DESC:FIELD OF INVENTION
[001] The present disclosure relates to a field of Pharmaceuticals. More particularly, the present disclosure provides a novel process for the preparation of Bexagliflozin, (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol a SGLT2 inhibitor and its salts, hydrates, solvates and intermediates thereof, in high yields and purity and suitable for manufacturing in commercial scale.

Formula I

BACKGROUND OF THE INVENTION
[002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[003] Diabetes Mellitus continues to be a major non-communicable disease with global burden of 370 million at present and projected to increase to 480 to 590 million by 2030. Treatment of type 2 diabetes (T2DM) continues to present challenges, with significant proportion of patients failing to achieve and maintain glycemic targets.
[004] Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are a class of anti-hyperglycemic agents acting on the SGLT-2 proteins expressed in the renal proximal convoluted tubules. SGLT2 inhibitors prevent the kidneys from re-absorbing glucose back into the blood by passing into the bladder. Glucose is re-absorbed back into the blood via the renal proximal tubules. SGLT2 is a protein predominantly expressed in the renal proximal tubules and is likely to be major transporter responsible for this uptake. Glucose-lowering effect of SGLT-2 inhibitors occurs via an insulin-independent mechanism mostly through glucosuria by increasing the urinary excretion of glucose. SGLT2 inhibitor indicated for the treatment of type 2 diabetes mellitus, heart failure, and chronic kidney disease. Bexagliflozin is an inhibitor of sodium-glucose co-transporter 2 (SGLT2), the compound is investigated in lowering hemoglobin Ale (HbAlc) levels in patients with type 2 diabetes mellitus (T2DM) and moderate renal impairment. The compound is for therapeutic intervention in diabetes and related disorders, SGLT2 is localized in the renal proximal tubule and is reportedly responsible for the majority of glucose reuptake by the kidneys and is marketed under the proprietary name Brenzavvy, Bexacat by THERAXOSBIO LLC is chemically named as (2S,3R,4R,5S,6R)-2-(4-Chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol and has the following chemical structure

Formula I
[005] Bexagliflozin shows pharmaceutical activity by functioning as a Sodium-glucose co-transporter-2 (SGLT-2) inhibitor and thus is indicated for the treatment of type 2 diabetes mellitus.
[006] Several synthetic methods have been reported in the literature to prepare Bexagliflozin, (2S,3R,4R,5S,6R)-2-(4-Chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol and its intermediates.
[007] U.S. Patent No.7838499 discloses the below process to prepare compound of formula (I) as per the following synthetic scheme

[008] WO2013152654 discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

[009] US9062087B2 discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

[0010] All the above prior art methods for the preparation of compound of formula (I) have inherent disadvantages such as the usage of unsafe reagents, high boiling solvents, extreme reaction conditions invariably resulting in the formation of low pure intermediates. Accordingly, there remains a need for the industrial preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triolwith high yield. Therefore, still there is need for the development of commercially viable, cost-effective process for the preparation of Bexagliflozin compound of formula (I).

OBJECTS OF THE INVENTION
[0011] The main objective of the present disclosure is to provide a simple, effective, and industrially feasible novel process for the preparation of Bexagliflozin, (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol and its salts, hydrates, solvates and intermediates thereof which is cost effective, environment friendly and commercially viable by avoiding repeated cumbersome and lengthy process and purification steps.
[0012] Another object of the present disclosure is to provide a method for preparation of compound of Formula VI.
[0013] Another objective of the present disclosure is to provide an one-pot process for the synthesis of a compound of the Formula VI starting from (5-halo-2-chlorophenyl)(4-fluorophenyl)methanone without isolation and purification of the intermediate compound of formula V.
[0014] Still another objective of the present disclosure is to provide a method of synthesis of a compound of Formula VI.
[0015] Another object of the present disclosure is to provide a compound of Formula V.
[0016] Yet another object of the present disclosure is to provide a method of preparation of compound of Formula V.

SUMMARY
[0017] This summary is provided to introduce a selection of concepts in a simplified form that are further described below in Detailed Description section. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.
[0018] Accordingly, in one aspect, the present disclosure relates to a method for preparation of benxagliflozin compound of Formula I comprising:
a) contacting 5-halo-2-chlorobenzoic acid of Formula II with a chlorinating agent in presence of a solvent to obtain 5-halo-2-chlorobezoyl chloride followed by adding fluorobenzene of Formula III in presence of a Lewis acid to obtain a compound of Formula IV;

Formula II Formula III Formula IV
b) contacting the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B in presence of a base and a solvent with or without a phase transfer catalyst to obtain a compound of Formula V;

Formula B Formula V
c) contacting the compound of Formula V with a reducing agent, a Lewis acid and a solvent to obtain a compound of Formula VI;

Formula VI
d) contacting the compound of Formula VI with glucolactone compound of formula D in presence of an organo-lithium compound and a solvent to obtain a compound of Formula VII;

Formula D Formula VII
e) contacting the compound of Formula VII with an alcohol or water in presence of an acid to form a compound of Formula VIII;

Formula VIII
f) reducing the compound of Formula VIII by a reducing agent with or without presence of a Lewis acid and a solvent to obtain a crude Bexagliflozin compound of Formula I; and

Formula I
g) optionally purifying the compound of formula (I) in a suitable solvent or mixture of solvents thereof.
[0019] Another aspect of the present disclosure provides a method for preparation of compound of Formula VI comprising the steps of:
(a1) coupling of 5-halo-2-chlorobenzoyl chloride as obtained from 5-halo-2- chlorobenzoic acid of Formula II, with fluorobenzene of Formula III in presence of a Lewis acid;

Formula II Formula III
with or without isolation of compound of Formula IV;

Formula IV
(b1) coupling of the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B in presence of a base, a Lewis acid and a solvent to obtain a compound of Formula V; and

Formula B Formula V
(c1) reducing the compound of Formula V in presence of a reducing agent and a solvent to obtain compound of the Formula VI;

Formula VI.
[0020] Another aspect of the present disclosure provides an one-pot process for the synthesis of a compound of the Formula VI starting from (5-halo-2-chlorophenyl)(4-fluorophenyl)methanone without isolation and purification of the intermediate compound of formula V;

Formula (VI)
stages, which comprises:
a2) compound of formula (IV) undergoes coupling reaction with 2-cyclopropoxyethan-1-ol of Formula B in presence of an alkali hydroxide or alkaline metal alkoxy base and a dipolar aprotic solvents to give compound of formula (V);

Formula (IV) Formula (V)
b2) compound of formula (V) undergoes ketoreduction with an organosilane and metal hydride reducing agents in presence of a Lewis acid and a solvent gives compound of formula (VI); and

Formula (VI)
c2) optionally purifying the compound of formula (VI) in a suitable solvent or mixture of solvents thereof.
[0021] Still another aspect of the present disclosure provides a method of synthesis of a compound of Formula VI comprising the steps of:

Formula (VI)
a3) compound of formula (IV) undergoes coupling reaction with 2-cyclopropoxyethan-1-ol of Formula B in presence of a phase transfer catalyst, a base, and a solvents to give compound of formula (V);

Formula (IV) Formula (V)
b3) compound of formula (V) undergoes ketoreduction with appropriate organosilane and metal hydride reducing agents in presence of Lewis acid and a solvent gives compound of formula (VI); and

Formula (VI)
c3) optionally purifying the compound of formula (VI) in a suitable solvent or mixture of solvents thereof.
[0022] Another aspect of the present disclosure is to provide a compound of Formula V comprising:

Formula V
wherein X is Br or I.
[0023] Yet another aspect of the present disclosure is to provide a method for preparation of compound of Formula V comprising the steps of:
(a4) coupling of 5-halo-2-chlorobenzoyl chloride as obtained from 5-halo-2- chlorobenzoic acid of Formula II, with fluorobenzene of Formula III in presence of a Lewis acid;

Formula II Formula III
with or without isolation of compound of Formula IV; and

Formula IV
(b4) coupling of the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B in presence of a base, a Lewis acid and a solvent to obtain a compound of Formula V

Formula B Formula V.
[0024] Various objects, features, aspects and advantages of the present disclosure will become more apparent from the following detailed description of preferred embodiments, along with the accompanying drawing figures in which like numerals represent like features.

DETAILED DESCRIPTION OF THE INVENTION
[0024] The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[0025] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
[0026] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[0027] In some embodiments, numbers have been used for quantifying weights, percentages, ratios, and so forth, to describe and claim certain embodiments of the invention and are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
[0028] The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
[0029] Unless the context requires otherwise, throughout the specification which follows, the word “comprise” and variations thereof, such as “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[0030] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.
[0031] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. Furthermore, the ranges defined throughout the specification include the end values as well, i.e., a range of 1 to 10 implies that both 1 and 10 are included in the range. For the avoidance of doubt, the applicant shall be entitled to any equivalents according to applicable law.
[0032] All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g., “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0033] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified.
[0034] The description that follows, and the embodiments described therein, is provided by way of illustration of an example, or examples, of particular embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.
[0035] It should also be appreciated that the present disclosure can be implemented in numerous ways, including as a system, a method or a device. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention.
[0036] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0037] The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus, if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
[0038] The term “or”, as used herein, is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
[0039] The term, “halogen” as used herein refers to chlorine, fluorine, bromine or iodine.
[0040] The term “one-pot” or "in-situ" typically means "in the reaction mixture" or "not in isolated form" or "existing as residue".
[0041] Various terms are used herein to the extent a term used is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[0042] In one embodiment the following Scheme-1 describes the process for the preparation of (3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol compound of formula (I)

Scheme 1
[0043] An embodiment of the present disclosure is to provide a method for preparation of benxagliflozin compound of Formula I comprising:
a) contacting 5-halo-2-chlorobenzoic acid of Formula II with a chlorinating agent in presence of a solvent to obtain 5-halo-2-chlorobezoyl chloride followed by adding fluorobenzene of Formula III in presence of a Lewis acid to obtain a compound of Formula IV;

Formula II Formula III Formula IV
b) contacting the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B in presence of a base and a solvent with or without a phase transfer catalyst to obtain a compound of Formula V;

Formula B Formula V
c) contacting the compound of Formula V with a reducing agent, a Lewis acid and a solvent to obtain a compound of Formula VI;

Formula VI
d) contacting the compound of Formula VI with glucolactone compound of formula D in presence of an organo-lithium compound and a solvent to obtain a compound of Formula VII;

Formula D Formula VII
e) contacting the compound of Formula VII with an alcohol or water in presence of an acid to form a compound of Formula VIII;

Formula VIII
f) reducing the compound of Formula VIII by a reducing agent with or without presence of a Lewis acid and a solvent to obtain a crude Bexagliflozin compound of Formula I; and

Formula I
g) optionally purifying the compound of formula (I) in a suitable solvent or mixture of solvents thereof.
[0044] In step a), 5-halo-2-chlorobenzoic acid of Formula II is converted into 5-halo-2-chlorobenzoyl chloride using chlorinating agent. In an embodiment, the chlorinating agent in step a) is selected from a group consisting of oxalyl chloride, thionyl chloride and combination thereof. In an embodiment, the solvent in step a) is selected from a group consisting of dichloromethane, chlorobenzene, nitromethane, toluene and dimethylformamide, dimethyl sulfoxide and combination thereof. The coupling of 5-halo-2-chlorobenzoyl chloride compound of Formula IV obtained from 5-halo-2-chlorobenzoic acid of Formula II, with fluorobenzene of Formula III is carried out in presence of Lewis acid. In an embodiment, the Lewis acid in step a) is selected from a group consisting of aluminum chloride, zinc chloride, ferric chloride, titanium chloride, zirconium chloride, boron trifluoride and combination thereof, preferably aluminum chloride.
[0045] In step b), coupling of the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B is carried out to obtain compound of Formula V. This coupling is carried out under basic conditions as nucleophilic substitution reaction. Suitable base for this coupling reaction is selected from the group comprising of alkali or alkaline earth metal salts, in particular carbonates, hydroxides, alkoholates and metal hydrides. In an embodiment, the base in step b) is selected from a group consisting of potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride and calcium hydride and combination thereof, preferably potassium carbonate, sodium hydroxide, sodium methoxide, potassium tert-butoxide and sodium hydride; and more preferably potassium hydoxide. Wherein the base characterized in that said base has a pKa value of from 10 to 25. The solvent is selected from the group comprising of polar and non-polar solvents. In an embodiment, the solvent in step b) is selected from a group consisting of acetonitrile, ethanol, isopropanol, butanol, acetone, toluene, water, dimethylformamide, dimethylacetamide, diglyme, monoglyme, N-methylpyrollidone, toluene, dimethylsulfoxide, tetrahydrofuran, 2-methylTHF, xylene, dioxane, dichloromethane and combination thereof, preferably, acetonitrile, ethanol, isopropanol, butanol, acetone, water, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, dichloromethane and combination thereof. In an embodiment, the catalyst in step b) is selected from a group consisting of a tetrabutylammoniumbromide (TBAB), tetrabutylammonium fluoride (TBAF), tetrabutylammonium hydroxide (TBAH), triethylbenzylammonium chloride (TEBA) and combination thereof.
[0046] In step c), the reduction of the compound of Formula V is carried out to obtain compound of the Formula VI. Suitable reducing agent is selected from the group comprising of silane and hydrides. In an embodiment, the reducing agent in step c) is selected from a group consisting of triethyl silane, tri isopropylsilane, tetramethyldisiloxane, tripropylsilane, diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, lithium aluminum hydride, diisobutylaluminum hydride borohydride and combination thereof, preferably tetramethyldisiloxane, triethyl silane, sodium borohydride. This reduction is preferably carried out in the presence of a Lewis acid. In an embodiment, the Lewis acid in step c) is selected from a group consisting of boron trifluoride etherate, tris(pentafluorophenyl) borane, trifluoroacetic acid, hydrochloric acid, aluminum chloride and combination thereof. The reactions are preferably carried out in solvents selected from the group comprising of halogenated hydrocarbons. In an embodiment, the solvent in step c) is selected from a group consisting of dichloromethane, 1,2-dichloroethane, acetone, toluene, dimethyl sulfoxide, dimethyl acetol, dimethylformamide, benzene, hexane, acetonitrile, ethanol, isopropanol, diglyme, monoglyme, N-methylpyrollidone, tetrahydrofuran, 2-methylTHF, xylene, dioxane and combination thereof.
[0047] In step d), firstly compound of Formula VI undergoes either halogen-metal exchange reaction or direct insertion of the metal into the carbon halogen bond and then finally get coupled with glucolactone compound of formula D to give compound of the Formula VII. The Grignard or Lithium derivative of compound of Formula VI are preferred. The halogen-metal exchange to synthesize the corresponding lithium derivative of compound VI may be carried out with an organo-lithium compound. In an embodiment, the organo-lithium compound in step d) is selected from a group consisting of n-butyllithium, sec-butyllithium or tert-butyllithium and hexamethylphosphoramide and combination thereof. The analogous magnesium compound may also be generated by a halogen-metal exchange with a suitable Grignard reagent such as C3-C4- alkylmagnesium chloride or bromide, for example isopropyl- or sec-butylmagnesium bromide or chloride or di-isopropyl- or di-sec-butylmagnesium without or in the presence of an additional salt such as e.g. lithium chloride. The organo-magnesium compound may also be generated in situ from suitable precursors. The halogen-metal exchange reaction is carried out in the solvent. In an embodiment, the solvent in step d) is selected from a group consisting of diethyl ether, dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, toluene, hexane, dimethyl sulfoxide, dichloromethane and combination thereof. and preferably tetrahydrofuran, diethylene glycol dimethyl ether, hexane and mixtures thereof. Alternatively, the metal derivative of compound VI is prepared by directly inserting a metal into the carbon-halogen bond of the compound of Formula VI. Lithium or magnesium are suitable elemental metals for this insertion. This insertion reaction is carried out in solvents selected from the group comprising of diethyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, toluene, hexane, dimethyl sulfoxide and mixtures thereof. Finally, this metal derivative of compound VI get coupled with glucolactone compound of formula D to give compound of the Formula VII. This coupling reaction is carried out in solvents selected from the group comprising of diethyl ether, di isopropyl ether, methyl tert-butyl ether, toluene, methylene chloride, hexane, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, N-methylpyrrolidone and mixtures thereof.
[0048] In step e), the compound of Formula VII is converted to compound of Formula VIII by treating it with an alcohol or water. In an embodiment, the alcohol in step e) is selected from a group consisting of C1-C4 alcohol and combination thereof. The C1-C4 is selected from a group consisting of methanol or ethanol or propanol or butanol, preferably, methanol or ethanol. This conversion reaction is performed in presence of an acid. In an embodiment, the acid in step e) is selected from a group consisting of acetic acid, methane sulfonic acid, toluene sulfonic acid, sulfuric acid, trifluoroacetic acid, hydrochloric acid and combination thereof, preferably methane sulfonic acid. During this reaction trimethylsilyl groups of compound of Formula VII are cleaved.
[0049] In step f), the compound of Formula VIII is reduced to crude Bexagliflozin of Formula I. In an embodiment, the reducing agent in step f) is selected from silanes or hydrides. In some embodiment, the silane is selected from a group consisting of triethylsilane, tri-n-propylsilane, triisopropylsilane, diphenylsilane and combination thereof. In some embodiment, the hydride is selected from a group consisting of sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, lithium aluminum hydride, diisobutylaluminum hydride and combination thereof, hydrogen with transition metal catalyst etc. This reduction reaction is carried out with or without Lewis acid. In an embodiment, the Lewis acid in step f) is selected from a group consisting of boron trifluoride etherate, trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, copper(II) triflate, zinc iodide, hydrochloric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, acetic acid and combination thereof, preferably boron trifluoride etherate. The reaction may be carried out in a solvent. In an embodiment, the solvent in step f) is selected from a group consisting of methylene chloride, chloroform, acetonitrile, toluene, hexane, diethylether, tetrahydrofuran, dioxane, ethanol, water and combination thereof. The solvent is preferably selected in view of the reducing agent and the optional Lewis acid. One particularly suitable combination of reagents comprising of triethylsilane and boron trifluoride etherate; preferably triethylsilane, which is conveniently used in acetonitrile.
[0050] In step g), the crude Bexagliflozin of Formula I is optionally purified to give pure Bexagliflozin of Formula I. This purification is carried out by techniques already known in prior art such as crystallization. In an embodiment, the solvent in step g) is selected from a group consisting of methanol, ethanol, isopropanol, n-propanol, n-butanol, water, ethyl acetate, isopropyl acetate, cyclohexane, acetonitrile, acetone, diethyl ether and combination thereof. Preferred solvents are selected from the group comprising of methanol, ethanol, isopropanol, water, ethyl acetate, acetonitrile, acetone, diethyl ether and mixture thereof.
[0051] In an embodiment, the method further comprises:
contacting compound of Formula VIII with aluminum chloride or BF3 etherate at a temperature in the range of 0 to 5 °C followed by adding triethyl silane with stirring for a period of 2 h and quenched with aqueous hydrochloric acid to obtain a crude product;
contacting L-proline to the crude product to obtain a proline complex of Formula IX;

Formula VIII Formula IX
adding ethanol/methanol and water to the proline complex at a temperature of 70 °C with stirring for a period of 1 h to obtain compound of Formula I.

Formula I.
[0052] In another embodiment the following Scheme-2 describes the process for the preparation of 4-bromo-1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)benzene compound of formula (VI).

Scheme 2
[0053] Another embodiment of the present disclosure is to provide a method for preparation of compound of Formula VI comprising the steps of:
(a1) coupling of 5-halo-2-chlorobenzoyl chloride as obtained from 5-halo-2- chlorobenzoic acid of Formula II, with fluorobenzene of Formula III in presence of a Lewis acid;

Formula II Formula III
with or without isolation of compound of Formula IV;

Formula IV
(b1) coupling of the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B in presence of a base, a Lewis acid and a solvent to obtain a compound of Formula V; and

Formula B Formula V
(c1) reducing the compound of Formula V in presence of a reducing agent and a solvent to obtain compound of the Formula VI;

Formula VI.
[0054] In step a1), coupling of 5-halo-2-chlorobenzoyl chloride obtained from 5-halo-2- chlorobenzoic acid of Formula II with fluorobenzene of Formula III is carried out in presence of Lewis acid. In an embodiment, the Lewis acid in step a1) is selected from aluminum chloride, zinc chloride, ferric chloride, titanium chloride, zirconium chloride, boron trifluoride and combination thereof, preferably aluminum chloride. 5-halo-2-chlorobenzoic acid of Formula II is converted into 5-halo-2-chlorobenzoyl chloride using chlorinating agent. In an embodiment, the chlorinating agent in step a1) is selected from oxalyl chloride, thionyl chloride and combination thereof. This reaction is carried out in presence of solvents selected from the group consisting of dichloromethane, chlorobenzene, nitromethane, toluene, dimethylformamaide and combination thereof.
[0055] In step b1), the coupling of the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B is carried out to obtain compound of Formula V. This coupling is carried out under basic conditions as nucleophilic substitution reaction. Suitable base for this coupling reaction is selected from the group comprising of alkali or alkaline earth metal salts coupling of the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B is carried out to obtain compound of Formula V. This coupling is carried out under basic conditions as nucleophilic substitution reaction. Suitable base for this coupling reaction is selected from the group comprising of alkali or alkaline earth metal salts, in particular hydroxides, carbonates, metal hydrides and alkoholates. In an embodiment, the base in step b1) is selected from a group consisting of potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium hydride and combination thereof, wherein the base characterized in that said base has a pKa value of from 10 to 25. Preferably potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide and sodium hydride. In an embodiment, the Lewis acid in step b1) is selected from a group consisting of boron trifluoride etherate, aluminum chloride, tris(pentafluorophenyl) borane, trifluoroacetic acid, hydrochloric acid and combination thereof. In an embodiment, the solvent in step b1) is selected from a group consisting of acetonitrile, ethanol, isopropanol, butanol, acetone, toluene, water, dimethylformamide, dimethylacetamide, diglyme, monoglyme, N-methylpyrollidone, toluene, dimethylsulfoxide, tetrahydrofuran, 2-methylTHF, xylene, dioxane, dichloromethane and combination thereof.
[0056] In step c1), the ketoreduction of the compound of Formula V is carried out to obtain compound of the Formula VI by suitable reducing agent is selected from the group comprising of silane and hydride. In an embodiment, the reducing agent in step c1) is selected from a group consisting of triethyl silane, tri isopropylsilane, tripropylsilane, tetramethyldisiloxane, polymethylhydrosiloxane, sodium borohydride, lithium aluminum hydride and combination thereof, preferably tetramethyldisiloxane, triethyl silane and polymethylhydrosiloxane. This reduction is preferably carried out in the presence of a Lewis acid such as boron trifluoride etherate, aluminum chloride, tris(pentafluorophenyl) borane, trifluoroacetic acid and hydrochloric acid. In an embodiment, the solvent in step c1) is selected from a group consisting of dichloromethane, 1,2-dichloroethane, toluene, benzene, hexane, diglyme, monoglyme, acetone, dimethyl sulfoxide, 2-methylTHF, THF, tert-butanol, acetonitrile, xylene, dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and combination thereof.
[0057] In further embodiment of the present invention relates to one-pot process for the preparation of Formula VI comprising the steps of (Scheme 3):

Scheme 3
[0058] Another embodiment of the present disclosure is to provide an one-pot process for the synthesis of a compound of the Formula VI starting from (5-halo-2-chlorophenyl)(4-fluorophenyl)methanone without isolation and purification of the intermediate compound of formula V;

Formula (VI)
stages, which comprises:
a2) compound of formula (IV) undergoes coupling reaction with 2-cyclopropoxyethan-1-ol of Formula B in presence of an alkali hydroxide or alkaline metal alkoxy base and a dipolar aprotic solvents to give compound of formula (V);

Formula (IV) Formula (V)
b2) compound of formula (V) undergoes ketoreduction with an organosilane and metal hydride reducing agents in presence of a Lewis acid and a solvent gives compound of formula (VI); and

Formula (VI)
c2) optionally purifying the compound of formula (VI) in a suitable solvent or mixture of solvents thereof.
[0059] In an embodiment, the alkali hydroxide or alkaline metal alkoxy base in step a2) is selected from a group consisting of potassium hydroxide, lithium hydroxide, lithium tert-butoxide, lithium ethoxide, lithium methoxide, potassium tert-butoxide, potassium ethoxide, potassium methoxide, sodium tert-butoxide, sodium ethoxide, sodium methoxide and combination thereof, preferably potassium hydroxide or mixture thereof. In an embodiment, the dipolar aprotic solvent in step a2) is selected from toluene, diglyme, monoglyme, acetone, dimethyl sulfoxide, 2-methyl THF, THF, tert-butanol, dichloromethane, dichloroethane, isopropyl acetate, ethyl acetate, acetonitrile, xylene, benzene, heptane, cyclohexane, dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and combination thereof.
[0060] In an embodiment, the organosilane in step b2) is selected form 1,1,3,3-tetramethyldisiloxane, (Et)3SiH, triisopropylsilane, polymethylhydrosiloxane, tris(trimethylsilyl)silane, diphenylsilane and combination thereof. In an embodiment, the metal hydride reducing agent in step b2) is selected from sodium borohydride, lithium borohydide, sodium cyanoborohydide, lithium aluminum hydride, lithium diethoxyaluminum hydride, lithium triethoxyaluminum hydride, lithium tributoxyaluminum hydride, lithium dibutoxyaluminum hydride, lithium diethylaluminum hydride, lithium triethylaluminum hydride, diisobutylaluminum hydride, tri-n- butyltin hydride and combination thereof, wherein the base characterized in that said base has a pKa value of from 10 to 25. In an embodiment, the Lewis acid in step b2) is selected from a group consisting of aluminum chloride, zinc chloride, ferric chloride, titanium chloride, zirconium chloride, BF3-OEt2, BF3 and combination thereof. In an embodiment, the solvent in step b2) is selected from a group consisting of dichloromethane, 1,2-dichloroethane, toluene, benzene, hexane, diglyme, monoglyme, acetone, dimethyl sulfoxide, 2-methylTHF, THF, tert-butanol, acetonitrile, xylene, dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and combination thereof.
[0061] In certain embodiment, the base for coupling reaction is selected from the group comprising of alkali hydroxide or metal hydride; wherein the base characterized in that said base has a pKa value of from 10 to 20.
[0062] Still another embodiment of the present disclosure is to provide method of synthesis of a compound of Formula VI comprising the steps of:

Formula (VI)
a3) compound of formula (IV) undergoes coupling reaction with 2-cyclopropoxyethan-1-ol of Formula B in presence of a phase transfer catalyst, a base, and a solvents to give compound of formula (V);

Formula (IV) Formula (V)
b3) compound of formula (V) undergoes ketoreduction with appropriate organosilane and metal hydride reducing agents in presence of Lewis acid and a solvent gives compound of formula (VI); and

Formula (VI)
c3) optionally purifying the compound of formula (VI) in a suitable solvent or mixture of solvents thereof.
[0063] In another embodiment, the coupling of the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B to obtain compound of Formula V in presence of base and with or without phase transfer catalyst.
[0064] In further embodiment, the coupling of the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B to obtain compound of Formula V in presence of phase transfer catalyst and base.
[0065] In further specific embodiment, the coupling of the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B to obtain compound of Formula V in presence of base.
[0066] In an embodiment, the phase transfer catalyst in step a3) is selected from tetrabutylammonium bromide(TBAB), tetrabutylammonium fluoride (TBAF), tetrabutylammonium hydroxide (TBAH), triethylbenzylammonium chloride (TEBA) and combination thereof. In an embodiment, the base in step a3) is selected from a group consisting of potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium hydride and combination thereof, wherein the base characterized in that said base has a pKa value of from 10 to 25. In an embodiment, the solvent in step a3) is selected from a group consisting of acetonitrile, ethanol, isopropanol, butanol, acetone, toluene, water, dimethylformamide, dimethylacetamide, diglyme, monoglyme, N-methylpyrollidone, toluene, dimethylsulfoxide, tetrahydrofuran, 2-methylTHF, xylene, dioxane, dichloromethane and combination thereof.
[0067] In an embodiment, the organosilane in step b3) is selected form 1,1,3,3-tetramethyldisiloxane, (Et)3SiH, triisopropylsilane, polymethylhydrosiloxane, tris(trimethylsilyl)silane, diphenylsilane and combination thereof. In an embodiment, the metal hydride reducing agent in step b3) is selected from sodium borohydride, lithium borohydide, sodium cyanoborohydide, lithium aluminum hydride, lithium diethoxyaluminum hydride, lithium triethoxyaluminum hydride, lithium tributoxyaluminum hydride, lithium dibutoxyaluminum hydride, lithium diethylaluminum hydride, lithium triethylaluminum hydride, diisobutylaluminum hydride, tri-n- butyltin hydride and combination thereof, wherein the base characterized in that said base has a pKa value of from 10 to 25. In an embodiment, the Lewis acid in step b3) is selected from a group consisting of aluminum chloride, zinc chloride, ferric chloride, titanium chloride, zirconium chloride, BF3-OEt2, BF3 and combination thereof.
[0068] In an embodiment, the solvent in step b3) is selected from a group consisting of dichloromethane, 1,2-dichloroethane, toluene, benzene, hexane, diglyme, monoglyme, acetone, dimethyl sulfoxide, 2-methylTHF, THF, tert-butanol, acetonitrile, xylene, dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and combination thereof.
[0069] In an embodiment, wherein the purification is carried out by taking a wet product in a solvent and then temperature raise up in the range of 55-60°C for a period in the range of 60-90 mins and further cool to 10-15°C followed by filtering the reaction mass and washed with isopropyl alcohol to get the pure compound with HPLC purity of 99.9%. The solvent for purification is selected from a group consisting of methanol, ethanol, isopropanol, n-propanol, n-butanol, water, ethyl acetate, isopropyl acetate, cyclohexane, acetonitrile, acetone, diethyl ether and combination thereof. In some embodiment, the wet material 10.0 gm taken in water (50.0ml) and then temperature raise up to 55-60°C. Maintain the reaction mass for 60-90 mins and further cool to 10-15°C. Filter the reaction mass and washed with isopropyl alcohol to get the pure compound with HPLC purity: 99.9%. In some embodiment, the wet material 10.0gm taken in cyclohexane (50.0 ml) and then temperature raise up to 55-60°C. Maintain the reaction mass for 60-90 mins and further cool to 10-15°C. Filter the reaction mass and washed with isopropyl alcohol to get the pure compound with HPLC purity: 99.9%. In some embodiment, the wet material 10.0gm taken in isopropyl acetate (50.0 ml) and then temperature raise up to 55-60°C. Maintain the reaction mass for 60-90 mins and further cool to 10-15°C. Filter the reaction mass and washed with isopropyl alcohol to get the pure compound with HPLC purity: 99.9%.
[0070] Still another embodiment of the present disclosure provides a compound of Formula V comprising:

Formula V
wherein X is Br or I.
[0071] Yet another embodiment of the present disclosure is to provide a method for preparation of compound of Formula V comprising the steps of:
(a4) coupling of 5-halo-2-chlorobenzoyl chloride as obtained from 5-halo-2- chlorobenzoic acid of Formula II, with fluorobenzene of Formula III in presence of a Lewis acid;

Formula II Formula III
with or without isolation of compound of Formula IV; and

Formula IV
(b4) coupling of the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B in presence of a base, a Lewis acid and a solvent to obtain a compound of Formula V

Formula B Formula V.
[0072] In an embodiment, the Lewis acid in step a4) is selected from aluminum chloride, zinc chloride, ferric chloride, titanium chloride, zirconium chloride, boron trifluoride and combination thereof.
[0073] In an embodiment, the base in step b4) is selected from a group consisting of potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium hydride and combination thereof. In an embodiment, the Lewis acid in step b4) is selected from a group consisting of boron trifluoride etherate, aluminum chloride, tris(pentafluorophenyl) borane, trifluoroacetic acid, hydrochloric acid and combination thereof. In an embodiment, the solvent in step b4) is selected from a group consisting of acetonitrile, ethanol, isopropanol, butanol, acetone, toluene, water, dimethylformamide, dimethylacetamide, diglyme, monoglyme, N-methylpyrollidone, toluene, dimethylsulfoxide, tetrahydrofuran, 2-methylTHF, xylene, dioxane, dichloromethane and combination thereof.
[0074] The process for the preparation of Bexagliflozin described in the present invention is demonstrated in the examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
[0075] The compounds obtained by the chemical transformations of the present application can be used for subsequent steps without further purification or can be effectively separated and purified by employing a conventional method well known to those skilled in the art, such as recrystallization, column chromatography, by transforming them into a salt followed by optionally washing with an organic solvent or with an aqueous solution, and eventually adjusting pH. Compounds at various stages of the process may be purified by precipitation or slurrying in suitable solvents, or by commonly known recrystallization techniques. The suitable recrystallization techniques include, but are not limited to, steps of concentrating, cooling, stirring, or shaking a solution containing the compound, combination of a solution containing a compound with an anti-solvent, seeding, partial removal of the solvent, or combinations thereof, evaporation, flash evaporation, or the like. An antisolvent as used herein refers to a liquid in which a compound is poorly soluble. Compounds can be subjected to any of the purification techniques more than one time, until the desired purity is attained.
[0076] Compounds may also be purified by slurrying in suitable solvents, for example, by providing a compound in a suitable solvent, if required heating the resulting mixture to higher temperatures, subsequent cooling, and recovery of a compound having a high purity. Optionally, precipitation or crystallization at any of the above steps can be initiated by seeding of the reaction mixture with a small quantity of the desired product. Suitable solvents that can be employed for recrystallization or slurrying include, but are not limited to: alcohols, such as, for example, methanol, ethanol, and 2-propanol; ethers, such as, for example, diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), and methyl THF; esters, such as, for example, ethyl acetate, isopropyl acetate, and t-butyl acetate; ketones, such as acetone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and the like; hydrocarbons, such as toluene, xylene, and cyclohexane; nitriles, such as acetonitrile and the like; water; and any mixtures of two or more thereof.
[0077] In another embodiment, the below are the abbreviations are used in the specification.
[0078] AlCl3- Aluminium Chloride anhydrous, HCl- Hydrochloric acid, DCM-Dichloromethane, TEA- Triethyl amine, DIPEA- Diisopropyl ethylamine, KOH-Potassium hydroxide, NaBH4-Sodium borohydride, NaOtbu-Sodium tertiary butoxide, SOCl2- Thionylchloride, C2O2Cl2-Oxallylchloride, Na2SO4- Sodium sulphate, NMT- not more than, HPLC- High performance liquid chromatography, THF-Tetrahydrofuran, 2-Methyl-THF-2-Methyltetrahydrofuran, TES-Triethylsilane,TMDS-Tetramethyldisiloxane, TBAB-tetrabutylammonium bromide, TBAF-tetrabutylammonium fluoride, TBAH-tetrabutylammonium hydroxide, TEBA-Triethylbenzylammonium chloride, TMDSO-Tetramethyldisiloxane,(Et)3SiH-Triethylsilane, MDC-Methylene Dichloride, DMSO-Dimethyl sulfoxide, NaOH- Sodium hydroxide, Na2CO3-Sodiumcarbonate,NBL-n-Butyllithium, HMPA-Hexamethylphosphoramide, NaH-Sodium hydride, MeOH-Methanol, EtOAc-Ethyl acetate, H2O-Water, ACN-acetonitrile, Monoglyme-Dimethoxyethane, Diglyme-1-Methoxy-2-(2-methoxyethoxy)ethane, ND-not detected, SM-starting material and SMI-Single maximum impurity.
[0079] While the foregoing describes various embodiments of the disclosure, other and further embodiments of the disclosure may be devised without departing from the basic scope thereof. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person skilled in the art.
EXAMPLES
[0080] The present invention is further explained in the form of following examples. However, it is to be understood that the following examples are merely illustrative and are not to be taken as limitations upon the scope of the invention.

Example 1
Example-1.1: Preparation of (5-bromo-2-chlorophenyl)(4-fluorophenyl)methanone

[0085] 100.0 gm of 5-bromo-2-chlorobenzoic acid was added to 300 gm of dichloromethane, then 1.0 g of DMF was added, the reaction temperature was controlled to 5-10°C, 120.0gm (2.2eq) of oxalyl chloride was added dropwise, and after the dropwise addition was completed, the mixture was stirred and dissolved. Atmospheric distillation to recover dichloromethane for use in the next batch of this step. After distillation, 100.0 ml of dichloromethane was added to obtain an acid chloride solution, which was stirred and dissolved to be clear for use. 500.0 ml of dichloromethane, 61.0 gm of anhydrous aluminium trichloride and 150.0 gm of fluoro benzene were alum added to the reaction mass at cooling condition and the reaction temperature was controlled at -10 to 10°C, and the dichloromethane solution of the acid chloride prepared above was added dropwise. After completion of reaction mass quench with 500.0 ml of water. Finally organic layer wash with 2x100ml of water, and dichloromethane was recovered at normal pressure, which can be reused after distillation. After distillation, crude diluted with methanol/isopropyl alcohol and cooled to isolate as the tittle product of yield 120.0 gm, purity 99.3%. M/z=3145(M+1); IR: 2987, 920.8; 1HNMR: 7.86(1H), 7.77(1H), 7.67(1H), 7.41(1H) and 7.39-7.22(3H).
Example 1.2: Preparation of (5-iodo-2-chlorophenyl)(4-fluorophenyl)methanone:

[0086] 100.0 gm of 5-iodo-2-chlorobenzoic acid was added to 300 gm of dichloromethane, then 1.0 g of DMF was added, the reaction temperature was controlled to 5-10°C, 120.0 gm (2.2eq) of oxalyl chloride was added dropwise, and after the dropwise addition was completed, the mixture was stirred and dissolved. Atmospheric distillation to recover dichloromethane for use in the next batch of this step. After distillation, 100.0 ml of dichloromethane was added to obtain an acid chloride solution, which was stirred and dissolved to be clear for use. 500.0 ml of dichloromethane, 61.0 gm of anhydrous aluminium trichloride and 150.0 gm of fluoro benzene were alum added to the reaction mass at cooling condition and the reaction temperature was controlled at -10 to 10°C, and the dichloromethane solution of the acid chloride prepared above was added dropwise. After completion of reaction mass quench with 500.0 ml of water. Finally organic layer wash with 2x100ml of water, and dichloromethane was recovered at normal pressure, which can be reused after distillation. After distillation, crude diluted with methanol/isopropyl alcohol and cooled to isolate as the tittle product of yield 120.0 gm, purity 99.3%.
Example 2
Example-2.1: (KOH/DMF/Toluene) Preparation of (5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanone

[0087] Under the protection of nitrogen, 500 ml of dimethyl formamide, 100g of (5-bromo-2-chlorophenyl)(4-fluorophenyl)methanone and 35.0g of 2-(cyclopropyloxy)ethanol were added, and the temperature was reduced to 0-5°C. Then charged 45.0 g (2.5eq) of potassium hydroxide powder as lot wise at control the temperature 0-10?. After addition charge tert butanol (40.0ml) keep the temperature and stir for 2 hours. After the reaction was completed, the reaction solution was transferred to 300 ml water for quenching. The organic layer was separated by standing, and the organic layer was concentrated and dried under reduced pressure. Charge 300.0ml of methanol and stir to dissolve it then lower the temperature and filter with suction to obtain a wet and dry for 8 hours at 50°C to obtain 110g (87.51%) product of title product. Product with a purity (HPLC) of 99.16% and a single maximum impurity of 0.05% IR: 2978.11, 2921.92, 1608.86, 1579.14, 1508.44; 1H NMR: 7.27 (m,3H), 7.09 (d,2H), 6.87 (m,2H), 4.09 (m,2H), 3.85 (m,2H), 3.40(m,1H), 0.642 (m,2H), 0.506 (m,2H); M\Z:395.6.
Example-2.2: (KOH/DMSO/Toluene) Preparation of (5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanone

[0088] Under the protection of nitrogen, 32ml of Dimethyl sulfoxide and Toluene 600.0ml, 100g of (5-bromo-2-chlorophenyl)(4-fluorophenyl)methanone and 35.0g of 2-(Cyclopropyloxy)ethanol were charged, and the temperature was reduced to 5-10°C. Then charged 45.0 g(2.5eq) of potassium hydroxide powder as lot wise at control the temperature 5-10?. After addition keep the temperature and stir for 2 hours at high temperature. After the reaction was completed, the reaction solution was transferred to 300 ml water for quenching. The organic layer extracted with toluene separated by standing, and the organic layer was concentrated and dried under reduced pressure. Charge 300.0ml of isopropyl alcohol and stir to dissolve it then lower the temperature and filter with suction to obtain a wet and dry for 8 hours at 60°C to obtain 97g (77.0%) product of title product. Product with a purity (HPLC) of 99.21% and a single maximum impurity of 0.05%.
Example-2.3: (KOtBu/THF/Toluene) Preparation of (5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanone

[0089] Under the protection of nitrogen, 500ml of THF, 100g of (5-bromo-2-chlorophenyl)(4-fluorophenyl)methanone and 40.0g of 2-cyclopropoxyethan-1-ol were added, and the temperature was reduced to 0-5°C. Then charged 46.0 g(2.5eq) of potassium tert-butoxide solution in THF as drop wise at control the temperature 5-10?. After addition keep the temperature and stir for 2 hours. After the reaction was completed, the reaction solution was transferred to 300 ml water for quenching. The organic layer extracted with toluene separated by standing, and the organic layer was concentrated and dried under reduced pressure. Charge 250.0ml of isopropyl alcohol and stir to dissolve it then lower the temperature and filter with suction to obtain a wet and dry for 8 hours at 39°C to obtain 105 g (81.3%) product of title product.
Example-2.4: (KOH/ TBAB/ Toluene) Preparation of (5-iodo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanone

[0090] Under the protection of nitrogen, 500ml of toluene, 100g of (5-iodo-2-chlorophenyl)(4-fluorophenyl)methanone and 35.0g of 2-(Cyclopropyloxy)ethanol were added, and the temperature was reduced to 0-5°C. Then charged 21.5 g(1.2eq) of potassium hydroxide powder as lot wise at control the temperature 0-10?. Finally charge tetra butyl ammonium bromide and stir for 2 hours. After the reaction was completed, the reaction solution was transferred to 300 ml water for quenching. The organic layer was separated by standing, and the organic layer was concentrated and dried under reduced pressure. Charge 300.0ml of methanol and stir to dissolve it then lower the temperature and filter with suction to obtain a wet and dry for 8 hours at 50°C to obtain 110g (87.51%) product of title product. Product with a purity (HPLC) of 99.16% and a single maximum impurity of 0.05%. IR: 2979.1, 2921.05, 1608.86, 1579.14, 1508.44; 1H NMR: 737 (m,3H), 7.09 (d,2H), 6.97 (m,2H), 4.09 (m,2H), 3.85 (m,2H), 3.40 (m,1H), 0.642 (m,2H), 0.506 (m,2H); M\Z:443.6.
Example-2.5: (KOH/DMSO/Toluene) Preparation of (5-iodo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanone

[0091] Under the protection of nitrogen, 32ml of Dimethyl sulfoxide and Toluene 600.0ml, 100g of (5-iodo-2-chlorophenyl)(4-fluorophenyl)methanone and 35.0g of 2-(Cyclopropyloxy)ethanol were charged, and the temperature was reduced to 5-10°C. Then charged 21.5 g(1.2eq) of potassium hydroxide powder as lot wise at control the temperature 5-10?. After addition keep the temperature and stir for 2 hours at high temperature. After the reaction was completed, the reaction solution was transferred to 300 ml water for quenching. The organic layer extracted with toluene separated by standing, and the organic layer was concentrated and dried under reduced pressure. Charge 300.0ml of isopropyl alcohol and stir to dissolve it then lower the temperature and filter with suction to obtain a wet and dry for 8 hours at 60°C to obtain 97g (77.0%) product of title product. Product with a purity (HPLC) of 99.21% and a single maximum impurity of 0.05%.
Example-2.6: (Potassium tert butoxide / THF) Preparation of (5-iodo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanone

[0092] Under the protection of nitrogen, 500ml of THF, 100g of (5-iodo-2-chlorophenyl)(4-fluorophenyl)methanone and 40.0g of 2-(Cyclopropyloxy)ethanol were added, and the temperature was reduced to 0-5°C. Then charged 46.0 g (2.5eq) of potassium tert-butoxide solution in THF as drop wise at control the temperature 5-10?. After addition keep the temperature and stir for 2 hours. After the reaction was completed, the reaction solution was transferred to 300 ml water for quenching. The organic layer extracted with toluene separated by standing, and the organic layer was concentrated and dried under reduced pressure. Charge 250.0 ml of isopropyl alcohol and stir to dissolve it then lower the temperature and filter with suction to obtain a wet and dry for 8 hours at 39°C to obtain 105 g (81.3%) product of title product.

Example 3
Example-3.1: Preparation of 4-bromo-1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)benzene

[0093] 100.0 g of (5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanone charged in to the toluene (500.0 ml) under nitrogen atmosphere. The reaction mass cooled to 0-5°. 2.02eq. of 1,1,3,3-Tetramethyldisiloxane was added into the reaction mass. The addition was completed, and the temperature was controlled at 10-15 °C and stirred for 1 h. Add 2.35eq of aluminum trichloride, heat to 50-55° C for 3-4 hours, and after the reaction was completed. The reaction mass with 500.0 ml of water, finally organic layer wash with 2x100ml of water, and toluene was recovered under vacuum, which can be reused after distillation. After distillation crude diluted with methanol/Hexanes and cooled to isolate as the tittle product of yield 90.1%, purity 99.9%. IR: 2925.83, 1610.98, 1583.14, 1509,28, 1136.58; 1HNMR: 7.253 (m,3H), 7.08 (d,2H), 6.867 (m,2H) 4.08 (m,2H), 3.97 (s,2H), 3.83 (m,2H), 3.402 (m,1H), 0.632 (m,2H), 0.504 (m,2H); M\Z:382.6.
Example-3.2: Preparation of 4-bromo-1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)benzene

[0094] 100.0 g of 5(5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanone charged in to the Toluene 200.0ml under nitrogen atmosphere. The reaction mass cooled to 0-5°. 2.5eq of triethylsilane was added into the reaction mass as lot wise, the addition was completed, and the temperature was controlled at 10-15 °C and stirred for 1 h. Add 2.8eq of aluminum trichloride, heat to 50-55° C. for 3-4 hours, and after the reaction was completed. Distilled solvent and add Toluene. The reaction mass with 500.0ml of water, finally organic layer wash with 2x100ml of water, and toluene was recovered under vacuum, which can be reused after distillation. After distillation crude diluted with methanol and cooled to isolate as the tittle product of yield 88.9%, purity 99.9%.
Example-3.3: Preparation of 4-bromo-1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)benzene

[0095] 100.0 g of 5(5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanone charged into the THF 200.0ml under nitrogen atmosphere. The reaction mass cooled to 0-5°. 2.5eq of sodium borohydride was added into the reaction mass as lot wise, the addition was completed, and the temperature was controlled at 10-15 °C and stirred for 1 h. Add 2.8eq of aluminum trichloride, heat to 60-65° C. for 3-4 hours, and after the reaction was completed. Distilled solvent and add toluene. The reaction mass with 500.0ml of water, finally organic layer wash with 2x100ml of water, and toluene was recovered under vacuum, which can be reused after distillation. After distillation crude diluted with methanol and cooled to isolate as the tittle product of yield 88.9%, purity 99.9%.
Example-3.4: Preparation of 4-iodo-1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)benzene

[0096] 100.0 g of (5-iodo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanone charged in to the toluene (500.0ml) under nitrogen atmosphere. The reaction mass cooled to 0-5°. 2.02 eq of 1,1,3,3-Tetramethyldisiloxane was added in to the reaction mass. The addition was completed, and the temperature was controlled at 10-15 °C and stirred for 1 h. Add 2.35eq of aluminium trichloride, heat to 50-55° C for 3-4 hours, and after the reaction was completed, the reaction mass with 500.0ml of water. Finally organic layer wash with 2x100ml of water, and toluene was recovered under vacuum, which can be reused after distillation. After distillation crude diluted with methanol/Hexanes and cooled to isolate as the tittle product of yield 90.1%, purity 99.8%.
Example-3.5: Preparation of 4-iodo-1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)benzene

[0097] 100.0 g of 5(5-iodo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanone charged in to the Dichloromethane 200.0ml under nitrogen atmosphere. The reaction mass cooled to 0-5°. 2.5eq of triethylsilane was added in to the reaction mass as lot wise, the addition was completed, and the temperature was controlled at 10-15 °C and stirred for 1 h. Add 2.8eq of aluminum trichloride, heat to 50-55° C. for 3-4 hours, and after the reaction was completed. Distilled solvent and add toluene. The reaction mass with 500.0ml of water. Finally organic layer wash with 2x100ml of water, and toluene was recovered under vacuum, which can be reused after distillation. After distillation crude diluted with methanol and cooled to isolate as the tittle product of yield 88.9%, purity 99.9%. IR: 2927.81, 1610.11, 1583.14, 1509.28, 1136.58; 1H NMR: 7.263 (m,3H), 7.18 (d,2H), 6.867 (m,2H), 4.18 (m,2H), 3.97 (s,2H), 3.83 (m,2H), 3.402 (m,1H), 0.632 (m,2H), 0.54 (m,2H); M\Z:429.6.
Example-3.6: Preparation of 4-iodo-1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)benzene

[0098] 100.0 g of 5(5-iodo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanone charged in to the THF 200.0ml under nitrogen atmosphere. The reaction mass cooled to 0-5°. 2.5 eq of sodium borohydride was added in to the reaction mass as lot wise, the addition was completed, and the temperature was controlled at 10-15 °C and stirred for 1 h. Add 2.8eq of aluminum trichloride, heat to 60-65° C for 3-4 hours, and after the reaction was completed. Distilled solvent and add toluene. The reaction mass with 500.0ml of water. Finally organic layer wash with 2x100ml of water, and toluene was recovered under vacuum, which can be reused after distillation. After distillation crude diluted with methanol and cooled to isolate as the tittle product of yield 88.9%, purity 99.9%.
Example 4
Example-4.1: One pot synthesis of 4-bromo-1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)benzene

[0099] Under the protection of nitrogen, 32mL of dimethyl sulfoxide and Toluene 600.0ml, 100g of (5-bromo-2-chlorophenyl)(4-fluorophenyl)methanone and 35.0g of 2-(cyclopropyloxy)ethanol were charged, and the temperature was reduced to 5-10°C. Then charged 45.0 g(2.5eq) of potassium hydroxide powder as lot wise at control the temperature 5-10?. After addition keep the temperature and stir for 2 hours at high temperature. After the reaction was completed, the reaction solution was transferred to 300 ml water for quenching. The organic layer extracted with toluene separated by standing, and the organic layer was concentrated and dried under reduced pressure, and then taken into RBF. The reaction mass cooled to 5-10°. 2.5eq of aluminium trichloride was added into the reaction mass as lot wise, the addition was completed, and the temperature was controlled at 10-15 °C and stirred for 1 h. Add 2.16eq 1,1,3,3-tetramethyldisiloxane to the reaction mass. Raise the reaction mass temperature to 50-55° C. for 3-4 hours. Reaction was completion, the reaction mass with 500.0ml of water, finally organic layer wash with 2x100ml of water, and toluene was recovered under vacuum, which can be reused after distillation. After distillation crude diluted with methanol/Hexanes and cooled to isolate as the tittle product of yield 91.3%, purity 99.91%.
Example-4.2: One pot synthesis of 4-iodo-1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)benzene:

[00100] Under the protection of nitrogen, 32ml of dimethyl sulfoxide and toluene 600.0ml, 100g of (5-iodo-2-chlorophenyl)(4-fluorophenyl)methanone and 35.0g of 2-(cyclopropyloxy)ethanol were charged, and the temperature was reduced to 5-10°C. Then charged 21.6 g(1.2eq) of potassium hydroxide powder as lot wise at control the temperature 5-10?. After addition keep the temperature and stir for 2 hours at high temperature. After the reaction was completed, the reaction solution was transferred to 300 ml water for quenching. The organic layer extracted with toluene separated by standing, and the organic layer was concentrated and dried under reduced pressure, and then taken into RBF. The reaction mass cooled to 5-10°. 2.5eq of aluminium trichloride was added in to the reaction mass as lot wise, the addition was completed, and the temperature was controlled at 10-15 °C and stirred for 1 h. Add 2.16eq 1,1,3,3-tetramethyldisiloxane to the reaction mass. Raise the reaction mass temperature to 50-55° C for 3-4 hours. Reaction was completion, the reaction mass with 500.0ml of water. Finally organic layer wash with 2x100ml of water, and toluene was recovered under vacuum, which can be reused after distillation. After distillation crude diluted with methanol/Hexanes and cooled to isolate as the tittle product of yield 91.3%, purity 99.91%.
Example 5
Example-5.1: Preparation of Bexagliflozin,(3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

[00101] To the solution of l-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)-4-nromobenzene in tetrahydrofuran, n-BuLi (2.5 mol) in hexane was added at a rate that maintains the reaction temperature below -80°C followed by addition of 1.8eq of 2,3,4,6-tetra-O-trimethylsilyl-D- glucolactone in toluene at a rate to maintain the reaction temperature below -80°C. The solution was stirred for 60-90 min at -75°C. After TLC complies the addition of methane sulfonic acid in methanol. The reaction mass was stirred till completion of reaction at 25°C to 35°C. After completion of reaction, the reaction was quenched by the addition of sodium carbonate and distilled out under vacuum. To the obtained residue water was added and extracted with ethylacetate. The combined ethylacetate fractions were washed with brine and dried over sodium sulfate. The reaction mixture was concentrated to get the compound of formula (3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. To the MDC solvent, 2.8eq of aluminum chloride was added and cooled the mass to the temperature 0°C to 5°C. To the triethyl silane was added followed by addition, stirred the reaction mass for about 2 h, the reaction was quenched by addition of aqueous hydrochloric acid solution. Aqueous layer was extracted with methylenechloride. Combined organic layer was washed with 5% aqueous hydrochloric acid solution followed by water and brine. The organic layer was distilled and to the obtained residue. The residue was titrated with ethyl acetate and hexanes to get the crystalline Bexagliflozin of formula white crystalline solid 78.9% yield, purity (HPLC): 99.5%).
Example-5.2: Preparation of (3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triolL-Proline

[00102] To the solution of l-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)-4-nromobenzenein tetrahydrofuran, n-BuLi (2.5 mol) in hexane was added at a rate that maintains the reaction temperature below -80°C followed by addition of 1.8eq of 2,3,4,6-tetra-0-trimethylsilyl-D- glucolactonein toluene at a rate to maintain the reaction temperature below -80°C. The solution was stirred for 60-90 min at -75°C. After TLC complies the addition of methane sulfonic acid in methanol. The reaction mass was stirred till completion of reaction at 25°C to 35°C. After completion of reaction, the reaction was quenched by the addition of sodium carbonate and distilled out under vacuum. To the obtained residue water was added and extracted with ethylacetate. The combined ethylacetate fractions were washed with brine and dried over sodium sulfate. The reaction mixture was concentrated to get the compound of formula (3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. To the MDC solvent, 2.8eq of aluminum chloride was added in and cooled the mass to the temperature 0°C to 5°C. To the triethyl silane was added followed by addition, stirred the reaction mass for about 2 h, the reaction was quenched by addition of aqueous hydrochloric acid solution. Aqueous layer was extracted with methylenechloride. Combined organic layer was washed with 5% aqueous hydrochloric acid solution followed by water and brine. To the crude product was added L-proline 1.2eq in ethanol/water and the mixture was stirred at 70°C for 1 h until it became a clear solution. MTBE was added dropwise over 50 min, while the temperature was maintained at about 50° C. The reaction mixture was stirred overnight at room temperature. The solid was filtered and washed with Ethanol, hexane (2×900 mL), and dried at 40°C under vacuum to give a white solid (209 g) HPLC purity 99.45%.
Example-5.3: Preparation of Bexagliflozin,(3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

[00103] To the solution of l-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)-4-iodobenzene in tetrahydrofuran, n-BuLi (2.5 mol) in hexane was added at a rate that maintains the reaction temperature below -90°C followed by addition of 1.8eq of 2,3,4,6-tetra-0-trimethylsilyl-D- glucolactone in toluene at a rate to maintain the reaction temperature below -80°C. The solution was stirred for 60-90 min at -75°C. After TLC complies the addition of methane sulfonic acid in methanol. The reaction mass was stirred until completion of reaction at 25°C to 35°C. After completion of reaction, the reaction was quenched by the addition of sodium carbonate and distilled out under vacuum. To the obtained residue, water was added and extracted with ethyl acetate. The combined ethyl acetate fractions were washed with brine and dried over sodium sulfate. The reaction mixture was concentrated to get the compound of formula (3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. To the MDC solvent, 2.8eq of BF3 etherate was added in and cooled the mass to the temperature 0°C to 5°C. To the triethyl silane was added followed by addition Stirred the reaction mass for about 2 h, the reaction was quenched by addition of aqueous hydrochloric acid solution. Aqueous layer was extracted with methylene chloride. Combined organic layer was washed with 5% aqueous hydrochloric acid solution followed by water and brine. The organic layer was distilled and to the obtained residue. The residue was titrated Ethanol(300.0mL) and Water(20.0mL) raised the residue temperature to reflux along with L-proline. This reaction mass stir up to clear solution formation and then add hexanes to get the crystalline Bexagliflozin L-proline salt of formula white crystalline solid 88.9% yield, purity (HPLC): 99.5%.
Salt breaking process:
[00104] The above L-proline salt was taken in to methanol (200.0ml) and then temperature raised to reflux temperature, water (200.0ml) was added slowly over a period of 60.0 minutes and then cool to Room temperature (25-35°C). Reaction mass stirred for 12.0 hrs at 25-35°C. Reaction mass filter to get the pure(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. HPLC purity: 99.89%.
[00105] The above L-proline salt was taken in to Acetone (200.0ml) and then temperature raised to reflux temperature. Water (200.0ml) was added slowly over a period of 60.0 minutes and then cool to Room temperature (25-35°C). Reaction mass stirred for 12.0 hrs at 25-35°C. Reaction mass filter to get the pure(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. HPLC purity: 99.81%.
Purification
[00106] (A) The wet material 10.0 gm taken in water (50.0ml) and then temperature raise up to 55-60°C. Maintain the reaction mass for 60-90 mins and further cool to 10-15°C. Filter the reaction mass and washed with isopropyl alcohol to get the pure compound with HPLC purity: 99.9%.
[00107] (B) The wet material 10.0gm taken in cyclohexane (50.0ml) and then temperature raise up to 55-60°C. Maintain the reaction mass for 60-90 mins and further cool to 10-15°C. Filter the reaction mass and washed with isopropyl alcohol to get the pure compound with HPLC purity: 99.9%.
[00108] (C) The wet material 10.0gm taken in isopropyl acetate (50.0ml) and then temperature raise up to 55-60°C. Maintain the reaction mass for 60-90 mins and further cool to 10-15°C. Filter the reaction mass and washed with isopropyl alcohol to get the pure compound with HPLC purity: 99.9%.
Preparation of Bexagliflozin:
[00109] To the solution of l-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)-4-iodobenzene in tetrahydrofuran, n-BuLi (2.5 mol) in hexane was added at a rate that maintains the reaction temperature below -95°C followed by addition of 1.8 eq of 2,3,4,6-tetra-0-trimethylsilyl-D- glucolactone in toluene at a rate to maintain the reaction temperature below -80°C. The solution was stirred for 60-90 min at -75°C. After TLC complies the addition of methane sulfonic acid in methanol. The reaction mass was stirred till completion of reaction at 25°C to 35°C. After completion of reaction, the reaction was quenched by the addition of sodium carbonate and distilled out under vacuum. To the obtained residue water was added and extracted with ethylacetate. The combined ethylacetate fractions were washed with brine and dried over sodium sulfate. The reaction mixture was concentrated to get the compound of formula (3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. To the MDC solvent, 2.8eq of aluminum chloride was added in and cooled the mass to the temperature 0°C to 5°C. To the triethyl silane was added followed by addition. Stirred the reaction mass for about 2 h, the reaction was quenched by addition of aqueous hydrochloric acid solution. Aqueous layer was extracted with methylenechloride. Combined organic layer was washed with 5% aqueous hydrochloric acid solution followed by water and brine. To the crude product was added L-proline 1.2 eq in ethanol/water and the mixture was stirred at 70° C for 1 h until it became a clear solution. MTBE was added dropwise over 50 min, while the temperature was maintained at about 50° C. The reaction mixture was stirred overnight at room temperature. The solid was filtered and washed with ethanol, hexane (2×900 mL), and dried at 40° C under vacuum for to give a white solid (209 g) HPLC purity 99.45%.

ADVANTAGES OF THE INVENTION
i. The present invention relates to a novel process for the preparation of Bexagliflozin and also relates to novel intermediates in the preparation of Bexagliflozin;
ii. using mixture of solvents and one-pot synthesis shows significant improvement in yields and purity;
iii. Bexagliflozin API produce with minimum reactions conversions with green chemistry conditions.
iv. with lower time cycle API produce huge commercial quantity.
v. Most economical and ecological industrial manufacturing process
vi. reactions carried out at low temperatures reduced additional energy; reduced reaction time duration faster results;
vii. use of phase transfer catalyst increases the reaction rate and reaction goes to completion in lesser time thus making the process economical and industrially feasible;
viii. in one aspect, the present invention relates to a novel process for the preparation of Bexagliflozin and its intermediates;
ix. using the inexpensive alkali hydroxide and alkaline metal alkoxy base characterized in that said bases has a pKa value of from 10 to 25 in reaction is cost- effective;
x. the present invention process produced a novel compound (2-chloro-5-iodophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanone;
xi. the present invention process produced a novel compound(5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanone;
xii. the comprehensive experimentation exemplifies an inventive and easily scaled-up synthetic technique;
xiii. toluene and THF has high recovery percentage in reaction; solvent recovered under vacuum, can be reused after distillation;
xiv. solvent recovery is a form of waste reduction eco-friendly and alternative to improving the greenness of industrial processes and which makes the process economic cost effective and environment friendly;
xv. the process avoids the use of tedious and cumbersome procedures like column chromatographic purifications and multiple isolations;
,CLAIMS:1. A method for preparation of benxagliflozin compound of Formula I comprising:
a) contacting 5-halo-2-chlorobenzoic acid of Formula II with a chlorinating agent in presence of a solvent to obtain 5-halo-2-chlorobezoyl chloride followed by adding fluorobenzene of Formula III in presence of a Lewis acid to obtain a compound of Formula IV;

Formula II Formula III Formula IV
b) contacting the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B in presence of a base and a solvent with or without a phase transfer catalyst to obtain a compound of Formula V;

Formula B Formula V
c) contacting the compound of Formula V with a reducing agent, a Lewis acid and a solvent to obtain a compound of Formula VI;

Formula VI
d) contacting the compound of Formula VI with glucolactone compound of formula D in presence of an organo-lithium compound and a solvent to obtain a compound of Formula VII;

Formula D Formula VII
e) contacting the compound of Formula VII with an alcohol or water in presence of an acid to form a compound of Formula VIII;

Formula VIII
f) reducing the compound of Formula VIII by a reducing agent with or without presence of a Lewis acid and a solvent to obtain a crude Bexagliflozin compound of Formula I; and

Formula I
g) optionally purifying the compound of formula (I) in a suitable solvent or mixture of solvents thereof.
2. The method as claimed in claim 1, wherein the chlorinating agent in step a) is selected from a group consisting of oxalyl chloride, thionyl chloride and combination thereof.
3. The method as claimed in claim 1, wherein the solvent in step a) is selected from a group consisting of dichloromethane, chlorobenzene, nitromethane, toluene and dimethylformamide, dimethyl sulfoxide and combination thereof.
4. The method as claimed in claim 1, wherein the Lewis acid in step a) is selected from a group consisting of aluminum chloride, zinc chloride, ferric chloride, titanium chloride, zirconium chloride, boron trifluoride and combination thereof.
5. The method as claimed in claim 1, wherein the base in step b) is selected from a group consisting of potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride and calcium hydride and combination thereof.
6. The method as claimed in claim 1, wherein the solvent in step b) is selected from a group consisting of acetonitrile, ethanol, isopropanol, butanol, acetone, toluene, water, dimethylformamide, dimethylacetamide, diglyme, monoglyme, N-methylpyrollidone, toluene, dimethylsulfoxide, tetrahydrofuran, 2-methylTHF, xylene, dioxane, dichloromethane and combination thereof.
7. The method as claimed in claim 1, wherein the catalyst in step b) is selected from a group consisting of a tetrabutylammoniumbromide (TBAB), tetrabutylammonium fluoride (TBAF), tetrabutylammonium hydroxide (TBAH), triethylbenzylammonium chloride (TEBA) and combination thereof.
8. The method as claimed in claim 1, wherein the reducing agent in step c) is selected from a group consisting of triethyl silane, tri isopropylsilane, tetramethyldisiloxane, tripropylsilane, diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, lithium aluminum hydride, diisobutylaluminum hydride borohydride and combination thereof.
9. The method as claimed in claim 1, wherein the Lewis acid in step c) is selected from a group consisting of boron trifluoride etherate, tris(pentafluorophenyl) borane, trifluoroacetic acid, hydrochloric acid, aluminum chloride and combination thereof.
10. The method as claimed in claim 1, wherein the solvent in step c) is selected from a group consisting of dichloromethane, 1,2-dichloroethane, acetone, toluene, dimethyl sulfoxide, dimethyl acetol, dimethylformamide, benzene, hexane, acetonitrile, ethanol, isopropanol, diglyme, monoglyme, N-methylpyrollidone, tetrahydrofuran, 2-methylTHF, xylene, dioxane and combination thereof.
11. The method as claimed in claim 1, wherein the organo-lithium compound in step d) is selected from a group consisting of n-butyllithium, sec-butyllithium or tert-butyllithium and Hexamethylphosphoramide and combination thereof.
12. The method as claimed in claim 1, wherein the solvent in step d) is selected from a group consisting of diethyl ether, dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, toluene, hexane, dimethyl sulfoxide, dichloromethane and combination thereof.
13. The method as claimed in claim 1, wherein the alcohol in step e) is selected from a group consisting of C1-C4 alcohol and combination thereof.
14. The method as claimed in claim 1, wherein the acid in step e) is selected from a group consisting of acetic acid, methane sulfonic acid, toluene sulfonic acid, sulfuric acid, trifluoroacetic acid, hydrochloric acid and combination thereof.
15. The method as claimed in claim 1, the method further comprises:
contacting compound of Formula VIII with aluminum chloride or BF3 etherate at a temperature in the range of 0 to 5 °C followed by adding triethyl silane with stirring for a period of 2 h and quenched with aqueous hydrochloric acid to obtain a crude product;
contacting L-proline to the crude product to obtain a proline complex of Formula IX;

Formula VIII Formula IX
adding ethanol/methanol and water to the proline complex at a temperature of 70 °C with stirring for a period of 1 h to obtain compound of Formula I.

Formula I.
16. The method as claimed in claim 1, wherein the reducing agent in step f) is selected from silanes or hydrides.
17. The method as claimed in claim 16, wherein the silanes is selected from a group consisting of triethylsilane, tri-n-propylsilane, triisopropylsilane, diphenylsilane and combination thereof.
18. The method as claimed in claim 16, wherein the hydride is selected from a group consisting of sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, lithium aluminum hydride, diisobutylaluminum hydride and combination thereof.
19. The method as claimed in claim 1, wherein the Lewis acid in step f) is selected from a group consisting of boron trifluoride etherate, trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, copper(II) triflate, zinc iodide, hydrochloric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, acetic acid and combination thereof.
20. The method as claimed in claim 1, wherein the solvent in step f) is selected from a group consisting of methylene chloride, chloroform, acetonitrile, toluene, hexane, diethylether, tetrahydrofuran, dioxane, ethanol, water and combination thereof.
21. The method as claimed in claim 1, wherein the solvent in step g) is selected from a group consisting of methanol, ethanol, isopropanol, n-propanol, n-butanol, water, ethyl acetate, acetonitrile, acetone, diethyl ether and combination thereof.
22. A method for preparation of compound of Formula VI comprising the steps of:
(a1) coupling of 5-halo-2-chlorobenzoyl chloride as obtained from 5-halo-2- chlorobenzoic acid of Formula II, with fluorobenzene of Formula III in presence of a Lewis acid;

Formula II Formula III
with or without isolation of compound of Formula IV;

Formula IV
(b1) coupling of the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B in presence of a base, a Lewis acid and a solvent to obtain a compound of Formula V; and

Formula B Formula V
(c1) reducing the compound of Formula V in presence of a reducing agent and a solvent to obtain compound of the Formula VI;

Formula VI.
23. The method as claimed in claim 22, wherein the Lewis acid in step a1) is selected from aluminum chloride, zinc chloride, ferric chloride, titanium chloride, zirconium chloride, boron trifluoride and combination thereof.
24. The method as claimed in claim 22, wherein the base in step b1) is selected from a group consisting of potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium hydride and combination thereof, wherein the base characterized in that said base has a pKa value of from 10 to 25.
25. The method as claimed in claim 22, wherein the Lewis acid in step b1) is selected from a group consisting of boron trifluoride etherate, aluminum chloride, tris(pentafluorophenyl) borane, trifluoroacetic acid, hydrochloric acid and combination thereof.
26. The method as claimed in claim 22, wherein the solvent in step b1) is selected from a group consisting of acetonitrile, ethanol, isopropanol, butanol, acetone, toluene, water, dimethylformamide, dimethylacetamide, diglyme, monoglyme, N-methylpyrollidone, toluene, dimethylsulfoxide, tetrahydrofuran, 2-methylTHF, xylene, dioxane, dichloromethane and combination thereof.
27. The method as claimed in claim 22, wherein the reducing agent in step c1) is selected from a group consisting of triethyl silane, tri isopropylsilane, tripropylsilane, tetramethyldisiloxane, polymethylhydrosiloxane, sodium borohydride, lithium aluminum hydride and combination thereof.
28. The method as claimed in claim 22, wherein the solvent in step c1) is selected from a group consisting of dichloromethane, 1,2-dichloroethane, toluene, benzene, hexane, diglyme, monoglyme, acetone, dimethyl sulfoxide, 2-methylTHF, THF, tert-butanol, acetonitrile, xylene, dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and combination thereof.
29. An one-pot process for the synthesis of a compound of the Formula VI starting from (5-halo-2-chlorophenyl)(4-fluorophenyl)methanone without isolation and purification of the intermediate compound of formula V;

Formula (VI)
stages, which comprises:
a2) compound of formula (IV) undergoes coupling reaction with 2-cyclopropoxyethan-1-ol of Formula B in presence of an alkali hydroxide or alkaline metal alkoxy base and a dipolar aprotic solvents to give compound of formula (V);

Formula (IV) Formula (V)

b2) compound of formula (V) undergoes ketoreduction with an organosilane and metal hydride reducing agents in presence of a Lewis acid and a solvent gives compound of formula (VI); and

Formula (VI)
c2) optionally purifying the compound of formula (VI) in a suitable solvent or mixture of solvents thereof.
30. The process as claimed in claim 29, wherein the alkali hydroxide or alkaline metal alkoxy base in step a2) is selected from a group consisting of potassium hydroxide, lithium hydroxide, lithium tert-butoxide, lithium ethoxide, lithium methoxide, potassium tert-butoxide, potassium ethoxide, potassium methoxide, sodium tert-butoxide, sodium ethoxide, sodium methoxide and combination thereof.
31. The process as claimed in claim 29, wherein the dipolar aprotic solvent in step a2) is selected from toluene, diglyme, monoglyme, acetone, dimethyl sulfoxide, 2-methyl THF, THF, tert-Butanol, dichloromethane, dichloroethane, isopropyl acetate, ethyl acetate, acetonitrile, xylene, benzene, heptane, cyclohexane, dioxane, dimethylformamide, dimethylacetamide, N-Methyl-2-pyrrolidone and combination thereof.
32. The process as claimed in claim 29, wherein the organosilane in step b2) is selected form 1,1,3,3-tetramethyldisiloxane, (Et)3SiH, triisopropylsilane, polymethylhydrosiloxane, tris(trimethylsilyl)silane, diphenylsilane and combination thereof.
33. The process as claimed in claim 29, wherein the metal hydride reducing agent in step b2) is selected from sodium borohydride, lithium borohydide, sodium cyanoborohydide, lithium aluminum hydride, lithium diethoxyaluminum hydride, lithium triethoxyaluminum hydride, lithium tributoxyaluminum hydride, lithium dibutoxyaluminum hydride, lithium diethylaluminum hydride, lithium triethylaluminum hydride, diisobutylaluminum hydride, tri-n- butyltin hydride and combination thereof, wherein the base characterized in that said base has a pKa value of from 10 to 25.
34. The method as claimed in claim 29, wherein the Lewis acid in step b2) is selected from a group consisting of aluminum chloride, zinc chloride, ferric chloride, titanium chloride, zirconium chloride, BF3-OEt2, BF3 and combination thereof.
35. The method as claimed in claim 29, wherein the solvent in step b2) is selected from a group consisting of dichloromethane, 1,2-dichloroethane, toluene, benzene, hexane, diglyme, monoglyme, acetone, dimethyl sulfoxide, 2-methylTHF, THF, tert-butanol, acetonitrile, xylene, dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and combination thereof.
36. A method of synthesis of a compound of Formula VI comprising the steps of:

Formula (VI)
a3) compound of formula (IV) undergoes coupling reaction with 2-cyclopropoxyethan-1-ol of Formula B in presence of a phase transfer catalyst, a base, and a solvents to give compound of formula (V);

Formula (IV) Formula (V)

b3) compound of formula (V) undergoes ketoreduction with appropriate organosilane and metal hydride reducing agents in presence of Lewis acid and a solvent gives compound of formula (VI); and

Formula (VI)
c3) optionally purifying the compound of formula (VI) in a suitable solvent or mixture of solvents thereof.
37. The method as claimed in claim 36, wherein the phase transfer catalyst in step a3) is selected from tetrabutylammonium bromide(TBAB), tetrabutylammonium fluoride (TBAF), tetrabutylammonium hydroxide (TBAH), triethylbenzylammonium chloride (TEBA) and combination thereof.
38. The method as claimed in claim 36, wherein the base in step a3) is selected from a group consisting of potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium hydride and combination thereof, wherein the base characterized in that said base has a pKa value of from 10 to 25.
39. The method as claimed in claim 36, wherein the solvent in step a3) is selected from a group consisting of acetonitrile, ethanol, isopropanol, butanol, acetone, toluene, water, dimethylformamide, dimethylacetamide, diglyme, monoglyme, N-methylpyrollidone, toluene, dimethylsulfoxide, tetrahydrofuran, 2-methylTHF, xylene, dioxane, dichloromethane and combination thereof.
40. The method as claimed in claim 36, wherein the organosilane in step b3) is selected form 1,1,3,3-tetramethyldisiloxane, (Et)3SiH, triisopropylsilane, polymethylhydrosiloxane, tris(trimethylsilyl)silane, diphenylsilane and combination thereof.
41. The process as claimed in claim 36, wherein the metal hydride reducing agent in step b3) is selected from sodium borohydride, lithium borohydide, sodium cyanoborohydide, lithium aluminum hydride, lithium diethoxyaluminum hydride, lithium triethoxyaluminum hydride, lithium tributoxyaluminum hydride, lithium dibutoxyaluminum hydride, lithium diethylaluminum hydride, lithium triethylaluminum hydride, diisobutylaluminum hydride, tri-n- butyltin hydride and combination thereof; wherein the base characterized in that said base has a pKa value of from 10 to 25.
42. The method as claimed in claim 36, wherein the Lewis acid in step b3) is selected from a group consisting of aluminum chloride, zinc chloride, ferric chloride, titanium chloride, zirconium chloride, BF3-OEt2, BF3 and combination thereof.
43. The method as claimed in claim 36, wherein the solvent in step b3) is selected from a group consisting of dichloromethane, 1,2-dichloroethane, toluene, benzene, hexane, diglyme, monoglyme, acetone, dimethyl sulfoxide, 2-methylTHF, THF, tert-butanol, acetonitrile, xylene, dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and combination thereof.
44. The method as claimed in claims 1, 29 and 36, wherein the purification is carried out by taking a wet product in a solvent and then temperature raise up in the range of 55-60°C for a period in the range of 60-90 mins and further cool to 10-15°C followed by filtering the reaction mass and washed with isopropyl alcohol to get the pure compound with HPLC purity of 99.9%.
45. A compound of Formula V comprising:

Formula V
wherein X is Br or I.
46. A method for preparation of compound of Formula V comprising the steps of:
(a4) coupling of 5-halo-2-chlorobenzoyl chloride as obtained from 5-halo-2- chlorobenzoic acid of Formula II, with fluorobenzene of Formula III in presence of a Lewis acid;

Formula II Formula III
with or without isolation of compound of Formula IV; and

Formula IV
(b4) coupling of the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B in presence of a base, a Lewis acid and a solvent to obtain a compound of Formula V

Formula B Formula V.
47. The method as claimed in claim 46, wherein the Lewis acid in step a4) is selected from aluminum chloride, zinc chloride, ferric chloride, titanium chloride, zirconium chloride, boron trifluoride and combination thereof.
48. The method as claimed in claim 46, wherein the base in step b4) is selected from a group consisting of potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium hydride and combination thereof.
49. The method as claimed in claim 46, wherein the Lewis acid in step b4) is selected from a group consisting of boron trifluoride etherate, aluminum chloride, tris(pentafluorophenyl) borane, trifluoroacetic acid, hydrochloric acid and combination thereof.
50. The method as claimed in claim 46, wherein the solvent in step b4) is selected from a group consisting of acetonitrile, ethanol, isopropanol, butanol, acetone, toluene, water, dimethylformamide, dimethylacetamide, diglyme, monoglyme, N-methylpyrollidone, toluene, dimethylsulfoxide, tetrahydrofuran, 2-methylTHF, xylene, dioxane, dichloromethane and combination thereof.