, n-heptane (11.5 L) was added at 25℃, stirred for 2 h, filtered the slurry mass, 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). [000100] The above reaction exhibited lesser formation of dibrominated compound of Formula 9 with the use of DCM and water as solvent. Further the amount of Pd present in the product formed was found to be less than 30 ppm. Synthesis of (S)-6-(5-(aminomethyl)-2-oxo oxazolidin-3-yl)-2H-pyrazino[2,3- b][1,4]oxazin-3(4H)-one (Formula 11)Formula 5A Formula 11 Step-10: (S)-6-(5-(aminomethyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3- b][1,4]oxazin-3(4H)-one (Formula 11)[000101] To a solution of compound Formula 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 stirred at 25oC for 16 h. To the stirred solution mass, Formula 5A (9.22 kg, 23.32 mol) and DCM (24.45 kg) were added and stirred for 16 h. After completion of the reaction, 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 in the filtrate was collected. The filter cake comprised a slurry of formic acid (4.10 kg), and water (53.90 kg) with the solvent (DCM). Then the reaction mass was stirred for 1 h, filtered, and rinsed with water (36.50 kg). The combined filtrate was diluted with DCM (85.65 kg), stirred for 5 min, and separated into layers. To the collected aqueous phase, 3- mercaptopropyl ethyl sulphide silica (3.70 kg, 0.20 w / w) was added, stirred for 16 h, and filtered and rinsed cake with water (35.70 kg). The filtrate was cooled to 10oC, basified with 20% NaOH solution to pH 9.0, stirred for 16 h, and the resultant slurry mass was filtered, rinsed with water (36.10 kg), and dried in vacuum to obtain a light-yellow solid of crude Formula 11 (9.7 kg, 36.58 mol). [000102] To the mixture of water (97.8 kg) and formic acid (3.5 kg, 76.09 mol), crude Formula 11 (9.7 kg, 36.58 mol) was added at 20℃ and stirred to get a clear solution. The solution was filtered through the charcoal cartridge twice. To the filtrate, Formula 11 seed was added at 10℃, stirred for 30 min, and basified with a 20% NaOH solution to pH 9.0. The resultant slurry mass was stirred for 16 hours, filtered, and rinsed with water (19.95 kg). The obtained wet material was dried in vacuum to obtain a light-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). [000103] For effective conversion of the compound of Formula 5A to the compound of Formula 11, the charging and stirring time after addition of hydrazine hydrate in the reaction mixture was essential. It was observed that, when the above reaction was carried out with lesser charging and stirring time (less than 6 hours) of hydrazine hydrate, then wall caking was observed. Thus the prolonged chargingtime (of at least 16 hours) eliminated wall caking and provided improved yield of Formula 11. Synthesis of 2-(7-fluoro-1-methyl-2-oxo-1,2-dihydroquinolin-8-yl) acetaldehyde (Formula 12)Step-11: 2-(7-fluoro-1-methyl-2-oxo-1,2-dihydroquinolin-8-yl) acetaldehyde (Formula 12) [000104] To a stirred mixture of HCl (inorganic acid, 5.74 kg), water (14.54 kg), and acetone (15.25 kg), Formula 10 (3.87 kg, 15.65 mol) was added, warmed to 40℃, and stirred for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to 4.5–5.5 volume, extracted with DCM (30.84 kg) twice, and washed with 10% Na2CO3 solution (25.57 kg) and water (23.18 kg). The organic phase concentrated to 2–3 volume under atmospheric pressure. To the residue, DCM (7.86 kg) was added at 20oC, concentrated to 2-3 volume under atmospheric pressure, and was cooled to 10oC. Then the residue was charged with n-heptane (21.4 kg) at 10oC. The slurry was stirred for 16 h, obtained solid was filtered, rinsed with n-heptane (10.68 kg), and dried in vacuum to obtain white solid of Formula 12 (3.23 kg, 93.1%).1H 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). [000105] The earlier described process of obtaining the compound of Formula 12 reported in WO2018225097 involved use of hazardous reagents such as allyl tributyltin, K2OsO4which were eliminated in the process of present disclosure. Further the yield of compound of Formula 12 obtained by the process of presentdisclosure was much higher compared to earlier reported procedure (WO2018225097). Synthesis of (S)-6-(5-(((2-(7-fluoro-1-methyl-2-oxo-1,2-dihydroquinolin-8-yl) ethyl) amino) methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b]3(4H)-one formate (Formula I)Step-12: (S)-6-(5-(((2-(7-fluoro-1-methyl-2-oxo-1,2-dihydroquinolin-8-yl) ethyl) amino) methyl)-2-oxooxazolidin-3-yl)-2H-pyrazino[2,3-b] [1,4]oxazin- 3(4H)-one formate (Formula I) [000106] To a solvent mixture of DCM (first solvent, 148.60 kg) and MeOH (first solvent, 88.25 kg), compound Formula 11 (7.57 kg, 28.54 mol) and compound Formula 12 (6.20 kg, 28.54 mol) were added and stirred at 25oC for 2 h. To the resulting mixture, 2-picoline borane complex (first reagent, 2.96 kg, 27.69 mol) was added and stirred at 25oC for 2 h. Then formic acid (first reagent, 6.45 kg, 140.22 mol) was added and stirred at 25oC for 16 h. After completion of the reaction, the slurry mass was filtered, rinsed with DCM (first solvent, 40.40 kg), and dried in vacuum to obtain crude material (12.91 kg) of Formula I with 95% purity. [000107] The compound of Formula I obtained by the process of present disclosure was devoid of any dimer impurity whereas the existing process of obtaining Formula I, had dimer impurity as depicted below, in about more than 10% by weight of final product obtained.[000108] The existing processes provided a yield of compound of Formula I in a range of 30 to 60%, whereas the process of the present disclosure resulted in a yield of at least 70%, upto 90%. Hence it is clearly evident that the process of the present disclosure involving the compounds of Formula 5A, and Formula 10A, thereby forming the compounds of Formulae 11 and 12 respectively, resulted in high pure compound of Formula I with improved yield. Thus, the process of present disclosure was found to be an efficient preparation method. Synthesis of high pure compound of Formula I [000109] To a stirred solution of formic acid (39.40 kg) and MeOH (10.25 kg), crude material of Formula I (12.85 kg, 24.98 mol) as obtained above, was added at 10oC, stirred to get a clear solution, filtered, and rinsed with MeOH (20.15 kg). To the filtrate, MeOH (20.40 kg) and Formula I seed (0.0643 kg, 0.12 mol) were added and stirred at 10oC for 30 min. MeOH (81.35 kg) was added to the slurry mass and stirred for 2 hours. The obtained solid was filtered, rinsed with MeOH (21 kg), and dried in vacuum to obtain an off-white solid of Formula I (11.66 kg, yield: 79.7%) with purity >99%. Methanol and Formula I were taken in a weight ratio range of 9: 1 to 10:1, particularly 9.5:1; and formic acid and Formula I were taken in a weight ratio range of 2.5:1 to 3.5:1, particularly 3:1 to obtain the high pure compound of Formula I.1H 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).[000110] The above purification process was carried out using acetonitrile as solvent, and it was observed that the obtained compound of Formula I was found to be unstable and acylation impurities were additionally formed. Thus, the polar protic solvent was found to be favorable in obtaining the high pure compound of Formula I of purity of at least 90%. ADVANTAGES OF PRESENT DISCLOSURE [000111] The present disclosure provides a facile process for preparing a clinical development drug candidate of Formula I. The compound of Formula I exhibits potent antibacterial activity against a variety of Gram-negative and Gram- positive bacteria, including multidrug resistance bacterial pathogens, and the process of the present disclosure provides novel processes for making the compound of Formula I with improved yield and higher purity. The process of the present disclosure is carried out in fewer number of steps and avoids use of hazardous reagents compared to the existing processes. The process of the present disclosure offers a more sustainable and cost-effective route to producing compound Formula I with high purity and yield. The process of the present disclosure provides an efficient synthetic method for large scale industrial production of the compound of Formula I.

Claims

I / We Claim:

1. A process for preparing a compound of Formula I, the process comprising: a) reacting a compound of Formula 5A with an amine to obtain a compound of Formula 11; andb) reacting the compound of Formula 11 with a compound of Formula 12 to obtain the compound of Formula I.

2. The process as claimed in claim 1, wherein the compound of Formula 12 is obtained by treating a compound of Formula 10 with an acid, wherein R is unsubstituted or substituted C1-6 alkyl.

3. The process as claimed in claim 1, wherein the amine is selected from hydrazine, C1-6 alkyl hydrazine, C1-6 alkyl amine, or combinations thereof.

4. The process as claimed in claim 1, wherein reacting the compound of Formula 11 with the compound of Formula 12 is carried out in presence of a first reagent and a first solvent at a temperature in a range of 5 to 50℃.

5. The process as claimed in claim 4, wherein the first reagent is selected from picoline borane complex, formic acid, or combinations thereof; and the first solvent is selected from dichloromethane, methanol, or combinations thereof.

6. The process as claimed in claim 1, wherein reacting the compound of Formula 5A with an amine is carried out at a temperature in a range of 5 to 50℃.

7. The process as claimed in claim 2, wherein treating a compound of Formula 10 is carried out at a temperature in a range of 20 to 60℃; and the acid is an inorganic acid, preferably hydrochloric acid.

8. The process as claimed in claim 1, wherein the compound of Formula I has a yield of at least 70%; and a purity of at least 90%.

9. The process as claimed in claim 1, wherein the compound of Formula 5A is obtained by reacting a compound of Formula 21 with a compound of Formula 1 in presence of a second reagent, a first base and a second solvent.

10. The process as claimed in claim 9, 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 combinations thereof; the second solvent is selected from toluene, dimethyl formamide, 1,4-dioxane, dimethyl acetamide, N-methyl pyrrolidine, n-butanol, or combinations thereof; and the first base is selected from potassium carbonate, potassium phosphate, triethyl amine, sodium t- butoxide, potassium t-butoxide, 1,8-diazabicyclo(5.4.0) undec-7-ene (DBU), 1,4-diazabicyclo(2.2.2) octane (DABCO), or combinations thereof.

11. The process as claimed in claim 9, wherein the process is carried out at a temperature in a range of 90 to 110℃.

12. The process as claimed in claim 9, wherein the compound of Formula 5A has yield of at least 70%; and purity of at least 90 %.

13. The process as claimed in claim 9, wherein the compound of Formula 21 is obtained by reacting a compound of Formula 2 with phthalimide.

14. The process as claimed in claim 13, wherein the compound of Formula 2 is obtained by treating 3-amino-1,2-propanediol with triphosgene, or treating 3-amino-1,2-propanediol with di-t-butyl dicarbonate (Boc anhydride) followed by treating with potassium t- butoxide.

15. The process as claimed in claim 2, wherein the compound of Formula 10 is obtained by reacting a compound of Formula 9 with a boric acid ester in presence of a first catalyst, a second base and a third solvent,wherein R is unsubstituted or substituted C1-6 alkyl.

16. The process as claimed in claim 15, 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 combinations thereof; the second base is selected from potassium carbonate, sodium carbonate, sodium acetate, potassium acetate or combinations thereof; and the third solvent is selected from dichloromethane, water, 2-methyl tetrahydrofuran, dimethoxy ethane or combinations thereof.

17. The process as claimed in claim 15, wherein the process is carried out at a temperature in a range of 20 to 80℃.

18. The process as claimed in claim 15, wherein the compound of Formula 10 has a yield of at least 70%; and a purity of at least 90%.

19. The process as claimed in claim 1, wherein the compound of Formula I is further subjected to a purification process to obtain a high pure compound of Formula I.

20. A process of obtaining the high pure compound of Formula I as claimed in claim 19, the process comprising: i. charging the compound of Formula I with a polar protic solvent and formic acid to obtain a first mixture; ii. adding a seed of compound of Formula I and the polar protic solvent to the first mixture under stirring at a temperature in a range of 5 to 20℃, followed by filtering to obtain a solid product; and iii. drying the solid product under reduced pressure at a temperature in a range of 50 to 70℃, to obtain the high pure compound of Formula I.

21. The process as claimed in claim 20, wherein the polar protic solvent is selected from methanol, ethanol, propanol, butanol, pentanol or combinations thereof.

22. The process as claimed in claim 20, wherein the high pure compound of Formula I has a yield of at least 70 %; and a purity of at least 95%.

23. The process as claimed in claim 20, wherein the compound of Formula I and the polar protic solvent are in a weight ratio range of 1:5 to 1:

15.

24. The process as claimed in claim 20, wherein the compound of Formula I and formic acid are in a weight ratio range of 1:1 to 1:

7.

25. A compound of Formula 5, its stereoisomers, racemates, hydrates, solvates, intermediates, or pharmaceutically acceptable salts thereof.Formula 5 26. A compound of Formula 5A, its hydrates, solvates, intermediates, or pharmaceutically acceptable salts thereof.Formula 5A27. A compound of Formula 10, its stereoisomers, hydrates, solvates, intermediates, or pharmaceutically acceptable salts thereof, wherein R is unsubstituted or substituted C1-6 alkyl.Formula 10 28. The compound of Formula 10 as claimed in claim 27, wherein the compound is Formula 10A having C2 alkyl as R.Formula 10A 29. A process for preparing a compound of Formula 5A, the process comprising reacting a compound of Formula 4 with phthalimide or its salt, in an organic solvent optionally in the presence of a basic agent.

30. The process for preparing a compound of Formula 5A as claimed in claim 29, wherein the basic agent is selected from potassium carbonate, sodium carbonate, ammonium carbonate or combinations thereof; and the organic solvent is selected from dimethyl formamide, dimethyl sulfoxide, or combinations thereof.

31. A process for preparing a compound of Formula 10A, the process comprising: reacting a compound of Formula 9 with a boric acid ester in presence of a first catalyst, a second base and a third solvent.

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